Structure of 330785-84-7
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CAS No. : | 330785-84-7 |
Formula : | C18H21ClN4O4 |
M.W : | 392.84 |
SMILES Code : | O=C(C1=CN=C(N2[C@H](CO)CCC2)N=C1NCC3=CC=C(OC)C(Cl)=C3)O |
MDL No. : | MFCD18072441 |
InChI Key : | KJYHORVTWSYSQP-LBPRGKRZSA-N |
Pubchem ID : | 67119335 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 27 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.39 |
Num. rotatable bonds | 7 |
Num. H-bond acceptors | 6.0 |
Num. H-bond donors | 3.0 |
Molar Refractivity | 104.9 |
TPSA ? Topological Polar Surface Area: Calculated from |
107.81 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.74 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.02 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.69 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.57 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.9 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.18 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.05 |
Solubility | 0.0354 mg/ml ; 0.0000901 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.95 |
Solubility | 0.00442 mg/ml ; 0.0000112 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.72 |
Solubility | 0.00754 mg/ml ; 0.0000192 mol/l |
Class? Solubility class: Log S scale |
Moderately 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) |
Yes |
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) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.55 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 |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
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) |
3.25 |
* 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 |
---|---|---|
98.9% | With sodium hydroxide; In N,N-dimethyl-formamide; at 40℃; | In the reaction flask, compound 4 (421 g, 1.0 mol) and DMF 632 mL were added and stirred to dissolve the reaction system.The temperature is controlled below 40 C, and 200 mL of sodium hydroxide solution with a mass fraction of 20% is slowly added dropwise. After the reaction of the raw materials, useThe pH of the diluted hydrochloric acid was adjusted to 7.0, and the temperature was lowered to 0 C, 500 mL of water was added dropwise, and the precipitated solid was suction filtered and washed with water to obtain compound 5 in a yield of98.9%, the purity was 98.7%. |
96.9% | With hydrogenchloride; potassium carbonate; In methanol; water monomer; at 20℃; for 2h;pH 3 - 4; | compound III (42.0g, 0.1mol), 150ml methanol,Potassium carbonate (41.5g, 0.3mol) was added to the reaction flask and stirred at room temperature until the reaction was completed. After filtration, the filtrate was concentrated and added with 200ml of water, adjusted to PH=3-4 with concentrated hydrochloric acid, stirred for 2h, filtered and washed to neutrality to obtain 38.1g of white solid compound IV with a yield of 96.9% |
93% | With sodium hydroxide; In water monomer; dimethyl sulfoxide; at 25 - 35℃;Large scale; | Ethyl (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4- (3-chloro-4-methoxybenzylamino)pyrimidine-5-carboxylate (Intermediate-MIII) 6.7kg, DMSO 29.5kg was added to the reactor, opened stirring to dissolve the reaction system temperature control 30 ± 5 C, Slowly add 8.7kg10% aqueous solution of sodium hydroxide, the reaction mildly exothermic, with 0.3% ammonium acetate solution - methanol (30:70) as mobile phase, the detection wavelength of 265nm; Column temperature: 30 C, flow rate: 1.0 ml / min, HPLC endpoint of the reaction. (No intermediate -MIII peak, the reaction was deemed complete; if the reaction is not complete, then add sodium hydroxide solution and extend the reaction time.) After the reaction (Figure 5), filtration; the filtrate was cooled to 25 ± 5 C, 20.2% aqueous citric acid solution was slowly added 40.2kg, temperature control, the detection system pH <3; The material was added, stirred and filtered. The solid was beaten with 67.0 kg of purified water at 30 ± 10 C. and filtered. 67.0 kg of ethanol was added to the mixture and hot filtered to obtain a white powder. The wet product was dried under reduced pressure at 55 ± 5 C to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)pyrimidine-5-carboxylic acid (Intermediate-MIV, Figure 6, retention time 3.505) 6.24kg dried product, the yield 93%, with 0.3% ammonium acetate solution - methanol (35:65) as the mobile phase, detection wavelength 265nm; Column temperature: 30 , flow rate: 1.0ml / min, HPLC detection of finished products, purity ≥ 99.5%. |
86% | With sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 3h; | To is equipped with a reflux condenser and a thermometer of the 250 ml to of the three-port bottle 25g type V compounds and shows 100 ml dimethyl sulfoxide, stirring to dissolve; ice to the reaction system under the conditions of adding 12g20% of sodium hydroxide aqueous solution; after dropping the reaction at room temperature 3 hours; after the reaction, the reaction system is poured into the 200g ice water, with concentrated hydrochloric acid to adjust pH to 5-6, a large number of solid precipitation, filtration, the filter cake washed with water, drying, to 20g a compound represented by the formula VI, strawcoloured solid, molar yield is 86%, HPLC purity 99% |
72% | With sodium hydroxide;Heating; | Add NaOH solution to the above oil containing M5, raise the temperature and heat overnight. After the reaction is complete, filter and adjust the pH with dilute hydrochloric acid to obtain a white solid, which is purified and dried to obtain pure M6 with a yield of 72%. |
70% | With sodium hydroxide; In water monomer; dimethyl sulfoxide; at 20℃;Cooling with ice; | To a 250 ml three-necked flask, the product of Example 3 (3.4 g, 8.095 mmol) was added successively,Dimethylsulfoxide (34 ml), stirred under ice-cooling to dissolve,A 10% aqueous NaOH solution (23 ml) was gradually added dropwise to the reaction solution. After the dropwise addition, the mixture was allowed to warm to room temperature and stirred overnight.Ice bath into the reaction solution by adding 10% acetic acid solution, adjust the pH to 6 ~ 7 or so, stirring 0.5h precipitation of white solid.Filtered, tetrahydrofuran beating, suction filter white solid, dried the target 2.23g, the yield of 70%. |
48.1% | With water monomer; sodium hydroxide; In methanol; | Methanol (50 mL) was added in ethyl (s)-4-((3-chloro-4-methoxybenzyl)amino) -2-(2-(hydroxymethyl)tetrahydropyrrole-1-yl)-5-pyrimidine carboxylate (8.75 g, 20.8 mmol). In water (20 mL) was dissolved sodium hydrate (1.66 g, 41.6 mmol), then the aqueous solution was added to the reaction solution. The reaction was conducted in an oil bath of 50 to 60 C overnight. The reaction was monitored by LC-MS. The organic solvent was removed by rotary evaporation. The residual aqueous phase was adjusted to a pH of 3 to 4. Then solid was precipitated. The precipitation was filtrated and dried to give a solid (3.9 g, 48.1% yield). |
With sodium hydroxide; water monomer; In dimethyl sulfoxide; at 20℃; for 15h; | (4) A mixture of the compound (3.4 g) obtained in the above (3), a 10 % aqueous sodium hydroxide solution (23 ml), and dimethylsulfoxide (34 ml) is stirred at room temperature for 15 hours. The reaction mixture is poured into a 10 % aqueous citric acid solution, and the precipitates are crystallized from a mixture of tetrahydrofuran and ether to give (S)-4-(3-chloro-4-methoxybenzylamino) -5-carboxy-2- (2-hydroxymethyl-1-pyrrolidinyl)pyrimidine (2.52 g). | |
23 g | With sodium hydroxide; In water monomer; at 25 - 100℃; for 8.16667h; | A mixture of (S)-ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl) pyrrolidin-l-yl)pyrimidine-5-carboxylate compound of formula- 10 (35 g), water (175 ml) and sodium hydroxide (8.31 g) was stirred for 10 minutes at 25-30C. Heated the reaction mixture to 95-100C and stirred for 8 hours. Cooled the reaction mixture to 45-50C and toluene was added to the reaction mixture. Both the organic and aqueous layers were separated. The aqueous layer was cooled to 25-30C and isopropanol (35 ml) was added to it. Acidifying the reaction mixture with acetic acid (52.5 ml) at 25-30C and stirred for 2 hours. Filtered the obtained solid and washed with water. Tetrahydrofuran (122.5 ml) was added to the obtained wet solid, heated the reaction mixture to 60-65C and stirred for 15 minutes. Cooled the reaction mixture to 25-30C and stirred for 1 hour at 25-30C. Filtered the precipitated solid, washed with tetrahydrofuran and then dried to get title compound.Yield: 23 g; MR: 180-185C; Purity by HPLC: 98.91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dicyclohexyl-carbodiimide; 1-hydroxy-1,2,3-benzotriazine-4(3H)-one; In N,N-dimethyl-formamide; at 0℃; | In the reaction flask, anhydrous DMF 3930 mL, compound 5 (393 g, 1.0 mol), 2-aminopyrimidine (163.5 g,1.5 mol), DCC (210 g, 1.02 mol) and 1-hydroxy-1,2,3-benzotriazine-4(3H)-one (166 g, 1.02 mol) at 0 CThe reaction was stirred, monitored until Compound 5 was completely reacted, filtered, and the filtrate was added to water, extracted with chloroform, washed with organic phase and dried.After the filtrate is too short, the silica gel layer is spin-dried to obtain crude avervavir, and the crude avervavir is purified by methanol to obtain pure avenue.The yield was 99.0% and the purity was 99.85%. |
91.2% | With 5,10,15,20-tetrakis[4-(dihydroxyboryl)phenyl]-21H,23H-porphine; In toluene; for 16h;Reflux; Green chemistry; | 4-[(3-Chloro-4-methoxyphenyl)methylamino]-2-[(S)-2-hydroxymethylpyrrol-1-yl]pyrimidine-5-carboxylic acid(39.3g, 100mmol, 1.0eq),2-Aminomethylpyrimidine (12.0 g, 110 mmol, 1.1 eq) and porphyrin borate (7.9 g, 10 mmol, 0.1 eq) were added to 500 mL of toluene.The mixture was heated to reflux to carry out a reaction for 16 hours.After the reaction,Slowly cool the reaction solution to 10-20 C.1000 mL of a 2 wt% aqueous hydrochloric acid solution was added dropwise.The temperature of the control system does not exceed 20 C,Stir for 30min,The boric acid porphyrin catalyst was recovered by filtration.Dispensing the lower aqueous phase,Add 500 mL of dichloromethane to wash the aqueous phase.Slowly add solid NaOH to adjust the pH of the aqueous phase to 7.0, and stir and crystallize for 2 h at room temperature.FiltrationThat is not crude, the filter cake is washed twice with purified water.Add the crude afarafatin to 1000 mL of anhydrous methanol and heat to reflux.After adding 3.0g of activated carbon, stirring and decolorizing for 30min,Hot filtered,The filtrate was stirred and cooled to 30 C, and crystallization was carried out for about 3 hours.filter,After ice-washing with methanol twice, it was dried at 50 C to obtain 44.1 g of a white needle solid (yield 91.2%, purity: 99.63%). |
90% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 20℃; for 4h; | To is equipped with a thermometer and constant pressure dropping funnel a 250 ml three-mouth bottle by adding 20g a compound represented by the formula VI, 6.9gHOBT, 6 g2-amine methyl pyrimidine and 100 ml dimethyl sulfoxide; at room temperature to the reaction system under the conditions of adding dropwisely 11g DCC, after dropping, stirring the mixture at room temperature for 4 hours; after the reaction, the reaction system into the dumping 200g ice water, a large amount of solid precipitated, filtered, the filter cake is washed with ethyl acetate to recrystallize, that shall be atorvastatin non -22g, white solid, molar yield is 90%, HPLC purity 99.8%. |
57% | With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; In dichloromethane; at 20℃; | add M6, EDCI, HOBT, DCM and SM5 into a three-necked flask, and react at room temperature for 10-15h. The reaction was quenched, the organic phase was separated and evaporated to dryness, a solvent was added for crystallization, and a large amount of white solid was obtained by filtration and drying, and the yield was 57%. |
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 8h; | (5) A mixture of the compound (600 mg) obtained in the above (4), 2-aminomethylpyrimidine (217 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (323 mg), 1-hydroxybenzotriazole monohydrate (227 mg) and N,N-dimethylformamide (12 ml) is stirred at room temperature for 8 hours, and the reaction mixture is poured into aqueous sodium hydrogen carbonate solution. The mixture is extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, and the residue is purified by a column chromatography on silica gel (solvent: chloroform:methanol = 50:1) to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine (610 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; | Preparations 2-4 The corresponding starting materials are treated in the same manner as described in Preparation 1 to give the compounds as listed in the following Table 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(4) A mixture of the compound (3.4 g) obtained in the above (3), a 10% aqueous sodium hydroxide solution (23 ml), and dimethylsulfoxide (34 ml) is stirred at room temperature for 15 hours. The reaction mixture is poured into a 10% aqueous citric acid solution, and the precipitates are crystallized from a mixture of tetrahydrofuran and ether to give (S)-4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine (2.52 g). | ||
(4) A mixture of the compound (3.4 g) obtained in the above (3), a 10% aqueous sodium hydroxide solution (23 ml), and dimethylsulfoxide (34 ml) is stirred at room temperature for 15 hours. The reaction mixture is poured into a 10% aqueous citric acid solution, and the precipitates are crystallized from a mixture of tetrahydrofuran and ether to give (S)-4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine (2.52 g), m.p. 205-208 C., MS (m/z): 391 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68 g | 4-(3-Chloro-4-methoxybenzylamino)-2-(2-hydroxymethyl-l-pyrrolidinyl)- pyrimidine-5-carboxylic acid (85 gm) was dissolved in N,N-dimethylformamide (1275 ml) and then added l -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47.7 gm) and 1 -hydroxybenzotriazole monohydrate (32.2 gm). The reaction mixture was stirred for 20 minutes at room temperature and then added triethylamine (32.8 gm) and 2- aminomethylpyrimidine acetic acid (41.5 gm). The reaction mixture was stirred for 9 hours at room temperature and the mixture was poured into aqueous sodium hydrogen carbonate solution. The reaction mixture was extracted with ethyl acetate and the organic layer was dried with sodium sulfate. The organic layer was then concentrated to obtain a residual solid. To the residual solid was added methanol (900 ml) and stirred for 45 minutes at room temperature. The separated solid was filtered and then dried to obtain 68 gm of avanafil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
145 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 5℃; for 14h; | Hydroxybenzotriazole (51.6 g) followed by (S)-4-(3-chloro-4-methoxybenzylamino)- 2-(2-(hydroxymethyl)pyrrolidin-l-yl) pyrimidine-5-carboxylic acid (150 g) and l -ethyl-3-(3- dimethylamino propyl)carbodiimide hydrochloride (128.1 g) were added to a pre-cooled mixture of pyrimidin-2-ylmethanamine hydrochloride compound of formula- 12a (72.3 g), triethylamine (77.3 g) and dimethylformamide (750 ml) at 0-5C and stirred for 14 hours at 0-5C. Quenched the reaction mixture with 5% aqueous potassium carbonate solution (3.75 lit) at a temperature below 30C and stirred for 3 hours at 25-30C. Filtered the solid and washed with water. Water followed by dichloromethane were added to the obtained solid and separated the organic and aqueous layers. Carbon (7.5 g) was added to the organic layer. Filtered the reaction mixture, washed with dichloromethane and distilled off the solvent completely from the filtrate and co-distilled with methanol. Cooled the obtained compound to 30-35C and methanol (1500 ml) was added to it. Heated the reaction mixture to 65-70C and stirred for 10 minutes. Cooled the reaction mixture to 25-30C and stirred for 1 hour. Filtered the solid, washed with methanol and then dried to get title compound. Yield: 145 g; Melting range: 158-163C; Purity by HPLC: 99.6%; Particle Size Distribution: D(0.1): 5.501 μιη; D(0.5): 20.469 um; D(0.9): 52.006 um; D(4,3): 25.457 μηι.PXRD pattern of the obtained compound is represented in figure- 1 and DSC thermogram of the obtained compound is represented in figure-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In ethyl acetate; at 50 - 55℃; for 6h; | A mixture of l -Ethyl-3-(3-dimethylaminopropyl)carbodiimide (48.8 g), Hydroxy benzotriazole (17.1 g), pyrimidin-2-ylmethanamine hydrochloride (12.9 g) and triethylamine (25.75 g) was added to a mixture of (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxy methyl)pyrrolidin-l-yl) pyrimidine-5-carboxylic acid compound of formula-l 1 (50 g) and ethyl acetate (500 ml) at 25-30C. Heated the reaction mixture to 50-55C and stirred for 6 hours. Cooled the reaction mixture to 25-30C and water followed by ethyl acetate were added to the reaction mixture. Separated the organic and aqueous layers and washed the organic layer with water. Distilled off the solvent from the organic layer and then co-distilled with methanol. Methanol (150 ml) was added to the reaction mixture at 25-30C and stirred for 45 minutes. The solvent was decanted from the reaction mixture and water (500 ml) was added to the reaction mixture and stirred for 5 hours. Filtered the precipitated solid, washed with water and then dried to get the title compound. The obtained compound was further purified by preparative HPLC to get pure title compound. Yield: 40 g; Purity by HPLC: 96%. NMR (CHC13, 300 MHz) δ 1.62-2.16 (m, 9H), 3.48-3.77 (m, 6H), 3.82-3.87 (d, 7H), 4.77- 4.78 (d, 2H), 4.24-4.27 (d, 2H), 4.43-4.45 (d, 2H), 4.57-4.59 (d, 4H), 4.78-4.79 (d, 2H), 6.79- 6.87 (d, 2H), 7.15-7.18 (d, 2H), 7.26-7.46 (m, 4H), 8.43 (s, 1H), 8.49 (s, 1 H), 8.71-8.72 (d, 2H), 9.0-9.04 (t, 1 H). EIMS (M+l) m/z = 858.3. FTIR: v 3339.55, 1678.41 cm'1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | In DMF (20 mL) was dissolved (s)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2 -(hydroxymethyl)tetrahydropyrrole-1-yl)-5-pyrimidine carboxylic acid (3.9 g, 10 mmol). The solution was cooled in an ice bath. HATU (5.67 g, 15 mmol) and DIPEA (1.93 g, 15 mmol) were added. After 20 min, trans-4-aminocyclohexanol (1.39 g, 12 mmol) was added in batches. The reaction was conducted overnight. LC-MS was used to monitor the reaction. Ethyl acetate (50 mL) and water (50 mL) were added. The separate aqueous phase was washed with ethyl acetate twice. The organic phase was combined, dried, concentrated and purified by silica gel column chromatography (VDCM:VMeOH = 15:1) to give the product (1.5 g, 31 % yield). Molecular formula: C24H32ClN5O4 Molecular weight: 489.21 LC-MS(M/e): 490.11 (M+H+) 1H-NMR (400 MHz, CDCl3): δ 9.63 (1H, s), 8.15 (1H, s), 7.35(1H, s), 7.19 (1H, d), 7.1 (1H, d), 6.26 (1H, s), 4.58 (2H, d), 4.05-4.13 (1H, m), 3.79-3.90 (6H, m), 3.56-3.69 (3H, m), 2.22-2.27 (2 H, m), 1.72-2.17 (8H, m), 1.26-1.45 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With trifluoroacetic acid; In dichloromethane; at 20℃; | The product of Example 4 (5.0 g, 11.14 mmol) was added to a 100 mL eggplant flask,Dichloromethane / trifluoroacetic acid (30 ml, v / v = 1: 1) and stirred at room temperature overnight.The reaction solution was concentrated, and the saturated aqueous solution of sodium hydrogencarbonate was slowly added dropwise to adjust the pH to about 6 to about 7, and the mixture was stirred for 0.5 hours to precipitate a white solid.Filtered, tetrahydrofuran beating, suction filter white solid, dried the target (3.8g, 87%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With thionyl chloride; at 80℃; for 4h; | The product of Example 5 (1.2 g, 3.1 mmol), thionyl chloride (10 ml) was added successively to a 50 ml three-necked flask at room temperature and heated to 80 C for 4 hours. 4-(3-chloro-4-methoxybenzylamino)-2-[(S)-2-hydroxymethylpyrrolidinyl-1-yl]-5-pyrimidinecarboxylic acid chloride, solid 1.2 g, yield 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | To a 50 ml three-necked flask was added 2-aminomethylpyrimidine acetate (0.65 g, 3.846 mmol)Triethylamine (0.36 g, 3.558 mmol) and N, N-dimethylformamide (10 ml) were added and stirred for 0.5 h.The product of Example 5 (1.00 g, 2.550 mmol), EDCI (0.54 g, 2.817 mmol) and 1-hydroxybenzotriazole (0.38 g, 2.812 mmol) were successively added to the reaction solution, and the reaction was stirred at room temperature for 8 hours.The reaction solution was poured into a sodium bicarbonate solution and extracted with ethyl acetate.The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the organic phase was concentrated to obtain crude product. The crude product was recrystallized to 0.74 g of avanafil, with a yield of 60%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 15 - 25℃; | 48.8 kg of DMF was put into a reaction vessel, and (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)pyrimidine-5-carboxylic acid (Intermediate-MIV) 6.1 kg, 2-aminomethylpyrimidine mesylate 3.8 kg Stirring; Add HOBT 2.9kg, EDCI 3.4kg, diisopropylethylamine 6.7kg, while controlling the feed liquid temperature at 20 ± 5 C; The reaction was completed 20 ± 5 C reaction, the reaction 24 ± 12 hours to 0.3% ammonium acetate solution - methanol (30:70) as the mobile phase, the detection wavelength of 265nm; Column temperature: 30 C, flow rate: 1.0 ml / min, reaction monitored by HPLC. (When the intermediate-MIV residue is less than 0.05%, the reaction is deemed complete.) The reaction was completed (Figure 7), 2.75kg of ethyl acetate was added to the reaction mixture, stir; Slowly add 79.3kg of purified water, the reaction system was slowly warmed to 25 ± 5 C; Add the material, stirring, filtration; add 61.0kg of purified water 30 ± 10 beating, filtration, to obtain the varnish non-crude. After refluxing with 146.0kg of methanol, the solution was slowly cooled to below 10 C, stirred and crystallized and filtered; Drying under reduced pressure at 55 ± 5 C gave 4.08 kg of (S)-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-4-[(3-chloro-4-methoxybenzyl)amino]-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine (avanafil API) finished product, yield 67% The mobile phase was 0.3% ammonium acetate-methanol (30:70), the detection wavelength was at 265nm. The column temperature was 30 C, the flow rate was 1.0ml / min, (Figure 8, retention time 10.088) or methanol - water (70:30) as the mobile phase, detection wavelength 265nm; Column temperature: 30 C, flow rate: 1.0 ml / min, final product by HPLC (Figure 9, retention time 10.222), purity> 99.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 30℃; for 24h; | In a 1L three bottle,Add (39.28 g, 0.10 mol) (S)-4-(3-chloro-4-methoxybenzylamino)-5-carboxylic acid-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine (AFZJT-3),(21.84 g, 0.15 mol) 2-aminomethylpyrimidine hydrochloride,(28.76 g, 0.15 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,(20.26 g, 0.15 mol) 1-hydroxybenzotriazole, 0.8L N,N-dimethylformamide,(30.36g, 0.30mol) triethylamine, reacted at 30C for 24h,HPLC showed that the reaction was complete, adding 1.2L of water, extraction with dichloromethane,Wash it twice with about 5% aqueous sodium carbonate,Deionized water was washed once, dried over anhydrous sodium sulfate, suction filtered, and the desiccant removed.Concentrate the dichloromethane solvent under reduced pressureAdd ethyl acetate to beat,The filter was filtered and dried under reduced pressure at 50 C for 5 h.40.72 g of atorvapine crude was obtained with a yield of 84.13%.The crude product prepared in the example is 10g,Perform column chromatography and recrystallize twice with methanol,5.48 g of purified valvafil was obtained with a purification yield of 54.80%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.9% | With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1-methyl-pyrrolidin-2-one; N,N-dimethyl acetamide; water; at 15 - 20℃; for 2h;pH 3 - 4; | add compound IV (35.0g, 0.09mol), EDCI (21.1g, 0.11mol), and 100ml DMA into the reaction flask, cool to 15 in an ice water bath, and slowly add ethylamine hydrochloride V (8.9 g, 0.11mol),The mixed solution of N-methylpyrrolidone (10.9g, 0.11mol) and 50ml DMA was added dropwise. Increase to room temperature to continue the reaction. Slowly add 5V water dropwise, slowly solids precipitate out, continue to stir for 2h, filter to obtain 34.8g white solid VI, the yield is 92.1%,(98.75% HPLC). |
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