RU2339631C1 - Method of obtaining esomeprazole - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method lies in enantioselective oxidation with organic peroxides of (S)-5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)-1H-benzo[d]imidazole in presence of catalytic complex of titanium (IV) with simultaneously two chiral ligands: chiral diol (preferably D-diethyltartrate) and chiral amine (preferably N,N-dimethyl-(R)-1-phenylethylamin).

EFFECT: increase of target product or its salt output.

1 cl, 1 dwg, 4 ex

Description

The invention relates to the field of chemistry of drugs, namely to the preparation of (S) -5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl) -1H-benzo [d] imidazole (esomeprazole ) of the general formula I and / or its salt.

Esomeprazole (I), a modern highly effective antiulcer drug, is the (S) -enantiomer of omeprazole and significantly exceeds the latter in clinical effect [T. Lapina Clinical Pharmacology and Therapy, 2002, 11, No. 2].

The only available effective method for the preparation of esomeprazole (I) until 1996 was the separation of the racemic mixture [Erlandsson P., Isaksson R., Lorentzon P., Lindberg P.J. Chromatogr. 1990, 532, 305; Kohl B., Senn-Bilfinger J. DE 4035455 (1990); Lindberg P., von Unge, S. WO 9427988 (1994); Deng J., Chi Y., Fu F., Cui X., Yu K., Zhu J., Jiang Y. Tetrahedron: Asymmetry, 2000, 11, 1729]. In 1996, a method was proposed for the enantioselective oxidation of 5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylthio) -1H-benzo [d] imidazole (II) to esomeprazole (I) [ Larsson EM, Stenhede UJ, Sorensen N., von Unge R.O. S., Cotton H.K. WO 9602535 (1996)], which included the preparation of a catalytic complex of titanium (IV) isopropylate, D-diethyl tartrate (D-DET) and water in the presence of sulfide (II), keeping the resulting catalytic complex at elevated temperature (before the addition of oxidizing agent) reactions in the presence of a base, preferably N, N-diisopropylethylamine, cumene hydroperoxide (CHP) was used as an oxidizing agent, and toluene was used as a solvent, and the catalyst was used in an amount of 30 mol% (Scheme 1). After treatment (extraction with aqueous ammonia, acidification of the aqueous layer with acetic acid, extraction with methyl isobutyl ketone), obtaining the sodium salt and recrystallization from acetonitrile, esomeprazole (I) was obtained with a yield of up to 55%. Similarly, other optically active dietethersulfides related to esomeprazole can be obtained. This method is chosen by us as a prototype.

Scheme 1.

Further research in this area mainly focused on changes in the processing of the reaction mixture in order to improve the quality of the resulting product and practically did not affect the stage of enantioselective oxidation [Hashimoto H., Maruyama H. WO 2001087874 (2001); Hashimoto H., Urai T. WO 2001083473 (2001)]. In the patent [Kawada M., Yamano T., Taya N. WO 2001014366 (2001)], 3A molecular sieves were added to the reaction mixture. Replacing the chiral diol D-DET with a monodentent ligand - methyl ester (S) - (+) - mandelic acid also made it possible to obtain esomeprazole (I), but with a significantly lower yield [Thennati R., Rehani RB, Soni RR, Chhabada VC, Patel vm W02003089408 (2003)].

The objective of the invention is to provide a method for producing esomeprazole I and / or its salt, which allows to obtain the target product in high yield and optical purity.

The problem is solved by a method consisting in the asymmetric oxidation of 5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylthio) -1H-benzo [d] imidazole (II) with organic peroxides (preferably cumene hydroperoxide ) in an organic solvent (preferably toluene) in the presence of a chiral catalytic complex formed from a chiral diol (preferably D-diethyl tartrate), a chiral amine (preferably N, N-dimethyl- (R) -1-phenylethylamine) and a titanium compound (IV) (preferably titanium (IV) isopropylate). N, N-Dimethyl- (R) -1-phenylethylamine can be obtained by methylation of (R) -1-phenylethylamine according to any of the existing methods, for example, aqueous formic acid [I. Angres, H.E. Zieger. J. Org. Chem .; 1975; 40 (10); 1457-1460].

The inventive method can significantly increase the yield of the target esomeprazole (I) and / or its salt.

The invention is illustrated by the following examples.

Example 1. Asymmetric synthesis of (S) -5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl) -1H-benzo [d] imidazole (esomeprazole) (I) and its sodium salts using a complex of chiral ligands of D-diethyl tartrate and N, N-dimethyl- (R) -1-phenylethylamine.

To a suspension of 0.545 g (1.66 mmol) of 5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylthio) -1H-benzo [d] imidazole (II) in 2.5 ml of toluene at 55 ° 9 μl (0.50 mmol) of water, 0.240 g (1.16 mmol) of D-diethyl tartrate and 0.220 g (0.77 mmol) of titanium (IV) isopropylate were added, and they were stirred for 1 h at 55 ° С. The reaction mixture was cooled to 30 ° C and 0.120 g (0.81 mmol) of N, N-dimethyl- (R) -1-phenylethylamine was added, stirred for 15 min, then 0.270 μl of cumene hydroperoxide (86.5% solution in cumene, 1.58 mmol) was added. ) The reaction mixture was stirred for 4.5 hours at 30 ° C. The solution was extracted with aqueous ammonia solution (12.5% NH ₃ , 3 × 3 ml). 3 ml of methylene chloride was added to the combined aqueous phases, neutralized with acetic acid, the organic phase was separated, and the aqueous phase was extracted with methylene chloride (2 × 5 ml). The solvent was distilled off, and 0.537 g of a mixture was obtained containing, according to HPLC, 82.3% sulfoxide, 8.8% sulfide and not more than 0.3% sulfone, the optical purity of sulfoxide was 83.8%.

To obtain the sodium salt, a solution of 0.070 g of NaOH in 0.075 ml of water was added to a solution of 0.440 g of the mixture in 3.5 ml of acetonitrile, stirred for 1 h at room temperature. The precipitate was filtered off, washed with acetone, and dried on a filter. 0.320 g of the sodium salt of (S) -5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl) -1H-benzo [d] imidazole (esomeprazole) (I) was obtained, total yield , taking into account the proportion of crude product taken to obtain salt, amounted to 64%, optical purity more than 99.5%.

The ¹ H NMR spectrum of (S) -5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl) -1H-benzo [d] imidazole (esomeprazole) (I) coincided with a spectrum of this compound previously published in the literature [Hanna Cotton, Thomas Elebring, Magnus Larsson, Lanna Li, Henrik Sorensen and Sverker von Unge, Tetrahedron: Asymmetry 11 (2000) 3819-3825].

Example 2. Asymmetric synthesis of (S) -5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl) -1H-benzo [d] imidazole (esomeprazole) (I) and its sodium salts using a complex of chiral ligands of D-diethyl tartrate and N, N-dimethyl- (S) -1-phenylethylamine.

To a suspension of 0.545 g (1.66 mmol) of 5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylthio) -1H-benzo [d] imidazole (II) in 2.5 ml of toluene at 55 ° 9 μl (0.50 mmol) of water, 0.240 g (1.16 mmol) of D-diethyl tartrate and 0.220 g (0.77 mmol) of titanium (IV) isopropylate were added, and they were stirred for 1 h at 55 ° С. The reaction mixture was cooled to 30 ° C, 0.120 g (0.81 mmol) of N, N-dimethyl- (S) -1-phenylethylamine was added, stirred for 15 min, then 0.270 μl of cumene hydroperoxide (86.5% solution in cumene, 1.58 mmol) was added. ) The reaction mixture was stirred for 4.5 hours at 30 ° C. The solution was extracted with aqueous ammonia solution (12.5% NH ₃ , 3 × 3 ml). 3 ml of methylene chloride was added to the combined aqueous phases, neutralized with acetic acid, the organic phase was separated, and the aqueous phase was extracted with methylene chloride (2 × 5 ml). The solvent was distilled off, and 0.514 g of a mixture was obtained containing, according to HPLC, 82.4% sulfoxide and not more than 0.3% sulfone, the optical purity of sulfoxide was 79%.

To obtain the sodium salt, a solution of 0.070 g of NaOH in 0.075 ml of water was added to a solution of 0.498 g of the mixture in 4 ml of acetonitrile, and stirred for 1 h at room temperature. The precipitate was filtered off, washed with acetone, and dried on a filter. 0.335 g of the sodium salt of (S) -5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl) -1H-benzo [d] imidazole (esomeprazole) (I) was obtained, total yield , taking into account the proportion of crude product taken to obtain salt, amounted to 57%, optical purity more than 99.5%.

Example 3. Asymmetric synthesis of (S) -5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl) -1H-benzo [d] imidazole (esomeprazole) (I) and its sodium salts using a complex of chiral ligands of D-diethyl tartrate and N, N-dimethyl- (R) -1-phenylethylamine at 35 ° C.

To a suspension of 0.530 g (1.61 mmol) of 5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylthio) -1H-benzo [d] imidazole (II) in 2.5 ml of toluene at 50 ° 10 μl (0.56 mmol) of water, 0.240 g (1.16 mmol) of D-diethyl tartrate and 0.200 g (0.70 mmol) of titanium (IV) isopropylate were added, and they were stirred for 1 h at 50 ° С. The reaction mixture was cooled to 35 ° C and 0.120 g (0.81 mmol) of N, N-dimethyl- (R) -1-phenylethylamine was added, stirred for 15 min, then 0.260 μl of cumene hydroperoxide (86.5% solution in cumene, 1.52 mmol) was added. ) The reaction mixture was stirred for 4 hours at 35 ° C. The solution was extracted with aqueous ammonia solution (12.5% NH ₃ , 3 × 3 ml). 3 ml of methyl isobutyl ketone was added to the combined aqueous phases, neutralized with acetic acid, the organic phase was separated, and the aqueous phase was extracted with methyl isobutyl ketone (2 × 5 ml). The solvent was distilled off, and 0.490 g of a mixture was obtained containing, according to HPLC, 81.3% sulfoxide, 7.5% sulfide and not more than 0.3% sulfone, the optical purity of sulfoxide was 82.2%.

Example 4. Asymmetric synthesis of (S) -5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl) -1H-benzo [d] imidazole (esomeprazole) (I) and its sodium salts using a complex of chiral ligands of D-diethyl tartrate and N, N-dimethyl- (R) -1-phenylethylamine at 25 ° C.

To a suspension of 0.560 g (1.70 mmol) of 5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylthio) -1H-benzo [d] imidazole (II) in 3 ml of toluene at 53 ° 10 μl (0.56 mmol) of water, 0.260 g (1.26 mmol) of D-diethyl tartrate and 0.200 g (0.70 mmol) of titanium (IV) isopropylate were added, stirred for 1 h at 50 ° С. The reaction mixture was cooled to 35 ° C and 0.130 g (0.87 mmol) of N, N-dimethyl- (R) -1-phenylethylamine was added, stirred for 25 min, then 0.280 μl of cumene hydroperoxide (86.5% solution in cumene, 1.64 mmol) was added. ) The reaction mixture was stirred for 6 hours at 25 ° C. The solution was extracted with aqueous ammonia solution (12.5% NH ₃ , 3 × 4 ml). 3 ml of methylene chloride was added to the combined aqueous phases, neutralized with acetic acid, the organic phase was separated, and the aqueous phase was extracted with methylene chloride (2 × 5 ml). The solvent was distilled off, and 0.542 g of a mixture was obtained containing, according to HPLC, 74.3% sulfoxide, 14.4% sulfide and not more than 0.3% sulfone, the optical purity of sulfoxide was 81.7%.

Enantiomeric excess was determined using chiral HPLC on a Kromasil CHI-DMB column (75 × 2 mm), eluent 10% solution of isopropyl alcohol in hexane, flow rate 100 μl / min, detectable wavelength 210 nm. The retention time of the (S) -enantiomer is 6.1 minutes, and that of the (R) -enantiomer is 7.5 minutes.

Claims (1)

A method of producing esomeprazole of formula (I) and / or its salt

by enantioselective oxidation with organic peroxides of 5-methoxy-2 - ((4-methoxy-3,5-dimethylpyridin-2-yl) methylthio) -1H-benzo [d] imidazole of the formula (II)

in an organic solvent in the presence of a catalytic complex of titanium (IV) with chiral ligands, characterized in that two different chiral ligands are used simultaneously - a chiral diol (preferably D-diethyl tartrate) and a chiral amine (preferably N, N-dimethyl- (R) -1 -phenylethylamine).