CN108218841A - A kind of synthetic method of high-purity drug for hypertension irbesartan - Google Patents
A kind of synthetic method of high-purity drug for hypertension irbesartan Download PDFInfo
- Publication number
- CN108218841A CN108218841A CN201810184408.7A CN201810184408A CN108218841A CN 108218841 A CN108218841 A CN 108218841A CN 201810184408 A CN201810184408 A CN 201810184408A CN 108218841 A CN108218841 A CN 108218841A
- Authority
- CN
- China
- Prior art keywords
- irbesartan
- reaction
- added
- hypertension
- synthetic method
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a kind of synthetic methods of high-purity drug for hypertension irbesartan, improve traditional synthetic method, traditional synthesis material composition are substituted, using raw material compound a:2 butyl 1,3 diazaspiracyclic [4,4] 1 alkene of nonyl, 4 keto hydrochloride and compound b:N (trityl group) 5 (2 base of 4' bromomethylbiphenyls) tetrazole synthesizes under the action of catalyst 4-butyl ammonium hydrogen sulfate obtains midbody compound c; then Deprotection triphenylmethyl group (Tr) under the action of acid solution; it is refined to obtain target product irbesartan; only need two-step reaction; reaction mechanism is simple, and by-product is less；The impurity content of each step is strictly controlled, for purification process suitable for putting into industrialized production, the reaction dissolvent and purification solvent used is generally cheap, and the irbesartan purity of preparation is high, is mass produced suitable for commercialization.
Description
Technical field
The invention belongs to pharmaceutical fields, and in particular to a kind of synthetic method of high-purity drug for hypertension irbesartan.
Background technology
Irbesartan is drug for hypertension, is angiotensinⅡ-l types (A II 1)-receptor antagonist, for treating height
Blood pressure.
The product are the products of French Sano-Synth labo and Bristol-Myers Squibb Co.'s joint development, and priority exists within 1997
Britain, Germany, Italy and Spain's listing, thereafter in multinational listing.2000, the irbesartan of Bristol Myers Squibb sale
Up to 3.81 hundred million dollars, increase by 49% on a year-on-year basis.The sales volume of Sano-Synth labo is 300,000,000 Euros, increases by 54% on a year-on-year basis.According to
The listing of Bei Shatan has driven the adjustment of sartans pattern, promotes it and is widely used.The product in 2001 is in the whole world
Sales volume estimation increases by 28% or so on a year-on-year basis, and the sales volume of two major companies is up to 8.89 hundred million dollars.In oral non-II receptors of peptides Ang
The 2nd is risen in the sale ranking of inhibitor.
Irbesartan is long-acting and potent AT1 acceptor inhibitors, and rapid after taking orally to absorb, side reaction is small, compares Losartan Potassium
It is more preferable with the antihypertensive effect of Valsartan.The medicine or European Union ratify to treat hypertension, diabetes B, nephrotic for the first time
Main decompression medication.
In United States Patent (USP) No.5,270,317,5,629,331 and PCT Publication No.WO 2005/051943 A1 and WO
The various preparation methods of irbesartan and related compound are disclosed in 2007/013101 A1.
Recorded in such as in United States Patent (USP) No.5,270,317 (referred to herein as " 317 patent "), irbesartan
By 2- normal-butyl -4- spiro cyclopentane -2- imidazoline-5-ketones and 4- bromomethyl -2- cyanobiphenyl bases existing for sodium hydroxide
In the case of react, 1- [(2 '-cyanobiphenyl base -4- bases) methyl] -2- normal-butyl -4- loop coils are then obtained by pillar layer separation
Then pentane -2- imidazoline-5-ketones react it with tributyl Azide tin and trityl chloride, then with hydrochloric acid remove-insurance probationer nurse
Into irbesartan.
The irbesartan obtained by the method for 317 patent notes does not have satisfactory purity.Emitting unacceptable amount
Impurity is formed together with irbesartan.The yield of the irbesartan of acquisition is very low, and this method needs chromatography post separation pure
Change.Usually without hope there is the method for being related to chromatography column separating purification in large-scale production, therefore this causes this method in business
It is undesirable in change.Method used in 317 patents also has as a drawback that, such as reagent cost is high, such as tributyl Azide tin
Use, product yield with the other reagent of trityl chloride are low, obtain final product needs additional purification step and harm
Health.
United States Patent (USP) 5,629,331 (hereinafter referred to as " 331 patent ") describes the method for preparing irbesartan,
In at 121-123 DEG C in the presence of triethylamine hydrochloride in inertia polar aprotic solvent with sodium azide handle the positive fourths of 2-
Base -3- [[2 '-cyanobiphenyl base -4- bases] methyl] -1,3- diaza spiros-[4.4] nonyl- 1- alkene -4- ketone, the solvent such as 1-
Methylpyrrolidin- 2- ketone.Its solvent for use is expensive and is not easy to recycle, so that this method is unsuitable for industrial production.And
And the irbesartan for the method acquisition for passing through 331 patent notes does not have satisfactory purity.Can not reception amount impurity with
Irbesartan is formed together, therefore causes product yield low.
PCT Publication No.WO 2007/013101 (hereinafter referred to as " 101 application "), which is described, prepares irbesartan
Method, wherein handling 2- normal-butyls -3- [[2 '-cyanobiphenyl base -4- bases] first in the presence of triethylamine and acetic acid with sodium azide
Base] -1,3- diaza spiros-[4.4] nonyl- 1- alkene -4- ketone.
The irbesartan prepared by the method that 101 applications are recorded does not have satisfactory purity and product yield
It is low.
Based on disadvantages mentioned above, the method for the prior art is not suitable for industrially producing irbesartan.
Invention content
The purpose of the present invention is to provide a kind of synthetic methods of high-purity drug for hypertension irbesartan, overcome existing
There are severe reaction conditions in technology, the advantage for having the mild product purity of reaction condition high is suitable for large-scale industrialized production.
The purpose of the present invention can be achieved through the following technical solutions：
A kind of synthetic method of high-purity drug for hypertension irbesartan, irbesartan d synthetic routes are as follows：
Specific synthesis includes the following steps：
The synthesis of S1, midbody compound c
Purified water and potassium hydroxide are sequentially added into reactor, postcooling is dissolved, then sequentially adds raw material a, raw material
B, catalyst and toluene, heating stirring carry out substitution reaction, after reaction, in being obtained after filtered, washing, crystallization, drying
Intermediate compounds therefor c；
The synthesis of S2, irbesartan d crude products
Acetone and midbody compound c are sequentially added into reactor, while stirring be added dropwise acid solution, be added dropwise after,
Stirring carries out deprotection reaction, after reaction, through cooling, adjusts pH, washs, filtering is dried to obtain irbesartan d crude products；
S3, irbesartan d it is refined
Ethyl alcohol and irbesartan d crude products are sequentially added into reaction narrow-necked earthen jar, is heated to reflux, after dissolving completely, cooling, stirring analysis
Crystalline substance, filtering, spreads filter wash cake using ethyl alcohol, is drying to obtain irbesartan d sterlings.
Further, the mass ratio of the volume of the addition purified water described in step S1 and potassium hydroxide is 5.5-5.8:2.9-
3.3(v/w)；
The molar ratio of raw material a, raw material b, catalyst, potassium hydroxide described in step S1 are 1.1-1.3:1:0.10-0.15:
4-4.5；
Catalyst described in step S1 is 4-butyl ammonium hydrogen sulfate；
The substitution reaction time described in step S1 is 1h.
Further, being filtered, washed, crystallizing described in step S1, to dry detailed process as follows：After substitution reaction, to
After addition purified water is uniformly mixed in reaction solution, at room temperature using diatomite filtering reacting liquid, first is added in filtrate
Benzene stands liquid separation after mixing, discards water layer, and purified water is continuously added into organic layer, stands and carries out secondary liquid separation, collects
Organic layer carries out reduced pressure toluene, and acetone is added in into concentrate, is heated to 54-60 DEG C of reflux, cold after object dissolving to be concentrated
But to 45 DEG C, crystal seed is added in, keeps the temperature 30min, 3-7 DEG C of heat preservation 1h is continued cool to and is crystallized, filtered under low temperature, using acetone
Filter wash cake is spread, filter cake 8-12h is dried under reduced pressure in the case where pressure is 7-13mmHg.
Further, the volume of the concentrate is 3.7% of total volume before concentrating.
Further, the mass ratio of the volume of the acetone described in step S2 and midbody compound c are 2.2-2.8:1(v/w)；
Acid solution described in step S2 is 2.5N HCl/water solution, and the rate of addition of acid solution is 4.4-4.7g/min；
Deprotection reaction temperature described in step S2 is 30-40 DEG C, reaction time 1-2h.
Further, the cooling described in step S2 adjusts pH, washs, filtering, and dry detailed process is as follows：Deprotection reaction
After, reaction solution is cooled to 5-15 DEG C, 13% KOH aqueous solutions is added in thereto when being stirred to react liquid, treats reaction solution
PH ＞ 12 after, stop adding in 13% KOH aqueous solutions, continue to stir 10-15min, measure reaction solution pH ＞ 12, pH adjusts knot
Beam；Then purified water and toluene are added in into the reaction solution after adjusting pH successively at room temperature, stirs 30min, stand liquid separation, give up
Abandon water layer continuously adds toluene into organic layer, stirs 30min, stands and carries out secondary liquid separation；After liquid separation, to organic layer
Crystallization is gradually precipitated in middle addition 2.5N HCl/waters solution, stirs 30min after 4.0-4.5, to continue after pH, filters out knot at room temperature
Crystalline substance spreads filter wash cake using purified water, and filter cake 12-16h is dried under reduced pressure in the case where pressure is 7-13mmHg.
Further, be heated to reflux temperature as 78.6 DEG C described in step S3, the cooling temperature, stirring and crystallizing temperature and
The temperature of filtering is 10 DEG C, mixing time 1h.
Beneficial effects of the present invention：
(1) synthetic method of a kind of high-purity drug for hypertension irbesartan provided by the invention, improves traditional
Traditional synthesis material composition is substituted, using raw material compound a in synthetic method:2- butyl -1,3- diazaspiracyclic [4,4]
Nonyl- 1- alkene -4- keto hydrochlorides and compound b:N- (trityl group) -5- (4'- bromomethylbiphenyl -2- bases) tetrazole is being catalyzed
Synthesis obtains midbody compound c under the action of agent 4-butyl ammonium hydrogen sulfate, then Deprotection three under the action of acid solution
Phenyl methyl group (- Tr), it is refined to obtain target product irbesartan, two-step reaction is only needed, reaction mechanism is simple, by-product
It is less；Strictly control the impurity content of each step, purification process is simple to operation, most afterwards through HPLC analyze detect, it is obtained according to
Bei Shatan purity is up to 99.9%, wherein remaining midbody compound c contents are 0.03%, specific impurity does not detect；
(2) in the purifying last handling process of midbody compound c, the stringent volume for controlling concentrate is concentrated under reduced pressure and removes
Toluene is precipitated in order to the crystallization of midbody compound c；After concentration, stringent control system is heated to reflux temperature, avoids
System temperature is too low, and reaction system curing causes next workshop section that can not operate；Post-processing approach is purified using this, in obtaining
The content of remaining compound b is less than 0.5% in intermediate compounds therefor c；
(3) during the purification process of irbesartan d crude products, the stringent adjusting process for controlling pH avoids the too low influences of pH
It is layered liquid separation；Using this purifying post-processing approach, the obtained purity of irbesartan d crude products is 98.7%, wherein remaining is intermediate
Body compound c contents are 0.24%, and specific impurity does not detect；
(4) a kind of synthetic method of high-purity drug for hypertension irbesartan provided by the invention, synthesis step are simple
Easy to control, raw material is easy to get, and for purification process suitable for putting into industrialized production, the reaction dissolvent and purification solvent used is generally cheap,
The irbesartan purity of preparation is high, is mass produced suitable for commercialization.
Specific embodiment
The technical solution in the embodiment of the present invention will be clearly and completely described below, it is clear that described implementation
Example is only part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common
All other embodiment that technical staff is obtained without creative efforts belongs to the model that the present invention protects
It encloses.
Embodiment 1
A kind of synthetic method of high-purity drug for hypertension irbesartan, irbesartan d synthetic routes are as follows：
Specific synthesis includes the following steps：
The synthesis of S1, midbody compound c
Purified water 56ml and potassium hydroxide 29.57g are sequentially added into reactor, exothermic dissolution postcooling to room temperature connects
It and sequentially adds raw material a34.17g, raw material b 70.00g, catalyst 5.11g and toluene 210mL, heating stirring 1h is replaced
Reaction, is analyzed through HPLC, and the survival rate of compound b terminates in≤1.5% reaction；Purified water 28mL stirrings are added in into reaction solution
After mixing, toluene 70mL is added in filtrate using diatomite filtering reacting liquid at room temperature, stands divide after mixing
Liquid discards water layer, and purified water 70mL is continuously added into organic layer, stands and carries out secondary liquid separation, and collected organic layer is depressurized
Toluene 259mL is concentrated, acetone is added in into concentrate, 56 DEG C of reflux is heated to, after object dissolving to be concentrated, is cooled to 45 DEG C, adds
Enter crystal seed 0.07g, keep the temperature 30min, continue cool to 5 DEG C of heat preservation 1h and crystallized, filtered under low temperature, filter wash is spread using acetone
Cake is dried under reduced pressure filter cake 10h in the case where pressure is 10mmHg；Dry cake is taken to analyze through HPLC to detect, remaining compound b's contains
Measure is 0.4%；
The synthesis of S2, irbesartan d crude products
Acetone 150mL and midbody compound c60.00g are sequentially added into reactor, side stirring was added dropwise with about 30 minutes
2.5N HCl/water solution 137.3g, after being added dropwise, stirring 1h carries out deprotection reaction, is analyzed through HPLC, midbody compound c
The reaction of survival rate≤1.0% terminate, reaction solution is cooled to 10 DEG C, adds in 13% KOH thereto when being stirred to react liquid
Aqueous solution 192.0mL after the pH ＞ 12 of reaction solution, stops adding in 13% KOH aqueous solutions, continues to stir 10min, measures anti-
Liquid pH ＞ 12 are answered, pH adjustings terminate；Then purified water 102mL and first are added in into the reaction solution after adjusting pH successively at room temperature
Benzene 234mL stirs 30min, stands liquid separation, discards water layer, and toluene 156mL is continuously added into organic layer, stirs 30min, quiet
It puts and carries out secondary liquid separation；After liquid separation, into organic layer, crystallization is gradually precipitated in addition 54mL 2.5N HCl/waters solution, treats pH
After 4.2, continue to stir 30min, filter out crystallization, filter wash cake is spread using purified water 240mL, depressurized in the case where pressure is 10mmHg
Dry cake 15h；Dry cake is taken to analyze through HPLC to detect, the purity of irbesartan d crude products is 98.7%, wherein remaining is intermediate
Body compound c contents are 0.24%, and specific impurity does not detect；
S3, irbesartan d it is refined
525mL ethyl alcohol and 169.45g irbesartan d crude products are sequentially added into reaction narrow-necked earthen jar, is heated to 78.6 DEG C of reflux, it is molten
After solution is complete, stirring 1h crystallizations at 10 DEG C, 10 DEG C are cooled to, filtering is spread filter wash cake using 169mL ethyl alcohol, is drying to obtain according to shellfish
Husky smooth d sterlings, purity 99.9%, wherein remaining midbody compound c contents are 0.03%, specific impurity does not detect.
Embodiment 2
A kind of synthetic method of high-purity drug for hypertension irbesartan, specific synthesis include the following steps：
The synthesis of S1, midbody compound c
Purified water 60ml and potassium hydroxide 30.11g are sequentially added into reactor, exothermic dissolution postcooling to room temperature connects
It and sequentially adds raw material a38.22g, raw material b 72.11g, catalyst 5.02g and toluene 220mL, heating stirring 1h is replaced
Reaction, is analyzed through HPLC, and the survival rate of compound b terminates in≤1.5% reaction；Purified water 30mL stirrings are added in into reaction solution
After mixing, toluene 75mL is added in filtrate using diatomite filtering reacting liquid at room temperature, stands divide after mixing
Liquid discards water layer, and purified water 75mL is continuously added into organic layer, stands and carries out secondary liquid separation, and collected organic layer is depressurized
Toluene 261mL is concentrated, acetone is added in into concentrate, 54 DEG C of reflux is heated to, after object dissolving to be concentrated, is cooled to 45 DEG C, adds
Enter crystal seed 0.07g, keep the temperature 30min, continue cool to 5 DEG C of heat preservation 1h and crystallized, filtered under low temperature, filter wash is spread using acetone
Cake is dried under reduced pressure filter cake 8h in the case where pressure is 7mmHg；Dry cake is taken to analyze through HPLC to detect, the content of remaining compound b
It is 0.3%；
The synthesis of S2, irbesartan d crude products
Acetone 160mL and midbody compound c60.00g are sequentially added into reactor, side stirring was added dropwise with about 30 minutes
2.5N HCl/water solution 140.1g, after being added dropwise, stirring 1h carries out deprotection reaction, is analyzed through HPLC, midbody compound c
The reaction of survival rate≤1.0% terminate, reaction solution is cooled to 5 DEG C, adds in 13% KOH water thereto when being stirred to react liquid
Solution 195.3mL after the pH ＞ 12 of reaction solution, stops adding in 13% KOH aqueous solutions, continues to stir 15min, measure reaction
Liquid pH ＞ 12, pH adjusting terminate；Then purified water 105mL and toluene are added in into the reaction solution after adjusting pH successively at room temperature
237mL stirs 30min, stands liquid separation, discards water layer, and toluene 160mL is continuously added into organic layer, stirs 30min, stands
Carry out secondary liquid separation；After liquid separation, into organic layer, crystallization is gradually precipitated in addition 55mL 2.5N HCl/waters solution, treats that pH is
After 4.5, continue to stir 30min, filter out crystallization, filter wash cake is spread using purified water 250mL, depressurized in the case where pressure is 7mmHg dry
Dry filter cake 12h；Dry cake is taken to analyze through HPLC to detect, the purity of irbesartan d crude products is 98.9%, wherein remaining intermediate
Compound c contents are 0.23%, and specific impurity does not detect；
S3, irbesartan d it is refined
530mL ethyl alcohol and 171.22g irbesartan d crude products are sequentially added into reaction narrow-necked earthen jar, is heated to 78.6 DEG C of reflux, it is molten
After solution is complete, stirring 1h crystallizations at 10 DEG C, 10 DEG C are cooled to, filtering is spread filter wash cake using 170mL ethyl alcohol, is drying to obtain according to shellfish
Husky smooth d sterlings, purity 99.9%, wherein remaining midbody compound c contents are 0.02%, specific impurity does not detect.
Embodiment 3
A kind of synthetic method of high-purity drug for hypertension irbesartan, specific synthesis include the following steps：
The synthesis of S1, midbody compound c
Purified water 52ml and potassium hydroxide 28.66g are sequentially added into reactor, exothermic dissolution postcooling to room temperature connects
It and sequentially adds raw material a33.65g, raw material b 70.00g, catalyst 4.88g and toluene 200mL, heating stirring 1h is replaced
Reaction, is analyzed through HPLC, and the survival rate of compound b terminates in≤1.5% reaction；Purified water 35mL stirrings are added in into reaction solution
After mixing, toluene 65mL is added in filtrate using diatomite filtering reacting liquid at room temperature, stands divide after mixing
Liquid discards water layer, and purified water 65mL is continuously added into organic layer, stands and carries out secondary liquid separation, and collected organic layer is depressurized
Toluene 255mL is concentrated, acetone is added in into concentrate, 60 DEG C of reflux is heated to, after object dissolving to be concentrated, is cooled to 45 DEG C, adds
Enter crystal seed 0.07g, keep the temperature 30min, continue cool to 15 DEG C of heat preservation 1h and crystallized, filtered under low temperature, filter wash is spread using acetone
Cake is dried under reduced pressure filter cake 12h in the case where pressure is 13mmHg；Dry cake is taken to analyze through HPLC to detect, remaining compound b's contains
Measure is 0.2%；
The synthesis of S2, irbesartan d crude products
Acetone 140mL and midbody compound c60.00g are sequentially added into reactor, side stirring was added dropwise with about 30 minutes
2.5N HCl/water solution 135.8g, after being added dropwise, stirring 1h carries out deprotection reaction, is analyzed through HPLC, midbody compound c
The reaction of survival rate≤1.0% terminate, reaction solution is cooled to 10 DEG C, adds in 13% KOH thereto when being stirred to react liquid
Aqueous solution 200.0mL after the pH ＞ 12 of reaction solution, stops adding in 13% KOH aqueous solutions, continues to stir 10min, measures anti-
Liquid pH ＞ 12 are answered, pH adjustings terminate；Then purified water 106mL and first are added in into the reaction solution after adjusting pH successively at room temperature
Benzene 240mL stirs 30min, stands liquid separation, discards water layer, and toluene 155mL is continuously added into organic layer, stirs 30min, quiet
It puts and carries out secondary liquid separation；After liquid separation, into organic layer, crystallization is gradually precipitated in addition 60mL 2.5N HCl/waters solution, treats pH
After 4.1, continue to stir 30min, filter out crystallization, filter wash cake is spread using purified water 255mL, depressurized in the case where pressure is 13mmHg
Dry cake 16h；Dry cake is taken to analyze through HPLC to detect, the purity of irbesartan d crude products is 98.5%, wherein remaining is intermediate
Body compound c contents are 0.25%, and specific impurity does not detect；
S3, irbesartan d it is refined
530mL ethyl alcohol and 175.11g irbesartan d crude products are sequentially added into reaction narrow-necked earthen jar, is heated to 78.6 DEG C of reflux, it is molten
After solution is complete, stirring 1h crystallizations at 10 DEG C, 10 DEG C are cooled to, filtering is spread filter wash cake using 180mL ethyl alcohol, is drying to obtain according to shellfish
Husky smooth d sterlings, purity 99.9%, wherein remaining midbody compound c contents are 0.01%, specific impurity does not detect.
Above content is only the design example and explanation to the present invention, affiliated those skilled in the art
Various modifications or additions are done to described specific embodiment or are substituted in a similar way, without departing from invention
Design or surmount range defined in the claims, be within the scope of protection of the invention.
Claims (7)
1. a kind of synthetic method of high-purity drug for hypertension irbesartan, it is characterised in that：Irbesartan d synthetic routes are such as
Under：
Specific synthesis includes the following steps：
The synthesis of S1, midbody compound c
Purified water and potassium hydroxide are sequentially added into reactor, postcooling is dissolved, then sequentially adds raw material a, raw material b, urges
Agent and toluene, heating stirring carry out substitution reaction, after reaction, intermediate are obtained after filtered, washing, crystallization, drying
Compound c；
The synthesis of S2, irbesartan d crude products
Acetone and midbody compound c are sequentially added into reactor, while stirring be added dropwise acid solution, be added dropwise after, stirring
Deprotection reaction is carried out, after reaction, through cooling, pH is adjusted, washs, filtering is dried to obtain irbesartan d crude products；
S3, irbesartan d it is refined
Ethyl alcohol and irbesartan d crude products are sequentially added into reaction narrow-necked earthen jar, is heated to reflux, after dissolving completely, cooling, stirring and crystallizing,
Filtering, spreads filter wash cake using ethyl alcohol, is drying to obtain irbesartan d sterlings.
2. a kind of synthetic method of high-purity drug for hypertension irbesartan according to claim 1, it is characterised in that：
The volume of addition purified water described in step S1 and the mass ratio of potassium hydroxide are 5.5-5.8:2.9-3.3(v/w)；
The molar ratio of raw material a, raw material b, catalyst, potassium hydroxide described in step S1 are 1.1-1.3:1:0.10-0.15:4-
4.5；
Catalyst described in step S1 is 4-butyl ammonium hydrogen sulfate；
The substitution reaction time described in step S1 is 1h.
3. a kind of synthetic method of high-purity drug for hypertension irbesartan according to claim 1, it is characterised in that：
Being filtered, washed, crystallizing described in step S1, to dry detailed process as follows：After substitution reaction, purifying is added in into reaction solution
After water is uniformly mixed, at room temperature using diatomite filtering reacting liquid, toluene is added in filtrate, is stood after mixing
Water layer is discarded in liquid separation, and purified water is continuously added into organic layer, is stood and is carried out secondary liquid separation, collected organic layer depressurize dense
Contracting toluene, acetone is added in into concentrate, is heated to 54-60 DEG C of reflux, after object dissolving to be concentrated, is cooled to 45 DEG C, additionization
The crystal seed of object c is closed, keeps the temperature 30min, 3-7 DEG C of heat preservation 1h is continued cool to and is crystallized, filtered under low temperature, filter wash is spread using acetone
Cake is dried under reduced pressure filter cake 8-12h in the case where pressure is 7-13mmHg.
4. a kind of synthetic method of high-purity drug for hypertension irbesartan according to claim 3, it is characterised in that：
The volume of the concentrate is 3.7% of total volume before concentrating.
5. a kind of synthetic method of high-purity drug for hypertension irbesartan according to claim 1, it is characterised in that：
The volume of acetone described in step S2 is 2.2-2.8 with the mass ratio of midbody compound c:1(v/w)；
Acid solution described in step S2 is 2.5N HCl/water solution, and the rate of addition of acid solution is 4.4-4.7g/min；
Deprotection reaction temperature described in step S2 is 30-40 DEG C, reaction time 1-2h.
6. a kind of synthetic method of high-purity drug for hypertension irbesartan according to claim 1, it is characterised in that：
Cooling described in step S2 adjusts pH, washs, filtering, and dry detailed process is as follows：After deprotection reaction, by reaction solution
5-15 DEG C is cooled to, adds in 13% KOH aqueous solutions thereto when being stirred to react liquid, after the pH ＞ 12 of reaction solution, is stopped
13% KOH aqueous solutions are added in, continue to stir 10-15min, measure reaction solution pH ＞ 12, pH adjustings terminate；Then at room temperature
Purified water and toluene are added in the reaction solution after pH is adjusted successively, stirs 30min, stands liquid separation, water layer is discarded, to organic layer
In continuously add toluene, stir 30min, stand and carry out secondary liquid separation；After liquid separation, 2.5N HCl/waters are added in into organic layer
Crystallization is gradually precipitated in solution, stirs 30min after 4.0-4.5, to continue after pH, filters out crystallization at room temperature, spread using purified water
Filter wash cake is dried under reduced pressure filter cake 12-16h in the case where pressure is 7-13mmHg.
7. a kind of synthetic method of high-purity drug for hypertension irbesartan according to claim 1, it is characterised in that：
The temperature that is heated to reflux described in step S3 is 78.6 DEG C, and the temperature of the cooling temperature, stirring and crystallizing temperature and filtering is
10 DEG C, mixing time 1h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810184408.7A CN108218841A (en) | 2018-03-06 | 2018-03-06 | A kind of synthetic method of high-purity drug for hypertension irbesartan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810184408.7A CN108218841A (en) | 2018-03-06 | 2018-03-06 | A kind of synthetic method of high-purity drug for hypertension irbesartan |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108218841A true CN108218841A (en) | 2018-06-29 |
Family
ID=62666955
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810184408.7A Pending CN108218841A (en) | 2018-03-06 | 2018-03-06 | A kind of synthetic method of high-purity drug for hypertension irbesartan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108218841A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5270317A (en) * | 1990-03-20 | 1993-12-14 | Elf Sanofi | N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present |
| CN1668612A (en) * | 2002-07-16 | 2005-09-14 | 特瓦制药工业有限公司 | Novel synthesis of irbesartan |
| US20090137648A1 (en) * | 2004-10-26 | 2009-05-28 | Srinivas Pathi L | Process for the preparation of irbesartan hydrochloride |
| CN105001209A (en) * | 2015-06-29 | 2015-10-28 | 千辉药业（安徽）有限责任公司 | Synthetic method of irbesartan |
-
2018
- 2018-03-06 CN CN201810184408.7A patent/CN108218841A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5270317A (en) * | 1990-03-20 | 1993-12-14 | Elf Sanofi | N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present |
| CN1668612A (en) * | 2002-07-16 | 2005-09-14 | 特瓦制药工业有限公司 | Novel synthesis of irbesartan |
| US20090137648A1 (en) * | 2004-10-26 | 2009-05-28 | Srinivas Pathi L | Process for the preparation of irbesartan hydrochloride |
| CN105001209A (en) * | 2015-06-29 | 2015-10-28 | 千辉药业（安徽）有限责任公司 | Synthetic method of irbesartan |
Non-Patent Citations (1)
| Title |
|---|
| BERTRAND LE BOURDONNEC等: ""Synthesis and Pharmacological Evaluation of New Pyrazolidine-3,5-diones as AT1 Angiotensin II Receptor Antagonists"", 《J. MED. CHEM.》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104860894B (en) | Method for preparing cardiotonic drug LCZ696 | |
| CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
| JP6471103B2 (en) | Benzimidazol-2-ylpyrimidine modulator of histamine H4 receptor | |
| CN104945299B (en) | A kind of high-efficiency synthesis method of vildagliptin | |
| CN103613558B (en) | A kind of preparation method of valsartan | |
| CN108864051A (en) | The method for being used to prepare pure nilotinib and its salt | |
| US20090286990A1 (en) | Process for preparing irbesartan | |
| CN106083826A (en) | A kind of irbesartan isomer and the preparation method of intermediate thereof | |
| TWI464162B (en) | Novel crystalline solvate | |
| CN102911128A (en) | Synthetic method of valsartan | |
| CN104530033A (en) | Novel process method for preparing arotinolol hydrochloride | |
| CN103554049B (en) | A kind of method preparing valsartan | |
| CN107980038A (en) | Sha Kuba song calcium salts | |
| CN108218841A (en) | A kind of synthetic method of high-purity drug for hypertension irbesartan | |
| CN105622595A (en) | Novel preparation method of azilsartan medoxomil sylvite and its intermediate | |
| CA2515138A1 (en) | Synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)-1,3-diazaspirol[4,4]-non-ene-4-one | |
| CN112979552A (en) | Preparation method of high-purity dexmedetomidine hydrochloride | |
| CN109666023B (en) | Preparation method and intermediate of nilotinib | |
| CN105330664B (en) | A kind of synthetic method of Xi Gelieting impurity | |
| CN107304204A (en) | A kind of method for preparing N- heterocyclic compounds | |
| CN103183663B (en) | Preparation method for azelnidipine | |
| EP1907379A1 (en) | Crystalline forms of (2r-trans)-6-chloro-5ýý4-ý(4-fluorophenyl)methyl¨-2,5-dimethyl-1-piperazinyl¨carbonyl¨-n,n, 1-trimethyl-alpha-oxo-1h-indole-3-acetamide monohydrochloride | |
| CN113993851A (en) | Valsartan refining method | |
| KR101163864B1 (en) | Method for preparing valsartan and novel intermediates used therein | |
| WO2023116514A1 (en) | High-purity losartan potassium and preparation method therefor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180629 |
|
| RJ01 | Rejection of invention patent application after publication |