Method for synthesizing chiral 4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrimidine through manganese-catalyzed asymmetric hydrogenation

Abstract

The invention discloses a method for synthesizing chiral 4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrimidine through manganese catalysis, which is characterized in that pentacarbonyl manganese bromide, a chiral NNP ligand and alkali are used as a catalytic system, a pyrazolo [1, 5-a] pyrimidine derivative is used as a substrate, and asymmetric hydrogenation is carried out to synthesize the chiral 4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrimidine derivative. The method has the advantages of simple and practical operation, easily available raw materials, high enantioselectivity, good yield, high atom economy of the reaction, environmental friendliness and the like.

Description

Technical Field

[0001] This invention relates to a method for synthesizing chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives by manganese-catalyzed asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine. Background Technology

[0002] In recent years, numerous achievements have been made in the study of manganese-catalyzed reductions of C=C, C=N, and C=O reactions using abundant metals. (Reference 1: Das, K.; Waiba, S.; Jana, A.; Maji, B. Chem. Soc. Rev. 2022, 51, 4386.) Among these, significant progress has been made in the study of manganese-catalyzed reductions of nitrogen-containing heterocycles through the unremitting efforts of chemists. In 2019, Liu Qiang's research group achieved the hydrogenation of quinoline for the first time using an NNP-Mn pincer catalyst and hydrogen gas. (Reference 2: Wang, Y.; Zhu, L.; Shao, Z.; Li, G.; Lan, Y.; Liu, Q. J Am. Chem. Soc. 2019, 141, 17337.) Subsequently, in 2021, Liu Qiang's research group and Lan Yu's research group collaborated to report the asymmetric hydrogenation reaction of nitrogen-containing aromatic heterocyclic compounds catalyzed by manganese, achieving the asymmetric hydrogenation of quinoline compounds with excellent enantioselectivity and reactivity. (Reference 3: Liu, C.; Wang, M.; Liu, S.; Wang, Y.; Peng, Y.; Lan, Y.; Liu, Q. Angew. Chem. Int. Ed. 2021, 60, 5108.) In addition, in 2023, Liu Qiang's research group used a similar catalytic system to achieve the asymmetric hydrogenation of disubstituted quinoxaline. By controlling the reaction conditions and ligands, different stereoisomers of tetrahydroquinoxaline could be obtained, realizing the stereodispersive asymmetric hydrogenation synthesis of disubstituted quinoxaline. (Reference 4: Liu, C.; Liu, X.; Liu, Q. Chem 2023, 9, 2585.) Although some important progress has been made in the asymmetric hydrogenation of nitrogen-containing aromatic heterocycles catalyzed by manganese, its application in the asymmetric reduction of polynitrogen-containing heterocycles has been rarely reported. Considering the importance of chiral polynitrogen-containing heterocycles and the advantages of manganese catalysts such as low cost, low toxicity and easy availability, it is urgent to develop a manganese-catalyzed asymmetric hydrogenation process for polynitrogen-containing aromatic heterocycles.

[0003] As an important functional molecular skeleton, chiral polynitrogenous heterocyclic compounds are widely used in biomedicine, pesticides, and materials. Among them, the chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine skeleton is a common structure in the development of bioactive compounds and drugs and has attracted increasing attention from chemists. (Reference 5: (a) Yakaiah, T.; Kurumurthy, C.; Lingaiah, BPV; Narsaiah, B.; Pamanji, R.; Velatooru, LR; Venkateswara) Rao.J.;Gururaj,S.;Parthasarathy,T.;Sridhar.B.Med.Chem.Res.2012,21,4261.(b)Asano,T.;Yamazaki,H.;Kasahara,C.;Kubota,H.;Kontani,T.;Harayama,Y.;Ohno,K.;Mizuhara,H.;Yokomoto,M.;Misumi,K.;Kinoshita,T.;Ohta,M.;Takeuchi,MJMed.Chem.2012,55,7772.) For example, Zanubrutinib, one of the five covalent Bruton's tyrosine kinase (BTK) inhibitors currently approved for use in cancer diseases, contains chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine in its core scaffold.(Reference 6: Li.G.; Liu,X.; Chen,X. Nat. Rev. Clin. Oncol. 2020, 17, 589.) In addition, the chiral tetrahydropyrazolo[1,5-a]pyrimidine skeleton is also present in the oral active bone anabolic metabolite TAK-075 for the treatment of osteoporosis and in the molecular structure of a potential drug for the treatment of drug-resistant tuberculosis (Reference 7: (a) Yoshida,M.; Mori,A.; Morimoto,S.). ; Kotani, E.; Oka, M.; Notoya, K.; Makino, H.; Ono, M.; Shirasaki, M.; Tada, N.; Fujita, H.; Ban, J.; I keda,Y.;Kawamoto,T.Goto,M.;Kimura,H.;Baba,A.;Yasuma,T.Bioorg.Med.Chem.2011,19,1881.( b) Yokokama, F.; Wang, G.; Chan, WL; Ang, SH; Wong, J.; Ma, I.; Rao, SPS; Manjunatha, U.; Lakshminarayana, SB; Herve, M.; Kounde, C.; Tan, BH; Thayalan, P.; Na, SW; Nanjundappa, M.; Ravindran, S.; Gee, P.;Tan,M.;Wei,L.;Goh,A.;Chen,PY.;Lee,KS;Zhong,C.;Wagner,T.;Dix,I.;Chatterjee,AK;Peth e, K.; Kuhen, K.; Glynne, R.; Smith, P.; Bifani, P.; Jiricek, J. ACS. Med. Chem. Lett. 2013, 4, 451.). Despite the relatively simple structure of chiral 4,5,6,7-tetrahydropyrazole[1,5-a]pyrimidine, its synthesis still faces some challenges. Currently, the acquisition of this type of compound mainly relies on chiral high-performance liquid chromatography and chemical resolution methods, but these methods produce 50% ineffective products, leading to increased drug costs and environmental pollution.(Reference 8: Guo, Y.; Liu, Y.; Hu, N.; Yu, D.; Zhou, C.; Shi, G.; Zhang, B.; Wei, M.; Liu, J.; Luo, L.; Tang, Z.; Song, X.; Guo, Y.; Liu, X.; Su, D.; Zhang, S.; Song, X.; Zhou, X.; Hong, Y.; Chen, S.; Cheng, Z.) Yong, S.; Wei, Q.; Wang, H.; Wang, Q.; Lv, L.; Wang, F.; Xu, H.; Sun, H.; Xing, H.; Li, N.; Zhang, W. ; Wang, Z.; Liu, G; Sun, Z.; Zhou, D.; Li, W.; Liu, L.; Wang, L. Wang, ZJMed. Chem. 2019, 62, 7923.).

[0004] Therefore, there is an urgent need to develop an efficient method for synthesizing chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine. Direct asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine is one of the most direct and atom-economical methods for synthesizing chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine. Among the various catalysts developed for the asymmetric catalytic hydrogenation of pyrazolo[1,5-a]pyrimidine, the central metals are mainly the noble metals iridium and rhodium. In 2023, Hou's research group achieved the asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine for the first time using a chiral rhodium catalyst in a hydrogen atmosphere, synthesizing chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives with a maximum ee of 98%. (Reference 9: Xie, C.; Xiao, G.; Guo, Q.; Wu, X.; Zi, G.; Ding, W.; Hou, G. Chem. Sci. 2023, 14, 9048.) In 2024, Zhou's research group and Nie's research group respectively achieved the asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine derivatives using chiral iridium catalysts, and synthesized key intermediates of Zanubrutinib containing a chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine core skeleton with excellent enantioselectivity. (Reference 10: (a) Yuan, H.; Yao, W.; Zhang, X.; Wei, Z.; Xi, J.; Hao, Y.; Liu, X.; Jiang, R.; Nie, H. Org. Chem. 2024, 89, 1748. (b) Li, B.; Zhou, G.; Zhang, D.; Yao, L.; Li, M.; Yang, G.; Zhang, S.; Nie, H. Org. Lett. 2024, 26) (2097.(c)Chen, M.-W.;Li, H.-W.;Wang, Y.-Q.;Wu, B.;Liu, Z.;Lai, X.;Deerberg, J.;Zhou, Y.-G. J.O. J.O. R. G. Chem. 2024, 89, 4336.) Although significant progress has been made in the asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine derivatives catalyzed by various rare metals, the relatively high cost of rare metals themselves limits their further application. Therefore, this invention employs abundant manganese metal as a catalyst to achieve the asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine derivatives, and obtains a series of chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives with high yield and enantioselectivity. Summary of the Invention

[0005] The purpose of this invention is to provide a manganese-catalyzed asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine to synthesize chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives. This method is simple and practical, uses inexpensive metal catalysts, has readily available raw materials, high enantioselectivity, good yield, high atom economy, and is environmentally friendly.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] A method for synthesizing chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives by manganese-catalyzed asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine derivatives is disclosed. The method uses manganese pentacarbonyl bromide (Mn(CO)5Br), chiral NNP ligand L, and a base as the catalytic system, and pyrazolo[1,5-a]pyrimidine derivative 1 as the substrate to synthesize chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivative 2 by asymmetric hydrogenation.

[0008] The reaction formula is as follows:

[0009]

[0010] In the formula:

[0011] In the substrate, R1 is a C1-C20 alkyl group (preferably C1-C10 alkyl, such as methyl or ethyl), a C2-C20 alkenyl group (preferably C1-C10 alkenyl, such as vinyl or propenyl), a C2-C20 alkynyl group (preferably C1-C10 alkynyl, such as ethynyl or propynyl), an unsubstituted or substituted phenyl group, an unsubstituted or substituted naphthyl group, or a thiophene-2-yl group, wherein the substituent on the substituted phenyl or naphthyl benzene ring is [missing information]. tOne, two, three, or four of the following: Bu, CF3, Me, MeO, F, Cl, and Br; the number of substituents is 1 to 5; the naphthyl group is 1- or 2-naphthyl; R2 is hydrogen, a C1-C20 alkyl group (preferably C1-C10 alkyl group, such as methyl, ethyl, or cyclohexyl), a C2-C20 alkenyl group (preferably C1-C10 alkenyl group, such as vinyl or propynyl), a C2-C20 alkynyl group (preferably C1-C10 alkynyl group, such as ethynyl or propynyl), an unsubstituted or substituted phenyl group, an unsubstituted or substituted naphthyl group, or a furan-2-yl group, wherein the substituent on the substituted phenyl or naphthyl benzene ring is one or more of the following: CF3, Me, MeO, F, Cl, and Br. Two, three, or four types of substituents, with 1 to 5 substituents; the naphthyl group is 1- or 2-naphthyl; R3 is hydrogen, a C1-C20 alkyl group (preferably C1-C10 alkyl group, such as methyl or ethyl), a C2-C20 alkenyl group (preferably C1-C10 alkenyl group, such as vinyl or propynyl), a C2-C20 alkynyl group (preferably C1-C10 alkynyl group, such as ethynyl or propynyl), an unsubstituted or substituted phenyl group, an unsubstituted or substituted naphthyl group, or a furan-2-yl group; the substituents on the substituted phenyl or naphthyl benzene ring are one, two, three, or four types of CF3, Me, MeO, F, Cl, Br, with 1 to 5 substituents; the naphthyl group is 1- or 2-naphthyl;

[0012] In the chiral NNP ligand, Ar is a 1-naphthyl group, an unsubstituted or substituent benzene ring, and the substituents on the benzene ring are F, Cl, CF3, Me, etc. t One or two of Bu and MeO, with 1 to 5 substituents; Ar' is an unsubstituted or substituent-containing benzene ring, with substituents on the benzene ring being F, Cl, CF3, Me, etc. t One or two of Bu, Ph, and MeO, with 1 to 4 substituents; R4 is H, a C1-C20 alkyl, a C2-C20 alkenyl, a C2-C20 alkynyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted naphthyl, or a thiophene-2-yl; the substituents on the substituted phenyl or naphthyl benzene ring are one, two, three, or four of CF3, Me, MeO, F, Cl, and Br, with 1 to 5 substituents; the naphthyl is a 1- or 2-naphthyl group;

[0013] The alkali is one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, and potassium tert-pentoxide, preferably sodium isopropoxide or sodium tert-butoxide.

[0014] Based on the above technical solution, further, the chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivative is one of 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s, 2t, 2u, 2v, 2w, 2x, 2y, 2z, 2aa, 2ab;

[0015]

[0016]

[0017] Based on the above technical solution, furthermore, the reaction temperature is 25-85℃, for example 25, 35, 65, 75℃; the hydrogen pressure is 200-1200psi, preferably 450-550psi, more preferably 500psi; and the reaction time is 8-72 hours, preferably 15-17 hours, more preferably 16 hours.

[0018] Based on the above technical solution, the steps of the method are further as follows:

[0019] Manganese pentacarbonyl bromide and chiral NNP ligand L were added to a solvent and stirred at room temperature for 5–15 minutes. The system was then transferred to a reactor containing pyrazolo[1,5-a]pyrimidine derivative 1 and a base was added. Hydrogen gas was then introduced at 200–1200 psi and stirred at 25–85 °C for 8–72 h. The target product was then obtained by column chromatography.

[0020] Based on the above technical solution, the reaction solvent is one or more of 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), toluene, chlorobenzene (PhCl), and trifluorotoluene (PhCF3), preferably 1,4-dioxane, tetrahydrofuran, or toluene.

[0021] Based on the above technical solution, further, the molar ratio of the pentacarbonyl manganese bromide and the pyrazolo[1,5-a]pyrimidine derivative 1 is 0.01:1 to 0.05:1, preferably 0.02:1 to 0.04:1, and more preferably 0.02:1.

[0022] Based on the above technical solution, the NNP ligand is further one of L1, L3, L4, and L5, preferably L1 or L5.

[0023]

[0024] Based on the above technical solution, further, the molar ratio of the NNP ligand and the pyrazolo[1,5-a]pyrimidine derivative 1 is 0.011:1 to 0.055:1, preferably 0.022:1.

[0025] Based on the above technical solution, further, the molar ratio of the base and the pyrazolo[1,5-a]pyrimidine is 0.075:1 to 0.375:1, preferably 0.075:1 to 0.15:1, and more preferably 0.075:1.

[0026] Based on the above technical solution, further, the amount of solvent used is 0.5 to 5 ml of solvent per 0.2 mmol of hydrogenated substrate 1, preferably 3 ml of solvent.

[0027] Based on the above technical solution, furthermore, the reaction formula is the manganese-catalyzed asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine derivatives to obtain the corresponding chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives, with the manganese precursor being abundant metal pentacarbonyl manganese bromide. In the NNP ligand (2 mol%), Ar is phenyl, Ar' is phenyl, and R is methyl. The base is sodium tert-butoxide, the solvent is 1,4-dioxane, the temperature is 35 degrees Celsius, and the hydrogen pressure is 500 psi. The results are optimal, with an enantiomeric excess reaching 97%.

[0028] The present invention has the following advantages:

[0029] 1. It has high reactivity and enantioselectivity, complete reaction, specific product, convenient separation, and can obtain high enantiomeric excess purity (enantiomeric excess can reach 97%).

[0030] 2. Various types of chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives can be obtained.

[0031] 3. The catalyst is cheap and readily available, and the reaction operation is simple and practical.

[0032] 4. The hydrogenation reaction is carried out under mild conditions, and the reaction can be carried out at 35 degrees Celsius.

[0033] 5. Compared with traditional synthesis methods, this invention can obtain a large number of chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives with a small amount of chiral catalyst, achieving chiral enhancement. Moreover, different configurations of chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives can be obtained by changing the configuration of the chiral NNP ligand, and the substrate range is relatively wide. Detailed Implementation

[0034] The present invention is described in detail below through embodiments; however, the present invention is not limited to the embodiments described below.

[0035] The chiral NNP ligand L used in the following examples was synthesized according to the methods described in the literature (Liu, C.; Wang, M.; Liu, S.; Wang, Y.; Peng, Y.; Lan, Y.; Liu, Q. Angew. Chem. Int. Ed. 2021, 60, 5108.; Ottesen, LK; Ek, F.; Olsson, R. Org. Lett. 2006, 8, 1771.); the substrate pyrazolo[1,5-a]pyrimidine 1 used in the following examples was synthesized according to the methods described in the literature (Tong, C.-L.; Lv, M.-Y.; Sun, X.-Y.; Yang, F.; Wang, C.-J. CN). 104250252B, 2017.; Attia, MH; Elrazaz, EZ; El-Emam, SZ; Taher, AT; Abdel-Aziz, HA; Abouzid, KAMBioorg. Chem. 2020, 94, 103458.).

[0036] Example 1: Condition Optimization

[0037] Weighed manganese pentacarbonyl bromide (2 mol%, 0.004 mmol) and chiral NNP ligand L (2.2 mol%, 0.0044 mmol) were added to an ampoule. 1.0 mL of solvent was added and stirred for 10 minutes. The system was then rinsed with 2.0 mL of solvent into an ampoule containing pyrazolo[1,5-a]pyrimidine 1a (0.2 mmol). Base (7.5 mol%, 0.015 mmol) was added. The ampoule was then placed in a stainless steel autoclave, and hydrogen gas was introduced at 500 psi. The reaction was carried out at 25–75 °C for 16 hours. Hydrogen gas was slowly released, and the solvent was removed using a rotary evaporator. The product was then separated by direct column chromatography (eluent: petroleum ether, dichloromethane, and methanol in a volume ratio of 10:10:1) to obtain the pure product. The reaction equation is as follows:

[0038]

[0039] The yields were the separation yields, and the enantiomeric excess of the products was determined by chiral liquid chromatography, as shown in Table 1.

[0040] Table 1. Screening of solvents, reactive bases, and chiral ligands [a]

[0041]

[0042]

[0043] [a]1a (0.2mmol), Mn(CO)5Br (0.004mmol), L (0.0044mmol), Base (7.5mol%), Solvent (3mL), H2 (500psi), 75℃, 16h. [b] Determined by 1 H NMR. [c] Determined by chiral HPLC. [d] 25℃. [e] 35℃

[0044] Example 2: Manganese-catalyzed asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine to synthesize chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives

[0045] Add the weighed manganese pentacarbonyl bromide (2 mol%, 0.004 mmol; or 4 mol%, 0.008 mmol) and chiral NNP ligands L1 or L5 (2.2 mol%, 0.0044 mmol) to an ampoule, along with 1.0 mL of solvent (1,4-dioxane). Stir for 10 minutes. Rinse the system with 2.0 mL of solvent (1,4-dioxane) into an ampoule containing pyrazolo[1,5-a]pyrimidine 1 (0.2 mmol). Add sodium tert-butoxide or sodium isopropoxide (7.5 mol%, 0.015 mmol; or 15 mol%, 0.030 mmol). Then place the ampoule in a stainless steel autoclave, purge with hydrogen at 500 psi, and react at 35–75 °C for 16 hours. Hydrogen gas was slowly released, and the solvent was removed using a rotary evaporator. The product was then directly separated by column chromatography (eluent: petroleum ether, dichloromethane, and methanol in a volume ratio of 10:10:1) to obtain the pure product. The reaction formula is as follows:

[0046]

[0047]

[0048] The yield was the separation yield, and the enantiomeric excess of the product was determined by chiral liquid chromatography.

[0049] This invention provides asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine derivatives catalyzed by manganese to obtain the corresponding 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives, with an enantiomeric excess of up to 97%. This invention is simple and practical to operate, exhibits high enantioselectivity and good yield, and also possesses advantages such as atom economy and environmental friendliness.

[0050] (-)-(S)-5-Phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2a):

[0051] 59.7 mg, 99% yield, white solid, known compound, R f = 0.15 (petroleum ether / dichloromethane / methanol 10 / 10 / 1), 96% ee, [α] 20 D Chiralpak IC column, 254 nm, 30 °C, hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min, retention time 10.0 min and 11.2 min (major).

[0052] (-)-(S)-5-(o-Tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2b):

[0053] 54.4 mg, 85% yield, white solid, melting range 125-126 °C, new compound, R f =0.15 (petroleum ether / dichloromethane / methanol 10 / 10 / 1), CDCl3) δ 145.7, 140.1, 139.1, 134.8, 130.8, 127.7, 126.7, 125.8, 86.5, 51.0, 44.7, 29.7, 19.1. The HPLC: Chiralpak AY-H column, 240 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow = 1.0 mL / min, retention time 13.7 min (major) and 20.8 min (minor). The HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 13 H 16 N3:214.1339; found:214.1343.

[0054] (-)-(S)-5-(m-Tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2c):

[0055] 62.1 mg, 97% yield, white solid, melting range 170-171 °C, new compound, R f =0.15 (petroleum ether / dichloromethane / methanol 10 / 10 / 1), 21.5. HPLC: Chiralpak IC column, 254 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min, retention times 22.5 min and 26.5 min (major). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 13 H 16 N3:214.1339; found:214.1336.

[0056] (-)-(S)-5-(p-Tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2d):

[0057] 62.1 mg, 97% yield, white solid, melting range 122-123 °C, new compound, R f =0.13 (petroleum ether / dichloromethane / methanol 10 / 10 / 1), The HPLC: Chiralpak IC column, 254nm, 30℃, n-hexane / isopropanol=85 / 15, flow=1.0mL / min, retention time 24.1min (minor) and 26.0min (major). The HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 13 H 16 N3:214.1339; found:214.1339.

[0058] (-)-(S)-5-(4-(tert-Butyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2e):

[0059] 75.9 mg, 99% yield, white solid, melting range 149-150 °C, new compound, R f =0.14 (petroleum ether / dichloromethane / methanol 10 / 10 / 1), HPLC: Chiralpak AS-H column, 254 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 1.0 mL / min, retention time 6.5 min (major) and 8.0 min (minor). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 22 N3:256.1808; found:256.1810.

[0060] (-)-(S)-5-(4-Methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2f):

[0061] 67.8 mg, 99% yield, white solid, melting range 127-128 °C, new compound, R f =0.12 (petroleum ether / dichloromethane / methanol 10 / 10 / 1),

[0062] 31.4. HPLC: Chiralpak IC, 254 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min, retention times 37.4 min and 41.9 min (major). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 13 H 16 N3O:230.1288; found:230.1290.

[0063] (-)-(S)-5-(4-Fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2g):

[0064] 65.0 mg, 99% yield, pale yellow solid, melting range 134-135 °C, new compound, R f = 0.11 petroleum ether / dichloromethane / methanol 128.2(d, 3 J C-H =8.0Hz), 115.7(d, 2 JC-H =21.3Hz),86.6,54.3,44.6,31.5. 19 F NMR (376MHz) δ -114.06. HPLC: Chiralpak AS-H column, 254nm, 30℃, n-hexane / isopropanol = 80 / 20, flow = 1.0mL / min, retention time 14.0min and 16.1min (major). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 12 H 13 FN3:218.1088; found:218.1094.

[0065] (-)-(S)-5-(4-(Trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2h):

[0066] 78.9 mg, 98% yield, pale yellow solid, melting range 105-106 °C, new compound, R f =0.11 (petroleum ether / dichloromethane / methanol) 2 J C-H =32.3Hz)126.9,125.8(q, 3 J C-H =4.7Hz), 124.0(q, 1 J C-H =270.3),86.8,54.5,44.4,31.3. 19 F NMR (376MHz) δ -62.54. HPLC: Chiralpak AY-H column, 205nm, 30℃, n-hexane / isopropanol = 70 / 30, flow = 1.0mL / min, retention time 5.2min and 6.6min (major). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 13 H 13 F3N3:268.1056; found:268.1060.

[0067] (-)-(S)-5-(Thiophen-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2i):

[0068] 60.5 mg, 98% yield, white solid, melting range 154-155 °C, new compound, R f =0.14 (petroleum ether / dichloromethane / methanol 10 / 10 / 1), 144.6, 139.1, 126.9, 124.8, 124.3, 86.9, 50.7, 44.3, 31.9. HPLC: Chiralpak AY-H column, 240 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow = 1.0 mL / min, retention time 32.5 min (major) and 38.4 min. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 10 H1N3S:206.6746; found:206.0750.

[0069] (+)-(R)-5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2j):

[0070] 38.6 mg, 94% yield, white solid, known compound, R f = 0.14 (petroleum ether / dichloromethane / methanol 10 / 10 / 1), 66% ee, [α] 20 D 30.2, 21.7. HPLC: Chiralpak AY-H column, 240 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow = 1.0 mL / min, retention time 5.8 min (major) and 6.8 min.

[0071] (-)-(S)-2,5-Diphenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2k):

[0072] 82.5 mg, 99% yield, white solid, melting range 226-227 °C, new compound, R f=0.35 (petroleum ether / dichloromethane / methanol 10 / 10 / 1), 146.4, 142.3, 134.0, 129.0, 128.6, 128.2, 127.6, 126.6, 125.5, 83.9, 54.9, 44.7, 31.4. HPLC: Chiralpak AY-H column, 240 nm, 30 °C, n-hexane / isopropanol = 50 / 50, flow rate = 0.8 mL / min, retention time 13.4 min and 21.9 min (major). The HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 18 N3:276.1495; found:276.1503.

[0073] (-)-(S)-2-(4-Methoxyphenyl)-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2l):

[0074] 90.4 mg, 97% yield, white solid, melting range 211-212 °C, new compound, R f =0.35 (petroleum ether / dichloromethane / methanol 10 / 10 / 1), 126.8, 126.7, 126.5, 113.9, 83.4, 55.3, 54.8, 44.6, 31.4. HPLC: Chiralpak AY-H column, 240 nm, 30 °C, n-hexane / isopropanol = 50 / 50, flow rate = 0.8 mL / min, retention time 19.4 min and 27.7 min (major). The HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 19 H 20 N3O:306.1601; found:306.1606.

[0075] (-)-(S)-2-(4-Bromophenyl)-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2m):

[0076] 102.4 mg, 96% yield, white solid, melting range 211-212 °C, new compound, R f =0.46 (petroleum ether / dichloromethane / methanol) NMR (100MHz, CDCl3) δ 149.6, 146.5, 142.2, 133.0, 131.7, 129.0, 128.3, 127.0, 126.5, 121.4, 83.8, 54.8, 44.7, 31.3. HPLC: Chiralpak AY-H column, 240nm, 30℃, n-hexane / isopropanol = 50 / 50, flow = 0.8mL / min, retention time 17.5min and 28.4min (major). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 17 BrN3:354.0600 ( 79 Br), 356.0582( 81 Br); found: 354.0594 ( 79 Br), 356.0574( 81 Br).

[0077] (-)-(S)-2,7-diphenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2n):

[0078] 82.0 mg, 99% yield, white solid, known compound, R f =0.50 (petroleum ether / ethyl acetate 3 / 1), 92% ee, [α] 20 D =-149.01 90 / 10, flow=1.0mL / min, retention time 18.0min and 22.4min(major).

[0079] (-)-(S)-2-Phenyl-7-(o-tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2o):

[0080] 53.0 mg, 61% yield, colored solid, melting range 179-180 °C, new compound, R f=0.52 (petroleum ether / tetrahydrofuran 5 / 1), 96% ee, 28.6,19.0.HPLC: Chiralpak AS-H column, 254nm, 30℃, n-hexane / isopropanol=95 / 5, flow=0.8mL / min, retention time 36.9min(major)and 43.8min(minor).The HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 19 H 20 N3:290.1652; found:290.1671.

[0081] (-)-(S)-2-Phenyl-7-(m-tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2p):

[0082] 86.0 mg, 99% yield, white solid, known compound, R f = 0.29 (petroleum ether / ethyl acetate 3 / 1), 95% ee, [α] 20 D =-143.13 123.3, 83.5, 58.4, 36.1, 31.0, 21.7. HPLC: Chiralpak AS-H column, 254 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow = 1.0 mL / min, retention time 8.3 min (major) and 12.9 min (minor).

[0083] (-)-(S)-2-Phenyl-7-(p-tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2q):

[0084] 86.0 mg, 99% yield, white solid, known compound, R f =0.45 (petroleum ether / ethyl acetate 3 / 1), 92% ee, [α] 20 D =-161.04 retention time 9.4min(major)and 13.1min.

[0085] (-)-(S)-7-(4-Mthoxyphenyl)-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2r):

[0086] 36.1, 31.2. HPLC: Chiralpak AS-H column, 254 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow = 1.0 mL / min, retention time 15.2 min (major) and 21.6 min.

[0087] (-)-(S)-2-Phenyl-7-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2s):

[0088] 86.0 mg, 84% yield, white solid, known compound, R f =0.35 (petroleum ether / ethyl acetate 3 / 1), 90% ee, [α] 20 D =-107.25 254 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow = 1.0 mL / min, retention time 7.5 min and 13.4 min (major).

[0089] (-)-(S)-7-(Furan-2-yl)-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2t):

[0090] 71.0 mg, 89% yield, white solid, known compound, R f =0.51 (petroleum ether / ethyl acetate / dichloromethane 5 / 1 / 2), 87% ee, Chiralpak AS-H column, 254nm, 30℃, hexane / isopropanol = 85 / 15, flow = 1.0mL / min, retention time 10.9min (major) and 24.8min.

[0091] (-)-(R)-7-Methyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2u):

[0092] 49.0 mg, 77% yield, white solid, known compound, R f =0.52 (petroleum ether / ethyl acetate / dichloromethane 5 / 1 / 2), 91% ee, 125.6, 83.9, 51.0, 38.1, 30.2, 21.5. HPLC: Chiralpak AS-H column, 254 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow = 1.0 mL / min, retention time 8.9 min (major) and 12.0 min (minor).

[0093] (-)-(S)-7-Cyclohexyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2v):

[0094] NMR (100MHz, CDCl3) δ 149.8, 146.7, 134.5, 128.5, 127.3, 125.6, 83.7, 59.5, 41.0, 39.0, 29.7, 27.4, 26.8, 26.6, 26.4, 23.9. HPLC: Chiralpak AS-H, 254nm, 30℃, n-hexane / isopropanol = 85 / 15, flow = 1.0mL / min, retention time 6.0min (major) and 7.0min.

[0095] (-)-(S)-7-Phenyl-2-(o-tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2w):

[0096] 72.1 mg, 84% yield, white solid, known compound, Rf =0.63 (petroleum ether / ethyl acetate / dichloromethane 5 / 1 / 2), 87% ee, 31.1, 21.2. HPLC: Chiralpak IA, 254 nm, 30 °C, n-hexane / isopropanol = 90 / 10, flow = 1.0 mL / min, retention time 13.0 min and 15.8 min (major).

[0097] (-)-(S)-7-Phenyl-2-(p-tolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2x):

[0098] 70.0 mg, 82% yield, pink solid, known compound, R f =0.62 (petroleum ether / ethyl acetate / dichloromethane 5 / 1 / 2), 93% ee, 125.5, 83.2, 58.3, 35.9, 30.9, 21.3. HPLC: Chiralpak IA, 254 nm, 30 °C, n-hexane / isopropanol = 75 / 25, flow = 0.8 mL / min, retention time 7.9 min and 9.7 min (major).

[0099] (-)-(S)-7-Phenyl-2-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2y):

[0100] 85.3 mg, 84% yield, white solid, known compound, R f =0.63 (petroleum ether / ethyl acetate / dichloromethane 5 / 1 / 2), 79% ee, 126.1,125.7,125.4(q, 3 J C-H =3.7)124.48(q, 1 J C-H =270.1)83.8,58.6,36.0,30.9. 19F NMR (376MHz, CDCl3) δ -62.34. HPLC: Chiralpak IB, 254nm, 30℃, n-hexane / isopropanol = 65 / 35, flow = 1.0mL / min, retention time 4.7min (major) and 8.8min.

[0101] (-)-(S)-2-(Furan-2-yl)-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2z):

[0102] 84.1 mg, 99% yield, white solid, known compound, R f =0.52 (petroleum ether / ethyl acetate / dichloromethane 5 / 1 / 2), 89% ee, 105.4, 83.2, 58.4, 35.8, 30.8. HPLC: Chiralpak IA, 254 nm, 30 °C, n-hexane / isopropanol = 75 / 25, flow = 0.8 mL / min, retention time 8.9 min and 10.2 min (major).

[0103] (-)-(S)-2-Methyl-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2aa):

[0104] 58.1, 36.2, 31.2, 14.2. HPLC: Chiralcel OD-H, 254 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow = 1.0 mL / min, retention time 9.9 min (major) and 14.5 min.

[0105] (-)-(S)-7-Phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(2ab):

[0106] 33.5 mg, 56% yield, white solid, known compound, R f =0.22 (petroleum ether / ethyl acetate / dichloromethane 5 / 1 / 2), 88% ee, min(major).

[0107] The core skeleton of the aforementioned chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives is a chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine structure. Currently approved Bruton's tyrosine kinase (BTK) inhibitor Zanubrutinib for cancer treatment, TAK-075 for osteoporosis treatment, and an anti-tuberculosis agent reported in the literature all contain a chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine structure in their core skeletons.

Claims

1. A method for synthesizing chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives by manganese-catalyzed asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidine derivatives, characterized in that, Using manganese pentacarbonyl bromide, chiral NNP ligand L, and a base as the catalytic system, and pyrazolo[1,5-a]pyrimidine derivative 1 as the substrate, chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivative 2 was synthesized by asymmetric hydrogenation. The reaction formula is as follows: In the formula: R1 is a C1–C20 alkyl, C2–C20 alkenyl, C2–C20 alkynyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, or thiophene-2-yl, wherein the substituent on the substituted phenyl or naphthyl benzene ring is [missing information]. t One, two, three, or four of the following are selected from Bu, CF3, Me, MeO, F, Cl, and Br; the number of substituents is 1 to 5; the naphthyl group is 1- or 2-naphthyl; R2 is hydrogen, a C1-C20 alkyl group, a C2-C20 alkenyl group, a C2-C20 alkynyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted naphthyl group, or a furan-2-yl group; the substituents on the substituted phenyl or naphthyl benzene ring are one or two of the following: CF3, Me, MeO, F, Cl, and Br. Three or four types of substituents, with 1 to 5 substituents; the naphthyl group is 1- or 2-naphthyl; R3 is hydrogen, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, or furan-2-yl; the substituents on the substituted phenyl or naphthyl benzene ring are one, two, three, or four of the following: CF3, Me, MeO, F, Cl, Br, with 1 to 5 substituents; the naphthyl group is 1- or 2-naphthyl. Ar represents a benzene ring with a 1-naphthyl group, either unsubstituted or substituent, where the substituent is F, Cl, CF3, Me, etc. t One or two of Bu and MeO, with 1 to 5 substituents; Ar' is an unsubstituted or substituent-containing benzene ring, with substituents on the benzene ring being F, Cl, CF3, Me, etc. t One or two of Bu, Ph, and MeO, with 1 to 4 substituents; R4 is H, a C1-C20 alkyl, a C2-C20 alkenyl, a C2-C20 alkynyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted naphthyl, or a thiophene-2-yl; the substituents on the substituted phenyl or naphthyl benzene ring are one, two, three, or four of CF3, Me, MeO, F, Cl, and Br, with 1 to 5 substituents; the naphthyl is a 1- or 2-naphthyl group; The alkali is one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, and potassium tert-pentoxide.

2. The method as described in claim 1, characterized in that: The reaction temperature is 25–85℃; the hydrogen pressure is 200–1200 psi; and the reaction time is 8–72 hours.

3. The method as described in claim 1, characterized in that: The steps of the method are as follows: Manganese pentacarbonyl bromide and chiral NNP ligand L were added to a solvent and stirred at room temperature for 5–15 minutes. The above system was then added to pyrazolo[1,5-a]pyrimidine derivative 1, followed by the addition of a base. Hydrogen gas was then introduced at 200–1200 psi, and the reaction was stirred at 25–85 °C for 8–72 h. The target product was then obtained by column chromatography.

4. The method as described in claim 1 or 2, characterized in that: The reaction solvent is one or more of 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, chlorobenzene, and trifluorotoluene.

5. The method as described in claim 1 or 2, characterized in that: The molar ratio of the pentacarbonyl manganese bromide and the pyrazolo[1,5-a]pyrimidine derivative 1 is 0.01:1 to 0.05:

1.

6. The method as described in claim 1 or 2, characterized in that: The molar ratio of the chiral NNP ligand to the pyrazolo[1,5-a]pyrimidine derivative 1 is 0.011:1 to 0.055:

1.

7. The method as described in claim 1 or 2, characterized in that: The molar ratio of the base to pyrazolo[1,5-a]pyrimidine is 0.075:1 to 0.375:

1.

8. The method as described in claim 1 or 2, characterized in that: The amount of solvent used is 0.5 to 5 mL of solvent per 0.2 mmol of pyrazolo[1,5-a]pyrimidine derivative 1.

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