CN110590587A - Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride - Google Patents
Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride Download PDFInfo
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- 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
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Abstract
The invention discloses a synthetic method of 3-chlorine-L-alanine methyl ester hydrochloride, which comprises the following steps: adding L-serine into a first solvent, cooling to 5-10 ℃, dropwise adding thionyl chloride A, heating to 38 ℃ after dropwise adding, reacting for 48 hours, and then cooling, crystallizing, centrifuging and drying the mixture to obtain L-serine methyl ester hydrochloride; adding L-serine methyl ester hydrochloride into a second solvent, then dropwise adding thionyl chloride B, carrying out segmented temperature control reaction, cooling to 15-25 ℃ after the reaction is finished, adding water for layering, and treating the obtained water phase to obtain the 3-chloro-L-alanine methyl ester hydrochloride. The invention adopts a segmented temperature control mode, has short reaction time, mild reaction conditions, high yield and few byproducts, and is convenient for improving the yield and the product purity; the L-serine methyl ester hydrochloride does not need to be purified, so that the process is optimized; the product yield and the product purity are further improved by adding water for layering, extracting the organic phase for multiple times and adsorbing the water phase by activated carbon.
Description
Technical Field
The invention relates to the technical field of preparation of ramipril intermediates, in particular to a synthesis method of 3-chloro-L-alanine methyl ester hydrochloride.
Background
Ramipril, chemical name (S) -2- [ N- (1-ethoxycarbonyl-3-phenyl-propyl) alanyl ] -2-azabicyclo [3.3.0] octane-3-carboxylic acid. Ramipril is a hypotensive drug and has good curative effect on severe hypertension patients. It has the features of fast acting, long lasting time, high tissue specificity, high tolerance, low toxic side effect, etc.
3-chloro-L-alanine methyl ester hydrochloride is a very important intermediate for synthesizing ramipril. In the prior art, L-serine methyl ester hydrochloride and thionyl chloride are generally added into dichloromethane, heated and refluxed for about 60 hours, and evaporated to dryness to obtain a product. However, the above method has disadvantages of severe reaction conditions, long reaction time, low yield, and many by-products. These disadvantages will affect the normal production of subsequent ramipril.
Disclosure of Invention
The invention aims to overcome the technical defects, provides a synthetic method of 3-chloro-L-alanine methyl ester hydrochloride, and solves the technical problems of long reaction time, low yield and more byproducts in the prior art.
In order to achieve the technical purpose, the invention adopts the technical scheme that:
adding L-serine into a first solvent, cooling to 5-10 ℃, dropwise adding thionyl chloride A, heating to 38 ℃ after dropwise adding, and reacting for 48 hours; after the reaction is finished, cooling and crystallizing the reaction mixture, centrifugally desolventizing and drying to obtain L-serine methyl ester hydrochloride;
adding the L-serine methyl ester hydrochloride into a second solvent, then dropwise adding thionyl chloride B, carrying out segmented temperature control reaction, cooling to 15-25 ℃ after the reaction is finished, adding water for layering, and then carrying out cooling crystallization, filter pressing and vacuum drying on the obtained water phase to obtain the 3-chloro-L-alanine methyl ester hydrochloride.
Compared with the prior art, the invention has the beneficial effects that:
in the method, the L-serine methyl ester hydrochloride does not need to be purified in the first step of synthesis process, so that the 3-chloro-L-alanine methyl ester hydrochloride with higher purity can be obtained, and the process is optimized.
The method adopts a segmented temperature control mode, has short reaction time, mild reaction conditions, high reaction yield and few byproducts, and is favorable for improving the yield and the product purity.
In the method, water is added to layer the reaction mixture, and the organic phase is extracted for a plurality of times and the water phase is adsorbed by active carbon, so that the product yield and the product purity are further improved.
Detailed Description
The embodiment provides a synthesis method of 3-chloro-L-alanine methyl ester hydrochloride, which comprises the following steps:
(a) adding L-serine into a first solvent, cooling to 5-10 ℃, dropwise adding thionyl chloride A, heating to 38 ℃ after dropwise adding, and reacting for 48 hours; after the reaction is finished, cooling and crystallizing the reaction mixture, centrifugally desolventizing and drying to obtain L-serine methyl ester hydrochloride;
(b) adding the L-serine methyl ester hydrochloride into a second solvent, then dropwise adding thionyl chloride B, carrying out segmented temperature control reaction, cooling to 15-25 ℃ after the reaction is finished, adding water for layering, and then carrying out cooling crystallization, filter pressing and vacuum drying on the obtained water phase to obtain the 3-chloro-L-alanine methyl ester hydrochloride.
In the invention, as the water adding and layering process in the second step can remove the residual impurities in the L-serine methyl ester hydrochloride obtained in the first step, the recrystallization of the L-serine methyl ester hydrochloride is not needed after the reaction in the first step is finished, and the reaction mixture is directly dried to obtain the high-purity 3-chloro-L-alanine methyl ester hydrochloride, thereby saving the production period and increasing the yield of the final product.
In the invention, by adopting a segmented temperature control mode, the reaction condition is mild, the reaction yield is high, the byproducts are few, the yield and the product purity are favorably improved, and the reaction time is favorably shortened.
In some embodiments, the first solvent is methanol or recovered methanol obtained after centrifugal desolvation, or a mixture of the two. The recovered methanol is matched with the methanol for use, the recovered methanol can be directly used without being purified, and meanwhile, the using amount of the methanol can be reduced, and the production cost can be reduced. Wherein, when the first solvent is a mixture of methanol and recovered methanol, the volume ratio of the methanol to the recovered methanol is (0.6-0.7): 1. In the proportion range, the L-serine methyl ester hydrochloride with higher purity and yield can be obtained, the using amount of the methanol can be controlled, and the waste of the recovered methanol is avoided. Furthermore, when the first solvent is a mixture of methanol and recovered methanol, the addition amount of the thionyl chloride A is 80% -85% of the addition amount of the first solvent only in methanol, and the content of the thionyl chloride A in the reaction system can be controlled within the range, so that the system can be kept stable.
In some embodiments, the temperature of the reaction system is controlled to be 12-15 ℃ during the dropwise addition of the thionyl chloride a.
In some embodiments, the second solvent is any one of dichloromethane, dichloroethane, chloroform, epichlorohydrin, or chlorobutane.
In some embodiments, the temperature of the reaction system is controlled to be 35-40 ℃ during the dropwise addition of the thionyl chloride B.
In some embodiments, the L-serine methyl ester hydrochloride is added to the second solvent in a liquid-to-solid ratio of (6-10): 1; wherein the unit of the liquid-solid ratio is L: kg. Within the range of the dosage ratio, the full reaction can be ensured, and the complex subsequent operation caused by the excessive dosage of the solvent is avoided.
In some embodiments, the mass ratio of the thionyl chloride B to the L-serine methyl ester hydrochloride is (1-3): 1, preferably (1.1-1.5): 1. Within the range of the dosage ratio, the full reaction can be ensured, the waste of raw materials is avoided, and the product with higher yield can be obtained.
In some embodiments, the temperature control process comprises controlling the temperature to 25-32 ℃, reacting for 1-4 hours, then heating to 35-42 ℃, reacting for 1-4 hours, then heating to 45-52 ℃, reacting for 4-8 hours, and finally heating to 55-60 ℃, and reacting for 6-12 hours. The reaction rate is slower in the low-temperature reaction, and the reaction rate is faster in the high-temperature reaction, but the number of byproducts is large. By means of the sectional temperature rise, side reactions caused by overlong high reaction temperature can be avoided, and the product yield and purity can be improved.
In some embodiments, after the water is added for layering, the obtained organic phase is extracted with ice water for 2 times, the organic phases are combined, and the second solvent is recovered under normal pressure; and combining the obtained water phases, adding activated carbon, stirring, filtering to remove the activated carbon, and obtaining the 3-chloro-L-alanine methyl ester hydrochloride aqueous solution.
After water is added for layering, most of 3-chloro-L-alanine methyl ester hydrochloride is left in the water phase, a small amount of 3-chloro-L-alanine methyl ester hydrochloride still exists in the organic phase, and the organic phase is extracted for multiple times by ice water, so that the 3-chloro-L-alanine methyl ester hydrochloride in the organic phase can be further separated, and the yield can be improved conveniently; meanwhile, the active carbon is used for removing impurities from the 3-chloro-L-alanine methyl ester hydrochloride in the water phase, so that the purity is improved conveniently.
In some embodiments, the liquid-solid ratio of the water added in the water adding and layering process to the L-serine methyl ester hydrochloride is (3-11): 1, and the liquid-solid ratio of the water added in each ice water extraction process to the L-serine methyl ester hydrochloride is (1-6): 1. Wherein the unit of the liquid-solid ratio is L: kg. For the convenience of operation and thorough separation, the amount of water added should not be too large or too small.
In some embodiments, the temperature of the aqueous phase cooling crystallization is 0 to 5 ℃.
In some embodiments, the temperature of vacuum drying is 40 ℃ and the time of vacuum drying is 4 h.
The synthesis reaction equation of the 3-chloro-L-alanine methyl ester hydrochloride of the invention is as follows:
(a)
(b)
in order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
The embodiment 1 of the invention provides a method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride, which comprises the following steps:
adding 200kg of L-serine and 700L of methanol into a reaction kettle, cooling to 10 ℃, and slowly dropwise adding 330kg of thionyl chloride; wherein the temperature in the dropping process is controlled to be 12 ℃; after the dropwise addition is finished for 10h, the temperature is raised to 38 ℃, the reaction is carried out for 48h, and finally the L-serine methyl ester hydrochloride (white solid, the yield is 93.8 percent, and the purity is 99.5 percent) is obtained after cooling crystallization, centrifugation and drying. Wherein, the solvent removed in the centrifugal process is used as the master batch for the next batch of the reaction.
Adding 90kg of L-serine methyl ester hydrochloride into 700L of dichloromethane, and then dropwise adding 100kg of thionyl chloride B; wherein the temperature in the dropping process is controlled to be 35 ℃; after the dropwise addition is finished for 2h, controlling the temperature of a reaction system to be 30 ℃, reacting for 2h, subsequently heating to 40 ℃, reacting for 3h, then heating to 50 ℃, reacting for 8h, finally heating to 60 ℃, reacting for 8h, cooling to 15 ℃ after the reaction is finished, adding 500ml of pure water for layering, extracting twice by using 100ml of ice water respectively, combining water phases to obtain an aqueous solution of 3-chloro-L-alanine methyl ester hydrochloride, and finally cooling, crystallizing, filter-pressing and vacuum drying to obtain the 3-chloro-L-alanine methyl ester hydrochloride (white solid, yield 97.4% and purity 99.3%).
Wherein, the chromatographic conditions are as follows: the type of the chromatographic column is Erit ODS 2C 18, the parameters of the chromatographic column are 250mm × 4.6mm × 5 μm, the gradient elution is carried out by taking buffer solution (4 ml triethylamine is added into 1000ml purified water, the pH value is adjusted to 2.5 +/-0.1 by phosphoric acid) as a mobile phase A and acetonitrile as a mobile phase B, the flow rate is 1.0ml/min, the sample injection amount is 20 μ l, and the detection wavelength is 210nm at the column temperature of 25 ℃.
Example 2
The embodiment 2 of the invention provides a method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride, which comprises the following steps:
adding 200kg of L-serine, 300L of methanol and 450L of recovered methanol into a reaction kettle, cooling to 10 ℃, and slowly dropwise adding 270kg of thionyl chloride; wherein the temperature in the dripping process is controlled to be 14 ℃; after 8h of dropwise addition, the temperature is raised to 38 ℃, the reaction is carried out for 48h, and finally L-serine methyl ester hydrochloride (white solid, yield 98.1% and purity 99.1%) is obtained after cooling crystallization, centrifugation and drying. Wherein, the solvent removed in the centrifugal process is used as the master batch for the next batch of the reaction.
Adding 90kg of L-serine methyl ester hydrochloride into 900L of dichloroethane, and then dropwise adding 270kg of thionyl chloride B; wherein the temperature in the dripping process is controlled to be 39 ℃; after the dropwise addition for 6h, controlling the temperature of the reaction system to be 28 ℃, reacting for 3h, then heating to 42 ℃, reacting for 3h, then heating to 52 ℃, reacting for 6h, finally heating to 58 ℃, reacting for 8h, cooling to 20 ℃ after the reaction is finished, adding 1000ml of pure water for layering, extracting twice by using 100ml of ice water respectively, combining water phases to obtain an aqueous solution of 3-chloro-L-alanine methyl ester hydrochloride, and finally cooling, crystallizing, filter-pressing and vacuum drying to obtain the 3-chloro-L-alanine methyl ester hydrochloride (white solid, yield 96.3% and purity 98.9%).
Example 3
Embodiment 3 of the present invention provides a method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride, comprising the following steps:
adding 200kg of L-serine, 300L of methanol and 450L of recovered methanol into a reaction kettle, cooling to 5 ℃, and slowly dropwise adding 270kg of thionyl chloride; wherein the temperature in the dropping process is controlled to be 15 ℃; after 8h of dropwise addition, the temperature is raised to 38 ℃, the reaction is carried out for 48h, and finally L-serine methyl ester hydrochloride (white solid, the yield is 97.6 percent, and the purity is 98.9 percent) is obtained after cooling crystallization, centrifugation and drying. Wherein, the solvent removed in the centrifugal process is used as the master batch for the next batch of the reaction.
Adding the 90kg of L-serine methyl ester hydrochloride into 540L of chloroform, and then dropwise adding 90kg of thionyl chloride B; wherein the temperature in the dropping process is controlled to be 40 ℃; after the dropwise addition is finished for 2h, controlling the temperature of a reaction system to be 25 ℃, reacting for 4h, subsequently heating to 35 ℃, reacting for 4h, then heating to 45 ℃, reacting for 5h, finally heating to 55 ℃, reacting for 10h, cooling to 25 ℃ after the reaction is finished, adding 300ml of pure water for layering, extracting twice by using 500ml of ice water respectively, combining water phases to obtain an aqueous solution of 3-chloro-L-alanine methyl ester hydrochloride, and then cooling, crystallizing, filter-pressing and vacuum drying to obtain the 3-chloro-L-alanine methyl ester hydrochloride (white solid, yield 93.5% and purity 98.1%).
Example 4
Embodiment 4 of the present invention provides a method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride, comprising the following steps:
adding 200kg of L-serine, 300L of methanol and 450L of recovered methanol into a reaction kettle, cooling to 8 ℃, and slowly dropwise adding 270kg of thionyl chloride; wherein the temperature in the dropping process is controlled to be 13 ℃; after 8h of dropwise addition, the temperature is raised to 38 ℃, the reaction is carried out for 48h, and finally L-serine methyl ester hydrochloride (white solid, yield 97.5% and purity 98.8%) is obtained after cooling crystallization, centrifugation and drying. Wherein, the solvent removed in the centrifugal process is used as the master batch for the next batch of the reaction.
Adding 90kg of L-serine methyl ester hydrochloride into 700L of chloroform, and then dropwise adding 135kg of thionyl chloride B; wherein the temperature in the dripping process is controlled to be 38 ℃; after the dropwise addition is completed for 3h, controlling the temperature of a reaction system to be 32 ℃, reacting for 1h, then heating to 38 ℃, reacting for 1h, then heating to 48 ℃, reacting for 4h, finally heating to 59 ℃, reacting for 12h, cooling to 18 ℃ after the reaction is completed, adding 800ml of pure water for layering, extracting twice by using 200ml of ice water respectively, combining water phases to obtain an aqueous solution of 3-chloro-L-alanine methyl ester hydrochloride, and then cooling, crystallizing, filter-pressing and vacuum drying to obtain the 3-chloro-L-alanine methyl ester hydrochloride (white solid, the yield is 97.3%, and the purity is 98.5%).
Comparative example 1
Comparative example 1 provides a method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride, comprising the following steps: the conditions were the same as in example 1 except that the obtained L-serine methyl ester hydrochloride was recrystallized. Wherein, the steps of recrystallizing the L-serine methyl ester hydrochloride are as follows: ethanol was added to the obtained L-serine methyl ester hydrochloride to conduct recrystallization. Then, the L-serine methyl ester hydrochloride obtained after recrystallization is used as a raw material to synthesize the 3-chloro-L-alanine methyl ester hydrochloride.
By adopting the method, the L-serine methyl ester hydrochloride obtained through the recrystallization process is white solid, the yield is 90.8 percent, and the purity is 99.8 percent; the 3-chloro-L-alanine methyl ester hydrochloride obtained by using the L-serine methyl ester hydrochloride obtained after recrystallization as a raw material was a white solid, the yield was 97.1%, and the purity was 99.4%
From the above, the purity of 3-chloro-L-alanine methyl ester hydrochloride obtained by the method is not much different from that of 3-chloro-L-alanine methyl ester hydrochloride obtained in example 1, because the product can be sufficiently purified by adding a water layering process, recrystallization of L-serine methyl ester hydrochloride is not required, and the increased recrystallization process also causes a decrease in the yield of L-serine methyl ester hydrochloride.
Comparative example 2
Comparative example 2 provides a method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride, comprising the following steps: the conditions were the same as in example 1 except that the stepwise temperature-controlled reaction process was replaced with a temperature-elevated reflux for 60 hours.
By adopting the method, the obtained 3-chloro-L-alanine methyl ester hydrochloride is white solid, the total yield is 89.7%, and the purity is 93.1%.
From the above, the product obtained by the method has lower yield and purity than those of the product obtained in example 1, and the reaction time is long, because the product performance is affected by direct temperature rise and reflux, long high-temperature reaction time and more side reactions in the comparative example 1.
Compared with the prior art, the invention has the beneficial effects that:
in the method, the L-serine methyl ester hydrochloride does not need to be purified in the first step of synthesis process, so that the 3-chloro-L-alanine methyl ester hydrochloride with higher purity can be obtained, and the process is optimized.
The method adopts a segmented temperature control mode, has short reaction time, mild reaction conditions, high reaction yield and few byproducts, and is favorable for improving the yield and the product purity.
In the method, water is added to layer the reaction mixture, and the organic phase is extracted for a plurality of times and the water phase is adsorbed by active carbon, so that the product yield and the product purity are further improved.
The solvent in the method can be used repeatedly, no solid waste is generated, the energy consumption and the labor cost are reduced, and the efficiency is improved.
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (9)
1. A synthetic method of 3-chloro-L-alanine methyl ester hydrochloride is characterized by comprising the following steps:
adding L-serine into a first solvent, cooling to 5-10 ℃, dropwise adding thionyl chloride A, heating to 38 ℃ after dropwise adding, and reacting for 48 hours; after the reaction is finished, cooling and crystallizing the reaction mixture, centrifugally desolventizing and drying to obtain L-serine methyl ester hydrochloride;
adding the L-serine methyl ester hydrochloride into a second solvent, then dropwise adding thionyl chloride B, carrying out segmented temperature control reaction, cooling to 15-25 ℃ after the reaction is finished, adding water for layering, and then carrying out cooling crystallization, filter pressing and vacuum drying on the obtained water phase to obtain the 3-chloro-L-alanine methyl ester hydrochloride.
2. The method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride according to claim 1, wherein the first solvent is one or a mixture of methanol or recovered methanol obtained by centrifugal desolvation.
3. The method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride according to claim 1, wherein the temperature of the reaction system is controlled to be 12-15 ℃ in the process of dropwise adding the thionyl chloride A.
4. The method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride according to claim 1, wherein the second solvent is any one of dichloromethane, dichloroethane, chloroform, epichlorohydrin or chlorobutane.
5. The method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride according to claim 1, wherein the temperature of the reaction system is controlled to be 35-40 ℃ in the process of dropwise adding the thionyl chloride B.
6. The method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride according to claim 1, wherein the L-serine methyl ester hydrochloride is added into the second solvent according to a liquid-solid ratio of (6-10) to 1; wherein the unit of the liquid-solid ratio is L: kg.
7. The method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride according to claim 1, wherein the mass ratio of the thionyl chloride B to the L-serine methyl ester hydrochloride is (1-3): 1.
8. The method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride according to claim 1, wherein the step of controlling the temperature in stages comprises controlling the temperature to 25-32 ℃ for reaction for 1-4 hours, then raising the temperature to 35-42 ℃ for reaction for 1-4 hours, then raising the temperature to 45-52 ℃ for reaction for 4-8 hours, and finally raising the temperature to 55-60 ℃ for reaction for 6-12 hours.
9. The method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride according to claim 1, wherein after the water is added for layering, the obtained organic phase is extracted with ice water for 2 times, the organic phases are combined, and the second solvent is recovered under normal pressure; and combining the obtained water phases, adding activated carbon, stirring, filtering to remove the activated carbon, and obtaining the 3-chloro-L-alanine methyl ester hydrochloride aqueous solution.
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| 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 |
| CN115872882A (en) * | 2021-09-27 | 2023-03-31 | 中国科学院大连化学物理研究所 | Synthetic method of 3-chloro-alanine |
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| CN105777611A (en) * | 2016-03-17 | 2016-07-20 | 浙江工业大学 | Synthesizing method using serine to prepare Ramipril key intermediate |
| CN106518695A (en) * | 2016-11-03 | 2017-03-22 | 安徽省诚联医药科技有限公司 | A synthetic method of (R)-methyl 2-amino-3-chloropropanoate hydrochloride |
| CN109678739A (en) * | 2018-12-27 | 2019-04-26 | 北京富盛嘉华国际贸易有限公司 | A kind of synthetic method of R-3- chlorine serine methyl ester hydrochloride |
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| CN105777611A (en) * | 2016-03-17 | 2016-07-20 | 浙江工业大学 | Synthesizing method using serine to prepare Ramipril key intermediate |
| CN106518695A (en) * | 2016-11-03 | 2017-03-22 | 安徽省诚联医药科技有限公司 | A synthetic method of (R)-methyl 2-amino-3-chloropropanoate hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN115872882A (en) * | 2021-09-27 | 2023-03-31 | 中国科学院大连化学物理研究所 | Synthetic method of 3-chloro-alanine |
| CN115872882B (en) * | 2021-09-27 | 2024-05-10 | 中国科学院大连化学物理研究所 | Synthesis method of 3-chloro-alanine |
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Application publication date: 20191220 |