Method for preparing 2-alkyl pyridine derivative with high selectivity

Abstract

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

Description

Technical Field

[0001] The present invention relates to the field of heterocyclic compounds and drug synthesis, and in particular to a method for synthesizing pyridine heterocyclic compounds and related bioactive substances, and more particularly to a method for preparing 2-alkylpyridine derivatives with high selectivity. Background Art

[0002] Nitrogen-containing heterocycles are the most common structural units in drug molecules [Vitaku, E. et al. J. Med. Chem. 2014, 57, 10257]. In addition, pyridine molecular skeletons are also widely used in natural products, pesticides, materials science and catalyst ligands; many of the 2-alkylpyridine alkaloids or derivatives have important biological activities. As shown in the following structural formula, musk pyridine (I, Muscopyridine) is a natural product isolated from musk and can be used in spices, etc. [Biemann, K. et al. J. Am. Chem. Soc. 1957, 79, 5558]. Nicotinic acid derivatives (II) are extracted from Tripterygium wilfordii and have anti-inflammatory, anti-platelet aggregation and immunosuppressive activities [Guo Yanlei et al., CN112321502A (2021)]. Compound (III) has excellent anti-tumor activity [Balzarini, J. et al. Invest New Drugs, 2014, 32, 200]; while compound (IV) has the activity of inhibiting factor X and is expected to become an anticoagulant drug [Corte, JR; Li, YLUS20060074103A1].

[0003]

[0004] Due to the wide range of uses and important biological activities of 2-alkylpyridine natural products and related derivatives, the efficient synthesis of such compounds has always been an important topic in organic synthesis. Pyridine heterocycles are typical electron-deficient aromatic rings, so it is very difficult to introduce alkyl or halogen groups through classical electrophilic substitution. At the same time, due to the complexing behavior of the pyridine N-atom and the different electron cloud densities at different positions on the ring (such as 2, 3, and 4), there are obvious regioselectivity challenges when introducing the desired group. In addition to the introduction of alkyl groups through the coupling of 2-halopyridines, there are generally two major methods for introducing alkyl groups through the 2-CH bond of the pyridine ring in the literature (see the schematic reaction formula below): one is the Minisci-type alkylation involving alkyl free radicals (R·) (Proctor, RSJ; Phipps, RJAngew.Chem.Int.Ed.2019,58,13666); the other is the addition and elimination (G removal process) type alkylation of pyridine N-derivatives with nucleophiles (RM).

[0005]

[0006] Although the Minisci reaction can use a variety of free radical precursors, the traditional reaction conditions are often severe, requiring strong oxidants and Ag salt catalysis, which is not conducive to scale-up production. In addition, in this type of reaction, there is an insurmountable problem of C2 / C4 regioselectivity. In the second type of reaction, it is often necessary to use metal reagents with poor tolerance to functional groups, and the subsequent removal of the functional group (G) on N also requires special reactions and operations (Andersson, H. et al. Org. Lett. 2007, 9, 1335). In recent years, there have been reports of alkylation using diboron reagents and quaternary phosphonium salts with pyridine N-oxides in the presence of strong bases (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, in addition to the limited source of raw materials (such as diboron reagents), the high temperature and strong base conditions prevent substrates with base-sensitive groups from participating in the reaction. In addition, for 3-substituted pyridine derivatives, C2 / C4 regioselectivity has always been a difficult problem to face. Summary of the invention

[0007] The purpose of the present invention is to overcome the defects in the existing technology for preparing 2-alkylpyridine derivatives, such as: (1) chemical selectivity in the alkylation process using metal reagents, i.e., the problem of functional group tolerance; (2) the C2 / C4 regioselectivity that is difficult to overcome in Minisci-type reactions; (3) the problem of C2 / C4 regioselectivity in the alkylation of 3-substituted pyridine derivatives; thereby providing a method for preparing various 2-alkylpyridine derivatives with a wide range of uses, no need for precious metals, and high chemical and regioselectivity.

[0008] To achieve the above object, the present invention adopts a new technical solution to achieve high chemical selectivity and high regioselectivity in the preparation of 2-alkylpyridine derivatives, the method comprising:

[0009] The cyclopropanetitanium reagent [Kulinkovich reagent] formed by an alkyl Grignard reagent and titanate or an olefin and titanate and an ethyl or propyl Grignard reagent reacts with pyridine N-oxides, and an electrophilic reagent is added in situ to react and obtain a 2-alkylated pyridine derivative.

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

[0011]

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

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

[0014] Preferably, the olefins are various olefins 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 aromatic group is one or more of alkyl, alkoxy, halogen, phenyl, keto, ester, cyano, and amide.

[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; 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 cyclopropenetitanium reagent and pyridine N-oxide is -20 to 25°C; and the subsequent reaction temperature with the electrophilic reagent is -20 to 25°C.

[0020] The previous methods often use Minisci reaction involving alkyl free radicals and addition of N-functionalized pyridine derivatives with metal reagents to introduce alkyl groups at the 2-position of the pyridine ring through a CH bond. These methods not only have certain limitations in chemical selectivity (functional group tolerance), but also face insurmountable challenges in the regioselectivity of C2 / C4 and C2 / C6. The alkylation method of the present invention is a process route with strong feasibility through breakthroughs in reaction types and innovations in reaction mechanisms. After careful design, continuous summarization and repeated exploration, new mechanisms and measures are proposed, namely, for the first time, two easily prepared reagents, Kulinkovich reagent, are combined with pyridine N-oxides. The present invention realizes a new alkylation reaction. The alkylation of the present invention can tolerate sensitive groups such as ester groups, amides, ketone carbonyl groups, halogens, etc., and exhibits high chemical selectivity; it also exhibits dual regioselectivity: on the pyridine ring, for any 3-substituted pyridine N-oxide, alkylation occurs at the 6-position; in the case of the cyclopropanetitanium reagent, the end with less steric hindrance 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 end with less steric hindrance forms CC with the pyridine ring, and the end with greater steric hindrance forms E + Forming a CE bond (see reaction mechanism). This not only allows the introduction of complex alkyl groups with functional groups on pyridine, but is also a breakthrough and innovation for Kulinkovich reagent.

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

[0022] 1) High chemical selectivity and regioselectivity

[0023] 2) The transition metal Ti used is abundant in the earth's crust, cheap, low in toxicity, and biocompatible.

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

[0025] 4) Wide application range, atomic economy and low cost. DETAILED DESCRIPTION

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

[0027] Example 1 Preparation of 6-phenylethyl nicotinate (method 1)

[0028]

[0029] Under nitrogen protection, Ti(OPr i )4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise at -10 °C with ethylmagnesium bromide (10 mL, 1 M, 10.0 mmol) solution and styrene (521 mg, 5 mmol). After stirring for half an hour, 3-(ethoxycarbonyl)pyridine nitrogen oxide (836 mg, 5 mmol) was added. The mixture was slowly returned to room temperature and stirred until the reaction was complete (TLC tracking, about 3-4 hours).

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

[0031] The product is 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 nicotinate (Method 2)

[0033]

[0034] Under nitrogen protection, Ti(OBu)4 (2127 mg, 6.25 mmol) and 10 mL of ether were added to a dry reaction bottle, and isopropylmagnesium bromide (10 mL, 1M, 10.0 mmol) solution and styrene (521 mg, 5 mmol) were added dropwise at 0°C. After stirring for half an hour, 3-(ethoxycarbonyl)pyridine nitrogen oxide (836 mg, 5 mmol) was added, and the temperature was slowly restored to room temperature and stirred until the reaction was complete (TLC tracking, about 3 hours).

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

[0036] Example 3 Preparation of 6-phenylethyl nicotinate (method three)

[0037] Under nitrogen protection, Ti(OEt)4 (1425 mg, 6.25 mmol) and 10 mL of toluene were added to a dry reaction bottle, and isopropylmagnesium bromide (10 mL, 1M, 10.0 mmol) solution and styrene (521 mg, 5 mmol) were dripped into it at 10°C. After stirring for half an hour, 3-(ethoxycarbonyl)pyridine nitrogen oxide (836 mg, 5 mmol) was added, and the temperature was slowly restored to room temperature and stirred until the reaction was complete (TLC tracking, about 3 hours).

[0038] 20 mL of deionized water was added to the system to terminate the reaction, and the product was extracted with dichloromethane. The extracts were combined, dried, and dichloromethane was recovered to obtain a 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-deuterated)pyridine

[0040]

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

[0042] 20 mL of deuterated water was added to the system to terminate the reaction, and the product was extracted with dichloromethane. The extracts were combined, dried, and dichloromethane was recovered to obtain a 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 DklD + [M+H] + 171.0799,Found 171.0796.

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

[0045]

[0046] Under nitrogen protection, Ti(OPr i )4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise at -10 °C to ethylmagnesium bromide (10 mL, 1 M, 10.0 mmol) solution and styrene (521 mg, 5 mmol). After keeping warm for half an hour, pyridine nitrogen oxide (476 mg, 5 mmol) was added and stirred until the reaction was complete (TLC tracking, about 4 hours). Then benzaldehyde (584 mg, 5.5 mmol) was weighed and added to the above system, warmed to room temperature, and stirred until the reaction was complete (TLC tracking, about 4 hours).

[0047] 20 mL of deionized water was added to the system to terminate the reaction, and the product was extracted with dichloromethane. The extracts were combined, dried, and dichloromethane was recovered to obtain a 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)propanoic acid

[0050]

[0051] Under nitrogen protection, Ti(OPr i )4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise at -10 °C to ethylmagnesium bromide (10 mL, 1 M, 10.0 mmol) solution and ethyl 4-vinylbenzoate (881 mg, 5 mmol). After stirring for half an hour, pyridine nitrogen oxide (476 mg, 5 mmol) was added and stirred until the reaction was complete (TLC tracking, about 4 hours). A sufficient amount of CO2 gas was introduced into the above system, the temperature was raised to room temperature, and the reaction was stirred until the reaction was complete (TLC tracking, about 6 hours).

[0052] 20 mL of deionized water was added to the system to terminate the reaction, and the product was extracted with dichloromethane. The extracts were combined, dried, and dichloromethane was recovered to obtain a 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-diphenylpropanamide

[0055]

[0056] Under nitrogen protection, Ti(OPr i)4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise at -10 °C to ethylmagnesium bromide (10 mL, 1 M, 10.0 mmol) solution and styrene (521 mg, 5 mmol). After stirring for half an hour, 3-methoxypyridine nitrogen oxide (626 mg, 5 mmol) was added and stirred until the reaction was complete (TLC tracking, about 4 hours). PhNCO (655 mg, 5.5 mmol) was added at room temperature and stirred until the reaction was complete (TLC tracking, about 4 hours).

[0057] 20 mL of deionized water was added to the system to terminate the reaction, and the product was extracted with dichloromethane. The extracts were combined, dried, and dichloromethane was recovered to obtain a 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-phenylpropan-2-yl)benzoate

[0060]

[0061] Under nitrogen protection, Ti(OPr i)4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise at -10 °C to ethylmagnesium bromide (10 mL, 1 M, 10.0 mmol) solution and ethyl 4-vinylbenzoate (881 mg, 5 mmol). After half an hour of warm reaction, 2-cyanopyridine nitrogen oxide (601 mg, 5 mmol) was added and the mixture was stirred and kept warm until the reaction was complete (TLC tracking, about 4 hours). The system was cooled to -20 °C, CuCN·2LiCl (960 mg, 5.5 mmol) and benzoyl chloride (772 mg, 5.5 mmol) were added to the above system, and the mixture was kept warm until the reaction was complete (TLC tracking, about 4 hours).

[0062] 20 mL of deionized water was added to the system to terminate the reaction, and the product was extracted with dichloromethane. The extracts were combined, dried, and dichloromethane was recovered to obtain a 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 Boscalid Derivative (I)

[0065]

[0066] Under nitrogen protection, Ti(OPr i)4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise at -10 °C with ethylmagnesium bromide (10 mL, 1 M, 10.0 mmol) solution. After stirring for half an hour, boscalid N-oxide (1796 mg, 5 mmol) was added. The mixture was slowly returned to room temperature and stirred until the reaction was complete (TLC tracking, about 4 hours).

[0067] 20 mL of deionized water was added to the system to terminate the reaction, and the product was extracted with dichloromethane. The extracts were combined, dried, and dichloromethane was recovered to obtain a 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 Boscalid Derivative (II)

[0070]

[0071] Under nitrogen protection, Ti(OPr i )4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise at -10 °C with ethylmagnesium bromide (10 mL, 1 M, 10.0 mmol) solution. After stirring for half an hour, boscalid nitrogen oxide (1796 mg, 5 mmol) was added, and the mixture was slowly returned to room temperature and stirred until the reaction was complete (TLC tracking, about 3 hours). A sufficient amount of CO2 gas was introduced into the above system and stirred until the reaction was complete (TLC tracking, about 6 hours).

[0072] 20 mL of deionized water was added to the system to terminate the reaction, and the product was extracted with dichloromethane. The extracts were combined, dried, and dichloromethane was recovered to obtain a 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 i )4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise with ethylmagnesium bromide (10 mL, 1 M, 10.0 mmol) solution and ethyl but-3-enoate (571 mg, 5 mmol) at -10 °C. After stirring for half an hour, loratadine nitrogen oxide (1994 mg, 5 mmol) was added and stirred until the reaction was complete (TLC tracking, about 4 hours).

[0077] 20 mL of deionized water was added to the system to terminate the reaction, and the product was extracted with dichloromethane. The extracts were combined, dried, and dichloromethane was recovered to obtain a 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,Found 497.2201.

[0079] Example 12 Preparation of Loratadine Derivative (II)

[0080]

[0081] Under nitrogen protection, Ti(OPr i )4 (1776 mg, 6.25 mmol) and 10 mL of tetrahydrofuran were added dropwise at -10 °C with ethylmagnesium bromide (10 mL, 1 M, 10.0 mmol) solution and ethyl but-3-enoate (571 mg, 5 mmol). After stirring for half an hour, loratadine nitrogen oxide (1994 mg, 5 mmol) was added and stirred until the reaction was complete (TLC tracking, about 4 hours). The system was cooled to -20 °C, CuCN·2LiCl (960 mg, 5.5 mmol) and benzoyl chloride (772 mg, 5.5 mmol) were added to the above system, and the reaction was kept warm until it was complete (TLC tracking, about 4 hours).

[0082] 20 mL of deionized water was added to the system to terminate the reaction, and the product was extracted with dichloromethane. The extracts were combined, dried, and dichloromethane was recovered to obtain a 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 following compounds were synthesized by the method for preparing 2-alkylpyridine derivatives with high selectivity according to the present invention, and the specific details are not described in detail one by one:

[0085]

[0086]

[0087]

[0088]

[0089] The process parameters (such as temperature, time, etc.) of the present invention can realize the method by taking upper and lower limits and interval values, and the embodiments are not listed one by one here.

[0090] Any contents not described in detail in the present invention can be based on the conventional technical knowledge in the art.

[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 the present invention. Although the present invention is described in detail with reference to the embodiments, it should be understood by those skilled in the art that any modification or equivalent replacement of the technical solutions of the present invention does not depart from the spirit and scope of the technical solutions of the present invention and should be included in the scope of the claims of the present invention.

Claims

1. A method for preparing 2-alkylpyridine derivatives with high selectivity, the method comprising: A cyclopropanetitanium reagent formed by an alkyl Grignard reagent and a titanate, or a cyclopropanetitanium reagent formed by an olefin, a titanate and an ethyl or propyl Grignard reagent, a cyclopropanetitanium reagent and a pyridine N-oxide are reacted in a solvent, and an electrophilic reagent is added in situ to react to obtain a 2-alkylated pyridine derivative.

2. The method for preparing 2-alkylpyridine derivatives with high selectivity according to claim 1, characterized in that: The alkyl Grignard reagent is an alkyl magnesium halide containing two or more carbon atoms of β-H.

3. The method for preparing 2-alkylpyridine derivatives with high selectivity according to claim 1, characterized in that: The titanate includes Ti(OR)4; wherein R=alkyl group of 1 to 4 carbons.

4. The method for preparing 2-alkylpyridine derivatives with high selectivity according to claim 1, characterized in that: The olefins are olefins having four or more carbon atoms.

5. The method for preparing 2-alkylpyridine derivatives with high selectivity according to claim 1, characterized in that: The pyridine in the pyridine N-oxide is one of pyridine, substituted pyridine, quinoline, substituted quinoline, isoquinoline, substituted isoquinoline, pyridazine, substituted pyridazine, benzopyridazine, substituted benzopyridazine, pyrazine, substituted pyrazine, benzopyrazine and substituted benzopyrazine; the substituent of the substituted aromatic group is one or more of alkyl, alkoxy, halogen, phenyl, keto, ester, cyano and amide.

6. The method for preparing 2-alkylpyridine derivatives with high selectivity according to claim 1, characterized in that: The electrophilic reagent is water, heavy water, carbon dioxide, aldehyde, acyl chloride or isocyanate.

7. The method for preparing 2-alkylpyridine derivatives with high selectivity according to claim 1, characterized in that: The solvent is one of tetrahydrofuran, toluene and ether or a mixture of at least two of them.

8. The method for preparing 2-alkylpyridine derivatives with high selectivity 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.

9. The method for preparing 2-alkylpyridine derivatives with high selectivity according to claim 1, characterized in that: The reaction temperature of the cyclopropenetitanium reagent and pyridine N-oxide is -20 to 25°C; and the subsequent reaction temperature with the electrophilic reagent is -20 to 25°C.

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