Asymmetrically catalyzed synthesis method of nitropyrazole amide compound

Abstract

A synthesis method of -nitropyrazole amide compound through asymmetrical catalyzing technique is provided, a nitroalkane and an ,-unsaturated pyrazole amide are applied as the raw material, a complex formed by a chiral amine oxide with a rare earth metal compound is served as the catalyst, a 4 molecular sieve is served as an additive, the -nitropyrazole amide compound can be obtained with a yield more than 99% and enantiomeric excess more than 99% ee. The catalytic system not only has the advantages of simple operation, mild reaction conditions, requiring no acid/base additives, convenient product purification, high yield and enatioselectivity, compliance with green atomic economy, and promising prospects for industrial application, but also allows the obtained -nitropyrazole amide compound to undergo some simple chemical conversions to produce some molecules having physiological activities.

Claims

1. An asymmetrically catalyzed synthesis method of a -nitropyrazole amide compound, wherein, in the reaction that a nitroalkane and an ,-unsaturated pyrazole amide are employed as raw materials, a complex formed by a chiral amine oxide with a rare earth metal compound is served as a catalyst, a 4 molecular sieve is served as an additive, after the reaction finished, to obtain a -nitropyrazole amide compound, wherein, the structure of the nitroalkane is RCH.sub.2NO.sub.2, in which RH, CH.sub.3, Et, or Bn; the structure of the ,-unsaturated pyrazole amide compound is ##STR00014## the -nitropyrazole amide compound has a structure of: ##STR00015## the structure of the chiral amine oxide ligand is ##STR00016## in which R.sup.1=C.sub.6H.sub.5, 4-FC.sub.6H.sub.4, 4-ClC.sub.6H.sub.4, 4-BrC.sub.6H.sub.4, 4-MeC.sub.6H.sub.4, 4-MeOC.sub.6H.sub.4, 3-BrC.sub.6H.sub.4, 3-MeC.sub.6H.sub.4, 2-BrC.sub.6H.sub.4, 2-MeOC.sub.6H.sub.4, 3,4-Cl.sub.2C.sub.6H.sub.3, 3,4-(MeO).sub.2C.sub.6H.sub.3, 2-Furyl, 2-Thienyl, CH.sub.3, Pr, Pent, .sup.iBu, EtO, or EtOOC; and R.sup.2CH.sub.3, Ph; R.sup.3H, Cl, Br, or I; and n=1, or 2; and R=Ph-, 2,6-Me.sub.2C.sub.6H.sub.3, 2,6-Et.sub.2C.sub.6H.sub.3, 2,6-iPr.sub.2C.sub.6H.sub.3, or Ph.sub.2CH; and the rare earth metal compound is gadolinium trifluoromethanesulfonate [Gd(OTf).sub.3], scandium trifluoromethanesulfonate [Sc(OTf).sub.3], holmium trifluoromethanesulfonate [Ho(OTf).sub.3], ytterbium trifluoromethanesulfonate [Yb(OTf).sub.3], erbium trifluoromethanesulfonate [Er(OTf).sub.3], or yttrium trifluoromethanesulfonate [Y(OTf).sub.3].

2. The preparation method according to claim 1, wherein, the reaction takes place in a solvent selected from pentane, hexane, dichloroethane, chloroform, toluene, ethylbenzene, cumene, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate and isopropyl acetate.

3. The preparation method according to claim 1, wherein, the reaction temperature is 25-50 C.

4. The preparation method according to claim 1, wherein, the nitroalkane and the ,-unsaturated pyrazole amide are employed as raw materials, the complex formed by a chiral amine oxide with a rare earth metal compound is served as a catalyst, the 4 molecular sieve is served as an additive, after a reaction of 12-120 hrs in the solvent of dichloromethane and at a temperature of 25-50 C. under normal pressure, to obtain the -nitropyrazole amide compound.

5. The preparation method according to claim 1 or 4, wherein, the molar ratio of the nitroalkane to the ,-unsaturated pyrazole amide compound is 1.86:1-55.8:1.

6. The preparation method according to claim 5, wherein, the molar ratio of the nitroalkane to the ,-unsaturated pyrazole amide compound is 9.3:1.

7. The preparation method according to claim 1 or 4, wherein, the molar ratio of the chiral amine oxide to the rare earth metal compound is 0.8:1.0-1.5:1.0.

8. The preparation method according to claim 7, wherein, the molar ratio of the chiral amine oxide to the rare earth metal compound is 1.2:1.0.

9. The preparation method according to claim 1 or 4, wherein, the amount of the 4 molecular sieve is such that 10-100 mg of the 4 molecular sieve is needed per 0.1 mmol of the ,-unsaturated pyrazole amide.

10. The preparation method according to claim 1 or 4, wherein, the rare earth metal compound is gadolinium trifluoromethanesulfonate [Gd(OTf).sub.3].

11. The preparation method according to claim 1 or 4, wherein, in the chiral amine oxide ligand, n=2, and R=2,6-iPr.sub.2C.sub.6H.sub.3.

12. The preparation method according to claim 1 or 4, wherein, the molar ratio of the ,-unsaturated pyrazole amide compound to the rare earth metal compound is 20:1-10:1.

13. The preparation method according to claim 1 or 4, wherein, 30-100 mg of the 4 molecular sieve is needed per 0.1 mmol of the ,-unsaturated pyrazole amide compound.

14. The preparation method according to any one of claims 1 to 4, further comprising the step of: reacting the -nitropyrazole amide compound with methanol in the presence of an organic base, to obtain an esterified product the esterified product has a structure of: ##STR00017## in which R and R.sup.1 is as defined in claim 1.

15. The preparation method according to claim 14, wherein, the organic base is selected from the group consisting of triethylamine, diisoproylethylamine, trimethylamine, tri-n-propylamine, tri-n-butylamine, dimethylaniline, diethylaniline, dim ethylbenzylamine, diethylbenzylamine and 1,8-azacyclo[5,4,0]undecene-7.

Description

DETAILED EMBODIMENTS

Example 1: Michael Addition of ,-Unsaturated pyrazole amide Compound with nitroalkane Compound, Being Catalyzed by a Complex Formed by a chiral amine oxide with Rare Earth Metal

(1) A rare earth metal compound (Nos. 1-11: 0.01 mmol, and Nos. 12-16: 0.0075 mmol), a chiral amine oxide ligand (Nos. 1-11: 0.012 mmol, and Nos. 12-16: 0.009 mmol), the ,-unsaturated pyrazole amide 1a (0.1 mmol), a 4 molecular sieve (30 mg), and a stirrer were added to a reaction vessel. The reaction vessel was purged 3 times with nitrogen, and then dichloromethane (6.2 mmol) and nitromethane (Nos. 1-11: 5.6 mmol, and Nos. 12-16: 0.93 mmol) were added and stirred at 25-50 C. for 12-120 hrs. The reaction was detected by TLC. The product was purified by column chromatography, and the enantiomeric excess of the product was determined by HPLC (Daicel chiralcel IE, V.sub.n-hexane:V.sub.isopropanol=90:10, flow rate: 1.0 mL/min). The result is shown in Table 1. The reaction formula and the structure of the chiral amine oxide ligand are shown as below:

(2) ##STR00008##

(3) TABLE-US-00001 TABLE 1 Optimized reaction conditions in asymmetric Michael addition of ,-unsaturated pyrazole amide compound with nitroalkane compound, being catalyzed by a complex formed by a chiral amine oxide with rare earth metal Chiral amine Rare earth Reaction Enantio- oxide metal temperature Reaction Yield selectivity No ligand compound ( C.) time (%) (% ee) 1 L1 Sc(OTf).sub.3 30 72 h trace n.d. 2 L2 Sc(OTf).sub.3 30 72 h trace n.d 3 L3 Sc(OTf).sub.3 30 72 h trace n.d 4 L4 Sc(OTf).sub.3 30 72 h 9 99 5 L5 Sc(OTf).sub.3 30 72 h 30 99 6 L5 Er(OTf).sub.3 30 72 h 87 98 7 L5 Ho(OTf).sub.3 30 72 h 74 97 8 L5 Yb(OTf).sub.3 30 72 h 91 98 9 L5 Y(OTf).sub.3 30 72 h 73 98 10 L5 Gd(OTf).sub.3 30 72 h 93 97 11 L6 Gd(OTf).sub.3 30 72 h 99 98 12 L6 Gd(OTf).sub.3 30 72 h 98 98 13 L6 Gd(OTf).sub.3 25 120 h 91 98 14 L6 Gd(OTf).sub.3 30 48 h 82 98 15 L6 Gd(OTf).sub.3 40 24 h 98 98 16 L6 Gd(OTf).sub.3 50 12 h 98 98 (n.d.: not detected)

Example 2: Michael Addition of ,-Unsaturated pyrazole amide Compound with nitroalkane Compound, Being Catalyzed by chiral amine oxide L6-Gd(OTf)3 Complex

(4) Gd(OTf).sub.3 (Nos. 1-16, 20-23, and 25-27: 0.0075 mmol, and Nos. 17-19, and 24: 0.01 mmol), chiral amine oxide L6 (Nos. 1-16, 20-23, and 25-27: 0.009 mmol, and Nos. 17-19, and 24: 0.012 mmol) (where the molar ratio of the chiral amine oxide L6 to gadolinium trifluoromethanesulfonate (Gd(OTf).sub.3) is 1.2:1.0), an ,-unsaturated amide (0.1 mmol), a 4 molecular sieve (Nos. 1-16, and 20-27: 30 mg, No. 18: 100 mg, No. 17 and 19: 60 mg), and a stirrer were added to a reaction vessel. The reaction vessel was purged 3 times with nitrogen, and then dichloromethane (6.2 mmol) and a nitroalkane (0.93 mmol) were added and stirred at 30 C. for 72 hrs. The product was purified by column chromatography, and the enantiomeric excess of the product was determined by chiral HPLC. The reaction formula is shown as below:

(5) ##STR00009##

(6) The result is shown in Table 2: (d.r: diastereoselectivity of compounds containing two or more chiral centers)

(7) TABLE-US-00002 TABLE 2 Asymmetric Michael addition of ,-unsaturated pyrazole amide compound with nitroalkane compound, being catalyzed by chiral amine oxide L6-Gd(OTf).sub.3 complex Yield Enantioselectivity No. R, R1, R2, and R3 (%) (% ee) 1 H, C.sub.6H.sub.5, CH.sub.3, H 99 99 2 H, 4-FC.sub.6H.sub.4, CH.sub.3, H 99 99 3 H, 4-ClC.sub.6H.sub.4, CH.sub.3, H 98 98 4 H, 4-BrC.sub.6H.sub.4, CH.sub.3, H 96 98 5 H, 4-MeC.sub.6H.sub.4, CH.sub.3, H 95 99 6 H, 4-MeOC.sub.6H.sub.4, CH.sub.3, H 89 99 7 H, 3-BrC.sub.6H.sub.4, CH.sub.3, H 98 98 8 H, 3-MeC.sub.6H.sub.4, CH.sub.3, H 96 99 9 H, 2-BrC.sub.6H.sub.4, CH.sub.3, H 99 99 10 H, 2-MeOC.sub.6H.sub.4, CH.sub.3, H 99 99 11 H, 3,4-Cl.sub.2C.sub.6H.sub.3, CH.sub.3, H 96 99 12 H, 3,4-(MeO).sub.2C.sub.6H.sub.3, CH.sub.3, H 83 99 13 H, 2-Furyl, CH.sub.3, H 56 97 14 H, 2-Thienyl, CH.sub.3, H 58 98 15 H, CH.sub.3, CH.sub.3, H 69 98 16 H, Pr, CH.sub.3, H 87 98 17 H, Pent, CH.sub.3, H 65 98 18 H, bu, CH.sub.3, H 77 98 19 H, EtO, CH.sub.3, H 53 95 20 H, EtOOC, CH.sub.3, H 67 95 21 H, 4-ClC.sub.6H.sub.4, CH.sub.3, Cl 94 99 22 H, 4-ClC.sub.6H.sub.4, CH.sub.3, Br 96 99 23 H, 4-ClC.sub.6H.sub.4, CH.sub.3, I 97 99 24 H, 4-ClC.sub.6H.sub.4, C.sub.6H.sub.5, H 39 81 25 CH.sub.3, 4-ClC.sub.6H.sub.4, CH.sub.3, H 94 98/98 (d.r. 1.6/1) 26 Et, 4-ClC.sub.6H.sub.4, CH.sub.3, H 87 99/98 (d.r. 1.2/1) 27 PhCH.sub.2, 4-ClC.sub.6H.sub.4, CH.sub.3, H 98 99/98 (d.r. 1.1/1)

Example 3: Asymmetric Michael Addition of ,-Unsaturated pyrazole amide Compound with nitroalkane Compound, Being Catalyzed by a Complex Formed by chiral amine oxide with Rare Earth Metal

(8) A rare earth metal compound (Nos. 1-11: 0.01 mmol, and No. 12-16: 0.0075 mmol), a chiral amine oxide ligand (No. 1-11: 0.012 mmol, and No. 12-16: 0.009 mmol), an ,-unsaturated pyrazole amide 1a (0.1 mmol), a 4 molecular sieve (30 mg) and a stirrer were added to a reaction vessel. The reaction vessel was purged 3 times with nitrogen, and then dichloromethane (6.2 mmol) and nitromethane (Nos. 1-11: 5.6 mmol, and Nos. 12-16: 0.93 mmol) were added and stirred at 25-50 C. for 12-120 hrs. The reaction was detected by TLC. The product was purified by column chromatography, and the enantiomeric excess of the product was determined by HPLC (Daicel chiralcel IE, V.sub.n-hexane:V.sub.isopropanol=90:10, flow rate: 1.0 mL/min). The result is shown in Table 3. The reaction formula and the structure of the chiral amine oxide ligand are shown as below:

(9) ##STR00010##

(10) TABLE-US-00003 TABLE 3 Asymmetric Michael addition of ,-unsaturated pyrazole amide compound with nitroalkane compound, being catalyzed by chiral amine oxide L6-Gd(OTf).sub.3 complex in various solvents at various temperatures Reaction Enantio- temperature Reaction Yield selectivity No. Reaction solvent ( C.) time (%) (% ee) 1 Tetrahydrofuran 30 72 h 94 98 2 Methyl t-butyl ether 30 72 h 92 98 3 Ethyl acetate 30 72 h 94 97 4 Toluene 30 72 h 97 98 5 Hexane 30 72 h 89 95 6 Tetrahydrofuran 40 72 h 92 98 7 Methyl t-butyl ether 50 72 h 92 97 8 Ethyl acetate 50 72 h 92 96 9 Toluene 25 72 h 96 98 10 Hexane 50 12 h 91 95

Example 4: Scaled-Up Experiment 1

(11) To a round-bottom flask equipped with a magnetic stirrer, the amine oxide ligand L6 (0.24 mmol), gadolinium trifluoromethanesulfonate (0.2 mmol), the unsaturated amide No. 2 (0.976 g, 4 mmol), and a 4 molecular sieve (1.2 g) were added, and purged 3 times with nitrogen. Then dichloromethane (186 mmol) and nitromethane (37.2 mmol) were added and stirred at 30 C. for 96 hrs. After separation by silica gel column chromatography, 1.217 g of a catalytic reaction product as white solid was obtained (Yield: 99%). The enantioselectivity of the product was determined to be 99% ee by HPLC (Daicel chiralcel IE, V.sub.n-hexane:V.sub.isopropanol=90:10, flow rate: 1.0 mL/min).

Example 5: Scaled-Up Experiment 2

(12) To a round-bottom flask equipped with a magnetic stirrer, the amine oxide ligand L6 (0.36 mmol), gadolinium trifluoromethanesulfonate (0.3 mmol), the unsaturated amide No. 3 (1.04 g, 4 mmol), and a 4 molecular sieve (1.2 g) were added, and purged 3 times with nitrogen. Then dichloromethane (186 mmol) and nitromethane (37.2 mmol) were added and stirred at 30 C. for 72 hrs. After separation by silica gel column chromatography, 1.278 g of a catalytic reaction product as white solid was obtained (Yield: 99%). The enantioselectivity of the product was determined to be 98% ee by HPLC (Daicel chiralcel IE, V.sub.n-hexane:V.sub.isopropanol=90:10, flow rate: 1.0 mL/min).

Example 6: Scaled-Up Experiment 3

(13) To a round-bottom flask equipped with a magnetic stirrer, the amine oxide ligand L6 (0.72 mmol), gadolinium trifluoromethanesulfonate (0.6 mmol), the unsaturated amide No. 18 (1.236 g, 6 mmol), and a 4 molecular sieve (6.5 g) were added, and purged 3 times with nitrogen. Then dichloromethane (325.5 mmol) and nitromethane (55.8 mmol) were added and stirred at 30 C. for 72 hrs. After separation by silica gel column chromatography, 1.34 g of a catalytic reaction product as colorless liquid was obtained (Yield: 83%). The enantioselectivity of the product was determined to be 99% ee by HPLC (Daicel chiralcel IE, V.sub.n-hexane:V.sub.isopropanol=90:10, flow rate: 1.0 mL/min).

Applying -nitropyrazole amide Compound in Synthesis

Example 7: Esterification of Catalytic Reaction Product

(14) After the catalytic reaction was complete (where the initial ,-unsaturated pyrazole amide was 0.1 mmol), DBU (0.067 mmol) and methanol (2.5 mmol) were added to a test tube containing the reaction solution 3a or 3b respectively, and stirred overnight at room temperature. The product was separated and purified by column chromatography, and analyzed by HPLC (3a: Daicel chiralcel IB, V.sub.n-hexane:V.sub.isopropanol=90:10, flow rate: 1.0 mL/min, and 3b: Daicel chiralcel IC, V.sub.n-hexane:V.sub.isopropanol=95:5, flow rate: 0.8 mL/min). The result is shown as below.

(15) ##STR00011##

(16) 5a and 5b can be used in the synthesis of drug molecules Baclofen and Paroxetine following a method as described in the literature (Org. Lett. 2012, 14, 1516).

(17) After the catalytic reaction was complete (where the initial ,-unsaturated pyrazole amide was 0.1 mmol), triethylamine (0.067 mmol) and methanol (2.5 mmol) were added to a test tube containing the reaction solution 3b, and stirred overnight at room temperature. The product was separated and purified by column chromatography, and analyzed by HPLC (3a: Daicel chiralcel IB, V.sub.n-hexane:V.sub.isopropanol=90:10, flow rate: 1.0 mL/min, and 3b: Daicel chiralcel IC, V.sub.n-hexane:V.sub.isopropanol=95:5, flow rate: 0.8 mL/min). (S)-5b was obtained (Yield 94.2%, 99% ee).

(18) After the catalytic reaction was complete (where the initial ,-unsaturated pyrazole amide was 0.1 mmol), dimethylaniline (0.08 mmol) and methanol (2.5 mmol) were added to a test tube containing the reaction solution 3a, and stirred overnight at room temperature. The product was separated and purified by column chromatography, and analyzed by HPLC (3a: Daicel chiralcel IB, V.sub.n-hexane:V.sub.isopropanol=90:10, flow rate: 1.0 mL/min), (3b: Daicel chiralcel IC, V.sub.n-hexane:V.sub.isopropanol=95:5, flow rate: 0.8 mL/min). (S)-5a was obtained (Yield 92%, 98.6% ee).

(19) Because the detection, separation and purification of fatty ester compounds are inconvenient, the esterification process is performed stepwise. 3t (46.2 mg, 0.173 mmol, 98% ee) was added to a reaction vessel, and then dichloromethane (7.8 mmol), DBU (0.1 mmol), and methanol (3.72 mmol) were added in sequence, and stirred for 5 hrs at room temperature. The product was separated and purified by column chromatography, and analyzed by HPLC (Daicel chiralcel IE, V.sub.n-hexane:V.sub.isopropanol=95:5, flow rate: 1.0 mL/min). The yield of the product is 95%, and the enantioselectivity is 98% ee. The result is shown as below.

(20) ##STR00012##

Example 8: Synthesis of pregabalin

(21) Chengdu Organic Chemicals Co., Ltd, Chinese Academy of Sciences discloses a method for converting racemic 5c into racemic 6c. In the method, 5c is subjected to a reductive ring-closing reaction by using Raney nickel-H.sub.2 as a hydrogenation reagent, to obtain 6c with a yield of 97%. Despite the good result to some extent, in operation, it is very complex. In addition, some dangerous reagents such as Raney nickel and hydrogen are used during the process (CN 102115449A. 06, 07, 2011).

(22) Herein, a method for synthesizing 6c compound with 5c compound is provided, the reaction condition is mild and the operation is simple, and the reaction is highly efficient.

(23) ##STR00013##

(24) To a round-bottom flask equipped with a magnetic stirrer, 5c (68.82 mg, 0.34 mmol), NiCl.sub.2.6H.sub.2O (80.6 mg, 0.34 mmol), and EtOH (33.9 mmol) were added, and left in an ice bath for 5 min. Then, NaBH.sub.4 (140.9 mg, 3.74 mmol) was slowly added, and the reaction solution was continuously stirred in the ice bath for 2 hrs. The reaction was quenched with 1 mL ethanol, and then returned back to room temperature. 1 mL of 6 mol/L sodium hydroxide solution was added to the reaction solution, and continuously stirred for 1 hr. After 1 hr, 2 mol/L hydrochloric acid solution was added to the reaction solution, adjusted to a pH below 7, and extracted with dichloromethane (46 mL). The organic layers were combined, dried over anhydrous sodium sulfate, then filtered under suction and rotarily dried, to obtain the product 6c (Yield: 95%). The enantioselectivity of the product was determined to be 97% ee by HPLC (Daicel chiralcel AD-H, V.sub.n-hexane:V.sub.isopropanol=96:4, flow rate: 1.0 mL/min).

(25) As described in the literature (Tetrahedron, 2011, 67, 636), after the compound 6c was refluxed for 10 hrs in 6 mol/L hydrochloric acid at 100 C., Pregabalin hydrochloride was obtained with a yield of 95% while ee was maintained.