tert-butyl N,N'-di(propan-2-yl)carbamimidate

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:

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

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

Procedure: A suspension of 6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (1 eq., prepared as described in WO2005/023819) in dry CH2Cl2 (0.19 M) was treated with tert-butyl N,N′-diisopropylimidocarbamate (2 eq.). The resulting clear solution was heated to reflux for 20 h. Addition of a further equivalent of isourea was required after 16 h to drive the reaction to complete conversion. After cooling down the solvent was evaporated in vacuo giving a residue that was purified by flash chromatography (PE:EtOAc, 10:1) affording the title compound (57%). 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 11.12 (bs, 1H), 7.55 (s, 1H), 7.08 (s, 1H), 2.60-2.50 (m, 1H), 1.99-1.67 (m, 5H), 1.51 (s, 9H), 1.45-1.19 (m, 5H). MS (ES+) m/z: 306 [M+H]+. The resulting clear solution was heated to reflux for 20 h the reaction After cooling down the solvent was evaporated in vacuo giving a residue that was purified by flash chromatography (PE:EtOAc, 10:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cooled solution of N-BOC-D-serine (10 g, 48.7 mmol) in methylene chloride (50 ml) was added N,N′-diisopropyl-O-tert-butylisourea (35 ml, 3.5 M) via addition funnel, over 30 min. The reaction mixture was maintained at 0° C. for 2 hrs and then warmed to room temperature over night. The material was again cooled to 0° C. and a second portion of N,N′-diisopropyl-O-tert-butylisourea (28 ml, 3.5 M) was added. The material was stirred for 2 hrs at 0° C. and then warmed again to room temperature over night. Purification by flash silica gel chromatography using (20%) ethyl acetate/hexanes as eluant gave O-tert-butyl-N-BOC-D-serine (7.97 g) as a viscous oil which solidified on standing. via addition funnel warmed to room temperature over night The material was again cooled to 0° C. warmed again to room temperature over night Purification by flash silica gel chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cooled solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid (7.0 g, 21.25 mmol) in dry methylene chloride was added N,N′-diisopropyl-O-tert-butylisourea (12.1 mL, 3.5M) via addition funnel over 45 min. The reaction mixture was maintained at 0° C. for 2 h and then allowed to warm to room temperature overnight. The reaction mixture was loaded onto a flash silica gel column and eluted with ethyl acetate/hexane (5%) to give 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid tert-butyl ester (7.02 g) as a white crystalline solid. via addition funnel over 45 min to warm to room temperature overnight eluted with ethyl acetate/hexane (5%)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cooled solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid (7.0 g, 21.25 mmol) in dry methylene chloride was added N,N′-diisopropyl-O-tert-butylisourea (12.1 mL, 3.5M) via addition funnel over 45 min. The reaction mixture was maintained at 0° C. for 2 h and then allowed to warm to room temperature overnight. The reaction mixture was loaded onto a flash silica gel column and eluted with ethyl acetate/hexane (5%) to give 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid tert-butyl ester (7.02 g) as a white crystalline solid. via addition funnel over 45 min to warm to room temperature overnight eluted with ethyl acetate/hexane (5%)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cooled solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid (30 g, 104.4 mmol), [prepared as described in Example 2, step 1 above], in methylene chloride was added N,N′-diisopropyl-O-tert-butylisourea [can be prepared by the procedure described in Lon J. Mathias, Synthesis, 561-576, (1979)] (75 mL, 3.5 M solution) via additional funnel over 45 min. The reaction mixture was maintained at 0° C. for 2 h, and then allowed to warm to room temperature overnight. Purification by flash chromatography on a silica gel column using (10-20%) ethyl acetate/hexanes as the eluant gave of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid tert-butyl ester (18 g) as a white crystalline solid. can be prepared by the procedure to warm to room temperature overnight Purification by flash chromatography on a silica gel column

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

Procedure: 2-tert-Butyl-1,3-diisopropylisourea (8.04 g, 40.1 mmol) was added to a mixture of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid hydrochloride salt (24) (2.91 g, 7.31 mmol) in THF (165 mL). After stirring for 2 hours at room temperature and 30 minutes at reflux, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with 10% K2CO3 and brine, dried (Na2SO4) and concentrated. The resulting residue was dissolved in CH2Cl2 and filtered. The filtrate was concentrated and purified by flash column chromatography using the Biotage system (CH2Cl2) to give the desired product (40) (3.28 g, 78%). at reflux the reaction mixture was cooled to room temperature The organic layer was washed with 10% K2CO3 and brine dried (Na2SO4) concentrated The resulting residue was dissolved in CH2Cl2 filtered The filtrate was concentrated purified by flash column chromatography

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

Procedure: To a solution of 1-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid in DCM (0.2 M), 3 eq of tert-butyl. N,N′-diisopropylimidocarbamate were added and the mixture was stirred at RT. After 30 min, a further 1.5 eq of tert-butyl N,N′-diisopropylimidocarbamate were added and the solution stirred for an additional hour. The solution was filtered through a pad of celite and then through a pad of silica gel to give the product (83%); MS (ES+) m/z 320 (M+H)+ the solution stirred for an additional hour The solution was filtered through a pad of celite