CN1840524A

CN1840524A - Process for preparing fudosteine

Info

Publication number: CN1840524A
Application number: CN 200510059733
Authority: CN
Inventors: 曲峰; 李彦
Original assignee: BEIJING D-VENTURE PHARM T CORP
Current assignee: Beijing D-Venturepharm Technology Development Co., Ltd.
Priority date: 2005-03-31
Filing date: 2005-03-31
Publication date: 2006-10-04
Anticipated expiration: 2025-03-31
Also published as: CN100543014C

Abstract

The invention provides a process for preparing Fudosteine, which has the chemical structural formula (I) disclosed in the specification. The Fudosteine can be used as the medicament for relieving cough and expectorant.

Description

A kind of preparation method of Fudosteine

Invention field

The present invention relates to the preparation method of Fudosteine, above-claimed cpd can be used as antibechic, apophlegmatisant.

Background of invention

Fudosteine (chemical name: 3-hydroxypropyl sulfo-L-Ala), have the following formula structure:

Fudosteine can effectively reduce the mucous secretion of chronic respiratory disease patient, thereby has good antibechic, the effect of reducing phlegm.

At present the method for synthetic Fudosteine is a starting raw material with the L-halfcystine all, is prepared with different branched building block butt joint, and disclosed synthetic method about Fudosteine is as follows:

See document Biochemistry 1991 by the method that L-halfcystine and 3-bromo-1 propyl alcohol are prepared under alkaline catalysis, 30,4078～4081, this method comprises: a) L-halfcystine and 3-bromo-1 propyl alcohol are put in the strong alkali aqueous solution such as sodium hydroxide; B) drip ethanol to obtaining homogeneous phase solution; C) stirring reaction spends the night; D) filter, regulate pH with strong acid; E) concentrating under reduced pressure; D) recrystallization obtains the product Fudosteine.There is following shortcoming in this method: the reaction times is long, and relates to materials such as bromide, strong acid, highly basic in the reaction, and is bigger to structure deteriorate, and because the existence of bromide has serious environmental issue, cause cost to raise.

See patent JP8119932 by the method that L-halfcystine and vinyl carbinol are prepared under free radical catalysts such as superoxide or high light catalysis, this method comprises: a) L-halfcystine and vinyl carbinol are added to the water; B) add free radical catalyst such as Sodium Persulfate or carry out strong illumination; C) add water-miscible organic solvent after reaction finishes and separate out solid, obtain the product Fudosteine.There is following shortcoming in this method: because employed catalyzer is salt, and the polarity of finished product Fudosteine is bigger, and the solvability in the aqueous solution is good, is difficult for finished product is well separated with catalyzer, thereby cause residual salts substances in the finished product, second-rate.With L-halfcystine and vinyl carbinol under strong illumination catalysis to being bonded into the method for Fudosteine, because strong illumination is difficult for realizing large-scale industrial production to the having relatively high expectations of production unit.Therefore be necessary to seek one more economically, the preparation method of efficient and environmental protection.

The method of catalysis free radical reaction commonly used roughly has three kinds, be that peroxide catalyst carries out catalysis, light-initiated or thermal initiation, we attempted peroxide catalyzed and light-initiated after, the thermal initiation test has been carried out in this reaction again, the result has obtained good reaction effect.

Goal of the invention

The preparation method who the purpose of this invention is to provide the Fudosteine of a kind of economy, efficient and environmental protection.

Summary of the invention

The preparation method of the Fudosteine that this patent provides comprises: in the aqueous solution L-halfcystine is mixed with vinyl carbinol, cause by heating, obtain the finished product Fudosteine.

Feature of the present invention is, avoided use strong acid or highly basic and bromide to react, and avoided strong acid, alkaline neutralization reaction in the process of aftertreatment equally, helps the protection to physical environment in suitability for industrialized production in the future; Avoided the use high light that reaction is caused, reduced requirement production unit; Avoided the use of free radical catalysts such as superoxide, thereby avoided in finished product, introducing salts substances, helped improving the quality of products.

Of the present invention open in detail:

In the aqueous solution, with the mol ratio of compound shown in compound shown in the formula (I) and the formula (II) with 1: 1～1: 3, preferred 1: 2 mol ratio is mixed, Heating temperature is 40 ℃～80 ℃, carry out addition under preferred 50～60 ℃, in reaction mixture, add water-miscible organic solvent at last and separate out precipitation, obtain Fudosteine.

Following embodiment is to describe in detail the present invention, and unrestricted the present invention.

The bibliographic reference example

Biochemistry?1991，30，4078～4081：P.4079

2.37 gram 3-bromo-1-propyl alcohol are joined in the mixed solution of 2.68 gram cysteine hydrochlorides and 10 milliliters of aqueous sodium hydroxide solutions (3.4M), drip ethanol to obtaining homogeneous system, stirring is spent the night.The small amount of precipitate that generates is filtered out, and filtrate is 5 with aqueous hydrochloric acid (5M) regulation system pH value, underpressure distillation, and gained solid water-ethanol mixed solvent recrystallization gets 0.6 gram product.

JP8119932 embodiment 1:

2.0g (16.5mmol) L-halfcystine is dissolved in 20ml water, adds 1.95 gram (33mmol) vinyl carbinols, stirring at room.Add the 200mg Potassium Persulfate, continue to stir 15 minutes.Reaction removes solvent under reduced pressure after finishing, and adds ethanol (25%) in residue, the filtering insolubles, and filtrate decompression concentrates, and residue water-ethanol system recrystallization gets the 2.5g clear crystal, yield 85%.

JP8119932 embodiment 2:

2.0g (16.5mmol) L-halfcystine is dissolved in 20ml water, adds 1.95 gram (33mmol) vinyl carbinols, stirring at room.Add 200mg iron protochloride and 200mg peroxy-disulfuric acid ammonia, continue to stir 15 minutes.Reaction removes solvent under reduced pressure after finishing, and adds ethanol (25%) in residue, the filtering insolubles, and filtrate decompression concentrates, and residue water-ethanol system recrystallization gets the 2.3g clear crystal, yield 80%.

JP8119932 embodiment 3:

2.0g (16.5mmol) L-halfcystine is dissolved in 20ml water, adds 1.95 gram (33mmol) vinyl carbinols, stirring at room.Add 200mg iron protochloride and 200mg peroxy-disulfuric acid ammonia, (250～310nm, 10W) irradiation is 30 minutes for low pressure mercury lamp.After reaction finished, residue washed with ethyl acetate, the water concentrating under reduced pressure, and residue water-ethanol system recrystallization gets the 2.78g clear crystal, yield 80%.

This patent embodiment

Embodiment 1:

8.5L distilled water and 1.9kg L-halfcystine are mixed, a small amount of insolubles is arranged.Add the 2.2L vinylcarbinol, turbid solution is white in color.Finish, be heated to 50～60 ℃ of stirring reactions more than 7 hours.Stop to stir, in reaction solution, be added dropwise to 45L acetone, separate out white solid.Drip and finish, continue to stir 45 minutes, left standstill 0.5～1.0 hour, suction filtration gets white solid, with 3～5L acetone drip washing upper strata solid.The gained solid got 2.0kg product, yield 80% in 24 hours in 45 ℃ of dryings.

Embodiment 2:

4.3L distilled water and 1.0kg L-halfcystine are mixed, a small amount of insolubles is arranged.Add the 0.6L vinylcarbinol, turbid solution is white in color.Finish, be heated to 50～60 ℃ of stirring reactions more than 7 hours.Stop to stir, in reaction solution, be added dropwise to 23L acetone, separate out white solid.Drip and finish, continue to stir 45 minutes, left standstill 0.5～1.0 hour, suction filtration gets white solid, with 1～2L acetone drip washing upper strata solid.The gained solid got 0.9kg product, yield 70% in 24 hours in 45 ℃ of dryings.

Embodiment 3:

5.0L distilled water and 1.1kg L-halfcystine are mixed, a small amount of insolubles is arranged.Add the 1.3L vinylcarbinol, turbid solution is white in color.Finish, be heated to 70～80 ℃ of stirring reactions more than 7 hours.Stop to stir, in reaction solution, be added dropwise to 26L acetone, separate out white solid.Drip and finish, continue to stir 45 minutes, left standstill 0.5～1.0 hour, suction filtration gets white solid, with 2～3L acetone drip washing upper strata solid.The gained solid got 1.1kg product, yield 75% in 24 hours in 45 ℃ of dryings.

Claims

1. preparation method as shown in the formula the Fudosteine shown in (I).

Formula (I)

Being characterized as of this method: with formula (II) compound

Formula (II)

With compound shown in the formula (III)

Formula (UI)

Under heating state, carry out addition reaction and obtain compound shown in the form (I).

2. claim 1 described method, wherein the reaction solvent of addition reaction is water, water-miscible organic solvent or its mixing solutions;

3. claim 1,2 described method, wherein the reaction solvent of addition reaction is a water;

4. claim 1,2,3 described methods, and wherein the temperature of reaction of addition reaction is 40～80 ℃;

5. the method that aforementioned any one claim requires, wherein the temperature of reaction of addition reaction is 50～60 ℃;

6. the method that aforementioned any one claim requires, wherein compound (I) is 1: 1 to 1: 3 with the mol ratio of compound (II).

7. the method that aforementioned any one claim requires, compound (I) is 1: 2 with the mol ratio of compound (II).