Note: Descriptions are shown in the official language in which they were submitted.
~5,261
7~ :
dl-2-Amino-l-butanol is produced by adding
butene-l and chlorine to acetonitrile, preferably simul-
taneously, to yield N-[l-(chloromethyl)propyl]acetimidoyl
chloride together with a certain amount of by-product
1,2-dichlorobutane; the N-[l-(chloromethyl)propyl]acet-
imidoyl chloride is hydrolyzed conveniently in situ to
N-ll-(chloromethyl)propyl]acetamide, which is further
hydrolyzed with convenient removal of excess acetoni-
trile and 1,2-dichlorobutane with presumably a ring
closing and reopening steps to dl-2-amino-1-hutanol,
conveniently as the hydrochloride. dl-2-Amino-l-butanol
has many uses as such, including resolution to d-2- :
-amino-l-butanol which is reacted with ethylene dichlor-
ide to produce ethambutol hydrochloride, d,d'-2,2'-
-~ethylenediimino)di-l-butanol dihydrochlorideD The dl-
30 -2-amino-1-butanol from the present process yielcls a ~:
~ .
7~
.: .
1 pharmaceutically elegant grade of ethambutol hydrochlor~
ide. .~:
This gives d-2-amino-1-butanol in a form .
which is particularly acceptable for reaction with ethyl-
ene dichloride to yield a pharmacelltically elegant grade
of d,d'-2,2'-(ethylenediimino)di-1-butanol dihydrochlor-
de .
These equations may be written~
CH3CH2CH=cH2 + C12 + ~ CH3CN
10 butene-l acetonitrile
CH3cH2cHcH2cL ''
N=CClCH3
N-[l-chloromethyl)propylJacetimidoyl chloride or
N-[1-(chloromethyl)propyl]ethanimidoyl chloride
..
I ~ CH3cH2cHcH2~l + HCl
H20 ' . ::
NHCOCH3 II
N-l-(chloromethyl)propyl]acetamide
II~ CH3cH2cH CH2
Heat l l
HN + O
Cl
CH3 III
4-ethyl-2-methyl-2-oxazoline hydrochloride or
4,5-dihydro~4-ethyl-2-methyl-oxazole hydrochloridb
~2
III -~ C~3CH2CH-CH20H + CH3COOCH3
CH30H
~ NH3C1
IV
dl-2-amino-1-butanol hydrochloride methyl acetate
. ~ - 3 -
- ~7~7~
This invention is concerned with the preparation
of ~ 2,2'~(ethylenediimino)di-1-butanol which comprises
mixing dl-2-amino-1-butanol containing dl-l amino-2-butanol
with L(+)- tartaric acid in anhydrous methanol, separating
the crystalline acid L(+)-tartrate of _-2-amino-1-butanol
from the salts of dl-2-amino-1-butanol and d- and 1- l-amino-
2-butanol which remain in solution in the methanol)dissolving
said _-2-amino-1-butanol L(+)- tartrate in water, adding an
alkali or alkaline earth hydroxide, separating out the
resultant alkali or alkaline earth L(+)- tartrate, thus
isolating _-2-amino-1-butanol, evaporating off remaining
water, adding ethylene dichloride, and reacting to form
d, -2,2'-(ethylenediimino)di-1-butanol, and isolating the
thus formed d,d-2,2'-(ethylenediimino)di-1-butanol as the
dihydrochloride salt.
The dl-2-amino-1-butanol used in the invention may
be conveniently synthesized by heating N-[l-(chloromethyl)
propyl]-acetamide in the presence of a lower alkanol and
water whereby the N-[l-(chloromethyl)propyl]acetamide is
hydrolyzed to dl-2-amino-1-butanol, and distilling off the
coproduced alkanol acetate, whereby side reactions are
suppressed, and the hydrolysis to dl-2-amino-1-butanol is
essentially quantitative.
~7~7::~0
1 Surprisingly, best results are obtained in
the reaction with acetonitrile if an excess oE acetoni-
trile is used. Acetonitrile is the expensive compon-
ent and routinely it is customary to attempt to use less
of the expensive component.
Here, chlorine also reacts with butene-l to
yield 1,2-dichlorobutene. ~n excess of acetonitrile
shifts the reaction towards N-[l-~chloromethyl)propyl]-
acetimidoyl chloride. An amount of water corresponding
to that required for the hydrolysis of N-[l-(chloromethyl)-
propyl]acetimidoyl chloride may be added before, with vr
after the addition of the chlorine and butene to the re-
action mixture to hydrolyze the N-[l-chloromethyl)propyll-
acetimidoyl chloride to N-[l-(chloromethyl)propyl~acet-
amide. The reaction o~ acetonitrile with hydrochloricacid formed in the hydrolysis is sufficiently slow that
at least 95% of the excess of acetonitrile may be dis-
tilled under reduced pressure from the reaction mixture
and recycled. The economical recovery of the acetoni-
trile in 5uch form that it may be recycled to the pro-
cess is essential to the low cost production being sought.
Too great an excess of acetonitrile requires
too large a reaction vessel. A continuous reaction may
be used, which permits smaller equipment, and a large
excess of acetonitrile, which is recycled to the start-
ing materials.
After stripping the acetonitrile, if hydroly-
sis of N-[l-(chloromethyl)propyl]acetimidoyl chloride to
N-[l-(chloromethyl)propyl~]acetamide has not been com-
pleted during the reaction, hydrolysis is completed by
- 4 -
~7~7~
1 adding water to the pot residue. Production of N-[l-
-(chloromethyl)propyl]acetamide by hydrolysis of N-[l-
-(chloromethyl)propyl]acetimidoyl chloride, is avored
by the presence of a weak base such as calcium carbon-
ate, calcium oxide, calcium hydroxide, sodium carbonate,sodil~m bicarbonate, potassium carbonate or bicarbonate,
barium carbonate, or strontium carbonate. The base is
not necessary if the M-[l-(chloromethyl)propyl]acetamide
is to be processed by fur~her hydrolysis to d}-2-amino-
-l-butanol. After hydrolysis, 1-2-dichlorobutane :Ls
stripped by distillation under reduced pressure.
After removal of the acetonitrile and 1,2-di- ~ ;
chlorobutane, the purity of the N-[l-(chloromethyl)-
propyl]acetamide is sufficiently high for convenient
processing through to dl-2-amino-1-butanol hydrochloride
of a grade which may be used in a resolution step, or
other purposes.
The N-[l-(chloromethyl)propyl]acetimidoyl
chloride may be recovered and utilized after its forma-
tion. Conveniently, water is added to the reactor tohydrolyze N-[l-(chloromethyl)propyl]acetimidoyl chloride
to N-[l-(chloromethyl)-propyl]acetamide, so that, in ef-
fect, the first two steps are simultaneously accomplish-
.
ed, exotherms are better controlled, and the processing
steps are simultaneous, Baving time and manipulation. A
slight excess over the calculated quantity of water nec-
essary for hydrolysis of M-[l-~chloromethyl)propyl~acet-
imidoyl chloride to N-[l-(chloromethyl)propyl~acetamide
may be added after the completion of chlorination.
The acetonitrile may be separated from the N-
~7~
1 -[l-(chloromethyl)propyl]acetimidoyl chloride or N-[l-
-~chloromethyl)propyl]acetamide. Conveniently, it is
separated after the hydrolysis to N-[l-(chloromethyl)-
propyl]acetamide. The 1,2-dichlorobutane may be separ-
ated in whole or in part by distillation after the syn-
thesis of N-[l-(chloromethyl)propyl]acetimidoyl chloride,
or after hydrolysis to N-[l-(chloromethyl)propyl]acet-
amide. At least part of the 1,2-di~hlorobutane may be
retained until the syn~hesis of the dl-2-amino-1-butanol
hydrochloride is completed. It is usually more conven
ient to separate the 1,2-dichlorobutane after the hy-
drolysis to the N-[l-(chloromethyl)propyl]acet~mide, as
the reaction mixture is then smaller, and more compact
equipment may be used for the reaction of the N-[l-~chlor-
omethyl)propyl~acetamide to ~ amino-l-butanol hydro-
chloride. Azeotropic distillation with water permits
convenient and effective complete removal of the 1,2-
-dichlorobutane from the dl-2 amino-l-butanol.
Subsequently, methanol is added to the aqueous
reaction ~ixture containing N-~l-(chloromethyl)propyl]-
acetamide, preferably with catalytic amounts of hydro-
chloric acid, which is refluxed to hydrolyze to dl-2-
-amino-~-butanol hydrochloride with by-product methyl
acetate. The methyl acetate is removed by distillation
leaving dl-2-amino-1-butanol hydrochloride.
For the production o~ N-[l-(chloromethyl)propyl~-
acetimidoyl chloride, the presence of water is to be
avoided, and vacuum distillation to remove acetonitrile
and l,2-dichlorobutane is necessary. If hydrolyzed to
N-[l~(chloromethyl)propyllacetamide, mild conditions for
71~
1 the removal of both acetonitrile and 1,2-dichlorobutane
are preferred. A weak base aids in controlled hydroly-
sis. Where hydrolysis to dl-2-amino-1-butanol is desir-
ed, the acid produced in h~drolysis can be used to form
the hydrochloride salts of the product.
In the production of dl-2-amino-1-butanol hy-
drochloride, the acetonitrile should be vacuum distilled
out at the N-[l-(chloromethly)propyl]acetamide stage, for
recycling. If the acetonitrile is perr~litted to remain
during the hydrolysis to dl-2-amino-1-butanol hydro-
chloride, the acetonitrile tends to hydrolyze to acetic
acid with production of ammonia, usually as the ammonium
chloride. The acetic acid from the hydrolysis of aceto-
nitrile is readily removed as the methyl ester, but the
15 loss of acetonitrile reduces the efficiency of the pro- ~;
cess
1,2-Dichlorobutane is preferably at least
partially removed by vacuum distillation at the N-[l-
-(chloromethyl)propyl]acetamide stage. It causes no com-
plications other than increasing the size of the reactorrequired. Conveniently, the last of the 1,2-dichloro-
butane is removed by azeotropic distillation from dl-2
-amino-l-butanol hydrochloride at the time acetic acid
is removed as the methyl ester. Conveniently, the inter~
mediate reactions to dl 2-amino-1-butanol hydrochloride
may overlay without the isolation of N-[l-~chloromethyl)-
propyl]acetimidoyl chloride and N-[l-(chloromethyl)propyl]-
acetamide.
By dissolving in methyl alcohol, or isopropanol,
or mixtures thereof, a solution of the dl-2-amino-:L-but-
. " ~ . . ~ ., ~ .
1 anol, predominantly as the hydrochloride, is obtainedwhich can be partially neutralized with ammonia to form
a mixture of dl-2-amino-1-butanol and dl-2-amino-1-but-
anol hydrochloride, with ammonium chloride being filtered
out. The mixture is approximately two parts dl-2-amino-
-l-butanol and one part dl-2-amino-1-butanol hydrochlor-
ide, a ratio which is close to the optimum desired for
reacting with L(+~- tartaric acid in the presence of an-
hydrous methanol to permit the separation of the d-2-
-amino-l-butanol tartrate as is set forth in detail in
United States Patent 3,553,257.
This process has unique and unexpected advant-
ages in the present system because part of the butene-l
adds chlorine and acetonitrile in the reverse of the de
lS sired position so that about 3 to 10~ dl-1-amino-2-butanol
is found in the dl-2-amino-1-butanol as an impurity. In
separation of the d- and l-isomers of dl-2-amino-1-but-
anol, both isomers of dl~l-amino-2-butanol remain with
the mother liquor, and a much purified d-2-amino-1-but-
anol separates out as the L(+)- tartrate saIt.
A starting material containing up to about 10%
of dl-l~amino-2-butanol yields a purified d-2~amino-1-
-butanoI, as the tartrate, having a content of less than
0.01~ of dl-1-amino-2-butanol, as its tartrate salts.
If washing is less thorough, up to 0.1% may be present.
A purity is readily obtained which can be used as a
starting material for ethambutol which is of pharmaceut-
ical grade with a minimum of addi~ional purification.
The facility of separating out impurities and
by-products is unobvious and of the essence of the pres-
~ 8 --
~707~(~
1 ent system of reactions.
Exa~ e 1
Preparation of dl-2-Amino~l-butanol Hydrochloricle
.
Acetonitrile (164 g., 4 moles) is placed in a
tared 500 ml. 4-necked Morton flask equipped with a
mechanical stirrer, a thermometer, two fritted glass
gas-inlet tubes, a syringe needle (attached to a syringe
pump), and a dry-ice condenser. The flask is cooled in
an ice-water bath to 3-5C. Chlorine (71 g., 1 mole)
10 and butene-l (56 g., 1 mole~ are passed through the well- ;~
-stirred acetonitrile at a ra*e of about 400 ml./min.
each while water (10 g., 0.55 mole) is added ~imultane-
ously at a linear rate with the syringe pump during the
course of the reaction (1 hour).
The reaction temperature rises to 20C. within
8 minutes and stays constant through the course of the
reaction. The reaction mixture is stirred for an addi-
tional 15-30 minutes. The reaction mixture is weighed
to insure that proper amounts of the gaseous reactants
have been introduced. Excess acetonitrile (b.p. 36-41C./-
150-170 mm.) is remo~ed by distillation (bath temperat-
ure up to 100C.) while using a 10-plate distillation col-
umn. A sudden temperature drop indicates the end of
acetonitrile distillation.
Th~ acetonitrile fraction conta ~s 1-2% HCl
and about 6% 1,2-dichlorobutane and can be recycled,
without further treatment to a subse~uent batch, or can
be purified before recycling.
The hsat temperature rises to 70 and by-prod-
uct lt2-diehlorobutane is distilled off between 70-40C~
g _ :
07~
1 at 150 to 25 mm. A dry-ice trap attached to the vacuum
line contains 15-25 g. of a material which consisted of
35% HCl, 10% 1,2-dichlorobutane and a crystalline solid
derived from the reaction of acetonitrile with anhydrous
H~l.
The residue in the flask, predominantly N-[l-
-(chloromethyl)propyl]acetamide, is mixed with water (45
g., 2.5 moles) and the mixture is brought ~o reflux. The
residual 1,2-dichlorobutane is removed by azeotropic
distillation (Dean-Stark trap) while the mixture is re-
fluxed for 2 hours. The water and some acetic acld
(formed during hydrolysis with water~ are removed at 80
(under reduced pressure (15-20 mm.) to leave a viscous
residue consisting of N-~l-(chloromethyl)propyl~acetamide,
and its hydrolysis products.
- Methanol (48 gO, 1.5 moles) and concentrated
hydrochloric acid (0.5 ml.) are added to the residue and
the reaction mixture is refluxed for 2 hours. After
removal of the volatiles tH20, methyl acetate, etc.),
- 20 the dl-2-amino-1-butanol hydrochloride is obtained as a
colorless viscous material which crystallizes on stand-
ing.
Example 2
dl-2-amino-1 butanol
A 30 g. portion of the crude dl-2-amino-1
-butanol hydrochloride from Example 1 is susper.ded in a
mixture o 100 ml. of toluene and 20 ml. of isopropanol.
Anhydrous ammonia tlO.2 g., 0.6 mole~ is introduced
over the sur~ace of the well-stirred suspension at 25C.
A dry-ice-acetone condenser controls ammonia loss during
-- 10 --
~0707~L~
1 reaction. Crystalline ammonium chloride starts precipi-
tatlng immediately and stirring is continued for 15 20
minutes to insure completion of the reaction. The dry-
-ice-acetone condenser is removed and excess NH3 is al-
lowed to volatilized (15~20 minutes). The precipitatedNH4Cl is filtered off and washed with a small amount of
toluene.
The filtrate and washings are combined and the
solvents evaporated under reduced pressure to obtain
d,1-2-amino-1-butanol (210 0 g. ) . The product by gas
liquid chromatography is 63% pure, and contains about 8%
of dl~l-amino-2-butanol. The same process can be used
to obtain the d- or 1- optical isomer as a free base from
its hyrochloride salt.
Example 3
.
d-2~amino-1-butanol tartrate from dl-2-amino-1-butanol
hydrochloride
A 50 g. sample of dl-2-amino-1-butanol hydro-
chloride from Example 1 is dissolved in 100 ml. of anhy-
drous methanol. One mole of anhydrous NH3 is condensed
in over a period of 40 minutes~ (A dry-ice-acetone con-
denser is used to prevent ammonLa loss during reaction.)
After stirring for 0.5 hour, the dry-ice-acetone conden~
ser is removed and excess NH3 is allowed to volatilize
(20-30 minutes). The precipitated NH4Cl is filtered off
tl3.2 gm., 0.246 mole, 62~) and the filtrate i~ concen-
trated to leave a viscous oil (43 gm.) which contains
58% by weight free dl-2-amino-1-butanol (the remainder
being unreacted dl-2-amino-1-butanol hydrochloride).
The mixture (42 g.) is dissolved in 120 ml. of
~L~7~)7:~LO
1 anhydrous Methanol and the solution is treated with 35
g. (0.233 mole) of L(~)- tartarlc acid. The reaction
temperature rises to 45-47C. during addition of tar-
taric acid. The solution is maintained at this temper-
ature for 1 hour and then cooled to 25C. over a periodof 4-5 hours. Crystallization can be expedited by seed-
ing the solution with d-2-amino-1-butanol L(~)- tartrate
to induce crystallization of the salt,
The precipi~ated salt is filtered off and wash-
ed four times with cold methanol and then dried in an
inert atmosphere. The salt i9 obtained as colorless
crystalline solid [30 g., 0.125 mole, 63%) m.p. 133-140C.
[a]D6= 23.52 (c = 5~, H2O) and in a typical run was in-
distinguishable rom authentic d-2-amino-1-butanol L(+)-
tartrate [m p. 137-141C.; [al26=23.74 (c = 5%, H2O)].
Up to about 8% of dl-1-amino-2-butanol may be formed in
the reactions from the addition of the imido group to the
1 position in butene-l, in effect, the reverse of that
desired. By analogous reactions, this is converted to
,
dl-1-amino-2-butanol. Both the d and 1 isomers remain
with the mother liquor in the crystallization, and per-
mit the separatian of d~2-amino-1-butanol L(~)- tartrate
substantially free from impurities.
The isolation of d 2-amino l-butanol from the
salt has been described in United States Patent No.
3,553,257, supra~
Conversion to ethambutol is described in
United States Patent 3,769,347.
Examvle 4
-
d-2~Amino-l butanol
- 12 ~
7~
1 d-2-Amino-l-butanol tartrate (150 g.) (0.63
mole) from Æxample 3 is added with stirrin~ to an aque-
ous solution of KOH prepared by dissolving 76 ~. KOH in
115 ml. of distilled water. d-2-Amino l-butanol which
forms the upper layer is extracted wit:h tetrahydrofuran
(100 ml. x 2). The tetrahydrofuran extract is dried
~Na2SO4) and concentrated under reduced pressure. The
crude, oily residue is distilled under reduced pressure
to give _-2-amino-1-butanol (b.p. 99-103 at 30 mm.).
The material is further fractionated to give pure d-2-
-amino-l-butanol having a b.p. of 174, and lal25- 9.9.
The yield of the distilled material is about 50% to 76%
and can be improved substantially if additional extrac-
tions are carried out with tetrahydrofuran.
Example 5
Ethambutol Hydrochloride
-
Following the procedure described in Example 1
of United States Patent 3,769,347, a mixture of 462 g.
of d-2-amino-1-butanol, produced in accordance with the
procedure of Example A, and 32 g. of ethylene dichloride
is heated to 80C. and the temperature is allowed to
rise exothermally to about 130C. After 1 hour, the mix-
ture is cooled to about 95C.~ 22.5 g. of sodium hydrox-
ide is slowly added, and a temperature of about 112
is maintained for 1 hour. The sodium hydroxide is in
the form of prills of about 4 nm. diameter. The mixture
is cooled to 70C. and unreacted d-2-amino~l-butanol is
recovered by vacuum distillation. The distillation is
at a pressure below 20 mm. mercury, and below 130Co ~
heat being applied at a rate within the capacity of the
- 13 -
~0~707~
1 condenser.
Isopropamol (290 g.) is added to the distilla-
tion residue at a temperature not above 90C., and fol-
lowed by a refluxing period of 30 minutes. The mixture
is cooled to and filtered at 60C~ to remove sodium
chloride, and the filter cake is washed with 47 g. of
isopropanol, at 60C. The volume of the filtrate is
diluted to 430 ml. with isopropanol and the temperature
is adjusted to 40-45C., 2 g. of diatomaceous earth filt~
er aid is added, and a second filtration is carried out.
To the clear filtrate there is added 120 g.
of methanol and 15 g. of water. The vessel is closed
and hydrogen chloride tabout 25 g.) is introduced over
the surface of the charge at a gas pressure of 5-7 psig
while the temperature is allowed to rise to 55C., to a
pH of 2 to 2.5. The charge is cooled very slowly to 28C.
and is stirred for about 1 hour.
Conveniently, a small aliquot is titrated, and
a calculated quantity of hydrogen chloride added. Proper
final p~ is confirmed by testing as acid to wet Congo
Red test paper. Other methods of measuring the pH can
be used. The white crystalline product, d,d'-2,2'-tethyl-
enediimino)-di-l-butanol dihydrochloride is separated by
filtration and washed with isopropanol. The product,
carefully dried at al!maximum temperature of 75~C., is
about 70 g., has a decomposition range of 198.5-204C.,
and an ash content of 0.1%.
This is a pharmaceutically acceptable, elegant
grade of ethambutol hydrochloride without further treat-
- 30 ment or refinement. The produck may be tabletted or en-
- 14 -
~ ~t~ 7 ~
1 capsulated by conventional procedures.
Example 6
N-[l-(Chloromethyl)propyl]acetamide
Into a 250 ml. 3-necked flask fitted with a
stirrer, dry-ice-acetone trap, a gas outlet, and a gas
inlet is charged 41.05 g. (1.0 mole) acetonitrile, 25 g.
(0.25 mole) CaCO3, 13.5 ml. (0.75 mole) water and 26.8
g. (0.475 mole) l-butene. The mixture is cooled to -5
to -8C. and chlorine added over 2 hours maintaining the
temperature at below 7C. until the reaction mixture
turns yellow indicating a slight excess of chlorine. The
mixture is filtered and the solvents distilled under re-
duced pressure to yield 28.6 g. of N-[l-(chloromethyl)-
propyl]acetamide (40.2% yield based on l-butene).
~ æ e 7
N-[l-(Chloromethyl)propyl]acetamide
A 500 ml. 3-necked flask fitted with a stirrer
and dry-ice-acetone trap is charged with 82.1 g. (2.0
moie) acetonitrile, 27.4 g. (1.52 mole) water, 27 g.
(0.25 mole) Na2CO3 and 28.1 g. (0.50 mole) l-butene and
cooled to 0C. Chlorine (0~50 mole) is added over 1/2
hour, the reaction temperature reaching a high of 32C~
After stirring for 2 hours at 25C., the reaction mix-
ture is filtered. The acetonitrile washings of the
solid phase and filtrate is combined and the solvents
removed by vacuum distillation to leave 33.0 g. of the
N-El-~chloromethyl)propyl]acetamide (44.0% yield based
on l-butene~
Example 8
dl-2-Amino-1-butanol
~7(~7~
1 Sodium hydroxide pels (97~ pure, 18. a g.,
0.45 mole) are stirred with 100 ml. of anhydrous methanol
and crude dl-2-amino-1-butanol hydrochloride, 50 g.
(87% real, 0.35 mole) from a run similar to that of Ex-
ample 1 is added with stirring over a period of O.S
hour. The reaction mixture warms up and precipitated
sodium chloride is removed by filtration, washed with
methanol and the washings combined with the main fil-
trate. Methanol and water (formed during neutralizationj
are removed under reduced pressure and the residual oil
distilled to yield dl-2-amino-1-butanol (b.p. 95-100%/-
30-35 mm.), 26.68 g. (86% of theory). The material con-
tains about 9.6~ of dl-1-amino-2-butanol.
dl-2-Amino-l-butanol can be used as a catalyst
as described in United States Patent 3,539,652 (CA 74,
23499) as a component of organosilicone compositions,
French P~tent No. 1,556,008 (CH 71, 115) or as a compon-
ent in a flame retardant composition, United States
Patent No. 3,413,380 (CA 70, 40).
~
dl-2-Amino-l-butanol
_
Sodium hydroxide pels (97% pure, 18.8 g~,
0.45 mole) are stirred with 100 ml. of isopropanol con-
taining 0.7 ml. of water. A part of the sodium hydrox-
ide goes into solution. Crude dl-2-amino-1-butanol hy
drochloride 50 g. (70~ real, 0.28 mole) is added with
stirri~.g over a period of 0.5 hour. The reaction mix-
ture warms up to about 45C. and crystalline sodium
chloride precipitates out of the reaction mixture. The
salt is removed by filtration, washed with isopropanol
- 16 -
7~
1 and the washings are combined with the main filtrate.
The filtrate is distilled under reduced pressure. Iso-
propanol and water are removed as a fore-run and dl-2-
-amino-l-butanol (25 g., 88.3~ yield) is distilled at
95-105 at 30 mm. Gas liquid chromatographic analysis
of this product showed lt to contain about 10% l-amino-
-2-butanol.
Example 10
_-2-Amino-l-butanol ;
10To a 15 g. portion of undistilled crude dl-2-
-amino-l-butanol (59% real, Ool mole) from a run similar
to that of Example 2, dissolved in 48 ml. of methanol
is added with stirring 17.5 g. (0.117 mole) of L(+)-
tartaric acid while the temperature is maintained at 45.
The solution is seeded with a small amount of crystals
of the L(+)- tartrate of d-2-amino l-butanol and the
temperature maintained at 45C. for 0.5 hour. An addi- ,
tional 4.2 g. ~0.028 mole) of tartaric acidlis added and
the mixture held at 45-47C. for an additional 0~5 hour.
The temperature is then lowered to 16-18 over a 4-hour
period and held at this temperature for 1 hour. The crys-
talline L(+~- tartrate of d-2-amino-1-butanol is removed
by filtration, washed with cold methanol (3 ml. x 3) and
dried in an inert atmosphere~ In one such run the d 2-
-amino~l-butanol L(+)- tartrate weighed 8.5 (0.035 mole,
71.0%~, melted at 137-138 and had a specific rotation
la]D6= 23.74 (c 5%, H2O). The crude feed dl-2-amino-
-l-butanol contained about 8% of dl-1-amino-2-butanol
as an impurity. This impurity is not carried through
the resolution process. The L)~)- tartrate salt o d-2-
- 17 -
07~0
1 -amino-l-butanol obtained a~ter resolution is found to
contain no detectable quantities of l--amino-2-butanol,
by gas liquid chromatography, which iS sensitive to
about 0.01% of the 1-amino-2-butanol.
Example 11
d-2-Amino-l butanol
.~
To 15 g. of distilled dl-2-amino-1-butanol
(38.5% pure by gas liquid chromatography), from a run
similar to Example 2, dissolved in 48 ml. of anhydrous
methanol is added with stirring 17.5 g. (0.117 mole) of
L(+)- tartaric acid while maintaining the temperature
below 47C. The resulting solution is stirred at 45-47
for 0.5 hour and an additional 4.21 g. (0.028 mole) of
tartaric acid is added and the solution stirred for an
additional 0.5 hour at 45-47~. The solution is seeded
with a small amount of the L(~)- tartrate of d-2-amino-
-1-butanol. The mixture is slowly cooled to 16-17C.
over a 4~hour period and the crystalline L(+)- tartrate
salt of d-2-amino-1-butanol is removed by filtration,
washed with cold methanol (3 ml. x 3) and dried in an
inert atmosphere. The white crystalline material (14.5
g., 0.061 mole, 81.9% yield) melts at 136-140 and has
a specific rotation of la]D = 23.74 (c = 5%, H20). The
feed dl-2-amino-1-butanol used for resolution contains
about 8% of dl-1-amino-2-butanol as an impurity. This
impurity is, however, not carried through the resolution
process. The ~(+~- tartrate salt of d-2-amino l-butanol
obtained after resolution is found to contain no detect-
able quantities of either d or 1 l~amino-2-butanol by gas
liquid chromatography which is sensitive to 0.01% of
- 18 -
~17[)7~L~
1 1-amino-2-butallol. ~pparently, all o~ the dl-l-amino-
-2-butanol remains with the mother liquor, and is re-
jected along with the 1-2-amino-1-butanol in the meth-
anol.
Example 12
dl-2-Amino-l-butanol
A A 137 g. sample of crude dl-2-amino-1-butanol
hydrochloride from a run similar to Example 1 is treat-
ed with a solution of 137 g. KOH in 200 ml. of water.
The mixture is extracted three times with tetrahydro
furan and the combined extracts dried (Na2SO~). The
solvent is removed under reduced pressure to give 95 g.
of a crude oil (60.6% dl-2-amino-1-butanol and 6% dl-l-
-amino-2-butanol).
B In a separate experiment a 250 g. sample of
a similar crude dl-2-amino-1-butanol hydrochloride dis-
solved in 200 ml. of anh~drous methanol is trea~ed with
3 moles of anhydrous ammonia. After a few hours stirr-
ing, the excess ammonia is allowed to evaporate. The
precipitated ammonium chloride is removed by filtration
and the filtrate concentrated gives 174.5 gm. of an oil
which contains both dl-2-amino-1-butanol and its hydro-
chloride together with some quantities of dl-l-amino-2-
-butanol and its hydrochloride ~total 5809~ dl-2-amino-
-l-butanol by gas liquid chromatography~
C A 7.5 gm. sample of crude dl-2-amino-1-butanol
from the fixst experiment (A) is mixed with a 7.5 gm.
portion of the material (dl-2-amino-1-butanol and its
hydrochloride) from the second experiment and the mix-
ture is dissolved in a mixture of 80 parts of anhydrous
-- 19 --
lQ7~7~
1 methanol and 20 parts of lsopropanol (v/v) (tile solu-
tion con-tains 0.1 mole of real dl-2-amino 1 butanol of
which 0.097 mole is ~resent as the free base. (L(~
tartaric acid (15 g., 0.1 mole) is added slowly keeping
S the temperature below 45C. unti1 the exotherm ceases.
After stirring the solution for an hour at 45C., the
temperature is lowered slowly and at 40C. the mixture
is seeded with a small amount of the L(~)- tartrate salt
of d~2-amino-1-butanol and then gradually cooled to 18
over a period of 4 hours. The crystalline L(+)- tar-
trate salt of _-2-amino-1-butanol formed in the reaction
mixture is removed by filtration, washed with cold meth-
anol (3 ml. x 3) and pumped dry. The yield of the ma-
terial is 9.0 g. (0.036 mole, 75.2~); m.p. 137.5-139.5;
[a]D5= 23.84 (c = 5%, H2O).
Example 13
N-[l-(Chloromethyl)propyl]acetimidoyl chlorlde
Reagent grade acetonitrile (S2 g., 2 moles)
is placed in a 500 ml. three-necked flask equipped with
a mechanical stirrer, a low-temperature thermometer and
two fritted inlet tubes. With vigorous stirring and
cooling (-20C.), butene-l (28 g., 0.5 mole) and chlor-
ine (35.5 g., 0.5 mole) are added simultaneously both at
a rate of about 375-400 ml./min. The addition is com-
plete in about 37 minutes and the reaction temperatureat the end of this period rises to -10C. (bath/20C.),
The mixture is fractionated to ~ive: Fraction I, as g.
(mostly acetonitrile) distilling under 20 mm. pressure
at a bath temperature of 50C.; Fraction II, 12.5 g.
distilling under 20 mm. pressure at a bath tem~erature
-- ~0 --
~LCl 7~:)73Lo
1 of 65C., 70~ 1,2-dichlorobutane, 30~ N-[l-chloromethyl)-
propyl]-acetimidoyl chloride; Fraction III, 35.9 g. dis-
tillin~ under 2 mm. pressure at a bath temperaturP of
60, about 90% N-[l-(chloromethyl)prop~l]acetimidoyl
chloride residue, 6.7 g. dark brown viscous oil. Based
on Fractions II and III, the yield of N-ll-(chloromethyl)-
oropyl]ace~imidoyl chloride is 39.7 g. (48%). A portion
of Fraction III is redistilled to yive a pale yellow oil
with a characteristic odor resembling that of thionyl
chloride. The product, N~ (chloromethyl)propyl]acet-
imidoyl chloride displays strong infrared bands at 3000,
1705, 1430, 1370, 1085, 960, 920, 840 and 740 cm~l.
NMR(CDC13): 0.88 ppm (t, 3H), 1.4-1~8 ppm (m, 2H), 245
ppm (s, 3H), 3.62 ppm (m, 2H, -CH2Cl), and about 3.9 ppm
15 (m, lH, CH).
Occasionally, a solid isomer of N-[l-(chloro-
methyl)propyl~acetimidoyl chloride ~often the ma~or prod-
uct is also obtained. The two forms seem to be intercon-
vertible in certain solvents. On reaction with water,
both hydrolyze to N-[l-(chloromethyl)propyl]acetamide.
The solid form has infrared bands at 3000, 1650, 1550,
1480, 1365, 1280, 1045, and 740 cm~l.
Example_14
N-[l-(Chloromethyl ? propyl]acetamide
A sample of N-[l-chloromethyl)propyl]acetimi-
doyl chloride from Example 8 is treated with an excess
of 10~ aqueous sodium carbonate solution at room temp-
erature. The organic material is extracted with ether
and dried over Mg504. Removal of the solvent under re-
duced pressure leaves N-[l-~chloromethyl)propyl]acetamide
- 21 -
~07[1710
1 as a crystalline solid in nearly quantitative yield. An
in~rared spectrum shows peaks at 3300(M), 3100(W), 1650(S),
and 550~S) cm l; nuclear magnetic resonanc~ (CDC13) shows
peaks 0.95 ppm (t, 3H0, 1.4-1.8 ppm (m, 2H), 2.03 ppm (s~
3EI), 3.67 ppm (d, 2H, CH2Cl), 3.8-4.4 ppm (m, lH).
The effects of conditions on yield~ is shown
in the following examples in which the chlorination re- -
actions were carried out at initial temperatures of -3
to ~23 and the acetonitrile to C12 ratio was varied
from 2 to 4. Additionally, the initial concentration
of butene-l was varied by either passing butene-l and
C12 simultaneously (low initial butene-l concentration) ~ :
into acetonitrile or by first condensing butene at -SC.
into acetonitrile and then passing C12 through the mlx-
ture (high initial butene-l concentration). The results
of these experiments in Table I show that the yield of .
N-~l-(chloromethyl)propyl]acetimidoyl chloride is depend- ~
ent primarily on the mole ratio of acetonitrile to C12 - : -
and amounts to about 50--55% when this ratio approaches
4.
- 22 -
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W
-- 23 --
1~7~171~)
1 Hydrolysis of l~-[l-(chloromethyl)pro~yl]acet-
imidoyl chloride is highl pH dependent. It has now been
found that a simple hydrolysis procedure is effective.
On re1uxing with water N-[l-(chloromethyl)propyl]acet-
imidoyl chloride is transformed into a mixture of dl~2
-amino-l-butanol (77~), dl-2-amino-1-butanol acetate
hydrochloride (17%), the N-[1-(hydroxymethyl)propyl]acet-
amide (7%) and acetic acid within one hour. The product
ratios appear to represent equilibrium compositions be-
cause additional heating (14 hrs) does not materially
change their distribution. If, however, the hydrolysis
is carried out with aqueous methanol or ethanol, it is
complete within 2 hours and the acetyl component of the
product can be removed as methyl or ethyl acetate by
distillation. This procedure not only decreases hydroly-
sis time, it also avoids the accumulation of salts in the
reaction mixture, gives essentially quantitative yields
of dl-2-amino-1-butanol from N-[l-(chloromethyl)propyl]-
acetimidoyl chloride through N-[l-(chloromethyl)propyl]-
acetamide, and facilitates product work~up. Methyl ace-
tate boils at 57C., and is readily distilled off~
In order to make this process as economical
as possible, excessively large volumes of aqueous meth- ~ ~
anol should be avoided. If insufficient quantities of
water are used (less than N-[l-(chloromethyl)propyl]acet-
imidoyl chloride:H2O:MeOH mole ratio 1:3:3) and espec-
ially if the hydrolysis is carried out in the presence
of the l,2-dichlorobutane by-product, a small fraction
(3-15~) of N~[l-(chloromethyl)propyl]acetimidoyl chlor-
ide hydrolyzes to 2-amino-1-chlorobutane hydrochloride~
- 24 -
~07~
l The formation of 2-amino-l-chlorobutane hydrochloride
can be totally suppressed if water and methanol are add-
ed sequentially/ and in that order, rather than together
in one step. Addition of water to N-[l-(chloromethyl)-
S propyl~acetimidoyl chloride almost instantaneously con-
verts it to the N-[l-(chloromethyl)propyl]acetamide
which then hydrolyzes via the oxazoline intermediate.
Three series of reactions (A, B and C) were
completed using as-is acetonitrile (water conc. (Karl-
-Fisher) = 0.059-0.2%). In each of these series, reac-
tions were carried out using 0.5 mole of butene, 0.5
mole of chlorine, and the acetonitrile:Cl2 mole ratio
(identical to the acetonitrile:butene) was varied from
l to 8.
In a series A (reaction time = l hr.) the re-
action temperature was maintained at 0C. while chlor-
ine and butene were passed simultaneously into acetoni-
trile in one hour. After removal of acetonitrile (40-
-50, 50 mm.), the crude reaction mixture con~aining
N-[l-(chloromethyl)propyl]acetimidoyl chloride and 1,2-
-dichlorobutane was hydrolyzed by refluxing with aqueous
methanol.
~:
- 25 -
a~ ~o
u ~
r
~ l ~
o ~ o ~ ~`L~ o o
.....
O ~ ~ ~ ~ ,~
~-rl O . . .
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o~o ~ ~c ~
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E~
o o o o o
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c)
H P~ ~rl O O O O O ~ :H 1~ O O O O O
É~ , : ~
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rl
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rd ~J ~;J N t J
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26
~L~'7(1~0
1 I~ is significant to note that N-~l (chloro-
methyl)propyl]acetimidoyl chloride can be hydrolyz~d
substantially quantitatively to ~-[l-(chlorom~tyl)-
propyl]acetamide, and then to dl-2-amino-1-butanol. Re-
porting as dl-2-amino-1-butanol hydrochlorlde is a very
convenient method of showing yields. Errors due to vol-
atile components are avoided. Small quantities of dl-l-
-amino-2-butanol report with the c -2-amino-1-butanol.
Even at a low acetonitrile:C12 ratio of one, the yield
0 of _-2-amino-1-butanol HCl is as high as 31%. Increas-
ing the acetonitrile:C12 mole ratio from 1 to 2 improves
the yield to 43%,~an increase of 12%. Further increases
in the acetonitrile:C12 ratios also improve the yields,
For each additional mole of acetonitrile (up to a total
of 5 moles (AN:C12 ratios 3 to 5) the yield o~ dl-2-
-amino-l-butanol HCl increases on average about 6
Still further addition of acetonitrile (AN:C12 mole
ratios 6 to 8) is considerably less effective; the aver-
age incremental yield of dl-2-amino-1-butanol ~Cl being
of the order of about 3% pex mole of acetonitrile. A
ratio of about 4:1 is a good compromise between yield
and a reasonable size reaction vessel and recycle ratio
of acetonitrile.
In both series B and C, the gaseous reactants
were run into acetonitrile over a period of 0.5 hr. The
initial reaction temperature was 0. This was allowed
to rise to a maximum of 35 during the course of the re-
action. Additionally, in series B, chlorin was passed
through a solution of butene in acetonitrile to maintain
- 30 a high initial concentration of butene. In series C
- 27
7~7~L~
1 both chlorine and butene were passed simultaneously
through acetonitrile allowing a-ttainment of a low in-
itial concentration of butene. The results of simultan-
eous and sequential additions of butene and chlorine on
the yield of N-[l-(chloromethyl)propy:l]acetimidoyl chlor-
ide at different acetonitrile/C12 mole ratios are sum-
- marized in Table III.
':
- 2~ -
~7~7~
o\o
U~
o a) ~
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o h O o ~ 1~ ~ ~o a~
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rC ~ I ~Q h . h O rl
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1 O ...... I ........ ..... ~ ,~ 3
O~) ~ ~:: ooooIoo ~oooo C)
O U ~ ~ O
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Z
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,, æ ~ ~ 0OOO Oo O~,0OOO ~
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m in . u~ o u~ ~ u~ ~ m tQ u~ i r~ C ~ tda) i.) ~ ~ t~ i a.i ~ `i ,i o b R ~
~H ri O I I I I I I ~ ~ril l l l l ~) O ri
O ' i E~ o o o o o o o ~o o o o o ~ rn ~ :
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iT i i Q
- 29 -
1~7[37~L0
1 In series B and C ma-terial balances show con-
version and recovery data on acetonitrile. In each case
the dis-tillate 1,2-dichlorobutane + acetoni-trile was
analyzed for 1,2-dichlorobutane and acetonitrile by gas
li~uid chromatography.
A less pure product is obtained if the N-[l-
-(chloromethyl)propyl]acetimidoyl chloride is allowed to
stand for 40-50 hours prior to work-up.
The data in the table shows that:
1. The yield of crude dl-2-amino-1-butanol HCl (or N-[l-
~(chloromethyl)propyl]acetimidoyl chloride) is primarily
dependent on the mole ratio of acetonitrile:C12 and var-
ies between 31 and 66% as the acetonitrile:C12:butene
mole ratio changes from 1:1:1 to 8:1:1.
2. Simultaneous addition of chlorine and butene to
acetonitrile rather than the alternate procedure of add-
ing chlorine to a mixture of butene and acetonitrile is
advantageous. The reaction is less exothermic; conse~
quently easier to control, and the yields of dl-2-amino-
-l-butanol HCl are somewhat better. A reaction time of
one hour generally appears to permit more con~rol over
the reaction exothermicity.
3. The reaction temperature does not appear to be a
controlling factor in determining the overall yield.
~owever, in view of the thermal instability of N-[l-
-(chloromethyl)propyl]acetimidoyl chloride above 50,
reaction temperatures between 0-25 are more desirable.
The process can vary depending on the size of
batches. Whereas the Examples are exemplary, for large
scale production, the process may be run continuously,
- 30 -
1~7~7~
l with the butene~l and chlorine being fed continuously
to a stirred continuous reactor. The recycle acetoni- .
trile is dis-tilled off and recycled continuously. Such
a continuous system permi-ts a higher ratio of acetoni-
trile to the butene-l and chlorine. Whereas, for a
batch process, a molar ratio of at least 2 of acetoni-
trile to butene-l and chlorine is preferred, more than
a ratio of 16 can require an uneconomically large reac-
tor. With a continuous process even higher ratios are
convenient.
Whereas both butene-l and chlorine are gaseous
at room temperature of about 20C., so that low temper-
atures, around 0C. and lower are convenient, a higher
temperature to reduce the need for cooling may be used
if a pressurized reactor i5 available.
The trade-off of the cost of a pressure reac-
tor against additional refrigeration can vary with
equipment available.
Other modifications within the scope of this
invention as defined by the appended claims are, of
course, obvious to those skilled in the arts.
.
~;
- 31 -
