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Patented Sept. 17, 1946
2,407,823 _
Louis F. Fieser, Belmont, Mass., ‘assign‘or to Re
search Corporation, New York, N. Y., a corpo
ration of New York
No'Drawing. Application December 23, 1939,
Serial No. 310,855
‘ 20 Claims.
(01. 260-457)
_ The ‘invention herein described relates to cer
tam‘ new ester derivatives of antihermorrhagic
neutralization this derivative can be converted
into various salts, such as the crystalline dipotas
sium salt. In an analogous manner, interaction
of I with phosphorus oxychloride affords the di
‘ principles having the distinctive property of being
readily soluble in‘water, and to methods of pro
ducing these’ derivatives. '
phosphoric acid III(MV=H) , which can be isolated
as such in the form of a nearly colorless
Among these substances, for instance,’ are the
sulfuric .and phosphoric acid derivatives of the
hydroquinones corresponding to vitamin ‘K1, 2
methyl-1,4-naphthoquinone, and‘ 2,3-dimethyl
1,4-naphthoquinone; the salts of these sulfuric 10
and phosphoric acid derivatives also come within
‘ Motion" (Phy‘tyl)
the scope of my invention.
Vitamin K1 the antihemorrhagic factor of al
falfa which can be isolated readily from this
sourceby a process previously described (appli
cation 294,318 issued as Pat. ‘No. 2,357,944 on ‘
Sept.~ 12, 1944), has been shown to ‘be identical
amorphous solid. The substance dissolves read
with 2 -méthyl-3-phytyl-L4-naphthoquinone, a _
ily in water and is precipitated by the addition
of hydrochloric acid, even from ‘a solutionof the
substance easily obtainable by synthesis (applica
tion 294,317).
_ The vitamin is‘fat-soluble, but it does not dis
solve to any appreciable extent in water, and the
sodium or potassium salt.
In the same way, Z-inethyl-IA-naphthdhydro
quinone and J2,3-dimethyl-1,4-naphthohydroqui
none can be converted into the corresponding sul
furic acid and phosphoric acid derivatives and
their salts; and indeed the process is entirely
general and applies to the production of a wide
variety of acidic ester derivatives of the ‘reduced
forms ‘of quinonoid antihemorrhagic principles.
In contrast to the fat-soluble vitamins K1 and
aqueous solution can be obtained, The same is
true of simpler quinones having antihemorrhagic 30 K2 occurring naturally in various foodstu?’s, the
new derivatives dissolve‘ readily in water, rather
activity, such as the substancesidescribed in a
than in lipoids, and are entirely suitable for ad
previous ‘application (application 282,427 issued
ministration in a small volume-of an aqueous
as Pat. No. 2,352,528 on June 27, 1944), including
Z-methyl-1,4-naphthoquinone and 2,3-dimethyl
solution. Furthermore,‘ when assayed by the
1,4¢naphthoquinone. In therapeutic practice it 35 usual procedure in vitamin K-de?cient chicks,
usual method of administration consists in giving
the material by mouth together with sufficient bile
salts to insure its absorption by ‘the system.
Aqueous dispersions, suitable for the intravenous
injection of the material, can bedmadeh only by
using. a large volume‘ of solvent, and no ‘true
is‘often highly desirable to administer a vitamin
many of the new‘ Water-soluble substances show
' K principle in a small volume of a true aqueous‘
' solutionhand my invention provides a means for
marked antihemorrhagic activity and compare
in potency with the lipoid-soluble ‘vitamin K1
and ‘with 2-methyl-1,4-naphthoquinone. ‘
accomplishing this objective.
‘Suitable methods for producing 2-methyl-3 40 Whether the esters are antihemorrhagic as such
or undergo hydrolysis and oxidation in the or
phytyl-1,4-naphthohydroquinone have been de
ganism cannot as yet be stated, but for prac
scribed (application 294,318), and the substance
will hereafter be referred to as “vitamin K1 hydro
quinone” and ascribed the formula I. When this
substance is treated in pyridine solution with
chlorosulfonic acid it is converted into the
ticalpurposes of medicine the new substances
provide the means for a distinct advancement
of vitamin K therapy. While vitamin K1 hereto
fore has been given either by mouth with ox
bile to aid in its absorption, or by intravenous
injection in a very large volume of a dispersion
in glucose solution, the new vitamin K1 hydro
50 quinone diphosphoric acid is suitable for admin
istration in a small volume of water or buffer
salt solution. Even when given by mouth, the
substance promptly reduces the blood clotting
time of K-de?cient chicks, and it can be properly
55 described as a "Water-soluble form of vitamin
disulfuric acid derivative (II,M=H) . By ‘suitable
It is noteworthy that the derivative, unlike the
mixture with a stirring rod and heating to the
boiling point for 10 min. the reaction product
natural vitamin, is a solid and not a liquid, that
‘ it does not absorb light in the visible region of
separates as a viscous mass.
After cooling and
the spectrum, and thatit iscvmore stable both
diluting with ether, the material isgobtained as
as such and in solution' than the vitamin and
a stickysolid which is collected and-washed with
etheri The'tmotherliquors" and washings afford
can be stored more successfully. "
Certain other antihemorrhagic substances have.
0.17 g. of oil which gives no color test with alco
been suggested for use in parenteral therapy but ‘ ' holic alkali (naphthotocopherol?). The collected
the new substances herein described. are of a1 _ 'solidjprobably thepyridine salt) is treated slow
quite different type and possess certain distinct" 10 ly'while cooling with suf?cient 10 N sodium hy
droxide to just produce a red color, indicating
$00., 61, 1923" (1939)) suggested‘the use of '7 that anfexcess" of ‘alkali is present. The oily mix
advantages. Almquist and Klose (J. Am. Chem..
phthiocol in the form of the‘so'l'u'ble'sodium salt,
but the substance suffers from being only feebly
active as compared with vitamin K1. Doisy, et al.
(J. Am. Chem. Soc., 61, 1932, 2563 (1939)) pro
posed the use of certain naphthohydroquinone
tureiis‘stirrediwithia portion of ether to dissolve
the pyridine,‘ and the sodium disulfate ester is
.separated from the liquor by .centrifugation‘ and '
Tobtain‘ed as a dark oil, which becomes waxy on
removal of adhering solvent at the water pump.
and aminonaphthol derivatives in aqueous solu-' "
This salt‘ is then stirred, with excess 25%' abso
tions of their salts, but the extreme sensitivity of
lute alcoholic potassium hydroxide to effect con
these substances to air oxidation imposes a se_ 20 version to the potassium-salt.- The latter s'epaa
rious limitation on their use. The new esters
rates inv a-crystallineicondition- and after 'dilu'i'
embodied in the present discovery differ in that
tion with absolute alcohol? the :light brown‘ solid
they"v are not subject to such oxidation, the'phe
nolic hydrogens being replaced,’ by acidic resi
dues of-adequate stability;
is collected and washed.
That the biological activity of vitamin K1 and
This} isipuri?‘ed by
crystallization from 95%1i‘etha-nolfusing' ‘Nori-tev
for clari?cation; and obtainedin theformjof
color-less‘? plates.- -The-lsubstance' gives a clears "
lutioningwater; Asamlpleldried at 8Q“ and'l?-m‘
other quinonoid substances‘in'certain cases would ‘
be retained on conversion tothe sulfuric or phos
phoric acid esters of thei'hydroquinones ‘was not
\ fori2fhrs.~gave the following-analysis.
Anal-(Called? for oam?osszKz-o; v54.04 ;- Hgavefl
predictable. Thus oestrone loses practically all
of its biological potency‘fonconversion to the
K; 11.35. Found-1 c, 5
water-soluble oestrone sulfate (Butenandt and
none‘ disulfate A-~"co‘ol ,dcl suspension" from? llf‘cc.
Hofste-tter, Z. physiol. "Chem; 259, 222 (1939)).
of’ pyridine,
Indeed vitamin K1 hydroquinone disulfate shows
> no activity in the chick, assays when adminis
if; K», 10.67.
(2) Sodium 2‘ - math
v ,.*of¥carbon tetrachloride and-0 5“
cc." of"chloroésulfon-ic'acidistreated with 0:5” ’ '
terefd' at: 'a"_level"o‘f"50_0B; ' The dipho'sphoric acid
2-methyl-lA-naphthohydroquinone andrtheL
ture'heated-for 10 min. on the steambath; [gi , t.
a yellow oil. The solvent?isidecante‘diafter coo ‘
derivative,v howeverygivesa' positive response at
25<Tand ‘ therefore‘ does ‘not fall'j very far“ short‘ of
ing vand the'oil neutralized'with 10% sodium lily-l‘
the potency of the naturalvitafrnin. The nature "~' droxide, using _a slightexcess ,to insureydeconi- ’
of thejacid‘radical is thus'ofj importance,‘ but the 40 position of any-chlorosul-fonic acid andlliberation
ofjpyridinek The mixture isthenfextracted‘ thor-"Z
oughly “with ether -' and the, residual re d’ oil? taken"
result" may depend" as' well ‘ upon the character of
thenuclear part'of the molecule;
" “
Particularly‘ potent fis'so‘diu‘m 2-methy1-'-1,4‘-'
up:~in~ a‘ftaww cc: of hot ‘ewaten; Alcohol’is-then'l
naphthohydroquinone disulfate, which showsa'c-' T345 ,added'inportions,>_:the1?rst ofiwhich precipitate s ‘ ’
tivity when‘ assayed‘. at dosages‘ down‘ to and in
a‘ smalr amount 'of" inorganic - material’, "wli is“?
eluding“v 26;" This‘ substance; v'ffurther‘m'ore; has‘
givenjsuccessful clinical’results'; promptly recluc
removed. 5 Furtheraddition' ofilalcoholegivé‘ _
ing the 'prothrombin' clotting‘time’when' given _ .
intravenously,‘ for example, using 101mg.‘ of‘ salt‘
dissolved in‘10 "cc, of physiological saline solution,
autoclaved'at 250° F.
' .
‘ the? mother liquor. f€rystallization ‘Gretel-erase;
The following procedures illustrate methods‘
salt-from- water gives?QA' g. of , colorless product
free from inorganic salts, and'this isjfurther purl-4
?ed by dissolving it in water andf-adding'lfalcoholj, '
The air dried material provedtobea di-hydi
suitable for the preparation ofa number‘of war‘
teresoluble derivatives of‘ the gene'ral'nature em-'
bodied'in my'invention and they ‘exemplifya type
g.‘ of tan,’ crystalline? precipitate: ‘o’fl’the sodium‘
salt‘; and ‘0.127, g. 'r'nore ‘is, obtainedfon{evaporating
’,An-al.r Calcd. for C11HsQ8S2N2§gL2H2O§Q ~31
Found»; o;
‘ ‘
55 H, 2.92; Na,’1-1.1_0; H20, 8.7-0;
of reaction and a‘type of compound which can‘
be‘ extended in“ many directions; 'Thus' a great"
many similar water-soluble'esters may‘ be‘ pro;
quinone disulfate.—The cooled 'susp'ensiofniof‘thev
duced' by the application of‘ the vfundamental : '
addition product- fr'om-L 055 cc; ofchlorosulfonic
<3) sodium as-dimeth'yzugrzaapmhe game
principle of the interaction of a‘ quinone of the 60 acid,-1-cc. ef'pyridine and- 10 cc._'of-carbon‘tet a»v
naphthalene or other series, in its ‘reduced form;
chlorideis treated with 0.5 g. of ZljBé‘dimethyF-IAEL“
with the halide of an acid such as sulfuric or‘
phosphoric acid.
The following examples provide a, few illustra=
tions of‘the application of the fundamental dis
(l)- Potassium vitamin K1 hydroquz'nonel-di
sulfate.—To a mixture of 2 cc. of! pyridine i and - 5 >
cc." of carbon tetrachloride 0:6’ cc. of- chlorosu-l—~
naphthohydroquinone and the mixture heated‘ for?
15 min. on the steam- bath, giving- a? pinkio'i'l-l
" which solidi?es on cooling; The solid: is fc‘ollect'e‘dj
and washed rapidly, as’it" is- quitehygi‘oscopic,‘
and it is at oncetreated with a little water and
neutralized with 10 N. sodium hydroxide. The
residue remaining after digestion with ether is
{7" crystallized once from water (0.8g) and further
purified by dissolvingit in water and adding alco
fonic acid is slowly added- and the resulting hot
hol. The sodium salt is thus obtainedras color
less plates. Drying in vacuum at 80° resulted
suspension containing > separated" salt -is ‘ cooled- to}
in some darkening, and analyses were conducted 1
room, temperature and treated‘ with 0.481 gig'ofl
on air-dried material, which appears to be the
vitamin K1 hydroquinone. On manipulating the‘ 75
“ " AnaLgCalcd. for C1'2I-I1dOsSzNazI2Ha057C; 33.64;
amount of water but dissolvestb a clear solution
when an adequate quantity of water is used. The
‘H, 3.29; Na, 10.74; H20, 8541-1 Found:"C,‘ 33.47;
H, 3.49; Na,'10.97; E20, 9.00.
-‘ I -' “
sample for analysis was dried at 100° and 1 mm.
I "(4) Sodium- ~2-methyl;Ldénqphtltohydroqui
Anal. Calcd. for C31H5008P2: C, 60.76, H, 8.23.
none 'driphosphatei (normal tetra-sodium salt.) .-'
Found: C, 60.92; H, 8.20.
‘A solution of v‘0.3 g‘. of 2'-methyl-1-',¢1‘-naphthohy
These examples are given to illustrate the na- '
droquinone in 0.8 cc. of pyridine/is added by
drops with ice cooling to a suspension prepared
‘byadding 0.5 cc. of phosphorus oxychloridé with
ice cooling to ‘1 ‘cc. oflpyridine. 1At‘ the end the
'mitxure ‘is removed from the‘ ice bath ‘and al
lowed to warm up untilthe‘exothermicereaction
ture of the invention but not by way of limita
tion. Obviously many modi?cations can be made
‘in the nature of the. phenolic and the acid halide
‘components and in the‘ proportions of reagents
and details of the‘ condensation and isolation
procedures without departing from the essential
is over. The white ‘suspension is then treated
spirit and scope of the disclosures herein pre
with (ice. of watenadded cautiously at ?rst with
ice‘coolingand later heating to‘dissolve the prod- -
I claim:
llct. 'Solidgsodium' carbonate is‘ added "until al
kaline‘to ‘litmus and the-pyridine layer whichsep
“arates'is removed and discarded. The solution
1. Process for the production of water soluble
ester derivatives of ‘-1,4-naphthohydroquinones
of sodium salts .is stirred with an equal volume
‘of absolute alcohol and the solvent decanted, 20
leaving an aqueoussolution of greatly diminished
which comprises condensing a 1,4-nap1hthohy-_
droquinone of the ‘general formula
volume. .Thelremainder otthe water can be re
movedby stirring f either with fresh-portions of
absolute alcohol or with two small portions of
pyridine, the dehydrating solvent being decanted
from the gummy sodium salt. Inorganic salts
can be largely eliminated by dissolving the gum
in which R stands for a member of the group
consisting of hydrogen and non-cyclic aliphatic
in the least amount of hot water, cooling in ice,
centrifuging and decanting from the crystal
hydrocarbon groups, with a halide of a polybasic
lizate. Alternately,’ the gum is treated in the 30 mineral acid of the group consisting of halogen
cold with methanol and enough water to bring the
sulfonic acids and phosphorus oxyhalides in the
presence of pyridine.
oily salt into solution; by adjusting the propor
tions of solvents inorganic salts are left undis
2. Process as de?ned in claim 1 in which It
stands for hydrogen.
solved and are removed by ?ltration. For crys
tallization of the product such a methanol-water 35
3. Process as de?ned in claim 1 in which R
stands for a phytyl group.
?ltrate is concentrated and cooled, oily salt is
brought into solution with a little water, pyridine
4. Process as de?ned in claim 1 in which the
is added by drops until the solution becomes
halide of a polybasic mineral acid is chlorsul
fonic acid.
cloudy, and On warming on the steam bath the
sodium diphosphate separates as an oil which 40
5. Process as de?ned in claim 1 in which the ‘
halide of a polybasic mineral acid is phosphorus
then crystallizes (the salt isless soluble hot than
cold). The colorless crystals are collected,
6. A compound of the formula:
washed with methanol, and air dried; yield 0.68
g. The substance is Very hydroscopic and lique
?es on exposure to moist air, The sample for 45
analysis was dried at 150° and 2 mm.
Anal. C'alcd. fOl‘ C11HaOsP2Na4.2I-I2O: C, 28.83;
H, 2.64. Found: C. 28.36; H, 2.21.
The potassium salt does not crystallize readily;
the calcium salt is precipitated from a dilute 50
aqueous solution of the sodium salt in a gelati
nous condition.
where R is a member of the group consisting of
(5) Vitamin K1 hydroquinone diphosphoric
hydrogen and non-cyclic aliphatic hydrocarbon
acid.—A solution of 0.48 g. of vitamin K1 hydro
quinone in 10 cc. of pyridine is cooled to 2° and
added to a similarly cooled solution of 1 cc. of
ing of SOsI-I and POsHz, and alkali metal salts
phosphorus oxychloride in 5 cc. of pyridine. The
temperature rises to about 15° and pyridine hy
drochloride crystallizes. The solvent is largely
groups, and A is a member of the group consist
7. A compound of the formula:
(iXP O 3M1
removed in vacuum at a temperature not above 60
45° and the residue is treated with 10 cc. of water
and extracted with ether. The ethereal extract
is then shaken with a slight excess of 1 N sodium
hydroxide and the alkaline layer is separated
and acidi?ed with hydrochloric acid. The di 65
‘ phosphoric acid thereby precipitated is extracted
with ether and obtained by complete evaporation
of the solvent as a light tan amorphous solid
(0.4 g.). The process of puri?cation is repeated,
the solid being dissolved in 1 N sodium hydroxide, 70
the solution extracted with ether, separated and
acidi?ed. The precipitated material is taken up
in ether and the solvent is evaporated, giving a
somewhat waxy, nearly colorless solid. The sub
stance forms a gel when treated with just a small 75
where M is selected from the group consisting of
hydrogen and alkali metal.
8. The compound of the formula:
0 P 03H;
sistinglof‘ the'di-sulphate ester of 2-methyl-V1, 4
' w 9: Y "A'eompoundof the jfo'rmul'az ‘
‘ V
I -
naphthohydroquinone; and ‘the. water-soluble
salts thereof.
14. A compoundselectedfrom the group con
sisting‘ of the di-phosphate ester of‘ 2-methy1-1,
4-naphthohydroquinone, and the ‘water-soluble
salts thereof.
15. 2-methyl-L4-dihydroxy vnaphthalene di
where M is selected'from the group consisting 10
ofihydrogen and. alkali metal. '
‘10. A compound of ‘the formula:
16. The method of preparing a sulfuric acid
2 - methyl-1,4-naphthohydroquinone
which comprises reacting _2-methy1-1,4'-naphtho—
,hydroquinone with chlorosulfonic acid.
1'7. The method of preparing a phosphoric, acid
15 ester of 2 - methyl -'1,4-naphthohydroquinone
which comprises reacting ‘Z-methyI-IA-naphthO
hydroquinone with phosphorus oxychloride.
18. A dig-phosphate ester of 2-methy1-1,4
P 0:11:
19. A water-soluble salt of adi-phosphate ester
11. Compounds as de?ned in claim 6 in which v20 of 2-methyl-1,4r-naphthohydroquinone.
R stands for hydrogen.
20. A’ water soluble salt of the disulfuric acid
12. Compounds as de?ned in claim 6 in which 7 ester of Z-methyl-1,4-naphthohydroquinone.
R stands for a phytyl group.
13. A compound selected from the group con
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