Hydrochloric Acid → 2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde

25 mg of crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine was treated with 135 mg of N,N-Dimethylglycine via Procedure B. This crude intermediate was then subjected to Procedure A to give 7.4 mg of 67. MS (Q1) 521.2 (M)+. 66: 400 mg of crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine was treated with 175 mg of L-Lactic Acid via Procedure B. This crude intermediate was then subjected to Procedure A to give 212 mg of 66. MS (Q1) 508.2 (M)+. 56: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (50 mg) was treated with 5 eq methyl chloroformate and 6 eq DIPEA in 1 mL of DMF. The reaction mixture was concentrated and extracted into Ethyl Acetate with Saturated Ammonium Chloride. The aqueous layer was back-extracted once with DCM. The organics were combined and concentrated to dryness. This crude intermediate was then subjected to Procedure A to give 3.7 mg of 56. MS (Q1) 494.2 (M)+. 55: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (50 mg) was treated with 5 eq ethyl chloroformate and 6 eq DIPEA in 1 mL of DMF. The reaction mixture was concentrated and extracted into Ethyl Acetate with Saturated Ammonium Chloride. The aqueous layer was back-extracted once with DCM. The organics were combined and concentrated to dryness. This crude intermediate was then subjected to Procedure A to give 35.4 mg of 55. MS (Q1) 508.2 (M)+. 54: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (50 mg) was treated with 3 eq Acetic Anhydride and 5 eq DIPEA in 1 mL of DCM. The reaction mixture was concentrated and extracted into Ethyl Acetate with Saturated Ammonium Chloride. The aqueous layer was back-extracted once with DCM. The organics were combined and concentrated to dryness. This crude intermediate was then subjected to Procedure A to give 20.2 mg of 54. MS (Q1) 478.2 (M)+. 53: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (50 mg) was treated with 5 eq of Formic Acid, 5 eq EDC and 5 eq DIPEA in 1 mL of DMF. This crude intermediate was then subjected to Procedure A to give 5.1 mg of 53. MS (Q1) 464.2 (M)+. 52: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (50 mg) was treated with 2.5 eq of pivaloyl chloride and 3 eq DIPEA in 1 mL of DCM. This crude intermediate was then subjected to Procedure A to give 36.7 mg of 52. MS (Q1) 520.3 (M)+. 48: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (50 mg) was treated with 2.5 eq of cyclopropanecarbonyl chloride and 3 eq DIPEA in 1 mL of DCM. This crude intermediate was then subjected to Procedure A to give 27.2 mg of 48. MS (Q1) 504.2 (M)+. 107: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (100 mg) was treated with 70 mg of D-Lactic Acid via Procedure B. This crude intermediate was then subjected to Procedure A to give (R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one. MS (Q1) 508.2 (M)+. 108: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (100 mg) was treated with 75 mg of 2-Hydroxyisobutyric Acid via Procedure B. This crude intermediate was then subjected to Procedure A to give 1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxy-2-methylpropan-1-one. MS (Q1) 522.2 (M)+. 109: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (100 mg) was treated with 55 mg of Glycolic Acid via Procedure B. This crude intermediate was then subjected to Procedure A to give 1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone. MS (Q1) 494.4 (M)+. 110: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (100 mg) was treated with 55 μL of Methoxyacetic Acid via Procedure B. This crude intermediate was then subjected to Procedure A to give 1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methoxyethanone. MS (Q1) 508 (M)+. 111: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (100 mg) was treated with 70 μL of tetrahydro-2-furoic acid via Procedure B. This crude intermediate was then subjected to Procedure A to give (4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone. MS (Q1) 534.3 (M)+. 112: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (100 mg) was treated with 100 mg of Boc-amino-cyclopropanecarboxylic acid via Procedure B. This crude intermediate was then subjected to Procedure A to give (4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-aminocyclopropyl)methanone. MS (Q1) 519.3 (M)+. 113: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (100 mg) was treated with 140 mg of Boc-Alanine via Procedure B. This crude intermediate was then subjected to Procedure A to give (S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-aminopropan-1-one. MS (Q1) 507.3 (M)+. 114: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (100 mg) was treated with 140 mg of Boc-D-Alanine via Procedure B. This crude intermediate was then subjected to Procedure A to give (R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-aminopropan-1-one. MS (Q1) 507.3 (M)+. 115: The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (100 mg) was treated with 100 mg of methanesulphonylacetic acid via Procedure B. This crude intermediate was then subjected to Procedure A to give 1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(methylsulfonyl)ethanone. MS (Q1) 556.3 (M)+. 116: To 700 mg of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde was added 645 mg 1-BOC-piperazine via Procedure C to give 1.12 g of 2-chloro-4-morpholino-6-((Boc-piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine. The crude HCl salt of 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine was then formed by treatment with 5 eq 4N HCl in dioxane in a solution of DCM and subsequent evaporation to dryness.

ORD record

ord-451e8bef41534544ace42c48ead44471

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08802670B2