Structure of 22536-65-8
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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.
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CAS No. : | 22536-65-8 |
Formula : | C5H5ClN2O |
M.W : | 144.56 |
SMILES Code : | ClC1=NC=C(C=N1)OC |
MDL No. : | MFCD08702770 |
InChI Key : | RSUBGBZOMBTDTI-UHFFFAOYSA-N |
Pubchem ID : | 589058 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 33.53 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.01 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.81 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.14 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.14 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.07 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.56 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.12 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.88 |
Solubility | 1.9 mg/ml ; 0.0131 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.47 |
Solubility | 4.91 mg/ml ; 0.0339 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.37 |
Solubility | 0.612 mg/ml ; 0.00424 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 |
Yes |
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) |
Yes |
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 |
-6.37 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 |
1.0 |
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) |
1.85 |
* 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 |
---|---|---|
91% | With hydrogen bromide; DL-methionine; In acetic acid; for 5h;Reflux; | Prepare 1L four-necked flask with a stirring device and thermometer.Add 100 g of 2-chloro-5-methoxypyrimidine,300 mL of acetic acid was added to the reaction flask,Stir well, then add 153g of 48% hydrobromic acid and 1g of methionine.Warming up to reflux reaction for 5 h,Sampling HPLC controlled until the end of the reaction, product content 96%, dihydroxy by-product 0.5%;After dropping to room temperature, 300 mL of water was added to the reaction solution, and the mixture was extracted three times with 300 mL of dichloromethane.The organic phases were combined and washed with saturated sodium bicarbonate solution.Then, it is dried over anhydrous sodium sulfate, and after filtration, the organic phase is concentrated under reduced pressure to give a crude product;The crude product was recrystallized from the crude product to give a pale yellow solid, 82 g.The yield was 91% and the purity was 98%. |
62% | 2-Chloro-5-methoxypyrimidine (0.46 g, 3.18 mmol) in methylene chloride (10 mL) was treated with 1.0 N boron tribromide (16 mL, 16 mmol) at room temperature. The solution was stirred overnight. After this time the reaction was partitioned between saturated NaHCO3 and DCM. The aqueous layer was extraxted with additional DCM. The combined organic layers were dried (MgSO4), filtered, and concnetrated. The residue was purified by flash column chromatography on silica gel to give 0.26 g of compound 112A (62%): 1H NMR (DMSO-D6): delta 10.03 (s, IH), 8.30 (s, 2H), ESI (-)/MS: 129 (M-H)-. | |
61% | With boron tribromide; In dichloromethane; at 20℃; for 20h; | Intermediate 4: 2-Chloro-5-hydroxypyrimidineTo a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to give 2-chloro-5-hydroxypyrimidine (5.7g, 61%).Mass: (ES-) 129NMR: 5H (d6-DMSO) 8.27 (2H, s) and 10.85 (1H, br s). |
55% | Intermediate 4: 2-Chloro-5-hydroxypyrimidine To a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to give 2-chloro-5-hydroxypyrimidine (5.0g, 55%).Mass: (ES-) 129NMR: 5H (d6-DMSO) 8.27 (2H, s) and 10.85 (1H, br s). | |
27% | With boron tribromide; In dichloromethane; at 0 - 20℃; for 16h; | Boron tribromide (30mL) was slowly added to a solution of 2-chloro-5-methoxypyrimidine (2g, 13.83mmol) in DCM (lOmL) at 0 C. Allowed the reaction mass to stir at room temperature for 16h. Then the reaction mixture was slowly quenched with ice cold water, warmed to room temperature and diluted with DCM (lOOmL). The aqueous layer was separated and extracted with DCM (3x25mL). The organic phase was washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography to afford desired title compound (0.5g, 27%) as a solid. LCMS: m/z = 129.0 (M-H)+ (Negative mode). |
With boron tribromide; In methanol; dichloromethane; carbon dioxide; | Reference Example 25 To a solution of 2-chloro-5-methoxypyrimidine (1.90 g) which is previously prepared by a method disclosed in J. Chem, Soc., 4590 (1960) in methylene chloride (30 ml) is added dropwise boron tribromide (4.97 ml) over a period of 15 minutes in a dry ice/acetone bath. The mixture is stirred at room temperature for 22 hours, and thereto is added dropwise methanol (30 ml) in a dry ice/acetone bath. The reaction mixture is concentrated under reduced pressure, and the pH value thereof is adjusted to pH 5 with aqueous sodium hydroxide solution. The mixture is extracted twice with ethyl acetate, and the extract is washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The resulting crystals are washed with n-hexane to give 2-chloro-5-hydroxypyrimidine (1.47 g) as colorless crystals. M.p. 194-195 C. | |
Example 152(S)-2-(1-(5-(2,4-dichlorobenzyloxy)pyrimidin-2-yl)pyrrolidin-2-yl)acetic acid 152A. (S)-methyl 2-(1-(5-(2,4-dichlorobenzyloxy)pyrimidin-2-yl)pyrrolidin-2-yl)acetate: To a round bottom flask was added 2-chloro-5-methoxypyrimidine (250 mg, 1.73 mmol) and CH2Cl2 (1 mL). The reaction mixture was cooled to -78 C. and 1N BBr3 (4 eq) was added slowly over 15 min. The reaction mixture was slowly warmed to rt and was stirred ovn. The mixture was cooled to 0 C. and 1N BBr3 (4 eq) was added. The reaction was slowly warmed to rt and then stirred for 24 h. The reaction was quenched via addition of methanol at 0 C., and the mixture was evaporated to dryness. The residue was dissolved in water (1 mL) and the pH of the solution was adjusted to 5 using 1N NaOH solution. The resulting mixture was extracted with EtOAc (2×25 mL), and the combined organics were washed successively with water (20 mL) and brine (20 mL), and the organic layer was dried (MgSO4) and concentrated to give 2-chloropyrimidin-5-ol (170 mg, 75% yield). The crude product was dissolved in DMF (3 mL) and 2,4-dichloro-1-(chloromethyl)benzene (0.215 mL, 1.57 mmol), K2CO3 (270 mg, 1.96 mmol) were added. The reaction mixture was stirred at 60 C. for 4 h. The resulting solution was diluted with EtOAc (50 mL), and the organic layer was washed successively with water (4×30 mL) and brine (30 mL), and the organic layer was dried (MgSO4) and concentrated. The residue was purified via silica gel chromatography to give 2-chloro-5-(2,4-dichlorobenzyloxy)pyrimidine (310 mg, 81% yield) as white solid containing 50% of 2-bromo-5-(2,4-dichlorobenzyloxy)pyrimidine. The material was used as is in the subsequent step. To a microwave vial was added 2-chloro-5-(2,4-dichlorobenzyloxy)pyrimidine (54 mg, 0.19 mmol), (S)-methyl 2-(pyrrolidin-2-yl)acetate (80 mg, 0.56 mmol), Hunig's Base (0.16 mL, 0.93 mmol) and DMF (1.2 mL). The reaction was heated in a microwave at 180 C. for 30 min. The reaction mixture was diluted with MeOH, and the mixture was purified via preparative RP-HPLC to give 152A (clear oil, 40 mg, 0.101 mmol, 54.1% yield). LC-MS Anal. Calc'd for C18H19Cl2N3O3: 396.27. found [M+H] 396.2. |
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