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Патент USA US3098107

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United States Patent 0
ice
3,098,097
Patented July 16, i963
1
2
3,098,097
with quinoline. By this means bis-compounds are ob
tained. For the production of the transisomers reduc
tion is prefer-ably carried out with an alkali metal, espe
cially sodium or lithium, in the presence of an alcohol,
UNSATURATED ALIPHATEC AMINO-DIOLS
Cyril Grob and Erwin F. Jenny, Basel, Switzerland, as
signors to Ciba Corporation, a corporation of Delaware
or with a di-metal hydride, such as lithium-aluminum hy
No Drawing. Filed July 3, 1958, Ser. No. 746,346
Claims priority, application Switzerland July 12, 1957
dride, or the cis-compound is isomerized with acid agents,
for example dilute aqueous sulfuric acid in dioxane.
5 Claims. (Cl. 260-584)
Alternatively, the nitro group and the triple bond may
be reduced simultaneously. To this end the nitro-alk-4-yn
This invention provides new unsaturated aliphatic
amino-diols of the formula
10 compounds are treated preferably with a di-metal halide,
such as lithium-aluminum hydride, and trans-amino-alk-4
enes obtained.
CH3 (CH2) n—A—CHOI-I—CHNH2—CH2OH
in which A stands for the radical of the formula
Corresponding cisecompounds ‘are ob
tained by treatment with catalytically activated hydrogen,
such as hydrogen in the presence of a Lindlar catalyst, the
15 ?rst stage, namely, the reduction of the triple :bond to
the double bond proceeding rapidly, and the second stage,
i.e. the reduction of the nitro group, proceeding slowly.
The reduction in the presence of the Lindlar catalyst is
—CI-I=CH-— or -——CEC——
and n for the whole numbers 7, 9 and primarily for 11,
preferably carried out in alcohol, cis-1,3-dihydroxy-2—
and their acyl compounds, in the form of their various
isomers, such as the threo- and erythro-compounds, their 20 nitro-alk-4-enes being obtained as intermediate products
after the combination of 1 molecular equivalent of hydro
cis- and trans-forms and their optical antipodes.
gen. If desired, these intermediate products can be iso
As acyl compounds there may be named especially
lated. When the treatment is per-formed with hydrogen
compounds acylated with an aliphatic car-boxylic acid,
in the presence of a platinum catalyst, the reduction is
preferably with a lower alkanoic acid, primarily acetic
acid.
The invention also provides processes for the manu
facture of these new compounds. The new compounds
possess valuable pharmacological activities and are in
tended for use as medicaments or as intermediate prod
ucts for the manufacture thereof. Thus they exhibit,
more especially the threo-cis-l:3-dihydroxy-2-amino
heptadec-4-ene, a strong activity against thrush and can
be used as fungicides. Moreover they possess also, pri
marily the threo-l:3-dihydroxy-2-amino-heptadec-4-yn,
:anti-?brillatory activity and are intended as cardiac reme
dies. In addition they retard bloodcoagulation.
25
interrupted when the quantity of hydrogen required for
the reduction has been absorbed. In these reductions
mixtures of different reaction products are often obtained.
They can be separated in the usual manner. The above
mentioned reactions are advantageously carried out in the
presence of recti?ed alcohol.
Resulting amino-diols can, when desired, be converted
in the manner known per se into acyl derivatives or re
sulting acyl derivatives into the free amino-diols. More
over resulting racernates can be resolved into their optical
35 antipodes, for example, by treatment with optically active
. glutamic acid or microbiological methods.
In a modi?ed form for this process, resulting com
The new compounds are obtained when compounds of
pounds of the formula
the formula CH3(CI-I2)n-—-CEC—CHO, in which n has
the above signi?cance, are condensed with B-nitroethanol, 40
CH3 (CH2) n——C“=" C-CHOH—CHNO2—CH2OH
the resulting compounds of the formula
are ?rst reacted with an aldehyde, whereupon in the re
sulting nitro-m-dioxanes, if desired after isomerization,
if desired after resolution into their stereo~isomers, re
duced to the corresponding 'Z-amino compounds and, if
desired, the triple bond converted into a double bond
and/or resulting amino-diols converted into the acyl
the nitro group is reduced, if desired the resulting amino
group acylated, then ‘the dioxane ring split up and, if de
sired, resulting acyl derivatives converted into the free
bases. Furthermore, if desired, at any stage after the
reduction of the nitro group the triple bond can be con
verted into a double bond. The reaction with an alde
derivatives and/ or resulting racemates resolved into their 50 hyde, especially an aromatic aldehyde, primarily benzal
dehyd-e, is preferably carried out in the presence of an acid
optical antipodes and/or resulting bases converted into
condensing agent such as zinc chloride, whereby S-m'tro
their salts or resulting salts into the free bases.
m-dioxanes are obtained. These can be easily isomerized
The condensation of the unsaturated aldehyde with
on the carbon atom attached to the nitro ‘group, for ex
,B-nitroethanol can be carried out in the manner known
ample by heating to elevated temperature or by treatment
per se. The reduction of the nitro diols is preferably
with alkaline agents. In this conversion the threo-con?g
carried out with zinc and hydrochloric acid or with iron
uration is preferably converted into the erythro-con?-gura
and acetic acid. It can, however, also be carried out in
tion. In the resulting nitro-m-dioxanes the nitro group is
other acidic media, for example, by means of aluminum
preferably reduced with aluminum amalgam. In order to
amalgam in ether and a little glacial acetic acid. Prior
to the speci?ed reduction, the compounds previously ob~ 60 facilitate the splitting of the dioxane ring, the resulting
amino group can also be acylated in the manner known
tained of the formula
per se.
The said splitting can be carried out with acid
agents such as ‘dilute hydrochloric acid.
According to the reaction conditions the amino-diols
are obtained as free bases or in the form of their salts,
can be resolved into their diastereo-isomer-s, preferably by 65 preferably as salts with acids, such as hydrohalic acids,
crystallization. The subsequent reactions can be carried
for example hydrochloric acid, or sulfuric acid, phosphoric
out in any desired sequence. Thus the resulting amino
acids, perchlor-ic acid, acetic acid, citric acid, oxalic ‘acid,
group can be acylated in the manner known per se. Also
tartaric acid, ascorbic acid, methane sulfonic acid, hy
the triple bond can be converted into ‘a double bond, for 70 droxy-ethane sulfonic acid, p-toluene sulfonic acid or sali
which purpose preferably hydrogen is used in the presence
cylic acid, p-amino-salicylic acid or acetyl salicylic acid
of a Lindlar-cat-alyst or a palladium catalyst poisoned
these are known pharm‘aceutically acceptable acids. The
3,098,097
3
bases can be converted into their salts in the manner
known per se and salts obtained can be converted in the
and
customary manner into their bases.
The alkyn-l-als used as starting materials can be pre
pared in the manner known per se. Thus corresponding
alkyl bromides can be condensed with sodium acetylide,
the resulting alkyns converted into their metal com
OzN
II
O
O
pounds, for example with ethyl magnesium bromide,
these reacted with orthoeformic acid ester and the result
ing lacetals hydrolyzed with acid agents to the aldehydes. 10
The invention also comprises any modi?cation of the
process in which a product obtainable as an intermediate
3.0 grams of this dioxane mixture are dissolved in 100
at any stage of the complete process is used as starting
material and the remaining step or steps are carried out
or in which the process is interrupted at any stage.
cc. of ether and 7 cc. of water added together with a quan
tity of aluminum amalgam obtained from 4 grams of alu
minum. The whole is allowed to stand for 15 hours at
room temperature and the sludge formed is ?ltered with
The following examples illustrate the invention:
Example 1
25.0 grams of pentadec-Z-ynal-(l) and 10.0 grams of
nitroethanol are cooled to 0° 0., treated with a cooled sus
suction and extracted three times with boiling ether. The
combined ether extracts are dried over sodium sulfate, ?l
20 tered and evaporated under vacuum. The residue, a
colorless oil, is a mixture of the threo-amino compounds
isomeric in position 2 of the m-dioxane ring.
pension of 1 gram of powdered potassium carbonate in
45 cc. of methanol, the whole rendered acid after 15 min
utes with 1.5 cc. of concentrated hydrochloric acid in 2.5
cc. of methanol and the solution extracted with ether.
3.0 grams of this dioxane mixture are dissolved in 5 cc.
of absolute pyridine, treated with 3 cc. of acetic anhydride
The ether extracts are washed with Water and dried over 25 and the whole allowed to stand for 15 hours at 20° C. with
exclusion of moisture. It is then evaporated under
sodium sulfate. The yellow syrup obtained after evapora
vacuum
at 40° C., the residue taken up in ether and the
tion of the ether is dissolved in 20 cc. of ether, the solu
ether solution washed with 2 N-hydrochloric acid, then
tion diluted with 200 cc. of pentane and the whole allowed
with 2 N-sodium carbonate solution and ?nally with water,
to stand for 16 hours at 22° C. The resulting crystals
are ?ltered off and the mother liquor evaporated and 30 dried over sodium sulfate and evaporated. 500 mg. of the
resulting isomer mixture are dissolved in 19 cc. of dioxane
treated with 125 cc. of pentane. Further crystals are
and treated with 19 cc. of 4 N-hydrochloric acid. The
thereby caused to deposit, which are combined with the
reaction mixture is heated for 30 minutes on a steam bath,
concentrated somewhat under vacuum, ether added and
?rst. On recrystallization from pentane the product melts
at 71-725” C.
It is the threo-l:3-dihydroxy-2-nitro
heptadec-4-yn of the formula
35 the whole extracted with water.
The aqueous, hydro
chloric acid extract is rendered alkaline with potassium
carbonate and the resulting amino-diol extracted with
ether. The ether extracts, after washing and drying over
sodium sulfate, are evaporated and the threo-1z3-dihy
OH
The ?ltrate obtained above is allowed to stand at 0° C.
for 48 hours and the resulting crystals ?ltered off. The
4.0 droxy-2-amino-heptadec-4-yn ‘obtained, which can be re
crystallized from chloroform-pentane and then melts at
78—80° C. It has the formula
compound thus obtained, namely erythro-1:3-dihydroxy
2-nitro-heptadec-4-yn of the formula
45
when recrystallized from chloroform-pentane, melts at
2.0 ‘grams of crude threo-l :3-dihydroxy-2-amino-hepta
50 dec-4—yn are heated on a steam bath for 4 hours in 50 cc.
100 mg. of the pure threo-compound in 0.5 cc. of freshly
of absolute tetrahydrofurane with 1.5 grams of lithium
distilled benzaldehyde are subjected to the addition of two
aluminum hydride. Decomposition is then carried out
portions taken on the end of a spatula of freshly ‘fused and
with 4 N-hydrochloric acid with ice cooling, followed by
powdered zinc chloride and the whole shaken for 8 days
at 18° C. in 5 cc. of absolute benzene. The liquid is ?l 55 concentration somewhat under vacuum, addition of ether
and washing of the ethereal solution with 4 N-hydrochloric
tered off and the zinc chloride residue Washed twice with
acid, 2 N-sodium carbonate solution and with Water. The
fresh benzene and the whole of the ?ltrate is freed from
ether extracts are dried over sodium sulfate and evapo
‘benzene under vacuum and from excess of benzaldehyde
rated under vacuum. The residue yields after recrystal
under high vacuum. The residue is distributed between
ether and water and the ether solution washed with 2 N 60 lization from chloroform-pentane, the colorless threo
trans - 1:3 - dihydroxy - 2 - amino-hept-adec-4-ene of the
sodium carbonate solution and then with water, dried over
formula
sodium sulfate and evaporated under vacuum. The resid
ual oil is a mixture of the m-dioxane compounds, isomeric
in position 2 of the formulae
44-47 ° C.
65
O
70 which melts at 88~91° C. A somewhat less pure product
is obtained when the lithium-aluminum hydride solution
U
is treated not with hydrochloric acid but with about 10 cc.
of water, followed by ?ltration and evaporation of the
?ltrate.
75
The same product is obtained by acid isomerization of
3,098,097
6
the threo-cis-l : 3~dihydroxy-2-amino-heptadec-4-ene of the
formula
described in Example 5, by heating for 45 minutes under
quantities of alcohol.
The reaction mixture is ?ltered
with suction, the excess of zinc dust Washed with water
and ethanol and the ?ltrate rendered alkaline with 10 N
caustic soda solution. Extraction is then carried out with
ether and the ethereal extract washed until neutral with
water, dried over sodium sulfate, ?ltered and evaporated.
The crystalline residue, on recrystallization from chloro
formpentane, gives the colorless threo-lz3-dihydroxy-2
aminoheptadec-4-yn of the formula
re?ux with dilute sulfuric acid in aqueous dioxane.
10
The pentadec-Z-ynal-(l) used as starting material can
be prepared in the ‘following manner:
Into a 6-liter ?ask with an acetone-Dry Ice cooler are
introduced 3000 cc. of liquid ammonia and this is treated,
It melts at 78—80° C.
with stirring, with 110 grams of sodium. Acetylene is si 15
The above reduction can also be carried out with a
multaneously passed in until decolorisation takes place.
weak acetic acid solution of aluminum amalgam or with
2000 cc. of dimethyl formamide and 850 gnams of lauryl
iron and acetic acid.
bromide ‘are then ‘added, and the ammonia is evaporated.
Example 3
The mixture is heated for 2 hours at 65° C. with stirring
under ‘a weak current of nitrogen, 1000 cc. of water are 20
slowly added dropwise with ice-cooling and the dark
brown mixture is extracted with ether. The ether frac
30 mg. of sodium are dissolved in 20 cc. of absolute
ethanol and 550 mg. are added of the mixture, obtained
in Example 1, of the threo-nitro-m-dioxane compound
isomeric in the 2-position 10f the dioxane ring. After 2
minutes, the solution is acidi?ed with glacial acetic acid
?ltered and evaporated. The resulting colorless tetra 25 and evaporated to dryness. The residue is distributed
between ether and water, the ether fraction washed until
decyn-(l) is distilled under a pressure of 0.7 mm. and
neutral with water, dried over sodium sulfate and evapo
passes over at 70—78° C.; nD2°=l.4400.
rated under vacuum to dryness. After addition of pen
In a four-necked, ground jointed ?ask with stirrer,
tane and recrystallization from pentane, a mixture is ob
cooler and dropping funnel 5 grams of magnesium, acti
vated with iodine, are covered with ether and subjected 30 tained of the erythro-2-phenyl-4-tetradec-l'-ynyl-5-nitro
m-dioxanes isomeric in position 2 of the dioxane ring.
to the dropwise addition of 32 grams of ethyl bromide in
The reduction of the nitro group and the acetylation of
50 cc. of absolute ether. To the Grignard-solution are
the amino group produced are carried out by methods
added slowly 31 grams of tetradecyn-(l) in 50 cc. of
analogous to those described in Example 1.
absolute ether and the whole is boiled for 5 hours under
420 mg. of the resulting S-acetamino-m-dioxane mix
re?ux. Thereupon 31 grams of ortho-formic acid ethyl 35
tions are washed 3 times with 2 N-hydrochloric acid and
then until neutral with Water, dried over sodium sulfate,
ester in 50 cc. of absolute ether are slowly allowed to
ture are heated on a steam bath in 32 cc. of a mixture
flow in and the mixture further boiled overnight under
re?ux. The reaction mixture is treated by the careful
dropwise addition of an about 20% aqueous ammonium
The solution is evaporated under vacuum to the com
mencement of crystallization and then diluted with 20 cc.
of 4 N-hydrochloric acid-dioxane (1:1) for 30 minutes.
chloride solution, with ice cooling and stirring, for the 40 of ether. The hydrochloride of the amino-diol, produced
in ?ne needles, is ?ltered with suction and well washed
purpose of decomposition. The ether phase is separated
with ether for complete removal of the benzaldehyde.
off and washed twice with water, dried over sodium sul
The hydrochloride is suspended in chloroform in a sep
fate, ?ltered and evaporated. The residue is subjected
to a p-redistillation under about 11 mm. pressure at a
arating funnel and shaken with 2 N-sodium carbonate
45 solution. The chloroform extracts are washed with water
and dried over sodium sulfate. After removal of the
sive foaming such as might take place on immediate high
chloroform under vacuum, the residue is dissolved in a
vacuum distillation. The pentadecynal-acetal then boils
little ether and pentane added. The erythro-1:3-dihy
at 118—124° C. under 0.15 mm. pressure. The colorless
droxy-2-amino-heptadec-4-yn of the formula
oil has a refractive index of 1.4472 at 20° C.
35.5 grams of the resulting acetal are boiled with 32 50
OH NHz
cc. of water, 3.2 cc. of 2. N-hydrochloric acid and about
bath temperature of 150° C. in order to avoid any exces
CHMCHQ11—~CEC——(BH—OH—CH;OH
100 cc. of dioxane in a four-necked, ground jointed ?ask
is thus obtained. It melts at 71—73.5° C.
provided with stirrer, cooler and introduction tube for 6
2.0 grams of crude erythro-l:S-dihydroxy-Z-amino
hours with stirring at about 110° C. bath temperature
in a nitrogen atmosphere. The majority of the dioxane 55 heptadec-4-yn are heated for 4 hours on a steam bath
is then distilled off in a water-jet vacuum at about 50°
in 50‘ cc. of absolute tetrahydrofurane with 1.5 grams
C., the residue taken up in ether and the ether solution
washed with 2 N-sodium carbonate solution and then
until neutral with water, dried over sodium sulfate,
of lithium-aluminum hydride. Decomposition is then
carried out with 4 N-hydrochloric acid with ice cooling,
followed by concentration somewhat under vacuum and
?ltered and evaporated. On distillation of the residue, 60 extraction with ether. The ethereal solution is washed
with 4 N-hydrochloric acid, 2 N-sodium carbonate solu
the resutling pentadec-2-ynal-(1) passes over at IDS-115°
C. under 0.3 mm. pressure; nD2°=l.4607.
Example 2
tion and water, dried over sodium sulfate and evaporated
under vacuum. In this manner there is obtained the color
less erythro-trans-l :3-dihydroxy-2-amino-heptadec-4-ene
4.0 grams of the threo-l:3-dihydroxy-2-nitro-heptadec 65 of the formula
4-yn described in Example 1 are dissolved in 30 cc. of
ethanol and slowly added dropwise, with ice cooling and
stirring, to a mixture of 10 cc. of concentrated hydro
chloric acid and 10 cc. of ethanol. At the same time 8.0
grams of zinc dust are added in small portions and the
reaction mixture is supplemented at intervals of about
5-10 minutes four times, each time with 5 cc. of con
centrated hydrochloric acid. Stirring is then continued
at room temperature for about a further 20-30 minutes.
Any foaming can be controlled by spraying ‘in small, 75
CH3(CH2)11——CH
OH NH:
HO-(‘JH-éH-GHP‘OH
which melts at 60-65“ C.
A somewhat less pure product is obtained when the
lithium-aluminum hydride solution is treated, not with
hydrochloric acid but with about 10 cc. of water, ?ltered
and evaporated.
The same product is obtained by acid isomerization, of
3,098,097
8
the erythro-cis-l :3-dihydroxy-2-amino-heptadec-4 - ene,
about a further 20-30 minutes. Any foaming can be con
described in Example 5 below, by heating under re?ux in
trolled by spraying in small quantities of alcohol. The
aqueous dioxane with dilute sulfuric acid for 45 minutes.
reaction mixture is ?ltered with suction, the excess of zinc
dust washed with water and ethanol and the ?ltrate
rendered alkaline with 10 N-caustic soda solution. Extrac
tion is then carried outwith ether and the ethereal extract
washed until neutral with water, dried over sodium sulfate,
?lhered ‘and evaporated. The crystalline residue, on
Example 4
When the erythro-l:3-dihydroxy-2-nitro-heptadec-4-yn,
described in Example 1, is reduced by the method de
scribed in Example 2, the crystalline erythro-123-dihy
droxy-Z-amino-heptadec-4—yn of the formula
OH NHz
recrystallization from chloroform-pentane, gives the color
10 less threo-l z3-dihydroxy-2-amino-tridec-4-yn of the for
mula
0113(0112)n—OEC-CH—OH—CH2OH
is obtained, which after recrystallization from ether and
pentane melts at 71—73.5° C. The above reduction can
also be carried out with a weak acetic acid solution of
aluminum amalgam or with iron and acetic acid.
15
It melts at 67—68° C.
Example 5
The above reduction can also be carried out with a
weak acetic acid solution of aluminum amalgam or with
4-yn described in Examples 1 and 2 are dissolved in 40
iron and acetic acid.
cc. of absolute alcohol, treated with 250 mg. of Lindlar 20
2.0 grams of crude threo-l:3-dihydroxy-2-amino-tridec
catalyst and shaken at room temperature under normal
4-yn are heated on a steam bath for 4 hours in 50 cc. of
pressure in a hydrogen atmosphere. After about 1 hour
absolute tetrahydrofurane with 1.5 grams of lithium~
the absorption of hydrogen ceases. The solution is freed
aluminum hydride. ‘Decomposition is then carried out
1.50 grams of threo-l:3-dihydroxy-2-amino-heptadec
from catalyst by ?ltration and evaporated under vacuum
with 4 N-hydrochloric acid with ice cooling, followed by
at 40—50° C. The solid, colorless residue yields from 25 concentration somewhat under vacuum, addition of ether
chloroform-pentane crystals of M.P. 77~79° C. to which
and washing of the ethereal solution with 4 N-hydro
is ascribed the structure of threo-cis-l:3-dihydroxy-2
chloric acid, 2 N-sodiurn carbonate solution and with
amino-heptadec-4-ene of the formula
water. The ether extracts are dried over sodium sulfate
and evaporated under vacuum. The residue yields after
30 recrystallization from chloroform-pentane, the colorless
threo-trans-l:3-dihydroxy-2-amino-tridec-4 - ene of the
formula
In an analogous manner the erythro—1:3-dihydroxy-2
35
amino-heptadec-4-yn described in Examples 3 and 4, after
recrystallization from acetonitrile, yields, the erythro-cis
1:3-dihydroxy-2-amino-heptadec-4-ene of the formula
CH3(OH2)11—?1'H
HO CHz-(|JH—(|JH—CH
NH; OH
which crystallizes in colorless crystals of M.P. 66-68" C.
Example 6
40
which melts at 73-78° C. A somewhat less pure product
is obtained when the lithium-aluminum hydride solution is
treated not with hydrochloric acid but with about 10 cc.
of water, followed by ?ltration and evaporation of the
?ltrate.
The undec-Z-ynal-(l) used as starting material can be
45 prepared in the following manner:
19.0 grams of undec-Z-ynal-(l) and 10.0 grams of
@Into a 6-liter ?ask with an acetone-dry ice cooler are
nitroethanol are cooled to 0° C., treated with a cooled
introduced 3000 cc. of liquid ammonia and this is treated,
suspension of 1 gram of powdered potassium carbonate in
with stirring, with 110 grams of sodium. Acetylene is
45 cc. of methanol, the whole rendered acid after 15
simultaneously passed in until decolorization takes place.
minutes with 1.5 cc. of concentrated hydrochloric acid in 50 2000 cc. of dimethyl formamide and 650 grams of octyl
2.5 cc. of methanol and the solution extracted with ether.
bromide are then added and the ammonia is evaporated.
The ether extracts are washed with water and dried over .
The mixture is heated for 2 hours at 65° C. with stirring
sodium sulfate. The yellow syrup obtained after evapora
under a Weak current of nitrogen. 1000 cc. of water are
tion of the ether is dissolved in 20 cc. of ether, the solu
slowly added dropwise with ice-cooling and the dark brown
tion diluted with 200 cc. of pentane and the Whole allowed 65 mixture is extracted with ether.
to stand for 16 hours at 22° C. The resulting crystals are
The ether fractions are washed 3 times with 2 N
?ltered off and the mother liquor evaporated and treated
hydrochloric acid and then until neutral with water,
with 125 cc. of pentane. Further crystals are thereby
dried over sodium sulfate, ?ltered and evaporated. The
caused to deposit, which are combined with the ?rst. On
resulting colorless decyn-(l) is distilled under a pressure
recrystallization from pentane the product melts at 53-55 ° 60
of 760 mm. and passes over at 162-165" C.; nD25=l.4262.
C. It is the threo-l:3-dihydroxy-2-nitro-tridec-4-yn of the
‘In a four-necked ‘ground jointed ?ask with stirrer,
formula
cooler and dropping funnel 5 grams of magnesium, ac
OI-I
tivated with iodine, are covered with ether and subjected
to the dropwise addition of 32 grams of ethyl bromide in
50 cc. of absolute ether. To the Grignard-solution are
N02
added slowly 22 grams of decyn-(l) in 50 cc. of absolute
4.0 grams of threo~lz3-dihydroxy-Q-nitro~tridec~4-yn
ether and the whole is boiled for 5 hours under re?ux.
described above are dissolved in 30 cc. of ethanol and
Thereupon 31 grams of ortho-formic acid ethyl ester in
slowly added dropwise, with ice cooling and stirring, to
50 cc. of absolute ether are slowly allowed to ?ow in and
a mixture of 10 cc. of concentrated hydrochloric acid and 70 the mixture further boiled overnight under re?ux. The re
10 cc. of ethanol. At the same time 8.0 grams of zinc dust
action mixture is treated by the careful dropwise addition
are added in small portions and the reaction mixture is
of an about 20% aqueous ammonium chloride solution,
supplemented at intervals of about 5-10 minutes four
with ice cooling and stirring, for the purpose of decomposi
times, each time with 5 cc. of concentrated hydrochloric
tion. The ether phase is separated off and washed twice
acid. Stirring is then continued at room temperature for 75 with water, dried over sodium sulfate, ?ltered and evap
CH3(CH2)7—-CEC—CH—GH—CH2OH
3,098,097
10
orated. The undecynal-acetal then boils at 147-152° C.
under 14 mm. pressure. The colorless oil has a refractive
index of 1.4395 at 25° C.
35.5 grams of the resulting acetal are boiled with 32
cc. of water, 3.2 cc. of 2 N-hydrochloric acid and about
100 cc. of dioxane in a four-necked, ground jointed ?ask
provided with stirrer, cooler and introduction tube for 6
hours with stirring at about 110° C. bath temperature in a
nitrogen atmosphere. The majority of the dioxane is then
distilled 01f in a water-jet vacuum at about 50° C. the
residue taken up in ether and the ether solution washed
with 2 N-sodium carbonate solution and then until neutral
with water, dried over sodium sulfate, ?ltered and evap
orated. On distillation of the residue, the resulting undec
2-ynal-(1) passes over at 118~124° C. under 13 mm. pres
four times, each time with 5 cc. of concentrated hydro
chloric acid. Stirring is then continued at room tempera
ture for about a further 20—30 minutes. Any foaming
can be controlled by spraying in small quantities of alco
hol. The reaction mixture is ?ltered with suction, the
excess of zinc dust washed with water and ethanol and
the ?ltrate rendered alkaline with ION-caustic soda solu
tion. Extraction is then carried out with ether and the
ethereal extract washed until neutral with water, dried
10 over sodium sulfate, ?ltered and evaporated. The crys
talline residue, on recrystallization from chloroformpen
tane, gives the colorless threo-l:3—dihydroxy-2-amino
pentadec-4-yn of the formula
15
sure; 111325: 1.4540.
Example 7
1.50 grams of the threo-l:3-dihydroxy-Z-amino-tridec
4-yn described in Example 6 are dissolved in 40 cc. of 20
absolute alcohol, treated with 250 mg. of Lindlar catalyst
and shaken at room temperature under normal pressure
It melts at 75—77° C.
The above reduction can also be carried out with a
weak acetic acid solution of aluminum amalgam or with
iron and acetic acid.
in a hydrogen atmosphere. After about 1 hour the absorp
2.0 grams of crude threo-l :3-dihydroxy-Z-amino-penta
tion of hydrogen ceases. The solution is freed from cata
dec-4-yn are heated on a steam ‘bath for 4 hours in
lyst by ?ltration and evaporated under vacuum at 40 25 50 cc. of absolute tetrahydrofurane with 1.5 grams of
50° C. The solid, colorless residue yield from chloro
lithium-aluminum ‘hydride. Decomposition is then carried
form-pentane crystals of M.P. 64-—66° C. to which is
out with 4 N-hydrochloric acid ‘with ice cooling, followed
ascribed the structure of threo-cis-l :3-dihydroxy~2-amino
by concentration somewhat under vacuum, addition of
tridec-4-ene of the formula
ether and washing of the ethereal solution with 4 N-hydro
CH3(CH2)7—CH
chloric acid, 2 N-sodium carbonate solution and with
water. The ether extracts are dried over sodium sulfate
OH
HO OHz—OH—éH-CH
llTHs
Example 8
and evaporated under vacuum. The residue yields after
recrystallization from chl-oro?orm-pentane, the colorless
35 threo-trans-l:3-dihydroxy-2-amino-pentadec-4-ene of the
formula
22.0 grams of tridec-Z-ynal-(l) and 10.0 grams of
nitroethanol are cooled to 0° C., treated with a cooled
suspension of 1 gram of powdered potassium carbonate 40
OH
in 45 cc. of methanol, the whole rendered acid after 15
minutes with 1.5 cc. of concentrated hydrochloric acid in
2.5 cc. of methanol and the solution extracted with ether.
The ether extracts are washed with water and dried over
which melts at 83—85 ° C. A somewhat less pure product
sodium sulfate. The yellow syrup obtained after evapora 45 is obtained when the lithium-aluminum hydride solution
tion of the ether is dissolved in 20 cc. of ether, the solu
is treated not with hydrochloric acid but with about 10 cc.
tion diluted with 200 cc. of pentane and the whole allowed
of water, followed by ?ltration and evaporation of the
to stand for 16 hours at 22° C. The resulting crystals are
?ltrate.
?ltered off and the mother liquor evaporated and treated
The tridec~2-ynal-(1) used as starting material can be
with 125 cc. of pentane. Further crystals are thereby 50 prepared in the following manner:
caused to ‘deposit, which are combined with the ?rst. On
Into a 6—liter ?ask with an acetone-Dry Ice cooler are
recrystallization. ‘from pentane the product melts at 62
introduced 3000 cc. of liquid ammonia and this is treated,
64° C. It is the threo-l :3-dihydroxy-2-nitro-pentadec
with stirring, with 110 grams of sodium. Acetylene is
4-yn of the formula
simultaneously passed in until decolorisation takes place.
55 2000 cc. of dimethyl formamide and 750 grams of decyl
OH
bromide are then added, ‘and the ammonia is evaporated.
CH3(CH2)Q-—CEC——(IJH—CH——CH2OH
llloz
The mixture is heated for 2 hours at 65° C. with stirring
under a weak current of nitrogen. 1000 cc. of Water are
The ?ltrate obtained above is allowed to stand at 0° C. 60 slowly added dropwise with ice-cooling and the dark
brown mixture is extracted with ether.
for 48 hours and the resulting crystals ?ltered oif. The
The ether fractions are washed 3 times with ‘2 N-hydro
compound thus obtained, namely erythro-lz3-dihydroxy
chloric acid and then until neutral with water, dried over
2-nitro-pentadec-4-yn of the formula
sodium sulfate, ?ltered and evaporated. The resulting
colorless dodecyn-(l) is distilled under a pressure of 14
65
mm. and passes over 96—-l00° C.; nD2°=1.4324.
when recrystallized from chloroform-pentane, melts at
In a four-necked, ground jointed ?ask with stirrer,
cooler and dropping funnel 5 grams of magnesium, ac
tivated with iodine, are covered with ether and subjected
4.0 grams of the threo-l :3~dihydroxy-2-nitro-pentadec
4-yn described above were dissolved in 30 cc. of ethanol 70 to the dropwise addition of 32 grams of ethyl bromide in
50 cc. of absolute ether. To the Grignard-solution are
and slowly added dropwise, with ice cooling and stirring,
added slowly 37 grams of dodecyn-(l) in 50 cc. of abso
to’ a mixture of 10 cc. of concentrated hydrochloric acid
lute ether and the whole is boiled for 5 hours under re
and 10 cc. of ethanol. At the sarne time 8.0 grams of
flux. Thereupon 31 grams of ortho-formic acid ethyl
zinc dust are added in small portions and the reaction mix~
ture is supplemented at intervals of about 5-10 minutes 75 ester in 50 cc. of absolute ether are slowly allowed to flow
40-41“ C.
3,098,097
1l
in and the mixture further boiled overnight under re
crystallization from acetonitibiig, yields the erythro-cis-1z3
?ux. The reaction mixture is treated by the careful drop
dihydroxy-Z-amino—pentadec-4-ene of the formula
wise addition of an about 20% aqueous ammonium chlo
CHs(CH2)u-CH
ride solution, with ice cooling and stirring, for the purpose
of decomposition. The ether phase ‘is separated off and
HOGHz—oH-oH—i|3I1
iTIIz (IJII
Washed twice with water, dried over sodium sulfate, ?l
tered and evaporated.
which crystallizes in colorless crystals of M.P. 49-52” C.
The tridecynal-acetal then boils at 170-175 ° C. under
12 mm. pressure. The colorless oil has a refractive index
of 1.4430 at 25° C.
Example 12
5 grams of pure threo-1,3-dihydroxy - 2 - nitro-hepta
35.5 grams of the resulting acetal are boiled with 32
dec-4-yn, obtained as described in Example 1, are dis
cc. of water, 3.2 cc. of 2 N-hydrochloric acid and about
solved in 40 cc. of absolute tetrahydrofurane and the
100 cc. of dioxane in a four-necked, ground jointed ?ask
solution slowly added dropwise, while stirring, into a
provided with stirrer, cooler and introduction tube for 6
solution of 5 .4 grams of lithium-aluminum hydride in 90‘
hours with stirring at about 110° C. bath temperature in 15 cc. of absolute tetrahydrofurane. The temperature rises
a nitrogen atmosphere. The majority of the dioxane is
to 65° C. There follows re?uxing for 5 hours. The
then distilled off in a water-jet vacuum at about 50° C.,
excess lithium-aluminum hydride is destroyed with 35 cc.
the residue taken up in ether and the ether solution washed
of water, the precipitated sludge removed by ?ltering with
with 2 N-sodium carbonate solution and then until neu
suction, and the ?ltrate evaporated at 40° ‘C. in a water
tral with water, dried over sodium sulfate, ?ltered and
pump vacuum. The residue is sublimed in a high vacuum
evaporated. On distillation of the residue, the resulting
at a bath temperature of 120° \C., and the sublimate crys
tridec-Z-ynal-(l) passes over at 148—l5‘2° C. under 14
tallized from a mixture of chloroform and pentane. A
mm. pressure; 111320: 1.4565.
product of melting point 89—91° C. is obtained which
gives no depression in the mixed melting point test in
Example 9
admixture with threo-trans~1,3-dihydroxy-Z-amino-hepta
When the erythro-1z3-dihydroxy - 2 - nitro-pentadec
dec-4-ene melting at SEE-91° C. and obtained in a differ
4-yn, described in Example 8, is reduced by the method
described in Example 2, the crystalline erythro-1z3-dihy
droxy-2-amino-pentadec-4~yn of the formula
0H NH:
ent manner.
Example 13
3O
CH3(CH2)9—CEC—CH—OH—CH2OH
10 grams of pure threo-1,3-dihydroxy-2-nitroheptadec
4-yn, obtained according to Example 1, are dissolved in
250 cc. of absolute ethyl acetate and the solution is treated
is obtained, which after recrystallization from ether and
with hydrogen at room temperature and atmospheric
pressure in the presence of 1 g. of Lindlar catalyst. On
absorption of one equivalent of hydrogen the reaction
ceases. The solution is freed from catalyst and eva
porated at 40° C. under reduced pressure. The residue
pentane melts at 56-58“ C. The above reduction can
also be carried out with a weak acetic acid solution of
aluminum amalgam or with iron and acetic acid.
Example 10
is recrystallized from a mixture of chloroform and pen
2.0 grams of crude erythro-1z3-dihydroxy - 2 - amino
tane and gives lustrous lea?ets of melting point 76-77“
pentadec-4~yn are heated for 4 hours on a steam bath ‘in
C. corresponding to the formula
50 cc. of absolute tetrahydrofurane with 1.5 grams of
lithium-aluminum hydride. Decomposition is then car
ried out with 4 N-hydrochloric acid with ice-cooling, fol
lowed by concentration somewhat under vacuum and ex
traction with ether. The ethereal solution is washed with 45
4 N-hydrochloric acid, 2 N-sodium carbonate solution
and Water, dried over sodium sulfate and evaporated
under vacuum. In this manner there is obtained the
colorless erythro~trans-1:3-dihydroxy - 2 - amino-pentadec
4-ene of the formula
OII3(OHz)9—OH
CH3(CHZ)11—CII
N02
HO CH2—C|H—CH—CII
(1)11:
Example 14
1 gram of pure threo-l,3-dihydroxy~2-nitro-heptadec
4-yn, obtained according to Example 1, is dissolved in
50 25 cc. of recti?ed alcohol and the solution shaken at room
OH NH:
HC—CII—CH—CH2OH
which melts at 56—60° C.
Example 11
temperature and under atmospheric pressure with 50
mg. of platinum oxide in the presence of hydrogen. When
about 3.8 molecular equivalents of hydrogen have been
consumed, the uptake of hydrogen slows down markedly.
Hydrogenation is interrupted, the crystalline product re
dissolved by heating, the solution ?ltered while warm,
and the ?ltrate evaporated. The residue is recrystallized
1.50 grams of the threo-lz3-dihydroxy - 2 - amino
from a mixture of chloroform and pentane. There is ob
pentadec-4-yn described in Example 8 are dissolved in 40
tained in this manner a mixture of melting point 72-83°
cc. of absolute alcohol, treated with 250 mg. of Lindlar 60 C. consisting mainly of threo-l,3-dihydroxy-2-amino-hep
tadecane and the unsaturated cis-threo-l,3-dihydroxy-2
catalyst and shaken at room temperature under normal
amino-heptadec-4-ene.
pressure in a hydrogen atmosphere. After about 1 hour
the absorption of hydrogen ceases. The solution is freed
Example 15
from catalyst by ?ltration and evaporated under vacuum
at 40—50° C. The solid, colorless residue yields from
chloroform-pentane crystals of M.P. 70—71° C. to which
is ascribed the structure of threo-cis-l:3-dihydroxy-2
amino-pentadec-4-ene of the formula
OH3(OI*I2)9—OH
OH
HOCH:—OII—~(IJH~CII
ilvm
In an analogous manner the erythro-l:3-dihydroxy-2~
amino-pentadec-Ll-yn described in Example 9, after re
1 gram of pure threo-1,3-dihydroxy-2-nitroheptadec-4
yn, obtained according to Example 1, is dissolved in ‘25
cc. of recti?ed alcohol and shaken at room temperature
under atmospheric pressure in the presence of 100 mg. of
Lindlar catalyst and hydrogen. One equivalent of hy
drogen is taken up very quickly. After the absorption of
another 2.6 molecular equivalents hydrogenation ceases.
The reaction solution is worked up in the usual manner
and crystallized from a mixture of chloroform and pen
tane to obtain a mixure of melting point 63-69° C. con
taining the desired threo-cis-1,3-dihydroxy—2-amino-hep
tadec-4-ene.
3,098, 097
13
Example 16
(a) 257 mg. of threo-trans-l,3-dihydroxy-2-aminopen
tadec-4-ene are dissolved in about 2.5 cc. of recti?ed
ethanol and mixed with an ethanolic solution of 126 mg.
of oxalic acid dihydrate in about 2 cc. of absolute ethanol.
A :white precipitate forms immediately. On ?ltering,
washing with ethanol and drying the resulting powder
melts at 212-214" C. with decomposition. This neu
tral oxalate is insoluble in water and all other customary
organic solvents.
|(b) Starting from 283 mg. of threo-1,3-dihydroxy-2
amino-heptadec-4-yn is obtained in analogous manner the
neutral oxalate of threo~l,3-dihydroxy-Z-amino-heptadec
4-yn which melts at 207—209° C. It is insoluble in Water 15
and in all other customary organic solvents.
(c) 257 mg. of erythro-trans-1,3-dihydroxy-2-amino
heptadec-4-ene are dissolved in 1.5 cc. of absolute ethyl
acetate and mixed with 0.5 cc. of a 2.0 N-solution of hy
drochloric acid in ethyl acetate. The solution of the hy
drochloride is evaporated to dryness and the residue
which dissolved in water to give a clear solution is re
crystallized from a mixture of absolute ethanol and
ether.
Sintering and decomposition of the resulting
needles begins at about 60° C.
25
Starting from 0.001 mol of another of the amino diols
described in the preceding examples and proceeding in
analogous manner there are obtained the corresponding
hydrochlorides forming colorless needles which dissolve
well in water and begin to sinter and decompose at about 30
the melting point of the free base.
What is claimed is:
1. A member of the group consisting of unsaturated
14
aliphatic amino-diols of the formula:
CH3 (CH2) n-A—CHOH-CHNH2—CH2OH
in which A stands for -—CH=CH— and n for the odd
whole number 7-11, their N-lower alkanoyl derivatives,
and their salts with pharmaceutically acceptable acids.
2. Threo-trans-l:3 ‘- dihydroxy - 2 - amino - heptadec
4-ene.
3. Threo - cis - 1:3 - dihydroxy - 2 - amino - heptadec
4-ene.
4. Threo-trans - 1:3 - dihydroxy - 2 - amino - tridec
4-ene.
5. Threo - cis - 1:3 - dihydroxy - 2 - amino - tridec
4-ene.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,163,720
Vaughn _____________ __ June 27, 1939
2,194,374
Maxwell ____________ __ Mar. 19, ‘1940
2,196,554
2,232,867
2,375,536
Guinot ______________ __ Apr. 9, 1940
Reppe _______________ __ Feb. 25, 1941
De Groote ____________ __ May 8, 1945
OTHER REFERENCES
Ahmad: “J. Indian Chem. Soc.," vol. 31, pages 309
310 (1954).
Grob et al.: “Experientia,” vol. 12, pages 334-335
(1956).
Grob et al.: “Chem. and 11nd,” 1956, pages 660-661
(1956).
(Copies of above references in Pat. Oif. Sci. Lib.)
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