CN104059004A - Method for preparing 2-[(4,4'-dihalo-diphenyl methyl) sulfydryl] acetate - Google Patents
Method for preparing 2-[(4,4'-dihalo-diphenyl methyl) sulfydryl] acetate Download PDFInfo
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- CN104059004A CN104059004A CN201410294971.1A CN201410294971A CN104059004A CN 104059004 A CN104059004 A CN 104059004A CN 201410294971 A CN201410294971 A CN 201410294971A CN 104059004 A CN104059004 A CN 104059004A
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- dihalo
- sulfydryl
- diphenyl
- acetic ester
- diphenyl methyl
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Abstract
The invention relates to a synthesis method of 2-[(4,4'-dihalo-diphenyl methyl) sulfydryl] acetate. The method comprises the following steps: (1) converting 4,4'-dihalo-diphenyl methyl alcohol into a 4,4'-dihalo-diphenyl methanol carboxylic ester; (2) converting the 4,4'-dihalo-diphenyl methanol carboxylic ester into 2-[(4,4'-dihalo-diphenyl methyl) sulfydryl] acetate; and (3) obtaining the 2-[(4,4'-dihalo-diphenyl methyl) sulfydryl] acetate in an extraction manner, heating and dissolving by using a mixed solvent, and obtaining a pure product of the 2-[(4,4'-dihalo-diphenyl methyl) sulfydryl] acetate after cooling. The invention aims at providing the method for directly obtaining high-purity 2-[(4,4'-dihalo-diphenyl methyl) sulfydryl] acetate at high yield without subsequent purification steps and seeking a process which is simple, easy to operate, high in yield and good in quality.
Description
Technical field
The present invention relates to organic chemistry filed, a kind of 2-[(4 specifically, 4 '-dihalo--diphenyl methyl) sulfydryl] preparation method of acetic ester.
Background technology
2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] acetic ester is 2-[(diphenyl methyl) sulfydryl] the Halogen derivative of acetic ester.
2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] acetic ester is for the synthesis of 4, the intermediate of 4 '-dihalo--modafinil, 2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] acetic ester and 2-[(diphenyl methyl) sulfydryl] acetate esters seemingly, synthetic method also has similar, according to 2-[(diphenyl methyl in the past) sulfydryl] the synthetic experience of acetic ester, through technological transformation, can synthesize this product.
In Chinese patent CN1735591A (S. Luo Si D. Jeanne Crain), 2-[(diphenyl methyl is described) sulfydryl] structure of methyl acetate, a kind of extensive synthetic 2-[(diphenyl methyl is disclosed) sulfydryl] route of methyl acetate, its result has higher yield.
In US Patent No. 4177290A, report, benzhydrol and thiocarbamide condensation, Mono Chloro Acetic Acid replace, synthesize 2-[(diphenyl methyl) sulfydryl] acetic acid.
In Chinese patent CN1871211A (Xi Niliang), use the reaction of halogenated acetic acids ester and thiocarbamide and benzhydrol, prepare diphenyl-methyl thioacetate.
In Chinese patent CN1986527A, report, benzhydrol is raw material, react with bromine and obtain intermediate diphenyl-bromomethane, then with Thiovanic acid condensation, reaction obtains intermediate hexichol first Thiovanic acid.
At document (" Chinese pharmaceutical chemistry impurity ", 1999,9 (2): 132), adopt and use with the following method diphenyl-chloromethane to react with ethyl thioglycolate, product carries out chromatographic separation and obtains 2-[(diphenyl methyl) sulfydryl] ethyl acetate.
The present invention tests under the basis of consulting lot of documents, summing up experience, its objective is to provide without carrying out subsequently purification step and can directly obtain with high yield highly purified 2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] method of acetic ester.Seek simple, easy handling, yield is high, the measured technique of matter.
Summary of the invention
The object of this invention is to provide and obtain with high yield highly purified 2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] method of acetic ester.Seek that technique is simple, easy handling, yield is high, the measured 2-[(4 of matter, 4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester.
The present invention adopts following technical scheme: a kind of 2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester, comprise the following steps:
(1) by 4,4 '-dihalo--diphenyl-carbinol is converted into 4,4 '-dihalo--diphenyl-carbinol carboxylicesters;
(2), by 4,4 '-dihalo--diphenyl-carbinol carboxylicesters is converted into 2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] acetic ester;
(3) obtain 2-[(4,4 '-dihalo--diphenyl methyl through extraction) sulfydryl] acetic ester, use mixed solvent heating for dissolving, cooling rear acquisition 2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] acetic ester sterling.
Described in step (1) 4, the synthetic method of 4 '-dihalo--diphenyl-carbinol carboxylicesters is specially: acid anhydrides is diluted in aprotic solvent, after cooling the solution obtaining, stir at a certain temperature and drip mineral acid, under suitable temperature of reaction, add 4,4 '-dihalo--diphenyl-carbinol reacts.
2-[(4 described in step (2), 4 '-dihalo--diphenyl methyl) sulfydryl] the concrete synthetic method of acetic ester is: in the described reaction solution of step (1), drips mercaptoacetate, then under suitable temperature of reaction, reacts.
In step (1), available acid anhydrides is diacetyl oxide or propionic anhydride or butyryl oxide.
In step (1), available aprotic solvent is methylene dichloride or trichloromethane or tetracol phenixin.
In step (1), available mineral acid is sulfuric acid or hydrochloric acid or butyric acid or phosphoric acid.
The described temperature of reaction of step (1) is-5～20 DEG C.
Described in step (2), mercaptoacetate is Methyl Thioglycolate or ethyl thioglycolate or Thiovanic acid propyl ester or Thiovanic acid isopropyl ester.
The temperature of reaction of step (2) is 10～30 DEG C.
The described mixed solvent of step (3) is methyl alcohol and ethyl acetate mixed solvent, and its ratio is methyl alcohol: ethyl acetate=1:1～10.
Advantage of the present invention is:
1, on the basis of conventional medicament synthesis technique, develop new product, adopt new raw material and crystallization method, technological process easy handling, mild condition, energy consumption is low.
2, reaction yield is good, and total recovery reaches as high as 80%, and purity is more than 98.5%.
Brief description of the drawings
Fig. 1 is 2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] structural formula of acetic ester, wherein X is halogen atom, comprises F, Cl, Br, R is alkyl, comprises-CH
3,-CH
2cH
3,-CH
2cH
2cH
3,-CH (CH
3cH
3)
2.
Embodiment
Following case study on implementation is used for illustrating the present invention, but is not used for limiting the scope of the invention.
Embodiment 1:
At 20 DEG C, 10.83g (0.105mol) diacetyl oxide is diluted in 40ml methylene dichloride.The solution obtaining is cooled to 0 ± 2 DEG C, slowly drips afterwards the sulphuric acid soln of 0.3ml96%.After stir about 10min, at 0 ± 2 DEG C, add 22.02g (0.1mol) 4,4 '-bis-fluoro-benzhydrols in batches, keep reaction medium at this temperature 2 hours.
At 0 ± 2 DEG C, introduce 10.83g (0.102mol) Methyl Thioglycolate.Then reaction mixture is heated to 20 ± 2 DEG C, and keeps 2h at this temperature.
In above-mentioned reaction solution, add 50ml water, separatory, the organic addition 50ml of gained washes once, concentrated organic phase, with the solvent 10ml heat of solution gained solid of methyl alcohol: ethyl acetate=1:10, after ice bath is cooling, obtain 2-[(4,4 '-bis-fluoro-diphenyl methyls) sulfydryl] methyl acetate fine work.Yield 80%, purity 98.5% (HPLC).
Embodiment 2:
At 20 DEG C, 10.83g (0.105mol) diacetyl oxide is diluted in 40ml methylene dichloride.The solution obtaining is cooled to 0 ± 2 DEG C, slowly drips afterwards the sulphuric acid soln of 0.3ml96%.After stir about 10min, at 0 ± 2 DEG C, add 25.31g (0.1mol) 4,4 '-bis-chloro-benzhydrols in batches, keep reaction medium at this temperature 2 hours.
At 0 ± 2 DEG C, introduce 12.26g (0.102mol) ethyl thioglycolate.Then reaction mixture is heated to 20 ± 2 DEG C, and keeps 2h at this temperature.
In above-mentioned reaction solution, add 50ml water, separatory, the organic addition 50ml of gained washes once, concentrated organic phase, with the solvent 10ml heat of solution gained solid of methyl alcohol: ethyl acetate=1:10, after ice bath is cooling, obtain 2-[(4,4 '-bis-fluoro-diphenyl methyls) sulfydryl] ethyl acetate fine work.Yield 79.8%, purity 98.0% (HPLC).
Embodiment 3:
At 20 DEG C, 10.83g (0.105mol) diacetyl oxide is diluted in 40ml methylene dichloride.The solution obtaining is cooled to 0 ± 2 DEG C, slowly drips afterwards the sulphuric acid soln of 0.3ml96%.After stir about 10min, at 0 ± 2 DEG C, add 25.31g (0.1mol) 4,4 '-bis-chloro-benzhydrols in batches, keep reaction medium at this temperature 2 hours.
At 0 ± 2 DEG C, introduce 12.26g (0.102mol) ethyl thioglycolate.Then reaction mixture is heated to 20 ± 2 DEG C, and keeps 2h at this temperature.
In above-mentioned reaction solution, add 50ml water, separatory, the organic addition 50ml of gained washes once, concentrated organic phase, with the solvent 10ml heat of solution gained solid of methyl alcohol: ethyl acetate=1:10, after ice bath is cooling, obtain 2-[(4,4 '-bis-fluoro-diphenyl methyls) sulfydryl] ethyl acetate fine work.Yield 79.8%, purity 98.0% (HPLC).
Claims (10)
1. a 2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester, it is characterized in that:
Comprise the following steps:
(1) by 4,4 '-dihalo--diphenyl-carbinol is converted into 4,4 '-dihalo--diphenyl-carbinol carboxylicesters;
(2), by 4,4 '-dihalo--diphenyl-carbinol carboxylicesters is converted into 2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] acetic ester;
(3) obtain 2-[(4,4 '-dihalo--diphenyl methyl through extraction) sulfydryl] acetic ester, use mixed solvent heating for dissolving, cooling rear acquisition 2-[(4,4 '-dihalo--diphenyl methyl) sulfydryl] acetic ester sterling.
2. 2-[(4 according to claim 1,4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester, it is characterized in that: in step (1) 4, the synthetic method of 4 '-dihalo--diphenyl-carbinol carboxylicesters is specially: acid anhydrides is diluted in aprotic solvent, after cooling the solution obtaining, control under charge temperature and stir and drip mineral acid, control under temperature of reaction and add 4,4 '-dihalo--diphenyl-carbinol reacts.
3. 2-[(4 according to claim 2,4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester, it is characterized in that: described acid anhydrides is diacetyl oxide or propionic anhydride or butyryl oxide.
4. 2-[(4 according to claim 2,4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester, it is characterized in that: described aprotic solvent is methylene dichloride or trichloromethane or tetracol phenixin.
5. 2-[(4 according to claim 2,4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester, it is characterized in that: described mineral acid is sulfuric acid or hydrochloric acid or butyric acid or phosphoric acid.
6. 2-[(4 according to claim 2,4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester, it is characterized in that: described charge temperature is-5～20 DEG C, described temperature of reaction is-5～20 DEG C.
7. 2-[(4 according to claim 1,4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester, it is characterized in that: the 2-[(4 in step (2), 4 '-dihalo--diphenyl methyl) sulfydryl] the concrete synthetic method of acetic ester is: in the described reaction solution of step (1), drips mercaptoacetate, then controls under temperature of reaction and react.
8. 2-[(4 according to claim 7,4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester, it is characterized in that: described mercaptoacetate is Methyl Thioglycolate or ethyl thioglycolate or Thiovanic acid propyl ester or Thiovanic acid isopropyl ester.
9. 2-[(4 according to claim 7,4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester, it is characterized in that: described temperature of reaction is 10～30 DEG C.
10. 2-[(4 according to claim 1,4 '-dihalo--diphenyl methyl) sulfydryl] synthetic method of acetic ester, it is characterized in that: the mixed solvent in step (3) is methyl alcohol and ethyl acetate mixed solvent, and its ratio is methyl alcohol: ethyl acetate=1:1～10.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4489095A (en) * | 1982-06-04 | 1984-12-18 | Laboratoire L. Lafon | Halogenobenzhydrylsulfinylacetohydroxamic acids |
| EP0258134A1 (en) * | 1986-08-13 | 1988-03-02 | Laboratoire L. Lafon | Therapeutical compositions containing benzhydryl thiomethane derivatives |
| US5571825A (en) * | 1995-03-31 | 1996-11-05 | Warner-Lambert Company | Method of selectively inhibiting prostaglandin G/H synthase-2 |
| CN1735591A (en) * | 2003-01-13 | 2006-02-15 | 欧西蒙德世界合成组织 | Method for preparing methyl 2-diphenylmethylsulfinylacetate |
-
2014
- 2014-06-25 CN CN201410294971.1A patent/CN104059004A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4489095A (en) * | 1982-06-04 | 1984-12-18 | Laboratoire L. Lafon | Halogenobenzhydrylsulfinylacetohydroxamic acids |
| EP0258134A1 (en) * | 1986-08-13 | 1988-03-02 | Laboratoire L. Lafon | Therapeutical compositions containing benzhydryl thiomethane derivatives |
| US5571825A (en) * | 1995-03-31 | 1996-11-05 | Warner-Lambert Company | Method of selectively inhibiting prostaglandin G/H synthase-2 |
| CN1735591A (en) * | 2003-01-13 | 2006-02-15 | 欧西蒙德世界合成组织 | Method for preparing methyl 2-diphenylmethylsulfinylacetate |
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Application publication date: 20140924 |