Chemistry Reference
In-Depth Information
in the synthetic sequence. Otherwise, you have to do large-scale reactions
throughout the sequence only to lose yield on a late reaction. If the low yield
reaction is early in the sequence, that reaction needs to be a large-scale reac-
tion, but subsequent steps can be done on a smaller scale.
Most syntheses involve sequential steps, but there are many advantages
to a convergent synthesis where the different segments are assembled at or
near the end of the synthetic process. One example of a convergent syn-
thesis is the synthesis of methotrexate. Methotrexate is used in chemother-
apy and acts by inhibiting the formation of folic acid. Methotrexate is also
used to treat rheumatoid arthritis. It can be prepared in a one-step convergent
(dubbed a shotgun reaction on the production floor) from tetraaminopyrimi-
dine, p-(N-methylamino)-benzoyl glutamic acid and a three-carbon synthon
such as dibromopropionaldehyde or 1,1,3-tribromoacetone [28].
O
CO
2
H
NH
2
H
CO
2
H
N
N
N
CH
3
H
2
N
N
N
Methotrexate
O
CO
2
H
OH
H
CO
2
H
N
N
H
H
2
N
N
N
Folic acid
O
CO
2
H
NH
2
H
CO
2
H
Br
CH
2
Br
NH
2
H
N
+
+
N
Methotrexate
O
H
2
N
N
NH
2
H
CH
3
The purity of the final product is a critical factor in selecting a synthetic
route. Any impurities must be below 0.1% by weight or must be studied for
their health effects. A synthesis which gives impurities which are difficult to
remove is often rejected even if the yields are higher. Scale-up considerations
are also important. The use of high pressures, flammable solvents, or pro-
cesses which create a lot of waste all add cost due to equipment, safety, and
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