CN110981832A - Preparation method of roxatidine acetate hydrochloride - Google Patents
Preparation method of roxatidine acetate hydrochloride Download PDFInfo
- Publication number
- CN110981832A CN110981832A CN201911063245.8A CN201911063245A CN110981832A CN 110981832 A CN110981832 A CN 110981832A CN 201911063245 A CN201911063245 A CN 201911063245A CN 110981832 A CN110981832 A CN 110981832A
- Authority
- CN
- China
- Prior art keywords
- reaction
- roxatidine acetate
- dichloromethane
- extracting
- acetate hydrochloride
- 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.)
- Pending
Links
- 229960000627 roxatidine acetate hydrochloride Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 135
- 238000006243 chemical reaction Methods 0.000 claims abstract description 72
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 42
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims abstract description 38
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000001914 filtration Methods 0.000 claims abstract description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 24
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003513 alkali Substances 0.000 claims abstract description 20
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 20
- 238000001035 drying Methods 0.000 claims abstract description 19
- 238000005406 washing Methods 0.000 claims abstract description 19
- SMTZFNFIKUPEJC-UHFFFAOYSA-N Roxane Chemical compound CC(=O)OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 SMTZFNFIKUPEJC-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229960003287 roxatidine acetate Drugs 0.000 claims abstract description 14
- 238000000746 purification Methods 0.000 claims abstract description 13
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 claims abstract description 11
- IHPRVZKJZGXTBQ-UHFFFAOYSA-N 3-chloropropan-1-amine;hydron;chloride Chemical compound Cl.NCCCCl IHPRVZKJZGXTBQ-UHFFFAOYSA-N 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000005893 bromination reaction Methods 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 229960001701 chloroform Drugs 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 238000000643 oven drying Methods 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 238000003756 stirring Methods 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 238000007865 diluting Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- KYPNQHWSJGEREB-UHFFFAOYSA-N 3-(3-methylphenoxy)propan-1-amine Chemical compound CC1=CC=CC(OCCCN)=C1 KYPNQHWSJGEREB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 229960003320 roxatidine Drugs 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- -1 1-piperidylmethyl Chemical group 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 208000028571 Occupational disease Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- DPCZALPCMCPHAK-UHFFFAOYSA-N hydron;2-hydroxy-n-[3-[3-(piperidin-1-ylmethyl)phenoxy]propyl]acetamide;chloride Chemical compound Cl.OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 DPCZALPCMCPHAK-UHFFFAOYSA-N 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003892 spreading Methods 0.000 description 2
- 230000007480 spreading Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- SIXYIEWSUKAOEN-UHFFFAOYSA-N 3-aminobenzaldehyde Chemical compound NC1=CC=CC(C=O)=C1 SIXYIEWSUKAOEN-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002243 Anastomotic ulcer Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 102000003710 Histamine H2 Receptors Human genes 0.000 description 1
- 108090000050 Histamine H2 Receptors Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010024769 Local reaction Diseases 0.000 description 1
- 206010035669 Pneumonia aspiration Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Abstract
The preparation method of the roxatidine acetate hydrochloride comprises the following steps: the method comprises the following steps: dissolving m-cresol and 3-chloropropylamine hydrochloride in a reaction solvent in proportion, extracting after the reaction of the raw material m-cresol is finished in the presence of alkali, and concentrating after simple purification to obtain an intermediate 1; step two: dissolving the intermediate 1 and alkali in a reaction solvent according to a certain proportion, dripping acetoxyacetyl chloride at low temperature, extracting and concentrating after the intermediate 1 reacts to obtain an intermediate 2; step three: carrying out bromination reaction on the intermediate 2 and N-bromosuccinimide, and directly washing and extracting to obtain an intermediate 3; step four: after the intermediate 3 and excessive piperidine react in the solvent, concentrating, extracting with dichloromethane, drying, and further purifying with acetic anhydride to obtain roxatidine acetate; step five: dissolving the intermediate 3 in acetone, dropwise adding hydrochloric acid to form salt, filtering, and drying; step six: mixing with absolute ethyl alcohol, filtering, cooling, crystallizing and drying to obtain the roxatidine acetate hydrochloride.
Description
Technical Field
The invention relates to the field of chemical preparation, in particular to a method for preparing roxatidine acetate hydrochloride, which particularly comprises the steps of preparing roxatidine acetate by taking m-cresol, 3-chloropropylamine hydrochloride, acetoxyacetyl chloride and piperidine as raw materials through four-step reactions of Willemson ether formation, condensation, benzyl bromination and haloalkane amination, and salifying with hydrochloric acid to obtain the roxatidine acetate hydrochloride.
Background
Roxatidine Acetate (RXTA) was developed by the organ pharmaceutical company of the imperial japan, and was first approved by the ministry of japan for marketing in 1986. Chemistry of RXTAIs named as 2-acetoxy-N- [3- [3- (1-piperidylmethyl) phenoxy ] methyl]Propyl radical]An acetamide; the molecular formula is as follows: c19H28N2O4(ii) a Molecular weight: 348.40. in vivo, the product is deacetylated by hydrolysis and then rapidly converted into an active metabolite Roxatidine (RXT), the latter can selectively block histamine H2 receptor, and the product is mainly used for preventing and treating digestive system diseases caused by high gastric acid secretion state, such as gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, acute gastritis and acute attack of chronic gastritis; also can be used for preventing inhalation pneumonia by pre-anesthesia administration (Drugs, 1991, 42 (2): 240-.
With regard to the synthesis of roxatidine acetate hydrochloride, the current reports mainly use m-hydroxybenzaldehyde as the starting material, and the reaction is carried out by reductive amination and Williamson ether formation to obtain 3- [3- (1-piperidinylmethyl) phenoxy) ] propylamine (intermediate II), and then obtain roxatidine acetate (CN1986535A, CN101717363B, Molecules 2009, 14(5), 1818-1824, Synthetic Communications (1999), 29(1), 15-20) through the following three routes.
The roxatidine acetate hydrochloride is prepared by the synthesis route, most basic benzaldehyde is taken as an initial material, the roxatidine acetate is prepared by a total synthesis six-step reaction, the step 1 is a nitration reaction, the operation requirement on workshop personnel is high, the nitration reaction is slightly careless, the local reaction overheating is too fast due to improper operation, and further the explosion danger is caused, the step 3 is not a clean and environment-friendly hydrogenation reduction mode due to the structural particularity of m-aminobenzaldehyde, only reducing agents such as iron, ferrous salt, zinc and the like are adopted for reduction, solid wastes are increased, the environment is extremely not protected, the atom utilization rate is low, phenol is prepared after diazotization reaction of arylamine compounds, the reaction is carried out under the condition of strong acid and is accompanied with generation of brown pungent gas, aniline compounds belong to genotoxic substances, the occupational diseases of operators are easy to be caused, and m-hydroxy benzaldehyde is taken as a key intermediate, the subsequent reaction has small batch production amount, is not suitable for industrial production, and can ensure the quality of finished products only after step separation and purification, so the m-hydroxybenzaldehyde is an unsuitable key intermediate material, an economic and enlargeable synthetic route is specially developed aiming at various defects, the environmental pollution is reduced, the occupational disease risk of operators is reduced, the atom utilization rate is improved as a starting point, the most basic m-cresol is taken as a starting material, the roxatidine acetate is prepared by four steps of reaction, and then the roxatidine acetate hydrochloride is prepared by salt formation and refining. The method has the advantages of reduced purification times, shortened synthesis route, easy research and control of impurities of raw materials, shortened working hours in process, reduced three wastes and reaction energy consumption, simple process, mild reaction conditions, easy operation, high total yield, and suitability for industrial production.
Disclosure of Invention
Aiming at the defects in the prior art, the preparation method of roxatidine acetate hydrochloride provided by the invention solves the technical problems, so that the post-treatment operation is simple and safe, the product purity is high, a stability investigation experiment is carried out on the roxatidine acetate hydrochloride, the roxatidine acetate hydrochloride meets various standards of raw material medicines through detection, the quality of an intermediate in each step is easy to control, particularly, the first step and the second step in a route can be subjected to the next reaction without further purification, the operation is simple, the reaction conditions are mild, the atom utilization rate of the whole route is high, the product is stable, and the industrial production is easier.
In order to achieve the purpose, the invention provides the following technical scheme:
the invention provides a preparation method of roxatidine acetate hydrochloride, which is prepared by the following reaction equation:
the preparation method of the roxatidine acetate hydrochloride comprises the following steps:
the reaction and post-treatment method comprises the following steps: : dissolving m-cresol and 3-chloropropylamine hydrochloride in a reaction solvent according to a ratio (the feeding ratio is 1.0: 1.0-1.0: 2.5), extracting after the reaction of the m-cresol serving as a raw material is finished in the presence of alkali (one of sodium hydroxide, potassium carbonate, sodium carbonate and cesium carbonate), and concentrating after simple purification to obtain an intermediate 1.
The reaction and post-treatment method in the second step is as follows: dissolving the intermediate 1 and alkali (one of triethylamine, pyridine, diisopropylethylamine and sodium bicarbonate) in a reaction solvent according to a molar ratio of 1.0: 1.0-1.0: 2.0, dropwise adding acetoxyacetyl chloride at low temperature, and extracting and concentrating the intermediate 1 after the reaction to obtain an intermediate 2 (without further purification).
The reaction and post-treatment method in the third step is as follows: and (3) carrying out bromination reaction on the intermediate 2 and the NBS in a solvent (dichloromethane, trichloromethane and carbon tetrachloride) according to a ratio (1.0: 0.9-1.0: 1.1), directly washing and extracting after the reaction is finished, concentrating to obtain an intermediate 3, and directly entering the next step.
The reaction and post-treatment method in the fourth step is as follows: and after the intermediate 3 and excessive piperidine react in the solvent, concentrating, extracting with dichloromethane, drying, and further purifying with acetic anhydride to obtain the roxatidine acetate.
The preparation method of the crude product in the step five is as follows: dissolving the intermediate 3 in acetone, dripping hydrochloric acid (or introducing hydrogen chloride gas) at low temperature to form salt, filtering, and drying.
The refining method in the sixth step is as follows: mixing with anhydrous ethanol, dissolving at controlled temperature, filtering, cooling, crystallizing, filtering, and oven drying to obtain roxatidine acetate hydrochloride.
Wherein the reaction conditions of the first step are as follows:
1) the feeding ratio of the m-cresol to the 3-chloropropylamine hydrochloride is 1.0: 1.0-1.0: 2.5; preferably 1.0: 2.0;
2) the alkali is inorganic alkali: sodium hydroxide, potassium carbonate, sodium carbonate and cesium carbonate, preferably sodium hydroxide;
3) the mol ratio of the m-cresol to the alkali is 2: 1-15: 1, preferably 3: 1;
4) the reaction solvent is: dimethyl sulfoxide, N-dimethylformamide, azomethylpyrrolidone and toluene, preferably dimethyl sulfoxide;
5) the reaction temperature is as follows: 0 to 120 ℃, preferably 20 to 40 ℃.
Wherein the reaction conditions of the second step are as follows:
1) the molar ratio of the intermediate 1 to acetoxyacetyl chloride is 1.0: 1.0-1.0: 2.0; preferably 1.0: 1.2;
2) the base is triethylamine, pyridine, diisopropylethylamine and sodium bicarbonate, preferably triethylamine;
3) the molar ratio of the intermediate 1 to the alkali is 1.0: 1.0-1.0: 2.0, preferably 1: 1.2;
4) the reaction solvent is dichloromethane, N-dimethylformamide and tetrahydrofuran, preferably dichloromethane;
5) the reaction temperature is as follows: -20 to 20 ℃, preferably 0 to 10 ℃.
Wherein the reaction conditions of the third step are as follows:
1) the molar ratio of the intermediate 2 to NBS (N-bromosuccinimide) or bromine is 1.0: 0.9-1.0: 1.1, the preferred brominating agent is NBS, and the preferred molar ratio is 1.0: 1.0;
2) the reaction solvent is dichloromethane, trichloromethane and carbon tetrachloride, preferably dichloromethane;
3) the reaction temperature is 20-70 ℃, and preferably 35-45 ℃.
Wherein, the reaction conditions of the step four are as follows:
1) the molar ratio of the intermediate 3 to the piperidine is 1.0: 2.0-1.0: 10.0, preferably 1.0: 3.0;
2) the reaction solvent is dichloromethane, acetonitrile, N-dimethylformamide, tetrahydrofuran and absolute ethyl alcohol, and acetonitrile is preferred;
3) the reaction temperature is 20-100 ℃, preferably 65-75 ℃.
Wherein, the purification method of the step four is as follows:
1) and (3) after the intermediate 3 and the piperidine are reacted, extracting by using dichloromethane, washing by using water, adding acetic anhydride into the dichloromethane phase, and reacting for 3-5 hours, preferably 4 hours at the temperature of 35-45 ℃.
2) The molar ratio of the added amount of acetic anhydride to the intermediate 3 is: 1.0: 1.0-2.0: 1.0, preferably 1.2: 1.0.
The invention has the beneficial effects that: the invention provides a method for preparing roxatidine acetate hydrochloride, which is operated in six steps, has simple operation and no dangerous operation, and the steps I, II and IV are the special characteristics of the preparation method, the reaction conversion rate of the steps I and II is high, side reactions are less, the next step of operation can be carried out after simple purification, after the reaction in the step IV is finished, the concentration is simple, roxatidine is contained after extraction treatment (acetic ester is hydrolyzed to generate impurity I due to existence of piperidine), in the process, acetic anhydride is added into extract liquid to convert the impurity I into roxatidine acetate, and the reaction equation is as follows:
through the above route, the impurity I is effectively controlled, and the quality requirement of the roxatidine acetate hydrochloride is guaranteed.
For a better understanding of the nature and technical aspects of the present invention, reference should be made to the following detailed description of the invention, taken in conjunction with the accompanying drawings, which are provided for purposes of illustration and description and are not intended to limit the invention.
Drawings
The technical solution and other advantages of the present invention will become apparent from the following detailed description of specific embodiments of the present invention, which is to be read in connection with the accompanying drawings.
FIG. 1 is an infrared spectrum of a process for preparing roxatidine acetate hydrochloride according to the present invention;
FIG. 2 is a chart of infrared spectra collected from the Chinese pharmacopoeia for roxatidine acetate hydrochloride;
FIG. 3 shows nuclear magnetic hydrogen chromatogram of roxatidine acetate hydrochloride;
FIG. 4 is a diagram of roxatidine acetate hydrochloride deuterium water exchange nuclear magnetic hydrogen spectrum;
FIG. 5 shows the molecular weight mass spectrum of roxatidine acetate hydrochloride.
Detailed Description
To further illustrate the technical means and effects of the present invention, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings.
Referring to fig. 1-5, the present invention provides a method for preparing roxatidine acetate hydrochloride, which comprises the following reaction equations:
the preparation method of the roxatidine acetate hydrochloride comprises the following steps:
the reaction and post-treatment method comprises the following steps: : dissolving m-cresol and 3-chloropropylamine hydrochloride in a reaction solvent according to a ratio (the feeding ratio is 1.0: 1.0-1.0: 2.5), extracting after the reaction of the m-cresol serving as a raw material is finished in the presence of alkali (one of sodium hydroxide, potassium carbonate, sodium carbonate and cesium carbonate), and concentrating after simple purification to obtain an intermediate 1.
The reaction and post-treatment method in the second step is as follows: dissolving the intermediate 1 and alkali (one of triethylamine, pyridine, diisopropylethylamine and sodium bicarbonate) in a reaction solvent according to a molar ratio of 1.0: 1.0-1.0: 2.0, dropwise adding acetoxyacetyl chloride at low temperature, and extracting and concentrating the intermediate 1 after the reaction to obtain an intermediate 2 (without further purification).
The reaction and post-treatment method in the third step is as follows: and (3) carrying out bromination reaction on the intermediate 2 and the NBS in a solvent (dichloromethane, trichloromethane and carbon tetrachloride) according to a ratio (1.0: 0.9-1.0: 1.1), directly washing and extracting after the reaction is finished, concentrating to obtain an intermediate 3, and directly entering the next step.
The reaction and post-treatment method in the fourth step is as follows: and after the intermediate 3 and excessive piperidine react in the solvent, concentrating, extracting with dichloromethane, drying, and further purifying with acetic anhydride to obtain the roxatidine acetate.
The preparation method of the crude product in the step five is as follows: dissolving the intermediate 3 in acetone, dripping hydrochloric acid (or introducing hydrogen chloride gas) at low temperature to form salt, filtering, and drying.
The refining method in the sixth step is as follows: mixing with anhydrous ethanol, dissolving at controlled temperature, filtering, cooling, crystallizing, filtering, and oven drying to obtain roxatidine acetate hydrochloride.
Wherein the reaction conditions of the first step are as follows:
1) the feeding ratio of the m-cresol to the 3-chloropropylamine hydrochloride is 1.0: 1.0-1.0: 2.5; preferably 1.0: 2.0;
2) the alkali is inorganic alkali: sodium hydroxide, potassium carbonate, sodium carbonate and cesium carbonate, preferably sodium hydroxide;
3) the mol ratio of the m-cresol to the alkali is 2: 1-15: 1, preferably 3: 1;
4) the reaction solvent is: dimethyl sulfoxide, N-dimethylformamide, azomethylpyrrolidone and toluene, preferably dimethyl sulfoxide;
5) the reaction temperature is as follows: 0 to 120 ℃, preferably 20 to 40 ℃.
Further, the reaction conditions of the second step are as follows:
1) the molar ratio of the intermediate 1 to acetoxyacetyl chloride is 1.0: 1.0-1.0: 2.0; preferably 1.0: 1.2;
2) the base is triethylamine, pyridine, diisopropylethylamine and sodium bicarbonate, preferably triethylamine;
3) the molar ratio of the intermediate 1 to the alkali is 1.0: 1.0-1.0: 2.0, preferably 1: 1.2;
4) the reaction solvent is dichloromethane, N-dimethylformamide and tetrahydrofuran, preferably dichloromethane;
5) the reaction temperature is as follows: -20 to 20 ℃, preferably 0 to 10 ℃.
Further, the reaction conditions of step three are as follows:
1) the molar ratio of the intermediate 2 to NBS (N-bromosuccinimide) or bromine is 1.0: 0.9-1.0: 1.1, the preferred brominating agent is NBS, and the preferred molar ratio is 1.0: 1.0;
2) the reaction solvent is dichloromethane, trichloromethane and carbon tetrachloride, preferably dichloromethane;
3) the reaction temperature is 20-70 ℃, and preferably 35-45 ℃.
Further, the reaction conditions of step four are as follows:
1) the molar ratio of the intermediate 3 to the piperidine is 1.0: 2.0-1.0: 10.0, preferably 1.0: 3.0;
2) the reaction solvent is dichloromethane, acetonitrile, N-dimethylformamide, tetrahydrofuran and absolute ethyl alcohol, and acetonitrile is preferred;
3) the reaction temperature is 20-100 ℃, preferably 65-75 ℃.
Further, the purification method of the step four is as follows:
1) and (3) after the intermediate 3 and the piperidine are reacted, extracting by using dichloromethane, washing by using water, adding acetic anhydride into the dichloromethane phase, and reacting for 3-5 hours, preferably 4 hours at the temperature of 35-45 ℃.
2) The molar ratio of the added amount of acetic anhydride to the intermediate 3 is: 1.0: 1.0-2.0: 1.0, preferably 1.2: 1.0.
Example 1
Preparation of 3-m-tolyloxypropylamine (intermediate 1):
adding 10.80kg of dimethyl sulfoxide, 1.08kg of m-cresol and 1.20kg of sodium hydroxide in sequence under the protection of nitrogen, stirring for 30 minutes, adding 1.56kg of 3-chloropropylamine hydrochloride in batches under the protection of nitrogen flow, reacting for 4 hours at room temperature after the addition, detecting by TLC (petroleum ether: ethyl acetate/3: 1), after the reaction is finished, diluting the reaction liquid with 54.00kg of purified water, extracting with isopropyl ether twice, using 8.60kg of isopropyl ether each time, combining the isopropyl ethers, adding 10.80kg of water into the organic layer, adjusting the pH to 5 with glacial acetic acid, discarding the organic layer, adding 8.60kg of isopropyl ether into the water layer, adjusting the pH to 10 with concentrated ammonia water, separating, extracting the water layer with 5.40kg of isopropyl ether once, combining the organic layer, drying with anhydrous magnesium sulfate, performing suction filtration, and concentrating to obtain 1.38kg of light yellow oily matter with the molar yield of 83.60%.
Preparation of ethyl 2-oxo-2- (3-m-tolylpropylamino) acetate (intermediate 2):
under the protection of nitrogen, 1.30kg of intermediate 1 and 0.95kg of triethylamine are mixed in 13.00kg of dichloromethane, acetoxyacetyl chloride is added dropwise after the temperature is reduced to 0 ℃ (the temperature does not exceed 10 ℃), the reaction is continued for 1h after the dropwise addition, the intermediate 2 is detected by TLC (dichloromethane: methanol/20: 1) after the reaction is finished, 6.50kg of water is washed, 6.5kg of 1N hydrochloric acid is washed, 6.50kg of water is washed, anhydrous magnesium sulfate is dried for 1h, and the paste is concentrated to obtain 1.82kg of paste, the molar yield is as follows: 87.30 percent.
Preparation of ethyl 2- (3- (3- (bromomethylphenoxy) propylamino) -2-oxoacetate (intermediate 3):
1.80kg of the intermediate 2 is dissolved in 9.00kg of dichloromethane, 18g of azobisisobutyronitrile is added, 1.20kg of N-bromosuccinimide is added in batches, a 1000W incandescent lamp is used after the addition, the temperature is reduced after the light reflux reaction for 16h, the mixture is washed twice with 5.40kg of water each time, and the anhydrous magnesium sulfate is dried for 1h and then concentrated to obtain 2.27kg of oily matter with the molar yield of 95.30%.
Preparation of roxatidine acetate:
dissolving 1.72kg of the intermediate 3 in 3.44kg of acetonitrile, adding 1.28kg of piperidine, performing reflux reaction for 8h, concentrating to obtain a paste, adding 6.88kg of water, performing dichloromethane extraction twice, using 8.66kg of dichloromethane each time, combining dichloromethane, adding 0.60kg of acetic anhydride, performing reflux reaction for 4h under the protection of nitrogen, concentrating until no obvious liquid drop exists, and directly entering the next step.
Preparation of roxatidine acetate hydrochloride (crude):
adding 13.76kg of acetone into the reactor in the previous step, cooling to 0 ℃, dropwise adding hydrochloric acid until the pH value is 2-3, continuously stirring for 1h while keeping the temperature at-5 ℃, carrying out centrifugal filtration, washing 1.00kg of acetone, and carrying out vacuum drying for 6h at 40 ℃ to obtain 1.76kg of crude roxatidine acetate hydrochloride (white-like solid), wherein the total yield of the two steps is 91.45%.
Preparation of roxatidine acetate hydrochloride:
adding 1.70kg of crude product and 13.6kg of absolute ethyl alcohol into a reaction kettle under the protection of nitrogen, heating to 50 ℃, dissolving and filtering after clearing, cooling to 0 ℃ after filtering, stirring for 2h, filtering, drying a filter cake at 40 ℃ under reduced pressure for 8h to obtain 1.38kg of white powder, wherein the yield is 81.18%. The infrared, nuclear magnetic and mass spectrograms are shown in figures 1, 3, 4 and 5.
And (4) conclusion: six steps total yield: 51.63 percent.
Example 2
Preparation of 3-m-tolyloxypropylamine (intermediate 1):
adding 5.40kg of DMF, 1.08kg of m-cresol and 1.20kg of sodium hydroxide in sequence under the protection of nitrogen, stirring for 30 minutes at 40 ℃, adding 1.56kg of 3-chloropropylamine hydrochloride in batches under the protection of nitrogen, reacting for 2 hours at 60 ℃, diluting the reaction solution with 54kg of water, extracting with isopropyl ether twice, using 8.60kg of isopropyl ether each time, combining the isopropyl ethers, drying with anhydrous magnesium sulfate, filtering, concentrating to obtain 1.85kg of oily matter, dissolving and diluting with 2kg of dichloromethane, spreading 2kg of silica gel in a suction filtration cylinder with the inner diameter of 50cm, protecting the upper layer interface with 3kg of anhydrous sodium sulfate, pouring the diluted concentrated matter into the suction filtration cylinder, performing suction filtration, leaching with 16.20kg of dichloromethane, and concentrating to obtain 1.27kg of light yellow oily matter, wherein the molar yield is 76.96%.
Preparation of ethyl 2-oxo-2- (3-m-tolylpropylamino) acetate (intermediate 2):
under the protection of nitrogen, 1.20kg of the intermediate 1 and 0.58kg of pyridine are mixed in 13.00kg of dichloromethane, acetoxyacetyl chloride is added dropwise after the temperature is reduced to 0 ℃ (the temperature does not exceed 10 ℃), the reaction is continued for 1 hour after the dropwise addition, 6.00kg of water washing, 6.00kg of 1N hydrochloric acid washing, 6.50kg of anhydrous magnesium sulfate drying for 1 hour after the water washing, and the oily matter is obtained by concentration, wherein the molar yield is 1.62 kg: 85.70 percent.
Preparation of ethyl 2- (3- (3- (bromomethylphenoxy) propylamino) -2-oxoacetate (intermediate 3):
1.60kg of the intermediate 2 is dissolved in 16.0kg of dichloromethane, 0.96kg of bromine is dropwise added at 0 ℃, color change is observed during the dropwise adding process, the dropwise adding is carried out after the color basically disappears, the reaction is continued for 2 hours after the dropwise adding, 1.00kg of water washing is carried out for liquid separation, 1kg of 5% sodium thiosulfate aqueous solution is washed, anhydrous sodium sulfate is dried for 1 hour after the saturated saline solution is washed, and the oily matter is concentrated to obtain 1.94kg of oily matter with the molar yield of 93.50%.
Preparation of roxatidine acetate:
dissolving 1.90kg of the intermediate 3 in 3.80kg of absolute ethyl alcohol, adding 2.35kg of piperidine, performing reflux reaction for 16h, concentrating to obtain paste, adding 7.60kg of water, performing dichloromethane extraction twice, using 7.60kg of dichloromethane each time, combining dichloromethane, adding 0.60kg of acetic anhydride, performing reflux reaction for 4h under the protection of nitrogen, concentrating until no obvious liquid drop exists, and directly entering the next step.
Preparation of roxatidine acetate hydrochloride (crude):
adding 15.20kg of acetone into the reactor in the previous step, cooling to 0 ℃, dropwise adding hydrochloric acid until the pH value is 2-3, continuously stirring for 1h while keeping the temperature at-5 ℃, centrifugally filtering, washing 1.00kg of acetone, and drying in vacuum at 40 ℃ for 6h to obtain 1.68kg of crude roxatidine acetate hydrochloride (white-like solid), wherein the total yield of the two steps is 79.0%.
Preparation of roxatidine acetate hydrochloride:
adding 1.65kg of crude product and 13.60kg of absolute ethyl alcohol into a reaction kettle under the protection of nitrogen, heating to 50 ℃, dissolving and filtering after clearing, cooling to 0 ℃ after filtering, stirring for 2h, filtering, drying a filter cake at 40 ℃ under reduced pressure for 8h to obtain 1.31kg of white powder, wherein the yield is 79.39%.
And (4) conclusion: six steps total yield: 40.18 percent.
Example 3
Preparation of 3-m-tolyloxypropylamine (intermediate 1):
adding 5.40kg of DMF, 1.08kg of m-cresol and 3.18kg of anhydrous sodium carbonate in turn under the protection of nitrogen, stirring for 30 minutes at 40 ℃, adding 1.56kg of 3-chloropropylamine hydrochloride in batches under the protection of nitrogen, cooling after the reaction is finished for 2 hours at 90 ℃, diluting the reaction liquid with 54.00kg of water, extracting with isopropyl ether twice, using 8.60kg of isopropyl ether each time, combining the isopropyl ether, drying with anhydrous magnesium sulfate, filtering, concentrating to obtain 1.95kg of oily matter, dissolving and diluting with 2kg of dichloromethane, spreading 2.00kg of silica gel in a suction filtration cylinder with the inner diameter of 50cm, protecting the upper layer interface with 3.00kg of anhydrous sodium sulfate, pouring the concentrated oily matter into the suction filtration cylinder, leaching with 16.00kg of dichloromethane, and concentrating to obtain 1.31kg of light yellow oily matter with the molar yield of 79.39%.
Preparation of ethyl 2-oxo-2- (3-m-tolylpropylamino) acetate (intermediate 2):
under the protection of nitrogen, 1.30kg of the intermediate 1 and 0.70kg of sodium bicarbonate are mixed in 3.90kg of DMF, acetoxyacetyl chloride is dropwise added after the temperature is reduced to 0 ℃ (the temperature does not exceed 10 ℃), the reaction is continued for 2 hours after the dropwise addition, 13.00kg of water is added, dichloromethane is extracted for 3 times, the dosage of each time is 4.20kg, dichloromethane phases are combined, 6.00kg of 1N hydrochloric acid is used for washing, 6.50kg of saturated saline water is used for washing, anhydrous magnesium sulfate is used for drying for 1 hour, and oil is obtained by concentration, wherein the molar yield is 1.74 kg: 83.40 percent.
Preparation of ethyl 2- (3- (3- (bromomethylphenoxy) propylamino) -2-oxoacetate (intermediate 3):
1.70kg of the intermediate 2 is dissolved in 16.00kg of trichloromethane, 0.96kg of bromine is dripped at 0 ℃, the color change is observed during the dripping process, the dripping is carried out after the color basically disappears, about 2h of dripping is finished, the reaction is continued for 2h, 1.00kg of water is separated for washing, 1.00kg of 5 percent sodium thiosulfate aqueous solution is used for washing, the anhydrous sodium sulfate is dried for 1h after the saturated saline solution is used for washing, and the oily matter is obtained by concentration, wherein the oily matter is 2.15kg, and the molar yield is 97.50 percent.
Preparation of roxatidine acetate:
2.10kg of the intermediate 3 is dissolved in 4.20kg of acetonitrile, 2.60kg of piperidine is added, the mixture is concentrated into paste after being refluxed for 16h, 8.40kg of water is added, dichloromethane is extracted twice, the amount of dichloromethane used for each time is 8.40kg, dichloromethane is combined, 0.7kg of acetic anhydride is added, the mixture is refluxed for 4h under the protection of nitrogen, and the mixture is concentrated until no obvious liquid drop exists, and then the next step is directly carried out.
Preparation of roxatidine acetate hydrochloride (crude):
adding 16.80kg of acetone into the reactor in the first step, cooling to 0 ℃, dropwise adding hydrochloric acid to pH 2-3, continuously stirring for 1h while keeping the temperature at-5 ℃, centrifugally filtering, washing 1.00kg of acetone, and drying in vacuum at 40 ℃ for 6h to obtain 1.88kg of roxatidine acetate hydrochloride crude product (white-like solid), wherein the total yield of the two steps is 88.4%
Preparation of roxatidine acetate hydrochloride:
adding 1.88kg of crude product and 15.00kg of absolute ethyl alcohol into a reaction kettle under the protection of nitrogen, heating to 50 ℃, dissolving and filtering after clearing, cooling to 0 ℃ after filtering, stirring for 2h, filtering, drying a filter cake at 40 ℃ under reduced pressure for 8h to obtain 1.53kg of white powder, wherein the yield is 81.40%.
And (4) conclusion: six steps total yield: 46.45 percent.
The results of the quality study analyses of roxatidine acetate hydrochloride prepared in examples 1, 2 and 3 are shown in the following table:
the results of quality analysis of roxatidine acetate hydrochloride are shown in the table:
remarking:
referring to fig. 3, for substances: measuring by high performance liquid chromatography (0512 in the four-part general regulation of 2015 edition in Chinese pharmacopoeia);
impurity I is roxatidine hydrochloride, and has the structure:
impurity II is deshydroxy roxatidine hydrochloride, and has the structure as follows:
the roxatidine acetate hydrochloride prepared in example 1 (batch No. 161205-1) was examined for long-term stability and the quality results were as follows:
in conclusion, the results show that the roxatidine acetate hydrochloride prepared by the method has stability meeting the quality requirement of the bulk drugs.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (6)
1. A preparation method of roxatidine acetate hydrochloride is characterized by comprising the following steps:
the method comprises the following steps: dissolving m-cresol and 3-chloropropylamine hydrochloride in a reaction solvent in proportion, extracting after the reaction of the raw material m-cresol is finished in the presence of alkali, and concentrating after simple purification to obtain an intermediate 1;
step two: dissolving the intermediate 1 and alkali in a reaction solvent according to a certain proportion, dripping acetoxyacetyl chloride at low temperature, extracting and concentrating after the intermediate 1 reacts to obtain an intermediate 2;
step three: carrying out bromination reaction on the intermediate 2 and N-bromosuccinimide in a solvent according to a certain proportion, directly washing and extracting after the reaction is finished, and concentrating to obtain an intermediate 3;
step four: after the intermediate 3 and excessive piperidine react in the solvent, concentrating, extracting with dichloromethane, drying, and further purifying with acetic anhydride to obtain roxatidine acetate;
step five: dissolving the intermediate 3 in acetone, dropwise adding hydrochloric acid at low temperature to form salt, filtering, and drying;
step six: mixing with anhydrous ethanol, dissolving at controlled temperature, filtering, cooling, crystallizing, filtering, and oven drying to obtain roxatidine acetate hydrochloride.
2. The method for preparing roxatidine acetate hydrochloride according to claim 1, wherein the reaction conditions in the first step are as follows:
the feeding ratio of the m-cresol to the 3-chloropropylamine hydrochloride is 1.0: 1.0-1.0: 2.5;
the alkali is inorganic alkali: one of sodium hydroxide, potassium carbonate, sodium carbonate and cesium carbonate;
the mol ratio of the m-cresol to the alkali is 2: 1-15: 1;
the reaction solvent is: one of dimethyl sulfoxide, N-dimethylformamide, N-methylpyrrolidone and toluene;
the reaction temperature is as follows: 0 to 120 ℃.
3. The method for preparing roxatidine acetate hydrochloride according to claim 1, wherein the reaction conditions in the second step are as follows:
the molar ratio of the intermediate 1 to acetoxyacetyl chloride is 1.0: 1.0-1.0: 2.0;
the base is one of triethylamine, pyridine, diisopropylethylamine and sodium bicarbonate;
the molar ratio of the intermediate 1 to the alkali is 1.0: 1.0-1.0: 2.0;
the reaction solvent is one of dichloromethane, N-dimethylformamide and tetrahydrofuran;
the reaction temperature is as follows: -20 to 20 ℃.
4. The method for preparing roxatidine acetate hydrochloride according to claim 1, wherein the reaction conditions in the third step are as follows:
the molar ratio of the intermediate 2 to the N-bromosuccinimide or bromine is 1.0: 0.9-1.0: 1.1;
the reaction solvent is one of dichloromethane, trichloromethane and carbon tetrachloride;
the reaction temperature is 20-70 ℃.
5. The method for preparing roxatidine acetate hydrochloride according to claim 1, wherein the reaction conditions in the fourth step are as follows:
the molar ratio of the intermediate 3 to the piperidine is 1.0: 2.0-1.0: 10.0;
the reaction solvent is one of dichloromethane, acetonitrile, N-dimethylformamide, tetrahydrofuran and absolute ethyl alcohol;
the reaction temperature is 20-100 ℃.
6. The method for preparing roxatidine acetate hydrochloride according to claim 1, wherein the purification method in the fourth step is as follows:
after the intermediate 3 and piperidine react, extracting by using dichloromethane, washing by using water, adding acetic anhydride into the dichloromethane phase, and reacting for 3-5 hours at 35-45 ℃;
the molar ratio of the added amount of acetic anhydride to the intermediate 3 is: 1.0: 1.0-2.0: 1.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911063245.8A CN110981832A (en) | 2019-11-01 | 2019-11-01 | Preparation method of roxatidine acetate hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911063245.8A CN110981832A (en) | 2019-11-01 | 2019-11-01 | Preparation method of roxatidine acetate hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110981832A true CN110981832A (en) | 2020-04-10 |
Family
ID=70082964
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911063245.8A Pending CN110981832A (en) | 2019-11-01 | 2019-11-01 | Preparation method of roxatidine acetate hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110981832A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114195739A (en) * | 2021-12-31 | 2022-03-18 | 广安凯特制药有限公司 | High-purity roxatidine acetate hydrochloride, intermediate thereof and preparation methods thereof |
| CN114276314A (en) * | 2021-12-31 | 2022-04-05 | 广安凯特制药有限公司 | High-purity roxatidine acetate hydrochloride and preparation method thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3099599A (en) * | 1960-03-03 | 1963-07-30 | Burroughs Wellcome Co | Method for treating infestations of nematodes |
| CN1490315A (en) * | 2002-10-18 | 2004-04-21 | 成都摩尔生物医药有限公司 | Synthesis of roxatidine acetate |
| WO2011130726A2 (en) * | 2010-04-16 | 2011-10-20 | The Regents Of The University Of California | Ligands for odor receptors and olfactory neurons |
| CN102993121A (en) * | 2012-12-11 | 2013-03-27 | 哈药集团三精制药股份有限公司 | Synthetic method for preparing roxatidine acetate hydrochloride with high purity |
| WO2013049096A1 (en) * | 2011-09-27 | 2013-04-04 | Bristol-Myers Squibb Company | Pyrrolinone carboxamide compounds useful as endothelial lipase inhibitors |
| WO2013048930A1 (en) * | 2011-09-30 | 2013-04-04 | Bristol-Myers Squibb Company | Pyridinedione carboxamide inhibitors of endothelial lipase |
| CN107857743A (en) * | 2017-10-20 | 2018-03-30 | 四环医药控股集团有限公司 | A kind of method for preparing hydrochloric acid roxatidine acetate and intermediate |
-
2019
- 2019-11-01 CN CN201911063245.8A patent/CN110981832A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3099599A (en) * | 1960-03-03 | 1963-07-30 | Burroughs Wellcome Co | Method for treating infestations of nematodes |
| CN1490315A (en) * | 2002-10-18 | 2004-04-21 | 成都摩尔生物医药有限公司 | Synthesis of roxatidine acetate |
| WO2011130726A2 (en) * | 2010-04-16 | 2011-10-20 | The Regents Of The University Of California | Ligands for odor receptors and olfactory neurons |
| WO2013049096A1 (en) * | 2011-09-27 | 2013-04-04 | Bristol-Myers Squibb Company | Pyrrolinone carboxamide compounds useful as endothelial lipase inhibitors |
| WO2013048930A1 (en) * | 2011-09-30 | 2013-04-04 | Bristol-Myers Squibb Company | Pyridinedione carboxamide inhibitors of endothelial lipase |
| CN102993121A (en) * | 2012-12-11 | 2013-03-27 | 哈药集团三精制药股份有限公司 | Synthetic method for preparing roxatidine acetate hydrochloride with high purity |
| CN107857743A (en) * | 2017-10-20 | 2018-03-30 | 四环医药控股集团有限公司 | A kind of method for preparing hydrochloric acid roxatidine acetate and intermediate |
Non-Patent Citations (1)
| Title |
|---|
| TARPANOV VELICHKO等: "A new synthesis of roxatidine acetate", 《SYNTHETIC COMMUNICATIONS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114195739A (en) * | 2021-12-31 | 2022-03-18 | 广安凯特制药有限公司 | High-purity roxatidine acetate hydrochloride, intermediate thereof and preparation methods thereof |
| CN114276314A (en) * | 2021-12-31 | 2022-04-05 | 广安凯特制药有限公司 | High-purity roxatidine acetate hydrochloride and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105732622B (en) | A kind of preparation method of Eliquis | |
| CN101838238B (en) | Method for synthesizing quinolone main cycle compound | |
| CN100391945C (en) | S-(-)-indolyl-2-carboxylic acid synthesizing method | |
| CN110950765B (en) | Preparation method of terbutaline sulfate | |
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| CN112174989B (en) | Preparation method of clenbuterol | |
| CN100429204C (en) | Process for the preparation of 4- (3'-chloro-4'-fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline | |
| CN110981832A (en) | Preparation method of roxatidine acetate hydrochloride | |
| CN110818631B (en) | Pyridine thiourea derivative and preparation method and application thereof | |
| CN103601645A (en) | Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof | |
| CN103288708B (en) | The preparation method of 1- aryl -2- indolinone derivative | |
| CN101671299A (en) | Method for synthesizing Nexavar | |
| CN104447355A (en) | Novel method for preparing bromhexine hydrochloride | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN101805265B (en) | Synthesis method of 2-nitro-4-substituted phenylacetic acid | |
| CN111747879B (en) | Large-process synthesis method of erexib | |
| CN108689957B (en) | Preparation method and application of 2R/2S-trifluoromethyl morpholine and hydrochloride thereof | |
| CN111100111B (en) | Method for preparing benzothiophene derivative | |
| CN111747874B (en) | Ericoxib intermediate and preparation method and application thereof | |
| CN111747873B (en) | Ericoxib intermediate and preparation method and application thereof | |
| CN105237547B (en) | A kind of preparation method of hydroxyl benzoxazole | |
| CN108752341A (en) | A kind of preparation method of bromo- 7 azaindoles of 5- | |
| CN108658931A (en) | A kind of preparation method of Raltitrexed key intermediate | |
| CN115057816B (en) | 4-aminoquinoline compound, preparation method thereof and application thereof in anti-tumor drugs | |
| CN108997247A (en) | A kind of preparation method of Rivaroxaban intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200410 |
|
| RJ01 | Rejection of invention patent application after publication |