Potassium Phosphate, Tribasic → methyl 3-((5-chloro-2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

HRID 539922노트

반응식

HRID 539922 반응식
Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]3)[CH:10]2[C:17]([O:19][CH3:20])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:30][C:31]1[CH:32]=[C:33]2[C:39](B3OC(C)(C)C(C)(C)O3)=[N:38][N:37]([C:49]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:34]2=[N:35][CH:36]=1.B([O-])[O-]>O.C1COCC1.CCOC(C)=O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:5]1[C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]3)[CH:10]2[C:17]([O:19][CH3:20])=[O:18])=[N:7][C:2]([C:39]2[C:33]3[C:34](=[N:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:37]([C:49]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:38]=2)=[N:3][CH:4]=1

참가 물질

10

반응물 4

HCID 62657Potassium Phosphate, TribasicHCID 679757175-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridineHCID 86707194Methyl 3-((2,5-dichloropyrimidin-4-yl)amino)-bicyclo-[2.2.2]octane-2-carboxylateHCID 178514824HCID 178514824, 화합물

생성물 1

HCID 86707193methyl 3-((5-chloro-2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate수율 83%

시약·촉매·용매 5

HCID 178418397HCID 178418397, 화합물촉매HCID 962Water용매HCID 6344Dichloromethane용매HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매2회

반응 조건

온도
90 °C

실험 절차

A solution of (+/−)-trans-(2,3)-methyl 3-((2,5-dichloropyrimidin-4-yl)amino)-bicyclo-[2.2.2]octane-2-carboxylate, 37, (0.50 g, 1.51 mmol) and K3PO4 (0.96 g, 4.54 mmol) in water (2.5 mL) and THF (10.00 mL) was degassed for 15 min with a stream of nitrogen. Then, 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine, 6, (0.84 g, 1.67 mmol) was added and the mixture was degassed for an additional 15 min. Then, Pd(PPh3)4 (0.09 g, 0.08 mmol) was added to the mixture. The vessel was sealed and heated to 90° C. After 2.5 hr., an additional 0.1 equivalent of boronate, 6, was added and the mixture was heated for an additional 30 min. The cooled solution was diluted with EtOAc, washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-35% EtOAc in DCM) gave the desired product (0.85 g, 83% yield) which was sufficiently pure for use in the next reaction: LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=3.85 min, (M+H) 673.27.

후처리

  1. customthe mixture was degassed for an additional 15 min
  2. customThe vessel was sealed
  3. temperaturethe mixture was heated for an additional 30 min
  4. washwashed with water
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo

출처 및 근거

ORD 기록
ord-bd525aa0983d435a95cbcdd02603b08f
출처 데이터셋
uspto-grants-2014_10
특허 번호
US08871774B2

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