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Chemical Structure| 1411774-27-0 Chemical Structure| 1411774-27-0

Structure of 1411774-27-0

Chemical Structure| 1411774-27-0

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Product Details of [ 1411774-27-0 ]

CAS No. :1411774-27-0
Formula : C4H7ClFNO2S
M.W : 187.62
SMILES Code : O=S(N1C[C@H](F)CC1)(Cl)=O
English Name :(3R)-3-Fluoropyrrolidine-1-sulfonyl chloride
MDL No. :MFCD30533071
InChI Key :KIKDRXJNIMWUMX-SCSAIBSYSA-N
Pubchem ID :97960733

Safety of [ 1411774-27-0 ]

Computational Chemistry of [ 1411774-27-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 39.85
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

45.76 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.55
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

0.84
Log Po/w (WLOGP)?

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

1.63
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.

0.52
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

0.35
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.98

Water Solubility

Log S (ESOL):?

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

-1.47
Solubility 6.41 mg/ml ; 0.0342 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-1.38
Solubility 7.75 mg/ml ; 0.0413 mol/l
Class?

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

Very 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

-0.92
Solubility 22.7 mg/ml ; 0.121 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

Yes
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

No
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

No
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.

-6.85 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

2.0
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<1.0
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)

2.84

Application In Synthesis of [ 1411774-27-0 ]

* 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 [ 1411774-27-0 ]

[ 1411774-27-0 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 2313547-52-1 ]
  • [ 1411774-27-0 ]
  • [ 2313547-53-2 ]
YieldReaction ConditionsOperation in experiment
With pyridine In dichloromethane at 10 - 90℃; 5 Compound 6, dichloromethane, and pyridine were cooled to 10-15° C. then 3-R-fluropyrrolidine sulfonyl chloride (Compound B) was charged and heated to 90±5° C. Once the reaction was deemed complete by HPLC it was cooled to 25° C. and dichloromethane was added to obtain a solution. The compound 7A was then dried onto silica gel and purified via silica plug. Compound 7A was carried forward to an aqueous work up followed by a carbon treatment and isolated from methyl t-butyl ether and heptane.
With pyridine In 1,4-dioxane at 20 - 50℃; 1.5 Step 5: Preparation of (R)-N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3 -fluoropyrrolidine-1-sulfonamide Compound 6 (15 g, 0.021 mole), 1,4 29 dioxane (150 mL), 30 pyridine (15 mL, 49.6 mole), and Compound B (3-R-fluropyrrolidine sulfonyl chloride, 11.81 g, 0.063 mole) were charged to a flask. The reaction was stirred at room temperature and then heated to 50° C. and allowed to react overnight. Then charged to the reaction flask were 31 ethyl acetate (60 mL) and 9 water (60 mL). The organic layer was separated, washed, treated with activated carbon (Darco KG-B, 2.25 g) and filtered through a celite pad to yield 32 Compound 7. 1H NMR (DMSO-d6, δ ppm): 9.70 (s, 1H), 9.02 (s, 2H), 8.81 (m, 2H), 8.57 (m, 2H), 7.71 (m, 2H), 7.38 (m, 2H), 5.24-5.37 (2s, 1H), 3.31-3.42 (m, 4H), 2.05-2.29 (m, 3H), 1.12 (m, 4H).
  • 2
  • [ 136725-55-8 ]
  • [ 1411774-27-0 ]
YieldReaction ConditionsOperation in experiment
With sulfuryl dichloride; triethylamine In dichloromethane at -25℃; for 19h; A 3-R-fluropyrrolidine HCl salt was dissolved in dichloromethane and triethylamine. The solution was slowly charge to sulfuryl chloride over 4 hours at -25±5° C. then held for 15 hours. The TEA salts were filtered off and the filtrates were concentrated down to dryness in order to isolate the 3-R-fluropyrrolidine sulfonyl chloride (Compound B).
  • 3
  • [ 1312941-98-2 ]
  • [ 1411774-27-0 ]
  • [ 2230956-48-4 ]
YieldReaction ConditionsOperation in experiment
6.4 g With pyridine; dmap at 40℃; for 12h; E Step E: Step E: (3R)-N-[3-([5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide To a solution of (3-amino-2,6-difluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (8.0 g, 22.79 mmol, 1.0 eq) in pyridine (25.0 g) was added (R)-3-fluoropyrrolidine-1-sulfonyl chloride (4.6 g, 24.60 mmol, 1.08 eq) and 4-dimethylaminopyridine (560.0 mg, 4.59 mmol, 0.2 eq). The reaction mixture was stirred for 12 hours at 40°C. The solvent was removed and water (20 mL) was added, adjusted pH=7-8 with aqueous sodium bicarbonate, extracted with ethyl acetate (100 mL2). The combined organic layer was washed with brine (50 mL2), dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with ethyl acetate/petroleum ether (3:1) to give (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (6.4 g) as a yellow solid LCMS (ES+): m/z 505.05 [M+H]+.
6.4 g With pyridine; dmap at 40℃; for 12h; E Step E: (3R)-N-[3-([5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl)-2,4- difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide. To a solution of (3-amino-2,6-difluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3- yl)methanone (8.0 g, 22.79 mmol, 1.0 eq) in pyridine (25.0 g) was added (R)-3- fluoropyrrolidine-1-sulfonyl chloride (4.6 g, 24.60 mmol, 1.08 eq ) and 4-dimethylaminopyridine (560.0 mg, 4.59 mmol, 0.2 eq). The reaction mixture was stirred for 12 hours at 40 °C. The solvent was removed and water (20 mL) was added, adjusted pH=7~8 with aqueous sodium bicarbonate, extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with ethyl (1480) acetate/petroleum ether (3:1) to give (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)- 2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (6.4 g) as a yellow solid LCMS (ES+): m/z 505.05 [M+H]+.
  • 4
  • [ 136725-55-8 ]
  • [ 1411774-27-0 ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: (3R)-3-fluoropyrrolidine hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane Inert atmosphere; Stage #2: With sulfuryl dichloride In dichloromethane at -70 - 20℃; for 2h; Inert atmosphere; Intermediate I14: (R)-3-fluoropyrrolidine-1-sulfonyl chloride In a 500 mL 4-necked flask (purged with argon; equipped with thermometer and dripping funnel) (R)-3-fluoropyrrolidine hydrochloride (7 g, 55.7 mmol, Eq: 1.0) was combined with DCM (200 mL) under constant argon flow. DIPEA (21.6 g, 29.2 mL, 167 mmol, Eq: 3.0) was added to give a light yellow solution and the reaction mixture was cooled to -70 °C. Sulfuryl dichloride (15 g, 9.01 mL, 111 mmol, Eq: 2.0) in DCM (20 mL) was slowly added through a dropping funnel while maintaining the temperature at -70 °C. The reaction mixture was stirred at -70 °C for 1 h and was then allowed to come to rt over 1 h. The reaction mixture was poured into iced water in an Erlenmeyer flask. The mixture was transferred into a separating funnel and the phases were separated. The organic layer was washed with 1 N aq. HCl (100 mL). The aqueous layers were extracted with two more portions of DCM (80 mL each). The organic layers were combined, dried over Na2SO4, filtered and evaporated to dryness, then dried under high vacuum for 1 h to give the title compound as a brown solid (11.0 g, quant. yield) which was stored at 4 °C prior to use. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.97 - 2.60 (m, 2 H) 3.53 - 3.92 (m, 4 H) 5.04 - 5.64 (m, 1 H)
74.4% With sulfuryl dichloride; N-ethyl-N,N-diisopropylamine In dichloromethane at -78 - 20℃; for 2h;
4.5 g With sulfuryl dichloride In dichloromethane at -30 - 20℃; for 6h; D Step D: Step D: (R)-3-fluoropyrrolidine-1-sulfonyl chloride An oven dried flask was charged with (R)-3-fluoropyrrolidine hydrochloride (3.0 g, 24 mmol). tRiethylamine (7.2 g, 72 mmol) and dichloromethane (150 mL). The mixture was stirred for 15 minutes at room temperature and then cooled to about -30°C. in a dryice/acetonitrile bath for 10 minutes. Sulfuryl chloride (6.0 g, 48 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at about -30°C. for an hour, then stirred at room temperature for 5 hours. The reaction mixture was diluted with aqueous HCl (1 N, 70 mL). The layers were separated and the aqueous layers were extracted with dichloromethane (50 mL3). The combined organic layer was washed with aqueous HCl (1 N, 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate. The solvent was concentrated to give (R)-3-fluoropyrrolidine-1-sulfonyl chloride (4.5 g) as a white solid, which was directly used to the next step without further purification.
With sulfuryl dichloride; trimethylamine In dichloromethane Large scale; 1 Compound B was obtained by combining commercially available 3-R-fluoropyrrolidine HCl salt (20 kg, 159.3 mole) and commercially available sulfuryl chloride (21 kg, 155.6 mole) in a solution of dichloromethane (293 kg) and trimethylamine (32 kg) to yield (R)-3 fluoropyrrolidine sulfonyl chloride (Compound B).
4.5 g Stage #1: (3R)-3-fluoropyrrolidine hydrochloride With triethylamine In dichloromethane at -30 - 20℃; for 0.166667h; Stage #2: With sulfuryl dichloride In dichloromethane at -30 - 20℃; for 6h; D Step D: (R)-3-fluoropyrrolidine-1-sulfonyl chloride An oven dried flask was charged with (R)-3-fluoropyrrolidine hydrochloride (3.0 g, 24 mmol). tRiethylamine (7.2 g, 72 mmol) and dichloromethane (150 mL). The mixture was stirred for 15 minutes at room temperature and then cooled to about -30 oC in a (1476) dryice/acetonitrile bath for 10 minutes. Sulfuryl chloride (6.0 g, 48 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at about -30 °C for an hour, then stirred at room temperature for 5 hours. The reaction mixture was diluted with aqueous HCl (1 N, 70 mL). The layers were separated and the aqueous layers were extracted with dichloromethane (50 mL x 3). The combined organic layer was washed with aqueous HCl (1 N, 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate. The solvent was concentrated to give (R)-3- fluoropyrrolidine-1-sulfonyl chloride (4.5 g) as a white solid, which was directly used to the next step without further purification.
253 mg With sulfuryl dichloride; N-ethyl-N,N-diisopropylamine In dichloromethane at -78 - 20℃; for 16h;
70 % With sulfuryl dichloride; N-ethyl-N,N-diisopropylamine In dichloromethane at -30℃;
With sulfuryl dichloride; N-ethyl-N,N-diisopropylamine In dichloromethane at -30 - 20℃; for 2h; 1.A14.1 Step 1: Into a 50 mL two-neck round-bottom flask containing a well-stirred solution of (3R)-3-fluoropyrrolidine (2a, 3.0 g, 23.89 mmol, HC1 salt) in dichloromethane (30 mL) was added N,N-diisopropylethylamine (38.23 mmol, 6.66 mL) at -30 °C followed by sulfuryl chloride (59.73 mmol,4.84 mL) addition in drop wise and stirred at room temperature for 2 hours. After completion of thereaction, the reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic layer was washed with 1.5 N HC1 (20 mL), driedover anhydrous ISfeSCU, filtered and concentrated under reduced pressure to afford crude (3R)-3 -fluoropyrrolidine- 1 -sulfonyl chloride (2b, 3.6 g, 19.19 mmol, 80% yield) as an off- white solid. 'HNMR (400 MHz, DMSO4): d 5.53-5.37 (m, 1H), 3.76-3.67 (m, 4H), 2.32-2.29 (m, 2H).

  • 5
  • [ 1411774-27-0 ]
  • [ 2304747-25-7 ]
  • [ 2304746-67-4 ]
YieldReaction ConditionsOperation in experiment
4.5% With pyridine; dmap In dichloromethane at 0℃; for 2h; 32 Example 32: Preparation of (Ji-N-(2-Chloro-3-((3,4-dihydro-2H-pyrimido[1,2- c]quinazolin- 10-yl)oxy)phenyl)-3-fluoropyrrolidine- 1-sulfonamide (Compound 40) [0219] To a solution of 2-chloro-3 -((3 ,4-dihydro-2H-pyrimido [1 ,2-cjquinazolin- 10- yl)oxy)aniline (120 mg, 0.37 mmol) and DMAP (2.2 mg) and pyridine (2 mL) in DCM (5 mL) wad added (R)-3-fluoropyrrolidine-1-sulfonyl chloride (630 mg, 3.3 mmol) at 0 °C. The reaction was stirred at 0 °C for 2 hours. The mixture was quenched with MeOH (2 mL) and concentrated. The residue was purified by Prep-HPLC to afford (R)-N-(2-chloro-3-((3,4- dihydro-2H-pyrimido[ 1 ,2-cjquinazolin- 10-yl)oxy)phenyl)-3-fluoropyrrolidine- 1-sulfonamide (8.0 mg, 4.5% yield) as a yellow solid. ‘H NMR (400 MHz, CD3OD): 8.25 (s, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.64 -7.61 (m, 2H), 7.38 (t, J = 8.4 Hz, 1H), 7.04 (dd, J= 8.4, 1.2 Hz, 1H), 5.24 (dt, J= 52.8, 3.6 Hz, 1H), 4.33 (t, J= 5.6 Hz, 2H), 3.67 (t, J= 5.6 Hz, 2H), 3.61-3.30 (m, 4H), 2.29-1.97 (m, 4H). LCMS (M+H) mlz: 478.1.
  • 6
  • [ 1411774-27-0 ]
  • [ 2413036-23-2 ]
  • [ 2413036-24-3 ]
YieldReaction ConditionsOperation in experiment
74.77% With pyridine; dmap at 45℃; for 24h; Sealed tube; 9 Step 9: Preparation of (R)-N-(3-((5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)oxy)-2,4- difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide Into a 8-mL sealed tube, was placed 3-([5-bromo-1H-pyrrolo[2,3-b]pyridin-3- yl]oxy)-2,4-difluoroaniline (200 mg, 0.59 mmol, 1 equiv), DMAP (14.4 mg, 0.12 mmol, 0.20 equiv) in pyridine (660 mL), to which was added (3R)-3-fluoropyrrolidine-1-sulfonyl chloride (220.6 mg, 1.18 mmol, 2.00 equiv) slowly at room temperature. The resulting solution was stirred for 24 h at 45 in an oil bath. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 2) and the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1/1). This resulted in 216 mg (74.77%) of (3R)-N-[3-([5-bromo-1H-pyrrolo[2,3-b]pyridin- 3-yl]oxy)-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide as a light brown solid. LC/MS (ESI) m/z: 490.75 [M+1] +.
  • 7
  • [ 1411774-27-0 ]
  • [ 2413036-99-2 ]
  • [ 2413037-00-8 ]
YieldReaction ConditionsOperation in experiment
17% With pyridine at 50℃; for 12h; 3 Step 3: Preparation of (R)-N-(3-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide To a solution of (3-amino-2,6-difluoro-phenyl)-[5-bromo-1-(2- trimethylsilylethoxymethyl) pyrrolo[2,3-b]pyridin-3-yl]methanone (985 mg, 1.90 mmol, 1 eq) in pyridine (15 mL) was added dimethylaminopyridine (464 mg, 3.80 mmol, 2 eq) and(3R)-3- fluoropyrrolidine-1-sulfonyl chloride (712 mg, 3.80 mmol, 2 eq).The mixture was stirred at 50 °C for 12 hours. The reaction mixture was washed with saturated brine (30mL x 2) and extracted with ethyl acetate (40mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Semi- preparative reverse phase HPLC. Saturated aqueous sodium bicarbonate was added to adjust the pH=9. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. Compound (3R)-N-[3-[5-bromo-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro- pyrrolidine-1-sulfonamide (210 mg, 0.33 mmol, 17 % yield) was obtained as a colorless oil.1H- NMR (400MHz, CDCl3) d 8.85 (d, J=2.0 Hz, 1H), 8.49 (d, J=2.4 Hz, 1H), 7.78 - 7.68 (m, 2H), 7.10 - 6.99 (m, 1H), 6.54 (s, 1H), 5.65 (s, 2H), 5.31 (s, 1H), 3.66 - 3.60 (m, 2H), 3.57 (d, J=8.4 Hz, 2H), 3.55 - 3.43 (m, 2H), 2.38 - 2.23 (m, 1H), 2.16 - 1.96 (m, 1H), 0.94 - 0.88 (m, 2H), -0.05 (s, 9H).
  • 8
  • [ 1411774-27-0 ]
  • [ 1968634-88-9 ]
  • [ 2413037-07-5 ]
YieldReaction ConditionsOperation in experiment
78% With pyridine; dmap at 40℃; for 12h; 4 Step 4: Preparation of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4- fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide To a solution of (5-amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl) methanone (680 mg, 2.04 mmol, 1 eq) and (3R)-3-fluoropyrrolidine-1-sulfonyl chloride (572 mg, 3.05 mmol, 1.5 eq) in pyridine (15 mL) was added 4-dimethylaminopyridine (49 mg, 0.4 mmol, 0.2 eq). The mixture was stirred at 40 °C for 12 hours. The reaction mixture was adjusted pH to 8 with saturated aqueous sodium bicarbonate. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column (3018) chromatography (dichloromethane: methanol = 400:1 to 10:1). Compound (3R)-N-[3- (5-bromo- 1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (780 mg, 1.61 mmol, 78% yield) was obtained as a brown solid. LC/MS (ESI) m/z: 486.9 [M+1] +; 1H-NMR (400MHz, CDCl3) d 8.89 (s, 1H), 8.47 (s, 1H), 7.77 (s, 1H), 7.46 - 7.36 (m, 2H), 7.18 (t, J=9.2 Hz, 1H), 6.69 (s, 1H), 5.42 - 5.14 (m, 1H), 3.78 - 3.59 (m, 4H), 3.54 - 3.43 (m, 2H), 2.97 - 2.88 (m, 1H).
  • 9
  • [ 1254567-33-3 ]
  • [ 1411774-27-0 ]
  • [ 2413037-11-1 ]
YieldReaction ConditionsOperation in experiment
39% With pyridine; dmap at 40℃; for 12h; 3 Step 3: Preparation of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2- fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide To a solution of (3-amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl) methanone (700 mg, 2.09 mmol, 1 eq) in pyridine (7 mL) was added (3R)-3-fluoropyrrolidine-1- sulfonyl chloride (589 mg, 3.14 mmol, 1.5 eq) and 4-dimethylaminopyridine (51 mg, 0.418 mmol, 0.2 eq). The mixture was stirred at 40 °C for 12 h. The mixture was added saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over sodium sulfate and concentrated. The residue was purified with prep-TLC (3039) (Dichloromethane: Methanol = 20:1). (3R)-N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3- carbonyl)-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (400 mg, 0.824 mmol, 39% yield) was obtained as a yellow solid. LC/MS (ESI) m/z: 486.9 [M+1] +; 1H-NMR (400MHz, CDCl3) d 11.12 (br s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.52 - 8.44 (m, 1H), 7.86 - 7.72 (m, 2H), 7.38 - 7.31 (m, 1H), 7.13 - 6.94 (m, 1H), 5.36 - 5.14 (m, 1H), 3.68 - 3.58 (m, 2H), 3.57 - 3.46 (m, 2H), 2.36 - 2.22 (m, 1H), 2.18 - 1.97 (m, 1H).
  • 10
  • [ 1402558-56-8 ]
  • [ 1411774-27-0 ]
  • [ 2413037-15-5 ]
YieldReaction ConditionsOperation in experiment
19% With pyridine; dmap at 40℃; for 12h; 4 Step 4: Preparation of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2- chloro-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide To a solution of (3-amino-2-chloro-6-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3- b]pyridin-3-yl) methanone (1 g, 2.71 mmol, 1 eq) and (3R)-3-fluoropyrrolidine-1-sulfonyl chloride (610 mg, 3.26 mmol, 1.2 eq) in pyridine (10 mL) was added 4-dimethylaminopyridine (66 mg, 0.54 mmol, 0.2 eq). The mixture was stirred at 40 °C for 12 hours. The reaction mixture was adjusted pH to 8 with saturated aqueous sodium bicarbonate. Water (100 mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative reverse phase HPLC. Compound (3R)-N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3- carbonyl)-2-chloro-4-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (270 mg, 0.51 mmol, 19% yield) was obtained as a yellow solid. LC/MS (ESI) m/z: 521.1 [M+1] +.
  • 11
  • [ 1392429-93-4 ]
  • [ 1411774-27-0 ]
  • [ 2573784-05-9 ]
YieldReaction ConditionsOperation in experiment
43% With pyridine at 20℃; for 48h; P71.1 Step 1: Preparation of (R)-N-(2-chloro-4-fluoro-3-iodophenyl)-3-fluoropyrrolidine-1-sulfonamide. To a solution of 2-chloro-4-fluoro-3-iodoaniline (197 mg, 0.726 mmol) in pyridine (3629 μL) was added (R)-3-fluoropyrrolidine-1-sulfonyl chloride (286 mg, 1.52 mmol) and the reaction mixture was stirred at ambient temperature for 48 hours. The reaction mixture was treated with 10% aqueous citric acid and extracted with EtOAc (2*) and the combined organic layers were washed with water and brine then dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase C18 chromatography, eluting with H2O/acetonitrile with 0.1% TFA and the isolated product was dissolved in DCM and washed with saturated NaHCO3 followed by brine. The organic layers were dried over Na2SO4, filtered, and concentrated to give (R)-N-(2-chloro-4-fluoro-3-iodophenyl)-3-fluoropyrrolidine-1-sulfonamide (200 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 7.68 (dd, 1H), 7.02 (dd, 1H), 6.78 (br-s, 1H), 3.59 (m, 3H), 3.47 (m, 2H), 2.24 (m, 1H), 2.05 (m, 1H).
  • 12
  • [ 1411774-27-0 ]
  • [ 2649444-12-0 ]
  • [ 2649444-01-7 ]
YieldReaction ConditionsOperation in experiment
16% With pyridine; dmap In dichloromethane at 75℃; for 21.5h; 12 Example 12: (3R)-N-[2-cyano-3-[(3-methyl-4-oxo-quinazolin-6-yl)amino]phenyl]-3-fluoro- pyrrolidine-1-sulfonamide I7 (20.5 mg, 70.4 µmol, Eq: 1.0) was dissolved in DCM (150 µL). At rt, pyridine (256 mg, 260 µL, 3.24 mmol, Eq: 46), DMAP (877 µg, 7.04 µmol, Eq: 0.1) and I14 (39.6 mg, 211 µmol, Eq: 3.0) were added. The reaction mixture was stirred at 75 °C for 21.5 h. The reaction mixture was taken up in 2-methyl-THF, ice and 1% aq. citric acid. The aqueous layer was back-extracted 2 × with 2-methyl-THF. The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was diluted with DCM, evaporated with silica gel to dryness and transferred to a column. Purification by flash chromatography (25 g silica, 100% EtOAc) gave the title compound as a light yellow solid (5.1 mg, 95% purity, 16% yield). MS (ESI) m/z: 443.2 [M+H]+.
  • 13
  • [ 871701-87-0 ]
  • [ 1411774-27-0 ]
  • [ 2665701-13-1 ]
YieldReaction ConditionsOperation in experiment
39% With pyridine In dichloromethane at 50℃; for 16h; Inert atmosphere; Sealed tube;
  • 14
  • [ 1411774-27-0 ]
  • [ 2573784-38-8 ]
  • [ 2754410-02-9 ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25h; Cooling with ice; Stage #2: (3R)-3-fluoropyrrolidine-1-sulfonyl chloride In tetrahydrofuran; mineral oil at 0 - 50℃; for 12h; 14.1 Step 1: Preparation of tert-butyl (R)-(2-chloro-4-fluoro-3-iodophenyl)((3-fluoropyrrolidin-1-yl)sulfonyl)carbamate. Tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (Intermediate P9; 20 g, 54 mmol) was dissolved in THF (269 mL) and cooled to 0 °C. The reaction mixture was treated with sodium hydride (4.3 g, 108 mmol, 60% wt in mineral oil) portion wise and then the ice bath was removed and the mixture was stirred for 15 minutes. The reaction mixture was treated with (R)-3-fluoropyrrolidine-1-sulfonyl chloride (20 g, 108 mmol) and then heated to 50 °C for 12 hours. The reaction mixture was cooled to ambient temperature and slowly poured into a stirring flask of ice water (500 mL) and then extracted with EtOAc (3 x 100 mL). The organic extracts were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50-100% Hexane/DCM). The desired fractions were combined and concentrated and then the resulting solids were sonicated with chilled MeOH, filtered, and rinsed with minimal MeOH to give tert-butyl (R)-(2-chloro-4-fluoro-3-iodophenyl)((3-fluoropyrrolidin-1-yl)sulfonyl)carbamate (21 g, 75%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 1H), 7.07-7.03 (m, 1H), 5.39-5.23 (m, 1H), 4.02-3.72 (m, 4H), 2.36-2.03 (m, 2H), 1.39 (s, 9H).
75% Stage #1: tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25h; Cooling with ice; Stage #2: (3R)-3-fluoropyrrolidine-1-sulfonyl chloride In tetrahydrofuran; mineral oil at 0 - 50℃; for 12h; 14.1 Step 1: Preparation of tert-butyl (R)-(2-chloro-4-fluoro-3-iodophenyl)((3-fluoropyrrolidin-1-yl)sulfonyl)carbamate. Tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (Intermediate P9; 20 g, 54 mmol) was dissolved in THF (269 mL) and cooled to 0 °C. The reaction mixture was treated with sodium hydride (4.3 g, 108 mmol, 60% wt in mineral oil) portion wise and then the ice bath was removed and the mixture was stirred for 15 minutes. The reaction mixture was treated with (R)-3-fluoropyrrolidine-1-sulfonyl chloride (20 g, 108 mmol) and then heated to 50 °C for 12 hours. The reaction mixture was cooled to ambient temperature and slowly poured into a stirring flask of ice water (500 mL) and then extracted with EtOAc (3 x 100 mL). The organic extracts were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50-100% Hexane/DCM). The desired fractions were combined and concentrated and then the resulting solids were sonicated with chilled MeOH, filtered, and rinsed with minimal MeOH to give tert-butyl (R)-(2-chloro-4-fluoro-3-iodophenyl)((3-fluoropyrrolidin-1-yl)sulfonyl)carbamate (21 g, 75%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 1H), 7.07-7.03 (m, 1H), 5.39-5.23 (m, 1H), 4.02-3.72 (m, 4H), 2.36-2.03 (m, 2H), 1.39 (s, 9H).
75% Stage #1: tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25h; Stage #2: (3R)-3-fluoropyrrolidine-1-sulfonyl chloride In tetrahydrofuran; mineral oil at 0 - 50℃; for 12h; 14.1.B Step 1: Preparation of tert-butyl (R)-(2-chloro-4-fluoro-3-iodophenyl)((3-fluoropyrrolidin-1-yl)sulfonyl)carbamate. Tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (Intermediate P9; 20 g, 54 mmol) was dissolved in THF (269 mL) and cooled to 0 °C. The reaction mixture was treated with sodium hydride (4.3 g, 108 mmol, 60% wt in mineral oil) portion wise and then the ice bath was removed and the mixture was stirred for 15 minutes. The reaction mixture was treated with (R)-3-fluoropyrrolidine-1-sulfonyl chloride (20 g, 108 mmol) and then heated to 50 °C for 12 hours. The reaction mixture was cooled to ambient temperature and slowly poured into a stirring flask of ice water (500 mL) and then extracted with EtOAc (3 x 100 mL). The organic extracts were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50-100% Hexane/DCM). The desired fractions were combined and concentrated and then the resulting solids were sonicated with chilled MeOH, filtered, and rinsed with minimal MeOH to give tert-butyl (R)-(2-chloro-4-fluoro-3-iodophenyl)((3-fluoropyrrolidin-1-yl)sulfonyl)carbamate (21 g, 75%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 1H), 7.07-7.03 (m, 1H), 5.39-5.23 (m, 1H), 4.02-3.72 (m, 4H), 2.36-2.03 (m, 2H), 1.39 (s, 9H).
 

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