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Product Details of [ 365996-05-0 ]

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

Safety of [ 365996-05-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P280-P305+P351+P338-P310

Computational Chemistry of [ 365996-05-0 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

96.69 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.54
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.39
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.49
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.75
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.81
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.6

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.32
Solubility 1.23 mg/ml ; 0.0048 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-3.02
Solubility 0.242 mg/ml ; 0.000946 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-2.01
Solubility 2.52 mg/ml ; 0.00986 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

Yes
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.87 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<0.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.03

Application In Synthesis of [ 365996-05-0 ]

* 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.

  • Downstream synthetic route of [ 365996-05-0 ]

[ 365996-05-0 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 17356-08-0 ]
  • [ 188869-05-8 ]
  • [ 365996-05-0 ]
YieldReaction ConditionsOperation 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

  • 2
  • [ 24424-99-5 ]
  • [ 17356-08-0 ]
  • [ 188869-05-8 ]
  • [ 365996-05-0 ]
YieldReaction ConditionsOperation 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)+.
  • 3
  • [ 24424-99-5 ]
  • [ 97817-23-7 ]
  • [ 365996-05-0 ]
YieldReaction ConditionsOperation 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
  • 4
  • [ 365996-05-0 ]
  • [ 97817-23-7 ]
YieldReaction ConditionsOperation 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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Technical Information

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