Process for the preparation of 2-substituted-2-(6-(substituted)-7-methylbenzo[D][1,3]dioxol-4-yl)acetic acid derivatives
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-309/12
C07D-317/64
C07F-007/18
C07C-043/23
C07C-059/64
C07C-069/734
출원번호
US-0408534
(2013-06-19)
등록번호
US-9227948
(2016-01-05)
우선권정보
IN-2429/CHE/2012 (2012-06-19)
국제출원번호
PCT/IN2013/000381
(2013-06-19)
국제공개번호
WO2013/190571
(2013-12-27)
발명자
/ 주소
Muddasani, Pulla Reddy
Chintalapudi, Manikumar
Nannapaneni, Venkaiah Chowdary
출원인 / 주소
Natco Pharma Limited
대리인 / 주소
Kilpatrick Townsend & Stockton LLP
인용정보
피인용 횟수 :
0인용 특허 :
1
초록▼
Present invention relates to an improved and commercial process for the preparation of 2-sustituted-2-(6-(substituted)-7-methylbenzod1,3dioxol-4-yl)acetic acid derivatives of formula-I the above Formula I, XII, XIII, XV, wherein R1 is a O-protecting group such as methoxymethyl, ethoxymethyl, trialky
Present invention relates to an improved and commercial process for the preparation of 2-sustituted-2-(6-(substituted)-7-methylbenzod1,3dioxol-4-yl)acetic acid derivatives of formula-I the above Formula I, XII, XIII, XV, wherein R1 is a O-protecting group such as methoxymethyl, ethoxymethyl, trialkylsilyl, arylmethyl, tetrahydropyran-2-yl, allyl; X is hydroxyl, halogen, mesylate, triflate, tosylate, acetate; Y is oxygen atom, NH or sulfur atom; R2 is C1-C6 alkyl. 2,4-Dihydroxy-3-methylbenzaldehyde is selectively protected at C-4 position in the form of an ether compound of formula-XII, oxidized the aldehyde function to get the diol of formula-XIII, and condensed with ethyl glyoxalate under Casiraghi reaction conditions to get the compound of formula-XV. Compound of formula-XV is converted to compound of formula-I by conventional chemistry. Compounds of formula-I are key intermediates in the synthesis of ecteinascidines like trabectedin.
대표청구항▼
1. A process for the preparation of 2-substituted-2-(6-(substituted)-7-methylbenzo[d][1,3]dioxol-4-yl)acetic acid derivatives of formula-I, wherein R1 is a O-protecting group selected from the group consisting of methoxymethyl, ethoxymethyl, trialkylsilyl, arylmethyl, tetrahydropyran-2-yl, and allyl
1. A process for the preparation of 2-substituted-2-(6-(substituted)-7-methylbenzo[d][1,3]dioxol-4-yl)acetic acid derivatives of formula-I, wherein R1 is a O-protecting group selected from the group consisting of methoxymethyl, ethoxymethyl, trialkylsilyl, arylmethyl, tetrahydropyran-2-yl, and allyl; X is selected from the group consisting of halogen, mesylate, triflate, tosylate, and acetate; Y is selected from the group consisting of an oxygen atom, NH and a sulfur atom; and R2 is C1-C6 alkylsaid process comprising:(i) reacting 2,4-dihydroxy-3-methylbenzaldehyde with an etherification reagent in the presence of a base (or acid in case of tetrahydropyran-2-yl protection) and a solvent at 0-100° C. to produce a mono-protected derivative of formula-XII, wherein R1 is selected from the group consisting of methoxymethyl, ethoxymethyl, trialkylsilyl, tetrahydropyran-2-yl, allyl, and arylmethyl;(ii) oxidizing said mono-protected derivative of formula-XII with an oxidizing agent in the presence of a base and a solvent at pH 7-14 to obtain a dihydroxy compound of formula-XIII, (iii) reacting said dihydroxy compound of formula-XIII with a base and an aldehyde compound of formula-XIV, wherein Y and R2 are as defined above; in the presence of a solvent at 0-100° C. to produce a compound of formula-XV, wherein R1, Y, and R2 are as defined above;(iv) reacting said compound of formula-XV with a dihalomethane in the presence of a base and a solvent at 15-120° C. to produce a methylenedioxy derivative of formula-XVI wherein R1, Y, and R2 are as defined above; and(v) converting the hydroxyl group of said methylenedioxy derivative of formula-XVI to X wherein X is as defined above using a suitable reagent in the presence of a base at −78 to 40° C. to obtain said 2-substituted-2-(6-(substituted)-7-methylbenzo[d][1,3]dioxol-4-yl)acetic acid derivative of formula-I 2. A process as claimed in claim 1 wherein the base used in step (i) is selected from the group consisting of trialkylamine, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. 3. A process as claimed in claim 1 wherein the solvent used in step (i) is selected from the group consisting of halogenated solvents, ethers, and hydrocarbons. 4. A process as claimed in claim 1 wherein the temperature of reaction in step (i) is 10-40° C. 5. A process as claimed in claim 1 wherein the oxidizing agent used in step (ii) is hydrogen peroxide, meta-chloroperbenzoic acid, or peracetic acid. 6. A process as claimed in claim 1 wherein the pH during oxidation in step (ii) is 7.5-8.5. 7. A process as claimed in claim 1 wherein the solvent used in step (ii) is water or aqueous alcohols. 8. A process as claimed in claim 1 wherein the base used in step (ii) is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and hydroxide. 9. A process as claimed in claim 1 wherein the base used in step (iii) is C1-C6 alkylmagnesium chloride or bromide, or magnesium C1-C6 alkoxide. 10. A process as claimed in claim 1 wherein the temperature of the reaction in step (iii) is 0-45° C. 11. A process as claimed in claim 1 wherein the solvent used in step (iii) is selected from the group consisting of dichloromethane, pentane, hexane, heptane, cyclohexane, toluene, xylene, diethyl ether, tetrahydrofuran (THF), diisopropyl ether, methyl tert-butyl ether, and combinations thereof. 12. A process as claimed in claim 1 wherein the base used in step (iv) is selected from the group consisting of sodium carbonate, potassium carbonate and cesium carbonate. 13. A process as claimed in claim 1 wherein the solvent used in step (iv) is selected from the group consisting of pentane, hexane, heptane, cyclohexane, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, THF, and acetonitrile. 14. A process as claimed in claim 1 wherein the temperature of the reaction in step (iv) is 25-50° C. 15. A process as claimed in claim 1 wherein the dihalomethane used in step (iv) is bromochloromethane, bromoiodomethane, dibromomethane, dichloromethane, or diiodomethane. 16. A process as claimed in claim 1 wherein the reagent used for conversion of hydroxyl to X in step (v) is thionyl chloride, methanesulfonyl chloride, triflic anhydride, acetyl chloride, acetic anhydride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, carbon tetrachloride/triphenylphosphine, or carbon tetrabromide/triphenylphosphine. 17. A process as claimed in claim 1 wherein the base used for conversion of hydroxyl to X in step (v) is selected from the group consisting of benzotriazole, diazabicycloundecane (DBU), N,N-diisopropylethylamine, and triethylamine. 18. A process as claimed in claim 1 wherein the temperature of the reaction for conversion of hydroxyl to X in step (v) is −40 to 25° C. 19. A compound of formula-XIII, wherein R1 is selected from the group consisting of methoxymethyl, ethoxymethyl, trialkylsilyl, arylmethyl, tetrahydropyran-2-yl, and allyl. 20. A compound of formula XV, whereinR1 is selected from the group consisting of methoxymethyl, ethoxymethyl, trialkylsilyl, arylmethyl, tetrahydropyran-2-yl, and allyl;Y is selected from the group consisting of an oxygen atom, NH and a sulfur atom; andR2 is C1-C6 alkyl. 21. A process as claimed in claim 2, wherein the trialkylamine is N,N-diisopropylethylamine. 22. A process as claimed in claim 3, wherein the halogenated solvent is methylene chloride. 23. A process as claimed in claim 4, wherein the temperature of reaction in step (i) is 10-25° C. 24. A process as claimed in claim 6, wherein the pH during oxidation in step (ii) is 7.8-8.3. 25. A process as claimed in claim 9, wherein the base used in step (iii) is methylmagnesium chloride or n-butylmagnesium chloride. 26. A process as claimed in claim 11, wherein the solvent in step (iii) is a combination of toluene and THF. 27. A process as claimed in claim 14, wherein the temperature of the reaction in step (iv) is 25-35° C.
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이 특허에 인용된 특허 (1)
Formanek Karel (Serezin Du Rhone FRX) Michelet Daniel (Tassin La Demi-Lune FRX) Petre Dominique (Lyons FRX), Preparation of polyphenols by oxidation of hydroxybenzaldehydes.
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