Technical Field

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

State of the Art

Lurasidone (also known as MK-3756, SM-13496, SMP-13496) is a dual antagonist of dopamine D2 and 5-HT2A receptors and is used in treating schizophrenia.

Lurasidone and its pharmaceutically acceptable salts were first described in EP patent 0464 846 (JP 180271/90) of Dainippon Sumitomo Pharma. Procedure of the synthesis (Scheme 1) starts from the diol of formula 4, which can be prepared by reduction of derivatives 2 or 3.

Scheme 1

Activation of hydroxyl groups by conversion to bis mesylate of formula 6 and its reaction in presence of a base with the piperazine derivative of formula 5 leads to formation of the spiro quaternary ammonium salt of formula 7. Claimed in the patent are also compounds of type 6, where the leaving group can be halogen or alkyl or aryl sulphonate. Compound 7 has both symmetry plane and axis and is then used for N-alkylation of imide 8 with formation of 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 forms are further protected by patent JP 2006-282527. Racemic lurasidone is then resolved with L-tartaric acid in methanol; the (+)-enantiomer crystallizes in the form of the salt; processing of mother liquors and formation of the salt with D-tartaric acid provided the corresponding salt of the (-)-enantiomer. Both salts are then converted to hydrochlorides. Absolute stereochemistry is not assigned in the basic patent. The conversion of the lurasidone base to hydrochloride in acetone with a 3-5 % aqueous solution of HCl is described in patent WO 2005/009999 Al .

Optically active lurasidone can be prepared by synthesis starting from optically pure diol 4, prepared from corresponding cbiral diacid 3 by resolution (e.g. Applequist, Veraer J. Org. Chem. 1963, 28, 48). The preparation and crystalline forms of the enantiomerically pure (lR,2R)-bismesyl derivative 5 are described and claimed in patent JP 2006-282527; priority March 31, 2005 (Sumitomo).

Hence, all known syntheses use resolution of racemic intermediates by means of chiral agents, where half of the starting material (inverse enantiomer) must be removed as a waste. Therefore, it was necessary to develop a procedure that would provide for preparing an optically active intermediate for production of lurasidone in an enantioselective way from achiral starting materials and thus improving economy of the process.

Disclosure of Invention

The invention provides a new diastereoselective procedure of preparing lurasidone, which is based on use of the new intermediate of formula 12.

The reduction of the nitro group of the intermediate of formula 12 provides the amino intermediate of formula 13,

which reacts in the next step with anhydride 14 to form lurasidone of formula 1, which can then be converted to any salt of lurasidone.

The invention further includes a method of preparing the new intermediate of formula 12, which consists in reductive amination of the chiral intermediate of formula 1 la with the heterocyclic intermediate of formula 6. The intermediate of formula 12 is subsequently diastereoisomerically purified by preparing a salt with an optically active acid.

The new method of preparing lurasidone according to the invention, including preparation of the intermediate of formula 12, is depicted in the following Scheme 2.

Scheme 2

Detailed description of invention

The method of preparing (3aR,4S,7R _} 7aS)-2-(((lR,2R)-2-((4-(benzo[d]isothiazol-3-yl) piperazin- 1 -yl)methyl)cyclohexyl)methyl)hexahydro- 1 H-4,7-methanoisoindole- 1 ,3(2H)-dione (lurasidone) of formula 1

of high optical purity comprises the following reaction steps or it can comprise just steps c) and

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

(9)

is reacted with nitromethane (stage A)

in presence of a catalyst and optionally a co-catalyst to produce a mixture of the diastereoisomers of formulae 11a and 1 lb

(11a) (lib)

b) the diastereoisomer of formula 11a, pure or enriched in a mixture with the diastereoisomer of formula 1 lb, is reacted with the amine of formula 6 (stage B)

(6)

to form the nitro compound of formula 12

(121

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 amino group with formation of the intermediate of formula 13 (stage C)

d) the crude reaction mixture is reacted with the anhydride of formula 15 (stage D)

to form, lurasidone of formula 1.

Lurasidone of formula 1 can be subsequently isolated from the reaction mixture in the form of a salt with an appropriate acid to form an optically pure, which, after releasing the base, is converted to the hydrochloride or other pharmaceutically acceptable salts.

Stage A: The Michael addition of nitromethane to 1-cyclohexene-1-carboxaldehyde runs with a high stereoselectivity (as described in WO 2011/047190 Gellman S.H.; Guo L; Giulia.no M.) in presence of a catalyst and possibly a co-catalyst with formation of two diastereoisomers 11a and 1 1 b. Table no. 1 shows some experiments in various solvents. The reaction can be performed under an inert atmosphere of nitrogen or argon at a temperature of 0 -35°C, preferably at 20°C, for 20-68 hours in presence of 1-18 molar % of a catalyst in various solvents, such as, for instance, alcohols, ethers, chlorinated solvents, preferably in ethanol. Table no. 1

Other optimizations relate to the ratio of the catalyst ((S)-(-)-a,a-diphenyl-2-pyrrolidine methanol trimethylsilyl ether) and the co-catalyst (benzoic acid). Other co-catalysts were also tested, such as, for instance, acetic acid; but, benzoic acid was chosen for optimization. Table no. 2 presents some selected examples.

Table no.2

* isolatec yield; ** acetic acid

The tests have shown that isolation and purification of the product has no effect oh the following stage and hence, after processing the reaction mixture, the crude product was used without purification in the following stage.

!

Stage B The crude mixture of nitro aldehydes 1 la and 1 lb is reacted with the amine of formula 6 (in a ratio of 0.86 - 2.3 equivalents) in DCM at temperature -5°C to +10°C under an inert (nitrogen, argon), wherein a reducing agent is gradually added from the group of complex boron hydrides, such as NaBH(OAch or NaBなCN, preferentially NaBH(OAc) ₃ (in an excess of 2.5-4.3 equivalent), and then stirred at 20°C for 16-18 hours. When a higher excess of amine 6 (ca. more than 1.3 equivalents) is used, amine 6 non-reacted during the processing is separated in high purity (HPLC 94.2%) and can be recycled. The product of formula 12 can be obtained from the crude reaction mixture in the form of a salt with an optically active acid, preferably with (+)-0,0'-Di-p-toluoyl-D-tartaric acid, which provides a product with purity around 93% and with a content of the undesirable isomer of ca. 1.5-2%. This salt can be easily recrystallized from methanol. The salt with D-tartaric acid can also be prepared, however, in this case just a minimum improvement of diastereoisomeric purity is reached (HPLC 8H9% + 11.27% isomer).

Stage C For the hydrogenation of the nitro group of the intermediate of formula 12 to the amine group of the intermediate of formula 13, it is appropriate to first release the base from the salt with the optically active acid (from step B). Of various possibilities and catalysts, the procedure with Raney nickel in methanol in a hydrogenation autoclave has been optimized for this reaction. An addition of acetic acid into the reaction mixture proved useful. The reduction with hydrogen on a metal catalyst is carried out in the temperature range of 20-60°C, preferably at room temperature, and at a pressure 100 kPa to 4000 kPa, preferably 1000 kPa (10 bars). The intermediate of formula 13 can be isolated from the reaction mixture, for instance, in the form of a dihydrochloride salt. Surprisingly, however, it has been found that in the next reaction step, using of the crude reaction mixture is preferred.

Stage D The crude reaction mixture containing the intermediate of formula 13 is dissolved in an appropriate inert organic solvent, such as, for instance, DMF, toluene, xylene; further, an organic or inorganic base (for instance TEA, DIPEA, K ₂ CO3, Na ₂ C0 ₃ ) and the anhydride of formula 14 (1.05-2.15 equivalents) can be added and the reaction mixture is heated to a temperature of 100-130°C under an inert atmosphere for 16-24 hours. The product can be isolated by column chromatography or by preparation of a salt. Direct preparation of lurasidone hydrochloride has not proven well; the yield, purity and, ee (enantiomeric excess) were low. 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%; it is prepared by the following method. The evaporation residue of the crude lurasidone base is dissolved in an appropriate solvent (such as, for instance, acetone, methanol, ethanol, isopropanol) at room temperature up to boiling temperature of the solvent; a solution of an optically active acid prepared at room temperature up to boiling temperature of the solvent, preferentially in alcohol, such as methanol, ethanol, isopropanol, is added. From the salt prepared in this way, the desired hydrochloride is easily obtained in high purity by releasing the base and subsequent preparation of the hydrochloride. The hydrochloride is best prepared in alcohols, such as methanol, ethanol, isopropanol, and their mixtures, by the action of an alcoholic solution of hydrogen chloride. Both salts can be easily recrystallized from methanol.

An advantage of this synthesis is represented by a minimum number of purification operations for obtaining pure isolated substances with high chemical and optical purity. As early as in the first stage, is the intermediate prepared with a high proportion (over 80%) of the desired diastereoisomer. The final lurasidone has ee > 99.8% without using classical resolution of racemates with an optically active acid to form diastereoisomeric salts, which sometimes requires re-purification by repeated crystallization. The preparation of salts with optically active acids serves only for isolation and for final chemical and optical purification of crude products. It is clear that the above-mentioned method of synthesis of lurasidone can also be utilized in preparing other salts of lurasidone than the HCl salt, possibly also in preparation of various solvates or co-crystallites of lurasidone.

The following working examples illustrate, however do not limit, universality of the method of production according to this invention.

Examples

Example 1: Preparation of (lR,2R)-2-(nitromethyl)cvclohexanecarbaldehvde (11a)

1-cyclohexene-1-carboxaldehyde (18.75 g, 170 mmol), a catalyst (_?)-(-)-a _s a-diphenyl-2- pyrrolidine methanol trimethylsilyl ether (5.27 g, 16.2 mmol, 9.5%), the co-catalyst benzoic acid (1.97 g, 16.1 mmol, 9.5%) are weighed into a dry flask of 500 ml, ethanol (100 ml) is added, and, after 5 minutes, nitromethane (26.8 ml, 496 mmol, 2.9 equivalent) is added into the solution stirred at room temperature under an inert atmosphere. The reaction mixture is stirred at room temperature under an inert atmosphere for 24 hours. The solvent is evaporated in a RVE (rotary vacuum evaporator) at the bath temperature of 40°C. Ethyl acetate (100 ml) and a 0.1M aqueous solution of HCl are added to the evaporation residue, the mixture is stirred for 5 minutes, and the upper organic layer is separated. The aqueous layer is shaken with ethyl acetate (30 ml). The combined organic portions are washed with brine (50 ml), dried above MgSd}, and evaporated in RVE. An orange oil (34.29 g, theory 29.14 g) is obtained containing, according to GC, 53.24% of the desirable diastereoisomer 11a and 10.566% of the second diastereoisomer l ib, which corresponds to the ratio 5.04 : 1 and a conversion of 75.08%. This crude mixture is used without purification in the next step. Example 2: Preparation of3-(4-{fflR,2R)-2-(nitromethyl)cvclohexylImethyl!piperazin- l-yl)- 1,2-benzisothiazole (12)

The orange oil (34.22 g; containing 21.83 g of the product; 127.5 mmol) from the previous step is dissolved in DCM (dichloromethane) (300 ml; dried, distilled), the amine of formula 6 (24.01 g; 109.5 mmol; 0.86 equivalent) is added, and the resulting solution is cooled under an inert to temperature of 0°C. NaBH(OAc) ₃ (67.67 g; 319.3 mmol; 2.5 equivalent) is gradually added during 15 min, the cooling is then switched off, and the reaction mixture is stirred at room temperature under an inert overnight (ca 16 hours). The excess of the agent is decomposed by a careful dropwise addition of water (30 ml) into the thick suspension. A IM aqueous solution of NaOH (75 ml) is then added and, after 10 minutes of stirring, the organic layer is separated, washed with brine (80 ml), dried with MgSC>4 _; and evaporated in RVE. The obtained brown evaporation residue (70 g) contains 57.33 % of the desirable product and 14.03 % of the undesirable diastereoisomer according to HPLC. Conversion is 100 %. The evaporation residue is dissolved in acetone (92 ml) to the total volume of 150 ml.

Example 3: Preparation of a salt with f+)-0,0 '-di-p-toluoyl-D-tartaric acid

The acetone solution from the previous example (80 ml, containing 21.86 g of the substance of formula 12; 58 mmol) is heated to 50°C and a solution of (+)-0,0'-di-p-toluoyl-D-tartaric acid (23.0 g; 59.5 mmol) in methanol (35 ml) heated to 50°C is added under stirring. Methanol (15 ml) is used for rinsing and the reaction mixture is stirred under slow cooling to room temperature for 5 hours. The formed crystals (24.90 g; 56.06 % of theoretic yield) are sucked off and washed with methanol (3 x 15 ml). The white crystals have a melting point 172.5 - 174.8°C, HPLC 92.9 %, and the content of the undesirable isomer of 1.98% (NMR).

Example 4: Preparation ofl-f(lR _t 2R)-2-f(4-(l,2-benzisothiazol-3-yl)piperazin-l-yll methyltevclohexyllmethanamine (13)

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

Example 5: Preparation of (3aR.4S.7R.7aS)-2-((aR.2R)-2-((4-(benzofdlisothiazol-3- \l)piperazin-l-yl)rnethyl)cvclohexyl)methyl)hexahvdro-lH-4J- m

dione (1)

The crude product 13 according to the previous example (2.48 g; HPLC 55.65 %; 4 mmol) was dissolved in DMF (10 ml) under an inert at room temperature. K ₂ C0 ₃ (1.24 g; 7.46 mmol; 1.86 equivalent) was added to the yellow solution, then anhydride 14 (1.02 g; 7.38 mmol; 1.85 equivalent) was added and the reaction mixture was slowly heated to the temperature of 120°C, at which it was stirred under an inert for 18 hours. After cooling down, 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 in RVE. The brown oil (1.93 g; conversion 98 %), HPLC 78.0%, was used in preparing the salt without further purification,

Example 6 Preparation of lurasidone salt with D-tartaric acid

The crude lurasidone (1.83 g; content 2.9 mmol) from the previous example was dissolved in methanol (5 ml) and a warm (40°C) solution of D-tartaric acid (0.46 g; 3.06 mmol) in methanol (5 ml) was poured into the solution at 40°C; rinsing with methanol (5 ml); the reaction mixture was stirred at 50°C for 5 minutes, and then left to cool down slowly to room temperature. After 25 minutes, IPA (15 ml) was added. The separated crystals were sucked off (1.64 g; 88.14% of theoretical yield); HPLC 96.52%, ee > 99.8%.

The crystals obtained in this way (1.59 g) can be recrystallized under boiling from methanol (70 ml). The white to almost white crystals (1.12 g; 70.30% of theory) with melting point 111 - 113°C, HPLC 98.5%, ee > 99.8%, were obtained.

Example 7 Preparation of lurasidone hydrochloride

The tartrate from the previous example (1.04 g; 1.6 mmol) is stirred in DCM (20 ml), 10% aqueous solution of Na ₂ C0 ₃ (20 ml) is added, and the suspension changes into a solution under stirring; the organic layer is separated and the solvent evaporated in RVE. A solution of HCl in ethanol (6 ml) and IPA (6 ml) is added to the formed white foam. The crystals of lurasidone hydrochloride are separated by stirring under an inert at 20°C (760 mg, 88.8% of theoretical yield), HPLC 99.46%, ee > 99.8%, melting point 235 - 237.7°C.

Lurasidone hydrochloride (704 mg, 1.33 mmol) is stirred in methanol (12 ml) and dissolved at 65°C. The resulting solution is left to cool down slowly. The separated crystals (492 mg, 70% of theoretical yield) are sucked off, washed with methanol (3 ml).

The white crystals have purity 99.83% according to HPLC, ee > 99.8%, and melting point 235 - 237.7°C

Ή NMR (dmso, 25°C) 6 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), 51 - 3.66(m, 4H), 3.46(m, 1H), 3.23 - 3.40(m, 4H), 3.06(m, 1H), 2.69(m, 2H), 2.50 (m, 1H),14(m, 1H), 1.74(m _s 1H), 1.45 - 1.62(m, 6H), 1.31(m ₅ 2H) ₅ 1.09 - 1.26(m, 4H), 0.97(m, 2H)C NMR (draso, 25 °C ) δ 179.0, 162.2, 152.1, 128.1, 127.0, 124.6, 124.0, 121.2, 59.4, 52.4, .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.