Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1058~98
The present invention relates to new carbonic acid
ester which is useful as an agent for introducing esterified
carboxy-type protective group(s) on amlno and/or imino group(s)
in amino and/or imino group(s)-containing compounds and to
processes for the preparation thereof.
Further, the present invention relates to a process
for the temporary protection of amino and/or imino group(s)
in amino and/or imino group(s)-containing compounds with
esterified carboxy-type protective group(s),
As is known, such a temporary protection of amino
and/or imino group(s) is of great importance in the ~ield o~
preparative chemistry as well as of degradation reactions, for
example, in peptide-chemistry, penicillin-chemistry, cephalo-
sporin-chemistry, alkaloid-chemistry, determination of the
constitution o~ unknown compounds such as natural products,
and the like.
The present invention i9 based on the observation
that a carbonic acid ester of the formula (I) as shown below
is a much more favourable agent for the temporary protection
of amino and,/or imino group(s) in the compound in comparison
with the agents which have been conventionally employed in the
arts in the following regards.
That i9 to sly:
(1) that said carbonic acid ester is present in stable
oil or crystals and is free from explosiveness,
corrosiveness or irritativeness which are oft~n
caused by the conventional agents so that it is
much more favourable and safe for handling in
experimentally as well as industrially practical use,
(2) that said carbonic acid ester can be easily prepared,
and
r
n
1058198
(3) that said caxbonic acid ester reacts rather rapidly
with amino and/or imino group(s)-containing organic
compounds under milder reaction conditions to give
protected amino and/or imino group(s)-containing
compound so that undesired troublesome side reactions
and production of by-products, which often occur
unfavourably in case of using the conventional
agents, can be minimized or in some case substantially
avoided.
And, in such a reaction of said carbonic acid ester
with the amino and/or imino group(s)-containing
co~pound, there may be produced a compound of the
formula:
R2 OH
wherein R2 is as defined below, as a substantially sole by-
product which can be so easily recovered in practical purity
from the reaction mixture by a conventional manner such a~
extraction and may be used repeatedly without any further
purification, as a starting material, for the preparation of
0 the compound (I) of the present invention,
Accordingly, the present invention provides a process
for the protection of amino and/or imino group(s) in an amino
and/or imino group(s)-containing compound, which co~prises
reacting an amino and/or imino group(s)-containing compound
with a carbonic acid ester of the formula:
RlOCOOR2 (I)
wherein Rl is lower alkyl which may have substituent(s)
selected from the group of halogen, lower alkoxy and aryloxy,
or ar(lower)alkyl which may have substituent(s) selected from
the group of lower alkoxy, halogen, nitro and cyano, and R2 is
a group represented by the formula:
Q 2 _
. ~
.
- 105~198
-N=C ~
~z
wherein ~ and Z are each aryl which may have substituent(~)
selected from the group of halogen, lower alkoxy, nitro, cyano
and halo(lower)alkyl, or an electron withdrawing group.
According to said reaction, the esterified carboxy
group (RlOCO-) in the carbonic acid ester (I) can be intro-
duced on the amino and/or imino group(s) in the amino and/or
imino group(s)-containing compound for the protection to pro-
vide the protected amino and/or imino group(s)-containing
compound,
For this purpoce, there may be used as starting
material any desired amino and/or imino group(s)-containing
compounds, especially an organic compound including all of an
aliphatic, an aromatic or a heterocyclic compound, etc., each
of which contains at least one amino or imino group in the
molecule.
In this specification and claims, the term "lower" is
intended to mean a group having 1 to 6 carbon atom(s) unless
otherwise indicated.
A suitable example of lower alkyl for Rl may include
one, which may be branched or cyclic and, having 1 to 6 carbon
atom(s) such as methyl, ethyl, propyl, isopropyl, butyl, iso-
butyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, 1-
cyclopropylethyl, cyclopropyl, cyclopentyl, cyclohexyl or the
like, and preferably one having 2 to 5 carbon atoms, and these
lower alkyl groups may have optionally at least one substituent
selected from the group of halogen (e.g., chlorine, bromine,
fluorine or iodine), lower alkoxy having 1 to 6 carbon atom(s)
(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-b~to~y,
pentyloxy, hexyloxy, etc.) and aryloxy having 6 to 10 carbon
lQ5~3~98
atoms (e.g., phenoxy, tolyloxy, xylyloxy, naphthyloxy, etc.).
A suitable example of ar(lower)alkyl for Rl may include
one having 7 to 10 carbon atoms such as benzyl, phenethyl,
tolylmethyl, xylylmethyl, mesitylmethyl or the like, and pre-
ferably one having 7 to 8 carbon atoms, and these ar(lower)alkyl
groups may have optionally at least one substituent selected
from the group of the aforementioned lower alkoxy, halogen,
nitro and cyano.
A suitable example of aryl for Y and Z may include one
having 6 to 10 carbon atoms such as phenyl, tolyl, xylyl,
mesityl, cumenyl, naphthyl or the like, and these aryl groups
may have optionally at least one substituent selected from the
group of the aforementioned halogen, lower alkoxy, nitro, cyano
and halo(lower)alkyl (e.g., trichloromethyl, trifluoromethyl,
etc.).
A suitable electron withdrawing group for Y and Z may
include cyano; nitro; an acyl such as lower alkanoyl having 1 to
6 carbon atom(s) (e.g., formyl, acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), aroyl having
7 to 11 carbon atoms (e.g., benzoyl, toluoyl, xyloyl, naphthoyl,
etc.), e~terified carboxy, for example, lower alkoxycarbonyl
having 2 to 7 carbon atoms (e.g., methoxycarbonyl, ethoxy-
carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, tert-butoxycarbonyl, l-cyclopropylethoxy-
carbonyl, cyclohexyloxycarbonyl, etc,), ar(lower)alkoxy-
carbonyl having 8 to 9 carbon atoms (e.g., benzyloxycarbonyl,
p~enethyloxycarbonyl, etc.) or aryloxycarbonyl having 7 to 8
carbon atoms (e.g., phenoxycarbonyl tolyloxycarbonyl, etc.),
carbamoyl, disubstituted carbamoyl, for example di(lower)alkyl-
carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, methyl-
ethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, dibutyl-
carbamoyl, etc.), lower alkylarylcarbamoyl (e.g., methylphenyl-
1~ 3 - 4 -
1058~98
carbamoyl, ethylphenylcarbamoyl, etc.) or diarylcarbamoyl (e.g.,
diphenylcarbamoyl, ditolylcarbamoyl, etc.) or the like: or the
like.
The present reaction may be conducted in a conventional
manner, i.e. under conditions which have been used in the known
reaction for the protection of amino and/or imino group(s) in the
compound with an esterified carboxy group. More particularly,
the reaction may be conducted in a conventional solvent such as
water, an alcohol (e.g., methanol, ethanol, propyl alcohol, butyl
alcohol, tert-butyl alcohol, etc.), ethyl acetate, chloroform,
dimethylformamide, methylene chloride, tetrahydrofuran, acetone
or the like, or a mixture thereof, or other solvents which do not
adversely affect the present reaction. The reaction may be
optionally carried out in the presence of a base such as an
inorganic base, for example, an alkali metal hydroxide (e.g.,
sodium hydroxide, potassium hydroxide, etc.), an alkaline earth
metal hydroxide (e.g., calcium hydroxide, ma~nesium hydroxide,
etc.), an alkali metal carbonate (e.g., sodium carbonate,-
potassium carbonate, etc.), an alkaline earth metal carbonate
(e.g., calcium carbonate, magnesium carbonate, etc.); an alkali
metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate,
etc.), or the like; an organic base, for example, an alkali metal
acetate (e.g., sodium acetate, potassium acetate, etc.), tri-
alkylamine ~e.g., trimethylamine, triethylamine, etc.), tri-
ethanolamine, ~,N-dimethylaniline, N,N-dimethylbenzylamine, N,N'-
; dimethylpiperazine, N-methylmorpholine, pyridine, quinoline, or
the like; or a basic ion-exchange resin, or a mixture thereof.
The reaction temperature is not particularly limited,
but the reaction is preferably carried out around room
temperature.
The product having the protected amino and/or imino
group(s) thus prepared can be isolated by a conventional method.
1058198
Thu~ prepared the protected amino and/or imino group(s)-
containing compound can be used for further synthesis of known
or new compounds, in which it is inevitable to protect amino
and/or imino group(s) in the compound in order to avoid any
side-reaction, production of by-product and the like, And,
the protected amino and/or imino group(s)-containing product
thus synthesized may be subsequently ~ubjected to scission of
the said protective group, i,e., e~terified carboxy group, to
regenerate the free amino and/or imino group(s)-containing
product, Such subsequent scission of the esterified carboxy
type protective ~roup(s) can be carried out by a conventional
method,
The representative examples of the present carbonic
acid ester (I) may be illustrated as follows:
2-Lower alkoxycarbonyloxyimino-2-cyanoacetamide (e.g., 2-ethoxy-
carbonyloxyimino-2-cyanoacetamide~ 2-i~obutoxycarbonyloxyimino-
2-cyanoacetamide or 2-methoxycarbonyloxyimino-2-cyanoacetamide),
di(lower)alkyl 2-lower alkoxycarbonyloxyiminomalonate (e.g.,
diethyl 2-ethoxycarbonyloxyiminomalonate or diethyl 2-tert-
butoxycarbonyloxyiminomalonate),lower alkyl 2-lower alkoxycarbonyloxyimino-2-cyanoacetate (e.g.,
ethyl 2-ethoxycarbonyloxyimino-2-cyanoacetate, ethyl~2-
i~obutoxycarbonyloxyimino-2-cyanoacetate, ethyl 2-methoxycarbonyl-
oxyimino-2-cyanoacetate or ethyl 2-tert-pentyloxycarbonyloxy-
imino-2-cyanoacetate),
lower alkyl 2-halo(lower)alkoxycarbonyloxyimino-2-cyanoacetate
[e.g., ethyl 2-(2,2,2-trichloroethoxycarbonyloxyimino)-2-cyâno-
acetate],
- lower alkyl 2-ar(lower)alkoxycarbonyloxyimino-2-cyanoacetate
(e.g., ethyl 2-benzyloxycarbonyloxyimino-2-cyanoacetate),
~ - 6 -
.~ ~
~058~98
lower alkyl 2-lower alkoxycarbonyloxyiminoacetoactetate (e,g.,
ethyl 2-tert-butoxycarbonyloxyimlnoacetonacetate),
di(lower)alkyl 2-lower alkoxysubstituted ar(lower)alkoxycarbonyl-
oxyiminomalonate ~e,g,, diethyl 2-(4-methoxybenzyloxycarbonyl-
oxyimino)malonate],
2-lower alkoxycarbonyloxyimino-1-aryl(lower)alkane-1,3-dione
(e,g,, 2-tert-butoxycarbonyloxyimino-1-phenylbutane-1,3-dione),
l-lower alkoxycarbonyloxy-6-halobenzotriazole (e,g,, l-tert-
butoxycarbonyloxy-6-chloro-lH-benzotriazole or l-ethoxycarbony~-
loxy-6-chloro-lH-benzotriazole), ,
1-artlower)alkoxycarbonyloxybenzotriazole (e,g., 1-benz~loxy-
carbonyloxy-IH-benzotriazole), 2-lowex alkoxycarbonyloxyimino-
2-arylacetonitrile [e,g,, 2-tert-butoxycarbonyloxyimino-2-
phenyl-acetonitrile, 2-tert-butoxycarbonyloxyimino-2-(l-
naphthyl)acetonitrile or 2-(1-cyclopropylethoxycarbonyloxy-
imino)-2-phenylacetonitrile~, benzophenone 0-lower alkoxycarbonyl-
oxime (e,g,, benzophenone 0-tert-butoxycarbonyloxime),
2-halo(lower)alkoxycarbonyloxyimino-2-arylacetonitrile [e,g,,
2-(2,2,2~trichloroethoxycarbonyloxyimino)-2-phenylacetonitrile],
2-lower alkoxy substituted or unsubstituted ar(lower)alkoxy-
carbonyloxyimino-2-arylacetonitrile [e,g,, 2-(4-methoxybenzyl-
oxycarbonyloxyimino)-2-phenylacetonitrile or 2-benzyloxy-
carbonyloxyimino-2-phenylacetonitrile),
2-lower alkoxycarbonyloxyimino-2-halogen substituted aryl-
acetonitrile [e,g., 2-tert-butoxycarbonyloxyimino-2-(4-
chlorophenyl)acetonitrile] or the like.
The carbonic acid ester o~ the ~ormula (I) to be used
for the said protection includes,new and known compounds, and
the present invention also provides new carbonic acid esters
and processes for the preparation thereof,
ni
L ~ ~ - 7 -
~058~98
The new carbonic acid ester is represented by the
following formula:
R'lOCOOR 2 (I')
wherein R'l i9 lower alkyl which may have substituent(s)
selected from the group of halogen, lcwer alkoxy and aryloxy,
or ar(lower)alkyl which may have substituent(s) selected from
the group of lower alkoxy, halogen, nitro and cyano, and R'2
is a group represented by the formula:
~ Z '
wherein Y' and Z' are each aryl which may have substituent(s)
selected from the group of halogen, lower alkoxy, nitro,
cyano and halo(lower)alkyl, cyano, nitro, carbamoyl, esterified
carboxy, lower alkanoyl, aroyl or disubstituted carbamoyl;
provided that when R'2 is a group represented by the formula:
~Y "
-N=C~
wherein Y' and Z' are each cyano, nitro, carbamoyl or esterified
carboxy, R'l is ar(lower)alkyl having substituent(s) selected
from the group of lower alkoxy, halogen, nitro and cyano, and
further provided that when R'l is lower alkyl and R'2 is a
group represented by the formula:
~ l
z
wherein Y' is cyano and Z' is aryl,;the number of carbon atoms
of lower alkyl for R'l is 4 or 5~
Suitable examples of lower alkyl and ar(lower)alkyl
for R'l and the substituents thereof may be the same ones as
illustrated as the examples of the definitions for Rl,
respectively.
~ , - 8 -
1058198
Suitable examples or aryl, the substitutents thereof,,
esterified carboxy, lower alkanoyl, aroyl and disubstituted
carbamoyl for Y' and z' may be the same ones as illustrated as
the examples of the definitions for Y and z.
The new carbonic acid ester o~ the formula (Il) can be
prepared by reacting a haloformic acid ester of'the formula:
X-COOR12 (II)
wherein X is halogen and R'2 is as defined above, with a
hydroxy-compound of the formula:
R'l - OH (III)
wherein Rll is as defined above.
A suitable example of halogen for X can be also referred
to the ones exemplified as the substitutent'of lower alkyl for Rl.
~ he reaction of the compound (II) with the compound
(III) is usually carried out in a conventional solvent such as
chloroform, tetrahydrofuran, ether, acetonitrile, ethyl acetate,
acetone, benzene, n-hexane, petroleum ether, dioxane or any other
organic solvent which does not adversely affect the reaction.
These solvents may also be used in a mixture thereof. The re-
action is preferably carried out in the presence of a base suchas inorganic base, for example, alkali metal hydroxide (e.g.,
sodium hydroxide, potassium hydroxide, etc~), alkaline earth metal
hydroxide (e.g., calcium hydroxide, magnesium hydroxide, etc.),
alkali metal carbonate (e.g., sodium carbonate, potassium
carbonate, etc.), alkaline earth metal carbonate (e.g., calcium
carbonate, magnesium carbonate, etc.), alkali metal bicarbonate
, (e.g., sodium bicarbonate, potassium bicarbonate, etc.) or the
like, or organic base (e.g., trimethylamine, triethylamine, tri-
ethanolamine, dimethylaniline, pyridine, qùinoline, etc.). These
bases may be used alone or in combination. The reaction tempera-
ture is not limitative, and the reaction is preferably carried
out around room temperature or comparatively lower temperature.
;1~ 9
1058198
Alternatively, the new carbonic acid ester (I') can
be prepared by reacting a formic acid ester of the formula:
R'l - OCOX' (IV)
wherein R~ as defined above and x' is halogen, with a
compound of the formula:
R 2 OH (V)
~herein R'2 is as defined above or a salt thereof.
The suitable halogen for X,' is also referred to the
ones exemplified as the substituent of lower alkyl for Rl,
The suitable salt of the compound (V) is also
referred to the ones exemplified below for the compound (VI).
In the present reaction, there can be employed almost
the same solvent, base and reaction temperature as those employed
in the reaction of the compound (II) with the compound (III) as
mentioned above, and in addition, water or its mixture with the
solvents mentioned above may also be used optionally according
to the property of the compound (IV).
The compound (I') can be also prepared by reacting
a mixture of the compounds (V) or a salt thereof, (III) and
(VII) or a reactive equivalent thereof, in which the reaction
may proceed via the same mechanism of reacting the compound (II)
with the compound (III) and/or reacting the compound (IV) with
the compound (V).
The starting compound (II) to be used in the above
process include partially new compounds, which are represented
by the following formula:
X - COOR"2 (II'~
wherein X is as defined abo~e and R"2 is a group represented by
the formu-la:
~Y
-N=C
~Z"
~ ..
1058~8
wherein Y" is aryl which may have substituent(s) selected from
the group of halogen, lower alkoxy, nitro, cyano and halo(lower)-
alkyl, cyano, nitro, carbamoyl, esterified carboxy, lower
alkanoyl, aroyl or disubstituted carbamoyl and Z" is naphthyl,
aryl having substituent(s) selected from the group of halogen,
lower alkoxy, nitro, cyano and halo(lower)alkyl, lower alkanoyl,
aroyl or disubstituted carbamoyl.
The said new starting compounds (II') can be prepared
by reacting a compound of the formula:
R"2 ~ OH (VI)
wherein R"2 is as defined above, or a salt thereof with a
carbonyl halide of the formula:
COX2 (VII)
wherein X is as defined above, or a reactive equivalent thereof.
A ~uitable salt of the compound (VI) may include alkali
metal salt (e.g., sodium salt, potassium salt, etc.), alkaline
earth metal salt (e.g., calcium salt, magnesium salt, etc.) or
the like.
A suitable reactive equivalent of the compound (VII)
may include polymer of the compound (VII), for example, the
dimer (trichloromethyl chloroformate) or trimer [di(trichloro-
methyl)carbonate] of the compound (VII), in which the suitable
halogen for X is chlorine.
The reaction of the compound (VI) with the compound
(VII) is usually carried out in a conventional solvent such as
benzene, toluene, tetrahydrofuran, dioxane or any other
organic solvent which does not adversely affect the reaction.
The solvent may be used alone or`in combination. The reaction
is preferably carried out in the presence of a base such as
inorganic base for example, alkali metal hydroxide (e.g.,
sodium hydroxide, potassium hydroxide, etc.), alkaline earth
, -- 11 --
~ .
105~98
metal hydroxide (e.g., calcium hydroxide, magnesium hydroxide,
etc.), alkali metal carbonate (e.g., sodîum carbonate, potassium
carbonate, etc.), alkaline earth metal carbonate (e.g., calcium
carbonate, magnesium carbonate, etc.), alkali metal bicarbonate
(e.g., sodium bicarbonate, potassium bicarbonate, etc.) or the
like, or organic base (e.g., triethylamine, pyridine, dimethyl-
aniline, etc.).
The reaction temperature is not limitative, and the
reaction is preferably carried out under cooling or around
room temperature.
In this process, the compound (II'), may be isolated
from the reaction mixture, and also the reaction mixture per se
can be preferably employed for the successive reaction with
the compound (III) without isolating the compound (II').
Among the carbonic acid ester of the formula (I) and
the haloformic acid ester of the formula (II), known compound
also can be prepared according to substantially the same method
as mentioned in the explanation of the processes for preparing
the new carbonic acid ester (I'),and the new haloformic acid
ester of the formula (II'), respectively.
The following examples are given for the purpose of
illustrating the present invention:
Example 1 [Process for the protection of amino and/or imino
group(s)]
(A) Triethylamine (0.42 ml.) was added to a suspension of
D-2-(3-mesylaminophenyl)glycine (488 mg.) and diethyl 2-tert-
butoxycarbonyloxyiminomalonate (770 mg.) in a mixture of tert-
butyl alcohol (10 ml.) and water (10 ml.), and the mixture was
stirred for 1.5 hours at room temperature. To the reaction
mixture were added water and a sodium bicarbonate aqueous solu-
tion, and then ethyl acetate, after which the mixture was
adjusted to pH 7 with a citric acid aqueous solution. The
, ~ - 12 -
1058~98
aqueous layer was separated, washed with e~hyl acetate, adjusted
to pH 3.5 with a citric acid aqueous solution and extracted
with ethyl acetate. The extract was washed with water, dried
over magnesium sulfate and concentrated to give ~-tert-
butoxycarbonyl-D-2-(3-mesylaminophenyl)glycine (634 mg.).
[~]D= -96~ (methanol, C=l)
Nuclear Magnetic Resonance Spectrum ~(CD3)2SO, ~]
ppm 7.00 - 7,60 (5H, m)
5.11 (lH, d, J=8Hz)
3.00 (3H, s)
~ 0 (9H, s)
(B) D-2-(3-Mesylaminophenyl)glycine (2.44 g.) was suspended
a mixture of methanol:water (1:1) (volume ratio) (25 ml.)
and dissolved by adding triethylamine (2.1 ml.). To the
solution was dropwise added a solution of diethyl 2-tert-
butoxycarbonyloxyiminomalonate (3~47 g.) in methanol (15 ml.)
over 10 minutes at 10 to 15C, and the mixture was stirred for
2 hours at room temperature. The solvent was distilled off
under reduced pressure to about 1/3 of the whole volume from
the reaction mixture and to the residue were added water (30 ml.)
and a saturated sodium bicarbonate aqueous solution (10 ml.).
Ethyl acetate (40 ml.) and 0.5N hydrochloric acid (26 ml.) were
added to the mixture and then the mixture was shaken. The
aqueous layer was separated and ethyl acetate (100 ml.) was
added thereto, after which the mixture was adjusted to pH 7.20
with 0.5~ hydrochloric acid (12 ml.). The aqueous layer was
again separated, adjusted to pH 2.6 with 0.5~ hydrochloric
acid (27 ml.), followed by addition of-`a saturated sodium
chloride aqueous solution, and extracted twice with ethyl
acetate (150 ml.). The extract was washed with a saturated
sodium chloride aqueous solution, dried over magnesium sulfate
D; 13
.. ,.., ~ ~
1058198
and treated with activated charcoal, and the solvent was
distilled off under reduced pressure to give ~-tert-butoxycar-
bonyl-D-2-(3-mesylaminophenyl)glycine (3.50 g.).
(C) A solution of diethyl 2-tert-butoxycarbonyloxyimino-
malonate (700 mg.) in acetone (5 ml.) was dropwise added to a
solution of D-2-(3-mesylaminophenyl)glycine (488 mg.) and
triethylamine (0.42 ml) in a mixture of acetone (5 ml.) and
water (5 ml.) over 5 minutes at room temperature, and the
mixture was stirred for 2 hours at the same temperature. The
reaction mixture was concentrated under reduced pressure and to
the residue were added a sodium bicarbonate aqueous solution and
water, which brought pH of the solution to 9 to 10. The solution
was adjusted to pH 7 with a 0.5M citric acid aqueous solution
and washed with ethyl acetate. This aqueous solution was
adjusted to pH 3.5 with a 0.5M citric acid aqueous solution and
extracted twice with ethyl acetate (30 ml.). ~he extract was
washed with a sodium chloride aqueous solution and dried over
magnesium sulfate, and the solvent was distilled off under
reduced pressure to give ~-tert-butoxycarbonyl-D-2-(3-mesyl-
aminophenyl)glycine (672 mg.) gummy.
(D) A solution of diethyl 2-tert-butoxycarbonyloxy-
iminomalonate (1.9 g.) in tert-butyl alcohol (5 ml.) was added
to a solutlon of L-isoleucine (656 mg.) in a lN sodium hydroxide
aqueous solution (5.0 ml.), and the mixture was stirred for 3
hours at room temperature. tert-Butyl alcohol was removed from
the reaction mixture under reduced pressure and water was added
to the residue. The mixture was washed with ether, adjusted to
pH 3 with a 5% citric acid aqueous solution and extracted with
ethyl acetate. The extract was washed with water, dried and
concentrated to give N-tert-butoxycarbonyl-L-isoleucine (1.2 g.)
oil.
~ - 14 -
1058198
(E) Diethyl 2-tert-butoxycarbonyloxyiminomalonate (1.93 g.)
was added to a solution of ~G-nitro-L-arginine (1.1 g.) and
sodium bicarbonate (0.63 g.) in a mixture of water (50 ml.) and
tert-butyl alcohol (20 ml.), and the mixture was stirred for 3
hours at room temperature. The reac~ion mixture was adjusted
to pH 7.0 with a citric acid aqueous solution, washed with ethyl
acetate, ad]usted to pH 3 with a citric acid aqueous solution and
extracted with ethyl acetate (100 ml.). The extract was washed
with water, dried over magnesium sulfate and concentrated under
reduced pressure. The residue was crystallized with a mixture
'of ethyl acetate and petroleum ether and the precipitates were
collected by filtration to give ~ -tert-butoxycarbonyl-~G-nitro-
L-arginine (1.1 g.), mp 114 to 116~C (dec.).
(F) L-Phenylalanine (330 mg.) and sodium bicarbonate (202
mg.) were dissolved in water (10 ml.) with heating and allowed
to stand. To the solution was added a solution of diethyl
2-(4-methoxybenzyloxycarbonyloxyimino)malonate (1.0 g.) in tert-
butyl alcohol (10 ml.) with stirring at room temperature and
water (10 ml.) was added thereto, after which the mixture was
stirred for 2 hours at room temperature. The reaction mixture
was brought to pH 9 by adding water (20 ml.) and a saturated
sodium bicarbonate aqueous solution (10 ml.), and water (10 ml.)
was added thereto, after which the mixture was washed twice with
ethyl acetate (20 ml.). The aqueous layer was adjusted to pH 7
with a 10% citric acid aqueous solution, washed twice with ethyl
acetate (30 ml.), adjusted to pH 3.5 with a l~/o citric acid
aqueous solution and extracted three times with ethyl acetate
(30 ml.). The extract was washed with a sodium chloride aqueous
solution and dried over magnesium sulfate, and the solvent was
distilled off under reduced pressure to give ~-~4-methoxybenzyl-
oxycarbonyl)-L-phenylalanine (410 mg.), oil.
~, - 15 -
~, ...i .~ .
~058198
(G) A solution of ethyl 2-tert-butoxycarbonyloxyiminoaceto-
acetate (646 mg.) in a mixture o~ tert-butyl alcohol ~5 ml . ) and
water (5 ml.) was added at once to a solution of L-phenylalanine
(330 mg,) and triethylamine (0.28 ml.) in a mixture of tert-
butyl alcohol (8 ml.) and water (8 ml.) at room temperature,
and the mixture was stirred for 2 hours at room temperature.
Water (100 ml.) was added to the reaction mixture and the
mixture was adjusted to pH 7 with a 0.5M citric acid aqueous
solution and washed twice with ethyl acetate (40 ml.) The
aqueous layer was adjusted to pH 3 with a 0. SM citric acid
aqueous solution, followed by addition of a sodium chloride
aqueous solution, and extracted twice with ethyl acetate (40 ml.).
The extract was washed with water and dried, and the solvent
was distilled off under reduced pressure to give N-tert-butoxy-
carbonyl-L-phenylalanine (286 mg.).
(H) Triethylamine (1.68 ml.) was added to a suspen.sion of
L-alanine (0.89 g.) in a mixture of water (5 ml.) and tert-
butyl alcohol (5 ml.) to give homogeneous solution. To the
solution was added diethyl 2-tert-butoxycarbonyloxyiminomalonate
(4.0 g.) and the mixture was stirred for 1 hour at room tempera-
ture. tert-Butyl alcohol was distilled bff from the reaction
mixture under reduced pressure and to the residue were added
ether and a 5% sodium bicarbonate aqueous solution, after which
the mixture was adjusted to pH 7 with a citric acid aqueous
solution. The aqueous layer was separated and ethyl acetate was
added thereto, and the mixture was adjusted to pH 3 with a citric
acid aqueous solution. The mixture was shaken enough and the
ethyl acetate layer was separated, washed with water and dried.
The solution was concentrated under reduced pressure and the
residue was recrystallized from a mixture of ether and petroleum
ether to give N-tert-butoxycarbonyl-L-alanine (1.59 g.),
- 16 ~
L~,
1~)5~3i98
mp 82 to 84~C.
(I) A suspension of l-tert-butoxycarbonyloxy-6-chloro-lH-
benzotriazole (2.7 g.), L-isoleucine (1.3 g) and triethylamine
(3.5 ml.) in a mixture of water (8 ml.) and tert-butyl alcohol
(12 ml.) was stirred for 2 hours at 60 to 62UC. tert-Butyl
alcohol was distilled off from the reaction mixture under
reduced pressure and water (15 ml.) was added to the residue.
The mixture was adjusted to pH 3 with a citric acid aqueous
solution under ice-cooling and extracted with ethyl acetate.
The extract was in turn washed with water and a saturated
Qodium chloride aqueous solution, and then precipitates were
filtered off, after which the filtrate was dried over magnesium
sulfate. The solution was concentrated and to the residue was
added a mixture of ether and petroleum ether (1 1). An insoluble
material was filtered off and the filtrate wa~ concentrated
under reduced pressure to give N-tert-butoxycarbonyl-L-
isoleucine (2.4 g.), oil.
Infrared Absorpotion Spectrum (Film)
2980, 1725 (~houlder), 1710, 1165 cm 1
(J) A solution of diethyl 2-tert-butoxycarbonyloxyimino-
malonate (4.5 g.) in tert-butyl alcohol (40 ml.) was added at
once to a solution of D-2-(3-dime~ylaminophenyl)glycine (3.22 g.
and sodium bicarbonate (1.26 g.) in a mixture of tert-butyl
alcohol (80 ml.) and water (120 ml.) under ice-cooling and
stirring. After stirring for 1.5 hours at room temperature,
an insoluble ~aterial was filtered off. The filtrate was
adjusted to pH 7.5 with a 0.2M citric acid aqueous solution and
tert-butyl alcohol was distilled off under reduced pressure.
The residue was washed with ether and adjusted to pH 3 with a
0.2M citric acid aqueous sol~tion. The aqueous solution was
~ 17 -
;~
~, .. ...
lOS8~98
saturated with sodium chloride and extracted with ethyl acetate.
The extract was washed with a saturated sodium chloride aqueous
solution and dried, and the solvent was distilled off under
reduced pressure to give N-tert-butoxycarbonyl-D-2(3-dimesyl-
aminophenyl)glycine (2.1 g.), foamy solid.
Nuclear Magnetic Resonance Spectrum ~(CD3)2SO, ~]
ppm 7.50 (4H, m)
5.20 (lH, d)
3.33 (6H, s)
1.40 (9H, s)
(K) N-tert-Butoxycarbonyl-L-phenylalanine was obtained
according to a similar manner to that of Example 1 (G) by
using L-phenyIalanine and 2-tert-butoxycarbonyloxyimino-1-
phenylbutane-1,3-dione.
(L) N-Benzyloxycarbonyl-L-phenylalanine was obtained
according to a similar manner to that of Example 1 (G) by using
L-phenylalanine and ethyl 2-benzyloxycarbonyloxyimino-2-
cyanoacetate.
(M) 6-Benzyloxycarbonylaminopenicillanic acid was obtained
according to a similar manner to that of Example 1 (G) by using
6-aminopenicillanic acid and ethyl 2-benzyloxycarbonyloxyimino-
2-cyanoacetate.
(N) 2-(4-Methoxybenzyl)oxycarbonyloxyimino-2-phenylaceto-
nitrile (1.55 g.) was added to a solution of L-phenylalanine
(826 mg.) and triethylamine (0~75 ml.) in a mixture of methanol
(10 ml.), dioxane (1.5 ml.) and water (7.5 ml.) at room tempera-
ture, and the mixture was stirred for 2 hours at room temperature.
The reaction mixture was concentrated, and to the residue were
added benzene and a sodium bicarbonate aqueous solution. After
shaking the resultant mixture, the aqueous layer was separated
D 18 -
1058~98
from the mixture, washed with ether, acidified with hydrochloric
acid and extracted with ethyl acetate. The extract was washed
with water, dried and concentrated. To the residue was added
n-hexane, and the precipitated crystals were collected by
filtration and dried to give N-(4-methoxybenzyl)oxycarbonyl-L-
phenylalanine (1.064 g.), mp 87 to 88C.
(o) 2-tert-Butoxycarbonyloxyimino-2-phenylacetonitrile
(1.25 g.) was added to a solution of L-proline (575 mg.) and
triethylamine (0.7 mI.) in a mixt;ure of methanol (7.5 ml.),
dioxane (2.5 ml.) and water (5.0 ml.) at room temperature, and
the mixture was stirred for 1.5 hours at room temperature. The
reaction mixture was concentrated under reduced pressure, and to
the residue were added benzene and water. After shaking the
resultant mixture, the aqueous layer was separated from the
mixture, washed with benzene, acidified with hydrochloric acid,
and extracted with ethyl acetate. The extract was washed with
water, dried over magnesium sulfate and concentrated. To the
residue was added a mixture of ether and n-hexane and the
precipitated crystals were collected by filtration and dried to
give N-tert-butoxycarbonyl-L-proline (845 mg.), mp 133 to 134~C.
(P) According to a similar manner to that of Example 1
(0), N-tert-butoxycarbonyl-L-leucine hemihydrate (899 mg.), mp
78 to 84~C, was obtained by using L-leucine (656 mg.) and 2-tert-
butoxycarbonyloxyimino-2-phenylacetonitrile (1.35 g.) as starting
materials.
(Q) According to a similar manner to that of Example I (O),
- ~-tert-butoxycarbonyl-L-methionine dicyclohexylamine salt (1.768
. . .
g.), mp 137 to 139C, was obtained by using L-methionine (746 mg.)
and 2-tert-butoxycarbonyloxyimino-2~phenylacetonitrile (1.35 g.)
as starting materials.
-- 19 --
D 1
105819~3 .
(R) According to a similar manner to that of Example 1 (0),
~-tert~butoxycarbonyl-L-phenylalanine dicyclohexylamine salt
(1.463 g.), mp 222 to 223~C ~dec.), was obtained by using
L-phenylalanine (826 mg.) and 2-tert-butoxycarbonyloxyimino-2-
~henylacetonitrile (1.25 g.) as starting materials.
(S) According to a similar manner to that of Example 1 (O),
~-tert-butoxycarbonyl-L-asparagine (918 mg.), mp 166 to 167~C
(dec.), was obtained by using L-asparagine hydrate (0.75 g.) and
2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (1.85 g.) as
starting materials. ~~
(T) According to a similar manner to that of Example 1 (0),
N -tert-butoxycarbonyl-~G-nitro-L-arginine (2.56 g.), mp 123 to
125~C, was obtained by using NG-nitro-L-arginine (2.20 g.) and
2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (2.71 g.) as
starting materials.
(U) According to a similar manner to that of Example 1 (0),
N-tert-butoxycarbonyl-L-threonine dicyclohexylamine salt (5.50 g.),
mp 152 to 153UC, was obtained by using L-threonine (2.4 g,) and
2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (5.4 g.) as
starting materials.
(V) According to a similar manner to that of Example l(O),
~-tert-butoxycarbonylglycine (1.523 g.), mp 86.5 to 87.5~C, was
obtained by using glycine (0.75 g.) and 2-tert-butoxycarbonyloxy-
imino-2-phenylacetonitrile (2.71 g.) as starting materials.
(W) In the similar manner as described in the foregoing
Examples 1 (A) to 1 (V), the process for the protection of amino
and/or imino group(s) is carried out by using the following
various carbonic acid esters, which give the similar results.
(1) 2-Ethoxycarbonyloxyimino-2-cyanoacetamide, mp 194 to 196~C.
(2) Diethyl 2-ethoxycarbonyloxyiminomalonate, oil.
-1 - 20 -
.~ .1
~,j_,.1
~, . . .
1058198
(3) Ethyl 2-ethoxycarbonyloxyimino-2-cyanoacetate, oil.
(4) 2-Isobutoxycarbonyloxyimino-2-cyanoacetamide~ mp 156 to
158UC.
(5) Ethyl 2-isobutoxycarbonyloxyimino-2-cyanoacetate, mp 60 to
62~C.
t6) 2-Methoxycarbonyloxyimi-no-2-cyanoacetamide, mp 174 to 175C
(dec.).
(7) Ethyl 2-methoxycarbonyloxyimino-2-cyanoacetate, mp 69 to
71C.
(8) Ethyl 2-(2,2,2-trichloroethoxycarbonyloxyimino)-2-cyano-
acetate, mp 51 to 53~C.
(9) Ethyl 2-tert-pentyloxycarbonyloxyimino-2-cyanoacetate, oil.
Infrared Absorption Spectrum
1810, 1740 cm L
~10) 1-Ethoxycarbonyloxy-6-chloro-lH-benzotriazole, mp 160 to
162~C.
(11) l-Benzyloxycarbonyloxy-lH-benzotriazole, mp 130 to l31~C.
(12) Benzophenone 0-tert-butoxycarbonyloxime, mp 131 to 133~C.
(13) 2-tert-Butoxycarbonyloxyimino-2-(4-chlorophenyl)acetonitrile,
mp 91 to 92C.
(14) 2-Benzyloxycarbonyloxyimino-2-phenylacetonitrile, mp 73 to
75UC
(15) 2-tert-Butoxycarbonyloxyimino-2-(1-naphthyl)acetonitrile,
mp 90 to 92~C.
(16) 2-(1-Cyclopropylethoxycarbonyloxyimino)-2-phenylacetonitrile,
mp 65 to 67UC.
(17) 2-(2,2,2-Trichloroethoxycarbonyloxyimino')-2-phenylaceto-
nitrile, mp 82 to 84UC.
Example 2 [Preparation of carbonic acid esters]
(A) Benzene (20 ml.) was added to a solution of phosgene
r ~ 21 -
~'
105~98
(2.5 g.) in benzene (11.4 ml.). To the solution was dropwise
added a solution of diethyl 2-hydroxyiminomalonate (4.73 g.) and
N,N-dimethylaniline (3.03 g,.) in benzene (30 ml.) over 40
minutes at 5~C in nitrogen stream. The mixture was stirred for
1 hour at the same temperature and overnight at room temperature.
To the resultant mixture containing diethyl 2-chlorocarbonyloxy-
iminomalonate was dropwise added a solution of 4-methoxybenzyl
alcohol (3.11 g.) and pyridine (4.04 ml.) in benzene (30 ml.)
over 40 minutes at 5VC. The mixture was stirred for 2 hours at
the same temperature, for 3 hours at room temperature and
allowed to stand overnight. Cold water (100 ml.) was added to
the reaction mixture to dissolve an insoluble material and
cooled lN-hydrochloric acid (20 ml.) was added thereto, after
which the mixture was shaken. The organic layer was in turn
washed 3 times with lN hydrochioric acid (20 ml.), 3 times
with a 5% sodium carbonate aqueous solution (20 ml.) and a
sodium chloride aqueous solution, and then dried over magnesium
sulfate. After drying the solvent was distilled off to give di-
ethyl 2-(4-methoxybenzyloxycarbonyloxyimino)malonate (6.89 g.),
pale brown oil, which was solidified on standing at ambient
temperature.
Nuclear Magnetic Resonance Spectrum (CCe4, ~)
ppm 6.88 7.38 (4H, ABq, J=9.0 Hz)
5,23 (2H, s)
4.39 (4H, q, J=7.1 Hz)
3.80 (3H, s)
1.37 (3H, t, J=7.1 Hz)
1.33 (3H, t, J=7.1 Hz)
(B) A solution of ethyl 2-hydroxyiminoacetoacetate (3.98 g.)
and pyridine (1.98 g.) in benzene (25 ml.) was dropwise added to
a solution of phosgene (2.48 g.) in benzene (30 ml.) over 30
- 22 -
. ~ , ~ , .
11)58~98
minutes at 4 to 5UC. After stirring for 1 hour at the same
temperature, the mixture was stirred for 1 hour at room tempera-
ture and allowed to stand overnight. To the resultant solution
containing ethyl 2-chlorocarbonyloxyiminoacetoacetate was drop-
wise added, over 30 minutes at 5 to 7~C, a solution of tert-
butyl alcohol (3.7 g.) and pyridine (3.96 g.) in benzene (25 ml.).
After stirring for 1 hour at the same temperature, the reaction
temperature was slowly elevated to room temperature, after which
the mixture was stirred for 6 hours at the same temperature and
allowed to stand overnight. A precipitate was dissolved by
adding about same volume of water to that of the organic layer
to the reaction mixture, after which the aqueous layer was
separated. The organic layer was in turn washed with a 0.5M
citric acid aqueous ~olution, a 5% sodium carbonate aqueous
solution and a sodium chloride aqueous solution, and dried over
magnesium sulfate. After drying the solvent was distilled off
to give ethyl 2-tert-butoxycarbonyloxyiminoacetoacetate (3.7 g.),
oil.
Infrared Absorption Spectrum (Film)
1780, 1730, 1690 cm~
~uclear Magnetic Resonance Spectrum (CCe4, 6
ppm 4.34 (3H, q)
2.48 (3H, s)
1.57 (9H, s)
1.37 (3H, t)
(C) A solution of 2-hydroxyimino-1-phenylbutane-1,3-dione
; - (3.82 g.) and pyridine (1.62 ml.) in benzene (30 ml.) was drop-
wise added to a solution of phosgene (1.98 g.) in benzene (25 mL)
over 40 minutes at 5 to 9~C. After stirring for 1 hour at the
same temperature, the mixture was allowed to stand overnight.
~,`
. . .
lOS8198
To the resultant solution containing 2-chlorocarbonyloxyimino-1-
phenylbutane-1,3-dione was dropwise added, over 30 minutes at
5UC, a solution of tert-butyl alcohol (2.96 g.) and pyridine
(3.16 g.) in benzene (30 ml.). After stirring for 1 hour at the
same temperature, the mixture was stirred for 6 hours at room
temperature, after which the mixture was allowed to stand over-
night. Cooled water (100 ml.) was added to the reaction mixture,
and the organic layer was in turn washed with water, a 0.5M
citric acid aqueous solution (20 ml.) (4 times) and a 5% sodium
carbonate aqueous solution (20 ml.) (4 times) until the aqueous
layer became almost colorless, and further washed with a sodium
chloride aqueous solution and then dried over magnesium sulfate.
After drying, the solution was treated with activated charcoal
and the solvent was distilled off to give oil (3.48 g.). The
oil was partly crystallized by allowing to ctand and to the
mixture was added ether to precipitate crystals. The precipitates
were collected by filtration and recrystallized from a mixed
solvent of carbon tetrachloride and petroleum ether to give 2-
tert-butoxycarbonyloxyimino-l-phenylbutane-1,3-dione (350 mg.),
mp 90 to 103~C (dec.~.
Infrared Absorption Spectrum (Nujol)
1785, 1700, 1680 cm~
Analysis : C15H17~ 5
Calcd. : C 61.85, H 5.88, N 4.81
Found : C 62.00, H 5.92, N 4.98
(D) A solution o~ phosgene (5 g.) in benzene (23.5 ml.)
was dropwise added under ice-cooling to a suspension of l-hydroxy-
6-chloro-lH-benzotriazole (8.5 g.) and pyridine (3.9 g.) in
benzene (50 ml.), and the mixture was stirred for 30 minutes at
the same temperature and allowed to stand overnight. To the
- 24 -
~1
....,i
lOS8198
resultant solution containing l-chlorocarbonyloxy-6-chloro-lH-
benzotriazole was dropwise added, over 20 minutes under ice-
cooling, a solution of tert-butyl alcohol (3.7 g.) and pyridine
(4.0 g.) in benzene (-50 ml.). The resultant mixture was stirred
for 2 hours at the same temperature and allowed to stand over-
night.
The reaction mixture was filtered, and the filtrate
was concentrated. Ether and petroleum ether were added to the
residue to pulverize the residue and obtained crystals were
collected by filtration to give 1-tert-butoxycarbonyloxy-6-
chloro-lH-benzotriazole (5.3 g.). The mother liquor was
concentrated to give the same object compound (0.6 g.). Both
crystals were put together and dissolved in benzene, after
which the solution was washed with a sodium bicarbonate aqueous
solution and water and then dried. The solvent was removed by
distillation to give the object compound (3.2 g.), powder,
mp 98 to lOO~C (dec.).
Analygi8 : CllH12N303C~
Calcd. : C 48.98, H 4.48, ~ 15.58, C~ 13.14
Found : C 49.25, H 4.32, N 15.88, C~ 13.36
(E) A solution of 2~hydroxyimino-2-phenylacetonitrile
(7.3 g.) and dimethylaniline (6.0 g.) in a mixture of benzene
(50 ml) and dioxane (5 ml.) was dropwise added to a solution of
phosgene (5.5 g.) in benzene (50 ml.) over 1 hour at 3 to 5~C,
and the mixture was stirred for 3.5 hours at the same temperature
and allowed to stand overnight. To the resultantsolution
containing 2-chlorocarbonyloxyimino-2-phenylacetonitrile was
dropwise added, over 1 hour un~der ice-cooling, a solution of
tert-butyl alcohol (7.4 g.) and pyridine (5.0 ml.) in benzene
(20 ml.). The resultant mixture was stirred for 4 hours at
.~.
1058198
the same temperature, and pyridine (3.0 ml.) was dropwise added
thereto, after which the mixture was stirred for 1 hour at
room temperature and allowed to stand overnight. Water was
added thereto and the organic layer was separated. The organic
layer was in turn washed with lN hydrochloric acid (3 tlmes),
a sodium chloride aqueous solution, a sodium bicarbonate aqueous
solution (twice) and a sodium chloride aqueous solution (twice)
and concentrated. The residue was allowed to stand to give
crystals. The crystals were triturated in aqueous methanol,
collected by filtration, washed with n-hexane and dried to give
2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (7.0 g.),
mp 84 to 86UC.
Infrared Absorption Spectrum (Nujol)
1785 cm 1
Nuclear Magnetic Resonance Spectrum (CDCe3, ~)
ppm 7.3 - 8.1 (5H, m)
1.60 (9H, s)
Analysis : C13H143~2
Calcd. : C 63.40, H 5.73, N 11.38
Found : C 63.69, H 5.71, N 11.20
(F) A solution of 2-hydroxyimino-2-phenylacetonitrile
(7.3 g), dimethylaniline (6.0 g.) and tert-butyl alcohol (3.7 g.)
in benzene (50 ml.) was dropwise added to a solution of phosgene
(5.0 g.) in benzene (50 ml.~ over 30 minutes under ice-cooling.
To the mixture was dropwise added a solution of pyridine (4.0 ml.)
in benzene (20 ml.) and the mixture was stirred for 1 hour at
- the same temperature and allowed to stand overnight. Water and
benzene were added to the reaction mixture and an insoluble
material was filtered off. The organic layer was in turn washed
with lN hydrochloric acid, water, a sodium bicarbonate aqueous
- 26 -
,~,
lOS8198
solution and water, and dried over magnesium sulfate. The
solvent was distilled of~ and to the residue were added n-hexane
and a small amount of methanol. An insoluble material was
filtered off and the filtrate was concentrated. Methanol was
added to the residue and the mixture was allowed to stand. The
precipitates were collected by filtration to give 2-tert-butoxy-
carbonyloxyimino-2-phenylacetonitrile (3.5 g.). Mp 83 to 85UC.
Water was added to the mother liquor and the mixture was allowed
to stand. The precipitates were collected by filtration to give
the object compound (1.5 g.). Total yield (5.0 g.).
(G) A solution of 2-hydroxyimino-2-phenylacetonitrile (14.6
g.) and dimethylaniline (13.2 g.) in a mixture of acetone (5 ml.)
and benzene (80 ml.) was dropwise added to a solution of
trichloromethyl chloroformate (phosgene dimer) (6.7 ml.) in
benzene (30 ml.) under ice-cooling. The mixture was stirred
for 6 hours at the same temperature and allowed to stand over-
night. To the resultant mixture containing 2-chlorocarbonyloxy-
imino-2-phenylacetonitrile was dropwise added a mixture of tert-
butyl alcohol ~;11.1 g.), pyridine (16.0 ml.) and benzene (20 ml.)
under ice-cooling, and the mixture was stirred for 7 hours at
room temperature and allowed to stand overnight. The reaction
mixture was treated as described in the above Examples 2(A) to
2(F) to give 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile
(17.0 g.), mp 84 to 86~C.
(H) A solution of dimethyIaniline (6.0 ml.) in benzene
(15nml.) was dropwise added to a suspension of 2-hydroxyimino-2-
phenylacetonitrile (7.3 g.) and phosgene (5.0 g.) in benzene
(50 ml.) over 40 minutes under ice-cooling. The mixture was
stirred for 2 hours at the same temperature and allowed to stand
overnight. To the mixture containing 2-chlorocarbonyloxyimino-
- 27 -
-
1058198
2-phenylacetonitrile was dropwise added a solution of 4-methoxy-
benzyl alcohol (6.9 g.) and pyridine (4.0 ml,) in benzene (20 ml.)
over 30 minutes under ice-cooling, and the mixture was stirred
for 7 hours at room temperature. The reaction mixture was in
turn washed with water, lN hydrochloric acid, water, a sodium
bicarbonate aqueous solution and water, and dried over magnesium
sulfate. The solution was concentrated, and the residual
crystals were triturated in n-hexane and collected by filtration.
The crystals were recrystallized from a mixture of ethyl acetate
and n-hexane to give 2-(4-methoxybenzyl)oxycarbonyloxyimino-2-
phenylacetonitrile (3.1 g.). Mp 112 to 113C. The mother
liquor was concentrated to give the object compound (2.4 g,),
Total Yield (5.5 g.),
Infrared Absorption Spectrum (Nujol)
1785 cm 1
Nuclear Magnetic Resonance Spectrum (CDCe3, ~)
. .,
ppm 6.8 - 8.0 (9H, m)
5.30 (2H,-s)
3,80 (3H, s)
Analysis : C17H~4O4N2
Calcd. : C 65.79, H 4~54, N 9.03
Found : C 65.99, H 4.38, N 9.03
(I) A solution of 2-hydroxyimino-2-phenylacetonitrile
(14.6 g.) and dimethylaniline (13.2 g.) in a mixture of benzene
(80 ml.) and dioxane (8 ml.) was dropwise added to a solution
of trichloromethyl chloroformate (phosgene dimer) (11 g.) in
benzene (50 ml,~ under ice-cooling, and the mixture was stirred
for 3 hours at the same temperature and allowed to stand over-
night. To the mixture containing 2-chlorocarbonyloxyimino-2-
phenylacetonitrile was dropwise added a solution of tert-
- 28 -
'~
.. ~
~058~98
butyl alcohol (14.8 g.) and pyridine (16.0 ml.) in benzene
(20 ml.) under ice-cooling. The reaction mixture was stirred
for 6 hours together with gradual elevation of the reaction
temperature to room temperature and allowed to stand overnight.
Water was added to the reaction mixture, and the organic layer
was separated. The organic layer was in turn washed with lN
hydrochloric acid, a sodium chloride aqueous solution, a sodium
bicarbonate a~ueous solution and water and then dried. The
solvent was distilled off,-and methanol was added to the residue.
The mixture was cooled by ice-w,ater, and the precipitates were
collected by filtration and washed with a small amount of cooled
methanol to give 2-tert-butoxycarbonyloxyimino-2-phenylaceto-
nitrile (9.5 g.). From the mother liquor the object compound
(9.4 g.) was further obtained. ~oth of the object compounds
obtained above were combined and recrystallized from methanol to
give the pure compound (14.6 g.), mp 84 to 86UC.
(J) A solution of benzophenone oxime (9.85 g.) and dimethyl-
aniline (6.6 g.) in a mixture of benzene (50 ml.) and dioxane
(10 ml.) was dropwise added to a solution of trichloromethyl
chloroformate (phosgene dimer) (5.5 g.) in benzene (15 ml.) under
ice-cooling, and the mixture was stirred for 1 hour at the same
temperature, for 2 hours at room temperature and allowed to stand
overnight. To the resultant mixture containing benzophenone
0-chlorocarbonyloximine was dropwise added a solution tert-butyl
alcohol (5.6 g.) and pyridine (6.0 ml.) in benzene (20 ml.) under
ice-cooling, and the mixture was stirred for 6 hours at the same
te~perature and allowed to stand overnight. The reaction mixture
was in turn washed with water, lN hydrochloric acid, water, a
sodium bicarbonate aqueous solution and water, and dried over
magnesium sulfate. The solvent was distilled off and to the
resulting crystals was added petroleum ether. The crystals
- 29 -
~ .
~, .
1(~58198
were collected by filtration and dried to give benzophenone 0-
tert-butoxycarbonyloxime ~10.5 g.), mp 126 to 133UC. A small
amount of the crystals was recrystallized from a mixture of
toluene and petroleum ether to give pure compound, mp 131 to
133~C.
Infrared Absorption Spectrum (Nujol)
1770 cm 1
Nuclear Magnetic Resonance Spectrum (CDC~3, ~)
ppm 7.17 - 7.65 (lOH, m)
1.48 (9H, s)
(K) A suspension of 2-hydroxyimino-2-(4-chlorophenyl)aceto-
nitrile (6.75 g.) and dimethylaniline (4.5 g.) in a mixture of
dichloromethane (70 ml.), dioxane (10 ml.) and tetrahydrofuran
(10 ml,) wa~ dropwise added to a solution of trichloromethyl
chloroformate (phosgenedimer) (16 g.) in benzene(`22 ml.) under
ice-cooling, and the mixture was stirred for S hours at the same
temperature and allowed to stand overnight. To the resultant
mixture containing 2-chlorocarbonyloxyimino-2-(4-chlorophenyl)-
acetonitrile was dropwise added a solution of tert-butyl alcohol
(8.9 g.) and pyridine (9.6 ml.) in dichloromethane (20 ml.) under
ice-cooling, and the mixture was stirred for 5 hours at the same
temperature and allowed to stand for 48 hours. The reaction
mixture was in turn washed with water, lN hydrochloric acid, water,
water, a sodium bicarbonate aqueous solution and water, and dried
over magnesium sulfate. The solvent was distilled off and n-
hexane was added to the residue. An insoluble material was
filtered off and the filtrate was concentrated. To the residue
was added petroleum ether and the mixture was allowed to stand
to precipitate crystals. The crystals were dissolved in hot
petroleum ether and the solution was filtered. The filtrate
~ ~ - 30 -
-
-
1058198
was cooled to precipitate crystals and the crystals were
collected by filtration to give 2-tert-butoxycarbonyloxyimino-2-
(4-chlorophenyl)acetonitrile (1.6 g.). These crystals were
recrystallized from methanol to give the pure compound (0~7 g.),
mp 91 to 92UC.
Infrared Absorption Spectrum (Nujol)
1790 cm~l
~uclear Magnetic Resonance Spectrum (CDC~3, ~)
ppm 7.90 (2H, ABq, J=4.5Hz)
7.50 (2H, ABq, J=4.5Hz)
1.63 (9H, s)
(L)
(1~ Preparation of the starting compound:
2-(1-naphthyl)acetonitrile (16.7 g.) was added to a
solution of sodium hydroxide (4.2 g.) in methanol (80 ml.), To
the mixture was introduced under ice-cooling gaseous methyl
nitrite which was prepared by adding a solution of conc sulfuric
acid t5 ml.) in water (10 ml.) to a solution of sodium nitrite
(8 J 3 g.) in a mixture of methanol (5,5 ml,) and water (5 ml.).
The mixture was stirred for 4 hours at the same temperature
and the reaction mixture was treated by conventional method to
give 2-hydroxyimino-2-(1-naphthyl)acetonitrile (7.1 g.), oil.
Infrared Absorption Spectrum (Film) ~
1700 cm~l
(2) Preparation of the object compound:
A solution of 2-hydroxyimino-2-(1-naphthyl)acetonitrile
(7.0 g.) and dimethylaniline (12.0 g,) in toluene ~100 ml.) was
dropwise added under ice-cooling to a solution of trichloromethyl
chloroformate (phosgene dimer) (3.56 g.~ in benzene (30 ml.).
The mixture was stirred for 3 hours at the same temperature and
~ l - 31 -
lOSt~198
allowed to stand overnight. To the resultant mixture containing
2-chlorocarbonyloxyimino-2-(1-naphthyl)acetonitrile was dropwise
added a solution of tert-butyl alcohol (11.1 g.) and pyridine
~12 ml.) in toluene (20 ml.) under ice-cooling, and the mixture
~as stirred for 6 hou~s at the same temperature and allowed to
stand overnight. The reaction mixture was in turn washed with
water, lN hydrochloric acid, water, a sodium bicarbonate aqueous
solution and water, and dried over magnesium sulfate. The
solution was concentrated under reduced pressure and to the
residue were added n-hexane and methanol. The mixture was
allowed to stand in a refrigerator, and the precipitated crystals
were collected by filtration and recrystallized twice from
methanol to give 2-tert-butoxycarbonyloxyimino-2-(1-naphthyl)-
acetonitrile (3.3 g.), mp 90 to 92UC.
Analy9is : C17H163N2'
Calcd. : C 68.90, H 5.44, N 9.46
Found : C 68.85, H 5.38, N 9.40
Infrared Absorption Spectrum (Nujol)
1790 cm 1
(M) A solution of 2-hydroxyimino-2-phenylacetonitrile
(2.2 g.) and dimethylaniline (1.80 g.) in a mixture of benzene
(25 ml.) and dioxane (3 ml.) was dropwise added to a solution of
trichloromethyl chloroformate (phosgene dimer) (1.5 g.) in ben-
zene (20 ml.) under ice-cooling. The mixture was stirred for
3 hours at the same temperature and allowed to stand overnight.
To the resultant mixture containing 2-chlorocarbonyloxyimino-2-
phenylacetonitrile was dropwise add~d a solution of l-cyclo-
propylethanol (1.4 g.) and pyridine (1.2 ml.) in benzene (lO ml.)
under ice-cooling. The mixture was stirred for 2 hours at the
same temperature, for 4 hours at room temperature and allowed
r~
- 32 _
.... . . .
lV58~98
to stand overnight. The reaction mixture was in turn washed ~
with lN hydrochloric acid, water, a sodium bicarbonate aqueous
solution and water, and dried over magnesium sulfate. The
solvent was distilled off and to the oily residue was added a
small amount of methanol. The mixture was allowed to stand in
a refrigerator, and the precipitated crystals were collected
by filtration and recrystallized from methanol to give 2-
(l-cyclopropylethoxycarbonyloxyimino)-2-phenylacetonitrile
(0.7 g;), mp 65 to 67~C.
Infrared Absorption Spectrum (Nujol)
1785 cm 1
Analysis : C14H143N2
Calcd. : C 65.ilO, H 5.46, N 10.85
Found : C 65.07, H 5.15, N 10.84
(N) The following compounds were obtained according to a
similar manner to those of Examples 2(A) to 2(M).
(1) 1-Ethoxycarbonyloxy-6-chloro-lH-benzotriazole, mp 160 to
162C.
(2) l-Benzyloxycarbonyloxy-lH-benzotriazole, mp 130 to 131C.
(3) 2-Benzyloxycarbonyloxyimino-2-phenylacetonitrile~ mp 73 to
75~CL
(4) 2-(2,2,2-Trichloroethoxycarbonyloxyimino)-2-phenylaceto-
nitrile, mp 82 to 84UC.
Example 3 ~Preparation of carbonic acid esters]
(A) Ether (10 ml.) was added to a solution of phosgene
(2 g.) in benzene (12.4 ml.). To the solution was dropwise
added a solution of 4-methoxybenzyl alcohol (2.76 g.) in ether
(10 ml.~ over 25 minutes at -10UC with stirring and paying
attention to exotherm. The mixture was stirred for 20 minutes
at -10 to -7C and phosgene was removed by introducing nitrogen
~ - 33 -
~, ',ib,
1058~98
stream for 15 minutes at the same temperature. To the resultant
solution containing 4-methoxybenzyl chloroformate was added a
solution of diethyl 2-hydroxyiminomalonate (3.78 g.) in benzene
(20 ml.) over 10 minutes and then was added a solution of
triethylamine (5.6 ml.) in benzene (20 ml.) over 30 minutes at
-7 to -2C. Benzene (20 ml.) was added thereto and the mixture
was stirred for 30 minutes at 5UC, for 1 hour at room temperature
and allowed to stand for 64 hours. Water was added to the
reaction mixture to dissolve an insoluble material and the
organic layer was in turn washed with water, 3 times with a
0.5M citric acid aqueous solution (20 ml.), 3 times with a 5%
sodium carbonate aqueous solution (20 ml.) and a sodium chloride
aqueous solution, and then dried over magnesium sulfate. After
drying the solvent was distilled off to give diethyl 2-(4-
methoxybenzyloxycarbonyloxyimino)malonate (5.62 g.), oil.
(B) A solution of ethyl chloroformate (2.17 g.) in benzene
(10 ml.) was dropwise added to a solution of 1-hydroxy-6-chloro-
lH-benzotriazole (3.38 g.) and triethylamine (2.80 ml.) in
benzene (30 ml.) under ice-cooling and stirring. Benzene (30 ml.)
was further added to the mixture and the reaction temperature
was slowly elevated to room temperature, and the mixture was
allowed to stand overnight. Precipitated crystals were filtered
off and the filtrate was concentrated. Benzene was added
to the residue and an insoluble material was filtered off, after
which the filtrate was concentrated to give l-ethoxycarbonyloxy-
6-chloro-lH-benzotriazole (2.2 g.), crystal. These crystals, the
precipitated crystals filtered off and the insoluble material in
~enzene were put together, in turn washed with water, a sodium
bicarbonate aqueous solution, 1~ hydrochloric acid and water, and
recrystallized from methanol (75 ml.) to give the object compound
- 34 -
r~
1058~98
(3.5 g.), white needles, mp 160 to I62C.
Analysis : CgH8N303C~
Calcd. : C 44.73, H 3.36, N 17.39, C~ 14.67
Found : C 44.71, H 3.25, ~ 17.34, C~ 14.72
(C) Benzyl chloroformate (8.5 g.) was dropwise added under
ice-cooling to a solution of l-hydroxy-lH-benzotriazole (6.8 g.
and triethylamine (7.0 ml.) in a mixture of benzene (100 ml.)
and water (50 ml.), and the mixture was stirred far 3 hours at
the same temperature. The reaction mixture was filtered and the
precipitated crystals were washed with water and dried. The
benzene iayer was washed with water, dried and concentrated.
The residue and the crystals above obtained were put together
and recrystallized from a mixed solvent of benzene and petroleum
ether to give l-benzyloxycarbonyloxy-lH-benzotriazole (12.1 g.),
mp 130 to 131~C.
Analysis : C14HllN303
Calcd. : C 62.44, H 4.12, ~ 15.61
Found : C 62.62, H 4.16, N 15.49
(D) A solution of benzyl chlbroformate (5.1 g.) in ether
(40 ml.) was added to a solution of 2-hydroxyimino-2-phenylaceto-
nitrile (4.4 g.) in a mixture of a lN potassium hydroxide
aqueous ~olution (30 ml.) and dioxane (10 ml.) under ice-cooling,
and the mixture was stirred for 1 hour at the same temperature
and for 4 hours at room temperature. The ether layer was
separated from the reaction mixture and the aqueous layer was
further extracted with ether. Both ether layers were combined,
washed with water and dried over magnesium sulfate. The solvent
was distilled off and to the residue was added n-hexane. The
precipitated crystals were collected by filtration to give 2-
benzyloxycarbonyloxylmino-2-phenylacetonitrile (5.2 g.), mp 73
to 75~C.
- 35 -
~'
1058~98
Infrared Absorption Spectrum (Nujol)
1795 cm 1
. . .
(E) A solution of 2,2,2~trichloroethyl chloroformate
(2.2 g.) in benzene (10 ml.) was dropwise added to a solution
of 2-hydroxyimino-2-phenylacetonitrile (l.S g.) and triethyl-
amine (1.40 ml.) in benzene (20 ml.) at room temperature, and
the mixture was stirred for 3 hours at the same temperature.
To the reaction mixture were added benzene and water, and the
organic layer was washed with water and dried over magnesium
sulfate. The solvent was distilled off and the residue was
crystallized by adding a small amount of ether and n-hexane.
The crystals were collected by filtration and recrystallized
from methanol to give 2-(2,2,2-trichloroethoxycarbonyloxyimino)-
2-phenylacetonitrile (2.7 g.), mp 82 to 84~C.
Infrared Absorption Spectrum (Nujol)
! 1800, 1790 cm~
Analysis CllH73N2C~3
Calcd. : C 41.08, H 2.19, ~ 8.71, C~ 33.08
Found : C 41.29, H 2.05, N 8.81j C~ 32.31
(F) The following compounds were obtained according to a
similar manner to those of Examples 3(A) to 3(E).
(1) Ethyl 2-tert-butoxycarbonyloxyiminoacetoacetate, oil.
~nfrared Absorption Spectrum (Film)
1780, 1730, 1690 cm 1
(2) 2-tert-Butoxycarbonyloxyimino-l-phenylbutane-1,3-dione, mp
90 to 103C (dec.).
(3) 1-tert-Butoxycarbonyloxy-6-chloro-lH-benzotriazole, mp 98
to lOOaC (dec.).
(4) 2-tert-Butoxycarbonyloxyimino-2-phenylacetonitrile, mp 84
to 86~C~
(5) 2-(4-Methoxybenzyloxycarbonyloxyimino)-2-phenylacetonitrile,
mp 112 to 113~C.
- 36 -
~J~
-
~058198
(6) Benzophenone O-tert-butoxycarbonyloxime, mp 131 to 133~C.
(7) 2-tert-Butoxycarbonyloxyimino-2-(4-chlorophenyl)acetonitrile,
mp 91 to 92~C.
(8) 2-tert-Butoxycarbonyloxyimino-2-(1-naphthyl)acetonitrile,
mp 90 to 92~C.
(9) 2-(1-Cyclopropylethoxycarbonyloxyimino)-2-phenylacetonitrile,
mp 65 to 67~C.
- 37 -
. . .
