methyl (2S)-3-iodo-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate

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

Procedure: To a solution of (2,3-difluorophenyl)acetonitrile (18.6 g, 122 mmol) in N,N-dimethylformamide (243 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (4.37 g, 109 mmol). After 20 min, methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (20.0 g, 60.8 mmol) was added, and the resulting mixture stirred 50 min. Saturated aqueous sodium bicarbonate was added, and the mixture was warmed to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate) gave the title compound. MS: m/z=377.3 (M+Na). the mixture was extracted with ethyl acetate (3×) The combined organic extracts were washed with water (3×), brine dried over magnesium sulfate filtered concentrated Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate)

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

Procedure: A mixture of cesium carbonate (9.80 g, 30.1 mmol) and methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (9.90 g, 30.1 mmol) in DMF (75 mL) was stirred at 23° C. for 45 min before 1-(3-chlorophenyl)propan-2-one (6.09 g, 36.1 mmol) and additional cesium carbonate (9.80 g, 30.1 mmol) were added. The resulting mixture was stirred for 2.5 h. The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C. The concentrated mixture was partitioned between water (100 mL) and ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the title compound as a 1:1 racemic mixture of cis and trans diastereomers, which was used without further purification. MS: m/z=392.1 (M+Na). were added The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C The concentrated mixture was partitioned between water (100 mL) and ethyl acetate (2×200 mL) The combined organic layers were washed with brine dried over sodium sulfate concentrated

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

Procedure: To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (5.00 g, 15.19 mmol) in DMF (20 mL) was added cesium carbonate (5.44 g, 16.71 mmol) and the mixture was stirred at 23° C. for 2 h. (2-Fluorophenyl)acetonitrile (5.87 mL, 45.6 mmol) and cesium carbonate (7.42 g, 22.8 mmol) were added and the resulting mixture was stirred for 1 h. The mixture was filtered and water was added to the filtrate. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate→50% ethyl acetate/hexane) gave the title compound as a racemic mixture of cis and trans diastereomers. MS: m/z=378.1 (M+CH3CN+1). were added The mixture was filtered water was added to the filtrate The mixture was extracted with ethyl acetate (3×) The combined organic extracts were washed with water (3×), brine dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (0% ethyl acetate→50% ethyl acetate/hexane)

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (1.58 g, 4.80 mmol) in DMF (24 mL) was added cesium carbonate (1.56 g, 4.80 mmol) and the mixture was stirred at 23° C. for 45 min. 1-(2-Methylphenyl)-propan-2-one (0.783 g, 5.28 mmol) and cesium carbonate (2.35 g, 7.20 mmol) were added and the resulting mixture was stirred for 18 h. The mixture was filtered and water was added to the filtrate. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate→40% ethyl acetate/hexane) gave the title compound. MS: m/z=350.1 (M+1). the resulting mixture was stirred for 18 h The mixture was filtered water was added to the filtrate The mixture was extracted with ethyl acetate (3×) The combined organic extracts were washed with water (3×), brine dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (5% ethyl acetate→40% ethyl acetate/hexane)

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

Procedure: A mixture of cesium carbonate (9.80 g, 30.1 mmol) and methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (9.90 g, 30.1 mmol) in DMF (75 mL) was stirred at 23° C. for 45 min before 1-(3-chlorophenyl)propan-2-one (6.09 g, 36.1 mmol) and additional cesium carbonate (9.80 g, 30.1 mmol) were added. The resulting mixture was stirred for 2.5 h. The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C. The concentrated mixture was partitioned between water (500 mL) and ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the title compound as a 1:1 racemic mixture of diastereomers, which was used without further purification. MS: m/z=314.1 (M−t-Bu+1). were added The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C The concentrated mixture was partitioned between water (500 mL) and ethyl acetate (2×200 mL) The combined organic layers were washed with brine dried over sodium sulfate concentrated

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

Procedure: To a solution of (2,3-difluorophenyl)acetonitrile (18.6 g, 122 mmol) in N,N-dimethylformamide (243 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (4.37 g, 109 mmol). After 20 min, methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (20.0 g, 60.8 mmol) was added, and the resulting mixture stirred 50 min. Saturated aqueous sodium bicarbonate was added, and the mixture was warmed to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate) gave the title compound (12.0 g). MS 377.3 (M+Na). the mixture was extracted with ethyl acetate (3×) The combined organic extracts were washed with water (3×), brine dried over magnesium sulfate filtered concentrated Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate)

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (5.00 g, 15.2 mmol) in DMF (20 mL) was added cesium carbonate (5.44 g, 16.7 mmol) and the mixture was stirred at 23° C. for 2 hours. (2-Fluorophenyl)acetonitrile (5.87 mL, 45.6 mmol) and cesium carbonate (7.42 g, 22.8 mmol) were added and the resulting mixture was stirred for 1 hour. The mixture was filtered and water was added to the filtrate. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate→+50% ethyl acetate/hexane) gave the title compound as a racemic mixture of cis and trans diastereomers. MS: m/z=378.1 (M+CH3CN+1). the resulting mixture was stirred for 1 hour The mixture was filtered water was added to the filtrate The mixture was extracted with ethyl acetate (3×) The combined organic extracts were washed with water (3×), brine dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (0% ethyl acetate→+50% ethyl acetate/hexane)

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

Procedure: A mixture of cesium carbonate (9.80 g, 30.1 mmol) and methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (9.90 g, 30.1 mmol) in DMF (75 mL) was stirred at 23° C. for 45 min before 1-(3-chlorophenyl)propan-2-one (6.09 g, 36.1 mmol) and additional cesium carbonate (9.80 g, 30.1 mmol) were added. The resulting mixture was stirred for 2.5 h. The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C. The concentrated mixture was partitioned between water (500 mL) and ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the title compound as a 1:1 racemic mixture of diastereomers, which was used without further purification. MS: m/z=314.1 (M−t-Bu+1). were added The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C The concentrated mixture was partitioned between water (500 mL) and ethyl acetate (2×200 mL) The combined organic layers were washed with brine dried over sodium sulfate concentrated

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

Procedure: A mixture of cesium carbonate (9.80 g, 30.1 mmol) and methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (9.90 g, 30.1 mmol) in DMF (75 mL) was stirred at ambient temperature for 45 min before 1-(3-chlorophenyl)propan-2-one (6.09 g, 36.1 mmol) and additional cesium carbonate (9.80 g, 30.1 mmol) were added. The resulting mixture was stirred for 2.5 h. The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C. The concentrated mixture was partitioned between water (500 mL) and ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound as a 1:1 racemic mixture of diastereomers, which was used without further purification. MS: m/z=314.1 (M−t-Bu+1). were added The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C The concentrated mixture was partitioned between water (500 mL) and ethyl acetate (2×200 mL) The combined organic layers were washed with brine dried over sodium sulfate concentrated in vacuo

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

Procedure: A mixture of cesium carbonate (9.80 g, 30.1 mmol) and methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (9.90 g, 30.1 mmol) in DMF (75 mL) was stirred at ambient temperature for 45 min before 1-(3-chlorophenyl)propan-2-one (6.09 g, 36.1 mmol) and additional cesium carbonate (9.80 g, 30.1 mmol) were added. The resulting mixture was stirred for 2.5 h. The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C. The concentrated mixture was partitioned between water (500 mL) and ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound as a 1:1 racemic mixture of diastereomers, which was used without further purification. MS: m/z=314.1 (M−t-Bu+1). were added The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C The concentrated mixture was partitioned between water (500 mL) and ethyl acetate (2×200 mL) The combined organic layers were washed with brine dried over sodium sulfate concentrated in vacuo

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

Procedure: A solution of N-t-butoxycarbonyl-3-iodo-D-alanine methyl ester (0.81 g, 2.46 mmol) in dry toluene (12 ml) and dry dimethylacetamide (0.8 ml) was added to a nitrogen purged flask charged with zink-copper couple (0.32 g, 4.92 mmol). The mixture was treated in an ultrasonic bath for 1 h until no starting material remained (as judged by TLC). A mixture of PdCl2 (23 mg, 0.13 mmol) and tri-o-tolylphosphine (79 mg, 0.26 mmol) was added followed by 2-bromo-7-chloro-3-diethylphosphonomethyl-6-methylquinoline (0.5 g, 1.23 mmol) and sonication was continued for 3 hours at 50°-60° C. After cooling the reaction mixture was diluted with ethyl acetate, extracted with saturated sodium hydrogen carbonate solution, dried over MgSO4 and evaporated. The crude product was subjected to chromatography on silica gel with ethyl acetate as eluant to yield 0.49 g of methyl (R)-α-t-butoxycarbonylamino-7-chloro-3-diethylphosphonomethyl-6-methyl-2-quinolinepropionate. The mixture was treated in an ultrasonic bath for 1 h until no starting material was added After cooling the reaction mixture extracted with saturated sodium hydrogen carbonate solution dried over MgSO4 evaporated

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

Procedure: A solution of N-t-butoxycarbonyl-3-iodo-D-alanine methyl ester (0.66 g, 2 mmol) in dry benzene (3 ml) and dry dimethylacetamide (0.5 ml) was added to a zinc-copper couple (0.31 g). The resulted mixture was sonicated at 40°-45° C. under nitrogen for 2.5-3 h until no starting material remained (as judged by TLC). Tri-o-tolylphosphine (0.06 g, 0.2 mmol) and palladium chloride (0.02 g, 0.1 mmol) were added followed by a solution of 6,7-dichloro-3-dimethylphosphonomethyl-2-bromoquinoline (0.4 g, 1 mmol) in dry benzene (3 ml) and dry dimethylacetamide (0.5 ml). The resulted mixture was stirred under nitrogen at 50°-60° C. for 2.5-3 h and then allowed to cool. Water was added and the mixture was filtered through Celite, the latter was washed with ethyl acetate. The combined organic phases were separated, dried, (MgSO4) and concentrated in vacuo. The residue was coevaporated several times with toluene to remove most of the dimethylacetamide and then purified on a silica gel column using 0-2% methanol in chloroform as eluent to give 0.33 g of methyl (R)-α-t-butoxycarbonylamino-6,7-dichloro-3-dimethylphosphonomethyl-2-quinolinepropionate. The resulted mixture was sonicated at 40°-45° C. under nitrogen for 2.5-3 h until no starting material to cool the mixture was filtered through Celite the latter was washed with ethyl acetate The combined organic phases were separated dried (MgSO4) and concentrated in vacuo to remove most of the dimethylacetamide purified on a silica gel column