Method for asymmetric hydrogenation of pyrazolopyrimidine multi-nitrogen aromatic compound under catalysis of manganese

Abstract

The invention discloses a method for asymmetric hydrogenation of a pyrazolopyrimidine multi-nitrogen aromatic compound under the catalysis of manganese, and belongs to the technical field of asymmetric catalytic synthesis. Manganese and a chiral hydroxypyridine oxazoline ligand are used as catalysts, under the alkaline condition, a pyrazolopyrimidine multi-nitrogen aromatic compound and hydrogen are subjected to asymmetric hydrogenation in a solvent, and the chiral pyrazolotetrahydropyrimidine compound is obtained. According to the method, asymmetric hydrogenation of the pyrazolopyrimidine multi-nitrogen aromatic compound can be realized, the pyrazoloectoine compound with optical purity is obtained at high yield, and the enantiomeric excess can reach 97%. The method has the advantages of high enantioselectivity, simple and easy operation, easy preparation of the catalyst, mild reaction conditions, low energy consumption, environmental friendliness and good yield.

Description

Technical Field

[0001] The invention belongs to the technical field of asymmetric catalytic synthesis, and specifically relates to a method for preparing chiral pyrazolotetrahydropyrimidine compounds by manganese-catalyzed asymmetric hydrogenation of pyrazolopyrimidine polynitrogen aromatic compounds. Background Art

[0002] Chiral 4,5,6,7-pyrazolo[1,5-a]tetrahydropyrimidines are important building blocks that are commonly found in drugs and bioactive molecules ((a) Lack, NA; Axerio-Cilies, P.; Tavassoli, P.; Han, FQ; Chan, KH; Feau, C.; LeBlanc, E.; Guns, ET; Guy, RK; Rennie, P.S. and Cherkasov, AJ Med. Chem. 2011, 54, 8563-8573. (b) Yakaiah, T.; Kurumurthy, C.; Lingaiah, BPV; Narsaiah, B.; Pamanji, R.; Velatooru, LR; Venkateswara Rao, J.; Gururaj, S.; Parthasarathy, T. and Sridhar, B. Med. Chem. Res. 2012, 21, 4261-4273. (c) Asano, T.; Yamazaki, H.; Kasahara, C.; Kubota, H.; Kontani, T.; Harayama, Y.; Ohno, K.; Mizuhara, H.; Yokomoto, M.; Misumi, K.; Kinoshita, T.; Ohta, M. and Takeuchi, MJ Med. Chem. 2012, 55, 7772-7785.), such as zabutinib, CDK9 selective inhibitors and selective KV1.5 blocker BMS394136. Therefore, the synthesis of this class of compounds has attracted the attention of synthetic chemists. Transition metal-catalyzed asymmetric hydrogenation of pyrazolopyrimidine compounds is considered to be an effective method for the synthesis of this class of compounds.

[0003] In recent years, some methods for manganese-catalyzed hydrogenation of asymmetric aromatic heterocycles have been reported ((a) Liu, C.; Wang, M.; Liu, S.; Wang, Y.; Peng, Y.; Lan, Y and Liu, Q. Angew. Chem. Int. Ed. 2021, 60, 5108-5113. (b) Liu, C.; Wang, M.; Xu, Y.; Li, Y. and Liu, Q. Angew. Chem. Int. Ed. 2022, 61, e202202814. (c) Liu, C.; Liu, X and Liu, Q. Chem. 2023, 10.1016 / j.chempr.2023.05.006.), however, there has been no report on the use of abundant manganese metal to achieve asymmetric hydrogenation of pyrazolopyrimidine polynitrogen aromatic compounds to synthesize the 4,5,6,7-pyrazolo[1,5-a]tetrahydropyrimidine structural skeleton. Summary of the invention

[0004] In view of this, the purpose of the present application is to provide a method for synthesizing chiral pyrazolotetrahydropyrimidine compounds by manganese-catalyzed asymmetric hydrogenation of pyrazolopyrimidine polynitrogen aromatic compounds.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] The present invention provides a chiral pyrazolotetrahydropyrimidine compound, wherein the chiral pyrazolotetrahydropyrimidine compound is selected from at least one of the structures shown in Formula II:

[0007]

[0008] Among them, R 1 , R 2 are independently aryl, C1-C6 alkyl or C1-C6 alkyl with a substituent;

[0009] The aryl group is selected from phenyl, naphthyl, thienyl, pyridyl, furyl or phenyl with a substituent;

[0010] The substituent is at least one of methoxy, fluorine, chlorine, bromine and trifluoromethyl.

[0011] Based on the above technical solution, further, the chiral pyrazolotetrahydropyrimidine compound is selected from any one of the structures shown below:

[0012]

[0013]

[0014] Another aspect of the present invention provides a method for preparing the chiral pyrazolotetrahydropyrimidine compound, wherein manganese and a chiral hydroxypyridine oxazoline ligand are used as catalysts, and under alkaline conditions, a pyrazolopyrimidine polynitrogen aromatic compound and hydrogen are asymmetric hydrogenated in a solvent to obtain the chiral pyrazolotetrahydropyrimidine compound;

[0015] The pyrazolopyrimidine polynitrogen aromatic compound is selected from one of the structures shown in Formula I;

[0016]

[0017] Among them, R 1 , R 2 are independently aryl, C1-C6 alkyl or C1-C6 alkyl with a substituent;

[0018] The aryl group is selected from phenyl, naphthyl, thienyl, pyridyl, furyl or phenyl with a substituent;

[0019] The substituent is at least one of methoxy, fluorine, chlorine, bromine and trifluoromethyl.

[0020] Based on the above technical solution, further, the chiral hydroxypyridine oxazoline ligand is selected from at least one of the structures shown below:

[0021]

[0022] Based on the above technical solution, further, the base includes an organic base and an inorganic base;

[0023] The inorganic base is selected from at least one of potassium tert-butoxide, sodium tert-butoxide, potassium isopropoxide, sodium isopropoxide, cesium carbonate, and potassium phosphate;

[0024] The organic base is selected from 1,5-diazabicyclo[5.4.0]-5-undecene or triethylamine.

[0025] Based on the above technical solution, further, the solvent is selected from at least one of tetrahydrofuran, toluene, trifluorotoluene, N,N-dimethylformamide, 1,4-dioxane, 1,2-dichloroethane, dichloromethane, ethyl acetate, methanol, and acetonitrile.

[0026] Based on the above technical solution, further, the molar ratio of the base to the pyrazolopyrimidine polynitrogen aromatic compound is 0.05:1 to 1:1.

[0027] Based on the above technical solution, further, the molar ratio of manganese to the pyrazolopyrimidine polynitrogen aromatic compound is 0.01:1 to 0.05:1.

[0028] Based on the above technical solution, further, the molar ratio of the chiral hydroxypyridine oxazoline ligand to manganese is 1.2:1 to 1:1.

[0029] Based on the above technical solution, further, the pressure of the hydrogen is 500psi to 800psi.

[0030] Based on the above technical solution, further, the concentration of the pyrazolopyrimidine polynitrogen aromatic compound is 0.05 mol / L to 0.2 mol / L.

[0031] Based on the above technical solution, further, the reaction temperature is 50-90° C., and the reaction time is 10-16 hours.

[0032] Compared with the prior art, this application has the following beneficial effects:

[0033] 1) The method of the present application can realize the asymmetric hydrogenation of pyrazolopyrimidine aromatic compounds and obtain chiral pyrazolotetrahydropyrimidine compounds with optical purity in high yield (enantiomeric excess can reach 97%).

[0034] 2) The present invention has high enantioselectivity and diastereoselectivity, is simple and practical to operate, has readily available raw materials, readily available catalysts, mild reaction conditions, low energy consumption, is environmentally friendly and has a good yield.

[0035] 3) The raw materials of the present application are simple and easy to obtain, the operation is simple, the reaction activity is high, the raw materials are completely converted, the separation is convenient, and a high-purity product can be obtained; the reaction conditions are mild, and the environment is friendly and green.

[0036] 4) The present invention has good stereoselectivity and can obtain optically pure products with high enantioselectivity and diastereoselectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 This is a single crystal structure diagram of the complex of metallic manganese and chiral hydroxypyridine oxazoline ligand of this application. DETAILED DESCRIPTION

[0038] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0039] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0040] The synthesis of pyrazolopyrimidine aromatic compounds in the following examples is based on the literature Xie, C.; Xiao, Q.; Guo, Q.; Wu, X.; Zi, G.; Ding, W. and Hou, G. Chem. Sci. 2023, 10.1039 / D3SC02086J.

[0041] In the present application, a BRUKER DRX 400 MHz nuclear magnetic resonance spectrometer is used to characterize the hydrogen spectrum, carbon spectrum and fluorine spectrum, an Applied Biosystems Mariner System 5303HRMS instrument is used to characterize the high-resolution mass spectrum, an Agilent 1100 high-performance liquid chromatography instrument is used to characterize the enantioselectivity, and a JASCO P-1020 optical rotation high-performance liquid chromatography instrument is used to characterize the optical rotation value.

[0042] The room temperature in the examples of the present application refers to 25°C.

[0043] Examples 1-26

[0044] Condition optimization: changing the type of base, organic solvent, chiral ligand and temperature.

[0045] Under nitrogen protection, metal manganese precursor Mn(CO)5Br (0.004 mmol) and chiral hydroxypyridine oxazoline ligand L (0.0044 mmol) were added to the ampoule, and then an organic solvent (1.0 mL) was added. After stirring at room temperature for 10 min, a base (0.01 mmol) was added under nitrogen and stirred for another 5 min. Subsequently, pyrazolopyrimidine aromatic compound 1a (0.2 mmol) and an organic solvent (1.0 mL) were added, and hydrogen was introduced. After stirring at T°C for complete reaction, the solvent was drained and separated by column chromatography to obtain chiral pyrazolotetrahydropyrimidine compounds.

[0046] The type of base, the type of organic solvent, the type of ligand L and the temperature are shown in Table 1; ee is the enantioselectivity.

[0047]

[0048] Table 1. Optimization of asymmetric hydrogenation conditions for pyrazolopyrimidine aromatic compounds

[0049]

[0050]

[0051] Embodiment 27-52

[0052] Asymmetric Hydrogenation of Pyrazolopyrimidine Aromatic Compounds

[0053] Under nitrogen protection, the manganese precursor Mn(CO)5Br (0.008 mmol) and the chiral hydroxypyridine oxazoline ligand L (0.0088 mmol) were added to the ampoule, and then DCE (1.0 mL) was added. After stirring at room temperature for 10 min, KO was added under nitrogen. iPr (0.02 mmol) was stirred for another 5 min, and then pyrazolopyrimidine aromatic compound 1 (0.2 mmol) and DCE (1.0 mL) were added, and 600 psi of hydrogen was introduced. After stirring at 70°C for complete reaction, the solvent was drained and the chiral pyrazolotetrahydropyrimidine compound was separated by column chromatography.

[0054] By changing the type of pyrazolopyrimidine aromatic compound 1 in the reaction, 26 pyrazolotetrahydropyrimidine compounds 2 with different chirality were obtained. The specific types of changes are as follows:

[0055]

[0056] The characterization data of the above compounds are as follows:

[0057] (-)-(S)-2,7-Diphenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2a):

[0058] [α] 20 D =+21.6(c 1.0,CH2Cl2)for 92%ee(R)]. 1 H NMR (400MHz, CDCl3) δ7.73 (d, J = 7.3Hz, 2H), 7.37-7.27 (m, 4H), 7.26-7.19 (m, 2H), 7.06-6.93 (m, 2H), 5.72(s,1H),5.64-5.53(m,1H),4.24(s,1H),3.19-3.05(m,2H),2.61-2.47(m,1H),2.20-2.08(m,1H). 13 C NMR (100MHz, CDCl3) δ150.7,146.9,142.4,134.0,128.4,128.3,127.4,127.2,126.0,125.5,83.3,58.2,35.8,30.8. HPLC: Chiralpak AS-H column, 254nm, 30℃, n-Hexane / i-PrOH=85 / 15, flow=1.0mL / min, retention time 10.5min (major) and 17.2min.

[0059] _______________________________________________________________ (-)-2-Phenyl-7-(p-tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2b):

[0060] δ7.73(d,J=7.3Hz,2H),7.36-7.29(m,2H),7.26-7.19(m,1H),7.14-7.07(m,2H),6.94-6.86(m,2H),5.72(s,1H),5.60-5.53(m,1H),4.22(s,1H),3.20-3.09(m,2H),2.57-2.47(m,1H),2.31(s,3H),2.17-2.09(m,1H). 13 C NMR(100MHz,CDCl3)δ150.6,146.8,139.4,136.8,134.0,129.1,128.3,127.3,125.9,125.5,83.3,58.1,35.9,30.9,21.0.HPLC:ChiralpakAS-H column,254nm,30℃,n-Hexane / i-PrOH=85 / 15,flow=1.0mL / min,retention time9.8min(major)and 13.4min.HRMS:Calculated for C 19 H 19 N3[M+H] + 290.1652,found:290.1655.

[0061] _______________________________________________________________ (-)-2-Phenyl-7-(m-tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2d):

[0062] 7.74(d,J=7.1Hz,2H),7.43-7.28(m,2H),7.27-7.14(m,2H),7.09-6.98(m,1H),6.91-6.66(m,2H),5.73(s,1H),5.63-5.46(m,1H),4.20(s,1H),3.33-3.04(m,2H),2.62-2.46(m,1H),2.30(s,3H),2.21-2.08(m,1H). 13 C NMR(100MHz,CDCl3)δ150.8,146.9,142.4,138.1,134.1,128.41,128.37,128.1,127.4,126.7,125.6,123.2,83.4,58.3,36.0,30.9,21.6.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane / i-PrOH=85 / 15,flow=1.0mL / min,retention time 8.6min(major)and 12.9min.HRMS:Calculated for C 19 H 19 N3[M+H] + 290.1652,found:290.1655.

[0063] _______________________________________________________________ (-)-7-(4-Methoxyphenyl)-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2e):

[0064] CDCl3)δ7.73(d,J=7.2Hz,2H),7.38-7.29(m,2H),7.26-7.20(m,1H),6.98-6.89(m,2H),6.88-6.78(m,2H),5.71(s,1H),5.60-5.49(m,1H),4.23(s,1H),3.76(s,3H),3.21-3.08(m,2H),2.58-2.45(m,1H),2.18-2.07(m,1H). 13C NMR(100MHz,CDCl3)δ158.7,150.6,146.8,134.5,134.0,128.3,127.3,127.1,125.5,113.8,83.3,57.8,55.2,35.9,31.0.HPLC:Chiralpak AS-Hcolumn,254nm,30℃,n-Hexane / i-PrOH=85 / 15,flow=1.0mL / min,retention time 15.6min(major)and 22.5min.HRMS:Calculated for C 19 H 19 N3O[M+H] + 306.1601,found:306.1601.

[0065] _______________________________________________________________ (-)-7-(4-(Methylthio)phenyl)-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2f):

[0066] CDCl3)δ7.79-7.66(m,2H),7.38-7.27(m,2H),7.26-7.22(m,1H),7.22-7.14(m,2H),6.98-6.87(m,2H),5.73(s,1H),5.60-5.50(m,1H),4.18(s,1H),3.23-3.09(m,2H),2.58-2.48(m,1H),2.43(s,3H),2.19-2.08(m,1H). 13 C NMR(100MHz,CDCl3)δ150.9,146.9,139.4,137.4,134.0,128.4,127.5,126.8,126.6,125.6,83.5,58.0,36.0,30.9,16.0.HPLC:ChiralpakAS-Hcolumn,254nm,30℃,n-Hexane / i-PrOH=85 / 15,flow=1.0mL / min,retention time19.5min(major)and 23.1min.HRMS:Calculated for C 19 H 19N3S[M+H] + 322.1372,found:322.1378.

[0067] _______________________________________________________________

[0068] (-)-7-(4-Chlorophenyl)-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2g):

[0069] CDCl3)δ7.71(d,J=7.1Hz,2H),7.38-7.21(m,5H),7.04-6.85(m,2H),5.71(s,1H),5.63-5.46(m,1H),4.24(s,1H),3.22-3.03(m,2H),2.62-2.43(m,1H),2.19-2.02(m,1H). 13 C NMR(100MHz,CDCl3)δ151.0,146.9,141.0,133.9,133.1,128.7,128.4,127.59,127.55,125.6,83.5,57.8,36.0,30.9.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane / i-PrOH=80 / 20,flow=1.0mL / min,retention time 8.5min(major)and 12.9min.HRMS:CalculatedforC 18 H 16 ClN3[M+H] + 310.1106( 35 Cl),312.1081( 37 Cl),found:310.1106( 35 Cl),312.1079( 37 Cl).

[0070] _______________________________________________________________

[0071] (-)-7-(4-Bromophenyl)-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2h):

[0072] CDCl3)δ7.76-7.65(m,2H),7.47-7.37(m,2H),7.36-7.28(m,2H),7.26-7.22(m,1H),6.88(d,J=8.3Hz,2H),5.71(s,1H),5.58-5.48(m,1H),4.18(s,1H),3.21-3.08(m,2H),2.60-2.47(m,1H),2.16-2.06(m,1H). 13 C NMR(100MHz,CDCl3)δ151.0,146.8,141.4,133.8,131.6,128.4,127.8,127.5,125.5,121.2,83.5,57.8,36.0,30.8.HPLC:Chiralpak AS-Hcolumn,254nm,30℃,n-Hexane / i-PrOH=85 / 15,flow=1.0mL / min,retention time12.4min(major)and 19.2min.HRMS:Calculated for C 18 H 16 BrN3[M+H] + 354.0600( 79 Br),356.0582( 81 Br),found:354.0602( 79 Br),356.0583( 81 Br).

[0073] _______________________________________________________________

[0074] (-)-2-Phenyl-7-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-

[0075] acetate / dichloromethane 5 / 1 / 2),90%ee,[α] 20 D=-122.96(c 0.64,CHCl3), 1 HNMR(400MHz,CDCl3)δ7.71(d,J=7.5Hz,2H),7.56(d,J=7.9Hz,2H),7.38-7.30(m,2H),7.28-7.22(m,1H),7.17-7.05(m,2H),5.74(s,1H),5.68-5.56(m,1H),4.28(s,1H),3.21-3.02(m,2H),2.64-2.48(m,1H),2.20-2.07(m,1H). 13 C NMR(100MHz,CDCl3)δ151.2,147.0,146.5,133.8,129.6(q,J=32Hz),128.5,127.7,126.6,125.6,125.5,124.1(q,J=270Hz),83.6,58.1,36.0,30.8. 19 F NMR(376MHz,CDCl3)-62.43.HPLC:ChiralpakIA column,254 nm,30℃,n-Hexane / i-PrOH=80 / 20,flow=1.0mL / min,retention time 7.4min(major)and12.7min(major).HRMS:Calculated forC 19 H 16 F3N3[M+H] + 344.1369,found:344.1373.

[0076] _______________________________________________________________

[0077] (-)-7-(Naphthalen-2-yl)-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimi-dine(2j):

[0078] CDCl3)δ7.85-7.69(m,5H),7.47-7.40(m,2H),7.38(s,1H),7.36-7.28(m,2H),7.26-7.16(m,2H),5.83-5.67(m,2H),4.26(s,1H),3.22-3.08(m,2H),2.63-2.49(m,1H),2.30-2.16(m,1H). 13 C NMR(100MHz,CDCl3)δ150.8,146.9,139.8,134.0,133.2,132.6,128.31,128.29,128.0,127.5,127.4,126.1,125.8,125.5,125.1,124.0,83.4,58.4,36.0,30.7.HPLC:Chiralpak AS-Hcolumn,254 nm,30℃,n-Hexane / i-PrOH=85 / 15,flow=1.0mL / min,retention time 12.9min(major)and 19.4min.HRMS:Calculated for C 22 H 19 N3[M+H] + 326.1652,found:326.1654.

[0079] _______________________________________________________________

[0080] (-)-7-(Furan-2-yl)-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2k):

[0081] -107.49(c 0.56,CH2Cl2), 1 H NMR(400MHz,DMSO-D6)δ7.72-7.57(m,3H),7.37-7.28(m,2H),7.26-7.19(m,1H),6.44-6.37(m,1H),6.30(s,1H),6.24-6.17(m,1H),5.65(s,1H),5.52-5.43(m,1H),3.24-3.14(m,2H),2.35-2.17(m,2H). 13C NMR(101MHz,DMSO)δ154.1,148.9,147.1,142.4,134.1,128.4,127.1,124.9,110.5,107.3,82.2,52.1,36.2,27.5.HPLC:Chiralpak AS-H column,254nm,30 ℃,n-Hexane / i-PrOH=80 / 20,flow=1.0mL / min,retention time 7.6min(major)and 15.6min.HRMS:Calculated for C 16 H 15 N3O[M+H] + 266.1288,found:266.1280.

[0082] _______________________________________________________________

[0083] (-)-2-Phenyl-7-(thiophen-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2l):

[0084] (hexanes / ethyl acetate / dichloromethane 5 / 1 / 2),69%ee,[α] 20 D =-153.64(c0.96,CH2Cl2), 1 H NMR(400MHz,DMSO-D6)δ7.71-7.64(m,2H),7.44-7.39(m,1H),7.37-7.30(m,2H),7.27-7.21(m,1H),7.01-6.95(m,1H),6.94-6.90(m,1H),6.32(s,1H),5.75-5.71(m,1H),5.67(s,1H),3.24-3.12(m,2H),2.46-2.34(m,1H),2.26-2.16(m,1H). 13C NMR(100MHz,DMSO-d6)δ149.0,146.9,145.9,134.1,128.4,127.1,126.6,125.1,124.9,124.6,82.1,53.9,35.6,30.3.HPLC:Chiralpak AS-H column,254 nm,30℃,n-Hexane / i-PrOH=80 / 20,flow=1.0mL / min,retention time 8.6min(major)and 12.2min.HRMS:Calculated forC 16 H 15 N3S[M+H] + 282.1059,found:282.1061.

[0085] _______________________________________________________________

[0086] (-)-2-Phenyl-7-(pyridin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2m):

[0087] 8.56(d,J=4.1Hz,1H),7.75-7.69(m,2H),7.63-7.51(m,1H),7.36-7.29(m,2H),7.25-7.22(m,1H),7.17-7.08(m,1H),6.78(d,J=7.9Hz,1H),5.74(s,1H),5.66-5.60(m,1H),4.17(s,1H),3.26-3.13(m,1H),3.11-2.97(m,1H),2.64-2.46(m,2H). 13 C NMR(100MHz,CDCl3)δ161.0,151.2,149.3,146.8,136.8,133.9,128.4,127.6,125.6,122.2,121.4,83.7,59.7,36.4,28.5.HPLC:Chiralpak AS-H column,254 nm,30℃,n-Hexane / i-PrOH=85 / 15,flow=1.0mL / min,retention time 12.1min(major)and 30.3min.HRMS:Calculated forC17 H 16 N4[M+H] + 277.1448,found:277.1446.

[0088] _______________________________________________________________

[0089] (-)-7-Cyclohexyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2n):

[0090] CHCl3), 1 H NMR(400MHz,CDCl3)δ7.84-7.68(m,2H),7.41-7.30(m,2H),7.28-7.22(m,1H),5.64(s,1H),4.12-4.04(m,1H),4.00(s,1H),3.41-3.17(m,2H),2.40-2.25(m,1H),2.14-1.97(m,2H),1.83-1.65(m,4H),1.54-1.45(m,1H),1.36-1.05(m,6H). 13 C NMR(100MHz,CDCl3)δ149.7,146.6,134.4,128.4,127.2,125.5,83.6,59.4,40.9,38.9,29.6,27.3,26.7,26.5,26.3,23.8.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane / i-PrOH=85 / 15,flow=1.0mL / min,retention time 5.7min(major)and 6.8min.HRMS:Calculatedfor C 18 H 23 N3[M+H] + 282.1965,found:282.1970.

[0091] _______________________________________________________________

[0092] (-)-7-Methyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2o):

[0093] -28.87(c 0.80,CHCl3), 1 H NMR(400MHz,CDCl3)δ7.74(d,J=7.3Hz,2H),7.39-7.30(m,2H),7.27-7.22(m,1H),5.64(s,1H),4.42-4.30(m,1H),4.04(s,1H),3.40-3.22(m,2H),2.30-2.20(m,1H),1.94-1.86(m,1H),1.60(d,J=6.5Hz,3H). 13 C NMR(100MHz,CDCl3)δ150.1,145.9,134.2,128.4,127.3,125.5,83.8,50.9,38.0,30.1,21.4.HPLC:Chiralpak AS-Hcolumn,254nm,30℃,n-Hexane / i-PrOH=85 / 15,flow=1.0mL / min,retention time8.4min(major)and 11.2min.HRMS:Calculated for C 13 H 15 N3[M+H] + 214.1339,found:214.1341.

[0094] _______________________________________________________________

[0095] (-)-7-Phenyl-2-(p-tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2p): =8.1Hz,2H),7.31-7.24(m,2H),7.23-7.18(m,1H),7.16-7.08(m,2H),6.97(d,J=7.3Hz,2H),5.66(s,1H),5.59-5.52(m,1H),4.31(s,1H),3.12-3.01(m,2H),2.53-2.43(m,1H),2.32(s,3H),2.14-2.06(m,1H).13 C NMR(100MHz,CDCl3)δ150.9,147.0,142.6,137.1,131.3,129.1,128.5,127.3,126.1,125.5,83.2,58.3,35.9,30.9,21.3.HPLC:ChiralpakIA column,254nm,30℃,n-Hexane / i-PrOH=65 / 35,flow=1.0mL / min,retention time5.3min and 6.4min(major).

[0096] _______________________________________________________________

[0097] (-)-7-Phenyl-2-(m-tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2q): 1H),7.53-7.47(m,1H),7.31-7.25(m,2H),7.24-7.18(m,2H),7.08-7.03(m,1H),7.01-6.94(m,2H),5.69(s,1H),5.61-5.55(m,1H),4.29(s,1H),3.14-3.01(m,2H),2.54-2.45(m,1H),2.32(s,3H),2.15-2.07(m,1H). 13 C NMR(100MHz,CDCl3)δ150.8,146.8,142.4,137.8,133.8,128.4,128.2,128.1,127.1,126.1,126.0,122.7,83.3,58.2,35.7,30.8,21.3.HPLC:Chiralpak IA column,254 nm,30 ℃,n-Hexane / i-PrOH=70 / 30,flow=1.0mL / min,retention time 5.2min and 6.3min(major).

[0098] _______________________________________________________________

[0099] (-)-7-Phenyl-2-(o-tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2r):

[0100] (m,1H),7.34-7.24(m,2H),7.24-7.11(m,4H),7.04-6.93(m,2H),5.60-5.47(m,2H),4.23(s,1H),3.19-3.02(m,2H),2.56-2.46(m,1H),2.42(s,3H),2.17-2.07(m,1H). 13 C NMR(100MHz,CDCl3)δ151.2,146.1,142.5,136.0,134.0,130.4,129.2,128.3,127.3,127.1,126.0,125.4,86.6,58.2,36.0,30.9,21.0.HPLC:Chiralpak IA column,254nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0mL / min,retention time 12.0min and 14.5min(major).

[0101] _______________________________________________________________

[0102] (-)-2-(4-Methoxyphenyl)-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2s):

[0103] =8.7Hz,2H),7.33-7.24(m,2H),7.24-7.19(m,1H),7.03-6.94(m,2H),6.92-6.81(m,2H),5.62(s,1H),5.58-5.50(m,1H),4.34(s,1H),3.77(s,3H),3.13-2.99(m,2H),2.55-2.41(m,1H),2.14-2.06(m,1H). 13C NMR(100MHz,CDCl3)δ159.2,150.7,147.0,142.6,128.5,127.3,126.9,126.8,126.1,113.8,83.0,58.2,55.3,35.9,30.9.HPLC:Chiralpak IA column,254nm,30℃,n-Hexane / i-PrOH=65 / 35,flow=1.0mL / min,retention time 6.7min and9.4min(major).

[0104] _______________________________________________________________

[0105] (-)-2-(4-Bromophenyl)-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2t):

[0106] =8.5Hz,2H),7.43(d,J=8.5Hz,2H),7.33-7.25(m,2H),7.25-7.20(m,1H),6.98(d,J=7.3Hz,2H),5.64(s,1H),5.59-5.49(m,1H),4.35(s,1H),3.15-3.04(m,2H),2.55-2.43(m,1H),2.17-2.07(m,1H). 13 C NMR(100MHz,CDCl3)δ149.7,147.2,142.3,133.0,131.5,128.6,127.4,127.2,126.1,121.3,83.3,58.4,35.9,30.8.HPLC:Chiralpak IA column,254nm,30℃,n-Hexane / i-PrOH=65 / 35,flow=1.0mL / min,retention time 5.8min and 7.4min(major).

[0107] _______________________________________________________________

[0108] (-)-7-Phenyl-2-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2u):66.7mg,97%yield,white solid,known compound, 8 R f =

[0109] 2H),7.27-7.22(m,1H),7.00(d,J=7.3Hz,2H),5.74(s,1H),5.64-5.54(m,1H),4.32(s,1H),3.20-3.07(m,2H),2.61-2.45(m,1H),2.22-2.11(m,1H). 13 C NMR(100MHz,CDCl3)δ149.4,147.2,142.2,137.5,129.1(q,J=32Hz),128.6,127.5,126.0,125.7,125.3(q,J=4Hz),124.4(q,J=270Hz),83.7,58.5,35.9,30.8. 19 F NMR(376MHz,CDCl3)-62.32.HPLC:Chiralpak IBcolumn,254nm,30℃,n-Hexane / i-PrOH=65 / 35,flow=1.0mL / min,retention time 4.7min(major)and 8.5min.

[0110] _______________________________________________________________

[0111] (-)-2-(Furan-2-yl)-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2v):

[0112] -134.17(c 0.98,CHCl3). 1H NMR(400MHz,CDCl3)δ7.40-7.34(m,1H),7.32-7.26(m,2H),7.24-7.18(m,1H),7.00-6.95(m,2H),6.56(d,J=3.2Hz,1H),6.43-6.36(m,1H),5.64(s,1H),5.58-5.53(m,1H),4.32(s,1H),3.16-3.07(m,2H),2.54-2.44(m,1H),2.16-2.08(m,1H). 13 C NMR(100MHz,CDCl3)δ149.5,146.6,143.4,142.3,141.4,128.5,127.3,126.0,111.1,105.4,83.2,58.4,35.7,30.7.HPLC:Chiralpak IA column,254nm,30℃,n-Hexane / i-PrOH=75 / 25,flow=1.0mL / min,retention time 8.6min and 9.8min(major).

[0113] _______________________________________________________________

[0114] (-)-7-Phenyl-2-(thiophen-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2w):

[0115] (m,4H),7.18-7.11(m,1H),7.03-6.92(m,3H),5.61(s,1H),5.57-5.51(m,1H),4.32(s,1H),3.14-3.03(m,2H),2.54-2.41(m,1H),2.15-2.06(m,1H). 13C NMR(100MHz,CDCl3)δ146.8,146.0,142.2,137.5,128.4,127.2,127.1,125.9,123.9,123.2,83.4,58.1,35.6,30.6.HPLC:Chiralpak IA column,254nm,30℃,n-Hexane / i-PrOH=75 / 25,flow=1.0mL / min,retention time 5.5min and 6.6min(major).

[0116] _______________________________________________________________

[0117] (-)-2-Cyclopropyl-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2x):45.0mg,94%yield,white solid,new compound,mp 80-81℃R f =0.30 (m,2H),7.24-7.18(m,1H),7.01-6.91(m,2H),5.46-5.39(m,1H),5.00(s,1H),4.19(s,1H),3.14-3.02(m,2H),2.50-2.40(m,1H),2.10-2.03(m,1H),1.87-1.75(m,1H),0.87-0.80(m,2H),0.70-0.58(m,2H). 13 C NMR(100MHz,CDCl3)δ155.3,146.5,142.6,128.5,127.2,126.1,81.6,58.0,36.0,31.1,9.7,8.1,7.7.HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane / i-PrOH=85 / 15,flow=1.0mL / min,retention time 11.5min(major)and14.4min.HRMS:Calculated for C 15 H 17 N3[M+H] + 240.1495,found:240.1502.

[0118] _______________________________________________________________

[0119] (-)-2-Methyl-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2y):

[0120] [α] 20 D =-97.44(c 0.90,CHCl3). 1 H NMR(400MHz,CDCl3)δ7.34-7.27(m,2H),7.25-7.19(m,1H),7.02-6.94(m,2H),5.47-5.40(m,1H),5.22(s,1H),4.11(s,1H),3.19-3.09(m,2H),2.55-2.42(m,1H),2.16(s,3H),2.12-2.06(m,1H). 13 C NMR(100MHz,CDCl3)δ148.5,146.6,142.6,128.5,127.3,126.0,85.9,58.0,36.2,31.2,14.1.HPLC:Chiralcel OD-H column,254nm,30℃,n-Hexane / i-PrOH=85 / 15,flow=1.0mL / min,retention time 9.6min(major)and 13.6min.HRMS:Calculated for C 13 H 15 N3[M+H] + 214.1339,found:214.1346.

[0121] (-)-7-Phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2z):

[0122] -67.97(c 0.74,CHCl3). 1H NMR (400MHz, CDCl3) δ7.29-7.19(m,3H),7.18-7.13(m,1H),6.96-6.84(m,2H),5.45-5.34( m,1H),5.30(s,1H),4.23(s,1H),3.15-3.00(m,2H),2.45-2.34(m,1H),2.10-2.01(m,1H). 13 C NMR (100MHz, CDCl3) δ146.2,142.3,139.5,128.6,127.4,126.1,86.1,58.6,36.6,31.3. HPLC: Chiralpak IA column, 254nm, 30℃, n-Hexane / i-PrOH=75 / 25, flow=1.0mL / min, retention time 6.8min (major) and 9.0min.

[0123] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A chiral pyrazolotetrahydropyrimidine compound, characterized in that: The chiral pyrazolotetrahydropyrimidine compound is selected from at least one of the structures shown in Formula II: Among them, R 1 , R 2 are independently aryl, C1-C6 alkyl or C1-C6 alkyl with a substituent; The aryl group is selected from phenyl, naphthyl, thienyl, pyridyl, furyl or phenyl with a substituent; The substituent is at least one of methoxy, fluorine, chlorine, bromine and trifluoromethyl.

2. The chiral pyrazolotetrahydropyrimidine compound according to claim 1, characterized in that: The chiral pyrazolotetrahydropyrimidine compound is selected from any one of the structures shown below; 3. The method for preparing a chiral pyrazolotetrahydropyrimidine compound according to claim 1 or 2, characterized in that: Using manganese and chiral hydroxypyridine oxazoline ligand as catalysts, under alkaline conditions, asymmetric hydrogenation of pyrazolopyrimidine polynitrogen aromatic compounds and hydrogen occurs in a solvent to obtain the chiral pyrazolotetrahydropyrimidine compound; The pyrazolopyrimidine polynitrogen aromatic compound is selected from one of the structures shown in Formula I; Among them, R 1 , R 2 are independently aryl, C1-C6 alkyl or C1-C6 alkyl with a substituent; The aryl group is selected from phenyl, naphthyl, thienyl, pyridyl, furyl or phenyl with a substituent; The substituent is at least one of methoxy, fluorine, chlorine, bromine and trifluoromethyl.

4. The preparation method according to claim 3, characterized in that: The chiral hydroxypyridine oxazoline ligand is selected from at least one of the structures shown below:

5. The preparation method according to claim 3, characterized in that: The base includes organic base and inorganic base; The inorganic base is selected from at least one of potassium tert-butoxide, sodium tert-butoxide, potassium isopropoxide, sodium isopropoxide, cesium carbonate, and potassium phosphate; The organic base is selected from 1,5-diazabicyclo[5.4.0]-5-undecene or triethylamine.

6. The preparation method according to claim 3, characterized in that: The solvent is selected from at least one of tetrahydrofuran, toluene, trifluorotoluene, N,N-dimethylformamide, 1,4-dioxane, 1,2-dichloroethane, dichloromethane, ethyl acetate, methanol, and acetonitrile.

7. The preparation method according to claim 3, characterized in that: The molar ratio of the base to the pyrazolopyrimidine polynitrogen aromatic compound is 0.05:1 to 1:1; the molar ratio of manganese to the pyrazolopyrimidine polynitrogen aromatic compound is 0.01:1 to 0.05:1; and the molar ratio of the chiral hydroxypyridine oxazoline ligand to manganese is 1.2:1 to 1:

1.

8. The preparation method according to claim 3, characterized in that: The pressure of the hydrogen is 500psi to 800psi.

9. The preparation method according to claim 3, characterized in that: The concentration of the pyrazolopyrimidine polynitrogen aromatic compound is 0.05 mol / L to 0.2 mol / L.

10. The preparation method according to claim 3, characterized in that: The reaction temperature is 50-90° C., and the reaction time is 10-16 hours.

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