HUP0201548A2 - Process for the preparation of n-(1,1-dimethylethyl)-4-[[5'-ethoxy-4-cis[2-(4-morfolino)ethoxy]-2'-oxospiro[cyclohexan-1,3'[h]indol]1'(2'h)-yl]-sulfonyl]-3-methoxybenzamide and its salts - Google Patents
Process for the preparation of n-(1,1-dimethylethyl)-4-[[5'-ethoxy-4-cis[2-(4-morfolino)ethoxy]-2'-oxospiro[cyclohexan-1,3'[h]indol]1'(2'h)-yl]-sulfonyl]-3-methoxybenzamide and its salts Download PDFInfo
- Publication number
- HUP0201548A2 HUP0201548A2 HU0201548A HUP0201548A HUP0201548A2 HU P0201548 A2 HUP0201548 A2 HU P0201548A2 HU 0201548 A HU0201548 A HU 0201548A HU P0201548 A HUP0201548 A HU P0201548A HU P0201548 A2 HUP0201548 A2 HU P0201548A2
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- HU
- Hungary
- Prior art keywords
- ethoxy
- indol
- cis
- formula
- oxospiro
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims abstract description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 title abstract description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 title abstract 3
- 238000000034 method Methods 0.000 title description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 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 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 abstract description 5
- FQBFGERKZZFZNX-UHFFFAOYSA-N 4-(tert-butylcarbamoyl)-2-methoxybenzenesulfonyl chloride Chemical compound COC1=CC(C(=O)NC(C)(C)C)=CC=C1S(Cl)(=O)=O FQBFGERKZZFZNX-UHFFFAOYSA-N 0.000 abstract description 3
- 125000003003 spiro group Chemical group 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical class OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- TWHXWYVOWJCXSI-UHFFFAOYSA-N phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O TWHXWYVOWJCXSI-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
Description
Találmányunk tárgya új eljárás az I képletü N-(l,l-dimetiletil)-4-[[5’-etoxi-4-cw-[2(4-morfolino)-etoxi] -2 ’ -oxospiro [ciklohexán-1,3’- [3Z/]indol]-1 ’ (2 ’ 77)-y 1] -szulfonil]-3 metoxi-benzamid (SR 121463 ) és sói előállítására, mely anyag, vazopresszin V2 antagonista hatású. A WO 9715556 számú szabadalmi leírás szerint az I képletü vegyület előállítására a II képletü spiro/cis-4-(beta-morfolino-etiloxi)-ciklohexánl,3'-(5'-etoxi)-[37/]indol-2'[rH]-ont III képletü 2-metoxi-4-(N-t-butilaminokarbonil)-benzolszulfokloriddal reagáltatják kálium-/-butilát alkalmazásával tetrahidrofuránban.The subject of our invention is a new process for the preparation of N-(l,l-dimethylethyl)-4-[[5'-ethoxy-4-cw-[2(4-morpholino)-ethoxy]-2'-oxospiro [cyclohexane-1,3'- [3Z/]indole]-1' (2' 77)-y1]-sulfonyl]-3-methoxybenzamide (SR 121463) of formula I and its salts, which substance has vasopressin V2 antagonist activity. According to patent specification WO 9715556, to prepare the compound of formula I, spiro/cis-4-(beta-morpholinoethyloxy)cyclohexanel,3'-(5'-ethoxy)-[37/]indol-2'[rH]-one of formula II is reacted with 2-methoxy-4-(N-t-butylaminocarbonyl)benzenesulfonyl chloride of formula III using potassium-t-butylate in tetrahydrofuran.
Az eljárás a felhasznált oldószer (tetrahidrofurán) és az alkalmazott hőmérséklet (-60 °C -40 °C között) miatt üzemi körülmények között csak nehezen valósítható meg, a termelés gyenge, a termék szennyezett, tisztítása többszöri átkristályosítást igényel.Due to the solvent used (tetrahydrofuran) and the temperature used (between -60 °C and -40 °C), the process is difficult to implement under operational conditions, the production is poor, the product is contaminated, and its purification requires multiple recrystallizations.
Meglepő módon azt találtuk, hogy a reakció dimetil-szulfoxidban szobahőmérsékleten való keveréssel igen jó termeléssel (85 - 92%) végrehajtható. A reakcióelegy feldolgozása egyszerű, míg az eredeti eljárásban a terméket extrahálással nyerték ki, addig ezen eljárásban vízzel hígítva a reakcióelegyet a bázis csapadék formájában kiszűrhető. Az így nyert bázis tisztasága 93 - 96 %-os, belőle a kívánalmaknak megfelelő tisztaságú só képezhető.Surprisingly, we found that the reaction can be carried out in dimethyl sulfoxide at room temperature with stirring in very good yield (85 - 92%). The workup of the reaction mixture is simple, while in the original process the product was obtained by extraction, in this process the reaction mixture can be filtered off as a precipitate by diluting with water. The purity of the base thus obtained is 93 - 96%, and a salt of the desired purity can be formed from it.
Fentieknek megfelelően találmányunk tárgya eljárás I képletü vegyület és sói előállítására II és III képletü vegyület reagáltatásával azzal jellemezve, hogy a reakciót dimetil-szulfoxidban, 10-40 °C-on, előnyösen szobahőmérsékleten végezzük, majd a kapott I képletü bázist ismert módon sójává alakítjuk.Accordingly, the subject of our invention is a process for preparing a compound of formula I and its salts by reacting a compound of formula II and III, characterized in that the reaction is carried out in dimethyl sulfoxide at 10-40 °C, preferably at room temperature, and then the base of formula I obtained is converted into its salt in a known manner.
A találmányunk szerinti eljárást az alábbi példákkal illusztráljuk.The process according to our invention is illustrated by the following examples.
.példa:.example:
180 ml dimetil-szulfoxidban 26,7 g kálium-/-butilátot oldunk. 10 perc keverés után 74,9 g II képletű vegyületet adunk 20 - 25 °C között az elegyhez, majd teljes oldódásig keverjük. Ezután gyors ütemben 25 °C alatt III képletű vegyületet adagolunk az elegyhez. A kapott világosbarna szuszpenziót 1,5 órán át keverjük 25 °C-on, majd 700 ml jeges vízzel megbontjuk. A csapadékot 1 óra keverés után szűrjük, 2x500 ml vízzel felszuszpendálva mossuk. Alapos leszívatás után 2x 100 ml 96 %-os etanollal mossuk. 117 g 95,2 %-os hatóanyag tartalmú (HPLC) I. képletű vegyületet kapunk. A termelés 90,8 %.26.7 g of potassium-/-butylate are dissolved in 180 ml of dimethyl sulfoxide. After stirring for 10 minutes, 74.9 g of compound of formula II are added to the mixture between 20 - 25 °C, then stirred until complete dissolution. Then, compound of formula III is added to the mixture at a rapid rate below 25 °C. The resulting light brown suspension is stirred for 1.5 hours at 25 °C, then dissolved with 700 ml of ice water. After stirring for 1 hour, the precipitate is filtered, suspended in 2x500 ml of water and washed. After thorough suction, it is washed with 2x100 ml of 96% ethanol. 117 g of compound of formula I with an active ingredient content of 95.2% (HPLC) are obtained. The yield is 90.8%.
. példaexample
Mól I. képletű bázist 3-5-szörös mennyiségű etanolban szuszpendálunk és 1.05-1 mól savat adunk a rendszerhez. Oldódás után az oldatot csontszénnel derítjük, szűrjük. Az oldatból lehűtésre kivált sót szűrjük, kevés hideg alkohollal fedjük, szárítjuk. Termelés 87-95% között mozog.Mole of base of formula I is suspended in 3-5 times the amount of ethanol and 1.05-1 mole of acid is added to the system. After dissolution, the solution is clarified with charcoal and filtered. The salt that precipitates from the solution upon cooling is filtered, covered with a little cold alcohol and dried. The yield ranges between 87-95%.
Dihidrogén-foszfát-monohidrát-só: Op.: 164.5°C Hidrogén-maleát-só: Op.: 184-185°CDihydrogen phosphate monohydrate salt: M.p.: 164.5°C Hydrogen maleate salt: M.p.: 184-185°C
Hidrogén-fumarát-só: Op.: 182-183°CHydrogen fumarate salt: M.p.: 182-183°C
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0201548A HUP0201548A3 (en) | 1999-07-15 | 2000-07-13 | Process for the preparation of n-(1,1-dimethylethyl)-4-[[5'-ethoxy-4-cis[2-(4-morfolino)ethoxy]-2'-oxospiro[cyclohexan-1,3'[h]indol]1'(2'h)-yl]-sulfonyl]-3-methoxybenzamide and its salts |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9902376A HUP9902376A3 (en) | 1999-07-15 | 1999-07-15 | Process for producing n-(1,1-dimethyl)-4-[[s'-ethoxi-4-cis-[2-(4-morpholino)-ethoxi]-2'-oxospiro[cyclohexane-1,3'-[3h]indole]-1'(2'h)yl]-sulfonyl]-3-methoxybenzamide and its salts |
| HU0201548A HUP0201548A3 (en) | 1999-07-15 | 2000-07-13 | Process for the preparation of n-(1,1-dimethylethyl)-4-[[5'-ethoxy-4-cis[2-(4-morfolino)ethoxy]-2'-oxospiro[cyclohexan-1,3'[h]indol]1'(2'h)-yl]-sulfonyl]-3-methoxybenzamide and its salts |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HUP0201548A2 true HUP0201548A2 (en) | 2002-09-28 |
| HUP0201548A3 HUP0201548A3 (en) | 2003-03-28 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HU0201548A HUP0201548A3 (en) | 1999-07-15 | 2000-07-13 | Process for the preparation of n-(1,1-dimethylethyl)-4-[[5'-ethoxy-4-cis[2-(4-morfolino)ethoxy]-2'-oxospiro[cyclohexan-1,3'[h]indol]1'(2'h)-yl]-sulfonyl]-3-methoxybenzamide and its salts |
Country Status (1)
| Country | Link |
|---|---|
| HU (1) | HUP0201548A3 (en) |
-
2000
- 2000-07-13 HU HU0201548A patent/HUP0201548A3/en unknown
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| Publication number | Publication date |
|---|---|
| HUP0201548A3 (en) | 2003-03-28 |
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