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CAS No. : | 40412-06-4 | MDL No. : | MFCD05150366 |
Formula : | C13H14O3S2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HLPRKWVEMYDPAU-UHFFFAOYSA-N |
M.W : | 282.38 | Pubchem ID : | 3682034 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 11 |
Fraction Csp3 : | 0.23 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 72.76 |
TPSA : | 79.99 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.72 cm/s |
Log Po/w (iLOGP) : | 2.84 |
Log Po/w (XLOGP3) : | 3.24 |
Log Po/w (WLOGP) : | 4.09 |
Log Po/w (MLOGP) : | 2.65 |
Log Po/w (SILICOS-IT) : | 3.68 |
Consensus Log Po/w : | 3.3 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.75 |
Solubility : | 0.0497 mg/ml ; 0.000176 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.59 |
Solubility : | 0.00721 mg/ml ; 0.0000255 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -5.04 |
Solubility : | 0.00256 mg/ml ; 0.00000908 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
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% | at 35℃; Cooling with ice | (0.87 mol) of 2-thiopheneethanol and 184 g (0.97 mol) of p-toluenesulfonyl chloride were sequentially added to a 1 L three-necked flask, 98 g (0.97 mol) of triethylamine was dropwise added thereto under ice-water bath, And keep the temperature of the reaction liquid not higher than 20 DEG C, dropping finished, heating to 35 DEG C to continue stirring, respectively 24h, 27h sampling, TLC, until the reaction is complete, stop reaction, filtration, filter cake with appropriate amount of dichloromethane And the methylene chloride layer was dried with anhydrous sodium sulfate for 2 hours. The desiccant was filtered off and the desiccant was washed with a small amount of methylene chloride. The filtrate was decompressed in vacuo and the filtrate was evaporated under reduced pressure. Concentrated to constant weight to be brown oil, weighing 203g, yield 98percent, |
96.37% | With triethylamine In toluene at 5 - 30℃; for 20.8333 h; | EXAMPLE 3 Preparation of 2-Thienylethyl Para-Toluenesulphonate (Formula VII) Using Toluene 400 liters of toluene and 163.2 kg of para-toluene sulfonyl chloride were charged into a clean and dry reactor followed by cooling to about 5° C. 100 kg of thiophene-2-ethanol was added at about 5° C. over about 20 minutes followed by addition of 130 kg of triethylamine over about 8 hours, 50 minutes. The reaction mixture temperature was raised to about 30° C. followed by stirring for about 12 hours. The reaction mass was filtered through a Nutsche filter and washed with 2*100 liters of toluene. The reaction filtrate was transferred into another reactor followed by washing with 5*200 liters of water. Organic and aqueous layers were separated and the organic layer was distilled completely at about below 70° C. under vacuum to afford 212 kg (yield: 96.37percent) of title compound. Purity by GC: 95.59percent. |
96.5% | With triethylamine In dichloromethane at -5 - 20℃; for 2 h; | 32.7 g (0.17 mol) of p-toluenesulfonyl chloride,40 ml of dichloromethane into the reaction flask, cooled to -5 ° C,20 g (0.16 mol)2-thiopheneethanol.28.4 g (0.28 mol) of triethylamine was slowly added dropwise and the temperature of the reaction solution was maintained at about 0 ° C.Plus Bi, incubated for 2h after the reaction was warmed to room temperature. 2-thiophene ethanol to be consumed until the raw materials, suction filtration,The solid was washed with a small amount of methylene chloride and the filtrate was washed with 50 ml of saturated sodium bicarbonate and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, light brown solid precipitated out,Filtered, washed with a small amount of petroleum ether to white,That isP-toluenesulfonate-2-thiophene ethyl ester42.5 g, yield 96.5percent (HPLC purity 99percent) |
95.5% | With triethylamine In dichloromethane at 7.5 - 22.5℃; for 5 h; | EXAMPLE 10 Preparation of 2-(2-Thiophene)Ethanol Tosylate (Formula VII) Using Dichloromethane 4 liters of dichloromethane was added into a reactor at a temperature of about 30° C., cooled to a temperature of about 7.5° C. to which was then added 1.784 kg of p-toluene sulphonyl chloride followed by 1 kg of thiophene-2-ethanol. 1.302 kg of triethylamine was added to the above reaction mass at a temperature of about 7.5° C. followed by slowly raising the temperature of the reaction mass to 22.5° C. for about 5 hours. The obtained reaction mass was filtered through a pressure Nutsche filter, washed with methylene chloride (2*1 liter) and the mother liquor was collected and transferred into another reactor. The organic layer was washed with water (5*2 liters). The organic layer thus obtained was subjected to distillation at a temperature below 70° C. using hot water circulation. The obtained residue was then cooled to about 30° C. to afford 2.1 kg (yield: 95.5percent) of title compound. |
93.6% | With triethylamine In toluene at 45℃; for 4 h; | Example 1 0.2. Conversion of (S)-1 ,2,3,4-tetrahydro-5-hvdroxy-N-propyl- naphthalen-2-ammonium hydrobromide (VIII) into hydrochloride salt of rotigotine; 10.2.1. Preparation of 2-(2-Thienyl)ethyl-4-toluene sulfonate; 4-toluenesulfonyl chloride (162 g), toluene (363.3 g) and 2-(2-Thienyl)ethanol (104 g) are combined. Triethylamine (93 g) is added maintaining the temperature lower than 45° C. After 4hrs, the mixture is washed with aqueous phosphoric acid, aqueous sodium hydroxide and then water. The organic phase is distilled off under vacuum. Isopropanol (314 g) and heptanes (365.9 g) are added. The batch is crystallized by cooling and isolated at -15° C. The crystals are filtered and washed with heptanes (175 mL). The crystals are then dried under vacuum at room temperature until a melting point of > 30° C is obtained.Yield ( 214 g): 93.6 percentHPLC analyses confirmed purity >99percent and 100 percent assay in comparison to a reference standard. |
93.6% | With triethylamine In toluene at 45℃; for 4 h; | 4-toluenesulfonyl chloride (162 g), toluene (363.3 g) and 2-(2-Thienyl)ethanol (104 g) are combined. Triethylamine (93 g) is added maintaining the temperature lower than 45° C. After 4 hrs, the mixture is washed with aqueous phosphoric acid, aqueous sodium hydroxide and then water. The organic phase is distilled off under vacuum. Isopropanol (314 g) and heptanes (365.9 g) are added. The batch is crystallized by cooling and isolated at −15° C. The crystals are filtered and washed with heptanes (175 mL). The crystals are then dried under vacuum at room temperature until a melting point of 30° C. is obtained. [0255] Yield (214 g): 93.6percent |
90% | With silica gel In dichloromethane for 2 h; Reflux | The 12.8g (0.1mol) 2- (2- thienyl) ethanol, 1000mL of dichloromethane, 21.0g (0.12mol) of p-toluenesulfonic acid chloride and 10.0g of silica gel into the reaction flask, the reaction was refluxed for 2h, cooled, filtered to remove silica gel.The reaction mixture was washed successively with distilled water, saturated sodium carbonate solution, brine, then the methylene chloride solvent was removed by distillation under reduced pressure, to give 26.0g of p-toluenesulfonic acid Preparation of 2- (2-thienyl) ethyl ester, 90percent yield . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With ferric nitrate In 1,2-dichloro-ethaneReflux | 12.8 g (0.1 mol) of 2-thiopheneethanol,20.0 g (0.12 mol) of p-toluenesulfonic acid,20.2 g (0.05 mol) of ferric nitrate,100 ml of 1,2-dichloroethane into the reaction flask,Reflux reaction to 2 - thiophene ethanol consumption is completed,filter,The filtrate was washed three times with water,concentrate,The solvent was distilled off under reduced pressure,2-thiophene ethyl p-toluenesulfonate 22g,Yield 78percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; at 35℃;Cooling with ice; | (0.87 mol) of 2-thiopheneethanol and 184 g (0.97 mol) of p-toluenesulfonyl chloride were sequentially added to a 1 L three-necked flask, 98 g (0.97 mol) of triethylamine was dropwise added thereto under ice-water bath, And keep the temperature of the reaction liquid not higher than 20 DEG C, dropping finished, heating to 35 DEG C to continue stirring, respectively 24h, 27h sampling, TLC, until the reaction is complete, stop reaction, filtration, filter cake with appropriate amount of dichloromethane And the methylene chloride layer was dried with anhydrous sodium sulfate for 2 hours. The desiccant was filtered off and the desiccant was washed with a small amount of methylene chloride. The filtrate was decompressed in vacuo and the filtrate was evaporated under reduced pressure. Concentrated to constant weight to be brown oil, weighing 203g, yield 98%, |
96.37% | With triethylamine; In toluene; at 5 - 30℃; for 20.8333h;Product distribution / selectivity; | EXAMPLE 3 Preparation of 2-Thienylethyl Para-Toluenesulphonate (Formula VII) Using Toluene 400 liters of toluene and 163.2 kg of para-toluene sulfonyl chloride were charged into a clean and dry reactor followed by cooling to about 5 C. 100 kg of thiophene-2-ethanol was added at about 5 C. over about 20 minutes followed by addition of 130 kg of triethylamine over about 8 hours, 50 minutes. The reaction mixture temperature was raised to about 30 C. followed by stirring for about 12 hours. The reaction mass was filtered through a Nutsche filter and washed with 2*100 liters of toluene. The reaction filtrate was transferred into another reactor followed by washing with 5*200 liters of water. Organic and aqueous layers were separated and the organic layer was distilled completely at about below 70 C. under vacuum to afford 212 kg (yield: 96.37%) of title compound. Purity by GC: 95.59%. |
96.5% | With triethylamine; In dichloromethane; at -5 - 20℃; for 2h; | 32.7 g (0.17 mol) of p-toluenesulfonyl chloride,40 ml of dichloromethane into the reaction flask, cooled to -5 C,20 g (0.16 mol)2-thiopheneethanol.28.4 g (0.28 mol) of triethylamine was slowly added dropwise and the temperature of the reaction solution was maintained at about 0 C.Plus Bi, incubated for 2h after the reaction was warmed to room temperature. 2-thiophene ethanol to be consumed until the raw materials, suction filtration,The solid was washed with a small amount of methylene chloride and the filtrate was washed with 50 ml of saturated sodium bicarbonate and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, light brown solid precipitated out,Filtered, washed with a small amount of petroleum ether to white,That isP-toluenesulfonate-2-thiophene ethyl ester42.5 g, yield 96.5% (HPLC purity 99%) |
95.5% | With triethylamine; In dichloromethane; at 7.5 - 22.5℃; for 5h;Product distribution / selectivity; | EXAMPLE 10 Preparation of 2-(2-Thiophene)Ethanol Tosylate (Formula VII) Using Dichloromethane 4 liters of dichloromethane was added into a reactor at a temperature of about 30 C., cooled to a temperature of about 7.5 C. to which was then added 1.784 kg of p-toluene sulphonyl chloride followed by 1 kg of thiophene-2-ethanol. 1.302 kg of triethylamine was added to the above reaction mass at a temperature of about 7.5 C. followed by slowly raising the temperature of the reaction mass to 22.5 C. for about 5 hours. The obtained reaction mass was filtered through a pressure Nutsche filter, washed with methylene chloride (2*1 liter) and the mother liquor was collected and transferred into another reactor. The organic layer was washed with water (5*2 liters). The organic layer thus obtained was subjected to distillation at a temperature below 70 C. using hot water circulation. The obtained residue was then cooled to about 30 C. to afford 2.1 kg (yield: 95.5%) of title compound. |
93.6% | With triethylamine; In toluene; at 45℃; for 4h; | Example 1 0.2. Conversion of (S)-1 ,2,3,4-tetrahydro-5-hvdroxy-N-propyl- naphthalen-2-ammonium hydrobromide (VIII) into hydrochloride salt of rotigotine; 10.2.1. Preparation of 2-(2-Thienyl)ethyl-4-toluene sulfonate; 4-toluenesulfonyl chloride (162 g), toluene (363.3 g) and 2-(2-Thienyl)ethanol (104 g) are combined. Triethylamine (93 g) is added maintaining the temperature lower than 45 C. After 4hrs, the mixture is washed with aqueous phosphoric acid, aqueous sodium hydroxide and then water. The organic phase is distilled off under vacuum. Isopropanol (314 g) and heptanes (365.9 g) are added. The batch is crystallized by cooling and isolated at -15 C. The crystals are filtered and washed with heptanes (175 mL). The crystals are then dried under vacuum at room temperature until a melting point of > 30 C is obtained.Yield ( 214 g): 93.6 %HPLC analyses confirmed purity >99% and 100 % assay in comparison to a reference standard. |
93.6% | With triethylamine; In toluene; at 45℃; for 4h; | 4-toluenesulfonyl chloride (162 g), toluene (363.3 g) and 2-(2-Thienyl)ethanol (104 g) are combined. Triethylamine (93 g) is added maintaining the temperature lower than 45 C. After 4 hrs, the mixture is washed with aqueous phosphoric acid, aqueous sodium hydroxide and then water. The organic phase is distilled off under vacuum. Isopropanol (314 g) and heptanes (365.9 g) are added. The batch is crystallized by cooling and isolated at -15 C. The crystals are filtered and washed with heptanes (175 mL). The crystals are then dried under vacuum at room temperature until a melting point of 30 C. is obtained. [0255] Yield (214 g): 93.6% |
90% | With silica gel; In dichloromethane; for 2h;Reflux; | The 12.8g (0.1mol) 2- (2- thienyl) ethanol, 1000mL of dichloromethane, 21.0g (0.12mol) of p-toluenesulfonic acid chloride and 10.0g of silica gel into the reaction flask, the reaction was refluxed for 2h, cooled, filtered to remove silica gel.The reaction mixture was washed successively with distilled water, saturated sodium carbonate solution, brine, then the methylene chloride solvent was removed by distillation under reduced pressure, to give 26.0g of p-toluenesulfonic acid Preparation of 2- (2-thienyl) ethyl ester, 90% yield . |
In pyridine; water; | (a) 2-(2-Hydroxyethyl)thiophene tosylate Toluene-4-sulphonyl chloride (4.125 g) was added portionwise over 5 mins to an ice-cold solution of 2-(2-hydroxyethyl)thiophene (1.723 g) in anhydrous pyridine (20 ml) and the resulting pale yellow solution was stirred at 0 C. After 3 h the reaction mixture was poured into vigorously stirred water (160 ml) producing a precipitate. After cooling the solid was collected and washed with water to give white crystals of the title tosylate (3.555 g), m.p. 33-34 C., lambdamax (EtOH) 227 nm (E11 612). | |
With triethylamine; In butanone; at 0 - 30℃; | Example 1 Preparation of 2-(2-Thienyl)-ethyl para-toluenesulfonate A mixture of p-toluenesulfonyl chloride (328 gm) and 2-(2-thienyl)-ethanol (200 gm) in methyl ethyl ketone (1000 ml) was cooled to 0C. This was followed by drop wise addition of triethyl amine (283.1 ml) at 0-5C over a period of 1 to 2 hours, and the reaction mass was stirred for 12 to 15 hours at 25-3O0C. The resulting mass was filtered and washed with methyl ethyl ketone (500 ml). The resulting organic layer was washed with water (500 ml) followed by washings with saturated sodium bicarbonate solution (500 ml) and brine solution (500 ml). The resulting organic layer was distilled under vacuum at below 50C to give 2-(2- thienyl)-ethyl para-toluenesulfonate as an oily mass (Weight of the oil: 505 gm; Purity by HPLC: 97%). | |
With triethylamine; In butanone; at 0 - 30℃; | Example 1 Preparation of 2-(2-Thienyl)-ethyl para-toluenesulfonate A mixture of p-toluenesulfonyl chloride (328 gm) and 2-(2-thienyl)-ethanol (200 gm) in methyl ethyl ketone (1000 ml) was cooled to 0 C. This was followed by drop wise addition of triethyl amine (283.1 ml) at 0-5 C. over a period of 1 to 2 hours, and the reaction mass was stirred for 12 to 15 hours at 25-30 C. The resulting mass was filtered and washed with methyl ethyl ketone (500 ml). The resulting organic layer was washed with water (500 ml) followed by washings with saturated sodium bicarbonate solution (500 ml) and brine solution (500 ml). The resulting organic layer was distilled under vacuum at below 50 C. to give 2-(2-thienyl)-ethyl para-toluenesulfonate as an oily mass (Weight of the oil: 505 gm; Purity by HPLC: 97%). | |
With potassium carbonate; In toluene; at 0 - 20℃; for 3.5h; | 500 ml of toluene was added to a 1000 ml reaction flask,50gThiophene ethanolAnd 80 g of p-toluenesulfonyl chloride,Turn on agitation,Controlled temperature was added dropwise at 0 C64 g of potassium carbonate,The addition was continued for about 30 min, Dropping finished warming to 20 C reaction for 3 hours,To the reaction solution was added 400 ml of water,Washed twice,The washed toluene layer was directly used for the next reaction. | |
With N-ethyl-N,N-diisopropylamine; In toluene; at 0 - 20℃; for 3.5h; | 500 ml of toluene was added to a 1000 ml reaction flask, 50 g of thiophene ethanol and 92 g of p-toluenesulfonyl chloride, stirred at 0 C, 62 g of N, N-diisopropylethylamine was dropped for about 30min. When dropping was completed, mixture was heated to 20 C and reacted for 3 hours. To the reaction solution was added 400 ml of water, washed twice, the washed toluene layer was directly used for the next reaction. | |
With triethylamine; In toluene; at 0 - 20℃; for 3h; | 500 ml of toluene, 50 g of thiophene ethanol and 80 g of p-toluenesulfonyl chloride were placed in a 1000 ml reaction flask,And the temperature was raised to 20 C for 3 hours. 400 ml of water was added to the reaction solution, washed twice, washed with toluene, Layer directly to the next step reaction. | |
With potassium carbonate; In toluene; at 0 - 20℃; for 3.5h; | 500 ml of toluene, 50 g of thiophene ethanol and 107 g of p-toluenesulfonyl chloride were placed in a 1000 ml reaction flask, agitation was turned on, the temperature was controlled at 0 C, dropwise addition of 64g potassium carbonate, addition lasted about 30min, after which it was warmed to 20 C and reacted for 3 hours, to the reaction solution was added 400 ml of water, washed twice, and the washed toluene layer was directly used for the next reaction. | |
With triethylamine; In toluene; at 0 - 25℃; for 3.5h; | Example 1The preparation method of ticlopidine hydrochloride as shown in Fig. 2 comprises the following steps:1. p-toluenesulfonyl protection:In a 1000 ml reaction flask, 500 ml of toluene, 50 g of thiophene ethanol and 80 g of p-toluenesulfonyl chloride were charged and stirred to controlAt a temperature of 0 C, 47 g of triethylamine was added dropwise, dropping for about 30 min, and the temperature was raised to 25 C for 3 hours.Add 400ml of water, washed twice, washed with toluene layer directly to the next step reaction.2. Condensation reactionThe reaction solution of toluene in the previous step was added to a 1000 ml reaction flask, followed by the addition of 114 g of o-chlorobenzylamine and heating to 90 C for 3 hours. After the reaction, the mixture was cooled to 25 C and stirred for 1 hour. The filtrate was added with 200 ml of water, and hydrochloric acidAdjust the pH of the system to 8.5, stratify the upper layer of toluene and continue dropping hydrochloric acid to adjust the pH to 5, then cool the system to 2 CThe crystals were mixed for 4 hours and filtered, and the filter cake was dried in vacuo at 50 C to give 96 g of the condensate hydrochloride.3 ? Closed loop reactionTo the 1000 ml reaction flask was added 96 g of the condensate hydrochloride, 400 ml of 1,3-dioxane and 5 ml of hydrochloric acid,To 90 C for 6 hours. After the reaction, the mixture was cooled to 7 C and stirred for 3 hours. The filter cake was washed with a small amount of 1,3-dioxetaneAfter 50 C vacuum drying, 95 g of ticlopidine hydrochloride was obtained4 ? RefinedIn a 1000 ml reaction flask, 95 g of crude ticlopidine hydrochloride and 500 ml of absolute ethanol were added and heated to 72 C with stirring,About 10 minutes after the solid is completely dissolved by adding 2g activated carbon, insulation bleaching 20 minutes after the hot filter, the filtrate gradually coolingThe crystals were crystallized at 4 C for 4 hours and filtered. The filter cake was washed with a small amount of absolute ethanol and dried in vacuo at 50 C to give 91 g of tithiol hydrochloridePrecision products. Total yield 82%, purity 99.9% | |
With sodium hydroxide; In water; toluene; at 10 - 55℃; for 11h; | In a three-necked flask, 97 g of p-toluenesulfonyl chloride and 180 ml of toluene were placed.Stir and dissolve, filter, keep warm at 15-20 C,60 g of 2-thiopheneethanol and 60 ml of toluene were placed in a three-necked flask.120g 40% aqueous sodium hydroxide, stirring,A solution of 97 g of p-toluenesulfonyl chloride dissolved in 180 ml of toluene was added dropwise at 10-20 C, and the mixture was stirred for 3 h, then heated to 45-55 C for 8 h, and allowed to stand for stratification.The organic phase is depressurized to remove toluene to give 2-(2-thiophene)ethanol p-toluenesulfonate.Reddish brown oil; the molecular formula is as follows: | |
235.1 g | With sodium hydroxide; In chloroform; at 0 - 5℃; for 12h; | To the reaction flask, the above step 2-thiophene ethanol: 112 g, chloroform 600 g, PTSC 249.4 g, and the mixture was cooled to 0-5 C.Add 834g of 10% by mass sodium hydroxide solution, control the temperature 0-5 C, keep warm for 12h, add hydrochloric acid to pH=12, layer, the water layer is extracted with 300g chloroform, and the chloroform layer is combined. After washing with 100 g of water, the organic layer was distilled to dryness to give 2-thiopheneethanol p-toluenesulfonate: 235.1 g yield 95.3%, purity 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Alkali free: Weigh 86g (0.3644mol) of raw material (S) -o-chlorophenylglycine methyl ester hydrochloride in a 2000ml three-necked bottle, add 300ml of pure water to dissolve, add 24g of sodium carbonate and 200ml of pure water dropwise with stirring at room temperature The prepared solution was neutralized to basicity, free (S) -o-chlorophenylglycine methyl ester, extracted three times with an equal volume of methylene chloride, the organic phase was washed three times with water, the organic phases of methylene chloride were combined, and the organic The phase was concentrated under reduced pressure to obtain (S) -o-chlorophenylglycine methyl ester concentrate, which was ready for use.Nucleophilic substitution: Put the above (S) -o-chlorophenylglycine methyl ester concentrated solution in a 2000ml three-necked bottle, add 350g of succinonitrile, warm to 70 C to dissolve, add the raw material thiophene-2-ethyl p-toluenesulfonate 102.8 g, stir, and add a mixture of 160 g of dipotassium hydrogen phosphate trihydrate and 8 ml of pure water.After the feeding is completed, the temperature is raised to 95 C, stirred, and the reaction timing is started.Using high performance liquid chromatography to monitor the progress of the reaction, to the reaction system, the reaction product (S) -2- (2-thiophenethylamino)-(2-chlorophenyl) -acetic acid methyl ester no longer increased, the reaction ended in 11 hours .Cool to room temperature, add 300ml of pure water and 300ml of dichloromethane, stir to dissolve, separate the liquid, collect the organic phase, add 300ml of dichloromethane to the aqueous phase and extract once, wash the organic phase twice with water, combine the organic phases, reduce the organic phase The pressure concentration is complete to obtain a (S) -2- (2-thienylethylamino)-(2-chlorophenyl) -acetic acid methyl ester concentrate, which is ready for use.Acidification to salt: put the above-mentioned (S) -2- (2-thienylethylamino)-(2-chlorophenyl) -acetic acid methyl ester concentrate into a 2000ml three-necked bottle, add 250ml of ethyl acetate to dissolve At room temperature, add a solution of 38g of 37% concentrated hydrochloric acid and 100ml of ethyl acetate dropwise, neutralize to a pH of about 1.5, stir, precipitate solids, and filter. 600 ml of mixed solvent was recrystallized to obtain 116.0 g of (S) -2- (2-thienylethylamino)-(2-chlorophenyl) -acetic acid methyl ester hydrochloride.The structure of the compound was confirmed by nuclear magnetic resonance spectroscopy, mass spectrometry and standard control.The purity of the product detected by high performance liquid chromatography was 99.8%, the specific optical rotation was 110.5 degrees, and the yield was 92.0% (calculated with the starting compound 1). | |
42% | Example (2); Preparation of methyl(2SV(+)-(2-chlorophenyl)-N-r2-(2-thieno)ethyllglvcinate using hydrochloride of methyl (25V(+)-amino-(2-chlorophenyl)acetate; A mixture of methyl(25)-amino-(2-chlorophenyl)acetate hydrochloride (10 gm,0.042 mole) and 2-(2-thienyl)ethyl-4-methylbenzenesulfonate (12 gm, 0.042 mole ) was refluxed at 78C to 820C in the presence of triethylamine (5.0 volumes) for 8 to 10 hrs. After the completion of reaction, ethyl acetate was added to the reaction mass, stirred for 10 to 15 mins. and the solid was filtered. The ethyl acetate solution was distilled out completely under vacuum, dissolved the residue in methylenedichloride, washed with water followed by saturated sodium chloride solution, and <n="8"/>methylenedichloride was distilled completely to get methyl (25)-(+)-(2-chlorophenyl)- N-[2-(2-thieno)ethyl] glycinate ( 5.5 gm). Yield = 42% and HPLC Purity = 98.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; at 78 - 82℃; for 8 - 10h;Product distribution / selectivity; | Example (4); Preparation of methyl(2S)-(2-chIorophenyl)(6,7-dihydrothieno[3,2-clpyridin- 5(4H)-vDacetate using free base of methyl (25r)-amino-(2-chlorophenv?acetate; A mixture of methyl(25)-amino-(2-chlorophenyl)acetate freebase (10 gm, 0.05 mole) and 2-(2-thienyl)ethyl-4-methylbenzenesulfonate (14.1 gm, 0.05 mole ) was refluxed at 78C to 82C in the presence of triethylamine (5.0 volumes) for 8 to 10 hrs. After completion of the reaction, ethyl acetate was added to the contents of reaction mass, stirred for 10 to 15 mins. and the solid was filtered. The ethyl acetate solution was distilled off completely under vacuum, dissolved the residue in methylenedichloride, washed with water followed by saturated sodium chloride solution, dried and distilled completely to get methyl(25)-(2-chlorophenyl)(6,7-dihydrothieno[3,2-c]pyridin-5(4H)- yl)acetate (7.2 gm) as residue. To the residual liquid aqueous formaldehyde (30%, 36 ml) was added and heated to 600C to get clear solution and maintained for 20 to 30 mins. After completion of reaction, water and methylenedichloride were added and the peta was adjusted between 7 to 8 by using solid sodium bicarbonate. Layer of methylenedichloride was separated, dried and evaporated to get methyl(2<S)-(2- <n="9"/>chlorophenyl)(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate (4.7 gm ).Yield = 29% and etaPLC Purity = 98.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; at 78 - 82℃; for 8 - 10h;Product distribution / selectivity; | Example (5); Preparation of methyI(2SV(2-chlorophenvI')f6,7-dihvdrothienof3,2-clpyridin- 5(4H)-vDacetate using hydrochloride of methyl (2.y)-ammo-(2- chlorophenvDacetate; A mixture of methyl (26)-amino-(2-chlorophenyl)acetate hydrochloride (10 gm, 0.042 mole )and 2-(2-thienyl)ethyl-4-methylbenzenesulfonate( 12 gm, 0.042 mole) was refluxed at 780C to 82C in the presence of triethylamine (5.0 volumes) for 8 to 10 hrs.After completion of the reaction, ethyl acetate was added to the contents of reaction mass, stirred for 10 to 15 mins. and the solid was filtered. The ethyl acetate solution was distilled out completely under vacuum, dissolved the residue in methylenedichloride and washed with water followed by saturated sodium chloride solution, dried and distilled completely to get methyl(2.S)-(2-chlorophenyl)(6,7-dihydrothieno[3,2- c]pyridin-5(4H)-yl)acetate ( 6.2 gm ) as residue . To the residual liquid aqueous formaldehyde (30%, 31 ml) was added and heated to 60C to get clear solution and maintained for 20 to 30 mins. After completion of reaction, water and methylenedichloride were added and the peta was adjusted between 7 to 8 by using solid sodium bicarbonate. Layer of methylenedichloride was separated, dried and evaporated to get methyl (25)-(2-chlorophenyl)(6,7-dihydrothieno [3,2-c] pyridin-5 (4H)-yl) acetate( 3.8 gm).Yield = 28% etaPLC Purity = 98.65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; potassium iodide; In acetonitrile; at 30 - 80℃; for 24h;Heating / reflux; | In (750 ml) acetonitrile at about 30-35C, (150g) DL-2-(2-chlorophenyl)glycine methyl ester is added followed by addition of (191 g) 2(2-thiophen.e)emanol tosylate, (76g) sodium bicarbonate and (12.5g) potassium iodide. The reaction mixture is refluxed at about 80C under vigorous stirring for 24 hours, (12.5g) potassium iodide is added and refluxed further for 24 hours. The solvent is distilled off completely under vacuum at 45-50C and the residual mass is degassed at 50-55C under vacuum for 30 minutes. It is dissolved in (2250ml) ethyl acetate at 30-35C and (750ml) water is added. The upper product enriched layer is washed with aq NaCl 10% soln and cooled to 0-5C. To this ethyl acetate layer is added con HC1 acid (110 ml con HC1 acid in 210ml of chilled water) at 0-5C with stirring and maintain for 2 hours. The product is filtered and washed with chilled ethyl acetate (2x15 Oml) and sucked to dryness. The product cake is washed with (2xl50ml) hexane and suck to maximum dryness and dried at 45-55C. (175g) |
Yield | Reaction Conditions | Operation in experiment |
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58% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 8.5h;Heating / reflux;Product distribution / selectivity; | Examples 29 to 31: Synthesis of methyl (S)- (+)-a- (o-chlorophenyl)-6, 7-dihydrothieno [3,2-c] pyridin-5 (4H) -acetate (compound of formula lb ; Clopidogrel); The procedure of Example 25 was repeated except that 2- (2-chloroethyl)-3-chloromethylthiophene obtained in Example 12, 2- (2-methanesulfonyloxyethyl) thiophene obtained in Example 13 and 2- (2-p-toluenesulfonyloxyethyl) thiophene obtained in Example 14 were employed, respectively, instead of 2- (2-bromoethyl)-3-bromomethylthiophene obtained in Example 7 as a starting material, to obtain the title compound at yields of 85%, 79% and 58%, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; | EXAMPLE 3 1,3-Dihydro-1-[3-(2-thienyl)propyl]-2H-imidazole-2-thione A mixture was prepared from 20.8 g of 2-[2-(4-toluenesulfonyloxy)ethyl]thiophene, 5.4 g of sodium cyanide and 175 ml of dimethylsulfoxide and this mixture was heated to 90 C. The mixture was quenched by pouring it into saturated aqueous ammonium chloride solution and the resulting solution was extracted into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give crude 2-thiophenepropionitrile. | |
In dimethyl sulfoxide; | EXAMPLE 4 1,3-Dihydro-1-[3-(2-thienyl)propyl]-2H-imidazole-2-thione A mixture was prepared from 20.8 g of 2-[2-(4-toluenesulfonyloxy)ethyl]thiophene, 5.4 g of sodium cyanide and 175 ml of dimethylsulfoxide and this mixture was heated to 90 C. The mixture was quenched by pouring it into saturated aqueous ammonium chloride solution and the resulting solution was extracted into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give crude 2-thiophenepropionitrile. | |
In dimethyl sulfoxide; | EXAMPLE 10 1,3-Dihydro-1-[3-(2-thienyl)propyl]-2H-imidazole-2-thione A mixture was prepared from 20.8 g of 2-[2-(4-toluenesulfonyloxy)ethyl]thiophene, 5.4 g of sodium cyanide and 175 ml of dimethylsulfoxide and this mixture was heated to 90 C. The mixture was quenched by pouring it into saturated aqueous ammonium chloride solution and the resulting solution was extracted into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give crude 2-thiophenepropionitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In ethyl acetate; N,N-dimethyl-formamide; | (b) 5-Chloro-1-[2-(2-thienyl)ethyl]pyrimidin-2-one A stirred suspension of 5-chloropyrimidin-2-one (131 mg), 2-(2-hydroxyethyl)thiophene tosylate (424 mg), anhydrous sodium carbonate (265 mg) and benzyltrimethylammonium chloride (4 mg) in dry N,N-dimethylformamide (5 ml) was heated at 90 C. After 41/2 h the reaction mixture was evaporated to dryness and the residue was suspended in ethyl acetate (50 ml) and washed with water (3*15 ml), dried (MgSO4) and evaporated to a solid. The solid was subjected to p.l.c. on silica developing with chloroform-ethanol, 19:1. The more polar band was eluted with ethyl acetate and crystallized twice from acetone to give white crystals of the title pyrimidinone (94 mg), m.p. 182-183 C., lambdamax (EtOH) 230 nm (epsilon 17,190), 335 nm (epsilon 3,470). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydrogensulfate; In water; acetone; | Example 41 2-thiophenepropanenitrile STR50 The product of Example 40 (31.1 g, 0.11 mol) was dissolved in a mixture of 540 ml of acetone and 60 ml of water. To this solution was added 19.0 g (0.3 mol) of potossium cyanide. After refluxing this mixture for 48 h under N2, it was cooled to room temperature and all solvent was removed under reduced pressure. The residue was diluted with 600 ml of H2 O and extracted 3*200 ml of Et2 O. The combined Et2 O extracts were washed with 150 ml of 0.5N KHSO4 and 150 ml of brine before drying over Na2 SO4. After the solvent was removed under reduced pressure the crude product was purified on a Waters Prep 500 chromotograph with a Porasil cartridge eluding with 100% toluene (yield=11.8 g). Analysis Calcd. for C7 H7 NS (MW=137.20): C, 61.28; H, 5.14; N, 10.20; S, 23.37. Found: C, 61.60; H, 5.08, N, 10.03; S, 22.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydrogensulfate; In pyridine; | Example 40 2-thiopheneethanol, 4-methylbenzenesulfonate STR49 2-thienylethonol (15.0 g 0.12 mol) dissolved in 75 ml of pyridine was cooled to 0 C. before 22.3 g (0.12 mol) of p-toluenesulfonylchloride were added to the stirred solution under N2. After stirring this reaction for 2 h at 0 C., it was poured onto ice (~200 g) and this mixture was stirred until all the ice had melted. This two phase mixture was extracted 3*200 ml of Et2 O and these ether extracts were washed 2*125 ml of H2 O, 3*125 ml of 0.5N KHSO4 and 1*200 ml of H2 O, dried over Na2 SO4, and stripped of all solvent under reduced pressure. The resulting pale red liquid product (33.0 g) was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15 parts (46.5%) | With sodium carbonate; In water; N,N-dimethyl-formamide; | EXAMPLE VIII A mixture of 19.6 parts of [2-(2-thienyl)ethyl] 4-methylbenzenesulfonate, 10 parts of 1-(2-chloroethyl)-1,4-dihydro-5H-tetrazol-5-one, 10 parts of sodium carbonate and 90 parts of N,N-dimethylformamide is stirred and heated overnight at 70 C. The reaction mixture is cooled, 100 parts of water are added and the product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and petroleumether (70:30 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 15 parts (46.5%) of 1-(2-chloroethyl)-1,4-dihydro-4-[2-(2-thienyl)ethyl]-5H-tetrazol-5-one as a residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In methanol; | EXAMPLE XXXVIII A mixture of 3.2 parts of N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2-amine, 2.9 parts of [2-(2-thienyl)ethyl] 4-methylbenzenesulfonate, 1 part of sodium carbonate and 135 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanone, yielding 1 part (23.2%) of N-[1-(2-phenylethyl)-4-piperidinyl]-1-[2-(2-thienyl)ethyl]-1H-benzimidazol-2-amine; mp. 118.3 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 parts (53%) | With potassium iodide; sodium carbonate; In methanol; N,N-dimethyl-formamide; | EXAMPLE XXVI A mixture of 2.8 parts of [2-(2-thienyl)ethyl]4-methylbenzenesulfonate, 4.9 parts of 1-[4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 2.1 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide is stirred overnight at 70 C. The reaction mixture is cooled and poured onto water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 2.3 parts (53%) of 1-(4-fluorophenylmethyl)-N-{1-[2-(2-thienyl)ethyl]-4-piperidinyl}-1H-benzimidazol-2-amine; mp. 151.6 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | (+)-o-chlorophenylglycine methyl ester (140 g, 0.70 mol) was sequentially added to a 1 L three-necked flask,(0.70 mol) of alpha-2-thiopheneethanol-p-toluenesulfonate and 420 ml of acetonitrile,118 g (1.4 mol) of sodium hydrogencarbonate was added with stirring,Potassium iodide 5g, stirring heated to 85 C, reaction 27h, Filtration, filter cake washed with acetonitrile to white, combined with acetonitrile, back into the three-necked flask, Stirring at room temperature with concentrated hydrochloric acid adjusted to pH = 1 ~ 4, continue stirring more than 2 hours, Filtration, cake drying 40 C 5h,(1-alpha - (2-thienylethylamino) -2- (2-chlorophenyl) acetate hydrochloride (IX)Weighing 155g, purity> 99%The filtrate was concentrated to dryness under reduced pressure and the acetonitrile solvent was recovered to give a yellow solid. Ethyl acetate (300 ml) was added and the mixture was stirred for 1 h.Filtration, filter cake with the right amount of ethyl acetate wash,Dried to give (+) - alpha- (2-thienylethylamino) -2- (2-chlorophenyl) acetic acid methyl ester hydrochloride (IX), Weighed 70g, purity> 95%, The 70 g of the solid was dissolved by stirring with 0. 8 times by weight of methanol under reflux,After the addition of 3. 6 times by weight of ethyl acetate, the crystals were separated and the temperature was lowered to room temperaturefilter,To obtain a purified product of (+) - alpha- (2-thienylethylamino) -2- (2-chlorophenyl) acetic acid methyl ester hydrochloride (IX)After drying, 65 g of white crystals were obtained,Purity & gt; 99%The purification yield was 92.8%. The filtrate was concentrated to dryness under reduced pressure, and ethyl acetate was recovered, the total yield of the reaction was 91%. | |
66.3% | 1.80 liters of tertiary-butyl acetate and 134.10 kg of dipotassium hydrogen phosphate were to S-(+)-isomer of methyl alpha-amino-(2-chlorophenyl)acetate of Formula II obtained from Example 4 at a temperature of about 30 C. 0.892 kg of 2-(2-thiophene)ethanol tosylate of Formula VII obtained from Example 5 were then added and the reaction mass was subjected to heating to a temperature of about 92.5 C. and maintained for about 24 hours followed by distilling of the solvent at a temperature below 60 C. under a vacuum of about 650 mm Hg. The obtained reaction mass was cooled to a temperature of about 12.5 C. and 2.52 liters of ethyl acetate and 2.52 liters of water were added. The mass was subjected to stirring for about 10 minutes and the solution was allowed to settle for about 15 minutes, followed by separating the aqueous layer from organic layer. The aqueous layer was extracted with ethyl acetate (2×1.8 liters). The organic layer was washed with demineralised water (3×1.12 liters). Organic layer was cooled to a temperature of about 12.5 C., and 280 ml of 36% aqueous hydrochloric acid was slowly added. The reaction mixture was stirred for about 25 minutes. The obtained reaction mass was filtered, and the solid was washed with 560 ml of ethyl acetate and subjected to spin-drying. The wet solid was transferred into a reactor followed by the addition of 2.24 liters of ethyl acetate and the mass was subjected to heating to a temperature of about 77 C. for about 75 minutes. The mass was cooled to 27.5 C. over a period of about 75 minutes, filtered and the solid washed with 560 ml of ethyl acetate. Finally the solid was subjected to spin drying followed by drying at a temperature of about 62.5 C. under vacuum of about 600 mm Hg over a period of 4 hours and cooled to a temperature of about 30 C. to afford 65 kg (yield: 66.3%) of title compound | |
45% | Example (1); Preparation of methvK2-y)-(+)-(2-chIorophenyl)-N-r2-(2-thieno)ethyllgIycinate using free base of methyl (2.y)-(+)-amino-(2-chIorophenvI')acetate; A mixture of methyl(25)-amino-(2-chlorophenyl)acetate freebase (10gm, 0.05mole) and 2-(2-thienyl)-ethyl-4-methylbenzenesulfonate (14 gm, 0.05mole) was refluxed at 78C to 82C in the presence of triethylamine (5.0 volumes) for 8 tolO hrs. After completion of the reaction, ethyl acetate was added to the reaction mass, stirred for 10 to 15 mins. and solid was filtered off. The ethyl acetate solution was distilled completely under vacuum, dissolved the residue in methylenedichloride and washed with water followed by saturated sodium chloride solution, dried and distilled completely to get methyl(2S)-(+)-(2-chlorophenyl)-N-[2-(2-thieno) ethyl] glycinate as free base (6.9 gm). This is treated with a solution of isopropyl alcohol hydrochloride to get methyl(2S)-(+)-(2-chlorophenyl)-N-[2-(2-thieno)ethyl]glycinate hydrochloride salt (7.8 gm) Yield = 45% and HPLC Purity = 98.2% |
EXAMPLE 4; (+)-Methyl alpha-(2-thienyl ethyl amino)-(2-chlorophenyl)acetate hydrochloride: 50 Kg of (+)-2-chlorophenyl glycine methyl ester was dissolved in acetonitrile (250 lit). To this solution, potassium bicarbonate (75 Kg) and 2-thienyl ethyl para toluene sulphonate (100 Kg) was added at 25-30 C. The reaction mass was heated upto 78-80 C. and maintained for 40 hours. The solvent was distilled off under reduced pressure to yield a residue. To this residue, water (75 lit) and ethyl acetate (250 lit) were added and stirred for 1 hour. The organic layer was separated, added hydrochloric acid (30% solution; 25 lit) to the reaction mass till the pH of 1.2-1.5 attained. The reaction mass was centrifuged to obtain (+)-methyl alpha-(2-thienyl ethyl amino)-(2-chlorophenyl)acetate hydrochloride in a crude form. The product was dried and subjected to crystallization in a mixture of toluene-methanol (4:1) ratio to achieve 99.5% enantiomeric purity.Yield: 65 Kg.[alpha]D/20=+110-112 (c=1 in methanol).Enantiomeric purity: 99.5% | ||
240 liters of demineralised water, 240 liters of dichloromethane and 120 kg of the L-(+)-tartaric acid salt of alpha-amino-(2-chlorophenyl)-acetic acid methyl ester of Formula III were charged into a clean and dry reactor followed by stirring at about 30 C. for about 10 minutes. The resultant reaction solution was cooled to about 5 C. followed by adjusting the pH to about 7.46 by the addition of 900 liters of 10% sodium bicarbonate solution at about 5 C. over about 1 hour, 40 minutes. Organic and aqueous layers were separated and the aqueous layer was extracted with 2×60 liters of dichloromethane. Both the organic layers were combined and the organic layer was washed with 3×120 liters of demineralised water followed by separation of organic and aqueous layers. Organic layer was distilled completely at about 30 C. over about 3.5 hours to afford a residue of the free base of Formula II. To the residue, 138.4 liters of toluene, 179.7 kg of dipotassium hydrogen phosphate and 118.2 kg of 2-(2-thiophene)ethanol tosylate of Formula VII were charged into a clean and dry reactor followed by heating to about 92.5 C. and maintained for about 30 hours. The reaction mass was cooled to 30 C. followed by charging 203 liters of toluene and 600 liters of water. The resultant reaction suspension was stirred for about 30 minutes followed by separation of organic and aqueous layers. The aqueous layer was extracted with 72 liters of toluene followed by separation of organic and aqueous layers. Both the organic layers were combined and the total organic layer was washed with 143 liters of water. Organic and aqueous layers were separated and to the organic layer 34.2 liters of 12 N hydrochloric was charged at about 12.5 C. followed by stirring for about 30 minutes. The resultant reaction mixture was heated to about 55 C. followed by stirring for about 15 minutes. Separated solid was filtered and the solid was washed with 69 liters of toluene. The wet reaction material was transferred into a reactor followed by the charging of 420 liters of acetone and 30.4 liters of 12N hydrochloric acid. The resultant reaction suspension was heated to about 58 C. followed by stirring for about 20 minutes. The above reaction solution was cooled to about 11 C. for about 45 minutes. The solid that formed was separated in a centrifuge and the solid was washed with 60 liters of acetone. Finally the solid was subjected to spin drying for about 1.5 hours followed by drying at about 62.5 C. under vacuum for about 7 hours to afford 75 kg (yield: 63.25%) of the title compound. | ||
To methyl (+)-(S)-alpha-amino(2-chlorophenyl)acetate hydrochloride (120 g) in water (200 mL) and toluene (500 mL) was added NaHCO3 and stirred at 25 to 300C and the layers were separated. To the organic layer was added water, stirred and the layers were separated. To the organic layer containing methyl (+)- alpha-amino(2-chlorophenyl)acetate was added (2-thienyl)ethyl-p-toluenesulphonate (180 gm); K2HPO4 (280 gm) and catalyst (10 g) and heated to 85 to 900C for about 15 - 20 hrs. After completion of the reaction; toluene was distilled out completely and the reaction mass was cooled followed by the addition of ethyl acetate and DM water. The reaction mass was stirred and the layers were separated. To organic layer methanol (50 mL) was added followed by 53 gm of 35% Con. HCl. The solid obtained was filtered and washed with ethyl acetate and dried under vacuum to yield methyl-(+)-alpha-(2-thienylethylamino)(2- chlorophenyl)acetate hydrochloride. (Yield: 105 g). | ||
Into a three-necked flask, compound 4 28 g, compound 2 48 g, and potassium carbonate 29 g were added.6.4ml of water, stirred and heated to 100-106 C for 14h,Filtration under cooling, the filtrate was added dropwise with 36% concentrated hydrochloric acid to pH = 1-2, and filtered.The filter cake was dried to give(S)-2-(2-thienylethylamino)(2-chlorophenyl)acetic acid methyl ester hydrochloride;Prepare the molecular formula as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2-methylpropyl acetate; at 110℃; for 10h;Product distribution / selectivity; | Example 1: Preparation of Rotigotine Hydrochloride[0060] Step 1: (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (3.02 g, 14.7 mmol) and 2-(2- thienyl)ethanol toluenesulfonate (8.30 g, 29.4 mmol) were suspended in isobutylacetate (30 mL) under an inert atmosphere. The reaction mixture was heated at 110 0C for 10 hours and then filtered while hot to give 2.62 g (6.96 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate and filtrate. Step 3: (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (1.41 g, 6.87 mmol) and 2-(2- thienyl)ethanol toluenesulfonate (3.88 g, 13.74 mmol) were suspended in isobutylacetate (15 mL) under an inert atmosphere. The reaction mixture was heated at 1100C for 10 hours and then filtered while hot to give 1.09 g (2.88 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate and filtrate. Step 5: (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (0.56 g, 2.75 mmol) and 2-(2- thienyl)ethanol toluensulfonate (1.55 mg, 5.50 mmol) were suspended in isobutylacetate (7 mL) under an inert atmosphere. The reaction mixture was heated at 1100C for 10 hours and then filtered while hot to give 0.41 g (1.10 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate and filtrate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.8 - 43.2% | (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (3.02 g, 14.7 mmol) and 2-(2-thienyl)ethanol toluenesulfonate (8.30 g, 29.4 mmol) were suspended in isobutylacetate (30 mL) under an inert atmosphere. The reaction mixture was heated at 110 0C for 10 hours and then filtered while hot to give 2.62 g (6.96 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin <n="10"/>toluenesulfonate and filtrate. The filtrate was evaporated to dryness, dissolved in a mixture of acetone-isopropanol when 1.91 g (5.30 mmol) of 1,5-naphthalenedisulfonic acid was added, and the resulting mixture was stirred at room temperature. The product was filtered, washed with 2-PrOH (30 mL) and dried under reduced pressure to yield 2.92 g (6.36 mmol, 43.2% yield based on starting 2-aminotetralin) of (S)-6-(propyl(2-thiophen-2- yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen- 1 -ol heminaphthalene- 1 ,5-disulfonate.; (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (1.41 g, 6.87 mmol) and 2-(2-thienyl)ethanol toluenesulfonate (3.88 g, 13.74 mmol) were suspended in isobutylacetate (15 mL) under an inert atmosphere. The reaction mixture was heated at 110 0C for 10 hours and then filtered while hot to give 1.09 g (2.88 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate and filtrate. The filtrate was evaporated to dryness, dissolved in a mixture of acetone-isopropanol when 0.87 g (2.40 mmol) of 1,5-naphthalenedisulfonic was added, and the resulting mixture was stirred at room temperature. The product was filtered, washed with 2-PrOH (15 mL) and dried under reduced pressure to yield 1.26 g (2.74 mmol, 39.9% yield based on starting 2-aminotetralin) of (S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)- 5,6,7,8-tetrahydronaphthalen- 1 -ol heminaphthalene- 1 ,5-disulfonate.; (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (0.56 g, 2.75 mmol) and 2-(2-thienyl)ethanol toluensulfonate (1.55 mg, 5.50 mmol) were suspended in isobutylacetate (7 mL) under an inert atmosphere. The reaction mixture was heated at 110 0C for 10 hours and then filtered while hot to give 0.41 g (1.10 mmol) of (-)-5-hydroxy-N-n-propyl -2-aminotetralin toluenesulfonate and filtrate. The filtrate was evaporated to dryness, dissolved in a mixture <n="11"/>of acetone-isopropanol when 0.35 g (0.96 mmol) of 1,5-naphtalenedisulfonic acid was added and the resulting mixture was stirred at room temperature.. The product was filtered, washed with 2-PrOH (8 mL) and dried under reduced pressure to yield 0.48 g (1.04 mmol, 37.8% yield based on starting 2-aminotetralin) of (S)-6-(propyl(2-thiophen-2- yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-l-ol heminaphthalene-l,5-disulfonate. | |
Example 1: Preparation of (S)-6-(Propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8- tetrahydronaphthalen-l-ol heminaphthalene-l,5-disulfonate[0026] (-)-5-Hydroxy-N-(n-propyl)-2-aminotetralin (3.02 g, 14.7 mmol) and 2-(2- thienyl)ethanol toluenesulfonate (8.30 g, 29.4 mmol) were suspended in isobutylacetate (30 mL) under an inert atmosphere. The reaction mixture was heated at 110 0C for 10 hours and then filtered while hot to give 2.62 g (6.96 mmol) of (-)-5-hydroxy-N-(n-propyl)-2- aminotetralin toluenesulfonate and filtrate. The filtrate was evaporated to dryness, dissolved in a mixture of acetone-isopropanol, and 1.91 g (5.30 mmol) of 1,5-naphthalenedisulfonic acid was added. The resulting mixture was stirred at room temperature. The product was filtered, washed with 2-PrOH (30 mL) and dried under reduced pressure to yield 2.92 g (6.36 mmol) of (S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen- 1 -ol heminaphthalene- 1 ,5-disulfonate. | ||
(-)-5-Hydroxy-N-n-propyl-2-arninotetralin (3.02 g, 14.7 mmol) and 2-(2- thienyl)ethanol toluenesulfonate (8.3O g, 29.4 mmol) were suspended in isobutylacetate (30 mL) under an inert atmosphere. The reaction mixture was heated at 110 0C for 10 hours and then filtered while hot to give 2.62 g (6.96 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate and filtrate. The filtrate was evaporated to dryness, dissolved in a mixture of acetone-isopropanol when 1.91 g (5.30 mmol) of 1,5-naphthalenedisulfonic acid was added, and the resulting mixture was stirred at room temperature. The product was filtered, washed with 2- PrOH (30 mL) and dried under reduced pressure to yield 2.92 g (6.36 mmol, 43.2% yield based on starting 2-aminotetralin) of (S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8- tetrahydronaphthalen- l-ol heminaphthalene- 1 ,5-disulfonate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Example 2 Preparation of (-)-(S)-5-methoxy-2-[N-2-(2-thienyl)ethylamino]tetralin hydrochloride (S)-2-Amino-5-methoxytetraline hydrochloride (100 gm), 2-(2-thienyl)-ethyl para- toluenesulfonate (158.52 gm) and potassium carbonate (142.25 g) were added to acetonitrile (1000 ml) under stirring at 20-250C, and the resulting mixture was heated at 80-85C for 20 to 22 hours. The resulting mass was filtered at 60-65C, washed with acetonitrile (260 ml) and the resulting filtrate was distilled under vacuum at 50-55C to remove acetonitrile. Water (400 ml) was added to the resulting residue, followed by the addition of ethyl acetate (400 ml) and then stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, and the total organic layer was washed with water (200 ml). Concentrated hydrochloric acid (40 ml) was added to the resulting organic layer and then heated to 80-850C for 15 to 20 min. The resulting mass was cooled to 0-50C and then stirred for 2 hours at the same temperature. The resulting solid was filtered, washed with pre-cooled ethyl acetate (150 ml) and then dried the material at 50-550C for 3-4 hours to give 107 gm of (-)-(S)-5-methoxy-2-[N-2-(2- thienyl)ethylamino]tetralin hydrochloride [Yield 70%; Purity by HPLC: 99.96%; SOR= - 55.7 (C=I, methanol)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With ferric nitrate; In 1,2-dichloro-ethane;Reflux; | 12.8 g (0.1 mol) of 2-thiopheneethanol,20.0 g (0.12 mol) of p-toluenesulfonic acid,20.2 g (0.05 mol) of ferric nitrate,100 ml of 1,2-dichloroethane into the reaction flask,Reflux reaction to 2 - thiophene ethanol consumption is completed,filter,The filtrate was washed three times with water,concentrate,The solvent was distilled off under reduced pressure,2-thiophene ethyl p-toluenesulfonate 22g,Yield 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.8 kg | With sodium sulfite; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Reflux; | Example 122.00 kg (9.74 mol) of (S)-5,6,7,8-tetrahydro-6-propylamino-l-naphthol, 4.12 kg (14.62 mol) of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate (with a sulfonate/starting material mole ratio of 1.5/1), 1.60 kg (12.67 mol) of sodium sulfite (with a sodium sulfite/starting material mole ratio of 1.3/1 , ) and 25 L of xylene were mixed to form a mixture, and the mixture was refluxed. After 48 hours, the reaction was stopped. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain 2.80 kg of a product (S)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl) ethyl] amino] -1-naphthol, which was converted into a hydrochlorate thereof. The yield was 81.7% |
3.06 kg | With sodium sulfite; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Reflux; Industrial scale; | 2.00 kg (11.28 mol) of (S)-5,6,7,8-tetrahydro-6-methylamino-1-naphthol, 4.78 kg (16.94 mol) of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate (with a sulfonate/starting material mole ratio of 1.5/1), 1.85 kg (14.68 mol) of sodium sulfite (with a sodium sulfite/starting material mole ratio of 1.3/1) and 25 L of xylene were mixed to form a mixture, and the mixture was refluxed. After 48 hours, the reaction was stopped. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain 3.06 kg of a product (S)-5,6,7,8-tetrahydro-6-[methyl[2-(2-thienyl)ethyl]amino]-1-naphthol, which was converted into a hydrochlorate thereof. The yield was 83.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | 10.2.2. Conversion of (S)-1 ,2,3,4-tetrahydro-5-hvdroxy-N-propyl-naphthalen-2- ammonium hydrobromide (VIII) into hydrochloride salt of rotigotine; (S)-1 ,2,3,4-tetrahydro-5-hydroxy-N-propyl-naphthalen-2-ammonium hydrobromide I (VIII) (44.5 g), sodium carbonate (24.0 g), o-xylene (390 g) and purified water (320 g)_are heated to 70-80 C and stirred until all the solids have dissolved. The pH of the aqueous phase is adjusted to 9.5-10.5 with phosphoric acid (25 %). The phases are separated and the organic phase is washed with water (105 g). The organic phase is partially distilled and added to sodium carbonate (20 g). To the organic phase is added 2-(2-Thienyl)ethyl-4- toluene sulfonate (64 g) obtained in 10.2.1., sodium carbonate (0.2 g) and o-xylene (130 g) and heated to reflux. When reaction was complete by HPLC, the batch was cooled and water added (290 mL) At 75-85C the pH of the aqueous phase was adjusted to 9.5-10.5 with phosphoric acid (25 %).The organic layer is then washed with water (290 mL). The organic layer was extracted with a premixed solution of water (220 mL) and phosphoric acid (25%, 91 g) and then twice with water (54 mL) and phosphoric acid (25%, 18 g) at 70-90C. The aqueous phase is passed through charcoal and celite and then toluene (270 g) and NaOH (50%, 30 g) are added. At 75-85C, the pH of the aqueous phase was adjusted to 5.5-6.5 and the phases separated. The organic phase was washed with water and then partially distilled. At 45-55C 2-propanol (72 g) and rotigotine hydrochloride seeds are added. Hydrochloric acid (37%, 14 g) was slowly added. After crystallization, the batch was cooled to 15-25C, filtered and washed with a premixed solution of toluene (60 g) and 2-propanol (20 g). The product is then dried under vacuum to a constant weight of 44.8 g.Yield is 82 % .HPLC analyses confirmed purity greater than and 100.8 % assay in comparison to a reference standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 20 - 85℃; | Example 2 Preparation of (-)-(S)-5-methoxy-2-[N-2-(2-thienyl)ethylamino]tetralin hydrochloride(S)-2-Amino-5-methoxytetraline hydrochloride (100 gm), 2-(2-thienyl)-ethyl para-toluenesulfonate (158.52 gm) and potassium carbonate (142.25 g) were added to acetonitrile (1000 ml) under stirring at 20-25 C., and the resulting mixture was heated at 80-85 C. for 20 to 22 hours. The resulting mass was filtered at 60-65 C., washed with acetonitrile (260 ml) and the resulting filtrate was distilled under vacuum at 50-55 C. to remove acetonitrile. Water (400 ml) was added to the resulting residue, followed by the addition of ethyl acetate (400 ml) and then stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, and the total organic layer was washed with water (200 ml). Concentrated hydrochloric acid (40 ml) was added to the resulting organic layer and then heated to 80-85 C. for 15 to 20 min. The resulting mass was cooled to 0-5 C. and then stirred for 2 hours at the same temperature. The resulting solid was filtered, washed with pre-cooled ethyl acetate (150 ml) and then dried the material at 50-55 C. for 3-4 hours to give 107 gm of (-)-(S)-5-methoxy-2-[N-2-(2-thienyl)ethylamino]tetralin hydrochloride [Yield 70%; Purity by HPLC: 99.96%; SOR=-55.7 (C=1, methanol)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.06 kg | With sodium sulfite; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Reflux; | Example 32.00 kg (11.28 mol) of (S)-5,6,7,8-tetrahydro-6-methylamino-l-naphthol, 4.78 kg (16.94 mol) of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate (with a sulfonate/starting material mole ratio of 1.5/1), 1.85 kg (14.68 mol) of sodium sulfite (with a sodium sulfite/starting material mole ratio of 1.3/1) and 25 L of xylene were mixed to form a mixture, and the mixture was refluxed. After 48 hours, the reaction was stopped. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain 3.06 kg of a product (S)-5,6,7,8-tetrahydro-6-[methyl [2-(2-thienyl)ethyl]amino]-l-naphthol, which was converted into a hydrochlorate thereof. The yield was 83.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.92 kg | With potassium sulfite; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Reflux; | Example 42.00 kg (10.46 mol) of (S)-5,6,7,8-tetrahydro-6-ethylamino-l-naphthol, 4.91 kg (15.70 mol) of 2-(2-thienyl)ethyl 4-nitrobenzenesulfonate (with a sulfonate/starting material mole ratio of 1.5/1), 2.15 kg (13.60 mol) of potassium sulfite (with a sodium sulfite/starting material mole ratio of 1.3/1) and 25 L of xylene were mixed to form a mixture, and the mixture was refluxed. After 48 hours, the reaction was stopped. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain 2.92 kg of a product (S)-5,6,7,8-tetrahydro-6-[ethyl[2-(2-thienyl) ethyl]amino]-l-naphthol, which was converted into a hydrochlorate thereof. The yield was 82.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.6 kg | With ammonium sulfite; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Reflux; | Example 52.00 kg (9.12 mol) of (S)-5,6,7,8-tetrahydro-4-methyl-6-propylamino-1-naphthol, 3.86 kg (13.70 mol) of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate (with a sulfonate/starting materialratio of 1.5/1), 1.38 kg (11.87 mol) of ammonium sulfite (with a sodium sulfite/starting material mole ratio of 1.3/1) and 25 L of xylene were mixed to form a mixture, and the mixturerefluxed. After 48 hours, the reaction was stopped. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain 2.60 kg of a product (S)-5,6,7,8-tetrahydro-4-methyl-6-[propyl[2-(2-thienyl)ethyl]amino]- 1 -naphthol, which was converted into a hydrochlorate thereof. The yield was 77.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.7 kg | With sodium sulfite; In 5,5-dimethyl-1,3-cyclohexadiene; for 60h;Reflux; | Example 142.00 kg (9.74 mol) of (+/-)-5,6,7,8-tetrahydro-6-propylamino- 1-naphthol, 4.12 kg (14.62 mol) of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate (with a sulfonate/starting material mole ratio of 1.5/1), 1.60 kg (12.67 mol) of sodium sulfite (with a sodium sulfite/starting material mole ratio of 1.3/1) and 25 L of xylene were mixed to form a mixture, and the mixture was refluxed. After 60 hours, the reaction was stopped. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain 2.70 kg of a product (+/-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl] amino]- 1-naphthol, which was converted into a hydrochlorate thereof. The yield was 78.8%. |
2.7 kg | With sodium sulfite; In 5,5-dimethyl-1,3-cyclohexadiene; for 60h;Reflux; Industrial scale; | 2.00 kg (9.74 mol) of (±)-5,6,7,8-tetrahydro-6-propylamino-1-naphthol, 4.12 kg (14.62 mol) of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate (with a sulfonate/starting material mole ratio of 1.5/1), 1.60 kg (12.67 mol) of sodium sulfite (with a sodium sulfite/starting material mole ratio of 1.3/1) and 25 L of xylene were mixed to form a mixture, and the mixture was refluxed. After 60 hours, the reaction was stopped. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain 2.70 kg of a product (±)-5,6,7,8-tetrahydro-64propyl[2-(2-thienyl)ethyl]amino]-1-naphthol, which was converted into a hydrochlorate thereof. The yield was 78.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.7 g | With sodium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Reflux; | 5.0 g of 5,6,7,8-tetrahydro-6-amino-1-naphthol, 3.0 g of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate, 4.8 g of sodium carbonate and 100 ml of xylene were mixed to form a mixture, and the mixture was refluxed for 48 h. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to obtain 1.7 g of 5,6,7,8-tetrahydro-6-[N,N-bis[(2-thienyl)ethyl]]amino-1-naphthol. Attributions of nuclear magnetic resonance (NMR) spectra of 5,6,7,8-tetrahydro-6-[N,N-bis[(2-thienyl)ethyl]]amino-1-naphthol were shown in Table 1. A high resolution mass spectrum of 5,6,7,8-tetrahydro-6-[N,N-bis[(2-thienyl)ethyl]]amino-1-naphthol was shown in Fig. 1. |
1.7 g | With sodium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Reflux; | 5.0 g of 5,6,7,8-tetrahydro-6-amino-1-naphthol, 3.0 g of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate, 4.8 g of sodium carbonate and 100 ml of xylene were mixed to form a mixture, and the mixture was refluxed for 48 h. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to obtain 1.7 g of 5,6,7,8-tetra-hydro-6-[N,N-bis[(2-thienyl)ethyl]]amino-1-naphthol. Attributions of nuclear magnetic resonance (NMR) spectra of 5,6,7,8-tetrahydro-6[N,N-bis[(2-thienyl)ethyl]]amino-1-naphthol were shown in Table 1. A high resolution mass spectrum of 5,6,7,8-tetrahydro-6-[N,N-bis[(2-thienyl)ethyl]]amino-1-naphthol was shown in . |
1.7 g | With sodium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Reflux; | Take 5,6,7,8-tetrahydro-6-amino-1-naphthol 5.0g,3.0 g of 2- (2-thienyl) ethyl p-toluenesulfonate,4.8 g of sodium carbonate and 100 ml of xylene were mixed and refluxed,Reflux 48h. Cooled to room temperature, washed with an appropriate amount of water,Add activated carbon for bleaching treatment, suction filtration, standing, retaining the organic phase,Concentration under reduced pressure, purification by column chromatography,get5,6,7,8-Tetrahydro-6- [N, N-Bis [(2-thienyl) ethyl]] amino-1-naphthol1.7g,Attributed to the nuclear magnetic resonance spectra shown in Table 1, high-resolution spectrum shown in Figure 1. |
1.7 g | With sodium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene; for 48h;Reflux; | Take 5,6,7,8-tetrahydro-6-amino-1-naphthol 5.0 g, `p-Toluenesulfonic acid2- (2-thienyl) ethyl ester 3.0 g,4.8 g of sodium carbonate and 100 ml of xylene were mixed and refluxed.Reflux 48 h.Drop to room temperature,With moderate amount of water,Add activated carbon for bleaching treatment,Suction filtration,Standing,Keep the organic phase,Concentrated under reduced pressure,Column chromatography purification,5,6,7,8-Tetrahydro-6- [N, N-bis [(2-thienyl) ethyl]] amino-1-naphthol was obtained1.7 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.7 g | With sodium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; | 5.0 g of (S)-5,6,7,8-tetrahydro-6-amino-l-naphthol, 3.0 g of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate, 4.8 g of sodium carbonate and 100 ml of xylene were mixed to form a mixture, and the mixture was refluxed for 48 h to 50 h. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to obtain 1.7 g of (S)-5,6,7,8-tetrahydro-6-[N,N-bis[(2-thienyl)ethyl]]amino-l-naphthol. Attributions of nuclear magnetic resonance (NMR) spectra of (S)-5,6,7,8-tetrahydro-6-[N,N-bis[(2-thienyl)ethyl]]amino-l-naphthol were shown in Table 2. |
1.7g | With sodium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; | 5.0 g of (S)-5,6,7,8-tetrahydro-6-amino-1-naphthol, 3.0 g of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate, 4.8 g of sodium carbonate and 100 ml of xylene were mixed to form a mixture, and the mixture was refluxed for 48 h to 50 h. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to obtain 1.7 g of (S)-5,6,7,8-tetrahydro-6-[N,N-bis[(2-thienyl)ethyl]]amino-1-naphthol. Attributions of nuclear magnetic resonance (NMR) spectra of (S)-5,6,7,8-tetrahydro-6-[N,N-bis[(2-thienyl)ethyl]]amino-1-naphthol were shown in Table 2. |
1.7 g | With sodium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; | (S) -5,6,7,8-Tetrahydro-6-amino-1-naphthol 5.0 g,3.0 g of 2- (2-thienyl) ethyl p-toluenesulfonate,4.8 g of sodium carbonate and 100 ml of xylene were mixed and refluxed,Reflux reaction 48 ~ 50h. Cooled to room temperature, washed with an appropriate amount of water,Add activated carbon bleaching treatment, suction filtration, standing,The organic phase was retained, concentrated under reduced pressure, purified by column chromatography,(S) -5,6,7,8-Tetrahydro-6- [N, N-Bis [(2-thienyl) ethyl]] amino-1-naphthol1.7g,Nuclear magnetic resonance spectra are shown in Table 2. |
1.7 g | With sodium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; | 5.0 g of (S) -5,6,7,8-tetrahydro-6-amino-1-naphthol and 3.0 g of 2- (2-thienyl) ethyl p-4.8 g of sodium carbonate and 100 ml of xylene were mixed and refluxed.Reflux reaction 48 ~ 50 h. Drop to room temperature,With moderate amount of water,Add activated carbon for bleaching treatment,Suction filtration, standing,Keep the organic phase,Concentrated under reduced pressure,Column chromatography purification,1.7 g of (S) -5,6,7,8-tetrahydro-6- [N, N-bis [(2- thiophene) ethyl] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(S)-1,2,3,4-tetrahydro-5-hydroxy-N-propyl-naphthalen-2-ammonium hydrobromide (VIII) (44.5 g), sodium carbonate (24.0 g), o-xylene (390 g) and purified water (320 g) are heated to 70-80 C. and stirred until all the solids have dissolved. The pH of the aqueous phase is adjusted to 9.5-10.5 with phosphoric acid (25%). The phases are separated and the organic phase is washed with water (105 g). The organic phase is partially distilled and added to sodium carbonate (20 g). To the organic phase is added 2-(2-Thienyl)ethyl-4-toluene sulfonate (64 g) obtained in 10.2.1., sodium carbonate (0.2 g) and o-xylene (130 g) and heated to reflux. When reaction was complete by HPLC, the batch was cooled and water added (290 mL) At 75-85 C. the pH of the aqueous phase was adjusted to 9.5-10.5 with phosphoric acid (25%). [0258] The organic layer is then washed with water (290 mL). The organic layer was extracted with a premixed solution of water (220 mL) and phosphoric acid (25%, 91 g) and then twice with water (54 mL) and phosphoric acid (25%, 18 g) at 70-90 C. The aqueous phase is passed through charcoal and celite and then toluene (270 g) and NaOH (50%, 30 g) are added. At 75-85 C., the pH of the aqueous phase was adjusted to 5.5-6.5 and the phases separated. The organic phase was washed with water and then partially distilled. At 45-55 C. 2-propanol (72 g) and rotigotine hydrochloride seeds are added. Hydrochloric acid (37%, 14 g) was slowly added. After crystallization, the batch was cooled to 15-25 C., filtered and washed with a premixed solution of toluene (60 g) and 2-propanol (20 g). The product is then dried under vacuum to a constant weight of 44.8 g. [0259] Yield is 82% [0260] HPLC analyses confirmed purity greater than and 100.8% assay in comparison to a reference standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.3 g | To methyl (+)-(S)-a-amino (2-chlorophenyl) acetate tartrate (100.0 gm.) in water (200 mL) and toluene (300mL) was added aqueous ammonia and stirred at 0 to 5C and the layers were separated. The separated organic layer was washed with water. The separated organic layer containing methyl (+)-a-amino (2-chlorophenyl) acetate was added (2-thienyl) ethyl-p-toluenesulphonic acid (129.2 gm.), K2HP04(99.5 gm.) and triethylbenzylammonium chloride (TEBAC) (4.0 gm.) then heated to 110 to 115C for about 15-20 hrs. Then reaction mass was cooled to 25-30C followed by the addition of water. The reaction mass was stirred and the layers were separated. To the organic layer methanol (25.0 mL) was added followed by 35% cone. HCI (28.0ml_). The solid obtained was filtered and washed with Toluene and dried under vacuum to yield S(+)-methyl-2-[2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride. (Yield: 69.3 gm.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96 g | A 1,000 ml reaction flask was charged with the toluene solution of the previous reaction,Then, 114 g of o-chlorobenzylamine was added,The temperature of the reaction was raised to 85C for 3 hours,After completion of the reaction, the mixture was cooled to 20 C and stirred for 3 hours.Filtered, and the filtrate was added with 200 ml of water,Dropping hydrochloric acid under stirring to adjust the pH value to 8.5,Layered,The upper layer of toluene was further added dropwise with hydrochloric acid to adjust the pH to 5,The system was then cooled to 2 C and stirred for 4 hours.The filter cake was dried in vacuo at 50 C to give 96 g of condensate hydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96 g | A 1,000 ml reaction flask was charged with the toluene solution of the previous reaction, then, 114 g of o-chlorobenzylamine wasadded, and heated to 85C for 3 hours. After the reaction, the mixture was cooled to 20C and stirred for 1 hour, filtered, and the filtrate was added with 200 ml of water. Hydrochloric acid was dropped under stirring to adjust the pH value to 8. 5, stratification, hydrochloric acid was further added to the upper layer of toluene to adjust the pH to 5, and then the system was cooled to 2 C and stirred for 4 hours. The filter cake was dried in vacuo at 50 C to give 96 g of the condensate hydrochloride. | |
96 g | A 1,000 ml reaction flask was charged with the toluene solution of the previous reaction,Then add 114g of o-chlorobenzylamine, heating to 85 C for 3 hours, after cooling down to 20 C stirring 1 hour, filtration, the filtrate by adding 200ml of water, stirring, dropping hydrochloric acid to adjust the pH value to 8.5. , The upper layer of toluene layer to hydrochloric acid to adjust the pH to 5, and then cooled to 2 C stirring crystallization crystallization 4 hours, filter cake vacuum drying at 50 C after 96g condensate hydrochloride. | |
96 g | A 1000 ml reaction flask was charged with the toluene solution of the previous reaction, then, 114 g of o-chlorobenzylamine was added, the temperature of the reaction was raised to 85 deg. C for 3 hours, after completion of the reaction, the mixture was cooled to 20 C and stirred for 1 hour, filtered, to the filtrate was added 200 ml of water, dropping hydrochloric acid under stirring to adjust the pH value to 8.5, layered, the upper layer of toluene was further added dropwise with hydrochloric acid to adjust the pH to 5, the system was then cooled to 2 C and stirred for 4 hours, filtered, and the filter cake was dried in vacuo at 50 C to give 96 g of condensate hydrochloride. |
96 g | Example 1The preparation method of ticlopidine hydrochloride as shown in Fig. 2 comprises the following steps:1. p-toluenesulfonyl protection:In a 1000 ml reaction flask, 500 ml of toluene, 50 g of thiophene ethanol and 80 g of p-toluenesulfonyl chloride were charged and stirred to controlAt a temperature of 0 C, 47 g of triethylamine was added dropwise, dropping for about 30 min, and the temperature was raised to 25 C for 3 hours.Add 400ml of water, washed twice, washed with toluene layer directly to the next step reaction.2. Condensation reactionThe reaction solution of toluene in the previous step was added to a 1000 ml reaction flask, followed by the addition of 114 g of o-chlorobenzylamine and heating to 90 C for 3 hours. After the reaction, the mixture was cooled to 25 C and stirred for 1 hour. The filtrate was added with 200 ml of water, and hydrochloric acidAdjust the pH of the system to 8.5, stratify the upper layer of toluene and continue dropping hydrochloric acid to adjust the pH to 5, then cool the system to 2 CThe crystals were mixed for 4 hours and filtered, and the filter cake was dried in vacuo at 50 C to give 96 g of the condensate hydrochloride.3 ? Closed loop reactionTo the 1000 ml reaction flask was added 96 g of the condensate hydrochloride, 400 ml of 1,3-dioxane and 5 ml of hydrochloric acid,To 90 C for 6 hours. After the reaction, the mixture was cooled to 7 C and stirred for 3 hours. The filter cake was washed with a small amount of 1,3-dioxetaneAfter 50 C vacuum drying, 95 g of ticlopidine hydrochloride was obtained4 ? RefinedIn a 1000 ml reaction flask, 95 g of crude ticlopidine hydrochloride and 500 ml of absolute ethanol were added and heated to 72 C with stirring,About 10 minutes after the solid is completely dissolved by adding 2g activated carbon, insulation bleaching 20 minutes after the hot filter, the filtrate gradually coolingThe crystals were crystallized at 4 C for 4 hours and filtered. The filter cake was washed with a small amount of absolute ethanol and dried in vacuo at 50 C to give 91 g of tithiol hydrochloridePrecision products. Total yield 82%, purity 99.9% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.3% | The 200mL dioxane, 1.45g (1.25mmol) of tetrakis (triphenylphosphine) palladium, 10.6g (75mmol) tripotassium phosphate, 14.1g (50mmol) of p-toluenesulfonic acid 2- (2-thienyl) ethyl ester, 14.3g (55mmol) of tris (2-thienyl) borane the reaction flask was added, under nitrogen to a reaction at 85 toluenesulfonic acid 2- (2-thienyl) ethyl conversion complete (by TLC test method), cooled to room temperature, was added 400mL of cyclohexane was added with stirring 25mL3.0mol / L sodium hydroxide solution, 25mL30% hydrogen peroxide, the reaction 1h, extracted with cyclohexane, washed with brine, dried, reduced pressure distillation 8.0g1,2- bis (2-thienyl) ethane, a yield of 82.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.5% | With formic acid; at 80℃; for 8.5h;Inert atmosphere; | 5.64 g (0.02 mol)Thiophene ethyl p-toluenesulfonate, 30 ml of formamide, 4.20 g (0.08 mol)Formic acid (88%) into the reaction flask,Heated to 80 C under nitrogen for 8.5 hours, cooled,The reaction mixture was added with 60 ml of water and extracted with methylene chloride (30 ml × 3). The organic phases were combined,Washed successively with 50 ml of saturated sodium bicarbonate, 50 ml of saturated brine,Anhydrous sodium sulfate, filtered,Concentrated under reduced pressure to give a light yellow liquid N-2-thienyl ethylformamide, yield 83.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In acetonitrile;Reflux; | Methyl alpha- (2-chlorophenylglycine) -chlorophenylacetate (20.0 g, 0.054 mol), 2- (2-thienyl) ethanol p-toluenesulfonate (30.8 g, 0.108 mol), 200 mL acetonitrile, triethylamine (16.2 g, 0.162 mol) Join 500mL reaction flask, The reaction was stirred under reflux overnight. TLC (TLC conditions: ethyl acetate: petroleum ether = 1: 2V / V) tracking reaction was completed, Filter out insolubles, The solvent was distilled off under reduced pressure, And silica gel column chromatography (ethyl acetate: petroleum ether = 1: 5 V / V) was isolated as an oily product, That is, 24.5 g of N-thiophene ethyl (2-chlorophenylglycinate) -p-chlorophenyl phenylacetate, Yield 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In acetonitrile; at 70℃; | A mixture of benzhydrylamine (0.50 mol), CH3CN (838 mL), <strong>[40412-06-4]2-(2-thienyl)ethyl toluene-p-sulfonate</strong> 6a (0.50 mol) and Na2CO3 (0.91 mol) was heatedto 70 C. After completion of the reaction, the reaction mixture was cooled,filtered and evaporated in vacuo. The residue was dissolved in benzene(1.03 L) and stirred at room temperature for 10 min, under a stream of N2,and then portions of DDQ (1.09 mol) were added over 10 min with stirring.The reaction mixture was heated under reflux for 5 h, evaporated in vacuoand treated with H2SO4 (1.40 M, 885 mL) at room temperature. Aftercompletion of the hydrolysis, the aqueous phase was extracted with CH2Cl2,followed by separation of organic and aqueous layers. The aqueous phasewas adjusted to a basic pH by sodium hydroxide solution (40%), extractedwith CH2Cl2 and then the organic phase was distilled under reducedpressure to yield the expected product 9a. 2-Thiophenylethylamine (9a): Colourless liquid; yield 91%; FTIR (KBr)(nmax cm-1): 3369, 3285 (N-H); 1H NMR (400 MHz, CDCl3): delta 7.11 (m,1H), 6.94-6.90 (m, 1H), 6.81 (s, 1H), 2.94 (m, 4H), 1.24 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
181.5 g | To the reaction flask, 216.5 g of the solid was added, and 2000 g of water was added thereto, and 156 g of sodium hydrogencarbonate was slowly added thereto, and the mixture was stirred until no bubbles were formed. Then, 1000 g of chloroform was added, stirred, and the mixture was allowed to stand, and the aqueous layer was extracted once with 300 g of chloroform. The combined chloroform layer was dried over 40 g of magnesium sulfate, filtered and evaporated to drynessTartaric acid recovery: adjust the water layer of this step with hydrochloric acid to adjust pH = 3-4, adjust the addition of 79.4g of calcium chloride, stir, cool to 0-10 C, extract the calcium tartrate by suction, and extract the calcium tartrate and 700g chloroform by suction filtration. Put into the reaction bottle, add 138.4g of sulfuric acid by stirring, add the drop, cool down 5-15 C, filter the filter cake as waste salt, distill the filtrate until the system is thick, cool down to 0-5 C, filter, dry the filter cake 185 g of L-(+) tartaric acid was recovered, and the recovery rate was 90.6%.Into another reaction flask, 134 g of oil which was evaporated to dryness in chloroform, 540 g of ethyl acetate, 235.1 g of 2-thiopheneethanol p-toluenesulfonate, and 190 g of sodium hydrogencarbonate were heated to reflux, and the reaction was refluxed for 55 hours.After the end of the heat preservation, the temperature was lowered to room temperature, washed with water 480 g, left to stand, layered, and the organic layer was washed with 270 g of water. The organic layer was dried with 40 g of magnesium sulfate, filtered, and 163 g of hydrochloric acid was added dropwise with filtration, and the mixture was cooled to 0-5 C, filtered. The crude product was obtained. The crude product, 109 g of methanol and 434 g of ethyl acetate were put into a reaction flask, and the mixture was heated to reflux for 1 hour, cooled to 0-5 C, filtered, and dried to obtain a product: 181.5 g, yield: 85.1%, purity 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl (S)-(+)-2-amino-2-(2-chlorophenyl)acetate With dipotassium hydrogenphosphate In acetonitrile at 20℃; for 1h; Stage #2: 2-(2-thienyl)ethyl tosylate In acetonitrile at 48℃; | 1-2 Add 600ml acetonitrile and 140g dipotassium hydrogen phosphate into a three-necked flask,Mix with (+) o-chlorophenylglycine methyl ester obtained in the previous step, and stir at 20°C for 1 hour. Then add 170g of 2-(2-thienyl)ethanol p-toluenesulfonate, and then increase the temperature to 48°C to keep the reaction temperature. After the reaction, centrifuge, collect the mother liquor into the reaction vessel, add appropriate amount of hydrochloric acid to pH 4 while stirring, stir for 4 hours, centrifuge, and dry the obtained solid at 50°C to obtain (+) α-(2-thiopheneethylamino) )-α-(2-Chlorophenyl)acetate methyl ester hydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / acetonitrile / 48 h / 60 - 70 °C 1.2: 2 h / -5 °C 2.1: formaldehyd; sulfuric acid; N,N-Dimethylformamide Hydrochloride / acetone; water |
Tags: 40412-06-4 synthesis path| 40412-06-4 SDS| 40412-06-4 COA| 40412-06-4 purity| 40412-06-4 application| 40412-06-4 NMR| 40412-06-4 COA| 40412-06-4 structure
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