CN105949074A - Synthesis method of O-methyl-D-serine - Google Patents
Synthesis method of O-methyl-D-serine Download PDFInfo
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- CN105949074A CN105949074A CN201610395009.6A CN201610395009A CN105949074A CN 105949074 A CN105949074 A CN 105949074A CN 201610395009 A CN201610395009 A CN 201610395009A CN 105949074 A CN105949074 A CN 105949074A
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- methyl
- serine
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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
- C07C227/12—Formation of amino and 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
- C07C227/30—Preparation of optical isomers
- C07C227/34—Preparation of optical isomers by separation of optical isomers
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- 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
Abstract
The invention discloses a synthesis method of O-methyl-D-serine. The synthesis method includes the following steps that 1, acrylic acid methyl ester is added into a reaction bottle, after the temperature is raised, bromine is dropwise added, after an addition reaction is conducted, decompression and distillation are conducted to remove excessive bromine, methyl alcohol is added to residues, after the temperature is lowered, sodium methylate is added, after an alcoholysis reaction, decompression and distillation are conducted to remove methyl alcohol, ammonium hydroxide is added, after an ammonium hydroxide, concentrated crystallization is conducted, and O-methyl-DL-serine is obtained; 2, acetic acid is added into the reaction bottle, the O-methyl-DL-serine, D-tartaric acid and salicylaldehyde are added in sequence, after the temperature is raised for a reaction, cooling and crystallization are conducted, separation is conducted, and O-methyl-D-serine double salt is obtained; 3, the O-methyl-D-serine double salt is dissolved in a methyl alcohol aqueous solution, ammonium hydroxide is added to regulate PH to be 7-8, crystallization and separation are conducted, and the O-methyl-D-serine is obtained. The synthesis method is mild in reaction temperature, safe to operate, low in cost and high in chirality purity, and raw materials are easy to obtain.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to the synthetic method of a kind of O-methyl D-serine.
Background technology
O-methyl D-serine is alpha-non-natural amino acid, does not has existence form in nature, is the master of synthesis scheme for lacosamide
Want intermediate, be widely used in the industry such as medicine.Scheme for lacosamide is treatment epilepsy and the medicine of neuropathic pain.It is a kind of
Novel nmda receptor Glycine site combines antagonist, belongs to new class functional amino, is to have brand-new double mechanism to make
Anticonvulsant drug.Its alternative promotion sodium channel slowly inactivates and regulates reaction mediating proteins 22 (CRMP22) of subsiding,
And CRMP22 may slow down and even stops epilepsy and alleviate the neuropathic pain of diabetes.The mechanism of action of this product is different
In other antuepileptics listed, use the patient of the uncontrollable symptom of existing medicine can use this product.Diabetic neuropathic
Pain annoyings diabetics greatly, and scheme for lacosamide is used for treating diabetic neuropathic pain well effect.
Being colourless to white crystal or crystalline powder under room temperature, micro-smelly, taste is micro-sweet, soluble in water, is insoluble in ethanol, insoluble in ether
And n-butyl alcohol.
The key intermediate of synthesis scheme for lacosamide is exactly O-methyl D-serine.
The route of report synthesis scheme for lacosamide has as follows
1) DL-serine methyl ester hydrochloride route, uses S-2-chloro mandelic acid costly, and route is the most long, unfavorable
In industrialization.
2) Merschaert Alain O-methyl DL-serine is raw material, splits or enzymatic conversion, although route is short,
But being because splitting is all 50% fractionation, so yield is the highest, adds post processing resin treatment and be unfavorable for industrialization.
3) also have been reported that and use acrylic acid route, but the most unresolved back segment chiral inversion yield problem.
4) present industrialization process, is substantially and synthesizes BOC-O-methyl D-serine with BOC-D-serine, then
Go with following route synthesis scheme for lacosamide.
But the greatest problem of this technique is exactly that BOC-D-serine is at synthesis BOC-O-methyl D-serine now
Time can racemization, obtain only chiral purity 95%.Because needs when that chirality causing synthesizing scheme for lacosamide below not
Just can be obtained the scheme for lacosamide of synthesis by purification repeatedly, such scheme for lacosamide comprehensive yield is the highest, high expensive.So it is honest and clean
It is the most critically important that valency obtains high chiral key intermediate O-methyl D-serine.
Summary of the invention
For above-mentioned problems of the prior art, the present invention provides a kind of integrated cost cheap, and reaction temperature compares
Gentle, it is easy to industrialization, safety, raw material is easy to get, low cost, and chiral purity more than 99.9%.
For solving the problem that above-mentioned prior art exists, the technical scheme that the present invention takes is: a kind of O-methyl D-silk ammonia
The synthetic method of acid, it is characterised in that comprise the steps:
1) adding acrylic acid methyl ester. in reaction bulb, drip bromine after intensification, after additive reaction, excess is removed in decompression distillation
Bromine, residue add methanol, after cooling add Feldalat NM, after alcoholysis reaction, decompression distillation remove methanol, add ammonia,
After ammonolysis reaction, condensing crystallizing obtains O-methyl DL-serine；
2) in reaction bulb add acetic acid, be sequentially added into O-methyl DL-serine, D-tartaric acid and salicylide, heat up into
After row reaction, decrease temperature crystalline, separate to obtain O-methyl D-serine double salt；
3) O-methyl D-serine double salt is dissolved in the aqueous solution of methanol, adds ammonia regulation PH to 7-8, crystallization, separate
Obtain O-methyl D-serine.
Synthetic route is:
Wherein, use D-tartaric acid as resolution reagent, acetic acid as solvent, make under the catalysis of salicylide O-methyl-
DL-serine generation asymmetric transformation react, with traditional method for splitting first than, the chiral purity obtaining product is higher, can reach
To more than 99.9%.
Preferably, step 2) in step 2) in D-tartaric acid, the mol ratio of salicylide and O-methyl DL-serine be 1-
1.1:0.028-0.03:1.Produce impurity under these process conditions few, and asymmetric transformation reaction is completely.
Preferably, step 2) reaction temperature 60-70 DEG C, the response time is 8-12h.
Preferably, step 3) in methanol aqueous solution the volumetric concentration of methanol be 65-80%.
Preferably, step 1) in the mol ratio of acrylic acid methyl ester. and bromine be 1:1.25-1.4.
Preferably, step 1) in Feldalat NM addition be 0.8-1.1 mole of acrylic acid methyl ester. times.
Preferably, step 1) in ammonia addition be 3-5 times of acrylic acid methyl ester. weight.
Preferably, step 1) in the reaction temperature of additive reaction be 45-60 degree, the response time is 1h.
Preferably, step 1) in the reaction temperature of additive reaction be-20--10 DEG C of degree, the response time is 4-7h.
Preferably, step 1) in the reaction temperature of additive reaction be 20-25 DEG C of degree, the response time is 2-5h.
The synthetic method of O-methyl D-serine of the present invention, relative to prior art, has the advantage that
1. yield is high, it is possible to obtain the product of chiral purity more than 99.9%.
The most with low cost: the raw material used by the method for the invention is all basic material that is cheap, that be readily available.
3. safety: reaction temperature is gentleer, easily realizes industrialized great production；
Detailed description of the invention
In order to deepen the understanding of the present invention, below in conjunction with embodiment, the invention will be further described, this embodiment
It is only used for explaining the present invention, is not intended that limiting the scope of the present invention.
Embodiment 1
1) in reaction bulb add acrylic acid methyl ester. 86g, be warmed up to 50 DEG C dropping bromine 200g, insulation reaction 1 hour, 60 DEG C
Concentrating under reduced pressure removes the bromine of excess, and residue adds methanol 500g, cools to-15 DEG C, adds Feldalat NM 50g, and insulation reaction 5 is little
Time, reaction terminates concentrating under reduced pressure and removes methanol, adds the ammonia of 300g, and 20-25 DEG C of insulation reaction 3 hours, condensing crystallizing obtains
O-methyl DL-serine 101g.
2) reaction bulb adds the acetic acid of 600g, sequentially adds 101g O-methyl DL-serine, D-tartaric acid
126g, and salicylide 3g, be warmed up to 65 DEG C of insulation reaction 10 hours, cool to 20 DEG C crystallize 2 hours, be filtrated to get O-methyl-
D-Ser double salt 210g.
3) reaction bulb adds the methanol aqueous solution 550g of 70% (v/v), adds O-methyl D-serine double salt 210g,
Regulate PH to 7-8 with ammonia, crystallize 2 hours, be filtrated to get O-methyl D-serine 83g, after testing, content: be more than
98.5%, chiral purity: more than 99.9%.
Embodiment 2
1) in reaction bulb add acrylic acid methyl ester. 215g, be warmed up to 55 DEG C dropping bromine 500g, insulation reaction 1 hour, 60
DEG C concentrating under reduced pressure removes the bromine of excess, and residue adds methanol 1260g, cools to-17 DEG C, adds Feldalat NM 127g, and insulation is anti-
Answering 5.5 hours, reaction terminates concentrating under reduced pressure and removes methanol, adds the ammonia of 750g, 20-25 DEG C of insulation reaction 3 hours, concentrates knot
Crystalline substance obtains O-methyl DL-serine 260g.
2) reaction bulb adds the acetic acid of 1500g, sequentially adds 260gO-methyl DL-serine, D-tartaric acid
315g, and salicylide 7.5g, be warmed up to 63 DEG C of insulation reaction 11 hours, cools to 20 DEG C and crystallizes 2 hours, is filtrated to get O-first
Base-D-Ser double salt 527g.
3) reaction bulb adds the methanol aqueous solution 1400g of 70% (v/v), adds O-methyl D-serine double salt 527g,
Regulate PH to 7-8 with ammonia, crystallize 2 hours, be filtrated to get O-methyl D-serine 210g, after testing, content: be more than
98.5%, chiral purity: more than 99.9%.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all essences in the present invention
Within god and principle, any modification, equivalent substitution and improvement etc. made, should be included within the scope of the present invention.
Claims (10)
1. the synthetic method of O-methyl D-serine, it is characterised in that comprise the steps:
1) adding acrylic acid methyl ester. in reaction bulb, drip bromine after intensification, after additive reaction, the bromine of excess is removed in decompression distillation
Element, residue adds methanol, adds Feldalat NM after cooling, and after alcoholysis reaction, methanol is removed in decompression distillation, adds ammonia, ammonolysis
After reaction, condensing crystallizing obtains O-methyl DL-serine；
2) acetic acid added in reaction bulb, is sequentially added into O-methyl DL-serine, D-tartaric acid and salicylide, and intensification is carried out
After reaction, decrease temperature crystalline, separate to obtain O-methyl D-serine double salt；
3) O-methyl D-serine double salt is dissolved in methanol aqueous solution, adds ammonia regulation PH to 7-8, crystallization, isolated O-
Methyl D-serine.
The synthetic method of a kind of O-methyl D-serine the most according to claim 1, it is characterised in that step 2) in D-
Tartaric acid, salicylide are 1-1.1:0.028-0.03:1 with the mol ratio of O-methyl DL-serine.
The synthetic method of a kind of O-methyl D-serine the most according to claim 1 and 2, it is characterised in that step 2)
Reaction temperature 60-70 DEG C, the response time is 8-12h.
The synthetic method of a kind of O-methyl D-serine the most according to claim 1, it is characterised in that first in step 3)
In alcohol-water solution, the volumetric concentration of methanol is 65-80%.
The synthetic method of a kind of O-methyl D-serine the most according to claim 1, it is characterised in that in step 1) third
The mol ratio of e pioic acid methyl ester and bromine is 1:1.25-1.4.
The synthetic method of a kind of O-methyl D-serine the most according to claim 1, it is characterised in that first in step 1)
Sodium alkoxide addition is 0.8-1.1 mole times of acrylic acid methyl ester..
The synthetic method of a kind of O-methyl D-serine the most according to claim 1, it is characterised in that ammonia in step 1)
Water addition is 3-5 times of acrylic acid methyl ester. weight.
The synthetic method of a kind of O-methyl D-serine the most according to claim 1, it is characterised in that add in step 1)
The reaction temperature becoming reaction is 45-60 degree, and the response time is 1h.
The synthetic method of a kind of O-methyl D-serine the most according to claim 1, it is characterised in that add in step 1)
The reaction temperature becoming reaction is-20--10 DEG C of degree, and the response time is 4-7h.
The synthetic method of a kind of O-methyl D-serine the most according to claim 1, it is characterised in that add in step 1)
The reaction temperature becoming reaction is 20-25 DEG C of degree, and the response time is 2-5h.
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| CN201610395009.6A CN105949074B (en) | 2016-06-03 | 2016-06-03 | A kind of synthetic method of O methyl D serines |
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| CN201610395009.6A CN105949074B (en) | 2016-06-03 | 2016-06-03 | A kind of synthetic method of O methyl D serines |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4182718A (en) * | 1977-10-25 | 1980-01-08 | Monsanto Company | 1,3-Dioxolane and 1,3-dioxane polycarboxylates, and precursors thereof |
| EP2487152A1 (en) * | 2010-11-17 | 2012-08-15 | UCB Pharma GmbH | Process for the preparation of Lacosamide including resolution of O-methyl-DL-serine |
| WO2014068333A2 (en) * | 2012-11-01 | 2014-05-08 | Cambrex Karlskoga Ab | New process |
| WO2014072992A1 (en) * | 2012-11-12 | 2014-05-15 | Aarti Industries Limited | A process for preparing triazole compounds |
| CN105237419A (en) * | 2015-09-18 | 2016-01-13 | 南京红杉生物科技有限公司 | Method for synthesizing L-norvaline |
-
2016
- 2016-06-03 CN CN201610395009.6A patent/CN105949074B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4182718A (en) * | 1977-10-25 | 1980-01-08 | Monsanto Company | 1,3-Dioxolane and 1,3-dioxane polycarboxylates, and precursors thereof |
| EP2487152A1 (en) * | 2010-11-17 | 2012-08-15 | UCB Pharma GmbH | Process for the preparation of Lacosamide including resolution of O-methyl-DL-serine |
| WO2014068333A2 (en) * | 2012-11-01 | 2014-05-08 | Cambrex Karlskoga Ab | New process |
| WO2014072992A1 (en) * | 2012-11-12 | 2014-05-15 | Aarti Industries Limited | A process for preparing triazole compounds |
| CN105237419A (en) * | 2015-09-18 | 2016-01-13 | 南京红杉生物科技有限公司 | Method for synthesizing L-norvaline |
Non-Patent Citations (1)
| Title |
|---|
| HAROLD D. WEST ETAL: "A Publication of Reliable Methods for the Preparation of Organic Compounds", 《ORGANIC SYNTHESES》 * |
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Denomination of invention: Synthesis method of O-methyl-D-serine Effective date of registration: 20181018 Granted publication date: 20180302 Pledgee: Bank of Jiangsu Limited by Share Ltd Nanjing Longjiang branch Pledgor: NANJING REDWOOD BIOTECHNOLOGY CO., LTD. Registration number: 2018320000235 |
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