CN102786428A - Preparation of methyldopa by hydrolyzing alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile by two-step hydrolysis method - Google Patents
Preparation of methyldopa by hydrolyzing alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile by two-step hydrolysis method Download PDFInfo
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Abstract
The invention belongs to the technical field of nitrile group hydrolysis and demethylation hydrolysis reaction which is one of the key steps for chemical synthesis of a methyldopa drug or a chiral drug of L-methyldopa [L-alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile, the same below], that is, a reaction for preparing alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile or L-alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile by nitrile group hydrolysis and demethylation hydrolysis. Under an acidic condition, the preparation of methyldopa by nitrile group hydrolysis and demethylation hydrolysis of alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile (or hydrochloride) requires a long period, a large material using amount, and heating hydrolysis of high-concentration acids (and the long-time heating of the high-concentration acids allows the acids to volatilize, so continuous acid addition is required during hydrolysis); however, the long-time high-concentration acid heating hydrolysis can cause unknown change of certain compound structures of alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile (or hydrochloride), and thus by-products are increased, and the purity and yield are decreased. Therefore, improvement of the hydrolysis technology is necessary.
Description
Technical field
Technical field of the present invention belongs to chemical synthetic drug methyldopa [Methyldopa; Alpha-Methyl-(3; The 4-dihydroxy phenyl)-α-An Jibingsuan, down together] or synthesis of chiral medicine L-methyldopa [L-methyldopa, L-Alpha-Methyl-(3; The 4-dihydroxy phenyl)-α-An Jibingsuan, down with] in one of committed step: itrile group hydrolysis and demethylation hydrolysis reaction.Be that Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile or L-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile prepares the chemical reaction of methyldopa or L-methyldopa through itrile group hydrolysis and demethylation hydrolysis.
Background technology
The L-methyldopa is a catecholamine hormones in the organism, is DCI [SLETA INGER M, CHEMERDA J M; W BOLL INGER F. Potent decarboxylase inhibitors. analogs of methyldopa [J]. J Med Chem; 1963,6 (2): 1012103.], has antihypertensive function; Clinically in order to treatment hypertension [XU J M; ZHENG H J. Clinical application and evaluation of methyldopa [J]. Chin J New Drugs Clin Rem (Chinese Journal of New Drugs and Clinical Remedies), 1990,9 (6): 367-369.].The L-methyldopa also is one of the parkinsonian main medicine of treatment [Bronstein; J. M., Stereotactic Pallidotomy in the Treatment of Parkinson Disease, Archives of Neurology; (1999) .56,1064-1069.].
Synthesizing methyl DOPA or L-methyldopa, commonly used is the aminopropionitrile method synthetic route of main raw material with veratone (3,4-dimethoxy Propiophenone descends together).With the veratone is raw material; With prepare DL-Alpha-Methyl-(3 after the reactions such as sodium cyanide and ammonium chloride; The 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride); After the itrile group hydrolysis of DL-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) and demethylation hydrolysis, obtain methyldopa.
DL-Alpha-Methyl-(3; The 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) is after splitting; Obtain L-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) [another enantiomorph D-Alpha-Methyl of fractionation-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) reuses] after racemization; L-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) obtains the L-methyldopa after itrile group hydrolysis and demethylation hydrolysis.Above-mentioned with veratone (3,4-dimethoxy Propiophenone, down with) also claim veratone method (also have document to claim the veratryl aldehyde method, synthetic route is formula as follows) for the synthetic route of main raw material.
In the different synthetic routes of existing synthesizing methyl DOPA or L-methyldopa; When itrile group hydrolysis and demethylation hydrolysis prepare methyldopa or L-methyldopa; Nearly all be with Hydrogen bromide (HBr content 48%; Mass/volume than) or concentrated hydrochloric acid (HCl content 37%, mass/volume than) come itrile group hydrolysis and demethylation hydrolysis.For example USP (US2868818) report is with concentrated hydrochloric acid (HCl content 36%; Mass/volume than) 100 ℃ can only Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile hydrolysis be become Alpha-Methyl-(3-hydroxyl-4-p-methoxy-phenyl)-α-An Jibingsuan with demethylation in 18 hours.If further demethylation becomes Alpha-Methyl-(3; The 4-dihydroxy phenyl)-α-An Jibingsuan (methyldopa) need to continue with concentrated hydrochloric acid (HCL content 36%; Mass/volume than) 150 ℃ of hydrolysis demethylations 2-4 hour, dark product (document is not reported output and purity).Document is also reported available hydrogen bromic acid (HBr content 48%, mass/volume than), 125 ℃ of back hydrolysis and demethylation 55 hours, obtains Alpha-Methyl-(3, the 4-dihydroxy phenyl)-α-An Jibingsuan (methyldopa).People such as Cervinka (Cs.270969,27.Feb.1991) with Hydrogen bromide (HBr content 48%, mass/volume than) through 70 ℃ 1.5 hours, 100 ℃ 24 hours, the method for segmentation and long-time heating is hydrolyzed and demethylation obtains the L-methyldopa.Concentrated hydrochloric acid (HCl content 36% is used in Japanese Patent (spy opens clear 61-275253) segmentation; Mass/volume compares) and Hydrogen bromide (HBr content 47%; The mass/volume ratio); Through 105～109 ℃ 35 hours, carry out L-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile hydrochloride (with the concentrated hydrochloric acid mass ratio be 1:7.5; With the Hydrogen bromide mass ratio be 1:1.9) hydrolysis and demethylation obtain the L-methyldopa.People such as Wu Fanhong (Guangzhou chemical industry; 2008 36 the 2nd phases of volume; P44) use concentrated hydrochloric acid (HCl content 35%; Mass/volume than) carry out L-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile hydrochloride (with the concentrated hydrochloric acid mass ratio be 1:6) obtain the L-methyldopa after itrile group hydrolysis and the demethylation hydrolysis.
Under acidic conditions, carry out Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) itrile group hydrolysis and demethylation hydrolysis and obtain methyldopa; Need heating hydrolysis (and long-time heating high concentrated acid long-time, heavy dose of, high concentrated acid; Make the acid volatilization, need in hydrolytic process, constantly to add acid), but this long-time; The high concentrated acid heating hydrolysis can cause Alpha-Methyl-(3; The 4-Dimethoxyphenyl)-and unknown variations on some compound structure of alpha-amino group propionitrile (or hydrochloride), by product is increased, purity, output descend.Therefore be necessary its hydrolysis process is reformed.
Summary of the invention
The present invention tests with 24% ~ 48% Hydrogen bromide (mass/volume ratio) or 18% ~ 36% concentrated hydrochloric acid (mass/volume ratio) and carries out DL-Alpha-Methyl-(3; The 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) [L-Alpha-Methyl-(3; The 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) is also identical, this describe under the situation with] itrile group hydrolysis and demethylation hydrolysis can obtain the methyldopa or the L-methyldopa of different output and quality.But test is found to have following problem: 1. need carry out hydrolysis of long-time heating itrile group and demethylation hydrolysis reaction, energy cost is very high; 2. if adopt Hydrogen bromide to carry out itrile group hydrolysis and demethylation hydrolysis, Hydrogen bromide costs an arm and a leg, and the Hydrogen bromide price is 10 times of concentrated hydrochloric acid; 3. even use concentrated hydrochloric acid, since big with the acid amount, behind itrile group hydrolysis and the demethylation hydrolysis reaction; Cause very big hydrochloric acid discharge of wastewater; What is more important increases by product because itrile group hydrolysis and demethylation hydrolysis cause the unknown variations on DL-Alpha-Methyl-some compound structure of (3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride); Part not hydrolysis or demethylation contain the nitrile refuse, and the nitrile compound of other unknown structure causes the pollution of certain environment.
The present invention is in order to overcome the problems referred to above, and the present invention has carried out the veratone legal system and has been equipped with the itrile group hydrolysis of methyldopa or L-methyldopa and the technical renovation of demethylation hydrolysis, and concrete technical scheme is following:
The present invention is the method that a kind of veratone legal system is equipped with the itrile group hydrolysis and the demethylation hydrolysis of methyldopa or L-methyldopa, under the different temperature gradient, itrile group and demethylation is used sour " bistep hydrolysis " that is hydrolyzed stage by stage.
The concrete steps of itrile group hydrolysis of the present invention are following:
(1) DL-Alpha-Methyl-(3; The 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride), L-2-amino-3-(3; The 4-Dimethoxyphenyl)-and the hydrolysis of 2-methyl-propionitrile (or hydrochloride) itrile group carries out at low temperatures, and the optimum temps of low temperature itrile group hydrolysis is-5 ~ 4 ℃;
(2) the itrile group low temperature hydrolysis needs vigorous stirring, and whisking appliance adopts propeller stirrer, and stirring velocity is 1000 ~ 1500 rpm;
(3) acid of hydrolysis use is 18% ~ 36% concentrated hydrochloric acid or 24% ~ 48% Hydrogen bromide (mass/volume ratio);
When (4) the itrile group low temperature hydrolysis uses 36% concentrated hydrochloric acid; With DL-2-amino-3-(3; The 4-Dimethoxyphenyl)-mol ratio of 2-methyl-propionitrile (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionitrile (hydrochloride) is 1:0.07 ~ 0.25; When the concentrated hydrochloric acid that uses 18%, be 1:0.07.
When (5) the itrile group low temperature hydrolysis uses 47 ~ 48% Hydrogen bromide; With DL-2-amino-3-(3; The 4-Dimethoxyphenyl)-mol ratio of 2-methyl-propionitrile (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionitrile (hydrochloride) is 1:0.07; When the Hydrogen bromide that uses 23 ~ 24%, be 1:0.14.
The concrete steps of demethylation hydrolysis of the present invention are following:
(1) DL-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-α-An Jibingsuan, L-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-α-An Jibingsuan can use acid to carry out the demethylation hydrolysis, and demethylation hydrolysis optimum temps is 100 ~ 110 ℃;
(2) acid of using is 18% ~ 36% concentrated hydrochloric acid (mass/volume ratio) or 24% ~ 48% Hydrogen bromide (mass/volume ratio);
When (3) 36% concentrated hydrochloric acid is used in the demethylation hydrolysis; With DL-2-amino-3-(3; The 4-Dimethoxyphenyl)-mol ratio of 2-methyl-propionic acid (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) is 1:0.083 ~ 0.167;
When (4) 47% Hydrogen bromide is used in the demethylation hydrolysis; With DL-2-amino-3-(3; The 4-Dimethoxyphenyl)-mol ratio of 2-methyl-propionic acid (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) is 1:0.167; When the Hydrogen bromide that uses 23.5%, be 1:0.33;
(5) after the demethylation hydrolysis is accomplished, need to divide the pH value of two steps with ammoniacal liquor adjustment solution, constant to the pH value to 6;
(6) DL-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) solid can be used washing with acetone;
(7) DL-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) solid can be 40 ~ 70 ℃ of dryings.
Technical scheme of the present invention needs before after-treatment products, directly slowly to feed N to reaction mixture after hydrolysis reaction is accomplished
2, underpressure distillation simultaneously extracts excessive HCl or Hydrogen bromide.
DL-2-amino-3-(3 of the present invention; The 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) or L-2-amino-3-(3; The 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) used water makes recrystallization solvent; Gac is made discoloring agent, recrystallization in the time of 80 ~ 90 ℃, and purity can reach more than 99.8%.
The present invention carries out DL-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride), L-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) itrile group hydrolysis and demethylation hydrolysis and was divided into for two steps:
1.DL-Alpha-Methyl-(3; The 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride), L-Alpha-Methyl-(3; The 4-Dimethoxyphenyl)-hydrolysis of alpha-amino group propionitrile (or hydrochloride) itrile group can carry out at low temperatures; The present invention finds that the optimum temps of low temperature itrile group hydrolysis is-5 ~ 4 ℃, and the acid of use is 24% ~ 48% Hydrogen bromide (mass/volume ratio) or 18% ~ 36% concentrated hydrochloric acid.The itrile group low temperature hydrolysis can obtain DL-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-α-An Jibingsuan (or L-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-α-An Jibingsuan, down with).
The present invention finds the solid particulate of DL-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) when low temperature hydrolysis, just solid particles surface and Hydrogen bromide or concentrated hydrochloric acid generation hydrolysis; The DL-Alpha-Methyl-(3 that the reaction back generates; The 4-Dimethoxyphenyl)-and α-An Jibingsuan can not spread rapidly on the surface, and the group of formation bunch causes DL-Alpha-Methyl-(3; The 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) solid particulate inside fails complete hydrolysis at low temperatures; Greatly reduced output, generally about 40 ~ 50%, so the itrile group low temperature hydrolysis needs vigorous stirring.Whisking appliance adopts propeller stirrer.Stirring velocity is 1000 ~ 1500 rpm, and best stirring velocity is 1200rpm.
2. the present invention finds that DL-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-α-An Jibingsuan carries out the demethylation hydrolysis at low temperatures, no matter still all can't demethylation with concentrated hydrochloric acid with Hydrogen bromide.The demethylation hydrolysis must at high temperature be carried out, and the present invention finds that the optimum temps of high temperature demethylation hydrolysis is 100 ~ 110 ℃, and the acid of use is 24% ~ 48% Hydrogen bromide (mass/volume ratio) or 18% ~ 36% concentrated hydrochloric acid.
The present invention finds that DL-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) itrile group low temperature hydrolysis reaches more than 95% with 36% concentrated hydrochloric acid hydrolysis, and cheap, and economical effectiveness obviously is better than 48% Hydrogen bromide on the industrial production.The optimum temps of DL-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-α-An Jibingsuan (or L-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-α-An Jibingsuan, down with) demethylation hydrolysis is 105 ℃.With Hydrogen bromide or concentrated hydrochloric acid result much at one.Can reach more than 95% with 36% concentrated hydrochloric acid hydrolysis.
When the decompression of the present invention after reaction is accomplished deacidifies, feed N
2To protection product easy oxidation discoloration and accelerate deacidification important effect is arranged not.The present invention never degenerates for the protection product, and controlling product vacuum-drying temperature generally speaking is 50 ℃, dry 5 hours.Through secondary recrystallization, purity can reach 99.8%.
The present invention is employed under the different temperature gradient; With itrile group and " bistep hydrolysis " that demethylation is hydrolyzed with identical acid or different acid stage by stage, reduced the energy and Financial cost, reduced sour discharge of wastewater; Reduce by product, improved degree of purity of production and output.
Embodiment
Through specific embodiment technical scheme of the present invention is described further below.
The embodiment medicine
Hydrogen bromide (HBr content 47%; Technical grade) and concentrated hydrochloric acid (HCL content 36%, technical grade), DL-Alpha-Methyl-(3; The 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride); L-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) is pressed document Span pat. 545751 and Belg pat. 633417 self-controls; Below each embodiment medicine identical; High performance liquid chromatograph (U.S. Agilent 1100), IR (U.S. Nicolet 470 class), NMR (German BRUKER 400MHz).
Embodiment 1
In the there-necked flask that TM, whisking appliance and reflux condensing tube are housed, add 36% concentrated hydrochloric acid 12.3 grams (0.12mol).Be cooled to 0 ~ 5 ℃ with frozen water.Slowly add 2.18 gram (0.0085mol) DL-2-amino-3-(3; The 4-Dimethoxyphenyl)-2-methyl-propionitrile hydrochloride [or L-2-amino-3-(3; The 4-Dimethoxyphenyl)-2-methyl-propionitrile hydrochloride, each embodiment is identical down] be dissolved in the ice-cold concentrated hydrochloric acid.Added the back vigorous stirring 2 hours.Reaction rises to room temperature after accomplishing, and directly slowly feeds N to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl.Solid gets white solid with 3 * 25ml washing with acetone.Then in 50 ℃ of vacuum-dryings 3 hours.Again 70 ℃ of dryings 5 hours.Product D L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic salt hydrochlorate (or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic salt hydrochlorate, each embodiment is identical down) 2.03 grams, productive rate 86.8%.
Embodiment 2
In the there-necked flask that TM, whisking appliance and reflux condensing tube are housed, add 36% concentrated hydrochloric acid 24.3 grams (0.24mol).With ice-cooled to 0 ~ 4 ℃.Slowly add 14.38 gram (0.056mol) DL--2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionitrile hydrochlorides and be dissolved in the ice-cold concentrated hydrochloric acid, after adding, keep 0 ~ 4 ℃ to continue vigorous stirring 2 hours.Reaction rises to room temperature after accomplishing, and directly slowly feeds N to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl.Solid gets white solid with 4 * 25ml washing with acetone.Then in 50 ℃ of vacuum-dryings 3 hours.Again 70 ℃ of dryings 5 hours.Get product D L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic salt hydrochlorate 14.70 grams, productive rate 95.2%.
Embodiment 3
In the there-necked flask that TM, whisking appliance and reflux condensing tube are housed, add 18% concentrated hydrochloric acid 24.3 grams (0.12mol).Be cooled to 0 ~ 5 ℃ with frozen water.Slowly adding 2.18 gram (0.0085mol) DL-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionitrile hydrochlorides is dissolved in the ice-cold concentrated hydrochloric acid.Added the back vigorous stirring 2 hours.Reaction rises to room temperature after accomplishing, and directly slowly feeds N to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl.Solid gets white solid with 3 * 25ml washing with acetone.Then in 50 ℃ of vacuum-dryings 3 hours.Again 70 ℃ of dryings 5 hours.Get product D L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic salt hydrochlorate 1.85 grams, productive rate 79.1%.
Embodiment 4
In the there-necked flask that TM, whisking appliance and reflux condensing tube are housed, add 47% Hydrogen bromide 20.7 grams (0.12mol).Be cooled to 0 ~ 5 ℃ with frozen water.Slowly adding 2.18 gram (0.0085mol) DL-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionitrile hydrochlorides is dissolved in the ice-cold Hydrogen bromide.Added the back vigorous stirring 2 hours.Reaction rises to room temperature after accomplishing, and directly slowly feeds N to reaction mixture
2, underpressure distillation simultaneously extracts excessive Hydrogen bromide.Solid gets white solid with 3 * 25ml washing with acetone.Then in 50 ℃ of vacuum-dryings 3 hours.Again 70 ℃ of dryings 5 hours.Get product D L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic salt hydrochlorate 2.23 grams, productive rate 95.4%.
Embodiment 5
In the there-necked flask that TM, whisking appliance and reflux condensing tube are housed, add 23.5% Hydrogen bromide 20.7 grams (0.06mol).Be cooled to 0 ~ 5 ℃ with frozen water.Slowly adding 2.18 gram (0.0085mol) DL-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionitrile hydrochlorides is dissolved in the ice-cold Hydrogen bromide.Added the back vigorous stirring 2 hours.Reaction rises to room temperature after accomplishing, and directly slowly feeds N to reaction mixture
2, underpressure distillation simultaneously extracts excessive Hydrogen bromide.Solid gets white solid with 3 * 25ml washing with acetone.Then in 50 ℃ of vacuum-dryings 3 hours.Again 70 ℃ of dryings 5 hours.Get product D L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic salt hydrochlorate 1.95 grams, productive rate 83.3%.
Embodiment 6
In the there-necked flask that TM, whisking appliance and reflux condensing tube are housed; Concentrated hydrochloric acid 24.3 grams (0.24mol) of adding 36%; Add 5.52 gram (0.02mol) DL-2-amino-3-(3; The 4-Dimethoxyphenyl)-2-methyl-propionic salt hydrochlorate [or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic salt hydrochlorate, each embodiment is identical down].Oil bath slowly was heated to 65-70 ℃ of (need 40 minutes) stirring reaction 6 hours then, reheat to 100 ~ 110 ℃, stirring reaction 24 hours.Reaction rises to room temperature after accomplishing, and directly slowly feeds N to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl.PH value with ammoniacal liquor adjustment solution has solid to occur, and it is constant to be stirred to pH.Then, carefully transfer pH to 6, left standstill solid filtering 1 hour.Solid gets white solid with 4 * 25ml washing with acetone.Then in 50 ℃ of vacuum-dryings 5 hours.Get product D L-2-amino-3-(3, the 4-dihydroxy phenyl)-2-methyl-propionic acid (C
10H
13NO
4H
2O
1.5) be methyldopa 4.56 grams, 95.8%.
Embodiment 7
In the there-necked flask that TM, whisking appliance and reflux condensing tube are housed, add 36% concentrated hydrochloric acid 12.3 grams (0.12mol), add 5.52 gram (0.02mol) DL-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic salt hydrochlorates.Oil bath slowly was heated to 65-70 ℃ of (need 40 minutes) stirring reaction 6 hours then, reheat to 100 ~ 110 ℃, stirring reaction 24 hours.Reaction rises to room temperature after accomplishing, and directly slowly feeds N to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl.PH value with ammoniacal liquor adjustment solution has solid to occur, and it is constant to be stirred to pH.Then, carefully transfer pH to 6, left standstill solid filtering 1 hour.Solid gets white solid with 4 * 25ml washing with acetone.Then in 50 ℃ of vacuum-dryings 5 hours.Get product D L-2-amino-3-(3, the 4-dihydroxy phenyl)-2-methyl-propionic acid (C
10H
13NO
4H
2O
1.5) be methyldopa 4.39 grams, 92.2%.
Embodiment 8
In the there-necked flask that TM, whisking appliance and reflux condensing tube are housed, add 47% Hydrogen bromide 20.7 grams (0.12mol), add 5.52 gram (0.02mol) DL-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic salt hydrochlorates.Oil bath slowly was heated to 65-70 ℃ of (need 40 minutes) stirring reaction 6 hours then, reheat to 100 ~ 110 ℃, stirring reaction 18 hours.Reaction rises to room temperature after accomplishing, and directly slowly feeds N to reaction mixture
2, underpressure distillation simultaneously extracts excessive Hydrogen bromide.PH value with ammoniacal liquor adjustment solution has solid to occur, and it is constant to be stirred to pH.Then, carefully transfer pH to 6, left standstill solid filtering 1 hour.Solid gets white solid with 4 * 25ml washing with acetone.Then in 50 ℃ of vacuum-dryings 5 hours.Get product D L-2-amino-3-(3, the 4-dihydroxy phenyl)-2-methyl-propionic acid (C
10H
13NO
4H
2O
1.5) be methyldopa 4.56 grams, 95.7%.
Embodiment 9
In the there-necked flask that TM, whisking appliance and reflux condensing tube are housed, add 23.5% Hydrogen bromide 20.7 grams (0.06mol), add 5.52 gram (0.02mol) DL-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic salt hydrochlorates.Oil bath slowly was heated to 65-70 ℃ of (need 40 minutes) stirring reaction 6 hours then, reheat to 100 ~ 110 ℃, stirring reaction 18 hours.Reaction rises to room temperature after accomplishing, and directly slowly feeds N to reaction mixture
2, underpressure distillation simultaneously extracts excessive Hydrogen bromide.PH value with ammoniacal liquor adjustment solution has solid to occur, and it is constant to be stirred to pH.Then, carefully transfer pH to 6, left standstill solid filtering 1 hour.Solid gets white solid with 4 * 25ml washing with acetone.Then in 50 ℃ of vacuum-dryings 5 hours.Get product D L-2-amino-3-(3, the 4-dihydroxy phenyl)-2-methyl-propionic acid (C
10H
13NO
4H
2O
1.5) be methyldopa 4.26 grams, 89.6%.
Embodiment 10
It is methyldopa [or L-2-amino-3-(3, the 4-dihydroxy phenyl)-2-methyl-propionic acid that 8 grams are grayish DL-2-amino-3-(3, the 4-dihydroxy phenyl)-2-methyl-propionic acid; Each embodiment is identical down] in 40ml water; 80-90 ℃ of heating for dissolving adds 0.4 gram gac, and 90 ℃ were stirred 10 minutes; Filtered while hot, cooling has solid to separate out.Placed 2 hours, suction filtration gets white solid.100 ℃ of dryings 3 hours, white solid 7.03 grams, yield 87.9%.MP.295-299 ℃ (variable color), 302 ℃ of decomposition.Product is through ultimate analysis, infrared, nuclear-magnetism spectrum evaluation.Purity detects through high performance liquid chromatograph.Through secondary recrystallization, purity can reach more than 99.8%.
At last, it is also to be noted that what more than enumerate only is several specific embodiment of the present invention; Obviously, the invention is not restricted to above embodiment, many distortion can also be arranged; So long as all distortion that disclosed content directly derives or associates all should be thought protection scope of the present invention.
Claims (5)
1. a veratone legal system is equipped with the method for the itrile group hydrolysis and the demethylation hydrolysis of methyldopa or L-methyldopa, it is characterized in that under the different temperature gradient " bistep hydrolysis " that itrile group and demethylation are hydrolyzed with acid stage by stage.
2. veratone legal system according to claim 1 is equipped with the method for the itrile group hydrolysis and the demethylation hydrolysis of methyldopa or L-methyldopa, it is characterized in that the concrete steps of itrile group hydrolysis are following:
(1) DL-Alpha-Methyl-(3; The 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride), L-2-amino-3-(3; The 4-Dimethoxyphenyl)-and the hydrolysis of 2-methyl-propionitrile (or hydrochloride) itrile group carries out at low temperatures, and the optimum temps of low temperature itrile group hydrolysis is-5 ~ 4 ℃;
(2) the itrile group low temperature hydrolysis needs vigorous stirring, and whisking appliance adopts propeller stirrer, and stirring velocity is 1000 ~ 1500 rpm;
(3) acid of hydrolysis use is 18% ~ 36% concentrated hydrochloric acid or 24% ~ 48% Hydrogen bromide (mass/volume ratio);
When (4) the itrile group low temperature hydrolysis uses 36% concentrated hydrochloric acid; With DL-2-amino-3-(3; The 4-Dimethoxyphenyl)-mol ratio of 2-methyl-propionitrile (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionitrile (hydrochloride) is 1:0.07 ~ 0.25; When the concentrated hydrochloric acid that uses 18%, be 1:0.07.
When (5) the itrile group low temperature hydrolysis uses 47 ~ 48% Hydrogen bromide; With DL-2-amino-3-(3; The 4-Dimethoxyphenyl)-mol ratio of 2-methyl-propionitrile (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionitrile (hydrochloride) is 1:0.07; When the Hydrogen bromide that uses 23 ~ 24%, be 1:0.14.
3. veratone legal system according to claim 1 is equipped with the method for the itrile group hydrolysis and the demethylation hydrolysis of methyldopa or L-methyldopa, it is characterized in that the concrete steps of demethylation hydrolysis are following:
(1) DL-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-α-An Jibingsuan, L-Alpha-Methyl-(3, the 4-Dimethoxyphenyl)-α-An Jibingsuan can use acid to carry out the demethylation hydrolysis, and demethylation hydrolysis optimum temps is 100 ~ 110 ℃;
(2) acid of using is 18% ~ 36% concentrated hydrochloric acid (mass/volume ratio) or 24% ~ 48% Hydrogen bromide (mass/volume ratio);
When (3) 36% concentrated hydrochloric acid is used in the demethylation hydrolysis; With DL-2-amino-3-(3; The 4-Dimethoxyphenyl)-mol ratio of 2-methyl-propionic acid (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) is 1:0.083 ~ 0.167;
When (4) 47% Hydrogen bromide is used in the demethylation hydrolysis; With DL-2-amino-3-(3; The 4-Dimethoxyphenyl)-mol ratio of 2-methyl-propionic acid (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) is 1:0.167; When the Hydrogen bromide that uses 23.5%, be 1:0.33;
(5) after the demethylation hydrolysis is accomplished, need to divide the pH value of two steps with ammoniacal liquor adjustment solution, constant to the pH value to 6;
(6) DL-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) solid can be used washing with acetone;
(7) DL-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) or L-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) solid can be 40 ~ 70 ℃ of dryings.
4. be equipped with the method for the itrile group hydrolysis and the demethylation hydrolysis of methyldopa or L-methyldopa according to claim 1 or 2 or 3 described veratone legal systems, it is characterized in that, after hydrolysis reaction is accomplished, need before after-treatment products, directly slowly feed N to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl or Hydrogen bromide.
5. veratone legal system according to claim 4 is equipped with the method for the itrile group hydrolysis and the demethylation hydrolysis of methyldopa or L-methyldopa; It is characterized in that DL-2-amino-3-(3, the 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) or L-2-amino-3-(3; The 4-Dimethoxyphenyl)-2-methyl-propionic acid (hydrochloride) used water makes recrystallization solvent; Gac is made discoloring agent, recrystallization in the time of 80 ~ 90 ℃, and purity can reach more than 99.8%.
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| CN201210208391.7A CN102786428B (en) | 2012-06-20 | 2012-06-20 | Methyldopa prepared by bistep hydrolysis hydrolysis Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile |
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| CN201210208391.7A CN102786428B (en) | 2012-06-20 | 2012-06-20 | Methyldopa prepared by bistep hydrolysis hydrolysis Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105906520A (en) * | 2016-05-19 | 2016-08-31 | 浙江野风药业股份有限公司 | Recycling method and application of L-methyldopa intermediate |
| WO2022140372A1 (en) * | 2020-12-23 | 2022-06-30 | Immunomolecular Therapeutics, Inc. | METHODS FOR PRODUCING D-α-METHYLDOPA |
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|---|---|---|---|---|
| US2868818A (en) * | 1953-12-15 | 1959-01-13 | Merck & Co Inc | Alpha methyl phenylalanines |
| JPS62298565A (en) * | 1986-06-19 | 1987-12-25 | Nippon Kayaku Co Ltd | Production of l-alpha-methyldopa |
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- 2012-06-20 CN CN201210208391.7A patent/CN102786428B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2868818A (en) * | 1953-12-15 | 1959-01-13 | Merck & Co Inc | Alpha methyl phenylalanines |
| JPS62298565A (en) * | 1986-06-19 | 1987-12-25 | Nippon Kayaku Co Ltd | Production of l-alpha-methyldopa |
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| KLAUS WEINGES, ET AL: "Die externe asymmetrische Strecker-Synthese von a-Methyl-aminosauren", 《CHEM. BER.》, vol. 104, 31 December 1971 (1971-12-31), pages 3594 - 3606 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105906520A (en) * | 2016-05-19 | 2016-08-31 | 浙江野风药业股份有限公司 | Recycling method and application of L-methyldopa intermediate |
| CN105906520B (en) * | 2016-05-19 | 2017-12-12 | 浙江野风药业股份有限公司 | A kind of recovery method of L-α-methyl-dopa intermediate and application |
| WO2022140372A1 (en) * | 2020-12-23 | 2022-06-30 | Immunomolecular Therapeutics, Inc. | METHODS FOR PRODUCING D-α-METHYLDOPA |
| US11702383B2 (en) | 2020-12-23 | 2023-07-18 | Immunomolecular Therapeutics, Inc. | Methods for producing D-α-methyldopa |
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