CN105017082B - A kind of preparation method of heart failure medicine Entresto key intermediates (R) tert-butyl group (base of 1 ([1,1` biphenyl] 4 bases) 3 hydroxy propane 2) carbamate - Google Patents
A kind of preparation method of heart failure medicine Entresto key intermediates (R) tert-butyl group (base of 1 ([1,1` biphenyl] 4 bases) 3 hydroxy propane 2) carbamate Download PDFInfo
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- CN105017082B CN105017082B CN201510465538.4A CN201510465538A CN105017082B CN 105017082 B CN105017082 B CN 105017082B CN 201510465538 A CN201510465538 A CN 201510465538A CN 105017082 B CN105017082 B CN 105017082B
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- 0 CO[C@](C(c1ccccc1)=*)C(OC)=O Chemical compound CO[C@](C(c1ccccc1)=*)C(OC)=O 0.000 description 6
- ICIPORXKZXHVHV-UHFFFAOYSA-N CC(Cc(cc1)ccc1-c1ccccc1)CO Chemical compound CC(Cc(cc1)ccc1-c1ccccc1)CO ICIPORXKZXHVHV-UHFFFAOYSA-N 0.000 description 1
- TVHYQWCGSSVZTH-INIZCTEOSA-N C[C@](Cc(cc1)ccc1-c1ccccc1)(CO)N Chemical compound C[C@](Cc(cc1)ccc1-c1ccccc1)(CO)N TVHYQWCGSSVZTH-INIZCTEOSA-N 0.000 description 1
- RCAIWVIQRMDTAV-UHFFFAOYSA-N NC(Cc(cc1)ccc1-c1ccccc1)CO Chemical compound NC(Cc(cc1)ccc1-c1ccccc1)CO RCAIWVIQRMDTAV-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to a kind of preparation method of key intermediate of medicament, (R) tert-butyl group (1 ([1 is specifically related to prepared by chiral resolution, 1' biphenyl] 4 bases) 3 hydroxy propane, 2 base) and carbamate method, the inventive method raw material is cheap and easily-available, and production cost is low；Separation yield is high, and product chiral purity is high；3) it is simple to operate, it is environment-friendly, it is adapted to industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of key intermediate of medicament, and in particular to prepares (R)-uncle by chiral resolution
The method of butyl (1- ([1,1'- biphenyl] -4- bases) -3- hydroxy propane -2- bases) carbamate, belongs to organic synthesis field.
Background introduction
Heart failure medicine Entresto (LCZ696) is a kind of Novel blood pressure-reducing medicine developed by Novartis (Novartis) company, should
Medicine combines hypertension drug Valsartan (Diovan, common name of Novartis：Valsartan) and experimental drug sacubitril (AHU-
377).Sacubitril can block threat to be responsible for the mechanism of action of 2 kinds of polypeptides reduced blood pressure, and Diovan can then improve blood vessel and relax
, stimulate body to drain sodium and water.The security threshold of cardiovascular drugs is high, and Entresto even shows and surmounted
The greater security of conventional medicine, industry thinks that Entresto outstanding performance makes during the medicine becomes history 10 years, cardiology
One of most important progress that field is obtained；Meanwhile, over the next several years, cardiovascular field will be without any medicine energy and Entresto
Contend with, therefore its prospect in medicine is wide.
Sacubitril chemistry is entitled：4- ((2S, 4R) -1- (1,1 '-biphenyl -4- base) -5- ethyoxyl -4- methyl -5- oxygen
For pentane -2- bases) amino) -4- ketobutyric acids (I), its structural formula such as following formula A；(R)-tert-butyl group (1- ([1,1'- biphenyl] -4-
Base) -3- hydroxy propane -2- bases) carbamate for synthesis Sacubitril key intermediate, its structural formula such as following formula B.
(R) synthetic method of-tert-butyl group (1- ([1,1'- biphenyl] -4- bases) -3- hydroxy propane -2- bases) carbamate
Some existing research reports, the structure of its chiral centre mainly has two methods.First method is reduced by chiral catalyst
Obtain, patent WO2013026773, WO2015024991 discloses a kind of compound B synthetic method, this method is urged using rhodium
Agent (two (1,5- cyclo-octadiene) tetrafluoro boric acid rhodiums (I)) and chiral ligand is (such as：S-PiPhos) catalysis reduction obtains chiralization
Compound, the catalyst and part are expensive and be not easy to obtain, and compound B is synthesized cost high, and severe reaction conditions (3MPa).
Second method with chiral raw material reaction by obtaining chipal compounds.Patent WO2014032627 discloses one kind
Compound B synthetic method, this method obtains chipal compounds 4, chiral compound using chipal compounds 5 and the reaction of compound 6
Thing 5 is expensive to be not easy to obtain, and equally has the shortcomings that to make compound B synthesis cost high, and grignard reaction initiation is difficult to control to, located afterwards
Manage complex operation.Triphenyl phosphorus is used in second step reaction, and its accessory substance triphenylphosphinc oxide is difficult complete removing.
Patent CN101362708 disclose the racemic tert-butyl group (1- ([1,1'- biphenyl] -4- bases) -3- hydroxy propanes -
2- yls) carbamate synthetic method, can using acetamidomalonate and 4- substituted biphenyls as initiation material, through condensation,
Decarboxylation, hydrolysis, reduction, acylated five steps reaction are obtained.
The inventors discovered that, using the racemic tert-butyl group of chiral resolution (1- ([1,1'- biphenyl] -4- bases) -3- hydroxyls third
Alkane -2- bases) carbamate method, the compound B of high chiral purity can be obtained with cheap raw material, and this method is operated
Simplicity, separation yield is high, and security is good, and environment-friendly, cost is low, is conducive to technology to produce.
The content of the invention
It is an object of the invention to provide a kind of (R)-tert-butyl group (1- ([1,1'- biphenyl] -4- bases) -3- hydroxy propanes -2-
Base) carbamate (formula B) preparation method, this method is easy to operate, and separation yield is high, and product chiral purity is high, security
Good, environment-friendly, cost is low, is conducive to technology to produce.
The preparation method of the present invention is described more particularly below.However, it should be understood that the invention is not limited in given below
The specific reaction condition gone out (such as the time required to the amount of solvent, compound used therefor, reaction temperature, reaction).
The preparation method of the present invention can be represented with below scheme：
More specifically, preparation method of the invention includes following process：
A. compound D reacts into salt with chiral selectors, obtains compound C
Described chiral selectors are conventional chiral selectors, such as：R-MA, R- o-chloromandelic acids, L- wine
Stone acid, L- bis- is to toluyl tartaric acid, N- acetyl group-D-Leu, D (+) -10- camphorsulfonic acids, D- (+)-malic acid,
D-Asp, D- pyroglutamic acids, D- (-)-quininic acid, D (+)-camphoric acid etc., preferably R-MA, described chirality are torn open
The molar feed ratio for dividing reagent and compound D is 0.5~3eq, preferably 0.8~1.5eq.
Described solvent is ethanol, methanol, isopropanol, tetrahydrofuran, 2- methyltetrahydrofurans, dichloromethane, acetonitrile, first
Any combination of benzene, dioxane etc. or above-mentioned solvent, preferably ethanol；Described solvent and compound D volume ratio are 20
~50:1.
Described reaction temperature is 0~100 DEG C.
The described cooling crystallization time is 2~24h, preferably 2~4h.
Method synthesis disclosed in compound D referenced patents CN101362708 commercially available is commercially available.
B. compound C is synthesized and is obtained chemical combination B in the basic conditions with Boc acid anhydrides
Described Boc acid anhydrides and compound C molar feed ratio are 1~5:1, preferably 1~2:1
Described alkali is sodium carbonate, potassium carbonate, cesium carbonate, sodium acid carbonate, saleratus, sodium hydroxide, potassium hydroxide, hydrogen
Lithia, the inorganic base such as barium hydroxide, or pyridine, triethylamine, diisopropyl ethyl amine, triethylene diamine (DABCO), 1,8-
Carbon -7- the alkene (DBU) of diazabicyclo [5.4.0] 11,1,5- diazabicyclo [4.3.0] nonyl- 5- alkene (DBN), 4- diformazan ammonia
Yl pyridines (DMAP), N-methylmorpholine, preferably tetramethylethylenediamine etc., sodium hydroxide, the mol ratio of the alkali and compound C
For 2~10:1, preferably 3~5:1.
Described solvent is water, methanol, ethanol, acetonitrile, DMF, dioxane, ethyl acetate, methyl tertiary butyl ether(MTBE), tetrahydrochysene
Furans, 2- methyltetrahydrofurans, dichloromethane, ether, toluene, or above-mentioned solvent any mixing, preferably water and tetrahydrochysene furan
Mutter.
Described reaction temperature is 0~100 DEG C.
The described reaction time with detect reaction complete untill, usually 1~24 hour, preferably 1~5 hour.
The advantage of the inventive method is essentially consisted in：
By attempting different chiral selectors, our pleasantly surprised discoveries are resolution reagent using R-MA, can be with
The high target product of chiral purity is obtained, and separation yield is higher, and (R)-tert-butyl group (1- ([1,1'- connection are synthesized using this method
Benzene] -4- bases) -3- hydroxy propane -2- bases) carbamate, raw material is cheap and easily-available, and production cost is low；Separation yield is high, product
Chiral purity is high；It is simple to operate, it is environment-friendly, it is adapted to industrial production.Methodology reference is provided for the synthesis of similar compound.
Specific embodiment：
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part is carried out.
Raw material used or reagent are commercially available in addition to special instruction in embodiment.
Room temperature described in embodiment refers both to 20~35 DEG C.Unless otherwise indicated, described reagent is not purified directly makes
With.All solvents are purchased from commercialization supplier, such as aldrich (Aldrich), and just can be used without processing.Reaction
Analyzed and/or analyzed by LC-MS by TLC, the termination of reaction is judged by the consumption of parent material.The thin layer of analysis
Chromatography (TLC) is the glass plate (EMD chemical companies (EMD in 0.25 millimeter of plate of pre-coated silica gel 60F254
Chemicals carried out on)), with the iodine developing on UV light (254nm) and/or silica gel, and/or with TLC product dyed therebies such as alcohol phosphorus
Molybdic acid, ninhydrin solution, liquor potassic permanganate or ceric sulfate solution are heated together.
The abbreviation used in the present invention has this area conventional sense, such as：DCM represents dichloromethane, and DMF represents N, N- bis-
NMF.
Embodiment 1
56.9g compound D (S are added in 3L there-necked flasks:R=4:6) (0.25mol, 1eq), adds 1.5L ethanol, is warming up to
70~80 DEG C, 30min is stirred, adds at R-MA 34.3g (0.225mol, 0.9eq), 70~80 DEG C and continues to stir 1h, delay
Slowly it is cooled to room temperature about 2 hours, then cools to frozen water 0~5 DEG C, filtering, filter cake is washed with 50mL ethanol.Filter cake is collected, will
Filter cake and 280mL ethanol are added to 500mL single port bottles, are heated to reflux 2~3 hours, cool to 5~10 DEG C, filtering, filter cake is used
The washing of 50mL ethanol, drying, obtain compound C 53.2g, yield：56%, purity 98.2%.
Embodiment 2
Compound C (1.4g, 3.7mmol, 1eq) is added in 100mL there-necked flasks, 10mL water is added, 30mLTHF is warming up to
70~80 DEG C, mixture dissolved clarification, plus the 4NNaOH aqueous solution (2.8mL, 11mmol, 3eq), slow cooling to room temperature, add BOC acid
Acid anhydride (1g, 4.5mmol, 1.2eq), is stirred at room temperature 3h.Reaction solution adds 50mL water, and DCM extractions (30mL*2) merge organic phase,
Dry, concentration, add the mashing of 5mL petroleum ethers, stir 15 minutes, filtering, filter cake drying obtains compound B (1.1g, yield：
92%, purity：98.4%, ee%：99.2%)
Embodiment 3
2.3g compound D (S are added in 3L there-necked flasks:R=4:6) (0.10mol, 1eq), adds 115mLTHF, is warming up to
70~80 DEG C, 30min is stirred, adds at R-MA 2.3g (0.15mol, 1.5eq), 70~80 DEG C and continues to stir 1h, slowly
It is cooled to room temperature about 4 hours, then cools to frozen water 0~5 DEG C, filtering, filter cake is washed with 20mLTHF.Filter cake is collected, by filter cake
100mL single port bottles are added to 50mLTHF, are heated to reflux 4 hours, 5~10 DEG C are cooled to, filtering, filter cake is washed with 20mL THF
Wash, dry, obtain compound C 1.9g, yield：49%, purity 97.9%.
Embodiment 4
Compound C (1.9g, 5mmol, 1eq) is added in 100mL there-necked flasks, 10mL water is added, 30mL acetonitriles are warming up to 70
~80 DEG C, mixture dissolved clarification, plus the 4N KOH aqueous solution (6.2mL, 25mmol, 5eq), slow cooling to room temperature, add BOC acid anhydrides
(2.2g, 4.5mmol, 2eq), is stirred at room temperature 3h.Reaction solution adds 50mL water, and EA extractions (30mL*2) merge organic phase, done
Dry, concentration adds the mashing of 5mL n-hexanes, stirred 15 minutes, filtering, and filter cake drying obtains compound B (1.4g, yield：
85%, purity：98.1%, ee%：99.1%)
Embodiment 5
2.3g compound D (S are added in 3L there-necked flasks:R=4:6) (0.10mol, 1eq), adds 46mL methanol, is warming up to
70~80 DEG C, 30min is stirred, adds at R-MA 1.2g (0.08mol, 0.8eq), 70~80 DEG C and continues to stir 1h, slowly
It is cooled to room temperature about 2 hours, then cools to frozen water 0~5 DEG C, filtering, filter cake is washed with 10mL methanol.Filter cake is collected, will be filtered
Cake and 40mL methanol are added to 100mL single port bottles, are heated to reflux 4 hours, cool to 5~10 DEG C, filtering, filter cake 10mL methanol
Washing, drying, obtain compound C 1.7g, yield：44%, purity 98.5%.
Embodiment 6
Compound C (1.7g, 4.5mmol, 1eq) is added in 100mL there-necked flasks, 20mL water is added, 30mL ethanol is warming up to
70~80 DEG C, triethylamine (1.8g, 18mmol, 4eq) is added dropwise in mixture dissolved clarification, and slow cooling to room temperature adds BOC acid anhydrides
(1g, 4.5mmol, 1eq), is stirred at room temperature 5h.Reaction solution is concentrated into about 20mL, adds 50mL water, and MTBE extractions (30mL*2) are closed
And organic phase, dry, concentration, add the mashing of 5mL normal heptanes, stir 15 minutes, filtering, filter cake drying obtains compound B
(1.3g, yield：89%, purity：98.4%, ee%：99.2%)
Embodiment 7
2g compound D (S are added in 250mL there-necked flasks:R=4:6) (9mmol, 1eq), adds 100mL2- methyl tetrahydrochysene furans
Mutter, be warming up to 70~80 DEG C, stir 30min, add at R-MA 1.2g (8.1mol, 0.9eq), 70~80 DEG C and continue to stir
1h, slow cooling to room temperature about 2 hours, then cool to frozen water 0~5 DEG C, filtering, filter cake 10mL 2- methyltetrahydrofurans
Washing.Filter cake is collected, filter cake and 100mL 2- methyltetrahydrofurans are added to 250mL single port bottles, are heated to reflux 2~3 hours,
5~10 DEG C are cooled to, filtering, filter cake is washed with 20mL 2- methyltetrahydrofurans, dried, and obtains compound C 1.6g, yield：
48%, purity 98%.
Embodiment 8
Compound C (1.6g, 4.2mmol, 1eq) is added in 100mL there-necked flasks, 10mL water is added, dichloromethane 30mL rises
Temperature is to 70 DEG C, and mixture dissolved clarification adds potassium carbonate (1.7g, 13mmol, 3eq), and slow cooling to room temperature adds BOC acid anhydrides
(1.1g, 5.7mmol, 1.2eq), is stirred at room temperature 3h.Reaction solution adds 50mL water, and DCM extractions (30mL*2) merge organic phase,
Dry, concentration, add the mashing of 5mL normal heptanes, stir 15 minutes, filtering, filter cake drying obtains compound B (1.2g, yield：
87%, purity 98%, ee%：99.1%)
Embodiment 9
2.3g compound D (S are added in 100ml there-necked flasks:R=4:6) (10mmol, 1eq), adds 50ml ethanol, heating
To 70~80 DEG C, 30min is stirred, adds at N- acetyl group-D leucines 1.4g (8mmol, 0.8eq), 70~80 DEG C and continues to stir
1h, slow cooling to room temperature about 3 hours, then cool to frozen water 0~5 DEG C, filtering, filter cake is washed with 20mL ethanol.Collect filter
Cake, 100mL single port bottles are added to by filter cake and 25mL ethanol, are heated to reflux 2~3 hours, cool to 5~10 DEG C, filtering, filter cake
Washed, dried with 10mL ethanol, obtain compound C-1 (1.2g, yield：30%, purity：97.8%).
Embodiment 10
Compound C-1 (1.2g, 3mmol, 1eq) is added in 100mL there-necked flasks, 20mL water is added, 30mLTHF is added dropwise
The 4NKOH aqueous solution (3.8mL, 15mmol, 5eq), adds BOC acid anhydrides (1.3g, 6mmol, 2eq), 5h is stirred at room temperature.Reaction solution adds
Enter 50mL water, ethyl acetate extraction (30mL*2) merges organic phase, dried, concentration adds the mashing of 5mL n-hexanes, stirs 15 points
Clock, filtering, filter cake drying obtains compound B (0.85g, yield：87%, ee%：52.1%)
Embodiment 11
2.3g compound D (S are added in 100ml there-necked flasks:R=4:6) (10mmol, 1eq), adds 50ml tetrahydrofurans,
70~80 DEG C are warming up to, 30min is stirred, adds at L-TARTARIC ACID 1.4g (9mmol, 0.9eq), 70~80 DEG C and continues to stir 1h,
Slow cooling was to room temperature about 4 hours, then cooled to frozen water 0~5 DEG C, and filtering, filter cake is washed with 20mL tetrahydrofurans.Collect filter
Cake, 100mL single port bottles are added to by filter cake and 25mL tetrahydrofurans, are heated to reflux 2~3 hours, cool to 5~10 DEG C, are filtered,
Filter cake is washed with 10mL tetrahydrofurans, dried, and obtains compound C-2 (1.9g, yield：50%, purity：97.7%).
Embodiment 12
Compound C-2 (1.9g, 5mmol, 1eq) is added in 100mL there-necked flasks, 10mL water is added, 30mL methanol is warming up to
70~80 DEG C, mixture dissolved clarification adds sodium carbonate (1.6g, 15mmol, 3eq), and slow cooling to room temperature adds BOC acid anhydrides
(1.1g, 5mmol, 1eq), is stirred at room temperature 5h.Reaction solution adds 100mL water, and ethyl acetate extraction (30mL*2) merges organic
Phase, is dried, concentration, is added the mashing of 5mL petroleum ethers, is stirred 15 minutes, filtering, filter cake drying, and obtaining compound B, (1.4g is received
Rate：85%, ee%：12.8%)
Embodiment 13
2.3g compound D (S are added in 100ml there-necked flasks:R=4:6) (10mmol, 1eq), adds 50ml acetonitriles, heating
To 70~80 DEG C, 30min is stirred, L- bis- is added to toluyl tartaric acid 5.8g (15mmol, 1.5eq), at 70~80 DEG C
Continue to stir 1h, slow cooling to room temperature about 4 hours, then cool to frozen water 0~5 DEG C, filtering, filter cake is washed with 20mL acetonitriles
Wash.Filter cake is collected, filter cake and 25mL acetonitriles are added to 100mL single port bottles, is heated to reflux 2~3 hours, cools to 5~10 DEG C,
Filtering, filter cake is washed with 10mL acetonitriles, dried, and obtains compound C-3 (3.3g, yield：53%, purity：97.5%).
Embodiment 14
Compound C-3 (3.3g, 5.3mmol, 1eq) is added in 100mL there-necked flasks, 10mL water, 30mL ethanol, heating is added
To 70~80 DEG C, mixture dissolved clarification adds potassium carbonate (2.2g, 15mmol, 3eq), and slow cooling to room temperature adds BOC acid anhydrides
(1.4g, 6mmol, 1.2eq), is stirred at room temperature 1h.Reaction solution adds 50mL water, and DCM extractions (30mL*2) merge organic phase, done
Dry, concentration adds the mashing of 5mL hexamethylenes, stirred 15 minutes, filtering, and filter cake drying obtains compound B (1.5g, yield：
85%, ee%：20.6%)
All documents referred in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can
To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (4)
1. a kind of preparation side of (R)-tert-butyl group (1- ([1,1'- biphenyl] -4- bases) -3- hydroxy propane -2- bases) carbamate
Method, it is characterised in that comprise the steps of:
Step A：Compound D reacts into salt with R-MA, obtains compound C；
Step B：Compound C is synthesized and is obtained chemical combination B in the basic conditions with Boc acid anhydrides
2. preparation method as claimed in claim 1, it is characterised in that comprised the steps of in the step A:
A1:Compound D is put into reactor, is dissolved in organic solvent I, the stirring that heats up stirs lower addition R-MA to complete molten,
Continue to stir 1-12h after adding；After the completion of reaction, 0-5 DEG C is cooled to, crystallization 1-24h, suction filtration by gained residue washing, dries
It is dry；
A2:Gained filter residue in step A1 is dissolved in organic solvent I, backflow is warming up to, stirs 2~4 hours, cool to 5~10
DEG C, crystallization 1-24h, suction filtration, by gained residue washing, drying；Obtain compound C.
3. preparation method as claimed in claim 1 or 2, it is characterised in that described R-MA and compound D's mole feeds intake
Than for 0.8~1.5.
4. preparation method as claimed in claim 2, it is characterised in that the organic solvent I described in step A1 is selected from ethanol, first
One or more in alcohol, isopropanol, tetrahydrofuran, 2- methyltetrahydrofurans, dichloromethane, acetonitrile, toluene, dioxane,
Itself and compound D volume ratio are 20~50:1.
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| CN105929031B (en) * | 2015-12-18 | 2018-08-21 | 重庆两江药物研发中心有限公司 | The separation method of impurity in the compound of a kind of angiotensin receptor antagonist and nep inhibitor |
| CN105585511B (en) * | 2016-01-08 | 2017-05-31 | 浙江大学 | (R) preparation method of N tertbutyloxycarbonyls biphenyl Propanolamine |
| CN106977415B (en) * | 2016-01-15 | 2021-03-26 | 广东东阳光药业有限公司 | Intermediate of shakubiqu and preparation method thereof |
| CN105753741A (en) * | 2016-04-26 | 2016-07-13 | 常州制药厂有限公司 | Method for preparing Sacubitril intermediate of anti-heart-failure medicine |
| WO2018007919A1 (en) | 2016-07-05 | 2018-01-11 | Novartis Ag | New process for early sacubitril intermediates |
| US10851059B2 (en) | 2016-08-17 | 2020-12-01 | Novartis Ag | Processes and intermediates for NEP inhibitor synthesis |
| US10774036B2 (en) | 2016-12-23 | 2020-09-15 | Novartis Ag | Process for early sacubitril intermediates |
| CN107382785B (en) * | 2017-08-09 | 2019-11-01 | 常州制药厂有限公司 | One seed sand library must bent key intermediate preparation method |
| CN111205204A (en) * | 2020-01-16 | 2020-05-29 | 南京红杉生物科技有限公司 | Sacubitril intermediate and synthetic method and application thereof |
| CN112552184B (en) * | 2020-12-18 | 2022-05-10 | 诚达药业股份有限公司 | Synthetic method of cyclopropyl-containing chiral amine hydrochloride |
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| CN101362708B (en) * | 2008-09-05 | 2012-05-16 | 浙江工业大学 | Synthesis method of tert-butyl- [2- (biphenyl-4-yl) -1- (hydroxymethyl) ethyl ] carbamate |
| CN101774941A (en) * | 2009-01-13 | 2010-07-14 | 浙江九洲药业股份有限公司 | Method for preparing and splitting 2-acyl amino-3-biphenylyl propionic acid |
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| JPWO2015037460A1 (en) * | 2013-09-10 | 2017-03-02 | 住友化学株式会社 | Process for producing optically active 3- (biphenyl-4-yl) -2-[(t-butoxycarbonyl) amino] propan-1-ol |
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