CN106518695A - A synthetic method of (R)-methyl 2-amino-3-chloropropanoate hydrochloride - Google Patents
A synthetic method of (R)-methyl 2-amino-3-chloropropanoate hydrochloride Download PDFInfo
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- CN106518695A CN106518695A CN201610952729.8A CN201610952729A CN106518695A CN 106518695 A CN106518695 A CN 106518695A CN 201610952729 A CN201610952729 A CN 201610952729A CN 106518695 A CN106518695 A CN 106518695A
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- methyl ester
- chlorine
- ester hydrochloride
- serine
- methanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
Abstract
A synthetic method of (R)-methyl 2-amino-3-chloropropanoate hydrochloride is disclosed. The method includes steps of 1) dissolving D-serine into methanol, adding thionyl chloride dropwise into the methanol, performing a refluxing reaction to achieve methyl esterification, concentrating methanol until a product is dry, adding ethyl acetate, pulping at room temperature, and performing filtration, rinsing and drying to obtain D-serine methyl ester hydrochloride, and 2) adding the D-serine methyl ester hydrochloride and thionyl chloride into dichloroethane, performing chlorination for 24 h, performing filtration to obtain a crude (R)-methyl 2-amino-3-chloropropanoate hydrochloride product, decoloring the crude product in methanol, cooling, crystallizing and then performing filtration and drying. The method is high in yield, side products are less, a mother liquor after the reaction can be recycled after treatment, and the production cost is reduced. Tail gas generated by the method can be absorbed by a strong alkaline solution to form a salt, and the generated salt is then separated and reutilized, thus achieving environment friendly requirements.
Description
Technical field
The present invention relates to medicament synthesis field, specifically a kind of synthetic method of R- chlorine serine methyl ester hydrochloride.
Background technology
Antibiotic is produced in life process by microorganism (including antibacterial, funguses, actinomyces) or high animals and plants
The raw class secondary metabolite with antipathogen or other activity, can disturb the chemistry of other living cells development functions
Material.Existing clinical conventional antibiosis have extract and chemically synthesis or half in transgenic engineered bacteria, culture fluid liquid
The compound of synthesis.Cycloserine also known as D-4- amino -3- isoxazole alkanones, are a kind of antibiotics, to tubercule bacillus
With good inhibiting effect.Because antibacterial is not likely to produce drug resistance to it, clinically it is mainly used in treating drug resistance tubercule bacillus
Infection.Research in addition finds that cycloserine is that one kind of excitatory amino acid nmda receptor in central nervous system is special
Regulatory factor, also has good auxiliary curative effect to mental illness such as the psychological phobia for the treatment of, depression, schizophrenia, while
It is also the important intermediate for synthesizing atypia β _ beta-lactam antibiotics.Therefore, cycloserine be with a wide range of applications and
Great market demand.R- chlorine serine methyl ester hydrochlorides are important intermediate of cycloserine, both at home and abroad to R- chlorine silks
The synthesis of propylhomoserin methyl ester hydrochloride does not temporarily have been reported that.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of R- chlorine serine methyl ester hydrochloride, to solve above-mentioned background
The problem proposed in technology.
For achieving the above object, the present invention provides following technical scheme：
A kind of synthetic method of R- chlorine serine methyl ester hydrochloride, comprises the following steps that：
Step one, the preparation of D-Ser methyl ester hydrochloride：D-Ser is dissolved in methyl alcohol, the Deca protochloride in methanol
Sulfone, carries out esterification by back flow reaction, adds ethyl acetate and is beaten at normal temperatures, then carry out after methanol is concentrated to dryness
Filter, rinse and dry, you can obtain first step intermediate D-Ser methyl ester hydrochloride；
Step 2, the preparation of R- chlorine serine methyl ester hydrochlorides：D-Ser methyl ester hydrochloride and thionyl chloride are put into into solvent
In dichloroethanes, chlorination is carried out 24 hours, then carry out being filtrated to get the crude product of R- chlorine serine methyl ester hydrochlorides, R- chlorine silks
The crude product of propylhomoserin methyl ester hydrochloride decolourizes in methyl alcohol and carries out decrease temperature crystalline, then is filtered and dried and obtain consolidating for white
Body R- chlorine serine methyl ester hydrochlorides.
As further scheme of the invention：The time of back flow reaction is 5-8 hours.
As further scheme of the invention：The temperature of chlorination is 40-50 degree Celsius.
Compared with prior art, the invention has the beneficial effects as follows：Preparation process is simple of the present invention, raw material sources are extensive, just
In large-scale industrial production；The method yield is high, and by-product is few, and the mother solution of reaction can be circulated after treatment and make
With, reducing production cost, the tail gas that the method is produced can be absorbed using strong base solution and generate salt, then will generate salt and carry out point
From recycling, the requirement of environmental protection is reached.
Specific embodiment
The technical scheme of this patent is described in more detail with reference to specific embodiment.
Embodiment 1
A kind of synthetic method of R- chlorine serine methyl ester hydrochloride, comprises the following steps that：
Step one, the preparation of D-Ser methyl ester hydrochloride：1200ml methanol is added into tri- mouthfuls of 2000ml with 250gD- serines
In bottle, less than 25 DEG C are cooled to, Deca 450g thionyl chloride, time for adding time control heat up in 2 hours, completion of dropping
To flowing back and continuing to react 6 hours, after back flow reaction terminates, methanol is concentrated to dryness, adds 1000ml ethyl acetate to beat
Slurry, then filtered and drying obtains D-Ser methyl ester hydrochloride.Concentration methanol out can be applied to reactions steps, acetic acid
Mashing step can be applied to after the distillation of ethyl ester mother solution；
Step 2,150g first steps intermediate and 150g thionyl chlorides is added in 1500ml dichloroethanes, is entered at 45 DEG C
24 hours of row chlorination, after reaction terminates, are filtrated to get the crude product of R- chlorine serine methyl ester hydrochlorides, R- chlorine serine first
The crude product of ester hydrochloride decolourizes to crystallize in methyl alcohol, you can obtain white solid R- chlorine serine methyl ester hydrochlorides.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of spirit or essential attributes without departing substantially from the present invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit is required rather than described above is limited, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
Moreover, it will be appreciated that although this specification is been described by according to embodiment, not each embodiment is only wrapped
Containing an independent technical scheme, this narrating mode of description is only that those skilled in the art should for clarity
Using description as an entirety, the technical scheme in each embodiment can also Jing it is appropriately combined, form those skilled in the art
Understandable other embodiment.
Claims (3)
1. a kind of synthetic method of R- chlorine serine methyl ester hydrochloride, it is characterised in that comprise the following steps that：
Step one, the preparation of D-Ser methyl ester hydrochloride：D-Ser is dissolved in methyl alcohol, the Deca protochloride in methanol
Sulfone, carries out esterification by back flow reaction, adds ethyl acetate and is beaten at normal temperatures, then carry out after methanol is concentrated to dryness
Filter, rinse and dry, you can obtain first step intermediate D-Ser methyl ester hydrochloride；
Step 2, the preparation of R- chlorine serine methyl ester hydrochlorides：D-Ser methyl ester hydrochloride and thionyl chloride are put into into solvent
In dichloroethanes, chlorination is carried out 24 hours, then carry out being filtrated to get the crude product of R- chlorine serine methyl ester hydrochlorides, R- chlorine silks
The crude product of propylhomoserin methyl ester hydrochloride decolourizes in methyl alcohol and carries out decrease temperature crystalline, then is filtered and dried and obtain consolidating for white
Body R- chlorine serine methyl ester hydrochlorides.
2. the synthetic method of R- chlorine serine methyl ester hydrochloride according to claim 1, it is characterised in that the backflow is anti-
The time answered is 5-8 hours.
3. the synthetic method of R- chlorine serine methyl ester hydrochloride according to claim 1 and 2, it is characterised in that the chlorine
The temperature of generation reaction is 40-50 degree Celsius.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610952729.8A CN106518695A (en) | 2016-11-03 | 2016-11-03 | A synthetic method of (R)-methyl 2-amino-3-chloropropanoate hydrochloride |
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| CN201610952729.8A CN106518695A (en) | 2016-11-03 | 2016-11-03 | A synthetic method of (R)-methyl 2-amino-3-chloropropanoate hydrochloride |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110590587A (en) * | 2019-09-23 | 2019-12-20 | 湖北宇阳药业有限公司 | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride |
| CN110606811A (en) * | 2019-09-23 | 2019-12-24 | 湖北宇阳药业有限公司 | Synthetic method of L-serine methyl ester hydrochloride |
| CN111018728A (en) * | 2019-12-27 | 2020-04-17 | 暨南大学 | Method and device for preparing 3-chloro-alanine hydrochloride by using water as auxiliary agent |
| WO2020134137A1 (en) * | 2018-12-27 | 2020-07-02 | 北京富盛嘉华医药科技有限公司 | Method for synthesizing r-3-chloroalanine methyl ester hydrochloride |
| CN113004160A (en) * | 2021-03-15 | 2021-06-22 | 淮北市博康生物科技有限公司 | Synthetic method of L-serine methyl ester sulfate |
| CN113316581A (en) * | 2019-01-11 | 2021-08-27 | Cj第一制糖株式会社 | L-glufosinate-ammonium intermediate and preparation method of L-glufosinate-ammonium |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2020134137A1 (en) * | 2018-12-27 | 2020-07-02 | 北京富盛嘉华医药科技有限公司 | Method for synthesizing r-3-chloroalanine methyl ester hydrochloride |
| CN113316581A (en) * | 2019-01-11 | 2021-08-27 | Cj第一制糖株式会社 | L-glufosinate-ammonium intermediate and preparation method of L-glufosinate-ammonium |
| CN110590587A (en) * | 2019-09-23 | 2019-12-20 | 湖北宇阳药业有限公司 | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride |
| CN110606811A (en) * | 2019-09-23 | 2019-12-24 | 湖北宇阳药业有限公司 | Synthetic method of L-serine methyl ester hydrochloride |
| CN110606811B (en) * | 2019-09-23 | 2022-12-02 | 湖北宇阳药业有限公司 | Synthetic method of L-serine methyl ester hydrochloride |
| CN111018728A (en) * | 2019-12-27 | 2020-04-17 | 暨南大学 | Method and device for preparing 3-chloro-alanine hydrochloride by using water as auxiliary agent |
| CN113004160A (en) * | 2021-03-15 | 2021-06-22 | 淮北市博康生物科技有限公司 | Synthetic method of L-serine methyl ester sulfate |
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