A method for synthesizing chiral tetrahydropyrazolo[1,5-a]pyrimidine

Abstract

The present invention discloses a method for synthesizing chiral tetrahydropyrazolo[1,5-a]pyrimidines. The method comprises the following steps: synthesizing chiral tetrahydropyrazolo[1,5-a]pyrimidines by asymmetric hydrogenation of substituted pyrazolo[1,5-a]pyrimidines in a solvent under a hydrogen atmosphere and catalyzed by a rhodium chiral catalyst. The method not only has the advantages of high atom economy and clean and green properties, but also has the advantages of simple and practical operation, high yield, and high ee value.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis methodology, and in particular to a method for synthesizing chiral tetrahydropyrazolo[1,5-a]pyrimidine. Background Art

[0002] Optically pure chiral tetrahydropyrazolo[1,5-a]pyrimidines are important building blocks for many pharmaceutically active molecules, such as anticancer, antimalarial, antiviral, antibacterial, and antidepressant drugs. Therefore, developing efficient and highly enantioselective methods for synthesizing chiral tetrahydropyrazolo[1,5-a]pyrimidines is crucial. Asymmetric catalytic hydrogenation has long been a key method for synthesizing chiral compounds due to its high efficiency, environmental friendliness, and atom economy.

[0003] Ryoichi Kuwano et al. disclosed in "Catalytic Asymmetric Hydrogenation of N-Boc-Imidazoles and Oxazoles" in J. Am. Chem. Soc. 2011, Vol. 133, pp. 7312-7315, the highly enantioselective hydrogenation of imidazole and oxazole compounds over a Ru chiral catalyst to obtain chiral nitrogen heterocyclic compounds.

[0004] Frank Glorius et al. disclosed in “Ruthenium–NHC-Catalyzed Asymmetric Hydrogenation of Indolizines: Access to Indolizidine Alkaloids”, Angew. Chem. Int. Ed., 2013, No. 52, pp. 9500-9503, the Ru-NHC-catalyzed asymmetric hydrogenation of indolizine to obtain chiral indolizidine alkaloids.

[0005] Qing-Hua Fan et al. disclosed in “Asymmetric Ruthenium-Catalyzed Hydrogenation of 2-and 2,9-Substituted 1,10-Phenanthrolines”, Angew. Chem. Int. Ed., 2013, No. 52, pp. 7172-7176, the Ru-catalyzed asymmetric hydrogenation of phenanthroline to obtain chiral nitrogen heterocyclic compounds.

[0006] Although there are reports on the synthesis of chiral heterocyclic compounds, the hydrogenation of substituted pyrazolo[1,5-a]pyrimidines has not been reported. Chiral tetrahydropyrazolo[1,5-a]pyrimidines are structural units of many pharmaceutically active molecules. Therefore, it is very important to establish a method for synthesizing chiral tetrahydropyrazolo[1,5-a]pyrimidines. How to provide a method for synthesizing chiral tetrahydropyrazolo[1,5-a]pyrimidines is an urgent problem that needs to be solved. Summary of the Invention

[0007] In order to solve the above problems, the present invention provides a method for synthesizing chiral tetrahydropyrazolo[1,5-a]pyrimidine. The method comprises the following steps: in a solvent, under a hydrogen atmosphere, and under the catalysis of a rhodium chiral catalyst, a substituted pyrazolo[1,5-a]pyrimidine represented by general formula I is used to synthesize a chiral tetrahydropyrazolo[1,5-a]pyrimidine represented by general formula II.

[0008]

[0009] In Formula II, where * represents a chiral carbon atom, in Formula I or Formula II, R 1 、R 2 and R 3 Selected from: C1-C 20 Alkyl, substituted C1-C 20 Alkyl, heterocyclic, phenyl, naphthyl or substituted phenyl, substituted C1-C 20 Alkyl is C1-C 20 One or more H groups on the alkyl group are replaced by a substituent A. 20 Alkyl, substituted phenyl is a phenyl group in which one or more H groups on the phenyl group are substituted by a substituent A, and the substituent A is selected from: halogen, -CF3, C1-C3 alkyl, C1-C3 alkoxy or phenyl.

[0010] As a further improvement of the present invention, the method comprises the following steps:

[0011] Step 1: Under a nitrogen atmosphere, a rhodium metal precursor and a chiral bisphosphine ligand are added to a solvent and stirred to react to obtain a rhodium chiral catalyst solution;

[0012] Step 2: Under a hydrogen atmosphere, a rhodium chiral catalyst solution is stirred and reacted with a substituted pyrazolo[1,5-a]pyrimidine to obtain a crude chiral tetrahydropyrazolo[1,5-a]pyrimidine product;

[0013] Step 3: Filter the reaction mixture to remove the rhodium chiral catalyst to obtain a pure chiral tetrahydropyrazolo[1,5-a]pyrimidine product.

[0014] As a further improvement of the present invention, the reaction mixture in step 3 is filtered through a silica gel column.

[0015] As a further improvement of the present invention, the molar ratio of the rhodium metal precursor and the chiral bisphosphine ligand in step one is: 0.5:1.0-0.5:2.0, specifically, the molar ratio of the rhodium metal precursor and the chiral bisphosphine ligand is selected from: 0.5:1.0, 0.5:1.1, 0.5:1.2, 0.5:1.3, 0.5:1.4, 0.5:1.5, 0.5:1.6, 0.5:1.7, 0.5:1.8, 0.5:1.9 or 0.5:2.0, preferably, the molar ratio of the rhodium metal precursor and the chiral bisphosphine ligand is 0.5:1.1.

[0016] As a further improvement of the present invention, the reaction time in step one is 0.2-0.8h. Specifically, the reaction time in step one is selected from: 0.2h, 0.3h, 0.4h, 0.5h, 0.6h, 0.7h or 0.8h. Preferably, the reaction time in step one is 0.5h.

[0017] As a further improvement of the present invention, the reaction temperature in step 1 is 15-35°C. Specifically, the reaction temperature in step 1 is selected from: 15°C, 20°C, 25°C, 30°C or 35°C.

[0018] As a further improvement of the present invention, the rhodium metal precursor in step 1 is cyclooctadiene rhodium chloride dimer.

[0019] As a further improvement of the present invention, in step 1, the chiral bisphosphine ligand is selected from: (S,R)-Duanphos, (R)-SITCP, (R)-SDP, (S)-DTBM-SegPhos, (R,R)-Ph-BPE, (R)-Segphos or (R,R)-f-spiroPhos. Preferably, the chiral bisphosphine ligand is (S)-DTBM-SegPhos, and the structural formula of (S)-DTBM-SegPhos is

[0020]

[0021] As a further improvement of the present invention, in step 1, the solvent is selected from: dichloromethane, chloroform, toluene, 1,4-dioxane, tetrahydrofuran or methanol. Preferably, the solvent is tetrahydrofuran.

[0022] As a further improvement of the present invention, the molar ratio of the rhodium metal precursor to the substituted pyrazolo[1,5-a]pyrimidine is: 0.5:50-0.5:110, specifically, the molar ratio of the rhodium metal precursor to the substituted pyrazolo[1,5-a]pyrimidine is selected from: 0.5:50, 0.5:60, 0.5:70, 0.5:80, 0.5:90, 0.5:100 or 0.5:110, preferably, the molar ratio of the rhodium metal precursor to the substituted pyrazolo[1,5-a]pyrimidine is 0.5:50.

[0023] As a further improvement of the present invention, the reaction time in step 2 is 12-48 hours. Specifically, the reaction time is selected from: 12 hours, 14 hours, 16 hours, 18 hours, 22 hours, 24 hours, 26 hours, 28 hours, 32 hours, 36 hours, or 48 hours. Preferably, the reaction time is 48 hours.

[0024] As a further improvement of the present invention, the reaction pressure in step 2 is 100-1200 psi. Specifically, the reaction pressure is selected from: 100 psi, 140 psi, 300 psi, 500 psi, 700 psi or 1200 psi. Preferably, the reaction pressure is 1200 psi.

[0025] As a further improvement of the present invention, the reaction temperature in step 2 is 40-100°C. Specifically, the reaction temperature is selected from: 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C. Preferably, the reaction temperature is 90°C.

[0026] As a further improvement of the present invention, the concentration of the substituted pyrazolo[1,5-a]pyrimidine in step 2 is 0.05-0.25 mmol / mL. Specifically, the concentration of the substituted pyrazolo[1,5-a]pyrimidine is selected from: 0.05 mmol / mL, 0.100 mmol / mL, 0.125 mmol / mL, 0.150 mmol / mL, 0.175 mmol / mL or 0.250 mmol / mL. Preferably, the concentration of the substituted pyrazolo[1,5-a]pyrimidine is 0.125 mmol / mL.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] 1. The present invention discloses a method for synthesizing chiral tetrahydropyrazolo[1,5-a]pyrimidine using a rhodium chiral catalyst, wherein the rhodium chiral catalyst has the advantages of low toxicity, high atom economy and environmental friendliness;

[0029] 2. The method for synthesizing chiral tetrahydropyrazolo[1,5-a]pyrimidine disclosed in the present invention has the advantages of simple and practical operation, high yield and high ee value. DETAILED DESCRIPTION

[0030] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts are within the scope of protection of the present invention.

[0031] Example 1: Selection of chiral phosphine ligands

[0032] The added chiral phosphine ligand is selected by controlling the variable method.

[0033] Cyclooctadiene rhodium chloride dimer (the molar ratio of cyclooctadiene rhodium chloride dimer to substituted pyrazolo[1,5-a]pyrimidine is 0.5:50) and chiral bisphosphine ligand (the molar ratio of cyclooctadiene rhodium chloride dimer to chiral bisphosphine ligand is 0.5:1.1) were added to a dry reaction flask. After nitrogen replacement, 1.0 mL of tetrahydrofuran was added and the mixture was stirred and reacted at 25°C for 0.5 h. Then, 1.0 mL of tetrahydrofuran was used to transfer the solution to a dry reaction flask to which substituted pyrazolo[1,5-a]pyrimidine substrate 1a (27.5 mg, 0.125 mmol) had been added in advance. The reaction flask was moved to a reactor and hydrogen (1200 psi) was introduced. The mixture was reacted at 60°C for 24 h. The hydrogen was released and the reaction mixture was filtered through a silica gel column to remove the catalyst to obtain the pure product. The reaction formula is as follows:

[0034]

[0035] Wherein, the chiral phosphine ligands are selected from: (S,R)-Duanphos, (R)-SITCP, (R)-SDP, (S)-DTBM-SegPhos, (R,R)-Ph-BPE, (R)-Segphos or (R,R)-f-spiroPhos.

[0036] The reaction results are shown in Table 1:

[0037] Table 1. Selection of chiral phosphine ligands for substituted pyrazolo[1,5-a]pyrimidine 1a

[0038] entry Chiral phosphine ligands Conversion rate (%) ee.(%) 1 (S,R)-Duanphos 17 82 2 (R)-SITCP 0 ND 3 (R)-SDP 5 30 4 (S)-DTBM-SegPhos 60 91 5 (R,R)-Ph-BPE 12 84 6 (R)-Segphos 20 86 7 (R,R)-f-spiroPhos 0 ND

[0039] It can be seen from Table 1 that when the chiral phosphine ligand is (S)-DTBM-SegPhos, the conversion rate of the reaction product 2a is the highest, and the ee value of compound 2a is the highest.

[0040]

[0041] Example 2: Selection of solvent

[0042] The added solvent is selected by controlling the variable method.

[0043] Cyclooctadiene rhodium chloride dimer (the molar ratio of cyclooctadiene rhodium chloride dimer to substituted pyrazolo[1,5-a]pyrimidine is 0.5:50) and chiral bisphosphine ligand (S)-DTBM-SegPhos (the molar ratio of cyclooctadiene rhodium chloride dimer to (S)-DTBM-SegPhos is 0.5:1.1) were added to a dry reaction flask. After nitrogen replacement, 1.0 mL of solvent was added and the mixture was stirred at 25°C for 0.5 h. Then, 1.0 mL of solvent was used to transfer the solution to a dry reaction flask pre-added with substituted pyrazolo[1,5-a]pyrimidine substrate 1a (27.5 mg, 0.125 mmol). The reaction flask was moved to a reactor and hydrogen (1200 psi) was introduced. The mixture was reacted at 60°C for 24 h. The hydrogen was released and the reaction mixture was filtered through a silica gel column to remove the catalyst to obtain a pure product. The reaction formula is as follows:

[0044]

[0045] Wherein, the solvent is selected from: dichloromethane, chloroform, toluene, 1,4-dioxane, tetrahydrofuran or methanol.

[0046] The reaction results are shown in Table 2:

[0047] Table 2. Solvent selection for substituted pyrazolo[1,5-a]pyrimidine 1a

[0048] entry solvent Conversion rate (%) ee.(%) 1 dichloromethane 22 92 2 Chloroform trace ND 3 Toluene 42 89 4 1,4-Dioxane trace ND 5 Tetrahydrofuran 60 91 6 Methanol trace ND

[0049] It can be seen from Table 2 that when the solvent is tetrahydrofuran, the conversion rate and ee value of compound 2a are the highest.

[0050] Example 3: Selection of reaction time in step 2

[0051] The hydrogen pressure is selected by the control variable method.

[0052] Cyclooctadiene rhodium chloride dimer (the molar ratio of cyclooctadiene rhodium chloride dimer to substituted pyrazolo[1,5-a]pyrimidine is 0.5:50) and (S)-DTBM-SegPhos (the molar ratio of cyclooctadiene rhodium chloride dimer to (S)-DTBM-SegPhos is 0.5:1.1) were added to a dry reaction flask. After nitrogen replacement, 1.0 mL of tetrahydrofuran was added and the mixture was stirred and reacted at 25°C for 0.5 h. Then, 1.0 mL of tetrahydrofuran was used to transfer the solution to a dry reaction flask to which substituted pyrazolo[1,5-a]pyrimidine substrate 1a (27.5 mg, 0.125 mmol) had been added. The reaction flask was moved to a reactor and hydrogen (1200 psi) was introduced. The mixture was reacted at 60°C to release hydrogen. The reaction mixture was filtered through a silica gel column to remove the catalyst to obtain the pure product. The reaction formula is as follows:

[0053]

[0054] The reaction flask was moved to a reaction kettle, hydrogen (1200 psi) was introduced, and the reaction time at 60° C. was selected from: 12 h, 24 h, 36 h or 48 h.

[0055] The reaction results are shown in Table 3:

[0056] Table 3. Reaction time selection for substituted pyrazolo[1,5-a]pyrimidine 1a

[0057] entry Reaction time (h) Conversion rate (%) ee.(%) 1 12 35 92 2 24 60 92 3 36 67 92 4 48 83 92

[0058] It can be seen from Table 3 that when the reaction time is 48 h, the conversion rate of compound 2a is the highest.

[0059] Example 4. Selection of reaction temperature in step 2

[0060] The reaction temperature is selected by the control variable method.

[0061] Cyclooctadiene rhodium chloride dimer (the molar ratio of cyclooctadiene rhodium chloride dimer to substituted pyrazolo[1,5-a]pyrimidine is 0.5:50) and (S)-DTBM-SegPhos (the molar ratio of cyclooctadiene rhodium chloride dimer to (S)-DTBM-SegPhos is 0.5:1.1) were added to a dry reaction flask. After nitrogen replacement, 1.0 mL of tetrahydrofuran was added and the mixture was stirred at 25°C for 0.5 h. The solution was then transferred to a dry reaction flask pre-added with substituted pyrazolo[1,5-a]pyrimidine substrate 1a (27.5 mg, 0.125 mmol) with 1.0 mL of tetrahydrofuran. The reaction flask was then transferred to a reactor and hydrogen (1200 psi) was introduced. The mixture was reacted at different temperatures for 48 h. The hydrogen was released and the reaction mixture was filtered through a silica gel column to remove the catalyst to obtain the pure product. The reaction formula is as follows:

[0062]

[0063] The reaction temperature is selected from 25°C, 60°C, 80°C or 90°C.

[0064] The reaction results are shown in Table 4:

[0065] Table 4. Reaction time selection for substituted pyrazolo[1,5-a]pyrimidine 1a

[0066] entry Reaction temperature (℃) Conversion rate (%) ee.(%) 1 25 16 91 2 60 83 92 3 80 90 92 4 90 99 92

[0067] It can be seen from Table 4 that when the reaction temperature is 90°C, the conversion rate of compound 2a is the highest.

[0068] Example 5: Synthesis of Chiral Tetrahydropyrazolo[1,5-a]pyrimidine

[0069] Standard reaction conditions: Cyclooctadiene rhodium chloride dimer (the molar ratio of cyclooctadiene rhodium chloride dimer to substituted pyrazolo[1,5-a]pyrimidine is 0.5:50) and (S)-DTBM-SegPhos (the molar ratio of cyclooctadiene rhodium chloride dimer to (S)-DTBM-SegPhos is 0.5:1.1) were added to a dry reaction flask. After nitrogen replacement, 1.0 mL of tetrahydrofuran was added and the reaction was stirred at 25°C for 0.5 h. The solution was then transferred to a dry reaction flask pre-added with substituted pyrazolo[1,5-a]pyrimidine substrate 1a (27.5 mg, 0.125 mmol) with 1.0 mL of tetrahydrofuran. The reaction flask was transferred to a reactor and hydrogen (1200 psi) was introduced. The reaction was carried out at 90°C for 48 h. The hydrogen was released and the reaction mixture was filtered through a silica gel column to remove the catalyst to obtain the pure product.

[0070] Preparation of (R)-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

[0071]

[0072] Chloroform-d)δ7.49(d,J=4.96Hz,1H),7.33(t,J=7.37Hz,2H),7.28(dtd,J=7.36,5.18,2.69Hz,1H),7.04–6.92(m,2H),5.55(s,1H),5.45(t,J =4.71Hz,1H),3.28(dq,J=12.08,4.09Hz,1H),3.18(dddd,J=12.08,10.5 7,3.28,1.35Hz,1H),2.57–2.33(m,1H),2.17(dq,J=13.07,4.15Hz,1H). 13 C NMR (151MHz, Chloroform-d) δ150.3,141.0,140.4,128.9,128.1,128.0,126.0,126.0,115.0,71.7,58.5,35.7,29.9,29.8; TOF-HRMSCalcd.for C 13 H 13 N4 + [M+H + ]:225.1135,found 225.1139.

[0073] Preparation of (R)-7-(2-methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-carbonitrile

[0074] Chloroform-d)δ7.49(s,1H),7.30–7.22(m,1H),6.95–6.79(m,2H),6.45(dd,J=7.55,1.68Hz,1H),5.80(dd,J=5.49,3.07Hz,1H),4.97( s,1H),3.85(s,3H),3.30(dt,J=11.88,4.11Hz,1H),3.20(td,J=11.61,3.28Hz,1H),2.47–2.31(m,1H),2.27(dq,J=13.97,3.48Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ155.5,150.4,140.8,129.1,128.3,126.9,120.7,114.8,110.7,71.8,55.4,54.0,36.0,27.2.TOF-HRMS Calcd.for C 14 H 15 N4O + [M+H + ]:255.1240,found 255.1240.

[0075] Preparation of (R)-7-(3-methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

[0076] MHz,Chloroform-d)δ7.48(s,1H),7.31–7.19(m,1H),6.81(ddd,J=8.35,2.57,0.97Hz,1H),6.61–6.53(m,1H),6.50(t,J =2.18Hz,1H),5.42(t,J=4.59Hz,1H),5.38(s,1H),3.76(s,3H),3.37–3.12(m,2H),2.52–2.34(m,1H),2.32–2.09(m,1H). 13 C NMR(101MHz,Chloroform-d)δ160.0,150.1,142.0,140.9,130.0,118.2,114.9,112.9,112.3,71.7,58.4,55.3,35.8,29.7.TOF-HRMS Calcd.for C 14 H 15 N4O +[M+H + ]:255.1240,found255.1240.

[0077] Preparation of (R)-7-(3-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

[0078]

[0079] Chloroform-d)δ7.50(s,1H),7.31–7.25(m,2H),6.98(q,J=1.44Hz,1H),6.90–6.81(m,1H),5.43(t,J=4.72Hz,1H),5.35–5.18(m,1H) ,3.42–3.30(m,1H),3.22(dddd,J=12.12,10.52,3.25,1.48Hz,1H),2.47(dddd,J=14.56,10.59,5.46,4.09Hz,1H),2.30–2.07(m,1H). 13 C NMR(101MHz,Chloroform-d)δ150.1,142.4,141.2,135.0,130.3,128.4,126.3,124.2,114.7,72.0,58.0,35.9,29.7.TOF-HRMS Calcd.for C 13 H 12 ClN4 + [M+H + ]:259.0745,found 259.0746.

[0080] Preparation of (R)-7-(3-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

[0081] Chloroform-d)δ7.50(d,J=1.36Hz,1H),7.31(tdd,J=7.54,5.79,1.33Hz,1H),7.06–6.90(m,1H),6.78(dd,J=7.79,1.59Hz,1H),6.68(dt,J=9.66, 2.10Hz,1H),5.55–5.34(m,2H),3.34(dp,J=11.05,3.50Hz,1H),3.21(tt, J=11.54,3.27Hz,1H),2.60–2.37(m,1H),2.19(dt,J=11.44,4.13Hz,1H).13 C NMR(151MHz,Chloroform-d)δ163.14(d,J=247.20Hz),150.19,142.99(d,J=6.72Hz),141.18,130.64(d,J=8.33Hz),121.69 (d,J=2.90Hz),115.13(d,J=20.90Hz),114.81,113.28(d,J=22.56Hz),71.94(d,J=3.64Hz),58.07,35.81,29.71.TOF-HRMS Calcd.for C 13 H 12 FN4 + [M+H + ]:243.1041,found 243.1043.

[0082] Preparation of (R)-7-(3-bromophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

[0083] Chloroform-d)δ7.50(s,1H),7.42(ddd,J=7.94,2.01,1.00Hz,1H),7.21(t,J= 7.87Hz,1H),7.14(t,J=1.93Hz,1H),6.91(ddt,J=7.76,1.75,0.83Hz,1H),5.41 (dd,J=9.99,5.12Hz,2H),3.39–3.30(m,1H),3.21(dddd,J=12.13,10.51,3.24, 1.47Hz, 1H), 2.45 (dddd, J=14.31, 10.56, 5.47, 4.03Hz, 1H), 2.26–2.12 (m, 1H). 13 C NMR(151MHz,Chloroform-d)δ150.1,142.6,141.2,131.3,130.5,129.2,124.7,123.1,114.7,72.0,58.0,35.8,29.7.TOF-HRMS Calcd.for C 13 H 12 BrN4 + [M+H + ]:303.0240,found 303.0242.

[0084] Preparation of (R)-7-(4-(tert-butyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

[0085] MHz,Chloroform-d)δ7.49(s,1H),7.35(d,J=8.38Hz,2H),6.96–6.86(m,2H),5.42(t,J=4.74Hz,1H),5.16 (s,1H),3.41–3.07(m,2H),2.44(dddd,J=14.08,9.87,5.36,4.20Hz,1H),2.31–2.08(m,1H),1.28(s,9H). 13 C NMR(151MHz,Chloroform-d)δ151.0,150.1,140.8,137.2,125.8,125.6,114.8,71.9,58.4,36.0,34.6,31.3,29.9.TOF-HRMSCalcd.for C 17 H 21 N4 + [M+H + ]:281.1761,found281.1763.

[0086] Preparation of (R)-7-(4-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

[0087]

[0088] Chloroform-d)δ7.49(s,1H),7.37–7.28(m,2H),7.01–6.85(m,2H),5.42(t,J=4.83Hz,1H),5.36(s,1H),3.35(ddt,J=12.27,5.0 8,3.60Hz,1H),3.21(dddd,J=12.03,10.26,3.31,1.52Hz,1H),2.45(dddd,J=14.06,9.79,5.43,4.06Hz,1H),2.24–2.10(m,1H). 13 C NMR(101MHz,Chloroform-d)δ150.1,141.1,138.8,134.0,129.1,127.5,114.8,71.9,58.0,35.9,29.9.TOF-HRMS Calcd.for C 13 H 12 ClN4+ [M+H + ]:259.0745,found259.0746.

[0089] Preparation of (R)-7-(4-bromophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

[0090]

[0091] MHz,Chloroform-d)δ7.59–7.37(m,3H),6.96–6.77(m,2H),5.40(t,J=4.87Hz,1H),5.32(s,1H),3.35(ddd,J=12.33, 5.85,3.62Hz,1H),3.22(dddd,J=11.98,10.26,3.21,1.47Hz,1H),2.53–2.39(m,1H),2.16(dq,J=13.66,4.39Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ150.1,141.1,139.3,132.1,127.8,122.1,114.7,72.0,58.1,35.9,29.8.TOF-HRMS Calcd.for C 13 H 12 BrN4 + [M+H + ]:303.0240,found 303.0242.

[0092] Preparation of (R)-7-(pyridin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

[0093]

[0094] ×4.60mm), hexane:isopropanol=70:30,210nm; t R =13.2min(minor),t R =24.7min(major); 1H NMR(600MHz,Chloroform-d)δ8.57(d,J=4.79Hz,1H),7.65(tt,J=7.76,1.65H z,1H),7.51(d,J=1.34Hz,1H),7.23–7.15(m,1H),6.86(d,J=7.84Hz,1H),5.51 (t,J=4.46Hz,1H),5.41(s,1H),3.33(dq,J=12.25,4.07Hz,1H),3.26–3.11(m ,1H),2.55(dt,J=11.48,3.62Hz,1H),2.43(ddt,J=14.55,12.51,4.96Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ159.0,150.1,149.7,141.1,137.1,122.9,121.2,114.9,71.9,59.4,36.0,27.4.TOF-HRMS Calcd.for C 12 H 12 N5 + [M+H + ]:226.1087,found 226.1089.

[0095] Preparation of Ethyl (R)-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate

[0096]

[0097] (600MHz,Chloroform-d)δ7.63(s,1H),7.31(td,J=7.59,2.01Hz,2H),7.27–7.22(m ,1H),7.08–6.84(m,2H),5.90(s,1H),5.44(q,J=4.80,3.54Hz,1H),4.26(qt,J=7.10 ,1.74Hz,2H),3.33(dp,J=11.70,3.91Hz,1H),3.23(tt,J=11.52,3.52Hz,1H),2.64 –2.39(m,1H),2.18(ddd,J=13.78,5.84,2.64Hz,1H),1.33(td,J=7.13,1.72Hz,3H). 13C NMR(151MHz,Chloroform-d)δ164.5,149.1,141.1,139.9,128.8,127.8,126.0,93.6,59.5,58.1,35.4,30.0,14.6.TOF-HRMS Calcd.for C 15 H 18 N3O2 + [M+H + ]:272.1394,found272.1395.

[0098] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing chiral tetrahydropyrazolo[1,5- a ] pyrimidine method, characterized in that, In a solvent, under a hydrogen atmosphere, under the catalysis of a rhodium chiral catalyst, a substituted pyrazolo[1,5- a ] pyrimidine is synthesized into a chiral tetrahydropyrazolo[1,5-a]pyrimidine represented by general formula II, ， In formula II, * represents a chiral carbon atom; Formula II is selected from: ； Under a nitrogen atmosphere, the rhodium chiral catalyst is prepared by adding a rhodium metal precursor and a chiral bisphosphine ligand to a solvent and stirring the reaction at 15-35°C for 0.2-0.8 h; wherein the rhodium metal precursor is cyclooctadiene rhodium chloride dimer, the chiral bisphosphine ligand is (S)-DTBM-SegPhos, and the solvent is toluene or tetrahydrofuran.

2. The method according to claim 1, characterized in that The method comprises the following steps: Step 1: Under a nitrogen atmosphere, a rhodium metal precursor and a chiral bisphosphine ligand are added to a solvent and stirred to react to obtain a rhodium chiral catalyst solution; Step 2: Under hydrogen atmosphere, the rhodium chiral catalyst solution is mixed with substituted pyrazolo[1,5- a ] pyrimidine reaction to obtain chiral tetrahydropyrazolo[1,5- a ] pyrimidine crude product; Step 3: Filter the reaction mixture to obtain chiral tetrahydropyrazolo[1,5- a ]Pyrimidine-pure product.

3. The method according to claim 2, characterized in that In the step 1, the molar ratio of the rhodium metal precursor to the chiral bisphosphine ligand is 0.5:1.0-0.5:2.

0.

4. The method according to claim 2, characterized in that The rhodium metal precursor and the substituted pyrazolo[1,5- a ]The molar ratio of pyrimidine is: 0.5:50-0.5:

110.

5. The method according to claim 2, characterized in that The reaction time in step 2 is 12h-48h; The reaction pressure in step 2 is 100-1200 psi; The reaction temperature in step 2 is 40-100°C; In step 2, the substituted pyrazolo[1,5- a ]The concentration of pyrimidine is 0.05-0.25 mmol / mL.

6. The method according to claim 2, characterized in that The reaction mixture in step 3 is filtered through a silica gel column.

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