Dimethylformamide → 2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde

HRID 341308Notes

Reaction equation

[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11]N3CCN(C(=O)[C@@H](O)C)CC3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.C([Li])CCC.CN(C)C=[O:38]>>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH:11]=[O:38])=[C:8]([CH3:23])[C:6]=2[N:7]=1

Participants

Reactant 3

HCID 6228Dimethylformamide

HCID 86623526(S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one

HCID 178418339Butyllithium

Product 1

HCID 566485822-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde

Procedure

Scheme 2 shows the synthesis of intermediate (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II from 4-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholino VI. Treatment of VI with isopropylmagnesium chloride Grignard reagent followed by n-butyllithium at −10° C. was followed by addition of dimethylformamide and quenching with aqueous acid gave formylated intermediate 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (Example 4). Reductive amination of IV was effected by mixing IV with the oxalate salt of (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V followed by a reducing agent, such as sodium triacetoxyborohydride (Method A), 2-picoline borane (Method B) or 5-Ethyl-2-methylpyridine borane to give II which was crystallized in toluene/heptane (Example 5) or Me-THF/heptane.

Workup

customquenching with aqueous acid

Sources & evidence

ORD record: ord-8a2177497ad74392b9d32152668fb33e
Source dataset: uspto-grants-2014_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08895729B2

Reaction notes

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