CN103804234A - Synthetic method of alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile - Google Patents
Synthetic method of alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile Download PDFInfo
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- CN103804234A CN103804234A CN201410091232.2A CN201410091232A CN103804234A CN 103804234 A CN103804234 A CN 103804234A CN 201410091232 A CN201410091232 A CN 201410091232A CN 103804234 A CN103804234 A CN 103804234A
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Abstract
The invention belongs to the field of the pharmacy, and particularly relates to a synthetic method of alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile. The synthetic method comprises the steps of: stirring and dissolving water, ammonium chloride and cyano acetone, then adding veratone, inhaling ammonia gas, performing a heat preservation reaction and then performing post-treatment to obtain the product, wherein the post-treatment comprises the steps of: cooling the reaction liquid obtained after the heat preservation reaction is ended to 20-30 DEG C, filtering, washing with water and then drying to obtain white solid; the mother liquid obtained after the filtration in the post-treatment is used for the next batch of material feeding, namely the mother liquid is used as a raw material for replacing water and ammonium chloride to prepare alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile. The synthetic method disclosed by the invention is used for a synthesis research on D,L-aminopropionitrile by replacing sodium cyanide with a low-toxicity raw material cyano acetone, the yield is over 96.5%, the purity is larger than 99.3% and the toxicity is also low, thus safe production is realized.
Description
Technical field
The invention belongs to pharmacy field, be specifically related to the synthetic method of a kind of Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile.
Background technology
L-α-methyl-dopa is a kind of decarboxylase inhibitor, belongs to acceptor accumulation type cardiovascular agent, is the Class B basic medical insurance product that United Nations is recommended, and is classified as one of national essential drugs in 1998 by country.There is antihypertensive effect, at present clinically as the hypertensive drug use for the treatment of.Moderate primary and renal hypertension patient are had to good curative effect.The synthetic route of prior art report is as follows: with veratone (3,4-dimethoxy Propiophenone) be raw material, after Strecker amino acid building-up reactions, prepare DL-aminopropionitrile with sodium cyanide and ammonium chloride etc., after splitting, obtain L-aminopropionitrile hydrochloride, after hydrolysis, obtain L-α-methyl-dopa.
Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile (being called for short D, L-aminopropionitrile) is the key intermediate of the synthetic L-α-methyl-dopa take veratone as raw material.Be prepared into after Strecker amino acid building-up reactions by veratone and sodium cyanide and ammonium chloride etc.
This route resource utilization is more reasonable, but critical materials used---sodium cyanide is severe poisonous chemicals, danger rule numbering A1001, and lethal dose is 0.1～1g.All very strict in transportation, use, management.
Summary of the invention
For the deficiencies in the prior art, the object of this invention is to provide a kind of Alpha-Methyl-(3,4-Dimethoxyphenyl) synthetic method of-alpha-amino group propionitrile, substitute sodium cyanide with the raw material cyano propanone of low toxicity and carry out D, the study on the synthesis of L-aminopropionitrile, yield is up to more than 96.5%, and purity is greater than 99.3%, and toxicity is low, realize safety in production.
The synthetic method of Alpha-Methyl of the present invention-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile, by adding veratone after water, ammonium chloride and cyano propanone stirring and dissolving, passes into ammonia, insulation reaction, and then aftertreatment obtains product.
Wherein: the mol ratio of veratone, cyano propanone, ammonium chloride and ammonia is 1:1.0-1.5:1.0-1.5:10-22, is preferably 1:1.3:1.3:22, the consumption of water is 5～6 times of veratone quality.
Aftertreatment is: the reaction solution after insulation reaction is cooled to 20～30 ℃, filters, and washing, dry, obtain white solid.
Insulation reaction temperature is 55～80 ℃, and the insulation reaction time is 1～3 hour.Drying temperature in aftertreatment is 45～55 ℃.
The mother liquid recycle obtaining after filtering in aftertreatment of the present invention feeds intake in next batch, replaces water and ammonium chloride to adopt above-mentioned preparation method to prepare Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile as raw material with mother liquor.
Be that synthetic method is: by adding veratone after mother liquor, cyano propanone stirring and dissolving, pass into ammonia, insulation reaction, is then cooled to 20～30 ℃ by the reaction solution after insulation reaction, filter, washing, dry, obtain white solid.
The present invention feeds intake the mother liquid recycle that obtains after filtering in aftertreatment in next batch, can apply mechanically more than 10 times at most, make synthetic method more economically, environmental protection.
The product that the present invention prepares is white solid, Mp85～87 ℃, and purity is greater than 99.3%.The D that the present invention prepares, L-aminopropionitrile adopts common process to prepare L-α-methyl-dopa.
Reaction equation of the present invention is:
The analytical procedure of Alpha-Methyl-(3,4-the Dimethoxyphenyl)-alpha-amino group propionitrile preparing adopts red, orange, green, blue, yellow (ROGBY):
Wherein: reagent: acetonitrile (chromatographically pure); Methyl alcohol (chromatographically pure); Water (redistilled water); Phosphoric acid (chromatographically pure); Potassium primary phosphate (top grade is pure).
Moving phase: add potassium primary phosphate 2g in 600ml water, add phosphatase 11 g, use 0.45um membrane filtration after dissolving, then add 200ml methyl alcohol, then add 200ml acetonitrile.
Need testing solution: take 0.01g trial-product, be settled to 10ml after the dissolve with hydrochloric acid solution with 0.1mol/l.Require need testing solution now to join now and do, must not exceed 1 hour storage period.
Chromatographic condition: chromatographic column: C18 post, 4.6mm × 250mm × 5um, flow velocity: 1.0ml/min; Wavelength: 278nm; Column temperature: 30 ℃, sample size: 5ul.Require main peak resolution > 2.0; Main peak tailing factor < 2.0; Theoretical plate number > 2000.Cubage: area normalization method.
In sum, the present invention has the following advantages:
(1) the present invention carries out D with the alternative sodium cyanide of raw material cyano propanone of low toxicity, the study on the synthesis of L-aminopropionitrile, and yield is up to more than 96.5%, and purity is greater than 99.3%, and toxicity is low, has realized safety in production.
(2) mother liquor after filtration not only can be applied mechanically, and can also apply mechanically up to more than 10 times, has saved water and ammonium chloride, has reduced cost, has saved resource and environmental protection.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1
In the 500ml four-hole reaction flask that stirring is housed, add purified water 100ml, ammonium chloride 0.15mol, cyano propanone 0.15mol to drop in reaction flask, after stirring and dissolving, add 0.1mol veratone, slowly pass into ammonia 15mol, in logical ammonia process, reacting liquid temperature rises to approximately 45 ℃ naturally.After logical ammonia finishes, be heated to 65 ℃, insulation reaction 2 hours.Be incubated completely, be cooled to 25 ℃, filter, washing, 50 ℃ be dry, obtains white solid, yield 97.25%, HPLC purity 99.35%.Mother liquid recycle after filtration feeds intake in next batch.
Embodiment 2
In the 500ml four-hole reaction flask that stirring is housed, add purified water 115ml, ammonium chloride 0.13mol, cyano propanone 0.10mol to drop in reaction flask, after stirring and dissolving, add 0.1mol veratone, slowly pass into ammonia 22mol, in logical ammonia process, reacting liquid temperature rises to approximately 45 ℃ naturally.After logical ammonia finishes, be heated to 65 ℃, insulation reaction 2 hours.Be incubated completely, be cooled to 25 ℃, filter, washing, 50 ℃ be dry, obtains white solid, yield 98.02%, HPLC purity 99.45%.
Embodiment 3
In the 500ml four-hole reaction flask that stirring is housed, add mother liquor 200ml, the cyano propanone 23ml that embodiment 1 obtains to drop in reaction flask, after stirring and dissolving, add 35g veratone.Slowly pass into ammonia 25g, in logical ammonia process, reacting liquid temperature rises to approximately 45 ℃ naturally.After logical ammonia finishes, be heated to 55 ℃, insulation reaction 3 hours.Be incubated completely, be cooled to 30 ℃, filter, washing, 50 ℃ be dry, obtains white solid, yield 97.01%, HPLC purity 99.43%.Mother liquid recycle after filtration feeds intake in next batch.
Embodiment 4
In the 500ml four-hole reaction flask that stirring is housed, add mother liquor 200ml, the cyano propanone 23ml that embodiment 3 obtains to drop in reaction flask, after stirring and dissolving, add 35g veratone.Slowly pass into ammonia 25g, in logical ammonia process, reacting liquid temperature rises to approximately 45 ℃ naturally.After logical ammonia finishes, be heated to 80 ℃, insulation reaction 1 hour.Be incubated completely, be cooled to, below 20 ℃, filter, washing, 50 ℃ be dry, obtains white solid, yield 96.51%, HPLC purity 99.42%.Mother liquid recycle after filtration feeds intake in next batch.
The product (D, L-aminopropionitrile) preparing with embodiment 1 is prepared L-α-methyl-dopa:
(1) D, the fractionation (preparation L-aminopropionitrile hydrochloride) of L-aminopropionitrile
Water 215g, hydrochloric acid 14.7g are added in reaction flask, stir the lower DL-of input aminopropionitrile 33g, after stirring to clarify, the mixing solutions that adds L-TARTARIC ACID 24g, NaOH5g, water 25g to be made into, stirs and is cooled to 0 ℃, stirs 30min.Filtration obtains the tartrate of D-aminopropionitrile, for next step racemization.Filtrate adds methylene dichloride 66g, and stirring separates, and with NaOH solution adjusting PH to 6.4～7.0, stirs 10min, static layering organic layer, and water layer extracts once with methylene dichloride 30g.Merge organic layer, add 12.7g hydrochloric acid and 10.8g water, at room temperature stir half an hour, water layer is chilled to 0 ℃ of crystallization, filters to obtain L-aminopropionitrile hydrochloride, HPLC content 99.2%.
(2) racemization of D-aminopropionitrile tartrate
In the 500ml four-hole reaction flask that stirring is housed, add purified water 200ml, 300g D-aminopropionitrile tartrate wet product, under stirring, pass into ammonia 40g.After logical ammonia finishes, be heated to 55 ℃, insulation reaction 1 hour.Be incubated completely, be cooled to below 30 ℃, filter, washing, 50 ℃ be dry, obtain mother liquid recycle after white solid filters in next batch racemization.
(3) prepare L-methyldopa
L-aminopropionitrile hydrochloride 150g (0.58mol), 35% hydrochloric acid 900g are dropped in reaction flask, under room temperature, stir 2h, be slowly warming up to 65 ℃～70 ℃, be incubated 2～3 hours, and then be slowly warming up to 105 ℃, be incubated 8 hours.Add oxidation inhibitor (oxysuccinic acid) to start underpressure distillation, steam to thickness, add 100g water, be adjusted to pH value=4.5 with ammoniacal liquor, be down to below 5 ℃, filtration, obtains crude product with a small amount of water washing.Crude product water recrystallization, dries and obtains white crystals L-methyldopa 86.4g(yield 70%), HPLC content 99.5%.
Claims (6)
1. the synthetic method of Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile, is characterized in that: by adding veratone after water, ammonium chloride and cyano propanone stirring and dissolving, pass into ammonia, and insulation reaction, then aftertreatment obtains product.
2. Alpha-Methyl according to claim 1-(3,4-Dimethoxyphenyl) synthetic method of-alpha-amino group propionitrile, it is characterized in that: the mol ratio of veratone, cyano propanone, ammonium chloride and ammonia is 1:1.0-1.5:1.0-1.5:10-22, the consumption of water is 5～6 times of veratone quality.
3. Alpha-Methyl according to claim 2-(3,4-Dimethoxyphenyl) synthetic method of-alpha-amino group propionitrile, it is characterized in that: the mol ratio of veratone, cyano propanone, ammonium chloride and ammonia is 1:1.3:1.3:22, the consumption of water is 5～6 times of veratone quality.
4. the synthetic method of Alpha-Methyl according to claim 1-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile, is characterized in that: aftertreatment is: the reaction solution after insulation reaction is cooled to 20～30 ℃, filter, washing, dry, obtain white solid.
5. the synthetic method of Alpha-Methyl according to claim 1-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile, is characterized in that: insulation reaction temperature is 55～80 ℃, and the insulation reaction time is 1～3 hour.
6. the synthetic method of Alpha-Methyl according to claim 4-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile, is characterized in that: drying temperature is 45～55 ℃.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20220194893A1 (en) * | 2020-12-23 | 2022-06-23 | Immunomolecular Therapeutics, Inc. | Methods for Producing D-alpha-Methyldopa |
| CN115286532A (en) * | 2022-08-26 | 2022-11-04 | 浙江野风药业股份有限公司 | Method for continuously synthesizing methyldopa intermediate DL-aminopropionitrile |
| CN116987004A (en) * | 2023-09-27 | 2023-11-03 | 新华制药（寿光）有限公司 | Synthesis method of 3- (3, 4-dimethoxy phenyl) -2-amino-2-methylpropanenitrile |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2868818A (en) * | 1953-12-15 | 1959-01-13 | Merck & Co Inc | Alpha methyl phenylalanines |
| CN102731236A (en) * | 2012-07-05 | 2012-10-17 | 重庆紫光化工股份有限公司 | Alpha-amino cyclo nitrile compound preparation method |
| CN103435507A (en) * | 2013-09-09 | 2013-12-11 | 山东新华制药股份有限公司 | Preparation method of L-alpha-methyl-3,4-dihydroxyphenylalanine |
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- 2014-03-13 CN CN201410091232.2A patent/CN103804234B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2868818A (en) * | 1953-12-15 | 1959-01-13 | Merck & Co Inc | Alpha methyl phenylalanines |
| CN102731236A (en) * | 2012-07-05 | 2012-10-17 | 重庆紫光化工股份有限公司 | Alpha-amino cyclo nitrile compound preparation method |
| CN103435507A (en) * | 2013-09-09 | 2013-12-11 | 山东新华制药股份有限公司 | Preparation method of L-alpha-methyl-3,4-dihydroxyphenylalanine |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20220194893A1 (en) * | 2020-12-23 | 2022-06-23 | Immunomolecular Therapeutics, Inc. | Methods for Producing D-alpha-Methyldopa |
| US11702383B2 (en) * | 2020-12-23 | 2023-07-18 | Immunomolecular Therapeutics, Inc. | Methods for producing D-α-methyldopa |
| CN115286532A (en) * | 2022-08-26 | 2022-11-04 | 浙江野风药业股份有限公司 | Method for continuously synthesizing methyldopa intermediate DL-aminopropionitrile |
| CN116987004A (en) * | 2023-09-27 | 2023-11-03 | 新华制药（寿光）有限公司 | Synthesis method of 3- (3, 4-dimethoxy phenyl) -2-amino-2-methylpropanenitrile |
| CN116987004B (en) * | 2023-09-27 | 2023-12-12 | 新华制药（寿光）有限公司 | Synthesis method of 3- (3, 4-dimethoxy phenyl) -2-amino-2-methylpropanenitrile |
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