WO2021223156A1 - Diboron glycol ester, preparation method therefor, intermediate thereof, and application thereof - Google Patents

Diboron glycol ester, preparation method therefor, intermediate thereof, and application thereof Download PDF

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WO2021223156A1
WO2021223156A1 PCT/CN2020/088988 CN2020088988W WO2021223156A1 WO 2021223156 A1 WO2021223156 A1 WO 2021223156A1 CN 2020088988 W CN2020088988 W CN 2020088988W WO 2021223156 A1 WO2021223156 A1 WO 2021223156A1
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group
independently
substituted
alkyl
halogen
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PCT/CN2020/088988
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French (fr)
Chinese (zh)
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汤文军
徐广庆
周明康
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中国科学院上海有机化学研究所
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Priority to PCT/CN2020/088988 priority Critical patent/WO2021223156A1/en
Publication of WO2021223156A1 publication Critical patent/WO2021223156A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a diol diborate, a preparation method, intermediates and applications thereof.
  • Glycol biborate has the advantages of non-toxicity, stability, easy operation, etc., and has a wide range of uses in organic synthesis. It can be divided into achiral diol diborates and chiral diol diborates according to different sources of diols. Among them, achiral diol diborates were first widely used in the Miyaura coupling reaction to prepare organoborate compounds (Org. Synth. 2000, 77, 176-185). With the development of organic chemistry in recent years, it has also been gradually applied to the addition of olefins, alkynes, aldehydes (ketones), imines and other compounds and the CH boron substitution reaction of aromatic compounds (Chem. Rev. 2016, 116,9091).
  • chiral 1,2-diamine is also widely used in the preparation of chiral catalysts in organic chemistry, such as the complexation of chiral 1,2-diamine with metals to produce high reactivity and selectivity. Catalysts are used in various types of reactions.
  • the chiral 1,2-diamine structure can also be used as a chiral resolution reagent to resolve the enantiomers of aldehydes. Therefore, the synthesis of 1,2-diamine has always been a hot spot for chemists.
  • the biggest drawback of the reductive coupling induced by chiral auxiliary groups is the use of expensive equivalent chiral auxiliary reagents, which are completely consumed in the reaction, which leads to the high cost of this method (Org.Lett.2004, 6, 4747; J. Am. Chem. Soc. 2008, 130, 12185).
  • the chiral 1,2-diamine is prepared by nucleophilic substitution reaction using chiral diol as the substrate. Not only is the preparation method of chiral diol limited, but the nucleophile uses NaN3, which is highly toxic and explosive. Usually, starting from the achiral substrate to the final chiral 1,2-diamine, it takes 3-5 steps to react, which is cost-effective (Chem. Rev.
  • the method of preparing by organic chiral small molecule catalysis has the advantages of diverse substrate types and can prepare asymmetric chiral 1,2-diamine, but different methods usually fluctuate greatly in enantioselectivity. More expensive chiral catalysts are used, and the substrate usually needs to be modified in advance to obtain higher stereoselectivity. This requires additional steps such as subsequent deprotection of the product.
  • the reaction is not easy to scale up and is suitable for gram scale in the laboratory. Prepared as follows.
  • the present invention provides a diol diborates, a preparation method, intermediates and applications thereof.
  • the diol biborate can be used to induce a reductive coupling reaction where the substrate is an imine.
  • the substrate can be obtained by the reaction of aldehyde and ammonia, which is very easy to obtain and has a relatively low cost; the product only requires acid and alkali operations and can be removed from the reaction system. It is separated, no need for column chromatography purification, convenient post-processing, and easy to operate; the yield of the obtained product is high and no protective group operation is required.
  • the diol diboronic acid ester has chirality, and the stereoselectivity of the reductive coupling reaction is generally excellent, and a chiral diamine with 99% ee can be obtained only by simple recrystallization.
  • the diol diborate can be obtained by reacting with diol and diol diborate.
  • the diol is easy to prepare, easy to scale up, and can be recovered and reused from the reaction solution after a simple acid-base operation. The recovery rate is up to 95%, further saving the preparation cost.
  • the present invention provides a glycol diborate as shown in formula 1;
  • C 1 and C 2 are both R configuration carbon atoms or S configuration carbon atoms;
  • R 1 is phenyl, or, halogen-substituted phenyl ⁇ the number of halogens can be 1, 2, 3, 4, or 5, and when there are more than 2 halogens, the The halogens are the same or different; the halogens can be independently fluorine, chlorine, bromine or iodine, or chlorine; the halogens can be mutually ortho, meta, or para positions independently of the C 1, turn the ortho to a C 1; the "halogen substituted phenyl", for example, 2-chlorophenyl ⁇ ;
  • R 2 is the same as R 1;
  • C 3 is an achiral carbon atom
  • R 3-1 is a phenyl substituted with R 3-1-1 ⁇ the number of R 3-1-1 can be 1, 2, 3, 4 or 5, when there are more than 2 In the case of R 3-1-1 , said R 3-1-1 is the same or different; said R 3-1-1 can be mutually ortho, meta or para position independently with said C 3 , And the said C 3 can be mutually ortho or meta positions; the "R 3-1-1 substituted phenyl" such as 2-methylphenyl, 4-methoxyphenyl, 2, 4-dimethylphenyl, 2,5-dimethylphenyl or 3,5-dimethylphenyl, for example 2,5-dimethylphenyl ⁇ ; said R 3-1-1 Independently C 1 ⁇ C 3 alkyl ⁇ e.g.
  • methyl, ethyl, n-propyl or isopropyl another example of methyl ⁇ or C 1 ⁇ C 3 alkoxy ⁇ e.g. methoxy, ethoxy Group, n-propoxy or isopropoxy, another example is methoxy ⁇ ;
  • R 3-2 is the same as R 3-1;
  • C 4 is an achiral carbon atom
  • R 4-1 is a phenyl substituted by R 4-1-1 ⁇ the number of R 4-1-1 can be 1, 2, 3, 4 or 5, when there are more than 2 In the case of R 4-1-1 , said R 4-1-1 is the same or different; said R 4-1-1 can independently be mutually ortho, meta or para positions with said C 4 , And the said C 4 can be mutually ortho or meta positions; the "R 4-1-1 substituted phenyl" such as 2-methylphenyl, 4-methoxyphenyl, 2, 4-dimethylphenyl, 2,5-dimethylphenyl or 3,5-dimethylphenyl, for example 2,5-dimethylphenyl ⁇ ; said R 4-1-1 Independently C 1 ⁇ C 3 alkyl ⁇ e.g.
  • methyl, ethyl, n-propyl or isopropyl another example of methyl ⁇ or C 1 ⁇ C 3 alkoxy ⁇ e.g. methoxy, ethoxy Group, n-propoxy or isopropoxy, another example is methoxy ⁇ ;
  • R 4-2 is the same as R 4-1.
  • the definitions of certain groups of the diol diboronic acid ester 1 can be as follows, and the definitions of uninvolved groups are as described in any of the above schemes:
  • Both R 1 and R 2 are phenyl groups.
  • the definitions of certain groups of the diol diboronic acid ester 1 can be as follows, and the definitions of uninvolved groups are as described in any of the above schemes:
  • the number of R 3-1-1 is one or two, and the number of R 4-1-1 is one or two.
  • the definitions of certain groups of the diol diboronic acid ester 1 can be as follows, and the definitions of uninvolved groups are as described in any of the above schemes:
  • R 3-1-1 is independently a C 1 ⁇ C 3 alkyl group; said R 4-1-1 is independently a C 1 ⁇ C 3 alkyl group is.
  • the definitions of certain groups of the diol diboronic acid ester 1 can be as follows, and the definitions of uninvolved groups are as described in any of the above schemes:
  • R 3-1 is the same as R 4-1.
  • the definitions of certain groups of the diol diboronic acid ester 1 can be as follows, and the definitions of uninvolved groups are as described in any of the above schemes:
  • R 1 and R 2 are both phenyl groups
  • R 3-1-1 is one or two, and the number of R 4-1-1 is one or two;
  • R 3-1-1 is independently a C 1 ⁇ C 3 alkyl group; said R 4-1-1 is independently a C 1 ⁇ C 3 alkyl group;
  • R 3-1 is the same as R 4-1.
  • the diol diborate 1 can be any of the following compounds:
  • the present invention also provides a diol as shown in formula 2;
  • C 2 , R 2 , C 4 , R 4-1 and R 4-2 are as defined above.
  • the diol 2 can be any of the following compounds:
  • the present invention also provides a method for preparing the above-mentioned glycol diboronic acid ester 1, which comprises the following steps: subjecting compound 2, compound 3 and compound 4 to an esterification reaction in a solvent to obtain the diboronic acid diboron Alcohol ester 1 is enough;
  • C 1 , R 1 , C 2 , R 2 , C 3 , R 3-1 , R 3-2 , C 4 , R 4-1 and R 4-2 are as defined above;
  • R 5-1 and R 5-2 are independently hydrogen or C 1 ⁇ C 3 alkyl ⁇ e.g. methyl, ethyl, n-propyl or isopropyl ⁇ , or R 5-1 and R 5-2 are joined to form - (CR 5-1-1 R 5-1-2) n - ⁇ e.g. -CH 2 C (CH 3) 2 CH 2 - ⁇ ; n is 1, 2 or 3, the R 5- 1 -1 and R 5-1-2 are independently hydrogen or C 1 ⁇ C 3 alkyl ⁇ e.g. methyl, ethyl, n-propyl or isopropyl, for example methyl ⁇ ;
  • R 5-3 and R 5-4 are independently hydrogen or C 1 ⁇ C 3 alkyl ⁇ e.g. methyl, ethyl, n-propyl or isopropyl ⁇ , or R 5-3 and R 5-4
  • the connection forms -(CR 5-3-1 R 5-3-2 ) m - ⁇ for example -CH 2 C(CH 3 ) 2 CH 2 - ⁇ ; m is 1, 2 or 3, said R 5- 3 -1 and R 5-3-2 are independently hydrogen or a C 1 -C 3 alkyl ⁇ e.g. methyl, ethyl, n-propyl or isopropyl, and another example is methyl ⁇ .
  • the esterification reaction can be carried out in the presence of nitrogen or inert gas.
  • the esterification reaction can be carried out in the presence of molecular sieves.
  • the molecular sieve can be 4A molecular sieve.
  • the solvent can be a conventional solvent for this type of esterification reaction in the art, for example, an ether solvent.
  • the ether solvent may be a conventional ether solvent in this type of esterification reaction in the art, such as tetrahydrofuran.
  • the volume molar ratio of the solvent to the compound 4 may be a conventional volume molar ratio of this type of esterification reaction, for example, 3.0-3.5 L/mol.
  • the molar ratio of the compound 2 to the compound 4 may be a conventional molar ratio of this type of esterification reaction, for example (1 to 1.2):1.
  • the molar ratio of the compound 3 to the compound 4 may be a conventional molar ratio of this type of esterification reaction, for example (1 to 1.2):1.
  • the temperature of the esterification reaction may be a conventional temperature of this type of esterification reaction in the art, such as 60-70°C, and for example 66°C.
  • the progress of the esterification reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC, NMR or GC). Generally, the end point of the reaction is when compound 4 is no longer reacting, and the reaction time can be 4 hours to 8 hours. .
  • R 5-1 , R 5-2 , R 5-3 and R 5-4 are independently a C 1 -C 3 alkyl group.
  • R 5-1 and R 5-2 are connected to form -(CR 5-1-1 R 5-1-2 ) n -, and R 5-3 and R 5-4 are connected to form -(CR 5-3-1 R 5-3-2 ) m -.
  • Compound 4 is tetrahydroxydiboron or
  • the present invention also provides a method for preparing the diamine represented by formula A, which comprises the following steps: in a solvent, the compound B is coupled with a coupling reagent to obtain the diamine A. ;
  • the coupling reagent is the above-mentioned compound 1 or the coupling reagent composition, and the coupling reagent composition is the compound 2, compound 3 and compound 4;
  • R 5-3 and R 5-4 are as described above;
  • C 5 is a chiral carbon atom, and its configuration is the same as C 1 ;
  • C 6 is a chiral carbon atom, and its configuration is the same as C 2;
  • R 6-1 is hydrogen or C 1 ⁇ C 3 alkyl ⁇ e.g. methyl, ethyl, n-propyl or isopropyl, another example is methyl ⁇ ;
  • R 6-2 is C 1 -C 20 alkyl ⁇ e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or n-undecyl ⁇ , C 3 -C 10 Cycloalkyl ⁇ e.g. cyclohexyl ⁇ , phenyl, naphthyl ⁇ e.g.
  • the number of heteroatoms is 1 to 2, and the heteroatoms are selected from one of N, O and S Or a variety of 5- to 6-membered heteroaryl groups " ⁇ for example, furanyl or thienyl; the furanyl group is for example furan-2-yl or furan-3-yl; the thienyl group is for example thiophene-2- Group or thiophen-3-yl ⁇ , R 6-2-2 substituted C 1 -C 20 alkyl ⁇ the number of R 6-2-1 can be 1, 2, 3, 4 One or five, when there are more than two R 6-2-1 , the R 6-2-1 is the same or different; the "R 6-2-2 substituted C 1 -C 20 Alkyl” such as benzyl, 2-bromobenzyl, 4-methylbenzyl, 3-chlorobenzyl, thiophen-2-ylmethyl, pent-4-yn-1-yl, pent-4-ene- 1-y
  • R 6-1 is connected to R 6-2 , and the connected Together to form a 4-7 membered heterocycloalkenyl ⁇ e.g.
  • the 4-7 membered heterocycloalkenyl is optionally substituted by a substituent ⁇ the substituted by a substituent may be independently connected to the 4-7 membered heterocycloalkenyl and ring, for example
  • the coupling reaction can be carried out in the presence of nitrogen or inert gas.
  • the solvent can be a conventional solvent for this type of coupling reaction in the art, for example, an ether solvent and/or an alcohol solvent.
  • the ether solvent may be a conventional ether solvent in this type of coupling reaction in the art, such as tetrahydrofuran.
  • the alcohol solvent may be a conventional alcohol solvent in this type of coupling reaction in the art, such as methanol.
  • the volume ratio of the ether solvent and the alcohol solvent may be 5:1.
  • the volume molar ratio of the solvent to the compound B may be a conventional volume molar ratio of this type of coupling reaction, for example, 15-25 L/mol, and for example 18-22 L/mol.
  • the molar ratio of the compound 1 to the compound B may be a conventional molar ratio of this type of coupling reaction, such as (0.5-0.6):1, or 0.55:1.
  • the molar ratio of the compound 2 to the compound B can be a conventional molar ratio of this type of coupling reaction, for example (0.2-1.0):1.
  • the molar ratio of the compound 3 to the compound B may be a conventional molar ratio of this type of coupling reaction, for example (0.2-1.0):1.
  • the molar ratio of the compound 4 to the compound B may be a conventional molar ratio of this type of coupling reaction, such as (0.7-0.8):1, or 0.75:1.
  • the temperature of the coupling reaction may be a conventional temperature of this type of coupling reaction in the art, such as 20-30°C, or 25-30°C.
  • the progress of the coupling reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC, NMR or GC). Generally, the reaction end point is when compound B no longer reacts, and the reaction time can be 12-24 hours.
  • the diamine A can be any of the following compounds:
  • the present invention also provides a diamine A, which is any of the following compounds:
  • the present invention also provides a compound B, which is
  • the reagents and raw materials used in the present invention are all commercially available.
  • room temperature in the present invention refers to 20-30°C, for example 25°C.
  • the positive progress effect of the present invention is that the diol diborate can be used to induce the reductive coupling reaction where the substrate is an imine, and the substrate can be obtained by the reaction of aldehyde and ammonia, which is very easy to obtain and has a relatively low cost; the product only requires acid and alkali
  • the operation can be separated from the reaction system without column chromatography purification, the post-processing method is convenient, and the operation is easy; the yield of the obtained product is high and no protective group operation is required.
  • the diol diboronic acid ester has chirality, and the stereoselectivity of the reductive coupling reaction is generally excellent, and a chiral diamine with 99% ee can be obtained only by simple recrystallization.
  • the diol diborate can be obtained by reacting with diol and diol diborate.
  • the diol is easy to prepare, easy to scale up, and can be recovered and reused from the reaction solution after a simple acid-base operation.
  • the recovery rate is up to 95%, further saving the preparation cost.
  • the unsubstituted or substituted R-mandelic acid methyl ester (0.11mol, 0.2eq) was dissolved in the redistilled THF (50mL) solution, and added dropwise to the Grignard reagent. The reaction was heated to reflux and reacted for about 4 hours. Once completed, the reaction was cooled to room temperature, poured into saturated ammonium chloride solution for quenching, adjusted to pH below 7, extracted with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, and column chromatography to obtain a mixed system containing the product. Petroleum ether was recrystallized to obtain a clean product with a yield of 60%.
  • the system was rotary evaporated to remove excess ammonia gas, added 1mL methanol, added hydrochloric acid (3.0M, 1mL) to adjust the pH to about 3, washed with dichloromethane, concentrated the organic phase and beaten with n-hexane to recover the chiral diol 5 (95%) Recovery rate).
  • the aqueous phase is added with sodium hydroxide solution to adjust the pH to about 12, extracted with dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, and the organic phase is spin-dried to obtain the product.
  • the ee value is determined by the high-pressure chiral liquid phase; the high-pressure liquid phase conditions: Chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20/0.1, 23°C, flow rate 0.8mL/min, 14.66min(S,S), 17.54min(R,R),
  • the retention time is the same as that of commercially available (1S,2S)-1,2-diphenylethylenediamine and (1R,2R)-1,2-diphenylethylenediamine under the same conditions.
  • Derivatization operation dissolve the chiral diamine (27.2mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) in DCM (4.0mL), and dissolve triphosgene (10mg, 0.033mmol) in DCM (2.0ml) ), added dropwise to the above system to keep the temperature below 5 degrees Celsius. After the dropwise addition is completed, the temperature is allowed to rise to room temperature, and the mixture is stirred for 3-4 hours, and the reaction is completed (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
  • Colorless liquid; 71% yield; 70% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1,23°C, flow rate 0.8mL/min,12.6min(S,S),18.5min(R,R).
  • Colorless liquid; 71% yield; 96.5% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1,23°C,flow rate 0.8mL/min,18.58min(S,S),19.38min(R,R).
  • the chiral diamine (31.2mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), triphosgene (10mg, 0.033mmol) was dissolved in DCM (2.0ml), and added dropwise In the above system, keep the temperature below 5 degrees Celsius. After the dropwise addition is completed, the temperature is allowed to rise to room temperature, and the mixture is stirred for 3-4 hours, and the reaction is completed (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
  • the chiral diamine (31.2mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), triphosgene (10mg, 0.033mmol) was dissolved in DCM (2.0ml), and added dropwise In the above system, keep the temperature below 5 degrees Celsius. After the dropwise addition is completed, the temperature is allowed to rise to room temperature, and the mixture is stirred for 3-4 hours, and the reaction is completed (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
  • the chiral diamine (47.8mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), triphosgene (10mg, 0.033mmol) was dissolved in DCM (2.0ml), and added dropwise In the above system, keep the temperature below 5 degrees Celsius. After the dropwise addition is completed, the temperature is allowed to rise to room temperature, and the mixture is stirred for 3-4 hours, and the reaction is completed (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
  • White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine 70/30/0.1, 23°C, flow rate 1.0mL/min,250nm,9.23min(S,S),14.62min(R,R).
  • White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine 70/30/0.1, 23°C, flow rate 1.0mL/min, 250nm, 4.44min(R,R), 5.58min(S,S).
  • White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine 70/30/0.1, 23°C, flow rate 1.0mL/min, 250nm, 5.42min(S,S), 6.39min(R,R).
  • White solid; 98%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column IA, n-hexane/isopropanol 60/40, 25°C, flow rate 0.7mL/min, 250nm, 10.35min (S,S),23.49min(R,R).
  • White solid; 98%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column IA, n-hexane/isopropanol 60/40, 25°C, flow rate 0.7mL/min, 250nm, 8.25min (S,S),11.87min(R,R).

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Abstract

Disclosed in the present invention are a diboron glycol ester, a preparation method therefor, an intermediate thereof, and an application thereof. The diboron glycol ester can be used for inducing a reduction coupling reaction in which imine is used as a substrate, and the substrate can be obtained by reacting aldehyde with ammonia, is very easy to obtain, and has a quite low cost; a product can be separated from a reaction system only by an acid-base operation, without needing column chromatography purification, so that the post-treatment mode is convenient and fast, and the operation is easy; and the obtained product has a high yield and no protective group operation is needed. The diboron glycol ester has chirality, the stereoselectivity of the reduction coupling reaction is generally excellent, and 99% ee of chiral diamine can be obtained only by simple recrystallization. The diboron glycol ester can be obtained by reacting diol and diboron glycol ester; and the diol is convenient to prepare and easy to amplify, and can be recycled from reaction liquid by means of a simple acid-base operation, the recovery rate is up to 95%, and preparation costs are further saved.

Description

一种联硼酸二醇酯、其制备方法、其中间体及其应用Glycol diborate, its preparation method, its intermediate and its application 技术领域Technical field
本发明涉及一种联硼酸二醇酯、其制备方法、其中间体及其应用。The invention relates to a diol diborate, a preparation method, intermediates and applications thereof.
背景技术Background technique
联硼酸二醇酯具有无毒、稳定、易于操作等优点，在有机合成中具有广泛的用途。其按照二醇的来源不同，可分为非手性联硼酸二醇酯和手性联硼酸二醇酯。其中非手性联硼酸二醇酯，最早被广泛应用于Miyaura偶联反应制备有机硼酸酯化合物(Org.Synth.2000,77,176-185)。随着近几年有机化学的发展，其还被逐渐应用于对烯烃、炔烃、醛(酮)、亚胺等化合物的加成以及芳香化合物的C-H硼取代反应中(Chem.Rev.2016,116,9091)。相较于非手性联硼酸二醇酯，由于手性二醇的来源有限，且价格普遍昂贵，这导致手性联硼酸二醇酯的研究相对较少，仅有为数不多的报道其应用于共轭二烯的双硼化反应(J.Chem.Soc.,Dalton Trans.,1998,1431)以及烯烃的双硼化反应(J.Am.Chem.Soc.2016,138,2508)。前不久，汤文军教授小组报道了首例采用联硼酸二醇酯诱导的异喹啉类化合物的还原偶联反应(J.Am.Chem.Soc.2017,139,9767)。他们经过研究发现当采用已知的手性联硼酸(二氢化苯偶姻)酯为手性诱导试剂时，能够制备一系列手性联二氢异喹啉骨架衍生物，其产率中等到优秀，且对映选择性最高达99％。Glycol biborate has the advantages of non-toxicity, stability, easy operation, etc., and has a wide range of uses in organic synthesis. It can be divided into achiral diol diborates and chiral diol diborates according to different sources of diols. Among them, achiral diol diborates were first widely used in the Miyaura coupling reaction to prepare organoborate compounds (Org. Synth. 2000, 77, 176-185). With the development of organic chemistry in recent years, it has also been gradually applied to the addition of olefins, alkynes, aldehydes (ketones), imines and other compounds and the CH boron substitution reaction of aromatic compounds (Chem. Rev. 2016, 116,9091). Compared with achiral diol diborates, due to the limited source of chiral diols and generally expensive prices, there are relatively few studies on chiral diol diborates, and there are only a few reports on their applications. In the diboration reaction of conjugated dienes (J. Chem. Soc., Dalton Trans., 1998, 1431) and the diboration reaction of olefins (J. Am. Chem. Soc. 2016, 138, 2508). Not long ago, Professor Tang Wenjun’s group reported the first case of reductive coupling reaction of isoquinoline compounds induced by diol biborate (J.Am.Chem.Soc.2017,139,9767). They found through research that when the known chiral diboronic acid (dihydrobenzoin) ester is used as a chiral inducing reagent, a series of chiral dihydroisoquinoline skeleton derivatives can be prepared, and the yield is moderate to excellent , And the enantioselectivity is up to 99%.
Figure PCTCN2020088988-appb-000001
Figure PCTCN2020088988-appb-000001
然而，该反应只适用于异喹啉类化合物的还原偶联，仅适用于制备手性联二氢异喹啉类产物，即其原料及产物都限制于特定的环状结构。相较于上述特定的手性联二氢异喹啉骨架产物，手性1,2-二胺结构更多的广泛存在于具有生物活性的天然产物及药物分子中，如：维生素H，对人体脂肪和蛋白质代谢有着不可或缺的作用。奥沙利铂(Oxaliplatin)作为一种新型的抗肿瘤药物，对多种癌种有效，其分子中也具有1,2-二胺结构。除此之外，手性1,2-二胺还被广泛的应用于制备有机化学的手性催化剂中，如手性1,2-二胺与金属络合生成具有高反应活性和选择性的催化剂，应用于各种各样的类型的反应当中。手 性的1,2-二胺结构也可以作为手性拆分试剂对醛的对映体进行拆分。因此，1,2-二胺的合成一直是化学家们研究的热点。However, this reaction is only applicable to the reductive coupling of isoquinoline compounds, and is only applicable to the preparation of chiral dihydroisoquinoline products, that is, the raw materials and products are limited to specific cyclic structures. Compared with the above-mentioned specific chiral dihydroisoquinoline framework products, chiral 1,2-diamine structures are more widely present in natural products and drug molecules with biological activity, such as vitamin H, which is beneficial to the human body. Fat and protein metabolism plays an indispensable role. Oxaliplatin, as a new type of anti-tumor drug, is effective against a variety of cancers, and its molecule also has a 1,2-diamine structure. In addition, chiral 1,2-diamine is also widely used in the preparation of chiral catalysts in organic chemistry, such as the complexation of chiral 1,2-diamine with metals to produce high reactivity and selectivity. Catalysts are used in various types of reactions. The chiral 1,2-diamine structure can also be used as a chiral resolution reagent to resolve the enantiomers of aldehydes. Therefore, the synthesis of 1,2-diamine has always been a hot spot for chemists.
Figure PCTCN2020088988-appb-000002
Figure PCTCN2020088988-appb-000002
传统的合成手性1,2-二胺的方法可以归纳为如下几种方式：1)通过消旋体拆分；2)手性辅助基团诱导的不对称合成；3)手性二醇底物亲核取代反应；4)不同类型的手性有机小分子催化反应。The traditional methods for synthesizing chiral 1,2-diamines can be summarized as follows: 1) Resolution by racemate; 2) Asymmetric synthesis induced by chiral auxiliary groups; 3) Chiral diol base Nucleophilic substitution reaction; 4) Different types of chiral small organic molecules catalyze reactions.
Figure PCTCN2020088988-appb-000003
Figure PCTCN2020088988-appb-000003
通过上述已知报道的方法，人们制备出了一系列手性的1,2-二胺产物，并应用于一系列手性催化剂及手性试剂的开发中去。然而，上述方法都有其一定的缺陷，如1)通过消旋体拆分方式需要繁琐的拆分试剂筛选及结晶条件考察，通常不同的产物往往需要 不同类型的手性拆分试剂，而且拆分势必造成其理论收率最高仅为50％，目前已报道方法，其产率普遍不理想(J.Org.Chem.2008,73,133；Org.Lett.2003,5,595)。2)手性辅助基团诱导的还原偶联的最大缺陷是用到当量昂贵的手性辅助试剂，手性辅剂在反应中完全消耗，这导致该方式成本较高(Org.Lett.2004,6,4747；J.Am.Chem.Soc.2008，130，12185)。3)采用手性二醇为底物进行亲核取代反应制备手性的1,2-二胺，不仅手性二醇的制备方法有限，而且亲核试剂用到剧毒且易爆炸的NaN3，通常从非手性的底物出发到最终的手性1,2-二胺要经过3-5步反应，性价比较低(Chem.Rev.1994,94,2483.)。4)通过有机手性小分子催化制备的方法，其优点是底物种类多样，并且可以制备不对称的手性1,2-二胺，但不同的方法通常对映选择性波动较大，普遍用到较为昂贵的手性催化剂，且底物通常需要预先修饰才能得到较高的立体选择性，这就需要产物后续的脱保护基等附加步骤，反应不易放大，适用于实验室内克级规模以下制备。Through the methods reported above, a series of chiral 1,2-diamine products have been prepared and applied to the development of a series of chiral catalysts and chiral reagents. However, the above methods all have certain drawbacks. For example, 1) The resolution of racemates requires tedious screening of resolution reagents and investigation of crystallization conditions. Generally, different products often require different types of chiral resolution reagents, and the resolution It is bound to cause its theoretical yield to be as high as 50%. The method has been reported, and its yield is generally unsatisfactory (J. Org. Chem. 2008, 73, 133; Org. Lett. 2003, 5, 595). 2) The biggest drawback of the reductive coupling induced by chiral auxiliary groups is the use of expensive equivalent chiral auxiliary reagents, which are completely consumed in the reaction, which leads to the high cost of this method (Org.Lett.2004, 6, 4747; J. Am. Chem. Soc. 2008, 130, 12185). 3) The chiral 1,2-diamine is prepared by nucleophilic substitution reaction using chiral diol as the substrate. Not only is the preparation method of chiral diol limited, but the nucleophile uses NaN3, which is highly toxic and explosive. Usually, starting from the achiral substrate to the final chiral 1,2-diamine, it takes 3-5 steps to react, which is cost-effective (Chem. Rev. 1994, 94, 2483.). 4) The method of preparing by organic chiral small molecule catalysis has the advantages of diverse substrate types and can prepare asymmetric chiral 1,2-diamine, but different methods usually fluctuate greatly in enantioselectivity. More expensive chiral catalysts are used, and the substrate usually needs to be modified in advance to obtain higher stereoselectivity. This requires additional steps such as subsequent deprotection of the product. The reaction is not easy to scale up and is suitable for gram scale in the laboratory. Prepared as follows.
因此，本领域亟需一种高效制备1,2-二胺化合物的方法。Therefore, there is an urgent need in the art for a method for efficiently preparing 1,2-diamine compounds.
发明内容Summary of the invention
本发明所要解决的技术问题是现有的联硼酸二醇酯的结构单一，故而，本发明提供了一种联硼酸二醇酯、其制备方法、其中间体及其应用。该联硼酸二醇酯可用于诱导底物为亚胺的还原偶联反应，底物可由醛及氨反应得到，非常易得且成本相当低廉；产物仅需酸碱操作，即可从反应体系中分离而来，无需柱色谱纯化，后处理方式便捷，易于操作；所得产物产率较高且无需保护基操作。该联硼酸二醇酯具备手性，所述还原偶联反应的立体选择性普遍优秀，仅需简单重结晶既可以得到99％ee的手性二胺。该联硼酸二醇酯可使用二醇可与联硼酸二醇酯反应获得，该二醇制备方便，易于放大，且其经过简单的酸碱操作，可以从反应液中回收重复利用，回收率达95％，进一步节约了制备成本。The technical problem to be solved by the present invention is that the existing diol diborates have a single structure. Therefore, the present invention provides a diol diborates, a preparation method, intermediates and applications thereof. The diol biborate can be used to induce a reductive coupling reaction where the substrate is an imine. The substrate can be obtained by the reaction of aldehyde and ammonia, which is very easy to obtain and has a relatively low cost; the product only requires acid and alkali operations and can be removed from the reaction system. It is separated, no need for column chromatography purification, convenient post-processing, and easy to operate; the yield of the obtained product is high and no protective group operation is required. The diol diboronic acid ester has chirality, and the stereoselectivity of the reductive coupling reaction is generally excellent, and a chiral diamine with 99% ee can be obtained only by simple recrystallization. The diol diborate can be obtained by reacting with diol and diol diborate. The diol is easy to prepare, easy to scale up, and can be recovered and reused from the reaction solution after a simple acid-base operation. The recovery rate is up to 95%, further saving the preparation cost.
本发明提供了一种如式1所示的联硼酸二醇酯；The present invention provides a glycol diborate as shown in formula 1;
Figure PCTCN2020088988-appb-000004
Figure PCTCN2020088988-appb-000004
其中，C 1和C 2同时为R构型碳原子或S构型碳原子； Wherein, C 1 and C 2 are both R configuration carbon atoms or S configuration carbon atoms;
R 1为苯基、或、卤素取代的苯基{所述的卤素的个数可为1个、2个、3个、4个或5个，当存在2个以上的卤素时，所述的卤素相同或不同；所述的卤素可独立地为氟、氯、溴或碘，又可为氯；所述的卤素可独立地与所述的C 1互为邻位、间位或对位，又可与所述的C 1互为邻位；所述的“卤素取代的苯基”例如2-氯苯基}； R 1 is phenyl, or, halogen-substituted phenyl {the number of halogens can be 1, 2, 3, 4, or 5, and when there are more than 2 halogens, the The halogens are the same or different; the halogens can be independently fluorine, chlorine, bromine or iodine, or chlorine; the halogens can be mutually ortho, meta, or para positions independently of the C 1, turn the ortho to a C 1; the "halogen substituted phenyl", for example, 2-chlorophenyl};
R 2与R 1相同； R 2 is the same as R 1;
C 3为非手性碳原子； C 3 is an achiral carbon atom;
R 3-1为R 3-1-1取代的苯基{所述的R 3-1-1的个数可为1个、2个、3个、4个或5个，当存在2个以上的R 3-1-1时，所述的R 3-1-1相同或不同；所述的R 3-1-1可独立地与所述的C 3互为邻位、间位或对位，又可与所述的C 3互为邻位或间位；所述的“R 3-1-1取代的苯基”例如2-甲基苯基、4-甲氧基苯基、2,4-二甲基苯基、2,5-二甲基苯基或3,5-二甲基苯基，又例如2,5-二甲基苯基}；所述的R 3-1-1独立地为C 1～C 3的烷基{例如甲基、乙基、正丙基或异丙基，又例如甲基}或C 1～C 3的烷氧基{例如甲氧基、乙氧基、正丙氧基或异丙氧基，又例如甲氧基}； R 3-1 is a phenyl substituted with R 3-1-1 {the number of R 3-1-1 can be 1, 2, 3, 4 or 5, when there are more than 2 In the case of R 3-1-1 , said R 3-1-1 is the same or different; said R 3-1-1 can be mutually ortho, meta or para position independently with said C 3 , And the said C 3 can be mutually ortho or meta positions; the "R 3-1-1 substituted phenyl" such as 2-methylphenyl, 4-methoxyphenyl, 2, 4-dimethylphenyl, 2,5-dimethylphenyl or 3,5-dimethylphenyl, for example 2,5-dimethylphenyl}; said R 3-1-1 Independently C 1 ～C 3 alkyl {e.g. methyl, ethyl, n-propyl or isopropyl, another example of methyl} or C 1 ～C 3 alkoxy {e.g. methoxy, ethoxy Group, n-propoxy or isopropoxy, another example is methoxy};
R 3-2与R 3-1相同； R 3-2 is the same as R 3-1;
C 4为非手性碳原子； C 4 is an achiral carbon atom;
R 4-1为R 4-1-1取代的苯基{所述的R 4-1-1的个数可为1个、2个、3个、4个或5个，当存在2个以上的R 4-1-1时，所述的R 4-1-1相同或不同；所述的R 4-1-1可独立地与所述的C 4互为邻位、间位或对位，又可与所述的C 4互为邻位或间位；所述的“R 4-1-1取代的苯基”例如2-甲基苯基、4-甲氧基苯基、2,4-二甲基苯基、2,5-二甲基苯基或3,5-二甲基苯基，又例如2,5-二甲基苯基}；所述的R 4-1-1独立地为C 1～C 3的烷基{例如甲基、乙基、正丙基或异丙基，又例如甲基}或C 1～C 3的烷氧基{例如甲氧基、乙氧基、正丙氧基或异丙氧基，又例如甲氧基}； R 4-1 is a phenyl substituted by R 4-1-1 {the number of R 4-1-1 can be 1, 2, 3, 4 or 5, when there are more than 2 In the case of R 4-1-1 , said R 4-1-1 is the same or different; said R 4-1-1 can independently be mutually ortho, meta or para positions with said C 4 , And the said C 4 can be mutually ortho or meta positions; the "R 4-1-1 substituted phenyl" such as 2-methylphenyl, 4-methoxyphenyl, 2, 4-dimethylphenyl, 2,5-dimethylphenyl or 3,5-dimethylphenyl, for example 2,5-dimethylphenyl}; said R 4-1-1 Independently C 1 ～C 3 alkyl {e.g. methyl, ethyl, n-propyl or isopropyl, another example of methyl} or C 1 ～C 3 alkoxy {e.g. methoxy, ethoxy Group, n-propoxy or isopropoxy, another example is methoxy};
R 4-2与R 4-1相同。 R 4-2 is the same as R 4-1.
在某一方案中，所述的联硼酸二醇酯1的某些基团的定义可如下所述，未涉及的基团的定义如上任一方案所述：In a certain scheme, the definitions of certain groups of the diol diboronic acid ester 1 can be as follows, and the definitions of uninvolved groups are as described in any of the above schemes:
R 1与R 2均为苯基。 Both R 1 and R 2 are phenyl groups.
在某一方案中，所述的联硼酸二醇酯1的某些基团的定义可如下所述，未涉及的基团的定义如上任一方案所述：In a certain scheme, the definitions of certain groups of the diol diboronic acid ester 1 can be as follows, and the definitions of uninvolved groups are as described in any of the above schemes:
所述的R 3-1-1的个数为1个或2个，所述的R 4-1-1的个数为1个或2个。 The number of R 3-1-1 is one or two, and the number of R 4-1-1 is one or two.
在某一方案中，所述的联硼酸二醇酯1的某些基团的定义可如下所述，未涉及的基团的定义如上任一方案所述：In a certain scheme, the definitions of certain groups of the diol diboronic acid ester 1 can be as follows, and the definitions of uninvolved groups are as described in any of the above schemes:
所述的R 3-1-1独立地为C 1～C 3的烷基；所述的R 4-1-1独立地为C 1～C 3的烷基。 Said R 3-1-1 is independently a C 1 ~ C 3 alkyl group; said R 4-1-1 is independently a C 1 ~ C 3 alkyl group is.
在某一方案中，所述的联硼酸二醇酯1的某些基团的定义可如下所述，未涉及的基团的定义如上任一方案所述：In a certain scheme, the definitions of certain groups of the diol diboronic acid ester 1 can be as follows, and the definitions of uninvolved groups are as described in any of the above schemes:
R 3-1和R 4-1相同。 R 3-1 is the same as R 4-1.
在某一方案中，所述的联硼酸二醇酯1的某些基团的定义可如下所述，未涉及的基团的定义如上任一方案所述：In a certain scheme, the definitions of certain groups of the diol diboronic acid ester 1 can be as follows, and the definitions of uninvolved groups are as described in any of the above schemes:
R 1与R 2均为苯基； R 1 and R 2 are both phenyl groups;
所述的R 3-1-1的个数为1个或2个，所述的R 4-1-1的个数为1个或2个； The number of R 3-1-1 is one or two, and the number of R 4-1-1 is one or two;
所述的R 3-1-1独立地为C 1～C 3的烷基；所述的R 4-1-1独立地为C 1～C 3的烷基； Said R 3-1-1 is independently a C 1 ～C 3 alkyl group; said R 4-1-1 is independently a C 1 ～C 3 alkyl group;
R 3-1和R 4-1相同。 R 3-1 is the same as R 4-1.
在某一方案中，所述的联硼酸二醇酯1可为以下任一化合物：In a certain scheme, the diol diborate 1 can be any of the following compounds:
Figure PCTCN2020088988-appb-000005
Figure PCTCN2020088988-appb-000005
本发明还提供了一种如式2所示的二醇；The present invention also provides a diol as shown in formula 2;
Figure PCTCN2020088988-appb-000006
Figure PCTCN2020088988-appb-000006
其中，C 2、R 2、C 4、R 4-1和R 4-2的定义如上所述。 Wherein, C 2 , R 2 , C 4 , R 4-1 and R 4-2 are as defined above.
在某一方案中，所述的二醇2可为以下任一化合物：In a certain scheme, the diol 2 can be any of the following compounds:
Figure PCTCN2020088988-appb-000007
Figure PCTCN2020088988-appb-000007
Figure PCTCN2020088988-appb-000008
Figure PCTCN2020088988-appb-000008
本发明还提供了一种上述的联硼酸二醇酯1的制备方法，其包括下述步骤：在溶剂中，将化合物2、化合物3与化合物4进行酯化反应，得到所述的联硼酸二醇酯1即可；The present invention also provides a method for preparing the above-mentioned glycol diboronic acid ester 1, which comprises the following steps: subjecting compound 2, compound 3 and compound 4 to an esterification reaction in a solvent to obtain the diboronic acid diboron Alcohol ester 1 is enough;
Figure PCTCN2020088988-appb-000009
Figure PCTCN2020088988-appb-000009
其中，C 1、R 1、C 2、R 2、C 3、R 3-1、R 3-2、C 4、R 4-1和R 4-2的定义如上所述； Wherein, C 1 , R 1 , C 2 , R 2 , C 3 , R 3-1 , R 3-2 , C 4 , R 4-1 and R 4-2 are as defined above;
R 5-1和R 5-2独立地为氢或C 1～C 3的烷基{例如甲基、乙基、正丙基或异丙基}，或者，R 5-1和R 5-2连接形成-(CR 5-1-1R 5-1-2) n-{例如-CH 2C(CH 3) 2CH 2-}；n为1、2或3，所述的R 5- 1-1和R 5-1-2独立地为氢或C 1～C 3的烷基{例如甲基、乙基、正丙基或异丙基，又例如甲基}； R 5-1 and R 5-2 are independently hydrogen or C 1 ～C 3 alkyl {e.g. methyl, ethyl, n-propyl or isopropyl}, or R 5-1 and R 5-2 are joined to form - (CR 5-1-1 R 5-1-2) n - { e.g. -CH 2 C (CH 3) 2 CH 2 -}; n is 1, 2 or 3, the R 5- 1 -1 and R 5-1-2 are independently hydrogen or C 1 ～C 3 alkyl {e.g. methyl, ethyl, n-propyl or isopropyl, for example methyl};
R 5-3和R 5-4独立地为氢或C 1～C 3的烷基{例如甲基、乙基、正丙基或异丙基}，或者，R 5-3和R 5-4连接形成-(CR 5-3-1R 5-3-2) m-{例如-CH 2C(CH 3) 2CH 2-}；m为1、2或3，所述的R 5- 3-1和R 5-3-2独立地为氢或C 1～C 3的烷基{例如甲基、乙基、正丙基或异丙基，又例如甲基}。 R 5-3 and R 5-4 are independently hydrogen or C 1 ～C 3 alkyl {e.g. methyl, ethyl, n-propyl or isopropyl}, or R 5-3 and R 5-4 The connection forms -(CR 5-3-1 R 5-3-2 ) m -{for example -CH 2 C(CH 3 ) 2 CH 2 -}; m is 1, 2 or 3, said R 5- 3 -1 and R 5-3-2 are independently hydrogen or a C 1 -C 3 alkyl {e.g. methyl, ethyl, n-propyl or isopropyl, and another example is methyl}.
所述的酯化反应可在氮气或惰性气体的存在下进行。The esterification reaction can be carried out in the presence of nitrogen or inert gas.
所述的酯化反应可在分子筛的存在下进行。所述的分子筛可为4A分子筛。The esterification reaction can be carried out in the presence of molecular sieves. The molecular sieve can be 4A molecular sieve.
所述的溶剂可为本领域该类酯化反应常规的溶剂，例如醚类溶剂。所述的醚类溶剂可为本领域该类酯化反应常规的醚类溶剂，例如四氢呋喃。The solvent can be a conventional solvent for this type of esterification reaction in the art, for example, an ether solvent. The ether solvent may be a conventional ether solvent in this type of esterification reaction in the art, such as tetrahydrofuran.
所述的溶剂与所述的化合物4的体积摩尔比可为该类酯化反应常规的体积摩尔比，例如3.0～3.5L/mol。The volume molar ratio of the solvent to the compound 4 may be a conventional volume molar ratio of this type of esterification reaction, for example, 3.0-3.5 L/mol.
所述的化合物2与所述的化合物4的摩尔比可为该类酯化反应常规的摩尔比，例如(1～1.2)：1。The molar ratio of the compound 2 to the compound 4 may be a conventional molar ratio of this type of esterification reaction, for example (1 to 1.2):1.
所述的化合物3与所述的化合物4的摩尔比可为该类酯化反应常规的摩尔比，例如(1～1.2)：1。The molar ratio of the compound 3 to the compound 4 may be a conventional molar ratio of this type of esterification reaction, for example (1 to 1.2):1.
所述的酯化反应的温度可为本领域该类酯化反应常规的温度，例如60～70℃，又例如66℃。The temperature of the esterification reaction may be a conventional temperature of this type of esterification reaction in the art, such as 60-70°C, and for example 66°C.
所述的酯化反应的进程可以采用本领域中常规监测方法(例如TLC、HPLC、NMR或GC)进行监测，一般以化合物4不再反应时为反应终点，反应时间可为4小时～8小 时。The progress of the esterification reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC, NMR or GC). Generally, the end point of the reaction is when compound 4 is no longer reacting, and the reaction time can be 4 hours to 8 hours. .
在某一方案中，所述的联硼酸二醇酯1的制备方法的某些参数可如下所述，未涉及的参数如上任一方案所述：In a certain scheme, some parameters of the preparation method of the diol diborate 1 can be described as follows, and the parameters not involved are as described in any of the above schemes:
R 5-1、R 5-2、R 5-3和R 5-4独立地为C 1～C 3的烷基。 R 5-1 , R 5-2 , R 5-3 and R 5-4 are independently a C 1 -C 3 alkyl group.
在某一方案中，所述的联硼酸二醇酯1的制备方法的某些参数可如下所述，未涉及的参数如上任一方案所述：In a certain scheme, some parameters of the preparation method of the diol diborate 1 can be described as follows, and the parameters not involved are as described in any of the above schemes:
R 5-1和R 5-2连接形成-(CR 5-1-1R 5-1-2) n-，且R 5-3和R 5-4连接形成-(CR 5-3-1R 5-3-2) m-。 R 5-1 and R 5-2 are connected to form -(CR 5-1-1 R 5-1-2 ) n -, and R 5-3 and R 5-4 are connected to form -(CR 5-3-1 R 5-3-2 ) m -.
在某一方案中，所述的联硼酸二醇酯1的制备方法的某些参数可如下所述，未涉及的参数如上任一方案所述：In a certain scheme, some parameters of the preparation method of the diol diborate 1 can be described as follows, and the parameters not involved are as described in any of the above schemes:
化合物4为四羟基二硼或
Figure PCTCN2020088988-appb-000010
Compound 4 is tetrahydroxydiboron or
Figure PCTCN2020088988-appb-000010
本发明还提供了一种如式A所示的二胺的制备方法，其包括下述步骤：在溶剂中，将化合物B与偶联试剂进行偶联反应，得到所述的二胺A即可；The present invention also provides a method for preparing the diamine represented by formula A, which comprises the following steps: in a solvent, the compound B is coupled with a coupling reagent to obtain the diamine A. ；
所述的偶联试剂为上述的化合物1或偶联试剂组合物，所述的偶联试剂组合物为化合物2、化合物3和化合物4；The coupling reagent is the above-mentioned compound 1 or the coupling reagent composition, and the coupling reagent composition is the compound 2, compound 3 and compound 4;
Figure PCTCN2020088988-appb-000011
Figure PCTCN2020088988-appb-000011
其中，C 1、R 1、C 2、R 2、C 3、R 3-1、R 3-2、C 4、R 4-1、R 4-2、R 5-1、R 5-2、R 5-3和R 5-4的定义如上所述； Among them, C 1 , R 1 , C 2 , R 2 , C 3 , R 3-1 , R 3-2 , C 4 , R 4-1 , R 4-2 , R 5-1 , R 5-2 , The definitions of R 5-3 and R 5-4 are as described above;
C 5为手性碳原子，其构型与C 1相同；C 6为手性碳原子，其构型与C 2相同； C 5 is a chiral carbon atom, and its configuration is the same as C 1 ; C 6 is a chiral carbon atom, and its configuration is the same as C 2;
R 6-1为氢或C 1～C 3的烷基{例如甲基、乙基、正丙基或异丙基，又例如甲基}； R 6-1 is hydrogen or C 1 ～C 3 alkyl {e.g. methyl, ethyl, n-propyl or isopropyl, another example is methyl};
R 6-2为C 1-C 20的烷基{例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或正十一烷基}、C 3-C 10的环烷基{例如环己基}、苯基、萘基{例如1-萘基或2-萘基}、“杂原子数为1～2个，杂原子选自N、O和S中的一种或多种的5～6元杂芳基”{例如呋喃基或噻吩基； 所述的呋喃基又例如呋喃-2-基或呋喃-3-基；所述的噻吩基又例如噻吩-2-基或噻吩-3-基}、R 6-2-2取代的C 1-C 20的烷基{所述的R 6-2-1的个数可为1个、2个、3个、4个或5个，当存在2个以上的R 6-2-1时，所述的R 6-2-1相同或不同；所述的“R 6-2-2取代的C 1-C 20的烷基”例如苄基、2-溴苄基、4-甲基苄基、3-氯苄基、噻吩-2-基甲基、戊-4-炔-1-基、戊-4-烯-1-基、丁-3-烯-1-基}、或、R 6-2-1取代的苯基{所述的R 6-2-1的个数可为1个、2个、3个、4个或5个，当存在2个以上的R 6-2-1时，所述的R 6-2-1相同或不同；所述的R 6-2-1可独立地与所述的亚胺双键互为邻位、间位或对位，或者，所述的R 6-2-1可独立地与所述的苯基并环连接；所述的“R 6-2-1取代的苯基”例如4-乙炔基苯基、3-乙氧基苯基、3,5-二氟苯基、3,5-二甲基苯基、4-(N-甲基-苯甲酰胺基)苯基、
Figure PCTCN2020088988-appb-000012
4-甲基苯基、4-甲氧基苯基、4-三氟甲氧基苯基、4-甲氧酰基苯基、4-氟苯基、2,4,6-三氟苯基、4-氯苯基、4-溴苯基、2-甲氧基苯基、2-甲基苯基、2-氯苯基、2-溴苯基、3-三氟甲基苯基、2-苯基-苯基、3-氯苯基或3-氯苯基}； R 6-2 is C 1 -C 20 alkyl {e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or n-undecyl}, C 3 -C 10 Cycloalkyl {e.g. cyclohexyl}, phenyl, naphthyl {e.g. 1-naphthyl or 2-naphthyl}, "the number of heteroatoms is 1 to 2, and the heteroatoms are selected from one of N, O and S Or a variety of 5- to 6-membered heteroaryl groups "{for example, furanyl or thienyl; the furanyl group is for example furan-2-yl or furan-3-yl; the thienyl group is for example thiophene-2- Group or thiophen-3-yl}, R 6-2-2 substituted C 1 -C 20 alkyl {the number of R 6-2-1 can be 1, 2, 3, 4 One or five, when there are more than two R 6-2-1 , the R 6-2-1 is the same or different; the "R 6-2-2 substituted C 1 -C 20 Alkyl" such as benzyl, 2-bromobenzyl, 4-methylbenzyl, 3-chlorobenzyl, thiophen-2-ylmethyl, pent-4-yn-1-yl, pent-4-ene- 1-yl, but-3-en-1-yl}, or, R 6-2-1 substituted phenyl {the number of R 6-2-1 can be 1, 2, 3 , 4 or 5, when there are more than 2 R 6-2-1 , the R 6-2-1 is the same or different; the R 6-2-1 can be independently The imine double bonds are ortho, meta, or para positions to each other, or the R 6-2-1 can be independently connected to the phenyl ring; the "R 6-2-1 substituted The phenyl" such as 4-ethynylphenyl, 3-ethoxyphenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 4-(N-methyl-benzamide Group) phenyl,
Figure PCTCN2020088988-appb-000012
4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-methoxyacylphenyl, 4-fluorophenyl, 2,4,6-trifluorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-methoxyphenyl, 2-methylphenyl, 2-chlorophenyl, 2-bromophenyl, 3-trifluoromethylphenyl, 2- Phenyl-phenyl, 3-chlorophenyl or 3-chlorophenyl};
所述的R 6-2-2和R 6-2-1独立地为-C(＝O)-O-C 1～C 3的烷基{其中，所述的“C 1～C 3的烷基”例如甲基、乙基、正丙基或异丙基}、卤素{例如氟、氯、溴或碘}、C 1～C 3的烷基{例如甲基、乙基、正丙基或异丙基}、卤素取代的C 1～C 3的烷基{所述的卤素的个数可为1个、2个、3个、4个或5个，当存在2个以上的卤素时，所述的卤素相同或不同；所述的卤素可独立地为氟、氯、溴或碘，又可为氟；所述的C 1～C 3的烷基例如甲基、乙基、正丙基或异丙基；所述的“卤素取代的C 1～C 3的烷基”例如三氟甲基}、C 2-C 20的烯基{例如丁-3-烯-1-基、丙-2-烯-1-基或乙烯基}、C 2-C 20的炔基{例如丁-3-炔-1-基、丙-2-炔-1-基或乙炔基}、N-(C 1～C 3的烷基)-苯甲酰胺基{其中，所述的“C 1～C 3的烷基”例如甲基、乙基、正丙基或异丙基}、苯基、C 1～C 3的烷氧基{例如甲氧基、乙氧基、正丙氧基或异丙氧基}、卤素取代的C 1～C 3的烷氧基{所述的卤素的个数可为1个、2个、3个、4个或5个，当存在2个以上的卤素时，所述的卤素相同或不同；所述的卤素可独立地为氟、氯、溴或碘，又可为氟；所述的C 1～C 3的烷氧基例如甲氧基、乙氧基、正丙氧基或异丙氧基；所述的“卤素取代的C 1～C 3的烷氧基”例如三氟甲氧基}、或、任选被羰基取代的C 3-C 20的环烷基{例如
Figure PCTCN2020088988-appb-000013
a侧与所述的苯基并环连接}； The R 6-2-2 and R 6-2-1 are independently -C(=O)-OC 1 ～C 3 alkyl {wherein, the "C 1 ～C 3 alkyl" e.g., methyl, ethyl, n-propyl or isopropyl group}, {a halogen such as fluorine, chlorine, bromine or iodine}, C 1 ~ C 3 alkyl group of {e.g., methyl, ethyl, n-propyl or isopropyl Group}, halogen-substituted C 1 ～C 3 alkyl {the number of halogens can be 1, 2, 3, 4 or 5, when there are more than 2 halogens, the The halogens are the same or different; the halogens may independently be fluorine, chlorine, bromine or iodine, or fluorine; the C 1 ～C 3 alkyl groups such as methyl, ethyl, n-propyl or iso Propyl; the "halogen substituted C 1 ～C 3 alkyl group" such as trifluoromethyl}, C 2 -C 20 alkenyl {e.g. but-3-en-1-yl, prop-2- En-1-yl or vinyl}, C 2 -C 20 alkynyl {for example, but-3-yn-1-yl, prop-2-yn-1-yl or ethynyl}, N-(C 1 ～ C 3 alkyl)-benzamide {wherein, the "C 1 ～C 3 alkyl" such as methyl, ethyl, n-propyl or isopropyl}, phenyl, C 1 ～C 3 alkoxy {for example, methoxy, ethoxy, n-propoxy or isopropoxy}, halogen-substituted C 1 ～C 3 alkoxy {the number of halogens can be one , 2, 3, 4 or 5, when there are more than 2 halogens, the halogens are the same or different; the halogens can be independently fluorine, chlorine, bromine or iodine, or fluorine ; The C 1 ～C 3 alkoxy group such as methoxy, ethoxy, n-propoxy or isopropoxy; the “halogen substituted C 1 ～C 3 alkoxy group” such as Trifluoromethoxy}, or, C 3 -C 20 cycloalkyl optionally substituted by carbonyl {e.g.
Figure PCTCN2020088988-appb-000013
a side is connected to the phenyl and ring};
或者，式B中，R 6-1与R 6-2相连，与其连接的
Figure PCTCN2020088988-appb-000014
一起形成4-7元杂环烯基{例如
Figure PCTCN2020088988-appb-000015
所述的4-7元杂环烯基任选被取代基取代{所述的被取代基取代可独立地与所述的4-7元杂环烯基并环连接，例如
Figure PCTCN2020088988-appb-000016
Or, in formula B, R 6-1 is connected to R 6-2 , and the connected
Figure PCTCN2020088988-appb-000014
Together to form a 4-7 membered heterocycloalkenyl {e.g.
Figure PCTCN2020088988-appb-000015
The 4-7 membered heterocycloalkenyl is optionally substituted by a substituent {the substituted by a substituent may be independently connected to the 4-7 membered heterocycloalkenyl and ring, for example
Figure PCTCN2020088988-appb-000016
所述的偶联反应可在氮气或惰性气体的存在下进行。The coupling reaction can be carried out in the presence of nitrogen or inert gas.
所述的溶剂可为本领域该类偶联反应常规的溶剂，例如醚类溶剂和/或醇类溶剂。所述的醚类溶剂可为本领域该类偶联反应常规的醚类溶剂，例如四氢呋喃。所述的醇类溶剂可为本领域该类偶联反应常规的醇类溶剂，例如甲醇。所述的醚类溶剂和所述的醇类溶剂的体积比可为5：1。The solvent can be a conventional solvent for this type of coupling reaction in the art, for example, an ether solvent and/or an alcohol solvent. The ether solvent may be a conventional ether solvent in this type of coupling reaction in the art, such as tetrahydrofuran. The alcohol solvent may be a conventional alcohol solvent in this type of coupling reaction in the art, such as methanol. The volume ratio of the ether solvent and the alcohol solvent may be 5:1.
所述的溶剂与所述的化合物B的体积摩尔比可为该类偶联反应常规的体积摩尔比，例如15～25L/mol，又例如18～22L/mol。The volume molar ratio of the solvent to the compound B may be a conventional volume molar ratio of this type of coupling reaction, for example, 15-25 L/mol, and for example 18-22 L/mol.
所述的化合物1与所述的化合物B的摩尔比可为该类偶联反应常规的摩尔比，例如(0.5～0.6)：1，又例如0.55：1。The molar ratio of the compound 1 to the compound B may be a conventional molar ratio of this type of coupling reaction, such as (0.5-0.6):1, or 0.55:1.
所述的化合物2与所述的化合物B的摩尔比可为该类偶联反应常规的摩尔比，例如(0.2～1.0)：1。The molar ratio of the compound 2 to the compound B can be a conventional molar ratio of this type of coupling reaction, for example (0.2-1.0):1.
所述的化合物3与所述的化合物B的摩尔比可为该类偶联反应常规的摩尔比，例如(0.2～1.0)：1。The molar ratio of the compound 3 to the compound B may be a conventional molar ratio of this type of coupling reaction, for example (0.2-1.0):1.
所述的化合物4与所述的化合物B的摩尔比可为该类偶联反应常规的摩尔比，例如(0.7～0.8)：1，又例如0.75：1。The molar ratio of the compound 4 to the compound B may be a conventional molar ratio of this type of coupling reaction, such as (0.7-0.8):1, or 0.75:1.
所述的偶联反应的温度可为本领域该类偶联反应常规的温度，例如20-30℃，又例如25-30℃。The temperature of the coupling reaction may be a conventional temperature of this type of coupling reaction in the art, such as 20-30°C, or 25-30°C.
所述的偶联反应的进程可以采用本领域中常规监测方法(例如TLC、HPLC、NMR或GC)进行监测，一般以化合物B不再反应时为反应终点，反应时间可为12～24小时。The progress of the coupling reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC, NMR or GC). Generally, the reaction end point is when compound B no longer reacts, and the reaction time can be 12-24 hours.
在某一方案中，所述的二胺A的制备方法的某些参数可如下所述，未涉及的参数如上任一方案所述：In a certain scheme, some parameters of the preparation method of diamine A can be described as follows, and the parameters not involved are as described in any of the above schemes:
所述的二胺A可为以下任一化合物：The diamine A can be any of the following compounds:
Figure PCTCN2020088988-appb-000017
Figure PCTCN2020088988-appb-000017
Figure PCTCN2020088988-appb-000018
Figure PCTCN2020088988-appb-000018
Figure PCTCN2020088988-appb-000019
Figure PCTCN2020088988-appb-000019
本发明还提供了一种二胺A，其为下述任一化合物：The present invention also provides a diamine A, which is any of the following compounds:
Figure PCTCN2020088988-appb-000020
Figure PCTCN2020088988-appb-000020
Figure PCTCN2020088988-appb-000021
Figure PCTCN2020088988-appb-000021
本发明还提供了一种化合物B，其为
Figure PCTCN2020088988-appb-000022
The present invention also provides a compound B, which is
Figure PCTCN2020088988-appb-000022
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
如无特别说明，本发明中的“室温”是指20-30℃，例如25℃。Unless otherwise specified, the "room temperature" in the present invention refers to 20-30°C, for example 25°C.
本发明的积极进步效果在于：该联硼酸二醇酯可用于诱导底物为亚胺的还原偶联反应，底物可由醛及氨反应得到，非常易得且成本相当低廉；产物仅需酸碱操作，即可从反应体系中分离而来，无需柱色谱纯化，后处理方式便捷，易于操作；所得产物产率较高且无需保护基操作。该联硼酸二醇酯具备手性，所述还原偶联反应的立体选择性普遍优秀，仅需简单重结晶既可以得到99％ee的手性二胺。该联硼酸二醇酯可使用二醇可与联硼酸二醇酯反应获得，该二醇制备方便，易于放大，且其经过简单的酸碱操作，可以从反应液中回收重复利用，回收率达95％，进一步节约了制备成本。The positive progress effect of the present invention is that the diol diborate can be used to induce the reductive coupling reaction where the substrate is an imine, and the substrate can be obtained by the reaction of aldehyde and ammonia, which is very easy to obtain and has a relatively low cost; the product only requires acid and alkali The operation can be separated from the reaction system without column chromatography purification, the post-processing method is convenient, and the operation is easy; the yield of the obtained product is high and no protective group operation is required. The diol diboronic acid ester has chirality, and the stereoselectivity of the reductive coupling reaction is generally excellent, and a chiral diamine with 99% ee can be obtained only by simple recrystallization. The diol diborate can be obtained by reacting with diol and diol diborate. The diol is easy to prepare, easy to scale up, and can be recovered and reused from the reaction solution after a simple acid-base operation. The recovery rate is up to 95%, further saving the preparation cost.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention will be further described by way of examples below, but the present invention is not limited to the scope of the described examples. In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions, or according to the product specification.
制备例1手性二醇的制备Preparation Example 1 Preparation of Chiral Diol
Figure PCTCN2020088988-appb-000023
Figure PCTCN2020088988-appb-000023
选取合适的三口瓶，称取表面光洁干燥的镁屑(19.5g,0.81mol,1.5eq)抽换氮气三次，氮气保护下加入重蒸THF(200ml)和两粒碘，然后加入适量的芳基溴试剂(共0.54mol,1.0eq)，然后电吹风加热使得格氏试剂引发，溶液黄色褪去变无色，继续加入芳基溴，保持反应体系微沸，说明格氏反应引发完成，加完芳基溴后，将未取代或取代的R-扁桃酸甲酯(0.11mol,0.2eq)溶于重蒸THF(50mL)溶液中，滴加入格氏试剂当中，反应加热回流，反应约4小时后已经完成，将反应冷至室温，倒入饱和氯化铵溶液淬灭，调pH在7以下，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，柱层析得到含有产物的混合体系，石油醚重结晶得到干净产物，产率为60％。Choose a suitable three-necked flask, weigh out the magnesium chips (19.5g, 0.81mol, 1.5eq) with a clean and dry surface. Purge nitrogen for three times. Add redistilled THF (200ml) and two iodine under the protection of nitrogen, and then add an appropriate amount of aryl. Bromine reagent (total 0.54 mol, 1.0 eq), and then heated by a hair dryer to initiate the Grignard reagent, the solution fades yellow and becomes colorless, continue to add aryl bromide, keep the reaction system slightly boiling, indicating that the Grignard reaction has been initiated, and the addition is complete. After the base bromide, the unsubstituted or substituted R-mandelic acid methyl ester (0.11mol, 0.2eq) was dissolved in the redistilled THF (50mL) solution, and added dropwise to the Grignard reagent. The reaction was heated to reflux and reacted for about 4 hours. Once completed, the reaction was cooled to room temperature, poured into saturated ammonium chloride solution for quenching, adjusted to pH below 7, extracted with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, and column chromatography to obtain a mixed system containing the product. Petroleum ether was recrystallized to obtain a clean product with a yield of 60%.
(R)-1,1-二(4-甲氧基苯基)-2-苯基乙二醇(报道于Supermolecular.1998,9,85-98)(R)-1,1-bis(4-methoxyphenyl)-2-phenylethylene glycol (reported in Supermolecular. 1998, 9, 85-98)
Figure PCTCN2020088988-appb-000024
Figure PCTCN2020088988-appb-000024
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性PC1柱，乙腈/水：80/20,25℃,流速0.7mL/min,7.13min(R),7.72min(S).旋光:[α] D 29＝200.0°[c＝0.5,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.58(m,2H),7.17(m,3H),7.05(m,2H),7.00(m,2H),6.95(m,2H),6.64(m,2H),5.52(d,J＝3.2Hz,1H),3.82(s,3H),3.71(s,3H),3.01(s,1H),2.42(d,J＝3.2Hz,1H). 13C NMR(125MHz,CDCl 3):158.9,158.4,139.2,137.5,136.2,128.5(2C),128.3(2C),127.8,127.7(2C),127.6(2C),114.0(2C),113.1(2C),80.5,78.5,55.5,55.3.HRMS(ESI)calcd.for C 22H 22NaO 4[M+Na] +:373.1410；found:373.1414. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral PC1 column, acetonitrile/water: 80/20, 25℃, flow rate 0.7mL/min, 7.13min(R), 7.72min(S). Optical rotation: [α] D 29 ＝200.0°[c＝0.5,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ):δ7.58(m,2H),7.17(m,3H) ,7.05(m,2H),7.00(m,2H),6.95(m,2H),6.64(m,2H),5.52(d,J=3.2Hz,1H),3.82(s,3H),3.71( s, 3H), 3.01 (s, 1H), 2.42 (d, J = 3.2 Hz, 1H). 13 C NMR (125MHz, CDCl 3 ): 158.9, 158.4, 139.2, 137.5, 136.2, 128.5 (2C), 128.3 (2C),127.8,127.7(2C),127.6(2C),114.0(2C),113.1(2C),80.5,78.5,55.5,55.3.HRMS(ESI)calcd.for C 22 H 22 NaO 4 (M+ Na] + :373.1410; found:373.1414.
(R)-2-(2-氯代苯基)-1,1-二(4-甲氧基苯基)乙二醇(R)-2-(2-chlorophenyl)-1,1-bis(4-methoxyphenyl)ethylene glycol
Figure PCTCN2020088988-appb-000025
Figure PCTCN2020088988-appb-000025
黄色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性OJ-H,正己烷/异丙醇：90/10,25℃,流速0.7mL/min,55.13min(R),46.65min(S).旋光:[α] D 29＝4.84°[c＝0.5,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.68(dd,J＝7.8,1.7Hz,1H),7.57(m,2H),7.23(ddd,J＝8.1,7.0,1.7Hz,1H),7.13(m,2H),6.96(m,4H),6.59(m,2H),6.12(dd,J＝4.3,1.6Hz,1H),3.83(s,3H),3.69(s,3H),3.21(m,1H),2.40(m,1H). 13C NMR(125MHz,CDCl 3):159.0,158.6,137.5,137.3,135.5,134.4,130.2,129.1,128.9,128.6(2C),128.4(2C),126.5,113.9(2C),112.8(2C),80.6,73.1,55.5,55.3.HRMS(ESI)calcd.for C 22H 21ClNaO 4[M+Na] +:407.1021；found:407.1023. Yellow solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral OJ-H, n-hexane/isopropanol: 90/10, 25℃, flow rate 0.7mL/min, 55.13min (R), 46.65min(S). Optical rotation: [α] D 29 ＝4.84°[c＝0.5,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ7.68(dd,J＝7.8,1.7 Hz, 1H), 7.57 (m, 2H), 7.23 (ddd, J = 8.1, 7.0, 1.7 Hz, 1H), 7.13 (m, 2H), 6.96 (m, 4H), 6.59 (m, 2H), 6.12 (dd,J=4.3,1.6Hz,1H), 3.83(s,3H), 3.69(s,3H), 3.21(m,1H), 2.40(m,1H). 13 C NMR(125MHz, CDCl 3 ) : 159.0, 158.6, 137.5, 137.3, 135.5, 134.4, 130.2, 129.1, 128.9, 128.6(2C), 128.4(2C), 126.5, 113.9(2C), 112.8(2C), 80.6, 73.1, 55.5, 55.3.HRMS (ESI)calcd.for C 22 H 21 ClNaO 4 [M+Na] + :407.1021; found:407.1023.
(R)-1,1-二(3,5-二甲基苯基)-2-苯基乙二醇(R)-1,1-bis(3,5-dimethylphenyl)-2-phenylethylene glycol
Figure PCTCN2020088988-appb-000026
Figure PCTCN2020088988-appb-000026
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱PC1,乙腈/水：80/20,25℃,流速0.7mL/min,10.88min(R),14.62min(S).旋光:[α] D 29＝176.0°[c＝0.5,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.32(s,2H),7.17(m,3H),7.06(m,2H),6.96(s,1H),6.75(m,3H),5.57(d,J＝3.2Hz,1H),2.99(s,1H),2.45(s,J＝3.2Hz,1H),2.37(s,6H),2.16(s,6H). 13C NMR(125MHz,CDCl 3):δ145.0,143.4,139.0,138.1(2C),137.1(2C),129.2,128.5,128.3,127.7,127.5,124.8,124.2,80.9,78.2,21.8(2C),21.6(2C).HRMS(ESI)calcd.for C 24H 26NaO 2[M+Na] +:369.1825；found:369.1828. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column PC1, acetonitrile/water: 80/20, 25℃, flow rate 0.7mL/min, 10.88min(R), 14.62min(S). Optical rotation: [α] D 29 ＝176.0°[c＝0.5,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ):δ7.32(s,2H),7.17(m,3H) ,7.06(m,2H),6.96(s,1H),6.75(m,3H),5.57(d,J=3.2Hz,1H),2.99(s,1H),2.45(s,J=3.2Hz, 1H), 2.37(s, 6H), 2.16(s, 6H). 13 C NMR (125MHz, CDCl 3 ): δ145.0, 143.4, 139.0, 138.1(2C), 137.1(2C), 129.2, 128.5, 128.3, 127.7 ,127.5,124.8,124.2,80.9,78.2,21.8(2C),21.6(2C).HRMS(ESI)calcd.for C 24 H 26 NaO 2 [M+Na] + : 369.1825; found: 369.1828.
(R)-1,1-二(2,5-二甲基苯基)-2-苯基乙二醇(R)-1,1-bis(2,5-dimethylphenyl)-2-phenylethylene glycol
Figure PCTCN2020088988-appb-000027
Figure PCTCN2020088988-appb-000027
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱PC3,乙腈/水：80/20,25℃,流速0.7mL/min,5.91min(R),6.69min(S).旋光:[α] D 30＝151.5°[c＝1.13,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.67(s,1H),7.13(m,1H),7.08(m,2H),7.04(dd,J＝7.7,1.7Hz,1H),6.99(m,3H),6.90(s,1H),6.74(dd,J＝7.7,1.8Hz,1H),6.70(d,J＝7.7Hz,1H),5.64(s,1H),3.16(s,1H),2.68(s,1H),2.43(s,3H),2.05(s,3H),1.96(s,3H),1.77(s,3H). 13C NMR(125MHz,CDCl 3):δ142.6,140.6,140.3,136.0,134.3,132.9,131.6,128.9,128.8,128.3,128.0,127.6,127.4,127.3,21.7,27.6,21.2,21.1.HRMS(ESI)calcd.for C 24H 26NaO 2[M+Na] +:369.1825；found:369.1828. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column PC3, acetonitrile/water: 80/20, 25℃, flow rate 0.7mL/min, 5.91min(R), 6.69min(S). Optical rotation: [α] D 30 ＝151.5°[c＝1.13,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ):δ7.67(s,1H),7.13(m,1H) ,7.08(m,2H),7.04(dd,J=7.7,1.7Hz,1H),6.99(m,3H),6.90(s,1H),6.74(dd,J=7.7,1.8Hz,1H), 6.70(d,J=7.7Hz,1H),5.64(s,1H),3.16(s,1H),2.68(s,1H),2.43(s,3H),2.05(s,3H),1.96(s ,3H),1.77(s,3H). 13 C NMR (125MHz, CDCl 3 ): δ142.6,140.6,140.3,136.0,134.3,132.9,131.6,128.9,128.8,128.3,128.0,127.6,127.4,127.3,21.7 ,27.6,21.2,21.1.HRMS(ESI)calcd.for C 24 H 26 NaO 2 [M+Na] + :369.1825; found:369.1828.
(R)-1,1-二(2,4-二甲基苯基)-2-苯基乙二醇(R)-1,1-bis(2,4-dimethylphenyl)-2-phenylethylene glycol
Figure PCTCN2020088988-appb-000028
Figure PCTCN2020088988-appb-000028
无色固体结晶；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱PC1,乙腈/水：80/20等度,25℃,流速0.7mL/min,7.27min(R),9.94min(S).旋光:[α] D 20＝-452.8°[c＝1.30,CHCl 3].HRMS(ESI)calcd.for C 24H 26NaO 2[M+Na] +:369.1825；found:369.1830. Colorless solid crystal; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column PC1, acetonitrile/water: 80/20 isocratic, 25℃, flow rate 0.7mL/min, 7.27min (R),9.94min(S). Optical rotation: [α] D 20 ＝-452.8°[c＝1.30,CHCl 3 ].HRMS(ESI)calcd.for C 24 H 26 NaO 2 [M+Na] + : 369.1825; found:369.1830.
(R)-2-苯基-1,1-邻二甲苯基乙二醇(R)-2-Phenyl-1,1-o-xylyl glycol
Figure PCTCN2020088988-appb-000029
Figure PCTCN2020088988-appb-000029
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱PC1,乙腈/水：80/20,25℃,流速0.7mL/min,7.27min(R),9.94min(S).旋光:[α] D 29＝223.8°[c＝0.5,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.87(d,J＝7.6Hz,1H),7.28(m,1H),7.23(m,1H),7.16(m,1H),7.10(m,4H),6.96(m,3H),6.83(m,2H),5.67(s,1H),3.28(brs,1H),1.98(s,3H),1.83(s,3H). 13C NMR(125MHz,CDCl 3):δ140.8,140.2,139.2,133.1,131.7,128.3,128.1(2C),127.8(2C),127.7(2C),127.4(2C),126.8,125.1(2C),22.1,21.6.HRMS(ESI)calcd.for C 22H 22NaO 2[M+Na] +:341.1512；found:341.1516. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column PC1, acetonitrile/water: 80/20, 25℃, flow rate 0.7mL/min, 7.27min(R), 9.94min(S). Optical rotation: [α] D 29 ＝223.8°[c＝0.5,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ):δ7.87(d,J＝7.6Hz,1H), 7.28 (m, 1H), 7.23 (m, 1H), 7.16 (m, 1H), 7.10 (m, 4H), 6.96 (m, 3H), 6.83 (m, 2H), 5.67 (s, 1H), 3.28 ( brs,1H),1.98(s,3H),1.83(s,3H). 13 C NMR (125MHz, CDCl 3 ): δ140.8,140.2,139.2,133.1,131.7,128.3,128.1(2C),127.8(2C) ,127.7(2C),127.4(2C),126.8,125.1(2C),22.1,21.6.HRMS(ESI)calcd.for C 22 H 22 NaO 2 [M+Na] + : 341.1512; found: 341.1516.
制备例2手性二硼DB4～DB7的制备Preparation Example 2 Preparation of chiral diboron DB4～DB7
Figure PCTCN2020088988-appb-000030
Figure PCTCN2020088988-appb-000030
选取一合适的Schlenk管，加入diol 5(30g,86mmol,2.0eq)，四羟基二硼(3.9g,43mmol,1.0eq)和适量的4A分子筛，抽换氮气三次，氮气保护下加入重蒸THF(150ml)，体系置于70℃油浴中回流，反应约4小时完成。将反应体系冷至室温，硅藻土过滤，二氯甲烷洗涤，滤液旋干，用石油醚洗涤，再次过滤，滤饼白色固体粉末即为双硼产物28.7g,产率为94％。(DB4)。Choose a suitable Schlenk tube, add diol 5 (30g, 86mmol, 2.0eq), tetrahydroxydiboron (3.9g, 43mmol, 1.0eq) and an appropriate amount of 4A molecular sieve, change nitrogen for three times, add redistilled THF under nitrogen protection (150ml), the system was refluxed in an oil bath at 70°C, and the reaction was completed in about 4 hours. The reaction system was cooled to room temperature, filtered through Celite, washed with dichloromethane, the filtrate was spin-dried, washed with petroleum ether, and filtered again. The white solid powder of the filter cake was 28.7 g of diboron product, and the yield was 94%. (DB4).
Figure PCTCN2020088988-appb-000031
Figure PCTCN2020088988-appb-000031
白色固体；94％产率；旋光:[α] D 29＝275.2°[c＝1.10,CHCl 3]. 1H NMR(400MHz,CDCl 3):δ7.70(s,2H),7.26(s,2H),7.07-6.99(m,14H),6.73(m,2H),6.59(m,4H),2.45(s,6H),2.14(s,6H),1.92(s,6H),1.53(s,6H). 13C NMR(100MHz,CDCl 3):δ141.1(2C),138.7 (2C),137.5(2C),135.8(2C),134.7(2C),134.2(2C),132.7(2C),131.1(2C),131.0(2C),128.6(2C),128.5(2C),127.7(2C),127.6(2C),127.4(4C),127.3(4C),126.1(2C),91.8(2C),84.3(2C),21.7(2C),21.4(2C),21.3(2C),21.0(2C). 11B NMR(CDCl 3,128MHz):δ31.4._HRMS(DART)calcd.for C 48H 49O 4 10B 2[M] +:709.3884；found:709.3881. White solid; 94% yield; optical rotation: [α] D 29 =275.2°[c=1.10,CHCl 3 ]. 1 H NMR (400MHz, CDCl 3 ): δ7.70(s, 2H), 7.26(s, 2H), 7.07-6.99 (m, 14H), 6.73 (m, 2H), 6.59 (m, 4H), 2.45 (s, 6H), 2.14 (s, 6H), 1.92 (s, 6H), 1.53 (s ,6H). 13 C NMR (100MHz, CDCl 3 ): δ141.1(2C), 138.7 (2C), 137.5(2C), 135.8(2C), 134.7(2C), 134.2(2C), 132.7(2C) , 131.1(2C), 131.0(2C), 128.6(2C), 128.5(2C), 127.7(2C), 127.6(2C), 127.4(4C), 127.3(4C), 126.1(2C), 91.8(2C) ,84.3(2C),21.7(2C),21.4(2C),21.3(2C),21.0(2C). 11 B NMR(CDCl 3 ,128MHz):δ31.4._HRMS(DART)calcd.for C 48 H 49 O 4 10 B 2 [M] + :709.3884; found:709.3881.
Figure PCTCN2020088988-appb-000032
Figure PCTCN2020088988-appb-000032
选取一合适的Schlenk管，加入diol 4(3.2g,10mmol,2.0eq)，四羟基二硼(0.45g,5.0mmol,1.0eq)和适量的4A分子筛，抽换氮气三次，氮气保护下加入重蒸THF(15ml)，体系置于70℃油浴中回流，反应约4小时完成。将反应体系冷至室温，硅藻土过滤，二氯甲烷洗涤，滤液旋干，用石油醚洗涤，再次过滤，滤饼白色固体粉末即为双硼产物3.1g,产率为95％。(DB5)。Choose a suitable Schlenk tube, add diol 4 (3.2g, 10mmol, 2.0eq), tetrahydroxydiboron (0.45g, 5.0mmol, 1.0eq) and an appropriate amount of 4A molecular sieve, change the nitrogen three times, add heavy THF (15ml) was evaporated, the system was placed in an oil bath at 70°C and refluxed, and the reaction was completed in about 4 hours. The reaction system was cooled to room temperature, filtered through Celite, washed with dichloromethane, the filtrate was spin-dried, washed with petroleum ether, and filtered again. The white solid powder of the filter cake was 3.1 g of diboron product, and the yield was 95%. (DB5).
Figure PCTCN2020088988-appb-000033
Figure PCTCN2020088988-appb-000033
白色固体；95％产率； 1H NMR(400MHz,CDCl 3):7.91(d,J＝7.6Hz,2H),7.30(m,2H),7.26(m,2H),7.20(m,2H),7.14(m,8H),7.04(m,6H),6.88(m,4H),6.58(s,2H),1.98(s,6H),1.73(s,6H). 11B NMR(CDCl 3,128MHz):δ30.4._HRMS(DART)calcd.for C 48H 40O 4 10B 2[M] +:654.4200；found:654.4205. White solid; 95% yield; 1 H NMR (400MHz, CDCl 3 ): 7.91 (d, J = 7.6 Hz, 2H), 7.30 (m, 2H), 7.26 (m, 2H), 7.20 (m, 2H) ,7.14(m,8H),7.04(m,6H),6.88(m,4H),6.58(s,2H),1.98(s,6H),1.73(s,6H). 11 B NMR(CDCl 3 , 128MHz):δ30.4._HRMS(DART)calcd.for C 48 H 40 O 4 10 B 2 [M] + :654.4200; found:654.4205.
Figure PCTCN2020088988-appb-000034
Figure PCTCN2020088988-appb-000034
选取一合适的Schlenk管，加入diol 6(350mg,1.0mmol,2.0eq)，四羟基二硼(45mg,0.50mmol,1.0eq)和适量的4A分子筛，抽换氮气三次，氮气保护下加入重蒸THF(5ml)，体系置于70℃油浴中回流，反应约4小时完成。将反应体系冷至室温，硅藻土过滤，二 氯甲烷洗涤，滤液旋干，用石油醚洗涤，再次过滤，滤饼白色固体粉末即为双硼产物330mg,产率为92％。(DB6)。Choose a suitable Schlenk tube, add diol 6 (350mg, 1.0mmol, 2.0eq), tetrahydroxydiboron (45mg, 0.50mmol, 1.0eq) and an appropriate amount of 4A molecular sieve, change nitrogen for three times, add redistill under nitrogen protection THF (5ml), the system was refluxed in an oil bath at 70°C, and the reaction was completed in about 4 hours. The reaction system was cooled to room temperature, filtered through Celite, washed with dichloromethane, the filtrate was spin-dried, washed with petroleum ether, and filtered again. The white solid powder of the filter cake was 330 mg of diboron product, and the yield was 92%. (DB6).
Figure PCTCN2020088988-appb-000035
Figure PCTCN2020088988-appb-000035
白色固体；92％产率； 1H NMR(500MHz,CDCl 3):δ7.62(m,4H),7.21(m,6H),7.15(m,4H),7.06(m,4H),6.99(m,4H),6.70(m,4H),5.58(d,J＝3.2Hz,2H),3.88(s,6H),3.75(s,6H). 11B NMR(CDCl 3,128MHz):δ28.5.HRMS(DART)calcd.for C 44H 40O 8 10B 2[M] +:718.2909；found:718.2903. White solid; 92% yield; 1 H NMR (500MHz, CDCl 3 ): δ 7.62 (m, 4H), 7.21 (m, 6H), 7.15 (m, 4H), 7.06 (m, 4H), 6.99 ( m, 4H), 6.70 (m, 4H), 5.58 (d, J = 3.2 Hz, 2H), 3.88 (s, 6H), 3.75 (s, 6H). 11 B NMR (CDCl 3 , 128MHz): δ28. 5. HRMS(DART)calcd.for C 44 H 40 O 8 10 B 2 [M] + : 718.2909; found: 718.2903.
Figure PCTCN2020088988-appb-000036
Figure PCTCN2020088988-appb-000036
选取一合适的Schlenk管，加入diol 8(346mg,1.0mmol,2.0eq)，四羟基二硼(45mg,0.50mmol,1.0eq)和适量的4A分子筛，抽换氮气三次，氮气保护下加入重蒸THF(5ml)，体系置于70℃油浴中回流，反应约4小时完成。将反应体系冷至室温，硅藻土过滤，二氯甲烷洗涤，滤液旋干，用石油醚洗涤，再次过滤，滤饼白色固体粉末即为双硼产物333mg,产率为94％。(DB8)。Select a suitable Schlenk tube, add diol 8 (346mg, 1.0mmol, 2.0eq), tetrahydroxydiboron (45mg, 0.50mmol, 1.0eq) and an appropriate amount of 4A molecular sieve, change nitrogen for three times, add redistill under the protection of nitrogen THF (5ml), the system was refluxed in an oil bath at 70°C, and the reaction was completed in about 4 hours. The reaction system was cooled to room temperature, filtered through Celite, washed with dichloromethane, the filtrate was spin-dried, washed with petroleum ether, and filtered again. The white solid powder of the filter cake was 333 mg of diboron product, and the yield was 94%. (DB8).
Figure PCTCN2020088988-appb-000037
Figure PCTCN2020088988-appb-000037
白色固体；94％产率；HRMS(DART)calcd.for C 48H 48O 4 10B 2[M] +:710.3739；found:710.3743. White solid; 94% yield; HRMS (DART) calcd. for C 48 H 48 O 4 10 B 2 [M] + : 710.3739; found: 710.3743.
实施例1芳香亚胺不对称还原偶联底物拓展Example 1 Development of Asymmetric Reductive Coupling Substrate of Aromatic Imine
Figure PCTCN2020088988-appb-000038
Figure PCTCN2020088988-appb-000038
在干净干燥的shlenk管中，加入芳基醛(0.2mmol,1.0eq)，体系抽换氮气三次，氮气保护，在氮气保护下，加入氨甲醇溶液(7.0M,3.0mmol,15.0eq)，加溶剂重蒸四氢呋喃(2mL)，体系密封，反应室温搅拌1h，在氮气保护下，加入DB4(0.11mmol,0.55eq)，室温(20-30℃)下搅拌12-24h。体系旋蒸除去多余氨气，加入1mL甲醇，加入盐酸(3.0M，1mL)调pH至3左右，二氯甲烷洗涤，将有机相浓缩后用正己烷打浆回收手性二醇diol 5(95％回收率)。而水相加入氢氧化钠溶液调pH至12左右，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，有机相旋干即得到产物。In a clean and dry shlenk tube, add the aryl aldehyde (0.2mmol, 1.0eq), the system was pumped with nitrogen three times, under the protection of nitrogen, under the protection of nitrogen, add ammonia methanol solution (7.0M, 3.0mmol, 15.0eq), add The solvent was redistilled with tetrahydrofuran (2 mL), the system was sealed, and the reaction was stirred at room temperature for 1 h. Under nitrogen protection, DB4 (0.11 mmol, 0.55 eq) was added and stirred at room temperature (20-30° C.) for 12-24 h. The system was rotary evaporated to remove excess ammonia gas, added 1mL methanol, added hydrochloric acid (3.0M, 1mL) to adjust the pH to about 3, washed with dichloromethane, concentrated the organic phase and beaten with n-hexane to recover the chiral diol 5 (95%) Recovery rate). The aqueous phase is added with sodium hydroxide solution to adjust the pH to about 12, extracted with dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, and the organic phase is spin-dried to obtain the product.
1a(1R,2R)-1,2-二苯基乙二胺1a(1R,2R)-1,2-diphenylethylenediamine
Figure PCTCN2020088988-appb-000039
Figure PCTCN2020088988-appb-000039
白色固体；82％产率；95％ee(其中，过量的对映体的绝对构型如结构式所示，本发明全文同此)；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,14.66min(S,S),17.54min(R,R),该保留时间与购得的(1S,2S)-1,2-二苯基乙二胺、(1R,2R)-1,2-二苯基乙二胺在同一条件下的保留时间相同.旋光:[α] D 21＝36.0°[c＝1.04,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.30-7.15(m,10H),4.09(s,2H),1.58(s,4H). 13C NMR(125MHz,CDCl 3):δ143.4(2C),128.2(4C),127.0(2C),126.9(4C),61.9(2C).HRMS(ESI)calcd.for C 14H 16N 2[M+H] +:213.1390；found:213.1386. White solid; 82% yield; 95% ee (wherein, the absolute configuration of the excess enantiomer is shown in the structural formula, and the full text of the present invention is the same); the ee value is determined by the high-pressure chiral liquid phase; the high-pressure liquid phase conditions: Chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20/0.1, 23℃, flow rate 0.8mL/min, 14.66min(S,S), 17.54min(R,R), The retention time is the same as that of commercially available (1S,2S)-1,2-diphenylethylenediamine and (1R,2R)-1,2-diphenylethylenediamine under the same conditions. :[α] D 21 ＝36.0°[c＝1.04,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ):δ7.30-7.15(m,10H),4.09(s,2H),1.58(s, 4H). 13 C NMR(125MHz, CDCl 3 ): δ143.4(2C), 128.2(4C), 127.0(2C), 126.9(4C), 61.9(2C).HRMS(ESI)calcd.for C 14 H 16 N 2 [M+H] + :213.1390; found:213.1386.
2a(1R,2R)-1,2-二(4-甲基苯基)乙二胺2a(1R,2R)-1,2-bis(4-methylphenyl)ethylenediamine
Figure PCTCN2020088988-appb-000040
Figure PCTCN2020088988-appb-000040
无色液体；71％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,12.57min(S,S),14.11min(R,R).旋光:[α] D 21＝-41.3°[c＝1.02,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.19-7.06(m,8H),4.07(s,2H),2.31(s,6H),1.82(s,4H). 13C NMR(125MHz,CDCl 3):δ140.2(2C),136.5(2C),128.9(4C),126.8(4C),61.4(2C),21.0(6C).HRMS(ESI)calcd.for C 16H 20N 2[M+H] +:241.1702；found:241.1699. Colorless liquid; 71% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1,23℃, flow rate 0.8mL/min, 12.57min(S,S), 14.11min(R,R). Optical rotation: [α] D 21 ＝-41.3°[c＝1.02,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7.19-7.06 (m, 8H), 4.07 (s, 2H), 2.31 (s, 6H), 1.82 (s, 4H). 13 C NMR (125MHz, CDCl 3 ): δ140.2(2C),136.5(2C),128.9(4C),126.8(4C),61.4(2C),21.0(6C).HRMS(ESI)calcd.for C 16 H 20 N 2 [M+H] + :241.1702; found:241.1699.
3a(1R,2R)-1,2-二(4-甲氧基苯基)乙二胺3a(1R,2R)-1,2-bis(4-methoxyphenyl)ethylenediamine
Figure PCTCN2020088988-appb-000041
Figure PCTCN2020088988-appb-000041
白色固体；68％产率；99％ee；ee值由其衍生物(4R,5R)-4,5-二(4-甲氧基苯基)2-咪唑烷酮测定所得.旋光:[α] D 22＝43.0°[c＝1.64,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.18(d,J＝7.50Hz,2H),7.12(t,J＝7.80Hz,2H),6.81(t,J＝7.50Hz,2H),6.76(d,J＝8.20Hz,2H),4.47(s,2H),3.79(s,6H),2.32(s,4H). 13C NMR(125MHz,CDCl 3):δ156.8(2C),131.3(2C),128.2(2C),127.8(2C),120.3(2C),110.3(2C),55.5(2C),55.2(6C).HRMS(ESI)calcd.for C 16H 20N 2O 2[M+H] +:273.1598；found:273.1598. White solid; 68% yield; 99% ee; ee value is determined by its derivative (4R,5R)-4,5-bis(4-methoxyphenyl)2-imidazolidinone. Optical rotation: [α ] D 22 ＝43.0°[c＝1.64,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ):δ7.18(d,J＝7.50Hz,2H),7.12(t,J＝7.80Hz,2H) , 6.81 (t, J = 7.50 Hz, 2H), 6.76 (d, J = 8.20 Hz, 2H), 4.47 (s, 2H), 3.79 (s, 6H), 2.32 (s, 4H). 13 C NMR( 125MHz, CDCl 3 ): δ156.8(2C), 131.3(2C), 128.2(2C), 127.8(2C), 120.3(2C), 110.3(2C), 55.5(2C), 55.2(6C).HRMS( ESI)calcd.for C 16 H 20 N 2 O 2 [M+H] + :273.1598; found:273.1598.
衍生化操作：将手性二胺(27.2mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，三光气(10mg,0.033mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在5摄氏度以下。滴加完成后，让温度上升到室温后，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 Derivatization operation: dissolve the chiral diamine (27.2mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) in DCM (4.0mL), and dissolve triphosgene (10mg, 0.033mmol) in DCM (2.0ml) ), added dropwise to the above system to keep the temperature below 5 degrees Celsius. After the dropwise addition is completed, the temperature is allowed to rise to room temperature, and the mixture is stirred for 3-4 hours, and the reaction is completed (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
(4R,5R)-4,5-二(4-甲氧基苯基)2-咪唑烷酮(4R,5R)-4,5-bis(4-methoxyphenyl)2-imidazolidinone
Figure PCTCN2020088988-appb-000042
Figure PCTCN2020088988-appb-000042
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：70/30/0.1,23℃,流速1.0mL/min,250nm,18.36min(S,S),38.57min(R,R).旋光:[α] D 27＝115.48°[c＝0.40,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.17(d,J＝8.3Hz,4H),6.87(d,J＝8.3Hz,4H),5.16(s,2H),4.49(s,2H),3.80(s,6H). 13C NMR(125MHz,CDCl 3):δ162.5(1C),159.6(2C),131.8(2C),127.7(4C),114.1(4C),65.85(2C),55.3(6C).HRMS(ESI)calcd.for C 17H 18N 2O 3[M+H] +:299.1395；found:299.1590；[M+Na] +:321.1214；found:321.1210. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 70/30/0.1, 23℃, Flow rate 1.0mL/min, 250nm, 18.36min(S,S), 38.57min(R,R). Optical rotation: [α] D 27 ＝115.48°[c＝0.40,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ7.17(d,J=8.3Hz,4H), 6.87(d,J=8.3Hz,4H), 5.16(s,2H), 4.49(s,2H), 3.80(s,6H). 13 C NMR(125MHz, CDCl 3 ): δ162.5(1C), 159.6(2C), 131.8(2C), 127.7(4C), 114.1(4C), 65.85(2C), 55.3(6C).HRMS(ESI) )calcd.for C 17 H 18 N 2 O 3 [M+H] + : 299.1395; found: 299.1590; [M+Na] + : 321.1214; found: 321.1210.
4a(1R,2R)-1,2-二(4-甲氧羰基苯基)乙二胺4a(1R,2R)-1,2-bis(4-methoxycarbonylphenyl)ethylenediamine
Figure PCTCN2020088988-appb-000043
Figure PCTCN2020088988-appb-000043
黄色固体；55％产率；81％ee；ee值由其衍生物测定所得.旋光:[α] D 21＝87.7°[c＝1.01,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.92(d,J＝7.6Hz,4H),7.29(d,J＝8.0Hz,4H),4.14(s,2H),3.89(s,6H),1.96(s,4H). 13C NMR(125MHz,CDCl 3):δ166.8(2C),129.6(4C),129.2(2C),127.5(2C),127.0(4C),61.9(2C),52.1(6C).HRMS(ESI)calcd.for C 18H 20N 2O 4[M+H] +:329.1498；found:329.1496. Yellow solid; 55% yield; 81% ee; ee value determined by its derivatives. Optical rotation: [α] D 21 ＝87.7°[c＝1.01,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7.92 (d, J = 7.6 Hz, 4H), 7.29 (d, J = 8.0 Hz, 4H), 4.14 (s, 2H), 3.89 (s, 6H), 1.96 (s, 4H). 13 C NMR (125MHz, CDCl 3 ): δ166.8(2C), 129.6(4C), 129.2(2C), 127.5(2C), 127.0(4C), 61.9(2C), 52.1(6C).HRMS(ESI)calcd. for C 18 H 20 N 2 O 4 [M+H] + :329.1498; found:329.1496.
(1R,2R)-1,2-二(4-甲氧羰基苯基)2-咪唑烷酮(1R,2R)-1,2-bis(4-methoxycarbonylphenyl)2-imidazolidinone
Figure PCTCN2020088988-appb-000044
Figure PCTCN2020088988-appb-000044
将手性二胺(32.8mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，三光气(10mg,0.033mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在5摄氏度以下。滴加完成后，让温度上升到室温后， The chiral diamine (32.8mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), triphosgene (10mg, 0.033mmol) was dissolved in DCM (2.0ml) and added dropwise In the above system, keep the temperature below 5 degrees Celsius. After the dripping is completed, let the temperature rise to room temperature,
搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到黄色固体。After stirring for 3-4 hours, the reaction is complete (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a yellow solid.
黄色固体；81％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：70/30/0.1,23℃,流速1.0mL/min,250nm,10.22min(S,S),14.77min(R,R).旋光:[α] D 26＝64.74°[c＝1.03,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ8.04(d,J＝8.5Hz,4H),7.33(d,J＝8.0Hz,4H),5.28(s,2H),4.62(s,2H),3.93(s,6H). 13C NMR(125MHz,CDCl 3):δ166.5(1C),162.2(2C),144.3(2C),130.6(2C),130.3(4C),126.5(4C),65.6(2C),52.3(6C).HRMS(ESI)calcd.for C 19H 18N 2O 5,[M+H] +:355.1290；found:355.1288. Yellow solid; 81% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 70/30/0.1, 23℃, Flow rate 1.0mL/min, 250nm, 10.22min(S,S), 14.77min(R,R). Optical rotation: [α] D 26 ＝64.74°[c＝1.03,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ8.04(d,J=8.5Hz,4H), 7.33(d,J=8.0Hz,4H), 5.28(s, 2H), 4.62(s, 2H), 3.93(s, 6H). 13 C NMR (125MHz, CDCl 3 ): δ166.5(1C), 162.2(2C), 144.3(2C), 130.6(2C), 130.3(4C), 126.5(4C), 65.6(2C), 52.3(6C) ).HRMS(ESI)calcd.for C 19 H 18 N 2 O 5, [M+H] + :355.1290; found:355.1288.
5a(1R,2R)-1,2-二(4-溴代苯基)乙二胺5a(1R,2R)-1,2-bis(4-bromophenyl)ethylenediamine
Figure PCTCN2020088988-appb-000045
Figure PCTCN2020088988-appb-000045
无色液体；78％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S- Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,23.16min(S,S),30.59min(R,R).Optical rotation:[α] D 20＝78.80°[c＝1.06,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.40-7.36(m,4H),7.11-7.06(m,4H),4.02(s,2H),2.15(s,4H). 13C NMR(125MHz,CDCl 3):δ141.5(2C),131.4(4C),128.7(4C),121.2(2C),61.4(2C).HRMS(ESI)calcd.for C 14H 14Br 2N 2[M+H] +:368.9600；found:368.9597. Colorless liquid; 78% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S- Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1,23℃,flow rate 0.8mL/min,23.16min(S,S),30.59min(R,R).Optical rotation:[α] D 20 ＝78.80°[c＝1.06,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7.40-7.36 (m, 4H), 7.11-7.06 (m, 4H), 4.02 (s, 2H), 2.15 (s, 4H). 13 C NMR (125MHz, CDCl 3 ):δ141.5(2C),131.4(4C),128.7(4C),121.2(2C),61.4(2C).HRMS(ESI)calcd.for C 14 H 14 Br 2 N 2 [M+H] + :368.9600; found:368.9597.
6a(1R,2R)-1,2-二(4-氟代苯基)乙二胺6a(1R,2R)-1,2-bis(4-fluorophenyl)ethylenediamine
Figure PCTCN2020088988-appb-000046
Figure PCTCN2020088988-appb-000046
无色液体；78％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,15.43min(S,S),18.15min(R,R).Optical rotation:[α] D 25＝45.9°[c＝1.04,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.16(dd,J＝8.40,5.40Hz,4H),6.93(t,J＝8.50Hz,4H),4.00(s,2H),1.76(s,4H). 13C NMR(125MHz,CDCl 3):δ161.8(d,J＝243.8Hz,2C),138.8(d,J＝3.2Hz 2C),128.4(d,J＝7.8Hz,4C),115.0(d,J＝21.0Hz,4C),61.6(2C). 19F NMR(376MHz,CDCl 3):δ-115.51(m,2F).HRMS(ESI)calcd.for C 14H 14F 2N 2[M+H] +:249.1202；found:249.1198. Colorless liquid; 78% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1,23℃,flow rate 0.8mL/min,15.43min(S,S),18.15min(R,R).Optical rotation:[α] D 25 ＝45.9°[c＝1.04,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7.16 (dd, J = 8.40, 5.40 Hz, 4H), 6.93 (t, J = 8.50 Hz, 4H), 4.00 (s, 2H), 1.76 (s, 4H). 13 C NMR (125MHz, CDCl 3 ): δ161.8 (d, J = 243.8Hz, 2C), 138.8 (d, J = 3.2Hz 2C), 128.4 (d, J = 7.8Hz, 4C), 115.0 (d ,J=21.0Hz,4C),61.6(2C). 19 F NMR(376MHz,CDCl 3 ):δ-115.51(m,2F).HRMS(ESI)calcd.for C 14 H 14 F 2 N 2 [M +H] + :249.1202; found:249.1198.
7a(1R,2R)-1,2-二(4-氯代苯基)乙二胺7a(1R,2R)-1,2-bis(4-chlorophenyl)ethylenediamine
Figure PCTCN2020088988-appb-000047
Figure PCTCN2020088988-appb-000047
无色液体；58％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,20.19min(S,S),26.58min(R,R).旋光:[α] D 21＝83.2°[c＝1.03,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.22(d,J＝8.50Hz,4H),7.14(d,J＝8.50Hz,4H),4.05(s,2H),2.23(s,4H). 13C NMR(125MHz,CDCl 3):δ140.9(2C),133.0(2C),128.5(4C),128.4(4C),61.3(2C).HRMS(ESI)calcd.for C 14H 14Cl 2N 2[M+H] +:281.0609；found:281.0607. Colorless liquid; 58% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1,23℃,flow rate 0.8mL/min,20.19min(S,S),26.58min(R,R). Optical rotation: [α] D 21 ＝83.2°[c＝1.03,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7.22 (d, J = 8.50 Hz, 4H), 7.14 (d, J = 8.50 Hz, 4H), 4.05 (s, 2H), 2.23 (s, 4H). 13 C NMR (125MHz,CDCl 3 ):δ140.9(2C),133.0(2C),128.5(4C),128.4(4C),61.3(2C).HRMS(ESI)calcd.for C 14 H 14 Cl 2 N 2 [ M+H] + :281.0609; found:281.0607.
8a(1R,2R)-1,2-二(2,4,6-三取代苯基)乙二胺8a(1R,2R)-1,2-bis(2,4,6-trisubstituted phenyl)ethylenediamine
Figure PCTCN2020088988-appb-000048
Figure PCTCN2020088988-appb-000048
无色液体；66％产率；93％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,13.77min(S,S),17.29min(R,R).旋光:[α] D 21＝23.5°[c＝1.00,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ6.48(t,J＝8.80Hz,4H),4.41(s,2H),2.04(s,4H). 13C NMR(125MHz,CDCl 3):δ161.6(d,J＝124.0Hz,2C),161.0(d,J＝124.0Hz,4C),114.7(t,J＝15.8Hz,2C),100.2(t,J＝26.8Hz,2C),52.0(2C). 19F NMR(376MHz,CDCl 3):δ-108.6(p,J＝7.40Hz,2F),-110.7(t,J＝7.50Hz,4F).HRMS(ESI)calcd.for C 14H 10F 6N 2[M+H] +:321.0826；found:321.0821. Colorless liquid; 66% yield; 93% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1,23℃,flow rate 0.8mL/min,13.77min(S,S),17.29min(R,R). Optical rotation: [α] D 21 ＝23.5°[c＝1.00,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ6.48(t, J=8.80Hz, 4H), 4.41(s, 2H), 2.04(s, 4H). 13 C NMR(125MHz, CDCl 3 ): δ161.6(d ,J=124.0Hz,2C),161.0(d,J=124.0Hz,4C),114.7(t,J=15.8Hz,2C),100.2(t,J=26.8Hz,2C),52.0(2C). 19 F NMR(376MHz, CDCl 3 ): δ-108.6(p,J＝7.40Hz,2F),-110.7(t,J＝7.50Hz,4F).HRMS(ESI)calcd.for C 14 H 10 F 6 N 2 [M+H] + :321.0826; found:321.0821.
9a(1R,2R)-1,2-二(2-甲氧基苯基)乙二胺9a(1R,2R)-1,2-bis(2-methoxyphenyl)ethylenediamine
Figure PCTCN2020088988-appb-000049
Figure PCTCN2020088988-appb-000049
白色固体；74％产率；95％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,13.63min(S,S),14.97min(R,R).旋光:[α] D 20＝37.2°[c＝1.07,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.18(d,J＝7.50Hz,2H),7.12(t,J＝7.80Hz,2H),6.81(t,J＝7.50Hz,2H),6.76(d,J＝8.20Hz,2H),4.47(s,2H),3.79(s,6H),2.32(s,4H). 13C NMR(125MHz,CDCl 3):δ156.8(2C),131.3(2C),128.2(2C),127.8(2C),120.3(2C),110.3(2C),55.5(2C),55.2(6C).HRMS(ESI)calcd.for C 16H 20N 2O 2[M+H] +:273.1598；found:273.1598. White solid; 74% yield; 95% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20/ 0.1,23℃, flow rate 0.8mL/min, 13.63min(S,S), 14.97min(R,R). Optical rotation: [α] D 20 ＝37.2°[c＝1.07,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.18 (d, J = 7.50 Hz, 2H), 7.12 (t, J = 7.80 Hz, 2H), 6.81 (t, J = 7.50 Hz, 2H), 6.76 (d, J = 8.20Hz, 2H), 4.47 (s, 2H), 3.79 (s, 6H), 2.32 (s, 4H). 13 C NMR (125MHz, CDCl 3 ): δ 156.8 (2C), 131.3 (2C), 128.2 (2C),127.8(2C),120.3(2C),110.3(2C),55.5(2C),55.2(6C).HRMS(ESI)calcd.for C 16 H 20 N 2 O 2 [M+H] + :273.1598; found:273.1598.
10a(1R,2R)-1,2-邻甲苯基乙二胺10a(1R,2R)-1,2-o-tolylethylenediamine
Figure PCTCN2020088988-appb-000050
Figure PCTCN2020088988-appb-000050
无色液体；71％产率；70％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,12.6min(S,S),18.5min(R,R).旋光:[α] D 21＝14.4°[c＝1.00,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.60(d,J＝7.65Hz,2H),7.19(t,J＝7.60Hz,2H),7.09(t,J＝7.50Hz,2H),7.00(d,J＝7.50Hz,2H),4.38(s,2H),2.10(s,6H),2.01(s,4H). 13C NMR(125MHz,CDCl 3):δ141.4(2C),135.3(2C),130.3(2C),126.8(2C),126.7(2C),126.0(2C),55.8(2C),19.5(6C).HRMS(ESI)calcd.for C 16H 20N 2[M+H] +:241.1703；found:241.1699. Colorless liquid; 71% yield; 70% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1,23℃, flow rate 0.8mL/min,12.6min(S,S),18.5min(R,R). Optical rotation: [α] D 21 ＝14.4°[c＝1.00,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ 7.60 (d, J = 7.65 Hz, 2H), 7.19 (t, J = 7.60 Hz, 2H), 7.09 (t, J = 7.50 Hz, 2H), 7.00 (d, J ＝7.50Hz, 2H), 4.38(s, 2H), 2.10(s, 6H), 2.01(s, 4H). 13 C NMR(125MHz, CDCl 3 ): δ141.4(2C), 135.3(2C), 130.3(2C),126.8(2C),126.7(2C),126.0(2C),55.8(2C),19.5(6C).HRMS(ESI)calcd.for C 16 H 20 N 2 [M+H] + : 241.1703; found:241.1699.
11a(1R,2R)-1,2-二(2-氯代苯基)乙二胺11a(1R,2R)-1,2-bis(2-chlorophenyl)ethylenediamine
Figure PCTCN2020088988-appb-000051
Figure PCTCN2020088988-appb-000051
白色固体；76％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,13.24min(S,S),16.62min(R,R).旋光:[α] D 27＝-28.43°[c＝1.47,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.57(d,J＝7.50Hz,2H),7.28(d,J＝7.50Hz,2H),7.23(t,J＝7.50Hz,2H),7.14(t,J＝7.50Hz,2H),4.76(s,2H),2.00(s,4H). 13C NMR(125MHz,CDCl 3):δ140.2(2C),133.0(2C),129.6(2C),128.6(2C),128.3(2C),126.8(2C),55.2(2C).HRMS(ESI)calcd.for C 14H 14Cl 2N 2[M+H] +:281.0615；found:281.0607. White solid; 76% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20/ 0.1,23℃, flow rate 0.8mL/min, 13.24min(S,S), 16.62min(R,R). Optical rotation: [α] D 27 ＝-28.43°[c＝1.47,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ 7.57 (d, J = 7.50 Hz, 2H), 7.28 (d, J = 7.50 Hz, 2H), 7.23 (t, J = 7.50 Hz, 2H), 7.14 (t, J =7.50Hz, 2H), 4.76 (s, 2H), 2.00 (s, 4H). 13 C NMR (125MHz, CDCl 3 ): δ 140.2 (2C), 133.0 (2C), 129.6 (2C), 128.6 ( 2C),128.3(2C),126.8(2C),55.2(2C).HRMS(ESI)calcd.for C 14 H 14 Cl 2 N 2 [M+H] + : 281.0615; found: 281.0607.
12a(1R,2R)-1,2-二(2-溴代苯基)乙二胺12a(1R,2R)-1,2-bis(2-bromophenyl)ethylenediamine
Figure PCTCN2020088988-appb-000052
Figure PCTCN2020088988-appb-000052
白色固体；65％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,14.63min(S,S),18.16min(R,R).旋光:[α] D 27＝-49.0°[c＝1.00,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.54(d,J＝7.90Hz,2H),7.46(d,J＝8.00Hz,2H),7.24(d,J＝8.00Hz,2H),7.04(t,J＝7.70Hz,2H),4.67(s,2H),1.78(s,4H). 13C NMR(125MHz,CDCl 3):δ142.2(2C),132.9(2C),128.8(2C),128.6(2C),127.5(2C),123.7(2C),58.1(2C).HRMS(ESI)calcd.for C 14H 14Br 2N 2[M+H] +:368.9601；found:368.9597. White solid; 65% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20/ 0.1,23℃, flow rate 0.8mL/min, 14.63min(S,S), 18.16min(R,R). Optical rotation: [α] D 27 ＝-49.0°[c＝1.00,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7.54 (d, J = 7.90 Hz, 2H), 7.46 (d, J = 8.00 Hz, 2H), 7.24 (d, J = 8.00 Hz, 2H), 7.04 (t, J =7.70Hz, 2H), 4.67 (s, 2H), 1.78 (s, 4H). 13 C NMR (125MHz, CDCl 3 ): δ142.2 (2C), 132.9 (2C), 128.8 (2C), 128.6 ( 2C),127.5(2C),123.7(2C),58.1(2C).HRMS(ESI)calcd.for C 14 H 14 Br 2 N 2 [M+H] + :368.9601; found: 368.9597.
13a(1R,2R)-1,2-二(2-取代呋喃)乙二胺13a(1R,2R)-1,2-bis(2-substituted furan)ethylenediamine
Figure PCTCN2020088988-appb-000053
Figure PCTCN2020088988-appb-000053
无色液体；77％yield；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,20.86min(S,S),23.13min(R,R).旋光:[α] D 21＝20.9°[c＝1.04,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.33(s,2H),6.28(d,J＝1.95Hz,2H),6.15(d,J＝3.20Hz,3H),4.27(s,2H),1.87(s,4H). 13C NMR(125MHz,CDCl 3):δ155.9(2C),141.6(2C),110.2(2C),106.0(2C),54.0(2C).HRMS(ESI)calcd.for C 10H 12N 2O 2[M+H] +:193.0966；found:193.0972.[M+Na] +:215.0785；found:215.0791. Colorless liquid; 77% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20/ 0.1,23℃, flow rate 0.8mL/min, 20.86min(S,S),23.13min(R,R). Optical rotation: [α] D 21 ＝20.9°[c＝1.04,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.33 (s, 2H), 6.28 (d, J=1.95 Hz, 2H), 6.15 (d, J = 3.20 Hz, 3H), 4.27 (s, 2H), 1.87 (s, 4H). 13 C NMR(125MHz, CDCl 3 ): δ155.9(2C), 141.6(2C), 110.2(2C), 106.0(2C), 54.0(2C).HRMS(ESI)calcd.for C 10 H 12 N 2 O 2 [M+H] + : 193.0966; found: 193.0972. [M+Na] + : 215.0785; found: 215.0791.
14a(1R,2R)-1,2-二(2-取代噻吩)乙二胺14a(1R,2R)-1,2-bis(2-substituted thiophene)ethylenediamine
Figure PCTCN2020088988-appb-000054
Figure PCTCN2020088988-appb-000054
无色液体；71％产率；96.5％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,18.58min(S,S),19.38min(R,R).旋光:[α] D 27＝39.8°[c＝1.80,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.20(d,J＝5.0Hz,2H),6.94(d,J＝4.4Hz,2H),6.90(d,J＝3.4Hz,2H),4.43(s,2H),1.81(s,4H). 13C NMR(125MHz,CDCl 3):δ147.3(2C),126.7(2C),124.1(2C),123.8(2C),58.4(2C).HRMS(ESI)calcd.for C 10H 12N 2S 2[M+H] +:225.0512；found:225.0515. Colorless liquid; 71% yield; 96.5% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1,23℃,flow rate 0.8mL/min,18.58min(S,S),19.38min(R,R). Optical rotation: [α] D 27 ＝39.8°[c=1.80,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7.20(d,J=5.0Hz,2H), 6.94(d,J=4.4Hz,2H), 6.90(d,J=3.4Hz,2H), 4.43(s,2H ), 1.81(s, 4H). 13 C NMR(125MHz, CDCl 3 ): δ147.3(2C), 126.7(2C), 124.1(2C), 123.8(2C), 58.4(2C).HRMS(ESI) calcd.for C 10 H 12 N 2 S 2 [M+H] + :225.0512; found:225.0515.
15a(1R,2R)-1,2-二(3-取代噻吩)乙二胺15a(1R,2R)-1,2-bis(3-substituted thiophene)ethylenediamine
Figure PCTCN2020088988-appb-000055
Figure PCTCN2020088988-appb-000055
无色液体；81％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,21.55min(S,S),22.68min(R,R).旋光:[α] D 27＝9.2°[c＝1.53,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.28-7.25(m,2H),7.12(d,J＝2.4Hz,2H),6.98(d,J＝5.0Hz,2H),4.23(s,2H),1.67(s,4H). 13C NMR(125MHz,CDCl 3):δ144.6(2C),126.3(2C),125.7(2C),121.0(2C),57.7(2C).HRMS(ESI)calcd.for C 10H 12N 2S 2[M+H] +:225.0512；found:225.0515. Colorless liquid; 81% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1,23℃,flow rate 0.8mL/min,21.55min(S,S),22.68min(R,R). Optical rotation: [α] D 27 ＝9.2°[c＝1.53,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7.28-7.25(m,2H), 7.12(d,J=2.4Hz,2H), 6.98(d,J=5.0Hz,2H), 4.23(s,2H), 1.67 (s,4H). 13 C NMR(125MHz, CDCl 3 ): δ144.6(2C), 126.3(2C), 125.7(2C), 121.0(2C), 57.7(2C).HRMS(ESI)calcd.for C 10 H 12 N 2 S 2 [M+H] + :225.0512; found:225.0515.
16a(1R,2R)-1,2-二(3-三氟甲基苯基)乙二胺16a(1R,2R)-1,2-bis(3-trifluoromethylphenyl)ethylenediamine
Figure PCTCN2020088988-appb-000056
Figure PCTCN2020088988-appb-000056
无色液体；59％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,13.39min(S,S),14.69min(R,R).Optical rotation:[α] D 27＝26.4°[c＝0.73,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.51-7.34(m,8H),4.12(s,2H),1.63(s,4H). 13C NMR(125MHz,CDCl 3):δ143.9(2C),130.6(q,J＝34.14Hz,2C),130.3(2C),128.7(2C),124.4(q,J＝270.8Hz,2C),124.1(2C),123.8(2C),61.9(2C). 19F NMR(376MHz,cdcl 3):δ-62.7(2F).HRMS(ESI)calcd.for C 16H 14F 6N 2[M+H] +:349.1139；found:349.1134. Colorless liquid; 59% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1,23℃,flow rate 0.8mL/min,13.39min(S,S),14.69min(R,R).Optical rotation:[α] D 27 ＝26.4°[c＝0.73,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7.51-7.34 (m, 8H), 4.12 (s, 2H), 1.63 (s, 4H). 13 C NMR (125MHz, CDCl 3 ): δ143.9 (2C), 130.6(q,J=34.14Hz,2C),130.3(2C),128.7(2C),124.4(q,J=270.8Hz,2C),124.1(2C),123.8(2C),61.9(2C). 19 F NMR(376MHz,cdcl 3 ):δ-62.7(2F).HRMS(ESI)calcd.for C 16 H 14 F 6 N 2 [M+H] + : 349.1139; found: 349.1134.
17a(1R,2R)-1,2-二(2-取代[1,1'-联苯基])乙二胺17a(1R,2R)-1,2-bis(2-substituted[1,1'-biphenyl])ethylenediamine
Figure PCTCN2020088988-appb-000057
Figure PCTCN2020088988-appb-000057
白色固体；33％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,8.43min(S,S),9.30min(R,R).旋光:[α] D 29＝33.7°[c＝0.50,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.34-7.33(m,6H),7.15-7.00(m,6H),6.99-6.87(m,6H),4.24(s,2H),2.80(s,4H). 13C NMR(125MHz,CDCl 3):δ141.8(2C),140.7(2C),138.3(2C),129.7(2C),129.4(2C),129.1(2C),128.4(2C),128.0(2C),127.9(2C),126.9(2C),126.9(2C),126.8(2C),56.7(2C).HRMS(ESI)calcd.for C 26H 24N 2,[M+H] +:365.2015；found:365.2012. White solid; 33% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20/ 0.1,23℃, flow rate 0.8mL/min, 8.43min(S,S), 9.30min(R,R). Optical rotation: [α] D 29 ＝33.7°[c＝0.50,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.34-7.33 (m, 6H), 7.15-7.00 (m, 6H), 6.99-6.87 (m, 6H), 4.24 (s, 2H), 2.80 (s, 4H). 13 C NMR (125MHz, CDCl 3 ): δ141.8(2C), 140.7(2C), 138.3(2C), 129.7(2C), 129.4(2C), 129.1(2C), 128.4(2C), 128.0(2C) ,127.9(2C),126.9(2C),126.9(2C),126.8(2C),56.7(2C).HRMS(ESI)calcd.for C 26 H 24 N 2, [M+H] + :365.2015; found :365.2012.
18a(1R,2R)-1,2-二(3-氯代苯基)乙二胺18a(1R,2R)-1,2-bis(3-chlorophenyl)ethylenediamine
Figure PCTCN2020088988-appb-000058
Figure PCTCN2020088988-appb-000058
黄色液体；65％产率；92％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速0.8mL/min,17.58min(S,S),18.29min(R,R).旋光:[α] D 27＝52.0°[c＝1.30,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.29(s,2H),7.20(d,J＝4.60Hz,4H),7.12-7.09(m,2H),4.03(s,2H),1.59(s,4H). 13C NMR(125MHz,CDCl 3):δ145.2(2C),126.3(2C),134.3(2C),129.6(2C),127.4(2C),127.0(2C),125.1(2C),61.4(2C).HRMS(ESI)calcd.for C 14H 14Cl 2N 2[M+H] +:281.0607；found:281.0607. Yellow liquid; 65% yield; 92% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20/ 0.1,23℃, flow rate 0.8mL/min, 17.58min(S,S), 18.29min(R,R). Optical rotation: [α] D 27 ＝52.0°[c＝1.30,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.29 (s, 2H), 7.20 (d, J = 4.60Hz, 4H), 7.12-7.09 (m, 2H), 4.03 (s, 2H), 1.59 (s, 4H). 13 C NMR (125MHz, CDCl 3 ): δ145.2(2C), 126.3(2C), 134.3(2C), 129.6(2C), 127.4(2C), 127.0(2C), 125.1(2C), 61.4(2C) ).HRMS(ESI)calcd.for C 14 H 14 Cl 2 N 2 [M+H] + :281.0607; found:281.0607.
19a(1R,2R)-1,2-二(2-取代萘基)乙二胺19a(1R,2R)-1,2-bis(2-substituted naphthyl)ethylenediamine
Figure PCTCN2020088988-appb-000059
Figure PCTCN2020088988-appb-000059
白色固体；64％产率；99％ee；ee值由其衍生物所得.旋光:[α] D 27＝61.23°[c＝1.00,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.83-7.68(m,8H),7.43(d,J＝6.6Hz,6H),4.46(s,2H),2.51(s,4H). 13C NMR(125MHz,CDCl 3):δ140.0(2C),133.2(2C),132.7(2C),128.0(2C),127.9(2C),127.6(2C),126.0(2C),125.7(4C),125.3(2C),61.3(2C).HRMS(ESI)calcd.for C 22H 20N 2[M+H] +:313.1701；found:313.1699. White solid; 64% yield; 99% ee; ee value obtained from its derivatives. Optical rotation: [α] D 27 ＝61.23°[c＝1.00, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7 .83-7.68(m,8H),7.43(d,J=6.6Hz,6H), 4.46(s,2H),2.51(s,4H). 13 C NMR(125MHz, CDCl 3 ): δ140.0( 2C), 133.2(2C), 132.7(2C), 128.0(2C), 127.9(2C), 127.6(2C), 126.0(2C), 125.7(4C), 125.3(2C), 61.3(2C).HRMS( ESI)calcd.for C 22 H 20 N 2 [M+H] + :313.1701; found:313.1699.
(4R,5R)-4,5-二(2-取代萘基)2-咪唑烷酮(4R,5R)-4,5-bis(2-substituted naphthyl)2-imidazolidinone
Figure PCTCN2020088988-appb-000060
Figure PCTCN2020088988-appb-000060
将手性二胺(31.2mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，三光气(10mg,0.033mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在5摄氏度以下。滴加完成后，让温度上升到室温后，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (31.2mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), triphosgene (10mg, 0.033mmol) was dissolved in DCM (2.0ml), and added dropwise In the above system, keep the temperature below 5 degrees Celsius. After the dropwise addition is completed, the temperature is allowed to rise to room temperature, and the mixture is stirred for 3-4 hours, and the reaction is completed (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：70/30/0.1,23℃,流速1.0mL/min,230nm,18.70min(S,S),28.63min(R,R).Optical rotation:[α] D 27＝151.37°[c＝0.25,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.87(t,J＝7.9Hz,4H),7.80-7.77(m,2H),7.71(s,2H),7.53-7.48(m,4H),7.44(dd,J＝8.5,1.8Hz,2H),5.05(s,2H),4.86(s,2H). 13C NMR(125MHz,CDCl 3):δ137.2(1C),133.4(2C),133.2(2C),129.0(2C),128.0(2C),127.8(2C),126.6(2C),126.4(2C),125.7(2C),124.0(2C),66.0(2C).HRMS(ESI)calcd.for C 23H 18N 2O,[M+H] +:339.1496；found:339.1492,[M+Na] +:361.1315；found:365.1311. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 70/30/0.1, 23℃, Flow rate 1.0mL/min,230nm,18.70min(S,S),28.63min(R,R).Optical rotation:[α] D 27 ＝151.37°[c＝0.25,CHCl 3 ]. 1 H NMR(500MHz, CDCl 3 ): δ7.87(t,J=7.9Hz,4H),7.80-7.77(m,2H),7.71(s,2H),7.53-7.48(m,4H),7.44(dd,J=8.5 , 1.8Hz, 2H), 5.05 (s, 2H), 4.86 (s, 2H). 13 C NMR (125MHz, CDCl 3 ): δ 137.2 (1C), 133.4 (2C), 133.2 (2C), 129.0 ( 2C),128.0(2C),127.8(2C),126.6(2C),126.4(2C),125.7(2C),124.0(2C),66.0(2C).HRMS(ESI)calcd.for C 23 H 18 N 2 O, [M+H] + : 339.1496; found: 339.1492, [M+Na] + : 361.1315; found: 365.1311.
20a(1R,2R)-1,2-二(1-取代萘基)乙二胺20a(1R,2R)-1,2-bis(1-substituted naphthyl)ethylenediamine
Figure PCTCN2020088988-appb-000061
Figure PCTCN2020088988-appb-000061
白色固体；61％yield；73％ee；ee值由其衍生物所得.旋光:[α] D 27＝-32.88°[c＝1.20,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ8.30(d,J＝8.50Hz,2H),7.88(d,J＝8.10Hz,2H),7.78(dd,J＝18.20,7.70Hz,4H).7.58(t,J＝7.60Hz,2H),7.48(dt,J＝15.50,7.60Hz,4H),5.12(s,2H),1.81(s,4H). 13C NMR(125MHz,CDCl 3):δ139.5(2C),133.9(2C),130.9(2C),129.1(2C),127.7(2C),126.0(2C),125.5(2C),125.4(2C),124.2(2C),122.9(2C),54.4(2C).HRMS(ESI)calcd.for C 22H 20N 2[M+H] +:313.1701；found:313.1699. White solid; 61% yield; 73% ee; ee value obtained from its derivatives. Optical rotation: [α] D 27 ＝-32.88°[c=1.20, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ8 .30(d,J＝8.50Hz,2H),7.88(d,J＝8.10Hz,2H),7.78(dd,J＝18.20,7.70Hz,4H).7.58(t,J＝7.60Hz,2H) ,7.48(dt,J=15.50,7.60Hz,4H),5.12(s,2H),1.81(s,4H). 13 C NMR(125MHz,CDCl 3 ):δ139.5(2C),133.9(2C) , 130.9(2C), 129.1(2C), 127.7(2C), 126.0(2C), 125.5(2C), 125.4(2C), 124.2(2C), 122.9(2C), 54.4(2C).HRMS(ESI) calcd.for C 22 H 20 N 2 [M+H] + :313.1701; found:313.1699.
(4R,5R)-4,5-二(1-取代萘基)2-咪唑烷酮(4R,5R)-4,5-bis(1-substituted naphthyl)2-imidazolidinone
Figure PCTCN2020088988-appb-000062
Figure PCTCN2020088988-appb-000062
将手性二胺(31.2mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，三光气(10mg,0.033mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在5摄氏度以下。滴加完成后，让温度上升到室温后，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (31.2mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), triphosgene (10mg, 0.033mmol) was dissolved in DCM (2.0ml), and added dropwise In the above system, keep the temperature below 5 degrees Celsius. After the dropwise addition is completed, the temperature is allowed to rise to room temperature, and the mixture is stirred for 3-4 hours, and the reaction is completed (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；73％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：70/30/0.1,23℃,流速1.0mL/min,250nm,18.28min(S,S),29.19min(R,R).旋光:[α] D  27＝-77.78°[c＝0.55,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.85(d,J＝8.2Hz,4H),7.80(d,J＝7.2Hz,2H),7.53(t,J＝7.7Hz,2H),7.40(dt,J＝15.0,8.1Hz,4H),7.11(t,J＝7.7Hz,2H),5.55(s,2H),5.43(s,2H). 13C NMR(125MHz,CDCl 3):δ162.6(1C),136.6(2C),133.9(2C),130.5(2C),129.0(2C),128.8(2C),126.1(2C),125.8(2C),125.6(2C),124.1(2C),122.8(2C),61.3(2C).HRMS(ESI)calcd.for C 23H 18N 2O,[M+H] +:339.1496；found:339.1492,[M+Na] +:361.1315；found:365.1311. White solid; 73% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 70/30/0.1, 23℃, Flow rate 1.0mL/min, 250nm, 18.28min(S,S), 29.19min(R,R). Optical rotation: [α] D 27 ＝-77.78°[c＝0.55,CHCl 3 ]. 1 H NMR(500MHz, CDCl 3 ): δ7.85(d,J=8.2Hz,4H), 7.80(d,J=7.2Hz,2H), 7.53(t,J=7.7Hz,2H), 7.40(dt,J=15.0, 8.1Hz, 4H), 7.11 (t, J = 7.7 Hz, 2H), 5.55 (s, 2H), 5.43 (s, 2H). 13 C NMR (125MHz, CDCl 3 ): δ 162.6 (1C), 136.6 (2C), 133.9(2C), 130.5(2C), 129.0(2C), 128.8(2C), 126.1(2C), 125.8(2C), 125.6(2C), 124.1(2C), 122.8(2C), 61.3 (2C).HRMS(ESI)calcd.for C 23 H 18 N 2 O, [M+H] + : 339.1496; found: 339.1492, [M+Na] + : 361.1315; found: 365.1311.
21a(1R,2R)-1,2-二(4-炔取代苯基)乙二胺21a(1R,2R)-1,2-bis(4-acetylenic substituted phenyl)ethylenediamine
Figure PCTCN2020088988-appb-000063
Figure PCTCN2020088988-appb-000063
黄色固体；90％yield；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,23℃,流速1.2mL/min,29.35min(R,R),33.11min(S,S).旋光:[α] D 25＝214.5[c＝1.00,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.38(d,J＝8.2Hz,4H),7.17(d,J＝8.2Hz,4H),4.03(s,2H),3.05(s,2H),1.64(s,4H). 13C NMR(126MHz,CDCl 3):δ143.9(2C),132.0(4C),126.9(4C),120.8(2C),83.4(2C),77.2(2C),61.8(2C).ESI-MS:M/z 261.00[M+H] +.HRMS(ESI)calcd.for C 18H 17N 2[M+H] +:261.1386；found:261.1389. Yellow solid; 90% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/0.1 , 23℃, flow rate 1.2mL/min, 29.35min(R,R), 33.11min(S,S). Optical rotation: [α] D 25 ＝214.5[c＝1.00,CHCl 3 ]. 1 H NMR(500MHz, CDCl 3 ): δ7.38(d,J=8.2Hz,4H),7.17(d,J=8.2Hz,4H),4.03(s,2H),3.05(s,2H),1.64(s,4H) . 13 C NMR(126MHz, CDCl 3 ): δ143.9(2C), 132.0(4C), 126.9(4C), 120.8(2C), 83.4(2C), 77.2(2C), 61.8(2C). ESI- MS: M/z 261.00[M+H] + .HRMS(ESI)calcd.for C 18 H 17 N 2 [M+H] + :261.1386; found: 261.1389.
22a(1R,2R)-1,2-二(4-三氟甲氧基取代苯基)乙二胺22a(1R,2R)-1,2-bis(4-trifluoromethoxy substituted phenyl)ethylenediamine
Figure PCTCN2020088988-appb-000064
Figure PCTCN2020088988-appb-000064
无色液体；79％yield；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,23℃,流速1.2mL/min,14.42min(R,R),22.76min(S,S).旋光:[α] D 20＝50.6[c＝1.61,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.24(d,J＝8.6Hz,4H),7.11(d,J＝8.2Hz,4H),4.04(s,2H),1.71(s,4H). 13C NMR(126MHz,CDCl 3):δ148.2(q,J＝1.9Hz,2C),141.7(2C),128.2(4C),120.7(4C),120.4(q,J＝257.5Hz,2C),61.5(2C). 19F NMR(376MHz,CDCl 3):δ-58.4(6F).ESI-MS:M/z 381.05[M+H] +.HRMS(ESI)calcd.for C 16H 15F 6N 2O 2[M+H] +:381.1032；found:381.1034. Colorless liquid; 79% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1,23℃, flow rate 1.2mL/min, 14.42min(R,R), 22.76min(S,S). Optical rotation: [α] D 20 ＝50.6[c＝1.61,CHCl 3 ]. 1 H NMR(500MHz ,CDCl 3 ):δ7.24(d,J=8.6Hz,4H),7.11(d,J=8.2Hz,4H),4.04(s,2H),1.71(s,4H). 13 C NMR(126MHz ,CDCl 3 ):δ148.2(q,J=1.9Hz,2C),141.7(2C),128.2(4C),120.7(4C),120.4(q,J=257.5Hz,2C),61.5(2C) . 19 F NMR(376MHz,CDCl 3 ):δ-58.4(6F).ESI-MS:M/z 381.05[M+H] + .HRMS(ESI)calcd.for C 16 H 15 F 6 N 2 O 2 [M+H] + :381.1032; found:381.1034.
23a(1R,2R)-1,2-二(3-乙氧基取代苯基)乙二胺23a(1R,2R)-1,2-bis(3-ethoxy substituted phenyl)ethylenediamine
Figure PCTCN2020088988-appb-000065
Figure PCTCN2020088988-appb-000065
白色固体；86％yield；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,23℃,流速1.2mL/min,22.04min(S,S),32.63min(R,R).旋光:[α] D 25＝50.1[c＝0.62,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.19(t,J＝7.8Hz,2H),6.90-6.83(m,4H),6.75(dd,J＝7.9,2.4Hz,2H),4.07(s,2H),4.04-3.94(m,4H),1.61(s,4H),1.39(t,J＝6.9Hz,6H). 13C NMR(126MHz,CDCl 3):δ158.9(2C),145.0(2C),129.2(2C),119.1(2C),113.1(2C),113.0(2C),63.3(2C),61.6(2C),14.9(2C).ESI-MS:M/z 301.15[M+H] +.HRMS(ESI)calcd.for C 18H 25N 2O 2[M+H] +:301.1911；found:301.1912. White solid; 86% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/0.1 ,23℃,flow rate 1.2mL/min,22.04min(S,S),32.63min(R,R). Optical rotation: [α] D 25 ＝50.1[c＝0.62,CHCl 3 ]. 1 H NMR(500MHz, CDCl 3 ): δ7.19(t,J=7.8Hz,2H), 6.90-6.83(m,4H), 6.75(dd,J=7.9,2.4Hz,2H), 4.07(s,2H), 4.04- 3.94 (m, 4H), 1.61 (s, 4H), 1.39 (t, J = 6.9 Hz, 6H). 13 C NMR (126MHz, CDCl 3 ): δ 158.9 (2C), 145.0 (2C), 129.2 ( 2C),119.1(2C),113.1(2C),113.0(2C),63.3(2C),61.6(2C),14.9(2C).ESI-MS:M/z 301.15(M+H) + .HRMS( ESI)calcd.for C 18 H 25 N 2 O 2 [M+H] + :301.1911; found:301.1912.
24a(1R,2R)-1,2-二(3,5-二氟取代苯基)乙二胺24a(1R,2R)-1,2-bis(3,5-difluoro-substituted phenyl)ethylenediamine
Figure PCTCN2020088988-appb-000066
Figure PCTCN2020088988-appb-000066
无色液体；90％yield；93％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：75/25/0.08,23℃,流速1.2mL/min,26.70min(S,S),30.56min(R,R).旋光:[α] D 20＝39.6[c＝1.52,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ6.82(d,J＝6.4Hz,4H),6.68(tt,J＝8.4,2.1Hz,2H),4.02(s,2H),1.55(s,4H). 13C NMR(126MHz,CDCl 3):δ162.9(dd,J＝248.8,12.7Hz,4C),147.1(t,J＝8.2Hz,2C),110.0-109.5(m,4C), 102.8(t,J＝25.5Hz,2C),61.2(2C). 19F NMR(376MHz,CDCl 3):δ-109.9(4F).ESI-MS:M/z 284.95[M+H] +.HRMS(ESI)calcd.for C 14H 13F 4N 2[M+H] +:285.1009；found:285.1002. Colorless liquid; 90% yield; 93% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 75/25/ 0.08,23℃, flow rate 1.2mL/min,26.70min(S,S),30.56min(R,R). Optical rotation: [α] D 20 ＝39.6[c＝1.52,CHCl 3 ]. 1 H NMR(500MHz ,CDCl 3 ):δ6.82(d,J=6.4Hz,4H),6.68(tt,J=8.4,2.1Hz,2H),4.02(s,2H),1.55(s,4H). 13 C NMR (126MHz, CDCl 3 ): δ 162.9 (dd, J = 248.8, 12.7 Hz, 4C), 147.1 (t, J = 8.2 Hz, 2C), 110.0-109.5 (m, 4C), 102.8 (t, J = 25.5Hz, 2C), 61.2(2C). 19 F NMR(376MHz, CDCl 3 ): δ-109.9(4F).ESI-MS: M/z 284.95[M+H] + .HRMS(ESI)calcd.for C 14 H 13 F 4 N 2 [M+H] + :285.1009; found:285.1002.
25a(1R,2R)-1,2-二(3,5-二甲基取代苯基)乙二胺25a(1R,2R)-1,2-bis(3,5-dimethyl substituted phenyl)ethylenediamine
Figure PCTCN2020088988-appb-000067
Figure PCTCN2020088988-appb-000067
无色液体；90％yield；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,23℃,流速1.2mL/min,6.16min(S,S),22.76min(R,R).旋光:[α] D 25＝38.4[c＝0.71,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ6.95(s,4H),6.87(s,2H),4.11(s,2H),2.36(s,4H),2.29(s,12H). 13C NMR(126MHz,CDCl 3):δ142.6(2C),137.8(4C),128.8(2C),124.7(4C),60.9(2C),21.4(4C).ESI-MS:M/z 269.10[M+H] +.HRMS(ESI)calcd.for C 18H 25N 2[M+H] +:269.2012；found:269.2015. Colorless liquid; 90% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20/ 0.1,23℃, flow rate 1.2mL/min, 6.16min(S,S), 22.76min(R,R). Optical rotation: [α] D 25 ＝38.4[c＝0.71,CHCl 3 ]. 1 H NMR(500MHz , CDCl 3 ): δ 6.95 (s, 4H), 6.87 (s, 2H), 4.11 (s, 2H), 2.36 (s, 4H), 2.29 (s, 12H). 13 C NMR (126MHz, CDCl 3 ):δ142.6(2C),137.8(4C),128.8(2C),124.7(4C),60.9(2C),21.4(4C).ESI-MS:M/z 269.10(M+H) + .HRMS (ESI)calcd.for C 18 H 25 N 2 [M+H] + :269.2012; found:269.2015.
26a(1R,2R)-1,2-二(呋喃3-取代)乙二胺26a(1R,2R)-1,2-bis(furan 3-substituted)ethylenediamine
Figure PCTCN2020088988-appb-000068
Figure PCTCN2020088988-appb-000068
无色液体；91％yield；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：95/5/0.05,23℃,流速0.8mL/min,12.87min(R,R),15.84min(S,S).旋光:[α] D 25＝-37.4[c＝0.41,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.38-7.37(m,2H),7.35(s,2H),6.32(s,2H),4.01(s,2H),1.56(s,4H). 13C NMR(126MHz,CDCl 3):δ143.1(2C),139.6(2C),127.5(2C),109.0(2C),53.3(2C).ESI-MS:M/z 192.95[M+H] +.HRMS(ESI)calcd.for C 10H 13N 2O 2,[M+H] +:193.0972；found:193.0974. Colorless liquid; 91% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 95/5/ 0.05,23℃, flow rate 0.8mL/min, 12.87min(R,R), 15.84min(S,S). Optical rotation: [α] D 25 ＝-37.4[c＝0.41,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ 7.38-7.37 (m, 2H), 7.35 (s, 2H), 6.32 (s, 2H), 4.01 (s, 2H), 1.56 (s, 4H). 13 C NMR (126MHz) ,CDCl 3 ):δ143.1(2C),139.6(2C),127.5(2C),109.0(2C),53.3(2C).ESI-MS:M/z 192.95[M+H] + .HRMS(ESI )calcd.for C 10 H 13 N 2 O 2, [M+H] + :193.0972; found:193.0974.
27a N,N’-(((1R,2R)-1,2-二胺基乙烷-1,2-二(4,1-苯基)-二氮甲基苯甲酰胺27a N,N’-(((1R,2R)-1,2-diaminoethane-1,2-bis(4,1-phenyl)-diazomethylbenzamide
Figure PCTCN2020088988-appb-000069
Figure PCTCN2020088988-appb-000069
微黄色液体；90％yield；96％ee；ee值由其衍生物所得.旋光:[α] D 25＝-39.4[c＝1.35,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.25-7.20(m,6H),7.13(t,J＝7.6Hz,4H),6.93(d,J＝8.2Hz,4H),6.86(d,J＝8.1Hz,4H),3.85(s,2H),3.44(s,6H),1.60(s,4H). 13C NMR(126 MHz,CDCl 3):δ170.6(2C),143.8(2C),141.1(2C),136.0(2C),129.6(2C),128.7(4C),127.7(4C),127.6(4C),126.5(4C),61.6(2C),38.4(2C).ESI-MS:M/z 501.45[M+Na] +；HRMS(ESI)calcd.for C 30H 30N 4NaO 2[M+Na] +:501.2261；found:501.2269. Slight yellow liquid; 90% yield; 96% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 ＝-39.4 [c=1.35, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7 .25-7.20 (m, 6H), 7.13 (t, J = 7.6 Hz, 4H), 6.93 (d, J = 8.2 Hz, 4H), 6.86 (d, J = 8.1 Hz, 4H), 3.85 (s, 2H), 3.44(s, 6H), 1.60(s, 4H). 13 C NMR(126 MHz, CDCl 3 ): δ170.6(2C), 143.8(2C), 141.1(2C), 136.0(2C), 129.6(2C), 128.7(4C), 127.7(4C), 127.6(4C), 126.5(4C), 61.6(2C), 38.4(2C). ESI-MS: M/z 501.45[M+Na] + ; HRMS(ESI)calcd.for C 30 H 30 N 4 NaO 2 [M+Na] + :501.2261; found:501.2269.
N,N'-(((4R,5R)-2-咪唑烷酮-4,5-双)二(4,1-苯基))-二氮甲基苯甲酰胺N,N'-(((4R,5R)-2-imidazolidinone-4,5-bis)bis(4,1-phenyl))-diazomethylbenzamide
Figure PCTCN2020088988-appb-000070
Figure PCTCN2020088988-appb-000070
将手性二胺(47.8mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，三光气(10mg,0.033mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在5摄氏度以下。滴加完成后，让温度上升到室温后，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (47.8mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), triphosgene (10mg, 0.033mmol) was dissolved in DCM (2.0ml), and added dropwise In the above system, keep the temperature below 5 degrees Celsius. After the dropwise addition is completed, the temperature is allowed to rise to room temperature, and the mixture is stirred for 3-4 hours, and the reaction is completed (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；96％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：70/30/0.1,23℃,流速1.3mL/min,250nm,35.45min(R,R),56.80min(S,S).旋光:[α] D  25＝57.8[c＝1.35,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.24(dd,J＝12.7,7.3Hz,6H),7.15(t,J＝7.6Hz,4H),6.96(s,8H),5.38(s,2H),4.34(s,2H),3.47(s,6H). 13C NMR(126MHz,CDCl 3):δ170.6(2C),143.8(2C),141.1(2C),136.0(2C),129.6(2C),128.7(4C),127.7(4C),127.6(4C),126.5(4C),61.6(2C),38.4(2C).ESI-MS:M/z 505.45[M+H] +；527.50[M+Na] +.ESI-MS:M/z 505.45[M+H] +.HRMS(ESI)calcd.for C 31H 29N 4O 3[M+H] +:505.2234；found:505.2229.C 31H 28N 4O 3Na[M+Na] +:527.2054；found:527.2053. White solid; 96% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 70/30/0.1, 23℃, Flow rate 1.3mL/min, 250nm, 35.45min(R,R), 56.80min(S,S). Optical rotation: [α] D 25 ＝57.8[c＝1.35,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ7.24(dd,J=12.7,7.3Hz,6H), 7.15(t,J=7.6Hz,4H), 6.96(s,8H),5.38(s,2H), 4.34(s,2H) , 3.47(s, 6H). 13 C NMR(126MHz, CDCl 3 ): δ170.6(2C), 143.8(2C), 141.1(2C), 136.0(2C), 129.6(2C), 128.7(4C), 127.7(4C),127.6(4C),126.5(4C),61.6(2C),38.4(2C).ESI-MS:M/z 505.45[M+H] + ;527.50[M+Na] + .ESI- MS: M/z 505.45[M+H] + .HRMS(ESI)calcd.for C 31 H 29 N 4 O 3 [M+H] + :505.2234; found: 505.2229. C 31 H 28 N 4 O 3 Na [M+Na] + :527.2054; found:527.2053.
28a(8S,9R,13R,14R)-3-((1R,2R)-1,2-二氨基-2-((8R,9S,13S,14S)-13-甲基-17-氧-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊[a]菲-3-基)乙基)-13-甲基-6,7,8,9,11,12,13,14,15,16-十氢-17H-环戊[a]菲-17-酮28a(8S,9R,13R,14R)-3-((1R,2R)-1,2-diamino-2-((8R,9S,13S,14S)-13-methyl-17-oxy-7 ,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta(a)phenanthrene-3-yl)ethyl)-13-methyl-6,7,8, 9,11,12,13,14,15,16-decahydro-17H-cyclopentan[a]phenanthrene-17-one
Figure PCTCN2020088988-appb-000071
Figure PCTCN2020088988-appb-000071
白色固体；70％yield；88:12dr；dr值由高压手性液相测定；高压液相条件：手性柱IC, 正己烷/异丙醇/二乙胺：80/20/0.1,25℃,流速1.0mL/min,3.74min(S,S),5.16min(R,R).旋光:[α] D 25＝98.9[c＝1.91,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.26(d,J＝7.7Hz,2H),7.16(d,J＝7.8Hz,2H),7.07(s,2H),4.11(s,2H),2.94-2.87(m,4H),2.56-2.37(m,4H),2.30(d,J＝9.7Hz,2H),2.07(m,8H),1.53(m,16H). 13C NMR(126MHz,CDCl 3):δ220.9(2C),141.0(2C),138.6(2C),136.4(2C),127.6(2C),125.4(2C),124.2(2C),60.8(2C),50.6(2C),48.1(2C),44.5(2C),38.3(2C),36.0(2C),31.7(2C),29.6(2C),26.7(2C),25.9(2C),21.7(2C),14.0(2C).ESI-MS:M/z 565.70[M+H] +；HRMS(ESI)calcd.for C 38H 49N 2O 2[M+H] +:565.3787；found:565.3788. White solid; 70% yield; 88: 12dr; dr value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column IC, n-hexane/isopropanol/diethylamine: 80/20/0.1, 25℃ , Flow rate 1.0mL/min, 3.74min(S,S), 5.16min(R,R). Optical rotation: [α] D 25 ＝98.9[c＝1.91,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ) :δ7.26(d,J=7.7Hz,2H), 7.16(d,J=7.8Hz,2H), 7.07(s,2H), 4.11(s,2H),2.94-2.87(m,4H), 2.56-2.37(m,4H), 2.30(d,J=9.7Hz,2H), 2.07(m,8H), 1.53(m,16H). 13 C NMR(126MHz, CDCl 3 ): δ220.9(2C ), 141.0(2C), 138.6(2C), 136.4(2C), 127.6(2C), 125.4(2C), 124.2(2C), 60.8(2C), 50.6(2C), 48.1(2C), 44.5(2C) ),38.3(2C),36.0(2C),31.7(2C),29.6(2C),26.7(2C),25.9(2C),21.7(2C),14.0(2C).ESI-MS:M/z 565.70 [M+H] + ;HRMS(ESI)calcd.for C 38 H 49 N 2 O 2 [M+H] + :565.3787;found:565.3788.
实施例2甲基取代的芳香亚胺底物拓展Example 2 Expansion of methyl-substituted aromatic imine substrates
Figure PCTCN2020088988-appb-000072
Figure PCTCN2020088988-appb-000072
在干净干燥的Shlenk管中，加入氮甲基取代的芳基亚胺(0.2mmol，1.0eq)，DB4(0.11mmol,0.55eq)，体系抽换氮气三次，氮气保护下，加入重蒸四氢呋喃2.0ml，密封，室温下搅拌12-24h。停止反应，加入盐酸(3.0M，1ml)调pH至3左右，二氯甲烷洗涤，有机相浓缩后经正己烷打浆回收diol 5(95％回收率)，水相加入氢氧化钠溶液调pH至12左右，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，旋干即得到产物。In a clean and dry Shlenk tube, add nitrogen methyl substituted arylimine (0.2mmol, 1.0eq), DB4 (0.11mmol, 0.55eq), the system is pumped with nitrogen three times, under the protection of nitrogen, add redistilled tetrahydrofuran 2.0 ml, seal, and stir at room temperature for 12-24h. Stop the reaction, add hydrochloric acid (3.0M, 1ml) to adjust the pH to about 3, wash with dichloromethane, concentrate the organic phase and beat with n-hexane to recover diol 5 (95% recovery), add sodium hydroxide solution to the aqueous phase to adjust the pH to At around 12, extract with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, and spin to dry to obtain the product.
1c(1R,2R)-N 1,N 2-二甲基-1,2-二(4-甲基苯基)乙二胺 1c(1R,2R)-N 1 ,N 2 -Dimethyl-1,2-bis(4-methylphenyl)ethylenediamine
Figure PCTCN2020088988-appb-000073
Figure PCTCN2020088988-appb-000073
白色固体；75％yield；97％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,7.65min_(S,S),_8.26min(R,R).旋光:[α] D 28＝38.53°[c＝0.38,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ6.99(d,J＝8.0Hz,4H),6.95(d,J＝8.0Hz,4H),3.52(s,2H),2.26(s,6H),2.24(s,6H),2.06(brs,2H). 13C NMR(125MHz,CDCl 3):δ138.0(2C),136.5(2C),128.8(2C),128.0(2C),70.7(2C),34.7(2C),21.3(2C).HRMS(ESI)calcd.for C 18H 25N 2[M+H] +:269.2012；found:269.2011. White solid; 75% yield; 97% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/0.1 , 25℃, flow rate 0.7mL/min, 7.65min_(S,S),_8.26min(R,R). Optical rotation: [α] D 28 ＝38.53°[c＝0.38,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ 6.99 (d, J = 8.0 Hz, 4H), 6.95 (d, J = 8.0 Hz, 4H), 3.52 (s, 2H), 2.26 (s, 6H), 2.24 (s, 6H), 2.06 (brs, 2H). 13 C NMR (125MHz, CDCl 3 ): δ 138.0 (2C), 136.5 (2C), 128.8 (2C), 128.0 (2C), 70.7 (2C), 34.7 (2C) ),21.3(2C).HRMS(ESI)calcd.for C 18 H 25 N 2 [M+H] + :269.2012; found:269.2011.
2c(1R,2R)-1,2-二(4-甲氧基苯基)-N 1,N 2-二甲基乙二胺 2c(1R,2R)-1,2-bis(4-methoxyphenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000074
Figure PCTCN2020088988-appb-000074
白色固体；76％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,16.78min(R,R),21.54min(S,S).旋光:[α] D 28＝9.4°[c＝0.90,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ6.95(d,J＝8.6Hz,4H),6.71(d,J＝8.6Hz,4H),3.74(s,6H),3.55(s,2H),2.27(s,6H). 13C NMR(125MHz,CDCl 3):δ158.7(2C),132.2(2C),129.2(4C),113.6(4C),70.2(2C),55.3(2C),34.3(2C).HRMS(ESI)calcd.for C 18H 25N 2O 2[M+H] +:301.1911；found:301.1918. White solid; 76% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1, 25℃, flow rate 0.7mL/min, 16.78min(R,R), 21.54min(S,S). Optical rotation: [α] D 28 ＝9.4°[c＝0.90,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ 6.95 (d, J = 8.6 Hz, 4H), 6.71 (d, J = 8.6 Hz, 4H), 3.74 (s, 6H), 3.55 (s, 2H), 2.27 (s, 6H). 13 C NMR (125MHz, CDCl 3 ): δ 158.7 (2C), 132.2 (2C), 129.2 (4C), 113.6 (4C), 70.2 (2C), 55.3 (2C), 34.3 (2C). HRMS(ESI)calcd.for C 18 H 25 N 2 O 2 [M+H] + :301.1911; found:301.1918.
3c(1R,2R)-1,2-二(4-氟代苯基)-N 1,N 2-二甲基乙二胺 3c(1R,2R)-1,2-bis(4-fluorophenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000075
Figure PCTCN2020088988-appb-000075
白色固体；55％产率；98％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,7.00min(R,R),10.20min(S,S).旋光:[α] D 28＝55.4°[c＝0.75,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ6.94(m,4H),6.84(m,4H),3.45(s,2H),2.23(s,6H),2.13(s,2H). 13C NMR(125MHz,CDCl 3):δ162.9(2C),161.0(2C),136.6(d,J＝3.0Hz,2C),129.4(d,J＝8.0Hz,4C),115.0(d,J＝21.3Hz,4C),70.8(2C),34.6(2C). 19F NMR(376MHz,CDCl 3):δ-114.8(2F).HRMS(ESI)calcd.for C 16H 19F 2N 2[M+H] +:277.1511；found:277.1516. White solid; 55% yield; 98% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1, 25℃, flow rate 0.7mL/min, 7.00min(R,R), 10.20min(S,S). Optical rotation: [α] D 28 ＝55.4°[c＝0.75,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ 6.94 (m, 4H), 6.84 (m, 4H), 3.45 (s, 2H), 2.23 (s, 6H), 2.13 (s, 2H). 13 C NMR (125MHz, CDCl 3 ): δ162.9(2C), 161.0(2C), 136.6(d, J=3.0Hz, 2C), 129.4(d, J=8.0Hz, 4C), 115.0(d, J=21.3Hz, 4C) ,70.8(2C),34.6(2C). 19 F NMR(376MHz, CDCl 3 ):δ-114.8(2F).HRMS(ESI)calcd.for C 16 H 19 F 2 N 2 [M+H] + : 277.1511; found:277.1516.
4c(1R,2R)-1,2-二(4-氯代苯基)-N 1,N 2-二甲基乙二胺 4c(1R,2R)-1,2-bis(4-chlorophenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000076
Figure PCTCN2020088988-appb-000076
白色固体；80％产率；98％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,7.70min(R,R),11.99min(S,S).旋光:[α] D 28＝89.7°[c＝0.08,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.14(d,J＝8.1Hz,4H),6.94(d,J＝8.1Hz,4H),3.47(s,2H),2.23(s,6H). 13C NMR(125MHz,CDCl 3):δ139.3(2C),132.9(2C),129.4(4C),128.5(4C),70.6(2C),34.6(2C).HRMS(ESI)calcd.for C 16H 19Cl 2N 2[M+H] +:309.0920；found:309.0917. White solid; 80% yield; 98% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1, 25℃, flow rate 0.7mL/min, 7.70min(R,R), 11.99min(S,S). Optical rotation: [α] D 28 ＝89.7°[c＝0.08,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.14 (d, J = 8.1 Hz, 4H), 6.94 (d, J = 8.1 Hz, 4H), 3.47 (s, 2H), 2.23 (s, 6H). 13 C NMR ( 125MHz, CDCl 3 ): δ139.3(2C), 132.9(2C), 129.4(4C), 128.5(4C), 70.6(2C), 34.6(2C).HRMS(ESI)calcd.for C 16 H 19 Cl 2 N 2 [M+H] + :309.0920; found:309.0917.
5c(1R,2R)-1,2-二(4-溴代苯基)-N 1,N 2-二甲基乙二胺 5c(1R,2R)-1,2-bis(4-bromophenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000077
Figure PCTCN2020088988-appb-000077
白色固体；73％产率；98％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,8.55min(R,R),13.00min(S,S).旋光:[α] D 28＝64.8°[c＝1.0,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.29(d,J＝8.3Hz,4H),6.88(d,J＝8.3Hz,4H),3.44(s,2H),2.22(s,6H),2.06(s,2H). 13C NMR(125MHz,CDCl 3):δ139.9(2C),131.4(4C),129.8(4C),121.1(2C),70.6(2C),34.6(2C).HRMS(ESI)calcd.for C 16H 19Br 2N 2[M+H] +:396.9910；found:396.9906. White solid; 73% yield; 98% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1, 25℃, flow rate 0.7mL/min, 8.55min(R,R), 13.00min(S,S). Optical rotation: [α] D 28 ＝64.8°[c＝1.0,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.29 (d, J = 8.3Hz, 4H), 6.88 (d, J = 8.3Hz, 4H), 3.44 (s, 2H), 2.22 (s, 6H), 2.06 (s, 2H). 13 C NMR(125MHz, CDCl 3 ): δ139.9(2C), 131.4(4C), 129.8(4C), 121.1(2C), 70.6(2C), 34.6(2C).HRMS(ESI)calcd .for C 16 H 19 Br 2 N 2 [M+H] + :396.9910; found:396.9906.
6c(1R,2R)-N 1,N 2-二甲基-1,2-二(4-三氟甲氧基苯基)乙二胺 6c(1R,2R)-N 1 ,N 2 -Dimethyl-1,2-bis(4-trifluoromethoxyphenyl)ethylenediamine
反应原料制备Reaction raw material preparation
在干净干燥的Shlenk管中，加入对位三氟甲氧基取代苯甲醛(5.7g,30mmol，1.0eq)，无水硫酸镁(7.2g,60mmol,2.0equiv)和甲胺盐酸盐(2.4g,36mmol,1.2equiv)溶解在二氯甲烷(25mL)，反应体系在0℃缓慢滴加三乙胺(8.4mL,60mmol,2.0equiv).反应室温下反应3小时，硅藻土过滤，滤渣用乙醚洗涤，滤液收集，合并并旋干，可以得到反应粗产物，可直接投入到反应当中。In a clean and dry Shlenk tube, add para-trifluoromethoxy-substituted benzaldehyde (5.7g, 30mmol, 1.0eq), anhydrous magnesium sulfate (7.2g, 60mmol, 2.0equiv) and methylamine hydrochloride (2.4 g, 36mmol, 1.2equiv) was dissolved in dichloromethane (25mL), and triethylamine (8.4mL, 60mmol, 2.0equiv) was slowly added dropwise to the reaction system at 0°C. The reaction was reacted at room temperature for 3 hours, filtered through Celite, and the residue was filtered. Wash with ether, collect the filtrate, combine and spin dry to obtain the crude reaction product, which can be directly put into the reaction.
(E)-N-甲基-1-(4-三氟甲氧基苯基)甲基亚胺(E)-N-methyl-1-(4-trifluoromethoxyphenyl)methylimine
Figure PCTCN2020088988-appb-000078
Figure PCTCN2020088988-appb-000078
黄色液体；95％产率. 1H NMR(500MHz,CDCl 3):δ8.32(m,1H),8.07(d,J＝8.4Hz,2H),7.76(d,J＝8.3Hz,2H),3.92(t,J＝2.3Hz,3H),3.54(d,J＝2.0Hz,3H)； 13C NMR(126MHz,CDCl 3):δ166.6,161.5,140.1,131.7,129.8,127.7,52.2,48.4；ESI-MS:M/z 178.25[M+H] +；HRMS(ESI)calcd.for C 10H 12NO 2[M+H] +:178.0863；found:178.0863. Yellow liquid; 95% yield. 1 H NMR (500MHz, CDCl 3 ): δ 8.32 (m, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H) ,3.92(t,J=2.3Hz,3H),3.54(d,J=2.0Hz,3H); 13 C NMR(126MHz,CDCl 3 ):δ166.6,161.5,140.1,131.7,129.8,127.7,52.2,48.4 ;ESI-MS:M/z 178.25[M+H] + ;HRMS(ESI)calcd.for C 10 H 12 NO 2 [M+H] + :178.0863;found:178.0863.
Figure PCTCN2020088988-appb-000079
Figure PCTCN2020088988-appb-000079
白色固体；49％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,8.55min(R,R),13.00min(S,S).旋光:[α] D 29＝22.8°[c＝0.48,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.02(m,8H),3.59(s,2H),2.75(s,2H),2.29(s,6H). 19F NMR(376MHz,CDCl 3):δ-58.0(2F).HRMS(ESI)calcd.for C 18H 19F 6N 2O 2[M+H] +:409.1345；found:409.1350. White solid; 49% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1, 25℃, flow rate 0.7mL/min, 8.55min(R,R), 13.00min(S,S). Optical rotation: [α] D 29 ＝22.8°[c＝0.48,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.02 (m, 8H), 3.59 (s, 2H), 2.75 (s, 2H), 2.29 (s, 6H). 19 F NMR (376MHz, CDCl 3 ): δ-58.0 ( 2F).HRMS(ESI)calcd.for C 18 H 19 F 6 N 2 O 2 [M+H] + :409.1345; found:409.1350.
7c(1R,2R)-1,2-二(2-甲氧基苯基)-N 1,N 2-二甲基乙二胺 7c(1R,2R)-1,2-bis(2-methoxyphenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000080
Figure PCTCN2020088988-appb-000080
白色固体；77％yield；80％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,8.07min(R,R),8.87min(S,S).旋光:[α] D 29＝44.4°[c＝0.30,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.12(d,J＝7.4Hz,2H),7.03(ddd,J＝8.3,7.4,1.8Hz,2H),6.74(t,J＝7.4Hz,2H),6.61(dd,J＝8.2Hz,2H),4.04(s,4H),3.60(s,6H),2.58(brs,2H),2.25(s,6H). 13C NMR(125MHz,CDCl 3):δ158.0 (2C),129.3(2C),127.6(2C),120.1(2C),110.2(2C)，110.1(2C),55.3(2C),34.7(2C).HRMS(ESI)calcd.for C 18H 25N 2O 2[M+H] +:301.1911；found:301.1912 White solid; 77% yield; 80% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/0.1 , 25℃, flow rate 0.7mL/min, 8.07min(R,R), 8.87min(S,S). Optical rotation: [α] D 29 ＝44.4°[c＝0.30,CHCl 3 ]. 1 H NMR(500MHz ,CDCl 3 ): δ7.12(d,J=7.4Hz,2H), 7.03(ddd,J=8.3,7.4,1.8Hz,2H), 6.74(t,J=7.4Hz,2H), 6.61(dd ,J = 8.2Hz, 2H), 4.04 (s, 4H), 3.60 (s, 6H), 2.58 (brs, 2H), 2.25 (s, 6H). 13 C NMR (125MHz, CDCl 3 ): δ158.0 (2C),129.3(2C),127.6(2C),120.1(2C),110.2(2C),110.1(2C),55.3(2C),34.7(2C).HRMS(ESI)calcd.for C 18 H 25 N 2 O 2 [M+H] + :301.1911; found:301.1912
8c(1R,2R)-N 1,N 2-二甲基-1,2-二邻甲苯基乙二胺 8c(1R,2R)-N 1 ,N 2 -Dimethyl-1,2-di-o-tolylethylenediamine
Figure PCTCN2020088988-appb-000081
Figure PCTCN2020088988-appb-000081
白色固体；67％产率；93％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,8.07min(R,R),8.87min(S,S).旋光:[α] D 28＝9.2°[c＝0.46,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.49(dd,J＝7.8,1.3Hz,2H),7.15(t,J＝7.4Hz,2H),7.02(td,J＝7.4,1.3Hz,2H),6.87(d,J＝7.4Hz,2H),3.93(s,2H),2.33(brs,2H),2.24(s,6H),1.92(s,6H). 13C NMR(125MHz,CDCl 3):δ139.7(2C),137.1(2C),130.0(2C),126.9(2C),126.7(2C),125.9(2C),65.5(2C),34.4(2C),19.7(2C).HRMS(ESI)calcd.for C 18H 25N 2[M+H] +:269.2012；found:269.2017. White solid; 67% yield; 93% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1, 25℃, flow rate 0.7mL/min, 8.07min(R,R), 8.87min(S,S). Optical rotation: [α] D 28 ＝9.2°[c＝0.46,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.49 (dd, J = 7.8, 1.3 Hz, 2H), 7.15 (t, J = 7.4 Hz, 2H), 7.02 (td, J = 7.4, 1.3 Hz, 2H), 6.87 ( d, J = 7.4Hz, 2H), 3.93 (s, 2H), 2.33 (brs, 2H), 2.24 (s, 6H), 1.92 (s, 6H). 13 C NMR (125MHz, CDCl 3 ): δ139. 7(2C), 137.1(2C), 130.0(2C), 126.9(2C), 126.7(2C), 125.9(2C), 65.5(2C), 34.4(2C), 19.7(2C).HRMS(ESI)calcd .for C 18 H 25 N 2 [M+H] + :269.2012; found:269.2017.
9c(1R,2R)-1,2-二(3-氯代苯基)-N 1,N 2-二甲基乙二胺 9c(1R,2R)-1,2-bis(3-chlorophenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000082
Figure PCTCN2020088988-appb-000082
白色固体；58％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,8.07min(R,R),8.87min(S,S).旋光:[α] D 20＝-452.8°[c＝1.30,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.16-7.08(m,6H),6.90(m,1H),3.58(s,2H),2.29(s,6H).HRMS(ESI)calcd.for C 16H 19Cl 2N 2[M+H] +:309.0920；found:309.0924. White solid; 58% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1, 25℃, flow rate 0.7mL/min, 8.07min(R,R), 8.87min(S,S). Optical rotation: [α] D 20 ＝-452.8°[c＝1.30,CHCl 3 ]. 1 H NMR (500MHz,CDCl 3 ):δ7.16-7.08(m,6H),6.90(m,1H),3.58(s,2H),2.29(s,6H).HRMS(ESI)calcd.for C 16 H 19 Cl 2 N 2 [M+H] + :309.0920; found: 309.0924.
10c(1R,2R)-1,2-二(3-氟代苯基)-N 1,N 2-二甲基乙二胺 10c(1R,2R)-1,2-bis(3-fluorophenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000083
Figure PCTCN2020088988-appb-000083
白色固体；83％产率；98％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,7.31min(R,R),8.73min(S,S).旋光:[α] D 28＝13.4°[c＝1.05,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.14-7.13(m,2H),6.85-6.78(m,6H),3.54(s 2H),2.65(brs,2H),2.27(s,6H). 13C NMR(125MHz,CDCl 3):δ163.9(2C),162.0(2C),143.0(2C),129.7(2C),123.8(2C),114.5(2C),70.7(2C),34.5(2C). 19F NMR(376MHz,CDCl 3):δ-113.4(2F).HRMS(ESI)calcd.for C 16H 19F 2N 2[M+H] +:277.1511；found:277.1517. White solid; 83% yield; 98% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1, 25℃, flow rate 0.7mL/min, 7.31min(R,R), 8.73min(S,S). Optical rotation: [α] D 28 ＝13.4°[c＝1.05,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.14-7.13 (m, 2H), 6.85-6.78 (m, 6H), 3.54 (s 2H), 2.65 (brs, 2H), 2.27 (s, 6H). 13 C NMR ( 125MHz, CDCl 3 ): δ163.9(2C), 162.0(2C), 143.0(2C), 129.7(2C), 123.8(2C), 114.5(2C), 70.7(2C), 34.5(2C). 19 F NMR(376MHz,CDCl 3 ):δ-113.4(2F).HRMS(ESI)calcd.for C 16 H 19 F 2 N 2 [M+H] + : 277.1511; found: 277.1517.
11c(1R,2R)-N 1,N 2-二甲基-1,2-二(1-取代萘基)乙二胺 11c(1R,2R)-N 1 ,N 2 -Dimethyl-1,2-bis(1-substituted naphthyl)ethylenediamine
Figure PCTCN2020088988-appb-000084
Figure PCTCN2020088988-appb-000084
白色固体；59％产率；70％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,8.07min(R,R),8.87min(S,S).旋光:[α] D 29＝-114.0°[c＝0.21,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ8.19(m,2H),7.71-7.58(m,6H),7.37-7.33(m,6H),4.74(s,2H),2.36(s,2H),2.25(s,6H). 13C NMR(125MHz,CDCl 3):δ137.1(2C),133.9(2C),132.4(2C),128.8(2C),127.8(2C),125.6(2C),125.4(2C),125.2(4C),123.3(2C),35.0(2C).HRMS(ESI)calcd.for C 24H 25N 2[M+H] +:341.2012；found:341.2014. White solid; 59% yield; 70% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1, 25℃, flow rate 0.7mL/min, 8.07min(R,R), 8.87min(S,S). Optical rotation: [α] D 29 ＝-114.0°[c＝0.21,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ8.19 (m, 2H), 7.71-7.58 (m, 6H), 7.37-7.33 (m, 6H), 4.74 (s, 2H), 2.36 (s, 2H), 2.25 ( s, 6H). 13 C NMR (125MHz, CDCl 3 ): δ137.1(2C), 133.9(2C), 132.4(2C), 128.8(2C), 127.8(2C), 125.6(2C), 125.4(2C) ),125.2(4C),123.3(2C),35.0(2C).HRMS(ESI)calcd.for C 24 H 25 N 2 [M+H] + :341.2012; found:341.2014.
12c(1R,2R)-N 1,N 2-二甲基-1,2-二(2-取代萘基)乙二胺 12c(1R,2R)-N 1 ,N 2 -Dimethyl-1,2-bis(2-substituted naphthyl)ethylenediamine
Figure PCTCN2020088988-appb-000085
Figure PCTCN2020088988-appb-000085
白色固体；59％产率；90％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,25℃,流速0.7mL/min,8.07min(R,R),8.87min(S,S).旋光:[α] D 29＝80.0°[c＝0.31,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.71(m,2H),7.66(d,J＝8.5Hz,2H),7.59(m,2H),7.39(m,4H),7.27(dd,J＝8.5,1.7Hz,2H),3.89(s,2H),2.29(s,6H),2.20(brs,2H). 13C NMR(125MHz,CDCl 3):δ138.3(2C),133.3(2C),132.9(2C),128.0(2C),127.9(2C),127.7(2C),127.3(2C),126.0(2C),125.9(2C),125.7(2C),70.9(2C), 34.8(2C).HRMS(ESI)calcd.for C 24H 25N 2[M+H] +:341.2012；found:341.2015. White solid; 59% yield; 90% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1, 25℃, flow rate 0.7mL/min, 8.07min(R,R), 8.87min(S,S). Optical rotation: [α] D 29 ＝80.0°[c＝0.31,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.71 (m, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.59 (m, 2H), 7.39 (m, 4H), 7.27 (dd, J = 8.5, 1.7 Hz, 2H), 3.89 (s, 2H), 2.29 (s, 6H), 2.20 (brs, 2H). 13 C NMR (125MHz, CDCl 3 ): δ 138.3 (2C), 133.3 (2C), 132.9 ( 2C), 128.0(2C), 127.9(2C), 127.7(2C), 127.3(2C), 126.0(2C), 125.9(2C), 125.7(2C), 70.9(2C), 34.8(2C).HRMS( ESI)calcd.for C 24 H 25 N 2 [M+H] + :341.2012; found:341.2015.
13c(1R,2R)-1,2-二苯基-N 1,N 2-二甲基乙二胺 13c(1R,2R)-1,2-Diphenyl-N 1 ,N 2 -Dimethylethylenediamine
Figure PCTCN2020088988-appb-000086
Figure PCTCN2020088988-appb-000086
白色固体；91％产率；98％ee；ee值由高压手性液相测定；高压液相条件：手性柱IB,正己烷/异丙醇/四氢呋喃：100/0.1/0.1,25℃,流速0.5mL/min,8.85min(S,S),9.53min(R,R).旋光:[α] D 25＝33.6[c＝0.90,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.14-7.13(m,2H),6.85-6.78(m,6H),3.54(s 2H),2.65(brs,2H),2.27(s,6H). 13C NMR(125MHz,CDCl 3):δδ7.17-7.10(m,6H),7.03(d,J＝7.3Hz,4H),3.54(s,2H),2.25(s,6H),2.17(s,2H). 13C NMR(126MHz,CDCl 3):δ140.5(2C),128.0(4C),127.9(4C),127.0(2C),71.0(2C),34.4(6C).ESI-MS:M/z 240.35[M+H] +.HRMS(ESI)calcd.for C 16H 21N 2[M+H] +:241.1699；found:241.1703. White solid; 91% yield; 98% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column IB, n-hexane/isopropanol/tetrahydrofuran: 100/0.1/0.1, 25℃, Flow rate 0.5mL/min, 8.85min(S,S), 9.53min(R,R). Optical rotation: [α] D 25 ＝33.6[c＝0.90,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ7.14-7.13 (m, 2H), 6.85-6.78 (m, 6H), 3.54 (s 2H), 2.65 (brs, 2H), 2.27 (s, 6H). 13 C NMR (125MHz, CDCl 3 ): δδ7.17-7.10 (m, 6H), 7.03 (d, J = 7.3Hz, 4H), 3.54 (s, 2H), 2.25 (s, 6H), 2.17 (s, 2H). 13 C NMR (126MHz, CDCl 3 ): δ140.5(2C), 128.0(4C), 127.9(4C), 127.0(2C), 71.0(2C), 34.4(6C). ESI-MS: M/z 240.35(M+H) + .HRMS(ESI)calcd.for C 16 H 21 N 2 [M+H] + :241.1699; found:241.1703.
14c(1R,2R)-1,2-二(4-甲酸甲酯取代苯基)-N 1,N 2-二甲基乙二胺 14c(1R,2R)-1,2-bis(4-methyl formate substituted phenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000087
Figure PCTCN2020088988-appb-000087
白色固体；83％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,23℃,流速1.0mL/min,6.97min(R,R),8.58min(S,S).旋光:[α] D 25＝77.2[c＝0.98,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.80(d,J＝8.2Hz,4H),7.06(d,J＝8.3Hz,4H),3.85(s,6H),3.56(s,2H),2.23(s,6H),2.07(s,2H). 13C NMR(126MHz,CDCl 3):δ166.8(2C),146.1(2C),129.4(4C),129.0(2C),127.9(4C),70.9(2C),52.0(2C),34.4(2C).ESI-MS:M/z 357.10[M+H] +.HRMS(ESI)calcd.for C 20H 25N 2O 2[M+H] +:357.1809；found:357.1810. White solid; 83% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1,23℃, flow rate 1.0mL/min, 6.97min(R,R), 8.58min(S,S). Optical rotation: [α] D 25 ＝77.2[c＝0.98,CHCl 3 ]. 1 H NMR(500MHz ,CDCl 3 ): δ7.80(d,J=8.2Hz,4H), 7.06(d,J=8.3Hz,4H), 3.85(s,6H),3.56(s,2H),2.23(s,6H) ), 2.07(s, 2H). 13 C NMR(126MHz, CDCl 3 ): δ166.8(2C), 146.1(2C), 129.4(4C), 129.0(2C), 127.9(4C), 70.9(2C) ,52.0(2C),34.4(2C).ESI-MS:M/z 357.10[M+H] + .HRMS(ESI)calcd.for C 20 H 25 N 2 O 2 [M+H] + :357.1809; found:357.1810.
15c(1R,2R)-1,2-二(4-乙炔取代苯基)-N 1,N 2-二甲基乙二胺 15c(1R,2R)-1,2-bis(4-acetylene substituted phenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000088
Figure PCTCN2020088988-appb-000088
灰色固体；93％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,23℃,流速1.0mL/min,5.05min(R,R),6.15min(S,S).旋光:[α] D 25＝154.4[c＝0.60,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.28(d,J＝7.4Hz,4H),6.95(d,J＝7.5Hz,4H),3.48(s,2H),3.02(s,2H),2.22(s,6H),1.97(s,2H). 13C NMR(126MHz,CDCl 3):δ141.2(2C),131.9(4C),127.9(4C),120.8(2C),83.5(2C),77.1(2C),70.5(2C),34.3(2C).ESI-MS:M/z 289.05[M+H] +.HRMS(ESI)calcd.for C 20H 21N 2[M+H] +:289.1699；found:289.1700. Gray solid; 93% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1,23℃, flow rate 1.0mL/min,5.05min(R,R),6.15min(S,S). Optical rotation: [α] D 25 ＝154.4[c＝0.60,CHCl 3 ]. 1 H NMR(500MHz ,CDCl 3 ):δ7.28(d,J=7.4Hz,4H), 6.95(d,J=7.5Hz,4H), 3.48(s,2H),3.02(s,2H),2.22(s,6H) ), 1.97(s, 2H). 13 C NMR(126MHz, CDCl 3 ): δ141.2(2C), 131.9(4C), 127.9(4C), 120.8(2C), 83.5(2C), 77.1(2C) ,70.5(2C),34.3(2C).ESI-MS:M/z 289.05[M+H] + .HRMS(ESI)calcd.for C 20 H 21 N 2 [M+H] + :289.1699; found: 289.1700.
16c(1R,2R)-1,2-二(2-氯代苯基)-N 1,N 2-二甲基乙二胺 16c(1R,2R)-1,2-bis(2-chlorophenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000089
Figure PCTCN2020088988-appb-000089
白色固体；88％产率；97％ee；ee值由其衍生物所得.旋光:[α] D 20＝-53.6[c＝0.86,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.47(d,J＝7.8Hz,2H),7.17(t,J＝7.5Hz,2H),7.13(d,J＝7.7Hz,2H),7.05(td,J＝8.1,1.6Hz,2H),4.37(s,2H),2.42(s,2H),2.27(s,6H). 13C NMR(126MHz,CDCl 3):δ134.8(2C),134.5(2C),129.5(2C),129.4(2C),129.1(2C),127.2(2C),63.8(2C),33.1(2C).ESI-MS:M/z 309.05[M+H] +.HRMS(ESI)calcd.for C 16H 19Cl 2N 2[M+H] +:309.0920；found:309.0926. White solid; 88% yield; 97% ee; ee value obtained from its derivatives. Optical rotation: [α] D 20 ＝ -53.6 [c = 0.86, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7 .47(d,J=7.8Hz,2H), 7.17(t,J=7.5Hz,2H), 7.13(d,J=7.7Hz,2H), 7.05(td,J=8.1,1.6Hz,2H) , 4.37 (s, 2H), 2.42 (s, 2H), 2.27 (s, 6H). 13 C NMR (126MHz, CDCl 3 ): δ 134.8 (2C), 134.5 (2C), 129.5 (2C), 129.4 (2C),129.1(2C),127.2(2C),63.8(2C),33.1(2C).ESI-MS:M/z 309.05[M+H] + .HRMS(ESI)calcd.for C 16 H 19 Cl 2 N 2 [M+H] + :309.0920; found: 309.0926.
N,N’-((1R,2R)-1,2-二(2-氯取代苯基)乙烷-1,2-取代)双氮甲基苯甲酰胺N,N’-((1R,2R)-1,2-bis(2-chloro-substituted phenyl)ethane-1,2-substituted)bisazamethylbenzamide
Figure PCTCN2020088988-appb-000090
Figure PCTCN2020088988-appb-000090
将手性二胺(31.0mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯 甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (31.0mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；97％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：97/3/0.03,23℃,流速1.2mL/min,250nm,9.68min(R,R),11.59min(S,S).旋光:[α] D 25＝-285.5[c＝1.30,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.49(dd,J＝7.8,1.3Hz,2H),7.15(t,J＝7.4Hz,2H),7.02(td,J＝7.4,1.3Hz,2H),6.87(d,J＝7.4Hz,2H),3.93(s,2H),2.33(s,2H),2.24(s,6H),1.92(s,6H). 13C NMR(126MHz,CDCl 3):δ139.7(2C),137.1(2C),130.0(2C),126.9(2C),126.7(2C),125.9(2C),65.5(2C),34.4(2C),19.7(2C).ESI-MS:M/z 517.30[M+H] +.HRMS(ESI)calcd.for C 30H 27N 2Cl 2O 2[M+H] +:517.1444；found:517.1450. White solid; 97% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 97/3/0.03, 23℃, Flow rate 1.2mL/min, 250nm, 9.68min(R,R), 11.59min(S,S). Optical rotation: [α] D 25 ＝-285.5[c＝1.30,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ7.49(dd,J=7.8,1.3Hz,2H), 7.15(t,J=7.4Hz,2H), 7.02(td,J=7.4,1.3Hz,2H), 6.87(d,J ＝7.4Hz, 2H), 3.93(s, 2H), 2.33(s, 2H), 2.24(s, 6H), 1.92(s, 6H). 13 C NMR(126MHz, CDCl 3 ): δ139.7(2C ),137.1(2C),130.0(2C),126.9(2C),126.7(2C),125.9(2C),65.5(2C),34.4(2C),19.7(2C).ESI-MS: M/z 517.30 [M+H] + .HRMS(ESI)calcd.for C 30 H 27 N 2 Cl 2 O 2 [M+H] + :517.1444; found:517.1450.
17c(1R,2R)-1,2-二(2-溴代苯基)-N 1,N 2-二甲基乙二胺 17c(1R,2R)-1,2-bis(2-bromophenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000091
Figure PCTCN2020088988-appb-000091
白色固体；84％产率；95％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：90/10/0.1,23℃,流速1.0mL/min,7.03min(S,S),7.83min(R,R).旋光:[α] D 20＝-122.3[c＝0.36,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.51(d,J＝7.8Hz,2H),7.31(d,J＝8.0Hz,2H),7.23(t,J＝7.6Hz,2H),6.97(t,J＝7.6Hz,2H),4.38(s,2H),2.53(s,2H),2.30(s,6H). 13C NMR(126MHz,CDCl 3):δ139.1(2C),132.4(2C),129.6(2C),128.7(2C),127.4(2C),125.3(2C),67.0(2C),33.8(2C).ESI-MS:M/z 398.95[M+H] +.HRMS(ESI)calcd.for C 16H 19Br 2N 2[M+H] +:396.9910；found:396.9913. White solid; 84% yield; 95% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 90/10/ 0.1,23℃, flow rate 1.0mL/min, 7.03min(S,S), 7.83min(R,R). Optical rotation: [α] D 20 ＝-122.3[c＝0.36,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.51(d,J=7.8Hz,2H), 7.31(d,J=8.0Hz,2H), 7.23(t,J=7.6Hz,2H), 6.97(t,J= 7.6Hz, 2H), 4.38 (s, 2H), 2.53 (s, 2H), 2.30 (s, 6H). 13 C NMR (126MHz, CDCl 3 ): δ 139.1 (2C), 132.4 (2C), 129.6 (2C),128.7(2C),127.4(2C),125.3(2C),67.0(2C),33.8(2C).ESI-MS:M/z 398.95[M+H] + .HRMS(ESI)calcd. for C 16 H 19 Br 2 N 2 [M+H] + :396.9910; found:396.9913.
18c(1R,2R)-1,2-二(3,5-二氟代苯基)-N 1,N 2-二甲基乙二胺 18c(1R,2R)-1,2-bis(3,5-difluorophenyl)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000092
Figure PCTCN2020088988-appb-000092
白色固体；85％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S- Chiral B,正己烷/异丙醇/二乙胺：95/5/0.05,23℃,流速1.2mL/min,4.37min(R,R),5.24min(S,S).旋光:[α] D 20＝66.6[c＝1.36,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ6.62-6.58(m,3.9Hz,6H),3.41(s,2H),2.24(s,6H),1.95(s,2H). 13C NMR(126MHz,CDCl 3):δ162.8(dd,J＝248.8,12.6Hz,4C),145.1(t,J＝8.0Hz,2C),110.6-110.2(m,2C),102.8(t,J＝25.4Hz),70.5(t,J＝2.2Hz,2C),34.4(s,2C). 19F NMR(376MHz,CDCl 3):δ-110.0(4F).ESI-MS:M/z 313.05[M+H] +.HRMS(ESI)calcd.for C 16H 17F 4N 2[M+H] +:313.1323；found:313.1328. White solid; 85% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S- Chiral B, n-hexane/isopropanol/diethylamine: 95/5/ 0.05,23℃, flow rate 1.2mL/min, 4.37min(R,R), 5.24min(S,S). Optical rotation: [α] D 20 ＝66.6[c＝1.36,CHCl 3 ]. 1 H NMR(500MHz , CDCl 3 ): δ6.62-6.58 (m, 3.9Hz, 6H), 3.41 (s, 2H), 2.24 (s, 6H), 1.95 (s, 2H). 13 C NMR (126MHz, CDCl 3 ): δ162.8(dd,J=248.8,12.6Hz,4C),145.1(t,J=8.0Hz,2C),110.6-110.2(m,2C),102.8(t,J=25.4Hz),70.5(t ,J=2.2Hz,2C),34.4(s,2C). 19 F NMR (376MHz, CDCl 3 ): δ-110.0(4F). ESI-MS: M/z 313.05[M+H] + .HRMS( ESI)calcd.for C 16 H 17 F 4 N 2 [M+H] + :313.1323; found:313.1328.
19c(1S,2S)-1,2-二(2-取代呋喃)-N 1,N 2-二甲基乙二胺 19c(1S,2S)-1,2-bis(2-substituted furan)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000093
Figure PCTCN2020088988-appb-000093
无色液体；85％产率；97％ee；ee值由其衍生物所得.旋光:[α] D 25＝-5.6[c＝0.45,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.27-7.25(m,2H),6.17(dd,J＝3.2,1.8Hz,2H),6.05(d,J＝3.2Hz,2H),3.93(s,2H),3.65(s,2H),2.31(s,6H). 13C NMR(126MHz,CDCl 3):δ153.4(2C),141.6(2C),109.8(2C),107.8(2C),61.8(2C),34.3(2C).ESI-MS:M/z 221.30[M+H] +.HRMS(ESI)calcd.for C 12H 17N 2O 2[M+H] +:221.1285；found:221.1286. Colorless liquid; 85% yield; 97% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 = -5.6 [c = 0.45, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7.27-7.25 (m, 2H), 6.17 (dd, J = 3.2, 1.8 Hz, 2H), 6.05 (d, J = 3.2 Hz, 2H), 3.93 (s, 2H), 3.65 (s, 2H) , 2.31 (s, 6H). 13 C NMR (126MHz, CDCl 3 ): δ 153.4 (2C), 141.6 (2C), 109.8 (2C), 107.8 (2C), 61.8 (2C), 34.3 (2C). ESI-MS:M/z 221.30[M+H] + .HRMS(ESI)calcd.for C 12 H 17 N 2 O 2 [M+H] + :221.1285; found:221.1286.
N,N’-((1S,2S)-1,2-二(2-取代呋喃)乙烷-1,2-取代)双氮甲基苯甲酰胺N,N’-((1S,2S)-1,2-bis(2-substituted furan)ethane-1,2-substituted)bisazamethylbenzamide
Figure PCTCN2020088988-appb-000094
Figure PCTCN2020088988-appb-000094
将手性二胺(22.0mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (22.0mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；97％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：97/3/0.03,23℃,流速1.0mL/min,250nm,18.72min(R,R),23.57min(S,S).旋光:[α] D  25＝-266.4[c＝0.95,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.45-7.42(m,5H),7.39-7.35(m,7H),6.85(s,2H),6.29(s,4H),2.91(s,6H). 13C NMR(126MHz,CDCl 3):δ172.0(2C),150.2(2C),142.4(2C),135.9(2C),129.8(2C),128.4(4C),127.2(4C),49.5(2C),33.6(2C).ESI-MS:M/z 451.25[M+Na] +.HRMS(ESI)calcd.for C 26H 24N 2NaO 4[M+Na] +:451.1628；found:451.1633. White solid; 97% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 97/3/0.03, 23℃, Flow rate 1.0mL/min, 250nm, 18.72min(R,R), 23.57min(S,S). Optical rotation: [α] D 25 ＝-266.4[c＝0.95,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ7.45-7.42 (m, 5H), 7.39-7.35 (m, 7H), 6.85 (s, 2H), 6.29 (s, 4H), 2.91 (s, 6H). 13 C NMR (126MHz, CDCl 3 ): δ172.0(2C), 150.2(2C), 142.4(2C), 135.9(2C), 129.8(2C), 128.4(4C), 127.2(4C), 49.5(2C), 33.6(2C) .ESI-MS:M/z 451.25[M+Na] + .HRMS(ESI)calcd.for C 26 H 24 N 2 NaO 4 [M+Na] + :451.1628; found:451.1633.
20c(1R,2R)-1,2-二(3取代呋喃)-N 1,N 2-二甲基乙二胺 20c(1R,2R)-1,2-bis(3-substituted furan)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000095
Figure PCTCN2020088988-appb-000095
黄色液体；88％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：98/2/0.02,23℃,流速1.2mL/min,6.70min(R,R),7.84min(S,S).旋光:[α] D 25＝-33.0[c＝1.09,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.31(t,J＝1.7Hz,2H),7.15(dd,J＝1.5,0.8Hz,2H),6.19-6.18(m,2H),3.50(s,2H),2.31(s,6H),1.80(s,2H). 13C NMR(126MHz,CDCl 3):δ142.9(2C),140.6(2C),124.6(2C),109.0(2C),61.0(2C),34.4(2C).ESI-MS:M/z 221.20[M+H] +.HRMS(ESI)calcd.for C 12H 17N 2O 2[M+H] +:221.1285；found:221.1284. Yellow liquid; 88% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 98/2/ 0.02,23℃, flow rate 1.2mL/min, 6.70min(R,R),7.84min(S,S). Optical rotation: [α] D 25 ＝-33.0[c＝1.09,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.31 (t, J = 1.7Hz, 2H), 7.15 (dd, J = 1.5, 0.8Hz, 2H), 6.19-6.18 (m, 2H), 3.50 (s, 2H), 2.31(s,6H), 1.80(s,2H). 13 C NMR(126MHz, CDCl 3 ): δ142.9(2C), 140.6(2C), 124.6(2C), 109.0(2C), 61.0(2C) ,34.4(2C).ESI-MS:M/z 221.20[M+H] + .HRMS(ESI)calcd.for C 12 H 17 N 2 O 2 [M+H] + : 221.1285; found: 221.1284.
21c(1R,2R)-1,2-二(2-取代噻吩)-N 1,N 2-二甲基乙二胺 21c(1R,2R)-1,2-bis(2-substituted thiophene)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000096
Figure PCTCN2020088988-appb-000096
无色液体；85％产率；97％ee；ee值由其衍生物所得.旋光:[α] D 25＝54.6[c＝0.45,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.15(d,J＝5.0Hz,2H),6.84-6.80(m,2H),6.65(d,J＝3.4Hz,2H),3.83(s,2H),2.37(s,6H),2.03(s,2H). 13C NMR(126MHz,CDCl 3):δ153.4(2C),141.6(2C),109.8(2C),107.8(2C),61.8(2C),34.3(2C).ESI-MS:M/z 253.15[M+H] +.HRMS(ESI)calcd.for C 12H 17N 2S 2[M+H] +:253.0828；found:253.0831. Colorless liquid; 85% yield; 97% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 =54.6 [c = 0.45, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ7 .15(d,J=5.0Hz,2H),6.84-6.80(m,2H),6.65(d,J=3.4Hz,2H),3.83(s,2H),2.37(s,6H),2.03( s, 2H). 13 C NMR(126MHz, CDCl 3 ): δ153.4(2C), 141.6(2C), 109.8(2C), 107.8(2C), 61.8(2C), 34.3(2C).ESI-MS :M/z 253.15[M+H] + .HRMS(ESI)calcd.for C 12 H 17 N 2 S 2 [M+H] + :253.0828; found: 253.0831.
N,N’-((1S,2S)-1,2-二(2-取代噻吩)乙烷-1,2-取代)双氮甲基苯甲酰胺N,N’-((1S,2S)-1,2-bis(2-substituted thiophene)ethane-1,2-substituted)bisazamethylbenzamide
Figure PCTCN2020088988-appb-000097
Figure PCTCN2020088988-appb-000097
将手性二胺(25.2mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (25.2mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；97％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：97/3/0.03,23℃,流速1.0mL/min,250nm,14.13min(R,R),18.37min(S,S).旋光:[α] D 25＝-232.2[c＝0.50,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.49-7.37(m,10H),7.27-7.23(m,2H),7.06(d,J＝8.0Hz,4H),6.91-6.89(m,2H),2.90(s,6H). 13C NMR(126MHz,CDCl 3):δ171.8(2C),139.2(2C),136.0(2C),129.9(2C),128.4(4C),127.8(2C), 127.0(4C),126.6(2C),125.7(2C),51.5(2C),32.8(2C).ESI-MS:M/z 483.25[M+Na] +.HRMS(ESI)calcd.for C 26H 24N 2NaO 2S 2[M+Na] +:483.1171；found:483.1173. White solid; 97% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 97/3/0.03, 23℃, Flow rate 1.0mL/min, 250nm, 14.13min(R,R), 18.37min(S,S). Optical rotation: [α] D 25 ＝-232.2[c＝0.50,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ7.49-7.37(m,10H), 7.27-7.23(m,2H), 7.06(d,J=8.0Hz,4H), 6.91-6.89(m,2H), 2.90(s,6H) . 13 C NMR(126MHz, CDCl 3 ): δ171.8(2C), 139.2(2C), 136.0(2C), 129.9(2C), 128.4(4C), 127.8(2C), 127.0(4C), 126.6( 2C),125.7(2C),51.5(2C),32.8(2C).ESI-MS:M/z 483.25[M+Na] + .HRMS(ESI)calcd.for C 26 H 24 N 2 NaO 2 S 2 [M+Na] + :483.1171; found:483.1173.
22c(1R,2R)-1,2-二(3取代噻吩)-N 1,N 2-二甲基乙二胺 22c(1R,2R)-1,2-bis(3-substituted thiophene)-N 1 ,N 2 -dimethylethylenediamine
Figure PCTCN2020088988-appb-000098
Figure PCTCN2020088988-appb-000098
白色固体；90％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：95/5/0.05,23℃,流速1.2mL/min,4.95min(R,R),5.88min(S,S).旋光:[α] D 20＝-21.6[c＝1.28,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.14(dd,J＝5.1,3.0Hz,2H),6.83(s,2H),6.78(d,J＝4.9Hz,2H),3.68(s,2H),2.28(s,6H),2.04(s,2H). 13C NMR(126MHz,CDCl 3):δ142.2(2C),126.4(2C),125.2(2C),122.1(2C),66.1(2C),34.6(2C).ESI-MS:M/z 253.15[M+H] +.HRMS(ESI)calcd.for C 12H 17N 2S 2[M+H] +:253.0828；found:253.0831. White solid; 90% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 95/5/ 0.05,23℃, flow rate 1.2mL/min, 4.95min(R,R), 5.88min(S,S). Optical rotation: [α] D 20 ＝-21.6[c＝1.28,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): δ7.14 (dd, J = 5.1, 3.0 Hz, 2H), 6.83 (s, 2H), 6.78 (d, J = 4.9 Hz, 2H), 3.68 (s, 2H), 2.28 ( s, 6H), 2.04 (s, 2H). 13 C NMR (126MHz, CDCl 3 ): δ142.2 (2C), 126.4 (2C), 125.2 (2C), 122.1 (2C), 66.1 (2C), 34.6 (2C).ESI-MS:M/z 253.15[M+H] + .HRMS(ESI)calcd.for C 12 H 17 N 2 S 2 [M+H] + : 253.0828; found: 253.0831.
实施例3链状烷基(或环烷基)亚胺底物拓展Example 3 Development of chain alkyl (or cycloalkyl) imine substrates
Figure PCTCN2020088988-appb-000099
Figure PCTCN2020088988-appb-000099
在干净干燥的shlenk管中，加入烷基腈化合物(0.6mmol，1.0eq)溶于四氢呋喃(1mL)，反应体系降至-78℃，体系中小心滴加DIBAL-H(0.6mmol,1.0M in toluene,1.0equiv),体系自然升温，反应3小时，然后降温至-78℃，加入DB4(0.3mmol,0.5eq)和甲醇(0.66mmol,1.1equiv)，自然升至室温，搅拌12h。停止反应，冰水浴条件下加入盐酸(3.0M，1ml)调pH至3左右，二氯甲烷洗涤，有机相浓缩后经正己烷打浆回收diol 5(95％回收率)，水相加入氢氧化钠溶液调pH至12左右，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，旋干即得到产物。In a clean and dry shlenk tube, add the alkyl nitrile compound (0.6mmol, 1.0eq) dissolved in tetrahydrofuran (1mL), the reaction system is reduced to -78℃, and DIBAL-H (0.6mmol, 1.0M in Toluene, 1.0equiv), the system naturally warmed up, reacted for 3 hours, then cooled to -78°C, added DB4 (0.3mmol, 0.5eq) and methanol (0.66mmol, 1.1equiv), naturally warmed to room temperature, and stirred for 12h. Stop the reaction, add hydrochloric acid (3.0M, 1ml) in an ice-water bath to adjust the pH to about 3, wash with dichloromethane, concentrate the organic phase and slurp with n-hexane to recover diol 5 (95% recovery), add sodium hydroxide to the water phase Adjust the pH of the solution to about 12, extract with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, and spin to dry to obtain the product.
1d(5S,6S)-5,6-癸二胺1d(5S,6S)-5,6-decanediamine
Figure PCTCN2020088988-appb-000100
Figure PCTCN2020088988-appb-000100
无色液体；53％产率；99％ee；ee值由其衍生物所得.旋光:[α] D 25＝-20.2[c＝1.20,CHCl 3]. 1H NMR(500MHz,CDCl 3):3.52(s,4H),2.68(s,2H),1.58-1.17(m,12H),0.87(t,J＝6.7Hz,6H)； 13C NMR(126MHz,CDCl 3):δ54.6,33.4,28.3,22.6,14.0；ESI-MS:M/z 173.05, [M+H] +；HRMS(ESI)calcd.for C 10H 25N 2[M+H] +:173.2012；found:173.2018. Colorless liquid; 53% yield; 99% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 =-20.2 [c = 1.20, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): 3.52 (s, 4H), 2.68 (s, 2H), 1.58-1.17 (m, 12H), 0.87 (t, J = 6.7 Hz, 6H); 13 C NMR (126MHz, CDCl 3 ): δ54.6, 33.4 ,28.3,22.6,14.0; ESI-MS: M/z 173.05, [M+H] + ; HRMS(ESI)calcd.for C 10 H 25 N 2 [M+H] + :173.2012; found: 173.2018.
N,N’-((5S,6S)—5,6二苯甲酰胺取代癸烷N,N’-((5S,6S)—5,6 dibenzamide substituted decane
Figure PCTCN2020088988-appb-000101
Figure PCTCN2020088988-appb-000101
将手性二胺(17.2mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (17.2mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱AD-H,正己烷/异丙醇90/10,23℃,流速1.0mL/min,250nm,6.73min(S,S),7.48min(R,R).旋光:[α] D 27＝98.9[c＝1.06,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.66(d,J＝7.0Hz,4H),7.37(t,J＝7.4Hz,2H),7.25(t,J＝7.7Hz,4H),6.89(d,J＝7.6Hz,2H),4.23-4.05(m,2H),1.83-1.77(m,2H),1.64-1.60(m,2H),1.47-1.34(m,8H),0.90(t,J＝7.0Hz,6H)； 13C NMR(126MHz,CDCl 3):δ168.5,134.3,131.2,128.4,126.9,54.3,31.9,28.2,22.6,14.0；ESI-MS:M/z 381.20[M+H] +,403.15[M+Na] +；HRMS(ESI)calcd.for C 24H 33N 2O 2[M+H] +:381.2537；found:381.2543,[M+Na] +:403.2356；found:403.2360. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column AD-H, n-hexane/isopropanol 90/10, 23℃, flow rate 1.0mL/min, 250nm, 6.73min(S,S),7.48min(R,R). Optical rotation: [α] D 27 ＝98.9[c＝1.06,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ7.66(d, J = 7.0Hz, 4H), 7.37 (t, J = 7.4 Hz, 2H), 7.25 (t, J = 7.7 Hz, 4H), 6.89 (d, J = 7.6 Hz, 2H), 4.23-4.05 (m, 2H), 1.83-1.77 (m, 2H), 1.64-1.60 (m, 2H), 1.47-1.34 (m, 8H), 0.90 (t, J = 7.0 Hz, 6H); 13 C NMR (126MHz, CDCl 3 ):δ168.5,134.3,131.2,128.4,126.9,54.3,31.9,28.2,22.6,14.0; ESI-MS: M/z 381.20[M+H] + ,403.15[M+Na] + ; HRMS(ESI)calcd .for C 24 H 33 N 2 O 2 [M+H] + :381.2537; found:381.2543,[M+Na] + :403.2356; found:403.2360.
2d(4S,5S)-4,5-辛二胺2d(4S,5S)-4,5-octanediamine
Figure PCTCN2020088988-appb-000102
Figure PCTCN2020088988-appb-000102
无色液体；54％产率；99％ee；ee值由其衍生物所得.旋光:[α] D 25＝-28.8[c＝1.20,CHCl 3]. 1H NMR(500MHz,CDCl 3):2.50(s,2H),1.49(s,4H),1.39(s,4H),1.32-1.16(m,4H),0.91-0.80(m,6H)； 13C NMR(126MHz,CDCl 3):δ54.9,37.0,19.7,14.2；ESI-MS:M/z 145.05[M+H] +；HRMS(ESI)calcd.for C 8H 21N 2[M+H] +:145.1699；found:145.1701. Colorless liquid; 54% yield; 99% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 =-28.8 [c = 1.20, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): 2.50 (s, 2H), 1.49 (s, 4H), 1.39 (s, 4H), 1.32-1.16 (m, 4H), 0.91-0.80 (m, 6H); 13 C NMR (126MHz, CDCl 3 ): δ54 .9,37.0,19.7,14.2; ESI-MS: M/z 145.05[M+H] + ; HRMS(ESI)calcd.for C 8 H 21 N 2 [M+H] + : 145.1699; found: 145.1701.
N,N’-((4S,5S)-4,5二苯甲酰胺取代辛烷N,N’-((4S,5S)-4,5 dibenzamide substituted octane
Figure PCTCN2020088988-appb-000103
Figure PCTCN2020088988-appb-000103
将手性二胺(14.5mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (14.5mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正 己烷/异丙醇/乙二胺70/30/0.1，1.0mL/min,250nm,12.49min(S,S),17.81min(R,R).旋光:[α] D 20＝-30.9[c＝0.18,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.68(d,J＝7.2Hz,4H),7.40(t,J＝7.4Hz,2H),7.29(t,J＝7.7Hz,4H),6.83(d,J＝7.6Hz,2H),4.22-4.07(m,2H),1.79-1.73(m,2H),1.65-1.58(m,2H),1.54-1.45(m,4H),0.95(t,J＝7.3Hz,6H)； 13C NMR(126MHz,CDCl 3):δ168.5,134.3,131.3,128.4,126.9,54.1,34.5,19.3,14.0；ESI-MS:M/z 353.15[M+H] +,375.10[M+Na] +；HRMS(ESI)calcd.for C 22H 29N 2O 2,[M+H] +:353.2224；found:353.2231,[M+Na] +:375.2043；found:375.2047. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/ethylenediamine 70/30/0.1, 1.0mL/min ,250nm,12.49min(S,S),17.81min(R,R). Optical rotation: [α] D 20 ＝-30.9[c＝0.18,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ7. 68 (d, J = 7.2 Hz, 4H), 7.40 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.7 Hz, 4H), 6.83 (d, J = 7.6 Hz, 2H), 4.22- 4.07 (m, 2H), 1.79-1.73 (m, 2H), 1.65-1.58 (m, 2H), 1.54-1.45 (m, 4H), 0.95 (t, J = 7.3 Hz, 6H); 13 C NMR ( 126MHz,CDCl 3 ):δ168.5,134.3,131.3,128.4,126.9,54.1,34.5,19.3,14.0; ESI-MS: M/z 353.15[M+H] + ,375.10[M+Na] + ; HRMS(ESI )calcd.for C 22 H 29 N 2 O 2 ,[M+H] + : 353.2224; found: 353.2231, [M+Na] + : 375.2043; found: 375.2047.
3d(4S,5S)-2,7-二甲基-4,5-辛二胺3d(4S,5S)-2,7-dimethyl-4,5-octanediamine
Figure PCTCN2020088988-appb-000104
Figure PCTCN2020088988-appb-000104
无色液体；50％产率；99％ee；ee值由其衍生物所得.旋光:[α] D 25＝-28.9[c＝1.60,CHCl 3]. 1H NMR(500MHz,CDCl 3):2.58(t,J＝5.6Hz,2H),1.89(s,4H),1.69(dp,J＝13.3,6.6Hz,2H),1.20(t,J＝6.6Hz,4H),0.87(dd,J＝16.7,6.6Hz,12H)； 13C NMR(126MHz,CDCl 3):δ53.2,44.0,24.9,23.7,22.0；ESI-MS:M/z 173.05[M+H] +；HRMS(ESI)calcd.for C 10H 25N 2,[M+H] +:173.2012；found:173.2018. Colorless liquid; 50% yield; 99% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 ＝-28.9 [c=1.60, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): 2.58 (t, J = 5.6Hz, 2H), 1.89 (s, 4H), 1.69 (dp, J = 13.3, 6.6 Hz, 2H), 1.20 (t, J = 6.6 Hz, 4H), 0.87 (dd, J = 16.7, 6.6 Hz, 12H); 13 C NMR (126MHz, CDCl 3 ): δ53.2, 44.0, 24.9, 23.7, 22.0; ESI-MS: M/z 173.05[M+H] + ; HRMS(ESI) calcd.for C 10 H 25 N 2 ,[M+H] + :173.2012; found:173.2018.
N,N’-((4S,5S)-2,7-二甲基-4,5-二苯甲酰胺取代辛烷N,N’-((4S,5S)-2,7-dimethyl-4,5-dibenzamide substituted octane
Figure PCTCN2020088988-appb-000105
Figure PCTCN2020088988-appb-000105
将手性二胺(17.2mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (17.2mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱OJ-H,正己烷/异丙醇90/10,23℃,流速1.0mL/min,250nm,3.23min(S,S),3.90min(R,R).旋光:[α] D 27＝10.9[c＝1.17,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.59(d,J＝6.8Hz,2H),7.32-7.21(m,2H),7.09(t,J＝7.8Hz,4H),7.04(d,J＝8.5Hz,2H),4.26(m,2H),1.78(dtd,J＝13.2,10.3,6.5Hz,2H),1.67(ddd,J＝13.9,10.4,3.7Hz,2H),1.54-1.48(m,2H),0.97(dd,J＝13.2,6.5Hz,12H)； 13C NMR(126MHz,CDCl 3):δ168.4(2C),134.3(2C),131.1,128.2,126.9,53.0,41.6,25.3,23.8,21.8；ESI-MS:M/z 381.45[M+H] +；403.15[M+Na] +；HRMS(ESI)calcd.for C 24H 33N 2O 2[M+H] +:381.2537；found:381.2542,[M+Na] +:403.2356；found:403.2357. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column OJ-H, n-hexane/isopropanol 90/10, 23℃, flow rate 1.0mL/min, 250nm, 3.23min(S,S),3.90min(R,R). Optical rotation: [α] D 27 ＝10.9[c＝1.17,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ7.59(d, J = 6.8Hz, 2H), 7.32-7.21 (m, 2H), 7.09 (t, J = 7.8Hz, 4H), 7.04 (d, J = 8.5Hz, 2H), 4.26 (m, 2H), 1.78 ( dtd, J = 13.2, 10.3, 6.5 Hz, 2H), 1.67 (ddd, J = 13.9, 10.4, 3.7 Hz, 2H), 1.54-1.48 (m, 2H), 0.97 (dd, J = 13.2, 6.5 Hz, 12H); 13 C NMR (126MHz, CDCl 3 ): δ168.4(2C), 134.3(2C), 131.1, 128.2, 126.9, 53.0, 41.6, 25.3, 23.8, 21.8; ESI-MS: M/z 381.45[ M+H] + ;403.15[M+Na] + ;HRMS(ESI)calcd.for C 24 H 33 N 2 O 2 [M+H] + :381.2537; found:381.2542,[M+Na] + :403.2356 ;Found:403.2357.
4d(3S,4S)-2,5-二甲基-3,4己二胺4d(3S,4S)-2,5-dimethyl-3,4-hexanediamine
Figure PCTCN2020088988-appb-000106
Figure PCTCN2020088988-appb-000106
无色液体；40％产率；99％ee；ee值由其衍生物所得.旋光:[α] D 20＝56.8[c＝0.73,CHCl 3]. 1H NMR(500MHz,CDCl 3):3.51(d,J＝6.5Hz,1H),2.73(t,J＝5.6Hz,1H),2.62(t,J＝5.5Hz,1H),1.70(s,2H),1.62-1.49(m,3H),0.95-0.88(m,16H)； 13C NMR(126MHz,CDCl 3):δ53.15(2C),44.0,24.9,23.7,22.0；ESI-MS:M/z 145.20[M+H] +；HRMS(ESI)calcd.for C 12H 27N 2[M+H] +:145.1699；found:145.1704. Colorless liquid; 40% yield; 99% ee; ee value obtained from its derivatives. Optical rotation: [α] D 20 ＝56.8 [c＝0.73, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): 3.51 (d,J=6.5Hz,1H), 2.73(t,J=5.6Hz,1H), 2.62(t,J=5.5Hz,1H), 1.70(s,2H),1.62-1.49(m,3H) , 0.95-0.88 (m, 16H); 13 C NMR (126MHz, CDCl 3 ): δ53.15(2C), 44.0, 24.9, 23.7, 22.0; ESI-MS: M/z 145.20[M+H] + ; HRMS(ESI)calcd.for C 12 H 27 N 2 [M+H] + :145.1699; found:145.1704.
N,N’-((3S,4S)-2,5-二甲基-3,4-二苯甲酰胺取代己烷N,N’-((3S,4S)-2,5-dimethyl-3,4-dibenzamide substituted hexane
Figure PCTCN2020088988-appb-000107
Figure PCTCN2020088988-appb-000107
将手性二胺(14.5mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (14.5mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺70/30/0.1,23℃,流速1.0mL/min,250nm,9.23min(S,S),14.62min(R,R).旋光:[α] D 27＝12.0[c＝1.23,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.68(d,J＝7.1Hz,4H),7.43(t,J＝7.4Hz,2H),7.35(t,J＝7.6Hz,4H),6.66(d,J＝7.4Hz,2H),4.17(ddt,J＝7.0,4.6,2.1Hz,2H),2.12(dt,J＝10.9,6.9Hz,2H),1.04(dd,J＝10.4,6.8Hz,12H)； 13C NMR(126MHz,CDCl 3):δ168.8,134.5,131.4,128.5,126.9,56.8,28.7,20.7,16.6；ESI-MS:M/z 353.15[M+H] +,375.10[M+Na] +；HRMS(ESI)calcd.for C 22H 29N 2O 2[M+H] +:353.2224；found:353.2230,[M+Na] +:375.2043；found:375.2046. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine 70/30/0.1, 23℃, flow rate 1.0mL/min,250nm,9.23min(S,S),14.62min(R,R). Optical rotation: [α] D 27 ＝12.0[c＝1.23,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ) :δ7.68(d,J=7.1Hz,4H),7.43(t,J=7.4Hz,2H),7.35(t,J=7.6Hz,4H),6.66(d,J=7.4Hz,2H) , 4.17 (ddt, J = 7.0, 4.6, 2.1 Hz, 2H), 2.12 (dt, J = 10.9, 6.9 Hz, 2H), 1.04 (dd, J = 10.4, 6.8 Hz, 12H); 13 C NMR (126MHz ,CDCl 3 ):δ168.8,134.5,131.4,128.5,126.9,56.8,28.7,20.7,16.6; ESI-MS: M/z 353.15[M+H] + ,375.10[M+Na] + ; HRMS(ESI) calcd.for C 22 H 29 N 2 O 2 [M+H] + :353.2224; found:353.2230,[M+Na] + :375.2043; found:375.2046.
5d(1S,2S)-1,2-二环己基-1,2-乙二胺5d(1S,2S)-1,2-dicyclohexyl-1,2-ethylenediamine
Figure PCTCN2020088988-appb-000108
Figure PCTCN2020088988-appb-000108
无色液体；70％产率；98％ee；ee值由其衍生物所得.旋光:[α] D 25＝-4.8[c＝0.70,CHCl 3]. 1H NMR(500MHz,CDCl 3):2.43(d,J＝5.6Hz,2H),1.82-1.72(m,6H),1.69-1.59(m,4H),1.38-1.18(m,12H),1.06-0.85(m,4H)； 13C NMR(126MHz,CDCl 3):δ56.6,40.5,30.4,28.7,26.6,26.4,26.3；ESI-MS:M/z 225.05,[M+H] +；HRMS(ESI)calcd.for C 14H 29N 2[M+H] +:225.2325；found:225.2332. Colorless liquid; 70% yield; 98% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 = -4.8 [c = 0.70, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): 2.43(d,J=5.6Hz,2H),1.82-1.72(m,6H),1.69-1.59(m,4H),1.38-1.18(m,12H),1.06-0.85(m,4H); 13 C NMR (126MHz, CDCl 3 ): δ56.6, 40.5, 30.4, 28.7, 26.6, 26.4, 26.3; ESI-MS: M/z 225.05, [M+H] + ; HRMS(ESI)calcd.for C 14 H 29 N 2 [M+H] + :225.2325; found:225.2332.
N,N’-((1S,2S)-1,2-二环己基-1,2-二苯甲酰胺乙烷N,N’-((1S,2S)-1,2-dicyclohexyl-1,2-dibenzamide ethane
Figure PCTCN2020088988-appb-000109
Figure PCTCN2020088988-appb-000109
将手性二胺(22.4mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (22.4mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺70/30/0.1,23℃,流速1.0mL/min,250nm,4.44min(R,R),5.58min(S,S).旋光:[α] D 20＝26.3[c＝0.80,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.70(d,J＝7.2Hz,4H),7.44(t,J＝7.4Hz,2H),7.36(t,J＝7.5Hz,4H),6.81(d,J＝7.5Hz,2H),4.13(q,J＝8.3,6.5Hz,2H),1.87-1.66(m,12H),1.29-1.22(m,5H),1.19-1.04(m,5H)； 13C NMR(126MHz,CDCl 3):δ168.5,134.5,131.4,128.5,126.9,56.0,38.8,31.0,27.6,26.3,26.3,26.2；ESI-MS:M/z 433.30[M+H] +,455.15[M+Na] +；HRMS(ESI)calcd.for C 28H 37N 2O 2[M+H] +:433.2850；found:433.2858,[M+Na] +:455.2669；found:455.2675. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine 70/30/0.1, 23℃, flow rate 1.0mL/min, 250nm, 4.44min(R,R), 5.58min(S,S). Optical rotation: [α] D 20 ＝26.3[c＝0.80,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ) :δ7.70(d,J=7.2Hz,4H),7.44(t,J=7.4Hz,2H),7.36(t,J=7.5Hz,4H),6.81(d,J=7.5Hz,2H) , 4.13 (q, J = 8.3, 6.5 Hz, 2H), 1.87-1.66 (m, 12H), 1.29-1.22 (m, 5H), 1.19-1.04 (m, 5H); 13 C NMR (126MHz, CDCl 3 ):δ168.5,134.5,131.4,128.5,126.9,56.0,38.8,31.0,27.6,26.3,26.3,26.2; ESI-MS: M/z 433.30[M+H] + ,455.15[M+Na] + ; HRMS (ESI)calcd.for C 28 H 37 N 2 O 2 [M+H] + : 433.2850; found: 433.2858, [M+Na] + : 455.2669; found: 455.2675.
6d(2S,3S)-1,4二苯基-2,3-丁二胺6d(2S,3S)-1,4-diphenyl-2,3-butanediamine
Figure PCTCN2020088988-appb-000110
Figure PCTCN2020088988-appb-000110
无色液体；70％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：80/20/0.1,25℃,流速1.2mL/min,9.01min(S,S),10.85min(R,R).旋光:[α] D 25＝-13.8[c＝1.08,CHCl 3]. 1H NMR(500MHz,CDCl 3):7.31(t,J＝7.5Hz,4H),7.22(dd,J＝16.4,7.4Hz,6H),3.03-2.88(m,4H),2.62(dd,J＝12.5,8.3Hz,2H),1.55(s,4H)； 13C NMR(126MHz,CDCl 3):δ139.4 129.2,128.6,126.3,56.3,41.6；ESI-MS:M/z 241.00[M+H] +；HRMS(ESI)calcd.for C 16H 21N 2，[M+H] +:241.1699；found:241.1706. Colorless liquid; 70% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 80/20 /0.1, 25℃, flow rate 1.2mL/min, 9.01min(S,S), 10.85min(R,R). Optical rotation: [α] D 25 ＝-13.8[c＝1.08,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): 7.31 (t, J = 7.5 Hz, 4H), 7.22 (dd, J = 16.4, 7.4 Hz, 6H), 3.03-2.88 (m, 4H), 2.62 (dd, J = 12.5, 8.3Hz, 2H), 1.55 (s, 4H); 13 C NMR (126MHz, CDCl 3 ): δ 139.4 129.2, 128.6, 126.3, 56.3, 41.6; ESI-MS: M/z 241.00[M+H] + ; HRMS(ESI)calcd.for C 16 H 21 N 2 , [M+H] + :241.1699; found:241.1706.
7d(2S,3S)-1,4-双(2-溴取代苯基)-2,3-丁二胺7d(2S,3S)-1,4-bis(2-bromo substituted phenyl)-2,3-butanediamine
Figure PCTCN2020088988-appb-000111
Figure PCTCN2020088988-appb-000111
无色液体；70％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：70/30/0.1,25℃,流速1.0mL/min,12.78min(S,S),17.12 min(R,R).旋光:[α] D 25＝-13.0[c＝0.95,CHCl 3]. 1H NMR(500MHz,CDCl 3):7.53(d,J＝8.5Hz,2H),7.22(d,J＝1.9Hz,4H),7.09-7.06(m,2H),3.11-3.06(m,4H),2.71(tt,J＝9.0,7.2,3.0Hz,2H),1.48(s,4H)； 13C NMR(126MHz,CDCl 3):δ139.0,133.0,131.5,128.0,127.4,124.9,54.9,42.0；ESI-MS:M/z 396.90[M+H] +；HRMS(ESI)calcd.for C 16H 19Br 2N 2[M+H] +:396.9910；found:396.9911. Colorless liquid; 70% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 70/30 /0.1, 25℃, flow rate 1.0mL/min, 12.78min(S,S), 17.12 min(R,R). Optical rotation: [α] D 25 ＝-13.0[c＝0.95,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): 7.53 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 1.9 Hz, 4H), 7.09-7.06 (m, 2H), 3.11-3.06 (m, 4H), 2.71 (tt, J = 9.0, 7.2, 3.0 Hz, 2H), 1.48 (s, 4H); 13 C NMR (126MHz, CDCl 3 ): δ 139.0, 133.0, 131.5, 128.0, 127.4, 124.9, 54.9, 42.0; ESI- MS: M/z 396.90[M+H] + ; HRMS(ESI)calcd.for C 16 H 19 Br 2 N 2 [M+H] + : 396.9910; found: 396.9911.
8d(2S,3S)-1,4-双对甲苯基-2,3-丁二胺8d(2S,3S)-1,4-bis-p-tolyl-2,3-butanediamine
Figure PCTCN2020088988-appb-000112
Figure PCTCN2020088988-appb-000112
无色液体；72％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：70/30/0.1,23℃,流速1.0mL/min,9.58min(S,S),10.54min(R,R).旋光:[α] D 27＝39.0[c＝1.25,CHCl 3]. 1H NMR(500MHz,CDCl 3):7.11(q,J＝8.1Hz,8H),2.97-2.82(m,4H),2.55(dd,J＝12.9,8.5Hz,2H),2.34(s,6H),1.43(s,4H)； 13C NMR(126MHz,CDCl 3):δ136.5,133.8,129.6,129.2,54.8,39.1,21.0；ESI-MS:M/z 269.10[M+H] +；HRMS(ESI)calcd.for C 18H 25N 2[M+H] +:269.2012；found:269.2011. Colorless liquid; 72% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 70/30 /0.1,23℃, flow rate 1.0mL/min, 9.58min(S,S), 10.54min(R,R). Optical rotation: [α] D 27 ＝39.0[c＝1.25,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): 7.11 (q, J = 8.1 Hz, 8H), 2.97-2.82 (m, 4H), 2.55 (dd, J = 12.9, 8.5 Hz, 2H), 2.34 (s, 6H), 1.43 ( s, 4H); 13 C NMR (126MHz, CDCl 3 ): δ136.5, 133.8, 129.6, 129.2, 54.8, 39.1,21.0; ESI-MS: M/z 269.10[M+H] + ; HRMS(ESI)calcd. for C 18 H 25 N 2 [M+H] + :269.2012; found:269.2011.
9d(2S,3S)-1,4-双(3-氯苯基)-2,3-丁二胺9d(2S,3S)-1,4-bis(3-chlorophenyl)-2,3-butanediamine
Figure PCTCN2020088988-appb-000113
Figure PCTCN2020088988-appb-000113
无色液体；82％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：70/30/0.1,23℃,流速1.0mL/min,13.00min(R,R),15.71min(S,S).旋光:[α] D 20＝24.9[c＝0.20,CHCl 3]. 1H NMR(500MHz,CDCl 3):7.27-7.17(m,6H),7.07(d,J＝6.9Hz,2H),2.96-2.83(m,4H),2.60(dd,J＝13.1,8.7Hz,2H),1.61(s,4H)； 13C NMR(126MHz,CDCl 3):δ141.4,134.4,129.8,129.2,127.4,126.6,56.0,41.3；ESI-MS:M/z 308.95[M+H] +；HRMS(ESI)calcd.for C 16H 19Cl 2N 2[M+H] +:309.0920；found:309.0926. Colorless liquid; 82% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 70/30 /0.1,23℃, flow rate 1.0mL/min, 13.00min(R,R), 15.71min(S,S). Optical rotation: [α] D 20 ＝24.9[c＝0.20,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): 7.27-7.17 (m, 6H), 7.07 (d, J = 6.9 Hz, 2H), 2.96-2.83 (m, 4H), 2.60 (dd, J = 13.1, 8.7 Hz, 2H), 1.61(s,4H); 13 C NMR(126MHz, CDCl 3 ): δ141.4, 134.4, 129.8, 129.2, 127.4, 126.6, 56.0, 41.3; ESI-MS: M/z 308.95[M+H] + ; HRMS( ESI)calcd.for C 16 H 19 Cl 2 N 2 [M+H] + :309.0920; found:309.0926.
10d(2S,3S)-1,4-双-(2-取代噻吩)-2,3-丁二胺10d(2S,3S)-1,4-bis-(2-substituted thiophene)-2,3-butanediamine
Figure PCTCN2020088988-appb-000114
Figure PCTCN2020088988-appb-000114
微黄液体；76％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：70/30/0.1,23℃,流速1.0mL/min,11.29min(R,R),12.62min(S,S).旋光:[α] D 27＝-77.8[c＝0.55,CHCl 3]. 1H NMR(500MHz,CDCl 3):7.16(d,J＝5.1 Hz,2H),6.95(dd,J＝5.0,3.5Hz,3H),6.85(d,J＝3.4Hz,2H),3.08(dd,J＝14.0,3.3Hz,3H),2.98-2.93(m,2H),2.89(dd,J＝13.8,8.5Hz,3H)； 13C NMR(126MHz,CDCl 3):δ141.8,126.9,125.7,123.9,56.4,36.0；ESI-MS:M/z 252.80[M+H] +；HRMS(ESI)calcd.for C 12H 17N 2S 2[M+H] +:253.0828；found:253.0830. Yellowish liquid; 76% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 70/30 /0.1,23℃, flow rate 1.0mL/min, 11.29min(R,R), 12.62min(S,S). Optical rotation: [α] D 27 ＝-77.8[c＝0.55,CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): 7.16 (d, J = 5.1 Hz, 2H), 6.95 (dd, J = 5.0, 3.5 Hz, 3H), 6.85 (d, J = 3.4 Hz, 2H), 3.08 (dd, J = 14.0, 3.3 Hz, 3H), 2.98-2.93 (m, 2H), 2.89 (dd, J = 13.8, 8.5 Hz, 3H); 13 C NMR (126MHz, CDCl 3 ): δ141.8, 126.9, 125.7, 123.9, 56.4,36.0; ESI-MS: M/z 252.80[M+H] + ; HRMS(ESI)calcd.for C 12 H 17 N 2 S 2 [M+H] + : 253.0828; found: 253.0830.
11d(6S,7S)-1,11-二炔基6,7-辛二胺11d(6S,7S)-1,11-diynyl 6,7-octanediamine
Figure PCTCN2020088988-appb-000115
Figure PCTCN2020088988-appb-000115
微黄液体；87％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱AD-H,正己烷/异丙醇：90/10,23℃,流速1.0mL/min,7.54min(R,R),8.58min(S,S).旋光:[α] D 27＝-12.9[c＝1.25,CHCl 3]. 1H NMR(500MHz,CDCl 3):2.51(d,J＝6.8Hz,2H),2.16(dd,J＝8.4,5.3Hz,4H),1.91(d,J＝3.0Hz,2H),1.62(dd,J＝14.8,7.7Hz,2H),1.52(qt,J＝12.2,7.8,5.7Hz,4H),1.38-1.21(m,6H)； 13C NMR(126MHz,CDCl 3):δ84.2,68.6,54.9,33.9,25.4,18.5；ESI-MS:M/z 192.95[M+H] +；HRMS(ESI)calcd.for C 12H 21N 2,[M+H] +:193.1699；found:193.1703. Yellowish liquid; 87% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column AD-H, n-hexane/isopropanol: 90/10, 23°C, flow rate 1.0mL/min, 7.54min(R,R), 8.58min(S,S). Optical rotation: [α] D 27 ＝-12.9[c＝1.25,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): 2.51(d,J=6.8Hz,2H),2.16(dd,J=8.4,5.3Hz,4H),1.91(d,J=3.0Hz,2H),1.62(dd,J=14.8,7.7Hz,2H ), 1.52 (qt, J = 12.2, 7.8, 5.7 Hz, 4H), 1.38-1.21 (m, 6H); 13 C NMR (126MHz, CDCl 3 ): δ 84.2, 68.6, 54.9, 33.9, 25.4, 18.5 ;ESI-MS:M/z 192.95[M+H] + ;HRMS(ESI)calcd.for C 12 H 21 N 2 ,[M+H] + :193.1699;found:193.1703.
12d(6S,7S)-1,11-二烯基-6,7-辛二胺12d(6S,7S)-1,11-dienyl-6,7-octanediamine
Figure PCTCN2020088988-appb-000116
Figure PCTCN2020088988-appb-000116
无色液体；85％产率；99％ee；ee值由其衍生物所得.旋光:[α] D 25＝-24.6[c＝0.90,CHCl 3]. 1H NMR(500MHz,CDCl 3):5.77(dt,J＝16.7,8.3Hz,2H),4.95(dd,J＝28.3,13.6Hz,4H),2.61-2.43(m,2H),2.10-1.97(m,4H),1.64-1.14(m,12H)； 13C NMR(126MHz,CDCl 3):δ138.6,114.6,55.0,34.3,33.8,25.8；ESI-MS:M/z 197.05[M+H] +；HRMS(ESI)calcd.for C 12H 25N 2,[M+H] +:197.2012；found:197.2017. Colorless liquid; 85% yield; 99% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 =-24.6 [c = 0.90, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): 5.77(dt,J=16.7,8.3Hz,2H), 4.95(dd,J=28.3,13.6Hz,4H),2.61-2.43(m,2H),2.10-1.97(m,4H),1.64-1.14( m,12H); 13 C NMR(126MHz, CDCl 3 ): δ138.6,114.6,55.0,34.3,33.8,25.8; ESI-MS: M/z 197.05[M+H] + ; HRMS(ESI)calcd.for C 12 H 25 N 2 ,[M+H] + :197.2012; found:197.2017.
N,N’-((6S,7S)-1,11-二烯基-6,7-二苯甲酰胺取代辛烷N,N’-((6S,7S)-1,11-dienyl-6,7-dibenzamide substituted octane
Figure PCTCN2020088988-appb-000117
Figure PCTCN2020088988-appb-000117
将手性二胺(20.0mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (20.0mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱IC,正己烷/异丙醇98/2,23℃,流速1.2mL/min,250nm,5.08min(S,S),6.65min(R,R).旋光:[α] D 25＝-15.5[c＝0.83,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.64(d,J＝7.3Hz,4H),7.33(t,J＝7.4Hz,2H),7.18(t,J＝7.7Hz,4H),7.06(d,J＝8.1Hz,2H),5.78(ddt,J＝16.9,10.2,6.7Hz,2H),5.05-4.93(m,4H),4.26-4.16(m,2H),2.10(m,4H),1.82(m,2H),1.58(m,6H)； 13C NMR(126MHz,CDCl 3):δ168.6,138.2,134.2,131.3,128.4,127.0,115.0,54.1,33.4,31.4,25.2；ESI-MS:M/z 405.35[M+H] +；427.35[M+Na] +；HRMS(ESI)calcd.for C 26H 33N 2O 2,[M+H] +:405.2537；found:405.2541.C 26H 32N 2O 2,[M+Na] +:427.2356；found:427.2358. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column IC, n-hexane/isopropanol 98/2, 23℃, flow rate 1.2mL/min, 250nm, 5.08min (S,S),6.65min(R,R). Optical rotation: [α] D 25 ＝-15.5[c＝0.83,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ):δ7.64(d,J =7.3Hz, 4H), 7.33 (t, J = 7.4 Hz, 2H), 7.18 (t, J = 7.7 Hz, 4H), 7.06 (d, J = 8.1 Hz, 2H), 5.78 (ddt, J = 16.9 ,10.2,6.7Hz,2H),5.05-4.93(m,4H),4.26-4.16(m,2H),2.10(m,4H),1.82(m,2H),1.58(m,6H); 13 C NMR (126MHz, CDCl 3 ): δ168.6, 138.2, 134.2, 131.3, 128.4, 127.0, 115.0, 54.1, 33.4, 31.4, 25.2; ESI-MS: M/z 405.35[M+H] + ; 427.35[M+Na ] + ;HRMS(ESI)calcd.for C 26 H 33 N 2 O 2 ,[M+H] + :405.2537; found:405.2541.C 26 H 32 N 2 O 2 ,[M+Na] + :427.2356; found: 427.2358.
13d(5S,6S)-1,9-二烯基-5,6-己二胺13d(5S,6S)-1,9-dienyl-5,6-hexamethylenediamine
Figure PCTCN2020088988-appb-000118
Figure PCTCN2020088988-appb-000118
无色液体；86％产率；99％ee；ee值由其衍生物所得.旋光:[α] D 25＝-24.8[c＝2.50,CHCl 3]. 1H NMR(400MHz,DMSO-d6)δ5.80(ddt,J＝16.9,10.2,6.6Hz,2H),5.05-4.88(m,4H),3.21(s,4H),2.41-2.32(m,2H),2.18-2.09(m,2H),2.05-1.96(m,2H),1.47-1.38(m,2H),1.28-1.19(m,2H)； 13C NMR(100MHz,DMSO-d6):δ139.2,114.4,54.5,33.6,30.5；ESI-MS:M/z 169.25[M+H] +；HRMS(ESI)calcd.for C 10H 21N 2,[M+H] +:169.1699；found:169.1701. Colorless liquid; 86% yield; 99% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 =-24.8 [c = 2.50, CHCl 3 ]. 1 H NMR (400MHz, DMSO-d6) δ5.80 (ddt, J=16.9, 10.2, 6.6Hz, 2H), 5.05-4.88 (m, 4H), 3.21 (s, 4H), 2.41-2.32 (m, 2H), 2.18-2.09 (m, 2H) ), 2.05-1.96 (m, 2H), 1.47-1.38 (m, 2H), 1.28-1.19 (m, 2H); 13 C NMR (100MHz, DMSO-d6): δ 139.2, 114.4, 54.5, 33.6, 30.5; ESI-MS: M/z 169.25[M+H] + ; HRMS(ESI)calcd.for C 10 H 21 N 2 ,[M+H] + :169.1699; found: 169.1701.
N,N’-((5S,6S)-1,9-二烯基-5,6-二苯甲酰胺取代己烷N,N’-((5S,6S)-1,9-dienyl-5,6-dibenzamide substituted hexane
Figure PCTCN2020088988-appb-000119
Figure PCTCN2020088988-appb-000119
将手性二胺(17.0mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (17.0mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱IC,正己烷/异丙醇98/2,23℃,流速1.2mL/min,250nm,6.56min(S,S),7.58min(R,R).旋光:[α] D 25＝-15.1[c＝0.60,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.71-7.60(m,4H),7.41-7.36(m,2H),7.29-7.24(m,4H),6.98-6.85(m,2H),5.88-5.78(m,2H),5.08-4.97(m,4H),4.20-4.19(m,2H),2.33-2.12(m,4H),1.95-1.82(m,2H),1.81-1.71(m,2H)； 13C NMR(126MHz,CDCl 3):δ168.4,137.7,134.2,131.4,128.4,126.9,115.5,53.8,31.5,30.3；ESI-MS:M/z 377.25[M+H] +；399.45[M+Na] +；HRMS(ESI)calcd.for C 24H 29N 2O 2,[M+H] +:377.2224；found:377.2230； C 24H 28N 2O 2Na,[M+Na] +:399.2043；found:399.2047. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column IC, n-hexane/isopropanol 98/2, 23℃, flow rate 1.2mL/min, 250nm, 6.56min (S,S),7.58min(R,R). Optical rotation: [α] D 25 ＝-15.1[c＝0.60,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ): δ7.71-7.60(m ,4H),7.41-7.36(m,2H),7.29-7.24(m,4H),6.98-6.85(m,2H),5.88-5.78(m,2H),5.08-4.97(m,4H),4.20 -4.19(m,2H),2.33-2.12(m,4H),1.95-1.82(m,2H),1.81-1.71(m,2H); 13 C NMR(126MHz,CDCl 3 ): δ168.4,137.7,134.2 ,131.4,128.4,126.9,115.5,53.8,31.5,30.3; ESI-MS: M/z 377.25[M+H] + ;399.45[M+Na] + ; HRMS(ESI)calcd.for C 24 H 29 N 2 O 2 ,[M+H] + : 377.2224; found: 377.2230; C 24 H 28 N 2 O 2 Na, [M+Na] + : 399.2043; found: 399.2047.
14d(12S,13S)-12,13-二十四二胺14d(12S,13S)-12,13-tetracosodiamine
Figure PCTCN2020088988-appb-000120
Figure PCTCN2020088988-appb-000120
无色液体；65％产率；99％ee；ee值由其衍生物所得.旋光:[α] D 25＝16.6[c＝0.90,CHCl 3]. 1H NMR(500MHz,CDCl 3):2.55(s,2H),2.41(s,4H),1.46-1.34(m,4H),1.23(m,36H),0.84(t,J＝6.9Hz,6H)； 13C NMR(126MHz,CDCl 3):δ54.8,34.3,31.9,29.7,29.6,29.3,26.4,22.6,14.0；ESI-MS:M/z 369.30[M+H] +；HRMS(ESI)calcd.for C 24H 53N 2,[M+H] +:369.4203；found:369.4202. Colorless liquid; 65% yield; 99% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 =16.6 [c=0.90, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): 2.55 (s,2H),2.41(s,4H),1.46-1.34(m,4H),1.23(m,36H),0.84(t,J=6.9Hz,6H); 13 C NMR(126MHz,CDCl 3 ) :δ54.8,34.3,31.9,29.7,29.6,29.3,26.4,22.6,14.0; ESI-MS: M/z 369.30[M+H] + ; HRMS(ESI)calcd.for C 24 H 53 N 2 , [M+H] + :369.4203; found:369.4202.
N,N’-((12S,13S)-12,13二苯甲酰胺取代正二十四烷N,N’-((12S,13S)-12,13 dibenzamide substituted n-tetracosane
Figure PCTCN2020088988-appb-000121
Figure PCTCN2020088988-appb-000121
将手性二胺(37.0mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (37.0mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺70/30/0.1,23℃,流速1.0mL/min,250nm,5.42min(S,S),6.39min(R,R).旋光:[α] D 20＝16.1[c＝0.55,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.69(d,J＝7.2Hz,4H),7.38(t,J＝7.4Hz,2H),7.28(t,J＝7.2Hz,4H),6.97(d,J＝8.2Hz,2H),4.17-4.10(m,2H),1.74(dtd,J＝13.4,6.4,2.8Hz,2H),1.56(ddq,J＝13.8,9.0,4.6Hz,2H),1.42(ddd,J＝12.4,8.5,4.9Hz,2H),1.30-1.24(m,34H),0.87(t,J＝7.0Hz,6H)； 13C NMR(126MHz,CDCl 3):δ168.4,134.4,131.2,128.4,127.0,54.3,32.1,31.9,29.6,29.5,29.3,25.9,22.7,14.1；ESI-MS:M/z 577.45[M+H] +,599.40[M+Na] +；HRMS(ESI)calcd.for C 38H 61N 2O 2[M+H] +:577.4728；found:577.4732,[M+Na] +:599.4547；found:599.4551. White solid; 99%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine 70/30/0.1, 23℃, flow rate 1.0mL/min, 250nm, 5.42min(S,S), 6.39min(R,R). Optical rotation: [α] D 20 ＝16.1[c＝0.55,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ) :δ7.69(d,J=7.2Hz,4H), 7.38(t,J=7.4Hz,2H), 7.28(t,J=7.2Hz,4H), 6.97(d,J=8.2Hz,2H) , 4.17-4.10 (m, 2H), 1.74 (dtd, J = 13.4, 6.4, 2.8 Hz, 2H), 1.56 (ddq, J = 13.8, 9.0, 4.6 Hz, 2H), 1.42 (ddd, J = 12.4, 8.5, 4.9 Hz, 2H), 1.30-1.24 (m, 34H), 0.87 (t, J = 7.0 Hz, 6H); 13 C NMR (126MHz, CDCl 3 ): δ 168.4, 134.4, 131.2, 128.4, 127.0, 54.3 ,32.1,31.9,29.6,29.5,29.3,25.9,22.7,14.1; ESI-MS: M/z 577.45[M+H] + ,599.40[M+Na] + ; HRMS(ESI)calcd.for C 38 H 61 N 2 O 2 [M+H] + :577.4728; found: 577.4732, [M+Na] + :599.4547; found: 599.4551.
实施例4环内烷基亚胺的底物拓展Example 4 Substrate Development of Intracyclic Alkylimines
Figure PCTCN2020088988-appb-000122
Figure PCTCN2020088988-appb-000122
在干净干燥的shlenk管中，加预先制备的环内亚胺(1.0mmol，1.0eq)，DB4(0.5 mmol,0.5eq)，体系抽换氮气三次，氮气保护下，加入重蒸四氢呋喃2.5ml，密封，室温下搅拌12h。停止反应，加入盐酸(3.0M，1ml)调pH至3左右，二氯甲烷洗涤，有机相浓缩后经正己烷打浆回收diol 5(95％回收率)，水相加入氢氧化钠溶液调pH至12左右，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，旋干即得到产物。In a clean and dry shlenk tube, add pre-prepared intracyclic imine (1.0 mmol, 1.0 eq), DB4 (0.5 mmol, 0.5 eq), and the system is pumped with nitrogen three times. Under nitrogen protection, add 2.5 ml of redistilled tetrahydrofuran, Seal and stir at room temperature for 12h. Stop the reaction, add hydrochloric acid (3.0M, 1ml) to adjust the pH to about 3, wash with dichloromethane, concentrate the organic phase and beat with n-hexane to recover diol 5 (95% recovery), add sodium hydroxide solution to the aqueous phase to adjust the pH to At around 12, extract with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, and spin to dry to obtain the product.
1e(2R,2’R)-2,2’-联吡咯烷1e(2R,2’R)-2,2’-bipyrrolidine
Figure PCTCN2020088988-appb-000123
Figure PCTCN2020088988-appb-000123
无色液体；68％产率；98％ee；ee值由其衍生物所得.旋光:[α] D 25＝-16.0[c＝1.60,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ2.84(d,J＝5.1Hz,2H),2.78-2.65(m,4H),2.02(s,2H),1.73-1.55(m,6H),1.27-1.21(m,2H)； 13C NMR(126MHz,CDCl 3):δ63.7,46.4,29.1,25.4；ESI-MS:M/z 140.95[M+H] +；HRMS(ESI)calcd.for C 8H 17N 2,[M+H] +:141.1386；found:141.1385. Colorless liquid; 68% yield; 98% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 = -16.0 [c = 1.60, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ 2.84 (d, J = 5.1 Hz, 2H), 2.78-2.65 (m, 4H), 2.02 (s, 2H), 1.73-1.55 (m, 6H), 1.27-1.21 (m, 2H); 13 C NMR (126MHz, CDCl 3 ): δ63.7, 46.4, 29.1,25.4; ESI-MS: M/z 140.95[M+H] + ; HRMS(ESI)calcd.for C 8 H 17 N 2 ,[M+ H] + :141.1386; found:141.1385.
(2R,2’R)-2,2’-联吡咯烷-1,1’-二苯甲酰胺(2R,2’R)-2,2’-Bipyrrolidine-1,1’-Dibenzamide
Figure PCTCN2020088988-appb-000124
Figure PCTCN2020088988-appb-000124
将手性二胺(14.0mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (14.0mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；98％ee；ee值由高压手性液相测定；高压液相条件：手性柱IA,正己烷/异丙醇60/40,25℃,流速0.7mL/min,250nm,10.35min(S,S),23.49min(R,R).旋光:[α] D 25＝130.9[c＝0.60,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.41(d,J＝7.3Hz,4H),7.27(dt,J＝14.4,7.2Hz,6H),4.61(d,J＝4.9Hz,2H),3.80(td,J＝9.6,5.1Hz,2H),3.27-3.11(m,2H).2.27-2.28(m,2H),2.04-1.98(m,2H),1.94-1.87(m,2H),1.80-1.76(m,2H)； 13C NMR(126MHz,CDCl 3):δ170.9,137.2,129.5,128.2,127.1,58.8,49.2,28.2,24.2；ESI-MS:M/z 349.20[M+H] +；HRMS(ESI)calcd.for C 22H 25N 2O 2,[M+H] +:349.1911；found:349.1914；[M+Na] +:371.1730；found:371.1734. White solid; 98%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column IA, n-hexane/isopropanol 60/40, 25℃, flow rate 0.7mL/min, 250nm, 10.35min (S,S),23.49min(R,R). Optical rotation: [α] D 25 ＝130.9[c＝0.60,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ):δ7.41(d,J＝ 7.3Hz, 4H), 7.27 (dt, J = 14.4, 7.2 Hz, 6H), 4.61 (d, J = 4.9 Hz, 2H), 3.80 (td, J = 9.6, 5.1 Hz, 2H), 3.27-3.11 ( m,2H).2.27-2.28(m,2H),2.04-1.98(m,2H),1.94-1.87(m,2H),1.80-1.76(m,2H); 13 C NMR(126MHz,CDCl 3 ) :δ170.9,137.2,129.5,128.2,127.1,58.8,49.2,28.2,24.2; ESI-MS: M/z 349.20[M+H] + ; HRMS(ESI)calcd.for C 22 H 25 N 2 O 2 , [M+H] + :349.1911; found:349.1914; [M+Na] + :371.1730; found:371.1734.
2e(2R,2’R)-2,2’-联哌啶2e(2R,2’R)-2,2’-Bipiperidine
Figure PCTCN2020088988-appb-000125
Figure PCTCN2020088988-appb-000125
无色液体；71％产率；99％ee；ee值由其衍生物所得.旋光:[α] D 25＝-10.0[c＝1.10,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ3.02(d,J＝13.5Hz,2H),2.50(td,J＝11.8,3.6Hz,2H),2.24-2.20(m,2H),2.17(s,2H),1.75(d,J＝4.4Hz,2H),1.64(d,J＝13.0Hz,2H),1.50(s,0H),1.39-1.21(m,4H),1.02(ddq,J＝15.9,11.8,7.2,5.3Hz,2H)； 13C NMR(126MHz,CDCl 3):δ63.8,46.4,29.1,25.4；ESI-MS:M/z 169.00[M+H] +；HRMS(ESI)calcd.for C 10H 21N 2,[M+H] +:169.1699；found:169.1698. Colorless liquid; 71% yield; 99% ee; ee value obtained from its derivatives. Optical rotation: [α] D 25 ＝-10.0 [c=1.10, CHCl 3 ]. 1 H NMR (500MHz, CDCl 3 ): δ3.02(d,J=13.5Hz,2H), 2.50(td,J=11.8,3.6Hz,2H), 2.24-2.20(m,2H), 2.17(s,2H), 1.75(d,J= 4.4Hz, 2H), 1.64 (d, J = 13.0 Hz, 2H), 1.50 (s, 0H), 1.39-1.21 (m, 4H), 1.02 (ddq, J = 15.9, 11.8, 7.2, 5.3 Hz, 2H ); 13 C NMR(126MHz, CDCl 3 ): δ63.8, 46.4, 29.1,25.4; ESI-MS: M/z 169.00[M+H] + ; HRMS(ESI)calcd.for C 10 H 21 N 2 ,[M+H] + :169.1699; found:169.1698.
(2R,2’R)-2,2’-联哌啶-1,1’-二苯甲酰胺(2R,2’R)-2,2’-Bipiperidine-1,1’-Dibenzamide
Figure PCTCN2020088988-appb-000126
Figure PCTCN2020088988-appb-000126
将手性二胺(17.0mg,0.1mmol)和Et 3N(0.044ml,0.3mmol)溶于DCM(4.0mL)中，苯甲酰氯(31mg,0.22mmol)溶于DCM(2.0ml)，滴加到上述体系中，使温度保持在室温，搅拌3-4小时，反应完成(由薄层色谱监测)。二胺完全消耗后，用水淬灭反应(2.0mL),DCM萃取，有机相合并，无水硫酸钠干燥，柱层析得到白色固体。 The chiral diamine (17.0mg, 0.1mmol) and Et 3 N (0.044ml, 0.3mmol) were dissolved in DCM (4.0mL), and benzoyl chloride (31mg, 0.22mmol) was dissolved in DCM (2.0ml). Add to the above system, keep the temperature at room temperature, stir for 3-4 hours, and complete the reaction (monitored by thin layer chromatography). After the diamine was completely consumed, the reaction was quenched with water (2.0 mL), extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography gave a white solid.
白色固体；98％ee；ee值由高压手性液相测定；高压液相条件：手性柱IA,正己烷/异丙醇60/40,25℃,流速0.7mL/min,250nm,8.25min(S,S),11.87min(R,R).旋光:[α] D 25＝129.0[c＝1.25,CHCl 3]. 1H NMR(500MHz,CDCl 3):δ7.34-7.26(m,10H),5.50(s,2H),3.70(td,J＝13.6,3.2Hz,2H),3.58(dd,J＝14.1,3.6Hz,2H),1.93(d,J＝13.8Hz,2H),1.77(t,J＝13.4Hz,2H),1.67-1.58(m,6H),1.40-1.31(m,2H)； 13C NMR(126MHz,CDCl 3):δ171.0,136.3,129.3,128.3,127.0,46.4,44.3,26.2,26.1,18.9；ESI-MS:M/z 377.25[M+H] +；HRMS(ESI)calcd.for C 24H 29N 2O 2[M+H] +:377.2224；found:377.2225；[M+Na] +:399.2043；found:399.2040. White solid; 98%ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column IA, n-hexane/isopropanol 60/40, 25℃, flow rate 0.7mL/min, 250nm, 8.25min (S,S),11.87min(R,R). Optical rotation: [α] D 25 ＝129.0[c＝1.25,CHCl 3 ]. 1 H NMR(500MHz,CDCl 3 ):δ7.34-7.26(m, 10H), 5.50 (s, 2H), 3.70 (td, J = 13.6, 3.2 Hz, 2H), 3.58 (dd, J = 14.1, 3.6 Hz, 2H), 1.93 (d, J = 13.8 Hz, 2H), 1.77 (t, J = 13.4 Hz, 2H), 1.67-1.58 (m, 6H), 1.40-1.31 (m, 2H); 13 C NMR (126MHz, CDCl 3 ): δ171.0, 136.3, 129.3, 128.3, 127.0, 46.4,44.3,26.2,26.1,18.9; ESI-MS: M/z 377.25[M+H] + ; HRMS(ESI)calcd.for C 24 H 29 N 2 O 2 [M+H] + : 377.2224; found :377.2225; [M+Na] + :399.2043; found:399.2040.
3e(1R,1'R)-1,1',2,2',3,3',4,4'-8氢-1,1'-联异喹啉3e(1R,1'R)-1,1',2,2',3,3',4,4'-8 hydrogen-1,1'-biisoquinoline
Figure PCTCN2020088988-appb-000127
Figure PCTCN2020088988-appb-000127
白色固体；80％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱S-Chiral B,正己烷/异丙醇/二乙胺：85/15/0.1,25℃,流速0.7mL/min,13.23min(S,S),14.39min(R,R).旋光:[α] D 27＝-248.7[c＝0.55,CHCl 3]. 1H NMR(500MHz,CDCl 3):7.38(d,J＝7.7Hz,2H),7.24(t,J＝7.8Hz,2H),7.18(t,J＝7.5Hz,2H),7.12(d,J＝7.6Hz,2H),4.70(s, 2H),3.21(dd,J＝11.7,4.8Hz,2H),3.03-2.88(m,2H),2.88-2.78(m,2H),2.63(d,J＝15.6Hz,2H),1.91(s,2H)； 13C NMR(126MHz,CDCl 3):δ137.4,136.6,129.4,126.3,126.2,125.2,60.1,42.9,30.4；ESI-MS:M/z 265.05[M+H] +；HRMS(ESI)calcd.for C 18H 21N 2,[M+H] +:265.1699；found:265.1701. White solid; 80% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column S-Chiral B, n-hexane/isopropanol/diethylamine: 85/15/ 0.1, 25℃, flow rate 0.7mL/min, 13.23min(S,S), 14.39min(R,R). Optical rotation: [α] D 27 ＝-248.7[c＝0.55,CHCl 3 ]. 1 H NMR( 500MHz, CDCl 3 ): 7.38 (d, J = 7.7 Hz, 2H), 7.24 (t, J = 7.8 Hz, 2H), 7.18 (t, J = 7.5 Hz, 2H), 7.12 (d, J = 7.6 Hz ,2H),4.70(s, 2H),3.21(dd,J=11.7,4.8Hz,2H),3.03-2.88(m,2H),2.88-2.78(m,2H),2.63(d,J=15.6 Hz, 2H), 1.91 (s, 2H); 13 C NMR (126MHz, CDCl 3 ): δ 137.4, 136.6, 129.4, 126.3, 126.2, 125.2, 60.1, 42.9, 30.4; ESI-MS: M/z 265.05[M +H] + ;HRMS(ESI)calcd.for C 18 H 21 N 2 ,[M+H] + :265.1699;found:265.1701.
4e(5R,5'R)-6,6',7,7'-4氢-5H,5'H-二苯并[c,e]吖庚因4e(5R,5'R)-6,6',7,7'-4hydro-5H,5'H-dibenzo[c,e]azepine
Figure PCTCN2020088988-appb-000128
Figure PCTCN2020088988-appb-000128
白色固体；55％产率；99％ee；ee值由高压手性液相测定；高压液相条件：手性柱AD-H,正己烷/异丙醇80/20,23℃,流速1.0mL/min,5.74min(S,S),6.94min(R,R).旋光:[α] D 25＝-9.1[c＝1.00,CHCl 3]. 1H NMR(500MHz,CDCl 3):77.66(t,J＝7.9Hz,2H),7.60(d,J＝7.4Hz,2H),7.52(dd,J＝16.6,7.5Hz,4H),7.42(t,J＝7.4Hz,2H),7.30(t,J＝7.2Hz,2H),7.12(t,J＝7.6Hz,2H),6.63(d,J＝7.9Hz,2H),5.07(s,2H),4.28(d,J＝12.7Hz,2H),3.88(s,2H),3.67(d,J＝12.7Hz,2H)； 13C NMR(126MHz,CDCl 3):δ140.7,139.4,131.2,131.0,130.3,129.5,129.2,128.9,128.2,127.9,127.6,126.8,53.2,46.9；ESI-MS:M/z 389.30[M+H] +；HRMS(ESI)calcd.for C 28H 25N 2,[M+H] +:389.2012；found:389.2017. White solid; 55% yield; 99% ee; ee value is determined by high-pressure chiral liquid phase; high-pressure liquid phase conditions: chiral column AD-H, n-hexane/isopropanol 80/20, 23°C, flow rate 1.0 mL /min,5.74min(S,S),6.94min(R,R). Optical rotation: [α] D 25 ＝-9.1[c＝1.00, CHCl 3 ]. 1 H NMR(500MHz, CDCl 3 ): 77.66( t,J=7.9Hz,2H),7.60(d,J=7.4Hz,2H),7.52(dd,J=16.6,7.5Hz,4H),7.42(t,J=7.4Hz,2H),7.30( t,J=7.2Hz,2H),7.12(t,J=7.6Hz,2H),6.63(d,J=7.9Hz,2H),5.07(s,2H),4.28(d,J=12.7Hz, 2H), 3.88 (s, 2H), 3.67 (d, J = 12.7 Hz, 2H); 13 C NMR (126MHz, CDCl 3 ): δ 140.7, 139.4, 131.2, 131.0, 130.3, 129.5, 129.2, 128.9, 128.2, 127.9,127.6,126.8,53.2,46.9; ESI-MS: M/z 389.30[M+H] + ; HRMS(ESI)calcd.for C 28 H 25 N 2 ,[M+H] + :389.2012; found: 389.2017.
实施例5Example 5
Figure PCTCN2020088988-appb-000129
Figure PCTCN2020088988-appb-000129
Figure PCTCN2020088988-appb-000130
Figure PCTCN2020088988-appb-000130
在干净干燥的shlenk管中，加入苯甲醛(0.2mmol,1.0eq)，体系抽换氮气三次，氮气保护，在氮气保护下，加入氨甲醇溶液(7.0M,3.0mmol,15.0eq)，加溶剂重蒸四氢呋喃(2mL)，体系密封，反应室温搅拌1h，在氮气保护下，加入{体系一：[双醇diol(1-8)(0.08mmol,0.4eq)和B 2(neo) 2(0.15mmol，0.75eq)]，或者，体系二：[DB(1-4)(0.11mmol,0.55eq)]}，室温(25-30℃)下搅拌12-24h。体系旋蒸除去多余氨气，加入1mL甲醇，加入盐酸(3.0M，1mL)调pH至3左右，二氯甲烷多次洗涤，水相加入氢氧化钠溶液调pH至12左右，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，有机相旋干即得到产物。产率和ee值见表1。 In a clean and dry shlenk tube, add benzaldehyde (0.2mmol, 1.0eq), change the system with nitrogen three times, and under nitrogen protection, add ammonia methanol solution (7.0M, 3.0mmol, 15.0eq), add solvent Re-evaporate tetrahydrofuran (2mL), seal the system, and stir the reaction at room temperature for 1h. Under nitrogen protection, add {System 1: [Dioldiol(1-8)(0.08mmol,0.4eq) and B 2 (neo) 2 (0.15 mmol, 0.75eq)], or system two: [DB(1-4)(0.11mmol, 0.55eq)]}, stirring at room temperature (25-30°C) for 12-24h. Rotate the system to remove excess ammonia gas, add 1 mL of methanol, add hydrochloric acid (3.0M, 1 mL) to adjust the pH to about 3, wash with dichloromethane several times, add sodium hydroxide solution to the aqueous phase to adjust the pH to about 12, and extract with dichloromethane , Combine the organic phases, dry with anhydrous sodium sulfate, and spin-dry the organic phase to obtain the product. The yield and ee value are shown in Table 1.
表1Table 1
序号Serial number 联硼酸酯Biborate 溶剂Solvent 产率(％)Yield(%) ee值(％)ee value (%)
11 DB 1DB 1 MeOHMeOH 3535 4545
22 DB 1DB 1 THFTHF 6161 5151
33 DB 1DB 1 DioxaneDioxane 5555 4242
44 DB 1DB 1 TolueneToluene 3535 4848
55 DB 1DB 1 MTBEMTBE 4040 4949
66 DB 2DB 2 THFTHF 7272 5757
77 DB 3DB 3 THFTHF 8080 2020
88 DB 4DB 4 THFTHF 8282 9595
99 DB 5DB 5 THFTHF 7373 8282
1010 DB 6DB 6 THFTHF 6868 7272
1111 DB 7DB 7 THFTHF 8181 9292
1212 diol 1+B 2(neo) 2 diol 1+B 2 (neo) 2 THFTHF 6060 3030
1313 diol 2+B 2(neo) 2 diol 2+B 2 (neo) 2 THFTHF <5<5 NdNd
1414 diol 4+B 2(neo) 2 diol 4+B 2 (neo) 2 THFTHF 7171 8080
1515 diol 5+B 2(neo) 2 diol 5+B 2 (neo) 2 THFTHF 8181 9393
1616 diol 6+B 2(neo) 2 diol 6+B 2 (neo) 2 THFTHF 7575 6868
1717 diol 8+B 2(neo) 2 diol 8+B 2 (neo) 2 THFTHF 7878 9292
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention. Revise. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims (17)

  1. 一种如式1所示的联硼酸二醇酯；A glycol diborate as shown in formula 1;
    Figure PCTCN2020088988-appb-100001
    Figure PCTCN2020088988-appb-100001
    其中，C 1和C 2同时为R构型碳原子或S构型碳原子； Wherein, C 1 and C 2 are both R configuration carbon atoms or S configuration carbon atoms;
    R 1为苯基、或、卤素取代的苯基；R 2与R 1相同； R 1 is phenyl, or phenyl substituted with halogen; R 2 is the same as R 1;
    C 3为非手性碳原子； C 3 is an achiral carbon atom;
    R 3-1为R 3-1-1取代的苯基，所述的R 3-1-1独立地为C 1～C 3的烷基或C 1～C 3的烷氧基；R 3-2与R 3-1相同； R 3-1 is a phenyl substituted by R 3-1-1 , said R 3-1-1 is independently a C 1 ～C 3 alkyl group or a C 1 ～C 3 alkoxy group; R 3- 2 Same as R 3-1 ;
    C 4为非手性碳原子； C 4 is an achiral carbon atom;
    R 4-1为R 4-1-1取代的苯基，所述的R 4-1-1独立地为C 1～C 3的烷基或C 1～C 3的烷氧基；R 4-2与R 4-1相同。 R 4-1 is a phenyl substituted by R 4-1-1 , said R 4-1-1 is independently a C 1 ～C 3 alkyl group or a C 1 ～C 3 alkoxy group; R 4- 2 The same as R 4-1.
  2. 如权利要求1所述的联硼酸二醇酯1，其特征在于，当所述的R 1为卤素取代的苯基时，所述的卤素的个数为1个、2个、3个、4个或5个，当存在2个以上的卤素时，所述的卤素相同或不同； The glycol diborate 1 according to claim 1, wherein when said R 1 is a halogen-substituted phenyl group, the number of halogens is 1, 2, 3, 4. One or five, when there are more than two halogens, the halogens are the same or different;
    和/或，当所述的R 1为卤素取代的苯基时，所述的卤素独立地为氟、氯、溴或碘； And/or, when said R 1 is a halogen-substituted phenyl group, said halogen is independently fluorine, chlorine, bromine or iodine;
    和/或，当所述的R 1为卤素取代的苯基时，所述的卤素独立地与所述的C 1互为邻位、间位或对位； And/or, when said R 1 is a halogen-substituted phenyl group, said halogen and said C 1 are mutually ortho, meta or para;
    和/或，所述的R 3-1-1的个数为1个、2个、3个、4个或5个，当存在2个以上的R 3- 1-1时，所述的R 3-1-1相同或不同； And/or, the number of R 3-1-1 is 1, 2, 3, 4 or 5. When there are more than two R 3- 1-1 , the R 3-1-1 3-1-1 the same or different;
    和/或，所述的R 3-1-1独立地与所述的C 3互为邻位、间位或对位； And/or, said R 3-1-1 and said C 3 are mutually ortho, meta or para;
    和/或，当所述的R 3-1-1为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R 3-1-1 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is methyl, ethyl, n-propyl or isopropyl ；
    和/或，当所述的R 3-1-1为C 1～C 3的烷氧基时，所述的C 1～C 3的烷氧基为甲氧基、乙氧基、正丙氧基或异丙氧基； And/or, when the R 3-1-1 is a C 1 ～C 3 alkoxy group, the C 1 ～C 3 alkoxy group is methoxy, ethoxy, n-propoxy Group or isopropoxy;
    和/或，所述的R 4-1-1的个数为1个、2个、3个、4个或5个，当存在2个以上的R 4- 1-1时，所述的R 4-1-1相同或不同； And/or, the number of R 4-1-1 is 1, 2, 3, 4, or 5, and when there are more than two R 4- 1-1 , the R 4-1-1 4-1-1 the same or different;
    和/或，所述的R 4-1-1独立地与所述的C 4互为邻位、间位或对位； And/or, said R 4-1-1 and said C 4 are mutually ortho, meta or para;
    和/或，当所述的R 4-1-1为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙 基或异丙基； And/or, when the R 4-1-1 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is methyl, ethyl, n-propyl or isopropyl ；
    和/或，当所述的R 4-1-1为C 1～C 3的烷氧基时，所述的C 1～C 3的烷氧基为甲氧基、乙氧基、正丙氧基或异丙氧基。 And/or, when the R 4-1-1 is a C 1 ～C 3 alkoxy group, the C 1 ～C 3 alkoxy group is methoxy, ethoxy, n-propoxy基 or isopropoxy.
  3. 如权利要求2所述的联硼酸二醇酯1，其特征在于，当所述的R 1为卤素取代的苯基时，所述的卤素的个数为1个或2个； 2. The glycol diborate 1 according to claim 2, wherein when said R 1 is a halogen-substituted phenyl group, the number of said halogens is 1 or 2;
    和/或，当所述的R 1为卤素取代的苯基时，所述的卤素独立地为氯； And/or, when said R 1 is a halogen-substituted phenyl group, said halogen is independently chlorine;
    和/或，当所述的R 1为卤素取代的苯基时，所述的卤素独立地与所述的C 1互为邻位； And/or, when said R 1 is a halogen-substituted phenyl group, said halogen is independently ortho to each other with said C 1;
    和/或，所述的R 3-1-1的个数为1个或2个； And/or, the number of R 3-1-1 is 1 or 2;
    和/或，所述的R 3-1-1独立地与所述的C 3互为邻位或间位； And/or, said R 3-1-1 and said C 3 are mutually ortho or meta positions independently;
    和/或，当所述的R 3-1-1为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基； And/or, when the R 3-1-1 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is a methyl group;
    和/或，当所述的R 3-1-1为C 1～C 3的烷氧基时，所述的C 1～C 3的烷氧基为甲氧基； And/or, when the R 3-1-1 is a C 1 ～C 3 alkoxy group, the C 1 ～C 3 alkoxy group is a methoxy group;
    和/或，所述的R 4-1-1的个数为1个或2个； And/or, the number of R 4-1-1 is 1 or 2;
    和/或，所述的R 4-1-1独立地与所述的C 4互为邻位或间位； And/or, said R 4-1-1 and said C 4 are mutually ortho or meta positions independently;
    和/或，当所述的R 4-1-1为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基； And/or, when the R 4-1-1 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is a methyl group;
    和/或，当所述的R 4-1-1为C 1～C 3的烷氧基时，所述的C 1～C 3的烷氧基为甲氧基。 And/or, when the R 4-1-1 is a C 1 -C 3 alkoxy group, the C 1 -C 3 alkoxy group is a methoxy group.
  4. 如权利要求3所述的联硼酸二醇酯1，其特征在于，当所述的R 1为卤素取代的苯基时，所述的“卤素取代的苯基”为2-氯苯基； 4. The glycol diboron 1 according to claim 3, wherein when said R 1 is a halogen-substituted phenyl group, the "halogen-substituted phenyl group" is 2-chlorophenyl;
    和/或，所述的R 3-1为2-甲基苯基、4-甲氧基苯基、2,4-二甲基苯基、2,5-二甲基苯基或3,5-二甲基苯基； And/or, said R 3-1 is 2-methylphenyl, 4-methoxyphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl or 3,5 -Dimethylphenyl;
    和/或，所述的R 4-1为2-甲基苯基、4-甲氧基苯基、2,4-二甲基苯基、2,5-二甲基苯基或3,5-二甲基苯基。 And/or, said R 4-1 is 2-methylphenyl, 4-methoxyphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl or 3,5 -Dimethylphenyl.
  5. 如权利要求1所述的联硼酸二醇酯1，其特征在于，R 1与R 2均为苯基； 2. The glycol diborate 1 of claim 1, wherein R 1 and R 2 are both phenyl groups;
    和/或，所述的R 3-1-1独立地为C 1～C 3的烷基；所述的R 4-1-1独立地为C 1～C 3的烷基； And / or said R 3-1-1 is independently a C 1 ~ C 3 alkyl group; said R 4-1-1 is independently a C 1 ~ C 3 alkyl group; and
    和/或，R 3-1和R 4-1相同。 And/or, R 3-1 and R 4-1 are the same.
  6. 如权利要求1所述的联硼酸二醇酯1，其特征在于，R 1与R 2均为苯基； 2. The glycol diborate 1 of claim 1, wherein R 1 and R 2 are both phenyl groups;
    所述的R 3-1-1独立地为C 1～C 3的烷基；所述的R 4-1-1独立地为C 1～C 3的烷基； Said R 3-1-1 is independently a C 1 ～C 3 alkyl group; said R 4-1-1 is independently a C 1 ～C 3 alkyl group;
    R 3-1和R 4-1相同。 R 3-1 is the same as R 4-1.
  7. 如权利要求1所述的联硼酸二醇酯1，其特征在于，其为以下任一化合物：The glycol diborate 1 according to claim 1, wherein it is any of the following compounds:
    Figure PCTCN2020088988-appb-100002
    Figure PCTCN2020088988-appb-100002
  8. 一种如式2所示的二醇；A diol as shown in formula 2;
    Figure PCTCN2020088988-appb-100003
    Figure PCTCN2020088988-appb-100003
    其中，C 2、R 2、C 4、R 4-1和R 4-2的定义独立地如权利要求1～7中任一项所述。 Wherein, the definitions of C 2 , R 2 , C 4 , R 4-1 and R 4-2 are independently as described in any one of claims 1-7.
  9. 如权利要求8所述的二醇2，其特征在于，其为以下任一化合物：The diol 2 of claim 8, wherein it is any of the following compounds:
    Figure PCTCN2020088988-appb-100004
    Figure PCTCN2020088988-appb-100004
  10. 一种如权利要求1～7中任一项所述的联硼酸二醇酯1的制备方法，其包括下述步骤：在溶剂中，将化合物2、化合物3与化合物4进行酯化反应，得到所述的联硼酸二醇酯1即可；A method for preparing glycol diboronic acid ester 1 according to any one of claims 1 to 7, which comprises the following steps: in a solvent, compound 2, compound 3 and compound 4 are subjected to an esterification reaction to obtain The diol diborate 1 is sufficient;
    Figure PCTCN2020088988-appb-100005
    Figure PCTCN2020088988-appb-100005
    其中，R 5-1和R 5-2独立地为氢或C 1～C 3的烷基，或者，R 5-1和R 5-2连接形成-(CR 5-1-1R 5- 1-2) n-；n为1、2或3，所述的R 5-1-1和R 5-1-2独立地为氢或C 1～C 3的烷基； Wherein, R 5-1 and R 5-2 are independently hydrogen or C 1 ~ C 3 alkyl group, or, R 5-1 and R 5-2 are joined to form - (CR 5-1-1 R 5- 1 -2 ) n -; n is 1, 2 or 3, and said R 5-1-1 and R 5-1-2 are independently hydrogen or C 1 ～C 3 alkyl;
    R 5-3和R 5-4独立地为氢或C 1～C 3的烷基，或者，R 5-3和R 5-4连接形成-(CR 5-3-1R 5-3-2) m-；m为1、2或3，所述的R 5-3-1和R 5-3-2独立地为氢或C 1～C 3的烷基。 R 5-3 and R 5-4 are independently hydrogen or a C 1 ～C 3 alkyl group, or R 5-3 and R 5-4 are connected to form -(CR 5-3-1 R 5-3-2 ) m -; m is 1, 2 or 3, said R 5-3-1 and R 5-3-2 are independently hydrogen or a C 1 ～C 3 alkyl group.
  11. 如权利要求10所述的联硼酸二醇酯1的制备方法，其特征在于，当所述的R 5-1为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； The method for preparing glycol diborate 1 according to claim 10, wherein when said R 5-1 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkane The group is methyl, ethyl, n-propyl or isopropyl;
    和/或，当所述的R 5-2为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R 5-2 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is a methyl, ethyl, n-propyl or isopropyl group;
    和/或，当所述的R 5-1-1为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R 5-1-1 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is methyl, ethyl, n-propyl or isopropyl ；
    和/或，当所述的R 5-1-2为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R 5-1-2 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is methyl, ethyl, n-propyl or isopropyl ；
    和/或，当所述的R 5-3为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R 5-3 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is a methyl group, an ethyl group, a n-propyl group or an isopropyl group;
    和/或，当所述的R 5-4为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R 5-4 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is a methyl group, an ethyl group, a n-propyl group or an isopropyl group;
    和/或，当所述的R 5-3-1为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R 5-3-1 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is methyl, ethyl, n-propyl or isopropyl ；
    和/或，当所述的R 5-3-2为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R 5-3-2 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is a methyl, ethyl, n-propyl or isopropyl group ；
    和/或，所述的酯化反应在氮气或惰性气体的存在下进行；And/or, the esterification reaction is carried out in the presence of nitrogen or inert gas;
    和/或，所述的酯化反应在分子筛的存在下进行；And/or, the esterification reaction is carried out in the presence of molecular sieves;
    和/或，所述的溶剂为醚类溶剂；And/or, the solvent is an ether solvent;
    和/或，所述的溶剂与所述的化合物4的体积摩尔比为3.0～3.5L/mol；And/or, the volume molar ratio of the solvent to the compound 4 is 3.0-3.5 L/mol;
    和/或，所述的化合物2与所述的化合物4的摩尔比为(1～1.2)：1；And/or, the molar ratio of the compound 2 to the compound 4 is (1 to 1.2):1;
    和/或，所述的化合物3与所述的化合物4的摩尔比为(1～1.2)：1；And/or, the molar ratio of the compound 3 to the compound 4 is (1 to 1.2):1;
    和/或，所述的酯化反应的温度为60～70℃。And/or, the temperature of the esterification reaction is 60-70°C.
  12. 如权利要求11所述的联硼酸二醇酯1的制备方法，其特征在于，当所述的R 5-1和R 5-2连接形成-(CR 5-1-1R 5-1-2) n-时，所述的-(CR 5-1-1R 5-1-2) n-为-CH 2C(CH 3) 2CH 2-； The method for preparing glycol diborates 1 according to claim 11, wherein when said R 5-1 and R 5-2 are connected to form -(CR 5-1-1 R 5-1-2 ) n -, said -(CR 5-1-1 R 5-1-2 ) n -is -CH 2 C(CH 3 ) 2 CH 2 -;
    和/或，当所述的R 5-3和R 5-4连接形成-(CR 5-3-1R 5-3-2) m-时，所述的-(CR 5-3-1R 5-3-2) m-为-CH 2C(CH 3) 2CH 2-； And/or, when said R 5-3 and R 5-4 are connected to form -(CR 5-3-1 R 5-3-2 ) m -, said -(CR 5-3-1 R 5-3-2 ) m -is -CH 2 C(CH 3 ) 2 CH 2 -;
    和/或，所述的酯化反应在4A分子筛的存在下进行；And/or, the esterification reaction is carried out in the presence of 4A molecular sieve;
    和/或，所述的溶剂为四氢呋喃；And/or, the solvent is tetrahydrofuran;
    和/或，所述的酯化反应的温度为60～66℃。And/or, the temperature of the esterification reaction is 60-66°C.
  13. 一种如式A所示的二胺的制备方法，其包括下述步骤：在溶剂中，将化合物B与偶联试剂进行偶联反应，得到所述的二胺A即可；A method for preparing diamine as shown in formula A, which comprises the following steps: in a solvent, compound B is coupled with a coupling reagent to obtain the diamine A;
    所述的偶联试剂为化合物1或偶联试剂组合物，所述的偶联试剂组合物为化合物2、化合物3和化合物4；The coupling reagent is compound 1 or a coupling reagent composition, and the coupling reagent composition is compound 2, compound 3 and compound 4;
    Figure PCTCN2020088988-appb-100006
    Figure PCTCN2020088988-appb-100006
    其中，C 1、R 1、C 2、R 2、C 3、R 3-1、R 3-2、C 4、R 4-1和R 4-2的定义独立地如权利要求1～7中任一项所述；R 5-1、R 5-2、R 5-3和R 5-4的定义独立地如权利要求10～12中任一项所述； Wherein, C 1 , R 1 , C 2 , R 2 , C 3 , R 3-1 , R 3-2 , C 4 , R 4-1 and R 4-2 are independently defined as in claims 1-7 The definitions of R 5-1 , R 5-2 , R 5-3 and R 5-4 are independently as described in any one of claims 10-12;
    C 5为手性碳原子，其构型与C 1相同；C 6为手性碳原子，其构型与C 2相同； C 5 is a chiral carbon atom, and its configuration is the same as C 1 ; C 6 is a chiral carbon atom, and its configuration is the same as C 2;
    R 6-1为氢或C 1～C 3的烷基； R 6-1 is hydrogen or C 1 ～C 3 alkyl;
    R 6-2为C 1-C 20的烷基、C 3-C 10的环烷基、苯基、萘基、“杂原子数为1～2个，杂原子选自N、O和S中的一种或多种的5～6元杂芳基”、R 6-2-2取代的C 1-C 20的烷基、或、R 6- 2-1取代的苯基； R 6-2 is a C 1 -C 20 alkyl group, a C 3 -C 10 cycloalkyl group, a phenyl group, a naphthyl group, "the number of heteroatoms is 1 to 2, and the heteroatoms are selected from N, O and S One or more 5- to 6-membered heteroaryl groups", C 1 -C 20 alkyl substituted with R 6-2-2 , or phenyl substituted with R 6- 2-1;
    所述的R 6-2-2和R 6-2-1独立地为-C(＝O)-O-C 1～C 3的烷基、卤素、C 1～C 3的烷基、卤素取代的C 1～C 3的烷基、C 2-C 20的烯基、C 2-C 20的炔基、N-(C 1～C 3的烷基)-苯甲酰胺基、苯基、C 1～C 3的烷氧基、卤素取代的C 1～C 3的烷氧基、或、任选被羰基取代的C 3-C 20的环烷基； Said R 6-2-2 and R 6-2-1 are independently -C(=O)-OC 1 ～C 3 alkyl, halogen, C 1 ～C 3 alkyl, halogen substituted C 1 ～C 3 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, N-(C 1 ～C 3 alkyl)-benzamide group, phenyl, C 1 ～ C 3 alkoxy, halogen-substituted C 1 -C 3 alkoxy, or, C 3 -C 20 cycloalkyl optionally substituted by carbonyl;
    或者，式B中，R 6-1与R 6-2相连，与其连接的
    Figure PCTCN2020088988-appb-100007
    一起形成4-7元杂环烯基；所述的4-7元杂环烯基任选被取代基取代。     Or, in formula B, R 6-1 is connected to R 6-2 , and the connected
    Figure PCTCN2020088988-appb-100007
    Together to form a 4-7 membered heterocycloalkenyl group; the 4-7 membered heterocycloalkenyl group is optionally substituted by a substituent.
  14. 如权利要求13所述的二胺A的制备方法，其特征在于，当所述的R 6-1为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； The method for preparing diamine A according to claim 13, wherein when the R 6-1 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is a methyl group. Group, ethyl, n-propyl or isopropyl;
    和/或，当所述的R 6-2为C 1-C 20的烷基或R 6-2-2取代的C 1-C 20的烷基时，所述的C 1-C 20的烷基和R 6-2-2取代的C 1-C 20的烷基里的C 1-C 20的烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或正十一烷基； And / or, when said R 6-2 is C 1 -C alkyl or R 6-2-2 20 substituted C 1 -C 20 alkyl, said C 1 -C 20 alkoxy is The C 1 -C 20 alkyl group in the C 1 -C 20 alkyl group substituted with R 6-2-2 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl or n-undecyl;
    和/或，当所述的R 6-2为C 3-C 10的环烷基时，所述的C 3-C 10的环烷基为环己基； And/or, when the R 6-2 is a C 3 -C 10 cycloalkyl group, the C 3 -C 10 cycloalkyl group is a cyclohexyl group;
    和/或，当所述的R 6-2为萘基时，所述的萘基为1-萘基或2-萘基； And/or, when the R 6-2 is naphthyl, the naphthyl is 1-naphthyl or 2-naphthyl;
    和/或，当所述的R 6-2为“杂原子数为1～2个，杂原子选自N、O和S中的一种或多种的5～6元杂芳基”时，所述的“杂原子数为1～2个，杂原子选自N、O和S中的一种或多种的5～6元杂芳基”为呋喃基或噻吩基； And/or, when said R 6-2 is a "5- to 6-membered heteroaryl group with 1 to 2 heteroatoms selected from one or more of N, O and S", The "5- to 6-membered heteroaryl group having 1 to 2 heteroatoms and one or more heteroatoms selected from N, O and S" is furyl or thienyl;
    和/或，当所述的R 6-2为R 6-2-1取代的苯基时，所述的R 6-2-1的个数为1个、2个、3个、4个或5个，当存在2个以上的R 6-2-1时，所述的R 6-2-1相同或不同； And / or, when the phenyl is substituted with R 6-2 R 6-2-1 and R 6-2-1 is the number 1, 2, 3, 4, or Five, when there are more than two R 6-2-1 , the R 6-2-1 is the same or different;
    和/或，当所述的R 6-2为R 6-2-1取代的苯基时，所述的R 6-2-1独立地与所述的亚胺双键互为邻位、间位或对位；或，当R 6-2-1为任选被羰基取代的C 3-C 20的环烷基时，R 6-2-1独立地与所述的苯基并环连接； And/or, when the R 6-2 is a phenyl substituted by R 6-2-1 , the R 6-2-1 independently and the imine double bond are mutually ortho and meta Position or para position; or, when R 6-2-1 is a C 3 -C 20 cycloalkyl group optionally substituted with a carbonyl group , R 6-2-1 is independently connected to the phenyl ring;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为-C(＝O)-O-C 1～C 3的烷基时，所述的“C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when said R 6-2-2 and R 6-2-1 are independently -C(=O)-OC 1 ～C 3 alkyl, said "C 1 ～C 3 The alkyl group is methyl, ethyl, n-propyl or isopropyl;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为卤素时，所述的卤素为氟、氯、溴或碘； And/or, when said R 6-2-2 and R 6-2-1 are independently halogen, said halogen is fluorine, chlorine, bromine or iodine;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R 6-2-2 and R 6-2-1 are independently C 1 ～C 3 alkyl, the C 1 ～C 3 alkyl is methyl, ethyl Group, n-propyl or isopropyl;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为卤素取代的C 1～C 3的烷基时，所述的卤素的个数为1个、2个、3个、4个或5个，当存在2个以上的卤素时，所述的卤素相同或不同； And/or, when R 6-2-2 and R 6-2-1 are independently halogen-substituted C 1 ～C 3 alkyl groups, the number of halogens is one or two , 3, 4 or 5, when there are more than 2 halogens, the halogens are the same or different;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为卤素取代的C 1～C 3的烷基时，所述的卤素独立地为氟、氯、溴或碘； And/or, when R 6-2-2 and R 6-2-1 are independently halogen-substituted C 1 ～C 3 alkyl groups, the halogen is independently fluorine, chlorine, bromine or iodine;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为卤素取代的C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when R 6-2-2 and R 6-2-1 are independently halogen-substituted C 1 ～C 3 alkyl groups, the C 1 ～C 3 alkyl groups are methyl Group, ethyl, n-propyl or isopropyl;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为C 2-C 20的烯基时，所述的C 2-C 20的烯基为丁 -3-烯-1-基、丙-2-烯-1-基或乙烯基； And/or, when the R 6-2-2 and R 6-2-1 are independently C 2 -C 20 alkenyl, the C 2 -C 20 alkenyl is but-3- En-1-yl, prop-2-en-1-yl or vinyl;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为C 2-C 20的炔基时，所述的C 2-C 20的炔基为丁-3-炔-1-基、丙-2-炔-1-基或乙炔基； And/or, when the R 6-2-2 and R 6-2-1 are independently C 2 -C 20 alkynyl, the C 2 -C 20 alkynyl is but-3- Alkyn-1-yl, prop-2-yn-1-yl or ethynyl;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为N-(C 1～C 3的烷基)-苯甲酰胺基时，所述的C 1～C 3的烷基为甲基、乙基、正丙基或异丙基； And/or, when said R 6-2-2 and R 6-2-1 are independently N-(C 1 ～C 3 alkyl)-benzamide group, said C 1 ～C The alkyl group of 3 is methyl, ethyl, n-propyl or isopropyl;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为C 1～C 3的烷氧基时，所述的C 1～C 3的烷氧基为甲氧基、乙氧基、正丙氧基或异丙氧基； And/or, when the R 6-2-2 and R 6-2-1 are independently a C 1 ～C 3 alkoxy group, the C 1 ～C 3 alkoxy group is methoxy Group, ethoxy, n-propoxy or isopropoxy;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为卤素取代的C 1～C 3的烷氧基时，所述的卤素的个数为1个、2个、3个、4个或5个，当存在2个以上的卤素时，所述的卤素相同或不同； And/or, when R 6-2-2 and R 6-2-1 are independently halogen-substituted C 1 ～C 3 alkoxy groups, the number of halogens is 1, 2 One, three, four or five, when there are more than two halogens, the halogens are the same or different;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为卤素取代的C 1～C 3的烷氧基时，所述的卤素独立地为氟、氯、溴或碘； And/or, when the R 6-2-2 and R 6-2-1 are independently halogen-substituted C 1 ～C 3 alkoxy groups, the halogen is independently fluorine, chlorine, bromine Or iodine;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为卤素取代的C 1～C 3的烷氧基时，所述的C 1～C 3的烷氧基为甲氧基、乙氧基、正丙氧基或异丙氧基； And/or, when R 6-2-2 and R 6-2-1 are independently halogen-substituted C 1 ～C 3 alkoxy groups, the C 1 ～C 3 alkoxy groups It is methoxy, ethoxy, n-propoxy or isopropoxy;
    和/或，当所述的R 6-2-2和R 6-2-1独立地为任选被羰基取代的C 3-C 20的环烷基时，所述的任选被羰基取代的C 3-C 20的环烷基独立地为
    Figure PCTCN2020088988-appb-100008
    a侧与所述的苯基并环连接；     And/or, when said R 6-2-2 and R 6-2-1 are independently a C 3 -C 20 cycloalkyl group optionally substituted with a carbonyl group, the said group optionally substituted with a carbonyl group The C 3 -C 20 cycloalkyl group is independently
    Figure PCTCN2020088988-appb-100008
    The a side is connected to the phenyl group ring;
    和/或，当式B中，R 6-1与R 6-2相连，与其连接的
    Figure PCTCN2020088988-appb-100009
    一起形成4-7元杂环烯基、所述的4-7元杂环烯基任选被取代基取代时，所述的4-7元杂环烯基为
    Figure PCTCN2020088988-appb-100010
    Figure PCTCN2020088988-appb-100011
    And/or, when in formula B, R 6-1 is connected to R 6-2 , the connected
    Figure PCTCN2020088988-appb-100009
    When together forming a 4-7 membered heterocycloalkenyl group, the 4-7 membered heterocycloalkenyl group is optionally substituted by a substituent, the 4-7 membered heterocycloalkenyl group is
    Figure PCTCN2020088988-appb-100010
    Figure PCTCN2020088988-appb-100011
    和/或，所述的偶联反应在氮气或惰性气体的存在下进行；And/or, the coupling reaction is carried out in the presence of nitrogen or inert gas;
    和/或，所述的溶剂为醚类溶剂和/或醇类溶剂；And/or, the solvent is ether solvent and/or alcohol solvent;
    和/或，所述的溶剂与所述的化合物B的体积摩尔比为15～25L/mol；And/or, the volume molar ratio of the solvent to the compound B is 15-25L/mol;
    和/或，所述的化合物1与所述的化合物B的摩尔比为(0.5～0.6)：1；And/or, the molar ratio of the compound 1 to the compound B is (0.5-0.6):1;
    和/或，所述的化合物2与所述的化合物B的摩尔比为(0.2～1.0)：1；And/or, the molar ratio of the compound 2 to the compound B is (0.2-1.0):1;
    和/或，所述的化合物3与所述的化合物B的摩尔比为(0.2～1.0)：1；And/or, the molar ratio of the compound 3 to the compound B is (0.2-1.0):1;
    和/或，所述的化合物4与所述的化合物B的摩尔比为(0.7～0.8)：1；And/or, the molar ratio of the compound 4 to the compound B is (0.7-0.8):1;
    和/或，所述的偶联反应的温度为20-30℃。And/or, the temperature of the coupling reaction is 20-30°C.
  15. 如权利要求14所述的二胺A的制备方法，其特征在于，当所述的R 6-1为C 1～C 3的烷基时，所述的C 1～C 3的烷基为甲基； The method for preparing diamine A according to claim 14, wherein when the R 6-1 is a C 1 ～C 3 alkyl group, the C 1 ～C 3 alkyl group is a methyl group. base;
    和/或，当所述的R 6-2为“杂原子数为1～2个，杂原子选自N、O和S中的一种或多种的5～6元杂芳基”时，所述的“杂原子数为1～2个，杂原子选自N、O和S中的一种或多种的5～6元杂芳基”为呋喃-2-基、噻吩-2-基、呋喃-3-基或噻吩-3-基； And/or, when said R 6-2 is a "5- to 6-membered heteroaryl group with 1 to 2 heteroatoms selected from one or more of N, O and S", The "5 to 6-membered heteroaryl group with 1 to 2 heteroatoms and one or more heteroatoms selected from N, O and S" is furan-2-yl and thiophen-2-yl , Furan-3-yl or thiophen-3-yl;
    和/或，当所述的R 6-2-1为卤素取代的C 1～C 3的烷基时，所述的“卤素取代的C 1～C 3的烷基”为三氟甲基； And/or, when the R 6-2-1 is a halogen-substituted C 1 ～C 3 alkyl group, the “halogen-substituted C 1 ～C 3 alkyl group” is a trifluoromethyl group;
    和/或，当所述的R 6-2-1为卤素取代的C 1～C 3的烷氧基时，所述的“卤素取代的C 1～C 3的烷氧基”为三氟甲氧基； And/or, when R 6-2-1 is a halogen-substituted C 1 ～C 3 alkoxy group, the “halogen-substituted C 1 ～C 3 alkoxy group” is trifluoromethyl Oxy;
    和/或，当所述的溶剂为醚类溶剂和/或醇类溶剂时，所述的醚类溶剂为四氢呋喃；And/or, when the solvent is an ether solvent and/or an alcohol solvent, the ether solvent is tetrahydrofuran;
    和/或，当所述的溶剂为醚类溶剂和/或醇类溶剂时，所述的醇类溶剂为甲醇；And/or, when the solvent is an ether solvent and/or an alcohol solvent, the alcohol solvent is methanol;
    和/或，当所述的溶剂为醚类溶剂和/或醇类溶剂时，所述的醚类溶剂和所述的醇类溶剂的体积比为5：1；And/or, when the solvent is an ether solvent and/or an alcohol solvent, the volume ratio of the ether solvent to the alcohol solvent is 5:1;
    和/或，所述的溶剂与所述的化合物B的体积摩尔比为18～22L/mol；And/or, the volume molar ratio of the solvent to the compound B is 18-22 L/mol;
    和/或，所述的化合物1与所述的化合物B的摩尔比为0.55：1；And/or, the molar ratio of the compound 1 to the compound B is 0.55:1;
    和/或，所述的化合物4与所述的化合物B的摩尔比为0.75：1；And/or, the molar ratio of the compound 4 to the compound B is 0.75:1;
    和/或，所述的偶联反应的温度为25-30℃。And/or, the temperature of the coupling reaction is 25-30°C.
  16. 如权利要求13所述的二胺A的制备方法，其特征在于，所述的二胺A为以下任一化合物：The method for preparing diamine A according to claim 13, wherein the diamine A is any one of the following compounds:
    Figure PCTCN2020088988-appb-100012
    Figure PCTCN2020088988-appb-100012
    Figure PCTCN2020088988-appb-100013
    Figure PCTCN2020088988-appb-100013
    Figure PCTCN2020088988-appb-100014
    Figure PCTCN2020088988-appb-100014
    Figure PCTCN2020088988-appb-100015
    Figure PCTCN2020088988-appb-100015
  17. 一种二胺A或化合物B，其为下述任一化合物：A diamine A or compound B, which is any of the following compounds:
    Figure PCTCN2020088988-appb-100016
    Figure PCTCN2020088988-appb-100016
    Figure PCTCN2020088988-appb-100017
    Figure PCTCN2020088988-appb-100017
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108929268A (en) * 2017-05-23 2018-12-04 中国科学院上海有机化学研究所 Chiral 1,2- diamine compound and its synthetic method
CN111440205A (en) * 2019-01-16 2020-07-24 中国科学院上海有机化学研究所 Biboric acid diol ester, preparation method thereof, intermediate thereof and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108929268A (en) * 2017-05-23 2018-12-04 中国科学院上海有机化学研究所 Chiral 1,2- diamine compound and its synthetic method
CN111440205A (en) * 2019-01-16 2020-07-24 中国科学院上海有机化学研究所 Biboric acid diol ester, preparation method thereof, intermediate thereof and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEN DONGPING, XU GUANGQING, ZHOU QINGHAI, CHUNG LUNG WA, TANG WENJUN: "Practical and Asymmetric Reductive Coupling of Isoquinolines Templated by Chiral Diborons", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 139, no. 29, 26 July 2017 (2017-07-26), pages 9767 - 9770, XP055863699, ISSN: 0002-7863, DOI: 10.1021/jacs.7b04256 *

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