Preparation of amino acid derivatives

Abstract

The present invention relates to the preparation of amino acid derivatives VII, including the use of catalysts. The structure of the catalyst disclosed by the invention can be shown as a formula (VI), or the catalyst is loaded on a molecular sieve, and the structure of the catalyst is shown as a formula (I). The invention also discloses preparation of the catalyst and intermediates thereof. A plurality of molecules prepared by the method are all of brand new structures, and are of great significance.

Description

Background Technology

[0001] Chiral crown ether catalysts are difficult to recycle and are costly.

[0002] As a mesoporous molecular sieve, MCM-41 has extremely high specific surface area, pore volume and excellent thermal stability. Summary of the Invention

[0003] This invention provides a chiral crown ether catalyst with the structure shown in formula (VI):

[0004] R2 and R3 are both phenyl groups, or R2 and R3 are connected to form ring A, which is a benzene ring or cyclohexane.

[0005] The present invention also provides a mesoporous material for supporting catalyst VI with MCM-41, the structure of which is shown in formula (I):

[0006] This invention also provides the application of the catalytic material of formula (I) in the catalytic synthesis of non-natural amino acids, such as (R)-amino acids of formula VII. In formula VII, R1 is phenyl, 3-chlorophenyl, tert-butyl, or cyclohexyl; formula VII can be synthesized from α-amino sulfone and KCN, as shown in the following reaction formula:

[0007] The preparation method of formula (I) of the present invention may include:

[0008] a. Under N2 protection, (R)-BINOL derivative (II) and triethylene glycol ether p-toluenesulfonate (III) are condensed in the presence of a base to prepare intermediate (IV);

[0009] b. Under N2 protection and in the presence of a base, intermediate (IV) condenses with N-Boc-diamine to obtain intermediate (V);

[0010] c. Under N2 protection, intermediate (V) is deprotected by HCl to obtain intermediate (VI); d. Under N2 protection, intermediate (VI) is condensed with chloropropylated mesoporous molecular sieve MCM-41-Cl in the presence of KI and base to obtain formula (I).

[0011] The specific synthetic route is as follows:

[0012]

[0013] Where R is phenyl, cyclohexyl, or 1,2-diphenylethyl, that is, when the N-Boc-diamine compound in step b is N-Boc-o-phenylenediamine, N-Boc-1,2-cyclohexanediamine, or N-Boc-1,2-diphenylethylenediamine, the corresponding catalysts obtained are, in order, formulas Ia, Ib, and Ic. In Ia and Ib, ring A is either a benzene ring or cyclohexane, and in Ic, R2 and R3 are both phenyl. Ic can be prepared as follows:

[0014]

[0015] The bases used in steps a, b, and d are independently selected from: Cs2CO3, K2CO3, and Na2CO3.

[0016] The preparation of MCM-41-Cl of the present invention can be carried out as follows:

[0017]

[0018] The catalyst material of the present invention, formula (I), can be separated by simple filtration, and the recovery rate of formula (I) is ≥97%. The recovered formula (I) can be recycled and reused 10 times without changing its catalytic activity. Detailed Implementation

[0019] Example 1

[0020] (R)-BINOL derivative (II) (582 mg, 1.0 mmol) was placed in a reaction flask, purged with nitrogen, and 50 mL of acetonitrile was added. Potassium carbonate powder (166 mg, 1.2 mmol) was then added, and the mixture was heated to reflux. Triethylene glycol ether p-toluenesulfonate (III) (503 mg, 1.1 mmol) was dissolved in 10 mL of acetonitrile and added to the reaction system. The reaction was monitored by TLC and maintained at this temperature for 8 hours. Acetonitrile was distilled off under reduced pressure, water was added, and the mixture was extracted with dichloromethane. After drying, the mixture was purified by silica gel column chromatography (PE / EA = 4:1) to obtain intermediate (IV) in 90% yield. ESI-MS (m / z): 868 [M] + ; 1 H NMR (300MHz, CDCl3)δ:

[0021] 8.49(s,1H),7.82(d,J=7.2Hz,2H),7.78(d,J=8.2Hz,1H),7.73(d,J=6.9Hz,2H),

[0022] 7.40(m,3H),7.33-7.23(m,3H),7.06(d,J=8.8Hz,2H),3.97-3.71(m,4H),3.29-3.24(m,8H),3.21(t,J=4.5Hz,2H),2.57(s,3H),2.43(s,3H).

[0023] Example 2

[0024] The preparation of intermediate (V) involves three parallel reactions:

[0025] Under a nitrogen atmosphere, intermediate (IV) (1.0 mmol) was added to 50 mL of acetonitrile, followed by cesium carbonate (1.2 mmol). The mixture was heated to reflux, and then 1.1 mmol of each of different N-Boc-diamines were added in parallel for condensation reactions (the diamines in each reaction were: a, N-Boc-o-phenylenediamine; b, N-Boc-1,2-cyclohexanediamine; c, N-Boc-1,2-diphenylethylenediamine). The reaction was carried out for 36 h. Acetonitrile was distilled off under reduced pressure, water was added, and the mixture was extracted with dichloromethane. After drying, the mixture was purified by silica gel column chromatography to obtain the respective intermediates (V).

[0026] The intermediate Va obtained using N-Boc-o-phenylenediamine is Its yield was 86%. ESI-MS (m / z): 905 [M+H] + ; 1 H NMR (300MHz, CDCl3)δ:

[0027] 8.54(s,1H),8.01(s,1H),7.79(t,J=8.9Hz,2H),7.77(d,J=8.2Hz,1H),7.43(t,J=7.4Hz,2H),7.33-7.27(m,2H),7.18-7.08(m,2H), 6.58-6.42(m,4H),4.95(s,1H),4.21(m,2H),3.97-3.71(m,8H),3.30-3.24(m,2H),3.21(t,J=4.5Hz,2H),2.57(s,3H),1.43(s,9H).

[0028] intermediate Vb Yield 91%. ESI-MS (m / z): 911 [M+H] + ; 1 H NMR (300MHz, CDCl3)δ:

[0029] 8.52(s,1H),8.00(s,1H),7.78(t,J=8.9Hz,2H),7.76(d,J=8.2Hz,1H),7 .42(t,J=7.4Hz,2H),7.33-7.27(m,2H),7.18-7.07(m,2H),4.22(m,2H), 3.97-3.71(m,9H),3.22(t,J=4.5Hz,2H),3.19(m,1H),2.83-2.72(m,2H) ,2.57(s,3H),2.01(s,1H),1.78-1.49(m,5H),1.40(s,9H),1.39(m,3H).

[0030] intermediate Vc Yield 89%. ESI-MS (m / z): 1009 [M+H] + ; 1 HNMR (300MHz, CDCl3) δ:

[0031] 8.54(s,1H),8.02(s,1H),7.79(t,J=8.9Hz,2H),7.77(d,J=8.2Hz,1H),7.42(t,J=7.4Hz,2H),7.33-7.27(m,2H),7.21-7.07(m,12H), 5.51(m,1H),4.93(m,1H),4.21(m,2H),3.97-3.71(m,8H),3.21(t,J=4.5Hz,2H),2.76(m,2H),2.57(s,3H),2.03(s,1H),1.41(s,9H).

[0032] Example 3

[0033] The preparation of catalyst (VI) involves three parallel reactions:

[0034] Under a nitrogen atmosphere, 1.0 mmol each of different intermediates V (Va, Vb, and Vc from Example 2) were added in parallel to 4 mL of methanol and 12 mL of dichloromethane. 50 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 24 h. A saturated sodium bicarbonate solution was added, and the mixture was stirred. The mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the respective catalysts (VI). Catalyst VIa was prepared using Va. Its yield is 90%. 1 H NMRδ:

[0035] 8.53(s,1H),8.00(s,1H),7.78(t,J=8.9Hz,2H),7.76(d,J=8.1Hz,1H),7.43(t,J=7.3Hz,2H),7.33-7.27(m,2H),7.18- 7.08(m,2H),6.57-6.41(m,4H),5.01(s,1H),4.21-4.15(m,2H),3.95-3.70(m,8H),3.57(s,2H),3.22(t,J=4.8Hz,2H).

[0036] Catalyst VIb The yield was 95%. 1 H NMRδ:

[0037] 8.52(s, 1H), 8.00(s, 1H), 7.78(t, J = 8.9Hz, 2H), 7.76(d, J = 8.2Hz, 1H), 7.42(t, J = 7.4Hz, 2H), 7.33-7.27(m, 2H), 7.17-7.07(m, 2H), 4.95(s, 1H), 4.19-4.15(m, 2H), 3.96-3.70(m, 9H), 3.21(t, J = 4.5Hz, 2H), 3.19-3.10(m, 1H), 2.04(s, 2H), 1.78-1.49(m, 5H), 1.39-1.21(m, 3H). Catalyst VIc Yield 92%; 1 H NMRδ:

[0038] 8.54(s,1H),7.79(t,J=8.9Hz,2H),7.77(d,J=8.2Hz,1H),7.42(t,J=7.4Hz,2H),7.33-7.27(m,2H),7. 21-7.07(m,12H),5.53(m,2H),5.02(s,1H),4.21(m,2H),3.97-3.71(m,8H),2.73(m,2H),2.03(s,3H).

[0039] Example 4

[0040] The preparation of catalytic material (I) involves three parallel reactions:

[0041] Under a nitrogen atmosphere, 1 g of MCM-41-Cl was added to 50 mL of acetonitrile, along with sodium carbonate (1.2 mmol) and KI (1.2 mmol). The mixture was stirred vigorously, and then 20 mL of an acetonitrile solution containing the three intermediates (VI) (2.0 mmol) from Example 3 was added in parallel. The mixture was heated under reflux for 48 h, cooled, filtered, and washed with water to obtain the MCM-41-supported catalyst formula (I). The loading of catalyst formula (Ia) was 0.95 mmol / g, the loading of catalyst formula (Ib) was 0.93 mmol / g, and the loading of catalyst formula (I) was 0.90 mmol / g.

[0042] Example 5

[0043] Under N2 protection, N-Boc-1-benzenesulfonyl-2,2-dimethylpropylamine (1.0 mmol) and KCN (1.1 mmol) were added to 15 mL of toluene, cooled to 0 °C, and 107 mg of formula (Ia) was added. The reaction was carried out for 60 h, filtered, and the filter cake was slurried with water and filtered. This process was repeated three times. Finally, the mixture was washed twice with methanol, dried under vacuum, and formula (I) was recovered for recycling. 6NHCl was added to the filtrate, and the mixture was refluxed for 3 h. After cooling to room temperature, the layers separated. The aqueous phase was refluxed for 3 h, cooled to room temperature, washed with ethyl acetate, concentrated under reduced pressure to dryness, and recrystallized from isopropanol to obtain (R)-tert-butylglycine hydrochloride with a yield of 87% and an ee of 97%. 1 H NMR (300MHz, D2O): δ3.83 (s, 1H), 1.10 (s, 9H).

[0044] Example 6

[0045] Using different α-amino sulfones More amino acids were synthesized according to Example 5, and the results are shown in Table 1 below:

[0046] serial number Catalyst material I R1 of amino sulfone product yield ee value 1 Ib Cyclohexyl (R)-Cyclohexylglycine hydrochloride 76％ 96％ 2 Ic Phenyl (R)-Phenylated glycine hydrochloride 81％ 99％ 3 Ic 3-Chlorophenyl (R)-3-chlorophenylglycine hydrochloride 72％ 96％

[0047] Example 7

[0048] Following the procedure in Example 5, the number of times the catalyst material of formula (I) could be recycled was investigated. The results are as follows:

[0049] Table 2 shows the number of recycling cycles for formula (Ia).

[0050]

Claims

1. A process for the preparation of the intermediate V, comprising condensing the intermediate (IV) with N-Boc-diamine ###0001### R is phenyl, cyclohexyl or 1,2-diphenylethyl, and the intermediate V is selected from any one of the following: ###0002### ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068 ​ 2. A process for preparing a chiral crown ether catalyst of formula (VI) comprising: ​ R2and R3are both phenyl, or R2and R3are joined to form a benzene ring or a cyclohexane. ​ 4. A process for the synthesis of (R)-amino acids of formula VII, catalyzed by a catalyst as claimed in any of the preceding claims, R1 is phenyl, 3-chlorophenyl, tert-butyl or cyclohexyl.

5. The method of claim 4, wherein, ​

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