CN116693469A - Synthesis and refining method of roxatidine acetate hydrochloride - Google Patents
Synthesis and refining method of roxatidine acetate hydrochloride Download PDFInfo
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- CN116693469A CN116693469A CN202210175530.4A CN202210175530A CN116693469A CN 116693469 A CN116693469 A CN 116693469A CN 202210175530 A CN202210175530 A CN 202210175530A CN 116693469 A CN116693469 A CN 116693469A
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- roxatidine
- reaction
- acetate
- solvent
- acetate hydrochloride
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- 229960000627 roxatidine acetate hydrochloride Drugs 0.000 title claims abstract description 95
- 238000000034 method Methods 0.000 title claims abstract description 74
- 238000007670 refining Methods 0.000 title claims abstract description 26
- 230000015572 biosynthetic process Effects 0.000 title description 19
- 238000003786 synthesis reaction Methods 0.000 title 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 83
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 64
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims abstract description 47
- 229940011051 isopropyl acetate Drugs 0.000 claims abstract description 47
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims abstract description 47
- 239000002904 solvent Substances 0.000 claims abstract description 33
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- 229960003287 roxatidine acetate Drugs 0.000 claims abstract description 29
- 238000001953 recrystallisation Methods 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims description 89
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 60
- 238000003756 stirring Methods 0.000 claims description 56
- 229960003320 roxatidine Drugs 0.000 claims description 54
- 239000000047 product Substances 0.000 claims description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 34
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 32
- 239000013078 crystal Substances 0.000 claims description 32
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 26
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 22
- 239000012043 crude product Substances 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 21
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 19
- 230000035484 reaction time Effects 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 15
- 239000007810 chemical reaction solvent Substances 0.000 claims description 15
- 239000012295 chemical reaction liquid Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 13
- 239000000463 material Substances 0.000 claims description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 12
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 10
- 235000019253 formic acid Nutrition 0.000 claims description 10
- -1 isopropyl hydrogen chloride acetate Chemical compound 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 9
- 238000010791 quenching Methods 0.000 claims description 9
- 230000000171 quenching effect Effects 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 238000007867 post-reaction treatment Methods 0.000 claims description 7
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 claims description 6
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 235000006408 oxalic acid Nutrition 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- BZFKSWOGZQMOMO-UHFFFAOYSA-N 3-chloropropan-1-amine Chemical compound NCCCCl BZFKSWOGZQMOMO-UHFFFAOYSA-N 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 22
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 238000011156 evaluation Methods 0.000 abstract description 2
- 238000000227 grinding Methods 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 239000000243 solution Substances 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 12
- SRDQKICJPUSODU-UHFFFAOYSA-N 2-hydroxy-n-[3-[3-(piperidin-1-ylmethyl)phenoxy]propyl]acetamide;oxalic acid Chemical compound OC(=O)C(O)=O.OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 SRDQKICJPUSODU-UHFFFAOYSA-N 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- 239000008213 purified water Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 239000012467 final product Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000009776 industrial production Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- ORGBERFQYFWYGX-UHFFFAOYSA-N 3-(piperidin-1-ylmethyl)phenol Chemical compound OC1=CC=CC(CN2CCCCC2)=C1 ORGBERFQYFWYGX-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000036632 reaction speed Effects 0.000 description 3
- VQSXCZMVUMSITD-UHFFFAOYSA-N 3-[3-(piperidin-1-ylmethyl)phenoxy]propan-1-amine Chemical compound NCCCOC1=CC=CC(CN2CCCCC2)=C1 VQSXCZMVUMSITD-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- IHPRVZKJZGXTBQ-UHFFFAOYSA-N 3-chloropropan-1-amine;hydron;chloride Chemical compound Cl.NCCCCl IHPRVZKJZGXTBQ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002243 Anastomotic ulcer Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 102100021022 Gastrin Human genes 0.000 description 1
- 108010052343 Gastrins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 240000007695 Nandina domestica Species 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009960 carding Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- HDRXZJPWHTXQRI-BHDTVMLSSA-N diltiazem hydrochloride Chemical compound [Cl-].C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC[NH+](C)C)C2=CC=CC=C2S1 HDRXZJPWHTXQRI-BHDTVMLSSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- ANBZWDBEKOZNHY-UHFFFAOYSA-N ethanol;oxalic acid Chemical compound CCO.OC(=O)C(O)=O ANBZWDBEKOZNHY-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 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 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for synthesizing and refining roxatidine acetate hydrochloride, belonging to the technical field of pharmaceutical chemistry. The invention provides a refining method of roxatidine acetate hydrochloride, which uses N, N-dimethylformamide as a good solvent and isopropyl acetate as a poor solvent for recrystallization. In addition, the invention also provides a preparation method of roxatidine acetate. Experimental results show that the total yield of the method for synthesizing and refining the roxatidine acetate hydrochloride provided by the invention reaches 57.1%, the total yield is higher than the existing level, the impurity level of the prepared roxatidine acetate hydrochloride is obviously reduced, the quality of the product is not lower than the original grinding level, the method has obvious advantages compared with similar products, the safety, the effectiveness and the quality controllability of the product are integrally improved, and the method meets the requirement of consistency evaluation.
Description
Technical Field
The invention relates to a method for synthesizing and refining roxatidine acetate hydrochloride, belonging to the technical field of pharmaceutical chemistry.
Background
Roxatidine acetate hydrochloride, chemical name is 2-acetoxy-N- [3- [3- (1-piperidylmethyl) phenoxy ] ]Propyl group]Acetamide hydrochloride, first marketed in Japan by the Japanese empire organ company in 8 months of 1986, is a new generation of selective histamine H 2 Receptor antagonists. The product is rapidly converted into active metabolite roxatidine after deacetylation by hydrolysis in vivo, and can inhibit gastric acid secretion caused by histamine, pentapeptide gastrin and M cholinergic receptor agonist in animals and human body, and inhibit basic gastric acid secretion and nocturnal gastric acid secretion caused by other factors such as food. Is mainly used for preventing and treating digestive system diseases caused by gastric acid high secretion state, such as gastric ulcer duodenal ulcer, anastomotic ulcer, etc.
The roxatidine acetate hydrochloride is easy to degrade, for example, the acetate in the structure is easy to degrade under the action of acid, alkali, water and the like to generate impurity roxatidine, and the impurity generated in the synthesis process is added, so that the purity of the bulk drug is low. The maximum single impurity of the original reference preparation is 0.27%. The final product purity can only reach 98.5% if the synthesis process is provided according to Synthetic Communications (see: A New Synthesis of Roxatidine acetate. SYNTHETIC COMMUNICATIONS,29 (l), 15-20, 1999). Thus, there is a need for better control of the roxatidine acetate hydrochloride related substance content.
In addition, the existing synthesis process of roxatidine acetate hydrochloride has the problems of long reaction time, high temperature, complex operation, low yield and the like. The carding literature currently has the following 3 synthetic routes:
route 1 (see: zhou Zhihua, lei Pengfei, xu Binghao, etc., luoxatidine acetate hydrochloride synthesis process optimization and preliminary quality study [ J ], nandina pharmaceutical 2020, 18, 2 nd edition: 205-209)
The method comprises the steps of reacting m-hydroxybenzaldehyde with piperidine under the action of a potassium borohydride which is an explosive reagent, preparing 3- (1-piperidylmethyl) phenol, reacting with 3-chloropropionamine hydrochloride under the action of sodium hydroxide and toluene to obtain 3- (3-piperidyl-1-ylmethyl phenoxy) propylamine, continuously reacting with chloroacetyl chloride to obtain 2-chloro-N- [3- [3- (piperidyl-1-ylmethyl) phenoxy ] propyl ] acetamide, reacting with potassium acetate to obtain roxatidine acetate, salifying with ethyl acetate chloride, and refining with ethyl acetate to obtain roxatidine acetate hydrochloride. The step 1 uses the explosive reagent potassium borohydride, the post treatment is complex, and the yield is low (88.6 percent); the reaction speed of the step 2 is very slow, and the conversion rate is low; step 4, the reaction temperature is high, the post-treatment operation mode is complex, the impurity roxatidine is easy to generate, and purification and removal are not easy to realize; and 5, in the purification and refining process, the roxatidine acetate hydrochloride is easy to degrade to produce impurity roxatidine. Therefore, the production cost of the route is high, the total yield is low (31.0%), the operation is complex, and the route is not suitable for industrial production.
Route 2 (see: xu Wei et al, method for synthesizing roxatidine acetate hydrochloride [ P ], CN 103058958)
The route increases the variety of materials when M2 is prepared, M2 is purified by a rectification mode, and the requirement on production equipment is high; the M4 is prepared by reacting with glycolic acid, and experiments show that if the step is performed under the condition of 90+/-5 ℃ described in the literature, the conversion rate is low, the reaction is slow, and the reaction is required to be performed better at a high temperature of 140 ℃; the degradation impurity roxatidine is easy to generate during the preparation of the API in the step 5. Therefore, this route is also unsuitable as a commercial production process.
Route 3 (see: guo Rongyao, wang Xiaofeng, et al, new Process for the preparation of 3- (1-piperidylmethyl) phenol, an intermediate of roxatidine acetate hydrochloride, [ P ], CN 107698538)
Step 1 of the route needs to use potassium iodide to catalyze the reaction, and the reaction temperature is 90-110 ℃ for 20 hours, the reaction temperature is high, and the reaction time is long; step 2, the reaction temperature is 160-165 ℃ and is high; the reaction temperature in the step 5 is reflux, the temperature is higher, the post-treatment needs to be processed such as washing, concentration and the like, the operation is complex, and the roxatidine is easily hydrolyzed again in the concentration process; finally, the acetone is used for dissolving, then the ethyl chloroacetate solution is dripped into the mixture for salifying at a low temperature, and the crude drug is not subjected to a refining step, so that the production in a crude drug workshop is not facilitated. Therefore, this route is also unsuitable as a commercialized route.
In order to solve the problems of long reaction time, high temperature, complex operation, low yield, easy degradation of raw materials in the production process, low product purity and the like in the process, development of a synthetic and refining method which is more suitable for industrial production and can prepare high-purity roxatidine acetate hydrochloride is urgently needed.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, a first object of the present invention is to provide a method for purifying roxatidine acetate hydrochloride. A second object of the present invention is to provide a process for the preparation of roxatidine acetate. A third object of the present invention is to provide a process for the preparation of roxatidine acetate hydrochloride.
The invention provides a refining method of roxatidine acetate hydrochloride, which uses N, N-dimethylformamide as a good solvent and isopropyl acetate as a poor solvent for recrystallization.
Further, the refining method comprises the following steps:
a. adding a good solvent: mixing a crude roxatidine acetate hydrochloride product with N, N-dimethylformamide, and heating to dissolve, wherein the crude roxatidine acetate hydrochloride product is: the mass ratio of the N, N-dimethylformamide is 1: (4-10); preferably, the crude product of roxatidine acetate hydrochloride: the mass ratio of the N, N-dimethylformamide is 1:6, preparing a base material;
b. Adding a poor solvent: adding isopropyl acetate into the solution obtained in the step a, cooling to-10-40 ℃ to separate out roxatidine acetate hydrochloride, and collecting to obtain a roxatidine acetate hydrochloride refined product, wherein the roxatidine acetate hydrochloride crude product is: the mass ratio of isopropyl acetate is 1: (4-10); preferably, the temperature is reduced to 0-10 ℃ to separate out roxatidine acetate hydrochloride; preferably, the crude product of roxatidine acetate hydrochloride: the mass ratio of isopropyl acetate is 1:6.
further, the refining method satisfies at least one of the following:
step a, heating to 50-80 ℃ for dissolution;
preferably, step a is heated to 50-60 ℃ for dissolution;
step a, carrying out hot filtration after heating and dissolving;
step b) adding isopropyl acetate in portions: firstly cooling to 30-40 ℃, adding 0.4-0.6 times of isopropyl acetate based on the mass of the crude product of the roxatidine acetate hydrochloride, adding seed crystals, stirring uniformly, then continuously adding the rest isopropyl acetate, cooling to 0-10 ℃ and separating out the roxatidine acetate hydrochloride;
preferably, 0.05 to 5 percent of seed crystal is added according to the mass of the crude product of the roxatidine acetate hydrochloride;
preferably, 0.1 to 2 percent of seed crystal is added according to the mass of the crude product of the roxatidine acetate hydrochloride;
Preferably, 0.5 to 1.5 percent of seed crystal is added according to the mass of the crude product of the roxatidine acetate hydrochloride;
preferably, 1% of seed crystal is added based on the mass of the crude product of roxatidine acetate hydrochloride;
preferably, stirring and crystallizing at 0-10 ℃ for more than 1 hour;
preferably, the crystallization is carried out at 0-10 ℃ for 1.5-2.5 hours.
The invention provides a preparation method of roxatidine acetate, which comprises the steps of taking roxatidine and acetic anhydride as raw materials, adding isopropyl acetate as a reaction solvent, and reacting at 10-50 ℃ to generate roxatidine acetate; wherein, based on the mass of the roxatidine half oxalate, the roxatidine half oxalate: the mass ratio of acetic anhydride is 3.5: (1.0-6.2).
Further, the preparation method meets at least one of the following:
reacting at 40-50 ℃;
the mass of the roxatidine half oxalate is calculated as the mass of the roxatidine half oxalate: the mass ratio of acetic anhydride is 3.5: (4.0 to 4.6);
the reaction time is 1.5 to 2.5 hours;
preferably, the reaction time is 2.0 hours;
adding 4-5 times of isopropyl acetate serving as a reaction solvent based on the mass of the roxatidine half oxalate;
the post-reaction treatment is to add an acetic anhydride quenching solvent or a mixed solvent of the acetic anhydride quenching solvent and isopropyl acetate, and uniformly stir the mixture; wherein the acetic anhydride quenching solvent is selected from lower alcohols;
Preferably, the acetic anhydride quenching solvent is at least one selected from methanol, ethanol, isopropanol and n-propanol.
Further, roxatidine is prepared by the following method:
step A, compound M1, 3-chloropropylamine or salt thereof and alkali are reacted in N, N-dimethylformamide to prepare an intermediate M2:
step B, reacting the intermediate M2 with acetoxyacetyl chloride to obtain an intermediate M3:
step C, hydrolyzing the intermediate M3 to obtain a crude product M4 of roxatidine:
step D, salifying the crude product M4 of roxatidine with oxalic acid to obtain an intermediate M5:
step E, reacting the intermediate M5 with alkali to obtain a roxatidine refined product M6:
further, the preparation method meets at least one of the following:
the alkali in the step A is sodium hydroxide;
the reaction temperature of the step A is 30-70 ℃;
preferably, the reaction temperature of the step A is 60-70 ℃;
the reaction time of the step A is 1.2 to 1.8 hours;
extracting the reaction liquid by using an organic solvent after the reaction of the step A is finished to prepare a solution of an intermediate M2, and entering the step B without purification;
preferably, the organic solvent of the extraction reaction liquid in the step A is at least one selected from dichloromethane, chloroform, ethyl acetate, isopropyl acetate and toluene;
Adding an acid binding agent into the reaction system in the step B;
preferably, the acid binding agent is triethylamine;
the reaction solvent in the step B is methylene dichloride;
the reaction temperature in the step B is-10-45 ℃;
preferably, the reaction temperature of the step B is 10-20 ℃;
after the reaction of the step B is finished, carrying out solid-liquid separation on the reaction liquid, collecting a liquid phase, concentrating to obtain an intermediate M3, and entering the step C without purification;
step C, performing alkali hydrolysis;
preferably, step C is alkaline hydrolyzed by adding sodium hydroxide;
the reaction solvent in the step C is ethanol or a mixed solvent of ethanol and water;
the reaction temperature in the step C is-10-45 ℃;
preferably, the reaction temperature of the step C is 30-40 ℃;
extracting the reaction liquid by using an organic solvent after the reaction in the step C is finished, concentrating to obtain a crude roxatidine product M4, and entering the step D without purification;
preferably, the organic solvent of the reaction liquid extracted in the step C is at least one selected from toluene, ethyl acetate, dichloromethane, chloroform and isopropyl acetate;
the reaction solvent in the step D is at least one selected from methanol, ethanol and isopropanol;
the reaction temperature of the step D is 20-90 ℃;
preferably, the reaction temperature of the step D is 75-85 ℃;
Cooling to 15-25 ℃ after the reaction in the step D is finished, and crystallizing;
step D comprises recrystallizing the intermediate M5, wherein the recrystallization solvent is a mixed solvent of water and at least one of methanol, ethanol and isopropanol;
preferably, the recrystallization solvent is 85% w/w ethanol aqueous solution;
adding 0.05% -5% of seed crystal in the recrystallization process in the step D by mass of the compound M1;
preferably, 0.1% -2% of seed crystal is added in the recrystallization process in the step D based on the mass of the compound M1;
preferably, 0.5% -1.5% of seed crystal is added in the recrystallization process in the step D based on the mass of the compound M1;
preferably, step D adds 1% seed crystals during recrystallization, based on the mass of compound M1;
the oxalic acid in the step D can be replaced by at least one of hydrochloric acid, methanesulfonic acid and tartaric acid;
the alkali in the step E is potassium hydroxide;
the reaction solvent in the step E is water;
the reaction temperature in the step E is-10-45 ℃;
preferably, the reaction temperature in the step E is 10-20 ℃;
extracting the reaction liquid by using an organic solvent after the reaction in the step E is finished, and concentrating to obtain a roxatidine refined product M6;
preferably, the organic solvent of the extraction reaction liquid in the step E is at least one selected from toluene, ethyl acetate, dichloromethane, chloroform and isopropyl acetate;
Controlling the moisture content of the roxatidine refined product M6 to be less than 6%;
preferably, the moisture content of the roxatidine concentrate M6 is controlled to be < 4%.
Further, compound M1 is prepared from step F:
m-hydroxybenzaldehyde and piperidine are reacted in formic acid to give compound M1.
Further, the preparation method meets at least one of the following:
step F, intermediate hydroxybenzaldehyde: the mass ratio of the piperidine is 1: (1.5-5.0);
preferably, step F is intermediate hydroxybenzaldehyde: the mass ratio of the piperidine is 1:2.43;
step F, intermediate hydroxybenzaldehyde: the mass ratio of formic acid is 1: (1.0 to 10.0);
preferably, step F is intermediate hydroxybenzaldehyde: the mass ratio of formic acid is 1:5.0;
the reaction temperature of the step F is 80-140 ℃;
preferably, the reaction temperature of the step F is 120-140 ℃;
the reaction time of the step F is 1.2 to 1.8 hours;
f, performing reaction post-treatment, namely adjusting the pH value to 8.0-12.0, and separating out a compound M1;
preferably, the post-reaction treatment end point in the step F is used for adjusting the pH to 10.0-11.0;
preferably, 0.05 to 5 percent of seed crystal precipitation compound M1 is added in the post-reaction treatment of the step F according to the mass of the M-hydroxybenzaldehyde;
preferably, 0.1% -2% of seed crystal precipitation compound M1 is added in the post-reaction treatment of the step F according to the mass of M-hydroxybenzaldehyde;
Preferably, 0.5 to 1.5 percent of seed crystal precipitation compound M1 is added in the post-reaction treatment of the step F according to the mass of the M-hydroxybenzaldehyde;
preferably, 1% seed crystal precipitation compound M1 is added in the post-reaction treatment of the step F based on the mass of the M-hydroxybenzaldehyde.
The invention provides a preparation method of roxatidine acetate hydrochloride, which comprises the following steps: the roxatidine acetate is obtained according to the preparation method, then the roxatidine acetate is formed into hydrochloride, and finally the roxatidine acetate hydrochloride refined product is obtained according to the refining method.
Further, the roxatidine acetate hydrochloride forming step comprises the following steps: adding hydrogen chloride into isopropyl acetate solution of roxatidine acetate, separating out roxatidine acetate hydrochloride, and collecting the material.
Further, the method for forming the hydrochloride of the roxatidine acetate meets at least one of the following steps:
hydrogen chloride is added at 0-45 ℃;
preferably, hydrogen chloride is added at 10-20 ℃;
hydrogen chloride is added in the form of isopropyl hydrogen chloride acetate solution;
preferably, the content of hydrogen chloride in the isopropyl hydrogen chloride acetate solution is 4.0-4.3%;
preferably, the isopropyl hydrogen chloride acetate solution is added in portions: adding 0.2-0.3 times of isopropyl hydrogen chloride acetate solution based on the mass of roxatidine oxalate, adding seed crystal, stirring uniformly, and then continuously adding 2-3 times of isopropyl hydrogen chloride acetate solution to separate out roxatidine acetate hydrochloride;
Preferably, 0.05 to 5 percent of seed crystal is added according to the mass of the roxatidine oxalate;
preferably, 0.1% -2% of seed crystal is added based on the mass of roxatidine oxalate;
preferably, 0.5% -1.5% of seed crystal is added based on the mass of roxatidine oxalate;
preferably, 1% seed crystal is added based on the mass of roxatidine oxalate;
stirring and crystallizing for 1.0-1.5 hours after hydrogen chloride is added.
The method for synthesizing and refining the roxatidine acetate hydrochloride provided by the invention has at least the following beneficial effects:
1. the refining method suitable for industrial production of the roxatidine acetate hydrochloride is developed, the product purity is effectively improved (99.95%), and the impurity level is reduced (single impurity is less than 0.05%). The relevant substances, content, melting point, burning residue, microorganism, endotoxin, solvent residue and the like of the roxatidine acetate hydrochloride bulk drug produced by the refining method all conform to ICH related guidelines and accord with JP standard.
2. The synthesis process provided by the invention shortens the reaction time as a whole, improves the production efficiency, and has milder and controllable reaction conditions, in particular: the reaction time for preparing M1 is short (within 2 hours), and the yield is high (more than 97 percent); the reaction temperature for preparing M2 is low (below 70 ℃), and the reaction time is short (within 2 hours); the reaction temperature for preparing M4 is low (below 45 ℃) and the reaction time is short (30 minutes); the reaction temperature for preparing M7 is low (below 50 ℃) and the reaction speed is high (within 2.5 hours).
3. The intermediate M2-M5 is designed optimally through continuous process, so that the post-treatment operation is simplified greatly, the yield and the production efficiency are further improved, and the production cost is reduced.
4. The total yield of the synthesis process provided by the invention reaches 57.1 percent (calculated by m-hydroxybenzaldehyde), which is higher than the existing level, the impurity level of the prepared roxatidine acetate hydrochloride is obviously reduced, the product quality is not lower than the original grinding level (the maximum single impurity of a reference preparation is 0.27 percent), compared with the like products, the synthesis process has obvious advantages, the safety, the effectiveness and the quality controllability of the product are integrally improved, and the consistency evaluation requirement is met.
5. The process verification of 15kg batch finally proves that the roxatidine acetate hydrochloride provided by the invention has stable synthesis process and potential of further stable amplification production.
Drawings
FIG. 1 is an HPLC profile of intermediate M1 in example 1;
FIG. 2 is an HPLC profile of intermediate M5 in example 1;
FIG. 3 is an HPLC chart of the final product roxatidine acetate hydrochloride in example 1;
FIG. 4 is a TGA-DSC spectrum of roxatidine acetate hydrochloride as the final product in example 1;
FIG. 5 is an XRD spectrum of the final product roxatidine acetate hydrochloride in example 1;
Fig. 6 is an HPLC profile of the final product roxatidine acetate hydrochloride in the comparative example.
Detailed Description
In a first aspect, the present invention provides a method for refining roxatidine acetate hydrochloride, wherein N, N-dimethylformamide is used as a good solvent, and isopropyl acetate is used as a poor solvent for recrystallization.
The above technical solution is obtained based on the following findings of the inventors: the roxatidine acetate hydrochloride is easy to degrade, for example, the acetate in the structure is easy to degrade under the action of acid, alkali, water and the like to generate impurity roxatidine, and the impurity generated in the synthesis process is added, so that the purity of the bulk drug is low. The maximum single impurity of the original reference preparation is 0.27%. If the synthesis process is provided according to Synthetic Communications, the final product purity can only reach 98.5% (see: A New Synthesis of Roxatidine acetate. SYNTHETIC COMMUNICATIONS,29 (l), 15-20,1999). Thus, the relevant substance level of roxatidine acetate hydrochloride is to be further controlled. In addition, in the prior art, when the product is refined, ethanol is required to be heated to 60 ℃ for recrystallization (see a route 1 in the background art), however, the inventor finds that the ethanol and the methanol are used as recrystallization solvents, and the roxatidine acetate hydrochloride is easy to degrade to generate impurities such as roxatidine, so that the quality stability of the product is poor, and the impurity level is further increased. Through investigation, the invention creatively selects N, N-dimethylformamide and isopropyl acetate as recrystallization solvents, thereby being capable of preparing the roxatidine acetate hydrochloride refined product with purity as high as 99.95 percent and single impurity of less than 0.05 percent, obviously improving the purity of the product and reducing the impurity level.
In a second aspect, the invention provides a preparation method of roxatidine acetate, wherein roxatidine and acetic anhydride are used as raw materials, isopropyl acetate as a reaction solvent is added, and the mixture is reacted at a temperature of between 10 and 50 ℃ to generate roxatidine acetate; wherein, based on the mass of the roxatidine half oxalate, the roxatidine half oxalate: the mass ratio of acetic anhydride is 3.5: (1.0-6.2).
The above technical solution is obtained based on the following findings of the inventors: when the existing synthesis process prepares roxatidine acetate by roxatidine, the reaction is required to be carried out at a higher temperature (acetic acid reflux, see the route 3), or the reaction temperature is reduced but the reaction time is prolonged (5 hours, see the route 2), which is not beneficial to reducing the production cost and improving the production efficiency. The method optimizes the process conditions of the step, particularly selects proper reaction solvent and acetic anhydride dosage, thereby fully reacting in a shorter time at a lower reaction temperature; in addition, under the process conditions adopted by the invention, the reaction is more complete and clean, so that the post-treatment is simplified, the next hydrochloride forming reaction can be directly carried out by adding the acetic anhydride quenching solvent after the reaction is finished, and complex post-treatment procedures such as concentration, water washing, alkali adjustment, extraction, sodium sulfate drying, filtration, re-concentration and the like are not needed as in the prior art, and the hydrolysis of the product roxatidine acetate during the post-treatment is avoided.
In a third aspect, the present invention provides a method for preparing roxatidine acetate hydrochloride, comprising the steps of: the roxatidine acetate prepared by the preparation method according to the second aspect is then formed into hydrochloride, and the roxatidine acetate refined product is finally obtained by the refining method according to the first aspect. Thus, the high-purity (99.95 percent, single impurity <0.05 percent) roxatidine acetate hydrochloride can be prepared with high total yield (57.1 percent), and all related substances, content, melting point, burning residues, microorganisms, endotoxin, solvent residues and the like of the raw material medicine accord with ICH related guidelines and accord with JP standard; the temperature in the reaction process is easy to control, the post-treatment operation is simple and convenient, and the industrial production is easy to realize.
The invention may also have the following additional technical features:
in some embodiments of the invention, roxatidine is prepared by the following method:
step A, compound M1, 3-chloropropylamine or salt thereof and alkali are reacted in N, N-dimethylformamide to prepare an intermediate M2:
step B, reacting the intermediate M2 with acetoxyacetyl chloride to obtain an intermediate M3:
step C, hydrolyzing the intermediate M3 to obtain a crude product M4 of roxatidine:
Step D, salifying the crude product M4 of roxatidine with oxalic acid to obtain an intermediate M5:
step E, reacting the intermediate M5 with alkali to obtain a roxatidine refined product M6:
in the preparation of 3- (3-piperidin-1-ylmethyl phenoxy) propylamine (intermediate M2), compared with solvents such as toluene, N-dimethylformamide, dimethyl sulfoxide and the like, the invention finds that the solubility of toluene to materials is poor, the reaction speed is seriously influenced, or the reaction is required at high temperature, and the conversion rate is low; dimethyl sulfoxide is easy to decompose under the action of strong alkali and is not easy to stir. The step is preferably to take N, N-dimethylformamide as a reaction solvent, and the reaction temperature for preparing the intermediate M2 is low, the reaction time is short and the conversion rate is high after optimization.
When the roxatidine is prepared, the crude roxatidine acetate (intermediate M3) is prepared by reacting the acetoxyacetyl chloride with the intermediate M2, and then the synthesis route of the crude roxatidine M4 is prepared by hydrolysis, so that the lower temperature for preparing the roxatidine (route 3: 160-165 ℃) is realized.
In some specific embodiments, the invention optimizes the post-treatment mode of preparing the intermediate M2, does not further purify, directly carries out the next reaction on the dichloromethane solution of the intermediate M2, avoids the high-temperature rectification operation as in the route 2, has simpler post-treatment and is more suitable for industrial production.
In some specific embodiments, the invention adopts a telescoping process, M2-M5 is produced without separation and purification, thus greatly simplifying subsequent operation, improving yield and production efficiency, reducing production cost, and being single in solvent, convenient to recycle and outstanding in the green and environment-friendly characteristics of the process.
In some embodiments of the invention, the post-treatment of the intermediate M6 uses purified water to wash the reaction liquid, so that the drying of anhydrous sodium sulfate is avoided, the generation of solid waste is reduced, the risk that the burning residue of the crude drug exceeds the limit is greatly reduced, and the QbD (quality source design) concept is penetrated in the research and development process of the crude drug, so that the process control of each key quality attribute of the crude drug is performed.
In some embodiments of the invention, compound M1 is prepared from step F:
m-hydroxybenzaldehyde and piperidine are reacted in formic acid to give compound M1.
In the preparation of the compound M1, the invention compares potassium borohydride, sodium borohydride with formic acid, and the reaction of formic acid is found to have fewer impurities and is easier to control.
In some embodiments, the present invention optimizes the amount of piperidine used to help shorten the reaction time.
In some embodiments, the invention optimizes the post-treatment mode of step F, adjusts the pH and simultaneously uses seed crystal to induce crystallization to separate out solid. Among them, the pH adjuster may be selected from inorganic bases such as ammonia water, sodium hydroxide, and potassium hydroxide, or organic bases such as triethylamine and diisopropylamine, and further preferably sodium hydroxide and potassium hydroxide.
The compound M1 prepared according to step F above has a purity of up to 99.85% in one embodiment and a yield of up to 97.2%.
In some embodiments of the present invention, roxatidine acetate hydrochloride comprises the steps of: adding hydrogen chloride into isopropyl acetate solution of roxatidine acetate, separating out roxatidine acetate hydrochloride, and collecting the material. In the process of technological investigation of the roxatidine acetate hydrochloride, the inventor unexpectedly finds that the roxatidine acetate hydrochloride obtained by using isopropyl acetate as a solvent has better properties, can prepare white crystalline particles, has large granularity, is easy to filter and dry, and can obtain the beneficial effects obviously superior to other solvents by using isopropyl acetate as a salifying solvent.
In summary, in order to solve the problems of long reaction time, high reaction temperature, complex operation, low yield, low purity of raw materials and the like of part of steps, which exist in the existing synthesis technology, the invention carries out innovative optimization design on a synthesis route, and the determined synthesis route which is most suitable for industrialization is as follows:
The method specifically comprises the following steps: firstly, M-hydroxybenzaldehyde is reacted with piperidine to prepare a high-purity compound M1 (3- (1-piperidylmethyl) phenol), the compound M1 is reacted with 3-chloropropylamine hydrochloride to prepare an intermediate M2 (3- (3-piperidyl-1-ylmethyl phenoxy) propylamine), the intermediate M2 is reacted with acetoxyacetyl chloride to prepare an intermediate M3 (coarse roxatidine acetate), the intermediate M3 is hydrolyzed to prepare an intermediate M4 (coarse roxatidine), the intermediate M4 is salified with oxalic acid and then recrystallized to prepare a high-purity intermediate M5 (roxatidine half oxalate), the intermediate M5 is salified to prepare an intermediate M6 (roxatidine refined product), the intermediate M6 is reacted with acetic anhydride to prepare an intermediate M7 (roxatidine acetate refined product), the intermediate M7 is salified with hydrogen chloride to prepare an intermediate M8 (coarse roxatidine acetate hydrochloride), and the intermediate M8 is salified to prepare high-purity roxatidine hydrochloride.
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
EXAMPLE 1 preparation of roxatidine acetate hydrochloride
1. Preparation of intermediate 1 (3- (1-piperidylmethyl) phenol, M1)
Sequentially adding 5.0 times 50.00kg of anhydrous formic acid and 1.0 times 10.00kg of m-hydroxybenzaldehyde into a 100L glass kettle, stirring and heating to 120-140 ℃, dropwise adding 2.43 times 24.30kg of piperidine, controlling the reaction temperature to 120-140 ℃, and carrying out heat preservation reaction for 1.5 hours after the addition.
Cooling the reaction liquid to 20-30 ℃ after the reaction is completed, adding 5.0 times of 50.00kg of purified water, transferring to a 300 liter reaction kettle, slowly adding 40% sodium hydroxide aqueous solution to adjust the pH to 8.5+/-0.5, adding 0.10kg of 1% seed crystal, continuously adjusting the pH until the solid in the reaction liquid is obviously separated out, stirring for 30-60 minutes for crystal growth, continuously adjusting the pH to 10.5+/-0.5, stirring for crystallization at 25+/-5 ℃ for 1-2After an hour, the mixture was filtered, and the cake was washed 3 times with 2.0 times 20.00kg of water, and the obtained solid was dried in vacuo at 40.+ -. 5 ℃ for 4 hours to yield 15.19kg of intermediate 1 in 97.2% yield (calculated as m-hydroxybenzaldehyde). ESI-MS m/z:192.2[ M+H ]]+； 1 H-NMR (400 MHz, DMSO-d 6) delta: 1.34-1.42 (m, 2H), 1.45-1.51 (m, 4H), 2.28 (s, 4H), 3.31 (s, 2H), 6.60-6.63 (m, 1H), 6.63-6.74 (m, 2H), 7.07 (t, j=7.7 hz, 1H), 9.44 (s, 1H); 13C-NMR (100 MHz, DMSO-d 6) delta: 24.52 26.06, 54.41, 63.43, 114.18, 115.93, 119.63, 129.36, 140.59, 157.82; HPLC purity: 99.85% (HPLC profile see FIG. 1); melting point: 137.2-138.8 ℃.
2. Preparation of intermediate 2 (3- (3-piperidin-1-ylmethyl-phenoxy) propylamine, M2)
Preparing 3-chloropropionamine hydrochloride solution: stirring is started, and 45.00kg of N, N-dimethylformamide which is 3.0 times and 12.15kg of 3-chloropropionamine hydrochloride which is 0.81 times are sequentially stirred and dissolved in a 50-liter reaction kettle at 30+/-5 ℃ for standby.
Stirring is started, 30.00kg of N, N-dimethylformamide with the concentration of 3.0 times and 15.00kg of intermediate 1 with the concentration of 1.0 times are sequentially added into a 100L reaction kettle, 21.75kg of sodium hydroxide with the concentration of 1.45 times is added under stirring, and the temperature is raised to 65+/-5 ℃ under stirring.
When the internal temperature is raised to 65+/-5 ℃, 3-chloropropionamine hydrochloride solution prepared in advance is added dropwise, the reaction is carried out at the temperature of 60-75 ℃, and the reaction is carried out for 1.5 hours at the temperature of 65+/-5 ℃ after the dropwise addition. Cooling to 20+/-5 ℃ at internal temperature, adding 30.00kg of 2.0 times of dichloromethane for dilution, putting into a transfer barrel, filtering, slowly eluting a filter cake by using 75.00kg of 5.0 times of dichloromethane, transferring the filter cake into a 300L reaction kettle after the filter cake is washed cleanly, adding 90.00kg of 6.0 times of purified water, stirring for 5-10 min, standing for separating liquid, extracting a water layer by using 45.00kg of 3.0 times of dichloromethane, merging organic phases obtained by the two times, washing for 4 times by using 60.00kg of 4.0 times of purified water, adding 30.00kg of 2.0 times of anhydrous sodium sulfate into the organic phase, stirring and drying for 2.5+/-0.5 hours, filtering, and slowly eluting the filter cake by using 30.00kg of 2.0 times of dichloromethane for 2 times to obtain a dichloromethane solution of M2. ESI-MS m/z:249.2[ M+H ] +;1H-NMR (400 MHz, DMSO-d 6) delta: 1.38 (q, j=6.2 Hz, j=6.8 Hz, 2H), 1.45-1.51 (m, 4H), 1.74-1.80 (m, 2H), 2.30 (d, j=5.9 Hz, 4H), 2.69 (t, j=6.7 Hz, 2H), 3.36 (s, 2H), 3.99 (t, j=6.4 Hz, 2H), 6.74-6.86 (m, 3H), 7.19 (t, j=8.0 Hz, 1H); 13C-NMR (100 MHz, DMSO-d 6) delta: 24.50, 26.05, 33.22, 38.88, 54.38, 63.30, 65.80, 113.08, 115.09, 121.19, 129.48, 140.77, 159.13.
3. Preparation of intermediate 3 (crude roxatidine acetate, M3)
The amount of material fed in this step is measured on the basis of M1.
Transferring the filtrate into a 300L reaction kettle, starting stirring, adding 10.20kg of triethylamine with the weight being 0.68 times, reducing the internal temperature to 15+/-5 ℃ under the protection of nitrogen, controlling the internal temperature to 15+/-5 ℃, dropwise adding 12.90kg of acetoxyacetyl chloride with the weight being 0.86 times, and keeping the internal temperature for 15+/-5 ℃ after the addition, and stirring for 1 hour. The reaction solution was filtered, the filter cake was slowly washed with 2.0 times of dichloromethane (30.00 kg), the filtrate was concentrated using a 200L reaction vessel until no significant fraction was distilled off, and 2.0 times of ethanol (30.00 kg) was added to obtain an M3 solution.
4. Preparation of intermediate 4 (crude roxatidine, M4)
The amount of material fed in this step is measured on the basis of M1.
Preparing 30% sodium hydroxide aqueous solution: 8.70kg of 0.58-fold purified water and 3.75kg of 0.25-fold sodium hydroxide are added into the transfer barrel, stirred and dissolved completely to prepare 30% sodium hydroxide aqueous solution, and the solution is cooled to room temperature for standby.
Preparing sodium chloride aqueous solution: 60.00kg of 4.0 times water and 15.00kg of 1.0 times sodium chloride are added into a 200 liter reaction kettle, and the mixture is stirred to prepare the catalyst.
Transferring the M3 solution to a 200-liter reaction kettle, starting stirring, cooling, controlling the internal temperature to be 35+/-5 ℃, dropwise adding the prepared 30% sodium hydroxide aqueous solution, and reacting for 0.5 hour at the internal temperature of 35+/-5 ℃ after the addition. Adding 30.00kg of 2.0 times of water and 45.00kg of 3.0 times of isopropyl acetate under stirring, stirring for 5-10 min, standing for separating liquid, extracting the water layer by using 45.00kg of 3.0 times of isopropyl acetate, combining organic layers, washing the organic layers for 4 times by using 75.00kg of 5.0 times of saline solution, and concentrating the organic phase under reduced pressure at the external temperature of 45+/-5 ℃ until no obvious fraction exists, thus obtaining crude roxatidine (M4).
5. Preparation of intermediate 5 (roxatidine oxalate, M5)
Adding 75.00kg of 5.0 times absolute ethyl alcohol into the residue M4, heating for dissolution, transferring to a 300 liter reaction kettle, heating to 80+/-5 ℃ with stirring, adding 25.94kg of 51% oxalic acid ethanol solution, adding 0.15kg of 1% oxalate seed crystal, after the addition, keeping the temperature and stirring for 30-45 minutes, continuing cooling to 20+/-5 ℃ for crystallization for 2.0 hours, filtering, leaching a filter cake with 30.00kg of 2.0 times absolute ethyl alcohol to obtain a coarse product of roxatidine oxalate, weighing 21.66kg, detecting that the dry wet weight of the wet product is 7.8% with fast water, and converting the dry weight into 19.97kg. Yield 71.9% (based on M1).
Starting stirring, sequentially adding 119.40kg of ethanol with the concentration of 6.0 times of 85% w/w and a wet product of the coarse roxatidine oxalate with the concentration of 1.0 times of the coarse roxatidine oxalate (dried 19.90 kg), starting external circulation, stirring and heating to 80+/-5 ℃, keeping the temperature and stirring for 2.0-2.5 hours, cooling to 60+/-5 ℃, adding 0.20kg of 1% seed crystal, keeping the temperature and stirring for 30-60 minutes, continuously cooling to the internal temperature of 20+/-5 ℃ for crystallization for 2.0 hours, filtering, slowly eluting a filter cake with 59.7kg of absolute ethanol with the concentration of 3.0 times of the coarse roxatidine oxalate, and vacuum-drying the wet product at the temperature of 40+/-5 ℃ for 4 hours to obtain a material, weighing 17.89kg, wherein the yield is 89.6% (calculated by the coarse product). ESI-MS m/z:307.2[ M+H ] +;1H-NMR (400 MHz, DMSO-d 6) delta: 1.44 (s, 2H), 1.60 (s, 4H), 1.85-1.92 (m, 2H), 2.67 (s, 4H), 3.27 (q, j=6.6 Hz, 2H), 3.79 (s, 4H), 3.98 (t, j=6.2 Hz, 2H), 6.88-6.96 (m, 3H), 7.27 (d, j=7.8 Hz, 1H), 7.85 (s, 1H); 13C-NMR (400 MHz, DMSO-d 6) delta: 23.19 24.39, 29.44, 35.83, 53.29, 61.35, 61.94, 65.98, 114.51, 116.32, 122.52, 129.93, 159.07, 165.13, 172.26; HPLC purity: 99.94% (HPLC profile see FIG. 2); melting point: 171.2-172.4 ℃.
6. Preparation of intermediate 6 (roxatidine concentrate, M6)
Preparing potassium hydroxide solution: 8.01kg of 0.45-fold purified water is added into the plastic bucket, 4.45kg of 0.25-fold potassium hydroxide is added dropwise under stirring, and the mixture is stirred and dissolved completely for standby.
Adding 89.00kg of purified water and 17.80kg of 1.0-time roxatidine oxalate into a 300L reaction kettle, stirring and cooling to 15+/-5 ℃, dropwise adding a prepared potassium hydroxide aqueous solution under stirring, controlling the temperature to 15+/-5 ℃, keeping the temperature and stirring for 20-30 minutes after adding, adding 53.40kg of 3.00-time isopropyl acetate, stirring for 5-10 minutes, standing and separating, extracting for 1 time by using 35.60kg of 2.00-time isopropyl acetate for the aqueous phase, stirring for 5-10 minutes, standing and separating, merging the organic layer, flushing the kettle wall of the reaction kettle by using the purified water, washing the organic layer for 4 times by using 106.80kg of purified water for 6.0-time, stirring for 5-10 minutes each time, standing and separating, concentrating the organic layer to vacuum degree < -0.085MPa at 45+/-5 ℃, continuing concentrating for 1-2 hours after no obvious distillate, sampling about 2g of detected water, stopping concentrating, adding 71.2kg of isopropyl acetate for dissolving, filtering, and merging the organic layer with the 17.0-time isopropyl acetate to obtain a finished product, namely, washing the finished product.
7. Preparation of intermediate 7 (roxatidine acetate concentrate, M7)
The amount of material fed in this step is measured on the basis of M5.
And (3) stirring the roxatidine refined product solution in a 300L reaction kettle, adding 18.16kg of 1.02 times acetic anhydride under stirring, stirring at 45+/-5 ℃ for 2.0 hours, cooling to room temperature, adding 35.60kg of 2.0 times isopropyl acetate and 12.10kg of 0.68 times isopropyl alcohol, and stirring for 30-60 minutes to obtain an M7 isopropyl acetate mixed solution.
8. Preparation of intermediate 8 (crude roxatidine acetate hydrochloride, M8)
The amount of material fed in this step is measured on the basis of M5.
Slowly dropwise adding 4.45kg of isopropyl hydrogen chloride acetate solution with the content of about 4.15% and 0.50 times of isopropyl hydrogen chloride acetate mixed solution at the temperature of 15+/-5 ℃ under stirring, adding 0.18kg of 1% seed crystal after dropwise adding, keeping the temperature and stirring for 10-20 minutes, continuously dropwise adding 44.5kg of isopropyl hydrogen chloride acetate solution with the content of about 4.15% and 2.50 times of isopropyl hydrogen chloride acetate, stirring and crystallizing for 1.0-1.5 hours after dropwise adding, filtering, washing a filter cake for 4 times by 53.40kg of isopropyl 3.0 times of isopropyl acetate to obtain a crude product wet product of roxatidine acetate hydrochloride, drying the wet product at the temperature of 40+/-5 ℃ for 8 hours, collecting M8, weighing 17.54kg, and obtaining the yield of 89.7% (calculated by M5).
9. Preparation of roxatidine acetate hydrochloride refined product
Adding 105.00kg of N, N-dimethylformamide and 17.50kg of crude roxatidine acetate hydrochloride with the concentration of 1.0 time into a 200 liter reaction kettle, heating to 55+/-5 ℃ under stirring, stirring for dissolving, filtering to a clean area, preheating to 55+/-5 ℃ with the concentration of 1.0 time, washing a pipeline by using the N, N-dimethylformamide, cooling to 35+/-5 ℃, dropwise adding 8.75kg of 0.5 isopropyl acetate, adding 0.01 time seed crystal 0.18kg, stirring for 30-60 minutes, continuously dropwise adding 96.25kg of 5.50 time isopropyl acetate, cooling to 5+/-5 ℃ and stirring for 2 hours, centrifugally filtering, washing the reaction kettle and a filter cake with the concentration of 3.0 time isopropyl acetate, obtaining a roxatidine acetate hydrochloride wet product, drying the wet product at 40+/-5 ℃ for 8 hours, and obtaining the roxatidine acetate hydrochloride refined product by weighing 15.96kg, wherein the yield is 91.2% (calculated by M8). ESI-MS m/z:349.2[ M+H ] +;1H-NMR (400 MHz, DMSO-d 6) delta: 1.29-1.39 (m, 1H), 1.66-1.78 (m, 1H), 1.80-1.84 (m, 4H), 1.86-1.92 (m, 2H), 2.08 (s, 3H), 2.76-2.86 (m, 2H), 3.22-3.27 (m, 4H), 4.01 (t, j=6.0 Hz, 2H), 4.19 (d, j=5.2 Hz, 2H), 4.43 (s, 2H), 6.99 (dd, j=8.4 Hz, j=2.0 Hz, 1H), 7.13 (d, j=7.6 Hz, 1H), 7.27 (s, 1H), 7.34 (t, j=8.0 Hz, 1H), 8.15 (t, j=5.2 Hz, 1H), 10.61 (s, 1H); 13C-NMR (100 MHz, DMSO-d 6) delta: 21.06, 21.94, 22.47, 29.21, 35.87, 51.99, 59.20, 62.73, 65.75, 115.93, 117.80, 123.87, 130.21, 131.73, 159.06, 167.22, 170.40. Melting point: 148.0-149.5 ℃; HPLC purity: 99.95% (single impurity < 0.05%). The HPLC pattern of the final product roxatidine acetate hydrochloride is shown in figure 3, the TGA-DSC pattern is shown in figure 4, and the XRD pattern is shown in figure 5.
Example 2 3 preparation of- (1-piperidylmethyl) phenol (Compound M1)
Sequentially adding 5.0 times of 50.0g anhydrous formic acid and 1.0 times of 10.0g m-hydroxybenzaldehyde into a reaction bottle, stirring and heating to 110-115 ℃ after the addition, dropwise adding 3.5 times of 35.0g piperidine, controlling the reaction temperature to 110-115 ℃, and carrying out heat preservation reaction for 1.5 hours after the addition, wherein TLC tracking is carried out, the reaction is incomplete, the reaction is carried out for 6 hours, and a small amount of unreacted products are complete. Cooling the reaction solution to 20-30 ℃, adding 5.0 times of 50.0g of purified water, slowly adding 40% sodium hydroxide aqueous solution to adjust the pH to 8.5+/-0.5, continuously adjusting the pH until the solid in the reaction solution is obviously separated out, stirring for 30-60 minutes for crystal growth, continuously adjusting the pH to 10.5+/-0.5, stirring for crystallization at 25+/-5 ℃ for 1-2 hours, filtering, washing a filter cake with 2.0 times of 20.0g of water for 3 times, and vacuum drying the obtained solid at 40+/-5 ℃ for 4 hours to obtain 12.6g of compound M1 with the yield of 81% (calculated by M-hydroxy benzaldehyde), wherein the purity of HPLC: 98.5%.
EXAMPLE 3 refining of crude roxatidine acetate hydrochloride
Adding 105.0g of N, N-dimethylformamide and 17.5g of crude roxatidine acetate hydrochloride 1.0 g of the crude roxatidine acetate hydrochloride into a reaction bottle (M8 prepared according to example 1 is taken), heating to 55+/-5 ℃ under stirring, filtering after stirring and dissolving, washing with N, N-dimethylformamide preheated to 55+/-5 ℃ 1.0 times, cooling to 35+/-5 ℃, dropwise adding 8.7g of 0.5 isopropyl acetate, adding 0.01 times seed crystal 0.2g, stirring for 30-60 minutes, continuously dropwise adding 96.2g of isopropyl acetate 5.50 times, cooling to 15-20 ℃ and stirring for 2 hours, centrifugally filtering, using 52.5g of isopropyl acetate to wash a reaction kettle and a filter cake to obtain a roxatidine acetate hydrochloride wet product, drying the wet product at 40+/-5 ℃ for 8 hours, obtaining a roxatidine acetate hydrochloride refined product, weighing 13.6g, and obtaining 78% (calculated by mass of the crude roxatidine acetate hydrochloride), and obtaining the product with the purity of HPLC: 99.95% (single impurity < 0.05%).
Comparative example refining of crude roxatidine acetate hydrochloride
The refining process of roxatidine acetate hydrochloride in reference to the document of the scheme 1 is used for recrystallizing a crude roxatidine acetate hydrochloride, namely M8 prepared according to the example 1.
Under mechanical stirring, 30.0g of crude roxatidine acetate hydrochloride and 150. 150 mL g of ethanol are added into a three-mouth bottle, heated to 60 ℃ for dissolution, 5.0g of active carbon is added for refluxing for 30min, the mixture is filtered while hot, the filtrate is cooled to 10 ℃, 450mL of ethyl acetate is slowly added dropwise, white solid is separated out, and stirring is continued for 4h. Suction filtration and decompression drying to obtain 23.2g of product with yield of 77.3%, purity of 98.9% and roxatidine content of 1.1%, and HPLC chart shown in figure 6.
It is to be noted that the particular features, structures, materials, or characteristics described in this specification may be combined in any suitable manner in any one or more embodiments. Furthermore, the various embodiments described in this specification, as well as the features of the various embodiments, can be combined and combined by one skilled in the art without contradiction.
Claims (12)
1. The refining method of the roxatidine acetate hydrochloride is characterized by comprising the following steps of: and (3) taking N, N-dimethylformamide as a good solvent and isopropyl acetate as a poor solvent for recrystallization.
2. The refining method according to claim 1, wherein: the method comprises the following steps:
a. adding a good solvent: mixing a crude roxatidine acetate hydrochloride product with N, N-dimethylformamide, and heating to dissolve, wherein the crude roxatidine acetate hydrochloride product is: the mass ratio of the N, N-dimethylformamide is 1: (4-10); preferably, the crude product of roxatidine acetate hydrochloride: the mass ratio of the N, N-dimethylformamide is 1:6, preparing a base material;
b. adding a poor solvent: adding isopropyl acetate into the solution obtained in the step a, cooling to-10-40 ℃ to separate out roxatidine acetate hydrochloride, and collecting to obtain a roxatidine acetate hydrochloride refined product, wherein the roxatidine acetate hydrochloride crude product is: the mass ratio of isopropyl acetate is 1: (4-10); preferably, the temperature is reduced to 0-10 ℃ to separate out roxatidine acetate hydrochloride; preferably, the crude product of roxatidine acetate hydrochloride: the mass ratio of isopropyl acetate is 1:6.
3. the refining method according to claim 2, characterized in that: at least one of the following is satisfied:
step a, heating to 50-80 ℃ for dissolution;
preferably, step a is heated to 50-60 ℃ for dissolution;
step a, carrying out hot filtration after heating and dissolving;
step b) adding isopropyl acetate in portions: firstly cooling to 30-40 ℃, adding 0.4-0.6 times of isopropyl acetate based on the mass of the crude product of the roxatidine acetate hydrochloride, adding seed crystals, stirring uniformly, then continuously adding the rest isopropyl acetate, cooling to 0-10 ℃ and separating out the roxatidine acetate hydrochloride;
Preferably, 0.05 to 5 percent of seed crystal is added according to the mass of the crude product of the roxatidine acetate hydrochloride;
preferably, 0.1 to 2 percent of seed crystal is added according to the mass of the crude product of the roxatidine acetate hydrochloride;
preferably, 0.5 to 1.5 percent of seed crystal is added according to the mass of the crude product of the roxatidine acetate hydrochloride;
preferably, stirring and crystallizing at 0-10 ℃ for more than 1 hour;
preferably, the crystallization is carried out at 0-10 ℃ for 1.5-2.5 hours.
4. The preparation method of roxatidine acetate is characterized by comprising the following steps: the method comprises the steps of taking roxatidine and acetic anhydride as raw materials, adding isopropyl acetate as a reaction solvent, and reacting at 10-50 ℃ to generate roxatidine acetate; wherein, based on the mass of the roxatidine half oxalate, the roxatidine half oxalate: the mass ratio of acetic anhydride is 3.5: (1.0-6.2).
5. The method of preparing as claimed in claim 4, wherein: at least one of the following is satisfied:
reacting at 40-50 ℃;
the mass of the roxatidine half oxalate is calculated as the mass of the roxatidine half oxalate: the mass ratio of acetic anhydride is 3.5: (4.0 to 4.6);
the reaction time is 1.5 to 2.5 hours;
preferably, the reaction time is 2.0 hours;
adding 4-5 times of isopropyl acetate serving as a reaction solvent based on the mass of the roxatidine half oxalate;
The post-reaction treatment is to add an acetic anhydride quenching solvent or a mixed solvent of the acetic anhydride quenching solvent and isopropyl acetate, and uniformly stir the mixture; wherein the acetic anhydride quenching solvent is selected from lower alcohols;
preferably, the acetic anhydride quenching solvent is at least one selected from methanol, ethanol, isopropanol and n-propanol.
6. The method of preparing as claimed in claim 4, wherein: the roxatidine is prepared by the following method:
step A, compound M1, 3-chloropropylamine or salt thereof and alkali are reacted in N, N-dimethylformamide to prepare an intermediate M2:
step B, reacting the intermediate M2 with acetoxyacetyl chloride to obtain an intermediate M3:
step C, hydrolyzing the intermediate M3 to obtain a crude product M4 of roxatidine:
step D, salifying the crude product M4 of roxatidine with oxalic acid to obtain an intermediate M5:
step E, reacting the intermediate M5 with alkali to obtain a roxatidine refined product M6:
7. the method of preparing as claimed in claim 6, wherein: at least one of the following is satisfied:
the reaction temperature of the step A is 30-70 ℃;
the reaction time of the step A is 1.2 to 1.8 hours;
extracting the reaction liquid by using an organic solvent after the reaction of the step A is finished to prepare a solution of an intermediate M2, and entering the step B without purification;
Adding an acid binding agent into the reaction system in the step B;
the reaction solvent in the step B is methylene dichloride;
the reaction temperature in the step B is-10-45 ℃;
after the reaction of the step B is finished, carrying out solid-liquid separation on the reaction liquid, collecting a liquid phase, concentrating to obtain an intermediate M3, and entering the step C without purification;
step C, performing alkali hydrolysis;
the reaction solvent in the step C is ethanol or a mixed solvent of ethanol and water;
the reaction temperature in the step C is-10-45 ℃;
extracting the reaction liquid by using an organic solvent after the reaction in the step C is finished, concentrating to obtain a crude roxatidine product M4, and entering the step D without purification;
the reaction solvent in the step D is at least one selected from methanol, ethanol and isopropanol;
the reaction temperature of the step D is 20-90 ℃;
cooling to 15-25 ℃ after the reaction in the step D is finished, and crystallizing;
step D comprises recrystallizing the intermediate M5, wherein the recrystallization solvent is a mixed solvent of water and at least one of methanol, ethanol and isopropanol;
adding 0.05% -5% of seed crystal in the recrystallization process in the step D by mass of the compound M1;
the oxalic acid in the step D can be replaced by at least one of hydrochloric acid, methanesulfonic acid and tartaric acid;
the alkali in the step E is potassium hydroxide;
the reaction solvent in the step E is water;
The reaction temperature in the step E is-10-45 ℃;
extracting the reaction liquid by using an organic solvent after the reaction in the step E is finished, and concentrating to obtain a roxatidine refined product M6;
the moisture content of the roxatidine refined product M6 is controlled to be less than 6 percent.
8. The method of preparing as claimed in claim 6, wherein: compound M1 is prepared by the following step F:
m-hydroxybenzaldehyde and piperidine are reacted in formic acid to give compound M1.
9. The method of preparing as claimed in claim 8, wherein: at least one of the following is satisfied:
step F, intermediate hydroxybenzaldehyde: the mass ratio of the piperidine is 1: (1.5-5.0);
step F, intermediate hydroxybenzaldehyde: the mass ratio of formic acid is 1: (1.0 to 10.0);
the reaction temperature of the step F is 80-140 ℃;
the reaction time of the step F is 1.2 to 1.8 hours;
and F, after the reaction, adjusting the pH to 8.0-12.0, and separating out a compound M1.
10. The preparation method of the roxatidine acetate hydrochloride is characterized by comprising the following steps of: the method comprises the following steps: the process according to any one of claims 4 to 9 to obtain roxatidine acetate, then the roxatidine acetate is formed into hydrochloride, and finally the refining process according to any one of claims 1 to 3 to obtain roxatidine acetate hydrochloride refined product.
11. The method of preparing as claimed in claim 10, wherein: the roxatidine acetate hydrochloride forming process includes the following steps: adding hydrogen chloride into isopropyl acetate solution of roxatidine acetate, separating out roxatidine acetate hydrochloride, and collecting the material.
12. The method for forming hydrochloride of roxatidine acetate according to claim 11, which is characterized in that: at least one of the following is satisfied:
hydrogen chloride is added at 0-45 ℃;
hydrogen chloride is added in the form of isopropyl hydrogen chloride acetate solution;
stirring and crystallizing for 1.0-1.5 hours after hydrogen chloride is added.
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