CN107857743B - Method for preparing roxatidine acetate hydrochloride and intermediate - Google Patents
Method for preparing roxatidine acetate hydrochloride and intermediate Download PDFInfo
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- CN107857743B CN107857743B CN201710983365.4A CN201710983365A CN107857743B CN 107857743 B CN107857743 B CN 107857743B CN 201710983365 A CN201710983365 A CN 201710983365A CN 107857743 B CN107857743 B CN 107857743B
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- 229960000627 roxatidine acetate hydrochloride Drugs 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 claims abstract description 34
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000002360 preparation method Methods 0.000 claims abstract description 28
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 18
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 18
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 claims abstract description 16
- VQSXCZMVUMSITD-UHFFFAOYSA-N 3-[3-(piperidin-1-ylmethyl)phenoxy]propan-1-amine Chemical compound NCCCOC1=CC=CC(CN2CCCCC2)=C1 VQSXCZMVUMSITD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- ORGBERFQYFWYGX-UHFFFAOYSA-N 3-(piperidin-1-ylmethyl)phenol Chemical compound OC1=CC=CC(CN2CCCCC2)=C1 ORGBERFQYFWYGX-UHFFFAOYSA-N 0.000 claims abstract description 9
- IHPRVZKJZGXTBQ-UHFFFAOYSA-N 3-chloropropan-1-amine;hydron;chloride Chemical compound Cl.NCCCCl IHPRVZKJZGXTBQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 239000008096 xylene Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- BZFKSWOGZQMOMO-UHFFFAOYSA-N 3-chloropropan-1-amine Chemical compound NCCCCl BZFKSWOGZQMOMO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000007112 amidation reaction Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 230000009435 amidation Effects 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000004537 pulping Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000007670 refining Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- FTKQHXNOTYHHLE-UHFFFAOYSA-N 2-(piperidin-1-ium-1-ylmethyl)phenolate Chemical compound OC1=CC=CC=C1CN1CCCCC1 FTKQHXNOTYHHLE-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- SMTZFNFIKUPEJC-UHFFFAOYSA-N Roxane Chemical compound CC(=O)OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 SMTZFNFIKUPEJC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229960003287 roxatidine acetate Drugs 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- RWKSIKQHBHYHCA-UHFFFAOYSA-N 2-n-bromobenzene-1,2-dicarboxamide Chemical compound NC(=O)C1=CC=CC=C1C(=O)NBr RWKSIKQHBHYHCA-UHFFFAOYSA-N 0.000 description 1
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 206010017866 Gastritis haemorrhagic Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 206010035669 Pneumonia aspiration Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 206010042220 Stress ulcer Diseases 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 description 1
- 230000037328 acute stress Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- -1 acyloxy acetyl chloride Chemical compound 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000002862 amidating effect Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 201000009807 aspiration pneumonia Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 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
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000002699 waste material Substances 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a method for preparing roxatidine acetate hydrochloride and an intermediate thereof, which comprises the following steps: dissolving m-hydroxybenzaldehyde in a solvent, dripping piperidine, then adding sodium borohydride, and obtaining 3- (1-piperidinylmethyl) phenol after post-treatment; adding a standby solution of 3-chloropropylamine hydrochloride into 3- (1-piperidinylmethyl) phenol to prepare an intermediate 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine; after the reaction is finished, adding acetoxyacetyl chloride to carry out reaction to obtain a final product of roxatidine acetate hydrochloride. The preparation method of the roxatidine acetate hydrochloride and the intermediate thereof has the characteristics of stable yield and quality, controllable quality, environmental friendliness and low cost, and is beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a new preparation method of roxatidine acetate hydrochloride and an intermediate thereof.
Background
Roxatidine acetate hydrochloride (roxatidine acetate hydrochloride), chemical name 2-acetoxy-N- [3- [3- (1-piperidine)Ylmethyl) phenoxy]Propyl radical]Acetamide hydrochloride, Histamine H developed by Imperial organ pharmaceuticals of Japan2-a receptor blocker. Japanese was first marketed in 1986 for the treatment of upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis, etc., and for pre-anesthesia administration for the prevention of aspiration pneumonia.
The literature reports the preparation method of roxatidine acetate hydrochloride:
reference 1 (Chenfen, synthetic methods for organic drugs, pp.772-775, 1999) reported the preparation of roxatidine acetate hydrochloride as shown below (see reaction scheme 1).
Reaction scheme 1
The method takes m-nitrobenzaldehyde as a starting material, calcium carbonate as a carrier is refluxed in an aqueous solution, an intermediate (A1) is prepared by reduction of ferrous sulfate and sodium bisulfite, the intermediate (A1) is diazotized and then hydrolyzed to prepare m-hydroxybenzaldehyde (A), and the total yield of the two steps is 24%; the intermediate (A) reacts with piperidine in ethanol solution under the action of sodium borohydride to prepare an intermediate (B), and the yield is 74.5%; the intermediate (B) is in N, N-dimethylformamide solution and reacts with N-bromophthalic diamide to form ether under the action of sodium hydride to prepare an intermediate (C), and the yield is 78%; amidation reaction of the intermediate (C) and glycollic acid at 200 deg.c to obtain intermediate (C)1) The crude product yield is 91%; intermediate (C)1) Esterifying with acetic anhydride at 100 deg.C, purifying with silica gel column, introducing dry hydrogen chloride gas into chloroform solution, and salifying to obtain roxatidine acetate hydrochloride.
The preparation method of roxatidine acetate hydrochloride disclosed in the document 2 (US 4293557A) is basically the same as that of the document 1, and the roxatidine acetate hydrochloride is prepared by directly using m-hydroxybenzaldehyde (a) as a starting material through the same route and method as that of the document 1. The preparation methods disclosed in documents 1-2 have long synthesis routes, many steps and low total yield; the step of preparing the intermediate (B) is not completely reacted; when the intermediate C is prepared, expensive sodium hydride is used, the cost is high, and the reaction condition is severe; when the intermediate C1 is prepared, the melting reaction is needed at high temperature (200 ℃), the operation is difficult, and the product is complex; after the intermediate (C1) is reacted, column chromatography purification is needed, a hydrogen chloride step is introduced in the salt forming step, hydrogen chloride has hygroscopicity, absolute drying conditions are not easy to control, products are easy to decompose, corrosivity is high, and requirements on process equipment are high. Therefore, it is not easy to be industrially produced.
Document 3 (US 5317026A) discloses a method for producing roxatidine acetate (F) shown below (see reaction scheme 2).
Reaction scheme 2
The method takes m-hydroxybenzaldehyde (A) as a starting material, and the m-hydroxybenzaldehyde (A) reacts with piperidine and sodium borohydride in a methanol solution to prepare an intermediate (B), wherein the yield is 84.7%; under the action of sodium hydroxide, the intermediate (B) and 3-chloropropylamine hydrochloride form ether in a mixed solution of dimethyl sulfoxide and benzene to prepare an intermediate (C), wherein the yield is 86%; amidating the intermediate (C) and acetoxyacetyl chloride (E) in anhydrous benzene and triethylamine system, and purifying with silica gel column to obtain roxatidine acetate (F), with yield higher than 95%. In the document 3, the solvent methanol used in the step 1 of the method is high in toxicity, incomplete in reaction, unstable in product yield and quality, column chromatography is required in the purification step, and a highly toxic solvent benzene is used in the steps 2 to 3, so that the industrial production is not facilitated.
Document 4 (CN 102993121A) improves the preparation method of document 3, and uses m-hydroxybenzaldehyde and piperidine as starting materials, sodium borohydride as a reducing agent, and ethanol as a solvent to perform a condensation reaction to obtain 3- (1-piperidinylmethyl) phenol (intermediate B); the intermediate B and 3-chloropropylamine hydrochloride react in N, N-Dimethylformamide (DMF) solution under the alkaline condition of sodium hydride/sodium hydroxide to prepare 3- (3- (1-piperidylmethyl) phenoxy) propylamine (intermediate C); dripping chloroacetyl chloride into the intermediate C in a dichloromethane solvent at low temperature for acylation reaction to prepare 2-chloro-N- [3- [3- (piperidine-1-ylmethyl) phenoxy ] propyl ] acetamide (intermediate D); and dissolving the intermediate D in a tetrahydrofuran solution, adding anhydrous potassium acetate powder, and after the heating reaction is finished, adding an HCl/tetrahydrofuran solution to prepare roxatidine acetate hydrochloride (white solid). The method disclosed in the document 4 uses expensive sodium hydride in the preparation of the intermediate B, has the problems of high cost, difficulty in controlling the reaction and the like, and has low product yield; the salifying step needs to prepare a hydrogen chloride solution, the hydrogen chloride has hygroscopicity, absolute drying conditions are not easy to control, products are easy to decompose, the corrosivity is strong, and the requirements on process equipment are high.
The preparation methods disclosed in documents 1 to 4 all require multi-step reactions to prepare final products, and have the defects of harsh reaction conditions, complex preparation process and operation, long production period, more three wastes, environmental friendliness, high preparation cost, incapability of being well applied to industrial production and the like.
Disclosure of Invention
The technical problem to be solved by the invention is to provide the method for preparing the roxatidine acetate hydrochloride, which has the advantages of stable process conditions, high yield, few reaction steps, mild reaction conditions, environmental friendliness, low cost and easiness in operation and is suitable for industrial production.
In one aspect of the present invention, there is provided a method for preparing roxatidine acetate hydrochloride, comprising the steps of: 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine reacts with acetoxyacetyl chloride in a solvent to prepare roxatidine acetate hydrochloride, which is characterized in that: the amidation and salification steps are completed in one step, and HCl gas is not required to be introduced in the salification step.
The preparation method comprises the following steps: dissolving an intermediate C3- [3- (1-piperidinylmethyl) phenoxy ] propylamine in a reaction solvent, dripping acyloxy acetyl chloride at low temperature, and stirring for reaction after dripping. After the reaction is finished, decompressing and concentrating, pulping the solid residue by using acetonitrile, filtering and drying in vacuum to obtain the roxatidine acetate hydrochloride. Wherein the 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine: the molar ratio of acetoxyacetyl chloride is 1-5:5-1, preferably 1: 1-1:1.5, the specific ratio may be 1; 1,1: 1.2,1: 1.3,1: 1.4,1: 1.5; the reaction solvent is any one or combination of benzene, toluene, xylene, carbon tetrachloride, chloroform, dichloromethane, dioxane, ethyl acetate and anhydrous ether, preferably toluene, xylene, dichloromethane and ethyl acetate; the reaction temperature is-20 to 30 ℃, and more preferably-10 to 25 ℃. Specifically, acetoxyacetyl chloride is dripped at the temperature of-10 to 0 ℃. After dripping, reacting at-10 ℃, and then heating to 20-30 ℃ to continue stirring and reacting.
Optionally, the acetoxyacetyl chloride may be purchased directly or may be prepared by the following method:
the preparation method according to the present invention further comprises the steps of: adding 3-chloropropylamine solution into 3- (1-piperidinylmethyl) phenol to prepare an intermediate 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine;
wherein, the standby liquid is obtained by dissolving 3-chloropropylamine hydrochloride in an alkaline solution and extracting by an organic solvent; wherein the organic solvent is selected from any one of toluene, xylene, carbon tetrachloride, chloroform, dichloromethane and dioxane or the combination thereof; the alkali is selected from any one or combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; the molar ratio of the 3- (1-piperidinylmethyl) phenol to the base can be 1-5:5-1, and is preferably 1: 1; the reaction solvent is selected from any one or combination of ethanol, isopropanol, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, toluene, xylene and dioxane; the reaction temperature is 0-150 ℃, preferably 100-150 ℃, and more preferably 110-130 ℃; the reaction time is 0.5 to 10 hours, preferably 1 to 5 hours; after the reaction is completed, the product is subjected to reduced pressure concentration and reduced pressure distillation to prepare the 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine.
The preparation method according to the present invention further comprises the steps of: dissolving m-hydroxybenzaldehyde in a solvent, dropwise adding piperidine, then adding sodium borohydride, and after-treating after the reaction is finished, preparing 3- (1-piperidinylmethyl) phenol;
wherein in the step, sodium borohydride is added in portions after m-hydroxybenzaldehyde and piperidine are mixed thoroughly for a certain period of time (for example, 2 to 5 hours, preferably 3 to 4 hours); the number of times can be 3-4, wherein the sodium borohydride is added in an equivalent manner, or the sodium borohydride is added in a gradient decreasing manner, and the first addition amount is not more than 50% of the total amount. The molar ratio of the m-hydroxybenzaldehyde to the piperidine to the sodium borohydride is 1-3: 1-5: 1-3, preferably 1:3: 1; the reaction solvent is selected from polar solvent, preferably any one or combination of N, N-dimethylformamide, dimethyl sulfoxide, ethanol, isopropanol and tetrahydrofuran; the reaction temperature is 0-100 ℃, preferably 25-75 ℃, and more preferably 25-40 ℃; the reaction time is 0.5 to 10 hours, preferably 1 to 5 hours; the post-treatment mode is to sequentially carry out acid washing, alkalization, filtration, water washing, refining and filter cake purification.
Compared with the prior art, the invention has the following beneficial effects:
1. the roxatidine acetate hydrochloride is prepared by reacting (3- [3- (1-piperidylmethyl) phenoxy ] propylamine) with acetoxyacetyl chloride in the presence of an acid-binding agent to form a salt through one-step coupling, so that HCl does not need to be introduced subsequently, intermediates in each step in the reaction process are not converted into oxalate for purification, impurities generated by introduction of the oxalate are reduced, reaction steps are shortened, subsequent treatment procedures are simplified, and the reaction cost is reduced; and avoids the hygroscopicity and corrosivity of hydrogen chloride. Has the advantages of environmental protection, low cost, simple and convenient operation and the like.
2. In the method, before the sodium borohydride is added for reduction in the step one, the raw material (A) and the piperidine are fully reacted in the ethanol for a period of time, and then the reducing agent is added in times, so that the problems of incomplete reaction of the raw materials and low yield of the product are effectively solved, and the yield is stable and reaches over 90 percent.
3. The preparation method of the invention does not use expensive reagents, does not need high-temperature melting reaction, has mild reaction conditions, is environment-friendly, has low production cost and simple and convenient operation, and is suitable for industrial production.
Detailed Description
The present invention will be described in detail with reference to the following examples, which are only for illustrating the technical solutions of the present invention and are not to limit the spirit of the present invention.
Example 13 preparation of (1-piperidinylmethyl) phenol (B)
160g (1.311 mol) of m-hydroxybenzaldehyde and absolute ethyl alcohol are added into a 2L three-neck flask, stirred and dissolved, 380ml (3.889 mol) of piperidine is added dropwise at room temperature, stirring is continued for 3 hours after the addition, 50g (1.315 mol) of sodium borohydride is added into the reaction flask in portions under the cooling of ice water, and the reaction is carried out at room temperature after the addition. After the reaction is completed, most of the solvent is concentrated under reduced pressure, cooled, added with water, stirred and cooled, and added with concentrated hydrochloric acid dropwise to make the system acidic, and washed by ethyl acetate. Collecting water layer, under the condition of ice water cooling, separating white solid from the alkalization reaction liquid, filtering, washing with water, draining, and refining and purifying filter cake. 230g of intermediate (B) was obtained as a white crystalline powder with yield: 91.6%, mp: 135 ℃ and 138 ℃.
Example 23 preparation of (1-piperidinylmethyl) phenol (B)
160g (1.311 mol) of m-hydroxybenzaldehyde and absolute ethyl alcohol are added into a 2L three-neck flask, stirred and dissolved, 255ml (2.60 mol) of piperidine is added dropwise at room temperature, stirring is continued for 3 hours after the addition, 50g (1.315 mol) of sodium borohydride is added into the reaction flask in portions under the cooling of ice water, and the reaction is carried out at room temperature after the addition. After the reaction is completed, most of the solvent is concentrated under reduced pressure, cooled, added with water, stirred and cooled, and added with concentrated hydrochloric acid dropwise to make the system acidic, and washed by ethyl acetate. Collecting water layer, under the condition of ice water cooling, separating white solid from the alkalization reaction liquid, filtering, washing with water, draining, and refining and purifying filter cake. Intermediate (B) 226.7g was obtained as a white crystalline powder, yield: 90.3%, mp: 135 ℃ and 138 ℃.
Example 33 preparation of (1-piperidinylmethyl) phenol (B)
160g (1.311 mol) of m-hydroxybenzaldehyde and absolute ethyl alcohol are added into a 2L three-necked bottle, stirred and dissolved, 380ml (3.889 mol) of piperidine is added dropwise at room temperature, after the addition, 50g (1.315 mol) of sodium borohydride is added into a reaction bottle in portions under the cooling of ice water, and the reaction is carried out at room temperature after the addition. After the reaction is completed, most of the solvent is concentrated under reduced pressure, cooled, added with water, stirred and cooled, and added with concentrated hydrochloric acid dropwise to make the system acidic, and washed by ethyl acetate. Collecting water layer, under the condition of ice water cooling, separating white solid from the alkalization reaction liquid, filtering, washing with water, draining, and refining and purifying filter cake. Intermediate (B) 203.9g was obtained as a white crystalline powder, yield: 81.2%, mp: 133 ℃ and 138 ℃.
EXAMPLE 43 preparation of (1-piperidinylmethyl) phenol (B)
160g (1.311 mol) of m-hydroxybenzaldehyde and absolute ethyl alcohol are added into a 2L three-neck flask, stirred and dissolved, 254ml (2.60 mol) of piperidine is added dropwise at room temperature, after the addition, 50g (1.315 mol) of sodium borohydride is added into the reaction flask in portions under the cooling of ice water, and the reaction is carried out at room temperature after the addition. After the reaction is completed, most of the solvent is concentrated under reduced pressure, cooled, added with water, stirred and cooled, and added with concentrated hydrochloric acid dropwise to make the system acidic, and washed by ethyl acetate. Collecting water layer, under the condition of ice water cooling, separating white solid from the alkalization reaction liquid, filtering, washing with water, draining, and refining and purifying filter cake. To give 208.9g of intermediate (B) as a white crystalline powder, yield: 83.2%, mp: 132-137 ℃.
Example 53 preparation of- [3- (1-piperidinylmethyl) phenoxy ] propylamine (C):
220g (1.152 mol) of the intermediate (B), 580ml of dimethyl sulfoxide, 400ml of toluene and 60g (1.500 mol) of sodium hydroxide are put into a dry 5L three-necked bottle provided with a water separator, heated under reflux to separate water, and then a 3-chloropropylamine solution is added dropwise. After dropping, the reaction was continued at reflux overnight. Then, cooled to room temperature, filtered, washed with a small amount of toluene, collected the filtrate, concentrated under reduced pressure, recovered the solvent, and distilled under reduced pressure to give intermediate (C) 231g as a pale yellow thick transparent oil, yield: 81.0 percent.
Example 6 preparation of roxatidine acetate hydrochloride:
190g (0.765 mol) of intermediate C was dissolved in xylene, and 157g (1.148 mol) of acetoxyacetyl chloride was added dropwise thereto at-10 to 0 ℃. After-dripping is finished, reacting at-10 ℃, and then heating to 20-30 ℃ to continue stirring and reacting. After the reaction, the mixture was concentrated under reduced pressure. Pulping the obtained residue with acetonitrile, filtering, and vacuum-drying at 50-60 ℃ to obtain roxatidine acetate hydrochloride with the yield: 90 percent.
Example 7 preparation of roxatidine acetate hydrochloride:
190g (0.765 mol) of intermediate C was dissolved in methylene chloride, and 157g (1.148 mol) of acetoxyacetyl chloride was added dropwise thereto at-10 to 0 ℃. After dripping, reacting at-10 ℃, and then heating to 20-30 ℃ to continue stirring and reacting. After the reaction, the mixture was concentrated under reduced pressure. Pulping the obtained residue with acetonitrile, filtering, and vacuum-drying at 50-60 ℃ to obtain roxatidine acetate hydrochloride with the yield: 88.6 percent.
Example 8 preparation of roxatidine acetate hydrochloride:
190g (0.765 mol) of intermediate C was dissolved in ethyl acetate, and 157g (1.148 mol) of acetoxyacetyl chloride was added dropwise at-10 to 0 ℃. After dripping, reacting at-10 ℃, and then heating to 20-30 ℃ to continue stirring and reacting. After the reaction, the mixture was concentrated under reduced pressure. Pulping the obtained residue with acetonitrile, filtering, and vacuum-drying at 50-60 ℃ to obtain roxatidine acetate hydrochloride with the yield: 77.9 percent.
Example 9 preparation of roxatidine acetate hydrochloride:
190g (0.765 mol) of intermediate C was dissolved in chloroform, and 157g (1.148 mol) of acetoxyacetyl chloride was added dropwise at-10 to 0 ℃. After dripping, reacting at-10 ℃, and then heating to 20-30 ℃ to continue stirring and reacting. After the reaction, the mixture was concentrated under reduced pressure. Pulping the obtained residue with acetonitrile, filtering, and vacuum-drying at 50-60 ℃ to obtain roxatidine acetate hydrochloride with the yield: 86.7 percent.
Example 10 preparation of roxatidine acetate hydrochloride:
190g (0.765 mol) of intermediate C are dissolved in xylene, and 125.3g (0.918 mol) of acetoxyacetyl chloride is dripped into the mixture at-10 to 0 ℃. After dripping, reacting at-10 ℃, and then heating to 20-30 ℃ to continue stirring and reacting. After the reaction, the mixture was concentrated under reduced pressure. Pulping the obtained residue with acetonitrile, filtering, and vacuum-drying at 50-60 ℃ to obtain roxatidine acetate hydrochloride with the yield: 85.3 percent.
Claims (11)
1. A method for preparing roxatidine acetate hydrochloride, which comprises the following steps: 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine reacts with acetoxyacetyl chloride in a solvent to prepare roxatidine acetate hydrochloride, and the method is characterized by comprising the following steps: the amidation and salification steps are completed in one step, and HCl gas does not need to be introduced in the salification step; wherein the 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine: the molar ratio of acetoxyacetyl chloride is 1-5: 5-1; the reaction solvent is any one or the combination of benzene, toluene, xylene, carbon tetrachloride, chloroform, dichloromethane, ethyl acetate, dioxane and anhydrous ether; the reaction temperature is-20 to 30 ℃.
2. The process according to claim 1, wherein the 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine: the molar ratio of acetoxyacetyl chloride is 1: 1-1: 1.5; the reaction solvent is toluene, xylene, dichloromethane or ethyl acetate; the reaction temperature is-10 to 25 ℃.
3. The method for preparing the compound of any one of claims 1 to 2, wherein the intermediate 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine is dissolved in a reaction solvent, acetoxyacetyl chloride is added dropwise at-10 to 0 ℃ to react at-10 to 10 ℃, and then the temperature is raised to 20 to 30 ℃ to continue the reaction with stirring.
4. The method of manufacturing according to claim 3, further comprising the steps of: adding 3-chloropropylamine solution into 3- (1-piperidinylmethyl) phenol to prepare an intermediate 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine, wherein the 3-chloropropylamine solution is prepared by dissolving 3-chloropropylamine hydrochloride in alkaline solution and extracting by using an organic solvent.
5. The method according to claim 4, wherein the molar ratio of the 3- (1-piperidinylmethyl) phenol to the base is 1-5: 5-1; the reaction solvent is selected from any one or combination of ethanol, isopropanol, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, toluene, xylene and dioxane; the reaction temperature is 0-150 ℃; the reaction time is 0.5 to 10 hours; after the reaction is completed, the product is subjected to reduced pressure concentration and reduced pressure distillation to prepare the 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine.
6. The method as claimed in claim 5, wherein the reaction temperature is 100-150 ℃ and the reaction time is 1-5 hours.
7. The method as claimed in claim 6, wherein the reaction temperature is 110-130 ℃.
8. The process according to any one of claims 4 to 7, which further comprises a step of preparing an intermediate compound, 3- (1-piperidinylmethyl) phenol: dissolving m-hydroxybenzaldehyde in a solvent, dropwise adding piperidine, then adding sodium borohydride, and after the reaction is finished, carrying out post-treatment to prepare the 3- (1-piperidinemethyl) phenol, wherein the sodium borohydride is added in several times after the m-hydroxybenzaldehyde and the piperidine are fully mixed for 2-5 hours.
9. The preparation method according to claim 8, wherein the molar ratio of m-hydroxybenzaldehyde, piperidine and sodium borohydride is 1-3: 1-5: 1-3; the reaction solvent is selected from polar solvents; the reaction temperature is 0-100 ℃; the reaction time is 0.5-10 hours.
10. The preparation method according to claim 9, wherein the molar ratio of m-hydroxybenzaldehyde, piperidine and sodium borohydride is 1:3: 1; the reaction solvent is selected from any one or combination of N, N-dimethylformamide, dimethyl sulfoxide, ethanol, isopropanol and tetrahydrofuran; the reaction temperature is 25-75 ℃.
11. The method according to claim 10, wherein the reaction temperature is 25 to 40 ℃.
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| CN110981832A (en) * | 2019-11-01 | 2020-04-10 | 山东美泰医药有限公司 | Preparation method of roxatidine acetate hydrochloride |
| CN112321534A (en) * | 2020-11-13 | 2021-02-05 | 哈药集团技术中心 | Preparation method of high-purity medicinal roxatidine acetate hydrochloride |
| CN113135874B (en) * | 2021-04-15 | 2022-11-04 | 福建海西新药创制有限公司 | Synthetic method of roxatidine acetate |
| CN114276314A (en) * | 2021-12-31 | 2022-04-05 | 广安凯特制药有限公司 | High-purity roxatidine acetate hydrochloride and preparation method thereof |
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| US4293557A (en) * | 1979-07-03 | 1981-10-06 | Teikoku Hormone Mfg. Co., Ltd. | Antiulcer phenoxypropylamine derivatives |
| US5317026A (en) * | 1992-03-04 | 1994-05-31 | Snow Brand Milk Products Co., Ltd. | Acetamide derivative and application thereof |
| CN102993121A (en) * | 2012-12-11 | 2013-03-27 | 哈药集团三精制药股份有限公司 | Synthetic method for preparing roxatidine acetate hydrochloride with high purity |
| CN107698538A (en) * | 2016-11-30 | 2018-02-16 | 内蒙古京东药业有限公司 | The intermediate 3 of roxatidine acetate hydrochloride（1 piperidine methyl）The new preparation method of phenol |
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| CN101717363B (en) * | 2009-12-04 | 2012-05-09 | 常州市宝盛龙城医药科技有限公司 | Method for preparing roxatidine acetate hydrochloride |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4293557A (en) * | 1979-07-03 | 1981-10-06 | Teikoku Hormone Mfg. Co., Ltd. | Antiulcer phenoxypropylamine derivatives |
| US5317026A (en) * | 1992-03-04 | 1994-05-31 | Snow Brand Milk Products Co., Ltd. | Acetamide derivative and application thereof |
| CN102993121A (en) * | 2012-12-11 | 2013-03-27 | 哈药集团三精制药股份有限公司 | Synthetic method for preparing roxatidine acetate hydrochloride with high purity |
| CN107698538A (en) * | 2016-11-30 | 2018-02-16 | 内蒙古京东药业有限公司 | The intermediate 3 of roxatidine acetate hydrochloride（1 piperidine methyl）The new preparation method of phenol |
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