ROUTE AND CHEMISTRY SELECTION
5.6 GOING FROM A ROUTE TO A PROCESS
Once the synthetic chemist is able to put together a route that appears to work, the next job is to see how well the chemistry actually works, and turn it into a workable process. Let’s take the first step of a drug synthesis as an example and see what a process chemist might start with:
F Me
Br t-BuO2C
F Me (1) Mg/THF
(2) (t-BuCO)2O
What is missing from this simple chemical route schematic? Do you know, for example, how much of each material is required, whether or not heating or cooling is involved, and if any separations are required? If you included all this information, what might this look like?
Figure 5.2 is a process flow diagram of this single step. As, hopefully, is readily apparent, a great many steps are actually required to carry out what is summarized in the schematic above. In Chapter 9 we go into greater detail about how to take all the various components of a process flow diagram and turn it into a mass and energy balance (i.e., account for everything that goes into and out of a process). For our purposes at this point, it is sufficient to understand that more than just the basic chemistry is depicted in most chemical reaction flowsheets involved in making the actual material.
PROBLEMS
5.1 In your own words, describe what a retrosynthetic analysis is and how this can be used to design a greener synthesis.
5.2 Look at the following molecules and identify key functional groups, points of disconnection, symmetry elements, and key bonds.
(a)
F
O O
(b)
O
H
H
(c)
O
O Cl
CH3 A.1aGrignard
Add 1hr45min T->29to34.5ºC
5-Bromo-2-fluoroethane,50kg Tetrahydrofuran,50kg
1,2-Dibromoethane,1.99kg
LineWash
A.1aIntermediate
~56.42kg+Rxmedia
A.1bC-Acylation Coolto-1ºC Additionduring
4hr50min Di-T-butyldicarbonate,57.8kg Tetrahydrofuran,162.5kg
Stir 30min T=3ºC Tetrahydrofuran wash,36kg
Stir 40min T->8.5to12ºC
AA
Tetrahydrofuran,16.5kg
Stir1hr25min T->25to30ºC
Ammoniumchloride,19.1kg Water,171.9kg
Stir pH=6 Water,101.97kg HCl,8.03kg
AA Distill
Patm Washand
Phase Separation
PhaseSeparation Aqueous Ethylacetate,120kg
Organic
NaCl,16kg
Water,64kg Product
38.51kg Washand
Phase Separation
Aqueous ca.556.82kg
THF,ca.320kg EthylAcetate,ca.100kg
Distill Patm
Residue:22.54
Crude SB-218182 61.05kg
FIGURE 5.2 Process flow diagram for a single reaction step.
5.3 Describe features of interest for the molecules in Problem 5.2 in terms of their topology and bond connectivity.
5.4 For the following reaction:
R′ OH
O
R′ OH
R′ = heterocycle
(a) Name the general class of reaction.
(b) Figure 5.1 has three different approaches that could potentially be used for this type of reaction. Which would you choose, and why?
5.5 For the following synthesis:
NH3 R'O
Cl +
–
O O N
N Cl H2N
Cl
base DMSO, heat
N H2N N
HN Cl
O O R′O
1 C fragment/n-BuOAc.
N N N N
Cl
O O R′O
cyclization
N N N N
R
O O R'O
nucleophile
heat N
N N N
R
HO OH R'O
H3O
step 1
step 3 step 4
step 2
DIPEA/i-PrOH,
(a) Draw an idealized synthesis route for this synthesis.
(b) Draw a retrosynthetic analysis from the final product.
(c) The chiral ammonium salt starting material is already a complex molecule.
Why?
(d) What is the last step of the synthesis, and how does this affect the overall greenness of the route?
5.6 Use this chapter and what you learned in Chapter 3 to describe the key elements of an ideal synthesis.
N N
SO3–Na+
C N N
N Br OEt
N
OEt O
N
OEt N OH
N
OEt NH2
N
N H
N
N CH3
NH2OH
2HOAc
CH3I
(a) Is this a linear or a convergent synthesis?
(b) If every step had a yield of 75%, what would the overall yield be?
(c) Draw a retrosynthetic representation of this synthesis.
(d) Which functional groups have a change in oxidation state?
(e) Compute the overall atom economy for this synthesis. Is this good? Why or why not?
(f) What are the key functional groups exploited in this synthesis?
5.8 Based on the information presented in Figure 5.2, estimate the mass efficiency, yield, and reaction mass efficiency for the production of the product.
5.9 Using the GSK green chemistry guide in Figure 5.1, what conclusions could be drawn about the reaction of Example 5.3? What would be any green chemistry concerns?
5.10 For esomeprazole, identify key functional groups, points of disconnection, symme- try elements, and key bonds.
N NH
S O
O N
O
esomeprazole
5.11 For sertraline, identify key functional groups, points of disconnection, symmetry elements, and key bonds.
N H
Cl Cl sertraline
5.12 From a green chemistry perspective, what are the advantages and disadvantages for the following synthesis for sertraline:
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