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CN-121991075-A - Method for synthesizing chiral 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine by manganese catalytic asymmetric hydrogenation

CN121991075ACN 121991075 ACN121991075 ACN 121991075ACN-121991075-A

Abstract

The invention discloses a method for synthesizing chiral 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine by manganese catalysis, which takes pentacarbonyl manganese bromide, chiral NNP ligand and alkali as a catalytic system, and pyrazolo [1,5-a ] pyrimidine derivatives as substrates, and synthesizes chiral 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine derivatives by asymmetric hydrogenation. The method has the advantages of simple and practical operation, easily obtained raw materials, high enantioselectivity, good yield, high atomic economy, environmental friendliness and the like.

Inventors

  • ZHOU YONGGUI
  • LIU ZHENG
  • YU YANJIANG
  • CHEN MUWANG
  • SUN LEI

Assignees

  • 中国科学院大连化学物理研究所

Dates

Publication Date
20260508
Application Date
20241108

Claims (8)

  1. 1. A method for synthesizing chiral 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine derivative by manganese catalysis and asymmetric hydrogenation of pyrazolo [1,5-a ] pyrimidine derivative is characterized in that manganese pentacarbonyl bromide, chiral NNP ligand L and alkali are used as a catalytic system, pyrazolo [1,5-a ] pyrimidine derivative 1 is used as a substrate, and chiral 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine derivative 2 is synthesized by asymmetric hydrogenation; The reaction formula is as follows: Wherein: R 1 is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, or thiophene-2-yl, the number of substituents on the substituted phenyl or naphthyl phenyl ring is one or two or three or four of t Bu、CF 3 , me, meO, F, cl, br, the number of substituents is 1-5, the number of substituents is 1-2-naphthyl, R 2 is hydrogen, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, or furan-2-yl, the number of substituents on the substituted phenyl or naphthyl phenyl ring is one or two or three or four of CF 3 , me, meO, F, cl, br, the number of substituents is 1-5, the number of substituents is 1-2-naphthyl, R 3 is hydrogen, C1-C20 alkyl, C2-alkenyl, C20 alkynyl, unsubstituted or substituted phenyl, or substituted phenyl on the phenyl ring is one or three or four of CF 3 , the number of substituents on the phenyl ring is one or three or four of CF 6272, the phenyl ring is unsubstituted or substituted phenyl or 2-phenyl ring is one or three of t Bu、CF 3 ; Ar is 1-position naphthyl, unsubstituted or benzene ring containing substituent groups, wherein the substituent groups on the benzene ring are one or two of F, cl, CF 3 、Me、 t Bu and MeO, the number of substituent groups is 1-5, ar' is the benzene ring which is unsubstituted or contains substituent groups, the number of substituent groups on the benzene ring is one or two of F, cl and CF 3 、Me、 t Bu, ph, meO, the number of substituent groups is 1-4, R 4 is H, C-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl or thiophene-2-yl, the number of substituent groups on the substituted phenyl or naphthyl benzene ring is one or two or three or four of CF 3 and Me, meO, F, cl, br, and the number of substituent groups is 1-5; The alkali is one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyl alcohol, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide and potassium tert-amyl alcohol.
  2. 2. The method of claim 1, wherein the reaction temperature is 25-85 ℃, the hydrogen pressure is 200-1200 psi, and the reaction time is 8-72 hours.
  3. 3. The method according to claim 1, wherein the method comprises the steps of: Adding manganese pentacarbonyl bromide and chiral NNP ligand L into a solvent, stirring at room temperature for 5-15 minutes, adding the system into pyrazolo [1,5-a ] pyrimidine derivative 1, adding alkali, charging hydrogen for 200-1200 psi, stirring at 25-85 ℃ for reaction for 8-72 hours, and performing column chromatography to obtain a target product.
  4. 4. The method according to claim 1 or 2, wherein the reaction solvent is one or more of 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, chlorobenzene, and benzotrifluoride.
  5. 5. The method according to claim 1 or 2, wherein the molar ratio of manganese pentacarbonyl bromide to pyrazolo [1,5-a ] pyrimidine derivative 1 is 0.01:1 to 0.05:1.
  6. 6. The method of claim 1 or 2, wherein the molar ratio of chiral NNP ligand to pyrazolo [1,5-a ] pyrimidine derivative 1 is 0.011:1 to 0.0.055:1.
  7. 7. The method of claim 1 or 2, wherein the molar ratio of the base to pyrazolo [1,5-a ] pyrimidine molar amount 1 is from 0.075:1 to 0.375:1.
  8. 8. The method according to claim 1 or 2, wherein the solvent is used in an amount of 0.5 to 5 ml per 0.2 mmol of pyrazolo [1,5-a ] pyrimidine derivative 1.

Description

Method for synthesizing chiral 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine by manganese catalytic asymmetric hydrogenation Technical Field The invention relates to a method for synthesizing chiral 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine derivatives by manganese catalysis pyrazolo [1,5-a ] pyrimidine asymmetric hydrogenation. Background In recent years, reaction studies of high-yield metal manganese catalytic reduction of c=c, c=n, and c=o have achieved a lot of results. Among them, there has been an important progress in the reduction research of manganese-catalyzed nitrogen-containing heterocycles through continuous efforts of chemists (document 1: das, k.; waiba, s.; jana, a.; maji, b.chem. Soc. Rev.2022,51,4386). In 2019, the Liu Jiang group of problems achieved the hydrogenation of quinoline for the first time under the use of NNP-Mn pincer catalyst and hydrogen. (literature 2: wang, y.; zhu, l.; shao, z.; li, g.; lan, y.; liu, q.j.am. Chem. Soc.2019,141, 17337.; group Liu Jiang, and group Lan Yu) subsequently reported, in 2021, that manganese catalyzes the asymmetric hydrogenation of nitrogen-containing aromatic heterocyclic compounds, achieving asymmetric hydrogenation of quinoline compounds with excellent enantioselectivity and reactivity. (document 3: liu, c.; wang, m.; liu, s.; wang, y.; peng, y.; lan, y.; liu, q. Angelw. Chem. Int. Ed.2021,60,5108.; in 2023, liu Jiang subject group achieved asymmetric hydrogenation of disubstituted quinoxalines using a similar catalytic system, and by controlling the reaction conditions and ligands, different stereoisomers of tetrahydroquinoxalines could be obtained, respectively, and the stereospecific asymmetric hydrogenation synthesis of the disubstituted quinoxalines was achieved. (document 4: liu, c.; liu, x.; liu, q. Chem2023,9,2585.) although some important developments have been made in the asymmetric hydrogenation of nitrogen-containing aromatic heterocycles catalyzed by manganese, the application in the field of the asymmetric reduction of polyazates has been recently reported, and in view of the importance of chiral polyazates and the advantages of cheap, low toxicity and easy availability of manganese catalysts, there is a great need to develop a process for the asymmetric hydrogenation of polyazate-containing aromatic heterocycles catalyzed by manganese. As an important functional molecular skeleton, chiral polyazacyclic compounds are widely used in the fields of biological medicine, pesticides, materials and the like. Among them, chiral 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine frameworks are attracting attention by chemists as a class of structures common in the development of bioactive compounds and pharmaceuticals. (literature 5：(a)Yakaiah,T.;Kurumurthy,C.;Lingaiah,B.P.V.;Narsaiah,B.;Pamanji,R.;Velatooru,L.R.;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,M.J.Med.Chem.2012,55,7772.) As one Zanubrutinib of five covalent Bruton Tyrosine Kinase (BTK) inhibitors currently approved for use in oncological diseases, the core skeleton of which contains chiral 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine (literature 6: li.G.; liu, X.; chen, X.Nat. Rev. Clin. Oncol.2020,17,589.; C.) furthermore, the chiral tetrahydropyrazolo [1,5-a ] pyrimidine skeleton is also present in the orally active bone anabolic agent TAK-075 for the treatment of osteoporosis and in the molecular structure of a drug potentially useful for the treatment of drug-resistant tuberculosis (literature 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.;Ikeda,Y.;Kawamoto,T.Goto,M.;Kimura,H.;Baba,A.;Yasuma,T.Bioorg.Med.Chem.2011,19,1881.(b)Yokokama,F.;Wang,G.;Chan,W.L.;Ang,S.H.;Wong,J.;Ma,I.;Rao,S.P.S.;Manjunatha,U.;Lakshminarayana,S.B.;Herve,M.;Kounde,C.;Tan,B.H.;Thayalan,P.;Na,S.W.;Nanjundappa,M.;Ravindran,S.;Gee,P.;Tan,M.;Wei,L.;Goh,A.;Chen,P-Y.;Lee,K.S.;Zhong,C.;Wagner,T.;Dix,I.;Chatterjee,A.K.;Pethe,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-tetrahydropyrazolo [1,5-a ] pyrimidine, its synthesis still faces difficulties; the current compounds are obtained mainly by means of chiral high performance liquid chromatography and chemical resolution, which lead to 50% ineffective product contamination and environmental pollution (literature.) 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,Z.J.Med.Chem.2019,62,7923.) There is therefore an urgent need to develop an efficient method for synthesizi