CZ306203B6 - Lurasidone synthesis process - Google Patents

Abstract

The present invention relates to a novel synthesis process of lurasidone, a substance of the chemical name (3aR,4S,7R,7aS)-2-(((1R,2R)-2-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione of the structural formula 1 and salts thereof. More specifically, the present invention relates to a diastereoselective process for preparing lurasidone that is characterized by the use of a novel intermediate of the general formula 12. Through the reduction of the nitro group of the intermediate of the general formula 12, there is obtained an amino intermediate of the general formula 13, which reacts in the next step with an anhydride of the general formula 14 to yield lurasidone of the general formula 1, which can be further converted to an arbitrary lurasidone salt.

Description

Method for synthesis of lurasidone

Field of technology

The present invention relates to a novel approach in the synthesis of lurasidone, the chemical name (3aR, 4S, 7R, 7aS) -2 - (((1R, 2R) -2 - ((4- (benzo [d] isothiazol-3-yl) piperazine)). -1-yl) methyl) cyclohexyl) methyl) hexahydro-1H-1,7-methanoisoindole-1,3 (2H) -dione of structure 1 and its salts.

Prior art

Lurasidone (also known as MK-3756, SM-13496, SMP-13496) is a dual antagonist of dopamine D2 and 5-HT ₂ receptors and is used to treat schizophrenia.

Lurasidone and its pharmaceutically acceptable salts were first described in EP 0 464 846 (JP 180271/90) by Dainippon Sumitomo Pharma. The synthetic procedure (Scheme 1) is based on a diol of formula 4, which can be prepared by reduction of derivatives 2 or 3.

Scheme 1

Activation of hydroxyl groups by conversion to the mesylate of formula 6 and its reaction in the presence of a base with a piperazine derivative of formula 5 leads to the formation of spiroquaternary ammonium salts of formula 7. The patent also claims compounds of type 6 where the leaving group may be halogen or alkyl or aryl sulfonate. Compound 7 has a plane and axis of symmetry and is then used to N-alkylate imide 8 to give Lurasidone 1, which was isolated by column chromatography and then converted to the hydrochloride.

The preparation of the mesylate of formula 6 and its crystalline form is further protected by JP 2006-282527. Racemic lurasidone is then optically resolved with L-tartaric acid in methanol, the (+) - enantiomer crystallizes out in the form of a salt, treating the mother liquors and forming a salt with D-tartaric acid gives the corresponding salt of the (-) - enantiomer. Both salts are then converted to the hydrochlorides. Absolute stereochemistry is not assigned in the basic patent.

The conversion of lurasidone base to the hydrochloride in acetone with 3 to 5% aqueous HCl is described in WO 2005/009999 A1.

Optically active Lurasidone can be prepared by synthesis starting from an optically pure diol 4 prepared from the corresponding chiral diacid 3 by optical resolution (e.g. Applequist, Verner J. Org. Chem. 1963, 28, 48).

The preparation and crystalline forms of the enantiomerically pure (1R, 2R) -bismethyl derivative 5 are then described and claimed in JP 2006-282527, priority 31.3. 2005 (Sumitomo).

Thus, all known syntheses use optical resolution of racemic intermediates using chiral reagents, where half of the starting material (opposite enantiomer) must be removed as waste. Therefore, there was a need to develop a process that would allow the preparation of an optically active intermediate for the production of Lurasidone enantioselectively from achiral starting materials and thus improve the economics of the process.

The essence of the invention

The present invention relates to a novel diastereoselective process for the preparation of lurasidone, which is based on the use of a novel intermediate of formula 12.

Reduction of the nitro group of intermediates of formula 12 affords the amino intermediate of formula 13, which in the next step is reacted with anhydride 14 to give lurasidone of formula 1, which can be further converted to any salt of lurasidone.

The invention further includes a process for the preparation of a novel intermediate of formula 12 which comprises reductive amination of a chiral intermediate of formula 11a with a heterocyclic intermediate of formula 6. The intermediate of formula 12 is further diastereomerically purified by preparation of a salt with an optically active acid.

-2 CZ 306203 B6

A novel process for the preparation of lurasidone according to the invention, including the preparation of an intermediate of formula 12, is shown in the following Scheme 2.

Scheme 2

⁺ —No ₂

11a

Description of the invention

Process for the preparation of (3aR, 4S, 7R, 7aS) -2 - (((1R, 2R) -2 - ((4- (benzo [d] isothiazol-3-yl) piperazin-1-yl) methyl) cyclohexyl) methyl ) hexahydro-1H-4,7-methanoisoindole-1,3 (2H) -dione (lurasidone) of formula 1

of high optical purity comprises the following reaction steps, or may comprise only steps c) and d):

a) 1-cyclohexene-1-carboxaldehyde of formula 9

(9) reacts with nitromethane (step A) in the presence of a catalyst and optionally a cocatalyst to form a mixture of diastereoisomers of formula 11a and 11b

(Ha)

(11b)

b) the diastereoisomer of formula 11a, pure or enriched in a mixture with the diastereoisomer of formula 11b, is reacted with an amine of formula 6 (step B)

(6) to give a nitro compound of formula 12

(12) which is isolated in the form of a salt of high diastereoisomeric purity

c) the nitro group of the intermediate of formula 12 is reduced to the amino group to give the intermediate of formula 13 (step C)

d) reacting the crude reaction mixture with the anhydride of formula 15 (step D) p

-4GB 306203 B6

to give lurasidone of formula 1.

Lurasidone of formula 1 can then be isolated from the reaction mixture as a salt with a suitable acid to give an optically pure salt which, upon liberation of the base, is converted to the hydrochloride or other pharmaceutically acceptable salts.

Step A The Michael addition of nitromethane to 1-cyclohexene-1-carboxaldehyde proceeds with high stereoselectivity (described in WO 2011/047 190 Gellman S.H .; Guo L .; Giuliano M.) in the presence of a catalyst and optionally a cocatalyst to give 2 diastereoisomers 11 and 11b. Table 1 shows some experiments in different solvents. The reaction can be carried out under an inert atmosphere of nitrogen or argon at 0 to 35 ° C, preferably at 20 ° C, for 20 to 68 hours in the presence of 1 to 18 mol% of catalyst in various solvents such as alcohols, ethers, chlorinated solvents, preferably in ethanol.

Table 1

number solvent conversion lla: llb 1 ethanol 39% 5.4: 1 2 methanol 38% 4.1: 1 3 isopropanol 29% 5.2: 1 4 dichloromethane 37% 4.6: 1

Further optimizations concerned the ratio of catalyst ((S) - (-) - α, α-diphenyl-2-pyrrolidine methanol (trimethylsilyl ether) to cocatalyst (benzoic acid). Other cocatalysts such as acetic acid were also tested, but benzoic acid was selected for optimization. Table 2 shows some selected examples.

Table No. 2

Number Catalyst Cocatalyst Conversion Ratio East substance Time (h) 5 16% 9% 65.2% 4.9: 1 2% 20 6 16.5% 26% 33.0% 4.8: 1 6.8% 20 7 16% 4% 48.0% 4.9: 1 0 20 8 4.2% 8.2% 67.3% 5.1: 1 7% 20 9 1.7% 12% 19.2% 5.0: 1 49% 20

-5CZ 306203 B6

10 1.7% 8.5% 22.2% 4.8: 1 3.5% 68 11 4.3% 7.2% 59.5% * 5.1: 1 11.5% 25 12 9.5% 9.5% 75.1% * 5.04: 1 0.9% 24 13 10.7% 37.5% ** 63.5% 4.8: 1 8.3% 20 14 16.6% 32% ** 61.4% 4.8: 1 0 20

* isolated yield; ** acetic acid

It was tested that the isolation and purification of the product did not affect the next step, so after working up the reaction mixture, the crude product was used in the next step without purification.

Step B A crude mixture of nitroaldehydes 11a and 11b is reacted with an amine of formula 6 (0.86 to 2.3 equivalents) in dichloromethane (DCM) at -5 ° C to + 10 ° C under an inert (nitrogen, argon), where a reducing agent from the group of complex boron hydrides, such as NaBH (OAc) ₃ or NaBH ₃ CN, preferably NaBH (OAc) ₃ (in an excess of 2.5 → 1.3 equivalents), is gradually added and then allowed to stir at 20 ° C for 16 to 48 hours. Using a larger excess of amine 6 (ca. more than 1.3 equivalents), unreacted amine 6 is precipitated in high purity (HPLC 94.2%) during processing and can be recycled. From the crude reaction mixture the product of formula 12 can be obtained in the form of a salt with an optically active acid, preferably with (+) - O, O'-di-p-toluoyl-D-tartaric acid, which gives a product with a purity of about 93% and of the undesired isomer is about 1.5 to 2%. This salt can be easily recrystallized from methanol. It is also possible to prepare a salt with D-tartaric acid, but in this case there is only a minimal improvement in diastereoisomeric purity (HPLC 81.9 + 11.27% isomer)

Step C To hydrogenate the nitro group of the intermediate of formula 12 to the amino group of the intermediate of formula 13, it is convenient to first release the base from the salt with the optically active acid (from step B). From various possibilities and catalysts, the process with Raney nickel in methanol in a hydrogenation autoclave was optimized for this reaction. The addition of acetic acid to the reaction mixture proved to be effective. The reduction with hydrogen on the metal catalyst is carried out in a temperature range of 20 to 60 ° C, preferably at room temperature, and a pressure of 100 kPa to 4000 kPa, preferably 1000 kPa (10 bar). The intermediate of formula 13 can be isolated from the reaction mixture, for example in the form of the dihydrochloride salt. Surprisingly, however, it has proved more advantageous to use the crude reaction mixture for the next reaction step.

Step D The crude reaction mixture containing the intermediate of formula 13 is dissolved in a suitable inert organic solvent such as dimethylformamide (DMF), toluene, xylene, an organic or inorganic base (e.g. triethylamine (TEA), diisopropylethylamine (D1PEA), K ₂ CO ₃ , Na ₂ CO ₃ ) and the anhydride of formula 14 (1.05-2.15 equivalents) and the reaction mixture is heated to 100-130 ° C for 16-24 hours under an inert atmosphere. The product can be isolated by column chromatography or salt preparation. Direct preparation of lurasidone hydrochloride has not been successful, yield is low, low in purity and ee. The salt with D-tartaric or mandelic acid, preferably with D-tartaric acid, was obtained in good yields with good purity and with ee. 100% is prepared as follows: The residue of crude lurasidone base is dissolved in a suitable solvent (such as acetone, methanol, ethanol, isopropanol (1PA)) at room temperature to the boiling point of the solvent and a solution of optically active acid prepared at room temperature to boiling of the solvent, preferably in an alcohol such as methanol, ethanol, isopropanol, The desired hydrochloride is easily obtained from the salt thus prepared in high purity by liberating the base and subsequent preparation of the hydrochloride.The hydrochloride is preferably prepared in alcohols such as methanol, ethanol, isopropanol and mixtures thereof by the action of an alcoholic solution of hydrogen chloride, both salts can be easily recrystallized from methanol.

-6GB 306203 B6

The advantage of this synthesis is the minimal number of purification operations to obtain pure isolated substances with high chemical and optical purity. Already in the first step, an intermediate with a high proportion (above 80%) of the desired diastereoisomer is prepared. The resulting lurasidone has an ee> 99.8% without the use of classical resolution of racemates with an optically active acid to give diastereomeric salts, which sometimes need to be purified by repeated crystallizations. The preparation of salts with optically active acids serves only for the isolation and chemical and optical purification of crude products.

It is clear that said method of synthesizing lurasidone can also be used in the preparation of lurasidone salts other than the HCl salt, or in the preparation of various solvates or cocrystals of lurasidone. The following examples illustrate, but do not limit, the generality of the production method according to the invention.

Examples of embodiments of the invention

Example 1 Preparation of (1R, 2R) -2- (nitromethyl) cyclohexanecarbaldehyde (IIa)

Weigh 1-cyclohexene-1-carboxaldehyde (18.75 g, 170 mmol), (5) - (-) - α, α-diphenyl-2-pyrrolidine methanol trimethylsilyl ether (5) to a 500 mL dry flask. , 27 g, 16.2 mmol, 9.5%), benzoic acid cocatalyst (1.97 g, 16.1 mmol, 9.5%), ethanol (100 mL) was added, and after 5 minutes After stirring at room temperature under an inert atmosphere, nitromethane (26.8 mL, 496 mmol, 2.9 eq) was added. The reaction mixture was stirred for 24 hours at room temperature under an inert atmosphere. The solvent was evaporated on an RVO (rotary evaporator) at a bath temperature of 40 ° C. Ethyl acetate (100 mL) and 0.1M aqueous HCl were added to the residue, the mixture was stirred for 5 minutes, and the upper organic layer was separated. The aqueous layer was shaken with ethyl acetate (30 mL). The combined organics were washed with brine (50 mL), dried over MgSO ₄ and evaporated to dryness. An orange oil (34.29 g, theory 29.14 g) is obtained with a GC content of 53.24% of the desired diastereoisomer 11a and 10.566% of the second diastereoisomer 11b, corresponding to a ratio of 5.04: 1 and a conversion of 75.08%. This crude mixture was used without purification in the next step.

Example 2 Preparation of 3- (4 - {[(1R, 2R) -2- (nitromethyl) cyclohexyl] methyl} piperazin-1-yl) -1,2-benzsothiazole (12)

The orange oil (34.22 g; containing 21.83 g of product; 127.5 mmol) from the previous step was dissolved in DCM (dichloromethane) (300 mL; dried, distilled) and the amine of formula 6 (24.01 g; 109.5 mmol; 0.86 equivalents) and the resulting solution was cooled to 0 ° C under inert. _{NaBH (OAc) 3} (67.67 g; 319.3 mmol; 2.5 eq.) Was added gradually over 15 min, then the cooling was turned off and the reaction mixture was allowed to stir overnight (ca. 16 h) at room temperature under inert . Excess reagent was quenched by careful dropwise addition of water (30 mL) to a thick suspension. Then 1M aqueous NaOH solution (75 ml) was added and after stirring for 10 minutes the organic layer was separated, washed with brine (80 ml), dried over MgSO ₄ and evaporated to RVO. A brown residue (70 g) is obtained which contains, according to HPLC, 57.33% of the desired product and 14.03% of the undesired diastereoisomer. The conversion is 100%. The residue was dissolved in acetone (92 mL) to a total volume of 150 mL.

Example 3 Preparation of a salt with (+) - O, O'-Di-p-toluoyl-D-tartaric acid

The acetone solution from the previous example (80 ml containing 21.86 g of the compound of formula 12; 58 mmol) is heated to 50 ° C and a solution of (+) - O, O'-Di-p-toluoyl-D- tartaric acid (23.0 g; 59.5 mmol) in methanol (35 mL) heated to 50 ° C. Methanol (15 mL) was used for rinsing and the reaction mixture was allowed to stir slowly to room temperature for 5 hours. The crystals formed (24.90 g; 56.06% of theory) are filtered off with suction and washed with methanol (3 * 15 ml). The white crystals have a mp of 172.5-174.8 ° C and an HPLC of 92.9% and the content of the undesired isomer is 1.98% (NMR).

-7EN 306203 B6

Example 4 Preparation of 1 - [(1R, 2R) -2 - {[4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] methyl} cyclohexyl] methanamine (13)

The salt (13.50 g; 17.74 mmol) prepared in the previous example was stirred in DCM (100 mL) and 0.5 M aqueous NaOH (50 mL) was added to the suspension and the mixture was stirred vigorously until dissolved (ca. 10 minutes). The organic layer was separated, the solvent was evaporated on a RVO. The hydrogenation was carried out in methanol (200 ml) on Raney nickel (10.5 g of wet catalyst) with the addition of acetic acid (4 ml) at a pressure of 1000 kPa at room temperature for 6 hours. The catalyst was filtered off, the solvent was evaporated on RVO, the residue was dissolved in DCM (50 ml) and shaken with brine (30 ml). The organic layer was separated, the solvent evaporated on RVO to give a brown oil (7.14 g), HPLC 60.32%, corresponding to a conversion of 70.5%.

Example 5 Preparation of (3aR, 4S, 7R, 7aS) -2 - (((1R, 2R) -2 - ((4- (benzo [d] isothiazol-3-yl) piperazin-1-yl) methyl) cyclohexyl) methyl) hexahydro-11,4,7-methano-isoindole-1,3 (211) -dione (1)

The crude product 13 of the previous example (2.48 g; HPLC 55.65%; 4 mmol) was dissolved in DMF (10 mL) under inert at room temperature. To the yellow solution was added K ₂ CO ₃ (1.24 g; 7.46 mmol; 1.86 eq), then anhydride 14 (1.02 g; 7.38 mmol; 1.85 eq) and the reaction mixture was slowly heated to 120 ° C where it was stirred under inert for 18 hours. After cooling, toluene (25 mL) and water (15 mL) were added to the reaction mixture. The organic layer was washed with brine (5 x 5 mL) and the solvents were evaporated on RVO. A brown oil (1.93 g; 98% conversion) with 78.0% HPLC was used to prepare the salt without further purification.

Example 6 Preparation of lurasidone salt with D-tartaric acid

The crude lurasidone (1.83 g; 2.9 mmol content) from the previous example was dissolved in methanol (5 mL) and a warm (40 ° C) solution of D-tartaric acid (0.46 mL) was added to the solution at 40 ° C. g; 3.06 mmol) in methanol (5 ml), rinse with methanol (5 ml), stir the reaction mixture for 5 minutes at 50 ° C, then allow to cool slowly to room temperature. After 25 minutes, 1PA (15 mL) was added. The precipitated crystals are filtered off with suction (1.64 g; 88.14% of theory); HPLC 96.52%, ee. > 99.8%.

The crystals thus obtained (1.59 g) can be recrystallized by boiling from methanol (70 ml). White to off-white crystals (1.12 g; 70.30% of theory) with m.p. 111-113 ° C, HPLC 98.5%, ee. > 99.8%.

Example 7 Preparation of lurasidone hydrochloride

The tartrate from the previous example (1.04 g; 1.6 mmol) was stirred in DCM (20 mL), 10% aqueous Na ₂ CO ₃ (20 mL) was added and the suspension went into solution with stirring, the organic layer was separated. and the solvent was evaporated on an RVO. A solution of HCl in ethanol (6 mL) and IPA (6 mL) was added to the resulting white foam. Crystals of lurasidone hydrochloride (760 mg, 88.8% of theory) precipitate with stirring under an inert temperature at 20 DEG C., HPLC 99.46%, ee> 99.8%, mp 235-237.7 ° C.

Lurasidone hydrochloride (704 mg, 1.33 mmol) was stirred in methanol (12 mL) and dissolved at 65 ° C. The resulting solution was allowed to cool slowly. The precipitated crystals (492 mg, 70% of theory) were filtered off with suction and washed with methanol (3 ml).

The white crystals have an HPLC purity of 99.83%, ee. > 99.8% and m.p. 235-237.7 ° C 1 H NMR (dmso, 25 ° C) δ 10.85 (b, 1H), 8.14 (d, J = 8.3 Hz, 1H), 8.1 l (d, J = 8.2 Hz, 1H ), 7.59 (td, J = 7.2 Hz, J = 0.7 Hz, 1H), 7.47 (td, J = 7.7 Hz, J = 0.7 Hz, 1H), 4.04 (m, 2H), 3.73 (m, 1H), 3.513.66 (m, 4H), 3.46 (m, 1H), 3.23-3.40 (m, 4H), 3.06 (m, 1H), 2.69 (m, 2H), 2.50 (m, 1H), 2.14 (m, 1H), 1.74 (m, 1H), 1.45-1.62 (m, 6H), 1.3 (m, 2H), 1.09-1.26 (m, 4H), 0.97 (m, 2H)

-8CZ 306203 B6 ¹³ C NMR (dmso, 25 ° C) δ 179.0, 162.2, 152.1, 128.1, 127.0, 124.6, 124.0, 121.2, 59.4, 52.4, 49.8, 47.9, 46.0, 45.97, 41.3, 39.1,39.0, 37.8 , 33.9, 32.9, 29.8, 28.7, 27.4, 27.3, 23.8.

Claims (25)

A process for the preparation of lurasidone of formula 1 or a salt thereof, O (1), characterized in that it comprises the reduction of the nitro group of the compound of formula 12 or a salt thereof, to a compound of formula 13, which further reacts with the anhydride of formula 14 (14) to give lurasidone of formula 1 or optionally further converted to pharmaceutically acceptable salts. Preparation process according to Claim 1, characterized in that the reduction of the compound of formula 12 to the compound of formula 13 is carried out with hydrogen on a metal catalyst in the temperature range of 20 to 60 ° C and a pressure of 100 to 4000 kPa. -9CZ 306203 B6 Preparation process according to Claim 2, characterized in that the metal catalyst used is Raney nickel. Preparation process according to Claims 2 and 3, characterized in that the reduction is carried out at room temperature and at a pressure of 1000 kPa. Preparation process according to Claims 2 to 4, characterized in that the reduction is carried out with the addition of an organic acid. Preparation process according to Claims 2 to 5, characterized in that the reduction is carried out with the addition of acetic acid. Process according to Claims 1 to 6, characterized in that the reaction of the compound of the formula 13 with the anhydride of the formula 14 is carried out in the presence of an inert organic solvent. Preparation process according to Claim 7, characterized in that the organic solvent is selected from the group consisting of dimethylformamide - DMF, toluene and xylene, preferably DMF is used. Preparation process according to Claims 7 and 8, characterized in that the reaction is carried out in the presence of an organic or inorganic base. Preparation process according to Claim 9, characterized in that the base is selected from the group consisting of triethylamide - TEA, diisopropylethylamine - DIPEA, K ₂ CO ₃ , Na ₂ CO ₃ , preferably K ₂ CO ₃ is used. Preparation process according to Claims 7 to 10, characterized in that the reaction is carried out at a temperature of 100 to 130 ° C and for 16 to 24 hours, preferably at 120 ° C for 18 hours. Preparation process according to Claim 1 or 7 to 11, characterized in that the amine of the formula 13 is reacted in the form of a crude reaction mixture from the previous reaction step. Process according to Claim 1, characterized in that the lurasidone of the formula I is converted into the lurasidone salt by reaction with an optically active acid. Preparation process according to Claim 13, characterized in that the optically active acid is D-tartaric acid or mandelic acid. Preparation process according to Claim 14, characterized in that the optically active acid is D - (-) - tartaric acid. The preparation method according to claims 13 to 15, further comprising releasing the lurasidone base from the optically active acid salt and preparing a pharmaceutically acceptable salt of lurasidone, preferably the HCl salt. Process according to Claim 16, characterized in that the HCl salt of lurasidone is prepared by the action of an alcoholic solution of hydrogen chloride based on lurasidone. Process according to Claim 17, characterized in that an ethanolic solution of hydrogen chloride is used. 19. A compound of formula 12 - 10GB 306203 B6 The preparation method according to claim 1, characterized in that the compound of formula 12 according to claim 19 is prepared by a reaction (Ha) with compound 6 (6) Process according to Claim 20, characterized in that the reaction is carried out in the presence of a reducing agent from the group of complex boron hydrides, for example NaBH (OAc) ₃ or NaBH ₃ CN, preferably NaBH (OAc) ₃ . Process according to claims 20 and 21, characterized in that the intermediate of formula 12 is further isolated from the reaction mixture in the form of a salt with an optically active acid. A process according to claim 22, characterized in that an optically active acid from the group consisting of (+) - 0,0di-p-toluoyl-D-tartaric acid, D-tartaric acid or mandelic acid is used for the preparation of the salt of the intermediate of formula 12. . Preparation process according to Claim 23, characterized in that optically active (+) - O, O'-di-p-toluoyl-D-tartaric acid is used. 25. A process according to claim 20, wherein the chiral intermediate of formula 11a