CN101985458A

CN101985458A - Novel method for preparing ademetionine 1,4-butanedisulfonate

Info

Publication number: CN101985458A
Application number: CN2010102968894A
Authority: CN
Inventors: 沈立新; 袁利; 刘福双; 吴鹏程; 周燕
Original assignee: WUXI HOWFOND BIOPHARMA Inc
Current assignee: WUXI HOWFOND BIOPHARMA Inc
Priority date: 2010-09-30
Filing date: 2010-09-30
Publication date: 2011-03-16

Abstract

The invention discloses a novel method for preparing ademetionine 1,4-butanedisulfonate, which comprises the following steps of: reacting diethylene glycol dimethyl ether with boron trifluoride ether solution in epoxy chloropropane to synthesize a compound (II); performing methylation reaction on the compound (II) by taking a compound (III) as an initial material to obtain a compound (IV); and salifying the compound (IV) to obtain the final product ademetionine 1,4-butanedisulfonate (I). In the method for preparing the ademetionine 1,4-butanedisulfonate, raw materials are easily available, the operation is simple, the total yield of reaction is higher, and the method is a complete synthesis route suitable for industrially producing stable salts of S-adenosyl methionine.

Description

A kind of new preparation S-ademetionine 1, the method for 4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate

Technical field

The present invention relates to the chemical pharmaceutical technical field, specifically, is a kind of new S-ademetionine 1, the preparation method of 4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate.

Background technology

(S-adenosyl-L-methionine, chemical molecular formula are C to S-ademetionine-L-methionine(Met) ₁₅H ₂₃N ₆O ₅S is called for short SAM, SAMe or AdoMet) be the sulfonyl compound of a kind of organic tetravalence sulphur form (metal sulphur) of methionine(Met), be called as " active methionine ", found by Cantoni in nineteen fifty-three.SAMe decomposes or degraded easily to temperature and potential of hydrogen sensitivity, and owing to itself height unstable, can only combine salifiable form with negatively charged ion and exist, and the easy moisture absorption of its salt, it is comparatively complicated process that separation and purification prepares the SAM product salt.SAMe has two kinds of isomeric forms, be respectively (R, S) and (S S), has only (S, S) SAMe of configuration biologically active.In vivo, SAMe is by the catalysis of S-adenosylmethionine synthetic enzyme, and is synthetic by ATP and the reaction of L-methionine(Met).

SAMe extensively is present in the various organisms as important mesostate, also is a kind of important physical active substance in the human body, participates in many pathways metabolisms and crucial biochemical reaction in the body, as methylation reaction, changes reaction of Salmon-Saxl and polyamine building-up reactions etc.Be mainly used in the treatment of hepatopathy, sacroiliitis and dysthymia disorders clinically.In addition, SAMe still is the chemicals of important preventing cancer, attracts much attention more and more. and SAMe also has good result of treatment to hyperlipidemia, arteriosclerosis, fibromyalgia, migraine, senile dementia and presenile dementia.

That the SAMe stable salt adopts at present mainly is two salt of SAMe sulfuric acid tosic acid and SAMe1,4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate.

At present relevant SAMe and stable salt synthetic document thereof and patent are many, but wherein the overwhelming majority adopts the method for biological fermentation to obtain SAMe, extracts with acid then, and last refabrication becomes required stable salt.For example Chinese patent 03126834.X is with methionine(Met) and the Triphosaden SAMe that has been the enzymic synthesis of prepared using methionine(Met); The Chinese patent 200610053835.9 usefulness ethyl acetate aqueous solution are extracting S-adenosine-L-methionine(Met) from the brewing yeast cell of cultivating by fermentation, converts it into SAMe1 then, 4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate.Chinese patent 200810020215.4 is with the activity of poly-hydroxy protective enzyme; with adenosine triphosphate acid precursor, L-methionine(Met) and phosphate anion is substrate; with glucose or maltose is energy donor, adds the composition of metal ion, utilizes the synthetic SAMe of the production strain whole-cell catalysis that permeability is arranged.

All there is the bad control of amount of impurities and kind thereof in above patent owing to adopt biosynthesizing, and technology is more loaded down with trivial details, is unfavorable for the problem that industrialization is produced.

Summary of the invention

The object of the invention is to provide a kind of SAMe1 of simple and practical economy newly, 4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate synthetic method, and this method reaction conditions gentleness, easy and simple to handle, raw material cheaply is easy to get, end product purity height, and total recovery is higher, is suitable for suitability for industrialized production.

The objective of the invention is to be achieved through the following technical solutions:

(1) at first use boron trifluoride ether solution and diethylene glycol dimethyl ether prepared in reaction methylating reagent (II) in epoxy chloropropane, temperature of reaction is less than 20 ℃, and the reaction times is 3-6 hour.

(2) compound (III) is dissolved in trifluoroacetic acid or the trifluoroacetic acid vitriolic mixing solutions, adds methylating reagent under the low temperature in batches, low-temp reaction 5-7 hour, after aftertreatment, make the aqueous solution of compound (IV).

(3) aqueous solution of compound (IV) is regulated the pH value to 4.0-7.0, join then in the activation Zeo-karb carefully, and add 1,4-fourth disulfonic acid carries out salify with preparation final product (I).Selected Zeo-karb is D155, D152, JK110.Used 1, the mol ratio of 4-fourth disulfonic acid and SAMe is 1:1.5-2.0, is preferably 1:1.6.The reaction back that finishes concentrates, and adds methyl alcohol or acetone again and carries out crystallization and promptly get final product.

Beneficial effect:

The present invention adopts chemical process synthetic, and synthesis step is few, products therefrom purity height, and amount of impurities and kind are all seldom.The mode that salify adopts resin directly to stir is carried out, and has avoided carrying out the inconvenience that salify brings to suitability for industrialized production with pillar.

Description of drawings

Accompanying drawing 1 is the synthetic route of methylating reagent;

Accompanying drawing 2 is the synthetic route of SAMe salt;

Embodiment:

Be that concrete embodiment is given an example below, so that technical scheme of the present invention is further described; But it should be considered as scope restriction of the present invention.

Embodiment 1:

The preparation of methylating reagent

In the 500 mL single port reaction that magnetic agitation is housed, nitrogen protection adds exsiccant 180 mL diethylene glycol dimethyl ethers and 55 mL exsiccant boron trifluoride ether solutions down, and ice bath is cooled to 0 ℃, slowly adds 41 mL exsiccant epoxy chloropropane, drips complete in one hour.Dropwise the back and be warming up to 5-10 ℃ of reaction 5 hours naturally, nitrogen atmosphere filters down, filter cake anhydrous diethyl ether (50 mL * 2) washing.After drying up, nitrogen gets methylating reagent 61 g, yield 75%.Low temperature (less than-10 ℃) is preserved.

SAMe's is synthetic

In 250 mL there-necked flasks, add trifluoroacetic acid 45 ml; be cooled to-10 ℃, under the nitrogen protection 5 g raw materials added, add methylating reagent in batches; finished in one hour; bathe nature with cryosel and be warming up to 0 ℃ of reaction, the HPLC monitoring, back (the raw material III is residual less than 1%) reacts completely; be cooled to once more below-5 ℃; slowly drip 20 mL water,, obtain water with the washing of 35 ml isopropyl ethers.Isopropyl ether (10 mL * 2) washing is used in organic phase water (5 mL * 2) extraction more again behind the merging water, get the SAMe aqueous solution 15 mL.

SAMe-1, the preparation of 4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate

(1) activation of weakly acidic cation-exchange resin

Get 50 mL D155 weakly acidic cation-exchange resins dress post, elder generation is washed till till the no bubble with deionized water, and then slowly washs with 200 mL, 1 N hydrochloric acid, washes complete in one hour.Wash complete back and be washed till about neutrality (pH=6-7), and then slowly wash, washed complete in one hour with 200 mL, 1 N sodium hydroxide with deionized water.Wash Bi Houzai and be washed till pH less than till 7.5 with deionized water.Slowly wash with 200 mL, 1 N hydrochloric acid more at last, washed completely in one hour, be washed till pH with deionized water again after finishing and get final product greater than 6.5.

(2) SAMe-1, the preparation of 4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate

Get SAMe reaction solution 5 mL, join in the good resin of above-mentioned activation, stirring at room one hour is filtered, and filter cake is washed till pH greater than 6.0 with deionized water.The filter cake taking-up is placed reaction flask; add 14 mL, 0.3 N 1; 4-fourth disulfonic acid, stirring at room one hour is filtered; filter cake is with 10 mL water washings; filtrate merges the back revolves less than 40 ℃ of following vacuum in temperature and steams to a small amount of thick liquid, adds mixed solvent (methyl alcohol: 6 mL of acetone=1:1); stirring at room is nitrogen protection filtration down after half an hour, dry white powder 1.2 g that get.

(1) activation of weakly acidic cation-exchange resin

Get 50 mL JK110 weakly acidic cation-exchange resins dress post, elder generation is washed till till the no bubble with deionized water, and then slowly washs with 200 mL, 1 N hydrochloric acid, washes complete in one hour.Wash complete back and be washed till about neutrality (pH=6-7), and then slowly wash, washed complete in one hour with 200 mL, 1 N sodium hydroxide with deionized water.Wash Bi Houzai and be washed till pH less than till 7.5 with deionized water.Slowly wash with 200 mL, 1 N hydrochloric acid more at last, washed completely in one hour, be washed till pH with deionized water again after finishing and get final product greater than 6.5.

Get SAMe reaction solution 5 mL, join in the good resin of above-mentioned activation, stirring at room one hour is filtered, and filter cake is washed till pH greater than 6.0 with deionized water.The filter cake taking-up is placed reaction flask, add 14 mL, 0.3 N 1,4-fourth disulfonic acid, stirring at room one hour is filtered, filter cake is with 10 mL water washings, filtrate merges the back revolves less than 40 ℃ of following vacuum in temperature and steams to a small amount of thick liquid, adds mixed solvent (methyl alcohol: 6 mL of acetone=1:1), stirring at room is nitrogen atmosphere filtration down after half an hour, dry white powder 1.1 g that get.

Claims

1. one kind prepares S-ademetionine 1, the method for 4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate may further comprise the steps:

(1) reacts in epoxy chloropropane with diethylene glycol dimethyl ether and boron trifluoride ether solution and obtain compound (II);

(2), in strong acid, carry out the reaction solution that methylation reaction obtains compound (IV) with compound (II) with compound (III);

(3) reaction solution of compound (IV) is adjusted to joins after the suitable pH value in the good weakly acidic cation-exchange resin of activation with 1,4-fourth disulfonic acid carries out salify and obtains final product S-ademetionine 1,4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate (I);

?。

2. according to claim 1 S-ademetionine 1,4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate preparation method is characterized in that step can add methylene chloride in (1), also can not add.

3. according to claim 1 S-ademetionine 1,4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate preparation method is characterized in that, the mol ratio of diethylene glycol dimethyl ether, boron trifluoride diethyl etherate and epoxy chloropropane is 1:1-5:1-2 in the step (1), is preferably 1:4.4:1.2.

4. according to claim 1 S-ademetionine 1,4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate preparation method is characterized in that, solvent for use is that trifluoroacetic acid or trifluoroacetic acid are followed the vitriolic mixed solvent in the step (2).

5. according to claim 1 S-ademetionine 1,4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate preparation method is characterized in that, the mol ratio of compound (III) and methylating reagent (II) is 1:1-2 in the step (2), is preferably 1:1.4.

6. according to claim 1 S-ademetionine 1,4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate preparation method is characterized in that, and the pH value of regulating is 4-7 in the step (3), is preferably 5.0, and used resin is weakly acidic cation-exchange resin D155, D152, a kind of among the JK110.