COMPOUND AND COMPOUND PREPARATION METHODS

专利摘要:
compound and methods for preparing a compound. the present invention relates to compounds of formula i, including all stereoisomers and their salts, wherein q1, q2 and r are as defined in the present invention. the present invention also relates to a method for the preparation of a compound of formula i, which comprises contacting a compound of formula ii with a compound of formula iii, optionally in the presence of a catalyst or a base for the formation of a compound of formula i. the present invention further relates to a method for the preparation of a compound of formula iv, which comprises reductive cyclization of a compound of formula i in the presence of a reducing agent.
公开号:BR112017009701B1
申请号:R112017009701-0
申请日:2015-12-01
公开日:2021-09-08
发明作者:Andrew Duncan Satterfield
申请人:Fmc Corporation；
IPC主号:

专利说明:

FIELD OF THE INVENTION
The present invention relates to certain 3-oxo-3-(arylamino)propanoates, their salts and compositions, a process for their preparation and their use in the preparation of certain pyrrolidinones useful as herbicides. BRIEF DESCRIPTION OF THE INVENTION
[0002] The present invention relates to a compound of Formula I and its salts
- wherein - Q1 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R1; or a fully unsaturated 5 to 6 membered heterocyclic ring or an 8 to 10 membered heteroaromatic bicyclic ring system, each ring or ring system containing the ring members selected from carbon atoms and from 1 to 4 independently selected heteroatoms from up to 2 O atoms, up to 2 S atoms and up to 4 N atoms, wherein up to 3 carbon ring members are independently selected from C(=O) and C(=S), and the sulfur atom ring members are independently selected from S(=O)u(=NR2)v, each ring or ring system optionally substituted with up to 5 substituents independently selected from R1 on the ring members from carbon atom and selected from R3 on the nitrogen atom members; - Q2 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R4; or a fully unsaturated 5 to 6 membered heterocyclic ring or an 8 to 10 membered heteroaromatic bicyclic ring system, each ring or ring system containing the ring members selected from carbon atoms and from 1 to 4 independently selected heteroatoms from up to 2 O atoms, up to 2 S atoms and up to 4 N atoms, wherein up to 3 carbon ring members are independently selected from C(=O) and C(=S), and the sulfur atom ring members are independently selected from S(=O)u(=NR2)v, each ring or ring system optionally substituted with up to 5 substituents independently selected from R4 on the ring members carbon atom and selected from R5 on the nitrogen atom ring members; - R is C1-C8 alkyl or phenyl; - each R1and R4, independently, is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 nitroalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 haloalkoxyalkoxy, C2-C8 nitroalkenyl, C2C8 alkynyl, C2-C8 haloalkynyl, C4-C10 cycloalkylalkyl, C4-C10 halocycloalkylalkyl, C5-C12 alkylcycloalkylalkyl, C5-C12 cycloalkylalkenyl, C5C12 cycloalkylalkynyl, C3-C8 cycloalkyl, C3-C6 cycloalkyl C3-C8 alkylcycloalkyl C10 alkylcycloalkyl , C3-C8 cycloalkenyl, C3-C8 halocycloalkenyl, C2-C8 alkoxyalkyl, C2-C8 haloalkoxyalkyl, C4-C10 cycloalkoxyalkyl, C3-C10 alkoxyalkoxyalkyl, C2-C8 alkylthioalkyl, C2-C8 alkylsulfinylalkyl, C8-C8 alkylsulfonylalkyl , C2C8 haloalkylaminoalkyl, C4-C10 cycloalkylaminoalkyl, C3-C10 dialkylaminoalkyl, -CHO, C2-C8 alkylcarbonyl, C2-C8 haloalkylcarbonyl, C4-C10 cycloalkylcarbonyl, -C(=O)OH, C2-C8 alkoxycarbonyl, C2-C8 haloalkoxycarbonyl, cycloalkoxycarb C4-C10 nyl, C5-C12 cycloalkylalkoxycarbonyl, -C(=O)NH2, C2-C8 alkylaminocarbonyl, C4-C10 cycloalkylaminocarbonyl, C3-C10 dialkylaminocarbonyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C2C8 alkoxyalkoxy, C2-C8 alkenyloxy , C2-C8 haloalkenyloxy, C3-C8 alkynyloxy, C3-C8 haloalkynyloxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C10 cycloalkylalkoxy, C3-C10 alkylcarbonylalkoxy, C2-C8 alkylcarbonyloxy, C2-C8 alkylcarbonyloxycarbonyl , C1-C8 alkylsulfonyloxy, C1C8 haloalkylsulfonyloxy, C1-C8 alkylthio, C1-C8 haloalkylthio, C3-C8 cycloalkylthio, C1-C8 alkylsulfinyl, C1-C8 haloalkylsulfinyl, C1-C8 alkylsulfonyl, C1-C8 haloalkylsulfonylaminoalkylsulfonyl, cyclo , C2-C8 alkylcarbonylamino, C2-C8 haloalkylcarbonylamino, C2-C8 alkoxycarbonylamino, C1-C6 alkylsulfonylamino, C1-C6 haloalkylsulfonylamino, -SF5, -SCN, C3-C12 trialkylsilyl, C4-C12 trialkylsilylalkyl or C4-C12 trialkylsilylalkoxy; - each R2 independently is H, cyano, C2-C3 alkylcarbonyl or C2-C3 haloalkylcarbonyl; - each R3and R5, independently, is cyano, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C3 cycloalkyl, C2-C3 alkoxyalkyl, C1-C3 alkoxy, C2-C3 alkylcarbonyl, C2-C3 alkoxycarbonyl , C2-C3 alkylaminoalkyl, C3-C4 dialkylaminoalkyl or C2-C3 haloalkyl; and - each u and v, independently, is 0, 1 or 2 in each instance of S(=O)u(=NR2)v, provided that the sum of u and v is 0, 1 or 2.
[0003] The present invention also relates to a method for preparing a compound of Formula I, which comprises contacting a compound of Formula II
with a compound of Formula III
optionally in the presence of a catalyst or a base to form a compound of Formula I.
[0004] The present invention further relates to a method for preparing a compound of Formula IV
which comprises the reductive cyclization of a compound of Formula I in the presence of a reducing agent. DETAILED DESCRIPTION OF THE INVENTION
[0005] As used herein, the terms "comprises", "comprises", "includes", "including", "possesses", "possessing", "contains", "containing", "characterized by" or any other of its variations, are intended to cover a non-exclusive inclusion, subject to any expressly stated limitations. For example, a composition, mixture, process, method, article or apparatus that comprises a list of elements is not necessarily limited to just those elements, but may include other elements that are not expressly listed or inherent in that composition, mixture, process, method, article or apparatus.
[0006] The transition phrase “consisting of” excludes any unspecified element, step or ingredient. If in the claim, this would restrict the claim to the inclusion of materials other than those cited, except for impurities normally associated with the same materials. When the phrase “consisting of” appears in a clause in the body of a claim, rather than immediately following the preamble, it will only limit the element presented in that clause; other elements are not excluded from the claim as a whole.
[0007] The transition phrase "consisting essentially of" is used to define a composition, method or apparatus that includes the materials, steps, aspects, components or elements, in addition to those described literally, from which these additional materials, steps , aspects, components or elements do not materially affect the basic and innovative feature(s) of the present claimed invention. The term "which consists essentially of" occupies an intermediate position between "which comprises" and "which consists of".
[0008] Where the Depositors have defined an invention or a part thereof with an open term such as "comprises" it should be readily understood that (unless otherwise indicated) the description should be interpreted also to describe such invention, using the terms "consisting essentially of" or "consisting of".
[0009] Furthermore, unless otherwise indicated, “or” refers to an inclusion and not an exclusion. For example, a condition A or B is satisfied by any of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or not present), and both A and B are true (or present).
[0010] Furthermore, the indefinite articles "a" and "an" that precede an element or component of the present invention are intended to be non-restrictive as to the number of cases (i.e., occurrences) of the element or component. Therefore, "a" or "an" must be read to include one or at least one, and the singular word form of the element or component also includes the plural, unless the number obviously means the singular.
[0011] In the above citations, the term "alkyl", used alone or in compound words, such as "alkylthio" or "haloalkyl", includes straight or branched chain alkyl, such as methyl, ethyl, n-propyl , i-propyl or the different butyl, pentyl and hexyl isomers. The term "alkenyl" includes straight or branched chain alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different isomers of butenyl, pentenyl and hexenyl. The term "alkenyl" also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. The term "alkynyl" includes straight or branched chain alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different isomers of butynyl, pentynyl and hexynyl. The term "alkynyl" can also include those moieties comprised of multiple triple bonds such as 2,5 hexadiinyl.
[0012] The term "alkoxy", for example, includes methoxy, ethoxy, n-propyloxy, isopropyloxy and the different isomers of butoxy, pentoxy and hexyloxy. The term "alkoxyalkyl" means the substitution of alkoxy to alkyl. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. The term "alkoxyalkoxy" means the substitution of alkoxy to alkoxy. The term "alkenyloxy" includes straight chain or branched alkenyloxy moieties. Examples of "alkenyloxy" include H2C=CHCH2O, (CH3)2C=CHCH2O, (CH3)CH=CHCH2O, (CH3)CH=C(CH3)CH2O, and CH2=CHCH2CH2O. The term "alkynyloxy" includes straight or branched chain alkynyloxy moieties. Examples of "alkynyloxy" include H2C=CHCH2O, (CH3)2C=CHCH2O, (CH3)CH=CHCH2O, (CH3)CH=C(CH3)CH2O, and CH2=CHCH2CH2O. The term "alkylthio" includes straight or branched chain alkylthio moieties such as methylthio, ethylthio, and the different isomers of propylthio, butylthio, pentylthio and hexylthio. The term "alkylsulfinyl" includes both enantiomers of an alkylsulfinyl group. Examples of "alkylsulfinyl" include CH3S(O)-, CH3CH2S(O)-, CH3CH2CH2S(O)-, (CH3)2CHS(O)- and the different isomers of butylsulfinyl, pentylsulfinyl and hexylsulfinyl. Examples of "alkylsulfonyl" include CH3S(=O)2-, CH3CH2S(=O)2-, CH3CH2CH2S(=O)2-, (CH3)2CHS(=O)2- and the different isomers of butylsulfonyl, pentylsulfonyl and hexylsulfonyl. The term "alkylthioalkyl" indicates the substitution of alkylthio to alkyl. Examples of "alkylthioalkyl" include CH3SCH2, CH3SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2. The term "alkylsulfinylalkyl" indicates the substitution of alkylsulfinyl for alkyl. Examples of "alkylsulfinylalkyl" include CH3S(=O)CH2, CH3S(=O)CH2CH2, CH3CH2S(=O)CH2 and CH3CH2S(=O)CH2CH2. The term "alkylamino", "alkylaminoalkyl", and the like are defined analogously to the above examples.
[0013] The term "cycloalkyl", for example, includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "alkylcycloalkyl" indicates alkyl substitution in a cycloalkyl moiety and includes, for example, ethylcyclopropyl, i-propylcyclobutyl, 3-methylcyclopentyl and 4-methylcyclohexyl. The term "cycloalkylalkyl" means the replacement of cycloalkyl in an alkyl moiety. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties attached to straight or branched chain alkyl groups. The term "cycloalkoxy" means cycloalkyl bonded through an oxygen atom such as cyclopentyloxy and cyclohexyloxy. The term "cycloalkylalkoxy" means cycloalkylalkyl bonded through an oxygen atom attached to the alkyl chain. Examples of "cycloalkylalkoxy" include cyclopropylmethoxy, cyclopentylethoxy and other cycloalkyl groups attached to straight or branched chain alkoxy groups.
The term "halogen", alone or in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" includes fluorine, chlorine, bromine or iodine. Furthermore, when used in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen", said alkyl may be partially or fully substituted with halogen atoms, which may be the same or many different. Examples of "haloalkyl" or "alkyl substituted with halogen" include F3C, ClCH2, CF3CH2- and CF3CCl2. The terms "halocycloalkyl", "haloalkoxy", "haloalkylthio", "haloalkenyl", "haloalkynyl" and the like are defined analogously to the term "haloalkyl". Examples of "haloalkoxy" include CF3O-, CCl3CH2O-, HCF2CH2CH2O- and CF3CH2O-. Examples of "haloalkylthio" include CCl3S-, CF3S-, CCl3CH2S-, and ClCH2CH2CH2S-. Examples of "haloalkenylsulfinyl" include CF3S(=O)- , CCl3S(=O)-, CF3CH2S(=O) - and CF3CF2S(=O)-. Examples of "haloalkylsulfonyl" include CF3S(=O)2-, CCl3S(=O)2-, CF3CH2S(=O)2- and CF3CF2S(=O)2-. examples of "haloalkenyl" include (Cl)2C=CHCH2 and CF3CH2CH=CHCH2. Examples of "haloalkynyl" include HC CCHCl-, CF3C C-, CCI3C C-, and FCH2C CCH2- Examples of "haloalkoxyalkoxy" include CF3OCH2O-, ClCH2CH2OCH2CH2O-, Cl3CCH2OCH2O- as well as branched alkyl derivatives.
[0015] The term "alkylcarbonyl" means a straight or branched chain alkyl moiety attached to a C(=O) moiety. Examples of "alkylcarbonyl" include CH3C(=O)-, CH3CH2CH2C(=O)- and (CH3)2CHC(=O)-. Examples of "alkoxycarbonyl" include CH3OC(=O)-, CH3CH2OC(=O)-, CH3CH2CH2OC(=O)-, (CH3)2CHOC(=O)- and the different isomers of butoxy or pentoxycarbonyl.
[0016] The total number of carbon atoms in a substituent group is indicated by the prefix "Ci-Cj", where i and j are numbers from 1 to 12. For example, C1-C4 alkylsulfonyl indicates from a methylsulfonyl to a butylsulfonyl; C2 alkoxyalkyl indicates CH3OCH2-; C3 alkoxyalkyl indicates, for example, CH3CH(OCH3)-, CH3OCH2CH2- or CH3CH2OCH2-; and C4 alkoxyalkyl indicates the various isomers of an alkyl group substituted with an alkoxy containing a total of four carbon atoms, examples include CH3CH2CH2OCH2- and CH3CH2OCH2CH2-.
[0017] When a compound is substituted with a substituent bearing a subscript indicating the number of said substituents may exceed 1, said substituents (when it exceeds 1) are independently selected from the group of defined substituents, e.g. (R1)n], n is 1, 2, 3, 4 or 5. When a group which contains a substituent which may be hydrogen, for example Q1, therefore, when this substituent is taken as hydrogen, it is recognized that this is equivalent to such an unsubstituted group. When a variable group is shown to be optionally attached to a position, eg R1, therefore, the hydrogen can be in the position, even if not recited in the variable group definition. When one or more positions in a group are said to be "unsubstituted" or "unsubstituted", therefore, the hydrogen atoms are attached to assume any free valence.
[0018] The term "fully saturated" in relation to a ring of atoms means that the bonds between the atoms in the ring are all simple. The term "fully unsaturated" with respect to a ring means that the bonds between the ring atoms are single or double bonds, according to the valence bond, and furthermore, the bonds between the ring atoms include the greatest number of double bonds as possible, without the double bonds being cumulative (ie, no C=C=C, N=C=C, and the like). The term "partially unsaturated" in relation to a ring indicates a ring which comprises at least one ring member connected to an adjacent ring member via a double bond and which conceptually potentially accommodates a series of unaccumulated double bonds across the adjacent ring members (ie, in their fully unsaturated homologous form) greater than the number of double bonds present (ie, in their partially unsaturated form). When a completely unsaturated ring satisfies Hückel's rule, therefore, it can also be described as aromatic.
[0019] Unless otherwise indicated, a "ring" or "ring system" as a component of Formula I (for example, the Q1 substituent) is carbocyclic or heterocyclic. The term "ring system" means two or more fused rings. The term "bicyclic ring system" means a ring system consisting of two fused rings, where the ring can be saturated, partially unsaturated, or completely unsaturated, unless otherwise indicated. The term "heteroaromatic bicyclic ring system" indicates a fused bicyclic ring system in which at least one ring atom is not carbon. The term "ring member" refers to an atom or other moiety (for example, the C(=O), C(=S), S(O) or S(O)2), forming the backbone of a ring or ring system.
[0020] The term "carbocyclic ring" means a ring system or a ring in which the atoms that form the main chain of the ring are selected only from carbon. Unless otherwise indicated, a carbocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a completely unsaturated carbocyclic ring satisfies Hückel's rule, therefore, this ring is also called an “aromatic ring”.
[0021] The term "heterocyclic ring" means a ring or ring system, in which at least one ring atom that forms the main carbon chain, for example, is not nitrogen, oxygen or sulfur. Normally, a heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygen atoms and no more than 2 sulfurs. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a fully unsaturated heterocyclic ring satisfies Hückel's rule, therefore, such ring is also called a "heteroaromatic ring" or "aromatic heterocyclic ring". Unless otherwise indicated, heterocyclic rings and ring systems may be attached through any available carbon or nitrogen atom by substituting a hydrogen for such carbon or nitrogen.
[0022] The term "aromatic" indicates that each of the atoms in the ring is essentially in the same plane and has a p-orbital perpendicular to the plane of the ring, and that (4n + 2) π electrons, where n is an integer positive, are associated with the ring according to Hückel's rule.
[0023] The term "optionally substituted" in connection with heterocyclic rings refers to groups that are unsubstituted or at least have a substituent other than hydrogen that does not extinguish the biological activity possessed by the unsubstituted analog. As used herein, the following definitions apply unless otherwise noted. The term “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” or with the term “(un)substituted”. Unless otherwise indicated, an optionally substituted group may contain a substituent at each substitution position in the group, and each substitution is independent of the other.
[0024] When Q1and Q2is a 5- or 6-membered heterocyclic ring containing the nitrogen, it may be attached to the remainder of Formula I via any available ring carbon or nitrogen atom, unless otherwise described. As mentioned above, Q1 or Q2 can be (among others) phenyl optionally substituted with one or more substituents selected from a group of substituents as defined in the Brief Description of the Invention. An example of phenyl optionally substituted with one to five substituents is the ring illustrated as U-1 in Table 1, where, for example, Rv is or R1 as defined in the Brief Description of the Invention for Q1 or Rv and R4 as defined in the Description Summary of the Invention for Q2, and r is an integer (from 0 to 5).
[0025] As mentioned above, Q1 and Q2 can be (among others) the fully unsaturated 5- or 6-membered heterocyclic ring, optionally substituted with one or more substituents selected from a group of substituents, as defined in the Brief Description of the Invention. Examples of a 5- or 6-membered fully unsaturated heterocyclic ring optionally substituted with one or more substituents include rings U-2 to U-61 illustrated in Exhibit 1, where Rv is any substituent as defined in the Brief Description of the Invention for Q1(ie R1or R3) or Q2(ie R4or R5) and r is an integer from 0 to 4, limited by the number of positions available in each U group. Since L-29, L-30, L -36, L-37, L-38, L-39, L-40, L-41, L-42 and L-43 only have one position available, for these U groups, r is limited to integers 0 or 1 , and r being 0 means that the U group is unsubstituted and a hydrogen is present at the position indicated by (Rv)r. SHOW 1



[0026] As mentioned above, Q1 and Q2 can be (among others) an 8 to 10 membered heteroaromatic bicyclic ring system optionally substituted with one or more substituents selected from a group of substituents as defined in the Brief Description of the Invention for Q1e Q2. Examples of the 8- to 10-membered heteroaromatic bicyclic ring system optionally substituted with one or more substituents include the rings U-62 to U-100 illustrated in Exhibit 2, where Rv is any substituent as defined in the Brief Description of the Invention for Q1or Q2e r is usually an integer from 0 to 4.DISPLAY 2


[0027] Although Rv groups are shown in structures U-1 to U-100, it should be noted that they do not need to be present as they are optional substituents. Note that when Rv is H when attached to an atom, this is the same as if that atom is unsubstituted. Nitrogen atoms that need replacement to fill their valence are replaced with H or Rv. Note that when the attachment point between (Rv)r and the U group is shown as floating, (Rv)r can be attached to any available carbon atom or nitrogen atom of the U group. Note that when the attachment point on the U group is illustrated as floating, the U group can be attached to the remainder of Formula I through any available carbon, or the U group nitrogen by replacement of a hydrogen atom. Note that some U groups can only be substituted with less than 4 Rv groups (eg U-2 to U-5, U-7 to U-48, U-52 to U-61).
[0028] A wide variety of synthetic methods are known in the state of the art to enable the preparation of aromatic and non-aromatic heterocyclic rings and ring systems; for extensive reviews see the eight-volume set of Comprehensive Heterocyclic Chemistry, AR editors-in-chief Katritzky and CW Rees, Pergamon Press, Oxford, 1984 and the twelve-volume set of Comprehensive Heterocyclic Chemistry II, AR Katritzky, editors-in-chief CW Rees and EFV Scriven, Pergamon Press, Oxford, 1996.
[0029] The compounds of the present invention may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. Stereoisomers are isomers of identical constitution but differing in the arrangement of their atoms in space and include enantiomers, diastereomers, cis-trans isomers (also known as geometric isomers and atropisomers). Atropisomers result from restricted rotation around single bonds where the rotation barrier is high enough to allow isolation of the isomeric species. A person skilled in the art will consider that a stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s) ). In addition, a person skilled in the art knows how to selectively separate, enrich and/or prepare said stereoisomers. The compounds of the present invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
[0030] For example, the portion C(O)N(Q2)(R6) (attached to the carbon at the 3 position of the pyrrolidinone ring) and Q1(attached to the carbon at the 4 position of the pyrrolidinone ring) are usually generally found in the trans configuration. These two carbon atoms (ie, at positions 3 and 4 each have the pyrroldinone ring of Formula IV) have a chiral center. The two most prevalent pairs of enantiomers are described as Formula IV' and Formula IV”, where chiral centers are identified (ie, as 3R, 4S or as 3S, 4R). While the present invention pertains to all stereoisomers, the preferred enantiomeric pair for biological operability is identified as Formula IV' (i.e., the 3R, 4S configuration). For a comprehensive discussion of all aspects of stereoisomerism, see Ernest L. Eliel and Samuel H. Wilen, Stereochemistry of Organic Compounds, John Wiley & Sons, 1994.

[0031] The molecular representations presented herein follow standard conventions for describing stereochemistry. To indicate stereoconfiguration, bonds arising from the plane of the drawing and towards the viewer are indicated by solid wedges, where the wide end of the wedge is attached to an atom arising from the plane of the drawing towards the viewer. Bonds that are below the plane of the drawing and away from the viewer are indicated by dashed wedges, where the narrowest part of the wedge is attached to the atom farthest from the viewer. Lines of constant width indicate links in an opposite or neutral direction relative to links presented by solid or dashed wedges; lines of constant width also show bonds in molecules or parts of the molecule where no specified stereoconfiguration is intended to be specified.
[0032] The present invention comprises racemic mixtures, for example, equal amounts of the enantiomers of Structural Formulas IV' and IV". In addition, the present includes those compounds that are enriched, compared to the racemic mixture, in an enantiomer of Formula IV. Also included are the essentially pure enantiomers of the compounds of Formula I, for example, Formula IV' or Formula IV".
[0033] When enantiomerically enriched, one enantiomer is present in greater amounts than the other, and the degree of enrichment can be defined by an enantiomeric ratio (ER), expressed as the percentage (%) of relative area of the two enantiomers determined through of chiral high performance liquid chromatography.
[0034] Preferably, the compositions of the present invention have at least an ER of 50%; more preferably at least an ER of 75%; even more preferably, at least an ER of 90%; and even more preferably, at least an ER of 94% of the most active isomer. Of special interest are the enantiomerically pure realizations of the most active isomer.
The compounds of Formula IV may contain additional chiral centers. For example, substituents and other molecular constituents such as R1, R3, R4and R5 may themselves contain chiral centers. The present invention encompasses the racemic mixtures as well as the enriched and essentially pure stereoconfigurations at these additional chiral centers.
[0036] The compounds of the present invention may exist as one or more of conformational isomers due to restricted rotation about the amide bond (eg, C(O)-N) in Formula I and IV. The present invention comprises mixtures of conformational isomers. Furthermore, the present invention includes those compounds which compounds which are enriched in one conformer over the others.
The compounds of Formula I normally exist in more than one form, and Formula I therefore includes all crystalline and non-crystalline forms of the compounds that Formula 1 represents. Non-crystalline forms include embodiments that are solid, such as waxes and gums, as well as embodiments that are liquid, such as solutions and melts. Crystalline forms include embodiments that essentially represent a single crystal type and embodiments that represent a mixture of polymorphs (i.e., different crystal types). The term “polymorph” refers to a particular crystalline form of a chemical compound that can crystallize into different crystalline forms, those forms with different arrangements and/or conformations of the molecules in the crystal structure. Although polymorphs can have the same chemical composition, they can also differ in composition due to the presence or absence of co-crystallized water or other molecules, which may be weakly or strongly bound in the structure. Polymorphs can differ in such chemical, physical and biological properties as crystal form, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendibility, dissolution rate and bioavailability. One skilled in the art will appreciate that a polymorph of a compound of Formula I may have beneficial effects (eg, suitability for preparing useful formulations, improved biological performance) over another polymorph or a mixture of polymorphs of the same compound represented by Formula I. The preparation and isolation of a special polymorph of a compound represented by Formula I can be accomplished by methods known to those skilled in the art, including, for example, crystallization using selected solvents and temperatures. For a comprehensive discussion of polymorphism, see R. Hilfiker, Ed., Polymorphism in the Pharmaceutical Industry, Wiley-VCH, Weinheim, 2006.
[0038] One skilled in the art will understand that not all nitrogen-containing heterocycles can form the N-oxides since nitrogen requires an available pair for oxidation to the oxide; a person skilled in the art will recognize the nitrogen-containing heterocycles that can form the N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are very well known to one skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperbenzoic acid (MCPBA ), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. Such methods for the preparation of N-oxides are extensively described and reviewed in the literature, see, for example: T.L. Gilchrist in Comprehensive Organic Synthesis, volume 7, pages 748 to 750, S.V. Ley, ed., Pergamon Press; Tisler M. and B. Stanovnik in Comprehensive Heterocyclic Chemistry, volume 3, pages 18-20, A.J. Boulton and A. McKillop, Eds., Pergamon Press; M.R. Grimmett and B.R.T. Keene in Advances in Heterocyclic Chemistry, volume 43, pages 149 to 161, A.R. Katritzky, ed., Academic Press; Tisler M. and B. Stanovnik in Advances in Heterocyclic Chemistry, volume 9, pages 285 to 291, A.R. Katritzky and A.J. Boulton, Eds. Academic Press; and G.W.H. Cheeseman and E.S.G. Werstiuk in Advances in Heterocyclic Chemistry, volume 22, pages 390 to 392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.
[0039] A person skilled in the art recognizes that because in the environment and under physiological conditions the salts of chemical compounds are in equilibrium with their corresponding non-salt forms, the salts share the biological utility of the non-salt forms. Accordingly, a wide variety of salts of the compounds of Formula I are useful for the control of invertebrate pests (i.e., they are agriculturally suitable). The salts of the compounds of Formula I include acid addition salts with inorganic or organic acids, such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, acids, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric. When a compound of Formula I contains an acidic moiety, such as a carboxylic acid or phenol, salts include those formed with organic or inorganic bases, such as pyridine, triethylamine or ammonia, or sodium amides, hydrides, hydroxides or carbonates, potassium, lithium, calcium, magnesium or barium. Accordingly, the present invention comprises the compounds selected from Formula I, their N-oxides and agriculturally suitable salts.
[0040] Embodiments of the present invention, as described in the Brief Description of the Invention, include (wherein Formula I, as used, in the following Embodiments, include its N-oxides and salts).
[0041] Achievement A1. A compound of Formula I as described in the Brief Description of the Invention.
[0042] Achievement A2. A compound of Embodiment A1, wherein Q1 is a phenyl ring optionally substituted with up to 5 substituents independently selected from R1.
[0043] Achievement A3. A compound of Embodiment A2, wherein Q1 is a phenyl ring substituted with 1 to 4 substituents independently selected from R1.
[0044] Achievement A4. A compound of Embodiment A3, wherein Q1 is a phenyl ring substituted with 1 to 3 substituents independently selected from R1.
[0045] Achievement A5. A compound of any one of Embodiments A1 to A4, wherein Q1 is a phenyl ring having a substituent selected from R1 in the meta(3-) position and optionally up to 2 additional R1 substituents.
[0046] Achievement A6. A compound of any one of Embodiments A1 to A4, wherein Q1 is a phenyl ring having a substituent selected from R1 at the (4-) position and optionally up to 2 additional R1 substituents.
[0047] Achievement A7. A compound of Embodiment A1, wherein Q1 is a fully unsaturated 5- to 6-membered heterocyclic ring optionally substituted with up to 5 substituents independently selected from R1 on the carbon atom ring members and selected from R3 on the atom ring members of nitrogen.
[0048] Achievement A8. A compound of Embodiment A7, wherein Q1 is an optionally substituted pyridyl ring with up to 2 R1.
[0049] Achievement A9. A compound of Embodiment A8, wherein Q1 is a 3-pyridyl ring substituted with R1 in the para position relative to the bond connecting Q1 to the remainder of the compound of Formula I.
[0050] Achievement A10. A compound of Embodiment A7, wherein Q1 is a thiophenyl or furanyl ring optionally substituted with up to 2 R1.
[0051] Achievement A11. A compound of Embodiment A1, wherein Q1 is an 8- to 10-membered heteroaromatic bicyclic ring system optionally substituted with R1and R3, the remainder of Formula I is attached to a fully unsaturated ring of said bicyclic ring system.
[0052] Achievement A12. A compound of Embodiment A1, wherein Q2 is a phenyl ring optionally substituted with up to 5 substituents independently selected from R4.
[0053] Achievement A13. A compound of Embodiment A12, wherein Q2 is a phenyl ring substituted with 1 to 4 substituents independently selected from R4.
[0054] Achievement A14. A compound of Embodiment A13, wherein Q2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R4.
[0055] Achievement A15. A compound of any one of Embodiments A12 to A14, wherein Q2 is a phenyl ring having a substituent selected from R4 in the ortho position (2) and optionally up to 2 additional R4 substituents.
[0056] Achievement A16. A compound of Embodiment A1, wherein Q2 is a pyridyl ring optionally substituted with up to 2 R4.
[0057] Achievement A17. A compound of Embodiment A16, wherein Q2 is a 2-pyridyl or 3-pyridyl ring optionally substituted with up to 2 R4.
[0058] Achievement A18. A compound of Embodiment A1 wherein Q2 is a fully unsaturated 5-membered heterocyclic ring optionally substituted with up to 2 R4.
[0059] Achievement A19. A compound of Embodiment A18, wherein Q2 is an oxazolyl ring optionally substituted with up to 2 R4.
[0060] Achievement A20. A compound of any one of Embodiments A1 to A19, wherein R is C1-C4 alkyl.
[0061] Achievement A21. A compound of Embodiment A20, where R is methyl or ethyl.
[0062] Achievement A22. A compound of Embodiment A21, where R is methyl.
[0063] Achievement A23. A compound of Embodiment A21, where R is ethyl.
[0064] Achievement A24. A compound of any of Embodiments A1 through A23, wherein R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 nitroalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 haloalkoxyalkoxy, C2-C8 nitroalkenyl, C2-C8 alkynyl or C2C8 haloalkynyl.
[0065] Achievement A25. A compound of Embodiment A24, where R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1C8 haloalkyl, or C2-C8 haloalkoxyalkoxy.
[0066] Achievement A26. A compound of Embodiment A25, where R1 independently is halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
[0067] Achievement A27. A compound of Embodiment A26, where R1 independently is halogen or C1-C3 haloalkyl.
[0068] Achievement A28. A compound of Embodiment A27, where R1, independently, is F or CF3.
[0069] Achievement A29. A compound from Embodiment A28, where R1 is CF3.
[0070] Realization A30. A compound of Embodiment A28, where R1 is F.
[0071] Achievement A31. A compound of any one of Embodiments A1 to A30, wherein R3 independently is C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, or C1-C3 alkoxy.
[0072] Achievement A32. A compound of Embodiment A31, where R3 independently is C1-C3 alkyl.
[0073] Achievement A33. A compound of any one of Embodiments A1 to A32, wherein R4, independently, is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 nitroalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl , C2-C8 haloalkoxyalkoxy, C2-C8 nitroalkenyl, C2-C8 alkynyl or C2-C8 haloalkynyl.
[0074] Achievement A34. A compound of Embodiment A33, where R4, independently, is halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
[0075] Achievement A35. A compound of Embodiment A34, where R4, independently, is halogen or C1-C3 haloalkyl.
[0076] Achievement A36. A compound of Embodiment A35, where R4, independently, is F or CF3.
[0077] Achievement A37. A compound of Embodiment A36, where R4 is F.
[0078] Realization A38. A compound from Embodiment A36, where R4 is CF3.
[0079] Achievement A39. A compound of any one of Embodiments A1 through A38, wherein the stereochemistry of the carbon center connecting Q1 to the remainder of Formula I is S.
[0080] Realization A40. A compound of any one of Embodiments A1 through A38, wherein the stereochemistry of the carbon center connecting Q1 to the remainder of Formula I is R.
[0081] Achievement B1. A method for preparing a compound of Formula I as described in the Brief Description of the Invention.
[0082] Achievement B2. A method of Embodiment B1, wherein Q1 is an optionally substituted phenyl ring with up to 5 substituents independently selected from R1.
[0083] Achievement B3. A method of Embodiment B2, wherein Q1 is a phenyl ring substituted with 1 to 4 substituents independently selected from R1.
[0084] Achievement B4. A method of Embodiment B3, wherein Q1 is a phenyl ring substituted with 1 to 3 substituents independently selected from R1.
[0085] Achievement B5. A method of any one of Embodiments B1 to B4, wherein Q1 is a phenyl ring having a substituent selected from R1 in the meta(3-) position and optionally up to 2 additional R1 substituents.
[0086] Achievement B6. A method of any one of Embodiments B1 to B5, wherein Q1 is a phenyl ring having a substituent selected from R1 at the (4-) position and optionally up to 2 additional R1 substituents.
[0087] Achievement B7. A method of Embodiment B1, wherein Q1 is a fully unsaturated 5- to 6-membered heterocyclic ring optionally substituted with up to 5 substituents independently selected from R1 on the carbon atom members and selected from R3 on the nitrogen atom members.
[0088] Achievement B8. A method of Embodiment B7, wherein Q1 is an optionally substituted pyridyl ring with up to 2 R1.
[0089] Achievement B9. A method of Embodiment B8, wherein Q1 is a 3-pyridyl ring substituted with R1 in the para position relative to the bond connecting Q1 to the remainder of the compound of Formula I.
[0090] Achievement B10. A method of Embodiment B7, wherein Q1 is a thiophenyl or furanyl ring optionally substituted with up to 2 R1.
[0091] Achievement B11. A method of Embodiment B1, wherein Q1 is an 8- to 10-membered heteroaromatic bicyclic ring system optionally substituted with R1and R3, the remainder of Formula I is attached to a fully unsaturated ring of said bicyclic ring system.
[0092] Achievement B12. A method of Embodiment B1, wherein Q2 is an optionally substituted phenyl ring with up to 5 substituents independently selected from R4.
[0093] Achievement B13. A method of Embodiment B12, where Q2 is a phenyl ring substituted with 1 to 4 substituents independently selected from R4.
[0094] Achievement B14. A method of Embodiment B13, where Q2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R4.
[0095] Achievement B15. A method of any one of Embodiments B12 to B14, wherein Q2 is a phenyl ring having a substituent selected from R4 in the ortho (2-) position and optionally up to 2 additional R4 substituents.
[0096] Achievement B16. A method of Embodiment B1, wherein Q2 is an optionally substituted pyridyl ring with up to 2 R4.
[0097] Achievement B17. A method of Embodiment B16, wherein Q2 is a 2-pyridyl or 3-pyridyl ring optionally substituted with up to 2 R4.
[0098] Achievement B18. A method of Embodiment B1, wherein Q2 is a fully unsaturated 5-membered heterocyclic ring optionally substituted with up to 2 R4.
[0099] Achievement B19. A method of Embodiment B18, wherein Q2 is an oxazolyl ring optionally substituted with up to 2 R4.
[0100] Achievement B20. A method of any of Embodiments B1 through B19, wherein R is C1-C4 alkyl.
[0101] Achievement B21. A method of Embodiment B20, where R is methyl or ethyl.
[0102] Achievement B22. A method of Embodiment B21, where R is methyl.
[0103] Achievement B23. A method of Embodiment B21, where R is ethyl.
[0104] Achievement B24. A method of any of Embodiments B1 through B23, wherein R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 nitroalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 haloalkoxyalkoxy, C2-C8 nitroalkenyl, C2-C8 alkynyl or C2C8 haloalkynyl.
[0105] Achievement B25. A method of Embodiment B24, wherein R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, or C2-C8 haloalkoxyalkoxy.
[0106] Achievement B26. A method of Embodiment B25, where R1 independently is halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
[0107] Achievement B27. A method of Embodiment B26, where R1 independently is halogen or C1-C3 haloalkyl.
[0108] Achievement B28. A method of Embodiment B27, where R1, independently, is F or CF3.
[0109] Achievement B29. A method of any of Embodiments B7 through B28, wherein R3 independently is C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, or C1-C3 alkoxy.
[0110] Achievement B30. A method of Embodiment B29, where R3 independently is C1-C3 alkyl.
[0111] Achievement B31. A method of any of Embodiments B1 to B30, wherein R4, independently, is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 nitroalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 haloalkoxyalkoxy, C2-C8 nitroalkenyl, C2-C8 alkynyl or C2C8 haloalkynyl.
[0112] Achievement B32. A method of Embodiment B31, wherein R4, independently, is halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
[0113] Achievement B33. A method of Embodiment B32, where R4, independently, is halogen or C1-C3 haloalkyl.
[0114] Achievement B34. A method of Embodiment B33, where R4, independently, is F or CF3.
[0115] Achievement B35. A method of any of Embodiments B1 through B34, wherein the stereochemistry of the carbon center connecting Q1 to the remainder of Formula I is S.
[0116] Achievement B36. A method of any of Embodiments B1 through B34, wherein the stereochemistry of the carbon center connecting Q1 to the remainder of Formula I is R.
[0117] Achievement B37. A method of any one of Embodiments B1 through B36, wherein a catalyst is present.
[0118] Achievement B38. A method of Embodiment B37, where the catalyst is an organometallic complex.
[0119] Achievement B39. A method of Embodiment B38, where the catalyst is a nickel complex.
[0120] Achievement B40. A method of Embodiment B39, where the nickel complex is chiral.
[0121] Achievement B41. A method of Embodiment B40, where the nickel complex is Ni(II) with the vicinal diamine ligands.
[0122] Achievement B42. A method of Embodiment B41, wherein the linkers are N-substituted cyclohexane-1,2-diamines or 1,1'-bi(tetrahydroisoquinoline)-diamines.
[0123] Achievement B43. A method of Embodiment B42, where the nickel complex is bis[(R,R)-N,N'-dibenzylcyclohexane-1,2-diamine]bromide or Ni(II)bis[(S,S) -N,N'-dibenzylcyclohexane-1,2-diamine].
[0124] Achievement B44. A method of any one of Embodiments B1 through B43, where a base is present.
[0125] Achievement B45. A method of Embodiments B44, wherein the base is an organic base.
[0126] Achievement B46. A method of Embodiments B45, wherein the base is triethylamine, morpholine or piperidine.
[0127] Achievement C1. A method for preparing a compound of Formula IV as described in the Brief Description of the Invention.
[0128] Achievement C2. A method of Embodiment C1, wherein Q1 is an optionally substituted phenyl ring with up to 5 substituents independently selected from R1.
[0129] Achievement C3. A method of Embodiment C2, wherein Q1 is a phenyl ring substituted with 1 to 4 substituents independently selected from R1.
[0130] Achievement C4. A method of Embodiment C3, wherein Q1 is a phenyl ring substituted with 1 to 3 substituents independently selected from R1.
[0131] Achievement C5. A method of any one of Embodiments C1 to C4, wherein Q1 is a phenyl ring having a substituent selected from R1 in the meta(3-) position and optionally up to 2 additional R1 substituents.
[0132] Achievement C6. A method of any one of Embodiments C1 to C4, wherein Q1 is a phenyl ring having a substituent selected from R1 at the (4-) position and optionally up to 2 additional R1 substituents.
[0133] Achievement C7. A method of Embodiment C1, wherein Q1 is a fully unsaturated 5- to 6-membered heterocyclic ring optionally substituted with up to 5 substituents independently selected from R1 on the carbon atom ring members and selected from R3 on the carbon atom ring members nitrogen.
[0134] Achievement C8. A method of Embodiment C7, wherein Q1 is an optionally substituted pyridyl ring with up to 2 R1.
[0135] Achievement C9. A method of Embodiment C8, wherein Q1 is a 3-pyridyl ring substituted with R1 in the para position relative to the bond connecting Q1 to the remainder of Formula IV.
[0136] Achievement C10. A method of Embodiment C7, wherein Q1 is a thiophene or furan ring optionally substituted with up to 2 R1.
[0137] Achievement C11. A method of Embodiment C1, wherein Q1 is an 8- to 10-membered heteroaromatic bicyclic ring system optionally substituted with R1and R3, the remainder of Formula I is attached to a fully unsaturated ring of said bicyclic ring system.
[0138] Achievement C12. A method of Embodiment C1, wherein Q2 is an optionally substituted phenyl ring with up to 5 substituents independently selected from R4.
[0139] Achievement C13. A method of Embodiment C12, where Q2 is a phenyl ring substituted with 1 to 4 substituents independently selected from R4.
[0140] Achievement C14. A method of Embodiment C13, where Q2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R4.
[0141] Achievement C15. A method of any one of Embodiments C12 to C14, wherein Q2 is a phenyl ring having a substituent selected from R4 in the ortho (2-) position and optionally up to 2 additional R4 substituents.
[0142] Achievement C16. A method of Embodiment C1, wherein Q2 is an optionally substituted pyridyl ring with up to 2 R4.
[0143] Achievement C17. A method of Embodiment C16, wherein Q2 is a 2-pyridyl or 3-pyridyl ring optionally substituted with up to 2 R4.
[0144] Achievement C18. A method of Embodiment C1, wherein Q2 is a fully unsaturated 5-membered heterocyclic ring optionally substituted with up to 2 R4.
[0145] Achievement C19. A method of Embodiment C18, wherein Q2 is an optionally substituted oxazole ring with up to 2 R4.
[0146] Achievement C20. A method of any of Embodiments C1 to C19, wherein R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 nitroalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 haloalkoxyalkoxy, C2-C8 nitroalkenyl, C2-C8 alkynyl or C2C8 haloalkynyl.
[0147] Achievement C21. A method of Embodiment C20, wherein R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, or C2-C8 haloalkoxyalkoxy.
[0148] Achievement C22. A method of Embodiment C21, wherein R1 independently is halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
[0149] Achievement C23. A method of Embodiment C22, where R1 independently is C1-C3 halogen or haloalkyl.
[0150] Achievement C24. A method of Embodiment C23, where R1, independently, is F or CF3.
[0151] Achievement C25. A method of any of Embodiments C7 to C24, wherein R3 independently is C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, or C1-C3 alkoxy.
[0152] Achievement C26. A method of Embodiment C25, where R3 independently is C1-C3 alkyl.
[0153] Achievement C27. A method of any of Embodiments C1 to C26, wherein R4 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 nitroalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 haloalkoxyalkoxy, C2-C8 nitroalkenyl, C2-C8 alkynyl or C2C8 haloalkynyl.
[0154] Achievement C28. A method of Embodiment C27, wherein R4, independently, is halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
[0155] Achievement C29. A method of Embodiment C28, wherein R4 independently is C1-C3 halogen or haloalkyl.
[0156] Achievement C30. A method of Embodiment C29, where R4 independently is F or CF3.
[0157] Achievement C31. A method of any one of Embodiments C1 to C30 wherein the stereochemistry of a compound of Formula IV is (3R,4S).
[0158] Achievement C31a. A method of any one of Embodiments C1 to C30 wherein the stereochemistry of a compound of Formula IV is (3S,4R).
[0159] Achievement C32. A method of any of Embodiments C1 through C31, wherein the reducing agent is hydrogen in the presence of a catalyst.
[0160] Achievement C33. A method of Embodiment C32, where the catalyst is Pd/C.
[0161] Achievement C34. A method of any one of Embodiments C1 through C31, wherein the reducing agent is metal in acid.
[0162] Achievement C35. A method of Embodiment C34 where the metal is zinc and the acid is acetic acid.
[0163] Embodiments of the present invention, including any of Embodiments A1 to A34, B1 to B41 and C1 to C35 above, as well as any other embodiments described herein, may be combined in any manner and variable descriptions in the embodiments they belong not only to compounds of Formula I and IV, but also to starting compounds and intermediate compounds useful for the preparation of compounds of Formula I and IV.
[0164] Combinations of Embodiments A1 to A34, B1 to B41 and C1 to C35 are illustrated by.
[0165] Realization AA1. A compound of Formula I, wherein -Q1 is a phenyl ring substituted with 1 to 3 substituents independently selected from R1; - Q2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R4; - R is C1-C4 alkyl; - R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl or C2-C8 haloalkoxyalkoxy; and - R4 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl.
[0166] Realization AA2. A compound of Embodiment AA1, wherein -Q1 is a phenyl ring having a substituent selected from R1 in the meta(3-) position and optionally up to 2 additional R1 substituents; - Q2 is a phenyl ring having a substituent selected from R4 in the ortho (2-) position and optionally up to 2 additional R4 substituents; - R is methyl or ethyl; - R1 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0167] AA3 Realization. A compound of Embodiment AA1 wherein -Q1 is a phenyl ring having a substituent selected from R1 in the para (4-) position and optionally up to 2 additional R1 substituents; - Q2 is a phenyl ring having a substituent selected from R4 in the ortho (2-) position and optionally up to 2 additional R4 substituents; - R is methyl or ethyl; - R1 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0168] AA4 Achievement. A compound of Formula I, wherein -Q1 is a fully unsaturated 5- to 6-membered heterocyclic ring optionally substituted with up to 5 substituents independently selected from R1 on the carbon atom ring members and selected from R3 on the atom ring members of nitrogen; - Q2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R4; - R is C1-C4 alkyl; - R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl or C2-C8 haloalkoxyalkoxy; - R3 independently is C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl or C1-C3 alkoxy; and - R4 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl.
[0169] AA5 Achievement. A compound of Embodiment AA4, wherein -Q1 is a pyridyl ring optionally substituted with up to 2 R1; - Q2 is a phenyl ring substituted with 1 to 2 substituents independently selected from R4; - R is methyl or ethyl; - R1 independently is halogen or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0170] AA6 Realization. A compound of AA4 wherein -Q1 is a 3-pyridyl ring substituted with R1 in the para position relative to the bond connecting Q1 to the remainder of the compound of Formula I; or Q1 is a thiophene or furan ring optionally substituted with up to 2 R 1; - Q2 is a phenyl ring substituted with 1 to 2 substituents independently selected from R4; - R is methyl or ethyl; - R1 independently is halogen or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0171] AA7 Achievement. A compound of Formula I, wherein -Q2 is a 2-pyridyl or 3-pyridyl ring optionally substituted with up to 2 R4; - R is methyl or ethyl; - R1 independently is halogen or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0172] AA8 Achievement. A compound of Formula I, wherein -Q2 is an oxazolyl ring optionally substituted with up to 2 R4; - R is methyl or ethyl; - R1 independently is halogen or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0173] AA9 Achievement. A compound of any one of the embodiments of AA1 to AA8, wherein - the stereochemistry of the carbon center connecting Q1 to the remainder of Formula I is either S or R.
[0174] Realization BB1. A method for preparing a compound of Formula I, as described in the Brief Description of the Invention, wherein -Q1 is a phenyl ring substituted with 1 to 3 substituents independently selected from R1; - Q2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R4; - R is C1-C4 alkyl; - R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl or C2-C8 haloalkoxyalkoxy; and - R4 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl.
[0175] BB2 Achievement. A method of Embodiment BB1, wherein -Q1 is a phenyl ring having a substituent selected from R1 in the meta(3-) position and optionally up to 2 additional R1 substituents; - Q2 is a phenyl ring having a substituent selected from R4 in the ortho (2-) position and optionally up to 2 additional R4 substituents; - R is methyl or ethyl; - R1 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl; - R4, independently, is halogen or C1-C3 haloalkyl.
[0176] BB3 Achievement. A method of any of Embodiments BB1 and BB2, wherein - the catalyst is a nickel complex; and - the base is an organic base.
[0177] BB4 Achievement. A method of Embodiment BB3, where - the nickel complex is Ni(II) with the chiral vicinal diamine ligands.
[0178] BB5 Achievement. A method of Embodiment BB4, wherein - the linkers are N-substituted cyclohexane-1,2-diamines or 1,1'-bi(tetrahydroisoquinoline)-diamines; and - the base is triethylamine, morpholine or piperidine.
[0179] BB6 Achievement. A method of any of Embodiments BB1 through BB5, wherein - the stereochemistry of the carbon center connecting Q1 to the remainder of Formula I is either S or R.
[0180] Realization CC1. A method for preparing a compound of Formula IV, as described in the Brief Description of the Invention, wherein -Q1 is a phenyl ring substituted with 1 to 3 substituents independently selected from R1; - Q2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R4; - R is C1-C4 alkyl; - R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl or C2-C8 haloalkoxyalkoxy; and - R4 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl.
[0181] Realization CC2. A method of Embodiment CC1, wherein -Q1 is a phenyl ring having a substituent selected from R1 in the meta(3-) position and optionally up to 2 additional R1 substituents; - Q2 is a phenyl ring having a substituent selected from R4 in the ortho (2-) position and optionally up to 2 additional R4 substituents; - R1 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl; - R4, independently, is halogen or C1-C3 haloalkyl; and
[0182] Realization CC3. A method for preparing a compound of Formula IV, as described in the Brief Description of the Invention, wherein -Q1 is a pyridyl ring optionally substituted with up to 2 R1; - Q2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R4; - R1 independently is halogen or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0183] Realization CC4. A method of any one of Embodiments CC1 to CC3, wherein - the stereochemistry of a compound of Formula IV is (3R,4S) or (3S,4R).
[0184] Realization CC5. A method of any one of Embodiments CC1 through CC4, wherein - the reducing agent is hydrogen in the presence of a catalyst or metal in acid.
[0185] Specific embodiments include compounds of Formula I selected from the group consisting of: - ((βS)-α-[[(2-fluorophenyl)amino]carbonyl]-β-(nitromethyl)-3-( ethyl trifluoromethyl)benzenepropanoate; - ethyl α-[[(2-fluorophenyl)amino]carbonyl]-β-(nitromethyl)-3-(trifluoromethyl)benzenepropanoate; - (3R,4S)-N-(2-fluorophenyl) -2-oxo-4-[3-(trifluoromethyl)phenyl]-3-pyrrolidinecarboxamide; and -rel-(3R,4S)-N-(2-fluorophenyl)-2-oxo-4-[3-(trifluoromethyl) phenyl]-3-pyrrolidinecarboxamide.
[0186] Pyrrolidinones of Formula IV are useful as herbicides as described in patent bPCT / US 2014/68,073.
[0187] The compounds of Formula I and IV can be prepared by the general methods known in the state of the art of synthetic organic chemistry. One or more of the following methods and variations as described in Schemes 1 to 5 can be used to prepare the compounds of Formula I and IV. The definitions of Q1, Q2, R in the compounds of Formulas I, II, III, IV, a, b, c, d, e and f below are as defined above in the Brief Description of the Invention, unless otherwise indicated. All substituents for Formulas a, b, c, d, e and f are as defined above for Formulas I, II, III and IV, unless otherwise indicated.
[0188] As illustrated in Scheme 1, a compound of Formula IV can be obtained by reduction of a compound of Formula I and further in situ cyclization of the resulting intermediate amine. A wide variety of methods for reducing the aliphatic nitro group in compounds of Formula I are known in the literature. Methods well known to those skilled in the art include catalytic hydrogenation in the presence of palladium on carbon, reduction using Raney nickel, iron or metal zinc in an acidic medium (see, for example, Berichte der Deutschen Chemischen Gesellschaft 1904, 37, 3.5203.). 525) and reduction using lithium aluminum hydride. Reduction can also be achieved with samarium(II) iodide in the presence of a proton source such as methanol (see, for example, Tetrahedron Letters 1991, 32 (14), 1.6991.702). Alternatively, sodium borohydride in the presence of a nickel catalyst such as nickel(II) acetate or nickel(II) chloride can be used (see, for example, Tetrahedron Letters 1985, 26(52), 6,4136,416). The method of using sodium borohydride in the presence of ethyl nickel (II) is illustrated in Step C of Synthesis Example 1. SCHEME 1

[0189] As illustrated in Scheme 2, a compound of Formula I can be prepared by reacting compounds of Formula (a) with nitromethane in the presence of a base. Suitable bases for the reaction include lower alkali metal alkoxides such as sodium methoxide in methanol or sodium ethoxide in ethanol. SCHEME 2

[0190] Alternatively, as illustrated in Scheme 3, a compound of Formula I can be prepared by reacting nitroalkenes of Formula II with malonates of Formula III in the presence of a catalyst, a base, or both a catalyst and a base . Suitable catalysts for this reaction include, but are not limited to a complex of Ni(II) with vicinal diamine ligands such as Ni[II]bis[(R,R)-N,N'-dibenzylcyclohexane-1, 2-diamine]bromide or Ni(II)Br2 complexed with the chiral 1,1'-Bi(tetrahydroisoquinoline)-diamines. Suitable bases for this reaction include, but are not limited to, lower alkali metal alkoxides such as sodium methoxide in methanol or sodium ethoxide in ethanol, organic bases such as piperidine, morpholine, triethylamine, N-methylmorpholine or N-amine ,N-diisopropylethyl or bases such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and lithium diisopropylamide in solvents such as tetrahydrofuran, toluene or dichloromethane. Typically, the reaction is carried out at a temperature from about -78°C to about 23°C optionally in the presence of 0 to 2 equivalents of catalyst and/or base. See Synthesis 2005, 2.239-2,245 for conditions to effect this transformation and see J. Am. Chem. Soc. 2005, 9,958-9,959 or Eur. J. Org. Chem. 2011, 5.441-5.446 for the conditions to perform this transformation stereoselectively. Conditions for effecting this transformation in reflux water in the absence of catalyst were reported in Synthetic Communications 2013, 43, 744-748. The Formula II nitroalkenes can be readily prepared from aldehydes and nitromethane by methods known to those skilled in the art.

[0191] As illustrated in Scheme 4, compounds of Formula (a) can be prepared by reacting malonates of Formula (d) with aldehydes of Formula and by methods known to those skilled in the art, for example, through condensation of aldehydes and malonates by Knoevenagel (see, for example, Jones, G., Organic Reactions, Volume 15, John Wiley & Sons, 1967). Also as illustrated in Scheme 4, malonates of Formula (d) can readily be prepared from lower alkyl malonyl chlorides of Formula (b) such as methyl malonyl chloride and amines of Formula (c) via the methods known to the technicians SCHEME 4

[0192] As illustrated in Scheme 5, compounds of Formula II can be prepared by reacting nitromethane with an aldehyde of Formula and in the presence of a base. Dehydration of intermediate (f) can be carried out by azeotropic distillation of water from the reaction mixture or by reaction with methanesulfonyl chloride in the presence of a base such as triethylamine. Suitable bases for this reaction include, but are not limited to, lower alkali metal alkoxides such as sodium hydroxide, sodium methoxide in methanol or sodium ethoxide in ethanol, ammonium acetate; or organic bases such as piperidine, morpholine or triethylamine in solvents such as methanol, toluene, acetic acid or 1-chlorobutane. Typically, the reaction is carried out at a temperature from about -78°C to 130°C in the presence of 0 to 2 equivalents of catalyst or base. For representative conditions for preparing the nitrostrienes, see publications WO 2012/158413, US 2011/207,944 and WO 2004/18455. SCHEME 5

[0193] It is recognized by one skilled in the art in the art that several functional groups can be converted to others to provide different compounds of Formula 1. For a valuable resource that illustrates the interconversion of functional groups in a simple and straightforward manner, see Larock, RC, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Ed., Wiley-VCH, New York, 1999. For example, intermediates for preparing compounds of Formula I may contain aromatic nitro groups, which may be reduced to amino groups and then converted through reactions well known in the art such as the Sandmeyer reaction, into various halides, giving the compounds of Formula I. The above reactions, in many cases, can also be performed in alternate order.
[0194] It is recognized that some reagents and reaction conditions described above for the preparation of the Formula I compounds may not be compatible with certain functionalities present in the intermediates. In these cases, the incorporation of protection/deprotection sequences or functional group interconversions in the synthesis will help to obtain the desired products. The use and selection of protecting groups will be apparent to one skilled in the art in chemical synthesis (see, for example, Greene, T.W., Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed., Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a particular reagent, as illustrated in any individual scheme, it may be necessary to perform additional routine synthesis steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the art will also recognize that it may be necessary to carry out a combination of the steps illustrated in the above schemes in a different order than that suggested by the special set forth for the preparation of the compounds of Formula I.
[0195] A person skilled in the art in the art will also recognize that the compounds of Formula I and the intermediates described herein may be subjected to various reactions of electrophile, nucleophile, radical, organometallic, oxidation and reduction to add substituents or modify the existing substitutes.
[0196] Without further elaboration, it is believed that a technician on the subject, using the previous description, can use the present invention to its fullest extent. The following Examples, therefore, may be interpreted as illustrative only, and not limiting the description in any way. The steps in the following Examples illustrate a procedure for each step in a general synthetic transformation, and the starting material for each step may not necessarily have been prepared by a special preparative operation whose procedure is described in other Steps and Examples. Percentages are by weight, except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages of chromatographic solvent mixtures are by volume, unless otherwise indicated. 1H NMR spectra are reported in ppm from tetramethylsilane in CDCl3 solution unless otherwise indicated; "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, and "bs" means broad singlet. 19F NMR mass spectra are reported in ppm from CFCl3 to CDCl3, unless otherwise indicated. The enantiomeric ratio (ER) was determined by chiral high performance liquid chromatography analysis using a Chiralpak AD-RHe column eluting with a 50:50 isopropanol/water mixture at 40°C at 0.3 ml/min. SYNTHESIS EXAMPLE1 PREPARATION OF REL-(3R,4S)-N-(2-FLUOROPENYL)-2-OXO-4-[3-(TRIFLUOROMETHYL)PHENYL]-3-PYRROLIDINECARBOXAMIDE STEP - PREPARATION OF 1-[(E)-2-NITROETHENIL]-3-(TRIFLUOROMETHYL) BENZENE
[0197] To a stirred solution of 3-(trifluoromethyl)benzaldehyde (12.2 g, 70.1 mmol) in methanol (50 mL) was added the nitromethane (4.34 g, 71.1 mmol). The mixture was cooled to 2°C and sodium hydroxide (5.65 g, 70.6 mmol) was added as a 50% solution in 24.3 mL of water dropwise over 15 min. An exotherm was observed and more ice was added to keep the internal temperature below 10°C while stirring for an additional 1 h. The reaction mixture was poured into 75 mL of 1N hydrochloric acid, rinsing the flask with 10 mL of methanol/water. The quenched reaction mixture was transferred to a separatory funnel and extracted with 150 mL of toluene. The aqueous layer was separated and the organic layer was concentrated in vacuo to provide 15.84 g of a yellow oil.
[0198] The yellow oil (15.84 g, 67.3 mmol) thus obtained was taken up in 160 ml of dichloromethane. The solution was cooled to 3°C and methanesulfonyl chloride (8.03 g, 71.1 mmol) was added via pipette as a solution in 50 mL of dichloromethane. A solution of triethylamine (14.2 g, 140 mmol) in 50 ml of dichloromethane was then added dropwise over 50 min. The mixture was stirred for 2 h and then poured into 150 mL of 1N hydrochloric acid and transferred to a separatory funnel. The layers were separated and the organic layer was washed with 150 ml of water and then filtered. The organic layer was concentrated under reduced pressure and the crude solid was triturated with the hexanes to provide 12.09 g (79.4% yield over two steps) of product as a yellow solid.
[0199] 1H NMR (500 MHz) δ from 7.96 to 8.08 (m, 1H), from 7.69 to 7.84 (m, 3H), from 7.54 to 7.66 (m, 2H) ). STEP B - PREPARATION OF ETHYL 3-[(2-FLUOROPENYL)AMINO]-3-OXOPROPANOATE
[0200] To a stirred solution of 2-fluoroaniline (10 g, 90.0 mmol) and triethylamine (9.1 g, 90.0 mmol) in dichloromethane (50 ml) at 0°C for 10 minutes was added dropwise to drop a solution of ethyl malonyl chloride (15.5 g, 90.0 mmol) in dichloromethane (30 mL). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then poured into water (100 mL), and the organic layer was separated, washed with water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to provide the title compound as an amber oil (19.0 g).
[0201] 1H NMR δ 9.46 (br s, 1H), 8.28 (m, 1H), 7.10 (m, 2H), 4.26 (m, 2H), 3.51 (s, 2H ), 1.32 (t, 3H). STEP C - PREPARATION OF A-[[(2-FLUOROPENYL)AMINO]CARBONYL]-B-(NITROMETHYL)-3-(TRIFLUOROMETHYL) ETHYL BENZENEPROPANOATE
[0202] A stirred solution of 1-[(E)-2-nitrovinyl]-3-(trifluoromethyl)benzene (ie, the product from Step A, 12 g, 55 mmol) and 3-[(2-fluorophenyl) Ethyl amino]-3-oxopropanoate (ie, step B product, 12.4 g, 55 mmol) in anhydrous tetrahydrofuran (55 mL) was cooled to -5°C under a nitrogen atmosphere. To this mixture was added triethylamine (7.7 mL, 55 mmol) as a solution in anhydrous tetrahydrofuran (15 mL) over 10 min. The reaction was stirred and allowed to warm to room temperature over 1.5 h. The solution was concentrated under reduced pressure. The resulting crude solid was triturated with Et2O, filtered and washed with a small amount of Et2O and then hexanes. After drying under suction under nitrogen, 16.25 g of a white solid was isolated. Concentration of the filtrate and trituration with 1-chlorobutane at 50°C yielded 3.45 g of additional product (NMR data is a 1:1 mixture of two diastereomers).
[0203] 1H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1H), 10.03 (s, 1H), from 7.44 to 7.88 (m, 8H), from 6.85 to 7.33 (m, 8H), from 4.95 to 5.16 (m, 4H), from 4.10 to 4.38 (m, 6H), from 3.84 to 4.01 (m, 2H) ), from 1.17 to 1.24 (m, 3H), from 0.90 to 1.00 (m, 3H); 19F NMR (471 MHz, DMSO-d6) δ -124.41 to -124.17 (m, 2F), -61.56 to -60.99 (m, 6F). STEP D - PREPARATION OF REL-(3R,4S)-N-(2-FLUOROPENYL)-2-OXO-4-[3-(TRIFLUOROMETHYL)PHENYL]-3-PYRROLIDINOCARBOXAMIDE
[0204] To a solution of ethyl α-[[(2-fluorophenyl)amino]carbonyl]-β-(nitromethyl)-3-(trifluoromethyl)benzenepropanoate (ie, the product of Step C, 15.1 g, 34 mmol) in anhydrous N,N-dimethylformamide (30 mL) and methanol (160 mL) was added the NiCl2.6H2O powder (8.1 g, 34 mmol) in one portion. After the solution became clear, the mixture was cooled to -7°C. NaBH4 (3.8 g, 100 mmol) was added (3.8 g, 100 mmol) in 0.5 g portions keeping the internal temperature lower at 0°C. The reaction mixture was warmed to room temperature with stirring overnight. The solution was concentrated under reduced pressure and the crude material was suspended in dichloromethane (300 ml) and adsorbed onto a mixture of silica gel (60 g) and celite (25 g). After concentration in vacuo, the sample was filtered through a silica gel plug (160 g), eluting with ethyl acetate until no product passed through the plug. Concentration under reduced pressure provided 9.55 g of the desired product as an off-white, oily solid. 1H NMR (500 MHz) δ 9.70 (br s, 1H), from 8.15 to 8.25 (m, 1H), from 7.42 to 7.68 (m, 4H), from 6.97 to 7.12 (m, 3H), 6.49 (br s, 1H) from 4.23 to 4.34 (m, 1H), from 3.81 to 3.89 (m, 1H), from 3.56 to 3.67 (m, 1H), from 3.41 to 3.53 (m, 1H).
[0205] 19F NMR (471 MHz) δ ppm -129.69- to -129.51 (m, 1F), -62.56 (s, 3F). SYNTHESIS EXAMPLE 2 PREPARATION OF (3R,4S)-N-(2-FLUOROPENYL)-2-OXO-4-[3-(TRIFLUOROMETHYL)PHENYL|- 3-PYRROLIDINECARBOXAMIDE STEP A - PREPARATION OF (BS)-A-[[(2-FLUOROPENYL)AMINO]CARBONYL]-P-(NITROMETHYL)-3-(TRIFLUOROMETHYL)ETHYL BENZENEPROPANOATE
[0206] To a mechanically stirred solution of 1-[(E)-2-nitroethenyl]-3-(trifluoromethyl)benzene (i.e. the product from Step A in Synthesis Example 1, 70 g, 0.32 mol) and ethyl 3-[(2-fluorophenyl)amino]-3-oxopropanoate (i.e. the product from Step B in Synthesis Example 1, 72.6 g, 0.3225 mol) in toluene (350 mL) was added o Ni(II)-bis[(R,R)-N,N'-dibenzylcyclohexane-1,2-diamine]bromide (3.9 g, 0.0048 mol). The resulting mixture was stirred for 48 h at room temperature. The solution was then diluted with dichloromethane (500 ml) and adsorbed onto silica gel and purified via chromatography (70/30 petroleum ether/ethyl acetate). After standing at room temperature, 130 g of a white solid were obtained. Analysis by chiral HPLC (Chiral Pak IA (250 x 4.6) mm 5 µ, 0.1% diethylamine in hexane ethanol (90:10) at 1.0 mL/min) showed an ER of 89:10 .
[0207] 1H NMR (500 MHz) δ 8.66 (br s, 2H), from 8.16 to 8.25 (m, 1H), from 7.99 to 8.09 (m, 1H), from 7 .52 to 7.62 (m, 3H), from 7.39 to 7.51 (m, 5H) (M, 2H), from 4.87 to 5.01 (m, 2H), from 4.39 to 4.46 (m, 1H), 4.30 (q, J = 7.15 Hz, 3H), 4.02 (Q, J = 7.20 Hz, 2H), from 3.82 to 3.91 ( m, 2H), from 1.28 to 1.37 (m, 3H), from 0.93 to 1.05 (m, 3H)
[0208] NMR 19F (471 MHz) δ -130.24 to -1.30.09 (m, 1F), -129.92 to -129.76 (m, 1F), -62.84 (s, 3F) ), -62.80 (s, 3F); NMR data is a 1:1 mixture of two diastereomers.
[0209] MP: from 130.6 to 134.6° C: ESI [M + 1] 443.6. ETAPAB - PREPARATION OF (3R,4S)-N-(2-FLUOROPENYL)-2-OXO-4-[3-(TRIFLUOROMETHYL)PHENYL]-3-PYRROLIDINECARBOXAMIDE
[0210] To a solution of ethyl (βS)-α-[[(2-fluorophenyl)amino]carbonyl]-β-(nitromethyl)-3-(trifluoromethyl)benzenepropanoate (ie, the product of Step C, 100 g (0.226 mol) in ethanol (1,000 mL) was added the zinc powder (144.7 g, 2.26 mol) in one portion. The reaction mixture was heated to 80°C. Acetic acid (108 g, 1.81 mol) was added dropwise over a period of 45 min. After the addition of acetic acid, the solution was heated to 90°C and stirred for 3 h. The solution was cooled to room temperature and diluted with the ethyl acetate (1 L) and filtered through a Celite® filter aid bed into diatomaceous earth.The filtrate was concentrated under reduced pressure and the residue was taken up in ethyl acetate (2 L).The organic layer was washed with 0.5N HCl, water and brine and then dried over Na2SO4, filtered and concentrated in vacuo The thick liquid obtained was triturated with 500 mL of methyl tert-butyl ether/10% petroleum ether to provide is a white solid. Filtration and drying provided the title compound as a white solid (56 g, 67% yield). Analysis by chiral HPLC (Chiral Pak IA (250 x 4.6) mm 5 µ, 0.1% DEA in hexane:ethanol (90:10) at 1.0 mL/min) showed an ER of 86: 14.
[0211] 1H NMR (500 MHz, acetone-d6) δ 10.05 (br s, 1H), from 8.24 to 8.33 (m, 1H), from 7.78 to 7.90 (m, 2H) ), from 7.57 to 7.65 (m, 2H) (M, 1H), from 4.20 to 4.29 (m, 1H), from 3.96 to 4.02 (m, 1H), from 3.83 to 3.92 (m, 1H), from 3.41 to 3.53 (m, 1H).
[0212] 19F NMR (471 MHz, acetone-d6) 5ppm -131.19 to -131.1 (m, 1F), 62.93 (s, 3F);
[0213] MP. From 141.8 to 144.7°C; ESI [M+1] 367.0.
[0214] By the procedures described herein together with the methods known in the prior art, the following compounds from Tables 1 to 688 can be prepared. The following abbreviations are used in the following Tables: t means tertiary, n means normal, i means iso, c means cyclo, Me means methyl, Et means ethyl, Pr means propyl, Bu means butyl, i-Pr means isopropyl, Bu means butyl, c-Pr means cyclopropyl, c-Bu means cyclobutyl, Ph means phenyl, OMe means methoxy, OEt means ethoxy, SMe means methylthio, SEt means ethylthio, NHMe means methylamino, -CN means cyano, -NO2 means nitro, TMS means trimethylsilyl, S(O)Me means methylsulfinyl, and S(O)2Me means methylsulfonyl.



































































































































[0215] Table 2 is constructed in the same way, except that the line title "R is Me; Q2 is Ph(2-F) and Q1 is "is replaced by the line title listed for Table 2 below (ie , "R is Me, Q2 is Ph(2,3-diF) and Q1 is"). Therefore, the first entry in Table 2 is a compound of Formula I, where R is Me; Q2 is Ph(2,3-diF) and Q1 is Ph(2-Cl) (i.e. 2-chlorophenyl). Tables 3 through 688 are constructed in a similar way.

权利要求:
Claims (14)
[0001]
1. COMPOUND, characterized by being selected from Formula I and its salts,
[0002]
2. COMPOUND according to claim 1, characterized in that: - Q1 is a phenyl ring substituted with from 1 to 3 substituents independently selected from R1; - Q2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R4; - R is C1-C4 alkyl; - R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl or C2-C8 haloalkoxyalkoxy; and - R4 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl.
[0003]
A COMPOUND according to claim 2, characterized in that: - Q1 is a phenyl ring having a substituent selected from R1 in the meta(3-) position and optionally up to 2 additional R1 substituents; - Q2 is a phenyl ring having a substituent selected from R4 in the ortho (2-) position and optionally up to 2 additional R4 substituents; - R is methyl or ethyl; - R1 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0004]
A COMPOUND according to claim 2, characterized in that: - Q1 is a phenyl ring having a substituent selected from R1 in the para (4-) position and optionally up to 2 additional R1 substituents; - Q2 is a phenyl ring having a substituent selected from R4 in the ortho (2-) position and optionally up to 2 additional R4 substituents; - R is methyl or ethyl; - R1 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0005]
A COMPOUND according to claim 1, characterized in that: - Q1 is a fully unsaturated 5- to 6-membered heterocyclic ring optionally substituted with up to 5 substituents independently selected from R 1 on the carbon atom ring members and selected from R3 on nitrogen atom ring members; - Q2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R4; - R is C1-C4 alkyl; - R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl or C2-C8 haloalkoxyalkoxy; - R3 independently is C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl or C1-C3 alkoxy; and - R4 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl.
[0006]
COMPOUND according to claim 5, characterized in that: - Q1 is a pyridyl ring optionally substituted with up to 2 R1; - Q2 is a phenyl ring substituted with 1 to 2 substituents independently selected from R4; - R is methyl or ethyl; - R1 independently is halogen or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0007]
A COMPOUND according to claim 5, characterized in that: - Q1 is a 3-pyridyl ring substituted with R1 in the para position relative to the bond connecting Q1 to the remainder of the compound of Formula I; or Q1 is a thiophene or furan ring optionally substituted with up to 2 R1; - Q2 is a phenyl ring substituted with 1 to 2 substituents independently selected from R4; - R is methyl or ethyl; - R1 independently is halogen or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0008]
COMPOUND according to claim 1, characterized in that: - Q2 is a 2-pyridyl or 3-pyridyl ring optionally substituted with up to 2 R4; - R is methyl or ethyl; - R , independently, is halogen or C1-C3 haloalkyl; and - R4 independently is halogen or C1-C3 haloalkyl.
[0009]
9. METHOD FOR THE PREPARATION OF A COMPOUND, of Formula I,
[0010]
10. METHOD according to claim 9, characterized in that - the catalyst is a nickel complex; and - the base is an organic base.
[0011]
11. METHOD, according to claim 10, characterized in that: - the nickel complex is Ni(II) with the vicinal chiral diamine ligands.
[0012]
12. METHOD, according to claim 11, characterized in that: - the binders are N-substituted cyclohexane-1,2-diamines or 1,1'-bi(tetrahydroisoquinoline)-diamines; and - the base is triethylamine, morpholine or piperidine.
[0013]
13. METHOD FOR THE PREPARATION OF A COMPOUND, of Formula IV, which has the stereochemistry (3R,4S)
[0014]
14. METHOD, according to claim 13, characterized in that: - Q1 is a phenyl ring substituted with from 1 to 3 substituents independently selected from R1; - Q2 is a phenyl ring substituted with 1 to 3 substituents independently selected from R4; - R is C1-C4 alkyl; - R1 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl or C2-C8 haloalkoxyalkoxy; and - R4 independently is halogen, C1-C3 alkyl or C1-C3 haloalkyl.

类似技术:

---

公开号 | 公开日 | 专利标题

---

BR112017009701B1|2021-09-08|COMPOUND AND COMPOUND PREPARATION METHODS

---

CA2454298A1|2003-02-27|Substituted 1h-dihydropyrazoles, their preparation and use

---

EA010740B1|2008-10-30|Substituted arylpyrazoles as parasiticidal agents

---

AU2016346207B2|2020-06-04|Intermediates to prepare pyridazinone herbicides, and a process to prepare them

---

MX2009013115A|2010-01-15|Prolinamide derivatives as nk3 antagonists.

---

EA019048B1|2013-12-30|Piperazin-1-yl-trifluoromethyl-substituted pyridines as fast dissociating dopamine 2 receptor antagonists

---

AU2016255424A1|2017-10-26|Benzimidazolone and benzothiazolone compounds and their use as AMPA receptor modulators

---

Yonezawa et al.2013|Conformational restriction approach to β-secretase | inhibitors III: Effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations

---

JPWO2004052871A1|2006-04-13|Benzomorpholine derivatives

---

Keglevich et al.2010|The synthesis of optically active P‐heterocycles

---

PT934930E|2009-02-11|Process for the preparation of 2-aryl-5-|pyrrole compounds from n-|arylimidoyl chloride compounds

---

JP6507267B2|2019-04-24|Heterocyclic alkyl derivative compounds as selective histone deacetylase inhibitors and pharmaceutical compositions containing the same

---

JP2011001309A|2011-01-06|Oxyindole derivative and nerve cell death inhibitor

---

AU2015247575C1|2019-04-11|Polycyclic hERG activators

---

JP2018514543A|2018-06-07|Indrone compounds and their use as AMPA receptor modulators

---

ES2626167T3|2017-07-24|Improved procedures for the preparation of 1-aryl-5-alkyl pyrazole compounds

---

JP2021532130A|2021-11-25|1,3,4-oxadiazole derivative compound as a histone deacetylase 6 inhibitor and a pharmaceutical composition containing the same.

---

JP6906449B2|2021-07-21|Heterocyclic sulfonamide derivative and pharmaceuticals containing it

---

Khoder2019|Copper-Catalyzed Synthesis of Heterocyclic Rings via Alkene Functionalization

---

KR100373485B1|2003-02-25|Novel isoxazole piperazine derivatives and preparation thereof

---

BR112016026193B1|2021-06-22|COMPOUND, METHOD FOR PREPARING A COMPOUND OF FORMULA I AND METHOD FOR PREPARING A COMPOUND OF FORMULA IV

---

CA3140660A1|2020-12-30|Urea derivatives as cb1 allosteric modulators

---

Dong2014|Rhodium-catalyzed direct CH functionalizations of sulfoximines and copper-catalyzed enantioselective synthesis of dihydropyrazoles

---

Nguyen2015|Synthetic routes to N-heterocycles and the development of small-molecule therapies for cystic fibrosis

---

Wilkerson2003|Benzotriazole-mediated Synthesis of N-acylbenzotriazoles and 2h-azirines

同族专利:

---

公开号 | 公开日

---

ES2759267T3|2020-05-08|

---

EP3230264B1|2019-09-11|

---

RU2017123114A3|2019-07-17|

---

JP6611816B2|2019-11-27|

---

PL3230264T3|2020-03-31|

---

JP2017538785A|2017-12-28|

---

CN107001260B|2020-11-10|

---

AU2015361018A1|2017-04-27|

---

EP3230264A1|2017-10-18|

---

RU2017123114A|2019-01-11|

---

IL252637A|2017-11-30|

---

RU2712831C2|2020-02-03|

---

TW201632497A|2016-09-16|

---

IL252637D0|2017-07-31|

---

HUE047582T2|2020-05-28|

---

SG11201702924WA|2017-05-30|

---

US20180057442A1|2018-03-01|

---

US10227286B2|2019-03-12|

---

KR20170090491A|2017-08-07|

---

BR112017009701A2|2018-02-20|

---

TWI694982B|2020-06-01|

---

AU2015361018B2|2020-01-16|

---

AR102939A1|2017-04-05|

---

CN107001260A|2017-08-01|

---

WO2016094117A1|2016-06-16|

---

MX2017007087A|2017-09-05|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

DE1262277B|1962-12-05|1968-03-07|Basf Ag|Process for the preparation of pyrrolidones|

---

US3741989A|1970-10-27|1973-06-26|Abbott Lab|Lactonic acetals|

---

JPS5356288A|1976-10-30|1978-05-22|Matsushita Electric Works Ltd|Preparation of phenolic resin|

---

JPS5488114A|1977-12-26|1979-07-13|Fuji Photo Film Co Ltd|Manufacturing device for photograph seal|

---

US4594094A|1983-04-04|1986-06-10|Shell Oil Company|Oxacycloalkane-alpha-carboxylic acid derivatives and use as plant growth regulators and herbicides|

---

US4874422A|1988-12-27|1989-10-17|Ici Americas Inc.|1-Phenyl-3-carboxyamidopyrrolidones and their use as herbicides|

---

JP3487669B2|1995-03-28|2004-01-19|積水化学工業株式会社|Unsaturated polyester resin composition|

---

WO2000009481A1|1998-08-11|2000-02-24|Takeda Chemical Industries, Ltd.|Cyclic amide compounds, process for producing the same, intermediates thereof and herbicides|

---

HU0401667A2|2001-10-08|2004-12-28|Ucb, S.A.|Use of 2-oxo-1-pyrrolidine derivatives for the preparation of a drug for treatment of dyskinesia and movement disorders|

---

EP1537099B1|2002-08-23|2010-08-11|Novartis Vaccines and Diagnostics, Inc.|Pyrrole based inhibitors of glycogen synthase kinase 3|

---

JP4398866B2|2002-10-18|2010-01-13|ビーエーエスエフソシエタス・ヨーロピア|1-phenylpyrrolidin-2-one-3-carboxamide|

---

AU2003277721A1|2002-11-15|2004-06-15|In Kwon Chung|Beta-nitrostyrene compound and telomerase inhibitor having an anticancer activity|

---

US7205318B2|2003-03-18|2007-04-17|Bristol-Myers Squibb Company|Lactam-containing cyclic diamines and derivatives as a factor Xa inhibitors|

---

KR100890696B1|2005-01-28|2009-03-26|아이알엠 엘엘씨|Synthesis of aryl pyrrolidones|

---

US20070123508A1|2005-05-27|2007-05-31|Roger Olsson|PAR2-modulating compounds and their use|

---

US8293926B2|2005-12-09|2012-10-23|Sumitomo Chemical Company, Limited|Method of producing optically active 4-amino-3-substituted phenylbutanoic acid|

---

ES2304220B1|2007-03-02|2009-09-11|Universidad De Zaragoza|COMPOSITION FOR THE TREATMENT OF INFECTIOUS DISEASES.|

---

EP2065380A1|2007-08-22|2009-06-03|F.Hoffmann-La Roche Ag|Pyridoneamide derivatives as focal adhesion kinase inhibitors and their use for the treatment of cancer|

---

CN101412711A|2007-10-15|2009-04-22|上海恒瑞医药有限公司|Carbamate derivatives and use thereof in medicine|

---

KR101667063B1|2008-09-02|2016-10-17|닛산 가가쿠 고교 가부시키 가이샤|Ortho-substituted haloalkylsulfonanilide derivative and herbicide|

---

US20110207944A1|2008-11-04|2011-08-25|Teijin Pharma Limited|Vitamin d3 lactam derivative|

---

JP2012518612A|2009-02-23|2012-08-16|エフ．ホフマン−ラロシュアーゲー|Novel orthoaminoamides for the treatment of cancer|

---

CN101747252A|2009-12-28|2010-06-23|嘉兴宜博生物医药科技有限公司|Synthetic method of R-structured Rolipram|

---

US9150591B2|2010-08-10|2015-10-06|Takeda Pharmaceutical Company Limited|Heterocyclic compound and use thereof|

---

EP2613782B1|2010-09-01|2016-11-02|Merck Sharp & Dohme Corp.|Indazole derivatives useful as erk inhibitors|

---

ES2615738T3|2011-05-13|2017-06-08|Array Biopharma, Inc.|Compounds of pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine as trkA kinase inhibitors|

---

CN102531918B|2012-01-18|2013-10-02|安阳工学院|Method for synthesizing enantiomorphous pure symmetric trans-dialkyl cyclohexylamine|

---

KR20130142477A|2012-06-19|2013-12-30|순천향대학교 산학협력단|Method for preparation of nitrocyclopropane derivatives|

---

US20160137639A1|2012-10-26|2016-05-19|Japan Tobacco Inc.|Triazole-isoxazole compound and medical use thereof|

---

MX2016007259A|2013-12-03|2016-08-04|Du Pont|Pyrrolidinones as herbicides.|

---

GB201321743D0|2013-12-09|2014-01-22|Ucb Pharma Sa|Therapeutic agents|

---

RU2555370C1|2014-02-12|2015-07-10|Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Самарский государственный технический университет"|Method for enanthioselective synthesis of diethyl[3-methyl--butyl]malonate of formula i|

---

WO2016003997A1|2014-07-02|2016-01-07|E. I. Du Pont De Nemours And Company|Piperidinone herbicides|

---

RU2710379C2|2015-04-10|2019-12-26|ЭфЭмСи Корпорейшн|Substituted cyclic amides as herbicides|

---

CA2979417A1|2015-04-27|2016-11-03|E I Du Pont De Nemours And Company|Butyrolactones as herbicides|

---

RU2750293C2|2015-05-12|2021-06-25|ЭфЭмСи Корпорейшн|Aryl-substituted bicyclic compounds as herbicides|

---

BR112017022743A2|2015-05-29|2018-07-17|Du Pont|"Compound, herbicidal composition, herbicide mixture and method for controlling unwanted vegetation growth"|

---

RU2017142979A3|2015-06-02|2019-10-11|

---

EP3328836B1|2015-07-31|2021-03-24|FMC Corporation|Cyclic n-carboxamide compounds useful as herbicides|

---

US20200115337A1|2016-12-21|2020-04-16|Fmc Corporation|Nitrone herbicides|

---

RU2019131524A3|2017-03-21|2021-07-16|

---

KR20190140911A|2017-03-21|2019-12-20|에프엠씨 코포레이션|Pyrrolidinone and its preparation method|MX2016007259A|2013-12-03|2016-08-04|Du Pont|Pyrrolidinones as herbicides.|

---

WO2016003997A1|2014-07-02|2016-01-07|E. I. Du Pont De Nemours And Company|Piperidinone herbicides|

---

RU2710379C2|2015-04-10|2019-12-26|ЭфЭмСи Корпорейшн|Substituted cyclic amides as herbicides|

---

CA2979417A1|2015-04-27|2016-11-03|E I Du Pont De Nemours And Company|Butyrolactones as herbicides|

---

RU2750293C2|2015-05-12|2021-06-25|ЭфЭмСи Корпорейшн|Aryl-substituted bicyclic compounds as herbicides|

---

BR112017022743A2|2015-05-29|2018-07-17|Du Pont|"Compound, herbicidal composition, herbicide mixture and method for controlling unwanted vegetation growth"|

---

RU2017142979A3|2015-06-02|2019-10-11|

---

EP3328836B1|2015-07-31|2021-03-24|FMC Corporation|Cyclic n-carboxamide compounds useful as herbicides|

---

GB201617050D0|2016-10-07|2016-11-23|Syngenta Participations Ag|Herbicidal mixtures|

---

KR20190140911A|2017-03-21|2019-12-20|에프엠씨 코포레이션|Pyrrolidinone and its preparation method|

---

WO2018177836A1|2017-03-30|2018-10-04|Bayer Aktiengesellschaft|N-cyclopropyl-2-oxopyrrolidine-3-carboxamide derivatives and related compounds as herbicidal plant protection agents|

---

WO2018177837A1|2017-03-30|2018-10-04|Bayer Aktiengesellschaft|4-cyclopentyl- and 4-cyclopropyl-2-oxopyrrolidine-3-carboxamide derivatives and related compounds as herbicidal plant protection agents|

---

AR111839A1|2017-05-30|2019-08-21|Fmc Corp|LACTAMAS 3-REPLACED HERBICIDES|

---

WO2019025156A1|2017-08-03|2019-02-07|Bayer Aktiengesellschaft|Substituted pyrrolidinones, salts thereof and use thereof as herbicidal agents|

---

GB201819747D0|2018-12-04|2019-01-16|Syngenta Participations Ag|Herbicidal compositions|

---

EP3923724A1|2019-02-15|2021-12-22|Syngenta Crop Protection AG|Herbicidal compositions|

法律状态:
2018-08-28| B25A| Requested transfer of rights approved|Owner name: FMC CORPORATION (US) |

---

2019-03-06| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 3A ANUIDADE. |

---

2019-04-02| B08G| Application fees: restoration [chapter 8.7 patent gazette]|

---

2019-10-15| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2021-06-29| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2021-08-17| B350| Update of information on the portal [chapter 15.35 patent gazette]|

---

2021-09-08| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 01/12/2015, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201462088971P| true| 2014-12-08|2014-12-08|

---

US62/088,971|2014-12-08|

---

PCT/US2015/063101|WO2016094117A1|2014-12-08|2015-12-01|3-oxo-3-propanoates, a process for their preparation, and their use in preparing pyrrolidinones|

---