CN103224489B

CN103224489B - Method for enhancing production yield and rate of esomeprazole

Info

Publication number: CN103224489B
Application number: CN201310186766.9A
Authority: CN
Inventors: 王明刚; 任莉; 陈阳生; 牛建兴; 臧云龙; 汪泓
Original assignee: Qingdao Chia Tai Haier Pharmaceutical Co Ltd
Current assignee: CP Pharmaceutical Qingdao Co Ltd
Priority date: 2013-05-20
Filing date: 2013-05-20
Publication date: 2015-03-04
Anticipated expiration: 2033-05-20
Also published as: CN103224489A

Abstract

The invention aims to enhance the conversion and generation yield and rate of esomeprazole from omeprazole precursor-thioether through a chiral catalyst Mn(salen). The method comprises the following steps: weighing a right amount of esomeprazole precursor-thioether, evenly mixing with dichloromethane, adding the chiral catalyst Mn(salen) and D-(-)diethyl tartrate to carry out chiral conversion, adding cumene hydroperoxide for oxidation to generate esomeprazole, filtering to remove the chiral catalyst, distilling out dichloromethane to obtain an esomeprazole crude product, and finally, crystallizing with acetone to obtain the esomeprazole pure product. High-performance liquid chromatography is utilized to detect the content. The chiral catalyst Mn(salen) can enhance the generation yield of esomeprazole sodium by 50%, and save the reaction time by 2 hours or so. The method is simple to operate, and has the advantages of low reagent toxicity, low required initial raw material cost and high product yield.

Description

A kind of method improving esomeprazole production yield and speed

Technical field

The present invention relates to and a kind ofly improve the method that esomeprazole produces yield and speed, by chiral catalyst Mn(salen) efficient catalytic effect, improve esomeprazole 50% yield, nearly 2 hours of Reaction time shorten, drastically increases speed of reaction.Belong to technical field of medicine synthesis.

Background technology

Esomeprazole is the levo form of omeprazole, is the optical purity proton pump inhibitor gone on the market the earliest, for treating the medicine that hydrochloric acid in gastric juice effect is best, have no side effect at present.

The domestic and international research to such medicine is more deep at present, and its synthetic route is catalyzer substantially with titanium isopropylate, catalysis sulfide oxidation synthesis esomeprazole.In the synthetic method of the patent " synthetic method of replacement Ya Sulfone compounds " (patent No. is 95194956.X) of current domestic employing, agents useful for same is as larger in toxicity such as toluene, the shortcomings such as operation steps is many, but disadvantage is that the titanium isopropylate reaction times is longer, large about 2.5h, yield is greatly about 40%.Domesticly take different starting raw materials to carry out the feasibility synthesizing to test esomeprazole synthesis at present more, the synthesis that 3 kinds of different starting materials carry out esomeprazole is described in the document " esomeprazole graphical Synthetic Routes " of the people such as Gu Weijun, Sui Qiang, do not solve the slow problem of oxidation catalysis, yield is not also improved.Therefore improve sulfide oxidation efficiency and improve yield and become the current problem being difficult to break through.

Chiral catalyst efficient catalytic compound a kind of novel method that to be chipal compounds be rises recently, and Mn(salen) catalyzer is one of most effective catalyst of current efficient catalytic asymmetric oxidation.The advantage of immobilized Chiral Mn (salen) catalyzer comparatively homogeneous phase Chiral Mn (salen) catalyzer is described in people's documents such as Liu Lingjun, Liu Jin " progress of the immobilized Chiral Mn of inorganic materials (salen) catalyzer ".Introduce in the document " progress of Chiral Mn (salen) catalyzed alkene asymmetric epoxidation reaction " of the people such as Luo Yunfei, Zou Xiaochuan, chiral catalyst Mn(salen) catalyzed oxidation yield reaches 95%, saves reaction times nearly 3h.

Document and patent in sum, does not also find the method for efficient oxidation catalysis omeprazole precursor-thioether at present both at home and abroad.Also nobody attempts utilizing chiral catalyst Mn(salen) efficient catalytic improve the successful model producing esomeprazole yield and speed.

Summary of the invention

The present invention is intended to overcome prior art shortcoming, improve and produce esomeprazole technique, there is provided a kind of and improved the method for producing esomeprazole reaction yield and speed by efficient chiral catalyst, utilize chiral catalyst Mn(salen) efficient catalytic asymmetric oxidation, make thioether at D-(-) be converted into S-esomeprazole under the space structure that provides of diethyl tartrate, relative titanium isopropylate catalysis can save more than 2 hour, and improves the yield of 50%.

To achieve these goals, of the present invention by chiral catalyst Mn(salen) improve the method for producing esomeprazole speed and comprise following step:

(1) dissolve: take appropriate starting material omeprazole precursor-thioether with ten thousand/electronic balance, and mix with 5 times amount (mass volume ratio) solvent-methylene dichloride, by recirculated water bath control temperature at 25 ~ 30 DEG C, under rotating speed 180r/min, stir 30min;

(2) mutarotation: add chiral catalyst Mn(salen in band glass reaction still with dissection), wherein thioether: chiral catalyst=1:0.3(mol ratio), by thioether: D-(-) diethyl tartrate=1:0.7 mol ratio input D-(-) diethyl tartrate, recirculated water bath control temperature is 25-30 DEG C;

(3) be oxidized: drip oxygenant-hydrogen phosphide cumene by constant pressure funnel, wherein thioether: hydrogen phosphide cumene=2:1 (mass ratio), by adding ice cube and Automatic-heating control temperature is 15-25 DEG C in recirculated water bath, be the S-esomeprazole having chirality by sulfide oxidation, reaction times about about 20min;

(4) removal of impurities: make Mn(salen by adding normal hexane) separate out, cross and filter chiral catalyst Mn(salen); Set temperature is 50 DEG C, and steam except methylene dichloride and normal hexane by filtrate with Rotary Evaporators, obtain esomeprazole crude product, lucifuge operates;

(5) crystallization: add proper amount of acetone in reactor, wherein esomeprazole: acetone=1:6(mass volume ratio); Stirring and dissolving esomeprazole at 25 DEG C, is then warming up to 53 DEG C of crystallizatioies, refluxes half an hour, and suction filtration is dried and obtained esomeprazole finished product;

(6) detect: utilize HPLC to detect isomer and its related substances in esomeprazole, wherein S-esomeprazole content reaches 99.8%, R-esomeprazole content and is only 0.2%, is always assortedly no more than 0.4%.

(7) contrasting: use titanium isopropylate and chiral catalyst Mn(salen) Comparative result of producing AS is as follows:

	Yield	Speed (oxidization time)	HPLC(purity)
				Titanium isopropylate	40%	2.5h	99.8%
Mn（salen）	92%	0.5h	99.8%

By above-mentioned contrast, we can find out: use chiral catalyst Mn(salen) under the prerequisite ensureing purity, productive rate 52% can be improved compared with titanium isopropylate, save the 2h reaction times.

Embodiment

Below in conjunction with example, the present invention will be further described.

Identical with summary of the invention of technique main procedure involved by this example.Comprise dissolving, mutarotation, oxidation, removal of impurities, crystallization, detection six steps.

Embodiment 1

Take 100g thioether with electronic balance, dissolve with 500ml methylene dichloride, 25-30 DEG C is stirred 30min, adds chiral catalyst 0.091molMn(salen), 0.213molD-(-) diethyl tartrate, stirs 25min at 55 DEG C.Reduce temperature to 15 ~ 25 DEG C, add hydrogen phosphide cumene 50g, 20min has been oxidized.Add normal hexane, filtering Mn(salen), then steam except methylene dichloride and normal hexane, finally add 600ml acetone normal-temperature dissolution esomeprazole, after dissolving, be warming up to 53 DEG C of crystallizatioies.Obtain esomeprazole fine work and be about 92g, detect esomeprazole content is 99.8% by high performance liquid phase.

Embodiment 2

Take 50g thioether with electronic balance, dissolve with 250ml methylene dichloride, 25-30 DEG C is stirred 30min, adds chiral catalyst 0.045molMn(salen), 0.106molD-(-) diethyl tartrate, stirs 25min at 55 DEG C.Reduce temperature to 15 ~ 25 DEG C, add hydrogen phosphide cumene 25g, 20min has been oxidized.Add normal hexane, filtering Mn(salen), then steam except methylene dichloride and normal hexane, finally add 300ml acetone normal-temperature dissolution esomeprazole, after dissolving, be warming up to 53 DEG C of crystallizatioies.Obtain esomeprazole fine work and be about 45g, detect esomeprazole content is 99.8% by high performance liquid phase.

Claims

1. improve the method that esomeprazole produces yield and speed, it is characterized in that technological process is:

(1), dissolve: take appropriate starting material omeprazole precursor-thioether with ten thousand/electronic balance, and add the methylene dichloride mixing of mass volume ratio 5 times amount, under temperature 25 ~ 30 DEG C, rotating speed 180r/min, stir 30min;

(2), mutarotation: add chiral catalyst Mn(salen in band glass reaction still with dissection), wherein thioether: chiral catalyst mol ratio is 1:0.3, by thioether: D-(-) diethyl tartrate mol ratio be 1:0.7 drop into D-(-) diethyl tartrate, temperature is 55 DEG C;

(3), be oxidized: drip hydrogen phosphide cumene, wherein thioether: hydrogen phosphide cumene mass ratio is 2:1, and temperature is 15-25 DEG C, reacts after 20 minutes, obtains S-esomeprazole;

(4), removal of impurities: add normal hexane separate out Mn(salen), cross filter Mn(salen); 50 DEG C of lucifuges are revolved and are steamed filtrate removing methylene dichloride and normal hexane, obtain esomeprazole crude product;

(5), crystallization: add acetone, wherein esomeprazole: acetone quality volume ratio is 1:6; Stirring and dissolving esomeprazole at 25 DEG C, is then warming up to 53 DEG C of crystallizatioies, refluxes 30 minutes, and suction filtration, dries to obtain esomeprazole finished product;

(6), detect: detect isomer and its related substances in esomeprazole with HPLC, wherein S-esomeprazole content reaches 99.8%, R-esomeprazole content and is only 0.1%, is always assortedly no more than 0.2%;

Described Mn(salen) be:

R1=-（CH2） _4-

R2=H

R3=H。

2. method according to claim 1, is characterized in that reaction equation is:

。