CA2502935A1 - Preparation of codeine from morphine - Google Patents
Preparation of codeine from morphine Download PDFInfo
- Publication number
- CA2502935A1 CA2502935A1 CA002502935A CA2502935A CA2502935A1 CA 2502935 A1 CA2502935 A1 CA 2502935A1 CA 002502935 A CA002502935 A CA 002502935A CA 2502935 A CA2502935 A CA 2502935A CA 2502935 A1 CA2502935 A1 CA 2502935A1
- Authority
- CA
- Canada
- Prior art keywords
- hydrocarbon solvent
- codeine
- approximately
- set forth
- morphine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 title claims abstract description 87
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 title claims abstract description 64
- 229960004126 codeine Drugs 0.000 title claims abstract description 51
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 229960005181 morphine Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 34
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 33
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 33
- 150000002430 hydrocarbons Chemical class 0.000 claims abstract description 33
- 239000002904 solvent Substances 0.000 claims abstract description 33
- 239000011541 reaction mixture Substances 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000012022 methylating agents Substances 0.000 claims abstract description 15
- 238000010992 reflux Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- HGPQAWTZLJXCTC-SSTWWWIQSA-N (4r,4ar,7s,7ar,12bs)-7,9-dimethoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline Chemical compound C([C@@H](N(CC1)C)[C@@H]2C=C[C@@H]3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 HGPQAWTZLJXCTC-SSTWWWIQSA-N 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 8
- 239000011707 mineral Substances 0.000 claims abstract description 8
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 8
- 150000007524 organic acids Chemical class 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 101
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- 239000012071 phase Substances 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- ZMGDXJGLGYNTSM-UHFFFAOYSA-N ethanolate;trimethyl(phenyl)azanium Chemical group CC[O-].C[N+](C)(C)C1=CC=CC=C1 ZMGDXJGLGYNTSM-UHFFFAOYSA-N 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 9
- 239000008346 aqueous phase Substances 0.000 claims description 7
- MQAYPFVXSPHGJM-UHFFFAOYSA-M trimethyl(phenyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)C1=CC=CC=C1 MQAYPFVXSPHGJM-UHFFFAOYSA-M 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000008096 xylene Substances 0.000 claims description 5
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims 2
- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 claims 1
- WRRSFOZOETZUPG-FFHNEAJVSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;hydrate Chemical compound O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC WRRSFOZOETZUPG-FFHNEAJVSA-N 0.000 description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 239000002002 slurry Substances 0.000 description 11
- 230000001035 methylating effect Effects 0.000 description 10
- 238000007069 methylation reaction Methods 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 3
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 238000004042 decolorization Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000004081 narcotic agent Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 241000628997 Flos Species 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 206010038584 Repetitive strain injury Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- -1 ethoxide anion Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000012066 reaction slurry Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical compound O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 description 1
- HADKRTWCOYPCPH-UHFFFAOYSA-M trimethylphenylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C1=CC=CC=C1 HADKRTWCOYPCPH-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/274,702 | 2002-10-21 | ||
| US10/274,702 US6579985B1 (en) | 2002-10-21 | 2002-10-21 | Preparation of codeine from morphine |
| PCT/US2003/032698 WO2004037826A2 (en) | 2002-10-21 | 2003-10-14 | Preparation of codeine from morphine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2502935A1 true CA2502935A1 (en) | 2004-05-06 |
Family
ID=23049276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002502935A Abandoned CA2502935A1 (en) | 2002-10-21 | 2003-10-14 | Preparation of codeine from morphine |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US6579985B1 (enExample) |
| EP (1) | EP1560833B1 (enExample) |
| JP (1) | JP2006505588A (enExample) |
| CN (1) | CN1692117A (enExample) |
| AT (1) | ATE356819T1 (enExample) |
| AU (1) | AU2003279287B2 (enExample) |
| CA (1) | CA2502935A1 (enExample) |
| DE (1) | DE60312543T2 (enExample) |
| ES (1) | ES2282689T3 (enExample) |
| MX (1) | MXPA05004162A (enExample) |
| WO (1) | WO2004037826A2 (enExample) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6949645B1 (en) | 2004-05-20 | 2005-09-27 | Acura Pharmaceuticals, Inc. | Process for the production of opiates |
| US6972332B1 (en) * | 2004-05-20 | 2005-12-06 | Acura Pharmaceuticals, Inc. | Process for the production of opiates |
| WO2008022285A1 (en) * | 2006-08-16 | 2008-02-21 | Auspex Pharmaceuticals, Inc. | Preparation and utility of opioid analgesics |
| CN105247038B (zh) * | 2013-03-15 | 2021-08-27 | 小利兰·斯坦福大学托管委员会 | 产生苄基异喹啉生物碱(bia)的微生物及其制备和使用方法 |
| CN112410379B (zh) | 2013-11-04 | 2024-12-31 | 小利兰·斯坦福大学托管委员会 | 产生苄基异喹啉生物碱(bia)前体的微生物以及制备和使用所述前体的方法 |
| JP7266966B2 (ja) | 2015-05-08 | 2023-05-01 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | エピメラーゼ及びベンジルイソキノリンアルカロイドを産生する方法 |
| CN120399912A (zh) | 2019-03-08 | 2025-08-01 | 小利兰·斯坦福大学托管委员会 | 产生莨菪烷生物碱(ta)的非植物宿主细胞及其制备和使用方法 |
| CN110261194B (zh) * | 2019-06-06 | 2022-02-22 | 深圳砺剑防卫技术有限公司 | 一种毒品探测设备校验品的制备方法及毒品探测设备校验品 |
| TR2021022252A2 (tr) * | 2021-12-31 | 2022-01-21 | Toprak Mahsulleri Ofisi Genel Mueduerluegue | Kodei̇n kamphosulfonat üreti̇mi̇ne dai̇r yeni̇ bi̇r yöntem |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3679327D1 (de) * | 1986-11-25 | 1991-06-20 | Council Scient Ind Res | Verfahren zur herstellung von codein aus morphin. |
| CS277517B6 (sk) * | 1990-12-12 | 1993-02-17 | Slovakofarma S P | Spósob čistenia kodeinu připraveného metylizáciou morfínu |
| US6204337B1 (en) * | 1996-11-19 | 2001-03-20 | The Board Of Regents Of The University And Community College System Of Neveda | Solid-phase synthesis of codeine from morphine |
-
2002
- 2002-10-21 US US10/274,702 patent/US6579985B1/en not_active Expired - Lifetime
-
2003
- 2003-10-14 MX MXPA05004162A patent/MXPA05004162A/es active IP Right Grant
- 2003-10-14 CA CA002502935A patent/CA2502935A1/en not_active Abandoned
- 2003-10-14 EP EP03770770A patent/EP1560833B1/en not_active Expired - Lifetime
- 2003-10-14 DE DE60312543T patent/DE60312543T2/de not_active Expired - Fee Related
- 2003-10-14 AT AT03770770T patent/ATE356819T1/de not_active IP Right Cessation
- 2003-10-14 JP JP2004546881A patent/JP2006505588A/ja not_active Withdrawn
- 2003-10-14 CN CN200380100724.3A patent/CN1692117A/zh active Pending
- 2003-10-14 ES ES03770770T patent/ES2282689T3/es not_active Expired - Lifetime
- 2003-10-14 WO PCT/US2003/032698 patent/WO2004037826A2/en not_active Ceased
- 2003-10-14 AU AU2003279287A patent/AU2003279287B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004037826A3 (en) | 2004-07-01 |
| WO2004037826A2 (en) | 2004-05-06 |
| AU2003279287A1 (en) | 2004-05-13 |
| DE60312543T2 (de) | 2007-11-15 |
| US6579985B1 (en) | 2003-06-17 |
| EP1560833A2 (en) | 2005-08-10 |
| AU2003279287B2 (en) | 2009-01-29 |
| ES2282689T3 (es) | 2007-10-16 |
| CN1692117A (zh) | 2005-11-02 |
| ATE356819T1 (de) | 2007-04-15 |
| DE60312543D1 (de) | 2007-04-26 |
| JP2006505588A (ja) | 2006-02-16 |
| MXPA05004162A (es) | 2005-06-22 |
| EP1560833B1 (en) | 2007-03-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 20101014 |