A method for the highly selective preparation of 2-alkylpyridine derivatives

Abstract

The application relates to a method for preparing 2-alkyl pyridine derivatives with high selectivity, which comprises the following steps: forming a cyclopropyl titanium reagent by an alkyl Grignard reagent and a titanate, or forming a cyclopropyl titanium reagent by an olefin, a titanate and an ethyl or propyl Grignard reagent, reacting the cyclopropyl titanium reagent with a pyridine N-oxide in a solvent, and adding an electrophilic reagent in situ to obtain 2-alkylated pyridine derivatives. The method has the advantages that 2-alkyl pyridine derivatives can be prepared with high chemical selectivity and high regioselectivity; the reaction is completed in one pot; the transition metal Ti used is a cheap metal with high abundance and low toxicity; the conditions are mild; various sensitive functional groups can be tolerated; the method has high regioselectivity; the method is suitable for a wide range of applications; and the method is easy to scale up.

Description

Technical Field

[0001] This invention relates to the field of heterocyclic compound and drug synthesis, specifically to a method for synthesizing pyridine heterocyclic compounds and related bioactive substances, and more specifically to a method for highly selectively preparing 2-alkylpyridine derivatives. Background Technology

[0002] Nitrogen-containing heterocycles are the most common structural units in drug molecules [Vitaku, E. et al. J. Med. Chem. 2014, 57, 10257]. Furthermore, pyridine molecular skeletons have very wide applications in natural products, pesticides, materials science, and catalyst ligands; many 2-alkylpyridine alkaloids or derivatives possess important biological activities. As shown in the structural formula below, muscopyridine (I) is a natural product isolated from musk and can be used in fragrances, etc. [Biemann, K. et al. J. Am. Chem. Soc. 1957, 79, 5558]. Nicotinic acid derivative (II) is extracted from Tripterygium wilfordii and possesses anti-inflammatory, antiplatelet aggregation, and immunosuppressive activities [Guo Yanlei et al., CN112321502A (2021)]. Compound (III) exhibits excellent antitumor activity [Balzarini, J. et al. Invest New Drugs, 2014, 32, 200]; while compound (IV) exhibits inhibitory activity against factor 10 and is expected to become an anticoagulant [Corte, JR; Li, YLUS20060074103A1].

[0003]

[0004] Due to the wide range of applications and important biological activities of 2-alkylpyridine natural products and related derivatives, the efficient synthesis of these compounds has always been an important topic in organic synthesis. Pyridine heterocycles are a typical class of electron-deficient aromatic rings, making the introduction of alkyl groups or halogens through classical electrophilic substitution extremely difficult. Furthermore, the complexing behavior of the N-atom in pyridine and the different electron cloud densities at different positions on the ring (e.g., 2, 3, 4-positions) present significant regioselectivity challenges when introducing the desired group. Besides the introduction of alkyl groups via coupling with 2-halopyridine, methods for introducing alkyl groups via the CH bond at the 2-position of the pyridine ring generally fall into two main categories (see the schematic reaction formulas below): one is Minisci-type alkylation involving the alkyl free radical (R·) (Proctor, RSJ; Phipps, RJ Angew. Chem. Int. Ed. 2019, 58, 13666); the other is addition and elimination (de-G process) alkylation of pyridine N-derived compounds with nucleophiles (RM).

[0005]

[0006] Although the Minisci reaction can utilize a variety of free radical precursors, traditional reaction conditions are often harsh, requiring strong oxidants and Ag salt catalysis, which is not conducive to scale-up production. Furthermore, these reactions face the insurmountable challenge of C2 / C4 regioselectivity. In the second type of reaction, metal reagents with poor tolerance to functional groups are often required, and subsequent removal of the nitrogen functional group (G) also necessitates specialized reactions and procedures (Andersson, H. et al. Org. Lett. 2007, 9, 1335). In recent years, there have been reports of alkylation using bisborone reagents and quaternary phosphine salts with pyridine N-oxides under strong base (t-BuOK or MeONa) at high temperatures (Jo, W. et al. Angew. Chem. Int. Ed. 2016, 55, 9690; Han, S. et al. Angew. Chem. Int. Ed. 2018, 57, 12737). However, besides the limited availability of starting materials (such as bisborone reagents), the high temperature and strong base conditions prevent substrates with base-sensitive groups from participating in the reaction. Furthermore, for 3-substituted pyridine derivatives, C2 / C4 regioselectivity remains a challenge. Summary of the Invention

[0007] The purpose of this invention is to overcome the defects in existing technologies for preparing 2-alkylpyridine derivatives, such as: (1) the chemoselectivity during alkylation using metal reagents, i.e., the functional group tolerance problem; (2) the C2 / C4 regioselectivity that is difficult to overcome in Minisci-type reactions; and (3) the C2 / C4 regioselectivity problem during the alkylation of 3-substituted pyridine derivatives; thereby providing a method for preparing various 2-alkylpyridine derivatives that has a wide range of applications, does not require precious metals, and has high chemoselectivity and regioselectivity.

[0008] To achieve the above objectives, this invention employs a novel technical solution to achieve high chemoselectivity and high regioselectivity in the preparation of 2-alkylpyridine derivatives, the method comprising:

[0009] The cyclopropanetitanium reagent (Kulinkovich reagent) formed by alkyl Grignard reagents with titanates or olefins with titanates and ethyl or propyl Grignard reagents reacts with pyridine N-oxides, and an electrophilic reagent is added in situ to react and give 2-alkylated pyridine derivatives.

[0010] The reaction mechanism of the method described in this invention is shown in the following equation:

[0011]

[0012] Preferably, the alkyl Grignard reagent includes various alkyl magnesium halides containing two or more carbons with β-H.

[0013] Preferably, the titanate comprises Ti(OR)4; wherein R = alkyl groups with 1 to 4 carbons.

[0014] Preferably, the olefin is any olefin with four or more carbon atoms.

[0015] Preferably, the pyridine N-oxide is pyridine or substituted pyridine, quinoline or substituted quinoline, isoquinoline or substituted isoquinoline, pyridazine or substituted pyridazine, benzopyridazine or substituted benzopyridazine, pyrazine or substituted pyrazine, benzopyrazine or substituted benzopyrazine; the substituent of the substituted aryl group is one or more of alkyl, alkoxy, halogen, phenyl, ketone, ester, cyano, and amide groups.

[0016] Preferably, the electrophilic reagent is water, heavy water, carbon dioxide, aldehyde, acyl chloride, or isocyanate.

[0017] Preferably, the solvent is tetrahydrofuran, diethyl ether, or a mixture of tetrahydrofuran and toluene, or diethyl ether and toluene.

[0018] Preferably, the molar ratio of the alkyl Grignard reagent, titanate, pyridine N-oxide, and electrophilic reagent is 2.0–3.0: 1.0–2.0: 1.0: 1.0–2.0; and the molar ratio of the olefin, titanate, ethyl or propyl Grignard reagent, pyridine N-oxide, and electrophilic reagent is 1.0–1.5: 1.0–2.0: 2.0–3.0: 1.0: 1.0–2.0.

[0019] Preferably, the reaction temperature of the cyclopropanetitanium reagent with pyridine N-oxide is -20 to 25°C; the subsequent reaction temperature with the electrophilic reagent is -20 to 25°C.

[0020] Previous methods for introducing alkyl groups at the 2-position of the pyridine ring via CH bonds often employed Minisci reactions involving alkyl free radicals and addition reactions of N-functionalized pyridine derivatives with metal reagents. These methods not only have limitations in chemoselectivity (functional group tolerance) but also face significant challenges in regioselectivity at C2 / C4 and C2 / C6. The alkylation method in this invention achieves a highly feasible process route through breakthroughs in reaction type and innovation in reaction mechanism. Through careful design, continuous summarization, and repeated exploration, a new mechanism and measures were proposed: for the first time, two easily prepared reagents—Kulinkovich reagent and pyridine N-oxides—were combined, resulting in a completely novel alkylation reaction. The alkylation of this invention is tolerant to sensitive groups such as esters, amides, ketone carbonyls, and halogens, exhibiting high chemoselectivity; moreover, it exhibits dual regioselectivity: on the pyridine ring, for any 3-substituted pyridine N-oxide, alkylation occurs at the 6-position; with cyclopropanetitanium reagents, the less sterically hindered end attacks the pyridine ring (see reaction mechanism). Importantly, both C-Ti bonds in the cyclopropanetitanium reagent can participate in the reaction to form two new chemical bonds; that is, the less sterically hindered end forms a C-C bond with the pyridine ring, and the more sterically hindered end forms an E-C bond with the pyridine ring. + The formation of CE bonds (see reaction mechanism) is a breakthrough and innovation not only in introducing complex alkyl groups with functional groups onto pyridine, but also in terms of Kulinkovich reagents.

[0021] The novel synthetic method for preparing 2-alkylpyridine derivatives provided by this invention has the following advantages:

[0022] 1) It has high chemoselectivity and regioselectivity.

[0023] 2) The transition metal Ti used is abundant and inexpensive in the Earth's crust, and has low toxicity; it is also biocompatible.

[0024] 3) Multi-step reactions are carried out in one pot, without the need for intermediate separation. The conditions are mild, easy to scale up, and suitable for industrial production.

[0025] 4) Wide range of applications, atom economy, and low cost. Detailed Implementation

[0026] The present invention will be further described in detail below with reference to the embodiments, but it should be noted that the present invention is not limited to the following embodiments.

[0027] Example 1: Preparation of 6-phenylethyl nicotinic acid ethyl ester (Method 1)

[0028]

[0029] Under nitrogen protection, Ti(OPr) was added to a dry reaction flask. i 4 (1776 mg, 6.25 mmol) and 10 mL tetrahydrofuran were added dropwise to ethyl magnesium bromide (10 mL, 1 M, 10.0 mmol) solution and styrene (521 mg, 5 mmol) at -10 °C. After stirring at this temperature for half an hour, 3-(ethoxycarbonyl)pyridine nitride (836 mg, 5 mmol) was added. The mixture was then slowly brought back to room temperature and stirred until the reaction was complete (TLC monitoring, approximately 3-4 hours).

[0030] The reaction was terminated by adding 20 mL of deionized water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 79%.

[0031] The product is a light yellow oil. 1 H NMR (CDCl3, 400MHz) δ (ppm) 9.16 (s), 8.15 (dd, J = 8.0, 2.0Hz), 7.28 (s), 7.25–7.11 (m), 4.40 (q, J = 7.1Hz), 3.16 (dd, J = 8.5, 6.0Hz), 3.11–3.05 (m), 1.40 (t, J = 7.1Hz); 13 C NMR (CDCl3, 100MHz) δ (ppm) 164.7, 164.5, 149.6, 140.1, 136.6, 127.6, 125.2, 123.2, 121.8, 60.4, 39.3, 34.7, 13.4; HRMS calcd for C 16 H 18 NO2 + [M+H] + 256.1337, Found 256.1334.

[0032] Example 2: Preparation of 6-phenylethyl nicotinic acid ethyl ester (Method 2)

[0033]

[0034] Under nitrogen protection, Ti(OBu)4 (2127 mg, 6.25 mmol) and 10 mL of diethyl ether were added to a dry reaction flask. Isopropyl magnesium bromide (10 mL, 1 M, 10.0 mmol) solution and styrene (521 mg, 5 mmol) were added dropwise at 0 °C. After stirring at this temperature for half an hour, 3-(ethoxycarbonyl)pyridine nitride (836 mg, 5 mmol) was added. The mixture was then slowly brought to room temperature and stirred until the reaction was complete (TLC monitoring, approximately 3 hours).

[0035] The reaction was terminated by adding 20 mL of deionized water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 75%.

[0036] Example 3: Preparation of 6-phenylethyl nicotinic acid ethyl ester (Method 3)

[0037] Under nitrogen protection, Ti(OEt)4 (1425 mg, 6.25 mmol) and 10 mL of toluene were added to a dry reaction flask. Isopropyl magnesium bromide (10 mL, 1 M, 10.0 mmol) solution and styrene (521 mg, 5 mmol) were added dropwise at 10 °C. After stirring at this temperature for half an hour, 3-(ethoxycarbonyl)pyridine nitride (836 mg, 5 mmol) was added. The mixture was then slowly brought to room temperature and stirred until the reaction was complete (TLC monitoring, approximately 3 hours).

[0038] The reaction was terminated by adding 20 mL of deionized water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 73%.

[0039] Example 4 Preparation of 2-chloro-6-(2-methylpropyl-2-deuterium)pyridine

[0040]

[0041] Under nitrogen protection, Ti(OPr) was added to a dry reaction flask. i 4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise to a solution of isobutylmagnesium bromide (10 mL, 1 M, 10.0 mmol) at -10 °C. After stirring at this temperature for half an hour, 2-chloropyridine nitrogen oxides (648 mg, 5 mmol) were added. The mixture was then slowly brought to room temperature and stirred until the reaction was complete (TLC monitoring, approximately 3-4 hours).

[0042] The reaction was terminated by adding 20 mL of deuterium water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 77% (98% D-incorp).

[0043] The product is a light yellow oil. 1 H NMR (CDCl3, 400Hz) δ (ppm) 7.52 (td, J = 7.8, 1.6Hz), 7.12 (dd, J = 7.9, 1.3Hz), 7.02–6.99 (m), 2.60 (s), 0.90 (s); 13C NMR (CDCl3, 100MHz) δ (ppm) 162.8, 150.7, 138.7, 122.0, 121.5, 47.2, 29.4, 29.1, 28.9 (t, J = 24.7Hz), 22.4; HRMScalcd for C9H 12 DClN + [M+H] + 171.0799, Found 171.0796.

[0044] Example 5 Preparation of 1,2-diphenyl-3-(pyridin-2-yl)prop-1-ol

[0045]

[0046] Under nitrogen protection, Ti(OPr) was added to a dry reaction flask. i 4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise to a solution of ethyl magnesium bromide (10 mL, 1 M, 10.0 mmol) and styrene (521 mg, 5 mmol) at -10 °C. After reacting at this temperature for half an hour, pyridine nitride (476 mg, 5 mmol) was added, and the mixture was stirred until the reaction was complete (TLC monitoring, approximately 4 hours). Then, benzaldehyde (584 mg, 5.5 mmol) was weighed and added to the above system, and the mixture was brought to room temperature and stirred until the reaction was complete (TLC monitoring, approximately 4 hours).

[0047] The reaction was terminated by adding 20 mL of deionized water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 82%.

[0048] The product is a yellow oil. 1 H NMR (CDCl3, 400Hz) δ (ppm) 8.48 (d, J = 4.6Hz), 7.50 (d, J = 7.7Hz), 7.21–7.09 (m), 7.00 (d, J = 7 .7Hz),4.92(d,J=5.5Hz),4.16(d,J=6.7Hz),3.59–3.52(m),3.36–3.27(m),3.14–3.06(m); 13 C NMR (CDCl3, 100MHz) δ (ppm) 159.7, 148.1, 142.1, 140.4, 137.0, 129.1, 129.0, 128.1, 127.9, 127.3, 126.7, 124.1, 121.4, 69.4, 53.2, 40.0.

[0049] Example 6 Preparation of 2-(4-(ethoxycarbonyl)phenyl)-3-(pyridin-2-yl)propionic acid

[0050]

[0051] Under nitrogen protection, Ti(OPr) was added to a dry reaction flask. i 4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise to a solution of ethyl magnesium bromide (10 mL, 1 M, 10.0 mmol) and ethyl 4-vinylbenzoate (881 mg, 5 mmol) at -10 °C. After stirring at this temperature for half an hour, pyridine oxide (476 mg, 5 mmol) was added, and the mixture was stirred at this temperature until the reaction was complete (TLC monitoring, approximately 4 hours). Sufficient CO2 gas was then introduced into the above system, and the mixture was brought to room temperature and stirred until the reaction was complete (TLC monitoring, approximately 6 hours).

[0052] The reaction was terminated by adding 20 mL of deionized water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 70%.

[0053] The product is a yellow oil. 1 H NMR (CDCl3, 400Hz) δ (ppm) 8.50 (d, J = 3.2Hz), 7.96 (d, J = 5.0Hz), 7.63–7.57 (m), 7.2 0–7.15(m),4.36(q,J=7.2Hz),4.10(t,J=5.2Hz),3.49–3.30(m),1.53(t,J=7.1Hz); 13 C NMR (CDCl3, 100MHz) δ (ppm) 177.3, 166.5, 160.5, 148.3, 137.2, 136.2, 131.1, 129.9, 127.5, 121.5, 121.0, 61.2, 52.4, 35.2, 14.5; HRMS calcd forC 17 H 18 NO4 + [M+H] + 300.1236, Found 300.1232.

[0054] Example 7 Preparation of 3-(5-methoxypyridin-2-yl)-N,2-diphenylpropionamide

[0055]

[0056] Under nitrogen protection, Ti(OPr) was added to a dry reaction flask. i4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise to a solution of ethyl magnesium bromide (10 mL, 1 M, 10.0 mmol) and styrene (521 mg, 5 mmol) at -10 °C. After stirring at this temperature for half an hour, 3-methoxypyridine N-oxide (626 mg, 5 mmol) was added, and the mixture was stirred until the reaction was complete (TLC monitoring, approximately 4 hours). PhNCO (655 mg, 5.5 mmol) was then added at room temperature, and the mixture was stirred until the reaction was complete (TLC monitoring, approximately 4 hours).

[0057] The reaction was terminated by adding 20 mL of deionized water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 73%.

[0058] The product is a light-colored oil. 1 H NMR(CDCl3,400Hz)δ(ppm)8.82(s),8.02(s),7.47–7.44(m),7.34–7.27(m ),7.25–7.15(m),4.18–4.14(m),3.95(s),3.11–3.06(m),3.04–3.00(m); 13 CNMR(CDCl3,100MHz)δ(ppm)171.6,154.2,152.4,139.3,136.7,132.7,131 .1,129.1,128.6,128.0,125.3,124.4,122.8,121.5,53.7,49.2,38.6; HRMS calcd for C 21 H 21 N2O2 + [M+H] + 333.1603, Found 333.1604.

[0059] Example 8 Preparation of ethyl 4-(3-(6-cyanopyridin-2-yl)-1-oxo-1-phenylprop-2-yl)benzoate

[0060]

[0061] Under nitrogen protection, Ti(OPr) was added to a dry reaction flask. i4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise to a solution of ethyl magnesium bromide (10 mL, 1 M, 10.0 mmol) and ethyl 4-vinylbenzoate (881 mg, 5 mmol) at -10 °C. After reacting at this temperature for half an hour, 2-cyanopyridine nitride (601 mg, 5 mmol) was added, and the mixture was stirred until the reaction was complete (TLC monitoring, approximately 4 hours). The system was then cooled to -20 °C, and CuCN·2LiCl (960 mg, 5.5 mmol) and benzoyl chloride (772 mg, 5.5 mmol) were added. The reaction was then stirred until complete (TLC monitoring, approximately 4 hours).

[0062] The reaction was terminated by adding 20 mL of deionized water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 76%.

[0063] The product is a light-colored oil. 1 H NMR (CDCl3, 400Hz) δ (ppm) 8.09 (d, J = 5.3Hz), 8.01–7.96 (m), 7.7–7.74 (m), 7.65–7.62 (m), 7.59–7.57 (m), 7.54–7.5 1 (m), 4.73 (t, J = 5.2Hz), 4.46 (q, J = 7.2Hz), 3.62 (dd, J = 10.6, 5.1Hz), 3.47 (dd, J = 10.6, 5.2Hz), 1.38 (t, J = 7.2Hz); 13 CNMR(CDCl3,100MHz)δ(ppm)201.9,166.4,164.3,142.4,138.1,133.0,131.4,131.3, 130.2,130.0,129.4,129.2,129.2,128.1,126.9,118.1,61.2,52.1,38.6,14.4.; HRMS calcd forC 24 H 21 N2O3 + [M+H] + 385.1552, Found 385.1556.

[0064] Example 9 Preparation of cyazofamid derivative (I)

[0065]

[0066] Under nitrogen protection, Ti(OPr) was added to a dry reaction flask. iAdd 4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran, and add ethyl magnesium bromide (10 mL, 1 M, 10.0 mmol) solution dropwise at -10 °C. After stirring for half an hour, add boscalid nitrogen oxides (1796 mg, 5 mmol), slowly restore to room temperature, and stir until the reaction is complete (TLC monitoring, about 4 hours).

[0067] The reaction was terminated by adding 20 mL of deionized water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 71%.

[0068] The product is a light-colored oil. 1 H NMR (CDCl3, 400Hz) δ (ppm) 8.42 (d, J = 8.5Hz), 8.31 (s), 8.17 (d, J = 8.3Hz), 7.4 9–7.44(m),7.35(t,J=5.5Hz),7.27(s),2.88(q,J=7.1Hz),1.30(t,J=7.0Hz); 13 C NMR(CDCl3,100MHz)δ(ppm)171.2,160.9,147.7,143.2,137.1,134.1,134.0,1 32.4,130.4,130.3,128.7,128.0,127.2,122.6,121.5,118.6,28.9,12.9; HRMS calcdfor C 20 H 17 Cl2N2O + [M+H] + 371.0718, Found 371.0716.

[0069] Example 10 Preparation of cytotoxic dimethoprim derivative (II)

[0070]

[0071] Under nitrogen protection, Ti(OPr) was added to a dry reaction flask. i Add 1776 mg (6.25 mmol) and 10 mL of tetrahydrofuran, and add 10 mL of ethyl magnesium bromide (10 mL, 1 M, 10.0 mmol) solution dropwise at -10 °C. After stirring for half an hour, add boscalid nitrogen oxides (1796 mg, 5 mmol), slowly restore to room temperature, and stir until the reaction is complete (TLC monitoring, approximately 3 hours). Then, introduce sufficient CO2 gas into the above system and stir until the reaction is complete (TLC monitoring, approximately 6 hours).

[0072] The reaction was terminated by adding 20 mL of deionized water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 62%.

[0073] The product is a yellow oil. 1 H NMR (CDCl3, 400Hz) δ (ppm) 8.42 (d, J = 8.4Hz), 8.32 (s), 8.12 (d, J = 8.3Hz), 7.51–7 .44(m),7.38–7.33(m),7.26(d,J=2.8Hz),3.13(t,J=3.7Hz),2.69(t,J=3.6Hz); 13 C NMR (CDCl3, 100MHz) δ (ppm) 177.7, 172.1, 162.9, 145.4, 140.3, 137.0, 133.9, 133. 9,132.3,130.2,130.1,128.6,127.8,127.0,124.0,122.4,118.5,35.2,28.9; HRMS calcd for C 21 H 17 Cl2N2O3 + [M+H] + 415.0616, Found 415.0613.

[0074] Example 11 Preparation of loratadine derivative (I)

[0075]

[0076] Under nitrogen protection, Ti(OPr) was added to a dry reaction flask. i 4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise to a solution of ethyl magnesium bromide (10 mL, 1 M, 10.0 mmol) and ethyl butyrate (571 mg, 5 mmol). After stirring at -10 °C for half an hour, loratadine oxynitrate (1994 mg, 5 mmol) was added and the mixture was stirred until the reaction was complete (TLC monitoring, approximately 4 hours).

[0077] The reaction was terminated by adding 20 mL of deionized water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 62%.

[0078] The product is a yellow oil. 1H NMR(CDCl3,400Hz)δ(ppm)7.36–7.30(m),7.18(dd,J=5.7,1.5Hz),7.03(d,J=1.3Hz),4.13–4.06(m),3.43(dd,J=5.1,3.5 Hz),3.08(t,J=6.0Hz),2.66(t,J=4.8Hz),2.55(td,J=4.3,1.5Hz),2.45(t,J=4.8Hz),1.74(p,J=4.5Hz),1.24–1.18(m); 13 C NMR(CDCl3,100MHz)δ(ppm)169.2,166.4,155.1,154.8,142.4,138.1,136.4,133.0,131.4,130.2,12 8.1,126.1,118.5,62.1,61.2,45.4,36.7,31.9,31.9,31.1,30.7,28.4,28.3,26.6,14.4,14.3; HRMS calcd for C 28 H 34 ClN2O4 + [M+H] + 497.2207,Found497.2201.

[0079] Example 12 Preparation of loratadine derivative (II)

[0080]

[0081] Under nitrogen protection, Ti(OPr) was added to a dry reaction flask. i 4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise to a solution of ethyl magnesium bromide (10 mL, 1 M, 10.0 mmol) and ethyl butyrate (571 mg, 5 mmol). After stirring at -10 °C for half an hour, loratadine oxynitride (1994 mg, 5 mmol) was added, and the mixture was stirred until the reaction was complete (TLC monitoring, approximately 4 hours). The system was then cooled to -20 °C, and CuCN·2LiCl (960 mg, 5.5 mmol) and benzoyl chloride (772 mg, 5.5 mmol) were added. The reaction was then incubated until complete (TLC monitoring, approximately 4 hours).

[0082] The reaction was terminated by adding 20 mL of deionized water to the system. The product was extracted with dichloromethane, the extracts were combined, dried, and the dichloromethane was recovered to obtain the crude product. The product was purified by column chromatography with a yield of 69%.

[0083] The product is a light-colored oil. 1H NMR(CDCl3,400Hz)δ(ppm)7.97(d,J=5.7Hz),7.65–7.63(m),7.52–7.48(m),7.27–7.19(m),7.18–7.15(m),6.96(s),4.48(td,J=4.3 ,1.5Hz),4.11(q,J=7.0Hz),3.51(t,J=7.2Hz),3.37–3.15(m),2.89–2.81(m),2.76–2.68(m),2.57(t,J=7.2Hz),1.34(t,J=7.2Hz); 13 C NMR(CDCl3,100MHz)δ(ppm)199.7,164.3,155.1,154.8,143.0,142.4,140.1,138.6,138.1,136.4,134.3,134.2,133.0, 132.3,131.4,130.9,130.2,130.1,128.1,126.0,118.5,61.2,53.1,45.4,42.2,37.0,31.9,31.9,31.1,30.7,14.4; HRMS calcd for C 37 H 36 ClN2O3 + [M+H] + 591.2414, Found 591.2411.

[0084] The method for highly selective preparation of 2-alkylpyridine derivatives described in this invention was also used for the synthesis of the following compounds, the details of which will not be elaborated further:

[0085]

[0086]

[0087]

[0088]

[0089] The upper and lower limits of the process parameters (such as temperature, time, etc.) and the range values ​​of the present invention can all achieve the method, and examples are not listed here.

[0090] All aspects not described in detail in this invention can be covered using conventional technical knowledge in the field.

[0091] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to the embodiments, those skilled in the art should understand that modifications or equivalent substitutions to the technical solutions of the present invention do not depart from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for highly selectively preparing 2-alkylpyridine derivatives, the method comprising: Cyclopropane reagent The reaction with pyridine N-oxide in a solvent, followed by in-situ addition of an electrophilic reagent, yields 2-alkylated pyridine derivatives; The cyclopropanetitanium reagent is an alkyl Grignard reagent. Forms with titanate esters; or the cyclopropanetitanium reagent is composed of olefins. Formed from titanate and ethyl Grignard reagent; or the cyclopropanetitanium reagent is composed of olefins. Formed by titanate and propyl Grignard reagent; The alkyl Grignard reagent It is an alkyl magnesium halide containing two or more carbons with β-H, wherein R L R indicates a sterically hindered group. S Indicates a group with relatively small steric hindrance; The titanate is Ti(OR)4; wherein R = alkyl group with 1 to 4 carbons; The olefins Alkenes with four or more carbons, wherein R L R indicates a sterically hindered group. S Indicates a group with relatively small steric hindrance; The electrophilic reagent is water, heavy water, or carbon dioxide.

2. The method for highly selectively preparing 2-alkylpyridine derivatives according to claim 1, characterized in that, The solvent is one or a mixture of at least two of tetrahydrofuran, toluene, and diethyl ether.

3. The method for highly selectively preparing 2-alkylpyridine derivatives according to claim 1, characterized in that, The molar ratio of the alkyl Grignard reagent, titanate, pyridine N-oxide, and electrophilic reagent is 2.0 ~ 3.0 : 1.0 ~ 2.0 : 1.0 : 1.0 ~ 2.0; the molar ratio of the olefin, titanate, ethyl or propyl Grignard reagent, pyridine N-oxide, and electrophilic reagent is 1.0 ~ 1.5 : 1.0 ~ 2.0 : 2.0 ~ 3.0 : 1.0 : 1.0 ~ 2.

0.

4. The method for highly selectively preparing 2-alkylpyridine derivatives according to claim 1, characterized in that, The reaction temperature of the cyclopropanetitanium reagent with pyridine N-oxide is -20 to 25 °C; the subsequent reaction temperature with the electrophilic reagent is -20 to 25 °C.

Images