CN107698538A - The intermediate 3 of roxatidine acetate hydrochloride（1 piperidine methyl）The new preparation method of phenol - Google Patents
The intermediate 3 of roxatidine acetate hydrochloride（1 piperidine methyl）The new preparation method of phenol Download PDFInfo
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- CN107698538A CN107698538A CN201611078100.1A CN201611078100A CN107698538A CN 107698538 A CN107698538 A CN 107698538A CN 201611078100 A CN201611078100 A CN 201611078100A CN 107698538 A CN107698538 A CN 107698538A
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- Prior art keywords
- compound
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- phenol
- acid
- mol ratio
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title claims abstract description 30
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 229960000627 roxatidine acetate hydrochloride Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 33
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000463 material Substances 0.000 claims abstract description 16
- 150000003053 piperidines Chemical class 0.000 claims abstract description 12
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims abstract description 10
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 9
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 8
- 230000000694 effects Effects 0.000 claims abstract description 7
- 230000000977 initiatory effect Effects 0.000 claims abstract description 7
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000003459 sulfonic acid esters Chemical class 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 68
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 32
- SMTZFNFIKUPEJC-UHFFFAOYSA-N Roxane Chemical compound CC(=O)OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 SMTZFNFIKUPEJC-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 229960003320 roxatidine Drugs 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 20
- -1 4 Chemical class 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000003513 alkali Substances 0.000 claims description 13
- 229940125904 compound 1 Drugs 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 150000003891 oxalate salts Chemical class 0.000 claims description 11
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 229940126062 Compound A Drugs 0.000 claims description 8
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 8
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000000758 substrate Substances 0.000 claims description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 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 4
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 229960004275 glycolic acid Drugs 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 4
- 229960003287 roxatidine acetate Drugs 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 claims description 3
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 230000003196 chaotropic effect Effects 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 claims description 3
- 229960002646 scopolamine Drugs 0.000 claims description 3
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 2
- 229910019020 PtO2 Inorganic materials 0.000 claims description 2
- 230000021736 acetylation Effects 0.000 claims description 2
- 238000006640 acetylation reaction Methods 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 230000003113 alkalizing effect Effects 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 2
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- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 235000021050 feed intake Nutrition 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- 150000002989 phenols Chemical class 0.000 claims description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 2
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- 125000003944 tolyl group Chemical group 0.000 claims description 2
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- HXWDNCGKKYUTTH-UHFFFAOYSA-N CN(N1CC=CC=2C=CC=NC12)C Chemical compound CN(N1CC=CC=2C=CC=NC12)C HXWDNCGKKYUTTH-UHFFFAOYSA-N 0.000 claims 2
- INGSNVSERUZOAK-VXGBXAGGSA-N (2r)-2-phenyl-2-[(2r)-piperidin-1-ium-2-yl]acetate Chemical compound C([C@@H]1[C@H](C(=O)O)C=2C=CC=CC=2)CCCN1 INGSNVSERUZOAK-VXGBXAGGSA-N 0.000 claims 1
- OSNIIMCBVLBNGS-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-2-(dimethylamino)propan-1-one Chemical compound CN(C)C(C)C(=O)C1=CC=C2OCOC2=C1 OSNIIMCBVLBNGS-UHFFFAOYSA-N 0.000 claims 1
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- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 claims 1
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- 229910052796 boron Inorganic materials 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
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000005204 hydroxybenzenes Chemical class 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- ZOORJGVSPXCZCJ-UHFFFAOYSA-N n,n-dimethylpyrrol-1-amine Chemical class CN(C)N1C=CC=C1 ZOORJGVSPXCZCJ-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 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
- 229940111202 pepsin Drugs 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
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 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
Abstract
The present invention relates to a kind of preparation method of intermediate -3 of roxatidine acetate hydrochloride (1 piperidine methyl) phenol.Using m-nitrobenzaldehyde as initiation material, under phase transfer catalyst effect, reduce to obtain corresponding benzylalcohol through metallic boron hydrides reducing agent；In the presence of a base, the organic sulfonic acid ester containing activity is generated with organic sulfonic acid chloride class substance reaction；Obtain N substituted piperidine derivatives through N alkylated reactions with piperidines in the presence of a base again；Nitro therein is reduced again to obtain corresponding amino-compound；This amino-compound hydrolyzes again in aqueous sulfuric acid medium after diazotising, alkalize after obtain 3 (1 piperidine methyl) phenol.The present invention solves the problems, such as that conventional synthesis raw material m-hydroxybenzaldehyde is insufficient so that the cost of synthesis roxatidine acetate hydrochloride greatly improves, and the inventive method is easy and safe, each reaction raw materials are cheap and easy to get, reaction yield is high, are more particularly suitable for industrialized production 3 (1 piperidine methyl) phenol.
Description
Technical field
The present invention relates to medicinal chemistry art, more particularly to the intermediate of medical compounds roxatidine acetate hydrochloride
Synthetic method.
Background technology
Roxatidine acetate hydrochloride (Roxatidine acetate hydrochloride) is by Nippon Zoki
Pharmaceutical Co., Ltd.s are developed, and Japanese health ministry approval listing was obtained from 1986 so far, in 9 country's listings.
The medicine by being quickly converted to active metabolite Roxatidine (Roxatidine) after hydrolysis deacetylation, after
Person can selective exclusion histamine H2Acceptor, clinic are mainly used in preventing and treating the Digestive caused by hydrochloric acid in gastric juice high secreting state
System disease, such as gastric ulcer, duodenal ulcer, anastomotic part ulcer, reflux esophagitis, acute gastritis, the acute hair of chronic gastritis
Make；It is also used for preanesthetic medication prevention aspiration pneumonia.
Roxatidine acetate hydrochloride is fat-soluble medicine, and has higher bioavilability (more than 95%).It
In small intestine, blood plasma and liver after deacetylate, active metabolin Roxatidine is rapidly transformed into.Roxatidine acetic acid
Ester and its metabolite Roxatidine can effective, selective and competitively blocking histamine H2Acceptor；Basic stomach can be suppressed
Gastric acid secretion caused by acid and stimulation, can also suppress the secretion of pepsin, to serum gastrin and prolactin(PRL etc. without bright
Development rings, and has Mucosa for Protective Effect.Therefore, the research of Roxatidine class medicine and industrialized production are particularly important.
The chemical constitution of roxatidine acetate hydrochloride is as follows：
The chemical constitution of Roxatidine is as follows：
Synthesize the key intermediate needed for roxatidine acetate hydrochloride：
Roxatidine (compound 8) crude product is obtained after compound A and hydroxyacetic acid reaction, crude product into half oxalates by carrying
It is pure to obtain the oxalates of Roxatidine half (compound 9).The free Roxatidine retrieved after purification of the warp of compound 9, then through second
Acylated, synthetic hydrochloric acid salt obtain can hyoscine roxatidine acetate hydrochloride.(reacting flow chart is referring to content of the invention portion
Point)
Synthesis compound A method has following two at present：
Method one：
Method two：
Both approaches compare：The quality of gained intermediate A is suitable, and method one does not have obvious advantage；Method one
Need deprotection steps；Industrialized production generally use is method two.
No matter which kind of method, prepare compound A is required for compound 1 as raw material, and compound 1 is general with the following method
Prepare, and due to the pressure of environmental protection, the supply of m-hydroxybenzaldehyde (compound 2) often runs out of goods, and price is accordingly significantly
Improve, cause the difficulty of production.
The content of the invention
In order to overcome hydroxy benzenes first between raw material required in the preparation method of prior art 3- (1- piperidine methyls) phenol
Aldehyde supply be not enough to and its price rises the problem of cost brought greatly improves, the invention provides a kind of each reaction price
It is honest and clean be easy to get, reaction method is easy and safety, high income, is more particularly suitable for industrial 3- (1- piperidine methyls) phenol and (changes
Compound 1) preparation method.
In order to solve above-mentioned the problems of the prior art, the technical scheme is that：One kind prepares 3- (1- piperidines first
Base) phenol method, it is characterised in that comprise the following steps：
1) with m-nitrobenzaldehyde (compound 3) for initiation material, under phase transfer catalyst effect, reduced through reducing agent
Obtain compound 4；
2) compound 4 in the presence of a base, the organic sulfonic acid containing activity is generated with organic sulfonic acid chloride class substance reaction
The compound (compound 5) of esters leaving group；
3) compound 5 obtains the (change of N- substituted piperidine derivatives with piperidines through N- alkylated reactions in the presence of a base
Compound 6)；
4) nitro in compound 6 obtains corresponding amino-compound (compound 7) through reduction；
5) compound 7 hydrolyzes again through diazotising, post-processes and corresponding phenolic compound (compound 1) is obtained after alkalizing.
Wherein, the reducing agent used in step 1) is metallic boron hydrides, including sodium borohydride, potassium borohydride or hydroboration
Lithium etc., preferably sodium borohydride；Molar ratio=0.25~1.0 of the reducing agent and m-nitrobenzaldehyde: 1.0, preferably 0.25
~0.35: 1.0；Solvent is toluene, dimethylbenzene, dichloromethane, ether, glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrochysene furan
Mutter, one or more of arbitrary proportion mixtures of 2- methyltetrahydrofurans, preferably toluene；0~40 DEG C of reaction temperature, it is preferably
10~30 DEG C；1~24hr of reaction time, preferably 1~4hr；Wherein TBAB, triethyl group can be selected in phase transfer catalyst
Benzyl chloride, trimethyl ammonia chloride benzyl or polyethylene glycol 200~2000, preferably TBAB；Phase transfer catalyst and a nitro
Molar ratio=0.001~0.01 of benzaldehyde: 1.0, preferably 0.003~0.006: 1；
Organic sulfonic acid chloride class material in step 2) from paratoluensulfonyl chloride, benzene sulfonyl chloride, 4-Nitrobenzenesulfonyl chloride or
Mesyl chloride etc., preferably paratoluensulfonyl chloride；The alkali of be used as acid binding agent from the inorganic base such as sodium hydroxide, potassium hydroxide or
Person TEA (triethylamine), DIEA (diisopropylethylamine), DBU (carbon -7- alkene of 1,8- diazabicylo 11), pyridine, DMAP (4-
N, N- dimethylamino naphthyridine) etc. organic base, preferably sodium hydroxide；The mol ratio of alkali and 3- nitrobenzyl alcohols (compound 4) for 1.0~
2.0: 1.0, preferably 1.1~1.3: 1.0；The dosage mol ratio of organic sulfonic acid chloride class material and 3- nitrobenzyl alcohols (compound 4)
For 1.0~1.5: 1.0, preferably 1.05~1.1: 1.0；0~40 DEG C of reaction temperature, preferably 15~30 DEG C；Reaction time 2~
24hr, preferably 2~5hr；
Alkali in step 3) as acid binding agent select the inorganic bases such as sodium hydroxide, potassium hydroxide or TEA (triethylamine),
DIEA (diisopropylethylamine), DBU (carbon -7- alkene of 1,8- diazabicylo 11), pyridine, DMAP (4-N, N- dimethylamino pyrroles
Pyridine) etc. organic base, preferably sodium hydroxide；The mol ratio of alkali and p-methyl benzenesulfonic acid-(3- nitrobenzyls) ester is 1.0~2.0: 1.0, excellent
Elect 1.1~1.3: 1.0 as；The mol ratio of piperidines and p-methyl benzenesulfonic acid-(3- nitrobenzyls) ester is 1.0~2.5: 1.0, preferably 1.1
~1.2: 1.0；0~40 DEG C of reaction temperature, preferably 15~30 DEG C；8~24hr of reaction time, preferably 12~16hr；
Catalytic hydrogenation is used in step 4), catalyst is from Raney Ni, Pt/C, PtO2Deng (we test with Pd/C work as
Catalyst reduction, not only nitro be reduced into amino, compound 7 also may proceed to react de- benzyl into m-toluidine), preferably
Raney Ni, hydrogen source select H2Gas, formic acid, ammonium formate, triethylammonium formate etc., preferably H2；Catalytic amount accounts for substrate (w/w)
5%~30%, preferably 15%~25%；Solvent selected by catalytic hydrogenation is C1-C4 primary alconol, tetrahydrofuran, ethyl acetate
One or more of arbitrary proportion mixtures, preferred methanol；20~100 DEG C of reaction temperature, preferably 40~60 DEG C；Reaction pressure
Power is 1~8atm, preferably 2~4atm；6~20hr of reaction time, preferably 8~12hr；
From sulfuric acid be reaction medium when diazol is prepared in step 5), the mass percent concentration of sulfuric acid for 10%~
50%, preferably 20%~25%, the mol ratio of sulfuric acid and substrate (compound 7) is 1.5~5.0: 1.0, preferably 1.8~2.5:
1.0；Then diazol is hydrolyzed into the reaction of hydroxyl, and reaction medium selects sulfuric acid, and the mass percent concentration of sulfuric acid is 10%
~50%, preferably 20%~25%, the mol ratio of sulfuric acid and gained diazol is 1.0~5.0: 1.0, preferably 1.3~1.8:
1.0；；50~100 DEG C of reaction temperature, preferably 70~90 DEG C；4~16hr of reaction time, preferably 6~10hr；Post-processed
Journey adds C1-C4 alcohols as chaotropic agent (in order to avoid alkalinization caking balling-up can not fully be alkalized), preferably methanol；Alkalization institute
With alkali from inorganic bases, preferably ammoniacal liquor such as ammoniacal liquor, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
The invention further relates to the process that the oxalates of Roxatidine half (compound 9) is further prepared using the above method, tool
Body is：
6) compound 1 is in DMSO (dimethyl sulfoxide (DMSO)), under sodium hydroxide, KI effect, with 3- chlorine propylamine hydrochloric acid
Salt obtains compound A through O- alkylated reactions；
7) compound A and hydroxyacetic acid obtain corresponding acid amides after high temperature dehydration reacts, i.e.,：Roxatidine crude product, should
Crude product into half oxalates by purifying to obtain the oxalates of Roxatidine half (compound 9).
The present invention still relates to the use of intermediate prepared by above-mentioned all methods to prepare roxatidine acetate hydrochloride
Process, i.e.,：
8) compound 9 is through the free Roxatidine retrieved after purification, then obtains Roxatidine vinegar with aceticanhydride acetylation
Acid esters, then with HCl react to obtain can hyoscine roxatidine acetate hydrochloride.
Due to the supply problem of m-hydroxybenzaldehyde, the present invention using less expensive and more facile m-nitrobenzaldehyde as
Initiation material, developing a new route and be used to synthesize compound 1, while it is desirable to more multi-step could synthesize compound 1, but
It is that many steps can be prepared using not separation of intermediates " one kettle way ", so as to simplify operation.Due between initiation material
Nitrobenzaldehyde is lower than m-hydroxybenzaldehyde more valency and is easy to get, and piperidines dosage is less in variation route (reduces from about 2.5 times of moles
To about 1.15 times of moles), the side reaction per single step reaction is less, and yield is almost quantitative, synthesis key intermediate compound 1
Cost is compared less expensive with the route cost of m-hydroxybenzaldehyde.
In an experiment, we attempt directly to react the variation route of prepare compound 6 with m-nitrobenzaldehyde and piperidines, use
Potassium borohydride or triethylammonium formate are as reducing agent, however, it was found that yield is substantially relatively low, accessory substance is more, are unfavorable for follow-up
Prepare Roxatidine class medicine.Therefore, by test of many times, it is determined that be reduced into first with m-nitrobenzaldehyde corresponding benzylalcohol,
The route that the hydroxyl of generation reacts with pyridine again after being substituted by sulfonyl, the route yield is more preferable, is replaced beneficial to synthesis Luo Sha is continued
Class D medicine.
The beneficial effects of the invention are as follows：Use m-nitrobenzaldehyde that is more cheap, being more easy to get to prepare for initiation material to synthesize
Key intermediate 3- (1- piperidine methyls) phenol of roxatidine acetate hydrochloride；With m-nitrobenzaldehyde (compound 3)
It is almost quantitative and may not necessarily purify for the intermediate reaction in each step of initiation material prepare compound 6, therefore can " one
Pot method " directly carries out the use that feeds intake in next step, beneficial to the easy operation of industrialization；Series reaction after compound 7 is obtained is all
It is popular response, to production equipment facility without particular/special requirement, and key intermediate 3- (1- piperidine methyls) benzene can be obtained in high yield
Phenol.So as to avoid situation about can not be fed intake by m-hydroxybenzaldehyde supply missing；Also it is avoided that because m-hydroxybenzaldehyde
The rise of price and caused by production cost increase the problem of.
Embodiment
Embodiment 1：The preparation of 3- (1- piperidine methyls) nitrobenzene (compound 6)
1500g toluene is added in reaction bulb, then adds 604g (4.00mol) m-nitrobenzaldehyde (compound 3),
Add 6.0g TBABs；It is cooled to 15 DEG C or so.Under stirring, the water-soluble of 45.5g (1.20mol) sodium borohydride will be contained
Drop is added in reaction solution, and control temperature is below 30 DEG C.After being added dropwise, control temperature reacts 2hr at 20~30 DEG C.Until
Untill m-nitrobenzaldehyde total overall reaction finishes.
After confirming the reaction completely of compound 3,1800g water is added into reaction solution, under stirring, adds 820g
(4.31mol) paratoluensulfonyl chloride, below 30 DEG C of controlling reaction temperature, be added dropwise prepare in advance contain 200g (5.00mol) hydrogen
The aqueous solution of sodium oxide molybdena, after being added dropwise, control temperature reacts 3~4hr at 20~30 DEG C, until the total overall reaction of compound 4 is complete
Finish and change into compound 5.
Then, the aqueous solution containing 200g (5.00mol) sodium hydroxide for being added dropwise below 30 DEG C of temperature and preparing in advance is controlled,
After being added dropwise, 30min is stirred, then 392g (4.604mol) piperidines is added dropwise, control temperature is below 30 DEG C, after being added dropwise,
Temperature is controlled to react 3~4hr at 20~30 DEG C, system is entirely molten.TLC monitoring reaction, until the total overall reaction of compound 5 finish for
Only.
Then, stand, liquid separation.Aqueous phase is extracted with 400g toluene.Merge organic phase, be washed with water (600g × 2).Again with containing
The aqueous solution washing of 90g sodium chloride once, separates organic phase anhydrous sodium sulfate drying.Filtering, filtrate is collected, is concentrated under reduced pressure,
Obtain the about 920g (theoretical amounts of compound 6 for grease：880.38g).
Nuclear magnetic data：1H NMR(CDCl3)：δ=8.23 (s, 1H), δ=8.12 (d, 1H), δ=7.73 (d, 1H), δ=
7.50 (t, 1H), δ=3.60 (s, 2H), δ=2.45 (m, 4H), δ=1.59-1.64 (m, 4H), δ=1.44-1.52 (m, 2H).
Embodiment 2：The preparation of 3- (1- piperidine methyls) aniline (compound 7)
All grease of gained in embodiment 1 (are calculated, 3.995mol with theoretical amount 880g；Compound 6) it is added to
In hydrogen kettle, 7700g methanol is then added, is stirring evenly and then adding into 176g catalyst Raney Ni, then by several times will with 1100g methanol
Catalyst is rinsed clean and added in hydrogenation kettle.Nitrogen displacement 2~3 times, hydrogen are replaced 2~3 times, then in pressure about 3atm, temperature
Degree is hydrogenated with 45~50 DEG C, untill reaction finishes.
Confirm that compound 6 is fully converted into after compound 7, be cooled to room temperature, filtration catalytic agent, collect filtrate, concentration
Methanol, solid is obtained, it is off-white powder 730g (theoretical amounts that compound 7 is obtained after drying：760.26g)；Yield：96.0%.
After sample is purified with petroleum ether is refined, mp：108.7~110.3 DEG C.
Nuclear magnetic data：1H NMR(CDCl3)：δ=7.16 (t, 1H), δ=6.76 (s, 1H), δ=6.74 (d, 1H), δ=
6.64 (d, 1H), δ=3.69 (s, 2H), δ=2.43 (m, 4H), δ=1.60-1.67 (m, 4H), δ=1.46-1.53 (m, 2H).
Comparative example：The preparation of 3- (1- piperidine methyls) aniline (compound 7)
(it will be calculated using the compound 6 prepared by embodiment 1 according to theoretical amount 22g, feed intake 15.1g m-nitrobenzaldehydes
Gained) it is added in hydrogenation kettle, methanol 200g is added, after stirring, 2g is added and catalyst 5% (is calculated) with butt
Pd/C (water content about 54%).Nitrogen displacement 2~3 times, hydrogen are replaced 2~3 times, then in pressure about 1~2atm, temperature 45~
50 DEG C of hydrogenation, untill reaction finishes.
After confirming that compound 6 is wholly absent, room temperature is cooled to, filtration catalytic agent, collects filtrate, methanol is concentrated, is glued
The oil half of thick shape half consolidates material, and through column chromatography for separation, it is off-white powder 8.4g (theoretical amounts to obtain compound 7：19.03g)；Receive
Rate：44.1% (yield for being significantly lower than embodiment 2).Another component that column chromatography for separation goes out is m-toluidine about 4.7g.
Embodiment 3：The preparation of 3- (1- piperidine methyls) phenol (compound 1)
Water 1750g is added into reaction bulb, is cooled between 10~15 DEG C, it is dense to stir lower dropwise addition 500g (about 5.000mol)
Sulfuric acid, control temperature is below 30 DEG C.After being added dropwise, 15 DEG C are cooled to, adds 475g (2.50mol) made from embodiment 2
Compound 7, stirring are completely dissolved it, are cooled to less than 0 DEG C, and the aqueous solution containing 181g (2.63mol) natrium nitrosum is added dropwise.Control
Temperature processed is below 5 DEG C.After being added dropwise, the reaction 0.5hr below 5 DEG C is incubated, TLC confirms that the total overall reaction of compound 7 finishes
Afterwards, standby (reserve liquid 1).
1250g water is added into another reaction bulb, 375g (about 3.75mol) concentrated sulfuric acid is added dropwise.After being added dropwise, heating
To temperature at 75 DEG C~80 DEG C.Reserve liquid 1 is added dropwise by dropping funel.Temperature is controlled at 80 DEG C ± 5 DEG C.After being added dropwise, protect
Hold temperature and 6hr~8hr, TLC monitoring reactions are reacted at 80 DEG C~85 DEG C.Until diazol disappears substantially.
Confirm after completion of the reaction, reaction system to be cooled into 30 DEG C or so, add 500g methanol, about 1350g is added dropwise (about
19.8mol) ammoniacal liquor, control temperature are adjusted pH=9~10 below 60 DEG C (with that can separate out solid in ammoniacal liquor alkalinization).Adjust
After section, system is cooled to less than 10 DEG C, 3~4hr of insulation crystallization.Filtering, 60~80 DEG C of air blast drying.Obtain light brown
Compound 1, dry weight 450g (theoretical amounts：477.45g)；Yield：94.3%.
After sample is purified with methanol/water is refined, mp：135.7~138.1 DEG C.
Nuclear magnetic data：1H NMR(CDCl3)：δ=7.10 (t, 1H), δ=6.76 (d, 1H), δ=6.70 (d, 1H), δ=
6.64 (s, 1H), δ=6.38 (br, heavy water disappear after exchanging), 3.43 (s, 2H), 2.45 (m, 4H), 1.57-1.60 (m, 4H),
1.42-1.44 (m, 2H).
Embodiment 4：The preparation of 3- (1- piperidine methyls) nitrobenzene (compound 6)
150g methanol is added into reaction bulb, lower addition 50g (0.331mol) m-nitrobenzaldehyde is stirred, stirs 1hr, it is cold
But to 10 DEG C or so, 70g (0.824mol) piperidines is added dropwise, is cooled back to less than 10 DEG C, 7.1g (0.132mol) boron is added portionwise
Hydrofining, temperature control are no more than 30 DEG C.Confirm after completion of the reaction, to concentrate methanol, residue is dissipated with 200g moisture, and it is dense to add 90g
Hydrochloric acid, it is sufficiently stirred, impurity (impurity is m-nitrobenzyl alcohol) is extracted with ethyl acetate, retain aqueous phase, pH=is adjusted with ammoniacal liquor
10 or so, then product is extracted with ethyl acetate, dried, filtered with sodium sulphate, collect filtrate, be concentrated under reduced pressure dry solvent, obtains residual
Stay thing (compound 6) 31.5g (theoretical amounts：72.88g)；Yield：43.2%.
Embodiment 5：The preparation of 3- (1- piperidine methyls) nitrobenzene (compound 6)
300g formic acid is added into reaction bulb, lower addition 40g (0.265mol) m-nitrobenzaldehyde is stirred, then adds
45g (0.530mol) piperidines, 40g (0.397mol) triethylamine is added, be first heated to 60~70 DEG C of reaction about 2~3hr；Again plus
Hot to 110~115 DEG C reaction about 3~4hr；Confirm after completion of the reaction；80~90 DEG C are cooled to, be concentrated under reduced pressure formic acid；To residual
200g moisture is added in thing to dissipate, and is added 70g concentrated hydrochloric acids, is sufficiently stirred, impurity is extracted with ethyl acetate, retains aqueous phase, use ammonia
Water regulation pH=10 or so, then product is extracted with ethyl acetate, dried, filtered with sodium sulphate, collected filtrate, be concentrated under reduced pressure dry molten
Agent, obtain residue (compound 6) 36.9g (theoretical amounts：58.30g)；Yield：63.3%.
Embodiment 6：The preparation of 3- (1- piperidine methyls) phenoxy group propylamine (compound A)
750g dimethyl sulfoxide (DMSO)s are added into reaction bulb, add 420g (2.196mol) compound 1 (embodiment 3 is made),
340g (8.5mol) sodium hydroxide is added, is heated, is warming up to about 90 DEG C, 14g KIs is added, under stirring, is added portionwise
340g (2.615mol) 3- chloro propyl amine hydrochloric acid salts, it is incubated and reacts 20hr at 100~110 DEG C.Confirm after completion of the reaction, to add
1000g water, pH=10~11 are adjusted with concentrated hydrochloric acid, are sufficiently stirred about 1.5hr, are stood, liquid separation, aqueous phase extracts one with 800g toluene
It is secondary, merge organic phase, washed once with the aqueous solution of the sodium chloride containing 50kg, liquid separation, organic phase concentrates dry solvent, weighs, obtains oily
Thing 500g (theoretical amounts：545.38g)；Yield：91.7%.
Nuclear magnetic data：1H NMR(DMSO-d6+D2O)：δ=7.14 (t, 1H), δ=6.79 (d, 1H), δ=6.72 (d,
1H), δ=6.68 (s, 1H), 3.99 (t, 2H), 3.36 (s, 2H), 2.68 (t, 2H), 2.31 (br, 4H), 1.81-1.75 (m,
2H), 1.51-1.45 (m, 4H), 1.38-1.35 (m, 2H).
Embodiment 7：The preparation of the oxalates of Roxatidine half (compound 9)
450g (1.812mol) compounds A (embodiment 6 is made) is added into reaction bulb, 80 DEG C is heated to, is added portionwise
150g (1.972mol) hydroxyacetic acid, continue to be warming up to 160~165 DEG C of temperature, about 4~5hr reactions finish, and cool to 70 DEG C of left sides
The right side, 800g ethyl acetate is added into reaction solution, and stirring dissolves reactant, is fully stirred with the aqueous solution of the potassium carbonate containing 45g
Washing is mixed, is stood, liquid separation, aqueous phase is extracted once with 300g ethyl acetate, merges organic phase, with the aqueous solution of the sodium chloride containing 50g
It washed once, separate organic phase, add anhydrous sodium sulfate and activated carbon, stir lower dry and decolourize, filtering, collect filtrate, concentration
Dry solvent, obtain (compound 8) 517g grease (theoretical amounts：555.16g)；Yield：93.1%.
All 517g (1.687mol) compound 8 of above-mentioned gained 1500g absolute ethyl alcohols are dissolved, add 106g
(0.840mol) oxalic acid dihydrate, after adding, backflow about 1hr is warming up under stirring, cooling down is to 0~5 DEG C, and stirring and crystallizing is about
4hr, filtering, obtains off-white powder (compound 9) about 600g (weight in wet base, crude product).
It is refined：Above-mentioned gained 600g wet products are recrystallized with the aqueous solution 2500g of 85% ethanol, the chemical combination after being refined
Thing 9, dry weight 423g (theoretical amounts：636.72g；Fed intake calculating with 450g compounds A)；Yield：66.4%.
Embodiment 8：The preparation of roxatidine acetate hydrochloride
By 58g (0.930mol, after being converted according to 90% content), potassium hydroxide is dissolved in 1160g water, it is cooled to 20~
25 DEG C, under stirring, 300g (0.854mol) Roxatidines oxalates (compound 9, embodiment 7 are made) is added, adds acetic acid
Ethyl ester extracts (600g+450g), merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate concentration, obtains product Roxatidine
(compound 8) 251g.
The 251g Roxatidines of above-mentioned gained 500g glacial acetic acid is dissolved, adds 170g aceticanhydrides, it is anti-to be heated to backflow
Answer 2hr；Confirm that be concentrated under reduced pressure acetic acid after completion of the reaction, be cooled to 15~20 DEG C, add 600g water, add 600g acetic acid second
Ester；Under stirring, pH=9~10, liquid separation are adjusted with the aqueous solution of the potassium carbonate containing 300g, (400g+ is extracted with ethyl acetate in aqueous phase again
300g), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate concentration, obtain roxatidine acetate (compound 10)
280g。
By 280g (0.804mol) roxatidine acetate of above-mentioned gained) 1400g acetone solutions are used, it is cooled to 0~5
DEG C, the ethyl acetate solution containing 32g hydrogen chloride is added dropwise, after separating out solid, stirring insulation is in 0~5 DEG C of 3~5hr of crystallization, mistake
Filter, drying, obtains product roxatidine acetate hydrochloric acid 295g (theoretical amounts：328.58g；Fed intake calculating with 300g compounds 9)；Receive
Rate：89.8%.
Claims (14)
1. the method that one kind prepares 3- (1- piperidine methyls) phenol, it is characterised in that comprise the following steps：
1) with m-nitrobenzaldehyde (compound 3) for initiation material, under phase transfer catalyst effect, reduce to obtain through reducing agent
Compound 4；
2) compound 4 in the presence of a base, the sulfonic acid esters leaving group containing activity is generated with organic sulfonic acid chloride class material
Compound (compound 5)；
3) compound 5 obtains N- substituted piperidine derivative (compounds with piperidines through N- alkylated reactions in the presence of a base
6)；
4) nitro in compound 6 obtains corresponding amino-compound (compound 7) through reduction；
5) compound 7 hydrolyzes again through diazotising, post-processes and corresponding phenolic compound (compound 1) is obtained after alkalizing；
2. the method according to claim 1 for preparing 3- (1- piperidine methyls) phenol, it is characterised in that：Used in step 1)
Reducing agent is metallic boron hydrides, selected from sodium borohydride, potassium borohydride or lithium borohydride；The throwing of reducing agent and m-nitrobenzaldehyde
Material mol ratio=0.25~1.0: 1.0；Solvent is toluene, dimethylbenzene, dichloromethane, ether, glycol dimethyl ether, diethylene glycol
Dimethyl ether, tetrahydrofuran, one or more of arbitrary proportion mixtures of 2- methyltetrahydrofurans；Reaction temperature is 0~40 DEG C；
Reaction time is 1~24hr；Wherein phase transfer catalyst be TBAB, triethyl group benzyl chloride, trimethyl ammonia chloride benzyl or
Polyethylene glycol 200~2000；Molar ratio=0.001~0.01 of phase transfer catalyst and m-nitrobenzaldehyde: 1.0.
3. the method according to claim 2 for preparing 3- (1- piperidine methyls) phenol, it is characterised in that：Used in step 1)
Reducing agent is sodium borohydride；Molar ratio=0.25~0.35 of sodium borohydride and m-nitrobenzaldehyde: 1.0；Solvent is first
Benzene；Reaction temperature is 10~30 DEG C；Reaction time is 1~4hr；Wherein phase transfer catalyst is TBAB；The tetrabutyl
Molar ratio=0.003~0.006 of ammonium bromide and m-nitrobenzaldehyde: 1.0.
4. the method according to claim 1 for preparing 3- (1- piperidine methyls) phenol, it is characterised in that：Having in step 2)
Machine sulfonic acid chloride class material, selected from paratoluensulfonyl chloride, benzene sulfonyl chloride, 4-Nitrobenzenesulfonyl chloride or mesyl chloride；It is used as tiing up
The alkali of sour agent be selected from sodium hydroxide, potassium hydroxide inorganic base or selected from TEA (triethylamine), DIEA (diisopropylethylamine),
DBU (carbon -7- alkene of 1,8- diazabicylo 11), pyridine, DMAP (4-N, N- dimethylamino naphthyridine) organic base；Alkali with it is organic
The mol ratio of sulfonic acid chloride class material is 1.0~2.0: 1.0；The use of organic sulfonic acid chloride class material and 3- nitrobenzyl alcohols (compound 4)
It is 1.0~1.5: 1.0 to measure mol ratio；Reaction temperature is 0~40 DEG C；Reaction time is 2~24hr.
5. the method according to claim 4 for preparing 3- (1- piperidine methyls) phenol, it is characterised in that：Having in step 2)
Machine sulfonic acid chloride class material is paratoluensulfonyl chloride；The alkali of be used as acid binding agent is sodium hydroxide；Sodium hydroxide with to toluene sulphur
The mol ratio of acyl chlorides is 1.1~1.3: 1.0；The dosage mol ratio of paratoluensulfonyl chloride and 3- nitrobenzyl alcohols (compound 4) is
1.05~1.1: 1.0；Reaction temperature is 15~30 DEG C；2~5hr of reaction time.
6. the method according to claim 1 for preparing 3- (1- piperidine methyls) phenol, it is characterised in that：Conduct in step 3)
The alkali of acid binding agent is selected from sodium hydroxide, the inorganic base of potassium hydroxide or selected from TEA (triethylamine), DIEA (diisopropyl second
Amine), DBU (carbon -7- alkene of 1,8- diazabicylo 11), pyridine, DMAP (4-N, N- dimethylamino naphthyridine) organic base；Alkali with
The dosage mol ratio of p-methyl benzenesulfonic acid-(3- nitrobenzyls) ester is 1.0~2.0: 1.0；Piperidines and p-methyl benzenesulfonic acid-(3- nitrobenzyls)
The mol ratio of ester is 1.0~2.5: 1.0；Reaction temperature is 0~40 DEG C；Reaction time is 8~24hr.
7. the method according to claim 6 for preparing 3- (1- piperidine methyls) phenol, it is characterised in that：Conduct in step 3)
The alkali of acid binding agent is sodium hydroxide；The dosage mol ratio of sodium hydroxide and p-methyl benzenesulfonic acid-(3- nitrobenzyls) ester is 1.1~1.3:
1.0；The mol ratio of piperidines and p-methyl benzenesulfonic acid-(3- nitrobenzyls) ester is 1.1~1.2: 1.0；Reaction temperature is 15~30 DEG C；Instead
It is 12~16hr between seasonable.
8. the method according to claim 1 for preparing 3- (1- piperidine methyls) phenol, it is characterised in that：Used in step 4)
Catalytic hydrogenation, catalyst select Raney Ni, Pt/C or PtO2, hydrogen source selects H2Gas, formic acid, ammonium formate or triethylamine formate
Salt；Catalyst accounts for 5%~30% (mass percent) of substrate compounds 6；Solvent selected by catalytic hydrogenation is the primary of C1-C4
Alcohol, tetrahydrofuran, one or more of arbitrary proportion mixtures of ethyl acetate；Reaction temperature is 20~100 DEG C；Reaction pressure
For 1~8atm；Reaction time is 6~20hr.
9. the method according to claim 8 for preparing 3- (1- piperidine methyls) phenol, it is characterised in that：Used in step 4)
Catalytic hydrogenation, catalyst are Raney Ni, hydrogen source H2Gas；Catalyst accounts for 15%~25% (quality hundred of substrate compounds 6
Divide ratio)；The solvent of catalytic hydrogenation is methanol；Reaction temperature is 40~60 DEG C；Reaction pressure is 2~4atm；Reaction time 8~
12hr。
10. the method according to claim 1 for preparing 3- (1- piperidine methyls) phenol, it is characterised in that：Made in step 5)
From sulfuric acid be reaction medium during standby diazol, the mass percent concentration of sulfuric acid is 10%~50%, sulfuric acid and substrate chemical combination
The mol ratio of thing 7 is 1.5~5.0: 1.0；Diazol is hydrolyzed into the reaction of hydroxyl, and reaction medium selects sulfuric acid, the matter of sulfuric acid
It is 10%~50% to measure percent concentration, and the mol ratio of sulfuric acid and gained diazol is 1.0~5.0: 1.0；Reaction temperature is 50
~100 DEG C；Reaction time is 4~16hr；C1-C4 alcohols is added in last handling process as chaotropic agent；Alkali used in alkalization selects
From the inorganic base of ammoniacal liquor, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
11. the method according to claim 10 for preparing 3- (1- piperidine methyls) phenol, it is characterised in that：Made in step 5)
The mass percent concentration of sulfuric acid used is 20%~25% during standby diazol, and the mol ratio of sulfuric acid and substrate compounds 7 is 1.8
~2.5: 1.0；Diazol is hydrolyzed into the reaction of hydroxyl, and the mass percent concentration of sulfuric acid used is 20%~25%, sulfuric acid
Mol ratio with gained diazol is 1.3~1.8: 1.0；Reaction temperature is 70~90 DEG C；Reaction time is 6~10hr；After locate
Methanol is added during reason and does chaotropic agent；Alkalization alkali used is ammoniacal liquor.
12. the method according to claim 1 for preparing 3- (1- piperidine methyls) phenol, it is characterised in that：By m-nitro
In each step of formaldehyde (compound 3) prepare compound 6, " one kettle way " is used to be synthesized, obtained compound 6 is directly carried out
Feed intake use in next step.
13. the method that one kind prepares the oxalates of Roxatidine half (compound 9), it is characterised in that：The step of using claim 1
1) 3- (1- piperidine methyls) phenol -5) is prepared, the reaction of below step then occurs：
6) compound 1 is in DMSO (dimethyl sulfoxide (DMSO)), in the presence of sodium hydroxide, KI, with 3- chloro propyl amine hydrochloric acid salts
Compound A is obtained through O- alkylated reactions；
7) compound A and hydroxyacetic acid obtain corresponding acid amides after high temperature dehydration reacts, i.e.,：Roxatidine (compound 8) is thick
Product, the crude product into half oxalates by purifying to obtain the oxalates of Roxatidine half (compound 9)；
A kind of 14. method for preparing roxatidine acetate hydrochloride, it is characterised in that：Using all steps of claim 13
The oxalates of Roxatidine half (compound 9) is prepared, the reaction of following chemical formula then occurs：Compound 9 retrieves through free
Roxatidine after purification, then roxatidine acetate is obtained with aceticanhydride acetylation, then with HCl react to obtain can hyoscine sieve
Sand replaces d ritalinic acid ester hydrochloride；
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| 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 |
| CN113735798A (en) * | 2021-09-27 | 2021-12-03 | 安徽美致诚药业有限公司 | Preparation method of roxatidine acetate hydrochloride |
| 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 |
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| 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 |
| CN107857743B (en) * | 2017-10-20 | 2020-08-18 | 北京四环制药有限公司 | Method for preparing roxatidine acetate hydrochloride and intermediate |
| CN113735798A (en) * | 2021-09-27 | 2021-12-03 | 安徽美致诚药业有限公司 | Preparation method of roxatidine acetate hydrochloride |
| 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 |
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