Preparation method of tamsulosin

A technology for tamsulosin and compound, applied in the field of preparation of tamsulosin, can solve the problems of high price, difficult to obtain, difficult to purify, etc., and achieves the effects of low cost, high purity, and easy availability of raw materials

Inactive Publication Date: 2008-10-15
2Y CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The starting materials used in these three methods are chiral materials, which are very expensive and not easy to obtain
[0004] The first method is reported by EP0257787, etc. This method is easy to generate dialkylated by-products, is not easy to purify, and needs to be purified through a column, which is not conducive to industrial production; the second method is reported by WO02068382, WO2005051897, etc.; the third method Reports include WO2005056521, JPH2-295767, JPH 2-306958 and WO20070896074, etc. The reducing agent used in the latter two methods is an organometallic aluminum reagent, which is harsh on anhydrous conditions and is not convenient for large-scale production

Method used

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  • Preparation method of tamsulosin
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  • Preparation method of tamsulosin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] N-[(R)-(1-phenethyl)]-(R)-[1-(4-methoxyphenyl)propyl]-2-amine hydrochloride.

[0046] in N 2 Under protection, 250 mL of dichloromethane and 11.3 g of sodium borohydride were added to a 500 mL three-necked flask, and a mixture of 52.4 mL of glacial acetic acid and 40 mL of dichloromethane was slowly added dropwise at a temperature lower than 30°C. After dropping, react at room temperature for 1 hour until no gas emerges. This method prepares sodium triacetoxy borohydride (NaBH(OAc) 3 ). Dissolve 32.8g of compound 1 and 25.4g of compound 2 in 40mL of dichloromethane, and slowly add the above mixed solution to NaBH(OAc) 3 , and reacted at room temperature for 3 hours until compound 1 disappeared. After the reaction, the reaction solution was quenched with sodium hydroxide solution, and after liquid separation, the organic phase was dried and concentrated to obtain a colorless liquid. The liquid was dissolved in ethyl acetate, and hydrochloric acid ethanol solution was...

Embodiment 2

[0049] N-(R)-(1-phenethyl)-N-(R)-2-[1-(4-methoxy)phenyl]propyl-2-chloroacetamide.

[0050] Add 300mL of dichloromethane, 30.6g of compound 3 and 60g of sodium hydroxide into a 500mL three-neck flask, and slowly add 31.8mL of chloroacetyl chloride dropwise at a temperature lower than 25°C for reaction. After the dropwise addition, the reaction was continued for 0.5 hour until compound 3 was complete. The reaction solution was neutralized with hydrochloric acid, then separated, dried and concentrated, with a purity of 99.03%.

[0051] A small amount of the solution was concentrated to obtain a pale yellow oil.

[0052] 1 H-NMR (400mHz, CDCl 3 ): δ7.42(m, 5H); 6.63(d, 2H, J=8.0Hz); 6.38(d, 2H, J=7.6Hz); 5.15(bm, 1H); 4.20(s, 2H); 3.72 (s, 3H); 3.17-3.07 (bm, 2H); 2.34 (m, 1H); 1.66 (d, 3H, J=6.8Hz); 1.28 (d, 3H, J=6.4Hz).

Embodiment 3

[0054] N-(R)-(1-phenethyl)-N-(R)-2-[1-(3-sulfonamido-4-methoxy)phenyl]propyl-2-chloroacetamide.

[0055] Add 66.0 mL of chlorosulfonic acid to a 250 mL three-necked flask with an acid scrubber, and slowly add 80.0 mL of compound 4 in dichloromethane dropwise at a temperature lower than 20°C, then react at room temperature for 5 hours until compound 4 disappeared completely. After the reaction was completed, the reaction solution was slowly poured into ice water to quench excess chlorosulfonic acid, then extracted twice with ethyl acetate, and the organic phase was concentrated to obtain a light yellow liquid. The liquid was dissolved in tetrahydrofuran, and 28.6 mL of 25-28% ammonia water was slowly added dropwise at a temperature lower than 25°C, and then reacted at room temperature for 1-2 hours until compound (5) disappeared. After the reaction was completed, tetrahydrofuran was removed by concentration, then water and ethyl acetate were added and fully dissolved by heatin...

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Abstract

The invention discloses a method for making tamsulosin, which takes methoxyphenylacetone as the initial raw material and (R)-1-phenethylamine or substituted phenethylamine as chiral auxiliary reagent, and obtains the final raw material drug, namely tamsulosin through diastereoselective reductive amination, salifying, haloacetylization, halosulfonation, amination, alkylation, acylamide reduction and debenzylation. The method for making the tamsulosin has the advantages that: the method has low cost and easy-obtaining raw materials, each reaction is suitable for industrial production, and the obtained chemical product has high purity.

Description

technical field [0001] The invention relates to a preparation method of tamsulosin. Background technique [0002] Tamsulosin was developed by Japan's Yamanouchi Pharmaceutical Company, mainly using its hydrochloride, the trade name is "Harnal", approved by the U.S. FDA in July 1992, and domestically approved in September 1996. On the 16th, it was granted administrative protection. Tamsulosin is a highly selective alpha in the treatment of benign prostatic hyperplasia 1A - receptor antagonists. The outstanding advantages of its treatment are rapid onset, low side effects, and low recurrence rate. [0003] So far, the synthetic routes reported in the literature mainly take R-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide as the direct alkylation of the starting material and first acylation and then reduction and First acylation and then alkylation and then reduction three methods. The starting materials used in these three methods are chiral materials, which are very e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/37C07C303/40
Inventor 王元何训贵吴建才褚运波王刚张忠明尤启冬
Owner 2Y CHEM
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