[ CAS No. 264916-06-5 ] {[proInfo.proName]}

Name: 264916-06-5|tert-Butyl 5-aminoisoindoline-2-carboxylate|95%
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SKU: A129361
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Quality Control of [ 264916-06-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 264916-06-5 ]

SDS Specification

Alternatived Products of [ 264916-06-5 ]

Product Details of [ 264916-06-5 ]

CAS No. :	264916-06-5	MDL No. :	MFCD08234717
Formula :	C₁₃H₁₈N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WJFWIRWHYIDBAQ-UHFFFAOYSA-N
M.W :	234.29	Pubchem ID :	22591361
Synonyms :

Calculated chemistry of [ 264916-06-5 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.46
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	71.22
TPSA :	55.56 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.66 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.57
Log Po/w (XLOGP3) :	1.5
Log Po/w (WLOGP) :	1.84
Log Po/w (MLOGP) :	1.68
Log Po/w (SILICOS-IT) :	1.45
Consensus Log Po/w :	1.81

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.3
Solubility :	1.17 mg/ml ; 0.005 mol/l
Class :	Soluble
Log S (Ali) :	-2.27
Solubility :	1.25 mg/ml ; 0.00531 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.83
Solubility :	0.345 mg/ml ; 0.00147 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.93

Safety of [ 264916-06-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 264916-06-5 ]

* 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 [ 264916-06-5 ]
Downstream synthetic route of [ 264916-06-5 ]

[ 264916-06-5 ] Synthesis Path-Upstream 1~6

1
[ 400727-63-1 ]
[ 264916-06-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogen In ethanol at 20℃; for 15 h;	A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with tert-butyl 5-nitroisoindoline-2-carboxylate (650 mg, 2.5 mmol) and C₂H₅OH (50 mL). This solution was hydrogenated with Pd/C (160mg) at room temperature for 15 h. It was then filtered and the filtrate was concentrated under reduced pressure to afford 231c as a yellow oil (585 mg, 99percent), which was used in the next step without further purification. MS: [M+H]⁺ 179.
92.2%	With palladium 10% on activated carbon; hydrogen In methanol at 50℃;	To a solution of tert-butyl 5-nitroisoindoline-2-carboxylate (1.4) (3.8 g, 14.4 mmol) in MeOH (50 mL) was added 10percent Pd/C (380 mg). The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ balloon at 50 C overnight. TLC showed the reaction was complete. The suspension was filtered through celite, which was washed three times with MeOH. The combined filtrate was concentrated and the residue was purified by column chromatography (eluted 50percent EtOAc in hexanes) to afford tert-butyl 5- aminoisoindoline-2-carboxylate (1.5) (3.1 g, 92.2 percent). [00327] LCMS: 235.3[M+1]⁺.

Reference： [1] Patent: WO2011/140488, 2011, A1, . Location in patent: Page/Page column 331
[2] Patent: WO2016/90079, 2016, A1, . Location in patent: Paragraph 00326-00327
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5533 - 5535
[4] Russian Journal of Organic Chemistry, 2006, vol. 42, # 8, p. 1174 - 1182
[5] Patent: WO2011/17296, 2011, A1, . Location in patent: Page/Page column 47

2
[ 24424-99-5 ]
[ 264916-06-5 ]

Reference： [1] Russian Journal of Organic Chemistry, 2006, vol. 42, # 8, p. 1174 - 1182
[2] Patent: WO2011/17296, 2011, A1,

3
[ 46053-72-9 ]
[ 264916-06-5 ]

Reference： [1] Patent: WO2011/17296, 2011, A1,
[2] Patent: WO2011/140488, 2011, A1,

4
[ 496-12-8 ]
[ 264916-06-5 ]

Reference： [1] Patent: WO2011/140488, 2011, A1,

5
[ 832-51-9 ]
[ 264916-06-5 ]

Reference： [1] Patent: WO2016/90079, 2016, A1,

6
[ 1059172-96-1 ]
[ 264916-06-5 ]

Reference： [1] Patent: WO2016/90079, 2016, A1,

[ 264916-06-5 ] Synthesis Path-Downstream 1~87

1
[ 108-55-4 ]
[ 264916-06-5 ]
[ 890628-75-8 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

2
[ 54997-92-1 ]
[ 264916-06-5 ]
[ 956094-24-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 400 - 405

3
[ 264916-06-5 ]
[ 784137-02-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 400 - 405

4
[ 264916-06-5 ]
4-butyl-N-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 400 - 405

5
[ 24424-99-5 ]
[ 264916-06-5 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182
[2]Patent: WO2011/17296,2011,A1

6
[ 264916-06-5 ]
[ 945488-79-9 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

7
[ 264916-06-5 ]
[ 945488-70-0 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

8
[ 264916-06-5 ]
[ 945488-73-3 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

9
[ 264916-06-5 ]
[ 945488-71-1 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

10
[ 264916-06-5 ]
[ 945488-77-7 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

11
[ 264916-06-5 ]
[ 945488-78-8 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

12
[ 264916-06-5 ]
[ 945488-72-2 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

13
[ 264916-06-5 ]
[ 945488-75-5 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

14
[ 264916-06-5 ]
N-[5-(isoindolin-5-yl)amino-5-oxopentanoyl]-β-alanine hydrochloride [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

15
[ 264916-06-5 ]
[ 945488-74-4 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

16
[ 264916-06-5 ]
[ 945488-76-6 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

17
[ 264916-06-5 ]
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-β-(p-methoxyphenyl)-β-alanine hydrochloride [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

18
[ 264916-06-5 ]
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-β-(p-ethoxyphenyl)-β-alanine hydrochloride [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

19
[ 264916-06-5 ]
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-β-(p-isopropoxyphenyl)-β-alanine hydrochloride [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

20
[ 264916-06-5 ]
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-β-(3,4-dimethoxyphenyl)-β-alanine hydrochloride [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

21
[ 264916-06-5 ]
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-β-(3,4-methylenedioxyphenyl)-β-alanine hydrochloride [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

22
[ 264916-06-5 ]
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-β-(p-isobutyloxyphenyl)-β-alanine hydrochloride [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

23
[ 264916-06-5 ]
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-β-(p-propoxyphenyl)-β-alanine hydrochloride [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

24
[ 264916-06-5 ]
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-β-(p-butoxyphenyl)-β-alanine hydrochloride [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

25
[ 264916-06-5 ]
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-β-(p-isopentyloxyphenyl)-β-alanine hydrochloride [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182

26
[ 264916-06-5 ]
[ 807627-83-4 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5533 - 5535

27
[ 264916-06-5 ]
[ 807627-85-6 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182
[2]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182
[3]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5533 - 5535

28
[ 264916-06-5 ]
[ 807627-84-5 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5533 - 5535

29
[ 264916-06-5 ]
[ 807627-86-7 ]

30
[ 264916-06-5 ]
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-β-alanine hydrochloride [ No CAS ]

31
[ 264916-06-5 ]
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-β-phenyl-β-alanine hydrochloride [ No CAS ]

32
5-nitroisoindoline hydrobromide [ No CAS ]
[ 264916-06-5 ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 1174 - 1182
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5533 - 5535

33
[ 24424-99-5 ]
1.) NaH; 2.) SOCl₂ [ No CAS ]
[ 264916-06-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5533 - 5535

34
[ 264916-06-5 ]
5-(4-isobutoxycarbonyloxy-4-oxo-butyrylamino)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5533 - 5535

Yield	Reaction Conditions	Operation in experiment
		Then, 2-diphenylmethyl-5-nitroisoindoline (12.8 g) was dissolved into methanol (200 ml) and 4N ethyl acetate solution (20 ml) of hydrogen chloride and palladium supported on carbon (10%) were added. The resulting mixture was subjected to hydrogenation under the conditions of ambient temperature and normal pressure. After the completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved into a mixed solution of water and tetrahydrofuran (1/1=v/v)(200 ml) and 1N sodium hydroxide aqueous solution (120 ml) was added thereto. To the resulting mixture was added di-tert-butyl dicarbonate (9.3 g) and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate and then the extract solution was dried over anhydrous magnesium sulfate, followed by removal of the solvent by evaporation. The residue was purified by a silica gel column chromatography to give 5-amino-2-tert-butoxycarbonylisoindoline (7.7 g) as an oil. 1H-NMR(CDCl3) delta: 1.51(9H, s), 3.65(2H, bs), 4.50-4.63(4H, m), 6.52-6.64(2H, m), 6.95-7.08(1H, m).

36
[ 1493-27-2 ]
[ 264916-06-5 ]
[ 264916-07-6 ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium carbonate; In N-methyl-acetamide;	(2) 2-tert-Butoxycarbonyl-5-(2-nitrophenylamino)isoindoline A dimethylformamide (10 ml) suspension of <strong>[264916-06-5]5-amino-2-tert-butoxycarbonylisoindoline</strong> (5.3 g, 22.6 mmol), o-fluoronitrobenzene (7.15 ml, 22.6 mmol) and potassium carbonate (3.12 g, 22.6 mmol) was stirred at 145 C. for 2 hours under nitrogen atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography to give 2-tert-butoxycarbonyl-5-(2-nitrophenylamino)isoindoline (4.9 g, 61%) as an oil. 1H-NMR(CDCl3) delta: 1.53(9H, s), 4.67(2H, s), 4.70(2H, s), 6.76(1H, t, J=6.8 Hz), 7.15-7.41(5H, m), 8.20(1H, d, J=8.8 Hz), 9.47(1H, bs).

Reference： [1]Patent: US2003/149027,2003,A1

37
[ 122775-35-3 ]
[ 298-12-4 ]
[ 264916-06-5 ]
[ 1036389-24-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	In N,N-dimethyl-formamide; acetonitrile; at 110℃; for 0.166667h;Microwave irradiation;	tert-Butyl 5-aminoisoindoline-2-carboxylate (200 mg, 0.854 mmol),3,4-dimethoxyphenylboronic acid (155 mg, 0.854 mmol) and monohydrate glycolic acid (63 mg, 0.854 mmol) were dissolved in acetonitrile/DMF (2 mL each). The reaction was heated at 110 0C for 10 min. in a microwave. The reaction was concentrated to an oil and purified with preparatory HPLC to yield 12A (309 mg, 0.721 mmol) in 84% yield. 1H NMR (400 MHz, CDCl3) delta ppm 1.45 - 1.51 (m, 9 H) 3.84 - 3.88 (m, 6 H) 4.48 - 4.56 (m, 4 H) 4.99 (d, J=6.59 Hz, 1 H) 6.36 - 6.55 (m, 2 H). MS (ESI) m/z 429.4 (M+H).

Reference： [1]Patent: WO2008/79759,2008,A1 .Location in patent: Page/Page column 113

38
[ 264916-06-5 ]
2-methylisoindolin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With lithium borohydride; In tetrahydrofuran; at 5 - 20℃;	To a cooled solution of 2.0 M of lithium tetrahydroborate in tetrahydrofuran (13 mL, 26 mmol) at 5C was added dropwise a solution of 5-amino-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester (1.0 g, 4.3 mmol) in tetrahydrofuran (50 mL). Gas evolution was noted. The mixture was stirred for 1 hour at 5C then warmed to room temperature and stirred for 24 hours. The mixture was cooled to 5C in a ice/water bath and the reaction was quenched by addition of sodium sulfate decahydrate (3 g). Gas evolution noted. The mixture was stirred for 2 hours at room temperature. The suspension was filtered through a plug of diatomaceous earth and rinsed with with tetrahydrofuran. The filtrate was dried over magnesium sulfate, filtered and evaporated. The residue was purified via flash chromatography (silica gel column and 0%?20% methanol: dichloromethane). 2-Methyl-2,3-dihydro-lH-isoindol-5-ylamine was isolated as an orange solid (0.271 g, 43%). 1H NMR (400 MHz, (D3C)2SO, delta, ppm): 6.82 (d, J=I .9 Hz, IH), 6.41 (s, IH), 6.37 (d, J=8.1 Hz, IH), 4.86 (br s, 2H), 3.64 (s, 2H), 3.62 (s, 2H), 2.42 (s, 3H). MS = 149 (MH)+.

Reference： [1]Patent: WO2010/141796,2010,A2 .Location in patent: Page/Page column 248; 249

39
[ 46053-72-9 ]
[ 264916-06-5 ]

Reference： [1]Patent: WO2011/17296,2011,A1
[2]Patent: WO2011/140488,2011,A1

40
[ 1264926-40-0 ]
[ 264916-06-5 ]
[ 1264924-32-4 ]

Yield	Reaction Conditions	Operation in experiment
		To 517 mg of P14 in 15 ml_ of THF at O0C was added 350 mg of 60% sodium hydride in mineral oil and the mixture stirred for 10 minutes. 570 mg of P15 was then added and the mixture warmed to room temperature. After three days the reaction mixture was quenched with water then extracted three times with ethyl acetate. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness. Purification by flash chromatography yielded 450mg of 8. LCMS: 433.2 (MH+)

Reference： [1]Patent: WO2011/17296,2011,A1 .Location in patent: Page/Page column 48

41
[ 1264926-40-0 ]
[ 264916-06-5 ]
[ 1264924-35-7 ]

Reference： [1]Patent: WO2011/17296,2011,A1

42
[ 496-12-8 ]
[ 264916-06-5 ]

Reference： [1]Patent: WO2011/140488,2011,A1

43
[ 264916-06-5 ]
[ 1456885-52-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

44
[ 264916-06-5 ]
N-(isoindolin-5-yl)-2-(phenylamino)-4-(4-(pyrrolidin-2-yl)piperidine-1-carbonyl)benzamide trifluoroacetic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

45
[ 264916-06-5 ]
C₃₅H₄₃N₅O₂ [ No CAS ]
N-(2-ethylisoindolin-5-yl)-2-(phenylamino)-4-(4-(pyrrolidin-2-yl)piperidine-1-carbonyl)benzamide trifluoroacetic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

46
[ 264916-06-5 ]
[ 1456885-57-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

47
[ 264916-06-5 ]
[ 1456885-59-8 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

48
[ 264916-06-5 ]
N-(2-ethylisoindolin-5-yl)-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)benzamide trifluoroacetic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

49
[ 264916-06-5 ]
C₂₉H₃₆N₄O₂*C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

50
[ 264916-06-5 ]
N-(2-ethylisoindolin-5-yl)-4-(4-(pyrrolidin-2-yl)piperidine-1-carbonyl)benzamide trifluoroacetic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

51
[ 264916-06-5 ]
N-(2-ethylisoindolin-5-yl)-3-(phenylamino)-4-(4-(pyrrolidin-2-yl)piperidine-1-carbonyl)benzamide trifluoroacetic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

52
[ 566155-75-7 ]
[ 264916-06-5 ]
C₄₁H₅₁N₅O₆ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

53
[ 566155-75-7 ]
[ 264916-06-5 ]
C₂₇H₂₇N₃O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

54
[ 585-76-2 ]
[ 264916-06-5 ]
[ 1456886-09-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

55
[ 20576-82-3 ]
[ 76-05-1 ]
[ 264916-06-5 ]
[ 1456885-50-9 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7358 - 7371

56
(R)-1-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]
[ 264916-06-5 ]
(R)-tert-butyl 5-((4-((1-acryloylpiperidin-3-yl)amino)-5-fluoropyrimidin-2-yl)amino)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In tert-Amyl alcohol; for 2h;Reflux; Inert atmosphere;	[00329] A mixture of <strong>[264916-06-5]tert-butyl 5-aminoisoindoline-2-carboxylate</strong> (1.5) (400 mg, 1.71 mmol), 1-[(3R)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-1-piperidyl]prop-2-en-1-one (intermediate B, 486.1 mg, 1.71mmol), Cs2CO3 (1.11g, 3.41mmol), Pd2(dba)3 (156 mg, 0.17 mmol) and DavePhos (168 mg, 0.43 mmol) in t-AmOH (10 mL) was heated to reflux for 2 h under nitrogen atmosphere. TLC showed the reaction was complete. The resulting mixture was cooled to room temperature and partitioned between EtOAc and water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluted with 50% EtOAc in hexanes) to afford (R)-tert-butyl 5-((4-((1-acryloylpiperidin-3-yl)amino)-5-fluoropyrimidin-2-yl)amino)iso-indoline-2- carboxylate (1.6) (700 mg, 85%). [00330] LCMS: 483.3[M+1]+.

Reference： [1]Patent: WO2016/90079,2016,A1 .Location in patent: Paragraph 00329-00330

57
[ 832-51-9 ]
[ 264916-06-5 ]