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Патент USA US3051748

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United tates
..
" atent
mamas
W?
Patented Aug. 28, 1962
1
2
3,051,738
wherein R represents a monocarboxylic acid radical, is
reacted with phosphorus oxychloride to form a l-mono
carboxylic acid ester of 2-methyl-3-phytyl-l,4-napthohy
ANTIHEMGRRHAGIC CGMPOUNDS AND PROC
ESSES FOR PREPARING THE SAME
droquinone-4-(dichloro)phosphate having the structure
Ralph F. Hirschmann, Scotch Plains, N.J., assignor t0
Merck & Co., Inc., Railway, N..l'., a corporation of
New Jersey
No Drawing. Original application Mar. 22, 1957, Ser.
. No. 647,747, new Patent No. 2,913,477, dated Nov.
17, 1959. Divided and this application Feb. 27, 1959,
Ser. No. 795,925
24 Claims. (Cl. 260—461)
This invention relates to water-soluble derivatives of
dihydro vitamin K1 (2-methyl-3-phytyl-1,4-naphthohy
droquinone) having anti-hemorrhagic activity and to the
processes for preparing these novel derivatives. More
particularly, this invention relates to l-monocarboxylic
acid esters of 2-rnethyl-3—phytyl—1,4-naphthohydroqui
whereinrR is as above. The above compound is treated
none-4-phosphate and to 2-rnethyl-3-phytyl-1,4-naphtho—
with alkali to form a mono- or di-alkali metal salt of
hydroquinone-ll-phosphate, ‘and to the intermediates pro
l-monocarboxylic acid ester of 2-methyl-3-phytyl-L4
duced in accordance with this invention.
2O naphthohydroquinone-4-phosphate having the structure
This application is a division of US. application Serial
No. 647,747, tiled March 22, 1957, now US. Patent No.
0-11
2,913,477.
‘
Due to an overdose of certain anticoagulants or where
a proper amount of the anticoagulant is administered but 25
CH3
the patient is hypersensitive to such drugs, such anti
coagulants may cause serious hemorrhaging in the patient.
CHz-—_CH=C——0H2—Ci5Ha1
The immediate concern of the clinician with a patient
having a dangerously low prothrombin level due to these
anticoagulants is to bring the prothrombin to a safe level
as rapidly as possible. Prior to this invention certain
CH3
l
30
1 ,
O=P—O R’
types of hemorrhage occurring spontaneously were
treated with vitamin K preparations, one of the most
wherein R’ is an alkali metal and vR" is hydrogen or an
active of which being an emulsion of vitamin K1
alkali metal.
(2-methyl-3-phytyl-1,4-naphthoquinone). 'In instances of
,hypoprothrombinemia and bleeding due to a variety of
anticoagulants, vitamin K1, for example vitamin K1 emul
sion, has been established as the only effective prepara
tion available. Nevertheless, in certain critical cases of
drug induced hypoprothrombinemia, the action of even
‘
The above compound is reacted with an aqueous acid
solution to form a l-monocarboxylic acid ester of Z-meth
yl-3-phythyl-l,4-naphthohydroquinone-4-phosphate which
may be indicated graphically as follows:
vitamin K1 emulsion was not as rapid as might be desired. '
Now an anti-hemorrhagic compound is available which
is capable of effecting a more rapid lowering of the pro
vthrombin time and blood clotting time than that noted
with previous preparations.
Water-soluble dihydro !vitamin K1 was found to be
appreciably more e?ective than vitamin K1 emulsion by
the intramuscular route.
Data obtained in prophylatic
and therapeutic studies indicate that wateresoluble dihy
dro vitamin K1 has a shorter duration of action than
vitamin K1 emulsion. Because of this property, water
soluble dihydro vitamin K1 should be capable of rapidly
reversing excessive hypoprothrombinemia with less like
lihood of inducing refractoriness to reinstitution of anti
coagulant therapy.
The novel compounds described in this invention,
namely, l-carboxylic acid esters of 2'methyl-3-phytyl
l,4-naphthohydroquinone-4-phosphate and 2-methyl-3
phytyl-l,4-naphthohydroquinone-4-phosphate are water
soluble and have been found to provide a prompt lowering
Reaction of the above compound with a concentrated
aqueous alcoholic metal hydroxide such as Claisen’s
55 alkali, which is a solution of potassium hydroxide in aque
ous methanol, results in the formation of the mono-, di
and tri-alkali metal salt of 2-methyl-3-phytyl-l,4~naphtho
hydroquinone-4-phosphate which can be represented by
the following formula
of prothrombin time and blood clotting time.
In accordance with this invention a il-monocarboxylic
acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone
represented by the following structure
wherein R’ and R" are as above.
CH
The above compound is reacted with an aqueous acid
3,051,738
4
treated with aqueous acid solution to form 2methyl-3
Solution and 2-methyl-3-phytyl-1,4-naphthohydroquinone
4-phosphate having the following structure is recovered.
phytyl-d,4-naphthohydroquinone-4aphosphate.
Instead of employing Claisen’s alkali the l-monocar
boxylic ester of 2-methyl-3-phytyl-l,4-naphthohyd1'oqui
none-4-phosphate can be reacted with methanolic sulfuric
acid to form directly the 2-methyl-3dphytyl-l,4-naphtho
hydroquinone-4~phosphate.
The described reaction may be speci?cally illustrated
A
by the reaction of 2-methyl-3-phytyl-1,4—naphthohydro
10 quinone-l-acetate with phosphorus oxychloride to form
2 - methyl - 3 - phytyl - 1,4 - naphthohydroquinone - 1
acetate ~ 4 - (dichloro)phosphate.
Similarly, 2 - methyl
3'-phytyl-1,4-naphthohydroquinone-l-propionate is reacted
with phosphorus oxychloride to produce 2-methyl—3
Instead of employing Claisen’s alkali, l-monocarbox-r
ylic acid ester of 2amethyl-3aphytyl-l,4-naphthohydroqui
none~4~phosphate may be reacted with an alcoholic solu 15 gphytyl - 1,4 - naphthohydroquinone - 1 - propionate - 4
(dichloro)phosphate. In like manner by starting with
tion in the presence of an acid catalyst such as sulfuric,
perchloric, paratoluene sulfonic or sulfosalicylic acid and
other appropriate reactants there is obtained
2 - methyl - 3 - phytyl - 1,4 - naphthohydroquinone - 4
2~methyl-3 -phytyl-1,4-naphthohydroquinone-1~valerate-4
phosphate is recovered.
(dichloro)phosphate,
1
In general, any suitable l-monocarboxylic acid ester 20 2-methyl-3-phytyl4 ,4-naphthohydroquinone-1-butyrate-4
of 2-methyl-3qphytylal,4-naphthohydroquinone can be
employed as the starting material in this process. Thus,
the acyloxy substituent present at the 1-position of the
naphthohydroquinone nucleus may be an alkyl-acyloxy,
( dichloro) phosphate, '
2-methyl-3-phytyl-1,4-naphthohydroquinone-l-caproate-ll
(dichloro)phosphate,
or arylacyloxy or aralkylacyloxy group derived from a 25
mono-carboxylic acid. Ordinarily, however, it is pre
ferred to effect the reaction using a l-monocarboxylic
acid ester of 2-methyl-3-phytyl-l,4-naphthohydroquinone
in which the acyloxy group contains eight carbons or less.
Speci?c examples of such compounds which can be used 30
in this invention that might be mentioned are
2-methyl-3aphytyl-1,4-naphthohydroquinone-l -acetate,
2-methyl-3-phytyl-1 ,=4-naphthohydro quinone-bpropionate,
2-methyl-3 aphytyl-l ,4-naphthohydro quinone-l-butyrate,
2-methyl-3 -phytyldl ,4-naphthohydroquinone-1-valerate,
v2?methyl-3~phytyl- 1,4-naphthohydroquinone-1-caproate,
2~methyl-3-gphytyl-1 ,4-naphthohydroquinone- l-caprylate,
’2-methyl-3~phytyl-l ,4-naJphthohydroquinone-1-phenyl
'
y
.
2-methyl-3-phytyl-1,4»naphthohydroquinone-l-caprylate
4-(diohloro) phosphate,
.
2-cmethyl-3-phytyl-1 ,4anaphthohydroquinone-1 -phenylace
tate-4-(dichloro)phosphate,
2-methyl-3 aphytyl-1,4-naphthohydroquinone-1-benzoate-4
-(dichloro)phosphate
'
i
and other similar l-monocarboxylic acid esters of 2-meth
yl - 3 -rphytyl - 1,4 - naphthohydroquinone - 4 - (di
ch1oro)phosphate.
V
.
e
_ Any of the l-monocarboxylic acid esters of 2-methyl-3
35 phytyl - 1,4 - naphthohydroquinone-4-( dichloro) phosphate
obtained above may be reacted with sodium. hydroxide
solution to form l-monocarboxylic acid esters of Z-methyl
_3-phytyl-1,4~naphthohydroquinone-4-phosphate as a mix
ture of the sodium :and disodium salt.
The mixture of the sodium and disodium l-monocar
acetate,
2-methyl-3-phytyl-1,4-naphthohydroquinone-l-benzoate,
boxylic acid esters of 2-methyl-3-phytyl-1,4-naphthohydro
and the like.
quinone-4-phosphate when reacted with water or hydro
chloric acid forms the l-monoearboxylic acid ester of 2
These and similar esters can be prepared
by reacting l-monocarboxylic acid ester of 2-methyl-1,4
naphthohydroquinone with phytol in the presence of
methyl-3-phytyl-1,4~naphthohydroquinone~4phosphate.
boron tri?uoride to produce the corresponding l-mono 45 'Ilhe l-monocarboxylic acid ester of 2-methyl-3-phytyl
1,4~naphthohydroquinone-4~phosphate may be reacted
carboxylic acid ester of 2-methyl-3-phytyl-l,4-napthohy
'with Claisen’s alkali. to form the mono-, di- and tri-sodium
droquinone.
salt of 2 - methyl - 3 - phytyl-1,4-naphthohydroquinone-4
The reaction of a l-monocarboxylic acid ester of
phosphate. . ‘In accordance with the reaction with Claisen’s
2amethyl-3-phytyl-1,4-naphthohydroquinone with phos
alkali, the l-monocarboxylic acid ester of 2-methyl-3
phytyl-1,4-naphthohydroquinone-4-phosphate is dissolved
phorous oxychloride is conveniently achieved by contact
ing the reactants in the presence of a suitable reaction
medium. Solvents such as pyridine, triethylamine and
other tertiary amines are examples of suitable reaction
media in which the reaction may be e?ected.
in a suitable solvent such as a low boiling petroleum
ether and the resulting solution is extracted with Claisen’s
alkali. IIn this manner puri?cation and unexpected solvoly
‘Following completion of this reaction the desired 55. sis of the acyl ‘group is achieved simultaneously to give
an alkaline solution of essentially pure 2_-methyl-3-phytyl
v1~monocarboxylic acid ester of 2~methyl-3aphytyl-'l,4
naphthohydroquinone-‘L(dichloro)phosphate is recovered
‘by removing the excess phosphorous oxychloride and
‘pyridine by evaporation. The product then may be re
l,4-naphthohydroquinone-4-phosphate as ‘a mixture of the
is extracted with ether and acidi?ed with dilute acid to
about pH 1. The mixture is then extracted with ether, 65
resulting in 2-methyl-3-phytyl-1,4-naphthohydroquinone
monosodium, disodium and trisodium salt. The phosphate
ester linkage is not cleaved. To isolate the free :acid, the
facted with ‘dilute aqueous alkali to form l-monocar 60 alkaline aqueous layer is extracted with petroleum ether
and then acidi?ed with dilute hydrochloric ‘acid to ‘about
boxylic acid ester of 2-methyl-3~phytyl-1,4-naphthohydro
pH 1. The ether is removed by evaporation and the
quinone-4-lphosphate in aqueous solution as a mixture of
"residual water is removed by codistillation with benzene
the alkali metal and dialkali metal salt. The solution
the ether layer separated and concentrated to dryness.
.
The l-monocarboxylic acid esterof 2-methyl-3Jphytyl
1,4-naphthohydroquinone-4~phosphate 'can then be reacted
with Claisen’s alkali to form a mixture, of‘ the mono-, di
and tri-alkali metal salt‘io'f 2_-methyl-3-phytyl-1,4-naph
,
_
’
Alternatively, a l-monocarboxylic ‘acid ester of 2
vmethyl - 3 - phytyl-l,4-naphthohydroquinone-4-phosphate
The last traces of water are then removed by co-distillation
with benzene. The residue thus obtained is the 1-mono~
carboxylic acid ester of 2-methyl-3-phytyl-l,4-naphtho
hydroquinone-4-phosphate.
‘lg-phosphate.
may be reacted with methanolic sulfuric acid to form di
rtiftly 2-methyl-3 -phytyl-1,4-naphthohydroquinone-4-phos
70
p a e.
The comparative e?iciencies of vitamin K1 emulsion (2
methyl-3~phyty1-1,4-naphthoquin0ne), 2-methyl-3-phytyl
1,4 - naphthohydroquinone '- 1,4-'diphosphate, 2-methyl-3
phytyl - 1,4 - naphthohydroquinone - 1-propionate-4-phos
Vthohydroquinone-4-phosphate. This latter mixture is then 75 phate and 2-methyl-3-phytyl-1,4-naphth-ohydroquinone-4
3,051,738
5
6
phosphate by intravenous administration in dogs ren~
particular embodiments of the invention as disclosed in
dered hypoprothrombinemic by 3,3'-methylenebisv (ll-hy
these examples.
droxy-coumarin) has been experimentally demonstrated
according to the following test:
The prothrombin time (in seconds) of ten well stand 5
I
EXAMPLE 1
2-Methyl-3-Phytyl-1,4-Naphlhohydroquinone-l-Acetate
4-Phosphate
ardized dogs was determined {and found to range between
nine :and ten seconds. Then these dogs were fed orally
2 rug/kg. of the anticoagulant 3,3’-methylenebis (4-hy
droxycoumarin) on two successive days.- -Prothrombin
'
II
O-U-CHa
'
tests were made each day and on the second day the pro 10
thrombin time had risen to between nineteen and thirty-one
CH3
seconds. Three dogs were used as controls and did not
GHrOH=é-—CH2—-G15H31
receive any of the vitamin K compounds. vThe other
seven dogs then received the vitamin K derivatives ‘and
1.
5
prothrombin determinations were made 2%, 5, 24, 48
and 120 hours after the vitamin K derivative injection.
The results of these tests are given in the following table:
CH3
P0013
a...
if
0- —CH3
TABLE
“CH.
Comparative E?‘icac'ies of Vitamin K Compounds in Reversing 20
3,3’-Methylenebis('é-?ydrowycoumarm) Induced Hypopro
thrombinem'ia
.
g
3
CH3
..
_
CHg——CH=J1—OH2—C15H31
NaOH
Prothrombin Time-Seconds
I
Test
Cmpd.
O=P-o1
Dose 1 Day Day Day Day Day Day Day Day
mg./kg.
0
1
(2)
(2)
Hrs. 0
2
(3)
2
2
3
4
25
7
i’
O—(]J—-CHs
Hrs. Hrs. Hrs. Hrs. Hrs.
Hrs. 0 2. 5
5
24
48
120
10
10
9. 5
9. 5
10
9
10
10
9. 5
12
10
12. 5
12
14
11
15
14
26. 5
26. 5
28
27
.13
24
25
18. 5
31
16
13
23. 5
ll. 5
26
26
14
19
13. 5
13
17
12
33
36
35. 5
11
11. 5
17
17
11
20
”
21. 5
24. 5
21. 5
31
19
29
26
30
25. 5
25
10
12
12
14. 5
11
28
10
10
11
10
9. 5
10
10
9
9. 5
l1. 5
24. 5
11.5
11
14
24
12
(51
.30‘
CH5-
1
in
gel
onz-onéd-onz-oum, H10
35
Legend:
wherein R" is hydrogen or sodium
A-Control (no vitamin K compound).
B—E1nulsion of 2-methyl-3-phyty1-1,4-naphthoquinone.
C—2-methyl-3-phytyl-1,4-naphthohydroquinone-1,4-diphosphate.
D——2-methy1 - 3 -phyty1- 1,4 -naphthohydroquinone - l - propionate-4
phosphate.
E—2-methyl-3-phytyl-1,4-11aphthohydroquinone-‘i-phosphate.
1 Dose given in terms of vitamin K1 molar equivalent.
23,3'-methylenebis(lt-hydroxycoumarin),
2
mg./kg.
administered
or ly.
.
3 The test compound was administered intravenously.
‘The table shows that even after four days the prothrom
bin time of the control dogs who received no vitamin K1
derivatives is between 25 and 37, very much above the
normal of 9 to 10 seconds. Vitamin K1 emulsion, 2
methyl-3-phytyl-1,4-naphthohydroquinone, at 1 and 2
mg./kg. showed little or no activity within 2% hours. At
5 hours ‘a signi?cant lowering of prothrombin time was
observable but this effect was less than with the 2-methyl
3-phytyl-1,4-naphthohydroquinone diphosphate and 2
methyl - 3 - phytyl-1,4-naphthohydroquinoneA-phosphate.
However, at both dose levels, prothrombin levels were es
sentially normal at the 24 hour interval and remained so
thereafter.
To a solution of 6.5 m1. of phosphorus oxychloride in
17 ml. of dry pyridine was added with vigorous stirring a
solution of 4.6 g. of crude Z-methyl-S-phytyl-1,4-naphtho
55 hydroquinone-l-acetate (which can be prepared as
described hereinbelow) in 17 ml. dry pyridine. The
reaction was allowed to continue in an ice bath for about
30 minutes during which time the temperature rose to
about 20-25 ‘’ C., and 2-methyl-3-phytyl-1,4-naphthohy
2 - methyl-3-phytyl-1,4-naphthohydroquinone
diphosphate, at 1 and 2 mg./kg., showed good activity in
reversing hypoprothrombinemia but reversal Was not 60 droquinone-l-acetate-4-(dichloro)phosphate was formed.
complete even at 5 hours. One day after treatment, pro
The excess phosphorus oxychloride and pyridine was
thrombin times rose again slightly and thereafter returned
removed at 40° C. in vacuo and the residue thus obtained
to normal. 2-methyl-3-phytyl-l,4-naphthohydroquinone
was neutralized with dilute aqueous sodium hydroxide to
1-propionate-4-phosphate exhibited de?nite activity. The
about pH 8 to form 2-methyl-3-phytyl-1,4-naphthohydro
most rapidly acting preparation, 2-methyl-3-phytyl-L4
quinone-l-acetate-4-phosphate as a mixture of the sodium
naphthohydroquinone-4-phosphate, brought about essen
and disodium salts.
tially complete reversal of hypothrom-binemia within two
The alkaline aqueous layer was ex
tracted portionwise with 150 ml. of ether and then acidi
?ed with dilute hydrochloric acid to about pH 1. The
aqueous solution was then extracted with about 100 ml.
70
of
ether, the ether layer separated and concentrated to
ing two days, after which they declined toward normal
and one-half hours after doses of 2 or 5 mg./kg. Pro
thrombin times remained low for the next two and one
half hours but then progressively increased on the follow
dryness in vacuo.
that the scope of the invention is not to be restricted to the l
The last portions of water were re
moved by codistillation with benzene. The residue thus
obtained was 2-methyl-3-phytyl-1,4-naphthohydroqui
‘The following examples are given to illustrate speci?c
applications of the invention but it should be recognized
75
none-l-acetate-4-phosphate.
3,051,738
8
vsium hydroxide. 'It was'then washed further with sodium
chloride solution and the petroleum ether ?nally removed
2-Methyl-3rPhytyl-1,4-Naphthohydroquinone;4- '
Phosphate
by concentration in vacuo to about 80° C. '
t
CH3
<8
o=i>-oNa
(‘)Na
wherein R" is hydrogen or sodium
0H
/\
70H;
To a mixture of 2.68 g. of 2 v- methyl-3-phytyl-1,4-'
V
1 | -oH,-oH=o-oH,—omH31 30 naphthohydroquinone-l=acetate-4-phosphate,
prepared as
6
who:
(KB
described in Example 1, in 10
of methanol, was
added 0.2 m1. of concentrated sulfuric acid. The solu~
tion was allowed to stand at room temperature. The
solution was diluted to 40 ml. with methanol and 160
A solution of 1.88 g. of 2-methyl-3-phytyl-1,4_naptho 35 ml. of a saturated solution of sodium chloride was
added. This mixture was extracted with three 80 m1.
hydroquinone-l-acetate-4-phosphate dissolved in 60 ml.
portions of ether. . The remaining aqueous ‘layer showed
of petroleum ether was extracted with 20 ml. of Claisen’s
no ultra-violet absorption.
methanolic alkali (prepared by dissolving 35 g. of potas
The combined ether layers
consisting of 240 ml. were washed twice with 50 ml. of
sium hydroxide in 25 ml. of water and diluting to 100 ml.
with methanol). This reaction mixture contains pre 40 saturated sodium chloride solution. The sodium chlo
'ride solution picked up some color, leaving behind a
dominantly disodium 2-methyl-3-phytyl-1,4-naphthohy
slightly brown colored ether layer. The ether layer was
droquinone-4-phosphate, however some mono and tri
sodium
evaporated to dryness and further dried ‘by azeotropic
2-methyl-3-phytyl-1,4-naphthohydroquinone-4
distillation with benzene.
phosphate may be present.
The Z-methyl - 3 - phytyl-1,4-naphthohydroquinone-4
The alkaline aqueous layer was extracted with 20 ml. 45
of petroleum ether and then acidi?ed with dilute hydro
chloric acid to about pH 1. The 2-methyl-3-phytyl-l,4
phosphate thus obtained showed the same infra-red spec
removed by co-distillation with benzene. The crude 2
higher pH 2-methyl-3-phytyl-1,4énaphthohydroquinone
'trum as described in the above example.
'
'Treatment of the 2-methyl-3-phytyl-1,4-naphthohydro
naphthohydroquinone-4-phosphate thus formed was then
>quinone-4-phosphate thus obtained with" one equivalent
extracted into 100 ml. of ether and the ether solution
evaporated to dryness in vacuo. The residual water was 50 of base results in the formation of 2-methyl-3-phytyl
l,4-11aphthohydroquinoneA-sodium phosphate, while at
methyl - 3 - phytyl-1,4-naphthohydroquinone-4-phosphate
4-disodium phosphate is formed.
"was puri?ed by precipitation from 10 ml. of acetone solu
tion with petroleum ether and benzene.
2-Methyl-3-Phytyl-1 ,4-Naphth0hydr0quinone-1
EXAMPLE 3
55:
Acetate
'
A mixture of 3.07 g. of phytol in 8 ml. of dioxane was
added slowly to 23.45 g. of 2-methy-l-1,4-naphthohydro
quinone-l-acetate in 20 ml. of dioxane to which about
0.54 ml. of boron trifluoride etherate had been added.
"
‘
7' pi0na'te-4-Phosphate
To a solution of 6.5 ml. of phosphorus‘ oxychloride in
17 ml. of dry pyridine was added ‘with vigorous stirring
The 2-methyl-3-phytyl - 1,4 - naphthohydroquinone-l
‘acetate utilized as the starting material in this example
was prepared as ‘follows:
2-Methyl-3-Phytyl-1,4-Naphthohydroquinoneel-Pra
60 a solution of 4.6 g. of. crude 2-methyl-3-phytyl-1,4-naph
'thohydroquinone-l-propionate '(which' can be prepared
as described hereinbelow) in 17 ml. dry pyridine. The
’ reaction Was allowed to'continue in an ice bath for about
30 minutes during which time the temperature rose to
The addition was carried out at about50° C. in an inert‘ 65 7about 20-25° C., and 2-methyl-3-phytyl-1,4-naphthohy
atmosphere and the reaction allowed to continue for a
.total of about 1 hour.
At the end of this time, the solution was cooled to
about 20° C. and diluted with 100 cc. of ether. The
'droquinone-l-propionate - 4 ,- (dichloro)phosphate was
formed.
'
,
The excess phosphorus oxychloride and pyridine was
removed at 40° C. in vacuo and the residue thus ob
‘ether solution was washed twice with 100 ml. portions 70 stained was neutralized with dilute aqueous sodium hy
droxide'to about pH 8' to'form 2-methyl-3-phytyl-1,4
‘of sodium bicarbonate, water and salt. It was then evap
orated to'dryness in vacuo and about 54 ml. of petroleum
naphthohydroquinone-1-propionate-4-phosphate as a mix
’ture of thersodiu'm and disodium saltsj The alkaline
'ether was vadded to the residue. Any solid was removed
aqueous layer was ‘extracted portionwise with 150 ml.
by ?ltration, and the ?ltrate treated with activated char
coal and subsequently extracted with 2% aqueous potas- . 75 of ether and then acidi?ed with dilute hydrochloric acid
‘3,6513%
.
,
to about pH 1.
9
.
V
10
.
up some color, leaving behind a slightly brown colored
other layer. The ether layer was evaporated to dryness
The aqueous solution was then ex
tracted with about 100 ml. of ether, the ether layer sepa
rated and concentrated to dryness in vacuo. The last
portions of water were removed by co-distillation with
benzene. The residue thus obtained was 2-methyl-3
and further dried by azeotropic distillation with benzene.
The
2 - methyl - 3-phytyl-l,4-naphthohydroquinone-4
phosphate thus obtained showed the same infra-red spec
trum as described in the above example.
phytyl-1,4 - naphthohydroquinone - 1 - propionate-4
phosphate.
droquinone-l-propionate-4-phosphate was dried at 100°
Treatment of the 2-methyl-3-phytyl-1,4-naphthohydro
quinone-4-phosphate thus obtained With one equivalent
of base results in the formation of 2-methyl-3-phytyl-L4
C. for 90 minutes and showed the following ultra-violet
naphthohydroquinone-4-sodium phosphate, while at high
properties in 1% sodium bicarbonate solution: A max.
235 my, Em=52,500; 291 mp Em=5,150.
er pH 2-methyl-3-phytyl-1,4-naphthohydroquinone-4-di
sodium phosphate is formed.
Various changes and modi?cations of the invention
A sample of 2 - methyl - 3 - phytyl - 1,4 - naphthohy
2-Methyl-3-Phytyl-1,4-Naphth0hydroquinone-4
Phosphate
A solution of 1.88 g. of 2-methyl-3-phytyl-1,4-naph
can be made and, to the extent that such variations in
15 corporate the spirit of this invention, they are intended to
be included within the scope of the appended claims.
What is claimed is:
l. l-lower fatty acid ester of 2-methyl-3-phytyl-l,4
thohydroquinone-1-propionate-4-phosphate dissolved in
v60 ml. of petroleum ether was extracted with 20 ml. of
Claisen’s methanolic alkali (prepared by dissolving 35 g.
naphthohydroquinone-4-(dichloro)phosphate.
,
of potassium hydroxide in 25 ml. of Water and diluting to 20
2. 2-methyl-3-phytyl-l,4 - naphthohydroquinone-l-ace
100 ml. with methanol). This reaction mixture contains
tate-4- ( dichloro ) phosphate.
predominantly disodium 2-methyl-3-phytyl-1,4-naphtho
3. 2 - methyl - '3 - phytyl-l,4-naphthohydroquinone-1
hydroquinone-4-phosphate, however some mono and tri
propionate-4-(dichloro)phosphate.
sodium 2-methyl-3-phytyl - 1,4 - naphthohydroquinone
4-phosphate may be present.
4. Sodium 2 - methyl - 3 - phytyl—l,-4-naphthohydroqui
25
The alkaline aqueous layer was extracted with 20 ml.
none-1—propionate-4-phosphate.
5. Disodium 2 - methyl-3-phytyl-1,4-naphthohydroqui
of petroleum ether and then acidi?ed with dilute hydro
chloric acid to about pH 1. The 2-methyl-3-phytyl-1,4
none-d-acetate-4-phosphate.
naphthohydroquinone-4-phosphate thus formed was then
extracted into 100 ml. of ether and the ether solution
evaporated to dryness in vacuo. The residual Water was
‘removed by co-distillation with benzene. The crude 2
pionate-4-phosphate.
I6. 2-methyl-3-phytyl-1,4 - naphthohydroquinone-l-pro
36
8. The process which comprises reacting 2-methyl-3
methyl - 3 - phytyl-l,4-naphthohydroquinoneA-phosphate
phytyl-1,4-naphth0hydroquinone-l-acetate with phosphor
was puri?ed by precipitation from 10 ml. of acetone solu
tion with petroleum ether and benzene.
us oxychloride to form 2-methyl-3-phytyl-1,4-naphtho
hydroquinone-1-acetate-4 - (dichloro) phosphate, reacting
the latter compound with sodium hydroxide to form a
mixture of sodium and disodium 2-methyl-3-phytyl-l,4
'
2-Methyl-3-Phytyl-J,4-Naphth0hydroquinone-1
Propionate
The
7. Dialkali metal ‘salt of 2-methyl-3-phytyl-l,4-naph
thohydroquinone-4-phosphate.
-
naphthohydroquinone-l-acetate-4~phosphate, reacting the
2 - methyl - 3-phytyl-1,4-naphthohydroquinone-l
latter compound with hydrochloric acid to form 2-methyl
propionate, utilized as the starting material in this ex 40 3-phytyl-1 ,4-naphthohydroquinone- 1 ~acetate-4-phosphate,
ample was prepared as follows:
>
reacting the latter compound with a concentrated aqueous
A mixture of 3.07 g. of phytol in 8 ml. of dioxane was
alcoholic metal hydroxide to form a mixture of the
added slowly to 23.45 g. of 2-rnethyl-1,4-naphthohydro
mono-, di- and tri-sodium salt of 2-methyl-3-phytyl-l,4
quinone-l-propionate in 20 ml. of dioxane to which about
naphthohydroquinone-4-phosphate and reacting the lat
0.54 ml. of boron tri?uoride etherate had been added. 45 _ter compound with hydrochloric acid to form 2-methyl-3
The addition was carried out at about 50° C. in an inert
phytyl-l,4-naphthohydroquinoneA-phosphate.
atmosphere and the reaction allowed to continue for a
9. The process which comprises reacting 2-methyl-3
total of about 1 hour.
phytyl-1,4-napthohydroquinoned-propionate with phos
At the end of this time, the solution was cooled to
phorus oxychloride to form 2-,methyl-3-phytyl-1,4-n-aph
about 20° C. and diluted with 100 cc. of ether. The ether 50
thohydroquinone-1-propionate-4-(dichloro)phosphate, re
solution was washed twice with 100 ml. portions of so—
acting the latter compound with sodium hydroxide to
dium bicarbonate, water and salt. It was then evapo
form a mixture of sodium and disodium 2-methyl-3-phy
rated to dryness in vacuo and about 54 ml. of petroleum
tyl - 1,4 - naphthohydroquinone-1-propionate-4~phosphate,
ether was added to the residue. Any solid was removed
by ?ltration, and the ?ltrate treated with activated char
coal and subsequently extracted with 2% aqueous potas
reacting the latter compound with hydrochloric'acid to
55 form 2-methyl-3-phytyl-l,4 - naphthohydroquinone-l-pro
pionate-4-phosphate, reacting the latter compound with a
sium hydroxide‘. It was then washed further with sodium
concentrated aqueous alcoholic metal hydroxide to form a
chloride solution and the petroleum ether ?nally removed
by concentration in vacuo to about 80° C.
EXAMPLE 4
mixture of the mono-, di- and tri-sodiurn salt of Z-methyl
3-phytyl-l,4-naphthohydroquinone - 4 - phosphate and re
60 acting the latter compound with hydrochloric acid to form
' 2-Methyl-3-Phytyl-1,4-Naphth0hydr0quin0ne-4
2-methyl-3-phytyl~l,4-naphthohydroquinone-4-phosphate.
10. The process which comprises reacting l-lower fatty
acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone
To a mixture of 2.68 g. of 2-n1ethyl-3-phytyl4l,4-naph~
with phosphorus oxychloride to form the l-lower fatty
thohydroquinone-l-propionate-4-phosphate, prepared as 65 acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone
described in Example 3, in 10 ml. of methanol, was added
4-(dichloro)phosphate, reacting the latter compound with
Phosphate
0.2 ml. of concentrated sulfuric acid. The solution was
alkali to ‘form a mixture of the mono- and di-alkali metal
allowed to stand at room temperature. The solution was
salt of l-lower fatty acid ester of 2-methyl-3-phytyl-l,4
diluted to 40 ml. with methanol and 160 ml. ‘of a satu
naphthohydroquinone-4-phoisphate, reacting the latter
rated solution of sodium chloride was added. This mix 70 compound with an inorganic acid to form l-lower fatty
ture was extracted with three 80 ml. portions of ether.
acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone
The remaining aqueous layer showed no ultra-violet ab
4-phosphate, and reacting the latter compound with an
sorption. The combined ether layers consisting of 240
lower alkanolic solution in the presence of an acid catalyst
ml. were washed twice with 50 ml. of saturated sodium
to form 2-methyl-3-phy-tyl-1,4-naphthohydroquinone-4
chloride solution. The sodium chloride solution picked 75
phosphate.
‘3,051,738
11
12
to-forma mixture-.of'themonoqdi- and tri-sodium salt of
'11‘ The process which comprises reacting Z-methyl
_2-methyl-3-phytyl~1,4-naphthohydroquinone-4—phosphate.
3-phytyl-1,4-naphthohydroquinone-1-acet-ate \‘vit'n phos
19. The process which comprises reacting a mixture of
the mono- and dit-alkali metal salt of _l-lo.wer ‘fatty acid
phorous'oxychloride to form 2-methyl-3-phy-tyl-1,4-naph
thohydroquinone-1-acetate-4-(dichloro)phosphate, react
ester of p-2qmethyl-3-phytyl-1,4-naphthohydroquinone4
ing the latter compound with sodium hydroxide to ‘form
phosphate with an inorganic acid to form lj-lower fatty
acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinonee
1,4-naphthohydroquinone-1-acetate-4-phosphate, reacting
4-phosphate, and reacting the latter compound with a con
the latter compound with hydrochloric acid to form 2
centrated. aqueous lower alkanolic alkali metal hydroxide
methyl-3-phytyl-1,4-naphthohydroquinone - 1 - acetate-4
phosphate, and reacting the latter compound with metha 10 to form amixture of the mono-, di- and tri-alkali metal
salt of 2-methyl-3-pl1ytyl - 1,4 - naphthohydroquinone<4¢
nolic sulfuric acid to form 2-methyl-3-phytyl-1,4¢naphtho
a mixture of ‘sodium and disodium~2-methyl-3-phytyl—
hydroquinone-4-phosphate.
phosphate.
7
~
7
V
a
p
20. The process which comprises ‘reacting a mixture of
12. Theprocess which comprises reacting l-lower fatty
acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone
so'diumwand di-sodium 2-m'ethyl-3-phytyl-1',4-naphthohy—
alkali metal hydroxide to form a mixture of the di- and
to -form_ 2-methyl-3-phytyb1,4-naphthohydroquinone-1
acetate-4-phosphate and reacting the latter compound with
4-phosphate with a concentrated aqueous lower alkanolic 15 droqui-none-laacetate-4-phosphate with hydrochloric acid
tri-metal salt of 2-methyl-3-phytyl-1,4-naphthohydro
a concentrated aqueous lowerralkanolic alkali metal hy
droxide to 'form a mixture of the mono-,' di- and tri-sodi
phytyl-1,4-naphthohydroquinone - 1 - propionate-4—phos 20 um salt of 2-methyl-3-phytyl-1,4-naphthohydroquinone
4-phosphate.
,
phate with a concentrated aqueous lower alkanolic sodi
i 21. The process which comprises reacting a mixture of
um hydroxide to form a mixture of the di- and tri-sodi
sodium and di-sodium 2-methyl-3-phytyl-1,4-naphtho
um salt of 2-methyl-3-phytyl-1,4-naphthohydroquinone
quinone-4-phosphate.
"13. The process which comprises reacting 2-methyl-3
4-phosphate,
14. Disodium Z-methyl -' 3 - phytyl-1,4-naphthohydro
quinone-4-phosphate.
'
hydroquinone-l-propiorrate-4-phosphate with hydrochloric
25 acid to form 2-methyl-3-phytyl-1,4-naphthohydroquinone
1-propionate-4-phosphate and reacting the latter com
pound with a concentrated aqueous lower alkanolic alkali
metal hydroxide to form a mixture of the mono-, di- and
15. The process which comprises reacting 2—methyl—
3-phytyl~1,4-naphthohydroquinone — 1 - acetate - 4 - phos
tri-sodium salt of 2-methyl-3-phytyl-1,4-naphthohydro
fphate with methanolic sulfuric acid to ‘form 2-methyl-3
phytyl-l,4-naphthohydroquinone-4-phosphate.
'
30
16. The process which comprises reacting l-lower fatty
quinone-4-phosphate.
v
22. The process which comprises reacting l-lower fatty
acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone~
acid ester of 2-met-hyl-3-phytyl-1,4-naphthohydroquinone
4-phosphate with a concentrated aqueous lower alkanolic
'4-(dichloro)pho=sphate with alkali to form a mixture of
alkali metal hydroxide to form a mixture of the mono-,
the mono- and di-alkali metal salt of l-lower fatty acid
‘ester of 2-methyl-3-p-hytyl-1,4~naphthohydroquinone-4~ 35 di- and tri-alkali metal salt' of 2-methyl-3-pl1ytyl-1,4
naphthohydroquinone-4-phosphate, and reacting the latter
phosphate, reacting the latter compound with an inorganic
compound with acid to form 2-methyl-3-phytyl-1,4-naph
‘acid to form l-lower fatty acid ester of 2-methyl-3
thohydroquinone-4-phosphate.
phytyl-1,4-naphthohydroquinone-4-phosphate and react
23. The process which comprises reacting 2-methyl
ing the latter compound with a concentrated aqueous
lower alkanolic alkali metal hydroxide to form a mix 40 3-phytyl-1 ,4-naphthohydroquinone- 1 -acetate - 4 - phosphate
with a concentrated aqueous lower alkanolic alkali metal
ture of the mono-, di- and tri~alkali metal salt of 2~methyl
3 -phytyl-1 ,4-naphthohydro quincne-4-phosphate.
hydroxide to form a mixture of the mono~, di- ‘and tri
sodium salt of 2-methyl-3-phytyl-1,4-naphthohydroqui
17. The process which comprises reacting 2-methyl-3
none-4-pho-sphate, and reacting the latter compound with
acid to form 2-methyl-3-phytyl-1,4-naphthohydroquinone
phytyl-l,4-naphthohydroquinone - 1 - acetate-4-(dichlo
ro)phosphate with sodium hydroxide to form a mixture
of sodium and di~sodium 2-methyl-3-phytyl-1,4-naph-tho
hydroque-n-one-l-acetate-4-phosphate, reacting the latter
compound with hydrochloric acid to form 2-methyl-3
4-phosphate.
phytyl-1,4-naphthohydroquinone - 1 - acetate-4-phosphate,
phate with a concentrated aqueous lower alkanolic alkali
metal hydroxide to form a mixture of the mono-, di- and
24. The process which comprises reacting Z-methyl
3 -phytyl- 1,4 -naphthohydroquinone-1-propionate-4-phos
and reacting the latter compound with a concentrated
aqueous lower alkanolic alkali metal hydroxide to ‘form
tri-sodium salt of 2-methyl-3-phytyl-1,4-naphthohydroqui
none-4-phosphate, and reacting the latter compound with
a mixture of the mono-, di- and tri-sodium salt of 2-meth
acid to form 2-methyl-3-phytyl-1,4-naphthohydroquinone
yl-3-phytyl-l,4-naphthohydroquinone-4-phosphate.
18. The process which comprises reacting 2-methyl-3
Vphytyl-1,4-naphthohydroquinone - 1 - propionate-4-(di
4-phosphate.
'
7
55
References Cited in the ?le of this patent
UNITED STATES PATENTS
chloro) phosphate with sodium hydroxide to form a mix
ture of sodium and di-sodium 2-methyl-3-phytyl-1,4-naph
_thohydroquinone-1-propionate-4-phosphate, reacting the
2,345,690
2,380,716
2,407,823
Solmssen ____________ __ Apr. 4, 1944
Baker ______________ __ July 31, 1945
Fieser _'_ ____________ __ Sept. 17, 1946
phosphate, and reacting the ‘latter compound with a con
2,465,320
tBergel et a1.v ______ __>___ Mar. 22, 1949
centrated aqueous lower alkanolic alkali metal hydroxide
2,913,477
Hirschmann , _______ __ Nov. 17, 1959
latter compound with hydrochloric acid to form Z-methyl
3-phytyl - 1,4 - naphthohydroquinone - 1 - propionate-4
60
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