CN116715618A - 地佐辛中间体杂质及其制备方法 - Google Patents
地佐辛中间体杂质及其制备方法 Download PDFInfo
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- CN116715618A CN116715618A CN202310668518.1A CN202310668518A CN116715618A CN 116715618 A CN116715618 A CN 116715618A CN 202310668518 A CN202310668518 A CN 202310668518A CN 116715618 A CN116715618 A CN 116715618A
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- dezocine
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- VTMVHDZWSFQSQP-VBNZEHGJSA-N dezocine Chemical compound C1CCCC[C@H]2CC3=CC=C(O)C=C3[C@]1(C)[C@H]2N VTMVHDZWSFQSQP-VBNZEHGJSA-N 0.000 title claims abstract description 54
- 229960003461 dezocine Drugs 0.000 title claims abstract description 54
- 239000012535 impurity Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 7
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 7
- 239000003444 phase transfer catalyst Substances 0.000 claims description 7
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 238000004809 thin layer chromatography Methods 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- XJWSAJYUBXQQDR-UHFFFAOYSA-M dodecyltrimethylammonium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)C XJWSAJYUBXQQDR-UHFFFAOYSA-M 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 abstract description 4
- 238000004451 qualitative analysis Methods 0.000 abstract description 2
- 238000004445 quantitative analysis Methods 0.000 abstract description 2
- 239000013558 reference substance Substances 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 32
- 239000000203 mixture Substances 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- GABLTKRIYDNDIN-UHFFFAOYSA-N 7-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical class C1CCC(=O)C2=CC(OC)=CC=C21 GABLTKRIYDNDIN-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 230000006838 adverse reaction Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000014 opioid analgesic Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- VNJOEUSYAMPBAK-UHFFFAOYSA-N 2-methylbenzenesulfonic acid;hydrate Chemical compound O.CC1=CC=CC=C1S(O)(=O)=O VNJOEUSYAMPBAK-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- UFHFLCQGNIYNRP-VVKOMZTBSA-N Dideuterium Chemical compound [2H][2H] UFHFLCQGNIYNRP-VVKOMZTBSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical class O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C407/00—Preparation of peroxy compounds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C407/00—Preparation of peroxy compounds
- C07C407/003—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C409/00—Peroxy compounds
- C07C409/02—Peroxy compounds the —O—O— group being bound between a carbon atom, not further substituted by oxygen atoms, and hydrogen, i.e. hydroperoxides
- C07C409/14—Peroxy compounds the —O—O— group being bound between a carbon atom, not further substituted by oxygen atoms, and hydrogen, i.e. hydroperoxides the carbon atom belonging to a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C409/00—Peroxy compounds
- C07C409/20—Peroxy compounds the —O—O— group being bound to a carbon atom further substituted by singly—bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
- C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
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- C07—ORGANIC CHEMISTRY
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- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
本发明提供了一种地佐辛中间体杂质及其制备方法,其中,地佐辛中间体杂质的结构式如式(Ⅰ)或式(Ⅱ)所示。本发明通过提供上述地佐辛中间体杂质,提供了一种监控优化地佐辛中间体化合物(Ⅲ)和地佐辛产品质量的标准对照品,进而有利于地佐辛中间体和地佐辛产品进行定性和定量分析。
Description
技术领域
本发明涉及药物合成领域,具体地,本发明涉及地佐辛中间体杂质及其制备方法。
背景技术
地佐辛,化学名:(5R,11S,13S)-13-氨基-5,6,7,8,9,10,11,12-八氢-5-甲基-5,11-亚甲基苯并环癸-3-醇,是一种新型的麻醉性、强效阿片类镇痛药。主要用于术后中重度疼痛、内脏绞痛、癌痛等。与传统的阿片类镇痛药相比,其在缓解术后急性疼痛方面效果更为显著,不易产生呼吸抑制、便秘、镇痛耐受和成瘾等不良反应,有望成为国内乃至国际市场前景最好的阿片生物碱类镇痛药。
地佐辛结构如下:
地佐辛是一种强效阿片类镇痛药,其药理作用、杂质、剂型、剂量、给药方法都可能导致不良反应,分析药品生产过程中的杂质,并将其控制在一定程度之下,可以降低不良反应的产生,对安全用药、放心用药有重要的指导作用。
现有的地佐辛合成路线如下:
在上述地佐辛合成路线中,化合物2-8是合成地佐辛的中间体,目前通过氢氧化钠水溶液为碱,四丁基溴化铵为相转移催化剂制备地佐辛中间体的传统合成方法产率较低。对于制备地佐辛中间体的烷基化反应低收率的原因及烷基化反应中产生的杂质未有提及。
化合物2-8所示的结构基础上通过改变苯环上取代基或六元环上的甲基可以得到多种不同的地佐辛中间体化合物,这些化合物均具备作为地佐辛合成路线上中间体的潜力。这类地佐辛中间体的通式结构如式(Ⅲ)所示:
其中,R1选自H、OCH3、Cl;R2选自H、Et。
在制备地佐辛中间体(Ⅲ)的过程中会产生与地佐辛中间体极性相近的杂质化合物,难以分离,这将导致地佐辛中间体(Ⅲ)收率低、纯度不高,继而影响地佐辛药品的安全性和有效性。现有技术中对地佐辛中间体(Ⅲ)杂质的认知不足,难以做到对地佐辛中间体(Ⅲ)生产过程的质量监控,难以对地佐辛药品的安全性和有效性进行有效控制。
发明内容
为解决现有技术中的问题,本发明提出了一种地佐辛中间体杂质及其制备方法。申请人对制备地佐辛中间体(Ⅲ)过程产生的杂质化合物(Ⅰ)和(Ⅱ)所示进行了制备分离。本发明得到的中间体杂质可直接作为监控地佐辛中间体或者地佐辛产品中杂质含量检测的标准品,具有较高的应用价值。
本发明的技术方案如下:
本发明提供了一种地佐辛中间体杂质化合物的制备方法,所述地佐辛中间体杂质化合物的结构式如式(Ⅰ)或式(Ⅱ)所示:
结构式(Ⅰ)和(Ⅱ)中,R1选自H、OCH3、Cl;R2选自H、Et;
所述地佐辛中间体杂质化合物的制备方法包括如下步骤:
1)将式(Ⅳ)所示化合物与1,5-二溴戊烷在碱和相转移催化剂的存在下反应,获得反应混合物;
R1选自H、OCH3、Cl;R2选自H、Et;
2)将所述反应混合物进行后处理、分离获得式(Ⅰ)和(Ⅱ)所示化合物和地佐辛中间体化合物(Ⅲ);
根据本发明的优选方案,步骤1)中所述的碱为氢氧化钾、氢氧化钠、碳酸钾、碳酸钠、碳酸铯或碳酸氢钠中的一种或多种;式(Ⅳ)所示化合物与碱的摩尔比为1:2~1:20。
根据本发明的优选方案,步骤1)中所述的相转移催化剂为四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丁基氟化铵、十二烷基三甲基溴化铵、三乙基苄基氯化铵、十二烷基硫酸钠或甲基三辛基氯化铵中的一种或多种;式(Ⅳ)所示化合物与相转移催化剂的摩尔比为1:0.05~1:0.5。
根据本发明的优选方案,步骤1)中所述反应在溶剂存在下进行,溶剂为甲苯、四氢呋喃、甲醇、乙醇、乙腈或水中的一种或多种。
根据本发明的优选方案,步骤1)所述反应的温度为0~25℃,反应时间为12~24h,化合物(Ⅳ)与1,5-二溴戊烷摩尔比为1:1~1:3。
根据本发明的优选方案,步骤2)中,反应混合物通过薄层层析色谱柱分离得到式(Ⅰ)和(Ⅱ)所示化合物,薄层层析色谱柱分离过程中,以石油醚和乙酸乙酯混合溶剂为洗脱剂,石油醚和乙酸乙酯的体积比为100:1~40:1。
与现有技术相比,本发明对杂质化合物(Ⅰ)和(Ⅱ)进行了制备,并采用薄层层析色谱柱分离得到杂质化合物(Ⅰ)和(Ⅱ)。薄层层析色谱柱分离过程中,以石油醚和乙酸乙酯混合溶剂为洗脱剂,得到的化合物(Ⅰ)和(Ⅱ)纯度高,可作为标准品对地佐辛中间体(Ⅲ)生产过程进行质量监控,可作为地佐辛原料药、片剂、缓释剂、胶囊、注射液的质量研究标准或对照品,保障药品的安全性。
附图说明
图1为化合物2-6的液相色谱图;
图2为化合物2-7的液相色谱图;
图3为化合物2-8的液相色谱图。
具体实施方式
本发明将会把确定的具体化的内容所对应的文献详细列出,实施例都伴有结构式和化学式的图解。本发明有预期地涵盖所有的选择余地、变体和同等物,这些可能如权利要求所定义的那样包括在本发明范围内。所属领域的技术人员将识别许多类似或等同于在此描述的方法和物质,这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。有很多文献和相似物质与本发明申请相区别或抵触,其中包括但绝不限于术语的定义,术语的用法,或如本发明申请所控制的范围。
本发明将应用以下定义除非其他方面表明。根据本发明的目的,化学元素根据元素周期表,CAS版本和化学物理手册75th Ed.,1994来定义。另外,有机化学一般原理见“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito,1999,和“March's Advanced Organic Chemistry”,Michael B.Smith和Jerry March,John Wi1cy&Sons,New York,2007,所有上述参考文献均通过引用并入本文中。
本发明中立体化学的定义和惯例的使用通常参考以下文献:S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill 11Book Company,NewYork;and Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,JohnWiley&Sons,Inc.,New York,1994。本发明的化合物可以包含不对称中心或手性中心,因此存在不同的立体异构体。本发明的化合物所有的立体异构形式,包括但绝不限于,非对映体、对映异构体、阻转异构体和它们的混合物,如外消旋混合物,组成了本发明的一部分。很多有机化合物都以光学活性形式存在,即它们有能力旋转平面偏振光的平面。这些立体异构体的化学结构是相同的,但是它们的立体结构不一样。特定的立体异构体可以是对映体、异构体的混合物通常称为对映异构体混合物。50:50的对映体混合物被称为外消旋混合物或外消旋体,这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物,缺乏光学活性。
术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变,如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。
在本发明的上下文中,当使用或者无论是否使用“大约”或“约”等字眼时,表示在给定的值或范围10%以内,适当地5%以内,特别是1%以内。或者,对于本领域普通技术人员而言,术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时,任何具有N+/-1%,N+/-2%,N+/-3%,N+/-5%,N+/-7%,N+/-8%或N+/-10%值以内的数字会被明确地公开,其中“+/-”是指加或减。
术语“包含”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。
“选自”指的是随后描述的事件或状况可能但不是必须出现的并且该描述包括其中所述事件或状况发生的情况以及所述事情或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代,包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R取代,而且每种情况下R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本发明采取下述缩略词:aq代表水;Aliquat 336代表甲基三辛基氯化铵;THF代表四氢呋喃;n-BuLi代表正丁基锂;TsOH·H2O代表甲苯磺酸一水合物;t-BuOK代表叔丁醇钾。
化合物经手工或者ChemDraw○R软件命名,市售化合物采用供应商目录名称。
本发明所述地佐辛中间体的通式结构如式(Ⅲ)所示:
其中,R1选自H、OCH3、Cl;R2选自H、Et;
在制备式(Ⅲ)时,本发明发现并成功分离了两种新产生的难分离的杂质,如式(Ⅰ)或式(Ⅱ)所示。
其中,杂质化合物(Ⅰ)的结构式为:
杂质化合物(Ⅱ)的结构式为:
结构式(Ⅰ)和(Ⅱ)中,R1选自H、OCH3、Cl;R2选自H、Et。
具体的,依据取代基的不同,杂质化合物(Ⅰ)的结构式可以为如下几种:
依据取代基的不同,杂质化合物(Ⅱ)的结构式可以为如下几种:
实施例1:式(Ⅳ)所示化合物(本发明原料)的制备;
R1选自H、OCH3、Cl;R2选自H、Et。
以下制备路线以R1选自Cl,R2选自H、Et为例,介绍式(Ⅳ)所示化合物的制备路线。
步骤1:化合物1-2的制备
氮气保护下,在0℃,向PPh3MeBr(15.20g,42.56mmol)的THF溶液(250mL)中缓慢滴加n-BuLi溶液(26.60mL,1.6mol/L,42.56mmol)并在0℃下反应两小时。向混合物中加入化合物1-1(5.12g,28.37mmol)并在0℃下反应两小时。反应温度缓慢上升至25℃后,继续搅拌2小时。用饱和的NH4Cl溶液(100mL)淬灭反应,除去溶剂THF后,水相用乙酸乙酯(200mL×3)萃取。合并后的有机相用饱和食盐水(100mL)洗涤,无水Na2SO4干燥,真空下浓缩,得到无色油状物1-2(4.31g,24.11mmol,85%yield)。该油状物无需进一步纯化。
步骤2:化合物1-3的制备:
化合物1-2(4.31g,24.11mmol)和对TsOH·H2O(917.19mg,4.82mmol)的CH2Cl2溶液中在室温下搅拌一夜。然后用饱和的NaHCO3(30mL)洗涤有机相,并用CH2Cl2(3×30mL)提取水层。结合的有机物用水(100mL)清洗,然后在MgSO4上干燥,以得到淡黄色油状物1-3(3.88g,21.70mmol,90%yield)。
步骤3:化合物1-4的制备:
向化合物1-3(1.79g,10mmol)、磷钨杂多酸盐催化剂PW4O24[PTC]3(2.26g,1mmol),硫酸钠(1.42g,10mmol)的甲苯(2.11mL,20mmol)溶液中,通过恒压滴液漏斗缓慢滴加用0.5mol/L的NaOH溶液调节pH至8.0的35%的过氧化氢溶液(1.94g,20mmol),在室温下反应12小时,用乙酸乙酯(30mL×3)。合并后的有机相用饱和食盐水(50mL)洗涤,无水Na2SO4干燥,真空下除去溶剂,得到黄色油状粗品。使用硅胶柱层析法分离纯化(洗脱液:石油醚/乙酸乙酯=5/1至2/1)得到淡黄色油状物1-4(1.32g,6.8mmol,68%yield)。
步骤4:化合物1-5的制备:
固体ZnI2(651.17mg,2.04mmol)在120℃的真空干燥箱中中干燥1小时。冷却后,将环氧化物1-4(1.32g,6.8mmol)的甲苯溶液(23mL)加入ZnI2中。在回流条件下搅拌1小时,冷却至室温,用水(25mL)清洗。在Na2SO4上干燥,减压过滤和浓缩后,使用硅胶柱层析法分离纯化(洗脱液:石油醚/乙酸乙酯=60/1至40/1)得到黄色油状物1-5(1.13g,5.78mmol,85%yield)。1H NMR(500MHz,CDCl3)δ1.48(d,3H),2.28–2.67(m,2H),2.78–3.2(m,2H),3.25–3.73(m,IH),7.0–7.35(m,3H).
实施例2-实施例5:采用与实施例1相同的制备路线制备其它取代基情况的式(Ⅳ)所示化合物。本发明实施例2-实施例5分别制备了式(Ⅳ)通式所示的具体化合物2-5、化合物3-5、化合物4-5和化合物5-5,见表1。
表1:式(Ⅳ)所示具体化合物的制备
实施例6:地佐辛中间体杂质的合成
氮气保护下,在0℃,向化合物2-5(380.48mg,2mmol)、1,5-二溴戊烷(811.55μL,6mmol)、Aliquat 336(甲基三辛基氯化铵,64.47mg,0.2mmol)的甲苯溶液(29mL)中缓慢滴加50%aq KOH溶液(4.04g,36mmol)。反应温度缓慢上升至25℃后,继续搅拌12小时。水相用乙酸乙酯(50mL×3)。合并后的有机相用饱和食盐水(50mL)洗涤,无水Na2SO4干燥,过滤,真空下浓缩,得到无色油状混合物。使用硅胶柱层析法分离纯化(洗脱液:石油醚/乙酸乙酯=60/1至40/1)得到黄色固体2-6(155.56mg,0.70mmol,38%yield)、黄色油状物2-7(108.33mg,0.52mmol,23%yield)和无色油状物2-8(251.07mg,0.74mmol,37%yield),见下表2。
液相色谱分析条件:色谱柱依利特液相色谱柱:SinoChrom ODS-BP,5μm,流动相:MeOH/H2O=85/15,flow rate=1.0mL/min,temperature=19.7℃,紫外检测器监测波长254nm,进样量5μL,tr:2.103min(化合物2-8,地佐辛中间体化合物Ⅲ)2.432min(化合物2-6,杂质化合物Ⅰ),2.618min(化合物2-7,杂质化合物Ⅱ)。图1为化合物2-6的液相色谱图;图2为化合物2-7的液相色谱图;图3为化合物2-8的液相色谱图。
表2:以化合物2-5为原料制备杂质化合物(Ⅰ)、杂质化合物(Ⅱ)和地佐辛中间体化合物(Ⅲ)
实施例7:以实施例1制备的式(Ⅳ)所示化合物1-5为原料,采用与实施例6相同的合成条件,所得产物见表3,表3中的化合物1-6、化合物1-7和化合物1-8分别对应制备得到的杂质化合物(Ⅰ)、杂质化合物(Ⅱ)和地佐辛中间体化合物(Ⅲ)。,
表3以化合物1-5为原料制备杂质化合物(Ⅰ)、(Ⅱ)和地佐辛中间体化合物(Ⅲ)
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实施例8:以实施例3制备的式(Ⅳ)所示化合物3-5为原料,采用与实施例6相同的合成条件,所得产物见表4,表4中的化合物3-6、化合物3-7和化合物3-8分别对应制备得到的杂质化合物(Ⅰ)、杂质化合物(Ⅱ)和地佐辛中间体化合物(Ⅲ)。
表4以化合物3-5为原料制备杂质化合物(Ⅰ)、(Ⅱ)和地佐辛中间体化合物(Ⅲ)
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实施例9:以实施例4制备的式(Ⅳ)所示化合4-5为原料,采用与实施例6相同的合成条件,所得产物见表5,表5中的化合物4-6、化合物4-7和化合物4-8分别对应制备得到的杂质化合物(Ⅰ)、杂质化合物(Ⅱ)和地佐辛中间体化合物(Ⅲ)。
表5以化合物4-5为原料制备杂质化合物(Ⅰ)、(Ⅱ)和地佐辛中间体化合物(Ⅲ)
实施例10:以实施例5制备的式(Ⅳ)所示化合5-5为原料,采用与实施例6相同的合成条件,所得产物见表6,表6中的化合物5-6、化合物5-7分别对应制备得到的杂质化合物(Ⅰ)、杂质化合物(Ⅱ)。
表6以化合物5-5为原料制备杂质化合物(Ⅰ)和(Ⅱ)
其中,化合物5-5与1,5-二溴戊烷在50%aq KOH和Aliquat 336的甲苯溶液中反应24小时,只得到地佐辛中间体类似物的杂质5-6和5-7。
将本发明所制备的杂质做为标准品,可以通过色谱法检测在地佐辛中间体化合物(Ⅲ)制备过程中产物中杂质的含量,进而有利于地佐辛中间体和地佐辛进行定性和定量分析,以更好地提高地佐辛的质量。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。
Claims (6)
1.一种地佐辛中间体杂质化合物的制备方法,其特征在于,所述地佐辛中间体杂质化合物的结构式如式(Ⅰ)或式(Ⅱ)所示:
结构式(Ⅰ)和(Ⅱ)中,R1选自H、OCH3、Cl;R2选自H、Et;
所述地佐辛中间体杂质化合物的制备方法包括如下步骤:
1)将式(Ⅳ)所示化合物与1,5-二溴戊烷在碱和相转移催化剂的存在下反应,获得反应混合物;
R1选自H、OCH3、Cl;R2选自H、Et;
2)将所述反应混合物进行后处理、分离获得式(Ⅰ)和(Ⅱ)所示化合物和地佐辛中间体化合物(Ⅲ);
2.根据权利要求1所述的方法,其特征在于,步骤1)中所述的碱为氢氧化钾、氢氧化钠、碳酸钾、碳酸钠、碳酸铯或碳酸氢钠中的一种或多种;式(Ⅳ)所示化合物与碱的摩尔比为1:2~1:20。
3.根据权利要求1所述的方法,其特征在于,步骤1)中所述的相转移催化剂为四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丁基氟化铵、十二烷基三甲基溴化铵、三乙基苄基氯化铵、十二烷基硫酸钠或甲基三辛基氯化铵中的一种或多种;式(Ⅳ)所示化合物与相转移催化剂的摩尔比为1:0.05~1:0.5。
4.根据权利要求1所述的方法,其特征在于,步骤1)中所述反应在溶剂存在下进行,溶剂为甲苯、四氢呋喃、甲醇、乙醇、乙腈或水中的一种或多种。
5.根据权利要求1所述的方法,其特征在于,步骤1)所述反应的温度为0~25℃,反应时间为12~24h,化合物(Ⅳ)与1,5-二溴戊烷摩尔比为1:1~1:3。
6.根据权利要求1所述的方法,其特征在于,步骤2)中,反应混合物通过薄层层析色谱柱分离得到式(Ⅰ)和(Ⅱ)所示化合物,薄层层析色谱柱分离过程中,以石油醚和乙酸乙酯混合溶剂为洗脱剂,石油醚和乙酸乙酯的体积比为100:1~40:1。
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