CN101648918B - Intermediate compound of candesartan cilexetil and synthesis method thereof - Google Patents
Intermediate compound of candesartan cilexetil and synthesis method thereof Download PDFInfo
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- CN101648918B CN101648918B CN2008100417387A CN200810041738A CN101648918B CN 101648918 B CN101648918 B CN 101648918B CN 2008100417387 A CN2008100417387 A CN 2008100417387A CN 200810041738 A CN200810041738 A CN 200810041738A CN 101648918 B CN101648918 B CN 101648918B
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- 0 *c1cc([N+]([O-])=O)c(*)c(*)c1 Chemical compound *c1cc([N+]([O-])=O)c(*)c(*)c1 0.000 description 7
- CSQDVUFCTBFGIJ-UHFFFAOYSA-N CCOc1cc2cccc(C(O)=O)c2[n]1Cc(cc1)ccc1-c1ccccc1-c1nnn[nH]1 Chemical compound CCOc1cc2cccc(C(O)=O)c2[n]1Cc(cc1)ccc1-c1ccccc1-c1nnn[nH]1 CSQDVUFCTBFGIJ-UHFFFAOYSA-N 0.000 description 1
- HTQMVQVXFRQIKW-UHFFFAOYSA-N CCOc1nc2cccc(C(O)=O)c2[n]1Cc(cc1)ccc1-c(cccc1)c1-c1nnn[nH]1 Chemical compound CCOc1nc2cccc(C(O)=O)c2[n]1Cc(cc1)ccc1-c(cccc1)c1-c1nnn[nH]1 HTQMVQVXFRQIKW-UHFFFAOYSA-N 0.000 description 1
- QSRSXEHFQCQDRK-UHFFFAOYSA-N NCc(cc1)ccc1-c(cccc1)c1-c1nnn[nH]1 Chemical compound NCc(cc1)ccc1-c(cccc1)c1-c1nnn[nH]1 QSRSXEHFQCQDRK-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention provides an intermediate compound of candesartan cilexetil as shown by a formula I or II and a synthesis method thereof, wherein M is H or O, R is H or C1-C4 straight-chain or branched-chain alkyl or benzyl, R' is a tetrazole protective group, X is H, and Y is halogen; or the R' is H or the tetrazole protective group, and the X and the Y are halogens independently and respectively. The intermediate compound is used for preparing candesartan cilexetil medicaments, wherein an expensive palladium catalyst and highly toxic tributyl tin azide are not used, and the operating method is simple and convenient (without an absolute anhydrous condition), thus the intermediate compound not only is suitable for a small amount of preparation in a laboratory, but also is suitable for industrial mass production.
Description
Technical field
The present invention be more particularly directed to a kind of midbody compound and synthetic method thereof of candesartan Cilexetil.
Background technology
Candesartan, English name is Candesartan, the chemical name of candesartan Cilexetil is 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLE-5-) [1,1 '-xenyl]-the 4-yl] methyl]-1-H-benzoglyoxaline-7-carboxylic acid-1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester, its structural formula is as follows.
Thereby Candesartan shows good clinical efficacy because the angiotensin-ii receptor blocking-up with highly selective is active, be widely used in clinically the treatment of essential hypertension, this medicine at first went on the market in Sweden in 1997, Astrazeneca AB in 2003 the global marketing volume reached 7.5 hundred million dollars.
At present, several main synthetic routes of Candesartan and candesartan Cilexetil are as follows:
1.US?5196444
The total recovery that this route reacts with 10% through eight steps take the 3-nitrophthalic acid as raw material obtains Candesartan, obtain candesartan Cilexetil through two-step reaction again, the longer complicated operation of route, and at the hypertoxic tributyl nitrine tin of needs use, tin is residual to exist very large potential safety hazard to product.
2.WO2006015134
This route obtains candesartan Cilexetil through six-step process with 36% total recovery take the 3-nitrophthalic acid as raw material, and total recovery is significantly improved, but needs equally to use tributyl nitrine tin.
3.WO2006134078
This route is take 2-chloro-3-nitrobenzoic acid as raw material, and 2-chloro-3-nitrobenzoic acid is synthetic loaded down with trivial details, price is higher, and this route utilizes the Suzuki linked reaction to realize the formation of biphenyl functional group, the Suzuki reaction requires relatively harsher to reaction conditions, be difficult to large-scale the application, the costliness of palladium complex is also brought pressure to production cost, and palladium residual also be a very large potential safety hazard.
Contrast above-mentioned three synthetic routes, all have certain limitation, bring certain difficulty for the suitability for industrialized production of candesartan Cilexetil.
Summary of the invention
Therefore, the technical problem to be solved in the present invention is exactly the defective that overcomes the tributyl nitrine tin that uses expensive Suzuki reaction palladium catalyst and severe toxicity in the existing candesartan Cilexetil synthetic route, a kind of midbody compound and synthetic method thereof of candesartan Cilexetil are provided, this midbody compound and synthetic method are simple, product is easy to purifying, can be used as the midbody compound of synthetic candesartan Cilexetil.
The present invention solves the problems of the technologies described above one of technical scheme of adopting: a kind of midbody compound of the candesartan Cilexetil shown in general formula I or II,
Wherein, M is H or O, and R is H or C
1～C
4Straight chain or alkyl or the benzyl of side chain, R ' is tetrazole protective group, X is H, Y is halogen; Perhaps R ' is H or tetrazole protective group, X and Y respectively alone be halogen.The preferred trityl of described tetrazole protective group, benzyl and the dimethyl tertiary butyl are silica-based.The preferred Cl of described halogen or Br.
The present invention solves the problems of the technologies described above two of the technical scheme that adopts: a kind of synthetic method of midbody compound of the candesartan Cilexetil shown in general formula 3, comprise the steps: in organic inert solvent, with alkaline matter as acid binding agent, compound shown in general formula 1 (being called for short compound 1) and the compound shown in general formula 2 (are called for short compound 2, lower with) or its salt carry out linked reaction, the midbody compound of formation shown in general formula 3
Wherein, R is H or C
1～C
4Straight chain or alkyl or the benzyl of side chain, X is H or halogen, Z is halogen.
Wherein, the compound shown in general formula 2 and salt thereof can be with reference to the easily synthetic acquisitions of patent of application number CN200810032533.2.Compound shown in general formula 1 is conventional chemical reagent, and is commercially available and get.The consumption of the compound shown in general formula 1 is better is 1～5 times of molar weight of the compound or its salt shown in general formula 2, and better is 1～2 times.What described alkaline matter was better is one or more organic basic material or inorganic base substances.Described organic basic material is better is selected from triethylamine, pyridine, N-methylmorpholine, quinoline and diisopropyl ethyl amine, and described inorganic base substance is better is selected from yellow soda ash and salt of wormwood.The consumption of alkaline matter is better is 1～5 times of molar weight of the compound or its salt shown in general formula 2, and better is 1～2 times.Described organic inert solvent better for being selected from lower alcohol, ketone, aromatic hydrocarbon, ether, halogenated alkane, DMF (DMF), N,N-dimethylacetamide, dimethyl sulfoxide (DMSO) and the acetonitrile one or more." lower alcohol " described in the present invention refers to the alcohol of carbon chain lengths C1～C4.Described lower alcohol is better is selected from methyl alcohol, ethanol, propyl alcohol, Virahol and butanols, what described ketone was better is acetone, described aromatic hydrocarbon is better is selected from toluene and dimethylbenzene, described ether is better is selected from tetrahydrofuran (THF), glycol dimethyl ether and dioxan, described halogenated alkane is better is selected from methylene dichloride, chloroform and 1,2-ethylene dichloride.The consumption of polar solvent is better is 1～100 times of molar weight of the compound or its salt shown in general formula 2, and better is 8～10 times.What the temperature of reaction was better is 50～120 ℃, and preferred temperature is the reflux temperature of reaction solvent.The reaction time better can be run out of by the TLC detecting reactant till.
The present invention solves the problems of the technologies described above three of the technical scheme that adopts: a kind of synthetic method of midbody compound of the candesartan Cilexetil shown in general formula 9 may further comprise the steps:
1) in organic inert solvent, at reductive agent, or under the effect of catalyzer and hydrogen source, the midbody compound shown in general formula 3 carries out reduction reaction, forms the midbody compound shown in general formula 10;
2) in organic inert solvent, the midbody compound shown in general formula 10 forms the benzoglyoxaline ring by reacting with tetraethyl orthocarbonate, forms the midbody compound shown in general formula 7;
3) when R be C
1～C
4Straight chain or when the alkyl of side chain or benzyl, the midbody compound shown in general formula 7 through saponification reaction with go the halogen reaction, obtains the midbody compound shown in general formula 9, saponification reaction and go the sequencing of halogen reaction can be any wherein; When R was H, the midbody compound shown in general formula 7 through going the halogen reaction, obtained the midbody compound shown in general formula 9;
Wherein R is H or C
1～C
4Straight chain or alkyl or the benzyl of side chain, X is halogen.
According to the present invention, better, described midbody compound shown in general formula 3 carries out first protecting group reaction in the tetrazole functional group, and then priority is carried out reduction reaction claimed in claim 8, the midbody compound of formation shown in general formula 5, with the benzoglyoxaline annulation, form the midbody compound shown in general formula 6;
Wherein, the method of protecting group reaction comprises step in the tetrazole functional group: in organic inert solvent, under the effect of acid binding agent, tetrazole protective group reagent and the midbody compound shown in general formula 3 react; the midbody compound of formation shown in general formula 4
Wherein R is H or C
1～C
4Straight chain or alkyl or the benzyl of side chain, R ' is tetrazole protective group, X is H or halogen;
When R is C
1～C
4Straight chain or alkyl or the benzyl of side chain, when X is halogen, comprise saponification reaction, Deprotection reaction and go the halogen reaction from the step of the compound of the preparation of the compound shown in general formula 6 shown in general formula 9, described saponification reaction, Deprotection reaction and the sequencing that goes halogen to react are any, be in the following order any: a, saponification reaction, Deprotection reaction, go the halogen reaction; B, removes halogen reaction, Deprotection reaction at saponification reaction; C, goes halogen reaction at Deprotection reaction, saponification reaction; D, goes halogen reaction, saponification reaction at Deprotection reaction; E goes halogen reaction, Deprotection reaction, saponification reaction; And f, remove halogen reaction, saponification reaction, Deprotection reaction;
A is:
B is:
C is:
D is:
E is:
F is:
Wherein, R is C
1～C
4Straight chain or alkyl or the benzyl of side chain, R ' is tetrazole protective group, X is halogen;
When R is H, when X is halogen, comprise Deprotection reaction and go the halogen reaction from the step of the compound of the preparation of the compound shown in general formula 6 shown in general formula 9, described Deprotection reaction and the sequencing that goes halogen to react are any, be in the following order any: g, remove halogen reaction, Deprotection reaction; And h, Deprotection reaction, go halogen reaction,
G is:
H is:
Wherein, R is H, and R ' is tetrazole protective group, and X is halogen.
When R is H or C
1～C
4Straight chain or alkyl or the benzyl of side chain, R ' is tetrazole protective group, when X is H, but realizes from the compound shown in the general formula 6 preparation compound reference literature US5196444 shown in general formula 9.
The present invention solves the problems of the technologies described above four of the technical scheme that adopts: a kind of synthetic method of midbody compound of the candesartan Cilexetil shown in general formula 11 may further comprise the steps:
1) in organic inert solvent, under the effect of acid binding agent, tetrazole protective group reagent and the midbody compound shown in general formula 3 react, and form the midbody compound shown in general formula 4;
2) in organic inert solvent, at reductive agent, or under the effect of catalyzer and hydrogen source, the midbody compound shown in general formula 4 carries out reduction reaction, forms the midbody compound shown in general formula 5;
3) in organic inert solvent, the midbody compound shown in general formula 5 forms the midbody compound shown in general formula 6 by forming the benzoglyoxaline ring with the tetraethyl orthocarbonate reaction;
4) obtain midbody compound shown in general formula 11 by the midbody compound shown in general formula 6;
Wherein, R is H or C
1～C
4Straight chain or alkyl or the benzyl of side chain, R ' is tetrazole protective group, X is halogen;
When R is C
1～C
4Straight chain or alkyl or the benzyl of side chain, when X is halogen, midbody compound shown in general formula 6, pass through saponification reaction and go the halogen reaction, obtain the midbody compound shown in general formula 11, wherein, saponification reaction and the sequencing that goes halogen to react can be any, be in the following order any: a, go halogen reaction, saponification reaction; And b, saponification reaction, go halogen reaction,
A is:
Wherein, R is C
1～C
4Straight chain or alkyl or the benzyl of side chain, R ' is tetrazole protective group, X is halogen;
When R is H, when X was halogen, the midbody compound shown in general formula 6 through past halogen reaction, obtained the midbody compound shown in general formula 11,
Wherein R is H, and R ' is tetrazole protective group, and X is halogen.
When X was H, the midbody compound shown in general formula 6 can according to prior art, prepare the midbody compound shown in general formula 11.
Among the present invention, (compound 3 reduction form compound 10 to described all reduction reactions, reduction forms compounds 5 with compound 4) technology and step can be the method for the reduction reaction of this area routine, that is: in organic inert solvent, at reductive agent, or under the effect of catalyzer and hydrogen source, compound 3 or 4 carries out reduction reaction, forms the compound shown in general formula 10 or 5.Wherein, what described reductive agent was better is two hydrated stannous chlorides, one or more among the preferred Pd-C of catalyzer (palladium carbon), Pt-C (platinum carbon) and the Raney-Ni, and that best is Pd-C.The consumption of reductive agent is preferably 1～10 times of molar weight of compound 3 or 4, is more preferred from 1～3 times, and catalyst levels is preferably 0.01～1 times of molar weight of compound 3 or 4, is more preferred from 0.02～0.2 times.In the preferred hydrogen of described hydrogen source, hydrazine hydrate, sodium formiate, formic acid, ammonium formiate and the triethylammonium formate one or more, best is hydrogen.The consumption of hydrogen source is better is 1～infinite times of molar weight of compound 3 or 4, and better is infinite times.Described organic inert solvent better for being selected from lower alcohol and the ester solvent one or more, better is ester solvent.Described lower alcohol particular methanol, ethanol, propyl alcohol, Virahol and butanols, described ester solvent ethyl acetate and n-butyl acetate.The consumption of organic inert solvent is better is 1～100 times of molar weight of compound 3 or 4, better is 8～20 times.What the temperature of reaction was better is 0～80 ℃, preferred 15～30 ℃.The pressure of reaction is preferably 1～10atm, preferred 1～1.2atm.Till time, preferred TLC detecting reactant ran out of of reaction.
Among the present invention, (compound 10 forms compound 7 in described all formation benzoglyoxaline rings reaction, form compounds 6 with compound 5) technology and step can be the method for the formation benzoglyoxaline ring reaction of this area routine, that is: in organic inert solvent, compound 10 or 5 is by with tetraethyl orthocarbonate reaction or by phosgene three-step reaction or methyl-chloroformate four-step reaction, form the benzoglyoxaline ring, form compound 7 or 6.Wherein, according to the present invention, the method with the tetraethyl orthocarbonate reaction wherein is better method.Phosgene three-step reaction or methyl-chloroformate four-step reaction can be respectively referring to document J.Med.Chem., and 1993,36,2343 and J.Med.Chem., 1993,36,2182.In the reaction of described and tetraethyl orthocarbonate, what the mol ratio that compound 10 or 5 reacts with tetraethyl orthocarbonate was better is 1: 1～1: 100, better is 1: 1～1: 4.Reaction is conducive to the carrying out that react under the acidic conditions of pH5～6.One or more of sour preferable formic acid, acetic acid, dilute hydrochloric acid and the dilute sulphuric acid that the manufacturing acidic conditions is used.Described organic inert solvent is better is selected from aromatic hydrocarbon, ether and halogenated alkane.The preferred toluene of described aromatic hydrocarbon and dimethylbenzene, the preferred tetrahydrofuran (THF) of described ether, glycol dimethyl ether and dioxan, the preferred methylene dichloride of described halogenated alkane, chloroform and 1,2-ethylene dichloride.The consumption of organic inert solvent is better is 1～20 times of molar weight of the midbody compound shown in general formula 10 or 5, better is 8～12 times.What the temperature of reaction was better is 60～150 ℃, the preferred solvent reflux temperature.Till time, preferred TLC detecting reactant ran out of of reaction.
Among the present invention; (compound 3 forms compound 4 in the protecting group reaction in described all tetrazole functional groups; form compounds 11 with compound 9) technology and step can be the method for protecting group reaction in the tetrazole functional group of this area routine; that is: in organic inert solvent; under the effect of acid binding agent; tetrazole protective group reagent and compound 3 or 9 react, and form compound 4 or 11.Compound 3 or 9 tetrazole have obtained protection, and the productive rate of the building-up reactions of this substrate is improved, and are conducive to the carrying out that reacts.Wherein said tetrazole protective group reagent can be this area routine with can with the tetrazole functional groups after; give the compound of the protection that tetrazole functional group provides; better is triphenylmethyl chloride, benzyl chlorine or benzyl bromine, the silica-based methyl chloride of dimethyl uncle fourth, and better is triphenylmethyl chloride.Compound 3 or 9 and the mol ratio of tetrazole protective group reagent react better be 1: 1～10: 1, best is 1: 1～1.1: 1.Described acid binding agent is this area acid binding agent commonly used, and better is selected from alkaline matter for being selected from triethylamine, pyridine, N-methylmorpholine, quinoline, diisopropyl ethyl amine, yellow soda ash and salt of wormwood, preferred triethylamine.The mole dosage of acid binding agent is better is compound 3 or 9 molar weights 1～10 times, preferably 1～2 times.What organic inert solvent was better is methylene dichloride.The consumption of organic inert solvent is better is 1～100 times of molar weight of compound 3 or 9, and best is 10～30 times.What temperature of reaction was better is-10～50 ℃, and the best is 0～10 ℃.Till time, preferred TLC detecting reactant ran out of of reaction.
In all technical scheme of the present invention, described saponification reaction, go halogen reaction, Deprotection reaction can adopt this area routine method condition and step, specifically be described below:
Saponification reaction and optimum condition thereof that each intermediate described in the present invention occurs are identical.Saponification reaction is: in polar solvent, under the alkaline matter effect, R is C in the described structural formula
1～C
4Straight chain or the alkyl of side chain or the compound of benzyl carry out saponification reaction, form that R is the compound of H in the described structural formula.Wherein, described alkaline matter is better is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, preferred sodium hydroxide.The preferred C1 of the described polar solvent～straight chain of C5 carbon or the alcohol and water mixture of side chain, preferred 0.1: 1～10: 1 of the ratio of alcohol and water, more preferably 0.5: 1～2: 1.The consumption of polar solvent is 1～20 times of molar weight of substrate, better is 8～10 times.What the temperature of reaction was better is 60～120 ℃, the preferred solvent reflux temperature.Till time, preferred TLC detecting reactant ran out of of reaction.
Each intermediate described in the present invention occurs goes halogen reaction and optimum condition thereof identical.Go the halogen reaction to be: in the mixed solvent of rudimentary alcohol and water, under the effect of catalyzer and hydrogen source, halogen-containing compound reacts in the described structural formula, forms not halogen-containing compound in the described structural formula.Wherein, one or more among the preferred Pd-C of described catalyzer, Pt-C and the Raney-Ni.Catalyst levels is 0.01～0.2 times of molar weight of the midbody compound shown in the substrate, is preferably 0.02～0.1 times.In the preferred hydrogen of described hydrogen source, hydrazine hydrate, formic acid and the formate one or more.In described formate preferable formic acid sodium, ammonium formiate and the formic acid triethylamine one or more, most preferably sodium formiate.The consumption of hydrogen source is 1～10 times of the midbody compound molar weight shown in the substrate, is preferably 2～4 times.Described lower alcohol particular methanol, ethanol, propyl alcohol, Virahol and butanols, most preferably methyl alcohol.The ratio of rudimentary alcohol and water is 0.1: 1～10: 1, is preferably 0.2: 1～2: 1.The consumption of the mixed solvent of rudimentary alcohol and water is better is 1～40 times of molar weight of reaction substrate, is preferably 8～20 times.What temperature of reaction was better is 50～120 ℃, the preferred solvent reflux temperature.Till the time preferred detection reactant consumption of reaction is complete.
Deprotection reaction and optimum condition thereof that each midbody compound described in the present invention occurs then as the standard practice that goes tetrazole protective group of this area, according to different protecting groups, adopt the different protecting group methods of going.
When described protecting group was trityl, described Deprotection reaction was: in lower alcohol solvent, under the effect of acid, R ' reacts for the compound of tetrazole protective group in the described structural formula, forms that R ' is the compound of H in the described structural formula.Wherein, the preferred C of described lower alcohol
1～C
5One or more of the straight chain of carbon or the alcohol of side chain, most preferably methyl alcohol; The consumption of lower alcohol is 1～20 times of reaction substrate molar weight, preferred 8～12 times; One or more of described sour preferable formic acid, acetic acid, dilute hydrochloric acid, dilute sulphuric acid and tosic acid, most preferably tosic acid; The consumption of acid is 0.1～10 times of the molar weight of substrate, preferred 1～2 times; What the temperature of reaction was better is 0～60 ℃, preferred 10～30 ℃.Till time, preferred TLC detecting reactant ran out of of reaction.
When described protecting group is benzyl; described Deprotection reaction is: in organic polar solvent; under the effect of catalyzer and hydrogen source, R ' reacts for the compound of tetrazole protective group in the described structural formula, forms that R ' is the compound of H in the described structural formula.Wherein, the preferred lower alcohol of described organic polar solvent, the preferred C of described lower alcohol
1～C
5One or more of the straight chain of carbon or the alcohol of side chain, most preferably methyl alcohol; The consumption of organic polar solvent is 1～20 times of substrate reactions molar weight, preferred 8～12 times; Among the preferred Pd-C of described catalyzer, Pt-C and the Raney-Ni one or more, that best is Pd-C; Described catalyst levels is preferably 0.01～1 times of substrate reactions molar weight, is more preferred from 0.02～0.2 times; In the preferred hydrogen of described hydrogen source, hydrazine hydrate, sodium formiate, formic acid, ammonium formiate and the triethylammonium formate one or more, best is hydrogen.The consumption of hydrogen source is better is 1 of substrate reactions molar weight～infinite times, and better is infinite times.What the temperature of reaction was better is 0～80 ℃, preferred 15～30 ℃.The pressure of reaction is preferably 1～10atm, preferred 1～1.2atm.Till time, preferred TLC detecting reactant ran out of of reaction.
When described protecting group is that the dimethyl tertiary butyl is when silica-based; described Deprotection reaction is: in ether solvent; under TBAF (tetrabutyl ammonium fluoride) effect; R ' reacts for the compound of tetrazole protective group in the described structural formula, forms that R ' is the compound of H in the described structural formula.Wherein, one or more of the preferred ether of described ether solvent, methyl tertiary butyl ether, THF (tetrahydrofuran (THF)), methyltetrahydrofuran, dioxane, most preferably THF; The consumption of ether solvent is 1～20 times of substrate reactions molar weight, preferred 8～12 times; Described TBAF consumption is 1～10 times of substrate reactions molar weight, preferred 1～2 times; What the temperature of reaction was better is 0～60 ℃, preferred 10～30 ℃.Till time, preferred TLC detecting reactant ran out of of reaction.
Above-mentioned midbody compound 3,4,5,10 is one of described midbody compound I, and midbody compound thing 6,7,12,13 is one of described midbody compound II.When X in the general formula is halogen, to compare when being H with X, the reaction raw materials of synthetic intermediate I and intermediate II more easily obtains, and synthetic route is simpler, and cost pressure is less.Above-mentioned midbody compound 9; it is Candesartan; can be according to prior art; as described in document US 5196444; tetrazole protective group radical reaction on the process; form midbody compound 11; then pass through esterification and deprotection reaction; final as shown in Equation 17 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLE-5-) [1 that forms; 1 '-xenyl]-the 4-yl] methyl]-1-H-benzoglyoxaline-7-carboxylic acid-1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester, i.e. candesartan cilexetil.
Agents useful for same of the present invention and raw material equal commercially available getting except specifying.
Than prior art, advantage of the present invention is as follows: midbody compound of the present invention and related methods of synthesis can be used for preparing the candesartan Cilexetil medicine, wherein can avoid using expensive, hypertoxic palladium catalyst and tributyl nitrine tin etc., working method more simple and convenient (need not absolute anhydrous condition), not only be fit to the laboratory and prepare on a small quantity, also be fit to large-scale industrialization production.
Embodiment
Further specify the present invention below in conjunction with embodiment, but the present invention is not limited.Those skilled in the art are on the basis of technical scheme provided by the present invention, and any improvement by simple logic analysis, reasoning or limited test are done is included in the technical scheme of the present invention.Normal temperature of the present invention is 20～40 ℃, and normal pressure is 0.8atm～1.2atm.
[1,1 '-xenyl]-4-yl of embodiment 1 2-[[(2 '-1H-TETRAZOLE-5-)] methylamino]-preparation of 3-nitrobenzene methyl
2-chloro-3-nitrobenzene methyl (4.5g, 21mmol) add in the 100mL ethanol with 4 '-amino methyl-2-(1H-tetrazole-5-yl) biphenyl hydrochloride salt (6.6g, 23mmol), add triethylamine (8mL, 63mmol), be heated to 100 ℃ of reaction 24h.Then desolventizing, with ethyl acetate-water extraction separatory, organic phase is collected, and adds 4N HCl acidifying crystallization, filters, and oven dry gets solid 7.8g, yield 86%.
1H?NMR(300MHz，CDCl
3)δ：3.81(s，3H，OCH
3)，4.25(d，2H，NHCH
2)，7.53-8.60(m，11H，ArH).
[1,1 '-xenyl]-4-yl of embodiment 2 2-[[(2 '-1H-TETRAZOLE-5-)] methylamino]-preparation of the positive butyl ester of 3-nitrobenzoic acid
Positive butyl ester (the 2.6g of 2-chloro-3-nitrobenzoic acid, 10mmol) with 4 '-amino methyl-2-(1H-tetrazole-5-yl) biphenyl hydrochloride salt (2.6g, 9mmol) add in the 100mL propyl carbinol, add diisopropyl ethyl amine (2.7mL, 20mmol), be heated to 100 ℃ of reaction 24h.Then desolventizing, with ethyl acetate-water extraction separatory, organic phase is collected, and adds 4N HCl acidifying crystallization, filters, and oven dry gets solid 3.4g, yield 80%.
1H?NMR(300MHz，CDCl
3)δ：1.05(t，3H，CH
2 CH 3 )，1.33(m，2H，
CH 2 CH
3)，1.75(m，2H，
CH 2 CH
2CH
3)，4.25(d，2H，NH
CH 2)，4.02(t，3H，OCH
2)，7.53-8.60(m，11H，ArH).
[1,1 '-xenyl]-4-yl of embodiment 3 2-[[(2 '-1H-TETRAZOLE-5-)] methylamino]-preparation of 3-nitrobenzoyl acid benzyl ester
2-chloro-3-nitrobenzoyl acid benzyl ester (5.8g, 20mmol) and [(2 '-1H-TETRAZOLE-5-) [1,1 '-xenyl]-4-yl] methylamine (5.5g, 22mmol) add in the 100mL dimethyl sulfoxide (DMSO), add pyridine (3.2g, 40mmol), be heated to 80 ℃ of reaction 24h.Then desolventizing, with ethyl acetate-water extraction separatory, organic phase is collected, and adds 4N HCl acidifying crystallization, filters, and oven dry gets solid 8.4g, yield 83%.
1H?NMR(300MHz，CDCl
3)δ4.25(d，2H，NH
CH 2)，7.53-8.41(m，16H，ArH).
Embodiment 4 2-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-4-yl] methylamino]-preparation of 3-nitrobenzene methyl
2-[[(2 '-1H-TETRAZOLE-5-) [1,1 '-xenyl]-the 4-yl] methylamino]-3-nitrobenzene methyl (4.0g, 9.3mmol) add in the 100mL methylene dichloride, add triethylamine (2.34mL, 18.6mmol), triphenylmethyl chloride (2.84g, 10.2mmol) adds under ice bath in batches, adds the recession deicing and bathes, the 2-3h afterreaction is complete, remove most of solvent, aforesaid liquid is added in the ethanol of 50mL heat (80 ℃) cooling crystallization after the dissolving, filter, oven dry gets solid 6.1g, yield 97%.
1H?NMR(300MHz，CDCl
3)δ：3.79(s，3H，OCH
3)，4.11(d，2H，NHB
CH 2)，7.09-8.51(m，26H，ArH).
Embodiment 5 2-[[[2 '-1-(benzyl-tetrazolium)-5-] [1,1 '-xenyl]-4-yl] methylamino]-preparation of 3-nitrobenzene methyl
[1,1 '-xenyl]-4-yl of 2-[[(2 '-1H-TETRAZOLE-5-)] methylamino]-3-nitrobenzene methyl (4.3g, 10mmol) adds among the 100mL DMF, add triethylamine (2.69mL, 20mmol) and bromobenzyl (1.86g, 11mmol), be warming up to 100 ℃ of reaction 8h, remove most of solvent, add 50mL water with ethyl acetate extraction, anhydrous sodium sulfate drying, column chromatography for separation after the filtering and concentrating, get incarnadine thick liquid 3.7g, yield 71%.
1H?NMR(300MHz，CDCl
3)δ：3.79(s，3H，OCH
3)，4.11(d，2H，NH
CH 2)，4.97(s，2H，N
CH 2)，6.99-8.51(m，16H，ArH).
Embodiment 6 2-[[[2 '-1-(the dimethyl tertiary butyl silica-based-tetrazolium)-5-] [1,1 ' xenyl]-4-yl] methylamino]-preparation of 3-nitrobenzene methyl
[1,1 '-xenyl]-4-yl of 2-[[(2 '-1H-TETRAZOLE-5-)] methylamino]-3-nitrobenzene methyl (0.43g, 1mmol) adds among the 10mL DMF, add imidazoles (0.14g, 2mmol), the lower TBDMSCl (0.17g, 1.1mmol) that adds of ice bath cooling, be warming up to 100 ℃ of reaction 2h, remove most of solvent, add entry with ethyl acetate extraction, column chromatography for separation after anhydrous sodium sulfate drying is concentrated, get white powder 0.32g, yield 57%.
1H?NMR(300MHz，CDCl
3)δ：0.08(s，6H，SiCH
3)，1.05(s，9H，SiC(CH
3)
3)，3.8(s，3H，OCH
3)，4.11(d，2H，NH
CH 2)，4.97(s，2H，N
CH 2)，7.13-8.29(m，11H，ArH).
Embodiment 7 2-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-4-yl] methylamino]-preparation of 3-amido methyl benzoate
2-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-the 4-yl] methylamino]-3-nitrobenzene methyl (6.0g, 9.0mmol) adding 60mL ethyl acetate and 10% palladium carbon (0.6g, 0.9mmol), 2h is stirred in 25 ℃ of reactions under 1～5atm hydrogen pressure, filter, the filtrate desolventizing gets solid 5.8g, yield 100%.
1H?NMR(300MHz，CDCl
3)δ：3.83(s，3H，OCH
3)，4.26(d，2H，NH
CH 2)，7.01-7.95(m，26H，ArH).
[1,1 '-xenyl]-4-yl of embodiment 8 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLEs-5-)] methyl]-preparation of 1-H-benzoglyoxaline-7-methyl benzoate
2-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-4-yl] methylamino]-3-amido methyl benzoate (5.0g, 7.8mmol) adds in the 50mL dimethylbenzene, add tetraethyl orthocarbonate (4.0mL, 19.5mmol), add the 0.2mL Glacial acetic acid, be heated to 120 ℃ of reactions, stopped reaction behind the 3h is with the washing of 5% sodium bicarbonate aqueous solution, again washing, organic phase is collected, desolventizing gets faint yellow solid 5.8g, and product is directly used in next step reaction.
1H?NMR(300MHz，CDCl
3)δ：1.29(t，3H，CH
2 CH 3)，3.79(s，3H，OCH
3)，4.25(q，2H，
CH 2CH
3)，5.72(s，2H，N
CH 2)，7.11-7.85(m，26H，ArH).
[1,1 '-xenyl]-4-yl of embodiment 9 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLEs-5-)] methyl]-preparation of 1-H-benzoglyoxaline-7-methyl benzoate
2-oxyethyl group-1-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-the 4-yl] methyl]-1-H-benzoglyoxaline-7-methyl benzoate (5.3g, 7.6mmol) adding 50mL methyl alcohol, add a hydration tosic acid (1.4g, 7.6mmol), 2h just has a large amount of white solids to separate out, rear filtration reacts completely, drain, remove solvent under reduced pressure, with ethyl acetate-water extraction separatory, organic phase is collected, dry concentrated crude product is directly used in next step reaction, gets solid 3.3g, yield 100%.
1H?NMR(300MHz，CDCl
3)δ：1.19(s，3H，CH
2 CH 3)，3.79(s，3H，OCH
3)，4.27(s，2H，
CH 2CH
3)，5.73(s，2H，N
CH 2)，7.11-7.78(m，11H，ArH).
[1,1 '-xenyl]-4-yl of embodiment 10 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLEs-5-)] methyl]-preparation of 1-H-benzoglyoxaline-7-methyl benzoate
2-oxyethyl group-1-[[[2 '-1-(benzyl-tetrazolium)-5-] [1,1 '-xenyl]-the 4-yl] methyl]-1-H-benzoglyoxaline-7-methyl benzoate (0.54g, 1.0mmol) adding 15mL methyl alcohol and 10% palladium carbon (0.05g, 0.1mmol), 4h is stirred in 25 ℃ of reactions under 1～5atm hydrogen pressure, filter, the filtrate desolventizing gets solid 0.46g, yield 100%.
[1,1 '-xenyl]-4-yl of embodiment 11 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLEs-5-)] methyl]-preparation of 1-H-benzoglyoxaline-7-methyl benzoate
2-oxyethyl group-1-[[[2 '-1-(the dimethyl tertiary butyl silica-based-tetrazolium)-5-] [1,1 '-xenyl]-the 4-yl] methyl]-1-H-benzoglyoxaline-7-methyl benzoate (0.54g, 1.0mmol) add the 10mL tetrahydrofuran (THF) and be cooled to 0 ℃ and drip 1M TBAF and get tetrahydrofuran solution (2mL, 2mmol), 12h is stirred in 25 ℃ of reactions, concentrated rear acetic acid ethyl dissolution, wash with water, organic layer is dry, and filtering and concentrating gets solid 0.36g, yield 72%.
[1,1 '-xenyl]-4-yl of embodiment 12 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLEs-5-)] methyl]-preparation of 1-H-benzoglyoxaline-7-methyl benzoate
2-[[(2 '-1H-TETRAZOLE-5-) [1,1 '-xenyl]-the 4-yl] methylamino]-3-nitrobenzene methyl (4.3g, 10.0mmol) adding 100mL methyl alcohol and Raney-Ni (59mg, 1mmol) and sodium formiate (2.01g, 30mmol), 24h is stirred in 80 ℃ of reactions, filters, and the filtrate desolventizing is directly used in next step reaction.Add 10mL tetraethyl orthocarbonate and 0.5mL acetic acid, be heated to 80 ℃ of reaction 4h.Concentrating under reduced pressure gets resistates to carry out column chromatography for separation and gets the 1.73g white solid, yield 37%.
[1,1 '-xenyl]-4-yl of embodiment 13 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLEs-5-)] methyl]-the benzoic preparation of 1-H-benzoglyoxaline-7-
2-oxyethyl group-1-[[(2 '-1H-TETRAZOLE-5-) [1,1 '-xenyl]-the 4-yl] methyl]-1-H-benzoglyoxaline-7-methyl benzoate (1.8g, 2.5mmol) add in the 20mL ethanol, add 20mL water, add 1.0g sodium hydroxide, heating reflux reaction, stopped reaction behind the 3h, remove ethanol, add ethyl acetate extraction, wash organic phase with water, water is collected, with 4N HCl aqueous pH values is transferred to 5-6, white solid is separated out, and filters, oven dry, ethyl alcohol recrystallization gets white cotton-shaped solid 1.5g, yield 83%
1H?NMR(300MHz，CDCl
3)δ：1.39(s，3H，CH
2 CH 3)，3.79(s，3H，OCH
3)，4.55(s，2H，
CH 2CH
3)，5.63(s，2H，N
CH 2)，6.97-7.67(m，11H，ArH).
[1,1 '-xenyl]-4-yl of embodiment 14 2-[[(2 '-1H-TETRAZOLE-5-)] methylamino]-preparation of 5-chloro-3-nitrobenzene methyl
2,5-, two chloro-3-nitrobenzene methyls (5.2g, 21mmol) and 4 '-amino methyl-2-(1H-tetrazole-5-yl) biphenyl hydrochloride salt (6.6g, 23mmol) add in the 100mL acetone, add N-methylmorpholine (8mL, 63mmol), be heated to 100 ℃ of reaction 24h.Then desolventizing, with ethyl acetate-water extraction separatory, organic phase is collected, and adds 4N HCl acidifying crystallization, filters, and oven dry gets solid 8.9g, yield 89%.
1H?NMR(300MHz，CDCl
3)δ：3.81(s，3H，OCH
3)，4.25(d，2H，NHCH
2)，7.53-8.60(m，10H，ArH).
[1,1 '-xenyl]-4-yl of embodiment 15 2-[[(2 '-1H-TETRAZOLE-5-)] methylamino]-preparation of 5-bromo-3-nitrobenzene methyl
2,5-, two bromo-3-nitrobenzene methyls (1.7g, 5mmol) and 4 '-amino methyl-2-(1H-tetrazole-5-yl) biphenyl hydrochloride salt (1.4g, 4.8mmol) add among the 50mL DMF, add yellow soda ash (1.3mL, 10mmol), be heated to 120 ℃ of reaction 24h.Then desolventizing, with ethyl acetate-water extraction separatory, organic phase is collected, and adds 4N HCl acidifying crystallization, filters, and oven dry gets solid 2.2g, yield 91%.
1H?NMR(300MHz，CDCl
3)δ：3.76(s，3H，OCH
3)，4.25(d，2H，NHCH
2)，7.53-8.42(m，10H，ArH).
Embodiment 16 2-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-4-yl] methylamino]-preparation of 5-chloro-3-nitrobenzene methyl
2-[[(2 '-1H-TETRAZOLE-5-) [1,1 '-xenyl]-the 4-yl] methylamino]-5-chloro-3-nitrobenzene methyl (4.3g, 9.3mmol) add in the 100mL methylene dichloride, add triethylamine (2.34mL, 18.6mmol), triphenylmethyl chloride (2.84g, 10.2mmol) adds under ice bath in batches, adds the recession deicing and bathes, 2～3h afterreaction is complete, remove most of solvent, aforesaid liquid is dissolved in the ethanol of 50mL heat (80 ℃) cooling crystallization, filter, oven dry gets solid 6.5g, yield 97%.
1H?NMR(300MHz，CDCl
3)δ：3.79(s，3H，OCH
3)，4.11(d，2H，NHCH
2)，7.09-8.51(m，25H，ArH).
Embodiment 17 2-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-4-yl] methylamino]-preparation of 5-chloro-3-amido methyl benzoate
2-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-the 4-yl] methylamino]-5-chloro-3-nitrobenzene methyl (6.4g, 9.0mmol) adding 60mL ethanol and two hydrated stannous chloride (6.12g, 27mmol), add the neutralization of 4N sodium hydroxide solution behind 80 ℃ of reaction 2h, ethyl acetate extraction, desolventizing get solid 4.77g, yield 82%.
1H?NMR(300MHz，CDCl
3)δ：3.83(s，3H，OCH
3)，4.26(d，2H，NH
CH 2)，7.01-7.95(m，25H，ArH).
Embodiment 18 2-oxyethyl group-1-[[2 '-1-(trityl-tetrazolium) [1,1 '-xenyl]-4-yls] methyl]-preparation of 1-H-benzoglyoxaline-5-chloro-7-methyl benzoate
2-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-4-yl] methylamino]-3-amido methyl benzoate (5.3g, 7.8mmol) adds in the 50mL toluene, add tetraethyl orthocarbonate (4.0mL, 19.5mmol), add the 0.2mL Glacial acetic acid, be heated to 120 ℃ of reactions, stopped reaction behind the 3h is with the washing of 5% sodium bicarbonate aqueous solution, again washing, organic phase is collected, desolventizing gets faint yellow solid 5.9g, and product is directly used in next step reaction.
1H?NMR(300MHz，CDCl
3)δ：1.29(t，3H，CH
2 CH 3)，3.79(s，3H，OCH
3)，4.25(q，2H，
CH 2CH
3)，5.72(s，2H，N
CH 2)，7.11-7.85(m，25H，ArH).
[1,1 '-xenyl]-4-yl of embodiment 19 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLEs-5-)] methyl]-preparation of 1-H-benzoglyoxaline-5-chloro-7-methyl benzoate
2-oxyethyl group-1-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-the 4-yl] methyl]-1-H-benzoglyoxaline-7-methyl benzoate (5.8g, 7.9mmol) adding 50mL methyl alcohol, add a hydration tosic acid (1.5g, 7.9mmol), 2h just has a large amount of white solids to separate out, rear filtration reacts completely, remove solvent under reduced pressure, with ethyl acetate-water extraction separatory, organic phase is collected, and dry concentrated crude product is directly used in next step reaction, get solid 3.3g, yield 96%.
1H?NMR(300MHz，CDCl
3)δ：1.20(s，3H，CH
2 CH 3)，3.83(s，3H，OCH
3)，4.31(s，2H，
CH 2CH
3)，5.71(s，2H，N
CH 2)，7.11-7.81(m，10H，ArH).
[1,1 '-xenyl]-4-yl of embodiment 20 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLEs-5-)] methyl]-1-H-benzoglyoxaline-benzoic preparation of 5-chloro-7-
2-oxyethyl group-1-[[(2 '-1H-TETRAZOLE-5-) [1,1 '-xenyl]-the 4-yl] methyl]-1-H-benzoglyoxaline-5-chloro-7-methyl benzoate (1.3g, 2.5mmol) add in the 20mL ethanol, add 20mL water, add 1.0g sodium hydroxide, heating reflux reaction, stopped reaction behind the 3h, remove ethanol, add ethyl acetate extraction, wash organic phase with water, water is collected, with 4N HCl aqueous pH values is transferred to 4～5, white solid is separated out, and filters, oven dry, ethyl alcohol recrystallization gets white cotton-shaped solid 1.01g, yield 82%
1H?NMR(300MHz，CDCl
3)δ：1.39(s，3H，CH
2 CH 3)，3.79(s，3H，OCH
3)，4.55(s，2H，
CH 2CH
3)，5.63(s，2H，N
CH 2)，6.97-7.67(m，10H，ArH).
[1,1 '-xenyl]-4-yl of embodiment 21 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLEs-5-)] methyl]-the benzoic preparation of 1-H-benzoglyoxaline-7-
2-oxyethyl group-1-[[(2 '-1H-TETRAZOLE-5-) [1,1 '-xenyl]-the 4-yl] methyl]-1-H-benzoglyoxaline-5-chloro-7-phenylformic acid (1.0g, 2.0mmol) adds in the 15mL ethanol, adds 15mL water, add sodium formiate (0.4g, 6.0mmol) and 10% palladium carbon (0.02g, 0.6mmol), heating reflux reaction, stopped reaction behind the 12h, remove ethanol, add ethyl acetate extraction, wash organic phase with water, water is collected, with 4N HCl aqueous pH values is transferred to 4-5, white solid is separated out, and filters, oven dry, ethyl alcohol recrystallization gets white cotton-shaped solid 0.85g, yield 87%.
1H?NMR(300MHz，CDCl
3)δ：1.39(s，3H，CH
2 CH 3)，3.79(s，3H，OCH
3)，4.55(s，2H，
CH 2CH
3)，5.63(s，2H，N
CH 2)，6.97-7.67(m，11H，ArH).
Embodiment 22 2-oxyethyl group-1-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-4-yl] methyl]-preparation of 1-H-benzoglyoxaline-7-methyl benzoate
2-oxyethyl group-1-[[[2 '-1-(trityl-tetrazolium)-5-] [1,1 '-xenyl]-the 4-yl] methyl]-1-H-benzoglyoxaline-5-chloro-7-methyl benzoate (1.4g, 2.0mmol) add in the water of 15mL ethanol and 15mL, add again Raney-Ni (12mg, 0.2mmol), logical hydrogen hydrogenation, 48h is stirred in the lower 25 ℃ of reactions of 30atm hydrogen pressure, filter, carry out recrystallization with the second alcohol and water after the filtrate desolventizing and must get white solid 0.79g, yield 57%.
[1,1 '-xenyl]-4-yl of embodiment 23 2-oxyethyl group-1-[[(2 '-1H-TETRAZOLEs-5-)] methyl]-the benzoic preparation of 1-H-benzoglyoxaline-7-
2-oxyethyl group-1-[[2 '-1-(trityl-tetrazolium) [1,1 '-xenyl]-the 4-yl] methyl]-1-H-benzoglyoxaline-5-chloro-7-methyl benzoate (0.73g, 1.0mmol) add 10mL ethanol and 10mL water, add LiOH (0.72mg, 3.0mmol) and be warming up to 60 ℃ of reaction 2h, the gained dope adds 10mL methyl alcohol and a hydration tosic acid (0.19mg after concentrated, 1.0mmol), 20 ℃ are stirred 2h, the concentrated rear ethyl acetate-moisture liquid that adds, ethyl acetate layer washs with saturated sodium bicarbonate solution, dry concentrated gained residue adds 10mL ethanol and 10mL water, adds sodium formiate (0.32g, 5.0mmol) and 10% platinum carbon (0.03g again, 0.05mmol), heating reflux reaction, stopped reaction behind the 12h is removed ethanol, add ethyl acetate extraction, wash organic phase with water, water is collected, and with 4N HCl aqueous pH values is transferred to 4-5, white solid is separated out, filter oven dry, ethyl alcohol recrystallization, get white cotton-shaped solid 92mg, yield 21%.
Claims (12)
1. the midbody compound of the candesartan Cilexetil shown in general formula I,
Wherein, M is H or O, and R is H or C
1～C
4Straight chain or alkyl or the benzyl of side chain, R ' is tetrazole protective group, X is H; Perhaps R ' is H or tetrazole protective group, and X is halogen; It is silica-based that described tetrazole protective group is selected from trityl, benzyl and the dimethyl tertiary butyl.
2. midbody compound according to claim 1 is characterized in that, described halogen respectively alone be Cl or Br.
3. the synthetic method of the midbody compound of the candesartan Cilexetil shown in general formula 3, it is characterized in that, comprise the steps: in organic inert solvent, with alkaline matter as acid binding agent, compound shown in general formula 1 and compound or its salt shown in general formula 2 are carried out linked reaction, the midbody compound of formation shown in general formula 3
Wherein R is H or C
1～C
4Straight chain or alkyl or the benzyl of side chain, X is H or halogen, Z is halogen.
4. synthetic method according to claim 3 is characterized in that, described alkaline matter is selected from triethylamine, pyridine, N-methylmorpholine, quinoline, diisopropyl ethyl amine, yellow soda ash and salt of wormwood.
5. synthetic method according to claim 3 is characterized in that, described organic inert solvent is selected from lower alcohol, ketone, aromatic hydrocarbon, ether, halogenated alkane, DMF, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO) and acetonitrile; Described lower alcohol is the alcohol of carbon chain lengths C1～C4.
6. synthetic method according to claim 3 is characterized in that, the temperature of reaction is 80～120 ℃, till the time of reaction runs out of with detecting reactant.
7. the synthetic method of the midbody compound of the candesartan Cilexetil shown in general formula 9 is characterized in that, may further comprise the steps:
1) in organic inert solvent, at reductive agent, or under the effect of catalyzer and hydrogen source, the midbody compound shown in general formula 3 carries out reduction reaction, forms the midbody compound shown in general formula 10;
2) in organic inert solvent, the midbody compound shown in general formula 10 forms the benzoglyoxaline ring by reacting with tetraethyl orthocarbonate, forms the midbody compound shown in general formula 7;
3) when R be C
1～C
4Straight chain or when the alkyl of side chain or benzyl, the midbody compound shown in general formula 7 through saponification reaction with go the halogen reaction, obtains the midbody compound shown in general formula 9, saponification reaction and go the sequencing of halogen reaction can be any wherein; When R was H, the midbody compound shown in general formula 7 through going the halogen reaction, obtained the midbody compound shown in general formula 9;
Wherein, R is H or C
1～C
4Straight chain or alkyl or the benzyl of side chain, X is halogen.
8. the preparation method of the compound shown in general formula 9 is characterized in that, 1) described midbody compound shown in general formula 3 carries out first protecting group reaction in the tetrazole functional group; 2) in organic inert solvent, at reductive agent, or under the effect of catalyzer and hydrogen source, the midbody compound shown in general formula 4 carries out reduction reaction, forms the midbody compound shown in general formula 5; 3) in organic inert solvent, the midbody compound shown in general formula 5 forms the benzoglyoxaline ring by reacting with tetraethyl orthocarbonate, finally forms the midbody compound shown in general formula 6;
Wherein, the method of protecting group reaction comprises step in the tetrazole functional group: in organic inert solvent, under the effect of acid binding agent, tetrazole protective group reagent and the midbody compound shown in general formula 3 react; the midbody compound of formation shown in general formula 4
Wherein R is H or C
1～C
4Straight chain or alkyl or the benzyl of side chain, R ' is tetrazole protective group, X is H or halogen;
When R is C
1～C
4Straight chain or alkyl or the benzyl of side chain, when X is halogen, comprise saponification reaction, Deprotection reaction and go the halogen reaction from the step of the compound of the preparation of the compound shown in general formula 6 shown in general formula 9, described saponification reaction, Deprotection reaction and the sequencing that goes halogen to react are any, be in the following order any: a, saponification reaction, Deprotection reaction, go the halogen reaction; B, removes halogen reaction, Deprotection reaction at saponification reaction; C, goes halogen reaction at Deprotection reaction, saponification reaction; D, goes halogen reaction, saponification reaction at Deprotection reaction; E goes halogen reaction, Deprotection reaction, saponification reaction; And f, remove halogen reaction, saponification reaction, Deprotection reaction;
A is:
B is:
C is:
D is:
E is:
F is:
Wherein, R is C
1～C
4Straight chain or alkyl or the benzyl of side chain, R ' is tetrazole protective group, X is halogen;
When R is H, when X is halogen, comprise Deprotection reaction and go the halogen reaction from the step of the compound of the preparation of the compound shown in general formula 6 shown in general formula 9, described Deprotection reaction and the sequencing that goes halogen to react are any, be in the following order any: g, remove halogen reaction, Deprotection reaction; And h, Deprotection reaction, go halogen reaction,
G is:
Wherein, R is H, and R ' is tetrazole protective group, and X is halogen.
9. the synthetic method of the midbody compound of the candesartan Cilexetil shown in general formula 11 is characterized in that, may further comprise the steps:
1) in organic inert solvent, under the effect of acid binding agent, tetrazole protective group reagent and the midbody compound shown in general formula 3 react, and form the midbody compound shown in general formula 4;
2) in organic inert solvent, at reductive agent, or under the effect of catalyzer and hydrogen source, the midbody compound shown in general formula 4 carries out reduction reaction, forms the midbody compound shown in general formula 5;
3) in organic inert solvent, the midbody compound shown in general formula 5 forms the midbody compound shown in general formula 6 by forming the benzoglyoxaline ring with the tetraethyl orthocarbonate reaction;
4) by the midbody compound shown in general formula 6, obtain the midbody compound shown in general formula 11;
Wherein, R is H or C
1～C
4Straight chain or alkyl or the benzyl of side chain, R ' is tetrazole protective group, X is halogen;
When R is C
1～C
4Straight chain or alkyl or the benzyl of side chain, when X is halogen, midbody compound shown in general formula 6, pass through saponification reaction and go the halogen reaction, obtain the midbody compound shown in general formula 11, wherein, saponification reaction and the sequencing that goes halogen to react can be any, be in the following order any: a, go halogen reaction, saponification reaction; And b, saponification reaction, go halogen reaction,
A is:
B is:
Wherein, R is C
1～C
4Straight chain or alkyl or the benzyl of side chain, R ' is tetrazole protective group, X is halogen;
When R is H, when X was halogen, the midbody compound shown in general formula 6 through past halogen reaction, obtained the midbody compound shown in general formula 11,
Wherein, R is H, and R ' is tetrazole protective group, and X is halogen.
10. according to claim 7, each described synthetic method in 8 and 9, it is characterized in that, described reductive agent is two hydrated stannous chlorides; Described catalyzer is selected from one or more among Pd-C, Pt-C and the Raney-Ni; Described hydrogen source is selected from one or more in hydrogen, hydrazine hydrate, sodium formiate, formic acid, ammonium formiate and the triethylammonium formate.
11. according to claim 7, each described synthetic method in 8 and 9, it is characterized in that, the described reaction conditions of halogen reaction that goes is: in the mixed solvent of rudimentary alcohol and water, under the effect of catalyzer and hydrogen source, halogen-containing compound reacts in the described structural formula, forms not halogen-containing compound in the described structural formula; Described lower alcohol is the alcohol of carbon chain lengths C1～C4.
12. synthetic method according to claim 11, it is characterized in that, described catalyzer is selected from one or more among Pd-C, Pt-C and the Raney-Ni, and described hydrogen source is selected from hydrogen, hydrazine hydrate, formic acid, sodium formiate, one or more in ammonium formiate and the triethylammonium formate; Temperature of reaction is 50～120 ℃, till the reaction times runs out of with detecting reactant.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5196444A (en) * | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
| CN1425654A (en) * | 2003-01-07 | 2003-06-25 | 江苏省药物研究所 | Process for preparing 2-alkoxybenzimidazole compound |
| CN1800179A (en) * | 2005-12-22 | 2006-07-12 | 浙江天宇药业有限公司 | Method for preparing candestartan |
| CN101200464A (en) * | 2007-12-04 | 2008-06-18 | 王俊华 | Method for preparing sartan drug candesartan treating hypertension |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5196444A (en) * | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
| CN1425654A (en) * | 2003-01-07 | 2003-06-25 | 江苏省药物研究所 | Process for preparing 2-alkoxybenzimidazole compound |
| CN1800179A (en) * | 2005-12-22 | 2006-07-12 | 浙江天宇药业有限公司 | Method for preparing candestartan |
| CN101200464A (en) * | 2007-12-04 | 2008-06-18 | 王俊华 | Method for preparing sartan drug candesartan treating hypertension |
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