CN103664793B - Azilsartan intermediate and preparation method thereof - Google Patents
Azilsartan intermediate and preparation method thereof Download PDFInfo
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract
The invention discloses an azilsartan intermediate and a preparation method thereof. The preparation method comprises the following step: in a solvent, mixing a compound 3B with chloroformate to react under the action of alkali to obtain a compound 4B. 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 medicinal chemistry art, and in particular to a kind of to be used to synthesize antihypertensive drug Azilsartan
The intermediate of (Azilsartan compounds 1) and preparation method thereof.
Background technology
Azilsartan is the antihypertensive drug of newest listing, and by Japanese force field pharmacy exploitation, on January 28th, 2012 is in day
Originally get the Green Light.Azilsartan is a kind of selective Angiotensin Ⅱ receptor antagonist, competitive reversibly can be blocked
The combination of angiotensin and AT1 receptors, plays the effect of reducing blood pressure, and is 10,000 to AT2 receptors to the affinity of AT1 receptors
Times more than, as which does not suppress ACE, therefore do not interfere with Kallidin I level, also will not with reference to and block other and regulation of blood vessels
The related receptor of effect or ion channel.Azilsartan is that Olmesartan and blood vessel are tight with human body AT1 receptor binding capacities respectively
Open element II 2 times and 30 times.Clinical studies show Azilsartan curative effect is better than candesartan Cilexetil, Valsartan and olmesartan medoxomil.
It is better with diuretic compound antihypertensive.
Compound patent application number 92105152.2 describes the preparation of Azilsartan and therapeutic use.Concrete synthetic route
It is as follows：
Compound 2A, i.e. 2- ethyoxyls -1- [(2 '-cyanobiphenyl -4- bases) methyl] -1H- benzimidazole -7- carboxylate methyl esters
It is the raw material for synthesizing candesartan Cilexetil, it is commercial conveniently to obtain.In above-mentioned route, 2- ethyoxyl -1- [(((2 '-hydroxyls
Base amine azomethine) xenyl) -4- bases) methyl] -1H- benzimidazole -7- carboxylate methyl esters equivalent to compound 3A be synthesis difficult point.
The preparation method of compound 3A is described in publication J.Med.Chem, and 1996,39 (26):5528-5235, China
In many documents such as number of patent application 201010245420.J.Med.Chem,1996,39(26):It is by chemical combination in 5528-5235
Thing 2A, i.e. 2- ethyoxyls -1- [(2 '-cyanobiphenyl -4- bases) methyl] -1H- benzimidazole -7- carboxylate methyl esters oxammonium hydrochloride.,
Under triethylamine effect, 60 hours prepared compound 3A are reacted in dimethyl sulfoxide, while can produce and object considerable amount ofization
Compound 6A impurity, response time are long, and impurity is more.Chinese patent（Application number 201010245420）In this is improved, will
Compound 2A is reacted with 50% aqueous hydroxylamine solution, and yield highest is carried to 71.7%, but its response time is very long, need 24h ~
40h, reactant liquor HPLC collection of illustrative plates shows amide impurities 6A：Compound 3A：Compound 2=5.04：79.66：0, but other impurity do not retouch
State.
In view of the defect of above synthetic method, it is necessary to which the synthetic method of Azilsartan is furtherd investigate.
The content of the invention
The technical problem to be solved is, in order to the preparation method for overcoming Azilsartan in prior art has
The defect such as process recovery ratio low, impurity is more, response time length, there is provided a kind of Azilsartan intermediate and preparation method thereof.This
The preparation method impurity of bright Azilsartan is less, the response time is short, process recovery ratio is higher, product purity is higher, it is adaptable to work
Industry metaplasia is produced.
The invention provides a kind of preparation method of Azilsartan 1, which comprises the following steps：
1）In solvent, compound 2B is mixed with azanol, is reacted, obtain compound 3B；
2）In solvent, in the presence of alkali, by step 1）Obtained compound 3B is mixed with chloro-formate, is reacted,
Obtain compound 4B；
3）In solvent, by step 2）Obtained compound 4B carries out ring-closure reaction, obtains compound 5B；
4）In solvent, in the presence of alkali, by step 3）Obtained compound 5B carries out ester hydrolysis reaction, obtains Archie husky
Smooth 1；
Wherein, R is C6~C10Aryl or C1~C4Straight or branched alkyl.
In the preparation method of described Azilsartan 1, step 1）In, described solvent is generally polar aprotic solvent or pole
Property aprotic solvent.The preferred alcoholic solvent of described polar aprotic solvent.The preferred methanol of described alcoholic solvent, ethanol or isopropanol,
More preferably ethanol or isopropanol, most preferred ethanol.The preferred N,N-dimethylformamide of described polar aprotic solvent（DMF）
Or dimethyl sulfoxide（DMSO）.The consumption of described solvent is not affect that what is reacted to be normally carried out, generally 5 ~ 20ml/gization
Compound 2B, preferably 8 ~ 11ml/g compound 2B.
Described azanol can in form of an aqueous solutions or solid form participate in reaction.When azanol participates in reacting with aqueous solution
When, the concentration preferably 10% ~ 50% of the aqueous solution of the azanol（Mass percent）.The mole of described azanol is preferably chemical combination
5 ~ 25 times of thing 2B, preferably 8 ~ 15 times.
Described step 1）Reaction in, organic base can also be added.The preferred triethylamine of described organic base, diisopropyl
Ethylamine, diethylamine, trimethylamine, pyridine or piperidines, preferred triethylamine or diisopropyl ethyl amine.Described organic base mole
Consumption is preferably 0.2 ~ 5 times, more preferably 0.5 ~ 1 times of compound 2B.
Described step 1）Preferably 50 ~ 110 DEG C, more preferably 65 ~ 100 DEG C, most preferably 75 ~ 95 DEG C of reaction temperature.
Described step 1）Reaction process can be monitored by TLC or HPLC, when typically being disappeared with compound 2B make
For the terminal of reaction.The present invention can reach the terminal of reaction in 5 ~ 10 hours, i.e. chemical combination in Jing HPLC detection reaction systems
Thing 2B disappears.
It is preferred that step 1）Reaction also carries out post processing to product 3B after terminating, to be further purified compound 3B.It is described
Post processing preferably include cooling crystallization.The temperature of described cooling is preferably 10 ~ 50 DEG C, preferably 20 ~ 40 DEG C.
In the preparation method of described Azilsartan 1, step 2）In, described solvent is generally organic solvent.Described
The preferred aprotic solvent of organic solvent.The preferred dichloromethane of described aprotic solvent or chloroform, more preferably dichloromethane.It is described
Solvent consumption be do not affect react be normally carried out, generally 5 ~ 15ml/g compound 3B, preferably 7 ~ 10ml/gization
Compound 3B.
Step 2）In, the preferred organic base of described alkali.The preferred triethylamine of described organic base, diisopropyl ethyl amine, two
Ethamine, trimethylamine, pyridine or piperidines, more preferably triethylamine, diisopropyl ethyl amine.The mole dosage of described alkali is preferably changed
1 ~ 5 times of compound 3B, more preferably 1 ~ 2 times.
Step 2）In, the preferred C of R1~C4Straight or branched alkyl.Described C1~C4The preferred first of straight or branched alkyl
Base, ethyl or isopropyl.Described C6~C10The preferred phenyl of aryl.
Step 2）In, the mole dosage of described chloro-formate is preferably 1 ~ 3 times of compound 3B, more preferably compound
1 ~ 1.5 times of 3B.
Step 2）In, preferably 10 ~ 40 DEG C, more preferably 20 ~ 35 DEG C of the temperature of described reaction.
Step 2）In, the process of described reaction can be monitored by TLC or HPLC, typically disappeared with compound 3B
The terminal of Shi Zuowei reactions.The reaction of the present invention preferably reached terminal in 1.5 ~ 2 hours, i.e. Jing HPLC detection compounds 3B
Disappear.
It is preferred that step 2）Reaction also carries out post processing to product 4B after terminating, to be further purified compound 4B.It is described
Post processing preferably include：Reaction system is mixed with water, is carried out successively extracting, is dried, filters, concentrating.Described extraction
Take.
In the preparation method of described Azilsartan 1, step 3）In, described solvent can be the normal of the such reaction in this area
With solvent, preferred alcohols solvent, aromatic hydrocarbon solvent or esters solvent.Described alcohols solvent preferred alcohol or isopropanol,
More preferably ethanol.The preferred toluene of described aromatic hydrocarbon solvent or dimethylbenzene.Described esters solvent ethyl acetate.It is described
Solvent consumption be do not affect react carrying out, generally 5 ~ 10ml/g compound 4B.
Step 3）In, preferably 60 ~ 130 DEG C, more preferably 60 ~ 115 DEG C of the temperature of described ring-closure reaction.
Step 3）In, the process of described ring-closure reaction can be monitored by TLC or HPLC, typically disappeared with compound 4B
As the terminal for reacting during mistake.Described ring-closure reaction preferably reacted in 14 ~ 15 hours and reaches terminal, i.e. HPLC detections are anti-
System compound 4B is answered to disappear.
It is preferred that step 3）Reaction also carries out post processing to product 5B after terminating, to be further purified compound 5B.It is described
Post processing preferably include：Cooling crystallization.Preferably 10 ~ 30 DEG C of the temperature of described cooling.
In the preparation method of described Azilsartan 1, step 4）In, described solvent is the conventional of the such reaction in this area
Solvent, can be organic solvent or water.The preferred methanol of described organic solvent and/or ethanol etc..The consumption of described solvent is
Do not affect the polarity reacted, generally 2 ~ 10ml/g compound 5B.
Step 4）In, the hydroxide of described alkali preferred as alkali.The described preferred hydrogen-oxygen of alkali-metal hydroxide
Change sodium or potassium hydroxide.Described alkali can participate in reaction in form of an aqueous solutions.The 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.
Step 4）In, preferably 60 ~ 80 DEG C, more preferably 65 ~ 75 DEG C of the temperature of described reaction.
Step 4）In, the process of described reaction can be monitored by TLC or HPLC, when typically being disappeared with compound 5B
As the terminal of reaction.Described reaction was preferably reacted in 1 ~ 3 hour and reaches terminal, i.e. HPLC detects reaction system chemical combination
Thing 5B disappears.
It is preferred that step 4）Reaction also carries out post processing to product 1 after terminating, to be further purified compound 1.Described
Post processing is preferably included：At 5 ~ 15 DEG C, reaction system is mixed with acid, adjust to pH=3 ~ 4, filter.
Present invention also offers a kind of preparation method of Azilsartan intermediate 3B, its step includes：In solvent, by chemical combination
Thing 2B is mixed with azanol, is reacted, and obtains compound 3B；
In the preparation method of described Azilsartan intermediate 3B, described solvent is generally polar aprotic solvent or polarity
Aprotic solvent.The preferred alcoholic solvent of described polar aprotic solvent.The preferred methanol of described alcoholic solvent, ethanol or isopropanol, more
Preferred alcohol or isopropanol, most preferred ethanol.The preferred N,N-dimethylformamide of described polar aprotic solvent（DMF）Or
Dimethyl sulfoxide（DMSO）.The consumption of described solvent is not affect that what is reacted to be normally carried out, generally 5 ~ 20ml/g chemical combination
Thing 2B, preferably 8 ~ 11ml/g compound 2B.
Described azanol can in form of an aqueous solutions or solid form participate in reaction.When azanol participates in reacting with aqueous solution
When, the concentration preferably 10% ~ 50% of the aqueous solution of the azanol（Mass percent）.The mole of described azanol is preferably chemical combination
5 ~ 25 times of thing 2B, preferably 8 ~ 15 times.
In the preparation method of described Azilsartan intermediate 3B, organic base can also be added.Described organic base is preferred
Triethylamine, diisopropyl ethyl amine, diethylamine, trimethylamine, pyridine or piperidines, preferred triethylamine or diisopropyl ethyl amine.Institute
The mole dosage of the organic base stated is preferably 0.2 ~ 5 times, more preferably 0.5 ~ 1 times of compound 2B.
In the preparation method of described Azilsartan intermediate 3B, preferably 50 ~ 110 DEG C of reaction temperature, more preferably 65 ~ 100
DEG C, most preferably 75 ~ 95 DEG C.
In the preparation method of described Azilsartan intermediate 3B, reaction process can be monitored by TLC or HPLC, and one
As using compound 2B disappear when as reaction terminal.The present invention can reach the terminal of reaction in 5 ~ 10 hours, i.e. Jing
In HPLC detection reaction systems, compound 2B disappears.
It is preferred that in the preparation method of described Azilsartan intermediate 3B, after reaction is also carried out to product 3B after terminating
Process, to be further purified compound 3B.Described post processing preferably includes cooling crystallization.The temperature of described cooling is preferably
10 ~ 50 DEG C, preferably 20 ~ 40 DEG C.
Present invention also offers a kind of preparation method of Azilsartan intermediate 4B, its step includes：In solvent, in alkali
Under effect, compound 3B is mixed with chloro-formate, is reacted, obtain compound 4B；
In the preparation method of described Azilsartan intermediate 4B, described solvent is generally organic solvent.Described has
The preferred aprotic solvent of machine solvent.The preferred dichloromethane of described aprotic solvent or chloroform, more preferably dichloromethane.Described
The consumption of solvent is not affect that what is reacted to be normally carried out, generally 5 ~ 15ml/g compound 3B, preferably 7 ~ 10ml/g chemical combination
Thing 3B.
In the preparation method of described Azilsartan intermediate 4B, the preferred organic base of described alkali.Described organic base is excellent
Select triethylamine, diisopropyl ethyl amine, diethylamine, trimethylamine, pyridine or piperidines, more preferably triethylamine, diisopropyl ethyl amine.
The mole dosage of described alkali is preferably 1 ~ 5 times, more preferably 1 ~ 2 times of compound 3B.
In the preparation method of described Azilsartan intermediate 4B, the preferred C of R1～C4Straight or branched alkyl.Described
C1～C4The preferred methyl of straight or branched alkyl, ethyl or isopropyl.Described C6~C10The preferred phenyl of aryl.
In the preparation method of described Azilsartan intermediate 4B, the mole dosage of described chloro-formate is preferably chemical combination
1 ~ 3 times of thing 3B, more preferably the 1 ~ 1.5 of compound 3B times.
In the preparation method of described Azilsartan intermediate 4B, preferably 10 ~ 40 DEG C of the temperature of described reaction, more preferably
20~35℃。
In the preparation method of described Azilsartan intermediate 4B, the process of described reaction can pass through TLC or HPLC
It is monitored, as the terminal for reacting when typically being disappeared using compound 3B.The reaction of the present invention was preferably reached in 1.5 ~ 2 hours
Terminal, i.e. Jing HPLC detection compounds 3B disappear.
It is preferred that in the preparation method of described Azilsartan intermediate 4B, after reaction is also carried out to product 4B after terminating
Process, to be further purified compound 4B.Described post processing is preferably included：Reaction system is mixed with water, is extracted successively
Take, be dried, filter, concentrate.Dichloromethane is preferably used in described extraction.
Present invention also offers a kind of preparation method of Azilsartan intermediate 5B, its step includes：In solvent, by chemical combination
Thing 4B carries out ring-closure reaction, obtains compound 5B；
In the preparation method of described Azilsartan intermediate 5B, described solvent can be the conventional of the such reaction in this area
Solvent, preferred alcohols solvent, aromatic hydrocarbon solvent or esters solvent.Described alcohols solvent preferred alcohol or isopropanol, more
Preferred alcohol.The preferred toluene of described aromatic hydrocarbon solvent or dimethylbenzene.Described esters solvent ethyl acetate.Described
The consumption of solvent be do not affect react carrying out, generally 5 ~ 10ml/g compound 4B.
In the preparation method of described Azilsartan intermediate 5B, preferably 60 ~ 130 DEG C of the temperature of described reaction is more excellent
Select 60 ~ 115 DEG C.
In the preparation method of described Azilsartan intermediate 5B, the process of described reaction can be entered by TLC or HPLC
Row monitoring, as the terminal for reacting when typically being disappeared using compound 4B.Described reaction was preferably reacted in 14 ~ 15 hours and is reached
Terminal, i.e. HPLC detection reaction system compound 4B disappear.
It is preferred that in the preparation method of described Azilsartan intermediate 5B, after reaction is also carried out to product 5B after terminating
Process, to be further purified compound 5B.Described post processing is preferably included：Cooling crystallization.The temperature of described cooling is preferred
10~30℃。
Present invention also offers following any bar reaction schemes：
Or,
Or,
Wherein, each step reaction condition is the same as those described above.
Present invention also offers a kind of midbody compound 3B, 4B or 5B；
Wherein, R is as described above.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can combination in any, obtain final product the present invention each preferably
Example.
Agents useful for same of the present invention and raw material are commercially available.
The present invention positive effect be：The Azilsartan of the present invention preparation method impurity is less, the response time
Short, process recovery ratio is higher, product purity is higher, it is adaptable to industrialized production.
Description of the drawings
Fig. 1 is the HPLC spectrograms of reactant liquor at the end of embodiment 1 is reacted；
Fig. 2 is the HPLC spectrograms of reactant liquor at the end of comparative example 1 reacts；
Fig. 3 is the HPLC spectrograms of the Azilsartan that embodiment 13 is prepared；
Fig. 4 is the HPLC spectrograms of the Azilsartan that comparative example 4 prepares.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Among applying a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product description is selected.
Embodiment 1
Compound（3B）Preparation
Raw material（Compound 2B）15.2 grams, it is placed in reaction bulb, adds ethanol 150ml, 3.6 grams of triethylamine, 50% azanol water
Solution 28ml, reacts 7h, and cooling crystallization obtains 14.1 grams of white solid（86.0%）.It is main in reactant liquor at the end of HPLC detection reactions
Want amide impurities（Compound 6B）：Product is 2.55%：97.44%（I.e. impurity and product ratio are 1：38.2）, see Fig. 1.
Table 1：HPLC detection datas analysis in Fig. 1
Mass spectrum shows：Molecular ion peak [M+1] is 459.
1HNMR is composed（DMSO-d6）：δppm 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℃.
Embodiment 2
Compound（3B）Preparation
Raw material（Compound 2B）15.0 grams, it is placed in reaction bulb, adds ethanol 150ml, triethylamine 1.8g（2.5mL）, 50%
Aqueous hydroxylamine solution 30ml, reacts 10h, and cooling crystallization obtains 15.4 grams of white solid（95.2%）.It is anti-at the end of HPLC detection reactions
Answer main amide impurities in liquid（Compound 6B）：Product is 2.55%：97.44%（I.e. impurity and product ratio are 1：38.2）, it is cold
But after crystallize, HPLC detections product purity is：98.49%.
Comparative example 1
Compound（3A）Preparation
Raw material（Compound 2A）20 grams, it is placed in reaction bulb, adds ethanol 200ml, 5 grams of triethylamine, 50% aqueous hydroxylamine solution
37 grams, 24h is reacted, cooling crystallization obtains 13.6 grams of white solid（63.0%）.It is main in reactant liquor at the end of HPLC detection reactions
Amide impurities（Compound 6A）：Product is 7.15%：92.84%（I.e. impurity and product ratio are 1：12.9）, see Fig. 2.
Table 2：HPLC detection datas analysis in Fig. 2
Mass spectrum shows：Molecular ion peak [M+1] is 459.
Fusing point：196-198℃.
Embodiment 3：
Compound（3B）Preparation
Raw material（Compound 2B）7.5 grams, it is placed in reaction bulb, adds ethanol 50ml, 50% aqueous hydroxylamine solution 15ml, reaction
10h, cooling crystallization obtain 6.2 grams of white solid（76.0%）.Main amide impurities (compound 6B) in HPLC detection reactant liquors：Produce
Thing is 12.16%：87.83%.
Embodiment 4
Compound（3B）Preparation
Raw material（Compound 2B）15.0 grams, it is placed in reaction bulb, adds the azanol water of ethanol 150ml, triethylamine 10ml, 50%
Solution 31ml, reacts 10h, and cooling crystallization obtains 13.1 grams of white solid（81.0%）.
Embodiment 5
Compound（3B）Preparation
Raw material（Compound 2B）15.2 grams, it is placed in reaction bulb, addition ethanol 150ml, 4.6 grams of diisopropyl ethyl amine,
50% aqueous hydroxylamine solution 22ml, reacts 8h, and cooling crystallization obtains 14.3 grams of white solid（87.3%）
Embodiment 6
Compound（3B）Preparation
According to document Inorganic Syntheses, 1939, vol1, page87 methods prepare azanol solid.
Raw material（Compound 2B）15.2 grams, it is placed in reaction bulb, addition ethanol 150ml, 4.6 grams of diisopropyl ethyl amine,
12 grams of azanol solid, reacts 8h, and cooling crystallization obtains 13.9 grams of white solid（84.8%）
Embodiment 7
Compound（4B, R=methyl）Preparation
Compound（3B）11.8 grams, it is placed in reaction bulb, adds dichloromethane 100ml, triethylamine 5.4ml Deca chloro-carbonic acids
3.0 grams of methyl ester, reacts 2 hours under room temperature.Water 60ml, stirring layering is added to separate dichloromethane layer, water layer uses dichloromethane again
Extract, combined dichloromethane layer, anhydrous sodium sulfate drying, filter, be concentrated to give crude product, be refining to obtain solid 11.9, yield 90%.
Mass spectrum shows：Molecular ion peak [M+1] is 517.
1HNMR is composed（DMSO-d6）：δppm 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
Compound（3A）9.5 grams, it is placed in reaction bulb, adds dichloromethane 100ml, triethylamine 5ml Deca chloro-carbonic acid first
2.5 grams of ester, reacts 2 hours under room temperature.Water 60ml, stirring layering is added to separate dichloromethane layer, water layer is carried with dichloromethane again
Take, combined dichloromethane layer, anhydrous sodium sulfate drying, filter, be concentrated to give crude product, be refining to obtain solid 8.2, yield 79%.
Mass spectrum shows：Molecular ion peak [M+1] is 503.
Fusing point：157-159℃.
Embodiment 8
Compound（4B, R=ethyl）Preparation
Compound（3B）11.8 grams, it is placed in reaction bulb, adds dichloromethane 100ml, triethylamine 5.4ml Deca chloro-carbonic acids
3.4 grams of ethyl ester, reacts 2 hours under room temperature.Water 60ml, stirring layering is added to separate dichloromethane layer, water layer uses dichloromethane again
Extract, combined dichloromethane layer, anhydrous sodium sulfate drying, filter, be concentrated to give crude product, be refining to obtain solid 11.2, yield 82.0%.
Mass spectrum shows：Molecular ion peak [M+1] is 531
1HNMR is composed（DMSO-d6）：δppm 1.0-1.3（6H, m）, 1.3-1.4（3H, t）, 4.0-4.3（4H, m）, 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
Compound（4B, R=isopropyl）Preparation
Compound（3B）11.8 grams, it is placed in reaction bulb, adds dichloromethane 100ml, triethylamine 5.4ml Deca chloro-carbonic acids
3.8 grams of isopropyl ester, reacts 2 hours under room temperature.Water 60ml, stirring layering is added to separate dichloromethane layer, water layer uses dichloromethane again
Alkane is extracted, combined dichloromethane layer, anhydrous sodium sulfate drying, is filtered, is concentrated to give crude product, is refining to obtain solid 12.0, yield
85.7%。
Mass spectrum shows：Molecular ion peak [M+1] is 545.
Embodiment 10
Compound（5B）Preparation
Compound（4B, R=methyl）9 grams, it is placed in reaction bulb, adds ethanol 60ml to flow back 15 hours, cooling crystallization must be consolidated
Body 7.2, yield 85.7%.
Mass spectrum shows：Molecular ion peak [M+1] is 485.
1HNMR is composed（DMSO-d6）：δppm 1.0-1.2（3H, t）, 1.3-1.4（3H, t）, 4.1-4.3（2H, q）, 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
Compound（5A）Preparation
Compound（4A, R=methyl）3.59 grams, it is placed in reaction bulb, adds ethanol 45ml to flow back 22 hours, cooling crystallization
Obtain 2.7 grams of solid, yield 80.3%.
Mass spectrum shows：Molecular ion peak [M+1] is 471.
Fusing point：183-185℃.
Embodiment 11
Compound（5B）Preparation
Compound（4B, R=ethyl）9 grams, it is placed in reaction bulb, adds ethanol 60ml to flow back 15 hours, cooling crystallization must be consolidated
Body 7.3, yield 89.0%.
Mass spectrum shows：Molecular ion peak [M+1] is 485.
Fusing point：176-178℃.
Embodiment 12
Compound（5B）Preparation
Compound（4B, R=isopropyl）9 grams, it is placed in reaction bulb, adds ethanol 60ml to flow back 15 hours, cooling crystallization is obtained
Solid 6.5, yield 81.2%.
Mass spectrum shows：Molecular ion peak [M+1] is 485.
Embodiment 13
The preparation of Azilsartan
Compound（5B）5 grams, it is placed in reaction bulb, adds 0.4mol/L sodium hydroxide 80ml, 73-75 DEG C is reacted 2 hours.
After reaction terminates, room temperature is cooled to, Deca aqueous acid to pH3-4 separates out white solid 4.1g, 87.2%.
Mass spectrum shows：Molecular ion peak [M+1] is 457.
1HNMR is composed（DMSO-d6）：δppm 1.2-1.3（3H, t）, 4.4-4.6 (2H, q), 5.5-5.6 (2H, s), 6.9-
7.6 (11H, m).
3 Azilsartan elementary analysiss result of table
| Elementary analysiss | Measured value | Theoretical value |
| C | 65.55 | 65.78 |
| H | 4.37 | 4.42 |
| N | 12.09 | 12.27 |
The purity of the Azilsartan that HPLC detections are obtained（Area normalization method）：100%, see Fig. 3.
Fusing point：189-191℃.
HPLC detection datas analysis in 4 Fig. 3 of table
Embodiment 14
The preparation of Azilsartan
Compound（5B）5 grams, it is placed in reaction bulb, adds 0.4mol/L sodium hydroxide 80ml, 73-75 DEG C is reacted 2 hours.
After reaction terminates, room temperature is cooled to, Deca aqueous acid to pH=3-4 separates out white solid 4.1g, 87.2%.
Embodiment 15
The preparation of Azilsartan
Compound（5B）5 grams, it is placed in reaction bulb, adds ethanol 30ml, Deca 2.5mol/L sodium hydroxide 13ml, 73-
75 DEG C are reacted 1.6 hours.After reaction terminates, room temperature is cooled to, Deca aqueous acid to pH=3-4 separates out white solid 4.2g,
89.3%。
Comparative example 4
The preparation of Azilsartan
Compound（5A）2.0 grams, it is placed in reaction bulb, adds 0.4mol/L sodium hydroxide 32ml, 73-75 DEG C of reaction 2 is little
When.After reaction terminates, room temperature is cooled to, Deca aqueous acid to pH=3-4 separates out white solid 1.5g, 77.4%.
Mass spectrum shows：Molecular ion peak [M+1] is 457.
190-192 DEG C of fusing point.
The purity of the Azilsartan that HPLC detections are obtained（Area normalization method）：99.45%, see Fig. 4.
HPLC detection datas analysis in 5 Fig. 4 of table
According to the studies above, Azilsartan prepared by Jing 5B can be learnt, product purity is high, HPLC purity（Area normalization
Method）For 100%, without single contaminant, Fig. 3 is seen.And Jing 5A prepare Azilsartan, product has the impurity for being difficult to remove, and product HPLC is pure
Degree（Area normalization method）For 99.45%, there are two larger impurity, respectively 0.25%, 0.17%, see Fig. 4.
Claims (8)
1. a kind of preparation method of Azilsartan intermediate 4B, it is characterised in that step includes：In solvent, in the presence of alkali,
Compound 3B is mixed with chloro-formate, is reacted, obtain compound 4B；
Wherein, R is methyl or isopropyl.
2. the preparation method of Azilsartan intermediate 4B as claimed in claim 1, it is characterised in that：Described alkali is organic
Alkali；Described organic base is triethylamine, diisopropyl ethyl amine, diethylamine, trimethylamine, pyridine or piperidines；Described alkali rubs
Your consumption is 1～5 times of compound 3B；1～3 times for compound 3B of the mole dosage of described chloro-formate.
3. the preparation method of Azilsartan intermediate 4B as claimed in claim 1, it is characterised in that：The temperature of described reaction
For 10～40 DEG C；The time of described reaction is 1.5～2 hours.
4. the preparation method of Azilsartan intermediate 4B as claimed in claim 3, it is characterised in that：The temperature of described reaction
For 20～35 DEG C.
5. the preparation method of Azilsartan intermediate 4B as claimed in claim 1, it is characterised in that：Also comprise the following steps：
In solvent, compound 2B is mixed with azanol, is reacted, obtain compound 3B；
6. the preparation method of Azilsartan intermediate 4B as claimed in claim 5, it is characterised in that：Prepare in the reaction of 3B,
Described solvent is polar aprotic solvent or polar non-solute；Described polar aprotic solvent is alcoholic solvent；Described alcohol
Solvent is methanol, ethanol or isopropanol；Described polar aprotic solvent is N,N-dimethylformamide or dimethyl sulfoxide；Institute
5～25 times for compound 2B of the mole of the azanol stated；Prepare in the reaction of 3B, reaction temperature is 50～110 DEG C；During reaction
Between be 5～10 hours.
7. the preparation method of Azilsartan intermediate 4B as claimed in claim 5, it is characterised in that：
Organic base is additionally added in the reaction for preparing 3B；Described organic base be triethylamine, diisopropyl ethyl amine, diethylamine, three
Methylamine, pyridine or piperidines；0.2～5 times for compound 2B of the mole dosage of described organic base.
8. the preparation method of Azilsartan intermediate 4B as claimed in claim 6, it is characterised in that：Prepare in the reaction of 3B,
Reaction temperature is 65～100 DEG C.
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| JP2018076258A (en) * | 2016-11-09 | 2018-05-17 | 株式会社トクヤマ | Azilsartan alkyl ester, method for producing azilsartan methyl ester, and method for producing azilsartan |
| JP6676491B2 (en) * | 2016-07-13 | 2020-04-08 | 株式会社トクヤマ | Method for producing azilsartan alkyl ester and method for producing azilsartan |
| JP6676487B2 (en) * | 2016-07-05 | 2020-04-08 | 株式会社トクヤマ | Method for producing amidoxime compound as intermediate of azilsartan, and method for producing azilsartan |
| JP2021059607A (en) * | 2021-01-21 | 2021-04-15 | 株式会社トクヤマ | Azilsartan alkyl ester, method for producing azilsartan methyl ester, and method for producing azilsartan |
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