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 - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 51293-47-1 | MDL No. : | MFCD00153314 |
Formula : | C9H17NO5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 219.24 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.78 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 52.75 |
TPSA : | 84.86 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.35 cm/s |
Log Po/w (iLOGP) : | 1.76 |
Log Po/w (XLOGP3) : | 0.41 |
Log Po/w (WLOGP) : | 0.61 |
Log Po/w (MLOGP) : | 0.01 |
Log Po/w (SILICOS-IT) : | -0.14 |
Consensus Log Po/w : | 0.53 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.0 |
Solubility : | 22.1 mg/ml ; 0.101 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.76 |
Solubility : | 3.82 mg/ml ; 0.0174 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.79 |
Solubility : | 35.2 mg/ml ; 0.161 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.97 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; | To 2.0 g (17 mmol) of C606-1 were added 35 ml of a IN aqueous sodium hydroxide solution and 35 ml of THF. A solution of di-tert- butyl dicarbonate (4.03 g, 18.5 mmol) in THF (15 mL) was then added with stirring at 0°C. The reaction mixture was stirred overnight at room temperature and concentrated by evaporation under reduced pressure. The aqueous phase was acidified to pH 4-5 with 10percent aqueous citric acid and extracted with ethyl acetate. The extract was washed with brine, dried (MgS04), and evaporated to give 3.6 g of compound 606-2 (98 percent yield). MS (ESI) m/z: 220.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Stage #1: With methanol; sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1 h; Stage #2: at 20℃; for 38 h; Stage #3: With citric acid In water |
A. (S)-2-(tert-Butoxycarbonylamino)-3-methoxypropanoic acid A sodium methanolate (NaOMe) solution was prepared by slowly adding MeOH (50 mL) to a suspension of sodium hydride (60percent in mineral oil, 28 g, 0.71 mol) in dry THF (1.2 L) at 0° C. The resulting mixture was stirred at RT for 2 h. A portion of the NaOMe solution (320 mL) was added to (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (36 g, 175 mmol) in dry THF (1.6 L), and the mixture was stirred at RT for 1 h. Methyl iodine (16 mL) was then added and the mixture was stirred at RT for 1 h. Another aliquot of NaOMe solution (540 mL) was added and the reaction mixture stirred at RT for 1 h. Additional methyl iodine (38 mL) in THF (200 mL) was added and the reaction mixture was stirred at RT for 36 h. Following reaction, the mixture was concentrated and the residue was dissolved in water and washed with diethyl ether (2.x.100 mL). The aqueous layer was acidified to pH 2 by the addition of solid citric acid and was extracted with EtOAc (3.x.200 mL) and dried over Na2SO4. The organic phase was concentrated, and the residue was dissolved in water and extracted with DCM (4.x.150 mL). The organic layers were combined and concentrated to give the title compound as an oil, which was used without further purification (10.9 g, 28percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
240.3 kg | at 10℃; for 44 h; Large scale | Example 2 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid (0033) (0034) 45percent 4 NaOH (746.3 kg; 8.40 kmoles) and DMS (1053.8 kg; 8.36 kmoles) were added to the reaction mixture below 10° C. over 38 h and for an additional 6 h to complete the reaction. 20percent 9 NH4OH (20.0 kg) was added to quench the reaction in the reaction mixture. The pH value was adjusted by 10 citric acid monohydrate (55.8 kg) and 32percent 11 HCl (180 kg) to around 3. The 12 product was extracted by toluene (1165 L) twice, and the organic layer was washed by 1percent NaOH (40 L) and H2O (39 L×2). The organic layer was concentrated, and stripped by IPA as oil residue (240.3 kg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | A. (S)-2-(tert-Butoxycarbonylamino)-3-methoxypropanoic acid A sodium methanolate (NaOMe) solution was prepared by slowly adding MeOH (50 mL) to a suspension of sodium hydride (60percent in mineral oil, 28 g, 0.71 mol) in dry THF (1.2 L) at 0° C. The resulting mixture was stirred at RT for 2 h. A portion of the NaOMe solution (320 mL) was added to (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (36 g, 175 mmol) in dry THF (1.6 L), and the mixture was stirred at RT for 1 h. Methyl iodine (16 mL) was then added and the mixture was stirred at RT for 1 h. Another aliquot of NaOMe solution (540 mL) was added and the reaction mixture stirred at RT for 1 h. Additional methyl iodine (38 mL) in THF (200 mL) was added and the reaction mixture was stirred at RT for 36 h. Following reaction, the mixture was concentrated and the residue was dissolved in water and washed with diethyl ether (2.x.100 mL). The aqueous layer was acidified to pH 2 by the addition of solid citric acid and was extracted with EtOAc (3.x.200 mL) and dried over Na2SO4. The organic phase was concentrated, and the residue was dissolved in water and extracted with DCM (4.x.150 mL). The organic layers were combined and concentrated to give the title compound as an oil, which was used without further purification (10.9 g, 28percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In 1,4-dioxane; for 18h; | Boc-L-Serine (OMe) -OH (2.4g, 6. Ommols) was dissolved in dioxan (20mis) and to this was added pyridine (0.31 mis), di-tert-butyl dicarbonate (1.7g, 7. 8mmols) and ammonium hydrogen carbonate (0.62g, 7. 2mmols). After stirring for 18 hours the crude reaction mixture was concentrated in vacuo and re-suspended in ethyl acetate. This was washed with 1 M KHS04 and the organic layer dried over magnesium sulphate. After concentration the crude product was purified by flash chromatography to yield 0.55g of a clear oil. This was dissolved in ethylene glycol dimethyl ether (20mis) and to this was added Lawesson's reagent (2. 78mmols). After stirring at room temperature for 3 hours the reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM) to give a yellow oil (2-Methoxy-1-thiocarbamoyl- ethyl)-carbamic acid tert-butyl ester (0.49g). The ester (0.25g, 1. 07mmols) was dissolved in ethanol (10mis) and 4- (2-Bromo-acetyl)- benzoic acid methyl ester (1. 18mmols, 0.30g) was added. The reaction was heated to 50°C for one hour. The crude product was purified by preparative HPLC (MeCN/H20) to yield 0.138g of a yellow solid. The Boc group was removed via treatment with 4M HCI/dioxan for one hour after which time the reaction mixture was concentrated in vacuo. The free amine (0.093g, 0. 265mmols) was then dimethylated. The crude HCI salt was dissolved in 5mis of methanol and buffered with 2. 5mis pH 5.5 Sodium acetate/acetic acid. Formaldehyde was added (0. 58mmols) and the reaction stirred for one hour. Sodium cyanoborohydride was then added (0. 58mmols, 0.036g) and the reaction stirred for a further thirty minutes. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to yield 60mg of a yellow solid. Finally, the methyl ester was hydrolyse with 1 M LiOH (5mis) and dioxan (5mis) at room temperature for two hours. The reaction mixture was concentrated in vacuo and lyophilised from water to yield 62mg of the desired acid as the lithium salt. ESMS (M + H = 307.04) | |
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In 1,4-dioxane; for 18h; | Boc-L-Serine(OMe)-OH (2.4g, beta.Ommols) was dissolved in dioxan (2OmIs) and to this was added pyridine (0.31 mis), di-tert-butyl dicarbonate (1.7g, 7.8mmols) and ammonium hydrogen carbonate (0.62g, 7.2mmols). After stirring for 18 hours the crude reaction mixture was concentrated in vacuo and re-suspended in ethyl acetate. This was washed with 1 M KHSO4 and the organic layer dried over magnesium sulphate. After concentration the crude product was purified by flash chromatography to yield 0.55g of a clear oil. This was dissolved in ethylene glycol dimethyl ether (2OmIs) and to this was added Lawesson's reagent (2.78mmols). After stirring at room temperature for 3 hours the reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM) to give a yellow oil (2-Methoxy-1-thiocarbamoyl- ethyl)-carbamic acid tert-butyl ester (0.49g). The ester (0.25g, 1.07mmols) was dissolved in ethanol (1OmIs) and 4-(2-Bromo-acetyl)- benzoic acid methyl ester (1.18mmols, 0.3Og) was added. The reaction was heated to 500C for one hour. The crude product was purified by preparative HPLC (MeCN/H2O) to yield 0.138g of a yellow solid. The Boc group was removed via treatment with 4M HCI/dioxan for one hour after which time the reaction mixture was concentrated in vacuo. The free amine (0.093g, 0.265mmols) was then dimethylated. The crude HCI salt was dissolved in 5mls of methanol and buffered with 2.5mls pH 5.5 Sodium acetate/acetic acid. Formaldehyde was added (0.58mmols) and the reaction stirred for one hour. Sodium cyanoborohydride was then added (0.58mmols, 0.036g) and the reaction stirred for a further thirty minutes. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to yield 60mg of a yellow solid. Finally, the methyl ester was hydrolysed with 1 M LiOH (5mls) and dioxan (5mls) at room temperature for two hours. The reaction mixture was concentrated in vacuo and lyophilised from water to yield 62mg of the desired acid as the lithium salt. ESMS (M + H = 307.04) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | [N-A-BOC-0-METHYL-L-SERINE] (2.19g, 10.0 mmol), HOBt (1.62g, 12.0 mmol), [1-ETHYL-3- (3APOS;-DIMETHYLAMINO-PROPYL) CARBODIIMIDE] hydrochloride (EDC, 2. [01G,] 10.5 mmol), and N-methylmorpholine (1.4 mL, 12.5 mmol) were stirred in 150 mL anhydrous dichloromethane. After 5 min, [2-AMINO-4-METHYL-L- (5-PHENYL-] [[1,] 3,4] oxadiazol-2-yl)-pentan-1-ol hydrochloride (2.61g, 10.0 mmol) dissolved in dichloromethane (50 [ML)] and more N-methylmorpholine (1.4 mL, 12.5 mmol) were added. After 3 hr, the reaction mixture was transferred to a separatory funnel and washed twice with 100 mL portions [OF 0. 5N] aqueous [HCI.] The organic phase was separated and once with water (50 mL) and twice with saturated aqueous sodium bicarbonate (100 mL). The organic phase was dried over anhydrous magnesium sulfate. Filtration and solvent evaporation gave a tan foam. This was flash chromatographed on silica gel, eluting with 5percent methanol in dichloromethane to give (1- 1- [hydroxy- (5-phenyl- [1, 3,4] oxadiazol-2-yl) methyl]-3-methyl-butylcarbamoyl}- 2-methoxyethyl) carbamic acid ter-butyl ester as a brittle, pale yellow foam, (3.65g, 79percent) as a mixture of diastereomers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; for 2h; | General procedure: A solution of the compound of Formula XIII(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionic acid benzyl ester (1.76 g, 5.09 mmol) in THF was stirred with 10percent Pd/C (360 mg) under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and concentrated to give the compound of Formula IV(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionic acid (1.3 g, 100percent) as a sticky, colorless oil. 1H NMR (300 MHz, CDCl3): delta (ppm) 6.21 (wt, 1H), 5.35 (d, 1H), 4.59 (m, 1H), 4.35 (m, 1H), 4.21 (m, 1H) and 1.42 (s, 9H). |
D. N(3,5-Dimethyltetrahydrothiopyran-4-yl)-t-butoxycarbonyl-D-O-methylserineamide STR115 Under anhydrous conditions, to a mixture of 1.96 g. (8.9 mmole) of N-t-Boc-D-O-methylserine obtained in Example 7, Part A, 1.98 g. (19 mmole) triethylamine and 40 ml. of tetrahydrofuran, cooled to -10° C., is added dropwise 0.96 g. (8.9 mmole) ethyl chloroformate and the resulting mixture stirred at this temperature for 20 minutes. To this is added 1.1 g. (7.5 mmole) of the mixture of isomers of 4-amino-3,5-dimethyltetrahydrothiopyran obtained in Part C and the resulting mixture stirred at -10° C. for 10 minutes then allowed to warm to room temperature. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate solution, dilute hydrochloric acid, water, brine then dried (Na2 SO4) and the solvent evaporated at reduced pressure to obtain the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(xiv) Where the commercially available or literature derived form of the amino acid starting material used in the examples was a salt, the free base was generated by use of an SCX column. A solution of the salt in methanol was loaded onto an SCX column and washed with methanol. The column was then be eluted with saturated methanol ammonia solution. Appropriate fractions were combined and evaporated to afford the free base form which was used as such without further purification.; The N2, O-dimethyl-L-serinamide used as starting material was prepared as follows: Sodium hydride (2.1 g, 52.4 mmol) was washed with iso-hexane under a nitrogen atmosphere. Tetrahydrofuran (20 ml) was added and the suspension cooled in an ice/water bath. A mixture of N- (tert-butoxycarbonyl)-O-methyl-L-serine (starting material obtained by converting the dicyclohexylamine salt to the free base as described above in the pre-amble to the Examples) (2.5 g, 11.4 mmol) and water (41 jj, l, 2. 28 mmol) in tetrahydrofuran (15 ml) was slowly added. The resulting mixture was allowed to stir for 20 minutes and dimethylsulfate (3.3 ml, 35.3 mmol) was slowly added. The mixture was stirred for 2 hours and treated with concentrated ammonium hydroxide (15 ml). The resulting mixture was stirred for a further 2 hours, then acidified with 2M hydrochloric acid, extracted with ethyl acetate, dried (MgS04) and concentrated under reduced pressure. The residues were dissolved in methanol, absorbed onto an NH2 column, washed with methanol and eluted with 7N ammonia in methanol. Appropriate fractions were combined and evaporated under reduced pressure to give N-(tert-butoxycarbonyl)-N, O-dimethyl-L-serine (1.5 g, 56 percent) as a viscous, colourless oil ; 1H NMR spectrum : (DMSO d6, 100°C) 1.40 (s, 9H), 2.77 (s, 3H), 3.26 (s, 3H), 3.67 (m, 2H), 4.51 (m, 1H). | ||
With citric acid; In water; | 2.50 g (6.24 mmol) of the dicyclohexylammonium salt of N-Boc-(S)-O-methyl-serine are dissolved in 20 ml 5percent citric acid, the aqueous phase is extracted 2.x. with 20 ml of ethyl acetate, the combined organic phases are dried over sodium sulphate and freed from solvent i. vac. The residue is dissolved together with 1.23 g (6.55 mmol) 4-bromo-1,2-phenylenediamine in 30 ml THF and 1.42 ml (14.0 mmol) triethylamine and 4.97 ml (7.80 mmol) of a 50percent solution of PPA in ethyl acetate are added with stirring in the ice bath. After 5 minutes stirring in the ice bath the mixture is heated to ambient temperature and stirred for 23 hours at ambient temperature. The reaction mixture is poured into 100 ml of water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are extracted with sat. sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac. Yield: 2.38 g (98percent) mixture of the two regioisomers C15H22BrN3O4 (388.26) Mass spectrum: (M+H)+=388/390 (bromine isotope) Rf value: 0.63/0.68 (silica gel; dichloromethane/ethanol=9:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In tetrahydrofuran; ethyl acetate; at 0 - 20℃; for 0.25h; | 30.0 g (137 mmol) N-Boc-(S)-O-methyl-serine are dissolved together with 21.9 g (154 mmol) 4-chloro-1,2-phenylenediamine in 658 ml THF, and 43.9 ml (316 mmol) triethylamine and 103 ml (173 mmol) of a 50percent solution of PPA in ethyl acetate are added with stirring in the ice bath. After 15 minutes stirring in the ice bath the mixture is heated to ambient temperature, poured into water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with sat. sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/methanol=30:1->9:1). Yield: 33.47 g (72percent) mixture of the two regioisomers C15H22ClN3O4 (343.81) Mass spectrum: (M-H)-342/344 (chlorine isotope) Rf value: 0.80 (silica gel; dichloromethane/methanol=9:1) | |
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In tetrahydrofuran; ethyl acetate; at 0℃; for 0.25h; | (e) /V-(2-amino-4-chloro-phenyl)-/V-Boc-(S)-O-methyl-serinamide and N'-(2- amino-5-chloro-phenyl)-lambda/-Boc-(S)-O-methyl-sehnamide; 30.0 g (137 mmol) lambda/-Boc-(S)-O-methyl-sehne together with 21.9 g (154 mmol) 4-chloro-1 ,2-phenylendiamine are dissolved in 658 ml THF, and 43.9 ml (316 mmol) triethylamine and 103 ml (173 mmol) of a 50 percent solution of PPA in ethyl <n="60"/>acetate are added with stirring in the ice bath. After 15 minutes stirring in the ice bath the mixture is heated to ambient temperature, poured into water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with sat. sodium carbonate solution and water, dried on sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant-gradient: dichloromethane/methanol = 30:1 -> 9:1 ). Ci5H22CIN3O4 (343.81 )Mass spectrum: (M-H)" = 342/344 (chlorine isotopes) Rf value: 0.80 (silica gel; dichloromethane/methanol = 9:1 ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h; | A solution of 2.00 g of methyl 2-amino-5-(1-methylethyl)thiazole-4-carboxylate, obtained in Example 1, in 100 ml of dimethylformamide at 0° C. is admixed with 1.01 g of N-methylmorpholine, 5.72 g of PyBOP and then 2.40 g of (S)-BOC-O-methylserine, dicyclohexylamine. The reaction is allowed to return to ambient temperature and the mixture is stirred for 18 h. The solvent is evaporated and the residue is taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution, once with water and once with a 1N aqueous solution of potassium hydrogen sulfate and then with saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a silica column, eluting with an 8:2 (v/v) petroleum ether/ethyl acetate mixture, to give 2.70 g of a white powder. LC/MS: MH+=402. NMR 300 MHz (CDC13): 1.33 (d, 6H); 1.48 (s, 9H); 3.32 (s, 3H); 3.33 and 3.99 (2m, 2H); 3.55 (m, 1H); 3.92 (s, 3H); 4.13 (m, 1H); 4.5 (broad s 1H); 5.40 (d, 1H). A solution of 4.30 g of the product obtained in the manner described above, in 60 ml of trifluoroacetic acid, is stirred at ambient temperature for 30 min, and then the solution is evaporated. The residue is taken up in ethyl acetate and washed twice with saturated aqueous sodium carbonate solution and then with saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate and then evaporated to give 0.50 g of a white solid, which is used without purification in the following step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In tetrahydrofuran; ethyl acetate; at 0 - 20℃; for 23.0833h; | 2.50 g (6.24 mmol) of the dicyclohexylammonium salt of N-Boc-(S)-O-methyl-serine are dissolved in 20 ml 5percent citric acid, the aqueous phase is extracted 2.x. with 20 ml of ethyl acetate, the combined organic phases are dried over sodium sulphate and freed from solvent i. vac. The residue is dissolved together with 1.23 g (6.55 mmol) 4-bromo-1,2-phenylenediamine in 30 ml THF and 1.42 ml (14.0 mmol) triethylamine and 4.97 ml (7.80 mmol) of a 50percent solution of PPA in ethyl acetate are added with stirring in the ice bath. After 5 minutes stirring in the ice bath the mixture is heated to ambient temperature and stirred for 23 hours at ambient temperature. The reaction mixture is poured into 100 ml of water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are extracted with sat. sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac. Yield: 2.38 g (98percent) mixture of the two regioisomers C15H22BrN3O4 (388.26) Mass spectrum: (M+H)+=388/390 (bromine isotope) Rf value: 0.63/0.68 (silica gel; dichloromethane/ethanol=9:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; | B. N-t-Boc-D-O-Methylserine N-(2,2,4,4-tetramethylthietan-3-yl)amide To a solution of 4.2 g. (18.6 mmole) N-t-Boc-D-O-methylserine in 90 ml. methylene chloride was added 2.08 ml. N-methylmorpholine, the mixture cooled to -15° C. and 1.78 ml. ethyl chloroformate added. After stirring for 8 minutes at -20° to -15° C., 2.70 g. (18.6 mole) 3-amino-2,2,4,4-tetramethylthietane dissolved in 10 ml. methylene chloride was added at the same temperature and the mixture allowed to warm to room temperature. After stirring for two hours the mixture was washed with dilute sodium hydroxide, dilute hydrochloric acid, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo to yield 6.04 g. (94percent) of colorless solid, Rf 0.35 (3:7 ethyl acetate/hexane, phosphomolybdate spray). The structure was verified by 1 H-NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine; In dichloromethane; at 0℃; for 3.5h; | To a 0° C. solution of N-Boc serine(methyl ether)-OH (43.8 g, 200 mmol), triethylamine (26.5 g, 260 mmol) and 4-(dimethylamino)pyridine in dichloromethane (1.2 L) was added a solution of benzyl chloroformate (41 g, 240 mmol) in dichloromethane (250 mL) over 30 minutes and the resulting mixture was stirred at the same temperature for another 3 hours. Saturated aqueous sodium bicarbonate (200 mL) was then added and the organic layer was washed with saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL). The organic layers were dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (hexane and ethyl acetate) to provide (076) (54 g) which was characterized by LC/MS (LCRS (MH) m/z: 310.16). | |
With triethylamine; In dichloromethane; at 0℃; for 3.5h; | Example 1; Synthesis of Compound 1; Synthesis of (A); To a 0° C. solution of N-Boc serine(methyl ether) (43.8 g, 200 mmol), triethylamine (26.5 g, 260 mmol) and 4-(dimethylamino)pyridine in dichloromethane (1.2 L) was added a solution of benzyl chloroformate (41 g, 240 mmol) in dichloromethane (250 mL) over 30 minutes. The resulting mixture was stirred at the same temperature for another 3 hours. Saturated aqueous sodium bicarbonate (200 mL) was added and organic layer was separated, the residual mixture was extracted with dichloromethane (2.x.400 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL), dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, hexane and ethyl acetate). Compound (A) (54 g) was isolated and characterized by LC/MS (LRMS (MH) m/z: 310.16). | |
54 g | With dmap; triethylamine; In dichloromethane; at 0℃; for 3.5h; | To a 00 C. solution of N-Hoc serine(methyl ether) (43.8 g, 200 mmol), triethylamine (26.5 g, 260 mmol) and 4-(dimethylamino)pyridine in dichloromethane (1.2 L) was added a solution ofbenzyl chloroformate (41 g, 240 mmol) in dichloromethane (250 mE) over 30 minutes. The resulting mixture was stirred at the same temperature for another 3hours. Saturated aqueous sodium bicarbonate (200 ml) was added and organic layer was separated, the residual mixture was extracted with dichloromethane (2x400 mE). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mE) and brine (200 mE), dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was punrified by flash chromatography (silica gel, hexane and ethyl acetate). Compound (A) (54 g) was isolated and characterized by LC/MS (LRMS (MH) mlz: 310.16). |
With dmap; triethylamine; In dichloromethane; at -5℃; for 3h;Inert atmosphere; | L) To a solution of Boc-methylserine (13) in DCM (Dichlormethane) TEA (Triethylamine) and DMAP (4-Dimethylaminopyridine) are added. The resulting solution is cooled to -5 °C, and benzyl chloroformate is then slowly added via an addition funnel under an atmosphere of argon. The reaction is kept at the same temperature for 3 h and then diluted with brine. The layers are separated, and the aqueous layer is extracted with DCM. The organic layers are combined and dried over Na2S04- The Na2S04 is removed by filtration, and the volatiles are removed under reduced pressure. The resulting residue is purified by flash chromatography using a mixture of hexane and ethyl acetate to provide intermediate (14) as white solid. | |
54 g | With dmap; triethylamine; In dichloromethane; at 0℃; for 3.5h; | To a 0°C. solution of N-Boc serine(methyl ether) (43.8 g, 200 mmol), triethylamine (26.5 g, 260 mmol) and 4-(dimethylamino)pyridine in dichloromethane (1.2 L) was added a solution of benzyl chloroformate (41 g, 240 mmol) in dichloromethane (250 mE) over 30 minutes. The resulting mixture was stirred at the same temperature for another 3 hours. Saturated aqueous sodium bicarbonate (200 mE) was added and organic layer was separated, the residual mixture was extracted with dichloromethane (2x400 mE). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mE) and brine (200 mE), dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, hexane and ethyl acetate). Compound (A) (54 g) was isolated and characterized by LC/MS (LRMS (MH) mlz: 310.16). |
54 g | With dmap; triethylamine; In dichloromethane; at 0℃; for 3.5h; | To a 0° C. solution of N-Boc serine(methyl ether) (43.8 g, 200 mmol), triethylamine (26.5 g, 260 mmol) and 4-(dimethylamino)pyridine in dichloromethane (1.2 L) was added a solution of benzyl chloroformate (41 g, 240 mmol) in dichloromethane (250 mL) over 30 minutes. The resulting mixture was stirred at the same temperature for another 3 hours. Saturated aqueous sodium bicarbonate (200 mL) was added and organic layer was separated, the residual mixture was extracted with dichloromethane (2×400 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL), dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, hexane and ethyl acetate). Compound (A) (54 g) was isolated and characterized by LC/MS (LRMS(MH) m/z: 310.16). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 5.16667h;pH ~ 8; | To a 0° C. solution of (077) (43.8 g, 200 mmol), N-Boc serine(methyl ether)-OH (36.7 g, 167 mmol), HOBT (27 g, 200 mmol) and HBTU (71.4 g, 200 mmol) in tetrahydrofuran (1.2 L) was added a solution of N,N-diisopropylethylamine (75 g, 600 mmol) in tetrahydrofuran (250 mL) over 10 minutes, and pH of the resulting mixture was 8. The mixture was stirred at room temperature for another 5 hours. Most of the solvent was then removed under reduced pressure and the resulting material diluted with ethyl acetate (1.0 L). It was then washed with saturated aqueous sodium bicarbonate (2.x.150 mL) and brine (200 mL) and the organic layers were dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (hexane and ethyl acetate) to provide (078) (65 g) which was characterized by LC/MS (LCRS (MH) m/z: 411.21). | |
65 g | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 5.16h;pH 8; | To a 0° C. solution of Compound (5) (43.8 g, 200mmol), N-Hoc serine(methyl ether) (36.7 g, 167 mmol), HOST (27 g, 200 mmol) and HHTU (71.4 g, 200 mmol) in tetrahydroffiran (1.2 E) was added a solution of N,N-diethylisopropylamine (75 g, 600 mmol) in tetrahydrofuran (250 mE) over 10 minutes, and the pH of the resulting mixture was 8. The mixture was stirred at room temperature for another 5 hours. Most of the solvent were removed under reduced pressure at room temperature and diluted with saturated aqueous sodium bicarbonate (400 mE). Then it was extracted with ethyl acetate (3x400 mE), washed with sodium bicarbonate (100 mE) and brine (100 mE). The combined organic layers were dried over sodium sulfate and filtered through Celite545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, hexane and ethyl acetate). Compound (C) (65 g) was isolated and characterized by LC/MS (LRMS (MH) m/z: 411.21). |
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -5℃; for 4h; | N) To a -5 °C mixture of aforementioned TFA salt (15), Boc-methylserine (13), HOBt (Hydroxybenzotriazole), and HBTU (2-(1 H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) in THF (Tetrahydrofuran) (600 ml.) is added DIEA slowly via an addition funnel. The reaction is kept at the same temperature for 4 h, followed by dilution with EtOAc (Ethylacetate) and brine. The layers are separated, and the aqueous layer is extracted with EtOAc (2 * 300 ml_). The organic layers are combined and dried over Na2S04. The Na2S04 is removed by filtration, and the volatiles are removed under reduced pressure. The resulting residue is purified by flash chromatography using a mixture of hexane and ethyl acetate to provide dipeptide (16) as white solid. |
65 g | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 5.16667h;pH 8; | To a 0° C. solution of Compound (B) (43.8 g, 200 mmol), N-Boc serine(methyl ether) (36.7 g, 167 mmol), HOBT (27 g, 200 mmol) and HBTU (71.4 g, 200 mmol) in tetrahydrofuran (1.2 L) was added a solution of N,N-diethylisopropylamine (75 g, 600 mmol) in tetrahydrofuran (250 mL) over 10 minutes, and the pH of the resulting mixture was 8. The mixture was stirred at room temperature for another 5 hours. Most of the solvent were removed under reduced pressure at room temperature and diluted with saturated aqueous sodium bicarbonate (400 mL). Then it was extracted with ethyl acetate (3×400 mL), washed with sodium bicarbonate (100 mL) and brine (100 mL). The combined organic layers were dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, hexane and ethyl acetate). Compound (C) (65 g) was isolated and characterized by LC/MS (LRMS (MH) m/z: 411.21). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 5.16667h; | To a 0° C. solution of N-Boc serine(methyl ether) (001) (2.5 g, 11.4 mmol), L-alanine benzyl ester hydrochloride (002) (3.3 g, 11.4 mmol), HOBT (2.5 g, 18.2 mmol) and HBTU (6.9 g, 18.24 mmol) in tetrahydrofuran (400 mL) was added a solution of N,N-diisopropylethylamine (8.0 mL, 45.6 mmol) in tetrahydrofuran (50 mL) over 10 minutes. The mixture was stirred at room temperature for another 5 hours. Most of the solvents were removed under reduced pressure and the resulting material diluted with ethyl acetate (300 mL). The solution was then washed with saturated aqueous sodium bicarbonate (2.x.50 mL) and brine (100 mL). The organic layers were dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and the residue was purified by flash chromatography (hexane and ethyl acetate), and the desired compound (003) (4.4 g) was isolated and characterized by LC/MS (LCRS (MH) m/z: 457.23). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃;pH 8; | Synthesis of (C); To a 0° C. solution of Compound (B) (43.8 g, 200 mmol), N-Boc serine(methyl ether) (36.7 g, 167 mmol), HOBT (27 g, 200 mmol) and HBTU (71.4 g, 200 mmol) in tetrahydrofuran (1.2 L) was added a solution of N,N-diethylisopropylamine (75 g, 600 mmol) in tetrahydrofuran (250 mL) over 10 minutes, and the pH of the resulting mixture was 8. The mixture was stirred at room temperature for another 5 hours. Most of the solvent were removed under reduced pressure at room temperature and diluted with saturated aqueous sodium bicarbonate (400 mL). Then it was extracted with ethyl acetate (3.x.400 mL), washed with sodium bicarbonate (100 mL) and brine (100 mL). The combined organic layers were dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, hexane and ethyl acetate). Compound (C) (65 g) was isolated and characterized by LC/MS (LRMS (MH) m/z: 411.21). | |
65 g | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 5.16667h;pH Ca. 8; | To a 0°C. solution of Compound (H) (43.8 g, 200 mmol), N-Boc serine(methyl ether) (36.7 g, 167 mmol), HOBT (27 g, 200 mmol) and HBTU (71.4 g, 200 mmol) in tetrahydrofuran (1.2 E) was added a solution of N,Ndiethylisopropylamine (75 g, 600 mmol) in tetrahydrofuran (250 ml) over 10 minutes, and the pH of the resulting mixture was 8. The mixture was stirred at room temperature for another 5 hours. Most of the solvent were removed under reduced pressure at room temperature and diluted with saturated aqueous sodium bicarbonate (400 mE). Then it was extracted with ethyl acetate (3x400 mE), washed with sodium bicarbonate (100 ml) and brine (100 ml). The combined organic layers were dried over sodium sulfate and filtered through Celite-545°. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, hexane and ethyl acetate). Compound (C) (65 g) was isolated and characterized by LC/MS (LRMS (MH) mlz: 411.21). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | B. (R)-tert-Butyl 1-hydroxy-3-methoxypropan-2-ylcarbamate To a mixture of <strong>[51293-47-1](S)-2-(tert-butoxycarbonylamino)-3-methoxypropanoic acid</strong> (10.9 g) and N-methylmorpholine (5.6 g, 55 mmol) in THF (50 mL) was added 2-methylpropylchloroformate (7.48 g, 55 mmol) in THF at -15° C. The reaction mixture was stirred -15° C. for 15 min, after which NaBH4 (6.0 g, 159 mmol) in water (10 mL) was added. The reaction mixture was stirred for 30 min, then diluted with EtOAc, and neutralized with dilute HCl. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc and petroleum ether (EtOAc/PE=1.5/1) to give the title compound (6.0 g, 58percent). 1H NMR (400 MHz, CDCl3) delta ppm 5.23 (s, 1H), 3.80 (d, J=8.0 Hz, 2H), 3.72-3.68 (m, 1H), 3.60-3.52 (m, 2H), 3.38 (s, 3H), 2.85 (s, 1H), 1.47 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
{(S)-1-[3-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}carbamic acid tert-butyl ester A mixture of N2-(4-chlorophenyl)pyridine-2,3-diamine (64 mg, 0.291 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (61 mg, 0.32 mmol), HOAt (44 mg, 0.32 mmol), 4-methylmorpholine (70 muL, 0.641 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol) in DCM (10 mL) was stirred at RT for 1 h then left standing at RT for 64 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried and concentrated in vacuo. The resulting {(S)-1-[2-(4-chlorophenylamino)pyridin-3-ylcarbamoyl]ethyl}carbamic acid tert-butyl ester, as a brown oil (136 mg), was dissolved in AcOH (5 mL) and heated at 70° C. for 4 h. After cooling to RT, the volatiles were removed under reduced pressure. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si-PCC, gradient 0-5percent MeOH in DCM) to afford the title compound as an orange/brown oil (99 mg, 91percent over two steps). LCMS (Method C): RT 3.33 min [M+H]+ 373.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | [(R)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethyl]carbamic acid tert-butyl ester A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (450 mg, 2.2 mmol), (S)-2-tertbutoxycarbonylamino-3-methoxypropionic acid (525 mg, 2.4 mmol), HOAt (330 mg, 2.4 mmol), 4-methylmorpholine (0.53 mL, 4.8 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (460 mg, 2.4 mmol) in DCM (10 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried (MgSO4) concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-30percent EtOAc in cyclohexane) to afford [(S)-1-(4-fluoro-2-phenylaminophenylcarbamoyl)-2-methoxyethyl]carbamic acid tert-butyl ester (0.655 g, 74percent). A solution of the compound thus obtained (0.655 g) in AcOH (10 mL) was heated at 70° C. for 56 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-30percent EtOAc in cyclohexane) to afford the title compound (227 mg, 28percent). LCMS (Method J): RT 3.59 and 3.70 min [M+H]+ 386.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(R)-1-(6-Fluoro-7-methyl-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethylamine A mixture of 4-fluoro-3-methyl-N2-phenylbenzene-1,2-diamine (560 mg, 2.59 mmol), (S)-2-tertbutoxycarbonylamino-3-methoxypropionic acid (624 mg, 2.85 mmol), HOAt (388 mg, 2.85 mmol), 4-methylmorpholine (626 muL, 5.69 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (547 mg, 2.85 mmol) in DCM (10 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM and the combined organic fractions washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in 4N HCl in dioxane (5 mL) and the mixture heated at 70° C. for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10percent MeOH in DCM) to afford the title compound (545 mg, 70percent). LCMS (Method C): RT 3.95 min [M+H]+ 300.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
{(S)-1-[3-(3-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}carbamic acid tert-butyl ester A mixture of N2-(3-chlorophenyl)pyridine-2,3-diamine (29 mg, 0.13 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (27 mg, 0.15 mmol), HOAt (20 mg, 0.15 mmol), 4-methylmorpholine (32 muL, 0.29 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol) in DCM (5 mL) was stirred at RT for 1 h then left standing at RT for 64 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting {(S)-1-[2-(3-chlorophenylamino)pyridin-3-ylcarbamoyl]ethyl}carbamic acid tert-butyl ester, as a brown oil (44 mg), was dissolved in AcOH (3 mL) and heated at 70° C. for 4 h. After cooling to RT, the volatiles were removed in vacuo. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si-PCC, gradient 0-5percent MeOH in DCM) to afford the title compound as an orange/brown oil (35 mg, 72percent over two steps). LCMS (Method C): RT 3.34 min [M+H]+ 373.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | (R)-1-(6,7-Difluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethylamine dihydrochloride To a solution of 3,4-difluoro-N2-phenylbenzene-1,2-diamine (400 mg, 1.8 mmol), Boc-ser(OMe)-OH (800 mg, 2.0 mmol), HOAT (340 mg, 2.0 mmol) and N-methylmorpholine (500 muA, 4.0 mmol) in DCM (5 mL) was added N-(3-dimethylaminopropyl)-n'-ethylcarbodiimide hydrochloride (480 mg, 2.0 mmol) and the reaction mixture stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with DCM (3.x.10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in HCl in dioxane (10 mL, 4 M) and the reaction mixture heated at 80° C. for 4 h. The reaction mixture was concentrated in vacuo and the resultant residue dissolved in EtOAc (10 mL). The solution was washed with sat. aq. NaHCO3 and the product extracted with EtOAc (3.x.10 mL). The combined organic extracts were washed with brine, dried (MgSO4), concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10percent methanol in DCM) to give the title compound as an off white solid (207 mg, 38percent). LCMS (Method C): RT=2.27 min, [M+H]+=304. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
{(S)-1-[3-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}carbamic acid tert-butyl ester A mixture of N2-(4-chlorophenyl)pyridine-2,3-diamine (64 mg, 0.291 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (61 mg, 0.32 mmol), HOAt (44 mg, 0.32 mmol), 4-methylmorpholine (70 muL, 0.641 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol) in DCM (10 mL) was stirred at RT for 1 h then left standing at RT for 64 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried and concentrated in vacuo. The resulting {(S)-1-[2-(4-chlorophenylamino)pyridin-3-ylcarbamoyl]ethyl}carbamic acid tert-butyl ester, as a brown oil (136 mg), was dissolved in AcOH (5 mL) and heated at 70° C. for 4 h. After cooling to RT, the volatiles were removed under reduced pressure. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si-PCC, gradient 0-5percent MeOH in DCM) to afford the title compound as an orange/brown oil (99 mg, 91percent over two steps). LCMS (Method C): RT 3.33 min [M+H]+ 373.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.08 g | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | To a solution of N- (tert-butoxycarbonyl) -O-methyl-L- serine (2.00 g) , 50percent aqueous dimethylamine solution (0.987 g) and N-ethyl-N- (1-methylethyl) propan-2-amine (2.36 g) in DMF (20 mL) was added 0- ( 7-azabenzotriazol-l-yl) -N, N, N' , N' - tetramethyluronium hexafluorophosphate (3.82 g) under ice- cooling. The reaction mixture was stirred at room temperature overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (2.08 g) .¾ NMR (300 MHz, DMSO-d6) delta 1.37 (9H, s) , 2.82 (3H, s) , 3.02 (3H, s), 3.22 (3H, s) , 3.32-3.51 (2H, m) , 4.50-4.65 (1H, m) , 6.92 (1H, d, J = 8.3 Hz) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | Part A. (S)-2-amino-l-(4-(3-bromopyrazolo[1.5-alpyrimidin-5-yl)piperazin-l-yl)-3- m eth oxyp ro pa n- l-o n e 3-Bromo-5-(piperazin-l-yl)pyrazolo[l,5-a]pyrimidine (300mg, l.lmmol) taken up in lOmL DMF. Boc-Ser(Me)-OH (280mg, 1.3mmol), HATU (368mg, 1.6mmol), and triethylamine (590uL, 4.25mmol) was added and stirred at room temp overnight. Reaction was diluted with DCM and washed with water. DCM layer was dried over magnesium sulfate reduced in vacuo. This was then taken up in 30percent TFA in DCM solution and stirred at room temperature for 2 hours. It was then cooled to Oo C and cone Aq NaOH added slowly until aqueous layer remains basic. DCM layer extracted dried over magnesium sulfate, reduced in vacuo for 405mg crude product for further reaction as is. LRMS (ESI) m/z 383/385 [(M+H)]+, calc'd for C14H19BrN602: 383.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
260 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 14h; | Example 52 (S)-2-[(4-Fluoro-benzenesulfonyl)-methyl-amino]-3-methoxy-N-(4'-trifluoromethyl-biphenyl-3- ylmethyl)-propionamide A solution of (4'-trifluoromethyl-biphenyl-3-yl)-methylamine from Example 1 (229 mg, 912 muiotaetaomicron) and (S)-2-teri-butoxycarbonylamino-3-methoxy-propionic acid (200 mg, 912 muiotaetaomicron) and N,N- diisopropylethylamine (478 muEpsilon, 2.74 mmol) in DMF (6 mL) at 25°C was treated with HATU (694 mg, 1.82 mmol). The reaction mixture was stirred for 14 h. The reaction mixture was then poured into saturated, aqueous NH4C1 and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50/50 hexanes/ethyl acetate) afforded (S)-2-teri-butoxycarbonylamino-3-methoxy-propionic acid 4'-trifluoromethyl- biphenyl-3-ylmethyl ester (260 mg) as a heavy oil. MH+ = 453.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; In toluene; for 0.5h;Inert atmosphere; Reflux; | suspension of Boc-L-Ser(OMe)[1] (1.0 g, 4.6 mmol), paraformaldehyde(0.9 g, 29.7 mmol) and p-toluenesulfonic acid (79 mg, 0.5mmol) in toluene (45 mL) was refluxed for 30 min with removalof azeotropic water. The solution was cooled down, washed with1 M aqueous NaHCO3 (2 × 20 mL), and dried over Na2SO4.Concentration in vacuo gave an oil product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 4-methyl-morpholine; O-(N-succinimidyl)-N,N,N',N'-bis(tetramethylene)-uronium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; | [0104j H-Ala-naphth TFA salt (0.24 mmol) was dissolved in 3 mL dimethylformamide and basified with N-methylmorpholine. Boc-Ser(OMe)-OH (96 mg, 0.24 mmol) was added to the solution. The mixture was cooled to 0 °C and dipyrrolidino(N-succinimidyloxy)carbenium hexafluorophosphate (103 mg, 0.25 mmol) were added in one portion. The reaction mixture wasallowed to warm to room temperature slowly and stirred at room temperature overnight. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated. The product was purified by silica gel column chromatography (eluent ethylacetate and hexane) to give 95 mg (92percent) of product. ?H NMR (500 MHz, DMSO-d6) oe 8.29 (t, J= 5.8 Hz, 1H), 8.11 (d, J= 7.4 Hz, 1H), 8.03 ? 8.01 (m,1H), 7.96 ? 7.94 (m, 1H), 7.85 (d, J= 8.0 Hz, 1H), 7.57 ? 7.53 (m, 2H), 7.48 ? 7.45 (m, 1H),7.42 (dd, J = 7.0, 1.4 Hz, 1H), 6.95 (d, J= 8.0 Hz, 1H), 4.75 (d, J= 5.6 Hz, 2H), 4.36 ?4.31 (m,1H), 4.19 ?4.15 (m, 1H), 3.47 ?3.39 (m, 2H), 3.15 (s, 3H), 1.37 (s, 9H), 1.25 (d, J= 7.1 Hz,3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | To a solution of C606-2 (3.6 g, 16 mmol) in DCM (40 mL) was added MeOH (2 mL), DIEA (8 mL) and EDCI (4.8 g, 25 mmol) at room temperature. The mixture was stirred at room temperature overnight, then diluted with DCM (200 mL) and brine (50 mL). The organic layer was dried over Na2S04. The solid was removed by filtration and purified by chromatography to give C606-3 (0.8 g, 20percent) as a white solid. MS (ESI) m/z: 234.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.2% | With triethylamine; In dichloromethane; at 20℃; for 4h; | General procedure: At first, N-Boc-l-Phenyl alanine (5.0g, 18.8mmol) was dissolved in dichloromethane (50mL); to the clear solution were added ASUD-diphenyl phosphate (8.1g, 18.8mmol) and triethylamine (2.1g, 20.73mmol). The reaction mixture was stirred at room temperature for 4h and washed with water (2×25mL), brine (2×25mL). The DCM layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield 8.5g (>100percent) of viscous oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.5% | isoButyl chloroformate (0.599 mL, 4.56 mmol) was added dropwise to (S)-2-((tert- butoxycarbonyl)amino)-3-methoxypropanoic acid (1 g, 4.56 mmol) and Nmethylmorpholine (0.50 1 mL, 4.56 mmol) in THF (6 mL) and cooled to 0 °C over a period of 15 minutes under nitrogen. The resulting suspension was stirred at 0 °C for a further 15minutes. Sodium borohydride (0.500 g, 13.23 mmol) dissolved in water (1.200 mL) was added slowly to the reaction at 0 °C. The reaction was stirred for 30 minutes before being diluted with EtOAc (50 mL) and neutralised with aqueous HC1 (2M). Water was added (50 mL) and the organic layer was separated, washed with brine (5OmL) and dried over Mg504. The evaporation of the solvent gave a crude product which was purified by flashsilica chromatography, elution gradient 0 to 50percent EtOAc in heptane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl (1 -hydroxy-3-methoxypropan-2- yl)carbamate (0.5 10 g, 54.5 percent) as a colourless oil. ?H NMR (500 MHz, CDC13, 27°C) 1.45 (9H, s), 3.36 (3H, s), 3.5-3.62 (2H, m), 3.64- 3.73 (1H, m), 3.74 - 3.84 (2H, m), 5.16 (1H, s). mlz: ES+ [M+Na]+ 228. | |
54.5% | iso-Butyl chloro formate (0.599 mL, 4.56 mmol) was added dropwise to (S)-2-((tert- butoxycarbonyl)amino)-3-methoxypropanoic acid (1 g, 4.56 mmol) and N- methylmorpholine (0.501 mL, 4.56 mmol) in THF (6 mL) and cooled to 0 °C over a period of 15 minutes under nitrogen. The resulting suspension was stirred at 0 °C for a further 15 minutes. Sodium borohydride (0.500 g, 13.23 mmol) dissolved in water (1.2 mL) was added slowly to the reaction at 0 °C. The reaction was stirred for 30 minutes before being diluted with EtOAc (50 mL) and neutralised with aqueous HC1 (2M). Water was added (50 mL) and the organic layer was separated, washed with brine (50mL) and dried over MgS04. The evaporation of the solvent gave a crude product which was purified by flash silica chromatography, elution gradient 0 to 50percent EtOAc in heptane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl (l-hydroxy-3-methoxypropan-2- yl)carbamate (Intermediate 59; 0.510 g, 54.5percent) as a colourless oil. H NMR (500 MHz, CDCls, 27 °C) 1.45 (9H, s), 3.36 (3H, s), 3.5 - 3.62 (2H, m), 3.64 - 3.73 (1H, m), 3.74 - 3.84 (2H, m), 5.16 (1H, s). m/z: ES+ [M+Na]+ 228 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 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 N,N-dimethyl-formamide; at 25℃; for 12h;Inert atmosphere; | N,O-dimethylhydroxylamine hydrochloride (13.35 g, 136.84 mmol) was added to (S)-2- ((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid (20 g, 91.23 mmol), HATU (38.2g, 100.35 mmol) and DIPEA (47.8 mL, 273.68 mmol) in DMF (100 mL) at 25°C under air. The resulting mixture was then stirred at 25 °C for 12 hours. The reaction mixture was then concentrated and diluted with EtOAc (500 mL), and the organic phases washed sequentially with water (150 mL) and saturated brine (2 x 200 mL). The organic layers were dried over Na2SO4, filtered and evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 0 to 25percent THF in petroleum ether. Pure fractions were evaporated to dryness to afford (S)-tert-butyl (3- methoxy- 1 -(methoxy(methyl)amino)- 1 -oxopropan-2-yl)carbamate (24 g, 100 percent) as a colourless oil. 1HNMR (400 MHz, CDC13, 22°C) oe 1.46(9 H, s), 3.25 (3 H, s), 3.37(3 H, s), 3.62 (2 H, ddd), 3.72 - 3.82 (3 H, m), 4.86 (1 H, s), 5.43 (1 H, d). mlz (ES+), [M+H]+ =263. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With O-(N-succinimidyl)-N,N,N',N'-bis(tetramethylene)-uronium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | Example 22-Preparation of tert-butyl ((S)-3-methoxy-1-(((S)-1-((naphthalen-1-ylmethyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (Boc-Ser(OMe)-Ala-naphth, DPLG-2032) H-Ala-naphth TFA salt (0.24 mmol) was dissolved in 3 mL dimethylformamide and basified with N-methylmorpholine. Boc-Ser(OMe)-OH (96 mg, 0.24 mmol) was added to the solution. The mixture was cooled to 0° C. and dipyrrolidino(N-succinimidyloxy)carbenium hexafluorophosphate (103 mg, 0.25 mmol) were added in one portion. The reaction mixture was allowed to warm to room temperature slowly and stirred at room temperature overnight. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated. The product was purified by silica gel column chromatography (eluent ethylacetate and hexane) to give 95 mg (92percent) of product. 1H NMR (500 MHz, DMSO-d6) delta 8.29 (t, J=5.8 Hz, 1H), 8.11 (d, J=7.4 Hz, 1H), 8.03-8.01 (m, 1H), 7.96-7.94 (m, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.57-7.53 (m, 2H), 7.48-7.45 (m, 1H), 7.42 (dd, J=7.0, 1.4 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.75 (d, J=5.6 Hz, 2H), 4.36-4.31 (m, 1H), 4.19-4.15 (m, 1H), 3.47-3.39 (m, 2H), 3.15 (s, 3H), 1.37 (s, 9H), 1.25 (d, J=7.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | A solution of (R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide (Example 869, 150 mg, 0.30 mmol), (25 -2-(teri-butoxycarbonylamino)-3-methoxypropanoic acid (99 mg, 0.45 mmol), HATU (137 mg, 0.360 mmol), and triethylamine (0.086 mL, 0.62 mmol) in DMF (3 mL) was stirred at rt overnight, then purified by flash column chromatography to yield the title compound as a yellow solid (188 mg, 89percent). |
89% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | A solution of (R)-5-(2-methyl-4-phenoxyphenyl) -4-oxo-N-(piperidin-3-yl) -4,5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide (Example 869, 150 mg, 0.30 mmol), (2S)-2-(tert-butoxycarbonylamino) -3-methoxypropanoic acid (99 mg, 0.45 mmol), HATU (137 mg, 0.360 mmol), and triethylamine (0.086 mL, 0.62 mmol) in DMF (3 mL) was stirred at rt overnight, then purified by flash column chromatography to yield the title compound as a yellow solid (188 mg, 89percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.3% | In isopropyl alcohol; at 25 - 75℃; | Example 3 Synthesis of (S)-1-phenylethanaminium(S)-2-((tert-butoxycarbonyl)amino)-3-methoxypropanoate The oil residue was dissolved in IPA (1490.0 kg), and (S)-(-)-alpha-methyl benzylamine (132.9 kg; 1.10 kmoles) was added to the mixture at 25 to 75° C. The solution was cooled to 0 to 5° C., and filtered off. The product was washed by cool IPA (390 kg), and dried to obtain the product (352.3 kg; 94.3percent). Purity was >99percent by HPLC; e.e. >99.5percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
116.8 g | With sodium hydroxide; In water; | Example 4 Purification of (S)-2-((tert-butoxycarbonyl)amino)-3-methoxypropanoic (0037) (0038) A wet cake of (S)-1-phenylethanaminium(S)-2-((tert-butoxycarbonyl)amino)-3-methoxypropanoate (305.2 g) was dissolved in H2O (485 g), and treated with 45percent NaOH (55.4 g). DCM (800 mL) was added to wash off the solution several times. The aqueous layer was acidified by citric acid (30 g) and 32percent HCl (61.3 g) to around pH=3. The product was extracted by toluene (300 mL×2). The combined organic layer was washed by 0.1percent NaOH (25 g) and H2O (100 mL×2). The organic layer was concentrated at 50° C. to obtain oil residue (116.8 g). Purity was >99percent by HPLC; e.e. >99.5percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
240.3 kg | With sodium hydroxide; at 10℃; for 44h;Large scale; | Example 2 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid (0033) (0034) 45percent 4 NaOH (746.3 kg; 8.40 kmoles) and DMS (1053.8 kg; 8.36 kmoles) were added to the reaction mixture below 10° C. over 38 h and for an additional 6 h to complete the reaction. 20percent 9 NH4OH (20.0 kg) was added to quench the reaction in the reaction mixture. The pH value was adjusted by 10 citric acid monohydrate (55.8 kg) and 32percent 11 HCl (180 kg) to around 3. The 12 product was extracted by toluene (1165 L) twice, and the organic layer was washed by 1percent NaOH (40 L) and H2O (39 L×2). The organic layer was concentrated, and stripped by IPA as oil residue (240.3 kg) |
[ 69942-12-7 ]
Methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate
Similarity: 0.98
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 |
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 |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :