CN102786428B - Methyldopa prepared by bistep hydrolysis hydrolysis Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile - Google Patents
Methyldopa prepared by bistep hydrolysis hydrolysis Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile Download PDFInfo
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Abstract
The technology of the present invention field belongs to chemical synthetic drug methyldopa or synthesis of chiral medicine L-methyldopa [L-methyldopa, L-Alpha-Methyl-(3,4-dihydroxy phenyl)-α-aminopropionic acid, lower with] in one of committed step: itrile group hydrolysis and demethylation hydrolysis reaction.I.e. Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile or L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile prepare the chemical reaction of methyldopa or L-methyldopa through itrile group hydrolysis and demethylation hydrolysis.In acid condition, carry out Alpha-Methyl-(3, 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) itrile group is hydrolyzed and demethylation hydrolysis obtains methyldopa, need long-time, heavy dose of, the heating hydrolysis of high concentrated acid (and long-time heating high concentrated acid, make acid volatilization, need in hydrolytic process continuous acid adding), but it is for a long time this, high concentrated acid heating hydrolysis can cause Alpha-Methyl-(3, 4-Dimethoxyphenyl) unknown variations on-alpha-amino group propionitrile (or hydrochloride) some compound structure, by product is increased, purity, production declining.Therefore be necessary its hydrolysis process reform.
Description
Technical field
The technology of the present invention field belongs to chemical synthetic drug methyldopa [Methyldopa, Alpha-Methyl-(3,4-dihydroxy phenyl)-α-aminopropionic acid, lower same] or synthesis of chiral medicine L-methyldopa [L-methyldopa, L-Alpha-Methyl-(3,4-dihydroxy phenyl)-α-aminopropionic acid, lower with] in one of committed step: itrile group hydrolysis and demethylation hydrolysis reaction.I.e. Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile or L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile prepare the chemical reaction of methyldopa or L-methyldopa through itrile group hydrolysis and demethylation hydrolysis.
Background technology
L-methyldopa is catecholamine hormones in organism, for decarboxylase inhibitor [SLETA INGER M, CHEMERDA J M, W BOLL INGER F.Potent decarboxylase inhibitors.analogs ofmethyldopa [J] .J Med Chem, 1963, 6 (2): 1012103.], there is antihypertensive function, clinically in order to treat hypertension [XU J M, ZHENG H J.Clinical application and evaluation ofmethyldopa [J] .Chin J New Drugs Clin Rem (Chinese Journal of New Drugs and Clinical Remedies), 1990, 9 (6): 367-369.].L-methyldopa is also one of the parkinsonian key agents for the treatment of [Bronstein, J.M., Stereotactic Pallidotomy in the Treatment of Parkinson Disease, Archives ofNeurology, (1999) .56,1064-1069.].
Synthesizing methyl DOPA or L-methyldopa, conventional take veratone (3,4-dimethoxy Propiophenone, lower with) as the aminopropionitrile method synthetic route of main raw material.Take veratone as raw material, DL-Alpha-Methyl-(3 are prepared after reacting with sodium cyanide and ammonium chloride etc., 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride), methyldopa is obtained after the itrile group hydrolysis and demethylation hydrolysis of DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride).
DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) through split after, obtain L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) [another enantiomorph D-Alpha-Methyl-(3 of fractionation, 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) reuses after racemization], L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) obtains L-methyldopa after itrile group hydrolysis and demethylation hydrolysis.Above-mentioned with veratone (3,4-dimethoxy Propiophenone, lower with) for the synthetic route of main raw material is also known as veratone method (also have document to claim veratryl aldehyde method, synthetic route is shown in following formula).
In the different synthetic routes of existing synthesizing methyl DOPA or L-methyldopa, when methyldopa or L-methyldopa are prepared in itrile group hydrolysis and demethylation hydrolysis, nearly all with Hydrogen bromide (HBr content 48%, mass/volume ratio) or concentrated hydrochloric acid (HCl content 37%, mass/volume ratio) carrys out itrile group hydrolysis and demethylation is hydrolyzed.Such as United States Patent (USP) (US2868818) report concentrated hydrochloric acid (HCl content 36%, mass/volume than) 100 DEG C within 18 hours, Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile hydrolysis can only be become Alpha-Methyl-(3-hydroxyl-4-p-methoxy-phenyl)-α-aminopropionic acid with demethylation.If demethylation becomes Alpha-Methyl-(3 further, 4-dihydroxy phenyl)-α-aminopropionic acid (methyldopa) need continue with concentrated hydrochloric acid (HCL content 36%, mass/volume ratio) at 150 DEG C of hydrolysis demethylation 2-4 hour, obtain dark product (document does not report output and purity).Available hydrogen bromic acid (HBr content 48%, mass/volume than) also reported by document, at 125 DEG C of back hydrolysis and demethylation 55 hours, obtains Alpha-Methyl-(3,4-dihydroxy phenyl)-α-aminopropionic acid (methyldopa).The people such as Cervinka (Cs.270969,27.Feb.1991) use Hydrogen bromide (HBr content 48%, mass/volume than) through 70 DEG C 1.5 hours, 100 DEG C 24 hours, the method for segmentation and long-time heating is hydrolyzed and demethylation obtains L-methyldopa.Japanese Patent (JP 61-275253) segmentation uses concentrated hydrochloric acid (HCl content 36%, mass/volume ratio) and Hydrogen bromide (HBr content 47%, mass/volume ratio), through 105 ~ 109 DEG C 35 hours, carrying out L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile hydrochloride (is 1:7.5 with concentrated hydrochloric acid mass ratio; Be 1:1.9 with Hydrogen bromide mass ratio) to be hydrolyzed and demethylation obtains L-methyldopa.The people such as Wu Fanhong (Chemical Industry in Guangzhou, 36 volumes the 2nd phase in 2008, p44) concentrated hydrochloric acid (HCl content 35% is used, mass/volume than) carry out L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile hydrochloride (be 1:6 with concentrated hydrochloric acid mass ratio) itrile group be hydrolyzed and demethylation be hydrolyzed after obtain L-methyldopa.
In acid condition, carry out Alpha-Methyl-(3, 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) itrile group is hydrolyzed and demethylation hydrolysis obtains methyldopa, need long-time, heavy dose of, the heating hydrolysis of high concentrated acid (and long-time heating high concentrated acid, make acid volatilization, need in hydrolytic process continuous acid adding), but it is for a long time this, high concentrated acid heating hydrolysis can cause Alpha-Methyl-(3, 4-Dimethoxyphenyl) unknown variations on-alpha-amino group propionitrile (or hydrochloride) some compound structure, by product is increased, purity, production declining.Therefore be necessary its hydrolysis process reform.
Summary of the invention
The present invention tests and carries out DL-Alpha-Methyl-(3 with 24% ~ 48% Hydrogen bromide (mass/volume ratio) or 18% ~ 36% concentrated hydrochloric acid (mass/volume ratio), 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) [L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) is also identical, this describe in situation with] itrile group hydrolysis and demethylation be hydrolyzed methyldopa or the L-methyldopa that can obtain different output and quality.But test finds that there are the following problems: 1. need carry out the hydrolysis of long-time heating itrile group and demethylation hydrolysis reaction, energy cost is very high; 2. carry out itrile group hydrolysis and demethylation hydrolysis according to Hydrogen bromide, Hydrogen bromide is expensive, and Hydrogen bromide price is 10 times of concentrated hydrochloric acid; Even if 3. use concentrated hydrochloric acid, due to large by acid amount, itrile group hydrolysis and demethylation hydrolysis reaction after, cause very large hydrochloric acid waste water discharge, what is more important causes DL-Alpha-Methyl-(3 because itrile group hydrolysis and demethylation are hydrolyzed, 4-Dimethoxyphenyl) unknown variations on-alpha-amino group propionitrile (or hydrochloride) some compound structure, by product is increased, part be not hydrolyzed or demethylation containing 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 invention has been the technical renovation that veratone legal system is hydrolyzed for itrile group hydrolysis and the demethylation of methyldopa or L-methyldopa, concrete technical scheme is as follows:
The present invention is a kind of veratone legal system for methyldopa or the itrile group hydrolysis of L-methyldopa and the method for demethylation hydrolysis, under different thermogrades, by itrile group and demethylation stage by stage with sour " bistep hydrolysis " that be hydrolyzed.
The concrete steps of itrile group hydrolysis of the present invention are as follows:
(1) DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride), L-2-amino-3-(3,4-Dimethoxyphenyl)-2-methyl-propanenitrile (or hydrochloride) itrile group hydrolysis carry out at low temperatures, low temperature itrile group hydrolysis optimum temps be-5 ~ 4 DEG C;
(2) itrile group low temperature hydrolysis needs vigorous stirring, and agitator adopts propeller stirrer, and stirring velocity is 1000 ~ 1500rpm;
(3) acid that hydrolysis uses is 18% ~ 36% concentrated hydrochloric acid or 24% ~ 48% Hydrogen bromide (mass/volume ratio);
(4) itrile group low temperature hydrolysis use 36% concentrated hydrochloric acid time, with DL-2-amino-3-(3,4-Dimethoxyphenyl) mol ratio of-2-methyl-propanenitrile (hydrochloride) or L-2-amino-3-(3,4-Dimethoxyphenyl)-2-methyl-propanenitrile (hydrochloride) is 1:0.07 ~ 0.25; Be 1:0.07 when the concentrated hydrochloric acid of use 18%.
(5) itrile group low temperature hydrolysis use 47 ~ 48% Hydrogen bromide time, with DL-2-amino-3-(3,4-Dimethoxyphenyl) mol ratio of-2-methyl-propanenitrile (hydrochloride) or L-2-amino-3-(3,4-Dimethoxyphenyl)-2-methyl-propanenitrile (hydrochloride) is 1:0.07; Be 1:0.14 when the Hydrogen bromide of use 23 ~ 24%.
The concrete steps of demethylation hydrolysis of the present invention are as follows:
(1) DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionic acid, L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionic acid can use acid to carry out demethylation hydrolysis, and demethylation hydrolysis optimum temps is 100 ~ 110 DEG C;
(2) acid used is 18% ~ 36% concentrated hydrochloric acid (mass/volume ratio) or 24% ~ 48% Hydrogen bromide (mass/volume ratio);
(3) when demethylation is hydrolyzed the concentrated hydrochloric acid of use 36%, with DL-2-amino-3-(3,4-Dimethoxyphenyl) mol ratio of-2-rnethyl-propanoic acid (hydrochloride) or L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid (hydrochloride) is 1:0.083 ~ 0.167;
(4) when demethylation is hydrolyzed the Hydrogen bromide of use 47%, with DL-2-amino-3-(3,4-Dimethoxyphenyl) mol ratio of-2-rnethyl-propanoic acid (hydrochloride) or L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid (hydrochloride) is 1:0.167; Be 1:0.33 when the Hydrogen bromide of use 23.5%;
(5), after demethylation has been hydrolyzed, the pH value of two step ammoniacal liquor adjustment solution need be divided, constant in 6 to pH value;
(6) DL-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid (hydrochloride) or L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid (hydrochloride) solid can use washing with acetone;
(7) DL-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid (hydrochloride) or L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid (hydrochloride) solid can 40 ~ 70 DEG C of dryings.
Technical solutions according to the invention, after hydrolysis reaction completes, slowly need pass into N directly to reaction mixture before after-treatment products
2, underpressure distillation simultaneously extracts excessive HCl or Hydrogen bromide.
DL-2-amino-3-(3 of the present invention, 4-Dimethoxyphenyl)-2-rnethyl-propanoic acid (hydrochloride) or L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid (hydrochloride) used water makes recrystallization solvent, gac makes discoloring agent, recrystallization 80 ~ 90 DEG C time, purity can reach more than 99.8%.
The present invention carries out DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride), the hydrolysis of L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) itrile group and demethylation be hydrolyzed and be divided into two steps:
1.DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride), L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) itrile group hydrolysis can carry out at low temperatures, the present invention finds that the optimum temps that low temperature itrile group is hydrolyzed is-5 ~ 4 DEG C, and the acid of use is 24% ~ 48% Hydrogen bromide (mass/volume ratio) or 18% ~ 36% concentrated hydrochloric acid.Itrile group low temperature hydrolysis can obtain DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionic acid (or L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionic acid, lower with).
The present invention finds DL-Alpha-Methyl-(3, 4-Dimethoxyphenyl) solid particulate of-alpha-amino group propionitrile (or hydrochloride) is when low temperature hydrolysis, just solid particles surface and Hydrogen bromide or concentrated hydrochloric acid are hydrolyzed, the DL-Alpha-Methyl-(3 generated after reaction, 4-Dimethoxyphenyl)-α-aminopropionic acid can not spread rapidly on surface, form cluster, cause DL-Alpha-Methyl-(3, 4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) solid particulate inside fails complete hydrolysis at low temperatures, significantly reduce output, general about 40 ~ 50%, therefore itrile group low temperature hydrolysis needs vigorous stirring.Agitator adopts propeller stirrer.Stirring velocity is 1000 ~ 1500rpm, and best stirring velocity is 1200rpm.
2. the present invention finds that DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionic acid carries out demethylation hydrolysis at low temperatures, no matter with Hydrogen bromide or all cannot demethylation with concentrated hydrochloric acid.Demethylation hydrolysis must at high temperature be carried out, and the present invention finds that the optimum temps that high temperature demethylation is hydrolyzed is 100 ~ 110 DEG C, and the acid of use is 24% ~ 48% Hydrogen bromide (mass/volume ratio) or 18% ~ 36% concentrated hydrochloric acid.
The present invention finds DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride) itrile group low temperature hydrolysis 36% concentrated hydrochloric acid hydrolysis reaches more than 95%, and cheap, in industrial production, economical effectiveness is significantly better than 48% Hydrogen bromide.The optimum temps of DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionic acid (or L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionic acid, lower with) demethylation hydrolysis is 105 DEG C.With Hydrogen bromide or concentrated hydrochloric acid result almost identical.Can more than 95% be reached with 36% concentrated hydrochloric acid hydrolysis.
When the present invention's decompression after completion of the reaction deacidifies, pass into N
2to protection product not easy oxidation discoloration, and quickening deacidification has important effect.The present invention never degenerates for protecting product, and generally controlling product vacuum-drying temperature is 50 DEG C, dry 5 hours.Through secondary recrystallization, purity can reach 99.8%.
The present invention adopts under different thermogrades, by itrile group with demethylation stage by stage with " bistep hydrolysis " that identical acid or different acid are hydrolyzed, reduce the energy and Financial cost, decrease sour discharge of wastewater, decrease by product, improve purity and the output of product.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described further.
Embodiment medicine
Hydrogen bromide (HBr content 47%, technical grade) and concentrated hydrochloric acid (HCL content 36%, technical grade), DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride), L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (or hydrochloride), makes by oneself by document Span pat.545751 and Belg pat.633417; Following embodiment medicine is identical; High performance liquid chromatograph (U.S. Agilent 1100), infrared spectrometer (U.S. Nicolet 470 class), nuclear magnetic resonance analyser (German BRUKERAdvance2B 400MHz).
Embodiment 1
In the there-necked flask that thermometer, agitator and reflux condensing tube are housed, add the concentrated hydrochloric acid 12.3 grams (0.12mol) of 36%.0 ~ 5 DEG C is cooled to frozen water.Slowly add 2.18 grams of (0.0085mol) DL-2-amino-3-(3,4-Dimethoxyphenyl)-2-methyl-propanenitrile hydrochloride [or L-2-amino-3-(3,4-Dimethoxyphenyl)-2-methyl-propanenitrile hydrochloride, lower each embodiment is identical] be dissolved in ice-cold concentrated hydrochloric acid.Add rear vigorous stirring 2 hours.Rise to room temperature after having reacted, slowly pass into N directly to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl.Solid 3 × 25ml washing with acetone, obtains white solid.Then in 50 DEG C of vacuum-dryings 3 hours.Again 70 DEG C of dryings 5 hours.Obtain product D L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid hydrochloride (or L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid hydrochloride, lower each embodiment is identical) 2.03 grams, productive rate 86.8%.
Embodiment 2
In the there-necked flask that thermometer, agitator and reflux condensing tube are housed, add the concentrated hydrochloric acid 24.3 grams (0.24mol) of 36%.Be ice-cooling to 0 ~ 4 DEG C.Slowly adding 14.38 grams of (0.056mol) DL--2-amino-3-(3,4-Dimethoxyphenyl)-2-methyl-propanenitrile hydrochlorides is dissolved in ice-cold concentrated hydrochloric acid, after adding, keeps 0 ~ 4 DEG C to continue vigorous stirring 2 hours.Rise to room temperature after having reacted, slowly pass into N directly to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl.Solid 4 × 25ml washing with acetone, obtains white solid.Then in 50 DEG C of vacuum-dryings 3 hours.Again 70 DEG C of dryings 5 hours.Obtain product D L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid hydrochloride 14.70 grams, productive rate 95.2%.
Embodiment 3
In the there-necked flask that thermometer, agitator and reflux condensing tube are housed, add the concentrated hydrochloric acid 24.3 grams (0.12mol) of 18%.0 ~ 5 DEG C is cooled to frozen water.Slowly add 2.18 grams of (0.0085mol) DL-2-amino-3-(3,4-Dimethoxyphenyl)-2-methyl-propanenitrile hydrochlorides to be dissolved in ice-cold concentrated hydrochloric acid.Add rear vigorous stirring 2 hours.Rise to room temperature after having reacted, slowly pass into N directly to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl.Solid 3 × 25ml washing with acetone, obtains white solid.Then in 50 DEG C of vacuum-dryings 3 hours.Again 70 DEG C of dryings 5 hours.Obtain product D L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid hydrochloride 1.85 grams, productive rate 79.1%.
Embodiment 4
In the there-necked flask that thermometer, agitator and reflux condensing tube are housed, add the Hydrogen bromide 20.7 grams (0.12mol) of 47%.0 ~ 5 DEG C is cooled to frozen water.Slowly add 2.18 grams of (0.0085mol) DL-2-amino-3-(3,4-Dimethoxyphenyl)-2-methyl-propanenitrile hydrochlorides to be dissolved in ice-cold Hydrogen bromide.Add rear vigorous stirring 2 hours.Rise to room temperature after having reacted, slowly pass into N directly to reaction mixture
2, underpressure distillation simultaneously extracts excessive Hydrogen bromide.Solid 3 × 25ml washing with acetone, obtains white solid.Then in 50 DEG C of vacuum-dryings 3 hours.Again 70 DEG C of dryings 5 hours.Obtain product D L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid hydrochloride 2.23 grams, productive rate 95.4%.
Embodiment 5
In the there-necked flask that thermometer, agitator and reflux condensing tube are housed, add the Hydrogen bromide 20.7 grams (0.06mol) of 23.5%.0 ~ 5 DEG C is cooled to frozen water.Slowly add 2.18 grams of (0.0085mol) DL-2-amino-3-(3,4-Dimethoxyphenyl)-2-methyl-propanenitrile hydrochlorides to be dissolved in ice-cold Hydrogen bromide.Add rear vigorous stirring 2 hours.Rise to room temperature after having reacted, slowly pass into N directly to reaction mixture
2, underpressure distillation simultaneously extracts excessive Hydrogen bromide.Solid 3 × 25ml washing with acetone, obtains white solid.Then in 50 DEG C of vacuum-dryings 3 hours.Again 70 DEG C of dryings 5 hours.Obtain product D L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid hydrochloride 1.95 grams, productive rate 83.3%.
Embodiment 6
In the there-necked flask that thermometer, agitator and reflux condensing tube are housed, add the concentrated hydrochloric acid 24.3 grams (0.24mol) of 36%, add 5.52 grams of (0.02mol) DL-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid hydrochloride [or L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid hydrochloride, lower each embodiment is identical].Then oil bath is slowly heated to 65-70 DEG C of (needing 40 minutes) stirring reaction 6 hours, reheats to 100 ~ 110 DEG C, stirring reaction 24 hours.Rise to room temperature after having reacted, slowly pass into N directly to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl.There is solid to occur by the pH value of ammoniacal liquor adjustment solution, be stirred to pH constant.Then, carefully adjust pH to 6, leave standstill 1 hour, solid filtering.Solid 4 × 25ml washing with acetone, obtains white solid.Then in 50 DEG C of vacuum-dryings 5 hours.Obtain product D L-2-amino-3-(3,4-dihydroxy phenyl)-2-rnethyl-propanoic acid (C
10h
13nO
4h
2o
1.5) i.e. methyldopa 4.56 grams, 95.8%.
Embodiment 7
In the there-necked flask that thermometer, agitator and reflux condensing tube are housed, add the concentrated hydrochloric acid 12.3 grams (0.12mol) of 36%, add 5.52 grams of (0.02mol) DL-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid hydrochlorides.Then oil bath is slowly heated to 65-70 DEG C of (needing 40 minutes) stirring reaction 6 hours, reheats to 100 ~ 110 DEG C, stirring reaction 24 hours.Rise to room temperature after having reacted, slowly pass into N directly to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl.There is solid to occur by the pH value of ammoniacal liquor adjustment solution, be stirred to pH constant.Then, carefully adjust pH to 6, leave standstill 1 hour, solid filtering.Solid 4 × 25ml washing with acetone, obtains white solid.Then in 50 DEG C of vacuum-dryings 5 hours.Obtain product D L-2-amino-3-(3,4-dihydroxy phenyl)-2-rnethyl-propanoic acid (C
10h
13nO
4h
2o
1.5) i.e. methyldopa 4.39 grams, 92.2%.
Embodiment 8
In the there-necked flask that thermometer, agitator and reflux condensing tube are housed, add the Hydrogen bromide 20.7 grams (0.12mol) of 47%, add 5.52 grams of (0.02mol) DL-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid hydrochlorides.Then oil bath is slowly heated to 65-70 DEG C of (needing 40 minutes) stirring reaction 6 hours, reheats to 100 ~ 110 DEG C, stirring reaction 18 hours.Rise to room temperature after having reacted, slowly pass into N directly to reaction mixture
2, underpressure distillation simultaneously extracts excessive Hydrogen bromide.There is solid to occur by the pH value of ammoniacal liquor adjustment solution, be stirred to pH constant.Then, carefully adjust pH to 6, leave standstill 1 hour, solid filtering.Solid 4 × 25ml washing with acetone, obtains white solid.Then in 50 DEG C of vacuum-dryings 5 hours.Obtain product D L-2-amino-3-(3,4-dihydroxy phenyl)-2-rnethyl-propanoic acid (C
10h
13nO
4h
2o
1.5) i.e. methyldopa 4.56 grams, 95.7%.
Embodiment 9
In the there-necked flask that thermometer, agitator and reflux condensing tube are housed, add the Hydrogen bromide 20.7 grams (0.06mol) of 23.5%, add 5.52 grams of (0.02mol) DL-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid hydrochlorides.Then oil bath is slowly heated to 65-70 DEG C of (needing 40 minutes) stirring reaction 6 hours, reheats to 100 ~ 110 DEG C, stirring reaction 18 hours.Rise to room temperature after having reacted, slowly pass into N directly to reaction mixture
2, underpressure distillation simultaneously extracts excessive Hydrogen bromide.There is solid to occur by the pH value of ammoniacal liquor adjustment solution, be stirred to pH constant.Then, carefully adjust pH to 6, leave standstill 1 hour, solid filtering.Solid 4 × 25ml washing with acetone, obtains white solid.Then in 50 DEG C of vacuum-dryings 5 hours.Obtain product D L-2-amino-3-(3,4-dihydroxy phenyl)-2-rnethyl-propanoic acid (C
10h
13nO
4h
2o
1.5) i.e. methyldopa 4.26 grams, 89.6%.
Embodiment 10
8 grams in grayish DL-2-amino-3-(3,4-dihydroxy phenyl)-2-rnethyl-propanoic acid and methyldopa [or L-2-amino-3-(3,4-dihydroxy phenyl)-2-rnethyl-propanoic acid, lower each embodiment is identical] in 40ml water, 80-90 DEG C of heating for dissolving, adds 0.4 gram of gac, and 90 DEG C are stirred 10 minutes, filtered while hot, cooling has solid to separate out.Place 2 hours, suction filtration obtains white solid.100 DEG C of dryings 3 hours, obtain white solid 7.03 grams, yield 87.9%.MP.295-299 DEG C (variable color), 302 DEG C of decomposition.Product is through ultimate analysis, infrared, nuclear-magnetism spectrum qualification.Purity detects through high performance liquid chromatograph.Through secondary recrystallization, purity can reach more than 99.8%.
Finally, it is also to be noted that what enumerate above is only several specific embodiment of the present invention; obviously, the invention is not restricted to above embodiment, many distortion can also be had; as long as all distortion that disclosed content directly derives or associates, protection scope of the present invention all should be thought.
Claims (3)
1. the method that is hydrolyzed for itrile group hydrolysis and the demethylation of methyldopa or L-methyldopa of a veratone legal system, under it is characterized in that different thermogrades, by itrile group with demethylation stage by stage with " bistep hydrolysis " that identical acid or different acid are hydrolyzed, itrile group hydrolysis concrete steps as follows:
(1) DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile or hydrochloride, L-2-amino-3-(3,4-Dimethoxyphenyl)-2-methyl-propanenitrile or hydrochloride itrile group hydrolysis carry out at low temperatures, low temperature itrile group hydrolysis optimum temps be-5 ~ 4 DEG C;
(2) itrile group low temperature hydrolysis needs vigorous stirring, and agitator adopts propeller stirrer, and stirring velocity is 1000 ~ 1500rpm;
(3) acid that hydrolysis uses is the concentrated hydrochloric acid of mass/volume than 18% ~ 36%;
(4) itrile group low temperature hydrolysis use 36% concentrated hydrochloric acid time, with DL-2-amino-3-(3,4-Dimethoxyphenyl) mol ratio of-2-methyl-propanenitrile or hydrochloride, L-2-amino-3-(3,4-Dimethoxyphenyl)-2-methyl-propanenitrile or hydrochloride is 1:0.07 ~ 0.25; Be 1:0.07 when the concentrated hydrochloric acid of use 18%.
2. the itrile group hydrolysis of veratone legal system according to claim 1 for methyldopa or L-methyldopa and the method for demethylation hydrolysis, it is characterized in that, the concrete steps that demethylation is hydrolyzed are as follows:
(1) DL-Alpha-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionic acid, L-Alpha-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionic acid can use acid to carry out demethylation hydrolysis;
(2) acid used is the concentrated hydrochloric acid of mass/volume than 18% ~ 36%;
(3) when demethylation is hydrolyzed the concentrated hydrochloric acid of use 36%, with DL-2-amino-3-(3,4-Dimethoxyphenyl) mol ratio of-2-rnethyl-propanoic acid or hydrochloride, L-2-amino-3-(3,4-Dimethoxyphenyl)-2-rnethyl-propanoic acid or hydrochloride is 1:0.083 ~ 0.167;
(4), after demethylation has been hydrolyzed, the pH value of two step ammoniacal liquor adjustment solution need be divided, constant in 6 to pH value.
3. the method that is hydrolyzed for itrile group hydrolysis and the demethylation of methyldopa or L-methyldopa of veratone legal system according to claim 1 and 2, is characterized in that, after hydrolysis reaction completes, slowly need pass into N before after-treatment products directly to reaction mixture
2, underpressure distillation simultaneously extracts excessive HCl.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US2868818A (en) * | 1953-12-15 | 1959-01-13 | Merck & Co Inc | Alpha methyl phenylalanines |
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| US2868818A (en) * | 1953-12-15 | 1959-01-13 | Merck & Co Inc | Alpha methyl phenylalanines |
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| Die externe asymmetrische Strecker-Synthese von a-Methyl-aminosauren;Klaus Weinges, et al;《Chem. Ber.》;19711231;第104卷;3594-3606 * |
| L-甲基多巴的合成工艺改进;吴范宏 等;《广州化工》;20081231;第36卷(第2期);第44-45页 * |
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