Preparation method of N-((1R,4R)-4-(4-(cyclopropylmethyl)piperazine-1-yl)cyclohexyl)acetamide

Abstract

The invention discloses a preparation method of N-((1R,4R)-4-(4-(cyclopropylmethyl)piperazine-1-yl)cyclohexyl)acetamide. The preparation method comprises the following steps: (1) reacting a compound represented by the structural formula (2) and a compound represented by the structural formula (3) in a solvent in the presence of a catalyst namely tetraisopropyl titanate; (2) adding an alcoholic solvent and a reducing agent, carrying out reactions (time B) at a room temperature, and collecting N-((1R,4R)-4-(4-(cyclopropylmethyl)piperazine-1-yl)cyclohexyl)acetamide from the reaction products. The method adopts a one-pot method; the reaction product is the target product 4, the yield is high, and the reactions are controllable. The results of a large amount of experiments show that the high yield of target product 4 can be realized only the following conditions are met: one pot method is adopted, and tetraisopropyl titanate, alcohol, and reducing agent exist at the same time. The preparation method has the advantages that the raw materials are easily-available, the conditions are mild, the post treatment is simple, the yield of target product is high, and the preparation method is suitable for massive industrial production.

Description

technical field

[0001] The present invention relates to the preparation method that is used for preparing PLK1 inhibitor Volasertib intermediate, specifically relates to intermediate N-((1R,4R)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl ) The preparation method of acetamide. Background technique

[0002] The World Health Organization (WHO) divides myeloid tumors into four categories, namely AML: characterized by the accumulation of immature myeloid cells in the bone marrow and suppression of bone marrow hematopoiesis; CMPD: chronic myeloproliferative disease, often accompanied by undifferentiated myeloid cells Increased number of hyperproliferative bone marrow, and increased peripheral blood cells; MDS: myelodysplastic syndrome, bone marrow ineffective hematopoiesis and peripheral blood cytopenias; MDS / MPD: myelodysplastic / myeloproliferative disorders.

[0003] Volasertib inhibits Paul-like kinase (PLK) 1 and is a highly potent PLK1 inhibitor with IC50 of 0.87nM, 6- ...

Examples

Embodiment 1

[0032] N-cyclopropylmethylpiperazine (1, 34.00g, 0.24mol), 4-acetamidocyclohexanone (2, 18.61g, 0.12mol), dissolved in 170mL of dichloromethane, then added tetraisotitanate Propyl ester (3.40g), reacted at 5°C for 15 hours, then added absolute ethanol (3.4mL), sodium cyanoborohydride (15.08g, 0.24mol) to the system, reacted for 2.0 hours, and slowly added water under an ice-water bath ( 200 mL), stirred for 15 min, filtered the precipitated solid, separated the organic phase, extracted the aqueous phase with dichloromethane (20 mL×3), concentrated, and dried in vacuo to obtain product 4 (56.28 g), yield 84.0%. Product 4: ESI-MS (m / z) = 280.25 [M+H] + ; 1 H-NMR (DMSO-D 6 )δ: 0.35(-CH 2 CH 2 CH-, 5H, m), 1.50(-CH 2 CH 2 -, 8H, m), 1.84(-CH 3 , 3H, s), 2.09(-CH 2 -, 2H, d), 2.35(-CH 2 CH 2 -, 8H, t), 2.57 (-NCH-, 1H, t), 3.54 (-NCH-, 1H, t), 8.03 (-CONH-, 1H, s).

Embodiment 2

[0034] N-cyclopropylmethylpiperazine (1, 34.00g, 0.24mol), 4-acetamidocyclohexanone (2, 37.22g, 0.24mol), dissolved in 238mL of dichloromethane, then added tetraisotitanate Propyl ester (17.00g), reacted at 8°C for 12 hours, then added methanol (6.8mL), sodium cyanoborohydride (30.16g, 0.48mol) to the system, reacted for 1.5 hours, slowly added water (200mL) under ice-water bath After stirring for 15 min, the precipitated solid was filtered, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20 mL×3), concentrated, and dried in vacuo to obtain product 4 (54.95 g), with a yield of 82.0%.

Embodiment 3

[0036] N-cyclopropylmethylpiperazine (1, 34.00g, 0.24mol), 4-acetamidocyclohexanone (2, 74.44g, 0.48mol), dissolved in 340mL tetrahydrofuran, then added tetraisopropyl titanate (34.00g), reacted at 10°C for 10 hours, then added isopropanol (10.2mL), sodium cyanoborohydride (45.24g, 0.72mol) to the system, reacted for 1.2 hours, slowly added water (200mL) under an ice-water bath After stirring for 15 min, the precipitated solid was filtered, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20 mL×3), concentrated, and dried in vacuo to obtain product 4 (56.97 g), with a yield of 85.0%.

technical field

[0001] The present invention relates to the preparation method that is used for preparing PLK1 inhibitor Volasertib intermediate, specifically relates to intermediate N-((1R,4R)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl ) The preparation method of acetamide. Background technique

[0002] The World Health Organization (WHO) divides myeloid tumors into four categories, namely AML: characterized by the accumulation of immature myeloid cells in the bone marrow and suppression of bone marrow hematopoiesis; CMPD: chronic myeloproliferative disease, often accompanied by undifferentiated myeloid cells Increased number of hyperproliferative bone marrow, and increased peripheral blood cells; MDS: myelodysplastic syndrome, bone marrow ineffective hematopoiesis and peripheral blood cytopenias; MDS / MPD: myelodysplastic / myeloproliferative disorders.

[0003] Volasertib inhibits Paul-like kinase (PLK) 1 and is a highly potent PLK1 inhibitor with IC50 of 0.87nM, 6- ...

Examples

Embodiment 1

[0032] N-cyclopropylmethylpiperazine (1, 34.00g, 0.24mol), 4-acetamidocyclohexanone (2, 18.61g, 0.12mol), dissolved in 170mL of dichloromethane, then added tetraisotitanate Propyl ester (3.40g), reacted at 5°C for 15 hours, then added absolute ethanol (3.4mL), sodium cyanoborohydride (15.08g, 0.24mol) to the system, reacted for 2.0 hours, and slowly added water under an ice-water bath ( 200 mL), stirred for 15 min, filtered the precipitated solid, separated the organic phase, extracted the aqueous phase with dichloromethane (20 mL×3), concentrated, and dried in vacuo to obtain product 4 (56.28 g), yield 84.0%. Product 4: ESI-MS (m / z) = 280.25 [M+H] + ; 1 H-NMR (DMSO-D 6 )δ: 0.35(-CH 2 CH 2 CH-, 5H, m), 1.50(-CH 2 CH 2 -, 8H, m), 1.84(-CH 3 , 3H, s), 2.09(-CH 2 -, 2H, d), 2.35(-CH 2 CH 2 -, 8H, t), 2.57 (-NCH-, 1H, t), 3.54 (-NCH-, 1H, t), 8.03 (-CONH-, 1H, s).

Embodiment 2

[0034] N-cyclopropylmethylpiperazine (1, 34.00g, 0.24mol), 4-acetamidocyclohexanone (2, 37.22g, 0.24mol), dissolved in 238mL of dichloromethane, then added tetraisotitanate Propyl ester (17.00g), reacted at 8°C for 12 hours, then added methanol (6.8mL), sodium cyanoborohydride (30.16g, 0.48mol) to the system, reacted for 1.5 hours, slowly added water (200mL) under ice-water bath After stirring for 15 min, the precipitated solid was filtered, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20 mL×3), concentrated, and dried in vacuo to obtain product 4 (54.95 g), with a yield of 82.0%.

Embodiment 3

[0036] N-cyclopropylmethylpiperazine (1, 34.00g, 0.24mol), 4-acetamidocyclohexanone (2, 74.44g, 0.48mol), dissolved in 340mL tetrahydrofuran, then added tetraisopropyl titanate (34.00g), reacted at 10°C for 10 hours, then added isopropanol (10.2mL), sodium cyanoborohydride (45.24g, 0.72mol) to the system, reacted for 1.2 hours, slowly added water (200mL) under an ice-water bath After stirring for 15 min, the precipitated solid was filtered, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20 mL×3), concentrated, and dried in vacuo to obtain product 4 (56.97 g), with a yield of 85.0%.

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