Method for constructing heterocyclic chiral pyrrolidine through asymmetric reductive amination

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a method for constructing heterocyclic chiral pyrrolidine through asymmetric reductive amination. On the first hand, an L8 ligand complexed Ir metal precursor is used as a catalyst, and a diphosphine ligand L8 based on ZhaoPhos and an iridium catalytic precursor have a synergistic effect, so that excellent catalytic activity and enantioselectivity are shown; compared with a primary amine substrate used in the prior art, secondary amine is used as a nitrogen source in the reaction, so that the application range of synthesis is expanded, the existing synthesis steps are simplified, the atom utilization rate is improved, two-step reaction is simplified into one-step reaction, and the feeding amount is reduced. And secondly, additives Ti (OiPr) 4 and AgN (Tf) 2 are adopted, so that the service life of the catalyst is prolonged, and the production cost is further reduced.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and particularly discloses a method for constructing heterocyclic chiral pyrrolidine through asymmetric reductive amination. Background Art

[0002] (S)-Nicotine is a natural alkaloid found in tobacco. Its molecular formula is C 10 H 14 N2, with a chiral center, is the most physiologically active of the optically active forms of nicotine. Its structure consists of a pyridine ring and a pyrrolidine ring. It primarily exists in nature in the left-handed form, accounting for over 99% of total nicotine. L-nicotine is widely found in plants of the Solanaceae family, particularly in tobacco (Nicotiana tabacum) and wild tobacco (Nicotiana rustica), and is the primary active ingredient in nicotine products. It is typically extracted through acid-base treatment of tobacco followed by distillation and is widely used in neuropharmacology research and in tobacco products.

[0003] Patent CN114230553A proposes a method for synthesizing heterocyclic compounds containing chiral tertiary amines, such as L-nicotine:

[0004]

[0005] Intermediate 2 is cyclized in an acidic organic solvent with the metal complex catalyst of Zhaophos and [Ir(COD)Cl]2 to obtain compound 3.

[0006]

[0007] Compound 3 is reacted with a mixture of formic acid and formaldehyde to obtain compound 4;

[0008] Since the catalyst ligand Due to the limitation of the method, patent CN114230553A requires two steps to synthesize L-nicotine. The second step requires methylation of the secondary amine on the tetrahydropyrrole ring group. The two-step reaction requires extraction, silica gel purification, spin drying and other operations, which not only increases the input of materials such as formic acid and formaldehyde, but also increases the purification process, reduces the yield in the synthesis process, and has low atom utilization. Summary of the Invention

[0009] In response to the problems raised by the prior art, the first aspect of the present invention provides a method for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination, comprising:

[0010] Under temperature control, an organic solvent, a substrate of formula I, a metal precursor, a ligand L8, and additives are mixed and pressurized under a hydrogen atmosphere to obtain a compound of formula II;

[0011]

[0012] The additive is selected from one or a combination of Ti(OiPr)4 and AgN(Tf)2;

[0013] The structure of the ligand L8 is as follows:

[0014] Ar is selected from a substituted or unsubstituted 5- to 12-membered heterocyclic group, a substituted or unsubstituted monocyclic aromatic group, or a substituted or unsubstituted condensed aromatic group;

[0015] The R 1 is selected from halogen, substituted or unsubstituted C1 to C3 alkyl, substituted or unsubstituted C1 to C3 alkoxy, hydrogen;

[0016] The R 2 is selected from substituted or unsubstituted C1 to C3 alkyl, substituted or unsubstituted C1 to C3 alkoxy, hydrogen;

[0017] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0018] In some first aspects of the method for constructing heterocyclic chiral pyrrolidine by asymmetric reductive amination, the R 1 and R 2 Each is independently selected from any one of methyl, ethyl, isopropyl, n-propyl, fluorine, chlorine, bromine and iodine, and the hydrogen on R2 is optionally replaced by an aryl group, and optionally, the aryl group is a monocyclic aryl group or a condensed ring aryl group.

[0019] In some methods of constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination according to the first aspect, the Ar is selected from substituted or unsubstituted monocyclic aromatic groups, substituted or unsubstituted pyridyl groups, and the Ar is optionally fused with one or more substituted or unsubstituted monocyclic aromatic groups, heterocyclic groups, and cycloalkyl groups.

[0020] In some methods of constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination according to the first aspect, Ar is selected from any one of quinolyl, isoquinolyl, naphthalene, anthracene, phenanthrene, and benzopyrene.

[0021] In some methods of constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination according to the first aspect, the substrate of formula I is specifically as follows:

[0022]

[0023] In some methods of constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination according to the first aspect, the compound of formula II is as follows:

[0024]

[0025] In some methods of the first aspect proposed for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination, the temperature of the temperature control is 25-50°C. In some methods of the first aspect proposed for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination, the temperature of the temperature control is optionally 30°C, 35°C, 40°C, or 45°C.

[0026] In some methods of constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination according to the first aspect, the organic solvent is selected from one of tetrahydrofuran, n-hexane, MTBE, dichloromethane, chloroform, methanol, ethanol, isopropanol, toluene, and xylene, or a mixture thereof.

[0027] In some of the methods of the first aspect for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination, the metal precursor is selected from Ir metal precursors.

[0028] In some of the methods for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination according to the first aspect, the Ir metal precursor is selected from [Ir(COD)Cl]2.

[0029] In some methods of the first aspect proposed for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination, the molar amount of the metal precursor mixed in each 1L of organic solvent is 0.003 to 0.008 mol. In some methods of the first aspect proposed for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination, the molar amount of the metal precursor mixed in each 1L of organic solvent is optionally 0.004 mol, 0.005 mol, 0.006 mol, or 0.007ol.

[0030] In some methods of the first aspect proposed for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination, the molar amount of the ligand L8 mixed in every 1 L of organic solvent is 0.008 to 0.015 mol. In some methods of the first aspect proposed for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination, the molar amount of the ligand L8 mixed in every 1 L of organic solvent is optionally 0.009 mol, 0.010 mol, 0.011 mol, 0.012 mol, 0.013 mol, or 0.014 mol.

[0031] In some first aspects, in the method for constructing heterocyclic chiral pyrrolidine by asymmetric reductive amination, the Ti(O i The molar amount of Pr)4 is 1 to 2 mol. In some first aspects, in the method for constructing heterocyclic chiral pyrrolidine by asymmetric reductive amination, the Ti(O i The molar amount of Pr)4 is optionally 1.2 mol, 1.4 mol, 1.6 mol, or 1.8 mol.

[0032] In some methods for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination proposed in the first aspect, the molar amount of AgN(Tf)2 mixed in every 1 L of organic solvent is 0.1 to 0.5 mol. In some methods for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination proposed in the first aspect, the molar amount of AgN(Tf)2 mixed in every 1 L of organic solvent is optionally 0.1 mol, 0.2 mol, 0.3 mol, or 0.4 mol.

[0033] In some methods of the first aspect proposed for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination, the pressure of the hydrogen mixed in each 1 L of organic solvent is 40 to 100 atm. In some methods of the first aspect proposed for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination, the pressure of the hydrogen mixed in each 1 L of organic solvent is optionally 40 atm, 50 atm, 60 atm, 70 atm, 80 atm, 90 atm, or 100 atm.

[0034] Unless otherwise specified, “about” in the present invention means that the allowable error is within ±20%, or further, within ±10%, and further within ±5%.

[0035] The terms "preferably," "more preferably," and the like, used herein refer to embodiments of the present invention that may provide certain benefits under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the present invention.

[0036] The term "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon radical, which may contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms. The partially unsaturated monocyclic or polycyclic hydrocarbon radical is a saturated cycloalkyl radical or may optionally contain one, two or more double bonds and / or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl radical.

[0037] Ligand L8 was synthesized according to the preparation method on page S11 in Chem.Eur.J.2020, 26, 11470-11477, in which the ammonia step was replaced with methylamine.

[0038] In some methods for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination proposed in the first aspect, the molar amount of the substrate of formula I mixed in every 1 L of organic solvent is 0.8 to 1.2 mol. In some methods for constructing heterocyclic chiral pyrrolidines by asymmetric reductive amination proposed in the first aspect, the molar amount of the substrate of formula I mixed in every 1 L of organic solvent is optionally 0.9 mol, 1.0 mol, or 1.1 mol.

[0039] In some embodiments, the room temperature is 5-45°C, in some embodiments, the room temperature is 10-40°C, in some embodiments, the room temperature is 15-35°C, in some embodiments, the room temperature is 20-30°C, and in some embodiments, the room temperature is 25°C.

[0040] The term "heterocyclyl" refers to a non-aromatic fully saturated or partially unsaturated cyclic group (e.g., a 3 to 7 membered monocycle) having at least one heteroatom in a ring containing at least one carbon atom. Preferably, the heterocyclyl is a 5- or 6-membered heterocyclyl. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Non-limiting exemplary heterocyclic groups include thienyl, furanyl, pyrrolyl, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, azetidinyl, azocanyl, diazepanyl, diazaoctanyl, morpholin-4-yl, oxazepanyl, pyrrolidinyl, thiomorpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, thiiranyl, 2-imidazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, 2H-pyrrolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2 -oxopiperazinyl, homopiperazinyl, 2-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolane, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, tetrahydrothienyl, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, tetrahydro-1,1-dioxathienyl, N-formylpiperazinyl.

[0041] The drugs used in the present invention are purchased from the open legal market and have not been further purified.

[0042] Advantages of the present invention:

[0043] The present invention is a further improvement of CN114230553A.

[0044] The present invention develops a method for constructing heterocyclic chiral pyrrolidines through asymmetric reductive amination. The method uses an L8 ligand complexed with an Ir metal precursor as a catalyst. The ZhaoPhos-based bisphosphine ligand L8 works synergistically with the iridium catalytic precursor to exhibit excellent catalytic activity and enantioselectivity. Compared with the primary amine substrate used in patent CN114230553A, the reaction uses a secondary amine as a nitrogen source, which expands the scope of application of the synthesis, simplifies the synthesis steps in patent CN114230553A, improves atom utilization, simplifies a two-step reaction into a one-step reaction, and reduces the amount of feed.

[0045] Intramolecular asymmetric reductive amination using secondary amines as nitrogen sources was achieved, leading to the direct synthesis of heterocyclic compounds containing chiral tertiary amines ((S)-Nicotine). By using a catalyst obtained by combining the spatially optimized ligand L8 with an iridium metal precursor, the catalyst exhibited excellent enantioselectivity for heterocyclic compounds of chiral tertiary amines (up to 99% ee) and broad substrate tolerance, effectively generating a variety of chiral nitrogen heterocyclic compounds, including biologically significant nicotine alkaloid derivatives.

[0046] The use of additives Ti(OiPr)4 and AgN(Tf)2 greatly reduces the production cost, and the turnover number TON of the catalyst is greatly improved, which can reach 1440. Compared with the existing technology, the service life of the catalyst is increased and the catalyst input is reduced, which reduces the production cost compared with the existing technology CN114230553A. DETAILED DESCRIPTION

[0047] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0048] Example 1:

[0049]

[0050] At 25 ° C, 1a (0.1 mmol, 1 equivalent), [Ir(COD)Cl]2 (0.5 mol%), ligand (1.1 mol%), tetraisopropoxytitanium (Ti(O i Pr) 4, 1.5 equivalents), the reaction vessel was replaced with nitrogen once, and then replaced with hydrogen three times, the hydrogen pressure was 50atm, and the reaction was carried out for 24 hours. The yield was determined by H NMR ( 1H NMR) was used as the internal standard, and the enantiomeric excess (ee%) was determined by chiral HPLC. The results are shown in Table 1:

[0051] Table 1 Intramolecular asymmetric reductive amination under different ligands

[0052] Group ligand Yield (%) Enantiomeric excess ee (%) 1 L1 NR —— 2 L2 NR —— 3 L3 NR —— 4 L4 18 5 5 L5 20 35 6 L6 20 55 7 L7 31 88 8 L8 52 96

[0053]

[0054] Example 2:

[0055] At 25°C, 1a (0.1 mmol, 1 equivalent), [Ir(COD)Cl]2 (0.5 mol%), ligand L8 (1.1 mol%), tetraisopropoxytitanium (Ti(O i Pr) 4, 1.5 equivalents), the reaction vessel was replaced with nitrogen once, and then replaced with hydrogen three times, the hydrogen pressure was 50atm, and the reaction was carried out for 24 hours. The yield was determined by H NMR ( 1 H NMR) was used as the internal standard, and the enantiomeric excess (ee%) was determined by chiral HPLC. The results are shown in Table 2:

[0056] Table 2 Intramolecular asymmetric reductive amination in different solvents

[0057] Group ligand solvent Yield (%) Enantiomeric excess (%) 9 L8 MeOH 25 94 10 L8 MTBE 55 94

[0058] Example 3:

[0059] At the temperature shown in Table 3, 1a (0.1 mmol, 1 equivalent), [Ir(COD)Cl]2 (0.5 mol%), ligand L8 (1.1 mol%), tetraisopropoxytitanium (Ti(O i Pr) 4, 1.5 equivalents), the reaction vessel was replaced with nitrogen once, and then replaced with hydrogen three times, the hydrogen pressure was 50atm, and the reaction was carried out for 24 hours. The yield was determined by H NMR ( 1 H NMR) was used as the internal standard, and the enantiomeric excess (ee%) was determined by chiral HPLC. The results are shown in Table 3:

[0060] Table 3 Intramolecular asymmetric reductive amination at different temperatures

[0061] Group ligand Temperature Yield (%) Enantiomeric excess (%) 11 L8 40 75 92 12 L8 50 80 89

[0062] Example 4:

[0063] At 25°C, 1a (0.1 mmol, 1 equivalent), [Ir(COD)Cl]2 (0.5 mol%), THF (0.1 ml) and the ligands and additives shown in Table 4 were mixed and reacted for 24 hours. The reaction vessel was purged with nitrogen once and then with hydrogen three times at a pressure of 50 atm. The yield was determined by H NMR spectroscopy ( 1 H NMR) was used as the internal standard, and the enantiomeric excess (ee%) was determined by chiral HPLC. The results are shown in Table 4:

[0064] Table 4 Intramolecular asymmetric reductive amination under different volumes and additives

[0065] Group Ligand (1.1 mol%) THF (ml) additive Yield (%) Enantiomeric excess (%) 13 L8 0.1 △ 85 98 14 L8 0.1 × 0 —— 15 L9 0.1 △ 71 -95 16 L7 0.1 △ 35 81

[0066] “△” indicates that the additive tetraisopropoxytitanium (Ti(O i Pr) 4, 1.5 equivalents);

[0067] “×” means no additive tetraisopropoxytitanium (Ti(O i Pr)4, 1.5 equiv.).

[0068]

[0069] Example 5:

[0070] At 25°C, 0.1 mmol (1 equivalent) of the reactants shown in Table 5, [Ir(COD)Cl]2 (0.5 mol%), THF (0.1 ml), ligand L8 (1.1 mol%), tetraisopropoxytitanium (Ti(O i Pr) 4, 1.5 equivalents) were added and mixed, and the reaction was carried out for 24 hours. The reaction vessel was replaced with nitrogen once and then replaced with hydrogen three times. The hydrogen pressure was increased to 50 atm. The yield was determined by H NMR ( 1 H NMR) was used as the internal standard, and the enantiomeric excess (ee%) was determined by chiral HPLC. The results are shown in Table 5:

[0071] Table 5

[0072] Group reactants product Yield (%) Enantiomeric excess (%) 17 Compound 1b Compound 1b 65 90 18 Compound 1e Compound 1e 73 99 19 Compound 1f Compound 1f 63 98 20 Compound 1i Compound 1i 75 98 21 Compound 1j Compound 1j 78 99 22 Compound 1k Compound 1k 65 95 23 Compound 11 Compound 11 70 98 24 Compound 1m Compound 1m 83 99 25 Compound 1n Compound 1n 82 99 26 Compound 1o Compound 1o 81 99

[0073]

[0074] Example 6:

[0075] At 25 ° C, 1a (0.2 mmol, 1 equivalent) was added to isopropanol (1 ml), and [Ir(COD)Cl]2, ligand L8, tetraisopropoxytitanium (Ti(O i Pr)4, 1.5 equivalents), AgN(Tf)2 (0.3 equivalents), the reaction vessel was replaced with nitrogen once, and then replaced with hydrogen three times, the hydrogen pressure was 50atm, and the reaction was carried out for 72 hours. The yield was determined by H NMR ( 1 HNMR) determination was performed using 1,3,5-trimethoxybenzene as an internal standard. The enantiomeric excess (ee%) was determined by chiral HPLC analysis. The results are shown in Table 6:

[0076]

[0077]

[0078]

[0079] “×” means no additives are added.

[0080] Example 7:

[0081] We next investigated the scalability of the reaction at a catalyst loading of 0.05 mol%.

[0082] At 25 ° C, 1a (5.61 mmol, 1 equivalent), [Ir (COD) Cl] 2 (0.5 mol%), ligand L8 (1.1 mol%), tetraisopropoxytitanium (Ti (O i Pr)4, 1.5 equivalents), AgN(Tf)2 (0.3 equivalents), the reaction vessel was replaced with nitrogen once, and then replaced with hydrogen three times, the hydrogen pressure was 50atm, and the reaction was carried out for 72 hours. The yield was determined by H NMR ( 1 The enantiomeric excess (ee%) was determined by chiral HPLC (HNMR) analysis using 1,3,5-trimethoxybenzene as the internal standard. The product yield was 72% (NMR analysis) and the enantioselectivity was 95%ee. The present invention achieved good results in terms of product yield and enantioselectivity under gram-scale amplification.

[0083] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for constructing a heterocyclic chiral pyrrolidine by asymmetric reductive amination, comprising: Under temperature control, an organic solvent, a substrate of formula I, a metal precursor, a ligand L8, and additives are mixed and pressurized under a hydrogen atmosphere to obtain a compound of formula II; The additive is selected from one or a combination of Ti(OiPr)4 and AgN(Tf)2; The structure of the ligand L8 is as follows: Ar is selected from a substituted or unsubstituted 5- to 12-membered heterocyclic group, a substituted or unsubstituted monocyclic aromatic group, or a substituted or unsubstituted condensed aromatic group; The R 1 is selected from halogen, substituted or unsubstituted C1 to C3 alkyl, substituted or unsubstituted C1 to C3 alkoxy, hydrogen; The R 2 is selected from substituted or unsubstituted C1 to C3 alkyl, substituted or unsubstituted C1 to C3 alkoxy, hydrogen; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

2. The method for constructing heterocyclic chiral pyrrolidine by asymmetric reductive amination according to claim 1, characterized in that: The R 1 and R 2 Each independently selected from methyl, ethyl, isopropyl, n-propyl, fluorine, chlorine, bromine, iodine, said R 2 The hydrogen atoms on the alkyl group are optionally substituted by aryl groups, and optionally, the aryl groups are monocyclic aryl groups or condensed ring aryl groups.

3. The method for constructing heterocyclic chiral pyrrolidine by asymmetric reductive amination according to any one of claims 1 or 2, characterized in that: The Ar is selected from substituted or unsubstituted monocyclic aromatic groups, substituted or unsubstituted pyridyl groups, and the Ar is optionally fused with one or more substituted or unsubstituted monocyclic aromatic groups, heterocyclic groups, and cycloalkyl groups.

4. The method for constructing heterocyclic chiral pyrrolidine by symmetric reductive amination according to any one of claims 1 to 3, characterized in that: The Ar is selected from any one of quinolyl, isoquinolyl, naphthalene, anthracene, phenanthrene and benzopyrene.

5. The method for constructing heterocyclic chiral pyrrolidine by symmetric reductive amination according to any one of claims 1 to 4, characterized in that: The substrate of formula I is specifically as follows:

6. The method for constructing heterocyclic chiral pyrrolidine by symmetric reductive amination according to any one of claims 1 to 5, characterized in that: The compound of formula II is specifically as follows:

7. The method for constructing heterocyclic chiral pyrrolidine by asymmetric reductive amination according to any one of claims 1 to 7, characterized in that: The temperature of the temperature control is 25-50° C.; and / or the organic solvent is selected from one of tetrahydrofuran, n-hexane, MTBE, dichloromethane, chloroform, methanol, ethanol, isopropanol, toluene, and xylene, or a mixture thereof.

8. The method for constructing heterocyclic chiral pyrrolidine by asymmetric reductive amination according to any one of claims 1 to 8, characterized in that: The metal precursor is selected from an Ir metal precursor; and / or, the Ir metal precursor is selected from [Ir(COD)Cl]2; and / or, the molar amount of the metal precursor mixed in each 1L of organic solvent is 0.003 to 0.008 mol; and / or, the molar amount of the ligand L8 mixed in each 1L of organic solvent is 0.008 to 0.015 mol.

9. The method for constructing heterocyclic chiral pyrrolidine by asymmetric reductive amination according to any one of claims 1 to 8, characterized in that: The Ti(O i The molar amount of Pr)4 is 1 to 2 mol; and / or the molar amount of AgN(Tf)2 mixed in each 1 L of organic solvent is 0.1 to 0.5 mol.

10. The method for constructing heterocyclic chiral pyrrolidine by asymmetric reductive amination according to any one of claims 1 to 9, characterized in that: The pressure of the hydrogen gas mixed in each 1 L of the organic solvent is 40 to 100 atm; and / or the molar amount of the substrate of formula I mixed in each 1 L of the organic solvent is 0.8 to 1.2 mol.

Images