CN103524366A - Synthesis process of -p-hydroxyphenylglycine - Google Patents
Synthesis process of -p-hydroxyphenylglycine Download PDFInfo
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- CN103524366A CN103524366A CN201310426025.3A CN201310426025A CN103524366A CN 103524366 A CN103524366 A CN 103524366A CN 201310426025 A CN201310426025 A CN 201310426025A CN 103524366 A CN103524366 A CN 103524366A
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Abstract
The invention discloses a synthesis process of -p-hydroxyphenylglycine, belonging to the field of pharmaceutical chemicals. The method comprises the steps of reacting phenol and 2-hydroxy glycine in an organic solvent in the presence of an acid catalyst, separating a compound salt of an R-type isomer from an S-type isomer through first chiral resolution, then resolving the S-type isomer after racemization to further obtain a compound salt of the R-type isomer, and combining the compound salts of the R-type isomers and then processing to obtain the -p-hydroxyphenylglycine. The method for preparing -p-hydroxyphenylglycine has the advantages of easily obtained raw materials, simple and convenient operation, low cost, high yield, high product purity, environmental friendliness and suitability for commercial production.
Description
Technical field
The present invention relates to the synthetic of a kind of medical chiral intermediate, particularly a kind of antibiotic medicine chiral intermediate is synthetic, belongs to field of medicine and chemical technology.
Background technology
(R)-D-pHPG, is called again D-(-)-D-pHPG, and structure, as shown in formula I, is a kind of antibiotic important intermediate, for the synthesis of the side chain of the semi-synthetic antibiotic of beta-lactam.
CN101362703 and EP530879 disclose the method for synthetic (the R)-D-pHPG of suitability for industrialized production, take phenol, oxoethanoic acid and thionamic acid prepares the D-pHPG of racemization as raw material, through separation and purification and chiral separation, obtains (R)-D-pHPG.The method technical maturity, cost is low, but (R)-D-pHPG yield of the method gained is low, separation of by-products difficulty, and refining cost is high, and amount of industrial wastewater is large, and environmental protection pressure is large.With regard to the D-pHPG of racemization is prepared yield, it is that to prepare yield be 65% to 61%, CN101362703 that EP530879 prepares yield.
Publication number is the synthetic method that the Chinese patent application of CN102816076A discloses a kind of D-pHPG, comprises following operation: phenol and 2-hydroxyglycine are reacted under catalyzer exists, obtain D-pHPG.This preparation method prepares D-pHPG raw material and is easy to get, and easy and simple to handle, cost is low, and yield is high, but the product obtaining is racemic, can not obtain (R)-D-pHPG.
Summary of the invention
The invention provides a kind of synthesis technique of (R)-D-pHPG, this synthesis technique is simple to operate, and the yield of (R)-D-pHPG and ee value are high, and environmental protection pressure is little, is produced on a large scale.
A synthesis technique for (R)-D-pHPG, comprises the steps:
(1) phenol, 2-hydroxyglycine and sulfuric acid are mixed, under organic solvent exists, react, after reaction finishes, add water stratification, water adds resolving agent to split, and filters and obtain the first filter cake and filtrate after having split;
(2) in the filtrate obtaining to step (1), add alkali and separate out (S)-D-pHPG, then to the salicylic aldehyde that adds water, resolving agent and catalytic amount in (the S)-D-pHPG obtaining, carry out racemization and fractionation simultaneously, after completing, filtration obtains the second filter cake, the first described filter cake and the second filter cake are merged in the rear vitriolization aqueous solution, add again alkali and neutralize, obtain described (R)-D-pHPG.
Wherein, after completing, the reaction of step (1) obtains the D-pHPG of racemization, react with resolving agent and obtain two kinds of composite salt, after filtering separation, the composite salt of S type isomer enters in step (2), through after adding alkali and separating out, racemization and resolution reaction occurs, S type isomer Partial Conversion is the composite salt of R type isomer and is separated, finally composite salt dissociated and can obtain required (R)-D-pHPG.Wherein, by further racemization and the fractionation to S type isomer in step (2), improved the yield of (R)-D-pHPG.
Reaction conditions in step (1) can be with reference to CN102816076A, and as preferably, in step (1), described organic solvent is at least one in toluene, chlorobenzene, dimethylbenzene, methylene dichloride and ethylene dichloride.In these organic solvents, the formation efficiency of the D-pHPG of racemization is high.
As preferably, described resolving agent is at least one in phenylethane sulfonic acid, camphorsulfonic acid and bromocamphor sulfonic acid, and the fractionation efficiency of these resolving agents is high, can improve the ee value of described (R)-D-pHPG.
During fractionation, the mole dosage of resolving agent be roughly racemization D-pHPG 1/2, wherein, the consumption of D-pHPG is determined according to the amount of raw material 2-hydroxyglycine used, as preferably, in step (1), the mol ratio of described 2-hydroxyglycine and described resolving agent is 1:0.45～0.55, this amount ranges can make the composite salt of described (R)-D-pHPG fully separate out, avoid the composite salt of (S)-D-pHPG to separate out simultaneously, make two kinds of isomer that separation occur preferably, improve yield and the purity of described (R)-D-pHPG.
In step (2), the mol ratio of described (S)-D-pHPG and described resolving agent is 1:0.45～0.55.
In step (1) and (2), the temperature of fractionation is 70～110 ℃.
In step (2), described alkali is mineral alkali, is selected from least one in ammoniacal liquor, sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide and lithium hydroxide.
As further preferably, in step (2), in the filtrate obtaining to step (1), add alkali to pH3.0～7.0, preferably 3.0～5.5, more excellent at this pH value range product yield and outward appearance.
As preferably, the consumption of described salicylic aldehyde is 0.1%～10% of described (S)-D-pHPG quality, preferably 0.2%～0.5%.Too much increase material cost, racemization is not thorough at least excessively.
Compared with the existing technology, the inventive method raw material is easy to get, and reaction conditions is gentle, and product purity is high, and operating procedure is simple, and the cycle is short, and cost is low, and yield is high, produces without specific installation, and aftertreatment is simple, and environmental pollution is little, is applicable to industrialized production.
Embodiment
In order to understand better technical scheme of the present invention, below in conjunction with specific embodiment, be further described, but those of ordinary skill in the art will be appreciated that, the present invention is not limited to these embodiment.
Embodiment 1
In ethylene dichloride (150g), add successively phenol (56.4g), 2-hydroxyglycine (45.5g) and sulfuric acid (10g), be warming up to 50-55 ℃ of reaction, TLC endpoint detection, reaction finishes, and adds water (150g), stir 30min, stratification, adds 37.2g(+ in water) phenylethane sulfonic acid, be warming up to 75-80 ℃, constant temperature 3 hours, cooling, filters, and filter cake is washed to obtain (R)-D-pHPG phenylethane sulfonic acid (+) double salt crude product.Filtrate with ammonia neutralization to pH be 5.5, filter, wash to obtain 50.7g D-pHPG crude product (this D-pHPG crude product composition is (S)-D-pHPG), in this crude product, add 18.6g(+) phenylethane sulfonic acid, 100g water and 0.15g salicylic aldehyde, be warming up to 75～80 ℃ of reaction 12h, cooling, filter, wash to obtain (+)-D-pHPG phenylethane sulfonic acid double salt crude product.
Get 50g(+)-D-pHPG phenylethane sulfonic acid double salt, be dissolved in 50g water, then add ammoniacal liquor and be neutralized to pH3.0, filter, washing, filter cake is dried, and obtains 18.9g (R)-D-pHPG, in and yield be 80%, optically-active is-157.6 °.Purity 99.5%, chiral purity 99.5%ee.
(R) the 1H-NMR data of-D-pHPG: 1H-NMR(400MHz, D
2o) δ: 7.18(d, J=8Hz, 2H), 6.80(d, J=8Hz, 2H), 4.59(s, 1H).
Embodiment 2
In toluene (150g), add successively phenol (56.4g), 2-hydroxyglycine (54.6g) and sulfuric acid (29.4g), be warming up to 55-60 ℃ of reaction, TLC endpoint detection, reaction finishes, and adds water (150g), stir 30min, stratification, adds 50.1g(+ in water) camphorsulfonic acid, be warming up to 90～95 ℃, constant temperature 3 hours, cooling, filters, and filter cake is washed to obtain (R)-D-pHPG camphorsulfonic acid (+) double salt crude product.Filtrate with ammonia neutralization to pH be 4.0, filter, wash to obtain 72.1g D-pHPG crude product, in this crude product, add 50.1g(+) camphorsulfonic acid, 100g water and 0.36g salicylic aldehyde, be warming up to 90～95 ℃ of reaction 12h, cooling, filter, wash to obtain (+)-D-pHPG camphorsulfonic acid double salt crude product.
Get 50g(+)-D-pHPG camphorsulfonic acid double salt, be dissolved in 50g water, then add ammoniacal liquor and be neutralized to pH to 5.5, filter, washing, dries, and obtains 20.1g (R)-D-pHPG, in and yield be 85%, product optically-active is-157.8 °.Product purity 99.6%, chiral purity 99.6%ee.
Embodiment 3
In chlorobenzene (150g), add successively phenol (56.4g), 2-hydroxyglycine (49.1g) and sulfuric acid (25g), be warming up to 58-62 ℃ of reaction, TLC endpoint detection, reaction finishes, and adds water (150g), stir 30min, stratification, adds 65.1g(+ in water) bromocamphor sulfonic acid, be warming up to 100～105 ℃, constant temperature 3 hours, cooling, filters, and washes to obtain (R)-D-pHPG bromocamphor sulfonic acid (+) double salt crude product.(+)-D-pHPG bromocamphor sulfonic acid double salt mother liquor with ammonia neutralization to pH be 5.5, filter, wash to obtain 62.8g D-pHPG crude product, in this crude product, add 61.9g(+) bromocamphor sulfonic acid, 100g water and 0.22g salicylic aldehyde, be warming up to 100～105 ℃ of reaction 12h, cooling, filter, wash to obtain (R)-D-pHPG bromocamphor sulfonic acid (+) double salt crude product.
Get 50g(+)-D-pHPG bromocamphor sulfonic acid double salt, be dissolved in 50g water, then add ammoniacal liquor and be neutralized to pH to 4.5, filter, washing, dries, and obtains 17.8g (R)-D-pHPG, in and yield be 75%, product optically-active is-158.2 °.Product purity 99.4%, chiral purity 99.7%ee.
Embodiment 4
In dimethylbenzene (150g), add successively phenol (56.4g), 2-hydroxyglycine (46.8g) and sulfuric acid (30g), be warming up to 60-65 ℃ of reaction, TLC endpoint detection, reaction finishes, and adds water (150g), stir 30min, stratification, adds 38.6g(+ in water) phenylethane sulfonic acid, be warming up to 80～85 ℃, constant temperature 3 hours, cooling, filters, and washes to obtain (R)-D-pHPG phenylethane sulfonic acid (+) double salt crude product.(R)-D-pHPG phenylethane sulfonic acid (+) double salt mother liquor with ammonia neutralization to pH be 5.5, filter, wash to obtain 63.2g D-pHPG crude product, in this crude product, add 35.2g(+) phenylethane sulfonic acid, 100g water and 0.22g salicylic aldehyde, be warming up to 80～85 ℃ of reaction 12h, cooling, filter, wash to obtain (+)-D-pHPG phenylethane sulfonic acid double salt crude product.
Get 50g(+)-D-pHPG phenylethane sulfonic acid double salt, be dissolved in 50g water, then add ammoniacal liquor and be neutralized to pH to 4.8, filter, washing, dries, and obtains 18.6g (R)-D-pHPG, in and yield be 78.6%, product optically-active is-157.9 °.Product purity 99.5%, chiral purity 99.5%ee.
It should be noted that, mention that in the present invention all documents quote as a reference in this application, as each piece of document, be alone applied as a reference; In addition should understand; the above is specific embodiments of the invention and the know-why used; after having read foregoing of the present invention; those skilled in the art can make various modifications and not deviate from the spirit and scope of the present invention the present invention, within the modification of these equivalents drops on protection scope of the present invention equally.
Claims (10)
1. a synthesis technique for (R)-D-pHPG, is characterized in that, comprises the steps:
(1) phenol, 2-hydroxyglycine and sulfuric acid are mixed, under organic solvent exists, react, after reaction finishes, add water stratification, water adds resolving agent to split, and filters and obtain the first filter cake and filtrate after having split;
(2) in the filtrate obtaining to step (1), add alkali and separate out (S)-D-pHPG, then to the salicylic aldehyde that adds water, resolving agent and catalytic amount in (the S)-D-pHPG obtaining, carry out racemization and fractionation simultaneously, after completing, filtration obtains the second filter cake, the first described filter cake and the second filter cake are merged in the rear vitriolization aqueous solution, add again alkali and neutralize, obtain described (R)-D-pHPG.
2. the synthesis technique of (R)-D-pHPG according to claim 1, is characterized in that, in step (1), described organic solvent is at least one in toluene, chlorobenzene, dimethylbenzene, methylene dichloride and ethylene dichloride.
3. the synthesis technique of (R)-D-pHPG according to claim 1, is characterized in that, described resolving agent is at least one in phenylethane sulfonic acid, camphorsulfonic acid and bromocamphor sulfonic acid.
4. according to the synthesis technique of (the R)-D-pHPG described in claim 1 or 3, it is characterized in that, in step (1), the mol ratio of described 2-hydroxyglycine and described resolving agent is 1:0.45～0.55.
5. according to the synthesis technique of (the R)-D-pHPG described in claim 1 or 3, it is characterized in that, in step (1) and (2), the temperature of fractionation is 70～110 ℃.
6. the synthesis technique of (R)-D-pHPG according to claim 1, it is characterized in that, described alkali is selected from least one in ammoniacal liquor, sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide and lithium hydroxide.
7. according to the synthesis technique of (the R)-D-pHPG described in claim 1 or 6, it is characterized in that, in step (2), in the filtrate obtaining to step (1), add alkali to pH3.0～7.0.
8. the synthesis technique of (R)-D-pHPG according to claim 7, is characterized in that, in step (2), in the filtrate obtaining, adds alkali to pH3.8～5.5 to step (1).
9. the synthesis technique of (R)-D-pHPG according to claim 1, is characterized in that, in step (2), the consumption of described salicylic aldehyde is 0.1%～10% of described (S)-D-pHPG quality.
10. the synthesis technique of (R)-D-pHPG according to claim 1, is characterized in that, the consumption of described salicylic aldehyde is 0.2%～0.5% of described (S)-D-pHPG quality.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110467537A (en) * | 2019-08-08 | 2019-11-19 | 河南新天地药业股份有限公司 | A kind of preparation process of D-HPG |
| CN113620826A (en) * | 2021-08-20 | 2021-11-09 | 湖北省宏源药业科技股份有限公司 | Preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production |
| CN113896645A (en) * | 2021-12-09 | 2022-01-07 | 天津市职业大学 | Clean production method of levo-p-hydroxyphenylglycine |
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| CN102816076A (en) * | 2012-08-28 | 2012-12-12 | 山东汉兴医药科技有限公司 | Synthetic method of p-hydroxyphenylglycine |
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| CN102816076A (en) * | 2012-08-28 | 2012-12-12 | 山东汉兴医药科技有限公司 | Synthetic method of p-hydroxyphenylglycine |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110467537A (en) * | 2019-08-08 | 2019-11-19 | 河南新天地药业股份有限公司 | A kind of preparation process of D-HPG |
| CN110467537B (en) * | 2019-08-08 | 2022-10-04 | 河南新天地药业股份有限公司 | Preparation process of L-p-hydroxyphenylglycine |
| CN113620826A (en) * | 2021-08-20 | 2021-11-09 | 湖北省宏源药业科技股份有限公司 | Preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production |
| CN113620826B (en) * | 2021-08-20 | 2024-02-02 | 湖北省宏源药业科技股份有限公司 | Preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production |
| CN113896645A (en) * | 2021-12-09 | 2022-01-07 | 天津市职业大学 | Clean production method of levo-p-hydroxyphenylglycine |
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Address after: 261312 No. 9, Hanxing Road, Binhai (Xiaying) Economic Development Zone, Changyi City, Weifang City, Shandong Province Patentee after: Shandong puluohanxing Pharmaceutical Co.,Ltd. Address before: 261313 Coastal Development Zone, Changyi City, Weifang City, Shandong Province Patentee before: CHANGYI HANXING MEDICAL SCIENCE CO.,LTD. |
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Effective date of registration: 20220524 Address after: 261312 No. 9, Hanxing Road, Binhai (Xiaying) Economic Development Zone, Changyi City, Weifang City, Shandong Province Patentee after: Shandong puluohanxing Pharmaceutical Co.,Ltd. Patentee after: APELOA PHARMACEUTICAL CO.,LTD. Address before: 261312 No. 9, Hanxing Road, Binhai (Xiaying) Economic Development Zone, Changyi City, Weifang City, Shandong Province Patentee before: Shandong puluohanxing Pharmaceutical Co.,Ltd. |