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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5949_Библиотеки_им_академика_М_И_Перельмана
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Vinorelbine 461
3
3
vinblastine
OH
3
3
3
CH
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Discussion. Essential medicines vinblastine and vincristine are alkaloids isolated from the dried leaves of the Madagascar
periwinkle C. roseus. With isolated yields of 0.01% for vinblastine and just 0.0003% for vincristine, there is an economic
incentive to manufacture semisynthetic vincristine by oxidation of vinblastine.
CH
3
N
H
CH
OH
3
N
H
CH3OOC
N
CH3O
N
OCOCH
H
COOCH
HO
3
OH
CH
N
3
N
N
H
CH3OOC
CH3O
H
CH
3
OH
N
OCOCH
H
CH
COOCH
3
3
Vinorelbine
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
N
H
CH3OOC
N
3
N
H
CH
OH
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. Vinorelbine (5′- noranhydrovinblastine) is semisynthetic. In the final step, vinorelbine is formed by loss of C5’ from
the 5′,6′- bridge of 7′- bromoanhydrovinblastine. (What is the fate of the lost 5′ carbon?) 7′- Bromoanhydrovinbastine is formed by
the bromination of anhydrovinblastine.
CH3O
N
H
CH
COOCH
OCOCH
3
V462
3
3
3
anhydrovinblastine
3
v in dol ine
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CH
N
3
N
N
H
CH3OOC
H
CH
OH
3
Br
N
CH3OOC
7′
N
H
CH3OOC
CH3O
CH3O
5′6′
CH3O
N
OCOCH
H
CH
N
CH
3
3
COOCH
3
N
H
CH
OH
N
3
OCOCH
H
CH
N
CH
3
3
COOCH
3
N
H
CH
OH
N
3
OCOCH
H
CH
3
COOCH
3
Anhydrovinblastine is formed by the iron(III) chloride- mediated coupling of vindoline and catharanthine followed by
reduction of the resulting iminium ion with borohydride. (Draw the structure of the iminium ion intermediate.) Indole
alkaloids catharanthine and vindoline are isolated from the leaves of the Madagascar periwinkle Catharanthus roseus.
N
CH
CH
3
3
H
H
N
OH
COOCH
N
CH
OCOCH
3
H
H
3
CH
3
3
N
OH
COO CH
OCOCH
3
CH
3
N
H
COOCH
cath ara nthine
N
H
CH3OOC
N
3
16
CH3O
N
CH
10
3
CH3O
Voriconazole 463
N
F F
N
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Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to vinorelbine utilizing a Polonovski- type fragmentation of an N- oxide. List the pros and cons for both routes. Is one route preferred?
Voriconazole
Anti- infective Medicines/Antifungal Medicines
A tertiary alcohol is often formed by the addition of an organometallic rea-
N
N
CH
N
3
F
HO
Discussion. Voriconazole, the (2R,3S)- enantiomer, is separated from the 1 : 1mixture of (2R,3S)- and (2S,3R)- enantiomers
by resolution in the final step. (What chiral acid is used for the resolution?) The 1 : 1mixture of enantiomers for the final
step is formed by hydrogenolysis of the 6- chloropyrimidines. A mixture of four stereoisomers is formed by the addition of
the alkylzinc bromide to the ketone. The desired (2R,3S)- and (2S,3R)- enantiomer pair is isolated from the mixture by crystallization. (What reagents and reaction conditions are associated with the highest yield of the (2R,3S)- and (2S,3R)enantiomers?) The alkylzinc bromide is formed from 4- (1- bromoethyl)- 6- chloro- 5- fluoropyrimidine.
gent RM or RMX (M=Li, Mg, Zn, X=Cl, Br, I) to a ketone.
V464
S2
S2
F F
S2
S2
F F
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F F
F F
HO
HO
N
N
N
N
N
N
NN
HO
HO
CH
CH
3
3
F F
F F
N
N
N
N
N
N
NN
NN
CH
CH
3
3
F
F
2R,3
2R,3
NN
F
F
N
N
N
N
N
N
NN
NN
F
F
CH
CH
S,3R
S,3R
OH
OH
3
3
FF
FF
N
N
N
HO
HO
F F
F F
N
N
N
N
N
N
N
N
N
NN
NN
Cl
Cl
Cl
Cl
CH
CH
2R,3
2R,3
O
O
3
3
BrZn
BrZn
F
F
NN
NN
Cl
Cl
CH
CH
F
3
F
3
NN
NN
F
F
N
N
CH
CH
S,3R
S,3R
Br
Br
N
N
N
N
OH
OH
3
3
CH
CH
F
3
F
3
FF
FF
NN
NN
Cl
Cl
4- (1- Bromoethyl)- 6- chloro- 5- fluoropyrimidine is formed by bromination of 4- chloro- 6- ethyl- 5- fluoropyrimidine. The
chloropyrimidine is formed from the hydroxypyrimidine/pyrimidinone. The pyrimidine ring is formed by the reaction of
the β- ketoester with formamidine (Pinner Pyrimidine Synthesis). Methyl 2- fluoro- 3- oxopentanoate is formed by fluori-
nation of methyl 3- oxopentanoate. One route to methyl 3- oxopentanoate is from Meldrum’s Acid and propanoyl chloride.
465Voriconazole
Br
3
F
FF
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H
NN
CH
F
3
CH
3
O
OH
H2N NH
CH
3
CH3CH
OO
O O
Cl
Meldrum'sAcid
O
O
OCH
F
3
CH
NN
CH
3
O
3
NN
Cl
F
CH
F
3
Cl
CH3CH
3
OO
O
OCH
3
O O
CH
3
OH
CH3OH
The ketone, 2′,4′- difluoro- 2- (1,2,4- triazolyl)acetophenone, is formed by displacement of chloride from the α–chloroketone by 1,2,4- triazole. 2- Chloro- 2′,4′- difluoroacetophenone is formed from 1,3- difluorobenzene and chloroacetyl chloride
(Friedel- Crafts Acylation).
N
N
Cl
N
N
NH
N
O
F
F
Cl
Cl
O
O
F
Extended Discussion
Provide details for one alternative route to voriconazole from 4- chloro- 6- ethyl- 5- fluoropyrimidine and 2′,4′- difluoro- 2- (1,2
,4- triazolyl)acetophenone. List the pros and cons for both routes.
466
O
O
O
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W
Warfarin
Medicines Affecting the Blood/Medicines Affecting Coagulation
A β- branched ketone is often formed by addition of a carbon nucleophile to
an α,β-
OH
CH
3
unsaturated ketone.
Discussion. Warfarin is a 1 : 1 mixture of the (R)- and (S)- enantiomers. Warfarin is formed by the reaction of
4- hydroxycoumarin with benzalacetone (Michael Addition). 4- Hydroxycoumarin is formed from 2′- hydroxyacetophenone
and diethyl carbonate (mixed Claisen Condensation).
O
CH
3
O
CH
3
OH
O
CH3CH2O OCH2CH
3
OH
O
O
CH
3
OH
O
O O
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to 4- hydroxycoumarin. Include the structures of the
retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials.
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
CH
3
CH
CH
CH
CH
3
3
X
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Xylometazoline
Ear, Nose, and Throat Medicines
467
3
H
N
3
3
CH
CH
N
3
The large tert- butyl group of a tert- butylbenzene blocks the approach of
reagents to the adjacent ring carbons.
Discussion. The imidazoline ring is formed by the reaction of the nitrile with ethylenediamine. 2- (4- tert- Butyl- 2,6- dimethyl
phenyl)acetonitrile is formed by displacement of chloride by cyanide. The benzyl chloride is formed by the reaction of
tert- butyl- 3,5- dimethylbenzene with formaldehyde and hydrochloric acid (Blanc Reaction). 1- tert- Butyl- 3,5- dimethyl
1benzene is formed by alkylation of meta- xylene with tert- butyl chloride (Friedel–Crafts Alkylation).
CH
CH
CH
3
H
N
3
3
CH
3
CH
3
CH
3
NaCN
N
CH
CH
CH
3
3
CH
3
CH
3
CN
CH
3
3
O
H H
Cl
CH
H
2
H2N
3
N
3
3
CH
3
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
CH
CH
CH
3
3
CH
3
CH
3
CH
CH
3
Cl
CH
CH
3
3
X468
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Extended Discussion
Propose alternative reagent(s) for formation of the benzyl chloride from 1- tert- butyl- 3,5- dimethylbenzene. Discuss pros
and cons for these reagents.
H
3
O
3
O
thymidine
O
O
Ph
3
Z
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Zidovudine
Anti- infective Medicines/Antiviral Medicines/Antiretrovirals/Nucleoside- Nucleotide Reverse Transcriptase Inhibitors
469
HN
CH
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.
O
O
N
N
O
Discussion. The primary alcohol is released by hydrolysis of the 5′- triphenylmethyl (trityl) ether in the final step.
The 3′α- azide is formed by nucleophilic displacement of the β-oxygen of 5′- O- triphenylmethyl- 2,3′- anhydrothymidine
by sodium azide. The 2,3′- anhydrothymidine is formed by nucleophilic displacement of the methanesulfonate. The
methanesulfonate is formed from the 3′- alcohol of 5′- O- tritylthymidine. 5′- O- Tritylthymidine is formed from thymidine.
CH
HN
HO
N
O
O
N
3
3
Ph3CO
HN
O
O
N
3
CH
3
N
Ph3CO
N
O
O
CH
3
N
HN
CO
3
CH3SO
Routes to Essential Medicines: A Workbook for Organic Synthesis, First Edition. Peter J. Harrington.
O
O
O
2
© 2022 John Wiley & Sons, Inc. Published 2022 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/Harrington/routes_essential_medicine
O
CH
3
N
O
Ph3C
CH3SO2Cl
O
OH
HN
O
O
N
CH
3
HO
Ph
O
CCl
3
HN
O
O
OH
CH
N
Z470
HO
O
O
OBz
O
3
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Thymidine (β- thymidine) is obtained from natural sources or is produced by fermentation or synthesis. In one synthetic
route, thymidine is manufactured from thymine via 5- methyluridine. Thymidine is formed when the alcohols are released
by cleavage of the acetate esters. The 2′- bromide is cleaved by hydrogenolysis. The 3′ and 5′- acetate esters are formed, and
the 2′- alcohol is replaced by bromide in the reaction of 5- methyluridine with acetyl bromide. 5- Methyluridine is
formed when the alcohols are released by cleavage of the benzoate (Bz) esters. 2′,3′,5′- Tri- O- benzoyl- 5- methyluridine is
formed by the reaction of 1- O- acetyl- 2,3,5- tri- O- benzoyl- β- - ribofuranose with thymine.
O
OH
HO
5-methyluridine
HN
N
O
thymidine
HN
O
O
OH
OH
CH
CH
CH
3
3
CH
3
CH
O
CH
3
N
O
CH
Br
3
O
3
O
CH
3
BzO
HN
O
O
O
O
N
O
O
HN
N
O
OBzOBz
CH
CH
CH
3
O
3
O
CH
3
3
BzO
HN
O
O
O
HN
O
O
O
Br
O
N
H
thymine
O
N
O
OBz
Extended Discussion
How is thymine produced? Draw the structures of a retrosynthetic analysis of one synthetic route to thymine. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials.
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