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Патент USA US2407674

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2,407,673
Patented Sept. 17, 1946
UNITED. STATES PATENT OFFICE
PROCESS FOR THE SYNTHESIS OF l-KETO
8~METHYLHEXAHYDROINDANOL-1
Nicholas A. Milas, Belmont, Mass., assignor to.
Research Corporation, New York, N. Y., a cor
poration of New York
No Drawing. Application June 20, 1941,
Serial No. 399,041
8 Claims. (Cl. 260-468)
2
1
brom-ethylpropionate in the presence of magne
In the synthesis of the antirachitic vitamins as
sium amalgam or metallic magnesium in an inert
solvent, the Compound V is formed as follows:
well as in the synthesis of sex hormones the ketc
alcohol (Compound I) constitutes an important
intermediate product. The present invention
deals with a new process for the synthesis of this 5 7 Compound ‘IV +
compound.
H |
E10
'10
15_
Compound I
The process makes use of the well known com
pound 2-methyl-2-carboethoxy cyclohexanone-l,
Compound II. Upon treatment with bromine or
Compound V
20
Compound V is dehydrated by heating it in an
inert solvent in the presence of small amounts of
iodine or p-toluene sulfonic acid to give Com
metallic or metallo derivative of an alcohol or 25 pound VI which is hydrogenated in the presence
of nickel or platinum catalysts to form Compound
phenol. I have chosen sodium phenolate for this
VII as follows:
purpose because the phenoxy Compound IV is
crystalline and easy to purify. The above de
51
scribed reactions are shown by the following
CO 0 CgHs
equations in which, for convenience, bromine is 30
shown as a representative halogen.
chlorine, Compound III results in excellent yields.
Compound III is converted into an alkoxy or
aryloxy derivative thereof by treatment with a
40
45
Pt or Ni H1O
Compound VI +
‘_
Hz
H2O
50
When Compound IV is heated with p-chloro or
Compound VII
2,407,673
3
4 ,
Compound VII may also be made by another
route through the well known Reformatsky re
action.
When Compound IV is treated with eth
ylbromo acetate in the presence of zinc dust or
wool, the Compound
resultsein ,goodzyieldsr 5
This is dehydrated by distilling imtheopresence: of
small amounts of iodine or p-toluene sulfonic
acid to yield Compound IX which is hydrogenated:
to Compound X as follows:
10,"
15..
20
25
30
Compound XIV
Compound XIV" is then :esteri?‘ed and the dies
ter Compound VII cyclized'by means of metallic
35 sodium or sodium alcoholaterto Compound XV as
40
45
When Compound X is partly"hydrolyzed with
dilute sodium hydroxide‘vCompound XI is formed
which is converted-into the .acid chloride XII by 55
When Compound XV is saponi?ed withvalco
gently heating with; phosphorus trichloride or
holic
potash, acidi?ed and the acid heated,;it de
thionyl chloride. Compound XII is converted to
carboxylates to give ‘Compound XVI which, when
Compound XIII by means of the well known re
hydrolyzed '_> witlir' hydriodic acid; givesfr' Com
action of diazo methane, and the latter is con
pound I.
verted to Compound, XIV by reaction with silver 60
oxide.
CH3 0
7 Hi
11,0
I
/\ )Oi
"
I
.
Compound XV
alcoholic KOH
——>
followed by acidi?cation and then
by heating
HzC
on,
I
C—CH2
\ /H
I
H-C
0
(I)
\
70
1151/ \CH
HC\ /CH
C
H
Compound XI
75
/
comnonmhxylii
HI
-——'
2,407,673
0
CH:
(‘3H3
/CHI
H?'—CHT—CHZ—CHI_C\IE:
I
5
.
/ \ /C<H
C ompoun(1 —-->
HI Hz?
IX
H2O
.
(EH;
7
Compound XVI + BtMg-?-CHg-CHz-CHr-C?
CH3
+ pheno1
H
CompoundXX
CH;
CH:
/oHi
H H?'f-CH2'-'CHI_CHT_CH
2
.
Compound XIX. Compound XIX is then hydro
which can be oxidized with chromic acid ‘or other 20
(‘3112
0H’
C‘-—CH2
/G
with p-toluene sulfonic acid to give Compound
XVIII which is hydrogenated catalytically to
oxidizing agents to the ketone Compound XXI.
(‘J
\ /
H in
To make the intermediate ketone XXI of vita- 10
min D, Compound XVI is treated with the Grig
nard of Z-bromo-G-methyl heptane to give Com
pound XVII which is dehydrated through the ac
tion of thionyl chloride in the presence of pyri
dine or merely by heating in an inert solvent 15
lyzed with hydriodic acid to give Compound XX
.
/C\ /C:\—H.
CrOa H2O
Compound ——>
XX
.
‘C
|
| I
‘
CH:
CH2
I
Acetic H2O
C———CH2
acid or
\ /|
(ill.
H1804
0 H
H
l O
CompoundXXI
A more detailed account of the principal re
actions of the process is given hereinafter.
Synthesis of Z-méthyZ-Z-carboethoxy-G-br0m0
cyclohexanone-I-Compound III .
Into a well stirred mixture of 100 g. of 2-meth
yl-2-carboethoxy cyclohexanone-l and 50 cc. of
ole?n-free petroleum ether was added dropwise
96 g. of bromine in the course of one hour, while
nitrogen was passed through the mixture to sweep ‘
V out the hydrobrornic acid formed. Stirring was
continued for one-half hour longer. The mix
ture was then fractionated under reduced pres
sure and the fraction boiling at 127—128° (2 mm.)
collected-and allowed to stand at 0° overnight.
This crystallized into a solid which upon recrys
tallization from petroleum ether had the M. P.
of 50~51°; yield, 110 g. In subsequent prepara
tion the distillation was omitted and crystals‘were
obtained by seeding the mother liquor after the
solvent had been removed.
Synthesis of Z-methyl-2-carboethoxy-6-chloro
cycZohexan0ne-1—Compound III
A mixture of 30 g. of Z-methyI-Z-carboethoxy
cyclohexanone-l and 30 cc. of ole?n-free petro
leum ether was placed in a 500 cc. three-necked
flask ?tted with a mechanical stirrer, reflux con
denser and a gas inlet. Chlorine gas was passed
into the mixture for one and three-quarters
hours, then the mixture was poured into water
and ‘the ether layer separated. The ether layer
was washed three times with water, twice with
sodium bicarbonate solution and twice again with
water. ‘After drying and removal of the ether,
the chloroketone crystallized from alcohol in col
orless prisms.
Synthesis of Z-methyZ-Z-caTDOethomy-G-phenoxy
cycloheacanone-1--Compound IV
Sodium phenolate (.21 mol) was made by re
?uxing a well stirred mixture of 20 g. of phenol
in 50 cc. of benzene and 4.37 g. (0.19 mol) of me
tallic sodium. When all of the sodium was used
up and the mixture cooled to room temperature,
50 g. (0.19 mol) of 2-methy1-2-carboethoxy-6
bromo cyclohexanone-l, Compound III, dissolved
in 100 cc. of dry benzene was added and. the mix
ture heated for four hours on the steam bath.
The mixture was then poured into dilute acetic
acid, the benzene layer separated and the aque
2,4075673
7
8
ous layer extracted twice with ether. The com
bined benzene and ether extracts were washed
with water and with'sodium bicarbonate and
once-againwith'water. After drying and re
colorless needles; yield, 0.9 g. (34%); M. P.
54.5-59". After two recrystallizations from alco
hol a constantv M. P. of ‘GO-61.5” was obtained.
Compounds IX and X are prepared from Com
moval of solvent, the phenoxy ketone crystallized
from
prisms.
benzene-petroleum
ether
in
pounds VIII and IX, vrespectively, by exactly the
colorless
same operations as those used for the prepara—
tions of Compounds VI and VII from Compounds
V and VI, respectively, and descriptions of these
procedures need not, therefore, be repeated.
Synthesis of 1-hydroxy-2-methyl-Z-carboethozry
G-phenory cycZohemanone-I -propionic ethyl
ester-Compotmd V
10
To prepare Compound XI, Compound X is sus
pended in dilute (about 0.1 N) sodium hydroxide
and heated gently. Since. there is a'diff‘erence
Compound V has been synthesized by re?ux
ing for 24 hours a mixture of ?-bromoethylpro
in the rate of hydrolysis of the two ester‘groups,
pionate (100% excess) and Z-methyl-Z-carbo
the acetoxy is more easily hydrolyzed than the
carboethoxy, and its sodium salt-is easily re_—~
moved from the unconverted neutral» ester. The
ethoxy-G-phenoxy cyclohexanone-l, Compound
IV, ",with excess freshly prepared magnesium
turnings. The reaction is activated in'the usual
salt ,is decomposed with dilute hydrochloric-acid
manner by adding small amounts of iodine.
whereby Compound XI is obtained‘: and puri?ed
When the mixture is Worked up a product is ob
tained which analyzes for Compound V.
Synthesis of 2-methyl-2-c‘arb0ethoxy-6-phenoa:y
cyclohea'ylidene
ethylpropionate-Compozmd
VI
by recrystallizationfrom alcohol.
20'
~
Synthesis‘ of the :acid chloride—C0mpoundiXII
When Compound XI is heated on the water
bath with. about 20% excess thionyl chloride or
phosphorus trichloride, Compound XII is formed
' This product is easily prepared from Com
25 which can be purified by high vacuum fractiona
poundV by simply heating it with-small amounts
tion or by recrystallization from benzene petro
of, iodine ,or anhydrous p-toluene sulfonic acid
leum ether or acetone.
in an inert solventsuch as toluene anddistilling
the water formed. An alternative method for
the preparation vof Compound 'VI consists in
treating Compound V with thionyl chloride in
pyridine whereby the chloride is formed and hy
drogen chloride removed by the same operation.
Synthesis of Z-methyZ-Z-carb0etho:i:y-6-pheho:cy
cycloheranone '-1 -ethylpropionate-ucompound
VII
.
.
~ Compound VII is easily prepared by catalytic
hydrogenation in- an alcoholic or glacial acetic
Synthesis of Compounds XIII and XIV
In this synthesis, diazomethane'is mixed in
excess with the acid chloride Compound XII
and the mixture allowed to stand'at'room tem
perature for some time. Without separation the
product may be treated directly with silver oxide
whereby Compound XIV is formed in fairly good
yields. This compound is thenresteri?ed in the
usual manner to give the diester, Compound VII.
Cyclization of Compound VII to. produce the Ice
tone Compound XV
acid solution ‘ in they presence of platinum or
nickel catalysts either in an atmosphere of hy
drogen or under several atmospheresof hydro
gen pressure;
'
'
Synthesis of 1~hydroa2y-2-methyZ-2-carboeth
oxy-6 - phenorry cyclohemanone - 1 - ethylace
tate—Compound VIII
'
Compound VII may also be prepared by an
' alternative route‘ from Compound IV’ via- Com
pounds VIII, IX, X, XI, XII, XIII and‘ XIV and
esteri?cation of the latter as outlined above.
Compound VIII has been prepared as'follows:
'IlWo g. of 2-methyl-2-carboethoxy-6-phenoxy
cyclohexanone-l, Compound IV, was added to a
mixture of 5 g. of amalgamated zinc (20 mesh,
cleansed with dilute hydrochloric acid, washed
with acetone and dried), 0.05
1.55 cc. of "ethyl 'bro-moacetate
benzene and 20 cc. of dry ether.
color had disappeared and a
'
About 0.5 g. of metallic sodium is added to
about 100 cc. of dry toluene and the mixture
stirred vigorously and heated to the boiling point
“ of the solvent. .To' this ‘mixture is then added
about 36.2 g. (0.1 mol) of Z-methyl-Z-carboeth
oxy - 6 ,- phenoxy
cyclohexanone-leethylpr'opio
nate, Compound VII, and‘ heating continued for
several hours.
The reaction mixture is then
The
toluene layer is separated, washed with’ water
and with sodium bicarbonate solutions, then with
water again, dried and the solvent removed un
der pressure. From the residue Compound XV
50 cooled and poured into dilute acetic acid.
I was obtained by recrystallization from alcohol.
Hydrolysis and decarboarylatioiz of Compound XV
to give Compound XVI
g. of'iodine and
in 20 cc, of dry
To hydrolyze Compound XV, one heats it on
.After the iodine 60 the water bath with alcoholic potash, then pours
yellow complex
started to form, further additions of zinc and
iodine were made every half hour for two'hours,
and 1.5 cc. of ethyl bromoacetate was added at
the end of this. time. The reaction mixture was
then re?uxed for two hours» longer, the complex
dissolved in a mixture of ethanol and acetic acid
into cold water and extracts the mixture with
ether. / From the ethereal extract one obtains a
oarboxylic acid whichloses carbon dioxide when
heated to form Compound XVI. To form Com
pound I from Compound XVI, one heats the lat
ter with constant boiling hydriodic acid, sepa
rates the products and puri?es the keto alcohol.
and. hydrolyzed with dilute acetic acid. The
I claim:
benzene-ether layer was then separated and the
.1.
Process which comprises the step of halo
water. layer extracted once more with benzene. 70 genating
2 - methyl - 2 - carboethoxy-cyclohexa
The combined non-aqueous extracts were washed
none-1 to the corresponding 6-ha1ogen derivative
several times with dilute ammonium. hydroxide,
and replacing the 6-halogen of said derivative by
then with, Water and dried over anhydrousv mag
a group having the formula -—O—R, in which R
nesium sulfate. When the solvent was removed,
is a member of the group consisting of alkyl and
the hydroxy ester crystallized from alcohol in 75 aryl.
_
'
2,407,673
10
of the preceding step, esterifying the product of
the preceding step, cyclizing the product of the
preceding step, saponifying the product of the
preceding step, decarboxylating the product of
the preceding step, and hydrolyzing the ether of
the preceding step.
2. Process which comprises reacting a com
pound of the formula
6. Process for the production of a compound of
the formula
CH:
10
in which R stands for a member of the group
consisting of alkyl and aryl with a B-halogeno
ethyl propionate in the presence of magnesium
and successively dehydrating and hydrogenat
ing the product.
15
3. Process which comprises the step of reacting
a compound of the formula
which comprises halogenating 2-methyl-2-carbo
H:
0 CH3
/
Hz?
H20
\li-oooolm
20 ethoxy cyclohexanone-l, reacting the product of
the preceding step with a metallo compound of
the formula MeOR, in which Me stands for a
metal or metallo group and R stands for a mem
ber of the group consisting of alkyl and aryl, re
25 acting the product of the preceding step with
ethyl-bromo acetate, dehydrating the product of
the preceding step, hydrogenating the product of
the preceding step, hydrolyzing the product of
the preceding step, converting the product of the
30 preceding step into the acid chloride thereof, re
acting said acid chloride with diazo methane, re
acting the product of the preceding step with sil
ver oxide, esterifying the product of the preced
ing step to the diester thereof, cyclizing said di
with an ethyl halogen acetate, successively dehy
drating, hydrogenating and hydrolyzing the re
sulting
1 -' hydroxy - Z-methyI-Z-carboethoxy- -
- phenoXy cyclohexanone-l-ethylacetate, convert
35
ing the product of these successive operations
ester, saponifying the product of the preceding
step, decarboxylating the product of the preced
ing step, and hydrolyzing the product of the
into the acid chloride thereof, reacting said acid
chloride with diazomethane, and reacting the re
preceding step.
'7. A compound of the formula
suiting product with silver oxide, and esterifying
the product of the silver oxide reaction.
40
4. Process which comprises cyclizing 2-methyl
2-carboethoxy-6-phenoxy cycloheXanone-l-ethyl
propionate by heating in the presence of metallic
sodium, hydrolyzing the cyclized product and de
carboxylating the hydrolyzed product.
45
l
H2
.
o-om-omoo o cam
\C/H
5. Process for the production of a compound
of the formula
CH1
50
8. A compound of the formula
65
Hz
which comprises halogenating 2-methyl-2-carbo
ethoxy cyclohexanone-l, reacting the product of
the preceding step with a metallo compound of 60
the formula MeOR, in which Me stands for a
metal or metallo group and R stands for a, mem
ber of the group consisting of alkyl and aryl, re
acting the product of the preceding step with a
in which R stands for a member of the group
groups.
p-halogeno propionate, dehydrating the product 65 consisting of alkyl and aryl
NICHOLAS A. MILAS.
of the preceding step, hydrogenating the product
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