CN108129343A - A kind of preparation method of R-2- acyl aminos -3- methoxy methyl propionates - Google Patents
A kind of preparation method of R-2- acyl aminos -3- methoxy methyl propionates Download PDFInfo
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- CN108129343A CN108129343A CN201711293340.8A CN201711293340A CN108129343A CN 108129343 A CN108129343 A CN 108129343A CN 201711293340 A CN201711293340 A CN 201711293340A CN 108129343 A CN108129343 A CN 108129343A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention discloses the preparation methods of R 2 acyl amino 3 methoxy methyl propionate of the one kind as shown in formula (I), it is characterised in that the preparation method is：The glycine protected using the N acyl groups shown in formula (II) is raw material; first and bis- (trichloromethyl) carbonic esters (III) and N; N bis- replaces formamide (IV) generation cyclization that intermediate (V) is obtained by the reaction; using alkali process, sour open loop; methyl-etherified obtains intermediate (VII), finally restores generation target product (I) by asymmetric hydrogenation.Preparation method raw material of the present invention is simple and easy to get, and at low cost, reaction condition is mild, high income, and post processing is simple, and the three wastes are few, good in economic efficiency, is the environmentally protective technique for being suitable for industrialized production.
Description
(1) technical field
The invention discloses a kind of preparation method of scheme for lacosamide intermediate, particularly a kind of R-2- acyl aminos-
The method of 3- methoxy methyl propionates.
(2) background technology
Scheme for lacosamide (Lacosamide), chemical name R- (-) -2- acetylaminohydroxyphenylarsonic acid 3- methoxyl group-N- benzyl propionamides are
The third generation treatment epilepsy of Belgian UCB Pharma SA exploitation and the drug of neuropathic pain, the medicine in Septembers, 2008 and
In October, 2008 obtains the approval of EU Committee and Food and Drug Adminstration of the US (FDA) respectively.The medical instrument has unique double
Weight binding mode, so as to stablize hyperexcitability neuron membrane and neuron is inhibited to discharge repeatedly, different from used in clinic at present
Other antiepileptics, which can be used for the auxiliary treatment of 16 years old and above epilepsy partial seizures patient, is widely closed
Note.
R-2- acetylaminohydroxyphenylarsonic acid 3- methoxypropionic acids are to synthesize the key intermediate of scheme for lacosamide, and structure is as follows：
From the point of view of the comprehensive synthetic method reported, at present, widely used synthetic route is former by starting of D-Ser
The preparation method of material：
D-Ser is used as raw material, first passes through amino Boc protection reactions, then generation methyl ether is reacted with dimethyl suflfate,
Then the deprotection reaction under trifluoromethanesulfonic acid effect, the progress of last and aceticanhydride is acetylated, obtains R-2- acetylaminohydroxyphenylarsonic acids 3-
Methoxypropionic acid (US20130035508A1, WO2011095995A1).This method D-Ser is expensive, dimethyl suflfate
Toxicity is big, and trifluoromethanesulfonic acid has strong corrosive, is not suitable for industrialization production.
Alternatively, D-Ser first carries out N- acylation reactions with chloroacetic chloride, then generation methyl ether is reacted with dimethyl suflfate, obtained
Target product (CN201510289014.4).Although the process step is simple, high income, the dosage of dimethyl suflfate is D-
4 times of equivalents of N- acetyl serines, while use expensive TBAB phase transfer catalysts.
The invention discloses a kind of new process route, this method is used to prepare scheme for lacosamide intermediate R-2- acyl group ammonia
Base -3- methoxy methyl propionates, reaction yield compared with it is high, at low cost, the three wastes are few, avoid using poisonous and harmful material and reagent, be
One green industrialization route.
(3) invention content
The present invention provides a kind of simple for process for insufficient existing for more than technology, and production safety is reliable and stable, and reaction is received
Rate is high, the technique that greenization at low cost prepares R-2- acyl amino -3- methoxy methyl propionates.
In order to solve the above technical problems, the technical solution adopted by the present invention is as follows：
A kind of preparation method of R-2- acyl amino -3- methoxy methyl propionates as shown in formula (I), feature
It is to comprise the following steps that：
Wherein, R1For the alkyl of C1~C4, phenyl or substituted phenyl, tert-butoxy or benzyloxy.
Step (1)：The glycine protected using the N- acyl groups shown in formula (II) is dissolved in N as raw material, and N- bis- replaces formamide
(IV) in, controlling reaction temperature is added dropwise the organic solvent A containing bis- (trichloromethyl) carbonic esters (III), drips at 0~5 DEG C
Bi Hou increases temperature, and reaction 6~24 hours is carried out at 20~80 DEG C, generates the intermediate shown in formula (V)；
Wherein, R1It is defined as above；R2And R3It may respectively be the alkyl of C1~C4, the cycloalkyl of C3~C6, benzyl or substituted
Benzyl or aromatic rings are selected from N, O and S containing 1~2 heterocycle selected from heteroatomic 3~6 yuan of N, O and S or containing 0~3
Heteroatomic 5~15 membered aromatic heterocycle or R1=R2To be selected from the heterocycle of heteroatomic 3~6 yuan of N, O and S containing 1~2,
Aromatic rings therein arbitrarily can arbitrarily be replaced by following 0~3 substituent group：Alkyl, alkoxy, halogen, the fluoroform of C1~C4
Base, nitro, hydroxyl, itrile group.
Step (2)：Intermediate shown in formula (V) is stirred at room temperature overnight instead in organic solvent B with alkali A aqueous solutions
Should, obtain the intermediate shown in formula (VI).
Wherein, R1It is defined as above；M is Na or K.
Step (3)：Intermediate shown in formula (VI), the first hydrogen chloride methanol solution with 5%~30% at -10~10 DEG C
Reaction is hydrolyzed, then in organic solvent C, under the catalysis of alkali B, reacts, obtain at 20~120 DEG C with methylating reagent A
Intermediate VII.
Wherein, R1It is defined as above.
Step (4)：Intermediate shown in formula (VII) is in organic solvent D, and under the catalysis of chiral catalyst A, it is not right to carry out
Claim hydro-reduction, obtain the target product R-2- acyl amino -3- methoxy methyl propionates shown in formula (I).
A kind of preparation method of R-2- acyl amino -3- methoxy methyl propionates as shown in formula (I), feature
It is in step (1), the organic solvent A is n-hexane, hexamethylene, dichloromethane, chloroform, dichloroethanes.It is described
The volumetric usage of organic solvent A 2~10mL/g is calculated as with the quality of (trichloromethyl) carbonic esters bis- shown in substrate formula (III)；
The glycine (II) of the raw material N- acyl groups protection：Bis- (trichloromethyl) carbonic esters (III)：N, N- bis- replaces formamide (IV)
The substance that feeds intake amount ratio be 1.0：0.32~1.0：1.0~4.0.
A kind of preparation method of R-2- acyl amino -3- methoxy methyl propionates as shown in formula (I), feature
It is in step (2), the organic solvent B is methanol, ethyl alcohol, acetonitrile, tetrahydrofuran；The volume of the organic solvent B
Dosage is calculated as 3~10mL/g with substrate formula (V) quality；The alkali A aqueous solutions are 2N sodium hydrate aqueous solutions, 2N potassium hydroxide
Aqueous solution；The dosage of the alkali A aqueous solutions is calculated as 1~5 times of the amount of the substance of substrate formula (V) with the amount of the substance of alkali A.
A kind of preparation method of R-2- acyl amino -3- methoxy methyl propionates as shown in formula (I), feature
It is in step (3), the organic solvent C is ketones solvent, preferably acetone, butanone, cyclohexanone；The alkali B is carbon
Sour potassium, sodium carbonate；The methylating reagent A is dimethyl suflfate, dimethyl carbonate；5%~30% hydrogen chloride
The dosage of methanol solution is calculated as 1~5 times of the amount of the substance of substrate formula (VI) with the amount of the substance of hydrogen chloride；Described is organic molten
The volumetric usage of agent C is calculated as 5~15mL/g with substrate formula (VI) quality；The raw material formula (VI)：Alkali B：Methylating reagent A's
Feed intake substance amount ratio be 1.0：1.0~5.0：0.5~5.0.
A kind of preparation method of R-2- acyl amino -3- methoxy methyl propionates as shown in formula (I), feature
It is in step (4), the organic solvent D is alcohols, ethers, chloralkane；The volumetric usage of the organic solvent D with
The quality of substrate formula (VI) is calculated as 15~30mL/g；The chiral catalyst A is transition metal-chiral ferrocene ligands complexing
Object catalyst；The amount ratio of the chiral catalyst A and the substance that feeds intake of substrate formula (VI) is 1.0：8,000~100,000；Institute
The reaction temperature stated is 30~100 DEG C；Hydrogen Vapor Pressure is 0.5~5.0MPa in the reaction system.
A kind of preparation method of R-2- acyl amino -3- methoxy methyl propionates as shown in formula (I), feature
It is in step (4), the organic solvent D is preferably methanol, ethyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, two chloroethenes
Alkane.
A kind of preparation method of R-2- acyl amino -3- methoxy methyl propionates as shown in formula (I), feature
It is in step (4), the chiral catalyst A is preferably [Rh ((R)-Josiphos) (cod)2]BF4、[Rh((R)-
XyliPhos)(cod)2]BF4。
A kind of preparation method of R-2- acyl amino -3- methoxy methyl propionates as shown in formula (I), feature
It is in step (4), the amount ratio preferably 1.0 of the chiral catalyst A and the substance that feeds intake of substrate formula (VI)：10,000~
50,000。
A kind of preparation method of R-2- acyl amino -3- methoxy methyl propionates as shown in formula (I), feature
It is in step (4), Hydrogen Vapor Pressure is preferably 1.0~3.0MPa in the reaction system.
A kind of preparation method of R-2- acyl amino -3- methoxy methyl propionates as shown in formula (I), feature
It is to specifically include following processing step：
Step (1)：According to the amount of substance than glycine (II) that N- acyl group is protected：Bis- (trichloromethyl) carbonic esters (III)：
N, N- bis- replaces formamide (IV) to be 1.0：0.32~1.0：1.0~4.0 feed intake；In dry reaction bulb, by formula (II) institute
The glycine of N- acyl groups protection shown, is dissolved in N, and N- bis- replaces in formamide (IV), and at 0~5 DEG C, dropwise addition contains controlling reaction temperature
There is the organic solvent A of bis- (trichloromethyl) carbonic esters (III), after being added dropwise, raising temperature carries out reaction 6 at 20~80 DEG C
~24 hours, after reaction, reaction solution is added in mixture of ice and water, adjust pH to 8 with ammonium hydroxide, layering takes organic phase, subtracts
Pressure be evaporated white solid is the intermediate shown in formula (V)；
Step (2)：In dry reaction bulb, the intermediate shown in formula (V) is dissolved in organic solvent B, adds in alkali A
Aqueous solution is stirred at room temperature overnight, and after reaction, evaporated under reduced pressure adds acetone recrystallization, in obtaining shown in formula (VI)
Mesosome sterling.
Step (3)：According to the amount of substance than formula (VI)：Alkali B：Methylating reagent A is 1.0：1.0~5.0：0.5~5.0 throws
Material；In the reaction bulb of dried and clean, by the intermediate shown in formula (VI), 5%~30% chlorination is added at -10~10 DEG C
Hydrogen methanol solution stirs 8 hours, reaction is hydrolyzed；After reaction, evaporated under reduced pressure methanol；Add organic solvent C stirrings
30 minutes, filter to obtain yellow liquid；Alkali B and methylating reagent A is added in, controlling reaction temperature is stirred to react 24 at 20~120 DEG C
~48 hours, evaporated under reduced pressure solvent added re crystallization from toluene, obtained yellow-brown solid as intermediate VII.
Step (4)：According to the amount of substance than chiral catalyst A：Substrate formula (VI) is 1.0：10,000~50,000 feed intake；
In the hydriding reactor of dried and clean, intermediate and organic solvent D shown in formula (VII) are added in, leads to nitrogen protection；Then, it is throwing
Material mouth puts into chiral catalyst A, leads to hydrogen to 1.0~3.0Mpa, controls the temperature of reaction system at 30~100 DEG C；HPLC with
The reaction was complete to raw material point for track, feeding, is concentrated under reduced pressure to give the target product R-2- acyl amino -3- methoxyl groups shown in formula (I)
Methyl propionate.
Compared with prior art, the present invention advantage is embodied in：The raw materials technology is simple and easy to get, at low cost, reaction
Mild condition, high income, post processing is simple, and the three wastes are few, good in economic efficiency, is one and is suitable for the environmentally protective of industrialized production
Technique.In addition, the technique carries out asymmetric hydrogenation using novel transition metal-chiral ferrocene ligands catalyst, obtain
Obtain the chiral product of more than 99% ee values.
(4) specific embodiment：
Technical scheme of the present invention is illustrated with specific embodiment below, but the scope of the present invention is not limited thereto：
Embodiment 1
(1) according to the amount of substance than N- acetoglycocoll：Bis- (trichloromethyl) carbonic esters：N,N-dimethylformamide is
1.0：0.32：1.0 it feeds intake；In the reaction bulb of 1L dryings, N- acetoglycocoll 35.1g, n,N-Dimethylformamide are added in
21.9g, controlling reaction temperature is at 0~5 DEG C；Will be bis- (trichloromethyl) carbonic ester 28.5g be dissolved in the n-hexane of 285mL, be added dropwise
Enter reaction bulb；After being added dropwise, raising temperature carries out reaction 12 hours at 60 DEG C, after reaction, reaction solution is added in ice
In aqueous mixtures, pH to 8 is adjusted with ammonium hydroxide, layering takes organic phase, evaporated under reduced pressure obtains white solid (E) -4- ((dimethylaminos
Base) methylene) -2- methyl oxazole -5 (4H) -one 27.9g, yield 60%；
Step (2)：In the reaction bulb of 1L dryings, intermediate (E) -4- ((dimethylaminos of gained in step (1) are added in
Base) methylene) -5 (4H) -one 23.1g and methanol 70mL of -2- methyl oxazole, the NaOH aqueous solutions 75mL of 2N is added at room temperature；It stirs
It mixes overnight, after reaction, evaporated under reduced pressure adds acetone recrystallization, obtains (E)-(2- methyl -5- oxos oxazoles -4 (5H)-Asia
Methyl) sodium methoxide 19.3g, yield 86.3%.
Step (3)：According to amount ratio (E)-(- 4 (5H)-methylene of 2- methyl -5- oxos oxazole) sodium methoxide of substance：Carbonic acid
Potassium：Dimethyl carbonate is 1.0：1.0：5.0 it feeds intake；In the reaction bulb of 1L dried and cleans, (E)-(2- methyl -5- oxos are added in
Oxazole -4 (5H)-methylene) sodium methoxide 17.9g, the hydrogen chloride methanol solution 90g of addition 5% at -10~10 DEG C, control is instead
Temperature is answered to stir 8 hours, after reaction, evaporated under reduced pressure methanol；Cyclohexanone 270mL is added in, stirs 30 minutes, filters to obtain yellow
Liquid；Potassium carbonate 16.6g, dimethyl carbonate 54.0g are added, is heated to 120 DEG C, is stirred to react 36 hours, decompression is steamed
Dry solvent, adds re crystallization from toluene, obtains yellow-brown solid (Z) -2- acetylaminohydroxyphenylarsonic acid 3- methoxy-methyl acrylate 15.0g,
Yield 72.2%.
Step (4)：According to the amount ratio [Rh ((R)-Josiphos) (cod) of substance2]BF4：(Z) -2- (acetylamino) -3-
Methoxy-methyl acrylate is 1.0：50,000 feed intake；In the hydriding reactor of 1L dried and cleans, addition (Z) -2- (acetylamino) -
3- methoxy-methyl acrylates 13.9g, methanol 200mL, lead to nitrogen displacement oxygen 3 times.After the completion of displacement, continue logical nitrogen and protect
Shield.Then, in feeding port input 1.7mg chiral catalysts [Rh ((R)-Josiphos) (cod)2]BF4, feeding port is covered tightly rapidly.
Logical hydrogen replaces nitrogen 3 times.After the completion, continue logical hydrogen to 3.0Mpa, control the temperature of reaction system at 30 DEG C.HPLC is tracked
To raw material point to the reaction was complete.Venting hydrogen is replaced 3 times with nitrogen, then, material is pressed out in flask with nitrogen, is depressurized
It is concentrated to give target product R-2- acetylaminohydroxyphenylarsonic acid 3- methoxy methyl propionate 11.7g, yield 83.5%, ee values 89.5%.
Embodiment 2
(1) according to the amount of substance than N- acetoglycocoll：Bis- (trichloromethyl) carbonic esters：N,N-dimethylformamide is
1.0：0.5：1.5 it feeds intake；In the reaction bulb of 1L dryings, N- acetoglycocoll 35.1g, n,N-Dimethylformamide are added in
32.9g, controlling reaction temperature is at 0~5 DEG C；Will be bis- (trichloromethyl) carbonic ester 44.5g be dissolved in the hexamethylene of 350mL, be added dropwise
Enter reaction bulb；After being added dropwise, raising temperature carries out reaction 24 hours at 20 DEG C, after reaction, reaction solution is added in ice
In aqueous mixtures, pH to 8 is adjusted with ammonium hydroxide, layering takes organic phase, evaporated under reduced pressure obtains white solid (E) -4- ((dimethylaminos
Base) methylene) -2- methyl oxazole -5 (4H) -one 24.6g, yield 53%；
Step (2)：In the reaction bulb of 1L dryings, intermediate (E) -4- ((dimethylaminos of gained in step (1) are added in
Base) methylene) -5 (4H) -one 23.1g and ethyl alcohol 140mL of -2- methyl oxazole, the NaOH aqueous solutions 225mL of 2N is added at room temperature；
Be stirred overnight, after reaction, evaporated under reduced pressure adds acetone recrystallization, obtain (E)-(2- methyl -5- oxos oxazoles -4 (5H) -
Methylene) sodium methoxide 20.9g, yield 93.5%.
Step (3)：According to amount ratio (E)-(- 4 (5H)-methylene of 2- methyl -5- oxos oxazole) sodium methoxide of substance：Carbonic acid
Potassium：Dimethyl carbonate is 1.0：3.0：3.0 it feeds intake；In the reaction bulb of 1L dried and cleans, (E)-(2- methyl -5- oxos are added in
Oxazole -4 (5H)-methylene) sodium methoxide 17.9g, the hydrogen chloride methanol solution 73g of addition 12% at -10~10 DEG C, control is instead
Temperature is answered to stir 8 hours, after reaction, evaporated under reduced pressure methanol；Butanone 140mL is added in, stirs 30 minutes, filters to obtain yellow liquid
Body；Potassium carbonate 49.8g, dimethyl carbonate 32.4g are added, is heated to 80 DEG C, is stirred to react 48 hours, evaporated under reduced pressure is molten
Agent adds re crystallization from toluene, obtains yellow-brown solid (Z) -2- acetylaminohydroxyphenylarsonic acid 3- methoxy-methyl acrylate 18.7g, yield
90.0%.
Step (4)：According to the amount ratio [Rh ((R)-Josiphos) (cod) of substance2]BF4：(Z) -2- acetylaminohydroxyphenylarsonic acids 3- first
Oxygroup methyl acrylate is 1.0：30,000 feed intake；In the hydriding reactor of 1L dried and cleans, (Z) -2- (acetylamino) -3- is added in
Methoxy-methyl acrylate 13.9g, ethyl alcohol 350mL, lead to nitrogen displacement oxygen 3 times.After the completion of displacement, continue logical nitrogen protection.
Then, in feeding port input 2.8mg chiral catalysts [Rh ((R)-Josiphos) (cod)2]BF4, feeding port is covered tightly rapidly.It is logical
Hydrogen displacement nitrogen 3 times.After the completion, continue logical hydrogen to 2.0Mpa, control the temperature of reaction system at 60 DEG C.HPLC is tracked to
Raw material point is to the reaction was complete.Venting hydrogen is replaced 3 times with nitrogen, then, material is pressed out in flask with nitrogen, and decompression is dense
Contracting obtains target product R-2- acetylaminohydroxyphenylarsonic acid 3- methoxy methyl propionate 12.1g, yield 86.3%, ee values 89.7%.
Embodiment 3
(1) according to the amount of substance than N- acetoglycocoll：Bis- (trichloromethyl) carbonic ester N, N- diethylformamides are
1.0：0.7：3.0 it feeds intake；In the reaction bulb of 1L dryings, N- acetoglycocolls 35.1g, N, N- diethylformamide is added in
91.0g, controlling reaction temperature is at 0~5 DEG C；Will be bis- (trichloromethyl) carbonic ester 62.3g be dissolved in the dichloromethane of 300mL, drip
Add in reaction bulb；After being added dropwise, raising temperature carries out reaction 16 hours at 40 DEG C, and after reaction, reaction solution is added in
In mixture of ice and water, pH to 8 is adjusted with ammonium hydroxide, layering takes organic phase, evaporated under reduced pressure obtains white solid (E) -4- ((diethyl aminos
Base) methylene) -2- methyl oxazole -5 (4H) -one 44.6g, yield 82%；
Step (2)：In the reaction bulb of 1L dryings, intermediate (E) -4- ((diethyl aminos of gained in step (1) are added in
Base) methylene) -5 (4H) -one 27.3g and acetonitrile 270mL of -2- methyl oxazole, the KOH aqueous solutions 225mL of 2N is added at room temperature；
Be stirred overnight, after reaction, evaporated under reduced pressure adds acetone recrystallization, obtain (E)-(2- methyl -5- oxos oxazoles -4 (5H) -
Methylene) potassium methoxide 23.3g, yield 94.0%.
Step (3)：According to amount ratio (E)-(- 4 (5H)-methylene of 2- methyl -5- oxos oxazole) potassium methoxide of substance：Carbonic acid
Sodium：Dimethyl suflfate is 1.0：3.0：1.0 it feeds intake；In the reaction bulb of 1L dried and cleans, (E)-(2- methyl -5- oxos are added in
Oxazole -4 (5H)-methylene) potassium methoxide 19.8g, the hydrogen chloride methanol solution 66g of addition 20% at -10~10 DEG C, control is instead
Temperature is answered to stir 8 hours, after reaction, evaporated under reduced pressure methanol；Acetone 100mL is added in, stirs 30 minutes, filters to obtain yellow liquid
Body；Sodium carbonate 38.1g, dimethyl suflfate 15.1g are added, is heated to 60 DEG C, is stirred to react 24 hours, evaporated under reduced pressure is molten
Agent adds re crystallization from toluene, obtains yellow-brown solid (Z) -2- acetylaminohydroxyphenylarsonic acid 3- methoxy-methyl acrylate 18.5g, yield
89.0%.
Step (4)：According to the amount ratio [Rh ((R)-XyliPhos) (cod) of substance2]BF4：(Z) -2- acetylaminohydroxyphenylarsonic acids 3- first
Oxygroup methyl acrylate is 1.0：30,000 feed intake；In the hydriding reactor of 1L dried and cleans, (Z) -2- acetylaminohydroxyphenylarsonic acid 3- first is added in
Oxygroup methyl acrylate 13.9g, isopropanol 350mL, lead to nitrogen displacement oxygen 3 times.After the completion of displacement, continue logical nitrogen protection.
Then, in feeding port input 2.8mg chiral catalysts [Rh ((R)-XyliPhos) (cod)2]BF4, feeding port is covered tightly rapidly.It is logical
Hydrogen displacement nitrogen 3 times.After the completion, continue logical hydrogen to 2.0Mpa, control the temperature of reaction system at 60 DEG C.HPLC is tracked to
Raw material point is to the reaction was complete.Venting hydrogen is replaced 3 times with nitrogen, then, material is pressed out in flask with nitrogen, and decompression is dense
Contracting obtains target product R-2- acetylaminohydroxyphenylarsonic acid 3- methoxy methyl propionate 12.9g, yield 92.0%, ee values 99.3%.
Embodiment 4
(1) according to the amount of substance than N- acetoglycocoll：Bis- (trichloromethyl) carbonic esters：N, N- diethylformamide is
1.0：1.0：4.0 it feeds intake；In the reaction bulb of 1L dryings, N- acetoglycocolls 35.1g, N, N- diethylformamide is added in
121.4g, controlling reaction temperature is at 0~5 DEG C；Will be bis- (trichloromethyl) carbonic ester 89.0g be dissolved in the dichloroethanes of 180mL, drip
Add in reaction bulb；After being added dropwise, raising temperature carries out reaction 6 hours at 80 DEG C, after reaction, reaction solution is added in ice
In aqueous mixtures, pH to 8 is adjusted with ammonium hydroxide, layering takes organic phase, evaporated under reduced pressure obtains white solid (E) -4- ((diethyl aminos
Base) methylene) -2- methyl oxazole -5 (4H) -one 29.7g, yield 54%；
Step (2)：In the reaction bulb of 1L dryings, intermediate (E) -4- ((diethyl aminos of gained in step (1) are added in
Base) methylene) -5 (4H) -one 27.3g and tetrahydrofuran 220mL of -2- methyl oxazole, the KOH aqueous solutions of 2N are added at room temperature
375mL；Be stirred overnight, after reaction, evaporated under reduced pressure adds acetone recrystallization, obtain (E)-(2- methyl -5- oxos oxazole -
4 (5H)-methylene) potassium methoxide 22.6g, yield 91.2%.
Step (3)：According to amount ratio (E)-(- 4 (5H)-methylene of 2- methyl -5- oxos oxazole) potassium methoxide of substance：Carbonic acid
Sodium：Dimethyl suflfate is 1.0：5.0：0.5 feeds intake；In the reaction bulb of 1L dried and cleans, (E)-(2- methyl -5- oxos are added in
Oxazole -4 (5H)-methylene) potassium methoxide 19.8g, the hydrogen chloride methanol solution 73g of addition 30% at -10~10 DEG C, control is instead
Temperature is answered to stir 8 hours, after reaction, evaporated under reduced pressure methanol；Butanone 160mL is added in, stirs 30 minutes, filters to obtain yellow liquid
Body；Sodium carbonate 63.6g, dimethyl suflfate 7.6g are added, is heated to 20 DEG C, is stirred to react 36 hours, evaporated under reduced pressure is molten
Agent adds re crystallization from toluene, obtains yellow-brown solid (Z) -2- acetylaminohydroxyphenylarsonic acid 3- methoxy-methyl acrylate 15.9g, yield
76.5%.
Step (4)：According to the amount ratio [Rh ((R)-XyliPhos) (cod) of substance2]BF4：(Z) -2- acetylaminohydroxyphenylarsonic acids 3- first
Oxygroup methyl acrylate is 1.0：10,000 feed intake；In the hydriding reactor of 1L dried and cleans, (Z) -2- acetylaminohydroxyphenylarsonic acid 3- first is added in
Oxygroup methyl acrylate 13.9g, dichloroethanes 400mL, lead to nitrogen displacement oxygen 3 times.After the completion of displacement, continue logical nitrogen and protect
Shield.Then, in feeding port input 8.4mg chiral catalysts [Rh ((R)-XyliPhos) (cod)2]BF4, feeding port is covered tightly rapidly.
Logical hydrogen replaces nitrogen 3 times.After the completion, continue logical hydrogen to 1.0Mpa, control the temperature of reaction system at 100 DEG C.HPLC with
Track is to raw material point to the reaction was complete.Venting hydrogen is replaced 3 times with nitrogen, then, material is pressed out in flask with nitrogen, is subtracted
Pressure is concentrated to give target product R-2- acetylaminohydroxyphenylarsonic acid 3- methoxy methyl propionate 12.5g, yield 89.2%, ee values 99.1%.
Embodiment 5
(1) compare HIPPURIC ACID according to the amount of substance：Bis- (trichloromethyl) carbonic esters：N,N-dimethylformamide is
1.0：0.7：3.0 it feeds intake；In the reaction bulb of 1L dryings, HIPPURIC ACID 53.8g, n,N-Dimethylformamide are added in
65.8g, controlling reaction temperature is at 0~5 DEG C；Will be bis- (trichloromethyl) carbonic ester 62.3g be dissolved in the dichloromethane of 300mL, drip
Add in reaction bulb；After being added dropwise, raising temperature carries out reaction 16 hours at 40 DEG C, and after reaction, reaction solution is added in
In mixture of ice and water, pH to 8 is adjusted with ammonium hydroxide, layering takes organic phase, evaporated under reduced pressure obtains white solid (E) -4- ((dimethylaminos
Base) methylene) -2- oxazolyl phenyls -5 (4H) -one 49.5g, yield 76%；
Step (2)：In the reaction bulb of 1L dryings, intermediate (E) -4- ((dimethylaminos of gained in step (1) are added in
Base) methylene) -2- oxazolyl phenyls -5 (4H) -one 32.4g and ethyl alcohol 190mL, at room temperature add in 2N NaOH aqueous solutions 225mL；
Be stirred overnight, after reaction, evaporated under reduced pressure adds acetone recrystallization, obtain (E)-(2- phenyl -5- oxos oxazoles -4 (5H) -
Methylene) sodium methoxide 29.3g, yield 92.5%.
Step (3)：According to amount ratio (E)-(- 4 (5H)-methylene of 2- phenyl -5- oxos oxazole) sodium methoxide of substance：Carbonic acid
Potassium：Dimethyl suflfate is 1.0：3.0：1.5 it feeds intake；In the reaction bulb of 1L dried and cleans, (E)-(2- phenyl -5- oxos are added in
Oxazole -4 (5H)-methylene) sodium methoxide 25.3g, the hydrogen chloride methanol solution 66g of addition 20% at -10~10 DEG C, control is instead
Temperature is answered to stir 8 hours, after reaction, evaporated under reduced pressure methanol；Acetone 130mL is added in, stirs 30 minutes, filters to obtain yellow liquid
Body；Potassium carbonate 49.8g, dimethyl suflfate 22.7g are added, is heated to 60 DEG C, is stirred to react 36 hours, evaporated under reduced pressure is molten
Agent adds re crystallization from toluene, obtains yellow-brown solid (Z) -2- benzamido -3- methoxy-methyl acrylate 24.4g, receives
Rate 86.4%.
Step (4)：According to the amount ratio [Rh ((R)-Josiphos) (cod) of substance2]BF4：(Z) -2- benzamidos -3-
Methoxy-methyl acrylate is 1.0：30,000 feed intake；In the hydriding reactor of 1L dried and cleans, addition (Z) -2- benzamidos -
3- methoxy-methyl acrylates 18.8g, dichloromethane 470mL, lead to nitrogen displacement oxygen 3 times.After the completion of displacement, continue logical nitrogen
Protection.Then, in feeding port input 2.8mg chiral catalysts [Rh ((R)-Josiphos) (cod)2]BF4, cover tightly feed intake rapidly
Mouthful.Logical hydrogen replaces nitrogen 3 times.After the completion, continue logical hydrogen to 2.0Mpa, control the temperature of reaction system at 60 DEG C.HPLC
Raw material point is tracked to the reaction was complete.Venting hydrogen is replaced 3 times with nitrogen, then, material is pressed out in flask with nitrogen,
It is concentrated under reduced pressure to give target product R-2- benzamido -3- methoxy methyl propionates 16.8, yield 88.5%, ee values
99.0%.
Embodiment 6
(1) according to the amount of substance than N- t-butoxycarbonyl glycine：Bis- (trichloromethyl) carbonic esters：N, N- dimethyl formyl
Amine is 1.0：0.7：3.0 it feeds intake；In the reaction bulb of 1L dryings, N- t-butoxycarbonyl glycines 52.6g, N, N- dimethyl is added in
Formamide 65.8g, controlling reaction temperature is at 0~5 DEG C；Will be bis- (trichloromethyl) carbonic ester 62.3g be dissolved in the dichloromethane of 300mL
In, it is added dropwise to reaction bulb；After being added dropwise, raising temperature carries out reaction 16 hours at 40 DEG C, after reaction, by reaction solution
It adds in mixture of ice and water, adjusts pH to 8 with ammonium hydroxide, layering takes organic phase, evaporated under reduced pressure obtains white solid (E) -4- ((diformazans
Base amino) methylene) -2- tert-butoxies oxazole -5 (4H) -one 45g, yield 71%；
Step (2)：In the reaction bulb of 1L dryings, intermediate (E) -4- ((dimethylaminos of gained in step (1) are added in
Base) methylene) -5 (4H) -one 31.8g and acetonitrile 190mL of -2- tert-butoxies oxazole, the NaOH aqueous solutions of 2N are added at room temperature
225mL；It is stirred overnight, after reaction, evaporated under reduced pressure adds acetone recrystallization, obtains (E)-(2- tert-butoxy -5- oxos
Oxazole -4 (5H)-methylene) sodium methoxide 28.1g, yield 90.4%.
Step (3)：According to amount ratio (E)-(- 4 (5H)-methylene of 2- tert-butoxy -5- oxos oxazole) sodium methoxide of substance：
Potassium carbonate：Dimethyl carbonate is 1.0：1.0：5.0 it feeds intake；In the reaction bulb of 1L dried and cleans, (E)-(tertiary fourth oxygen of 2- is added in
- 4 (5H)-methylene of base -5- oxos oxazole) sodium methoxide 24.9g, the hydrogen chloride methanol solution of addition 20% at -10~10 DEG C
66g, controlling reaction temperature stir 8 hours, after reaction, evaporated under reduced pressure methanol；Cyclohexanone 370mL is added in, is stirred 30 minutes,
Filter to obtain yellow liquid；Potassium carbonate 49.8g, dimethyl carbonate 21.6g are added, 100 DEG C is heated to, it is small to be stirred to react 36
When, evaporated under reduced pressure solvent adds re crystallization from toluene, obtains yellow-brown solid (Z) -2- t-butoxycarbonyl amino -3- methoxyl groups
Methyl acrylate 21.9g, yield 78.9%.
Step (4)：According to the amount ratio [Rh ((R)-Josiphos) (cod) of substance2]BF4：(Z) -2- tertbutyloxycarbonyls ammonia
Base -3- methoxy-methyl acrylates are 1.0：30,000 feed intake；In the hydriding reactor of 1L dried and cleans, the tertiary fourth oxygen of (Z) -2- is added in
Carbonylamino -3- methoxy-methyl acrylates 18.5g, tetrahydrofuran 200mL, lead to nitrogen displacement oxygen 3 times.After the completion of displacement,
Continue logical nitrogen protection.Then, in feeding port input 2.8mg chiral catalysts [Rh ((R)-Josiphos) (cod)2]BF4, it is fast
Speed covers tightly feeding port.Logical hydrogen replaces nitrogen 3 times.After the completion, continue logical hydrogen to 2.0Mpa, the temperature of reaction system is controlled to exist
60℃.HPLC tracks to raw material point to the reaction was complete.Venting hydrogen is replaced 3 times with nitrogen, then, is extruded material with nitrogen
Into flask, it is concentrated under reduced pressure to give target product R-2- t-butoxycarbonyl amino -3- methoxy methyl propionate 16.8g, yield
87.3%, ee value 89.3%.
Claims (10)
1. a kind of preparation method of R-2- acyl amino -3- methoxy methyl propionates as shown in formula (I), it is characterised in that including
Following processing step：
Wherein, R1For the alkyl of C1~C4, phenyl or substituted phenyl, tert-butoxy or benzyloxy；
Step (1)：The glycine protected using the N- acyl groups shown in formula (II) is dissolved in N as raw material, and N- bis- replaces formamide (IV)
In, controlling reaction temperature is added dropwise the organic solvent A containing bis- (trichloromethyl) carbonic esters (III), is added dropwise at 0~5 DEG C
Afterwards, temperature is increased, reaction 6~24 hours is carried out at 20~80 DEG C, generates the intermediate shown in formula (V)；
Wherein, R1It is defined as above；R2And R3It may respectively be the alkyl of C1~C4, the cycloalkyl of C3~C6, benzyl or substituted benzyl
Or aromatic rings, containing 1~2 selected from heteroatomic 3~6 yuan of N, O and S heterocycle or containing 0~3 be selected from the miscellaneous original of N, O and S
5~15 membered aromatic heterocycles or R of son1=R2To be selected from the heterocycle of heteroatomic 3~6 yuan of N, O and S containing 1~2, wherein
Aromatic rings arbitrarily can arbitrarily be replaced by following 0~3 substituent group：Alkyl, alkoxy, halogen, trifluoromethyl, the nitre of C1~C4
Base, hydroxyl, itrile group；
Step (2)：Intermediate shown in formula (V) is stirred at room temperature overnight with alkali A aqueous solutions and reacts, obtain in organic solvent B
To the intermediate shown in formula (VI)；
Wherein, R1It is defined as above；M is Na or K；
Step (3)：Intermediate shown in formula (VI), the hydrogen chloride methanol solution first with 5%~30% at -10~10 DEG C carry out
Hydrolysis, then in organic solvent C, under the catalysis of alkali B, reacted at 20~120 DEG C with methylating reagent A, obtain centre
Body VII；
Wherein, R1It is defined as above
Step (4)：Intermediate shown in formula (VII) is in organic solvent D, under the catalysis of chiral catalyst A, carries out asymmetric hydrogen
Change reduction, obtain the target product R-2- acyl amino -3- methoxy methyl propionates shown in formula (I).
2. the preparation method of R-2- acyl aminos -3- methoxy methyl propionates as described in claim 1, it is characterised in that step
(1) in, the organic solvent A is n-hexane, hexamethylene, dichloromethane, chloroform, dichloroethanes, and described is organic molten
The volumetric usage of agent A is calculated as 2~10mL/g with the quality of (trichloromethyl) carbonic esters bis- shown in substrate formula (III)；The original
Expect the glycine (II) of N- acyl groups protection：Bis- (trichloromethyl) carbonic esters (III)：N, N- bis- replaces the object that feeds intake of formamide (IV)
The amount ratio of matter is 1.0：0.32~1.0：1.0~4.0.
3. the preparation method of R-2- acyl aminos -3- methoxy methyl propionates as described in claim 1, it is characterised in that step
(2) in, the organic solvent B is methanol, ethyl alcohol, acetonitrile, tetrahydrofuran；The volumetric usage of the organic solvent B is the bottom of with
Object formula (V) quality is calculated as 3~10mL/g；The alkali A aqueous solutions are 2N sodium hydrate aqueous solutions, 2N potassium hydroxide aqueous solutions；
The dosage of the alkali A aqueous solutions is calculated as 1~5 times of the amount of the substance of substrate formula (V) with the amount of the substance of alkali A.
4. the preparation method of R-2- acyl aminos -3- methoxy methyl propionates as described in claim 1, it is characterised in that step
(3) in, the organic solvent C is ketones solvent, preferably acetone, butanone, cyclohexanone；The alkali B is potassium carbonate, carbonic acid
Sodium；The methylating reagent A is dimethyl suflfate, dimethyl carbonate；5%~30% hydrogen chloride methanol solution
Dosage is calculated as 1~5 times of the amount of the substance of substrate formula (VI) with the amount of the substance of hydrogen chloride；The volume of the organic solvent C
Dosage is calculated as 5~15mL/g with substrate formula (VI) quality；The raw material formula (VI)：Alkali B：The substance that feeds intake of methylating reagent A
Amount ratio be 1.0：1.0~5.0：0.5~5.0.
5. the preparation method of R-2- acyl aminos -3- methoxy methyl propionates as described in claim 1, it is characterised in that step
(4) in, the organic solvent D is alcohols, ethers, chloralkane；The volumetric usage of the organic solvent D is with substrate formula
(VI) quality is calculated as 15~30mL/g；The chiral catalyst A is transition metal-chiral ferrocene ligands complex catalysis
Agent；The amount ratio of the chiral catalyst A and the substance that feeds intake of substrate formula (VI) is 1.0：8,000~100,000；Described is anti-
It is 30~100 DEG C to answer temperature；Hydrogen Vapor Pressure is 0.5~5.0MPa in the reaction system.
6. the preparation method of the R-2- acyl amino -3- methoxy methyl propionates as described in claim 1 or 5, it is characterised in that
In step (4), the organic solvent D is methanol, ethyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, dichloroethanes.
7. the preparation method of the R-2- acyl amino -3- methoxy methyl propionates as described in claim 1 or 5, it is characterised in that
In step (4), the chiral catalyst A is [Rh ((R)-Josiphos) (cod)2]BF4、[Rh((R)-XyliPhos)
(cod)2]BF4。
8. the preparation method of the R-2- acyl amino -3- methoxy methyl propionates as described in claim 1 or 5, it is characterised in that
In step (4), the amount ratio of the chiral catalyst A and the substance that feeds intake of substrate formula (VI) is 1.0：10,000~50,000.
9. the preparation method of the R-2- acyl amino -3- methoxy methyl propionates as described in claim 1 or 5, it is characterised in that
In step (4), Hydrogen Vapor Pressure is 1.0~3.0MPa in the reaction system.
10. the preparation method of R-2- acyl aminos -3- methoxy methyl propionates as described in claim 1, it is characterised in that tool
Body comprises the following steps that：
Step (1)：According to the amount of substance than glycine (II) that N- acyl group is protected：Bis- (trichloromethyl) carbonic esters (III)：N,N-
Two substitution formamides (IV) are 1.0：0.32~1.0：1.0~4.0 feed intake；It, will be shown in formula (II) in dry reaction bulb
The glycine of N- acyl groups protection is dissolved in N, and N- bis- replaces in formamide (IV), and controlling reaction temperature is added dropwise at 0~5 DEG C containing double
The organic solvent A of (trichloromethyl) carbonic ester (III), after being added dropwise, raising temperature carries out reaction 6~24 at 20~80 DEG C
Hour, after reaction, reaction solution is added in mixture of ice and water, adjusts pH to 8 with ammonium hydroxide, layering takes organic phase, and decompression is steamed
It is dry that white solid is the intermediate shown in formula (V)；
Step (2)：In dry reaction bulb, the intermediate shown in formula (V) is dissolved in organic solvent B, it is water-soluble to add in alkali A
Liquid is stirred at room temperature overnight, and after reaction, evaporated under reduced pressure adds acetone recrystallization, obtains the intermediate shown in formula (VI)
Sterling；
Step (3)：According to the amount of substance than formula (VI)：Alkali B：Methylating reagent A is 1：1.0~5.0：0.5~5.0 feeds intake；
In the reaction bulb of dried and clean, by the intermediate shown in formula (VI), 5%~30% hydrogen chloride first is added at -10~10 DEG C
Alcoholic solution stirs 8 hours, reaction is hydrolyzed；After reaction, evaporated under reduced pressure methanol；It adds organic solvent C and stirs 30 points
Clock filters to obtain yellow liquid；Alkali B and methylating reagent A is added in, controlling reaction temperature is stirred to react 24~48 at 20~120 DEG C
Hour, evaporated under reduced pressure solvent adds re crystallization from toluene, obtains yellow-brown solid as intermediate VII；
Step (4)：According to the amount of substance than chiral catalyst A：Substrate formula (VI) is 1.0：10,000~50,000 feed intake；Dry
In the hydriding reactor of dry cleaning, intermediate and organic solvent D shown in formula (VII) are added in, leads to nitrogen protection；Then, in feeding port
Chiral catalyst A is put into, leads to hydrogen to 1.0~3.0Mpa, controls the temperature of reaction system at 30~100 DEG C；HPLC is tracked to
The reaction was complete for raw material point, feeding, is concentrated under reduced pressure to give the target product R-2- acyl amino -3- methoxypropionic acids shown in formula (I)
Methyl esters.
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| CN114478424A (en) * | 2022-01-21 | 2022-05-13 | 浙江工业大学 | Preparation method of azlactone derivative with beta-substituted cycloalkenyl |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011005052A2 (en) * | 2009-07-10 | 2011-01-13 | Green Gross Corporation | Novel arylpiperazine-containing imidazole 4-carboxamide derivatives and pharmaceutical composition comprising same |
| WO2012041986A1 (en) * | 2010-10-01 | 2012-04-05 | Ucb Pharma Gmbh | Process for the preparation of amino acid derivatives |
| CN105330557A (en) * | 2015-09-11 | 2016-02-17 | 天台宜生生化科技有限公司 | Preparation method of chiral alpha-amino acid |
-
2017
- 2017-12-08 CN CN201711293340.8A patent/CN108129343A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011005052A2 (en) * | 2009-07-10 | 2011-01-13 | Green Gross Corporation | Novel arylpiperazine-containing imidazole 4-carboxamide derivatives and pharmaceutical composition comprising same |
| WO2012041986A1 (en) * | 2010-10-01 | 2012-04-05 | Ucb Pharma Gmbh | Process for the preparation of amino acid derivatives |
| CN105330557A (en) * | 2015-09-11 | 2016-02-17 | 天台宜生生化科技有限公司 | Preparation method of chiral alpha-amino acid |
Non-Patent Citations (2)
| Title |
|---|
| PABLO ETAYO 等: "Chiral Rhodium Complexes Derived From Electron-Rich Phosphine-Phosphites as Asymmetric Hydrogenation Catalysts", 《ORGANOMETALLICS》 * |
| 周明: "铑催化不对称氢化合成手性胺的研究", 《中国博士学位论文全文数据库 工程科技I辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114478424A (en) * | 2022-01-21 | 2022-05-13 | 浙江工业大学 | Preparation method of azlactone derivative with beta-substituted cycloalkenyl |
| CN114478424B (en) * | 2022-01-21 | 2023-09-26 | 浙江工业大学 | Preparation method of azlactone derivative with cycloalkenyl substituted at beta position |
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