A method for synthesizing cis-N,N'-dimethyl-1,2-cyclohexanediamine

Abstract

The invention discloses a synthetic method of cis-N, N'-dimethyl-1,2-cyclohexanediamine, and belongs to the technical field of organic chemistry. The synthetic method includes: the first step, N, N'-dimethylsulfonamide and sodium hypobromite react in acetonitrile to generate compound I; the second step, compound I and cyclohexene react under iodine and tetrakis (3,5-bis-trifluoromethylphenyl) sodium borate catalysis to generate compound II; the third step, compound II generates cis-N, N'-dimethyl-1,2-cyclohexanediamine under the action of hydrazine hydrate. The method is simple to operate, avoids the use of lithium aluminum tetrahydride sensitive in the air, utilizes cyclohexene to react with compound I to obtain cyclic intermediate compound II, and then opens the ring through hydrazine hydrate to obtain a high-purity cis stereo configuration product, which provides a new synthetic path for the synthesis of cis-N, N'-dimethyl-1,2-cyclohexanediamine.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and specifically relates to a method for synthesizing cis-N,N'-dimethyl-1,2-cyclohexanediamine. Background Art

[0002] Ortho-diamines are not only excellent ligands for metal ions (Li+, Mg 2 +、Zn 2 +), and is also used in a variety of pharmaceutical research. For example, Pt(II) compounds of cyclic ortho-diamines are effective in cancer treatment. Among them, cis-N,N′-dimethyl-1,2-cyclohexanediamine, English name: cis-N,N′-DiMethyl-1,2-diaMinocyclohexane, CAS: 75599-23-4, is an organic intermediate and can also be used as a catalyst for the synthesis of rigid polyurethane foam plastics.

[0003] At present, there are few methods for synthesizing cis-N,N′-dimethyl-1,2-cyclohexanediamine reported in the literature. Basically, cis-1,2-cyclohexanediamine is used as a raw material, reacted with ethyl formate to form a diamide, and then reduced with lithium aluminum hydroxide to obtain the target product (reference Journal of the American Chemical Society, 2002, vol. 124, 39, p. 11684-11688). This method uses air-sensitive lithium aluminum hydroxide, which is prone to spontaneous combustion during the process. A large amount of hydrogen is released during the post-treatment process, which poses a safety hazard and is not suitable for industrial production.

[0004] Therefore, it is necessary to conduct in-depth research on the synthesis process of cis-N,N′-dimethyl-1,2-cyclohexanediamine and provide a better, safer, more stable and industrially scaled synthesis method to meet market demand. Summary of the invention

[0005] In order to overcome the above technical defects, the present invention discloses a method for synthesizing cis-N,N′-dimethyl-1,2-cyclohexanediamine. The synthesis method comprises three steps: N,N′-dimethylsulfonamide and sodium hypobromite react in acetonitrile to generate compound I; compound I reacts with cyclohexene under the catalysis of iodine and sodium tetrakis(3,5-bistrifluoromethylphenyl)borate to generate compound II; compound II reacts with hydrazine hydrate to generate cis-N,N′-dimethyl-1,2-cyclohexanediamine. The method is simple to operate and avoids the use of lithium aluminum tetrahydride, which is sensitive to air. Cyclohexene is reacted with compound I to obtain a cyclic intermediate compound II, which is then opened with hydrazine hydrate to obtain a high-purity cis stereo configuration product, providing a new synthesis route for the synthesis of cis-N,N′-dimethyl-1,2-cyclohexanediamine.

[0006] The method for synthesizing cis-N,N′-dimethyl-1,2-cyclohexanediamine of the present invention comprises the following steps:

[0007] In the first step, N,N′-dimethylsulfonamide and sodium hypobromite react in an organic solvent to generate compound I;

[0008] In the second step, compound I reacts with cyclohexene in an ether solvent under the catalysis of iodine and sodium tetrakis(3,5-bistrifluoromethylphenyl)borate to generate compound II;

[0009] In the third step, compound II is reacted with hydrazine hydrate to generate cis-N,N′-dimethyl-1,2-cyclohexanediamine.

[0010] The reaction route is expressed by the following equation:

[0011]

[0012] Sodium tetrakis(3,5-bis(trifluoromethylphenyl)borate (NaBArF 24 )The structural formula is as follows:

[0013]

[0014] Furthermore, in the first step, the molar ratio of N,N′-dimethylsulfonamide to sodium hypobromite is 1.0:1.0.

[0015] Furthermore, in the second step, the molar ratio of compound I, cyclohexene, iodine and sodium tetrakis(3,5-bistrifluoromethylphenyl)borate is 1:1.0-1.2:0.03-0.08:0.03-0.08.

[0016] Furthermore, in the second step, the ether solvent is selected from diethyl ether, isopropyl ether or cyclopentyl methyl ether, preferably cyclopentyl methyl ether.

[0017] Furthermore, in the second step, the reaction temperature is selected from 20-80°C, preferably 40-50°C.

[0018] Furthermore, in the third step, the molar ratio of compound II to hydrazine hydrate is 1:3-20.

[0019] Furthermore, in the third step, the reaction temperature is 80-120°C.

[0020] Beneficial effects of the invention:

[0021] 1. The method of the present invention utilizes cyclohexene to react with compound I to obtain a cyclic intermediate compound II, which is then ring-opened in an alkaline hydrazine hydrate solution to ensure the cis stereo configuration of the product, with a product purity of >98%, without having to solve the problem of difficulty in separating and purifying cis and trans isomers; in the second step, by adding an anionic ligand NaBArF 24 , which improves the conversion rate of raw materials. The raw materials can be completely converted after 4-5 hours of reaction, with a yield of 80-83%.

[0022] 2. It avoids the use of lithium aluminum tetrahydride, which is expensive and has safety hazards. It is safe, stable, and easy to operate, providing a new synthetic route for the synthesis of cis-N,N′-dimethyl-1,2-cyclohexanediamine. DETAILED DESCRIPTION

[0023] Example 1

[0024] Add 37.25 g (0.30 mol) of N,N′-dimethylsulfonamide, 35.70 g (0.30 mol) of sodium hypobromite and 500 mL of acetonitrile to the reaction bottle, stir at room temperature for 2 hours, control the residual N,N′-dimethylsulfonamide by GC to be less than 0.2%, concentrate the solvent under reduced pressure, add 200 ml of methyl tert-butyl ether, stir at room temperature for 0.5 hour, filter, and obtain 65.68 g of white solid compound (I), with a yield of 97.3%. 1 H-NMR (400MHz, d6-Acetone): δ3.22(3H,s),3.14(3H,s).

[0025] Example 2

[0026] To the reaction flask, 600 mL of cyclopentyl methyl ether, 65.68 g (0.29 mol) of compound I obtained by the method in Example 1, 3.68 g (14.5 mmol) of iodine and NaBArF were added. 24 12.8g (14.5mmol), temperature controlled at 40-50℃, cyclohexene 26.29g (0.32mol) was added dropwise, and the mixture was kept at 40-50℃ for 4 hours. The concentration of compound I in HPLC was controlled to be less than 0.5%. 200mL of 10% sodium bisulfite was added dropwise at 0-10℃. After the addition, the mixture was stirred at room temperature for 0.5 hours, and extracted with dichloromethane (200mL×3). The organic layers were combined and washed with saturated brine, and concentrated under reduced pressure to obtain a crude product. The crude product was distilled under reduced pressure to obtain a colorless liquid compound II 49.52g, with a purity of 97.2% and a yield of 83.6%. 1 H-NMR (400MHz, CDCl3): δ3.13(s,6H),2.94(m,2H),1.72-0.97(m,8H).

[0027] Example 3

[0028] Add 600 mL of ether, 65.68 g (0.29 mol) of compound I obtained by the method in Example 1, 5.89 g (23.2 mmol) of iodine and NaBArF to the reaction flask. 24 20.5g (23.2mmol), control the temperature at 40-50℃, add cyclohexene 28.59g (0.35mol), keep warm at 40-50℃ for 4 hours, control compound I in HPLC <0.5%, control the temperature at 0-10℃ and add 10% sodium bisulfite 300mL, stir at room temperature for 0.5 hour, extract with dichloromethane (200mL×3), wash the organic layers with saturated brine, and concentrate under reduced pressure to obtain a crude product. The crude product is distilled under reduced pressure to obtain 38.20g of colorless liquid compound II with a purity of 97.0% and a yield of 64.5%.

[0029] Example 4

[0030] 300 mL of cyclopentyl methyl ether, 32.84 g (0.145 mol) of compound I obtained by the method in Example 1 and 1.84 g (7.25 mmol) of iodine were added to the reaction bottle, the temperature was controlled at 40-50°C, 11.91 g (0.145 mol) of cyclohexene was added dropwise, and the mixture was kept at 40-50°C for 12 hours. The remaining compound I was controlled to be 36.8% by HPLC. The reaction time was extended for 6 hours, and the remaining compound I was controlled to be 36.6% by HPLC. 100 mL of 10% sodium bisulfite was added dropwise at 0-10°C. After the addition, the mixture was stirred at room temperature for 0.5 hour, extracted with dichloromethane (100 mL×3), the organic layers were combined and washed with saturated brine, and concentrated under reduced pressure to obtain a crude product. The crude product was distilled under reduced pressure to obtain 14.04 g of colorless liquid compound II with a purity of 95.6% and a yield of 47.4%.

[0031] Example 5

[0032] To the reaction flask, 1200 mL of cyclopentyl methyl ether, 135.0 g (0.60 mol) of compound I obtained by the method in Example 1, 4.6 g (18 mmol) of iodine and NaBArF were added. 24 16.0g (18mmol), control the temperature at 40-50℃, add cyclohexene 54.2g (0.66mol), keep warm at 40-50℃ for 4 hours, control compound I in HPLC <0.5%, control the temperature at 0-10℃ and add 10% sodium bisulfite 400mL, stir at room temperature for 0.5 hour, extract with dichloromethane (400mL×3), wash the organic layer with saturated brine, and concentrate under reduced pressure to obtain a crude product. The crude product is distilled under reduced pressure to obtain 101.5g of colorless liquid compound II with a purity of 97.6% and a yield of 82.8%.

[0033] Example 6

[0034] Add 49.52 g (0.242 mol) of compound II obtained by the method in Example 2 and 155.16 g (75%, 3.64 mol) of hydrazine hydrate into the reaction bottle, heat to 110-120°C, stir for 12 hours, control the reaction to end by GC, cool, and evaporate the excess hydrazine under reduced pressure. Add 200 ml of methyl tert-butyl ether to the residue, stir and filter, dropwise add 130 g of 15% hydrochloric acid to the filtrate, separate the layers, adjust the pH of the aqueous layer to 10-12 with 30% NaOH, extract with dichloromethane 3 times (100 mL each time), combine the organic layers, concentrate the solvent under reduced pressure, and distill under reduced pressure to obtain 31.12 g (bp 76-80°C / 2Torr) of light yellow liquid cis-N,N′-dimethyl-1,2-cyclohexanediamine with a purity of 98.4% and a yield of 90.4%. 1 H-NMR (400MHz, CDCl3): δ2.47 (m, 2H), 2.32 (s, 6H), 1.66-0.83 (m, 8H).

[0035] Example 7

[0036] To the reaction flask, 101.5 g (0.497 mol) of compound II obtained by the method in Example 5 and 424.0 g (75%, 9.94 mol) of hydrazine hydrate were added, heated to 110-120° C., stirred for 12 hours, the reaction was controlled to be complete by GC, the temperature was lowered, and the excess hydrazine was evaporated under reduced pressure. 400 ml of methyl tert-butyl ether was added to the residue, and the mixture was filtered after stirring. 280 g of 15% hydrochloric acid was added dropwise to the filtrate, and the layers were separated. The aqueous layer was adjusted to pH = 10-12 with 30% NaOH, and extracted with dichloromethane 3 times (250 mL each time). The organic layers were combined, and the solvent was concentrated under reduced pressure. After that, 62.4 g (bp 76-80° C. / 2 Torr) of light yellow liquid cis-N,N′-dimethyl-1,2-cyclohexanediamine was obtained by reduced pressure distillation with a purity of 98.8% and a yield of 88.3%.

[0037] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for synthesizing cis-N,N'-dimethyl-1,2-cyclohexanediamine, characterized in that: The steps include: In the first step, N,N'-dimethylsulfonamide and sodium hypobromite react in an organic solvent to generate compound I; In the second step, compound I reacts with cyclohexene in an ether solvent under the catalysis of iodine and sodium tetrakis(3,5-bistrifluoromethylphenyl)borate to generate compound II; In the third step, compound II is reacted with hydrazine hydrate to generate cis-N,N'-dimethyl-1,2-cyclohexanediamine.

2. The method for synthesizing cis-N,N'-dimethyl-1,2-cyclohexanediamine according to claim 1, characterized in that: In the first step, the organic solvent is selected from acetonitrile.

3. The method for synthesizing cis-N,N'-dimethyl-1,2-cyclohexanediamine according to claim 1, characterized in that: In the first step, the molar ratio of N,N'-dimethylsulfonamide to sodium hypobromite is 1.0:1.

0.

4. The method for synthesizing cis-N,N'-dimethyl-1,2-cyclohexanediamine according to claim 1, characterized in that: In the second step, the molar ratio of compound I, cyclohexene, iodine and sodium tetrakis(3,5-bistrifluoromethylphenyl)borate is 1:1.0-1.2:0.03-0.08:0.03-0.

08.

5. The method for synthesizing cis-N,N'-dimethyl-1,2-cyclohexanediamine according to claim 1, characterized in that: In the second step, the ether solvent is selected from diethyl ether, isopropyl ether or cyclopentyl methyl ether.

6. The method for synthesizing cis-N,N'-dimethyl-1,2-cyclohexanediamine according to claim 1, characterized in that: In the second step, the reaction temperature is selected from 20-80°C.

7. The method for synthesizing cis-N,N'-dimethyl-1,2-cyclohexanediamine according to claim 1, characterized in that: In the third step, the molar ratio of compound II to hydrazine hydrate is 1:3-20.

8. The method for synthesizing cis-N,N'-dimethyl-1,2-cyclohexanediamine according to claim 1, characterized in that: In the third step, the reaction temperature is selected from 80-120°C.

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