[ CAS No. 1208007-67-3 ] {[proInfo.proName]}

Name: 1208007-67-3|(S)-tert-Butyl 2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate|97%
Brand: Ambeed
SKU: A520923
Rating: 97 (32 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

2D 3D

Structure of 1208007-67-3 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 1208007-67-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1208007-67-3 ]

SDS Specification

Alternatived Products of [ 1208007-67-3 ]

Product Details of [ 1208007-67-3 ]

CAS No. :	1208007-67-3	MDL No. :	MFCD22418840
Formula :	C₁₆H₂₀BrN₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PZDCXMKEQLOWNP-ZDUSSCGKSA-N
M.W :	366.25	Pubchem ID :	56605032
Synonyms :

Safety of [ 1208007-67-3 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313	UN#:
Hazard Statements:	H315-H319	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1208007-67-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1208007-67-3 ]

[ 1208007-67-3 ] Synthesis Path-Downstream 1~6

1
[ 15761-39-4 ]
[ 1575-37-7 ]
[ 1208007-67-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 0 - 20℃; for 4.5h;	1.9 Step 9) the preparation of compound 1-11 To a solution of compound 1-10 (20 g. 107 mmol) and compound HATU (48.82 g. 128.4 mmol) in THF (250 mL) was added DIPEA (19.5 mL, 118 mmol) at 0 °C. After stirring at 0 °C for 0.5 hr. to the solution was added the compound 1 -10-2 (25.6 g, 119 mmol) in a portionwise manner, then the reaction mixture was stirred at rt for 4 hrs. After the reaction was completed, the reaction was quenched with water (100 mL), the solvent THF was removed, and the resulting mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was dissolved in glacial acetic acid (100 mL). The solution was stirred at 40 °C overnight, and HOAc was removed. The resulting mixture was dissolved in EtOAc (400 mL), washed with Na2C03 aq (150 mL x 3) and dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound (35 g, 81 %). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 367.3 [M+H] +; NMR (400 MHz, CDC13) 0 (ppm): 7.68 (s, 1 H), 7.42-7.40 (m, 1 H), 7.30-7.28 (m. 1 H), 5.11 -5.09 (m. 1 H), 3.45-3.43 (m. 2H). 2.94-2.93 (m. 1 H), 2.21-2.18 (m, 2H). 2.01 -1.91 (m, 1 H), 1 .49 (s, 9H).
81%	With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 20℃; for 3.5h; Cooling with ice;	3.4 Step 4) the preparation of compound 3-3-2 To a solution of compound C-2 (20 g, 93 mmol), compound C-1 (19.1 g, 102 mmol) and HATU (38.9 g, 102 mmol) in THF (500 mL) in an ice bath was added DIPEA (20.5 mL, 118 mmol). The mixture was stirred in the ice bath for 0.5 hour and at rt for 3 hours. The resulting mixture was quenched with water. THF was removed in vacuo. The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used for the next step without further purification. A solution of the above residue in glacial acetic acid (100 mL) was stirred at 40 °C overnight, basified with NaHCO3 and extracted with EtOAc (150 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give compound C-3 (27.6 g, 81%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H). [0292] To a mixture of compound C-3 (3.0 g, 8.2 mmol), bis(pinacolato)diboron (4.29 g, 16.9 mmol), Pd(dppf)Cl2·CH2Cl2 (653 mg, 0.8 mmol) and KOAc (2.09 g, 21.3 mmol) in a 50 mL of two-necked flask under N2 was added DMF (30 mL) via syringe. The resulting mixture was stirred at 90 °C overnight, cooled to rt naturally, and water (60 mL) was added. The mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give compound 3-3-2 as a beige solid (2.1 g). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.45-7.43 (m, 1H), 7.32-7.30 (m, 1H), 5.12-5.10 (m, 1H), 3.45-3.43 (m, 2H), 2.95-2.94 (m, 1H), 2.25-2.22 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.35 (s, 12H).
81%	Stage #1: 1-(tert-butoxycarbonyl)-L-proline With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 4-Bromo-benzene-1,2-diamine In tetrahydrofuran Stage #3: With acetic acid at 40℃;	3.15 Step 15) the preparation of compound 3-16 To a solution of compound 1-11 (23 g, 107 mmol) and HATU (48.82 g, 128.4 mmol) in THF (250 mL) at 0 °C was added DIPEA (19.5 mL, 118 mmol). The mixture was stirred at this temperature for 0.5 hour and then compound 3-16-0 (22.1 g, 119 mmol) was added in portions. After the reaction was completed, the reaction was quenched with water (100 mL) and the THF was removed in vacuo. The resulting mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was dissolved in glacial acetic acid (100 mL) and the solution was stirred at 40 °C overnight. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (400 mL). The solution was washed with sodium carbonate aqueous solution (150 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as colorless oil (31.6 g, 81%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion ) mlz: 367.3 [M+H]+; and H NMR (400 MHz, CDC13): δ 7.68 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H) ppm.

81%	Stage #1: 1-(tert-butoxycarbonyl)-L-proline With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 4-Bromo-benzene-1,2-diamine In tetrahydrofuran at 20℃; for 4h; Stage #3: With acetic acid at 40℃;	1.9 10709] Step 9) the Preparation of Compound 1-11 10710] To a solution of compound 1-10 (20 g, 107 mmol) and compound HATU (48.82 g, 128.4 mmol) in THF (250 mE) was added DIPEA (19.5 mE, 118 mmol) at 0° C. After stirring at 0° C. for 0.5 hr, to the solution was added the compound 1-10-2 (25.6 g, 119 mmol) in a portionwise manner, then the reaction mixture was stirred at it for 4 hrs. After the reaction was completed, the reaction was quenched with water (100 mE), the solvent THF was removed, and the resulting mixture was extracted with EtOAc (200 mEx3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo. The residue was dissolved in glacial acetic acid (100 mE). The solution was stirred at 40° C. overnight, and HOAc was removed. The resulting mixture was dissolved in EtOAc (400 mE), washed with Na2CO3 aq (150 mEx3) and dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by a silica gel colunm chromatography (PE/EtOAc (v/v)=1/2) to give the title compound (35 g, 81%). The compound was characterized by the following spectroscopic data:10711] MS (ESI, pos.ion) mlz: 367.3 [M+H]10712] ‘H NMR (400 MHz, CDC13) ö (ppm): 7.68 (s, 1H),7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H),3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 2H),2.01-1.91 (m, 1H), 1.49 (s, 9H).
71%	Stage #1: 1-(tert-butoxycarbonyl)-L-proline With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: 4-Bromo-benzene-1,2-diamine In tetrahydrofuran at 20℃; Stage #3: With acetic acid at 40℃; for 12h;	1a; 2 To a solution of N-Boc-L-Pro-OH (29 g, 135 mmol) and DIPEA (29 g, 225 mmol) in THF (500 mL) was added HATU (51 g, 135 mmol) at rt. After stirring at rt for 10 min, 4-bromobenzene-l,2-diamine (1-5) (25 g, 135 mmol) was added and the resulting solution was stirred at rt for another several hours. Subsequently, the reaction mixture was concentrated and the residue was diluted with EtOAc (500 mL). The resulting mixture was washed with water for several times (100 mL x 3) and dried with anhydrous Na2S04. The solvent was removed and the residue was dried in vacuo to give a mixture of acylated products, which were used for the next step without further purification.A mixture of acylated products from above in AcOH (1000 mL) was stirred at 40 °C for 12 hrs. After cooling, the reaction mixture was carefully neutralized by adding saturated aqueous sodium bicarbonate solution to adjust the pH value to 8. The resulting mixture was extracted with EtOAc (250 mL x 3). The combined extract was washed with water, and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 4/1 (v/v)) to give (S)-tert- butyl 2-(6-bromo-lH-benzo[d]imidazol-2-yl)pyrrolidine-l-carboxylate (la-6) (35 g, 71% yield in 2 steps) as a yellow solid. LC-MS (ESI): m/z 366.1 [M+H]+.
71%	Stage #1: 1-(tert-butoxycarbonyl)-L-proline With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: 4-Bromo-benzene-1,2-diamine In tetrahydrofuran at 20℃; Stage #3: With acetic acid at 40℃; for 12h;	11-1; 11.e; 11.f To a solution of N-Boc-L-Pro-OH (29 g, 135 mmol) and DIPEA (29 g, 225 mmol) in THF (500 mL) was added HATU (51 g, 135 mmol) at rt. After stirring at rt for 10 min, compound 42 (25 g, 135 mmol) was added and the resulting solution was stirred at rt for another several hours. Subsequently, the reaction mixture was concentrated and the residue was diluted with EtOAc (500 mL). The resulting mixture was washed with ¾0 several times (100 mL x 3) and dried with anhydrous Na2S04. The solvent was removed and the residue was dried in vacuo to give a mixture of crude compounds 43 and 43', which were used for the next step without further purification. LC-MS (ESI): m/z 384.1 (M+H)+. A mixture of crude compounds 43 and 43' obtained from the reaction above in AcOH (1000 mL) was stirred at 40 °C for 12 h. Subsequently, the reaction mixture was carefully neutralized by adding saturated aqueous sodium bicarbonate solution to adjust the pH value to 8. The resulting mixture was extracted with EtOAc several times (250 mL x 3). The extracts were combined, washed with water, and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 4/1 (v/v)) to give compound 44 (35 g, 71% yield, two steps from compound 42) as a yellow solid. LC-MS (ESI): m/z 366.1 (M+H)+.
69%	Stage #1: 1-(tert-butoxycarbonyl)-L-proline With 1,1'-carbonyldiimidazole In pyridine; N,N-dimethyl-formamide at 45℃; for 2h; Stage #2: 4-Bromo-benzene-1,2-diamine In pyridine; N,N-dimethyl-formamide at 20℃; Stage #3: With acetic acid at 100℃; for 0.5h;	1.1 To a solution of Boc-L-Proline (2669 mg, 12.4 mmol) in pyridine/DMF (30 mL, 1/1) was added di(lH-imidazol-l-yl)ketone (2205 mg, 13.6 mmol). The mixture was stirred at 45°C for 2 hours. 4-bromobenzene-l,2-diamine (2319 mg, 12.4 mmol) was added and the mixture was stirred at ambient temperature overnight. The solvent was removed and the residue heated in acetic acid (15 mL) at 100°C for 30 minutes. After concentration of the residue, the mixture was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The organic phase was separated and washed with water. After drying over Na2SC"4, the mixture was filtered and the filtrate was concentrated in vacuo. The obtained residue was purified by flash chromatography using DCM/EtOAc 90/10 to 50/50, resulting in compound II (3.146 g, 69 %).
69%	Stage #1: 1-(tert-butoxycarbonyl)-L-proline With pyridine; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 45℃; for 2h; Stage #2: 4-Bromo-benzene-1,2-diamine In N,N-dimethyl-formamide at 20℃;	1.1 1.1 preparation of intermediate Ila (PG= Boc; X= Br)Ma; To a solution of Boc-Z-Proline (2669 mg, 12.4 mmol) in pyridine/DMF (30 mL, 1/1) was added di(lH-imidazol-l-yl)ketone (2205 mg, 13.6 mmol). The mixture was stirred at 45°C for 2 hours. 4-bromobenzene-l,2-diamine (2319 mg, 12.4 mmol) was added and the mixture was stirred at ambient temperature overnight. The solvent was removed and the residue heated in acetic acid (15 mL) at 100°C for 30 minutes. Afterconcentration of the residue, the mixture was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The organic phase was separated and washed with water, after drying over Na2SC"4, the mixture was filtrated and the filtrate was concentrated in vacuum. The obtained residue was purified by flash chromatography using CH2Cl2/EtOAc 90/10 to 50/50, resulting in compound Ila (3.146 g, 69 %).
63%	Stage #1: 1-(tert-butoxycarbonyl)-L-proline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20 - 25℃; for 1h; Inert atmosphere; Large scale; Stage #2: With HATU In tetrahydrofuran at 20 - 25℃; Inert atmosphere; Large scale; Stage #3: 4-Bromo-benzene-1,2-diamine Large scale; Further stages;	2.1 Step 1. Referring to Scheme 2, N-Boc-L-Proline (4.02 kg, 1.0 eq.) and THF (52.5 L, 15.0 volume) were charged into a 200 L reactor under nitrogen atmosphere. The mixture was cooled to 20 - 25 °C and N, N-diisopropylethylamine (4.8 L, 1.5 eq.) was added over a period of 60 min. Next, HATU (7.11 kg, 1.0 eq.) was slowly added by portion wise over a period of 90 - 120 min at 20 - 25 °C under an atmosphere of nitrogen. After stirring at the same temperature for 15 min, 4-bromo-l, 2-diaminobenzene (3.50 kg, 1.0 eq.) was added into the reactor portion- wise over a period of 90 - 120 min. The resulting reaction mass was stirred at the same temperature. After stirring for 4 - 5 hrs, HPLC analysis indicated that > 97% of 4-bromo-l, 2-diaminobenzene was consumed. The reaction mass was concentrated under vacuum (600 mmHg) to remove THF at < 40 °C and the residue was diluted with ethyl acetate (40.0 L, 10.0 volume) and purified water (25.0 L, 7.0 volume). The resulting mixture was well stirred and the organic layer was separated. Subsequently, the organic layer was washed with purified water (25 L x 3, 7.0 volume) and with saturated brine solution (25 L x1, 7.0 volume) and dried over anhydrous Na2S04. The solvent was removed under high vacuum at 97% of the intermediate was consumed. AcOH was completely distilled off under high vacuum at 40 - 45 °C. The resulting syrup mass was diluted with EtOAc (50.0 L, 14.0 volume) and was purified by washing with water (25.0 L, 7.0 volume) with stirring. The organic layer was separated, washed twice with 5.0 % (w/w) aqueous NaHC03 solution (25.0 L x 2, 7.0 volume), twice with purified water (25.0 L x 2) and once with saturated brine (25 L x 1, 7.0 volume), and dried over anhydrous Na2S04. The solution was treated with active carbon before it was filtered and concentrated under vacuum (600 mrnHg) at 40 - 45 °C to give crude product as a foamy solid (5.20 kg). The residue was suspended with stirring in MTBE (5.2 L, 1.5 volume), the solid was collected by filtration, washed with MTBE (1.75 L, 0.5 volume) and dried in a vacuum tray drier at 40 - 45 °C for 12 hrs to give compound 2-2a (4.20 kg, 63% yield) as pale brown solid with a purity of > 98.0% determined by HPLC analysis. LC-MS (ESI): m/z 366.1 [M + H]+. 1H NMR (400 MHz, -DMSO): δ 12.40 (m, 1H), 7.58 - 7.70 (m, 1H), 7.37 - 7.46 (m, 1H), 7.24 (m, 1H), 4.85 - 4.94 (m, 1H), 3.54 (, 1H), 3.35 - 3.53 (m, 1H), 2.20 -2.32 (m, 1H), 1.88 - 1.96 (m, 3H), 1.38 and 0.98 (s, s, 9H) ppm.
	Stage #1: 1-(tert-butoxycarbonyl)-L-proline; 4-Bromo-benzene-1,2-diamine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 19h; Stage #2: With acetic acid at 65℃; for 1.5h;	M1.a EDCI-HCl (2.348 g, 12.25 mmol) was added to a mixture of 4- bromobenzene-l52-diamine (2.078 gs 11.11 mmol), N-Boc-L-proline (2.311 g, 10.74 mmol) and l-hydroxybenzotriazole (1.742 g, 12.89 mmol) in CH2Cl2 (40 mL), and stirred at ambient conditions for 19 h. The mixture was then diluted with CH2Cl2J washed with water (2x), dried (brine; MgSO4), filtered, and concentrated in vacuo to provide a brown foam. Acetic acid (40 mL) was added to the foam, and the mixture was heated at 65 0C for 90 min. The volatile component was removed in vacuo, and the residue was dissolved in EtOAc and washed carefully with saturated NaHCO3 solution (2x), and the organic phase was dried (brine; MgSO4), filtered, and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; EtOAc) to provide benzimidazole MIa as a tan foam (2.5 g). 1H NMR (DMSO-de, 6 = 2.5 ppm, 400 MHz): 12.49-12.33 (four br s, IH), 7.71 (d, J = 2, 0.54H), 7.60 (app br s, 0.46H), 7.50 (d, J = 8.6, 0.45H), 7.40 (d, J = 8.4, 0.55H), 7.26 (m, IH), 4.96-4.87 (m, IH), 3.64-3.51 (m, IH), 3.44-3.38 (m, IH), 2.38- 2.21 (m, IH), 1.99-1.85 (m, 3H), 1.39 (s, 3.7H), 1.06 (s, 5.3H). LC/MS: Anal Calcd. for [M+H]+ Ci6H2181BrN3O2: 368.03; found: 368.18.
	Multi-step reaction with 2 steps 1.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 16 h / 20 °C 2.1: acetic acid / 2 h / 85 °C
	Stage #1: 1-(tert-butoxycarbonyl)-L-proline; 4-Bromo-benzene-1,2-diamine With 4-methyl-morpholine; HATU In N,N-dimethyl-formamide for 16h; Stage #2: In ethanol at 110 - 130℃; for 48h; Sealed tube;	AK1 To a mixture of 4-Bromo-benzene-1,2-diamine (5.0 g), Boc-L-proline (6.0 g), and 4- methylmorpholine (5.88 mL) in DMF (100 mL) was added HATU (10.7 g). Reaction mixture was stirred for 16 hours and then concentrated. Residue was dissolved in ethyl acetate and washed with 5% lithium chloride solution (2x), brine and dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 30 to 60% ethyl acetate/hexanes) to a dark brown foam. Brown foam was dissolved in ethanol (100 mL) and heated in a sealed tube at 110- 130°C for 2 days. Reaction mixture was cooled and concentrated. Residue was dissolved in ethyl acetate and extracted with IN HCl (3x). Aqueous layer was basified with 50% NaOH solution to pH 10 and extracted with ethyl acetate (2x). The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 10% isopropanol/hexanes) to give 2-(6-Bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (6.5 g) as an off-white foam: LCMS-ESI+: calc'd for C16H2IBrN3O2: 367.26 (M+H+); Found: 365.8, 367.8 (M+H+).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2014/19344, 2014, A1 Location in patent: Paragraph 00335
[2]Current Patent Assignee: ZHANG (inventors); SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - EP2730572, 2015, B1 Location in patent: Page/Page column 0291-0292
[3]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2014/131315, 2014, A1 Location in patent: Page/Page column 116
[4]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - US2015/79028, 2015, A1 Location in patent: Paragraph 0679; 0709; 0710; 0711; 0712
[5]Current Patent Assignee: PRESIDIO PHARMACEUTICALS, INC. - WO2011/156543, 2011, A2 Location in patent: Page/Page column 27; 28
[6]Current Patent Assignee: PRESIDIO PHARMACEUTICALS, INC. - WO2011/150243, 2011, A1 Location in patent: Page/Page column 143-145
[7]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2011/26920, 2011, A1 Location in patent: Page/Page column 19
[8]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2011/54834, 2011, A1 Location in patent: Page/Page column 30
[9]Current Patent Assignee: EVOTEC AG; PRESIDIO PHARMACEUTICALS, INC. - WO2013/123092, 2013, A1 Location in patent: Paragraph 0100
[10]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2010/17401, 2010, A1 Location in patent: Page/Page column 39
[11]Current Patent Assignee: NANJING SANHOME INVESTMENT GROUP CO LTD - US2016/297804, 2016, A1
[12]Current Patent Assignee: GILEAD SCIENCES INC - WO2010/132601, 2010, A1 Location in patent: Page/Page column 482

2
[ 15761-39-4 ]
[ 1575-37-7 ]
[ 1208007-67-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 1-(tert-butoxycarbonyl)-L-proline; 4-Bromo-benzene-1,2-diamine With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran at 0 - 20℃; for 3.5h; Stage #2: With acetic acid at 40℃;	3.4 To a solution of compound C-2 (20 g, 93 mmol), compound C-1 (19.1 g, 102 mmol) and HATU (38.9 g, 102mmol) in THF (500 mL) in an ice bath was added DIPEA (20.5 mL, 118 mmol). The mixture was stirred in the ice bathfor 0.5 hour and at rt for 3 hours. The resulting mixture was quenched with water. THF was removed in vacuo. Theresulting mixture was extracted with EtOAc (150 mL x 3). The combined organic phases were dried over anhydrousNa2SO4 and concentrated in vacuo. The residue was used for the next step without further purification. A solution of theabove residue in glacial acetic acid (100 mL) was stirred at 40 °C overnight, basified with NaHCO3 and extracted withEtOAc (150 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give compound C-3 (27.6 g, 81%).The compound was characterized by the following spectroscopic data:1H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m,2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H).
6%	Stage #1: 1-(tert-butoxycarbonyl)-L-proline; 4-Bromo-benzene-1,2-diamine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; Stage #2: With acetic acid In dichloromethane at 40℃; for 2h;	31 Preparation of compound 81. To a solution of Boc-Pro-OH (10.68 mmol) in DCM were added EDCI (11.73mmol) and 4-bromo-1,2-diaminobenzene (10.69 mmol). The reaction was completed after 2 hrs at room temperature.Dichloromethane (30 mL) was added and the mixture was washed with water. The aqueous phase was extracted withdichloromethane and the combined organics were evaporated in vacuo. The crude was chromatographied to give amixture of bis-acylated analogues. This mixture was heated in acetic acid (14 mL) at 40 °C for 2 hrs. Once cooled,saturated Na2CO3 solution was carefully added to adjust the mixture to pH ∼8. The mixture was extracted with ethylacetate and the organic layers were washed with saturated NaHCO3 solution and water, dried over Na2SO4, and decolourizedwith activate charcoal. The mixture was filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (eluent: DCM to DCM/ MeOH 2%) to give compound 81 as an white solid in 6% yield. MS (ESI,EI+) m/z = 368 (MH+).
	Stage #1: 1-(tert-butoxycarbonyl)-L-proline With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 4-Bromo-benzene-1,2-diamine In tetrahydrofuran at -20 - 20℃; Stage #3: With acetic acid at 50℃; for 2h;	1-1.1a; 1-1.1b; 2-1a.1a-a; 2-1a.1a-b; 3-335.335a; 3-335.335b Example 1-1.Step Ia. A mixture of JV-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 niL, 26.7 mmol) in THF (60 mL) at -20 0C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-l,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20 0C for 1 hour and then slowly warmed up to rt and stirred at rt overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a dark brown foam (10.7 g). ESIMS m/z = 384.18, 386.18 [M+H]+. Step Ib. A solution of the crude compound from step Ia (10.7 g, theo. 26.7 mmol) in glacial acetic acid (100 mL) was heated at 50 0C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHCOs). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown foam (5.78 g, 59%). ESIMS m/z = 366.17, 368.17 [M+H]+. 1H NMR (CDCl3) 10.96, 10.93 (2 s, IH), 7.81, 7.30 (2 s, IH), 7.53, 7.17 (2d, J= 8.5 Hz,PAGE 98 OF 191 IH), 7.23, 7.03 (2d, J= 8.5 Hz, IH), 5.09, 5.07 (2s, IH), 3.42-3.49 (m, 2H), 2.75-2.85 (m, IH), 2.13-2.23 (m, 2H), 1.97-2.00 (m, IH), 1.48 (s, 9H).

	Stage #1: 1-(tert-butoxycarbonyl)-L-proline; 4-Bromo-benzene-1,2-diamine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 19h; Stage #2: With acetic acid at 65℃; for 1.5h;	J.10 EDCI'HCl (2.35 g, 12.25 mmol) was added to a mixture of 4-bromobenzene- 1,2-diamine (2.078 g, 1 1.1 1 mmol), N-Boc-L-proline (2.31 1 g, 10.74 mmol) and 1- hydroxybenzotriazole (1.742 g, 12.89 mmol) in dichloromethane (40 mL), and stirred at ambient conditions for 19 h. The mixture was then diluted with dichloromethane, washed with water (2x), dried (brine; MgSC^), filtered, and concentrated in vacuo to provide a brown foam. Acetic acid (40 mL) was added to the foam, and the mixture was heated at 65 °C for 90 min. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate and washed carefully with saturated aHC03 solution (2x), and the organic phase was dried (brine; MgSC^), filtered, and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; ethyl acetate) to provide J.10 as a tan foam (2.5 g). lH NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): 12.49-12.33 (four br s, IH), 7.71 (d, J = 2, 0.54H), 7.60 (app br s, 0.46H), 7.50 (d, J = 8.6, 0.45H), 7.40 (d, J = 8.4, 0.55H), 7.26 (m, IH), 4.96-4.87 (m, IH), 3.64-3.51 (m, IH), 3.44-3.38 (m, IH), 2.38-2.21 (m, IH), 1.99-1.85 (m, 3H), 1.39 (s, 3.7H), 1.06 (s, 5.3H). (Cond.-D2) LC/MS: Anal. Calcd. for [M+H]+ Ci6H21Br 302: 368.03; found: 368.18.
	Stage #1: 1-(tert-butoxycarbonyl)-L-proline With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 4-Bromo-benzene-1,2-diamine In tetrahydrofuran at -20 - 20℃; Stage #3: With acetic acid at 50℃; for 2h;	1-1.1-1a; 1-1.1-1b Step 1-la. A mixture of N-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20 0C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo- 1 ,2- diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20 0C for 1 hour and then slowly warmed up to rt and stirred at rt overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a dark brown foam (10.7 g). ESIMS m/z = 384.18, 386.18 [M+H]+. Step 1-lb. A solution of the crude compound from step 1-la (10.7 g, 26.7 mmol at most) in glacial acetic acid (100 mL) was heated at 50 0C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - aqueous NaHCOs). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown foam (5.78 g, 59%). ESIMS m/z = 366.17, 368.17 [M+H]+. 1H NMR (CDCl3) 10.96, 10.93 (2 s, IH), 7.81, 7.30 (2 s, IH), 7.53, 7.17 (2d, J= 8.5 Hz, IH), 7.23, 7.03 (2d, J= 8.5 Hz, IH), 5.09, 5.07 (2s, IH), 3.42-3.49 (m, 2H), 2.75-2.85 (m, IH), 2.13-2.23 (m, 2H), 1.97-2.00 (m, IH), 1.48 (s, 9H).
5.78 g	Stage #1: 1-(tert-butoxycarbonyl)-L-proline With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 4-Bromo-benzene-1,2-diamine In tetrahydrofuran at -20 - 20℃; Stage #3: With acetic acid at 50℃; for 2h;	1.1a; 1.1b Step 1a. A mixture of N-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20° C. was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-1,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20° C. for 1 hour and then slowly warmed up to rt and stirred at rt overnight. The volatiles were evaporated and the residue was partitioned (EtOAc-water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a dark brown foam (10.7 g). ESIMS m/z=384.18, 386.18 [M+H]+.; Step 1b. A solution of the crude compound from step 1a (10.7 g, 26.7 mmol at most) in glacial acetic acid (100 mL) was heated at 50° C. for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc-aqueous NaHCO3). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown foam (5.78 g, 59%). ESIMS m/z=366.17, 368.17 [M+H]-. 1H NMR (CDCl3) 10.96, 10.93 (2 s, 1H), 7.81, 7.30 (2 s, 1H), 7.53, 7.17 (2d, J=8.5 Hz, 1H), 7.23, 7.03 (2d, J=8.5 Hz, 1H), 5.09, 5.07 (2s, 1H), 3.42-3.49 (m, 2H), 2.75-2.85 (m, 1H), 2.13-2.23 (m, 2H), 1.97-2.00 (m, 1H), 1.48 (s, 9H).

Reference： [1]Current Patent Assignee: ZHANG (inventors); SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - EP2730572, 2015, B1 Location in patent: Paragraph 0287; 0291
[2]Current Patent Assignee: MERCK & CO INC - EP2513113, 2018, B1 Location in patent: Paragraph 0368; 0370
[3]Current Patent Assignee: ENANTA PHARMACEUTICALS INC - WO2010/91413, 2010, A1 Location in patent: Page/Page column 98-99; 119-120; 131-132
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2012/18325, 2012, A1 Location in patent: Page/Page column 158-159
[5]Current Patent Assignee: ENANTA PHARMACEUTICALS INC - WO2010/99527, 2010, A1 Location in patent: Page/Page column 96
[6]Current Patent Assignee: ENANTA PHARMACEUTICALS INC - US2020/2314, 2020, A1 Location in patent: Paragraph 0184; 0185

3
[ 1208007-67-3 ]
[ 4612-26-4 ]
[ 1239649-51-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 100℃; for 2h;	1 ,1 -dimethylethyl(2S)-2-(5-bromo-1 H-benzimidazol-2-yl)-1 -pyrrolidinecarboxylate (intermediate 45a) (5.00g, 12.76 mmol), benzene-1 ,4-diyldiboronic acid 3 (1 .057 g, 6.38 mmol), PdCI2(dppf)-CH2CI2 adduct (0.512 g, 0.638 mmol), potassium carbonate (2.76 g, 20 mmol) in 1 ,2-dimethoxyethane (30 mL) and water (10 mL) were heated in an oil bath at 100°C for 2 hours. The sample was filtered through celite and washed with DCM. The sample was concentrated and the residue partitioned between DCM and water, the organic layer dried with MgSO^ filtered and concentrated. The residue was chromatographed on a silica using 0-5percent (2N NH3 in MeOH) in DCM. Fractions were concentrated to yield bis(1, 1- dimethylethyl) (2S,2'S)-2,2'-[benzene-1 -diylbis(1H-benzimidazole-5,2-diyl)]di pyrrolidinecarboxylate) (2.50 g, yield 55percent) as an orange solid. 1H NMR (400 MHz, DMSO-c/e) delta ppm 12.03 (br. s., 2 H) 7.83 - 7.89 (m, 1 H) 7.75 (s, 5 H) 7.61 (s, 1 H) 7.52 (br. s., 3 H) 4.99 (br. s., 2 H) 3.79 (td, J=3.4, 1 .6 Hz, 1 H) 3.61 (br. s., 2 H) 3.48 (dt, J=10.2, 7.1 Hz, 2 H) 3.20 (d, J=5.3 Hz, 2 H) 2.34 (br. s., 2 H) 2.05 (d, J=5.9 Hz, 4 H) 1 .93 (d, J=7.1 Hz, 2 H) 1 .28 (br. s., 18 H). ES LC-MS m/z =672.2 (M+H).Intermediate 5
23%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene;Reflux; Inert atmosphere;	Step Ic. A mixture of the compound from step Ib (0.500 g, 1.37 mmol), benzene-1,4- diboronic acid (0.103 g, 0.621 mmol) and Pd(PPh3)4 (35.8 mg, 31.0 mumol) in ethanol (6 mL), toluene (6 mL) and aqueous Na2CO3 (2 M, 0.4 mL) was degassed and heated to reflux under N2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCO3). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a yellow solid (0.158 g, 23percent). ESIMS m/z = 649.50 [M+H]+.

Reference： [1]Patent: WO2011/50146,2011,A1 .Location in patent: Page/Page column 15-16
[2]Patent: WO2010/91413,2010,A1 .Location in patent: Page/Page column 99

4
[ 1208007-67-3 ]
[ 99770-93-1 ]
[ 1256385-57-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;Microwave irradiation;	A mixture 2-(6-Bromo-1H-benzoimidazol-2- yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.257 g), 1,4-benzenediboronic acid, pinacol ester (1.158 g), Pd(PPh3)4 (0.041 g) and potassium carbonate (0.485 g) in H2O (2.0 mL)/dimethoxyethane (5.0 mL) was heated in microvave at 120C for 30 minutes. Reaction mixture was cooled and diluted with ethyl acetate, washed with brine, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 70% ethyl acetate/hexanes) to give 2-{6-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H- benzoimidazol-2-yl} -pyrrolidine- 1-carboxylic acid tert-butyl ester (0.187 g): LCMS-ESI+: calc'd for C28H37BN3O4: 490.42 (M+H+); Found: 490.0 (M+H+).

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2033 - 2046
[2]Patent: WO2010/132601,2010,A1 .Location in patent: Page/Page column 482

5
[ 1208007-67-3 ]
[ 444120-91-6 ]
[ 1352212-48-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 110℃; for 6h;	Preparation 23: fert-Butyl (2S)-2-[5-(6-chloropyridin-3-yl)-1 H-benzimidazol-2-yl]pyrrolidine-1 - carboxylateTo ieri-butyl (2S)-2-(5-bromo-1 H-benzimidazol-2-yl)pyrrolidine-1-carboxylate obtained from Preparation 6 (187 mg, 0.510 mmol) and 2-chloro-5-pyridine boronic acid (88 mg, 0.561 mmol) in 1 ,4-dioxane (2 mL), were added Pd2(dba)3 (5 mg, 0.005 mmol) and tricyclohexylphosphine (4 mg, 0.012 mmol). A solution of potassium phosphate (184 mg, 0.867 mmol) in water (683 uL) was added and the resulting reaction mixture was heated at 1 10 C for 16 hours. After this time, the suspension formed was cooled to room temperature and the solvent evaporated under reduced pressure. The crude residue was purified by flash chromatography (heptane : ethyl acetate, 70:30 to 20:80) to give the title compound as a white solid (143 mg).LCMS (run time = 2 minutes, System A): Rt = 1.29 minutes; m/z 399, 401 [MH+]H NMR (400 MHz, CDCI3): delta = 8.64 (d, 1 H), 7.87 (dd, 1 H), 7.76-7.66 (br, 2H), 7.42 (s, 1 H), 7.40 (d, 1 H), 5.15 (dd, 1 H), 3.47-3.44 (m, 2H), 3.09-3.02 (m, 1.5H), 2.08-2.01 (m, 1.5H), 1.53 (s, 9H).

Reference： [1]Patent: WO2011/154871,2011,A1 .Location in patent: Page/Page column 86-87

6
[ 1208007-67-3 ]
[ 1303533-81-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate / water; 1,2-dimethoxyethane / 80 °C / Inert atmosphere; Large scale 2.1: hydrogenchloride / isopropyl alcohol / 18 - 30 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.17 h 3.2: 0.5 h / 2 °C 3.3: 4.5 h / 3 - 25 °C 4.1: hydrogenchloride / ethanol / 0.33 h / 20 - 25 °C / Inert atmosphere; Large scale

Reference： [1]Current Patent Assignee: EVOTEC AG; PRESIDIO PHARMACEUTICALS, INC. - WO2013/123092, 2013, A1

Same Skeleton Products

Related Products

Historical Records

Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1208007-67-3 ] {[proInfo.proName]}

Quality Control of [ 1208007-67-3 ]

Related Doc. of [ 1208007-67-3 ]

Product Details of [ 1208007-67-3 ]

Safety of [ 1208007-67-3 ]

Application In Synthesis of [ 1208007-67-3 ]

[ 1208007-67-3 ] Synthesis Path-Downstream 1~6

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry