CN106083629A - The preparation method of D-pHPG - Google Patents
The preparation method of D-pHPG Download PDFInfo
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- CN106083629A CN106083629A CN201610425491.3A CN201610425491A CN106083629A CN 106083629 A CN106083629 A CN 106083629A CN 201610425491 A CN201610425491 A CN 201610425491A CN 106083629 A CN106083629 A CN 106083629A
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- hour
- phpg
- hydroxyphenyl hydantoin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/24—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from hydantoins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
- C07D233/78—Radicals substituted by oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides the preparation method of a kind of D-pHPG, it comprises the steps: that A synthesizes 4-Hydroxyphenyl hydantoin, and B. hydroxy benzenes glycolylurea is hydrolyzed, the preparation method that the present invention provides, and efficiency is high, and yield is high, is suitable for large-scale mass production.
Description
Technical field
The present invention relates to the preparation method of wide-spectrum antiseptic medicine, particularly relate to the preparation side of a kind of D-pHPG
Method.
Background technology
To this glycine of hydroxyl, being a kind of medicine fine chemicals, outward appearance is white crystalline powder, is synthesis beta-lactam
Class, the side chain of semi-synthetic antibiotics, for amoxicillin (being commonly called as amoxicillin) cefoperazone, cefradine, cephalo stands
Newly, ceftriaxone sodium and hydroxyl EPCP, the antibiotic medicine such as 7ADCA, these medicinal usages are extensive, not only injectable but also orally available,
It it is broad-spectrum antiseptic.
Summary of the invention
The invention provides the preparation method of a kind of D-pHPG, it comprises the steps:
.A synthesizing 4-Hydroxyphenyl hydantoin, phenol, carbamide are mixed in proportion and are dissolved in aqueous hydrochloric acid solution, at relatively low temperature by (1)
Degree lower dropping glyoxylic acid solution 8-10 hour, first condensation forms 2-urea groups phenylacetic acid intermediate, carries out the most at relatively high temperatures
Annulation generates 4-Hydroxyphenyl hydantoin；
. reactant liquor is cooled to 35 DEG C by (2), and vacuum filters the white 4-Hydroxyphenyl hydantoin crystallization separated out, by 40-50 DEG C of heat
Water wash crystallization, methanol embathes, and dries, obtains 4-Hydroxyphenyl hydantoin product；
. mother solution strong aqua ammonia is neutralized to PH4-6 by (3), is cooled to 10-15 DEG C, and vacuum filters the precipitation separated out, and washes,
Obtain the filter cake containing D-pHPG, 4-Hydroxyphenyl hydantoin and by-product；
(4) filter cake is dissolved in 15% sodium hydroxide solution, is placed in reaction bulb and adds pyrohydrolysis, use after hydrolyzed solution cooling
20% hydrochloric acid neutralizes PH4-6, and solution is further cooled to 10-15 DEG C, and vacuum filters the crystallization separated out, washing, and methanol embathes,
Dry, obtain D-pHPG side-product.
B. hydroxy benzenes glycolylurea is hydrolyzed.
Preferably, when reaction feeds intake, raw material glyoxalic acid, phenol, urea mol ratio are 1: 1.0-1.1: 1-1.5.
Preferably, it is temperature 50-60 DEG C that condensation forms the optimal conditions of 2-urea groups phenylacetic acid intermediate, response time 8-10
Hour.
Preferably, it is insulation reaction 4-6 hour at 80 DEG C that 2-urea groups phenylacetic acid carries out the optimal conditions of annulation, 105
Insulation reaction 2-4 hour at DEG C.
Preferably, filter cake hydrolysis temperature 100-110 DEG C containing 4-Hydroxyphenyl hydantoin and by-product, hydrolysis time 12-18 is little
Time.
Accompanying drawing explanation
Fig. 1 be in embodiment the preparation method of D-pHPG figure is synthesized.
It is embodied as content
The molecular formula of D-pHPG is C8H9NO3, molecular weight is 167.16.An enforcement according to the present invention
Example, the molecular structural formula of D-pHPG is
Generally, to this glycine of hydroxyl, being a kind of medicine fine chemicals, outward appearance is white crystalline powder.
It is synthesis beta-lactam to this glycine of hydroxyl, the side chain of semi-synthetic antibiotics.
Organic polymer comprises various chain link.Chain link refers to recursive structure list minimum in macromolecular compound
Unit.Having main chain in chain link, main chain refers in organic molecule the longest, comprises the carbochain that side chain is most.Side chain is to have point
Prop up chain shorter in the open-chain hydrocarbons molecule of structure, be considered as base.To this glycine of hydroxyl as synthesis beta-lactam, narrow
Become the side chain of antibiotics, can be used for amoxicillin (being commonly called as amoxicillin) cefoperazone, cefradine, Cefalexin, head
Spore Qusong sodium and hydroxyl EPCP, the antibiotic medicine such as 7ADCA.These medicinal usages are extensive, not only injectable but also orally available, are wide spectrums
Antibacterial.
The preparation reaction principle of the preparation method that the invention provides D-pHPG is as follows:
In conjunction with Fig. 1, the preparation method of a kind of D-pHPG, it comprises the steps:
.A synthesizing 4-Hydroxyphenyl hydantoin, phenol, carbamide are mixed in proportion and are dissolved in aqueous hydrochloric acid solution, at relatively low temperature by (1)
Degree lower dropping glyoxylic acid solution 8-10 hour, first condensation forms 2-urea groups phenylacetic acid intermediate, carries out the most at relatively high temperatures
Annulation generates 4-Hydroxyphenyl hydantoin；
. reactant liquor is cooled to 35 DEG C by (2), and vacuum filters the white 4-Hydroxyphenyl hydantoin crystallization separated out, by 40-50 DEG C of heat
Water wash crystallization, methanol embathes, and dries, obtains 4-Hydroxyphenyl hydantoin product；
. mother solution strong aqua ammonia is neutralized to PH4-6 by (3), is cooled to 10-15 DEG C, and vacuum filters the precipitation separated out, and washes,
Obtain the filter cake containing D-pHPG, 4-Hydroxyphenyl hydantoin and by-product；
(4) filter cake is dissolved in 15% sodium hydroxide solution, is placed in reaction bulb and adds pyrohydrolysis, use after hydrolyzed solution cooling
20% hydrochloric acid neutralizes PH4-6, and solution is further cooled to 10-15 DEG C, and vacuum filters the crystallization separated out, washing, and methanol embathes,
Dry, obtain D-pHPG side-product.
B. hydroxy benzenes glycolylurea is hydrolyzed.
. when reaction feeds intake, raw material glyoxalic acid, phenol, urea mol ratio are 1: 1.0-1.1: 1-1.5: 0.2-0.5.
. it is temperature 50-60 DEG C that condensation forms the optimal conditions of 2-urea groups phenylacetic acid intermediate, 8-10 hour response time.
.2-urea groups phenylacetic acid carries out the optimal conditions of annulation is insulation reaction 4-6 hour at 80 DEG C, protects at 105 DEG C
Temperature reaction 2-4 hour.
Filter cake hydrolysis temperature 100-110 DEG C containing 4-Hydroxyphenyl hydantoin and by-product, hydrolysis time 12-18 hour.
Generating intermediate product with glyoxalic acid, carbamide with phenol effect in step A, obtained intermediate product is p-hydroxyl
Benzene glycolylurea.
P-hydroxy benzenes glycolylurea is a kind of white powder, is slightly soluble in water, fusing point 270-271 DEG C, density 1.408.It is that production is right
The important medicine intermediate of hydroxyphenylglycine.Molecular formula is C9H8N2O3, molecular weight is 192.17.Molecular structural formula is
Intermediate product p-hydroxy benzenes glycolylurea obtained by step B, through hydrolysis, can obtain target compound to hydroxyl
This glycine.
The described prepared finished product that is eventually fabricated is C to hydroxyl this glycine molecule formula8H9NO3, molecular weight is 167.16, its
Structural formula is as follows:
Claims (5)
1. the preparation method of D-pHPG, it comprises the steps:
A. synthesizing 4-Hydroxyphenyl hydantoin, phenol, carbamide are mixed in proportion and are dissolved in aqueous hydrochloric acid solution, at a lower temperature by (1)
Dropping glyoxylic acid solution 8-10 hour, first condensation forms 2-urea groups phenylacetic acid intermediate, carries out cyclization the most at relatively high temperatures
Reaction generates 4-Hydroxyphenyl hydantoin；
(2) reactant liquor being cooled to 35 DEG C, vacuum filters the white 4-Hydroxyphenyl hydantoin crystallization separated out, by 40-50 DEG C of hot water wash
Washing crystallization, methanol embathes, and dries, obtains 4-Hydroxyphenyl hydantoin product；
(3) mother solution strong aqua ammonia being neutralized to PH4-6, be cooled to 10-15 DEG C, vacuum filters the precipitation separated out, washing, is contained
The filter cake of D-pHPG, 4-Hydroxyphenyl hydantoin and by-product；
(4) filter cake is dissolved in 15% sodium hydroxide solution, is placed in reaction bulb and adds pyrohydrolysis, after hydrolyzed solution cooling, use 20% salt
Acid neutralizes PH4-6, and solution is further cooled to 10-15 DEG C, and vacuum filters the crystallization separated out, washing, and methanol embathes, and dries,
Obtain D-pHPG side-product.
B. hydroxy benzenes glycolylurea is hydrolyzed.
Method the most according to claim 1, it is characterised in that when reaction feeds intake, raw material glyoxalic acid, phenol, urea mol ratio are 1
∶1.0-1.1∶1-1.5。
Method the most according to claim 1, it is characterised in that condensation forms the optimal conditions of 2-urea groups phenylacetic acid intermediate and is
Temperature 50-60 DEG C, 8-10 hour response time.
Method the most according to claim 1, it is characterised in that it is 80 that 2-urea groups phenylacetic acid carries out the optimal conditions of annulation
Insulation reaction 4-6 hour at DEG C, insulation reaction 2-4 hour at 105 DEG C.
Method the most according to claim 1, it is characterised in that the filter cake hydrolysis temperature containing 4-Hydroxyphenyl hydantoin and by-product
100-110 DEG C, hydrolysis time 12-18 hour.
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| CN201610425491.3A CN106083629A (en) | 2016-06-14 | 2016-06-14 | The preparation method of D-pHPG |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022007288A1 (en) * | 2020-07-09 | 2022-01-13 | 定陶三化药业有限公司 | Dl-p-hydroxybenzene hydantoin and urea sulfate/ammonium sulfate production process thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030113880A1 (en) * | 2001-07-10 | 2003-06-19 | Ajinomoto Co., Inc. | DNA for encoding D-hydantoin hydrolases, DNA for encoding N-carbamyl-D-amino acid hydrolases, recombinant DNA containing the genes, cells transformed with the recombinant DNA, methods for producing proteins utilizing the transformed cells and methods for producing D-amino acids |
| CN101973941B (en) * | 2010-11-22 | 2012-11-28 | 天津市职业大学 | Method for preparing 4-hydroxyphenyl hydantoin |
-
2016
- 2016-06-14 CN CN201610425491.3A patent/CN106083629A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030113880A1 (en) * | 2001-07-10 | 2003-06-19 | Ajinomoto Co., Inc. | DNA for encoding D-hydantoin hydrolases, DNA for encoding N-carbamyl-D-amino acid hydrolases, recombinant DNA containing the genes, cells transformed with the recombinant DNA, methods for producing proteins utilizing the transformed cells and methods for producing D-amino acids |
| CN101973941B (en) * | 2010-11-22 | 2012-11-28 | 天津市职业大学 | Method for preparing 4-hydroxyphenyl hydantoin |
Non-Patent Citations (1)
| Title |
|---|
| 张彦岭等: "D-对羟基苯甘氨酸的合成研究", 《许昌学院学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022007288A1 (en) * | 2020-07-09 | 2022-01-13 | 定陶三化药业有限公司 | Dl-p-hydroxybenzene hydantoin and urea sulfate/ammonium sulfate production process thereof |
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