LT3584B - Improved method for omeprazole synthesis - Google Patents
Improved method for omeprazole synthesis Download PDFInfo
- Publication number
- LT3584B LT3584B LTIP1711A LTIP1711A LT3584B LT 3584 B LT3584 B LT 3584B LT IP1711 A LTIP1711 A LT IP1711A LT IP1711 A LTIP1711 A LT IP1711A LT 3584 B LT3584 B LT 3584B
- Authority
- LT
- Lithuania
- Prior art keywords
- omeprazole
- process according
- aqueous phase
- methoxy
- naoh
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 18
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960000381 omeprazole Drugs 0.000 title claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 title abstract description 3
- 238000003786 synthesis reaction Methods 0.000 title abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000008346 aqueous phase Substances 0.000 claims abstract description 11
- -1 alkyl formate Chemical compound 0.000 claims abstract description 9
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002425 crystallisation Methods 0.000 claims abstract description 6
- 230000008025 crystallization Effects 0.000 claims abstract description 6
- 239000011541 reaction mixture Substances 0.000 claims abstract description 5
- 239000012074 organic phase Substances 0.000 claims abstract description 4
- XURCIPRUUASYLR-UHFFFAOYSA-N Omeprazole sulfide Chemical compound N=1C2=CC(OC)=CC=C2NC=1SCC1=NC=C(C)C(OC)=C1C XURCIPRUUASYLR-UHFFFAOYSA-N 0.000 claims abstract description 3
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 10
- 239000000872 buffer Substances 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 230000003068 static effect Effects 0.000 claims description 2
- 238000004448 titration Methods 0.000 claims description 2
- 238000003541 multi-stage reaction Methods 0.000 claims 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Feeding, Discharge, Calcimining, Fusing, And Gas-Generation Devices (AREA)
Description
Šis išradimas susijęs su patobulintu 5-metoksi-2-[ (4metoksi-3,5-dimetil-2-piridinil)-metil] sulfinil-lH-benzimidazolo, pateikto tolesniame aprašyme ir išradimo apibrėžtyje supaprastintu pavadinimu omeprazolas, sintezės būdu.
Patente US-A-4 255 431 aprašytas omeprazolo gavimo būdas, apimantis 5-metoksi-2-[ (4-metoksi-3,5-dimetil-2piridinil)-metiltio] -ΙΗ-benzimidazolo metilchlorido tirpale reakcijos su m-chloroperoksibenzoine rūgštimi sradijas, gaunant omeprazolą ir m-chlorbenzoinę rūgštį.
Omeprazolas labai jautrus rūgščių poveikiui, todėl reaguojantis mišinys laikomas žemoje temperatūroje, siekiant išvengti per didelio skilimo reaguojančiame mišinyje.
Produktas išskiriamas, nufiltruojant m-chlorbenzoinę rūgštį, susidariusią reakcijos metu. Filtratas praskiedžiamas metilenchloridu, ekstrahuojamas natrio karbonato tirpalu, džiovinamas ir išgarinamas. Tokiu būdu gautas omeprazolas yra užterštas išeities medžiagomis ir šalutiniais produktais.
Šiame išradime pateikiamas patobulintas omeprazolo gavimo būdas, neturintis anksčiau žinomiems būdams būdingų trūkumų.
Tikslas pasiektas šiuo išradimu, besiskiriančiu tuo, kad 5-metoksi-2-[ (4-metoksi-3,5-dimetil-2-piridinil)metil-tio] -ΙΗ-benzimidazolo (žemiau vadinamo I junginys) sąveikos su m-chlorperoksibenzoine rūgštimi stadijos metilenchlorido tirpale vyksta esant praktiškai pastoviai pH apie 8,0-8,6; reakcijos mišinys ekstrahuojamas vandeniniu NaOH tirpalu; vandeninė fazė atskiriama nuo organinės fazes; prie vandeninės fazes pridedama alkilformato, dėl to kristalizuojasi omeprazolas.
Paprastai m-chlorperoksibenzoinės rūgšties imama 0, Ί1,4 molinių ekvivalentų I junginiui, pageidautina 0, ΟΙ, 2 molinių ekvivalentų.
Pagal vieną išradimo variantą, alkilformatas yra metilformatas arba etilformatas, priimtiniausias yra metilformatas.
Alkilformato paprastai imama 1,2-2,0 I junginio molinių ekvivalentų, geriau 1,5-1,8 molinių ekvivalentų.
Reikšmingas išradimo būdo bruožas yra tas, kad nesureagavęs sulfidas nepereina į vandeninę fazę, ekstrahuojant vandeniniu NaOH tirpalu.
Kitas reikšmingas išradimo būdo bruožas yra tas, kad mchlorbenzoinė rūgštis nesikristalizuoja, pridėjus į vandennę fazę metilformato, todėl nėra būtinumo nufiltruoti m-chlorbenzoinę rūgštį ankstesnėje stadijoje.
Reaguojančio mišinio pH galima palaikyti intervale 8,08,6, atliekant pH statinį titravimą su NaOH tirpalu, arba naudojant buferį. Tinkamiausi buferiai yra natrio bikarbonatas ir kalio bikarbonatas.
Reikšmingas išradimo būdo privalumas yra tas, kad reakcija vyksta metilenchlorido organinėje fazėje, o reakcijos metu susidariusi m-chlorbenzoinė rūgštis yra vandeninėje fazėje, turinčioje buferį (tuomet, kai buferis naudojamas). Todėl susidarantis omeprazolas nekontaktuoja su rūgštimi ir reakcija gali būti atliekama temperatūroje, aukštesnėje kaip 0°C.
Pagal vieną išradimo variantą vandeninės NaOH fazės pH išlaikoma aukštesnė, maždaug 12.
Pagal kitą išradimo variantą omeprazolo kristalizacija vykdoma esant pH aukštesnei už 9.
Išradimą iliustruoja žemiau pateiktas neapriboj antis pavyzdys.
Pavyzdys
5-metoksi-2-[ (4-metoksi-3,5-dimetil-2-piridinil)-metiltio] -lH-benzimidazolas (16,2 g; 0,0492 mol) reaguoja su m-chlorperoksibenzoine rūgštimi (13,6 g; 0,0537 mol) metilenchloride, veikiančiame kaip tirpiklis, esant pH 8,6, kuri palaikoma reakcijoje dalyvaujančio kalio bikarbonato (5,6 g; 0,056 mol), veikiančio kaip buferis. Temperatūra, pridedant reagentus, palaikoma apie 0°C.
Pridedamas ištirpintas NaOH iki pHl2 ir atskiriama metilenchlorido fazė. Į vandeninę fazę sudedamas metilformatas (4,7 g) ir palaikoma pH apie 9, dėl to kristalizuojasi omeprazolas. Kristalai nufiltruojami ir plaunami vandeniu ir metanoliu, esant temperatūrai apie 0°C. Nuplauti kristalai džiovinami vakuume. Išeiga 15,6 g (92%) .
Claims (9)
- IŠRADIMO APIBRĖŽTIS ·1. Patobulintas omeprazolo gavimo būdas, besiskiriantis tuo, kad stadijomis reaguoja 5-metoksi2-[ (4-metoksi-3,5-dimetil-2-piridinil)-metiltio] -lH-benzimidazolas (I junginys) su m-chlorperoksibenzoine rūgštimi metileno chlorido tirpale, procesas vyksta esant praktiškai pastoviai pH apie 8,0-8,6; reakcijos mišinį ekstrahuoja vandeniniu NaOH tirpalu;- vandeninę fazę atskiria nuo organinės fazės; į vandeninę fazę prideda alkilformato, dėl to kristalizuojasi omeprazolas.
- 2. Būdas pagal 1 punktą, besi skiria n. tis tuo, kad m-chloroperoksibenzoinės rūgšties ima 0,7-1,4,geriau 0,9-1,2, (I) junginio molinių ekvivalentų.
- 3. Būdas pagal 1 arba 2 punktą, besiskiriantis tuo, kad alkilformatas yra metilformatas.
- 4. Būdas pagal 1-3 punktus, besiskiriantis tuo, kad reakcijos mišinio pH palaiko intervale 8,0-8,6, atliekant statinį pH titravimą su NaOH.
- 5. Būdas pagal 1-4 punktus, besiskiriantis tuo, kad reakcijos mišinio pH palaiko intervale 8,0-8,6, naudojant buferį.
- 6. Būdas pagal 5 punktą, besiskiriantis tuo, kad buferiu naudoja natrio bikarbonatą arba kalio bikarbonatą.
- 7. Būdas pagal i - 6 punktus, 'besiskiriant i s tuo, kad vandeninės 'NaOH fazės p K. išlaiko: maždaug virš 12.
- 8. Būdas pagal 1-7 punktus, b e s i s k i t i s tuo, kad alkilformato prideda 1,2-2, 1,5-1,8, (I) junginio molinių ekvivalentų.
- 9. Būdas pagal 1-8 punktus, b e s i s k i t i s tuo, kad omeprazolo kristalizaciją esant pH virš 9.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9002043A SE9002043D0 (sv) | 1990-06-07 | 1990-06-07 | Improved method for synthesis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| LTIP1711A LTIP1711A (en) | 1995-07-25 |
| LT3584B true LT3584B (en) | 1995-12-27 |
Family
ID=20379708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LTIP1711A LT3584B (en) | 1990-06-07 | 1993-12-30 | Improved method for omeprazole synthesis |
Country Status (42)
| Country | Link |
|---|---|
| US (1) | US5386032A (lt) |
| EP (1) | EP0533752B1 (lt) |
| JP (1) | JP2993122B2 (lt) |
| KR (1) | KR0178045B1 (lt) |
| CN (1) | CN1040536C (lt) |
| AP (1) | AP216A (lt) |
| AT (1) | ATE162790T1 (lt) |
| AU (1) | AU640246B2 (lt) |
| BG (1) | BG61265B1 (lt) |
| CA (1) | CA2083605C (lt) |
| CZ (1) | CZ279928B6 (lt) |
| DE (1) | DE69128832T2 (lt) |
| DK (1) | DK0533752T3 (lt) |
| DZ (1) | DZ1504A1 (lt) |
| EG (1) | EG19392A (lt) |
| ES (1) | ES2113378T3 (lt) |
| FI (1) | FI102967B (lt) |
| GR (1) | GR3026642T3 (lt) |
| HK (1) | HK1003831A1 (lt) |
| HR (1) | HRP920770B1 (lt) |
| HU (1) | HU214323B (lt) |
| IE (1) | IE911845A1 (lt) |
| IL (1) | IL98274A (lt) |
| IS (1) | IS1752B (lt) |
| LT (1) | LT3584B (lt) |
| LV (1) | LV10271B (lt) |
| MA (1) | MA22171A1 (lt) |
| NO (1) | NO300541B1 (lt) |
| NZ (1) | NZ238224A (lt) |
| PL (1) | PL165433B1 (lt) |
| PT (1) | PT97873B (lt) |
| RO (1) | RO111366B1 (lt) |
| RU (1) | RU2061693C1 (lt) |
| SA (1) | SA91120027B1 (lt) |
| SE (1) | SE9002043D0 (lt) |
| SG (1) | SG48053A1 (lt) |
| SK (1) | SK278505B6 (lt) |
| TN (1) | TNSN91042A1 (lt) |
| UA (1) | UA32524C2 (lt) |
| WO (1) | WO1991018895A1 (lt) |
| YU (1) | YU47570B (lt) |
| ZA (1) | ZA913779B (lt) |
Families Citing this family (62)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE521100C2 (sv) * | 1995-12-15 | 2003-09-30 | Astra Ab | Förfarande för framställning av en bensimidazolförening |
| US6645988B2 (en) | 1996-01-04 | 2003-11-11 | Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US6699885B2 (en) | 1996-01-04 | 2004-03-02 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and methods of using same |
| US6489346B1 (en) * | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| SE508669C2 (sv) * | 1996-04-26 | 1998-10-26 | Astra Ab | Nytt förfarande |
| SK283805B6 (sk) * | 1996-09-09 | 2004-02-03 | Slovakofarma, A. S. | Spôsob prípravy omeprazolu |
| SE510666C2 (sv) * | 1996-12-20 | 1999-06-14 | Astra Ab | Nya Kristallmodifikationer |
| US6437139B1 (en) | 1997-05-06 | 2002-08-20 | Pdi-Research Laboratories, Inc. | Synthesis of pharmaceutically useful pyridine derivatives |
| CA2204580A1 (en) * | 1997-05-06 | 1998-11-06 | Michel Zoghbi | Synthesis of pharmaceutically useful pyridine derivatives |
| KR100463031B1 (ko) * | 1997-05-26 | 2005-04-06 | 동아제약주식회사 | 5-메톡시-2-[3,5-디메틸-4-메톡시피리딜메틸)설피닐]-1h-벤즈이미다졸의신규제조방법 |
| SE510650C2 (sv) * | 1997-05-30 | 1999-06-14 | Astra Ab | Ny förening |
| SE510643C2 (sv) * | 1997-06-27 | 1999-06-14 | Astra Ab | Termodynamiskt stabil omeprazol natrium form B |
| ES2137862B1 (es) * | 1997-07-31 | 2000-09-16 | Intexim S A | Preparacion farmaceutica oral que comprende un compuesto de actividad antiulcerosa y procedimiento para su obtencion. |
| SE9704183D0 (sv) | 1997-11-14 | 1997-11-14 | Astra Ab | New process |
| US6174548B1 (en) | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6096340A (en) * | 1997-11-14 | 2000-08-01 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| SI20019A (sl) * | 1998-07-13 | 2000-02-29 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Izboljšan postopek sinteze 5-metoksi -2-/(4-metoksi-3,5-dimetil-2-piridil)metil/ sulfinil-1H-benzimidazola |
| US6191148B1 (en) | 1998-08-11 | 2001-02-20 | Merck & Co., Inc. | Omerazole process and compositions thereof |
| US6166213A (en) * | 1998-08-11 | 2000-12-26 | Merck & Co., Inc. | Omeprazole process and compositions thereof |
| US6733778B1 (en) | 1999-08-27 | 2004-05-11 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| UA72748C2 (en) * | 1998-11-10 | 2005-04-15 | Astrazeneca Ab | A novel crystalline form of omeprazole |
| IL142703A (en) | 1998-11-10 | 2006-04-10 | Astrazeneca Ab | Crystalline form of omeprazole |
| US6362202B1 (en) | 1999-03-02 | 2002-03-26 | Sepracor Inc. | Methods and compositions using (−) norcisapride in combination with proton pump inhibitors or H2 receptor antagonists |
| US6353005B1 (en) | 1999-03-02 | 2002-03-05 | Sepracor, Inc. | Method and compositions using (+) norcisapride in combination with proton pump inhibitors or H2 receptor antagonist |
| US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
| US6316020B1 (en) | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
| US6780880B1 (en) | 1999-08-26 | 2004-08-24 | Robert R. Whittle | FT-Raman spectroscopic measurement |
| US6369087B1 (en) * | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6312712B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
| US6326384B1 (en) | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
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| DE19951960C2 (de) * | 1999-10-28 | 2002-06-27 | Gruenenthal Gmbh | Verfahren zur Herstellung als Ulkustherapeutika geeigneter Benzimidazol-Derivate |
| SK10792003A3 (sk) | 2001-02-02 | 2004-07-07 | Teva Pharmaceutical Industries Ltd. | Spôsob výroby substituovaných 2-(2-pyridylmetyl) sulfinyl -1H-benzimidazolov |
| KR100783020B1 (ko) * | 2001-03-23 | 2007-12-07 | 동아제약주식회사 | 2-메틸클로라이드 피리딘 유도체 및 이를 이용한 벤즈이미다졸 유도체의 제조 방법 |
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| IN148930B (lt) * | 1977-09-19 | 1981-07-25 | Hoffmann La Roche | |
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1990
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| US4255431A (en) | 1978-04-14 | 1981-03-10 | Aktiebolaget Hassle | Gastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion |
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