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] HEXANEInfo
- 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- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 title description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- QRDSDKAGXMWBID-UHFFFAOYSA-N 5-azabicyclo[3.1.0]hexane Chemical class C1CCN2CC21 QRDSDKAGXMWBID-UHFFFAOYSA-N 0.000 abstract description 4
- 150000007660 quinolones Chemical class 0.000 abstract description 4
- 239000004599 antimicrobial Substances 0.000 abstract description 2
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- -1 sulphonylamino Chemical group 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- OLSSGGJWAJDZTE-UHFFFAOYSA-N 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane Chemical compound C1C2(C)CC2CN1CC1=CC=CC=C1 OLSSGGJWAJDZTE-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 235000008694 Humulus lupulus Nutrition 0.000 description 1
- 244000025221 Humulus lupulus Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 244000000059 gram-positive pathogen Species 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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 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.
Landscapes
- 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.
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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1675828A1 true EP1675828A1 (en) | 2006-07-05 |
Family
ID=34308047
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP04769411A Withdrawn EP1675828A1 (en) | 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 |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP1675828A1 (en) |
| WO (1) | WO2005026122A1 (en) |
Families Citing this family (3)
| 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 |
| WO2007110782A1 (en) | 2005-12-30 | 2007-10-04 | Ranbaxy Laboratories Limited | Muscarinic receptor antagonists |
| WO2009068876A1 (en) * | 2007-11-30 | 2009-06-04 | Summit Corporation Plc | Compositions for the treatment of skin disorders |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5164402A (en) * | 1989-08-16 | 1992-11-17 | Pfizer Inc | Azabicyclo quinolone and naphthyridinone carboxylic acids |
-
2004
- 2004-09-17 EP EP04769411A patent/EP1675828A1/en not_active Withdrawn
- 2004-09-17 WO PCT/IB2004/003037 patent/WO2005026122A1/en not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2005026122A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005026122A1 (en) | 2005-03-24 |
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