EP1670759A1 - PROCESS FOR THE PREPARATION OF (1a, 5a, 6a)-6-AMINOME THYL-3-BENZYL-3-AZABICYCLO 3.1.0 HEXANE - Google Patents
PROCESS FOR THE PREPARATION OF (1a, 5a, 6a)-6-AMINOME THYL-3-BENZYL-3-AZABICYCLO 3.1.0 HEXANEInfo
- Publication number
- EP1670759A1 EP1670759A1 EP04769348A EP04769348A EP1670759A1 EP 1670759 A1 EP1670759 A1 EP 1670759A1 EP 04769348 A EP04769348 A EP 04769348A EP 04769348 A EP04769348 A EP 04769348A EP 1670759 A1 EP1670759 A1 EP 1670759A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- azabicyclo
- benzyl
- 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- Withdrawn
Links
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
- C07D209/52—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 indiistrially 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, which are useful as antimicrobials, and fox the synthesis of various azabicyclo [3.1.0]hexane derivatives, which are useful as muscarinic receptor antagonists.
- azabicyclo quinolone derivatives are disclosed 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 reportedly are useful in the treatment of bacterial infections of broad spectrum, particularly against sensitive and resistant strains of gram positive pathogens, such as methicillin resistant staphylococcus aureus (MRS A), methicillin resistant staphylococcus epidermidis (MRSE), quinolone resistant staphylococcus aureus (QRSA) and Vancomycin resistant enterococci (VRSE).
- MRS A methicillin resistant staphylococcus aureus
- MRSE methicillin resistant staphylococcus epidermidis
- QRSA quinolone resistant staphylococcus aureus
- VRSE Vancomycin resistant enterococci
- 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 [l ⁇ ,5 ⁇ ,6 ⁇ ]-3-benzyl-6-hydroxymethyl-3- azabicyclo[3.1.0]hexane of Formula II
- Such limitations include the following: (i) the process requires the use of oxalyl chloride, which is corrosive, toxic, moisture sensitive and hence difficult to handle on commercial scale; (ii) very low temperature conditions are employed (i.e., 65°C), which are very difficult to maintain at commercial scale, requiring special equipment to maintain such temperature conditions; (iii) the process requires the use of lithium aluminum hydride, which is corrosive, air sensitive, highly flammable and hygroscopic, and thus, poses a handling problem; (iv) lithium aluminum hydride is an expensive reagent that increases the overall cost of preparation of final product; and
- the reaction of the compound of Formula II with methane sulphonyl chloride can be carried out in an organic solvent, which can be selected from, for example, dichloromethane, dichloroethane, chloroform, ethyl acetate, and a mixture thereof.
- the reaction of the compound of Formula II with methane sulphonyl chloride can be carried out in the presence of an organic base, which can be selected from, for example, triethylamine, pyridine and a mixture thereof. In some embodiments, the organic base is triethylamine.
- the reaction of the compound of Formula II with methane sulphonyl chloride can be carried out in the presence of a catalyst, wherein the catalyst is 4-dimethylamino pyridine.
- the reaction of the compound of Formula II with methane sulphonyl chloride is carried out at a temperature of from about 0 °C to about 30 °C.
- reaction of the compound of Formula V with sodium azide to give the compound of Formula VI is carried out in an organic solvent, for example, dimethylformamide, dimethylsulphoxide, and a mixture thereof.
- reaction of the compound of Formula V with sodium azide is carried out at a temperature from about 50 °C to about 100 °C.
- the reduction of the compound of Formula VI to give the compound of Formula I is carried out in an organic solvent, for example, tetrahydrofuran, 1,4-dioxolane, and a mixture thereof.
- the reduction of the compound of Formula VI is carried out with a reducing agent, wherein the reducing agent is triphenyl phosphine.
- the reaction in step i) can be carried out in an organic solvent and in the presence of a catalyst and an organic base at a temperature from about 0 °C to about 30 °C.
- the catalyst can be N,N-dimethyl amino pyridine.
- the organic base can be triethylamine, pyridine or a mixture thereof.
- the organic solvent can be dichloromethane, dichloroethane, chloroform, ethyl acetate, or a mixture thereof.
- the reaction in step ii) can be carried out in an organic solvent at a temperature ranging from about 90 to about 110°C.
- the organic solvent can be dimethylformamide, dimethylsulphoxide, or a mixture thereof.
- the reaction in step iii) can be carried out using a reducing agent in an organic solvent.
- the reducing agent can be triphenyl phosphine.
- the organic solvent can be tetrahydrofuran, dimethylsulphoxide, 1,4-dioxolane, or a mixture thereof.
- reaction mixture was diluted with dichloromethane and washed with saturated aqueous solution of sodium bicarbonate.
- the organic layer was separated, washed with a water and brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound with a yield of 74%.
Abstract
The present invention relates to a n 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
Field of the Invention
The present invention relates to a new and indiistrially 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, which are useful as antimicrobials, and fox the synthesis of various azabicyclo [3.1.0]hexane derivatives, which are useful as muscarinic receptor antagonists.
Background of the Invention
Various azabicyclo quinolone derivatives are disclosed 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 reportedly are useful in the treatment of bacterial infections of broad spectrum, particularly against sensitive and resistant strains of gram positive pathogens, such as methicillin resistant staphylococcus aureus (MRS A), 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. A method for the synthesis of the compound of Formula I was disclosed 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-benzyl-6-hydroxymethyl-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
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; and
H-^^NOH
Formula IV
(3) reacting a compound of Formula IV 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. Previous methods for the manufacture of compound of (lα,5α,6α)-6- aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane Formula I, including the aforementioned method, suffers from various limitations and are not suitable for the commercial production. Such limitations include the following: (i) the process requires the use of oxalyl chloride, which is corrosive, toxic, moisture sensitive and hence difficult to handle on commercial scale; (ii) very low temperature conditions are employed (i.e., 65°C), which are very difficult to maintain at commercial scale, requiring special equipment to maintain such temperature conditions; (iii) the process requires the use of lithium aluminum hydride, which is corrosive, air sensitive, highly flammable and hygroscopic, and thus, poses a handling problem; (iv) lithium aluminum hydride is an expensive reagent that increases the overall cost of preparation of final product; and
(v) the purification of the compound of Formula III in the first step of the above method involves column chromatography, which is cumbersome, tedious and impractical on an industrial scale.
Accordingly, there remains a need for a simple, commercially viable, and efficient process for the preparation of [lα,5α,6α]-6-aminomethyl-3-benzyl-3- azabicyclo[3.1.0]hexane of Formula I.
Summary of the Invention
Herein is provided a process for the preparation of (lα,5α,6α)-6-aminomethyl-3- benzyl-3-azabicyclo[3.1.0]hexane of Formula I
Formula
comprising the steps of: i. reacting (lα,5α,6α)-6-hydroxymethyl-3-benzyl-3-azabicyclo [3.1.0]hexane of Formula II
Formula II
with methane sulphonyl chloride in an organic solvent, and in the presence of an organic base and a catalyst to give (lα,5α,6α)-6-(methylsulphonyloxy) methyl-3-benzyl-3- azabicyclo[3.1.0]hexane of Formula V;
Formula V ii. reacting (lα,5α,6α)-6-(methylsulphonyloxy) methyl-3-benzyl-3- azabicyclo[3.1.0]hexane of Formula V with sodium azide in a suitable organic solvent to give (lα,5α,6α)-6-azidomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula VI;
-N,
Formula VI
and iii. reducing (lα,5α,6α)-6-azidomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula VI in an organic solvent with a reducing agent to give the compound of Formula I. In one embodiment, the reaction of the compound of Formula II with methane sulphonyl chloride can be carried out in an organic solvent, which can be selected from, for example, dichloromethane, dichloroethane, chloroform, ethyl acetate, and a mixture thereof. In another embodiment, the reaction of the compound of Formula II with methane sulphonyl chloride can be carried out in the presence of an organic base, which can be selected from, for example, triethylamine, pyridine and a mixture thereof. In some embodiments, the organic base is triethylamine.
In yet another embodiment, the reaction of the compound of Formula II with methane sulphonyl chloride can be carried out in the presence of a catalyst, wherein the catalyst is 4-dimethylamino pyridine. In another embodiment, the reaction of the compound of Formula II with methane sulphonyl chloride is carried out at a temperature of from about 0 °C to about 30 °C.
In one embodiment, the reaction of the compound of Formula V with sodium azide to give the compound of Formula VI is carried out in an organic solvent, for example, dimethylformamide, dimethylsulphoxide, and a mixture thereof. In another embodiment, the reaction of the compound of Formula V with sodium azide is carried out at a temperature from about 50 °C to about 100 °C.
In one embodiment, the reduction of the compound of Formula VI to give the compound of Formula I is carried out in an organic solvent, for example, tetrahydrofuran, 1,4-dioxolane, and a mixture thereof. In another embodiment, the reduction of the compound of Formula VI is carried out with a reducing agent, wherein the reducing agent is triphenyl phosphine.
Detailed Description of the Invention
Herein is provided a process for the preparation of a compound [lα,5α,6α]-6- aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula I
Formula I
comprising the steps of: i) reacting (1 α,5α,6α)-6-hydroxymethyl-3-benzyl-3-azabicyclo [3.1.OJhexane of Formula II
-OH
II
with methane sulphonyl chloride to yield (lα,5α,6α)-6-(methylsulphonyloxy)methyl-3- benzyl-3-azabicyclo [3.1.0] hexane of Formula V;
Formula V ii) reacting the compound of Formula V with sodium azide to give
(lα,5α,6α)-6-(azidomethyl-3-benzyl-3-oxabicyclo[3.1.0]hexane of Formula VI;
-N,
Formula VI
and
iii) reducing the compound of Formula VI to give (lα,5α,6α)-6-aminomethyl- 3-benzyl-3-azabicyclo[3.1.0]hexane of Formula I.
The reaction in step i) can be carried out in an organic solvent and in the presence of a catalyst and an organic base at a temperature from about 0 °C to about 30 °C. The catalyst can be N,N-dimethyl amino pyridine. The organic base can be triethylamine, pyridine or a mixture thereof. The organic solvent can be dichloromethane, dichloroethane, chloroform, ethyl acetate, or a mixture thereof.
The reaction in step ii) can be carried out in an organic solvent at a temperature ranging from about 90 to about 110°C. The organic solvent can be dimethylformamide, dimethylsulphoxide, or a mixture thereof.
The reaction in step iii) can be carried out using a reducing agent in an organic solvent. The reducing agent can be triphenyl phosphine. The organic solvent can be tetrahydrofuran, dimethylsulphoxide, 1,4-dioxolane, or a mixture thereof.
In the following section particular embodiments are described by way of examples to illustrate some aspects of the invention. However, these do not limit the scope of the present invention.
Examples
Example 1 Preparation of (lα,5α,6α)-6-aminomethyl-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)
4-dimethylamino pyridine (0.3 g, 2.5 millimoles) in dichloromethane was added to a solution of (lα,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexane (25 g, 123.2 millimoles) and triethylamine (35 ml, 246.4 millimoles) in dichloromethane. Methane sulphonyl chloride (14.5 ml, 185 millimoles) then was added dropwise at 0-5 °C. The reaction mixture was stirred at 0-5 °C followed by warming to 25-30°C with constant stirring for approximately 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 a 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-azidomethyl-3-benzyl-3- azabicyclo[3.1.Ojhexane (Formula VI)
(lα,5α,6α)-6-aminomethyl-3-benzyl-3-azabicyclQ[3.1.0]hexane obtained from step a) above (25.7 g, 91.4 millimoles) was dissolved in dimethylformamide (approximately 130 mL) and sodium azide (17.8 g, 274.3 millimoles) was added to the solution. The reaction mixture was stirred for approximately 12 hours at 100-110°C followed by another addition of sodium azide (10 g). The resulting reaction mixture was stirred for four hours. The reaction mixture was cooled to room temperature and poured onto ice cold water with constant stirring. The organic compound was extracted with ethylacetate (300 mL) and the organic layer was washed with a water and brine solution, dried and concentrated under vacuum to give the title compound with a yield of 95%. Ste c): Preparation of (lα,5α,6α)-6-aminomethyl-3-benzyl-3- azabicyclo[3.1.0]hexane (Formula I)
(lα,5α,6α)-6-azidomethyl-3-benzyl-3-azabicyclo[3.1. Ojhexane (Formula VI) obtained from step b) above (20.8 g, 91.2 millimoles) was dissolved in tetrahydrofuran (740 mL) and water (140 mL) and triphenyl phosphine (36 g, 136.8 millimoles) was added to the solution. The reaction mixture was refluxed for 6 hours with constant stirring. Tetrahydrofuran was evaporated and the residue thus obtained was diluted with water. The pH of the solution was adjusted to 1-2 with IN hydrochloric acid and washed with dichloromethane. The pH of the aqueous layer was adjusted to 13-14 with IN sodium hydroxide. The organic compound was extracted with dichloromethane, washed with a brine solution, dried and concentrated under reduced pressure to give the title compound with a yield of 98%.
Claims
We Claim:
1. A process for the preparation of (lα,5α,6α)-6-aminomethyl-3-benzyl-3- azabicyclo[3.1. Ojhexane of Formula I
Formula
comprising the steps of: i. reacting (lα,5α,6α)-6-hydroxymethyl-3-benzyl-3-azabicyclo [3.1. Ojhexane of Formula II
Formula II with methane sulphonyl chloride in an organic solvent, and in the presence of an organic base and a catalyst to give (lα,5α,6α)-6- (methylsulphonyloxy) methyl-3-benzyl-3-azabicyclo[3.1. Ojhexane of Formula V;
Formula V
ii. reacting (lα,5α,6α)-6-(methylsulphonyloxy) methyl-3-benzyl-3- azabicyclo[3.1. Ojhexane of Formula V with sodium azide in a suitable organic solvent to give (lα,5α,6α)-6-azidomethyl-3-benzyl-3- azabicyclo [3.1. Ojhexane of Formula VI;
-N,
Formula VI
and
iii. reducing (lα,5α,6α)-6-azidomethyl-3-benzyl-3-azabicyclo[3.1. Ojhexane of Formula VI in an organic solvent with a reducing agent to give the compound of Formula I.
The process of claim 1, wherein the reaction of the compound of Formula II with methane sulphonyl chloride is carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, ethyl acetate, and a mixture thereof.
3. The process of claim 1 , wherein the reaction of the compound of Formula II with methane sulphonyl chloride is carried out in the presence of an organic base selected from the group consisting of triethylamine, pyridine and a mixture thereof.
4. The process of claim 3, wherein the organic base is triethylamine.
5. The process of claim 1, wherein the reaction of the compound of Formula II with methane sulphonyl chloride is carried out in the presence of a catalyst, wherein the catalyst is 4-dimethylamino pyridine.
6. The process of claim 1, wherein the reaction of the compound of Formula II with methane sulphonyl chloride is carried out at a temperature of from about 0°C to about 30°C.
7. The process of claim 1, wherein the reaction of the compound of Formula V with sodium azide to give the compound of Formula VI is carried out in an organic solvent selected from group consisting of dimethylfonnamide, dimethylsulphoxide, and a mixture thereof.
8. The process of claim 1 , wherein the reaction of the compound of Formula V with sodium azide is carried out at a temperature from about 50 °C to about 100 °C.
9. The process of claim 1 , wherein the reduction of the compound of Formula VI to give the compound of Formula I is carried out in an organic solvent selected from a group consisting of tetrahydrofuran, 1,4-dioxolane, and a mixture thereof.
10. The process of claim 1 , wherein the reduction of the compound of Formula VI is carried out with a reducing agent, wherein the reducing agent is triphenyl phosphine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1168DE2003 | 2003-09-18 | ||
| PCT/IB2004/002956 WO2005026121A1 (en) | 2003-09-18 | 2004-09-13 | PROCESS FOR THE PREPARATION OF (1α, 5α, 6α)-6-AMINOMETHYL-3-BENZYL-3-AZABICYCLO[3.1.0]HEXANE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1670759A1 true EP1670759A1 (en) | 2006-06-21 |
Family
ID=34308046
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP04769348A Withdrawn EP1670759A1 (en) | 2003-09-18 | 2004-09-13 | PROCESS FOR THE PREPARATION OF (1a, 5a, 6a)-6-AMINOME THYL-3-BENZYL-3-AZABICYCLO 3.1.0 HEXANE |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP1670759A1 (en) |
| WO (1) | WO2005026121A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1934184A1 (en) | 2005-10-05 | 2008-06-25 | Ranbaxy Laboratories, Ltd. | 3 -azabicyclooctane derivatives as muscarinic receptor antagonists |
| US20090137623A1 (en) | 2005-12-30 | 2009-05-28 | Naresh Kumar | Muscarinic receptor antagonists |
| BR112013007566A2 (en) | 2010-09-28 | 2016-08-02 | Panacea Biotec Ltd | new bicyclic compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2049777C1 (en) * | 1989-08-16 | 1995-12-10 | Пфайзер Инк. | Azabicyclo-quinolone caroboxylic acids or their pharmaceutically acceptable acid-additive salts and intermediate products for their synthesis |
-
2004
- 2004-09-13 WO PCT/IB2004/002956 patent/WO2005026121A1/en not_active Application Discontinuation
- 2004-09-13 EP EP04769348A patent/EP1670759A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2005026121A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005026121A1 (en) | 2005-03-24 |
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