Process for the preparation of a polychiral center diamine derivative

Abstract

The application relates to the technical field of medicine preparation, in particular to a synthesis method of an oxalate or L-tartarate of a compound of a multi-chiral-center diamine derivative represented by formula I, which is obtained through oximation, reduction and resolution. Raw materials used in the reaction process are cheap and easy to obtain, the reaction process is simple, the requirement for reaction equipment is low, and the method is very beneficial to industrial production; wherein Boc represents a tert-butyloxy carbonyl group.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediates, and in particular to a method for preparing a multi-chiral central diamine derivative. Background Technology

[0002] Edoxaban is a small-molecule oral anticoagulant, a factor X (FXa) blocker. Global sales of edoxaban formulations have steadily increased in recent years, reaching 154.1 billion yen in 2020, 189.4 billion yen in 2021, and 212 billion yen in 2022, representing an average annual growth of 18.8% in yen. Daiichi Sankyo's edoxaban tosylate tablets were approved for the Chinese market at the end of 2018, and were included in the National Reimbursement Drug List (Category B) in 2020 through negotiations, leading to rapid sales growth and a corresponding surge in the raw material market.

[0003] [(1R,2R,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]tert-butyl carbamate is a key intermediate of edoxaban, and its structure is as follows:

[0004] .

[0005] The synthesis route of Daiichi Sankyo, which is also the main production process route at present, is as follows:

[0006] .

[0007] The synthetic route is cumbersome, and sodium azide, a flammable and explosive hazardous reagent, is used twice during the synthesis process, making it difficult to scale up for production. Furthermore, this method generates a large amount of waste liquid, which is detrimental to environmental protection and practical production. Summary of the Invention

[0008] The objective of this invention is to provide a method for preparing multi-chiral diamine derivatives. This method is characterized by low cost, stable process, high product purity, high chiral purity, simple production process, low requirements for production equipment, and ease of industrial-scale production.

[0009] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0010] A method for preparing an optically active diamine derivative, wherein the optically active diamine derivative is an oxalate or L-tartrate of the compound shown in Formula 1. The preparation method includes the following steps:

[0011] ;

[0012] 1) Under the action of an alkali, compound VI reacts with hydroxylamine hydrochloride to form compound V;

[0013] 2) Under the action of a reducing agent, compound V is reduced to compound IV;

[0014] 3) Compound IV reacts with oxalic acid or L-tartaric acid in an organic solvent to form a salt, generating compound III or compound II.

[0015] Further, the specific steps in step 1) are as follows: add compound VI, hydroxylamine hydrochloride, and base to an organic solvent, stir at 0-120°C for 12 hours, and after the reaction is complete, proceed with post-treatment to obtain compound V.

[0016] Furthermore, the base in step 1) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium acetate, sodium formate, pyridine, triethylamine, etc.

[0017] Furthermore, the solvent in step 1) is selected from one or more of dichloromethane, ethanol, and methanol, or one of them mixed with water as a solvent.

[0018] Furthermore, the solvent in step 1) can also be a liquid base such as pyridine or triethylamine.

[0019] Furthermore, the reaction temperature in step 1) is 0-120℃, and more preferably the reaction temperature range is 60-100℃.

[0020] Further, the specific steps in step 2) are as follows: add organic solvent and compound V, nickel chloride to the reaction flask, stir and cool to 0-5℃, add reducing agent to the reaction flask in batches, after the addition is complete, keep the reaction at the temperature for 8-12 hours, and after the reaction is complete, obtain compound IV.

[0021] Furthermore, the reducing agent in step 2) is selected from sodium borohydride, potassium borohydride, sodium borohydride-nickel chloride, potassium borohydride-nickel chloride (lithium chloride, aluminum chloride, etc.), palladium on carbon, nickel on carbon, etc.

[0022] Furthermore, the solvent mentioned in step 2) can be methanol, ethanol, dichloromethane, tetrahydrofuran, isopropanol, etc.

[0023] Furthermore, step 3) specifically includes dissolving compound III in an organic solvent, heating to 40-60°C, adding oxalic acid, oxalic acid monohydrate or L-tartaric acid in batches, precipitating a large amount of white solid, filtering and drying to obtain compound III or compound II.

[0024] The solvent mentioned in step 3) can be methanol, ethanol, dichloromethane, tetrahydrofuran, isopropanol, acetonitrile, or a mixture of one of them and water.

[0025] The beneficial effects of adopting the technical solution of the present invention are:

[0026] This invention discloses a method for preparing multi-chiral diamine derivatives. The raw materials are readily available, the reaction steps are short, and it avoids the use of hazardous or unstable raw materials such as NaN3 or Burgess reagents in existing technologies. It employs a route that forms an oxime intermediate (V), utilizing the dominant transition state of the six-membered ring to control the chiral configuration of the amino group generated during reduction. This significantly improves the chiral purity of the newly generated amino group after reduction, resulting in a relatively high salt-forming and resolution yield. During the study of the reduction process, it was found that using sodium borohydride as a reducing agent exhibits a certain selectivity in the generated amino group. Furthermore, adding a Lewis acid catalyst to the reduction system can significantly improve the ee value after reduction. Attached Figure Description

[0027] Figure 1 This is the HPLC chromatogram of the product purity from Example 7;

[0028] Figure 2 This is the chiral HPLC chromatogram of the product from Example 8;

[0029] Figure 3 This is the NMR spectrum of the product of Example 1;

[0030] Figure 4 This is the NMR spectrum of the product of Example 4;

[0031] Figure 5 This is the NMR spectrum of the product from Example 7;

[0032] Figure 6 This is the NMR spectrum of Example 8. Detailed Implementation

[0033] The preparation method of a multi-chiral central diamine derivative of the present invention will be further described below with reference to specific embodiments.

[0034] Example 1: Synthesis of Compound V

[0035] The synthesis route is as follows:

[0036] ;

[0037] Add 250.0 ml ethanol, 50.0 ml water, 50.0 g (1.00 eq) of compound VI, 18.3 g hydroxylamine hydrochloride (1.50 eq), and 28.8 g sodium acetate (2.0 eq) to a three-necked reaction flask. After addition, continue the reaction at 90-100 °C for 6-10 h. TLC monitoring showed no remaining starting material. Desolventize under reduced pressure at 40-50 °C until no obvious fraction remains. Add 200 mL water and 200 mL dichloromethane, and separate the aqueous phase. Extract the organic phase again with 200 mL dichloromethane. Combine the organic phases, wash with saturated sodium bicarbonate solution, and then wash with 200 mL saturated brine. Desolventize under reduced pressure at 40-50 °C to obtain 47.2 g of an off-white solid. Yield: 89.6%, HPLC: 97.37%. [M+1]=300, HMMR(DMSO-d6): δ=1.28-1.32 (2H), δ=1.34-1.39 (9H), δ=1.58-1.78 (3H), δ=2.07-2.15 (1H), δ=2.80-2.82 (3H), δ=2.93-2.97 (1H), δ=2.97-3.05 (3H), δ=3.17-3.23 (1H), δ=4.26 (1H), δ=7.25 (1H), δ=10.52 (1H).

[0038] Example 2: Synthesis of Compound V

[0039] The synthesis route is as follows:

[0040] ;

[0041] Add 250.0 mL of ethanol, 50.0 g (1.00 eq) of compound VI, 18.3 g of hydroxylamine hydrochloride (1.50 eq), and 27.8 g of pyridine (2.0 eq) to a three-necked reaction flask. After addition, continue the reaction at 90-100 °C for 8-15 h. TLC monitoring showed no remaining starting material. Desolventize under reduced pressure at 40-50 °C until no obvious fraction remains. Add 200 mL of water and 200 mL of dichloromethane. Separate the aqueous phase and extract with 200 mL of dichloromethane from the organic phase. Combine the organic phases and wash with saturated sodium bicarbonate solution. Wash the organic phase with 200 mL of saturated brine. Desolventize under reduced pressure at 40-50 °C to obtain 48.3 g of off-white solid. Yield: 91.7%. HPLC: 98.15% [M+1] = 300. HMMR (DMSO-d6): δ = 1.28-1.32. (2H), δ=1.34-1.39 (9H), δ=1.58-1.78(3H), δ=2.07-2.15 (1H), δ=2.80-2.82 (3H), δ=2.93-2.97 (1H), δ=2.97-3.05 (3H), δ=3.17-3.23 (1H), δ=4.26 (1H), δ=7.25 (1H), δ=10.52 (1H).

[0042] Example 3: Synthesis of Compound V

[0043] The synthesis route is as follows:

[0044] ;

[0045] Add 250.0 mL of pyridine, 50.0 g (1.00 eq) of compound VI, and 18.3 g of hydroxylamine hydrochloride (1.50 eq) to a three-necked reaction flask. After addition, continue the reaction at 90-100 °C for 6-12 h. TLC monitoring showed no remaining starting material. Desolventize under reduced pressure at 40-50 °C until no obvious fraction remains. Add 200 mL of water and 200 mL of dichloromethane. Separate the aqueous phase and extract with 200 mL of dichloromethane from the organic phase. Combine the organic phases and wash with saturated sodium bicarbonate solution. Wash the organic phase with 200 mL of saturated brine. Desolventize under reduced pressure at 40-50 °C to obtain 44.3 g of off-white solid. Yield: 84.1%. HPLC: 96.67% HPLC: 98.15%, [M+1]=300, HMMR (DMSO-d6): δ=1.28-1.32 (2H), δ=1.34-1.39 (9H), δ=1.58-1.78 (3H), δ=2.07-2.15 (1H), δ=2.80-2.82 (3H), δ=2.93-2.97 (1H), δ=2.97-3.05 (3H), δ=3.17-3.23 (1H), δ=4.26 (1H), δ=7.25 (1H), δ=10.52 (1H).

[0046] Example 4: Synthesis of Compound IV

[0047] The synthesis route is as follows:

[0048] ;

[0049] Add 200 mL of ethanol, 40 g (1.00 eq) of compound IV, and 2.0 g of nickel chloride hexahydrate (0.1 eq) to a three-necked reaction flask. Start stirring and add 6.1 g of sodium borohydride (1.20 eq) in portions. Control the temperature in the reaction flask between 20-30 °C. Monitor by TLC until no raw material remains. Desolvent under reduced pressure at 40-50 °C until no obvious fraction is obtained. Add 200 mL of water and 200 mL of dichloromethane for separation. Extract the aqueous phase with 200 mL of dichloromethane from the organic phase and separate. Combine the organic phases and wash with saturated sodium bicarbonate solution. Wash the organic phase with 200 mL of saturated brine and separate. Desolvent under reduced pressure at 40-50 °C to obtain 32.1 g of off-white solid. Yield: 84.3%, HPLC: 93.55%, [M+1]=286, HIMR (DMSO-d6): δ=1.21-1.31 (2H). δ=1.39-1.42(9H), δ=1.47-1.50 (2H), δ=1.63-1.70 (2H), δ=1.85-1.92 (1H), δ=2.78 (3H), δ=2.92-2.97 (1H), δ=3.04 (3H), δ=3.47 (1H), δ=3.58 (1H), δ=4.63 (1H), δ=6.83-6.85 (1H).

[0050] Example 5: Synthesis of Compound IV

[0051] The synthesis route is as follows:

[0052] ;

[0053] Add 200 mL of ethanol and 40 g (1.00 eq) of compound IV to a three-necked flask, start stirring, and add 6.1 g of sodium borohydride (1.20 eq) in portions. Control the temperature in the flask between 20-30 °C. Monitor with TLC until no raw material remains. Desolvent under reduced pressure at 40-50 °C until no obvious fraction is obtained. Add 200 mL of water and 200 mL of dichloromethane for separation. Extract the aqueous phase with 200 mL of dichloromethane from the organic phase and separate. Combine the organic phases and wash with saturated sodium bicarbonate solution. Wash the organic phase with 200 mL of saturated brine and separate. Desolvent under reduced pressure at 40-50 °C to obtain 28.2 g of off-white solid. Yield: 74.1%, HPLC: 90.19%, [M+1]=286, HIMR (DMSO-d6): δ=1.21-1.31 (2H), δ=1.39-1.42 (9H). δ=1.47-1.50 (2H), δ=1.63-1.70 (2H), δ=1.85-1.92 (1H), δ=2.78 (3H), δ=2.92-2.97 (1H), δ=3.04 (3H), δ=3.47 (1H), δ=3.58 (1H), δ=4.63 (1H), δ=6.83-6.85 (1H).

[0054] Example 6: Synthesis of Compound IV

[0055] The synthesis route is as follows:

[0056] Add 200 mL of ethanol and 40 g (1.00 eq) of compound IV to a three-necked flask, start stirring, add 4.0 g of palladium on carbon (10% w / w) in portions to displace hydrogen gas, control the temperature in the flask between 40-50 °C, monitor by TLC until no raw material remains, filter, desolvent under reduced pressure at 40-50 °C until no obvious fraction remains, add 200 mL of water and 200 mL of dichloromethane, separate the aqueous phase, extract the organic phase with 200 mL of dichloromethane, combine the organic phases, wash with saturated sodium bicarbonate solution, wash with 200 mL of saturated brine, desolvent under reduced pressure at 40-50 °C to obtain 33.3 g of off-white solid, yield: 87.6%, HPLC: 96.93%, [M+1]=286, HIMR (DMSO-d6): δ=1.21-1.31 (2H), δ=1.39-1.42 (9H). δ=1.47-1.50(2H), δ=1.63-1.70 (2H), δ=1.85-1.92 (1H), δ=2.78 (3H), δ=2.92-2.97 (1H), δ=3.04 (3H), δ=3.47 (1H), δ=3.58 (1H), δ=4.63 (1H), δ=6.83-6.85 (1H). \

[0057] Example 7: Synthesis of Compound III

[0058] The synthesis route is as follows:

[0059] ;

[0060] Add 120 mL of acetonitrile, 30 mL of water, and 30 g (1.00 eq) of compound IV to a three-necked reaction flask. Start stirring and heat to 40-50 °C, stirring until dissolved. Add 15.8 g of L-tartaric acid in portions, precipitating a large amount of white solid. Maintain the temperature at 40-50 °C and stir for 4-6 h. Cool to 0-10 °C and stir for 2-3 h. Filter, wash the filter cake with a small amount of acetonitrile, and dry in a forced-air environment at 40-50 °C for 10-20 h to obtain 24.6 g of white solid. Yield: 62.4%, HPLC: 99.63%, ee: 100%, [M+1]=286, ¹H MMR (DMSO-d6): δ=1.11 (3H), δ=1.33-1.42 (10H), δ=1.61-1.67 (5H), δ=2.78 (3H), δ=3.00 (4H), δ=3.08 (1H), δ=3.16-3.17 (1H), δ=3.86 (2H), δ=4.01-4.02 (1H), δ=7.03-7.05(1H).

[0061] Example 8: Synthesis of Compound II

[0062] The synthesis route is as follows:

[0063] ;

[0064] Add 120 mL of acetonitrile, 30 mL of water, and 30 g (1.00 eq) of compound IV to a three-necked reaction flask. Start stirring and heat to 40-50 °C, stirring until dissolved. Add 13.3 g of dihydrate in portions, precipitating a large amount of white solid. Maintain the temperature at 40-50 °C and stir for 4-6 h. Cool to 0-10 °C and stir for 2-3 h. Filter, wash the filter cake with a small amount of acetonitrile, and dry in a forced-air environment at 40-50 °C for 10-20 h to obtain 24.6 g of white solid. Yield: 62.4%, HPLC: 99.83%, ee: 100%, [M+1]=286, HIMR (DMSO-d6): δ=1.33-1.36 (1H), δ=1.41 (9H), δ=1.63-1.71 (5H), δ=2.78 (3H), δ=2.99 (4H). δ=3.18-3.21 (1H), δ=4.03-4.04 (1H), δ=7.03-7.05 (1H), δ=7.95 (3H).

[0065] Example 9: Synthesis of Compound II

[0066] The synthesis route is as follows:

[0067] Add 150 mL of ethanol, 30 mL of water, and 30 g (1.00 eq) of compound IV to a three-necked flask. Start stirring and heat to 40-50 °C. Stir until dissolved. Add 13.3 g of dihydrate in portions, precipitating a large amount of white solid. Maintain the temperature at 40-50 °C and stir for 4-6 h. Cool to 0-10 °C and stir for 2-3 h. Filter, wash the filter cake with a small amount of ethanol, and dry in a forced-air environment at 40-50 °C for 10-20 h to obtain 22.4 g of white solid. Yield: 56.8%, HPLC: 99.35%, ee: 100%, [M+1]=286, HIMR (DMSO-d6): δ=1.33-1.36 (1H), δ=1.41 (9H), δ=1.63-1.71 (5H), δ=2.78 (3H), δ=2.99 (4H). δ=3.18-3.21 (1H), δ=4.03-4.04 (1H), δ=7.03-7.05 (1H), δ=7.95 (3H).

[0068] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary experimental examples described above, and that the invention can be implemented in other specific forms without departing from its spirit and essential characteristics. Therefore, the embodiments should be considered illustrative and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention, and no reference numerals in the claims should be construed as limiting the scope of the claims.

[0069] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent claim. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for preparing an optically active diamine derivative, which is an oxalate salt or an L-tartrate salt of a compound represented by Formula 1, ###000001### Formula 1 ; characterized by: The preparation method comprises the following steps: ​ ； 1) Compound VI reacts with hydroxylamine hydrochloride under the action of a base to form compound V; 2) Compound V is reduced to compound IV under the action of a reducing agent; 3) Compound IV reacts with oxalic acid or L-tartaric acid in an organic solvent to form a salt to form compound III or compound II; The base in step 1) is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium acetate, sodium formate, pyridine and triethylamine; The reducing agent in step 2) is selected from one or more of sodium borohydride, potassium borohydride, sodium borohydride-nickel chloride, potassium borohydride-nickel chloride, palladium on carbon and nickel on carbon.

2. The method for preparing an optically active diamine derivative according to claim 1, characterized in that: The solvent in step 1) is selected from one or more of dichloromethane, ethanol and methanol, or a mixed solvent of one of the aforementioned solvents and water.

3. The method for preparing an optically active diamine derivative according to claim 1, characterized in that: The solvent in step 1) is selected from pyridine or triethylamine.

4. The method for preparing an optically active diamine derivative according to claim 1, characterized in that: The reaction temperature in step 1) is 0-120°C.

5. The method for preparing an optically active diamine derivative according to claim 4, characterized in that: The reaction temperature in step 1) is 60-100°C.

6. The method for preparing an optically active diamine derivative according to claim 1, characterized in that: The solvent in step 2) is selected from one or more of methanol, ethanol, dichloromethane, tetrahydrofuran and isopropanol.

7. The method for preparing an optically active diamine derivative according to claim 1, characterized in that: The solvent in step 3) is selected from one or more of methanol, ethanol, dichloromethane, tetrahydrofuran, isopropanol and acetonitrile, or a mixed solvent of one of them and water.

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