*Storage: {[sel_prStorage]}
*Shipping: {[sel_prShipping]}
The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Oxalic acid is a strong dicarboxylic acid occurring in many plants and vegetables.
Synonyms: Ethanedioic acid; Wood bleach
4.5
*For Research Use Only !
Change View
Size | Price | VIP Price | US Stock |
Global Stock |
In Stock | ||
{[ item.pr_size ]} |
Inquiry
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.discount_usd) ]} {[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} |
Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]} | Inquiry {[ item.pr_usastock ]} In Stock Inquiry - | {[ item.pr_chinastock ]} {[ item.pr_remark ]} In Stock 1-2 weeks - Inquiry - | Login | - + | Inquiry |
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days
1-2weeks
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price, item.pr_usd) ]}
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
In Stock
- +
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
CAS No. : | 144-62-7 |
Formula : | C2H2O4 |
M.W : | 90.03 |
SMILES Code : | O=C(O)C(O)=O |
Synonyms : |
Ethanedioic acid; Wood bleach
|
MDL No. : | MFCD00002573 |
InChI Key : | MUBZPKHOEPUJKR-UHFFFAOYSA-N |
Pubchem ID : | 971 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302+H312-H318-H402 |
Precautionary Statements: | P264-P270-P273-P280-P301+P312+P330-P302+P352+P312-P305+P351+P338+P310-P362+P364-P501 |
* 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 |
---|---|---|
75.6% | Stage #1: With sodium hydride In N,N-dimethyl acetamide at 70℃; for 0.333333 h; Stage #2: at 110℃; for 1 h; |
DX-A 03 (2.0 g, 0.011 mol)Was dissolved in dimethylacetamide (100 mL)A solution of 60percent sodium hydride (463 mg, 0.012 mol)Dropwise.The resulting mixture was heated at 70 ° C. for 20 minutes.1-Fluoronaphthalene (1.27 mL, 0.012 mol)Was added dropwise to this mixed solution,And heated at 110 ° C. for 60 minutes.The reaction mixture was diluted with water,And extracted twice with diethyl ether.The extracts are combined,Wash with water,Then washed with saturated sodium chloride solution,It was dried over anhydrous sodium sulfate,After concentration under reduced pressure,To obtain an oily compound (DX-A 04, 3.28 g, 75.6percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.2% | at 20℃; for 21 h; | Example 10; Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 moles, 0.8 eq) in water (30 mL) was then added. The resulting mixture was stirred for 21 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 40° C. to yield 10.87 g of the product as a white solid (Yield: 84.2percent; HPLC (peak area at 220 nm) oxalic acid 1.78percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.10percent, 1-naphthol 0.35percent, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 97.65percent; Titration: 99.5percent; Karl Fischer: 0.06percent; XRD as shown in FIG. 1 (Form A); IR essentially as shown in FIG. 3 (Form A); TGA DSC as shown in FIG. 2, mp onset 152.6° C.). |
78.6% | at 20℃; for 2 h; | Example 12Preparation of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in isopropanol (30 mL) was then added dropwise. The resulting mixture was stirred for 2 hours and filtered. The filter cake was dried under vacuum at 50° C. to yield 10.14 g of the product as a white solid (Yield: 78.6percent; HPLC (peak area at 220 nm) oxalic acid 1.56percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.36percent; Titration: 99.4percent; Karl Fischer: 0.06percent; IR essentially as shown in FIG. 3, Form A). |
78.9% | at 20℃; for 16 h; | Example 11Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in methanol (4 mL) was then added. An additional volume of isopropyl acetate (50 mL) was added for improved stirring. The resulting mixture was stirred for 16 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 55° C. to yield 10.21 g of the product as a white solid (Yield: 78.9percent; HPLC (peak area at 220 nm) oxalic acid 1.66percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.24percent; Titration: 100.1percent; Karl Fischer: 0.22percent; XRD as shown in FIG. 1 (Form A); IR as shown in FIG. 3 (Form A). |
77% | at 20℃; for 1 h; | Preparation of DNT Oxalate Example 6 To a solution of 2.1 g of DNT-base (12percent enantiomer R) dissolved in 12 ml of ethyl acetate was added a solution of 0.6 g of oxalic acid in 12 ml of ethyl acetate. The resulting mixture was stirred at room temperature for an hour, filtrated and washed with ethyl acetate. After drying, in a vacuum oven for overnight, 2 g (77percent yield) of DNT-oxalate were obtained containing 12percent of enantiomer R. |
88 % ee | Stage #1: With pyridine-SO3 complex In dimethyl sulfoxide; toluene for 0.5 h; Stage #2: for 16 h; |
Example 1Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl) Propylamine Oxalic Acid Salt(S-3-Dimethylamino-1-(2-thienyl)-1-propanol (50 g, 0.270 moles) and sodium hydroxide (21.6 g, 0.540 moles, 2 eq.) were heated in DMSO (500 mL) at 60-80° C. for 1 hour. The temperature was controlled at 60° C.+/-4° C. before 1-fluoronaphthalene (43.6 g, 38.5 mL, 0.299 moles) was added. The mixture heated at this temperature for 64 hours. Water (500 mL) was added, and the mixture extracted with toluene (2.x.500 mL). The organic layers were then combined and washed with water (500 mL). HPLC analysis of an evaporated aliquot showed the molar ratio of Compound IV to Compound S-II to be 90:10 and Compound IV to be 88percent ee. Pyridine sulfur trioxide (6.4 g, 0.040 moles) was added to the mixture, the mixture was stirred for 30 minutes, and was then washed with water (500 mL). The organic layers were then concentrated by distillation until 600 mL of solvent was removed, and ethyl acetate (500 mL) was added. Oxalic acid dihydrate (27.2 g, 0.216 moles) was then added. The resulting suspension was stirred for 16 hours and filtered to yield the product as a white solid. The resulting product was slurried in additional ethyl acetate (200 mL), filtered and dried under vacuum to yield 63.3 g of the product as a white solid (0.158 moles, Yield: 59percent). The resulting product had a molar ratio of Product:(S)-3-dimethylamino-1-(2-thienyl)-1-propanol: 1-fluoronaphthalene of 99.53:0.46:0.02 and 88percent ee. |
92 % ee | Stage #1: With pyridine-SO3 complex In Isopropyl acetate; dimethyl sulfoxide at 20℃; for 1 h; Stage #2: at 15 - 20℃; for 16 h; |
Example 6Preparation of (S)-N-methyl-(3-(1-naphthyloxy)-3-thien-2-yl) Propylamine Hydrochloride (Duloxetine Hydrochloride)Sodium hydroxide (0.324 kg, 8.1 moles, 2 eq), potassium carbonate (126 kg, 9.1 moles, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (750 g, 4.05 moles), were heated in DMSO (7.5 L) at 80° C. for 3 hours and cooled to 40° C. 1-fluoronaphthalene (770'gi.5.3 mol, 1.3 eq) was then added over 5 minutes. Next, the mixture was heated at 40° C. for 17 hour and then at 50-60° C. for 40 hours. The molar ratio of product (Compound IV) to staring alcohol (Compound S-II) was 85.3:14.7, and Compound IV was 92percent ee as determined by HPLC of an aliquot. The mixture was then cooled to 20° C. and quenched with water (5 L). The mixture was divided in two and each portion was extracted twice with isopropyl acetate (2.x.2 L). The four organic phases were combined, washed with water (5 L), and pyridine sulphur trioxide complex (110 g, 0.69 moles, 0.17 eq.) was added. The mixture was then stirred at 20° C. for 30 minutes, and washed with water (5 L). Oxalic acid dihydrate (0.38 kg, 3.0 moles, 0.75 eq.) was then added, and the mixture stirred at 15-20° C. for 16 hours. The mixture was then filtered and slurried in acetone (2.5 L) and isopropyl acetate (5 L) for one hour, and then filtered to yield 2.1 kg (wet product) of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt as an off-white solid (Yield: 75percent; equivalent to 1.21 kg, (dry product)). The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was 98.7:1.3 as determined by HPLC. Compound IV oxalate salt was 92percent ee as determined by chiral HPLC.Example 7Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine Oxalic Acid SaltSodium hydroxide (8.635 g, 216 mmol, 2 eq), potassium carbonate (33.565 g, 243 mmol, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (20 g, 108 mmol), were heated in DMSO (200 mL) at 80° C. (temperature inside flask) under vacuum such that approximately 100 mL of DMSO were distilled in 1 hour. An additional 100 mL of DMSO were then added, and the mixture heated at 80° C. for a further 2 hours. Thereafter, the mixture was cooled to 40° C. and stirred under an atmosphere of nitrogen. 1-Fluoronaphthalene (17.35 g, 119 mmol, 1.1 eq) was then added, and the mixture maintained with stirring at 40° C. Samples were taken periodically and analysed by NMR. Once an approximately 92percent conversion had been achieved (24 hours), as determined by the ratio of Compounds IV and S-II in the 1H-NMR spectrum, the mixture was cooled to 25° C., quenched with water (150 mL) and extracted twice with isopropyl acetate (2.x.100 mL). The two organic phases were combined, washed with water (75 mL), and pyridine sulphur trioxide complex (1.72 g, 10.8 mmol, 0.1 eq.) was added. The mixture was then stirred at 20° C. for 60 minutes and washed with water (150 mL). The aqueous layer was analysed to be pH 6.8. Oxalic acid dihydrate (10.9 g, 86 mmol, 0.8 eq.) was then added, and the mixture stirred at 15-20° C. for 16 hours. The mixture was then filtered and homogenized to yield 41.83 g of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt as an off-white solid (Loss on drying: 6.94percent, Titration: 98.1percent, Karl Fischer: 0.06percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.7% | Stage #1: at 0 - 21℃; Stage #2: With methanesulfonic acid In dichloromethane; water at 0 - 21℃; for 18.25 h; Sealed tube |
6.2 Example 29:; Preparation of (1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole- 1 - carboxylic acid t-butyl ester oxalic acid 1 : 1 salt from (lS,3aR,6aS)- octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride.; [0419] Step 1 : To a 1650 mL thick- walled glass pressure bottle (Ace Glass, Inc., 8648-157) equipped with a magnetic stirring bar was charged 75 g (306.9 mmol) of the (lS,3aR,6aS)- octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride / ammonium chloride admixture prepared in Example 28, 375 mL dichloromethane, and 497 mL t-butyl acetate. The resulting mixture was stirred vigorously at ambient temperature (about 210C) to break large aggregates to provide a free-stirring suspension. This suspension was cooled to an internal temperature of 00C using a brine - ice bath and 75.4 mL (1162 mmol) methanesulfonic acid was added dropwise over 15 minutes, during which the internal temperature rose to 5°C. The pressure bottle was sealed and the reaction mixture was allowed to warm to ambient temperature (about 210C) with vigorous stirring over 18 hours, during which the reaction mixture became a suspension of white inorganic salts in an amber solution. The mixture was cooled in an ice bath and the pressure bottle carefully vented and uncapped. The mixture was transferred to a 3 L flask and cooled in an ice bath with stirring. 400 mL of 50percent (wt:wt) NaOH in water was added to the mixture over 35 minutes while maintaining its temperature below 200C. The stirring was halted and the phases were allowed to separate. The organic phase (-850 mL) was removed to a separate vessel. The remaining aqueous phase and rag layer (pH 13, -800 mL) were extracted with 375 mL dichloromethane. The organic phases were combined (-1250 mL) and washed with water (2 x 225 mL). The resulting organic phase was filtered to remove a rag layer and any insoluble material, and the solvent was removed by rotary vacuum evaporation to give 48.3 g dark-amber oil. The 1H NMR spectrum of the oil showed (lS,3aR,6aS)- octahydrocyclopenta[c]pyrrole-l-carboxylic acid ?-butyl ester.[0420] A second preparation following the same procedure yielded was 50.6 g of the trans- (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester oil.[0421] Step 2: 97.9 g (463.3 mmol) of (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester from the two preparations according to Step 1 were dissolved in 750 mL t-butyl acetate and charged to a 3 L four-neck flask equipped with overhead mechanical stirring, a thermometer, addition funnel, and reflux condenser. With stirring at ambient temperature (-210C), a solution of 44.0 g (488.6 mmol) of oxalic acid in 750 mL 2-propanol was added dropwise over 37 minutes, increasing the mixture's temperature to 31°C. Solids began to precipitate after addition of -50 mL of the oxalic acid solution, and resulted in a thick suspension after the addition of 450 mL. After addition of 500 mL of the oxalate solution, the precipitated solids redissolved to provide a dark yellow solution. Solids precipitated again rapidly after the addition of 600 mL of the oxalic solution and persisted through the end of the oxalic acid addition. This suspension was then heated 78°C to provide a thin suspension which was allowed to cool passively with stirring to ambient temperature (-210C). After 16 hours since the cooling began, the precipitated solids were collected by filtration and washed successively with isopropanol (450 mL), isopropyl acetate (450 mL), and methyl t-butyl methyl ether (450 mL). The solids were dried in a vacuum oven (300C, 25" vacuum, N2 stream) to provide 118.1 g (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester oxalic acid 1 : 1 salt (64percent yield from (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid hydrochloride) as a dense, tan free flowing powder (99.7percent purity by GC analysis), which exhibited the expected 1H-NMR spectrum for (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid ?-butyl ester oxalic acid (1 : 1) salt.[0422] Recrystallization of (1 S,3aR,6aS)- octahydrocyclopenta[c]pyrrole- 1 -carboxylic acid t-butyl ester oxalic acid (1 :1) salt: The tan powder from Step 2 above (118. I g, 391.9 mmol) and isopropanol (1950 mL) were charged to a 3 L four neck flask equipped with a mechanical stirring, a thermometer, and a reflux condenser. The suspension was stirred and heated to 74°C to completely dissolve the salt, resulting in a yellow solution. The stirring was slowed and the solution was allowed to cool passively to ambient temperature (-210C). After 20 hours since the cooling began, the precipitated solids collected by filtration and washed successively with isopropanol (1 L), isopropyl acetate (1 L), and methyl ?-butyl methyl ether (1 L). The solids were dried in a vacuum oven (400C, 28" vacuum, N2 stream) to provide 110.45 g (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester oxalic acid 1 :1 salt (59.7percent yield from (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride) as fine, off-white needles of 99.9percent purity by GC analysis). Chiral GC analysis showed only the desired (lS,3aR,6aS)-stereoisomer. Its (2S)-epimer was not detected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.08 g | Stage #1: With methanesulfonic acid In chloroform at 0 - 25℃; for 18 h; Stage #2: at 75 - 80℃; for 0.5 h; |
[Isolation of Hydrogenoxalate] [0155] To 250 mg of the mixture of the hydrochloride of amino acid (i) and ammonium chloride prepared in Example 29 were added 4 mL of chloroform and 1.7 mL of tert-butyl acetate. The resulting suspension was cooled to 0° C. and then 0.25 mL of methanesulfonic acid was added. The mixture was warmed slowly to 25° C. and then stirred at this temperature for 18 hours. The resulting white suspension was cooled to 0° C., and then 1.3 mL of a 50percent aqueous sodium hydroxide solution was added carefully with the temperature kept at 20° C. or lower. Water (15 mL) and chloroform (15 mL) were added and then stirred for 15 minutes. The layers were separated and the aqueous layer was subjected to extraction with 15 mL of chloroform three times. The organic layers were combined, dried over magnesium sulfate, and filtered. The solvent was then evaporated under reduced pressure. To the pale green residue was added a solution of 2.5 mL of tert-butyl acetate and 146.7 mg of oxalic acid in 2-propanol (2.5 mL). The resulting mixture was heated to 75 to 80° C., stirred for 30 minutes, allowed to cool to ambient temperature (about 20° C.), stirred for 18 hours, and then filtered. The resulting cake was washed with 5 mL of 2-propanol and with 5 mL of methyl tert-butyl ether respectively and then dried, affording 0.08 g (0.27 mmol: overall yield from nitrile (h): 25percent) of hydrogenoxalate of tert-butyl (j) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: With sodium hydrogen sulfate In tert-butyl methyl ether; water for 0.5 h; Stage #2: With dmap; sodium hydrogen sulfate; di-<i>tert</i>-butyl dicarbonate In tert-butyl methyl ether; water at 20 - 25℃; for 5 - 6 h; |
A mixture of the (S)-1,2,3,4-tetrahydro-1-naphthylammonium salt prepared as in Example 3, Method 1 (81.7 g, 0.203 mol), t-butyl methyl ether (400 mL) and 5percent NaHSO4-H2O (867 mL, 0.304 mol) was stirred for 30 minutes until all solids were dissolved. The organic phase was washed with water (334 mL) then concentrated to 259 mL. t-Butyl methyl ether (334 mL) was added and the solution was concentrated again to 259 mL. The addition-concentration process was repeated twice more. After the final concentration, t-BuOH (158 mL) and dimethylaminopyridine (5.04 g, 41.3 mmol) were added. A solution of Boc2O (67.6 g, 0.31 mol) in t-butylmethyl ether (52.0 mL) was added. After stirring for 5 hours at ambient temperature, t-butyl methyl ether (158 mL) and 5percent aqueous NaHSO4-H2O (260 mL) were added and the resultant mixture was stirred. The organic phase was washed with 5percent aqueous NaCl (twice, 260 mL each). The organic phase was concentrated to 320 mL, and tetrahydrofuran (320 mL) was added. The organic phase was concentrated again to 320 mL, and tetrahydrofuran (320 mL) was added. After concentrating to 320 mL once more, methane sulfonic acid (80.1 g, 0.62 mol) was added and the solution was stirred at ambient temperature for 4.5 hours. The reaction mixture was added to a 30percent aqueous solution of K2CO3 (571 mL) and stirred. The aqueous phase was extracted with isopropyl acetate (320 mL). The combined organic phases were concentrated to 320 mL, and isopropyl acetate (320 mL) was added. The organic solution was concentrated again to 320 mL. The organic phase was washed with water (320 mL). Isopropyl acetate (320 mL) was added to the organic phase and the solution was concentrated to 192 mL. Isopropyl acetate (320 mL) was added a second time, and the organic solution was concentrated to 192 mL. A solution of oxalic acid (24.1 g, 267 mmol) in isopropyl acetate (448 mL) was added to the organic solution over 2 hours. The mixture was stirred for 2-4 hours, and the slurry was filtered. The white solids were rinsed with isopropyl acetate (100 mL) and dried at 35-40° C. under vacuum to yield 52.6 g of the title compound (85percent yield); A mixture of (S)-1,2,3,4-tetrahydro-1-naphthylammonium salt as prepared by the method of Example 3, Method 2 (148 g, 0.609 mol), t-butyl methyl ether (726 mL) and 5percent NaHSO4-H2O (1.58 L, 0.913 mol) was stirred until all of the solids had dissolved. The phases were separated and the organic phase washed with water (726 mL). The organic phase was concentrated to about 400 mL. t-Butyl methyl ether (726 mL) was added and the mixture concentrated to 590 mL. The addition of t-butyl methyl ether and concentration was repeated to give a final volume of 350 mL. Dimethylaminopyridine (8.42 g, 68.9 mmol) and t-butyl alcohol (260 mL) were added, followed by addition of a solution of Boc2O (112 g, 0.52 mol) in MTBE (88 mL) over 0.5 hour. The mixture was stirred for 5 hours at 22-25° C. A solution of 5percent sodium bisulfate in water was added and the mixture stirred for 0.5 hour. The organic phase was washed with 5percent sodium chloride (twice, 440 mL each) and concentrated to 270 mL. Tetrahydrofuran (540 mL) was added and the mixture concentrated to 270 mL; this procedure was repeated twice more to give a final volume of 270 mL. Methane sulfonic acid (67 mL) was added over 0.5 hour while maintaining a temperature of lower than 30° C. and the mixture stirred at 22-25° C. for 12 hours. The mixture was added to a 30percent aqueous solution of potassium carbonate (478 mL) while maintaining a temperature of 22-25° C. The mixture was filtered, the phases separated and the aqueous phase extracted with isopropyl acetate (twice, 540 mL each). The organic phase was concentrated to 270 mL, then twice evaporated with isopropyl acetate (540 ml) to give a final volume of 540 mL. The organic phase was washed with water (twice, 540 mL), then twice evaporated with isopropyl acetate (320 mL) to give a final volume of 320 mL. Additional isopropyl acetate (429 mL) was added followed by addition of a solution of oxalic acid (40.4 g, 0.448 mol) in t-butylmethyl ether (321 mL) over 2 hours maintaining a temperature of 22-25° C. The mixture was stirred for 3 hours at 22-25° C. then filtered. The filter cake was washed with isopropyl acetate (100 mL) and the product dried at 35-40° C. under vacuum to give the title compound as a white solid (88.4 g, 81percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 20℃; for 1h; | To a solution of 2.1 g of DNT-base (12% enantiomer R) dissolved in12 ml of ethyl acetate was added a solution of 0.6 g of oxalic acid in 12 ml of ethyl acetate. The resulting mixture was stirred at room temperature for an hour, filtrated and washed with ethyl acetate. After drying, in a vacuum oven for overnight, 2 g (77% yield) of DNT-oxalate were obtained containing 12% of enantiomer R. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.2% | In Isopropyl acetate; water; at 20℃; for 21h;Product distribution / selectivity; | Example 10; Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 moles, 0.8 eq) in water (30 mL) was then added. The resulting mixture was stirred for 21 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 40 C. to yield 10.87 g of the product as a white solid (Yield: 84.2%; HPLC (peak area at 220 nm) oxalic acid 1.78%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.10%, 1-naphthol 0.35%, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 97.65%; Titration: 99.5%; Karl Fischer: 0.06%; XRD as shown in FIG. 1 (Form A); IR essentially as shown in FIG. 3 (Form A); TGA DSC as shown in FIG. 2, mp onset 152.6 C.). |
78.6% | In Isopropyl acetate; isopropyl alcohol; at 20℃; for 2h;Product distribution / selectivity; | Example 12Preparation of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in isopropanol (30 mL) was then added dropwise. The resulting mixture was stirred for 2 hours and filtered. The filter cake was dried under vacuum at 50 C. to yield 10.14 g of the product as a white solid (Yield: 78.6%; HPLC (peak area at 220 nm) oxalic acid 1.56%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.36%; Titration: 99.4%; Karl Fischer: 0.06%; IR essentially as shown in FIG. 3, Form A). |
78.9% | In methanol; Isopropyl acetate; at 20℃; for 16h;Product distribution / selectivity; | Example 11Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in methanol (4 mL) was then added. An additional volume of isopropyl acetate (50 mL) was added for improved stirring. The resulting mixture was stirred for 16 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 55 C. to yield 10.21 g of the product as a white solid (Yield: 78.9%; HPLC (peak area at 220 nm) oxalic acid 1.66%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.24%; Titration: 100.1%; Karl Fischer: 0.22%; XRD as shown in FIG. 1 (Form A); IR as shown in FIG. 3 (Form A). |
77% | In ethyl acetate; at 20℃; for 1h; | Preparation of DNT Oxalate Example 6 To a solution of 2.1 g of DNT-base (12% enantiomer R) dissolved in 12 ml of ethyl acetate was added a solution of 0.6 g of oxalic acid in 12 ml of ethyl acetate. The resulting mixture was stirred at room temperature for an hour, filtrated and washed with ethyl acetate. After drying, in a vacuum oven for overnight, 2 g (77% yield) of DNT-oxalate were obtained containing 12% of enantiomer R. |
Example 1Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl) Propylamine Oxalic Acid Salt(S-3-Dimethylamino-1-(2-thienyl)-1-propanol (50 g, 0.270 moles) and sodium hydroxide (21.6 g, 0.540 moles, 2 eq.) were heated in DMSO (500 mL) at 60-80 C. for 1 hour. The temperature was controlled at 60 C.+/-4 C. before 1-fluoronaphthalene (43.6 g, 38.5 mL, 0.299 moles) was added. The mixture heated at this temperature for 64 hours. Water (500 mL) was added, and the mixture extracted with toluene (2×500 mL). The organic layers were then combined and washed with water (500 mL). HPLC analysis of an evaporated aliquot showed the molar ratio of Compound IV to Compound S-II to be 90:10 and Compound IV to be 88% ee. Pyridine sulfur trioxide (6.4 g, 0.040 moles) was added to the mixture, the mixture was stirred for 30 minutes, and was then washed with water (500 mL). The organic layers were then concentrated by distillation until 600 mL of solvent was removed, and ethyl acetate (500 mL) was added. Oxalic acid dihydrate (27.2 g, 0.216 moles) was then added. The resulting suspension was stirred for 16 hours and filtered to yield the product as a white solid. The resulting product was slurried in additional ethyl acetate (200 mL), filtered and dried under vacuum to yield 63.3 g of the product as a white solid (0.158 moles, Yield: 59%). The resulting product had a molar ratio of Product:(S)-3-dimethylamino-1-(2-thienyl)-1-propanol: 1-fluoronaphthalene of 99.53:0.46:0.02 and 88% ee. | ||
Example 14Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-3dimethylamino-1-(2-thienyl)-1-propanol (50 g, 269.8 mmoles), sodium hydroxide (21.58 g, 539.7 mmoles), potassium carbonate (83.91 g, 607.2 mmoles) and 1-methyl-2-pyrrolidinone (500 mL) were charged in a reactor. The suspension was heated to 80 C. and 10 mL of solvent distilled under vacuum in 4 hours. The mixture then was allowed to cool to 40 C. under argon and 1-fluoronaphthalene (38 mL, 296.8 mmoles) was added. The mixture was stirred at 40 C. for 40 hours, and then at 60 C. for 24 hours. The mixture was allowed to cool to ambient temperature. Water (350 mL) and isopropyl acetate (150 mL) were added; the mixture was stirred and the layers were separated. The aqueous layer was extracted with isopropyl acetate (130 mL). The organic layers were combined and washed with water (250 mL). To this solution pyridine sulfur trioxide complex (4.3 g, 27.0 mmoles) was added and the mixture stirred at room temperature for 1 hour. The mixture was washed with water (300 mL). The aqueous pH was 6. To the organic layer was added oxalic acid dihydrate (27.2 g, 215.8 moles). The mixture was stirred for 20 hours at ambient temperature and then filtered. The filter cake was washed with isopropyl acetate (2×40 mL) and dried under vacuum at 50 C. to yield 57.39 g of the product as a-white solid (Yield: 53%; HPLC (peak area at 220 nm) oxalic acid 2.69%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.21%, 1-naphthol 0.43%, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 95.42%; XRD analysis as shown in FIG. 6, Form B; IR as shown in FIG. 7, Form B; Titration 93.14%). | ||
Example 13Preparation of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-3-dimethylamino-1-(2-thienyl)-1-propanol (20 g, 108 mmoles), potassium hydroxide (12.11 g, 216 mmoles) and DMSO (300 mL) were charged in a reactor. The suspension was heated to 75-80 C. and 100 mL of solvent distilled under vacuum in 1 hour. The mixture then was allowed to cool to 40 C. under nitrogen and 1-fluoronaphthalene (15.3 mL, 119 mmoles) was added. The mixture was stirred at 40 C. for 46 hours. The mixture was allowed to cool to ambient temperature. Water (300 mL) and isopropyl acetate (200 mL) were added; the mixture was stirred and the layers were separated. The aqueous layer was extracted with isopropyl acetate (100 mL). The organic layers were combined and washed with water (100 mL). To this solution pyridine sulfur trioxide complex (1.7 g, 11 mmoles) was added and the mixture stirred at room temperature for 1 hour. The mixture was washed with water (50 mL). The aqueous pH was 6.5. To the organic layer was added oxalic acid dihydrate (10.9 g, 86 mmoles). The mixture was stirred for 1 hour at ambient temperature and then filtered. The filter cake was washed with isopropyl acetate (25 mL) and dried under vacuum at 50 C. to yield 28.96 g of the product as a white solid (Yield: 67%; Titration 89.68%; HPLC (peak area at 220 nm) oxalic acid 2.09%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.045%, 1-naphthol 0.20%, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 95.19%; XRD analysis as shown in FIG. 4, Form C; IR as shown in FIG. 5, Form C). | ||
Example 15Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid SaltSodium hydroxide (34.2 kg), potassium carbonate (133 kg) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (80 kg), were heated in DMSO (1328 kg) at 70-80 C. for one hour and then distilled under vacuum at this temperature such that approximately 445 kg of DMSO were distilled within 4 hours. After this time the mixture was cooled to 40-45 C. and stirred under an atmosphere of nitrogen. 1-Fluoronaphthalene (69 kg) was then added and the mixture maintained with stirring at 40 C. Samples were taken periodically and analysed by HPLC. Once approximately 92% conversion had been achieved (24 hours), the mixture was cooled to 25 C., quenched with water (533 kg) and extracted twice with isopropyl acetate (2×460 kg). The two organic phases were combined, washed with water (400 kg), and added to pyridine sulphur trioxide complex (6.8 kg.). The mixture was then stirred at 20-25 C. for 30 minutes and then a solution made from ammonium chloride (32 kg) in water (533 kg) was added and the mixture stirred for 30 minutes. The aqueous layer was adjusted to pH 6.5-pH 7.0, the mixture stirred for an additional 30 minutes before the aqueous phases were separated. Oxalic acid dihydrate (44 kg) was dissolved in methanol (173 kg.) and this solution was added over a period of 2 hours to the organic mixture above maintained at 40-45 C. The mixture was placed under vacuum at this temperature and 500 kg of solvent removed by distillation. Isopropyl Acetate (1000 kg) was added and a further 500 kg removed by distillation under vacuum. At this point precipitation occurred and the mixture was cooled to 0-5 C. and stirred for 2 hours. The product was filtered in a centrifuge filter, washed with isopropyl acetate (40 kg) and homogenised to yield 161.93 kg of the moist product as an off-white solid (Loss on Drying: 16.35%; Titration: 97.45%; Chiral Assay: 96% (S), 4% (R)-enantiomer; HPLC: oxalic acid 1.65%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.005%, 1-naphthol 0.02%, N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine 98.09%; XRD as shown in FIG. 8, Form E; IR as shown FIG. 9, Form E). | ||
Example 5Preparation of (S)-N-methyl-(3-(1-naphthyloxy)-3-thien-2-yl) Propylamine Hydrochloride (Duloxetine Hydrochloride)Sodium tert-pentoxide (1.06 kg of a 40% solution in toluene, 3.85 moles, 0.95 eq.) was added over 10 minutes to a suspension of (S)-3-dimethylamino-12-thienyl)-1-propanol (750 g, 4.05 moles) dissolved in DMSO (3 L) at a temperature of 13-15 C. The (S)-3-dimethylamino-1-(2-thienyl)-1-propanol was dissolved completely to form a brown solution. The mixture was then heated to 70 C. for one hour before 1-fluoronaphthalene (710 g, 4.86 moles) was added over 5 minutes. The mixture was then heated at 70 C. for 7 hours. The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was observed to be 91.6:8.4 as determined by HPLC of an aliquot. The mixture was next cooled to 20 C., quenched with water (5 L), and extracted twice with isopropyl acetate (4+3 L). The organic layers were then combined, washed with water (4 L), and pyridine sulphur trioxide complex (64 g, 0.4 moles, 0.1 eq.) was added. The mixture was stirred at 20 C. for 30 minutes, and washed with water (5 L). Oxalic acid dihydrate (0.41 kg, 3.2 moles, 0.8 eq.) was then added, and the mixture was stirred at 25 C. for 2.5 hours and then at 20 C. for 2 days. The mixture was next filtered and washed with isopropyl acetate (2.5 L) to yield (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt as an off-white solid (2.3 kg (wet product), equivalent to 1.3 kg (dry product) in 80% yield). The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was 99.6:0.4 as determined by HPLC. | ||
Example 6Preparation of (S)-N-methyl-(3-(1-naphthyloxy)-3-thien-2-yl) Propylamine Hydrochloride (Duloxetine Hydrochloride)Sodium hydroxide (0.324 kg, 8.1 moles, 2 eq), potassium carbonate (126 kg, 9.1 moles, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (750 g, 4.05 moles), were heated in DMSO (7.5 L) at 80 C. for 3 hours and cooled to 40 C. 1-fluoronaphthalene (770'gi.5.3 mol, 1.3 eq) was then added over 5 minutes. Next, the mixture was heated at 40 C. for 17 hour and then at 50-60 C. for 40 hours. The molar ratio of product (Compound IV) to staring alcohol (Compound S-II) was 85.3:14.7, and Compound IV was 92% ee as determined by HPLC of an aliquot. The mixture was then cooled to 20 C. and quenched with water (5 L). The mixture was divided in two and each portion was extracted twice with isopropyl acetate (2×2 L). The four organic phases were combined, washed with water (5 L), and pyridine sulphur trioxide complex (110 g, 0.69 moles, 0.17 eq.) was added. The mixture was then stirred at 20 C. for 30 minutes, and washed with water (5 L). Oxalic acid dihydrate (0.38 kg, 3.0 moles, 0.75 eq.) was then added, and the mixture stirred at 15-20 C. for 16 hours. The mixture was then filtered and slurried in acetone (2.5 L) and isopropyl acetate (5 L) for one hour, and then filtered to yield 2.1 kg (wet product) of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt as an off-white solid (Yield: 75%; equivalent to 1.21 kg, (dry product)). The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was 98.7:1.3 as determined by HPLC. Compound IV oxalate salt was 92% ee as determined by chiral HPLC.Example 7Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine Oxalic Acid SaltSodium hydroxide (8.635 g, 216 mmol, 2 eq), potassium carbonate (33.565 g, 243 mmol, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (20 g, 108 mmol), were heated in DMSO (200 mL) at 80 C. (temperature inside flask) under vacuum such that approximately 100 mL of DMSO were distilled in 1 hour. An additional 100 mL of DMSO were then added, and the mixture heated at 80 C. for a further 2 hours. Thereafter, the mixture was cooled to 40 C. and stirred under an atmosphere of nitrogen. 1-Fluoronaphthalene (17.35 g, 119 mmol, 1.1 eq) was then added, and the mixture maintained with stirring at 40 C. Samples were taken periodically and analysed by NMR. Once an approximately 92% conversion had been achieved (24 hours), as determined by the ratio of Compounds IV and S-II in the 1H-NMR spectrum, the mixture was cooled to 25 C., quenched with water (150 mL) and extracted twice with isopropyl acetate (2×100 mL). The two organic phases were combined, washed with water (75 mL), and pyridine sulphur trioxide complex (1.72 g, 10.8 mmol, 0.1 eq.) was added. The mixture was then stirred at 20 C. for 60 minutes and washed with water (150 mL). The aqueous layer was analysed to be pH 6.8. Oxalic acid dihydrate (10.9 g, 86 mmol, 0.8 eq.) was then added, and the mixture stirred at 15-20 C. for 16 hours. The mixture was then filtered and homogenized to yield 41.83 g of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt as an off-white solid (Loss on drying: 6.94%, Titration: 98.1%, Karl Fischer: 0.06%). | ||
Example 8Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine Oxalic Acid SaltSodium hydroxide (34.2 kg), potassium carbonate (133 kg) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (80 kg), were heated in DMSO (1328 kg) at 70-80 C. for one hour and then distilled under vacuum at this temperature such that approximately 445 kg of DMSO were distilled within 4 hours. After this time the mixture was cooled to 40-45 C. and stirred under an atmosphere of nitrogen. 1-Fluoronaphthalene (69 kg) was then added, and the mixture maintained with stirring at 40 C. Samples were taken periodically and analyzed by HPLC. Once approximately 92% conversion had been achieved (24 hours), the mixture was cooled to 25 C., quenched with water (533 kg) and extracted twice with isopropyl acetate (2×460 kg). The two organic phases were combined, washed with water (400 kg), and added to pyridine sulphur trioxide complex (6.8 kg.). The mixture was then stirred at 20-25 C. for 30 minutes and then a solution made from ammonium chloride (32 kg) in water (533 kg) was added and the mixture stirred for 30 minutes. The aqueous layer was adjusted to pH 6.5-pH 7.0, the mixture stirred for an additional 30 minutes before the aqueous phases were separated. Oxalic acid dihydrate (44 kg) was dissolved in methanol (173 kg), and this solution was added over a period of 2 hours to the organic mixture above maintained at 40-45 C. The mixture was placed under vacuum at this temperature and 500 kg of solvent removed by distillation. Iso-propyl acetate (1000 kg) was added and a further 500 kg removed by distillation under vacuum. At this point precipitation occurred, and the mixture was cooled to 0-5 C. and stirred for 2 hours. The product was filtered in a centrifuge filter, washed with isopropyl acetate (40 kg) and homogenized to give 161.93 kg of the moist product as an off-white solid (Loss on drying: 16.35%, Titration: 97.45%, Chiral assay (HPLC): 96% (S), 4% (R)-enantiomer, HPLC: oxalic acid 1.65%, 4-(3-Dimethylamino-1-thiophen-2-yl-propyl)-naphthalen-1-ol 0.005%, 1-naphthol 0.02%, N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine 98.09%). | ||
In methanol; ethyl acetate; for 1h; | Stage-IV: Preparation of (3S)-N, N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl) propan-1-ammonium oxalateCharge DMSO (500 ml) to the flask. Charge S-(-)-3-(dimethylamino)-l-(2-thienyl) propan-1-ol (100 g) to the flask. Stir the reaction mass for 10 mins to get clear solution. Cool to 10-150C. Charge Sodium hydride (23.84 g) to the reaction mass at 10-150C. Stir the reaction mixture for 30 min at ambient temperature. Add Potassium Iodide (9.0 g) at 20-250C. Heat the reaction mixture to 65-75C. Add a solution of 1-Fluoronaphthalene in DMSO (71.6 ml in 100 ml) to the reaction mixture. Stir the reaction mixture for 5 hrs. After the completion of the reaction, cool the reaction mixture to 20-250C. Add methanol (5 ml) at 20-250C under nitrogen. Add D M Water (6000 ml) to the reaction mixture. Add Ethyl acetate (500 ml) to the reaction mixture. Stir the reaction mixture for 15 mins. Separate the org. layer. Re-extract the org. layer with Ethyl acetate (500 ml). Combine both org. layer and wash with D M Water (300 ml). Remove Ethyl acetate (-500 ml) under vacuum at below 500C. Add Ethyl acetate (500 ml) to the residual mass. Add Oxalic acid dihydrate (71.5 g) to the reaction mass. Add Methanol (50 ml) to the reaction mass. Stir the reaction mixture for 1 hr. Cool the reaction mixture to 0-50C. Stir the reaction mixture for 2 hrs. at 0-50C. Filter the content. Wash the wet cake with Ethyl acetate (100 ml). Suck dry the wet cake. Dry the wet material in hot air oven at 50-600C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 20℃; for 1h; | To a solution of 2.1 g of DNT-base (12% enantiomer R) dissolved in12 ml of ethyl acetate was added a solution of 0.6 g of oxalic acid in 12 ml of ethyl acetate. The resulting mixture was stirred at room temperature for an hour, filtrated and washed with ethyl acetate. After drying, in a vacuum oven for overnight, 2 g(77% yield) of DNT-oxalate were obtained containing 12% of enantiomer R. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example (T):Preparation of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate:1 -Fluoronaphthalene (118.3g) and (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3- hydroxypropanamine (10Og) was taken in a 500 mL round bottom flask and stirred for 10 minutes. Powdered potassium tertiary butoxide was added to the reaction mass, heated to 90-1000C and maintained for 20-22 hrs for the completion of the reaction. After completion of the reaction; the reaction mass was cooled and to it was added toluene and stirred. The layers were separated and the aqueous layer was extracted with toluene. The combined toluene layer was washed with water followed by 5% HCl solution. The acidic aqueous layer was extracted with dichloromethane and combined organic layer was washed with 5% sodium hydroxide then with water. The organic layer <n="9"/>was distilled atmospherically and finally under vacuum to get the thick mass. Ethyl acetate was added to the thick mass and distilled out dichloromethane completely under vacuum and stirred the reaction mass followed by the addition of ethyl acetate under stirring at 25-300C. A solution of methanol and oxalic acid were added to the reaction mass at 25-300C and stirred for 60-90 minutes at 0-50C. The solid was filtered washed with cold ethyl acetate twice and dried to yield the titled compound. Yield 154.g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.7 - 66.8% | Example 1 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate After adding 21.1 g (119.7 mmol) of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 20.0 g (144.4 mmol) of 2-chloro-3-cyanopyridine, and 16.6 g (164.1 mmol) of triethylamine to 42 g of dimethylformamide, the mixture was reacted at 125 to 130 °C for 24 hours under a nitrogen atmosphere. After distilling out triethylamine and dimethylformamide from the reactant solution under a reduced pressure, the residue was added with 32 ml of water and 87 g of ethyl acetate, and then a pH value thereof was adjusted to 8 to 9 with 10 percent aqueous sodium hydroxide solution. After phase-separating the solution, an organic layer was added with 24 g of methanol, and then 15.2 g of oxalic acid. This solution was filtrated to collect crystals, and then the crystals collected were dried to obtain 31.6 g of an objective compound (HPLC content: 86.1 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 61.7 percent). IR (KBr) gamma=3039, 2223, 1733, 1636, 1578, 1567, 1436, 758, 701 cm-11H-NMR (CDC13, 400 MHz) delta ppm: 8.29, 7.77, 6.76 (dd, each 1H); 7.1-7.44 (m, 5H); 5.46 (t, 1H, CHPh); 3.83, 3.59 (m, each H); 2.95 (dd, 1H); 2.65-2.80 (m, 4H); 2.25 (m, 1H); 2.33 (s, 3H, NCH3). Example 2 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate After adding 21.1 g (119.7 mmol) of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 24.0 g (173.2 mmol) of 2-chloro-3-cyanopyridine, and 16.6 g (164.1 mmol) of triethylamine to 42 g of dimethylformamide, the mixture was reacted at 125 to 130 °C for 24 hours under a nitrogen atmosphere. After distilling out triethylamine and dimethylformamide from the reactant solution under a reduced pressure, the solution was added with 32 ml of water and 87 g of ethyl acetate, and then a pH value thereof was adjusted to 8 to 9 with 10 percent aqueous sodium hydroxide solution. After phase-separating the solution, an organic layer was added with 24 g of methanol, and then 15.2 g of oxalic acid. This solution was filtrated to collect crystals, and then the crystals collected were dried to obtain 31.9 g of an objective compound (HPLC content: 92.4 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 66.8 percent). Example 3 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate In 57.3 kg of dimethylformamide solution containing 21.3 kg of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 22.2 kg of 2-chloro-3-cyanopyridine and 15.3 kg of triethylamine were added, the mixture was reacted at 114 to 125 °C for 17 hours under a nitrogen atmosphere. The reaction solution was concentrated under a reduced pressure. The distillated amount was 36 kg. The residue was added with 29.3 kg of water and then a pH value thereof was adjusted to 8.45 with 25 percent aqueous sodium hydroxide solution. This solution was added with 79.2 kg of ethyl acetate, washed with 20 kg of 5 percent sodium chloride solution, and then subjected to a phase separation. An organic layer was added with 23.1 kg of methanol, and then added with 13.9 kg of oxalic acid dihydrate at a temperature of 45 to 48 °C for about 1 hour. The solution was stirred at the temperature for 1 hour, filtrated at around 35 °C to collect crystals, and then the crystals collected were washed with a mixture of 42.2 kg of ethyl acetate and 12.4 kg of methanol. The crystals were dried at around 50 °C under a reduced pressure to obtain 32.65 kg of an objective compound (HPLC content: 90.2 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 66.2 percent). | |
56.6% | Comparative Example 1 After adding 21.1 g (119.7 mmol) of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 20.0 g (144.4 mmol) of 2-chloro-3-cyanopyridine, 12.8 g (126.3 mmol) of triethylamine, and 2.0 g (12.0 mmol) of potassium iodide to 42 g of dimethylformamide, the mixture was reacted at 125 to 130 °C for 24 hours under a nitrogen atmosphere. After distilling out triethylamine and dimethylformamide from the reactant solution under a reduced pressure, the residue was added with 32 ml of water and 87 g of ethyl acetate, and then a pH value thereof was adjusted to 8 to 9 with 10 percent aqueous sodium hydroxide solution. After phase-separating the solution, an organic layer was added with 24 g of methanol, and then 15.2 g of oxalic acid. This solution was filtrated to collect crystals, and then the crystals collected were dried to obtain 26.6 g of 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate (HPLC content: 93.8 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 56.6 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 g of N,N-Dimethyl-3-hydroxy-3-(2-thienyl) propanamine mandelate was mixed with 250 ml water and 500ml dichloromethane. The pH of the reaction mixture was adjusted between 1 1 - 12 using 30% sodium hydroxide solutions. The reaction mixture was stirred at 20-25C for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane ( 100 ml). The organic layers were combined and washed with water, The organic layer was concentrated under vacuum. The resulting mass was taken in 450ml dimethylsulphoxide and was stirred at room temperature. To this, 28.4 g sodium hydride was added and the mixture was stirred. To the resulting mass, 103.6 g of 1 - fluoronaphthalene was added and the reaction mass was stirred at 48-50C for 14-16 hours. After completion of the reaction, the reaction mass was cooled to room temperature. The resulting mass was transfer to another flask containing water at temperature 5- 10C. The pH of the resulting mixture was adjusted to 5-6 using acetic acid and cyclohexane was added under stirring at 10- 1 5C. The layers were separated and to the aqueous layer, toluene was added, pH was adjusted between 10- 1 1 .0 using 30% sodium hydroxide solution. The resulting mass was stirred at room temperature for few minutes. The organic layer was separated and aqueous layer was extracted with toluene. The organic layers were combined and distilled out. The resulting reaction mass was taken in 1400ml ethyl acetate at room temperature and 71 .0 g oxalic acid was added. The reaction mass was stirred for 5hr at room temperature. The resulting solid was filtered and washed with ethyl acetate and dried under vacuum at 50-55C for 4hr to obtain title compound.Yield : 90-92% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.08% | In acetone; at 24 - 26℃;Product distribution / selectivity; | Example 6. Preparation of l-[4-(l,l-dimethylethyl)phenyl]-4-[4-(diphenyimethoxy)-l- piperidinyl]-l-butanone oxalate I".H2C204 (<strong>[90729-43-4]Ebastine</strong> Oxalate)1 - [4-( 1 , 1 -dimethylethyl)phenyl] -4-[4-(diphenylmethoxy)- 1 -piperidinyl] - 1 -butanone I" (5.00 g, 10.66 mmol, batch DP023-Su040a, a light pink solid) was dissolved in acetone (25 mL) and oxalic acid (0.96 g, 1 1 mmol) was added. Precipitation of a salt was evident during the addition and a slight exotherm was noted (the internal temperature rose from 24 to 26 C). The crude salt was isolated by filtration and was washed with 7 mL of acetone and then with two ice-cold 10 mL portions of acetone. The moist product (9.17 g) was dried in a drying oven at 60 C to afford the oxalate salt I".H2C204 (4.7 g, 84.08 %). HPLC 97.09 %; NMR (300 MHz, DMSO-D6) delta: 7.54 (2H, d, J= 6, Ar CH tBu), 7.39 (2H, d, 3=6, Ar CH), 7.37-7.24 (10H, m, Ar), 5.59 (1H, s, CHPh2), 4.60-4.50 (2H, m, OH, NH), 3.61-3.59 (1H, m, CHO), 3.22-2.96 (8H, m), 1.98-1.83 (6H, m), 1.30 (9H, s, CH3x3); 13C NMR (75 MHz, DMSO-D6) delta: 198.15 (CO), 164.20 (CO oxalate), 156.15 (Ar CCO), 142.59 (Ar), 133.81 (Ar), 128.19 (Ar), 127.71 (Ar), 127.12, 126.47, 125.32, 79.25, 55.08, 48.75, 34.81, 34.68, 30.67 (3xCH3), 28.01, 18.41. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.08% | In acetone; at 24 - 26℃;Product distribution / selectivity; | 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone I" (5.00 g, 10.66 mmol, batch DP023-Su040a, a light pink solid) was dissolved in acetone (25 mL) and oxalic acid (0.96 g, 11 mmol) was added. Precipitation of a salt was evident during the addition and a slight exotherm was noted (the internal temperature rose from 24 to 26 C). The crude salt was isolated by filtration and was washed with 7 mL of acetone and then with two ice-cold 10 mL portions of acetone. The moist product (9.17 g) was dried in a drying oven at 60 C to afford the oxalate salt I".H2C2O4 (4.7 g, 84.08 %). HPLC 97.09 %; 1H NMR (300 MHz, DMSO-D6) delta: 7.54 (2H, d, J= 6, Ar CH tBu), 7.39 (2H, d, J=6, Ar CH), 7.37-7.24 (10H, m, Ar), 5.59 (1H, s, CHPh2), 4.60-4.50 (2H, m, OH, NH), 3.61-3.59 (1H, m, CHO), 3.22-2.96 (8H, m), 1.98-1.83 (6H, m), 1.30 (9H, s, CH3x3); 13C NMR (75 MHz, DMSO-D6) delta: 198.15 (CO), 164.20 (CO oxalate), 156.15 (Ar CCO), 142.59 (Ar), 133.81 (Ar), 128.19 (Ar), 127.71 (Ar), 127.12, 126.47, 125.32, 79.25, 55.08, 48.75, 34.81, 34.68, 30.67 (3xCH3), 28.01, 18.41. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.16 mg; 0.02 mg; 0.009 mg; 0.096 mg; 0.38 mg; 0.9 mg; 0.15 mg; 0.015 mg; 0.13 mg | With ferric sulfate nonahydrate; at 80℃; for 24h;pH 12.0; | General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.11 mg; 0.005 mg; 0.0023 mg; 0.071 mg; 0.12 mg; 0.01 mg; 0.09 mg | With magnesium sulfate; at 80℃; for 24h;pH 12.0; | General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.11 mg; 0.15 mg; 0.006 mg; 0.0028 mg; 0.0019 mg; 0.002 mg | With zinc(II) chloride; at 80℃; for 24h;pH 12.0; | General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In water; for 7h;Reflux; Inert atmosphere; | 85.2g (0.3 mol) of 1,2,4,5-benzenetetraamine hydrochloride, 56.7 g (0.63 mol) of oxalic acid and 300 g of water were charged into a three-necked flask. After 20 minutes of nitrogen flow, the reaction was carried out for 7 hours under reflux. A large amount of yellow granular solid Insoluble, room temperature, suction and drying, resulting in 88.6g of intermediate A, the yield of 100percent, product solubility is poor, unable to carry out purity testing, direct feeding. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.2% | at 65℃; | The 95g2_ bromophenylhydrazine 152.5ml30% pure product was dissolved in oxalic acid, and stirred at 65 C until the reaction mixture to precipitate crystals, cooled to 20 C, filtered, the filter cake was rinsed with acetone, and drying to obtain finished bromophenyl hydrazine oxalate 133g, content 99.4%, yield 42.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 50℃; for 2h; | [0056] An oxalate salt of ITI-007 is obtained in the course of salt screening from a slurry in ethyl acetate. FT-JR of the JTJ-007 oxylate salt formed in the experiments using oxalic acid shows 80% similarity with the FT-JR of the free base and -5- 10% similarity with that of oxalic acid itself. Jn addition, LC analysis shows no decomposition of the free base moiety of the formed salt, meaning an oxalate salt of JTJ-007 has formed. This experiment is then repeated at gram scale and a concentration of lOOmg/mL of JTJ-007 free base is used. The free base and oxalic acid are added in a 1:1 ratio, and then ethyl acetate is added. The mixture is slurried at 50C for 2 hours. The mixture is allowed to cool down to room temperature and is filtered and dried to give a yellow (sticky) solid. XRPD analysis shows the oxalate to be a poor crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.4 g | With hydrogenchloride; In water; at 20 - 100℃; for 12.5h;Inert atmosphere; | 5. 1g of 1,2,4,5-benzenetetraaminium tetrachloride was added to the solution at room temperature 3g oxalic acid 10percent dilute hydrochloric acid solution, purged with nitrogen mixture 0.5 hours; then heated to 100C stirred for 12 hours, cooled to room temperature, a brown solid was precipitated, suction filtered, washed with distilled water to Pumping down the water PH value of about 7.0, and then the resulting solid was vacuum dried, weighed brown solid 4. 40g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.6% | DX-A 03 (2.0 g, 0.011 mol)Was dissolved in dimethylacetamide (100 mL)A solution of 60% sodium hydride (463 mg, 0.012 mol)Dropwise.The resulting mixture was heated at 70 C. for 20 minutes.1-Fluoronaphthalene (1.27 mL, 0.012 mol)Was added dropwise to this mixed solution,And heated at 110 C. for 60 minutes.The reaction mixture was diluted with water,And extracted twice with diethyl ether.The extracts are combined,Wash with water,Then washed with saturated sodium chloride solution,It was dried over anhydrous sodium sulfate,After concentration under reduced pressure,To obtain an oily compound (DX-A 04, 3.28 g, 75.6%). |
Tags: 144-62-7 synthesis path| 144-62-7 SDS| 144-62-7 COA| 144-62-7 purity| 144-62-7 application| 144-62-7 NMR| 144-62-7 COA| 144-62-7 structure
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 :
Total Compounds: mg
The concentration of the dissolution solution you need to prepare is mg/mL