CN103664680A - New process for synthesizing tamibarotene - Google Patents
New process for synthesizing tamibarotene Download PDFInfo
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- CN103664680A CN103664680A CN201210361469.9A CN201210361469A CN103664680A CN 103664680 A CN103664680 A CN 103664680A CN 201210361469 A CN201210361469 A CN 201210361469A CN 103664680 A CN103664680 A CN 103664680A
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- Prior art keywords
- tetramethyl
- tamibarotene
- carbamyl
- dihydronaphthalene
- novel method
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- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229950010130 tamibarotene Drugs 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims description 14
- 230000002194 synthesizing effect Effects 0.000 title 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 12
- -1 4,5,6,7-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl Chemical group 0.000 claims abstract description 11
- 229940095102 methyl benzoate Drugs 0.000 claims abstract description 8
- 238000010189 synthetic method Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 5
- REIDAMBAPLIATC-UHFFFAOYSA-N 4-methoxycarbonylbenzoic acid Chemical compound COC(=O)C1=CC=C(C(O)=O)C=C1 REIDAMBAPLIATC-UHFFFAOYSA-N 0.000 claims description 21
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 4
- 239000003054 catalyst Substances 0.000 claims 3
- 239000005711 Benzoic acid Substances 0.000 claims 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 abstract 2
- REIDAMBAPLIATC-UHFFFAOYSA-M 4-methoxycarbonylbenzoate Chemical compound COC(=O)C1=CC=C(C([O-])=O)C=C1 REIDAMBAPLIATC-UHFFFAOYSA-M 0.000 abstract 1
- AMDKYPNODLTUMY-UHFFFAOYSA-N 5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-amine Chemical compound NC1=CC=C2C(C)(C)CCC(C)(C)C2=C1 AMDKYPNODLTUMY-UHFFFAOYSA-N 0.000 abstract 1
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 238000006482 condensation reaction Methods 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 208000032839 leukemia Diseases 0.000 abstract 1
- 229910000027 potassium carbonate Inorganic materials 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 150000004508 retinoic acid derivatives Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a synthetic method of tamibarotene, namely a medicament for treating leukemia and provides a new synthetic route. The synthetic method mainly comprises the following steps: carrying out condensation reaction on raw materials 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-amine and mono-methyl terephthalate to obtain 4-[(4,5,6,7-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]methyl benzoate; further hydrolyzing the intermediate in potassium carbonate to obtain 4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-yl)carbamoyl]benzoic acid, namely tamibarotene. The synthetic route is simple and environment-friendly and is beneficial to industrial production.
Description
Technical field
The present invention relates to the synthetic novel process of a kind of Tamibarotene, belong to synthesis technical field.
Background technology
Tamibarotene is the complete synthesis retinoid compound of developing for ATRA resistance, is acute promyelocytic leukemia patients with recurrent to be had to the medicine of remarkable induction ability.This medicine shows that ATRA is alleviated to the rear APL recurring has unusual effect, replys the validity of Patients with Difficult and also can expect to ATRA.The in vivo test of Tamibarotene has shown anti-tumor activity and good tolerance, and external validity approximately surpasses 10 times of all-trans-retinoic acids, and such novel anti-leukemia medicine will have market application foreground widely.Tamibarotene is developed by Japanese Dong Kwang Co., Ltd, June 13 in 2005 in Japanese Initial Public Offering.
The synthetic method of the Tamibarotene that present domestic and foreign literature relates to mainly contains three kinds:
(1) J.Med.Chem.1988,31 (11): 2182-2191, announces a kind of synthetic method
With 5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-amine and terephthalic acid monomethyl ester's acyl chlorides are raw material, through amidation and hydrolysis, obtain Tamibarotene.
In this method, terephthalic acid monomethyl ester's acyl chlorides is prepared by terephthalic acid monomethyl ester and sulfur oxychloride, and sulfur oxychloride can produce a large amount of waste gas hydrogenchloride and sulfurous gas in reaction, very large for the pollution of environment.
(2) patent WO9114673 has announced another synthetic method
With 5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-ethanamide is raw material, under the condition of the existence of phosphorus pentachloride, carries out acyl permutoid reaction with terephthalic acid monomethyl ester's acyl chlorides, and further hydrolysis obtains Tamibarotene.
Terephthalic acid monomethyl ester acyl chlorides in synthetic the topsoil beyond the region of objective existence such as meeting generation hydrogenchloride and sulfurous gas of the method except using, phosphorus pentachloride in use also can produce a large amount of hydrogen chloride emissions, in product postprocessing, also there is a large amount of phosphoric acid, need to increase the processing of spent acid, contaminative is larger.
(3) domestic synthetic method, patent CN101121675 has announced a kind of new synthetic method
The method is chloro-2 to phenylcarbamoyl methyl benzoate and 2,5-bis-, and the alkylation of 5-dimethylhexane obtains Tamibarotene methyl esters, and rear hydrolysis obtains Tamibarotene.
Although the method has adopted a new route, but due to very bad to phenylcarbamoyl methyl benzoate solvability in reaction, when doing friedel-crafts reaction, need to use a large amount of organic solvents, cause solvent unit consumption excessive, yield neither be very desirable, and adopt NaOH to do basic hydrolysis, and easily produce by product, cause the difficult purifying of product.
Summary of the invention
Under above-mentioned background, a kind of new preparation 4-[(5,5 have been researched and developed in this discovery, 8,8-tetramethyl--6,7-dihydronaphthalene-2-yl) carbamyl] method of phenylformic acid (Tamibarotene), synthesis technique is simple, and product is easily purified, and can effectively reduce environmental pollution simultaneously.
Key step of the present invention is as follows:
(1) with 5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-amine is raw material, reacts condensation and obtains 4-[(4,5,6,7-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene with terephthalic acid monomethyl ester) carbamyl] methyl benzoate (II)
(2) 4-[(4,5,6,7-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene) carbamyl] methyl benzoate and wet chemical reflux, product acid out obtains Tamibarotene product.
Specific embodiments
Example 1
4-[(4,5,6,7-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene) carbamyl] preparation of methyl benzoate (II)
By 20.1g5, 5, 8, 8-tetramethyl--5, 6, 7, 8-naphthane-2-amine and 19.4g terephthalic acid monomethyl ester are dissolved in 200mL methylene dichloride, after add successively each 33.6 grams of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC.HCl) and triethylamines, under room temperature, stir 24 hours, in reactant, continue to add 100mL hydrochloric acid and 500mL water, divide water-yielding stratum, 500mL washing one time, saturated sodium bicarbonate solution 300mL washes one time, saturated common salt washing one time, anhydrous magnesium sulfate drying, filter out siccative, underpressure distillation obtains faint yellow solid.This solid is added to 300mL ethanol, and 50 ℃ are stirred filtration in 12 hours and obtain 29.5 grams of white solids.
Example 2
29.5 digest the 10%K that adds 200mL in compound (II)
2cO
3, reflux 30min, reaction finishes rear cooling, with hydrochloric acid, adjusts PH to reach 2 left and right, filters and obtains white solid.By being dissolved in after this solid drying in 300mL ethanol, slowly drip 300mL water, separate out white solid, solid obtains 25.4 grams of Tamibarotenes after drying, and product purity is 99.6% after testing.
Claims (5)
1. prepare a 4-[(5,5,8,8-tetramethyl--6,7-dihydronaphthalene-2-yl) carbamyl] novel method of phenylformic acid (Tamibarotene), key step is as follows:
(1) with 5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-amine is raw material, reacts condensation and obtains 4-[(4,5,6,7-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene with terephthalic acid monomethyl ester) carbamyl] methyl benzoate (II)
(2) 4-[(4,5,6,7-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene) carbamyl] methyl benzoate and wet chemical reflux, product acid out obtains Tamibarotene product.
2. a kind of 4-[(5 for preparing as claimed in claim 1,5,8,8-tetramethyl--6,7-dihydronaphthalene-2-yl) carbamyl] novel method of phenylformic acid (Tamibarotene), it is characterized in that: in synthesis step 5,5,8,8-tetramethyl--5,6, in 7,8-naphthane-2-amine and terephthalic acid monomethyl ester's reaction, terephthalic acid monomethyl ester is excessive, and optimum mole ratio is 5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-amine is 1 than terephthalic acid monomethyl ester: 1.01-1: 1.3.
3. a kind of 4-[(5 for preparing as claimed in claim 1,5,8,8-tetramethyl--6,7-dihydronaphthalene-2-yl) carbamyl] novel method of benzoic acid (Tamibarotene), it is characterized in that: in synthetic, add condensation catalyst can select N, N-dicyclohexylcarbodiimide (DCC) and DMAP (DMAP); 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride EDC.HCl) and triethylamine; The combination catalysts such as 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC.HCl) and DMAP (DMAP).
4. a kind of 4-[(5 for preparing as claimed in claim 3,5,8,8-tetramethyl--6,7-dihydronaphthalene-2-yl) carbamyl] novel method of phenylformic acid (Tamibarotene), it is characterized in that: in reaction, the mol ratio of combination catalyst and reactant is 1: 1-1: 3.
5. a kind of 4-[(5 for preparing as claimed in claim 1,5,8,8-tetramethyl--6,7-dihydronaphthalene-2-yl) carbamyl] novel method of phenylformic acid (Tamibarotene), it is characterized in that: in synthetic method (2), hydrolysis adopts the K of 10%-20%
2cO
3solution hydrolysis, obtains purity and is not less than 99.5% Tamibarotene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210361469.9A CN103664680A (en) | 2012-09-26 | 2012-09-26 | New process for synthesizing tamibarotene |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210361469.9A CN103664680A (en) | 2012-09-26 | 2012-09-26 | New process for synthesizing tamibarotene |
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| Publication Number | Publication Date |
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| CN103664680A true CN103664680A (en) | 2014-03-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210361469.9A Pending CN103664680A (en) | 2012-09-26 | 2012-09-26 | New process for synthesizing tamibarotene |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4703110A (en) * | 1984-07-07 | 1987-10-27 | Koichi Shudo | Benzoic acid derivatives having a para substituent which is a substituted phenyl group connected by a linking radical; useful in neoplastic cell differentiation and diagnosis |
| US5668156A (en) * | 1990-10-12 | 1997-09-16 | Centre International De Recherches Dermatologiques Galderma (Cird Galderma) | Di (aromatic) compounds and their use in human and veterinary medicine and in cosmetics |
| CN101121675A (en) * | 2007-07-25 | 2008-02-13 | 中国药科大学 | A new synthesis process of tamibarotene |
| JP2008094727A (en) * | 2006-10-06 | 2008-04-24 | Research Foundation Itsuu Laboratory | Retinoid prodrug compound |
| CN101888991A (en) * | 2007-10-31 | 2010-11-17 | 财团法人乙卯研究所 | Retinoid prodrug compound |
| US7923579B2 (en) * | 2003-12-12 | 2011-04-12 | Exonhit Therapeutics S.A. | Tricyclic hydroxamate and benzamide derivatives, compositions and methods |
| CN102633673A (en) * | 2012-03-30 | 2012-08-15 | 上海共价化学科技有限公司 | Synthesis method of tamibarotene |
-
2012
- 2012-09-26 CN CN201210361469.9A patent/CN103664680A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4703110A (en) * | 1984-07-07 | 1987-10-27 | Koichi Shudo | Benzoic acid derivatives having a para substituent which is a substituted phenyl group connected by a linking radical; useful in neoplastic cell differentiation and diagnosis |
| US5668156A (en) * | 1990-10-12 | 1997-09-16 | Centre International De Recherches Dermatologiques Galderma (Cird Galderma) | Di (aromatic) compounds and their use in human and veterinary medicine and in cosmetics |
| US7923579B2 (en) * | 2003-12-12 | 2011-04-12 | Exonhit Therapeutics S.A. | Tricyclic hydroxamate and benzamide derivatives, compositions and methods |
| JP2008094727A (en) * | 2006-10-06 | 2008-04-24 | Research Foundation Itsuu Laboratory | Retinoid prodrug compound |
| CN101121675A (en) * | 2007-07-25 | 2008-02-13 | 中国药科大学 | A new synthesis process of tamibarotene |
| CN101888991A (en) * | 2007-10-31 | 2010-11-17 | 财团法人乙卯研究所 | Retinoid prodrug compound |
| CN102633673A (en) * | 2012-03-30 | 2012-08-15 | 上海共价化学科技有限公司 | Synthesis method of tamibarotene |
Non-Patent Citations (1)
| Title |
|---|
| 边海勇等: "他米巴罗汀的合成", 《中国医药工业杂志》 * |
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