Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5429_Библиотеки_им_академика_М_И_Перельмана
.pdf
Omeprazole 321
CH3O
CH
H
3
CH3O
NH
CH3O
NO
CH3O
CH
3
3
https://t.me/medicina_free
Discussion. Omeprazole is chiral at sulfur and is manufactured as a 1 : 1mixture of (R)- and (S)- enantiomers by oxidation
of the thioether to the sulfoxide in the final step. (List the options for oxidizing agents and reaction conditions and draw
structures for side products formed for each option.) The thioether is formed by displacement of chloride from 2ethyl-
4- methoxy- 3,5- dimethylpyridine by the thiol, 5- methoxy- 2- mercaptobenzimidazole.
chlorom
O
N
CH
3
OCH
3
S
N
H
CH
3
N
OCH
3
O
3
N
CH
3
OCH
3
CH
3
CH
S
N
H
N
CH
3
CH3O
Cl
N
N
SH
N
The benzimidazole ring is formed from 4- methoxybenzene- 1,2- diamine and potassium ethyl xanthate. The diamine is
formed by reduction from 44-
Methoxy- 2- nitroacetanilide is formed by nitration of 4- methoxyacetanilide. 4- Methoxyacetanilide is formed from para-
methoxy- 2- nitroaniline. The nitroaniline is formed by hydrolysis of the nitroacetanilide.
anisidine and acetic anhydride.
NH
2
2
N
SH
N
H
2
NH
2
EtO SK
S
O
3
The 2- chloromethylpyridine is formed from the alcohol. The alcohol is formed by hydrolysis of the acetate. The
2- acetoxymethylpyridine is formed by the reaction of 4- methoxy- 2,3,5- trimethylpyridine- N- oxide with acetic anhydride
(Boekelheide Reaction). The ether at C4 is formed by displacement of a nitro group by methanol. 2,3,5- Trimethyl- 4- nitr
opyridine- N- oxide is formed by nitration of 2,3,5- trimethylpyridine- N- oxide. The pyridine- N- oxide is formed by oxidation
of 2,3,5- trimethylpyridine (2,3,5- collidine).
NO
N
H
CH3O
CH
CH3O
3
O
NH
2
N
H
CH
3
CH
O
O
O
CH
2
O
O322
OCH
OCH
OCH
N
CH
3
https://t.me/medicina_free
3
CH
3
Cl
CH
3
CH
3
HO
N
3
CH
3
N
3
CH
3
OCH
3
CH
3
N
O
OCH
CH
CH
CH
3
3
3
3
CH
N
O
OO
O CH
3
CH
3
CH
3
3
NO
N
O
2
CH3OH
CH
CH
3
CH
3
N
3
O
CH
CH
3
3
CH
3
CH
3
N
2,3,5-collidine
Ondansetron
Medicines for Pain and Palliative Care/Medicines for Other Common Symptoms in Palliative Care
Gastrointestinal Medicines/Antiemetic Medicines
3
O
N
An indole is often formed by Fischer Indole Synthesis
from an arylhydrazone. The arylhydrazone is often
formed from an arylhydrazine and an aldehyde or
ketone.
N
CH
Discussion. Ondansetron is a 1 : 1mixture of (R)- and (S)- enantiomers. Dimethylamine is displaced by 2- methylimidazole
in the final step. The dimethylaminomethyl group is formed by the reaction of 9-
methyl- 4- oxo- 1,2,3,4- tetrahydrocarbazo
le with formaldehyde and dimethylamine (Mannich Reaction). The tetrahydrocarbazole is methylated at N9with dime-
thyl sulfate. 4Indole Synthesis).
Oxo- 1,2,3,4- tetrahydrocarbazole is formed from phenylhydrazine and 1,3- cyclohexanedione (Fischer
Oseltamivir 323
CH
O
3
2
CH
CH
https://t.me/medicina_free
3
O
N
N
O
CH
3
N
CH
CH
3
3
N
CH
N
CH
3
3
HN
(CH3)2NH
O
O
N
O
O
N
CH
3
H H
N
H
O
CH3OS
OCH
3
O
NHNH
2
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to ondansetron that does not utilize a Fischer
Indole Synthesis to construct the indole. Include the structures of the retrosynthetic analysis of any organic starting
material(s) from petrochemical or biochemical raw materials. List pros and cons for the two routes and select one route as
the preferred route.
Oseltamivir
Anti- infective Medicines/Antiviral Medicines/Other Antivirals
3
O
O
N
3
H
CH
NH
O
3
OCH2CH
A trans- cycloalkane- 1,2- diamine is often formed by the
ring-
opening of an aziridine with an azide or amine.
O324
3
OH
https://t.me/medicina_free
Discussion. The 5α- primary amine is formed by azide reduction in the final step. The amide is formed by reaction of the
4β-
primary amine with acetic anhydride. The 4β- primary amine and the 5α- azide are formed by ring- opening of the 4β,
aziridine with sodium azide. (What is the regioselectivity of the aziridine ring- opening?) The 4β,5- aziridine is formed
5from a mixture of two azido alcohols. (What reagent(s) are used for this reaction?) The mixture of azido alcohols is formed
by ring-
opening of the 4α,5- epoxide with sodium azide. (What is the regioselectivity of the epoxide ring- opening?)
CH
3
CH
CH
CH
3
3
3
O
and
CH
O
O
N
H
NH
CH
3
O
3
CH
3
CH
O
3
O
OCH2CH
3
2
CH
O
3
O
OCH2CH
3
CH
CH
O
N
3
H
N
3
3
CH
3
O
O
OCH2CH
OCH2CH
3
O
H2N
O
CH
3
CH
N
3
O
3
HN
O
OCH2CH
HO
3
CH
3
CH
O
N
3
O
3
OCH2CH
3
CH
3
CH
O
3
O
O
OCH2CH
3
N
3
The key 4α,5- epoxide intermediate is formed in six steps from ()- shikimic acid. The epoxide ring is formed by nucleophilic displacement of the 5β- methanesulfonate by the 4α- alcohol. The 4α- alcohol and the 3α- ether are formed by reductive cleavage of the acetal. (What is the regioselectivity of this reductive cleavage?) The acetal is formed from the acetone
acetal and 3- pentanone by acid- catalyzed transacetalization. The 5β- methanesulfonate is formed from the 5β- alcohol. The
acetone acetal is formed from ethyl shikimate. (Why is 3-
pentanone not used in this step to avoid the transacetalization in
a later step?) Ethyl shikimate is formed from ()- shikimic acid (Fischer Esterification). ()- Shikimic acid is isolated
from Chinese star anise.
Oxamniquine 325
CH
CH
OH
3
3
3
3
HO
https://t.me/medicina_free
CH
3
3
3
CH3SO2Cl
CH
CH
CH
O
3
CH
3
O
OCH2CH
3
CH
O
3
O
OCH2CH
3
HO
O
O
SO2CH
3
O
O
SO2CH
3
CH3CH2OH
OH
(–)-shikimic acid
OCH2CH
O
3
O
SO2CH
O
O
OCH2CH
3
OCH2CH
CH
CH
O
3
3
O
3
CH
O
CH
3
CH
3
O
HO
3
OCH2CH
HO
O
OH
HO
3
HO
CH
3
O
O
3
O
O
OH
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative azide- free route to oseltamivir from ()- shikimic acid.
Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical
raw materials.
or
Draw the structures of the retrosynthetic analysis of one alternative route to oseltamivir which does not use ()- shikimic
acid as the starting material. Include the structures of the retrosynthetic analysis of any organic starting material(s) from
petrochemical or biochemical raw materials.
Oxamniquine
Anti- infective Medicines/Anthelminthics/Antischistosomals and Other Antitrematode Medicines
A 1,2,3,4- tetrahydroquinoline is often formed by hydro-
O2N
H
N
H
N
CH
CH
genation of a quinoline.
O326
HO
3
3
3
CH
CH
CH
2
3
https://t.me/medicina_free
Discussion. Oxamniquine is a 1 : 1mixture of the (R)- and (S)- enantiomers. The 1,2,3,4- tetrahydroquinoline ring suggests
a late-
stage hydrogenation of a quinoline. Since the nitro group would be reduced during a ring hydrogenation, the nitration must be after the ring hydrogenation. The benzylic alcohol would be reduced during a ring hydrogenation and would
be oxidized during a nitration so the benzyl alcohol must be formed last.
The alcohol is produced by fermentation in the final step. Nitration of the 6-
in a mixture of regioisomers. (Why is the 7-
nitro isomer the major product?) The tetrahydroquinoline is formed by hydro-
methyl- 1,2,3,4- tetrahydroquinoline results
genation of the quinoline.
CH
3
H
N
H
N
CH
CH
CH
3
CH
O2N
CH
H
N
H
3
N
H
N
H
N
CH
CH
CH
3
3
CH
3
3
O2N
CH
3
N
H
N
The secondary amine is formed by displacement of chloride by isopropylamine. (What conditions are used to ensure the
secondary amine is the major product?) 22,6-
dimethylquinoline. (Why is the chlorination selective for the 2- methyl group?) 2,6- Dimethylquinoline is formed from
toluidine and crotonaldehyde (Skraup–Doebner- von Miller Synthesis).
para-
3
H
N
CH
CH
3
3
CH
N
3
Chloromethyl- 6- methylquinoline is formed by chlorination of
3
N
3
H
H2N CH
Cl
O
CH
3
3
N CH
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to 2,6- dimethylquinoline. Include the structures
of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials. List the
pros and cons for both routes to 2,6- dimethylquinoline. Is one route preferred?
3
NH
CH
Oxytocin 327
H-Cys-Tyr
2
HS
α
O
H-
Bo
Boc-Cys(Acm)-Tyr(tBu)-Ile-Gln(Trt)-A sn(Trt)- Cys(Acm)-Pro-Leu-G ly-NH-Resin
https://t.me/medicina_free
Oxytocin
Oxytocics and Antioxytocics/Oxytocics
-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH
A polypeptide is often constructed from the constituent amino acids by forming the amide bonds. The amide bonds are
formed via a solidphase and solution- phase methods.
Discussion. To simplify polypeptide synthetic schemes, the amino acids are represented by acronyms and are assumed to
be in the -
configuration. Protecting groups used in construction of the polypeptide are also represented by acronyms. A
disulfide is represented by a bridge connecting the amino acids involved in the bridge. Polypeptide amino acid sequences
are drawn with the Cthe left. (Create a Table of acronyms used in the analysis. Draw the structure associated with each acronym.)
phase peptide synthesis, a solution- phase peptide synthesis, or a hybrid approach using both solid-
terminal amino acid (carboxylic acid) on the right and the N- terminal amino acid (amino group) on
O
OH
NH
2
L-cyst eine
H-Cys-OH
Hofα-NHOHofCOOH
CH
3
N
H
Fmoc-Cys (Acm)- OH
protecting group
-amino
for
S
O
OH
HN
protecting group
of fthe pep tide chain
O
O
High- purity oxytocin is constructed by solid- phase peptide synthesis (SPPS). The final step in one SPPS is a global depro-
tection and release of the amide from a Rink Amide resin. The disulfide is formed on-
resin by reaction of the two
acetamidomethyl(Acm) thioethers with iodine.
Cys-Tyr-Ile-Gln-Asn-Cy s-Pro-Leu- Gly-NH
c-Cys-Tyr(tBu)-Ile-Gln(Trt)-Asn(Trt)-Cys-Pro-Leu-Gly-NH- Re sin
2
The nonapeptide chain is constructed right- to- left starting with the C- terminal amino acid. The amide is formed by reaction of Fmoc- Gly- OH and a polymer- bound amino group. An amino group is released by Fmoc- deprotection. An amide
bond is formed by reaction of this amino group with the carboxylic acid of the next Fmoc- protected amino acid. Fmocdeprotection and amide bond formation are repeated six times to produce the polymer- bound octaapeptide. The final
Fmoc- deprotection is followed by reaction of the amino group with the carboxylic acid of Boc- Cys(Acm)- OH.
O328
Boc-Cys(Acm)-Tyr(tBu )-Ile-Gln(Trt)-Asn(Trt)-Cy s(Acm)-Pro-Leu-G ly-NH-Resin
Bo
n
Fm
Fm
Fm
Fm
Fm
Fm
https://t.me/medicina_free
c-Cys(Acm)-OHH-Tyr (t Bu)-Ile-Gln(Trt)-Asn(Trt)-Cys(Acm)-Pro-Leu-Gly-NH-Resin
Fmoc-Tyr(tBu)-Ile-Gln(Trt)-Asn(Trt)- Cys(Acm)-Pro-Leu-Gly-NH-Resi
oc-Tyr(tBu)-OH H-Ile-Gln(Trt)-Asn(Trt)-Cys(Acm)-Pro-Leu-Gly-NH-Resin
Fmoc-Ile-G ln (Trt)-Asn(Trt)-Cys (Acm)-Pro-Leu-Gly-NH-Resin
oc-Ile-O HH-Gln(Trt)-Asn(Trt)-Cys(Acm)-Pro-Le u-Gly-NH -Resin
Fmoc-Gln(Trt)-Asn(Trt)-Cys(Acm)-Pro-Leu-Gly-NH-R esin
Fmoc-Gln(Trt)-OH H-Asn(Trt)-Cys(Acm)-Pro-Leu-Gly-NH-Resin
Fmoc-Asn(Trt)-Cys(Acm)-Pro-Leu-Gly-NH-Resin
oc-Asn(Trt)-OH H-Cys(Ac m)-Pro-Leu-Gly-NH- Re sin
Fmoc-Cys(Acm)-Pr o-Leu-Gly-NH-R esin
oc-Cys(Acm)-OH H-Pro-Leu-Gly-NH-Resin
Fmoc-Pro-L eu-Gly-NH-Re sin
Fmoc-Pro-OHH-Leu-Gly-NH- Resin
Fmoc-Leu-Gly-NH-Resin
oc-Leu-OHH-Gly-NH-Re sin
Fmoc-Gly-NH- Re sin
oc-Gly-OHNH2-Resin
In summary, the nonapeptide backbone is constructed by forming eight amides in a solid- phase peptide synthesis. Each
amide is formed via an active ester which is formed in situ from the carboxylic acid. Eight of the active esters can be racemized during the amide bond formation (List reagent(s) used to form the active esters in peptide synthesis.) Eight Fmoc
protecting groups are used. (List reagents used to remove Fmoc protecting groups in peptide synthesis.)
Routes to the protected amino acid starting materials are presented. (Draw the structure of each protected amino acid
starting material.) Cysteine, tyrosine, isoleucine, glutamine, proline, and leucine are produced by fermentation.
Oxytocin 329
Fm
Fm
Fm
Fm
Fm
Boc-Cys( Acm)-OHH-Cys (Acm)-OH H-Cys- OH
Fm
Fm
Fm
https://t.me/medicina_free
(Boc)2O
oc-Tyr(tBu)-OH Fmoc-Tyr(tBu)-OCH3Fmoc-T yr -O CH
oc-Ile-OHH-Ile-OH
Fmoc-Cl
oc-Gln(Trt)-OH H-Gln(Trt)-OHZ-Gln(Trt)-OH Z-Gln- OH H-Gln-OH
Fmoc-Cl
oc-Asn(Trt)-OH H-Asn(Trt) -OHZ-Asn(Trt )-OH Z-Asn-OH
Fmoc-Cl
oc-Cys(Acm)-OH H- Cys(Acm)-O HH-Cys-OH
Fmoc-Cl
oc-Pro-O HH-Pro-OH
Fmoc-Cl
oc-Leu-OHH-Leu-OH
Fmoc-Cl
oc-Gly-OH
H-Gly-OH
Fmoc-Cl
Acm-OH
CH
=C(CH3)
2
Acm-OH
3
2
H-Tyr-OCH
Fmoc-Cl
Trt-Cl Z-Cl
Trt-Cl Z-Cl
3
H-Asn-OH
Extended Discussion
H-Tyr-OH
CH
OH
3
Solution- phase syntheses of oxytocin were developed by du Vigneaud, Stoll, Nobuhara, Velluz, and others. Draw a scheme
for the retrosynthetic analysis of one solution-
phase synthesis of oxytocin.
330
3
O
https://t.me/medicina_free
P
Paclitaxel
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
O
O
O
CH
3
CH
CH
O
NH
OH
3
O
O
3
CH
OH
OH
CH
3
3
H
O
O
H
O
CH
O
A singlechiral carbons is often formed by the modification of a natural product which has most or
all of the chiral carbons already in place.
Taxanes are often formed by modification of
10III is a diterpenoid isolated from the leaves of
the European yew Taxus baccata.
enantiomer molecule with multiple
deacetylbaccatin III. 10- Deacetylbaccatin
Discussion. Paclitaxel is a natural diterpenoid first isolated from the Pacific yew Taxus brevifola. Paclitaxel is currently
manufactured by plant cell fermentation (PCF) using cells cultured from the needles of the Chinese yew Taxus chinensis.
Some paclitaxel is still semisynthetic. In the semisynthesis, the final step is the release of the hydroxyl at C7 from the
silyl ether and release of the hydroxyl at C2′ and the amide NH at C3′ from the oxazolidine. The ester at C13 is formed
from the carboxylic acid and secondary alcohol.
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
Соседние файлы в папке Библиотека им академика М.И. Перельмана