AP746A - Process for preparing dioxoazabicyclohexanes. - Google Patents
Process for preparing dioxoazabicyclohexanes. Download PDFInfo
- Publication number
- AP746A AP746A APAP/P/1996/000885A AP9600885A AP746A AP 746 A AP746 A AP 746A AP 9600885 A AP9600885 A AP 9600885A AP 746 A AP746 A AP 746A
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- Prior art keywords
- organic solvent
- process according
- base
- compound
- mixture
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- HGCBTXNRSHFSOF-UHFFFAOYSA-N 1-cyclohexylpiperidine-2,3-dione Chemical class O=C1C(=O)CCCN1C1CCCCC1 HGCBTXNRSHFSOF-UHFFFAOYSA-N 0.000 title description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 57
- 239000003960 organic solvent Substances 0.000 claims abstract description 40
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 14
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims abstract description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims abstract description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000011541 reaction mixture Substances 0.000 claims abstract description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 7
- 238000011084 recovery Methods 0.000 claims abstract description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 7
- 239000001488 sodium phosphate Substances 0.000 claims abstract description 7
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims abstract description 7
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims abstract description 7
- 235000019801 trisodium phosphate Nutrition 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 239000011698 potassium fluoride Substances 0.000 claims abstract description 6
- 235000003270 potassium fluoride Nutrition 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 30
- DNPRVXJGNANVCZ-UHFFFAOYSA-N bromo(nitro)methane Chemical compound [O-][N+](=O)CBr DNPRVXJGNANVCZ-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- CGKPGVZMSKVVOF-UHFFFAOYSA-N chloro(nitro)methane Chemical group [O-][N+](=O)CCl CGKPGVZMSKVVOF-UHFFFAOYSA-N 0.000 claims description 2
- 239000011877 solvent mixture Substances 0.000 claims description 2
- 230000003019 stabilising effect Effects 0.000 claims 1
- MKRBAPNEJMFMHU-UHFFFAOYSA-N 1-benzylpyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1CC1=CC=CC=C1 MKRBAPNEJMFMHU-UHFFFAOYSA-N 0.000 description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000011065 in-situ storage Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- -1 dimethyiacetamide Chemical compound 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 2
- 229910052792 caesium Inorganic materials 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- ZFDWWDZLRKHULH-UHFFFAOYSA-N 1,2-dimethyl-5,6-dihydro-4h-pyrimidine Chemical compound CN1CCCN=C1C ZFDWWDZLRKHULH-UHFFFAOYSA-N 0.000 description 1
- 102100034741 Cyclin-dependent kinase 20 Human genes 0.000 description 1
- OTUKPXUUYJTFFJ-UHFFFAOYSA-N F.CC(C)=O Chemical compound F.CC(C)=O OTUKPXUUYJTFFJ-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 101000874141 Homo sapiens Probable ATP-dependent RNA helicase DDX43 Proteins 0.000 description 1
- 101500014379 Lymnaea stagnalis Ovulation hormone Proteins 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 101100074988 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) nmp-1 gene Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100035724 Probable ATP-dependent RNA helicase DDX43 Human genes 0.000 description 1
- ZIYVAZASIRJRHP-UHFFFAOYSA-N acetonitrile;hydron;fluoride Chemical compound F.CC#N ZIYVAZASIRJRHP-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- UGQFBHVUOLHZJK-UHFFFAOYSA-L dicesium propan-2-one carbonate Chemical compound C([O-])([O-])=O.[Cs+].CC(=O)C.[Cs+] UGQFBHVUOLHZJK-UHFFFAOYSA-L 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 239000003643 water by type Substances 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
A process for preparing a compound of the formula (I): wherein R is CrC6 alkyl, C3-Ce cycloalkyl or benzyl, and wherein the phenyl moiety of said benzyl group is optionally substituted by one or more substituents each independently selected from halo, nitro, d-Cealkyl, CrC6 alkoxy, amino and trifluoromethyl. which comprises adding a solution comprising a compound of the formula (II) a halonitromethane and an organic solvent selected from acetone, dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide, N-methylpyrrolidinone and dimethoxyethane,wherein R is as defined above, to a mixture comprising a base and an organic solvent, said organic solvent being as defined above and the said base being selected from potassium carbonate, sodium carbonate, cesium carbonate, trisodium phosphate, and potassium fluoride, so that a compound of the formula (I) is produced, any excess base being eliminated from the/reaction mixture prior to recovery of the product (I).
Description
O.N H
• ro wherein R is C,-Cs alkyl, C3-C5 cycloalkyl or benzyl, and wherein the phenyl moiety of said benzyl group is optionally substituted by one or more substituents each independently selected from halo, nitro, C,-Cs alkyl, Ci-Cs alkoxy, amino and trifiuoromethyl.
which comprises adding a solution comprising a compound of the formula (II), a halonitromethane and an organic solvent selected from acetone, dimethylformamide, dimethyiacetamide, acetonitrile, dimethylsulfoxide, Nmethylpyrralidinane and dimethaxyethane,
R wherein R is as defined above, to a mixture comprising a base and an organic solvent, said organic solvent being as defined above and the said base being selected from potassium carbonate, sodium carbonate, cesium carbonate, trisodium phosphate, and potassium fluoride, so that a compound of the formula (1) is produced, any excess base being eliminated from th&'reactibp mixture prior to recovery of the product (I).
Documents Citerl· wo 03 ι son ι λ
Inventors continued
JOHN ARTHUR RUMPUS Pfizer Limited Ramsgate Road Sandwich, Kent CT13 9NJ United Kingdom.
SPC 9406 (PLC 662) ftp . 0 0 7 4 6
Process for preparing dioxoazabicyclohexanes.
This invention relates to a process for preparing an exo-compound of the formula (1):-
wherein R is Ci-C6 alkyl, C3-C6 cycloalkyi or benzyl, and wherein the phenyl moiety of said benzyl group is optionally substituted by one or more substituents each independently selected from halo, nitro, C-i-C6 alkyl, Ci-C6 alkoxy, amino and trifluoromethyl.
Halo means fluoro, chloro, bromo or iodo.
The compounds (I) are useful as synthetic intermediates in the manufacture of the antibiotics of EP-B-0413455 as explained in WO-A93/18001.
AP/P/ 9 6 / 0 0 8 8 5
International patent application publication no. WO-A-93/18001 describes a process for preparing a compound of the formula (I) by reaction of a compound of the formula (II):-
with a halonitromethane in the presence of a base, R being as defined for formula (I).
SPC 9406 (PLC 662)
AP.00746
2'
Example 1 of that application describes the preparation of 1a, 5a, 6a3-benzyl-6-nitro-2,4-dioxo-3-azabicyclo [3.1.0]hexane by adding the base DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) in toluene dropwise to a mixture of N-benzylmaleimide and bromonitromethane in toluene. However the yield of the end product isolated was only 17%. In terms of grams of activity, the yield would have been less than 17%.
WO-A-95/19361 describes the use of 1,2-dimethyl-1,4,5,6tetrahydropyrimidine (DMTHP) as the base in that process and the isolated yield was 26.7% (less in terms of grams of activity).
We have now found that if certain specific bases and solvents are used, if the order of addition of the reactants is reversed [i.e., if the halonitromethane and maleimide (ll)are added to the base in the solvent], and if any excess base is eliminated from the reaction mixture before recovery of the product (I), then very significant improvements in the yield of (I) are obtained.
AP/P/ 9 6 / 0 0 8 8 5
Thus the present invention provides a process for preparing a compound of the formula (I):-
wherein R is C-|-C6 alkyl, C3-C6 cycloalkyl or benzyl, and wherein the phenyl moiety of said benzyl group is optionally substituted by one or more substituents each independently selected from halo, nitro, Ci-C6 alkyl, C1-C6 alkoxy, amino and trifluoromethyl,
SPC 9406 (PLC 662)
AP.00746 which comprises adding a solution comprising a compound of the formula (II), a halonitromethane and an organic solvent selected from acetone, dimethylformamide, dimethyiacetamide, acetonitrile, dimethylsulfoxide, Nmethylpyrrolidinone and dimethoxyethane,
R wherein R is as defined above, to a mixture comprising a base and an organic solvent, said organic solvent being as defined above and said base being selected from potassium carbonate, sodium carbonate, cesium carbonate, trisodium phosphate, and potassium fluoride, so that a compound of the formula (I) is produced, any excess base being eliminated from the reaction mixture prior to recovery of the product (I).
In one aspect, the process comprises adding a solution of a compound of the formula (11) in a mixture of a halonitromethane and an organic solvent, said organic solvent being selected from acetone, dimethylformamide, dimethyiacetamide, acetonitrile, dimethylsulfoxide, N-methylpyrrolidone and dimethoxyethane,
AP/P/ 9 6 / 0 0 8 8 5 wherein R is defined for formula (I), to a mixture of a base in an organic solvent, said organic solvent being as defined above and the base being selected from potassium carbonate, sodium carbonate, cesium carbonate, trisodium phosphate, and potassium fluoride, so that a compound of the formula (I) is produced, any excess base being eliminated from the reaction mixture prior to recovery of the product (I).
AP.00746
SPC 9406 (PLC 662) '
Preferably R is Ci-C6 alkyl, C3-C6 cycloalkyl or benzyl, the phenyl moiety of the benzyl group being optionally substituted by 1 or 2 substituents as. defined above.
Preferably, R is Ci-Ce alkyl or benzyl.
Most preferably, R is benzyl.
Preferably, the halonitromethane is chloronitromethane or bromonitromethane, most preferably bromonitromethane.
Bromonitromethane is conveniently purchased as a solution in a stabilizing amount of an inert organic solvent, such as toluene, and preferably as a solution in from 25 to 50%w/w toluene. The presence of the inert solvent, such as toluene, does not significantly affect the yield of the compound (I), so that the solution of bromonitromethane in the inert solvent can be used as such in the process of the invention.
Mixtures of the stated organic solvents, and of the bases, may also be used.
Λ.Ρ/Ρ/ 9 6 / 0 0 8 8 5
Preferably, the ratio of the volume of the organic solvent in the mixture of the base and the organic solvent: the volume of the organic solvent in the solution of the compound (II) and bromonitromethane is from approximately 1:1 to 7:1, preferably from 1:1 to 4:1.
Preferably, the compound (II) and the halonitromethane are used in a molar ratio of from 1:1 to 1:1.25. Most preferably, the molar ratio is about 1:1.
Typically, the solution of the compound (II) in the mixture of the halonitromethane and organic solvent is slowly added to the base/solvent mixture, e.g. over a period of from 30 minutes to 4 hours.
·* ϋ
AP.00746
SPC 9406 (PLC 662)
Preferably, the mixture of the base and the organic solvent contains up to 5%, more preferably 1 -3%, by volume water based on the total volume of the organic solvent(s).
In one preferred aspect, the organic solvent is dimethylformamide and the base is potassium carbonate.
In another preferred aspect, the organic solvent is dlmethylsulfoxide and the base is potassium carbonate.
The process is preferably carried out at a temperature of from 5 to 50°C, preferably from 20°C to 30°C, and most preferably at ambient temperature.
Preferably, any excess base is eliminated from the reaction mixture by filtration, or by neutralisation with an acid. Most preferably, any excess base is removed by neutralisation with acetic or dilute hydrochloric acid.
Preferably, the particle size of the base is less than 75, more preferably less than 45, microns.
Whilst the process as described produces the exo compound (I) in good to excellent yield it is believed that a portion of (I) is produced via the epimerisation of the endo isomer (ill), which is also produced in this process:NO2
H
AP/P/ 9 6 / 0 0 8 8 5
O
R is as defined for formula (I).
AP.00746
SPC 9406 (PLC 662)
6'
The following Examples illustrate the high yields obtainable by the process of the present invention :gA=grams of activity.
Example 1 a, 5a, 6a-3-Benzyl-6-nitro-2,4-dioXo-3-azabicvclor3.1 .Olhexane.'
To a stirred slurry of potassium carbonate (7.5g;0.054 mole) in acetone (40 ml) and water (1 ml) at ambient temperature was added dropwise, over a period of about 2 hours, a solution of bromonitromethane (5 g - 4.48gA,
0.032 mole) and N-benzylmaleimide (5 g; 0.026 mole) in acetone (40 ml).
When reaction was complete (in situ yield 61%), powdered molecular sieves (10 g) were added and the solvent exchanged with toluene by constant volume distillation. The resulting slurry was filtered to remove unreacted potassium carbonate/sieves/tar and the filter cake washed with toluene.
The combined toluene filtrates were washed with diiute hydrochloric acid (2M), then concentrated under reduced pressure to approximately 20 mi then cooled to 0-5°C. The desired product was subsequently isolated by filtration and dried in vacuo to yield the title compound (3.03gA, 46%) as a white to pale yellow crystalline solid, m.p. 115°C. NMR (CDCH): δ 3.34 (s,2H), 4.46 (s,1H), 4.53 (s, 2H), 7.3 (s, 5H).
Example 2
1g, 5a, 6a-3-Benzyl-6-nitro-2,4-dioxo-3-azabicvclo Γ3.1 .Olhexane.
To a stirred slurry of potassium carbonate (7.5 g, 0.054 mole) in dimethylformamide (40 ml) and water (1 ml) at ambient temperature was added dropwise, over a period of about 2 hours, a solution of bromonitromethane (5 g - 4.48gA, 0.032 mole) and N-benzylmaleimide (5 g; 0.026 mole) in dimethylformamide (40 ml).
When the reaction was complete (in situ 72%), the excess potassium carbonate was neutralised by the addition of acetic acid (4.68 g, 0.078 mole) and then water (160 ml) was added. The resulting precipitate was isolated by filtration and dried in vacuo to yield the title compound (4.2 gA, 66%) as an
AP/P/ 9 6 / 0 0 8 8 5
AP.00746
SPC 9406 (PLC 662) off-white/light brown solid, m.p. 114°C. NMR (CDCI3) :δ 3.34 (s, 2H), 4.46 (s, 1H), 4.53 (s, 2H), 7.3 (s, 5H).
Example 3
1α, 5a, 6a-3-Benzvi-6-nitro-2,4-dioxo-3-azabicycio [3.1.01 hexane.
To a stirred slurry of potassium carbonate (7.5 g, 0.054 mole) in dimethylformamide (40 ml) and water (1 ml) at ambient temperature was added dropwise, over a period of about 2 hours, a solution of bromonitromethane (5 g - 4.48gA, 0.032 mole) and N-benzylmaleimide (5 g; 0.026 mole) in dimethylformamide (40 ml).
When the reaction was complete, the excess potassium carbonate was removed by filtration and then water (160 ml) was added.. The resulting precipitate was isolated by filtration and dried in vacuo to yield the title compound (3.5gA, 54%) as a light brown solid, m.p. 116-117°C. NMR (CDCI3) : δ 3.34 (s, 2H), 4.46 (s, 1H), 4.53 (s, 2H), 7.3 (s, 5H).
Examples 4-17
1g, 5g, 6g-3-Benzyl-6-nitro-2,4-dioxo-3-azabicyclo [3.1.01 hexane was prepared similarly to the procedure of Example 1 using N-benzylmaleimide and bromonitromethane in the presence of water and using the stated base/solvent combinations. Although the title compound was not actually isolated in these Examples, the in situ yields of it were measured using hplc following the end of reaction. The isolated yields will be about 5 -15% lower than the jn situ yields.
AP/P/ 9 6 / 0 0 8 8 5
SPC 9406 (PLC 662)
AP.00746
8'
| Example No | Base | Solvent | Molar Ratio NBM:BNM | Water (by.vol. based on the total vol.of the organic solvent) | In Situ Yield |
| 4 | Pot.Carbonate | Acetonitrile | 1:1.25 | 1.25% | 60% |
| 5 | Pot.Carbonate | DMSO | 1:1.25 | 1.25% | 69% |
| 6 | Pot.Carbonate | DMF | 1:1 | 1.25% | 74% |
| 7 | Pot. Carbonate | DMF | 1:1 | 1.25% | 75% |
| 8 | Pot.Carbonate | DMAC | 1:1:25 | 1.25% | 66% |
| 9 | Pot.Carbonate | NMP | 1:1.25 | 1.25% | 68% |
| 10 | Pot.Carbonate | DME | 1:1.25 | 1.25% | 54% |
| 11 | Cesium Carbonate | Acetone | 1:1.25 | 0.5% | 63% |
| 12 | Cesium Carbonate | DMF | 1:1.25 | 1.25% | 78% |
| 13 | Sodium Carbonate | DMF | 1:1.25 | 1.25% | 61% |
| 14 | Trisodium Phosphate | DMF | 1:1 | 1.25% | 58% |
| 15 | Pot. Fluoride | Acetonitrile | 1:1.25 | 1.25% | 47% |
| 16 | Pot. Fluoride | Acetone | 1:1.25 | 1% | 54% |
| 17 | Pot. Fluoride | DMF· | 1:1.25 | 1.25% | 68% |
Hplc Method:
Column: Mobile Phase:
Flow rate:
Waters “Novapak” C18 15 cm x 3.9 mm i.d.
60:40 0.02 M aqueous sodium dihydrogen phosphate:acetonitrile.
1.0 ml. min '1l.
UV detection at 220 nm
Approx, retention times:
N-Benzylmaleimide 3.47 minutes.
Bromonitromethane 1.88 minutes.
Title compound 4.59 minutes.
DMSO = Dimethylsulfoxide. DMF = dimethylformamide.
DMAC = dimethylacetamide. NMP = N-methylpyrrolidinone.
DME = dimethoxy ethane.
NBM = N-benzylmaleimide. BNM = Bromonitromethane. Pot. = potassium.
L«Γ
AP.00746
SPC 9406 (PLC 662) .
Example 18
To a stirred slurry of potassium carbonate (30g, 0.2136 mole) in DMF (140 mi) and water (4 ml) at ambient temperature was added dropwise, over a period of about 2 hours, a solution of bromonitromethane [36.2g of a 47.5% w/w solution in toluene (about 20 ml), equivalent to 17.19 gA, 0.123 mole] and N-benzyimaleimide (20g, 0.1068 mole) in DMF (20 ml). When the reaction was complete (in situ yield 75%) the excess potassium carbonate was neutralised via the addition of acetic acid (19.4 mi, 20.35 g, 0.34 mole) and then water (160 ml) was added.
The resulting precipitate was isolated by filtration, washed with water (3 x 40 ml) and then isopropanol (3 x 20 ml) to give the title compound (17.54 gA, 66.7%).
NMR (CDCI3) : 0 3.34 (s,2H), 4.46 (s,1H), 4.53 (s,2H), 7.3 (s,5H).
in the above Examples, the particle size of the bases used was less than 75 microns.
Claims (22)
1. A process for preparing a compound of the formula (I);o2n h
H
H
O wherein R is Ci-C6 alkyl, C3-Cs cycloalkyl or benzyl, and wherein the phenyl moiety of said benzyl group is optionally substituted by one or more substituents each independently selected from halo, nitro, C-t-Ce alkyl, C-i-Ce alkoxy, amino and trifluoromethyl.
which comprises adding a solution comprising a compound of the formula (II), a halonitromethane and an organic solvent selected from acetone, dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide, Nmethylpyrrolidinone and dimethoxyethane,
H
R
AP/P/ 9 6 / 0 0 8 8 5 wherein R is as defined above, to a mixture comprising a base and an organic solvent, said organic solvent being as defined above and said base being selected from potassium carbonate, sodium carbonate, cesium carbonate, trisodium phosphate, and potassium fluoride, so that a compound of the formula (I) is produced, any excess base being eliminated from the reaction mixture prior to recovery of the product (I).
2. A process according to claim 1, which comprises adding a solution of a compound of the formula (II) as defined in claim 1 in a mixture of a halonitromethane and an organic solvent, said organic solvent being selected from acetone, dimethylformamide, dimethylacetamide, acetonitrile, /·
SPC 9406 (PLC 662)
AP.00746
11 .
dimethylsuifoxide, N-methylpyrrolidone and dimethoxyethane, to a mixture of a base in an organic solvent, said organic solvent being as defined above and the base being selected from potassium carbonate, sodium carbonate, cesium carbonate, trisodium phosphate, and potassium fluoride, so that a compound of the formula (I) is produced, any excess base being eliminated from the reaction mixture prior to recovery of the product (I).
3. A process according to claim 1 or 2, wherein R is Ci-C6 alkyl or benzyl..
4. A process according to claim 3, wherein R is benzyl.
5. A process according to any one of the preceding claims, wherein the halonitromethane is chloronitromethane or bromonitromethane.
6. A process according to claim 5, wherein the halonitromethane is bromonitromethane.
7 A process according to claim 6, where the bromonitromethane is used as a solution in a stabilising amount of an inert organic solvent.
8. A process according to claim 7, wherein the bromonitromethane is used as a solution containing from 25 to 50% w/w toluene.
9. A process according to any one of the preceding claims, wherein the compound (ii) and the halonitromethane are used in a molar ratio of from 1:1 to 1:1.25.
10. A process according to claim 8, wherein the molar ratio is about 1:1.
11. A process according to any one of the preceding claims, wherein the mixture of the base and the organic solvent contains up to 5% by volume water based on the total volume of the organic solvent(s).
12. A process according to claim 10, wherein the mixture contains from 13% by volume water.
13. A process according to any one of the preceding claims, wherein the organic solvent is dimethylformamide and the. base is potassium carbonate.
14. A process according to any one of claims 1 to 12, wherein the organic solvent is dimethyisulfoxide and the base is potassium carbonate.
15. A process according to any one of the preceding claims, which is carried out at a temperature of from 5 to 50°C.
AP/P/ 9 6 / 0 0 8 8 5
AP. 0 0 7 4 6
SPC 9406 (PLC 662)
12'
16. A process according to claim 14, which is carried out at a temperature of from 20°C to 30°C. ·
17. A process as claimed in claim 16, which is carried out at ambient temperature.
18. A process according to any one of the preceding claims, wherein any excess base is eliminated from the reaction mixture either by filtration, or by neutralisation with an acid.
19. A process according to claim 18, wherein any excess base is removed by neutralisation with acetic or dilute hydrochloric acid.
20. A process according to any one of the preceding claims, wherein the particle size of the base is less than 75 microns.
21. A process according to any one of the preceding claims wherein the solution of the compound (II) in the mixture of the halonitromethane and organic solvent is slowly added to the base/solvent mixture.
22. A process according to any one of the preceding claims wherein the ratio of the volume of the organic solvent in the mixture of the base and organic solvent: the volume of the organic solvent in the solution of compound (ll) and bromonitromethane is from approximately 1:1 to 7:1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9524466.1A GB9524466D0 (en) | 1995-11-30 | 1995-11-30 | Process |
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| AP9600885A0 AP9600885A0 (en) | 1997-01-31 |
| AP746A true AP746A (en) | 1999-04-29 |
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| APAP/P/1996/000885A AP746A (en) | 1995-11-30 | 1996-11-28 | Process for preparing dioxoazabicyclohexanes. |
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| EP (1) | EP0863874B1 (en) |
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| JPH1087617A (en) * | 1996-07-09 | 1998-04-07 | Pfizer Inc | Preparation of intermediates useful for the synthesis of quinoline antibiotics |
| HN1998000106A (en) | 1997-08-01 | 1999-01-08 | Pfizer Prod Inc | PARENTERAL COMPOSITIONS OF ALATROFLAXACINO |
| US7019142B2 (en) | 1998-01-16 | 2006-03-28 | Pfizer Inc. | Process for preparing naphthyridones and intermediates |
| CN1320360C (en) * | 2002-03-25 | 2007-06-06 | 科学和工业研究委员会 | The protein map of super acidic plants |
| NL2000192C2 (en) * | 2006-08-23 | 2008-02-26 | Veenvoort B V De | Stable bitumen foam and its preparation and use. |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993018001A1 (en) * | 1992-03-02 | 1993-09-16 | Pfizer Inc. | Preparation of intermediates in the synthesis of quinoline antibiotics |
| WO1995019361A1 (en) * | 1994-01-18 | 1995-07-20 | Pfizer Inc. | Process and intermediates for preparing naphthyridonecarboxylic acid salts |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993018001A1 (en) * | 1992-03-02 | 1993-09-16 | Pfizer Inc. | Preparation of intermediates in the synthesis of quinoline antibiotics |
| WO1995019361A1 (en) * | 1994-01-18 | 1995-07-20 | Pfizer Inc. | Process and intermediates for preparing naphthyridonecarboxylic acid salts |
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