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    • 专利摘要:
    Procedure to reduce carbonyl derivatives of vitamin D and corresponding use. The present invention deals with an industrial production of key intermediates for the synthesis of calcipotriol: 20 (R) - (3 '- (S) -cyclopropyl-3'-hydroxyprop-1' (E) -enyl) -1 (S) , 3 (R) -dihydroxy-9, 10-secopregna-5 (Z), 7 (E), 10 (19) -triene, by a reduction procedure of 20 (R), 1 (S), (3 (R) -bis (tert-butyldimethylsilyloxy) -20- (3'-cyclopropyl-3'-oxyprop-1 '(E) -enyl) -1 (S) -9, 10-secopregna-5 (Z), 7 (E), 10 (19) -triene or 20 (R), 1 (S), (3 (R) -bis (tert-butyldimethylsilyloxy) -20- (3'-cyclopropyl-3'-oxiprop-1 '(E) -enyl) -1 (S) -9, 10-secopregna-5 (E), 7 (E), 10 (19) -triene, where the reaction is carried out in polar aprotic solvents, which allow to obtain a higher proportion of 24S isomer, which is the pharmacologically active. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2674336A1
    申请号:ES201631702
    申请日:2016-12-28
    公开日:2018-06-28
    发明作者:Antonio BUXADÉ VIÑAS；Antonio Conchillo Teruel；Carlos Mola Soler
    申请人:Laboratorios Vinas SA；
    IPC主号:
    专利说明:

    PROCEDURE FOR REDUCING CARBONY DERIVATIVES OF VITAMIN D AND CORRESPONDING USE

    Description
     5
    Technical Field

    The present invention concerns an industrial production of key intermediates for the synthesis of calcipotriol: 20 (R) - (3 '- (S) -cyclopropyl-3'-hydroxypropy-1' (E) -enil) -1 (S) , 3 (R) -dihydroxy-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene, by a new method 10 of reduction of 20 (R), 1 (S), ( 3 (R) -bis (tert-butyldimethylsilyloxy) -20- (3'-cyclopropyl-3'-oxiprop-1 '(E) -enyl) -1 (S) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene or 20 (R), 1 (S), (3 (R) -bis (tert-butyldimethylsilyloxy) -20- (3'-cyclopropyl-3'-oxiprop-1 '(E) -enil) -1 (S) -9,10-secopregna-5 (E), 7 (E), 10 (19) -trieno
     fifteen
    The reaction is carried out in aprotic polar solvents, which allow a higher proportion of 24S isomer to be obtained, which is the pharmacologically active one.


    State of the Art 20

    Calcipotriol (I) or its corresponding monohydrate is an active substance that is currently used in the treatment of psoriasis. Its activity depends on the correct configuration of each chiral center. According to most of the calcipotriol synthesis methodologies, the last chiral center that is formed during the synthesis process is in the C-24 carbon, with the 24S isomer active and the 24R inactive.




     5
     OHHOHOHH
    C-24


    Calcipotriol (I)
     10
    Two methodologies have been used to obtain intermediate allylic alcohols:


    Reaction of an alkenyl-iododerivative (II) with tert-butyllithium and cyclopropanealdehyde (ES 2,234,423).
     5


     OR1R2OHIHOR1R2OHOHH
    image 1
    CyPr-CHO
    tert-but-li

     10


                             (II) (III, IV))
    Reduction of a carbonyl located in carbon C-24 (IV) and (VI). 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.

     5 OR1R2OHOH
    BH4Na
    or LiAlH4
    image2


                   (V) (III, IV)

     10 OR1R2OHOHOR1R2OHOHH
    image3
    BH4Na
    or LiAlH4


                   (VI) (VII, VIII)
       fifteen
    In all cases, mixtures of the two 24R and 24S isomers are obtained, requiring a subsequent separation step, which can be preparative chromatography or enzymatic resolution (WO 03/060094).

    For industrial scaling, various problems were observed according to the process: the use of hazardous reagents such as tert-butyllithium and expensive and toxic reagents such as Cl2Cr to obtain alkenyl-iododerivative. The ratio of 24S / 24R isomers is 1.

    The reduction by means of achirales reductores is realized by means of hydrides of boron or 10 solid aluminum that are added to the solution of the ketone, generating a great evolution of hydrogen. The ratio of 24S / 24R isomers is low (0.66), with a significant reduction in the adjacent double bond C22-C23 also occurring. By adding CeCl3, the sum of saturated alcohols (IX) and (X) or (XI) and (XII) has been reduced to 1%. fifteen


     OR1R2OHOHH

     twenty
    (IX)


     OR1R2OHOHH

    (X)
     OR1R2OHOHH
    (XI)




     5 OR1R2OHOHH


    (XII)

    The reduction by chiral reducers provides better ratios of 10 24S / 24R isomers, which reach 3.17 in the case of using (R) -2-amino-3-methyl-1,1-diphenyl-1-butanol and diethylaniline- borane But the use of boranos is dangerous on an industrial scale since they are very flammable and give off hydrogen in contact with water. Another problem with boranos is their tendency to add to double bonds, reducing the yield of the reaction and complicating its purification. To eliminate this problem, double bonds of carbons 5 and 7 have been protected by the formation of SO2 adducts, but the double bond reagent in C22-C23 remains free and exposed to hydrogenation and hydroboration. In addition, the formation of SO2 adducts implies an additional step of deprotection and the obtaining of exclusively trans alcohols, which would have to be photoisomerized subsequently to 20 cis alcohols.

    Another major disadvantage of chiral catalysts is their high price.

    Therefore, it is necessary to have a safe procedure for obtaining allyl alcohols derived from vitamin D2 and that is applicable both on a pilot scale and on an industrial scale, compared to traditional processes. Said process must allow to obtain allylic alcohols with a high degree of purity and with good chemical and optical performance and in industrially viable conditions.

    Object of the present invention
     10
    The authors of the present invention, during investigations for scaling the reduction of carbonyl derivatives (ketones) (V and VI) to allyl alcohols (III, IV, VII and VIII), according to the following scheme:

     fifteen

    image4


                   (V) (III, IV)
    twenty




     5

    image5


                   (VI) (VII, VIII)
     10
    they used aprotic polar solvents to dissolve the different compounds involved in the reaction. Surprisingly, the authors discovered that the ratio of 24S / 24R isomers had gone from 0.66 to 1.13, thus obtaining a greater proportion of the desired 24S isomer, without using any chiral reagent.
     fifteen
    Thus, the object of the invention is a process for reducing carbonyl compounds derived from vitamin D of general structure (V) or (VI) (ketones), preferably with borohydrides, where R1 and R2 can be the same or different and represent hydrogen or groups hydroxyl protectors, to give compounds of general structure (III) and (IV) or (VII) and (VIII), useful as intermediates for the synthesis of calcipotriol, in which the reduction reaction is carried out with both the product being reduce as reagents dissolved in an aprotic polar solvent.

    The corresponding dependent claims show further improvements and / or advantageous alternatives of the process according to the invention.

    A subject of the invention is also a process for manufacturing calcipotriol, in which it includes a step of reducing a compound of general structure (V) or 5 (VI) to give compounds of general structure (III) and (IV) or ( VII) and (VIII) according to the method according to the invention.

    The object of the invention is also the use of a process according to the invention for the manufacture of calcipotriol. 10


    Detailed description of embodiments of the invention

    1) Description of the reduction reaction 15

    The reduction process refers to the conversion of carbonyl derivatives (V) and (VI) (ketones) into allyl alcohols (III and IV or VII and VIII), the reaction being carried out with aprotic polar solvents, according to the following scheme :
     twenty
    BH4M
    image6
    Cl3Ce


                                      (V) (III, IV)

         5 (VI) (VII, VIII)
    BH4M
    image7
    Cl3Ce
     R 1 and R 2 protecting groups, esters such as 10 acetates or benzoates and silyl ethers such as tert-butyldimethylsilyl, texyl and tert-butyldiphenylsilyl are preferred, and of these, tert-butyldimethylsilyl is preferred.

    Any salt of the lanthanide elements that is compatible with the reaction conditions can be used as an inhibitor salt of double bond reduction. Of these, Cl3Ce.6 H2O is preferred because it is easily affordable. Anhydrous salts give worse results. Other salts such as Cl3Cr.6 H2O, Cl2Ca.2 H2O or Cl2Zn are ineffective.

    As the reducing agent, a metal borohydride (M = Metal or 20 ammonium radical), soluble in an aprotic solvent, can be used. Examples of such borohydrides are sodium borohydrides, potassium, lithium, tetrabutylammonium, benzyltriethylammonium, zinc, sodium cyanoborohydride, sodium triacetoxyborohydride, etc. Preferred borohydrides are sodium, potassium and tetrabutylammonium.

    As the solvent of the reducer, any polar and aprotic organic solvent can be used. Examples of such solvents are: dimethylformamide (DMF), methylformamide, N-methylpyrrolidone, tetramethylurea, 1,3-dimethyltetrahydro-2-pyrimidone, tetramethylenediamine amine, etc., DMF and N-methylpyrrolidone or mixtures thereof or with others being preferred aprotic polar solvents, and most preferably it is DMF.

    As solvent of the inhibitory salt any of the solvents described above can be used, preferably DMF and N-methylpyrrolidone.
     10
    Preferred as ketone solvents are ethers such as tert-butyl methyl ether, dioxane, furan, diethyl ether, tetrahydrofuran, etc. and among them, tetrahydrofuran is preferably.

    The reaction can be carried out at a temperature between 0 ° and 60 ° C, with temperatures between 20 ° C and 30 ° C being preferred, such as 25 ° C.

    Preferably the reaction is carried out in a continuous flow microreactor, which allows to minimize the evolution of hydrogen. The reaction is basically carried out in a spiral of steel, glass or Teflon several meters long that is maintained at the desired temperature in a thermostatic bath, the reagents and the product being driven by two pumps. The equipment can run continuously for 24 hours or more and allows the reduction during this time of 0.25 to 1 kg of ketone, depending on the reaction conditions. Under the above conditions, the reduction of double bond C22-C23 occurs in an amount less than 1%. The lower proportion of isomers and by-products compared to conventional batch reactions allows scaling with good yields and with crudes much easier to purify.
     30
    Many different proportions are possible between the ketone, the lanthanide salt, the reductant and the solvent and in general they have little influence on the final proportion of
    isomers But it is convenient not to use a large excess of reductant as it can cause precipitation of lanthanic salts and seal the microreactor.

    A proportion that gives good results is for example: 50 grams of ketone / 1 liter THF and 100 grams of CeCl3.H2O / 1 liter DMF and these two components are mixed and 5 are reacted in the microreactor with a solution of 100 grams of BH4Na in 1 liter of DMF, in a proportion that can range from 1 / 0.1 to 1/1, the preferred ratio being 1 / 0.5 to 1 / 0.8 (Ketone mixture volume + salt of cerium / volume reducing solution). For poorly soluble borohydrides, saturated solutions will be used. 10

    Under these conditions it is possible to keep the saturated alcohol below 1% and the ratio of 24S / 24R isomers above 1.

    It was also considered advantageous to carry out the reduction with aquatic borohydrides, since the price of chiral catalysts and the danger of diborans did not compensate for obtaining a greater amount of 24S isomer.

    The reduction reaction was carried out continuously and in a microreactor, using sodium borohydride dissolved in dimethylformamide. The reduction occurred without problems, with a good yield of alcohols in C-24. Also, the saturated alcohol resulting from the reduction of the double bond in C-22 / C-23 remained below 1%.

    2 Description of an example of the continuous flow microreactor used in the reduction of allyl alcohols

    A continuous flow reactor has been used, which allows working with small volumes at any time and in this way there is never an accumulation of H2 that could become uncontrollable, as it could happen in the reactions in 30 “batch”.

    The reactor consists of several parts:

    1) 2 containers (5 to 200 liters each) to contain the solutions of the product (together with the inhibitor salt) and the reducer
    2) 2 peristaltic pumps to boost the solutions to the mixer
    3) 1 mixer (0.5 ml to 10 ml) in which both solutions are mixed 5
    4) Reactor itself (spiral tube made of Teflon, steel or glass, 0.5 m to 10 m long and with an inside diameter between 0.5 mm and 20 mm)
    5) System to fully or partially thermostatize the equipment
    5) Flask for collecting the solution with alcohols and excess reagents.
    6) Detachment tube to remove excess H2. 10

    In the collection flask, the crude is diluted with hexane or heptane and brine. The organic phase is decanted, filtered by Celite, washed with sodium bicarbonate solution, dried and concentrated to dryness. The residue obtained is purified and separated by methods known in the state of the art including crystallization, filtration, distillation or "Flash" chromatography. The separation between the 24R and 24S isomers and of these with the saturated alcohols is carried out by preparative HPLC.

    The allyl alcohols (III) and (VII) prepared in this invention are key intermediates for obtaining calcipotriol. twenty

    The epimeric allyl alcohols (IV) and (VIII) prepared in this invention are also useful since they can be re-oxidized to the original ketone and re-initiated or reversed to convert them into the allylic alcohols (III) and (VII).
     25

    The procedures described in this patent application have the following advantages over the above methods, which used reactions in protic solvents or reagents dissolved in protic solvents:
     30
    - Crudes with a higher proportion of 24S isomer can be obtained using aprotic polar solvents compared to crudes with a higher proportion of 24R isomer when protic polar solvents are used.

    - raw alcohol with impurity saturated alcohol (IX) and (X) can be obtained below 1% starting from the trans ketone (V) and below 0.5% starting from the ketone cis (VI)
     5
    - The reduction is carried out by means of DMF borohydride solutions, which are stable and in a slightly flammable solvent.

    - The solvents used in the reaction need not be anhydrous.
     10
    - chiral catalysts are not used.

    - Boranos, highly reactive and flammable compounds are not used.

     fifteen
    Experimental

    Industrial Reactor:

    The reactor used has been described in the previous pages. The material used in the spiral is Teflon. The internal length and diameter is specified in each example.

    Masterflex ® peristaltic pumps with Teflon tube have been used.

    Reactor for pilot scale reactions: 25

    A microreactor with a 5 mm internal diameter Teflon tube has been used, as described in the previous pages. Likewise, Masterflex peristaltic pumps with Teflon tube have been used.
     30
    The spiral outlet is connected to a collection reactor with Hexane and sodium chloride solution to destroy the excess reducer.

    General data:

    Thin layer chromatography (TLC) was performed with Merck Silicagel 60 F254 plates.
     5
    Preparative "flash" chromatography was performed with Silicagel of 60 Aº and 35 - 70 µ and at a pressure of 1.5 - 3 atmospheres, using steel columns of 26.9x136 cm or, for smaller quantities of product, columns of 12x110 cm glass and a pressure of 0.75-1 atmospheres.
     10
    Preparative high pressure chromatography was performed with a Varian Prep-Star equipment, using 100x50 mm Sunfire Waters columns.

    DMF means dimethylformamide
     fifteen
    THF means tetahydrofuran

    EBM means: t-butylmethyl ether.

    NMP means N-methylpyrrolidone 20

    TBA means tetrabutylammonium

    Si (tBDM) means: silyl-t-butyldimethyl.
     25

    The trans ketone (V) has been obtained according to: Calverley M.J .; Tetrahedron, 43, 20, 4609 (1987) from the aldehyde (XIII), the cis ketone (VI) has been obtained by photoisomerization of the trans ketone.
     30
    The two ketones have also been obtained by oxidation of the respective 24R epimers (IV) and (VIII) with active MnO2.

    Below are some illustrative examples of this invention, which are the subject of this patent application, but are not limited thereto.


     5 OR1R2OHCHOH

    (XIII)

    Example 1: 1 (S), 3 (R) -bis (tert-Butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3'-oxoprop-1'-enyl) -9,10-secopregna-5, 7 (E), 10 (19) -tetraen. (Compound V). 10

    100 gr of 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3 '(R) -hydroxypropyl-1' (E) - are placed in a reactor enil) -9,10-secopregna-5 (E), 7 (E), 10 (19) -tetraeno, 100 liters of pentane and 300 g of active MnO2 are added. Stir vigorously for 3 hours. fifteen

    It is filtered by Celite and concentrated in vacuo. The resulting crude is purified by flash chromatography, eluting with increasing mixtures of Hexane / EBM (from 1 to 10%), obtaining 96.2 g (95.9%) as a white solid.
     twenty
    Example 2: 1 (S), 3 (R) -bis (tert-Butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3'-oxoprop-1'-enyl) -9,10-secopregna-5 ( Z), 7 (E), 10 (19) -tetraen. (Compound VI).

    Preparation 1:
    Likewise, from 100 g of 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3 '(R) -hydroxypropyl-1' (E) - enil) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -tetraeno, 94.9 gr (94.6%) of 1 (S), 3 (R) -bis are obtained (tert-butyldimethylsilyloxy) -20 (R) - (3'-5 cyclopropyl-3'-oxoprop-1'-enyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) - tetraene (Compound VI) in the form of yellowish oil.

    Preparation 2:
    100 g of 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3) are placed in the tank of a continuous microreactor and coupled to a UV lamp. '-oxoprop-1'-enyl) -9,10-secopregna-5,7 (E), 10 (19) -tetraeno. (Compound V) dissolved in 10 liters of EBM and 8 g of 9-methylantracene. The lamp is turned on and the solution is circulated at a flow of 60 ml / min. The photoisomerized solution is concentrated and the resulting crude is purified by flash chromatography, eluting with increasing mixtures of Hexane / EBM (1 to 10%), yielding 91.7 g (91.4%) as a yellowish oil.

    Example 3: 1 (S), 3 (R) -bis (tert-Butyldimethylsilioxy) -20 (R) - (3'-cyclopropyl-3'-hydroxypropyl-1'-enyl) -9,10-secopregna-5 ( E), 7 (E), 10 (19) -tetraen. (Compounds 24S 20 (III) and 24R (IV)).

    Solution A: 100 g of 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3'-oxoprop-1'-enyl) -9,10-secopregna -5 (E), 7 (E), 10 (19) -tetraen (V) in 2.5 liters of tetrahydrofuran. 25

    Solution B: 200 g of Cl3Ce.6H2O in 2.5 liters of dimethylformamide.

    Solution C: 20 g of BH4Na in 2 liters of dimethylformamide.
     30
    Solution A and solution B are placed together in one of the containers of the equipment described in the previous pages (spiral length = 5 m, spiral diameter = 5 mm, mixing volume M1 = 3 ml) and solution C in the other container of it
    team. The pumps corresponding to a flow of 20 ml / min and C at a flow of 10 ml / min are started, mixing in the mixer M1.

    The reaction is carried out at room temperature (about 25 ° C).
     5
    The liquid leaving the microreactor is collected in a mixture of hexane and brine. It is filtered by Celite, the two phases are separated and the upper one is washed with brine, dried and concentrated in vacuo.

    The resulting crude is purified by flash chromatography, eluting with increasing mixtures of Hexane / EBM (from 10 to 25%), obtaining 96.9 g (96.6%) as a white-transparent oil.

    The separation of the two isomers is carried out by preparative chromatography with hexane / EBM 100: 25 eluent. fifteen

    The allyl alcohols obtained (III) and (IV) are known compounds and coincide with the tR of standards, by HPLC analysis:

    HPLC analysis: heptane / EBM 100: 15 at 2 ml / min and at 275 nm for the control of the reaction.

    HPLC analysis: heptane / AcOEt 100: 4 at 1 ml / min and at 275 nm for impurity control.
     25
    Example 4: Reduction of the trans ketone (V) in aprotic polar solvent.

    Table 1 details other reductions of the trans ketone, performed according to the method described in Example 3 and using the same proportions. The borohydride used and the polar and aprotic solvent used to prepare the 5B and C solutions are indicated. Solution A has always been prepared in tetrahydrofuran. Other changes are indicated at the bottom of the table.

    It can be seen how the addition of only 5% 0.05 N NaOH already decreases the proportion of 24S isomer. It also happens when the temperature increases. On the other hand, the decrease in temperature increases the proportion of saturated alcohols, as well as the use of lithium borohydride.

    Example 5: Reduction of cis ketone (VI) in aprotic polar solvent.
     fifteen
    Table 2 details other reductions of the ketone cis, made according to the method set forth in example 3 and using the same proportions. The borohydride used and the polar and aprotic solvent used to prepare solutions B and C are indicated. Solution A has always been prepared in tetrahydrofuran. Other changes are indicated at the bottom of the table. twenty

    Cetones cis give a lower proportion of 24S isomer with respect to trans, but in any case higher than when using protic solvents. On the contrary, they give a lower proportion of saturated C22 / C23 alcohol.
     25



    Table 1

     Reducer / Solvent  Residual ketone Saturated alcohol 24R, 24S Allyl alcohol 24R Allyl alcohol 24S Ratio 24S / 24R
     BH4Na / DMF  2.85 0.8 44.9 50.6 1.13
     BH4Na / DMF (*)  6.8 0.28 / 0.32 44.6t 47.5 1,065
     BH4TBA / DMF  6.7 0.48 43.2 49.25 1.14
     BH4K / DMF  6.7 0.38 43.4 49.2 1.13
     BH4Li / DMF  0.8 1.6 / 1.9 44.85 50.5 1.13
     BH4Li / THF  0.2 1.4 / 1.6 45.4 51.0 1.12
     BH4Na / NMP  0.47 1.0 45.5 52.7 1.16
     BH4Na / DMF (2 ° C)  0.9 1.2 45.6 52.3 1.15
     BH4Na / DMF (45 ° C)  7.2 0.75 43.5 47.3 1.09
    (*) BH4Na in DMF + 5% NaOH

    Table 2

     Reducer / Solvent  Residual ketone Saturated alcohol 24R, 24S Allyl alcohol 24R Allyl alcohol 24S Ratio 24S / 24R
     BH4Na / DMF  2.1 0.2 42.1 45.0 1.07
     BH4TBA / DMF  8.3 0.1 38.7 42.05 1.09
     BH4K / DMF  1.6 0.1 42.2 44.5 1.05
     BH4Na / DMF (*)  --- 15.2 / 16.9 30.1 23.0 0.76

    (*) Using Cl2Ca instead of Cl3Ce

    权利要求:
    Claims (1)
    [1]
    Claims
    1 - Procedure for reducing carbonyl derivatives of vitamin D of general structure (V) or (VI), where R1 and R2 may be the same or different and represent hydrogen or hydroxyl protecting groups, to give compounds of general structure (III) and (IV) or (VII) and (VIII), useful as intermediates for the synthesis of calcipotriol, characterized in that the reduction reaction is carried out in aprotic polar solvents.
     10

    (V)

    (III)


    (IV)


    (SAW)

    image 1






    (VII)




    (VIII) 5

    2 - Method according to claim 1, characterized in that said aprotic polar solvent is a solvent of the group consisting of dimethylformamide, methylformamide, N-methylpyrrolidone, tetramethylurea, 1,3-dimethyltetrahydro-2-pyrimidone, tetramethylenediamine, tert-butyl methyl ether, dioxane , furan, diethyl ether, tetrahydrofuran and mixtures of the foregoing.
    3 - Method according to one of claims 1 or 2, characterized in that the carbonyl derivative to be reduced (V) or (VI) is dissolved in an aprotic polar solvent of the group consisting of tert-butyl methyl ether, dioxane, furan, diethyl ether, tetrahydrofuran and mixtures of the foregoing, and preferably it is tetrahydrofuran.
    4 - Method according to any one of claims 1 to 3, characterized in that the reduction is carried out with a borohydride as a reductant, preferably with an achiral borohydride, and most preferably with a borohydride of the group consisting of sodium borohydride, potassium borohydride and borohydride of tetrabutylammonium
    5 - Method according to claim 4, characterized in that the reducer is dissolved in an aprotic polar solvent of the group consisting of dimethylformamide, methylformamide, N-methylpyrrolidone, tetramethylurea, 1,3-dimethyltetrahydro-2-pyrimidone, tetramethylenediamine amine and mixtures of the foregoing , preferably dimethylformamide, N-methylpyrrolidone or a mixture of both, and most preferably dimethylformamide. 5
    6 - Method according to any of claims 1 to 5, characterized in that the reduction is carried out in the presence of an inhibitor salt, wherein said inhibitor salt is preferably a salt of a lanthanide element.
     10
    7 - Method according to claim 6, characterized in that said lanthanide element salt is Cl3Ce.6H2O.
    8 - Method according to one of claims 6 or 7, characterized in that said salt of the lanthanide element is dissolved in an aprotic polar solvent of group 15 formed by dimethylformamide, methylformamide, N-methylpyrrolidone, tetramethylurea, 1,3-dimethyltetrahydro-2- pyrimidone, tetramethylenediamine and mixtures of the foregoing, preferably dimethylformamide, N-methylpyrrolidone or a mixture of both, and most preferably dimethylformamide.
     twenty
    9 - Method according to any of claims 1 to 8, characterized in that compounds are used in which R1 and R2 represent a silyl group.
    10 - Process according to claim 9, characterized in that R1 and R2 represent a tert-butyldimethylsilyl group. 25
    11 - Method according to any of claims 1 to 10, characterized in that it is carried out in a continuous flow reactor.
    12 - Method according to claim 11, characterized in that the temperature at which the reduction is carried out to obtain the compounds of general structure (III) and (IV) or (VII) and (VIII), is between 0 ° C and 60 ° C, preferably is between 20 ° C to 30 ° C.
    13 - Method according to any of claims 1 to 12, characterized in that it is done in the absence of chiral catalysts or chiral borohydrides.
    14 - Calcipotriol manufacturing process, characterized in that it includes a step of reduction of a compound of general structure (V) or (VI) to give a compound of general structure (III) and (IV) or (VII) and ( VIII) according to any of claims 1 to 13.
    15 - Use of a process according to any of claims 1 to 13 for the manufacture of calcipotriol.
    .
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO1991000271A1|1989-06-29|1991-01-10|Leo Pharmaceutical Products Ltd. A/S |Novel vitamin d analogues|
    WO2005095336A2|2004-04-02|2005-10-13|Leo Pharma A/S|Novel method for the preparation of intermediates useful for the synthesis of vitamin d analogues|
    WO2009057136A2|2007-08-03|2009-05-07|Glenmark Generics Limited|Epimerization by stereoselective synthesis of vitamin d analogues|
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