CN103951587A - Synthetic method for intermediate of benserazide hydrochloride - Google Patents
Synthetic method for intermediate of benserazide hydrochloride Download PDFInfo
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- CN103951587A CN103951587A CN201410144012.1A CN201410144012A CN103951587A CN 103951587 A CN103951587 A CN 103951587A CN 201410144012 A CN201410144012 A CN 201410144012A CN 103951587 A CN103951587 A CN 103951587A
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Abstract
A provided synthetic method for an intermediate of benserazide hydrochloride comprises the following steps: step (a), taking DL-serine and thionyl chloride as initial raw materials, reacting to generate methyl-DL-serine hydrochloride, concentrating the reaction solution to dry, so as to obtain serine methyl ester, dissolving with methanol for usage in the reaction of step (b); step (b), adding serine methyl ester obtained in the step (a) into hydrazine hydrate, after reaction is finished, adding an alcohol, and adjusting ph to crystallize and further to obtain serine hydrazide; and step (c), reacting serine hydrazide obtained in the step (b) with 2,3,4-trihydroxybenzaldehyde in a methanol system, so as to obtain N-(DL-seryl)-2,3,4-trihydroxybenzaldehyde hydrazone. The preparation method disclosed by the invention is high in yield, low in cost, short in reaction period, environment-friendly and suitable for industrialized production.
Description
Technical field
The present invention relates to chemosynthesis technical field, refer to especially a kind of synthetic method of intermediate of benserazide hydrochloride.
Background technology
About the synthetic method of the intermediate of benserazide hydrochloride, as follows in prior art:
1, serine methylester is synthetic:
The reaction of serine methylester finishes, and existing technique is, after reaction solution is concentrated, then to add water and alcohol crystal
Defect: the production cycle is long, yield is low.
2, Serine hydrazides is synthetic:
Existing technique is directly dissolved serine methylester, then adds greatly excessive hydrazine hydrate, and insulation reaction is concentrated, the crystallization of alcohols system.
Defect: the production cycle is long, yield is low.
3, hydrochloric acid benzyl silk hydrazone is synthetic:
Existing technique is Serine hydrazides and 2,3,4-tri hydroxybenzaldehyde reactive crystallization in aqueous systems, and then alcohols is refining.
Defect: the production cycle is long.
Summary of the invention
The present invention proposes a kind of synthetic method of intermediate of benserazide hydrochloride, has solved the problem that in prior art, the production cycle is long, yield is low.
Synthetic route of the present invention is as follows:
Technical scheme of the present invention is achieved in that
A synthetic method for the intermediate of benserazide hydrochloride, comprises the steps:
(a) take DL-serine and thionyl chloride as initial feed, reaction generates the hydrochloride of serine methylester, then reaction solution is directly concentrated into dryly, obtains serine methylester, after dissolve with methanol, for step (b), reacts;
(b) serine methylester of gained in step (a) is added in hydrazine hydrate, after reaction finishes, add alcohols, adjust pH crystallization, obtain Serine hydrazides;
(c) the Serine hydrazides and 2,3, the 4-tri hydroxybenzaldehyde that with step (b), obtain react at methanol system, obtain hydrochloric acid benzyl silk hydrazone.
As preferred technical scheme, the temperature of reaction of described step (a) is 5-15 ℃.
As preferred technical scheme, the temperature of reaction of described step (b) is 20-30 ℃.
As preferred technical scheme, the alcohols of described step (b) is propyl carbinol, Virahol or ethanol.
As preferred technical scheme, described step (b) is used salt acid for adjusting pH.
As preferred technical scheme, described step (b) Tc is 10-15 ℃.
As preferred technical scheme, described step (c) temperature of reaction is 50-55 ℃.
Beneficial effect
Therefore (1) step of the present invention (a) does not need alcohol crystal technique, is directly concentrated into dryly, has shortened the production cycle, has improved product yield; Methyl alcohol in this step reaction process is directly used in next step reaction simultaneously.Avoid the loss of methyl esters in crystallisation process, improved product yield.
(2) the present invention is in the building-up process of Serine hydrazides, and the consumption of hydrazine hydrate is few, reduces costs, and reduces environmental pollution, environmental protection; Remove concentration of reaction solution step, yield improves, quality improves, with short production cycle near half.
(3) preparation of hydrochloric acid benzyl silk hydrazone of the present invention is to react in methanol system, product convenient post-treatment out, and the production cycle shorten to original 1/5th.
Embodiment
Below the technical scheme in the embodiment of the present invention is clearly and completely described, obviously, described embodiment is only the present invention's part embodiment, rather than whole embodiment.Embodiment based in the present invention, those of ordinary skills, not making the every other embodiment obtaining under creative work prerequisite, belong to the scope of protection of the invention.
The initial main raw material of the present invention is DL-serine, thionyl chloride, and reaction generates the hydrochloride of serine methylester, and the impurity producing in building-up process seldom, because the amino of Serine is by protonated, so lost nucleophilie nucleus ability, thereby not attack carbonyl carbon does not produce by product substantially.So we removed existing technique with alcohol crystal this part, serine methylester reaction solution is concentrated into dry, after dissolve with methanol for next step reaction.So not only can shorten the production cycle, the yield of product can be improved to 20 percentage points simultaneously.Serine methylester is added drop-wise in hydrazine hydrate after dissolving, and after reaction finishes, adds Virahol in reaction solution, and hydrochloric acid is adjusted PH crystallization.Through serial lab scale, pilot scale and production checking, this time process modification has obtained more satisfactory achievement.First, in the first step reaction, we have removed former this step of technique crystallization, after steaming with methyl alcohol top, as far as possible material is drawn dryly, be directly used in next step reaction, so not only shortened the production cycle, also avoided the loss of methyl esters in crystallisation process, improved product yield simultaneously.Secondly, in Serine hydrazides synthetic, we have greatly reduced the consumption of hydrazine hydrate, have saved the use of hydrazine hydrate raw material, have reduced production cost, have also reduced the pollution to environment.Removed this step of concentration of reaction solution, direct acid adjustment crystallization after reaction finishes, product yield so out exceeds 20% than former technique, and quality also increases, the production cycle shortened near half.Finally, from production cost, analyze, after process modification, cost decreases 30%.The preparation of hydrochloric acid benzyl silk hydrazone was formerly carried out before this in the system of water, now made into react in methanol system, and product out is easily dried, and without dehydration, refining, can be directly used in hydrogenation.After improvement, in the situation that not affecting yield and quality, the production cycle shortens to original 1/5th.Specifically, refer to embodiment description.
Embodiment 1
A synthetic method for the intermediate of benserazide hydrochloride, comprises the steps:
Step S1: add 300ml methyl alcohol in 500ml four-hole bottle, be cooled to 15 ℃; 55g sulfur oxychloride is added drop-wise in methyl alcohol, drips and finish, add 50gDL-Serine, back flow reaction 4 hours is evaporated to dry, standby by reaction solution under 45 ℃ of water-baths.
Step S2: the preparation of Serine hydrazides:
95g hydrazine hydrate is joined in 500ml four-hole bottle, by the appropriate dissolve with methanol for serine methylester of test one preparation, 20 ℃ drip serine methylester to hydrazine hydrate, drip to finish, 20 ℃ of insulation reaction one hour, are cooled to room temperature, with concentrated hydrochloric acid, adjust PH4.0-5.0, add 100ml Virahol, be cooled to 10 ℃, stirred crystallization 3 hours; Filter to obtain product.
Step S3: the preparation of hydrochloric acid benzyl silk hydrazone:
In 500ml four-hole bottle, drop into successively 20g2,3,4-tri hydroxybenzaldehyde, 250ml methyl alcohol, add 20g Serine hydrazides, 10g water; At 50～55 ℃, stirring reaction is after 2 hours, and sampling TLC detection reaction is complete, is cooled to room temperature, filters, and with a small amount of Virahol drip washing, drains, and obtains hydrochloric acid benzyl silk hydrazone wet product.
Mass yield 195%, liquid phase purity >=98.0%.
Embodiment 2
A synthetic method for the intermediate of benserazide hydrochloride, comprises the steps:
Step S1: add 315ml methyl alcohol in 500ml four-hole bottle, be cooled to 10 ℃; 60g sulfur oxychloride is added drop-wise in methyl alcohol, drips and finish, add 50gDL-Serine, back flow reaction 3 hours, is evaporated to reaction solution dry, standby.
Step S2: the preparation of Serine hydrazides:
100g hydrazine hydrate is joined in 500ml four-hole bottle, appropriate dissolve with methanol for serine methylester prepared by step S1,25 ℃ drip serine methylester to hydrazine hydrate, drip to finish, 25 ℃ of insulation reaction one hour, are cooled to room temperature, with concentrated hydrochloric acid, adjust PH4.0-5.0, add 100ml propyl carbinol, be cooled to 12 ℃, stirred crystallization 3 hours; Filter to obtain product.
Step S3: the preparation of hydrochloric acid benzyl silk hydrazone:
In 500ml four-hole bottle, drop into successively 20g2,3,4-tri hydroxybenzaldehyde, 350ml methyl alcohol, add 20g Serine hydrazides, 10g water; At 50～55 ℃, stirring reaction is after 2 hours, and sampling TLC detection reaction is complete, is cooled to room temperature, filters, and with a small amount of Virahol drip washing, drains, and obtains hydrochloric acid benzyl silk hydrazone wet product.
Mass yield 185%, liquid phase purity >=98.0%.
Embodiment 3
A synthetic method for the intermediate of benserazide hydrochloride, comprises the steps:
Step S1: add 350ml methyl alcohol in 500ml four-hole bottle, be cooled to 5 ℃; 65g sulfur oxychloride is added drop-wise in methyl alcohol, drips and finish, add 50gDL-Serine, back flow reaction 5 hours, is evaporated to reaction solution dry, standby.
Step S2: the preparation of Serine hydrazides:
105g hydrazine hydrate is joined in 500ml four-hole bottle, appropriate dissolve with methanol for serine methylester prepared by step S1,30 ℃ drip serine methylester to hydrazine hydrate, drip to finish, 30 ℃ of insulation reaction one hour, are cooled to room temperature, with concentrated hydrochloric acid, adjust PH4.0-5.0, add 100ml ethanol, be cooled to 15 ℃, stirred crystallization 3 hours; Filter to obtain product.
Step S3: the preparation of hydrochloric acid benzyl silk hydrazone:
In 500ml four-hole bottle, drop into successively 20g2,3,4-tri hydroxybenzaldehyde, 300ml methyl alcohol, add 20g Serine hydrazides, 10g water; At 50～55 ℃, stirring reaction is after 2 hours, and sampling TLC detection reaction is complete, is cooled to room temperature, filters, and with a small amount of Virahol drip washing, drains, and obtains hydrochloric acid benzyl silk hydrazone wet product.
Mass yield 190%, liquid phase purity >=98.0%.
The foregoing is only preferred embodiment of the present invention, in order to limit the present invention, within the spirit and principles in the present invention not all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (7)
1. a synthetic method for the intermediate of benserazide hydrochloride, is characterized in that comprising the steps:
(a) take DL-serine and thionyl chloride as initial feed, reaction generates the hydrochloride of serine methylester, then reaction solution is directly concentrated into dryly, obtains serine methylester, after dissolve with methanol, for step (b), reacts;
(b) serine methylester of gained in step (a) is added in hydrazine hydrate, after reaction finishes, add alcohols, adjust pH crystallization, obtain Serine hydrazides;
(c) the Serine hydrazides and 2,3, the 4-tri hydroxybenzaldehyde that with step (b), obtain react at methanol system, obtain hydrochloric acid benzyl silk hydrazone.
2. the synthetic method of the intermediate of a kind of benserazide hydrochloride according to claim 1, is characterized in that, the temperature of reaction of described step (a) is 5-15 ℃.
3. the synthetic method of the intermediate of a kind of benserazide hydrochloride according to claim 1, is characterized in that, the temperature of reaction of described step (b) is 20-30 ℃.
4. the synthetic method of the intermediate of a kind of benserazide hydrochloride according to claim 1, is characterized in that, the alcohols of described step (b) is propyl carbinol, Virahol or ethanol.
5. the synthetic method of the intermediate of a kind of benserazide hydrochloride according to claim 1, is characterized in that, described step (b) is used salt acid for adjusting pH.
6. the synthetic method of the intermediate of a kind of benserazide hydrochloride according to claim 1, is characterized in that, described step (b) Tc is 10-15 ℃.
7. the synthetic method of the intermediate of a kind of benserazide hydrochloride according to claim 1, is characterized in that, described step (c) temperature of reaction is 50-55 ℃.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104788338A (en) * | 2014-10-17 | 2015-07-22 | 上海益生源药业有限公司 | Preparation method of benserazide hydrochloride |
| CN108558690A (en) * | 2018-03-28 | 2018-09-21 | 浙江海正药业股份有限公司 | The crystal form and preparation method thereof of seromycin carboxylate hydrochloride |
| CN111484425A (en) * | 2019-01-25 | 2020-08-04 | 上海科胜药物研发有限公司 | Preparation method of benserazide hydrochloride impurity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1250279A (en) * | 1968-08-16 | 1971-10-20 | ||
| PL209729B1 (en) * | 2006-07-12 | 2011-10-31 | Inst Farmaceutyczny | Method for the manufacture of 2-[(2, 3, 4-trihydroxiphenyl) methyl) hydrazide D , L-serine hydrochloride |
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2014
- 2014-04-11 CN CN201410144012.1A patent/CN103951587A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1250279A (en) * | 1968-08-16 | 1971-10-20 | ||
| PL209729B1 (en) * | 2006-07-12 | 2011-10-31 | Inst Farmaceutyczny | Method for the manufacture of 2-[(2, 3, 4-trihydroxiphenyl) methyl) hydrazide D , L-serine hydrochloride |
Non-Patent Citations (2)
| Title |
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| THACKER, NATHAN C.等: "Preparation of D-cycloserine and 13C-labeled D-cycloserine", 《HETEROCYCLES》, vol. 86, no. 2, 31 December 2012 (2012-12-31), pages 1575 - 1582 * |
| ZEGROCKA-STENDEL: "Benserazide - drug used in the treatment of Parkinson"s disease. Synthesis of a high-purity compound", 《PRZEMYSL CHEMICZNY》, vol. 85, no. 5, 31 December 2006 (2006-12-31), pages 349 - 350 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104788338A (en) * | 2014-10-17 | 2015-07-22 | 上海益生源药业有限公司 | Preparation method of benserazide hydrochloride |
| CN108558690A (en) * | 2018-03-28 | 2018-09-21 | 浙江海正药业股份有限公司 | The crystal form and preparation method thereof of seromycin carboxylate hydrochloride |
| CN108558690B (en) * | 2018-03-28 | 2021-04-20 | 浙江海正药业股份有限公司 | Crystal form of cycloserine esterified substance hydrochloride and preparation method thereof |
| CN111484425A (en) * | 2019-01-25 | 2020-08-04 | 上海科胜药物研发有限公司 | Preparation method of benserazide hydrochloride impurity |
| CN111484425B (en) * | 2019-01-25 | 2023-06-23 | 上海科胜药物研发有限公司 | Preparation method of benserazide hydrochloride impurity |
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