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Патент USA US3027419

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United States PatentO?ice
3,027,409
Patented Mar. 27, 1962
1
2
3,027,409
9//10-SECOPROGESTERONES
to give the corresponding 3-alkoxy-9//10-seco-1,3,5(10)~
pregnatriene-11,20-dione (II), ketalizing the said 3-alkoxy
steroid to produce a separable mixture of 3-alrkoxy-9//10‘
John A. Hogg, Kalamazoo Township, Kalamazoo County,
and Barney J. Magerlein, Kalamazoo, Mich, asslgnors
seco-1.3,5(10)-pregnatriene — 11,20 - dione 11,20-diketal
to The upjuhn Company, Kalamazoo’ Mich‘, a comm 5 and the corresponding 20-monoketal (III), reducing the‘
ration of Michigan
said ZO-monoketal steroid to yield 11a-hydroxy-9//10
No Drawing. Filed May 19, 1958, Ser. No. 735,998
4 Claims. (Cl. 260-586)
seco-4-pregnene-3,ZO-dione ZO-ketal (11a-hydroxy-9/ / 10- I
secoprogesterone 20*ketal) (IV), oxidizing the said 11a
.
_
_ com
hydroxy-ZO-ketal steroid to give 11-keto-9//10-seco
The present lnvention
relates to novel stero1d
pounds and a process for their preparation and is more 10 progesterone ZO-ketal (V), and reducing and hydrolyzing ’
particularly concerned with 11~oxygenated-9//l0-seco
the said ZO-ketal compound to produce a separable mix
progesterone and intermediates and process for the pro
duction thereof.
ture of llot-hydroxy (VI) and 11/3~hydroXy-9//10-seco
progesterone (VII).
Alternatively, the 110: - hydroxy
This application is a continuation-in-part of applicants’
ma ’
9//l0-secoprogesterone ZO-ketal (IV) can be hydrolyzed
copending7 application Serial No. 559,778, ?led January 15 directly to lla-hydroxy - 9// 10 - secoprogesterone (VI).
18, 1956, now US. Patent No. 2,835,698.
In addition, the 1l-keto-9//lO-secoprogesterone 20-ketal
The products and process of the present invention may
(V) can likewise be deketalized to yield 11-keto-9//10
be represented by the ‘following reaction scheme:
secoprogesterone (VIII), or the latter compound can be
CH3
CH3
c=o
I
1° /
no
CH3 1
CH3
VIII €_______h_
0/’
VII
/
'
wherein R is an alkyl group containing from one to eight
carbon atoms, inclusive.
The process of the present invention comprises, ?rst,
obtained by oxidation of lla-hydroxy (VI) or ll?-hy
droxy—9//lO-secoprogesterone (VII).
It is an object of the present invention to provide
the alkoxylation of 3-hydroxy - 9//10 - seco - 1,3,5 ( 10)- 70 ll-oxygenated - 9//10 - secoprogesterones and a process
pregnauiene-11,20-dione (I), prepared according to the
method of said copending application Serial No. 559,778,
for their preparation. Another object is the provision of
1104 - hydroxy-9// l?-secoprogesterone, 11;8-hydroxy-9//
3,027,409
4
1,3,5(10)‘-pregnatriene-l1,20-dione in 120 milliliters of
IO-secoprogesterone and 11-keto-9// l0-secoprogesterone
benzene, 360 milligrams of para-toluenesulfonic acid, and
and a process for their production. A further object is
two grams of ethylene glycol is heated for a period of
to provide 11-oxygenated-9//10-secoprogesterone 11,20
four hours at reflux temperature. Thereafter the solvent
and unused ethylene glycol are removed by distillation
diketals and 20-monoiketals and a process for their prep
aration. Other objects will be apparent to those skilled
in the art to which this invention pertains.
under reduced pressure. The remaining oily liquid is the
20 - monoethylene ketal of 3 - methoxy » 9/ / l0 - seco
The products of the present invention, namely, 11
1,3,5 (l0)-pregnatriene - 11,20 - dione. Recrystallization
hydroxy-9//10-seco-4-pregnene-3,20-dione (ll - hydroxy
from ethylacetate-Skellysolve B hexanes fails to convert
the oil to crystalline ZO-monoethylene ketal of 3-rnethoxy
10
3,11,20-trione (11~keto-9//lO-secoprogesterone) possess
9//l0-seco-l,3,5(l0)-pregnatriene-l1,20-dior1e (III). If
9/ / lO-secoprogesterone) and 9/ / 10 - seco - 4 - pregnene
progestational, luteoid, anti-estrogenic, and fungicidal
desired the 1].,20-diketal of 3-methoxy - 9/ / l0 - seco
activities in varying degree and in addition serve as inter
l,3,5(10)-pregnatriene-11,20-dione can be separated from
the ZO-ketal by chromatography.
Example 3.-—] I ot-Hydr0xy-9//10~Sec0pr0gester0ne 201
Ethylene Monoketal (IV)
The thus obtained 3-methoxy-9//lO-seco-l,3,5(10)
pregnatriene-ll,20-dione 20-ethylene monoketal is dis
mediate compounds in the preparation of the 9/ / lO-seco
hydrocortisone acylates and 9/ / IO-secocortisone acylates
which possess in modi?ed degree the activities commonly
associated with hydrocortisone and cortisone acylates.
In accord with applicants’ said copending application
Serial No. 559,778, 3-hydroxy - 9//l0 - seco - l,3,5(l0)
pregnatriene-l1,20-dione (I) is treated with an alkaline
solved in ?fty milliliters of ethanol and stirred thereupon
metal alkoxide wherein the alkyl group is preferably one 20 into 6% milliliters of liquid ammonia. To this solution
having one to eight carbon atoms, inclusive, such as
is added six grams of lithium in small pieces under rapld
sodium methoxide, to give, in the preferred embodiment,
stir-ring. Thereafter, the reaction mixture is decomposed
3*methoxy - 9//lO-seco - 1,3,5(l0) - pregnatrlene - 11,20
with 100 milliliters of water, and evaporated under re‘
duced pressure to a volume of 110 milliliters. The solu~
tion is acidi?ed with hydrochloric acid having an excess
dione (II), which is then ketalized with an alkanediol
such as ethylene glycol in the presence of minor quanti
ties of an acid catalyst such as para-toluenesulfonic acid,
of hydrochloric acid so that a ?ve percent acidic solue
tion is obtained. This solution, containing a suspension,
according to the procedures of US. Patent No. 2,707,184.
The thus obtained 3 - methoxy - 9//l0 - seco - 1,3,5( 10)
pregnatriene-ll,20-dione 20-ketal (III) and 11,20-diketal,
preferably the ethylene ketals, are separated, if desired,
and the 20-monoketal is reduced, preferably with metallic
tr
30
lithium in liquid ammonia and an alkanol, e.g., ethanol,
to give a mixture from which 11a-hydroxy-9//10-seco—
is then shaken with sixty milliliters of ethyl acetate which
dissolves the solids while the hydrolysis proceeds. The
ethyl acetate solution is washed with water, dried over
anhydrous sodium sulfate and evaporated under reduced
pressure. The remaining residue is taken up in ten milli
liters of ethyl ‘acetate and chromatographed on Florisil
progesterone ZO-ketal (IV) can be separated. Oxidation,
magnesium silicate in the same solvent. The main frac'
35
as with acetic acid and chromic anhydride, yields ll-keto
tion from the chromatographic separation is evaporated
9//10 -secoprogesterone 20 - ketal (V). The said 20~
and the solids added to a solution of thirty milliliters of
monoketal can then be reduced, preferably with lithium
ethanol containing thirty milligrams of sodium hydroxide.
aluminum hydride, to give the ll?-hydroxy-9/ /10- seco
This mixture is kept at a temperature of ?fty degrees for
progesterone (VII). Alternatively, the said mono-ketal
live minutes under a nitrogen atmosphere. After acidi'
(V) can be hydrolyzed by any convenient hydrolysis
?cation with a few drops of acetic acid the solvent is re—
procedure, e.g., sulfuric acid in ethanol, to produce 11
moved under reduced pressure and the residue washed
keto-9//IO-secoprogesterone (VIII). If desired, the 11oz
with water, taken up in ten milliliters, of ethyl acetate
hydIoxy-9//10-secoprogesterone ZO-ketal (IV) can in
and chromatographed over alumina in ethyl acetate. The
like manner he hydrolyzed to give lla-hydroxy-9//10
first fractions thus obtained consist of lla-hydroxy-9// 10
secoprogesterone (VI). The said 1le-hydroxy-9/ / l0 45 secoprogesterone ZO-ethylene monoketal (IV).
secoprogesterone can then be oxidized, as with acetic acid
and chromic anhydride, to yield 11 - keto - 9/ / 10 - seco
progesterone (VIII), which in turn can be converted by
selective reduction, as with metallic lithium in ethanol
and liquid ammonia, the lil?-hydroxy-9//lO-secoproges
Example 4.——] 1~Ket0-9//10-Smoprogesterone 20'
Ethylene Ketal (V)
A SOO-rnilligrarn portion of the solid lloz-hYtlI‘OXY
terone (VII).
The following examples are illustrative of the products
9/ / lO-secoprogesterone 20-ethylene monoketal is dis
solved in twelve milliliters ‘of acetic acid, and 400 milli
grams of chromic anhydride is added thereto. The mix
and processes of the present invention but are not to be
ture is allowed to remain at room temperature under con
construed as limiting.
Example 1 .—3-Meth0'xy -9/ /] O-Seco-l ,3 ,5 ( 1 0 ) -
tinuous shaking for a period of two hours. Thereafter
the reaction mixture is poured onto ?fty milliliters ‘of ice
and the solid l1el<eto-9//ltl-secoprogesterone 20-ethylene
rnonoketal (V) is collected on the ?lter, washed with
water and recrystallized from ethyl acetate and Skelly
Pregnatriene-I1,20-Di0ne (II)
To a solution of two grams of 3-hydroxy-9//10-seco
1,3,5 (lO)-pregnatriene-l1,20-dione, dissolved in ?fteen
milliliters of methanol denatured alcohol and heated to 60
solve B hexanes.
seventy degrees centigrade, is added, at ?ve-minute inter~
vals, one milliliter of sodium hydroxide solution contain
Example 5 .—1 I u-HydrOxy-Q/ /10-Sec0pr0gesterone (VI )1
ing 400 milligrams of anhydrous sodium hydroxide per
progesterone ZO-ethylene monoketal (IV) is dissolved in.
Twenty-?ve milligrams of 1la-hydroxy~9//l0-seco~
milliliter of water, and one milliliter of dimethyl sulfate.
one milliliter of ethanol containing four drops of water‘
The additions are repeated ?ve times and thereafter the 65 and one drop of sulfuric acid, and the mixture is boiled.
solution is poured into water and the methyl ether ex
?ve minutes. Thereafter the reaction mixture is neu-
tracted with methylene dichloride. After washing the
methylene dichloride solution with water and drying over
anhydrous sodium sulfate, the solvent is evaporated to
tralized and evaporated to dryness. The product is washed
with water and recrystallized from ethanol to give llcx-hy
Example 2.-—3-Meth0xy-9//10-Sec0-1,3,5(10)-Preg
ene monoketal, prepared as described in Example 4, is
dissolved in ?fty milliliters of ether and admixed there
after with 25 milliliters of tetrahydrofuran containing 0.5
droxy-9// l0—secoprogesterone (VI).
give 2.10 grams of oily 3-methoxy-9//lO-seoo-l,3,5(l0) 70 Example 6 .—1 I/S-Hydroxy-Q/ / 1 O-Secopmgesterone (VII)
pregnatriene-l1,20-dione (II) .
One gram of ll-keto-9//10-secoprogesterone ZO-ethyl
natriene-l I ,ZO-Dione ZO-Monoethylene Ketml (III)
A solution of two grams of 3-methoxy-9//l0-seco~
icw'vre-
3,027,409
.
.
inurn hydride.
The mixture is heat
gfam of 111213111131:
period of one hour, then cooled to
edogdtigqperatllfé and diluted with 25 milliliters of 25
{31mm aqueous sulfuric acid. The thus obtained reac
6
25 milliliters of water. The resulting solution is there
upon dried and the solvent distilled to give crude 3-keto
1 1;8-hydroxy-9// l0-seco-4,17(20)-pregnadien-2l-oic acid
methyl ester which is puri?ed by recrystallization from
tion mixture is heated for a period of ten minutes on the m hot ethyl acetate and Skellysolve B hexane hydrocarbons
steam bath and thereafter cooled and neutralized with
to yield essentially pure 3~keto-l1,6-hydroxy-9//l0-seco
sodium hydroxide. The neutral solution is extracted
4,17(20)-pregnadien-2l-oic acid methyl ester.
with methylene dichloride, the extracts repeatedly washed
A solution of two grams of 3-keto-llB-hydroxy-9/l l0
seco-4,l7(20)~pregnadien-21-oic acid methyl ester, two
with water, dried over anhydrous sodium sulfate and
evaporated to give a solid residue. The mixture contain 10 milliliters of pyrrolidine and 250 milliliters of benzene is
heated at re?ux temperature for a period of six hours,
one is chromatographed to separate the isomers and ‘ob
during which time the water formed in the reaction is re
tain essentially pure l1p-hydroxy-9// 10-secoprogesterone
moved from the reaction mixture by codistillation with
benzene. The benzene is then removed by distillation
(VII).
under reduced pressure. The thus obtained residue is
Example 7.—]1-Ket0-9//10-Sec0pr0gester0ne (VIII)
triturated in methanol to give 85 percent of a compound
ing lloc-hydroxy- and ll?-hydroxy-W/l0-secoprogester
Twenty-?ve milligrams of 1l-keto-9// lO-secoprogester
one 20-ethylene monoketal is hydrolyzed in the manner
which is recrystallized from ethyl acetate and Skelly
solve B to give 3-(N-pyrrolidyl)-ll?-hydroxy-W/ lO-seco
described for the llot-hydroxy-9//lo-secoprogesterone
3,5,l7(20)-pregnatrien-21-oic acid methyl ester.
ZO-ethylene monoketal in Example 5 to give, after recrys
tallization from Skellysolve B hexanes and ethyl acetate,
seco-3,5,l7(20)-pregnatrien-21-oic acid methyl ester, dis
essentially pure ll-keto-9//lO-secoprogesterone (VIII).
Example 8 .——1 7ot-Hydroxy-I1[3,21-Diacel0xy-9//10-Sec0
4-Pregnene~3,20-Di0ne (9//10-Secohydrocortisone Di
acetate)
Nineteen milliliters of ethyl oxalate and 21.2 milliliters
of a 2.2 normal methanolic solution of sodium methoxide
are added to a solution of 6.8 grams of ll?-hydroxy
9//l0-secoprogesterone, dissolved in 100 milliliters of
anhydrous tertiary butyl alcohol, at about ?fty degrees
centrigrade. The mixture is maintained ‘for a period of
three hours at twenty to thirty degrees centigrade, where
Two grams of 3-(N-pyrrolidyl)-ll?-hydroxy-9//10
solved in 150 milliliters of benzene, is mixed at ten de
grees centrigrade with two grams of lithium aluminum
hydride in 100 milliliters of ether by dropwise addition
The resulting mixture is maintained at about
ten degrees centrigrade for one-half hour. Thereafter
?fty milliliters of water is added dropwise. The organic
solvent layer is separated and the solvent removed. The
thus obtained residue is triturated with ethyl acetate and
thereafter recrystallized from methanol to give 3-pyr
25 thereto.
rolidyl - l1,8,2l-dihydroxy-9//10-seco-3,5',17(20)~pregna
triene.
A suspension of one gram of 3-(N-pyrrolidyl)-ll}8,2l
after the precipitated sodium dienolate of 2,2l-diethoxy
dihydroxy - 9// l0 - seco-3,5,l7(20)-pregnatriene in 125
oxalyl-11?-hydroxy~9/ / lO-secoprogesterone is ?ltered, 35 milliliters of methanol is heated at 35 to 40 degrees centi
washed with ether and dissolved in water. The aqueous
grade with seven milliliters of a ?ve percent aqueous
solution is acidi?ed with dilute hydrochloric acid and
sodium hydroxide solution until solution is complete. The
the precipitate ?ltered therefrom and dried to give 2,21
time of heating is less than ten minutes. The resulting
diethoxyoxalyl - 11B - hydroxy~9// lO-secoprogesterohe, a
solution is cooled, neutralized with ‘acetic acid and the
yellow amorphous powder which exhibits a reddish color 40 solvent distilled at reduced pressure. The residue thus
in alcoholic ferric chloride solution.
obtained is mixed with water and repeatedly extracted
A solution of eight grams of 2,21-diethoxyoxalyl-1l5
with ether. The ether extract after evaporation of the
hydroxy-9//10-sec0progesterone and 5.9 grams of an
solvent and recrystallization of the residue from ethyl
hydrous potassium acetate in 140 milliliters of methanol
acetate yields essentially pure 11,8,21-dihydroxy-9// l0
is cooled to zero degrees centigrade in an ice-bath and. 45 seco-4,17(20)-pregnadien-3-one.
a solution of 7.4 grams (0.46 mole) of bromine in 74
A solution containing the 11,8,2l-dihydroxy-9/ / l0
milliliters of methanol is added dropwise thereto over
seco-4.l'7(20)-pregnadien-3-one in ten milliliters of pyr
a period of about one-half hour, thus producing 2,21,21
idine and ?ve milliters of acetic anhydride is allowed
tribromo - 2,2l-diethoxyoxalyl-3-keto-1 1,8-hydroxy-9// l0
to stand at room temperature for a period of two hours.
secoprogresterone. To this mixture is then added about 50 Thereafter the mixture is poured over 100 milliliters of
?fty milligrams of phenol and 67 milliliters of a 1.5
ice water and the resulting precipitate collected on a ?lter.
normal methanolic solution of sodium methoxide. The
This precipitate is recrystallized from Skellysolve B hex
mixture is heated for ?ve minutes on a steam bath, then
ane ethyl acetate mixtures to give essentially pure 115,21
cooled and poured into water. The resulting ?occulent,
diacetoxy-9/ / liO-seco-4, l7 (20)-pregnadien-3-one.
white precipitate of 2-bromo-1lB-hydroxy-9H IO-seco 55 To a solution of one gram of ll?,21-diacetoxy-9// 10
4,l7(20)-pregnadien-2l-oic acid methyl ester is thor
seco-4,l7(20)-pregnadien-3—one in ?fty milliliters of
oughly washed with water and dried in a vacuum desicca
tertiary buty alcohol is added at room temperature nine
tor. The thus produced crude 2-bromo-3-keto-11B-hy—
milliliters of a 0.65 molar solution of hydrogen peroxide
droxy-9//10-seco~4,l7(20)-pregnadien-2l-oic acid methyl
in sodium-dried tertiary butyl alcohol, followed by the
ester is chromatographed from benzene, benzene-Skelly 60 dropwise addition of 75 milligrams of osmium tetroxide
solve B hexanes and Skellysolve B hexanes and acetone.
in eight milliliters of sodium-dried tertiary butyl alcohol
The Skellysolve B hexanes plus acetone eluates contains
over a period of eight hours. The resulting mixture is
the
maintained at room temperature for an additional 48
hours and is thereafter worked up as follows: One gram
desired
2-bromo-3-keto-1lp-hydroxy - 9// l0 - seco
4,l7(20)-pregnadien-2l-oic acid methyl ester.
To a solution of three grams of 2-bromo-3-keto-1l? 65 of sodium sul?te dissolved in 25 milliliters of water is
hydroxy ~ 9// 10 - seco - 4,17(20) -pregnadien-2l-oic
acid
added, and after stirring for ?ve minutes the resulting
methyl ester, dissolved in a mixture of sixty milliliters of
mixture is concentrated to about twenty milliliters by
benzene, 25 milliliters of methanol, and ?ve milliliters o?
distillation at a pressure of about ?fty millimeters of mer
acetic acid, is added 2.4 grams of zinc dust, and the
cury absolute and the resulting concentrate then extracted
whole is stirred vigorously for a period of four hours. 70 with methylene chloride. The methylene chloride extract
is dried over anhydrous sodium sul?te and chromato
The solid material is ?ltered off, washed with warm
graphed over 125 grams of synthetic magnesium silicate
benzene, and the benzene washings added to the ?ltrate
(Florisil). The column is developed with ethylene chlo
and the whole, ?ltrate and washings combined, is then
ride containing increasing amounts of acetone. The frac
washed successively with sixty milliliters of water, sixty
milliliters of a saturated sodium bicarbonate solution and 75 tions containing the 17a-hydroxy-11/8,21-diacetoxy-9// 10
3,027,409
7
seco - 4 - pregnene-3,20-dione
8
oxy, hemimoleyloxy, hemifumaryloxy, crotonyloxy, acryl
(9// IO-secohydrocortisone
diacetate) are collected, combined, evaporated after dry
yloxy, ?-methylcrotonyloxy, cyclohexanecarbonyloxy,
ing over anhydrous sodium sulfate and the residue re
crystallized from acetone Skellysolve B hexanes to give
essentially pure 9// 10-secohydrocortisone diacetate.
chloroacetoxy, dichloroacetoxy, trichloroacetoxy, bromo
acetoxy, hemiquinolinoyloxy, nicotinyloxy, piperonyloxy,
2wfurolyloxy, thioglycollyloxy, para-chlorobenzoyloxy,
para-bromobenzoyloxy, meta-nitrobenzoyloxy, 3,5-dini
Example
9.——~17a-Hydr0xy - 21 - Acetoxy-9//10-Sec0-4
trobenzoyloxy, and the like.
Pregnene-3,11,20-Trione (9//] O-Secocartisone Acetate)
It is to be understood that this invention is not to be
One-half gram of 11,8,l7a-dihydroxy-2l-acetoxy
limited to the exact details of operation or exact com
9// l0-seco-4-pregnene-3,ZO-dione is dissolved in ?ve 10 pounds shown and described as obvious modi?cations
milliliters of acetic acid. To this solution is added 0.200
and equivalents will be apparent to one skilled in the art
gram of chromic anhydride, dissolved in two milliliters
and the invention is therefore to be limited only by the
of acetic acid. The solution is repeatedly shaken and
scope of the appended claims.
maintained at room temperature (twenty to thirty de
We claim:
grees centigrade) for a period of four hours. Thereafter 15
1. A compound having the following formula:
the material is poured onto ?fty milligrams of ice and
CH3
the resulting precipitate collected on ?lter paper, washed
on,
with water, and recrystallized from methanol to give es
0:0
sentially pure l7a-hydroxy-21-acetoXy-9//10-seco-4-preg
nene-3 ,l1,20-trione.
R
The 9/ / 10-secohydrocortisone and 9//10-secocor 'sone
are prepared from the corresponding 9//1‘0-sec0hydro
cortisone acetate and 9//10-secocortisone acetate by by
drolyzing these compounds in methyl or ethyl alcohol in
the presence of sodium or potassium hydroxide, meth
CH3
,_
oxide, or ethoxide, under a nitrogen atmosphere at tem
peratures between ?fteen and ?fty degrees centigrade.
l
\/
wherein R is a member selected from the group consisting
Other esters of 9//10-secohydrocortisone and 9//10
of whydroxy, ,B-hydroxy and keto.
2. 1 1a-hydroXy-9// l‘0-secoprogesterone.
1118,17a,2l - trihydroxy-9// lO-seco-4-pregnene-3,ZO-dione 30
3. l 1,8»hydroxy-9/ / IO-secoprogesterone.
and l7ct,21 - dihydroxy — 9// l0 - seco-4-pregnene-3,1l,20
4. l1-keto-9// 10~secoprogesterone.
trione in conventional manner, such as by heating these
compounds in pyridine solution with the acid chlorides,
References €ited in the file of this patent
secocortisone are obtained by acylating the corresponding
acid bromides or acid anhydrides of hydrocarbon car
boxylic acids containing from one to eight carbon atoms,
or other carboxylic acids containing from one to eight
carbon atoms, to obtain the corresponding 1119,17ot-dihy
droxy-21-acyloXy-9/ / 10-seco-4-pregnene-3,20-dione
UNITED STATES PATENTS
2,707,184
OTHER REFERENCES
Sarett et al.: J. Am. Chem. Soc., vol. 74, pages 4974-6
and
l7a-hydroxy-21-acyloxy-9//10-seco - 4-pregnene-3,11,20
trione, wherein the acyloxy groups are for example, form
yloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy,
valeryloxy, isovaleryloxy, hexanoyloxy, heptanoyloxy,
octanoyloxy, benzoyloxy, [i-cyclopentyl-propionyloxy,
dimethylacetoxy, trimethylacetoxy, phenylacetoxy, to
luyloxy, anisoyloxy, gallyloxy, salicyloyloxy, cinnamyl
oxy, hemisuccinyloxy, hemitartaryloxy, dihydrogencitryl
Hogg et a1. ___________ __ Apr. 26, 1955
4O
(1952).
Pincus et al.: The Hormones, vol. 111, page 607 ( 1955).
A. A. Morton, Laboratory Technique in Organic
Chemistry, McGraw-Hill, New York, 1938, pages 147
to 149; page 195.
45
(Copies of above in Library.)
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