CN102816136A - Method for preparing naftopidil - Google Patents
Method for preparing naftopidil Download PDFInfo
- Publication number
- CN102816136A CN102816136A CN2012103448754A CN201210344875A CN102816136A CN 102816136 A CN102816136 A CN 102816136A CN 2012103448754 A CN2012103448754 A CN 2012103448754A CN 201210344875 A CN201210344875 A CN 201210344875A CN 102816136 A CN102816136 A CN 102816136A
- Authority
- CN
- China
- Prior art keywords
- naftopidil
- preparing
- add
- reaction
- midbody
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing chemical active pharmaceutical ingredients, i.e. a method for preparing naftopidil. The method for preparing naftopidil comprises the following steps that 1-naphthol and epichlorohydrin are directly reacted; after excessive epichlorohydrin is removed from an organic phase, dimethylbenzene is added, and an intermediate I is obtained after reduced pressure distillation; 1-(2-methoxyphenyl) piperazine monohydrochloride and sodium hydroxide aqueous solution are reacted, an aqueous phase is removed, and the organic phase is maintained, so an intermediate II is obtained; the intermediate I and the intermediate II are reacted in purified water, and a crude product is obtained after cleaning and drying; and after acetone adding, activated carbon hot reflowing, filtering and drying are carried out on the crude product, the naftopidil active pharmaceutical ingredient is obtained by refining with 95% ethanol. The method for preparing naftopidil has moderate reaction conditions, no high-temperature and high-pressure reaction, high yield and high product purity, and is easy for industrial production. Through the process optimization, the total yield of naftopidil is effectively increased.
Description
Technical field
The present invention relates to a kind of chemical feedstocks medicament preparation, i.e. process for preparing naftopidil.
Background technology
In the prior art, naftopidil, chemistry (±)-1-[4-(2-p-methoxy-phenyl)-1-piperazinyl] by name-3-(1-naphthyloxy)-2-propyl alcohol, molecular formula: C
24H
28N
2O
3Belonging to the benzene bridged piperazine derivatives, be selectivity α 1 receptor blocking agent, is a kind of treatment of benign prostate hyperplasia medicine.Its mechanism α 1 acceptor for distributing in blocking-up prostate gland and the urethra of curing the disease reduces in the urethra and presses, and improves the dysuria that hyperplasia of prostate causes.This medical instrument has couple α 1 receptor-selective strong; To cns and the little advantage of cardiovascular systems spinoff; When effectively improving the BPH symptom, do not have " first dose of phenomenon ", have characteristics such as rapid-action, safe, reliable, the treatment of benign prostate hyperplasia is superior to traditional curative; Compare with other α 1 receptor blocking agents (as: Vasocard), these article untoward reaction rate is lower.This medicine succeed in developing the misery that has greatly alleviated the benign prostate hyperplasia patient, for more old hyperplasia of prostate patient has brought Gospel.
Through inquiry, the Chinese invention patent specification sheets has announced that name is called " preparation method of naftopidil " license, the patent No.: CN200910265323.2, the applying date: 2009.12.29, Shen Qing Publication day: 2010.06.23.It comprises 1-(2-p-methoxy-phenyl) piperazine hydrochloride, 1-naphthols and mineral alkali are heated to solvent boiling point in organic solvent, under the condition of refluxing and stirring, reacts, and reaction is accomplished after aftertreatment obtains naftopidil.Naftopidil directly adopts 1-naphthols and epichlorohydrin reaction not to appear in the newspapers.
Summary of the invention
The objective of the invention is to provide the process for preparing naftopidil of a kind of reaction temperature and, process optimization to above-mentioned situation.
Technical solution of the present invention is: process for preparing naftopidil, and its step is following:
(1) directly adopts 1-naphthols and epichlorohydrin reaction; Mass ratio=the 1:4.4 of 1-naphthols and epoxy chloropropane.
(2) after organic phase is removed excessive epoxy chloropropane, add YLENE, obtain midbody-I after the underpressure distillation.
(3) use the reaction of 1-(2-p-methoxy-phenyl) piperazine hydrochloride and aqueous sodium hydroxide solution again, aqueous phase discarded keeps organic phase and obtains midbody-II.
(4) after midbody-I and midbody-II were reacted in purified water, washing and drying got bullion.
(5) add acetone, gac thermal backflow, filtration, drying, again with the refining naftopidil bulk drug that obtains of 95% ethanol.
Described organic phase is an ETHYLE ACETATE; 1-naphthols and ETHYLE ACETATE mass ratio=1:3.1.
Temperature of reaction 85-90 degree in above-mentioned steps (1), reaction times 2h ± 10 minute.
In above-mentioned steps (3), add methylene dichloride, the mass ratio=1:4.2 of 1-(2-p-methoxy-phenyl) piperazine hydrochloride and methylene dichloride; Mass ratio=the 1:1.33 of 1-naphthols and 1-(2-p-methoxy-phenyl) piperazine hydrochloride.
Reaction times 2h ± 10 minute add zeyssatite afterwards, and consumption is 5% of 1-(2-p-methoxy-phenyl) piperazine hydrochloride, stir, and filter filtrating;
In above-mentioned steps (4), maintain the temperature between the 40-50 degree and react 3h ± 10min, centrifugal purification water washing, oven dry get light yellow solid naftopidil bullion.Preferred process for preparing naftopidil step is following:
(1) in reaction kettle, the suction epoxy chloropropane, stir add the 1-naphthols down, (be V-Brite B, be strong reductant to vat powder.In the naftopidil building-up process, can make 1-naphthols and epoxy chloropropane form condensation product and HCl rapidly), sodium hydroxide, temperature of reaction 85-90 degree, reaction times 2h;
(2) add ETHYLE ACETATE, stirring, filtration, filtrating, the filtrate decompression distillation removes ETHYLE ACETATE and excessive epoxy chloropropane, lowers the temperature, and gets the liquid material; Feed liquid is added YLENE, and heating continuation decompression is steamed and is slipped, cooling, and blowing gets garnet midbody-I; (3) add methylene dichloride in the reaction kettle, the aqueous sodium hydroxide solution that drops into 1-(2-p-methoxy-phenyl) piperazine hydrochloride and prepare in advance, reaction times 2h; Add zeyssatite afterwards, stir, filter; Filtrating is left standstill layering; Water discards, and the direct evaporated under reduced pressure of organic layer gets yellow oil midbody-II;
(4) midbody-II is added purified water, stir, add midbody-I, maintain the temperature between the 40-50 degree and react 3h, centrifugal purification water washing, oven dry get light yellow solid naftopidil bullion; (5) acetone is added in the reaction kettle, stir, add naftopidil bullion and gac; Reflux, heat filter, filtrating is returned in the clean still, logical circulating water cooling (or the terepthaloyl moietie after refrigeration) cooling (0～5 ℃); The chilled brine cooling, crystallization, filtration, drying; (6) with in the 95% ethanol adding reaction kettle, stir, add naftopidil and gac that step (5) obtains, heating refluxes, and clean area is arrived in press filtration while hot, circulating water cooling, chilled brine (or the terepthaloyl moietie after refrigeration) cooling (0～5 ℃), crystallization; Centrifugal, solid 50 degree vacuum-dryings get the white solid naftopidil.
Advantage of the present invention is: 1, adopt epoxy chloropropane as raw material.Epoxy chloropropane is one of staple in the secondary condensation reaction, and reaction process is following:
Condensation for the first time
Condensation once more
2, the powder (V-Brite B) that when preparation midbody-I, takes a policy in this production technique can make reaction conditions gentle more, prevents to react bumping, has effectively improved industrial security.3, add zeyssatite in preparation midbody-II process, have filtrating aid function (, helping the filter back to improve product gas purity) and chemical property stable (not participating in the chemical reaction of this building-up process) if any sieving action, adsorption, effect of depth.4, the preparation process condition gentleness that this project adopted, no high temperature, reaction under high pressure, yield are high, product purity is high, are easy to suitability for industrialized production.Through process optimization, the naftopidil total recovery has obtained effective raising.
To combine embodiment that embodiment of the present invention is described in further detail below.
Embodiment
Embodiment 1
Process for preparing naftopidil is characterized in that step is following:
1, in reaction kettle, add, the suction epoxy chloropropane adds 1-naphthols, vat powder, sodium hydroxide, temperature of reaction 85-90 degree, reaction times 2h under stirring.
2, add ETHYLE ACETATE, stirring, filtration, filtrating, underpressure distillation remove ETHYLE ACETATE and excessive epoxy chloropropane, and cooling gets the liquid material; Feed liquid is added YLENE, and heating continuation decompression is steamed and is slipped, cooling, and blowing gets garnet midbody NPDE-1.3, add methylene dichloride in the reaction kettle, the aqueous sodium hydroxide solution that drops into 1-(2-p-methoxy-phenyl) piperazine hydrochloride and prepare in advance, reaction times 2h; Add zeyssatite afterwards, stir, filter; Filtrating is left standstill layering; Water discards, and the direct evaporated under reduced pressure of organic layer gets yellow oil midbody NPDE-2.
4, NPDE-2 is added purified water, stir, add NPDE-1, maintain the temperature between the 40-50 degree and react 3h, centrifugal purification water washing, oven dry get light yellow solid naftopidil bullion.5, acetone is added in 1 ton of reaction kettle, stir, add naftopidil bullion and gac, reflux, heat filter, filtrating is returned in the clean still, logical circulating water cooling, chilled brine cooling, crystallization, filtration, drying.6, with in 1 ton of reaction kettle of 95% ethanol adding, stir, add naftopidil and gac that step 5 obtains, heating refluxes, and clean area is arrived in press filtration while hot, circulating water cooling, chilled brine cooling, crystallization; Centrifugal, solid 50 degree vacuum-dryings get the white solid naftopidil.
Embodiment 2
Embodiment 3
Claims (7)
1. process for preparing naftopidil is characterized in that step is following:
(1) directly adopts 1-naphthols and epichlorohydrin reaction;
(2) after organic phase is removed excessive epoxy chloropropane, add YLENE, obtain midbody-I after the underpressure distillation;
(3) use the reaction of 1-(2-p-methoxy-phenyl) piperazine hydrochloride and aqueous sodium hydroxide solution again, aqueous phase discarded keeps organic phase and obtains midbody-II;
(4) after midbody-I and midbody-II were reacted in purified water, washing and drying got bullion;
(5) add acetone, gac thermal backflow, filtration, drying, again with the refining naftopidil bulk drug that obtains of 95% ethanol.
2. according to the described process for preparing naftopidil of claim 1, it is characterized in that 1-naphthols and epoxy chloropropane mass ratio=1:4.4 in the step (1).
3. according to the described process for preparing naftopidil of claim 1, it is characterized in that organic phase is an ETHYLE ACETATE in the step (2); 1-naphthols and ETHYLE ACETATE mass ratio=1:3.1.
4. according to the described process for preparing naftopidil of claim 1, it is characterized in that temperature of reaction 85-90 degree in the step (1), reaction times 2h ± 10min.
5. according to the described process for preparing naftopidil of claim 1, it is characterized in that adding in the step (3) methylene dichloride, 1-(2-p-methoxy-phenyl) piperazine hydrochloride and methylene dichloride mass ratio=1:4.2, reaction times 2h ± 10min; Add zeyssatite afterwards, consumption is 5% of 1-(2-p-methoxy-phenyl) piperazine hydrochloride, stirs, and filters filtrating.
6. according to the described process for preparing naftopidil of claim 1, it is characterized in that maintaining the temperature between the 40-50 degree in the step (4) and react 3h ± 10min, centrifugal purification water washing, oven dry get light yellow solid naftopidil bullion.
7. according to the arbitrary described process for preparing naftopidil of claim 1-6, it is characterized in that step is following:
(1) in reaction kettle, the suction epoxy chloropropane adds 1-naphthols, vat powder, sodium hydroxide, temperature of reaction 85-90 degree, reaction times 2h under stirring;
(2) add ETHYLE ACETATE, stirring, filtration, filtrating, the filtrate decompression distillation removes ETHYLE ACETATE and excessive epoxy chloropropane, lowers the temperature, and gets the liquid material; Feed liquid is added YLENE, and heating continuation decompression is steamed and is slipped, cooling, and blowing gets garnet midbody-I; (3) add methylene dichloride in the reaction kettle, the aqueous sodium hydroxide solution that drops into 1-(2-p-methoxy-phenyl) piperazine hydrochloride and prepare in advance, reaction times 2h; Add zeyssatite afterwards, stir, filter; Filtrating is left standstill layering; Water discards, and the direct evaporated under reduced pressure of organic layer gets yellow oil midbody-II;
(4) midbody-II is added purified water, stir, add midbody-I, maintain the temperature between the 40-50 degree and react 3h, centrifugal purification water washing, oven dry get light yellow solid naftopidil bullion; (5) acetone is added in the reaction kettle, stir, add naftopidil bullion and gac, reflux, heat filter, filtrating is returned in the clean still, logical circulating water cooling, chilled brine cooling, crystallization, filtration, drying; (6) with in the 95% ethanol adding reaction kettle, stir, add naftopidil and gac that step (5) obtains, heating refluxes, and clean area is arrived in press filtration while hot, circulating water cooling, chilled brine cooling, crystallization; Centrifugal, solid 50 degree vacuum-dryings get the white solid naftopidil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103448754A CN102816136A (en) | 2012-09-18 | 2012-09-18 | Method for preparing naftopidil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103448754A CN102816136A (en) | 2012-09-18 | 2012-09-18 | Method for preparing naftopidil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102816136A true CN102816136A (en) | 2012-12-12 |
Family
ID=47300628
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012103448754A Pending CN102816136A (en) | 2012-09-18 | 2012-09-18 | Method for preparing naftopidil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102816136A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3997666A (en) * | 1974-02-23 | 1976-12-14 | Boehringer Mannheim G.M.B.H. | 1-[3-(Naphth-1-yloxy)-2-hydroxypropvl]-piperazine compounds and therapeutic compositions |
| US20010008893A1 (en) * | 1997-01-30 | 2001-07-19 | Kazumi Ogata | Hydroquinone derivatives |
| CN1473820A (en) * | 2002-08-08 | 2004-02-11 | 贵州合成药物研究所 | Process for preparing naftopidil |
| CN101671317A (en) * | 2009-10-09 | 2010-03-17 | 蚌埠丰原涂山制药有限公司 | Preparation method of Naftopidil |
| CN101747293A (en) * | 2009-12-29 | 2010-06-23 | 蚌埠丰原涂山制药有限公司 | Naftopidil preparing method |
-
2012
- 2012-09-18 CN CN2012103448754A patent/CN102816136A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3997666A (en) * | 1974-02-23 | 1976-12-14 | Boehringer Mannheim G.M.B.H. | 1-[3-(Naphth-1-yloxy)-2-hydroxypropvl]-piperazine compounds and therapeutic compositions |
| US20010008893A1 (en) * | 1997-01-30 | 2001-07-19 | Kazumi Ogata | Hydroquinone derivatives |
| CN1473820A (en) * | 2002-08-08 | 2004-02-11 | 贵州合成药物研究所 | Process for preparing naftopidil |
| CN101671317A (en) * | 2009-10-09 | 2010-03-17 | 蚌埠丰原涂山制药有限公司 | Preparation method of Naftopidil |
| CN101747293A (en) * | 2009-12-29 | 2010-06-23 | 蚌埠丰原涂山制药有限公司 | Naftopidil preparing method |
Non-Patent Citations (1)
| Title |
|---|
| 王绍杰 等: "萘哌地尔的合成", 《沈阳药科大学学报》, vol. 18, no. 1, 31 January 2001 (2001-01-31), pages 16 - 17 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103435518A (en) | Preparation method of metformin hydrochloride | |
| CN101450918B (en) | Metformin hydrochloride purification method | |
| CN104788345A (en) | High-purity metformin hydrochloride preparation method | |
| CN112694470A (en) | Preparation process of sertaconazole nitrate | |
| CN105622609A (en) | Preparation method for linagliptin | |
| CN105061414A (en) | Method for preparing Brexpiprazole with one-pot process | |
| CN109437245A (en) | The method of organic solvent Isolating chlorinated sodium and sodium bromide | |
| CN102617489B (en) | Preparation method of sulfaclozine sodium | |
| CN106316986A (en) | Method for preparing 1-[2-(2,4-dimethyl phenyl thioalkyl)phenyl]piperazine hydrobromide alpha-type crystal | |
| CN102816136A (en) | Method for preparing naftopidil | |
| CN102617509B (en) | Chlorpromazine hydrochloride synthesis process | |
| CN101492430B (en) | Method for preparing high-purity cetirizine hydrochloride | |
| CN101296894B (en) | Novel method for preparing quaternary acid and ammonium salts | |
| CN109384738A (en) | A kind of preparation method of high-purity 4- (4- aminophenyl) morpholine -3- ketone | |
| CN101851209B (en) | Imidazole ethyl vanillic acid ether, preparation method and medicinal application thereof | |
| CN110343108A (en) | A kind of synthetic method of dramamine | |
| CN102180864B (en) | Preparation method of strontium ranelate | |
| CN102617460A (en) | Compounding method of midbody required in compounding of montelukast sodium | |
| CN108675953A (en) | The method for purifying 2,3- dichloropyridines | |
| CN101781215A (en) | Method for preparing propyl gallate bulk drug by chemical semi-synthesis | |
| CN106187864B (en) | A method of high-purity Bupivacaine alkali is prepared by bupivacaine HCl | |
| CN1238344C (en) | Method for preparing tetramethyl pyrazine | |
| CN105175316B (en) | A kind of method for preparing laxative picosulfate sodium | |
| JP6764998B2 (en) | How to make hydronidon | |
| JP6764999B2 (en) | How to make hydronidon |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20121212 |