Process for the asymmetric catalytic synthesis of chiral 3-aminopiperidines and derivatives thereof

Abstract

The application discloses an asymmetric catalytic synthesis method of chiral 3-amino piperidine and derivatives thereof, and relates to the technical field of asymmetric catalysis, which comprises the following steps: (1) a mixture containing compound 2 and iodine is reacted to obtain intermediate 3; (2) a mixture containing intermediate 3 and a sulfilimine compound is subjected to a free radical asymmetric cross-coupling reaction to obtain chiral compound 4; (3) chiral compound 4 is subjected to desulfilimine protection to obtain intermediate 5; and (4) intermediate 5 is subjected to deprotection to obtain 3-amino piperidine; the intermediate 5 is a 3-amino piperidine derivative. The application is aimed at important synthesizers such as chiral 3-amino piperidine and derivatives thereof, and the synthesizers are rapidly synthesized through a free radical asymmetric cross-coupling method; a free radical asymmetric cross-coupling reaction catalyzed by copper and a chiral anion ligand is utilized to construct chiral 3-amino piperidine and derivatives thereof under mild conditions.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of asymmetric catalysis, and specifically discloses an asymmetric catalytic synthesis method of chiral 3-aminopiperidine and derivatives thereof. BACKGROUND

[0002] Chiral 3-aminopiperidine and derivatives thereof are important drug molecular skeletons, and are widely used in the fields of pharmaceuticals, pesticides, and perfumes. Representative drugs include ibrutinib (global sales of 68.6 billion US dollars in 2023), licogliflozin, alogliptin, and razabrutinib.

[0003] At present, the most common method is to synthesize chiral 3-aminopiperidine and derivatives thereof by using chiral ornithine as a raw material. Although this method can obtain products with high optical purity from chiral raw materials, non-natural amino acids are relatively expensive, and the intermediate process is prone to racemization. In addition, the current asymmetric catalytic method only constructs such intermediates through asymmetric hydrogenation, but needs to use the noble metal rhodium, and the reaction needs to be carried out at high temperature and high pressure, which is complex and highly dangerous.

[0004] The present application aims to rapidly synthesize chiral 3-aminopiperidine and derivatives thereof through a free radical asymmetric cross-coupling method. SUMMARY

[0005] The present application utilizes a free radical asymmetric cross-coupling reaction catalyzed by copper and a chiral anion ligand to construct chiral 3-aminopiperidine and derivatives thereof under mild conditions.

[0006] According to a first aspect of the present application, the present application provides an asymmetric catalytic synthesis method of chiral 3-aminopiperidine and derivatives thereof, which comprises the following steps:

[0007] (1) mixing a mixture containing compound 2, , and elemental iodine, and reacting to obtain intermediate 3, ;

[0008] (2) mixing a mixture containing intermediate 3, , and a sulfilimine compound, and performing a free radical asymmetric cross-coupling reaction to obtain chiral compound 4, ;

[0009] (3) de-sulfilimine protecting chiral compound 4 to obtain intermediate 5, ;

[0010] (4) de-protecting intermediate 5 to obtain 3-aminopiperidine;

[0011] Specifically, the asymmetric catalytic synthesis method comprises the following steps:

[0012] Step S1: a mixture containing compound 2, triphenylphosphine, iodine, imidazole, solvent 1, reaction 1, to obtain intermediate 3;

[0013] Step S2: a mixture containing copper catalyst, chiral ligand, cesium carbonate, solvent 2, intermediate 3, sulfilimine compound, free radical asymmetric cross-coupling reaction, to obtain chiral compound 4;

[0014] Step S3: under an inactive atmosphere, a mixture containing magnesium turnings, chiral compound 4, solvent 3, reaction 2, to obtain intermediate 5;

[0015] Step S4: under a hydrogen atmosphere, a mixture containing catalyst, solvent 4, intermediate 5, reaction 3, to obtain 3-aminopiperidine.

[0016] In some embodiments of the first aspect, the molar ratio of compound 2 to triphenylphosphine is 1: (1-1.2).

[0017] In some embodiments of the first aspect, the molar ratio of compound 2 to iodine is 1: (1-1.2).

[0018] In some embodiments of the first aspect, the molar ratio of compound 2 to imidazole is 1: (1.3-1.5).

[0019] In some embodiments of the first aspect, the molar volume ratio of compound 2 to solvent 1 is 1: (5-10) mol / L.

[0020] In some embodiments of the first aspect, the solvent 1 is selected from dichloromethane and / or toluene.

[0021] In some embodiments of the first aspect, the temperature of reaction 1 is 0-30°C.

[0022] In some embodiments of the first aspect, the chiral ligand has the structure shown in formula I:

[0023] .

[0024] In some embodiments of the first aspect, the molar ratio of chiral ligand to copper catalyst is 1: (1-1.5).

[0025] In some embodiments of the first aspect, in step S2, the sulfilimine compound is p-bromophenyl sulfilimine.

[0026] In some embodiments of the first aspect, the copper catalyst is selected from at least one of Cul, CuBr, CuCl, CuOAc, copper triflate, copper acetate, copper thienylcarboxylate, copper hexafluoroacetylacetonate, and copper thien-2-carboxylate.

[0027] In some embodiments of the first aspect, the solvent 2 is selected from at least one of diethyl ether, isopropyl ether, t-butyl methyl ether, butyl ether, toluene, trifluorotoluene, anhydrous chlorobenzene, xylene, n-pentane, n-hexane, n-heptane, and cyclohexane.

[0028] In some embodiments of the first aspect, the molar ratio of the copper catalyst to the intermediate 3 in the step S2 is 1: (10-100).

[0029] In some embodiments of the first aspect, the molar ratio of the intermediate 3 to the cesium carbonate is 1: (4-8).

[0030] In some embodiments of the first aspect, the molar ratio of the intermediate 3 to the sulfilimine compound is 1: (1-1.5).

[0031] In some embodiments of the first aspect, the molar volume ratio of the intermediate 3 to the solvent 2 is 1: (10-20) mol / L.

[0032] In some embodiments of the first aspect, the temperature of the radical asymmetric cross-coupling reaction is -40°C to 0°C.

[0033] In some embodiments of the first aspect, the non-reactive gas atmosphere in the step S3 is selected from at least one of nitrogen, argon, and helium.

[0034] In some embodiments of the first aspect, the molar ratio of the chiral compound 4 to the magnesium turnings is 1: (10-20).

[0035] In some embodiments of the first aspect, the molar volume ratio of the chiral compound 4 to the solvent 3 is 1: (6-10) mol / L.

[0036] In some embodiments of the first aspect, the solvent 3 in the step S3 is selected from at least one of tetrahydrofuran, diethyl ether, methyl t-butyl ether, dichloromethane, toluene, t-butyl ether, and methanol.

[0037] In some embodiments of the first aspect, the temperature of the reaction 2 is 0-30°C.

[0038] In some embodiments of the first aspect, the catalyst in the step S4 is palladium on carbon.

[0039] In some embodiments of the first aspect, the mass ratio of the intermediate 5 to the catalyst is 1: (0.1-2).

[0040] In some embodiments of the first aspect, the mass-volume ratio of the intermediate 5 to the solvent 4 is 1: (10-20).

[0041] In some embodiments of the first aspect, the solvent 4 is at least one selected from the group consisting of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dichloromethane, toluene, tert-butyl ether, and methanol.

[0042] In some embodiments of the first aspect, the temperature of the reaction 3 is 20-30℃.

[0043] According to another aspect of the present application, the present application provides 3-aminopiperidine and 3-aminopiperidine derivatives synthesized by the asymmetric catalytic synthesis method described above.

[0044] As an optional implementation, the present application is implemented by the following technical solutions:

[0045]

[0046] The asymmetric catalytic synthesis method of the chiral 3-aminopiperidine and its derivatives comprises the following steps:

[0047] (1) starting from the compound 2, the intermediate 3 is obtained through iodination;

[0048] (2) the intermediate 3 is subjected to a free radical asymmetric cross-coupling reaction with a sulfilimine to obtain a chiral compound 4;

[0049] (3) the chiral compound 4 is subjected to a desulfilimine protection to obtain the intermediate 5, which is a 3-aminopiperidine derivative;

[0050] (4) the intermediate 5 is subjected to a deprotection to obtain the 3-aminopiperidine.

[0051] The reagents used in the present application are all purchased from public legal markets and are not subjected to further processing.

[0052] The present application can produce the following beneficial effects:

[0053] The present application is directed to the important synthon of chiral 3-aminopiperidine and its derivatives, which are rapidly synthesized by a free radical asymmetric cross-coupling method. The chiral 3-aminopiperidine and its derivatives are constructed by a free radical asymmetric cross-coupling reaction catalyzed by copper and a chiral anion ligand under mild conditions. The preparation conditions are mild, the functional group tolerance is high, the free radical reaction activity is good, and a cheap copper catalyst is used, so that the entire asymmetric catalytic synthesis method is economical. DETAILED DESCRIPTION

[0054] The application will be described in greater detail below with reference to the following examples. The application is not limited to these examples.

[0055] Unless otherwise indicated, the chemicals used in the application were purchased from commercial suppliers and used without further purification. The solvents used in the experiments, such as dichloromethane, tetrahydrofuran, etc., were anhydrous solvents. Thin layer chromatography (TLC) used 60F254 silica gel plates. Silica gel column chromatography used Qingdao Marine silica gel (particle size 0.040-0.063 mm). TLC visualization used UV light (254 nm) or iodine. NMR spectra were characterized using a Bruker DPX 400 nuclear magnetic resonance instrument, 1 HNMR was 400 MHz, the solvent was deuterated chloroform, and tetramethylsilane (TMS) was used as an internal standard. The unit of chemical shift was ppm, and the unit of coupling constant was Hz. In 1 In HNMR, δ represents chemical shift, s represents singlet, d represents doublet, t represents triplet, q represents quartet, p represents quintet, and m represents multiplet.

[0056] Method for preparing chiral ligand

[0057]

[0058] Step 1: Weigh magnesium chips into a 500 ml double-necked flask containing a magnetic stirrer, and place a reflux condenser on the flask. Replace the atmosphere with argon. Dissolve compound S1 (200 mmol) in 200 mL of tetrahydrofuran (THF) and add it to the constant pressure dropping funnel, then slowly add it to the flask, and then incubate at 60°C for 2 hours to prepare Grignard reagent S2. Without further treatment, cool to 0°C, and then add diethyl phosphite (60 mmol) dropwise. Slowly warm to room temperature, and then react for 2 hours. Post-treatment: Add 200 mL of 3.0M hydrochloric acid, stir until the solid is completely dissolved, then extract with ethyl acetate, separate the organic layer, dry with anhydrous sodium sulfate, filter, and concentrate under vacuum. The residue obtained is purified by silica gel column chromatography to obtain intermediate S3 (50% yield).

[0059] Step 2: Place intermediate S3 (100 mmol), methyl o-iodobenzoate (150 mmol), alpha-methylbenzylamine (20 mmol), cuprous iodide (20 mmol), and potassium carbonate (300 mmol) in a 500 mL round-bottom flask, replace the atmosphere with argon three times, and then add toluene (250 mL). Then reflux for 24 hours, then quench with water, separate the organic layer, extract with ethyl acetate three times, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under vacuum. The residue obtained is purified by silica gel column chromatography to obtain the product (40-80% yield).

[0060] Step 3: Intermediate S4 (100 mmol), aryl boronic acid (450 mmol), tetrakis triphenylphosphine palladium (5 mmol) and sodium carbonate (600 mmol) were placed in a 2000 mL round bottom flask, flushed with argon three times, toluene (600 mL) and water (600 mL) were added. After refluxing for 24 hours, ethyl acetate was extracted three times, the organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue thus obtained was purified by silica gel column to obtain the product S5 (40-80% yield).

[0061] Step 4: Intermediate S5 (100 mmol), triphenylphosphine (150 mmol) and trichlorosilane (1 mol) were placed in a 500 mL round bottom flask, toluene (100 mL) and tetrahydrofuran (100 mL) were added. After refluxing for 24 hours, ice water was added to quench, ethyl acetate was extracted three times, the organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue thus obtained was purified by silica gel column to obtain the product S6 (60-80% yield).

[0062] Step 5: Intermediate S6 (100 mmol) and lithium hydroxide (2 mol) were placed in a 500 mL round bottom flask, water (150 mL) and tetrahydrofuran (150 mL) were added. After refluxing for 24 hours, the solid was dissolved with 3.0 M hydrochloric acid, ethyl acetate was extracted three times, the organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue thus obtained was purified by silica gel column to obtain the product S7 (60-80% yield).

[0063] Step 6: Intermediate S7 (100 mmol), intermediate S8 (100 mmol), EDCI (150 mmol) and DMAP (10 mmol) were placed in a 500 mL round bottom flask, dichloromethane DCM (250 mL) was added. After reacting at room temperature for 16 hours, the reaction was quenched with saturated ammonium chloride solution, dichloromethane was extracted three times, the organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue thus obtained was purified by silica gel column to obtain the final product chiral ligand, the yield of step 6 was 80% according to the different aryl boronic acid.

[0064]

[0065] 1H NMR (400 MHz, CDC13) δ 8.18 (d, J = 8.6 Hz, 2H), 8.07 - 7.83 (m, 5H), 7.80 - 7.53 (m, 5H), 7.53 - 7.35 (m, 5H), 7.32 (s, 8H), 7.23 (dd, J = 8.6, 2.7 Hz, 2H), 5.22 (dd, J = 8.6, 6.6 Hz, 1H), 3.83 (s, 3H), 3.47 (dt, J = 6.6, 5.5 Hz, 1H), 3.39 - 2.51 (m, 4H), 2.10 - 1.49 (m, 22H), 1.49 - 1.18 (m, 50H), 0.87 (td, J = 7.5, 1.5 Hz, 3H), 0.74 (s, 72H).

[0066] Example 1

[0067] Preparation of compound 3:

[0068]

[0069] Triphenylphosphine (100 mmol) and iodine (100 mmol) were added into a 500 ml flask, after adding dichloromethane 300 ml, stirring until completely dissolved. Then, imidazole (130 mmol) was added, stirring at room temperature for one hour. After cooling to 0 ℃, compound 2 (100 mmol) was dissolved in 50 ml dichloromethane and added dropwise to the reaction system, slowly rising to room temperature and stirring overnight. TLC tracking to the end of the reaction, adding saturated sodium bisulfite solution to quench, extracting with dichloromethane three times, then washing the combined organic phase with saturated sodium chloride solution, concentrating and re-adding 330 ml of a mixture of ethyl acetate and petroleum ether (volume ratio 1:10) to slurry. After filtering off the solids, concentration. Column chromatography separation (ethyl acetate / petroleum ether = 1:10) to obtain compound 3, yield 61%.

[0070] 1H NMR (400 MHz, CDC13) δ 7.35 - 7.25 (m, 5H), 5.15 (d, J = 1.2 Hz, 2H), 4.13 (tt, J = 5.4, 3.8 Hz, 1H), 3.83 (dd, J = 12.3, 3.8 Hz, 1H), 3.68 (dd, J = 12.3, 3.8 Hz, 1H), 3.56 - 3.42 (m, 2H), 2.16 - 1.99 (m, 2H), 1.76 (tdtd, J = 12.3, 8.5, 6.3, 3.7 Hz, 2H).

[0071] Example 2

[0072] Preparation of compound 4

[0073]

[0074] Thiophene-2-carboxylic acid copper (5 mmol), chiral ligand (5 mmol) and 65.2 g cesium carbonate (200 mmol) were weighed into a 1 L round bottom flask, after three times of argon replacement, 500 ml isopropyl ether was added, and stirred at 50 °C for 2 hours. Then, 17.3 g of compound 3 (50 mmol) and p-bromophenyl sulfinylimine 10.9 g (50 mmol) were added to the solution, and stirring was continued at 50 °C for 1 hour. The system was cooled to -30 °C, and 33.9 g of Mes2IBF4 (75 mmol) and 10 ml of dichloromethane were added. After TLC detection of the reaction to completion, the catalyst was recovered by filtering through diatomite, and after concentrating the filtrate to obtain the crude product, column chromatography was performed to obtain 18.3 g of compound 4, with a yield of 98% and an ee value of 91%.

[0075] 1 H NMR (400 MHz, CDC13) δ 7.93 - 7.67 (m, 4H), 7.65 - 7.45 (m, 4H), 7.41 - 7.28 (m, 5H), 5.24 - 4.97 (m, 2H), 4.20 - 3.95 (m, 1H), 3.95 - 3.70 (m, 1H), 3.22 - 2.78 (m, 3H), 2.08 - 1.89 (m, 1H), 1.83 - 1.70 (m, 1H), 1.70 - 1.53 (m, 1H), 1.48 - 1.33 (m, 1H).

[0076] The structural formula of the chiral ligand is as follows:

[0077]

[0078] Example 3

[0079] Preparation of compound 5

[0080]

[0081] Compound 5 was prepared by dissolving 11.8 g of magnesium turnings in a 1 L flask under argon protection, and adding 300 ml of anhydrous methanol, then cooling to 0 °C. 18.3 g of compound 4 (49 mmol) was dissolved in 100 ml of methanol, and slowly added to the system. After stirring until the magnesium turnings were completely dissolved, the temperature was raised to room temperature, and TLC was used to determine that the reaction was complete. The temperature was again lowered to 0 °C, and 4.0 M hydrochloric acid in 1,4-dioxane (200 ml) was added, and the reaction was stirred until it was complete. The system was rotary evaporated, and water was added to dissolve it, and it was extracted with ethyl acetate three times, and the organic phase was combined and concentrated to obtain the crude product of compound 5. Without separation, the next step was directly performed.

[0082] Example 4

[0083] Preparation of compound 1

[0084]

[0085] Compound 1 was prepared by dissolving 1.8 g of wet palladium on carbon in a 500 ml flask, and adding 200 ml of anhydrous methanol, and then replacing it with hydrogen. The crude product of compound 4 was dissolved in 100 ml of methanol, and added to the system. After stirring until the reaction was complete, it was filtered through celite, and the solution was rotary evaporated, and 100 ml of 4.0 M hydrochloric acid in 1,4-dioxane was added, and it was concentrated under reduced pressure to obtain the hydrochloride salt of compound 1, with a yield of 90%.

[0086] 1 H NMR (400 MHz, CDCl3) δ 3.16 (dd,J = 12.3,7.2 Hz, 1H),2.98 – 2.78(m, 2H), 2.74 – 2.61 (m, 2H), 1.92 – 1.76 (m, 2H), 1.73 – 1.59 (m, 1H),1.44 – 1.30 (m, 1H), 1.12 (s, 1H), 1.03 (s, 2H).

[0087] The above merely describes several embodiments of the present application, and does not limit the present application in any form. Although the present application is disclosed with the preferred embodiments, it is not intended to limit the present application. Any skilled person in the art can make some changes or modifications to the disclosed technical contents without departing from the scope of the technical solutions of the present application, and the equivalent embodiments are equivalent to the equivalent embodiments, which are within the scope of the technical solutions.

Claims

1. A process for the asymmetric catalytic synthesis of chiral 3-aminopiperidines and derivatives thereof, characterized in that, The asymmetric catalytic synthesis method comprises the following steps: Step S1 : A mixture containing compound 2 , triphenylphosphine, iodine, imidazole, solvent 1, reaction 1, to obtain intermediate 3 ; Step S2: mixture containing copper catalyst, chiral ligand, cesium carbonate, solvent 2, intermediate 3, sulfilimine compound, free radical asymmetric cross-coupling reaction, to obtain chiral compound 4 ; Step S3: A mixture containing magnesium turnings, chiral compound 4, solvent 3, desulfinyl protection reaction 2, to obtain intermediate 5 under an inert atmosphere ; Step S4: under a hydrogen atmosphere, a mixture containing a catalyst, a solvent 4, and an intermediate 5, a deprotection reaction 3, to obtain 3-aminopiperidine; The chiral ligand has a structure shown in formula I: ； The molar ratio of the chiral ligand to the copper catalyst is 1: (1-1.5); The copper catalyst is at least one selected from CuI, CuBr, CuCl, CuOAc, copper triflate, copper acetate, thienylcarboxylic acid cuprous, copper hexafluoroacetylacetone, and thien-2-carboxylic acid cuprous; In the chiral compound 4, Ar = 4-BrC6H4; The intermediate 5 is a 3-aminopiperidine derivative.

2. The asymmetric catalytic synthesis method according to claim 1, characterized by, The molar ratio of the compound 2 to the triphenylphosphine is 1: (1-1.2); The molar ratio of the compound 2 to the iodine is 1: (1-1.2); The molar ratio of the compound 2 to the imidazole is 1: (1.3-1.5); The molar volume ratio of the compound 2 to the solvent 1 is 1: (5-10) mol / L; The solvent 1 is selected from dichloromethane and / or toluene; The temperature of the reaction 1 is 0-30°C.

3. The asymmetric catalytic synthesis method according to claim 1, wherein, In the step S2, the sulfilimine compound is p-bromophenyl sulfilimine; The solvent 2 is at least one selected from diethyl ether, isopropyl ether, tert-butyl methyl ether, butyl ether, toluene, trifluorotoluene, anhydrous chlorobenzene, xylene, n-pentane, n-hexane, n-heptane, and cyclohexane.

4. The asymmetric catalytic synthesis method according to claim 1, wherein, In the step S2, the molar ratio of the copper catalyst to the intermediate 3 is 1: (10-100); The molar ratio of the intermediate 3 to the cesium carbonate is 1: (4-8); The molar ratio of the intermediate 3 to the sulfilimine compound is 1: (1-1.5); The molar volume ratio of the intermediate 3 to the solvent 2 is 1: (10-20) mol / L; The temperature of the free radical asymmetric cross-coupling reaction is -40°C-0°C.

5. The asymmetric catalytic synthesis method according to claim 1, wherein, In the step S3, the non-active atmosphere is at least one selected from nitrogen, argon, and helium; The molar ratio of the chiral compound 4 to the magnesium chips is 1: (10-20); The molar volume ratio of the chiral compound 4 to the solvent 3 is 1: (6-10) mol / L.

6. The asymmetric catalytic synthesis method according to claim 1, wherein, In the step S3, the solvent 3 is at least one selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dichloromethane, toluene, and tert-butyl ether; The temperature of the reaction 2 is 0-30°C.

7. The asymmetric catalytic synthesis method according to claim 1, characterized in that, In the step S4, the catalyst is palladium on carbon; The mass ratio of the intermediate 5 to the catalyst is 1: (0.1-2); The mass volume ratio of the intermediate 5 to the solvent 4 is 1: (10-20).

8. The asymmetric catalytic synthesis method according to claim 1, characterized in that, In the step S4, the solvent 4 is at least one selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dichloromethane, toluene, and tert-butyl ether; The temperature of the reaction 3 is 20-30°C.

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