CN102807564A - Preparation method of irbesartan - Google Patents
Preparation method of irbesartan Download PDFInfo
- Publication number
- CN102807564A CN102807564A CN2012103158925A CN201210315892A CN102807564A CN 102807564 A CN102807564 A CN 102807564A CN 2012103158925 A CN2012103158925 A CN 2012103158925A CN 201210315892 A CN201210315892 A CN 201210315892A CN 102807564 A CN102807564 A CN 102807564A
- Authority
- CN
- China
- Prior art keywords
- butyl
- alkene
- ninth
- irbesartan
- preparation
- 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
Images
Abstract
The invention discloses a preparation method of irbesartan, which comprises the following steps of: 1) using irbesartan imidazole hydrochloride and 2-cyano-4'-bromomethylbiphenyl as raw materials, conducting alkylation reaction in a water-aprotic solvent non-homogeneous system under the effect of inorganic base and phase transfer catalyst to prepare irbesartan hydrocarbon; and 2) taking the irbesartan hydrocarbon prepared in the step 1 and azimino compounds and conducting cyclization reaction in polar solvent under the effect of cyclization catalyst to prepare irbesartan. The preparation method of irbesartan provided by the invention has the advantages of simplicity and convenience in operation, easiness in obtaining raw materials, easiness in realization of reaction conditions, high yield, low cost, environmental friendly and the like, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of irbesartan.
Background technology
Hypertension is one of modal cardiovascular disorder in the world today, and epidemiological study shows that there are hyperpietic 600,000,000 people in the whole world at present, and the hypertension morbidity is about 10%.In the past few decades; The hypertensive morbidity of China increases fast; Point out in " the Chinese residents nutrition and the investigation of health conditions report " of issuing in information office of State Council on the 12nd news briefing October in 2004 that China adult hypertension morbidity is 18.8%, number of patients is 1.6 hundred million; And the numeral that " 2007 Chinese hypertension subject disease treatment standard and development strategy forum " that certificate was held in 2007 announces: China hyperpietic existing 200,000,000; Annual newly-increased hyperpietic more than 300 ten thousand; Other has 1,500,000 people to die from the apoplexy that is caused by hypertension; Hyperpietic's treatment rate has only 24.7%, and inverse amplification factor is merely 6.1%.These numerals make China become one of the most serious country of hypertension harm in the world, and this situation is very important.
Irbesartan (chemical name: 2-butyl-3-{ [2'-(1H-tetrazolium-5-yl)-[1; 1'-biphenyl]-the 4-yl] methyl }-1; 3-diaza spiro [4; 4] ninth of the ten Heavenly Stems-1-alkene-4-ketone) be angiotensin (Angiotensinv II, Ang II) receptor antagonist, the nervous plain II acceptor (AT1) of antagonizing vessel specifically.The antagonistic action of AT1 greater than 8500 times of angiotensin 2 receptors (AT2), through optionally blocking combining of Ang II and AT1 acceptor, is suppressed the release of vasoconstriction and aldosterone, the generation hypotensive effect.Characteristics such as that irbesartan has is efficient, long-acting, safety, taking orally and better tolerance, and have the inclination, brain, kidney provide protection, be a milestone in the cardiovascular agent.At present, the preparation method of irbesartan mainly contains following several kinds:
The preparation method one: 2-butyl-1; Alkylation reaction takes place at strong basicity reagent sodium hydride, solvent N in 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride (compound 1) and 2-cyanic acid-4'-bromomethylbiphenyl (compound 2) in the dinethylformamide (DMF); Obtain compound 3; Carry out ring-closure reaction through alkyl tin chloride and sodium azide or alkyl diazoimide tin again, form tetrazole, make irbesartan.(referenced patent document: EP0454511, FR 2659967, FR 2665702, JP 1992506222, JP 1998279566, US 5270317, WO 9114679, CN1415614A.）
This method has following shortcoming:
⑴ sodium hydride is a hazardous agents, meets water, wet air releasing hydrogen gas explosibility, uses and store danger;
⑵ reaction solvent is DMF, and DMF and water dissolve each other, and boiling point is high, after reaction finishes,, be difficult to handle because of DMF dissolves each other with water, and easy contaminate environment, and can not reclaim use, cause cost higher;
⑶ ring-closure reaction adopts alkyl tin chloride and sodium azide or alkyl diazoimide tin, and this type of material has severe corrosive, and equipment and operator are all had threat; In addition, tin remains in the product easily, causes heavy metals exceeding standard; And expensive, increased the cost of product.
The preparation method two: 2-butyl-1; 3-diazaspiracyclic [4; 4] ninth of the ten Heavenly Stems-alkylation reactions take place in the compound 4 shown in 1-alkene-4-keto hydrochloride (compound 1) and the following formula; With the compound 6 shown in the following formula alkylation reaction takes place again, make the trityl irbesartan, hydrolysis obtains irbesartan under the acid catalysis.(referenced patent document: CN1759113A.）
This method shortcoming: compound 4 is not the chemical reagent of using always all with compound 6, needs polystep reaction just can obtain, and is difficult for buying and preparation, and raw materials cost is high, is unfavorable for industrialized production.
The preparation method three: 2-butyl-1; 3-diazaspiracyclic [4; 4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride (compound 1) and N-(trityl group)-5-(4 '-bromomethylbiphenyl-2-yl) tetrazole (TTBB, compound 7) react, and makes the trityl irbesartan; Through acid-catalyzed hydrolysis, make irbesartan again.
This method adopts TTBB as starting raw material, can avoid the use of alkyl azide, but the price of TTBB is quite a few times of bromo biphenyl, adopts this route to produce irbesartan, and raw materials cost is too high, so industrialized production is restricted.
Summary of the invention
Based on this, the present invention improves traditional irbesartan synthesis technique, and a kind of new irbesartan preparation method is provided.Advantages such as that irbesartan preparation method of the present invention has is easy and simple to handle, raw material sources are easy to get, reaction conditions is prone to realize, productive rate is high, cost is low, environmental protection and suitable suitability for industrialized production.
A kind of preparation method of irbesartan may further comprise the steps:
1) with 2-butyl-1,3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride (abbreviating " shellfish imidazole hydrochloride in distress " as) is a raw material with 2-cyanic acid-4'-bromomethylbiphenyl; In the non-even phase system of water-aprotic solvent, under the effect of mineral alkali and phase-transfer catalyst, carry out alkylation reaction; Make 2-butyl-3-[(2'-cyanic acid-1; 1'-biphenyl-4-yl) methyl]-1,3-diaza spiro [4,4] ninth of the ten Heavenly Stems-1-alkene-4-ketone (abbreviating " shellfish hydrocarbonylation thing in distress " as);
2) get 2-butyl-3-[(2'-cyanic acid-1,1'-biphenyl-4-yl) methyl]-1 that step 1) makes, 3-diaza spiro [4; 4] ninth of the ten Heavenly Stems-1-alkene-4-ketone and triazo-compound, in polar solvent, under the effect of cyclization catalyst; Carry out ring-closure reaction, make described irbesartan.
In the alkylation reaction of step 1), described aprotic solvent is methylene dichloride, trichloromethane, tetrachloromethane, ETHYLE ACETATE or ethyl formate etc., wherein preferably methylene dichloride or trichloromethane, more preferably methylene dichloride.
In the alkylation reaction of step 1), described mineral alkali is sodium hydroxide, Pottasium Hydroxide, sodium amide, potassium amide, yellow soda ash or salt of wormwood etc., wherein preferably sodium hydroxide or Pottasium Hydroxide, more preferably sodium hydroxide.
In the alkylation reaction of step 1); Described phase-transfer catalyst is benzyltriethylammoinium chloride (TEBA), Tetrabutyl amonium bromide (TBAB), tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, DTAC, tetradecyl trimethyl ammonium chloride or triethylamine hydrochloride etc.; Wherein preferably benzyltriethylammoinium chloride or Tetrabutyl amonium bromide, more preferably benzyltriethylammoinium chloride.
In the alkylation reaction of step 1), 2-butyl-1, the mol ratio of 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride and 2-cyanic acid-4'-bromomethylbiphenyl is 1 ︰, 1～1 ︰ 3; 2-butyl-1, the mol ratio of 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride and mineral alkali is 1 ︰, 1～1 ︰ 8, wherein 1 ︰, 2～1 ︰ 5 preferably; The consumption of phase-transfer catalyst is a 2-butyl-1,0.1%～10% of the quality of 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride, wherein preferably 1%～5%; The consumption of aprotic solvent is a 2-butyl-1,1～8 times of the quality of 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride, wherein preferably 2～6 times, more preferably 3～4 times; In the non-even phase system of water-aprotic solvent, the mass ratio of aprotic solvent and water is 0.5 ︰, 1～3 ︰ 1, wherein 1 ︰, 1～2 ︰ 1 preferably.
In the alkylation reaction of step 1), temperature of reaction is set at 0～50 ℃, and preferably 10～30 ℃, more preferably 20～25 ℃; Reaction times is set at 2～7 hours, preferably 3～4 hours.
In step 2) ring-closure reaction in, described triazo-compound is sodium azide or nitrine potassium etc.
In step 2) ring-closure reaction in, the high bp polar solvent of described polar solvent for not dissolving each other mutually with water is selected from butyl propionate, propylene glycol monomethyl ether or jasmal etc.
In step 2) ring-closure reaction in, described cyclization catalyst is triethylamine hydrochloride, zinc chloride, ammonium chloride or zinc bromide etc.
In step 2) ring-closure reaction in, 2-butyl-3-[(2'-cyanic acid-1,1'-biphenyl-4-yl) methyl]-1, the mol ratio of 3-diaza spiro [4,4] ninth of the ten Heavenly Stems-1-alkene-4-ketone and triazo-compound is 1 ︰, 1～1 ︰ 5, wherein 1 ︰, 1～1 ︰ 3 preferably; 2-butyl-3-[(2'-cyanic acid-1,1'-biphenyl-4-yl) methyl]-1, the mol ratio of 3-diaza spiro [4,4] ninth of the ten Heavenly Stems-1-alkene-4-ketone and cyclization catalyst is 1 ︰, 1～1 ︰ 6, wherein 1 ︰, 2～1 ︰ 4 preferably; The consumption of polar solvent is 2-butyl-3-[(2'-cyanic acid-1,1'-biphenyl-4-yl) methyl]-1,1～8 times of the quality of 3-diaza spiro [4,4] ninth of the ten Heavenly Stems-1-alkene-4-ketone, wherein preferably 2～6 times.
In step 2) ring-closure reaction in, temperature of reaction is set at 80～130 ℃, wherein preferably 90～120 ℃; Reaction times is set at 10～30 hours.
Irbesartan preparation method of the present invention, further comprising the steps of: after the alkylation reaction of step 1) finished, standing separation went out solvent layer; The concentrated solvent layer obtains crude product; Adopt acetone to carry out recrystallization then, obtain the product 2-butyl-3-[(2'-cyanic acid-1,1'-biphenyl-4-yl) methyl]-1 of purifying; 3-diaza spiro [4,4] ninth of the ten Heavenly Stems-1-alkene-4-ketone.
Irbesartan preparation method of the present invention, further comprising the steps of: step 2) ring-closure reaction finish after, add Sodium Nitrite to reaction mixture; Then the pH value is transferred to 4～5; After treating that crude product is separated out, adopt acetone to carry out recrystallization, obtain the product irbesartan of purifying.
Irbesartan preparing method's of the present invention synthetic route is following:
Irbesartan preparation method of the present invention has following beneficial effect:
⑴ the alkylation reaction of step 1) has adopted heterogeneous reaction system, has replaced the DMF that uses in the traditional technology with aprotic solvent such as methylene dichloride, adds the phase-transfer catalyst of minute quantity; Can react completely at normal temperatures, need not heating, reduce energy consumption; And reaction to finish aftertreatment simple, can shorten the production cycle, and solvent can recycling use; Reduced production cost, also reduced pollution environment.
⑵ the alkylation reaction of step 1) has adopted mineral alkalis such as NaOH or KOH, has replaced the NaH that uses in the traditional technology, and its low price uses and storage security.
⑶ ring-closure reaction step 2) has adopted salt such as triethylamine hydrochloride, zinc chloride, ammonium chloride or zinc bromide as cyclization catalyst; Replaced the alkyl tin chloride and sodium azide or the alkyl diazoimide tin that use in the traditional technology; Avoided residual heavy metal in product; Improve quality product, reduced production cost.
⑷ ring-closure reaction step 2) has adopted butyl propionate, and propylene glycol monomethyl ether or jasmal etc. and the high bp polar solvent that water does not dissolve each other have mutually replaced the DMF, the N that use in the traditional technology; N-N,N-DIMETHYLACETAMIDE or pyrrolidone, its advantage is: during reaction, shellfish hydrocarbonylation thing in distress can be dissolved in the reaction system under 100 ℃; After reaction finishes; The pH value is transferred to 4～5,, reduced labour intensity and production cycle widely even irbesartan is separated out fully; And this kind solvent is also recyclable recycles, and can reduce production costs.
In sum, irbesartan preparation method of the present invention has easy and simple to handle, efficient, economic dispatch advantage, can improve the quality of product, reduces " three wastes " discharging, is fit to suitability for industrialized production.
Description of drawings
Fig. 1 is the mass spectrum of shellfish hydrocarbonylation thing in distress;
Fig. 2 is the infrared spectrogram of shellfish hydrocarbonylation thing in distress;
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of shellfish hydrocarbonylation thing in distress;
Fig. 4 is the carbon-13 nmr spectra figure of shellfish hydrocarbonylation thing in distress;
Fig. 5 is the mass spectrum of irbesartan;
Fig. 6 is the infrared spectrogram of irbesartan;
Fig. 7 is the hydrogen nuclear magnetic resonance spectrogram of irbesartan;
Fig. 8 is the carbon-13 nmr spectra figure of irbesartan.
Embodiment
Embodiment one: shellfish hydrocarbonylation thing in distress synthetic
The 400g methylene dichloride is added in the retort of 500ml, at room temperature add 118g (0.433mol) 2-cyanic acid-4'-bromomethylbiphenyl, stir and made its dissolving in 10 minutes; Add 200g pure water, 100g (0.433mol) 2-butyl-1 then, 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride and 5g benzyltriethylammoinium chloride stirs and made its dissolving in 10 minutes; Under 20 ℃, be that 10% the NaOH aqueous solution is added dropwise in the retort with the 400g mass concentration; Dropwise the back sampling and detect, reaction in about 3～4 hours finishes.
Embodiment two: shellfish hydrocarbonylation thing in distress synthetic
The 300g methylene dichloride is added in the retort of 500ml, at room temperature add 125g (0.459mol) 2-cyanic acid-4'-bromomethylbiphenyl, stir and made its dissolving in 10 minutes; Add 200g pure water, 100g (0.433mol) 2-butyl-1 then, 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride and 3g Tetrabutyl amonium bromide stirs and made its dissolving in 10 minutes; Under 20 ℃, be that 5% the KOH aqueous solution is added dropwise in the retort with the 450g mass concentration; Dropwise the back sampling and detect, reaction in about 3～4 hours finishes.
Embodiment three: shellfish hydrocarbonylation thing in distress synthetic
The 300g methylene dichloride is added in the retort of 500ml, at room temperature add 285g (1.047mol) 2-cyanic acid-4'-bromomethylbiphenyl, stir and made its dissolving in 10 minutes; Add 430g pure water, 210g (0.911mol) 2-butyl-1 then, 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride and 6g benzyltriethylammoinium chloride stirs and made its dissolving in 10 minutes; Under 20 ℃, be that 8% the KOH aqueous solution is added dropwise in the retort with the 700g mass concentration; Dropwise the back sampling and detect, reaction in about 3～4 hours finishes.
Embodiment four: the structure of shellfish hydrocarbonylation thing in distress is identified
Shellfish hydrocarbonylation thing in distress of the present invention has with the chemical structure shown in the following formula (1):
Get embodiment one to three prepared shellfish hydrocarbonylation thing in distress, through electron impact ionization (EI) mass spectroscopy, its mass spectrum is as shown in Figure 1 on the DSQ mass spectrograph, and the ownership at leading ion peak is following:
Adopt elemental analyser to measure C, H, the N constituent content of embodiment one to three prepared shellfish hydrocarbonylation thing in distress, it is as shown in table 1 to measure the result.
The constituent content test result of table 1 shellfish hydrocarbonylation in distress thing
Adopt IR that embodiment one to three prepared shellfish hydrocarbonylation thing in distress is carried out structure and identify that its ir spectra is as shown in Figure 2.
Adopt nuclear magnetic resonance spectrometer, with deuterochloroform (CDCl
3) be solvent, TMS is interior mark, embodiment one to three prepared shellfish hydrocarbonylation thing in distress carried out structure identifies, its nuclear magnetic resonance map such as Fig. 3～shown in Figure 4, its nuclear magnetic resonance map data are shown in table 2～table 3.
Table 2 shellfish hydrocarbonylation in distress thing
1H-NMR collection of illustrative plates determination data and parsing
Table 3 shellfish hydrocarbonylation in distress thing
13C-NMR collection of illustrative plates determination data and parsing
The said structure qualification result shows that embodiment one to three prepared end product is title product 2-butyl-3-[(2'-cyanic acid-1,1'-biphenyl-4-yl) methyl]-1,3-diaza spiro [4,4] ninth of the ten Heavenly Stems-1-alkene-4-ketone (shellfish hydrocarbonylation thing in distress).
Embodiment five: irbesartan synthetic
The 500g propylene glycol monomethyl ether is dropped in the retort, stir and drop into 120g (0.311mol) shellfish hydrocarbonylation in distress thing, 25g (0.385mol) sodium azide and 98.3g (0.715mol) triethylamine hydrochloride down, be heated to 90 ℃, reacted 25 hours.
Reaction is reduced to room temperature after finishing, and adds 1000g pure water and 10g Sodium Nitrite, and in order to decompose deleterious by product hydrazoic acid, the hydrochloric acid with 6N transfers to 4～5 with the pH value then, separates out crude product, centrifugal collection crude product, and drying is 24 hours under 80 ℃.Mother liquor standing demix after centrifugal, concentrating under reduced pressure reclaims propylene glycol monomethyl ether.
Get crude product, weigh, add the acetone of its 4 times of quality, heating is dissolved crude product fully; Add the 5g gac then, reflux decolour 30min, filtered while hot is after filtrating is chilled to 5 ℃; Centrifugally get rid of filter, filter cake is with cold washing with acetone, then 80 ℃ dry 24 hours down; Obtain the product irbesartan 114.7g of purifying, productive rate is 86%, and purity is 99.7%.
Embodiment six: irbesartan synthetic
The 500g butyl propionate is dropped in the retort, stir and drop into 140g (0.363mol) shellfish hydrocarbonylation in distress thing, 47.2g (0.726mol) sodium azide and 88.6g (0.905mol) zinc bromide down, be heated to 110 ℃, reacted 15 hours.
Reaction is reduced to room temperature after finishing, and adds 1000g pure water and 10g Sodium Nitrite, and in order to decompose deleterious by product hydrazoic acid, the hydrochloric acid with 6N transfers to 4～5 with the pH value then, separates out crude product, centrifugal collection crude product, and drying is 24 hours under 80 ℃.Mother liquor standing demix after centrifugal, concentrating under reduced pressure reclaims butyl propionate.
Get crude product, weigh, add the acetone of its 4 times of quality, heating is dissolved crude product fully; Add the 5g gac then, reflux decolour 30min, filtered while hot is after filtrating is chilled to 5 ℃; Centrifugally get rid of filter, filter cake is with cold washing with acetone, then 80 ℃ dry 24 hours down; Obtain the product irbesartan 136.1g of purifying, productive rate is 87.5%, and purity is 99.8%.
Embodiment seven: irbesartan synthetic
The 600g butyl propionate is dropped in the retort, stir and drop into 250g (0.648mol) shellfish hydrocarbonylation in distress thing, 58.8g (0.726mol) nitrine potassium and 72.2g (1.350mol) ammonium chloride down, be heated to 120 ℃, reacted 15 hours.
Reaction is reduced to room temperature after finishing, and adds 1500g pure water and 14g Sodium Nitrite, and in order to decompose deleterious by product hydrazoic acid, the hydrochloric acid with 6N transfers to 4～5 with the pH value then, separates out crude product, centrifugal collection crude product, and drying is 24 hours under 80 ℃.Mother liquor standing demix after centrifugal, concentrating under reduced pressure reclaims butyl propionate.
Get crude product, weigh, add the acetone of its 4 times of quality, heating is dissolved crude product fully; Add the 10g gac then, reflux decolour 30min, filtered while hot is after filtrating is chilled to 5 ℃; Centrifugally get rid of filter, filter cake is with cold washing with acetone, then 80 ℃ dry 24 hours down; Obtain the product irbesartan 241.7g of purifying, productive rate is 87%, and purity is 99.8%.
Embodiment eight: the structure of irbesartan is identified
Irbesartan of the present invention has with the chemical structure shown in the following formula (2):
Getting embodiment five to seven prepared irbesartans, through fast atom bombardment(FAB) ionization (FAB) mass spectroscopy, is matrix with the 3-nitrobenzyl alcohol on VG ZAB-HS mass spectrograph, and its mass spectrum is as shown in Figure 5, and the ownership at leading ion peak is following:
Other leading ion peak m/z 41,69,77,89,107,120,136,154,279,289,307 among Fig. 5 etc. are by matrix 3-nitrobenzyl alcohol is produced; M/z 149 is the background peak.
Adopt elemental analyser to measure C, H, the N constituent content of embodiment five to seven prepared irbesartans, it is as shown in table 4 to measure the result.
The constituent content test result of table 4 irbesartan
Adopt IR that embodiment five to seven prepared irbesartans are carried out structure and identify that its ir spectra is as shown in Figure 6.
Adopt nuclear magnetic resonance spectrometer, with deuterochloroform (CDCl
3) be solvent, TMS is interior mark, embodiment five to seven prepared irbesartans carried out structure identifies, its nuclear magnetic resonance map such as Fig. 7～shown in Figure 8, its nuclear magnetic resonance map data are shown in table 5～table 6.
Table 5 irbesartan
1H-NMR collection of illustrative plates determination data and parsing
Table 6 irbesartan
13C-NMR collection of illustrative plates determination data and parsing
The said structure qualification result shows that embodiment five to seven prepared end products are the title product irbesartan.
The above embodiment has only expressed several kinds of embodiments of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to claim of the present invention.Should be pointed out that for the person of ordinary skill of the art under the prerequisite that does not break away from the present invention's design, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with accompanying claims.
Claims (10)
1. the preparation method of an irbesartan may further comprise the steps:
1) with 2-butyl-1,3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride and 2-cyanic acid-4'-bromomethylbiphenyl are raw material; In the non-even phase system of water-aprotic solvent, under the effect of mineral alkali and phase-transfer catalyst, carry out alkylation reaction; Make 2-butyl-3-[(2'-cyanic acid-1; 1'-biphenyl-4-yl) methyl]-1,3-diaza spiro [4,4] ninth of the ten Heavenly Stems-1-alkene-4-ketone;
2) get 2-butyl-3-[(2'-cyanic acid-1,1'-biphenyl-4-yl) methyl]-1 that step 1) makes, 3-diaza spiro [4; 4] ninth of the ten Heavenly Stems-1-alkene-4-ketone and triazo-compound, in polar solvent, under the effect of cyclization catalyst; Carry out ring-closure reaction, make described irbesartan.
2. preparation method according to claim 1; It is characterized in that; In the alkylation reaction of step 1), described phase-transfer catalyst is benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, DTAC, tetradecyl trimethyl ammonium chloride or triethylamine hydrochloride.
3. preparation method according to claim 1 is characterized in that, in the alkylation reaction of step 1), described aprotic solvent is methylene dichloride, trichloromethane, tetrachloromethane, ETHYLE ACETATE or ethyl formate.
4. preparation method according to claim 1 is characterized in that, in the alkylation reaction of step 1), described mineral alkali is sodium hydroxide, Pottasium Hydroxide, sodium amide, potassium amide, yellow soda ash or salt of wormwood.
5. preparation method according to claim 1 is characterized in that, in step 2) ring-closure reaction in, described triazo-compound is sodium azide or nitrine potassium.
6. preparation method according to claim 1 is characterized in that, in step 2) ring-closure reaction in, described cyclization catalyst is triethylamine hydrochloride, zinc chloride, ammonium chloride or zinc bromide.
7. preparation method according to claim 1 is characterized in that, in step 2) ring-closure reaction in, described polar solvent is butyl propionate, propylene glycol monomethyl ether or jasmal.
8. preparation method according to claim 1 is characterized in that, in the alkylation reaction of step 1); 2-butyl-1, the mol ratio of 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride and 2-cyanic acid-4'-bromomethylbiphenyl is 1 ︰, 1～1 ︰ 3; 2-butyl-1, the mol ratio of 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride and mineral alkali is 1 ︰, 1～1 ︰ 8; The consumption of phase-transfer catalyst is a 2-butyl-1,0.1%～10% of the quality of 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride; The consumption of aprotic solvent is a 2-butyl-1,1～8 times of the quality of 3-diazaspiracyclic [4,4] ninth of the ten Heavenly Stems-1-alkene-4-keto hydrochloride; The aprotic solvent in the non-even phase system of water-aprotic solvent and the mass ratio of water are 0.5 ︰, 1～3 ︰ 1, and the alkylation reaction temperature is 0～50 ℃; In step 2) ring-closure reaction in, 2-butyl-3-[(2'-cyanic acid-1,1'-biphenyl-4-yl) methyl]-1; The mol ratio of 3-diaza spiro [4,4] ninth of the ten Heavenly Stems-1-alkene-4-ketone and triazo-compound is 1 ︰, 1～1 ︰ 5,2-butyl-3-[(2'-cyanic acid-1; 1'-biphenyl-4-yl) methyl]-1, the mol ratio of 3-diaza spiro [4,4] ninth of the ten Heavenly Stems-1-alkene-4-ketone and cyclization catalyst is 1 ︰, 1～1 ︰ 6; The consumption of polar solvent is 2-butyl-3-[(2'-cyanic acid-1,1'-biphenyl-4-yl) methyl]-1,3-diaza spiro [4; 4] ninth of the ten Heavenly Stems-1～8 times of quality of 1-alkene-4-ketone, the ring-closure reaction temperature is 80～130 ℃.
9. preparation method according to claim 1 is characterized in that, after the alkylation reaction of step 1) finishes; Standing separation goes out solvent layer, and the concentrated solvent layer obtains crude product, adopts acetone to carry out recrystallization then; Obtain product 2-butyl-3-[(2'-cyanic acid-1 of purifying; 1'-biphenyl-4-yl) methyl]-1,3-diaza spiro [4,4] ninth of the ten Heavenly Stems-1-alkene-4-ketone.
10. preparation method according to claim 1 is characterized in that step 2) ring-closure reaction finish after; Add Sodium Nitrite to reaction mixture, then the pH value transferred to 4～5, treat that crude product is separated out after; Adopt acetone to carry out recrystallization, obtain the product irbesartan of purifying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103158925A CN102807564A (en) | 2012-08-30 | 2012-08-30 | Preparation method of irbesartan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103158925A CN102807564A (en) | 2012-08-30 | 2012-08-30 | Preparation method of irbesartan |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102807564A true CN102807564A (en) | 2012-12-05 |
Family
ID=47231450
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012103158925A Pending CN102807564A (en) | 2012-08-30 | 2012-08-30 | Preparation method of irbesartan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102807564A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418612A (en) * | 2015-12-23 | 2016-03-23 | 北京颐方生物科技有限公司 | Preparation method of doxofylline |
| CN106083826A (en) * | 2016-06-22 | 2016-11-09 | 浙江华海药业股份有限公司 | A kind of irbesartan isomer and the preparation method of intermediate thereof |
| CN106117146A (en) * | 2016-06-22 | 2016-11-16 | 浙江华海药业股份有限公司 | A kind of method preparing irbesartan condensation substance |
| CN106674205A (en) * | 2016-12-09 | 2017-05-17 | 浙江华海药业股份有限公司 | Sartan compound discoloration method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101006064A (en) * | 2004-08-23 | 2007-07-25 | 布里斯托尔-迈尔斯斯奎布公司 | Method for preparing irbesartan and intermediates thereof |
| WO2010116380A2 (en) * | 2009-04-08 | 2010-10-14 | Ctx Life Sciences Pvt. Ltd. | A one pot process for preparing 2-butyl-3-[[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro [4, 4] non-1-en-4-one (irbesartan) |
-
2012
- 2012-08-30 CN CN2012103158925A patent/CN102807564A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101006064A (en) * | 2004-08-23 | 2007-07-25 | 布里斯托尔-迈尔斯斯奎布公司 | Method for preparing irbesartan and intermediates thereof |
| WO2010116380A2 (en) * | 2009-04-08 | 2010-10-14 | Ctx Life Sciences Pvt. Ltd. | A one pot process for preparing 2-butyl-3-[[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro [4, 4] non-1-en-4-one (irbesartan) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418612A (en) * | 2015-12-23 | 2016-03-23 | 北京颐方生物科技有限公司 | Preparation method of doxofylline |
| CN105418612B (en) * | 2015-12-23 | 2017-03-22 | 北京颐方生物科技有限公司 | Preparation method of doxofylline |
| CN106083826A (en) * | 2016-06-22 | 2016-11-09 | 浙江华海药业股份有限公司 | A kind of irbesartan isomer and the preparation method of intermediate thereof |
| CN106117146A (en) * | 2016-06-22 | 2016-11-16 | 浙江华海药业股份有限公司 | A kind of method preparing irbesartan condensation substance |
| CN106674205A (en) * | 2016-12-09 | 2017-05-17 | 浙江华海药业股份有限公司 | Sartan compound discoloration method |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102807564A (en) | Preparation method of irbesartan | |
| CN113072509B (en) | Method for synthesizing 7-amino clonazepam compound | |
| CN102627594A (en) | Preparation method of waterless aziridine compound | |
| CN102690225A (en) | New synthetic method of bazedoxifene | |
| WO2009086753A1 (en) | Preparation methods of aminomethyl biphenyl tetrazole compounds and their salts, intermediates and preparation methods thereof | |
| CN104768936B (en) | Prepare the method and its intermediate of Telmisartan | |
| CN102617637A (en) | Preparation method of organophosphorus nitrogen system flame retardant with hydroquinone phosphate ester serving as framework | |
| CN103613549B (en) | A kind of preparation method of afloqualone | |
| CN103012287B (en) | Preparation method of 6-chlorine-3-methyl uracil | |
| CN108840860A (en) | The method that one kettle way prepares Irbesartan | |
| CN101781286B (en) | Method for preparing candesartan cilexetil | |
| CN101362730B (en) | Method for preparing losartan side chain compound | |
| CN102391254A (en) | Preparation method of Candesartan | |
| CN101475501B (en) | Preparation method of N-methyl formyl aniline | |
| CN101759666B (en) | Preparation method of pinaverium bromide | |
| CN102516123B (en) | Method for preparing candesartan intermediate | |
| CN104447757B (en) | Method for synthesizing epinastine | |
| CN102863373B (en) | Method for synthesizing 5-benzylazaspiro[2,4]heptane | |
| CN101921235A (en) | Preparation method of telmisartan | |
| CN101838242B (en) | Method for synthesizing 2-normal-butyl-4-chloro-5-formylimidazole | |
| CN106008336A (en) | Preparation method of 4-chloro-6,7-dimethoxyquinoline | |
| CN102408353A (en) | Preparation method of candesartan intermediate | |
| CN106317060B (en) | A kind of preparation method of hydrochloric acid conivaptan | |
| CN104817504A (en) | Green fluorescent compound containing triphenylamine and bis-benzimidazole constitutional units, and preparation method and application thereof | |
| CN107573345A (en) | A kind of Ai Dailalisi and its intermediate preparation method |
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: 20121205 |