[ CAS No. 1408074-83-8 ] {[proInfo.proName]}

Name: 1408074-83-8|tert-Butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate|95%
Brand: Ambeed
SKU: A230176
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Quality Control of [ 1408074-83-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1408074-83-8 ]

CAS No. :	1408074-83-8	MDL No. :	MFCD23105898
Formula :	C₉H₁₆F₂N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DODJSPBKCAGGTQ-UHFFFAOYSA-N
M.W :	222.23	Pubchem ID :	72207756
Synonyms :

Calculated chemistry of [ 1408074-83-8 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.89
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	54.63
TPSA :	55.56 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.17 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.13
Log Po/w (XLOGP3) :	0.68
Log Po/w (WLOGP) :	1.66
Log Po/w (MLOGP) :	0.86
Log Po/w (SILICOS-IT) :	0.51
Consensus Log Po/w :	1.17

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.45
Solubility :	7.92 mg/ml ; 0.0356 mol/l
Class :	Very soluble
Log S (Ali) :	-1.42
Solubility :	8.38 mg/ml ; 0.0377 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.19
Solubility :	14.3 mg/ml ; 0.0644 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.93

Safety of [ 1408074-83-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1408074-83-8 ]

* 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.

Upstream synthesis route of [ 1408074-83-8 ]
Downstream synthetic route of [ 1408074-83-8 ]

[ 1408074-83-8 ] Synthesis Path-Upstream 1~4

1
[ 1610703-68-8 ]
[ 1408074-83-8 ]

Reference： [1] Patent: WO2014/75393, 2014, A1, . Location in patent: Page/Page column 65; 66
[2] Patent: US2015/141402, 2015, A1, . Location in patent: Paragraph 0742; 0743

2
[ 1648727-30-3 ]
[ 1408074-83-8 ]

Reference： [1] Patent: WO2014/75393, 2014, A1,

3
[ 203434-45-1 ]
[ 1408074-83-8 ]

Reference： [1] Patent: WO2014/75393, 2014, A1,

4
[ 1434141-81-7 ]
[ 1408074-83-8 ]

Reference： [1] Patent: US2015/141402, 2015, A1,

[ 1408074-83-8 ] Synthesis Path-Downstream 1~13

1
[ 1610703-67-7 ]
[ 1408074-83-8 ]
[ 1610703-91-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; at 20 - 90℃; for 120.0h;	To a solution of tert-butyl 4-amino-3, 3-difluoropyrrolidine-l-carboxylate (880 mg, 4 mmol) in t-BuOH (5 mL) was added DIEA (0.7 mL, 4 mmol) and Intermediate IA (400 mg, 1.5 mmol) at RT. The mixture was heated to 90 °C and stirred at this temperature for 5 days. The solution was then cooled and the solvents were removed under reduced pressure. The residue obtained was purified by reverse-phase preparative HPLC (Column: Xbridge Prep C18 10 um OBD, 19 x 250 mm; Mobile phase: A: water (10 mM NH4HCO3), B: MeCN; Flow rate: 30 mL/min; UV detection: 214/254 nm) to afford tert-butyl 4-(9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6- ylamino)-3,3-difluoropyrrolidine-l-carboxylate (1-21). 1H NMR (400 MHz, CD3OD) delta 9.22 - 9.10 (m, 2H), 8.39 (s, 1H), 5.52 - 5.43 (m, 1H), 4.41 (q, / = 7.2 Hz, 2H), 4.10 - 3.73 (m, 3H), 3.52 - 3.39 (m, 1H), 2.83 (s, 3H), 1.49 (s, 9H), 1.46 (t, / = 7.2 Hz, 3H). MS (ESI) calc'd for (C21H27F2N8O2) [M+H]+, 461 ; found, 461.

Reference： [1]Patent: WO2014/75393,2014,A1 .Location in patent: Page/Page column 66

2
[ 1648727-30-3 ]
[ 1408074-83-8 ]

Reference： [1]Patent: WO2014/75393,2014,A1

3
[ 203434-45-1 ]
[ 1408074-83-8 ]

Reference： [1]Patent: WO2014/75393,2014,A1

4
[ 1610703-68-8 ]
[ 1408074-83-8 ]

Yield	Reaction Conditions	Operation in experiment
	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 15.0h;Inert atmosphere;	To a stirred solution of tert-butyl 4-azido-3, 3-difluoropyrrolidine-l-carboxylate (1.4 g, 5.6 mmol) in MeOH (10 mL) was added Pd/C (10percent by weight) (0.2 g, 10percent by weight, 0.188 mmol) at RT. The mixture was degassed with nitrogen, and subsequently the mixture was stirred under a balloon at RT for 15 h . The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to provide tert-butyl 4-amino-3, 3-difluoropyrrolidine-l-carboxylate. MS (ESI) calc'd for (C5H9F2N202) [M-tBu+2H]+, 167; found, 167.
	With palladium on carbon; hydrogen; In ethanol; for 16.0h;	A solution of tert-butyl 4-azido-3,3-difluoropyrrolidine-1-carboxylate (3.01 g, 12.1 mmol) in ethanol (300 mL) was degassed with nitrogen and 20percent Pd/C (300 mg) was added. The resulting mixture was stirred under hydrogen atmosphere (balloon) for 16 hr. The catalyst was removed by filtration. The filtrate was evaporated to give the title product as an oil (2.63 g, 98percent yield, >85percent purity). 1H NMR (400 MHz, chloroform-d) delta ppm 3.73-3.87 (m, 2H) 3.69 (d, J=10.64 Hz, 1H) 3.50-3.62 (m, 1H) 3.13 (d, J=6.85 Hz, 1H) 1.45-1.48 (m, 9H). 19F NMR (376 MHz, chloroform-d) delta ppm ?115.05-?110.78 (m, 1F) ?120.95-?117.90 (m, 1F). m/z (APCI+) for C9H16F2N2O2 123 (M+H)+

Reference： [1]Patent: WO2014/75393,2014,A1 .Location in patent: Page/Page column 65; 66
[2]Patent: US2015/141402,2015,A1 .Location in patent: Paragraph 0742; 0743

5
[ 1434141-81-7 ]
[ 1408074-83-8 ]

Reference： [1]Patent: US2015/141402,2015,A1

6
tert-butyl 3,3-difluoro-4-[(trifluoromethyl)sulfonyl]oxy}pyrrolidine-1-carboxylate [ No CAS ]
[ 1408074-83-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With tetrabutylammoniun azide; In N,N-dimethyl-formamide; at 20℃; for 3.0h;Inert atmosphere; Cooling with ice;	tert-butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)pyrrolidine-1-carboxylate (1500 mg, 4.22 mmol), prepared following WO2017103611 example 160, was dissolved in DMF (20 mL) and cooled in an ice bath under N2 atmosphere. tetrabutylammonium azide (1200 mg, 4.22 mmol) in DMF (20 mL) was added slowly over 15 min via an addition funnel. The reaction mixture was stirred in the cold bath and allowed to warm to ambient temperature gradually and stirred for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with sat. aq. NaHCO3 (×2) and brine (×2). The organic phase was dried over a phase separator and purged with vacuum/N2 (3 times) followed by 10 the addition of palladium, 10 wt. % on carbon powder, dry (150 mg, 1.4 mmol).3 cycles vacuum/H2 were then performed and the reaction was left stirring at RT overnight under an atmosphere of hydrogen. The crude was filtered through a plug of CeliteTM and the solvent removed in vacuo. The product was purified by silica column chromatography using as eluting with 0-5% MeOH in DCM to afford [tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (934 mg, 4.2 mmol, 99% yield) ] as a 15 colourless oil. UPLC-MS (ES+, Method A), 1.04 min, m/z 167.0 [M-(tBu)+H]+

Reference： [1]Patent: WO2019/145729,2019,A1 .Location in patent: Page/Page column 259
[2]Patent: US2015/141402,2015,A1

7
[ 645-83-0 ]
[ 1408074-83-8 ]
tert-butyl 3,3-difluoro-4-[3-(methylsulfonyl)propanoyl]amino}pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2.0h;Inert atmosphere;	To a reaction flask was added tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (1.36 g, 6.12 mmol), <strong>[645-83-0]3-(methylsulfonyl)propanoic acid</strong> (1.02 g, 6.73 mmol, 1.1 mol eq), DCM (31 mL, 0.4 M), NMM (1.35 mL, 12.2 mmol, 2 mol eq), HOBt (1.31 g, 9.2 mmol, 1.5 mol eq) and EDC-HCl (1.85 g, 9.2 mmol, 1.5 mol eq). The resulting suspension was stirred at ambient temperature under a nitrogen atmosphere for 2 hr. The reaction was diluted with DCM (80 mL), washed with aqueous NaHCO3 (2×30 mL) and the organic layer was dried over Na2SO4 and evaporated to give a residue that was purified via silica flash chromatography eluting with gradients from 100percent heptane to 100percent ethyl acetate to give the title product as a white foamy solid (1.65 g, 76percent yield, >95percent purity). 1H NMR (400 MHz, chloroform-d) delta ppm 6.45 (br. s., 1H) 4.68-4.89 (m, 1H) 3.94 (dd, J=10.70, 8.62 Hz, 1H) 3.62-3.86 (m, 2H) 3.43 (t, J=7.15 Hz, 2H) 3.18 (br. s., 1H) 2.97 (s, 3H) 2.84 (td, J=7.15, 1.96 Hz, 2H) 1.47 (s, 9H). 19F NMR (376 MHz, chloroform-d) delta ppm ?112.79-?110.52 (m, 1F) ?114.51-?113.30 (m, 1F). m/z (APCI+) for C13H22F2N2O5S 257.1 (M+H)+

Reference： [1]Patent: US2015/141402,2015,A1 .Location in patent: Paragraph 0744; 0745

8
[ 1408074-83-8 ]
4-chloro-3-nitroquinoline-6-carbonitrile [ No CAS ]
tert-butyl 4-[(6-cyano-3-nitroquinolin-4-yl)amino]-3,3-difluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 14.0h;	tert-Butyl 4-am ino-3,3-difluoropyrrolidine-1 -carboxylate (prepared using themethod described by D. C. Behenna et al., in U.S. Published Patent Application 20150141402 Al, May 21, 2015; 2.30 g, 10.3 mmol) was dissolved in acetonitrile (20 mL). N,N-Diisopropylethylamine (2.01 g, 15.5 mmol) and C224 (3.04 g, 13.0 mmol) were added to this solution, and the reaction mixture was stirred for 14 hours at 20 °C. After removal of volatiles in vacuo, purification via silica gel chromatography (Gradient: 9percent to17percent tetrahydrofuran in petroleum ether) provided the product as a pale yellow solid.Yield: 3.20 g, 7.63 mmol, 74percent. H NMR (400 MHz, CDCI3) 9.52 (5, 1H), 9.21-9.04 (brm, 1H), 8.48 (br s, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.00 (dd, J=8.6, 1.5 Hz, 1H), 4.88-4.74(m, 1H), 4.23 (br dd, J=9.7, 8.8 Hz, 1H), 4.05-3.89 (br m, 1H), 3.89-3.75 (m, 1H), 3.60(ddd, J=ii.4, 8.4, 1.3 Hz, 1H), 1.51 (5, 9H).
74%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 14.0h;	tert-Butyl 4-amino-3,3-difluoropyrrolidine-1 -carboxylate (prepared using the method described by D. C. Behenna et al., in U.S. Patent Application 2015 0141402 Al May 21 2015; 2.30 g, 10.3 mmol) was dissolved in acetonitrile (20 mL). N,N15 Diisopropylethylamine (2.01 g, 15.5 mmol) and CII (3.04 g, 13.0 mmol) were added tothis solution, and the reaction mixture was stirred for 14 hours at 20 °C. After removal of volatiles in vacuo, purification via silica gel chromatography (Gradient: 9percent to 17percent tetrahydrofuran in petroleum ether) provided the product as a pale yellow solid. Yield:3.20g, 7.63mmol, 74percent. H NMR(400MHz, CDCI3)E9.52(s, 1H), 9.21-9.04(brm,1 H), 8.48 (br s, 1 H), 8.20 (d, J=8.8 Hz, 1 H), 8.00 (dd, J=8.6, 1.5 Hz, 1 H), 4.88-4.74 (m,1 H), 4.23 (br dd, J=9.7, 8.8 Hz, 1 H), 4.05-3.89 (br m, 1 H), 3.89-3.75 (m, 1 H), 3.60 (ddd, J=ll.4, 8.4, 1.3 Hz, 1H), 1.51 (5, 9H).

Reference： [1]Patent: WO2018/163030,2018,A1 .Location in patent: Page/Page column 75; 76
[2]Patent: WO2018/163066,2018,A1 .Location in patent: Page/Page column 61; 62

9
[ 1408074-83-8 ]
[ 99010-07-8 ]
tert-butyl 3,3-difluoro-4-[(6-fluoro-3-nitroquinolin-4-yl)amino]pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 48.0h;	To a 15°C solution of 4-chloro-6-fluoro-3-nitroquinoline (10.0 g, 44.1 mmol) inacetonitrile (50 mL) was added N,N-diisopropylethylamine (6.84 g, 52.9 mmol), followed by addition of <strong>[1408074-83-8]tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate</strong> (prepared usingthe method described by D. C. Behenna et al., in U.S. Patent Application 2015 0141402 Al May 21 2015; 9.81 g, 44.1 mmol). The reaction mixture was stirred at 20 °C for 48 hours, whereupon it was concentrated in vacuo and purified via chromatography onsilica gel (Gradient: 9percent to 17percent tetrahydrofuran in petroleum ether) to afford the product as a pale yellow solid. Yield: 16.8 g, 40.7 mmol, 92percent. 1H NMR (400 MHz, CDCI3) 9.39(5, 1H), 8.87-8.69(brm, 1H), 8.13(dd, J=9.5, 5.5 Hz, 1H), 7.79-7.70(brd, J=8 Hz, 1H),7.63 (ddd, J=9.0, 7.5, 2.5 Hz, 1H), 4.87-4.71 (br m, 1H), 4.31 -4.09 (br m, 1H), 4.04-3.84 (br m, 1 H), 3.84-3.69 (m, 1 H), 3.63-3.51 (br m, 1 H), 1.50 (5, 9H).

Reference： [1]Patent: WO2018/163066,2018,A1 .Location in patent: Page/Page column 86

10
[ 1408074-83-8 ]
[ 39487-85-9 ]
tert-butyl 4-[(6-chloro-3-nitroquinolin-4-yl)amino]-3,3-difluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 32.0h;	To a solution of C7 (13.1 g, 53.9 mmol) in acetonitrile (60 mL) was added N,Ndiisopropylethylamine (11.3 mL, 64.9 mmol), followed by addition of a solution of tertbutyl 4-amino-3,3-difluoropyrrolidine-1 -carboxylate (prepared using the methoddescribed by D. C. Behenna et al., in U.S. Patent Application 2015 0141402 Al, May21 2015; 12.0 g, 54.0 mmol) in acetonitrile (5 mL). After the reaction mixture had beenstirred at 20 °C for 32 hours, it was diluted with water (100 mL). The resulting solid wascollected by filtration and purified via chromatography on silica gel (Gradient: 0percent to25percent tetrahydrofuran in petroleum ether), affording the product as a yellow solid. Yield:12.0 g, 28.0 mmol, 52percent. LCMS m/z 428.7 (chlorine isotope pattern observed) [M+H].1H NMR (400 MHz, CDCl3)9.4l (5, 1H), 8.91-8.78(brm, 1H), 8.08 (brs, 1H), 8.06(d, J=9.0 Hz, 1H), 7.79(dd, J=9.0, 2.0 Hz, 1H), 4.86-4.72 (brm, 1H), 4.30-4.12(brm, 1H), 4.03-3.86 (br m, 1 H), 3.86-3.71 (m, 1 H), 3.64-3.52 (br m, 1 H), 1.51 (5, 9H).

Reference： [1]Patent: WO2018/163066,2018,A1 .Location in patent: Page/Page column 88

11
[ 1408074-83-8 ]
5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid [ No CAS ]
tert-butyl 4-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinamido)-3,3-difluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 23℃; for 2.0h;	To a solution of 5-(4- amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (130 mg, 0.368 mmol), <strong>[1408074-83-8]tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate</strong> (82 mg, 0.368 mmol) and DIPEA (0.193 mL, 1.104 mmol) in DMF (2 mL) was added BOP (195 mg, 0.442 mmol). The reaction mixture was stirred at 23 °C for 2 h. The reaction mixture was diluted with EtOAc (80 mL) which was washed with 10 percent LiCl solution (2 x 30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. Filtration and concentration yielded tert-butyl 4-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2- methoxynicotinamido)-3,3-difluoropyrrolidine-1-carboxylate (248 mg, 0.439 mmol, ~100 percent yield). (1207) MS ESI m/z 558.1 (M+H)+ (1208) 1H NMR (400 MHz, DMSO-d6) delta 8.94 (d, J=2.4 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.65 (d, J=8.7 Hz, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 5.14 - 4.94 (m, 1H), 4.03 (s, 3H), 3.90 - 3.47 (m, 4H), 1.43 (s, 9H).

Reference： [1]Patent: WO2019/147782,2019,A1 .Location in patent: Page/Page column 378; 379

12
[ 27746-99-2 ]
[ 1408074-83-8 ]
2,2,2-trifluoroethyl N-(4,4-difluoropyrrolidin-3-yl)carbamate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,2,2-trifluoroethyl carbonochloridate; tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.333333h; Stage #2: With hydrogenchloride In 1,4-dioxane; water monomer at 20℃; for 4h;	Intermediate 208. 2,2,2-trifluoroethyl N-(4,4-difluoropyrrolidin-3- yl)carbamate;hydrochloride To an ice cold solution of tert-butyl 4-amino-3,3-difluoro-pyrrolidine-1-carboxylate (0.258 g, 1.16 mmol, 1 equiv) in DCM (5 mL) was added N,N-Diisopropylethylamine (0.243 mL, 1.39 mmol, 1.2 equiv) and 2,2,2-trifluoroethyl carbonochloridate (0.201 g, 1.24 mmol, 1.07 equiv). After stirring at 0oC for 20 min, the reaction mixture was purified by SiO2 chromatography (0-50% EtOAc/Hex). Fractions were combined and concentrated. The residue obtained was treated with 4M HCl/dioxane (10 mL) and was further stirred for 8h at room temperature. The reaction mixture was concentrated and was dried at high vacuum overnight to afford 2,2,2-trifluoroethyl N-(4,4-difluoropyrrolidin-3-yl)carbamate; hydrochloride. ES/MS m/z: 249.10 [M+H].
	Stage #1: 2,2,2-trifluoroethyl carbonochloridate; tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.333333h; Stage #2: With hydrogenchloride In 1,4-dioxane; water monomer at 20℃; for 4h;	Intermediate 208. 2,2,2-trifluoroethyl N-(4,4-difluoropyrrolidin-3- yl)carbamate;hydrochloride To an ice cold solution of tert-butyl 4-amino-3,3-difluoro-pyrrolidine-1-carboxylate (0.258 g, 1.16 mmol, 1 equiv) in DCM (5 mL) was added N,N-Diisopropylethylamine (0.243 mL, 1.39 mmol, 1.2 equiv) and 2,2,2-trifluoroethyl carbonochloridate (0.201 g, 1.24 mmol, 1.07 equiv). After stirring at 0oC for 20 min, the reaction mixture was purified by SiO2 chromatography (0-50% EtOAc/Hex). Fractions were combined and concentrated. The residue obtained was treated with 4M HCl/dioxane (10 mL) and was further stirred for 8h at room temperature. The reaction mixture was concentrated and was dried at high vacuum overnight to afford 2,2,2-trifluoroethyl N-(4,4-difluoropyrrolidin-3-yl)carbamate; hydrochloride. ES/MS m/z: 249.10 [M+H].

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/222522, 2021, A1 Location in patent: Paragraph 0960
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/222522, 2021, A1 Location in patent: Paragraph 0960

13
[ 1408074-83-8 ]
[ 141-97-9 ]
[ 553-97-9 ]
[ 100-51-6 ]
tert-butyl 4-(5-(benzyloxy)-2,6-dimethylbenzofuran-3-carboxamido)-3,3-difluoropyrrolidine-1-carboxylate [ No CAS ]
tert-butyl 4-(5-(benzyloxy)-2,7-dimethylbenzofuran-3-carboxamido)-3,3-difluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: ethyl 3-oxobutanoate; 2-Methyl-1,4-benzoquinone With anhydrous zinc chloride In toluene for 16h; Inert atmosphere; Reflux; Dean-Stark; Stage #2: benzylic alcohol With tributylphosphine; 1,1'-(azodicarboxylic)dipiperidide In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; Stage #3: tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate Overall yield = 0.9 g; Further stages;	1; 2; 3; 4 Step 1: To a pre-stirred solution of 2-methylcyclohexa-2,5-diene-1,4-dione (10.0 g, 81.96 mmol) in toluene (250 mL) was added ethyl 3-oxobutanoate (31.9 g, 245.89 mmol) followed by anhydrous ZnCl2 (13.4 g, 98.35 mmol) at RT under argon atmosphere. The resulting RM was heated to reflux and maintained for 16 h using a Dean-Stark apparatus. The reaction progress was monitored by TLC. The RM was cooled to RT, filtered through celite pad and the celite pad was washed with EtOAc (300 mL). The combined clear filtrate was concentrated under reduced pressure. The crude product was purified by FCC over silica gel using 0-10% EtOAc in pet-ether as an eluent to afford a mixture of ethyl 5-hydroxy-2,7-dimethylbenzofuran-3-carboxylate and ethyl 5-hydroxy- 2,6-dimethylbenzofuran-3-carboxylate (10.0 g, 52%). Phenylmethanol (4.7 g, 32.05 mmol), ADDP (7.53 g, 29.91 mmol) and tri-n-butylphosphine (7.36 mL, 29.91 mmol) were added sequentially to a pre-stirred solution of mixture of ethyl 5-hydroxy-2,7- dimethylbenzofuran-3-carboxylate and ethyl 5-hydroxy-2,6-dimethylbenzofuran-3-carboxylate (5.0 g, 21.36 mmol) in THF (250 mL) at 0oC under argon atmosphere. The RM was allowed to attain RT and stirred for 3 h. The reaction progress was monitored by TLC. The RM was poured into water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by GRACE flash chromatography using 0- 60% acetonitrile and 0.1% FA in water as an eluent to afford a mixture of ethyl 5-(benzyloxy)-2,7- dimethylbenzofuran-3-carboxylate and ethyl 5-(benzyloxy)-2,6-dimethylbenzofuran-3-carboxylate (4.0 g, 41%). A solution of NaOH (2.4 g, 61.7 mmol) in water (32 mL) was added to a pre-stirred solution of mixture of ethyl 5-(benzyloxy)-2,7-dimethylbenzofuran-3-carboxylate and ethyl 5-(benzyloxy)-2,6- dimethylbenzofuran-3-carboxylate (4.0 g, 12.3 mmol) in a mixture of MeOH (40 mL) and THF (40 mL) at RT. The resulting RM was heated to 60oC and maintained for 3 h. The reaction progress was monitored by TLC. The RM was cooled to RT, poured into ice cold water (200 mL) and acidified with 1N HCl (pH~2). The crude product was extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with water (2 x 100 mL) followed by brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a mixture of 5-(benzyloxy)-2,7-dimethylbenzofuran-3-carboxylic acid and 5-(benzyloxy)-2,6-dimethylbenzofuran- 3-carboxylic acid (2.0 g, 54%). The obtained crude product mixture was used for next step without further purification. To a pre-stirred solution of mixture of 5-(benzyloxy)-2,7-dimethylbenzofuran-3-carboxylic acid and 5-(benzyloxy)-2,6-dimethylbenzofuran-3-carboxylic acid (1 5.g, 5.1 mmol) and tert-butyl 4-amino-3,3- difluoropyrrolidine-1-carboxylate (1.12 g, 5.1 mmol) in DMF (20 mL) was added DIPEA (2.7 mL, 15.2 mmol) followed by HATU (3.85 g, 10.1 mmol) at 0oC under argon atmosphere. The RM was allowed to attain RT and stirred for 3 h. The reaction progress was monitored by TLC. The RM was diluted with ice cold water (50 mL) and filtered. The obtained solid was washed with water (200 mL), dried under reduced pressure to afford a mixture of tert-butyl 4-(5-(benzyloxy)-2,7-dimethylbenzofuran-3-carboxamido)-3,3-difluoropyrrolidine-1-carboxylate and tert-butyl.4-(5-(benzyloxy)-2,6-dimethylbenzofuran-3-carboxamido)-3,3-difluoropyrrolidine-1- carboxylate (0.9 g, 65%).
	Stage #1: ethyl 3-oxobutanoate; 2-Methyl-1,4-benzoquinone With anhydrous zinc chloride In toluene for 16h; Inert atmosphere; Reflux; Dean-Stark; Stage #2: benzylic alcohol With tributylphosphine; 1,1'-(azodicarboxylic)dipiperidide In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; Stage #3: tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate Overall yield = 0.9 g; Further stages;	1; 2; 3; 4 Step 1: To a pre-stirred solution of 2-methylcyclohexa-2,5-diene-1,4-dione (10.0 g, 81.96 mmol) in toluene (250 mL) was added ethyl 3-oxobutanoate (31.9 g, 245.89 mmol) followed by anhydrous ZnCl2 (13.4 g, 98.35 mmol) at RT under argon atmosphere. The resulting RM was heated to reflux and maintained for 16 h using a Dean-Stark apparatus. The reaction progress was monitored by TLC. The RM was cooled to RT, filtered through celite pad and the celite pad was washed with EtOAc (300 mL). The combined clear filtrate was concentrated under reduced pressure. The crude product was purified by FCC over silica gel using 0-10% EtOAc in pet-ether as an eluent to afford a mixture of ethyl 5-hydroxy-2,7-dimethylbenzofuran-3-carboxylate and ethyl 5-hydroxy- 2,6-dimethylbenzofuran-3-carboxylate (10.0 g, 52%). Phenylmethanol (4.7 g, 32.05 mmol), ADDP (7.53 g, 29.91 mmol) and tri-n-butylphosphine (7.36 mL, 29.91 mmol) were added sequentially to a pre-stirred solution of mixture of ethyl 5-hydroxy-2,7- dimethylbenzofuran-3-carboxylate and ethyl 5-hydroxy-2,6-dimethylbenzofuran-3-carboxylate (5.0 g, 21.36 mmol) in THF (250 mL) at 0oC under argon atmosphere. The RM was allowed to attain RT and stirred for 3 h. The reaction progress was monitored by TLC. The RM was poured into water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by GRACE flash chromatography using 0- 60% acetonitrile and 0.1% FA in water as an eluent to afford a mixture of ethyl 5-(benzyloxy)-2,7- dimethylbenzofuran-3-carboxylate and ethyl 5-(benzyloxy)-2,6-dimethylbenzofuran-3-carboxylate (4.0 g, 41%). A solution of NaOH (2.4 g, 61.7 mmol) in water (32 mL) was added to a pre-stirred solution of mixture of ethyl 5-(benzyloxy)-2,7-dimethylbenzofuran-3-carboxylate and ethyl 5-(benzyloxy)-2,6- dimethylbenzofuran-3-carboxylate (4.0 g, 12.3 mmol) in a mixture of MeOH (40 mL) and THF (40 mL) at RT. The resulting RM was heated to 60oC and maintained for 3 h. The reaction progress was monitored by TLC. The RM was cooled to RT, poured into ice cold water (200 mL) and acidified with 1N HCl (pH~2). The crude product was extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with water (2 x 100 mL) followed by brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a mixture of 5-(benzyloxy)-2,7-dimethylbenzofuran-3-carboxylic acid and 5-(benzyloxy)-2,6-dimethylbenzofuran- 3-carboxylic acid (2.0 g, 54%). The obtained crude product mixture was used for next step without further purification. To a pre-stirred solution of mixture of 5-(benzyloxy)-2,7-dimethylbenzofuran-3-carboxylic acid and 5-(benzyloxy)-2,6-dimethylbenzofuran-3-carboxylic acid (1 5.g, 5.1 mmol) and tert-butyl 4-amino-3,3- difluoropyrrolidine-1-carboxylate (1.12 g, 5.1 mmol) in DMF (20 mL) was added DIPEA (2.7 mL, 15.2 mmol) followed by HATU (3.85 g, 10.1 mmol) at 0oC under argon atmosphere. The RM was allowed to attain RT and stirred for 3 h. The reaction progress was monitored by TLC. The RM was diluted with ice cold water (50 mL) and filtered. The obtained solid was washed with water (200 mL), dried under reduced pressure to afford a mixture of tert-butyl 4-(5-(benzyloxy)-2,7-dimethylbenzofuran-3-carboxamido)-3,3-difluoropyrrolidine-1-carboxylate and tert-butyl.4-(5-(benzyloxy)-2,6-dimethylbenzofuran-3-carboxamido)-3,3-difluoropyrrolidine-1- carboxylate (0.9 g, 65%).

Reference： [1]Current Patent Assignee: KATHOLIEKE UNIVERSITEIT LEUVEN - WO2022/112345, 2022, A1 Location in patent: Paragraph 0272-0275
[2]Current Patent Assignee: KATHOLIEKE UNIVERSITEIT LEUVEN - WO2022/112345, 2022, A1 Location in patent: Paragraph 0272-0275

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Fluorinated Building Blocks

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