阅读说明：本技术 一种高纯度依利格鲁司他的制备方法 (Preparation method of high-purity eliagliptat ) 是由 刘素云 于 2018-12-31 设计创作，主要内容包括：本发明涉及一种戈谢氏病治疗药物依利格鲁司他的制备方法,以S-异丙基-2-噁唑烷酮为原料,经缩合反应、溴代反应、取代反应、水解反应、缩合反应以及还原反应得到依利格鲁司他；依利格鲁司他再经成盐和两部纯化步骤,得到高纯度的酒石酸依利格鲁司他。本发明从起始物料开始,对手性中心进行全合成,在减少反应步骤、缩短生产周期的同时,提高了手性中心的合成效率,并提高终产物收率,成盐步骤详细优化,保证了原料药的合格质控。(The invention relates to a preparation method of a drug for treating gaucher' S disease, namely eligerstat, which takes S-isopropyl-2-oxazolidinone as a raw material and obtains the eligerstat through condensation reaction, bromination reaction, substitution reaction, hydrolysis reaction, condensation reaction and reduction reaction; and salifying and purifying the epristeride by two steps to obtain the high-purity epristeride tartrate. The invention carries out full synthesis on the chiral center from the starting material, improves the synthesis efficiency of the chiral center, improves the yield of the final product, optimizes the salifying step in detail and ensures the qualified quality control of the raw material medicaments while reducing the reaction steps and shortening the production period.)

1. The preparation method of eliaglucol is characterized by comprising the following steps:

a, carrying out condensation reaction by taking S-isopropyl-2-oxazolidinone and (E) -3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) acryloyl chloride as starting materials to obtain a compound 4, namely (S, E) -3- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) acryloyl) -4-isopropyl-2-ketone;

the compound 4 is subjected to bromination reaction to obtain (S) -3- ((2R, 3R) -2-bromo-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3-hydroxypropionyl) -4-isopropyl-2-one, namely a compound 5;

performing nucleophilic substitution reaction on the compound 5 to obtain (S) -3- ((2S, 3R) -2-azido-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3-hydroxypropionyl) -4-isopropyl-2 ketone, namely a compound 6;

hydrolyzing the compound 6 to obtain (2S, 3R) -2-azido-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3-hydroxypropionic acid, namely a compound 7;

e, carrying out condensation reaction on the compound 7 to obtain an acyl chloride product compound 7-1, and carrying out condensation reaction again without purification to obtain (1R,2R) -2-azido-1- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3- (pyrrolidine-1-yl) propan-1-ol, namely a compound 8;

the compound 8 is reduced to obtain (1R,2R) -2-amino-1- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3- (pyrrolidine-1-yl) propan-1-ol, namely a compound 9;

g compound 9 reacts with 2, 5-dioxopyrrolidin-1-yl octanoate to produce eliglutacteostat.

2. The preparation method of high-purity eliagliptat tartrate is characterized by comprising the following steps of:

placing the eligerrata prepared in the claim 1 into a solanaceous bottle, adding purified water, stirring for dissolving, adding 1N sodium hydroxide solution, extracting twice with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain an oily substance, dissolving with a mixed organic solution, dripping a previously heated and dissolved L-tartaric acid mixed solution, completely dripping, stirring for 2 hours, filtering, leaching with acetone, and drying by air blast to constant weight to obtain white-like powder of the eligerrata tartrate; and putting the solid in an eggplant-shaped bottle, adding purified water, stirring for dissolving, adding a 1N sodium hydroxide solution, extracting twice by using dichloromethane, combining organic phases, washing the organic phases by using purified water, drying the organic phases by using anhydrous sodium sulfate, filtering, leaching by using acetone, decompressing and concentrating to obtain an oily substance, dissolving the oily substance by using a mixed solution of acetone and isopropanol, dripping a preheated and dissolved L-tartaric acid mixed solution, stirring for 2 hours, filtering, leaching by using acetone, and drying by air blast to constant weight to obtain the high-purity eggerlat tartrate.

3. The method of claim 2, wherein the mixed organic solution has a composition selected from any 2 of acetone, methanol, ethanol, and isopropanol.

4. The mixed solution according to claim 3, wherein the ratio of the two components is 1-20: 99-80.

5. The preparation method according to claim 2, wherein the mixed solution component of L-tartaric acid is selected from any 2 of acetone, methanol, ethanol, and isopropanol.

6. The mixed solution according to claim 5, wherein the ratio of L-tartaric acid to the two components is 1:10 to 20:90 to 80.

Technical Field

The invention relates to a medicine for treating gaucher's disease, namely a preparation method of eligerstat, and belongs to the technical field of medicines.

Background

Eliglustat (Eliglustat), chemically N- [ (1R,2R) -1- (2, 3-dihydro-1, 4-benzodioxan-6-yl) -2-hydroxy-1- (1-pyrrolidinemethyl) ethyl ] octanamide, is the first small molecule compound used to treat specific type I gaucher disease and has the following structural formula:

gaucher's disease is the most common inherited rare disease of lysosomal storage disease, which is characterized by massive deposition of glucocerebrosidase in the mononuclear macrophage system and massive proliferation of histiocytes due to reduction or lack of β -glucocerebrosidase.

Eliaglucol is the first small molecule oral drug to treat gaucher's disease, used as a first line oral therapy for adult patients with specific type I gaucher disease. Eliglutacter is a potent, highly specific ceramide analogue inhibitor, targeting glucosylceramide synthase (GCS), and is able to reduce the production and accumulation of glucosylceramide. At present, the medicine is not on the market at home. As the first oral drug for treating the gaucher disease type I, the drug is convenient to apply clinically, completely subverts the market pattern of gaucher disease depending on injection drugs at present, and becomes a unique and very important new practical treatment option for gaucher disease type I groups.

There are several methods for synthesizing eliglutason.

CN104557851A provides a preparation method of ibrutinstat (eliaglutistat), in the route, pyrrolidine is used as a raw material to react with 1-halogen-2-nitroethane to generate N- (2-nitro) ethyl pyrrolidine, then the N- (2-nitro) ethyl pyrrolidine and an intermediate phenylpropanedioxane-6-ketone are subjected to Henry reaction under the catalysis of a chiral ligand to obtain a required configuration intermediate, and after the nitro is reduced by palladium, the intermediate reacts with intermediate N-hydroxysuccinimide caprylate to obtain a final target product. The most essential part is directly synthesized into a required configuration intermediate through a Henry reaction, the rest steps are conventional reactions, the whole route requires few steps and has strong selectivity, but the defects are that the chiral ligand required by the method is too expensive and is not suitable for industrial production.

Another route is provided in the literature "Synthesis and Evaluation of Hybrid Structures compounded of two glucopyranoside synthsylators" (Richard J.B.H.N, van der Berg, et al [ J. Chemedchem, 2015,10(12))2042-2062 "), which is a starting intermediate with a specific configuration, is subjected to a desilication reaction under acidic conditions, then to a reaction with tetrahydropyrrole after the hydroxyl group is activated with methanesulfonyl chloride, and the heterocyclic structure of carbamic acid is subjected to a ring-opening reaction under alkaline conditions to give an intermediate with the corresponding configuration, which is then reacted with N-hydroxysuccinimide octanoyl ester as an intermediate to give the final target product. The method is simple to operate and common reactions, but raw materials with required special configurations are difficult to obtain and are huge resistance which limits the application and achieves industrial production.

The above-mentioned route or cost is too high, or raw materials are difficult to obtain, or yield is too low, so that it is not suitable for industrial production, therefore, it is necessary to develop a safer, more economical and more environment-friendly route suitable for industrial production.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects and research and design an industrial production method of the eliaglucol tartrate. The invention carries out full synthesis on the chiral center from the starting material, improves the synthesis efficiency of the chiral center, improves the yield of the final product, optimizes the salifying step in detail and ensures the qualified quality control of the raw material medicaments while reducing the reaction steps and shortening the production period.

Specifically, the invention provides a preparation method of eliaglucostat, which comprises the following steps:

a, carrying out condensation reaction by taking S-isopropyl-2-oxazolidinone and (E) -3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) acryloyl chloride as starting materials to obtain a compound 4, namely (S, E) -3- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) acryloyl) -4-isopropyl-2-ketone;

the compound 4 is subjected to bromination reaction to obtain (S) -3- ((2R, 3R) -2-bromo-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3-hydroxypropionyl) -4-isopropyl-2-one, namely a compound 5;

performing nucleophilic substitution reaction on the compound 5 to obtain (S) -3- ((2S, 3R) -2-azido-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3-hydroxypropionyl) -4-isopropyl-2 ketone, namely a compound 6;

hydrolyzing the compound 6 to obtain (2S, 3R) -2-azido-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3-hydroxypropionic acid, namely a compound 7;

e, carrying out condensation reaction on the compound 7 to obtain an acyl chloride product compound 7-1, and carrying out condensation reaction again without purification to obtain (1R,2R) -2-azido-1- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3- (pyrrolidine-1-yl) propan-1-ol, namely a compound 8;

the compound 8 is reduced to obtain (1R,2R) -2-amino-1- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3- (pyrrolidine-1-yl) propan-1-ol, namely a compound 9;

g compound 9 reacts with 2, 5-dioxopyrrolidin-1-yl octanoate to produce eliglutacteostat.

Further, the invention also provides a preparation method of the high-purity eliaglucol tartrate, which is characterized by comprising the following steps of:

putting the Eliguslatus prepared by the reaction into a eggplant-shaped bottle, adding purified water, stirring for dissolving, adding a 1N sodium hydroxide solution, extracting twice by using dichloromethane, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain an oily substance, dissolving by using a mixed organic solution, dripping a previously heated and dissolved L-tartaric acid mixed solution, completely dripping, stirring for 2 hours, filtering, leaching by using acetone, and drying by air blasting to constant weight to obtain white-like powder Eliguslatus tartrate; and putting the solid in an eggplant-shaped bottle, adding purified water, stirring for dissolving, adding a 1N sodium hydroxide solution, extracting twice by using dichloromethane, combining organic phases, washing the organic phases by using purified water, drying the organic phases by using anhydrous sodium sulfate, filtering, leaching by using acetone, decompressing and concentrating to obtain an oily substance, dissolving the oily substance by using a mixed solution of acetone and isopropanol, dripping a preheated and dissolved L-tartaric acid mixed solution, stirring for 2 hours, filtering, leaching by using acetone, and drying by air blast to constant weight to obtain the high-purity eggerlat tartrate.

Wherein the components of the mixed organic solution are selected from any 2 of acetone, methanol, ethanol and isopropanol, and the ratio of the two components is 1-20: 99-80.

The mixed solution of the L-tartaric acid comprises 2 components selected from acetone, methanol, ethanol and isopropanol, and the ratio of the L-tartaric acid to the two components is 1: 10-20: 90-80.

Drawings

FIG. 1 is an HPLC chromatogram of eliglutacter tartrate prepared by the invention

FIG. 2 is a H-NMR spectrum of eliglutacter tartrate prepared in accordance with the present invention

FIG. 3 shows the eliglutacostat tartrate prepared by the method¹³C-NMR spectrum

Detailed Description

The present invention is described below with reference to specific examples, but it should be understood that the examples do not limit the present invention.