WO2004108660A1 - Novel halo-substituted active methylene compounds - Google Patents

Novel halo-substituted active methylene compounds Download PDF

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Publication number
WO2004108660A1
WO2004108660A1 PCT/IN2003/000216 IN0300216W WO2004108660A1 WO 2004108660 A1 WO2004108660 A1 WO 2004108660A1 IN 0300216 W IN0300216 W IN 0300216W WO 2004108660 A1 WO2004108660 A1 WO 2004108660A1
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WO
WIPO (PCT)
Prior art keywords
formula
compounds
formula iii
compound
iii
Prior art date
Application number
PCT/IN2003/000216
Other languages
French (fr)
Inventor
Joy Mathew
Tom Thomas Puthiaparampil
Madhavan Sridharan
Shanker Padudevastana Sathya
Sambasivam Ganesh
Original Assignee
Biocon 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 Biocon Limited filed Critical Biocon Limited
Priority to PCT/IN2003/000216 priority Critical patent/WO2004108660A1/en
Priority to AU2003242989A priority patent/AU2003242989A1/en
Priority to EP03817135A priority patent/EP1644319A4/en
Priority to US10/483,533 priority patent/US7179942B2/en
Priority to JP2005500509A priority patent/JP2006527164A/en
Publication of WO2004108660A1 publication Critical patent/WO2004108660A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/80—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

  • the compounds of formula I can be prepared by a novel process comprising, a) a) halogenation of compound of formula II to afford a compounds of formula HI, b) reaction of compounds of formula III with compounds of formula IV.
  • G any alkyl or aryl
  • HMG Co-A reductase inhibitors are important intermediates for the preparation of drug molecules especially, HMG Co-A reductase inhibitors.
  • the HMG Co-A reductase inhibitors are useful as inhibitors of the enzyme 3-hydroxy-3- methylglutaryl-coenzyme A reductase (HMG CoA reductase) and are thus useful as hvpolipidemic or hypocholesterolemic agents.
  • G any alkyl or aryl
  • FORMULA I The process of the present invention is new, economical, and commercially feasible method for preparing intermediates used for the preparation of HMG CoA reductase inhibitors.
  • reaction between compounds of formula II and III is carried out in the presence of reagents selected from Bromine, N-bromosuccinimide, thionyl chloride, Br 2 (CN) 2 , 4-(dimethylamino)pyridinium bromide or any such suitable halogenating agent.
  • reagents selected from Bromine, N-bromosuccinimide, thionyl chloride, Br 2 (CN) 2 , 4-(dimethylamino)pyridinium bromide or any such suitable halogenating agent.
  • the compounds of formula III can be further used for preparation of 4-
  • Fluoro- ⁇ -[2-methyl-l-oxopropyl] ⁇ -oxo-N- ⁇ -diphenylbenzene butane amide which is key intermediate for manufacture of [R-(R*,R*)]-2-(4-Fluorophenyl)-B,D-Dihydroxy- 5-(l-Methylethyl)-3-Phenyl-4-[(Phenyl amino) Carbonyl]-lh-Pyrrole-l-Heptanoic Acid, by reacting with compound of formula IV.
  • the reaction between compounds of formula III and formula IV is carried out in the presence of reagents selected from Lithium diisopropylamide, sodium hydride n-butyllithium, sodium ethoxide or any such suitable base.
  • Halogenation X any halogen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A novel process for the preparation of compounds of formula (I) by employing novel halo-substituted active methylene compounds of formula (III) and process of preparation thereof.

Description

Figure imgf000003_0001
X = any halogen
Formula III The present invention also relates to novel process for preparation compounds of formula I.
Figure imgf000003_0002
G = any alkyl or aryl Formula I
As mentioned earlier the compounds of formula I can be prepared by a novel process comprising, a) a) halogenation of compound of formula II to afford a compounds of formula HI, b) reaction of compounds of formula III with compounds of formula IV.
Figure imgf000003_0003
Formula II
Figure imgf000003_0004
X = any halogen
Formula III
Figure imgf000004_0001
G = any alkyl or aryl
Formula IV
Detailed Description of the invention
Compounds of formula I are important intermediates for the preparation of drug molecules especially, HMG Co-A reductase inhibitors. The HMG Co-A reductase inhibitors are useful as inhibitors of the enzyme 3-hydroxy-3- methylglutaryl-coenzyme A reductase (HMG CoA reductase) and are thus useful as hvpolipidemic or hypocholesterolemic agents.
Figure imgf000004_0002
G = any alkyl or aryl
FORMULA I The process of the present invention is new, economical, and commercially feasible method for preparing intermediates used for the preparation of HMG CoA reductase inhibitors.
The reaction between compounds of formula II and III is carried out in the presence of reagents selected from Bromine, N-bromosuccinimide, thionyl chloride, Br2(CN)2, 4-(dimethylamino)pyridinium bromide or any such suitable halogenating agent. The compounds of formula III can be further used for preparation of 4-
Fluoro-α-[2-methyl-l-oxopropyl]γ-oxo-N-β-diphenylbenzene butane amide which is key intermediate for manufacture of [R-(R*,R*)]-2-(4-Fluorophenyl)-B,D-Dihydroxy- 5-(l-Methylethyl)-3-Phenyl-4-[(Phenyl amino) Carbonyl]-lh-Pyrrole-l-Heptanoic Acid, by reacting with compound of formula IV. The reaction between compounds of formula III and formula IV is carried out in the presence of reagents selected from Lithium diisopropylamide, sodium hydride n-butyllithium, sodium ethoxide or any such suitable base.
The following non-limiting examples illustrate the inventors' preferred method for preparing the compounds of the invention.
EXAMPLES
Example 1
Preparation of 2-Bromo-4-methyl-3-oxo-pentanoic acid phenylamide:
To a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048 mol) in chloroform (100 mL), liquid bromine (7.8 g, 0.048 mol) was added. After stirring for 30 minutes, the reaction mixture was concentrated and product was isolated by column chromatography(silica gel: 60-120 mesh, eluent: Pet. Ether/ethyl acetate-
60:40)
Yield: 11.0 g, 80%
Example 2 Preparation of 2-Bromo-4-methyl-3-oxo-pentanoic acid phenylamide:
To a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048 mol) in acetone 100 mL), N-bromosuccinimide (8.5 g, 0.048 mol) was added. After stirring for 3 hours, the reaction mixture was concentrated and product was isolated by crystallization from Pet. Ether/ethyl acetate. Yield: 12.5 g, 92% Example 3
Preparation of 4-Fluoro-α- [2-methyl-l-oxopropyl]γ-oxo-N-β-diphenylbenzene butane amide:
To a chilled solution of dϋsopropylamine (8 mL, 0.056 mol) in dry THF(50 mL), n-butyl lithium (35 mL, 1.6 M, 0.056 mol) in hexane was added dropwise under nitrogen atmosphere, maintaining the temperature between -10° C and -25° C and stirred for 30 minutes at the same temperature. A solution of l-(4-Fluoro-phenyl)-2- phenyl-ethanone (10 g, 0.047 mol) in THF (20 mL) was added to the reaction mixture dropwise, maintaining the temperature between -60° C and -78° C and stirred for 1 hour at the same temperature. 2-Bromo-4-methyl-3-oxo-pentanoic acid, phenylamide (13.4 g, 0.047 mol) in THF (30 mL) was added dropwise to the reaction mixture , maintaining the temperature between -60° C and -78° C and stirred for 30 minutes. The reaction mixture was slowly warmed 10-15° C, over a period of 1 hour and quenched with water (50 mL). The product was extracted with ethyl acetate (2 x 50 mL). Combined organic extract was washed with water (2 x 50 mL) brine (2 x 50 mL) and concentrated to obtain title compound. Yield: 16 g, 85%. Example 4
Preparation of 4-Fluoro-α- [2-methyl-l-oxopropyl]γ-oxo-N-β-diphenylbenzene butane amide:
To a chilled solution of diisopropylamine (8 mL, 0.056 mol) in dry THF (50 mL), n-butyl lithium (35 mL, 1.6 M, 0.056 mol) in hexane was added dropwise under nitrogen atmosphere, maintaining the temperature between —10° C and —25° C and stirred for 30 minutes at the same temperature. A solution of l-(4-Fluoro- ρhenyl)-3-methyl-butan-l-one (8.4 g, 0.047 mol) in THF (20 mL) was added to the reaction mixture dropwise, maintaining the temperature between —60° C and —78° C and stirred for 1 hour at the same temperature. 2-Bromo-4-methyl-3-oxo-pentanoic acid phenylamide (13.4 g, 0.047 mol) in THF (30 mL) was added dropwise to the reaction mixture , maintaining the temperature between —60° C and -78° C and stirred for 30 minutes. The reaction mixture was slowly warmed 10-15° C, over a period of 1 hour and quenched with water (50 mL). The product was extracted with ethyl acetate (2 x 50 mL). Combined organic extract was washed with water (2 x 50 mL) brine (2 x 50 mL) and concentrated to obtain title compound. Yield: 15 g, 87%.
Scheme I:
Halogenation
Figure imgf000007_0002
Figure imgf000007_0001
X = any halogen
Figure imgf000007_0003

Claims

CLAIMSWe claim:
1. A process for preparing compound of formula I
Figure imgf000008_0001
G = any alkyl or aryl
Formula I comprising the steps of reaction of the compound of formula III with compounds of formula IV to obtain compound of formula I
Figure imgf000008_0002
X = any halogen
Formula III
Figure imgf000008_0003
G = any alkyl or aryl Formula IV
2. A process as in claim 1, wherein the reaction between compounds of formula III and formula IV is carried out in the presence of reagents selected from lithium dϋsopropylamide, sodium hydride n-butyllithium, sodium ethoxide or any such suitable base.
3. A process as in claim 1, wherein the compounds of formula III is prepared
Figure imgf000009_0001
X = any halogen FORMULA III by halogenation of compound of formula II to afford a compound of formula II.
Figure imgf000009_0002
Formula II
4. A process as in claim 3, wherein the halogenation is carried out in the presence of reagents selected from Bromine, N-bromosuccinimide, thionyl chloride, Br2(CN)2, 4-(dimethylamino)pyridinium bromide or any such suitable halogenating agent.
5. An intermediate of formula III
Figure imgf000009_0003
X = any halogen Formula III
PCT/IN2003/000216 2002-07-05 2003-06-09 Novel halo-substituted active methylene compounds WO2004108660A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/IN2003/000216 WO2004108660A1 (en) 2003-06-09 2003-06-09 Novel halo-substituted active methylene compounds
AU2003242989A AU2003242989A1 (en) 2003-06-09 2003-06-09 Novel halo-substituted active methylene compounds
EP03817135A EP1644319A4 (en) 2003-06-09 2003-06-09 Novel halo-substituted active methylene compounds
US10/483,533 US7179942B2 (en) 2002-07-05 2003-06-09 Halo-substituted active methylene compounds
JP2005500509A JP2006527164A (en) 2003-06-09 2003-06-09 Novel halogen-substituted active methylene compounds

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AU (1) AU2003242989A1 (en)
WO (1) WO2004108660A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1784384A1 (en) * 2004-08-26 2007-05-16 Biocon Limited Process for preparation of 4-fluoro-alpha-[2-methyl-1-oxopropyl]gamma-oxo-n-beta-diphenylbenzene butane amide
CN114195670A (en) * 2021-12-31 2022-03-18 河南豫辰药业股份有限公司 Refining method of atorvastatin mother nucleus M4

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5124482A (en) 1988-02-22 1992-06-23 Warner-Lambert Company Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis
US5216174A (en) 1988-02-22 1993-06-01 Warner-Lambert Co. Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
WO2003004457A2 (en) 2001-07-04 2003-01-16 Ciba Specialty Chemicals Holding Inc. Preparation process for atorvastatin and intermediates

Family Cites Families (3)

* Cited by examiner, † Cited by third party
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JPH0638157B2 (en) * 1985-05-11 1994-05-18 コニカ株式会社 Silver halide photographic light-sensitive material
AU2000254249A1 (en) * 2000-03-28 2001-10-08 Biocon India Limited Synthesis of (r-(r*,r*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-
WO2002057229A1 (en) * 2001-01-19 2002-07-25 Biocon India Limited FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5124482A (en) 1988-02-22 1992-06-23 Warner-Lambert Company Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis
US5216174A (en) 1988-02-22 1993-06-01 Warner-Lambert Co. Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
WO2003004457A2 (en) 2001-07-04 2003-01-16 Ciba Specialty Chemicals Holding Inc. Preparation process for atorvastatin and intermediates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1644319A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1784384A1 (en) * 2004-08-26 2007-05-16 Biocon Limited Process for preparation of 4-fluoro-alpha-[2-methyl-1-oxopropyl]gamma-oxo-n-beta-diphenylbenzene butane amide
EP1784384A4 (en) * 2004-08-26 2007-12-05 Biocon Ltd Process for preparation of 4-fluoro-alpha-[2-methyl-1-oxopropyl]gamma-oxo-n-beta-diphenylbenzene butane amide
CN114195670A (en) * 2021-12-31 2022-03-18 河南豫辰药业股份有限公司 Refining method of atorvastatin mother nucleus M4
CN114195670B (en) * 2021-12-31 2024-03-15 河南豫辰药业股份有限公司 Refining method of atorvastatin mother nucleus M4

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EP1644319A4 (en) 2007-10-31
AU2003242989A1 (en) 2005-01-04
JP2006527164A (en) 2006-11-30

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