DS-1040, Activated thrombin activatable fibrinolysis (TAFIa) inhibitor

DS-1040
Daiichi Sankyo Co Ltd
Ischemic stroke
(2S)-5-amino-2-[[1-(4-methylcyclohexyl)imidazol-4-yl]methyl]pentanoic acid
1H-​Imidazole-​4-​propanoic acid, α-​(3-​aminopropyl)​-​1-​(trans-​4-​methylcyclohexyl)​-​, (αS)​-
(2S)-5-amino-2-{[1-(trans-4-methylcyclohexyl)-1H-imidazol-4-yl]methyl}pentanoic acid
free form cas 1335138-62-9
1:1 TOSYLATE 1335138-89-0
1335138-90-3  1:1:1 TOSYLATE HYDRATE
phase 2, Ischemic stroke

Molecular Formula:	C16H27N3O2
Molecular Weight:	293.40448 g/mol

TAFIa inhibitors, useful for treating myocardial infarction, angina, pulmonary hypertension and deep vein thrombosis.
In March 2016, DS-1040 was reported to be in phase 2 C clinical development, and the study was expected to complete in June 2017.
https://clinicaltrials.gov/ct2/show/NCT02560688

• 01 Feb 2016Daiichi Sankyo initiates a phase I trial in Healthy volunteers in United Kingdom (NCT02647307)
• 09 Jan 2016Daiichi Sankyo plans a phase I trial in Healthy volunteers in United Kingdom (NCT02647307)
• 29 Sep 2015Daiichi Sankyo plans a drug-interaction phase I trial in Healthy volunteers in United Kingdom (IV) (NCT02560688)

SYNTHESIS

COMPLETE SYNTHESIS





Patent
WO201111506
PATENT
WO2013039202
PATENT
WO 2016043254

PATENT

WO2016043253
COMPLETE SYN..........

WO2016043253

The optical purity of the obtained compound was measured by the following HPLC analysis conditions.
(2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans -4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valeric acid (S)-2-amino 1-propanol salt (A1 step, A2 step, A3 step), (2S) -5 - [ (tert- butoxycarbonyl) amino] -2 - {[1- (trans -4- methylcyclohexyl)-lH-imidazole 4-yl] methyl} optical purity measurement conditions valerate (A4 step):
column: CHIRAL AGP 4.6mmI. D. × 250mm (5μm),
mobile phase: methanol / 10mM phosphate buffer solution (pH7.0) = 95/5,
temperature: 40 ℃,
flow rate: 0.5mL / min,
detection method: UV at 220nm,
retention time: R body: 5.9 minutes, S body: 7.3 minutes.

(2S)-5-amino-2 - Optical purity measurement conditions {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate p- toluenesulfonate (A5 Step) :
column: CHIRLCEL OZ-H 4.6mmI. D. × 250mm (5μm),
mobile phase: hexane / ethanol / methanol / isopropanol / trifluoroacetic acid / triethylamine = 860/100/20/2/2
temperature: 30 ℃
flow rate: 1.0mL / min
detection method: UV at 220nm
retention time: R body: 16.1 minutes, S body: 13.0 minutes 　(example 　1) (1-1) 5 - [(Tert- butoxycarbonyl) amino] -2-methoxy-carbonyl) valeric acid morpholine salt

[Of 11]

　In methanol (400mL) solution of di -tert- butyl (100.0g) and 3-chloro-propylamine hydrochloride (71.5g), was added dropwise triethylamine (51.0g) at 0 ℃, at the same temperature It was stirred for 16 hours. To the reaction solution was added toluene (400 mL) and water (400 mL), then were separated, and the organic layer was washed with water. Toluene 400mL was added to the organic layer, was concentrated under reduced pressure to 300 mL, N, N-dimethylacetamide (210 mL) was added and concentrated in vacuo to 300 mL. Potassium carbonate solution (126.66g), tetrabutylammonium bromide (44.32g), was added dimethyl malonate (90.82g) and N, N-dimethylacetamide (100 mL), stirred for 20 hours at 55 ° C. did. Toluene (400 mL) and water (700 mL) was added to the reaction mixture, after separation, The organic layer was washed with water, with 1M aqueous sodium hydroxide and water, and concentrated under reduced pressure to 150 mL. This solution methanol (1870mL) and 1M sodium hydroxide solution (430.8mL) in addition to, and the mixture was stirred for 27.5 hours at 0 ℃. Concentrated hydrochloric acid to the reaction solution (2.5 mL) was added, the pH was adjusted to 7-9, and concentrated in vacuo to 375 mL. After addition of ethyl acetate (500mL) to the reaction solution, concentrated hydrochloric acid (35.1mL) was added, the pH was adjusted to 2.2-2.5, and the layers were separated. The aqueous layer was extracted with ethyl acetate (500 mL), after mixing the organic layer under reduced pressure, and prepared by dehydration condensation of ethyl acetate (250 mL) solution. The resulting solution of ethyl acetate (500 mL) and morpholine (37.5 g) was added to and stirred overnight. The precipitated crystals were filtered, washed with ethyl acetate, and dried under reduced pressure, to give the title compound (136.1g, 81.9% yield).

¹ H-NMR _{(DMSO-d- . 6} ) [delta]: 6.79 (1H, t, J = 5.5 Hz), 3.61 (4H, t, J = 4.9 Hz), 3.58 The (3H, s) , 3.14 (1H, t, J = 7.8Hz), 2.90-2.80 (6H, m), 1.74-1.59 (2H, m), 1.37 (9H, s) , 1.34-1.25 (2H, m).

(1-2) [1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methanol

[Of 12]

　N, and stirred for 4 h methanol (56 mL) solution at 5 ~ 10 ℃ of N- dimethylformamide dimethyl acetal (77.4 g) and ethyl isocyanoacetate (70.0g).The reaction solution was cooled to 0 ℃, water (5.3mL) and trans-4- methylcyclohexyl amine (105.1g) was added, and the mixture was stirred for 24 hours at 60 ~ 65 ℃. The reaction was cooled to room temperature, toluene (420 mL), supplemented with 10% brine (280 mL) and concentrated hydrochloric acid (68 mL), After separation, the organic layer was washed with 10% brine (140 mL). Organic layer to 10% sodium chloride solution (280mL) and concentrated hydrochloric acid were added for liquid separation after (78.4g), was added to separate liquid further 10% saline solution into the organic layer (210mL) and concentrated hydrochloric acid (31.3g). After dissolving sodium chloride (70.0 g) in aqueous layer, adding toluene (420 mL) and 50% aqueous sodium hydroxide (85 mL), after separation, toluene (350 mL) the organic layer was added, under reduced pressure, dehydration concentrated was prepared in toluene (420 mL) solution was. The solution was cooled to 0 ℃, dropped the hydrogenated bis (2-methoxyethoxy) aluminum sodium (70% toluene solution) (207.4g), and the mixture was stirred at room temperature for 1 hour. The reaction was cooled to 0 ° C., was added dropwise 12.5% ​​aqueous sodium hydroxide solution (700 mL), stirred for 1 hour at room temperature. After the solution was separated and the organic layer was washed successively with 12.5% ​​aqueous solution of sodium hydroxide (700mL) and 20% sodium chloride solution (140mL), toluene in the organic layer (140mL), 1- butanol (14mL), water ( 280mL) and was added to aliquots of concentrated hydrochloric acid (48mL). It was further added to liquid separation with water (140 mL) and concentrated hydrochloric acid (2 mL) to the organic layer. Met The aqueous layer was stirred in for 1 hour activated carbon (10.5 g), activated charcoal was filtered off, the activated carbon was washed with water (210 mL). Matches the filtrate and washings, sodium chloride (140 g), toluene was added (980 mL) and 50% aqueous sodium hydroxide (42 mL), After separation, under reduced pressure and the organic layer was dried concentrated toluene (210 mL) It was prepared in solution. The solution was stirred 30 minutes at 50-55 ° C., cooled to room temperature, it was added dropwise heptane (560 mL), and stirred at the same temperature for 3 hours. The precipitated crystals were filtered to give after washing with toluene / heptane (1/4) mixture solution, the title compound was dried under reduced pressure (77.2 g, 64.2% yield).

　¹ H-NMR (CDCl ₃ ) [delta]: 7.49 (1H, s), 6.91 (1H, s), 4.58 (2H, s), 3.83 (1H, tt, J = 12.0 , 3.9Hz), 2.10-2.07 (2H, m), 1.87-1.84 (2H, m), 1.70-1.61 (2H, m), 1.48-1 .42 (1H, m), 1.15-1.06 (2H, m), 0.95 (3H, d, J = 6.5Hz).

(1-3) (2E) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1-trans-4- methylcyclohexyl]-lH-imidazol-4-yl} methylidene} methyl valerate

[Of 13]

　(1-2) The compound obtained in (50.0 g) in toluene (350 mL) and acetic acid (150 mL) was dissolved in a mixed solution, 2,2,6,6-tetramethylpiperidine -N- oxyl at 30 ° C. It was added (966mg) and ortho-periodic acid (16.9g), and the mixture was stirred for 1 hour at 30-35 ℃. The reaction mixture was added 10% aqueous sodium bisulfite solution (150 mL), after stirring for 30 minutes at room temperature, toluene was added (400 mL), and concentrated in vacuo to 300 mL. The solution further by the addition of toluene (400 mL), after concentration under reduced pressure again to 300 mL, was added toluene (500 mL), water (200 mL) and 50% aqueous sodium hydroxide (118 mL). Were separated, the organic layer was washed with 20% brine (150 mL), addition of toluene (200 mL), under reduced pressure and dehydrated concentrated prepared in toluene (400 mL) solution. The compound obtained in the solution (1-1) (116.5g), N, N- dimethylformamide (175 mL) and acetic acid (4.2 mL) was added, under reduced pressure, and dried for 8 hours under reflux. The reaction was cooled to room temperature, adding toluene (400 mL), washed once with 3 times with 5% aqueous sodium bicarbonate solution (400 mL) and 10% brine (250 mL), under reduced pressure and the organic layer was dried concentrated toluene It was prepared (900 mL) solution. This solution was added activated charcoal (15 g) at 35 ~ 40 ° C., after stirring for 30 minutes at the same temperature, filtered and the activated carbon was washed with toluene. Meet the filtrate and washings, after which was concentrated under reduced pressure until 250mL, it was added dropwise heptane (500mL) at room temperature. After stirring for 1.5 hours at the same temperature, then cooled to 0 ℃, and the mixture was stirred for 1 hour. The precipitated crystals were filtered to give after washing with toluene / heptane (1/2) mixture solution, the title compound was dried under reduced pressure (85.0 g, 81.5% yield).

　¹ H-NMR (CDCl ₃ ) [delta]: 7.59 (1H, s), 7.47 (1H, s), 7.15 (1H, s), 7.08 (1H, brs), 3.92- 3.87 (1H, m), 3.78 (3H, s), 3.16-3.12 (2H, m), 2.96 (2H, t, J = 7.5Hz), 2.14- 2.11 (2H, m), 1.90-1.87 (2H, m), 1.77-1.65 (5H, m), 1.47 (9H, s), 1.17-1. 10 (2H, m), 0.96 (3H, d, J = 6.5Hz).

　(1-4) (2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate (S ) -2-amino-1-propanol salt (A1 process, A2 process, A3 process)

[Of 14]

　The compound obtained in (1-3) (40.0g), (R) -2,2'- bis (di-3,5-xylyl) -1,1'-binaphthyl (507.4Mg) and dichloro (p- cymene) ruthenium (II) (dimer) and (211.4mg), were dissolved in degassed 2,2,2 trifluoroethanol (400 mL), hydrogen under pressure (400-450kPa) , and the mixture was stirred for 24 hours at 60 ℃. The reaction was cooled to room temperature, after nitrogen substitution, and then concentrated under reduced pressure to 60 mL.Tetrahydrofuran (200 mL) was added, was concentrated under reduced pressure to 120 mL, of tetrahydrofuran was added (200 mL).

　To the resulting solution was added water (160mL), cooled to 0 ℃, was added a 50% aqueous solution of sodium hydroxide (24.0mL). After stirring the reaction mixture at room temperature for 26 hours, and the addition of 50% sodium hydroxide solution (8.00mL), and the mixture was stirred for a further 4 hours. The reaction mixture under ice-cooling was added dropwise concentrated hydrochloric acid (28 mL), activated carbon was added (2.0 g) was stirred at room temperature for 10 minutes. The active carbon was filtered off, washed with tetrahydrofuran / water (2/1) mixed solvent (180 mL), sodium chloride (40 g) was separated by adding and re-extract the aqueous layer with tetrahydrofuran (400 mL). The organic layer was matched, and concentrated in vacuo to 200 mL. After addition of toluene (400 mL) to this solution, under reduced pressure and dehydrated concentrated prepared in toluene (200 mL) solution.

　After adding tetrahydrofuran (400 mL) to the resulting solution was added (S) -2- amino-1-propanol (8.2 g) at room temperature and stirred for 3 hours. The solution was cooled to 0 ℃, and was filtered after stirring for 1.5 hours, it was precipitated crystals. The crystals were washed with tetrahydrofuran and dried under reduced pressure to give the title compound (45.4g, 98.2% yield, optical purity: ee 97.5%) was obtained.

　¹ H-NMR _(CD 3 OD) [delta]: 7.57 (1H, s), 6.94 (1H, s), 3.98-3.85 (1H, yd), 3.69-3.64 ( 1H, m), 3.47-3.42 (1H , m), 3.29-3.23 (1H, m), 3.01 (2H, t, J = 6.5Hz), 2.84 ( 1H, dd, J = 14.6,8.4Hz) , 2.55 (1H, dd, J = 14.6,6.2Hz), 2.52-2.45 (1H, m), 2.03 (2H, d, J = 12.7Hz ), 1.83 (2H, d, J = 13.3Hz), 1.71 (2H, q, J = 12.5Hz), 1.60-1.44 ( 5H, m), 1.41 (9H , s), 1.23-1.20 (3H, m), 1.18-1.09 (2H, m), 0.94 (3H, d, J = 6.8Hz).

　(1-5) (2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate (A4 process)

[Of 15]

　(1-4) The compound obtained in (40.0 g) in tetrahydrofuran (400 mL) and dissolved in a mixed solvent of water (160 mL), concentrated hydrochloric acid (7.3 mL) and added separation of sodium chloride (40 g) and washed 3 times with the organic layer 20% (w / w) brine (160 mL). The organic layer under reduced pressure, dehydrated concentrated prepared in toluene (320 mL) solution was dissolved after addition of tetrahydrofuran (80 mL) was warmed precipitated 83 ° C. crystal. After stirring overnight and cooled to room temperature, and stirred for a further 3 hours at 0 ℃, and filtered the precipitated crystals. After washing the crystals with toluene / tetrahydrofuran (4/1) mixed solution, and dried under reduced pressure to give the title compound (30.9g, 92.1% yield, optical purity: 97.4% ee) was obtained.

　¹ H-NMR (CDCl ₃ ) [delta]: 7.59 (1H, s), 6.73 (1H, s), 4.67 (1H, brs), 3.85-3.80 (1H, yd), 3.12-3.08 (2H, m), 2.88 (1H, dd, J = 15.2,8.8Hz), 2.79 (1H, dd, J = 15.2,3.6Hz) , 2.70-2.64 (1H, m), 2.13-2.06 (2H, m), 1.90-1.82 (2H, m), 1.79-1.52 (5H, m), 1.49-1.44 (2H, m ), 1.43 (9H, s), 1.15-1.05 (2H, m), 0.95 (3H, d, J = 6. 5Hz).

　(1-6) (2S) -5- amino -2 - {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate p- toluenesulfonate (A5 Step)

[Of 16]

　In tetrahydrofuran (100 mL), was dissolved the compound obtained in (1-5) (25.0 g) and p- toluenesulfonic acid monohydrate (13.3 g), activated charcoal (1 to this solution. 25 g) was added and stirred for 1 hour at 20 ~ 30 ℃. The charcoal was filtered and washed with tetrahydrofuran (50 mL).It matches the filtrate and washings, p- toluenesulfonic acid monohydrate (13.3 g) and water (7.5 mL) and the mixture was heated under reflux for 6 hours. The reaction was cooled to room temperature, it was added triethylamine (7.7 g), at room temperature and stirred overnight. To the reaction solution was added dropwise tetrahydrofuran (350 mL), after stirring for 3 hours at room temperature and filtered the precipitated crystal. After washing with tetrahydrofuran / water (50/1) mixed solution, and dried under reduced pressure to give the title compound (27.7g, 93.5% yield, optical purity: 98.4% ee) was obtained.

　¹ H-NMR _(CD 3 OD) [delta]: 8.18 (1H, s), 7.70 (2H, d-, J = 8.1 Hz), 7.22 (2H, d-, J = 7.5 Hz), 7.16 (1H, s), 4.06 (1H, tt, J = 12.0,3.9Hz), 2.94-2.86 (3H, m), 2.69 (1H, dd, J = 14.6,5.8Hz), 2.62-2.59 (1H, m), 2.36 (3H, s), 2.08-2.05 (2H, m), 1.86-1 .83 (2H, m), 1.76-1.46 (7H, m), 1.18-1.11 (2H, m), 0.94 (3H, d, J = 6.5Hz).

　(Example
2) (2-1) (2S) -5 - [(tert-butoxycarbonyl) amino] -2 - {[1- (trans -4- methylcyclohexyl)-lH-imidazol-4-yl] methyl } methyl valerate

[Of 17]

　It was asymmetrically reduced using a number of catalysts. The reaction conversion and the optical purity of the obtained title compound was determined by the following HPLC analysis conditions.

　Reaction conversion rate measurement:
Column: Waters XBridge C18 4.6mmI. D. × 150mm (3.5μm),
mobile phase: (A) 10mM aqueous ammonium acetate solution, (B)
acetonitrile, Gradient conditions: B: conc. ; 20% (0-5 minutes), 20-90% (5-20 minutes), 90% (20-24 minutes),
temperature: 40 ℃,
flow rate: 1.0mL / min,
detection method: UV at 215nm
retention time: raw material: 21.1 minutes, the product: 19.1 minutes,
(peak area of peak area + product of raw materials) peak area / of the reaction conversion rate = product.

　Optical purity measurement conditions:
column: CHIRALPAK IA 4.6mmI. D. × 250mm (5μm),
mobile phase: ethanol / hexane = 20/80
Temperature: 35 ℃,
flow rate: 1.0mL / min,
detection method: UV at 210nm,
retention time: R body: 6.8 minutes, S body: 7.8 minutes.

PATENT
Daiichi Sankyo Company,Limited, 第一三共株式会社
WO2011115064.....
http://www.google.co.in/patents/WO2011115064A1?cl=en
[Reference Example 1] 5 - [(tert- butoxycarbonyl) amino] -2- (diethoxyphosphoryl) valeric acid tert- butyl

Diethylphosphonoacetate tert- butyl (20.0g) was dissolved in tetrahydrofuran (500mL), sodium hydride (63%, 3.32g) was added at 0 ℃, 15 min at 0 ℃, and stirred for 1 hour at room temperature . (3-bromopropyl) tetrahydrofuran carbamic acid tert- butyl (20.0g) (20mL) was slowly at room temperature, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 1/1-ethyl acetate) to give the title compound (26.6g).
¹ H-NMR (CDCl ₃₎ ^δ: 1.31-1.36 (6H, m), 1.44 (9H, m), 1.48 (9H, m), 1.51-1.59 (2H, m), 1.78-2.00 (2H, m) , 2.83 (1H, ddd, J = 22.9, 10.7, 4.4 Hz), 3.06-3.18 (2H, m), 4.10-4.18 (4H, m), 4.58 (1H, br).
[Reference Example 2] 5 - [(tert- butoxycarbonyl) amino] -2- (1H- imidazol-4-ylmethyl) valeric acid tert- butyl

In acetonitrile (100mL) solution of the compound obtained in Reference Example 1 (8.35g), at room temperature 1,8-diazabicyclo [5.4.0] undec-7-ene (4.58mL) and lithium chloride (1 .30g) and we were added. The suspension was added with 1-trityl--1H- imidazole-4-carbaldehyde (6.90g) was stirred at room temperature overnight, under vacuum, and the solvent was evaporated. After the solution separated by adding ethyl acetate and 10% citric acid aqueous solution, an organic layer, saturated brine, and then washed with a saturated aqueous sodium bicarbonate solution and brine. Dried over anhydrous sodium sulfate, (2E) -5 - [(tert- butoxycarbonyl) amino] -2 - [(1-trityl--1H- imidazol-4-yl) methylene] valeric acid tert- butyl and (2Z) -5 - obtain [(1-trityl--1H- imidazol-4-yl) methylene] valeric acid tert- butyl mixture (11.3g) - [(tert- butoxycarbonyl) amino] -2. The mixture was suspended in methanol (500mL), 10% palladium-carbon catalyst (water content, 4g) was added and stirred for 3 days at room temperature under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Silica gel chromatography gave (eluting solvent: methylene chloride / methanol = 9/1) the title compound (5.60g).
¹ H-NMR (CDCl ₃₎ ^δ: 1.41 (9H, s), 1.44 (9H, s), 1.48-1.57 (3H, m), 1.57-1.66 (1H, m), 2.58-2.68 (1H, m) , 2.73 (1H, dd, J = 14.7, 5.3 Hz), 2.89 (1H, dd, J = 14.7, 8.4 Hz), 3.02-3.19 (2H, m), 4.67 (1H, br s), 6.79 (1H, s), 7.54 (1H, s).
[Reference Example 3] 5 - [(tert- butoxycarbonyl) amino] -2- (methoxycarbonyl) valeric acid

Sodium methoxide in dimethyl malonate (102mL) - methanol (28%, 90.4mL) was added at room temperature and stirred at 60 ℃ 30 minutes. After cooling the white suspension solution to room temperature, (3-bromopropyl) was added carbamic acid tert- butyl (106g) in one portion and stirred at room temperature for 12 hours. Water was added to the reaction solution and the organics extracted with diethyl ether. The organic layer was successively washed with 1 N sodium hydroxide aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure {3 - [(tert- butoxycarbonyl) amino] propyl} malonic I got acid dimethyl of crude product. The resulting ester (94g) was dissolved in methanol (100mL), water lithium hydroxide monohydrate (13.6g) (300mL) - was added to methanol (300mL) solution at 0 ℃, 15 h stirring at room temperature It was. The methanol was distilled off under reduced pressure and the organics were extracted with ethyl acetate. 2N hydrochloric acid (160mL) was added to the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography: - is purified (eluent methylene chloride methylene chloride / methanol = 10/1) to give the title compound (69.1g).
¹ H-NMR (CDCl ₃₎ ^δ: 1.44 (9H, m), 1.50-1.60 (2H, m), 1.86-2.01 (2H, m), 3.07-3.20 (2H, m), 3.43 (1H, m) , 3.77 (3H, s), 4.64 (1H, br).
[Reference Example 4] 1- (trans-4- methylcyclohexyl) -1H- imidazole-4-carbaldehyde [Step 1] 1- (trans-4- methylcyclohexyl) -1H- imidazole-4-carboxylic acid ethyl

Was dissolved in 3- (dimethylamino) -2-isocyanoethyl ethyl acrylic acid (Liebigs Annalen der Chemie, 1979 years 1444 pages) (1.52g) and the trans-4- methyl cyclohexylamine (3.07g), 70 ℃ in it was stirred for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 2 / 1-1 / 2) to give the title compound (1.90g).
¹ H-NMR (CDCl ₃₎ ^δ: 0.96 (3H, d, J = 6.6 Hz), 1.13 (2H, m), 1.39 (3H, d, J = 7.0 Hz), 1.47 (1H, m), 1.68 ( 2H, m), 1.88 (2H, m), 2.12 (2H, m), 3.91 (1H, tt, J = 12.1, 3.9 Hz), 4.36 (2H, q, J = 7.0 Hz), 7.54 (1H, s ), 7.66 (1H, s).
[Step 2] [1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methanol

Lithium aluminum hydride (92%, 0.31g) it was suspended in tetrahydrofuran (6mL). The compound obtained in Step 1 of this reference example (1.50g) was dissolved in tetrahydrofuran (6mL), it was slowly added dropwise to the suspension at 0 ℃.0 After stirring for 30 min at ℃, the reaction solution was diluted with diethyl ether, it was added a saturated aqueous solution of sodium sulfate. After stirring for 1 hour at room temperature, the resulting inorganic salt was removed by filtration through Celite. The filtrate to give the crude product was concentrated under reduced pressure. Mixed solvent of this from hexane and ethyl acetate: water (5 1), to give the title compound (1.09g).
¹ H-NMR (CDCl ₃₎ ^δ: 0.95 (3H, d, J = 6.6 Hz), 1.04-1.17 (2H, m), 1.44 (1H, m), 1.59-1.73 (2H, m), 1.81-1.89 (2H, m), 2.04-2.13 (2H, m), 2.78 (1H, br), 3.84 (1H, tt, J = 12.1, 3.9 Hz), 4.59 (2H, s), 6.91 (1H, s), 7.49 (1H, s).
[Step 3] 1- (trans-4- methylcyclohexyl) -1H- imidazole-4-carbaldehyde

The compound obtained in Step 2 of this reference example (1.04g) was dissolved in toluene (10mL). Aqueous solution of sodium hydrogen carbonate (1.35g) (5mL), iodine (2.72g) and 2,2,6,6-tetramethyl-1-sequential piperidinyloxy (84mg) was added and stirred for 2 hours at room temperature It was. The reaction solution was added saturated aqueous sodium thiosulfate solution and the organics were extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 1 / 1-1 / 2) to give the title compound (0.900g).
¹ H-NMR (CDCl ₃₎ ^δ: 0.97 (3H, d, J = 6.8 Hz), 1.09-1.19 (2H, m), 1.48 (1H, m), 1.65-1.75 (2H, m), 1.87-1.93 (2H, m), 2.11-2.18 (2H, m), 3.95 (1H, tt, J = 12.2, 3.9 Hz), 7.62 (1H, s), 7.68 (1H, s), 9.87 (1H, s).
[Example 15] (2R) -5- amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valeric acid and (2S) -5- amino-2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valeric acid [Step 1] 5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans 4-methylcyclohexyl) -1H- imidazole-4-yl] methyl} methyl valerate

The compound obtained in Reference Example 4 (300mg) and the compound obtained in Reference Example 3 (860mg) was suspended in cyclohexane (10mL). Piperidine (0.154mL) and cyclohexane propionic acid (0.116mL) and (10mL) solution was added, and the mixture was heated under reflux for 48 hours. After cooling, aqueous potassium carbonate solution was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained crude product was dissolved in ethanol (12mL), 10% palladium-carbon catalyst (water, 250mg) was added and atmospheric pressure hydrogen atmosphere at room temperature for 4 hours and stirred at 60 ℃ 2.5 hours. After Celite filtration, to give the crude product and the filtrate was concentrated under reduced pressure. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 2 / 1-1 / 3) to give the title compound (562mg).
¹ H-NMR (CDCl ₃₎ ^δ: 0.94 (3H, d, J = 6.6 Hz), 1.02-1.15 (2H, m), 1.34-1.69 (7H, m), 1.43 (9H, s), 1.80-1.87 (2H, m), 1.99-2.09 (2H, m), 2.69 (1H, dd, J = 13.7, 6.3 Hz), 2.79 (1H, m), 2.88 (1H, dd, J = 13.7, 7.4 Hz), 3.03-3.13 (2H, m), 3.63 (3H, s), 3.79 (1H, tt, J = 12.1, 3.9 Hz), 4.76 (1H, br), 6.67 (1H, s), 7.47 (1H, s) .
[Step 2] (2R) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate and ( 2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate

The compound obtained in Step 1 of this Example (40mg) was dissolved in hexane (1.5mL) and ethanol (0.5mL), using CHIRALPAK IA semi-preparative column (2.0cm × 25.0cm) It was optically resolved by high performance liquid chromatography. Flow rate: 15mL / min, elution solvent: hexane / ethanol = 75/25, detection wavelength: 220nm.
The solvent of the divided solution was evaporated under reduced pressure to give both enantiomers each (15mg). Both enantiomers were confirmed to be optically pure by analytical HPLC. Column: CHIRALPAK IA (0.46cm × 25.0cm), flow rate: 1mL / min, elution solvent: hexane / ethanol = 80/20 <v / v>, detection wavelength: 220nm, retention time: (2R) -5- [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate (7.2 min), (2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate (11.2 min).
[Step 3] (2R) -5- amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valerate

Obtained in Step 2 of this Example (2R) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl } the methyl valerate (15.0mg) was added to 5 N hydrochloric acid (2mL), and the mixture was heated under reflux for 4 hours. After cooling, the solvent it was evaporated under reduced pressure. The resulting crude hydrochloride salt was dissolved in methanol, was added DOWEX50WX8-200. After the resin was washed with water and eluted with 4% aqueous ammonia. The eluate was concentrated, the crude product was washed with acetone to give the title compound (2.2mg).
[Step 4] (2S) -5- amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valerate

Obtained in Step 2 of this Example (2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl } the methyl valerate (15.0mg) was added to 5 N hydrochloric acid (2mL), and the mixture was heated under reflux for 4 hours. After cooling, the solvent it was evaporated under reduced pressure. The resulting crude hydrochloride salt was dissolved in methanol, was added DOWEX50WX8-200 (200mg). After the resin was washed with water, ammonia water (4%, 80mL) and eluted with. The eluate was concentrated, the crude product was washed with acetone to give the title compound (1.8mg).
[Example 16] 5-amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valeric acid benzyl hydrochloride [Step 1] 5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valerate

The compound obtained in step 1 of Example 15 (7.00g) was dissolved in a mixed solvent consisting of tetrahydrofuran (70mL) and water (14mL), lithium hydroxide monohydrate and (1.26g) at room temperature The mixture was stirred overnight.The reaction solution 2 N hydrochloric acid (8.6mL) was added to neutralize, followed by distilling off the solvent under reduced pressure. The resulting residue was dried with anhydrous sodium sulfate added methylene chloride was to give the crude product was distilled off the solvent under reduced pressure the title compound. This it was used in the next reaction.
MS (ESI) m / z 394 [M ⁺ H] +.
[Example 40] (2S) -5- Amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valerate · p- toluenesulfonate, anhydrous

The compound obtained in Step 4 of Example 15 (2.04g) was suspended stirring in tetrahydrofuran (15mL), p- toluenesulfonate monohydrate (1.32g) was added, at room temperature for 1 day the mixture was stirred. The precipitated crystals were collected by vacuum filtration to obtain dried in one day like the title compound (3.01g).
¹ H-NMR (CD ₃ OD) ^δ: 0.95 (3H, d, J = 6.5 Hz), 1.11-1.21 (2H, m), 1.43-1.79 (7H, m), 1.83-1.89 (2H, m), 2.05-2.10 (2H, m), 2.37 (3H, s), 2.57-2.64 (1H, m), 2.70 (1H, dd, J = 14.5, 5.5 Hz), 2.85-2.95 (3H, m), 4.07 ( 1H, tt, J = 11.7, 3.9 Hz), 7.18 (1H, s), 7.23 (2H, d, J = 7.8 Hz), 7.70 (2H, d, J = 8.2 Hz), 8.22 (1H, s).
Elemental _{analysis: C 16} H ₂₇ N _{3 O 2} · C 7 H ₈ O ₃ S,
Theoretical value: C; 59.33, H; 7.58, N; 9.02, O; 17.18, S; 6.89,
Measured value: C; 59.09, H; 7.53, N; 8.92, O; 17.22, S; 6.78.
----------------------------------.
[Example 41] (2S) -5- Amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valerate · p- toluenesulfonate & 1 Water hydrate

The obtained compound (101.6mg) in 6% water-containing tetrahydrofuran (600μL) was added in Example 40, was dissolved by heating at 60 ℃. Was allowed to stand at room temperature for 1 day, it was collected by filtration and the precipitated crystals were obtained by dried for one day wind the title compound (79.3mg).
Elemental _{analysis: C 16 H 27} N ₃ O ₂ · C 7 H 8 O ₃ S · _{1H 2} O,
Theoretical value: C; 57.12, H; 7.71, N; 8.69, O; 19.85, S; 6.63,
Measured value: C; 56.90, H; 7.69, N; 8.67, O; 19.81, S; 6.42.

References
Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of DS-1040b in Subjects With Acute Ischemic Stroke (NCT02586233
Phase I Study to Evaluate the Safety and Tolerability of DS-1040b Intravenous Infusion With Clopidogrel in Healthy Subjects (NCT02560688)
Study of the Effects of Ethnicity on the Pharmacokinetics, Pharmacodynamics and Safety of DS-1040b (NCT02647307)
Edo, N.; Noguchi, K.; Ito, Y.; Morishima, Y.; Yamaguchi, K.
Hemorrhagic risk assessment of DS-1040 in a cerebral ischemia/reperfusion model of rats with hypertension and hyperglycemia
41st Int Stroke Conf (February 17-19, Los Angeles) 2016, Abst TP283

Noguchi, K.; Edo, N.; Ito, Y.; Morishima, Y.; Yamaguchi, K.
Improvement of cerebral blood flow with DS-1040 in a rat thromboembolic stroke model
41st Int Stroke Conf (February 17-19, Los Angeles) 2016, Abst TP271
Lapchak, P.A.; Boitano, P.D.; Noguchi, K.
DS-1040 an inhibitor of the activated thrombin activatable fibrinolysis inhibitor improves behavior in embolized rabbits
41st Int Stroke Conf (February 17-19, Los Angeles) 2016, Abst WP282 
A first-in-human, single ascending dose study of DS-1040, an inhibitor of the activated form of thrombinactivatable fibrinolysis inhibitor (TAFIa), in healthy subjects
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO621-MON
Dow, J.; Puri, A.; McPhillips, P.; Orihashi, Y.; Dishy, V.; Zhou, J.
A drug-drug interaction study of DS-1040 and aspirin in healthy subjects
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO603-TUE
Noguchi, K.; Edo, N.; Ito, Y.; Yamaguchi, K.
Effect of DS-1040 on endogenous fibrinolysis and impact on bleeding time in rats
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst AS145
Noguchi, K.; Edo, N.; Ito, Y.; Maejima, T.; Yamaguchi, K.
DS-1040: A novel selective inhibitor of activated form of thrombin-activatable fibrinolysis inhibitor
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO203-MON
DS1040b/Aspirin Drug/Drug Interaction Study (NCT02071004)
ClinicalTrials.gov Web Site 2014, February 26

Patent ID	Date	Patent Title
US2014178349	2014-06-26	Cycloalkyl-Substituted Imidazole Derivative
US8609710	2013-12-17	Cycloalkyl-substituted imidazole derivative

//////DS-1040, DS 1040, phase 2, Daiichi Sankyo Co Ltd, Ischemic stroke
O=C(O)[C@@H](CCCN)Cc1cn(cn1)[C@@H]2CC[C@@H](C)CC2
O=S(=O)(O)c1ccc(C)cc1.O=C(O)[C@@H](CCCN)Cc1cn(cn1)[C@@H]2CC[C@@H](C)CC2

AZD 7594

.
Picture credit....Bethany Halford

AZD 7594
$AZN's asthma candidate
AZ13189620; AZD-7594
Bayer Pharma Aktiengesellschaft, Astrazeneca Ab

Molecular Formula:	C32H32F2N4O6
Molecular Weight:	606.616486 g/mol

3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-(oxolan-3-yl)benzamide

 

Benzamide, 3-​[5-​[(1R,​2S)​-​2-​[(2,​2-​difluoro-​1-​oxopropyl)​amino]​-​1-​(2,​3-​dihydro-​1,​4-​benzodioxin-​6-​yl)​propoxy]​-​1H-​indazol-​1-​yl]​-​N-​[(3R)​-​tetrahydro-​3-​furanyl]​-

Cas 1196509-60-0

AZD-7594 is in phase II clinical trials by AstraZeneca for the treatment of mild to moderate asthma.
It is also in phase I clinical trials for the treatment of chronic obstructive pulmonary disorder (COPD).
https://clinicaltrials.gov/ct2/show/NCT02479412

Company	AstraZeneca plc
Description	Inhaled selective glucocorticoid receptor (GCCR) modulator
Molecular Target	Glucocorticoid receptor (GCCR)

• Phase II Asthma
• Phase I Chronic obstructive pulmonary disease

• 01 Feb 2016 AstraZeneca completes a phase II trial in Asthma in Bulgaria and Germany (Inhalation) (NCT02479412)
• 09 Jan 2016 AstraZeneca plans to initiate a phase I trial in Healthy volunteers in USA (IV and PO) (NCT02648438)
• 01 Jan 2016 Phase-I clinical trials in Chronic obstructive pulmonary disease (In volunteers) in USA (PO, IV, Inhalation) (NCT02648438)

PATENT
http://www.google.com/patents/WO2009142569A1
PATENT
US20100804345
UNWANTED ISOMER

WANTED COMPD

PATENT

WO 2009142571
Example 6
WANTED ISOMER

3-(5- { TC 1 R,2SV2-r(2,2-difluoropropanoyl)aminol- 1 -(2,3-dihydro-l ,4-benzodioxin-6-5 yDpropylioxy) - 1 H-indazol- 1 -ylVN-[(3R)-tetrahydrofuran-3-vnbenzamide. APCI-MS: m/z 607 [MH⁺] ¹H NMR ^OO MHz, DMSOd₆) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s), 7.90 - 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 - 6.78 (3H, m), 5.17 (IH, d), 4.48 (IH, m), 4.23 - 4.10 (5H, m), 3.89 - 3.82 (2H, m), 3.72 (IH, td), 3.61 (IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d). LC (method A) rt = 12.03 min LC (method B) rt = 11.13 min Chiral SFC (method B) rt = 4.71 min M.p. = 177 °C
UNWANTED

o 3-(5- { IY 1 R,2S V2-r(2,2-difluoropropanoyl^')amino^'|- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6- yl)propyl]oxy } - 1 H-indazol- 1 -yP-N-IO S)-tetrahydrofuran-3 -yl^"|benzamide
APCI-MS: m/z 607 [MH⁺]
¹H NMR (400 MHz, DMSO-J₆) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s),
7.90 - 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 - 6.78 (3H,s m), 5.17 (IH, d), 4.48 (IH, m), 4.24 - 4.11 (5H, m), 3.90 - 3.81 (2H, m), 3.72 (IH, td), 3.61
(IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d).
LC (Method A) rt = 12.02 min
LC (Method B) rt = 11.12 min
Chiral SFC (method B) rt = 5.10 min o M.p. = 175 ⁰C

PATENT

WO 2011061527
http://www.google.com/patents/WO2011061527A1?cl=en
Intermediate 12
( 1 R,2S)-2-amino- 1 -(2,3 -dihydrobenzo b [ 1 ,41dioxin-6-yl)propan- 1 -ol hydrochloride. (12)

5-6 N HC1 in 2-propanol (8 mL, 40-48 mmol) was added to tert-butyl (lR,2S)-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxypropan-2-ylcarbamate (I2a) (3.1 g, 10.02 mmol) in ethyl acetate (40 mL) at 40°C and stirred for 3 hours. The reaction mixture was allowed to reach r.t. and was concentrated by evaporation. Ether was added and the salt was filtered off and washed with ether. The salt was found to be hygroscopic. Yield 2.10 g (85%)
APCI-MS: m/z 210 [MH⁺-HC1]
1H-NMR (300 MHz, DMSO-^): δ 8.01 (brs, 3H), 6.87-6.76 (m, 3H), 5.93 (brd, 1H), 4.79 (brt, 1H), 4.22 (s, 4H), 3.32 (brm, 1H), 0.94 (d, 3H).
tert-butyl (1R,2S)- 1 -(2,3-dihvdrobenzorbl Γ 1 ,41dioxin-6-yl)- 1 -hvdroxypropan-2-ylcarbamate.

The diastereoselective catalytic Meerwein-Ponndorf-Verley reduction was made by the method described by Jingjun Yin et. al. J. Org. Chem. 2006, 71, 840-843.
(S)-tert-butyl 1 -(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)- 1 -oxopropan-2-ylcarbamate (I2b) (3.76 g, 12.23 mmol), aluminium isopropoxide (0.5 g, 2.45 mmol) and 2-propanol (12 mL, 157.75 mmol) in toluene (22 mL) were stirred at 50°C under argon for 16 hours. The reaction mixture was poured into 1M HC1 (150 mL) and the mixture was extracted with ethyl acetate (250 mL). The organic phase was washed with water (2x50 mL) and brine (100 mL), dried over Na₂SC"4, filtered and concentrated. The crude product was purified by flash- chromatography on silica using ethyl acetate/hexane (1/2) as eluent. Fractions containing product were combined. Solvent was removed by evaporation to give the desired product as a colourless solid. Yield 3.19 g (84%) APCI-MS: m/z 236, 210, 192 [MH -tBu-18, MH -BOC, MH -BOC- 18]
1H NMR (300 MHz, DMSO-^): δ 6.80-6.70 (m, 3H), 6.51 (d, IH), 5.17 (d, IH), 4.36 (t, IH),
4.19 (s, 4H), 3.49 (m, IH), 1.31 (s, 9H), 0.93 (d, 3H).
(S)-tert-butyl 1 -(2,3-dihydrobenzo[bl [ 1 ,41dioxin-6-yD- 1 -oxopropan-2-ylcarbamate. (I2b)

A suspension of (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) in THF (30 mL) was placed under a protective atmosphere of argon and cooled down to -15 to -20°C. Isopropylmagnesium chloride, 2M in THF (6.5 mL, 13.00 mmol), was added keeping the temperature below -10°C. The temperature was allowed to reach 0°C. A freshly prepared solution of (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)magnesium bromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The temperature was allowed to reach r.t. overnight. The reaction mixture was poured into ice cooled IN HC1 (300 mL). TBME (300 mL) was added and the mixture was transferred to a separation funnel. The water phase was back extracted with TBME (200 mL). The ether phases were washed with water, brine and dried (Na₂S0₄). The crude product was purified by flash chromatography using TBME /Heptane 1/2 as eluent. Fractions containing the product were combined and solvents were removed by evaporation to give the subtitle compound as a slightly yellow sticky oil/gum. Yield 3.76g
(95%)
APCI-MS: m/z 208 [MH⁺ - BOC]
1H NMR (300 MHz, DMSO-^): δ 7.50 (dd, IH), 7.46 (d, IH), 7.24 (d, IH), 6.97 (d, IH), 4.97 (m, IH), 4.30 (m, 4H), 1.36 (s, 9H), 1.19 (d, 3H).
Intermediate 13
(lR,2S)-2-amino-l-(4H-benzo[dl[l,31dioxin-7- l)propan-l-ol hydrochloride (13)

Tert-butyl ( 1 R,2S)- 1 -(4H-benzo[d] [ 1 ,3]dioxin-7-yl)- 1 -hydroxypropan-2-ylcarbamate (I3b) (403 mg, 1.30 mmol) was dissolved in ethyl acetate (5 mL) and 5-6 N HC1 solution in 2- propanol (1.5 mL, 7.5-9 mmol) was added. The mixture was stirred at 50 °C for 1.5 hours. The solvents was removed by evaporation. The residual sticky gum was treated with ethyl acetate and evaporated again to give a solid material that was suspended in acetonitrile and stirred for a few minutes. The solid colourless salt was collected by filtration and was found to be somewhat hygroscopic. The salt was quickly transferred to a dessicator and dried under reduced pressure. Yield 293 mg (92%)
APCI-MS: m/z 210 [MH⁺ -HC1]
1H NMR (300 MHz, DMSO-^) δ 8.07 (3H, s), 7.05 (IH, d), 6.92 (IH, dd), 6.85 (IH, d), 6.03 (IH, d), 5.25 (2H, s), 4.87 (3H, m), 3.42 - 3.29 (IH, m), 0.94 (3H, d).
(4S.5R -5-(4H-benzordiri.31dioxin-7-vn- -methyloxazolidin-2-one (I3a

A mixture of (lR,2S)-2-amino-l-(4H-benzo[d][l,3]dioxin-7-yl)propan-l-ol hydrochloride (I3b) (120 mg, 0.49 mmol), DIEA (0.100 mL, 0.59 mmol) and CDI (90 mg, 0.56 mmol) in THF (2 mL) was stirred at r.t. for 2 hours. The reaction mixture was concentrated by evaporation and the residual material was partitioned between ethyl acetate and water. The organic phase was washed with 10% NaHS0₄, dried over MgS0₄, filtered and evaporated. The crude product was analysed by LC/MS and was considered pure enough for further analysis by NMR. Yield 66 mg (57%)
The relative cis conformation of the product was confirmed by comparing the observed 1H- NMR with the literature values reported for similar cyclised norephedrine (Org. Lett. 2005 (07), 13, 2755-2758 and Terahedron Assym. 1993, (4), 12, 2513-2516). In a 2D NOESY experiment a strong NOE cross-peak was observed for the doublet at 5.64 with the multiplet at 4.19 ppm. This also confirmed the relative czs-conformation.
APCI-MS: m/z 236 [MH⁺]
1H NMR (400 MHz, CDC1₃) δ 6.99 (d, J= 8.0 Hz, IH), 6.88 (dd, J= 8.0, 1.4 Hz, IH), 6.83 (s, IH), 5.81 (brs,lH), 5.64 (d, J= 8.0 Hz, IH), 5.26 (s, 2H), 4.91 (s, 2H), 4.19 (m, IH), 0.85 (d, J = 6.4 Hz, 3H). Tert-butyl ( 1 R,2S)- 1 -(4H-benzord1 Γ 1 ,31dioxin-7-yl)- 1 -hvdroxypropan-2-ylcarbamate (I3b)

A mixture (S)-tert-butyl l-(4H-benzo[d][l,3]dioxin-7-yl)-l-oxopropan-2-ylcarbamate (I3c) (680 mg, 2.21 mmol), triisopropoxyaluminum (140 mg, 0.69 mmol) and propan-2-ol (3 mL, 38.9 mmol) in toluene (3 mL) was stirred at 65 °C for 15 hours. The reaction mixture was allowed to cool down, poured into 1M HC1 (50 mL) and extracted with ethyl acetate (2x50 mL). The organic phase was washed with water, brine, dried over MgS0₄, filtered and solvents were removed by evaporation to afford a colourless solid. The crude product was purified by flash chromatography, (solvent A = Heptane, solvent B = EtOAc + 10% MeOH. A gradient of 10%B to 50%B in A was used). The obtained product was crystallised from DCM / heptane to afford the subtitle compound as colourless needles. Yield 414 mg (60%)
APCI-MS: m/z 210 [MH⁺ -BOC]
1H NMR (400 MHz, DMSO- ¾ δ 6.97 (1H, d), 6.88 (1H, d), 6.77 (1H, s), 6.56 (1H, d), 5.27 (1H, d), 5.22 (2H, s), 4.83 (2H, s), 4.44 (1H, t), 3.53 (1H, m), 1.32 (9H, s), 0.93 (3H, d). (S)-Tert-butyl 1 -(4H-benzord1 Γ 1 ,31dioxin-7-vD- 1 -oxopropan-2-ylcarbamate (I3c)

7-Bromo-4H-benzo[d][l,3]dioxine (1 g, 4.65 mmol) was dissolved in THF (5 mL) and added to magnesium (0.113 g, 4.65 mmol) under a protective atmosphere of argon. One small iodine crystal was added. The coloured solution was heated with an heat gun in short periods to initiate the Grignard formation. When the iodine colour vanished the reaction was allowed to proceed at r.t. for 1.5 hours.
In a separate reaction tube (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopropan-2- ylcarbamate (1 g, 4.31 mmol) was suspended in THF (5 mL) and cooled in an ice/acetone bath to below -5 °C. Isopropylmagnesium chloride, 2M solution in THF (2.5 mL, 5.00 mmol) was slowly added to form a solution. To this solution was added the above freshly prepared Grignard reagent. The mixture was allowed to reach r.t. and stirred for 4 hours. The reaction mixture was slowly poured into ice-cold 150 mL 1M HC1. Ethyl acetate (150 mL) was added and the mixture was stirred for a few minutes and transferred to a separation funnel. The organic phase was washed with water and brine, dried over MgS04, filtered and concentrated. The obtained crude product was further purified by flash chromatography using a prepacked 70g silica column with a gradient of 10% TBME to 40% TBME in heptane as eluent. The subtitle compound was obtained as a colourless solid. Yield 790 mg (59%>)
APCI-MS: m/z 208 [MH⁺ -BOC]
1H NMR (400 MHz, DMSO-^) δ 7.53 (IH, dd), 7.39 (IH, s), 7.30 (IH, d), 7.22 (IH, d), 5.30 (2H, s), 4.98 (IH, m), 4.95 (2H, s), 1.35 (9H, s), 1.20 (3H, d).
Preparation 4
3-(5-([(lR,2S)-2-[(2,2-difluoropropanoyl)aminol-l-(2,3-dihydro-l,4-benzodioxin-6- yl)propyl]oxy| - 1 H-indazol- 1 -yl)-N-[(3R)-tetrahydrofuran-3-yllbenzamide

TEA (2.0 g, 20.65 mmol) was added to a mixture of 3-(5-((lR,2S)-2-(2,2- difluoropropanamido)- 1 -(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)propoxy)-l H-indazol-1 - yl)benzoic acid (14) (3.6 g, 6.70 mmol), (R)-tetrahydrofuran-3 -amine hydrochloride (0.99 g, 8.0 mmol) and HBTU (2.65 g, 6.99 mmol) in DCM (15 mL). The reaction was stirred at r.t. for 3h, then quenched by addition of a mixture of water and ethyl acetate. The mixture was shaken and the organic layer was collected. The water phase was extracted twice with ethyl acetate. The combined organic layers were washed with a small portion of water and dried over magnesium sulphate. The product was purified by flash chromatography (silica, eluent: a gradient of ethyl acetate in heptane). The residue was crystallized by dissolving in refluxing acetonitrile (50 mL) and then allowing to cool to r.t. over night. The solid was collected by filtration, washed with a small volume of acetonitrile and dried at 40°C in vaccum to give the title compound (2.5 g, 61%).
APCI-MS: m/z 607 [MH⁺]
1H NMR (400 MHz, DMSO-d₆) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s), 7.90 - 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 - 6.78 (3H, m), 5.17 (IH, d), 4.48 (IH, m), 4.23 - 4.10 (5H, m), 3.89 - 3.82 (2H, m), 3.72 (IH, td), 3.61 (IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d).
LC (method A) rt = 12.03 min
LC (method B) rt = 11.13 min
Chiral SFC (method B) rt = 4.71 min
M.p. = 177 °C

Patent ID	Date	Patent Title
US2015080434	2015-03-19	PHENYL AND BENZODIOXINYL SUBSTITUTED INDAZOLES DERIVATIVES
US8916600	2014-12-23	Phenyl and benzodioxinyl substituted indazoles derivatives
US8211930	2012-07-03	Phenyl and Benzodioxinyl Substituted Indazoles Derivatives

REFERENCES
https://www.astrazeneca.com/content/dam/az/press-releases/2014/Q2/Pipeline-table.pdf

////////AZD 7594, AZ13189620, AZD-7594 , phase 2, astrazeneca, 1196509-60-0
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