Method for preparing chiral cyclic amine by asymmetric hydrogenation, catalyst used therein, and catalyst preparation method

Abstract

A catalyst for asymmetric hydrogenation to prepare a chiral cyclic amine and a catalyst preparation method, formed by complexing manganese pentacarbonyl bromide with a chiral ligand. Further provided are a method for preparing a chiral cyclic amine by asymmetric hydrogenation and a use thereof. Starting materials are various cyclic imine compounds, which can be prepared by reported methods. The compounds are subjected to an asymmetric hydrogenation reaction using a chiral manganese catalyst to obtain chiral cyclic amine compounds. The corresponding selectivity can reach up to ≥99 %ee. By using the above method, a series of chiral pyrrolidine or chiral piperidine compounds can be efficiently and selectively prepared. The method can be used to industrially prepare important chiral amine drug intermediates and has important practical value and application prospects.

Description

Method for preparing chiral cyclic amine by asymmetric hydrogenation, catalyst used therein and catalyst preparation method Technical Field

[0001] The invention belongs to the technical field of chemical catalytic reactions, and particularly relates to a method for preparing chiral cyclic amines by asymmetric hydrogenation, a catalyst used therein, and a method for preparing the catalyst. Background Art

[0002] [Corrected 05 / 09 / 2024 in accordance with Regulation 26] Chiral pyrrolidine molecules are an important class of chiral building blocks that can be used as intermediates in the synthesis of a variety of drugs, natural products, and pesticides. Examples include nicotine, the active ingredient in tobacco and e-cigarettes, and a new insecticide, S-quinoline.

[0003] [Corrected 05.09.2024 according to Rule 26] In the field of drug synthesis, the new anticancer drug Selitrectinib is a new-generation selective TRK inhibitor that can inhibit the growth of tumor cells by inhibiting the TRKA receptor kinase; the anticancer drug Larotrectinib, which was launched in China in 2017, targets the NTRK gene to restore the normal function of TRK, thereby preventing the growth and spread of tumor cells. The drug is suitable for a variety of cancers; the active drug MSC2530818 is a potent and selective inhibitor of CDK8 that has anti-rectal cancer effects.

[0004] These drugs all contain chiral pyrrolidine building blocks, and the preparation of chiral pyrrolidine is a key step in the synthesis of these drugs. Currently, the main methods for preparing chiral pyrrolidines are noble metal catalysis, such as the work published by Zhou Qilin's research group in 2015 (J.Am.Chem.Soc.2015,137,90-93). Zhou Qilin et al. reported the use of metal iridium catalysts to asymmetric hydrogenate substituted myosin derivatives, because the substituents can reduce the coordination effect of the two nitrogen atoms on the myosin molecule on the catalytic active center, but due to the influence of pyridine nitrogen coordination, myosin cannot be directly hydrogenated; Zhang Xumu et al. used the metal iridium catalyst they designed (Nature Communications, 2023,14,3718, CN 116102464) to first asymmetric hydrogenate aromatic ketones and then perform a chemical ring closure method to synthesize nicotine, rather than directly asymmetric hydrogenating cyclic imines to prepare nornicotine. It has the defects of long reaction steps, poor selectivity and low yield, while the use of noble metal catalysis can cause the increase of production cost and heavy metal residue problem. Harald Groger et al. utilize enzyme catalysis to prepare Larotrectinib intermediate (Org.Process Res.Dev.2022, 26, 2067-2074), but bioenzyme catalyzed reaction, product separation and purification are more difficult, bioenzyme is easily inactivated, and the substrate catalyzed by the work has only three kinds, which may be due to the specificity of enzyme to substrate adaptability, and the application range is not wide. There are also reports on the synthesis of some drugs, in which cyclic imine is directly hydrogenated to a rotic product and then split (European Journal of Medicinal Chemistry 235 (2022) 114303), but this most traditional method can cause more than half of the waste of raw materials.

[0005] Summary of the Invention

[0006] Since manganese is a non-precious metal, it is cheap and has low preparation cost. By designing a novel chiral ligand, manganese is regulated to catalyze the asymmetric hydrogenation of cyclic imines to form a single chiral amine, which has the characteristics of a short reaction route and low cost, and has potential value in the synthesis of drugs and natural compounds. Therefore, the purpose of the present invention is to provide a method for preparing chiral cyclic amines by asymmetric hydrogenation, a catalyst used therein, and a method for preparing the catalyst. The present invention synthesizes several novel PNN-type chiral phosphine nitrogen ligands, reacts them with Mn(CO)5Br to synthesize a chiral manganese catalyst, and utilizes the chiral manganese catalyst to carry out asymmetric hydrogenation of cyclic imines, thereby achieving the highly selective synthesis of chiral pyrrolidine compounds under mild conditions, and has broad application prospects in drug synthesis.

[0007] The technical solution of the present invention:

[0008] [Corrected 05.09.2024 according to Rule 26] A catalyst for preparing chiral cyclic amines by asymmetric hydrogenation, comprising a complex of pentacarbonyl manganese bromide and a chiral ligand, the catalyst comprising the following four compounds: Mn-1, Mn-2, Mn-3, and Mn-4, with the structural formula:

[0009] A method for preparing a catalyst for preparing chiral cyclic amines by asymmetric hydrogenation comprises the following steps: dissolving S1, 1-S-diphenylphosphino-2-R-aminoethylferrocene and 6,7-dihydroquinolin-8-(5H)-one in an organic solvent, reacting in an acidic environment under the action of a reducing agent to generate (R c , S P )-N-5,6,7,8-tetrahydroquinolinyl 1-(2-diarylphosphino)ferrocenylethylamine;

[0010] [Corrected 05.09.2024 according to Rule 26] The chemical reaction formula is:

[0011] S2、(R C , S P )-N-5,6,7,8-tetrahydroquinolinyl-1-(2-diarylphosphino)ferrocenylethylamine reacts with Mn(CO)5Br in an organic solvent to generate a catalyst and Mn-1, Mn-2, Mn-3 and Mn-4.

[0012] [Corrected 05.09.2024 according to Rule 26] The chemical reaction formula is:

[0013] Preferably, the molar ratio of 1-S-diphenylphosphino-2-R-aminoethylferrocene to 6,7-dihydroquinolin-8-(5H)-one in S1 is 0.9:1-2:1;

[0014] The organic solvent in S1 is dichloromethane, 1,4-dioxane, tetrahydrofuran, acetonitrile, and 1,2-dichloroethane, and the amount of the organic solvent used is 20 ml to 100 ml per gram of 6,7-dihydroquinolin-8-(5H)-one;

[0015] In S1, an acid is added to generate an acidic environment. The acid is formic acid, acetic acid, or trifluoroacetic acid. The amount of the acid used is 10% to 100% of the molar amount of 1-S-diphenylphosphino-2-R-aminoethylferrocene used.

[0016] The reducing agent used in S1 is sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, and the molar ratio of 1-S-diphenylphosphino-2-R-aminoethylferrocene to the reducing agent is 1:1-1:5;

[0017] In S1, the reaction temperature is 0°C-80°C, and the reaction time is 2h-24h.

[0018] Preferably, the molar ratio of (RC, SP)-N-5,6,7,8-tetrahydroquinolinyl-1-(2-diarylphosphino)ferrocenylethylamine to Mn(CO)5Br in S2 is 1:1-2:1;

[0019] The organic solvent in S2 is tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene or methyl tert-butyl ether, and the amount of the organic solvent is 100ml-400ml per gram of Mn(CO)5Br;

[0020] In S2, the reaction temperature is 20°C-100°C, and the reaction time is 2h-24h;

[0021] The reaction of S2 is carried out under the protection of inert gas or nitrogen.

[0022] [Corrected 05.09.2024 according to Rule 26] A method for preparing chiral cyclic amines by asymmetric hydrogenation, the chemical reaction equation is as follows:

[0023] In the general chemical formulas a and b, R represents a benzene ring, a pyridine ring, a benzene ring with a substituent or a pyridine ring with a substituent, and n=1-2, representing a ring containing 4-5 carbon atoms.

[0024] Preferably, the amount of catalyst added is 0.05%-5% of the molar amount of substrate a;

[0025] The asymmetric hydrogenation reaction temperature is 40-110° C., and the asymmetric hydrogenation reaction pressure is 0.5 MPa-8 MPa.

[0026] Preferably, a co-catalyst is also added, the co-catalyst includes potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, potassium hydroxide or sodium hydroxide, and the amount of the co-catalyst added is 10%-50% of the molar amount of substrate a.

[0027] Preferably, the catalyst is Mn-5, and the co-catalyst is potassium tert-butoxide.

[0028] Preferably, it is used to prepare nornicotine, S-quinoline, larotrectinib intermediates, selitrectinib intermediates and MSC2530818 intermediates.

[0029] [Corrected 05.09.2024 according to Rule 26] Preferably, R is:

[0030] [Corrected 05.09.2024 according to Rule 26] A method for preparing a catalyst for preparing chiral cyclic amines by asymmetric hydrogenation, when R is a pyridine ring and n=1, for preparing nornicotine, a precursor of nicotine, according to the following formula:

[0031] [Corrected 05.09.2024 according to Rule 26] A method for preparing a catalyst for preparing chiral cyclic amines by asymmetric hydrogenation, when R is a pyridine ring and n=2, for preparing S-quinoline, the preparation method is as follows:

[0032] [Corrected 05.09.2024 in accordance with Rule 26] A method for preparing a catalyst for asymmetric hydrogenation of chiral cyclic amines, when R is 2,5-difluorophenyl and n=1, for preparing a larotrectinib intermediate, the preparation method being as follows:

[0033] [Corrected 05.09.2024 in accordance with Rule 26] A method for preparing a catalyst for asymmetric hydrogenation of chiral cyclic amines, when R is 3-(2-chloro-5-fluoropyridinyl)-yl or 3-2-methoxy-5-fluoropyridine, and n=1, for preparing a selitrectinib intermediate, the preparation method being as follows:

[0034] [Corrected 05.09.2024 according to Rule 26] A method for preparing a catalyst for preparing chiral cyclic amines by asymmetric hydrogenation, when R is 4-chlorophenyl and n=1, the method can be used to prepare an intermediate of the drug MSC2530818, and the preparation method is as follows:

[0035] Beneficial effects of the present invention:

[0036] The present invention provides four chiral manganese catalysts for the asymmetric hydrogenation of chiral cyclic imine compounds to prepare chiral cyclic amine compounds. The method is easy to scale up industrially, has simple post-processing, and is environmentally friendly. Since manganese is a non-precious metal and is inexpensive, the method is more cost-effective. The catalyst has high optical selectivity, and the resulting product can meet downstream product requirements without the need for splitting. DETAILED DESCRIPTION

[0037] In order to further illustrate the technical means and effects adopted by the present invention to achieve the predetermined purpose of the invention, the specific implementation methods, structures, features and effects of the present invention are described in detail below in combination with preferred embodiments.

[0038] Catalyst Preparation Example: Preparation of Manganese Catalysts Mn-1, Mn-2, Mn-3 and Mn-4

[0039] [Corrected 05.09.2024 according to Rule 26] (1) Preparation (R C , S P )-1-(2-Diarylphosphino)ferroceneethylamine (Refer to Organometallics 2014, 33, 2109-2114.)

[0040] As shown in the above formula, 1 (2.57 g, 10 mmol) was dissolved in 20 mL of methyl tert-butyl ether. Under nitrogen protection, 1-3 M tert-butyl lithium n-pentane solution (8.5 mL, 11.05 mol) was added dropwise at 0°C. After the addition was complete, the temperature was raised to room temperature and stirred for 1.5 h.

[0041] The system was cooled to -80°C, and a solution of phosphorus trichloride (1.57 g, 11.46 mmol) in 1 mL of methyl tert-butyl ether was added dropwise to the system. After the addition was complete, the system was heated to room temperature and stirred for 4 h.

[0042] The system was then cooled to -80°C, and 25 mmol of a suspension of ArLi in methyl tert-butyl ether was added dropwise (prepared by reacting equimolar amounts of ArBr and n-butyl lithium in methyl tert-butyl ether at -40°C under nitrogen protection; when ArBr is bromo-3,5-2-s-terphenyl, the solvent for preparing the aryl lithium is tetrahydrofuran, and the reaction temperature is -80°C). After the addition was completed, the system was slowly cooled from -80°C to room temperature, the reaction was allowed to proceed overnight, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 3 crude products, which were purified by silica gel chromatography to obtain 3 pure products.

[0043] 3-1: Ar=2-naphatlene, orange foamy solid, yield 60%;

[0044] 3-2: Ar=3,5-Ph2-C6H3, yellow foamy solid, yield 71%;

[0045] 3-3: Ar=3,5-Me2-4-OMe-C6H2, orange foamy solid, yield 68%.

[0046] 3-4: Ar=3,5-tgu2-C6H3, yellow foamy solid, yield 52%;

[0047] [Corrected 05.09.2024 according to Rule 26] (2) Preparation of 1-S-diarylphosphino-2-R-aminoethylferrocene (Refer to Angew. Chem. Int. Ed. 2022, e202202814.)

[0048] 3 (3.4 mmol) was dissolved in 5 mL of acetic anhydride, and the temperature was raised to 50°C under nitrogen protection for 3 h. The acetic anhydride was removed on a rotary evaporator to obtain a crude product 4.

[0049] To the crude product 4, 10 mL of isopropanol was added, followed by 7.5 mL of concentrated aqueous ammonia. The mixture was heated to 60°C under nitrogen for 12 h, cooled to room temperature, extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate to obtain the crude product 5, which was purified by silica gel chromatography to obtain the pure product 5.

[0050] Note: When Ar = 5-Ph2-C6H3, add 10 mL of tetrahydrofuran and 10 mL of methanolamine solution to the crude product 4, heat to 60°C under nitrogen protection, react for 12 h, cool to room temperature, extract with ethyl acetate, wash with saturated sodium chloride solution, and dry over anhydrous sodium sulfate to obtain crude product 5, which is purified by silica gel chromatography to obtain pure product 5.

[0051] 5-1: Ar=2-naphatlene, orange foamy solid, yield 40%;

[0052] 5-2: Ar=3,5-Ph2-C6H3, yellow foamy solid, yield 20%;

[0053] 5-3: Ar=3,5-Me2-4-OMe-C6H2, orange foamy solid, yield 67%.

[0054] 5-4: Ar=3,5- t Bu2-C6H3, yellow foamy solid, yield 60%;

[0055] Steps (1) and (2) use the existing technology, and step (3) and the beginning use the technical solution of the present invention.

[0056] [Corrected 05.09.2024 in accordance with Rule 26](3)(R C , S P Preparation of )-N-5,6,7,8-tetrahydroquinolinyl-1-(2-diarylphosphino)ferrocenylethylamine (catalyst ligand):

[0057] 5 (2.3 mmol) and 6 (0.35 g, 2.4 mmol) were dissolved in 14 mL of 1,2-dichloroethane, and sodium triacetoxyborohydride (1.5 g, 7 mmol, 3 equiv) and acetic acid (69 mg, 1.15 mmol, 0.5 equiv) were added. Under nitrogen protection, the mixture was stirred at 30° C. and reacted overnight. The reaction was then quenched with saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain crude 7. The crude 7 was purified by silica gel column chromatography to obtain pure 7.

[0058] 7-1: Ar=2-naphatlene, yellow foamy solid, yield 71%.

[0059] 1 H NMR (400MHz, CDCl3) δ8.25 (d, J=9.7Hz, 1H), 8.11 (s, 1H), 7.87 (d, J=6.4Hz, 2H), 7.81 (d, J=8 .0Hz, 1H), 7.71-7.56(m, 4H), 7.48-7.37(m, 3H), 7.35-7.18(m, 2H), 6.76-6.57(m, 2H), 4.64( s, 1H), 4.41 (s, 1H), 4.30 (s, 1H), 4.05 (d, J=19.9Hz, 5H), 3.90 (s, 1H), 3.82 (s, 1H), 2.39-2.2 2 (m, 1H), 1.96 (d, J = 16.4Hz, 1H), 1.81 (d, J = 20.6Hz, 2H), 1.72 (d, J = 5.4Hz, 3H), 1.62 (s, 1H).

[0060] 13C NMR (101MHz, CDCl3) δ157.35, 146.30, 138.20, 138.11, 136.94, 136.30, 136.18, 136.01, 135.31, 135.22, 133.53, 133 .14, 133.03, 132.87, 132.81, 132.67, 132.30, 132.13, 131.87, 131.77, 129.50, 129.31, 128.24, 127.93, 127.74, 127. 50, 127.43, 127.37, 126.82, 126.76, 126.27, 125.72, 125.67, 122.49, 121.09, 99.32, 99.08, 74.79, 74.72, 71.72, 71.68, 70.85, 69.67, 69.29, 69.25, 68.86, 54.02, 47.52, 47.45, 30.72, 29.80, 28.36, 26.99, 26.55, 19.51, 18.48, 17.99.

[0061] 7-2: Ar=3,5-Ph2-C6H3, yellow foamy solid, yield 70%.

[0062] 1 H NMR (400MHz, CDCl3) δ8.72 (d, J=2.4Hz, 1H), 8.15-8.06 (m, 3H), 8.01 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.68 (d, J=7 .4Hz, 4H), 7.63 (d, J=9.0Hz, 2H), 7.45 (dd, J=13.2, 6.7Hz, 8H), 7.35 (td, J=15.3, 7.3Hz, 8H), 6.97 (d, J=7.3Hz, 1H), 3.00 (t, J=5.7Hz, 1H), 2.83-2.78 (m, 1H), 2.34 (d, J=16.5Hz, 1H), 2.23-2.07 (m, 3H), 1.88 (s, 1H), 1.74 (d, J=5.5Hz, 3H).

[0063] 13C NMR (101MHz, CDCl3) δ196.88, 157.96, 149.15, 148.21, 146.56, 141.59, 141.46, 140.87, 140.84, 140.74, 140. 19, 140.13, 137.71, 137.28, 136.49, 136.25, 136.21, 135.23, 132.37, 129.46, 129.35, 129.25, 129.15, 129.0 4, 128.91, 128.72, 128.32, 127.94, 127.53, 127.30, 127.20, 127.04, 121.12, 98.66, 98.56, 74.01, 73.85, 70.54, 70.44, 70.31, 70.06, 69.94, 65.31, 54.39, 53.57, 46.50, 39.71, 29.15, 28.75, 27.01, 22.70, 18.65, 18.44.

[0064] 7-3: Ar=3,5-Me2-4-OMe-C6H2, yellow foamy solid, yield 74%.

[0065] 1 H NMR (400MHz, CDCl3) δ8.29 (s, 1H), 7.21 (dd, J=20.3, 10.8Hz, 3H), 7.04-6.94 (m, 1H), 6.78 (d , J=7.2Hz, 2H), 5.33 (s, 1H), 4.67 (d, J=51.0Hz, 1H), 4.25 (d, J=27.1Hz, 2H), 4.03 (d, J=12.0 Hz, 5H), 3.83 (d, J=8.5Hz, 1H), 3.77 (s, 3H), 3.60 (d, J=8.5Hz, 3H), 2.57-2.42 (m, 2H), 2.4 2-2.27 (m, 8H), 2.02 (d, J = 18.4Hz, 7H), 1.71 (s, 3H), 1.40 (s, 1H), 1.30 (d, J = 12.3Hz, 1H).

[0066] 7-4: Ar=3,5- t B u2 -C6H3, yellow foamy solid, yield 83%.

[0067] 1H NMR (400MHz, CDCl3) δ8.32 (d, J=4.3Hz, 1H), 7.43-7.33 (m, 3H), 7.14 (d, J=9.1Hz, 2H) , 7.04 (d, J=7.8Hz, 2H), 6.93 (dd, J=7.5, 4.8Hz, 1H), 4.58 (s, 1H), 4.29 (dd, J=12.8, 9. 4Hz, 2H), 4.04(s, 5H), 3.89(t, J=4.4Hz, 1H), 3.67(s, 1H), 2.48-2.37(m, 1H), 2.28(dt , J=16.5, 5.3Hz, 1H), 1.69 (d, J=6.2Hz, 3H), 1.45 (s, 1H), 1.31 (s, 22H), 1.08 (s, 18H).

[0068] 13 C NMR (101MHz, CDCl3) δ158.18, 150.69, 150.58, 149.81, 149.74, 149.69, 146.78, 139.24, 139.18, 13 6.54, 132.45, 129.86, 129.65, 126.94, 126.76, 126.53, 126.42, 125.56, 122.59, 121.40, 121.10, 9 9.16, 98.92, 76.25, 76.17, 71.01, 70.97, 69.48, 69.03, 69.00, 68.70, 54.85, 47.68, 47.59, 35.04, 34.87, 34.62, 31.53, 31.38, 31.31, 28.41, 26.94, 26.89, 22.75, 22.71, 19.52, 17.76, 14.26, 14.22.

[0069] [Corrected 05.09.2024 according to Rule 26] (4) Preparation of catalyst

[0070] (R C , S P )-N-5,6,7,8-tetrahydroquinolinyl-1-(2-diarylphosphino)ferrocenylethylamine (various catalyst ligands) (4.48 mmol), pentacarbonylmanganese bromide (1.35 g, 4.93 mmol) were dissolved in 190 mL of 2-methyltetrahydrofuran, the temperature was raised to 80°C under nitrogen protection, the reaction was carried out for 8 hours, the mixture was cooled to room temperature, the mixture was dissolved in 10 mL of dichloromethane, the insoluble matter was removed by filtration, a large amount of n-hexane was added to the filtrate until a solid was precipitated, the mixture was stirred for 0.5 hours and then filtered. The obtained solid was catalyst Mn-1-Mn-4.

[0071] 7-4: Ar=3,5- t Bu2-C6H3, yellow powder, yield 75%;

[0072] 7-1: Ar=2-naphatlene, yellow powder, yield 66%;

[0073] 7-2: Ar=5-Ph2-C6H3, yellow powder, yield 65%;

[0074] 7-3: Ar=3,5-Me2-4-OMe-C6H2, orange powder, yield 64%.

[0075] Examples 1 to 5 are methods for preparing catalysts used in asymmetric hydrogenation to prepare chiral cyclic amines.

[0076] [Corrected 05.09.2024 according to Rule 26] Example 1: When R is a pyridine ring and n=1,

[0077] Catalyst Mn-4 (9.6 mg, 0.0086 mmol) and potassium tert-butoxide (0.1 g, 1 mmol) were added to a reactor. After the addition was complete, 2.5 mL of methanol was added and stirred to dissolve. Substrate a-1 (5 mmol, 0.73 g) was then added to the reactor. The reactor was then sealed and replaced with hydrogen three times. 5 MPa of hydrogen was then added to the reactor, and stirring was started. The temperature was raised to 80°C and the reaction was allowed to proceed for 16 hours. After the reaction was complete, the reactor was cooled to room temperature and hydrogen was slowly released. The conversion rate was measured by NMR and the ee value was measured by HPLC to be 94.1%.

[0078] b-1: light yellow oily liquid, 1 H NMR (400MHz, CDCl3) δ8.55 (s, 1H), 8.42 (d, J=4.4Hz, 1H), 7.72 (d, J=7.8Hz, 1H), 7.21 (dd, J=7.6, 4.9Hz, 1H), 4.22-4.12 (m, 1H), 4 .07 (s, 1H), 3.24-3.12 (m, 1H), 3.04 (dd, J=16.5, 8.7Hz, 1H), 2.27-2.13 (m, 1H), 1.99-1.80 (m, 2H), 1.71 (dq, J=12.1, 8.6Hz, 1H).

[0079] 13 C NMR (101MHz, CDCl3) δ148.56, 148.45, 138.58, 134.47, 123.46, 60.09, 46.55, 33.75, 25.17.

[0080] OJ-H column, detection wavelength 254nm, mobile phase n-hexane: isopropanol = 95:5, containing 0.1% ethylenediamine, flow rate 0.9mL / min, S-type t R =15.5min, R type t R =14.6min.

[0081] According to the screening experiment of catalysts in Example 1: using a-1 as the standard substrate, the catalytic performance screening of catalysts Mn-1-Mn-4 is shown in Table 1

[0082] [Corrected 05.09.2024 in accordance with Rule 26] Table 1

[0083] According to the method provided in Example 1, the operation of each reaction in the above table is basically the same as the operation in Example 1, except that different catalysts are used, different catalyst amounts are used, different reaction temperatures, and different reaction times are used.

[0084] [Corrected 05.09.2024 according to Rule 26] Taking the best reaction result item 11 as an example, the best catalyst is Mn-4:

[0085] Catalyst Mn-4 (2.8 mg, 0.0025 mmol) and potassium tert-butoxide (0.1 g, 1 mmol) were added to a reactor. After the addition was complete, 2.5 mL of methanol was added and stirred to dissolve. Substrate a-1 (5 mmol, 0.73 g) was then added to the reactor. The reactor was then sealed and replaced with hydrogen three times. 5 MPa of hydrogen was then added to the reactor, and stirring was started. The temperature was raised to 80°C and the reaction was allowed to proceed for 16 hours. After the reaction was complete, the reactor was cooled to room temperature and hydrogen was slowly released. The conversion rate was measured by NMR and the ee value was measured by HPLC to be 96.1%.

[0086] [Corrected 05.09.2024 according to Rule 26] Example 2: Preparation of S-quinoline

[0087] Catalyst Mn-4 (9.8 mg, 0.0087 mmol, 1.7% mol) and potassium tert-butoxide (0.11 mg, 0.1 mmol, 20% mol) were added to a reactor. After the addition was complete, 2.5 mL of methanol was added and stirred to dissolve. Substrate a-2 (0.5 mmol, 80 mg) was then added to the reactor. The reactor was then sealed and replaced with hydrogen three times. 5 MPa of hydrogen was then added to the reactor, stirring was started, and the temperature was raised to 80°C and the reaction was allowed to proceed for 16 hours. After the reaction was complete, the reactor was cooled to room temperature and hydrogen was slowly released. The conversion rate was measured by NMR and the ee value was measured by HPLC to be 89.3%.

[0088] b-2: red oily liquid, 1 H NMR (400MHz, CDCl3) δ8.57 (s, 1H), 8.46 (d, J=4.0Hz, 1H), 7.74 (d, J=7.8Hz, 1H), 7.24 (dd, J=7.7, 4.8Hz, 1H), 3.70-3.57 (m, 1H), 3.18 (s, 1H), 2.88-2.69 (m, 1H), 1.90 (d, J=9.8Hz, 1H), 1.78 (d, J=11.2Hz, 1H), 1.67 (d, J=11.7Hz, 1H), 1.60-1.48 (m, 3H), 1.26 (d, J=11.7Hz, 1H).

[0089] 13 C NMR (101MHz, CDCl3) δ148.58, 140.19, 134.49, 123.56, 59.69, 47.50, 34.46, 25.38, 25.04.

[0090] AD-H column, detection wavelength 254nm, mobile phase n-hexane: isopropanol = 90:10, containing 0.1% triethylamine, flow rate 1mL / min, R type t R =9.0min, S type t R =9.2min.

[0091] [Corrected 05.09.2024 according to Rule 26] Example 3: Preparation of Larotrectinib Intermediates

[0092] Catalyst Mn-4 (9.8 mg, 0.0087 mmol, 0.17% mmol) and potassium tert-butoxide (0.11 g, 1 mmol, 20% mmol) were added to a reactor. After the addition was complete, 2.5 mL of methanol was added and stirred to dissolve. Substrate a-3 (5 mmol, 0.9 g) was then added to the reactor. The reactor was then sealed and replaced with hydrogen three times. 5 MPa of hydrogen was then added to the reactor, stirring was started, and the temperature was raised to 80°C and the reaction was allowed to proceed for 16 hours. After the reaction was complete, the reactor was cooled to room temperature and hydrogen was slowly released. The conversion rate was measured by NMR and the ee value was measured by HPLC to be 99.3%.

[0093] b-3: yellow oily liquid, 1H NMR (400MHz, CDCl3) δ7.27 (ddd, J=9.1, 5.3, 2.4Hz, 1H), 6.97 (td, J=9.2, 4.5Hz, 1H), 6.91-6.82 (m, 1H), 4.42 (t, J=7.5Hz, 1H), 3.24-3.1 2 (m, 1H), 3.06 (dd, J=9.8, 7.8Hz, 1H), 2.28 (td, J=13.1, 7.7Hz, 1H), 2.03-1.96 (m, 1H), 1.95-1.76 (m, 2H), 1.63 (dt, J=16.1, 7.8Hz, 1H).

[0094] 13 C NMR (101MHz, CDCl3) δ160.08, 157.70, 157.57, 155.18, 134.59, 134.53, 134.43, 134.36, 116.14, 116.05, 115 .89, 115.81, 114.25, 114.19, 114.14, 114.05, 114.00, 113.94, 113.90, 113.81, 55.48, 46.81, 33.19, 25.52.

[0095] AD-H column, detection wavelength 254nm, mobile phase n-hexane: isopropanol = 95:5, containing 0.1% triethylamine, flow rate 1mL / min, R type t R =5.3min, S type t R =6.0min.

[0096] [Corrected 05.09.2024 according to Rule 26] Example 41: First Preparation of Selitrectinib Intermediate

[0097] Catalyst Mn-4 (9.8 mg, 0.0087 mmol, 4.3% mmol) and potassium tert-butoxide (4.5 mg, 0.04 mmol, 20% mmol) were added to a reactor. After the addition was complete, 2.5 mL of methanol was added and stirred to dissolve. Substrate a-4 (0.2 mmol, 39.7 mg) was then added to the reactor. The reactor was then sealed and replaced with hydrogen three times. 5 MPa of hydrogen was then added to the reactor, stirring was started, and the temperature was raised to 40°C and the reaction was allowed to proceed for 48 hours. After the reaction was complete, the reactor was cooled to room temperature and hydrogen was slowly released. The conversion rate was 83.4% by NMR and the ee value was 99.6% by HPLC.

[0098] b-4: colorless oily liquid, 1H NMR (400MHz, CDCl3) δ8.06 (d, J=2.5Hz, 1H), 7.83 (dd, J=8.9, 2.6Hz, 1H), 4.46 (t, J=7.3Hz, 1H), 3.11 (h, J=9.7Hz , 2H), 2.40 (dq, J=14.6, 7.4Hz, 1H), 2.02 (d, J=30.6Hz, 1H), 1.82 (p, J=7.0Hz, 2H), 1.50 (dq, J=14.3, 7.2Hz, 1H).

[0099] 13 C NMR (101MHz, CDCl3) δ160.56, 158.02, 144.07, 142.69, 142.66, 135.04, 134.78, 123.91, 123.69, 57.77, 47.08, 33.02, 25.50.

[0100] AD-H column, detection wavelength 254nm, mobile phase n-hexane: isopropanol = 95:5, containing 0.1% triethylamine, flow rate 1mL / min, R type t R =8.1min, S type t R =10.8min.

[0101] [Corrected 05.09.2024 according to Rule 26] Example 42: Second Preparation of Selitrectinib Intermediate

[0102] Catalyst Mn-4 (9.8 mg, 0.0087 mmol, 1.7% mmol) and potassium tert-butoxide (11.2 mg, 0.1 mmol, 20% mmol) were added to a reactor. After the addition was complete, 2.5 mL of methanol was added and stirred to dissolve. Substrate a-5 (0.5 mmol, 97 mg) was then added to the reactor. The reactor was then sealed and replaced with hydrogen three times. 5 MPa of hydrogen was then added to the reactor, stirring was started, and the temperature was raised to 80°C and the reaction was allowed to proceed for 16 hours. After the reaction was complete, the reactor was cooled to room temperature and hydrogen was slowly released. The conversion rate measured by NMR was 100.0%, and the ee value measured by HPLC was 96.2%.

[0103] b-5: colorless oily liquid, 1H NMR (400MHz, CDCl3) δ7.89 (d, J=2.6Hz, 1H), 7.60 (dd, J=8.5, 2.6Hz, 1H), 4.38 (t, J=7.6Hz, 1H), 4.02-3.93 (m, 3H), 3.66 (s, 1H), 3.24 (dt, J=13.5, 6.9Hz, 1H), 3.17-3.05 (m, 1H), 2.27 (qd, J=12.9, 7.6Hz, 1H), 1.98-1.83 (m, 2H), 1.69 (qd, J=15.7, 7.7Hz, 1H).

[0104] 13 C NMR (101MHz, CDCl3) δ157.40, 156.82, 154.38, 131.18, 130.93, 123.92, 123.69, 56.66, 53.81, 46.50, 31.79, 25.07.

[0105] AD-H column, detection wavelength 254nm, mobile phase n-hexane: isopropanol = 95:5, containing 0.1% triethylamine, flow rate 1mL / min, R type t R =6.8min, S type t R =5.7min.

[0106] [Corrected 05.09.2024 according to Rule 26] Example 5: Preparation of intermediates of active pharmaceutical ingredient MSC2530818

[0107] Catalyst Mn-4 (9.8 mg, 0.0087 mmol, 1.7% mmol) and potassium tert-butoxide (11.2 mg, 0.1 mmol, 20% mmol) were added to a reactor. After the addition was complete, 2.5 mL of methanol was added and stirred to dissolve. Substrate a-5 (0.5 mmol, 90 mg) was then added to the reactor. The reactor was then sealed and replaced with hydrogen three times. 5 MPa of hydrogen was then added to the reactor, stirring was started, and the temperature was raised to 80°C and the reaction was allowed to proceed for 16 hours. After the reaction was complete, the reactor was cooled to room temperature and hydrogen was slowly released. The conversion rate was measured by NMR and the ee value was measured by HPLC to be 92.9%.

[0108] b-6: yellow oily liquid, 1H NMR (400MHz, CDCl3) δ7.38-7.22 (m, 4H), 4.13 (t, J=7.8Hz, 1H), 3.21 (dd, J=14.8, 9.0Hz, 2 H), 3.04 (dd, J=16.6, 8.4Hz, 1H), 2.27-2.14 (m, 1H), 1.98-1.80 (m, 2H), 1.74-1.60 (m, 1H).

[0109] 13 C NMR (101MHz, CDCl3) δ142.43, 132.59, 128.49, 128.07, 61.92, 46.72, 34.20, 25.34.

[0110] AD-H column, detection wavelength 254nm, mobile phase n-hexane: isopropanol = 95:5, containing 0.1% triethylamine, flow rate 1mL / min, R type t R =7.7min, S type t R =8.2min.

[0111] Example 6: Substrate adaptability screening

[0112] To further explore the applicability of the catalyst, the table below screens the adaptability of the Mn-4 catalyst to substrates. The chiral cyclic imines generated by asymmetric hydrogenation of the substrates listed in the table below have many potential applications in pharmaceutical synthesis.

[0113] Catalyst Mn-4 (9.8 mg, 0.0087 mmol) and potassium tert-butoxide (20% of the substrate molar amount) were added to the reactor. After the addition was complete, 2.5 mL of methanol was added and stirred to dissolve. Substrate a-7-a-24 was then added to the reactor, which was then sealed and replaced with hydrogen three times. 5 MPa of hydrogen was then added to the reactor, and stirring was started. The reaction mixture was heated to 80° C. and allowed to react for 16 h. After the reaction was complete, the reactor was cooled to room temperature, hydrogen was slowly released, and the conversion was measured by NMR. The ee value was measured by HPLC, as shown in Table 2 below.

[0114] [Corrected 05.09.2024 in accordance with Rule 26] Table 2

[0115] Note: [a] The molar amount of catalyst is 0.5% of the molar amount of substrate

[0116] [b] The temperature of the catalytic reaction is 100°C.

[0117] The method provided in Example 6 is characterized in that in each asymmetric hydrogenation experiment of the substrate, the amount of catalyst used remains unchanged, which is 9.8 mg (0.0087 mmol).

[0118] According to the method provided in Example 6, the method for adjusting the ratio of catalyst to substrate is to keep the amount of catalyst and the volume of solvent unchanged, increase or decrease the molar amount of the substrate, so as to achieve the effect of adjusting the molar ratio of catalyst to substrate.

[0119] According to the method provided in Example 6, the amount of potassium tert-butoxide used is 20% of the molar amount of the substrate.

[0120] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as a preferred embodiment as above, it is not intended to limit the present invention. Any person skilled in the art can make some changes or modifications to equivalent embodiments using the technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any brief modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. [Corrected 05.09.2024 in accordance with Rule 26] A catalyst for preparing chiral cyclic amines by asymmetric hydrogenation, characterized in that: It is a complex of pentacarbonyl manganese bromide and a chiral ligand. The catalyst includes the following four types, namely Mn-1, Mn-2, Mn-3 and Mn-4, and its structural formula is:

2. A method for preparing a catalyst for preparing chiral cyclic amines by asymmetric hydrogenation, characterized in that: The following steps are involved: S11, 1-S-diphenylphosphino-2-R-aminoethylferrocene and 6,7-dihydroquinolin-8-(5H)-one are dissolved in an organic solvent and reacted in an acidic environment under the action of a reducing agent to generate (R C , S P )-N-5,6,7,8-tetrahydroquinolinyl-1-(2-diarylphosphino)ferrocenylethylamine; S12, (R C , S P )-N-5,6,7,8-tetrahydroquinolinyl-1-(2-diarylphosphino)ferrocenylethylamine reacts with Mn(CO)5Br in an organic solvent to generate catalysts Mn-1, Mn-2, Mn-3 and Mn-4.

3. The method for preparing a catalyst for preparing chiral cyclic amines by asymmetric hydrogenation according to claim 2, characterized in that: The molar ratio of 1-S-diphenylphosphino-2-R-aminoethylferrocene to 6,7-dihydroquinolin-8-(5H)-one in S11 is 0.9:1-2:1; The organic solvent in S11 is dichloromethane, 1,4-dioxane, tetrahydrofuran, acetonitrile, and 1,2-dichloroethane, and the amount of the organic solvent used is 20 ml to 100 ml per gram of 6,7-dihydroquinolin-8-(5H)-one; In S11, an acid is added to generate an acidic environment, wherein the acid is formic acid, acetic acid, or trifluoroacetic acid, and the amount of the acid used is 10% to 100% of the molar amount of 1-S-diphenylphosphino-2-R-aminoethylferrocene used; The reducing agent used in S11 is sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, and the molar ratio of 1-S-diphenylphosphino-2-R-aminoethylferrocene to the reducing agent is 1:1-1:5; In S11, the reaction temperature is 0°C-80°C, and the reaction time is 2h-24h.

4. The method for preparing a catalyst for preparing chiral cyclic amines by asymmetric hydrogenation according to claim 3, characterized in that: In S12, the molar ratio of (RC, SP)-N-5,6,7,8-tetrahydroquinolyl-1-(2-diarylphosphino)ferrocenylethylamine to Mn(CO)5Br is 1:1-2:1; The organic solvent in S12 is tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene or methyl tert-butyl ether, and the amount of the organic solvent is 100ml-400ml per gram of Mn(CO)5Br; In S12, the reaction temperature is 20°C-100°C, and the reaction time is 2h-24h; The reaction of S12 is carried out under the protection of inert gas or nitrogen.

5. [Corrected 05.09.2024 in accordance with Rule 26] A method for preparing chiral cyclic amines by asymmetric hydrogenation, characterized in that: The chemical reaction equation is as follows: The catalyst used is the catalyst described in any one of claims 1 to 4; In the chemical formula a and b, R represents a benzene ring, a pyridine ring, a benzene ring with a substituent or a pyridine ring with a substituent, and n=1-2, representing a ring containing 4-5 carbon atoms.

6. The method for preparing chiral cyclic amines by asymmetric hydrogenation according to claim 5, characterized in that: The amount of catalyst added is 0.05%-5% of the molar amount of substrate a; The asymmetric hydrogenation reaction temperature is 40-110° C., and the asymmetric hydrogenation reaction pressure is 0.5 MPa-8 MPa.

7. The method for preparing chiral cyclic amines by asymmetric hydrogenation according to claim 5, characterized in that: A promoter is also added, the promoter includes potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, potassium hydroxide or sodium hydroxide, and the added amount of the promoter is 10%-50% of the molar amount of the substrate a.

8. The method for preparing chiral cyclic amines by asymmetric hydrogenation according to claim 7, characterized in that: The catalyst is Mn-4, and the co-catalyst is potassium tert-butoxide.

9. The method for preparing chiral cyclic amines by asymmetric hydrogenation according to claim 5, characterized in that: Used for preparing nornicotine, S-nicotine, Larotrectinib intermediate, Selitrectinib intermediate and MSC2530818 intermediate.

10. [Corrected 05.09.2024 according to Rule 26] The method for preparing chiral cyclic amines by asymmetric hydrogenation according to claim 5, characterized in that: R is:

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