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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- tetramethyl
- tamibarotene
- carbamyl
- dihydronaphthalene
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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.
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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 | Synthetic technique for 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 | Synthetic technique for 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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Application publication date: 20140326 |