CN111377879A - Preparation method of L-thiazolidine-4-formic acid - Google Patents
Preparation method of L-thiazolidine-4-formic acid Download PDFInfo
- Publication number
- CN111377879A CN111377879A CN202010288146.6A CN202010288146A CN111377879A CN 111377879 A CN111377879 A CN 111377879A CN 202010288146 A CN202010288146 A CN 202010288146A CN 111377879 A CN111377879 A CN 111377879A
- Authority
- CN
- China
- Prior art keywords
- thiazolidine
- cysteine
- formic acid
- water
- sodium carbonate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims abstract description 28
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 26
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 235000013878 L-cysteine Nutrition 0.000 claims abstract description 14
- 239000004201 L-cysteine Substances 0.000 claims abstract description 14
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 13
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 239000007858 starting material Substances 0.000 claims abstract description 3
- DZLNHFMRPBPULJ-GSVOUGTGSA-N D-thioproline Chemical compound OC(=O)[C@H]1CSCN1 DZLNHFMRPBPULJ-GSVOUGTGSA-N 0.000 claims abstract 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000008098 formaldehyde solution Substances 0.000 claims description 8
- 239000008213 purified water Substances 0.000 claims description 4
- 239000008399 tap water Substances 0.000 claims description 4
- 235000020679 tap water Nutrition 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 5
- 230000007547 defect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- DZLNHFMRPBPULJ-VKHMYHEASA-N L-thioproline Chemical compound OC(=O)[C@@H]1CSCN1 DZLNHFMRPBPULJ-VKHMYHEASA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 4
- UUTKICFRNVKFRG-WDSKDSINSA-N (4R)-3-[oxo-[(2S)-5-oxo-2-pyrrolidinyl]methyl]-4-thiazolidinecarboxylic acid Chemical compound OC(=O)[C@@H]1CSCN1C(=O)[C@H]1NC(=O)CC1 UUTKICFRNVKFRG-WDSKDSINSA-N 0.000 description 3
- 229960001163 pidotimod Drugs 0.000 description 3
- 238000005034 decoration Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a preparation method of L-thiazolidine-4-formic acid, which takes L-cysteine as a starting material to directly synthesize L-thiazolidine-4-carboxylic acid by cyclization with formaldehyde in the presence of a catalyst sodium carbonate. The invention adopts sodium carbonate as the catalyst, overcomes the defect of using pyridine as the catalyst in the prior art, reduces the discharge of three wastes, obviously improves the quality and the appearance, simultaneously reduces the production cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of L-thiazolidine-4-formic acid.
Background
L-thiazolidine-4-carboxylic acid, english name: l (-) -Thiazolidine-4-carboxylic acid; CAS number: 34592-47-7; the molecular formula is as follows: C5H7NO 2S; the structural formula is as follows:
l-thiazolidine-4-formic acid is a key intermediate for synthesizing pidotimod. PIDOTIMOD (PIDOTIMOD), an immunomodulator, is suitable for patients with low immune function, and can be used for preventing acute infection, shortening course of disease, reducing severity of disease, and promoting nonspecific and specific immune reactions.
The preparation of L-thiazolidine-4-formic acid, the synthesis method adopted at present is that L-cysteine is mixed with water, formaldehyde solution is added, and L-thiazolidine-4-formic acid is obtained by cyclization in the presence of catalyst pyridine. Pyridine is used as a catalyst, so that the discharge of three wastes is increased, and the production cost is increased.
Disclosure of Invention
The invention aims to provide a preparation method of L-thiazolidine-4-formic acid, which adopts sodium carbonate as a catalyst, overcomes the defect of using pyridine as a catalyst in the prior art, reduces the discharge of three wastes, obviously improves the quality and the appearance, reduces the production cost and is suitable for industrial production.
In order to achieve the purpose, the technical scheme of the invention is to design a preparation method of L-thiazolidine-4-formic acid, which takes L-cysteine as a starting material and directly synthesizes the L-thiazolidine-4-carboxylic acid with formaldehyde in the presence of a catalyst of sodium carbonate.
The preparation method of the L-thiazolidine-4-formic acid comprises the following steps: mixing L-cysteine with water, adding formaldehyde solution and catalyst sodium carbonate, performing cyclization reaction,
the chemical reaction formula of the cyclization reaction is as follows:
and cooling, crystallizing and drying the obtained substance to obtain the L-thiazolidine-4-formic acid.
Preferably, the water used is tap water, purified water or distilled water.
Preferably, the mass ratio of the L-cysteine to the water is 1: 2-5.
Preferably, the mass ratio of the L-cysteine to the formaldehyde is 1: 0.1-0.5.
Preferably, the mass ratio of the L-cysteine to the catalyst sodium carbonate is 1: 0.1-0.5.
Preferably, the temperature of the cyclization reaction is 10-40 ℃.
Preferably, the cyclization reaction time is 3-6 h.
Preferably, the concentration of the formaldehyde solution used is between 10% and 40%.
The invention has the advantages and beneficial effects that: the preparation method of the L-thiazolidine-4-formic acid adopts sodium carbonate as a catalyst, overcomes the defect of using pyridine as a catalyst in the prior art, reduces the discharge of three wastes, obviously improves the quality and the appearance, simultaneously reduces the production cost, and is suitable for industrial production.
Detailed Description
The following further describes embodiments of the present invention with reference to examples. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
The invention provides a preparation method of L-thiazolidine-4-formic acid, which comprises the following steps: adding 1 part by mass of L-cysteine and 2-5 parts by mass of water into a reaction container, stirring for 30min, adding 0.1-0.5 part by mass of formaldehyde, adding 0.1-0.5 part by mass of sodium carbonate, stirring for 3-6 h, controlling the reaction temperature at 10-40 ℃, performing suction filtration and drying after the reaction is finished, and obtaining a dry product of L-thiazolidine-4-formic acid; the water is tap water, purified water or distilled water.
The specific embodiment of the invention is as follows:
example 1
Adding 50g (0.41 mol) of L-cysteine into 150g of purified water in a reaction kettle, stirring for 30min, and keeping at 20 ℃ for 30 min; adding 32.5g of 40% formaldehyde solution and 10g of sodium carbonate, and continuously stirring for 4 hours at 20 ℃; after the reaction is finished, the L-thiazolidine-4-formic acid is filtered, filtered and dried to obtain 43.8g of L-thiazolidine-4-formic acid with the yield of 80.2 percent. Melting point: 195.6-196.3 ℃.
Example 2
The synthesis according to example 1; the pure water is replaced by tap water, and the rest is unchanged, so that 42.7g of L-thiazolidine-4-formic acid is obtained, and the yield is 78.2%. Melting point: 195.5-196.2 ℃.
Example 3
The synthesis according to example 1; the 20% formaldehyde solution was used in place of the 40% formaldehyde solution (the molar ratio of formaldehyde was not changed), and the remainder was unchanged to give 42.3g of L-thiazolidine-4-carboxylic acid in a yield of 77.5%. Melting point: 195.6-196.4 ℃.
Example 4
The synthesis according to example 1; the reaction temperature was raised to 40 ℃ and the remainder was kept constant to give 35.5g of L-thiazolidine-4-carboxylic acid in a yield of 65%. Melting point: 194.6-196.8 ℃.
Example 5
The synthesis according to example 1; the amount of sodium carbonate added was increased to 25g, and the remainder was unchanged to give 40.7g of L-thiazolidine-4-carboxylic acid in a yield of 74.5%. Melting point: 195.5-197.5 ℃.
Example 6
The synthesis according to example 1; the reaction time was prolonged to 6 hours, and the remainder was kept unchanged to give 42.1g of L-thiazolidine-4-carboxylic acid in 77.1% yield. Melting point: 195-196.5 ℃.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A preparation method of L-thiazolidine-4-formic acid is characterized in that L-cysteine is used as a starting material, and is directly cyclized with formaldehyde in the presence of a catalyst sodium carbonate to synthesize the L-thiazolidine-4-carboxylic acid.
2. The method according to claim 1, comprising the steps of: mixing L-cysteine with water, adding a formaldehyde solution and a catalyst sodium carbonate, carrying out cyclization reaction, and cooling, crystallizing and drying a substance obtained by the reaction to obtain the L-thiazolidine-4-formic acid.
3. The method according to claim 2, wherein the water is tap water, purified water or distilled water.
4. The method for producing L-thiazolidine-4-carboxylic acid according to claim 2, wherein the mass ratio of L-cysteine to water is 1:2 to 5.
5. The method according to claim 2, wherein the mass ratio of L-cysteine to formaldehyde is 1:0.1 to 0.5.
6. The method according to claim 2, wherein the mass ratio of the L-cysteine to the catalyst sodium carbonate is 1: 0.1-0.5.
7. The method for producing L-thiazolidine-4-carboxylic acid according to claim 2, wherein the temperature of the cyclization reaction is 10 to 40 ℃.
8. The method for producing L-thiazolidine-4-carboxylic acid according to claim 2, wherein the cyclization reaction time is 3 to 6 hours.
9. The process according to claim 2, wherein the concentration of the formaldehyde solution is 10 to 40%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010288146.6A CN111377879A (en) | 2020-04-14 | 2020-04-14 | Preparation method of L-thiazolidine-4-formic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010288146.6A CN111377879A (en) | 2020-04-14 | 2020-04-14 | Preparation method of L-thiazolidine-4-formic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111377879A true CN111377879A (en) | 2020-07-07 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010288146.6A Pending CN111377879A (en) | 2020-04-14 | 2020-04-14 | Preparation method of L-thiazolidine-4-formic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111377879A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101125835A (en) * | 2006-08-15 | 2008-02-20 | 代斌 | N-[2-(3-phenyl-2-acryloylamino)ethylsulfony]-timonacic ester and preparation method for derivative thereof |
| CN101239956A (en) * | 2008-03-04 | 2008-08-13 | 江苏工业学院 | Method for preparing (R)-4-carboxyl acid thiazoline |
| CN102234252A (en) * | 2010-05-05 | 2011-11-09 | 张永昶 | Preparation method of bioregulator folcisteine |
| CN102952172A (en) * | 2011-08-18 | 2013-03-06 | 北京澳林森科技有限公司 | Pidotimod preparation method |
| CN104926922A (en) * | 2015-04-09 | 2015-09-23 | 常州工程职业技术学院 | Preparation method for pidotimod |
-
2020
- 2020-04-14 CN CN202010288146.6A patent/CN111377879A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101125835A (en) * | 2006-08-15 | 2008-02-20 | 代斌 | N-[2-(3-phenyl-2-acryloylamino)ethylsulfony]-timonacic ester and preparation method for derivative thereof |
| CN101239956A (en) * | 2008-03-04 | 2008-08-13 | 江苏工业学院 | Method for preparing (R)-4-carboxyl acid thiazoline |
| CN102234252A (en) * | 2010-05-05 | 2011-11-09 | 张永昶 | Preparation method of bioregulator folcisteine |
| CN102952172A (en) * | 2011-08-18 | 2013-03-06 | 北京澳林森科技有限公司 | Pidotimod preparation method |
| CN104926922A (en) * | 2015-04-09 | 2015-09-23 | 常州工程职业技术学院 | Preparation method for pidotimod |
Non-Patent Citations (3)
| Title |
|---|
| PIETRO CAMPIGLIA ET,AL.: "Conformational Stability of Ab-(25–35) in the Presence of Thiazolidine Derivatives", 《CHEM BIOL DRUG DES》 * |
| 夏明德: "L-硫代脯氨酸的合成", 《江苏化工》 * |
| 王斌: "匹多莫德的合成工艺研究", 《济南大学硕士毕业论文》 * |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
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| RJ01 | Rejection of invention patent application after publication | ||
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Application publication date: 20200707 |