Preparation method of 5-[(4-ethyl piperazine-1-yl) methyl] pyridine-2-amine and salt thereof

Abstract

The invention discloses a preparation method of 5-[(4-ethyl piperazine-1-yl) methyl] pyridine-2-amine and salt thereof, which comprises the following steps: reacting a compound in a formula II with an amide compound # imgabs0 # in the presence of a catalyst cuprous iodide and a ligand to prepare a compound in a formula III, and preparing a compound in a formula IV from the compound in the formula III under an alkaline condition. Easily available amide is used as an ammonia source, so that a tank sealing reaction of ammonia water is avoided, and the operation convenience is improved. And the ligand is used, so that the yield reaches about 90%, the two-step reaction experiment adopts one-pot synthesis, the operation is simplified, the yield is improved, and the industrial production is more favorably realized. The method is low in cost, safe to operate, high in total yield and more suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical intermediates, and in particular to a method for preparing an abemaciclib intermediate 5-[(4-ethylpiperazine-1-yl)methyl]pyridine-2-amine and a salt thereof. Background Art

[0002] 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine and its corresponding salts are important intermediates of the CDK4 / 6 inhibitor Abemaciclib. Abemaciclib, which is currently approved by the FDA for marketing, was developed by Eli Lilly and Company in the United States and is used to treat advanced or metastatic breast cancer.

[0003] There are many reported methods for synthesizing 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine and its corresponding salts:

[0004] 1. Patent WO2009141386 uses 6-aminonicotinic acid ethyl ester as the starting material, undergoes Boc protection, lithium aluminum hydroxide reduction, mesylation, and then reacts with N-ethylpiperazine and deprotects to prepare:

[0005]

[0006] 2. Patent CN109761959 uses 2-chloro-5-bromopyridine as the starting material and is prepared by Grignard reaction, reductive amination reaction and copper-catalyzed amination reaction:

[0007]

[0008] The total yield of the two steps is 69%, but the reproducibility is not high and has no industrial value.

[0009] 3. Patent CN106316935 uses 6-nitronicotinic acid as the starting material, and is prepared by condensation reaction, Pd / C hydrogenation reaction and lithium aluminum tetrahydride reduction reaction:

[0010]

[0011] 4. Patent CN108191747 uses 5-(4-ethylpiperazine-1-carbonyl)-2-nitropyridine as the starting material, and is prepared by Ga(OTf)3 catalytic reduction and Pd / C or Raney nickel reduction:

[0012]

[0013] 5. Patent CN108440401 uses 2-chloro-5-chloromethylpyridine as the starting material, reacts with N-ethylpiperazine, and then undergoes a copper-catalyzed amination reaction to prepare:

[0014]

[0015] The two-step yield of patent CN108440401 is only 34%, and copper powder is used as catalysis, so the yield is relatively low and has no industrial value.

[0016] The above synthetic routes have the disadvantages of high initial raw material / reagent cost, harsh reaction conditions (anhydrous and oxygen-free operation), complex post-treatment and difficult product purification (column chromatography is required). Summary of the invention

[0017] The invention discloses a method for preparing 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine and its salt, which uses amide as an ammonia source, avoids the need for a sealed can reaction when using ammonia water, uses a simpler, easier to obtain, and lower-cost ligand, greatly improves the yield, and solves the problems of high cost and harsh conditions in the preparation process of the prior art.

[0018] The present invention discloses the following technical solution:

[0019] A method for preparing 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine and its salt comprises the following steps:

[0020]

[0021] R is an alkyl group,

[0022] The compound of formula II is reacted with an amide compound under the conditions of a catalyst, cuprous iodide and a ligand. The compound of formula III is prepared by reaction, and the compound of formula IV is prepared by the compound of formula III under alkaline conditions.

[0023] Further, the ligand comprises:

[0024]

[0025] Furthermore, the amide compounds include formamide, acetamide, propionamide, butyramide, isobutyramide, valeramide, and isovaleramide.

[0026] Furthermore, the molar ratio of the compound of formula II to the catalyst is 10:0.5-4.

[0027] Furthermore, the molar ratio of the catalyst to the ligand is 1:0.2-4.

[0028] Furthermore, the molar ratio of the compound of formula II to the amide compound is 1:1-8.

[0029] Furthermore, the temperature for the reaction of the compound of formula II with the amides is 80-150°C.

[0030] Furthermore, the temperature for the reaction of the compound of formula III with the base is 80-120°C.

[0031] Furthermore, the solvent is cyclohexanol, 1,4-dioxane, tert-amyl alcohol, or dimethyl sulfoxide.

[0032] Further, the compound of formula II is prepared from the compound of formula I,

[0033]

[0034] Compared with the prior art, the present invention has the following technical effects:

[0035] The use of readily available amide as ammonia source avoids the need for ammonia water to seal the reaction tank, which improves the convenience of operation. The use of ligands makes the yield reach about 90%, and the two-step reaction experiment is a one-pot synthesis, which simplifies the operation and improves the yield, making it more conducive to industrial production. Low cost, safe operation, high total yield, more suitable for industrial production. [Specific embodiment]

[0036]

[0037] Step a, the compound of formula I, 2-chloro-5-chloromethylpyridine, is reacted with N-ethylpiperazine to prepare the compound of formula II.

[0038] The reaction conditions are as follows: N-ethylpiperazine is dissolved in an aqueous solution of alkali, an organic solvent is added, the temperature is maintained at -5 to 5°C, 2-chloro-5-chloromethylpyridine, a compound of formula I, is added, and the temperature is raised to 10 to 30°C to prepare a compound of formula II.

[0039] The bases used include potassium carbonate, sodium carbonate, potassium hydroxide,

[0040] The temperature was further maintained at 0°C, and the temperature after heating was 15 to 25°C.

[0041] Step b1, the compound of formula II is reacted with an amide compound in the presence of a catalyst, cuprous iodide and a ligand. Reaction to prepare the compound of formula III.

[0042] Ligands include the following compounds:

[0043]

[0044] Amide compounds Including: formamide, acetamide, propionamide, butyramide, isobutyramide, valeramide, and isovaleramide.

[0045] The molar ratio of the compound of formula II to the catalyst is 10:0.5 to 4, preferably 10:1 to 3, further 10:1, 10:2, 10:3.

[0046] The molar ratio of the catalyst cuprous iodide to the ligand is 1:0.2 to 4. Preferably 1:0.5 to 2, further: 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.

[0047] The molar ratio of the compound of formula II to the amide compound is 1:1 to 8. Preferably, 1:1 to 6, further: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6.

[0048] The temperature for the reaction of the compound of formula II with the amides is 80-150°C, preferably 90-145°C, further 95-145°C.

[0049] The solvents used in the reaction are: cyclohexanol, 1,4-dioxane, tert-amyl alcohol, and dimethyl sulfoxide.

[0050] In some embodiments, the ligands are selected from L8, L9, L10, and L11. In some embodiments, the amide compounds are selected from formamide, acetamide, propionamide, and butyramide. In some embodiments, the solvents selected are cyclohexanol and 1,4-dioxane.

[0051] The conditions for reacting the compound of formula II with the amide compound also include potassium carbonate, sodium carbonate, sodium bicarbonate, and sodium phosphate under alkaline conditions, and the molar ratio of the compound of formula II to the base in this step is 1:1 to 5, further 1:1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.

[0052] Step b2, the compound of formula III is prepared under alkaline conditions to obtain a compound of formula IV or a salt thereof, which is a hydrochloride in some embodiments.

[0053] Alkaline conditions include sodium hydroxide solution, potassium carbonate solution, sodium carbonate solution, and sodium phosphate solution.

[0054] The temperature for the reaction of the compound of formula III with the base is 80-120°C. Preferably, the temperature is 90-110°C, further, 95-105°C.

[0055] Steps b1 and b2 can be prepared by a one-pot process.

[0056] Example 1: Synthesis of 1-[(6-chloropyridin-3-yl)methyl)-4-ethylpiperazine

[0057]

[0058] Add water (100.0g) and potassium carbonate (102.4g) to a 1L three-necked flask, stir to dissolve the potassium carbonate, then add tetrahydrofuran (100.0g) and N-ethylpiperazine (84.6g), then add 2-chloro-5-chloromethylpyridine (100.0g) under an ice bath, and then stir and react at room temperature for 24h. After HPLC monitoring, the reaction is complete, and the tetrahydrofuran is removed by concentration under reduced pressure, and water (300.0g) is added to the residue, and then extracted twice with dichloromethane (250g*2), the organic phases are combined, and concentrated under reduced pressure to obtain 137.6g of orange-red oily liquid 1-[(6-chloropyridin-3-yl)methyl)-4-ethylpiperazine, with a yield of 93%. LCMS(ESI)m / z=240.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.30(d,J=2.4Hz,1H),7.75(dd,J=8.0,2.4Hz,1H),7 .46(d,J=8.8Hz,1H),3.46(s,2H),2.50-2.11(m,10H),0.95(t,J=7.2Hz,3H).

[0059] Example 2: Synthesis of 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine

[0060]

[0061] Example 2-1

[0062]

[0063] 1,4-dioxane (400.0 g), L8 (4.1 g), cuprous iodide (7.9 g), 1-[(6-chloropyridin-3-yl)methyl)-4-ethylpiperazine (100.0 g), formamide (36.1 g) and anhydrous sodium phosphate (68.9 g) were added to a 1L three-necked flask in sequence, and the mixture was stirred and reacted at 95°C for 24 hours under nitrogen protection. After the disappearance of the raw materials monitored by HPLC, the mixture was cooled to 100°C, and a solution of potassium carbonate (66.9 g) in water (300.0 g) was added, and the mixture was stirred and reacted at 100°C for 16 hours. After the hydrolysis was complete, the mixture was cooled to room temperature, the pH value was adjusted to 2 with concentrated hydrochloric acid, the mixture was filtered with diatomaceous earth, the filtrate was separated into layers, the aqueous phase was extracted twice with dichloromethane (100 g*2), the organic phase was discarded, the aqueous phase was adjusted to pH value to 11 with 50% aqueous sodium hydroxide solution, and then extracted three times with dichloromethane (200 g*3), the organic phases were combined, concentrated under reduced pressure, and the residue was recrystallized with ethyl acetate (100 g) to obtain 75.3 g of off-white solid 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine, with a yield of 82%. LCMS (ESI) m / z=221.1[M+H]+. 1H NMR (400MHz, CDCl3) δ7.93 (d, J=2.2Hz, 1H), 7.39 (dd, J=8.4, 2.2Hz, 1H), 6.44 (d, J=8.4,1H),4.44(s,2H),3.35(s,2H),2.56-2.31(m,10H),1.04(t,J=7.2Hz,3H).

[0064] Example 2-2

[0065]

[0066] Cyclohexanol (400.0 g), L10 (N, N'-dimethylethylenediamine) (3.7 g), cuprous iodide (7.9 g), 1-[(6-chloropyridin-3-yl)methyl)-4-ethylpiperazine (100.0 g), acetamide (98.6 g) and anhydrous sodium phosphate (102.6 g) were added to a 1L three-necked flask in sequence, and the mixture was stirred and reacted at 140°C for 24 hours under nitrogen protection. After the disappearance of the raw materials monitored by HPLC, the mixture was cooled to 100°C, and a solution of sodium hydroxide (66.9 g) in water (300.0 g) was added, and the mixture was stirred and reacted at 100°C for 16 hours. After the hydrolysis was complete, the mixture was cooled to room temperature, the pH value was adjusted to 2 with concentrated hydrochloric acid, the mixture was filtered with diatomaceous earth pad, the filtrate was separated into layers, the aqueous phase was extracted twice with dichloromethane (100 g*2), the organic phase was discarded, the aqueous phase was adjusted to pH value to 11 with 50% aqueous sodium hydroxide solution, and then extracted three times with dichloromethane (200 g*3), the organic phases were combined, concentrated under reduced pressure, and the residue was recrystallized with ethyl acetate (100 g) to obtain 79.2 g of off-white solid 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine, with a yield of 86%. LCMS (ESI) m / z=221.1[M+H]+. 1H NMR (400MHz, CDCl3) δ7.93 (d, J=2.2Hz, 1H), 7.39 (dd, J=8.4, 2.2Hz, 1H), 6.44 (d, J=8.4,1H),4.44(s,2H),3.35(s,2H),2.56-2.31(m,10H),1.04(t,J=7.2Hz,3H).

[0067] Example 2-3

[0068]

[0069] Add dimethyl sulfoxide (400.0 g), L11 (8.5 g), cuprous iodide (7.9 g), 1-[(6-chloropyridin-3-yl)methyl)-4-ethylpiperazine (100.0 g), acetamide (98.6 g) and anhydrous sodium phosphate (137.7 g) to a 1L three-necked flask in sequence, and stir and react at 130°C for 24 hours under nitrogen protection. After the disappearance of the raw material by HPLC monitoring, cool to 95°C, add a solution of sodium hydroxide (66.9 g) in water (300.0 g), and continue to stir and react at 100°C for 16 hours. After the hydrolysis was complete, the mixture was cooled to room temperature, the pH value was adjusted to 2 with concentrated hydrochloric acid, the mixture was filtered with diatomaceous earth, the filtrate was separated into layers, the aqueous phase was extracted twice with dichloromethane (100 g*2), the organic phase was discarded, the aqueous phase was adjusted to pH value to 11 with 50% aqueous sodium hydroxide solution, and then extracted three times with dichloromethane (200 g*3), the organic phases were combined, concentrated under reduced pressure, and the residue was recrystallized with ethyl acetate (100 g) to obtain 76.4 g of off-white solid 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine, with a yield of 83%. LCMS (ESI) m / z=221.1[M+H]+. 1H NMR (400MHz, CDCl3) δ7.93 (d, J=2.2Hz, 1H), 7.39 (dd, J=8.4, 2.2Hz, 1H), 6.44 (d, J=8.4,1H),4.44(s,2H),3.35(s,2H),2.56-2.31(m,10H),1.04(t,J=7.2Hz,3H).

[0070] Embodiment 2-4

[0071]

[0072] Cyclohexanol (400.0 g), L10 (5.4 g), cuprous iodide (7.9 g), 1-[(6-chloropyridin-3-yl)methyl)-4-ethylpiperazine (100.0 g), acetamide (23.7 g) and anhydrous sodium phosphate (275.4 g) were added to a 1L three-necked flask in sequence, and the mixture was heated to 145°C and stirred for 24 hours under nitrogen protection. After the disappearance of the raw materials by HPLC monitoring, the mixture was cooled to 100°C, and a solution of sodium hydroxide (66.9 g) in water (300.0 g) was added, and the mixture was stirred for 16 hours at 105°C. After the hydrolysis was complete, the mixture was cooled to room temperature, the pH value was adjusted to 2 with concentrated hydrochloric acid, the mixture was filtered with diatomaceous earth, the filtrate was separated into layers, the aqueous phase was extracted twice with dichloromethane (100 g*2), the organic phase was discarded, the aqueous phase was adjusted to pH value to 11 with 50% aqueous sodium hydroxide solution, and then extracted three times with dichloromethane (200 g*3), the organic phases were combined, concentrated under reduced pressure, and the residue was recrystallized with ethyl acetate (100 g) to obtain 74.6 g of off-white solid 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine, with a yield of 81%. LCMS (ESI) m / z=221.1[M+H]+. 1H NMR (400MHz, CDCl3) δ7.93 (d, J=2.2Hz, 1H), 7.39 (dd, J=8.4, 2.2Hz, 1H), 6.44 (d, J=8.4,1H),4.44(s,2H),3.35(s,2H),2.56-2.31(m,10H),1.04(t,J=7.2Hz,3H).

[0073] Embodiment 2-5

[0074]

[0075] Add tert-amyl alcohol (400.0 g), L9 (3.7 g), cuprous iodide (7.9 g), 1-[(6-chloropyridin-3-yl)methyl)-4-ethylpiperazine (100.0 g), propionamide (177.4 g) and anhydrous sodium phosphate (102.0 g) to a 1L three-necked flask in sequence, and stir and react at 145°C for 24 hours under nitrogen protection. After the disappearance of the raw materials monitored by HPLC, cool to 100°C, add a solution of sodium hydroxide (66.9 g) in water (300.0 g), and continue to stir and react at 100°C for 16 hours. After the hydrolysis was complete, the mixture was cooled to room temperature, the pH value was adjusted to 2 with concentrated hydrochloric acid, the mixture was filtered with diatomaceous earth, the filtrate was separated into layers, the aqueous phase was extracted twice with dichloromethane (100 g*2), the organic phase was discarded, the aqueous phase was adjusted to pH value to 11 with 50% aqueous sodium hydroxide solution, and then extracted three times with dichloromethane (200 g*3), the organic phases were combined, concentrated under reduced pressure, and the residue was recrystallized with ethyl acetate (100 g) to obtain 74.2 g of off-white solid 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine, with a yield of 80.5%. LCMS (ESI) m / z=221.1[M+H]+. 1H NMR (400MHz, CDCl3) δ7.93 (d, J=2.2Hz, 1H), 7.39 (dd, J=8.4, 2.2Hz, 1H), 6.44 (d, J=8.4,1H),4.44(s,2H),3.35(s,2H),2.56-2.31(m,10H),1.04(t,J=7.2Hz,3H).

[0076] Embodiment 2-6

[0077]

[0078] Cyclohexanol (400.0 g), L10 (3.7 g), cuprous iodide (7.9 g), 1-[(6-chloropyridin-3-yl)methyl)-4-ethylpiperazine (100.0 g), propionamide (117.0 g) and anhydrous sodium phosphate (103.0 g) were added to a 1L three-necked flask in sequence, and the mixture was stirred and reacted at 140°C for 24 hours under nitrogen protection. After the disappearance of the raw materials monitored by HPLC, the mixture was cooled to 100°C, and a solution of sodium hydroxide (66.9 g) in water (300.0 g) was added, and the mixture was stirred and reacted at 100°C for 16 hours. After the hydrolysis was complete, the mixture was cooled to room temperature, the pH value was adjusted to 2 with concentrated hydrochloric acid, the mixture was filtered with diatomaceous earth, the filtrate was separated into layers, the aqueous phase was extracted twice with dichloromethane (100 g*2), the organic phase was discarded, the aqueous phase was adjusted to pH value to 11 with 50% aqueous sodium hydroxide solution, and then extracted three times with dichloromethane (200 g*3), the organic phases were combined, concentrated under reduced pressure, and the residue was recrystallized with ethyl acetate (100 g) to obtain 73.9 g of off-white solid 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine, with a yield of 80%. LCMS (ESI) m / z=221.1[M+H]+. 1H NMR (400MHz, CDCl3) δ7.93 (d, J=2.2Hz, 1H), 7.39 (dd, J=8.4, 2.2Hz, 1H), 6.44 (d, J=8.4,1H),4.44(s,2H),3.35(s,2H),2.56-2.31(m,10H),1.04(t,J=7.2Hz,3H).

[0079] Comparative Example

[0080]

[0081] Using aqueous ammonia as the ammonia source and reacting according to the conditions of Example 2-1, different ligands were used, and the yield was low, or even no product was obtained.

[0082]

[0083]

[0084]

[0085]

Claims

1. A method for preparing 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine and its salt, characterized in that: The following steps are involved: R is an alkyl group, The compound of formula II is reacted with an amide compound under the conditions of a catalyst, cuprous iodide and a ligand. The compound of formula III is prepared by reaction, and the compound of formula IV is prepared by the compound of formula III under alkaline conditions.

2. The method for preparing 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine and its salt according to claim 1, characterized in that: The ligands include:

3. The method for preparing 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine and its salt according to claim 1, characterized in that: The amide compounds include formamide, acetamide, propionamide, butyramide, isobutyramide, valeramide and isovaleramide.

4. The method for preparing 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine and its salt according to claim 1, characterized in that: The molar ratio of the compound of formula II to the catalyst is 10:0.5-4.

5. The method for preparing 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine and its salt according to claim 1, characterized in that: The molar ratio of the catalyst to the ligand is 1:0.2-4.

6. The method for preparing 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine and its salt according to claim 1, characterized in that: The molar ratio of the compound of formula II to the amide compound is 1:1-8.

7. The method for preparing 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine and its salt according to claim 1, characterized in that: The temperature for the reaction of the compound of formula II with the amides is 80-150°C.

8. The method for preparing 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine and its salt according to claim 1, characterized in that: The temperature for the reaction of the compound of formula III with the base is 80-120°C.

9. The method for preparing 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine and its salt according to claim 1, characterized in that: The solvents are cyclohexanol, 1,4-dioxane, tert-amyl alcohol, and dimethyl sulfoxide.

10. A method for preparing 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine and a salt thereof according to any one of claims 1 to 9, characterized in that: The compound of formula II is prepared from the compound of formula I,

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