Structure of 365996-05-0
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CAS No. : | 365996-05-0 |
Formula : | C11H17N3O2S |
M.W : | 255.34 |
SMILES Code : | O=C(N1CCC2=C(SC(N)=N2)C1)OC(C)(C)C |
MDL No. : | MFCD08448157 |
InChI Key : | BMLHPGOMLGKYIJ-UHFFFAOYSA-N |
Pubchem ID : | 11357283 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.64 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 71.7 |
TPSA ? Topological Polar Surface Area: Calculated from |
96.69 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.54 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.39 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.49 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.75 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.81 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.6 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.32 |
Solubility | 1.23 mg/ml ; 0.0048 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.02 |
Solubility | 0.242 mg/ml ; 0.000946 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.01 |
Solubility | 2.52 mg/ml ; 0.00986 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) |
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) |
Yes |
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 |
-6.87 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 |
0.55 |
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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.03 |
* 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 |
---|---|---|
99% | In isopropyl alcohol; at 90℃; for 1h; | To a solution of i-butyl 3-bromo-4-oxopiperidine-1-carboxylate (1.0 g, 3.59 mmol) in isopropanol (10 mL), thiourea (0.33 g, 4.30 mmol) was added and the reaction mixture was refluxed at 90 °C for 1 h. Completion of the reaction was monitored by TLC. The reaction mixture was then concentrated under vacuum and the resulting crude material was washed with diethyl ether to afford the title compound. Yield: 99percent (0.9 g, white solid). 1H NMR (400 MHz, DMSO-d6): delta 9.05 (bs, 2H), 4.32 (m, 2H), 3.61-3.58 (m, 2H), 2.50 (s, 2H), 1.41 (s, 9H). LCMS: (Method A) 256.0 (M+H), Rt. 2.5 min, 64.8percent (Max). |
47% | In N,N-dimethyl-formamide; at 120℃; for 3h; | To the stuffing solution of <strong>[188869-05-8]tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate</strong> (5.0 g,18 mmol) in DMF (50 mL) was added thiourea (1.37 g, 18 mmol), resulting solution wasthen heated at 120 C for 3h. The solvents were evaporated and the residue purified bycolumn separation to afford desired product as pale yellow oil (2.2 g, yield:47%). LCMS:256.1 (M+1). |
In isopropyl alcohol; for 1h;Reflux; | Step (ii): Preparation of 2-Amino-6,7-dihydro-4H-thiazolo[5,4-c|pyridine-5-carboxylic acid tert - butyl esterA suspension of 3-Bromo-4-oxo-piperidine- l-carboxylic acid tert-butyl ester (10 grams, 35 mmol, obtained in above step) and thiourea (3.28 grams, 42 mmol) in isopropanol ( 100 mL) was refluxed for 1 hour. After completion of reaction, reaction mass was concentrated and resulted crude was triturated with diethyl ether (50 mL), solids were filtered and dried under vacuum to obtain the title compound (10 grams). - NMR (delta ppm): 1 .39 (9H, s), 2.52 (2H, m), 3.56 - 3.59 (2H, t), 4.30 (2H, s), 7.10 (2H, bs); Mass (m/z): 256 (M+H)+. |
In ethanol; for 2h;Reflux; | General procedure for the synthesis of Z2-a and Z2-b To a stirred solution of Zl-a or Zl-b (5.98 mmol) in EtOH (20 mL) was added thiourea (6.28 mmol) and the mixture was stirred at reflux temperature for 2 hours. After reaction completion, the reaction mixture was diluted with methylene chloride (20 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous MgS04 and concentrated in vacuo to give Z2-a or Z2-b. Z2-a; ]H NMR (400 MHz, DMSO-< 6 6.62 (brs, 2H, N), 4.03 - 4.10 (m, 2H), 2.59 - 2.72 (m, 2H), 2.39 - 2.44 (m, 2H), 1.99 - 2.03 (m, 1H), 1.69 - 1.79 (m, 1H), 1.49 - 1.18 (m, 3H). Z2-b; FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDC13) delta 4.77 (brs, 2H, NH2), 4.42 (s, 2H), 3.67 - 3.71 (m, 2H), 2.61 - 2.65 (m, 2H), 1.46 (s, 9H). | |
Intermediate 77 1.1-Dimethylethyl 2-amino-6.7-dihvdroH ,31thiazolof5.4-clpyridine-5(4/-/)-carboxylate; ourea (0.153g) was added to a solution of 1 ,1-dimethylethyl 3-bromo-4-oxo-1- piperidinecarboxylate (Ref. WO2004012684) (0.557g) in acetone (15ml) at ambient temperature and stirred overnight. Triethylamine (418ul) was then added and after 20min the reaction mixture was evaporated in vacuo. The residue was loaded onto a 2Og SCX cartridge preconditioned with MeOH and then eluted with 0%-20% 2M methanolic ammonia in MeOH. Appropriate f ractions were combined and evaporated in vacuo to provide a solid (0.383g) which was stirred in water (5ml) for 10min, filtered, then washed with water and dried in vacuo at 450C to give the title compound (0.319g) as a pale yellow solid.Mass spectrum: Found: MH+ 256 H.p.l.c. R,2.09min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 79 Synthesis of 2-[6-(lH-indazol-6-ylcarbamoyl)-lH-benzimidazol-2-ylamino]-6,7-dihydro-4H- thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl esterTo a solution of l-Boc-4-piperidone (5 mmol) in dry THF (20 mL) was added solidBa2CC>3 (10 mmol). The resulting mixture was stirred vigorously. The reaction mixture was treated with pyrrolidone hydrotribromide (5.5 mmol) in portions at room temperature. After 3h, the contents were filtered and the solvent removed. The crude reaction mixture containing the product, 3-bromo-4-oxo-piperidine-l -carboxylic acid terf-butyl ester, was used for further transformation without further purification.To a solution of the bromo compound (5 mmol) , obtained as above, in acetone (20 mL) was added solid thiourea (6 mmol) and solid K2CO3 (10 mmol), and the reaction mixture was stirred at room temperature for 12h. To the reaction mixture was added BOC anhydride (5 mmol), and the reaction was stirred for 4h. The contents were then filtered, and the solvent was removed. The residue obtained was purified by silica gel chromatography using DCM/methanol as eluent. The product, 2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5- carboxylic acid tert-butyl ester, was obtained a light yellow solid. <n="66"/>The amine (0.5 mmol) from above was converted to corresponding isothiocyanate using general procedure A, which was then reacted with 334-diamino-N-(lH-indazol-6-yl)- benzamide (0.5 mmol; see Example 25) according to general procedure B to yield 2-[6-(1H- indazol-6-ylcarbamoyl)-lH-benzimidazol-2-ylamino]-6,7-dihydro-4H-thiazolo[5,4- cjpyridine-S-carboxylic acid tert-butyl ester. MS: m/z 531 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.6 g | With potassium carbonate; In 1,4-dioxane; water; at 0 - 20℃; for 3h; | 6.01.16.03 2-Amino-6,7-dihydro-4H-thiazolo(5,4-c)pyridine-5-carboxylic acid tert-butyl ester 15.8 g <strong>[97817-23-7]4,5,6,7-tetrahydro-thiazolo(5,4-c)pyridin-2-ylamine</strong> and 100 mL dioxane was added to 15.2 g potassium carbonate in 158 mL water. 13.1 g di tert-butyl dicarbonate in 58 mL dioxane was added at 0 C. The reaction mixture was allowed to stir for 3 h at ambient temperature. The reaction mixture was diluted with water and the solid was filtered through silica gel, washed with water (2*50 mL) to afford the desired product. The filtrate was concentrated, diluted with waterand extracted with ethyl acetat. The organic layer was dried over magnesium sulfate and concentrated to afford 11.6 g desired product. 1H NMR (400 MHz, DMSO-d6): delta 1.41 (s, 9H), 2.43 (t, 2H), 3.56 (t, 2H), 4.28 (s, 2H), 6.80 (s, 2H) |
11.6 g | With potassium carbonate; In 1,4-dioxane; water; at 0 - 20℃; for 3h; | 6.01.08.03 2-Amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester 15.8 g <strong>[97817-23-7]4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl-amine</strong> and 100 mL dioxane was added to 15.2 g potassium carbonate in 158 mL water. 13.1 g di tert-butyl dicarbonate in 58 mL dioxane was added at 0 C. The reaction mixture was allowed to stir for 3 h at ambient temperature. The reaction mixture was diluted with water and the solid was filtered through silica gel, washed with water (2*50 mL) to afford the desired product. The filtrate was concentrated, diluted with water and extracted with ethyl acetat. The organic layer was dried over magnesium sulfate and concentrated to afford 11.6 g of the desired product. 1H NMR (400 MHz, DMSO-d6): delta 1.41 (s, 9H), 2.43 (t, 2H), 3.56 (t, 2H), 4.28 (s, 2H), 6.80 (s, 2H); (M+H)+: 256 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With hydrogenchloride; In ethyl acetate; at 20℃; for 3h; | [0126] Method F-Step b: 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine [0127] Tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(200 mg, 0.78 mmol) was dissolved in 3M HCl/ethyl acetate (3 mL). The mixture was stirred at room temperature for 3 hours, then the solvent was removed by vacuum, and the residue was portioned between CH2CI2 (20 mL) and saturated aqueous sodium bicarbonate (5 mL), the organic layer was separated, dried over Na2S04 and concentrated to give a white solid (105mg, 87%). |
With trifluoroacetic acid; In dichloromethane; at 20℃; for 1h; | The confirmed TR-03a was then treated with 1 : 1 ratio ofdichloromethane and trifluoroacetic acid and stirred for 1 hat room temperature. The reaction mixture was concentratedand washed with water and diethyl ether. Then the reactionmixture was dissolved in dichloromethane, washed with water and brine, and concentrated by drying over anhydrous Na2SO4 to obtain TR-03. The purity of the compound wasconfirmed by NMR spectra; 1H NMR (300MHz, DMSO-d6) delta= 2.32 (t, 2H, J = 5.4Hz), 2.86 (t, 2H, J = 5.4Hz), 3.59 (s,2H), 6.63 (s, 2H, NH2). | |
With hydrogenchloride; In 1,4-dioxane; water; at 20℃; for 3h; | To a solution of compound 20q (1.42 g, 5.6 mmol) indioxane (5 mL) was added 10 mL 4 N hydrochloric acid in dioxane.The resulting mixture was stirred at room temperature for 3 h. Thereaction mixture was filtered and solid was washed with ethylacetate, then dried under vacuum to obtain the hydrochloride 20r,which was used in the next step without further purification. |
With trifluoroacetic acid; In dichloromethane; at 5℃; for 2h; | Step (2), shown in the structural formula (CAS: 365996-05-0)2-Amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (80.00 g, 303.91 mmol)As raw material, it was mixed with 300 mL of trifluoroacetic acid in 300 mL of dichloromethane, reacted at 5 C for 2 h, concentrated, without purification.Directly obtained as shown in the structural formula (CAS: 97817-23-7)4,5,6,7-tetrahydrothiazole [5,4-C]pyridin-2-amine (303.91 mmol, yield 100%); |
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