The preparation of LCZ696 key intermediate
Technical field
The invention belongs to medical chemistry field, relate to LCZ696 key intermediate (4S, 2R)-5-([1,1'-biphenyl]-4-Base) preparation method of-4-amino-2-methyl valerate hydrochloride.
Background technology
LCZ696 is a kind of angiotensin receptor and enkephalinase double inhibitor, English Entresto by name,Within 2015, FDA ratifies this medicine as angiotensin ii receptor blocker based on its excellent clinical test results, to reduce windThe cardiovascular death of danger heart failure patient and hospitalization chronic heart failure (NYHAII-IV level) and LVEF reduceLCZ696. LCZ696 is drug for hypertension Valsartan and a kind of novel antihypertensive medicament that has lost patent protection at presentThe combination drug of Sacubitril (enkephalinase inhibitor), its structural formula is as follows:
In the preparation technology of LCZ696, relate to key intermediate (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-Synthesizing of methylpent acid esters. Patent WO2014/032627 and patent EP1903027 disclose (2R, 4S)-5-([1,1'-connectionBenzene]-4-yl) preparation method of-4-amino-2-methyl pentanoate derivant. The method is using 4-bromo biphenyl as starting material,After preparing RMgBr and chirality (S)-epoxychloropropane or (S)-epoxy-tertbutyl ether reaction, obtain corresponding hydroxy compoundThing; Under the effect of diethyl azodiformate/triphenylphosphine, Mitsunobu to occur anti-for hydroxy compounds and succinimide subsequentlyShould obtain pyrrolidines-2 of configuration inversion, 5-diketone intermediate; The latter uses concentrated hydrochloric acid deprotection base and under alkali conditionOccur to obtain corresponding (R)-3-([1,1'-biphenyl]-4-yl) 2-aminopropan-1-ols hydrochloride after nucleophilic substitution; This saltAmino to use the product oxidation of primary hydroxyl under NaClO/TEMPO condition after Boc protection be corresponding aldehyde product, occur subsequentlyAfter Wittig reaction and use LiOH hydrolysis ethyl ester, obtain (R)-5-biphenyl-4-base-4-Boc amino-2-methyl penta-2-olefin(e) acid;The latter is at metallic catalyst [RuI2(p-cymene)]2With under the effect of chiral ligand mandyphosSL-M004-1, occur not rightClaim hydrogenating reduction, obtain (2R, 4S)-5-biphenyl-4-base-4-Boc amino-2-methyl valeric acid; It is complete that ethyl esterization is carried out in this acid subsequentlyBecome the preparation of (2R, 4S)-5-biphenyl-4-amino-2-methyl pentanoic acid ethyl ester. This route not only synthesis step is many, and processIn used the metallic catalyst [RuI that very expensive and commercialization is difficult for a large amount of buyings2(p-cymene)]2And chiral ligandMandyphosSL-M004-1, therefore suitability for industrialized production is restricted. Patent WO2014/032627 and patent EP1903027 closeBecome route as follows:
Summary of the invention
Through a large amount of research and development experiments, the present invention develops preparation (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-ammoniaThe variation route of base-2 methyl valeric acid ester, its reaction equation is as follows:
。
Technical characterictic of the present invention is as follows:
1, initiation material 4-bromo biphenyl (formula I) generates the THF solution of 4-xenyl lithium (formula II) under the effect of n-BuLi, shouldSolution is direct and chirality (S)-epoxy halogenopropane (formula III) reaction subsequently, generates (S)-1-([1,1'-biphenyl]-4-yl)-3-Halo-propyl-2-alcohol (formula IV);
Wherein in formula III, IV, X is halogen, preferably chlorine.
2, the hydroxyl of (S)-1-([1,1-biphenyl]-4-yl)-3-halo-propyl-2-alcohol (formula III) uses silicon protecting group to enterRow protection, preparation (S)-1-([1,1-biphenyl]-4-yl)-3-halo-2-siloxy propane (formula V);
Wherein to react the silica reagent using be tert-butyl chloro-silicane or tert-butyl diphenyl chlorosilane to this step;
R in formula V1TBS or TBDPS protecting group.
3, (S)-1-([1,1'-biphenyl]-4-yl)-3-halo-2-siloxy propane (formula V) does the condition of solvent at THFUnder, add magnesium metal to prepare RMgBr (S)-1-([1,1'-biphenyl]-4-yl)--2-siloxy propane-3-magnesium halide (formulaVI) THF solution, then with (the R)-2-fluoroform sulphonyl oxygen propionic acid tert-butyl ester (formula VII) reaction, realization (2R, 4R)-5-(1,1'-xenyl) preparation of-4-siloxy-2 methyl valeric acid tert-butyl ester (formula VIII);
R in its Chinese style VII2Trifyl (CF3SO2-) group;
R in its Chinese style V, VI, VIII1TBS or TBDPS protecting group.
4, (2R, 4R)-5-([1,1'-biphenyl]-4-yl)-4-siloxy-2 methyl valeric acid tert-butyl ester (formula VIII) existsUnder TBAF effect, remove the reaction of silicon protecting group and realize (2R, 4R)-5-([1,1'-biphenyl]-4-yl)-4-hydroxy-2-methylThe preparation of the valeric acid tert-butyl ester (formula IX);
The solvent that wherein this step reaction is used is selected from THF, EtOAc, Dioxane, CH3CN;
R in its Chinese style VIII1TBS or TBDPS protecting group.
5, (2R, 4R)-5-([1,1'-biphenyl]-4-yl)-4-hydroxy-2-methyl valeric acid tert-butyl ester (formula IX) and succinylImines (formula X) or phthalimide (formula XI) generation Mitsunobu reaction realization (2R, 4S)-(5-([1,1'-biphenyl]-4-yl)-2 methyl valeric acid the tert-butyl ester-4-yl)-pyrrolidines-2,5-diketone (formula XII) or (2R, 4S)-5-([1,1'-biphenyl]-4-yl) preparation of-2-methyl-4-phthaloyl imino-valeric acid tert-butyl ester (formula XII)
The phosphonate reagent that wherein Mitsunobu reaction is used is selected from triphenylphosphine or tri-n-butyl phosphine; The coupling reagent usingBe selected from diethyl azodiformate (DEAD) or azoformic acid isopropyl ester (DIAD).
6, (2R, 4S)-(5-([1,1'-biphenyl]-4-yl)-2 methyl valeric acid tert-butyl ester-4-yl)-pyrrolidines-2,5-bis-Ketone (formula XII) or (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-phthaloyl imino-valeric acid tert-butyl ester(formula XII) does at alkylol under the condition of solvent and removes succinimide or phthalimide protecting group and uncle with HClButyl protecting group is carried out esterification simultaneously, obtains (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl pentaAcid esters hydrochloride;
The alkylol that wherein reaction is used is selected from methyl alcohol, ethanol.
Use technique of the present invention to synthesize (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl valerateThe step of hydrochloride is shorter, and two chiral centres in product are all to use chirality fragment to introduce, avoided using expensive andCommercialization is difficult for chiral metal catalyst and the chiral ligand reagent of a large amount of buyings, easily realizes the large production of commercialization.
Detailed description of the invention
Can understand more specifically the present invention by the following examples, but it is to illustrate instead of limit the present inventionScope.
Embodiment 1:(S) preparation of-1-([1,1'-biphenyl]-4-yl)-3-chloro-propyl-2-alcohol (formula IV, X=Cl)
In 500ml there-necked flask, add 5 grams of 4-bromo biphenyls and anhydrous THF (80ml), after system stirs, be cooled to-78 DEG C,Then in nitrogen protection downhill reaction liquid, slowly add the hexane solution (1.6Minn-hexane, 15ml) of n-BuLi. DripAfter adding, system keeps about-78 DEG C to stir 30 minutes, is slowly warming up to subsequently about-10 DEG C and stirs 2 hours. To reaction bodyIn system, slowly add the THF solution (3 grams, 40mlTHF) of (S)-epoxychloropropane (formula III, X=Cl). Dropwise rear anti-The system of answering is warming up to room temperature reaction 5 hours naturally, with slowly adding 100ml saturated aqueous ammonium chloride to quench in backward reaction systemThe reaction of going out. System adds CH2Cl2Extraction (3 × 50ml), merges organic phase, and anhydrous sodium sulfate is dried organic phase, mistakeFilter, decompression desolvation, residue use column chromatography carry out purifying, (S)-1-([1,1'-biphenyl]-4-yl)-3-chloro-4.5 grams of light yellow solids of propan-2-ol (85%).
Embodiment 2:(S) preparation of-1-([1,1'-biphenyl]-4-yl)-3-chloro-propyl-2-alcohol (formula IV, X=Cl)
In 10L glass four-hole bottle, add 200 grams of 4-bromo biphenyls and anhydrous THF (3.2L), after system stirs, be cooled to-78DEG C (dry ice acetone bath), then under nitrogen protection by dropping funel to the hexane solution that slowly adds n-BuLi in reactant liquor(1.6Minn-hexane, 600mL). Dropwise rear system and keep about-78 DEG C to stir 1 hour, slowly heat up subsequentlyTo about-10 DEG C stirrings 4 hours. In reaction system, slowly add the THF of (S)-epoxychloropropane (formula III, X=Cl) moltenLiquid (120 grams, 2LTHF). Dropwise rear reaction system and be naturally warming up to room temperature reaction 7 hours, with slow in backward reaction systemSlowly add 2L saturated aqueous ammonium chloride cancellation reaction. System adds CH2Cl2Extraction (3 × 2L), merges organic phase, anhydrous sulphurAcid sodium is dried organic phase, removes by filter sodium sulphate solid, decompression desolvation, and residue uses column chromatography to carry out pureChange, obtain (S)-1-([1,1'-biphenyl]-4-yl)-3-chloro-propyl-2-172 grams of yellow solids of alcohol (81%).
Embodiment 3:(S)-1-([1,1'-biphenyl]-4-yl)-3-chloro-propyl-2-tertiary butyl dimethyl Si base-propane(formula V, R1=TBS) preparation
In tri-mouthfuls of round-bottomed flasks of 250mL, be equipped with thermometer and magnetic agitation, add (S)-1-([1,1'-biphenyl]-4-yl)-3-8.2 grams of chloro-propyl-2-alcohol (formula IV, X=Cl), then add anhydrous CH2Cl2(80mL) and DMF (2mL). Reactant liquor stirsAfter mixing evenly, add DMAP (50mg), system ice-water bath is cooled to 0 DEG C of left and right. Then by dropping funel in reaction systemSlowly add the CH of TBSCl2Cl2Solution (6 grams, 20mLCH2Cl2), dropping process keeps temperature of reaction system lower than 5 DEG C. DripAfter adding, system is warming up to stirring at room temperature reaction 6 hours naturally. TLC point plate is followed the tracks of removal of solvent under reduced pressure after completion of the reaction, residualExcess column chromatography purification obtains (S)-1-([1,1'-biphenyl]-4-yl)-3-chloro-propyl-2-tertiary butyl dimethyl Si base-the thirdAlkane (light yellow foam-like solid, 10.7 grams, 89%).
Embodiment 4:(S)-1-([1,1'-biphenyl]-4-yl)-3-chloro-propyl-2-tert-butyl diphenyl siloxy-propane(formula V, R1=TBDPS) preparation
In 3L four-hole round-bottomed flask, be equipped with thermometer and mechanical agitation, add (S)-1-([1,1'-biphenyl]-4-yl)-3-chlorine89 grams of generation-propyl-2-alcohol (formula IV, X=Cl), then add anhydrous CH2Cl2(1L) and DMF (20mL). Reactant liquor stirs allAfter even, add DMAP (600mg), system ice-water bath is cooled to 0 DEG C of left and right. Then delay in reaction system by dropping funelSlowly add the CH of TBDPSCl2Cl2Solution (150 grams, 100mLCH2Cl2), dropping process keeps temperature of reaction system lower than 5 DEG C.Dropwise rear system and be naturally warming up to stirring at room temperature reaction 18 hours. TLC point plate is followed the tracks of removal of solvent under reduced pressure after completion of the reaction,Residue column chromatography purification obtain (S)-1-([1,1'-biphenyl]-4-yl)-3-chloro-propyl-2-tert-butyl diphenyl siloxy-Propane (light yellow solid, 144 grams, 82%).
Embodiment 5:(R) the preparation of-2-fluoroform sulphonyl oxygen propionic acid tert-butyl ester (formula VII)
Tri-mouthfuls of round-bottomed flasks of 3L, are equipped with thermometer and magnetic agitation, add 50 grams of D-ALPHA-Hydroxypropionic acid tert-butyl esters (ee > 99%) and anhydrousCH2Cl2(1.2L), system stir after ice-water bath be cooled to 0 DEG C of left and right. In reaction system, add 2,6-lutidines(50mL) after, slowly drip trifluoromethanesulfanhydride anhydride (70mL) by dropping funel, dropping process keeps temperature of reaction system not highIn 5 DEG C. Dropwise rear reaction system stirs 2 hours between 0-5 DEG C. Then in reaction system, slowly add saturated chlorineChange aqueous ammonium (500mL) reaction is carried out to cancellation. Separate CH2Cl2Organic phase, water CH2Cl2Extraction (3 × 800mL),Merge organic phase, 0.5N watery hydrochloric acid (500mL) washs once, and then washs once anhydrous slufuric acid with saturated aqueous common salt (1L)Magnesium is dried organic phase, removes by filter magnesium sulfate solid, decompression desolvation, and residue (81 grams, 85%) does not need purifying straightConnect use.
Embodiment 6:(2R, 4R)-5-([1,1'-biphenyl]-4-yl)-4-tertiary butyl dimethyl Si base-2 methyl valeric acidThe tert-butyl ester (formula VIII, R1=TBS) preparation
In 1L flask, add 1 gram of metal magnesium chips and 100ML oxolane, open magnetic agitation. In this reactant liquor, add simultaneouslyA small amount of iodine and 2 grams of (S)-1-([1,1'-biphenyl]-4-yl)-3-chloro-propyl-2-tertiary butyl dimethyl Si base-propane (formula V,R1=TBS) continue to be stirred to grignard reaction start cause. Then, to cause after reaction liquid in slowly add 9 grams (S)-1-([1,1'-biphenyl]-4-yl)-3-chloro-propyl-2-tertiary butyl dimethyl Si base-propane (formula V, R1=TBS) THFSolution (100mL), dropwises rear whole reaction system insulation 35 degree left and right and stirs 2 hours. Subsequently by the Ge Shi examination preparingAgent is transferred in dropping funel, slowly drops to (R)-2-fluoroform sulphonyl oxygen propionic acid tert-butyl ester prepared by 8.5 grams of embodiment 5In the THF solution of (formula VII), dropping process keeps 0 to 5 DEG C of temperature of reaction system. Dropwise rear insulation reaction 2 hours, soBackward reaction system adds saturated NH4The Cl aqueous solution (300ml) cancellation reaction, system is used dichloromethane extraction (3 × 300L),Merge organic phase, 0.5N desalinization of soil by flooding or leaching acid (100mL) is washed once, and then washs once anhydrous sulphur with saturated aqueous common salt (100mL)Acid magnesium is dried organic phase, removes by filter magnesium sulfate solid, decompression desolvation, and residue uses column chromatography purification to obtain(2R, 4R)-5-([1,1'-biphenyl]-4-yl)-4-tertiary butyl dimethyl Si base-2 methyl valeric acid tert-butyl ester (formula VIII, R1=TBS) (10.5 grams, 76%).
Embodiment 7:(2R, 4R)-5-([1,1'-biphenyl]-4-yl)-4-tert-butyl diphenyl siloxy-2-methylpentTert-butyl acrylate (formula VIII, R1=TBDPS) preparation
In tri-mouthfuls of round-bottomed flasks of 1L, add 2 grams of metal magnesium chips and 150mL oxolane. Under agitation in this reactant liquor, add lessAmount iodine grain and 3 grams of (S)-1-([1,1'-biphenyl]-4-yl)-3-chloro-propyl-2-tertiary butyl dimethyl Si base-propane (formula V,R1=TBDPS) continue to be stirred to grignard reaction start cause. Then, to cause after reaction liquid in slowly add 25 grams(S)-1-([1,1'-biphenyl]-4-yl)-3-chloro-propyl-2-tert-butyl diphenyl siloxy-propane (formula V, R1=TBDPS) THF solution (200mL), dropwises rear whole reaction system insulation 35 degree left and right and stirs 2 hours. To make subsequentlyThe RMgBr of getting ready is transferred in dropping funel, slowly drops to (R)-2-fluoroform sulphonyl oxygen prepared by 24 grams of embodiment 5In the THF solution of the propionic acid tert-butyl ester (formula VII), dropping process keeps 0 to 5 DEG C of temperature of reaction system. Dropwise rear insulation anti-Answer after 4 hours and slowly add saturated NH in reaction system4The Cl aqueous solution (500mL) cancellation reaction, system is used carrene extractionGet (3 × 500L), merge organic phase, 0.5N desalinization of soil by flooding or leaching acid (300mL) is washed once, and then washes with saturated aqueous common salt (300mL)Wash once, anhydrous magnesium sulfate is dried organic phase, removes by filter magnesium sulfate solid, decompression desolvation, and residue usesColumn chromatography purification obtains (2R, 4R)-5-([1,1'-biphenyl]-4-yl)-4-tert-butyl diphenyl siloxy-2 methyl valeric acid uncleButyl ester (formula VIII, R1=TBDPS) (22.2 grams, 66.5%).
Embodiment 8:(2R, 4R)-5-([1,1'-biphenyl]-4-yl)-4-hydroxy-2-methyl valeric acid tert-butyl ester (formula IX)Preparation
8 grams of (2R, 4R-5-(1,1'-xenyl)-4-tertiary butyl dimethyl Si base-2 methyl valeric acid tert-butyl ester (formula VIII, R1=TBS) be dissolved in THF solution (100mL), stir lower reactant liquor cryosel bath and be cooled to 0 to 5 DEG C, then in this reaction system, delaySlowly add TBAF solution (1MinTHF, 20mL). Dropwise rear reaction system and be naturally warming up to stirring at room temperature 12 hours. InsteadThe system of answering adds saturated NH4The Cl aqueous solution (100mL) cancellation reaction, system is used dichloromethane extraction (3 × 100L). MergeOrganic phase, uses saturated aqueous common salt (100mL) to wash once, and anhydrous magnesium sulfate is dried organic phase, removes by filter magnesium sulfateSolid, decompression desolvation, residue uses column chromatography purification to obtain (2R, 4R)-5-([1,1'-biphenyl]-4-yl)-4-hydroxylBase-2 methyl valeric acid tert-butyl ester (formula IX) (5.2 grams, 87%).
Embodiment 9:(2R, 4R)-5-([1,1'-biphenyl]-4-yl)-4-hydroxy-2-methyl valeric acid tert-butyl ester (formula IX)Preparation
20 grams (2R, 4R)-5-(1,1'-xenyl)-4-tert-butyl diphenyl siloxy-2 methyl valeric acid tert-butyl ester (formula VIII,R1=TBDPS) be dissolved in THF solution (200mL), stir lower reactant liquor cryosel bath and be cooled to 0 to 5 DEG C, in this reaction system, delaySlowly add TBAF solution (1MinTHF, 42mL). Dropwise rear reaction system and be naturally warming up to stirring at room temperature 12 hours. InsteadThe system of answering adds saturated NH4The Cl aqueous solution (200mL) cancellation reaction, system is used dichloromethane extraction (3 × 150mL). MergeOrganic phase, uses saturated aqueous common salt (150mL) to wash once, and anhydrous magnesium sulfate is dried organic phase, removes by filter magnesium sulfateSolid, decompression desolvation, residue uses column chromatography purification to obtain (2R, 4R)-5-([1,1'-biphenyl]-4-yl)-4-hydroxylBase-2 methyl valeric acid tert-butyl ester (formula IX) (10.6 grams, 90%).
Embodiment 10:(2R, 4S)-(5-([1,1'-biphenyl]-4-yl)-2 methyl valeric acid tert-butyl ester-4-yl)-pyrrolesAlkane-2, the preparation of 5-diketone (formula XII)
Under nitrogen protection, in reaction bulb, add successively 6.0 grams (2R, 4R)-5-(1,1'-xenyl)-4-hydroxy-2-methyl pentaTert-butyl acrylate (formula IX), THF (80mL), triphenylphosphine (7.0 grams) and succinimide (formula X) (2.1 grams), system stirs allAfter even, be cooled to 0-5 DEG C, then slowly drip the THF solution (10mL) of 4.6 grams of diethyl azodiformates, after dropwisingReaction system is warming up to room temperature reaction 6 hours naturally. System adds the 100mL shrend reaction of going out, and EtOAc extracts (3 × 100mL).Merge organic phase, use saturated aqueous common salt (100mL) to wash once, anhydrous magnesium sulfate is dried organic phase, removes by filter sulphurAcid magnesium solid, decompression desolvation, residue use column chromatography purification obtain (2R, 4S)-(5-([1,1'-biphenyl]-4-yl)-The 2 methyl valeric acid tert-butyl ester-4-yl)-pyrrolidines-2,5-diketone (formula XII) (5.1 grams, 69%).
Embodiment 11:(2R, 4S)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-phthaloyl imino-valeric acidThe preparation of the tert-butyl ester (formula XII)
Under nitrogen protection, in reaction bulb, add successively 7.2 grams (2R, 4R)-5-(1,1'-xenyl)-4-hydroxy-2-methyl pentaTert-butyl acrylate (formula IX), THF (100mL), triphenylphosphine (8.3 grams) and phthalimide (formula XI) (3.7 grams), systemAfter stirring, be cooled to 0-5 DEG C, then slowly drip the THF solution (20mL) of 6.5 grams of diisopropyl azodiformates, dripAfter adding, reaction system is warming up to room temperature reaction 6 hours naturally. System adds the 100mL shrend reaction of going out, EtOAc extraction (3 ×150mL). Merge organic phase, use saturated aqueous common salt (150mL) to wash once, anhydrous magnesium sulfate is dried organic phase, filtersRemove magnesium sulfate solid, decompression desolvation, residue uses column chromatography purification to obtain (2R, 4S)-5-([1,1'-biphenyl]-4-Base)-2-methyl-4-phthaloyl imino-valeric acid tert-butyl ester (formula XII) (6.2 grams, 62%).
Embodiment 12:(2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl methyl valerate hydrochloridePreparation
4.0 grams (2R, 4S)-(5-(1,1'-the xenyl)-2 methyl valeric acid tert-butyl ester-4-yl)-pyrrolidines-2,5-diketone(formula XII) is dissolved in 30mL methanol solvate, then in reaction system, adds 50mL hydrochloric acid, whole reaction system after addingHeating is back to raw material and disappears. Reaction system is cooled to room temperature naturally, and high vacuum is except desolventizing, and residue uses methyl alcohol/acetic acidEthyl ester be recrystallized (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl methyl valerate hydrochloride (2.6 grams,81.5%)。
Embodiment 13:(2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl ethyl valerate hydrochloridePreparation
4.8 grams (2R, 4S)-5-(1,1'-xenyl)-2-methyl-4-phthaloyl imino-valeric acid tert-butyl ester (formulaXII) be dissolved in 50mL alcohol solvent, then in reaction system, add 65mL hydrochloric acid, after adding, whole reaction system addsHot reflux to raw material disappears. Reaction system is cooled to room temperature naturally, and high vacuum is except desolventizing, and residue uses ethanol/acetic acid secondEster be recrystallized (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl ethyl valerate hydrochloride (2.4 grams,68%)。