Process for the preparation of a budesonide intermediate

Abstract

The present invention relates to a process for the preparation of a budesonide intermediate, in particular the compound of formula (I).

Description

[0001] “Process for the preparation of a budesonide intermediate” *************

[0002] DESCRIPTION

[0003] The present invention relates to a process for the preparation of a budesonide intermediate, in particular the compound of formula (I)

[0004] Corticosteroids are a group of hormones, produced by the cortex of the adrenal glands, belonging to the steroid class.

[0005] They are involved in a variety of physiological mechanisms, such as those regulating inflammation, the immune system, carbohydrate and protein metabolism, and blood electrolyte levels. These compounds are widely used for their anti-inflammatory and immunosuppressive activity as well as for their effect on metabolism.

[0006] Some corticosteroids, such as budesonide, are prepared from a specific steroid derivative, 16a-hydroxy prednisolone.

[0007] 16a-hydroxy prednisolone, also known as 1 ip,16a,17a,21-tetrahydroxypregna-1,4- diene-3, 20-dione, has the following chemical formula (I): The known processes for the preparation of 16a-hydroxy prednisolone, such as for example those described in WO 2016 / 120891 and in CN 105566426 B provide for the following synthetic sequence shown in scheme 1 : dihydroxylation of tetraene acetate (1), bromination of the compound (2) thus formed to give the corresponding bromohydrin (3), subsequent debromination and deacetylation of compound (4) to give 16a-hydroxy prednisolone.

[0008] Scheme 1 crude 16c / .-hydroxy-Prednisolone However, this methodology has several drawbacks, such as the use of toxic and malodorous reagents such as thioglycolic acid, bearing a thiol function and chromium. The wastewater deriving from these processes therefore requires further treatment with potassium persulfate (Oxone®) to destroy the thiol function by oxidation and with sodium metabisulfite to eliminate any presence of hexavalent chromium.

[0009] Furthermore, it has been noted that the intermediates (2), (3) and (4) having the unprotected hydroxyl function in position 16, if subjected to the reaction conditions described, appear to be more prone to the formation of D-homo derivatives such as example the compounds of figure 1 shown below.

[0010] The elimination of these compounds from the reaction mixture would necessarily involve further purification steps by crystallization or column chromatography with a negative impact on production costs and times.

[0011] Finally, the processes described in WO 2016 / 120891 and in CN 105566426 B allowed to isolate the intermediate 16a-hydroxy prednisolone only with an average weight yield of about 40%.

[0012] Furthermore, in the patent CN 105566426 a specific debromination is described which makes use of a radical initiator such as azoisobutyronitrile. This type of debromination was performed in the laboratory on the bromine derivative of unprotected 16a-hydroxy prednisolone, leading to the preparation of compounds having a purity unsuitable for use in the pharmaceutical area.

[0013] The need was therefore felt for an effective process to prepare 16a-hydroxy prednisolone capable of solving the problems above described, allowing the active ingredient budesonide to be produced in specification according to the main pharmacopoeias and improving from the point of view of production capacity.

[0014] We have now found a process for the preparation of 16a-hydroxy prednisolone which does not have the drawbacks of the known methods and which allows the desired compound to be obtained with a yield of around 60% by weight and a purity higher than 99.7%.

[0015] The object of the present invention is therefore a process for the preparation of 16a- hydroxy prednisolone of formula (I) which comprises the following steps: a) dihydroxylation of tetraene acetate of formula (II) to give the corresponding diol of formula (III) b) selective acetylation of the diol of formula (III) at position 16 to give the compound of formula (IV)

[0016] c) bromination of the acetate of formula (IV) thus obtained to give bromohydrin of formula (V) d) debromination of the compound of formula (V) to give the corresponding compound of formula (VI) e) deacetylation of compound (VI) to give the desired 16a-hydroxy prednisolone of formula (I).

[0017] According to the present invention, in step a) of the process of the present invention the tetraene acetate of formula (II), also known by the IIIPAC name 2-((10S, 13S, 14S)- 10, 13-dimethyl-3-oxo- 6,7,8,10,12,13,14,15-octahydro-3H- cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate is subjected to a dihydroxylation reaction. As it is well known to the person skilled in the art, the tetraene acetate of formula (II) dissolved in an organic solvent, such as for example acetone mixed with water, is reacted with an oxidizing agent.

[0018] Examples of suitable oxidizing agents according to the present invention are osmium tetraoxide and potassium permanganate. Preferably it is potassium permanganate.

[0019] Preferably, the dihydroxylation reaction is carried out at a temperature ranging from - 10°C to 25°C, more preferably at a temperature of about -5°C ± 5°C in the presence of an acid catalyst, such as for example formic acid.

[0020] Contrary to what is described in the prior art, the process of the present invention (step b)) provides for the thus formed vicinal diol of formula (III) to be selectively acetylated at position 16, before being subjected to bromination in step c).

[0021] In fact, this step allows to prevent the formation of specific degradation impurities such as D-homo. Furthermore, the isolation of the acetylated intermediate in C16 allows an optimal purification with yields above 95%.

[0022] The acetylation conditions are those known to the expert in the field, i.e. to a solution of the diol of formula (III) in an organic solvent, such as for example tetra hydrofuran, an acylating agent selected from acetic anhydride and acetyl chloride is added, preferably acetic anhydride.

[0023] Said acylating agent is added to the reaction mixture in a molar amount comprised between 1 to 2 equivalents, preferably of about 1 .6 equivalents, with respect to the molar amount of diol of formula (III).

[0024] The acetylation reaction preferably takes place at room temperature in the presence of an organic base, selected from pyridine, dimethylaminopyridine, triethylamine, diisopropylethylamine, more preferably in the presence of dimethylaminopyridine. Once the acetylation reaction is complete, the compound of formula (IV) is isolated according to techniques well known to those skilled in the art, such as for example filtration, precipitation, crystallization.

[0025] According to the present invention, in step c), the compound of formula (IV) is converted into the corresponding bromohydrin of formula (V) through a bromination reaction.

[0026] The formation of the above bromohydrin of formula (V) takes place at a temperature between -5°C and 5°C, preferably of about 0°C ±5°C by adding a brominating agent to the solution containing the compound of formula (V) dissolved in an organic solvent mixed with water, for example in an acetone / water mixture.

[0027] Preferably, said brominating agent is selected from N-bromosuccinimide, Br2, 1 ,3- dibromo-5,5-dimethyl hydantoin (also known as dibromantin), more preferably it is 1 ,3-dibromo-5,5-dimethyl hydantoin.

[0028] Once the bromohydrin of formula (V) has been isolated by means of conventional techniques known to those skilled in the art, this compound is debrominated in step d) of the process.

[0029] The debromination reaction occurs in the presence of a radical initiator in an aprotic organic solvent.

[0030] Said radical initiator is preferably a chemical species which is activated by temperature-dependent degradation. Specifically, azoisobutyronitrile, 2,2'- Azobis(2,4-dimethylvaleronitrile) V-65, 2,2'-Azobis(4-methoxy-2,4- dimethylvaleronitrile) V-70, preferably azoisobutyronitrile, can be used.

[0031] According to the present invention, the use of a radical initiator, contrary to the experimental conditions described in CN 10556642 B, does not lead to the formation of D-homo derivatives since the hydroxyl function in position 16 of the steroid nucleus of compound (V) is protected as acetyl, thus preventing rearrangement of the D ring to give the compounds of figure 1.

[0032] According to a particularly preferred embodiment of the present invention, bis (tributyltin) oxide is added to a solution of bromohydrin of formula (V) in tetrahydrofuran in the presence of polymethylhydroxysiloxane and azobisisobutyronitrile (Al BN).

[0033] The amount of AIBN used in this reaction is particularly critical, as it could lead to the formation of the impurity 1 ,2-dihydro if it were used in excess of the starting bromohydrin of formula (V).

[0034] Therefore, according to the present invention, the molar amount of AIBN used is comprised between 0.01 equivalent and 0.02 equivalent, preferably between 0.015 equivalent and 0.017 equivalent, with respect to the molar amount of bromohydrin of formula (V).

[0035] The debromination is preferably carried out at the reflux temperature of the aprotic organic solvent used for two hours, subsequently maintained at 40°C until completion of the reaction. Optionally, the compound of formula (VI) thus obtained can be subjected to purification to eliminate any by-products formed in the reaction mixture.

[0036] Any purification method known to the expert in the field can be used in step d) of the process of the present invention.

[0037] According to a preferred embodiment of the present invention, the prednisolone 16,21-diacetate of formula (VI) is dissolved in an acetone / water mixture to which charcoal is added and left under stirring at reflux temperature of the solvent for a time comprised between 10 minutes and an hour. Subsequently the charcoal is filtered off and the rich mother liquors are concentrated at atmospheric pressure up to residual 5V.

[0038] This purification operation allows to isolate the desired product with a degree of purity of about 99%. Furthermore, this purification has a very high yield, greater than 95%, so it can be repeated without incurring a substantial loss of yield.

[0039] According to the invention, 16a-hydroxy prednisolone of formula (I) is subsequently obtained by deacetylation of the compound of formula (VI).

[0040] This deacetylation reaction takes place under conditions well known to the expert in the field, i.e. by adding an inorganic base selected from sodium hydroxide, potassium hydroxide, potassium acetate, potassium carbonate, preferably in the presence of sodium hydroxide.

[0041] The above reaction is carried out in a polar solvent, preferably in an alcoholic solvent, more preferably in methanol.

[0042] Preferably, the temperature of the reaction mixture is maintained between 0°C and room temperature, more preferably at about 10°C.

[0043] In the event that the 16a-hydroxy prednisolone of formula (I) does not have the purity requirements for use in the preparation of pharmaceutical compounds, it is possible to subject it to a further purification, as step f) of the process of the present invention. Preferably, 16a-hydroxyprednisolone of formula (I) is dissolved in a dichloromethane / methanol mixture in a ratio comprised between 1 :0.5 and 1 :1.5, more preferably about 1 :1.

[0044] The mixture thus obtained is brought to the reflux temperature of the solvent and charcoal is added, in an amount by weight between 0.05 and 0.15, preferably about 0.1. After a time of about 30 minutes, the reaction mixture is filtered and washed with a mixture (1 :1) of dichloromethane / methanol to continue with a distillation at atmospheric pressure of the organic solvent up to about residual 3V. This purification allows to provide a final product having a purity greater than 99.5%.

[0045] As stated above, the process of the present invention differs from those previously described by the presence of an additional step, such as step b) of mono-acetylation of the vicinal diol of formula (III) to provide the compound of formula (IV). In fact, the known processes use intermediate compounds having two hydroxyl groups in the 16 and 17 positions of the steroid.

[0046] Thanks to this additional acetylation step, it has been noted that the purity of the intermediates obtained is about 98%, without the presence of D-homo derivatives. In addition, the reactions were found to be reproducible on an industrial scale with a weight average yield of approximately 90% for each chemical step.

[0047] Below is a comparison of 16a-hydroxy prednisolone obtained by the process described in patent application WO 2016 / 120891 , i.e. a process that does not go through the protection of 16a- OH (ET668 / 44) with a batch synthesized by the process of present invention (ET700 / 20).

[0048] As it can be seen, the overall yield of the process according to the present invention is clearly higher than that of the prior art process with a low content of D-homo derivatives.

[0049] A further object of the present invention is therefore the use of the compounds of formula (IV), (V) and (VI) as intermediates in the preparation of 16a-hydroxy prednisolone of formula (I). Furthermore, the 16a-hydroxy prednisolone thus obtained can then subsequently be subjected to further chemical processes aimed at preparing corticosteroids of formula (VII) wherein R1is a hydrogen atom or a methyl group;

[0050] R2is a linear or branched Ci-Ce alkyl group, cycloalkyl group, aryl or heteroaryl group. The conversion of 16a-hydroxy prednisolone obtained according to the process of the present invention into a corticosteroid of formula (VII) represents a further object of the invention.

[0051] While the invention has been described in its characteristic aspects, modifications and equivalents which are apparent to those skilled in the art are included in the following invention.

[0052] The present invention will now be illustrated by means of some examples, which are not to be seen as limiting the scope of the invention.

[0053] EXAMPLES

[0054] The1H and13C NMR spectra were obtained with a Bruker Avance Neo spectrometer (400MHz) at 25°. Chemical shifts are expressed in ppm with respect to tetramethylsilane and spectra were obtained by dissolving the sample in DMSO. Mass analyzes were conducted using a Varian 500MS instrument in ESI+.

[0055] Example 1 Into a 5000 ml flask, in an inert environment and at 25°C, acetone (2000mL), tetraene acetate (50 g) and water (105 ml) are introduced. The mixture is cooled and kept under stirring at -5°C ± 2°C.

[0056] Formic acid (13.8 g) and potassium permanganate (25.8 g) are introduced in about 90 minutes without exceeding 0°C.

[0057] When the reaction is complete, the reaction is stopped by adding a solution consisting of sodium metabisulfite (5 g) and water (40 ml).

[0058] 2.5 g of celite are loaded into the flask and the mixture is heated at 30735°C for about 15 minutes.

[0059] The contents of the flask are filtered. The filtered solution is concentrated under vacuum at 45°C to eliminate the organic solvent. Once the atmospheric pressure has been restored, it is cooled to about 20°C and 280 ml of water are loaded.

[0060] The mixture is cooled to 10°C / 15°C and left under stirring for about 90 minutes.

[0061] The diol acetate product is isolated by filtration by washing the product with H2O (300 ml), the product is then left to dry under vacuum for 18 hours at 65°C.

[0062] 50 g of diol acetate of 95% purity and 90% yield are obtained.

[0063] 1H NMR (DMSO-d6, 400MHz, 298K, significant signals): 7.40 (1 H, d); 6.15 (1 H, dd); 5.99 (1 H, s); 5.53 (1 H, d); 5.33 (1 H, d); 4.97 (1 H, s); 4.95 (1 H, d); 4.85 (1 H, d); 4.76 (1 H, m); 2.09 (3H, s); 1.37 (3H, s); 0.58 (3H, s).

[0064] Into a 2000 ml flask, in an inert environment and at 25°C, diol acetate (100 g) and DMAP (3.3 g) are introduced. THF (250 ml) is added, the mixture is stirred and AC2O (38 ml) is added dropwise without exceeding 30°C. When the reaction is complete, after 30 min at 25°C, H2O (1000 ml) is added over 30 min without exceeding 25°C. When the precipitation of the product is complete, the mixture is left under stirring for 60 min at 25°C, the product is filtered by washing with H2O (300 ml) and dried under vacuum for 18 hours at 50°C. 108 g of A9(11)-prednisolone-16,21-diacetate of a purity not lower than 97% are obtained. Yield= 98%

[0065] 1H NMR (DMSO-d6, 400MHz, 298K, significant signals): : 7.41 (1 H, d); 6.16 (1 H, d); 6.00 (1 H, s); 5.75 (1 H, s); 5.55 (1 H, bd); 5.52 (1 H, m); 4.89 (1 H,d); 4.86 (1 H, d); 2.71-

[0066] 2.65 (2H, m); 2.40 (1 H, m); 2.33 (1 H, m); 2.10 (3H, s); 2.01 (3H, s); 1.81 (1 H, dd);

[0067] 1.65 (1 H, m); 1.38 (3H, s); 1.06 (1 H, qd); 0.61 (3H, s).

[0068] MS-positive ES: 443.1 m / z [M+H]+; 465.1 m / z [M+Na]+

[0069] Example 3

[0070] Step a - formation of 9a-bromoprednisolone-16,21 -diacetate (“bromohydrin”).

[0071] A9(11)-prednisolone-16,21-diacetate (108 g) and acetone (605 ml) are loaded into a 2000 ml flask, in an inert environment and at 25°C. The resulting mixture is stirred and cooled to -10°C. H2O (160 ml) is added and then 70% HCIO4 (5 ml), allowing the temperature to rise to 0°C. 1 ,3-dibromo-5,5-dimethylhydantoin (56 g) is charged in 10 min and left to react for 45 min at 0°C. When the reaction is complete, a solution of Na2S2C>5 (20 g) and NaOAc (54 g) in H2O (421 ml) is slowly added without exceeding 10°C. Subsequently, still without exceeding 10°C, the mixture is diluted with H2O (324 ml) in 30 min and stirred for further 60 min at 10°C. The suspension is filtered washing the bromohydrin with H2O (605 ml) and then it is crushed for 30 min at 25°C in H2O (1008 ml). It is filtered by washing the bromohydrin with H2O (605 ml). The bromohydrin is crushed again for 120 min at 25°C in diisopropyl ether (702 ml), filtered and washed with diisopropyl ether (216 ml).

[0072] Step b - formation of prednisolone-16,21-diacetate.

[0073] Into a 2000 ml flask, in an inert environment and at 25°C, the bromohydrin and THF (1000 ml) are loaded. The solution is stirred and bis (tributyltin) oxide (230 ml), polymethylhydrosiloxane (67 ml) and azobisisobutyronitrile (1 g) are introduced. The mixture is refluxed for 10 min and then cooled to 40°C and maintained under these conditions until complete reaction. The distillation is carried out under vacuum up to an internal volume of about 760 ml, diisopropylether (400 ml) is charged and the distillation is continued up to an internal volume of about 320 ml. Diisopropylether (800 ml) is charged, brought to 20°C and stirred for 120 min. The solution is filtered and washed with diisopropylether (200 ml). The debrominated product is crushed for 60 min at 25°C in diisopropylether (500 ml), filtered and washed with diisopropylether (200 ml).

[0074] Step c - prednisolone- 16,21 -diacetate purification.

[0075] In a 3000 ml flask, in an inert environment and at 25°C, the crude debrominated, acetone (1500 ml) and H2O (370 ml) are charged. The mixture is heated to reflux and charcoal (10 g) is loaded and maintained at reflux for 30 min. The suspension is filtered while hot, washing the charcoal with a mixture of acetone (80 ml) and H2O (20 ml). The solution is distilled at atmospheric pressure up to an internal volume of about 540 ml, cooled to 10°C, filtered, washing the product with a mixture of acetone (60 ml) and H2O (240 ml). The product is left to dry under vacuum for 18 hours at 70°C. 88 g of prednisolone- 16,21 -diacetate of 99% NLT purity are obtained. Yield= 80%1H NMR (DMSO-d6, 400MHz, 298K, significant signals): 7,32 (1 H, d); 6,17 (1 H, dd); 5,93 (1 H, s); 5,54 (1 H, s); 5,46 (1 H, m); 4,93 (1 H, d); 4,83 (1 H, d); 4,79 (1 H, d); 4,29 (1 H, m); 2,52 (1 H, m); ; 2,29 (1 H, dd); 2,10 (3H, s); 2,04 (1 H, dd); 1 ,99 (3H, s); 1 ,65 (1 H, dd); 1 ,49 (1 H, m); 1 ,39 (3H, s); 1 ,01 (1 H, td); 0,93 (1 H, dd); 0,89 (3H, s).

[0076] MS-positive ES: 461.1 m / z [M+H]+; 443.1 m / z [M-H2O]+; 483.1 m / z [M+Na]+Example 4

[0077] In a 5000 ml flask, in an inert environment and at 25°C, prednisolone-16,21-diacetate (88 g) and methanol (2024 ml) are introduced, stirred and cooled to 10°C. Na2EDTA (3.5 g) is charged and a mixture of 30% NaOH (3.3 ml) and methanol (220 ml) is added dropwise while maintaining the temperature at 10°C. After 30 min at 10°C, the insoluble residue is filtered, washing it with CH2CI2 (440 ml) and it is left to react for further 30 min. When the reaction is complete, pH is brought to 5-6 with 80% AcOH (2.4 ml) and distilled under vacuum up to an internal volume of about 220 ml. The temperature of the resulting solution is brought to 10°C, H2O (352 ml) is added, the suspension is filtered at 10°C by washing with a mixture of methanol (66 ml) and H2O (154 ml). The produuct is left to dry under vacuum for 18 hours at 50°C.

[0078] 65 g of crude 16a-hydroxy prednisolone of 99% NLT purity are obtained. Yield=93%

[0079] Crude 16a-hydroxy prednisolone (65 g), MeOH (450 ml), CH2CI2 (450 ml) and 80% AcOH (0.6 ml) are loaded into a 2000 ml flask, in an inert environment and at 25°C. The resulting solution is stirred, heated to reflux, after 10 min charcoal (6.4 g) is introduced and left under reflux for 30 min. The solution is filtered while hot, washing the charcoal with a mixture of MeOH (65 ml) and CH2CI2 (65 ml). The suspension is distilled at atmospheric pressure up to an internal volume of about 190 ml, cooled to 0°C and stirred for 60 min. The suspension is then filtered, by washing the product with MeOH (65 ml). The product is left to dry under vacuum for 18 hours at 50°C.

[0080] 58 g of 16a-hydroxy prednisolone of 99.5% NLT purity are obtained. Yield= 90%1H NMR (DMSO-d6, 400MHz, 298K, significant signals): 7,30 (1 H, d,); 6,16 (1 H, d); 5,91 (1 H, s); 5,37 (1 H, d); 4,76 (1 H, m); 4,65 (2H, m); 4,53 - 4,46 (2H, m); 4,49 (1 H, dd); 4,26 (1 H, m); 4,08 (1 H, dd); 2,48 (1 H, m); 2,28 (1 H, dd); 1 ,88 (1 H, dd); 1 ,51 (1 H, dd); 1 ,38 (3H, s); 0,98 (1 H, m); 0,90 (1 H, dd); 0,85 (3H, s).

[0081] 13C NMR (DMSO-d6, 100.6 MHz, 289K): 17,1 (18CH3); 20,9 (19CH3); 30,7 (8CH); 31 ,3 (6CH2); 33,9 (CH2); 34,1 (CH2); 39,2 (12CH2); 43,8 (C); 47,0 (C); 49,8 (14CH); 55,2 (9CH); 66,7 (21CH2); 68,3 (11CH); 71 ,4 (16CH); 87,7 (17C); 121 ,6 (4CH); 127,1 (2CH); 156,6 (1CH); 170,3 (5C); 185,1 (3C); 211 ,8 (20C).

[0082] MS-positive ES: 377.1 m / z [M+H]+; 359.1 m / z [M-H2O+H]+; 341.1 m / z [M-2H2O+H]+; 323.0 m / z [M-3H2O+H]+

Claims

CLAIMS1) Process for the preparation of 16a-hydroxy prednisolone of formula (I)comprising the following steps: a) dihydroxylation of the tetraene acetate of formula (II)to give the corresponding diol of formula (111)b) selective acetylation of the diol of formula (III) in position 16 to provide the compound of formula (IV)c) bromination of the acetate of formula (IV) thus obtained to give the corresponding bromohydrin of formulad) debromination of the compound of formula (V) to provide the correspondinge) deacetylation of compound (VI) to give the desired 16a-hydroxy prednisolone of formula (I).2) Process according to claim 1, in which said step a) is performed in the presence of an oxidizing agent selected from osmium tetroxide, potassium permanganate, preferably potassium permanganate.3) Process according to any one of the preceding claims, in which said step b) is performed in the presence of an acetylating agent selected from acetic anhydride o acetyl chloride, preferably acetic anhydride.4) Process according to claim 3, in which said acetylating agent is used in a molar amount comprised between 1 equivalent and 2 equivalents, preferably of about 1.6 equivalents, with respect to the molar amount of the compound of formula (III).5) Process according to any one of the preceding claims, in which said step c) is performed in the presence of a brominating agent selected from N-bromo succinimide, bromine and 1 ,3-dibromo-5,5-dimethylhydantoin, preferably 1 ,3-dibromo-5,5- dimethylhydantoin.6) Process according to any one of the preceding claims, in which said step d) is performed by adding a radical initiator selected from azobisisobutyronitrile, 2,2'- Azobis(2,4-dimethylvaleronitrile) V-65, 2,2'-Azobis(4-methoxy-2,4- dimethylvaleronitrile) V-70, preferably azobisisobutyronitrile.7) Process according to any one of the preceding claims, characterized in that it comprises a step f) of purification of 16a-hydroxy prednisolone of formula (I).8) Process according to claim 7, in which said purification is performed by washing with a mixture of dichloromethane / methanol, preferably in a ratio (1 :1).9) Use of compounds of formula (IV), (V), (VI)as intermediates in the preparation of 16a-hydroxy prednisolone of formula (I). 10) Process for the preparation of a corticosteroid of formula (VII)In which R1is a hydrogen atom or a methyl group;R2is a linear or branched Ci-Ce alkyl group, a cycloalkyl group, an aryl or heteroaryl group, comprising the process for the preparation of 16a-hydroxy prednisolone of formula (I) according to any one of the preceding claims.

Images