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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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Levamisole 241
Fm
3
Fm
Fm
Fm
Fm
OC
SN
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In summary, the nonapeptide backbone is constructed by forming eight amides, four in the solid- phase synthesis and four
in solution-
phase synthesis. Each amide is formed via an active ester which is formed in situ from the carboxylic acid. Each
active ester can be racemized during the amide bond formation. (List reagent(s) used to form active esters used in this
peptide synthesis.) Six 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.) Pyroglutamic acid is formed from glutamic acid. -
Leucine can be formed from - leucine. Leucine,
arginine, proline, glutamic acid, histidine, tryptophan, serine, and tyrosine are all produced by fermentation.
oc-D -Leu-OH
oc-Arg(pbf)-OH H-Arg(pbf)-OHH-Arg(pbf)-OCH2CH
H-Pro-NHCH2CH
pGlu-OHH-Glu-OH
Fmoc-His(Trt)-OH H- His(Trt)-O HH-His-OH
oc-Trp(Boc)-OH H-Trp(Boc)-OHZ-Trp(Boc)-OCH2Ph Z-Trp-OCH2Ph
oc-Ser(t Bu)-OH H-Ser(tBu)-O HH-Ser(tBu)-OCH3H-Ser-OCH
oc-Tyr(tBu)-OH Fm oc -Tyr(tBu)- OCH
3
H-D-Leu-OH
Fmoc-Cl
Fmoc-Cl
Boc- Arg-OCH
pbf-Cl (Boc)
H-Pro-OH
CH
3CH2NH2
Fmoc-ClTrt-Cl
Fmoc-Cl
H-Trp-OCH
Z-Cl PhCH2OH
Fmoc-Cl
2CH3
Ph H-Trp- OH
2
H-Arg-OCH2CH
Fmoc-T yr -O CH
3
2
CH2=C(CH3)
2
3
3
Boc-Arg(pbf)-OCH2CH
3
H-Arg-OH
(Boc)
CH2=C(CH3)
H-Tyr-OCH
Fmoc-Cl
H3CH2OH
3
2
3
O
2
H-Ser-OH
H-Tyr-OH
CH3OH
CH3OH
Extended Discussion
Draw the structures of the retrosynthetic analysis of 2,2,4,6,7- pentamethyl- 2,3- dihydrobenzofuran- 5- sulfonyl chloride (pbf–Cl).
Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw
materials.
Levamisole
Anti- infective Medicines/Anthelminthics/Intestinal Anthelminthics
N
A single- enantiomer molecule is often manufactured by
resolution when it can form a salt with a Bronsted acid
or Bronsted base and when the “wrong” enantiomer can
be racemized and returned to the resolution.
L242
S
CH
3
O
OH
O
3
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Discussion. Levamisole is produced by resolution of tetramisole. (List the known resolving agents. Select one resolving
agent as preferred.) The (R)-
enantiomer, dexamisole, is converted back to tetramisole and tetramisole is returned to the
resolution. (List the reagents and conditions used for the racemization.) The imidazoline ring of tetramisole is formed by
nucleophilic displacement of chloride by nitrogen of the 2hol. The 2formed by the ring-
iminothiazolidine hydrochloride is formed by reaction of the aziridine with thiourea. The β- aziridinyl alcohol is
opening of styrene oxide by aziridine. (Review a safety data sheet [SDS] for aziridine. List your concerns
iminothiazolidine. The alkyl chloride is formed from the alco-
regarding the use of aziridine as a starting material.)
N
Cl
HN
HCl
O
N
OH
N
N
HN
HCl
N
S
S
N
tetramisole
OH
S
N
S
H2N NH
HN
2
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to levamisole which does not have aziridine as a
starting material.
Levofloxacin
Anti- infective Medicines/Antibacterials/Antituberculosis Medicines
F
N
N
Discussion. Fluoride at position 7 of the quinolone ring is displaced by 1- methylpiperazine in the final step. The carbox-
ylic acid is released by ester hydrolysis.
Substitution of a leaving group (F, Cl, NO
) on an aromatic
2
ring by a nucleophile is often facilitated by an electronwithdrawing group (NO
, SO2R, COOR, CN) on an ortho or
2
para ring carbon. No electron- withdrawing group is
N
required when the displacement results in formation of a
five- or six- membered ring.
O
CH
Levofloxacin 243
O
O
3
3
3
F
F
OH
OH
F
O
O
F
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F
OH
OH
N
CH
3
O
O
F
OCH2CH
F
N
O
CH
CH
N
CH
N
3
O
O
O
F
F
NH
N
O
N
CH
3
A ring and the ether at quinolone C8 are formed by intramolecular displacement of fluoride by oxygen. The quinolone ring
is formed by intramolecular displacement of fluoride by nitrogen. An enamine is formed by reaction of the enol ether with
(S)- 2- amino- 1- propanol (- alaninol).
OCH2CH
O
F
3
O
OCH2CH
3
N
O
CH
3
O
O
F
F
OH
N
CH
3
O
O
F
OCH2CH
F
F
NH
H
CH
3
F
F OCH2CH
F
3
OCH2CH
3
3
NH
2
H
CH
3
The enol ether is formed by reaction of the β- ketoester with triethyl orthoformate. The β- ketoester is formed from
2,3,4,5- tetrafluorobenzoyl chloride. In one preferred approach, diethyl malonate supplies the added functionality. (The fourstep conversion of the 2- fluorobenzoyl chloride to the quinolone is known as the Grohe–Heitzer Sequence.) The acid chloride is formed from the carboxylic acid.
L244
F
O
CH
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O
F
F
F
F
F
F OCH2CH
O
OCH2CH
O
CH3CH2O
Cl
F
3
3
O O
F
F
OCH2CH
F
3
O
F
F
F
F
O
OCH2CH
HC(OCH2CH3)
O
OH
F
3
2
Extended Discussion
List the reagents and conditions used for the reduction of - alanine and esters of - alanine to form - alaninol. List the pros
and cons for each method.
Levonorgestrel
Hormones, Other Endocrine Medicines and Contraceptives/Contraceptives/Oral Hormonal Contraceptives
Hormones, Other Endocrine Medicines and Contraceptives/Contraceptives/Intrauterine Devices
Hormones, Other Endocrine Medicines and Contraceptives/Contraceptives/Implantable Contraceptives
3
H
H
H H
Discussion. Levonorgestrel is manufactured in six steps from 13- ethyl- 3- methoxygona- 1,3,5(10),8,14- pentaen- 17β- ol ace-
tate and in 11 steps from 6- methoxy- 1- tetralone.
The 4- ene- 3- one of levonorgestrel is formed in the final step from the 3- methoxy- 2,5- diene by hydrolysis of the enol ether
and migration of the double bond. The tertiary alcohol at C17 is formed by addition of a metal acetylide to the C17ketone.
OH
Steroids with an ethyl group at C13 on the gonane
structure are often manufactured by total synthesis.
The gonane is constructed from 6vinyl chloride, and 2-
ethyl- 1,3- cyclopentanedione
methoxy- 1- tetralone,
(Torgov–Smith Synthesis). Chirality at C13 is established by microbial reduction of a 2,2-disubstituted1,3-cyclopentanedione intermediate.
Levonorgestrel 245
CH
CH
CH
CH
CH
3
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The C17ketone is formed by oxidation of the C17 secondary alcohol (Oppenauer Oxidation). The 3- methoxy- 2,5- diene
is formed by reduction of the aromatic ring (Birch Reduction). The 8,9-
alkene is also reduced under the conditions used
for reduction of the aromatic ring. The C17 secondary alcohol is released by ester hydrolysis. The C14 alkene of the gona1,3,5(10),8,14- pentaene is reduced by catalytic hydrogenation.
3
H
3
O
5
4
H
9
8
H H
6
CH
3
13
OH
17
CH3O
O
3
H
H H
CH
3
OH
OH
HC CH
H H
CH
3
H
O
O
CH
3
H
H
H H
O
3
CH
3
OH
CH3O
H
O
3
CH3O
O
CH
3
O
CH
3
O
The gona- 1,3,5(10),8,14- pentaene is formed from the secosteroid. The C17 acetate of the secosteroid is formed from the C17
alcohol by reaction 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- tetrahydronaph
L246
O
O
CH
CH
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thalen- 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.
CH3O
3
CH
3
O
CH
3
11
CH
3
12
9
13
14
17
O
CH
3
O
CH3O
O
CH
3
OH
CH
3
O
O
CH
O
3
O
CH3O
O
CH
3
3
O
CH
O
MgCl
Cl
OH
O
O
CH3O
CH3O
2- Ethyl- 1,3- cyclopentanedione is formed from succinic anhydride and butanoic anhydride.
3
O
O
O
O O
O
CH
3
O
O
CH
3
Levothyroxine 247
I
HO
I
OH
O
I
O
3
3
CH
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Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to levonorgestrel. 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 and select one route as the preferred route.
Levothyroxine
Hormones, Other Endocrine Medicines and Contraceptives/Thyroid Hormones and Antithyroid Medicines
A chiral carbon in a single- enantiomer molecule is
I
NH
2
I
O
Discussion. Iodination of the phenol ring of 3,5- diiodothyronine is the final step. The phenol, carboxylic acid, and amine
diiodothyronine are released from ether, ester, and amide protecting groups in a single step. The diaryl ether is
of 3,5formed by O-
arylation of N- acetyl- 3,5- diiodo- - tyrosine ethyl ester with a bis(4- methoxyphenyl)iodonium salt.
often delivered in a starting material.
HO
O
3
I
HO I
CH3O I
X
I
I
O
O
3,5-diiodothyronine
O
OCH
OH
I
I
I
I
3
HO
HN
I
NH
NH
2
2
O
O
CH
OH
OCH2CH
O
3
HN
3
O
OCH2CH
O
CH
L248
HO
O
HO
CH
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The ester is formed from the carboxylic acid (Fischer Esterification). N- Acetyl- 3,5- diiodo- - tyrosine is formed by reaction of 3,5-
diiodo- - tyrosine with acetic anhydride. 3,5- Diiodo- - tyrosine is formed by iodination of - tyrosine. - Tyrosine
is produced by fermentation.
O
I
HN
I
I
NH
I
CH
2
CH
O
3
OCH2CH
O
3
OH
O
3
O
O
CH
3
HO
HO
I
HN
I
NH
tyrosine
OH
O
CH
3
O
OH
2
CH
3CH2
OH
The bis(4- methoxyphenyl)iodonium salt is formed from 4- iodoanisole and anisole. (What is the counterion X and what is
the procedure for manufacturing the salt?)
O
3
OCH
CH3O
3
OCH
3
X
II
Extended Discussion
Draw the structure for one alternative O- arylation reagent used to prepare levothyroxine from 3,5- diiodotyrosine. What
reagents and conditions are used for the O-
arylation step using the alternative reagent? Draw the structures of a
retrosynthetic analysis of the reagent. Include the structures of the retrosynthetic analysis of any organic starting material(s)
from petrochemical or biochemical raw materials.
Lidocaine
Anesthetics/Preoperative Medicines and Medical Gases/Local Anesthetics
Cardiovascular Medicines/Antiarrhythmic Medicines
Linezolid 249
CH
3
3
3
O
3
O
O
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3
H
N
CH
O
N
CH2CH
CH2CH
3
Tertiary amines are ubiquitous in drug structures. A tertiary
amine is often formed by alkylation of a secondary amine.
The alkylation is most efficient when the amine is used in
excess and the carbon with the leaving group (Cl, Br, I, OTs,
OMs) is primary or benzylic.
Discussion. Lidocaine is manufactured in just two steps. The tertiary amine is formed in the final step by displacement
of chloride from the α2,6-
dimethylaniline with chloroacetyl chloride.
CH
3
H
N
O
CH
3
chloroacetamide by N,N- diethylamine. The α- chloroacetamide is formed by the reaction of
CH2CH
N
CH2CH
Cl
3
(CH3CH2)2NH
H
N
O
CH
3
CH
3
Cl
CH
3
3
NH
CH
O
2
Cl
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to 2,6- dimethylaniline. Discuss the pros and cons
for both routes to this starting material and select one route as the preferred route.
Linezolid
Anti- infective Medicines/Antibacterials/Other Antibacterials
infective Medicines/Antibacterials/Other Antibacterials/Antituberculosis Medicines
Anti-
When a single- enantiomer target molecule is manufac-
O
N
F
N
H
N
CH
Discussion. In the final step, the acetamide is formed by reaction of the amine with acetic anhydride. The amine is formed
by reduction of the azide. The azide is formed by displacement of methanesulfonate. The methanesulfonate is formed from
the alcohol. The oxazolidinone is formed by reaction of the benzyl carbamate with (R)-glycidyl butyrate. (Draw structures
for the byproduct(s) in this reaction.)
tured using a resolution, the resolution is likely an early
step in the preferred route.
L250
O
O
O
O
O
OH
O
F
O
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O
N
N
H
N
CH
3
F
O
O
CH
O
O
3
O
O
N
N
NH
F
O
O
N
N
CH
3
O
O
O
NO
2
N
N
3
F
O
O
NO
N
O
SO2CH
F
3
F
CH3SO2Cl
O
OCH2Ph
N
F
NH
O
H
O CH2CH2CH
3
The carbamate is formed from the aniline and benzyl chloroformate. The aniline is formed by reduction of the nitroaromatic. Morpholine is introduced by displacement of a fluoride para to the nitro group. 1,2formed from 1-
chloro- 2,4- dinitrobenzene.
O
N
F
N
NH
NO
2
OCH2Ph
NO
NO
F
2
Cl
O
N
H
F NO
F
Cl OCH2Ph
NH
2
O2N
O
Difluoro- 4- nitrobenzene is
2
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