Method for producing 6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexan-1-amine

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to a method for producing 6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexan-1-amine. The method involves reacting camphor with an excess of diamine by boiling in the presence of zinc 2-ethylhexanoate, isolating the product by extraction with an organic solvent, drying the separated organic layer over sodium sulphate and evaporating the extractant. The method is characterized by the fact that zinc 2-ethylhexanoate is used as a catalyst, the reaction takes place for 20 hours in a toluene medium with azeotropic distillation of water at a molar ratio of camphor: diamine: zinc carboxylate equal to 1:(3-5):0.1, before extraction the reaction mass is washed with a 1N aqueous solution of KOH and water, extracted with a 1N aqueous solution of HCl, 1N NaOH is added to the aqueous layer until the medium is alkaline, methyl chloride is used as an organic extractant.EFFECT: increase in the yield and selectivity for the formation of 6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexan-1-amine.1 cl, 4 ex

Description

[0001] The present invention relates to a method for producing 6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexan-1-amine, which can be used as a precursor for the synthesis of biologically active substances.

[0002] A method for producing (1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)hydrazine is known (ET da Silva, A. da Silva Araújo, AM Moraes, LA de Souza, MCS Lourenço, MVN de Souza, JL Wardell, SMSV Wardell, Scientia Pharmaceutica, 2016, Vol. 84, pp. 467-483), which consists of reacting camphor with hydrazine hydrate in an equivalent ratio of 1:10 while boiling in n-propanol for 48 hours with a yield of 90%.

[0003] The disadvantage of this method is the long duration of the synthesis, and the example does not indicate the possibility of obtaining amines containing an iminocamphor fragment from aliphatic diamines.

[0004] A method for obtaining 2-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)ethan-1-amine is known (Guryeva Ya.A., Alekseev I.N., Zalevskaya O.A., Slepukhin P.A., Kuchin A.V. Russian Journal of Organic Chemistry. 2016, Vol. 52, Issue 6, pp. 796-799), based on the interaction of camphor with ethylenediamine in the presence of boron trifluoride etherate (BF3⋅Et2O), taken in a molar ratio of 1:3.2:0.34, by boiling in an absolute benzene environment for 5 hours. After completion of the reaction, the solvent was removed in vacuo, and the resulting product was isolated by column chromatography on silica (SiO2) using a mixture of chloroform and methanol (CHCl3-MeOH) as eluent. The yield of the product was 97%.

[0005] The disadvantage of this method is the use of benzene, a toxic and carcinogenic solvent, and the use of flammable and volatile boron trifluoride as a catalyst, which is deactivated by the reaction water, resulting in the formation of highly toxic hydrogen fluoride. The description of the method does not provide information on the use of other diamines with extended hydrocarbon substituents.

[0006] A method for producing 2-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)ethane-1-amine is known (Guryeva Ya.A., Zalevskaya O.A., Alekseev I.A., Slepukhin P.A., Kuchin A.V., Zhurnal Organicheskoy Chemii, 2018, Vol. 54, Iss. 9, pp. 1274-1278), which consists in the interaction of (-)-3-bromocamphor with ethylenediamine in a ratio of 1:25 at 120° for 10 hours. Upon completion of the reaction, a saturated aqueous solution of sodium chloride (NaCl) is added to the reaction mixture. The resulting mixture is extracted with diethyl ether (3×50 ml). The combined extracts are washed with saturated NaCl solution and dried over anhydrous magnesium chloride (MgCl2), after which the solvent is removed under vacuum. The residue is purified by column chromatography on silica (SiO2). The yield of the target compound is 51%.

[0007] The disadvantage of this method is the use of a significant molar excess of ethylenediamine with a relatively low yield of the target product, and the use of high temperatures leads to technological losses of ethylenediamine due to its high volatility.

[0008] A method for producing 6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexan-1-amine is known (E.V. Rasskazova, A.A. Aleksanyan, V.V. Burmistrov, G.M. Butov, Bulletin of the Volgograd State Technical University, 2020, No. 5 (240), pp. 25-30), which consists in the interaction of camphor with 1,6-hexamythelenediamine in the presence of a catalyst (p-toluenesulfonic acids, bentonite), taken in a molar ratio of 1: (0.5-3): 0.03, respectively, by boiling with azeotropic distillation of reaction water using toluene or o-xylene for 10.5-26 hours with a yield 31-41%.

[0009] The disadvantage of this method is the low selectivity for the formation of a monosubstituted product.

[0010] The closest method is for obtaining 6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexan-1-amine (AS Sokolova, OI Yarovaya, AV Shernyukov, Yu.V. Gatilov, Yu.V. Razumova, VV Zarubaev, TS Tretiak, AG Pokrovsky, OI Kiselev, NF Salakhutdinov, European Journal of Medicinal Chemistry, 2015, Vol. 105, pp. 263-273), which consists in the interaction of camphor with an excess of 1,6-hexamitelenediamine in a ratio of 1:2.5 under boiling without solvent in the presence of anhydrous zinc chloride (ZnCl2) for 5-12 hours. After completion of the reaction, the reaction mixture Diethyl ether was added. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The technical product was purified by flash chromatography on a silica gel column (eluent hexane-ethyl acetate). The yield of 6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexan-1-amine was 20%.

[0011] The disadvantages of this method are the use of a hygroscopic catalyst - zinc chloride, which is deactivated during the reaction by the resulting water; boiling the reaction mixture in the absence of a solvent leads to the removal of volatile starting materials (camphor, 1,6-hexamethylenediamine); the need for complex purification and low product yield.

[0012] The objective of the invention is to develop a technological method for producing amines containing an iminocamphor fragment, which will make it possible to achieve high yield values ​​for the target product.

[0013] The technical result is an increase in the selectivity for the formation of a monosubstituted reaction product, as well as an increase in the yield of the target compound.

[0014] The technical result is achieved in the method for producing 6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexan-1-amine, which consists in the interaction of camphor with an excess of diamine during boiling in the presence of a zinc-containing catalyst, and the isolation of the product, including extraction with an organic solvent, drying the separated organic layer over sodium sulfate and evaporation of the extractant, while zinc 2-ethylhexanoate is used as a catalyst, the reaction is carried out for 20 hours in a toluene medium with azeotropic distillation of water at a molar ratio of camphor: diamine: zinc carboxylate equal to 1: (3-5): 0.1, before extraction, the reaction mass is washed with a 1N aqueous solution of KOH and water, extracted with a 1N aqueous solution of HCl, in 1N NaOH is added to the aqueous layer until the medium is alkaline; methyl chloride is used as an organic extractant.

[0015] The essence of the method lies in the condensation reaction of camphor with 1,6-diaminohexane in a toluene medium in the presence of a catalyst - zinc 2-ethylhexanoate.

[0016] The method is as follows.

[0017] Camphor, diamine, toluene as an azeotropic agent, and zinc 2-ethylhexanoate are added to a reactor equipped with a Dean-Stark trap and a reflux condenser. The reaction mixture is refluxed for 20 hours, with the water of reaction being removed by azeotropic distillation.

[0018] To isolate the synthesized monosubstituted diamines, the reaction mixture is washed with 1N aqueous KOH and water, then the target product is extracted with 1N aqueous HCl. After separation, 1N NaOH is added to the aqueous layer until the solution is alkaline, and the product is extracted with methylene chloride. The mixture is then dried over sodium sulfate, filtered, and the methylene chloride is removed by vacuum distillation.

[0019] The excess diamine used is largely removed by washing with water.

[0020] The invention is illustrated by the following examples:

[0021] Example 1. 0.0065 mol (0.989 g) of Rac-camphor, 0.0195 mol (2.266 g) of 1,6-diaminohexane in toluene, and 0.00065 mol (0.229 g) of zinc 2-ethylhexanoate are charged into a reactor equipped with a Dean-Stark trap and a reflux condenser. The reaction mixture is boiled for 20 hours, distilling off the reaction water as an azeotrope with toluene.

[0022] To isolate the synthesized monosubstituted diamines, the reaction mixture is washed with 1N aqueous KOH and water, after which the target product is extracted with 1N aqueous HCl. After separation, 1N aqueous KOH is added to the aqueous hydrochloric acid layer until the solution is alkaline. The product is extracted with methylene chloride, dried over sodium sulfate, filtered, and the methylene chloride is removed by distillation on a rotary evaporator.

[0023] 0.98 g of 6-((1RS,4RS)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexan-1-amine was obtained, yield 60.4% (purity 79.3%).

[0024] NMR Spectrum 1 H (CDCl3), δ, m.d.: 0.73 s (3H, H-8), 0.90 s (3H, H-9), 0.94 s (3H, H-10), 1.10–1.47 m (9H), 1.51–1.67 m (3H–1.8), 1.7 t (1H, J = 4.4 Hz, H-3), 2.30 d.t (2H, J = 16.4, 3.5 Hz, H-2), 2.62–2.69 m (2H), and 3.09–3.25 m (2H). NMR spectrum 13 C{ 1 H} (CDCl3), δ, m.d.: 11.4 (1C, C-10), 19.0 (1C, C-8), 19.5 (1C, C-9), 26.8 (1C, C-15), 27.4 (1C, C-14), 27.5 (1C, C-4), 27.5 (1C, C-4). 32.2 (1C, C-5), 33.9 (1C, C-16), 35.4 (1C, C-2), 42.1 (1C, C-12), 43.9 (1C, C-3), 46.8 (1C, C-7), 51.3 (1C, C-16 (C-16), 5 C-1). The mass spectrum, m / z (I отн ., %): 250 (16%, [M] + ), 234 (20%), 220 (100%), 207 (18%), 179 (28%), 152 (12%). Found, %: C 76.70; H 12.10; No 11.15. C 16 H 30 N2. Calculated, %: C 76.74; H 12.08; No. 11.19.

[0025] Example 2. The synthesis is carried out similarly to Example 1 using 0.0197 mol (2.999 g) of Rac-camphor, 0.0985 mol (11.447 g) of 1,6-diaminohexane and 0.00197 mol (0.693 g) of zinc 2-ethylhexanoate. 3.43 g of 6-((1RS,4RS)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexane-1-amine are obtained, yield 69.5% (purity 84.5%).

[0026] Example 3. The synthesis is carried out similarly to Example 1 using 0.0066 mol (1.005 g) of L-camphor, 0.033 mol (3.835 g) of 1,6-diaminohexane and 0.00066 mol (0.232 g) of zinc 2-ethylhexanoate. 1.17 g of 6-((1S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexane-1-amine are obtained, yield 72.1% (purity 87.7%).

[0027] NMR spectrum 1 H (CDCl3), δ, ppm: 0.73 s (3H, H-8), 0.91 s (3H, H-9), 0.95 s (3H, H-10), 1.10-1.47 m (9H), 1.51-1.67 m (3H), 1.75-1.83 m (2H), 1.90 t (1H, J = 4.4 Hz, H-3), 2.30 dt (2H, J = 16.4, 3.5 Hz, H-2), 2.62-2.70 m (2H), 3.10-3.25 m (2H). NMR spectrum 13 C{ 1H} (CDCl3), δ, ppm: 11.4 (1C, C-10), 19.0 (1C, C-8), 19.5 (1C, C-9), 26.9 (1C, C-15), 27.4 (1C, C-14), 27.5 (1C, C-4), 30.5 (1C, C-13), 32.2 (1C, C-5), 33.9 (1C, C-16), 35.4 (1C, C-2), 42.1 (1C, C-12), 43.9 (1C, C-3), 46.8 (1C, C-7), 52.3 (1C, C-11), 53.5 (1C, C-6), 181.2 (1C, C-1). Mass spectrum, m / z (I отн ., %): 250 (13%, [M] + ), 234 (21%), 220 (100%), 207 (19%), 179 (25%), 152 (10%). Found, %: C 76.75; H 12.10; N 11.20. C 16 H 30 N2. Calculated, %: C 76.74; N 12.08; N 11.19.

[0028] Example 4. The synthesis is carried out similarly to Example 1 using 0.0066 mol (1.005 g) of D-camphor, 0.033 mol (3.835 g) of 1,6-diaminohexane and 0.00066 mol (0.232 g) of zinc 2-ethylhexanoate. 6-((1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexane-1-amine (1.03 g) is obtained, yield 63.46% (purity 86.4%).

[0029] NMR spectrum 1H (CDCl3), δ, m.d.: 0.74 s (3H, H-8), 0.90 s (3H, H-9), 0.95 s (3H, H-10), 1.10–1.47 m (9H), 1.51–1.67 m (3H–1.8), 1.7 t (1H, J = 4.4 Hz, H-3), 2.30 d.t (2H, J = 16.4, 3.5 Hz, H-2), 2.63-2.70 m (2H), 3.10-3.25 m (2H). NMR spectrum 13 C{ 1 H} (CDCl3), δ, m.d.: 11.4 (1C, C-10), 19.1 (1C, C-8), 19.5 (1C, C-9), 26.9 (1C, C-15), 27.4 (1C, C-14), 27.5 (1C, C-14), 27.5 (1C, C-4), 32.1 (1C, C-5), 34.0 (1C, C-16), 35.4 (1C, C-2), 42.1 (1C, C-12), 43.9 (1C, C-3), 46.8 (1C, C-7), 51.3 (1C, C-16 (C-16), 5 C-1). The mass spectrum, m / z (I отн ., %): 250 (14%, [M] + ), 234 (22%), 220 (100 %), 207 (16%), 179 (23%), 152 (11%). Found, %: C 76.75; H 12.05; N 11.20. C 16 H 30 N2. Calculated, %: C 76.74; H 12.08; No. 11.19.

[0030] Thus, the method for producing 6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexan-1-amine, which consists in reacting camphor with an excess of diamine and zinc 2-ethylhexanoate by boiling for 20 hours in a toluene medium with azeotropic distillation of water, at a molar ratio of camphor: diamine: zinc carboxylate equal to 1:(3-5):0.1 and isolating the product by washing the reaction mass with a 1N aqueous solution of KOH and water, extracting with a 1N aqueous solution of HCl, adding 1N NaOH to the aqueous layer until the medium is alkaline, extracting with methyl chloride, drying the separated organic layer over sodium sulfate and evaporating the extractant, provides an increase in selectivity for the formation monosubstituted reaction product, as well as an increase in the yield of the target compound.

Claims

A method for producing 6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexan-1-amine, which consists in reacting camphor with an excess of diamine upon boiling in the presence of a zinc-containing catalyst and isolating the product, including extraction with an organic solvent, drying the separated organic layer over sodium sulfate and evaporating the extractant, characterized in that zinc 2-ethylhexanoate is used as a catalyst, the reaction is carried out for 20 hours in a toluene medium with azeotropic distillation of water at a molar ratio of camphor: diamine: zinc carboxylate equal to 1: (3-5): 0.1, before extraction the reaction mass is washed with a 1N aqueous solution of KOH and water, extracted with a 1N aqueous solution of HCl, 1N NaOH is added to the aqueous layer to an alkaline medium, as Methyl chloride is used as an organic extractant.