ethyl 2-(dimethylamino)acetate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzaldehyde, N,N-dimethylglycine ethyl ester and sodium hydride were reacted in ether with the addition of a catalytic amount of ethanol according to the method described in Lieb. Ann. Chem. 703 (1967) 37°-43 to give ethyl α-dimethylaminocinnamate. This compound was then reacted according to the method described in Tetrahedron Letters, 46, (1978) 4573°-4574 with oxalyl chloride and hydrazine in 60% yield to give ethyl 4-phenyl-3-pyrazolecarboxylate, melting point 164°-165° after recrystallization from ethanol/diethyl ether.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 75 g of ethyl N,N-dimethylglycinate, 75 g of 1-methyl-2-piperidylmethanol and 1 g of titanium tetra(n-butoxide) was heated at 45° C. until the amount of ethanol collected indicated the reaction was complete. After cooling a small amount of water was added, the mixture was filtered, and the filtrate was distilled under reduced pressure to provide N-methyl-2-piperidylmethyl N,N-dimethylaminoacetate. collected After cooling a small amount of water was added the mixture was filtered the filtrate was distilled under reduced pressure

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 65.5 g (0.5 mol) of ethyl N,N-dimethylglycinate, 44.6 g (0.5 mol) of N,N-dimethylethanolamine and 0.82 g of dibutyltin oxide was heated at about 130° C. The ethanol by-product was collected in a Dean-Stark trap. When the rate of ethanol evolution and amount of ethanol collected showed that the reaction was essentially complete, the reaction was heated at about 180° C. until ethanol evolution ceased. The liquid product was purified by distillation at reduced pressure to provide 2-(N,N-dimethylamino)ethyl N,N-dimethylaminoacetate. The ethanol by-product was collected in a Dean-Stark trap When the rate of ethanol evolution and amount of ethanol collected the reaction was heated at about 180° C. until ethanol evolution The liquid product was purified by distillation at reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 from Example 11 (50 mg, 0.2 mmol) in CH2Cl2 (4 mL) was added Et3N (84 μL, 0.6 mmol) and dimethylglycine ethyl ester (0.3 mmol). The reaction stirred 18-48 h at room temperature before being quenched with water. The aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo to give N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(dimethylamino)acetamide which was utilized in a Suzuki coupling according to General Procedure A. The crude material was purified by reversed phase HPLC to give 350 (10 mg). MS (Q1) 452 (M)+ before being quenched with water The aqueous layer was extracted with EtOAc The combined organics were dried over Na2SO4 concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 from Example 11 (50 mg, 0.2 mmol) in CH2Cl2 (4 mL) was added Et3N (84 μL, 0.6 mmol) and dimethylglycine ethyl ester (0.3 mmol). The reaction stirred 18-48 h at room temperature before being quenched with water. The aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo to give N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(dimethylamino)acetamide which was utilized in a Suzuki coupling according to General Procedure A. The crude material was purified by reversed phase HPLC to give 350 (10 mg). MS (Q1) 452 (M)+ before being quenched with water The aqueous layer was extracted with EtOAc The combined organics were dried over Na2SO4 concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl (dimethylamino)acetate (0.16 mL, 1.11 mmol) was dissolved in THF (10 mL) and cooled to −78° C. LiHMDS (1.2 mL, 1M solution in THF) was added. The reaction was allowed to stir about 30 minutes. Tert-butyl 4-(bromomethyl)benzoate (0.3063 g, 1.13 mmol) in THF (3 mL) was slowly added to the reaction. The reaction was allowed to stir overnight under nitrogen, slowly warming to room temperature. The reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The resulting mixture was separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried with sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography. 1H NMR 600 MHz (CDCl3) δ 7.87 (m, 2H), 7.24 (m, 2H), 4.08 (m, 1H), 4.06 (m, 1H), 3.41 (dd, 1H, J=9.2, 6.0), 3.07 (dd, 1H, J=13.5, 9.3), 2.97 (dd, 1H, J=13.4, 5.8), 2.39 (s, 6H), 1.56 (s, 9H), 1.16 (m, 3H). MS: cal'd 322 (MH+), exp 322 (MH+). to stir overnight under nitrogen slowly warming to room temperature The reaction was quenched with saturated ammonium chloride diluted with ethyl acetate The resulting mixture was separated The aqueous layer was extracted three times with ethyl acetate The combined organic layer was dried with sodium sulfate filtered concentrated The resulting residue was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The process of example 4 was repeated using N,N-dimethylglycine ethyl ester in place of N,N-dimethylalanine ethyl ester in part (a), and using p-bromoanisole in place of 4-bromochlorobenzene in part (c) to yield the title compound which was isolated as the hydrobromide salt.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The process of example 4 was repeated using N,N-dimethylglycine ethyl ester in place of N,N-dimethylalanine ethyl ester in part (a), and using 5-bromo-2-chlorobenzotrifluoride in place of 4-bromochlorobenzene in part (c) to yield the title compound which was isolated as the hydrochloride salt.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The process of example 4 was repeated using N,N-dimethylglycine ethyl ester in place of the N,N-dimethylalanine ethyl ester in part (a), and using 4-bromotoluene in place of the 4-bromochlorobenzene in part (c) to yield the title compound, m.p. 114°-116° C.