Structure of Cyanoacetamide
CAS No.: 107-91-5
*Storage: {[sel_prStorage]}
*Shipping: {[sel_prShipping]}
The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
*For Research Use Only !
Change View
Size | Price | VIP Price | US Stock |
Global Stock |
In Stock | ||
{[ item.pr_size ]} |
Inquiry
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.discount_usd) ]} {[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]} |
Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]} | Inquiry {[ item.pr_usastock ]} In Stock Inquiry - | {[ item.pr_chinastock ]} {[ item.pr_remark ]} In Stock 1-2 weeks - Inquiry - | Login | - + | Inquiry |
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days
1-2weeks
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price, item.pr_usd) ]}
Inquiry
{[ getRatePrice(item.pr_usd,item.pr_rate,1,item.pr_is_large_size_no_price, item.vip_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price, item.pr_usd) ]}
In Stock
- +
Please Login or Create an Account to: See VIP prices and availability
US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
CAS No. : | 107-91-5 |
Formula : | C3H4N2O |
M.W : | 84.08 |
SMILES Code : | C(C#N)C(N)=O |
MDL No. : | MFCD00008024 |
InChI Key : | DGJMPUGMZIKDRO-UHFFFAOYSA-N |
Pubchem ID : | 7898 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 6 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 19.19 |
TPSA ? Topological Polar Surface Area: Calculated from |
66.88 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.34 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.97 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.61 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.36 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.74 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.67 |
Log S (ESOL):? ESOL: Topological method implemented from |
0.32 |
Solubility | 174.0 mg/ml ; 2.07 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.05 |
Solubility | 94.5 mg/ml ; 1.12 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
0.15 |
Solubility | 119.0 mg/ml ; 1.41 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.5 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.22 |
* 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 |
---|---|---|
70% | With piperidine; pyridine; acetic acid; In water; at 20℃; for 20h;Reflux; | To a solution of 480mL of water (E / Z) -2- methyl-3-oxo-1-ene-1-ol Sodium (77.6g, 0.64mol) was added cyanoacetamide (49.0g, 0.70mol). To this mixture was added a solution of piperidine-acetic acid(From acetic acid (9.16g, 8.75mL, 0.15mol),21.2mL of water and pyridine (13.0g, 15.1mL, 0.15mol) was obtained), and the mixture was heated at reflux through 4h, then stirred at room temperature for 16h. Acetic acid (75.5g, 72mL, 1.26mol) was added to the reaction mixture, the precipitated pale yellow solid. The latter was filtered off with suction, washed with water and dried under reduced pressure at 2h at 55 . To give 66.4 g of (70% of theory) of a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Preparation of 2-cyano-3,3-bis(methylthio)acrylamide 1-2 A mixture of 2-cyanoacetamide (10 g, 118.9 mmol) and potassium hydroxide (6.661 g, 118.9) in ACN (100 mL) was stirred at room temperature for 1 hr followed by slow addition of carbon disulfide (9.054 g, 118.9 mmol) at room temperature. After the solution was stirred for 3 hrs at room temperature, dimethylsulfate (19.5 g, 154.6 mmol) was added and the reaction mixture was stirred overnight at room temperature. The volatiles were then removed under vacuum, and the residual was redissolved in EtOAc and washed sequentially with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting solid was triturated with EtOAc/hexanes, filtered, and dried to give compound I-2 (9.4 g, 42% yield, 99.0% purity) as a yellow solid. | |
With potassium hydroxide; In N,N-dimethyl-formamide; at 0 - 5℃; for 2h; | General procedure: 2-cyano-N-(substituted phenyl)acetamide (0.00523 mol) was addedto the solution of potassium hydroxide (0.01046 mol) containing 5 mLof water at cooled temperature of 0-5 C with continuous stirring. Tothat carbon disulphide (0.00523 mol) was added drop wise followed by15 mL of dimethyl formamide (DMF). Further dimethylsulphate(0.01046 mol) was added drop wise followed by 2 h of stirring. Aftercompletion of stirring pour the reaction into ice-cold mixture to obtainthe solid. The solid was filtered, washed with water and recrystallizedfrom methanol to obtain colorless crystalline product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperazine; In ethanol; at 20 - 65℃; for 15.5h; | Reference Example 15 3-Cyano-6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid ethyl ester While stirring at room temperature, 19.2 g of 2-cyanoacetamide was added to 300 ml of ethanol solution containing 41.9 g of <strong>[21080-80-8]2,4-dioxocyclopropanebutyric acid ethyl ester</strong>.. After completely dissolving the reagent by warming up to 65° C., 7.4 ml of piperazine was added dropwise to the solution.. One hour thereafter, this was cooled to room temperature and stirred for additional 15 hours and 30 minutes.. The thus precipitated crystals were collected by filtration and then washed with diethyl ether to obtain 24.1 g of the title compound.. This compound was used in the subsequent reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.9% | Water (546 mL) was added to 2-methyl-3-oxobutanal sodium salt (1-013-01) (34.73 g), and to the reaction mixture was added 2-cyanoacetamide (23.91 g) and 1.76 mol/L piperidinium acetate (119.4 mL), and the reaction mixture was stirred under reflux in an oil bath at 127 C. After 21 h, to the reaction mixture was added gradually dropwise acetic acid (42.7 mL) at 65 C as internal temperature for 15 min. After the stirring was continued until internal temperature became to 24 C, the resulting crystal was filtered, and washed with water to give 3-cyano-5,6-dimethyl-2-pyridone (1-013-02) (27.76 g, 65.9%, m.p. 258-263 C).1H NMR (300 MHz, DMSO): delta 1.98 (s, 3H), 2.23 (s, 3H), 7.95 (s, 1H), 12.45 (br s, 1H). | |
65.9% | Water was added to 2-methyl-3-oxobutanal sodium salt (1-013-01) (34.73 g), and to the reaction mixture was added 2-cyanoacetamide (23.91 g) and 1.76 mol/L piperidinium acetate (119.4 mL), and the reaction mixture was stirred under reflux in an oil bath at 127 DEG C. After 21 h, to the reaction mixture was added gradually dropwise acetic acid (42.7 mL) at 65 DEG C as internal temperature for 15 min. After the stirring was continued until internal temperature became to 24 DEG C, the resulting crystal was filtered, and washed with water to give 3-cyano-5,6-dimethyl-2-pyridone (1-013-02) (27.76 g, 65.9%, m.p. 258-263 DEG C).<1>H NMR (300 MHz, DMSO): delta 1.98 (s, 3H), 2.23 (s, 3H), 7.95 (s, 1H), 12.45 (br s, 1H). | |
33% | Step (ii): Synthesis of 2-oxo-l,2, dihydro-5,6-dimethyl pyridine-3-carbonitrile; Cyano acetamide (3.78 g, 0.237 mol) was added to a solution of the sodium salt of 3-formyl-2-butanone (5.00 g, 40.9 mmol) in water (100 niL), and this reaction was allowed to stir at room temperature for 1 h. Afterwards, a 2 M solution of piperidine acetate in water (10 mL) was added, and the reaction mixture was allowed to reflux for 24 h. This mixture was allowed to cool and was acidified with acetic acid. The suspension was filtered and the precipitate was washed with toluene. The filtrate was collected and was concentrated to afford a sticky residue, which was washed with diethyl ether followed by ethyl acetate, to afford the title compound (2.00 g), yield: 33 %, as a light brown solid. Mp: 103 0C1H NMR (DMSO-rfft 200 MHz): d 12.44 (s, IH), 7.94 (s, IH), 2.23 (s, 3H), 1.98 (s, 3H) m/z (CI-MS): 148 (M+, 100%) |
To a solution of sodium (ljE)-2-methyl-3-oxobut-l-en-l-olate (20.0 g) in H2O (310 mL) was added 2-cyanoacetamide (14.5 g). This solution (15.5 mL) was distributed to two flasks and to the one flask was added piperidinium acetate (7.35 g) and to another flask were added piperidine (5.0 mL) and acetic acid (2.9 mL). Both solutions were stirred at reflux for 30 min. To the remaining solution prepared first wrere added piperidine (90.5 mL). After cooling, to the mixture was added acetic acid (52.3 mL). All reaction mixtures were stirred at reflux for i4 h and cooled down. At 60 0C, to each solution was added acetic acid (1.25 mL, 1.25 mL, 22.5 mL) the mixture was stirred to ambient temperature. The precipitate was collected by filtration, washed with H2O, dried under reduced pressure, and suspended in 50% MeOH in CHCl3. The mixture was heated by a dryer and filterd. The insoluble material was suspended in 50% MeOH in CHCl3 and the mixture was stirred at reflux for 1 h and filterd. The two filtrates were concentrated under reduced pressure to give 5,6-dimethyl-2- EPO <DP n="92"/>oxo-l,2-dihydropyridine-3-carbonitrile (5.95 g) as a yellow solid.1HNMR (300 MHz, DMSO-d6, delta): 1.98 (s, 3H), 2.23 (s, 3H), 7.94 (s, IH), 12.43 (brs, IH); ESI MS m/z 149 (M++., 55%), 171 (M^+23, 100%). | ||
With piperidine; acetic acid; In water; for 14.5h;Heating / reflux;Product distribution / selectivity; | To a solution of sodium (ljE)-2-methyl-3-oxobut-l-en-l-olate (20.0 g) in H2O (310 mL) was added 2-cyanoacetamide (14.5 g). This solution (15.5 mL) was distributed to two flasks and to the one flask was added piperidinium acetate (7.35 g) and to another flask were added piperidine (5.0 mL) and acetic acid (2.9 mL). Both solutions were stirred at reflux for 30 min. To the remaining solution prepared first wrere added piperidine (90.5 mL). After cooling, to the mixture was added acetic acid (52.3 mL). All reaction mixtures were stirred at reflux for i4 h and cooled down. At 60 0C, to each solution was added acetic acid (1.25 mL, 1.25 mL, 22.5 mL) the mixture was stirred to ambient temperature. The precipitate was collected by filtration, washed with H2O, dried under reduced pressure, and suspended in 50% MeOH in CHCl3. The mixture was heated by a dryer and filterd. The insoluble material was suspended in 50% MeOH in CHCl3 and the mixture was stirred at reflux for 1 h and filterd. The two filtrates were concentrated under reduced pressure to give 5,6-dimethyl-2- EPO <DP n="92"/>oxo-l,2-dihydropyridine-3-carbonitrile (5.95 g) as a yellow solid.1HNMR (300 MHz, DMSO-d6, delta): 1.98 (s, 3H), 2.23 (s, 3H), 7.94 (s, IH), 12.43 (brs, IH); ESI MS m/z 149 (M++., 55%), 171 (M^+23, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In N-methyl-acetamide; water; acetonitrile; | D-1. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile Alternatively named 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile--To a mixture containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g. of alpha-cyanoacetamide dissolved in 400 cc. of dimethylformamide was added with stirring 14 g. of sodium methoxide and the resulting reaction mixture was heated in an oil bath under gentle reflux for one hour. TLC analysis showed no starting material in the reaction mixture which was then concentrated in vacuo on a rotary vaporator to a volume of about 80 cc. The concentrate was treated with about 160 cc. of acetonitrile and the resulting mixture was stirred on a rotary vaporator with warming until homogenuous and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55 C. to yield 28 g. of tan crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis. An 8 g. portion of said sodium salt was dissolved in 75 cc. of hot water, the aqueous solution treated with decolorizing charcoal filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to produce 3.75 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. 300 C. Acid-addition salts of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile in about 40 ml. of aqueous methanol the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a small pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, phosphate, respectively. | |
With sodium methylate; In N-methyl-acetamide; water; acetonitrile; | D-1. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)-nicotinonitrile, alternatively named 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile--To a mixture containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g. of alpha-cyanoacetamide dissolved in 400 cc. of dimethylformamide was added with stirring 14 g. of sodium methoxide and the resulting reaction mixture was heated in an oil bath under gentle reflux for one hour. TLC analysis showed no starting material in the reaction mixture which was then concentrated in vacuo on a rotary vaporator to a volume of about 80 cc. The concentrate was treated with about 160 cc. of acetonitrile and the resulting mixture was stirred on a rotary vaporator with warming until homogenuous and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55 C. to yield 28 g. of tan crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis. An 8 g. portion of said sodium salt was dissolved in 75 cc. of hot water, the aqueous solution treated with decolorizing charcoal filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to produce 3.75 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. 300 C. Acid-addition salts of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile in about 40 ml. of aqueous methanol the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a small pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, phosphate, respectively. | |
With sodium methylate; In N-methyl-acetamide; water; acetonitrile; | D-1. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, alternatively named 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile--To a mixture containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g. of alpha-cyanoacetamide dissolved in 400 cc. of dimethylformamide was added with stirring 14 g. of sodium methoxide and the resulting reaction mixture was heated in an oil bath under gentle reflux for one hour. TLC analysis showed no starting material in the reaction mixture which was then concentrated in vacuo on a rotary vaporator to a volume of about 80 cc. The concentrate was treated with about 160 cc. of acetonitrile and the resulting mixture was stirred on a rotary vaporator with warming until homogenuous and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55 C. to yield 28 g. of tan crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis. An 8 g. portion of said sodium salt was dissolved in 75 cc. of hot water, the aqueous solution treated with decolorizing charcoal filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to produce 3.75 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. 300 C. Acid-addition salts of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile in about 40 ml. of aqueous methanol the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a small pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, phosphate, respectively. |
With sodium methylate; In N-methyl-acetamide; water; acetonitrile; | I-1. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, alternatively named 1,6-dihydro-2-methyl-6-oxo[3,4'-bipyridin]-5-carbonitrile--To a mixture containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g. of alpha-cyanoacetamide dissolved in 400 cc. of dimethylformamide was added with stirring 14 g. of sodium methoxide and the resulting reaction mixture was heated in an oil bath under gentle reflux for one hour. TLC analysis showed no starting material in the reaction mixture which was then concentrated in vacuo on a rotary evaporator to a volume of about 80 cc. The concentrate was treated with about 160 cc. of acetonitrile and the resulting mixture was stirred on a rotary evaporator with warming until homogeneous and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55 C. to yield 28 g. of tan crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis. An 8 g. portion of said sodium salt was dissolved in 75 cc. of hot water, the aqueous solution treated with decolorizing charcoal filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to produce 3.75 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. 300 C. Acid-addition salts of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile in about 40 ml. of aqueous methanol the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a small pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, phosphate, respectively. | |
With sodium methylate; In N-methyl-acetamide; water; acetonitrile; | B-1. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, alternatively named 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile To a mixture containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g. of alpha-cyanoacetamide dissolved in 400 ml. of dimethylformamide was added with stirring 14 g. of sodium methoxide and the resulting reaction mixture was heated in an oil bath under gentle reflux for one hour. TLC analysis showed no starting material in the reaction mixture which was then concentrated in vacuo on a rotary evaporator to a volume of about 80 ml. The concentrate was treated with about 160 ml. of acetonitrile and the resulting mixture was stirred on a rotary evaporator with warming until homogenuous and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55 C. to yield 28 g. of tan crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis. An 8 g. portion of said sodium salt was dissolved in 75 ml. of hot water, the aqueous solution treated with decolorizing charcoal filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N-hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to produce 3.75 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p., >300 C. Acid-addition salts of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile in about 40 ml. of aqueous methanol the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, phosphate, respectively. | |
With sodium methylate; In N-methyl-acetamide; water; acetonitrile; | B. 1-R1 -1,2-DIHYDRO-6-(LOWER-ALKYL)-2-OXO-5-PY-NICOTINONITRILES B-1.--1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, alternatively named 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile-- To a mixture containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g. of alpha-cyanoacetamide dissolved in 400 cc. of dimethylformamide was added with stirring 14 g. of sodium methoxide and the resulting reaction mixture was heated in an oil bath under gentle reflux for one hour. TLC analysis showed no starting material in the reaction mixture which was then concentrated in vacuo on a rotary evaporator to a volume of about 80 cc. The concentrate was treated with about 160 cc. of acetonitrile and the resulting mixture was stirred on a rotary evaporator with warming until homogenous and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55 C. to yield 28 g. of tan crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis. An 8 g. portion of said sodium salt was dissolved in 75 cc. of hot water, the aqueous solution treated with decolorizing charcoal filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N-hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to produce 3.75 g of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. >300 C. | |
With sodium methylate; In N-methyl-acetamide; water; acetonitrile; | B. 1,2-DIHYDRO-6-(LOWER-ALKYL)-2-OXO-5-PY-NICOTINONITRILES B-1.--1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, alternatively named 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile-To a mixture containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g. of alpha-cyanoacetamide dissolved in 400 ml. of dimethylformamide was added with stirring 14 g. of sodium methoxide and the resulting mixture was heated in an oil bath under gentle reflux for one hour. TLC analysis showed no starting material in the reaction mixture which was then concentrated in vacuo on a rotary evaporator to a volume of about 80 ml. The concentrate was treated with about 160 ml. of acetonitrile and the resulting mixture was stirred on a rotary evaporator with warming until homogeneous and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55 C. to yield 28 g. of tan crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis. An 8 g. portion of said sodium salt was dissolved in 75 ml. of hot water, the aqueous solution treated with decolorizing charcoal filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N-hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to produce 3.75 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. >300 C. | |
With sodium methylate; In N-methyl-acetamide; water; acetonitrile; | B. 1-R1 -1,2-DIHYDRO-6-(LOWER-ALKYL)-2-OXO-5-PY-NICOTINONITRILES B-1.--1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, alternatively named 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile--To a mixture containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g. of alpha-cyanoacetamide dissolved in 400 cc. of dimethylformamide was added with stirring 14 g. of sodium methoxide and the resulting reaction mixture was heated in an oil bath under gentle reflux for one hour. TLC analysis showed no starting material in the reaction mixture which was then concentrated in vacuo on a rotary evaporator to a volume of about 80 cc. The concentrate was treated with about 160 cc. of acetonitrile and the resulting mixture was stirred on a rotary evaporator with warming until homogenuous and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55 C. to yield 28 g. of tan crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis. An 8 g. portion of said sodium salt was dissolved in 75 cc. of hot water, the aqueous solution treated with decolorizing charcoal filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N-hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to produce 3.75 g. of 1,2-dihydro-6 -methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. >300 C. | |
With sodium methylate; In N-methyl-acetamide; water; acetonitrile; | D-1. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, alternatively named 1,6-dihydro-2-methyl-6-oxo-[3,4-b]bipyridine'-5-carbonitrile-To a mixture containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g. of alpha-cyanoacetamide dissolved in 400 cc. of dimethylformamide was added with stirring 14 g. of sodium methoxide and the resulting reaction mixture was heated in an oil bath under gentle reflux for one hour. TLC analysis showed no starting material in the reaction mixture which was then concentrated in vacuo on a rotary evaporated to a volume of about 80 cc. The concentrate was treated with about 160 cc. of acetonitrile and the resulting mixture was stirred on a rotary evaporator with warming until homogeneous and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55 C. to yield 28 g., of tan crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis. An 8 g. portion of said sodium salt was dissolved in 75 cc. of hot water, the aqueous solution treated with decolorizing charcoal filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to produce 3.75 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. 300 C. Acid-addition salts of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile in about 40 ml. of aqueous methanol the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, phosphate, respectively. | |
With sodium methylate; In N-methyl-acetamide; water; acetonitrile; | J-1. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, alternatively named 1,6-dihydro-2-methyl-6-oxo[3,4'-bipyridin]-5-carbonitrile To a mixture containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g. of alpha-cyanoacetamide dissolved in 400 cc. of dimethylformamide was added with stirring 14 g. of sodium methoxide and the resulting reaction mixture was heated in an oil bath under gentle reflux for one hour. TLC analysis showed no starting material in the reaction mixture which was then concentrated in vacuo on a rotary evaporator to a volume of about 80 cc. The concentrate was treated with about 160 cc. of acetonitrile and the resulting mixture was stirred on a rotary evaporator with warming until homogeneous and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55 C. to yield 28 g. of tan crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis. An 8 g. portion of said sodium salt was dissolved in 75 cc. of hot water, the aqueous solution treated with decolorizing charcoal filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to produce 3.75 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. 300 C. Acid-addition salts of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile in about 40 ml. of aqueous methanol the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a small pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, phosphate, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; | 3-Cyano-6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid ethyl ester While stirring at room temperature, 19.2 g of 2-cyanoacetamide was added to 300 ml of ethanol solution containing 41.9 g of <strong>[21080-80-8]2,4-dioxocyclopropanebutyric acid ethyl ester</strong>. After completely dissolving the reagent by warming up to 65°C, 7.4 ml of piperazine was added dropwise to the solution. One hour thereafter, this was cooled to room temperature and stirred for additional 15 hours and 30 minutes. The thus precipitated crystals were collected by filtration and then washed with diethyl ether to obtain 24.1 g of the title compound. This compound was used in the subsequent reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.5% | With sodium hydroxide; acetic acid; In methanol; water; | B.14. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile--To a solution containing 2.6 g of sodium hydroxide pellets dissolved in 41 ml of methanol was added 2.5 g of cyanoacetamide with stirring. After dissolution was complete (about 5 minutes), to the solution was added a solution containing 5.0 g of 1-(4-pyridinyl)ethenyl methyl ketone in 15 ml of methanol and the reaction mixture was heated to reflux for one hour, cooled to 50 C. and treated with 4.2 ml of acetic acid. The methanol was distilled off at atmospheric pressure and the residue treated with 55 ml of water. Since the pH was 6.0, there was no need to adjust it. The mixture was cooled to 5 C. and the separated solid was collected, washed successively with 50 ml portions of cold water, ethanol and ether, and air-dried to produce 4.7 g (85.5% yield) of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. >300 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | General procedure: A substituted alkyl methyl ketone or cyclic ketone (1 equiv) and ethyl formate or ethyl acetic(1 equiv) was added dropwise to absolute ether solution of sodium metal (1 equiv) for 1 h whilemaintained below 20 C. After the addition, the reaction was allowed to stir in an ice bath untilthe sodium metal had disappeared. The precipitate was filtered, washed with absolute ether anddried to give the corresponding compound which was directly used for the next step without further purification. To a solution of previous product (1 equiv), and cyanoacetamide (1.05 equiv) in water was stirred6 min at room temperature. The mixture was added dropwise piperidine acetate solution (0.3 equiv),which was prepared from piperidine (1 equiv), acetic acid (1 equiv) and water (5 equiv). The solutionwas heated to reflux for 2 h. Then, the reactor was cooled to room temperature, and adjusted to pH 4 by 4 N hydrochloric acid. The resulting solid was filtered, respectively washed with water and ether,and dried to give the corresponding compound which was purified by recrystallizing using menthol as solvent. | |
Reference Example 63 2-chloro-3-cyano-5,6-dimethylpyridine To a mixture of 28% sodium methoxide methanol solution (59 mL) and diethyl ether (380 mL) was added dropwise a mixture of 2-butanone (20.9 g, 290 mmol) and ethyl formate (23.0 g, 310 mmol) over 45 min while maintaining an inside temperature at 4-5C. The mixture was stirred at room temperature for 6 hr, and the resulting precipitate was collected by filtration. A solution of the solid, 2-cyanoacetamide (14.1 g, 168 mmol), piperidine (12.3 mL, 124 mmol) and acetic acid (7.50 g, 124 mmol) in water (336 mL) was heated under reflux for 17 hr. Then, acetic acid (26 mL) was added dropwise while maintaining an inside temperature at 65C, and the mixture was cooled to room temperature. The resulting precipitate was collected by filtration and suspended in a mixed solvent of acetonitrile and diisopropyl ether, and the precipitate was collected by filtration, and dried under reduced pressure. The solid was added to phosphorus oxychloride (80 mL), and the mixture was stirred at 100C for 6 hr. The reaction mixture was added to ice water, ethyl acetate was added thereto, and the mixture was neutralized with potassium carbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with diethyl ether and dried to give the title compound (16.1 g, yield 33%). 1H NMR (DMSO-d6) delta2.28 (3H, s), 2.50 (3H, s), 8.22 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium hydroxide; In ethanol; water; at 20 - 50℃; for 7h; | General procedure: To a solution of appropriate p-aminobenzaldehyde 1a-n (20 mmol) and cyanoacetamide (20 mmol) in ethanol (20 ml) a few drops of potassium hydroxide solution (10% in water) at 50 C was added. The solution was set aside for seven hours at room temperature. The precipitatewas filtered off and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethylamine; In ethanol; at 20℃; for 72h; | Step K: 3-hydroxy-l-isopropyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (13; R=R=H). To a solution of 2-isobutyrylcyclohexanone (12; 4.33 g, 25.76 mmol) and 2-cyanoacetamide (2.17 g, 25.76 mmol) in 26 mL of EtOH was added diethylamine (2.7 mL, 25.76 mmol). The reaction mixture was stirred at room temperature for 72 hours until LC-MS indicated the complete formation of the product. The reaction mixture was then heated to reflux and enough EtOH was added to make a clear solution. After cooling back to room temperature, the desired product and its regioisomer were precipitated out from EtOH solution. After vacuum filtration and air-dry, 4.1 g of the title compound together with its regioisomer were obtained as a mixture of white solid and used without further purification in the next step. MS (ES) M+H expected 217.1 , found 217.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With piperidine; In ethanol; at 20℃; | To a solution of 2-isobutyrylcyclohexanone (13g, 0.0772 mol) in ethanol (250 mL) were added 2-cyano acetamide (6.5 g, 0.0772 mol) and catalytic amount of piperidine (3 mL) at RT. After completion of the reaction (by LCMS), the precipitated solids were collected by filtration and dried under vacuum. It was slurred with ethyl acetate to afford (10 g, 59percent) of the titled compound as white solid. 1H NMR (400MHz, DMSO-d6) delta 11.87 (s, 1 H), 3.17-3.10 (m, 1 H), 2.74 (s, 2H), 2.50-2.47 (m, 2H), 1.66 (s, 4H), 1.19-1.17 (d, J = 7.0 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In neat (no solvent); at 200℃; for 0.5h; | General procedure: The mixture of o-phenylenediamine (1) and cyanoacetamide (2) were stirred in 200 °C for 30 min without any solvent. After cooling, the mixture was dissolved in ethanol. The crude product was purified by silica gel column chromatography using dichloromethane-methanol (60:1) as eluant to give the pure compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.4% | Cyanoacetamide (2.35 g, 0.028 mol) was taken in ethanol (50 mL) containing sodium ethoxide (shining sodium metal was dissolved in anhydrous ethanol at 0C, 0.87 g, 0.038 mol) and raised the temperatureup to 60C for 30 min, cooled to RT and 4-butoxy-1,1,1-trifluoro-but-3-en-2-one (5.0 g, 0.025 mol) was added drop-wise for 20 min. Reaction was allowed to reflux for 5 h and the overall reaction was monitored by TLC. After completion of the reaction, it was neutralized with 15% HCl solution, residue was extracted with ethyl acetate, dried over anhydrous sodium sulphate and distilled under vacuum, the obtained residue was purified using 60-120 mesh silica gel column chromatography. Compound was eluted with 25% ethyl acetate in n-hexane (1:3). Yield 70.4% (Pale yellow solid). m.p. 210-11C. FTIR (KBr): 2230 (CN), 1672 cm-1 (C=O); 1H NMR: (DMSO-d6, 300 MHz) delta ppm: 7.26 (d, J = 7.74, 1H, =CH-), delta 8.18 (d, J = 7.55, 1H, =CH-); 13C NMR (DMSO-d6, 75 MHz): delta 99.20(C-CN), 110.06 (Ar-C), 113.70 (CN), 119.52 (q, J = 275.09 Hz) (CF3), 144.58 (Ar-C), 146.81 (q, J = 35.21 Hz) (C-CF3), 163.58 (C=O); ESI-MS: m/z 189 (M+1), 211 (M + Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.80g | NaH (0.776 g, 19.39 mmol, 60percent weight) was added to a 5°C solution of 2-cyanoacetamide (0.815 g, 9.70 mmol) in DMF (12 ml). The mixture was brought to it for 15 mm then back to 5°C. Methyl 6-chloro-5- nitronicotinate (2.00 g, 9.23 mmol) in THE (6 ml) was added slowly to the previous solution and then brought to rt. After 3h of stirring, the solution was cooled to 5°C and quenched with 24 ml of water followed 10 mm later by HCICOC (0.81 ml, 9.7 mmol). The solid obtained was filtered and dried overnight under vacuum to give 0.80g of methyl 6-(2-amino-1-cyano-2-oxoethyl)-5-nitronicotinate. LCMS m/z 263.2 (M-H); 1H NMR (400 MHz, DMSO-d6) oe ppm 3.95 (5, 3 H) 5.99 (5, 1 H) 7.81 (5, 1 H), 8.15 (5, 1 H) 8.86 (d, Jz2.0 Hz, 1 H) 9.38 (d, J= 2.0 Hz, 1 H) with some of the regioisomer (Z)-methyl 6-(2-amino-1-cyano-2- oxoethylidene)-5-nitro-1 , 6-di hydropyridi ne-3-carboxyl ate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.3% | With sodium ethanolate; In ethanol; at 0 - 5℃; | After 490g of sodium ethylate was added to ethanol containing 6480ml 10L reaction flask was heated slightly to dissolve with stirring, was added 263g of cyanoacetamide, wait until the clear solution, then intermediate II was added and heated to reflux for 90min.After cooling to room temperature, cooled to (0 ~ 5 ), solid separated.Suction filtered, the filter cake was dissolved in water, activated charcoal was added 40g, stirred for 15min after filtration to remove carbon, the filtrate was adjusted with acetic acid to pH 6.5 to 7.0, the precipitated solid was suction filtered washed with water, and then the filter cake rinsed with a small amount of ethanol.80 vacuum dried to give a yellow powder 235g, yield: 46.4%.The crude 235g milrinone was added to the 5L flask and 10-fold amount by volume of dimethylformamide 2350ml, after dissolved by heating, added with stirring in 10 times the volume of boiling water 2350ml, and then slowly cooled to room temperature with stirring to cool (0 ~ 5 ), there is precipitation of crystals.Filtration washed with water and a small amount of ethanol and then rinsed cake.80 vacuum drying solid white powder 191g, good crystal form, impurities were not detected, yield: 81.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.2% | With sodium hydroxide; In ethanol; at -5 - 0℃; for 16.0h;Large scale; | 1-ethoxy-2- (4-pyridyl) vinyl methyl ketone 2 kg (10.5 mol)Add 70vt% ethanol 22L dissolved,Put cyanoacetamide 1 kg (11.9mo 1),Stirring dissolved,Dropping 80% of sodium hydroxideEthanol solution 6.5L (sodium hydroxide content 1.3kg),Temperature control below 0 C;After dripping at -5 ~ 0 C for 16 h,The reaction solution was added with 15 L of water,Plus activated carbon 500g,Stirred at room temperature for 20 min,filter,The filtrate was adjusted to pH 7 with dilute hydrochloric acid,filter,Wash the filter cake to the filtrate colorless,Milletton wet goods 2.2kg,Plus 50vt% ethanol 45L reflux dissolved,filter,Filtrate -5 ~ 0 C stirring crystal 6h,filter,60 ~ 70 C dry 6h,White crystalsMilrinon1.86kg,Yield 84.2%Purity 99.993 (HPLC method). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.1% | With piperidine; sulfur; In ethanol; at 45 - 50℃; for 5.0h; | To a 100 mL three-necked flask was added 2.0 g (9.2 mmol) of 4- (4-ethoxyphenyl) cyclohexanone,Cyanoacetamide (0.8 g, 9.2 mmol)Sulfur (sublimation) 0.3 g (9.2 mmol), anhydrous ethanol 6.0 mL,A solution of 0.8 g (9.2 mmol) of piperidine was added dropwise and incubated at 45-50 CAnd the reaction was stirred for 5 h at the above temperature after the dropwise addition.After completion of the reaction, the reaction solution was frozen for 2 hours, and the precipitated solid was filtered off, washed twice with ethanol and once with petroleum ether. After natural drying, 1.6 g of orange-red solid was obtained and the yield was 56.1%. |
56.1% | With piperidine; sulfur; In ethanol; at 45 - 50℃; for 5.0h; | To a 100 mL three-necked flask was added 2.0 g (9.2 mmol) of 4- (4-ethoxyphenyl) cyclohexanone,0.8 g (9.2 mmol) of sulfuric acid (sublimation), 0.3 g (9.2 mmol) of sulfuric acid (sublimed) and 6.0 mL of absolute ethanol were added dropwise to a solution of 0.8 g of piperidine(9.2 mmol) and incubated at 45-50 C. After the dropwise addition, the reaction was stirred at the above temperature for 5 h. After completion of the reaction, the reaction solution was ice-driedFrozen 2h, filter the precipitated solid, ethanol washed 2 times, petroleum ether washed 1 times, natural air-dried orange red solid 1.6g, the yield56.1%. |
56.1% | With piperidine; sulfur; In ethanol; at 45 - 50℃; for 5.0h; | <strong>[163671-48-5]4-(4-ethoxyphenyl)cyclohexanone</strong> 2.0 g (9.2 mmol) was sequentially added to a 100 mL three-necked flask.Cyanoacetamide 0.8g (9.2mmol), sulfur powder (sublimation) 0.3g (9.2mmol), anhydrous ethanol 6.0mL,Then, 0.8 g (9.2 mmol) of piperidine was added dropwise, and the temperature was controlled at 45-50 C. After the dropwise addition, the reaction was stirred at the above temperature for 5 h.After the reaction was completed, the reaction solution was frozen for 2 hours, and the precipitated solid was filtered by suction, and washed twice with ethanol.The petroleum ether was washed once, and after natural air drying, 1.6 g of an orange-red solid was obtained, and the yield was 56.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.8% | With sodium hydroxide; In methanol; for 3.0h; | Add 1400 ml of anhydrous methanol and the above oil,196.3 g (2.0 mol) of alpha-cyanoacetamide were added with stirring.20% sodium hydroxide solution 1200 g (6.0 mol), reaction time is 3 hr.After the reaction was completed, the solid was precipitated with an acetic acid solution adjusted to pH 6.5 to 7.2, and crude milrinone was obtained by filtration.The solid is recrystallized from an ethanol-water system (volume fraction of ethanol 30 to 90%).Obtained white milrinone crystals 101.04g, HPLC: 99.98%, yield 85.8%;D-spacing = 8.39 angstroms. |
83% | With sodium methylate; In methanol; at 1.5℃;Reflux; | 3) 210ml of methanol and 50g of 30% sodium methoxide mixed heated to dissolve, add cyanoacetamide lg, then add 1-Ethoxy-2- (4-pyridyl) vinyl methyl ketone 12g, heated to reflux 1.5h. Cooled to 0 ~ 5 C with stirring crystallization, filtration, the filter cake with a suitable amount of methanol was beaten pale yellow solid, pale yellow solid dissolved in water, acetic acid to adjust the pH to neutral, filtration, water, ethanol washing cake, 80 C was dried under vacuum to give white milrinone crude 9.4g, yield 71%. 9g milrinone crude dissolved in 90ml N, N-dimethylformamide, heated to full solubility, 0.45g activated carbon was added, filtered while hot, the filtrate was added 90ml hot water, slowly cooled to room temperature, suction filtered , Water, washed with ethanol cake, 80 C and dried in vacuo to give white milrinone fine 7.5 g, yield 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With morpholine; sulfur; In ethanol; for 4h;Reflux; | General procedure: Cyclohexanone (for 18a), 1-benzoylpiperidin-3-one (for 18b) or 1-benzoylpiperidin-4-one (for 18c) (0.42mmol), cyanoacetamide (34mg, 0.40mmol) and sulfur (16mg, 0.50mmol) were suspended in EtOH (1mL). To this was added morpholine (70mg, 0.80mmol). The resulting mixture was refluxed gently with stirring for 4h, and was allowed to cool to room temperature. Solvent was removed and the residue was purified by flash chromatography on silica gel using hexanes:EtOAc (1:2) to give compounds 18a-c as off white powder. |
A201515 [7336-15-4]
3-(2-Oxoazepan-1-yl)propanenitrile
Similarity: 0.55