Organic Chemistry of Drug Synthesis. Volume 7

of methyl 4-methylacetoacetate ( 73 ) withp-fluorobenzaldehyde to afford
the acrylate ( 74 ). This last intermediate is then reacted with thiourea. In
a variation on the standard scheme for preparing pyrimidines. The reaction
in this case involves conjugate addition to the double bond followed
imine formation with the ketone though not necessarily in that order.
The resulting dihydropyrimidine is then dehydrogenated with dichloro-
dicynanoquinone (DDQ) to afford 75. The thioether function is next oxi-
dized to the sulfoxide by mean of m-perbenzoic acid (MCPBA) to
afford 76. Treatment with methylamine replaces the sulfoxide by nitrogen
by an addition–elimination sequence. The thus-introduced amino group is
then converted to the sulfonamide ( 77 ) by reaction with methanesulfonyl
chloride. The ester group is then reduced to the corresponding alcohol
by means of DIBAL-H and back-oxidized to aldehyde ( 78579 ) required
for attachment of the side chain.

F

CH=O

72

C 2 H 5 O 2 C

O

C 2 H 5 O 2 C

O

F

+

73 74

HN

SCH 3

NH 2

C 2 H 5 O 2 C

N

1. F
   2. DDQ N

SCH 3

75

MCPBA

C 2 H 5 O 2 C

N

F

N

O 2 SCH 3

1. CH 3 NH 2


2. CH 3 SO 2 Cl

76

C 2 H 5 O 2 C

N

F

N

NSO 2 CH 3

77

CH 3

1. DIBAL


2. [O]

CH=O

N

F

N

NSO 2 CH 3

78

CH 3

Condensation of aldehyde 79 with the ylide from chiral phosphorane
( 80 ) attaches the moiety that will become the statin side chain in a one
fell swoop ( 81 ). The silyl protecting group on the alcohol is removed
next by treatment with hydrogen fluoride. The side-chain ketone is
reduced using a mixture of sodium borohydride and diethyl methoxyboron.
This last reagent forms a chelate between the ketone and hydroxyl group in
the starting material, in effect transferring the chirality of the hydroxyl to
that which is to be introduced. The diol product ( 82 ) thus comprises a
single enantiomer. Saponification of the ester group affordsrosuvastatin
( 83 ) as its sodium salt.^12

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