CN114685301A - Production improvement method of 2-amino malonamide - Google Patents
Production improvement method of 2-amino malonamide Download PDFInfo
- Publication number
- CN114685301A CN114685301A CN202210356726.3A CN202210356726A CN114685301A CN 114685301 A CN114685301 A CN 114685301A CN 202210356726 A CN202210356726 A CN 202210356726A CN 114685301 A CN114685301 A CN 114685301A
- Authority
- CN
- China
- Prior art keywords
- diethyl
- ammonia gas
- aminomalonate
- stirring
- improved process
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
Abstract
The invention provides a method for producing and improving 2-amino malonamide, which has the advantages of simple operation, recyclable solvent, less three wastes, high yield, high purity of a product Gas Chromatography (GC) up to more than 99 percent, and suitability for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a production improvement method of a Favipiravir intermediate 2-amino malonamide.
Background
Favipiravir (favipiravir), chemically named 6-fluoro-3-hydroxypyrazine-2-carboxamide, is a viral RNA polymerase inhibitor developed by Fushan chemical industries, Japan, and can selectively block the synthesis of viral RNA, and does not have any inhibitory effect on the synthesis of RNA in mammalian cells. Approved by the japanese government for marketing in 3 months 2014 under the trade name Avigan, and indicated as influenza a (including avian influenza and influenza a H1N1 influenza infection), primarily for new or emerging influenza virus infections. 15 days 2 and 2020, Zhejiang Haizheng pharmaceutical industry is approved by the Chinese national drug administration for marketing, and the indication is adult new or recurrent influenza (only used when other anti-influenza virus drugs are ineffective or have poor effects). On 20/6/2020, the Favipiravir drug substance and formulation developed by Glenmark pharmaceuticals has been accelerated by the Indian drug administration for the treatment of patients with mild to moderate novel coronavirus pneumonia (COVID-19). Favipiravir is a safe broad-spectrum antiviral drug, can resist various RNA viruses such as HIV, Ebola virus, yellow fever virus and the like, and has wider market prospect with continuous expansion of indications and continuous marketing in other countries in the world.
At present, the existing document (WO2010087117, journal of Chinese medicine industry, 2014,45(11):1009-1012) discloses a synthesis route of Favipiravir, the route adopts 2-amino malonamide (1) as a key intermediate, and the Favipiravir is prepared by cyclization, bromination, dichlorination, difluorination, substitution, hydrolysis and other reactions, the route has simple operation and high yield, is a synthesis route generally adopted at home and abroad at present, and is necessary for researching the synthesis of the compound of the formula (1).
At present, the method for preparing 2-amino malonamide mainly comprises the following modes:
patent document WO2007064883 uses diethyl 2-aminomalonate hydrochloride as a starting material, and reacts with a methanol solution of ammonia gas in a closed container overnight, and then the target product is obtained after filtration, washing a filter cake with methanol and vacuum drying overnight. The yield thereof was found to be 91%. The technical scheme has pressure resistance requirement on a reaction vessel, and because the solubility of methanol to ammonium chloride is low (about 3.3g of ammonium chloride is dissolved in 100g of methanol at 18-25 ℃), the ammonium chloride generated in the reaction process can not be completely washed and removed, so that the obtained product contains a large amount of ammonium chloride and has low product content.
In the literature (WO2018136265, WO2007144686), diethyl 2-aminomalonate hydrochloride is used as a starting material, the pH of an aqueous solution of diethyl 2-aminomalonate hydrochloride is firstly adjusted to be more than 7 by sodium bicarbonate, then an organic solvent (ethyl acetate and the like) is used for extraction, the organic phase is separated and distilled under reduced pressure to obtain free diethyl 2-aminomalonate, and finally, the free diethyl 2-aminomalonate reacts with a methanolic ammonia solution to obtain a target product with the yield of 60-70%. According to the technical scheme, the free 2-amino diethyl malonate is obtained through separation, the intermediate is unstable, and the intermediate is easy to deteriorate in the amplification production process, so that the yield of the subsequent ammoniation step is reduced, and the impurity content of the ammoniated product is increased.
In the literature (J.Pharmacology, 2015,42(2):220-224), diethyl 2-aminomalonate hydrochloride is used as a starting material, the starting material is dissolved in methanol, ammonia water is added, the reaction is carried out for 24 hours at room temperature in a closed manner, ethanol is added to precipitate a product, and the target product is obtained after suction filtration and vacuum drying, wherein the yield is 82.5%. This technical scheme adopts the aqueous ammonia to be ammoniation reagent, can produce a large amount of nitrogenous dangers useless in the production process, and environmental pollution is serious, and organic solvent can't retrieve, and manufacturing cost is high. A
Disclosure of Invention
The technical problem to be solved by the invention is that the existing 2-amino malonamide preparation process has the defects of high three wastes, serious pollution, high requirement on reaction equipment, complicated operation process, low product purity and unsuitability for industrial production.
The invention provides a method for producing and improving 2-amino malonamide, which has the advantages of simple operation, recyclable solvent, less three wastes, high yield, high purity of a product Gas Chromatography (GC) up to more than 99 percent, and suitability for industrial production.
The invention provides an improved method for producing 2-amino malonamide, which is characterized by comprising the following steps:
a: sequentially adding an alcohol solvent and 2-diethyl aminomalonate hydrochloride, continuously introducing ammonia gas at-10-25 ℃, stirring for reacting for 0.5-2h, and carrying out solid-liquid separation;
b: and (b) heating the filtrate obtained in the step (a) to 40-70 ℃, continuously introducing ammonia gas, continuously stirring for reacting for 5-12h, cooling to-10-35 ℃, carrying out solid-liquid separation, and carrying out forced air drying at 25-35 ℃ to obtain the compound shown in the formula (1).
The technical scheme of the invention is an improved method for producing 2-amino malonamide, which is characterized in that:
as the solid-liquid separation, there may be used a method of separating a solid from a liquid, such as filtration, centrifugation, and pressure filtration.
The alcohol solvent in the step a comprises methanol and ethanol.
The mass ratio of the alcohol solvent to the diethyl 2-aminomalonate in the step a is 2:1-5: 1.
The mol ratio of the ammonia gas to the diethyl 2-aminomalonate in the step a is 1.5:1-3: 1.
The mol ratio of the ammonia gas to the diethyl 2-aminomalonate in the step b is 3:1-5: 1.
Drawings
Figure 1 is a blank solvent GC plot.
FIG. 2 is a GC spectrum of 2-aminomalonamide obtained in example 1.
FIG. 3 is a GC spectrum of 2-aminomalonamide obtained in example 3.
Detailed Description
The present invention will be described in further detail with reference to the following examples, but the present invention is not limited thereto.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, kg means kg, L means liter, min means minute, and h means hour.
Example 1
Preparation of 2-aminomalonamide
Pumping 100kg of methanol into a 500L reaction kettle, adding 50kg of 2-diethyl aminomalonate hydrochloride, cooling to-10 ℃, continuously introducing ammonia (6.04 kg in total), stirring for reaction for 2h, centrifuging, pumping the filtrate obtained by centrifuging into the 500L reaction kettle with a condensing device, heating to 40 ℃, continuously introducing ammonia (12.1 kg in total), continuously stirring for reaction for 12h, cooling to-10 ℃, centrifuging, and drying by air blowing at 25 ℃ for 10h to obtain 25.3kg of yellow solid with the GC purity of 99.5%.
Example 2
Preparation of 2-aminomalonamide
Pumping 500kg of ethanol into a 1000L reaction kettle, adding 50kg of 2-diethyl aminomalonate hydrochloride, stirring and reacting for 0.5h at 25 ℃ while continuously introducing ammonia (12.07 kg in total), centrifuging, pumping the filtrate obtained by centrifuging into the 1000L reaction kettle with a condensing device, heating to 70 ℃, continuously introducing ammonia (20.1 kg in total), continuously stirring and reacting for 5h, cooling to 35 ℃, centrifuging, and drying for 10h at 35 ℃ by air blast to obtain 24.7kg of yellow solid with the GC purity of 99.4%.
Example 3
Preparation of 2-aminomalonylamide
Pumping 150kg of ethanol into a 500L reaction kettle, adding 50kg of 2-diethyl aminomalonate hydrochloride, cooling to 0 ℃, continuously introducing ammonia gas (total 8.05kg), stirring for reaction for 1h, centrifuging, pumping the filtrate obtained by centrifuging into the 500L reaction kettle with a condensing device, heating to 55 ℃, continuously introducing ammonia gas (total 16.1kg), continuously stirring for reaction for 8.5h, cooling to 0 ℃, centrifuging, and drying by air blast at 30 ℃ for 10h to obtain 25.8kg of yellow solid with the GC purity of 99.4%.
Example 4
Preparation of 2-aminomalonamide
Pumping 200kg of methanol into a 500L reaction kettle, adding 50kg of 2-diethyl aminomalonate hydrochloride, cooling to 10 ℃, continuously introducing ammonia (10.1 kg in total), stirring for reaction for 1.5h, centrifuging, pumping the filtrate obtained by centrifuging into the 500L reaction kettle with a condensing device, heating to 55 ℃, continuously introducing ammonia (12.1 kg in total), continuously stirring for reaction for 7h, cooling to 10 ℃, centrifuging, and carrying out forced air drying at 25 ℃ for 10h to obtain 24.4kg of yellow solid with the GC purity of 99.5%.
Example 5
GC purity detection method of 2-amino malonamide:
the instrument comprises: gas chromatograph (Agilent 6890N), carrier gas flow rate: 1.5mL/min, column: HP-5(30m 0.32mm 0.25um), split ratio: 5:1, sample injection amount: 0.5uL, injection port temperature: 300 ℃, column temperature setting: keeping at 80 deg.C for 2min, increasing to 150 deg.C at 10 deg.C/min for 5min, increasing to 300 deg.C at 25 deg.C/min for 11min, and detecting: hydrogen Flame Ionization Detector (FID), detector temperature: 300 ℃, sample injection mode: and directly injecting a sample.
Sample preparation: a proper amount of sample is precisely measured, and N, N-dimethylformamide is added to dissolve the sample to prepare a solution containing 0.05mg of the N, N-dimethylformamide per 1mL of the solution.
It should be understood that the above-mentioned embodiments are only preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, and any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. An improved process for the production of 2-aminomalonamide, which comprises the steps of:
a: sequentially adding an alcohol solvent and 2-diethyl aminomalonate hydrochloride, continuously introducing ammonia gas at-10-25 ℃, stirring for reacting for 0.5-2h, and carrying out solid-liquid separation;
b: heating the filtrate obtained in the step a to 40-70 ℃, continuously introducing ammonia gas, continuously stirring for reacting for 5-12h, cooling to-10-35 ℃, carrying out solid-liquid separation, carrying out forced air drying at 25-35 ℃ to obtain a compound shown in the formula (1),
2. the improved process of claim 1 wherein said solid-liquid separation is performed by filtration, centrifugation, or pressure filtration.
3. The improved method as claimed in claim 1, wherein the alcoholic solvent in step a comprises one or a mixture of methanol and ethanol.
4. The improved method as claimed in claim 1, wherein the mass ratio of said alcoholic solvent to diethyl 2-aminomalonate in step a is 2:1-5: 1.
5. The improved process of claim 1 wherein the molar ratio of ammonia gas to diethyl 2-aminomalonate in step a is from 1.5:1 to 3: 1.
6. The improved process of claim 1 wherein the molar ratio of ammonia gas to diethyl 2-aminomalonate in step b is from 3:1 to 5: 1.
7. The improved process as claimed in claim 1, wherein 150kg of ethanol is pumped into a 500L reactor, 50kg of diethyl 2-aminomalonate hydrochloride is added, the temperature is reduced to 0 ℃, 8.05kg of ammonia gas is continuously pumped in, and the reaction is carried out for 1h while stirring and centrifuging; pumping the filtrate obtained by centrifugation into a 500L reaction kettle with a condensing device, heating to 55 ℃, continuously introducing 16.1kg of ammonia gas, simultaneously stirring and reacting for 8.5h, cooling to 0 ℃, centrifuging, and drying by air blast at 30 ℃ for 10h to obtain 25.8kg of 2-amino malonamide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210356726.3A CN114685301A (en) | 2022-03-31 | 2022-03-31 | Production improvement method of 2-amino malonamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210356726.3A CN114685301A (en) | 2022-03-31 | 2022-03-31 | Production improvement method of 2-amino malonamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114685301A true CN114685301A (en) | 2022-07-01 |
Family
ID=82142978
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210356726.3A Pending CN114685301A (en) | 2022-03-31 | 2022-03-31 | Production improvement method of 2-amino malonamide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114685301A (en) |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101560171A (en) * | 2009-05-19 | 2009-10-21 | 建德市紫山湾精细化工有限公司 | Method for preparing 5-(N,N-dibenzylglycyl) salicylamide |
| WO2011091677A1 (en) * | 2010-01-30 | 2011-08-04 | 浙江华海药业股份有限公司 | Preparation method of aliskiren intermediate 3-amino-2,2-dimethyl propanamide |
| CN102180823A (en) * | 2011-03-12 | 2011-09-14 | 浙江华海药业股份有限公司 | Method for refining prolinamide |
| CN105481721A (en) * | 2015-12-24 | 2016-04-13 | 湖南化工研究院有限公司 | Preparing method of 2,3-dicyanopropionate |
| CN105732634A (en) * | 2005-12-02 | 2016-07-06 | 拜尔健康护理有限责任公司 | Substituted 4-amino-pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
| CN110446709A (en) * | 2017-01-23 | 2019-11-12 | 锐新医药公司 | Bicyclic compound as allosteric SHP2 inhibitor |
| CN111440083A (en) * | 2020-04-30 | 2020-07-24 | 贵州联科中贝制药科技有限公司 | Preparation method of (S) - (+) -2-aminobutanamide hydrochloride |
| CN111484456A (en) * | 2020-05-11 | 2020-08-04 | 常熟市金申医化制品有限责任公司 | Refining process of 5-methoxy-4, 6-dichloropyrimidine |
| CN112939797A (en) * | 2021-02-03 | 2021-06-11 | 山东邹平大展新材料有限公司 | Preparation method of Favipiravir intermediate 2-amino malonamide |
| WO2021120982A1 (en) * | 2019-12-16 | 2021-06-24 | 上海交通大学 | Method for preparing m-phenylenediamine |
| WO2021231784A1 (en) * | 2020-05-13 | 2021-11-18 | Hibercell, Inc. | Perk inhibiting imidazolopyrazine compounds |
| CN113831255A (en) * | 2021-11-25 | 2021-12-24 | 山东诚创蓝海医药科技有限公司 | Preparation method of 2-amino malonamide |
-
2022
- 2022-03-31 CN CN202210356726.3A patent/CN114685301A/en active Pending
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732634A (en) * | 2005-12-02 | 2016-07-06 | 拜尔健康护理有限责任公司 | Substituted 4-amino-pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
| CN101560171A (en) * | 2009-05-19 | 2009-10-21 | 建德市紫山湾精细化工有限公司 | Method for preparing 5-(N,N-dibenzylglycyl) salicylamide |
| WO2011091677A1 (en) * | 2010-01-30 | 2011-08-04 | 浙江华海药业股份有限公司 | Preparation method of aliskiren intermediate 3-amino-2,2-dimethyl propanamide |
| CN102180823A (en) * | 2011-03-12 | 2011-09-14 | 浙江华海药业股份有限公司 | Method for refining prolinamide |
| CN105481721A (en) * | 2015-12-24 | 2016-04-13 | 湖南化工研究院有限公司 | Preparing method of 2,3-dicyanopropionate |
| CN110446709A (en) * | 2017-01-23 | 2019-11-12 | 锐新医药公司 | Bicyclic compound as allosteric SHP2 inhibitor |
| WO2021120982A1 (en) * | 2019-12-16 | 2021-06-24 | 上海交通大学 | Method for preparing m-phenylenediamine |
| CN111440083A (en) * | 2020-04-30 | 2020-07-24 | 贵州联科中贝制药科技有限公司 | Preparation method of (S) - (+) -2-aminobutanamide hydrochloride |
| CN111484456A (en) * | 2020-05-11 | 2020-08-04 | 常熟市金申医化制品有限责任公司 | Refining process of 5-methoxy-4, 6-dichloropyrimidine |
| WO2021231784A1 (en) * | 2020-05-13 | 2021-11-18 | Hibercell, Inc. | Perk inhibiting imidazolopyrazine compounds |
| CN112939797A (en) * | 2021-02-03 | 2021-06-11 | 山东邹平大展新材料有限公司 | Preparation method of Favipiravir intermediate 2-amino malonamide |
| CN113831255A (en) * | 2021-11-25 | 2021-12-24 | 山东诚创蓝海医药科技有限公司 | Preparation method of 2-amino malonamide |
Non-Patent Citations (1)
| Title |
|---|
| 王欢等: "法匹拉韦的合成" * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102633799B (en) | Method for synthesizing sapropterin dihydrochloride from racemate intermediate separation route | |
| CN106083691B (en) | A kind of preparation method of arbidol HCl monohydrate | |
| CN113956312A (en) | Preparation method of mopilavir | |
| CN110437228B (en) | Preparation method of tadalafil and intermediate thereof | |
| CN115232055A (en) | Synthesis method of arbidol hydrochloride | |
| CN114685301A (en) | Production improvement method of 2-amino malonamide | |
| CN107698606B (en) | Preparation method of tadalafil-related substance F | |
| CN110194728B (en) | Continuous synthesis method of oseltamivir phosphate intermediate | |
| CN103709221A (en) | Preparation method for cordycepin | |
| CN113336706B (en) | Synthetic method for preparing olmesartan medoxomil intermediate by continuous flow | |
| CN111925317B (en) | Ropivacaine hydrochloride impurity and preparation method thereof | |
| EP3896057B1 (en) | Method for continuously preparing citalopram diol | |
| CN112500357B (en) | Synthesis method of 1, 1-diamino-2, 2-dinitroethylene (FOX-7) | |
| CN110804022B (en) | Preparation method of dexrazoxane | |
| CN114315626A (en) | Preparation method of oseltamivir dealkylation impurity | |
| CN112457204A (en) | Preparation method of S-configuration phenethylamine hydrochloride compound | |
| CN105439978A (en) | Preparation method of acotiamide intermediate | |
| CN111793037A (en) | Crystallization and purification method of favipiravir key intermediate 3, 6-difluoropyrazine-2-carbonitrile | |
| CN111807933A (en) | Novel preparation method of medical intermediate 3-bromocatechol | |
| CN111471027A (en) | Synthesis process of ribavirin intermediate and intermediate | |
| CN111675663A (en) | Preparation method of Favipiravir | |
| CN111269168A (en) | Preparation method of arbidol intermediate | |
| CN114751853B (en) | Process for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane compounds | |
| CN110343056A (en) | A kind of preparation method of N- tertbutyloxycarbonyl-N- methyl-2-amino -4,4- dimethyl valeric acid | |
| CN112745324B (en) | Method for synthesizing nucleoside analogue by continuous flow reactor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |