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    • 专利摘要:
    Method for converting 24R epimer of vitamin D precursors into the corresponding 24S isomer and procedure for obtaining calcipotriol. Method for converting a 24R epimer of a vitamin D precursor into the corresponding 24S isomer in which the hydroxyl is esterified at C-24 of the precursor to obtain a precursor esterified at C-24, and the ester is hydrolyzed at C-24 by silica gel, to obtain a mixture of alcohols 24R and 24S. This hydrolysis by silica gel makes it possible to obtain a 1: 1 mixture of alcohols 24R and 24S. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2718417A1
    申请号:ES201731500
    申请日:2017-12-07
    公开日:2019-07-01
    发明作者:Vinas Antonio Buxade；Teruel Antonio Conchillo；Soler Carlos Mola
    申请人:Laboratorios Vinas SA；
    IPC主号:
    专利说明:

    [0001]
    [0002] Field of the Invention
    [0003]
    [0004] Calcipotriol (of formula (I)), or its corresponding monohydrate is an active substance used in the treatment of psoriasis. Its activity depends on the correct configuration of each chiral center.
    [0005]
    [0006]
    [0007]
    [0008]
    [0009] Calcipotriol as well as many of its precursors have a hydroxyl at position 24, being of the S configuration. In the various formation synthesis of this 24S alcohol, large amounts of the corresponding Epimer 24R are produced. This Epimer must be separated (usually by chromatographic methods) and once isolated it is important to have industrial methods to recycle it to the 24S isomer of interest.
    [0010]
    [0011] The industrial process described in this patent is carried out in continuous flow reactors.
    [0012]
    [0013] State of the Art
    [0014]
    [0015] According to the majority of Calcipotriol synthesis methodologies, the last chiral center that is formed is in the C-24 carbon, with the 24S isomer active and the 24R inactive.
    [0016] Two methodologies have been used to obtain intermediate allylic alcohols:
    [0017]
    [0018] 1) Reaction of an alkenyl-iododerivative of formula (II) (5E) with íerf-Butyl-lithium and Cyclopropanoaldehyde (ES 2234423), to give a racemic alcohol (III) (5E) in C-24.
    [0019]
    [0020]
    [0021]
    [0022]
    [0023] The reaction has also been carried out with the alkenyl-iododerivatives of 5Z configuration. In both cases a racemic alcohol is obtained, 24R / 24S: 1/1.
    [0024]
    [0025] 2) Reduction of a carbonyl located in the C-24 carbon. The reduction has been carried out by means of aquiral reducers: Calverley M.J .; Tetrahedron, 43, 20, 4609 (1987) or by chiral reducers: WO 2005/095336 and WO 2005/087719. The reduction also proceeds in 5Z configuration ketones.
    [0026]
    [0027]
    [0028] In the aquiral reduction, Epimer 24R is formed up to 60%. Using various chiral reducers, the Epimer is reduced to 25-30%, but mixtures of the two 24R and 24S isomers are always obtained, requiring a subsequent separation step, which can be by preparative chromatography or by enzymatic resolution (WO 03 / 060094).
    [0029]
    [0030] Once the isomers are separated, the corresponding 24R Epimers are obtained: 5Z (VI) or 5E (VIII), depending on the starting product. If the separation is not very precise (up to 10% of the remaining Epimer) and the processes of desililation and crystallization continue, then we will have the Epimers 24R: 5Z (V) or 5E (Vil) distilled in the crystallization mother liquors, from where they can recover.
    [0031]
    [0032] Then, the most common 24R isomers are the following:
    [0033]
    [0034]
    [0035]
    [0036]
    [0037]
    [0038] The conversion of the Epimers (V), (VI), (VII) and (VIII) into their corresponding 24S isomers is usually carried out by the Mitsunobu inversion reaction, using as reagents: Diethylazadicarboxylate and an acid, obtaining a mixture of esters 24S and 24R with the majority 24S, but in various proportions, depending on the conditions and reagents used. The ester mixture is subsequently hydrolyzed to obtain the mixture of 24S and 24R alcohols. The reaction is going well, but the Diethylazadicarboxylate has several problems when industrializing the process: This reagent is potentially explosive and carcinogenic and so is the reaction product (Diethylcarboxyhydrazine). On the other hand, this inversion reaction is not applicable to compounds (V) and (VII), since the chiral centers would also be reversed in C-1 and C-3, which already have the correct configuration.
    [0039]
    [0040] Another method is the oxidation of Epimer 24R to the corresponding ketone and subsequent reduction to alcohols. This method is also not applicable to compounds (V) and (VII), since the allylic alcohol would be oxidized in C-3 and also the alcohol in C-1 depending on the oxidant. The reduction provides a low amount of 24S isomer, unless chiral catalysts are used, with the disadvantage that chiral catalysts have a high price.
    [0041]
    [0042] Therefore, it is necessary to have a simple procedure to obtain allylic alcohols of 24S configuration, derived from Vitamin D2, which is applicable, both pilot scale, and industrial scale, compared to traditional processes. Said process must allow obtaining 24S allylic alcohols with a high degree of purity and good chemical and optical performance, under industrially viable conditions from their corresponding 24R Epimers.
    [0043] The present invention details said process.
    [0044]
    [0045] Exhibition of the invention
    [0046]
    [0047] The authors of the present invention, during the investigations for scaling the conversion of compounds (V), (VI), (VII) and (VIII) into their 24S isomers, studied the displacement of active esters (mesylates, tosylates, trifluoroacetates, chlorides, etc.) by nucleophiles such as OH-, AcO-, BzCOO-, etc. However, the reaction more important that occurs in this type of reactions is the opening of the cyclopropane ring, with nucleophilic entry or the opening of the ring with dehydration. This had already been observed in similar cases: hydrolysis of trifluoroacetates (WO 91/00855) or opening of cyclopropyl-allyl alcohols by means of Br ions (Synth. Commun., 25, 3351 (1995). Within this context some esters were prepared (acetates, benzoates, etc.), which unlike mesylates, trifluoroacetates, etc. were stable, and could even be purified by silica gel flash chromatography.
    [0048]
    [0049] But surprisingly, it was discovered that chromatography in which it was slowly eluted to obtain a better separation produced a hydrolysis of the ester, obtaining an equimolecular mixture of 24R and 24S alcohols.
    [0050]
    [0051] This result has allowed the development of a simple and cheap method to recycle the 24R Epimers from their esters, obtaining 50% of the 24S isomer. The method is also applicable to distilled compounds, via tri esters, since only the ester of position 24 is hydrolyzed.
    [0052]
    [0053] Thus, the object of the invention is a process for converting a 24R epimer of formula (XVI) or (XVIII) into the corresponding 24S isomer of formula (XVII) or (XIX)
    [0054]
    [0055]
    [0056]
    [0057] R1 and R2, each being a hydroxyl or hydrogen protecting group,
    [0058] characterized by that
    [0059] if R1 and R2 are each a hydroxyl protecting group, the C-24 hydroxyl of the compound of formula (XVI) or (XVIII) is esterified to obtain a compound of formula (X) or (IX), respectively,
    [0060]
    [0061] where R is a chain of 1 to 12 carbon atoms, saturated or unsaturated, unsubstituted or substituted with one or more substituents of the group consisting of alkyls and halogens, or is an aromatic ring or hete roa rom attic,
    [0062]
    [0063] and said C-24 ester is hydrolyzed from the compounds of formula (X) or (IX), wherein said hydrolysis is performed by silica gel, to obtain a mixture of 24R and 24S alcohols of formula (XVI) and (XVII) or ( XVIII) and (XIX), respectively,
    [0064]
    [0065] and, if Ri and R2 are hydrogen, the hydroxyls are esterified in C-1, C-3 and C-24 of the compound of formula (XVI) or (XVIII) to obtain a compound of formula (XII) or (XI), respectively ,
    [0066]
    [0067]
    [0068]
    [0069]
    [0070] where R is a chain of 1 to 12 carbon atoms, saturated or unsaturated, unsubstituted or substituted with one or more substituents of the group consisting of alkyls and halogens, or is an aromatic ring or hete roa rom attic,
    [0071]
    [0072] and said C-24 ester is hydrolyzed from the compounds of formula (XII) or (XI), wherein said hydrolysis is performed by silica gel, to obtain a mixture of 24R and 24S alcohols of formula (XXI) and (XXII) or ( XX) and (XXIII)
    [0073]
    [0074] A subject of the invention is also a process for obtaining calcipotriol, characterized in that the compound of formula (XX), obtained according to the procedure indicated above, is hydrolyzed with methanol and NaOH to obtain calcipotriol.
    [0075]
    [0076]
    [0077]
    [0078]
    [0079] Therefore, the process of reversing the 24R Epimers into 24S Epimers described in this invention is to prepare the corresponding 24R (IX) or (X) monoesters or 24R (XI) or (XII) tri-esters. The crude acylation reaction is preferably purified by eluting on a silica gel column, yielding a 1: 1 mixture of 24R and 24S alcohols.
    [0080]
    [0081]
    [0082] It is particularly advantageous that the elution in the silica gel column is slow, preferably with a residence time greater than or equal to 4 hours. In this way, the hydrolysis of the ester in C-24 and the separation of the mixture of the alcohols 24R and 24S obtained, which is preferably carried out by chromatography, are simultaneously achieved.
    [0083]
    [0084] Preferably the esters are synthesized in a microreactor, and most preferably they are continuously hydrolyzed in a column connected to the microreactor.
    [0085]
    [0086] Brief description of the drawings
    [0087]
    [0088] Fig. 1, a scheme of a continuous microreactor.
    [0089]
    [0090] Detailed description of embodiments of the invention
    [0091]
    [0092] 1) Description of the acylation reaction
    [0093]
    [0094] The acylation process refers to the conversion of the Epimeric alcohols 24R (V), (VI), (VII), (VIII), (XXIV) and (XXVI) into the Epimeric esters 24R (IX), (X), (XI), (XII), (XXV) and (XXVII), by the usual acylation reactions, according to the following scheme:
    [0095]
    [0096] Episers Cis (5Z):
    [0097]
    [0098] where COR represents the acyl group of the ester, and representing Ri and R2 or H or a hydroxyl protecting group, such as silyl ethers such as fe / f-Butyldimethylsilyl, Texyl and te / f-Butyldiphenylsilyl.
    [0099] Trans epimers (5E):
    [0100]
    [0101]
    [0102]
    [0103] where COR represents the acyl group of the ester, and R1 and R2 represent either H or a hydroxyl protecting group, such as silyl ethers such as ferf-Butyldimethylsilyl, Texyl and the butyl-Butyldiphenylsilyl.
    [0104]
    [0105] In general, R is a chain of 1 to 12 carbon atoms, saturated or unsaturated, unsubstituted or substituted with one or more substituents of the group consisting of alkyls and halogens, or is an aromatic or heteroaromatic ring, although preferably R is CH3 , CH2CH3, CH- (CH3) 2, C- (CH3) 3 or C6H5, and most preferably R is CH3.
    [0106]
    [0107] On the other hand, advantageously R1 and R2 are hydrogen. Alternatively, R1 and R2 are a hydroxyl protecting group. In the latter case, a preferred alternative is that they are each a silyl group and, in particular, that they are each a tert-Butyldimethylsilyl group. However, another preferred alternative is that the hydroxyl protecting group is an acyl group, in particular CO-CH3, CO-CH2CH3, CO-CH- (CH3) 2, CO-C- (CH 3 ) 3 or CO- C 6 H 5 , and most preferably R is CO-CH 3 . Indeed, as will be seen below, in the case of hydrolyzing the compounds triesterified by silica gel, only the C-24 ester is hydrolyzed. This means that the result of the hydrolysis will be a mixture of 24R and 24S alcohols, but that they will have C-1 and C-3 esters. For the therefore, once the alcohols 24R are separated from the alcohols 24S, the alcohols 24R (having two esters in C-1 and C-3) can be subjected again to the process according to the invention.
    [0108]
    [0109] Any of the acylation reactions known to a person skilled in the art is useful for obtaining the esters. However, as a simple and economical industrial process is desired, acylation reactions using the anhydride or the acid chloride and a base are preferred. Pyridine is usually used as a base, but since it is toxic it is preferred to replace it with Imidazole, Methyl-Imidazole, Triazole, etc.
    [0110]
    [0111] Acetic anhydride, Propionic anhydride, Isobutyric or benzoic anhydride are preferred as anhydrides and as acid chlorides are Acetyl chloride, Propionyl chloride, Pivaloyl chloride, Benzoyl chloride and Phenylacetyl chloride. Of all of them, due to its availability and low price, acetic anhydride is mainly preferred.
    [0112]
    [0113] 2) Description of obtaining the mixture of alcohols 24R and 24S
    [0114]
    [0115] From cis esters (5Z)
    [0116]
    [0117]
    [0118]
    [0119] From trans esters (5E):
    [0120]
    [0121] where the acyl group represents COR ester (for example R being CH3, C6H5, etc.), and R1 and R2 representing silyl ethers such as te / t-butyldimethylsilyl, the thexyl and tert- butyldiphenylsilyl. Of these, te / t-Butyldimethylsilyl is preferred.
    [0122]
    [0123] The crude from obtaining the esters is dissolved in Hexane / EBM: 2/1 and eluted through a column packed with silica gel. Once the whole solution of the raw esters has been introduced, it is continued eluting with Hexane / EBM: 2/1. The elution rate will be such that the alcohols obtained take at least 4 hours to elute. First elute the 24R isomer and then the 24S isomer. The column is regenerated by eluting with EBM and then conditioned with Hexane / EBM: 2/1, and another elution process can be initiated.
    [0124]
    [0125] For an ester solution obtained from 500 grams of Epimer 24R it is convenient to use a steel column of at least 25 cm x 130 cm, eluting at a rate of the order of 10 liters / hour, in this way they can be obtained 230 g of 24R isomer and 235 g of 24S isomer in about 10 hours.
    [0126]
    [0127] For one skilled in the art, it is clear that the column can have various shapes and sizes, with columns long enough to allow slow elution.
    [0128]
    [0129] Silicagel of various microns can be used: from 5 to 200 microns, the silica gel of 35-70 microns being preferable.
    [0130]
    [0131] As eluents various proportions of Hexane / EBM (from 1/1 to 10/1) can be used, with 2/1 to 4/1 being preferable. Hexane can be substituted by other hydrocarbons such as Heptane, Cyclohexane, Iso-Octane. EBM can also be substituted by other ethers such as Tetrahydrofuran, Dioxane, etc. or esters such as ethyl acetate, t-butyl acetate, etc.
    [0132]
    [0133] Continuous reaction
    [0134]
    [0135] The synthesis of esters (X), (XII), (XIII) and (XIV) can be carried out in a conventional batch reactor, but it is advantageous to perform it in a continuous microreactor, the The outlet of which is connected to a column packed with silica gel, where the inversion and hydrolysis of the esters previously formed in the microreactor takes place.
    [0136]
    [0137] Description of the microreactor:
    [0138]
    [0139] The microreactor used for unprotections consists of the following elements (Fig. 1):
    [0140]
    [0141] - A 1 Teflon spiral 1 mm to 2 mm internal diameter and 100 meters long. - A preparative HPLC 2 pump (for example: Prep Star Varian preparatory equipment), where the HPLC column has been replaced by Teflon spiral 1.
    [0142] - A 3 peristaltic pump type Masterflex, also attached to spiral 1 Teflon.
    [0143] - The union of the tubes that leave the respective pumps 2, 3 is carried out in a T-tube, which also serves as a mixer, from which from the third outlet another tube comes out that connects with the spiral 1.
    [0144] - Teflon spiral 1, which forms the microreactor, is in a thermostatic bath (to heat the reaction) and its end connected to an additional 4 meters of Teflon tube, submerged in another thermostatic bath (to cool the reaction solution ) and the outlet is connected to a collection reactor. But it is much more convenient to connect the outlet with a column 4 filled with silica gel, where the inversion and hydrolysis of the esters formed in the microreactor will occur.
    [0145] - The peristaltic pump 3 is connected with a Teflon tube to a container 5 containing the reagents (anhydrides or acid chlorides) dissolved in Dichloromethane, EBM or Acetonitrile.
    [0146] - In the configuration described herein, use the preparative HPLC system, the product (Epimer 24R) and the bases are introduced into the system, by means of the injector 6, previously dissolved in Dichloromethane, EBM or Acetonitrile and filtered by 0 , 45 microns.
    [0147]
    [0148] As a column, different types of columns can be used, such as those described above that can be connected to the Teflon spiral. Long columns are preferable, for better hydrolysis. Good results have been obtained with glass columns of sizes 40x10 and 40x7 cm, filled with silica gel from 30 to 70 p.
    [0149] 4 Obtaining the 24R Epimers.
    [0150]
    [0151] The various 24R Epimers are known compounds and have been prepared according to procedures described in the literature:
    [0152]
    [0153] The 24R Epimers of the trans (5E) configuration are obtained by chromatographic separation of the reduction ketones of the trans (IV) ketone (Calverley MJ; Tetrahedron, 43, 20, 4609 (1987)) or of the reaction crude between Iodo-derived trans (II) and cyclopropanealdehyde (ES P200302875).
    [0154]
    [0155] Obtaining the 24R epimers of cis (5Z) configuration is made from the reduction ketones of the cis ketone or the crude of the reaction between the iododerivative cis and cyclopropanoaldehyde, separating the 24R and 24S isomers by preparative chromatography. It can also be obtained by photoisomerizing the mixture of trans alcohols and then separating or photoisomerizing the trans 24R Epimer (WO 2007/082533.
    [0156]
    [0157] The 24R, cis or trans Epimers, where R1 = R2 = H, are obtained by preparative chromatography of the mother liquors from the crystallization of Calcipotriol (I).
    [0158]
    [0159] The final 24S isomers are also known compounds (Calverley M.J .; Tetrahedron, 43, 20, 4609 (1987)).
    [0160]
    [0161] Below are some illustrative examples of this invention, which are the object of this patent, but are not limited thereto.
    [0162]
    [0163] Experimental
    [0164]
    [0165] General data:
    [0166]
    [0167] Nuclear Magnetic Resonance (NMR, 5) spectra have been performed at 300 MHz in CDCl3 solution, using internal standard TMS or CHCl3. Coupling constants J are given in Hertz: s = singlet; d = double; t = triplet; dd = double double; AB = AB system; m = multiplet, sc = complex signal and ba = broadband or sum of several signals.
    [0168]
    [0169] Thin layer chromatography (TLC) was performed with Merck Silicagel 60 F254 plates
    [0170]
    [0171] Flash preparative chromatography has been performed with Silicagel of 60 A ° and 35 - 70 p and at a pressure of 1.5 - 3 atmospheres, using steel columns of 26.9x136 cm or, for smaller quantities of product, glass columns of 12x110 cm and at a pressure of 0.75-1 atmospheres.
    [0172] One of these columns has been used for the hydrolysis of tri-esters or monoesters, connected to a Varian PreStar preparatory equipment with a flow rate of 800 ml and a maximum pressure of 2500 psies.
    [0173]
    [0174] For the reversal of the epimers in continuous, the used microreactor has the configuration set forth above. A teflon spiral of 100 meters in length and 2 mm internal diameter has been used.
    [0175]
    [0176] The column that has been connected to the exit of the spiral, has been a 10x40 cm Buchi column, filled with 20-45 micron silicagel.
    [0177]
    [0178] To boost the solutions with the Epimer, a Knauer Wellchrom pump, with a 250 ml / minute maximum flow and 1500 psi pressure, has been used.
    [0179]
    [0180] To boost the reagent solution, a Masterflex peristaltic pump has been used, with a Teflon tube with a maximum flow rate of 60 ml / minute and 100 psi pressure.
    [0181]
    [0182] EBM means: f-Butyl methyl ether.
    [0183]
    [0184] TBDMS means: f-Butyldimethylsilyl.
    [0185]
    [0186] DCM means Dichloromethane
    [0187] Preparation of Acetate of 20 (R), 1 (S), (3 (R) -Bis (fert-butyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl-3'-hydroxypropyl-1' (E) - enil) -1 (S) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -trieno
    [0188]
    [0189] 320 g (0.5 mol) of 20 (R), 1 (S), (3 (R) -Bis (fe / f-butyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl are placed in a reactor -3'-hydroxypropy-1 '(E) -enyl) -1 (S) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene, 68 g (1 mol) of Imidazole and 5 liters of Methylene Chloride It is heated to 45 ° C and then 61.2 g (0.6 mol) of Acetic Anhydride dissolved in 2 liters of Methylene Chloride are slowly added, heated for one hour.
    [0190]
    [0191] After this time, it is cooled and distributed between 10 liters of Hexane and 5 liters of Water. The organic phase is washed with 2x5 liters of brine, dried with sodium sulfate and concentrated in vacuo. The oily residue is dissolved in Hexane / EBM: 2/1 and purified by flash chromatography, eluting with the previous mixture. Thus 327 g of a white solid are obtained.
    [0192]
    [0193] 1 H NMR / CDCh):
    [0194] 0.060 (s, 12H (CH 3 -Si)), 0.54 (s, 3H (C-18)), 0.85 and 0.88 (2s, 18H, ((CH 3 ) 3 C)), 1 , 01 (d, J: 6.6 Hz, 3H (C-21)), 2.04 (COCH 3 ), 4.20 (m, 1H (C-3)), 4.50 and 4.53 ( dd, 1H (C-1)), 4.69 (dd, 1H (C-20), 4.94 (d, 1H, J = 13.5 Hz (C-19)), 5.28-5, 60 (AMX, J = 15 Hz, 2H, (C-23 / C-24), 6.00 (d, J = 11.4 Hz, 1H (C-7)), 6.23 (d, J = 11.4 Hz, 1H (C-6)) ppm.
    [0195]
    [0196] 20 (R), 1 (S), (3 (R) -Bis (fert-butyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl-3'-hydroxypropy-1' (E) -enyl) benzoate -1 (S) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -trieno
    [0197]
    [0198] Substituting acetic anhydride for benzoic anhydride gives the corresponding benzoate.
    [0199]
    [0200] 1 H NMR / CDCl3):
    [0201] 0.060 and 0.070 (s, 12H (CH 3 -SO), 0.53 (s, 3H (C-18)), 0.87 and 0.89 (2s, 18H, ((CH 3 ) 3 C)), 1.04 (d, J = 9.9 Hz, 3H (C-21)), 4.18 (m, 1H (C-3)), 4.37 (sc, 1H (C-1)), 4.975 (dd, J = 10 Hz, 1H (C-20)), 4.845 (d, J = 3 Hz, 1H (C-19)), 5.17 (d, J = 3 Hz, 1H (C-19) ), 5.40-5.75 (AMX, J = 23 Hz, 2H, (C-23 / C-24), 6.00 (d, J = 16 Hz, 1H (C-7)), 6, 23 (d, J: 17 Hz, 1H, (C-6)), 7.045-7.60 (m, 1H, p-Ar-H), 7.46 (d, J = 11.4 Hz, 2H, (m-AR-H), 8.06 (d, J = 11.4 Hz, 2H, (o-AR-H) ppm.
    [0202] Acetate of 20 (R), 1 (S), (3 (R) -Bis (fert-butyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl-3'-hydroxypropyl-1' (E) -enil) -1 (S) -9,10-secopregna-5 (E), 7 (E), 10 (19) -trieno
    [0203]
    [0204] In a reactor 64 g (0.1 moles) of 20 (R), 1 (S), (3 (R) -Bis (fe / f-butyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl are placed -3'-hydroxypropy-1 '(E) -enyl) -1 (S) -9,10-secopregna-5 (E), 7 (E), 10 (19) -triene, 17 g (0.25 mol ) of Imidazole and 1 liter of Methylene Chloride, heated to 45 ° C and then 20.4 g (0.2 mol) of Acetyl Chloride dissolved in 0.5 liters of Methylene Chloride are slowly added. 30 minutes.
    [0205]
    [0206] After this time, it cools and distributes between 3 liters of Hexane and 3 liters of Water. The organic phase is washed with 2x3 liters of brine and 3 liters of 5% sodium bicarbonate solution, dried with sodium sulfate and concentrated in vacuo. The oily residue is dissolved in Hexane / EBM: 2/1 and purified by flash chromatography, eluting with the previous mixture. Concentrating the fractions gives a residue that is triturated with Acetonitrile, the white solid is filtered and dried, yielding 62.4 g.
    [0207]
    [0208] 1 H NMR / CDCh):
    [0209] 0.044 (s, 12H (CH 3 -Si)), 0.53 (s, 3H (C-18)), 0.875 and 0.895 (2s, 18H, ((CH 3 ) 3 C)), 1.03 (d , J: 6.6 Hz, 3H (C-21)), 2.06 (COCH 3 ), 4.18 (m, 1H (C-3)), 4,355 and 4,375 (dd, J = 3 Hz, 1H (C-1)), 4.69 (dd, J = 7.5 Hz, 1H (C-20), 4.85 (d, 1H, J = 3 Hz (C-19)), (4.94 (d, 1H, J = 3 Hz (C-19)), 5.28-5.60 (AMX, J = 15 Hz, 2H, (C-23 / C-24), 5.80 (d, J : 11.4 Hz, 1H (C-7)), 6.43 (d, J: 11.4 Hz, 1H (C-6)) ppm.
    [0210]
    [0211] Isobutylate of 20 (R), 1 (S), (3 (R) -Bis (fert-butyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl-3'-hydroxypropyl-1' (E) -enyl) -1 (S) -9,10-secopregna-5 (E), 7 (E), 10 (19) -trieno
    [0212]
    [0213] Substituting the Acetyl Chloride for Isobutyl Chloride gives the corresponding isobutylate in the form of a yellowish oil.
    [0214]
    [0215] 1 H NMR / CDCl3):
    [0216] 0.044 (s, 12H (CH 3 -SO), 0.53 (s, 3H (C-18)), 0.85 and 0.88 (s, 18H, ((CH 3 ) 3 C)), 1, 01 (d, J: 6.6 Hz, 3H (C-21)), 1,135 and 1,155 (dd, 6H, J = 3 Hz (CH 3 ) 2 C)), 4.20 (m, 1H (C- 3)), 4.51 (sc, 1H (C-1)), 4.67 and 4.69 (dd, J = 7 Hz, 1H (C-20), 4.94 (d, J = 13, 5 Hz, 2H (C-19)), 5.31-5.59 (AMX, J = 15 Hz, 2H, (C-23 / C-24), 5.80 (d, J: 11.7 Hz , 1H (C-7)), 6.44 (d, J: 11.7 Hz, 1H (C-6)) ppm.
    [0217] 20 (R), 1 (S), (3 (R) -Bis (fert-butyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl-3'-hydroxypropy-1' (E) -enyl) pivalate -1 (S) -9,10-secopregna-5 (E), 7 (E), 10 (19) -trieno
    [0218]
    [0219] Substituting Acetyl Chloride for Pivaloyl Chloride gives the corresponding pivalate in the form of a yellowish oil.
    [0220]
    [0221] 1H NMR / CDCh):
    [0222] 0.044 (s, 12H (CH3-Si)), 0.52 (s, 3H (C-18)), 0.84 and 0.87 (s, 18H, ((CH ^ C)), 1.01 ( d, J: 6.6 Hz, 3H (C-21)), 1.17 (s, 9H, J = 3 (CH3) 3C)), 4.20 (m, 1H (C-3)), 4 , 50 and 4.54 (sc, 1H (C-1)), 4.68 and 4.73 (dd, J = 7 Hz, 1H (C-20), 4.94 (d, J = 13.5 Hz, 2H (C-19)), 5.31-5.58 (AMX, J = 15 Hz, 2H, (C-23 / C-24), 5.80 (d, J: 11.7 Hz, 1H (C-7)), 6.44 (d, J: 11.7 Hz, 1H (C-6)) ppm.
    [0223]
    [0224] Preparation of Tri-Acetate 20 (R) - (3 '- (R) -Cyclopropyl-3'-hydroxypropyl-1' (E) -enyl) -1 (S), 3 (R) -dihydroxy-9,10 -secopregna-5 (Z), 7 (E), 10 (19) -trieno
    [0225]
    [0226] In a reactor 64.0 g (0.1 mol) of 20 (R) - (3 '- (R) -Cyclopropyl-3'-hydroxypropy-1' (E) -enyl) -1 (S) are placed, 3 (R) -dihydroxy-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene, 68 g (1 mol) of Imidazole and 3 liters of Methylene Chloride. It is heated to 45 ° C and then 35.7 g (0.35 mol) of Acetic Anhydride dissolved in 1 liter of Methylene Chloride are slowly added. It heats for an hour.
    [0227]
    [0228] After this time, it is cooled and distributed between 6 liters of Hexane and 6 liters of Water. The organic phase is washed with 2x5 liters of brine, dried with sodium sulfate and concentrated in vacuo. The oily residue is dissolved in Hexane / EBM: 2/1 and purified by flash chromatography, eluting with the previous mixture. Thus 66 g of a white solid are obtained.
    [0229]
    [0230] 1H NMR / CDCh):
    [0231] 0.53 (s, 3H (C-18)), 1.03 (d, J = 6.6 Hz, 3H (C-21)), 2.03, 2.05, and 2.06 (COCH3) , 4.19 (m, 1H (C-3)), 4.69 (dd, J = 7 Hz, 1H (C-20), 5.18 (m, 1H (C-3)), 5.035 (d , J = 1.8 Hz, 2H (C-19)), 5.30 (d, J = 1.8 Hz, 1H (C-19)), 5.31-5.58 (AMX, J = 15 Hz, 2H, (C-23 / C-24)), 5.47 (m, 1H (C-1)), 5.91 (d, J = 11.4 Hz, 1H (C-7)), 6.35 (d, J = 11.4 Hz, 1H (C-6)) ppm.
    [0232] Tris-Acetate of 20 (R) - (3 '- (R) -Cyclopropyl-3'-hydroxypropyl-1' (E) -enyl) -l (S), 3 (R) -dihydroxy-9,10-secopregna -5 (E), 7 (E), 10 (19) -triene
    [0233]
    [0234] Starting from 20 (R) - (3 '- (R) -Cyclopropyl-3'-hydroxypropy-1' (E) -enyl) -l (S), 3 (R) -dihydroxy-9,10-secopregna-5 (E), 7 (E), 10 (19) -thrien, the corresponding triester is obtained.
    [0235]
    [0236] 1 H NMR / CDCl3):
    [0237] 0.53 (s, 3H (C-18)), 1.03 (d, J = 6.6 Hz, 3H (C-21)), 2.03, 2.05, and 2.06 (COCH 3 ), 4.19 (m, 1H (C-3)), 4.69 (dd, J = 7 Hz, 1H (C-20), 5.18 (m, 1H (C-3)), 5.035 ( d, J = 1.8 Hz, 2H (C-19)), 5.30 (d, J = 1.8 Hz, 1H (C-19)), 5.31-5.58 (AMX, J = 15 Hz, 2H, (C-23 / C-24)), 5.47 (m, 1H (C-1)), 5.77 (d, J = 11.4 Hz, 1H (C-7)) , 6.35 (d, J = 11.4 Hz, 1H (C-6)) ppm.
    [0238]
    [0239] 20 (R), 1 (S), (3 (R) -Bis (fert-butyldimethylsilyloxy) -20- (3 '- (S) -Cyclopropyl-3'-hydroxypropy-1' (E) -enyl) -1 (S) -9,10-secopregna-5 (E), 7 (E), 10 (19) -trieno
    [0240]
    [0241] 250 grams of Acetate of 20 (R), 1 (S), (3 (R) -Bis (terf-butyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl-3'-hydroxypropy-1' (E) -enil) -1 (S) -9,10-secopregna-5 (E), 7 (E), 10 (19) -triene are dissolved in 5 liters of Hexane / EBM: 2/1 and eluted through a 26.9x136 cm steel column at 250 ml / min After 4-5 hours it elutes a small fraction of unhydrolyzed esters and decomposition products and then elutes the hydrolyzed alcohols, mixture of 24R and 24S isomers.
    [0242]
    [0243] Fractions containing mostly the 24S isomer are collected separately from those containing mostly the 24R isomer. Both fractions are purified by preparative chromatography, eluting with Hexane / EBM: 100/15. 110 grams of 20 (R), 1 (S), (3 (R) -Bis (terf-butyldimethylsilyloxy) -20- (3 '- (S) -Cyclopropyl-3'-hydroxypropy-1' (E) are obtained -enil) -1 (S) -9,10-secopregna-5 (E), 7 (E), 10 (19) -trieno and 106.5 grams of 20 (R), 1 (S), (3 ( R) -Bis (terfbutyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl-3'-hydroxypropy-1' (E) -enyl) -1 (S) -9,10-secopregna-5 (E), 7 (E), 10 (19) -thorn.
    [0244] 20 (R), 1 (S), (3 (R) -Bis (fert-butyldimethylsilyloxy) -20- (3 '- (S) -Cyclopropyl-3'-hydroxypropy-1' (E) -enyl) -1 (S) -9,10-secopregna-5 (Zl, 7 (E), 10 (19) -trieno
    [0245]
    [0246] 25 grams of Benzoate 20 (R), 1 (S), (3 (R) -Bis (te / f-butyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl-3'-hydroxypropy-1' ( E) -enil) -1 (S) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene are dissolved in 1 liter of Hexane / EBM 2: 1 and eluted through from a glass column of 40x100 cm at 25 ml / min, after 5-6 hours, it elutes a small fraction of unhydrolyzed esters and decomposition products and subsequently elutes the fractions containing the hydrolyzed alcohols, mixture of 24R and 24S isomers.
    [0247]
    [0248] Fractions containing mostly the 24S isomer are collected separately from those containing mostly the 24R isomer. Both fractions are purified by preparative chromatography, eluting with Hexane / EBM: 100/15. Thus 10.8 grams of 20 (R), 1 (S), (3 (R) -Bis (te / f-butyldimethylsilyloxy) -20- (3 '- (S) -Cyclopropyl-3'-hydroxypropy- 1 '(E) -enil) -1 (S) -9,10-secopregna-5 (E), 7 (E), 10 (19) -trieno and 10.6 grams of 20 (R), 1 (S ), (3 (R) -Bis (te / f-butyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl-3'-hydroxypropy-1' (E) -enyl) -1 (S) -9, 10-secopregna-5 (E), 7 (E), 10 (19) -trieno.
    [0249]
    [0250] Continuous reaction (Microreactor)
    [0251]
    [0252] 20 (R) - (3 '- (S) -Cyclopropyl-3'-hydroxypropy-1' (E) -enyl) -1 (S), 3 (R) -dihydroxy-9,10-secopregna -5 (Z ) 7 (E), 10 (19) -triene (Calcipotriol)
    [0253]
    [0254] In the 1-liter flask (a) of the HPLC pump and under N2 atmosphere (Figure 1), 50 g (0.12 mol) of 20 (R) - (3 '- (R) -Cyclopropyl-3 are placed '-hydroxypropy-1' (E) -enyl) -1 (S), 3 (R) -dihydroxy-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene, 41, 4 grams (0.6 moles) of triazole, 1 liter of EBM and 0.5 liters of Acetonitrile. In the flask (b) of the peristaltic pump (Figure 1), 40.8 grams (0.4 moles) of acetic anhydride dissolved in 1 liter of EBM are placed.
    [0255]
    [0256] Using the microreactor described above, the solutions are aspirated at a rate of 50 ml / min (3000 ml / h). The solutions when they leave the mixer are circulated through a spiral steel 100 meters long and 2 mm internal diameter, which is in a thermostated bath at 45 ° C. The microreactor outlet is connected to a 40x100 column, packed with a 35-40 micron silica gelgel.
    [0257] After approximately 4-5 hours, the entire solution will have circulated, eluting the products at the end of the column. Finally, the flask, microreactor and column assembly is washed with EBM. The solution that leaves the column is collected in successive 1 liter flasks.
    [0258]
    [0259] The fractions containing mostly the diacetylated 24S isomer are combined and concentrated to dryness. The resulting crude is dissolved in 1 liter of Methanol, 20 grams of NaOH are added and heated to 50 ° C. After 1 hour of hydrolysis, it is concentrated until a paste is formed. It is divided between EBM and saturated sodium bicarbonate solution. The ethereal solution is dried with sodium sulfate, filtered and concentrated to dryness.
    [0260]
    [0261] The crude obtained is purified by preparative chromatography, eluting with Hexane / EBM / MeOH: 50/50/1, obtaining 21 grams of pure 24S isomer and 2 grams of pure 24R isomer.
    [0262]
    [0263] The fractions containing mostly the diacetylated 24R isomer are combined and concentrated to dryness, 22.5 g are obtained which can be used in a new process in a new inversion process or purified under the same conditions as the 24S isomer.
    权利要求:
    Claims (1)
    [0001]
    Claims
    1 - Procedure to convert a 24R epimer of formula (XVI) or (XVIII) into the corresponding 24S isomer of formula (XVII) or (XIX)

    R1 and R2, each being a hydroxyl or hydrogen protecting group,
    characterized by that
    if R and R2 are each a hydroxyl protecting group, the C-24 hydroxyl of the compound of formula (XVI) or (XVIII) is esterified to obtain a compound of formula (X) or (IX), respectively,

    (X) (IX)
    where R is a chain of 1 to 12 carbon atoms, saturated or unsaturated, unsubstituted or substituted with one or more substituents of the group consisting of alkyls and halogens, or is an aromatic ring or hete roa rom attic,
    and said C-24 ester is hydrolyzed from the compounds of formula (X) or (IX), wherein said hydrolysis is performed by silica gel, to obtain a mixture of 24R and 24S alcohols of formula (XVI) and (XVII) or ( XVIII) and (XIX), respectively,
    and, if Ri and R2 are hydrogen, the hydroxyls are esterified in C-1, C-3 and C-24 of the compound of formula (XVI) or (XVIII) to obtain a compound of formula (XII) or (XI), respectively ,

    where R is a chain of 1 to 12 carbon atoms, saturated or unsaturated, unsubstituted or substituted with one or more substituents of the group consisting of alkyls and halogens, or is an aromatic or heteroaromatic ring,
    and said ester is hydrolyzed in C-24 of the compounds of formula (XII) or (XI), wherein said hydrolysis is performed by silica gel, to obtain a mixture of alcohols 24R and 24S of formula (XXI) and (XXII) or ( XX) and (XXIII).

    29
    2 - Method according to claim 1, characterized in that R1 and R2 are each a silyl group.
    3 - Process according to claim 2, characterized in that R1 and R2 are each a tert-Butyldimethylsilyl group.
    4 - Method according to claim 1, characterized in that R1 and R2 are each an acyl group.
    5 - Method according to claim 1, characterized in that R1 and R2 are hydrogen.
    6 - Method according to any one of claims 1 to 5, characterized in that R is CH 3 , CH 2 CH 3 , CH- (CH3) 2, C- (CH3) 3 or C 6 H 5 .
    7 - Method according to claim 6, characterized in that R is CH3.
    8 - Method according to any one of claims 1 to 7, characterized in that said C-24 ester is hydrolyzed by elution on a silica gel column.
    9 - Method according to claim 8, characterized in that said elution has a residence time greater than or equal to 4 hours.
    Method according to any one of claims 1 to 9, characterized in that said compound of formula (X), (IX), (XII) or (XI) is synthesized in a microreactor.
    11 - Method according to claim 10, characterized in that said compound of formula (X), (IX), (XII) or (XI) is synthesized in a microreactor and continuously hydrolyzed in a column connected to the microreactor.
    12 - Method according to any of claims 1 to 11, characterized in that the alcohols 24R and 24S obtained are separated by chromatography.
    13 - Procedure for obtaining calcipotriol, characterized in that the compound of formula (XX), obtained according to any of claims 1 to 12 is hydrolyzed with methanol and NaOH to obtain calcipotriol.
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    同族专利:
    公开号 | 公开日
    FR3074635A3|2019-06-14|
    ES2718417B2|2019-10-31|
    FR3074635B3|2020-01-03|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CN101738447A|2008-11-05|2010-06-16|重庆华邦制药股份有限公司|Method for determining content of compound by utilizing relative correction factor|
    ES2411834A1|2011-12-30|2013-07-08|Laboratorios Viñas S.A.|Industrial process to obtain intermediates suitable for the synthesis of vitamin d analogues |
    CN105717206A|2016-01-27|2016-06-29|重庆华邦制药有限公司|Method for separating and determining calcipotriol intermediate F and impurities thereof|
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