NO144344B - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE N-ARYLSULPHONYL N`- (3-AZABICYCLOALKYL) - Google Patents
PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE N-ARYLSULPHONYL N`- (3-AZABICYCLOALKYL) Download PDFInfo
- Publication number
- NO144344B NO144344B NO742425A NO742425A NO144344B NO 144344 B NO144344 B NO 144344B NO 742425 A NO742425 A NO 742425A NO 742425 A NO742425 A NO 742425A NO 144344 B NO144344 B NO 144344B
- Authority
- NO
- Norway
- Prior art keywords
- azabicyclo
- compound
- general formula
- azabicycloalkyl
- azabicycloalkane
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title claims description 3
- 230000001225 therapeutic effect Effects 0.000 title description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 229960000583 acetic acid Drugs 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 235000013877 carbamide Nutrition 0.000 claims description 7
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 150000003672 ureas Chemical class 0.000 claims description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 9
- FSCBDDOKZIRLCN-UHFFFAOYSA-N 2-nitroso-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrole Chemical compound C1CCC2CN(N=O)CC21 FSCBDDOKZIRLCN-UHFFFAOYSA-N 0.000 description 8
- 239000004202 carbamide Substances 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- RLEPMHBHXGEBBX-UHFFFAOYSA-N 2,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-3-one Chemical compound C1CCC2C(=O)NCC21 RLEPMHBHXGEBBX-UHFFFAOYSA-N 0.000 description 4
- FJYWNYLUZBMVKI-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-amine Chemical compound C1CCC2CN(N)CC21 FJYWNYLUZBMVKI-UHFFFAOYSA-N 0.000 description 4
- QCWDCTDYSDJKTP-UHFFFAOYSA-N 4,5,6,6a-tetrahydro-3ah-cyclopenta[c]pyrrole-1,3-dione Chemical compound C1CCC2C(=O)NC(=O)C21 QCWDCTDYSDJKTP-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- -1 arylsulfonyl urethane Chemical compound 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- BOVGTQGAOIONJV-UHFFFAOYSA-N gliclazide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CC2CCCC2C1 BOVGTQGAOIONJV-UHFFFAOYSA-N 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- WPYNXKFLSQEEFE-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-amine;hydrochloride Chemical compound Cl.C1CCC2CN(N)CC21 WPYNXKFLSQEEFE-UHFFFAOYSA-N 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- AEJRNONYXDAILM-UHFFFAOYSA-N [Ba+2].[O-][Cr]([O-])=O Chemical compound [Ba+2].[O-][Cr]([O-])=O AEJRNONYXDAILM-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 235000010288 sodium nitrite Nutrition 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- TXAQXDWPENKEDF-UHFFFAOYSA-N ethyl 2-cyanocyclopentane-1-carboxylate Chemical compound CCOC(=O)C1CCCC1C#N TXAQXDWPENKEDF-UHFFFAOYSA-N 0.000 description 2
- OKQXTJACOYBNJC-UHFFFAOYSA-N ethyl 2-cyanocyclopentene-1-carboxylate Chemical compound CCOC(=O)C1=C(C#N)CCC1 OKQXTJACOYBNJC-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- HVZRRRPCVOJOLJ-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole;hydrochloride Chemical compound Cl.C1NCC2CCCC21 HVZRRRPCVOJOLJ-UHFFFAOYSA-N 0.000 description 1
- WRMOWNXORINHPP-UHFFFAOYSA-N 1-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-3-(4-chlorophenyl)sulfonylurea Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)NC(=O)NN1CC2CCCC2C1 WRMOWNXORINHPP-UHFFFAOYSA-N 0.000 description 1
- WNHZTXOJJUDJHP-UHFFFAOYSA-N 1-(3-azabicyclo[3.2.0]heptan-3-yl)-3-(4-ethylphenyl)sulfonylurea Chemical compound C(C)C1=CC=C(C=C1)S(=O)(=O)NC(=O)NN1CC2CCC2C1 WNHZTXOJJUDJHP-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DSRXQXXHDIAVJT-UHFFFAOYSA-N acetonitrile;n,n-dimethylformamide Chemical compound CC#N.CN(C)C=O DSRXQXXHDIAVJT-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- ASJCSAKCMTWGAH-UHFFFAOYSA-N cyclopentane-1,2-dicarboxylic acid Chemical compound OC(=O)C1CCCC1C(O)=O ASJCSAKCMTWGAH-UHFFFAOYSA-N 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 201000002249 diabetic peripheral angiopathy Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Nærværende oppfinnelse fremskaffer.en fremgangsmåte for fremstilling av N-arylsulfonyl N'-(3-azabicykloalkyl)urinstoffer av den generelle formel I The present invention provides a process for the preparation of N-arylsulfonyl N'-(3-azabicycloalkyl)ureas of the general formula I
hvor X betegner et halogenatom eller et alkylradikal med where X denotes a halogen atom or an alkyl radical with
fra 1 til 5 karbonatomer, og from 1 to 5 carbon atoms, and
n er en indeks fra 1 til 3, n is an index from 1 to 3,
og syreaddisjonssalter av disse, og da mere spesielt fysiolo- and acid addition salts of these, and then more especially physiological
gisk aksepterbare salter av disse med egnede syrer eller baser. mechanically acceptable salts thereof with suitable acids or bases.
Fransk patent nr. 1.510.714 vedrører de N-substituerte azabicykloalkaner som fremstilles i henhold til foreliggende opp-finnelse. Forbindelsene med formel I er således'kjent fra det nevnte franske patent, men foreliggende fremgangsmåte må an-sees å representere et teknisk fremskritt i forhold til den tidligere kjente fremgangsmåte. French patent no. 1,510,714 relates to the N-substituted azabicycloalkanes which are produced according to the present invention. The compounds of formula I are thus known from the aforementioned French patent, but the present method must be considered to represent a technical advance in relation to the previously known method.
I henhold til det nevnte patent beskrives en fremgangsmåte ved fremstilling av N-arylsulfonyl N<1->(3-azabicykloalkyl)-urear med formel I: According to the aforementioned patent, a method is described for the production of N-arylsulfonyl N<1->(3-azabicycloalkyl)-urea with formula I:
hvori en N-amino-3-azabicykloalkan med formel(II): omsettes med et arylsulfonyluretan med formel(III): Ved foreliggende fremgangsmåte fremstilles forbindelsene med formel I ved å redusere, enten ved katalytisk hydrogenering eller med diboran, en forbindelse av den generelle formel in which an N-amino-3-azabicycloalkane of formula (II): is reacted with an arylsulfonyl urethane of formula (III): In the present process, the compounds of formula I are prepared by reducing, either by catalytic hydrogenation or with diborane, a compound of the general formula
hvor n har forannevnte betydning, og where n has the aforementioned meaning, and
Z betegner -CH0- eller -C- , Z denotes -CH0- or -C-,
2 II 2 II
O O
nitrosere det slik dannede 3-azabicykloalkan-i henhold til følgende reaksjon nitrosate the 3-azabicycloalkane thus formed according to the following reaction
hvorpå det slik oppnådde N-nitroso-3-azabicykloalkan reduseres, enten ved katalytisk hydrogenering eller med en blanding av natrium, etanol; ammoniakk, for oppnåelse av N-amino-3-azabicykloalkan av den generelle formel som deretter kondenseres, enten i form av base eller hydroklorid, med et urinstoff av den generelle formel whereupon the N-nitroso-3-azabicycloalkane thus obtained is reduced, either by catalytic hydrogenation or with a mixture of sodium, ethanol; ammonia, to obtain N-amino-3-azabicycloalkane of the general formula which is then condensed, either in the form of base or hydrochloride, with a urea of the general formula
Foreliggende fremgangsmåte som adskiller seg fra den beskrevet i det nevnte franske patent er også mest interessant i lys av det oppnådde utbytte og renhet av sluttproduktet. F.eks. når forbindelsen N-(4-metylbenzensulfonyl)-N'-[3-azabicyklo (3,3,0) okt-3-yl] urea fremstilles i henhold til eksempel 1 The present method, which differs from that described in the aforementioned French patent, is also most interesting in light of the obtained yield and purity of the final product. E.g. when the compound N-(4-methylbenzenesulfonyl)-N'-[3-azabicyclo (3,3,0)oct-3-yl]urea is prepared according to example 1
i det nevnte franske patent ble det oppnådd et utbytte på 59%. Når forbindelsen ble fremstilt i henhold til det som er angitt i foreliggende søknads eksempel lcA var utbyttene alltid bedre enn 60%, uansett anvendte betingelser. in the aforementioned French patent, a yield of 59% was obtained. When the compound was prepared according to what is indicated in the present application's example lcA, the yields were always better than 60%, regardless of the conditions used.
Ytterligere når forbindelsen fremstilles i henhold til foreliggende fremgangsmåte slik som angitt i eksempel lcA er forbindelsen renere enn når den fremstilles i fremgangsmåten beskrevet i eksempel 1 i det nevnte franske patent, idet forbindelsen i dette tilfelle vil inneholde ca. 5% paratoluensulfon-amid som urenhet. Furthermore, when the compound is prepared according to the present method as indicated in example 1cA, the compound is purer than when it is prepared in the method described in example 1 of the aforementioned French patent, as the compound in this case will contain approx. 5% paratoluenesulfonamide as an impurity.
Utgangsmaterialet av den generelle formel II, hvor Z betegner The starting material of the general formula II, where Z denotes
-C- , ble fremstilt med utgang fra den tilsvarende 1,2-cyklo-6 -C- , was prepared starting from the corresponding 1,2-cyclo-6
alkandikarboksvlsvrp av fnrmplen. alkanedicarboxvlsp of the fnrmple.
hvor n har foran angitte betydning. where n has the above meaning.
Utgangsmaterialet av den generelle formel II, hvor Z betegner The starting material of the general formula II, where Z denotes
-CH2-, ble selv fremstilt:-CH2-, was produced itself:
enten ved eléktrolytisk reduksjon av forbindelsen II, hvor Z betegner -C- , either by electrolytic reduction of the compound II, where Z denotes -C-,
i in
■ eller ved hydrogenering av etyl 2-cyahocykloalkarikarboksylat eller etyl 2-cyano-l-cykloalkenkarboksylat av de respektive generelle formler: ■ or by hydrogenation of ethyl 2-cyanocycloalkarycarboxylate or ethyl 2-cyano-1-cycloalkenecarboxylate of the respective general formulas:
hvor n har foran angitte betydning. where n has the above meaning.
Denne hydrogenering utfores i et opplosningsmiddel, f.eks. slik som isopropanol i nærvær av ammoniakk, med Raney-nikkel, under et trykk av hydrogen pa fra 17 til 20 kg/cm 2og ved en temperatur innen området 60 - 100°C. This hydrogenation is carried out in a solvent, e.g. such as isopropanol in the presence of ammonia, with Raney nickel, under a pressure of hydrogen of from 17 to 20 kg/cm 2 and at a temperature within the range 60 - 100°C.
En av de mest tilfredsstillende måter for å utfore en slik prosess består i å utfore den katalytiske hydrogenering av forbindelsen II i et opplosningsmiddel slik som f.eks. dioksan, med kobber- og bariumkromitt, ved en temperatur innen området 250 til 300°C, under et hydrogentrykk innen området 100 til 180 kg/cm 2 , eller ved a o utfore reduksjonen av forbindelsen II ved hjelp av diboran og tilbakelopsbehandling i et opplosningsmiddel, slik som f.eks. tetrahydrofuran. Nitroseringen ay forbindelsene III utfores ved hjelp av natriumnitritt. i vandig One of the most satisfactory ways of carrying out such a process consists in carrying out the catalytic hydrogenation of the compound II in a solvent such as e.g. dioxane, with copper and barium chromite, at a temperature in the range of 250 to 300°C, under a hydrogen pressure in the range of 100 to 180 kg/cm 2 , or by a o carrying out the reduction of compound II by means of diborane and reflux treatment in a solvent, such as e.g. tetrahydrofuran. The nitrosation and the compounds III are carried out with the aid of sodium nitrite. in aqueous
fase. phase.
Den katalytiske hydrogenering av N-nitroso 3-azabicykloalkaner utfores i vandig fase, ved hjelp av palladisert trekull med 5% palladium i nærvær av ferrosulfat og urinstoff, ved en temperatur på ca. 30°C under et hydrogentrykk innen området 7 til 10 kg/cm 2. The catalytic hydrogenation of N-nitroso 3-azabicycloalkanes is carried out in the aqueous phase, using palladium charcoal with 5% palladium in the presence of ferrous sulphate and urea, at a temperature of approx. 30°C under a hydrogen pressure in the range 7 to 10 kg/cm 2.
Det må anfores at prosessene bestående i en katalytisk hydrogenering oppviser verdifull industriell interesse, ved at disse måtte muliggjore å oppnå et rent produkt og utfore det f 61-gende syntesetrinn direkte på den filtrerte hydrogeneringsvæ-ske uten at det er nodvendig å isolere produktet. It must be stated that the processes consisting of a catalytic hydrogenation show valuable industrial interest, in that these must make it possible to obtain a pure product and carry out the following synthesis step directly on the filtered hydrogenation liquid without it being necessary to isolate the product.
Kondensasjonen av forbindelsene IV og V utfores med fordel i et opplosningsmiddel som iseddik0 Den ene av forbindelsene IV og V krystalliseres hensiktsmessig fra eddiksyre, eller når forbindelsen IV anvendes i form av hydroklorid kan dens kondensa-sjon med forbindelsen V med fordel utføres, ikke bare i iseddik, men også i dimetylformamid eller i en blanding av ace-tonitrildimetylformamid. The condensation of the compounds IV and V is advantageously carried out in a solvent such as glacial acetic acid. One of the compounds IV and V is conveniently crystallized from acetic acid, or when the compound IV is used in the form of hydrochloride its condensation with the compound V can advantageously be carried out, not only in glacial acetic acid, but also in dimethylformamide or in a mixture of acetonitrile dimethylformamide.
Forbindelsene av generell formel I kan overfores til syreaddisjonssalter med syrer, slik som f.eks. saltsyre, bromhydrogen-syre, sulfonsyre, eddiksyre, malonsyre, maleinsyre, fumarsyre, vinsyre og malinsyre, eller med alkali- eller jordalkalimetall-hydroksyder og-karbonater, eller med alkalimetallbikarbonater. The compounds of general formula I can be converted into acid addition salts with acids, such as e.g. hydrochloric acid, hydrobromic acid, sulphonic acid, acetic acid, malonic acid, maleic acid, fumaric acid, tartaric acid and malic acid, or with alkali or alkaline earth metal hydroxides and carbonates, or with alkali metal bicarbonates.
Forbindelsene av den generelle formel I og fysiologisk aksepterbare salter av disse har verdifulle farmakologiske og tera-peutiske egenskaper, og særlig en meget interessant hypoglyee-misk virkning. Dessuten, reduserer de blodplate-klebrighet og den kapillare permeabilitet, oker det fibrinolytiske potensial og den kapillare motstand og oppviser lav giftighet. Folgelig kan forbindelsene av generell formel I og fysiologisk aksepterbare salter anvendes som legemidler, særlig ved behandlingen av diabetes og diabetisk angiopati. The compounds of the general formula I and physiologically acceptable salts thereof have valuable pharmacological and therapeutic properties, and in particular a very interesting hypoglycemic effect. Moreover, they reduce platelet stickiness and capillary permeability, increase fibrinolytic potential and capillary resistance and exhibit low toxicity. Consequently, the compounds of general formula I and physiologically acceptable salts can be used as pharmaceuticals, particularly in the treatment of diabetes and diabetic angiopathy.
De folgende eksempler illustrerer oppfinnelsen, og smeltepunk-tene er bestemt etter Kofler-metoden. The following examples illustrate the invention, and the melting points are determined according to the Kofler method.
EKSEMPEL la EXAMPLE la
N- nitroso- 3- azabicyklo ( 3, 3, 0) oktan N- nitroso-3- azabicyclo (3, 3, 0) octane
A) 83,4 g 1,2-cyklopentandikarboksimid, i opplosning i 278 ml vannfritt dioksan, ble hydrogenert med 24 g kobber- og bariumkromitt (fremstilt etter metoden beskrevet av A. DUNET et al. Bull. Soc. Chim. Frankrike (1956) 906-10) ved 276°C under et hydrogentrykk innen omradet 110 kg/cm 2, inntil absorpsjonen av "hydrogen opphorer, hvilket krever 5 til 6 "timer. Katalysatoren ble filtrert fra, og filtratet ble samlet opp i 57,6 g' eddiksyre. Opplosningsmidlet ble derpå fordampet under vakuum, og resten ble tatt opp med 390 ml vann. A) 83.4 g of 1,2-cyclopentanedicarboximide, in solution in 278 ml of anhydrous dioxane, was hydrogenated with 24 g of copper and barium chromite (prepared according to the method described by A. DUNET et al. Bull. Soc. Chim. France (1956 ) 906-10) at 276°C under a hydrogen pressure in the range of 110 kg/cm 2 , until the absorption of hydrogen ceases, which requires 5 to 6 hours. The catalyst was filtered off, and the filtrate was collected in 57.6 g of acetic acid. The solvent was then evaporated under vacuum, and the residue was taken up with 390 ml of water.
Den slik oppnådde opplosning ble ekstrahert med kloroform for The solution thus obtained was extracted with chloroform for
å eliminere de ikke-basiske produkter, deretter ble den nitrosert ved 70°C ved å tilsette hurtig 41,4 g natriumnitritt i 131 ml vann, og deretter oppvarme blandingen ved 70°C i 1 time. Etter avkjoling ble reaksjonsblandingen ekstrahert med eter, ekstraktene ble vasket med en natriumbikarbonatopplosning; derpå med vann. Disse ekstrakter ble torket, opplosningsmidlet ble eliminert ved destillasjon og produktet ble destillert. Ca. 56,7 til 59,7 g N-nitroso-3-azabicyklo (3,3,0) oktan, gul olje (k.p. / 0,1 mm Hg: 90-95°C, n^° 1.5153) ble oppnådd. to eliminate the non-basic products, then it was nitrosated at 70°C by rapidly adding 41.4 g of sodium nitrite in 131 ml of water, and then heating the mixture at 70°C for 1 hour. After cooling, the reaction mixture was extracted with ether, the extracts were washed with a sodium bicarbonate solution; then with water. These extracts were dried, the solvent was eliminated by distillation and the product was distilled. About. 56.7 to 59.7 g of N-nitroso-3-azabicyclo(3,3,0) octane, yellow oil (b.p. / 0.1 mm Hg: 90-95°C, n^° 1.5153) were obtained.
Utgangsmaterialet 1,2-cyklopentandikarboksimid ble selv fremstilt med utgang fra 1,2-cyklopentandikarboksylsyre. B) N-nitroso-3-azabicyklo (3,3,0) oktan ble også fremstilt som folger: 25 g 3-azabicyklo (3,3,0) oktan-2-on, i opplosning i 250 ml vannfritt dioksan, ble hydrogenert med 7,2 g kobber- og bariumkromitt ved 300°C under et hydrogentrykk innen- " ' <<>-.'..-■■■■.. for omradet 140 til 130 kg/cm , inntil absorpsjonen av hydrogen opphorte. Reaksjonsblandingen, behandlet som beskrevet foran, muliggjorde at det oppnås 19,2 g N-nitroso-3-azabicyklo (3,3,0) oktan, k.p. / 0,1 mm Hg: 90-95°C, n^<4> •= 1.513. Utgangsmaterialet 3-azabicyklo (3,3,0) oktan-2-on kan fremstilles enten ved elektrolytisk reduksjon av 1,2-cyklopentandikarboksimid ifolge metoden av K.N. Menon og J.L. Simonsen, J. Chem. Soc. (1929), s. 302-305, eller ved hydrogenering av etyl 2-cyanocyklopentankarboksylat eller etyl 2-cyanocyklopent-l-enkarboksylat ifolge folgende metoder: a) 33,4 g etyl 2-cyanocyklopentankarboksylat, i opplosning i 334 ml isopropanol og 4 g NH^, ble hydrogenert i nærvær av Raney-nikkel under et hydrogentrykk innen området 17 til 20 kg/ cm 2 i.nntil absorpsjonen av hydrogen opphbrte. Katalysatoren ble filtrert fra, og opplosningsmidlet eliminert ved destillasjon. Resten, omkrystallisert fra 130 ml isopropyleter, ga 18,2 g 3-azabicyklo (3,3,0) oktan-2-on, s.p.: 88-90°C. The starting material 1,2-cyclopentanedicarboximide was prepared itself starting from 1,2-cyclopentanedicarboxylic acid. B) N-nitroso-3-azabicyclo (3,3,0) octane was also prepared as follows: 25 g of 3-azabicyclo (3,3,0) octan-2-one, in solution in 250 ml of anhydrous dioxane, was hydrogenated with 7.2 g of copper and barium chromite at 300°C under a hydrogen pressure within " ' <<>-.'..-■■■■.. for the range 140 to 130 kg/cm , until the absorption of hydrogen ceased. The reaction mixture, treated as described front, made it possible to obtain 19.2 g of N-nitroso-3-azabicyclo (3,3,0) octane, b.p. / 0.1 mm Hg: 90-95°C, n^<4> •= 1.513. The starting material 3-azabicyclo (3,3,0)octan-2-one can be prepared either by electrolytic reduction of 1,2-cyclopentanedicarboximide according to the method of K.N. Menon and J.L. Simonsen, J. Chem. Soc. (1929), pp. 302-305, or by hydrogenation of ethyl 2-cyanocyclopentanecarboxylate or ethyl 2-cyanocyclopentane-1-enecarboxylate according to the following methods: a) 33.4 g of ethyl 2-cyanocyclopentanecarboxylate, in solution in 334 ml of isopropanol and 4 g NH 2 , was hydrogenated in the presence of Raney nickel under a hydrogen pressure in the range of 17 to 20 kg/cm 2 until the absorption of hydrogen ceased. The catalyst was filtered off and the solvent eliminated by distillation. The residue, recrystallized from 130 ml of isopropyl ether, gave 18.2 g of 3-azabicyclo(3,3,0)octan-2-one, m.p.: 88-90°C.
b) 49,5 g etyl 2-cyanocyklopent-l-en-karboksylat, i oppløsning i 459 ml isopropanol og 5,1 g NH^ ble hydrogenert i nærvær av b) 49.5 g of ethyl 2-cyanocyclopent-1-ene-carboxylate, in solution in 459 ml of isopropanol and 5.1 g of NH 3 were hydrogenated in the presence of
Raney-nikkel ved 60°C under et hydrogentrykk innen området 17 til 20 kg/cm 2, inntil absorpsjonen av hydrogen opphorte. Katalysatoren ble filtrert fra, opplosningsmidlet ble destillert fra og resten ble omkrystallisert i 300 ml cykloheksan. Det ble oppnådd ca. 20,5 til 21 g 3-azabicyklo (3,3,0) oktan-2-on, s.p. 89-90°C. C) En annen fremgangsmåte særlig interessant for fremstilling av N-nitroso-3-azabicyklo (3,3,0) oktan ble utfort som folger: Diboran, fremstilt ved å tilsette 40,8 g BH^Na i 1000 ml diglym til 228 g (<C>2H5)2 0BF3 i 400 ml diglym, ble tilsatt ved 0°C i 5 timer til en opplosning av 27,8 g 1,2-cyklopentandikarboksim.id i 500 ml vannfritt tetrahydrofuran. Blandingen ble rort om ved 0 O C i 2 timer, fikk henstå o i 24 timer, tilbakelopsDehandlét i 8 timer, forsiktig hydrolysert ved å tilsette 150 ml av en 6N HC1 opplosning, og derpå tilbakelopsbehandlét igjen' i 5 timer. Raney nickel at 60°C under a hydrogen pressure in the range of 17 to 20 kg/cm 2 , until the absorption of hydrogen ceased. The catalyst was filtered off, the solvent was distilled off and the residue was recrystallized in 300 ml of cyclohexane. It was achieved approx. 20.5 to 21 g of 3-azabicyclo(3,3,0)octan-2-one, m.p. 89-90°C. C) Another particularly interesting process for the production of N-nitroso-3-azabicyclo (3,3,0) octane was carried out as follows: Diborane, prepared by adding 40.8 g of BH^Na in 1000 ml of diglyme to 228 g (<C>2H5)2 0BF3 in 400 ml of diglyme, was added at 0°C over 5 hours to a solution of 27.8 g of 1,2-cyclopentanedicarboximide in 500 ml of anhydrous tetrahydrofuran. The mixture was stirred at 0°C for 2 hours, allowed to stand for 24 hours, refluxed for 8 hours, carefully hydrolyzed by adding 150 ml of a 6N HCl solution, and then refluxed again for 5 hours.
Etter avkjoling ble uopploselig stoff filtrert fra, og den slik oppnådde opplosning gjort alkalisk med 200 ml av en lo N NaOH opplosning, derpå dampdestillert og destillatet samlet opp i en 12 N HC1 opplosning. Det sure medium ble bragt til torrhet ved hjelp av 100 ml etanol, deretter 100 ml aceton for å eliminere de siste spor av vann. Resten ble suspendert i 100 ml vannfri aceton og etter filtrering ble det oppnådd 12,8 g 3-azabicyklo (3,3,0) oktanhydroklorid, s.p.: 136-137°C, som ble nitrosert med natriumnitritt,slik som nevnt foran, for å gi N-nitroso-3-azabicyklo(3,3,0) oktan, k.p. / 0,1 mm Hg = 90-95°C. After cooling, insoluble material was filtered off, and the solution thus obtained made alkaline with 200 ml of a 10 N NaOH solution, then steam distilled and the distillate collected in a 12 N HCl solution. The acidic medium was brought to dryness using 100 ml of ethanol, then 100 ml of acetone to eliminate the last traces of water. The residue was suspended in 100 ml of anhydrous acetone and after filtration, 12.8 g of 3-azabicyclo (3,3,0) octane hydrochloride was obtained, m.p.: 136-137°C, which was nitrosated with sodium nitrite, as mentioned above, for to give N-nitroso-3-azabicyclo(3,3,0) octane, b.p. / 0.1 mm Hg = 90-95°C.
EKSEMPEL lb EXAMPLE lb
N- amino- 3- azabicyklo( 3, 3, 0) oktan N-amino-3-azabicyclo(3,3,0) octane
A) 1050 g N-nitroso-3-azabicyklo(3,3,0)oktan i suspensjon i 3500 ml vann ble hydrogenert i nærvær av 6 g FeSO^, 7H20 og 17,5 g urinstoff med 21 g palladisert trekull med 5% Pd under et hydrogentrykk innen omradet 10 til 7 kg/cm ved en temperatur på 30°C inntil absorpsjonen av hydrogen opphorte. Katalysatoren ble filtrert fra, 1000 ml benzen ble tilsatt og 2400 g kaliumkarbonat ble opplost. Reaksjonsblandingen ble dekantert fra, ekstrahert med benzen og torket over kaliumkarbonat. Den slik oppnådde opplosning gjorde det mulig å oppnå 690 g N-amino-3-azabicyklo(3,3,0)oktan, k.p. / 18 mm Hg: 86°C. B) N-amino-3-azabicyklo(3,3,0)oktan ble også fremstilt som folger: Til 28 g N-nitroso-3-azabicyklo(3,3,0)oktan og 36,8 g absolutt etanol i 500 ml flytende NH2 ble tilsatt 18,4 g natrium i 90 minutter under opprettholdelse av et konstant nivå. Reaksjonsblandingen ble deretter rort om i 1 time, derpå ble NH^ lang-somt drevet ut ved samtidig tilsetning av 300 ml vann og 200 A) 1050 g of N-nitroso-3-azabicyclo(3,3,0)octane in suspension in 3500 ml of water was hydrogenated in the presence of 6 g of FeSO^, 7H2O and 17.5 g of urea with 21 g of palladated charcoal with 5% Pd under a hydrogen pressure in the range of 10 to 7 kg/cm at a temperature of 30°C until the absorption of hydrogen ceased. The catalyst was filtered off, 1000 ml of benzene was added and 2400 g of potassium carbonate was dissolved. The reaction mixture was decanted from, extracted with benzene and dried over potassium carbonate. The solution thus obtained made it possible to obtain 690 g of N-amino-3-azabicyclo(3,3,0)octane, b.p. / 18 mmHg: 86°C. B) N-amino-3-azabicyclo(3,3,0)octane was also prepared as follows: To 28 g of N-nitroso-3-azabicyclo(3,3,0)octane and 36.8 g of absolute ethanol in 500 ml of liquid NH2 was added to 18.4 g of sodium over 90 minutes while maintaining a constant level. The reaction mixture was then stirred for 1 hour, after which NH 3 was slowly expelled by the simultaneous addition of 300 ml of water and 200
ml eter. Den vandige fase ble mettet med 100 g pellettisert natriumhydroksyd. Etter dekantering, ekstraksjon med.eter og torking ble opplosningsmidlet eliminert. Det ble oppnådd 13 g N-amino-3-aza-bicyklo(3,3,0)oktan, k.p. / 18 mm Hg = 86°C. ml of ether. The aqueous phase was saturated with 100 g of pelletized sodium hydroxide. After decantation, extraction with ether and drying, the solvent was eliminated. 13 g of N-amino-3-aza-bicyclo(3,3,0)octane were obtained, b.p. / 18 mm Hg = 86°C.
EKSEMPEL lc N-( 4- metylbenzensulfonyl) - N' - | 3- azabicyklo ( 3, 3 , 0) okt- 3- yl |-urinstoff A) 8,1 g N-amino-3-azabicyklo(3,3,0)oktanhydroklorid ble tilsatt til en lunken opplosning (40-50°C) av 10,7 g para-toluen-sulfonylurinstoff og 100 ml av en blanding (4/1) av acetonitrill og dimetylformamid, og derpå ble alt tilbakelopsbehandlet. En svak uklarhet ble iakttatt, hvilken forsterkes ved dannelsen av en felling av NH^Cl. Etter tilbakelopsbehandling i 45 minutter ble reaksjonsblandingen fortynnet med 90 ml vann. Den slik dannede felling ble filtrert fra ved sugning og omkrystallisert fra 100 ml etanol. Det ble oppnådd 12 g N-(4-metylbenzensulfonyl)-N'-[3-azabicyklo(3,3,0)okt-3-yl]urinstoff, s.p.: 178°C. Utbytte 7 4%. EXAMPLE 1c N-(4-methylbenzenesulfonyl) - N' - | 3-azabicyclo (3,3,0)oct-3-yl |-urea A) 8.1 g of N-amino-3-azabicyclo(3,3,0)octane hydrochloride was added to a lukewarm solution (40-50° C) of 10.7 g of para-toluenesulfonylurea and 100 ml of a mixture (4/1) of acetonitrile and dimethylformamide, and then everything was refluxed. A slight turbidity was observed, which is enhanced by the formation of a precipitate of NH^Cl. After refluxing for 45 minutes, the reaction mixture was diluted with 90 ml of water. The precipitate thus formed was filtered off by suction and recrystallized from 100 ml of ethanol. 12 g of N-(4-methylbenzenesulfonyl)-N'-[3-azabicyclo(3,3,0)oct-3-yl]urea were obtained, m.p.: 178°C. Dividend 7 4%.
En slik syntese ble også utfort med fordel ved å arbeide i dimetylformamid ved 80°C i 45 minutter. Det ble deretter oppnådd 10 g N-(4-metylbenzensulfonyl)-N'-[3-azåbicyklo( 3,3,0)-okt-3-yl]urinstoff, s.p.: 178°C, utbytte 62%, eller ved å arbeide i krystalliserbar eddiksyre ifølge den følgende metode: 10,7 g para-toluensulfonyl-urinstoff, 8,1 g N-amino-3-azabicyklo ( 3 , 3 ,0)oktanhydroklorid og 50 g krystalliserbar eddiksyre ble oppvarmet ved 80°C i 30 minutter. Blandingen ble homogen etter 10 minutter, da en svak felling ble iakttatt. Blandingen ble fortynnet med 50 ml vann og den slik dannede felling ble filtrert fra ved sugning og omkrystallisert fra 90 ml tilbakelopsbehandlet etanol. Det ble oppnådd 11,5 g N-(4-metylbenzen-sulf onyl)-N ' - |_3-azabicyklo( 3 , 3 ,0)okt-3-yl]urinstof f , s.p. 178°C . Such a synthesis was also carried out with advantage by working in dimethylformamide at 80°C for 45 minutes. 10 g of N-(4-methylbenzenesulfonyl)-N'-[3-azabicyclo(3,3,0)-oct-3-yl]urea were then obtained, m.p.: 178°C, yield 62%, or by work in crystallizable acetic acid according to the following method: 10.7 g of para-toluenesulfonyl urea, 8.1 g of N-amino-3-azabicyclo(3,3,0)octane hydrochloride and 50 g of crystallizable acetic acid were heated at 80°C in 30 minutes. The mixture became homogeneous after 10 minutes, when a slight precipitation was observed. The mixture was diluted with 50 ml of water and the precipitate thus formed was filtered off by suction and recrystallized from 90 ml of reflux treated ethanol. 11.5 g of N-(4-methylbenzene-sulfonyl)-N'-|_3-azabicyclo(3,3,0)oct-3-yl]urea were obtained, m.p. 178°C.
I dette siste eksempel kan 8,1 g N-amino-3-azabicyklo(3,3,0)-oktanhydroklorid erstattes med 6,3 g av den tilsvarende base, og det ble da oppnådd 11,7 g N-(4-metylbenzensulfonyl)-N'-[3-azabicyklo(3,3,0)okt-3-yl]-urinstoff, s.p. 178°C, utbytte 72%. In this last example, 8.1 g of N-amino-3-azabicyclo(3,3,0)-octane hydrochloride can be replaced with 6.3 g of the corresponding base, and 11.7 g of N-(4- methylbenzenesulfonyl)-N'-[3-azabicyclo(3,3,0)oct-3-yl]-urea, m.p. 178°C, yield 72%.
EKSEMPEL 2 til 8 EXAMPLE 2 to 8
De folgende forbindelser ble fremstilt ifolge fremgangsmåtene beskrevet i eksemplene la til lc under anvendelse av de tilsvarende utgangsmaterialer: 2. N-(4-etylbenzensulfonyl)-N'-[3-azabicyklo(3,3,0)okt-3-yljurinstoff, s.p.: 149°C (etanol). 3. N-(4-klorbenzensulfonyl)-N'-[3-azabicyklo(3,3,0)okt-3-yl]-urinstoff, s.p.: 207-208°C (etanol).. 4. N-(4-brombenzensulfonyl)-N1-[3-azabicyklo(3,3,0)okt-3-ylJ-urinstoff, s.p. 213°C (toluen). 5. N-(4-metylbenzensulfonyl) - N 1 -[3-azabicyklo(3,2,0)nept-3-yl]-urinstoff, s.p. 228-230°C (dimetylformamid/vann). 6 . N- ( 4-etylbenzensulf onyl)-N' - [3-azabicyklo (3,2,0)hept- 3-yl]-urinstoff, s.p. 200-201°C (etanol). 7. N-(4-klorbenzensulfonyl)-N'-[3-azabicyklo(3,2,O)hept-3-ylJ-urinstoff, s.p. 234-236°C (dimetylformamid/vann). 8. N-(4-metylbenzensulfonyl)-N'-[3'-azabicyklo(3,1,0)heks-3-yljurinstoff, s.p.: 206-207°C (dimetylformamid/vann). The following compounds were prepared according to the procedures described in examples 1a to 1c using the corresponding starting materials: 2. N-(4-ethylbenzenesulfonyl)-N'-[3-azabicyclo(3,3,0)oct-3-ylurea, m.p.: 149°C (ethanol). 3. N-(4-chlorobenzenesulfonyl)-N'-[3-azabicyclo(3,3,0)oct-3-yl]-urea, m.p.: 207-208°C (ethanol).. 4. N-( 4-bromobenzenesulfonyl)-N1-[3-azabicyclo(3,3,0)oct-3-yl]-urea, m.p. 213°C (toluene). 5. N-(4-methylbenzenesulfonyl)-N 1 -[3-azabicyclo(3,2,0)nept-3-yl]-urea, m.p. 228-230°C (dimethylformamide/water). 6. N-(4-ethylbenzenesulfonyl)-N'-[3-azabicyclo(3,2,0)hept-3-yl]-urea, m.p. 200-201°C (ethanol). 7. N-(4-Chlorobenzenesulfonyl)-N'-[3-azabicyclo(3,2,O)hept-3-yl]urea, m.p. 234-236°C (dimethylformamide/water). 8. N-(4-methylbenzenesulfonyl)-N'-[3'-azabicyclo(3,1,0)hex-3-ylurea, m.p.: 206-207°C (dimethylformamide/water).
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YU (1) | YU40105B (en) |
ZA (1) | ZA744313B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4183857A (en) * | 1978-07-06 | 1980-01-15 | Shell Oil Company | 3-Benzyl-3-azabicyclo(3.1.0)hexane-2,4-dione |
CA1121355A (en) * | 1978-10-27 | 1982-04-06 | Ronald F. Mason | Pyrrolidine derivatives and process for the preparation of such compounds |
FR2610321B1 (en) * | 1987-02-04 | 1989-04-07 | Oril Sa | NEW PROCESS FOR THE SYNTHESIS OF N-AMINO AZA-3 BICYCLO (3, 3, 0) OCTANE |
CN105061293B (en) * | 2015-07-28 | 2017-11-07 | 江苏瑞科医药科技有限公司 | A kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride |
CN110372545B (en) * | 2019-08-06 | 2022-01-04 | 山东海佑福瑞达制药有限公司 | Preparation method of high-purity gliclazide intermediate p-toluenesulfonylurea |
CN110372568A (en) * | 2019-08-22 | 2019-10-25 | 山东海佑福瑞达制药有限公司 | A kind of crystallization and preparation method thereof of gliclazide intermediate |
RU2754708C1 (en) * | 2021-03-02 | 2021-09-06 | Акционерное общество "Щелково Агрохим" | Method for obtaining gliclazide |
-
1974
- 1974-06-05 YU YU1566/74A patent/YU40105B/en unknown
- 1974-06-11 IN IN1269/CAL/74A patent/IN139716B/en unknown
- 1974-06-27 AR AR254427A patent/AR203750A1/en active
- 1974-06-27 OA OA55236A patent/OA04735A/en unknown
- 1974-07-01 CS CS7400004621A patent/CS185566B2/en unknown
- 1974-07-02 RO RO7479387A patent/RO70080A/en unknown
- 1974-07-02 DK DK354474AA patent/DK137752B/en not_active IP Right Cessation
- 1974-07-02 DD DD179654A patent/DD113223A5/xx unknown
- 1974-07-03 HU HUSI1420A patent/HU168450B/hu not_active IP Right Cessation
- 1974-07-03 PH PH7416011A patent/PH12355A/en unknown
- 1974-07-03 SU SU2041822A patent/SU552896A3/en active
- 1974-07-03 FI FI2036/74A patent/FI61880C/en active
- 1974-07-03 NO NO742425A patent/NO144344C/en unknown
- 1974-07-03 SE SE7408755A patent/SE399424B/en not_active IP Right Cessation
- 1974-07-03 JP JP7624474A patent/JPS5333584B2/ja not_active Expired
- 1974-07-04 ZA ZA00744313A patent/ZA744313B/en unknown
- 1974-07-04 AT AT553074A patent/AT339914B/en not_active IP Right Cessation
- 1974-07-04 ES ES427972A patent/ES427972A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
YU40105B (en) | 1985-08-31 |
AR203750A1 (en) | 1975-10-15 |
IN139716B (en) | 1976-07-24 |
DK137752B (en) | 1978-05-01 |
FI61880B (en) | 1982-06-30 |
NO742425L (en) | 1975-02-03 |
AT339914B (en) | 1977-11-10 |
CS185566B2 (en) | 1978-10-31 |
JPS5333584B2 (en) | 1978-09-14 |
JPS5062971A (en) | 1975-05-29 |
SU552896A3 (en) | 1977-03-30 |
OA04735A (en) | 1980-08-31 |
ATA553074A (en) | 1977-03-15 |
DD113223A5 (en) | 1975-05-20 |
NO144344C (en) | 1981-08-12 |
DK137752C (en) | 1978-10-02 |
YU156674A (en) | 1983-01-21 |
ES427972A1 (en) | 1976-08-16 |
SE7408755L (en) | 1975-01-07 |
PH12355A (en) | 1979-01-29 |
HU168450B (en) | 1976-04-28 |
ZA744313B (en) | 1975-07-30 |
DK354474A (en) | 1975-02-24 |
SE399424B (en) | 1978-02-13 |
RO70080A (en) | 1980-06-15 |
FI203674A (en) | 1975-01-05 |
FI61880C (en) | 1982-10-11 |
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