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    • 专利摘要:
    Procedure for the enantiomeric conversion of calcipotriol intermediates and corresponding use. Procedure to convert a 24R, 5E epimer of general formula (IV) into the corresponding 24S, 5E isomer of general formula (VI): {IMAGE-01} or to convert a 24R, 5Z epimer of general structure (V) into the corresponding 24S, 5Z isomer of general formula (VII): {IMAGE-02} where R1 and R2, each one being a hydroxyl protecting group, where esterifies the hydroxy at C-24 of said epimer 24R, 5E or 5Z by means of an acid in the presence of an azacarboxylate and a phosphine, the hydrolyzed mixture of inverted and non-inverted esters obtained is subsequently hydrolyzed, obtaining a mixture of inverted and non-inverted alcohols, of formulas (IV) and (VI) or of formulas (V) and (VII) respectively, and the compound of formula (VI) or (VII) is subsequently separated. The procedure can be used to obtain Calcipotriol. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2769952A1
    申请号:ES201831299
    申请日:2018-12-28
    公开日:2020-06-29
    发明作者:Vinas Antonio Buxade；Teruel Antonio Conchillo；Soler Carles Mola
    申请人:Laboratorios Vinas SA；
    IPC主号:
    专利说明:

    [0002] PROCEDURE FOR THE INTERMEDIATE ENANTIOMERIC CONVERSION
    [0004] Field of the Invention
    [0006] Calcipotriol (I), or its corresponding monohydrate, is an active ingredient that is currently used in the treatment of psoriasis. Its activity depends on the correct configuration of each chiral center.
    [0011] Calcipotriol (I)
    [0013] In the synthesis of Calcipotriol from Vitamin D2 two new chiral centers are introduced in positions 3 and 24 by formation of the corresponding alcohols. The syntheses of said alcohols are not enantiomerically pure, mixtures of the two possible epimers being formed. Once these mixtures have been separated, it is important to have industrial methods to recycle the incorrectly configured isomer.
    [0014] State of the Art
    [0016] The introduction of the hydroxyl (OH) group in position 3 of Vitamin D2 is carried out by reaction of SeO2 and N-Methyl-Morpholine Oxide (NMO) with trans-Vitamin D2 (R1 = H or tert-Butildimethylsilyl), forming the two epimers a (II) and p (III), in the ratio of 6 to 1. The mixture can be separated chromatographically or by crystallization, once the mixture has been silylated. The isomer of interest is the epimer a (II).
    [0021] C-1: a-OH, C-3: OSi-t-BDM (II) C-1: (3-OH, C-3: OSi-t-BDM (III)
    [0023] To recover the p (III) isomer, the hydrolysis of the hydroxyl acetates or benzoates in C-1 was studied under the conditions described in Spanish Patent Application No. P201731500. But unlike the hydroxyl esters at C-24, the esters at C-1 are much more stable, giving low yields in the hydrolysis with SiO 2 , this methodology being of little use in this case.
    [0025] As an alternative, the investment was proposed through the use of Diethyl Azadicarboxylate / Tributylphosphine and an acid (Acetic Acid and Benzoic Acid). Acetylation only occurred in 20% (80% of unreacted starting product), but with Benzoic acid, the reaction was practically 100%, obtaining a mixture of Benzoates, This hydrolyzed mixture with NaOH / MeOH yielded the product (II) in 30% (5% of non-inverted p isomer and 55% of an allylic rearrangement isomer). However, these results do not make viable a commercial use of the p-isomer with this technique of inversion of the hydroxyl group (OH) in C-1.
    [0027] However, the good isomer a / p: 6/1 isomer ratio has led to investigation of the inversion of the hydroxyl (OH) group in C-24 using the prior art.
    [0029] The most common 24R isomers are as follows:
    [0034] The usual methods to invert the OH configuration in C-24 are:
    [0036] Oxidation with active MnO2 and subsequent reduction of the ketone obtained (WO 87/00834). The proportion of C-24S isomer depends on whether the reaction is chiral or not. With NaBH 4 / CeCl3 only 40% of 24S isomer is obtained. This isomer can reach 70-75% using chiral catalysts, but the main problem is the use of active MnO 2 , a solid that is used in excess, which does not allow its use in a continuous reactor or in microreactors. Non-chiral reduction it gives low yields of the 24S isomer, while the use of chiral catalysts makes the process much more expensive. On the other hand, another drawback is that a certain amount of C22-C23 saturated ketone is produced during reduction. Chiral reductions have also been carried out with Borano, but the trienic system must be protected with SO2 to avoid the addition of Borano to the double bonds; subsequently, SO2 must be removed to obtain the free alcohols.
    [0038] Hydrolysis of various esters of 24R alcohol with SiO2 (Spanish Patent Application No. P201731500), is a simple system, but only gives a 1/1 mixture of 24R / 24S alcohols, together with small amounts of by-products resulting from ring opening cyclopentane or alcohol dehydration.
    [0040] Therefore, it would be interesting to have a procedure with high yields: optical and chemical, for the recovery of isomers derived from Vitamin D2 and which, in turn, is applicable both on a pilot scale and on an industrial scale.
    [0042] The present invention describes and details a procedure for carrying out this recovery of isomers.
    [0043] Disclosure of the present invention
    [0045] The present invention describes and details a new procedure for converting a 24R, 5E epimer of general formula (IV) to the corresponding 24S, 5E isomer of general formula (VI):
    [0050] or to convert a 24R, 5Z epimer of general structure (V) to the corresponding 24S, 5Z isomer of general formula (VII):
    [0056] Ri and R2 each being a hydroxyl protecting group. In the new procedure, the hydroxyl in C-24 of the epimer 24R, 5E or 5Z is esterified by means of an acid in the presence of an azacarboxylate and a phosphine, subsequently the mixture of invert and non-invert esters obtained is hydrolyzed, obtaining a mixture of invert alcohols and not inverted, of formulas (IV) and (VI) or of formulas (V) and (VII) respectively, and subsequently the compound of formula (VI) or (VII) is separated. From this mixture the desired isomer is obtained, preferably by chromatography.
    [0058] For industrial production, it was thought to use a microreactor and work continuously in order to minimize the explosive character of the Dietilazadicarboxilato (DEAD). It was also tested by replacing Diethylazadicarboxylate with Diisoproilazadicarboxylate (DIAD), which is more stable. Finally, the Triphenylphosphine that was initially used was replaced by Tributylphosphine to prevent Triphenylphosphine oxide (reaction by-product) from precipitating inside the microreactor, since Tributylphosphine oxide is much more soluble.
    [0060] Initially, the authors of the present invention investigated the inversion of alcohol (IV), using acetic or benzoic acids. Hydrolysis of the ester mixture gave a ratio of 24S / 24R alcohol: 1 -1.2 / 1 using Acetic and 1 -1.4 / 1 using Benzoic. The chemical yield was 85-90% in alcohols. Unlike the inversion of type (III) alcohols, Acetic Acid reacts completely and only a small proportion of by-products of transposition, dehydration or opening of the cyclopentane ring are produced. Benzoic Acid, in addition, gives better results than Acetic Acid in reversing the C-24 position.
    [0062] On the other hand, to minimize the formation of by-products due to prolonged contact with acid during industrial production, the effect of an added base in the mixture containing the alcohol to be isomerized was investigated. In most cases, no positive or only weak effect was observed, except when he used DBU (1,8-Diazabicyclo (5.4.0) undec-7-ene) or DABCO (1,4-diazabicyclo [2.2.2] octane, also called triethylene diamine). From these results, a study was started to compare the results of a series of aliphatic acids (Table 2) with another series of aromatic acids Table (3). Surprisingly, the aromatic acids and especially the p-substituted gave very good results, reaching the ratio of 24S / 24R alcohol: 2-2,2 / 1.
    [0064] Surprisingly, with this latest innovation, and using psubstituted aromatic acids (especially p-Methoxybenzoic acids (Table (4)), the ratio of 24S / 24R alcohols grew again: from 2.3-2.6 / 1, with the by-products less than 5 % and it is also possible to make the inversion of the epimers in C-24 with an overall yield of around 70% in invert alcohol and a recovery of 20-22% of alcohol without inverting.
    [0066] Brief description of the drawings
    [0068] Other advantages and characteristics of the invention are appreciated from the following description, in which, without any limiting character, some preferred ways of carrying out the invention are described, making reference to the accompanying drawings. The figures show:
    [0070] Fig. 1, two microreactors connected in series to carry out a continuous process according to the invention.
    [0072] Fig. 2, a microreactor for carrying out a process according to the invention in batch (discontinuous, that is, in batches).
    [0073] Detailed description of some embodiments of the invention
    [0075] 1) Description of the inversion acylation reaction
    [0077] The inversion acylation process refers to the conversion of the epimeric alcohols 24R (IV) and (V) into epimeric esters of opposite configuration 24S to the initial one (VIII) and (X), by reaction with an acid and Azadicarboxylate of diisopropyl, in the presence of an amine and a phosphine, according to the following scheme:
    [0078] where COR represents the acyl group of the ester (R being, for example, CH3, C6H5, etc.), and where R1 and R2 preferably represent silyl ethers such as tert - butyldimethylsilyl, the thexyl and tert-butyldiphenylsilyl and most preferably represent tert-Butyldimethylsilyl.
    [0080] As the acid any organic acid can be used, but aromatic and / or heteroaromatic acids are preferably used and, of these, preferably the p-substituted aromatic organic acids. In the latter case, a preferred substituent is the methoxy group (OCH 3 ).
    [0082] As the azadicarboxylate any commercial azadicarboxylate can be used. Diethylazadicarboxylate (DEAD), Diisopropylazadicarboxylate (DIAD), Dibenzilazadicarboxylate, Di-tert-Butylazadicarboxylate and 1,1'-Azodicarbonyldipiperidine (ADD) are preferably used. DIAD is the reagent of choice, as it combines better performance with greater stability for large-scale reactions.
    [0084] Various commercial phosphines can be used as the phosphine. Triphenylphosphine, Tritolylphosphine, Tributylphosphine or Tri-tertbutylphosphine are preferably used. Tributylphosphine is preferred as it gives better results.
    [0086] Advantageously, the esterification of the hydroxyl at C-24 by an acid in the presence of an azacarboxylate and a phosphine is also done in the presence of a base, which is preferably an amine. Advantageously the amine is 1,8-Diazabicyclo (5.4.0) undec-7-ene (DBU) or 1,5-Diazabicyclo (4.3.0) non-5-ene (DBN). Other bases are ineffective or give not so good results (DMAP).
    [0088] As solvents, apolar solvents such as Toluene, Benzene, Dichloromethane, Chloroform, etc. are preferred. and mixtures thereof. Hydrocarbons such as Hexane, Cyclohexane, etc. give problems when it comes to solubilizing all the reagents. The best results are obtained with apolar aromatic solvents, in particular Toluene, with Dichloromethane giving a somewhat worse result, although the latter allows greater reagent solubility. For reactions in continuous, a Toluene / Dichloromethane mixture (preferably with a Dichloromethane content of between 10% and 50% by volume with respect to the total volume of the solvent mixture) is the solvent of choice (it is advantageous not to use Benzene due to its toxicity).
    [0090] The reaction is carried out at a temperature from 0 ° C to 25 ° C, preferably at 10 ° C to 5 ° C.
    [0092] 2) Description of obtaining the mixture of alcohols 24S 24R
    [0094]
    [0096] (X, Ri = R 2 = t-ButDMSi) (VII, Ri = R 2 = t-ButDMSi)
    [0097] The alcohol mixture (24S 24R) is obtained from the hydrolysis of the ester mixture. It is not necessary to isolate the esters when they are obtained, since the hydrolysis can be carried out "in situ". However, the mixture of esters obtained can be isolated and purified by flash or preparative chromatography.
    [0099] The solution leaving the reactor ( MR1 ) (Fig. 1, see below) is introduced into the mixer ( M2 ), together with an alcoholic solution of a base. As the base, alkali metal hydroxides or alkoxides (preferably NaOH, KOH and LiOH or MeONa and Kt-BuO) and alcohols (preferably MeOH, EtOH, iso-Propanol, etc.), mixed in various proportions, can be used. A preferred solution for hydrolysis is a 96% 1M KOH in Ethanol solution.
    [0101] Another way to carry out this invention is by collecting the solution leaving the reactor ( MR ' ) (Fig. 2, see below) and mixing with a base (preferably alkali or alkaline earth metal oxides, hydroxides or alkoxides) and an alcohol , preferably low molecular weight, and heat the mixture to 40-100 ° C, preferably 55-65 ° C. For reactions carried out on aromatic hydrocarbons, it is advantageous to carry out the hydrolysis with pulverized KOH and a crown ether, preferably 18-Crown-6 or Dibenzo-18-Crown-6. The powdered NaOH and 15-Crown-5 combination is also effective. In these cases the reaction is carried out at room temperature.
    [0103] The resulting alcohol mixture is isolated by methods known to one skilled in the art. Finally, the mixture is purified and separated by chromatography, obtaining invert alcohol and a part of non-invert alcohol. Uninverted alcohol can be re-subjected to a new investment reaction.
    [0104] 3 Description of the microreactors to carry out the continuous reaction
    [0106] In order to carry out the inversion reaction and the subsequent hydrolysis of the inverted esters, two microreactors connected in series are used (Fig. 1). In the case of hydrolysis in “Batch”, a microreactor will suffice (Fig. 2).
    [0108] The kit for continuous reactions consists of the following elements (Fig. 1): three containers containing the alcohols to be inverted ( a ) and the reagents ( b, c ).
    [0110] Container ( b ) contains the azadicarboxylate and container ( c ), the solution to hydrolyze (KOH / EtOH). The rest of the reagents to carry out the inversion are mixed with the alcohols to be inverted in the container ( a ).
    [0112] The contents of containers ( a ) and ( b ) are mixed in the mixer ( M1 ), driven by peristaltic pumps ( BP ).
    [0114] The reaction occurs in the microreactor ( MR1 ) keeping the temperature between 5 and 20 ° C (usually at 10 ° C). The microreactor ( MR1 ) is made of a glass, Teflon or steel spiral.
    [0116] The inverted ester solution is mixed in the mixer ( M2 ) with the hydrolysis solution (KOH / EtOH 96 1M, usually), which comes from the container ( c ), driven by another peristaltic pump ( BP ).
    [0118] The mixture leaving the mixer ( M2 ), enters the microreactor ( MR2 ), where hydrolysis occurs. The microreactor ( MR2 ) is also made of a steel or Teflon coil and is kept in a bath at 40-100 ° C, usually between 55 ° C and 65 ° C.
    [0120] Finally, the solution of the hydrolyzed esters is collected in a bottle or flask ( B ) (immersed in a cold water bath) or sent directly to a rotavapor to be concentrated.
    [0121] The equipment for the reactions in "Batch" (discontinuous, that is to say, in batches) is shown in Fig. 2, and consists of the following elements: two containers containing the alcohols to be inverted ( a ' ) and the reagents ( b ' ), a mixer ( M' ), peristaltic pumps ( BP ' ), a microreactor ( MR' ) and a bottle or flask ( B ' ).
    [0123] 4 Obtaining the 24R Epimers.
    [0125] The various 24R epimers are known compounds and have been prepared according to procedures described in the literature:
    [0127] The 24R Epimers of trans 5E configuration are obtained by chromatographic separation of the trans ketone reduction crudes (XII) (Calverley MJ; Tetrahedron, 43, 20, 4609 (1987)) or the crudes of the reaction between the Iododerivative trans (XIII) and Cyclopropanoaldehyde (ES P200302875).
    [0132] (XII, Ri = R 2 = t-ButDMSi) (XIII, Ri = R 2 = t-ButDMSi)
    [0134] Obtaining the 24R epimers of the cis 5Z configuration is carried out from the cis ketone reduction crudes (XIV) (US 2007/0027333) or from the reaction crudes between the cis iodine derivative (XV) and Cyclopropanoaldehyde (ES P200302875), 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).
    [0139] (XIV, Ri = R 2 = t-ButDMSi) (XV, Ri = R 2 = t-ButDMSi)
    [0141] Experimental
    [0143] Microreactor:
    [0145] The microreactors used for the deprotections are made up of the following elements:
    [0147] Reactor MR1 and MR ' : Glass spiral 2 to 5 mm and 10 to 20 meters long, as specified)
    [0149] MR2 Reactor: A 1mm or 2mm steel coil or 2mm Teflon (as specified) internal diameter and 200 meters long.
    [0150] The BP and BP ' pumps used to supply the liquids are Masterflex peristaltic pumps with Teflon tubes.
    [0152] Chromatography
    [0154] Thin Layer Chromatography (TLC) was performed with Merck Silicagel 60 F 254 plates
    [0156] Preparative flash chromatography has been performed with Silicagel of 60 A ° and 35 - 70 g and at a pressure of 1.5 - 3 atmospheres, using 26.9x136 cm steel columns or, for smaller quantities of product, glass columns of 12x110 cm and at a pressure of 0.75 - 1 atmospheres.
    [0158] Preparative chromatography was performed on a Varian Prep Star preparative kit, using 5x10 cm and 5 micron steel columns.
    [0160] General data:
    [0162] Nuclear Magnetic Resonance Spectra (NMR, or) have been performed at 300 MHz in CDCl3 solution using internal standard TMS or CHCl3. The coupling constants J are given in Hertz. s = singlet; d = doublet; t = triplet; dd = double doublet; AB = AB system; m = multiplet, sc = complex signal and ba = broadband or sum of several signals.
    [0164] TBDMS stands for: i-Butyldimethylsilyl.
    [0166] EBM stands for: i-Butylmethyl Ether.
    [0168] DCM stands for Dichloromethane
    [0170] TOL stands for Toluene
    [0171] DBU stands for 1,8-Diazabicyclo (5.4.0) undec-7-ene
    [0173] DIAD stands for Diisopropylazadicarboxylate
    [0175] Bu3P stands for Tributylphosphine
    [0177] Below are some illustrative examples of this invention, object of this patent, but without being limiting of it.
    [0179] Preparation of 1 (S), (3 (R) -Bis (ferf-butyldimethylsilyloxy) -20R- (3 '- (S) -Cyclopropyl-3'-hydroxyprop-1' (E) -enyl) -1 (S) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (VII)
    [0181] 200 g of 20 (R) - (3 '- (R) -Cyclopropyl-3'-hydroxyprop-1' (E) - are placed in the 5-liter bottle ( a) in an N2 atmosphere (Figure 1). enyl) -1 (S), 3 (R) -dihydroxy-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (V) , 300 ml of DBU, 250 ml of Bu3P and 475 grams of 4-Methoxybenzoic Acid, 1 liter of Dichloromethane and 2 liters of Toluene. 200 ml of DIAD dissolved in 1 liter of Toluene are placed in the flask (or bottle) ( b) . 4000 ml of 1M KOH in 96% EtOH are placed in bottle ( c) .
    [0183] Using the equipment described in Fig. 1, the solutions are aspirated at a rate of 50 ml / min (3000 ml / h). The solutions, when they leave the mixer ( M1 ), are circulated through a glass spiral, 12 meters long and 2 mm internal diameter, which is in a thermostated bath at 10 ° C (it is the microreactor ( MR1 ) ). The solutions containing the inverted asters are sent to the mixer ( M2 ), mixing with the contents of the bottle ( c) (which is also introduced into the mixer ( M2 ) at 50 ml / min). The solutions, when they come out of the mixer ( M2 ), are circulated through a 200 meter long, 2 mm internal diameter steel spiral, which is in a bath maintained at 60 ° C (it is the microreactor ( MR2 ) ). The microreactor outlet ( MR2 ) is connected to a rotavapor (bottle ( B )) that concentrates the hydrolyzed solutions that come out of the microreactor ( MR2 ).
    [0184] After approximately 12 hours, all the solution in the bottle ( a) containing the alcohol will have circulated and finally the whole of the bottles, mixers and microreactors is washed with 1 liter of toluene.
    [0186] The rotavaporated crude is dissolved in 4 liters of Hexane and 5 liters of sodium bicarbonate solution are added. The organic phase is washed with 2x5 liters of brine and dried with sodium sulfate and concentrated in vacuo. The oily residue (containing about 70 % of (VII), is dissolved in Hexane / EBM 2/1 and purified by flash chromatography. The ether solution is dried with sodium sulfate, filtered and concentrated to dryness.
    [0188] The crude obtained is purified by preparative chromatography, eluting with Hexane / EBM 100: 15, obtaining 137.9 grams of pure 24S isomer (VII) and 53.2 grams of pure 24R isomer (V) .
    [0190] The 53.2 grams of pure 24R (V) isomer can be used directly in a new inversion process.
    [0192] Preparation of 1 (S), (3 (R) -Bis (ferf-butyldimethylsilyloxy) -20- (3 '- (R) -Cyclopropyl-3'-hydroxyprop-1' (E) -enyl) -1 (S) -9,10-secopregna-5 (E), 7 (E), 10 (19) -triene (VI).
    [0194] 200 g of 20 (R) - (3 '- (R) -Cyclopropyl-3'-hydroxyprop-1' (E) are placed in the 5-liter bottle ( a) in a N2 atmosphere (Fig. 2). -enyl) -1 (S), 3 (R) -dihydroxy-9,10-secopregna-5 (E), 7 (E), 10 (19) -triene (IV) , 300 ml of DBU, 250 ml of BusP and 660 grams of 3,4,5-Trimethoxybenzoic Acid, 5 liters of Toluene. 200 ml of DIAD dissolved in 1 liter of Toluene are placed in the flask ( b) .
    [0196] Using the equipment described in Fig. 2, the solutions are aspirated at a rate of 50 ml / min (3000 ml / h). The solutions when they come out of the mixer ( M ' ) are circulated through a glass spiral, 12 meters long and 4 mm internal diameter, which is in a thermostated bath at 10 ° C (it is the microreactor ( MR ' )). The solutions containing the inverted esters are collected in a 10 liter bottle ( B ' ), provided with mechanical agitation and containing 75 grams of 18-Crown-6, 350 of powdered KOH and 4 liters of toluene.
    [0198] When the content of the bottle ( a ) is finished, the whole of the bottles, mixer and microreactor is washed with 1 liter of toluene and the agitation is maintained in the collection bottle for an additional 30 minutes.
    [0200] The solution containing the hydrolyzed esters is mixed with 4 liters of Hexane and 5 liters of sodium bicarbonate solution are added. The organic phase is washed with 2x5 liters of brine and dried with sodium sulfate and concentrated in vacuo. The oily residue (containing about 70% (VI) ), is dissolved in Hexane / EBM 2/1 and purified by flash chromatography. The ether solution is dried over sodium sulfate, filtered, and concentrated to dryness.
    [0202] The crude obtained is purified by preparative chromatography, eluting with Hexane / EBM 100: 15, obtaining 138.4 grams of pure 24S isomer (VI) and 53.3 grams of pure 24R isomer (IV) .
    [0204] The 53.3 grams of pure 24R (IV) isomer can be used directly in a new inversion process.
    [0206] Tables of results
    [0208] The tables presented below show the results obtained.
    [0210] In all cases it has been used as azadicarboxylate: Diisopropilazadicarboxilato (DIAD); as phosphine: Tributylphosphine (Bu3P); as a base: the 1,8-Diazabicyclo (5.4.0) undec-7-ene (DBU) amine; and as solvent: Toluene / Dichloromethane mixture containing between 10% and 50% v / v of Dichloromethane.
    [0211] The ratio of chemical equivalents used in each test is indicated at the bottom of each table.
    [0212] Table 1 24R, 5E (IV) epimeric inversion (no DBU added)
    [0213]
    [0215] Equivalent ratio: R-OH / DBU / Bu3P / Acid = 1 / - / 3/3
    [0216] Table 2 24R, 5E (IV) epimeric inversion (with added DBU)
    [0217] Aliphatic acids
    [0218]
    [0220] Equivalent ratio: R-OH / DBU / Bu3P / Acid = 1 / 6.6 / 3.3 / 10. These conditions also apply to Tables 3 and 4.
    [0221] Table 3. 24R, 5E (IV) Epimeric Inversion (with added DBU) Aromatic Acids
    [0222]
    [0224] Table 4 24R, 5Z (IV) epimeric inversion (with added DBU) Methoxiaromatic Acids
    [0225]
    权利要求:
    Claims (1)
    [0001]
    1- Procedure to convert a 24R, 5E epimer of general formula (IV) into the corresponding 24S, 5E isomer of general formula (VI):

    (IV) (VI)
    or to convert a 24R, 5Z epimer of general structure (V) to the corresponding 24S, 5Z isomer of general formula (VII):

    (V) (VII)
    Ri and R2 being, each one, a hydroxyl protecting group, characterized in that the hydroxyl is esterified in C-24 of said epimer 24R, 5E or 5Z by means of an acid in the presence of an azacarboxylate and a phosphine, it is subsequently hydrolyzed the mixture of inverted and non-inverted esters obtained, obtaining a mixture of inverted and non-inverted alcohols, of formulas (IV) and (VI) or of formulas (V) and (VII) respectively, and subsequently the compound of formula ( VI) or (VII).
    2 - Process according to claim 1, characterized in that R1 and R2, each of them, is a silyl group, preferably is a silyl group from the group consisting of tert-Butyldimethylsilyl, Texyl and tert-Butyldiphenylsilyl, and most preferably it is tert- Butyldimethylsilyl.
    3 - Process according to one of claims 1 or 2, characterized in that said acid is an organic acid, preferably it is an aromatic or heteroaromatic acid and very preferably it is a psubstituted aromatic organic acid.
    4 - Process according to any of claims 1 to 3, characterized in that said acid is an aromatic organic acid p-substituted with a methoxyl group.
    5 - Process according to any of claims 1 to 4, characterized in that said azadicarboxylate is an azadicarboxylate from the group consisting of Dietilazadicarboxylate, Diisopropylazadicarboxylate, Dibenzilazadicarboxylate, Di-tert-Butylazadicarboxylate and 1,1'-Azodicarbonyl-dihydrodicaridyl, preferably.
    6 - Process according to any of claims 1 to 5, characterized in that said phosphine is a phosphine from the group consisting of Triphenylphosphine, Tritolylphosphine, Tributylphosphine and Tri-tertbutylphosphine, and is preferably Tributylphosphine.
    7 - Process according to any of claims 1 to 6, characterized in that the esterification of the hydroxyl at C-24 by an acid in the presence of an azacarboxylate and a phosphine is also done in the presence of a base, preferably an amine.
    8 - Process according to claim 7, characterized in that said base is an amine from the group consisting of 1,8-Diazabicyclo (5.4.0) undec-7-ene or 1,5-Diazabicyclo (4.3.0) non-5- ene.
    9 - Process according to any of claims 1 to 8, characterized in that said epimer 24R, 5E or 5Z is dissolved in an apolar solvent, preferably from the group consisting of Toluene, Benzene, Dichloromethane, Chloroform and mixtures of the above.
    10 - Process according to claim 9, characterized in that said solvent is an aromatic apolar solvent, and is preferably Toluene.
    11 - Process according to claim 9, characterized in that said solvent is a mixture of apolar solvents.
    12 - Process according to claim 11, characterized in that said solvent is a mixture of Toluene and Dichloromethane and preferably with a Dichloromethane content of between 10% and 50% by volume with respect to the total volume of the solvent mixture.
    13 - Process according to any of claims 1 to 12, characterized in that said esterification is carried out at a temperature between 0 ° C and 25 ° C, preferably between 5 ° C and 15 ° C.
    14 - Procedure according to any of claims 1 to 13, characterized in that said esterification is carried out continuously, using a microreactor (MR1, MR ').
    15 - Procedure according to claim 14, characterized in that said hydrolysis is carried out continuously in a second reactor (MR2) using an alcoholic solution of a base.
    16 - Process according to claim 15, characterized in that said alcoholic solution of a base is 1% KOH in Ethanol of 96%.
    17 - Process according to any of claims 1 to 13, characterized in that said hydrolysis is carried out in "Batch", using powdered KOH and 18-Crown-6.
    18 - Process according to any of claims 1 to 17, characterized in that said separation is carried out by chromatography.
    19 - Process according to any of claims 1 to 18, characterized in that the non-inverted isomer resulting from the process is recycled with the same process.
    20 - Use of a process according to any of claims 1 to 19, to obtain Calcipotriol (I).
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2003106412A1|2002-06-13|2003-12-24|Teva Pharmaceutical Industries Ltd.|Epimerization of analogs of vitamin d|
    WO2006024296A1|2004-09-01|2006-03-09|Leo Pharma A/S|Epimerisation of allylic alcohols|
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