disubstituted amino acids and their methods of preparation and use

专利摘要:
"disubstituted amino acids and their methods of preparation and use". The invention relates to α, α-disubstituted crystalline amino acids and their crystalline salts containing a terminal alkene in one of their side chains, as well as optionally halogenated and deuterated analogues of α, α-disubstituted crystalline amino acids and their salts; methods of doing these and methods of using them.
公开号:BR112015009470A2
申请号:R112015009470
申请日:2013-11-01
公开日:2019-12-17
发明作者:Darlak Krzysztof；Kawahata Noriyuki；Ahmed Athamneh Sameer
申请人:Aileron Therapeutics Inc；
IPC主号:

专利说明:

CRYSTALLINE COMPOUND, ITS SALT, COMPOSITION AND ITS PREPARATION METHOD.
Background of the Invention [001] α, α-disubstituted amino acids having a terminal alkene in one of its side chains and their salts (α, unsubstituted alkene) are useful for making cross-linked macrocyclic peptides. For example, the international order. PCT / US2004 / 038403 (application 403) discloses to incorporate into a peptide two amino acids a, a-disubstituted which each contain a side chain having a terminal alkene, and to cross-link the groups of terminal alkene to form a cross-linked macrocyclic peptide ( stapled). The crosslinking can, for example, stabilize a secondary structure (for example, an α-helix) present in the stapled macrocyclic peptide.
[002] International application publication N ^Q WO2008 / 121767 (publication 767) discloses using amino acids a, α-disubstituted alkene to form sewn polypeptides (e.g., crosslinked and multiple tandem polypeptides) having seam-stabilized secondary structures. Order 403, publication 767 and other applications, publications and patents, disclose that stitched and stitched macrocyclic peptides are useful in the treatment and prevention of various diseases, including cancer.
A, α-disubstituted alkene amino acids are therefore important and useful building blocks for forming stitched and stapled polypeptides and their precursors. The use of amino acids a, substituted alkene, however, has been limited by the inability to provide these important molecules in crystalline form. For example, commercially available preparations of amino acids a, substituted alkene are usually sold as pre-made solutions. Pre-made solutions limit the amount of amino acids to, a-disubstituted that can be sent per unit volume, lim
16/17
2/63 list the chemical reactions that are available to be performed with the amino acids a, α-unsubstituted alkene, subject the amino acids to, α-unsubstituted alkene at an advanced rate of degradation and are not environmentally friendly. Thus, there is still an urgent need for amino acids a, α-disubstituted crystalline alkenes and their crystalline salts and the processes for producing and using these crystalline amino acids.
[004] Additionally, replacing one or more hydrogen atoms of an amino acid a, α-disubstituted alkene with deuterium or a halogen atom can alter one or more of the properties of the amino acid. For example, dipolar moment, hydrophobicity, hydrophilicity, steric volume or reactivity of an amino acid a, substituted alkene can be altered by replacing one or more hydrogen atoms with one or more deuterium or halogen atoms. Thus, there also remains a need for amino acids a, a-optionally substituted alkene and optionally their crystalline salts, having one or more hydrogen atoms replaced with deuterium or halogen and the methods for making and using these.
SUMMARY OF THE INVENTION [005] The above and other needs are addressed in this document. The inventive modalities provided in this summary of the invention should be illustrative only and should provide an overview of the selected inventive modalities disclosed in this document. The summary of the invention, being illustrative and selective, does not limit the scope of any claim, does not provide the entire scope of inventive modalities disclosed or contemplated in this document and should not be interpreted as limiting or restricting the scope of disclosure or any claimed inventive modality.
[006] Provided in this document are crystalline compounds of
3/63 formula (I) and its crystalline salts:
Formula (I) [007] where R1 is C1-C3 alkyl, C1-C3 deuteroalkyl, or C1-C3 haloalkyl; * is a stereocenter; n is an integer from 1 to 20; R ₂ is = H or a nitrogen protecting group; and R ₃ is = H or a protecting or activating group.
[008] Also provided herein are methods for preparing a polypeptide, comprising making the polypeptide with one or more crystalline compounds of formula (I) or its crystalline salts.
[009] Additionally provided in this document are methods for making crystalline compounds of formula (I) or their crystalline salts, comprising at least one of the following purifications:
[0010] crystallize a metal complex of the formula (Xlb)
[0011] of one or more solvents, optionally a cyclic ether, optionally tetrahydrofuran and tert-butyl methyl ether, or optionally an alcohol, optionally isopropyl alcohol, optionally an ester, optionally isopropyl acetate, optionally acetate
4/63 ethyl, where Ri is C1-C3 alkyl, C1-C3 deuteroalkyl, or C1-C3 haloalkyl, * and * * are each independently stereocenters and R ', R ”, R'”, R ””, and R '”” are, in order, passing around the aromatic ring from R' to R '””, selected from [0012] Η, H, Cl, Cl, H;
[0013] F, F, F, F, F;
[0014] F, F, OiPr, F, F;
[0015] F, F, OMe, F, F;
[0016] Cl, Η, Η, Η, H; or [0017] Η, H, Me, Me, H;
[0018] 2) precipitate a compound of formula (Ia) as its salt
HCI:
Formula (Ia) [0019] where R1 is C1-C3 alkyl, C1-C3 deuteroalkyl, or C1-C3 haloalkyl, n is an integer from 1 to 20, and * is a stereocenter;
[0020] 3) form an addition salt of the formula (XlVb):
Formula (XlVb) [0021] where R1 is C1.C3 alkyl, C1-C3 deuteroalkyl, or C1-C3 haloalkyl, R ₂ is a nitrogen protecting group, n is an in number
5/63 from 1 to 20, and * is a stereocenter; or [0022] 4) crystallize a compound of formula (I) or its salt from one or more solvents, optionally chloroform and / or hexanes.
[0023] In some embodiments, the compound of formula (Xlb) crystallizes in a mixture of tetrahydrofuran and methyl tert-butyl ether. In some embodiments, the ratio of tetrahydrofuran and methyl tert-butyl ether is between: 1:10 and 3:10. For example, the ratio is 1.5: 10.
[0024] In some embodiments, the compound of formula (I) or its salt crystallizes from a mixture of chloroform and hexanes. In some embodiments, the ratio of chloroform to hexanes is between 1: 5 and 1: 1. For example, the ratio is 1: 3 or 1: 2. Also provided in this document are methods for preparing a polypeptide, comprising making the polypeptide with one or more crystalline compounds of formula (I) or its crystalline salts.
BRIEF DESCRIPTION OF THE FIGURES [0025] Fig. 1 is a chiral HPLC trace of N-Fmoc- (S) -alfamethyl-alpha-amino-6-enoic acid.
[0026] Fig. 2 is a chiral HPLC trace of N-Fmoc- (S) -alfamethyl-alpha-amino-6-enoic acid spiked with N-Fmoc- (R) -alpha-methylalpha-amino-6- acid enoic.
[0027] Fig. 3 is an HPLC trace of N-Fmoc- (S) -alpha-methyl-alpha-amino-6-enoic acid with the detector set to 215 nm.
[0028] Fig. 4 is an HPLC trace of N-Fmoc- (S) -alpha-methyl-alpha-amino-6-enoic acid with the detector set to 254 nm.
[0029] Fig. 5 is an HPLC trace of an N-Fmoc (S) -alpha-methyl-alpha-amino-6-enoic acid standard.
[0030] Fig. 6 is a chiral HPLC trace of N-Fmoc- (R) -alfamethyl-alpha-amino-9-enoic acid.
[0031] Fig. 7 is a chiral HPLC trace of N-Fmoc- (R) -alpha acid
6/63 methyl-alpha-aminodec-9-enoic acid spiked with N-Fmoc- (S) -alfamethyl-alpha-aminodec-9-enoic acid.
[0032] Fig. 8 is an HPLC trace of N-Fmoc- (R) -alpha-methylalpha-aminodec-9-enoic acid with the detector set to 215 nm.
[0033] Fig. 9 is an HPLC trace of N-Fmoc- (R) -alpha-methylalpha-aminodec-9-enoic acid with the detector set to 254 nm.
INCORPORATION FOR REFERENCE [0034] All publications, patents, and patent applications cited in this document are incorporated by reference in this document in their entirety. In the event of a conflict between a term incorporated in this document and a term incorporated by reference, you control the term in this document.
DETAILED DESCRIPTION OF THE INVENTION [0035] Details of one or more embodiments of the invention are set out in the accompanying drawings, claims and description below. Other resources, objects and advantages of inventive modalities disclosed and contemplated in this document will be evident from the description and figures, and from the claims.
Initial Definitions [0036] As used in this document, unless otherwise stated, article one means one or more, unless explicitly provided otherwise.
[0037] As used herein, unless otherwise stated, terms such as containing, containing, including, including and the like means comprising.
[0038] As used in this document, unless otherwise stated, the term may be either conjunctive or disjunctive.
[0039] In this document, unless otherwise stated, any modality may be combined with any other modali
7/63.
[0040] In this document, unless otherwise indicated, some inventive modalities in this document include numerical ranges. When numeric bands are present, the bands include the end points of the bands. In addition, each sub-range and value within the range is present, as if written explicitly.
[0041] In this document, unless otherwise indicated, the symbol D means deuterium or a respective radical.
[0042] In this document, unless otherwise indicated, the term halo or the term halogen each refers to fluorine, chlorine, bromine or iodine or a radical thereof.
[0043] In this document, unless otherwise indicated, the term alkyl refers to a hydrocarbon chain that is a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Cr C ₃ alkyl group indicates that the group has 1 to 3 carbon atoms (inclusive) in it.
[0044] Deuteroalkyl refers to a deuterated alkyl chain, in which the hydrogen atoms of the alkyl chain are replaced at least at the 90% level with deuterium atoms.
[0045] In this document, unless otherwise indicated, the term haloalkyl refers to a halogenated alkyl chain, in which the hydrogen atoms in the alkyl chain are replaced by halogen atoms. In some embodiments, the halogen atoms are all the same (for example, all F or all Cl).
[0046] In this document, unless otherwise indicated, Y is a double bond (eg, alkene).
[0047] As used in this document, unless otherwise stated, the term peptidomimetic macrocycle or cross-linked polypeptide refers to a compound consisting of a plurality of amino acid residues joined by a plurality of peptide bonds
8/63 and at least one macrocycle-forming linker that forms a macrocycle between a first naturally occurring or non-naturally occurring amino acid (or analog) and a second naturally occurring or non-naturally occurring (or analog) amino acid residue within the same molecule . Peptidomimetic macrocycles include modalities in which the macrocycle-forming linker attaches to an α-carbon of the first amino acid residue (or analog) to the carbon-α of the second amino acid residue (or analog) in the peptide. Peptidomimetic macrocycles include one or more non-peptide bonds between one or more amino acid residues and / or analogous amino acid residues and, optionally, include one or more non-naturally occurring amino acid residues or analogous amino acid residues in addition to any that form the macrocycle.
[0048] As used herein, unless otherwise indicated, a corresponding de-crosslinked polypeptide when referred to in the context of a peptidomimetic macrocycle should be understood as with respect to a polypeptide of the same length as the macrocycle and comprising the equivalent natural amino acids of the sequence. wild type corresponding to the macrocycle.
[0049] As used herein, unless otherwise stated, the term amino acid refers to a molecule containing an amino group and a carboxyl group. Suitable amino acids include, for example, both naturally occurring D- and L-isomers of naturally occurring amino acids, as well as non-naturally occurring amino acids prepared by organic synthesis or other metabolic routes. The term amino acid includes, for example, α-amino acids, natural amino acids, unnatural amino acids and analogous amino acids.
[0050] As used here, unless otherwise stated, the term α-amino acid refers to a molecule containing an amino group
9/63 no and a carboxyl group attached to a carbon atom which is referred to as the α-carbon atom.
[0051] As used here, unless otherwise stated, the term naturally occurring amino acid refers to any of the 20 amino acids commonly found in peptides synthesized in nature and known by the abbreviations of a letter A, R, N, C, D, Q, E, G, Η, I, L, K, M, F, P, S, T, W, Y and V.
[0052] Here, unless otherwise indicated, the term amino acid side chain refers to a fraction attached to the acarbon atom (or another structure atom) in an amino acid. For example, the amino acid side chain for alanine is methyl, the amino acid side chain for phenylalanine is phenylmethyl, the amino acid side chain for cysteine is thiomethyl, the amino acid side chain for aspartate is carboxymethyl, the amino acid side chain for tyrosine is 4-hydroxyphenylmethyl, etc. Other non-naturally occurring amino acid side chains are also included, for example, those that occur in nature (for example, an amino acid metabolite) or those that are made synthetically (for example, an α-a, di-substituted amino acid).
[0053] In this document, unless otherwise stated, the term a, the disubstituted amino acid refers to a molecule or fraction containing an amino group and a carboxyl group attached to a carbon atom (for example, the α atom -carbon) which is also attached a side chain of natural and unnatural amino acid, or two natural or unnatural.
[0054] In this document, unless otherwise indicated, the term polypeptide can encompass two or more amino acids occurring naturally or not naturally linked by a covalent bond (for example, an amide bond). Polypeptides as described in this document may include full-length proteins (for example,
10/63 example, fully processed proteins) as well as shorter amino acid sequences (for example, naturally occurring protein fragments or synthetic polypeptide fragments).
[0055] In this document, unless otherwise indicated, the term macrocycling reagent or macrocycle forming reagent can refer to any reagent that can be used to prepare a peptidomimetic macrocycle mediating the reaction between two reactive groups of olefins in it. The reactive groups that, once reacted, close the linker, can be, for example, terminal olefins (alkenes), deuterated or non-deuterated.
[0056] Macrocycling reagents or macrocycle forming reagents can be metathesis catalysts, including, but not limited to, complex stabilized, late transition carbene catalysts such as group VIII carbene transition catalysts. catalysts may contain metal center Os and Ru having an oxidation state + 2, an electron count of 16 and pentacoordinate. Catalysts can have Mo or W centers. Several catalysts are disclosed in Grubbs et al., Ring ClosingMetathesis and Related Processes in Organic Synthesis Acc. Chem. Fies. 1995.28, 446-452; Pat. USA. No. 5,811,515; Pat. USA. No. 7,932,397; Pat. USA. Pub Order. No. 2011/0065915; Pat. USA. Pub Order. No. 2011/0245477; Yu et a!., Synthesis of Macrocyclic Natural Products by Catalyst-Controlled Stereoselective Ring-Closing Metathesis, Nature 2011,479, 88; and Peryshkov etal., ZSelective Olefin Metathesis Reactions Promoted by Tungsten Oxo Alkylidene Complexes, J. Am. Chem. Soo. 2011, 133, 20754.
[0057] In this document, unless otherwise indicated, ο the term treatment is defined as the application or administration of a therapeutic agent to a patient, or the application or administration of a therapeutic agent to a tissue or cell line isolated from a
11/63 patient, who has an illness, a symptom of illness or a predisposition to an illness, in order to cure, recover from, alleviate, alleviate, alter, remedy, improve, help against or affect the disease, the symptoms of disease or predisposition to the disease.
[0058] Provided in this document are crystalline compounds of formula (I) or their crystalline salts:
lk ψ * [] R3 r ₂ o
Formula (I) [0059] wherein R1 is C1-C3 alkyl, C1-C3 deuteroalkyl, or C1-C3 haloalkyl; * is a stereocenter; n is an integer from 1 to 20; R ₂ is = H or a nitrogen protecting group; and R ₃ is = H or a protecting or activating group.
[0060] [0061] In the crystalline compound of formula (I) or its crystalline salt, R1 can be C1-C3 alkyl. R1 can be, for example, methyl, ethyl, npropyl or isopropyl.
[0062] In the crystalline compound of formula (I) or its crystalline salt, R1 can be C1-C3 deuteroalkyl. R1 can be, for example, -CD ₃ , CD2CD3, -CD2CD2CD3, or —00 (003) 2 · [0063] In the crystalline compound of formula (I) or its crystalline salt, R1 can be C1-C3 haloalkyl. Halogen can be, for example, -F, -Cl, -Br, or -I. R1 can be, for example, -CX ₃ , -CX ₂ CX ₃ , -ΟΧ ₂ ΟΧ ₂ ΟΧ ₃ , or -CX (CX ₃ ) ₂ , where X is a halogen.
[0064] fí ₂ [0065] In the crystalline compound of formula (I) or its crystalline salt, R ₂ can be, for example, -H, or a nitrogen protecting group selected from the group consisting of: 9-Fluorenylmethoxycarbonyl
12/63 (Fmoc), Trityl (Trt), 4-Methoxytrityl (Mmt), 2- (3,5-Dimethoxyphenyl) propane2-yloxycarbonyl (Ddz), 2- (p-Biphenylyl) -2-propyloxycarbonyl (Bpoc), 2- (4Nitrophenylsulfonyl) ethoxycarbonyl (NSC), (1,1-Dioxobenzo [b] thiophene-2-yl) methyloxycarbonyl (Bsmoc), (1,1-Dioxonaphto [1,2-b] thiophene-2-yl) methyloxycarbonyl (α-Nsmoc), 1 - (4,4-dimethyl-2,6-dioxocyclohex-1-ylidene) -3-methylbutyl (ivDde), 2, -Di-tert-butyl-Fmoc (Fmoc *), 2-Fluoro-Fmoc (Fmoc (2F)), 2-Monoisooctyl-Fmoc (mio-Fmoc), 2,7-Di-isooctyl-Fmoc (dio-Fmoc), 2- [Phenyl (methyl) sulfonium] ethyloxycarbonyl tetrafl uoroborate (Pms), Ethanesulfonylethoxycarbonyl (Esc), 2- (4-Sulfofinylsulfonyl) ethoxycarbonyl (Sps), Terc-butyloxycarbonyl (Boc), Benzyloxycarbonyl (Z), Allyloxycarbonyl (Alloc), 2,2,2-Trichlorethyloxycarbonyl (Troc), p -Nitrobenzyloxycarbonyl (pNZ), Propargyloxycarbonyl (Poc), o-Nitrobenzenesulfonyl (oNBS), 2,4-Dinitrobenzenesulfonyl (dNBS), Benzothiazol-2-sulfonyl (Bts), o-Nitrobenzyloxycarbonyl (oNz), 4 ila (NVCO), 2- (2-Nitrophenyl) propyloxycarbonyl (NPPOC), 2, (3,4-Methylethenedioxy-6-nitrophenyl) propyloxycarbonyl (MNPPOC), 9- (4Bromophenyl) -9-fluorenyl (BrFF), Azidomethoxycarbonyl ( Azoc), Hexafluoroacetone (HFA), 2-Chlorobenzyloxycarbonyl (Cl-Z), 4-Methyltrityl (Mtt), Trifluoroacetyl (tfa), (Methylsulfonyl) ethoxycarbonyl (Msc), Phenyldisulfanylethyloxycarbonyl (Fdec), 2-Pyridyl, and o-Nitrobenzenesulfonyl (O-NBS).
[0066] Nitrogen protecting groups can be found, for example, in Isidro-Llobet, A., et al., Amino Acid-Protecting Groups, Chem. Rev.2455-2504 (2009) [0067] In the crystalline compound of formula (I) or its crystalline salt, R ₂ can be, for example, a nitrogen protecting group selected from the group consisting of 9-Fluorenylmethoxycarbonyl (Fmoc) , Trityl (Trt), 4-Methoxytrityl (Mmt), 2- (3,5-dimethoxyphenyl) propane-2yloxycarbonyl (Ddz), [0068] 2- (p-biphenylyl) -2-propyloxycarbonyl (Bpoc), 2- ( 4-Nitrophenyl
13/63 sulfonyl) ethoxycarbonyl (NSC) [0069] 1,1-Dioxobenzo [b] thiophene-2-yl) methyloxycarbonyl (Bsmoc), [0070] 1 - (4,4-dimethyl-2,6-dioxocycle-hex -1 -i (idene) -3-methyl (ivDde), Tert-butyloxycarbonyl (Boc), [0071] Benzyloxycarbonyl (Z), Allyloxycarbonyl (Alloc), 2,2,2-Trichlorethyloxycarbonyl (Troc), [ 0072] p-Nitrobenzyloxycarbonyl (pNZ), o-Nitrobenzenesulfonyl (oNBS), [0073] 2,4-Dinitrobenzenesulfonyl (dNBS), o-Nitrobenzyloxycarbonyl (oNz), [0074] 4-Nitroveratryloxycarbonyl (NVCO), 2- Nitrophenyl) propyloxycarbonyl (NPPOC), [0075] Hexafluoroacetone (HFA), 2-Chlorobenzyloxycarbonyl (Cl-Z),
4-Methyltrityl (Mtt), [0076] Trifluoroacetyl (tfa), (Methylsulfonyl) ethoxycarbonyl (Msc), and oNitrobenzenesulfonyl (O-NBS).
[0077] In the crystalline compound of formula (I) or its crystalline salt, R ₂ can be, for example, a nitrogen protecting group, selected from the group consisting of 9-fluorenylmethoxycarbonyl (Fmoc), trityl (Trt), [ 0078] 4-Methoxytrityl (Mmt), 2- (3,5-dimethoxyphenyl) propane-2-yloxycarbonyl (Ddz) [0079] 2- (p-biphenylyl) -2-propyloxycarbonyl (Bpoc), Terc-butyloxycarbonyl (Boc) , Benzyloxycarbonyl (Z) [0080] Allyloxycarbonyl (Alloc), 2,2,2-Trichloroethyloxycarbonyl (Troc), o-Nitrobenzenesulfonyl (oNBS), [0081] Trityl (Trt), 4-Methyltrityl (Mtt), and o-Nitrobenzenesulfonyl (O-NBS).
[0082] In the crystalline compound of formula (I) or its crystalline salt, R ₂ can be, for example, the nitrogen protecting group 9-fluore
14/63 nilmethoxycarbonyl (Fmoc).
R ₃ [0083] In the crystalline compound of formula (I) or its crystalline salt, R ₃ can be, for example, -H, or a protecting or activating group selected from the group consisting of: tert-butyl (tBu), [0084] 2-Chlorotrityl (2-CI-Trt), 2,4-Dimethoxybenzyl (DMB), Benzyl (Bn), 2-Phenylisopropyl (2-PhiPr), [0085] 5-Phenyl-3,4-ethylenedioxythenyl, 9-Fluorenylmethyl (Fm), [0086] 4- (N- [1- (4,4-dimethyl-2,6-dioxocyclohexylidene) -3-methylbutyl] amino) benzyl (Dmab), [0087] Methyl ( Me), Ethyl (Et), Carbamoylmethyl (Cam), Allila (Al),
Phenacyl (Pac), p-Nitrobenzyl (pNB), [0088] 2-Trimethylsilylethyl (TMSE), (2-Phenyl-2-trimethylsilyl) ethyl (PTMSE), 2- (Trimethylsilyl) isopropyl (Tmsi), Trimethylsilyl (TMS) , 2,2,2-Trichloroethyl (Tce), p-Hydroxyphenacyl (pHP), [0089] 4,5-Dimethoxy-2-nitrobenzyl (Dmnb), 1,1-Dimethylallila (Dma), cobalt Penta-amine (III ), [0090] Succinimide, p-nitrophenyl, Pentaflurophenyl and 2,4,5-trichlorophenyl.
[0091] In the crystalline compound of formula (I) or its crystalline salt, R ₃ can be, for example, -H.
n [0092] The crystalline compound of formula (I) or its crystalline salt, n cannot be in the range, for example, 1-20, 3-11 or 3-6. n can be, for example, 3 or 6 or 11. n can be 3. n can be 6. n can be
11.
* [0093] In the crystalline compound of formula (I) or its crystalline salt, the stereocenter * can be (R). In the crystalline compound of formula (I) or its crystalline salt, the stereocenter * can be (S).
15/63 [0094] In one embodiment, in the crystalline compound of formula (I) or its crystalline salt, Ri can be Cr C ₃ alkyl; R ₂ can be 9Fluorenylmethoxycarbonyl (Fmoc); R ₃ can be selected from the group consisting of -H tert-Butyl (tBu), 2-Chlorotrityl (2-CI-Trt), 2,4Dimethoxybenzyl (DMB), Benzyl (Bn), 2-Phenylisopropyl (2-PhiPr ), 5-phenyl-3,4-ethylenedioxythenyl, 9-fluorenylmethyl (Fm), [0095] 4- (N- [1- (4,4-dimethyl-2,6-dioxocyclohexylidene) -3-methylbutyl] amino) benzyl (Dmab), [0096] Methyl (Me), Ethyl (Et), Carbamoylmethyl (Cam), Allila (Al),
Phenacyl (Pac), p-Nitrobenzyl (pNB), [0097] 2-Trimethylsilylethyl (TMSE), (2-Phenyl-2-trimethylsilyl) ethyl (PTMSE), 2- (Trimethylsilyl) isopropyl (Tmsi), Trimethylsilyl (TMS) , 2,2,2-Trichlorethyl (Tce), p-Hydroxyphenacyl (pHP), [0098] 4,5-Dimethoxy-2-nitrobenzyl (Dmnb), 1,1-Dimethylallila (Dma), cobalt Penta-amine (III ), [0099] Succinimide, p-Nitrophenyl, Pentaflurophenyl, and 2,4,5-trichlorophenyl; n can be an integer in the range 3 to 11; and the stereocenter * can be (R).
[00100] In one embodiment, in the crystalline compound of formula (I) or its crystalline salt, Ri can be Cr C ₃ alkyl; R ₂ can be 9Fluorenylmethoxycarbonyl (Fmoc); R ₃ can be selected from the group consisting of -H tert-Butyl (tBu), 2-Chlorotrityl (2-CI-Trt), 2,4Dimethoxybenzyl (DMB), Benzyl (Bn), 2-Phenylisopropyl (2-FiPr ), 5-Phenyl-3,4-ethylenedioxythenyl, 9-Fluorenylmethyl (Fm), [00101] 4- (N- [1 - (4,4-dimethyl-2,6-dioxocyclohexylidene) -3-methylbutyl] amino) benzyl (Dmab), [00102] Methyl (Me), Ethyl (Et), Carbamoylmethyl (Cam), Allila (Al), Phenacyl (Pac), p-Nitrobenzyl (pNB), [00103] 2-Trimethylsilylethyl (TMSE ), (2-Phenyl-2-trimethylsilyl) ethyl (PTMSE), 2- (Trimethylsilyl) isopropyl (Tmsi), Trimethylsilyl (TMS), 2,2,2-Triclo
16/63 roethyl (Tee), p-Hydroxyphenacyl (pHP), [00104] 4,5-Dimethoxy-2-nitrobenzyl (Dmnb), 1,1-Dimethylallila (Dma), cobalt Penta-amine (III), [00105 ] Succinimide, p-Nitrophenyl, Pentaflurophenyl, and 2, 4, 5-trichlorophenyl; n can be an integer in the range 3 to 11; and the stereocenter * can be (S).
[00106] In one embodiment, in the crystalline compound of formula (I) or its crystalline salt, Ri can be methyl, R ₂ can be 9-Fluorenylmethoxycarbonyl (Fmoc); R ₃ can be -Η, n can be 3, 6, or 11 and the stereocenter * can be (R).
[00107] In one embodiment, in the crystalline compound of formula (I) or its crystalline salt, Ri can be methyl, R ₂ can be 9-Fluorenylmethoxycarbonyl (Fmoc); R ₃ can be -Η, n can be 3, 6, or 11 and the stereocenter * can be (S).
Chemical purity [00108] Here, unless otherwise stated, any compound, its crystalline compounds, salts, or crystalline salt of a compound, can have a degree of chemical purity. Chemical purity can be defined, for example, as the degree to which a substance is undiluted or not mixed with foreign materials, and can normally be expressed as a percentage. Any compound, its salt, crystalline compound, or crystalline salt of a compound in this document can, for example, have a chemical purity, ranging from about 90% to 100%. Chemical purity can be, for example, about 92% to 100%, about 94% to 100%, about 96% to 100%, about 98% to 100%, about 90%, about 91% , about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%. The percentage can be, for example, based on the total weight of your compound, its salt, crystalline compound or its salt. The percentage can, for example, be reached
17/63 when using HPLC. The percentage can be achieved by, for example, using NMR, for example, proton NMR. Chemical purity can be achieved by, for example, using elementary analysis.
Enantiomeric excess:
[00109] Here, unless otherwise stated, any compound, its crystalline compound, salt, or crystalline salt of a compound, may have an enantiomeric excess. The enantiomeric excess can be, for example, about 80% to 100%, about 85% to 100%, about 90% to 100%, about 95% to 100%, about 96% to 100%, from about 97% to 100%, from about 98% to 100%, from about 99% to 100%, about 95%, about 96%, about 97%, about 97, 2%, about 98%, about 99% or 100%. The enantiomeric excess can be, for example, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%. In this document, unless otherwise stated, the enantiomeric excess can be calculated, for example, by the formula: enantiomeric excess (ee) = ((PS) / (P + S)) x 100%, where P and S represent the numbers, respectively, of the predominant and sub-dominant enantiomer produced or present in a sample. For example, if the additional enantiomer cores (R) are produced where the enantiomer cores (S), enantiomer cores (R) are designated as R and enantiomer cores (S) are designated as S, then excess formula enantiomeric becomes: ee (%) = ((RS) / (R + S)) x 100%. In this document, unless otherwise indicated, the amount (e.g. ,ols) or enantiomer produced can be determined, for example, by chiral HPLC, chiral GC, or through a chiral NMR displacement reagent using NMR spectroscopy.
Optical purity [00110] Here, unless otherwise stated, any compound, its crystalline compounds, salts, or crystalline salt of a compound,
18/63 can have an optical purity degree. Optical purity can be, for example, about 80% to 100%, about 85% to 100%, about 90% to 100%, about 95% to 100%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%. In this document, unless otherwise stated, optical purity can be calculated using the formula: optical purity (%) = ([a] observed / [a] maximum) * 100%, where observed [a] is the specific rotation of the sample, and maximum [a] is the specific rotation of the pure enantiomer. In this document, unless otherwise indicated, specific rotation can be defined as the observed angle of optical rotation, a, when planopolarized light passes through a sample with a path length of 1 decimeter and a sample concentration of 1 gram per 1 milliliter. The specific rotation can be achieved, for example, at 20 ° C and at a light wavelength of 589 nanometers (for example, the sodium line D). In this document, unless otherwise stated, specific rotation can be achieved, for example, with a polarimeter. In this document, unless otherwise stated, the sample is dissolved in a solvent can be any suitable solvent or solvent combination, for example, ethanol, methanol, chloroform, dichloromethane, carbon tetrachloride, water, DMSO, N, N-DMF , ethyl ether, tetrahydrofuran, hexane, pentane, acetone or any combination thereof.
Diastereomeric Excess [00111] In this document, unless otherwise indicated, the compounds, salts, crystalline compounds or crystalline salts of compounds in this document may be diastereomers. When so, the compounds, crystalline compounds or crystalline salts of compounds in this document may have a diastereomeric excess of, for example, from about 80% to 100%, from about 85% to 100%, from about 90% to 100%, from about 95% to 100%, about 95%, about
19/63
96%, about 97%, about 98%, about 99% or 100%. In this document, unless otherwise indicated, the diastereomeric excess, for example, in a mixture of two diastereomers, can be calculated, for example, by the formula:% of diastereomeric excess = (((D1-D2) / (D1 + D2 )) * 100%, where D1 represents, for example, the mol or percentage weight of a first and most abundant diastereomer, and D2 represents, for example, the mol or percentage weight of a second and less abundant diastereomer, in which mol percent is used consistently (for example, alone) in the calculation, or where the percentage weight is used consistently (for example, alone) in the calculation.
Converted Enantiomeric Excess or Optical Purity [00112] Unless otherwise stated, any compound, its salt, crystalline compound, or its crystalline salt, in this document, which is a diastereomer, can be converted to an enantiomer or enantiomeric mixture having a stereocenter (for example, * in formula (I)) by, for example, removal of a nitrogen protecting group (e.g., removal of the nitrogen protecting group R ₂ in the crystalline compound of formula (I) or its crystalline salt which, together with the stereocenter *, it creates a diastereomer), and the resulting enantiomer or enantiomeric mixture can then have its enantiomeric excess or optical purity determined as described in this document. The resulting enantiomeric excess or optical purity in these circumstances is called a converted enantiomeric excess or converted optical purity. The converted enantiomeric excess can be, for example, from about 80% to 100%, from about 85% to 100%, from about 90% to 100%, from about 95% to 100%, from about 96 % to 100%, from about 97% to 100%, from about 98% to 100%, from about 99% to 100%, about 95%, about 96%, about 97%, about 97 , 2%, about 98%, about 99% or 100%. Enantiomic excess
20/63 converted wealth can be, for example, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%. The converted optical purity can be, for example, about 80% to 100%, about 85% to 100%, about 90% to 100%, about 95% to 100%, about 95% , about 96%, about 97%, about 98%, about 99% or 100%. Thus, any optionally crystalline diastereomer or its optionally crystalline salt in this document, unless otherwise indicated, may have a converted enantiomeric excess or converted optical purity.
Crystalline Compounds and Their Specific Exemplified Crystalline Salts [00113] In this document, unless otherwise stated, the crystalline compound of formula (I) or its crystalline salt may be a compound of formula (Ha) or its crystalline salt:
[00114] In this document, unless otherwise indicated, the crystalline compound of formula (I) or its crystalline salt may be a compound of formula (llb) or its crystalline salt:
O
HO HN * w- (iib) [00115] In this document, unless otherwise indicated, the crystalline compound of formula (I) or its crystalline salt may be a compound of formula (IIIa) or its crystalline salt:
21/63
[00116] In this document, unless otherwise indicated, the crystalline compound of formula (I) or its crystalline salt may be a compound of formula (IIIb) or its crystalline salt:
HO X '' 'NH
NH (lllb)
Haloaenated and Deuterated Compounds and Their Salts [00117] Also presented here, unless otherwise stated, are optionally crystalline compounds and their optionally crystalline salts, of formula (IV):
nhr ₂ .or.
Formula (IV) [00118] Where R ₂ , R3, n, and * are the same as in the crystalline compound or its crystalline salt of formula (I), each E is independently selected from the group consisting of deuterium and halogen and R ₄ is selected from the group consisting of C1-C3 alkyl, C1-C3 deuteroalkyl and C1-C3 haloalkyl.
Deuterium [00119] In this document, unless otherwise indicated, for any deuterate: compound, its salt, crystalline compound or its salt
Crystalline 22/63; greater than 90%, greater than 92%, greater than 94%, greater than 96% or greater than 98%, of the deuterate: compound, its salt, crystalline compound or its crystalline salt; it has a deuterium atom in each position designated as deuterium (D) in the deuterate: compound, its salt, the crystalline compound or its crystalline salt.
Production Methods [00120] - The compounds and their salts in this document can be advantageously made by methods disclosed in this document that result in at least one of the following advantages:
[00121] - The compounds or their salts that are produced are crystalline;
[00122] - The compounds and their salts (both of which can be crystalline) are advantageously produced in high yield;
[00123] - The compounds and their salts (both of which can be crystalline) are advantageously produced in high chemical purity;
[00124] - The compounds and their salts (both of which can be crystalline) are advantageously produced in high enantiomeric excess, optical purity, diastereomeric excess, high converted enantiomeric excess, or high converted optical purity; or [00125] - The compounds and their salts (both of which can be crystalline) are produced without chromatographic purification (for example, without chromatography).
[00126] Unless otherwise indicated, the compounds, their salts, crystalline compounds and their crystalline salts, in this document can be produced using, for example, exemplary scheme I (with modifications that would be easily perceptible to a person skilled in the art). Scheme I illustrates the formation of crystalline N-Fmoc- (R) -amethyl-a-aminodec-9-enoic acid (i.e., the crystalline compound of formula (Ha)). Sequence I begins with Boc-D-proline (i.e., the compound of formula (V)). It is understood that, when starting with Boc-L-proline,
23/63 compounds with the opposite stereochemistry of the compound of formula (Ila) can be produced (for example, the compound of formula (llb) can be produced). It is also understood that the stereochemistry of the amino acid used to form the metal complex (for example, alanine used to form the metal complex of formula (XI) in scheme I) is not a device for the stereochemistry of the resulting crystalline compound (for example, the formula (Ila)) or its crystalline salt.
Scheme I

(IX) (XI)
(xiv) [00127] In scheme I, Boc-D-proline (compound of formula (V)) is first reacted with 2-aminobenzophenone (compound of formula (VI))
24/63 to form the compound of formula (VII). Then, the compound of formula (VII) is deprotected to form the HCI salt of the compound of formula (VIII). a person skilled in the art would readily understand that the synthetic regime contemplates the use of acids other than HCI, including organic acids and inorganic acids, for example, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrochloric acid, hydrobromic acid and perchloric acid .
[00128] The salt of the compound of formula (VIII) is then reacted with benzyl bromide and, for example, a base, to form the compound of formula (IX). A person well versed would readily understand that substituted benzyl halides could be used in place of benzyl bromide. For example, the following benzyl halides, where X = Cl, Br or I, could be used:
(Xa) (X _b ) ( ^X c) ( ^X d) [00129] Representative benzyl halides are found in Belokon, YN, etal., Halo-substituted (S) -N- (2-benzoylphenyl) -1- benzylpyrolidine-2-carboxamides as new chiral auxiliaries for the asymmetric synthesis of (S) -a-amino acids, Russian Chemical Bulletin, international edition, 51 (8): 1593-1599 (2002). Additional and different benzyl halides can also be used:
Me Me (X _e ) ( ^x f) [00130] These representative benzyl halides are found in Saghiyan, AS, etal., New chiral Nill complexes of Schiff's bases
25/63 of glycine and alanine for efficient asymmetric synthesis of a-amino acids, Tedrahedron: Asymmetry 17: 455-467 (2006) [00131] Then, the compound of formula (IX) is reacted with Lalanine and Ni (NO ₃ ) ₂ to form the metal complex of the formula (XI). The person skilled in the art would understand that amino acids other than alanine can be used in Scheme I. For example, glycine; 2-aminobutanoic acid, 2-aminopentanoic acid and valine, for example, in their D or L forms, can be used. Ni (NO ₃ ) ₂ can be a hydrate, for example, a hexahydrate. The reaction can be carried out in an alcoholic solvent, for example, methanol. The reaction can be carried out at an elevated temperature, for example, from about 40 ° C to about 60 ° C. The reaction can be carried out in the presence of a base, for example, a hydroxide, for example an inorganic hydroxide, for example, potassium hydroxide. Other hydroxides are contemplated, including sodium hydroxide, cesium hydroxide, lithium hydroxide, magnesium hydroxide and ammonium hydroxide.
[00132] To increase the purity of the final product of Scheme I, the metal complex of formula (XI) can be crystallized one or more times from one or more solvents, for example, a cyclic ether and a non-cyclic ether. In one embodiment, the solvent is tetrahydrofuran and methyl tert-butyl ether. In some cases, the ratio of cyclic ether to non-cyclic ether is at most 0.5: 10, 1.0: 10, 1.5: 10, 2.0: 10, 2.5: 10, 3.0: 10, 3.5: 10.4.0: 10, 4.5: 10 or 5:10. In other cases, the ratio of cyclic ether to non-cyclic ether is at least 0.5: 10, 1.0: 10, 1.5: 10, 2.0: 10, 2.5: 10, 3.0: 10, 3.5: 10.4.0: 10, 4.5: 10 or 5:10. For example, in some cases the metal complex of formula (XI) crystallizes from a mixture of tetrahydrofuran and methyl tert-butyl ether in the ratio of at most 0.5: 10, 1.0: 10, 1.5: 10, 2.0: 10 , 2.5: 10, 3.0: 10,3.5: 10, 4.0: 10, 4.5: 10 or 5:10. In other cases the ratio of e tetrahydrofuran and methyl tert-butyl ether is at least 0.5: 10,
26/63
1.0: 10, 1.5: 10, 2.0: 10, 2.5: 10, 3.0: 10, 3.5: 10.4.0: 10, 4.5: 10 or 5:10. In some cases, the ratio of tetrahydrofuran and methyl tert-butyl ether is 1.5: 10. The metal complex of formula (XI) can also be crystallized with esters, for example, with ethyl acetate or isopropylail acetate. The product or crystallized product of formula (IX) can alternatively or additionally be crystallized or recrystallized from a solvent, for example, an alcohol, for example propyl alcohol. Other alcohols are contemplated, including methanol, ethanol, n-propanol, butanol, n-butanol, isobutanol, sec-butanol and tert-butanol.
[00133] The metal complex of formula (XI) is then alkylated with 8-bromooct-1-ene to form the alkylated metal complex of formula (XII). The person skilled in the art would understand that other alkylating agents, including other halo alkyl olefins, could be used in place of 8-bromooct-1-ene. For example, the alkylating agents of formula (XV) can be used:
(XV) [00134] where X is Cl, Br or I, and n is an integer from 1 to 20. For example, n can be 3 to 11, 3 to 6, or 3 or 6. Some or all the hydrogen atoms present in the compound of formula (XV) can be replaced with deuterium atoms or halogen atoms. Alkylation can be performed in one or more solvents, for example, a polar aprotic solvent, for example, N, N-dimethyl formamide (DMF). The alkylation can be carried out, for example, at a temperature of less than 20 ° C, for example, less than 20 ° C to 5 ° C, less than 20 ° C to 10 ° C, or at about 10 ° Ç. The person skilled in the art would also understand that when glycine is used to form the metal complex, two alkylations could be performed one after the other. For example, first alkylation can be
27/63 carried out using a C1-C3 alkane with a labile group such as a halogen (eg, methyl bromide, ethyl bromide, n-propyl bromide), or a Ci-C ₃ deuteroalkane with a labile group, such as a halogen (for example, CD ₃ Br, CD ₃ CD ₂ Br, CD ₃ CD ₂ CD ₂ Br), or a Ci-C ₃ haloalkane with a labile group, such as a more reactive halogen than the other halogens in the haloalkane (e.g. CF ₃ Br, CF ₃ CF ₂ Br, CF ₃ CF ₂ CF ₂ Br). Then, the second alkylation can be performed using the alkylating agent of formula (XV). The order of the first and second alkylation can be reversed.
[00135] The purification of formula (XII) can be achieved by crystallizing in one or more times from one or more solvents including cyclic and non-cyclic ethers, esters, hexanes and heptane. For example, crystallization can be achieved using a combination of ethyl acetate and hexanes, ethyl acetate and heptanes, isopropyl acetate and hexanes, isopropyl acetate and heptanes, tert-butyl methyl ether and hexanes, tert-butyl methyl ether and heptanes or isopropyl acetate and methyl tert-butyl ether.
[00136] Next, the metal complex of formula (XII) is cleaved with an acid, for example, HCI, using one or more solvents, for example an ether, for example a cyclic ether, for example, tetrahydrofuran, to form the amino acid HCI salt of formula (XIII). A person skilled in the art would readily understand that other acids in addition to HCI are contemplated, for example, organic acids or inorganic acids, for example, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrochloric acid, hydrobromic acid or perchloric acid. The salt of formula (XIII) can be further purified by crystallization one or more times with one or more solvents. The solvent can be any suitable solvent including tetrahydrofuran, tert-butyl methyl ether, ethyl acetate, isopropylail acetate, ethanol, methanol, isopropanol, acetonitrile or one with
28/63 combination of these. In one embodiment, the solvent is acetonitrile.
[00137] The amino acid salt of the formula (XIII) then has the nitrogen protected with a nitrogen protecting group, in this case an Fmoc group and the cyclohexylamine addition salt of protected amino acids is formed, producing the cyclo-amino acid salt. hexylamine protected from formula (XIV). The formation of the salt of formula (XIV) can be achieved in any suitable solvent including acetonitrile, tert-butyl methyl ether, tetrahydrofuran or a combination thereof. In one embodiment, the solvent is tert-butyl methyl ether. A person skilled in the art would understand that other amines, for example, other cyclic amines, for example, cyclopropylamine, chloroformate amine, cyclopenylamine, cycloheptylamine and cyclooctylamine, are contemplated. A person skilled in the art would also readily understand that other nitrogen protecting groups are contemplated, for example, the nitrogen protecting group for R ₂ in the crystalline compound of formula (I) or its crystalline salt in this document.
[00138] The protected amino acid cyclohexylamine salt of formula (XIV) can then be crystallized from one or more ethers, for example, two ethers, for example, a cyclic ether and a non-cyclic ether, for example, tetrahydrofuran. hydrofuran and methyl tert-butyl ether.
[00139] The protected cyclohexylamine amino acid salt of formula (XIV) is then treated with sulfuric acid and then crystallized to form the crystalline compound of formula (Ila). The person skilled in the art would readily understand that other acids in addition to sulfuric acid are contemplated, for example, organic acids or inorganic acids, for example, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrochloric acid, hydrobromic acid or perchloric acid. Crystallization can be carried out using one or more solvents, for example, two solvents, for example, an alkane and haloalkane, for example, hexanes and chloroform. In some cases, the alkane ratio
29/63 for haloalkane is at least 6: 1.5: 1, 4: 1, 3: 1, 2: 1, or 1:10. In some cases, the ratio of alkane to haloalkane is at most 6: 1, 5: 1, 4: 1, 3: 1, 2: 1, or 1:10. For example, the crystalline compound of formula (Ha) can be obtained by crystallizing a mixture of hexanes and chloroform in the ratio of at least 6: 1, 5: 1, 4: 1, 3: 1, 2: 1 or 1: 1. Crystallized Ha can also be obtained by crystallizing a mixture of hexanes and chloroform in the ratio of a maximum of 6: 1.5: 1.4: 1, 3: 1.2: 1, or 1: 1. In some cases, the ratio of hexanes to chloroform is 3: 1.
[00140] Crystallization can be carried out at a temperature in the range, for example, about -5 ° C to about -20 ° C, about-10 ° C to about-20 ° C, or about-15 ° C to -20 ° C.
[00141] The person skilled in the art would understand, for example, that the crystalline compound of formula (Ha) could be additionally activated or protected in its function as carboxylic acid with, for example, a protecting group or R ₃ activation of the crystalline complex. of formula (I) or its crystalline salt. Unless otherwise indicated, the compounds, their salts, crystalline compounds and their crystalline salts, in this document can be produced using, for example, exemplary scheme II (with modifications that would be readily apparent to a person skilled in the art). Scheme II illustrates the formation of crystalline N-Fmoc- (S) -a-methyl-a-aminodec-6-enoic acid (i.e., the crystalline compound of formula (Hla)). Sequence II begins with Boc-Lproline (ie, the compound of formula (Va)). It is understood that, when starting with Boc-D-proline, compounds with the opposite stereochemistry of the formula compound (Hla) can be produced (for example, the formula compound (Hlb) can be produced). It is also understood that the stereochemistry of the amino acid used to form the metal complex, and whose alpha carbon atom is subsequently alkylated by halo-olefin (for example, alanine in the formula (Xla)) is not dispositive
30/63 of the stereochemistry of the resulting crystalline compound (for example, of formula (lla)) or its crystalline salt.
[00142] Scheme II

1) Alanine
Ni (NO ₃ ) ₂
2) Crystallize
(Xla)

(Xlla)
(Xllla)
1) Fmoc-Onsu
DCrystallize θ Crystalline Compound of Formula (lla) [00143] In Scheme II, Boc-L-proline (compound of formula (Va)) is first reacted with 2-aminobenzophenone (compound of formula (VI)) to form the compound of formula (Village). Then, the compound of formula (Vila) is deprotected to form the HCI salt of the compound of formula (Villa). A craftsman versed in the technique readily understand
31/63 ia that the synthetic regime contemplates the use of acids other than HCI, including organic acids and inorganic acids, for example, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrochloric acid, hydrobromic acid and perchloric acid.
[00144] The salt of the compound of formula (Villa) is then reacted with benzyl bromide and, for example, a base, to form the compound of formula (IXa). A knowledgeable person would readily understand that substituted benzyl halides could be used in place of benzyl bromide. For example, the following benzyl halides, where X = Cl, Br or I, could be used:
f ^x— f /
F OiPr
F OMe (Xa) (Xb) (Xc) (Xd) [00145] Representative benzyl halides are found in Belokon, YN, et al., Halo-substituted (S) -N- (2-benzoylphenyl) -1benzylpyrolidine- 2-carboxamides as new chiral auxiliaries for the asymmetric synthesis of (S) -a-amino acids, Russian Chemical Bulletin, international edition, 51 (8): 1593-1599 (2002). Additional and different benzyl halides can also be used:
Me Me (X _e ) [00146] These representative benzyl halides are found in Saghiyan, AS, et al., New chiral Nill complexes of Schiff's bases of glycine and alanine for efficient asymmetric synthesis of a-amino acids, Tedrahedron: Asymmetry / 7: 455-467 (2006) [00147] Then, the compound of formula (IXa) is reacted with L
32/63 alanine and Ni (NO ₃ ) ₂ to form the metal complex of the formula (Xia). The person skilled in the art would understand that amino acids other than alanine can be used in Scheme II. For example, glycine; valine, 2-aminopentanoic acid and 2-aminobutanoic acid could be used, for example, in their D or L forms. Ni (NO ₃ ) ₂ can be a hydrate, for example, a hexahydrate. The reaction can be carried out in an alcoholic solvent, for example, methanol. The reaction can be carried out at an elevated temperature, for example, from about 40 ° C to about 60 ° C. The reaction can be carried out in the presence of a base, for example, a hydroxide, for example an inorganic hydroxide, for example, potassium hydroxide. Other hydroxides are contemplated, including sodium hydroxide, cesium hydroxide, lithium hydroxide, and magnesium hydroxide.
[00148] To increase the purity of the final product of Scheme II, the metal complex of formula (Xla) can be crystallized one or more times from one or more solvents, for example, a cyclic ether and a non-cyclic ether , for example a tetrahydrofuran and methyl tert-butyl ether. In some cases, the ratio of cyclic ether to non-cyclic ether is at most 0.5: 10, 1.0: 10, 1.5: 10, 2.0: 10, 2.5: 10, 3.0: 10, 3.5: 10, 4.0: 10.4.5: 10 or 5:10. In other cases, the ratio of cyclic ether to non-cyclic ether is at least 0.5: 10, 1.0: 10, 1.5: 10, 2.0: 10, 2.5: 10, 3.0: 10, 3.5: 10.4.0: 10, 4.5 : 10 or 5:10. For example, in some cases the metal complex of formula (Xla) crystallizes from a mixture of tetrahydrofuran and methyl tert-butyl ether in the ratio of a maximum of 0.5: 10, 1.0: 10.1.5: 10, 2.0: 10, 2.5: 10, 3.0: 10, 3.5: 10, 4.0: 10, 4.5: 10 or 5:10. In other cases the ratio of e tetrahydrofuran and methyl tert-butyl ether is at least 0.5: 10, 1.0: 10, 1.5: 10, 2.0: 10, 2.5: 10, 3.0: 10, 3.5: 10.4.0: 10, 4.5: 10 or 5:10. In some cases, the ratio of tetrahydrofuran and methyl tert-butyl ether is 1.5: 10. The product or crystallized product of formula (IXa) may alternatively or
33/63 be crystallized or recrystallized from a solvent, for example, an alcohol, for example propyl alcohol. Other alcohols are contemplated, including methanol, ethanol, n-propanol, butanol, n-butanol, isobutanol, iso-butanol, sec-butanol and t-butanol. Other solvents suitable for crystallization or recrystallization of the formula (Xla) include esters, for example, ethyl acetate or isopropyl acetate.
[00149] The metal complex of formula (Xla) is then alkylated with 5-bromopent-1-ene to form the alkylated metal complex of formula (Xlla). The person skilled in the art would understand that other alkylating agents, including other halo alkyl olefins, could be used in place of 5-bromopent-1-ene. For example, the alkylating agents of formula (XV) can be used:
(XV) [00150] where X is Cl, Br or I, and n is an integer from 1 to 20. For example, n can be 3 to 11, 3 to 6, or 3 or 6. Some or all the hydrogen atoms present in the compound of formula (XV) can be replaced with deuterium atoms or halogen atoms. Alkylation can be performed in one or more solvents, for example, a polar aprotic solvent, for example, N, N-dimethyl formamide (DMF). The alkylation can be carried out, for example, at a temperature of less than 20 ° C, for example, less than 20 ° C to 5 ° C, less than 20 ° C to 10 ° C, or at about 10 ° Ç. The person skilled in the art would also understand that when glycine is used to form the metal complex, two alkylations could be performed one after the other. For example, the first alkylation can be carried out using a C1-C3 alkane with a labile group such as a halogen (for example, methyl bromide, ethyl bromide, n-propyl bromide), or a C1-C3 deuteroalkane with a labile group such as
34/63 a halogen (for example, CD ₃ Br, CD ₃ CD2Br, CD ₃ CD ₂ CD ₂ Br), or a Ci-C ₃ haloalkane with a labile group, such as a more reactive halogen than the other halogens in haloalkane (e.g. CF ₃ Br, CF ₃ CF ₂ Br, CF ₃ CF ₂ CF ₂ Br). Then, the second alkylation can be performed using the alkylating agent of formula (XV). The order of the first and second alkylation can be reversed.
[00151] The purification of formula (Xlla) can be achieved by crystallization in one or more times of one or more solvents including cyclic and non-cyclic ethers, esters, hexanes and heptanes. For example, crystallization can be achieved using a combination of ethyl acetate and hexanes, ethyl acetate and heptanes, isopropyl acetate and hexanes, isopropyl acetate and heptanes, tert-butyl methyl ether and hexanes, tert-methyl ether butyl and heptanes or isopropyl acetate and tert-butyl methyl ether.
[00152] Next, the metal complex of formula (Xlla) is cleaved with an acid, for example, HCI, using one or more solvents, for example an ether, for example a cyclic ether, for example, tetrahydrofuran, to form the amino acid HCI salt of formula (Xllla). A skilled artisan would readily understand that other acids in addition to HCI are contemplated, for example, organic acids or inorganic acids, for example, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrochloric acid, hydrobromic acid or perchloric acid.
[00153] The salt of formula (Xllla) can be further purified by crystallization one or more times with one or more solvents. The solvent can be any suitable solvent including tetrahydrofuran, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, ethanol, methanol, isopropanol, acetonitrile or a combination thereof. In one embodiment, the solvent is acetonitrile.
[00154] The amino acid salt of the formula (Xllla) then has the ni
35/63 trogen protected with a nitrogen protecting group, in this case an Fmoc group and the protected amino acid cyclohexylamine addition salt is formed, producing the formula protected cyclohexylamine amino acid salt (XlVa). In some embodiments, the formula compound (XlVa) is brought to crystallization in its current state. In other embodiments, the compound of formula (XlVa) is converted to a salt before crystallization. The formation of the formula salt (XlVa) can be achieved in any suitable solvent including acetonitrile, tert-butyl methyl ether, tetrahydrofuran or a combination thereof. A person skilled in the art would also readily understand that other nitrogen protecting groups are contemplated, for example, the nitrogen protecting group for R ₂ in the crystalline compound of formula (I) or its crystalline salt in this document. For example, a protected cyclohexylamine amino acid salt (XlVa) can then be crystallized from one or more ethers, for example, two ethers, for example a cyclic ether and a non-cyclic ether, for example tetrahydrofuran and ether of methyl tert-butyl.
[00155] The protected cyclohexylamine amino acid salt of formula (XlVa) can then be crystallized to form the crystalline compound of formula (lla).
[00156] Crystallization can be carried out using one or more solvents, for example, two solvents, for example an alkane and haloalkane, for example, hexanes and chloroform. In some cases, the ratio of alkane to haloalkane is at least 6: 1.5: 1, 4: 1, 3: 1, 2: 1, or 1:10. In some cases, the ratio of alkane to haloalkane is at most 6: 1.5: 1, 4: 1, 3: 1.2: 1, or 1:10. For example, the crystalline compound of formula (IIa) can be obtained by crystallizing a mixture of hexanes and chloroform in the ratio of at least 6: 1, 5: 1, 4: 1, 3: 1, 2: 1 or 1: 1. Crystallized llla can also be obtained by crystallizing a mixture of hexanes and chloroform in a maximum 6: 1 ratio,
36/63
5: 1, 4: 1, 3: 1, 2: 1, or 1: 1. In some cases, the ratio of hexanes to chloroform is 2: 1.
[00157] Crystallization can be performed at a temperature in the range of, e.g., about -20 to about -5Ό Ό about 10O to about-20 ^C-C, or about 15O-20O-a. In this document, unless otherwise stated, any compound or its salt may be crystalline. In this document, unless otherwise indicated, any compound or salt thereof may be crystalline at a temperature, for example, of about 0Ό or less, about -5Ό or less, about 100 or less, about -150 or less, about -2 OO or less, about -50, about -60, about -70, about -80, about 90, about -10O, about -110, about -120, about -130, about -140, about -150, about -160, about -170, about -180, about -190, or about -200.
[00158] The person skilled in the art would understand, for example, that the crystalline compound of formula (llla) could be additionally activated or protected in its function as carboxylic acid with, for example, a protection group or R ₃ activation of the crystalline complex of formula (I) or its crystalline salt.
Stapled and stitched polypeptides [00159] The crystalline compounds and their crystalline salts of the formula (I), including the crystalline compounds and their crystalline salts of the formulas (Ha), (Hb), (llla) and (Hlb), as well as the compounds , optionally, crystalline and their optionally crystalline salts, of formula (IV), can be used to synthesize cross-linked peptides and polypeptides and polypeptides that are useful in the treatment and prevention of diseases.
[00160] Chitosan polypeptides can contain secondary structures such as a helix, for example, an alpha helix. The cross-linking agent can stabilize secondary structures in
37/63 relation to an identical polypeptide, if not because it is reticulated. And the crosslinking agent can be formed by, for example, joining the terminal alkene side chains of, for example, two amino acids a, α-disubstituted crystalline alkenes or their crystalline salts in this document which are incorporated into a polypeptide via, for example, a metal reaction catalyzed by olefin metathesis (for example, forming a stapled peptide). This process is described in Scheme III, below: Scheme III
Polypeptide
Side chains of, for example, disubstituted alpha, alpha crystalline amino acids that have been incorporated into a polypeptide
Metal-catalyzed Metathesis Reaction
Cross-linked Polypeptide Crosslinker
Cross-linked polypeptide ("Stapled") [00161] Examples of stapled polypeptides are found, inter alia, for example, in International Order no. PCT / US2004 / 038403.
[00162] The crystalline compounds and their crystalline salts of the formula (I), including the crystalline compounds and their crystalline salts of the formulas (Ha), (Hb), (Hla) and (Hlb), as well as the optionally crystalline compounds and its optionally crystalline salts, of formula
38/63 (IV), can be used to synthesize stapled peptides and polypeptides and polypeptides that are useful in the treatment and prevention of diseases.
[00163] For example, two of the crystalline compounds and their crystalline salts of formula (I), a spine polypeptide structure may be incorporated, together with an amino acid a, substituted having terminal olefins in each of its side chains, for example, the compound of formula (XVI):
(XVI) [00164] as shown in scheme IV. Reaction of olefin-catalyzed metal metathesis produces a stitched peptide.
Scheme IV
Polypeptide
Side chains of, for example, alpha, alpha crystalline disubstituted amino acids that have been incorporated into a polypeptide
Metal-catalyzed Metathesis Reaction
Stitched Polypeptide gtit _c Stitched Polypeptide stitching
39/63 [00165] Examples of sewn polypeptides are found, for example, in International Order Publication No. ² . WO2008 / 121767.
[00166] Methods for effecting the formation of peptidomimetic macrocycles which are known in the art can be employed. For example, the preparation of peptidomimetic macrocycles are described in Schafmeister et al., J. Am. Chem, Soc. 122: 5891-5892 (2000); Schafmeister & Verdine, J. Am. Chem. Soc. 122: 5891 (2005); Walensky et al., Science 305: 1466-1470 (2004); US Patent No. 7,192,713 and International Patent. App. Pub. No. ² WO 2008/121767.
[00167] Here, unless otherwise stated, the term peptide synthesis encompasses the coupling of two or more amino acids, with the help of a coupling reagent. The peptide synthesis can be carried out in a liquid phase or solution in which the coupling of the amino acids is done in a solvent system. Peptide synthesis can also, or alternatively, be carried out in the solid phase, where an amino acid is attached to a solid or polymeric support by a covalent bond at the N- or C- terminus of an amino acid. Peptides can be made, for example, by chemical synthesis methods, such as those described in Fields et al., Capt 3 in Synthetic Peptides: A User's Guide, ed grant, WH Freeman & Co, New York, NY, 1992, p. 77, and Goodman, M., et al., Houben-Weyl Methods in Organic Chemistry: Synthesis of Peptides and Peptidomimetics, Thieme Publishers, Volumes 1-5 (1994). For example, peptides can be synthesized using Merrifield's automated solid phase synthesis techniques with the amino groups of the amino acids employed in the protected synthesis, for example, by t-Boc or Fmoc protecting groups. An automated peptide synthesizer (eg, Applied Biosystems (Foster City, CA), model 430A, 431, or 433) can be employed in the production of peptides.
40/63 [00168] In this document, unless otherwise indicated, peptidomimetic precursors and peptidomimetic macrocycles and their salts described herein can be produced using the synthesis of solid phase peptide (SPPS), in which, for example, an amino acid C -terminal is attached to a cross-linked polystyrene resin via an acid or labile base bond with a binder. The resin may, for example, be insoluble in solvents used for synthesis, making it relatively simple and quick to wash excess by-products and reagents. The N-terminus of each amino acid added to the growing peptide chain can be protected, for example, with an Fmoc group, which is stable in acid, but removable by the base. Side chain functional groups can be protected, as necessary or desirable, for example, with stable acid base labile groups.
[00169] Here, unless otherwise indicated, peptidomimetic precursors can be made, for example, in a high-productivity, combinatorial manner using, for example, a combinatorial multi-channel high-productivity synthesizer (eg, multi-channel TETRAS peptide synthesizer) ThuramedCreoSalus, Louisville, KY or Model Apex 396 multichannel peptide synthesizer from AAPPTEC, Inc., Louisville, KY).
[00170] Here, unless otherwise indicated, synthesis of the solution peptide can be carried out in a way in which the reagents are totally or partially dissolved in, for example, an appropriate solvent, for example, a polar aprotic solvent. In a representative case employing, for example, a solid N-terminally crystalline protected olefinic amino acid with a removable protecting group (for example, t-Butyloxycarbonyl, benzyloxycarbonyl, Fluorenylmethoxycarbonyl) and a C-protected amino acid with a selectively removable ester (for example , methyl, benzyl, t-butyl), the amino acids can be totally or partially dissolved in a sol
41/63 and an activating agent is added to achieve the formation of a peptide bond between the amino acids. Solution peptide synthesis can also use the first formation of active esters of N-protected olefinic amino acids (eg, N-hydroxysuccinamide, p-nitrophenyl, 2, 4, 6-trichlorophenyl, pentafluorophenyl) and then subsequent reaction of the amino acid activated with an unprotected or C-protected amino acid. The active esters of olefinic amino acids can be prepared, for example, by reacting a solid N-protected olefinic amino acid with an appropriate alcohol with the help of the condensing agent (for example, dicyclohexylcarbodiimide). These same procedures can also be used, for example, when one or both of the amino acids to be reacted are part of and incorporated, respectively, for example, in one or two peptides.
[00171] Formation of the terminally protected olefinic amino acids can easily be facilitated by the reaction of dry solid olefinic amino acid (s) with an appropriate alcohol (eg methyl, ethyl, benzyl) under, for example example, anhydrous conditions. The formation of a peptide in which the olefinic amino acid is in the C-terminal position can be carried out, for example, in a similar way. Solution methods of peptide preparation can be easily adapted to the process scale. The raw materials and reagents used in this document in the preparation of any compound in this document and as disclosed above and below, unless otherwise stated, for example, may be available from commercial sources such as Aldrich, Sigma or Bachem or may be prepared by methods known to those skilled in the art following established procedures, for example, in references such as: Reagents for Org, by Fieser and Fieser, for Org. Syn Vol. 1-17, Organic Reactions vol. 1-40, Advanced Organic Synthesis, de March, Buy
42/63 hensive Organic Transformations, by Larock, The Practice of Peptide Synthesis, by Bodansky and Bodansky, Protective Groups in Organic Synthesis, by Greene, Wei, Q., et al., Tetrahedron: 56: 25772582 (2000), Belokon, YN, et al., Tetrahedron Asymmetry 9: 42494252 (1998), Belokon, Y, Pure & App. Chem. 64 (12): 1917-1924 (1992), Ueki, H., et al.J.Org. Chem.68: 7104-7107 (2003).
[00172] These schemes in this document are illustrative of some methods by which compounds and their salts (which can be crystalline) can be synthesized, and various modifications to these schemes can be made and will be suggested to a person skilled in the art having referred to this description .
[00173] The raw materials and intermediates of the reactions of any modality in this document, in this document and as disclosed above, unless otherwise indicated, can be isolated and purified if desired using conventional techniques, including, but not limited to filtration , distillation, crystallization, chromatogram, rapid chromatography, HPLC, MPLC, Chromatotron ®, ion exchange chromatography, crystallization with Mosher acids or Mosher esters and the like. Such materials can be characterized using conventional means, including physical constructions and spectral data, for example, proton NMR, carbon NMR, IR spectroscopy, polarimetry, atomic absorption, elemental analysis, UV spectroscopy, FTIR spectroscopy and the like. In any embodiment described here and above, unless otherwise indicated, chromatography can be excluded by making any of the compounds or their salts.
[00174] Unless otherwise specified, the reactions described herein can occur, for example, from about 0.001 to about 100 atmospheres (atm), for example, about 0.001 atm, about 0.01 atm, about 0.1 atm, about 1 atm, about 2 atm, about 3 atm, about 4 atm, about 5 atm, about 10 atm, about 20 atm,
43/63 about 50 atm, or about 100 atm.
[00175] Reactions in any form in this document, unless otherwise indicated, may be performed, unless otherwise indicated, for example, opening to the atmosphere, or under an atmosphere of inert gas such as, for example, nitrogen or argon.
[00176] Reactions in any form in this document, unless otherwise indicated, may be performed, unless otherwise indicated, for example, at temperatures from about -78Ό to about 150Ό, for example, from about - 78Ό, cer aC-50, about-20 ^{and C} about 0Ό about 10Ό about 20Ό about 23Ό about 25Ό about 27Ό about 30Ό about 40Ό about 50Ό , about 100Ό, about 125Ό, about 150 ° C, about room temperature, or about room temperature.
[00177] Reactions in this document, unless otherwise indicated, may have a yield, unless explicitly stated otherwise, based on theoretical yield, for example, ranging from about 1% to about 99%. The yield can be, for example, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5%.
[00178] Reactions in this document, unless otherwise indicated, can be performed, unless otherwise indicated, for example, for a time in the range of about 0.1 to about 96 hours, eg, for about about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours,
44/63 about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 48 hours, about 72 hours, or about 96 hours,
Selective uses of Reticulated Peptidomimetic Macrocycles (stitched and stapled peptides) [00179] Reticulated Peptidomimetic Macrocycles (stitched and stapled peptides), made with, for example, at least one of the crystalline compounds and their crystalline salts of formula (I), including crystalline compounds and its salts of formulas (Ha), (llb), (llla) and (lllb), as well as the optionally crystalline compounds and their optionally crystalline salts of formula (IV), can be used to treat or prevent diseases . For example, Reticulated Peptidomimetic Macrocycles (stitched and stapled peptides) can be used to treat or prevent cancer. Selected examples of cancers include, for example, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliossarcoma, synovioma, cancer, sarcoma, sarcoma, sarcoma, sarcoma, sarcoma, sarcoma, sarcoma rectal, pancreatic cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, brain cancer, squamous cell carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma , bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonic carcinoma, Wilm's sarcoma, cervical cancer, testicular cancer, small cell lung carcinoma, non-small cell lung carcinoma, bladder carcinoma carcinoma
45/63 epithelial, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, or sarcoma.
[00180] Diseases that can be treated by stitched or stapled peptides can be found, for example, in international application ² . PCT / US2004 / 038403 (application '403) and in international publication application ² WO2008 / 121767 (publication' 767).
[00181] Although several inventive modalities have been shown and described in this document, it will be obvious to those skilled in the art that such modalities are provided by way of example only. Numerous variations, changes, and substitutions will now occur for those skilled in the art without departing from the inventive description in this document. The following examples are illustrative and should not be construed as limiting.
Examples
Example 1: Preparation of crystalline N-Fmoc- (R) -a-methyl-a-aminodec-9-acid
Example 1a: Preparation of (R) -2- [N- (N'-Boc-Drolil) amino] benzophenone-
[00182] Tetrahydrofuran and 9.6 kg (1.0 equiv.) Of Boc-D-proline (V) were added to a reactor and cooled to -5 °. 5.3 kg (1.15 equiv.) Of N-methylmorpholine was loaded followed by a slow addition of 6.1 kg (1.0 equiv.) Of isobutyl chloroformate in tetra
46/63 hydrofuran, maintaining the internal temperature at <5 ° C. The mixture was allowed to stir at 20-25 ° for 45-60 minutes and then was analyzed by TLC for completion. A 8.2 kg (0.9 equiv.) Solution of 2-aminobenzophenone / tetrahydrofuran was charged and the mixture was allowed to stir at 20-25 ° until the reaction was considered complete. The mixture was concentrated to ^1/2 volume and isopropyl acetate was charged. The organic product layer was then washed with a 5% sodium bicarbonate solution, water was charged and then the pH was adjusted to 2.0-2.5 with 25% sulfuric acid. The layers were divided and the organic product layer was washed again with water. The organic product solution was then concentrated and crystallized from isopropyl acetate and washed with tert-butyl methyl ether. Product (VII) was isolated and dried under heat and vacuum. Yield: 12 kg, 66.7%.
Example 1b: Preparation of D-proline-2-Aminobenzophenone amide
[00183] 12.0 kg (1.0 equiv.) Of Boc-D-proline-2-aminobenzophenone (VII) amide was dissolved in acetonitrile. 2.2 kg (2.0 equiv.) Of hydrogen chloride gas was then charged / bubbled into the solution. The resulting mixture was then left to stir at 20-25 ° until the reaction was complete. Methyl tert-butyl ether was added and the solid product was isolated out of the reaction solution and washed with additional tert-butyl methyl ether. The product (VIII) was isolated and dried under heat and vacuum. Yield: 9.1 kg, 100%.
Example 1c: Preparation of (R) -2- [N- (N'-benzylprolyl) amino] benzo47 / 63 phenone (D-BPB)
THF / H _x O / MTBE / Heptanes
Benzyl Bromide Triethylamine
[00184] 9.1kg (1.0 equiv.) Of D-proline-2-aminobenzophenone amide
HCI (VIII) was dissolved in water and tetrahydrofuran. 8.1 kg (2.4 equiv.) Of triethylamine was then loaded, followed by a slow addition of 7.9 kg (1.4 equiv) of benzyl bromide. The mixture was then left to stir at 20-25 ° until the reaction was complete. Methyl tert-butyl ether and water were added and the resulting solution had its pH adjusted to 2.0-2.5 with a 1N hydrochlorochloric acid solution. The mixture was concentrated to remove all of the tetrahydrofuran. The product slurry was then isolated and washed with tert-butyl methyl ether. The product (IX) was isolated and dried under heat and vacuum. Yield: 10.5 kg, 82.7%.
Example 1d: Preparation of (R) -Ala-Ni-BPB

Ni (NO ₃ ) ₉
[00185] 10.5 kg (1.0 equiv.) Of D-BPB (IX), 14.1 kg (1.78 equiv.) Nickel (II) nitrate hexahydrate 4.9 kg (2.0 equiv.) of L-alanine and methanol were loaded into a reactor. The mixture was heated to 40Ό and a 12.2 kg (8.0 equiv.) Solution of potassium hydroxide
48/63 sodium / methanol was added slowly, maintaining an internal temperature of <500. The reaction mixture was then heated to 600 ° C and allowed to stir at temperature until the reaction was complete. The mixture was then cooled to 20-250 ° C and 8.2 kg (5.0 equiv.) Of acetic acid was charged slowly, maintaining an internal temperature of <350 ° C. The reaction solution was concentrated to a solid. Tetrahydrofuran and isopropyl acetate were then added to dissolve the solid (s) and the organic product layer was washed 2x with water. The solution was then concentrated and again and the material was subsequently crystallized from tetrahydrofuran and methyl tert-butyl ether. The product was isolated, washed with additional methyl tert-butyl ether and analyzed for purity. To improve purity, the product (XI) was recrystallized from isopropyl alcohol and then isolated, and dried under heat and vacuum. Yield: 6.8 kg, 48.6%.
Recrystallization procedure [00186] THF was added to the crude product (15 mL per 10 g of raw material (D-BPB)) and the resulting mixture was heated to 50Ό. The mixture was kept at 50Ό for 1 h and then methyl tert-butyl ether was added (50 ml per 10 g of raw material (D-BPB)). The mixture was kept at 50Ό for an additional 1 h after which it was cooled to 35Ό. The mixture was filtered and the resulting solid was washed with tert-butyl methyl ether (20 ml per 10 g of raw material (D-BPB)) to obtain crystalline product XI.
Alternative recrystallization procedure [00187] Isopropyl acetate was added to the crude product (40 mL per 4 g of raw material (D-BPB)) and the resulting mixture was kept at room temperature for 30 min. Then, the mixture was filtered to obtain crystalline product XI.
Example 1e: Preparation of R8-NÍ-BPB
49/63
(XI)
NaOH (powder)
AcOH / DMF / DCM
[00188] 6.8 kg (1.0 equiv.) Of (R) -Ala-Ni-BPB (XI) was loaded into a reactor and dissolved in dimethylformamide and cooled to 100. 1.4 kg (2.5 equiv) .) of sodium hydroxide (powder) was then charged to the same reactor and the mixture was sparged with nitrogen and stirred until a solution formed at 100. 5.2 kg (2.0 equiv.) of 8-bromo-1- octene was charged to the reactor, maintaining an internal temperature <200. The mixture was then left to stir at 20-250 ° C until the reaction was complete. Once the reaction was complete, the solution was cooled to 100 and 0.5 kg (0.6 equiv.) Of acetic acid was charged maintaining the internal temperature <250. Water was then charged followed by tert-methyl ether. butyl and the organic layer was washed. The organic layer was then washed twice with water and then concentrated. The product oil was then codified with methylene chloride and dissolved in additional methylene chloride. The product solution (XII) was taken to the next processing step.
Example 1f: Preparation of (R) -2-Amino-2-methyl-dec-9-enoic acid
(IX) [00189] The DCM solution R8-NÍ-BPB (X11) / was loaded into a 50-L reactor of chemical glass and stripped to an oil. Tetrahydrofuran,
Then 50/63 was added and the mixture was stirred at 20-25Ό until a solution was formed. 7.8 kg (5.0 equiv.) Of 32% hydrochloric acid was loaded slowly, maintaining an internal temperature <30Ό. The mixture was then left to stir for 6-8 hours at room temperature. The mixture was then concentrated to remove tetrahydrofuran to yield a sludge. Additional water was added and the slurry was stirred at room temperature for 1-2 hours. The solid BPB salts were isolated by filtration and washed with additional water followed by methyl tert-butyl ether. The product filtrates were then refilled to the reactor producing a three-phase solution. The lowest layer was divided from the top two layers. The two combined organic layers were then washed 3x with water and concentrated to an oil. Acetonitrile was then added and the mixture was heated to 700 ° C for 30 minutes. The mixture was then cooled to 25-300 ° C and the solid product was isolated. The solid filter cake was washed with acetonitrile and methyl tert-butyl ether, then analyzed for purity. The product was then slushed from additional acetonitrile and washed with acetonitrile and methyl tert-butyl ether. The material (XIII) was isolated and dried under heat and vacuum. Yield: 1.55 kg, 48%.
Recrystallization Procedure [00190] Acetonitrile (23 mL per 10 g of raw material (oil of (R) Ala-Ni-BPB (XI)) was added to the crude product and the resulting mixture was heated to 70Ό for 30 min after which it was cooled to 20Ό. The mixture was filtered and the resulting solid was washed with acetonitrile (5 ml) and methyl tert-butyl ether (8.5 ml) to obtain crystalline product XIII.
Alternative recrystallization procedure to prepare Xlll-I [00191] Acetonitrile (30 ml per 10 g of raw material (oil of (R) Ala-Ni-BPB (XI)) was added to the crude product and the resulting mixture
51/63 was heated to 60Ό for 30 min after which it was cooled to 30Ό. The mixture was filtered and washed with acetonitrile (5 ml) to obtain crystalline product XIII.
Alternative recrystallization procedure to prepare Xlll-ll [00192] Acetonitrile (23 mL per 10 g of raw material (oil of (R) Ala-Ni-BPB (XI)) was added to the crude product and the resulting mixture was heated at 40Ό for 30 min, then cooled to room temperature. The mixture was then filtered and washed twice with 5 ml of acetonitrile to obtain crystalline product XIII.
Example 1q of: Preparation of crystalline N-Fmoc- (R) -a-methyl-a-aminodec9-enoic acid
CyciohexyCyclohexylamine

(XIV)
[00193] 1.55 kg (1.0 equiv.) · 2-amino-2-methyl-dec-9-enoic acid
HCI (XIII) was suspended in water and polished filtered to remove traces of D-BPB HCI from the solution. Methyl tert-butyl ether was added and the aqueous product layer was extracted at once with tert-butyl methyl ether. The aqueous product layer was refilled and tetrahydrofuran was added. A 20% aqueous sodium carbonate solution (2.75 equiv.) Was charged to the mixture followed by Fmoc-OSu (0.89 equiv.). The mixture was left to react at 20-25Ό, maintaining the pH between 8.5 - 9.0 with additional amounts of 20% sodium carbonate solution until the reaction was complete. The mixture had its pH adjusted to pH 2.0 - 2.5 with the hydrochloric acid HCL. Tetrahydrofuran was distilled off and methyl tert-butyl ether was charged. The layers were separated and the organic layer was washed an additional 3 times with additional water. The organic layer was then concentrated in vacuo and coded with tert-butyl methyl ether. O
The resulting crude oil was redissolved in methyl tert-butyl ether and cyclohexylamine (1.10 equiv.) Was added slowly to obtain a pH range of 8.5 - 9.0. The slurry was stirred at room temperature (20 to 25Ό) for 3 hours and the solid product salt (XIV) was isolated by filtration. The solids were rinsed twice with additional methyl tert-butyl ether and the solid wet cake was refilled in a clean reactor. The wet cake was recrystallized from tetrahydrofuran and methyl tert-butyl ether to improve purity. The solid salt was suspended in methyl tert-butyl ether and the pH adjusted to 2.0-2.5 with 25% sulfuric acid. The organic product layer was washed with water until all of the cyclohexylamine was removed. The organic product layer was concentrated and coded with hexanes for a loose oil. The product (Ha) was then crystallized from chloroform and hexanes and dried at <0% with a nitrogen sweep of 1.0 cfm. Yield: 1.12 kg, 41.5% Crystallization procedure [00194] Methyl tert-butyl ether (800 mL per 36 grams of raw material XIII) was added to the crude product and the pH of the resulting mixture was adjusted to 8-9 using 20A CHA. The mixture was mixed at 20Ό, and after 1 h, crystals started to form. Additional tert-butyl methyl ether (200 ml) was added and the resulting slurry was mixed for 18 h. The mixture was filtered and the resulting solid was washed twice with methyl tert-butyl ether (200 ml and 8.5 ml) to obtain crystalline product XIII. The product was analyzed for chiral purity and if the results were less than 95% Fmoc-R8 vs Fmoc-S8, then crystallization was performed to improve chiral purity by dissolving dry FmocR / S (50 g) in THF (50 mL) . Once FmocR / S was dissolved, tert-butyl methyl ether was added (900 mL) and the mixture was mixed at 20Ό for 18 h. The mixture was then filtered and washed twice with tert-butyl methyl ether (100 ml each). Chiral purity re
53/63 Result of crystalline product XIV was about 97.8% Alternative recrystallization procedure for XIV-I [00195] Methyl tert-butyl ether (1500 mL per 47 g of raw material XIII) was added to the crude product and the pH of the resulting mixture was adjusted to 8-9 using 20Ό CHA. The mixture was mixed at this temperature for 3 h, then it was filtered and the resulting solid was washed with tert-butyl methyl ether (250 ml).
Alternative recrystallization procedure for XIV-II [00196] Methyl-tert-butyl ether (400 mL per 20 g of raw material XIII) was added to the crude product and the pH of the resulting mixture was adjusted to 8-9 using CHA at 20Ό. Another 200mL of methyl tert-butyl ether was added and the mixture was mixed at this temperature for 2h, then it was filtered and the resulting solid was washed with methyl tert-butyl ether (10ml).
Alternative recrystallization procedure for XIV-III [00197] Methyl tert-butyl ether (50 mL per 4 g of raw material XIII) was added to the crude product and the pH of the resulting mixture was adjusted to 8-9 using CHA at 20Ό . The mixture was mixed at this temperature for 45 min, then it was filtered and the resulting solid was washed with tert-butyl methyl ether (10 ml).
Recrystallization procedure for Ila [00198] Chloroform (70 ml) was added to the crude product (25 g) and the resulting mixture was cooled to 0Ό. Hexanes (210 mL) were then added slowly in order to maintain the temperature at 0Ό. The mixture was further maintained at this temperature for 1 h, then it was filtered cooled and the resulting solid was dried under vacuum at 0Ό. Alternative recrystallization procedure for lla-l [00199] Chloroform (2200 m L) was added to the crude product (1100 g). Hexanes (6600 L) were then added slowly and the resulting mixture was cooled to less than 0Ό. The mixture was
54/63 further mixed at a temperature below OO for 1 h, after which it was filtered at less than 0Ό and the resulting solid was dried under vacuum at a temperature below 0Ό.
Example 2: Preparation of crystalline N-Fmoc- (S) -a-methyl-a-aminodec-6-acid
Example 2a: Preparation of (S) -2- [N- (N'-Boc-prolyl) amino] benzophenone-
[00200] Tetrahydrofuran and 7.5 kg (1.0 equiv.) Of Boc-L-proline (Va) were added to a reactor and the resulting solution was cooled to 5Ό. 4.2 kg (1.05 equiv.) Of N-methylmorpholine were loaded followed by a slow addition of 5.3 kg (1.0 equiv.) Of isobutyl chloroformate in tetrahydrofuran, maintaining an internal temperature of <5¾ . The mixture was allowed to stir at 20-25 ° for 45-60 minutes and was then analyzed by TLC for completion. A 6.2 kg (0.9 equiv.) Solution of 2-aminobenzophenone / tetrahydrofuran was charged and the mixture was allowed to stir at 20-25 ° C until the reaction was shown complete by TLC. The mixture was concentrated to% by volume and isopropyl acetate was loaded. The organic product layer was then washed with a 5% sodium bicarbonate solution, water was charged, and then the pH was adjusted to 2.0-2.5 with 25% sulfuric acid. Layers were divided and the organic product layer was washed again with water. The organic product solution / layer was then concentrated and crystallized from isopropyl acetate and washed with tert-butyl methyl ether. Product (Vila) was
55/63 then isolated and dried under heat and vacuum. Yield: 9.3 kg, 75%.
Example 2b: Preparation of L-Droline-2-Aminobenzophenone amide

H.HCI (vnia) [00201] 9.4 kg (1.0 equiv.) Of Boc-L-proline-2-aminobenzophenone (Vila) amide was dissolved in acetonitrile. 1.7 kg (2.0 equiv.) Of hydrogen chloride gas was then charged / bubbled into the solution. The mixture was then allowed to stir at 20-25Ό until the reaction was demonstrated complete by TLC. Methyl tert-butyl ether was added and a solid product was isolated out of the reaction solution and washed with additional tert-butyl methyl ether. The product (Villa) was isolated and dried under heat and vacuum. Yield: 7.0 kg, 100%.
Example 2c: Preparation of (S) -2- [N- (N'-benzylprolyl) amino] benzophenone (L-BPB)
[00202] 7.1 kg (1.0 equiv.) Of L-proline-2-aminobenzophenone amide
HCI (Villa) was dissolved in water and tetrahydrofuran. 5.8 kg (2.4 equiv.) Of triethylamine were then loaded, followed by a slow addition of 5.9 kg (1.4 equiv) of benzyl bromide. The mixture was then left to stir at 20-25 ° until the reaction was complete. Ether
56/63 of methyl tert-butyl and water were added and the resulting solution had its pH adjusted to 2.0-2.5 with a 1N hydrochloric acid solution. The mixture was concentrated to remove all of the tetrahydrofuran. The product slurry was then isolated and washed with tert-butyl methyl ether. The product (IXa) was isolated and dried under heat and vacuum. Yield: 7.7 kg, 84.0%.
Example 2d: Preparation of (S) -Ala-Ni-BPB
[00203] 7.9 kg (1.0 equiv.) Of L-BPB (IXa), 12.1 kg (1.78 equiv.) Nickel (II) nitrate hexahydrate 3.7 kg (2.0 equivs) of L-alanine and methanol were loaded into a reactor. The mixture was heated to 40Ό and a solution of 8.2 kg (8.0 equiv.) Of potassium hydroxide / methanol was added slowly, maintaining an internal temperature of <50Ό. The reaction mixture was then heated to 60Ό and allowed to stir at temperature until the reaction was complete. The mixture was subsequently cooled to 20-25Ό and 8.9 kg (5.0 equiv.) Of acetic acid was loaded slowly, maintaining an internal temperature of <35Ό. The reaction solution was then concentrated to a solid. Tetrahydrofuran and isopropyl acetate were then added to dissolve solids and the organic product layer was washed 2x with water. The solution was then concentrated and again and the material was subsequently crystallized from tetrahydrofuran and methyl tert-butyl ether. The product was isolated, washed with additional methyl tert-butyl ether and analyzed for purity. To improve the purity, the product (Xla) was recrystallized from propyl alcohol and then isolated, and dried under heat and vacuum. Yield: 6.0 kg, 56.0%.
57/63
Recrystallization procedure for Xla [00204] Tert-butyl methyl ether (550 mL per 50 g of raw material L-BPB) was added to the crude product (S) - Ala - Ni- BPB and the sludge was then heated to 500 before to cool it to 200 ° C. The mixture was mixed at 200 ° C for 16 h. The mixture was filtered and the resulting solid was washed with tert-butyl methyl ether (100 ml) to obtain the crystalline product Xla.
Alternative recrystallization procedure for Xla-I [00205] Methyl tert-butyl ether (600 mL per 50 g of raw material L-BPB) was added to the crude product (S) - Ala - Ni- BPB and the sludge was then heated 50-60Ό and maintained at this temperature for 1 hr. The mixture was then filtered at 35 ° and washed with methyl tertiary butyl ether (100 ml) to obtain the crystalline product Xla.
Alternative recrystallization procedure for Xla-ll [00206] Methyl tert-butyl ether (500 mL per 50 g of raw material L-BPB) was added to the crude product (S) - Ala - Ni- BPB and the slurry was then heated to 45-50Ό and maintained at this temperature for 1 h. The mixture was then filtered at 35 ° and washed with tert-butyl methyl ether (100 ml) to obtain the crystalline product Xla.
Alternative recrystallization procedure-lll [00207] Methyl tert-butyl ether (2000 mL per 280 g of raw material L-BPB) was added to the crude product (S) - Ala - Ni- BPB and the slurry was then heated to 45 -50Ό and maintained at this temperature for 30min. The mixture was then cooled to 20 ° and mixed at this temperature for 8 h. The resulting solid was then filtered and washed with methyl tert-butyl ether (100 ml).
[00208] (S) - Ala - Ni-BPB (300 g) was recrystallized, when dissolving in THF (450 mL). The mixture was heated to 50Ό for 1 h, followed by the addition of methyl tert-butyl ether (1500 mL) at 50Ό. The resulting mixture was mixed at this temperature for an additional 1h. THE
58/63 sludge was then cooled to 20Ό and mixed to 20Ό for 1 h. The mixture was then filtered and washed with tert-butyl methyl ether (300 ml) to obtain the crystalline product Xla.
Example 2e: Preparation of S5-NÍ-BPB
(Xla) (XI Ia) [00209] 5.8 kg (1.0 equiv.) Of (S) -Ala-Ni-BPB (Xla) was charged to a reactor and dissolved in dimethylformamide and cooled to 10Ό. 1.2 kg (2.5 equiv.) Of sodium hydroxide (powder) was then charged into the same reactor and the mixture was sparged with nitrogen and stirred until a solution formed at 10Ό. 3.3 kg (2.0 equiv.) Of 5-bromo-1 pentene was charged to the reactor, maintaining an internal temperature <20Ό. The mixture was then allowed to stir at 20-25 ° C until the reaction was complete. Once the reaction was complete, the solution was cooled to 10Ό and 0.4 kg (1.5 equiv.) Of acetic acid was loaded maintaining an internal temperature of <25Ό. Water was then charged followed by tert-butyl methyl ether and the organic layer was washed. The organic layer was then washed twice with water and then concentrated. The product (X11a) was crystallized from isolated isopropyl acetate and dried under heat and vacuum. Yield: 2.2 kg, 32.4%.
Recrystallization Procedure [00210] Isopropyl acetate (200 mL per 12.5 g of raw material Xla) was added to the crude product S5-NÍ-BPB and the mixture was mixed at 20Ό for 30 min, then hexanes were added (500 mL). The mixture was additionally mixed for 30 min and after that,
59/63 it was filtered to obtain the crystalline product XIla.
Alternative recrystallization procedure-1 [00211] Isopropyl acetate (80 mL per 39 g of raw material Xla) was added to the crude product S5-NÍ-BPB and the mixture was mixed at 20Ό for 2h. The mixture was filtered and washed with isopropyl acetate (35 ml). The filtrate and the wash were combined and heptane (170 ml) was added. The resulting slurry was mixed for 1 h, then filtered and washed with heptane (360 ml) to obtain the crystalline product X11a. Alternative recrystallization procedure -11 [00212] Isopropyl acetate (1000 mL per 205 g of raw material Xla) was added to the crude product S5-NÍ-BPB and the mixture was dissolved at 70-80Ό. The solution was cooled to 20Ό and the mixture was mixed at this temperature for 1 h, during which no crystallization was observed. The mixture was filtered through celite and the solvent was removed under vacuum at 40 °. Methyl tert-butyl ether (1000 mL) was added and the mixture was heated to 60Ό and then cooled to 20Ό and mixed for 24 h. The solid was then filtered and washed with tert-butyl methyl ether (300 ml) to obtain the crystalline product X11a.
Alternative recrystallization procedure-II [00213] Ethyl acetate (100 mL per 12.5 g of raw material Xla) was added to the crude product S5-NÍ-BPB and the mixture was mixed at 20Ό for 30 min. Hexanes (500 mL) were added and the resulting slurry was mixed for an additional 30 min, then filtered to obtain the crystalline product Xlla.
Alternative recrystallization procedure-IV [00214] Methyl tert-butyl ether (100 mL per 12.5 g of raw material Xla) was added to the crude product S5-NÍ-BPB and the mixture was heated to 45-50Ό. Heptanes (400 ml) were added at 45-50 °. The resulting slurry was cooled to 20 ° and filtered to obtain the crystalline product Xlla.
60/63
Example 2f: Preparation of (S) -2-Amino-2-methyl-hept-6-enoic acid
HCI / THF

(Xllla) (Xlla) (IXa) [00215] 2.2 kg (1.0 equiv.) Of S5-NÍ-BPB (Xlla) was loaded into a 15-L chemical glass reactor. Tetrahydrofuran was added and the mixture stirred at 20-25 °, until a solution formed. 1.8 kg (4.5 equiv.) Of 32% hydrochloric acid was loaded slowly, maintaining an internal temperature <30Ό. The mixture was then left to stir for 6-8 hours at room temperature. The mixture was then concentrated to remove tetrahydrofuran to yield a sludge. Additional water was added and the slurry was stirred at room temperature for 1-2 hours. The solid BPB salts were isolated by filtration and washed with additional water followed by methyl tert-butyl ether. The product filtrates were then refilled to the reactor producing a three-phase solution. The lowest layer was divided from the top two layers. The two combined organic layers were then washed 3x with water and concentrated to an oil. Acetonitrile was added and the mixture was heated to 700 ° C for 30 minutes. The mixture was then cooled to 25-300 ° C and the solid product was isolated. The solid filter cake was washed with acetonitrile and methyl tert-butyl ether, then analyzed for purity. The product was then re-made in mud from additional acetonitrile and washed with acetonitrile and methyl tert-butyl ether. The material (Xllla) was isolated and dried under heat and vacuum. Yield: 0.585 kg, 80.0%
Recrystallization procedure for Xllla
61/63 [00216] Acetonitrile (100 ml per 20 g of raw material S5-NÍ-BPB (Xlla)) was added to the crude product and the mixture was mixed at 200 ° C for 1 h. The mixture was then filtered and washed with acetonitrile (40mL) to obtain the crystalline product XIIla.
Alternative recrystallization procedure for Xllla-I [00217] Acetonitrile (500 mL per 185g of raw material Xlla) was added to the crude product S5-NÍ-BPB and the slurry was dissolved in 45500. The solvent was removed under vacuum at 45- 500, 500 ml of acetonitrile was added and the resulting mixture was heated to 45-500 ° C. The mixture was then cooled to 350 ° C, filtered and washed with acetonitrile (50 ml) to obtain the crystalline product XIIla.
Alternative recrystallization procedure for Xllla-ll [00218] Acetonitrile (270 mL per 35 grams of raw material Xlla) was added and the sludge was heated to 45-500 ° C. The mixture was then cooled to 200 ° C and mixed at this temperature for 2 h. The mixture was then filtered and washed with acetonitrile (50mL) and tertiary butyl methyl ether (50mL) to obtain the crystalline product XIIla.
Alternative recrystallization procedure for Xllla-lll [00219] Isopropyl acetate (60 ml per 15 g of Xllla) was added and the mixture was heated to 700 ° C. Acetonitrile (180 ml) was added and the resulting mixture was cooled to 200 ° C. The mixture was filtered and the resulting solid was washed with acetonitrile (50 ml) to obtain the crystalline product X11la.
Example 2q: Preparation of N-Fmoc- (S) -a- methyl -a- aminohept6-enoic acid
62/63
(Illa) [00220] 0.585 kg (1.0 equiv.) · 2-amino-2-methyl-hept-6enoic acid HCI (Xllla) was suspended in water and polished filtered to remove traces of L-BPB HCI from the solution. Methyl tert-butyl ether was added and the aqueous product layer was extracted once with tert-butyl methyl ether. The aqueous product layer was refilled and tetrahydrofuran was added. A 20% aqueous sodium carbonate solution (2.75 equiv.) Was charged to the mixture followed by Fmoc-OnSu (0.95 equiv.). The mixture was left to react at 20-25Ό, maintaining the pH between 8.5 - 9.0 with additional amounts of the 20% sodium carbonate solution until the reaction was complete. The mixture had its pH adjusted to pH 2.0 - 2.5 with the hydrochloric acid HCL. Tetrahydrofuran was distilled off and methyl tert-butyl ether is charged. The layers were separated and the organic layer was washed an additional 3 times with additional water. The organic layer was then concentrated in vacuo and coded with tert-butyl methyl ether. The organic product layer was concentrated and coded with hexanes for a loose oil. The product (llla) was then crystallized from chloroform and hexanes and dried at <O'Sob under a nitrogen sweep of 1.0 cfm. Yield: 0.831 kg, 76.0%.
Recrystallization procedure for llla [00221] Chloroform (30 mL per 9 grams of raw material Xllla) was added to the crude product. Hexanes (100 mL) were added and the mixture was cooled to 0Ό. The resulting solid was filtered at 0 ° and washed with cold hexanes to obtain the crystalline product llll.
63/63
Recrystallization process for cyclohexylamine salt of llla [00222] Acetonitrile (300ml per 19.04 grams of raw material Xllla) was added to the crude product and the pH was adjusted to 8-9 using 20Ό cyclohexylamine. The resulting mixture was mixed at 20 ° for 2 h and then filtered and washed with acetonitrile (50 ml) to obtain the crystalline cyclohexylamine salt of lla.
Alternative recrystallization process for llla-l cyclohexylamine salt [00223] Tert-butyl methyl ether (200ml per 5 grams of raw Xllla) was added to the crude product and the pH was adjusted to 8-9 using cyclohexylamine to 20Ό. The resulting mixture was mixed at 20 ° for 1 h and then filtered and washed with tert-butyl methyl ether (50 ml) to obtain the crystalline cyclohexylamine salt of ll.

权利要求:
Claims (15)
[1]
1. Crystalline compound, characterized by the fact that it has formula (I) or its crystalline salt:

[2]
2. Crystalline compound according to claim 1, characterized by the fact that:
(i) R 1 is C 1 -C ₃ alkyl;
(ii) n is an integer from 3 to 11;
(iii) R ₂ is selected from the group consisting of:
- H
9-Fluorenylmethoxycarbonyl (Fmoc),
Trityl (Trt),
4-Methoxytrityl (Mmt),
2- (3,5-Dimethoxyphenyl) propane-2-yloxycarbonyl (Ddz), 2- (p-Biphenylyl) -2-propyloxycarbonyl (Bpoc), 2- (4-Nitrophenylsulfonyl) ethoxycarbonyl (NSC),
5/17
2/8 (1,1-Dioxobenzo [b] thiophene-2-yl) methyloxycarbonyl (Bsmoc), (1,1-Dioxonafto [1,2-b] thiophene-2-yl) Methyloxycarbonyl (a-Nsmoc),
1 - (4,4-dimethyl-2,6-dioxocyclohex-1-ylidene) -3methylbutyl (ivDde),
2-Di-tert-butyl-Fmoc (Fmoc *), 2-Fluoro-Fmoc (Fmoc (2F)), 2-Monoisooctyl-Fmoc (mio-Fmoc), 2,7-Diisooctyl-Fmoc (dio-Fmoc), 2- [Phenyl (methyl) sulfonium] ethyloxycarbonyl tetrafluoroborate (Pms),
Ethanesulfonylethoxycarbonyl (Esc), 2- (4-Sulfofinylsulfonyl) carbonyl ethoxy (Sps), Tert-butyloxycarbonyl (Boc), Benzyloxycarbonyl (Z), Allyloxycarbonyl (Alloc),
2,2,2-Trichloroethyloxycarbonyl (Troc), p-Nitrobenzyloxycarbonyl (pNZ), Propargyloxycarbonyl (Poc), o-Nitrobenzenesulfonyl (oNBS),
2,4-Dinitrobenzenesulfonyl (dNBS), Benzothiazol-2-sulfonyl (Bts), o-Nitrobenzyloxycarbonyl (oNz), 4-Nitroveratryloxycarbonyl (NVCO), 2- (2-nitrophenyl) propyloxycarbonyl (NPPOC), 2, (3,4 -Methylethenedodioxy-6-nitrophenyl) propyloxycarbonyl (MNPPOC),
9- (4-Bromophenyl) -9-fluorenyl (BrPhF), Azidomethoxycarbonyl (Azoc),
6/17
[3]
3/8
Hexafluoroacetone (HFA), 2-Chlorobenzyloxycarbonyl (Cl-Z),
[4]
4- Methyltrityl (Mtt), Trifluoroacetyl (tfa), (Methylsulfonyl) ethoxycarbonyl (Msc), Phenyldisulfanylethyloxycarbonyl (Phdec), 2-Pyridyldisulfanylethyloxycarbonyl (Pydec), and o-Nitrobenzenesulfonyl (O-NBS); and (iv) R3 is selected from the group consisting of:
-Η, tert-butyl (* Bu), 2-Chlorotrityl (2-CI-Trt),
2,4-Dimethoxybenzyl (DMB), Benzyl (Bn), 2-Phenylisopropyl (2-Ph'Pr),
[5]
5- phenyl-3,4-ethylenedioxythenyl, 9-fluorenylmethyl (Fm),
4- (N- [1- (4,4-dimethyl-2,6-dioxocyclohexylidene) -3methylbutyl] -amino) benzyl (Dmab),
Methyl (Me), Ethyl (Et), Carbamoylmethyl (Cam), Alila (Al), Phenacyl (Pac), p-Nitrobenzyl (pNB), 2-Trimethylsilylethyl (TMSE), (2-Phenyl-2-trimethylsilyl) ethyl ( PTMSE), 2- (trimethylsilyl) isopropyl (Tmsi), Trimethylsilyl (TMS),
2,2,2-Trichlorethyl (Tee),
7/17
4/8 p-Hydroxyphenacyl (pHP),
4,5-dimethoxy-2-nitrobenzyl (Dmnb), 1,1-dimethylalyl (Dma), Penta-amine (III) cobalt, Succinimide, p-nitrophenyl,
Pentaflurophenyl, and 2,4,5-trichlorophenyl.
3. Crystalline compound according to claim 1 or 2, characterized by the fact that:
(i) R (is CrC ₃ alkyl;
(ii) n is an integer from 3 to 11;
(iii) R ₂ is selected from the group consisting of:
9-Fluorenylmethoxycarbonyl (Fmoc), 4-Methoxytrityl (Mmt), 2- (3,5-dimethoxyphenyl) propane-2-yloxycarbonyl (Ddz), 2- (p-biphenylyl) -2-propyloxycarbonyl (Bpoc), Terc-butyloxycarbonyl (Boc), Benzyloxycarbonyl (Z), Allyloxycarbonyl (Alloc),
2,2,2-Trichloroethyloxycarbonyl (Troc), o-Nitrobenzenesulfonyl (oNBS), Trityl (Trt),
4-Methyltrityl (Mtt), and o-Nitrobenzenesulfonyl (O-NBS); and (iv) R ₃ is -H.
Crystalline compound according to any one of claims 1 to 3, characterized by the fact that:
(i) Ri is methyl;
(ii) R ₂ is 9-Fluorenylmethoxycarbonyl (Fmoc);
8/17
5/8 (iii) R ₃ is -H; and (iv) n is selected from a group consisting of: 3 and 6.
Crystalline compound according to any one of claims 1 to 4, characterized by the fact that it presents:
(i) the formula (Ha):

[6]
6/8 (Hla) which, optionally, has an enantiomeric excess of about 95% to 100%; or (iv) the formula (lllb):

[7]
7. Salt, characterized by the fact that it is a crystalline salt of the compound, as defined in any one of claims 1 to 5.
[8]
8. Salt according to claim 7, characterized by the fact that it is an organic amino salt.
[9]
9. Salt according to claim 7, characterized by the fact that it is an organic amine salt and the amine is a cyclic amine.
[10]
10. Crystalline compound according to any one of claims 1 to 9, characterized by the fact that it has a degree of chemical purity, in the range of about 90% to 100%.
[11]
Crystalline compound according to any one of claims 1 to 10, characterized by the fact that it has an enantiomeric excess, in the range of about 95% to 100%.
[12]
12. Composition, characterized by the fact that it comprises the crystalline compound or its crystalline salt, as defined in any one of claims 1 to 11, an alkane compound and a haloalkane compound.
10/17
7/8
[13]
13. Composition, characterized by the fact that it comprises the crystalline compound or its crystalline salt, as defined in any one of claims 1 to 11, an alkane compound and a haloalkane compound, the alkane compound being haxane and the haloalkane compound is chloroform .
[14]
14. Method for preparing a polypeptide, characterized in that it comprises: (i) reacting the crystalline compound of Formula (I) or its crystalline salt, as defined in claim 1, with an amino acid building block, in the presence of a coupling agent, thereby forming a peptide bond;
(ii) reacting the crystalline compound of Formula (I) or its crystalline salt, as defined in claim 1, with an amino acid building block, in the presence of a coupling agent, thus forming a peptide bond, wherein the polypeptide comprises an α-helix; or (iii) reacting the crystalline compound of Formula (I) or its crystalline salt, as defined in claim 1, with an amino acid building block, in the presence of a coupling agent, thereby forming a peptide bond; and further comprising cross-linking a pair of terminal alkenes side chains of at least two amino acids of the peptide; or (iv) reacting the crystalline compound of Formula (I) or its crystalline salt, as defined in claim 1, with an amino acid building block, in the presence of a coupling agent, thereby forming a peptide bond; and which further comprises crosslinking a pair of terminal alkenes side chains of at least two amino acids of the peptide, wherein the crosslinking comprises a metal catalyzed olefin metathesis reaction.
[15]
15. Invention, in any form of its realizations
11/17
8/8 or in any applicable category of claim, for example, product or process, or use, among others, for example, crystalline compound, its crystalline salt, composition and method for preparing a polypeptide, or any other type of claim encompassed by matter initially described, revealed or illustrated in the patent application.

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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-06| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-13| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-20| B06I| Publication of requirement cancelled [chapter 6.9 patent gazette]|Free format text: ANULADA A PUBLICACAO CODIGO 6.6.1 NA RPI NO 2462 DE 13/03/2018 POR TER SIDO INDEVIDA. |

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2019-05-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-08-20| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-11-10| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 7A ANUIDADE. |

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2021-03-02| B08K| Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]|Free format text: EM VIRTUDE DO ARQUIVAMENTO PUBLICADO NA RPI 2601 DE 10-11-2020 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDO O ARQUIVAMENTO DO PEDIDO DE PATENTE, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |

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2021-10-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201261721457P| true| 2012-11-01|2012-11-01|

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US201361799917P| true| 2013-03-15|2013-03-15|

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PCT/US2013/068147|WO2014071241A1|2012-11-01|2013-11-01|Disubstituted amino acids and methods of preparation and use thereof|

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