CN105968035A - Preparation method of Fudosteine - Google Patents
Preparation method of Fudosteine Download PDFInfo
- Publication number
- CN105968035A CN105968035A CN201610599373.4A CN201610599373A CN105968035A CN 105968035 A CN105968035 A CN 105968035A CN 201610599373 A CN201610599373 A CN 201610599373A CN 105968035 A CN105968035 A CN 105968035A
- Authority
- CN
- China
- Prior art keywords
- fudosteine
- preparation
- reaction
- water
- ethanol
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/18—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by addition of thiols to unsaturated compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of Fudosteine, and relates to a preparation method suitable for industrially producing Fudosteine. Water and ethyl alcohol are adopted as reaction solvent, amine substances serves as the catalyst, cooling and crystallization are conducted after reaction, and the product is obtained in the form of sedimentation. The whole process is easy to control, repeatability is high, the yield of Fudosteine is stabilized at 95%, the residual amount is controlled within 0.05%, and the preparation method completely conforms to the medicinal standard and is quite suitable for industrial production.
Description
Technical field
The present invention relates to the preparation of a kind of relieving cough and reducing sputum medicine Fudosteine, belong to pharmaceutical technology field.
Background technology
Fudosteine (chemical name: 3-hydroxypropyl thioalanine) is the compound in the class that 1988 develop by SSP Pharmaceutical Co., Ltd of Japan with department's smooth (steine) basic framework, lists in Japan first October calendar year 2001.Pharmacological evaluation proves that it has suppression goblet cell hyperplasia, promotes all multiactions such as the secretion of serosity trachea and suppression bronchitis, owing to having strong drug action, side effect is little, and indication is wide, the advantages such as market potential is big, Fudosteine is expected to become the substitute products of similar drug.
At present the synthetic method of this compound is broadly divided into two classes:
One class method is that Cys reacts under the effects such as light, microwave, heat, free radical catalyst (such as peroxide) with 1-propenol-3, prepare Fudosteine, such as Chinese patent application 200510059733.3,201410554898.7,200910244823.8,201310040183.5 etc.:
Although the preparation technology of this type of method is simple, but the problem existed can not be ignored.Luminescence method and microwave method are the highest to the requirement of equipment, are difficulty with industrialized production；The technique that peroxide radical catalyst promotes, easily causes blast due to peroxide, and big production exists serious potential safety hazard；Although thermal initiation operates relatively easy, the highest to equipment requirements, but in actual production process, there is the shortcoming that yield is low.
Another kind of method is Cys and Fudosteine is prepared in the reaction in the basic conditions of halo propanol:
The shortcoming of the method maximum is in finished product that inorganic salt is difficult to remove, and is easily caused residue higher.Such as US5047428 reports Cys and prepares Fudosteine with 3-bromo-1-propanol reaction, the method response time is long, course of reaction can produce equimolar inorganic salt, and Fudosteine is dissolved in water, insoluble in organic solvent, it is difficult to from product remove inorganic salt, causes product residue high, be unfavorable for industrialized production；Chinese patent application 200910167947.0 reports Cys and prepares Fudosteine with trimethylene chlorohydrin reaction, the dissolubility difference utilizing Fudosteine and sodium chloride is purified Fudosteine, but experimentation needs heat filtering (>=95 DEG C), complex steps, operation complexity, product has more loss.
Summary of the invention
It is an object of the invention to provide a kind of easy and simple to handle, yield is high, quality good, be suitable for industrialized production Fudosteine preparation method.
The technical scheme is that the preparation method of a kind of Fudosteine, it is characterised in that do solvent, Cys and propenyl with water and ethanol and react under aminated compounds effect, obtain Fudosteine.
According to the present invention, described aminated compounds one in triethylamine, n-propylamine or 2-aminopropane., preferably n-propylamine.
According to the present invention, in described solvent, water used is W(water with the mass ratio of ethanol): W(ethanol)=1:2 ~ 3, preferably 1:2.5.
According to the present invention, described Fudosteine preparation method can be carried out at normal temperatures, it is also possible to carries out in a heated condition, it is preferred that reaction temperature is 20-60 DEG C, more preferably 40 DEG C.
According to the present invention, when Cys surplus is less than 2.0%, it is believed that reacting complete, then reaction system is cooled to 0 ~ 10 DEG C of stirring and crystallizing, sucking filtration obtains white solid, i.e. Fudosteine.
The invention has the beneficial effects as follows that employing Cys and 1-propenol-3 make raw material, fundamentally avoid the generation of inorganic salt during Cys reacts with halo propanol, improve the quality of product, level of residue can control within 0.05%, meets medicinal standard；It addition, the present invention has done further improvement in terms of operating procedure and yield, reactant liquor directly carries out low temperature stirring, need not repeatedly recrystallization, through sucking filtration, dry and i.e. can get qualified products so that technique is greatly simplified, and yield is not less than 93%.
Detailed description of the invention:
Content for a better understanding of the present invention, is described further below in conjunction with specific embodiment, but the present invention is not only limited to this.
Embodiment 1
Under room temperature, 100gL-cysteine is dissolved in a certain amount of water and the mixed solvent of ethanol (300g:750g), adds propenyl 96g, add n-propylamine 0.05ml, stir molten clearly.It is warming up to 40 DEG C, stirring reaction 4.0h.Being cooled to 0 DEG C of stirring and crystallizing after completion of the reaction 2 hours, sucking filtration obtains white solid.45 DEG C of forced air dryings, to constant weight, obtain white solid powder 140.5g, and content is 99.1%, and residue is determined as 0.01%.Yield 94.9%.
Embodiment 2
Under room temperature, 100gL-cysteine is dissolved in a certain amount of water and the mixed solvent of ethanol (300g:750g), adds propenyl 96g, add 2-aminopropane. 0.05ml, stir molten clearly.It is warming up to 40 DEG C, stirring reaction 4.0h.Being cooled to 0 DEG C of stirring and crystallizing after completion of the reaction 2 hours, sucking filtration obtains white solid.45 DEG C of forced air dryings, to constant weight, obtain white solid powder 144.6g, analyze through HPLC, and content is 99.2%, and residue is determined as 0.01%.Yield 97.7%.
Embodiment 3
Under room temperature, 100gL-cysteine is dissolved in a certain amount of water and the mixed solvent of ethanol (300g:750g), adds propenyl 96g, add triethylamine 0.05ml, stir molten clearly.It is warming up to 40 DEG C, stirring reaction 4.0h.Being cooled to 0 DEG C of stirring and crystallizing after completion of the reaction 2 hours, sucking filtration obtains white solid.45 DEG C of forced air dryings, to constant weight, obtain white solid powder 145.9g, and content is 99.0%, and residue is determined as 0.01%.Yield 98.6%.
Embodiment 4
Under room temperature, 100gL-cysteine is dissolved in a certain amount of water and the mixed solvent of ethanol (300g:900g), adds propenyl 96g, add n-propylamine 0.05ml, stir molten clearly.It is warming up to 40 DEG C, stirring reaction 4.0h.Being cooled to 0 DEG C of stirring and crystallizing after completion of the reaction 2 hours, sucking filtration obtains white solid.45 DEG C of forced air dryings, to constant weight, obtain white solid powder 140.5g, and content is 99.4%, and residue is determined as 0.01%.Yield 95.9%.
Embodiment 5
Under room temperature, 100gL-cysteine is dissolved in a certain amount of water and the mixed solvent of ethanol (300g:600g), adds propenyl 96g, add n-propylamine 0.05ml, stir molten clearly.It is warming up to 40 DEG C, stirring reaction 4.0h.Being cooled to 0 DEG C of stirring and crystallizing after completion of the reaction 2 hours, sucking filtration obtains white solid.45 DEG C of forced air dryings, to constant weight, obtain white solid powder 139.0g, and content is 99.4%, and residue is determined as 0.01%.Yield 93.9%.
Embodiment 6
Under room temperature, 100gL-cysteine is dissolved in a certain amount of water and the mixed solvent of ethanol (300g:750g), adds propenyl 96g, add n-propylamine 0.05ml, stir molten clearly.It is warming up to 60 DEG C, stirring reaction 4.0h.Being cooled to 0 DEG C of stirring and crystallizing after completion of the reaction 2 hours, sucking filtration obtains white solid.45 DEG C of forced air dryings, to constant weight, obtain white solid powder 139.66g, and content is 99.2%, and residue is determined as 0.01%.Yield 94.5%.
Embodiment 7
Under room temperature, 100gL-cysteine is dissolved in a certain amount of water and the mixed solvent of ethanol (300g:750g), adds propenyl 96g, add n-propylamine 0.05ml, stir molten clearly.Temperature maintains 20 DEG C, stirring reaction 4.0h.Being cooled to 0 DEG C of stirring and crystallizing after completion of the reaction 2 hours, sucking filtration obtains white solid.45 DEG C of forced air dryings, to constant weight, obtain white solid powder 138.4g, and content is 98.9%, and residue is determined as 0.02%.Yield 93.5%.
Claims (4)
1. the preparation method of a Fudosteine, it is characterised in that water and ethanol do solvent, Cys and propenyl and reacts under aminated compounds effect and obtain Fudosteine.
Preparation method the most according to claim 1, it is characterised in that described aminated compounds one in triethylamine, n-propylamine or 2-aminopropane., preferably n-propylamine.
Preparation method the most according to claim 1, it is characterised in that in described solvent, water is W(water with the mass ratio of ethanol): W(ethanol)=1:2 ~ 3.
Preparation method the most according to claim 1, it is characterised in that in described solvent, water is W(water with the mass ratio of ethanol): W(ethanol)=1:2.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610599373.4A CN105968035A (en) | 2016-07-28 | 2016-07-28 | Preparation method of Fudosteine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610599373.4A CN105968035A (en) | 2016-07-28 | 2016-07-28 | Preparation method of Fudosteine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105968035A true CN105968035A (en) | 2016-09-28 |
Family
ID=56950945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610599373.4A Pending CN105968035A (en) | 2016-07-28 | 2016-07-28 | Preparation method of Fudosteine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105968035A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108358820A (en) * | 2018-01-17 | 2018-08-03 | 威海迪素制药有限公司 | A kind of preparation method of high-quality Fudosteine bulk pharmaceutical chemicals |
| CN110922345A (en) * | 2019-12-03 | 2020-03-27 | 济南大学 | Synthesis method of fudosteine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777595A (en) * | 2016-04-23 | 2016-07-20 | 威海迪素制药有限公司 | Preparation method of fodor stanozolol suitable for industrialized production |
-
2016
- 2016-07-28 CN CN201610599373.4A patent/CN105968035A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777595A (en) * | 2016-04-23 | 2016-07-20 | 威海迪素制药有限公司 | Preparation method of fodor stanozolol suitable for industrialized production |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108358820A (en) * | 2018-01-17 | 2018-08-03 | 威海迪素制药有限公司 | A kind of preparation method of high-quality Fudosteine bulk pharmaceutical chemicals |
| CN108358820B (en) * | 2018-01-17 | 2021-09-03 | 迪嘉药业集团有限公司 | Preparation method of high-quality fudosteine raw material medicine |
| CN110922345A (en) * | 2019-12-03 | 2020-03-27 | 济南大学 | Synthesis method of fudosteine |
| CN110922345B (en) * | 2019-12-03 | 2021-06-11 | 济南大学 | Synthesis method of fudosteine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103601686A (en) | Method for synthesizing fluorine-containing pyrimidine compounds by virtue of one-pot method | |
| CN106188116A (en) | A kind of method of synthesizing pyrazole 4 boric acid pinacol ester | |
| CN105669496B (en) | A kind of preparation method of O Methyl Isourea Sulfates | |
| CN105968035A (en) | Preparation method of Fudosteine | |
| CN104710310B (en) | O-maleoyl lactate ester compound and preparation method thereof and the application in polycarboxylate water-reducer synthesizes | |
| CN105777595A (en) | Preparation method of fodor stanozolol suitable for industrialized production | |
| CN104788340A (en) | Method for preparing n-phenylglycinenitrile | |
| CN104370830B (en) | A kind of synthetic method of 5-trifluoromethyl uracil | |
| CN104326954A (en) | Synthesis method of fudosteine | |
| CN105085595B (en) | A kind of method of deacylation base protection 2,6 halosubstituted purine nucleosides of synthesis | |
| CN110117234B (en) | Synthesis method of N-fatty acyl glutamic acid alkali metal salt | |
| CN107056691B (en) | Method for preparing etoricoxib crystal form V | |
| CN101781212B (en) | Method for synthesizing 2-hydroxymethyl acrylate compound | |
| CN104230759B (en) | A kind of preparation method of 3,4,4 '-Amolden MCM 400 | |
| CN106316950A (en) | Gliquidone preparation method | |
| CN102643208B (en) | Preparation method of agomelatine I crystal form | |
| CN108976228A (en) | A kind of preparation method of 7- azaindole | |
| CN101898973A (en) | Preparation method of L-valine methyl ester hydrochloride | |
| CN107245041A (en) | A kind of preparation method of arginine Ibuprofen | |
| CN103880747B (en) | The preparation method of amorphous tolvaptan | |
| CN110981795B (en) | Method for preparing 2-aminoacyl isonicotinic acid by using methyl 2-cyanoisonicotinate | |
| CN107056653A (en) | Synthetic method of the blonanserin intermediate to fluorobenzoyl acetonitrile | |
| CN106749043A (en) | A kind of adenine intermediate pyrimidine azo and preparation method thereof | |
| CN108892103A (en) | A kind of synthetic method of sodium cyanoborohydride | |
| CN110713455A (en) | Preparation method of 4-pyridine acrylic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160928 |