Chiral amino alcohol compound containing carbamate structure and preparation method thereof

Abstract

The invention relates to a chiral amino alcohol compound containing a carbamate structure and a preparation method thereof, the compound is an N-substituted 1, 2-chiral amino alcohol compound, and the structural formula of the compound is as shown in formula (I): # imgabs0. Under the catalysis of a non-C2 symmetric azaspiropyrrolidine oxazoline chiral ligand, cuprous acetate and potassium iodide, the chiral amino alcohol compound containing the carbamate structure is synthesized into a chiral amino alcohol compound containing the carbamate structure, and the chiral amino alcohol compound containing the carbamate structure and the preparation method of the chiral amino alcohol compound containing the carbamate structure are synthesized into the chiral amino alcohol compound containing the carbamate structure. According to the method, serinol and a derivative thereof are desymmetrical by using isocyanate, a higher enantiomer excess value (82%-97%) is obtained, a series of N-substituted 1, 2-chiral amino alcohol compounds with carbamate structures are prepared with higher yield, and the method has better scientific significance and application prospects.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry, and specifically relates to a chiral amino alcohol compound containing a carbamate structure and a preparation method thereof. Background Art

[0002] Chiral amino alcohol structures are not only widely present in drug and natural product molecules, but also play an important role in asymmetric organic synthesis. As cheap chemical products, serinol and its derivatives can be converted into high-value chiral amino alcohols by means of desymmetrization. So far, the desymmetrization work reported on serinol and its derivatives can be divided into two categories according to the desymmetrization reagent: first, the reaction of alcohol with electrophilic reagents, and the desymmetrization reagents include acyl, sulfonyl, aldehyde, ester, anhydride and isocyanate; second, the alcohol substrate contains unsaturated bonds such as carbon-carbon triple bonds, and desymmetrization is achieved through its intramolecular reaction with hydroxyl groups.

[0003] At present, the research on the desymmetrization of serinol and its derivatives using isocyanate is not ideal, and the maximum enantiomeric excess value can only be 66% under the catalysis of Box ligand and copper trifluoromethanesulfonate. The present invention reports the desymmetrization of serinol and its derivatives using isocyanate under the catalysis of non-C2 symmetric azaspiro pyrrolidine oxazoline chiral ligand, cuprous acetate and potassium iodide, and obtains a higher enantiomeric excess value. Summary of the invention

[0004] In view of the problems existing in the prior art, the purpose of the present invention is to provide a chiral amino alcohol compound containing a carbamate structure and a preparation method, which is specifically achieved through the following technical scheme:

[0005] A chiral amino alcohol compound containing a carbamate structure, the compound is an N-substituted 1,2-chiral amino alcohol compound, and its structural formula is shown in formula (I):

[0006]

[0007] In formula (I):

[0008] R 1 Any one of hydrogen, methyl, ethyl, phenyl, benzyl, p-methylphenyl, p-methoxyphenyl, p-methylphenyl, p-fluorophenyl, p-trifluoromethylphenyl, o-methoxyphenyl, o-methylphenyl, m-methylphenyl, m-methoxyphenyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl and ethynyl;

[0009] R 2 Any one of p-methylphenyl, p-nitrophenyl, o-nitrophenyl and ethyl;

[0010] R3 It is any one of p-methylphenyl, p-ethylphenyl, p-methoxyphenyl, p-trifluoromethoxyphenyl, p-trifluoromethylphenyl, p-cyanophenyl, m-methylphenyl, m-methoxyphenyl, m-fluorophenyl, m-dimethylphenyl, o-trifluoromethoxyphenyl, o-fluorophenyl, 1-naphthyl, cyclohexyl, cyclopentyl, tert-butyl and isopropyl.

[0011] Furthermore, the N-substituted 1,2-chiral amino alcohol compound containing a carbamate structure is one of the following:

[0012] When R 1 is methyl, R 2 When it is p-methylphenyl, R 3 It is any one of p-ethylphenyl, p-methoxyphenyl, p-trifluoromethoxyphenyl, p-trifluoromethylphenyl, m-methylphenyl, m-methoxyphenyl, m-fluorophenyl, m-dimethylphenyl, o-trifluoromethoxyphenyl, o-fluorophenyl, 1-naphthyl and cyclopentyl.

[0013] Furthermore, the N-substituted 1,2-chiral amino alcohol compound containing a carbamate structure is any one of the following compounds:

[0014]

[0015] A method for preparing a chiral amino alcohol compound containing a carbamate structure, the method specifically comprising:

[0016] In an air atmosphere, Lewis acid, additives, and a compound represented by formula (IV) are added to a diluent, stirred at room temperature for 30 minutes, a compound represented by formula (II) is added, the temperature is lowered to 0 degrees Celsius, a compound represented by formula (III) is added, and the mixture is stirred at -80-25 degrees Celsius for 16 hours. The reaction is monitored using petroleum ether and ethyl acetate in a volume ratio of 1:1 as a developing solvent. After the reaction is completed, the magnet is removed, and the reaction solution is subjected to silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 3:1 as an eluent, eluting for 5-10 column volumes at an elution rate of 5-15 mL / min. TLC monitoring is performed using petroleum ether and ethyl acetate in a volume ratio of 1:1 as a developing solvent, and an effluent having an Rf value of 0.2-0.3 is collected, and the mixture is evaporated to dryness under reduced pressure to obtain an N-substituted 1,2 chiral amino alcohol compound containing a carbamate structure represented by formula (I); the reaction formula is as follows:

[0017]

[0018] In formula (II), R 1is any one of hydrogen, methyl, ethyl, phenyl, benzyl, p-methylphenyl, p-methoxyphenyl, p-methylphenyl, p-fluorophenyl, p-trifluoromethylphenyl, o-methoxyphenyl, o-methylphenyl, m-methylphenyl, m-methoxyphenyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl and ethynyl; R 2 Any one of p-methylphenyl, p-nitrophenyl, o-nitrophenyl and ethyl;

[0019] In formula (III), R 3 is any one of p-methylphenyl, p-ethylphenyl, p-methoxyphenyl, p-trifluoromethoxyphenyl, p-trifluoromethylphenyl, p-cyanophenyl, m-methylphenyl, m-methoxyphenyl, m-fluorophenyl, m-dimethylphenyl, o-trifluoromethoxyphenyl, o-fluorophenyl, 1-naphthyl, cyclohexyl, cyclopentyl, tert-butyl, and isopropyl;

[0020] In formula (IV), R 4 is any one of isopropyl, tert-butyl, phenyl or benzyl, preferably phenyl;

[0021] In formula (I), R 1 Same as R in formula (II) 1 In formula (I), R 2 Same as R in formula (II) 2 In formula (I), R 3 Same as R in formula (III) 3 .

[0022] Further, the Lewis acid is any one of cupric chloride, cupric bromide, cupric iodide, cupric trifluoromethanesulfonate, cupric acetate, cuprous chloride, cuprous bromide, cuprous iodide, cuprous trifluoromethanesulfonate, and cuprous acetate, preferably cuprous acetate;

[0023] Further, the additive is sodium iodide, potassium iodide, potassium chloride, potassium bromide, tetrabutylammonium iodide, tetrabutylammonium bromide, preferably potassium iodide;

[0024] Furthermore, the diluent is water or an inert organic solvent, and the inert organic solvent includes any one of benzene, toluene, chlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ether, diisopropyl ether, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, and dimethyl sulfoxide, preferably dichloromethane.

[0025] Furthermore, the ratio of the amount of the compound represented by formula (II) to the Lewis acid feed material is 1:0.1, the ratio of the amount of the compound represented by formula (II) to the additive feed material is 1:0.1; the ratio of the amount of the compound represented by formula (II) to the compound represented by formula (III) is 1:1; the ratio of the amount of the compound represented by formula (II) to the compound represented by formula (IV) is 1:0.11; the volume of the diluent used is 10mL / mmol based on the amount of the compound represented by formula (II).

[0026] The present invention provides a chiral amino alcohol compound containing a carbamate structure and a preparation method thereof. Compared with the reported studies, the method can obtain a higher enantiomeric excess value (82%-97%), and compared with other desymmetrization agents, the method does not require the addition of an additional acid absorber or oxidant, which is conducive to industrial scale preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Compound Ⅰ-1 1 H NMR spectra;

[0028] Figure 2 Compound Ⅰ-1 13 C NMR spectra;

[0029] Figure 3 For compound Ⅰ-11 1 H NMR spectra;

[0030] Figure 4 For compound Ⅰ-11 13 C NMR spectrum. DETAILED DESCRIPTION

[0031] The present invention is further described below in conjunction with specific embodiments to facilitate a better understanding of the present technical solution.

[0032] Example 1: (S)-3-Hydroxy-2-methyl-2-((4-methylphenyl)sulfonamido)propyl(4-ethylphenyl)carbamate

[0033] The reaction formula is:

[0034]

[0035] In an air atmosphere, cuprous acetate (0.01 mmol), potassium iodide (0.01 mmol), azaspirocyclic pyrrolidine oxazoline chiral ligand of formula (IV), and dichloromethane (1.0 mL) were added to a 10 mL reaction tube, stirred at room temperature for 30 minutes, N-(1,3-dihydroxy-2-methylpropane-2-yl)-4-methylbenzenesulfonamide (0.1 mmol) of formula (II) was added, cooled to -0 degrees Celsius, and phenethyl isocyanate (0.1 mmol) of formula (III) was added. After the addition, the system temperature was maintained at 0°C and stirred for 16 hours. After the reaction is completed, the reaction solution is subjected to silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 3:1 as the eluent, eluting for 5-10 (preferably 7) column volumes, and an elution rate of 5-15 mL / min (preferably 10 mL / min). TLC monitoring is performed using petroleum ether and ethyl acetate in a volume ratio of 1:1 as the developing solvent. The effluent with an Rf value of 0.2-0.3 is collected, and the effluent is evaporated to dryness under reduced pressure and dried at 40°C for 2h to obtain 21.5 mg of a white solid, namely (S)-3-hydroxy-2-methyl-2-((4-methylphenyl)sulfonamido)propyl(4-ethylphenyl)carbamate, with a yield of 53%, and Mp=79.8-81.5°C. [α] 2 D 5 =10.00 (c 0.1, MeOH). 1 H NMR Figure 1 , 13 C NMR Figure 2 .

[0036] 1 H NMR (500MHz, CDCl3) δ7.76(d,J=8.0Hz,2H),7.19(d,J=8.2Hz,4H),7.05(d,J=8.5Hz,2H),5.95(s,1H),4.13(d,J=11.4Hz,1H),3.97 (d,J=11.5Hz,1H),3.48-3.36(m,2H),3.31(d,J=6.7Hz,1H),2.54(q,J=7.6Hz,2H),2.30(s,3H),1.15(t,J=7.6Hz,3H),1.09(s,3H).

[0037] 13 C NMR (125MHz, CDCl3) δ142.54,138.71,134.10,128.73,127.32,125.84,76.24,66.15,65.05,58.50,27.18,20.44,16.96,14.64.

[0038] HRMS (ESI-TOF) m / z calcd.for C 20 H 26 N2O5S(M+Na) + :429.1455, found 429.1437.

[0039] Enantiomeric excess was determined to be 95% (determined by HPLC using chiral IA column, hexane / 2-propanol=65 / 35, λ=254nm, 30℃, 1mL / min, t major =13.5min,t minor =9.7min).

[0040] Example 2: (S)-3-Hydroxy-2-methyl-2-((4-methylphenyl)sulfonyl)naphthylpropyl ester-1-carbamate

[0041] The reaction formula is:

[0042]

[0043] In an air atmosphere, cuprous acetate (0.01 mmol), potassium iodide (0.01 mmol), azaspirocyclic pyrrolidine oxazoline chiral ligand of formula (IV), and dichloromethane (1.0 mL) were added to a 10 mL reaction tube, stirred at room temperature for 30 minutes, N-(1,3-dihydroxy-2-methylprop-2-yl)-4-methylbenzenesulfonamide (0.1 mmol) of formula (II) was added, cooled to -0 degrees Celsius, and 1-naphthyl isocyanate (0.1 mmol) of formula (III) was added. After the addition, the system temperature was maintained at 0°C and stirred for 16 hours. After the reaction is completed, the reaction solution is subjected to silica gel column chromatography with a volume ratio of 3:1 petroleum ether and ethyl acetate as the eluent, eluting for 5-10 (preferably 7) column volumes, and an elution rate of 5-15 mL / min (preferably 10 mL / min). TLC monitoring is performed with a volume ratio of 1:1 petroleum ether and ethyl acetate as the developing solvent. The effluent with an Rf value of 0.2-0.3 is collected, and the effluent is evaporated to dryness under reduced pressure and dried at 40°C for 2h to obtain 21.5 mg of a white solid, namely (S)-3-hydroxy-2-methyl-2-((4-methylphenyl)sulfonyl)naphthylpropyl ester-1-carbamate, with a yield of 68%. [α]25D=11.00 (c 0.1, MeOH). 1H NMR see Figure 3 , 13C NMR see Figure 4 .

[0044] 1H NMR(500MHz, CDCl3)δ7.90–7.65(m,6H),7.53–7.41(m,4H),7.21(d,J=7.8Hz,2H),4.30–4.2 1(m,1H),4.14(d,J=11.4Hz,1H),3.60–3.44(m,2H),3.33(s,1H),2.33(s,3H),1.18(s,3H).

[0045] 13C NMR (125MHz, CDCl3) δ 143.48, 139.79, 134.06, 132.05, 129.69, 128.63, 126.85, 126.35, 126.13, 125.65, 67.61, 66.12, 59.54, 21.44, 18.02.

[0046] HRMS(ESI-TOF)m / z calcd.For C22H24N2O5S(M+Na)+:451.1298,found451.1303.

[0047] Enantiomeric excess was determined to be 94% (determined by HPLC using chiral IA column, hexane / 2-propanol=65 / 35, λ=254nm, 30°C, 1mL / min, tmajor=8.6min, tminor=7.7min).

[0048] Using the same method, (II) and (III) in the preparation process of compound (I-1) were replaced according to the corresponding substituents in Table 1 to prepare compounds (I-2)-(I-12) respectively. The NMR data are shown in Table 1.

[0049] Table 1 Structural data of compounds Ⅰ-1-Ⅰ-12

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

Claims

1. A chiral amino alcohol compound containing a carbamate structure, characterized in that: The compound is an N-substituted 1,2-chiral amino alcohol compound, and its structural formula is shown in formula (I): In formula (I): R 1 Any one of hydrogen, methyl, ethyl, phenyl, benzyl, p-methylphenyl, p-methoxyphenyl, p-methylphenyl, p-fluorophenyl, p-trifluoromethylphenyl, o-methoxyphenyl, o-methylphenyl, m-methylphenyl, m-methoxyphenyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl and ethynyl; R 2 Any one of p-methylphenyl, p-nitrophenyl, o-nitrophenyl and ethyl; R 3 It is any one of p-methylphenyl, p-ethylphenyl, p-methoxyphenyl, p-trifluoromethoxyphenyl, p-trifluoromethylphenyl, p-cyanophenyl, m-methylphenyl, m-methoxyphenyl, m-fluorophenyl, m-dimethylphenyl, o-trifluoromethoxyphenyl, o-fluorophenyl, 1-naphthyl, cyclohexyl, cyclopentyl, tert-butyl and isopropyl.

2. A chiral amino alcohol compound containing a carbamate structure as claimed in claim 1, characterized in that: The N-substituted 1,2-chiral amino alcohol compound containing a carbamate structure is one of the following: When R 1 is methyl, R 2 When it is p-methylphenyl, R 3 It is any one of p-ethylphenyl, p-methoxyphenyl, p-trifluoromethoxyphenyl, p-trifluoromethylphenyl, m-methylphenyl, m-methoxyphenyl, m-fluorophenyl, m-dimethylphenyl, o-trifluoromethoxyphenyl, o-fluorophenyl, 1-naphthyl and cyclopentyl.

3. A chiral amino alcohol compound containing a carbamate structure as claimed in claim 1, characterized in that: The N-substituted 1,2-chiral amino alcohol compound containing a carbamate structure is any one of the following compounds:

4. The method for preparing a chiral amino alcohol compound containing a carbamate structure according to any one of claims 1 to 3, characterized in that: The method is as follows: In an air atmosphere, Lewis acid, additives, and a compound represented by formula (IV) are added to a diluent, stirred at room temperature for 30 minutes, a compound represented by formula (II) is added, the temperature is lowered to 0 degrees Celsius, a compound represented by formula (III) is added, and the mixture is stirred at -80-25 degrees Celsius for 16 hours. The reaction is monitored using petroleum ether and ethyl acetate in a volume ratio of 1:1 as a developing solvent. After the reaction is completed, the magnet is removed, and the reaction solution is subjected to silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 3:1 as an eluent, eluting for 5-10 column volumes at an elution rate of 5-15 mL / min. TLC monitoring is performed using petroleum ether and ethyl acetate in a volume ratio of 1:1 as a developing solvent, and an effluent having an Rf value of 0.2-0.3 is collected, and the mixture is evaporated to dryness under reduced pressure to obtain an N-substituted 1,2 chiral amino alcohol compound containing a carbamate structure represented by formula (I); the reaction formula is as follows: In formula (II), R 1 is any one of hydrogen, methyl, ethyl, phenyl, benzyl, p-methylphenyl, p-methoxyphenyl, p-methylphenyl, p-fluorophenyl, p-trifluoromethylphenyl, o-methoxyphenyl, o-methylphenyl, m-methylphenyl, m-methoxyphenyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl and ethynyl; R 2 Any one of p-methylphenyl, p-nitrophenyl, o-nitrophenyl and ethyl; In formula (III), R 3 is any one of p-methylphenyl, p-ethylphenyl, p-methoxyphenyl, p-trifluoromethoxyphenyl, p-trifluoromethylphenyl, p-cyanophenyl, m-methylphenyl, m-methoxyphenyl, m-fluorophenyl, m-dimethylphenyl, o-trifluoromethoxyphenyl, o-fluorophenyl, 1-naphthyl, cyclohexyl, cyclopentyl, tert-butyl, and isopropyl; In formula (IV), R 4 is any of isopropyl, tert-butyl, phenyl or benzyl; In formula (I), R 1 Same as R in formula (II) 1 In formula (I), R 2 Same as R in formula (II) 2 In formula (I), R 3 Same as R in formula (III) 3 .

5. The method for preparing a chiral amino alcohol compound containing a carbamate structure according to claim 4, characterized in that: The Lewis acid is any one of cupric chloride, cupric bromide, cupric iodide, copper trifluoromethanesulfonate, cupric acetate, cuprous chloride, cuprous bromide, cuprous iodide, cuprous trifluoromethanesulfonate, and cuprous acetate; the additive is any one of sodium iodide, potassium iodide, potassium chloride, potassium bromide, tetrabutylammonium iodide, and tetrabutylammonium bromide; the diluent is water or an inert organic solvent, and the inert organic solvent includes any one of benzene, toluene, chlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ether, diisopropyl ether, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, and dimethyl sulfoxide.

6. The method for preparing a chiral amino alcohol compound containing a carbamate structure according to claim 4, characterized in that: The ratio of the amount of the compound represented by formula (II) to the Lewis acid feed material is 1:0.1, the ratio of the amount of the compound represented by formula (II) to the additive feed material is 1:0.1; the ratio of the amount of the compound represented by formula (II) to the compound represented by formula (III) is 1:1; the ratio of the amount of the compound represented by formula (II) to the compound represented by formula (IV) is 1:0.11; the volume of the diluent used is 10mL / mmol based on the amount of the compound represented by formula (II).

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