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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
302
Pharmaceutical Chemistry of Natural Products
OAc
H H
H
AcO
O
OH
H H
H
HO
OH
Oestriol
LiAlH
4
Route 2
O
H H
H
Methyl ether of oestrone
O
H H
H
NOH
OH
H H
H
O
H
OH
H H
H
OH
OH
H H
H
HO
Oestriol
HCO
3
C H ONO
(CH ) COK
511
33
HCO
3
Zn dust
CH CO H
32
HCO
3
HBr
CH CO H
32
OH
Na/(CH ) CHOH
32
HCO
3
Steroids and Hormones
303
Oestradiol
1
2
3
4
5
6
7
8
9
10
11
12
13
14 15
16
17
18
HO
OH
HH
H
Oestradiol or (9 ,14 )-13-methyl-7,8,9,11,12,13,14,15,16,17-
decahydro-6 -cyclopenta[ ]phenanthrene-3,17-diol
SS
Ha
It exists as two stereoisomeric oestradiols (i.e. α and β). Between them, β-isomer is much more
active than oestrone, whereas α-isomer is much less active.
Doisy et al. in 1935 isolated the β-isomer from the ovaries of cow. The α-isomer was isolated
by Winterstein and co-workers in 1938 from the pregnancy urine of mare.
Oestrone
HO
O
HH
H
Oestradiol
OH
HH
H
HO
(or) LiAlH
4
Aluminium isopropoxide
Synthesis of oestrogen derivatives:
C
CH
C
C
C
O
HCO
3
CH Br
2
1-(3-Bromopropyl)-3-
methoxybenzene
HCO
3
Et NH
2
HCHO
HCO
3
HSO
24
Hg
2
⫹
NEt
2
HCO
3
2-Methylcyclopentane-
1,3-dione
O
O
NEt
2
HC
2
CNa
HC
–
OH
304
Pharmaceutical Chemistry of Natural Products
O
H
O
H
HCO
3
TsOH
HCO
3
H /Ni
2
C
O
O
O
HCO
3
HC
2
K/NH
NH Cl
3
4
Catalytic reduction
Alu. isopropoxide or LiAlH
4
OH
HO
C CH
CH
CH
OH
H
H
H
HCO
3
(i) CrO
3
(ii) HBr/AcOH
O
HO
H
H
H
( )Oestrone⫾
K/NH
3
17 -Ethinyl oestradiol␣
HO
O
Pyridine
C O
2
OH
Oestradiol
CH (CH ) COCl
323
(CH ) -COCl
22
OCO(CH )
23
CH
3
(CH )
23
KCO
CH OH
23
3
CH
3
KCO
CH OH
23
3
(H C) OCO
22
OCO(CH )
22
Steroids and Hormones
305
HO
OCO(CH )
23
CH
3
Oestradiol valerate
HO
Oestradiol cypionate
OCO(CH )
22
Synthetic oestrogens
17
α
-Ethinyl oestradiol
HO
H
H
H
OH
CCH
17 -Ethinyl oestradiola
It is a very active synthetic oestrogen. Its main advantage is that it is more active when taken orally.
The ethinyl radical of this agent delays the inactivation of oestradiol molecule in the stomach,
intestine and liver. 17α-Ethinyl oestradiol (as well as its 3-methyl ether, mestranol) is used as one
of the components in most of the currently marketed oral contraceptive.
Synthesis of 17␣-ethinyl oestradiol:
OH
O
OH
OH
C
CH
KNH
–
3
Acetylene
Oestrone
17- -Ethinyl oestradiola
306
Pharmaceutical Chemistry of Natural Products
Chemical Relationship Between Oestrone, Oestriol and Oestradiol
1. Interconversion taking place during metabolism is given as follows:
OH
HO
OH
OH
HO
Oestradiol dehydrogenase
Oestradiol dehydrogenase
16 ydroxylase
-Ha
Oestradiol
Oestrone
16 ydroxylaseH-a
HO
O
O
OH
Oestriol 16 -Hydroxyestronea
HO
2. Oestrone upon reduction with aluminium isopropoxide or lithium aluminium hydride forms
oestradiol.
HO
O
H
HH
Oestrone
Aluminium isopropoxide
(or) LiAIH
4
HO
HH
H
OH
Oestradiol
3. Oestriol undergoes dehydration when heated with potassium hydrogen sulphate to yield
oestrone.
KHSO
4
Dehydration
HO
OH
H
HH
OH
Oestriol Oestrone
HO
O
H
HH
Steroids and Hormones
307
4. Oestrone can be converted to oestriol as follows:
O
HO
HH
H
Oestrone
AcO
H
H
H
OAc
Isopropenyl acetate
C H COOOH
Perbenzoic acid
65
HO
OH
OH
HH
LiAlH4
AcO
HH
H
OAc
O
Oestriol
H
5. Oestrone can also be converted to oestriol as follows:
HCO
3
H
H
H
O
Methyl ether of oestrone
C H ONO
511
(CH ) COK
33
HCO
3
H
H
H
O
NOH
Zn dust
CH CO H
32
H
OH
O
H
H
H
HCO
3
Na/(CH ) CHOH
32
OH
OH
H
H
H
HCO
3
HBr
CH CO H
32
OH
OH
H
H
H
HO
Oestriol
H
H
308
Pharmaceutical Chemistry of Natural Products
Nonsteroidal Oestrogens or Artificial Hormones
A large number of synthetic oestrogens have been prepared which have oestrogenic activity without
having steroid skeleton. Because of their relatively low cost and effi ciency when administered
orally, they are preferred over oestrogens of natural origin.
Stilboesterol (diethylstilboestrol, stilbetin, stilphstrol)
HO C C OH
CH
25
CH
25
4,4-Dihydroxydiethylstilbene
Synthesis
It can be synthesized by the following methods:
Method 1—From anisaldehyde (Dodds method):
2 H CO
3
CHO
KCN
HCO
3
CHOH.CO
OCH
3
SnCl
2
HCO
3
CH .CO
2
OCH
3
Deoxyanisoin
4-Methoxy benzaldehyde
or anisaldehyde
Anisoin
C H ONa
25
CHI
25
C H MgI
25
PBr
3
⫺HO
2
OCH
3
CH.C
CH
25
CH
25
OH
HCO
3
CH.CO
HCO
3
OCH
3
CH
25
Steroids and Hormones
309
CH
25
HO
3
C
CC
CH
25
OCH
3
Ethanolic KOH
CH
25
CC
CH
25
HO
OH
Stilboesterol (trans)
Method 2—From anethole:
2 H CO
3
CC
H
H
CH
3
HBr
Anethole
Anethole hydrobromide
2 H CO
3
C
H
Br
CH
23
CH
NaNH
2
Liq. NH
3
HCO
3
CC
C
25
H
C
25
H
O
3
CH
Alkali
HO OH
C
25
H
CC
C
25
H
Diethylstilboesterol
Properties: It is a white crystalline powder, insoluble in water and soluble in alcohol.
310
Pharmaceutical Chemistry of Natural Products
Hexoestrol
Hexoestrol contains two asymmetric carbon atoms, and therefore, it exists in diastereomeric forms.
The meso form is much more potent than the racemic form and it is only the meso form which is
of commercial importance. It is synthesized from anethole hydrobromide.
HCO
3
CHBrC H
25
Na, Mg, etc.
or C H MgBr
65
(Wurtz type)
HCO
3
C
H
CH
25
C
H
CH
25
OCH
3
KOH–C H OH
25
Anethole hydrobromide
HH
CH
25
CH
25
CC
HO
OH
Hexoestrol
Dienoestrol (estragard)
OH
CHCH
3
CHCH
3
C
C
HO
It has two double bonds in the side chain the name indicates. It is about one-fourth as potent as
stilboestrol.
Synthesis of dienoestrol
Method 1:
HO
CH
25
CC
CH
25
OH
CH COCl
3
H COC
3
O
CH
25
CC
CH
25
O
COCH
3
Diethylstilboesterol diacetate
Br
2
Diethylstilboesterol
Steroids and Hormones
311
OH
CHCH
3
CHCH
3
C
C
HO
Dienestrol
O
COCH
3
CH
25
CH
25
C
C
Br
Br
H COC
3
O
Pyridine
Heat
⫺HO
2
COCH
3
O
C
C
H COC
3
O
CH
CH
CH
3
CH
3
NaOH
Method 2:
HCO
3
CHBrCHBrCH
3
HCO
3
Pyridine
KOCH
3
C
CH
HBr
HCO
3
C CHCH
3
Br
OCH
3
CHCH
3
CHCH
3
C
C
HCO
3
Demethylation
OH
CHCH
3
CHCH
3
C
C
HO
Dienoestrol
Mg
CuCl
2