CN102020574B - Derivant of propofol γ-aminobutyric acid ester and preparation method thereof - Google Patents
Derivant of propofol γ-aminobutyric acid ester and preparation method thereof Download PDFInfo
- Publication number
- CN102020574B CN102020574B CN200910190856.9A CN200910190856A CN102020574B CN 102020574 B CN102020574 B CN 102020574B CN 200910190856 A CN200910190856 A CN 200910190856A CN 102020574 B CN102020574 B CN 102020574B
- Authority
- CN
- China
- Prior art keywords
- organic solvent
- acid
- propofol
- halogen
- solvent
- 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.)
- Active
Links
- 229960004134 propofol Drugs 0.000 title claims abstract description 76
- -1 propofol γ-aminobutyric acid ester Chemical class 0.000 title claims abstract description 35
- 229960003692 aminobutyric acid Drugs 0.000 title claims abstract description 13
- 229940013945 gamma-Aminobutyric Acid Drugs 0.000 title claims abstract description 13
- 241001597008 Nomeidae Species 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- OLBCVFGFOZPWHH-UHFFFAOYSA-N Propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims abstract description 59
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000002253 acid Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000011780 sodium chloride Substances 0.000 claims abstract description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 239000003960 organic solvent Substances 0.000 claims description 58
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 28
- 150000002148 esters Chemical class 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- 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 17
- 150000002367 halogens Chemical class 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- 230000000875 corresponding Effects 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 claims description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000005712 crystallization Effects 0.000 claims description 8
- 238000004108 freeze drying Methods 0.000 claims description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 6
- 229960000583 Acetic Acid Drugs 0.000 claims description 5
- 230000003444 anaesthetic Effects 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- 229940038926 butyl chloride Drugs 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 150000003141 primary amines Chemical class 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- BGGHCRNCRWQABU-UHFFFAOYSA-N 2-azaniumyl-5-oxo-5-phenylmethoxypentanoate Chemical compound OC(=O)C(N)CCC(=O)OCC1=CC=CC=C1 BGGHCRNCRWQABU-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- OIOAKXPMBIZAHL-UHFFFAOYSA-N 2-azaniumyl-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoate Chemical compound CC(C)(C)OC(=O)CCC(N)C(O)=O OIOAKXPMBIZAHL-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 229960000448 Lactic acid Drugs 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229960005137 Succinic Acid Drugs 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229940099690 malic acid Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 14
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 10
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 5
- OWAQXCQNWNJICI-UHFFFAOYSA-N benzene;chloroform Chemical compound ClC(Cl)Cl.C1=CC=CC=C1 OWAQXCQNWNJICI-UHFFFAOYSA-N 0.000 claims 5
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims 5
- 239000008079 hexane Substances 0.000 claims 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-Chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 claims 1
- 229940035674 ANESTHETICS Drugs 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000003193 general anesthetic agent Substances 0.000 claims 1
- 229920005555 halobutyl Polymers 0.000 claims 1
- 125000004968 halobutyl group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 238000010992 reflux Methods 0.000 claims 1
- 239000000651 prodrug Substances 0.000 abstract description 19
- 229940002612 prodrugs Drugs 0.000 abstract description 19
- 238000002347 injection Methods 0.000 abstract description 6
- 239000007924 injection Substances 0.000 abstract description 6
- 206010002091 Anaesthesia Diseases 0.000 abstract description 4
- 230000037005 anaesthesia Effects 0.000 abstract description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 abstract description 2
- 230000003301 hydrolyzing Effects 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 210000002381 Plasma Anatomy 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000004519 grease Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- AOKCDAVWJLOAHG-UHFFFAOYSA-N 4-(methylamino)butyric acid Chemical compound C[NH2+]CCCC([O-])=O AOKCDAVWJLOAHG-UHFFFAOYSA-N 0.000 description 4
- 210000004369 Blood Anatomy 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- SMCBROTVHCSQQT-UHFFFAOYSA-N 4-(propan-2-ylazaniumyl)butanoate Chemical compound CC(C)NCCCC(O)=O SMCBROTVHCSQQT-UHFFFAOYSA-N 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N GABA Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000001949 anaesthesia Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000001187 sodium carbonate Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- YARMASSTSUTDQJ-HTXNQAPBSA-N (1E)-1-[(2-methylphenyl)hydrazinylidene]naphthalen-2-one Chemical compound CC1=CC=CC=C1N\N=C\1C2=CC=CC=C2C=CC/1=O YARMASSTSUTDQJ-HTXNQAPBSA-N 0.000 description 1
- UNEATYXSUBPPKP-UHFFFAOYSA-N 1,3-bis(propan-2-yl)benzene Chemical compound CC(C)C1=CC=CC(C(C)C)=C1 UNEATYXSUBPPKP-UHFFFAOYSA-N 0.000 description 1
- VCDKZPMRQQQCAZ-UHFFFAOYSA-N 4-[methyl(phenylmethoxycarbonyl)amino]butanoic acid Chemical compound OC(=O)CCCN(C)C(=O)OCC1=CC=CC=C1 VCDKZPMRQQQCAZ-UHFFFAOYSA-N 0.000 description 1
- 206010002216 Anaphylactoid reaction Diseases 0.000 description 1
- 208000006218 Bradycardia Diseases 0.000 description 1
- 210000004556 Brain Anatomy 0.000 description 1
- 102000013392 Carboxylesterase Human genes 0.000 description 1
- 108010051152 Carboxylesterase Proteins 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229960000239 Fospropofol Drugs 0.000 description 1
- 229940025708 Injectable Product Drugs 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M Monopotassium phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010063181 Propofol infusion syndrome Diseases 0.000 description 1
- 241000862969 Stella Species 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 210000003462 Veins Anatomy 0.000 description 1
- QVNNONOFASOXQV-UHFFFAOYSA-N [2,6-di(propan-2-yl)phenoxy]methyl dihydrogen phosphate Chemical compound CC(C)C1=CC=CC(C(C)C)=C1OCOP(O)(O)=O QVNNONOFASOXQV-UHFFFAOYSA-N 0.000 description 1
- SRXKIZXIRHMPFW-UHFFFAOYSA-N [4-[6-[amino(azaniumylidene)methyl]naphthalen-2-yl]oxycarbonylphenyl]-(diaminomethylidene)azanium;methanesulfonate Chemical compound CS([O-])(=O)=O.CS([O-])(=O)=O.C1=CC(N=C([NH3+])N)=CC=C1C(=O)OC1=CC=C(C=C(C=C2)C([NH3+])=N)C2=C1 SRXKIZXIRHMPFW-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002429 anti-coagulation Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000001580 bacterial Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 238000007675 cardiac surgery Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L disodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 229940000406 drug candidates Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035786 metabolism Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229950009865 nafamostat Drugs 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000003285 pharmacodynamic Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000002980 postoperative Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002773 propofol effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000028527 righting reflex Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000020681 well water Nutrition 0.000 description 1
- 239000002349 well water Substances 0.000 description 1
Abstract
The invention discloses water soluble compound (II) that the derivant of propofol gamma aminobutyric acid ester and these derivants become salt to be formed with acid and preparation method thereof.The present invention is that raw material obtains above-claimed cpd (II) with propofol (I).Such water soluble compound has logical formula (II),
Description
Technical field
The present invention relates to derivant of propofol γ-aminobutyric acid ester and preparation method thereof.
Background technology
Propofol (2,6-Bis(1-methylethyl)phenol, propofol), for fugitive general intravenous anesthesia medicine, onset is rapid, without substantially
Accumulation, revives fast and complete, and its injection is clinically for induction and the maintenance of general anesthesia.But because in its water, dissolubility is very
Little and clinic can only be applied to the form of Emulsion.But Emulsion has the disadvantages that 1, physical stability is poor；2, due to bigger
Droplet size may cause thromboembolism；3, injection causes pain；4, it is only capable of mixing with minority injectable product selectivity before medication
Close；5, Emulsion is prone to bacterial growth；6, heart aspect toxic and side effects etc. is easily caused.Disadvantage mentioned above limits 2,6-diisopropyl benzene
The use of phenol (see 1, Propofol and bradycardia:causation, frequency and
severity.British Journal of Anaesthesia 1997；78:642；Apotential mechanism of
propofol-induced pain on injection based on studiesusing nafamostat
Mesilate.British Journal of Anaesthesia.83:397.1999；2, McLeond G, Dick J, Wallis
C, et al.Propofol 2% in critically ill patients:effecton lipids.Crit Care Med
1997；25:1975-81；3、POSTOPERATIVEINFECTIONS TRACED TO CONTAMINATION OF AN
INTRAVENOUSANESTHETIC, PROPOFOL.N Engl J Med 1995；333:147-54；4、POSTOPERATIVE
INFECTIONS TRACED TO CONTAMINATION OF ANINTRAVENOUS ANESTHETIC, PROPOFOL.N
Engl J Med1995；333:147-54；5、Propofol-Induced Anaphylactoid Reaction
DuringAnesthesia for Cardiac Surgery。Journal of
CardiothoracicandVascularAnesthesia, Vol 14, No 2 (April), 2000:pp 200-201；6、
Propofol-infusion syndrome in shildren.The LANCET.VOL353.1999,1117).For a long time,
People always strive to propofol is carried out structural modification, have good aqueous solubility to obtaining and keep propofol effect
Prodrug.
Trapani in 1998 et al. discloses them first and (sees about the result of study of water-soluble prodrugs of propofol
International Journal of Pharmaceutics, 1998,175:195-204).This article discloses 8 propofol
Derivant, wherein 7 derivants can form water soluble compound with acid.Due to the 2 of propofol hydroxyl place phenyl ring, each on 6-position
Being associated with an isopropyl, have bigger steric hindrance, the most in vivo, carboxy-lesterase is difficult near the designed conjunction of Trapani et al.
The ester carbonyl group become, thus be difficult to by enzyme hydrolysis.Trapani et al. points out in conclusion, " although having in acid condition well
Water solublity, but owing to there being good stability in the homogenised tissue of blood plasma and brain ", thus traditional prodrug can not be developed into.
Hendler in 1999 et al. (seeing Water-soluble prodrugs of propofol, WO9958555) is public
Cloth propofol hydroxyl is by phosphoric acid direct esterification or by some derivants of aliphatic dicarboxylic acid mono-esterification.Also it is because propofol to divide
Isopropyl steric hindrance problem in son, esterase is difficult to hydrolyze the ester bond of these compounds, still can not develop into prodrug.
2003, Altomare et al. (saw Highly water-soluble derivatives of
Theanesthetic agent propofol:in vitro and in vivo evaluation of cyclic amino
Acidesters, European Journal of Pharmaceutical Sciences 2003,20:17-26) disclose number
The propofol prodrugs of individual cyclic amino acid esters, it is believed that the L-PROLINE ester of propofol may develop into prodrug, but does not has follow-up report
Road.
2005, there is document to disclose a series of multistage prodrug and (see Preparation ofaminoacid-derived
Prodrugs of propofol, US 2005004381；Aromatic prodrugsof propofol, their
Preparation, compositions, and therapeutic uses WO2005023204), but these prodrugs prepare ten
Divide trouble.
2006, Li Qingeng et al. disclosed the prodrug derivant of a series of propofol amino-acid ester.But these compounds
There is shortcoming in various degree, make troubles to clinical practice.
In propofol prodrugs is studied, the Fospropofol of most successful Stella of being et al. report (sees Water
Soluble Prodrugs of Hindered Alcohols, US6451776), the most push city as endoscope's medication
?.But there is a defect the biggest in this medicine, can discharge the formaldehyde that toxicity is the biggest, see below before discharging former medicine the most in vivo
Formula:
In view of the foregoing, it is necessary to propofol prodrugs is improved.
Summary of the invention
It is an object of the invention to provide the hydroxyl utilized in propofol, become deriving containing amine by chemical reaction
Thing, recycling amine becomes salt, the method preparing water solublity propofol γ-aminobutyric acid ester type compound with acid.Some of them
Compound by injection enter internal after can quickly hydrolyze and discharge propofol, produce anaesthetic effect, overcome propofol poorly water-soluble
Shortcoming.
The formula of the compound that the present invention relates to is
Wherein R=H, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl or isobutyl group；HB refers to can be as medicinal nothing
The acid of machine hydrochlorate, phosphoric acid, sulphuric acid or carbonic acid；Or can as medicinal organic acid acetic acid, lactic acid, methanesulfonic acid, succinic acid, citric acid or
Malic acid.
Its synthetic method specifically includes:
Method A: react formation ester in organic solvent A with γ-halo butyryl halogen by propofol (I), can add in reaction
Enter pyridine, DMAP or tertiary amine catalyst or go acid agent, reaction temperature-78 DEG C-backflow；Again in organic solvent A with containing ammonia or
The compound of primary amine replaces halogen and forms nitrogenous thing, reaction temperature-20 DEG C-50 DEG C；Then become with corresponding acid in solvent B
Salt, here, solvent B can be water or be organic solvent A, if solvent B is water, can obtain compound by lyophilization
(II)；If by organic solvent A, the crystallization of gained can be dried to obtain compound (II) by filtering under decompression or normal pressure.
Method B: by propofol (I) in organic solvent A with γ-halo butanoic acid at DCC/DMAP, or other are lived accordingly
Property material effect under reaction formed halogen ester, reaction temperature-20 DEG C-50 DEG C；Again with the change containing ammonia or primary amine in organic solvent A
Compound replaces halogen and forms nitrogenous thing, reaction temperature-20 DEG C-50 DEG C；Then in solvent B with corresponding acid become salt, here,
Solvent B can be water or be organic solvent A, if solvent B is water, can obtain compound (II) by lyophilization；If with having
Machine solvent orange 2 A, the crystallization of gained can be dried to obtain compound (II) by filtering under decompression or normal pressure.
Method C: by propofol (I) in organic solvent A with γ-Cbz-aminobutyric acid or derivatives thereof at DCC/DMAP,
Or reaction forms ester, reaction temperature-20 DEG C-50 DEG C under other corresponding active substance effects；Then in organic solvent C,
Pd-C (5 or 10%)/H2Sloughing Cbz under effect, finally become salt with corresponding acid in solvent B, here, solvent B can be
Water or be organic solvent A, if solvent B is water, can obtain compound (II) by lyophilization；If with organic solvent A, gained
Crystallization can by filter, decompression or normal pressure under be dried to obtain compound (II).
Method D: by propofol (I) in organic solvent A with γ-Boc-aminobutyric acid or derivatives thereof at DCC/DMAP,
Or reaction forms ester, reaction temperature-20 DEG C-50 DEG C under other corresponding active substance effects；Then it is passed through in organic solvent A
HCl, obtains compound (II).
Method E: propofol (I) carboxylic acid halides with γ-Cbz-aminobutyric acid or derivatives thereof in organic solvent A is reacted,
Also formation ester, reaction temperature-20 DEG C-50 can be reacted under pyridine or DMAP or tertiary amine, or other corresponding active substance effects
℃；Then in organic solvent C, at H2Cbz is sloughed under/Pd-C (5 or 10%) effect, finally sour with corresponding in solvent B
Becoming salt, here, solvent B can be water or be organic solvent A, if solvent B is water, can obtain compound by lyophilization
(II)；If by organic solvent A, the crystallization of gained can be dried to obtain compound (II) by filtering under decompression or normal pressure.
It is significant, good water-soluble that the salt (II) of part propofol γ-aminobutyric acid ester of the present invention has fertilising
Property, they decomposable asymmetric choice net in rabbit plasma discharge propofol, and mouse experiment shows have certain anesthetic action.
The fusing point of various salt of propofol γ-aminobutyric acid ester, dissolubility and corresponding pH value
Part of compounds in the present invention, on the premise of not changing the pharmacologically active that propofol is intrinsic, passes through chemical reaction
Obtain water soluble compound, it is intended to reduce toxic and side effects.
Detailed description of the invention
Embodiment 1: the synthesis of propofol γ-aminobutyric acid ester hydrochloride
1. propofol γ-Boc-aminobutyric acid ester: by Boc-NHCH2CH2CH2COOH 2.12g, DCC1.16g, in room temperature
Under be dissolved in the anhydrous CH of 20ml2Cl2In, stirring is lower adds propofol 1g and 0.34gDMAP, normal-temperature reaction 12h, reacts to propofol
Substantially completely, filtering, filtrate water is washed till neutrality, organic layer anhydrous Na2SO4It is dried overnight.Filter, fling to CH2Cl2, obtain light
Yellow oil.
2. propofol γ-aminobutyric acid ester hydrochloride: by embodiment 1 gained grease 10mlCH2Cl2Dissolve, be passed through
HCl gas, stirs 30min, flings to CH2Cl2, obtain faint yellow semi-solid thing, dissolve with ethyl acetate 5ml, add ether knot
Crystalline substance, obtains white solid 1.34g, fusing point: 137.2-138.6 DEG C, purity 97.5% (HPLC), yield 70%.
Embodiment 2: propofol N-methyl-γ-aminobutyric acid ester hydrochloride synthesis (Boc protects route)
1. propofol N-Boc-N-methyl-γ-aminobutyric acid ester: 4.66g γ-N-Boc-N-methylaminobutyric acid is dissolved in
40ml CH2Cl2In, adding DCC7.98g and DMAP1.8g, stirring is lower adds 3.44g propofol, room temperature reaction 60 hours.Cross
Filtering, filtrate is washed with dilute hydrochloric acid, 5% sodium carbonate liquor, saturated common salt aqueous solution successively, and organic stratification anhydrous sodium sulfate is dried,
Filtering, filtrate is concentrated to give grease.
2. propofol N-methyl-γ-aminobutyric acid ester hydrochloride: by above-mentioned propofol N-Boc-N-methyl-gamma-amino fourth
Acid esters grease is dissolved in 50ml ethyl acetate, is passed through HCl gas 1h, concentrating under reduced pressure, adds ether to precipitation completely in residual liquid,
Filtering, obtain white solid, with methanol/petroleum ether/ethyl ether system recrystallization, drying under reduced pressure obtains 3.13g white solid, yield
51.74% (in terms of propofol), HPLC measures, and purity is 99.05%.
Embodiment 3: propofol N-methyl-γ-aminobutyric acid ester hydrochloride synthesis (acid chloride route)
1.N-Cbz-N-methyl-gamma-amino butyl chloride: 4.30g N-Cbz-N-methyl-γ-aminobutyric acid is dissolved in 20ml
CH2Cl2In, it is slowly added to 4.1g SOCl under ice bath2；React 3 hours.Reaction is finished, and flings to CH2Cl2With unnecessary SOCl2, obtain N-
Cbz-N-methyl-gamma-amino butyl chloride.
2. propofol N-Cbz-N-methyl-γ-aminobutyric acid ester: 3.05g propofol is dissolved in 20ml CH2Cl2With 7ml pyrrole
In pyridine, under ice bath, it is slowly added to 4.61gN-Cbz-N-methyl-gamma-amino butyl chloride, drips and finish, room temperature reaction 24 hours.Reactant liquor
Wash with dilute HCl solution, then use H2O is washed till neutrality, and organic layer anhydrous sodium sulfate is dried, and flings to solvent, residue silica gel
Layer post analysis (flowing phase: petroleum ether: ethyl acetate=10: 1), obtains white solid 2.73g, yield 51.49%.
3. propofol N-methyl-γ-aminobutyric acid ester hydrochloride: by above-mentioned for 2.73g propofol N-Cbz-N-methyl-γ-
Aminobutyric acid ester is dissolved in the mixed solvent of 10ml methanol and 2ml glacial acetic acid, adds 0.3gPd/C1 (10%), is passed through under stirring
Hydrogen, reacts 6 hours.Filter, decompression remove solution, residue is dissolved in 10ml dilute hydrochloric acid (wherein the amount of HCl be equivalent to put into
The mole of propofol N-Cbz-N-methyl-γ-aminobutyric acid ester), aqueous solution 10ml petroleum ether extraction 3 times, freezing dry
Dry, obtain white solid 1.73g, yield 83.5%.HNMR (δ): 1.038～1.193 (12H), 1.951～2.044 (2H),
2.732～2.943 (7H), 3.312～3.445 (3H), 7.129～7.256 (3H), 9.162 (2H).
Embodiment 4
Propofol N--isopropyl-γ-aminobutyric acid ester hydrochloride
1.N-isopropyl-γ-aminobutyric acid: 2g γ-aminobutyric acid be dissolved in 7.2ml acetone and 13ml methanol, adds
0.16g 10% palladium charcoal, is stirred at room temperature down and is passed through hydrogen 24 hours, filters, and filtrate decompression is vacuum dried, and obtains white solid 2.7g,
Yield 95%, m.p.:159.2-162.7 DEG C.
2.N-Cbz-N-isopropyl-γ-aminobutyric acid: 2g N-isopropyl-γ-aminobutyric acid (0.0138mol) is dissolved in
In the mixed solvent of 8ml water and 24ml methanol, add sodium carbonate 2.4g, be slowly added dropwise Cbz-C1, room temperature reaction 12 hours, fling to
Methanol, adds 60ml water and is dissolved by grease, wash with ether, and water layer 1N HCl solution adjusts pH to be about 3, solution acetic acid second
Ester extracts, and organic layer anhydrous sodium sulfate is dried, and filters, and decompression volatilizes ethyl acetate, obtains pale yellow oil 1.42g, yield
36.9%.
3.N-Cbz-N-isopropyl-gamma-amino butyl chloride: 1.8g N-Cbz-N-isopropyl-4-Aminobutanoicacid is dissolved in
In 20ml dichloromethane, less than 5 DEG C, drip 0.55ml SOCl2, dripping and finish, room temperature reaction 4-6 hour, evaporated under reduced pressure is organic molten
Agent, obtains brown oil.
4. propofol N-Cbz-N-isopropyl-4-Aminobutanoicacid ester: 0.5g propofol is dissolved in 1.5ml pyridine, ice bath
The cooling lower dropping 10ml dichloromethane solution containing 1.5g N-Cbz-N-isopropyl-4-aminobutyryl chlorine, drips and finishes, be stirred at room temperature
React more than 1 hour；Reaction is finished, and addition 1N HCl solution, to about pH3, is washed to neutrality, and anhydrous sodium sulfate is dried organic layer,
Filter, fling to solvent, participate in thing column chromatography (silica gel: 200-300 mesh；Flowing phase: petroleum ether: ethyl acetate=20: 1) purification,
Decompression volatilizes solvent, obtains grease 0.96g, yield 78.5%.
5. propofol N-isopropyl-γ-aminobutyric acid ester hydrochloride: by 1.3g propofol N-Cbz-N-isopropyl-4-ammonia
Base butyrate is dissolved in 10ml acetic acid, adds 0.25g10% palladium charcoal, is passed through hydrogen 3h under room temperature, and reaction is finished, and add water 5ml, mistake
Filter, adds solid NaHCO under filtrate ice bath3Producing to bubble-free, ether extraction (15mlX3), ether layer anhydrous sodium sulfate is done
Dry, filter, concentration ether to 6ml, under ice bath stirring, drip the diethyl ether solution of saturated HCl, white solid separates out, and filters, room
Temperature drying under reduced pressure, obtains white solid 1.25g, yield 46.3%, fusing point 223.9-225.1 DEG C.
(cm-1): 3584,3490,2965,2786,2488,2421,1756,1467,1266,1163；HNMR (δ): 0.921
～1.195 (12H), 1.247～1.329 (6H), 2.033 (2H), 2.858～2.943 (6H), 3.254 (1H), 7.131～
7.264 (3H), 9.134 (2H).
Embodiment 5
Propofol prodrug rabbit plasma decomposition experiment result
1, the preparation of need testing solution: it is appropriate that precision weighs following 7 kinds of samples, is dissolved in water and dilutes and make every 1ml and contain
The solution of 1mg, shakes all, to obtain final product.
2, chromatographic condition: be chromatographic column with C18 (150*4.6mm, 5 μm), buffers molten with the potassium dihydrogen phosphate of 0.01mol/L
Liquid (every 100ml 0.5ml Han triethylamine, phosphoric acid adjusts pH to 3.0)-methanol (36-65) is flowing phase, detects wavelength 210nm, flow velocity
For 1.5ml per minute, sample size 100 μ l.
3, blood plasma decomposition experiment method: take in the EP pipe that rabbit whole blood 1ml puts 5ml, uses EDTA-2Na anticoagulant, standby.Accurate
Measure each three parts of above-mentioned 7 kinds of solution 0.1ml to be separately added in above-mentioned whole blood, at 38.0 DEG C of shake wells, respectively 2 minutes, 10
Minute and take out whole blood 1 respectively when 20 minutes, add methanol 3ml, vortex 3 minutes, 12000 revs/min 10 minutes, take supernatant
Sample introduction, calculates prodrug and the ratio of propofol in area normalization method.Result see table:
Table propofol prodrugs metabolism result in rabbit whole blood
Result: 7 samples all have preferable decomposition rate in rabbit plasma, in 10min, substantially all complete hydrolysis becomes
Propofol.
Embodiment 6
Pharmacodynamics in Mice is tested
Laboratory animal: Kun Ming mice 140, male and female half and half, body weight 19-25g.
Experimental drug: take off respectively and state medicine 25mg, is dissolved in 5ml normal saline.
Experimental technique: mice is divided into 14 groups, often group 10, use tail vein injection to be administered, observe whether righting reflex disappears
Lose.
Experimental result such as following table:
Table propofol prodrugs test of pesticide effectiveness result
Claims (9)
1. the derivant of propofol γ-aminobutyric acid ester becomes the water soluble compound that salt is formed with acid, it is characterised in that this change
Compound has a general formula:
Wherein R=H, methyl, ethyl；HB represents can be as medicinal acid.
The most according to claim 1, the derivant of propofol γ-aminobutyric acid ester becomes the water solublity chemical combination that salt is formed with acid
Thing, it is characterised in that: HB refers to can be as medicinal mineral acid hydrochloric acid, phosphoric acid, sulphuric acid or carbonic acid；Or can be as medicinal organic
Acid acetic acid, lactic acid, methanesulfonic acid, succinic acid, citric acid or malic acid.
3. the synthetic method of compound described in claim 1 or 2, it is characterised in that the method is:
By propofol (I) more than 3 times in the organic solvent A of weight with more than or equal to the γ-halogen of propofol (I) mole
Form ester for butyl chloride reaction, reaction adds pyridine or DMAP or tertiary amine catalyst or goes acid agent, reaction temperature-78 DEG C
Reflux temperature；Formed contain described ester organic solvent A more than 3 times of weight replaces halogen with excess of ammonia or primary amine again
Nitrogen thing, reaction temperature-20 DEG C 50 DEG C；Then described nitrogenous thing is dissolved in solvent B and becomes salt with corresponding acid HB, finally
To compound (II)；
Described organic solvent A is halogen-containing organic solvent dichloromethane, chloroform or chlorobenzene；Or the most halogen-containing organic solvent
Benzene, toluene, hexane or hexamethylene；Or containing other heteroatomic organic solvent acetonitriles, acetone, DMF, DMSO, THF or ether;
Described solvent B is described organic solvent A or water；When using water as solvent, obtain compound (II) by lyophilization；With institute
When stating organic solvent A, the crystallization of gained, by filtering, is dried to obtain compound (II), is dried and carries out under decompression or normal pressure.
4. the synthetic method of compound described in claim 1 or 2, it is characterised in that the method is:
By in the propofol (I) organic solvent A more than 3 times of weight with excess γ-halo butanoic acid in DCC/DMAP effect
Lower reaction forms halogen ester, reaction temperature-20 DEG C 50 DEG C；Again by described halogen ester organic solvent A more than 3 times of weight
Replace halogen with excess of ammonia or primary amine and form nitrogenous thing；Then described nitrogenous thing is dissolved in solvent B and becomes salt with corresponding acid,
Finally obtain compound (II)；
Described organic solvent A is halogen-containing organic solvent dichloromethane, chloroform or chlorobenzene；Or the most halogen-containing organic solvent
Benzene, toluene, hexane or hexamethylene；Or containing other heteroatomic organic solvent acetonitriles, acetone, DMF, DMSO, THF or ether;
Described solvent B is described organic solvent A or water；When using water as solvent, obtain compound (II) by lyophilization；With institute
When stating organic solvent A, the crystallization of gained, by filtering, is dried to obtain compound (II), is dried and carries out under decompression or normal pressure.
5. the synthetic method of compound described in claim 1 or 2, it is characterised in that the method is:
By in the propofol (I) organic solvent A more than 3 times of weight with excess γ-Cbz-aminobutyric acid appropriate
The lower reaction of DCC/DMAP effect forms ester, reaction temperature-20 DEG C 50 DEG C；Then by described ester having more than 3 times of weight
In machine solvent C, at H2Slough Cbz under/Pd-C effect, finally the ester of the described Cbz of sloughing is dissolved in solvent B and corresponding acid
Become salt, obtain compound (II)；
Described organic solvent A is halogen-containing organic solvent dichloromethane, chloroform or chlorobenzene；Or the most halogen-containing organic solvent
Benzene, toluene, hexane or hexamethylene；Or containing other heteroatomic organic solvent acetonitriles, acetone, DMF, DMSO, THF or ether;
Described solvent B is described organic solvent A or water；When using water as solvent, obtain compound (II) by lyophilization；With institute
When stating organic solvent A, the crystallization of gained, by filtering, is dried to obtain compound (II), is dried and carries out under decompression or normal pressure;
Described organic solvent C is the most halogen-containing organic solvent THF, ether, methanol, ethanol, ethyl acetate or acetic acid.
6. the synthetic method of compound described in claim 1 or 2, it is characterised in that the method is:
By in the propofol (I) organic solvent A more than 3 times of weight with excess γ-Boc-aminobutyric acid appropriate
The lower reaction of DCC/DMAP effect forms ester, reaction temperature-20 DEG C 50 DEG C；Then described ester is passed through in organic solvent A
HCl, obtains compound (II)；
Described organic solvent A is halogen-containing organic solvent dichloromethane, chloroform or chlorobenzene；Or the most halogen-containing organic solvent
Benzene, toluene, hexane or hexamethylene；Or containing other heteroatomic organic solvent acetonitriles, acetone, DMF, DMSO, THF or ether.
7. the synthetic method of compound described in claim 1 or 2, it is characterised in that the method is:
By the propofol (I) organic solvent A more than 3 times of weight is reacted with excessive γ-Cbz-aminobutyryl halogen, also may be used
Under pyridine or DMAP or tertiary amine effect, reaction forms ester, reaction temperature-20 DEG C 50 DEG C simultaneously；Then by described ester 3
In organic solvent C more than times weight, at H2Slough Cbz under/Pd-C effect, finally by slough the ester of Cbz in solvent B with
Corresponding acid becomes salt, obtains compound (II)；
Described organic solvent A is halogen-containing organic solvent dichloromethane, chloroform or chlorobenzene；Or the most halogen-containing organic solvent
Benzene, toluene, hexane or hexamethylene；Or containing other heteroatomic organic solvent acetonitriles, acetone, DMF, DMSO, THF or ether;
Described solvent B is described organic solvent A or water；When using water as solvent, obtain compound (II) by lyophilization；With institute
When stating organic solvent A, the crystallization of gained, by filtering, is dried to obtain compound (II), is dried and carries out under decompression or normal pressure;
Described organic solvent C is the most halogen-containing organic solvent THF, ether, methanol, ethyl acetate or acetic acid.
Method the most according to claim 3, it is characterised in that the halogen atom in described halo butyl chloride is chlorine or bromine.
9. the derivant of the propofol γ-aminobutyric acid ester described in claim 1 or 2 is become with acid the water solublity that salt is formed
Compound (II) produces the anesthetics of anesthetic action for preparation to animal and people.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910190856.9A CN102020574B (en) | 2009-09-14 | Derivant of propofol γ-aminobutyric acid ester and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910190856.9A CN102020574B (en) | 2009-09-14 | Derivant of propofol γ-aminobutyric acid ester and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102020574A CN102020574A (en) | 2011-04-20 |
| CN102020574B true CN102020574B (en) | 2016-12-14 |
Family
ID=
Non-Patent Citations (1)
| Title |
|---|
| water-soluble salts of aminoacid esters of the anaesthetic agent propofol;Giuseppe Trapani et al.;《International Journal of Pharmaceutics》;19981231;第175卷;第195-204页 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4913796B2 (en) | Crystalline form of γ-aminobutyric acid analog | |
| CN103596566B (en) | Polycyclic LPA1Antagonist and its use | |
| JP2009046486A (en) | Analogue or derivative of quercetin (prodrug) | |
| JP2022502510A (en) | Nitroxoline prodrug and its use | |
| WO2016192560A1 (en) | Tenofovir monobenzyl ester phosphamide prodrug, preparation method and use thereof | |
| CN106866572B (en) | Nitric oxide donator type β elemene derivatives and its production and use | |
| JP6952911B2 (en) | 2- (α-Hydroxypentyl) benzoic acid organic amine ester derivative drug | |
| CN1907954B (en) | Water-soluble derivative of anesthetic 2,6-diisopropyl phenol and preparation method thereof | |
| CN102762554A (en) | (r)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2h-pyran-4-ol, a partial agonist of 5-ht4 receptors | |
| JP7050336B2 (en) | Deuterated compounds and their pharmaceutical uses | |
| CN102382005B (en) | Propofol ester derivative containing amino carboxylic acid amide structure, its preparation method and its purpose | |
| EP2767533B1 (en) | Derivative of butylphthalide and preparation method and use thereof | |
| CN111253412B (en) | Alpha-mangostin derivative and application thereof | |
| CN102020574B (en) | Derivant of propofol γ-aminobutyric acid ester and preparation method thereof | |
| CN104761610A (en) | Novel alpha-hederin derivative and preparation method and use thereof | |
| CN102260184B (en) | Propofol derivative as well as preparation method thereof and application thereof | |
| KR101247137B1 (en) | Process for the preparation of N-[O-(P-Pivaloyloxybenzenesulfonylamino)-benzoyl]glycin and for the formulation of the lyophilization containing its mononatrium saltㆍ4 hydrate | |
| CN102020574A (en) | diisopropylphenyl gamma-aminobutyrate derivatives and preparation methods thereof | |
| CN106146612B (en) | A kind of glyoxalase I irreversible inhibitor and its preparation method and application | |
| CN104262292B (en) | Phenylacetate compound and its application | |
| CN111285900B (en) | Coupling molecule DCZ0847 compound based on pterostilbene and apocynin, preparation method and application thereof | |
| CN110092799B (en) | Cyclic compound, preparation method and application thereof | |
| CN117736201A (en) | Targeted histone deacetylase 8 proteolytic chimera, preparation method and application thereof | |
| CN104402818B (en) | A kind of compound or pharmaceutically acceptable salt thereof with tumour response release medicine and preparation, application | |
| KR101366706B1 (en) | Process for the preparation of N-[O-(P-Pivaloyloxybenzenesulfonylamino)-benzoyl]glycin and for the formulation of the lyophilization containing its mononatrium saltㆍ4 hydrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20161011 Address after: Guangdong city of Zhongshan province Southern China Nanlang 528451 modern Chinese Medicine City Branch Chong Park No. 2 Applicant after: Zhong Shanwanhan Pharmaceutical Technology Co., Ltd Address before: 400016 Institute of medicine, Medical University Of Chongqing, 1 Medical College Road, Yuzhong, Chongqing Applicant before: Li Qingeng |
|
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: Guangdong city of Zhongshan province Southern China Nanlang 528451 modern Chinese Medicine City Branch Chong Park No. 2 Patentee after: Zhongshan Wan Han Pharmaceutical Co., Ltd. Address before: Guangdong city of Zhongshan province Southern China Nanlang 528451 modern Chinese Medicine City Branch Chong Park No. 2 Patentee before: Zhong Shanwanhan Pharmaceutical Technology Co., Ltd |