CN101717363A - Method for preparing roxatidine acetate hydrochloride - Google Patents
Method for preparing roxatidine acetate hydrochloride Download PDFInfo
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- CN101717363A CN101717363A CN200910231984A CN200910231984A CN101717363A CN 101717363 A CN101717363 A CN 101717363A CN 200910231984 A CN200910231984 A CN 200910231984A CN 200910231984 A CN200910231984 A CN 200910231984A CN 101717363 A CN101717363 A CN 101717363A
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- roxatidine
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- cooled
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- oxalate
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- 229960000627 roxatidine acetate hydrochloride Drugs 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000000047 product Substances 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 19
- SRDQKICJPUSODU-UHFFFAOYSA-N 2-hydroxy-n-[3-[3-(piperidin-1-ylmethyl)phenoxy]propyl]acetamide;oxalic acid Chemical compound OC(=O)C(O)=O.OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 SRDQKICJPUSODU-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 239000000706 filtrate Substances 0.000 claims abstract description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000005406 washing Methods 0.000 claims abstract description 14
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000012044 organic layer Substances 0.000 claims abstract description 13
- 239000008367 deionised water Substances 0.000 claims abstract description 12
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012346 acetyl chloride Substances 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 8
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 150000003053 piperidines Chemical class 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 16
- 230000008025 crystallization Effects 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- 239000010410 layer Substances 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 230000003068 static effect Effects 0.000 claims description 12
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 8
- 238000009413 insulation Methods 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- -1 3-chloro propyl amine hydrochloric acid salt Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 229960004756 ethanol Drugs 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- XECYHHJJUAAEFH-UHFFFAOYSA-N C(C(=O)O)(=O)O.C(C)(=O)NO Chemical compound C(C(=O)O)(=O)O.C(C)(=O)NO XECYHHJJUAAEFH-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012267 brine Substances 0.000 claims description 4
- 230000018044 dehydration Effects 0.000 claims description 4
- 238000006297 dehydration reaction Methods 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 238000005070 sampling Methods 0.000 claims description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 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
- 150000002148 esters Chemical class 0.000 claims 1
- 239000004576 sand Substances 0.000 claims 1
- 238000001035 drying Methods 0.000 abstract description 5
- 238000001816 cooling Methods 0.000 abstract description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract 2
- 239000000203 mixture Substances 0.000 abstract 2
- VQSXCZMVUMSITD-UHFFFAOYSA-N 3-[3-(piperidin-1-ylmethyl)phenoxy]propan-1-amine Chemical compound NCCCOC1=CC=CC(CN2CCCCC2)=C1 VQSXCZMVUMSITD-UHFFFAOYSA-N 0.000 abstract 1
- 229910021529 ammonia Inorganic materials 0.000 abstract 1
- 238000005086 pumping Methods 0.000 abstract 1
- 239000011780 sodium chloride Substances 0.000 abstract 1
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 230000027119 gastric acid secretion Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 3
- 229960003320 roxatidine Drugs 0.000 description 3
- 206010013786 Dry skin Diseases 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
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 101710095468 Cyclase Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a method for preparing roxatidine acetate hydrochloride, comprising the following steps: preparing 3-piperidine methyl phenol and N-[3-(3-amino-propoxy)-benzyl] piperidine; adding and stirring deionized water to raw material of roxatidine oxalate, dissolving the deionized water into the roxatidine oxalate, pumping 15% ammonia into the solution, extracting the solution for three times with chloroform, combining organic layers, washing the organic layers for one time with saturated sodium chloride solution, adding anhydrous magnesium sulfate to the organic layers to dehydrate the organic layers, filtering the organic layer, cooling filtrate to below -3 DEG C with chilled saline, dropwise adding acetyl chloride solution to the filtrate by controlling the temperature below 0 DEG C, increasing the temperature of the mixture to 20-25 DEG C by water bath after finishing dropwise adding the acetyl chloride solution, continuously increasing the temperature of the mixture to 40-45 DEG C after the acetyl chloride solution and the filtrate reacting for half a hour, preserving the heat to make the acetyl chloride solution and the filtrate react for 1 to 3 hours, judging whether the raw material point exists by analyzing with TCL, adding and stirring evenly acetone if no raw material point exists, standing to crystallize the product of reaction, cooling to 0 DEG C, centrifuging, washing with acetone b to obtain wet product, drying the wet product in vacuum to obtain the roxatidine acetate hydrochloride. The method for preparing roxatidine acetate hydrochloride has simple steps and low cost, ensures the high yield of the roxatidine acetate hydrochloride and is safe.
Description
Technical field
The present invention relates to a kind of medicine chemical material synthetic technology, be meant the preparation method of roxatidine acetate hydrochloride especially.
Background technology
Roxatidine acetate hydrochloride is the stomach ulcer curative by the exploitation of internal organs company of Japanese kingdom, at first obtains Japanese health ministry approval listing in 1986, up to the present in nine country's listings such as Germany.Roxatidine is a kind of histamine H
2Receptor antagonist.The H of histamine
2Effect be by with the adenosine cyclase of receptors bind, intracellular CAMP level is risen, thereby the activation proton pump impels gastric acid secretion.Two big main H of histamine
2Act as 1. gastric acid secretion effect; 2. immunosuppressive action; And H
2These some effects of receptor antagonist competitive antagonism.
Roxatidine acetate hydrochloride after enzyme turns usefulness into, is transformed into activated metabolite--roxatidine rapidly in small intestine, blood plasma and liver.Experiment in vivo and vitro proof roxatidine acetate hydrochloride and metabolite roxatidine are effectively, selective and emulative histamine H
2Receptor antagonist.With other most of H
2Receptor antagonist is the same, and roxatidine acetate hydrochloride is effective inhibitors to animal and human's basal gastric acid secretion with stimulating the gastric acid secretion that causes, and does not have the effect of androgen antagonist sample, does not disturb the metabolism of other drug in liver.
At present, the production technique of roxatidine acetate hydrochloride is complicated, and yield is lower, and purification ratio is difficulty, thereby has increased production cost, influences quality product and as the security of the use of medicine.
Summary of the invention
It is simple to the purpose of this invention is to provide a kind of production technique, and cost is low, the preparation method of the roxatidine acetate hydrochloride that yield is higher and safe.
For achieving the above object, the present invention adopts following technical scheme to realize:
A kind of preparation method of roxatidine acetate hydrochloride is characterized in that: may further comprise the steps:
A, preparation 3-piperidine methyl phenol
In reactor, drop into methyl alcohol, piperidines, m-hydroxybenzaldehyde under the room temperature successively, be stirred to whole dissolvings, be cooled to 0-20 ℃, beginning drops into POTASSIUM BOROHYDRIDE in batches, and temperature is no more than 10-30 ℃; Throw and finish, be warming up to 30-50 ℃, reacted 1-3 hour, reclaim solvent, cool off 40-60 ℃ to basic dripless, add entry in still, stir, suction 31% hydrochloric acid transfers to pH=3, is cooled to 0-20 ℃, regulate pH=9 with strong aqua, separate out crystallization, centrifugal, use deionised water; Under 50-70 ℃ of hot air circulation, dry 6-10 hour, obtain 3-piperidine methyl phenol;
B, preparation N-[3-(the amino propoxy-of 3-)-benzyl] piperidines
In reactor, add dimethyl sulfoxide (DMSO), 3-piperidine methyl phenol, 3-chloro propyl amine hydrochloric acid salt and sheet alkali, stir, be warming up to 50-70 ℃, insulation reaction 1-3 hour, question response finishes, be cooled to room temperature, change the extraction still over to, add entry a, toluene, stir, static, branch vibration layer, the upper strata adds water b, stir, static, divide and get the upper toluene layer, with toluene layer suction still kettle, toluene is reclaimed in underpressure distillation, be decompressed to Nei Wenda 95-110 ℃, vacuum tightness is-0.09Mpa that the raffinate that obtains is N-[3-(the amino propoxy-of 3-)-benzyl] piperidines;
C, preparation roxatidine oxalate
1) in reactor, drop into N-[3-(3-amino propoxy-)-benzyl] piperidines, oxyacetic acid, stirring and dissolving, heat is to 140-160 ℃, reacted 3-7 hour, sampling TLC analyzes no raw material spot and then reacts end, changes the decolouring still over to, in the suction dehydrated alcohol a still, add gac a again, 50-70 ℃ of decolouring 1-3 hour, press filtration, filtrate are cooled to 30-40 ℃, add oxalic acid to pH=6 in batches, with being water-cooled to 0-5 ℃, crystallization 6-10 hour, centrifugal, product must wet;
2) in reactor, drop into 95% ethanol, the wet product of roxatidine oxalate, gac b stirs, reflux decolouring 1-3 hour.Press filtration, filtrate are cooled to 0-5 ℃, and crystallization is spent the night, and be centrifugal, and filter cake got hydroxyl ethanamide oxalate with dehydrated alcohol b washing, the product that must wet, filter cake at 70-80 ℃ of dry 6-10 hour;
D, roxatidine acetate hydrochloride
In reactor, drop into deionized water, the roxatidine oxalate, stirring and dissolving, suction 15% ammoniacal liquor is used chloroform extraction three times, merges organic layer, with saturated sodium-chloride water solution washing 1 time, organic layer is added the anhydrous magnesium sulfate dehydration, filter, filtrate is cooled to below-3 ℃ with chilled brine, beginning dripping acetyl chloride solution, and temperature is controlled at below 0 ℃, after dripping off, warming-in-water is reacted half an hour to 20-25 ℃, continue 40-45 ℃ of intensification, insulation reaction 1-3 hour, TLC analyzed no raw material point, added acetone a, stir, static crystallization, be cooled to 0 ℃ centrifugal, with acetone b washing, the product that must wet, vacuum-drying obtains roxatidine acetate hydrochloride.
The weight ratio of the raw material that adds in the described a step is:
Methyl alcohol: 300-500
Piperidines: 70-100
M-hydroxybenzaldehyde: 90-110
31% hydrochloric acid: 210-250
The weight ratio of the raw material that adds in the described b step is:
Dimethyl sulfoxide (DMSO): 400-500
3-piperidine methyl phenol: 90-110
3-chloro propyl amine hydrochloric acid salt: 75-90
Sheet alkali: 70-80
Water a:900-1100
Toluene: 400-500
Water b:300-400
The weight ratio of the raw material that adds in the described c step is:
N-[3-(the amino propoxy-of 3-)-benzyl] piperidines: 250-350
Oxyacetic acid: 80-150
Dehydrated alcohol: a:700-900
Gac a:5-15
95% ethanol: 1200-1400
Roxatidine oxalate product: the 400-450 that wets
Gac b:3-8
Dehydrated alcohol: 20-40
The weight ratio of the raw material that adds in the described d step is:
Deionized water: 900-1100
Roxatidine oxalate: 190-210
15% ammoniacal liquor: 350-450
Three consumptions of chloroform are respectively: 250-350,250-350,150-250
Saturated sodium-chloride water solution: 150-250
Acetyl Chloride 98Min.: 50-70
Acetone a:750-850
Acetone b:80-110
Beneficial effect of the present invention is: production technique is simple, and cost is low, the higher and safety of yield.
Embodiment
Embodiment 1,
A, preparation 3-piperidine methyl phenol
In the 1000L reactor, drop into 400kg methyl alcohol, 90kg piperidines, 100kg m-hydroxybenzaldehyde under the room temperature successively, be stirred to whole dissolvings, be cooled to 10 ℃, beginning drops into POTASSIUM BOROHYDRIDE in batches, and temperature is no more than 20 ℃; Throw and finish, heat up,, reclaim solvent, cool off 50 ℃ to basic dripless 45 ℃ of reactions 2 hours, add 400kg water in still, stir, suction 31% hydrochloric acid 230kg transfers to pH=3, is cooled to 10 ℃, regulate pH=9 with strong aqua, separate out crystallization, centrifugal, use deionised water.60 ℃ of heat-wind circulate dryings 8 hours, 150kg, yield is 95.8%;
B, preparation N-[3-(the amino propoxy-of 3-)-benzyl] piperidines
Suction 460kg dimethyl sulfoxide (DMSO) in the 1000L reactor, 100kg3-piperidine methyl phenol and 3-chloro propyl amine hydrochloric acid salt 84kg, sheet alkali 75kg, stir, be warming up to 60 ℃, insulation reaction 2 hours, reaction finishes, and water quench changes 2000L over to and extracts still to room temperature, add 1000kg water, 430kg toluene stirs, static, branch vibration layer, the upper strata adds water 350kg, stir, static, divide and get upper toluene layer, toluene layer suction 1000L still kettle, toluene is reclaimed in underpressure distillation, be decompressed to 105 ℃ of Nei Wenda, vacuum tightness is-0.09Mpa that raffinate is N-[3-(the amino propoxy-of 3-)-benzyl] piperidines, get 120kg, yield 91.6%;
C, preparation roxatidine oxalate
In the 500L reactor, drop into N-[3-(the amino propoxy-of 3-)-benzyl] piperidines 300KG, oxyacetic acid 110kg, stirring and dissolving, heat was reacted 5 hours to 150 ℃, and sampling TLC analyzes should not have the raw material spot, reaction finishes, and changes 2000L decolouring still over to, again in the suction 800kg dehydrated alcohol still, add gac 10kg, 60 ℃ decoloured press filtration 2 hours, filtrate is cooled to 30-40 ℃, adds oxalic acid to pH=6 in batches, with being cooled to-5 ℃, crystallization 8 hours, centrifugal, product 440kg must wet;
In the 2000L reactor, drop into 1300kg95% ethanol, the wet product 440kg of roxatidine oxalate, gac 5kg, stir reflux decolouring 2 hours, press filtration, filtrate is cooled to 0-5 ℃, crystallization is spent the night, and is centrifugal, filter cake 30kg absolute ethanol washing, product must wet, filter cake is 70-80 ℃ of drying 8 hours, hydroxyl ethanamide oxalate 340kg, total recovery 80.0%;
D, preparation roxatidine acetate hydrochloride
In the 2000L reactor, drop into 1000kg deionized water, 200kg roxatidine oxalate, stirring and dissolving is taken out people 15% ammoniacal liquor 400kg.With chloroform extraction three times (300kg, 300kg, 200kg), merge organic layer, with saturated sodium-chloride 200kg washing 1 time, organic layer adds the anhydrous magnesium sulfate dehydration, filter, filtrate is cooled to below-3 ℃ with chilled brine, beginning dripping acetyl chloride 65kg solution, temperature is controlled at below 0 ℃, and after dripping off, warming-in-water is to 20-25 ℃, reaction half an hour hour, continue 40-45 ℃ of intensification, insulation reaction 2 hours, TLC analyzes no raw material point, add 800kg acetone, stir static crystallization, cooling, 0 ℃ centrifugal, and with cold acetone 100kg washing, product must wet, vacuum-drying gets 197kg, yield 90.0%;
Embodiment 2,
A, preparation 3-piperidine methyl phenol
In the 1000L reactor, drop into 500kg methyl alcohol, 90kg piperidines, 100kg m-hydroxybenzaldehyde under the room temperature successively, be stirred to whole dissolvings, be cooled to 10 ℃, beginning drops into POTASSIUM BOROHYDRIDE in batches, and temperature is no more than 20 ℃, throw and finish, heat up, 40 ℃ of reactions 2 hours, reclaim solvent to basic dripless, cool off 50 ℃, in still, add 500kg water, stir, suction 31% hydrochloric acid 250kg transfers to pH=3.Be cooled to 10 ℃, regulate pH=9, separate out crystallization with strong aqua, centrifugal, use deionised water.
60 ℃ of heat-wind circulate dryings 8 hours, 145kg, yield is 92.5%;
B, preparation N-[3-(the amino propoxy-of 3-)-benzyl] piperidines
Suction 500kg dimethyl sulfoxide (DMSO) in the 1000L reactor, 100kg3-piperidine methyl phenol and 3-chloro propyl amine hydrochloric acid salt 84kg, sheet alkali 80kg, stir, be warming up to 60 ℃, insulation reaction 2 hours, reaction finishes, and water quench changes 2000L over to and extracts still to room temperature, add 1200kg water, 400kg toluene stirs, static, branch vibration layer, the upper strata adds water 300kg, stir, static, divide and get upper toluene layer, toluene layer suction 1000L still kettle, toluene is reclaimed in underpressure distillation, be decompressed to 100 ℃ of Nei Wenda, vacuum tightness is-0.09Mpa that raffinate is N-[3-(the amino propoxy-of 3-)-benzyl] piperidines, get 123kg, yield 93.9%;
C, preparation roxatidine oxalate
In the 500L reactor, drop into N-[3-(the amino propoxy-of 3-)-benzyl] piperidines 300KG, oxyacetic acid 130kg, stirring and dissolving, heat was reacted 5 hours to 145-150 ℃, and sampling TLC analyzes should not have the raw material spot.Reaction finishes, and changes 2000L decolouring still over to, in the suction 750kg dehydrated alcohol still, adds gac 10kg again, 60 ℃ decoloured 2 hours, press filtration, and filtrate is cooled to 30-40 ℃, adds oxalic acid to pH=6 in batches, with being cooled to 3 ℃, crystallization 8 hours, centrifugal, product 450kg must wet;
In the 2000L reactor, drop into 1200kg95% ethanol, the wet product 450kg of roxatidine oxalate, gac 5kg stirs, reflux decolouring 2 hours.Press filtration, filtrate are cooled to 0 ℃, and crystallization is spent the night, and be centrifugal, and filter cake 30kg absolute ethanol washing, the product that must wet, filter cake be 70-80 ℃ of drying 8 hours, hydroxyl ethanamide oxalate 345kg, total recovery 81.2%;
D, preparation roxatidine acetate hydrochloride
In the 2000L reactor, drop into 900kg deionized water, 200kg roxatidine oxalate, stirring and dissolving is taken out people 15% ammoniacal liquor 400kg.Three times (300kg, 300kg 200kg), merge organic layer, with saturated sodium-chloride 250kg washing 1 time with chloroform extraction.Organic layer adds anhydrous magnesium sulfate dehydration, filters, and filtrate is cooled to below-3 ℃ with chilled brine, beginning dripping acetyl chloride 65kg solution, and temperature is controlled at below 0 ℃, after dripping off, warming-in-water to 20 ℃, reaction half an hour hour.Continue to heat up 40 ℃, insulation reaction 2 hours, TLC analyzes no raw material point, adds 800kg acetone, stir, static crystallization, cooling, 0 ℃ is centrifugal, and with cold acetone 100kg washing, the product that must wet, vacuum-drying gets 200kg, yield 91.4%.
Claims (2)
1. the preparation method of a roxatidine acetate hydrochloride is characterized in that: may further comprise the steps:
A, preparation 3-piperidine methyl phenol
In reactor, drop into methyl alcohol, piperidines, m-hydroxybenzaldehyde under the room temperature successively, be stirred to whole dissolvings, be cooled to 0-20 ℃, beginning drops into POTASSIUM BOROHYDRIDE in batches, and temperature is no more than 10-30 ℃; Throw and finish, be warming up to 30-50 ℃, reacted 1-3 hour, reclaim solvent, cool off 40-60 ℃ to basic dripless, add entry in still, stir, suction 31% hydrochloric acid transfers to pH=3, is cooled to 0-20 ℃, regulate pH=9 with strong aqua, separate out crystallization, centrifugal, use deionised water; Under 50-70 ℃ of hot air circulation, dry 6-10 hour, obtain 3-piperidine methyl phenol;
B, preparation N-[3-(the amino propoxy-of 3-)-benzyl] piperidines
In reactor, add dimethyl sulfoxide (DMSO), 3-piperidine methyl phenol, 3-chloro propyl amine hydrochloric acid salt and sheet alkali, stir, be warming up to 50-70 ℃, insulation reaction 1-3 hour, question response finishes, be cooled to room temperature, change the extraction still over to, add entry a, toluene, stir, static, branch vibration layer, the upper strata adds water b, stir, static, divide and get the upper toluene layer, with toluene layer suction still kettle, toluene is reclaimed in underpressure distillation, be decompressed to Nei Wenda 95-110 ℃, vacuum tightness is-0.09Mpa that the raffinate that obtains is N-[3-(the amino propoxy-of 3-)-benzyl] piperidines;
C, preparation roxatidine oxalate
1) in reactor, drop into N-[3-(3-amino propoxy-)-benzyl] piperidines, oxyacetic acid, stirring and dissolving, heat is to 140-160 ℃, reacted 3-7 hour, sampling TLC analyzes no raw material spot and then reacts end, changes the decolouring still over to, in the suction dehydrated alcohol a still, add gac a again, 50-70 ℃ of decolouring 1-3 hour, press filtration, filtrate are cooled to 30-40 ℃, add oxalic acid to pH=6 in batches, with being water-cooled to 0-5 ℃, crystallization 6-10 hour, centrifugal, product must wet;
2) in reactor, drop into 95% ethanol, the wet product of roxatidine oxalate, gac b stirs, reflux decolouring 1-3 hour.Press filtration, filtrate are cooled to 0-5 ℃, and crystallization is spent the night, and be centrifugal, and filter cake got hydroxyl ethanamide oxalate with dehydrated alcohol b washing, the product that must wet, filter cake at 70-80 ℃ of dry 6-10 hour;
D, roxatidine acetate hydrochloride
In reactor, drop into deionized water, the roxatidine oxalate, stirring and dissolving, suction 15% ammoniacal liquor is used chloroform extraction three times, merges organic layer, with saturated sodium-chloride water solution washing 1 time, organic layer is added the anhydrous magnesium sulfate dehydration, filter, filtrate is cooled to below-3 ℃ with chilled brine, beginning dripping acetyl chloride solution, and temperature is controlled at below 0 ℃, after dripping off, warming-in-water is reacted half an hour to 20-25 ℃, continue 40-45 ℃ of intensification, insulation reaction 1-3 hour, TLC analyzed no raw material point, added acetone a, stir, static crystallization, be cooled to 0 ℃ centrifugal, with acetone b washing, the product that must wet, vacuum-drying obtains roxatidine acetate hydrochloride.
2. according to the preparation method of claims 1 described sand for the d ritalinic acid ester hydrochloride, it is characterized in that: the weight ratio of the raw material that adds in the described a step is:
Methyl alcohol: 300-500
Piperidines: 70-100
M-hydroxybenzaldehyde: 90-110
31% hydrochloric acid: 210-250
The weight ratio of the raw material that adds in the described b step is:
Dimethyl sulfoxide (DMSO): 400-500
3-piperidine methyl phenol: 90-110
3-chloro propyl amine hydrochloric acid salt: 75-90
Sheet alkali: 70-80
Water a:900-1100
Toluene: 400-500
Water b:300-400
The weight ratio of the raw material that adds in the described c step is:
N-[3-(the amino propoxy-of 3-)-benzyl] piperidines: 250-350
Oxyacetic acid: 80-150
Dehydrated alcohol a:700-900
Gac a:5-15
95% ethanol: 1200-1400
Roxatidine oxalate product: the 400-450 that wets
Gac b:3-8
Dehydrated alcohol: 20-40
The weight ratio of the raw material that adds in the described d step is:
Deionized water: 900-1100
Roxatidine oxalate: 190-210
15% ammoniacal liquor: 350-450
Three consumptions of chloroform are respectively: 250-350,250-350,150-250
Saturated sodium-chloride water solution: 150-250
Acetyl Chloride 98Min.: 50-70
Acetone a:750-850
Acetone b:80-110.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103058958A (en) * | 2011-10-22 | 2013-04-24 | 杭州福斯特药业有限公司 | Synthetic method of roxatidine acetate hydrochloride |
| CN104311510A (en) * | 2014-09-18 | 2015-01-28 | 哈药集团三精制药股份有限公司 | Preparation method of key intermediate of roxatidine acetate hydrochloride |
| 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 |
| CN108239040A (en) * | 2016-12-26 | 2018-07-03 | 中国医学科学院药物研究所 | Nitric acid 2-（4- methylthiazol -5- bases）The preparation method of carbethoxy hydrochloride |
| WO2019075976A1 (en) * | 2017-10-20 | 2019-04-25 | 北京澳合药物研究院有限公司 | Method for preparing roxatidineacetatehydrochloride and intermediate thereof |
| 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 |
| 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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- 2009-12-04 CN CN2009102319843A patent/CN101717363B/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058958A (en) * | 2011-10-22 | 2013-04-24 | 杭州福斯特药业有限公司 | Synthetic method of roxatidine acetate hydrochloride |
| CN104311510A (en) * | 2014-09-18 | 2015-01-28 | 哈药集团三精制药股份有限公司 | Preparation method of key intermediate of roxatidine acetate hydrochloride |
| 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 |
| CN107698538B (en) * | 2016-11-30 | 2020-02-14 | 内蒙古京东药业有限公司 | Preparation method of intermediate 3- (1-piperidinylmethyl) phenol of roxatidine acetate hydrochloride |
| CN108239040A (en) * | 2016-12-26 | 2018-07-03 | 中国医学科学院药物研究所 | Nitric acid 2-（4- methylthiazol -5- bases）The preparation method of carbethoxy hydrochloride |
| WO2019075976A1 (en) * | 2017-10-20 | 2019-04-25 | 北京澳合药物研究院有限公司 | Method for preparing roxatidineacetatehydrochloride and intermediate thereof |
| 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 |
| 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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