Structure of 369-35-7
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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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Flavio S.P. Cardoso ; Appasaheb L. Kadam ; Ryan C. Nelson ; John W. Tomlin ; Dipendra Dahal ; Christopher S. Kuehner , et al.
Abstract: A low-cost, protecting group-free route to 6-(2-fluoro-4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane (1), the starting material for the in-development tuberculosis treatment TBI-223, is described. The key bond forming step in this route is the creation of the azetidine ring through a hydroxide-facilitated alkylation of 2-fluoro-4-nitroaniline (2) with 3,3-bis(bromomethyl)oxetane (BBMO, 3). After optimization, this ring formation reaction was demonstrated at 100 g scale with isolated yield of 87% and final product purity of >99%. The alkylating agent 3 was synthesized using an optimized procedure that starts from tribromoneopentyl alcohol (TBNPA, 4), a commercially available flame retardant. Treatment of 4 with sodium hydroxide under Schotten–Baumann conditions closed the oxetane ring, and after distillation, 3 was recovered in 72% yield and >95% purity. This new approach to compound 1 avoids the previous drawbacks associated with the synthesis of 2-oxa-6-azaspiro[3,3]heptane (5), the major cost driver used in previous routes to TBI-223. The optimization and multigram scale-up results for this new route are reported herein.
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Keywords: tuberculosis ; TBI-223 ; azaspiro[3.3]heptane ; spiroamine
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CAS No. : | 369-35-7 |
Formula : | C6H5FN2O2 |
M.W : | 156.12 |
SMILES Code : | NC1=CC=C([N+]([O-])=O)C=C1F |
MDL No. : | MFCD00034560 |
InChI Key : | LETNCFZQCNCACQ-UHFFFAOYSA-N |
Pubchem ID : | 101254 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H312-H332 |
Precautionary Statements: | P280 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 39.63 |
TPSA ? Topological Polar Surface Area: Calculated from |
71.84 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.99 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.27 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.74 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.7 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.59 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.82 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.95 |
Solubility | 1.77 mg/ml ; 0.0113 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.38 |
Solubility | 0.654 mg/ml ; 0.00419 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.69 |
Solubility | 3.22 mg/ml ; 0.0207 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) |
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 |
-6.35 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 |
3.0 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 |
---|---|---|
80% | With hydrogenchloride; In acetonitrile;Heating / reflux; | A mixture of 4- chloro-6,7-dimethoxy-quinazoline (548mg, 2. 4mmol), 2-fluoro-4-nitro-phenylamine (392mg, 2. 5mmol), AcCN (10ML), and conc'd HC1 (O. 050ml) was heated to reflux for several hrs. After the reaction mixture was allowed to cool to room temperature, the resulting solids were filtered, washed with AcCN and air-dried to give (6,7-dimethoxy- QUINAZOLIN-4-YL)- (2-FLUORO-4-NITRO-PHENYL)-AMINE (673mgs, 80%). |
69% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; | Step 1. N-(2-fluoro-4-nitrophenyl)-6,7-dimethoxyquinazolin-4-amine (41) A stirred suspension of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (40) (prepared according to A. J. Bridges et al., J. Med. Chem., 1996, 39, 267) (1.00 g, 4.45 mmol), 2-fluoro-4-nitroaniline (940 mg, 6.02 mmol) and cesium carbonate (3.20 g, 9.82 mmol) in anhydrous DMF (20 mL) was heated at 90 C. overnight under nitrogen. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with AcOEt, successively washed with water and a saturated solution of ammonium chloride, concentrated and triturated with AcOEt/hexanes. After filtration, the cake was adsorbed on silica gel and purified by flash column chromatography on (eluents MeOH/DCM: 2/98→10/90) to afford the title compound 41 (1.06 g, 69% yield) as a yellow-green solid. MS (m/z): 345.0 (M+H). |
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