CN1510031A - Ester compounds of bezimidazole and their preparations and uses in preparation of medicinal compound - Google Patents
Ester compounds of bezimidazole and their preparations and uses in preparation of medicinal compound Download PDFInfo
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Abstract
A benzimidazole ester compound, 2-ethoxy-1-(p-halophenyl) methyl-1H-benzimidazole-7-carboxylate-1-[[(cyclohexoxy)carbonyl] oxy] ethylester, its preparing process, and its application in preparing medicinal compound candesartan ester are disclosed.
Description
Technical field
What the present invention relates to is a kind of ester compound of benzoglyoxaline, the preparation method of this compound, and with the method for this compound as feedstock production medicinal compound candesartan Cilexetil.
Background technology
Candesartan Cilexetil is a kind of existing AngII-1 receptor antagonist pharmaceuticals that oneself comes into operation, the compound that belongs to a kind of benzimidazoles, chemistry is by name: (±)-2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester.
The preparation method of this medicinal compound is provided in the Chinese patent literature of notification number for CN1048486C, comprise that the O-Phenylene Diamine compounds (as the formula IV compound in the document) that replaces the benzimidazoles compound (as the formula II in the document and formula V ' compound) of form with difference respectively or replace is a starting raw material, prepare through multiple reaction path.Its synthetic route is longer relatively, and has the tetrazyl with greater activity because of having introduced earlier in the reaction process, thus in whole synthetic route, have to increase corresponding on the additional step of protecting group and deprotection base, make complicated operationization.
Summary of the invention
According to above-mentioned situation, the present invention's purpose at first provides an ester class important intermediate compound that can make the operation benzoglyoxaline that obtains simplifying of the above-mentioned candesartan Cilexetil of preparation, and the ester class midbody compound of this benzoglyoxaline can be prepared by diverse ways.Further, second purpose of the present invention provides the preparation method of the ester class midbody compound of this benzoglyoxaline, and the method that is prepared above-mentioned medicinal compound candesartan Cilexetil by the ester class midbody compound of this benzoglyoxaline.
The ester compound intermediate of the said benzoglyoxaline of the present invention, chemical name are 2-oxyethyl group-1-(to halogenophenyl) methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester, structure is suc as formula shown in (I):
X in above-mentioned [I] formula structure can be the Cl in the haloid element, Br or I.
Above-claimed cpd (I) preparation, can be by after corresponding 1-(to halogenophenyl) methyl-2-oxyethyl group benzo imidazoles-7-carboxylic acid, ethyl ester (VI) hydrolysis obtains corresponding esters carboxylic acid cpd (VII), obtain again with after 1-chloroethyl-cyclohexyloxy carbonic ether condensation, reaction process is as follows:
In above-mentioned reaction, the X in the reactant structure can be haloid element Cl, Br or I.
Obtain the hydrolysis reaction of corresponding carboxylic acid cpd (VII) by compound (VI), generally can under alkaline condition, carry out.Test shows, at water commonly used, alcohols commonly used such as methyl alcohol, ethanol, ether, butyl ether, tetrahydrofuran (THF) ethers commonly used such as (THF), and arene compounds commonly used such as benzene, toluene is in the reaction medium, adopt under the conventional alkaline condition such as alkali metal hydroxide such as potassium hydroxide, sodium hydroxide or its corresponding carbonate, can successfully obtain corresponding carboxylic acid compound (VII).Obtain compound (I) by compound (VII) and 1-chloroethyl-cyclohexyloxy carbonic ether, it also is a kind of condensation reaction of routine, generally can or relax under the condition of heating, in organic solvents such as dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) or benzene, finish reaction in room temperature.
Said compound (VI) in the above-mentioned preparation process can be prepared by multiple mode.For example, can be with reference to relevant document, as: J.A.C.S.2459 (1947), or J.Heterocycl.Chem.41 (1965), or J.Med.Chem.2216 (1987)) document such as, or adopt with it similarly method, by 2-(tert-butoxycarbonyl) amino-3-ethyl nitrobenzoate (II) with condensation obtains intermediate (IV) to halogen benzyl halogen (III), obtain the compound intermediate (V) of O-Phenylene Diamine form then through reduction, obtain again with after the cyclization of carbonic acid tetra-ethyl ester, reaction process is as follows:
In above-mentioned reaction, X in the reactant structure and X ' can be identical or different haloid element Cl, Br or I.
Used in the above-mentioned reaction process to the commercially available industrial chemicals of bromobenzyl bromine compounds (III) for being easy to get, compound (II) can be with reference to existing document, as J.A.C.S.2459 (1947), or J.Heterocycl.Chem.41 (1965), or the method for J.Med.Chem.2216 documents such as (1987) prepares.The condensation reaction of compound (II) and compound (III), generally can be in conventional reaction medium such as methyl alcohol, ethanol, acetonitrile, DMF, THF, DMSO, carry out in 50 ℃-100 ℃ heating with under the condition that disacidify agent such as carbonate commonly used, sodium hydride exist, obtain intermediate (IV).In this intermediate (IV)-NO
2In alcohol, acetic acid or benzene equal solvent, with hydrogen, or under acidic conditions, use metal or its corresponding reductibility compounds such as zinc commonly used, iron, tin, be reduced to-NH
2, further obtain corresponding O-Phenylene Diamine intermediate (V).Intermediate (V),, heats in cyclization under the condition of (as 60 ℃-100 ℃) perhaps as in the aromatic hydrocarbons reaction mediums such as benzene, toluene as alkane such as normal hexane, sherwood oils commonly used, carries out cyclization and obtains said this compound (VI) with the carbonic acid tetra-ethyl ester.
Except that above-mentioned method, said this compound (VI) can also adopt other preparation method to obtain, for example, can be with reference to the method for pertinent literature report, as J.C.S. (Perkin I) 349 (1960), or J.C.S.236 (1965), or J.Med.Chem.815 (1990)) method of document such as, or similar method, by 2-oxyethyl group benzo imidazoles-7-carboxylic acid, ethyl ester (VIII) with halogen benzyl halogen (III) is obtained through condensation reaction, reaction process is as follows:
Equally, X in the reactant structure and X ' also can be identical or different haloid element Cl, Br or I.
Test-results shows, the ester compound of the benzoglyoxaline of the above-mentioned form of the present invention can be used as an important midbody compound in preparation medicinal compound candesartan Cilexetil.For example, during by above-claimed cpd (I) preparation candesartan Cilexetil, one of method that can adopt, be with the ester compound (I) of this benzoglyoxaline and 5-(2-halogenophenyl)-1H-tetrazotized zole compound after the grignard reaction condensation, directly obtain candesartan Cilexetil (IX), reaction process is as follows:
Wherein, in above-mentioned reaction, the X in the reactant structure can be haloid element Cl, Br or I; X ' can be Br in the haloid element or I; R is H or trityl.When R is trityl, can under solutions of weak acidity, remove usually by hydrolysis reaction.
Above-mentioned reaction is a kind of coupling reaction of aryl, can adopt in ether solvents such as ether, fourth mystery, THF, room temperature or a little heat and as Cl
2Ni (PPh
3)
2Carry out under the condition etc. the coupled catalyzer existence of common metal organic compound class.Wherein carrying out this used 5-of coupling reaction (2-halogenophenyl)-1H-tetrazotized zole compound can be with reference to as US5,371,233 (1994), US 5,039, the method for 814 documents such as grade, or with it similarly mode prepare.
In addition to the above methods, when being feedstock production medicinal compound candesartan Cilexetil, can also adopt other method to realize with above-claimed cpd (I).For example, can be carried out the aryl cross-coupling reaction and obtained by above-claimed cpd (I) and 5-(2 '-zinc halide substituted-phenyl)-2-(1H) tetrazotized zole compound, reaction process be as follows:
Wherein, the X in the reactant can be haloid element Cl, Br or I equally; R can be H or trityl.Equally, when R is trityl, can under solutions of weak acidity, remove usually by hydrolysis reaction.
5-in the above-mentioned reactant (2 '-the zinc halide substituted-phenyl)-2-(1H) tetrazotized zole compound can be with reference to existing document, the method of reporting as Tetrahedron Tetter 39:6441 (1998) and J.O.C.56:1445 documents such as (1991), or with it similarly method prepare.
When adopting the ester compound (I) of above-mentioned benzoglyoxaline of the present invention to prepare candesartan Cilexetil (IX) as important midbody compound; a significant advantage has been to solve in the related manufacturing processes that document is reported has as described above introduced midbody compound owing to will have the tetrazyl of greater activity earlier; thereby make and have to increase unfavorable that the corresponding additional step that goes up protecting group and deprotection base brings in the polystep reaction process that also need carry out afterwards; make operation more easy; also make the synthetic route of preparation candesartan Cilexetil more simple and direct, and reduced cost.On the other hand, because the ester compound (I) of this benzoglyoxaline can obtain by multiple preparation method or source, ester compound (I) with this benzoglyoxaline further prepares the mode of candesartan Cilexetil (IX) more than a kind of, thereby in preparation during candesartan Cilexetil, helping maybe also can having greater flexibility and suitability aspect the then suitable raw material of needs choosing and/or the route according to different situations.
According to foregoing, under the prerequisite that does not break away from the above-mentioned basic fundamental thought of the present invention,, modification, replacement or the change of various ways can also be arranged to above-mentioned content according to the ordinary skill knowledge and the customary means of this area.
The embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment
Example 1:
One of preparation method of 1-(to bromophenyl) methyl-2-oxyethyl group benzo imidazoles-7-carboxylic acid, ethyl ester (VI)
A) preparation of 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate (II)
2-carboxyl-3-ethyl nitrobenzoate 24g (0.1mol), sulfur oxychloride 20ml and toluene 100ml are added in the reaction flask successively heating reflux reaction 3 hours.Reaction mixture is concentrated into dried.The gained acyl chlorides is dissolved among the trichloromethane 100ml, stirs down and drips the solution that sodiumazide 10g (0.15mol) is become with DMF50ml, finishes, and continues reaction 3 hours.Add 500ml water in reaction mixture, place separating funnel, tell organic layer, the water layer chloroform extraction washes organic layer with water, drying, distillating recovering solvent.Residue is dissolved in the trimethyl carbinol, heating gradually under the solution stirring condition, and back flow reaction 2 hours, vacuum concentration promptly gets target intermediate (II), for yellow soup compound, is directly used in the next step.
B) methyl 2-[(4 '-bromophenyl)] amino]-preparation of 3-ethyl nitrobenzoate (IV)
Acetonitrile 200ml is added in the above-mentioned intermediate 2-t-butoxycarbonyl amino that makes-3-ethyl nitrobenzoate (II), stir adding salt of wormwood 20g (0.15mol) down.After the mixture stirring at room 20 minutes, add p-bromobenzyl bromide [III] 25g (0.1mol) and potassiumiodide 1.5g again, insulation back flow reaction 10 hours, distillating recovering solvent.Residue is poured in the mixed solution of water 100ml and hexanaphthene 100ml, tells organic layer, washing, adds anhydrous sodium sulfate drying, concentrate yellow slurry.Add the hydrochloride ethanol liquid 40ml of 25-30%, stirred 1 hour.Concentrated reaction mixture adds hexanaphthene 100ml in resistates, separate out crystallization, suction filtration, and drying obtains pale yellow crystals product (IV) 24.6g (yield 65%), mp.104-106 ℃
C) 3-amino-2-[(is to bromophenyl) methyl] amino] preparation of ethyl benzoate (V)
Upwards the 2-[(that obtains is to bromophenyl the step) methyl] amino]-the 100ml ethanolic soln of 3-ethyl nitrobenzoate 40g (0.1mol) in, add tindichloride dihydrate 45g (0.2mol), backflow stirring reaction 2 hours, solvent evaporation is to doing.Resistates is added among the ethyl acetate 200ml, stir down, drip 2N NaOH to reaction solution pH11, suction filtration, filtrate is told organic layer, washing, drying.Solvent evaporation is to doing, and resistates is a yellow pulpous state product (V), directly uses for the next step.
D) preparation of 1-(to bromophenyl) methyl-2-oxyethyl group benzo imidazoles-7-carboxylic acid, ethyl ester (VI)
With 3-amino-2-[(to bromophenyl) methyl] amino] ethyl benzoate 35g, ethyl orthocarbonate 25g, acetate 2g add in the reaction flask successively, in 80 ℃ of stirring reactions 1 hour.Concentrated reaction mixture, and enriched material is dissolved in the ethyl acetate, sodium bicarbonate aqueous solution and water washing used successively.Concentrate, the resistates crystallization, diafiltration, drying, product is light yellow crystallization, fusing point: 132-135 ℃.
Example 2
The preparation method's of 1-(to bromophenyl) methyl-2-oxyethyl group benzo imidazoles-7-carboxylic acid, ethyl ester (VI) two
A) preparation of 2-phenetole-1H and imidazoles-7-carboxylic acid, ethyl ester (VIII) (i.e. [1-1])
With 2,3-2-aminobenzoic acid ethyl ester 36g (0.1mol), ethyl orthocarbonate 60g, acetate 5g added in the reaction flask successively, in 80 ℃ of stirring reactions 5 hours.Concentrated reaction mixture, and enriched material is dissolved in the ethyl acetate, sodium bicarbonate aqueous solution and water washing used successively.Steam solvent, resistates obtains yellow solid 16g, yield 70%, mp.125-130 ℃ with ethyl acetate-benzene recrystallization
B) preparation of 1-(to bromophenyl) methyl-2-oxyethyl group benzo imidazoles-7-carboxylic acid, ethyl ester (VI)
Acetonitrile 200ml is added among the above-mentioned intermediate 2-phenetole-1H that makes and imidazoles-7-carboxylic acid, ethyl ester (VIII) 23.4g (0.1mol), stir adding salt of wormwood 20g (0.15mol) down.After the mixture stirring at room 20 minutes, add p-bromobenzyl bromide [2-3] 25g (0.1mol) and potassiumiodide 1.5g, insulation back flow reaction 10 hours, distillating recovering solvent.Residue is poured in the mixed solution of water 100ml and hexanaphthene 100ml, tells organic layer, washing, adds anhydrous sodium sulfate drying, concentrate yellow slurry, through column chromatography purification, crystallization, diafiltration, drying, product is light yellow crystallization.Fusing point is 132-135 ℃.
Example 3
The preparation of 1-(to bromophenyl) methyl-2-oxyethyl group benzo imidazoles-7-carboxylic acid (VII)
With 1-(to bromophenyl) methyl-2-oxyethyl group benzo imidazoles-7-carboxylic acid, ethyl ester (VI) 40g that obtains in a manner described, add among 1N NaOH 150ml and the ethanol 100ml, backflow stirring reaction 6 hours, concentrate, add entry 200ml in the enriched material, extract with ethyl acetate, water layer is adjusted to pH3-4 with 1NHCl and separates out crystal, its recrystallization in ethyl acetate-ethanol is got clear crystal product (VII) 16g, and calculated yield is 42%, 175-180 ℃ of mp. (fusing point).
Elementary composition theoretical value % measured value (%)
C
17H
15BrN
2O
3 C54.41 54.28
375.217 H4.03 4.15
N7.46 7.47
Br21.32 21.06
Example 4
2-oxyethyl group-1-(to bromophenyl) methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid 1-[[(cyclohexyloxy) carbonyl] oxygen] preparation of ethyl ester (I)
A) preparation of 1-chloro-ethyl carbonate cyclohexyl
With benzoyl peroxide 6g, add in the mixed solution of Vinyl chloroformate 2.7kg (23.5mol) and sulfuryl chloride 3.7kg (27mol), stir and be warming up to backflow, insulation reaction 4 hours, 118-124 ℃ gold-plating branch is collected in fractionation, is 1-chloroethyl-chloro-formic ester.
Get said products 2.65kg and hexalin 18.3kg (18.3mol) and mix, cooling drips pyridine 1.4kg (17.5mol), finish, stirring at room is reacted half an hour, and reaction solution is poured in ethyl acetate and the water, tells organic layer, water, 5% yellow soda ash water washing successively, dried over mgso steams solvent, fractionation, collect 100-115 ℃ of cut, be target compound.
B) carbonyl 2-oxyethyl group-1-(to bromophenyl) methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid 1-[[(cyclohexyloxy)] oxygen] preparation of ethyl ester (I)
Successively among the 1-chloro-ethyl carbonate cyclohexyl 20.5g (0.1mol) and salt of wormwood 15g (0.11mol) adding DMF200ml that 1-(to bromophenyl) methyl-2-oxyethyl group benzo imidazoles-7-carboxylic acid (VII) 37.5g (0.1mol) that will be obtained by example 3, above-mentioned a) step obtain, in 65 ℃ of stirring reactions 10 hours.The reactant dilute with water, and use dichloromethane extraction, merge organic layer, wash with water, add anhydrous magnesium sulfate drying, concentrate, through column chromatography purification, with methylene dichloride/ethanol (20/1) wash-out, concentrate eluant obtains buff powder product (I) 32g, and yield is 60%, mp.98-100 ℃.
Elementary composition theoretical value % measured value (%)
C
26H
29BrN
2O
6?C57.25 C57.19
545.422 H5.36 H5.48
N5.13 N5.17
Br14.65 Br14.81
IR: absorption peak cm
-1
V
N-H3428；V
C-H2940；V
C＝O1752，1710；V
C＝H1614，1549；
1H-NMR(200MHz、CDCl
3)δ：1.31-1.81(16H，m)，4.53-4.59(3H，m)，5.38-5.51(2H，d)，6.76-6.77(1H，d)，6.86-6.87(2H，d)，，7.20-7.21(1H，m)，7.41-7.47(3H，m)，7.71-7.73(1H，m)。
Example 5
(±)-2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid 1-[[(cyclohexyloxy) carbonyl] oxygen] one of the preparation method of ethyl ester (IX) (candesartan Cilexetil)
A) preparation of 5-(2 '-chloro-phenyl-)-2-trityl group tetrazole
Add methylene dichloride 100ml in the above-mentioned solid 9.0g (0.05mol) that makes, the ice bath cooling drips the dichloromethane solution of triphenylmethyl chloride 20g (0.072mol) down, with the about 10g conditioned reaction of triethylamine liquid potential of hydrogen, keeps stirring reaction 10 hours.Reaction mixture washes with water, adds anhydrous sodium sulfate drying, filters, and filtrate concentrates, the resistates freezing and crystallizing.Filter, filter cake washs with Diluted Alcohol, gets light yellow solid, yield 45%.
According to aforesaid method, adopt 2-bromobenzene cyanogen, 2-iodobenzene cyanogen to make raw material respectively, also can make 5-(2 '-bromophenyl)-2-trityl group tetrazole and 5-(2 '-iodophenyl)-2-trityl group tetrazole.
B) (±)-2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid 1-[[(cyclohexyloxy) carbonyl] oxygen] preparation of ethyl ester (IX) (candesartan Cilexetil)
Feeding under the nitrogen, magnesium chips 2.4g (0.01mol) is added in the 50ml anhydrous tetrahydro furan, drip above-mentioned 2-oxyethyl group-1-(to bromophenyl) methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid 1-[[(cyclohexyloxy that obtains) carbonyl] oxygen] anhydrous tetrahydrofuran solution of ethyl ester (I) 5.5g (0.01mol), little magnesium chips that is back to dissolves, being chilled to room temperature continues to stir 1 hour, continue to be chilled to 0 ℃, add an amount of 1M zinc chloride diethyl ether solution.
In addition with 1.26gCl
2Ni (PPh
3)
2Be dissolved in the 50ml anhydrous tetrahydro furan, feeding under the nitrogen, the 20ml THF solution of Dropwise 5 g 5-(2-iodophenyl)-2-trityl group-2H-tetrazole stirs, and is catalyst solution.Under 0 ℃ of stirring,, be added dropwise in the catalyst solution stirring at room reaction 3-5 hour with the above-mentioned grignard reagent solution that makes.
Drip 100ml water and add in the reaction mixture, suction filtration is after filtrate uses salt saturated, with ethyl acetate extraction, united extraction liquid is adjusted to solution with HCl-ethanol liquid and is slightly acidic, stirring at room 1 hour, elimination precipitate, the filtrate water washing concentrates crystallization behind column chromatography purification to neutral.Crystallization is separated out in diafiltration, gets the off-white color solid, is Candesartan ester products (IX) fusing point 152-156 ℃.
IR: absorption peak cm
-1
V
N-H3400；V
C-H2940；V
C＝O1754，1717；V
C＝H1613，1549；
Elementary composition theoretical value % measured value (%)
C
33H
34N
6O
6 C64.90 64.96
610.660 H5.61 5.68
N13.76 13.81
Example 6
(±)-2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester (IX) (candesartan Cilexetil) the preparation method two
A) preparation of 5-(2 '-zinc chloride phenyl)-2-trityl group tetrazole solution
5-(2 '-chloro-phenyl-)-2-trityl group tetrazole 18g (0.1mol) is dissolved among the THF 50ml, is cooled to-10 ℃, drips the n-Butyl Lithium hexane solution, stirs 1 hour.Temperature of reaction goes back up to 0 ℃, adds the THF solution of zinc chloride, continues to stir 1 hour, makes 5-(2 '-zinc chloride phenyl)-2-trityl group tetrazole solution, directly uses for the aryl linked reaction.
B) (±)-2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid 1-[[(cyclohexyloxy) carbonyl] oxygen] preparation of ethyl ester (IX) (candesartan Cilexetil)
With 2-oxyethyl group-1-(to bromophenyl) methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester (I) 5.5g (0.01mol) is dissolved in the 50ml anhydrous tetrahydro furan, feeding under the nitrogen, drips 1.26g Cl successively
2Ni (PPh
3)
2Anhydrous tetrahydrofuran solution and contain the THF solution of 6g 5-(2 '-zinc chloride phenyl)-2-trityl group-2H-tetrazole (X).Drip to finish, 40 ℃ stirring reaction 3-5 hour.
Drip 100ml water and add in the reaction mixture, suction filtration is after filtrate uses salt saturated, with ethyl acetate extraction, united extraction liquid is adjusted to pH value of solution 1-2 with HCl-ethanol liquid, stirring at room 1 hour, elimination precipitate, the filtrate water washing concentrates crystallization behind column chromatography purification to neutral.Crystallization is separated out in diafiltration, gets the off-white color solid, is Candesartan ester products (IX) fusing point 154-157 ℃.
IR: absorption peak cm
-1
V
N-H3400；V
C-H2940；V
C＝O1754，1717；V
C＝H1613，1549；
Elementary composition theoretical value % measured value (%)
C
33H
34N
6O
6 C64.90 64.90
610.660 H5.61 5.64
N13.76 13.69
The preparation of reference example: 5-(2 '-chloro-phenyl-)-2 (1H) tetrazole (can be used for one of preparation raw material of compound (IX))
2-chlorobenzene cyanogen 14g (0.1mol), azide tributyl tin 33g (0.1mol) are added among the toluene 200ml successively, under nitrogen protection, back flow reaction 2 days.Add ethanol 100ml, be adjusted to pH12 with 1N NaOH, backflow stirring reaction 1 hour, suction filtration, filtrate is put in the separating funnel, divides water-yielding stratum, regulates water layer to pH3-4 with 1NHCl, with ethyl acetate extraction, drying, concentrated extract, crystallization, fusing point: 172-175 ℃.
Elementary composition theoretical value % measured value (%)
C
7H
5ClN
4 C46.55 C46.42
180.594 H2.79 H2.93
N31.00 N30.84
Claims (6)
1. the ester compound of benzoglyoxaline, chemical name is 2-oxyethyl group-1-(to halogenophenyl) methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester, structure is suc as formula shown in (I):
Wherein, (I) X in the formula is haloid element Cl, Br or I.
2. prepare the method for formula (I) structural compounds according to claim 1, it is characterized in that by after 1-(to halogenophenyl) methyl-2-oxyethyl group benzo imidazoles-7-carboxylic acid, ethyl ester (VI) hydrolysis obtains corresponding carboxylic acid compound (VII), obtain again with after 1-chloroethyl-cyclohexyloxy carbonic ether condensation, reaction process is as follows:
Wherein, the X in the formula is haloid element Cl, Br or I.
3. preparation method as claimed in claim 2, it is characterized in that said formula (VI) compound can be by 2-tert-butoxycarbonyl amino-3-ethyl nitrobenzoate (II) with condensation obtains intermediate (IV) to halogen Bian halogen (III), obtain the compound intermediate (V) of O-Phenylene Diamine form then through reduction, obtain again with after the cyclization of carbonic acid tetra-ethyl ester, reaction process is as follows:
Wherein, X in the formula and X ' can be identical or different haloid element Cl, Br or I.
4. preparation method as claimed in claim 2, it is characterized in that said formula (VI) compound can by 2-oxyethyl group benzo imidazoles-7-carboxylic acid, ethyl ester (VIII) with to obtaining after halogen benzyl halogen (III) condensation, under the reaction process:
Wherein, the X in the formula, X ' can be identical or different haloid element Cl, Br or I.
5. the method for preparing the drug candesartan ester with the ester compound of the described benzoglyoxaline of claim 1, it is characterized in that the ester compound (I) of said benzoglyoxaline and 5-(2 '-halogenophenyl)-2 (1H) tetrazotized zole compound after the grignard reaction condensation, obtain candesartan Cilexetil (IX), reaction process is as follows:
Wherein, X in the formula and X ' can be identical or different haloid element Cl, Br or I; R can be H or trityl.
6. the method for preparing the medicinal compound candesartan Cilexetil with the ester compound of the described benzoglyoxaline of claim 1, after it is characterized in that the ester compound (I) of said benzoglyoxaline and 5-(2 '-zinc halide substituted-phenyl)-2 (1H) tetrazotized zole compound carried out the aryl cross-coupling reaction, obtain candesartan Cilexetil (IX), reaction process is as follows:
Wherein, X in the formula and X ' can be haloid element Cl, Br or I; R can be H or trityl.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006063578A2 (en) * | 2004-12-16 | 2006-06-22 | Ratiopharm Gmbh | Method for production of candesartan |
| WO2006134078A1 (en) * | 2005-06-17 | 2006-12-21 | Quimica Sintetica, S.A. | Method for obtaining benzimidazole derivatives and intermediates thereof |
| CN100344625C (en) * | 2005-12-22 | 2007-10-24 | 浙江天宇药业有限公司 | Method for preparing candestartan |
| CN104496822A (en) * | 2014-12-15 | 2015-04-08 | 扬州三友合成化工有限公司 | Preparation method of 1-chloroethyl cyclohexyl propyl carbonate |
| CN114163391A (en) * | 2021-12-14 | 2022-03-11 | 迪嘉药业集团有限公司 | Candesartan intermediate and preparation method of candesartan |
-
2002
- 2002-12-23 CN CN 02128079 patent/CN1207287C/en not_active Expired - Lifetime
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006063578A2 (en) * | 2004-12-16 | 2006-06-22 | Ratiopharm Gmbh | Method for production of candesartan |
| WO2006063578A3 (en) * | 2004-12-16 | 2006-10-12 | Ratiopharm Gmbh | Method for production of candesartan |
| WO2006134078A1 (en) * | 2005-06-17 | 2006-12-21 | Quimica Sintetica, S.A. | Method for obtaining benzimidazole derivatives and intermediates thereof |
| ES2264641A1 (en) * | 2005-06-17 | 2007-01-01 | Quimica Sintetica, S.A. | Method for obtaining benzimidazole derivatives and intermediates thereof |
| CN100344625C (en) * | 2005-12-22 | 2007-10-24 | 浙江天宇药业有限公司 | Method for preparing candestartan |
| CN104496822A (en) * | 2014-12-15 | 2015-04-08 | 扬州三友合成化工有限公司 | Preparation method of 1-chloroethyl cyclohexyl propyl carbonate |
| CN104496822B (en) * | 2014-12-15 | 2016-10-26 | 扬州三友合成化工有限公司 | A kind of preparation method of 1-chloroethyl Cyclohexylpropyl carbonic ester |
| CN114163391A (en) * | 2021-12-14 | 2022-03-11 | 迪嘉药业集团有限公司 | Candesartan intermediate and preparation method of candesartan |
| CN114163391B (en) * | 2021-12-14 | 2024-02-02 | 迪嘉药业集团股份有限公司 | Candesartan intermediate and preparation method of Candesartan |
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| CN1207287C (en) | 2005-06-22 |
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