CN104926922A - Preparation method for pidotimod - Google Patents
Preparation method for pidotimod Download PDFInfo
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- CN104926922A CN104926922A CN201510167302.2A CN201510167302A CN104926922A CN 104926922 A CN104926922 A CN 104926922A CN 201510167302 A CN201510167302 A CN 201510167302A CN 104926922 A CN104926922 A CN 104926922A
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- thiazolidine
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Abstract
The invention relates to a preparation method for pidotimod. The method comprises the following steps: synthesis of L-thiazolidine-4-formic acid, preparation of metal-ion-loaded type cation exchange resin and synthesis of the pidotimod. The invention has the following beneficial effects: with metal-ion-loaded type strong acid cation exchange resin as a catalyst, and L-cysteine and L-pyroglutamic acid as raw materials, pidotimod is directly synthesized under the action of the catalyst, so the number of synthetic reaction steps are shortened from conventional four steps to two steps; the total yield of the pidotimod is increased from conventional reported 55% to 64%; and through HPLC detection, the content of the pidotimod reaches 98.5%; meanwhile, substances with great toxicity are prevented from being used in reaction process, and a solid catalyst is used, so synthesis process is safer and more environmentally friendly, and product purity is guaranteed.
Description
Technical field
The present invention relates to a kind of preparation method of pidotimod, belong to the field of chemical synthesis.
Background technology
Pidotimod (pidotimod) chemistry (R)-3-[(S)-(the chloro-2-pyrrolidyl of 5-) carbonyl]-thiazolidyl-4-formic acid by name, it is the immunomodulator of Italian Poli company research and development, within 1993, go on the market in Italy first, be mainly used in prevention and therapy children recurrent respiratory infection, urinary system infection, allergic rhinitis and asthma, a treatment and prevention acute attack, upper respiratory tract infection slowly, also can be used for multiple virus infection, malignant tumour and other chronic disease and causes body's immunity low.
The existing synthetic method of pidotimod is with Cys and L-Glutimic acid for starting raw material, respectively after the reaction such as acidylate or esterification generates corresponding intermediate, then obtains target compound by two intermediates by N-acylation reaction.But due to acylating agent in N-acylation reaction and to be acylated thing activity all lower, and there is other active group that side reaction occurs in reactant, make N-acylation reaction yield lower, the total recovery directly causing synthesis pidotimod is low.For improving N-acylation reaction yield, the shortcomings such as current some processes takes diverse ways on the raw material (i.e. the synthesis of intermediate) of N-acylation reaction and the catalyzer of N-acylation reaction, but still it is large to there is material toxicity, and intermediate is unstable.
Summary of the invention
The technical problem to be solved in the present invention is: based on the problems referred to above, the invention provides a kind of preparation method of pidotimod.
The present invention solves the technical scheme that its technical problem adopts: a kind of preparation method of pidotimod, comprises the following steps:
(1) synthesis of L-thiazolidine-4-formic acid: drip formaldehyde solution in Cys solution, stirring at room temperature, filters, obtains L-thiazolidine-4-formic acid;
(2) preparation of metal ion loading type Zeo-karb: storng-acid cation exchange resin is converted to Hydrogen with hydrochloric acid, hydro-strong acidic cation exchange resin is added in metal ion compound solution, 40 ~ 80 DEG C are reacted 1 ~ 6 hour, be cooled to room temperature, drying, obtains metal ion loading type Zeo-karb;
(3) synthesis of pidotimod: using the L-thiazolidine-4-formic acid in step (1), the metal ion loading type Zeo-karb as catalyzer in step (2), L-Glutimic acid and N, dinethylformamide mixes, 40 ~ 80 DEG C are reacted 1 ~ 4 hour, filter, obtain white solid, by white solid hcl acidifying, obtain finished product pidotimod.
Further, in step (1), the mol ratio of Cys and formaldehyde is 1:1.0 ~ 1:1.8.
Further, in step (2), metal ion is Zn
2+, Fe
3+or Al
3+.
Further, in step (2), the mass ratio of hydro-strong acidic cation exchange resin and metal ion compound is 1:1.0 ~ 1:1.5.
Further, in step (3), the mol ratio of L-thiazolidine-4-formic acid and L-Glutimic acid is 1:1.1 ~ 1:2.0, the mass ratio of metal ion loading type Zeo-karb and L-thiazolidine-4-formic acid is 0.2:1 ~ 2:1, the mass ratio of DMF and L-thiazolidine-4-formic acid is 15:1 ~ 60:1.
Further, in step (3), the massfraction of acidifying hydrochloric acid is 37%.
Further, step (2) middle strong acidity Zeo-karb is macropore low crosslinking degree resin, and degree of crosslinking is 4 ~ 10.
The invention has the beneficial effects as follows: with the storng-acid cation exchange resin of metal ion loading type for catalyzer, Cys and L-Glutimic acid are raw material, directly pidotimod is synthesized under catalyst action, building-up reactions step shortens to 2 steps by existing 4 steps, the total recovery of product by existing report higher 55% bring up to 64%, detect through HPLC, pidotimod content reaches 98.5%; And avoid the material using toxicity larger in reaction process, the use of solid catalyst also makes the safer environmental protection of synthesis technique, and product purity is guaranteed.
Embodiment
The invention will be further described in conjunction with specific embodiments now, and following examples are intended to the present invention instead of limitation of the invention further are described.
Embodiment one
(1) synthesis of L-thiazolidine-4-formic acid
In 500mL four-hole bottle, add 20g Cys, 250mL water, stir, make it fully dissolve, be added dropwise to 20mL massfraction 37% formalin, stirring at room temperature, after having crystal to separate out, continue to stir 15min, filter, obtain L-thiazolidine-4-formic acid 9g, yield is about 82%, survey fusing point 194 ~ 195 DEG C (literature value mp:196 ~ 197 DEG C), detect through HPLC, L-thiazolidine-4-formic acid purity is 95%.
(2) preparation of modified ion-exchange resin catalyst
With the hydrochloric acid of 1mol/L, storng-acid cation exchange resin is converted to Hydrogen, dry.Getting above-mentioned h type resin 20g pours in four-hole bottle, adds 28gZnCl
2120mL ethanolic soln, 65 DEG C reaction 4 hours.Be chilled to room temperature, add deionized water and fully stir, be hydrolyzed unnecessary zinc dichloride, take out and filter, then be washed till without chlorion (detecting with Silver Nitrate) with deionized water, after 80 DEG C of dry constant weights, be placed in moisture eliminator for subsequent use.
(3) synthesis of pidotimod
In four-hole bottle, add 10g L-thiazolidine-4-formic acid, 11.3g g L-Glutimic acid, 320mL DMF, 12g modified resin, 70 DEG C are reacted 2 hours.Suction filtration, revolves steaming by reaction solution, after remove portion solvent, puts into ice bath and cools, and separate out solid, suction filtration, obtains white solid, by this white solid 37% hcl acidifying, leaves standstill, crystallization in 10 DEG C, filters, obtain white product 14.4g, yield 78.3%.Survey fusing point 192 ~ 194 DEG C, [α]
25 d=-150 ° of (literature value mp:192 ~ 194 DEG C, [α]
25 d=-150 °).The total recovery of whole preparation feedback pidotimod is 64%.Detect through HPLC, pidotimod content is 98.5%.
Embodiment two
Step (1), (2) are with embodiment one.
In step (3), temperature of reaction is 60 DEG C, and all the other steps are with embodiment one, and the yield of pidotimod is 69.8%.The total recovery of whole preparation feedback pidotimod is 57%.Temperature of reaction rises to 80 DEG C, and resin occurs obviously damaged, and reaction yield declines.
Embodiment three
Step (1), (2) are with embodiment one.
In step (3), the reaction times is 1 hour, and all the other steps are with embodiment one, and the yield of pidotimod is 70.3%.The total recovery of whole preparation feedback pidotimod is 57%.
Embodiment four
Step (1), (2) are with embodiment one.
In step (3), the reaction times is 3 hours, and all the other steps are with embodiment one, and the yield of pidotimod is 78.2%.The total recovery of whole preparation feedback pidotimod is 64%.
Embodiment five
Step (1), (2) are with embodiment one.
In step (3), modified resin consumption is 16g, and all the other steps are with embodiment one, and the yield of pidotimod is 78.2%.The total recovery of whole preparation feedback pidotimod is 64%.
Embodiment six
Step (1), (2) are with embodiment one.
In step (3), L-Glutimic acid consumption is 10.9g, and all the other steps are with embodiment one, and the yield of pidotimod is 76.5%.The total recovery of whole preparation feedback pidotimod is 63%.
Embodiment seven
Step (1), (2) are with embodiment one.
In step (3), L-Glutimic acid consumption is 11.6g, and all the other steps are with embodiment one, and the yield of pidotimod is 77.1%.The total recovery of whole preparation feedback pidotimod is 63%.
With different metal ion modification agent modified cation-exchange resin, prepare metal ion loading type resin catalyst, catalyze and synthesize pidotimod, by the yield of pidotimod in calculation procedure (3), investigate loading type resin catalyst to the catalytic activity of pidotimod condensation reaction, the results are shown in following table:
The impact of table 1 different metal ion pair loading type resin catalyst activity
With different metal ion modification agent modified cation-exchange resin, the catalytic activity of its metal ion loading type resin catalyst is all strong than the Zeo-karb of non-load, but through Zn
2+the activity of the loading type Zeo-karb of modification is the strongest.
Claims (7)
1. a preparation method for pidotimod, is characterized in that: comprise the following steps:
(1) synthesis of L-thiazolidine-4-formic acid: drip formaldehyde solution in Cys solution, stirring at room temperature, filters, obtains L-thiazolidine-4-formic acid;
(2) preparation of metal ion loading type Zeo-karb: storng-acid cation exchange resin is converted to Hydrogen with hydrochloric acid, hydro-strong acidic cation exchange resin is added in metal ion compound solution, 40 ~ 80 DEG C are reacted 1 ~ 6 hour, be cooled to room temperature, drying, obtains metal ion loading type Zeo-karb;
(3) synthesis of pidotimod: using the L-thiazolidine-4-formic acid in step (1), the metal ion loading type Zeo-karb as catalyzer in step (2), L-Glutimic acid and N, dinethylformamide mixes, 40 ~ 80 DEG C are reacted 1 ~ 4 hour, filter, obtain white solid, by white solid hcl acidifying, obtain finished product pidotimod.
2. the preparation method of pidotimod according to claim 1, is characterized in that: in described step (1), the mol ratio of Cys and formaldehyde is 1:1.0 ~ 1:1.8.
3. the preparation method of pidotimod according to claim 1, is characterized in that: in described step (2), metal ion is Zn
2+, Fe
3+or Al
3+.
4. the preparation method of pidotimod according to claim 1, is characterized in that: in described step (2), the mass ratio of hydro-strong acidic cation exchange resin and metal ion compound is 1:1.0 ~ 1:1.5.
5. the preparation method of pidotimod according to claim 1, it is characterized in that: in described step (3), the mol ratio of L-thiazolidine-4-formic acid and L-Glutimic acid is 1:1.1 ~ 1:2.0, the mass ratio of metal ion loading type Zeo-karb and L-thiazolidine-4-formic acid is 0.2:1 ~ 2:1, the mass ratio of DMF and L-thiazolidine-4-formic acid is 15:1 ~ 60:1.
6. the preparation method of pidotimod according to claim 1, is characterized in that: in described step (3), the massfraction of acidifying hydrochloric acid is 37%.
7. the preparation method of pidotimod according to claim 1, is characterized in that: described step (2) middle strong acidity Zeo-karb is macropore low crosslinking degree resin, and degree of crosslinking is 4 ~ 10.
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| CN201510167302.2A CN104926922A (en) | 2015-04-09 | 2015-04-09 | Preparation method for pidotimod |
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| CN201510167302.2A CN104926922A (en) | 2015-04-09 | 2015-04-09 | Preparation method for pidotimod |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749515A (en) * | 2016-11-28 | 2017-05-31 | 无锡福祈制药有限公司 | A kind of synthetic method of Pidotimod |
| CN108715598A (en) * | 2018-06-13 | 2018-10-30 | 峨眉山宏昇药业股份有限公司 | A kind of preparation method of Pidotimod |
| CN111377879A (en) * | 2020-04-14 | 2020-07-07 | 苏州敬业医药化工有限公司 | Preparation method of L-thiazolidine-4-formic acid |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102167727A (en) * | 2011-01-29 | 2011-08-31 | 浙江金立源药业有限公司 | Synthesis method of pidotimod |
| CN102234313A (en) * | 2011-08-16 | 2011-11-09 | 青岛康地恩药业股份有限公司 | Method for synthesizing pidotimod |
| CN102952172A (en) * | 2011-08-18 | 2013-03-06 | 北京澳林森科技有限公司 | Pidotimod preparation method |
| CN103897025A (en) * | 2012-12-27 | 2014-07-02 | 山东新时代药业有限公司 | Preparation method of pidotimod |
| CN104447947A (en) * | 2014-11-18 | 2015-03-25 | 成都医路康医学技术服务有限公司 | Process for producing pidotimod |
-
2015
- 2015-04-09 CN CN201510167302.2A patent/CN104926922A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102167727A (en) * | 2011-01-29 | 2011-08-31 | 浙江金立源药业有限公司 | Synthesis method of pidotimod |
| CN102234313A (en) * | 2011-08-16 | 2011-11-09 | 青岛康地恩药业股份有限公司 | Method for synthesizing pidotimod |
| CN102952172A (en) * | 2011-08-18 | 2013-03-06 | 北京澳林森科技有限公司 | Pidotimod preparation method |
| CN103897025A (en) * | 2012-12-27 | 2014-07-02 | 山东新时代药业有限公司 | Preparation method of pidotimod |
| CN104447947A (en) * | 2014-11-18 | 2015-03-25 | 成都医路康医学技术服务有限公司 | Process for producing pidotimod |
Non-Patent Citations (4)
| Title |
|---|
| 叶连宝 等: "匹多莫德的合成工艺改进", 《中国药房》 * |
| 张文雯 等: "双酚F合成反应的负载型树脂催化剂研究", 《化学世界》 * |
| 李会 等: "固体酸催化剂应用", 《工业催化》 * |
| 李运山 等: "金属负载型阳离子交换树脂催化合成乙酸正丁酯", 《化工技术与开发》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749515A (en) * | 2016-11-28 | 2017-05-31 | 无锡福祈制药有限公司 | A kind of synthetic method of Pidotimod |
| CN106749515B (en) * | 2016-11-28 | 2020-02-21 | 无锡福祈制药有限公司 | Method for synthesizing pidotimod |
| CN108715598A (en) * | 2018-06-13 | 2018-10-30 | 峨眉山宏昇药业股份有限公司 | A kind of preparation method of Pidotimod |
| CN111377879A (en) * | 2020-04-14 | 2020-07-07 | 苏州敬业医药化工有限公司 | Preparation method of L-thiazolidine-4-formic acid |
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