WO2004103957A1 - Novel dithioketal - Google Patents

Novel dithioketal Download PDF

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Publication number
WO2004103957A1
WO2004103957A1 PCT/IN2003/000194 IN0300194W WO2004103957A1 WO 2004103957 A1 WO2004103957 A1 WO 2004103957A1 IN 0300194 W IN0300194 W IN 0300194W WO 2004103957 A1 WO2004103957 A1 WO 2004103957A1
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WIPO (PCT)
Prior art keywords
formula
compound
mol
phenyl
methyl
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PCT/IN2003/000194
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French (fr)
Inventor
Joy Mathew
Tom Thomas Puthiaparampil
Madhavan Sridharan
Padudevastana Sathya Shanker
Sambasivam Ganesh
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Biocon Limited
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Priority to PCT/IN2003/000194 priority Critical patent/WO2004103957A1/en
Priority to AU2003238680A priority patent/AU2003238680A1/en
Publication of WO2004103957A1 publication Critical patent/WO2004103957A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms

Definitions

  • the present invention relates to a novel dithioketal compound of formula I and process for its preparation.
  • US 5124482 and US 5216174 disclose manufacture and use of 4- Fluoro- ⁇ -[2-methyl-l-oxopropyl] ⁇ -oxo-N- ⁇ -diphenylbenzenebutane amide for preparation of [R-(R*,R*)]-2-(4-fluorophenyl)-B,D-dihydroxy -5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lh-pyrrole-l- heptanoic acid.
  • the present invention relates to novel compound of formula I.
  • the present invention also relates to a process for preparation of compound of formula I.
  • Ri and R are any suitable alkyl group or Ri and R 2 can join together to form any cyclic structure.
  • the compound of formula I can be used to synthesize 4-Fluoro- ⁇ -[2-methyl-l- oxopropyl] ⁇ -oxo-N- ⁇ -diphenylbenzenebutaneamide.
  • the compound of formula I is an important intermediate for the preparation of drug molecules especially, HMG Co-A reductase inhibitors.
  • 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 hypolipidemic or hypocholesterolemic agents.
  • the compound of formula I of the present invention is new.
  • FORMULA I The process of the present invention is also new, economical, and commercially feasible method for preparing intermediate used for the preparation of HMG CoA reductase inhibitors.
  • the process of the present invention is outlined in Scheme I.
  • the novel process comprises reaction of compound of formula II with compound of formula III.
  • Ri and R 2 are any suitable alkyl group, preferably C 2 H 5 or Ri and R 2 can join together to form any cyclic structures, preferably - CH 2 _ CH -CH - ,
  • reaction between compounds of formula II and III is carried 5 out in the presence of reagents selected from n-butyl lithium, NaH or LDA or any such suitable base.
  • reaction can also be performed with above mentioned reagents in presence of Copper or Magnesium chloride or any suitable 10 Lewis acid to give compound of formula I in better yield.
  • the compound of formula I 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- i5 Phenyl-4-[(Phenyl amino) Carbonyl]-lh-Pyrrole-l-Heptanoic Acid .
  • Example 1 20 Preparation of l-[bis(ethylthio)methyl]-4- fluorobertzene: A solution of 4-fluorobenzaidehyde (25 g, 0.2 mol) in dry THF (250 ml) was stirred under nitrogen and ethanethiol (21.2 ml, 0.6 mol) and iodine (2.6 g, 0.01 « mol) were added. After stirring the reaction mixture for 45 minutes at room temperature, pH of the 25 mixture was adjusted to about 8.0 using 10% aqueous sodium hydroxide solution.

Abstract

A novel compound of formula (I) and a process for the preparation of compounds of formula (I): by reacting a compound of formula (II): Formula (III): with a compound of formula (III) where R1 and R2 are any suitable alkyl group, preferably C2H5 or R1 and R2 can join together to form any cyclic structure, preferably -CH2-Ch2-CH2-.

Description

Novel Dithioketal FIELD OF INVENTION
The present invention relates to a novel dithioketal compound of formula I and process for its preparation.
BACKGROUND OF INVENTION
US 5124482 and US 5216174 disclose manufacture and use of 4- Fluoro-α-[2-methyl-l-oxopropyl]γ-oxo-N-β-diphenylbenzenebutane amide for preparation of [R-(R*,R*)]-2-(4-fluorophenyl)-B,D-dihydroxy -5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lh-pyrrole-l- heptanoic acid. [R-(R*,R*)]-2-(4-fluorophenyl)-B,D-dihydroxy -5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lh-pyrrole-l- heptanoic acid is inhibitor of HMG CoA reductase and thus is used as antihypercholesterolemic agent. Hitherto unknown compound of the formula I
Figure imgf000002_0001
Formula I
Is an extremely useful novel intermediates for preparation 4-Fluoro-α- [2-methyl-l-oxopropyl]γ-oxo-N-β-diphenylbenzenebutaneamide. SUMMARY OF THE INVENTION
The present invention relates to novel compound of formula I. The present invention also relates to a process for preparation of compound of formula I.
Figure imgf000003_0001
Formula I As mentioned earlier the compounds of formula I can be prepared by a novel process comprising, reaction of compound of formula II with compound of formula III.
Figure imgf000003_0002
Formula II
Figure imgf000004_0001
Formula III where Ri and R are any suitable alkyl group or Ri and R2 can join together to form any cyclic structure.
In the other embodiment of the invention, the compound of formula I can be used to synthesize 4-Fluoro-α-[2-methyl-l- oxopropyl]γ-oxo-N-β-diphenylbenzenebutaneamide.
DETAILED DESCRIPTION OF THE INVENTION
The compound of formula I is an important intermediate 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 hypolipidemic or hypocholesterolemic agents.
The compound of formula I of the present invention is new.
Figure imgf000004_0002
FORMULA I The process of the present invention is also new, economical, and commercially feasible method for preparing intermediate used for the preparation of HMG CoA reductase inhibitors. The process of the present invention is outlined in Scheme I.
The novel process comprises reaction of compound of formula II with compound of formula III.
Figure imgf000005_0001
Formula II
Figure imgf000005_0002
Formula III where Ri and R2 are any suitable alkyl group, preferably C2H5 or Ri and R2 can join together to form any cyclic structures, preferably - CH2 _CH -CH - ,
The reaction between compounds of formula II and III is carried 5 out in the presence of reagents selected from n-butyl lithium, NaH or LDA or any such suitable base.
The reaction can also be performed with above mentioned reagents in presence of Copper or Magnesium chloride or any suitable 10 Lewis acid to give compound of formula I in better yield.
The compound of formula I 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- i5 Phenyl-4-[(Phenyl amino) Carbonyl]-lh-Pyrrole-l-Heptanoic Acid .
The following non-limiting examples illustrate the inventors' preferred method for preparing the compounds of the invention.
EXAMPLES
Example 1 20 Preparation of l-[bis(ethylthio)methyl]-4- fluorobertzene: A solution of 4-fluorobenzaidehyde (25 g, 0.2 mol) in dry THF (250 ml) was stirred under nitrogen and ethanethiol (21.2 ml, 0.6 mol) and iodine (2.6 g, 0.01 « mol) were added. After stirring the reaction mixture for 45 minutes at room temperature, pH of the 25 mixture was adjusted to about 8.0 using 10% aqueous sodium hydroxide solution. The reaction mixture was extracted with ether (2 x 100 ml) and combined organic extract was washed with water (2 x 50 ml) brine (2 x 50 ml) and concentrated to obtain title compound. Yield: 20 g, 43.4%. Example 2
Preparation of 2-(4-fluorophenyl)-l,3-dithϊane: A solution of 4-fluorobenzaldehyde (20 g, 0.16 mol) in dry THF (200 ml) was stirred under nitrogen and 1,3-proanethiol (26 g, 0.24 mol) and iodine (2 g, 0.008 mol) were added. After stirring the reaction mixture for 2 h, at room temperature, pH of the mixture was adjusted to about 8.0 using 10% aqueous sodium hydroxide solution. The reaction mixture was extracted with ether (2 x 100 ml) and combined organic extract was washed with water (2 x 50 ml) brine (2 x 50 ml) and concentrated to obtain title compound. Yield: 28 g, 79%. Example 3
Preparation of 2-[2,2-bis-ethylsulphanyl-2-(4-fluoro- phenyl)-l-phenyl-ethyϊ]-4-methyl-3-oxo-pentanoic acid phenylamide: To a chilled solution of l-[bis(ethylthio)methyl]-4- fluorobenzene (5 g, 0.021 mol) in dry THF(50 ml), n-butyl lithium (18 ml, 0.021 mol) in hexane was added dropwise under nitrogen atmosphere, maintaining the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. A solution of 2- isobutyryl-/V,3-diphenylacrylamide (6.3 g, 0.021 mol) in THF (20 ml) was added to the reaction mixture dropwise, maintaining the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. After warming to room temperature, it was further stirred for one hour. The reaction mixture was quenched with water (50 ml) and 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.
5 Yield: 8.5 g, 77%. Example 4
Preparation of 2-[2,2-bis-ethylsulphanyl-2-(4~fIuoro- phenyI)-l-phenyl-ethyI]-4-methyI-3-oxo-pentanoic acid phenylamide: To a chilled mixture of l-[bis(ethylthio)methyl]-4- ιo fluorobenzene (5 g, 0.021 mol) and copper (II) chloride (0.15 g,
0.00011 mol) in dry THF(50 mL), n-butyl lithium (18 mL, 0.021 mol) in hexane was added dropwise under nitrogen atmosphere, maintaning the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. A solution of 2-isobutyryl-/V,3- i5 diphenylacrylamide (6.3 g, 0.021 mol) in THF (20 mL) was added to the reaction mixture dropwise, maintaning the temperature between - 20° C and -25° C and stirred for 30 minutes at the same temperature. After warming to room temperature, it was further stirred for one hour. The reaction mixture was quenched with water (50 mL) and
20 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: 9.5 g, 86%. Example 5
25 Preparation of 2-{[2-(4-fluoro-phenyl)-[l,3]dithian-2- yl]-phenyl-methyl>-4-methyl-3-oxo-pentanoic acid phenylamide: To a chilled solution of 2-(4-fluorophenyl)-l,3-dithiane (1 g, 0.005 mol) in dry THF (10 ml), n-butyl lithium (18 ml, 0.021 mol) in hexane was added dropwise under nitrogen atmosphere, maintaining the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. A solution of 2-isobutyryl- /V,3-diphenylacrylamide (1.6 g, 0.0055 mol) in THF (10 ml) was added to the reaction mixture dropwise, maintaining the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. After warming to room temperature, it was further stirred for one hour. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (2 x 25 ml). Combined organic extract was washed with water (2 x 25 ml) brine (2 x 25 ml) and concentrated to obtain title compound. Yield: 0.8 g, 54%. Example 6 Preparation of 2-{[2-(4-fluoro-phenyl)-[l,3]dϊthian-2- yl]-phenyl-methyl>-4-methyl-3-oxo-pentanoic acϊd phenylamide: To a chilled mixture of 2-(4-fluorophenyl)-l,3-dithiane (1 g, 0.005 mol) and magnesium chloride (250 mg, 0.00025 mol) in dry THF (10 mL), n-butyl lithium (18 mL, 0.021 mol) in hexane was added dropwise under nitrogen atmosphere, maintaning the temperature between -20° C and -25° C and stirred for 30 minutes at the same temperature. A solution of 2-isobutyryl-/V,3- diphenylacrylamide (1.6 g, 0.0055 mol) in THF (10 mL) was added to the reaction mixture dropwise, maintaning the temperature between - 20° C and -25° C and stirred for 30 minutes at the same temperature. After warming to room temperature, it was further stirred for one hour. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 25 mL). Combined organic extract was washed with water (2 x 25 mL) brine (2 x 25 mL) and concentrated to obtain title compound. Yield: 2.0 g, 71%. Example 7
Preparation of 2-[2-(4-fluoro-phenyl-2-oxo-l-phenyl- ethyl]-4-methyl~3-oxo-pentanoic acid phenylamide: To a stirred solution of red mercury(II) oxide (4.13 g, 0.0190 mol) and boron trifluoride etherate (2.4 ml, 0.019 mol) in 15% aqueous THF (50 ml) a solution of 2-[2,2-bis-ethylsulphanyl-2-(4-fluoro-phenyl)-l- phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide (5 g, 0.0095 mol) in THF (20 ml) was added dropwise and stirred for 30 minutes. After adding diethyl ether (100 ml), the reaction mixture was filtered. The organic layer was washed with 10% sodium carbonate solution, brine and concentrated. Precipitated product was filtered. Yield: 2 g, 49%. Example 8
Preparation of 2-[2-(4-fluoro-phenyl-2-oxo-l-phenyl- ethyl]-4-methyϊ-3-oxo-pentanoic acid phenylamide: A solution of 2-{[2-(4-fluoro-phenyl)-[l,3]dithian-2-yl]-phenyl-methyl}-4-methyl- 3-oxo-pentanoic acid phenylamide (5g, 0.0098 mol), copper(II) chloride (2.65 g, 0.02 mol) and copper(II) oxide (3.1 g, 0.04 mol) in 995 aqueous acetone (50 ml) was refluxed for 1 h. The reaction mixture was filtered and concentrated. The residue was redissolved in diethyl ether (50 ml) and filtered again. The filtrate was concentrated and precipitated product was filtered. Yield: 2.2 g, 54%. Scheme I:
Figure imgf000011_0001

Claims

CLAIMSWe claim:
1. A Compound of formula I
Figure imgf000012_0001
where Ri and R2 are any suitable alkyl group, preferably C2H5 or Ri and R2 can join together to form any cyclic structures, preferably -CH2-Ch2-CH2- .
2. A process for the preparation of compounds of formula I comprising reacting a compound of formula II with a compound of formula III to get compounds of formula
Figure imgf000012_0002
Formula II
Figure imgf000013_0001
Formula III
where Ri and R2 are any suitable alkyl group, preferably C2H5 or Ri and R2 can join together to form any cyclic structures, preferably - CH2-Ch2-CH2- .
3. A process in claim 2, wherein the reaction between compounds of formula II and III is carried out in the presence of a base.
4. A process in claim 2, wherein the reaction between compounds of formula II and III is carried out in the presence of a base and a suitable Lewis acid.
5. A process in claim 3, wherein the base is selected one or more among n-butyi lithium, NaH or LDA.
6. A process in claim 4, wherein the Lewis acid is selected from salts of copper or magnesium.
7. A compound of formula I as in claim 1, wherein the compound is used for production of 4-Fluoro-α-[2-methyl-l-oxopropyl]γ-oxo- N-β-diphenylbenzenebutaneamide.
PCT/IN2003/000194 2003-05-22 2003-05-22 Novel dithioketal WO2004103957A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008057859A3 (en) * 2006-11-01 2008-12-31 Bristol Myers Squibb Co Modulators of glucocorticoid receptor, ap-i and/or nf-kappab activity and use thereof
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 (2)

* 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
WO2003004457A2 (en) * 2001-07-04 2003-01-16 Ciba Specialty Chemicals Holding Inc. Preparation process for atorvastatin and intermediates

Patent Citations (2)

* 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
WO2003004457A2 (en) * 2001-07-04 2003-01-16 Ciba Specialty Chemicals Holding Inc. Preparation process for atorvastatin and intermediates

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008057859A3 (en) * 2006-11-01 2008-12-31 Bristol Myers Squibb Co Modulators of glucocorticoid receptor, ap-i and/or nf-kappab activity and use thereof
US8222247B2 (en) 2006-11-01 2012-07-17 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-kappabeta activity and use thereof
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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