CN106380421A - Synthetic method for Sacubitril - Google Patents
Synthetic method for Sacubitril Download PDFInfo
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- CN106380421A CN106380421A CN201610740391.XA CN201610740391A CN106380421A CN 106380421 A CN106380421 A CN 106380421A CN 201610740391 A CN201610740391 A CN 201610740391A CN 106380421 A CN106380421 A CN 106380421A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
- C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/10—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
- C07C29/103—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes of cyclic ethers
- C07C29/106—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes of cyclic ethers of oxiranes
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/24—Synthesis of the oxirane ring by splitting off HAL—Y from compounds containing the radical HAL—C—C—OY
- C07D301/26—Y being hydrogen
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- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention provides a preparation method for Sacubitril as one component of a novel hypotensive drug Entresto. According to the method, chiral synthons, obtained in the oxydative degradation wastes of steroid sapogenin, are adopted as raw materials. The raw materials are subjected to five steps of reactions, and then the high-yield synthesis of Sacubitril is realized. The raw materials of the method are simple, easily available and low in cost. Meanwhile, the synthetic method is characterized by being mild in condition, simple in operation, high in yield and few in by-product. The method can be applied to the industrial production.
Description
Technical field
The invention provides a kind of synthesis treatment hypertension becomes with the composition of heart failure drugs Entresto (LCZ696)
The method of/mono- Sha Kubi song (Sacubitril).This method is to obtain from steroid sapogeniness oxidative degradation garbage
(2R, 4R) -4- methyl isophthalic acid, 2,5- triol chiral synthons are raw material, bent with high yield synthesis Sha Kubi through 5 step reactions.This
Synthetic method feature be chiral synthesis material be conveniently easy to get, cheap, reaction condition is gentle, easy and simple to handle, need not use valency
The expensive metal reagent of lattice, reaction yield is high, by-product is few, suitable industrialized production.
Technical background
Entresto is a new treatment hypertension and the heart failure drugs of Novartis Co., Ltd's research and development, 2015
It is approved by the FDA in the United States listing.It is by enkephalinase inhibitor Sha Kubi song (Sacubitril, AHU-377) and angiotensin
Acceptor inhibitor Valsartan (Diovan) form, the double inhibitor as angiotensin receptor and enkephalinase it is contemplated that
Entresto will play remarkable effect in the treatment of hypertension and heart failure disease.The bent structural formula of Sha Kubi is as follows：
Sha Kubi song chemical constitution is 2R- methyl -4S- Carboxypropionyl amido -5- xenyl ethyl valerate, and it synthesizes difficult point
It is the structure of 2R- methyl -4S- Carboxypropionyl amido chiral centre.Nineteen ninety-five, the research worker of Ciba-Geigy company is reported first
Road using non-natural D-Tyrosine be the bent method of Material synthesis Sha Kubi (US5217996, WO2008031567,
WO2010136474 and WO2012025501).The trifluoromethane sulfonic acid ester of N-Boc-D- methyl-P-tyrosine phenolic hydroxyl group and phenyl boron
Acid obtains the biphenylalanine ester with protection group through Suzuki coupling reaction.It is through ester hydrolysis, acyl hydroxylamination and tetrahydrochysene lithium aluminium also
Former provide corresponding biphenyl third ammonium aldehyde.Biphenyl third ammonium aldehyde reacts through Wittig, catalytic hydrogenation and de- Boc protection group obtain Sha Kubi
Bent free amine precursor.It is reacted with succinic anhydride and provides Sha Kubi song.This synthetic method is used synthesis initiation material expensive
And many noble metal expensive reagents, reactions steps are more.Subsequently, Novartis company reports that from L-Glutimic acid be initiation material
The bent method (WO2008083967, WO2011088797, WO2012025502 and WO2014198195) of synthesis Sha Kubi.L- is burnt
L-Glutamine is with biphenyl metal reagent addition, selective reduction ketone carbonyl, amido are protected, methylate, alcohol solves 2R- methyl -4S-
Amido -5- xenyl ethyl valerate.It is reacted with succinic anhydride and provides Sha Kubi song.It is many to there are reactions steps in synthetic method,
Operating condition is harsh, selectivity not high problem when chiral amino ketone is easy to isomerization and introduces chirality methyl.Recently,
Novartis company and univ cambridge uk's joint study report are from biphenyl acetaldehyde, chiral t-butyl sulfonamide and 2- bromomethyl
The method that acrylate synthesizes Sha Kubi song (Org.Lett.2015,17,5436).The bright and sharp Pharmaceutical Technology Co., Ltd in Suzhou
Be given and synthesize the bent method (CN 104557600 of Sha Kubi from chiral auxiliary reagent BETTY BOOP alkali and 2R- methyl -4- ketobutyric acid
A,2015).But the chiral auxiliary reagent BETTY BOOP alkali that the method is adopted and 2R- methyl -4- ketobutyric acid source are difficult.
The synthetic route common problem of above-mentioned report is exactly that chiral raw material valency is high rare, is required for structure in synthesis
Build chirality methyl, its reaction chiral reagent used is expensive, operating condition is also more harsh, is not suitable for preparing in a large number.
We have conveniently realized to react from it in steroid sapogeniness cleaning method for oxidation research and have reclaimed handss garbage
Property compound (2R, 4R) -2,5- dihydroxy -4- methylvaleric acid (Chinese patent CN03141641.1 and
CN201410131436.4).
We protect through TBS further, and (2R, 4R) -2,5- dihydroxy -4- methylvaleric acid are converted by reduction simple operationss
Become (2R, 4R) -1,2,5- penta triols and its derivant of the chiral reagent 1-TBS protection that can provide in a large number, thus being work
Industry produces and provides cheap chiral reagent.The purpose of the present invention is exactly to synthesize Sha Kubi song by this chiral reagent.
Content of the invention
The technical scheme that the present invention solves is the synthetic method that offer one planting sand storehouse must be bent.
The bent structure of Sha Kubi of the present invention is as follows：
The synthetic method of Sha Kubi song compound of the present invention passes through step 1)～5) synthesis；
Concrete synthesis step is as follows：
1) in aprotic solvent, under organic base effect, compound 2 and leaving group react 1 under 0 DEG C to room temperature～
5 hours, obtain compound 3；The mol ratio of compound 2, organic base and leaving group is 1：1～6：1～3；Described organic base
For triethylamine, diisopropyl ethyl amine, pyridine or 1,8- diazabicylo 11 carbon -7- alkene；Described leaving group is methane
Sulfonic acid chloride, paratoluensulfonyl chloride or perfluoro butyl sulfonic acid fluoride；
2) in non-protonic solvent, under the catalysis of cuprous salt, compound 3 is with biphenyl grignard reagent at -78 DEG C extremely
React 0.5～3 hour under room temperature, obtain compound 4；The mol ratio of compound, biphenyl grignard reagent and cuprous salt is 1：1～
4：0.01～0.1；Described cuprous salt is Cu-lyt. or cuprous bromide dimethylsulfide complex；
3) in non-protonic solvent, under organic base effect, compound 4 and sulphonyl chloro thing are anti-under 0 DEG C to room temperature
Answer 1～5 hour, then in dimethylformamide, react 1～15 hour at room temperature is to 100 DEG C with nitrine salt dissolving, changed
Compound 5；The mol ratio of compound 4, organic base and sulphonyl chloro thing is 1：1～6：1～3；Compound 4 and nitrine salt dissolving mole
Than for 1：1～4；Described organic base is triethylamine, diisopropyl ethyl amine or pyridine；Described sulphonyl chloro thing is methane sulphur
Acyl chlorides, paratoluensulfonyl chloride；Described nitrine salt dissolving is Hydrazoic acid,sodium salt or potassium azide；
4) in acetone, compound 5 and Jones oxidation agent reacts 1～7 hour under 0 DEG C to room temperature, then in ethanol,
React 5～24 hours under 0 DEG C to room temperature with acid, obtain compound 6；Compound 5 is 1 with the mol ratio of Jones oxidation agent：1～
3；Compound 5 is 1 with the mol ratio of acid：1～3；Described acid is sulphuric acid and thionyl chloride；
5) in non-protonic solvent, compound 6 and phosphorus reagent react 1～18 hour under room temperature to reflux temperature,
Add organic base and succinic anhydride, react 7～48 hours under room temperature to reflux temperature, obtain compound 1；Compound 6 with
The mol ratio of phosphorus reagent is 1：1～4；Compound 6 is 1 with the mol ratio of organic base and succinic anhydride：1～10：1～5；Described
Phosphorus reagent be trimethyl-phosphine, tri-n-butyl phosphine, triphenylphosphine, NSC 6513, NSC 5284 or phosphorous acid three
Phenyl ester；Described organic base is triethylamine, pyridine or 1,8- diazabicylo 11 carbon -7- alkene.
Using the method for the present invention, the method for step 5 can be quenched with water reaction.Final product compound 1 can be with having
Machine solvent extraction, saturated common salt is washed, and is dried, and filters, distillation, and column chromatographic isolation and purification is processed.
In above-mentioned reaction, described compound 5 can also pass through step 1), 2) and 3) " one kettle way " method one-step synthesis
Compound 5；I.e. step 1 and 2 product directly carry out next step reaction without isolating and purifying.
In above-mentioned reaction, described non-protonic solvent is dichloromethane, chloroform, oxolane or their mixing
Thing；
The chiral synthon that the present invention is obtained with steroid sapogeniness oxidative degradation garbage, as raw material, reacts through 5 steps
The synthesis Sha Kubi of high yield is bent.First the present invention raw material sources in steroid sapogeniness oxidative degradation garbage it is not necessary to
Chiral separation or asymmetric synthesis build chiral radicals, and raw material is cheap and easily-available, secondly method of the present invention mild condition, operation
Simplicity, high income, by-product is few, and agents useful for same low price is easy to get, and has reached a gram level scale at present, be applied to industry from now on
Metaplasia is produced.
Specific implementation method
Will be helpful to understand the present invention by implementation in detail below, but be not intended to limit present disclosure.
Method synthesis (Chinese patent CN201010530595.3) of starting compound 2 reference literature of the present invention.
The synthesis of embodiment 1 compound 3
Take 10g compound 2 (40mmol) to be dissolved in 100mL dichloromethane, at 0 DEG C, be separately added into 14mL DBU
(2.4eq) with 6mL RfSO2F (1.2eq), stirs 3h at 0 DEG C, adds water and be quenched, dichloromethane extraction aqueous phase 3 times, organic faciess
Washed 1 time with saturated common salt after merging, filter after anhydrous sodium sulfate drying, decompression boils off solvent, and column chromatography for separation obtains chemical combination
Thing 3 (8.2g, yield 88%).
[α]D 23+5.3(c 0.82,CHCl3)；
IR(cm-1):3410(OH)；
1H NMR(400MHz,CDCl3) 3.42-3.52 (m, 2H), 2.94-2.99 (m, 1H), 2.77 (t, J=4.4Hz,
1H), 2.46 (dd, J=5.1,2.7Hz, 1H), 1.82-1.90 (m, 1H), 1.64-1.70 (m, 1H), 1.27-1.33 (m, 1H),
0.97 (d, J=6.7Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H)；
13C NMR(100MHz,CDCl3)δ68.3,51.2,47.7,36.5,34.1,26.1,18.5,16.8,-5.2,-
5.3；HRMS-EI(m/z):[M-C(CH3)3]+calcd for C8H17O2Si:173.0998,found:173.0996.
The synthesis of embodiment 2 compound 3
Take 10g compound 2 (40mmol) to be dissolved in 100mL dichloromethane, under room temperature, be separately added into 13mL pyridine (4eq)
With 15g paratoluensulfonyl chloride (2eq), 3h is stirred at room temperature, adds water and be quenched, dichloromethane extraction aqueous phase 3 times, organic faciess merge
Washed 1 time with saturated common salt afterwards, filter after anhydrous sodium sulfate drying, decompression boils off solvent, and column chromatography for separation obtains compound 3
(8.4g, yield 90%).
The synthesis of embodiment 3 compound 3
Take 10g compound 2 (40mmol) to be dissolved in 100mL chloroform, under room temperature, be separately added into 33mL triethylamine
(6eq) with 9mL methane sulfonyl chloride (3eq), 4h is stirred at room temperature, adds water and be quenched, dichloromethane extraction aqueous phase 3 times, organic faciess
Washed 1 time with saturated common salt after merging, filter after anhydrous sodium sulfate drying, decompression boils off solvent, and column chromatography for separation obtains chemical combination
Thing 3 (8.1g, yield 87%).
The synthesis of embodiment 4 compound 3
Take 10g compound 2 (40mmol) to be dissolved in 100mL chloroform, at 10 DEG C, be separately added into 35mL diisopropyl
Ethylamine (5eq) and 19g paratoluensulfonyl chloride (2.5eq), lower stirring 5h at 10 DEG C, adding water is quenched, dichloromethane extraction water
Phase 3 times, organic faciess are washed 1 time with saturated common salt after merging, and filter, decompression boils off solvent, column chromatography after anhydrous sodium sulfate drying
Separate and obtain compound 3 (8.4g, yield 90%).
The synthesis of embodiment 5 compound 3
Take 10g compound 2 (40mmol) to be dissolved in 100mL dichloromethane, at 0 DEG C, be separately added into 18mL DBU (3eq)
With 10mL RfSO2F (2eq), stirs 4h at 0 DEG C, adds water and be quenched, dichloromethane extraction aqueous phase 3 times, and organic faciess are used after merging
Saturated common salt is washed 1 time, filters after anhydrous sodium sulfate drying, and decompression boils off solvent, column chromatography for separation obtain compound 3 (8.5g,
Yield 92%).
The synthesis of embodiment 6 compound 4
6.25g Mg (1.2eq) is taken to add 70mLTHF under Ar gas shielded, then Deca 50g 4- bromine under reflux conditions
The 130mLTHF solution of biphenyl (0.2mol), is stirred at room temperature 1h after completion of dropping, stand-by, and concentration is 1mol/L.
Take 803mg CuBr.Me2S (0.1eq) adds 20mLTHF under Ar gas shielded, Deca 4- bromo biphenyl at -30 DEG C
Grignard reagent 117mL (3eq), stirs 30 minutes, the 80mLTHF solution of Deca compound 3 (9g, 39mmol), completion of dropping, stirs
Mix 2 hours, be naturally warmed to room temperature, add saturated aqueous ammonium chloride that reaction, ethyl acetate extraction aqueous phase 3 time, organic faciess are quenched
Washed 1 time with saturated common salt after merging, filter after anhydrous sodium sulfate drying, decompression boils off solvent, and column chromatography for separation obtains chemical combination
Thing 4 (13.3g, yield 89%).
[α]D 24+7.6(c 1.24,CHCl3)；
IR(cm-1):3419(OH)；
1H NMR(400MHz,CDCl3) δ 7.56 (dd, J=21.1,7.8Hz, 4H), 7.43 (t, J=7.6Hz, 2H),
7.31 (dd, J=14.9,7.7Hz, 3H), 3.91-3.97 (m, 1H), 3.53 (dd, J=9.9,5.0Hz, 1H), 3.42 (dd, J
=9.9,7.5Hz, 1H), 2.75-2.85 (m, 2H), 1.77-1.88 (m, 1H), 1.44-1.52 (m, 2H), 0.90 (s, 9H),
0.88 (d, J=6.8Hz, 3H), 0.07 (s, 6H).
13C NMR(100MHz,CDCl3)δ141.2,139.3,138.2,130.1,128.9,127.3,127.2,127.1,
71.4,69.4,44.4,42.3,34.2,26.1,18.5,17.8,-5.2,-5.3；
HRMS-EI(m/z):[M-C(CH3)3-H2O]+calcd for C20H25OSi:309.1675,found:
309.1677.
The synthesis of embodiment 7 compound 4
6.25g Mg (1.2eq) is taken to add 70mLTHF under Ar gas shielded, then Deca 50g 4- bromine under reflux conditions
The 130mLTHF solution of biphenyl (0.2mol), is stirred at room temperature 1h after completion of dropping, stand-by, and concentration is 1mol/L.
Take 401mg CuBr.Me2S (0.05eq) adds 20mLTHF under Ar gas shielded, Deca 4- bromine connection at -78 DEG C
Benzene grignard reagent 156mL (4eq), stirs 1 hour, the 80mLTHF solution of Deca compound 3 (9g, 39mmol), completion of dropping,
Stirring 1 hour, is warmed to room temperature naturally, adds saturated aqueous ammonium chloride that reaction be quenched, and ethyl acetate extracts aqueous phase 3 times, organic
Washed 1 time with saturated common salt after mutually merging, filter after anhydrous sodium sulfate drying, decompression boils off solvent, column chromatography for separation
Compound 4 (13.5g, yield 90%).
The synthesis of embodiment 8 compound 4
6.25g Mg (1.2eq) is taken to add 70mLTHF under Ar gas shielded, then Deca 50g 4- bromine under reflux conditions
The 130mLTHF solution of biphenyl (0.2mol), is stirred at room temperature 1h after completion of dropping, stand-by, and concentration is 1mol/L.
Take 482mg CuBr.Me2S (0.06eq) adds 20mLTHF under Ar gas shielded, Deca 4- bromo biphenyl at 0 DEG C
Grignard reagent 78mL (2eq), stirs 0.5 hour, the 80mLTHF solution of Deca compound 3 (9g, 39mmol), completion of dropping, stirs
Mix 1.5 hours, be naturally warmed to room temperature, add saturated aqueous ammonium chloride that reaction be quenched, ethyl acetate extracts aqueous phase 3 times, organic
Washed 1 time with saturated common salt after mutually merging, filter after anhydrous sodium sulfate drying, decompression boils off solvent, column chromatography for separation
Compound 4 (13.4g, yield 89%).
The synthesis of embodiment 9 compound 4
6.25g Mg (1.2eq) is taken to add 70mLTHF under Ar gas shielded, then Deca 50g 4- bromine under reflux conditions
The 130mLTHF solution of biphenyl (0.2mol), is stirred at room temperature 1h after completion of dropping, stand-by, and concentration is 1mol/L.
Take 321mg CuBr.Me2S (0.04eq) adds 20mLTHF, Deca 4- bromo biphenyl at room temperature under Ar gas shielded
Grignard reagent 98mL (2.5eq), stirs 0.5 hour, the 80mLTHF solution of Deca compound 3 (9g, 39mmol), completion of dropping,
Stirring 0.5 hour, is warmed to room temperature naturally, adds saturated aqueous ammonium chloride that reaction, ethyl acetate extraction aqueous phase 3 time are quenched, has
Machine phase is washed 1 time with saturated common salt after merging, and filters, decompression boils off solvent, and column chromatography for separation obtains after anhydrous sodium sulfate drying
Compound 4 (12.8g, yield 85%).
The synthesis of embodiment 10 compound 4
6.25g Mg (1.2eq) is taken to add 70mLTHF under Ar gas shielded, then Deca 50g 4- bromine under reflux conditions
The 130mLTHF solution of biphenyl (0.2mol), is stirred at room temperature 1h after completion of dropping, stand-by, and concentration is 1mol/L.
Take 80mg CuBr.Me2S (0.01eq) adds 20mLTHF, Deca 4- bromo biphenyl at room temperature under Ar gas shielded
Grignard reagent 39mL (1eq), stirs 2 hours, the 80mLTHF solution of Deca compound 3 (9g, 39mmol), completion of dropping, stirring
1 hour, naturally it is warmed to room temperature, adds saturated aqueous ammonium chloride that reaction be quenched, ethyl acetate extracts aqueous phase 3 times, organic be harmonious
And after with saturated common salt wash 1 time, after anhydrous sodium sulfate drying filter, decompression boil off solvent, column chromatography for separation obtains compound 4
(12.8g, yield 85%).
The synthesis of embodiment 11 compound 5
Take 13g compound 4 (34mmol) to be dissolved in 120mL dichloromethane, at 0 DEG C, be separately added into 14mL triethylamine
(3eq) with 4mL methane sulfonyl chloride (1.5eq), stir 3h, add water and be quenched, dichloromethane extraction aqueous phase 3 times, after organic faciess merge
Washed 1 time with saturated common salt, filter after anhydrous sodium sulfate drying, decompression boils off solvent, is then dissolved in 120mL DMF, plus
Enter 6.59g Hydrazoic acid,sodium salt (3eq), stir 7h at 60 DEG C, add water and be quenched, ethyl acetate extraction aqueous phase 3 times, after organic faciess merge
Washed 1 time with saturation water lithium chloride solution, saturated common salt is washed 1 time, filter after anhydrous sodium sulfate drying, decompression boils off solvent, post
Chromatography obtains compound 5 (12.5g, yield 90%).
[α]D 25+11(c 1.10,CHCl3)；
IR(cm-1):2101(C-N3)；
1H NMR(400MHz,CDCl3) δ 7.53-7.60 (m, 4H), 7.43 (t, J=7.6Hz, 2H), 7.27-7.35 (m,
3H), 3.63-3.70 (m, 1H), 3.50 (dd, J=9.8,5.2Hz, 1H), 3.42 (dd, J=9.8,5.6Hz, 1H), 2.84 (t,
J=6.0Hz, 2H), 1.82-1.90 (m, 1H), 1.67-1.74 (m, 1H), 1.34-1.41 (m, 1H), 0.95 (d, J=6.8Hz,
3H),0.87(s,9H),0.02(s,6H)；
13C NMR(100MHz,CDCl3)δ141.0,139.7,137.0,129.8,128.9,127.4,127.3,127.2,
67.5,62.5,41.0,38.0,32.9,26.1,18.4,17.7,-5.2,-5.3；
HRMS-ESI(m/z):[M+H]+calcd for C24H36ON3Si:410.2622,found:410.2622.
The synthesis of embodiment 12 compound 5
Take 13g compound 4 (34mmol) to be dissolved in 120mL dichloromethane, at 10 DEG C, be separately added into 19mL triethylamine
(4eq) with 13g paratoluensulfonyl chloride (2eq), stir 4h, add water and be quenched, dichloromethane extraction aqueous phase 3 times, after organic faciess merge
Washed 1 time with saturated common salt, filter after anhydrous sodium sulfate drying, decompression boils off solvent, is then dissolved in 120mL DMF, plus
Enter 4.39g Hydrazoic acid,sodium salt (2eq), stir 8h at 80 DEG C, add water and be quenched, ethyl acetate extraction aqueous phase 3 times, after organic faciess merge
Washed 1 time with saturation water lithium chloride solution, saturated common salt is washed 1 time, filter after anhydrous sodium sulfate drying, decompression boils off solvent, post
Chromatography obtains compound 5 (12g, yield 87%).
The synthesis of embodiment 13 compound 5
Take 13g compound 4 (34mmol) to be dissolved in 120mL dichloromethane, at 0 DEG C, be separately added into 16mL pyridine (6eq)
With 19g paratoluensulfonyl chloride (3eq), stir 5h, add water and be quenched, dichloromethane extraction aqueous phase 3 times, organic faciess use saturation after merging
Sal is washed 1 time, filters after anhydrous sodium sulfate drying, and decompression boils off solvent, is then dissolved in 120mL DMF, adds 11g to fold
Potassium nitride (4eq), is stirred at room temperature 15h, adds water and be quenched, ethyl acetate extraction aqueous phase 3 times, and organic faciess use saturation chlorine after merging
Change lithium aqueous solution to wash 1 time, saturated common salt is washed 1 time, filter after anhydrous sodium sulfate drying, decompression boils off solvent, column chromatography for separation
Obtain compound 5 (11.7g, yield 85%).
The synthesis of embodiment 14 compound 5
Take 13g compound 4 (34mmol) to be dissolved in 120mL dichloromethane, under room temperature, be separately added into 28mL diisopropyl
Amine ethylamine (5eq) and 6.5mL methane sulfonyl chloride (2.5eq), stir 2h, add water and be quenched, and dichloromethane extraction aqueous phase 3 times has
Machine phase is washed 1 time with saturated common salt after merging, and filters, decompression boils off solvent, is then dissolved in 120mL after anhydrous sodium sulfate drying
In DMF, add 6.6g Hydrazoic acid,sodium salt (3eq), stir 3h at 100 DEG C, add water and be quenched, ethyl acetate extraction aqueous phase 3 times, organic
Washed 1 time with saturation water lithium chloride solution after mutually merging, saturated common salt is washed 1 time, filter after anhydrous sodium sulfate drying, decompression boils off
Solvent, column chromatography for separation obtains compound 5 (12.3g, yield 89%).
The synthesis of embodiment 15 compound 5
Take 13g compound 4 (34mmol) to be dissolved in 120mL dichloromethane, under room temperature, be separately added into 14mL triethylamine
(3eq) with 5mL methane sulfonyl chloride (2eq), stir 4h, add water and be quenched, dichloromethane extraction aqueous phase 3 times, organic faciess are used after merging
Saturated common salt is washed 1 time, filters after anhydrous sodium sulfate drying, and decompression boils off solvent, is then dissolved in 120mL DMF, adds
5.5g Hydrazoic acid,sodium salt (2.5eq), stirs 10h at 40 DEG C, adds water and be quenched, and ethyl acetate extraction aqueous phase 3 times, after organic faciess merge
Washed 1 time with saturation water lithium chloride solution, saturated common salt is washed 1 time, filter after anhydrous sodium sulfate drying, decompression boils off solvent, post
Chromatography obtains compound 5 (12.4g, yield 90%).
The synthesis of embodiment 16 compound 6
By 26.72 grams of chromic acids with a small amount of water dissolution, then it is slowly dropped into 23 milliliters of concentrated sulphuric acids, then is diluted to water
100 milliliters obtain final product, and concentration is 2.6mol/L.
12g compound 5 (29mmol) is taken to be dissolved in 300mL acetone, Deca Jones oxidation reagent 17mL at 10 DEG C
(1.5eq), stir 6h at this temperature, add isopropanol to be quenched, kieselguhr filters the solid separating out, decompression boils off solvent.So
After be dissolved in 200mL ethanol, add 3mL concentrated sulphuric acid (2eq), be stirred at room temperature 18 hours, add saturated aqueous sodium carbonate quench
Go out, decompression is extracted with ethyl acetate after boiling off solvent, organic faciess are washed 1 time with saturated common salt after merging, anhydrous sodium sulfate drying
After filter, decompression boil off solvent, column chromatography for separation obtains compound 6 (8.8g, yield 89%).
[α]D 26-33(c 1.24,CHCl3)；
IR(cm-1):2108(C-N3), 1731 (C=O)；
1H NMR(400MHz,CDCl3) δ 7.57 (dd, J=14.4,7.6Hz, 4H), 7.43 (t, J=7.6Hz, 2H),
7.31 (dd, J=23.8,7.6Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.59-3.66 (m, 1H), 2.87 (d, J=
6.7Hz, 2H), 2.70-2.76 (m, 1H), 1.91-1.98 (m, 1H), 1.47-1.56 (m, 1H), 1.25 (t, J=7.1Hz,
3H), 1.19 (d, J=7.1Hz, 3H)；
13C NMR(100MHz,CDCl3)δ176.1,140.9,139.9,136.5,129.8,128.9,127.4,127.3,
127.2,62.5,60.7,41.2,38.5,36.8,18.2,14.4；
HRMS-ESI(m/z):[M+H]+calcd for C20H24O2N3:338.1863,found:338.1864.
The synthesis of embodiment 17 compound 6
12g compound 5 (29mmol) is taken to be dissolved in 300mL acetone, Deca Jones oxidation reagent 23mL at 0 DEG C
(2eq), stir 5h at this temperature, add isopropanol to be quenched, kieselguhr filters the solid separating out, decompression boils off solvent.Then
It is dissolved in 200mL ethanol, adds 4.2mL thionyl chloride (2eq), be stirred at room temperature 5 hours, add saturated aqueous sodium carbonate to quench
Go out, decompression is extracted with ethyl acetate after boiling off solvent, organic faciess are washed 1 time with saturated common salt after merging, anhydrous sodium sulfate drying
After filter, decompression boil off solvent, column chromatography for separation obtains compound 6 (8.5g, yield 86%).
The synthesis of embodiment 18 compound 6
12g compound 5 (29mmol) is taken to be dissolved in 300mL acetone, Deca Jones oxidation reagent 34mL at room temperature
(3eq), stir 3h at this temperature, add isopropanol to be quenched, kieselguhr filters the solid separating out, decompression boils off solvent.Then
It is dissolved in 200mL ethanol, adds 7.8mL thionyl chloride (3eq), stir 14 hours at 0 DEG C, add saturated aqueous sodium carbonate
It is quenched, decompression is extracted with ethyl acetate after boiling off solvent, organic faciess are washed 1 time with saturated common salt after merging, and anhydrous sodium sulfate is done
Filter after dry, decompression boils off solvent, and column chromatography for separation obtains compound 6 (8.4g, yield 85%).
The synthesis of embodiment 19 compound 6
12g compound 5 (29mmol) is taken to be dissolved in 300mL acetone, Deca Jones oxidation reagent 28mL at room temperature
(2.5eq), stir 4h at this temperature, add isopropanol to be quenched, kieselguhr filters the solid separating out, decompression boils off solvent.So
After be dissolved in 200mL ethanol, add 2.3mL concentrated sulphuric acid (1.5eq), under room temperature stir 24 hours, add saturated sodium carbonate water
Solution is quenched, and decompression is extracted with ethyl acetate after boiling off solvent, and organic faciess are washed 1 time with saturated common salt after merging, anhydrous slufuric acid
Sodium filters after being dried, and decompression boils off solvent, and column chromatography for separation obtains compound 6 (8.7g, yield 88%).
The synthesis of embodiment 20 compound 6
12g compound 5 (29mmol) is taken to be dissolved in 300mL acetone, Deca Jones oxidation reagent 23mL at 0 DEG C
(2eq), stir 7h at this temperature, add isopropanol to be quenched, kieselguhr filters the solid separating out, decompression boils off solvent.Then
It is dissolved in 200mL ethanol, adds 3mL concentrated sulphuric acid (2eq), stir 18 hours under room temperature, add saturated aqueous sodium carbonate to quench
Go out, decompression is extracted with ethyl acetate after boiling off solvent, organic faciess are washed 1 time with saturated common salt after merging, anhydrous sodium sulfate drying
After filter, decompression boil off solvent, column chromatography for separation obtains compound 6 (8.9g, yield 90%).
The synthesis of embodiment 21 compound 1
Take 8g compound 6 (24mmol) to be dissolved in 120mL oxolane, add 25g triphenylphosphine at room temperature
(4eq), stir 14 hours at this temperature, be then separately added into 16mL triethylamine (5eq) and 7.1g succinic anhydride at room temperature
(3eq), stir 40 hours at this temperature, add water quenching to go out, dchloromethane, aqueous phase dichloromethane extraction, organic faciess
Washed 1 time with saturated common salt after merging, filter after anhydrous sodium sulfate drying, decompression boils off solvent, and column chromatography for separation obtains chemical combination
Thing 1 (8g, yield 82%).
[α]D 26-22(c 0.45,CHCl3)；
IR(cm-1):3276 (C-N), 1718,1647,1559 (C=O)；
1H NMR(400MHz,CDCl3) δ 7.54 (dd, J=20.3,7.3Hz, 4H), 7.42 (t, J=7.5Hz, 2H),
7.33 (t, J=7.3Hz, 1H), 7.23 (d, J=7.9Hz, 2H), 5.87 (d, J=8.7Hz, 1H), 4.19-4.29 (m, 1H),
4.12 (q, J=7.1Hz, 2H), 2.84 (t, J=6.2Hz, 2H), 2.63 (t, J=6.5Hz, 2H), 2.50-2.60 (m, 1H),
2.42 (t, J=6.5Hz, 2H), 1.90-1.97 (m, 1H), 1.50-1.57 (m, 1H), 1.23 (t, J=7.1Hz, 3H), 1.15
(d, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ176.6,172.1,140.8,139.5,136.7,130.0,128.9,127.3,
127.2,127.1,60.8,48.9,40.6,37.4,36.6,31.0,30.0,17.8,14.3；
HRMS-ESI(m/z):[M+H]+calcd for C24H30O5N:412.2118,found:412.2109.
The synthesis of embodiment 22 compound 1
Take 8g compound 6 (24mmol) to be dissolved in 120mL dichloromethane, add 7.5mL trimethyl-phosphine at room temperature
(3eq), stir 8 hours at this temperature, be then separately added into 19mL pyridine (10eq) and 11.8g succinic anhydride at room temperature
(5eq), stir 24 hours at this temperature, add water quenching to go out, aqueous phase dichloromethane extraction, organic faciess are eaten with saturation after merging
Salt is washed 1 time, filters after anhydrous sodium sulfate drying, and decompression boils off solvent, and column chromatography for separation obtains compound 1 (7.8g, yield
80%).
The synthesis of embodiment 23 compound 1
Take 8g compound 6 (24mmol) to be dissolved in 120mL dichloromethane, add 15mL tri-n-butyl phosphine at room temperature
(2.5eq), stirred under reflux temperature 4 hours, are then separately added into 29mL DBU (8eq) and 9.4g succinic anhydride at room temperature
(4eq), stirred under reflux temperature 15 hours, add water quenching to go out, aqueous phase dichloromethane extraction, and organic faciess are eaten with saturation after merging
Salt is washed 1 time, filters after anhydrous sodium sulfate drying, and decompression boils off solvent, and column chromatography for separation obtains compound 1 (7.8g, yield
80%).
The synthesis of embodiment 24 compound 1
Take 8g compound 6 (24mmol) to be dissolved in 120mL chloroform, add 5.7mL phosphorous acid front three at room temperature
Ester (2eq), stirred under reflux temperature 3 hours, then it is separately added into 19mL triethylamine (6eq) and 4.7g succinic anhydride at room temperature
(2eq), stirred under reflux temperature 8 hours, add water quenching to go out, aqueous phase dichloromethane extraction, and organic faciess are eaten with saturation after merging
Salt is washed 1 time, filters after anhydrous sodium sulfate drying, and decompression boils off solvent, and column chromatography for separation obtains compound 1 (7.9g, yield
81%).
The synthesis of embodiment 25 compound 1
Take 8g compound 6 (24mmol) to be dissolved in 120mL chloroform, add 6.2mL phosphorous triethylenetetraminehexaacetic acid at room temperature
Ester (1.5eq), stirred under reflux temperature 5 hours, then it is separately added into 13mL triethylamine (4eq) and 3.5g succinic acid at room temperature
Acid anhydride (1.5eq), stirred under reflux temperature 12 hours, add water quenching to go out, aqueous phase dichloromethane extraction, organic faciess are used full after merging
Wash 1 time with Sal, filter after anhydrous sodium sulfate drying, decompression boils off solvent, column chromatography for separation obtains compound 1, and (7.6g produces
Rate 78%).
It is pointed out that above-described embodiment technology design only to illustrate the invention and feature, its object is to allow ripe
The personage knowing technique will appreciate that present disclosure and implements according to this, can not limit the protection model of the present invention with this
Enclose.All equivalence changes made according to spirit of the invention or modification, all should be included within the scope of the present invention.
Claims (5)
1. a kind of method of synthesis Sha Kubi song compound, is characterized in that by step 1)～5) synthesis：
1) in aprotic solvent, under organic base effect, it is little that compound 2 and leaving group react 1～5 under 0 DEG C to room temperature
When, obtain compound 3；The mol ratio of compound 2, organic base and leaving group is 1：1～6：1～3；Described organic base is three
Ethamine, diisopropyl ethyl amine, pyridine or 1,8- diazabicylo 11 carbon -7- alkene；Described leaving group is sulfonyl methane
Chlorine, paratoluensulfonyl chloride or perfluoro butyl sulfonic acid fluoride；
2) in non-protonic solvent, under the catalysis of cuprous salt, compound 3 and biphenyl grignard reagent are at -78 DEG C to room temperature
Lower reaction 0.5～3 hour, obtains compound 4；The mol ratio of compound, biphenyl grignard reagent and cuprous salt is 1：1～4：
0.01～0.1；Described cuprous salt is Cu-lyt. or cuprous bromide dimethylsulfide complex；
3) in non-protonic solvent, under organic base effect, compound 4 and sulphonyl chloro thing react 1 under 0 DEG C to room temperature～
5 hours, then in dimethylformamide, react 1～15 hour at room temperature is to 100 DEG C with nitrine salt dissolving, obtain compound
5；The mol ratio of compound 4, organic base and sulphonyl chloro thing is 1：1～6：1～3；Compound 4 with the mol ratio of nitrine salt dissolving is
1：1～4；Described organic base is triethylamine, diisopropyl ethyl amine or pyridine；Described sulphonyl chloro thing is sulfonyl methane
Chlorine, paratoluensulfonyl chloride；Described nitrine salt dissolving is Hydrazoic acid,sodium salt or potassium azide；
4) in acetone, compound 5 and Jones oxidation agent are reacted 1～7 hour, then in ethanol, with acid under 0 DEG C to room temperature
React 5～24 hours under 0 DEG C to room temperature, obtain compound 6；Compound 5 is 1 with the mol ratio of Jones oxidation agent：1～3；Change
Compound 5 is 1 with the mol ratio of acid：1～3；Described acid is sulphuric acid and thionyl chloride；
5) in non-protonic solvent, compound 6 and phosphorus reagent react 1～18 hour under room temperature to reflux temperature, then plus
Enter organic base and succinic anhydride, react 7～48 hours under room temperature to reflux temperature, obtain compound 1；Compound 6 with phosphorous
The mol ratio of reagent is 1：1～4；Compound 6 is 1 with the mol ratio of organic base and succinic anhydride：1～10：1～5；Described contains
Phosphorus reagent is trimethyl-phosphine, tri-n-butyl phosphine, triphenylphosphine, NSC 6513, NSC 5284 or triphenyl phosphite；
Described organic base is triethylamine, pyridine or 1,8- diazabicylo 11 carbon -7- alkene；
In above-mentioned reaction, compound 1～6 has following structure：
2. sand storehouse as claimed in claim 1 is than bent synthetic method, it is characterized in that described step 1 and 2 product without
Isolate and purify, directly carry out next step reaction, that is, pass through step 1), 2) and 3) " one kettle way " method one-step synthesis acquisition chemical combination
Thing 5.
3. the bent synthetic method of Sha Kubi as claimed in claim 1, is characterized in that described non-protonic solvent is dichloromethane
Alkane, chloroform, oxolane or their mixture.
4. sand storehouse as claimed in claim 1 than bent synthetic method, is characterized in that described step 5) reaction be quenched with water
Reaction.
5. sand storehouse as claimed in claim 1, than bent synthetic method, is characterized in that described final product organic solvent carries
Take, washing, be dried, filter, distillation, column chromatographic isolation and purification is processed.
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| CN107382779A (en) * | 2017-07-27 | 2017-11-24 | 江苏中邦制药有限公司 | One planting sand storehouse must bent intermediate preparation method |
| CN108727213A (en) * | 2018-06-29 | 2018-11-02 | 中国科学院上海有机化学研究所 | One planting sand library must be bent preparation method |
| CN113387841A (en) * | 2020-03-13 | 2021-09-14 | 凯特立斯（深圳）科技有限公司 | Synthetic method of shakubiqu intermediate |
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| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
| WO2011088797A1 (en) * | 2010-01-22 | 2011-07-28 | Novartis Ag | Intermediates of neutral endopeptidase inhibitors and preparation method thereof |
| CN104557600A (en) * | 2015-01-26 | 2015-04-29 | 苏州明锐医药科技有限公司 | Preparation method of sacubitril |
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| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
| WO2011088797A1 (en) * | 2010-01-22 | 2011-07-28 | Novartis Ag | Intermediates of neutral endopeptidase inhibitors and preparation method thereof |
| CN104557600A (en) * | 2015-01-26 | 2015-04-29 | 苏州明锐医药科技有限公司 | Preparation method of sacubitril |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107382779A (en) * | 2017-07-27 | 2017-11-24 | 江苏中邦制药有限公司 | One planting sand storehouse must bent intermediate preparation method |
| CN107382779B (en) * | 2017-07-27 | 2020-04-17 | 江苏中邦制药有限公司 | Preparation method of shakubiqu intermediate |
| CN108727213A (en) * | 2018-06-29 | 2018-11-02 | 中国科学院上海有机化学研究所 | One planting sand library must be bent preparation method |
| CN108727213B (en) * | 2018-06-29 | 2021-06-08 | 中国科学院上海有机化学研究所 | Preparation method of shakubiqu |
| CN113387841A (en) * | 2020-03-13 | 2021-09-14 | 凯特立斯（深圳）科技有限公司 | Synthetic method of shakubiqu intermediate |
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