A method for the iridium-catalyzed synthesis of chiral 2-acylaminodiphenylmethanol

Abstract

The present invention provides a method for synthesizing chiral 2-acylaminodiphenylmethanol. Using 2-acylaminobenzophenone as the raw material, a complex formed by iridium metal and a PNN ligand with a phenyl skeleton as the catalyst, and methanol as the solvent, a hydrogenation reaction occurs in this homogeneous catalytic system to obtain chiral 2-acylaminodiphenylmethanol with a high yield (>99%) and a high ee value (99%). This reaction has high activity, mild reaction conditions, and the starting materials are cheap and easily available, and has high industrial application value.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly to a synthetic method for preparing chiral 2-acylaminodiphenylmethanol by asymmetric hydrogenation of 2-acylaminobenzophenone catalyzed by iridium. Background Art

[0002] Chiral diaryl compounds are widely present in natural products and bioactive compounds [(a) Beck, J. J.; Chou, S. J. Nat. Prod. 2007, 70, 891 - 900. (b) Knepper, K.; Ziegert, R. E.; Brase, S. Tetrahedron 2004, 60, 8591 - 8603]. At present, asymmetric hydrogenation of ketones catalyzed by transition metals such as Ir, Rh, Ru, etc. is one of the most effective methods for obtaining chiral alcohols [(c) Chen, X.; Hou, C.; Qin, C.; Liu, H.; Liu, Y.; Huang, D.; Hu, X. RSC Adv. 2017, 7, 12871. (d) Császár, Z.; Szabó, E. Z.; Bényei, A. C.; Bakos, J.; Farkas, G. Catal. Commun. 2020, 146, 2938.]. So far, significant achievements have been made in the asymmetric hydrogenation of benzophenone with halogen, hydroxyl, alkyl or alkoxy as the ortho-direct group [(e) Ohkuma, T.; Koizumi, M.; Ikehira, H.; Yokozawa, T.; Noyori, R. Org. Lett. 2000, 2, 659 - 662. (f) Wu, J.; Ji, J.; Guo, R.; Yeung, C.; Chan, A. S. C. Chem. Eur. J. 2003, 9, 2963 - 2968. (g) Kokura, A.; Tanaka, S.; Ikeno, T.; Yamada, T. Org. Lett. 2006, 8, 3025 - 3027. (h) Touge, T.; Nara, H.; Fujiwhara, M.; Kayaki, Y.; Ikariya, T. J. Am. Chem. Soc. 2016, 138, 10084 - 10087. (i) Zhang, L.; Tang, Y.; Han, Z.; Ding, K. Angew. Chem. Int. Ed. 2019, 58, 4973 - 4977.], but there are few successful examples with acetamido as the ortho-direct group [(j) Zheng, Y.; Clarkson, G. J.; Wills, M. Org. Lett. 2020, 22, 3717 - 3721]. In addition, chiral amino alcohols are also an important part of medicinal chemistry.

[0003] For the above purposes, we used 2-acylaminobenzophenone as the raw material and obtained chiral 2-acylaminodiphenylmethanol through the method of transition metal-catalyzed asymmetric hydrogenation, and successfully obtained 2-acylaminodiphenylmethanol with a high yield (up to 99%) and a high ee value (up to 99%). Summary of the Invention

[0004] The object of the present invention is to provide a synthesis method of a chiral 2-acylaminodiphenylmethanol compound, which provides an efficient hydrogenation catalytic system and has the advantages of simple operation, easy availability of raw materials, and high reaction activity, greatly reducing the reaction cost and having high industrial application value.

[0005] Specifically, the present invention provides a synthesis method of a chiral 2-acylaminodiphenylmethanol compound, using 2-acylaminobenzophenone and hydrogen as raw materials, and using a complex formed by iridium metal and a phenyl-skeleton PNN ligand to carry out a hydrogenation reaction in an alcohol solvent to generate chiral 2-acylaminodiphenylmethanol with a high yield and a high ee value. The specific steps are as follows:

[0006] In a glove box, iridium metal and a PNN ligand with a phenyl skeleton were vigorously stirred in a solvent at a molar ratio of 1:1.1 - 1:2.2 for 1 hour, and then a solution of 2-acetylaminobenzophenone was added thereto. It was placed in a high-pressure reaction kettle, purged with hydrogen 3 times, filled with hydrogen to 3 - 5 MPa, and reacted at 20 - 60 °C for 1 - 24 hours. After cooling to room temperature, hydrogen was slowly released, the solvent was removed, and the residue was separated by column chromatography to obtain 2-acetylaminodiphenylmethanol.

[0007]

[0008] R, R 1 , R 2 are each independently selected from hydrogen, a C1-C 40 (preferably C1-C 30 , more preferably C1-C6) alkane group, a cycloalkyl group with 3 - C 12 (preferably C3-C8, more preferably C3-C6) carbon atoms in the ring, phenyl and substituted phenyl, benzyl and substituted benzyl; the substituents of the phenyl and benzyl groups are each independently selected from a C1-C 40 (preferably C1-C 30 , more preferably C1-C6) alkane group, a C1-C 40 (preferably C1-C 30 , more preferably C1-C6) alkoxy group, halogen, nitro, ester group or cyano group; R, R 1 , R 2 are the same, or pairwise the same, or different groups.

[0009] The reaction medium is selected from at least one of toluene, benzene, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide. Methanol is preferred.

[0010] The iridium metal is selected from IrCl3, [Ir(COD)Cl]2, Ir(COD)2BF4, Ir(CO)2(PPh)2Cl. [Ir(COD)Cl]2 is preferred.

[0011] The complex formed in-situ by the iridium metal and the PNN ligand of the aryl skeleton is used as the catalyst, and the general structural formula of the PNN ligand is as follows:

[0012]

[0013] In the formula:

[0014] Two Ar are respectively phenyl groups, and the aromatic rings of 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted or 2,4,6-trisubstituted aryl groups have 6 to C 60 (preferably 6 to C 30 , more preferably 6 to C 24 ) aromatic groups; the substituents are C1-C 40 (preferably C1-C 30 , more preferably C1-C6) alkyl groups, C1-C 40 (preferably C1-C 30 , more preferably C1-C6) alkoxy groups, halogens, nitro groups, ester groups or cyano groups, one or more of them;

[0015] R 1 、R 2 are the same or different groups, and are respectively hydrogen, C1-C 40 (preferably C1-C 30 , more preferably C1-C6) alkyl groups, aromatic groups with 6 to C 60 (preferably 6 to C 30 , more preferably 6 to C 24 ) (the aromatic group is phenyl, 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted or 2,4,6-trisubstituted aryl group, and the substituents are C1-C 40 (preferably C1-C 30 , more preferably C1-C6) alkyl groups, C1-C 40 (preferably C1-C 30, more preferably one or more of C1-C6 alkoxy, halogen, nitro, ester group or cyano group), or an aromatic ring having one or more N, S, O, P heteroatoms and having 3 to C carbon atoms on the aromatic ring 60 Aromatic group (the aromatic group is phenyl, a 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted or 2,4,6-trisubstituted aryl group, and the substituents are C1-C 40 (preferably C1-C 30 , more preferably C1-C6) alkyl group, C1-C 40 (preferably C1-C 30 , more preferably one or more of C1-C6 alkoxy, halogen, nitro, ester group or cyano group) (preferably C3-C 30 , more preferably C3-C 24 );

[0016] R 1 、R 2 can jointly form a cyclic group as shown below with the N atom, where n is a natural number from 1 to 6 (preferably 1 to 5, more preferably 3 to 5).

[0017]

[0018] The chiral phenylphosphine-1,2-diphenylethylenediamine ligand, and the above cycloalkyl group and cycloalkyl-derived group are preferably a six-membered piperidine ring L-1a.

[0019]

[0020] The molar ratio of the substrate to the catalyst is 100-50000:1

[0021] The catalytic reaction conditions are as follows:

[0022] Temperature: room temperature - 100 °C, preferably 20 °C;

[0023] Pressure: 3 MPa;

[0024] Time: 0.1-24 hours, preferably 12 hours.

[0025] The present invention has the following advantages:

[0026] 1. The starting materials are easily available

[0027] 2. The reaction conditions are mild, the reaction activity is high, the enantioselectivity is high, and the product yield is high.

[0028] 3. The catalyst is simple and efficient to prepare, and the whole process is suitable for industrial production.

[0029] Under this homogeneous catalytic system, the hydrogenation reaction of the present invention gives chiral 2 - acylaminodiphenylmethanol in high yield (>99%) and high ee value (99%). BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The accompanying drawings forming a part of this invention are used to provide a further understanding of the present invention. The schematic embodiments and descriptions thereof of the present invention are used to explain the present invention and do not unduly limit the present invention. Hereinafter, the embodiments of the present invention will be described in detail with reference to the drawings, wherein:

[0031] Figure 1 1H NMR spectrum of 2 - acetamidodiphenylmethanol II - A prepared in Example 1

[0032] Figure 2 13C NMR spectrum of 2 - acetamidodiphenylmethanol II - A prepared in Example 1

[0033] Figure 3 1H NMR spectrum of 2 - acetamido(p - methylphenyl)benzyl alcohol II - B prepared in Example 2

[0034] Figure 4 13C NMR spectrum of 2 - acetamido(p - methylphenyl)benzyl alcohol II - B prepared in Example 2

[0035] Figure 5 1H NMR spectrum of 2 - acetamido(2,3 - dimethoxyphenyl)benzyl alcohol II - C prepared in Example 3

[0036] Figure 6 13C NMR spectrum of 2 - acetamido(2,3 - dimethoxyphenyl)benzyl alcohol II - C prepared in Example 3 DETAILED DESCRIPTION OF THE INVENTION

[0037] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following examples are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0038] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. The reagents or raw materials used in the present invention can be obtained through conventional channels. Unless otherwise specified, the reagents or raw materials used in the present invention are used in the conventional manner in the art or according to the product instructions. In addition, any methods and materials similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described herein are only for illustrative purposes. The nuclear magnetic resonance in the examples of the present invention was measured by a Bruker 400 or 700M nuclear magnetic resonance spectrometer.

[0039] Example 1: Chiral 2-acetamidodiphenylmethanol II-A was prepared from 2-acetamidobenzophenone I-A as the raw material.

[0040]

[0041] In a glove box, iridium metal (0.001 mmol) and ligand L-1a (0.0011 mmol) were vigorously stirred in methanol (0.001 M) at a molar ratio of 1:1.1 for 1 h. Subsequently, a methanol solution (0.5 M) of 2-acetamidobenzophenone I-A (1 mmol) was added thereto, and then placed in a high-pressure reactor. After purging with hydrogen three times, hydrogen was charged to 3 MPa, and the reaction was carried out at 20 °C for 12 hours. After the reaction was completed, hydrogen was slowly released, the solvent was removed, and the residue was separated by column chromatography to obtain 2-acetamidodiphenylmethanol II-A with a yield of 99% and 99% ee.

[0042] The 1H NMR and 13C NMR spectra of 2-acetamidodiphenylmethanol II-A are as Figure 1 、 Figure 2 shown below: 1 1H NMR (400 MHz, CDCl3): δ 8.62 (s, 1H), 7.89 - 7.05 (m, 9H), 5.80 (s, 1H), 4.26 (s, 1H), 1.84 (s, 3H).; 13 13C NMR (101 MHz, CDCl3): δ 169.0, 141.7, 136.4, 132.9, 128.9, 128.7, 128.4, 127.6, 126.0, 124.4, 123.5, 75.0, 24.2. HRMS (ESI): m / z calcd for C 15 H 16 NO2 [M + H] + : 242.1176, found: 242.1173.

[0043] Example 2: Methanol in Example 1 was replaced with dichloromethane, and the remaining processes and conditions were the same as in Example 1. The reaction gave 2-acetamidodiphenylmethanol II-A with a yield of 99% and 98% ee.

[0044] Example 3: Methanol in Example 1 was replaced with toluene, and the remaining processes and conditions were the same as in Example 1. The reaction gave 2-acetamidodiphenylmethanol II-A with a yield of 99% and 95% ee.

[0045] Example 4: [Ir(COD)Cl]2 in Example 1 was replaced with Ir(COD)2BF4, and the remaining processes and conditions were the same as in Example 1. The reaction gave 2-acetamidodiphenylmethanol II-A with a yield of 99% and 98% ee.

[0046] Example 5 Replace I-A in Example 1 with I-B, and keep the remaining processes and conditions the same as in Example 1.

[0047] The reaction gives 2-acetamido(p-tolyl)benzyl alcohol II-B with a yield of 99% and 99% ee.

[0048]

[0049] The 1H NMR and 13C NMR spectra of 2-acetamido(p-tolyl)benzyl alcohol II-B are as Figure 3 , Figure 4 shown: 1 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 7.93 - 7.04 (m, 8H), 5.78 (s, 1H), 4.06 (s, 1H), 2.31 (s, 3H), 1.87 (s, 3H).; 13 13C NMR (101 MHz, CDCl3): δ 168.9, 138.6, 137.3, 136.5, 132.8, 129.2, 128.8, 128.6, 126.1, 124.3, 123.3, 75.0, 24.3, 21.1.; HRMS (ESI): m / z calcd for C16H18NO2 [M + H] + : 256.1332, found: 256.1337.

[0050] Example 6 Replace I-A in Example 1 with I-C, and keep the remaining processes and conditions the same as in Example 1. The reaction gives chiral 2-acetamido(2,3-dimethoxyphenyl)benzyl alcohol II-C with a yield of 99% and 99% ee.

[0051]

[0052] The 1H NMR and 13C NMR spectra of 2-acetamido(2,3-dimethoxyphenyl)benzyl alcohol II-C are as Figure 5 , Figure 6 shown: 1 1H NMR (700 MHz, CD3OD): δ 7.56 - 6.96 (m, 5H), 6.20 (s, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 3.33 (s, 1H), 2.01 (s, 3H).; 1313C NMR (176 MHz, CD3OD): δ 170.4, 152.6, 145.7, 139.2, 135.8, 133.4, 130.5, 127.0, 126.9, 126.2, 124.0, 118.9, 111.8, 66.1, 59.8, 54.9, 22.2.; HRMS (ESI): m / z calculated for C17H19ClNO4 [M+H] + : 336.0997, found: 334.1003.

[0053] Example 7 Replace I-A in Example 1 with I-D, and the remaining processes and conditions are the same as in Example 1. The reaction gives chiral 2-acetamidophenylethanol II-D in 99% yield and 99% ee.

[0054]

[0055] 2-acetamidophenylethanol II-D. 1 1H NMR (400 MHz, CDCl3): δ 9.18 (s, 1H), 7.98 - 7.03 (m, 4H), 4.90 (q, J = 6.8 Hz, 1H), 3.67 (s, 1H), 2.08 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H).; 13 13C NMR (101 MHz, CDCl3): δ 169.0, 136.4, 133.5, 128.2, 126.7, 124.3, 122.9, 70.2, 24.6, 22.6.; HRMS (ESI): m / z calculated for C 10 H 14 NO2 [M+H] + : 180.1019, found: 180.1026.

[0056] Example 8 Replace I-A in Example 1 with I-E, and the remaining processes and conditions are the same as in Example 1. The reaction gives chiral 2-acetamido-6-chlorophenylbenzyl alcohol II-E in 99% yield and 99% ee.

[0057]

[0058] 2-acetamido-6-chlorophenylbenzyl alcohol II-E. 1 1H NMR (700 MHz, CDCl3): δ 7.49 (s, 1H), 7.34 - 7.14 (m, 8H), 5.86 (s, 1H), 4.33 (s, 1H), 2.04 (s, 3H).; 1313C NMR (176 MHz, CDCl3): δ 170.7, 143.2, 142.2, 132.0, 131.9, 129.1, 128.5, 128.3, 127.8, 127.4, 126.2, 72.1, 23.1.; HRMS (ESI): m / z calcd for C15H15ClNO2 [M+H] + : 276.0786, found: 276.0790.

[0059] Example 9 Replace I-A in Example 1 with I-F, and the remaining processes and conditions are the same as in Example 1. The reaction gives chiral 2-benzamido diphenylmethanol II-F in 99% yield and 99% ee.

[0060]

[0061] 2-benzamido diphenylmethanol II-F. 1 1H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 8.02 - 7.05 (m, 14H), 5.70 (s, 1H), 4.28 (s, 1H), 1.82 (s, 3H).; 13 13C NMR (101 MHz, CDCl3): δ 169.0, 141.7, 137.3, 136.5, 136.4, 132.9, 129.8, 129.0, 128.9, 128.7, 128.4, 127.6, 126.0, 124.4, 123.5, 75.0, 24.2. HRMS (ESI): m / z calcd for C20H18NO2 [M+H] + : 304.1332, found: 304.1333.

[0062] At room temperature, NaOH (4 equiv.) was added to the ethanol solution (0.5 M) of product II-C (1 equiv.), and the reaction solution was refluxed at 80 °C in an oil bath for 10 h. 2-Amino(2,3-dimethoxyphenyl)benzyl alcohol III-C was obtained in 87% yield and 99% ee value, 1 1H NMR (700 MHz, CDCl3): δ 7.33 - 6.62 (m, 7H), 5.78 (s, 1H), 3.91 (s, 1H), 3.83 (s, 3H), 3.70 (s, 3H), 2.89 (s, 1H).; 1313C NMR (176 MHz, CDCl3): δ 144.8, 142.0, 129.0, 128.7, 128.5, 127.6, 127.6, 126.6, 118.4, 117.0, 74.9, 58.8, 54.2. HRMS (ESI): m / z calcd for C15H18NO3 [M+H] + : 260.1281, found: 260.1284. 2-Amino(2,3-dimethoxyphenyl)benzyl alcohol III-C is an intermediate of the drug molecule TAK-457 (Miki, T.; Kori, M.; Mabuchi, H. Tozawa, R.; Nishimoto, T.; Sugiyama, Y.; Teshima, K.; Yukimasa, H. J. Med. Chem. 2002, 45, 4571 - 4580).

[0063]

[0064] The above-described embodiments merely represent the implementation manners of the present invention and are not used to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing chiral 2-acylaminodiphenylmethanol, characterized in that: Using 2-acylaminobenzophenone and hydrogen as raw materials, a hydrogenation reaction occurs under a catalytic system with a complex formed by iridium metal and a phenyl skeleton PNN ligand to produce 2-acylaminodiphenylmethanol; The general structural formula of the PNN ligand is as follows: ； The 2-acylaminobenzophenone compound has the following structure: ； The 2-acylaminodiphenylmethanol compound has the following structure: ； R, R 1 , R 2 are each independently selected from hydrogen, a C1-C 40 alkyl group, a cycloalkyl group having 3 to C 12 carbon atoms in the ring, a phenyl group or a substituted phenyl group, a benzyl group or a substituted benzyl group; the substituents of the phenyl group and the benzyl group are each independently selected from a C1-C 40 alkyl group, a C1-C 40 alkoxy group, a halogen, or one or more of them; R, R 1 , R 2 are the same, or two of them are the same, or they are different groups.

2. According to the synthesis method described in claim 1, characterized in that: R, R 1 , R 2 are each independently selected from one or more of hydrogen, a C1-C 30 alkane group, a cycloalkyl group having 3 to 8 carbon atoms in the ring, a phenyl group and a substituted phenyl group, a benzyl group and a substituted benzyl group; the substituents of the phenyl group and the benzyl group are each independently selected from one or more of a C1-C 30 alkane group, a C1-C 30 alkoxy group, and a halogen.

3. The synthesis method according to claim 2, characterized in that: R, R 1 , R 2 are each independently selected from one or more of hydrogen, C1-C6 alkane groups, C3-C6 cycloalkyl groups with 3 to 6 carbon atoms in the ring, phenyl and substituted phenyl, benzyl and substituted benzyl; the substituents of the phenyl and benzyl are each independently selected from one or more of C1-C6 alkyl groups, C1-C6 alkoxy groups, and halogens.

4. The synthesis method according to claim 1, characterized in that: The reaction is carried out in the presence of a reaction medium, and the reaction medium is at least one or more of toluene, benzene, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide.

5. The synthesis method according to claim 1, characterized in that: The molar ratio of the 2-acylaminobenzophenone to the catalyst Ir / L-1a is 100 - 50000:

1.

6. The synthesis method according to claim 5, characterized in that: The molar ratio of the 2-acylaminobenzophenone to the catalyst Ir / L-1a is 100 - 5000:

1.

7. The synthesis method according to claim 6, characterized in that: The molar ratio of the 2-acylaminobenzophenone to the catalyst Ir / L-1a is 100 - 1000:

1.

8. The synthesis method according to any one of claims 1-7, characterized in that: The specific process of this method is as follows: Iridium metal and the PNN ligand with a phenyl skeleton are stirred in a reaction medium at a molar ratio of 1:1.1 - 1:2.2 for 0.5 - 1 hour. Subsequently, the reaction medium solution of 2-acylaminobenzophenone is added thereto, and it is placed in a high-pressure reaction kettle, purged with hydrogen, and hydrogen is charged to 3 - 5 MPa. The reaction is carried out at 20 - 60 °C for 1 - 24 hours. After cooling to room temperature, the hydrogen is released, the solvent is removed, and 2-acylaminodiphenylmethanol is separated.

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