CN110128309A - A kind of novel 2- mercaptoisobutyric acid preparation method - Google Patents

A kind of novel 2- mercaptoisobutyric acid preparation method Download PDF

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Publication number
CN110128309A
CN110128309A CN201910509968.XA CN201910509968A CN110128309A CN 110128309 A CN110128309 A CN 110128309A CN 201910509968 A CN201910509968 A CN 201910509968A CN 110128309 A CN110128309 A CN 110128309A
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novel
mercaptoisobutyric acid
acid preparation
kind according
mercaptoisobutyric
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胡国勤
刘景辉
薛冰凡
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Zhengzhou University
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Zhengzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A kind of novel 2- mercaptoisobutyric acid preparation method, comprising: 2- isobutyl ethyl bromide, thiocarbamide, lye, solvent, hydrolyzate.This method has in high yield, high-purity, reagent is cheap and easy to get, reaction condition is mild, process flow is simple, advantages of environment protection compared to other synthetic methods.

Description

A kind of novel 2- mercaptoisobutyric acid preparation method
Technical field
The present invention relates to a kind of novel 2- mercaptoisobutyric acid preparation methods, belong to 2- mercaptoisobutyric acid preparation field.
Background technique
2- mercaptoisobutyric acid is a kind of important biological medicine and materials synthesis intermediate.
In terms of biological medicine synthesis, including Bucillamine, prevention or treatment nonalcoholic fatty liver disease drug, resist it is white Blood disease active medicine, the angiotensin converting enzyme inhibitors based on mercaptan, can be relieved head at potassium channel openers vasodilator The Cgrp receptor antagonist of pain, orexin receptor antagonists, the opener in the channel KATP, ligand based on mercaptoacetylamide Hdac inhibitor etc. is used for the synthesis of 2- thiazole sulphur (alkane) ketone derivatives, Novel ring disulphide and episulfide derivative, also Synthesis for nematicide and fungicide.
In terms of materials synthesis, for synthesizing a kind of concrete high-molecular compound, low epoxy mercaptan carboxylic acid polyol ester.
There is a strong market demand in 2- mercaptoisobutyric acid downstream, and be not yet reported that being capable of scale metaplasia for presently relevant document Produce the domestic and international company of the product.For the needs for meeting domestic and international market, it is necessary for studying 2- mercaptoisobutyric acid new preparation process And urgent.
It is reported according to domestic and foreign literature, the synthetic route of 2- mercaptoisobutyric acid specifically includes that
Synthetic route 1
2- bromo acid and ethoxy-dithioformic acid nak response, obtain 2- ethoxy-dithioformic acid base isobutyric acid (A), compound A are hydrolyzed 2- mercaptoisobutyric acid can be obtained.
Synthetic route 2
In the autoclave being saturated under H2S environment, 2- isobutyl ethyl bromide is reacted with the methanol solution of NaSH, obtains 2- sulfydryl 2- mercaptoisobutyric acid can be obtained in compound B hydrolysis by ethyl isobutyrate (B).
For said synthesis route, the reagent ehtyl potassium xanthate in synthetic method 1 is expensive and is not easy to make a big purchase in large quantities, Be not suitable for realizing industrialized production；Synthetic method 2, though NaHS inexpensively easily obtains, production needs high-tension apparatus and vulcanization Hydrogen, hydrogen sulfide meet water and become sour severe corrosion to equipment, while having the potential risk of hypertoxic stench hydrogen sulfide leakage, intermediate There is also huge challenges to production environment by product B.
In face of above-mentioned technical problem, it is badly in need of a kind of raw material cheap and easy to get, production operation safety and stability, environmental-friendly green New technique for synthesizing.
Summary of the invention
To solve the deficiencies in the prior art, the object of the present invention is to provide a kind of novel 2- mercaptoisobutyric acid preparations Method, this method have in high yield, high-purity, reagent is cheap and easy to get, reaction condition is mild, work compared to other synthetic methods Skill process is simple, advantages of environment protection.
The technical solution adopted by the present invention to solve the technical problems is:
A kind of novel 2- mercaptoisobutyric acid preparation method, comprising: 2- isobutyl ethyl bromide, thiocarbamide, lye, solvent, hydrolysis Liquid.
In the novel 2- mercaptoisobutyric acid preparation method of above-mentioned one kind, lye includes pyridine, triethylamine, ethylenediamine, second Sour potassium, lithium acetate, copper acetate, sodium acetate are one such.
In the novel 2- mercaptoisobutyric acid preparation method of above-mentioned one kind, solvent includes acetone, acetic acid, isopropanol, positive third Alcohol, n-butanol, isobutanol, ethyl alcohol are one such.
In the novel 2- mercaptoisobutyric acid preparation method of above-mentioned one kind, 2- isobutyl ethyl bromide, thiocarbamide and lye The optimum mole ratio of three is 1:1.6:1.4.
In the novel 2- mercaptoisobutyric acid preparation method of above-mentioned one kind, the alkali in hydrolyzate includes lithium hydroxide, hydrogen-oxygen It is one such to change potassium, sodium hydroxide.
In the novel 2- mercaptoisobutyric acid preparation method of above-mentioned one kind, sodium acetate is best in lye；Ethyl alcohol is in solvent Most preferably；Alkali sodium hydroxide in hydrolyzate is best, meanwhile, compared to sodium hydrate aqueous solution and ethyl alcohol (methanol, isopropanol, just The organic solvents such as propyl alcohol, n-butanol, isobutanol) mixed solution, the aqueous solution of sodium hydroxide is optimum hydrolysis liquid.
It is a kind of specific the preparation method is as follows: 2- bromo in the novel 2- mercaptoisobutyric acid preparation method of above-mentioned one kind Ethyl isobutyrate, thiocarbamide, the anhydrous sodium acetate back flow reaction in ethyl alcohol generate -4 thiazolidone of -2 imino group of 5,5- dimethyl, Referred to as compound C；Later by compound C and sodium hydroxide reaction hydrolysis, 2- mercaptoisobutyric acid can be obtained.
In the novel 2- mercaptoisobutyric acid preparation method of above-mentioned one kind, the optimal reaction temperature of first step reaction is 82 DEG C, optimum reacting time is 12 hours；The optimal reaction temperature of second step reaction is 105 DEG C, and optimum reacting time is 36 hours.
In the novel 2- mercaptoisobutyric acid preparation method of above-mentioned one kind, sodium hydroxide and 5, -2 imino group of 5- dimethyl - The optimum mole ratio of 4- thiazolidone is 4:1；The best in quality score of sodium hydrate aqueous solution is 5%.
The beneficial effects of the present invention are:
2- mercaptoisobutyric acid is at home there are no realizing to industrialize, compared to the yield of document report 70% or so, 2- in the present invention Mercaptoisobutyric acid yield is up to 83%；2- mercaptoisobutyric acid reagent purity on the market only has 96%, and moderate purity of the present invention is up to 99.17%；
In addition, there are also the raw materials such as 2- isobutyl ethyl bromide, thiocarbamide, anhydrous sodium acetate, sodium hydroxide, ethyl alcohol are honest and clean for the synthetic method The advantages that valence is easy to get, and reaction intermediates colorless and odorless is convenient for separation, and reaction condition is mild.
Detailed description of the invention
Fig. 1 is the synthesis technology flow diagram of 2- mercaptoisobutyric acid.
Fig. 2 is the possible reaction principle schematic diagram of this synthetic method.
Specific embodiment
The invention will be further described below in conjunction with the accompanying drawings.Following embodiment is only used for clearly illustrating the present invention Technical solution, and not intended to limit the protection scope of the present invention.
A kind of novel 2- mercaptoisobutyric acid preparation method, comprising: 2- isobutyl ethyl bromide, thiocarbamide, anhydrous sodium acetate, Ethyl alcohol, sodium hydroxide；
Wherein, the optimum mole ratio of 2- isobutyl ethyl bromide, thiocarbamide and lye three is 1:1.6:1.4；
Wherein, sodium hydroxide and 5, the optimum mole ratio of -2 imino group -4- thiazolidone of 5- dimethyl are 4:1；Sodium hydroxide water The best in quality score of solution is 5%.
Embodiment 1
A kind of novel 2- mercaptoisobutyric acid preparation method of the present embodiment, steps are as follows:
Step 1
By 2- isobutyl ethyl bromide (80g, 410mmol), thiocarbamide (49.95g, 656mmol), anhydrous sodium acetate (47.10g, 574mmol) in 1000mL there-necked flask, 300mL dehydrated alcohol is measured with graduated cylinder and is poured into there-necked flask；
The mouth of left, center, right three of there-necked flask connects the thermometer that spherical condensation tube, mechanical agitator, range are greater than 100 DEG C respectively, will There-necked flask is put into constant temperature oil bath magnetic agitation pot, is warming up to (85 DEG C) until the temperature that thermometer is shown no longer rises, reaction 12 hours, after reaction, there-necked flask is placed in 5 DEG C or so of low temperature water-bath and is cooled to room temperature 45 DEG C or so；
Reaction solution in there-necked flask is poured into single port bottle, and the residue in there-necked flask is all flushed to 1000mL's with ethyl alcohol In single port bottle, by the temperature of rotary evaporator be set as 45 DEG C, revolving speed be set as 70, by single port bottle be connected to above, remove reaction solution in Ethyl alcohol；
With sodium bromide, unreacted thiocarbamide and sodium acetate in 180mL distilled water dissolved residue, dissolved up to abundant；
It is filtered using sand core suction funnel, obtains white solid 5, -2 imino group -4- thiazolidone of 5- dimethyl, and carry out It is dry, obtain 50g(yield 85%, purity 99.54%), referred to as compound C.
Step 2
By (compound C) 5, -2 imino group -4- thiazolidone (50g, 347mmol) of 5- dimethyl, 1111g sodium hydroxide solution (mass fraction 5%) is added in 2000mL there-necked flask；
The mouth of left, center, right three of there-necked flask connects the thermometer that spherical condensation tube, mechanical agitator, range are greater than 150 DEG C respectively, will There-necked flask is put into constant temperature oil bath magnetic agitation pot, is warming up to (105 DEG C) until the temperature that thermometer is shown no longer rises, reaction 36 hours, after reaction, there-necked flask is placed in 5 DEG C of low temperature water-bath and is cooled to 5 DEG C or so；
Reaction solution is acidified to pH=1 using about 136mL concentrated hydrochloric acid (36%), is then extracted 2 times with 400mL, after merging extraction phase, It is dried, is collected in the round-bottomed flask of 1000mL using anhydrous sodium sulfate；
By the temperature of rotary evaporator be set as 45 DEG C, revolving speed be set as 70, by conical flask be connected to above, remove extract liquor in methyl Tertbutyl ether, remaining residue are product 2- mercaptoisobutyric acid, are dried in vacuo 5h, dry 2- mercaptoisobutyric acid can be obtained 40.81g(yield 98%, purity 99.17%), two-step reaction total recovery is 83%.
Performance test:
The infared spectrum of resulting compound C is reacted in step 1 are as follows:
IR (KBr, cm-1): 3230 (s, ν NH)； 2978(s , νasCH3)；1671(s, νC=O)；1513(ν, C=N)； 623(w, νC-S)；1H NMR (400 MHz, DMSO) δ 8.95 (s, 1H,NH),δ8.71 (s, 1H,NH), δ1.49 (s, 6H,CH3)。
The infared spectrum of resulting final product 2- mercaptoisobutyric acid is reacted in step 2 are as follows:
IR (KBr, cm-1): 3419 (m, br, ν OH)；2973 (m, νasCH3)；2562 (w, ν SH) 1698 (s, ν CO)； 1295 (m, ν C-O)；656 (νC-S).1H NMR (400 MHz, CDCl3) δ 1.63 (s, 6H, CH3-2 CH3-3) , 2.55 (s, 1H, SH), 11.09 (s, 1H, COOH).13C NMR (101 MHz, CDCl3) δ 181.74 (s, CO- 4), 44.54 (s, C-1), 28.59 (s, CH3-2, CH3-3).MS (ESI), m/z:119 [M-H]-
In conclusion a kind of novel 2- mercaptoisobutyric acid preparation method of the present invention, this method is compared to other synthetic methods, tool Have in high yield, high-purity, reagent is cheap and easy to get, reaction condition is mild, process flow is simple, advantages of environment protection, has good Good application prospect.

Claims (9)

1. a kind of novel 2- mercaptoisobutyric acid preparation method, it is characterised in that: include: 2- isobutyl ethyl bromide, thiocarbamide, alkali Liquid, solvent, hydrolyzate.
2. the novel 2- mercaptoisobutyric acid preparation method of one kind according to claim 1, it is characterised in that: lye includes pyrrole Pyridine, triethylamine, ethylenediamine, potassium acetate, lithium acetate, copper acetate, sodium acetate are one such.
3. the novel 2- mercaptoisobutyric acid preparation method of one kind according to claim 1, it is characterised in that: solvent includes third Ketone, acetic acid, isopropanol, normal propyl alcohol, n-butanol, isobutanol, ethyl alcohol are one such.
4. the novel 2- mercaptoisobutyric acid preparation method of one kind according to claim 1, it is characterised in that: 2- bromo isobutyl The optimum mole ratio of acetoacetic ester, thiocarbamide and lye three is 1:1.6:1.4.
5. the novel 2- mercaptoisobutyric acid preparation method of one kind according to claim 1, it is characterised in that: in hydrolyzate Alkali includes that lithium hydroxide, potassium hydroxide, sodium hydroxide are one such.
6. the novel 2- mercaptoisobutyric acid preparation method of one kind according to claim 1, it is characterised in that: acetic acid in lye Sodium is best；Ethyl alcohol is best in solvent；Alkali sodium hydroxide in hydrolyzate is best, meanwhile, compared to sodium hydrate aqueous solution and The mixed solution of ethyl alcohol (organic solvents such as methanol, isopropanol, normal propyl alcohol, n-butanol, isobutanol), the aqueous solution of sodium hydroxide are Optimum hydrolysis liquid.
7. a kind of novel 2- mercaptoisobutyric acid preparation method, preparation method are as follows:
2- isobutyl ethyl bromide, thiocarbamide, the anhydrous sodium acetate back flow reaction in ethyl alcohol generate -2 imino group -4 of 5,5- dimethyl Thiazolidone, referred to as compound C；Later by compound C and sodium hydroxide reaction hydrolysis, 2- mercaptoisobutyric acid can be obtained.
8. the novel 2- mercaptoisobutyric acid preparation method of one kind according to claim 7, it is characterised in that: first step reaction Optimal reaction temperature be 82 DEG C, optimum reacting time be 12 hours；The optimal reaction temperature of second step reaction is 105 DEG C, most The good reaction time is 36 hours.
9. the novel 2- mercaptoisobutyric acid preparation method of one kind according to claim 7, it is characterised in that: sodium hydroxide with The optimum mole ratio of -2 imino group -4- thiazolidone of 5,5- dimethyl is 4:1；The best in quality score of sodium hydrate aqueous solution is 5%。
CN201910509968.XA 2019-06-13 2019-06-13 A kind of novel 2- mercaptoisobutyric acid preparation method Pending CN110128309A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3843669A (en) * 1971-05-07 1974-10-22 Ici Ltd Certain carbamoyloxyimino-azolidines
US4378357A (en) * 1977-02-03 1983-03-29 Rohm And Haas Company Novel heterocyclic compounds
CN1190434C (en) * 1996-12-31 2005-02-23 雷迪实验室有限公司 Novel heterocyclic compounds process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
JP2008260725A (en) * 2007-04-13 2008-10-30 Ohara Yakuhin Kogyo Kk Method for producing 2-imino-4-thiazolidinone

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3843669A (en) * 1971-05-07 1974-10-22 Ici Ltd Certain carbamoyloxyimino-azolidines
US4378357A (en) * 1977-02-03 1983-03-29 Rohm And Haas Company Novel heterocyclic compounds
CN1190434C (en) * 1996-12-31 2005-02-23 雷迪实验室有限公司 Novel heterocyclic compounds process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
JP2008260725A (en) * 2007-04-13 2008-10-30 Ohara Yakuhin Kogyo Kk Method for producing 2-imino-4-thiazolidinone

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ASPELUND, HELGE 等: "Effect of sodium hydroxide on several 2,4-thiazolidinediones and 2-imino-4-thiazolidinones.II", 《ACTA ACAD. ABOENSIS, MATH. PHYS.》 *
GLENN S.SKINNER 等: "Some derivatives of 2,3-dihydro-4H-1,4-thiazin-3-one and 1,4-thiazane", 《J.AM.CHEM.SOC.》 *
KACHHADIA V V 等: "Heterocyclic systems containing S/N regioselective nucleophilic competition:facile synthesis,antitubercular and antimicrobial activity of thiohydantoins and iminothiazolidinones containing the benzo", 《JOURNAL OF THE SERBIAN CHEMICAL SOCIETY》 *
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Application publication date: 20190816