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| CAS No. : | 132335-44-5 |
| Formula : | C9H15NOS |
| M.W : | 185.29 |
| SMILES Code : | CN(CC[C@@H](C1=CC=CS1)O)C |
| English Name : | (S)-N,N-Dimethyl-3-hydroxy-3-(2-thienyl)propanamine |
| MDL No. : | MFCD07782107 |
| InChI Key : | XWCNSHMHUZCRLN-QMMMGPOBSA-N |
| Pubchem ID : | 9964277 |
| GHS Pictogram: | |
| Signal Word: | |
| Hazard Statements: | |
| Precautionary Statements: | |
| Class: | |
| UN#: | |
| Packing Group: |
* 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 |
|---|---|---|
| 92.1% | With glucose dehydrogenase; D-glucose; Rhodosporidium toruloides carbonyl reductase 9 from Escherichia coli; NADPH; sodium hydroxide; In aq. phosphate buffer; at 30℃; for 4h;pH 7;Enzymatic reaction;Kinetics; | In a 2-L bioreactor, 2a (1000mM), glucose (6000mM), NADP+ (0.75mM), and sonicated cells of co-expressing E. coli/RtSCR9-GDH (10gDCWL-1) were mixed in a total volume of 1L phosphate buffer (100mM, pH 7.0). The resulting mixture was stirred at 30C with 200rpm shaking for 240min. The pH was maintained at 7.0 with 2M NaOH during the reaction. After reaching completion, the pH was adjusted to 11-12 followed by extraction using ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give (S)- 3a. Yield: 92.1%. 1H NMR (500MHz, DMSO-d6): delta=7.36 (dd, J=4.9, 1.2Hz, 1H), 6.93 (m, 2H), 5.79 (s, 1H), 4.86 (m, 1H), 2.30 (qt, J=12.0, 7.1Hz, 2H), 2.12 (s, 6H), 1.79 (m, 2H). 13C NMR (126MHz, DMSO-d6): delta=150.72, 126.40, 123.79, 122.51, 67.39, 55.96, 45.15, 36.92. [alpha]25D=-4.9 (c=10mg/mL, ethyl acetate). |
| With hydrogen; sodium hydrogencarbonate; (2R,4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphino-methyl)-N-methyl-aminocarbonyl-pyrrolidine;di-mu-chloro-bis(1,5-cyclooctadiene)dirhodium; In methanol; water; at 30℃; under 75007.5 Torr; for 20h; | 70 g (0.32 mol) of 1-(N,N-dimethylamino)-3-(2-thienyl)-propan-3-one-hydrochloride are suspended in 630 ml of methanol and 70 ml of water under nitrogen; 16.5 mg bis-(1.5-cyclooctadiene)-dirhodium(I)-dichloride, 34.9 mg (2R, 4R)-4-dicyclohexylphosphino)-2-(diphenylphosphino-methyl)-N-methyl-aminocarbonyl) pyrrolidine and 140 mg sodium hydrogen carbonate are added and the suspension is hydrogenated at 30 C. and 100 bar hydrogen pressure for about 20 hours. Then the reaction mixture is evaporated down and the residue obtained is divided between 350 ml of water and 250 ml organic solvent (toluene or dichloromethane). The pH is adjusted to 1.6 with 32% hydrochloric acid and the mixture is stirred for 10 minutes, then the aqueous phase is separated off. The organic phase is again combined with 250 ml of water, stirred and the aqueous phase is again separated off. The combined aqueous phases are adjusted to pH 9.0 with 400 ml organic solvent and 45% sodium hydroxide solution, stirred, and then the phases are separated. The aqueous phase is extracted again with 200 ml solvent and the combined organic phases are evaporated down at 60 C. and 5 mbar. The yield of crude product is 50.0 g (85% of theory), chemical purity >98% (NMR). The crude product is recrystallised from 150 ml n-heptane, washed with another 50 ml of n-heptane and dried overnight at 40 C. and 5 mbar. 46.8 g (79% of theory) of S-N, N-dimethyl-3-hydroxy-3-(2-thienyl)-propylamine are obtained as a white solid, purity >98% (NMR), enantiomeric purity 94% (HPLC), melting point 76-78 C. | |
| The duloxetine alkyl carbamate represented by the formula (Ib) was synthesized by a known method (steps 1 to 4 of the above scheme).Specifically, 2-acetylthiophene (63.1 g; 0.5 mol), dimethylamine hydrochloride (53.0 g; 0.65 mol), paraformaldehyde (19.8 g; 0.22 mol) and ethanol (80 ml) (1 ml) to give 3-dimethylamino-1- (2-thienyl) -1-propanone hydrochloride,Reduction with sodium borohydride, resolution with optically active mandelic acid yielded optically active (S) N, N-dimethyl-3- (2-thienyl) -3-hydroxypropylamine.Next, by reaction of 1-fluoronaphthalene with sodium hydride, N, N-dimethyl-duloxetine was obtained.Subsequently, the reaction with the corresponding alkyl chloroformate (4.6 ml; 48.5 mmol) gave the duloxetine alkyl carbamate represented by the above formula (Ib). The ethanol solution (10 mL) of the potassium hydrate (87% of purity, 2.16g;33.5mmol) was added to the toluene solution (10 mL) of the obtained duloxetine ethyl carbamate (Ib) and (2.5g;6.7mmol) at the room temperature. It heated until it flowed back at 85 to 90 degree C about mixed liquor, and the solvent was distilled off until the internal temperature became 100 degrees C from there. Repeating distilling off of a solvent furthermore, in the range of 95 to 100 degree C, temperature was maintained and it stirred for 2 hours. It cooled to the room temperature and washed the organic layer obtained by adding water (10 mL) and ethyl acetate (10 mL) with water (20 mL). With sodium sulfate, it dried, concentration drying was filtered and carried out, and the compound of the title was obtained at 1.96 g (yield: 98.4%, optical isomer:0.16%).[0054]1H-NMR(400-MHz, DMSO-d6):8.23-8.20 (m, 1H), 7.86-7.82 (m, 1H), 7.53-7.49 (m, 2H), 7.44-7.41 (m, 2H), 7.33 (t, 1H), 7.21 (dd, 1H), 7.05(d,1H),6.97(dd,1H),5.99(t,1H),2.62(2H,t)2.26(3H,s),2.36-2.29(m,1H),2.12-2.03(m,1H) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With phosphoric acid In hexane; water; dimethyl sulfoxide; mineral oil | 1 (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, phosphoric acid salt EXAMPLE 1 (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, phosphoric acid salt A 13.5 g portion of (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine was dissolved in 80 ml of dimethylsulfoxide at 25° C. To the solution was slowly added 3 g of sodium hydride as a 60% dispersion in mineral oil, with vigorous stirring. After 15 minutes of stirring, 1.17 g of potassium benzoate was added and stirring was continued at approximately constant temperature for another 15 minutes. Then, 12.8 g of 1-fluoronaphthalene was slowly added to the reaction mixture, and after the addition was complete, the mixture was heated and was stirred for 2.5 hours at 60°-65° C. The mixture was then poured slowly into 190 ml of cold water and the DH was adjusted to 4.8 by addition of acetic acid. The temperature of the mixture was brought to 25° C., and 75 ml of hexane was added and stirring was continued for 10 minutes. The layers were then separated and the aqueous phase was stirred again with 75 ml of hexane and the phases separated. The pH of the aqueous phase was adjusted to 10.2 by addition of aqueous sodium hydroxide, and 75 ml of ethyl acetate was added. That mixture was stirred for 15 minutes at 25° C., and the 2-phase mixture was vacuum filtered through a pad of filter aid. The phases of the filtrate were allowed to separate, and the aqueous phase was extracted with 75 ml of ethyl acetate. The extract was combined with the previous ethyl acetate layer, and that mixture was washed with 100 ml of water. The organic layer was stirred at 25° C., and to it was added, dropwise, 7 g of 85% phosphoric acid. After the addition was complete, the mixture was stirred for 20 minutes more and was then cooled to 0° C. and stirred for 1 hour at that temperature. The slurry was then filtered and the solids washed three times with 20 ml portions of cold ethyl acetate. The solid was dried at 60° C. to afford 24.19 g of the title compound as a white solid, 98.1% potency, adjusted yield 79.6%, 91% EE. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: 1-Fluoronaphthalene; (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol With potassium hydroxide In diethylene glycol dimethyl ether at 120℃; for 3 - 6h; Stage #2: With phosphoric acid In water; ethyl acetate for 1.08333 - 1.25h; | 1 EXAMPLE 1; Arylation of (S)-(-)-N,N-dimethyl-3(2-thienyl)-3-hydroxypropanamine To a 25 mL 3-neck round bottom flask equipped with a condenser, N2 inlet, thermocouple, and overhead stirrer charge Compound Ib (0.55 g, 3 mMol), powdered KOH (0.9 g, 14.2 mMol), diglyme (6 mL) and 1-fluoronaphthalene (0.5 mL). Heat the mixture with good agitation to 120° C. for 3 to 6 hrs. Cool to ambient temp. and dilute with water (6 mL) and EtOAc (6 mL). Separate layers, back extract aqueous with EtOAc (6 mL). Separate layers and combine organic layers. Place organic layers in a 25 mL 3-neck round bottom flask with overhead agitation. Slowly add 85% H3PO4 (0.25 mL). Seed after 10 drops have been added. Stir 5-15 minutes, complete acid addition and stir 1 hr. Filter and wash cake with EtOAc (10 mLs). Dry under reduced pressure to yield 1.0 g of the title compound. % ΔR:0.2. Monitor the % R enantiomer by chiral HPLC under the following conditions: Column; Diacel Chiralcel OD-H, 5micron silica, 4.6×250 mm internal diameter, 40° C.; Solvent: 95% hexane, 5% isopropanol+0.2% DEA, 1 mL/min; detection UV 280 nm. | |
| Stage #1: (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol With sodium hydride In dimethyl sulfoxide at 20℃; for 2h; Stage #2: 1-Fluoronaphthalene With potassium 4-methylbenzoate In dimethyl sulfoxide at 20 - 65℃; for 5h; Stage #3: With phosphoric acid In ethyl acetate for 0.5h; | 1 100 gm of (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine is dissolved in DMSO (500 ml) at room temperature. Sodium hydride (23 gm) is added over a period of 1 hour in three equal lots at room temperature and stirred for 1 hour. 10 gm of potassium 4-methyl benzoate as added and stirred for 15 minutes. The reaction mixture was heated to about 55 °C and then 4-fluoronapthalene (100 gm) was added slowly for 45 minutes. The reaction mixture was maintained for 4 hours at about 65 0C. After completion of the reaction, the reaction mass is quenched into ice cold water (600 ml) and pH was adjusted to about 4 with 140 ml of acetic acid. Reaction mixture was washed with pet ether (3 X 100 ml). Aqueous layer was separated and pH adjusted about 8.5 with caustic soda and extracted with ethyl acetate (2 X 200 ml; 1 X 150 ml). The organic layer was washed with saturated aqueous sodium chloride solution (3x200) and further dried with sodium chloride. The organic layer pH was adjusted to about 2 with phosphoric acid and maintain for 30 minutes. The precipitated phosphate salt was filtered and washed with ethyl acetate to obtain 230 gm of the title compound as wet solid. |
| 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 |
Tags: (S)-(-)-N,N-Dimethyl-3-hydroxy-3-(2-thienyl)propanamine | 132335-44-5
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| 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.
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