CN103664920A - Preparation method of azilsartan intermediate and azilsartan - Google Patents
Preparation method of azilsartan intermediate and azilsartan Download PDFInfo
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The invention discloses a preparation method of an intermediate 5B and azilsartan 1. The preparation method of the azilsartan 1 comprises the following steps: 1) in a solvent, mixing a compound 2B with hydroxylamine to react to obtain a compound 3B; 2) in a solvent, mixing the compound 3B prepared in the step 1) with chloroformate to react under the action of alkali to obtain a compound 4B; 3) in a solvent, carrying out cyclization reaction on the compound 4B prepared in the step 2) to obtain a compound 5B; and 4) in a solvent, carrying out esterolysis reaction on the compound 5B prepared in the step 3) under the action of alkali to obtain the azilsartan 1, wherein R is a C6-C10 aryl group or C1-C4 straight-chain or branched-chain alkyl group. The preparation method of the azilsartan intermediate 5B is described as the step 3). The preparation method has the advantages of fewer impurities, short reaction time, higher technical yield and higher product purity, and is suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to a kind of intermediate for the synthesis of antihypertensive drug Archie sand smooth (Azilsartan compound 1) and the preparation method smooth with Archie sand thereof.
Background technology
Archie sand is smooth is the antihypertensive drug of up-to-date listing, by Japan's military field pharmacy, is developed, and on January 28th, 2012 gets the Green Light in Japan.Archie sand is smooth is a kind of optionally Angiotensin Ⅱ receptor antagonist, can competitive reversibly block the combination of Angiotensin and AT1 acceptor, play the effect of reducing blood pressure, to the avidity of AT1 acceptor, be to more than 10,000 of AT2 acceptor times, because it does not suppress ACE, therefore can not affect bradykinin level, also not can in conjunction with and block other acceptor or ionic channels relevant to regulation of blood vessels effect.Azilsartan and human body AT1 receptor binding capacity are respectively Olmesartan and angiotensinⅡ 2 times and 30 times.The husky smooth curative effect of clinical studies show Archie is better than candesartan Cilexetil, valsartan and olmesartan medoxomill.Better with hydragog(ue) compound antihypertensive effect.
Compound number of patent application 92105152.2 has been described Archie husky smooth preparation and therepic use.Concrete synthetic route is as follows:
Compound 2A, i.e. 2-oxyethyl group-1-[(2 '-cyanobiphenyl-4-yl) methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester is the raw material for the synthesis of candesartan Cilexetil, commercial can conveniently acquisition.In above-mentioned route, 2-oxyethyl group-1-[(((2 '-oxyamine azomethine) xenyl)-4-yl) methyl] to be equivalent to compound 3A be synthetic difficult point to-1H-benzoglyoxaline-7-carboxylate methyl ester.
The preparation method of compound 3A is described in publication J.Med.Chem, and 1996,39 (26): in many documents such as 5528-5235, Chinese Patent Application No. 201010245420.J.Med.Chem, 1996,39 (26): in 5528-5235, be by compound 2A, be 2-oxyethyl group-1-[(2 '-cyanobiphenyl-4-yl) methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester is under oxammonium hydrochloride, triethylamine effect, in methyl-sulphoxide, react and within 60 hours, make compound 3A, can produce the compound 6A impurity with target compound a great deal of simultaneously, long reaction time, impurity is many.In Chinese patent (application number 201010245420), this is improved, compound 2A is reacted with 50% aqueous hydroxylamine, yield is the highest to be carried to 71.7%, but its reaction times is very long, need 24h ~ 40h, reaction solution HPLC collection of illustrative plates shows amide impurities 6A: compound 3A: compound 2=5.04:79.66:0, but other impurity is not described.
Consider the defect of above synthetic method, be necessary the husky smooth synthetic method of Archie to further investigate.
Summary of the invention
Technical problem to be solved by this invention is, the defects such as the process recovery ratio that in prior art, the husky smooth preparation method of Archie has is low in order to overcome, impurity is many, long reaction time, provide the husky smooth intermediate of a kind of Archie and with the preparation method of Archie sand smooth 1.The husky smooth preparation method's impurity of Archie of the present invention is less, the reaction times is short, process recovery ratio is higher, product purity is higher, is applicable to suitability for industrialized production.
The preparation method who the invention provides a kind of Archie husky smooth 1, it comprises the following steps:
1) in solvent, compound 2B is mixed with azanol, react, obtain compound 3B;
2), in solvent, under the effect of alkali, the compound 3B that step 1) is made mixes with chloro-formic ester, reacts, and obtains compound 4B;
3) in solvent, by step 2) the compound 4B that makes carries out ring-closure reaction, obtains compound 5B;
4) in solvent, under the effect of alkali, the compound 5B that step 3) is made carries out ester hydrolysis reaction, obtains Archie husky smooth 1;
Wherein, R is C
6~ C
10aryl or C
1~ C
4straight or branched alkyl.
In the preparation method of described Archie husky smooth 1, in step 1), described solvent is generally polar aprotic solvent or polar aprotic solvent.Described polar aprotic solvent preferred alcohols solvent.Described alcoholic solvent particular methanol, ethanol or Virahol, more preferably ethanol or Virahol, most preferred ethanol.The preferred DMF of described polar aprotic solvent (DMF) or methyl-sulphoxide (DMSO).The consumption of described solvent for do not affect reaction normally, be generally 5 ~ 20ml/g compound 2B, preferably 8 ~ 11ml/g compound 2B.
Described azanol can participate in reaction with form or the solid form of the aqueous solution.When azanol participates in reaction with the aqueous solution, the concentration of the aqueous solution of described azanol is 10% ~ 50%(mass percent preferably).The molar weight of described azanol is preferably 5 ~ 25 times of compound 2B, preferably 8 ~ 15 times.
In the reaction of described step 1), can also add organic bases.The preferred triethylamine of described organic bases, diisopropyl ethyl amine, diethylamine, Trimethylamine 99, pyridine or piperidines, preferably triethylamine or diisopropyl ethyl amine.The mole dosage of described organic bases is preferably 0.2 ~ 5 times of compound 2B, more preferably 0.5 ~ 1 times.
Preferably 50 ~ 110 ℃ of the temperature of reaction of described step 1), more preferably 65 ~ 100 ℃, most preferably 75 ~ 95 ℃.
The reaction process of described step 1) can be monitored by TLC or HPLC, when the compound 2B of generally usining disappears as the terminal of reaction.The present invention can reach the terminal of reaction in 5 ~ 10 hours, that is, in HPLC detection reaction system, compound 2B disappears.
Preferably, after finishing, step 1) reaction also product 3B is carried out to aftertreatment, to be further purified compound 3B.Described aftertreatment preferably includes cooling crystallization.Described cooling temperature is preferably 10 ~ 50 ℃, preferably 20 ~ 40 ℃.
In the preparation method of described Archie husky smooth 1, step 2) in, described solvent is generally organic solvent.The preferred aprotic solvent of described organic solvent.The preferred methylene dichloride of described aprotic solvent or chloroform, more preferably methylene dichloride.The consumption of described solvent for do not affect reaction normally, be generally 5 ~ 15ml/g compound 3B, preferably 7 ~ 10ml/g compound 3B.
Step 2) in, the preferred organic bases of described alkali.The preferred triethylamine of described organic bases, diisopropyl ethyl amine, diethylamine, Trimethylamine 99, pyridine or piperidines, more preferably triethylamine, diisopropyl ethyl amine.The mole dosage of described alkali is preferably 1 ~ 5 times of compound 3B, more preferably 1 ~ 2 times.
Step 2) in, the preferred C of R
1~ C
4straight or branched alkyl.Described C
1~ C
4straight or branched alkyl preferable methyl, ethyl or sec.-propyl.Described C
6~ C
10the preferred phenyl of aryl.
Step 2) in, the mole dosage of described chloro-formic ester is preferably 1 ~ 3 times of compound 3B, more preferably 1 ~ 1.5 of compound 3B times.
Step 2) in, preferably 10 ~ 40 ℃ of the temperature of described reaction, more preferably 20 ~ 35 ℃.
Step 2), in, the process of described reaction can be monitored by TLC or HPLC, when the compound 3B of generally usining disappears as the terminal of reaction.Reaction of the present invention preferably reached terminal in 1.5 ~ 2 hours, that is, through HPLC detection compound 3B, disappear.
Preferably, step 2) reaction is also carried out aftertreatment to product 4B after finishing, to be further purified compound 4B.Described aftertreatment preferably includes: reaction system is mixed with water, extract successively, be dried, filter, concentrate.Methylene dichloride is preferably used in described extraction.
In the preparation method of described Archie husky smooth 1, in step 3), described solvent can be the common solvent of this type of reaction of this area, preferred alcohols kind solvent, aromatic hydrocarbon solvent or esters solvent.Described alcoholic solvent preferred alcohol or Virahol, more preferably ethanol.The preferred toluene of described aromatic hydrocarbon solvent or dimethylbenzene.Described esters solvent ethyl acetate.The consumption of described solvent, for not affect the carrying out of reaction, is generally 5 ~ 10ml/g compound 4B.
In step 3), preferably 60 ~ 130 ℃ of the temperature of described reaction, more preferably 60 ~ 115 ℃.
In step 3), the process of described reaction can be monitored by TLC or HPLC, when the compound 4B of generally usining disappears as the terminal of reaction.Described reaction was preferably reacted and is reached terminal in 14 ~ 15 hours, that is, HPLC detection reaction architecture compound 4B disappears.
Preferably, after finishing, step 3) reaction also product 5B is carried out to aftertreatment, to be further purified compound 5B.Described aftertreatment preferably includes: cooling crystallization.Preferably 10 ~ 30 ℃ of described cooling temperature.
In the preparation method of described Archie husky smooth 1, in step 4), described solvent is the common solvent of this type of reaction of this area, can be organic solvent or water.Described organic solvent particular methanol and/or ethanol etc.The consumption of described solvent, for not affecting the polarity of reaction, is generally 2 ~ 10ml/g compound 5B.
In step 4), the oxyhydroxide of described alkali preferred as alkali.The described preferred sodium hydroxide of alkali-metal oxyhydroxide or potassium hydroxide.Described alkali can participate in reaction with the form of the aqueous solution.The volumetric molar concentration of described alkali is preferably 0.3 ~ 5mol/L.The mole dosage of described alkali is preferably 1 ~ 5 times of compound 5B.
In step 4), preferably 60 ~ 80 ℃ of the temperature of described reaction, more preferably 65 ~ 75 ℃.
In step 4), the process of described reaction can be monitored by TLC or HPLC, when the compound 5B of generally usining disappears as the terminal of reaction.Described reaction was preferably reacted and is reached terminal in 1 ~ 3 hour, that is, HPLC detection reaction architecture compound 5B disappears.
Preferably, after finishing, step 4) reaction also product 1 is carried out to aftertreatment, to be further purified compound 1.Described aftertreatment preferably includes: at 5 ~ 15 ℃, reaction system is mixed with acid, be adjusted to pH=3 ~ 4, filter.
The present invention also provides the preparation method of the husky smooth intermediate 3B of a kind of Archie, and its step comprises: in solvent, compound 2B is mixed with azanol, react, obtain compound 3B;
In the preparation method of the described husky smooth intermediate 3B of Archie, described solvent is generally polar aprotic solvent or polar aprotic solvent.Described polar aprotic solvent preferred alcohols solvent.Described alcoholic solvent particular methanol, ethanol or Virahol, more preferably ethanol or Virahol, most preferred ethanol.The preferred DMF of described polar aprotic solvent (DMF) or methyl-sulphoxide (DMSO).The consumption of described solvent for do not affect reaction normally, be generally 5 ~ 20ml/g compound 2B, preferably 8 ~ 11ml/g compound 2B.
Described azanol can participate in reaction with form or the solid form of the aqueous solution.When azanol participates in reaction with the aqueous solution, the concentration of the aqueous solution of described azanol is 10% ~ 50%(mass percent preferably).The molar weight of described azanol is preferably 5 ~ 25 times of compound 2B, preferably 8 ~ 15 times.
In the preparation method of the described husky smooth intermediate 3B of Archie, can also add organic bases.The preferred triethylamine of described organic bases, diisopropyl ethyl amine, diethylamine, Trimethylamine 99, pyridine or piperidines, preferably triethylamine or diisopropyl ethyl amine.The mole dosage of described organic bases is preferably 0.2 ~ 5 times of compound 2B, more preferably 0.5 ~ 1 times.
In the preparation method of the described husky smooth intermediate 3B of Archie, preferably 50 ~ 110 ℃ of temperature of reaction, more preferably 65 ~ 100 ℃, most preferably 75 ~ 95 ℃.
In the preparation method of the husky smooth intermediate 3B of described Archie, reaction process can be monitored by TLC or HPLC, when the compound 2B of generally usining disappears as the terminal of reaction.The present invention can reach the terminal of reaction in 5 ~ 10 hours, that is, in HPLC detection reaction system, compound 2B disappears.
Preferably, in the preparation method of the described husky smooth intermediate 3B of Archie, after finishing, reaction also product 3B is carried out to aftertreatment, to be further purified compound 3B.Described aftertreatment preferably includes cooling crystallization.Described cooling temperature is preferably 10 ~ 50 ℃, preferably 20 ~ 40 ℃.
The present invention also provides the preparation method of the husky smooth intermediate 4B of a kind of Archie, and its step comprises: in solvent, under the effect of alkali, compound 3B is mixed with chloro-formic ester, react, obtain compound 4B;
In the preparation method of the described husky smooth intermediate 4B of Archie, described solvent is generally organic solvent.The preferred aprotic solvent of described organic solvent.The preferred methylene dichloride of described aprotic solvent or chloroform, more preferably methylene dichloride.The consumption of described solvent for do not affect reaction normally, be generally 5 ~ 15ml/g compound 3B, preferably 7 ~ 10ml/g compound 3B.
In the preparation method of the described husky smooth intermediate 4B of Archie, the preferred organic bases of described alkali.The preferred triethylamine of described organic bases, diisopropyl ethyl amine, diethylamine, Trimethylamine 99, pyridine or piperidines, more preferably triethylamine, diisopropyl ethyl amine.The mole dosage of described alkali is preferably 1 ~ 5 times of compound 3B, more preferably 1 ~ 2 times.
In the preparation method of the described husky smooth intermediate 4B of Archie, the preferred C of R
1～C
4straight or branched alkyl.Described C
1～C
4straight or branched alkyl preferable methyl, ethyl or sec.-propyl.Described C
6~ C
10the preferred phenyl of aryl.
In the preparation method of the described husky smooth intermediate 4B of Archie, the mole dosage of described chloro-formic ester is preferably 1 ~ 3 times of compound 3B, more preferably 1 ~ 1.5 of compound 3B times.
In the preparation method of the described husky smooth intermediate 4B of Archie, preferably 10 ~ 40 ℃ of the temperature of described reaction, more preferably 20 ~ 35 ℃.
In the preparation method of the husky smooth intermediate 4B of described Archie, the process of described reaction can be monitored by TLC or HPLC, when the compound 3B of generally usining disappears as the terminal of reaction.Reaction of the present invention preferably reached terminal in 1.5 ~ 2 hours, that is, through HPLC detection compound 3B, disappear.
Preferably, in the preparation method of the described husky smooth intermediate 4B of Archie, after finishing, reaction also product 4B is carried out to aftertreatment, to be further purified compound 4B.Described aftertreatment preferably includes: reaction system is mixed with water, extract successively, be dried, filter, concentrate.Methylene dichloride is preferably used in described extraction.
The present invention also provides the preparation method of the husky smooth intermediate 5B of a kind of Archie, and its step comprises: in solvent, compound 4B is carried out to ring-closure reaction, obtain compound 5B;
In the preparation method of the described husky smooth intermediate 5B of Archie, described solvent can be the common solvent of this type of reaction of this area, preferred alcohols kind solvent, aromatic hydrocarbon solvent or esters solvent.Described alcoholic solvent preferred alcohol or Virahol, more preferably ethanol.The preferred toluene of described aromatic hydrocarbon solvent or dimethylbenzene.Described esters solvent ethyl acetate.The consumption of described solvent, for not affect the carrying out of reaction, is generally 5 ~ 10ml/g compound 4B.
In the preparation method of the described husky smooth intermediate 5B of Archie, preferably 60 ~ 130 ℃ of the temperature of described reaction, more preferably 60 ~ 115 ℃.
In the preparation method of the husky smooth intermediate 5B of described Archie, the process of described reaction can be monitored by TLC or HPLC, when the compound 4B of generally usining disappears as the terminal of reaction.Described reaction was preferably reacted and is reached terminal in 14 ~ 15 hours, that is, HPLC detection reaction architecture compound 4B disappears.
Preferably, in the preparation method of the described husky smooth intermediate 5B of Archie, after finishing, reaction also product 5B is carried out to aftertreatment, to be further purified compound 5B.Described aftertreatment preferably includes: cooling crystallization.Preferably 10 ~ 30 ℃ of described cooling temperature.
The present invention also provides following arbitrary reaction scheme:
Or,
Or,
Wherein, each step reaction condition all the same described in.
The present invention also provides a kind of midbody compound 3B, 4B or 5B;
Wherein, R as mentioned above.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is: the husky smooth preparation method's impurity of Archie of the present invention is less, the reaction times is short, process recovery ratio is higher, product purity is higher, is applicable to suitability for industrialized production.
Accompanying drawing explanation
The HPLC spectrogram of reaction solution when Fig. 1 is embodiment 1 reaction end;
The HPLC spectrogram of reaction solution when Fig. 2 is comparative example's 1 reaction end;
Fig. 3 is the husky smooth HPLC spectrogram of Archie that embodiment 13 prepares;
The husky smooth HPLC spectrogram of Archie that Fig. 4 prepares for comparative example 4.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to ordinary method and condition, or selects according to catalogue.
The preparation of compound (3B)
15.2 grams of raw materials (compound 2B), are placed in reaction flask, add ethanol 150ml, 3.6 grams of triethylamines, and 50% aqueous hydroxylamine 28ml, reaction 7h, cooling crystallization, obtains 14.1 grams of white solids (86.0%).Main amide impurities (compound 6B) in reaction solution when HPLC detection reaction finishes: product is that 2.55%:97.44%(impurity and product ratio are 1:38.2), see Fig. 1.
Table 1: in Fig. 1, HPLC detects data analysis
Mass spectrum shows: molecular ion peak [M+1] is 459.
1hNMR composes (DMSO-d6): δ ppm 1.1-1.3(3H, t), 1.3-1.4(3H, t), 3.2-3.3(2H), 4.1-4.3(2H, q), 4.5-4.7 (2H, q), 5.4-5.5(1H, s), 5.5-5.6 (2H, s), 6.9-7.8 (11H, m).
Fusing point: 210-212 ℃.
Impurity 6B
Mass spectrum shows: molecular ion peak [M+1] is 444;
Fusing point: 187-189 ℃.
The preparation of compound (3B)
15.0 grams of raw materials (compound 2B), are placed in reaction flask, add ethanol 150ml, triethylamine 1.8g(2.5mL), 50% aqueous hydroxylamine 30ml, reaction 10h, cooling crystallization, obtains 15.4 grams of white solids (95.2%).Main amide impurities (compound 6B) in reaction solution when HPLC detection reaction finishes: product is that 2.55%:97.44%(impurity and product ratio are 1:38.2), after cooling crystallization, HPLC detection product purity is: 98.49%.
Comparative example 1
The preparation of compound (3A)
20 grams of raw materials (compound 2A), are placed in reaction flask, add ethanol 200ml, 5 grams of triethylamines, and 50% 37 grams of aqueous hydroxylamines, reaction 24h, cooling crystallization, obtains 13.6 grams of white solids (63.0%).Main amide impurities (compound 6A) in reaction solution when HPLC detection reaction finishes: product is that 7.15%:92.84%(impurity and product ratio are 1:12.9), see Fig. 2.
Table 2: in Fig. 2, HPLC detects data analysis
Mass spectrum shows: molecular ion peak [M+1] is 459.
Fusing point: 196-198 ℃.
Embodiment 3:
The preparation of compound (3B)
7.5 grams of raw materials (compound 2B), are placed in reaction flask, add ethanol 50ml, 50% aqueous hydroxylamine 15ml, and reaction 10h, cooling crystallization, obtains 6.2 grams of white solids (76.0%).Main amide impurities (compound 6B) in HPLC detection reaction liquid: product is 12.16%:87.83%
Embodiment 4
The preparation of compound (3B)
15.0 grams of raw materials (compound 2B), are placed in reaction flask, add ethanol 150ml, triethylamine 10ml, and 50% aqueous hydroxylamine 31ml, reaction 10h, cooling crystallization, obtains 13.1 grams of white solids (81.0%).
Embodiment 5
The preparation of compound (3B)
15.2 grams of raw materials (compound 2B), are placed in reaction flask, add ethanol 150ml, 4.6 grams of diisopropyl ethyl amines, and 50% aqueous hydroxylamine 22ml, reaction 8h, cooling crystallization, obtains 14.3 grams of white solids (87.3%)
Embodiment 6
The preparation of compound (3B)
According to document Inorganic Syntheses, 1939, vol1, page87 method prepares azanol solid.
15.2 grams of raw materials (compound 2B), are placed in reaction flask, add ethanol 150ml, 4.6 grams of diisopropyl ethyl amines, and 12 grams of azanol solids, reaction 8h, cooling crystallization, obtains 13.9 grams of white solids (84.8%)
Embodiment 7
The preparation of compound (4B, R=methyl)
11.8 grams of compounds (3B), are placed in reaction flask, add methylene dichloride 100ml, and triethylamine 5.4ml drips 3.0 grams of methyl-chloroformates, reacts 2 hours under room temperature.Add water 60ml, stir layering, separate dichloromethane layer, water layer is used dichloromethane extraction again, combined dichloromethane layer, and anhydrous sodium sulfate drying, filters, and concentrates to obtain crude product, refining solid 11.9, the yield 90% of obtaining.
Mass spectrum shows: molecular ion peak [M+1] is 517.
1hNMR composes (DMSO-d6): δ ppm 1.1-1.2(3H, t), 1.3-1.4(3H, t), 3.7-3.8(3H, s), 4.1-4.3(2H, q), 4.5-4.7 (2H, q), 5.5-5.6(2H, s), 6.4-6.5 (2H, broad peak), 6.9-7.8 (11H, m).
Fusing point: 150-153 ℃.
Comparative example 2
The preparation of compound 4A
9.5 grams of compounds (3A), are placed in reaction flask, add methylene dichloride 100ml, and triethylamine 5ml drips 2.5 grams of methyl-chloroformates, reacts 2 hours under room temperature.Add water 60ml, stir layering, separate dichloromethane layer, water layer is used dichloromethane extraction again, combined dichloromethane layer, and anhydrous sodium sulfate drying, filters, and concentrates to obtain crude product, refining solid 8.2, the yield 79% of obtaining.
Mass spectrum shows: molecular ion peak [M+1] is 503.
Fusing point: 157-159 ℃.
The preparation of compound (4B, R=ethyl)
11.8 grams of compounds (3B), are placed in reaction flask, add methylene dichloride 100ml, and triethylamine 5.4ml drips 3.4 grams of Vinyl chloroformates, reacts 2 hours under room temperature.Add water 60ml, stir layering, separate dichloromethane layer, water layer is used dichloromethane extraction again, combined dichloromethane layer, and anhydrous sodium sulfate drying, filters, and concentrates to obtain crude product, refining solid 11.2, the yield 82.0% of obtaining.
Mass spectrum shows: molecular ion peak [M+1] is 531
1hNMR composes (DMSO-d6): δ ppm 1.0-1.3(6H, m), 1.3-1.4(3H, t), 4.0-4.3(4H, m) and, 4.5-4.7 (2H, q), 5.5-5.6(2H, s), 6.4-6.6 (2H, broad peak), 6.9-7.8 (11H, m).
Fusing point: 145-147 ℃.
Embodiment 9
The preparation of compound (4B, R=sec.-propyl)
11.8 grams of compounds (3B), are placed in reaction flask, add methylene dichloride 100ml, and triethylamine 5.4ml drips 3.8 grams of isopropyl chlorocarbonates, reacts 2 hours under room temperature.Add water 60ml, stir layering, separate dichloromethane layer, water layer is used dichloromethane extraction again, combined dichloromethane layer, and anhydrous sodium sulfate drying, filters, and concentrates to obtain crude product, refining solid 12.0, the yield 85.7% of obtaining.
Mass spectrum shows: molecular ion peak [M+1] is 545.
The preparation of compound (5B)
9 grams of compounds (4B, R=methyl), are placed in reaction flask, add ethanol 60ml to reflux 15 hours, and cooling crystallization obtains solid 7.2, yield 85.7%.
Mass spectrum shows: molecular ion peak [M+1] is 485.
1hNMR composes (DMSO-d6): δ ppm 1.0-1.2(3H, t), 1.3-1.4(3H, t), 4.1-4.3(2H, q) and, 4.5-4.7 (2H, q), 5.5-5.6(2H, s), 6.9-7.8 (11H, m).
Fusing point: 176-178 ℃.
Comparative example 3
The preparation of compound (5A)
3.59 grams of compounds (4A, R=methyl), are placed in reaction flask, add ethanol 45ml to reflux 22 hours, and cooling crystallization obtains 2.7 grams of solids, yield 80.3%.
Mass spectrum shows: molecular ion peak [M+1] is 471.
Fusing point: 183-185 ℃.
Embodiment 11
The preparation of compound (5B)
9 grams of compounds (4B, R=ethyl), are placed in reaction flask, add ethanol 60ml to reflux 15 hours, and cooling crystallization obtains solid 7.3, yield 89.0%.
Mass spectrum shows: molecular ion peak [M+1] is 485.
Fusing point: 176-178 ℃.
Embodiment 12
The preparation of compound (5B)
9 grams of compounds (4B, R=sec.-propyl), are placed in reaction flask, add ethanol 60ml to reflux 15 hours, and cooling crystallization obtains solid 6.5, yield 81.2%.
Mass spectrum shows: molecular ion peak [M+1] is 485.
Embodiment 13
The husky smooth preparation of Archie
5 grams of compounds (5B), are placed in reaction flask, add 0.4mol/L sodium hydroxide 80ml, and 73-75 ℃ is reacted 2 hours.After reaction finishes, be cooled to room temperature, drip aqueous acid to pH3-4, separate out white solid 4.1g, 87.2%.
Mass spectrum shows: molecular ion peak [M+1] is 457.
1hNMR composes (DMSO-d6): δ ppm 1.2-1.3(3H, t), 4.4-4.6 (2H, q), 5.5-5.6 (2H, s), 6.9-7.6 (11H, m).
The husky smooth results of elemental analyses of table 3 Archie
| Ultimate analysis | Measured value | Theoretical value |
| C | 65.55 | 65.78 |
| H | 4.37 | 4.42 |
| N | 12.09 | 12.27 |
HPLC detects the husky smooth purity (area normalization method) of the Archie obtaining: 100%, see Fig. 3.Fusing point: 189-191 ℃.
In table 4 Fig. 3, HPLC detects data analysis
Embodiment 14
The husky smooth preparation of Archie
5 grams of compounds (5B), are placed in reaction flask, add 0.4mol/L sodium hydroxide 80ml, and 73-75 ℃ is reacted 2 hours.After reaction finishes, be cooled to room temperature, drip aqueous acid to pH=3-4, separate out white solid 4.1g, 87.2%.
The husky smooth preparation of Archie
5 grams of compounds (5B), are placed in reaction flask, add ethanol 30ml, drip 2.5mol/L sodium hydroxide 13ml, and 73-75 ℃ is reacted 1.6 hours.After reaction finishes, be cooled to room temperature, drip aqueous acid to pH=3-4, separate out white solid 4.2g, 89.3%.
Comparative example 4
The husky smooth preparation of Archie
2.0 grams of compounds (5A), are placed in reaction flask, add 0.4mol/L sodium hydroxide 32ml, and 73-75 ℃ is reacted 2 hours.After reaction finishes, be cooled to room temperature, drip aqueous acid to pH=3-4, separate out white solid 1.5g, 77.4%.
Mass spectrum shows: molecular ion peak [M+1] is 457.
Fusing point 190-192 ℃.
HPLC detects the husky smooth purity (area normalization method) of the Archie obtaining: 99.45%, see Fig. 4.
In table 5 Fig. 4, HPLC detects data analysis
According to above-mentioned research, can learn that the Archie sand of preparing through 5B is smooth, product purity is high, and HPLC purity (area normalization method) is 100%, without single contaminant, sees Fig. 3.And it is smooth to prepare Archie sand through 5A, product has the impurity that is difficult to removal, and product HPLC purity (area normalization method) is 99.45%, has two larger impurity, is respectively 0.25%, 0.17%, sees Fig. 4.
Claims (14)
1. a preparation method for Archie husky smooth 1, is characterized in that comprising the following steps:
1) in solvent, compound 2B is mixed with azanol, react, obtain compound 3B;
2), in solvent, under the effect of alkali, the compound 3B that step 1) is made mixes with chloro-formic ester, reacts, and obtains compound 4B;
3) in solvent, by step 2) the compound 4B that makes carries out ring-closure reaction, obtains compound 5B;
4) in solvent, under the effect of alkali, the compound 5B that step 3) is made carries out ester hydrolysis reaction, obtains Archie husky smooth 1;
Wherein, R is C
6~ C
10aryl or C
1~ C
4straight or branched alkyl.
2. the preparation method of Archie as claimed in claim 1 husky smooth 1, is characterized in that: in step 1), described solvent is polar aprotic solvent or polar aprotic solvent; Described polar aprotic solvent is alcoholic solvent; Described alcoholic solvent is methyl alcohol, ethanol or Virahol; Described polar aprotic solvent is DMF or methyl-sulphoxide.
3. the preparation method of Archie as claimed in claim 1 husky smooth 1, is characterized in that: in step 1), described azanol participates in reaction with form or the solid form of the aqueous solution; The molar weight of described azanol is 5 ~ 25 times of compound 2B.
4. the preparation method of Archie as claimed in claim 1 husky smooth 1, is characterized in that: in the reaction of step 1), also add organic bases; Described organic bases is triethylamine, diisopropyl ethyl amine, diethylamine, Trimethylamine 99, pyridine or piperidines; The mole dosage of described organic bases is 0.2 ~ 5 times of compound 2B.
5. the preparation method of Archie as claimed in claim 1 husky smooth 1, is characterized in that: the temperature of reaction of step 1) is 50 ~ 110 ℃; The time of described reaction is 5 ~ 10 hours.
6. the preparation method of Archie as claimed in claim 1 husky smooth 1, is characterized in that: step 2) in, described alkali is organic bases; Described organic bases is triethylamine, diisopropyl ethyl amine, diethylamine, Trimethylamine 99, pyridine or piperidines; The mole dosage of described alkali is 1 ~ 5 times of compound 3B; The mole dosage of described chloro-formic ester is 1 ~ 3 times of compound 3B; Step 2), in, the temperature of described reaction is 10 ~ 40 ℃; Step 2), in, the time of described reaction is 1.5 ~ 2 hours.
7. the preparation method of Archie as claimed in claim 1 husky smooth 1, is characterized in that: described C
1~ C
4straight or branched alkyl be methyl, ethyl or sec.-propyl; Described C
6~ C
10aryl be phenyl.
8. the preparation method of Archie as claimed in claim 1 husky smooth 1, is characterized in that: in step 3), described solvent is alcoholic solvent, aromatic hydrocarbon solvent or esters solvent; Described alcoholic solvent is ethanol or Virahol; Described aromatic hydrocarbon solvent is toluene or dimethylbenzene; Described esters solvent is ethyl acetate.
9. the preparation method of Archie as claimed in claim 1 husky smooth 1, is characterized in that: in step 3), the temperature of described reaction is 60 ~ 130 ℃; In step 3), the time of described reaction is 14 ~ 15 hours.
10. the preparation method of Archie as claimed in claim 1 husky smooth 1, is characterized in that: in step 4), described solvent is organic solvent or water; Described organic solvent is methyl alcohol and/or ethanol; In step 4), described alkali is alkali-metal oxyhydroxide; Described alkali-metal oxyhydroxide is sodium hydroxide or potassium hydroxide; In step 4), described alkali participates in reaction with the form of the aqueous solution; In step 4), the mole dosage of described alkali is 1 ~ 5 times of compound 5B; In step 4), the temperature of described reaction is 60 ~ 80 ℃; In step 4), the time of described reaction is 1 ~ 3 hour.
The preparation method of 11. 1 kinds of husky smooth intermediate 5B of Archie, is characterized in that comprising the following steps:, in solvent, compound 4B being carried out to ring-closure reaction, obtains compound 5B;
Wherein, each reaction conditions of preparing compound 5B by compound 4B is all described in step 3) as claimed in claim 1, claim 7 ~ 9 any one.
The preparation method of the husky smooth intermediate 5B of 12. Archie as claimed in claim 11, characterized by further comprising the following step: in solvent, under the effect of alkali, compound 3B is mixed with chloro-formic ester, react, obtain compound 4B;
Wherein, each reaction conditions step 2 all as claimed in claim 1 of being prepared compound 4B by compound 3B), described in claim 6 or claim 7.
The preparation method of the husky smooth intermediate 5B of 13. Archie as claimed in claim 12, characterized by further comprising the following step: in solvent, compound 2B is mixed with azanol, react, obtain compound 3B;
Wherein, each reaction conditions of preparing compound 3B by compound 2B is all described in step 1) as claimed in claim 1 or claim 2 ~ 5 any one.
14. 1 kinds of compound 5B,
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| CN104803998A (en) * | 2015-03-26 | 2015-07-29 | 晋江市托美汀生物科技有限公司 | Impurity content decreasing method |
| WO2016058563A1 (en) * | 2014-10-15 | 2016-04-21 | Zentiva, K.S. | A process for preparing highly pure azilsartan |
| WO2018008219A1 (en) * | 2016-07-05 | 2018-01-11 | 株式会社トクヤマ | Azilsartan intermediate, azilsartan, method for producing azilsartan intermediate, and method for producing azilsartan |
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| JP2018002672A (en) * | 2016-07-05 | 2018-01-11 | 株式会社トクヤマ | Manufacturing method of amidoxime compound which become intermediate of azilsartan, and manufacturing method of azilsartan |
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