A Preparation Method of cis-(1S,2R)-N-Boc-1,2-Cyclohexanediamine

Abstract

The present invention provides a method for preparing cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine, which includes: 1. cis-1,2-cyclohexanediamine is salted with an acid and then reacted with di-tert-butyl dicarbonate to obtain cis-N-Boc-1,2-cyclohexanediamine; 2. Subsequently, it is resolved and dissociated with L-mandelic acid to obtain cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine; 3. The mother liquor of the above resolution is dissociated and racemized under the condition of an organic base to obtain cis-N-Boc-1,2-cyclohexanediamine, and finally resolution is carried out again. Compared with the prior art, the new method reduces the waste of raw materials, lowers the production cost, and the solvents can all be recycled and reused. The new method of the present invention realizes the industrial-scale production of cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine more economically and efficiently.

Description

Technical Field

[0001] The present invention relates to a method for preparing cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine, belonging to the technical field of organic synthesis. Background Art

[0002] Cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine and its derivatives with a structural scaffold are an important class of compounds and have extensive applications in the pharmaceutical field. A variety of bioactive drugs have been made using various optically active cis-1,2-cyclohexanediamine and its derivatives. Cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine can be used to prepare spleen tyrosine kinase (SYK) inhibitors. Spleen tyrosine kinase (SYK) inhibitors play an important role in various diseases such as cardiovascular, inflammatory, and autoimmune diseases. It can be combined with other drugs to treat diseases mediated by Syk kinase activity. For example, the compound provided in Patent WO2014 / 152768, 2014, A1 has a structure represented as:

[0003] In existing published patents or literature, the mainstream synthesis method uses cyclohexene oxide as a raw material, and through multiple steps, N-((2S,1S)-2-hydroxycyclohexyl) carbamic acid tert-butyl ester is synthesized. Subsequently, it reacts with MsCl to form a readily leaving mesylate group, and then reacts with sodium azide to synthesize (1R,2S)-2-(N-tert-butoxycarbonylamino)-1-azidocyclohexane. Platinum oxide is used for catalytic hydrogenation to obtain cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine. The main literature includes [Bioorganic and Medicinal Chemistry Letters, 2007, vol.17, #16, p.4683-4688] and [Journal of Organic Chemistry, 2004, vol.69, #6, p.1858-1865]. From the reaction route, these literatures all use explosive substances such as sodium azide and have many steps, so they are not suitable for industrial production. The reaction route is as follows:

[0004]

[0005] Patent WO2014 / 152768, 2014, A1 uses cis-1,2-cyclohexanediamine to first adjust the pH to neutral with an ethanol solution containing hydrogen chloride, then adds di-tert-butyl dicarbonate, and subsequently resolves and dissociates with D-mandelic acid in an ethyl acetate solvent to obtain cis-(1S,2R)-N-tert-butoxycarbonyl-1,2-cyclohexanediamine. The advantages are that the raw materials are easy to obtain and the reaction steps are short, but the disadvantages are that it is relatively difficult to adjust the pH with a hydrogen chloride / ethanol solution in actual operation, and the product with an optical purity above 99.0% cannot be obtained in one step by resolution with D-mandelic acid, and it is necessary to perform resolution again after dissociation, and the steps are relatively troublesome. The reaction route is as follows:

[0006]

[0007] In the actual process, only the 1S,2R-configuration has relatively market potential. Therefore, how to racemize the mother liquor after resolution and re-resolve it is very important for improving the resolution efficiency. This application optimizes and deeply improves the route of Patent WO2014 / 152768, 2014, A1, and researches and develops a process route with easily available raw materials, safety and stability, less three wastes, and higher yield. Summary of the Invention

[0008] In order to overcome the above technical defects, the present invention provides a method for preparing cis-(1S,2R)-N-tert-butoxycarbonyl-1,2-cyclohexanediamine, which includes: 1. Reacting cis-1,2-cyclohexanediamine with an acid to form a salt and then reacting with di-tert-butyl dicarbonate to obtain cis-N-tert-butoxycarbonyl-1,2-cyclohexanediamine; 2. Subsequently resolving and dissociating with L-mandelic acid to obtain cis-(1S,2R)-N-tert-butoxycarbonyl-1,2-cyclohexanediamine; 3. Dissociating the mother liquor of the above resolution, racemizing under the condition of an organic base to obtain cis-N-tert-butoxycarbonyl-1,2-cyclohexanediamine, and finally performing resolution again. Compared with the prior art, the new method reduces raw material waste, reduces production costs, and the solvents can all be recycled and reused. The new method of the present invention more economically and efficiently realizes industrial-scale production of cis-(1S,2R)-N-tert-butoxycarbonyl-1,2-cyclohexanediamine.

[0009] The preparation method of cis-(1S,2R)-N-tert-butoxycarbonyl-1,2-cyclohexanediamine according to the present invention is characterized in that the reaction route is as follows:

[0010]

[0011] 1) Add cis-1,2-cyclohexanediamine to p-toluenesulfonic acid to form a salt, then mix with alcohol and water, dropwise add an alcohol solution of di-tert-butyl dicarbonate, end the reaction, and add a base to free to obtain cis-N-Boc-1,2-cyclohexanediamine;

[0012] 2) Mix cis-N-Boc-1,2-cyclohexanediamine with L-mandelic acid in an organic solvent, heat it up for salt formation reaction, filter after cooling to obtain (1S,2R)-N-Boc-1,2-cyclohexanediamine mandelate, and free it with a base to obtain (1S,2R)-N-Boc-1,2-cyclohexanediamine; add a base to the mother liquor for dissociation to obtain a product rich in (1R,2S)-N-Boc-1,2-cyclohexanediamine;

[0013] 3) Heat the product rich in (1R,2S)-N-Boc-1,2-cyclohexanediamine to 120 - 150 °C, add DBU or DMAP, and react to obtain racemic cis-N-Boc-1,2-cyclohexanediamine.

[0014] Further, in the above technical solution, the alcohol in step 1) is selected from methanol or ethanol.

[0015] Further, in the above technical solution, the molar ratio of p-toluenesulfonic acid to cis-1,2-cyclohexanediamine in step 1) is 1 - 1.05:1.

[0016] Further, in the above technical solution, the molar ratio of cis-1,2-cyclohexanediamine to di-tert-butyl dicarbonate in step 1) is 1.05 - 1.10:1.

[0017] Further, in the above technical solution, the organic solvent in step 2) is selected from isopropyl acetate or n-butyl acetate.

[0018] Further, in the above technical solution, the molar ratio of cis-N-Boc-1,2-cyclohexanediamine to L-mandelic acid in step 2) is 1:0.49 - 0.50.

[0019] Further, in the above technical solution, the molar ratio of DBU or DMAP to cis N-Boc-1,2-cyclohexanediamine (1R,2S + 1S,2R) in step 3) is 0.03 - 0.20:1.

[0020] The present invention also provides a method for synthesizing cis-octahydrobenzimidazol-2-one, which includes the following steps: heat racemic or chiral cis-N-Boc-1,2-cyclohexanediamine to 170 - 220 °C to obtain cis-octahydrobenzimidazol-2-one.

[0021]

[0022] Further, in the above technical solution, the above reaction is accelerated under the catalysis of an inorganic base (such as KOH, NaOH, t-BuOK).

[0023] Advantages of the invention

[0024] 1) Mono-Boc protection of cis-1,2-cyclohexanediamine. By using p-toluenesulfonic acid to form an equivalent salt and then introducing the Boc group, more mono-Boc protected products are obtained, and the amounts of raw materials and by-products (di-Boc protected products) are relatively less.

[0025] 2) The resolution is changed to use L-mandelic acid in isopropyl acetate or butyl acetate, and the resolution effect is good. The optical purity can reach over 99.0% at one time, and the solvents of isopropyl acetate or butyl acetate are relatively stable and can be recycled.

[0026] 3) The mother liquor can be racemized by reacting with a non-nucleophilic strong base such as DBU / DMAP under normal pressure and high temperature (at the same temperature, adding inorganic strong bases such as KOH, NaOH, t-BuOK, etc. is beneficial to the formation of by-products), and the Boc protecting group is migrated. Then it can be continuously resolved and the materials can be reused. Specific Examples

[0027] The present invention will be further described below through specific examples. These examples should be understood as only for illustrating the present invention and not for limiting the protection scope of the present invention. After reading the content recorded in the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention. Synthesis of cis-(1S,2R)-N-tert-butoxycarbonyl-1,2-cyclohexanediamine

[0028] Example 1

[0029]

[0030] Mix 119.9 g (1.05 mol) of cis-1,2-cyclohexanediamine with 400 mL of methyl tert-butyl ether, add 180.8 g (1.05 mol) of p-toluenesulfonic acid, heat up to 55 °C and react for 2 hours, concentrate under reduced pressure at 40 °C until no distillate flows out; add 450 mL of ethanol and 200 mL of water and mix, control the reaction system temperature at 10 - 20 °C, dropwise add a mixture composed of 218.3 g (1.0 mol) of di-tert-butyl dicarbonate and 40 mL of ethanol, after the dropping is completed, react for 2 hours, concentrate under reduced pressure at 40 °C until no distillate flows out, add 300 mL of dichloromethane, add 30% aqueous sodium hydroxide solution to adjust the pH = 10.5 - 11.0, separate the layers, retain the organic phase, extract the aqueous phase with 300 mL * 2 of dichloromethane, combine the organic phases, wash with a small amount of ammonia water with pH = 9.5, concentrate the organic phase under reduced pressure at 30 - 40 °C until no distillate flows out, replace with isopropyl acetate once, and obtain 167.9 g of an oily substance, with a yield of 74.6%, HPLC: 96.3%.

[0031] Example 2

[0032]

[0033] Dissolve 165 g of cis-N-Boc-1,2-cyclohexanediamine in 1000 mL of isopropyl acetate, heat up to 40 - 45 °C, and drip a mixture composed of 57.4 g (0.377 mol) of S-mandelic acid and 320 mL of isopropyl acetate. Then heat up to 75 - 80 °C and stir for 5 - 6 hours. Subsequently, slowly cool down to 15 - 20 °C. At this temperature, add 220 mL of n-heptane and stir for 3 hours. Filter, and wash the filter cake with isopropyl acetate to obtain the white solid cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine S-mandelate. The mother liquor is reserved. Mix the solid with 800 mL of dichloromethane, add 5% aqueous sodium hydroxide solution to adjust the pH to 11.0 - 12.0. Extract the aqueous phase with dichloromethane, combine the organic phases, concentrate under reduced pressure at 30 - 40 °C, and then add n-heptane for low-temperature pulping. Filter to obtain 66.7 g of cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine with a yield of 40.4%. 99.4% ee, HPLC 99.7%. 1 HNMR(400MHz,CDCl3):5.00(s,1H),3.59 - 3.56(m,1H),3.01 - 2.98(m,1H),1.61 - 1.30(m,19H).

[0034] Add 5% sodium hydroxide solution to the mother liquor to adjust the pH to 10.5 - 11.0, separate the aqueous phase, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure at 45 °C until no distillate flows out to obtain 104 g of an oily product rich in (1R,2S)-N-Boc-1,2-cyclohexanediamine with 74.2% ee and HPLC 93.7%.

[0035] Example 3

[0036]

[0037] Dissolve 149 g of cis-N-Boc-1,2-cyclohexanediamine in 1100 mL of butyl acetate, heat up to 40 - 45 °C, and dropwise add a mixture composed of 52.9 g (0.348 mol) of L-mandelic acid and 400 mL of butyl acetate. Heat up to 80 - 85 °C and stir for 5 - 6 hours, then slowly cool down to 15 - 20 °C and stir for 3 hours. Filter, and wash the filter cake with butyl acetate to obtain the white solid (1S,2R)-N-Boc-1,2-cyclohexanediamine L-mandelate. Keep the mother liquor for further use. Mix the solid with 800 mL of dichloromethane, add 5% aqueous sodium hydroxide solution to adjust the pH to 11.0 - 12.0. Extract the aqueous phase with dichloromethane, combine the organic phases, concentrate under reduced pressure at 30 - 40 °C, and then add n-heptane for low-temperature pulping. Filter to obtain 57.7 g of cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine with a yield of 38.7%. 99.8% ee, HPLC 99.6%.

[0038] Add 5% sodium hydroxide solution to the mother liquor to adjust the pH to 10.5 - 11.0, separate the aqueous phase, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure at 45 - 50 °C until no distillate flows out to obtain 88 g of an oily product rich in (1R,2S)-N-Boc-1,2-cyclohexanediamine, 67.3% ee, HPLC 93.3%.

[0039] Example 4

[0040]

[0041] Mix 104 g of the oily substance rich in (1R,2S)-N-Boc-1,2-cyclohexanediamine obtained from the mother liquor in Example 2 with 500 mL of xylene and 8.9 g of DMAP, heat up to reflux, and react for 11 - 16 hours. Detect the degree of racemization by HPLC reverse-phase column (as shown in Table 1 for the degree of racemization). Concentrate under reduced pressure at 60 - 65 °C until no distillate flows out, add 300 mL of dichloromethane, add phosphorous acid aqueous solution to adjust the pH to 6.6 - 7.2, separate the aqueous phase, wash the organic layer once with a small amount of ammonia water with pH = 9.5, and concentrate the organic phase under reduced pressure at 35 - 40 °C until no distillate flows out to obtain 99.6 g of racemic cis-N-Boc-1,2-cyclohexanediamine, with an HPLC external standard content of 88.7% and 0.16% ee, which can be directly reused for resolution.

[0042] Example 5

[0043]

[0044] The oily substance containing 88 g of (1R,2S)-N-Boc-1,2-cyclohexanediamine obtained from the mother liquor in Example 2 was mixed with 610 mL of chlorobenzene and 2 g of DBU, and the temperature was raised to reflux. The reaction was carried out for 11 - 16 hours, and the degree of racemization was detected by HPLC reverse-phase column (the degree of racemization is shown in Table 1). It was concentrated under reduced pressure at 60 - 65 °C until no distillate flowed out. 300 mL of dichloromethane was added, and the organic layer was washed once with a small amount of ammonia water with pH = 9.5. The organic phase was concentrated under reduced pressure at 35 - 40 °C until no distillate flowed out, obtaining 81.4 g of racemic cis-N-Boc-1,2-cyclohexanediamine, with an HPLC external standard content of 90.9% and an ee of 0.54%, which was directly used for resolution again.

[0045] Table 1 Degree of racemization

[0046]

[0047]

[0048] Synthesis of cis-octahydrobenzimidazol-2-one

[0049] Example 6

[0050]

[0051] In a reaction flask, 50 g of (1R,2S)-N-Boc-1,2-cyclohexanediamine was added and heated to 170 °C. An atmospheric distillation device was connected, and distillate began to distill out (tert-butanol). Then the temperature was raised to a maximum of 220 °C until no distillate was distilled out. The whole process lasted for 8 hours. The residue was added with 120 mL of heptane, cooled to room temperature, and a white solid precipitated. After filtration, 31.1 g of cis-octahydrobenzimidazol-2-one was obtained with a yield of 95%. 1 HNMR(400MHz,CDCl3):4.77(s,2H),4.01 - 3.94(m,2H),1.68 - 1.65(m,2H),1.53 - 1.50(m,2H),1.35 - 1.29(m,4H). 13 CNMR(100MHz,CDCl3):164.1,51.3,27.2,20.2.

[0052] Example 7

[0053]

[0054] In a reaction flask, 70 g of the racemate of cis-N-Boc-1,2-cyclohexanediamine was stirred and mixed with 2.4 g of solid potassium hydroxide, and the temperature was raised to 170 °C. An atmospheric distillation apparatus was connected, and a distillate (tert-butanol) was distilled off. Then the temperature was raised to a maximum of 220 °C until no more distillate was obtained. The whole process took 1.5 hours. The residue was cooled to 10-20 °C, 400 mL of dichloromethane was added, and it was washed with 0.5 M hydrochloric acid until the pH was 5-6. The organic layer was washed with saturated brine, dried, filtered, concentrated under reduced pressure until no more distillate flowed out, and then slurried with n-heptane and filtered to obtain 42.7 g of cis-octahydrobenzimidazol-2-one, with a yield of 93%.

[0055] As described above, only the preferred specific embodiments of the present invention are provided, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes should be covered within the protection scope of the present invention.

Claims

1. A method for preparing cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine, characterized in that, It includes the following steps: ; 1) Cis-1,2-cyclohexanediamine is added to p-toluenesulfonic acid to form a salt, and then mixed with alcohol and water. An alcohol solution of di-tert-butyl dicarbonate is added dropwise. After the reaction is completed, alkali is added for liberation to obtain racemic cis-N-Boc-1,2-cyclohexanediamine; the molar ratio of p-toluenesulfonic acid to cis-1,2-cyclohexanediamine is 1-1.05:1; the alcohol is selected from methanol or ethanol; 2) Mix racemic cis-N-Boc-1,2-cyclohexanediamine with L-mandelic acid in an organic solvent, heat for salt formation reaction, filter after cooling to obtain (1S,2R)-N-Boc-1,2-cyclohexanediamine mandelate, and free it with alkali to obtain (1S,2R)-N-Boc-1,2-cyclohexanediamine; Add alkali to the mother liquor for dissociation to obtain a product rich in (1R,2S)-N-Boc-1,2-cyclohexanediamine; The organic solvent is selected from isopropyl acetate or n-butyl acetate; 3) Heat the product rich in (1R,2S)-N-Boc-1,2-cyclohexanediamine to 120-150 °C, add DBU or DMAP, and react to obtain racemic cis-N-Boc-1,2-cyclohexanediamine.

2. The preparation method of cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine according to claim 1, characterized in that: In step 1), the molar ratio of cis-1,2-cyclohexanediamine to di-tert-butyl dicarbonate is 1.05-1.10:

1.

3. The preparation method of cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine according to claim 1, wherein: In step 2), the molar ratio of racemic cis-N-tert-butoxycarbonyl-1,2-cyclohexanediamine to L-mandelic acid is 1:0.49-0.

50.

4. The preparation method of cis-(1S,2R)-N-Boc-1,2-cyclohexanediamine according to claim 1, characterized in that: In step 3), the molar ratio of DBU or DMAP to the product rich in (1R,2S)-N-Boc-1,2-cyclohexanediamine is 0.03-0.20:1.

Images