CS277517B6 - Process for purifying codeine being prepared by morphine methylation - Google Patents
Process for purifying codeine being prepared by morphine methylation Download PDFInfo
- Publication number
- CS277517B6 CS277517B6 CS906197A CS619790A CS277517B6 CS 277517 B6 CS277517 B6 CS 277517B6 CS 906197 A CS906197 A CS 906197A CS 619790 A CS619790 A CS 619790A CS 277517 B6 CS277517 B6 CS 277517B6
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- codeine
- aqueous
- solution
- methylation
- morphine
- Prior art date
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- 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 57
- 229960004126 codeine Drugs 0.000 title claims abstract description 28
- 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 28
- 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 18
- 230000011987 methylation Effects 0.000 title claims abstract description 10
- 238000007069 methylation reaction Methods 0.000 title claims abstract description 10
- 229960005181 morphine Drugs 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title claims description 9
- 239000000243 solution Substances 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 4
- 150000007524 organic acids Chemical class 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- DKSZLDSPXIWGFO-BLOJGBSASA-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;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 claims description 5
- 229960004415 codeine phosphate Drugs 0.000 claims description 5
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 239000002244 precipitate Substances 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract description 2
- 230000008025 crystallization Effects 0.000 abstract description 2
- 238000000605 extraction Methods 0.000 abstract 2
- 238000004090 dissolution Methods 0.000 abstract 1
- IBIRZFNPWYRWOG-UHFFFAOYSA-N phosphane;phosphoric acid Chemical compound P.OP(O)(O)=O IBIRZFNPWYRWOG-UHFFFAOYSA-N 0.000 abstract 1
- 238000001556 precipitation Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 239000006227 byproduct Substances 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- GQBWEWWRCVJAEL-OLZVCHQQSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3,7-dimethyl-1,2,4,4a,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@](C)(O)[C@@H]1OC1=C2C3=CC=C1OC GQBWEWWRCVJAEL-OLZVCHQQSA-N 0.000 description 1
- HGPQAWTZLJXCTC-UHFFFAOYSA-N 6-Methylcodeine Natural products COC1C=CC2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 HGPQAWTZLJXCTC-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- FDKWIYSUAOSQFH-WMRVMTBBSA-N ClC(=CCl)OC=1C=CC=2C[C@@H]3[C@@H]4C=C[C@@H]([C@H]5[C@@]4(C=2C=1O5)CCN3C)O Chemical class ClC(=CCl)OC=1C=CC=2C[C@@H]3[C@@H]4C=C[C@@H]([C@H]5[C@@]4(C=2C=1O5)CCN3C)O FDKWIYSUAOSQFH-WMRVMTBBSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 235000008753 Papaver somniferum Nutrition 0.000 description 1
- 240000001090 Papaver somniferum Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Vynález rieši přípravu kodeinu v liekopisnej kvalitě bez vediajších látok vznikajúcich pri metylizácii morfínu extrakciou připraveného kodeinu v organickom rozpúšťadle do vodného roztoku anorganické] alebo organickej kyseliny v rozmedzí hodnot pH 7 až 5,4 s výhodou v rozmedzí 6,8 až 6,0, po oddělení vodnej vrstvy jej extrakciou chlórovaným organickým rozpúšťadlom, vyzrážaním kodeinovej bázy, jej rozpuštěním v etanole a kryštalizáciou z vodnoalkoholického roztoku kyseliny fosforečnej vo formě fosforečnanu kodeinu v liekopisnej kvalitě podl’a požiadavky německého liekopisu DAB 9. Oblasťou použitia je farmaceutický priemysel.The invention addresses the preparation of codeine in pharmacopoeia quality without the side-effects of methylation morphine by extraction of the produced codeine in an organic solvent to an aqueous solution inorganic] or organic acid in pH ranges from 7 to 5.4, preferably within the range 6.8 to 6.0, after separation of the aqueous layer by extraction with a chlorinated organic solvent, precipitation of codeine base, dissolution thereof in ethanol and crystallization from water-alcohol phosphoric acid solution Phosphine Phosphate Pharmacopoeia requirements of the German DAB 9 pharmacopoeia use is the pharmaceutical industry.
Description
Spósob čistenia kodeinu připraveného metylizáciou morfinuMethod for purifying codeine prepared by methylation of morphine
Oblast technikyField of technology
Vynález sa týká spósobu výroby chemických substanci!, konkrétné čistenia kodeinu připraveného metylizáciou morfinu.The invention relates to a process for the production of chemical substances, in particular to the purification of codeine prepared by the methylation of morphine.
Doteraiší stavCurrent state
Požiadavky liekopisných kvalitatívnych parametrov farmaceutických substanci! připravených synteticky obmedzujú alebo úplné vylučujú přítomnost vedlajších látok.Requirements for pharmacopoeial quality parameters of pharmaceutical substances! prepared synthetically reduce or completely eliminate the presence of by-products.
Kodein, ako účinná látka pre výrobu farmaceutických prípravkov je v prevažnej miere vyrábaná synteticky metylizáciou morfinu izolovaného z toboliek maku. Vedlajšie látky vznikájúce pri metylizácii morfinu boli identifikované. Přítomnost 6-metylkodeinu bola popísaná S. Pfeiferom: Pharmazie 18, 409,Codeine, as an active ingredient in the manufacture of pharmaceutical preparations, is predominantly produced synthetically by the methylation of morphine isolated from poppy capsules. By-products from the methylation of morphine have been identified. The presence of 6-methylcodeine has been described by S. Pfeifer: Pharmazie 18, 409,
1963, ktorý ho izoloval viacnásobnou kryštalizáciou kodeinu připraveného metylizáciou. Demina, L.G. a spol.: Ž.prikl.chim. 38, 399, 1965 popísali izoláciu alfa-metylmorfínmetínu izolovaného kombináciou delenia na ionomeničoch a frakčnej kryštalizácie síranových solí. Čs. autorské osvedčenie č. 223 100 popisuje přítomnost chlórovaných 2-0-alkyl a 3-0-alkenylderivátov a rieši spósob čistenia kodeinu syntetizovaného z morfinu extrakciou vodného roztoku solí kodeinu chlórovaným organickým rozpúštadlom v rozmedzí pH 4,0 až 5,5. Z vyššie popísaných postupov pre priemyselné čistenie kodeinu je vhodný len postup podlá čs. autorského osvedčenia č. 223 100. v priemyselne vyrábanom kodeine a jeho soliach čištěných postupom podlá čs. autorského osvedčenia č. 223 100 bola dokázaná přítomnost chlórovaného 3-0-(l,2-dichlórvinyl)-morfín.1963, which isolated it by multiple crystallization of codeine prepared by methylation. Demina, L.G. et al .: Ž.prikl.chim. 38, 399, 1965 described the isolation of alpha-methylmorpholinemetin isolated by a combination of separation on ion exchangers and fractional crystallization of sulfate salts. Cs. Author's Certificate No. 223 100 describes the presence of chlorinated 2-O-alkyl and 3-O-alkenyl derivatives and solves the process for purifying codeine synthesized from morphine by extracting an aqueous solution of codeine salts with a chlorinated organic solvent in the range of pH 4.0 to 5.5. Of the procedures described above for the industrial purification of codeine, only the procedure according to MS. author's certificate No. 223 100. in industrially produced codeine and its salts purified by the process according to MS. The presence of chlorinated 3-O- (1,2-dichlorovinyl) -morphine was proved by the author's certificate No. 223 100.
Podstata vynálezuThe essence of the invention
Čistenie kodeinu a jeho solí od vyššie popísaných vedlejších látok bolo vyriešené postupom, ktorého podstata spočívá v tom, že sa kodein extrahuje z organického rozpúštadla, s výhodou z toluénového roztoku postupným přidáváním vodného roztoku anorganickej alebo organickej kyseliny s počtom uhlíkov 1 alebo 2 v rozmedzí hodnot pH 7,0 až 5,4, s výhodou v rozmedzí 6,8 až 6,0, vodný roztok po oddělení toluénovej vrstvy sa extrahuje chlórovaným organickým rozpúštadlom, s výhodou trichlóretylénom, z vodnéj vrstvy sa vyzráža kodeinová báza úpravou pH v rozmedzí 8 až 9, po oddělení sa kodeinová báza rozpustí v 3 až 5-násobnom množstve vodného alebo vodnoalkoholického roztoku kyseliny fosforečnej, pH roztoku sa upraví v rozmedzí 4,0 až 4,5 a nechá sa vykryštalizovat fosforečnan kodeinu, z ktorého po oddělení sa uvolní kodeinová báza bez vedlajších látok.Purification of codeine and its salts from the above-described by-products has been solved by extracting codeine from an organic solvent, preferably a toluene solution, by gradually adding an aqueous solution of an inorganic or organic acid having 1 or 2 carbons in the range of values. pH 7.0 to 5.4, preferably in the range of 6.8 to 6.0, the aqueous solution after separation of the toluene layer is extracted with a chlorinated organic solvent, preferably trichlorethylene, the codeine base is precipitated from the aqueous layer by adjusting the pH in the range of 8 to 9, after separation, the codeine base is dissolved in 3 to 5 times the amount of aqueous or aqueous-alcoholic phosphoric acid solution, the pH of the solution is adjusted to 4.0 to 4.5 and the codeine phosphate is allowed to crystallize, from which the codeine base is released after separation. without by-products.
Podrobnosti postupu podlá vynálezu sú zřejmé z příkladu prevedenia.The details of the process according to the invention are apparent from the exemplary embodiment.
Příklad provedeniaExemplary embodiment
Příklad 1Example 1
K 500 1 toluénového roztoku kodeinu připraveného metylizáciou morfínu s obsahom 35 kg kodeinovej bázy sa postupné za miešania přidává 160 1 3,5%ného vodného roztoku kyseliny mravčej, potom sa zmeria pH vodnej vrstvy a upraví sa dalším přidáním na 10 až 20 1 vodného roztoku kys. mravčej na hodnotu 6,8. Vodná vrstva sa oddělí, s vodnou parou sa oddestilujú zbytky toluénu a extrahuje sa trikrát 50 1 trichlóretylénu za miešania po dobu vždy 10 až 15 minút. Vodný roztok sa prefúkaním vodnou parou zbaví zbytkov trichlóretylénu a přečistí sa s 0,5 kg aktívneho uhlia. Z vodného roztoku mravčanu kodeinu sa vyzráža kodeinová báza čpavkovou vodou do pH 8,5. Kodeinová báza sa odfiltruje, vysuší. Získá sa cca 32 kg kodeinovej bázy, zbavenej vedlajších produktov metylizácie, ktorá sa rozpustí v 90 1 etanolu, přidá sa 20 1 40%ného vodného roztoku kyseliny fosforečnej a nechá sa vykryštalizovaů fosforečnan kodeinu pri pH 4,2. Vykryštalizovaný fosforečnan kodeinu sa odfiltruje, premyje 15 1 50%ného vodného etanolu a vysuší. Získá sa fosforečnan kodeinu vyhovujúci kvalitatívnymi parametrami německému liekopisu DAB 9 čistotou a farebnostou roztoku s obsahom 99,95 %.To 500 L of a toluene solution of codeine prepared by methylation of morphine containing 35 kg of codeine base was gradually added 160 L of a 3.5% aqueous formic acid solution with stirring, then the pH of the aqueous layer was measured and adjusted by further addition to 10 to 20 L of aqueous solution. formic acid to 6.8. The aqueous layer is separated, the residual toluene is distilled off with steam and extracted three times with 50 l of trichlorethylene with stirring for 10 to 15 minutes each time. The aqueous solution is stripped of trichlorethylene residues by steam blowing and purified with 0.5 kg of activated carbon. From an aqueous solution of codeine formate, codeine base is precipitated with ammonia water to pH 8.5. The codeine base is filtered off and dried. Approximately 32 kg of codeine base, free of methylation by-products, are obtained, which is dissolved in 90 l of ethanol, 20 l of a 40% strength aqueous solution of phosphoric acid are added and the codeine phosphate is allowed to crystallize at pH 4.2. The crystallized codeine phosphate is filtered off, washed with 15 l of 50% aqueous ethanol and dried. Codeine phosphate meeting the quality parameters of the German Pharmacopoeia DAB 9 is obtained with the purity and color of a solution containing 99.95%.
Využitelnost vynálezuApplicability of the invention
Vynález je využitelný vo farmaceutickom priemysle.The invention is useful in the pharmaceutical industry.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS906197A CS277517B6 (en) | 1990-12-12 | 1990-12-12 | Process for purifying codeine being prepared by morphine methylation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS906197A CS277517B6 (en) | 1990-12-12 | 1990-12-12 | Process for purifying codeine being prepared by morphine methylation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS619790A3 CS619790A3 (en) | 1992-08-12 |
| CS277517B6 true CS277517B6 (en) | 1993-02-17 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS906197A CS277517B6 (en) | 1990-12-12 | 1990-12-12 | Process for purifying codeine being prepared by morphine methylation |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS277517B6 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004037826A3 (en) * | 2002-10-21 | 2004-07-01 | Mallinckrodt Inc | Preparation of codeine from morphine |
| US20220154232A1 (en) * | 2013-03-15 | 2022-05-19 | The Board Of Trustees Of The Leland Stanford Junor University | Benzylisoquinoline Alkaloids (BIA) Producing Microbes, and Methods of Making and Using the Same |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100396685C (en) * | 2003-09-25 | 2008-06-25 | 中国医药集团总公司四川抗菌素工业研究所 | A new method of synthesizing codeine from morphine |
-
1990
- 1990-12-12 CS CS906197A patent/CS277517B6/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004037826A3 (en) * | 2002-10-21 | 2004-07-01 | Mallinckrodt Inc | Preparation of codeine from morphine |
| US20220154232A1 (en) * | 2013-03-15 | 2022-05-19 | The Board Of Trustees Of The Leland Stanford Junor University | Benzylisoquinoline Alkaloids (BIA) Producing Microbes, and Methods of Making and Using the Same |
Also Published As
| Publication number | Publication date |
|---|---|
| CS619790A3 (en) | 1992-08-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| IF00 | In force as of 2000-06-30 in czech republic | ||
| MM4A | Patent lapsed due to non-payment of fee |
Effective date: 20071212 |