CN105601524B - The preparation of LCZ696 key intermediates - Google Patents
The preparation of LCZ696 key intermediates Download PDFInfo
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Abstract
The preparation of LCZ696 key intermediates, the present invention relates to LCZ696 key intermediates (4S,2R) 5 ([1,1' biphenyl] 4 bases) 4 amino 2 methylvaleric acid ester hydrochloride preparation method.(the 4 of this method preparationS,2R) 5 ([1,1' biphenyl] 4 bases) 4 amino 2 methylvaleric acid ester hydrochloride two chiral centres both from chiral fragment, metallic catalyst and chiral ligand that expensive and commercialization is difficult largely to purchase are not directed to use with, are easily realized and are commercially produced.
Description
Technical field
The invention belongs to medicinal chemistry arts, it is related to LCZ696 key intermediates (4S,2R) -5- ([1,1'- biphenyl] -4-
Base) -4- amino-2-methyl valeric acid ester hydrochlorides preparation method.
Background technology
LCZ696 is a kind of angiotensin receptor and enkephalinase double inhibitor, English entitled Entresto,
FDA in 2015 ratifies the medicine as angiotensin ii receptor blocker based on its excellent clinical test results, to reduce wind
The cardiovascular death of dangerous heart failure patient and hospitalization chronic heart failure（NYHAII-IV grades）With LVEF reduction
LCZ696.LCZ696 is the drug for hypertension Valsartan and a kind of novel antihypertensive medicament for having lost patent protection at present
Sacubitril (enkephalinase inhibitor) combination drug, its structural formula is as follows：
It is related to key intermediate (2 in LCZ696 preparation technologyR,4S) -5- ([1,1'- biphenyl] -4- bases) -4- ammonia
The synthesis of base -2 methyl valeric acid ester.Patent WO2014/032627 and patent EP1903027 disclose (2R, 4S) -5- ([1,1'-
Biphenyl] -4- bases) -4- amino-2-methyl pentanoate derivants preparation method.This method using 4- bromo biphenyls as starting material,
After RMgBr is prepared and it is chiral (S)-epoxychloropropane or (S)-epoxy-tertbutyl ether reaction, obtains corresponding hydroxylating
Compound；Under diethyl azodiformate/triphenylphosphine effect Mitsunobu occurs for subsequent hydroxy compounds and succinimide
Reaction obtains the pyrrolidine-2,5-dione intermediate of configuration inversion；The latter is using concentrated hydrochloric acid deprotection base and in alkalescence condition
Obtained after lower generation nucleophilic substitution it is corresponding (R) -3- ([1,1'- biphenyl] -4- bases) 2- aminopropan-1-ols hydrochlorides；Should
Product after the amino of salt is protected using Boc aoxidizes primary hydroxyl for corresponding aldehyde product under the conditions of NaClO/TEMPO, then hair
Raw Wittig reactions and using being obtained after LiOH hydrolyzed ethyls (R) the amyl- 2- alkene of -5- biphenyl -4- base -4-Boc amino-2-methyls
Acid；The latter is in metallic catalyst [RuI2(p-cymene)]2Occur with the presence of chiral ligand mandyphos SL-M004-1
Asymmetric hydrogenation is reduced, and obtains (2R, 4S) -5- biphenyl -4- base -4-Boc amino-2-methyl valeric acids；The subsequent acid carries out ethyl ester
Change and complete (2R,4S) -5- biphenyl-4-amino-2-methyl pentanoic acid ethyl esters preparation.Not only synthesis step is more for the route, and
During use to very expensive and commercialization is difficult the metallic catalyst [RuI that largely purchases2(p-cymene)]2And chirality
Part mandyphos SL-M004-1, therefore industrialized production is restricted.Patent WO2014/032627 and patent
EP1903027 synthetic routes are as follows：
The content of the invention
Tested by substantial amounts of research and development, the present invention develops preparation (2R,4S) -5- ([1,1'- biphenyl] -4- bases) -4- ammonia
The variation route of base -2 methyl valeric acid ester, its reaction equation is as follows：
。
The technical characteristic of the present invention is as follows:
1st, initiation material 4- bromo biphenyls (Formulas I) generated in the presence of n-BuLi 4- xenyls lithium (Formula II) THF it is molten
Liquid, the solution then directly and it is chiral (S)-epoxy halogenopropane (formula III) reacts, generation (S) -1- ([1,1'- biphenyl] -4-
Base) -3- halos -propyl- 2- alcohol (formula IV);
Wherein X is halogen in formula III, IV, preferably chlorine.
2、(S) hydroxyl of-1- ([1,1-biphenyl]-4- bases)-3- halos -propyl- 2- alcohol (formula III) entered using silicon protection group
Row protection, prepare (S)-1- ([1,1-biphenyl]-4- bases)-3- halo-2- siloxies propane (Formula V);
Wherein silica reagent used in step reaction is tert-butyl chloro-silicane or tert-butyl diphenyl chlorosilane；
R in Formula V1It is TBS or TBDPS protection groups.
3、(S) -1- ([1,1'- biphenyl] -4- bases) -3- halo -2- siloxies propane (Formula V) does the condition of solvent in THF
Under, add magnesium metal prepare RMgBr (S) -1- ([1,1'- biphenyl] -4- bases) -- 2- siloxy propane -3- magnesium halide (formulas
VI THF solution), then and (R) -2- trifluoro methylsulfonyl oxygen propanoic acid tert-butyl esters (Formula VII) reaction, realize (2R,4R)-5-(1,
1'- xenyls) -4- siloxies -2 methyl valeric acid tert-butyl ester (Formula VIII) preparation；
Wherein R in Formula VII2It is trifyl（CF3SO2-）Group；
Wherein R in Formula V, VI, VIII1It is TBS or TBDPS protection groups.
4、(2R,4R) -5- ([1,1'- biphenyl] -4- bases) -4- siloxies -2 methyl valeric acid tert-butyl ester (Formula VIII) exists
The lower progress removing silicon protection group reaction of TBAF effects realizes (2R,4R) -5- ([1,1'- biphenyl] -4- bases) -4- hydroxy-2-methyls
The preparation of pentanoate (Formula IX)；
The solvent that wherein step reaction is used is selected from THF, EtOAc, Dioxane, CH3CN;
Wherein R in Formula VIII1It is TBS or TBDPS protection groups.
5、(2R,4R) -5- ([1,1'- biphenyl] -4- bases) -4- hydroxy-2-methyls pentanoates (Formula IX) and succinyl
Imines (Formula X) or phthalimide (Formula X I) occur Mitsunobu reactions and realize (2R,4S)-(5- ([1,1'- biphenyl]-
4- yls) -2 methyl valeric acid the tert-butyl ester -4- bases)-pyrrolidine-2,5-dione (Formula X II) or (2R,4S) -5- ([1,1'- biphenyl] -
4- yls) -2- methyl -4- phthaloyl iminos-pentanoate (Formula X II) preparation
The phosphonate reagent that wherein Mitsunobu reactions are used is selected from triphenylphosphine or tri-n-butyl phosphine；Used coupling
Reagent is selected from diethyl azodiformate (DEAD) or azoformic acid isopropyl ester (DIAD).
6、(2R,4S)-(5- ([1,1'- biphenyl] -4- the bases) -2 methyl valeric acid tert-butyl ester -4- bases)-pyrrolidines -2,5- two
Ketone (Formula X II) or (2R,4S) -5- ([1,1'- biphenyl] -4- bases) -2- methyl -4- phthaloyl iminos-pentanoate
(Formula X II) removes succinimide or phthalimide protecting group and uncle under conditions of alkylol makees solvent with HCl
Butyl protection group, while carrying out esterification, obtains (2R,4S) -5- ([1,1'- biphenyl] -4- bases) -4- amino-2-methyls penta
Acid esters hydrochloride；
Wherein react the alkylol used and be selected from methanol, ethanol.
Use the technique synthesis (2 of the present inventionR,4S) -5- ([1,1'- biphenyl] -4- bases) -4- amino-2-methyl valerates
The step of hydrochloride, is shorter, two in product chiral centre is introduced using chiral fragment, it is to avoid using expensive and
Commercialization is difficult the chiral metal catalyst and chiral ligand reagent largely purchased, and easily realizes the big production of commercialization.
Embodiment
It can more specifically understand the present invention by the following examples, but it illustrates rather than the limitation present invention
Scope.
Embodiment 1: (S) -1- ([1,1'- biphenyl] -4- bases) -3- chloros -propyl- 2- alcohol (formula IV, X=Cl) preparation
In 500ml there-necked flasks, 5 grams of 4- bromo biphenyls and anhydrous THF (80ml) are added, system is cooled to -78 after stirring
DEG C, then nitrogen protection under be slowly added into reaction solution n-BuLi hexane solution (1.6M in n-hexane,
15ml).System is kept for -78 DEG C or so stir 30 minutes after completion of dropping, is then to slowly warm up to -10 DEG C or so and is stirred 2 hours.
(S)-epoxychloropropane (formula III, X=Cl) THF solution (3 grams, 40ml THF) is slowly added into reaction system.It is added dropwise
Finish rear reaction system and warm naturally to room temperature reaction 5 hours, then to being slowly added to 100ml saturated ammonium chlorides in reaction system
Reaction is quenched in the aqueous solution.System adds CH2Cl2Extract (3 × 50ml), merge organic phase, anhydrous sodium sulfate is carried out to organic phase
Dry, filtering, removed under reduced pressure solvent, residue is purified using column chromatography, obtain (S) -1- ([1,1'- biphenyl] -4- bases) -3-
Chloro -propyl- 4.5 grams of 2- alcohol light yellow solid (85%).
Embodiment 2: (S) -1- ([1,1'- biphenyl] -4- bases) -3- chloros -propyl- 2- alcohol (formula IV, X=Cl) preparation
In 10L glass four-hole bottles, 200 grams of 4- bromo biphenyls and anhydrous THF (3.2L) are added, system is cooled down after stirring
To -78 DEG C (dry ice acetone bath), then nitrogen protection it is lower by dropping funel be slowly added into reaction solution n-BuLi just oneself
Alkane solution (1.6M in n-hexane, 600mL).System is kept for -78 DEG C or so stir 1 hour after completion of dropping, then slow
- 10 DEG C or so are warming up to stir 4 hours.(S)-epoxychloropropane (formula III, X=Cl) is slowly added into reaction system
THF solution (120 grams, 2L THF).Reaction system warms naturally to room temperature reaction 7 hours after completion of dropping, then to reactant
2L saturated aqueous ammonium chlorides are slowly added in system reaction is quenched.System adds CH2Cl2Extract (3 × 2L), merge organic phase,
Organic phase is dried anhydrous sodium sulfate, is filtered to remove solid sodium sulfate, and removed under reduced pressure solvent, residue is entered using column chromatography
Row purifying, obtain (S) -1- ([1,1'- biphenyl] -4- bases) -3- chloros -propyl- 172 grams of 2- alcohol yellow solid (81%).
Embodiment 3：(S) -1- ([1,1'- biphenyl] -4- bases) -3- chloros -propyl- 2- tertiary butyl dimethyl Sis base-propane
(Formula V, R1=TBS) preparation
In 250mL three neck round bottom flask, thermometer and magnetic agitation are equipped with, add (S) -1- ([1,1'- biphenyl] -4-
Base) 8.2 grams of -3- chloros -propyl- 2- alcohol (formula IV, X=Cl), then add anhydrous CH2Cl2(80mL) and DMF (2mL).Instead
Liquid is answered to be stirring evenly and then adding into DMAP (50mg), system ice-water bath is cooled to 0 DEG C or so.Then by dropping funel to reaction
TBSCl CH is slowly added in system2Cl2Solution (6 grams, 20mL CH2Cl2), process is added dropwise and keeps temperature of reaction system to be less than 5
℃.System warms naturally to that reaction 6 hours is stirred at room temperature after completion of dropping.The tracking of TLC points plate is removed under reduced pressure molten after completion of the reaction
Agent, residue column chromatography purifying obtains (S) -1- ([1,1'- biphenyl] -4- bases) -3- chloros -propyl- 2- tertiary butyl dimethyl Sis
Base-propane (pale yellow foam solid, 10.7 grams, 89%).
Embodiment 4：(S) -1- ([1,1'- biphenyl] -4- bases) -3- chloros -propyl- 2- tert-butyl diphenyls siloxy-propane
(Formula V, R1=TBDPS) preparation
In 3L four round flask, thermometer and mechanical agitation are equipped with, add (S) -1- ([1,1'- biphenyl] -4- bases) -3-
89 grams of chloro -propyl- 2- alcohol (formula IV, X=Cl), then adds anhydrous CH2Cl2(1L) and DMF (20mL).Reaction solution is stirred
DMAP (600mg) is added after uniform, system ice-water bath is cooled to 0 DEG C or so.Then by dropping funel into reaction system
It is slowly added to TBDPSCl CH2Cl2Solution (150 grams, 100mL CH2Cl2), process is added dropwise and keeps temperature of reaction system to be less than 5
℃.System warms naturally to that reaction 18 hours is stirred at room temperature after completion of dropping.The tracking of TLC points plate is removed under reduced pressure molten after completion of the reaction
Agent, residue column chromatography purifying obtains (S) -1- ([1,1'- biphenyl] -4- bases) -3- chloros -propyl- 2- tert-butyl diphenyl silica
Base-propane (light yellow solid, 144 grams, 82%).
Embodiment 5: (R) -2- trifluoro methylsulfonyl oxygen propanoic acid tert-butyl esters (Formula VII) preparation
3L three neck round bottom flask, is equipped with thermometer and magnetic agitation, adds the 50 grams of D-ALPHA-Hydroxypropionic acid tert-butyl ester (ee>And nothing 99%)
Water CH2Cl2(1.2L), ice-water bath is cooled to 0 DEG C or so after system stirs.2,6- dimethyl pyrazoles are added into reaction system
After pyridine (50mL), trifluoromethanesulfanhydride anhydride (70mL) is slowly added dropwise by dropping funel, process is added dropwise and keeps temperature of reaction system not
Higher than 5 DEG C.Reaction system is stirred 2 hours between 0-5 DEG C after completion of dropping.Then saturation is slowly added into reaction system
Reaction is quenched aqueous ammonium chloride solution (500mL).Separate CH2Cl2Organic phase, aqueous phase CH2Cl2Extract (3 × 800mL),
Merge organic phase, 0.5 N watery hydrochloric acid (500mL) washed once, then washed once again with saturated aqueous common salt (1L), anhydrous slufuric acid
Organic phase is dried magnesium, is filtered to remove magnesium sulfate solid, removed under reduced pressure solvent, it is straight that residue (81 grams, 85%) is not required to purifying
Connect and use.
Embodiment 6: (2R,4R) -5- ([1,1'- biphenyl] -4- bases) -4- tertiary butyl dimethyl Sis base -2 methyl valeric acid
The tert-butyl ester (Formula VIII, R1=TBS) preparation
1 gram of metal magnesium chips and 100ML tetrahydrofurans are added in 1L flasks, magnetic agitation is opened.Simultaneously into the reaction solution
Add a small amount of iodine and 2 grams of (S) -1- ([1,1'- biphenyl] -4- bases) -3- chloros -propyl- 2- tertiary butyl dimethyl Sis base-propane
(Formula V, R1=TBS) continue stir to grignard reaction start trigger.Then, 9 are slowly added into the reaction liquid after initiation
Gram (S) -1- ([1,1'- biphenyl] -4- bases) -3- chloros -propyl- 2- tertiary butyl dimethyl Sis base-propane (Formula V, R1 =
TBS whole reaction system is incubated 35 degree or so and stirred 2 hours after THF solution (100mL)), completion of dropping.It will then prepare
Good RMgBr is transferred in dropping funel, and (the R) -2- trifluoro methylsulfonyls oxygen third prepared to 8.5 grams of embodiments 5 is slowly added dropwise
In the THF solution of tert-butyl acrylate (Formula VII), process is added dropwise and keeps 0 to 5 DEG C of temperature of reaction system.Insulation reaction 2 after completion of dropping
Hour, then add saturation NH to reaction system4The Cl aqueous solution（300ml）Reaction is quenched, system uses dichloromethane extraction (3
× 300L), merge organic phase, 0.5N desalinization of soil by flooding or leaching acid (100mL) washed once, and then wash one with saturated aqueous common salt (100mL) again
Secondary, organic phase is dried anhydrous magnesium sulfate, is filtered to remove magnesium sulfate solid, and removed under reduced pressure solvent, residue uses post layer
Analysis purifying obtains (2R, 4R) -5- ([1,1'- biphenyl] -4- the bases) -4- tertiary butyl dimethyl Sis 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- bases) -4- tert-butyl diphenyl siloxy -2- methylpents
Tert-butyl acrylate (Formula VIII, R1=TBDPS) preparation
2 grams of metal magnesium chips and 150mL tetrahydrofurans are added in 1L three neck round bottom flask.Add under agitation into the reaction solution
Enter a small amount of iodine grain and 3 grams of (S) -1- ([1,1'- biphenyl] -4- bases) -3- chloros -propyl- 2- tertiary butyl dimethyl Sis base-propane
(Formula V, R1=TBDPS) continue stir to grignard reaction start trigger.Then, slowly add into the reaction liquid after initiation
Enter 25 grams of (S) -1- ([1,1'- biphenyl] -4- bases) -3- chloros -propyl- 2- tert-butyl diphenyls siloxy-propane (Formula V, R1 =
TBDPS whole reaction system is incubated 35 degree or so and stirred 2 hours after THF solution (200mL)), completion of dropping.Then will system
The RMgBr got ready is transferred in dropping funel, and (the R) -2- trifluoro methylsulfonyl oxygen prepared to 24 grams of embodiments 5 is slowly added dropwise
In the THF solution of propanoic acid tert-butyl ester (Formula VII), process is added dropwise and keeps 0 to 5 DEG C of temperature of reaction system.It is incubated after completion of dropping anti-
Answer and be slowly added to saturation NH after 4 hours in reaction system4The Cl aqueous solution（500mL）Reaction is quenched, system is extracted using dichloromethane
Take (3 × 500L), merge organic phase, 0.5N desalinization of soil by flooding or leaching acid (300mL) washed once, then be washed again with saturated aqueous common salt (300mL)
Wash once, organic phase is dried anhydrous magnesium sulfate, be filtered to remove magnesium sulfate solid, removed under reduced pressure solvent, residue is used
Column chromatography purifying obtains (2R, 4R) -5- ([1,1'- biphenyl] -4- bases) -4- tert-butyl diphenyls siloxy -2 methyl valeric acid uncle
Butyl ester (Formula VIII, R1=TBDPS) (22.2 grams, 66.5%).
Embodiment 8: (2R,4R) -5- ([1,1'- biphenyl] -4- bases) -4- hydroxy-2-methyls pentanoate (Formula IX)
Prepare
8 grams of (2R, 4R-5- (1,1'- xenyls) -4- tertiary butyl dimethyl Sis bases-the 2 methyl valeric acid tert-butyl ester (formula
VIII, R1=TBS) it is dissolved in THF solution (100mL), the lower reaction solution ice salt bath of stirring is cooled to 0 to 5 DEG C, then to the reaction
TBAF solution (1M in THF, 20mL) is slowly added in system.Reaction system warms naturally to be stirred at room temperature after completion of dropping
12 hours.Reaction system adds saturation NH4The Cl aqueous solution（100mL）Be quenched reaction, system extracted using dichloromethane (3 ×
100L) .Merge organic phase, washed once with saturated aqueous common salt (100mL), organic phase is dried anhydrous magnesium sulfate, filter
Magnesium sulfate solid is removed, removed under reduced pressure solvent, residue obtains (2R, 4R) -5- ([1,1'- biphenyl] -4- using column chromatography purifying
Base) -4- hydroxy-2-methyls pentanoate (Formula IX) (5.2 grams, 87%).
Embodiment 9: (2R,4R) -5- ([1,1'- biphenyl] -4- bases) -4- hydroxy-2-methyls pentanoate (Formula IX)
Prepare
20 grams of (2R, 4R) -5- (1,1'- the xenyls) -4- tert-butyl diphenyls siloxy -2 methyl valeric acid tert-butyl ester (formulas
VIII, R1=TBDPS) it is dissolved in THF solution (200mL), the lower reaction solution ice salt bath of stirring is cooled to 0 to 5 DEG C, to the reactant
TBAF solution (1M in THF, 42mL) is slowly added in system.Reaction system warms naturally to be stirred at room temperature 12 after completion of dropping
Hour.Reaction system adds saturation NH4The Cl aqueous solution（200mL）Be quenched reaction, system extracted using dichloromethane (3 ×
150mL) .Merge organic phase, washed once with saturated aqueous common salt (150mL), organic phase is dried anhydrous magnesium sulfate, mistake
Filter out magnesium sulfate solid, removed under reduced pressure solvent, residue using column chromatography purifying obtain (2R, 4R) -5- ([1,1'- biphenyl] -
4- yls) -4- hydroxy-2-methyls pentanoate (Formula IX) (10.6 grams, 90%).
Embodiment 10: (2R,4S)-(5- ([1,1'- biphenyl] -4- the bases) -2 methyl valeric acid tert-butyl ester -4- bases)-pyrroles
The preparation of alkane -2,5- diketone (Formula X II)
Under nitrogen protection, 6.0 grams of (2R, 4R) -5- (1,1'- xenyl) -4- hydroxyl -2- first are sequentially added into reaction bulb
Base pentanoate (Formula IX), THF (80mL), triphenylphosphine (7.0 grams) and succinimide (Formula X) (2.1 grams), system is stirred
0-5 DEG C is cooled to after mixing uniformly, the THF solution (10mL) of 4.6 grams of diethyl azodiformates is then slowly added dropwise, drips
Reaction system warms naturally to room temperature reaction 6 hours after finishing.System adds 100mL water quenchings and gone out reaction, EtOAc extract (3 ×
100mL).Merge organic phase, washed once with saturated aqueous common salt (100mL), organic phase is dried anhydrous magnesium sulfate, filter
Remove magnesium sulfate solid, removed under reduced pressure solvent, residue using column chromatography purifying obtain (2R, 4S)-(5- ([1,1'- biphenyl]-
4- yls) -2 methyl valeric acid the tert-butyl ester -4- bases)-pyrrolidines -2,5- diketone (Formula X II) (5.1 grams, 69%).
Embodiment 11: (2R,4S) -5- ([1,1'- biphenyl] -4- bases) -2- methyl -4- phthaloyl iminos-valeric acid
The preparation of the tert-butyl ester (Formula X II)
Under nitrogen protection, 7.2 grams of (2R, 4R) -5- (1,1'- xenyl) -4- hydroxyl -2- first are sequentially added into reaction bulb
Base pentanoate (Formula IX), THF (100mL), triphenylphosphine (8.3 grams) and phthalimide (Formula X I) (3.7 grams),
System is cooled to 0-5 DEG C after stirring, the THF solution (20mL) of 6.5 grams of diisopropyl azodiformates is then slowly added dropwise,
Reaction system warms naturally to room temperature reaction 6 hours after completion of dropping.System adds 100mL water quenchings and gone out reaction, and EtOAc extracts (3
×150mL).Merge organic phase, washed once with saturated aqueous common salt (150mL), organic phase is dried anhydrous magnesium sulfate, mistake
Filter out magnesium sulfate solid, removed under reduced pressure solvent, residue using column chromatography purifying obtain (2R, 4S) -5- ([1,1'- biphenyl] -
4- yls) -2- methyl -4- phthaloyl iminos-pentanoate (Formula X II) (6.2 grams, 62%).
Embodiment 12: (2R,4S) -5- ([1,1'- biphenyl] -4- bases) -4- amino-2-methyl methyl valerate hydrochlorides
Prepare
4.0 grams (2R, 4S)-(5- (1,1'- the xenyls) -2 methyl valeric acid tert-butyl ester -4- bases)-pyrrolidines -2,5- two
Ketone (Formula X II) is dissolved in 30mL methanol solvates, and 50mL hydrochloric acid, addition whole reactant after finishing then are added into reaction system
System is heated to reflux to raw material disappearing.Reaction system is naturally cooling to room temperature, and high vacuum removes solvent, and residue uses methanol/second
Acetoacetic ester recrystallizes (2R, 4S) and -5- ([1,1'- biphenyl] -4- bases) -4- amino-2-methyl methyl valerates hydrochloride (2.6
Gram, 81.5%).
Embodiment 13: (2R,4S) -5- ([1,1'- biphenyl] -4- bases) -4- amino-2-methyl ethyl valerate hydrochlorides
Prepare
4.8 grams of (2R, 4S) -5- (1,1'- xenyls) -2- methyl -4- phthaloyl iminos-pentanoates
(Formula X II) is dissolved in 50mL alcohol solvents, and 65mL hydrochloric acid, addition whole reaction system after finishing then are added into reaction system
It is heated to reflux to raw material disappearing.Reaction system is naturally cooling to room temperature, and high vacuum removes solvent, and residue uses ethanol/acetic acid
Ethyl ester recrystallizes (2R,4S) -5- ([1,1'- biphenyl] -4- bases) -4- amino-2-methyl ethyl valerates hydrochloride (2.4 grams,
68%)。
Claims (5)
1. one kind prepares the technique of (2R, 4S) -5- ([1,1'- biphenyl] -4- bases) -4- amino-2-methyl valeric acid ester hydrochlorides,
(2R, 4S) -5- ([1,1 '-biphenyl] -4- bases) -4- amino-2-methyl valeric acid ester hydrochlorides
Wherein R3It is methyl or ethyl；
The technique reacted including Formula X II under hydrochloric acid and alcohols solvent obtain (2R, 4S) -5- ([1,1'- biphenyl] -4- bases) -
4- amino-2-methyl valeric acid ester hydrochlorides, Formula X II has following structural formula：
Alcohols solvent is selected from methanol or ethanol.
2. technique as claimed in claim 1, Formula X II is that occur Mitsunobu reactions by Formula IX and Formula X or XI to obtain, formula
IX, Formula X and XI chemical structural formula are as follows：
The phosphonate reagent that Mitsunobu reactions are used is selected from triphenylphosphine or tri-n-butyl phosphine；Mitsunobu reacts coupling reagent
Selected from diethyl azodiformate (DEAD) or azoformic acid isopropyl ester (DIAD).
3. technique as claimed in claim 2, Formula IX is to remove silicon-based protecting group by Formula VIII to obtain, Formula VIII chemical constitution
Formula is as follows：
The solvent that step reaction is used is selected from THF, EtOAc, Dioxane, CH3CN；
R in Formula VIII1It is TBS or TBDPS protection groups.
4. technique as claimed in claim 3, Formula VIII is chemical combination shown in the RMgBr Formula IV and Formula VII prepared by Formula V
Thing reaction is obtained, and Formula V, Formula IV and Formula VII have following chemical constitution：
In Formula V, X is halogen；
In Formula V, R1It is TBS or TBDPS；
In Formula IV, X is halogen；
In Formula IV, R1It is TBS or TBDPS；
In Formula VII, R2It is Tf.
5. technique as claimed in claim 4, Formula V is to protect the hydroxyl in formula IV to obtain by TBSCl or TBDPSCl, formula IV
With following chemical constitution：
In formula IV, X is halogen.
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| JP7001597B2 (en) | 2015-12-10 | 2022-01-19 | ノバルティス アーゲー | New processes and intermediates |
| WO2018007919A1 (en) | 2016-07-05 | 2018-01-11 | Novartis Ag | New process for early sacubitril intermediates |
| CN107602399B (en) * | 2016-07-11 | 2020-09-25 | 江西东邦药业有限公司 | Preparation method of enkephalinase inhibitor intermediate |
| JP6945619B2 (en) | 2016-08-17 | 2021-10-06 | ノバルティス アーゲー | New methods and intermediates for NEP inhibitor synthesis |
| WO2018116203A1 (en) | 2016-12-23 | 2018-06-28 | Novartis Ag | New process for early sacubitril intermediates |
| CN106966926B (en) * | 2017-04-01 | 2018-10-19 | 沧州那瑞化学科技有限公司 | A kind of preparation method of LCZ696 intermediates |
| CN108047092A (en) * | 2018-01-12 | 2018-05-18 | 重庆市碚圣医药科技股份有限公司 | A kind of synthetic method of LCZ696 intermediates |
| UY38072A (en) | 2018-02-07 | 2019-10-01 | Novartis Ag | COMPOSITIONS DERIVED FROM BUTANOIC ESTER SUBSTITUTED WITH BISPHENYL AS INHIBITORS OF NEP, COMPOSITIONS AND COMBINATIONS OF THE SAME |
| CN110183357B (en) * | 2019-06-13 | 2021-09-24 | 甘肃皓天医药科技有限责任公司 | Preparation method for preparing Sacubitril intermediate |
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