CN113004160A - Synthetic method of L-serine methyl ester sulfate - Google Patents
Synthetic method of L-serine methyl ester sulfate Download PDFInfo
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- CN113004160A CN113004160A CN202110275321.2A CN202110275321A CN113004160A CN 113004160 A CN113004160 A CN 113004160A CN 202110275321 A CN202110275321 A CN 202110275321A CN 113004160 A CN113004160 A CN 113004160A
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- methyl ester
- ester sulfate
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- -1 L-serine methyl ester sulfate Chemical compound 0.000 title claims abstract description 39
- 238000010189 synthetic method Methods 0.000 title claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 201
- 238000006243 chemical reaction Methods 0.000 claims abstract description 69
- 238000000034 method Methods 0.000 claims abstract description 62
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims abstract description 54
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000001816 cooling Methods 0.000 claims abstract description 40
- 239000012452 mother liquor Substances 0.000 claims abstract description 27
- 229960001153 serine Drugs 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 239000011541 reaction mixture Substances 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 239000007787 solid Substances 0.000 claims description 21
- 238000001291 vacuum drying Methods 0.000 claims description 21
- 230000002194 synthesizing effect Effects 0.000 claims 4
- 239000000047 product Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002910 solid waste Substances 0.000 abstract description 4
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000004904 shortening Methods 0.000 abstract 1
- 238000005119 centrifugation Methods 0.000 description 31
- 238000002425 crystallisation Methods 0.000 description 16
- 230000008025 crystallization Effects 0.000 description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 5
- 229960003401 ramipril Drugs 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 1
- 125000001980 alanyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method of L-serine methyl ester sulfate, which comprises the following steps: initial reaction: adding L-serine into a solvent, controlling the temperature to be 20-30 ℃, dropwise adding sulfuric acid, heating to 35-40 ℃ after dropwise adding, and reacting for 24-48 hours to obtain a reaction mixture; cooling and crystallizing the reaction mixture, centrifugally removing the solvent, and drying to obtain L-serine methyl ester sulfate; the recovered methanol removed in the centrifugal solvent removal process is directly used as the next circulating mother liquor; mechanically applying reaction: the solvent in the initial reaction was changed to a mixture of methanol B and recovered methanol. In the method, the mother liquor in the last step is used as a raw material, so that the using amount of the solvent is small, and the yield of the final product is improved conveniently; the solvent can be used repeatedly without limitation, no solid waste is generated, the energy consumption and the production cost are reduced, and the efficiency is improved; the product does not need to be recrystallized, thereby being convenient for shortening the production period and improving the yield.
Description
Technical Field
The invention relates to the technical field of preparation of ramipril intermediates, in particular to a synthesis method of L-serine methyl ester sulfate.
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.
L-serine methyl ester sulfate is a very important intermediate for the synthesis of ramipril. In the prior art, the preparation method of L-serine methyl ester hydrochloride is to add L-serine into methanol, dropwise add thionyl chloride, then carry out reflux reaction at 60 ℃, evaporate the reaction solution to dryness after the reaction is finished, add ethanol for cooling crystallization, and centrifugally dry to obtain the product. However, in the above scheme, the thionyl chloride solvent has strong corrosivity and strong irritation, and can cause burn of a human body, the usage amount of the methanol solvent is large, sulfur dioxide is generated in the reaction, so that not only equipment corrosion is caused, but also pollution is caused, in addition, the synthesis process needs to recover methanol, on one hand, methanol loss is caused, environmental pollution is caused, and on the other hand, the methanol recovery work also increases the cost.
Therefore, the search for a green and efficient synthesis method to obtain L-serine methyl ester sulfate with high yield and small solvent consumption is very important for the synthesis of ramipril.
Disclosure of Invention
The invention aims to overcome the defect of large usage amount of L-serine methyl ester sulfate solvent in the prior art and provide a synthetic method of L-serine methyl ester sulfate.
In order to solve the technical problems, the invention provides the following technical scheme:
a synthetic method of L-serine methyl ester sulfate comprises the following steps:
initial reaction:
adding L-serine into methanol, cooling to 20-30 ℃, dropwise adding sulfuric acid, heating to 35-40 ℃ after dropwise adding, and reacting for 24-48 hours to obtain a reaction mixture;
cooling and crystallizing the reaction mixture, centrifugally desolventizing, and drying to obtain L-serine methyl ester sulfate;
the recovered methanol removed in the centrifugal solvent removal process is directly used as circulating mother liquor;
mechanically applying reaction:
adding L-serine into methanol and circulating mother liquor, cooling to 20-30 ℃, dropwise adding sulfuric acid, heating to 35-40 ℃ after dropwise adding, and reacting for 24-48 hours to obtain a reaction mixture; the total volume of the methanol and the circulating mother liquor in the indiscriminate reaction is 1.05-1.1 times of the volume of the methanol in the initial reaction;
cooling and crystallizing the reaction mixture, centrifugally desolventizing, and drying to obtain L-serine methyl ester sulfate; the recovered methanol removed in the centrifugal solvent removal process is directly used as circulating mother liquor;
the dripping amount of the sulfuric acid in the indiscriminate reaction is 60-70% of that of the sulfuric acid in the initial reaction.
Further, the liquid-solid ratio of the methanol to the L-serine is (3-5): 1; the liquid-solid ratio of methanol to circulating mother liquor to L-serine in the indiscriminate reaction is (3-5): 1; wherein the unit of the liquid-solid ratio is L: kg;
further, the mass ratio of the sulfuric acid to the L-serine is (1.35-1.7): 1.
further, the temperature of the reaction system is controlled to be 20-30 ℃.
Further, the drying is vacuum drying, the temperature of the vacuum drying is 60 ℃, and the time of the vacuum drying is 10 hours.
The invention has the following beneficial effects: the synthesis process does not generate volatile gas sulfur dioxide, the solvent methanol does not need to be recovered and is directly used, the cost can be saved, the use amount of the solvent is small, and the yield of the final product is convenient to improve. In the method, the solvent can be used repeatedly, no solid waste is generated, the energy consumption and the production cost are reduced, and the efficiency is improved. In the method, the product does not need to be recrystallized, so that the production period is convenient to shorten and the yield is improved.
Detailed Description
The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention.
Example 1
A synthetic method of L-serine methyl ester sulfate comprises the following steps:
initial reaction:
adding 200kg of L-serine and 700L of methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 330kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is 40 kg/h; after the dropwise addition, the temperature is raised to 38 ℃, the reaction is carried out for 48 hours, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10 hours at the temperature of 60 ℃.
By adopting the method, 390.6kg of white solid is obtained, the yield is 94.5 percent, and the purity is 99.6 percent.
The recovered methanol removed in the above centrifugation process is directly used as a mother liquor for the next step of circulation.
The first application is as follows:
adding 200kg of L-serine, 300L of methanol and 460L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 200kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is 40 kg/h; after the dropwise addition, the temperature is raised to 38 ℃, the reaction is carried out for 48 hours, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10 hours at the temperature of 60 ℃. The tail gas generated in the reaction process is absorbed by NaOH aqueous solution.
By adopting the method, 404.7kg of white solid is obtained, the yield is 98 percent, and the purity is 99.5 percent.
The recovered methanol removed in the above centrifugation process is directly used as a mother liquor for the next step of circulation.
The second application is as follows:
adding 200kg of L-serine, 300L of methanol and 450L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 200kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is 40 kg/h; after the dropwise addition, the temperature is raised to 38 ℃, the reaction is carried out for 48 hours, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10 hours at the temperature of 60 ℃. The tail gas generated in the reaction process is absorbed by NaOH aqueous solution.
By adopting the method, 410.1kg of white solid is obtained, the yield is 99.3 percent, and the purity is 99.3 percent.
The recovered methanol removed in the centrifugation process is directly used as mother liquor for the next circulation, and then the same two times of mechanical application operation as the steps are carried out.
For the fifth use
Adding 200kg of L-serine, 300L of methanol and 450L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 200kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is 40 kg/h; after the dropwise addition, the temperature is raised to 38 ℃, the reaction is carried out for 48 hours, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10 hours at the temperature of 60 ℃.
By adopting the method, 410.9kg of white solid is obtained, the yield is 99.5 percent, and the purity is 99.1 percent.
The recovered methanol removed in the above centrifugation was directly used as a mother liquor for the next cycle, followed by the same four application operations as in the above step.
For the tenth application
Adding 200kg of L-serine, 300L of methanol and 450L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 200kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is 40 kg/h; after the dropwise addition, the temperature is raised to 38 ℃, the reaction is carried out for 48 hours, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10 hours at the temperature of 60 ℃.
By adopting the method, 411.3kg of white solid is obtained, the yield is 99.6%, and the purity is 99.1%.
The recovered methanol removed in the above centrifugation process is directly used as a mother liquor for the next step of circulation.
Wherein, the chromatographic conditions are as follows: the type of the chromatographic column was elette ODS 2C 18, the chromatographic column parameters were 250mm × 4.6mm × 5 μm, gradient elution was carried out with buffer (4 ml triethylamine was added to 1000ml purified water, pH was adjusted to 2.5. + -. 0.1 with phosphoric acid) as mobile phase A and acetonitrile as mobile phase B at a flow rate of 1.0ml/min, a sample introduction amount of 20 μ l, a column temperature of 25 ℃ and a detection wavelength of 210 nm.
Example 2:
a synthetic method of L-serine methyl ester sulfate comprises the following steps:
initial reaction:
adding 200kg of L-serine and 600L of methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 340kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is 35 kg/h; after the dropwise addition, the temperature is raised to 35 ℃, the reaction is carried out for 36h, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10h at the temperature of 60 ℃. The tail gas generated in the reaction process is absorbed by KOH aqueous solution.
By adopting the method, 385.7kg of white solid is obtained, the yield is 93.4%, and the purity is 99.3%.
The recovered methanol removed in the above centrifugation process is directly used as a mother liquor for the next step of circulation.
The first application is as follows:
adding 200kg of L-serine, 290L of methanol and 360L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 210kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is 35 kg/h; after the dropwise addition, the temperature is raised to 35 ℃, the reaction is carried out for 36h, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10h at the temperature of 60 ℃. The tail gas generated in the reaction process is absorbed by KOH aqueous solution.
By adopting the method, 396.9kg of white solid is obtained, the yield is 96.1 percent, and the purity is 99.1 percent.
The recovered methanol removed in the above centrifugation process is directly used as a mother liquor for the next step of circulation.
The second application is as follows:
adding 200kg of L-serine, 300L of methanol and 350L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 210kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is 35 kg/h; after the dropwise addition, the temperature is raised to 35 ℃, the reaction is carried out for 36h, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10h at the temperature of 60 ℃.
By adopting the method, 407.2kg of white solid is obtained, the yield is 98.6 percent, and the purity is 98.7 percent.
The recovered methanol removed in the centrifugation process is directly used as mother liquor for the next circulation, and then the same two times of mechanical application operation as the steps are carried out.
The fifth application is as follows:
adding 200kg of L-serine, 300L of methanol and 350L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 210kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is 35 kg/h; after the dropwise addition, the temperature is raised to 35 ℃, the reaction is carried out for 36h, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10h at the temperature of 60 ℃. The tail gas generated in the reaction process is absorbed by KOH aqueous solution.
By adopting the method, 410.1kg of white solid is obtained, the yield is 99.3 percent, and the purity is 98.6 percent.
The recovered methanol removed in the above centrifugation was directly used as a mother liquor for the next cycle, followed by the same four application operations as in the above step.
The tenth application is as follows:
adding 200kg of L-serine, 300L of methanol and 350L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 210kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is 35 kg/h; after the dropwise addition, the temperature is raised to 35 ℃, the reaction is carried out for 36h, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10h at the temperature of 60 ℃.
By adopting the method, 411.3kg of white solid is obtained, the yield is 99.5 percent, and the purity is 98.5 percent.
The recovered methanol removed in the above centrifugation process is directly used as a mother liquor for the next step of circulation.
Example 3:
a synthetic method of L-serine methyl ester sulfate comprises the following steps:
initial reaction:
adding 200kg of L-serine and 1000L of methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 270kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is controlled to be 30 kg/h; after the dropwise addition, the temperature is raised to 40 ℃, the reaction is carried out for 24 hours, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10 hours at the temperature of 60 ℃. The tail gas generated in the reaction process is absorbed by the sodium carbonate aqueous solution.
By adopting the method, 381.6kg of white solid is obtained, the yield is 92.4%, and the purity is 98.7%.
The recovered methanol removed in the above centrifugation process is directly used as a mother liquor for the next step of circulation.
The first application is as follows:
adding 200kg of L-serine, 300L of methanol and 760L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 220kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is controlled to be 30 kg/h; after the dropwise addition, the temperature is raised to 40 ℃, the reaction is carried out for 24 hours, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10 hours at the temperature of 60 ℃. The tail gas generated in the reaction process is absorbed by the sodium carbonate aqueous solution.
By adopting the method, 281.6kg of white solid is obtained, the yield is 95.1 percent, and the purity is 98.5 percent.
The recovered methanol removed in the above-mentioned centrifugation process is directly used as mother liquor for next circulation.
The second application is as follows:
adding 200kg of L-serine, 300L of methanol and 750L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 220kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is controlled to be 30 kg/h; after the dropwise addition, the temperature is raised to 40 ℃, the reaction is carried out for 24 hours, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10 hours at the temperature of 60 ℃. The tail gas generated in the reaction process is absorbed by the sodium carbonate aqueous solution.
By adopting the method, 407.2kg of white solid is obtained, the yield is 98.6 percent, and the purity is 98.2 percent.
The recovered methanol removed in the centrifugation process is directly used as mother liquor for the next circulation, and then the same two times of mechanical application operation as the steps are carried out.
The fifth application is as follows:
adding 200kg of L-serine, 300L of methanol and 750L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 220kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is controlled to be 30 kg/h; after the dropwise addition, the temperature is raised to 40 ℃, the reaction is carried out for 24 hours, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10 hours at the temperature of 60 ℃. The tail gas generated in the reaction process is absorbed by the sodium carbonate aqueous solution.
By adopting the method, 410.1kg of white solid is obtained, the yield is 99.3 percent, and the purity is 97.8 percent.
The recovered methanol removed in the above centrifugation was directly used as a mother liquor for the next cycle, followed by the same four application operations as in the above step.
The tenth application is as follows:
adding 200kg of L-serine, 300L of methanol and 750L of recovered methanol into a reaction kettle, cooling to 20 ℃, and slowly dropwise adding 220kg of sulfuric acid; wherein the temperature in the dripping process is controlled to be 20-30 ℃, and the dripping speed is controlled to be 30 kg/h; after the dropwise addition, the temperature is raised to 40 ℃, the reaction is carried out for 24 hours, and after the processes of cooling crystallization and centrifugation, the L-serine methyl ester sulfate is finally obtained after vacuum drying for 10 hours at the temperature of 60 ℃. The tail gas generated in the reaction process is absorbed by the sodium carbonate aqueous solution.
By adopting the method, 411.3kg of white solid is obtained, the yield is 99.6%, and the purity is 97.7%.
The recovered methanol removed in the above centrifugation process is directly used as a mother liquor for the next step of circulation.
From the above, the reaction solution removed by the centrifugation process can be directly used as the mother solution for the next cycle, and by using the mother solution, the yield of the product can be improved, and the generation of solid waste can be effectively reduced; meanwhile, after ten solvent recycling processes, the purity of the obtained product is relatively stable, which shows that the method provided by the invention can realize unlimited recycling of the solvent and no solid waste is generated.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. A synthetic method of L-serine methyl ester sulfate is characterized by comprising the following steps:
initial reaction:
adding L-serine into methanol, cooling to 20-30 ℃, dropwise adding sulfuric acid, heating to 35-40 ℃ after dropwise adding, and reacting for 24-48 hours to obtain a reaction mixture;
cooling and crystallizing the reaction mixture, centrifugally desolventizing, and drying to obtain L-serine methyl ester sulfate;
the recovered methanol removed in the centrifugal solvent removal process is directly used as circulating mother liquor;
mechanically applying reaction:
adding L-serine into methanol and circulating mother liquor, cooling to 20-30 ℃, dropwise adding sulfuric acid, heating to 35-40 ℃ after dropwise adding, and reacting for 24-48 hours to obtain a reaction mixture; the total volume of the methanol and the circulating mother liquor in the indiscriminate reaction is 1.05-1.1 times of the volume of the methanol in the initial reaction;
cooling and crystallizing the reaction mixture, centrifugally desolventizing, and drying to obtain L-serine methyl ester sulfate; the recovered methanol removed in the centrifugal solvent removal process is directly used as circulating mother liquor;
the dripping amount of the sulfuric acid in the indiscriminate reaction is 60-70% of that of the sulfuric acid in the initial reaction.
2. The method for synthesizing L-serine methyl ester sulfate according to claim 1, wherein in the initial reaction, the liquid-solid ratio of methanol to L-serine is (3-5): 1; the liquid-solid ratio of methanol to circulating mother liquor to L-serine in the indiscriminate reaction is (3-5): 1; wherein the unit of the liquid-solid ratio is L: kg.
3. The method for synthesizing L-serine methyl ester sulfate according to claim 1, wherein the mass ratio of the sulfuric acid to the L-serine in the initial reaction is (1.35-1.7): 1.
4. the method for synthesizing L-serine methyl ester sulfate according to claim 1, wherein the temperature of the reaction system is controlled to be 20 to 30 ℃ in the process of dropwise adding sulfuric acid.
5. The method for synthesizing L-serine methyl ester sulfate according to claim 1, wherein the drying is vacuum drying, the temperature of the vacuum drying is 60 ℃, and the time of the vacuum drying is 10 h.
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Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02256653A (en) * | 1988-12-27 | 1990-10-17 | Mitsui Toatsu Chem Inc | Production of mineral acid salt of amino acid methyl ester |
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| JPH02256653A (en) * | 1988-12-27 | 1990-10-17 | Mitsui Toatsu Chem Inc | Production of mineral acid salt of amino acid methyl ester |
| CN102850232A (en) * | 2011-06-27 | 2013-01-02 | 天津天成制药有限公司 | Preparation method of L-serine nitrate |
| CN104003894A (en) * | 2013-02-21 | 2014-08-27 | 浙江嘉华化工有限公司 | Method for preparing N-acetyl-beta-chlorine-L-alanine methyl ester |
| CN105777611A (en) * | 2016-03-17 | 2016-07-20 | 浙江工业大学 | Synthetic method for preparing ramipril key intermediate from serine |
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