CN1771246A - Novel synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)-1,3-diazaspiro[4.4]-non-ene-4-one - Google Patents
Novel synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)-1,3-diazaspiro[4.4]-non-ene-4-one Download PDFInfo
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- CN1771246A CN1771246A CN 200480009456 CN200480009456A CN1771246A CN 1771246 A CN1771246 A CN 1771246A CN 200480009456 CN200480009456 CN 200480009456 CN 200480009456 A CN200480009456 A CN 200480009456A CN 1771246 A CN1771246 A CN 1771246A
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- trityl
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- tetrazolium
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Abstract
Provided is a novel method of making 2-butyl-3-[[2'(1-trityl- 1 H-tetrazol-5-yl)biphen-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-ene-4-one, which can be converted to irbesartan. Also provided are methods of making irbesartan.
Description
Relevant application
The present invention requires the applying date right of U.S. Provisional Patent Application 60/445,218 of applying on February 5th, 2003 and the U.S. Provisional Patent Application 60/465,905 of applying on April 28th, 2003, and its content is attached to herein.
Invention field
The present invention relates to the preparation method of irbesartan, especially its precursor.
Background of invention
Irbesartan is known angiotensin II receptor antagonists (receptor-blocking agent).Angiotensin is the important component in the renin-angiotensin-aldosterone system (RAAS), and blood pressure is had considerable influence.The chemical name of irbesartan is 2-butyl-3-[[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] methyl]-1,3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone.The structure of irbesartan is shown in (I).
Especially at United States Patent (USP) 5,270, the synthetic of irbesartan has been discussed in 317 and 5,559,233; Both by reference integral body be attached to herein.In its disclosed synthesizing, step reaction third from the bottom (do not comprise and handling and purifying) relates to cyano group on the cyclohexyl biphenyl and for example azide tributyl tin reaction of trinitride.The required reaction times was 210 hours.Referring to for example 5,270,317 patents.
United States Patent (USP) 5,629,331 also disclose the application dipolar aprotic solvent, with sodiumazide from 2-normal-butyl-3-[(2 '-4-cyanobiphenyl-4-yl) methyl]-1, the synthetic irbesartan of 3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone precursor.As 5,629, admit in 331 patents, use trinitride to have security risk (the 4th hurdle 39 row).And the boiling point of dipolar aprotic solvent (for example methyl-2-pyrrolidone) is higher relatively, is difficult to remove.
Therefore need to improve the synthetic route of irbesartan, its derivative and precursor thereof.
Summary of the invention
On the one hand, the present invention relates to prepare the method for following formula: compound.
Structure I I
Comprise step: especially under refluxing, at mineral alkali especially NaOH, KOH or Na
2CO
3The aliphatic ether of (or its mixture), especially maximum 8 carbon atoms of solvent or aromatic hydrocarbon (especially dry toluene), phase-transfer catalyst especially sulfuric acid TBuA exist down, and 1-(N '-valeryl amino) cyclopentane formamide and 5-(4 '-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium is reacted; Cooling mixture; Water added in the mixture and obtain two-phase; Separating obtained two-phase; Recovery type II compound.Formula II compound can be converted into irbesartan, and the irbesartan of Huo Deing is to the present invention relates on the other hand like this.
In another embodiment, the present invention relates to the method for preparation formula II compound, comprise step: in the presence of first kind of acid especially HCl and organic solvent especially dry toluene, with penta imidic acid derivative especially penta imidic acid ethyl ester or its salt and first kind of amine especially 5 '-(4 '-aminomethyl biphenyl-2-yl)-1-trityl-1H-tetrazolium or the reaction of 1-Aminocyclopentane ethyl formate about 2-24 hour, the formation mixture; Cool off this mixture; With mixture and second kind of amine especially 5 '-(4 '-aminomethyl biphenyl-2-yl)-1-trityl-1H-tetrazolium or 1-Aminocyclopentane ethyl formate (prerequisite be first kind different) with second kind of amine, and second kind of acid of catalytic amount especially acetate merge; Under refluxing the about 2-24 of heated mixt hour; The aqueous solution of mixture with alkali especially alkali is contacted, obtain two-phase; Separate the phase that obtains; Recovery type II compound.Gained formula II compound can be converted into irbesartan, and Zhi Bei irbesartan is another aspect of the present invention like this.
On the other hand, the present invention relates to the method for preparation formula II compound, comprise step: in the presence of organic solvent especially dry toluene, with valeramide derivative especially penta imidic acid ethyl ester and alkali scavenging agent especially 2,6-lutidine and oxalyl chloride mix; Cooling gained mixture; Kept 0.25-4 hour, and inferred wherein to form the imine acyl chloride intermediate; Again with organic solvent and amine, especially 5 '-(4 '-aminomethyl biphenyl-2-yl)-1-trityl-1H-tetrazolium or 1-Aminocyclopentane ethyl formate mix with said composition; The about 0.1-1 of resulting composition reflux hour; With compound and alkali, the especially aqueous solution of amine organic bases contact obtains two-phase then; Separating obtained phase; Recovery type II compound.The formula II compound of Huo Deing can be converted into irbesartan like this, and the irbesartan that makes like this is the another aspect that the present invention relates to.
And on the other hand, the present invention relates to prepare the irbesartan method, comprise by removing trityl group, with 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl) biphenyl 4-yl] methyl isophthalic acid, 3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone is converted into the step of irbesartan.
And another aspect the invention still further relates to the pharmaceutical composition that contains the irbesartan that makes through novel method of the present invention.
Detailed Description Of The Invention
The invention provides single pot process; in the presence of phase-transfer catalyst; in being initially the heterogenetic system at least; from 1-valeryl Aminocyclopentane methane amide (N-valeryl-1-amino-1-carbamyl pentamethylene; IRB-23) and 5-(4 '-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium (IRB-02) preparation 2-butyl-3-[2 '-(1-trityl-1H-tetrazolium-5-yl) biphenyl-4-methyl]-1; 3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone (structural formula II; IRB-03, the trityl irbesartan).This heterogeneous system can be two-phase (solid phase-liquid phase), or can be three-phase (solid phase-liquid phase-liquid phase).
In two-phase embodiment of the present invention, in the presence of the IRB-02 of phase-transfer catalyst and aequum, IRB-23 is in the first solvent suspension liquid of alkali metal hydroxide and alkaline carbonate.
Preferred alkali metal carbonate is K
2CO
3IRB-02 can use about 1.5 equivalent alkaline carbonates whenever amount, is preferably 2 equivalents.Preferred alkali metal hydroxide is NaOH.IRB-02 can use 3 equivalent alkali metal hydroxides whenever amount, is preferably 3.5 equivalents.
First solvent is an organic compound, is liquid in the time of 20 ℃, solubilized IRB-02, but water insoluble substantially.If liquid organic compound may be dissolved in the water less than 5%, this liquid organic compound is exactly largely insoluble so, if like this that isopyknic insoluble substantially organic liquid and water is mixed, the original volume that the cumulative volume of the two-phase of formation (liquid-liquid) system is approximately equal to water adds the original volume of insoluble substantially organic liquid.
First solvent that is used for the present invention's practice comprises line style and the cyclic aliphatic ethers with maximum 8 carbon atoms, as methyl tertiary butyl ether and tetrahydrofuran (THF), and aromatic hydrocarbon, as toluene.The amount of first solvent is inessential, as long as first solvent that uses is enough to make IRB-02 to be in the solution.First solvent that the IRB-02 of every mole of merging and IRB-23 preferably use about 3-4 to rise.
Phase-transfer catalyst is that the technician in organic synthesis field is known.When first kind that reacts to each other and second kind of compound dissolution degree characteristic differ greatly, when not having practical general solvent, with they one of solvent can form two-phase system when merging with alternative solvent, phase-transfer catalyst is particularly useful at this moment.
Generally when this compound reacts, first kind of reactant is dissolved in first kind of solvent, second kind of reactant is dissolved in second kind of solvent.Substantially be insoluble to the solvent that is used for second kind of reactant because be used for the solvent of first kind of reactant, thereby can form two-phase system and react at the biphase interface.Use phase-transfer catalyst (PTC) and can accelerate the speed of this surface reaction greatly.
The well-known compound that can be used as phase-transfer catalyst of several classes has, and for example quaternary ammonium compound is with phosphonium compounds, and the back will be mentioned these two kinds.Preferably sulfuric acid hydrogen tetrabutylammonium is used for practice of the present invention as PTC.Whenever the IRB-23 about 0.1 normal phase-transfer catalyst of amount question response is just enough usually, still can use more or less.
IRB-23 can make 1-amino-1-formamyl pentamethylene and valeryl chloride that Xiao Te-Bao Man (Schotten-Baumann) reaction takes place in tetrahydrofuran solvent and obtain by doing acid scavenger with triethylamine.
In the two-phase embodiment, IRB-02, IRB-23, alkaline carbonate, alkali metal hydroxide, phase-transfer catalyst and first solvent are mixed with random order, and heating, preferably between about 80 ℃ and the reflux temperature, most preferably to about 90 ℃.This reaction can proceed to till the basic completely consumed of IRB-02 quilt.Reaction process can be monitored by the thin layer chromatography (TLC) of for example using hexane/ethyl acetate (1: 1) elutriant.
When basic whole IRB-02 are consumed, reaction mixture and dilute with water (1-2 of about reaction mixture volume is doubly).Separate first solvent phase (organic phase) and optional use the salt water washing.Preferably by handle the water-content that reduces in first solvent phase as solid drier.
Produce residue by concentrating first organic phase, and (4: 1-1: 1) silica gel column chromatography of elutriant separates IRB-03 wherein, separable required product IRB-03 by using hexane/ethyl acetate.The composition of chromatography fraction can pass through as nuclear magnetic resonance measuring.By for example fractionation by distillation elutriant, can from the fraction that comprises IRB-03, separate IRB-03.
The similar two-phase embodiment of three-phase embodiment of the present invention, and comprise it being second solvent of water substantially, thereby have a part of alkaline carbonate (if there is) and alkali metal hydroxide at least in the solution of second solvent.In these embodiments, alkaline carbonate is chosen wantonly.
Therefore in the three-phase embodiment, IRB-03, IRB-23, alkali metal hydroxide, optional alkaline carbonate, phase-transfer catalyst and first solvent and second solvent.Be used for the amount of reactant of three-phase embodiment basic with the two-phase embodiment in identical, yet preferably IRB-23 is excessive, as many as excessive about 100%.The volume of second solvent is about 1/4-1/2 of first solvent volume.
To the step in the similar two-phase embodiment of the processing of reaction mixture.Separate first solvent phase, and merge with optional first solvent phase that obtains with first solvent extraction, second solvent phase.Can separate IRB-03 as handling first solvent phase in the two-phase embodiment.
In another embodiment, the invention provides the novel synthesis method of irbesartan, its analogue, especially its precursor (for example trityl irbesartan), comprise penta imidic acid derivative and amine reaction are formed the ester intermediate, and further the reaction of this ester intermediate and amine is formed 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl) biphenyl-4-yl] methyl]-1, the step of 3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone.This step is carried out in the presence of acid.Preferred this step is being carried out whenever amount penta imidic acid derivative has in the presence of 1 angelic acid.Penta imidic acid derivative can be to be fit to derivative arbitrarily, includes but not limited to ether and ester.Preferred valerimidate derivatives comprises penta imidic acid methyl esters, ethyl ester, propyl ester, butyl ester, benzene methyl, pentyl ester and aromatic ester (penta imidoether for example; R
1-C (=NH)-O-R
2R
1=C
4H
9)), or its salt especially.Most preferred ester is an ethyl ester.
Be reflected in the organic solvent and carry out.The example of preferred organic solvent includes but not limited to N, dinethylformamide (DMF), N,N-DIMETHYLACETAMIDE (DMA), toluene, hexane, 1,2-glycol dimethyl ether (DME), methylene diethyl ether, tetrahydrofuran (THF) (THF), benzene, m-xylene, o-Xylol, 1,2,3,4-tetraline, formal, glyme and its mixture.Most preferably organic solvent is a dry toluene.Other hydrocarbon that are used for the present invention's practice are conspicuous for those skilled in the art.
The novel method for synthesizing of irbesartan precursor of the present invention, irbesartan self and its analogue comprises the ester intermediate with penta imidic acid derivative and amine reaction formation N-substituted imine esters of gallic acid, and further the reaction of this ester intermediate and amine is formed 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl) biphenyl-4-yl] methyl]-1, the step of 3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone.Preferred amines comprises 5 '-(4 '-aminomethyl biphenyl-2-yl)-1-trityl-1H-tetrazolium (2-(1-trityl-1H-tetrazolium-5-yl)-4 '-aminomethyl biphenyl; Formula III; IRB-09) and 1-Aminocyclopentane ethyl formate (IRB-13).
Preferred valerimidate derivatives is penta an imidic acid ethyl ester as its mesylate.When amine is IRB-09, intermediate have formula IV (2-(1-trityl-1H-tetrazolium-5-yl)-4 '-(1 " oxyethyl group pentylidene amino) biphenyl) (2-(1-trityl-1H-tetrazol-5-yl)-4 '-structure of (1 "-ethoxypentanaminyl) biphenyl).When amine was 1-amino-1-cyclopentane-carboxylic acid ethyl ester, intermediate had the structure of formula V.
This step is carried out in the organic solvent reaction system.A certain amount of penta imidic acid derivative and a certain amount of acidic substance are added this organic solvent.These acidic substance can be any suitable acid, comprise mineral acid, hydrosulfate, trifluoroacetic acid, formic acid, Hydrogen bromide, acetate and formic acid.Most preferred acid is a hydrochloric acid.The ratio of penta imidic acid derivative and acidic substance can be between about 5: 1 to about 1: 0.5, and most preferred ratio is 1: 1.Stirred the gained mixture about 6-24 hour under the room temperature.About 12 hours of preferred stirred reaction mixture.Utilize thin layer chromatography to be convenient to the monitoring reaction time.After reaction was finished, reaction mixture was also removed sedimentary by product.Preferably reaction mixture is cooled between-15 ℃ to 15 ℃.Most preferably reaction mixture is cooled to about 0 ℃.A certain amount of suitable amine is added in the reaction mixture, as IRB-09 and IRB-13, and the acidic substance of adding catalytic amount.The preferred acidic material comprises mineral acid, hydrosulfate, trifluoroacetic acid, formic acid, Hydrogen bromide, acetate and formic acid.Most preferred acid is an acetate.Refluxed the about 2-10 of reacting by heating mixture hour down.Preferred the about 3-5 of stirred reaction mixture hour.Utilize thin layer chromatography to be convenient to the monitoring reaction time.After reaction is finished, reaction mixture is contacted preferred mineral alkali, more preferably inorganic base aqueous solution, especially NaHCO with alkali
3The aqueous solution, thereby the acidic group in the reaction mixture originally all is neutralized.When using the aqueous solution of alkali, form two-phase system (liquid phase-liquid phase).If the use solid alkali can form two-phase system (solid phase-liquid phase).In arbitrary situation, separating obtained two-phase reaction system.Preferred washing and dry this organic phase are isolated reaction product 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl) biphenyl-4-yl] methyl]-1,3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone (IRB-03).Separation can adopt any well-known method to carry out, but is undertaken by filtration and evaporated under reduced pressure usually.
Not to wish to be bound by theory, what think reaction is by producing the imidoether intermediate, for example 5 '-N-penta imidoether 5 in the reaction of (4 '-aminomethyl biphenyl-2-yl)-1-trityl-1H-tetrazolium (IRB-09) and penta imidic acid ethyl ester mesylate '-(4 '-aminomethyl biphenyl-2-yl)-1-trityl-1H-tetrazolium (IRB-20), or N-penta imidoether in the reaction of 1-Aminocyclopentane ethyl formate (IRB-09) and penta imidic acid ethyl ester mesylate-1-Aminocyclopentane ethyl formate (IRB-26).
On the other hand, the novel synthesis of irbesartan of the present invention and its analogue, comprise acid amides and alkali scavenging agent, preferred 2,6-lutidine and oxalyl chloride reaction, add amine then and form 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl) biphenyl-4-yl] methyl]-1, the step of 3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone.
The novel synthesis of irbesartan of the present invention and analogue thereof comprises penta imidic acid derivative and 2,6-lutidine and oxalyl chloride reaction form reaction mixture, add amine again and form 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl) biphenyl-4-yl] methyl]-1, the step of 3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone (IRB-03).Preferred valerimidate derivatives comprises cyclopentyl valeramide (IRB-23) and 5-(4 '-methylpent acid amides-biphenyl-2-yl)-1-trityl-1H-tetrazolium (IRB-10).Preferred amines comprises 2 '-(1-trityl-1H-tetrazolium-5-yl) biphenyl-4-base methylamine (IRB-09) and 1-Aminocyclopentane ethyl formate (IRB-13).This step is carried out in the organic solvent reaction system.In this organic solvent, add a certain amount of valeramide derivative and 2, the 6-lutidine.Reaction mixture is cooled to-15 ℃ to 15 ℃ approximately, and adds oxalyl chloride.Most preferably reaction mixture is cooled to about 0 ℃.2, the ratio of 6-lutidine and oxalyl chloride can be between about 10: 1 to 1: 5, and most preferred ratio is about 2: 1.With gained mixture stir about 0.25-4 hour.Preferably with reaction mixture stir about 1 hour.With suitable amine aqueous solution, add to this reaction mixture as the suitable organic solvent solution of IRB-09 and IRB-13, and stirred 0.1-1 hour down at 0 ℃, at room temperature stirred then 0.1-1 hour.Utilize thin layer chromatography to be convenient to the monitoring reaction time.After reaction is finished, with the alkali of molar excess, preferred NaHCO
3Aqueous solution neutralization reaction mixture, and separating obtained two-phase reaction system.Washing and dry organic phase are isolated reaction product 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl) biphenyl-4-yl] methyl]-1,3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone (IRB-03).Separate available any known method and carry out, but undertaken by filtration and evaporated under reduced pressure usually.
Be not to wish to be bound by theory, what think reaction is by producing the imine acyl chloride intermediate.
For obtaining irbesartan, the formula II compound that obtains by any embodiment of the present invention can be dissolved in appropriate solvent such as acetone, and with this solution and combined (with respect to the trityl compound 2-4 equivalent of formula II).The aqueous solution of mixture of Huo Deing and mineral alkali such as KOH like this.From the gained mixture, remove and desolvate (as evaporate to dryness), and filter the trityl alcohol precipitation.Regulate pH value of filtrate to 4, cooling and the precipitate of irbesartan of collecting gained.
Irbesartan also can obtain by the trityl compound of any other method known in the art from formula II.
The irbesartan that makes with the method that comprises any embodiment of the inventive method can be formulated as various forms of pharmaceutical compositions, its available thinner or vehicle such as carrier, weighting agent, swelling agent, tackiness agent, wetting agent, disintegrating agent, tensio-active agent, slipping agent or the like preparation.The various administration unit forms of pharmaceutical composition can be selected according to therapeutic purpose, as tablet, pill, powder, liquid agent, suspension agent, emulsion, granule, capsule, suppository, injection (solution and suspension) or the like.Any vehicle known, widespread use all can be used for pharmaceutical composition in this area.Carrier includes but not limited to lactose, white sugar, sodium-chlor, glucose, urea, starch, lime carbonate, kaolin, crystalline cellulose and silicic acid.Tackiness agent includes but not limited to water, ethanol, propyl alcohol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, lac, methylcellulose gum, potassiumphosphate and polyvinylpyrrolidone.Disintegrating agent includes but not limited to fatty acid ester, sodium lauryl sulphate, stearic monoglyceride, starch and the lactose of dry starch, sodiun alginate, agar powder, kelp powder, sodium bicarbonate, lime carbonate, polyethenoxy sorbitan.The disintegration inhibitor comprises but is not limited to white sugar, tristearin, theobroma oil and winterized stearin.Absorption enhancer includes but not limited to quaternary ammonium hydroxide and sodium lauryl sulphate.Wetting agent includes but not limited to glycerine and starch.Sorbent material includes but not limited to starch, lactose, kaolin, bentonite and collodial silica.Lubricant includes but not limited to purified talc, stearate, boric acid powder and polyoxyethylene glycol.The also available conventional coating material dressing of tablet, for example coated tablet, gelatin film coating tablet, enteric coating coating tablet, thin membrane coated tablet, double-layer tablets and multilayer tablet.
When pharmaceutical composition is shaped to oral dosage form, any known excipients that can use this area to use.For example, carrier includes but not limited to lactose, starch, theobroma oil, hardened vegetable oils, kaolin and talcum powder.Tackiness agent includes but not limited to gummi arabicum pulveratum, tragacanth gum powder, gelatin and ethanol.Disintegrating agent includes but not limited to agar and kelp.
For described pharmaceutical composition is shaped to suppository form, can use any known excipient used in the art.For example, excipient includes but not limited to ester, gelatin and the semisynthetic glyceryl ester of polyoxyethylene glycol, theobroma oil, higher alcohols, higher alcohols.
When preparation injectable (parenteral) pharmaceutical composition, sterile solution and suspension and preferably make it and blood etc. oozes.Injection can be used carrier as known in the art.For example, the carrier that is used for injectable formulation includes but not limited to the fatty acid ester of water, ethanol, propylene glycol, ethoxylation isooctadecane alcohol, the pure and mild polyethenoxy sorbitan of polyoxy baseization (polyoxylated) isooctadecane.Those of ordinary skills can be hardly be easy to determine make injectable formulation etc. to ooze the amount of required sodium-chlor, glucose or glycerine with maybe testing.Can add other compositions, as solubility promoter, buffer reagent and pain killer.If necessary, can in required preparation, add tinting material, sanitas, spices, seasonings, sweeting agent and other drug.
The amount that is contained in the irbesartan in the pharmaceutical composition is not specifically limited, however the symptom that dosage should be enough to treat, improve or reduction is relevant with osteoporosis.
Administering mode to pharmaceutical composition of the present invention is not specifically limited, and can be depending on patient age, sex, symptom and gives various preparations.But for example orally give tablet, pill, solution, suspension, emulsion, granule and capsule.Injection formulations can give separately, perhaps with the injection for example mixed intravenous administration of glucose solution and amino acid solution of infusing.If necessary, intramuscular, intracutaneous, subcutaneous or intraperitoneal give individually with injection formulations.But suppository drop rectum with drug.
The dosage of pharmaceutical composition of the present invention will depend on using method, patient's age, sex and situation.
Certain embodiments of the present invention are by following unrestricted embodiment explaination.
Embodiment 1:
Prepare trityl irbesartan (IRB-03) through imidoether
A) from 4 '-aminomethyl-2-(1-trityl-1H-tetrazolium-5-yl) biphenyl is through intermediate compound I RB-20's
The preparation method:
1-Aminocyclopentane ethyl formate (IRB-09 under the argon gas; 2.2g, 4.46mmol) and penta imidic acid ethyl ester mesylate (1.0g, 4.45mmol) mixed in dry toluene (20mL), and stirred reaction mixture 12 hours at room temperature, with TLC monitoring (hexane/ethyl acetate 2: 1 and methylene chloride 10: 1).Gained suspension is cooled to 0 ℃ and filter sedimentary methylsulfonic acid ammonium.(0.7g 4.46mmol), stirred the gained mixture 2 hours under the room temperature to disposable adding amino ester IRB-13 in the filtrate that comprises IRB-20 (25mL).Add acetate (catalytic amount, 4), back flow reaction thing 5 hours and with TLC monitoring (hexane/ethyl acetate 2: 1).Reaction mixture is cooled to room temperature, uses 10%NaHCO
3The aqueous solution, water and salt water washing, Na
2SO
4Drying is filtered and evaporated under reduced pressure.Residue chromatography on silicagel column obtain 0.6g (from IRB-09 20%) IRB-03 that NMR is pure.
B)
From 4 '-the ammonia first its-2-(1-triphen first its-1H-tetrazolium-5-its) biphenyl through intermediate 1-(1 '-ethoxy Base) preparation of pentylidene Aminocyclopentane ethyl formate (IRB-26)
(0.7g, 4.46mmol) (1.0g 4.45mmol) mixes in dry toluene, at room temperature stirs this reaction mixture 24 hours with penta imidic acid ethyl ester mesylate with IRB-13 under inert atmosphere.Gained suspension is cooled to 0 ℃ and filter sedimentary methylsulfonic acid ammonium.(2.2g 4.46mmol), adds acetate (catalytic amount, 4) to disposable adding amine IRB-09 in the filtrate of containing IRB-26 (25mL) then.Reactant refluxed 3 hours and with TLC monitoring (hexane/ethyl acetate 2: 1), was cooled to room temperature, the NaHCO with 10%
3The aqueous solution, water and salt water washing, Na
2SO
4Drying is filtered and evaporated under reduced pressure.Residue chromatography on silicagel column obtain 1.5g (from IRB-09 50%) IR-03 that NMR is pure.
Embodiment 2:
Prepare trityl irbesartan (IRB-03) through imine acyl chloride
A) prepare by raw material IRB-23:
Under the argon gas with cyclopentyl valeramide, IRB-13 (1.0g, 4.67mmol) and 2, the 6-lutidine (dry toluene 11.68mmol) (10mL) solution is cooled to 0 ℃ for 1.25g, 1.36mL, and drip oxalyl chloride (0.65g, 0.45mL, 5.14mmol).Stir the gained mixture 1 hour in the time of 0 ℃, and slowly add IRB-09 (2.31g, anhydrous toluene solution 4.67mmol) (25mL).Stirred reaction mixture is 30 minutes in the time of 0 ℃, at room temperature stirs then 30 minutes, refilters.Use 10%NaHCO
3Solution, water and salt solution wash filtrate, Na
2SO
4Drying is filtered and evaporated under reduced pressure.HPLC detects about 40% IRB-03 in residue.With residue crystallization in Virahol obtain 0.94g IRB-03 (from IRB-09 30%).
B) prepare by raw material IRB-10:
(0.7g, 1.21mmol) with 2, (anhydrous toluene solution 2.42mmol) (7ml) is cooled to 0 ℃ to the 6-lutidine for 0.26g, 0.28mL with acid amides, IRB-10 under the argon gas.The dropping oxalyl chloride (0.17g, 0.12mL, 1.33mmol).Stir the gained mixture 1 hour in the time of 0 ℃, slowly add IRB-13 (0.29g, anhydrous toluene solution 1.21mmol) (3ml).Reaction stirred is 30 minutes in the time of 0 ℃, at room temperature stirs then 30 minutes, refilters.NaHCO with 10%
3Solution, water and salt solution wash filtrate, Na
2SO
4Drying is filtered and evaporated under reduced pressure.HPLC detects 30% IRB-03 in residue.Residue chromatography on silicagel column obtain 0.20g (from IRB-10 25%) IRB-03 that NMR is pure.
Embodiment 3:
| Mw | Gram, volume | mmol | Equivalent | |
| IRB-23 | 212.1 | 3.0g | 14.2 | 1.0 |
| IRB-02 | 557.5 | 7.9g | 14.2 | 1.0 |
| NaOH | 40.1 | 2.0g | 49.5 | 3.5 |
| K 2CO 3 | 138.1 | 3.9g | 28.3 | 2.0 |
| Bu 4NHSO 4 | 339.54 | 0.48g | 1.42 | 0.1 |
| Toluene | Be total to 100mL | |||
| 9.5g | ||||
In the time of 50 ℃, under agitation to IRB-23, NaOH fine powder, K
2CO
3And Bu
4NHSO
4Toluene suspension (50ml) in dripped the toluene solution (50mL) of IRB-02 through 1 hour.Finish and drip back lasting stirring 3 hours (TLC monitoring: Hex/EtOAc 1: 1, two point: IRB-03 and IRB-17) in the time of 90 ℃.The gained mixture is cooled to 50 ℃.Add entry (150mL), separating obtained two-phase mixture.With salt water washing organic phase (first solvent), Na
2SO
4Drying is filtered and evaporated under reduced pressure.This semi-solid residue is carried out chromatography on short silicagel column (hexane/EtOAc 4: 1-1: 1), obtain the pure 5.0g of NMR (53%) IRB-03 and 3.0g (32%) IRB-17.
Embodiment 4:
| Mw | Gram, volume | mmol | Equivalent | |
| IRB-23 | 212.1 | 3.3g | 15.6 | 1.5 |
| IRB-02 | 557.5 | 5.8g | 10.4 | 1.0 |
| Potassium hydroxide, 85% | 56.11 | 1.85g | 28.0 | 2.7 |
| Water | 15mL | |||
| Bu 4NHSO 4 | 339.54 | 0.53g | 1.56 | 0.15 |
| Toluene | 60mL | |||
| 7.0g/4.7g | ||||
Under the room temperature, under agitation to IRB-23 at KOH and Bu
4NHSO
4The toluene solution that adds IRB-02 in the suspension in the aqueous solution.Stir under the room temperature that TLC detects less than reaction after 20 minutes.This reactant is heated to 90 ℃ and stirred 1.5 hours, up to IRB-02 (the TLC monitoring: hexane/ethyl acetate 6: 1) that disappears.This mixture is cooled to room temperature, adds entry (70mL), separate phase.With toluene (30mL) aqueous layer extracted (second solvent), and the organic phase of water (30mL) and salt water washing merging, Na
2SO
4Drying is filtered and evaporated under reduced pressure obtains the semi-solid residuum (HPLC purity is about 87%) of 7.4g.Part residuum (3.7g) crystallization in IPA obtains the white powder (HPLC purity is about 98%) of 3.0g (86% productive rate) IRB-03.Another part (3.7g) residue is dissolved in acetone (30ml), adds the 7.5mL 3N HCl aqueous solution (about 3 equivalents).(remove trityl) after finishing deprotection, slowly add the 10ml aqueous solution and the evaporated under reduced pressure acetone of KOH (1.3g) by the TLC monitoring.Filtering-depositing (trityl alcohol) also washes (2 * 10mL) with water; The filter liquor that merges with ethyl acetate 15mL washing also slowly is acidified to pH4 with the 3N HCl aqueous solution.The cooling of gained suspension is reduced to 0-4 ℃, and restir 30 minutes also filters.Wash filter cake drying under reduced pressure several times and in the time of 50-60 ℃ with water, obtain 2.0g (from about 85% productive rate of IRB-02) IRB-00 (HPLC purity is 96%).
Embodiment 5:
| Mw | Gram, volume | mmol | Equivalent | |
| 1-Aminocyclopentane ethyl formate | 128.2 | 12.8g | 100 | 1.0 |
| Valeryl chloride | 120.6 | 13.3g，13.0mL | 110 | 1.1 |
| Triethylamine | 101.2 | 13.2g，18.1mL | 130 | 1.3 |
| Tetrahydrofuran (THF) | Be total to 100mL | |||
| 21.2g | ||||
1-Aminocyclopentane methane amide is suspended in anhydrous THF (80mL) and Et
3In the mixed liquid of N and be cooled to 10 ℃.THF (20mL) solution that in vigorous stirring (preferred mechanical stirring), slowly adds valeryl chloride.Temperature of reaction is remained on below 30 ℃, and vigorous stirring gained suspension (TLC monitoring: CH in 1 hour at room temperature
2Cl
2/ MeOH 8: 1).The evaporated under reduced pressure solvent is suspended in white residue in the water (200mL), at room temperature stirs 20 minutes.Filter solids, water (100ml altogether) and methyl tertiary butyl ether (30mL) washing 2 times are dried to constant weight under 50 ℃/10mmHg, obtain the white powder of 18.5g (87.3% productive rate) IRB-23 that NMR is pure.This product need not purifying and can use.
By the present invention that concrete preferred embodiment of reference and illustrative embodiment are described, those skilled artisans will appreciate that modification of the present invention described herein and explanation is not broken away from disclosed scope and spirit of the present invention in the specification sheets.Illustrating of embodiment helps to understand the present invention, limits its scope by any way but should not be construed as.Embodiment does not comprise the detailed description of traditional method.These methods are well known to those of ordinary skill in the art and describe to some extent in multiple publication.All reference integral body of mentioning are attached to herein.
Claims (41)
1. the method for a preparation I compound
Said method comprising the steps of:
A) in the presence of mineral alkali, solvent and phase-transfer catalyst, with 1-(N '-valeryl amino) cyclopentane formamide and 5-(4 '-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium reaction;
B) cool off described mixture;
C) in mixture, add entry and obtain two-phase;
D) separating obtained two-phase;
E) recovery type I compound.
2. the process of claim 1 wherein that mineral alkali is selected from alkali metal hydroxide, alkaline carbonate or its mixture.
3. the method for claim 2, wherein alkali metal hydroxide is NaOH or KOH, alkaline carbonate is K
2CO
3
4. the method for claim 2, wherein mineral alkali is the mixture of alkali, and uses as solid.
5. the process of claim 1 wherein that organic solvent is aliphatic ether or the aromatic hydrocarbons with maximum 8 carbon atoms.
6. the method for claim 5, wherein aliphatic ether is methyl tertiary butyl ether or tetrahydrofuran (THF).
7. the method for claim 5, wherein aromatic hydrocarbons is toluene.
8. the process of claim 1 wherein that phase-transfer catalyst is selected from quaternary ammonium compound with phosphonium compounds.
9. the method for claim 8, wherein phase-transfer catalyst is the hydrogen sulfate TBuA.
10. the process of claim 1 wherein temperature of reaction about 80 ℃ between the reflux temperature.
11. the method for claim 10, wherein temperature of reaction is about 90 ℃.
12. the method for a preparation I compound
Said method comprising the steps of:
A) in the presence of first kind of acid and organic solvent, penta imidic acid derivative and first kind of amine were reacted about 2-24 hour, form mixture;
B) cool off described mixture;
C) second kind of acid with second kind of amine and catalytic amount mixes with described mixture;
D) under refluxing the about 2-24 of heated mixt hour;
E) alkali is contacted with described mixture and obtain two-phase;
F) separating obtained phase;
G) recovery type I compound.
13. the method for claim 12, wherein penta imidic acid derivative is the salt of penta imidic acid ether, penta imidoether or penta imidoether.
14. the method for claim 13, wherein said penta imidic acid derivative is selected from penta imidic acid methyl esters, ethyl ester, propyl ester, butyl ester, benzyl ester, pentyl ester and aromatic ester or its salt.
15. the method for claim 14, wherein said penta imidic acid derivative is penta imidic acid ethyl ester.
16. the method for claim 12, wherein first kind and second kind of amine be selected from 5 '-(4 '-aminomethyl biphenyl-2-yl)-1-trityl-1H-tetrazolium and 1-Aminocyclopentane ethyl formate, precondition be first kind different with second kind of amine.
17. the method for claim 16, wherein the penta imidic acid derivative of step a is penta imidic acid ethyl ester mesylate, first kind of amine is 5 '-(4 '-aminomethyl biphenyl-2-yl)-1-trityl-1H-tetrazolium, thereby in mixture, form N-penta imidoether 5 '-(4 '-aminomethyl biphenyl-2-yl)-1-trityl-1H-tetrazolium.
18. the method for claim 16, wherein the penta imidic acid derivative of step a is penta imidic acid ethyl ester mesylate, and first kind of amine is 1-Aminocyclopentane ethyl formate, thereby forms N-penta imidoether in mixture-1-Aminocyclopentane ethyl formate.
19. the method for claim 12, wherein organic solvent is selected from N, dinethylformamide (DMF), N,N-DIMETHYLACETAMIDE (DMA), toluene, hexane, 1,2-glycol dimethyl ether (DME), methylene diethyl ether, tetrahydrofuran (THF) (THF), benzene, m-xylene, o-Xylol, 1,2,3,4-tetraline, formal, glyme and its mixture.
20. the method for claim 19, wherein solvent is a toluene.
21. the method for claim 12, wherein first kind of acid is selected from mineral acid, hydrosulfate, trifluoroacetic acid, formic acid, Hydrogen bromide, acetate and formic acid.
22. the method for claim 21, wherein first kind of acid among the step a is hydrochloric acid.
23. the method for claim 12, wherein second kind of acid among the step c is acetate.
24. the method for claim 12, wherein the mixture among the step b is cooled to approximately between-15 ℃ to 15 ℃.
25. the method for claim 24, wherein said mixture are cooled to about 0 ℃.
26. the method for claim 12, wherein the mixture heating up in the steps d refluxed about 2-10 hour.
27. the method for claim 12, the alkali that wherein is used for step e is NaHCO
3
28. the method for claim 12 is wherein by filtering and evaporated under reduced pressure recovery type I compound.
29. the method for a preparation I compound
Said method comprising the steps of:
A) in the presence of organic solvent with valeramide derivative and 2,6-lutidine and oxalyl chloride mix;
B) cool off described mixture;
C) keep mixture 0.25-4 hour, thereby form the imine acyl chloride intermediate;
D) again amine and organic solvent are mixed with mixture;
E) the gained mixture heating up refluxed about 0.1-1 hour;
F) alkali is contacted with described mixture and obtain two-phase;
G) separating obtained phase;
H) recovery type I compound.
30. the method for claim 29, wherein the valeramide derivative is selected from cyclopentyl valeramide and 5-(4 '-methylpent acid amides-biphenyl-2-yl)-1-trityl-1H-tetrazolium.
31. the method for claim 29, wherein organic solvent is a toluene.
32. the method for claim 29, wherein the mixture of step b is cooled to-15 ℃ to about 15 ℃ approximately.
33. the method for claim 32, wherein mixture is cooled to about 0 ℃.
34. the method for claim 29, wherein said amine be selected from 5 '-(4 '-aminomethyl biphenyl-2-yl)-1-trityl-1H-tetrazolium and 1-Aminocyclopentane ethyl formate.
35. a method for preparing irbesartan said method comprising the steps of:
A) in the presence of alkali, solvent and phase-transfer catalyst, with 1-(N '-valeryl amino)] cyclopentane formamide and 5-(4 '-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium reaction;
B), thereby obtain two-phase with water and reaction mixture;
C) separating obtained phase;
D) reclaim 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl)-biphenyl-4-yl] methyl]-1,3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone;
E) product with steps d is converted into irbesartan.
36. a method for preparing irbesartan said method comprising the steps of:
A) in the presence of acid and organic solvent, with penta imidic acid derivative and first kind of amine reaction;
B) kept mixture 6-24 hour;
C) cool off described mixture;
D) acid of second kind of amine of adding and catalytic amount in mixture;
E) be heated to backflow;
F) kept mixture 2-24 hour;
G) use the alkali neutralise mixt;
H) separating obtained phase;
I) reclaim 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl)-biphenyl-4-yl] methyl]-1,3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone;
J) product with step I is converted into irbesartan.
37. a method for preparing irbesartan said method comprising the steps of:
A) in the presence of organic solvent, with valeramide derivative and 2,6-lutidine and oxalyl chloride reaction;
B) cooling mixture;
C) kept described mixture 0.25-4 hour;
D) in described mixture, add amine and organic solvent;
E) reflux;
F) kept described mixture 0.1-1 hour;
G) use in the alkali and described mixture;
H) separating obtained phase;
I) reclaim 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl)-biphenyl-4-yl] methyl]-1,3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone;
J) product with step I is converted into irbesartan.
38. 1-(1 '-oxyethyl group) pentylidene Aminocyclopentane manthanoate.
39. 4 '-pentylidene amino-2-(1-trityl-1H-tetrazolium-5-yl) biphenyl.
40. 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl)-biphenyl-4-yl] methyl isophthalic acid, in 3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone, described compound is by each method preparation of claim 1-37.
41. a pharmaceutical composition, described pharmaceutical composition comprises at least a medicine can accept vehicle and irbesartan; Wherein irbesartan is by by each 2-butyl-3-[[2 '-(1-trityl-1H-tetrazolium-5-yl)-biphenyl-4-yl of method preparation of claim 1-37] methyl isophthalic acid, 3-diaza spiro [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone preparation.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US44521803P | 2003-02-05 | 2003-02-05 | |
| US60/445,218 | 2003-02-05 | ||
| US60/465,905 | 2003-04-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007103073945A Division CN101239974A (en) | 2003-02-05 | 2004-02-05 | Synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)methyl-1,3-diazaspirol[4,4]-non-ene-4-one |
| CNA2007103073930A Division CN101239930A (en) | 2003-02-05 | 2004-02-05 | Synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)methyl-1,3-diazaspirol[4,4]-non-ene-4-one |
| CNA200710307395XA Division CN101239975A (en) | 2003-02-05 | 2004-02-05 | Synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)methyl-1,3-diazaspirol[4,4]-non-ene-4-one |
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| CNA200710307395XA Pending CN101239975A (en) | 2003-02-05 | 2004-02-05 | Synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)methyl-1,3-diazaspirol[4,4]-non-ene-4-one |
| CN 200480009456 Pending CN1771246A (en) | 2003-02-05 | 2004-02-05 | Novel synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)-1,3-diazaspiro[4.4]-non-ene-4-one |
| CNA2007103073945A Pending CN101239974A (en) | 2003-02-05 | 2004-02-05 | Synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)methyl-1,3-diazaspirol[4,4]-non-ene-4-one |
| CNA2007103073930A Pending CN101239930A (en) | 2003-02-05 | 2004-02-05 | Synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)methyl-1,3-diazaspirol[4,4]-non-ene-4-one |
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| CNA2007103073930A Pending CN101239930A (en) | 2003-02-05 | 2004-02-05 | Synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)methyl-1,3-diazaspirol[4,4]-non-ene-4-one |
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| CN102050761A (en) * | 2010-12-10 | 2011-05-11 | 江苏江神药物化学有限公司 | Key intermediate of Erbesartan, synthesis method thereof and method for synthesizing Erbesartan therefrom |
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| CN103787999B (en) * | 2013-12-18 | 2016-08-24 | 吉林修正药业新药开发有限公司 | The synthetic method of Irbesartan impurity |
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| CN102050761A (en) * | 2010-12-10 | 2011-05-11 | 江苏江神药物化学有限公司 | Key intermediate of Erbesartan, synthesis method thereof and method for synthesizing Erbesartan therefrom |
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