CN106542961A - A kind of synthetic method of racecadotril intermediate - Google Patents
A kind of synthetic method of racecadotril intermediate Download PDFInfo
- Publication number
- CN106542961A CN106542961A CN201610962067.2A CN201610962067A CN106542961A CN 106542961 A CN106542961 A CN 106542961A CN 201610962067 A CN201610962067 A CN 201610962067A CN 106542961 A CN106542961 A CN 106542961A
- Authority
- CN
- China
- Prior art keywords
- racecadotril
- synthetic method
- reaction
- benzyl acrylic
- organic layer
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses there is provided a kind of synthetic method of racecadotril intermediate.After the method is reacted using phenylpropyl alcohol acetoacetic ester, dimethylamine and metaformaldehyde, Jing HCl treatments obtain benzyl acrylic ethyl ester, then hydrolyze to obtain benzyl acrylic in the basic conditions.The synthetic method of present invention toxicity larger benzyl chloride with benzenpropanoic acid ethyl substituted, and synthetic route is shortened, production efficiency is improve, is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic method of racecadotril intermediate, belongs to technical field of medicine synthesis.
Background technology
Racecadotril is a kind of diarrhea medicine of new mechanism of action, directly suppresses intestinal excessive secretion, quick to improve
Symptom of diarrhea, treatment infant rotaviral diarrhoea are evident in efficacy, can substantially shorten the course of disease, reduce the pain of infant, it is adaptable to
Adult and the acute diarrhea of January above baby and child.Racecadotril is researched and developed into by the Bioprojet companies of France earliest
Work(, was listed with trade name Tiorfan in France first in 1993, and soon, Canadian department of pediatrics association and U.S.'s disease are pre- for listing
Anti- center (abbreviation CDC) just lists racecadotril in the indispensable medication of children's diarrhae treatment, has also listed Chinese state within 2011
The recommended drug of family's department of pediatrics diarrhoeal diseasess treatment common recognition.At present the pediatrician of a domestic clinical line using racecadotril as
The highly effective and safe medicine of clinical children's diarrhae treatment.
Benzyl acrylic is a used important intermediate in racecadotril building-up process.Existing main conjunction
Into route it is:Benzyl chloride and diethyl malonate reaction generate diethyl benzyl malonate, then hydrolyze in the presence of acid or alkali
Generate benzyl malonic acid, then with formaldehyde or paraformaldehyde and diethylamine reaction generate benzyl acrylic (Wang Guiwen, Gu Zhiping,
Li Fenge. the synthesising process research of racecadotril. Chinese Pharmaceutical Association Annual Conference .2004).
Said synthesis route is longer, and uses with very big toxicity and irritating raw material benzyl chloride, and production environment is easily made
Into very big pollution, huge pressure is brought to environmental protection, production cost is higher, is unfavorable for industrialized production.
The content of the invention
Instant invention overcomes above-mentioned the deficiencies in the prior art, there is provided a kind of racecadotril intermediate benzyl acrylic
Synthetic method.The method is carried out after Mannich reactions using phenylpropyl alcohol acetoacetic ester, dimethylamine and metaformaldehyde, and Jing HCl treatments are obtained
Benzyl acrylic ethyl ester, then hydrolyzes to obtain benzyl acrylic in the basic conditions.The synthetic method of the present invention is with phenylpropyl alcohol acetoacetic ester
The larger benzyl chloride of toxicity is instead of, and shortens synthetic route, improve production yield, be suitable for industrialized production.
The technical scheme is that:A kind of synthetic method of racecadotril intermediate benzyl acrylic, including it is following
Step:
(1) phenylpropyl alcohol acetoacetic ester (compounds I), metaformaldehyde (compound ii) and dimethylamine (compound III) are reacted
Afterwards, then Jing HCl treatments obtain benzyl acrylic ethyl ester (compound III);
(2) benzyl acrylic ethyl ester (compound III) is hydrolyzed in the basic conditions and obtains benzyl acrylic (compound VI).
Chemical equation is as follows:
Said synthesis route specifically includes following steps:
(1) phenylpropyl alcohol acetoacetic ester and solvent ethyl acetate are added in reaction vessel, is cooled to 0-10 DEG C of Deca dimethylamine water-soluble
Liquid;Completion of dropping, 10-15 DEG C of temperature control continue reaction 0.5~1.5 hour;Then metaformaldehyde, temperature rising reflux reaction 2 are added
~5 hours;Room temperature is down to after the completion of reaction, adds stratification after hydrochloric acid and water stirring reaction, organic layer to reduce pressure after washing
It is concentrated to dryness to obtain benzyl acrylic ethyl ester;
(2) methylene chloride, sodium hydroxide solution and ethanol or methanol, control and then in benzyl acrylic ethyl ester are added
Warm 10-20 DEG C is reacted 2~5 hours;Stratification, adds hydrochloric acid to adjust pH=1 in organic layer after completion of the reaction;Stand again and divide
Layer, organic layer are evaporated to Jing washing, after being dried and dry obtain benzyl acrylic crude product;Obtain product again Jing after recrystallization.
Preferably, the concentration of step (1) dimethylamine agueous solution is 30~50%, more preferably 40%.
Preferably, step (1) the phenylpropyl alcohol acetoacetic ester, dimethylamine, the mol ratio of metaformaldehyde are 1:1.1~1.5:0.35
~0.45.
Preferably, the mol ratio of step (1) the phenylpropyl alcohol acetoacetic ester and hydrochloric acid is 1:1.0~1.5.
Preferably, step (2) concentration of sodium hydroxide solution is 15~30%, more preferably 20%.The benzenpropanoic acid second
The mol ratio of ester and sodium hydroxide is 1:1.0~1.5.
Preferably, step (2) recrystallization adopts dehydrated alcohol as solvent.The process of concrete recrystallization is as follows:Benzyl
Dehydrated alcohol, temperature rising reflux is added to be cooled to -5 DEG C of crystallizes to all molten clear rear stirrings, filter in base acrylic acid crude product,
Filter cake decompression drying at 40-50 DEG C obtains product.
Preferably, in the step (2), dichloromethane and the amount ratio of ethanol are 8~12:1.
The invention has the beneficial effects as follows:The synthetic method of present invention toxicity larger benzyl chloride with benzenpropanoic acid ethyl substituted,
And shorten synthetic route, product yield height (>=90.0%), purity height (>=99.5%), it is easy to industrialized production.
Specific embodiment
With reference to embodiments technical scheme is further illustrated, but the invention is not limited in this.
Embodiment 1:
(1) 70g phenylpropyl alcohols acetoacetic ester and 400ml ethyl acetate are added in 1000ml reaction bulbs, is stirred, lowered the temperature, control
The dimethylamine of temperature 0-10 DEG C Deca 54.7g concentration 40% in reaction bulb processed, completion of dropping, 10-15 DEG C of temperature control are reacted 1 hour,
14.2g metaformaldehydes are subsequently adding, back flow reaction 3 hours after intensification;Room temperature is down to after the completion of reaction, concentrated hydrochloric acid (concentration is added
35%, similarly hereinafter) 56g, purified water 60ml, stir 40 minutes, and stratification, organic layer are washed once with 200ml purified water, decompression
Concentration of organic layers is to dry;
(2) 500ml dichloromethane, 20% sodium hydroxide solution 80g and 50g dehydrated alcohol, 10-20 DEG C of temperature control are subsequently adding
Reaction 4 hours;After standing, water layer is separated, in organic layer, add 40g concentrated hydrochloric acid to adjust pH=1;Water layer is separated again, uses 300ml
Purification water washing organic layer, is evaporated to after adding 25g anhydrous sodium sulfate dryings dry in organic layer;Be subsequently adding 130g without
Water-ethanol, temperature rising reflux to all molten clear rear stirrings are cooled to -5 DEG C of crystallizes, filter, filter cake decompression drying at 40-50 DEG C
Obtain white crystalline solid 58.8g, purity 99.8%, yield 92.3%.
Embodiment 2:
(1) 70g phenylpropyl alcohols acetoacetic ester and 400ml ethyl acetate are added in 1000ml reaction bulbs, is stirred, lowered the temperature, control
The dimethylamine of temperature 0-10 DEG C Deca 55.0g concentration 40% in reaction bulb processed, completion of dropping, 10-15 DEG C of temperature control are reacted 50 minutes,
14.5g metaformaldehydes are subsequently adding, back flow reaction 2.5 hours after intensification;Room temperature is down to after the completion of reaction, adds concentrated hydrochloric acid (dense
Degree 35%) 58g, purified water 65ml, stirring 40 minutes, stratification, organic layer are washed once with 200ml purified water, are reduced pressure dense
Contracting organic layer is to dry;
(2) 500ml dichloromethane, 20% sodium hydroxide solution 85g and 50g dehydrated alcohol, 10-20 DEG C of temperature control are subsequently adding
Reaction 3.5 hours;After standing, water layer is separated, in organic layer, add 45g concentrated hydrochloric acid to adjust pH=1;Water layer is separated again, is used
300ml purification water washing organic layers, are evaporated to after adding 25g anhydrous sodium sulfate dryings dry in organic layer;It is subsequently adding
150g dehydrated alcohol, temperature rising reflux to all molten clear rear stirrings are cooled to -5 DEG C of crystallizes, filter, and filter cake subtracts at 40-50 DEG C
Pressure dries to obtain white crystalline solid 59.1g, purity 99.8%, yield 92.8%.
Embodiment 3:
(1) 70g phenylpropyl alcohols acetoacetic ester and 400ml ethyl acetate are added in 1000ml reaction bulbs, is stirred, lowered the temperature, control
The dimethylamine of temperature 0-10 DEG C Deca 54.5g concentration 40% in reaction bulb processed, completion of dropping, 10-15 DEG C of temperature control are reacted 70 minutes,
14.0g metaformaldehydes are subsequently adding, back flow reaction 3.5 hours after intensification;Room temperature is down to after the completion of reaction, adds concentrated hydrochloric acid (dense
Degree 35%) 55g, purified water 60ml, stirring 40 minutes, stratification, organic layer are washed once with 200ml purified water, are reduced pressure dense
Contracting organic layer is to dry;
(2) 500ml dichloromethane, 20% sodium hydroxide solution 80g and 50g dehydrated alcohol, 10-20 DEG C of temperature control are subsequently adding
Reaction 4 hours;After standing, water layer is separated, in organic layer, add 40g concentrated hydrochloric acid to adjust pH=1;Water layer is separated again, uses 300ml
Purification water washing organic layer, is evaporated to after adding 25g anhydrous sodium sulfate dryings dry in organic layer;Be subsequently adding 130g without
Water-ethanol, temperature rising reflux to all molten clear rear stirrings are cooled to -5 DEG C of crystallizes, filter, filter cake decompression drying at 40-50 DEG C
Obtain white crystalline solid 58.6g, purity 99.9%, yield 92.0%.
Claims (10)
1. a kind of synthetic method of racecadotril intermediate,
The racecadotril intermediate is benzyl acrylic, and it comprises the following steps:
(1) after phenylpropyl alcohol acetoacetic ester, metaformaldehyde and dimethylamine are reacted, then Jing HCl treatments obtain benzyl acrylic ethyl ester;
(2) benzyl acrylic ethyl ester is hydrolyzed in the basic conditions and obtains benzyl acrylic.
2. a kind of synthetic method of racecadotril intermediate as claimed in claim 1, is characterized in that,
(1) phenylpropyl alcohol acetoacetic ester and solvent ethyl acetate are added in reaction vessel, is cooled to 0-10 DEG C of Deca dimethylamine agueous solution;Drop
Add complete, 10-15 DEG C of temperature control continuation reaction 0.5~1.5 hour;Then metaformaldehyde is added, temperature rising reflux reaction 2~5 is little
When;Room temperature is down to after the completion of reaction, adds stratification after hydrochloric acid and water stirring reaction, organic layer to be evaporated to after washing
Do to obtain benzyl acrylic ethyl ester;
(2) methylene chloride, sodium hydroxide solution and ethanol or methanol, temperature control and then in benzyl acrylic ethyl ester are added
10-20 DEG C is reacted 2~5 hours;Stratification, adds hydrochloric acid to adjust pH=1 in organic layer after completion of the reaction;Stand again and divide
Layer, organic layer are evaporated to Jing washing, after being dried and dry obtain benzyl acrylic crude product;Obtain product again Jing after recrystallization.
3. a kind of synthetic method of racecadotril intermediate as claimed in claim 2, is characterized in that, the step (1) two
The concentration of methylamine water solution is 30~50%.
4. a kind of synthetic method of racecadotril intermediate as claimed in claim 3, is characterized in that, the step (1) two
The concentration of methylamine water solution is 40%.
5. a kind of synthetic method of racecadotril intermediate as claimed in claim 2, is characterized in that, step (1) benzene
Ethyl propionate, dimethylamine, the mol ratio of metaformaldehyde are 1:1.1~1.5:0.35~0.45.
6. a kind of synthetic method of racecadotril intermediate as claimed in claim 2, is characterized in that, step (1) benzene
The mol ratio of ethyl propionate and hydrochloric acid is 1:1.0~1.5.
7. a kind of synthetic method of racecadotril intermediate as claimed in claim 2, is characterized in that, step (2) hydrogen
Sodium hydroxide solution concentration is 15~30%.
8. a kind of synthetic method of racecadotril intermediate as claimed in claim 7, is characterized in that, the sodium hydroxide is molten
Liquid concentration is 20%.
9. a kind of synthetic method of the racecadotril intermediate as described in any one in claim 2-8, is characterized in that, institute
Step (2) recrystallization is stated using dehydrated alcohol as solvent.
10. a kind of synthetic method of the racecadotril intermediate as described in right wants 9, is characterized in that, the mistake of the recrystallization
Journey is as follows:Dehydrated alcohol, temperature rising reflux is added to be cooled to -5 DEG C of analysis to all molten clear rear stirrings in benzyl acrylic crude product
Crystalline substance, filters, and filter cake decompression drying at 40-50 DEG C obtains product.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610962067.2A CN106542961B (en) | 2016-11-04 | 2016-11-04 | A kind of synthetic method of racecadotril intermediate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610962067.2A CN106542961B (en) | 2016-11-04 | 2016-11-04 | A kind of synthetic method of racecadotril intermediate |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106542961A true CN106542961A (en) | 2017-03-29 |
CN106542961B CN106542961B (en) | 2019-02-01 |
Family
ID=58394004
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610962067.2A Active CN106542961B (en) | 2016-11-04 | 2016-11-04 | A kind of synthetic method of racecadotril intermediate |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106542961B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109580825A (en) * | 2018-12-27 | 2019-04-05 | 山东铂源药业有限公司 | The detection method of p-methyl benzenesulfonic acid Ester in racecadotril |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0061745A1 (en) * | 1981-03-27 | 1982-10-06 | Tanabe Seiyaku Co., Ltd. | Tetrahydroisoquinoline compounds, processes for preparation thereof and pharmaceutical composition containing them |
US4889869A (en) * | 1986-02-07 | 1989-12-26 | Ciba-Geigy Corporation | Antihypertensive 5-amino-4-hydroxyvaleryl derivatives substituted by sulphur-containing groups |
US5312838A (en) * | 1992-09-21 | 1994-05-17 | G. D. Searle & Co. | β-alanineamide aryl/alkylsulfide/sulfonyl-terminated amino-diol compounds for treatment of hypertension |
JPH09278746A (en) * | 1996-04-04 | 1997-10-28 | Kanegafuchi Chem Ind Co Ltd | Production of optically active 2-aralkyl-3-acylthiopropionate ester |
-
2016
- 2016-11-04 CN CN201610962067.2A patent/CN106542961B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0061745A1 (en) * | 1981-03-27 | 1982-10-06 | Tanabe Seiyaku Co., Ltd. | Tetrahydroisoquinoline compounds, processes for preparation thereof and pharmaceutical composition containing them |
US4889869A (en) * | 1986-02-07 | 1989-12-26 | Ciba-Geigy Corporation | Antihypertensive 5-amino-4-hydroxyvaleryl derivatives substituted by sulphur-containing groups |
US5312838A (en) * | 1992-09-21 | 1994-05-17 | G. D. Searle & Co. | β-alanineamide aryl/alkylsulfide/sulfonyl-terminated amino-diol compounds for treatment of hypertension |
JPH09278746A (en) * | 1996-04-04 | 1997-10-28 | Kanegafuchi Chem Ind Co Ltd | Production of optically active 2-aralkyl-3-acylthiopropionate ester |
Non-Patent Citations (2)
Title |
---|
BERNARD R.NEUSTADT等: "Mercaptoacyl Amino Acid Inhibitors of Atriopeptidase. 1. Structure - Activity Relationship Studies of Methionine and S-Alkylcysteine Derivatives", 《J.MED.CHEM.》 * |
DAN YANG等: "Effect of calcination temperature on the catalytic activity of VPO for aldol condensation of acetic acid and formalin", 《CHEMICAL ENGINEERING JOURNAL》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109580825A (en) * | 2018-12-27 | 2019-04-05 | 山东铂源药业有限公司 | The detection method of p-methyl benzenesulfonic acid Ester in racecadotril |
Also Published As
Publication number | Publication date |
---|---|
CN106542961B (en) | 2019-02-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102395591B (en) | Method for preparing prasugrel | |
CN113233975B (en) | Preparation method of bevacizidine acid | |
CN112079848A (en) | Synthesis method of baroxavir key intermediate | |
CN103864802B (en) | The preparation method of maleic acid asenapine | |
CN102351778A (en) | Preparation method of arbidol hydrochloride | |
CN102731605B (en) | A kind of purification process of Abiraterone acetate | |
CN103664923B (en) | The preparation method of Nifuratel | |
WO2005023753A1 (en) | A method of preparing memantine hydrochloride | |
CN106542961A (en) | A kind of synthetic method of racecadotril intermediate | |
CN103588765A (en) | Synthesis method for azilsartan medoxomil or salt thereof, intermediate of azilsartan medoxomil or salt thereof and synthesis method for intermediate | |
CN102382050A (en) | Preparation method of substituted 1, 2, 3 and 4- tetrahydroquinoline -4-one hydrochloride | |
CN103980134B (en) | A kind of preparation method of succsinic acid S-metoprolol | |
CN103342707B (en) | For the preparation of the preparation method of A Sainaping intermediate | |
CN114671859B (en) | Preparation method of rosuvastatin calcium and intermediate thereof | |
CN101531660A (en) | Industrialization production process of entecavir-monohydrate | |
CN101245067B (en) | Process for producing entecavir and midbody | |
CN102030807B (en) | Theasapogenol derivative with anti-HIV (Human Immunodeficiency Virus) activity, preparation method and application thereof | |
CN103508898A (en) | Novel preparation method of alverine citrate | |
CN110615751B (en) | Preparation method of 2-oxo-thiopropionamide | |
CN115124473B (en) | Method for synthesizing cimetidine related substance B | |
CN102086147B (en) | Preparation method of substituted phenol | |
CN103857679A (en) | Methods for the preparation of 5-[2-[7-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]ethynyl]-2-pyridinamine | |
CN114736217B (en) | Preparation method of toraseplug Mi Huange impurity | |
CN102311362A (en) | Method for preparing ethyl hydrazinoacetate hydrochloride | |
CN100546973C (en) | The preparation method of 3-(N-methyl-N-penta amino) propionic salt hydrochlorate |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CP03 | Change of name, title or address | ||
CP03 | Change of name, title or address |
Address after: 251400 No. 12, Taixing East Street, Jibei Economic Development Zone, Jiyang District, Jinan City, Shandong Province Patentee after: Shandong Baoyuan Pharmaceutical Co.,Ltd. Address before: Strong in Jiyang County of Ji'nan City, 251400 North Street, Shandong Province Economic Development Zone Patentee before: SHANDONG BOYUAN PHARMACEUTICAL Co.,Ltd. |