Method for preparing S-(-)-amlodipine and R-(+)-amlodipine by chirally resolving racemic amlodipine

A technology for amlodipine and chiral separation, applied in chemical instruments and methods, organic racemization, organic chemical methods, etc., can solve the problems of large amount of separation solvent, cumbersome operation, solvent residue, etc., and achieve product yield High, good optical purity, the effect of a small amount of solvent

Active Publication Date: 2010-08-11
石家庄润柏医药科技有限公司
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Problems solved by technology

The above-mentioned resolution process has the following disadvantages: 1, using solvents such as DMSO or DMSO-d6, DMAC, the price is higher, and the boiling point is also higher, and there are easy solvent resi

Method used

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  • Method for preparing S-(-)-amlodipine and R-(+)-amlodipine by chirally resolving racemic amlodipine
  • Method for preparing S-(-)-amlodipine and R-(+)-amlodipine by chirally resolving racemic amlodipine
  • Method for preparing S-(-)-amlodipine and R-(+)-amlodipine by chirally resolving racemic amlodipine

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Experimental program
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Effect test

Embodiment 1

[0034] Example 1 Preparation of S-(-)-amlodipine-semi-dibenzoyl-D-tartrate

[0035] Dissolve 5g (0.0122mol) (R, S) amlodipine in 20mL of absolute ethanol, heat to dissolve, add 1.1g (0.0031mol) of dibenzoyl-D-tartaric acid dissolved in 10mL of absolute ethanol, stir React until there is a large amount of precipitation, and then continue the crystallization reaction at room temperature for 4 hours, put it in the refrigerator overnight, and filter to obtain S-(-)-amlodipine-semi-dibenzoyl-D-tartrate. Refined with ethanol and vacuumed at 50°C for 2 hours to obtain 2.89 g of S-(-)-amlodipine-semi-dibenzoyl-D-tartrate, with a yield of 80.4%. The diastereomeric excess (d.e) was determined to be 99.08% by chiral HPLC. M.p. is 117~118℃, measured value of elemental analysis: C59.16%, H5.53%, N4.67%; calculated value: C 20 h 25 N 20 o 5 Cl 0.5(C 18 h 14 o 8 ): C59.23%, H5.49%, N4.76%. 1 HNMR agrees with the molecular structure, see attached Figure 5 .

Embodiment 2

[0036] Example 2 Preparation of S-(-)-amlodipine-semi-dibenzoyl-D-tartrate

[0037] Dissolve 5g (0.0122mol) (R, S) amlodipine in 20mL of absolute ethanol, heat to dissolve, add 10mL of absolute ethanol dissolved with 2.2g (0.0061mol) of dibenzoyl-D-tartaric acid, stir React until there is a large amount of precipitation, then continue the crystallization reaction at room temperature for 4h, and then crystallize at -10°C for 4h, filter to obtain S-(-)-amlodipine-semi-dibenzoyl-D-tartrate, the crude product is used Refined with absolute ethanol and vacuumed at 50°C for 2 hours to obtain 3.11 g of S-(-)-amlodipine-hemi-dibenzoyl-D-tartrate, with a yield of 86.52%. The diastereomeric excess (d.e) was determined to be 98.54% by chiral HPLC.

Embodiment 3

[0038] Example 3 Preparation of S-(-)-amlodipine-semi-dibenzoyl-D-tartrate

[0039] Dissolve 5 grams (0.0122mol) of (R, S) amlodipine in 40ml of dehydrated ethanol, heat to dissolve, add 10ml of dehydrated ethanol dissolved with 2.2 grams (0.0061mol) of dibenzoyl-D-tartaric acid, Following the operation according to Example 2, 2.45 grams of S-(-)-amlodipine-semi-dibenzoyl-D-tartrate was obtained, with a yield of 68.2%. The diastereomeric excess (d.e) determined by chiral HPLC was 98.36%.

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Abstract

The invention discloses a method for preparing S-(-)-amlodipine and R-(+)-amlodipine by chirally resolving racemic amlodipine. The resolving solvent is ethanol or a mixed solvent containing ethanol, chiral dibenzoyl-D-tartaric acid or dibenzoyl-L-tartaric acid is used as the resolving agent, the chiral resolving agent and the racemic amlodipine selectively form chiral amlodipine dibenzoyl tartrate, and the chiral amlodipine dibenzoyl tartrate is alkalified to obtain the chiral amlodipine. The invention adopts the ethanol as the resolving solvent; and when using industrial ethanol as the resolving solvent, the invention can also acquire good resolving effect and obtain the qualified medicinal amlodipine raw material, thereby obviously reducing the cost. The invention has the characteristics of simple reaction operation, easy control, low toxicity, environmental protection, high efficiency and the like, and is suitable for green large-scale production.

Description

technical field [0001] The invention relates to a method for preparing S-(-)-amlodipine and R-(+)-amlodipine and their diastereomeric salts by chiral resolution of racemic amlodipine, which belongs to organic medicinal chemistry technology field. technical background [0002] Amlodipine is a compound with the following chemical structural formula. It is a long-acting calcium ion antagonist. It is clinically used to treat hypertension and angina pectoris. It has very important uses in the field of cardiovascular and cerebrovascular. Currently, racemic ammonia Clodipine predominates. [0003] [0004] According to J.E.Arrowsmiith etc. in J.Med.Chem.(1986) 29; 1696 report, the main ingredient of amlodipine pharmacological activity is S-(-)-amlodipine, and its calcium ion antagonistic activity is about R-(+)- 1000 times that of amlodipine and 2 times that of the racemate. J.W.Young reported in WO93 / 10779 that the use of S-(-)-amlodipine can reduce side effects such as acra...

Claims

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Application Information

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IPC IPC(8): C07D211/90C07B57/00
Inventor 孙京国冯玉玲
Owner 石家庄润柏医药科技有限公司
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