CN112521311A - Improved lacosamide intermediate preparation method - Google Patents
Improved lacosamide intermediate preparation method Download PDFInfo
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- CN112521311A CN112521311A CN201910884922.6A CN201910884922A CN112521311A CN 112521311 A CN112521311 A CN 112521311A CN 201910884922 A CN201910884922 A CN 201910884922A CN 112521311 A CN112521311 A CN 112521311A
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- Prior art keywords
- benzylamine
- preparation
- tert
- formula
- reaction
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 title abstract description 7
- 229960002623 lacosamide Drugs 0.000 title abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 claims description 5
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 5
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- RFGMSGRWQUMJIR-ZCFIWIBFSA-N (2r)-3-methoxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound COC[C@H](C(O)=O)NC(=O)OC(C)(C)C RFGMSGRWQUMJIR-ZCFIWIBFSA-N 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000012304 carboxyl activating agent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims 1
- 238000007670 refining Methods 0.000 claims 1
- 239000012074 organic phase Substances 0.000 description 14
- 239000005457 ice water Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 3
- CEYAFLQMWYRDFA-LURJTMIESA-N (2S)-3-hydroxy-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyloxy]amino]propanoic acid Chemical compound OC[C@@H](C(O)=O)N(C)OC(=O)OC(C)(C)C CEYAFLQMWYRDFA-LURJTMIESA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 2
- 229930195711 D-Serine Natural products 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- 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
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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 preparation method of an improved lacosamide intermediate, belongs to the field of pharmaceutical chemistry, and mainly relates to a preparation method of 2- (1-butyric acid-4-yl) -amino-substituted butyramide.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and mainly relates to a preparation method of 2- (1-butyric acid-4-yl) -amino-substituted butyramide shown in a formula I.
Background
(R) -2-acetamido-N-benzyl-3-methoxypropionamide (lacosamide) is an anticonvulsant useful in the treatment of epilepsy and pain. Two methods for preparing this compound are disclosed in US6, 048, 899.
Method 2 of US6, 048, 899 comprises the formation of a benzamide followed by O-methylation. However, this method generates various impurities, which can be removed by chromatography, but are industrially difficult to realize. And the single-step yield is only 80-85 percent
Method 1 of US6, 048, 899 comprises O-methylation of N-protected D-serine followed by formation of benzylamide, N-deprotection and N-acetylation. Although this preparation method is a promising starting point for high standards, it has the major disadvantage that O-methylation of N-protected D-serine using silver oxide and methyl iodide is costly, and most importantly, results in racemization of a portion of the product (about 15%), resulting in a reduced yield. Furthermore, there is a lack of efficient removal of the S-enantiomer produced during the preparation of (R) -2-acetamido-N-benzyl-3-methoxypropionamide.
Disclosure of Invention
The invention provides a preparation method of a compound shown as a formula I and a preparation method of Boc- (1- (benzylamine) -3-methoxy-1-oxypropane-2-yl) carbamate, wherein R isxIs a protecting group.
The preparation method comprises the following steps:
(1) in an organic solvent, Boc-O-methyl-D-serine (formula II) and benzylamine (formula III) react to obtain the compound of formula (I).
(2) After the reaction is finished, the product is refined by hydrochloric acid and sodium bicarbonate, and then petroleum ether is used for crystallization.
Wherein, the first step is condensation reaction of carboxylic acid and amino, and the following conditions are preferred:
the organic solvent is recommended to be dichloromethane;
the dosage of the solvent is recommended to be 8-15 ml/g; preferably 10-11 ml/g;
adopting ethyl chloroformate as a carboxyl activating agent;
the acid-binding agent in the reaction process can be organic alkali such as triethylamine, 4-methylmorpholine, 2, 6-di-tert-butylpyridine and the like, and 2-6-tert-butylpyridine is preferred;
when ethyl chloroformate and 2, 6-di-tert-butylpyridine are added dropwise, an ice-water bath condition is recommended;
the reaction temperature is recommended to be 0-10 ℃;
after the benzylamine is dropwise added, the reaction time is 1-3 hours, preferably 2 hours;
the invention has the characteristic of simple operation
The reagent used in the invention is a conventional reagent, and has little pollution to the environment
The invention has mild reaction condition and easy temperature reaching.
The invention can be used for industrial production
The invention can greatly eliminate the S-enantiomer generated in the preparation process of lacosamide
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example 1:
50.0 g N- (tert-butyloxycarbonyl) -O-methylserine and 500 ml dichloromethane were weighed into a three-necked flask, cooled in an ice-water bath and stirred. 27.2 g of ethyl chloroformate and 25 ml of 2, 6-di-tert-butylpyridine were successively added dropwise. After diluting 25.0 g of benzylamine with 50 ml of methylene chloride, it was slowly added dropwise to the system under ice-water bath conditions. Reacting for 1 hour and 40 minutes at the temperature of 0-10 ℃. The reaction was stopped, 500 ml of water was added for liquid separation, and the organic phase was collected. 125 ml of 3N hydrochloric acid was added to the organic phase, followed by liquid separation and collection of the organic phase. To the organic phase, 200 ml of a saturated sodium bicarbonate solution was added, and the organic phase was collected by liquid separation. The organic phase was washed with 500 ml of water and separated. Collecting the organic phase, removing the solvent by rotation, adding 350 ml of petroleum ether, cooling in ice water bath and crystallizing. Filtration gave 55.1 g of solid. The optical purity is 99.98%
Example 2:
100.0 g N- (tert-butyloxycarbonyl) -O-methylserine and 1000 ml dichloromethane were weighed into a three-necked flask, cooled in an ice-water bath, and stirred. 54.4 g of ethyl chloroformate and 50 ml of 2, 6-di-tert-butylpyridine were successively added dropwise. After 50.0 g of benzylamine was diluted with 100 ml of methylene chloride, it was slowly added dropwise to the system under ice-water bath conditions. Reacting for 2 hours and 10 minutes at the temperature of 0-10 ℃. The reaction was stopped, 1000 ml of water was added for liquid separation, and the organic phase was collected. 250 ml of 3N hydrochloric acid was added to the organic phase, and the organic phase was collected by liquid separation. 400 ml of a saturated sodium bicarbonate solution was added to the organic phase, and the organic phase was collected by liquid separation. 1000 ml of water was added to wash the organic phase and the layers were separated. Collecting organic phase, removing solvent, adding 700 ml petroleum ether, cooling in ice water bath, and crystallizing. Filtration gave 112.5 g of solid. The optical purity was 99.97%.
Claims (6)
- A process for the preparation of Boc- (1- (benzylamine) -3-methoxy-1-oxopropan-2-yl) carbamate comprising the steps of:(1) in an organic solvent, reacting Boc-O-methyl-D-serine (formula II) with benzylamine (formula III) to obtain a compound of formula (I);(2) after the reaction is finished, refining the product by hydrochloric acid and sodium bicarbonate, and then crystallizing by petroleum ether;。
- 2. the process according to claim 1, wherein the organic solvent used in step 1 is preferably dichloromethane, and the amount of the solvent is 8 to 15 ml/g; preferably 10-11 ml/g.
- 3. The method according to claim 1, wherein step 1 employs ethyl chloroformate as the carboxyl activating agent.
- 4. The method of claim 1, wherein the acid-binding agent used in step 1 is selected from organic bases such as triethylamine, 4-methylmorpholine, 2, 6-di-tert-butylpyridine, etc., preferably 2-6-tert-butylpyridine.
- 5. The process according to claim 1, wherein the reaction temperature in step 1 is recommended to be-10 to 20 ℃.
- 6. The process according to claim 1, wherein the reaction time after the dropwise addition of benzylamine in step 1 is 1 to 3 hours, preferably 2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910884922.6A CN112521311A (en) | 2019-09-19 | 2019-09-19 | Improved lacosamide intermediate preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910884922.6A CN112521311A (en) | 2019-09-19 | 2019-09-19 | Improved lacosamide intermediate preparation method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112521311A true CN112521311A (en) | 2021-03-19 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910884922.6A Pending CN112521311A (en) | 2019-09-19 | 2019-09-19 | Improved lacosamide intermediate preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112521311A (en) |
-
2019
- 2019-09-19 CN CN201910884922.6A patent/CN112521311A/en active Pending
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| PB01 | Publication | ||
| PB01 | Publication | ||
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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20210319 |