WO2006090256A1 - Procede de preparation d'une n-methyle anilino acroleine - Google Patents

Procede de preparation d'une n-methyle anilino acroleine Download PDF

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Publication number
WO2006090256A1
WO2006090256A1 PCT/IB2006/000395 IB2006000395W WO2006090256A1 WO 2006090256 A1 WO2006090256 A1 WO 2006090256A1 IB 2006000395 W IB2006000395 W IB 2006000395W WO 2006090256 A1 WO2006090256 A1 WO 2006090256A1
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WO
WIPO (PCT)
Prior art keywords
formula
methyl
process according
reaction mixture
phenylaminoacrolein
Prior art date
Application number
PCT/IB2006/000395
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English (en)
Inventor
Keshav Deo
Seema Kanwar
Anand Pandey
Mohan Prasad
Yatendra Kumar
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2006090256A1 publication Critical patent/WO2006090256A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • Fluvastatin is a racemate of (3R,5S) and (3S.5R) erythro-7-[3-(4-fluorophenyl)-l-(l- methylethyl)-lH-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid of Formula II.
  • Fluvastatin is available commercially in the form of its monosodium salt which is indicated as an adjunct to diet to reduce elevated total cholesterol (Total-C), LDL-C, TG and Apo B levels, and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type Ha and lib) whose response to dietary restriction of saturated fat and cholesterol and other non-pharmacological measures has not been adequate. It is also indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total and LDL cholesterol to target levels. Fluvastatin sodium is the first entirely synthetic HMG-CoA reductase inhibitor, and is in part structurally distinct from the fungal derivatives of this therapeutic class.
  • GB Specification 945536 and U.S. Patent No. 5, 118,853 disclose synthesis of 3-N- methyl-N-phenylaminoacrolein using N-methylformanilide and ethyl vinyl ether in the presence of phosgene or oxalyl chloride followed by hydrolysis of the resultant complex.
  • U. S. Application No. 2004/0229958 discloses the preparation of 3-N-methyl-N- phenylaminoacrolein by a similar procedure reported in U.S. Patent No. 5,118,853, except that dioxane is used as a solvent in place of chlorinated hydrocarbons.
  • German Patent Specification Nos. 944,852 and 948,871 disclose processes for preparation of beta-aminoacroleins but do not exemplify the preparation of 3-N-methyl-N- phenylaminoacrolein.
  • U.S. Patent No. 4,739,073 (“the '073 Patent”) and US Patent No. 5,354,772 provide a process for preparation of racemic fluvastatin sodium, which involves lyophilization of an aqueous solution of fluvastatin sodium.
  • the '073 Patent further provides a process for the preparation of enantiomerically pure (3 S, 5R) or (3 R, 5S) forms of fluvastatin sodium which comprises resolution of racemic fluvastatin sodium by High Performance Liquid Chromatography (HPLC) and by using chiral auxiliaries.
  • HPLC High Performance Liquid Chromatography
  • the present inventors have now prepared N-methyl-N-phenylaminoacrolein of structural Formula I, by a process using cheap and easily available propargyl alcohol and N- methyl aniline.
  • the process can readily and desirably be carried out in a single step.
  • Formula I wherein the process comprises: a) reacting N-methylaniline and propargyl alcohol in presence of an oxidizing agent; and b) isolating 3-N-methyl-N-phenylaminoacrolein of Formula I from the resulting reaction mass.
  • N-methylaniline and propargyl alcohol are dissolved in an organic solvent until a clear solution is obtained.
  • the solution so obtained is oxidized with an oxidizing agent at about 15 to about 60 0 C by stirring for about 5 to about 25 h.
  • the reaction can be readily monitored by thin layer chromatography (TLC), followed by filtration.
  • TLC thin layer chromatography
  • the residual solid is washed with an organic solvent and de-ionized water.
  • the combined filtrate is taken and the aqueous layer discarded.
  • the organic layer can be is treated with activated charcoal.
  • the solvent can be completely recovered, for example, under reduced pressure, and the product can be recrystallized from solvent or a mixture of solvents to afford pure 3-N-methyl-N- phenylaminoacrolein of Formula I.
  • the organic solvent can be chosen from aromatic hydrocarbons, chlorinated hydrocarbons, ethers, polar aprotic solvents, ketones or mixtures thereof.
  • the aromatic hydrocarbon can be, for example, toluene, benzene or xylene.
  • the chlorinated hydrocarbon can be, for example, chloroform, dichloromethane, 1,2-dichloroethane and the like.
  • the ether can be, for example tetrahydrofuran, 1,4-dioxane and the like.
  • the ketone can be, for example, acetone, ethyl methyl ketone, methyl isobutyl ketone, diisobutyl ketone and the like.
  • the polar aprotic solvent can be, for example, N,N-dimethylformamide, N 5 N- dimethylacetamide, dimethylsulphoxide, acetonitrile, N-methylpyrrolidone and the like.
  • the oxidizing agent which can be used is one that can convert -CH 2 OH (a primary alcohol) group to -CHO (an aldehyde) group and is known to a person of ordinary skill in the art. Some of the oxidizing agents that can be used are exemplified hereinafter but they do not limit the scope of the invention.
  • the oxidizing agent can be selected from, for example, manganese dioxide, potassium dichromate, potassium permanganate, chromium trioxide, Jones reagent, eerie ammonium nitrate, oxalyl chloride/dimethylsulphoxide and the like.
  • Solvents for recrystallization can be selected from, for example, hydrocarbons, ketones or mixtures thereof.
  • the hydrocarbon can be, for example, petroleum ether, hexane, cyclohexane, cyclopentane, cycloheptane, toluene, benzene, xylene and the like.
  • the ketone can be, for example, acetone, ethyl methyl ketone, methyl isobutyl ketone, diisobutyl ketone and the like.
  • 3-N-methyl-N-phenylaminoacrolein of Formula I as obtained by processes described herein can have purity greater than about 98%. More preferably the purity is greater than about 99.8%. Most preferably the purity is greater than about 99.94%.
  • Formula I wherein the process comprises: a) oxidizing propargyl alcohol; b) treating the solution of step a) in situ with N-methylaniline; and c) isolating 3-N-methyl-N-phenylaminoacrolein of Formula I from the reaction mass thereof.
  • a solution of an oxidizing agent in de-ionized water can be cooled to about -10 to about 30 0 C and added to a solution of propargyl alcohol in an organic solvent at about -10 to about 30 0 C.
  • the reaction mixture can be quenched, for example, with methanol, and filtered.
  • the residue can be washed with an organic solvent.
  • the organic solvent can be completely recovered from the filtrate.
  • the reaction mass can be extracted with an organic solvent, dried and treated with N-methylaniline.
  • the reaction can be easily monitored by thin layer chromatography (TLC), followed by treatment with activated charcoal.
  • TLC thin layer chromatography
  • the solvent can be completely recovered, under reduced pressure and the product recrystallized from solvent or a mixture of solvents, to afford pure 3-N-methyl-N-phenylaminoacrolein of Formula I.
  • the oxidizing agent, organic solvent and solvent for recrystallization can be chosen as discussed herein.
  • 3-N-methyl-N-phenylammoacrolein of Formula I obtained by the process of the present invention can be converted to statins by processes known in the art.
  • it can be converted to fluvastatin by the process disclosed, for example, in U.S. Patent No. 2004/0229958, U. S. Patent No. 4,739,073 or U.S. Patent No. 5,354,772, which are incorporated herein as reference in their entireties.
  • Formula II wherein the process comprises: a) reacting N-methylaniline and propargyl alcohol in presence of an oxidizing agent; b) optionally isolating 3-N-methyl-N-phenylaminoacrolein of Formula I, from the reaction mixture of step a); c) treating the reaction mixture or the product of step b) with a compound of structural Formula V
  • step d) treating the reaction mixture of step c) with alkyl acetoacetate of Formula VII,
  • 3-N-methyl-N-phenylaminoacrolein of Formula I can be prepared, for example, by any of the processes described above.
  • 3-N-methyl-N-phenylaminoacrolein of Formula I can be optionally isolated from the reaction mass thereof and used for the preparation of fluvastatin or salt, ester or lactone form thereof.
  • Compound of Formula VI (obtained by reaction of 3-N-methyl-N-phenylaminoacrolein of Formula I with compound of Formula V) can be converted to fluvastatin, salt or ester or lactone form thereof essentially by the process described in, for example, Examples 5 and 6 of U.S. Patent No. 4,739,073 or U.S. Patent No. 5,354,772.
  • processes for the preparation of fluvastatin of Formula II, or salt, ester or lactone form thereof are provided,
  • Formula II wherein the process comprises: a) oxidizing propargyl alcohol; b) treating the reaction mixture of step a) with N-methylaniline; c) optionally isolating 3-N-methyl-N-phenylaminoacrolem of Formula I from the reaction mixture of step b); d) treating the reaction mixture or the product of step c) with a compound of structural Formula V
  • 3-N-methyl-N-phenylaminoacrolein of Formula I can be prepared, for example, by any of the processes described above.
  • 3-N-methyl-N-phenylarninoacrolein of Formula I can be optionally isolated from the reaction mass thereof and used for the preparation of fluvastatin or salt or ester or lactone form thereof.
  • Compound of Formula VI (obtained by reaction of 3 -N-methyl-N-phenylaminoacrolein of Formula I with compound of Formula V) can be converted to fluvastatin, salt or ester or lactone form thereof essentially by the process described, for example, in Examples 5 and 6 of U.S. Patent No. 4,739,073 or U.S. Patent No. 5,354,772.
  • 3 -N-methyl-N-phenylaminoacrolein of Formula I can also be used as an intermediate in the preparation of other statins by processes known to one skilled in the art. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and do not limit the scope of the present invention.
  • Example 4 Preparation of 3-N-methyl-N-phenylaminoacrolein Into a 500 ml three neck round bottom flask containing a solution of chromium trioxide (60.70 gm, 607.47 m mole) and 325 ml deionized water cooled to 0-5°C, was added sulphuric acid (86 g). This reagent was slowly added into a solution of propargyl alcohol (31.40 g, 560.71 mmole) in acetone (500 ml) at 0-5 0 C. The reaction mixture was stirred and quenched with methanol. The reaction mixture was filtered and the residue washed with acetone.
  • chromium trioxide 60.70 gm, 607.47 m mole
  • 325 ml deionized water cooled to 0-5°C
  • Acetone was recovered completely under reduced pressure and the propargyl aldehyde was extracted with toluene (2 x 150 ml). The toluene layer was dried over sodium sulphate and N-methylaniline (50 g, 467.29 mmole) was added. After monitoring the reaction it was treated with activated carbon (3 g) and the carbon filtered through hyflo supercel. Toluene was recovered completely under reduced pressure and the product was crystallized from toluene: hexanes (25 ml : 100 ml respectively) to afford the title compound. Yield: 62.25 g (83 %); Purity: 98.0%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

La présente invention se rapporte à des procédés de préparation de la 3-N-méthyle-N-phénylaminoacroline.
PCT/IB2006/000395 2005-02-28 2006-02-27 Procede de preparation d'une n-methyle anilino acroleine WO2006090256A1 (fr)

Applications Claiming Priority (2)

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IN431DE2005 2005-02-28
IN431/DEL/2005 2005-02-28

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WO2006090256A1 true WO2006090256A1 (fr) 2006-08-31

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603546A (zh) * 2012-02-17 2012-07-25 浙江工业大学 一种n-取代基-3-胺基丙烯醛的合成方法
CN104876861A (zh) * 2014-02-27 2015-09-02 上海泰禾化工有限公司 一种生产2-氯烟酸的方法
CN106431942A (zh) * 2016-07-26 2017-02-22 江苏兢业制药有限公司 一种3‑(n‑甲基‑n‑苯基)氨基丙烯醛的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE948871C (de) * 1954-05-22 1956-09-06 Basf Ag Verfahren zur Herstellung von ª‰-Aminovinylcarbonylverbindungen
US2808437A (en) * 1954-05-21 1957-10-01 Basf Ag Process of manufacturing beta-aminovinyl carbonyl compounds
US5118853A (en) * 1988-10-13 1992-06-02 Sandoz Ltd. Processes for the synthesis of 3-disubstituted aminoacroleins

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2808437A (en) * 1954-05-21 1957-10-01 Basf Ag Process of manufacturing beta-aminovinyl carbonyl compounds
DE948871C (de) * 1954-05-22 1956-09-06 Basf Ag Verfahren zur Herstellung von ª‰-Aminovinylcarbonylverbindungen
US5118853A (en) * 1988-10-13 1992-06-02 Sandoz Ltd. Processes for the synthesis of 3-disubstituted aminoacroleins

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MAKIN, S. M. ET AL: "Synthesis and study of .beta.-alkyl(aryl)aminoacroleins", XP002387863, retrieved from STN Database accession no. 76:13712 *
ZHURNAL ORGANICHESKOI KHIMII , 7(10), 2120-4 CODEN: ZORKAE; ISSN: 0514-7492, 1971 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603546A (zh) * 2012-02-17 2012-07-25 浙江工业大学 一种n-取代基-3-胺基丙烯醛的合成方法
CN102603546B (zh) * 2012-02-17 2014-07-02 浙江工业大学 一种n-取代基-3-胺基丙烯醛的合成方法
CN104876861A (zh) * 2014-02-27 2015-09-02 上海泰禾化工有限公司 一种生产2-氯烟酸的方法
CN104876861B (zh) * 2014-02-27 2017-05-24 上海泰禾国际贸易有限公司 一种生产2‑氯烟酸的方法
CN106431942A (zh) * 2016-07-26 2017-02-22 江苏兢业制药有限公司 一种3‑(n‑甲基‑n‑苯基)氨基丙烯醛的制备方法

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