Synthesis method of beta alkylamine

Abstract

The invention discloses a synthesis method of beta alkylamine, and belongs to the field of organic synthesis. According to the method, 3-phenyl-1, 4, 2-dioxazole-5-ketone and 1, 1-disubstituted alkyl olefin are subjected to a mixed coupling reaction in an organic solvent system in the presence of a transition metal catalyst, a nitrogen ligand, a reducing agent, alkali and an additive to synthesize the beta-alkylamine. Cheap cobalt metal is used as a catalyst, a coupling reaction of beta-alkylamine is constructed, and the method has the advantages of mild reaction conditions, high economical efficiency and the like.

Description

A method for synthesizing β-alkylamines Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing β-alkylamines. Background Technology

[0002] β-alkylamines, as a class of nitrogen-containing compounds with unique structures and excellent biological activities, possess irreplaceable synthetic value and strategic significance in drug development, total synthesis of natural products, and materials science, and are currently one of the research hotspots in organic synthesis and medicinal chemistry. Hydroamidation, as a highly efficient amine addition synthesis strategy, can introduce amine or amide groups into olefin substrates with 100% atom economy. In recent years, this field has attracted great attention from synthetic scientists, and a series of new catalytic modes have been developed for the efficient synthesis of various amines and their derivatives. Therefore, the synthesis and modification of transition metal-catalyzed amine compounds have significant scientific research and market application value.

[0003] Summary of the Invention

[0004] This invention provides a method for synthesizing β-alkylamines. The method utilizes cobalt-catalyzed coupling reactions of 1,1-disubstituted alkylolefins with 3-phenyl-1,4,2-dioxazol-5-one to yield a variety of β-alkylamines with biological activity and pharmaceutical value. This direct and easy-to-operate method for synthesizing β-alkylamines is simple and efficient.

[0005] The method for synthesizing β-alkylamines of the present invention includes the following steps:

[0006] Using 1,1-disubstituted alkylene (Formula 1) and 3-phenyl-1,4,2-dioxazol-5-one (Formula 2) as substrates, a reductive cross-coupling reaction was carried out in an organic solvent system in the presence of a transition metal catalyst, a nitrogen ligand, a reducing agent, a base, and additives to synthesize the β-alkylamine (Formula 3). The synthetic route is shown below:

[0007]

[0008] in:

[0009] R1 is selected from substituted or unsubstituted alkyl groups, or substituted or unsubstituted cycloalkyl groups; R2 is selected from alkyl groups, and further selected from C1-C6 alkyl groups, such as methyl, ethyl, etc.

[0010] Substituents include one or more of the following: heteroatom substitution (O, N, S, etc.), C1-C6 alkyl substitution, benzoyl substitution, benzyloxycarbonyl substitution, sulfonyl substitution, and cyano substitution.

[0011] Furthermore, the 1,1-disubstituted alkyl olefin is selected from compounds with the following structures:

[0012]

[0013] The transition metal catalyst is a cobalt catalyst, and more preferably cobalt thiocyanate.

[0014] The nitrogen ligand is 4,4'-di-tert-butyl-2,2'-dipyridine.

[0015] The organic solvent is tetrahydrofuran.

[0016] The reducing agent is selected from methyldiethoxysilane.

[0017] The alkali is cesium fluoride.

[0018] The additive is a proton-based reagent, more preferably methanol.

[0019] In the reaction, the molar ratio of the 1,1-disubstituted alkyl olefin shown in Formula 1, the 3-phenyl-1,4,2-dioxazol-5-one shown in Formula 2, and the transition metal catalyst is 2:1:0.1.

[0020] The reaction was carried out under the protection of inert argon gas at a temperature of 25°C.

[0021] The method of this invention can achieve one-pot production of β-alkylamines, reducing reaction steps and thus improving product yield; the raw materials used in the synthesis method are simple and economical; R1 and R2 in this invention can be selected from multiple options, making it more widely applicable.

[0022] ENPP1 inhibitors are compounds that target and inhibit the activity of exonucleotide pyrophosphatase / phosphodiesterase 1, and have significant research and application value in metabolic diseases, tumor immunology, and bone metabolism disorders. Patent WO2020190912A1 disclosed a synthetic route for an ENPP1 inhibitor. 1-tert-butyloxycarbonyl-4-(1-aminopropyl-2-yl)piperidine is an important synthetic intermediate for N-(2-(1-(6,7-dimethoxyquinazoline-4-yl)piperidin-4-yl)propyl)sulfonamide, and can be efficiently synthesized from 1-tert-butyloxycarbonyl-4-isopropenylpiperidine using this method.

[0023] Attached Figure Description

[0024] Figure 1 shows the proton NMR spectrum of compound 1.

[0025] Figure 2 shows the proton NMR spectrum of compound 2.

[0026] Figure 3 shows the proton NMR spectrum of compound 3.

[0027] Figure 4 shows the proton NMR spectrum of compound 5.

[0028] Figure 5 shows the proton NMR spectrum of compound 6. Detailed Implementation

[0029] Unless otherwise specified, the terminology used in this document is intended for understanding by those skilled in the art.

[0030] The process of optimizing and screening reaction conditions:

[0031] (1) Screening of catalysts

[0032]

[0033]

[0034] (2) Screening of nitrogen ligands

[0035]

[0036]

[0037] (3) Screening of bases

[0038]

[0039]

[0040] (4) Screening of additives

[0041]

[0042]

[0043] The technical solution of the present invention will be further analyzed and explained through specific embodiments below.

[0044] Example 1:

[0045]

[0046] In a glove box, cobalt thiocyanate (10 mol%, 0.10 equivalent), 4,4'-di-tert-butyl-2,2'-dipyridine (10 mol%, 0.10 equivalent), 3-phenyl-1,4,2-dioxazol-5-one (0.1 mmol, 1.0 equivalent), and cesium fluoride (50 mg, 0.3 mmol) were added sequentially to a screw-top reaction flask equipped with a magnetic stirrer. Then, dry tetrahydrofuran (0.7 mL), 1,1-disubstituted alkyl olefin (0.2 mmol, 2.0 equivalent), methanol (0.2 mmol, 2.0 equivalent), and methyldiethoxysilane (0.3 mmol, 3.0 equivalent) were added via a 1 mL syringe and microsyringe. The reaction tube was then sealed and removed from the glove box. The reaction tube was placed at 25 °C and stirred for 12 hours. Thin-layer chromatography yielded compound 1 (colorless oily liquid, 70% yield).

[0047] 1 H NMR (401 MHz, Chloroform-d) δ 7.79 – 7.70 (m, 2H), 7.52 – 7.46 (m,1H), 7.46 – 7.38 (m, 2H), 6.24 (s, 1H), 4.13 (s, 2H), 3.73 – 3.41 (m, 1H), 3.46 – 3.12 (m, 1H), 2.63 (s, 2H), 1.72 – 1.60 (m, 3H), 1.44 (s, 9H), 1.35 –1.13 (m, 3H), 0.93 (d, J = 6.9 Hz, 3H).

[0048] Example 2:

[0049]

[0050] In a glove box, cobalt thiocyanate (10 mol%, 0.10 equivalent), 4,4'-di-tert-butyl-2,2'-dipyridine (10 mol%, 0.10 equivalent), 3-phenyl-1,4,2-dioxazol-5-one (0.1 mmol, 1.0 equivalent), and cesium fluoride (50 mg, 0.3 mmol) were added sequentially to a screw-top reaction flask equipped with a magnetic stirrer. Then, dry tetrahydrofuran (0.7 mL), 1,1-disubstituted alkyl olefin (0.2 mmol, 2.0 equivalent), methanol (0.2 mmol, 2.0 equivalent), and methyldiethoxysilane (0.3 mmol, 3.0 equivalent) were added via a 1 mL syringe and microsyringe. The reaction tube was then sealed and removed from the glove box. The reaction tube was placed at 25 °C and stirred for 12 hours. Compound 2 (colorless oily liquid, 65% yield) was obtained by thin-layer chromatography.

[0051] 1 H NMR (600 MHz, Chloroform-d) δ 7.79 – 7.70 (m, 2H), 7.54 – 7.45 (m,1H), 7.46 – 7.39 (m, 2H), 7.37 – 7.34 (m, 4H), 7.33 – 7.28 (m, 1H), 6.24 (s,1H), 5.12 (s, 2H), 4.23 (s, 2H), 3.57 – 3.44 (m, 1H), 3.38 – 3.20 (m, 1H), 2.72 (s, 2H), 1.77 – 1.58 (m, 2H), 1.52 – 1.41 (m, 1H), 1.37 – 1.27 (m, 2H),0.94 (d, J = 6.9 Hz, 3H).

[0052] Example 3:

[0053]

[0054] In a glove box, cobalt thiocyanate (10 mol%, 0.10 equivalent), 4,4'-di-tert-butyl-2,2'-dipyridine (10 mol%, 0.10 equivalent), 3-phenyl-1,4,2-dioxazol-5-one (0.1 mmol, 1.0 equivalent), and cesium fluoride (50 mg, 0.3 mmol) were added sequentially to a screw-top reaction flask equipped with a magnetic stirrer. Then, dry tetrahydrofuran (0.7 mL), 1,1-disubstituted alkyl olefin (0.2 mmol, 2.0 equivalent), methanol (0.2 mmol, 2.0 equivalent), and methyldiethoxysilane (0.3 mmol, 3.0 equivalent) were added via a 1 mL syringe and microsyringe. The reaction tube was then sealed and removed from the glove box. The reaction tube was placed at 25 °C and stirred for 12 hours. Compound 3 (white solid, 63% yield) was obtained by thin-layer chromatography.

[0055] 1 H NMR (600 MHz, Chloroform-d) δ 7.89 – 7.70 (m, 2H), 7.51 – 7.47 (m,1H), 7.46 – 7.39 (m, 2H), 6.20 (s, 1H), 4.53 – 3.79 (m, 2H), 3.57 – 3.49 (m,1H), 3.40 – 3.32 (m, 2H), 3.32 – 3.26 (m, 1H), 1.68 – 1.63 (m, 1H), 1.62 –1.55 (m, 2H), 1.55 – 1.45 (m, 2H), 1.45 – 1.36 (m, 1H), 0.96 (d, J = 6.9 Hz, 3H).

[0056] Example 4:

[0057]

[0058] In a glove box, cobalt thiocyanate (10 mol%, 0.10 equivalent), 4,4'-di-tert-butyl-2,2'-dipyridine (10 mol%, 0.10 equivalent), 3-phenyl-1,4,2-dioxazol-5-one (0.1 mmol, 1.0 equivalent), and cesium fluoride (50 mg, 0.3 mmol) were added sequentially to a screw-top reaction flask equipped with a magnetic stirrer. Then, dry tetrahydrofuran (0.7 mL), 1,1-disubstituted alkyl olefin (0.2 mmol, 2.0 equivalent), methanol (0.2 mmol, 2.0 equivalent), and methyldiethoxysilane (0.3 mmol, 3.0 equivalent) were added via a 1 mL syringe and microsyringe. The reaction tube was then sealed and removed from the glove box. The reaction tube was placed at 25 °C and stirred for 12 hours. Compound 4 (white solid, 27% yield) was obtained by thin-layer chromatography.

[0059] Example 5:

[0060]

[0061] In a glove box, cobalt thiocyanate (10 mol%, 0.10 equivalent), 4,4'-di-tert-butyl-2,2'-dipyridine (10 mol%, 0.10 equivalent), 3-phenyl-1,4,2-dioxazol-5-one (0.1 mmol, 1.0 equivalent), and cesium fluoride (50 mg, 0.3 mmol) were added sequentially to a screw-top reaction flask equipped with a magnetic stirrer. Then, dry tetrahydrofuran (0.7 mL), 1,1-disubstituted alkyl olefin (0.2 mmol, 2.0 equivalent), methanol (0.2 mmol, 2.0 equivalent), and methyldiethoxysilane (0.3 mmol, 3.0 equivalent) were added via a 1 mL syringe and microsyringe. The reaction tube was then sealed and removed from the glove box. The reaction tube was placed at 25 °C and stirred for 12 hours. Compound 5 (colorless oily liquid, 56% yield) was obtained by thin-layer chromatography.

[0062] 1 H NMR (600 MHz, Chloroform-d) δ 7.78 (dt, J = 7.1, 1.4 Hz, 2H), 7.54– 7.49 (m, 1H), 7.48 – 7.37 (m, 2H), 6.10 (s, 1H), 3.90 – 3.50 (m, 1H), 3.41– 2.94 (m, 1H), 1.59 – 1.49 (m, 1H), 0.98 (d, J = 5.7 Hz, 12H).

[0063] Example 6:

[0064]

[0065] In a glove box, cobalt thiocyanate (10 mol%, 0.10 equivalent), 4,4'-di-tert-butyl-2,2'-dipyridine (10 mol%, 0.10 equivalent), 3-phenyl-1,4,2-dioxazol-5-one (0.1 mmol, 1.0 equivalent), and cesium fluoride (50 mg, 0.3 mmol) were added sequentially to a screw-top reaction flask equipped with a magnetic stirrer. Then, dry tetrahydrofuran (0.7 mL), 1,1-disubstituted alkyl olefin (0.2 mmol, 2.0 equivalent), methanol (0.2 mmol, 2.0 equivalent), and methyldiethoxysilane (0.3 mmol, 3.0 equivalent) were added via a 1 mL syringe and microsyringe. The reaction tube was then sealed and removed from the glove box. The reaction tube was placed at 25 °C and stirred for 12 hours. Compound 6 (colorless oily liquid, 50% yield) was obtained by thin-layer chromatography.

[0066] 1 H NMR (600 MHz, Chloroform-d) δ 7.81 – 7.71 (m, 2H), 7.53 – 7.46 (m,1H), 7.46 – 7.39 (m, 2H), 6.21 – 6.08 (s, 1H), 3.51 – 3.38 (m, 1H), 3.33 –3.20 (m, 1H), 1.84 – 1.34 (m, 14H), 0.91 (d, J = 6.9 Hz, 3H).

[0067] Example 7:

[0068]

[0069] In a glove box, cobalt thiocyanate (10 mol%, 0.10 equivalent), 4,4'-di-tert-butyl-2,2'-dipyridine (10 mol%, 0.10 equivalent), 3-phenyl-1,4,2-dioxazol-5-one (0.1 mmol, 1.0 equivalent), and cesium fluoride (50 mg, 0.3 mmol) were added sequentially to a screw-top reaction flask equipped with a magnetic stirrer. Then, dry tetrahydrofuran (0.7 mL), 1,1-disubstituted alkyl olefin (0.2 mmol, 2.0 equivalent), methanol (0.2 mmol, 2.0 equivalent), and methyldiethoxysilane (0.3 mmol, 3.0 equivalent) were added via a 1 mL syringe and microsyringe. The reaction tube was then sealed and removed from the glove box. The reaction tube was placed at 25 °C and stirred for 12 hours. Compound 6 (colorless oily liquid, 38% yield) was obtained by thin-layer chromatography.

[0070] Example 8:

[0071]

[0072] In a glove box, cobalt thiocyanate (10 mol%, 0.10 equivalent), 4,4'-di-tert-butyl-2,2'-dipyridine (10 mol%, 0.10 equivalent), 3-phenyl-1,4,2-dioxazol-5-one (0.1 mmol, 1.0 equivalent), and cesium fluoride (50 mg, 0.3 mmol) were added sequentially to a screw-top reaction flask equipped with a magnetic stirrer. Then, dry tetrahydrofuran (0.7 mL), 1,1-disubstituted alkyl olefin (0.2 mmol, 2.0 equivalent), methanol (0.2 mmol, 2.0 equivalent), and methyldiethoxysilane (0.3 mmol, 3.0 equivalent) were added via a 1 mL syringe and microsyringe. The reaction tube was then sealed and removed from the glove box. The reaction tube was placed at 25 °C and stirred for 12 hours. Compound 8 (white solid, 36% yield) was obtained by thin-layer chromatography.

Claims

1. A method for synthesizing β-alkylamines, characterized in that: Using 1,1-disubstituted alkylene (Formula 1) and 3-phenyl-1,4,2-dioxazol-5-one (Formula 2) as substrates, a reductive cross-coupling reaction was carried out in an organic solvent system in the presence of a transition metal catalyst, a nitrogen ligand, a reducing agent, a base, and additives to synthesize the β-alkylamine (Formula 3). The synthetic route is shown below: Wherein: R1 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups; R2 is selected from alkyl groups.

2. The synthesis method according to claim 1, characterized in that: The transition metal catalyst is a cobalt catalyst.

3. The synthesis method according to claim 2, characterized in that: The transition metal catalyst is cobalt thiocyanate.

4. The synthesis method according to claim 1, characterized in that: The nitrogen ligand is 4,4'-di-tert-butyl-2,2'-dipyridine.

5. The synthesis method according to claim 1, characterized in that: The reducing agent is selected from methyldiethoxysilane.

6. The synthesis method according to claim 1, characterized in that: The alkali is cesium fluoride.

7. The synthesis method according to claim 1, characterized in that: The additive is methanol.

8. The synthesis method according to claim 1, characterized in that: The molar ratio of the 1,1-disubstituted alkyl olefin shown in Formula 1, the 3-phenyl-1,4,2-dioxazol-5-one shown in Formula 2, and the transition metal catalyst is 2:1:0.

1.

9. The synthesis method according to claim 1, characterized in that: The reaction was carried out under the protection of inert argon gas at a temperature of 25°C.

Images