EP1675828A1 - PROCESS FOR THE PREPARATION OF (1alpha, 5alpha, 6alpha)-6-AMINOME THYL-3-BENZYL-3-AZBICYCLO [3.1.0] HEXANE - Google Patents

PROCESS FOR THE PREPARATION OF (1alpha, 5alpha, 6alpha)-6-AMINOME THYL-3-BENZYL-3-AZBICYCLO [3.1.0] HEXANE

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Publication number
EP1675828A1
EP1675828A1 EP04769411A EP04769411A EP1675828A1 EP 1675828 A1 EP1675828 A1 EP 1675828A1 EP 04769411 A EP04769411 A EP 04769411A EP 04769411 A EP04769411 A EP 04769411A EP 1675828 A1 EP1675828 A1 EP 1675828A1
Authority
EP
European Patent Office
Prior art keywords
formula
reaction
compound
hexane
carried out
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP04769411A
Other languages
German (de)
French (fr)
Inventor
Mohammad Salman
Pakala Kumara Savithru Sarma
Sankaranarayanan Dharmarajan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of EP1675828A1 publication Critical patent/EP1675828A1/en
Withdrawn legal-status Critical Current

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    • 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
    • C07D209/52—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 condensed with a ring other than six-membered

Definitions

  • the present invention relates to a new and industrially advantageous process for the preparation of (l ⁇ , 5 ⁇ , 6 ⁇ )-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula I,
  • This compound is a key intermediate for the synthesis of azabicyclo quinolone derivatives as antimicrobials and for the synthesis of various azabicyclo[3.1.0]hexane derivatives as muscarinic receptor antagonists.
  • azabicyclo quinolone derivatives are known in U.S. Patent Nos. 5,164,402; 5,391,763; 5,229,396; 5,266,569 and European Patent Application No. 0413455 A2.
  • the azabicyclo quinolone derivatives are useful in the broad spectrum treatment of bacterial infections. They are particularly active against sensitive and resistant strains of gram-positive pathogens like methicillin resistant staphylococcus aureus (MRSA), methicillin resistant staphylococcus epidermidis (MRSE), quinolone resistant staphylococcus aureus (QRSA) and Vancomycin resistant enterococci (VRSE).
  • MRSA methicillin resistant staphylococcus aureus
  • MRSE methicillin resistant staphylococcus epidermidis
  • QRSA quinolone resistant staphylococcus aureus
  • VRSE Vancomycin resistant enterococci
  • WO 2004/052857 and WO 04/004629 disclose 3, 6-disubstituted azabicyclo [3.1.0] hexane derivatives useful as muscarinic receptor antagonists.
  • WO 04/005252 discloses azabicyclo derivatives as musacrinic receptor antagonists.
  • WO 04/014853, WO 04/067510 and WO 04/014363 disclose derivatives of 3, 6-disubstituted azabicyclohexane useful as muscarinic receptor antagonists.
  • WO 2004/056810 discloses xan bine derivatives as muscarinic receptor antagonists.
  • WO 2004/056811 discloses flaxavate derivatives as muscarinic receptor antagonists.
  • WO 2004/056767 discloses 1-substituted- 3-pyrrolidine derivatives as muscarinic receptor antagonists.
  • WO 2004/018422 disclose fluoro and sulphonylamino containing 3, 6-disubstituted azabicyclo[3.1.0] hexane derivatives as muscarinic receptor antagonists.
  • the processes require the use of oxalyl chloride, which is a corrosive, toxic, moisture-sensitive reagent and hence difficult to handle on commercial scale.
  • the processes require the use of lithium aluminum hydride, which is a very corrosive, air sensitive, hygroscopic and flammable reagent, which thus pose a handling problem.
  • the reaction conditions involve the use of tetrahydrofuran, which is unsafe and can involve the risk of explosion and fire due to peroxide formation. Tetrahydrofuran and lithium aluminum hydride are expensive reagents and add significant factor in the overall cost of preparation of final product. Removal of dimethylsulhoxide is difficult as it is high temperature evaporating solvent.
  • Formula V in the presence of a catalyst and an organic base in an organic solvent at a temperature ranging from 0-5°C.
  • the reaction can be carried out in the presence of a hypernucleophilic catalyst, such as, for example, N,N-dimethyl amino pyridine.
  • Trie organic base can be selected from for example triethylamine and pyridine.
  • the organic solvent can be selected from for example, dichloromethane, dichloroethane, chloroform and ethyl acetate.
  • the compound of Formula V is further reacted with aqueous ammonia solution to give a compound of Formula I in an organic solvent at a temperature ranging from 75-80°C.
  • the organic solvent can be selected from for example metlranol, ethanol, n-propanol and isopropyl alcohol in acetonitrile.
  • liquid ammonia solution can also be used in place of aqueous ammonia solution.
  • reaction mixture was diluted with dichloromethane and washed with saturated aqueous solution of sodium bicarbonate.
  • the organic layer was separated, washed with water and brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound with a yield of 74%.
  • Step b Preparation of (l ⁇ ,5 ⁇ ,6 ⁇ )-6-aminomethyl-3-azabicyclo[3.1.0]hexane (Formula I) To a solution of a compound obtained from step a above (1 g) in methanol was added aqueous ammonia solution (25% w ⁇ v, 10 ml). The reaction mixture was placed in autoclave and sealed tightly and heated at 75-80°C for approx. 12 hours followed by cooling it to room temperature. The solvent was removed under vacuum and the residue was diluted with water. The pH of the solution was adjusted to 1-2 with 2N hydrochloric acid followed by washing with toluene. The pH of the aqueous layer was adjusted to 13- 14 with 2N sodium hydroxide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to a new and industrially advantageous process for the preparation of (1α , 5α , 6α )-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane, a key intermediate for the synthesis of azabicyclo quinolone derivatives as antimicrobials and for the synthesis of various azabicyclo[3.1.0]hexane derivatives.

Description

PROCESS FOR THE PREPARATION OF (lα, 5α, 6α)-6-AMINOMETHYL-3- BENZYL-3-AZABICYCLO[3.1.0]HEXANE
Technical Field of the Invention
The present invention relates to a new and industrially advantageous process for the preparation of (lα, 5α, 6α)-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula I,
This compound is a key intermediate for the synthesis of azabicyclo quinolone derivatives as antimicrobials and for the synthesis of various azabicyclo[3.1.0]hexane derivatives as muscarinic receptor antagonists. Background of the Invention
Various azabicyclo quinolone derivatives are known in U.S. Patent Nos. 5,164,402; 5,391,763; 5,229,396; 5,266,569 and European Patent Application No. 0413455 A2. The azabicyclo quinolone derivatives are useful in the broad spectrum treatment of bacterial infections. They are particularly active against sensitive and resistant strains of gram-positive pathogens like methicillin resistant staphylococcus aureus (MRSA), methicillin resistant staphylococcus epidermidis (MRSE), quinolone resistant staphylococcus aureus (QRSA) and Vancomycin resistant enterococci (VRSE). These compounds can be administered by either oral or parental routes.
WO 2004/052857 and WO 04/004629 disclose 3, 6-disubstituted azabicyclo [3.1.0] hexane derivatives useful as muscarinic receptor antagonists. WO 04/005252 discloses azabicyclo derivatives as musacrinic receptor antagonists. WO 04/014853, WO 04/067510 and WO 04/014363 disclose derivatives of 3, 6-disubstituted azabicyclohexane useful as muscarinic receptor antagonists. WO 2004/056810 discloses xan bine derivatives as muscarinic receptor antagonists. WO 2004/056811 discloses flaxavate derivatives as muscarinic receptor antagonists. WO 2004/056767 discloses 1-substituted- 3-pyrrolidine derivatives as muscarinic receptor antagonists. WO 2004/018422 disclose fluoro and sulphonylamino containing 3, 6-disubstituted azabicyclo[3.1.0] hexane derivatives as muscarinic receptor antagonists.
Methods for the synthesis of intermediate of Formula I were reported in U.S. Patent Nos. 5,164,402; 5,391,763; 5,229,396; 5,266,569 and European Patent Application No. 0413455 A2 which comprises (1) oxidizing [lα,5α,6α]-3-beιιzyl-6-hydroxymettryl-3- azabicyclo [3.1.0]hexane of Formula II
Formula II with a mixture of oxalyl chloride and dimethylsulphoxide in dichloromethane at -65° C to give [lα,5α,6α]-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxaldehyde of Formula III
Formula III followed by its purification by column chromatography, (2) reacting a compound of Formula III with hydroxylamine hydrochloride and sodium acetate in ethanol, for 18 hours to give [lα,5α,6α]-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxaldehyde oxime of Formula IV,
Formula IV (3) reacting a compound of Formula TV with lithium aluminum hydride in tetrahydrofuran followed by, refluxing for 12 hours to give (lα,5α,6α)-6-aminomethyl-3-benzyl-3- azabicyclo[3.1.0]hexane of Formula I.
The above-mentioned prior art methods for the manufacture of desired compound of Formula I suffer from the following limitations and for various reasons stated below are not suitable for commercial production.
The processes require the use of oxalyl chloride, which is a corrosive, toxic, moisture-sensitive reagent and hence difficult to handle on commercial scale. The processes require the use of lithium aluminum hydride, which is a very corrosive, air sensitive, hygroscopic and flammable reagent, which thus pose a handling problem. The reaction conditions involve the use of tetrahydrofuran, which is unsafe and can involve the risk of explosion and fire due to peroxide formation. Tetrahydrofuran and lithium aluminum hydride are expensive reagents and add significant factor in the overall cost of preparation of final product. Removal of dimethylsulhoxide is difficult as it is high temperature evaporating solvent. Very low temperature conditions need to be employed (e.g., -65°C), which are very difficult to maintain at commercial scale, as it require special equipment is required to maintain these conditions. The purification of an intermediate compound in the first step involves column chromatography, which is cumbersome, tedious and not practical on an industrial scale. Detailed Description of the Invention
Herein is provided a simple, commercially viable, and efficient process for the preparation of (lα,5α,6α)-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.O]hexane of Formula I.
It is advantageous to avoid the use of hazardous, expensive, toxic and commercially difficult- to-handle raw materials.
More particularly is provided a process for the preparation of [1 α,5α,6α]-6- aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula I, comprising reacting (lα,5α,6α)-6-hydroxymethyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula II (prepared by following the process described in EP 0413455) with methane sulphonyl chloride to give (lα,5α,6α)-6-(methylsulphonyloxy) methyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula V,
Formula V in the presence of a catalyst and an organic base in an organic solvent at a temperature ranging from 0-5°C. The reaction can be carried out in the presence of a hypernucleophilic catalyst, such as, for example, N,N-dimethyl amino pyridine. Trie organic base can be selected from for example triethylamine and pyridine. The organic solvent can be selected from for example, dichloromethane, dichloroethane, chloroform and ethyl acetate. The compound of Formula V is further reacted with aqueous ammonia solution to give a compound of Formula I in an organic solvent at a temperature ranging from 75-80°C. The organic solvent can be selected from for example metlranol, ethanol, n-propanol and isopropyl alcohol in acetonitrile.
Alternatively, liquid ammonia solution can also be used in place of aqueous ammonia solution.
In the following section several preferred embodiments are described by way of examples to illustrate the progress of the invention. However, these do not limit the scope of the present invention.
Example 1: Preparation of (lα,5α,6αV6-ammomethyl-3-benzyl-3- azabicyclo 3.1.0]hexane (Formula I)
Step a: Preparation of (lα,5α,6α)-6-(methylsulphonyloxy)methyl-3-benzyl-3- azabicyclo [3.1.0]hexane (Formula V)
To a solution of (lα,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexane (25 g, 123.2 miUimoles), triethylamine (35 ml, 246.4 miUimoles) in dichloromethane, was added 4-dimethylamino pyridine (0.3 g, 2.5 miUimoles) in dicliloromethane followed by the addition of methane sulphonyl chloride (14.5 ml, 185 miUimoles) dropwise at 0-30°C. The reaction mixture was stirred at same temperature followed by warming to 25-30°C with constant stirring for approx. 15 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water and brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound with a yield of 74%.
Step b: Preparation of (lα,5α,6α)-6-aminomethyl-3-azabicyclo[3.1.0]hexane (Formula I) To a solution of a compound obtained from step a above (1 g) in methanol was added aqueous ammonia solution (25% w\v, 10 ml). The reaction mixture was placed in autoclave and sealed tightly and heated at 75-80°C for approx. 12 hours followed by cooling it to room temperature. The solvent was removed under vacuum and the residue was diluted with water. The pH of the solution was adjusted to 1-2 with 2N hydrochloric acid followed by washing with toluene. The pH of the aqueous layer was adjusted to 13- 14 with 2N sodium hydroxide. The organic compound was extracted with ether. The combined ether layer was washed with water and brine solution, dried and concentrated under reduced pressure to yield the title compound with a yield of 95%. 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 are included within the scope of the present invention.

Claims

We Claim: 1. A process for the preparation of (lα,5α,6α)-6-aminomethyl-3-benzyl-3- azabicyclo[3.1.0]hexane of Formula I,
as shown in the accompanied drawings, comprising reacting (lα,5α,6α)-6- hydroxymethyl-3-benzyl-3-azabicyclo[3.1.0] hexane of Formula II,
with methane sulphonyl chloride in an organic solvent in the presence of organic base and
Formula II a catalyst to give (lα,5α,6α)-6-(methylsulphonyloxy)methyl-3-benzyl-3-azabicyclo [3.1.0] hexane of Formula V,
Formula V which on reaction with aqueous ammonia solution in an organic solvent yields the compound of Formula I.
2. The process of claim 1 wherein the reaction of a compound of Formula II
Formula II with methane sulphonyl chloride to give a compound of Formula V
Formula V is carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform and ethyl acetate.
3. The process of claim 2 wherein the reaction is carried out in dichloromethane.
4. The process of claim 1 wherein the reaction of a compound of Formula II
Formula II with methane sulphonyl chloride is carried out in the presence of an organic base selected from a group consisting of triethylamine and pyridine.
5. The process of claim 4 wherein the reaction is carried out in triethylamine.
6. The process of claim 1 wherein the reaction of a compound of Formula II
Formula II with methane sulphonyl chloride is carried out in the presence of a catalyst.
7. The process of claim 6 wherein the reaction is carried out in 4-dimethyl amino pyridine.
8. The process of claim 1 wherein the reaction of a compound of Formula II
Formula II with methane sulphonyl chloride is carried out at a temperature ranging from about 0 to • about 30°C.
9. The process of claim 1 wherein the reaction of a compound of Formula V
Formula V with aqueous ammonia solution to give a compound of Formula I,
is carried out in a organic solvent selected from the group consisting of methanol, ethanol, propanol and isopropyl alcohol in acetonitrile.
10. The process of claim 9, wherein the reaction is carried out in methanol.
11. The process of claim 1 wherein the reaction of a compound of Formula V
Formula V with aqueous ammonia solution is carried out at a temperature ranging from about 75 to about 80°C.
EP04769411A 2003-09-18 2004-09-17 PROCESS FOR THE PREPARATION OF (1alpha, 5alpha, 6alpha)-6-AMINOME THYL-3-BENZYL-3-AZBICYCLO [3.1.0] HEXANE Withdrawn EP1675828A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1169DE2003 2003-09-18
PCT/IB2004/003037 WO2005026122A1 (en) 2003-09-18 2004-09-17 PROCESS FOR THE PREPARATION OF (1α, 5α, 6α)-6-AMINOMETHYL-3-BENZYL-3-AZBICYCLO[3.1.0]HEXANE

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EP1675828A1 true EP1675828A1 (en) 2006-07-05

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Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007039884A1 (en) 2005-10-05 2007-04-12 Ranbaxy Laboratories Limited 3 -azabicyclooctane derivatives as muscarinic receptor antagonists
EP1968980A1 (en) 2005-12-30 2008-09-17 Ranbaxy Laboratories, Ltd. Muscarinic receptor antagonists
WO2009068876A1 (en) * 2007-11-30 2009-06-04 Summit Corporation Plc Compositions for the treatment of skin disorders

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Publication number Priority date Publication date Assignee Title
US5164402A (en) * 1989-08-16 1992-11-17 Pfizer Inc Azabicyclo quinolone and naphthyridinone carboxylic acids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005026122A1 *

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