Asymmetric catalytic synthesis method of chiral 3-aminopiperidine and derivatives thereof

Abstract

The invention discloses an asymmetric catalytic synthesis method of chiral 3-aminopiperidine and derivatives thereof, and relates to the technical field of asymmetric catalysts.The asymmetric catalytic synthesis method comprises the following steps that 1, a mixture containing a compound 2 and an iodine elementary substance reacts to obtain an intermediate 3; (2) carrying out free radical asymmetric cross-coupling reaction on a mixture containing the intermediate 3 and a sulfoximide compound to obtain a chiral compound 4; (3) removing sulfinyl protection from the chiral compound 4 to obtain an intermediate 5; (4) the intermediate 5 is subjected to deprotection, and 3-aminopiperidine is obtained; the intermediate 5 is a 3-aminopiperidine derivative. According to the chiral 3-aminopiperidine and the derivative thereof, important synthons such as chiral 3-aminopiperidine and the derivative thereof are rapidly synthesized by a free radical asymmetric cross-coupling method, and the chiral 3-aminopiperidine and the derivative thereof are constructed under mild conditions by utilizing a free radical asymmetric cross-coupling reaction catalyzed by copper and a chiral anion ligand.

Description

Technical Field

[0001] The invention relates to the technical field of asymmetric catalysis, and specifically discloses an asymmetric catalytic synthesis method for chiral 3-aminopiperidine and derivatives thereof. Background Art

[0002] Chiral 3-aminopiperidine and its derivatives are an important class of drug molecular skeletons, widely used in pharmaceuticals, pesticides, fragrances and other fields. Representative drugs include ibrutinib (global sales of US$6.86 billion in 2023), linagliptin, alogliptin, and ruzabrutinib.

[0003] At present, the most common method is to synthesize chiral 3-aminopiperidine and its derivatives using chiral ornithine as a raw material. Although this method starts from chiral raw materials and can obtain products with high optical purity, the price of non-natural amino acids is relatively high, and the intermediate process is prone to racemization. In addition, the asymmetric catalytic method currently only constructs such intermediates through asymmetric hydrogenation, but it requires the use of precious metal rhodium, and the reaction must be carried out under high temperature and high pressure, which is complex and dangerous.

[0004] The present invention is directed to important synthons such as chiral 3-aminopiperidine and its derivatives, and is rapidly synthesized by a free radical asymmetric cross-coupling method. Summary of the invention

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

[0006] According to the first aspect of the present invention, the present invention provides a method for asymmetric catalytic synthesis of chiral 3-aminopiperidine and its derivatives, the method comprising the following steps: (1) containing compound 2, , a mixture of iodine and elemental iodine, react to obtain intermediate 3, ; (2) The intermediate 3 is contained, , a mixture of sulfinyl imide compounds, free radical asymmetric cross coupling reaction to obtain chiral compound 4, ; (3) Desulfinylating the chiral compound 4 to obtain the intermediate 5. ; (4) Deprotecting the intermediate 5 to obtain 3-aminopiperidine; Specifically, the asymmetric catalytic synthesis method comprises the following steps: Step S1: reacting a mixture containing compound 2, triphenylphosphine, iodine, imidazole and solvent 1 to obtain intermediate 3; Step S2: subjecting a mixture containing a copper catalyst, a chiral ligand, cesium carbonate, a solvent 2, an intermediate 3, and a sulfenyl imide compound to a free radical asymmetric cross-coupling reaction to obtain a chiral compound 4; Step S3: Under an inert atmosphere, a mixture containing magnesium chips, chiral compound 4, and solvent 3 is reacted with 2 to obtain intermediate 5; Step S4: Under a hydrogen atmosphere, a mixture containing a catalyst, a solvent 4, and an intermediate 5 is reacted 3 to obtain 3-aminopiperidine.

[0007] In some specific embodiments of the first aspect, the molar ratio of the compound 2 to the triphenyl phosphine is 1:(1-1.2).

[0008] In some specific embodiments of the first aspect, the molar ratio of the compound 2 to the iodine element is 1:(1~1.2).

[0009] In some specific embodiments of the first aspect, the molar ratio of the compound 2 to the imidazole is 1: (1.3~1.5).

[0010] In some specific embodiments of the first aspect, the molar volume ratio of the compound 2 to the solvent 1 is 1: (5~10) mol / L.

[0011] In some specific embodiments of the first aspect, the solvent 1 is selected from dichloromethane and / or toluene.

[0012] In some specific embodiments of the first aspect, the temperature of reaction 1 is 0-30°C.

[0013] In some specific embodiments of the first aspect, the chiral ligand has a structure shown in Formula I: .

[0014] In some specific embodiments of the first aspect, the molar ratio of the chiral ligand to the copper catalyst is 1:(1-1.5).

[0015] In some specific embodiments of the first aspect, in step S2, the sulfenyl imide compound is p-bromophenylsulfenyl imide.

[0016] In some specific embodiments of the first aspect, the copper catalyst is selected from at least one of CuI, CuBr, CuCl, CuOAc, copper trifluoromethanesulfonate, copper acetate, cuprous thiophenecarboxylate, copper hexafluoroacetylacetonate, and cuprous thiophene-2-carboxylate.

[0017] In some specific embodiments of the first aspect, the solvent 2 is selected from at least one of diethyl ether, isopropyl ether, tert-butyl methyl ether, butyl ether, toluene, trifluorotoluene, anhydrous chlorobenzene, xylene, n-pentane, n-hexane, n-heptane, and cyclohexane.

[0018] In some specific embodiments of the first aspect, in step S2, the molar ratio of the copper catalyst to the intermediate 3 is 1:(10~100).

[0019] In some specific embodiments of the first aspect, the molar ratio of the intermediate 3 to the cesium carbonate is 1:(4-8).

[0020] In some specific embodiments of the first aspect, the molar ratio of the intermediate 3 to the sulfenyl imide compound is 1:(1-1.5).

[0021] In some specific embodiments of the first aspect, the molar volume ratio of the intermediate 3 to the solvent 2 is 1: (10-20) mol / L.

[0022] In some specific embodiments of the first aspect, the temperature of the free radical asymmetric cross-coupling reaction is -40°C to 0°C.

[0023] In some specific embodiments of the first aspect, in step S3, the inert atmosphere is selected from at least one of nitrogen, argon, and helium.

[0024] In some specific embodiments of the first aspect, the molar ratio of the chiral compound 4 to the magnesium chips is 1:(10-20).

[0025] In some specific embodiments of the first aspect, the molar volume ratio of the chiral compound 4 to the solvent 3 is 1: (6-10) mol / L.

[0026] In some specific embodiments of the first aspect, in step S3, the solvent 3 is selected from at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dichloromethane, toluene, tert-butyl ether, and methanol.

[0027] In some specific embodiments of the first aspect, the temperature of reaction 2 is 0-30°C.

[0028] In some specific embodiments of the first aspect, in step S4, the catalyst is palladium on carbon.

[0029] In some specific embodiments of the first aspect, the mass ratio of the intermediate 5 to the catalyst is 1:(0.1~2).

[0030] In some specific embodiments of the first aspect, the mass volume ratio of the intermediate 5 to the solvent 4 is 1:(10-20).

[0031] In some specific embodiments of the first aspect, the solvent 4 is selected from at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dichloromethane, toluene, tert-butyl ether, and methanol.

[0032] In some specific embodiments of the first aspect, the temperature of reaction 3 is 20-30°C.

[0033] According to another aspect of the present invention, the present invention provides 3-aminopiperidine and 3-aminopiperidine derivatives synthesized by the asymmetric catalytic synthesis method described above.

[0034] As an optional implementation mode, the present invention is implemented by the following technical solution:

[0035] The asymmetric catalytic synthesis method of chiral 3-aminopiperidine and its derivatives comprises the following steps: (1) Starting from compound 2, intermediate 3 is obtained through iodination; (2) Intermediate 3 reacts with sulfenyl imine via a free radical asymmetric cross-coupling reaction to obtain chiral compound 4; (3) Chiral compound 4 is desulfenylated to obtain intermediate 5, which is a 3-aminopiperidine derivative; (4) Intermediate 5 is deprotected to give 3-aminopiperidine.

[0036] The reagents used in the present invention are all purchased from the open legal market and have not been further processed.

[0037] The beneficial effects that the present invention can produce are: The invention aims at important synthons such as chiral 3-aminopiperidine and its derivatives, and rapidly synthesizes them by a free radical asymmetric cross coupling method. The chiral 3-aminopiperidine and its derivatives are constructed under mild conditions by using a free radical asymmetric cross coupling reaction catalyzed by copper and a chiral anionic ligand. The preparation conditions are mild, the functional group tolerance is high, the free radical reaction activity is good, and a cheap metal copper catalyst is used, so that the entire asymmetric catalytic synthesis method is economical. DETAILED DESCRIPTION

[0038] The present application is described in detail below with reference to embodiments, but the present invention is not limited to these embodiments.

[0039] Unless otherwise specified, the chemicals of the present invention were purchased from commercial products and were not further purified. The dichloromethane, tetrahydrofuran and other solvents used in the experiment were all anhydrous solvents. Thin layer chromatography (TLC) used 60F254 silica gel plates. Silica gel column chromatography used Qingdao Ocean Silica Gel (particle size 0.040-0.063mm). TLC color development used UV light (254nm) or iodine. NMR spectra were characterized using a Bruker DPX 400 nuclear magnetic resonance instrument, 1 HNMR is 400MHz, the solvent is deuterated chloroform, and tetramethylsilane (TMS) is used as the internal standard. The unit of chemical shift is ppm, and the unit of coupling constant is Hz. 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.

[0040] Preparation method of chiral ligand

[0041] Step 1: Weigh magnesium chips in a 500 ml double-necked bottle containing a magnetic rod, place a reflux condenser on the bottle and a constant pressure dropping funnel, and replace the argon protection. Dissolve compound S1 (200 mmol) in 200 mL tetrahydrofuran (THF) and add a constant pressure dropping funnel, slowly add it to the bottle, and then keep it at 60 ° C for 2 hours to prepare the Grignard reagent S2. No post-treatment is required, cool to 0 ° C, add diethyl phosphite (60 mmol) dropwise, slowly warm to room temperature, and react for 2 hours. Post-treatment: Add 200 mL of 3.0 M hydrochloric acid, stir until the solid is completely dissolved, then extract with ethyl acetate, separate the organic layer, dry over anhydrous sodium sulfate, filter and concentrate in vacuo, and the residue obtained is chromatographed on a silica gel column to obtain intermediate S3 (50% yield).

[0042] Step 2: Intermediate S3 (100 mmol), methyl o-iodobenzoate (150 mmol), alpha-methylbenzylamine (20 mmol), cuprous iodide (20 mmol) and potassium carbonate (300 mmol) were placed in a 500 mL round-bottom flask, argon was replaced three times, and toluene (250 mL) was added. After reflux for 24 hours, water was added to quench, the organic layer was separated, and ethyl acetate was extracted three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column to obtain the product (40-80% yield).

[0043] Step 3: Intermediate S4 (100 mmol), arylboronic acid (450 mmol), tetrakistriphenylphosphine palladium (5 mmol) and sodium carbonate (600 mmol) were placed in a 2000 mL round-bottom flask, argon was replaced three times, and toluene (600 mL) and water (600 mL) were added. After reflux for 24 hours, ethyl acetate was extracted three times, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column to obtain product S5 (40-80% yield).

[0044] Step 4: Intermediate S5 (100 mmol), triphenylphosphine (150 mmol) and trichlorosilane (1 mol) were placed in a 500 mL round-bottom flask, and toluene (100 mL) and tetrahydrofuran (100 mL) were added. After reflux for 24 hours, ice water was added to quench, and ethyl acetate was extracted three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column to obtain product S6 (60-80% yield).

[0045] Step 5: Intermediate S6 (100 mmol) and lithium hydroxide (2 mol) were placed in a 500 mL round-bottom flask, and water (150 mL) and tetrahydrofuran (150 mL) were added. After reflux for 24 hours, 3.0 M hydrochloric acid was added to dissolve the solid, extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column to obtain product S7 (60-80% yield).

[0046] 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 and dichloromethane (250 mL) was added. After reacting at room temperature for 16 hours, a saturated ammonium chloride solution was added to quench the reaction, and the dichloromethane was extracted three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue thus obtained was purified by a silica gel column, and the final product chiral ligand was obtained according to the different arylboronic acids added. The yield of step 6 was 80%.

[0047]

[0048] 1H NMR (400 MHz, CDCl3) 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). Example 1 Preparation of compound 3:

[0049] Triphenylphosphine (100 mmol) and iodine (100 mmol) were added to a 500 ml flask, and 300 ml of dichloromethane was added, and the mixture was stirred until completely dissolved. Then, imidazole (130 mmol) was added and stirred at room temperature for one hour. After cooling to 0 °C, compound 2 (100 mmol) was dissolved in 50 ml of dichloromethane and added dropwise to the reaction system, and the temperature was slowly raised to room temperature and stirred overnight. TLC was followed until the reaction was completed, and a saturated sodium bisulfite solution was added to quench the reaction. After extraction with dichloromethane three times, the organic phases were combined and washed with a saturated sodium chloride solution, concentrated, and then added to a mixed solution of 330 ml of ethyl acetate and petroleum ether (volume ratio 1:10) for slurrying. After filtering out the solid, the mixture was concentrated. Column chromatography (ethyl acetate / petroleum ether = 1:10) was used to obtain compound 3 with a yield of 61%.

[0050] 1H NMR (400 MHz, CDCl3) 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). Example 2 Preparation of compound 4

[0051] Thiophene-2-carboxylic acid cuprous acid (5 mmol), chiral ligand (5 mmol) and 65.2 g cesium carbonate (200 mmol) were weighed into a 1 L round-bottom flask. After changing the argon gas three times, 500 ml of isopropyl ether was added and stirred at 50 °C for 2 hours. Then, 17.3 g of compound 3 (50 mmol) and 10.9 g of p-bromophenylsulfenyl imide (50 mmol) were added to the solution and stirred at 50 °C for 1 hour. The temperature was lowered to -30 °C, and 33.9 g of Mes2IBF4 (75 mmol) and 10 ml of dichloromethane were added to the system. After the reaction was completed by TLC detection, the catalyst was recovered by diatomaceous earth filtration, the filtrate was concentrated to obtain a crude product, and 18.3 g of compound 4 was obtained by column chromatography with a yield of 98% and an ee value of 91%.

[0052] 1 H NMR (400 MHz, CDCl3) 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). The structural formula of the chiral ligand is as follows:

[0053] Example 3 Preparation of compound 5

[0054] Weigh 11.8g of magnesium chips in a 1L flask, add 300ml of anhydrous methanol under argon protection, and cool to 0℃. Dissolve 18.3g of compound 4 (49 mmol) in 100ml of methanol and slowly add it to the system. Stir until the magnesium chips are completely dissolved, warm to room temperature, and detect the end of the reaction by TLC. Lower the temperature to 0℃ again, add 4.0M hydrochloric acid 1,4-dioxane solution (200ml), and stir until the reaction ends. After the system is spin-dried, add water to dissolve, extract with ethyl acetate three times, combine the organic phases and concentrate to obtain the crude product of compound 5. Proceed directly to the next step without separation.

[0055] Example 4 Preparation of compound 1

[0056] 1.8 g of wet palladium carbon was weighed into a 500 ml double-necked bottle, and 200 ml of anhydrous methanol was added, and then replaced with hydrogen. The crude product compound 4 was dissolved in 100 ml of methanol and added to the system. Stir until the reaction was completed. After filtering through diatomaceous earth, the solution was spin-dried, 100 ml of 4.0 M hydrochloric acid 1,4-dioxane solution was added, and the solution was concentrated under reduced pressure to obtain the hydrochloride of compound 1 with a yield of 90%.

[0057] 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). The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for asymmetric catalytic synthesis of chiral 3-aminopiperidine and its derivatives, characterized in that: The asymmetric catalytic synthesis method comprises the following steps: (1) containing compound 2, , a mixture of iodine and elemental iodine, react to obtain intermediate 3, ; (2) The intermediate 3 is contained, , a mixture of sulfinyl imide compounds, free radical asymmetric cross coupling reaction to obtain chiral compound 4, ; (3) Desulfinylating the chiral compound 4 to obtain the intermediate 5. ; (4) Deprotecting the intermediate 5 to obtain 3-aminopiperidine; The intermediate 5 is a 3-aminopiperidine derivative; In the chiral compound 4, Ar=4-BrC6H4.

2. The asymmetric catalytic synthesis method according to claim 1, characterized in that: The asymmetric catalytic synthesis method comprises the following steps: Step S1: reacting a mixture containing compound 2, triphenylphosphine, iodine, imidazole and solvent 1 to obtain intermediate 3; Step S2: subjecting a mixture containing a copper catalyst, a chiral ligand, cesium carbonate, a solvent 2, an intermediate 3, and a sulfenyl imide compound to a free radical asymmetric cross-coupling reaction to obtain a chiral compound 4; Step S3: Under an inert atmosphere, a mixture containing magnesium chips, chiral compound 4, and solvent 3 is reacted with 2 to obtain intermediate 5; Step S4: Under a hydrogen atmosphere, a mixture containing a catalyst, a solvent 4, and an intermediate 5 is reacted 3 to obtain 3-aminopiperidine.

3. The asymmetric catalytic synthesis method according to claim 2, characterized in that: The molar ratio of the compound 2 to the triphenyl phosphine is 1:(1-1.2); The molar ratio of the compound 2 to the iodine element 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.

4. The asymmetric catalytic synthesis method according to claim 2, characterized in that: 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).

5. The asymmetric catalytic synthesis method according to claim 2, characterized in that: In the step S2, the sulfenyl imide compound is p-bromophenyl sulfenyl imide; The copper catalyst is selected from at least one of CuI, CuBr, CuCl, CuOAc, copper trifluoromethanesulfonate, copper acetate, cuprous thiophenecarboxylate, copper hexafluoroacetylacetonate, and cuprous thiophene-2-carboxylate; The solvent 2 is selected from at least one of diethyl ether, isopropyl ether, tert-butyl methyl ether, butyl ether, toluene, trifluorotoluene, anhydrous chlorobenzene, xylene, n-pentane, n-hexane, n-heptane and cyclohexane.

6. The asymmetric catalytic synthesis method according to claim 2, characterized in that: 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 sulfenyl imide 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 to 0°C.

7. The asymmetric catalytic synthesis method according to claim 2, characterized in that: In step S3, the inert atmosphere is selected from at least one of 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.

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

9. The asymmetric catalytic synthesis method according to claim 2, 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).

10. The asymmetric catalytic synthesis method according to claim 2, characterized in that: In the step S4, the solvent 4 is selected from at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dichloromethane, toluene, tert-butyl ether, and methanol; The temperature of the reaction 3 is 20-30°C.

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