Sodium Iodide → (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine

HRID 1749057Notes

Reaction equation

HRID 1749057 reaction equation
[CH3:1][S-:2].[Na+].CS(O[CH2:9][C:10]1[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=[C:12]([Cl:23])[N:11]=1)(=O)=O.ClC1N=C(N2CCOC[C@H]2C)C=C(CCl)N=1.[I-].[Na+]>CC#N.CCOC(C)=O>[Cl:23][C:12]1[N:13]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[CH:15]=[C:10]([CH2:9][S:2][CH3:1])[N:11]=1

Participants

7

Reactant 4

HCID 5238Sodium IodideHCID 4378561Sodium methanethiolateHCID 86651636(R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonateHCID 86660211(R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine

Product 1

HCID 86660210(R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholineYield 91%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a 3 L fixed vessel, sodium thiomethoxide (21% in water) (216 g, 646.69 mmol) was added dropwise over 5 minutes to a stirred solution of a mixture of approximately two thirds (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate and one third (R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine (130.2 g, 431 mmol) and sodium iodide (1.762 ml, 43.11 mmol) in MeCN (1 L) at RT (temperature dropped from 20° C. to 18° C. over the addition and then in the next 5 minutes rose to 30° C.). The reaction mixture was stirred for 16 hours and then diluted with EtOAc (2 L), and washed sequentially with water (750 ml) and saturated brine (1 L). The organic layer was dried over MgSO4, filtered and then evaporated to afford (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (108 g, 91%); 1H NMR (400 MHz, DMSO-d6) 1.20 (3H, d), 2.07 (3H, s), 3.11-3.26 (1H, m), 3.44 (1H, td), 3.53 (2H, s), 3.59 (1H, dd), 3.71 (1H, d), 3.92 (1H, dd), 3.92-4.04 (1H, br s), 4.33 (1H, s), 6.77 (1H, s); m/z: (ES+) MH+, 274.36.

Workup

  1. additiondropped from 20° C. to 18° C. over the addition
  2. customin the next 5 minutes
  3. customrose to 30° C.
  4. washwashed sequentially with water (750 ml) and saturated brine (1 L)
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. customevaporated

Sources & evidence

ORD record
ord-29de9d297d374fc5b0a4aaa24f8e0d7f
Source dataset
uspto-grants-2015_10
Patent number
US09155742B2

Reaction notes

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