Catalyst and Its Applications

Abstract

A chiral crown ether catalyst and its application. The catalyst structure is shown in formula (VI), wherein R2 and R3 are both phenyl groups, or R2 and R3 are linked to form ring A, which is a benzene ring or cyclohexane. The supported material of catalyst (VI) can be used to catalyze the synthesis of unnatural amino acids. The material can be separated by simple filtration and can be recycled.

Description

Background Art

[0001] Chiral crown ether catalysts are difficult to recycle and have high costs.

[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] The present invention provides a chiral crown ether catalyst, the structure of which is shown in formula (VI):

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

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

[0006] The present invention also provides the use of the catalytic material of formula (I) in the catalytic synthesis of non-natural amino acids, such as (R)-amino acids of formula VII Wherein, R1 is phenyl, 3-chlorophenyl, tert-butyl, or cyclohexyl; Formula VII can be synthesized by α-aminosulfone and KCN, such as the reaction formula:

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

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

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

[0010] c. Under N2 protection, intermediate (V) is deprotected under the action of HCl to obtain intermediate (VI);

[0011] d. Under N2 protection, intermediate (VI) is condensed with chloropropylated mesoporous molecular sieve MCM-41-Cl in the presence of KI and a base to obtain compound (I);

[0012] Its specific synthetic route can be shown as follows:

[0013]

[0014] Wherein 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, and N-Boc-1,2-diphenylethylenediamine, respectively, the corresponding catalytic materials prepared are respectively represented by Formulas Ia, Ib, and Ic, wherein the A ring of Ia and Ib is respectively a benzene ring or cyclohexane, and the R2 and R3 of Ic are both phenyl. Ic can be prepared as follows:

[0015]

[0016] The base in steps a, b and d is independently selected from: Cs2CO3, K2CO3, Na2CO3.

[0017] The preparation of MCM-41-Cl of the present invention can be as follows:

[0018]

[0019] 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 can be recycled 10 times without changing the catalytic activity. DETAILED DESCRIPTION

[0020] Example 1

[0021] (R)-BINOL derivative (II) (582 mg, 1.0 mmol) was placed in a reaction flask. After nitrogen was replaced, 50 mL of acetonitrile was added, followed by potassium carbonate powder (166 mg, 1.2 mmol). 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 maintained at this temperature for 8 hours, monitored by TLC. The acetonitrile was evaporated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. After drying, the mixture was separated and purified by silica gel column chromatography (PE / EA = 4:1) to obtain intermediate (IV) in a 90% yield. ESI-MS (m / z): 868 [M] + ; 1 H NMR (300MHz, CDCl3) δ: 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), 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).

[0022] Example 2

[0023] The preparation of intermediate (V) involves three parallel reactions:

[0024] Under a nitrogen atmosphere, intermediate (IV) (1.0 mmol) was added to 50 mL of acetonitrile, cesium carbonate (1.2 mmol) was added, and the mixture was heated to reflux. Different N-Boc-diamines (1.1 mmol each) were then 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. The acetonitrile was evaporated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. After drying, the mixture was separated and purified by silica gel column chromatography to obtain the respective intermediates (V).

[0025] The intermediate Va prepared using N-Boc-o-phenylenediamine is The yield is 86%. ESI-MS (m / z): 905 [M+H] + ; 1 H NMR(300MHz, CDCl3)δ: 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).

[0026] Intermediate Vb Yield: 91%. ESI-MS (m / z): 911 [M+H] + ; 1 H NMR (300MHz, CDCl3) δ: 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).

[0027] Intermediate Vc Yield: 89%. ESI-MS (m / z): 1009 [M+H] + ; 1 HNMR (300MHz, CDCl3) δ: 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).

[0028] Example 3

[0029] The preparation of catalyst (VI) involves three parallel reactions:

[0030] Under nitrogen atmosphere, 1.0 mmol of each of different intermediates V (Va, Vb, and Vc in Example 2) were added 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, stirred, extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain the respective catalysts (VI). Catalyst VIa prepared using Va The yield is 90%, 1 H NMRδ: 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).

[0031] Catalyst VIb The yield is 95%, 1H NMRδ: 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).

[0032] Catalyst VIc Yield: 92% 1 H NMRδ: 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).

[0033] Example 4

[0034] The preparation of the catalytic material formula (I) involves three parallel reactions:

[0035] Under a nitrogen atmosphere, 1 g of MCM-41-Cl was added to 50 mL of acetonitrile, followed by the addition of sodium carbonate (1.2 mmol) and KI (1.2 mmol), followed by vigorous stirring. A 20 mL acetonitrile solution of the three intermediates (VI) (2.0 mmol) from Example 3 was then added in parallel. The mixture was heated to reflux for 48 h, cooled, filtered, and washed with water to obtain the MCM-41-supported catalytic material (I). The loading of the catalyst (Ia) was 0.95 mmol / g, the loading of the catalyst (Ib) was 0.93 mmol / g, and the loading of the catalyst (I) was 0.90 mmol / g.

[0036] Example 5

[0037] 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 continued for 60 h, filtered, and the filter cake was slurried with water and filtered. This was repeated three times, and finally washed twice with methanol, dried under vacuum, and formula (I) was recovered and recycled. 6N HCl was added to the filtrate, refluxed for 3 h, cooled to room temperature, separated, and the aqueous phase was heated to reflux for 3 h, cooled to room temperature, washed with ethyl acetate, concentrated to dryness under reduced pressure, and recrystallized from isopropanol to obtain (R)-tert-butylglycine hydrochloride with a yield of 87% and 97% ee. 1 H NMR (300MHz, D2O): δ3.83 (s, 1H), 1.10 (s, 9H).

[0038] Example 6

[0039] Using different α-aminosulfones More amino acids were synthesized with reference to Example 5. The results are shown in Table 1 below:

[0040] serial number Catalytic Materials I R1 of aminosulfone product Yield ee value 1 Ib Cyclohexyl (R)-Cyclohexylglycine hydrochloride 76％ 96％ 2 Ic Phenyl (R)-Phenylglycine hydrochloride 81％ 99％ 3 Ic 3-Chlorophenyl (R)-3-Chlorophenylglycine hydrochloride 72％ 96％

[0041] Example 7

[0042] The operation of Example 5 was followed to examine the recycling times of the catalytic material of formula (I). The results are as follows:

[0043] Table 2 Number of cycles of formula (Ia)

[0044]

Claims

1. A chiral crown ether catalyst, the structure of which is shown in formula (VI): R2 and R3 are both phenyl groups, or R2 and R3 are connected to form ring A, and ring A is a benzene ring or cyclohexane.

2. Intermediate V, whose structure is selected from any one of the following:

3. A mesoporous material containing the catalyst of claim 1 loaded by MCM-41, wherein the structure is shown in formula (I):

4. Use of the mesoporous material according to claim 3 in the catalytic synthesis of R-amino acids of formula VII, R1 is phenyl, 3-chlorophenyl, tert-butyl or cyclohexyl.

5. The use according to claim 4, wherein: The amino acid of formula VII is synthesized from α-aminosulfone and KCN.

6. The method for preparing the catalyst according to claim 1, comprising: Removing the hydroxyl protecting group of the intermediate V according to claim 2.

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