3-Bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine → (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine

HRID 1472368Notes

Reaction equation

HRID 1472368 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[Br:29][C:30]1[CH:31]=[C:32]2[C:43]3([CH2:48][CH2:47][O:46][C:45]([NH2:49])=[N:44]3)[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([C:50]4[C:51]([F:56])=[N:52][CH:53]=[CH:54][CH:55]=4)[CH:41]=3)[O:36][C:33]2=[N:34][CH:35]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[Br:29][C:30]1[CH:31]=[C:32]2[C@@:43]3([CH2:48][CH2:47][O:46][C:45]([NH2:49])=[N:44]3)[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([C:50]4[C:51]([F:56])=[N:52][CH:53]=[CH:54][CH:55]=4)[CH:41]=3)[O:36][C:33]2=[N:34][CH:35]=1

Participants

4

Reactant 2

HCID 584658843-Bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amineHCID 58465920(R)-3-bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine

Product 2

HCID 58465877(S)-3-bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amineHCID 58465920(R)-3-bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine

Procedure

In a 150-mL resealable flask, potassium carbonate (1.557 g, 11.27 mmol 3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (intermediate 25 1.97 g, 4.17 mmol), 2-fluoropyridin-3-ylboronic acid (0.441 g, 3.13 mmol), and PdCl2-dppf-dcm (0.225 g, 0.275 mmol) were suspended in dioxane (18 mL) and water (6 mL). Argon was blown through the vessel, which was sealed and heated in an 85° C. oil bath for 2 h. The reaction was concentrated to remove most of the dioxane. The aqueous residue was diluted further with dilute brine (50 mL), and the aqueous phase was extracted with 10% MeOH-DCM (3×100 mL). The organics were combined, washed with dilute brine (30 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (4% MeOH/DCM), to afford (3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) (1.03 g). MS (m/z) 441/443 (M+H)+. Step 2: Intermediates ((S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) (intermediate 26A, 350 mg), and its enantiomer ((R)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (intermediate 26 B, 500 mg) were obtained from racemic (3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) using similar chiral separation conditions as described herein for intermediate 10. MS (m/z) 441/443 (M+H)+.

Sources & evidence

ORD record
ord-7d7118f35f9e4a0e8ca4639908efa375
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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