Cesium fluoride → Methyl 4-amino-3-chloro-6-(4-cyclopropylphenyl)-5-fluoropicolinate

HRID 1754144

반응식

HRID 1754144 반응식
[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]=1[Cl:23].[CH:24]1([C:27]2C=CC(B(O)O)=C[CH:28]=2)[CH2:26][CH2:25]1.NC1C(F)=C(Cl)N=C(C(OC)=O)C=1Cl.[F-].[Cs+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.[Na+].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[CH2:16][CH2:17]3)=[CH:13][CH:14]=2)[N:5]=[C:4]([C:18]([O:20][CH2:21][C:22]2[CH:28]=[CH:27][CH:24]=[CH:25][CH:26]=2)=[O:19])[C:3]=1[Cl:23].[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[CH2:16][CH2:17]3)=[CH:13][CH:14]=2)[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:23]

참가 물질

10

반응물 5

HCID 25953Cesium fluorideHCID 28494284-Cyclopropylbenzeneboronic acidHCID 6099338Trisodium 3,3',3''-phosphinetriyltris(benzene-1-sulphonate)HCID 22677265Methyl 4-amino-3,6-dichloro-5-fluoropicolinateHCID 70496775Ethyl 4-amino-3-chloro-6-(4-cyclopropylphenyl)-5-fluoropicolinate

생성물 2

HCID 70497242Methyl 4-amino-3-chloro-6-(4-cyclopropylphenyl)-5-fluoropicolinate수율 78%HCID 70497682Benzyl 4-amino-3-chloro-6-(4-cyclopropylphenyl)-5-fluoropicolinate

시약·촉매·용매 3

HCID 167845palladium(II) acetate촉매HCID 962Water용매HCID 18373917Acetonitrile--water (1/1)용매

반응 조건

온도
150 °C

실험 절차

Ethyl 4-amino-3-chloro-6-(4-cyclopropylphenyl)-5-fluoropicolinate. 4-Cyclopropylphenylboronic acid (250 mg, 1.5 mmol, 1.2 equiv) and methyl 4-amino-3,6-dichloro-5-fluoropicolinate (300 mg, 1.3 mmol, 1.0 equiv) were sequentially added to a 5 mL Biotage microwave vessel, followed by CsF (380 mg, 2.5 mmol, 2.0 equiv), palladium(II) acetate (14 mg, 0.063 mmol, 0.05 equiv), and sodium 3,3′,3″-phosphinetriyl-tribenzenesulfonate (71 mg, 0.13 mmol, 0.10 equiv). A 3:1 mixture of water-acetonitrile (2.5 mL) was added, and the resulting brown mixture was heated in a benchtop microwave at 150° C. for 5 min. The cooled reaction mixture was diluted with water (150 mL) and extracted with CH2Cl2 (4×50 mL). The combined organic extracts were dried (MgSO4), gravity filtered, and concentrated by rotary evaporation. The residue was purified by RP-HPLC (eluting with a 5% acetonitrile to 100% acetonitrile gradient) to afford the desired product, methyl 4-amino-3-chloro-6-(4-cyclopropylphenyl)-5-fluoropicolinate as a white powder (310 mg, 78%): mp 116-119° C.; IR (thin film) 3475 (s), 3357 (s), 3089 (w), 3013 (w), 2954 (w), 1724 (m), 1607 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.81 (m, 2H), 7.15 (m, 2H), 4.85 (br s, 2H), 3.98 (s, 3H), 1.94 (m, 1H), 1.01 (m, 2H), 0.74 (m, 2H); ESIMS m/z 321 ([M+H]+).

후처리

  1. additionwas added
  2. customThe cooled reaction mixture
  3. extractionextracted with CH2Cl2 (4×50 mL)
  4. dry with materialThe combined organic extracts were dried (MgSO4), gravity
  5. filtrationfiltered
  6. concentrationconcentrated by rotary evaporation
  7. customThe residue was purified by RP-HPLC (
  8. washeluting with a 5% acetonitrile to 100% acetonitrile gradient)

출처 및 근거

ORD 기록
ord-96ef6ba1121842899f2e42ef649759a0
출처 데이터셋
uspto-grants-2015_10
특허 번호
US09169217B2

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