CN103804234B - The synthetic method of Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile - Google Patents
The synthetic method of Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile Download PDFInfo
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- CN103804234B CN103804234B CN201410091232.2A CN201410091232A CN103804234B CN 103804234 B CN103804234 B CN 103804234B CN 201410091232 A CN201410091232 A CN 201410091232A CN 103804234 B CN103804234 B CN 103804234B
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Abstract
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.Add veratone by after water, ammonium chloride and cyano propanone stirring and dissolving, pass into ammonia, insulation reaction, then aftertreatment obtains product.Aftertreatment is: the reaction solution after insulation reaction is cooled to 20 ~ 30 DEG C, filters, and washing is dry, obtains white solid.The mother liquid recycle obtained after filtering in aftertreatment feeds intake in next batch, namely replaces water and ammonium chloride to prepare Alpha-Methyl-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile as raw material with mother liquor.The present invention substitutes sodium cyanide to carry out the study on the synthesis of D, L-aminopropionitrile with the raw material cyano propanone of low toxicity, and yield is up to more than 96.5%, and purity is greater than 99.3%, and toxicity is low, achieves safety in production.
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 receptor block type cardiovascular agent, is the Class B basic medical insurance product that United Nations is recommended, 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.Good curative effect is had to moderate primary and renal hypertension patient.The synthetic route of prior art report is as follows: with veratone (3,4-dimethoxy Propiophenone) be raw material, after Strecker Amino acid synthesis reacts, DL-aminopropionitrile is prepared 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 (be called for short D, L-aminopropionitrile) take veratone as the key intermediate of Material synthesis L-α-methyl-dopa.Be prepared into after Strecker Amino acid synthesis reacts by veratone and sodium cyanide and ammonium chloride etc.
This path resource availability is comparatively reasonable, but critical materials used---sodium cyanide is severe poisonous chemicals, and danger rule numbering A1001, lethal dose is 0.1 ~ 1g.All very strict in transport, 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, sodium cyanide is substituted to carry out D with the raw material cyano propanone of low toxicity, 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, achieve safety in production.
The synthetic method of Alpha-Methyl of the present invention-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile, add veratone by after water, ammonium chloride and cyano propanone stirring and dissolving, pass into ammonia, insulation reaction, 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, be 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 DEG C, filters, and washing is dry, obtains white solid.
Insulation reaction temperature is 55 ~ 80 DEG C, and the insulation reaction time is 1 ~ 3 hour.Drying temperature in aftertreatment is 45 ~ 55 DEG C.
The mother liquid recycle obtained after filtering in aftertreatment of the present invention feeds intake in next batch, namely 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.
Namely synthetic method is: add veratone by after mother liquor, cyano propanone stirring and dissolving, pass into ammonia, insulation reaction, then the reaction solution after insulation reaction is cooled to 20 ~ 30 DEG C, filters, and washing is dry, obtains white solid.
The mother liquid recycle that obtains after filtering in aftertreatment feeds intake in next batch by the present invention, 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, and Mp85 ~ 87 DEG C, 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 the Alpha-Methyl prepared-(3,4-Dimethoxyphenyl)-alpha-amino group propionitrile 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, adds phosphatase 11 g, uses 0.45um membrane filtration, then add 200ml methyl alcohol, then add 200ml acetonitrile after dissolving.
Need testing solution: take 0.01g trial-product, is settled to 10ml with after the dissolve with hydrochloric acid solution of 0.1mol/l.Require that need testing solution is now joined now to do, storage period must not more than 1 hour.
Chromatographic condition: chromatographic column: C18 post, 4.6mm × 250mm × 5um, flow velocity: 1.0ml/min; Wavelength: 278nm; Column temperature: 30 DEG C, 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 substitutes sodium cyanide to carry out the study on the synthesis of D, L-aminopropionitrile with the raw material cyano propanone of low toxicity, and yield is up to more than 96.5%, and purity is greater than 99.3%, and toxicity is low, achieves safety in production.
(2) mother liquor after filtering not only can be applied mechanically, and can also apply mechanically up to more than 10 times, save water and ammonium chloride, reduced cost, save resource and environmental protection.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1
Add in purified water 100ml, ammonium chloride 0.15mol, cyano propanone 0.15mol input reaction flask in 500ml tetra-mouthfuls of reaction flasks that stirring is housed, 0.1mol veratone is added after stirring and dissolving, slowly pass into ammonia 15mol, in logical ammonia process, reacting liquid temperature rises to about 45 DEG C naturally.After logical ammonia terminates, be heated to 65 DEG C, insulation reaction 2 hours.Be incubated complete, be cooled to 25 DEG C, filtration, washing, 50 DEG C of dryings, obtain white solid, yield 97.25%, HPLC purity 99.35%.Mother liquid recycle after filtration feeds intake in next batch.
Embodiment 2
Add in purified water 115ml, ammonium chloride 0.13mol, cyano propanone 0.10mol input reaction flask in 500ml tetra-mouthfuls of reaction flasks that stirring is housed, 0.1mol veratone is added after stirring and dissolving, slowly pass into ammonia 22mol, in logical ammonia process, reacting liquid temperature rises to about 45 DEG C naturally.After logical ammonia terminates, be heated to 65 DEG C, insulation reaction 2 hours.Be incubated complete, be cooled to 25 DEG C, filtration, washing, 50 DEG C of dryings, obtain white solid, yield 98.02%, HPLC purity 99.45%.
Embodiment 3
In 500ml tetra-mouthfuls of reaction flasks that stirring is housed, add mother liquor 200ml, the cyano propanone 23ml that embodiment 1 obtains 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 about 45 DEG C naturally.After logical ammonia terminates, be heated to 55 DEG C, insulation reaction 3 hours.Be incubated complete, be cooled to 30 DEG C, filtration, washing, 50 DEG C of dryings, obtain white solid, yield 97.01%, HPLC purity 99.43%.Mother liquid recycle after filtration feeds intake in next batch.
Embodiment 4
In 500ml tetra-mouthfuls of reaction flasks that stirring is housed, add mother liquor 200ml, the cyano propanone 23ml that embodiment 3 obtains 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 about 45 DEG C naturally.After logical ammonia terminates, be heated to 80 DEG C, insulation reaction 1 hour.Be incubated complete, be cooled to, less than 20 DEG C, filtration, washing, 50 DEG C of dryings, obtain white solid, yield 96.51%, HPLC purity 99.42%.Mother liquid recycle after filtration feeds intake in next batch.
The product (D, L-aminopropionitrile) prepared with embodiment 1 prepares L-α-methyl-dopa:
(1) fractionation (preparation L-aminopropionitrile hydrochloride) of D, L-aminopropionitrile
Water 215g, hydrochloric acid 14.7g are added in reaction flask, stir and lower drop into DL-aminopropionitrile 33g, after stirring to clarify, add L-TARTARIC ACID 24g, NaOH5g, mixing solutions that water 25g is made into, stir and be cooled to 0 DEG C, stir 30min.Filter the tartrate obtaining D-aminopropionitrile, for next step racemization.Filtrate adds methylene dichloride 66g, and stirring separates, and regulates PH to 6.4 ~ 7.0 by NaOH solution, stirs 10min, static layering organic layer, and water layer methylene dichloride 30g extracts once.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 DEG C of crystallization, filters to obtain L-aminopropionitrile hydrochloride, HPLC content 99.2%.
(2) racemization of D-aminopropionitrile tartrate
In 500ml tetra-mouthfuls of reaction flasks that stirring is housed, add purified water 200ml, 300g D-aminopropionitrile tartrate wet product, under stirring, pass into ammonia 40g.After logical ammonia terminates, be heated to 55 DEG C, insulation reaction 1 hour.Be incubated complete, be cooled to less than 30 DEG C, filtration, washing, 50 DEG C of dryings, obtain the mother liquid recycle after white solid filtration in next batch racemization.
(3) L-methyldopa is prepared
L-aminopropionitrile hydrochloride 150g (0.58mol), 35% hydrochloric acid 900g are dropped in reaction flask, stirred at ambient temperature 2h, is slowly warming up to 65 DEG C ~ 70 DEG C, is incubated 2 ~ 3 hours, and then is slowly warming up to 105 DEG C, is incubated 8 hours.Add oxidation inhibitor (oxysuccinic acid) and start underpressure distillation, steam to thickness, add 100g water, be adjusted to pH value=4.5 with ammoniacal liquor, be down to less than 5 DEG C, filter, obtain 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 (1)
1. Alpha-Methyl-(3,4-Dimethoxyphenyl) synthetic method of-alpha-amino group propionitrile, it is characterized in that: in 500ml tetra-mouthfuls of reaction flasks that stirring is housed, add purified water 115ml, ammonium chloride 0.13mol, cyano propanone 0.10mol, 0.1mol veratone is added after stirring and dissolving, pass into ammonia 22mol, in logical ammonia process, reacting liquid temperature rises to 45 DEG C naturally, after logical ammonia terminates, be heated to 65 DEG C, insulation reaction 2 hours, is incubated complete, is cooled to 25 DEG C, filtration, washing, 50 DEG C of dryings, obtain white solid.
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| EP4267123A1 (en) * | 2020-12-23 | 2023-11-01 | ImmunoMolecular Therapeutics, Inc. | Methods for producing d-?-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 |
| 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 |
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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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 |
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