US20050261500A1 - Process for the production of opiates - Google Patents
Process for the production of opiates Download PDFInfo
- Publication number
- US20050261500A1 US20050261500A1 US10/850,015 US85001504A US2005261500A1 US 20050261500 A1 US20050261500 A1 US 20050261500A1 US 85001504 A US85001504 A US 85001504A US 2005261500 A1 US2005261500 A1 US 2005261500A1
- Authority
- US
- United States
- Prior art keywords
- codeine
- morphine
- suspension
- solution
- hydrogencarbonate
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 55
- 238000004519 manufacturing process Methods 0.000 title description 9
- 229940127240 opiate Drugs 0.000 title description 5
- 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 claims abstract description 127
- 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 claims abstract description 77
- 229960004126 codeine Drugs 0.000 claims abstract description 68
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims abstract description 68
- 229960005181 morphine Drugs 0.000 claims abstract description 60
- 239000000725 suspension Substances 0.000 claims abstract description 44
- 239000002904 solvent Substances 0.000 claims abstract description 39
- 239000004615 ingredient Substances 0.000 claims abstract description 29
- 239000012458 free base Substances 0.000 claims abstract description 20
- 239000012022 methylating agents Substances 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 230000001035 methylating effect Effects 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 240000001090 Papaver somniferum Species 0.000 claims abstract description 10
- 239000012141 concentrate Substances 0.000 claims abstract description 10
- 235000008753 Papaver somniferum Nutrition 0.000 claims abstract description 9
- 239000010902 straw Substances 0.000 claims abstract description 9
- 239000012442 inert solvent Substances 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 90
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 47
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- -1 aromatic halide Chemical class 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000011736 potassium bicarbonate Substances 0.000 claims description 8
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 8
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 8
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 8
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 150000008378 aryl ethers Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- ZNEOHLHCKGUAEB-UHFFFAOYSA-N trimethylphenylammonium Chemical class C[N+](C)(C)C1=CC=CC=C1 ZNEOHLHCKGUAEB-UHFFFAOYSA-N 0.000 claims description 3
- ZKLXUUYLEHCAMF-UUWFMWQGSA-N Oripavine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 ZKLXUUYLEHCAMF-UUWFMWQGSA-N 0.000 claims description 2
- ZKLXUUYLEHCAMF-UHFFFAOYSA-N Oripavine Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(O)C5=C4C23C1O5 ZKLXUUYLEHCAMF-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 3
- 125000001931 aliphatic group Chemical group 0.000 claims 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims 2
- 239000012046 mixed solvent Substances 0.000 claims 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 claims 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 1
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 35
- OROGSEYTTFOCAN-DNJOTXNNSA-O codeine(1+) Chemical compound C([C@H]1[C@H]([NH+](CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-O 0.000 description 63
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 239000002244 precipitate Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- MQAYPFVXSPHGJM-UHFFFAOYSA-M trimethyl(phenyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)C1=CC=CC=C1 MQAYPFVXSPHGJM-UHFFFAOYSA-M 0.000 description 15
- 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 description 12
- 229960004415 codeine phosphate Drugs 0.000 description 12
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 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 9
- HGPQAWTZLJXCTC-UHFFFAOYSA-N 6-Methylcodeine Natural products COC1C=CC2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 HGPQAWTZLJXCTC-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- 239000008896 Opium Substances 0.000 description 7
- 239000006227 byproduct Substances 0.000 description 7
- 229960001027 opium Drugs 0.000 description 7
- 229940062627 tribasic potassium phosphate Drugs 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 6
- 229940011051 isopropyl acetate Drugs 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000007069 methylation reaction Methods 0.000 description 6
- 125000001453 quaternary ammonium group Chemical group 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000005909 Kieselgur Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
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- 229930013053 morphinan alkaloid Natural products 0.000 description 5
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
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- 239000007858 starting material Substances 0.000 description 3
- UHAUNWBFEUXSNO-UHFFFAOYSA-N (2,3,4-trimethylphenyl)azanium;iodide Chemical compound [I-].CC1=CC=C([NH3+])C(C)=C1C UHAUNWBFEUXSNO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
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- 238000002425 crystallisation Methods 0.000 description 2
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- 238000001514 detection method Methods 0.000 description 2
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- ZMGDXJGLGYNTSM-UHFFFAOYSA-N ethanolate;trimethyl(phenyl)azanium Chemical compound CC[O-].C[N+](C)(C)C1=CC=CC=C1 ZMGDXJGLGYNTSM-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
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- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 description 2
- GKLKDABQTQDINH-UHFFFAOYSA-N methanolate;trimethyl(phenyl)azanium Chemical compound [O-]C.C[N+](C)(C)C1=CC=CC=C1 GKLKDABQTQDINH-UHFFFAOYSA-N 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
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- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
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- FOJYFDFNGPRXDR-SQILNHJXSA-N (4r,4ar,7s,7ar,12bs)-10-[(4r,4ar,7s,7ar,12bs)-7,9-dihydroxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-10-yl]-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol Chemical compound C([C@H]12)=C[C@H](O)[C@@H]3OC4=C(O)C(C=5C=C6C7=C(C=5O)O[C@@H]5[C@]77CCN([C@H](C6)[C@@H]7C=C[C@@H]5O)C)=CC5=C4[C@]13CCN(C)[C@@H]2C5 FOJYFDFNGPRXDR-SQILNHJXSA-N 0.000 description 1
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- 230000002411 adverse Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
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- 239000002168 alkylating agent Substances 0.000 description 1
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- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- LNNWVNGFPYWNQE-GMIGKAJZSA-N desomorphine Chemical compound C1C2=CC=C(O)C3=C2[C@]24CCN(C)[C@H]1[C@@H]2CCC[C@@H]4O3 LNNWVNGFPYWNQE-GMIGKAJZSA-N 0.000 description 1
- 229950003851 desomorphine Drugs 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- AABLHGPVOULICI-BRJGLHKUSA-N hydromorphinol Chemical compound O([C@H]1[C@H](CC[C@]23O)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O AABLHGPVOULICI-BRJGLHKUSA-N 0.000 description 1
- 229950008720 hydromorphinol Drugs 0.000 description 1
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 1
- 229960001410 hydromorphone Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229960000938 nalorphine Drugs 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 229950006134 normorphine Drugs 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 229960005118 oxymorphone Drugs 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- ZOCTZZQDDXGIRB-WXRFYESLSA-N α-codeimethine Chemical compound C([C@H]([C@@]12CCN(C)C)C=C3)=C[C@H](O)[C@@H]2OC2=C1C3=CC=C2OC ZOCTZZQDDXGIRB-WXRFYESLSA-N 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
Definitions
- the invention pertains to an improved process for preparing codeine or thebaine starting from a morphine component.
- Opiates the alkaloids derived from opium, have long been used to alleviate pain and suffering in humans.
- opiates have also been used as illicit narcotics.
- the unique ability of these compounds to elicit an analgesia accompanied by euphoria has captured the interest of civilization for more than five thousand years, e.g., see P. T. White, et al., National Geographic, 1985, vol. 167, p. 142.
- Opium (the dried latex of unripe poppy plant capsules) contains over 40 alkaloids.
- the chief alkaloid constituent of opium is morphine, which is present in varying amounts of 5 to 24% depending on the opium source.
- Codeine is the opiate of most interest to the pharmaceutical industry. However, codeine is available from natural sources such as opium and poppy straw only in limited quantities, e.g., 2-4%. Since the demand for codeine far exceeds the available natural supply, there is a continuous search for a synthetic method that is capable of producing codeine of high purity in large amount. The pharmaceutical industry is particularly interested in producing codeine in the most cost effective and environmentally friendly manner possible.
- morphine may be methylated at the phenolic hydroxy end (i.e., position 3) to obtain codeine.
- an undesired second methylation at the free hydroxyl end i.e., position 6 also occurs, e.g., see S. Pfeifer, Pharmazie, 1963, vol. 18, p. 409 and E. Brochmann-Hannsen et al., J. Pharm. Sci., 1967, vol. 56, p. 1207.
- Another competing reaction at the nitrogen end i.e., position 17 leads to yet another undesirable product, e.g., see W. Debska et al., Chem. Anal . (Warsaw), 1979, vol. 24, p.
- methylating agents A variety of methylating agents has been reported in the scientific literature as being capable of converting morphine to codeine, see W. Heumann, Bull. Narcotics, 1958, vol. 3, p. 15. The earliest attempt to convert morphine into codeine dates back to 1881 and involved the use of methyl iodide, a commonly used methylating agent (see M. Grimaux, C. R. Acad. Sci., 1881, vol. 92, p. 1140). Alkylating agents such as methyl chloride (see M. A. Phillips, Chemist Druggist, 1965, vol. 183, pp. 661 and 4454), dimethyl sulfate (see, M. A Phillips, Ibid .
- the present invention provides a controlled synthetic route leading to codeine that is free or substantially free of impurities.
- a process for the preparation of codeine includes the steps of providing a solution or suspension of a morphine component in an inert solvent or a mixture of solvents, methylating the resultant solution or suspension with a methylating agent in the presence of an alkaline ingredient wherein the alkaline ingredient is selected from the group consisting of sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium hydrogencarbonate, and potassium hydrogencarbonate, and recovering the resultant codeine as the free base or as a salt.
- a process for the preparation of codeine includes the steps of providing a solution or suspension of a morphine component in an inert solvent or a mixture of solvents, methylating the resultant solution or suspension with a methylating agent in the presence of an alkaline ingredient wherein the alkaline ingredient comprises a hydrogencarbonate, and recovering the resultant codeine as the free base or as a salt.
- a process for the preparation of codeine includes the steps of providing a solution or suspension of a morphine component in an inert solvent or a mixture of solvents, methylating the resultant solution or suspension with a phenyltrimethylammonium salt in the presence of an alkaline ingredient wherein the alkaline ingredient comprises a hydrogencarbonate; and recovering the resultant codeine as the free base or as a salt.
- the present invention centers on the ability to control a reaction of converting morphine into codeine such that the omnipresent impurity, 6-methylcodeine is not formed or is significantly reduced. Under the disclosed reaction conditions the formation of 6-methylcodeine is not detected, employing analytical test methods with the detection limit of 0.05% w/w (a commonly used limit of detection).
- a major byproduct as a result of methylation reactions involving quaternary ammonium reagents is dimethylaniline, which is toxic as well as cumbersome to remove from the main product.
- An increased cost of waste disposal and elevated environmental concerns are a result of the processes employing such methylating agents. Since the recovery or the removal of unreacted morphine and/or dimethylaniline is mandatory, the corresponding capital cost of the production plant and the cost of carrying out the reaction are high.
- Embodiments of the invention disclose a simple isolation procedure that removes the byproduct very effectively.
- the process takes advantage of the differences in basicity between dimethylaniline and codeine to enable a preferential precipitation of codeine.
- codeine phosphate can be selectively precipitated out of the solution as a white solid while the other component remains dissolved in the solution.
- a straightforward filtration will ensure the separation of the desired product from the byproduct, while the filtrate may be subjected to a distillation procedure to recover most of the solvent in high purity.
- the recycled solvent is suitable for use as reaction solvent in the subsequent production runs.
- the process described herein provides for an efficient way of producing codeine or salt thereof, starting from a morphine component.
- Embodiments of the present invention prepare codeine in high purity and high yield using the techniques described below. As described in the following paragraphs, embodiments of the present invention can be described as involving: a bicarbonate process, and a phosphate process.
- the starting material for carrying out the processes of the invention comprises a “morphine component”.
- morphine component shall be understood to encompass morphine itself, a morphine salt or any material, composition, mixture or formulation that contains morphine or a morphine salt such as opium or a concentrate of poppy straw. This term also shall be understood to encompass all phenolic moieties in various opiates and/or opioids.
- the phenolic analog of thebaine is also included under the term “morphine component.”
- suitable starting materials include but are not limited to normorphine, oxymorphone, hydromorphone, dihydromorphine, hydromorphinol, morphine N-oxide, desomorphine, pseudomorphine, nalorphine, naloxone, and naltrexone.
- the preferred starting material includes a concentrate of poppy straw. Such concentrates typically contain about 50 to about 85 wt. % morphine component on a wet or dry weight basis. In one embodiment, concentrates can contain about 50 to 99 wt. % morphine component on a dry weight basis.
- the present invention provides previously unknown methods by which concentrate of poppy straw can be converted to codeine.
- embodiments of the process of the invention include the following steps:
- Embodiments of the invention including the Bicarbonate and Phosphate Processes are discussed in more detail below.
- suitable examples of the alkaline ingredients employed for the step (b) include but are not limited to alkali metal hydroxides, alkaline earth metal hydroxides, and alkali metal hydrogen carbonates such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium hydrogencarbonate, and potassium hydrogencarbonate.
- alkali metal hydrogen carbonates such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium hydrogencarbonate, and potassium hydrogencarbonate.
- preferred alkaline ingredients include potassium hydrogencarbonate.
- the present invention includes using a bicarbonate process of the present invention, to convert morphine to codeine using a weak base.
- the quantity of alkaline ingredients in step (b) can be in the range of about 0.3 to about 15 grams, dissolved or suspended in a given amount of solvent.
- the amount of solvent employed can depend upon the amount of morphine in the morphine component, which is described below.
- the concentration of the alkaline ingredient in the solvent can be from about 0.0005 grams per ml. solvent to about 1.0 grams per ml. solvent.
- the concentration of alkaline ingredient can be from about 0.0005 grams per ml. solvent to about 0.05 grams per ml. solvent.
- the solvent can be employed per 1 gram of morphine in the morphine component.
- suitable examples of the solvent include but are not limited to alcohols, ketones, alkyl halides, aromatic halides, aliphatic ethers, aromatic ethers and aromatic hydrocarbons such as methanol, ethanol, n-butanol, acetone, methylethylketone, cyclohexanone, dichloroethane, chlorobenzene, t-butylmethyl ether, anisole, toluene and xylene or any combination of the mentioned type of solvents (i.e., two or more combined).
- a preferred solvent includes toluene.
- Suitable methylating agents include quaternary ammonium halides and quaternary ammonium alkoxides or salts thereof, including but not limited to such as phenyltrimethylammonium chloride, phenyltrimethylammonium bromide, phenyltrimethylammonium iodide, phenyltrimethylammonium methoxide, and phenyltrimethylammonium ethoxide.
- the preferred methylating agent comprises phenyltrimethylammonium chloride.
- the methylating agent is utilized in an amount of about 0.8 to about 2.5 moles per mole of morphine in the morphine component.
- step (b) is carried out at a temperature of about 20 to about 225° C. In another embodiment, step (b) is carried out at a temperature of about 50 to about 150° C. In yet another embodiment, step (b) is carried out at a temperature of about 90 to about 110° C. In one embodiment, the residence time of the reaction is in the range of about 15 minutes to about 72 hours, typically 30 minutes to 28 hours.
- the codeine is recovered from the reaction medium as the free base or as an addition salt such as the phosphate, sulfate, hydrochloride, or acetate.
- a process for recovery of the codeine involves separating an alkaline ingredient by filtration, washing the organic layer with an aqueous alkali and water, acidifying an extract of the organic layer with an appropriate acid, filtering the precipitated solid as codeine acid addition salt, and repeatedly washing with hot toluene and ethanol as exemplified in Examples 1 through 3, set forth below. Purification of the isolated material is also described further in Examples 1 through 3.
- the isolated codeine salt may be purified by crystallization using an alcohol/water mixture. If desired, the codeine salt may be converted to its free base.
- suitable examples of the alkaline ingredients employed for the step (b) include but are not limited to alkali metal phosphates (tribasic, dibasic and monobasic), alkali metal acetates, and alkali metal halides such as sodium phosphate, tribasic potassium phosphate, potassium dihydrogen phosphate, potassium hydrogenphosphate, potassium acetate, and potassium fluoride.
- the preferred alkaline ingredient comprises tribasic potassium phosphate. The conversion of morphine to codeine using such weak bases has not been previously reported.
- the quantity of alkaline ingredients in step (b) can be in the range of about 0.3 to about 15 grams, dissolved or suspended in a given amount of solvent.
- the amount of solvent employed can depend upon the amount of morphine in the morphine component. Similar to the above, in one embodiment about 15 to about 100 grams of the solvent can be employed per 1 gram of morphine in the morphine component.
- the concentration of the alkaline ingredient in the solvent can be from about 0.0005 grams per ml. solvent to about 1.0 grams per ml. solvent. In some embodiments, the concentration of alkaline ingredient can be from about 0.0005 grams per ml. solvent to about 0.05 grams per ml. solvent.
- suitable examples of the solvent include but are not limited to alcohols, ketones, alkyl halides, aromatic halides, aliphatic ethers, aromatic ethers and aromatic hydrocarbons such as methanol, ethanol, n-butanol, acetone, methylethylketone, cyclohexanone, dichloroethane, chlorobenzene, t-butylmethyl ether, anisole, toluene and xylene or any combination of the mentioned type of solvents.
- a preferred solvent includes toluene or acetone.
- Suitable methylating agents include quaternary ammonium halides and quaternary ammonium alkoxides such as phenyltrimethylammonium chloride, phenyltrimethylammonium bromide, phenyltrimethylammonium iodide, phenyltrimethylammonium methoxide, and phenyltrimethylammonium ethoxide.
- a preferred methylating agent includes phenyltrimethylammonium chloride.
- a methylating agent is utilized in an amount of about 0.8 to about 2.5 moles per mole of morphine in the morphine component.
- step (b) is carried out at a temperature of about 20 to about 225° C. In another embodiment, step (b) is carried out at a temperature of about 50 to about 150° C. In yet another embodiment, step (b) is carried out at a temperature of about 90 to about 110° C. In one embodiment, the residence time of the reaction is in the range of about 15 minutes to about 25 hours, typically 30 minutes to 7 hours. The reactions involving tribasic potassium phosphate are fast, often complete in 30-45 minutes. This is another unique attribute of the present invention.
- the codeine is recovered from the reaction medium as the free base or as an addition salt such as the phosphate, sulfate, hydrochloride, or acetate.
- the process for recovery of the codeine involves separating alkaline ingredient by filtration, washing the organic layer with an aqueous alkali and water, acidifying an extract of the organic layer with an appropriate acid, filtering the precipitated solid as codeine acid addition salt, and repeatedly washing with hot toluene and ethanol as exemplified in Example 4 set forth below.
- purification of the isolated material is described further under Example 4.
- the isolated codeine salt may be purified by crystallization using an alcohol/water mixture. If desired, the codeine salt may be converted to its free base, also as exemplified in Example 4 set forth below.
- a major byproduct as a result of methylation reactions involving quaternary ammonium reagents is dimethylaniline, which is toxic as well as cumbersome to remove from the main product.
- An increased cost of waste disposal and elevated environmental concerns are an inherent nature of the processes employing such methylating agents. Since the recovery or the removal of unreacted morphine and/or dimethylaniline is mandatory, the corresponding capital cost of the production plant and the cost of carrying out the reaction are high.
- This invention discloses a simple isolation procedure that removes the byproduct very effectively. In one embodiment, the process takes advantage of the differences in basicity between dimethylaniline and codeine to enable a preferential precipitation of codeine.
- codeine phosphate can be selectively precipitated out of the solution as a white solid while the other component remains dissolved in the solution.
- a straightforward filtration will ensure the separation of the desired product from the byproduct, while the filtrate may be subjected to a distillation procedure to recover most of the solvent in high purity.
- the recycled solvent is suitable for use as reaction solvent in the subsequent production runs.
- the process described herein thus provides for an efficient way of producing codeine or salt thereof, starting from a morphine component.
- a 1 L three-neck round bottom flask is charged with 9.980 g of morphine alkaloid purified and 500.0 g of toluene.
- the reaction flask is equipped with a mechanical stirrer, a thermometer, a Dean-Stark trap, a water condenser, an inlet and an outlet for nitrogen.
- a temperature controller i2R, Therm-O-Watch brand
- an Aldrich Instatherm oil bath is used to control the reaction temperature.
- the toluene suspension is stirred mechanically and dried azeotropically at 90-115° C. for 1 hour.
- the suspension is cooled to 50-60° C., 5.973 g of phenyltrimethylammonium chloride and 131.755 g of potassium hydrogen carbonate are charged. The contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 28 hours.
- the reaction is cooled to room temperature and into this solution is charged 1.000 g of activated carbon (charcoal) and the contents are stirred mechanically at room temperature.
- the black suspension is filtered using a sintered glass funnel over a bed of diatomaceous earth and the filtrate is collected in a 1-L round bottom flask.
- the flask containing the filtrate is fitted with a mechanical stirrer and a solution of 3.997 g of 85% phosphoric acid dissolved in 20-g of 95% aqueous ethanol is added dropwise while stirring. A white precipitate is formed which is stirred for 30 minutes at room temperature.
- the white precipitate is filtered using a large Buchner funnel.
- the filter cake is washed with hot toluene (3 ⁇ 30 ml), and 95% aqueous ethanol (3 ⁇ 60 ml) and dried under house vacuum for 18 hours to yield a white solid of codeine phosphate (weight 13.320 g, 99.6% yield).
- the isolated codeine phosphate is taken in a 250 ml round bottom flask and is charged with 30 g of 10% (w/w) acetic acid and 30 g of water.
- the resulting solution is mixed with 30 ml of toluene and the two-phase solution is stirred using a magnetic stir bar.
- the bi-phasic solution of codeine is charged with 115 ml of 1.0 N sodium hydroxide solution dropwise initially and in portions afterwards.
- a white precipitate of codeine free base is formed within 30 minutes of stirring in an icebath.
- the pH of the solution at the end of sodium hydroxide addition is about 11. If codeine is the desired final product the white precipitate may be filtered and dried at this stage to obtain codeine in the form of free base.
- the suspension is charged with 120 ml of toluene and stirred, upon which the entire solid dissolved back into the solution.
- the two-phase solution is taken in a 500 ml separatory funnel and the layers are separated.
- the aqueous layer is extracted with toluene (3 ⁇ 30 ml) and the extracts are combined, dried over sodium sulfate, filtered, and the filtrate is collected in a 1 L round bottom flask.
- the precipitate is filtered using a large Buchner funnel, washed with hot toluene (3 ⁇ 30 ml), 95% aqueous ethanol (2 ⁇ 60 ml), and dried under vacuum oven.
- a 1 L three-neck round bottom flask is charged with 9.975 g of morphine alkaloid purified and 500.0 g of toluene.
- the reaction flask is equipped with a mechanical stirrer, a thermometer, a water condenser, an inlet and an outlet for nitrogen.
- a temperature controller i2R, Therm-O-Watch brand
- the toluene suspension is stirred mechanically and refluxed at 90-115° C. for 1 hour.
- the suspension is cooled to 50-60° C., 6.151 g of phenyltrimethylammonium chloride and 19.850 g of potassium hydrogen carbonate are charged.
- the contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 8 hours.
- the reaction is cooled to room temperature and into this solution is charged 1 g of activated carbon (charcoal) and the contents are stirred mechanically at room temperature.
- the black suspension is filtered using a sintered glass funnel over a bed of diatomaceous earth and the filtrate is collected in a 1-L round bottom flask.
- the flask containing the filtrate is fitted with a mechanical stirrer and a solution of 4.272 g of 85% phosphoric acid dissolved in 20 g of 95% aqueous ethanol is added dropwise while stirring. A white precipitate is formed which is stirred for 30 minutes at room temperature.
- the white precipitate is filtered using a large Buchner funnel.
- the filter cake is washed with hot toluene (3 ⁇ 30 ml), and 95% aqueous ethanol (3 ⁇ 60 ml) and dried under vacuum oven at 30-35° C. for 18 hours to yield a white solid of codeine phosphate (weight 13.333 g, 99.8% yield).
- the isolated codeine phosphate is purified as stated in Example 1.
- a 500 ml three-neck round-bottom flask is charged with 10.20 g of a concentrate of poppy straw having morphine content of 80.8 wt. %, 425 g of toluene.
- the reaction flask is equipped with a mechanical stirrer, a thermometer, a Dean-Stark trap, a water condenser, an inlet and an outlet for nitrogen.
- a temperature controller i2R, Therm-O-Watch brand
- an Aldrich Instatherm oil bath is used to control the reaction temperature.
- the toluene suspension is stirred mechanically and dried azeotropically at 90-115° C. for 1 hour.
- the suspension is cooled to 50-60° C., 6.010 g of phenyl-trimethylammonium chloride and 9.720 g of sodium hydrogencarbonate are charged.
- the contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 48 hours.
- the reaction mixture is worked up and purified as stated in Example 1 to obtain codeine free base in a 84% yield.
- a 500 mL three-neck round bottom flask is charged with 5.000 g of morphine alkaloid purified and 250.3 g of toluene.
- the reaction flask is equipped with a mechanical stirrer, a thermometer, a Dean-Stark trap, a water condenser, an inlet and an outlet for nitrogen.
- a temperature controller i2R, Therm-O-Watch brand
- an Aldrich Instatherm oil bath is used to control the reaction temperature.
- the toluene suspension is stirred mechanically and dried azeotropically at 90-115° C. for 1 hour.
- the suspension is cooled to 50-60° C., 6.085 g of phenyltrimethylammonium chloride and 35.03 g of tribasic potassium phosphate are charged. The contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 2.5 hours.
- the reaction suspension is cooled to room temperature, filtered, and the filtrate is washed with saturated aqueous sodium chloride (1 ⁇ 60 ml), water (2 ⁇ 60 ml), and 30% aqueous acetic acid solution (4 ⁇ 60 ml).
- the aqueous layer after the acetic acid washing is concentrated to 100 g and to this solution is charged 0.100 g of activated carbon (charcoal) and the contents are stirred mechanically at room temperature.
- the black suspension is filtered using a sintered glass funnel over a bed of diatomaceous earth and the filtrate is collected.
- the filtrate is made alkaline with dilute sodium hydroxide solution to a pH of 12 and the codeine free base is extracted employing isopropyl acetate (3 ⁇ 60 ml).
- the solvent is evaporated to yield an off-white solid.
- the solid is taken in a 500 ml round bottom flask fitted with a mechanical stirrer and 35 g of denatured ethanol is added to dissolve the solid.
- a solution of 1.57 g of 85% phosphoric acid dissolved in 20-g of 95% aqueous ethanol is added dropwise while stirring.
- a white precipitate is formed which is stirred for 30 minutes at room temperature.
- the white precipitate is filtered using a large Buchner funnel.
- the filter cake is washed with hot toluene (3 ⁇ 30 ml), and 95% aqueous ethanol (3 ⁇ 60 ml) and dried under house vacuum for 18 hours to yield a white solid of codeine phosphate (weight 5.81 g, 87% yield).
- a 500 mL three-neck round bottom flask is charged with 5.002 g of morphine alkaloid purified and 250 g of toluene.
- the reaction flask is equipped with a mechanical stirrer, a thermometer, a Dean-Stark trap, a water condenser, an inlet and an outlet for nitrogen.
- a temperature controller i2R, Therm-O-Watch brand
- an Aldrich Instatherm oil bath is used to control the reaction temperature.
- the toluene suspension is stirred mechanically and dried azeotropically at 90-115° C. for 1 hour.
- the suspension is cooled to 50-60° C., 3.187 g of phenyltrimethylammonium chloride and 14.919 g of tribasic potassium phosphate are charged. The contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 6.5 hours.
- the reaction suspension is cooled to room temperature, filtered, and the filtrate is washed with saturated aqueous sodium chloride (1 ⁇ 60 ml), water (2 ⁇ 60 ml), and 30% aqueous acetic acid solution (4 ⁇ 60 ml).
- the aqueous layer after the acetic acid washing is concentrated to 100 g and to this solution is charged 60 ml of isopropyl acetate.
- the biphasic solution is made alkaline (to a pH of 14) with aqueous sodium hydroxide.
- the resulting solution is extracted with isopropyl acetate (3 ⁇ 60 ml), dried organic layer over sodium sulfate, charcoal treated, filtered and the solvent is removed to obtain an off-white solid. This solid is dried under house vacuum for 18 hours to yield a final product of codeine free base (weight 4.070 g, 82% yield).
- a 100 ml three-neck round bottom flask is charged with 1.002 g of morphine alkaloid purified and 30.3 g of acetone.
- the reaction flask is equipped with a mechanical stirrer, a thermometer, a water condenser, an inlet and an outlet for nitrogen.
- a temperature controller i2R, Therm-O-Watch brand
- an Aldrich Instatherm oil bath is used to control the reaction temperature.
- Powdered tribasic potassium phosphate (4.840 g) and 0.570 g of phenyltrimethylammonium chloride are charged.
- the contents of the flask are stirred mechanically and the suspension is refluxed between 50-60° C. for 25 hours.
- the reaction mixture is cooled to room temperature, the insoluble components are filtered, and the filtrate is treated with activated charcoal.
- the black suspension is filtered using a sintered glass funnel over a bed of diatomaceous earth and the filtrate is collected in a round bottom flask.
- a solution of 0.410 g of 85% phosphoric acid dissolved in 4.5 g of acetone is added dropwise while stirring.
- a white precipitate is formed which is stirred for 30 minutes at room temperature.
- a near quantitative yield of codeine phosphate is isolated. This product may be purified according to the procedure given under Example 1.
- a 500 ml three-neck round-bottom flask is charged with 24.986 g of a concentrate of poppy straw having morphine content of 80.8 wt. %, 507 g of toluene.
- the reaction flask is equipped with a mechanical stirrer, a thermometer, a Dean-Stark trap, a water condenser, an inlet and an outlet for nitrogen.
- a temperature controller i2R, Therm-O-Watch brand
- an Aldrich Instatherm oil bath is used to control the reaction temperature.
- the toluene suspension is stirred mechanically and dried azeotropically at 90-115° C. for 1 hour.
- the suspension is cooled to 70° C., 14.620 g of phenyltrimethylammonium chloride and 45.006 g of tribasic potassium phosphate are charged. The contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 2 hours.
- the reaction mixture is cooled to room temperature and into this solution is charged 1.050 g of charcoal and the contents are stirred mechanically at room temperature.
- the black suspension is filtered using a sintered glass funnel over a bed of diatomaceous earth and the filtrate is collected in a 1-L round bottom flask.
- the insoluble matter is washed with hot toluene (3 ⁇ 50 g) and denatured ethanol (3 ⁇ 100 g).
- the flask containing the filtrate is fitted with a mechanical stirrer and a previously prepared solution of 8.929 g of 85% phosphoric acid dissolved in 25-g of 95% aqueous ethanol is added dropwise while stirring. A slight exotherm is observed and care is taken that the temperature of solution did not exceed 30° C. A white precipitate is formed which is stirred for 45 minutes at room temperature.
- the white precipitate is filtered using a large Buchner funnel.
- the filter cake is washed with hot toluene (3 ⁇ 100 g), and hot 95% aqueous ethanol (3 ⁇ 100 g) and dried under house vacuum for 18 hours to yield a white solid of codeine phosphate.
- the isolated codeine phosphate is taken in a 500 ml Erlenmeyer flask and is charged with 75 ml of water.
- the resulting solution is mixed with 30 ml of isopropyl acetate and the two-phase solution is stirred using a magnetic stir bar.
- the bi-phasic solution of codeine is charged with 136 ml of 1.0 N sodium hydroxide solution dropwise initially and in portions afterwards.
- a white precipitate of codeine free base is formed within 30 minutes of stirring in an icebath.
- the pH of the solution at the end of sodium hydroxide addition is about 9. If codeine is the desired final product the white precipitate may be filtered and dried at this stage to obtain codeine in the form of free base.
- the suspension is charged with 60 ml of toluene and stirred, upon which the entire solid dissolved back into the solution.
- the two-phase solution is taken in a 500 ml separatory funnel and the layers are separated.
- the aqueous layer is extracted with isopropyl acetate (3 ⁇ 45 ml) and the extracts are combined, washed with water (2 ⁇ 25 ml), dried over sodium sulfate, filtered, and the filtrate is collected in a 1 L round bottom flask.
- the precipitate is filtered using a large Buchner funnel, washed with hot isopropyl acetate (3 ⁇ 30 ml), 95% aqueous ethanol (2 ⁇ 60 ml), and dried under vacuum oven. The resulting white solid corresponded to a yield of 82%.
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Abstract
Description
- The invention pertains to an improved process for preparing codeine or thebaine starting from a morphine component.
- Opiates, the alkaloids derived from opium, have long been used to alleviate pain and suffering in humans. Unfortunately, opiates have also been used as illicit narcotics. The unique ability of these compounds to elicit an analgesia accompanied by euphoria has captured the interest of mankind for more than five thousand years, e.g., see P. T. White, et al., National Geographic, 1985, vol. 167, p. 142.
- Opium (the dried latex of unripe poppy plant capsules) contains over 40 alkaloids. The chief alkaloid constituent of opium is morphine, which is present in varying amounts of 5 to 24% depending on the opium source. Codeine is the opiate of most interest to the pharmaceutical industry. However, codeine is available from natural sources such as opium and poppy straw only in limited quantities, e.g., 2-4%. Since the demand for codeine far exceeds the available natural supply, there is a continuous search for a synthetic method that is capable of producing codeine of high purity in large amount. The pharmaceutical industry is particularly interested in producing codeine in the most cost effective and environmentally friendly manner possible.
- It is known that morphine may be methylated at the phenolic hydroxy end (i.e., position 3) to obtain codeine. However, an undesired second methylation at the free hydroxyl end (i.e., position 6) also occurs, e.g., see S. Pfeifer, Pharmazie, 1963, vol. 18, p. 409 and E. Brochmann-Hannsen et al., J. Pharm. Sci., 1967, vol. 56, p. 1207. Another competing reaction at the nitrogen end (i.e., position 17) leads to yet another undesirable product, e.g., see W. Debska et al., Chem. Anal. (Warsaw), 1979, vol. 24, p. 407; C. Mannich, Arch. Pharm., 1916, vol. 254, p. 349; and B. Proksa et al., Chem. Zvesti., 1983, vol. 37, no. 6, pp. 837-842.
- A variety of methylating agents has been reported in the scientific literature as being capable of converting morphine to codeine, see W. Heumann, Bull. Narcotics, 1958, vol. 3, p. 15. The earliest attempt to convert morphine into codeine dates back to 1881 and involved the use of methyl iodide, a commonly used methylating agent (see M. Grimaux, C. R. Acad. Sci., 1881, vol. 92, p. 1140). Alkylating agents such as methyl chloride (see M. A. Phillips, Chemist Druggist, 1965, vol. 183, pp. 661 and 4454), dimethyl sulfate (see, M. A Phillips, Ibid. and German Patent 418,391), diazomethane (see H. von Pechmann, Ber., 1894, vol. 27, p. 1888; Ibid. 1895, vol. 28, p. 1624 and other reagents (see German Patent 39,887; and L. Small et al., Chemistry of the Opium Alkaloids, 1932, US Gov. Printing Office, p. 175) have also been employed in the past. However, virtually all of these prior art methods are accompanied by an uncontrollable decomposition reaction, thereby rendering them of limited value from a commercial standpoint.
- One of the biggest disadvantages of methylation reactions is that the nitrogen of the morphine readily reacts with the methylating agent resulting in quaternary ammonium species. These ammonium compounds undergo further degradation compromising both yield and purity. With the introduction of quaternary ammonium reagents containing methyl groups as methylating agents these problems have been greatly reduced. Phenyltrimethylammonium chloride or a modification of it has become the reagent of choice for the manufacture of codeine from morphine since its launch in 1909, see German Patent 247180. Rodionov (Bull. Soc. Chim. (France), 1926, vol. 4, no.39, p. 305) was the first to use the free quaternary ammonium base in lieu of the corresponding chloride. Use of quaternary ammonium bases in the form of alkoxides was among the improvements made to optimize the methylation process, see C. K. Ingold et al., J. Chem. Soc. (London), 1933, vo. 1, p. 69; and K. Ikonovski, Acta. Pharm. Jugoslav., 1973, vol. 23, pp. 169-171; Ibid., 1982, vol. 32, pp. 241-246; and U.S. Pat. No. 6,579,985. More recently, Ayyangar et al. (U.S. Pat. No. 4,764,615) have disclosed a method to prepare codeine using phenyltrimethylammonium chloride in the presence of an alkali metal carbonate. O-Methylation of phenols with phenyltrimethylammonium chloride has also been reported (see Carlsen et al. Acta Chemica Scandinavica, 1997, 51, pp. 343-344). A solid-phase synthesis using a polymer-bound methylating agent is a new variation in methylating morphine to codeine (see U.S. Pat. No. 5,981,750).
- All of the known synthetic routes employ rigorous conditions (very high temperatures and/or high pressures, strong alkaline media, or hazardous reagents/byproducts) and are regularly plagued by problems such as competing secondary reactions, incomplete alkylation, excessive alkylation and/or low yields. Currently, nearly all of the industrial conversions of morphine to codeine are carried out using quaternary ammonium salts. According to reported procedures employing phenyltrimethylammonium chloride it is imperative that exact stoichiometric quantities of morphine and the methylating agent be used to minimize secondary products. Under industrial conditions, an adverse dimethylated product (6-methylcodeine) is invariably produced. In large-scale productions of codeine, it is customary to use morphine in slight stoichiometric excess over the methylating agent to minimize the formation of the over-methylated product. In these cases, however, the unreacted morphine must be removed at the end of the reaction, resulting in additional capital and production costs.
- In one embodiment, the present invention provides a controlled synthetic route leading to codeine that is free or substantially free of impurities.
- In one embodiment, a process for the preparation of codeine includes the steps of providing a solution or suspension of a morphine component in an inert solvent or a mixture of solvents, methylating the resultant solution or suspension with a methylating agent in the presence of an alkaline ingredient wherein the alkaline ingredient is selected from the group consisting of sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium hydrogencarbonate, and potassium hydrogencarbonate, and recovering the resultant codeine as the free base or as a salt.
- In another embodiment of the invention, a process for the preparation of codeine includes the steps of providing a solution or suspension of a morphine component in an inert solvent or a mixture of solvents, methylating the resultant solution or suspension with a methylating agent in the presence of an alkaline ingredient wherein the alkaline ingredient comprises a hydrogencarbonate, and recovering the resultant codeine as the free base or as a salt.
- In yet another embodiment, a process for the preparation of codeine, includes the steps of providing a solution or suspension of a morphine component in an inert solvent or a mixture of solvents, methylating the resultant solution or suspension with a phenyltrimethylammonium salt in the presence of an alkaline ingredient wherein the alkaline ingredient comprises a hydrogencarbonate; and recovering the resultant codeine as the free base or as a salt.
- With reference to reaction Scheme 1 below, it is believed no previously disclosed process is available to avoid the formation of 6-methylcodeine (II) in the preparation of codeine (III) from morphine (I) especially for industrial application. In addition, once formed the complete removal of 6-methylcodeine from codeine is virtually impossible or impractical as evidenced by its significant presence in practically all commercial sources including the USP reference standards. Also, converting 6-methylcodeine back to codeine is not a viable option since an efficient and selective industrial process is yet to be established.
- Accordingly, in one aspect the present invention centers on the ability to control a reaction of converting morphine into codeine such that the omnipresent impurity, 6-methylcodeine is not formed or is significantly reduced. Under the disclosed reaction conditions the formation of 6-methylcodeine is not detected, employing analytical test methods with the detection limit of 0.05% w/w (a commonly used limit of detection).
- It is believed that the basicity of the reaction medium under the mentioned reaction conditions (hydrogencarbonate salts) is ideal for the formation of the desired product but not the dimethylated impurity. While stronger bases lead to small amounts of 6-methylcodeine, weaker bases do not lead to complete conversion of morphine to codeine. The capability to direct the reaction so that 6-methylcodeine is not formed is a major contributor to the efficiency of the process, which is reflected in the high yield and purity of the product.
- A major byproduct as a result of methylation reactions involving quaternary ammonium reagents is dimethylaniline, which is toxic as well as cumbersome to remove from the main product. An increased cost of waste disposal and elevated environmental concerns are a result of the processes employing such methylating agents. Since the recovery or the removal of unreacted morphine and/or dimethylaniline is mandatory, the corresponding capital cost of the production plant and the cost of carrying out the reaction are high.
- Embodiments of the invention disclose a simple isolation procedure that removes the byproduct very effectively. In one embodiment, the process takes advantage of the differences in basicity between dimethylaniline and codeine to enable a preferential precipitation of codeine. As demonstrated in the Examples 1 to 7, when dimethylaniline and codeine are present in reaction mixture, codeine phosphate can be selectively precipitated out of the solution as a white solid while the other component remains dissolved in the solution. A straightforward filtration will ensure the separation of the desired product from the byproduct, while the filtrate may be subjected to a distillation procedure to recover most of the solvent in high purity. In one embodiment, the recycled solvent is suitable for use as reaction solvent in the subsequent production runs.
- In yet another embodiment, the process described herein provides for an efficient way of producing codeine or salt thereof, starting from a morphine component.
- Embodiments of the present invention prepare codeine in high purity and high yield using the techniques described below. As described in the following paragraphs, embodiments of the present invention can be described as involving: a bicarbonate process, and a phosphate process.
- The starting material for carrying out the processes of the invention comprises a “morphine component”. For the purposes of this invention, the term “morphine component” shall be understood to encompass morphine itself, a morphine salt or any material, composition, mixture or formulation that contains morphine or a morphine salt such as opium or a concentrate of poppy straw. This term also shall be understood to encompass all phenolic moieties in various opiates and/or opioids. For instance, oripavine, the phenolic analog of thebaine is also included under the term “morphine component.” Other examples of suitable starting materials include but are not limited to normorphine, oxymorphone, hydromorphone, dihydromorphine, hydromorphinol, morphine N-oxide, desomorphine, pseudomorphine, nalorphine, naloxone, and naltrexone. From a commercial point of view, the preferred starting material includes a concentrate of poppy straw. Such concentrates typically contain about 50 to about 85 wt. % morphine component on a wet or dry weight basis. In one embodiment, concentrates can contain about 50 to 99 wt. % morphine component on a dry weight basis.
- The present invention provides previously unknown methods by which concentrate of poppy straw can be converted to codeine.
- Generally, embodiments of the process of the invention include the following steps:
-
- (a) providing a solution or suspension of a morphine component in an inert solvent or a mixture of solvents;
- (b) methylating the resultant solution or suspension with a methylating agent in the presence of an alkaline ingredient; and
- (c) recovering the resultant codeine as the free base or as a salt.
- Embodiments of the invention, including the Bicarbonate and Phosphate Processes are discussed in more detail below.
- A. Bicarbonate Process
- In one embodiment, suitable examples of the alkaline ingredients employed for the step (b) include but are not limited to alkali metal hydroxides, alkaline earth metal hydroxides, and alkali metal hydrogen carbonates such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium hydrogencarbonate, and potassium hydrogencarbonate. In one embodiment, preferred alkaline ingredients include potassium hydrogencarbonate.
- In one embodiment, the present invention includes using a bicarbonate process of the present invention, to convert morphine to codeine using a weak base. In one embodiment, the quantity of alkaline ingredients in step (b) can be in the range of about 0.3 to about 15 grams, dissolved or suspended in a given amount of solvent. In some embodiments, the amount of solvent employed can depend upon the amount of morphine in the morphine component, which is described below. In one embodiment, the concentration of the alkaline ingredient in the solvent can be from about 0.0005 grams per ml. solvent to about 1.0 grams per ml. solvent. In some embodiments, the concentration of alkaline ingredient can be from about 0.0005 grams per ml. solvent to about 0.05 grams per ml. solvent.
- In one embodiment, about 15 to about 100 grams of the solvent can be employed per 1 gram of morphine in the morphine component. Suitable examples of the solvent include but are not limited to alcohols, ketones, alkyl halides, aromatic halides, aliphatic ethers, aromatic ethers and aromatic hydrocarbons such as methanol, ethanol, n-butanol, acetone, methylethylketone, cyclohexanone, dichloroethane, chlorobenzene, t-butylmethyl ether, anisole, toluene and xylene or any combination of the mentioned type of solvents (i.e., two or more combined). A preferred solvent includes toluene.
- Suitable methylating agents include quaternary ammonium halides and quaternary ammonium alkoxides or salts thereof, including but not limited to such as phenyltrimethylammonium chloride, phenyltrimethylammonium bromide, phenyltrimethylammonium iodide, phenyltrimethylammonium methoxide, and phenyltrimethylammonium ethoxide. The preferred methylating agent comprises phenyltrimethylammonium chloride. Typically the methylating agent is utilized in an amount of about 0.8 to about 2.5 moles per mole of morphine in the morphine component.
- In one embodiment, step (b) is carried out at a temperature of about 20 to about 225° C. In another embodiment, step (b) is carried out at a temperature of about 50 to about 150° C. In yet another embodiment, step (b) is carried out at a temperature of about 90 to about 110° C. In one embodiment, the residence time of the reaction is in the range of about 15 minutes to about 72 hours, typically 30 minutes to 28 hours.
- After step (b) has been completed, the codeine is recovered from the reaction medium as the free base or as an addition salt such as the phosphate, sulfate, hydrochloride, or acetate. In one embodiment, a process for recovery of the codeine involves separating an alkaline ingredient by filtration, washing the organic layer with an aqueous alkali and water, acidifying an extract of the organic layer with an appropriate acid, filtering the precipitated solid as codeine acid addition salt, and repeatedly washing with hot toluene and ethanol as exemplified in Examples 1 through 3, set forth below. Purification of the isolated material is also described further in Examples 1 through 3.
- Alternatively, the isolated codeine salt may be purified by crystallization using an alcohol/water mixture. If desired, the codeine salt may be converted to its free base.
- B. Phosphate Process
- In certain embodiments of the present invention, suitable examples of the alkaline ingredients employed for the step (b) include but are not limited to alkali metal phosphates (tribasic, dibasic and monobasic), alkali metal acetates, and alkali metal halides such as sodium phosphate, tribasic potassium phosphate, potassium dihydrogen phosphate, potassium hydrogenphosphate, potassium acetate, and potassium fluoride. The preferred alkaline ingredient comprises tribasic potassium phosphate. The conversion of morphine to codeine using such weak bases has not been previously reported.
- In one embodiment, the quantity of alkaline ingredients in step (b) can be in the range of about 0.3 to about 15 grams, dissolved or suspended in a given amount of solvent. In some embodiments, the amount of solvent employed can depend upon the amount of morphine in the morphine component. Similar to the above, in one embodiment about 15 to about 100 grams of the solvent can be employed per 1 gram of morphine in the morphine component.
- In one embodiment, the concentration of the alkaline ingredient in the solvent can be from about 0.0005 grams per ml. solvent to about 1.0 grams per ml. solvent. In some embodiments, the concentration of alkaline ingredient can be from about 0.0005 grams per ml. solvent to about 0.05 grams per ml. solvent.
- Similar to the above, suitable examples of the solvent include but are not limited to alcohols, ketones, alkyl halides, aromatic halides, aliphatic ethers, aromatic ethers and aromatic hydrocarbons such as methanol, ethanol, n-butanol, acetone, methylethylketone, cyclohexanone, dichloroethane, chlorobenzene, t-butylmethyl ether, anisole, toluene and xylene or any combination of the mentioned type of solvents. In one embodiment, a preferred solvent includes toluene or acetone.
- Suitable methylating agents include quaternary ammonium halides and quaternary ammonium alkoxides such as phenyltrimethylammonium chloride, phenyltrimethylammonium bromide, phenyltrimethylammonium iodide, phenyltrimethylammonium methoxide, and phenyltrimethylammonium ethoxide. In one embodiment, a preferred methylating agent includes phenyltrimethylammonium chloride. Typically a methylating agent is utilized in an amount of about 0.8 to about 2.5 moles per mole of morphine in the morphine component.
- In one embodiment, step (b) is carried out at a temperature of about 20 to about 225° C. In another embodiment, step (b) is carried out at a temperature of about 50 to about 150° C. In yet another embodiment, step (b) is carried out at a temperature of about 90 to about 110° C. In one embodiment, the residence time of the reaction is in the range of about 15 minutes to about 25 hours, typically 30 minutes to 7 hours. The reactions involving tribasic potassium phosphate are fast, often complete in 30-45 minutes. This is another unique attribute of the present invention.
- After step (b) has been completed, the codeine is recovered from the reaction medium as the free base or as an addition salt such as the phosphate, sulfate, hydrochloride, or acetate. In one embodiment, the process for recovery of the codeine involves separating alkaline ingredient by filtration, washing the organic layer with an aqueous alkali and water, acidifying an extract of the organic layer with an appropriate acid, filtering the precipitated solid as codeine acid addition salt, and repeatedly washing with hot toluene and ethanol as exemplified in Example 4 set forth below. In one embodiment, purification of the isolated material is described further under Example 4. Alternatively, the isolated codeine salt may be purified by crystallization using an alcohol/water mixture. If desired, the codeine salt may be converted to its free base, also as exemplified in Example 4 set forth below.
- A major byproduct as a result of methylation reactions involving quaternary ammonium reagents is dimethylaniline, which is toxic as well as cumbersome to remove from the main product. An increased cost of waste disposal and elevated environmental concerns are an inherent nature of the processes employing such methylating agents. Since the recovery or the removal of unreacted morphine and/or dimethylaniline is mandatory, the corresponding capital cost of the production plant and the cost of carrying out the reaction are high. This invention discloses a simple isolation procedure that removes the byproduct very effectively. In one embodiment, the process takes advantage of the differences in basicity between dimethylaniline and codeine to enable a preferential precipitation of codeine. As demonstrated in the Examples 4 through 7, when dimethylaniline and codeine are present in reaction mixture, codeine phosphate can be selectively precipitated out of the solution as a white solid while the other component remains dissolved in the solution. A straightforward filtration will ensure the separation of the desired product from the byproduct, while the filtrate may be subjected to a distillation procedure to recover most of the solvent in high purity. The recycled solvent is suitable for use as reaction solvent in the subsequent production runs.
- Virtually all reported procedures require the use of temperatures greater than 100° C. to bring about the conversion of morphine to codeine (K. Ikonovski, Acta. Pharm. Jugoslav., 1973, vol. 23, pp. 169-171 and W. Heumann, Bull. Narcotics, 1958, vol. 3, p. 15). In one embodiment, this invention teaches a process to prepare codeine at 50-60° C. under much milder conditions, in contrast to earlier reports requiring elevated temperatures. This variation also provides for the use of inexpensive solvents such as acetone (as described in Example 6).
- The process described herein thus provides for an efficient way of producing codeine or salt thereof, starting from a morphine component.
- The following examples are given to illustrate the present invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in these examples. Unless otherwise indicated to the contrary, amounts and percentages are on a weight basis. Throughout the specification, any and all references to a publicly available document, including but not limited to a U.S. patent, are specifically-incorporated by reference.
- A 1 L three-neck round bottom flask is charged with 9.980 g of morphine alkaloid purified and 500.0 g of toluene. The reaction flask is equipped with a mechanical stirrer, a thermometer, a Dean-Stark trap, a water condenser, an inlet and an outlet for nitrogen. A temperature controller (i2R, Therm-O-Watch brand) coupled with an Aldrich Instatherm oil bath is used to control the reaction temperature. The toluene suspension is stirred mechanically and dried azeotropically at 90-115° C. for 1 hour. The suspension is cooled to 50-60° C., 5.973 g of phenyltrimethylammonium chloride and 131.755 g of potassium hydrogen carbonate are charged. The contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 28 hours.
- The reaction is cooled to room temperature and into this solution is charged 1.000 g of activated carbon (charcoal) and the contents are stirred mechanically at room temperature. The black suspension is filtered using a sintered glass funnel over a bed of diatomaceous earth and the filtrate is collected in a 1-L round bottom flask. The flask containing the filtrate is fitted with a mechanical stirrer and a solution of 3.997 g of 85% phosphoric acid dissolved in 20-g of 95% aqueous ethanol is added dropwise while stirring. A white precipitate is formed which is stirred for 30 minutes at room temperature.
- The white precipitate is filtered using a large Buchner funnel. The filter cake is washed with hot toluene (3×30 ml), and 95% aqueous ethanol (3×60 ml) and dried under house vacuum for 18 hours to yield a white solid of codeine phosphate (weight 13.320 g, 99.6% yield). The isolated codeine phosphate is taken in a 250 ml round bottom flask and is charged with 30 g of 10% (w/w) acetic acid and 30 g of water. The resulting solution is mixed with 30 ml of toluene and the two-phase solution is stirred using a magnetic stir bar.
- The bi-phasic solution of codeine is charged with 115 ml of 1.0 N sodium hydroxide solution dropwise initially and in portions afterwards. A white precipitate of codeine free base is formed within 30 minutes of stirring in an icebath. The pH of the solution at the end of sodium hydroxide addition is about 11. If codeine is the desired final product the white precipitate may be filtered and dried at this stage to obtain codeine in the form of free base.
- The suspension is charged with 120 ml of toluene and stirred, upon which the entire solid dissolved back into the solution. The two-phase solution is taken in a 500 ml separatory funnel and the layers are separated. The aqueous layer is extracted with toluene (3×30 ml) and the extracts are combined, dried over sodium sulfate, filtered, and the filtrate is collected in a 1 L round bottom flask.
- With continuous stirring the filtrate is charged with 100 g of denatured ethanol. A previously prepared solution of 3.958 g 85% phosphoric acid in 25 g of 95% aqueous ethanol is added slowly. The container used for the preparation of phosphoric acid solution is rinsed with 95% aqueous ethanol (3×5 g) and the rinses are added to the flask. The formation of codeine phosphate as a white precipitate is observed during the addition of phosphoric acid solution.
- The precipitate is filtered using a large Buchner funnel, washed with hot toluene (3×30 ml), 95% aqueous ethanol (2×60 ml), and dried under vacuum oven. The resulting white solid corresponded to a yield of 90% and a purity (by HPLC) of 100% codeine (a/a %), morphine=Not Detected, 6-methylcodeine=Not Detected, α-codeimethine=Not Detected.
- A 1 L three-neck round bottom flask is charged with 9.975 g of morphine alkaloid purified and 500.0 g of toluene. The reaction flask is equipped with a mechanical stirrer, a thermometer, a water condenser, an inlet and an outlet for nitrogen. A temperature controller (i2R, Therm-O-Watch brand) coupled with an Aldrich Instatherm oil bath is used to control the reaction temperature. The toluene suspension is stirred mechanically and refluxed at 90-115° C. for 1 hour. The suspension is cooled to 50-60° C., 6.151 g of phenyltrimethylammonium chloride and 19.850 g of potassium hydrogen carbonate are charged. The contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 8 hours.
- The reaction is cooled to room temperature and into this solution is charged 1 g of activated carbon (charcoal) and the contents are stirred mechanically at room temperature. The black suspension is filtered using a sintered glass funnel over a bed of diatomaceous earth and the filtrate is collected in a 1-L round bottom flask. The flask containing the filtrate is fitted with a mechanical stirrer and a solution of 4.272 g of 85% phosphoric acid dissolved in 20 g of 95% aqueous ethanol is added dropwise while stirring. A white precipitate is formed which is stirred for 30 minutes at room temperature.
- The white precipitate is filtered using a large Buchner funnel. The filter cake is washed with hot toluene (3×30 ml), and 95% aqueous ethanol (3×60 ml) and dried under vacuum oven at 30-35° C. for 18 hours to yield a white solid of codeine phosphate (weight 13.333 g, 99.8% yield). The isolated codeine phosphate is purified as stated in Example 1.
- A 500 ml three-neck round-bottom flask is charged with 10.20 g of a concentrate of poppy straw having morphine content of 80.8 wt. %, 425 g of toluene. The reaction flask is equipped with a mechanical stirrer, a thermometer, a Dean-Stark trap, a water condenser, an inlet and an outlet for nitrogen. A temperature controller (i2R, Therm-O-Watch brand) coupled with an Aldrich Instatherm oil bath is used to control the reaction temperature. The toluene suspension is stirred mechanically and dried azeotropically at 90-115° C. for 1 hour. The suspension is cooled to 50-60° C., 6.010 g of phenyl-trimethylammonium chloride and 9.720 g of sodium hydrogencarbonate are charged. The contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 48 hours. The reaction mixture is worked up and purified as stated in Example 1 to obtain codeine free base in a 84% yield.
- A 500 mL three-neck round bottom flask is charged with 5.000 g of morphine alkaloid purified and 250.3 g of toluene. The reaction flask is equipped with a mechanical stirrer, a thermometer, a Dean-Stark trap, a water condenser, an inlet and an outlet for nitrogen. A temperature controller (i2R, Therm-O-Watch brand) coupled with an Aldrich Instatherm oil bath is used to control the reaction temperature. The toluene suspension is stirred mechanically and dried azeotropically at 90-115° C. for 1 hour. The suspension is cooled to 50-60° C., 6.085 g of phenyltrimethylammonium chloride and 35.03 g of tribasic potassium phosphate are charged. The contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 2.5 hours.
- The reaction suspension is cooled to room temperature, filtered, and the filtrate is washed with saturated aqueous sodium chloride (1×60 ml), water (2×60 ml), and 30% aqueous acetic acid solution (4×60 ml). The aqueous layer after the acetic acid washing is concentrated to 100 g and to this solution is charged 0.100 g of activated carbon (charcoal) and the contents are stirred mechanically at room temperature. The black suspension is filtered using a sintered glass funnel over a bed of diatomaceous earth and the filtrate is collected. The filtrate is made alkaline with dilute sodium hydroxide solution to a pH of 12 and the codeine free base is extracted employing isopropyl acetate (3×60 ml). The solvent is evaporated to yield an off-white solid. The solid is taken in a 500 ml round bottom flask fitted with a mechanical stirrer and 35 g of denatured ethanol is added to dissolve the solid. A solution of 1.57 g of 85% phosphoric acid dissolved in 20-g of 95% aqueous ethanol is added dropwise while stirring. A white precipitate is formed which is stirred for 30 minutes at room temperature.
- The white precipitate is filtered using a large Buchner funnel. The filter cake is washed with hot toluene (3×30 ml), and 95% aqueous ethanol (3×60 ml) and dried under house vacuum for 18 hours to yield a white solid of codeine phosphate (weight 5.81 g, 87% yield).
- A 500 mL three-neck round bottom flask is charged with 5.002 g of morphine alkaloid purified and 250 g of toluene. The reaction flask is equipped with a mechanical stirrer, a thermometer, a Dean-Stark trap, a water condenser, an inlet and an outlet for nitrogen. A temperature controller (i2R, Therm-O-Watch brand) coupled with an Aldrich Instatherm oil bath is used to control the reaction temperature. The toluene suspension is stirred mechanically and dried azeotropically at 90-115° C. for 1 hour. The suspension is cooled to 50-60° C., 3.187 g of phenyltrimethylammonium chloride and 14.919 g of tribasic potassium phosphate are charged. The contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 6.5 hours.
- The reaction suspension is cooled to room temperature, filtered, and the filtrate is washed with saturated aqueous sodium chloride (1×60 ml), water (2×60 ml), and 30% aqueous acetic acid solution (4×60 ml). The aqueous layer after the acetic acid washing is concentrated to 100 g and to this solution is charged 60 ml of isopropyl acetate. The biphasic solution is made alkaline (to a pH of 14) with aqueous sodium hydroxide. The resulting solution is extracted with isopropyl acetate (3×60 ml), dried organic layer over sodium sulfate, charcoal treated, filtered and the solvent is removed to obtain an off-white solid. This solid is dried under house vacuum for 18 hours to yield a final product of codeine free base (weight 4.070 g, 82% yield).
- A 100 ml three-neck round bottom flask is charged with 1.002 g of morphine alkaloid purified and 30.3 g of acetone. The reaction flask is equipped with a mechanical stirrer, a thermometer, a water condenser, an inlet and an outlet for nitrogen. A temperature controller (i2R, Therm-O-Watch brand) coupled with an Aldrich Instatherm oil bath is used to control the reaction temperature. Powdered tribasic potassium phosphate (4.840 g) and 0.570 g of phenyltrimethylammonium chloride are charged. The contents of the flask are stirred mechanically and the suspension is refluxed between 50-60° C. for 25 hours. The reaction mixture is cooled to room temperature, the insoluble components are filtered, and the filtrate is treated with activated charcoal. The black suspension is filtered using a sintered glass funnel over a bed of diatomaceous earth and the filtrate is collected in a round bottom flask. A solution of 0.410 g of 85% phosphoric acid dissolved in 4.5 g of acetone is added dropwise while stirring. A white precipitate is formed which is stirred for 30 minutes at room temperature. A near quantitative yield of codeine phosphate is isolated. This product may be purified according to the procedure given under Example 1.
- A 500 ml three-neck round-bottom flask is charged with 24.986 g of a concentrate of poppy straw having morphine content of 80.8 wt. %, 507 g of toluene. The reaction flask is equipped with a mechanical stirrer, a thermometer, a Dean-Stark trap, a water condenser, an inlet and an outlet for nitrogen. A temperature controller (i2R, Therm-O-Watch brand) coupled with an Aldrich Instatherm oil bath is used to control the reaction temperature. The toluene suspension is stirred mechanically and dried azeotropically at 90-115° C. for 1 hour. The suspension is cooled to 70° C., 14.620 g of phenyltrimethylammonium chloride and 45.006 g of tribasic potassium phosphate are charged. The contents of the flask are stirred mechanically and the suspension is refluxed between 105-115° C. for 2 hours.
- The reaction mixture is cooled to room temperature and into this solution is charged 1.050 g of charcoal and the contents are stirred mechanically at room temperature. The black suspension is filtered using a sintered glass funnel over a bed of diatomaceous earth and the filtrate is collected in a 1-L round bottom flask. The insoluble matter is washed with hot toluene (3×50 g) and denatured ethanol (3×100 g). The flask containing the filtrate is fitted with a mechanical stirrer and a previously prepared solution of 8.929 g of 85% phosphoric acid dissolved in 25-g of 95% aqueous ethanol is added dropwise while stirring. A slight exotherm is observed and care is taken that the temperature of solution did not exceed 30° C. A white precipitate is formed which is stirred for 45 minutes at room temperature.
- The white precipitate is filtered using a large Buchner funnel. The filter cake is washed with hot toluene (3×100 g), and hot 95% aqueous ethanol (3×100 g) and dried under house vacuum for 18 hours to yield a white solid of codeine phosphate. The isolated codeine phosphate is taken in a 500 ml Erlenmeyer flask and is charged with 75 ml of water. The resulting solution is mixed with 30 ml of isopropyl acetate and the two-phase solution is stirred using a magnetic stir bar.
- The bi-phasic solution of codeine is charged with 136 ml of 1.0 N sodium hydroxide solution dropwise initially and in portions afterwards. A white precipitate of codeine free base is formed within 30 minutes of stirring in an icebath. The pH of the solution at the end of sodium hydroxide addition is about 9. If codeine is the desired final product the white precipitate may be filtered and dried at this stage to obtain codeine in the form of free base.
- The suspension is charged with 60 ml of toluene and stirred, upon which the entire solid dissolved back into the solution. The two-phase solution is taken in a 500 ml separatory funnel and the layers are separated. The aqueous layer is extracted with isopropyl acetate (3×45 ml) and the extracts are combined, washed with water (2×25 ml), dried over sodium sulfate, filtered, and the filtrate is collected in a 1 L round bottom flask.
- With continuous stirring the filtrate is charged with 60 ml of 95% aqueous ethanol. A previously prepared solution of 7.433 g 85% phosphoric acid in 15 g of 95% aqueous ethanol is added slowly. The container used for the preparation of phosphoric acid solution is rinsed with 95% aqueous ethanol (3×15 g) and the rinses are added to the flask. The formation of codeine phosphate as a white precipitate is observed during the addition of phosphoric acid solution.
- The precipitate is filtered using a large Buchner funnel, washed with hot isopropyl acetate (3×30 ml), 95% aqueous ethanol (2×60 ml), and dried under vacuum oven. The resulting white solid corresponded to a yield of 82%.
- While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. Thus, it is intended that the present invention covers the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents. Further, each and every reference disclosed herein is hereby incorporated by reference.
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WO2013019825A1 (en) * | 2011-08-02 | 2013-02-07 | Mallinckrodt Llc | Stepwise process for the production of alkaloid salts |
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SG172940A1 (en) * | 2009-01-16 | 2011-08-29 | Teva Pharma | New stable formulations of recombinant human albumin-human granulocyte colony stimulating factor fusion protein |
TWI471289B (en) | 2010-06-11 | 2015-02-01 | Rhodes Technologies | Process for n-dealkylation of tertiary amines |
CA2936749C (en) | 2010-06-11 | 2019-07-09 | Joshua R. Giguere | Transition metal-catalyzed processes for the preparation of n-allyl compounds and use thereof |
US11247999B1 (en) | 2021-07-02 | 2022-02-15 | Joseph DeGraw | Facile conversion of morphine to normorphine |
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US4764615A (en) * | 1986-11-25 | 1988-08-16 | Council Of Scientific & Industrial Research | Process for the preparation of codeine from morphine |
US5981750A (en) * | 1995-11-21 | 1999-11-09 | The Board Of Regents Of The University And Community College System Of Nevada | Solid-phase synthesis of codeine from morphine |
US20020150214A1 (en) * | 2001-04-17 | 2002-10-17 | Siemens Aktiengesellschaft | X-ray installation with wireless communication betwwen the radiation receiver and control unit |
US6579985B1 (en) * | 2002-10-21 | 2003-06-17 | Mallinckrodt Inc. | Preparation of codeine from morphine |
US6590958B2 (en) * | 2001-11-15 | 2003-07-08 | Ge Medical Systems Global Technology | X-ray positioner having integrated display |
US20030142788A1 (en) * | 2001-11-21 | 2003-07-31 | Kenneth Cho | Portable medical digital radiography assembly |
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DE39887C (en) | Dr. phil. A. KNOLL in Ludwigshafen a. Rh | Process for the preparation of methylmorphine (codeine and ethylmorphine | ||
DE418391C (en) | 1923-10-05 | 1925-09-09 | Merck Chem Fab Fa E | Process for the preparation of alkyl ethers of the morphine series |
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US4764615A (en) * | 1986-11-25 | 1988-08-16 | Council Of Scientific & Industrial Research | Process for the preparation of codeine from morphine |
US5981750A (en) * | 1995-11-21 | 1999-11-09 | The Board Of Regents Of The University And Community College System Of Nevada | Solid-phase synthesis of codeine from morphine |
US20020150214A1 (en) * | 2001-04-17 | 2002-10-17 | Siemens Aktiengesellschaft | X-ray installation with wireless communication betwwen the radiation receiver and control unit |
US6590958B2 (en) * | 2001-11-15 | 2003-07-08 | Ge Medical Systems Global Technology | X-ray positioner having integrated display |
US20030142788A1 (en) * | 2001-11-21 | 2003-07-31 | Kenneth Cho | Portable medical digital radiography assembly |
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WO2013019825A1 (en) * | 2011-08-02 | 2013-02-07 | Mallinckrodt Llc | Stepwise process for the production of alkaloid salts |
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