CN106542961B - A kind of synthetic method of racecadotril intermediate - Google Patents
A kind of synthetic method of racecadotril intermediate Download PDFInfo
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- CN106542961B CN106542961B CN201610962067.2A CN201610962067A CN106542961B CN 106542961 B CN106542961 B CN 106542961B CN 201610962067 A CN201610962067 A CN 201610962067A CN 106542961 B CN106542961 B CN 106542961B
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- racecadotril
- synthetic method
- added
- reaction
- benzyl acrylic
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- ODUOJXZPIYUATO-UHFFFAOYSA-N Racecadotril Chemical compound C=1C=CC=CC=1COC(=O)CNC(=O)C(CSC(=O)C)CC1=CC=CC=C1 ODUOJXZPIYUATO-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229960002281 racecadotril Drugs 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 27
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-Trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 claims abstract description 11
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-phenylpropan-1-ol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 claims abstract description 11
- XYIBRDXRRQCHLP-UHFFFAOYSA-N Ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract description 11
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims abstract description 11
- FVLGPYFFONYLRZ-UHFFFAOYSA-N ethyl 2-benzylprop-2-enoate Chemical compound CCOC(=O)C(=C)CC1=CC=CC=C1 FVLGPYFFONYLRZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 26
- 239000012044 organic layer Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229960000935 Dehydrated Alcohol Drugs 0.000 claims description 8
- 239000010410 layer Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 230000000630 rising Effects 0.000 claims description 7
- 238000007792 addition Methods 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229960004756 ethanol Drugs 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- -1 hydrogen Sodium hydroxide Chemical class 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N Ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims 2
- 238000004458 analytical method Methods 0.000 claims 1
- FBKNTCBXMUWTGH-UHFFFAOYSA-N benzene;ethyl propanoate Chemical compound C1=CC=CC=C1.CCOC(=O)CC FBKNTCBXMUWTGH-UHFFFAOYSA-N 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 229940073608 benzyl chloride Drugs 0.000 abstract description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic Effects 0.000 abstract description 3
- 150000005524 benzylchlorides Chemical class 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000005712 crystallization Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000002194 synthesizing Effects 0.000 description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N Benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 3
- 206010012735 Diarrhoea Diseases 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 201000008286 diarrhea Diseases 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- JAEJSNFTJMYIEF-UHFFFAOYSA-N 2-benzylpropanedioic acid Chemical compound OC(=O)C(C(O)=O)CC1=CC=CC=C1 JAEJSNFTJMYIEF-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N Phenylpropanoic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 201000009840 acute diarrhea Diseases 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000001142 anti-diarrhea Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- ICZLTZWATFXDLP-UHFFFAOYSA-N diethyl 2-benzylpropanedioate Chemical compound CCOC(=O)C(C(=O)OCC)CC1=CC=CC=C1 ICZLTZWATFXDLP-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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
Abstract
The invention discloses provide a kind of synthetic method of racecadotril intermediate.After this method is reacted using phenylpropyl alcohol acetoacetic ester, dimethylamine and metaformaldehyde, benzyl acrylic ethyl ester is obtained through HCl treatment, then hydrolyzes to obtain benzyl acrylic under alkaline condition.Synthetic method of the invention shortens synthetic route with the benzenpropanoic acid ethyl substituted benzyl chloride being more toxic, and improves yield, is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic methods of racecadotril intermediate, belong to technical field of medicine synthesis.
Background technique
Racecadotril is a kind of anti diar rhea medicine of new mechanism of action, directly inhibition enteron aisle excessive secretion, is quickly improved
Symptom of diarrhea, treatment infant rotaviral diarrhea is significant in efficacy, and the pain that can be obviously shortened the course of disease, reduce infant is suitable for
Adult and the January above baby and children acute diarrhea.Racecadotril earliest by France Bioprojet company research and development at
Function, in 1993 first in France with trade name Tiorfan listing, soon, Canadian paediatrics association and U.S.'s disease are pre- for listing
Anti- center (abbreviation CDC) is just included in racecadotril the indispensable medication of children's diarrhae treatment, has also been included in Chinese state within 2011
The recommended drug of family's paediatrics diarrhoeal diseases treatment common recognition.At present the pediatrician of a domestic clinical line using racecadotril as
The highly effective and safe drug of clinical children's diarrhae treatment.
Benzyl acrylic is an important intermediate used in racecadotril synthesis process.Existing main conjunction
At route are as follows: benzyl chloride and diethyl malonate reaction generate diethyl benzyl malonate, then hydrolyze under the action of acid or alkali
Generate benzyl malonic acid, then with formaldehyde or paraformaldehyde and diethylamine reaction generate benzyl acrylic (Wang Guiwen, Gu Zhiping,
The synthesising process research Chinese Pharmaceutical Association Annual Conference .2004 of Lee's wind pretty young woman's racecadotril).
Said synthesis route is longer, and uses with very big toxicity and irritating raw material benzyl chloride, easily makes to production environment
At very big pollution, huge pressure is brought to environmental protection, production cost is higher, is unfavorable for industrialized production.
Summary of the invention
The present invention overcomes above-mentioned the deficiencies in the prior art, a kind of racecadotril intermediate benzyl acrylic is provided
Synthetic method.After this method carries out Mannich reaction using phenylpropyl alcohol acetoacetic ester, dimethylamine and metaformaldehyde, obtained through HCl treatment
Then benzyl acrylic ethyl ester hydrolyzes to obtain benzyl acrylic under alkaline condition.Synthetic method of the invention is with phenylpropyl alcohol acetoacetic ester
Instead of the benzyl chloride being more toxic, and synthetic route is shortened, improve yield, is suitable for industrialized production.
The technical solution of the present invention is as follows: a kind of synthetic method of racecadotril intermediate benzyl acrylic, including it is following
Step:
(1) phenylpropyl alcohol acetoacetic ester (chemical compounds I), metaformaldehyde (compound ii) and dimethylamine (compound III) are reacted
Afterwards, then through HCl treatment benzyl acrylic ethyl ester (compound III) is obtained；
(2) benzyl acrylic ethyl ester (compound III) hydrolyzes obtain benzyl acrylic (compound VI) under alkaline condition.
Chemical equation is as follows:
Said synthesis route specifically includes the following steps:
(1) phenylpropyl alcohol acetoacetic ester and solvent ethyl acetate are added in reaction vessel, it is water-soluble to be cooled to 0-10 DEG C of dropwise addition dimethylamine
Liquid；It is added dropwise, the reaction was continued 0.5~1.5 hour for 10-15 DEG C of temperature control；Then metaformaldehyde, temperature rising reflux reaction 2 are added
~5 hours；It is down to room temperature after the reaction was completed, hydrochloric acid is added and water is stirred to react rear stratification, organic layer depressurizes after washing
It is concentrated to dryness to obtain benzyl acrylic ethyl ester；
(2) methylene chloride, sodium hydroxide solution and ethyl alcohol or methanol, control are then added into benzyl acrylic ethyl ester
Warm 10-20 DEG C is reacted 2~5 hours；Hydrochloric acid tune pH=1 is added into organic layer for stratification after completion of the reaction；It stands and divides again
Layer, organic layer washed, dry after be concentrated to dryness to obtain benzyl acrylic crude product；Product is obtained after recrystallizing again.
Preferably, the concentration of step (1) dimethylamine agueous solution is 30~50%, more preferable 40%.
Preferably, step (1) the phenylpropyl alcohol acetoacetic ester, dimethylamine, metaformaldehyde molar ratio be 1:1.1~1.5:0.35
~0.45.
Preferably, the molar 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 preferable 20%.The benzenpropanoic acid second
The molar ratio of ester and sodium hydroxide is 1:1.0~1.5.
Preferably, step (2) recrystallization is using dehydrated alcohol as solvent.The process specifically recrystallized is as follows: benzyl
Dehydrated alcohol, temperature rising reflux are added in base acrylic acid crude product, until being cooled to -5 DEG C of crystallizations under stirring after whole dissolved clarifications, filters,
Filter cake decompression drying at 40-50 DEG C obtains product.
Preferably, the amount ratio of methylene chloride and ethyl alcohol is 8~12:1 in the step (2).
The beneficial effects of the present invention are: synthetic method of the invention is with the benzenpropanoic acid ethyl substituted benzyl chloride being more toxic,
And synthetic route is shortened, product yield height (>=90.0%), (>=99.5%) with high purity is easy to industrialized production.
Specific embodiment
Technical solution of the present invention is further illustrated with reference to embodiments, but the present invention is not limited thereto.
Embodiment 1:
(1) 70g phenylpropyl alcohol acetoacetic ester and 400ml ethyl acetate are added into 1000ml reaction flask, stirs evenly, cools down, control
The dimethylamine of 0-10 DEG C of temperature dropwise addition 54.7g concentration 40%, is added dropwise in reaction flask processed, and 10-15 DEG C of temperature control is reacted 1 hour,
Then 14.2g metaformaldehyde, back flow reaction 3 hours after heating are added；It is down to room temperature after the reaction was completed, concentrated hydrochloric acid (concentration is added
35%, similarly hereinafter) 56g, purified water 60ml, it stirs 40 minutes, stratification, organic layer washed once with 200ml purified water, decompression
Concentration of organic layers is to dry；
(2) then be added 500ml methylene chloride, 20% sodium hydroxide solution 80g and 50g dehydrated alcohol, 10-20 DEG C of temperature control
Reaction 4 hours；After standing, water layer is separated, 40g concentrated hydrochloric acid tune pH=1 is added into organic layer；Water layer is separated again, uses 300ml
Water washing organic layer is purified, is concentrated to dryness after the drying of 25g anhydrous sodium sulfate is added into organic layer；Then be added 130g without
Water-ethanol, temperature rising reflux filter, filter cake decompression drying at 40-50 DEG C until being cooled to -5 DEG C of crystallizations under stirring after whole dissolved clarifications
Obtain white crystalline solid 58.8g, purity 99.8%, yield 92.3%.
Embodiment 2:
(1) 70g phenylpropyl alcohol acetoacetic ester and 400ml ethyl acetate are added into 1000ml reaction flask, stirs evenly, cools down, control
The dimethylamine of 0-10 DEG C of temperature dropwise addition 55.0g concentration 40%, is added dropwise in reaction flask processed, and 10-15 DEG C of temperature control is reacted 50 minutes,
Then 14.5g metaformaldehyde, back flow reaction 2.5 hours after heating are added；It is down to room temperature after the reaction was completed, it is (dense that concentrated hydrochloric acid is added
35%) 58g, purified water 65ml are spent, is stirred 40 minutes, stratification, organic layer washed once with 200ml purified water, depressurize dense
Contracting organic layer is to dry；
(2) then be added 500ml methylene chloride, 20% sodium hydroxide solution 85g and 50g dehydrated alcohol, 10-20 DEG C of temperature control
Reaction 3.5 hours；After standing, water layer is separated, 45g concentrated hydrochloric acid tune pH=1 is added into organic layer；Water layer is separated again, is used
300ml purifies water washing organic layer, is concentrated to dryness after the drying of 25g anhydrous sodium sulfate is added into organic layer；Then it is added
150g dehydrated alcohol, temperature rising reflux filter until being cooled to -5 DEG C of crystallizations under stirring after whole dissolved clarifications, 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 alcohol acetoacetic ester and 400ml ethyl acetate are added into 1000ml reaction flask, stirs evenly, cools down, control
The dimethylamine of 0-10 DEG C of temperature dropwise addition 54.5g concentration 40%, is added dropwise in reaction flask processed, and 10-15 DEG C of temperature control is reacted 70 minutes,
Then 14.0g metaformaldehyde, back flow reaction 3.5 hours after heating are added；It is down to room temperature after the reaction was completed, it is (dense that concentrated hydrochloric acid is added
35%) 55g, purified water 60ml are spent, is stirred 40 minutes, stratification, organic layer washed once with 200ml purified water, depressurize dense
Contracting organic layer is to dry；
(2) then be added 500ml methylene chloride, 20% sodium hydroxide solution 80g and 50g dehydrated alcohol, 10-20 DEG C of temperature control
Reaction 4 hours；After standing, water layer is separated, 40g concentrated hydrochloric acid tune pH=1 is added into organic layer；Water layer is separated again, uses 300ml
Water washing organic layer is purified, is concentrated to dryness after the drying of 25g anhydrous sodium sulfate is added into organic layer；Then be added 130g without
Water-ethanol, temperature rising reflux filter, filter cake decompression drying at 40-50 DEG C until being cooled to -5 DEG C of crystallizations under stirring after whole dissolved clarifications
Obtain white crystalline solid 58.6g, purity 99.9%, yield 92.0%.
Claims (9)
1. a kind of synthetic method of racecadotril intermediate,
The racecadotril intermediate be benzyl acrylic, it the following steps are included:
(1) phenylpropyl alcohol acetoacetic ester and solvent ethyl acetate are added in reaction vessel, is cooled to 0-10 DEG C of dropwise addition dimethylamine agueous solution；Drop
Add complete, the reaction was continued 0.5~1.5 hour for 10-15 DEG C of temperature control；Then metaformaldehyde is added, temperature rising reflux reaction 2~5 is small
When；It is down to room temperature after the reaction was completed, hydrochloric acid is added and water is stirred to react rear stratification, organic layer is concentrated under reduced pressure into after washing
Do to obtain benzyl acrylic ethyl ester；
(2) methylene chloride, sodium hydroxide solution and ethyl alcohol or methanol, temperature control are then added into benzyl acrylic ethyl ester
10-20 DEG C is reacted 2~5 hours；Hydrochloric acid tune pH=1 is added into organic layer for stratification after completion of the reaction；It stands and divides again
Layer, organic layer washed, dry after be concentrated to dryness to obtain benzyl acrylic crude product；Product is obtained after recrystallizing again.
2. a kind of synthetic method of racecadotril intermediate as described in claim 1, characterized in that the step (1) two
The concentration of methylamine water solution is 30~50%.
3. a kind of synthetic method of racecadotril intermediate as claimed in claim 2, characterized in that the step (1) two
The concentration of methylamine water solution is 40%.
4. a kind of synthetic method of racecadotril intermediate as described in claim 1, characterized in that step (1) benzene
Ethyl propionate, dimethylamine, metaformaldehyde molar ratio be 1:1.1~1.5:0.35~0.45.
5. a kind of synthetic method of racecadotril intermediate as described in claim 1, characterized in that step (1) benzene
The molar ratio of ethyl propionate and hydrochloric acid is 1:1.0~1.5.
6. a kind of synthetic method of racecadotril intermediate as described in claim 1, characterized in that step (2) hydrogen
Sodium hydroxide solution concentration is 15~30%.
7. a kind of synthetic method of racecadotril intermediate as claimed in claim 6, characterized in that the sodium hydroxide is molten
Liquid concentration is 20%.
8. a kind of synthetic method of racecadotril intermediate as described in any one of claim 1-7, characterized in that institute
Step (2) recrystallization is stated using dehydrated alcohol as solvent.
9. a kind of synthetic method of racecadotril intermediate as described in right wants 8, characterized in that the process of the recrystallization
It is as follows: dehydrated alcohol, temperature rising reflux to be added in benzyl acrylic crude product, until being cooled to -5 DEG C of analysis under stirring after whole dissolved clarifications
Crystalline substance, filtering, filter cake decompression drying at 40-50 DEG C obtain product.
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| CN201610962067.2A CN106542961B (en) | 2016-11-04 | 2016-11-04 | A kind of synthetic method of racecadotril intermediate |
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|---|---|---|---|---|
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (3)
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| Effect of calcination temperature on the catalytic activity of VPO for aldol condensation of acetic acid and formalin;Dan Yang等;《Chemical Engineering Journal》;20160423;第160-168页 * |
| Mercaptoacyl Amino Acid Inhibitors of Atriopeptidase. 1. Structure - Activity Relationship Studies of Methionine and S-Alkylcysteine Derivatives;Bernard R.Neustadt等;《J.Med.Chem.》;19941231;第37卷;第2461-2476页 * |
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