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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5429_Библиотеки_им_академика_М_И_Перельмана
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Etonogestrel 171
CH
CH
CH
3
CH
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The 4- ene- 3- one is formed by hydrolysis of the enol ether and migration of the 5(10)- alkene. The C17ketone is formed
by oxidation of the C17 secondary alcohol (Oppenauer Oxidation). The 3- methoxy- 2,5(10)- diene is formed by reduction
of the aromatic ring (Birch Reduction). The 8- alkene is also reduced under the conditions used for reduction of the aromatic ring. The C17 secondary alcohol is released by ester hydrolysis. The 14- alkene of the gona- 1,3,5(10),8,14- pentaene is
reduced by catalytic hydrogenation.
3
H
H H
O
CH
3
H
H H
O
3
CH
3
O
OH
O
CH3O
CH3O
O
CH
3
3
H
H H
CH
3
CH
3
O
OH
H
O
O
CH
O
3
H
CH3O
The gona- 1,3,5(10),8,14- pentaene is formed from the secosteroid. The acetate ester of the secosteroid is formed by reaction of the C17 alcohol with acetic anhydride. The chiral carbons at C13 and C17 are formed by microbiological reduction
of the secodione. The C12⏤C13 bond of the secodione is formed by the reaction of 6- methoxy- 1- vinyl- 1,2,3,4- tetrahydron
aphthalen- 1- ol with 2- ethyl- 1,3- cyclopentanedione. 6- Methoxy- 1- vinyl- 1,2,3,4- tetrahydronaphthalen- 1- ol is formed by
addition of vinylmagnesium chloride to 6- methoxy- 1- tetralone (Grignard Reaction). Vinylmagnesium chloride is formed
from vinyl chloride.
E172
O
CH
O
CH
O
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O
CH3O
3
CH
3
O
CH
3
CH
3
O
CH
3
O
CH3O
O
CH
3
OH
CH
3
O
O
CH
3
O
O
CH3O
O
CH
3
3
12
11
9
13
O
17
CH
O
MgCl
Cl
O
OH
O
CH3O
CH3O
2- Ethyl- 1,3- cyclopentanedione is formed from succinic anhydride and butanoic anhydride.
3
O
O
O O
O
CH
3
O
CH
3
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to etonogestrel from 6- methoxy- 1- tetralone.
Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials. How many steps are there in the linear sequence from 6- methoxy- 1- tetralone to etonogestrel in the
alternative route?
Etoposide
OH
3
CH
CH
3
OH
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Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
Etoposide 173
3
O
O
HO
O
O
CH3O
O
O
OH
H
O
H
O
OCH
A single- enantiomer molecule with multiple chiral carbons is
often formed by modification of a natural product which has most
or all of the chiral carbons already in place.
Discussion. Etoposide is semisynthetic. In the final step of one preferred route, the two secondary alcohols are released by
cleavage of dichloroacetate esters. The ether link between the sugar and the aglycone is formed by reaction of the
β- - glucopyranose with the alcohol at C4 of 4′- demethylepipodophyllotoxin.
3
O
O
HO
O
O
O
O
OH
H
O
H
O
CH
Cl2CH
3
O
O
Cl2CH
O
O
O
O
O
O
O
O
H
O
H
O
CH3O
CH
3
O
Cl2CH
O
O
O
Cl2CH
OH
OH
CH3O
H
H
O
OCH
OH
O
3
OCH
3
O
O
OH
O
O
O
CH3O
OCH
E174
OH
Br
3
OH
podophyllotoxin
CH
OH
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The alcohol at C4 of 4′- demethylepipodophyllotoxin is formed by hydrolysis of the benzylic bromide. Reaction of podophyllotoxin with hydrogen bromide results in formation of the benzylic bromide and demethylation of the ether at C4′.
Podophyllotoxin is a non- alkaloid lignan isolated from the rhizomes of Podophyllum peltatum, the North American
Mayapple.
H
O
O
H
O
CH3O
OH
OCH
O
O
O
3
CH3O
OH
H
O
O
O
H
O
OCH
3
CH3O
4
1
1'
4'
OCH
H
O
H
O
OCH
3
The hemiacetal at C1 of the β- - glucopyranose is released by hydrogenolysis of the benzyl carbonate. The alcohols at C2
and C3 are protected as dichloroacetate esters. The benzyl carbonate is formed by reaction of 4,6- O- ethylidene- - glucopyr
anose with benzyl chloroformate. The acetal of 4,6- O- ethylidene- - glucopyranose is formed by reaction of - glucose with
acetaldehyde.
CH
3
Cl2CH
O
O
O
O
OH
O
CH
Cl2CH
3
O
O
O
O
O
O
O
OCH2Ph
O
Cl2CH
O
O
HO
Cl2CH Cl
O
O
OH
O
3
O
O
OCH2Ph
CH
3
O
O
HO
PhCH2O Cl
O
Cl2CH
O
OH
OH
O
HO
HO
HO
O
O
OH
O
CH
3
H
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to etoposide from podophyllotoxin. List the pros
and cons for both routes and select one route as the preferred route.
O
CH
3
F
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Fentanyl
Medicines for Pain and Palliative Care/Opioid Analgesics
A tertiary amine is often formed by alkylation of a secondary amine.
N
N
The alkylation is most efficient when the amine is used in excess
and when the carbon with the leaving group (Cl, Br, I, OTs, OMs) is
primary or benzylic.
175
Discussion. The fentanyl amide is formed in the final step from propanoyl chloride and the secondary amine, N- [1- (2-
phenylethyl)- 4- piperidinyl]aniline. The secondary amine is formed by reductive amination from the piperidinone and aniline.
N-
Phenylethylpiperidin- 4- one is formed by N- alkylation of piperidin- 4- one with (2- bromoethyl)benzene.
O
CH
O
N
N
N
O
H2N
CH
3
Cl
N
HN
Br
NH
3
O
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to fentanyl. List the pros and cons for both routes
and select one route as the preferred route.
Routes to Essential Medicines: A Workbook for Organic Synthesis, First Edition. Peter J. Harrington.
© 2022 John Wiley & Sons, Inc. Published 2022 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/Harrington/routes_essential_medicine
F176
F F
F
3
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Fluconazole
Antifungal Medicines
N
N
N
OH
N
N
N
Fluorine on an aromatic ring is often delivered in a fluorinated starting
material.
Discussion. The tertiary alcohol is formed in the final step by ring- opening of the epoxide with 1,2,4- triazole. The epoxide is
formed by reaction of the ketone with trimethylsulfoxonium iodide (Corey- Chaykovsky
difluoro- 2- (1,2,4- triazolyl)acetophenone, is formed by displacement of chloride by 1,2,4- triazole. 2- Chloro- 2′,4′- difluoroa
2′,4′cetophenone is formed from 1,3-
N
N
N
OH
difluorobenzene and chloroacetyl chloride (Friedel–Crafts Acylation).
N
N
N
N
N
N
HN
N
N
O
Reaction). The ketone,
F F
N
N
N
F
O
O
I
CH3S CH
CH
F F
3
F F
N
NH
N
Cl
Cl
O
O
F F
Cl
Extended Discussion
Draw the structures of a retrosynthetic analysis of a route to fluconazole starting with 1,3- dichloroacetone. List the pros
and cons for the two routes and select one route as the preferred route.
Flucytosine
H
F
NH
O
H
NH
O
NH
H
F
O
Cl
NH
HO
OH
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Anti- infective Medicines/Antifungal Medicines
Fludarabine Phosphate 177
2
An oxygen or nitrogen substituent on C2 or C4 of a pyrimidine is often introduced by displacement
N
N
of chloride.
Discussion. Flucytosine (5- fluorocytosine) is manufactured in three steps from the essential medicine 5- fluorouracil.
The final step is hydrolysis of 42,4-
dichloropyrimidine. The 2,4-dichloropyrimidine is formed from the pyrimidine- 2,4- dione of 5- fluorouracil.
2
N
N
F
amino- 2- chloro- 5- fluoropyrimidine. The 4- amino- 2- chloropyrimidineis formed from the
2
N
Cl
N
F
N
Cl
N
F
HN
O
N
Extended Discussion
Flucytosine is also formed by the direct fluorination of cytosine. This alternative route is attractive when cytosine is comparable in cost to uracil. Draw the structures of a retrosynthetic analysis of one route to cytosine. Include the structures of
the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials.
Fludarabine Phosphate
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
2
N
F
O
O
P
OH
N
N
N
OH
O
A single- enantiomer molecule with multiple chiral carbons is often formed by
modification of a natural product which has most or all of the chiral carbons
already in place.
F178
NH
HO
NH
NH
3SO2
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Discussion. Fludarabine phosphate is formed from fludarabine in the final step. The alcohols at C2′, C3′, and C5′ are
released by hydrolysis of 2′,3′,5′of a trifluoromethanesulfonate on the α-
tri- O- acetylfludarabine. The β- face acetate at the 2′- position is formed by displacement
face. The α- trifluoromethanesulfonate is formed from the α- alcohol of 3′,5′- diO- acetyl- 2- fluoroadenosine. 3′,5′- Di- O- acetyl- 2- fluoroadenosine is formed from 2′,3′,5′- tri- O- acetyl- 2- fluoroadenosine.
(Draw the structures for all the products formed in this reaction. What reaction conditions are associated with the highest yield of 3′,5′-
di- O- acetyl- 2- fluoroadenosine? How is 3′,5′- di- O- acetyl- 2- fluoroadenosine separated from the other
products?)
2
N
O
OH
NH
2
N
O
OAc O
OH
N
N
N
N
SO2CF
F
HO
F
AcO
CH3COOH
3
N
F
O
O
P
OH
N
F
AcO
N
N
2
N
5'
O
3'
OH
NH
2
N
O
OAc OH
OH
2
N
N
2'
N
N
CF
Cl
N
F
AcO
N
F
AcO
N
OAc
O
OAc
NH
2
N
O
OAc OAc
N
N
N
N
2′,3′,5′- Tri- O- acetyl- 2- fluoroadenosine is formed from 2- fluoroadenosine. 2- Fluoroadenosine is formed from 2- aminoadenosine
via the diazonium salt (
Balz–Schiemann Reaction). 2- Aminoadenosine is formed from guanosine. Guanosine is produced by
fermentation.
Fludrocortisone Acetate 179
NH
guanosine
NH
Ac
O
O
H
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N
F
O
Ac Ac
N
H2N
HO
2
N
O
O O
NH
2
N
O
2
N
N
N
N
HO
H2N
HO
N
F
N
OH OH
O
HN
N
N
CH
O O
3
O CH
3
N
O
N
N
O
OH OH
OH OH
Extended Discussion
Draw the structures of a retrosynthetic analysis of an alternative route to fludarabine starting with - arabinose. Include the
structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or
biochemical raw
materials.
Fludrocortisone Acetate
Hormones, Other Endocrine Medicines and Contraceptives/Adrenal Hormones and Synthetic Substitutes
A single- enantiomer molecule with multiple chiral carbons is often
formed by modification of a natural product which has most or all of
the chiral carbons already in place. A halogen atom at C9 on the α-
face of a corticosteroid is often introduced by ring- opening of a
9(11)- epoxide on the β- face.
HO
CH
CH
3
H
3
F
H
OH
O
F180
O
O
O
hydrocortisone
H
O
O
F
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Discussion. Fludrocortisone acetate is manufactured in five steps from another essential medicine, hydrocortisone. Fluorine
is introduced at C9 on the α-
epoxide is formed from the bromohydrin. The bromohydrin is formed from the 9(11)- alkene. The 9(11)- alkene is
9(11)-
face in the final step by ring- opening of the 9(11)- epoxide with hydrogen fluoride. The
formed by dehydration of hydrocortisone acetate. Hydrocortisone acetate is formed by reaction of the C21 alcohol of hydrocortisone with acetic anhydride.
O
O
OH
HO
CH
CH
3
H
3
F
H
O
CH
3
O
CH
3
O
O
O
O
OH
HO
CH
CH
3
H
3
Br
H
O
CH
3
CH
3
O
O
CH
3
O
OH
CH
3
H
H
O
O
CH
3
O
OH
CH
3
H
H
O
HO
O
CH
3
O
OH
CH
3
HO
O
CH
3
OH
OH
CH
H
3
H
Fluorouracil
Anti- infective Medicines/Antifungal Medications
HN
N
CH
H
O
H
3
CH
O
3
H
H
O
O
CH
3
A fluorine substituent on a heterocycle is often delivered in a starting material used to construct the
heterocycle.
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