CN110407733A - One seed sand library Ba Qu impurity compound - Google Patents
One seed sand library Ba Qu impurity compound Download PDFInfo
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- CN110407733A CN110407733A CN201810382614.9A CN201810382614A CN110407733A CN 110407733 A CN110407733 A CN 110407733A CN 201810382614 A CN201810382614 A CN 201810382614A CN 110407733 A CN110407733 A CN 110407733A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
Abstract
The invention belongs to organic synthesis fields, specifically disclose a seed sand library Ba Qu impurity compound (2R, 4R) -4- (3- carboxyl -1- oxo propylamine) -5- [(1,1'- biphenyl) -4- base] -2 methyl valeric acid ethyl ester, the invention also discloses the preparation methods of the impurity compound, the impurity compound purity obtained according to the technical solution of the present invention reaches 99.8%, can study directly as standard items for Sha Kuba song related impurities.
Description
Technical field
The invention belongs to organic chemistry fileds, and in particular to a kind of cardiotonic agents Sha Kuba song impurity compound and this
The synthetic method and purposes of kind impurity compound.
Background technique
With the development of society, the disease incidence of heart failure gradually increases, since its pathogenic factor is more, treatment difficulty is big,
The health for seriously affecting the mankind is one of adult most important cause of death.Entresto is Novartis Co., Ltd's research and development
One novel treatment hypertension and heart failure drugs, are approved by the FDA in the United States listing in 2015.It is inhibited by enkephalinase
Agent Sha Kuba bent (Sacubitrl, AHU-377) and angiotensin receptor inhibitor Valsartan (Diovan) composition.Sha Kuba
Song is a kind of enkephalinase inhibitor, can inhibit enkephalinase and blocks II receptor of Ang (AT1), and enkephalinase degradation makes benefit
The peptide levels such as sodium peptide increase, and then improve heart failure patient angiocarpy and renal function, are the conventional medicines of clinical treatment heart failure.
Valsartan can inhibit II receptor of Ang by selective exclusion AT1 receptor, increase angiotensinⅡ blood plasma level,
Unclosed AT2 receptor is stimulated, to inhibit the release of II dependence aldosterone of vessel retraction and Ang, achievees the effect that decompression,
Slow down congestive heart failure.Double inhibitor of the Entresto as angiotensin receptor and enkephalinase, it is contemplated that
Entresto will play remarkable effect in the treatment of hypertension and heart failure disease.
The structural formula of Sha Kuba song is as follows:
Due to there are two chiral centre, easily generating the different impurity of configuration in synthesis process in its bent structure of Sha Kuba.
There are potential threats for safety of the generation of these impurity to clinical application, in order to which the economy and society of the drug are better achieved
Benefit, must keep under strict control in standard every impurity, and specifying each impurity item is urgent problem.
Summary of the invention
The purpose of the present invention is to provide a seed sand library Ba Qu impurity compound, (2R, 4R) -4- (3- carboxyl -1- oxos third
Amine) -5- [(1,1'- biphenyl) -4- base] -2 methyl valeric acid ethyl ester, structural formula as shown in formula I,
The present invention also provides a kind of preparation methods of type I compound, are hydrogenated by intermediate II through specific chiral catalysis
Reaction obtains type I compound, and reaction equation is as follows:
Wherein, above-mentioned intermediate II can be prepared by following methods:
Oxidation of primary alcohols is aldehyde through Anelli method by intermediate III, reacts to obtain intermediate II through wittig, reaction equation is such as
Under:
Above-mentioned intermediate III can be prepared by following methods:
Substitution reaction occurs under alkaline condition and generates intermediate III for intermediate IV, and reaction equation is as follows:
Intermediate IV can be prepared by following methods:
Intermediate V obtains intermediate IV by fusion method with succinic anhydride, and reaction equation is as follows:
The fusion method temperature is 120 DEG C~260 DEG C, preferably 180~220 DEG C.
Intermediate V is prepared by following methods:
Intermediate VI and maleic imine reaction obtain intermediate V at salt with acidic alcohol again, and reaction equation is as follows:
Intermediate VI can be prepared by following methods:
4- diphenyl magnesium bromide reacts under the action of catalyst with (R)-epoxyhalopropane generates intermediate VI, and reaction equation is such as
Under:
The catalyst is cuprous iodide, protobromide ketone or stannous chloride.
A kind of preferably preparation method of type I compound, includes the following steps:
(1) 4- diphenyl magnesium bromide reacts under the action of catalyst with (R)-epoxyhalopropane generates intermediate VI, (R)-
1- [(1,1'- biphenyl) -4- base] -2- hydroxyl halopropane；
(2) intermediate VI and maleic imine reaction obtain intermediate V at salt with acidic alcohol again, (S) -1- [(1,1'- connection
Benzene) -4- base] -2- amino halopropane hydrochloride；
(3) intermediate V is reacted with succinic anhydride by fusion method again generates intermediate IV, (S) -1- (2- ([1,1'- connection
Benzene] -4- base) -1- halogen) pyrrolidine-2,5-dione；
(4) intermediate IV substitution reaction occurs under alkaline condition obtains intermediate III, (S) -1- (2- ([1,1'- biphenyl] -
4- yl) -1- hydroxyl) pyrrolidine-2,5-dione；
(5) oxidation of primary alcohols is aldehyde with Anelli method by intermediate III, reacts to obtain intermediate II through wittig, (S, E) -5-
([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methyl -2- pentenoic acid ethyl ester；
(6) the chiral catalytic hydrogenation of intermediate II obtains type I compound (2R, 4R) -4- (3- carboxyl -1- oxo propylamine) -
5- [(1,1'- biphenyl) -4- base] -2 methyl valeric acid ethyl ester.
Wherein, (the R)-epoxyhalopropane is (R)-epoxychloropropane, (R)-epoxy bromopropane or (R)-epoxy iodine
Propane.
Catalyst used in step (1) is protobromide ketone, stannous chloride or cuprous iodide.
Fusion method temperature described in step (3) is 120~260 DEG C, preferably 180~220 DEG C.
Alkali described in step (4) be sodium hydroxide solution, preferably mass fraction be 30% sodium hydroxide solution.
Chiral catalysis hydrogenation catalyst described in step (6) is RuHCl (CO) (PPh3)3With Mandyphos SL-M004-
1.Its reaction route is as follows:
A kind of more priority method for preparing of type I compound, specific steps are as follows:
(1) preparation of intermediate VI (R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl halopropane:
Under nitrogen protection, in organic solvent, 4- diphenyl magnesium bromide and (R)-epoxyhalopropane in catalyst cuprous iodide,
It reacts under the action of protobromide ketone or stannous chloride and generates intermediate VI, intermediate VI is extracted, and drying is evaporated under reduced pressure to
Solid, it is intermediate VI (R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl that vacuum drying, which obtains white solid, after a small amount of water washing
The preparation of base halopropane.
(2) preparation of intermediate V (S) -1- [(1,1'- biphenyl) -4- base] -2- amino halopropane hydrochloride:
Intermediate VI is added in organic solvent, heating stirring to intermediate VI dissolves, cooling, is added under nitrogen protection
Triphenylphosphine, succimide and diethyl azodiformate, reaction.Reaction solution is evaporated under reduced pressure to solvent-free outflow, adds water dilute
Rear enriching hydrochloric acid is released, is heated to flowing back, reaction overnight, adds organic solvent and continues back flow reaction, cooling, liquid separation, water phase tune
Organic solvent back flow reaction is added again, is down to room temperature, liquid separation repetitive operation is primary by pH to 8.Organic phase heating and saturation hydrochloric acid
Ethanol solution reaction, is down to room temperature, filters, and filter cake is washed, dry, and residue alkali soluble solution is stirred at room temperature and reacts to obtain intermediate
V (S) -1- [(1,1'- biphenyl) -4- base] -2- amino halopropane hydrochloride.
(3) preparation of intermediate IV (S) -1- (2- ([1,1'- biphenyl] -4- base) -1- halogen) pyrrolidine-2,5-dione:
Intermediate V and succinic anhydride are added in round-bottomed flask, 120~260 DEG C of melting reactions are heated to.Residue warp
The mixed solution of n-hexane and petroleum ether recrystallization, up to intermediate IV (S) -1- (2- ([1,1'- biphenyl] -4- after crystal is dry
Base) -1- halogen) pyrrolidine-2,5-dione.
(4) preparation of intermediate III (S) -1- (2- ([1,1'- biphenyl] -4- base) -1- hydroxyl) pyrrolidine-2,5-dione:
Intermediate IV is added in there-necked flask, pours into sodium hydroxide solution, back flow reaction, after TLC detects fully reacting,
PH is adjusted, is filtered, washing, dry intermediate III.
(5) intermediate II (S, E) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methyl -
The preparation of 2- pentenoic acid ethyl ester:
Intermediate III, water, isopropyl acetate, sodium bromide, sodium bicarbonate, 2,2,6,6- tetramethyl are sequentially added into reaction flask
Phenylpiperidines-nitrogen-oxide, the sodium hypochlorite containing chlorine are stirred to react to end.Sodium thiosulfate and water are added into reaction solution,
Heating is stirred to react, and organic phase is collected in liquid separation, and wittig reagent is added in organic phase, is stirred to react to end, removes second under reduced pressure
Water, ethyl alcohol and a hydronium(ion) lithia back flow reaction are added into product to terminating, pours into spirit of vinegar, returns again for isopropyl propionate
Stream reaction, is down to room temperature, is filtered, washed, dries to obtain intermediate II.
(6) type I compound (2R, 4R) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- first
The preparation of base ethyl valerate:
In hydriding reactor, intermediate II and hydrogen are in catalyst RuHCl (CO) (PPh3)3Make with Mandyphos SL-M004-1
Under, hydrogenation occurs at 50 DEG C, is down to room temperature after reaction, filters out solid, filtrate decompression concentration, residue is through dichloromethane
Alkane and n-hexane mixed solution crystallization, filtering, repeat that crystallization is primary, and crystal obtains type I compound through filtration drying.
The following contents introduces the preparation method of type I compound in more detail.
(1) preparation of intermediate VI (R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl halopropane:
Under nitrogen protection, catalyst cuprous iodide, protobromide ketone or stannous chloride are added to 4- diphenyl magnesium bromide
THF solution in, be cooled to -25 DEG C, be stirred to react 2h, the THF solution of (R)-epoxyhalopropane, -25 DEG C of temperature control reactions are added dropwise
6h, reaction terminate, and are warmed to room temperature, and reaction solution is poured into aqueous hydrochloric acid solution, liquid separation, and water phase is extracted with appropriate THF, merge organic
Phase, dry, evaporated under reduced pressure adds water that 2h is stirred at room temperature, and filters, and filter cake is washed with water, and 55~60 DEG C of vacuum dryings obtain white solid
As intermediate VI.
(2) preparation of intermediate V (S) -1- [(1,1'- biphenyl) -4- base] -2- amino halopropane hydrochloride:
Intermediate VI is added in toluene, heating, stirring and dissolving, triphenyl is added in ice bath cooling under nitrogen protection
Phosphine, succimide and diethyl azodiformate, 0~5 DEG C of temperature control is stirred to react, and evaporated under reduced pressure to no toluene flows out, and uses water
Concentrated hydrochloric acid is added dropwise after dilution, drop finishes, and is warming up to reflux, and reaction overnight, is cooled to 70 DEG C, refluxing toluene 1h is added, is down to naturally
Room temperature, liquid separation, water phase sodium hydroxide solution tune pH to 8 are added refluxing toluene 1h, are down to room temperature liquid separation, and repetitive operation is primary,
Merge organic phase, organic phase stirring is warming up to 50 DEG C, quickly instills saturation ethanol solution hydrochloride, is stirred to react 2h, restores to room
Temperature, filtering, filter cake are beaten with toluene and are washed, and 55~60 DEG C of vacuum drying, residue is dissolved with 30%NaOH, and reaction is stirred at room temperature
20h, obtaining white solid is intermediate V.
(3) preparation of intermediate IV (S) -1- (2- ([1,1'- biphenyl] -4- base) -1- halogen) pyrrolidine-2,5-dione:
Intermediate IV is added in round-bottomed flask, succinic anhydride is added, electric jacket is heated to 120~260 DEG C, melts anti-
It answers.Residue is through n-hexane: petroleum ether=5:1 recrystallization, 55~60 DEG C of vacuum drying, obtaining white solid is intermediate IV.
(4) preparation of intermediate III (S) -1- (2- ([1,1'- biphenyl] -4- base) -1- hydroxyl) pyrrolidine-2,5-dione:
Intermediate IV is added in there-necked flask, 30%NaOH aqueous solution is poured into, back flow reaction 15h, TLC detection has been reacted
Entirely, with hydrochloric acid tune pH to 7, filtering is beaten with second alcohol and water and is washed, 55~60 DEG C be dried in vacuo solid is intermediate III.
(5) intermediate II (S, E) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methyl -
The preparation of 2- pentenoic acid ethyl ester:
Intermediate III, water, isopropyl acetate, sodium bromide, sodium bicarbonate are successively added into reaction flask, is cooled to -5 DEG C,
2,2 are added, the sodium hypochlorite containing chlorine 15% is slowly added dropwise in 6,6- tetramethyl piperidines-nitrogen-oxide, temperature control -5~0 DEG C, is added dropwise
It finishes, continues to be stirred to react 2.5h, TLC detection, fully reacting is added the mixed liquor of sodium thiosulfate and water, is warmed to room temperature, stirs
Mix reaction 30min.Wittig reagent is added into organic phase for liquid separation, is stirred to react 2.5h, and TLC detects end of reaction, and decompression is steamed
Except isopropyl acetate, water, ethyl alcohol and a hydronium(ion) lithia, back flow reaction are added into product, TLC detection reaction terminates,
Enter dilute acetic acid solution, again back flow reaction 1h, be down to room temperature, filter, with ethanol in proper amount and water mashing washing, 55~60 DEG C of vacuum
Dry, obtaining white solid is intermediate II.
(6) type I compound (2R, 4R) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- first
The preparation of base ethyl valerate:
Intermediate II is added to hydriding reactor, pours into acetonitrile, nitrogen is replaced three times, is warming up to 50 DEG C, is added under nitrogen protection
Enter catalyst RuHCl (CO) (PPh3)3With Mandyphos SL-M004-1, hydrogen replaces three times, is forced into 2Mpa, maintains 50
DEG C hydrogenation 8h, reaction are finished, and nitrogen displacement is cooled to room temperature, and are filtered and are removed solid, and filtrate decompression concentration is finished to concentration
Methylene chloride is added in residue, dichloromethane solution is poured into crystallization in n-hexane, filters, filter cake is tied with same method again again
Brilliant primary, filtering, 55~60 DEG C of vacuum drying, obtaining white solid is type I compound.
The present invention using using 4- diphenyl magnesium bromide and (R)-epoxyhalopropane as raw material, by nucleophilic addition elimination reaction,
Secondary aminating reaction, oxidation reaction, wittig reaction and chiral catalysis hydrogenation obtain type I compound.By technology of the invention
The type I compound purity of scheme synthesis has reached 99.8%, can study directly as standard items for Sha Kuba song related impurities.
Specific embodiment
The above is only the general introductions of summary of the invention, and method of the invention is further illustrated below by embodiment.It should be understood that
It is that the preparation method of the embodiment of the present invention is only used for illustrating the present invention, rather than limiting the invention, of the invention
The scope of protection of present invention is belonged to the simple modifications of synthetic method of the present invention under concept thereof.
Raw material used in each embodiment and organic solvent etc. can be obtained through commercial channels.
The preparation of embodiment 1 (R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl chloropropane
Under nitrogen protection, by cuprous iodide (4.8g, 25mmol) be added to 0.5N 4- diphenyl magnesium bromide (64.4g,
In THF (1L) solution 0.25mol), -25 DEG C are cooled to, is stirred to react 2h, 100ml (R)-epoxychloropropane is added dropwise
The THF solution of (0.5mol), -25 DEG C of reaction 6h of temperature control, reaction terminate, are warmed to room temperature, and the hydrochloric acid that reaction solution is poured into 1N is water-soluble
In liquid (500ml), liquid separation, water phase is extracted with appropriate THF, merges organic phase, and dry, evaporated under reduced pressure adds water (200ml) room temperature to stir
2h is mixed, is filtered, filter cake is washed with water (150ml), and 55~60 DEG C of vacuum dryings, obtaining white solid is intermediate VI (R) -1-
[(1,1'- biphenyl) -4- base] -2- hydroxyl chloropropane, molar yield 91.40%, HPLC purity are 98.92%, ee value 99.6%.
148~149 DEG C of mp.ESI-MS(m/z):246.2[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.75~7.69 (m,
4H), 7.58~7.51 (m, 3H), 7.36 (d, J=7.3Hz, 2H), 5.43 (s, 1H), 4.12~4.07 (m, 1H), 3.14 (d, J
=6.8Hz, 2H), 2.31 (d, J=6.8Hz, 2H).
The preparation of embodiment 2 (R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl N-Propyl Bromide
Under nitrogen protection, by stannous chloride (2.5g, 25mmol) be added to 0.5N 4- diphenyl magnesium bromide (64.4g,
In THF (1L) solution 0.25mol), -25 DEG C are cooled to, is stirred to react 2h, 100ml (R)-epoxy bromopropane is added dropwise
The THF solution of (0.5mol), -25 DEG C of reaction 6h of temperature control, reaction terminate, are warmed to room temperature, and the hydrochloric acid that reaction solution is poured into 1N is water-soluble
In liquid (500ml), liquid separation, water phase is extracted with appropriate THF, merges organic phase, and dry, evaporated under reduced pressure adds water (200ml) room temperature to stir
2h is mixed, is filtered, filter cake is washed with water (150ml), and 55~60 DEG C of vacuum dryings, obtaining white solid is intermediate VI (R) -1-
[(1,1'- biphenyl) -4- base] -2- hydroxyl N-Propyl Bromide, molar yield 88.61%, HPLC purity are 97.69%, ee value 99.2%.
148~149 DEG C of mp.ESI-MS(m/z):290.1[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.73~7.68 (m,
4H), 7.56~7.50 (m, 3H), 7.39 (d, J=7.3Hz, 2H), 5.47 (s, 1H), 4.12~4.09 (m, 1H), 3.16 (d, J
=6.8Hz, 2H), 2.29 (d, J=6.8Hz, 2H).
The preparation of embodiment 3 (R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl iodopropane
Under nitrogen protection, by cuprous iodide (4.8g, 25mmol) be added to 0.5N 4- diphenyl magnesium bromide (64.4g,
In THF (1L) solution 0.25mol), -25 DEG C are cooled to, is stirred to react 2h, 100ml (R)-Epiiodohydrin is added dropwise
The THF solution of (0.5mol), -25 DEG C of reaction 6h of temperature control, reaction terminate, are warmed to room temperature, and the hydrochloric acid that reaction solution is poured into 1N is water-soluble
In liquid (500ml), liquid separation, water phase is extracted with appropriate THF, merges organic phase, and dry, evaporated under reduced pressure adds water (200ml) room temperature to stir
2h is mixed, is filtered, filter cake is washed with water (150ml), and 55~60 DEG C of vacuum dryings, obtaining white solid is intermediate VI (R) -1-
[(1,1'- biphenyl) -4- base] -2- hydroxyl iodopropane, molar yield 87.93%, HPLC purity are 98.6%, ee value 99.1%.
149~150 DEG C of mp.ESI-MS(m/z):337.9[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.74~7.70 (m,
4H), 7.57~7.52 (m, 3H), 7.37 (d, J=7.3Hz, 2H), 5.45 (s, 1H), 4.10~4.05 (m, 1H), 3.12 (d, J
=6.8Hz, 2H), 2.29 (d, J=6.8Hz, 2H).
The preparation of embodiment 4 (R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl chloropropane
Under nitrogen protection, by cuprous bromide (3.6g, 25mmol) be added to 0.5N 4- diphenyl magnesium bromide (64.4g,
In THF (1L) solution 0.25mol), -25 DEG C are cooled to, is stirred to react 2h, 100ml (R)-epoxychloropropane is added dropwise
The THF solution of (0.5mol), -25 DEG C of reaction 6h of temperature control, reaction terminate, are warmed to room temperature, and the hydrochloric acid that reaction solution is poured into 1N is water-soluble
In liquid (500ml), liquid separation, water phase is extracted with appropriate THF, merges organic phase, and dry, evaporated under reduced pressure adds water (200ml) room temperature to stir
2h is mixed, is filtered, filter cake is washed with water (150ml), and 55~60 DEG C of vacuum dryings, obtaining white solid is intermediate VI (R) -1-
[(1,1'- biphenyl) -4- base] -2- hydroxyl chloropropane, molar yield 90.27%, HPLC purity are 98.46%, ee value 99.0%.
148~149 DEG C of mp.ESI-MS(m/z):246.2[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.75~7.69 (m,
4H), 7.58~7.51 (m, 3H), 7.34 (d, J=7.3Hz, 2H), 5.43 (s, 1H), 4.12~4.07 (m, 1H), 3.14 (d, J
=6.8Hz, 2H), 2.31 (d, J=6.8Hz, 2H).
The preparation of embodiment 5 (R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl chloropropane
Under nitrogen protection, by cuprous iodide (4.8g, 25mmol) be added to 0.5N 4- diphenyl magnesium bromide (64.4g,
In THF (1L) solution 0.25mol), -25 DEG C are cooled to, is stirred to react 2h, 100ml (R)-epoxychloropropane is added dropwise
The THF solution of (0.5mol), -15 DEG C of reaction 6h of temperature control, reaction terminate, are warmed to room temperature, and the hydrochloric acid that reaction solution is poured into 1N is water-soluble
In liquid (500ml), liquid separation, water phase is extracted with appropriate THF, merges organic phase, and dry, evaporated under reduced pressure adds water (200ml) room temperature to stir
2h is mixed, is filtered, filter cake is washed with water (150ml), and 55~60 DEG C of vacuum dryings, obtaining white solid is intermediate VI (R) -1-
[(1,1'- biphenyl) -4- base] -2- hydroxyl chloropropane, molar yield 80.16%, HPLC purity are 95.37%, ee value 99.4%.
148~149 DEG C of mp.ESI-MS(m/z):246.2[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.75~7.69 (m,
4H), 7.58~7.51 (m, 3H), 7.35 (d, J=7.3Hz, 2H), 5.43 (s, 1H), 4.12~4.07 (m, 1H), 3.14 (d, J
=6.8Hz, 2H), 2.31 (d, J=6.8Hz, 2H).
The synthesis of embodiment 6 (S) -1- [(1,1'- biphenyl) -4- base] -2- amino chloropropane hydrochloride
(R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl chloropropane (49.2g, 0.2mol) is added to toluene
In (450ml), triphenylphosphine (55.4g, 0.21mol), fourth two is added in heating, stirring and dissolving, ice bath cooling under nitrogen protection
Acid imide (20.9g, 0.21mol) and diethyl azodiformate (72.8g, 0.42mol), 0~5 DEG C of temperature control is stirred to react 5h,
Evaporated under reduced pressure to no toluene flows out, and concentrated hydrochloric acid (81.1g, 0.8mol) is added dropwise after being diluted with water, and drop finishes, and is warming up to reflux, reacts
Overnight, 70 DEG C are cooled to, toluene (300ml) reflux 1h is added, is down to room temperature, liquid separation, 25% sodium hydroxide tune of water phase naturally
PH to 8 is added toluene (200ml) reflux 1h, is down to room temperature liquid separation, and repetitive operation is primary, merges organic phase, and organic phase stirring rises
Temperature quickly instills the saturation ethanol solution hydrochloride of 22.8g to 50 DEG C, is stirred to react 2h, restores to room temperature, filtering, filter cake first
Benzene (200ml) mashing washing, 55~60 DEG C of vacuum drying, residue are dissolved with 30%NaOH, and reaction 20h is stirred at room temperature, obtains white
Solid is intermediate V (S) -1- [(1,1'- biphenyl) -4- base] -2- amino chloropropane hydrochloride, molar yield 96.18%,
HPLC purity 97.66%, ee value 98.5%.156~157 DEG C of mp.ESI-MS(m/z):281.1[M+H]+；1H NMR
(400MHz,DMSO-d6) δ: 10.33 (s, 2H), 7.79~7.64 (m, 4H), 7.57~7.49 (m, 3H), 7.34 (d, J=
7.2Hz, 2H), 3.54~3.48 (m, 1H), 3.19 (d, J=6.8Hz, 2H), 2.28 (d, J=6.8Hz, 2H).
The synthesis of embodiment 7 (S) -1- [(1,1'- biphenyl) -4- base] -2- amino N-Propyl Bromide hydrochloride
(R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl N-Propyl Bromide (58.0g, 0.2mol) is added to toluene
In (450ml), triphenylphosphine (55.4g, 0.21mol), fourth two is added in heating, stirring and dissolving, ice bath cooling under nitrogen protection
Acid imide (20.9g, 0.21mol) and diethyl azodiformate (72.8g, 0.42mol), 0~5 DEG C of temperature control is stirred to react 5h,
Evaporated under reduced pressure to no toluene flows out, and concentrated hydrochloric acid (81.1g, 0.8mol) is added dropwise after being diluted with water, and drop finishes, and is warming up to reflux, reacts
Overnight, 70 DEG C are cooled to, toluene (300ml) reflux 1h is added, is down to room temperature, liquid separation, 25% sodium hydroxide tune of water phase naturally
PH to 8 is added toluene (200ml) reflux 1h, is down to room temperature liquid separation, and repetitive operation is primary, merges organic phase, and organic phase stirring rises
Temperature quickly instills the saturation ethanol solution hydrochloride of 22.8g to 50 DEG C, is stirred to react 2h, restores to room temperature, filtering, filter cake first
Benzene (200ml) mashing washing, 55~60 DEG C of vacuum drying, residue are dissolved with 30%NaOH, and reaction 20h is stirred at room temperature, obtains white
Solid is intermediate V (S) -1- [(1,1'- biphenyl) -4- base] -2- amino chloropropane hydrochloride, molar yield 94.80%,
HPLC purity 96.81%, ee value 98.2%.156~157 DEG C of mp.ESI-MS(m/z):325.3[M+H]+；1H NMR
(400MHz,DMSO-d6) δ: 10.01 (s, 2H), 7.75~7.68 (m, 4H), 7.53~7.48 (m, 3H), 7.39 (d, J=
7.2Hz, 2H), 3.52~3.49 (m, 1H), 3.17 (d, J=6.8Hz, 2H), 2.25 (d, J=6.8Hz, 2H).
The synthesis of embodiment 8 (S) -1- [(1,1'- biphenyl) -4- base] -2- amino iodopropane hydrochloride
(R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl iodopropane (67.6g, 0.2mol) is added to toluene
In (450ml), triphenylphosphine (55.4g, 0.21mol), fourth two is added in heating, stirring and dissolving, ice bath cooling under nitrogen protection
Acid imide (20.9g, 0.21mol) and diethyl azodiformate (72.8g, 0.42mol), 0~5 DEG C of temperature control is stirred to react 5h,
Evaporated under reduced pressure to no toluene flows out, and concentrated hydrochloric acid (81.1g, 0.8mol) is added dropwise after being diluted with water, and drop finishes, and is warming up to reflux, reacts
Overnight, 70 DEG C are cooled to, toluene (300ml) reflux 1h is added, is down to room temperature, liquid separation, 25% sodium hydroxide tune of water phase naturally
PH to 8 is added toluene (200ml) reflux 1h, is down to room temperature liquid separation, and repetitive operation is primary, merges organic phase, and organic phase stirring rises
Temperature quickly instills the saturation ethanol solution hydrochloride of 22.8g to 50 DEG C, is stirred to react 2h, restores to room temperature, filtering, filter cake first
Benzene (200ml) mashing washing, 55~60 DEG C of vacuum drying, residue are dissolved with 30%NaOH, and reaction 20h is stirred at room temperature, obtains white
Solid is intermediate V (S) -1- [(1,1'- biphenyl) -4- base] -2- amino chloropropane hydrochloride, molar yield 93.37%,
HPLC purity 97.75%, ee value 96.9%.157~158 DEG C of mp.ESI-MS(m/z):373.1[M+H]+；1H NMR
(400MHz,DMSO-d6) δ: 10.21 (s, 2H), 7.73~7.66 (m, 4H), 7.52~7.47 (m, 3H), 7.32 (d, J=
7.2Hz, 2H), 3.54~3.48 (m, 1H), 3.20 (d, J=6.8Hz, 2H), 2.24 (d, J=6.8Hz, 2H).
The synthesis of embodiment 9 (S) -1- [(1,1'- biphenyl) -4- base] -2- amino chloropropane hydrochloride
(R) -1- [(1,1'- biphenyl) -4- base] -2- hydroxyl chloropropane (49.2g, 0.2mol) is added to methylene chloride
In (450ml), triphenylphosphine (55.4g, 0.21mol), fourth two is added in heating, stirring and dissolving, ice bath cooling under nitrogen protection
Acid imide (20.9g, 0.21mol) and diethyl azodiformate (72.8g, 0.42mol), 0~5 DEG C of temperature control is stirred to react 5h,
Evaporated under reduced pressure to no methylene chloride flows out, and concentrated hydrochloric acid (81.1g, 0.8mol) is added dropwise after being diluted with water, and drop finishes, and is warming up to reflux,
Reaction overnight, is cooled to 70 DEG C, and methylene chloride (300ml) reflux 1h is added, is down to room temperature, liquid separation, 25% hydrogen of water phase naturally
Sodium oxide molybdena tune pH to 10.0 is added methylene chloride (200ml) reflux 1h, is down to room temperature liquid separation, and repetitive operation is primary, merges organic
Phase, organic phase stirring are warming up to 50 DEG C, quickly instill the saturation ethanol solution hydrochloride of 22.8g, are stirred to react 2h, restore to room
Temperature, filtering, filter cake are beaten with methylene chloride (200ml) and are washed, and 55~60 DEG C of vacuum drying, residue is dissolved with 30%NaOH, room
Temperature is stirred to react 20h, and obtaining white solid is intermediate V (S) -1- [(1,1'- biphenyl) -4- base] -2- amino chloropropane hydrochloric acid
Salt, molar yield 83.86%, HPLC purity 91.26%, ee value 96.8%.156~157 DEG C of mp.ESI-MS(m/z):281.1
[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 10.33 (s, 2H), 7.79~7.65 (m, 4H), 7.57~7.49 (m, 3H),
7.34 (d, J=7.2Hz, 2H), 3.54~3.48 (m, 1H), 3.19 (d, J=6.8Hz, 2H), 2.28 (d, J=6.8Hz, 2H).
Embodiment 10 (S) -1- (synthesis of 2- ([1,1'- biphenyl] -4- base -1- chlorine) pyrrolidine-2,5-dione
(S) -1- [(1,1'- biphenyl) -4- base] -2- amino chloropropane hydrochloride (28.1g, 0.1mol) is added to
250ml round-bottomed flask is added succinic anhydride (12g, 0.12mol), and electric jacket is heated to 180~220 DEG C, melting reaction 1h.It is residual
Slag is through n-hexane: petroleum ether=5:1 recrystallization, 55~60 DEG C of vacuum drying, obtaining white solid is (the S) -1- of intermediate IV (2-
([1,1'- biphenyl] -4- base -1- chlorine) pyrrolidines -2,5- diketone, molar yield 89.07%, HPLC purity 99.64%, ee value
99.5%.Mp175~176 DEG C.ESI-MS(m/z):327.5[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.75~7.62
(m, 4H), 7.52~7.45 (m, 3H), 7.35 (d, J=7.3Hz, 2H), 4.37 (m, 1H), 3.62~3.58 (m, 2H), 3.16
(d, J=6.6Hz, 2H), 2.59 (m, 4H).
Embodiment 11 (S) -1- (synthesis of 2- ([1,1'- biphenyl] -4- base -1- bromine) pyrrolidine-2,5-dione
(S) -1- [(1,1'- biphenyl) -4- base] -2- amino N-Propyl Bromide hydrochloride (32.5g, 0.1mol) is added to
250ml round-bottomed flask is added succinic anhydride (12g, 0.12mol), and electric jacket is heated to 120~180 DEG C, melting reaction 2h.It is residual
Slag is through n-hexane: petroleum ether=5:1 recrystallization, 55~60 DEG C of vacuum drying, obtaining white solid is (the S) -1- of intermediate IV (2-
([1,1'- biphenyl] -4- base -1- bromine) pyrrolidines -2,5- diketone, molar yield 82.43%, HPLC purity 99.18%, ee value
99.3%.Mp176~177 DEG C.ESI-MS(m/z):371.1[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.74~7.63
(m, 4H), 7.50~7.46 (m, 3H), 7.31 (d, J=7.3Hz, 2H), 4.38 (m, 1H), 3.66~3.59 (m, 2H), 3.14
(d, J=6.6Hz, 2H), 2.55 (m, 4H).
Embodiment 12 (S) -1- (synthesis of 2- ([1,1'- biphenyl] -4- base -1- iodine) pyrrolidine-2,5-dione
(S) -1- [(1,1'- biphenyl) -4- base] -2- amino iodopropane hydrochloride (37.3g, 0.1mol) is added to
250ml round-bottomed flask is added succinic anhydride (12g, 0.12mol), and electric jacket is heated to 180~260 DEG C, melting reaction 1h.It is residual
Slag is through n-hexane: petroleum ether=5:1 recrystallization, 55~60 DEG C of vacuum drying, obtaining white solid is (the S) -1- of intermediate IV (2-
([1,1'- biphenyl] -4- base -1- bromine) pyrrolidines -2,5- diketone, molar yield 85.1%, HPLC purity 99.72%, ee value
99.3%.175~176 DEG C of mp.ESI-MS(m/z):419.2[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.75~
7.65 (m, 4H), 7.55~7.48 (m, 3H), 7.37 (d, J=7.3Hz, 2H), 4.33 (m, 1H), 3.65~3.59 (m, 2H),
3.10 (d, J=6.6Hz, 2H), 2.51 (m, 4H).
Embodiment 13 (S) -1- (synthesis of 2- ([1,1'- biphenyl] -4- base -1- chlorine) pyrrolidine-2,5-dione
(S) -1- [(1,1'- biphenyl) -4- base] -2- amino chloropropane hydrochloride (28.1g, 0.1mol) is added to
It in 500ml toluene, is added succinic anhydride (12g, 0.12mol), is heated to 100 DEG C, react 1h.Residue is through n-hexane: petroleum ether
=5:1 recrystallization, 55~60 DEG C of vacuum drying, obtaining white solid is intermediate IV (S) -1- (2- ([1,1'- biphenyl] -4-
Base -1- chlorine) pyrrolidines -2,5- diketone, molar yield 60.07%, HPLC purity 94.67%, ee value 93.7%.Mp 175~
176℃。ESI-MS(m/z):327.5[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.75~7.61 (m, 4H), 7.52~
7.45 (m, 3H), 7.35 (d, J=7.3Hz, 2H), 4.37 (m, 1H), 3.62~3.58 (m, 2H), 3.16 (d, J=6.6Hz,
2H),2.59(m,4H)。
Embodiment 14 (S) -1- (synthesis of 2- ([1,1'- biphenyl] -4- base -1- chlorine) pyrrolidine-2,5-dione
(S) -1- [(1,1'- biphenyl) -4- base] -2- amino chloropropane hydrochloride (28.1g, 0.1mol) is added to
250ml round-bottomed flask is added succinic anhydride (12g, 0.12mol), and electric jacket is heated to 180~220 DEG C, melting reaction 1h.It is residual
Slag is recrystallized through n-hexane, 55~60 DEG C of vacuum drying, and obtaining white solid is intermediate IV (S) -1- (2- ([1,1'- connection
Benzene] -4- base -1- chlorine) pyrrolidines -2,5- diketone, molar yield 80.12%, HPLC purity 98.33%, ee value 97.9%.mp
175~176 DEG C.ESI-MS(m/z):327.5[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.75~7.62 (m, 4H),
7.52~7.45 (m, 3H), 7.35 (d, J=7.3Hz, 2H), 4.36 (m, 1H), 3.62~3.58 (m, 2H), 3.16 (d, J=
6.6Hz,2H),2.59(m,4H)。
Embodiment 15 (S) -1- (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) pyrrolidine-2,5-dione
Synthesis
By (S) -1-, (2- ([1,1'- biphenyl] -4- base -1- chlorine) pyrrolidine-2,5-dione (24.5g, 75mmol) is added to
In 500ml there-necked flask, 30%NaOH aqueous solution 300ml (4v/n) is poured into, 3N is used in back flow reaction 15h, TLC detection fully reacting
Hydrochloric acid tune pH to 7, filtering are beaten with second alcohol and water (100ml × 3) and are washed, 55~60 DEG C be dried in vacuo solid is intermediate
Body III (S) -1- (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) pyrrolidines -2,5- diketone, molar yield
82.49%, HPLC purity 98.66%, ee value 99.6%.188~189 DEG C of mp.ESI-MS(m/z):309.2[M+H]+；1H
NMR(400MHz,DMSO-d6) δ: 7.73~7.66 (m, 4H), 7.55~7.50 (m, 3H), 7.38 (d, J=7.3Hz, 2H),
4.55 (s, 1H), 3.75~3.69 (m, 1H), 3.28 (d, J=6.6Hz, 2H), 2.77 (m, 4H), 2.62 (d, J=6.8Hz,
2H)。
Embodiment 16 (S) -1- (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) pyrrolidine-2,5-dione
Synthesis
By (S) -1-, (2- ([1,1'- biphenyl] -4- base -1- bromine) pyrrolidine-2,5-dione (27.8g, 75mmol) is added to
In 500ml there-necked flask, 30%NaOH aqueous solution 300ml (4v/n) is poured into, 3N is used in back flow reaction 15h, TLC detection fully reacting
Hydrochloric acid tune pH to 7, filtering are beaten with second alcohol and water (100ml × 3) and are washed, 55~60 DEG C be dried in vacuo solid is intermediate
Body III (S) -1- (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) pyrrolidines -2,5- diketone, molar yield
84.28%, HPLC purity 97.63%, ee value 99.4%.188~189 DEG C of mp.ESI-MS(m/z):309.2[M+H]+；1H
NMR(400MHz,DMSO-d6) δ: 7.73~7.66 (m, 4H), 7.55~7.50 (m, 3H), 7.38 (d, J=7.3Hz, 2H),
4.55 (s, 1H), 3.75~3.69 (m, 1H), 3.28 (d, J=6.6Hz, 2H), 2.77 (m, 4H), 2.62 (d, J=6.8Hz,
2H)。
Embodiment 17 (S) -1- (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) pyrrolidine-2,5-dione
Synthesis
By (S) -1-, (2- ([1,1'- biphenyl] -4- base -1- iodine) pyrrolidine-2,5-dione (31.4g, 75mmol) is added to
In 500ml there-necked flask, 30%NaOH aqueous solution 300ml (4v/n) is poured into, 3N is used in back flow reaction 15h, TLC detection fully reacting
Hydrochloric acid tune pH to 7, filtering are beaten with second alcohol and water (100ml × 3) and are washed, 55~60 DEG C be dried in vacuo solid is intermediate
Body III (S) -1- (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) pyrrolidines -2,5- diketone, molar yield
85.94%, HPLC purity 96.85%, ee value 99.3%.188~189 DEG C of mp.ESI-MS(m/z):309.2[M+H]+；1H
NMR(400MHz,DMSO-d6) δ: 7.73~7.66 (m, 4H), 7.55~7.50 (m, 3H), 7.38 (d, J=7.3Hz, 2H),
4.55 (s, 1H), 3.75~3.69 (m, 1H), 3.28 (d, J=6.6Hz, 2H), 2.77 (m, 4H), 2.62 (d, J=6.8Hz,
2H)。
Embodiment 18 (S, E) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methyl is amyl-
The synthesis of 2- olefin(e) acid ethyl ester
Successively into reaction flask be added intermediate III (15.5g, 50mmol), water (80ml), isopropyl acetate (200ml),
Sodium bromide (7.7g, 75mmol), sodium bicarbonate (5.1g, 40mmol) are cooled to -5 DEG C, and 2,2,6,6- tetramethyl piperidines-are added
Nitrogen-oxide (TEMPO, 0.16g, 1mmol), temperature control -5~0 DEG C, be slowly added dropwise containing chlorine 15% sodium hypochlorite (45g,
0.13mol), it being added dropwise, continues to be stirred to react 2.5h, TLC is detected, fully reacting, addition sodium thiosulfate (0.80g,
50mmol) with the mixed liquor of water (80g), it is warmed to room temperature, is stirred to react 30min.Wittig reagent is added into organic phase for liquid separation
(19.1g, 52.5mmol), is stirred to react 2.5h, and TLC detects end of reaction, removes isopropyl acetate under reduced pressure, be added into product
Water (70ml), ethyl alcohol (150ml) and a hydronium(ion) lithia (419.5g, 0.1mol), back flow reaction, TLC detection reaction terminate,
Dilute acetic acid solution (mixed liquor of 56.3g acetic acid and 193.8g water) is poured into, back flow reaction 1h, is down to room temperature again, filtering, with suitable
The mashing washing of second alcohol and water is measured, 55~60 DEG C of vacuum drying, obtaining white solid is intermediate II (S, E) -5- ([1,1'- connection
Benzene] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) amyl- 2- olefin(e) acid ethyl ester of -2- methyl, molar yield 90.14%, HPLC is pure
Spend 99.82%, ee value 99.7%.201~202 DEG C of mp.ESI-MS(m/z):391.2[M+H]+；1H NMR(400MHz,DMSO-
d6) δ: 7.76~7.64 (m, 4H), 7.52~7.47 (m, 3H), 7.29 (d, J=7.3Hz, 2H), 6.74 (s, 1H), 4.42~
4.37 (m, 1H), 4.20 (m, 2H), 3.14 (d, J=6.5Hz, 2H), 2.94 (s, 3H), 2.77 (m, 4H), 1.20 (m, 3H).Through
It is amyl- that NOESY spectral data parses (S, E) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methyl
2- olefin(e) acid ethyl ester is E formula.
Embodiment 19 (S, E) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methyl is amyl-
The synthesis of 2- olefin(e) acid ethyl ester
Successively into reaction flask be added intermediate III (15.5g, 50mmol), water (80ml), isopropyl acetate (200ml),
Sodium bromide (7.7g, 75mmol), sodium bicarbonate (5.1g, 40mmol) are cooled to -5 DEG C, and 2,2,6,6- tetramethyl piperidines-are added
Nitrogen-oxide (TEMPO, 0.16g, 1mmol), temperature control -5~0 DEG C, be slowly added dropwise containing chlorine 12% sodium hypochlorite (45g,
0.13mol), it being added dropwise, continues to be stirred to react 2.5h, TLC is detected, fully reacting, addition sodium thiosulfate (0.80g,
50mmol) with the mixed liquor of water (80g), it is warmed to room temperature, is stirred to react 30min.Wittig reagent is added into organic phase for liquid separation
(19.1g, 52.5mmol), is stirred to react 2.5h, and TLC detects end of reaction, removes isopropyl acetate under reduced pressure, be added into product
Water (70ml), ethyl alcohol (150ml) and a hydronium(ion) lithia (419.5g, 0.1mol), back flow reaction, TLC detection reaction terminate,
Dilute acetic acid solution (mixed liquor of 56.3g acetic acid and 193.8g water) is poured into, back flow reaction 1h, is down to room temperature again, filtering, with suitable
The mashing washing of second alcohol and water is measured, 55~60 DEG C of vacuum drying, obtaining white solid is intermediate II (S, E) -5- ([1,1'- connection
Benzene] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) amyl- 2- olefin(e) acid ethyl ester of -2- methyl, molar yield 72.58%, HPLC is pure
Spend 94.26%, ee value 98.9%.201~202 DEG C of mp.ESI-MS(m/z):391.2[M+H]+；1H NMR(400MHz,DMSO-
d6) δ: 7.76~7.64 (m, 4H), 7.52~7.47 (m, 3H), 7.29 (d, J=7.3Hz, 2H), 6.74 (s, 1H), 4.42~
4.37 (m, 1H), 4.20 (m, 2H), 3.14 (d, J=6.5Hz, 2H), 2.94 (s, 3H), 2.77 (m, 4H), 1.20 (m, 3H).Through
It is amyl- that NOESY spectral data parses (S, E) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methyl
2- olefin(e) acid ethyl ester is E formula.
Embodiment 20 (S, E) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methyl is amyl-
The synthesis of 2- olefin(e) acid ethyl ester
Successively into reaction flask be added intermediate III (15.5g, 50mmol), water (80ml), isopropyl acetate (200ml),
Sodium bromide (7.7g, 75mmol), sodium bicarbonate (5.1g, 40mmol) are cooled to -5 DEG C, and 2,2,6,6- tetramethyl piperidines-are added
Nitrogen-oxide (TEMPO, 0.16g, 1mmol), temperature control -5~0 DEG C, be slowly added dropwise containing chlorine 20% sodium hypochlorite (45g,
0.13mol), it being added dropwise, continues to be stirred to react 1h, TLC is detected, fully reacting, addition sodium thiosulfate (0.80g,
50mmol) with the mixed liquor of water (80g), it is warmed to room temperature, is stirred to react 30min.Wittig reagent is added into organic phase for liquid separation
(19.1g, 52.5mmol), is stirred to react 2.5h, and TLC detects end of reaction, removes isopropyl acetate under reduced pressure, be added into product
Water (70ml), ethyl alcohol (150ml) and a hydronium(ion) lithia (419.5g, 0.1mol), back flow reaction, TLC detection reaction terminate,
Dilute acetic acid solution (mixed liquor of 56.3g acetic acid and 193.8g water) is poured into, back flow reaction 1h, is down to room temperature again, filtering, with suitable
The mashing washing of second alcohol and water is measured, 55~60 DEG C of vacuum drying, obtaining white solid is intermediate II (S, E) -5- ([1,1'- connection
Benzene] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) amyl- 2- olefin(e) acid ethyl ester of -2- methyl, molar yield 80.28%, HPLC is pure
Spend 96.24%, ee value 98.9%.201~202 DEG C of mp.ESI-MS(m/z):391.2[M+H]+；1H NMR(400MHz,DMSO-
d6) δ: 7.76~7.64 (m, 4H), 7.52~7.47 (m, 3H), 7.29 (d, J=7.3Hz, 2H), 6.73 (s, 1H), 4.42~
4.37 (m, 1H), 4.20 (m, 2H), 3.14 (d, J=6.5Hz, 2H), 2.94 (s, 3H), 2.77 (m, 4H), 1.20 (m, 3H).Through
It is amyl- that NOESY spectral data parses (S, E) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methyl
2- olefin(e) acid ethyl ester is E formula.
Embodiment 21 (2R, 4R) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methylpent
The synthesis of acetoacetic ester
By (S, E) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) the amyl- 2- olefin(e) acid of -2- methyl
Ethyl ester (3.9g, 10mmol) is added to hydriding reactor, pours into acetonitrile (300ml), and nitrogen is replaced three times, is warming up to 50 DEG C, nitrogen is protected
Shield is lower to be added catalyst 0.030g RuHCl (CO) (PPh3)3With 0.036g (α R, α R) -2,2,-bis- (α-N, N- dimethylaminos
Phenyl methyl)-(S, S) -1,1,-bis--[two (3,5- dimethyl -4- methoxyphenyl) phosphines]-ferrocene (=Mandyphos
SL-M004-1 ethanol (250ml)), hydrogen replace three times, are forced into 2Mpa, maintain 50 DEG C of hydrogenation 8h, react
Finish, nitrogen displacement is cooled to room temperature, and is filtered and is removed solid, and filtrate decompression is concentrated, and methylene chloride is added in the residue complete to concentration
Dichloromethane solution is poured into crystallization 8h in 30ml n-hexane by (15ml), filtering, and filter cake is again with same method recrystallization one
Secondary, filtering, 55~60 DEG C of vacuum drying, obtaining white solid is type I compound (2R, 4R) -5- ([1,1'- biphenyl] -4- base) -
4- (2,5- dioxypyrrole alkane -1- base) -2 methyl valeric acid ethyl ester, molar yield 91.67%, HPLC purity 99.81%, ee value
99.8%.Mp188~189 DEG C.ESI-MS(m/z):393.1[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.73~7.66
(m, 4H), 7.53~7.47 (m, 3H), 7.33 (d, J=7.2Hz, 2H), 4.22~4.16 (m, 2H), 3.98~3.88 (m,
1H), 3.21~3.08 (m, 2H), 2.63~2.58 (m, 4H), 2.13~2.08 (m, 1H), 1.84 (dd, J=12.2 6.2Hz,
2H), 1.32 (m, 3H), 1.18 (d, J=6.4Hz, 3H)；13C NMR(150MHz,DMSO-d6)δ:179.7(2C),176.4,
140.9,138.3,137.5,130.6(2C),129.8(2C),127.2(2C),127.1(2C),127.6,61.4,50.9,
42.3,37.5,32.2,27.3(2C),16.9,15.1。
Embodiment 22 (2R, 4R) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methylpent
The synthesis of acetoacetic ester
By (S, E) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) the amyl- 2- olefin(e) acid of -2- methyl
Ethyl ester (3.9g, 10mmol) is added to hydriding reactor, pours into acetonitrile (300ml), and nitrogen is replaced three times, is warming up to 50 DEG C, nitrogen is protected
Shield is lower to be added catalyst 0.030g diiodo- (p-cymene) ruthenium (II) dimer and 0.036g (α R, α R) -2,2,-bis- (α-N, N-
Dimethylamino-phenylmethyl)-(S, S) -1,1,-bis--[two (3,5- dimethyl -4- methoxyphenyl) phosphines]-ferrocene (=
Mandyphos SL-M004-1) ethanol (250ml), hydrogen replaces three times, is forced into 2Mpa, it is anti-to maintain 50 DEG C of hydrogenations
8h is answered, reaction is finished, and nitrogen displacement is cooled to room temperature, suction filtration removing solid, filtrate decompression concentration, is added in the residue complete to concentration
Enter methylene chloride (15ml), dichloromethane solution is poured into crystallization 8h in 30ml n-hexane, filter, filter cake uses same method again
Recrystallization is primary, filtering, 55~60 DEG C of vacuum drying, and obtaining white solid is type I compound (2R, 4R) -5- ([1,1'- connection
Benzene] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2 methyl valeric acid ethyl ester, molar yield 86.73%, HPLC purity
99.34%, ee value 98.8%.188~189 DEG C of mp.ESI-MS(m/z):393.1[M+H]+；1H NMR(400MHz,DMSO-
d6) δ: 7.73~7.66 (m, 4H), 7.53~7.47 (m, 3H), 7.33 (d, J=7.2Hz, 2H), 4.22~4.16 (m, 2H),
3.98~3.88 (m, 1H), 3.21~3.08 (m, 2H), 2.63~2.58 (m, 4H), 2.13~2.08 (m, 1H), 1.84 (dd, J
=12.26.2Hz, 2H), 1.32 (m, 3H), 1.18 (d, J=6.4Hz, 3H)；13C NMR(150MHz,DMSO-d6)δ:179.7
(2C),176.4,140.9,138.3,137.5,130.6(2C),129.8(2C),127.2(2C),127.1(2C),127.6,
61.4,50.9,42.3,37.5,32.2,27.3(2C),16.9,15.1。
Embodiment 23 (2R, 4R) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) -2- methylpent
The synthesis of acetoacetic ester
By (S, E) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxypyrrole alkane -1- base) the amyl- 2- olefin(e) acid of -2- methyl
Ethyl ester (3.9g, 10mmol) is added to hydriding reactor, pours into acetonitrile (300ml), and nitrogen is replaced three times, is warming up to 50 DEG C, nitrogen is protected
Shield is lower to be added catalyst 0.030g diiodo- (p-cymene) ruthenium (II) dimer and 0.036g (Mandyphos SL-M004-2)
Ethanol (250ml), hydrogen are replaced three times, and 2Mpa is forced into, and maintain 50 DEG C of hydrogenation 8h, and reaction is finished, and nitrogen displacement is cold
But it to room temperature, filters and removes solid, methylene chloride (15ml) is added to being concentrated in complete residue, by dichloro in filtrate decompression concentration
Dichloromethane pours into crystallization 8h in 30ml n-hexane, filtering, and filter cake is recrystallized once with same method again, filters, 55~60
DEG C vacuum drying, obtaining white solid is type I compound (2R, 4R) -5- ([1,1'- biphenyl] -4- base) -4- (2,5- dioxy pyrroles
Cough up alkane -1- base) -2 methyl valeric acid ethyl ester, molar yield 79.31%, HPLC purity 90.62%, ee value 90.2%.Mp 188~
189℃。ESI-MS(m/z):393.1[M+H]+；1H NMR(400MHz,DMSO-d6) δ: 7.73~7.66 (m, 4H), 7.53~
7.46 (m, 3H), 7.33 (d, J=7.2Hz, 2H), 4.22~4.16 (m, 2H), 3.98~3.88 (m, 1H), 3.21~3.08
(m, 2H), 2.63~2.58 (m, 4H), 2.13~2.08 (m, 1H), 1.84 (dd, J=12.26.2Hz, 2H), 1.32 (m, 3H),
1.18 (d, J=6.4Hz, 3H)；13C NMR(150MHz,DMSO-d6)δ:179.7(2C),176.4,140.9,138.3,
137.5,130.6(2C),129.8(2C),127.2(2C),127.1(2C),127.6,61.4,50.9,42.3,37.5,32.2,
27.3(2C),16.9,15.1。
Claims (10)
1. seed sand library Ba Qu impurity compound (2R, 4R) -4- (3- carboxyl -1- oxo propylamine) -5- [(1,1'- biphenyl) -4-
Base] -2 methyl valeric acid ethyl ester, structural formula as shown in formula I,
2. a kind of preparation method of type I compound, which is characterized in that obtain formula I by the chiral catalytic hydrogenation of intermediate II
Compound, reaction equation are as follows:
3. preparation method according to claim 2, which is characterized in that intermediate II is prepared by following methods: intermediate
Oxidation of primary alcohols is aldehyde through Anelli method by body III, reacts to obtain intermediate II through wittig, reaction equation is as follows:
4. preparation method according to claim 3, which is characterized in that intermediate III is prepared by following methods: intermediate
Substitution reaction occurs under alkaline condition and generates intermediate III for body IV, and reaction equation is as follows:
5. the preparation method according to claim 4, which is characterized in that intermediate IV is prepared by following methods: intermediate
Body V obtains intermediate IV by fusion method with succinic anhydride, and reaction equation is as follows:
6. preparation method according to claim 5, which is characterized in that fusion method temperature be 120~260 DEG C, preferably 180
~220 DEG C.
7. preparation method according to claim 5, which is characterized in that intermediate V is prepared by following methods: intermediate
Body VI and maleic imine reaction obtain intermediate V at salt with acidic alcohol again, and reaction equation is as follows:
8. preparation method according to claim 7, which is characterized in that intermediate VI is prepared by following methods: 4-
Diphenyl magnesium bromide reacts under the action of catalyst with (R)-epoxyhalopropane generates intermediate VI, and reaction equation is as follows:
9. preparation method according to claim 8, which is characterized in that the catalyst is cuprous iodide, stannous chloride
Or protobromide ketone.
10. compound shown in a kind of formula I is for the purposes in the research of cardiotonic agents Sha Kuba song Valsartan sodium impurity.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110878039A (en) * | 2019-12-18 | 2020-03-13 | 株洲千金药业股份有限公司 | Preparation method of Sacubitril valsartan sodium impurity |
| CN112666294A (en) * | 2020-12-29 | 2021-04-16 | 重庆三圣实业股份有限公司 | Method for separating and determining Shakubatu calcium salt and impurities thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101631765A (en) * | 2007-01-12 | 2010-01-20 | 诺瓦提斯公司 | Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid |
| CN106187808A (en) * | 2015-05-08 | 2016-12-07 | 苏州鹏旭医药科技有限公司 | The preparation method of AHU-377, AHU-377 intermediate and the preparation method of AHU-377 intermediate |
-
2018
- 2018-04-26 CN CN201810382614.9A patent/CN110407733A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101631765A (en) * | 2007-01-12 | 2010-01-20 | 诺瓦提斯公司 | Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid |
| CN106187808A (en) * | 2015-05-08 | 2016-12-07 | 苏州鹏旭医药科技有限公司 | The preparation method of AHU-377, AHU-377 intermediate and the preparation method of AHU-377 intermediate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110878039A (en) * | 2019-12-18 | 2020-03-13 | 株洲千金药业股份有限公司 | Preparation method of Sacubitril valsartan sodium impurity |
| CN112666294A (en) * | 2020-12-29 | 2021-04-16 | 重庆三圣实业股份有限公司 | Method for separating and determining Shakubatu calcium salt and impurities thereof |
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