CN103193663A - Novel synthesis process of DL-p-hydroxyphenylglycine - Google Patents
Novel synthesis process of DL-p-hydroxyphenylglycine Download PDFInfo
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- CN103193663A CN103193663A CN2012100022711A CN201210002271A CN103193663A CN 103193663 A CN103193663 A CN 103193663A CN 2012100022711 A CN2012100022711 A CN 2012100022711A CN 201210002271 A CN201210002271 A CN 201210002271A CN 103193663 A CN103193663 A CN 103193663A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/584—Recycling of catalysts
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Abstract
The invention relates to a novel synthesis process of DL-p-hydroxyphenylglycine (DL-HPG), and belongs to the field of pharmaceutical and chemical intermediate production. A purpose of the invention is realized by that: under the effect of a phase transfer catalyst quaternary ammonium salt, phenol, glyoxylic acid, water, and 4-nitro-phthalimide are subjected to a one-pot reaction; the material is cooled to 25 DEG C, and is filtered, such that 4-nitro-phthalic acid solid is obtained; a filtrate is cooled in ice water, and is subjected to pump filtration; a filter cake is sequentially washed by using ice water and ethanol, until the filter cake is colorless; the filter cake is dried, such that a white powdery DL-HPG product is obtained; a mother liquor with main components of glyoxylic acid and the phase transfer catalyst is subjected to reduced-pressure distillation concentration, and is used for replacing partial raw material in DL-HPG synthesis. The process provided by the invention overcomes defects of the productions of large amounts of ammonia-nitrogen, strong acids and phenolic wastewater of current DL-HPG synthesis methods. With the process provided by the invention, a byproduct 4-nitro-phthalic acid is easy to separate and recover, excessive glyoxylic acid and phase transfer catalyst can be recycled, wastewater amount is low, and wastewater is easy to process.
Description
Technical field
Technical field of the present invention is pharmaceutical-chemical intermediate production, is the technology of preparing about the compound with following structure:
Chemical name DL-D-pHPG (being called for short DL-HPG), what obtain by chemosynthesis is racemic mixture, making D-D-pHPG (being called for short D-HPG) after splitting, is the requisite side-chain acids of medicine such as synthetic amoxycillin, S 578, cefoperazone, cephalo Luo Qi and SKF-60771.
Background technology
The synthetic technology synthetic method of D-HPG is roughly divided two classes, and a class is biological synthesis process, and another kind of is chemical synthesis.Chemical synthesis is to produce the D-HPG main method at present owing to the advantage at aspects such as raw material, cost, production cycle and maturation process.The domestic and international consistent DL-HPG that tends to earlier synthetic racemization of chemical synthesis, and then split and obtain D-HPG, have about the method for synthesizing the DL-D-pHPG both at home and abroad: (1) Strerker amino acid synthesis method, namely generate hydroxyl-alpha-amino group benzyl cyanide with p-Hydroxybenzaldehyde and prussiate effect, acidic hydrolysis generates target compound then, this method technology is ripe, but use the prussiate of expensive p-Hydroxybenzaldehyde and severe toxicity, environmental requirement is very high, progressively is eliminated.(2) with oxoethanoic acid and phenol effect, generate parahydroxymandelic acid, the ammonia solution generates target compound again, and this method needs high-speed stirring, aftertreatment complexity in condensation reaction.(3) with oxoethanoic acid, urea and the right-hydroxybenzene glycolylurea of phenol effect generation, be hydrolyzed again target compound, this method raw material is easy to get, and is inexpensive, but long reaction time, and yield is not high yet.(4) oxoethanoic acid-phenol-ammonium salt one-step synthesis it be the domestic and international novel process of exploitation in recent years, make oxoethanoic acid, phenol and ammonium salt effect, single stage method is synthesized the DL-D-pHPG, this method raw material is easy to get, low price, yield reaches as high as 61.0%, but a large amount of ammonia nitrogens, strong acid and phenols wastewater in producing be difficult to handle.
The present invention has overcome above-mentioned shortcoming, and through the synthetic DL-D-pHPG that obtains of one kettle way, its quality index can satisfy the resolution process requirement.Have the easily separated recovery of by product 4-nitrophthalic acid, excessive oxoethanoic acid and phase-transfer catalyst are easy to recovery of applied, and wastewater flow rate is easily handled less.
Summary of the invention
1, ingredient proportion: 29% oxoethanoic acid: phenol: 4-nitro phthalic imidine: dodecyl benzyl dimethyl ammonium chloride: water=100: 30: 60: 6: 24 (weight ratio).
2, feeding sequence: water, dodecyl benzyl dimethyl ammonium chloride, 29% oxoethanoic acid, 4-nitro phthalic imidine, phenol.
3, reaction conditions: at 65 ± 2 ℃ of insulated and stirred reaction 10h, be cooled to 25 ℃ then, filter 4-nitrophthalic acid solid.Filtrate is put into frozen water and is cooled off 1h, and suction filtration, filter cake are successively with frozen water, ethanol filter wash and extremely colourless, dry down in 70～80 ℃.Obtain white powder DL-HPG product, content (HPLC) 〉=99%, product quality indicator can satisfy the resolution process requirement.
4, the recovery set of oxoethanoic acid and phase-transfer catalyst is used: above-mentioned mother liquor master composition is oxoethanoic acid and phase-transfer catalyst, and it is synthetic for the DL-D-pHPG directly to substitute part oxoethanoic acid and phase-transfer catalyst after underpressure distillation concentrates.
Embodiment
Example 1:
1, in the 5000L enamel reaction still, drop into 240Kg, dodecyl benzyl dimethyl ammonium chloride 30Kg, 29% oxoethanoic acid 1000Kg, 4-nitro phthalic imidine 600Kg, phenol 300Kg, stir fast, at 65 ± 2 ℃ of following stirring reaction 10h, be cooled to 25 ℃ then, filter the about 600Kg of 4-nitrophthalic acid solid, the rate of recovery 〉=90%.
2, above-mentioned filtrate is put into frozen water and cool off 1h, suction filtration, filter cake are used frozen water, ethanol filter wash and extremely colourless successively.The dry about 395Kg of Off-white solid, yield 〉=74% of getting under 70～80 ℃.
3, the recovery set of oxoethanoic acid and phase-transfer catalyst is used: above-mentioned mother liquor underpressure distillation is concentrated into 1/3rd of original volume, about 400Kg, main composition is oxoethanoic acid and phase-transfer catalyst, and it is synthetic for the DL-D-pHPG directly to substitute part oxoethanoic acid and phase-transfer catalyst.
Example 2:
1, in the 5000L enamel reaction still, drop into the recovery mother liquor 400Kg of oxoethanoic acid and phase-transfer catalyst, dodecyl benzyl dimethyl ammonium chloride 5Kg, 29% oxoethanoic acid 800Kg, 4-nitro phthalic imidine 600Kg, phenol 240Kg, stir fast, at 65 ± 2 ℃ of following stirring reaction 10h, be cooled to 25 ℃ then, filter the about 600Kg of 4-nitrophthalic acid solid, the rate of recovery 〉=90%.
2, above-mentioned filtrate is put into frozen water and cool off 1h, suction filtration, filter cake are used frozen water, ethanol filter wash and extremely colourless successively.The dry about 380Kg of Off-white solid, yield 〉=71% of getting under 70～80 ℃.
3, the recovery set of oxoethanoic acid and phase-transfer catalyst is used: above-mentioned mother liquor is applied mechanically by example 1 method.
Claims (5)
1. the new synthetic process of DL-D-pHPG of the present invention, it is characterized in that: drop into water, phase-transfer catalyst, 29% oxoethanoic acid, 4-nitro phthalic imidine, phenol by a certain percentage, react certain hour at a certain temperature, be cooled to 25 ℃ then, filter 4-nitrophthalic acid solid.Filtrate is put into frozen water and is cooled off, and suction filtration, filter cake use frozen water, washing with alcohol filter cake to colourless successively, and drying obtains white powder DL-HPG product, content (HPLC) 〉=99%, and product quality indicator can satisfy the resolution process requirement.The mother liquor underpressure distillation that is oxoethanoic acid and phase-transfer catalyst with above-mentioned main composition is concentrated into 1/3rd of original volume again, and it is synthetic for the DL-D-pHPG directly to substitute part oxoethanoic acid and phase-transfer catalyst.
2. according to the phase-transfer catalyst described in the right 1, it is characterized in that: a kind of in quaternary ammonium salt such as dodecyl benzyl dimethyl ammonium chloride, palmityl trimethyl ammonium chloride, dodecyl dimethyl benzyl ammonium bromide, the octadecyl dimethyl benzyl brometo de amonio etc.
3. according to the water of input by a certain percentage described in the right 1, dodecyl benzyl dimethyl ammonium chloride, 29% oxoethanoic acid, 4-nitro phthalic imidine, phenol, it is characterized in that: 29% oxoethanoic acid: phenol: 4-nitro phthalic imidine: dodecyl benzyl dimethyl ammonium chloride: water=100: 30: 60: 6: 24 (weight ratio).
4. according to the certain hour of reaction at a certain temperature described in the right 1, it is characterized in that: at 65 ± 2 ℃ of insulated and stirred reaction 10h.
5. use according to the recovery set of the oxoethanoic acid described in the right 1 and phase-transfer catalyst, it is characterized in that: main composition is that the mother liquor underpressure distillation of oxoethanoic acid and phase-transfer catalyst is concentrated into 1/3rd of original volume, and it is synthetic for the DL-D-pHPG directly to substitute part oxoethanoic acid and phase-transfer catalyst.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100022711A CN103193663A (en) | 2012-01-06 | 2012-01-06 | Novel synthesis process of DL-p-hydroxyphenylglycine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100022711A CN103193663A (en) | 2012-01-06 | 2012-01-06 | Novel synthesis process of DL-p-hydroxyphenylglycine |
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| CN103193663A true CN103193663A (en) | 2013-07-10 |
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| CN2012100022711A Pending CN103193663A (en) | 2012-01-06 | 2012-01-06 | Novel synthesis process of DL-p-hydroxyphenylglycine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973753A (en) * | 2017-11-27 | 2018-05-01 | 天津市职业大学 | A kind of method of phase-transfer Wittig reaction 4-Hydroxyphenyl hydantoin |
| CN109020823A (en) * | 2018-09-12 | 2018-12-18 | 山西卓联锐科科技有限公司 | A kind of processing method of D-pHPG mother liquor waste water |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995014656A1 (en) * | 1993-11-29 | 1995-06-01 | Dsm N.V. | Process for the preparation of 4-hydroxyphenyl glycine with enhanced optical purity |
| CN101759582A (en) * | 2008-12-08 | 2010-06-30 | 河南新天地药业有限公司 | New process for producing DL-p-hydroxyphenylglycine |
| CN102285894A (en) * | 2010-06-17 | 2011-12-21 | 河南新天地药业股份有限公司 | Method for preparing D-L-p-hydroxyphenylglycine |
-
2012
- 2012-01-06 CN CN2012100022711A patent/CN103193663A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995014656A1 (en) * | 1993-11-29 | 1995-06-01 | Dsm N.V. | Process for the preparation of 4-hydroxyphenyl glycine with enhanced optical purity |
| CN101759582A (en) * | 2008-12-08 | 2010-06-30 | 河南新天地药业有限公司 | New process for producing DL-p-hydroxyphenylglycine |
| CN102285894A (en) * | 2010-06-17 | 2011-12-21 | 河南新天地药业股份有限公司 | Method for preparing D-L-p-hydroxyphenylglycine |
Non-Patent Citations (2)
| Title |
|---|
| 项东升: "DL-对羟基苯甘氨酸的合成新工艺", 《化工中间体》 * |
| 项东升: "DL―对羟基苯甘氨酸的合成新工艺", 《化工科技市场》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973753A (en) * | 2017-11-27 | 2018-05-01 | 天津市职业大学 | A kind of method of phase-transfer Wittig reaction 4-Hydroxyphenyl hydantoin |
| CN109020823A (en) * | 2018-09-12 | 2018-12-18 | 山西卓联锐科科技有限公司 | A kind of processing method of D-pHPG mother liquor waste water |
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Application publication date: 20130710 |