CA1240991A - 3-amino-3-carbamoyloxyalkylacrylic acid derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

3-amino-3-carbamoyloxyalkylacrylic acid deriva-tives represented by the general formula:

(II) which are intermediates in the preparation of 2-carbamoyloxy-alkyl-1,4-dihydropyridine derivatives represented by the general formula:

(I) In the above formula R1 is halogen, cyano, nitro, hydroxyl, di-lower alkyl substituted amino or lower alkoxy, each of R2 and R3 is lower alkyl, haloalkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, hydroxyalkyl, lower alkoxy-alkyl, lower alkenyloxyalkyl, aralkyloxyalkyl, aryloxyalkyl or

Description

lZ4~991 The present invention relates to a process for prepariny 2-carbamoyloxyalkyl-1,4-dihydropyridine deriva-tives and particularly intermediates useful for the process.
More particularly, the present invention relates to a pro-cess for the preparation of 2-carbamoyloxyalkyl-1,4-dihydro-pyridine derivatives which have pharmacological activities, and novel 3-amino-3-carbamoyloxyalkylacrylic acid deriva-tives and 3-carbamoyloxyalkylpropiolic acid derivatives which are useful as intermediates for the preparation of the dihydropyridine derivatives.

This application is a divisional application of copending applicantion No. 434,005 filed August 5, 1983.

lS 2-Carbamoyloxyalkyl-1,4-dihydropyridine deriva-tives which have substituents with asymmetric structures at

2- and 6~positions of the dihydropyridine ring, are dis-closed in Japanese Unexamined Patent Publications No.
118,565/1982 and No. 175,166tl982 by the present inventors.
The dihydropyridine derivatives have coronary vasodilation activitles or hypotensive activities and are expected to be useful as medicines for the treatment of disorders of circu-latory organs.

Processes for the preparation of such asyrnmetric l.,4-dihydropyridine derivatives have been proposed in which 4-substi.tuted acetoacetic acid esters, 4-substituted-2-yli-deneacetoacetic acid esters or 4-substituted-3-aminocrotonic I acid esters are used as the starting materials (Japanese ~nexamined Patent Publications No. 5,777/1977 and No. 79,873/
1978). ~lowever, these processes are not so efficient in that they involve a plurality of process steps to prepare the final products, i.e. the asymmetric 1,4-dihydropyridine derivat:ives, from the respective starting materials.
As a result of extensive researches, the present .~

~99~ ~

inven-tors have been successful in the preparation of novel

3-amino-3-carbamoyloxyalkylacrylic acid deriva-tives and 3-carbamoyloxyalkylpropiolic acid derivatives which are useful as intermediates or starting materials for the preparation of the asymmetric 1,4-dihydropyridine derivatives. It has been found that with use of these novel intermediates as the starting materials, the asymmetric 1,4-dihydropyridine deri-vatives can readily be prepared in a single step reaction.

In copending application No. 434,005, there is disclosed and claimed a process for preparing a 2-carbamoy-loxyalkyl-1,4-dihydropyridine derivative represented by the general formula:

~ Rl 1~2OOC ~ COOR3 S (I) Il ~ ~ R
n4 Nl ~-OCON ~ R6 where l~l is halogen, cyano, nitro, hydroxyl, di-lower all;yl substituted amino or lower alkoxy, each of R2 and R3 is lower alkyl, haloalkyl, lower alkenyl, lower alkynyl, ar-alkyl, aryl, hydroxyalkyl, lower alkoxyalkyl, lower alkeny-loxyalkyl, aralkyloxyalkyl, aryloxyalkyl or _g_N<~I~8 (where B is straiyht-chained or branched alkylene, and :~

~ 35 ':
~ 2 ' ~

, '~ ~24099~

each of R7 and R8 is lower alkyl, aralkyl or aryl, or R7 and R8 form, together with the adjacent nitrogen atom, a heterocyclic group), R is hydrogen or lower alkyl, A is alkylene, and each of R5 and R6 is hydrogen, lower alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aralkyl or aryl, or R5 and R6 form, together with the adjacent nitrogen atom, a heterocyclic group, which comprises:
(a) reacting a 3-amino-3-carbamoyloxyalkylacrylic acid derivative represented by the general formula:

6>NCOO--A--C =CHCOOR (II) where R3, R5, R6 and A are as deffned above, with a benzylidene compound represented by the general formula:

Rl COOR2 ~CH=C--CO--R4 (III) .; 15 where R1, R2 and R4 are as defined above;
(b) reacting the 3-amino-3-carbamoyloxyalkylacrylic acid derivative of the general formula II with an aldehyde compound represented by the general formula:
Rl ~CHO (IV) where R is as defined above, and a ,B-keto-ester compound represent-ed by the general formula:

.,, .

.
.

-~24099~

R~ - CO - C}12 - COOR (V) where R2 and R4 are as defined above; reacting a 3-carbamoy-loxyalkylpropiolic acid derivative represented by the gen-enera:! formula:
1~ >~COO - A - C - CCO01~ (V1) 1~
where 1~3, R5, R6 and A are as defined above, with the benzy-lidene compound of the general formula III and ammonia or its sal.t; or reacting the 3-carbamoyloxyalkylpropiolic acid derivative of the general formula VI with the aldehyde com-pound of the general formula IV, the ~-keto-ester compound of the general formula V and amonia or its salt.
The 3-amino-3-carbamoyloxyalkylacrylic acid derivative of the the general formula II which forms the subject matter of the present invent.ion and the 3-carbamoyloxyalkylpropiol:ic acid derivative of the general formula VI used as starting mater-ia]s :i.n the above process, are novel compounds of the pre-sen t inven tion .

: The 3-amino-3-carbamoyloxyalkylacrylic acid deri-vative of the general formula II can be prepared by reacting the 3-carbamoyloxyalkylpropiolic acid derivative of the genera:L formula VI with ammonia or its salt.

The 3-carbamoyloxyalkylpropiolic acid derivative I of the general formula VI can be prepared by: reacting an ace~:y:Lene compound represented by the general formu:l.a:

ccoo~3 (V11) . where R and A are as defined above, with an isocyanate rep-, ~
~ resented by the general formula:
: 35 .::

. ~: - 4 -- lZ4099~

R NCO
where R9 is chlorosulfonyl, dichlorophosphoryl, trichloroacetyl, hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl or aryl, or a compound capable of forming the isocyanate under the reaction condition, followed by hydrolysis, if necessary, or with a carbamic acid chloride represented by the general formula:
B6 > NCOC Q

where R5 and R6 are as defined above but excluding hydrogen;
(b) reacting the acetylene compound of the general formula VII
with phosgene or trichloromethylchloroformate to form a chloroformic acid ester derivative represented by the general formula:
C QCOO--A--C CCoOR3 (VIII ) where R3 and A are as defined above, which is then reacted with an amine compound represented by the general formula:

R6 ~
where R5 and R6 are as defined above; or (c) reacting an acetylene compound represented by the general formula:
HO--A--C 9 CH (IX) where A is as defined above, with phosgene or trichloromethyl-chloroformate to form a chloroformic acid ester derivative represented by the general formula:
C QCOO--A--C 3 CH (X) where A is as defined above, which is then reacted with an amine compound represented by the general formula:

124~991 . .

6 ~NH
R

where R5 and R6 are as de~lned abo~e, to form a carbamate derivative represented by the general formula:
R6 ~NCOO--A--C CH (XI) R
where R5, R6 and A are as deflned above, which is in turn reacted with a metallizing reagent to form an organic metal compound, which is in turn reacted with a chloroformate represented by the general formula:
C ~COOR
where R is as defined above.
Now, the present invention will be described in detail with reference to the preferred embodiments.
R1 is halogen such as fluorine, chlorine, bromine or iodine;
15 cyano; nitro; hydroxyl; di-substituted amino such as dimethylamino, diethylamino or dipropylamino; lower alkoxy such as methoxy, ethoxy, propoxy or butoxy.
Each of R2 and R3 is lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl or hexyl; haloalkyl 20 such as B-chloroethyl, ~-bromoethyl, ~-chloropropyl, y chloro-propyl, w-chlorobutyl, ~, B-dichloroethyl, trifluoromethyl or B ,~
trichloroethyl; lower alkenyl such as vinyl, allyl, 3-butenyl or isopropenyl; lower alkynyl such as propargyl or 2-butynyl; aralkyl such as benzyl, a-methylbenzyl or phenethyl; aryl such as phenyl, ;nD I yl 25 pyridyl, naphthyl or quinonyl; hydroxyalkyl such as ~-hydroxyethyl, hydroxypropyl, ~-hydroxybutyl, y-hydroxypropyl, ~-hydroxybutyl .~

` lZ4~991 or 13,y-~ihydroxypropyl; lower alkoxyalkyl such as ~-methoxyethyl, ,~-ethoxyethyl, ~-propoxyethyl, ~-isopropoxyethyl, ~-buto~cyethyl, - ,~-isobutoxyethyl, ~-tertiary-butoxyethyl, ~-methoxypropyl, ~-ethoxy-propyl, ~-propo~ypropyl, ~-isopropoxypropyl, B-butoxypropyl, y-methoxypropyl, y-ethoxypropyl, y-propoxypropyl, y-butoxypropyl or ~-propoxybutyl; lower alkenyloxyalkyl such as ~-vinyloxyethyl, ~-allyloxyethyl, ~-(3-butenyloxy)ethyl, ~-isopropenyloxyethyl or ~-allyloxypropyl; aralkyloxyalkyl such as ~-benzyloxyethyl, ~-phenethyl-oxyethyl or ~ -methylbenzyloxy)ethyl;; aryloxyalkyl such as ~-phenoxyethyl, ~-pyridyloxyethyl, ~-phenoxypropyl or ~-phenoxybutyl;
-B-N<I~g such as ~-dimethylaminoethyl, ~-diethylaminoethyl, B -methyl-ethyl.~ inoethyl, ,~dimethylaminopropyl, ~ -dimethylaminopropyl, ~-dimethylaminobutyl, ,B-N-methylbenzylaminoethyl, B-N-methylbenzyl-u~ opropyl, ~-N-methylbenzylaminobutyl, y-N-methylbenzylamino-propyl, ~N-methylbenzylaminobutyl, B-piperidinoethyl, ~-(4-methyl-pipet azino) ethyl, ~ - ( 4- ethylpiperazino) ethyl, ~ - propylpiperazino) -elllyl, 13-(4-methylhomopiperazino)ethyl~ B-morpholinoethyl, y-morpholino-propyl, ~-morpholinobutyl, ~-homomorpholinoethyl, ~-(1-pyrrolidinyl)-ethyl, ~-(1-imidazolidinyl)ethyl, ~-(1-imidazolinyl)ethyl, ~-(1-pyrazo-lidinyl)etllyl, ,~-(l-indolinyl)ethyl, B-(2-isoindolinyl)ethyl, or ~- N - methylanilinoethyl .
Ic4 is hydrogen; or lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tertiary butyl.
A is allcylene such as methylene, methylmethylene, ethylmethylene, pllcnylnletllylene, dimethylmethylene, methylethylmethylene, methyliso-butylmcthylene, phenylmethylmethylene, ethylene, methylethylene, ~ ethyletllylene, trimethylene or tetramethylene.

124099~

Each of R and R6 is hydrogen; lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tertiarybutyl; haloalkyl such as ,B-chlorGethyl, ~B-bromoethyl, ~-chloropropyl, ~-chloropropyl, ("-chlorobutyl, B,B-dichloroethyl, ,B,~,~-trichloroethyl or tri~luoro-methyl, hydroxyalkyl such as ,B-hydroxyethyl, ~ -hydroxypropyl, y -hydroxypropyl or ~-hydroxybutyl; cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; lower alkenyl such as vinyl, allyl, 3-butenyl or isopropenyl; aralkyl such as benzyl, ,~ $~C~oro,o~Se~,y~ 3~Y~/fc~/oro,~e~y~
,~ a-methylbenzyl or phenethyl; aryl su~h a~phenyl,lpyridyl o naphthyl, or R5 and R6 form, together with the adjacent nitrogen atom, a heterocyclic group such as piperidino, 4- methylpiperazino,

4-ethylpiperazino, 4-propylpiperazino, 4-methylhomopiperazino, morpholino, homomorpholino, l-pyrrolidinyl, 1-imidazolidinyl, 1-imidazolinyl, l-pyrazolidinyl, 1-indolinyl or 2-isoindolinyl.
The aromatic rings contained in the aralkyl, aryl, aralkyloxy-, alkyl, and aryloxyallcyl of R to R8 may be substituted by 1 to 3 substituents. As such substituents, there may be mentioned halogen - such as fluorine, chlorine, bromine or iodine; cyano; nitro; hydroxyl;
di-substituted amino such as dimethylamino, diethylamino or diiso-propylamino; lower alkoxy such as methoxy, ethoxy, propoxy or butoxy; lower alkyl such as methyl, ethyl, propyl or butyl; and trifluoromethyl .
Now, the process for the preparation of the 2-carbamoyloxy-alkyl-1,4-dihydropyridine derivatives of the general formula I will be specifically described.

:, , .
`:

~ i 124~0991 In a preferred embodiment of this process, R5 is hydrogen and R6 is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl or aryl, R to R4 and A being as defined above with respect to the general formula 1. More specifically, it is preferred that R is o-nitro, m-nitro, o-chloro, o-cyano or o-methoxy, each of R2 and R3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ~-chloro-ethyl, allyl, propargyl, benzyl, phenyl, ~-methoxyethyl, B-ethoxyethyl, ~-propoxyethyl, B-isopropoxyethyl, ~-allyloxyethyl, ~-benzyloxyethyl, ~-phnoxyethyl, ~-N-methylbenzylaminoethyl, ~-piperidinoethyl, B-(4-methylpiperazino)ethyl or~-morpholinoethyl, R4 is methyl or ethyl, A is methylene or ethylene, R5 is hydrogen and R6 is hydrogen, methyl, ethyl, propyl, cyclohexyl, phenyl,p-chlorophenyl or m,p-dichlorophenyl.
Among the four methods (a), (b), (c) and (d), the methods (a) and (c) are particularly preferred.

' ~
': , , `

, , :, `'' .

~ `
~Ogs~

I~eferring to the methods (a) and (b), the compound of the general formula I is obtained by reacting a 3-amino-3-carbamoyloxy-alkylacrylic acid derivative of the general formula II(hereinafter sometimes referred to simply as "an enamine compound" ) with the benzylidene compound of the general formula III (method (a)) or witll the aldehyde compound of the general formula IV and the ~-keto-ester compound of the general formula V (method (b)).
The reaction conditions for the methods (a) and (b) are suitably selected depending upon the particular types of the starting materials to be used. In general, the benzylidene compound of the general formula III, or the aldehyde compound of the general formula IV and the B-keto-ester compound of the general formula V, are used sub-stantially in stoichiometric amounts, i . e . equimolar amounts, relative to the enamine compound of the general formula II. The molar ratio of the reactants can be varied within a wide range without adversely affecting the reaction.
The reaction is usually carried out under cooling, at room temperature, or under warming or heating.
As the solvent for the reaction, there may be used water, an inert organic solvent or a solvent mixture of water with an inert organic solvent. As the inert organic solvent, there may be used an alcohol such as methanol, ethanol, propanol, isopropanol or butanol, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, acetone, dimethylformamide, ethylacetate, benzene or chloroform.
The reaction may be facilitated by using a catalyst, for example, an acid such as acetic acid, a base such as piperidine or a salt of an acid with a base.
. .

~2~09~

I~eferring to the methods (c) and (d), the compound of the general formula I is prepared by reacting a 3-carbamoyloxyalkyl-propiolic acid derivative of the general formula VI (hereinafter sometimes referred to simply as "an acetylene compound") with the benzylidene compound of the general formula III and ammonia or its salt, or with the aldehyde compound of the general formula IV, the ,~-keto-ester compound of the general formula V and ammonia or its salt .
The reaction conditions for the methods (c) and (d) are optionally selected depending upon the particular types of the starting materials to be used . I n general, the acetylene compound of the general formula VI, the benzylidene compound of the general formula III, the aldehyde compound of the general formula IV and the ~-]ceto-ester of the general formula V are used substantially in stoichiometric I5 amounts, i.e. equimolar amounts, in the respective reactions, and the ammonia or its salt is used in a stoichiometrically excess amount.
The molar ratio of the reactants can be varied within a wide range without adversely affecting the reaction.
As the salt of ammonia, there may be used an ammonium salt of an organic acid such as acetic acid, formic acid, citric acid, benzoic acid or phenylacetic acid, or an ammonium salt of an inorganic acid such as carbonic acid, bicarbonic acid or boric acid.
The reaction is usually carried out under cooling, at room tem-perature or under warming or heating.
The solvent for the reaction may be water, an inert organic solvent or a solvent mixture of water with an inert organic solvent.

lZ9c~3991 As the inert organic solvent, there may be used an alcohol such as methanol, ethanol, propanol, isopropanol, or butanol, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, acetone, dimethylformamide, ethylacetate, benzene or chloroform.
The reaction may be facilitated by using a catalyst such as an acid, a base or a salt of an acid with a base.
The compounds of the general formula I thus prepared by the process of the present invention may be refined, isolated or collected by usual methods such as extraction treatment by means of an organic solvent, separation and purification by chromatography by means of a carrier such as silica gel or alumina, or crystallization. Further, in a case where the compounds thus prepared are capable of forming a salt, they may be converted to the respective salts with use of an inorganic acid such- as hydrochloric acid or an organic acid such as citric acid.
The compounds of the general formula I obtained by the present invention have vasodilation activities and hypotensive activities.
Particularly, they have strong coronary vasodilation activities and extremely weak toxicity, and thus, they are expected to be quite useful as medicines for the treatment of disorders of the circulatory organs, such as hypertension, cardiac insufficiency, angina pectoris, myocardial infarction or intracerebral vascular disorders.
PIII~RMACOLOGY -Pharmacological and toxicity tests have been conducted with respect to 2-carbamoyloxyalkyl~ -dihydropyridine derivatives obtained by the process of the present invention.

~.24099~

1. T est methods a) Coronary vasodilation According to Langendorff method (O. Langendorff; Pflugers arch. ges. phisiol., 61, 291-332 (1895)), the coronary vasodilation

5 effects were tested using isolated hearts of rabbits. The strength of coronary vasodilation was evaluated by ICD50(g/mQ) i.e. the dosage of a sample required to increase the coronary outflow by 50%.
b) Acute toxicity Samples were intravenously administered to DM strain male mice 10 (18 to 22 g), and LD50 values were obtained according to the up-and-down method.
c) Coronary effects on dogs Beagle dogs (13 to 16 kg, ~) were subjected to thoracotomy under anesthesia with sodium pentobarbital, and a probe was attached to the 15 heart left coronary anterior descending artery of each animal, where-upon the coronary blood flow (CF) was measured by an electromagnetic flowmeter. On the other hand, a probe was attached to the exposed right femoral artery, and the femoral artery blood flow (FAF) was measured by an electromagnetic flowmeter. A canule was inserted to 20 the left femoral artery, ar.d the systemic blood pressure (BP) was bloody measured by a transducer.
The heart rate (HR) was measured by an electrocardiogram.
The sample solution was intravenously injected to the right femoral vein.
The coronary blood flow (CF), the femoral artery blood flow (FAF) and the heart rate (HR) were represented by a ~6 increase upon the injection of each sample as compared with the respective control -- value upon the injection of a saline.

~Z4099~

The systemic blood pressure (BP) was represented by a %
decrease as compared with the control.
2. Results The coronary vasodilation effects on the isolated heart preparations 5 of rabbits and acute toxicity against the mice are shown in Tables 1-1(a) and I-l(b). It is se~n that the compounds obtained by the present invention exhibit strong coronary vasodilation effects against the coronary vessels. The acute toxicity thereof is as low as 1/6 to 1/17 of the acture toxicity of nifedipine.
The coronary effects against the beagle dogs are shown in Table I-2. It is seen that the five representative compounds obtained by the present invention increase the coronary blood flow (CF) in corre-spondence with the increase of their doses, and their effectiveness is equivalent to or greater than the nifedipine. It is also seen that the coronary effects are thereby obt~inable without substantially decreasing the systemic blood pressure (BP) or without substantially affecting the heart rate (HR). Thus, no excessive load will be given to the heart, which, coupled with the minimized toxicity, makes the compounds obtained by the present invention quite useful coronary vasodilators.
Further, from the results of a separate pharmacological test where 1 to 1011g/kg of the compounds of Examples I-3, I-26 and 1-38 were intravenously administered, it was found that they increased the cerebr~l blood flow and the peripheral blood flow by from 40 to 50%, thus indicating that the compounds of the present invention are useful also as cerebral vasodilators and peripheral vasodilators.

Table I-1(a): Coronary vasodilation and acute toxicity Coronary Acute vasoi~ilationtoxi city No . Compounds: I CD 5 0 LD 5 0 glm Qmg/kg ,i . v .
Reference compound:
2, 6-Dimethyl- 4- (o-nitrophenyl~ 3, 5-dimethoxy- 2, 9 x 10 11. 5 carbonyl- 1, 4-dihydropyridine ( nifedipine) Compounds of the present invention:
~1) 2-Carbamoyloxymethyl-6-methyl-4-(m- 2.4 x 10 207 nitrophenyl~ - 3, 5-diethoxycarbonyl- 1, 4-dihydropyridine (2) 2-N-Methylcarbamoyloxymethyl-6- 3.2 x 10 7 71 methyl- 4- (m-nitrophenyl) - 3, 5- diethoxy -carbonyl- 1, 4- dihydropyridine - 7 ( 3) 2- C arbamoyloxymethyl - 6- methyl- 4- ( m - 3 . 6 x 10 167 nitrophenyl)- 3, 5-dimethoxycarbonyl -1, 4-dihydropyridine - 7 (4) 2-N-Methylcarbamoyloxymethyl-6- 3.6 x 10 84 methyl- 4- (m- nitrophenyl) - 3, 5-dimethoxy-carbonyl- 1, 4-dihydropyridine - 7 ( 5) 2- C arb amoyloxy methyl- 6- methyl- 4- (o- 4 . 8 x 10 104 nitrophenyl)- 3, 5-diethoxycarbonyl- 1, 4-dihydropyridine - 7

(6) 2-N-Methylcarbamoyloxymethyl-6- 4.5 x 10 30 methyl- 4- (o-nitrophenyl) - 3, 5-diethoxy-carbonyl- 1, 4-dihydropyridine

(7) 2-Carbamoyloxymethyl-G-methyl-4-(m- 2. 4 x 10 76 nitrophenyl)- 3-ethoxycarbonyl- 5-isopropoxycarbonyl- 1, 4-dihydropyridine

(8) 2-N-Methylcarbamoyloxymethyl-6- 2.3 x 10 37 methyl-4-(m-n;trophenyl)-3-ethoxy-carbony- S-isopropoxycarbonyl- 1, 4-dihydropyridine ~240g91 'l'rlblc l- 1(b): Coronrlry vasoclil~tion and acute toxic~tY
_ _ _ _ __ _ _ _ . ~orollrlry l~cute vnso~lilu~ioll toxicity No. Conll~oul-lcls: ICD5~ ~ 0 E~ l Q
__ _ l~f~ o~ )ound; ~7 2,G-l)i~ yl-4-(o-nitrop]leTlyl)-3~5- 2.2 x 10 11.5 dinlclllox~c~rbollyl- 1, 4-dil~ydropyricline ( llir~ ille) Conll~o~ s of tlle present invention:
, (~)) 2-~nll)nllloyloxylrl~tl~yl-~ etllyl-4- 3.4 x 10 13G
(nl-lliLlopl~ellyl)- 3-'ethoxycarborlyl-5-( ~-plopo~yel}~o~cy),carbonyl-l, 9-dihydro-l~Y r i(line (10) 2-(~nl11nllloyloxyllletllyl-G-metllyl-4- 3.0 x10 7 8~1 ilro~ enyl)-3-et]loxycarbonyl-5-(,B-l~t l~oxyellloxy)carbollyl- 1, 4-dihydro-I~yl i(lille (11) 2 ('nl l)allloyloxylllcl]lyl-G-metllyl-4- 2.5 x10 123 (m-~ ol)llel]yl) - 5-etlloxycarbonyl- 3- ( ,B-propo,Yycllloxy)carbonyl-l,~l-dillyclro-l~yl i(lillc -7 (12) 2-(~n: l~allloylo,yyllletllyl-G-metl~yl-4- 1.5 x10 123 ~n -llilro~ cnyl) - 3, 5-bis[ ( R-propoxYetl~oxy) carl)ollylJ- 1, ~-clihydropyridine (13) 2-N~ lllylcar;:~rllnoyloxymetlly1-G- 4. 0 x 10 104 nl(~lllyl-~-(m-nitrophenyl)-3~5-bis[ ( B-prc)L~oxyell~oxy)carbonyl]-1, 4-dihydro-1~ yridille ( 1~) ~l(~]~L~fcylc~1~ netl~1~-(rr~nit~ 3. 5 x 10 7 88 . [I r3-~y.l ) -5~t~rbcr~1-3- (~ netl~e~7) c~
~ lr( ~ idir~ .
(15) 2-(,nrl~rlllloyloxyllletllyl-G-nletllyI-4-(lll- 4.0 x 1() > 200 nil I ol~llcnyJ.) - 3-lnctlloxycarbonyl- 5- ( ,B-N-nlclllyll~ell7,ylalllilloetlloxy)carbonyl- 1, 4-di 1 lycl ropyl icline (1(;) 2-N-!\~ctllylcurbrlrlloyloxyl1lethyl-G- 2.5 x 10 1~G
' IllCtll yl- ~- (111- nitropllellyl) - 3-metlloxy-cllrl)ollyl- 5- ( ~-N -metllylbellzylaminoetlloxy) carbollyl- 1, ~-dilly~lropyridine (17) 2-(~arbr~ oyloxyllletlly1-~-metllyl-~-(m- 2.0 x 10 GG8 nitrol~]~enyl) - 3-metlloxycarbonyl- 5- [ ~ - .
Illct]lyl- l-piper.lzinyl)etlloxycarbony~-1,4-dillyd rol~yri(line .( 18) 2- ~l<ll balTloyloxyln~tllyl- G-methyl- 9- (m- 1. 5 x10 > 200 nitl ol)llcny]) - 3-metlloxycarbonyl- 5- ( ~-morl)llolilloctlloxy)carbonyl- 1, 4-dilly(ll ol~yri(line , ____ i240991 Table l-l(b) (cont'd) Coronary Acute vasodilation toxicity No. C~mpounds: ICD50 LD50 _ g. m Q m glk~ ,i . v .
(19) 2-Carbamoyloxymethyl-6-methyl-4- 1.8 x 10 7 168 (~-nitrophenyl)- 3- ( ,B-propoxyethoxy) carbonyl- 5- ( ,B-N - methylbenzylaminoethoxy) carbonyl- 1, 4- dihydropyridine (20) 2-Carbamoy]oxymethyl-6-methyl-4- 3.6 x 10 184 (o - chlorop henyl ~ - 3, 5 - bi s [ ( ~ - methoxy -ethoxy) carbonyl] -1, 4-dihydropyridine (21) 2-N-~p-Chlorophenyl)carbamoyloxymethyl- 2.8 x 10 83 6-methyl- 4- (m nitrophenyl)- 3-ethoxy-carbonyl- 5-isopropoxycarbonyl- 1, 4-dihydropyridine ( 22) 2-N-Phenylcarbamoyloxymethyl- 6- 3. 3 x 10 80 methyl- 4- (m-nitrophenyl} 3-ethoxycarbonyl-S-isopropoxycarbonyl- 1, 4- dihydropyridine -' ~240g~

Table I-2:
. Dose No. Compound ~g/kg CF
i.v.% increase Nifedipine 1 10 . 10 88 (1) ~ ~2 C2H500C ~ COO C2H5 1 30 C H3 ~ H20-CON H ~ 10 74 (2) ~ N02 n-C3H70CH2C H2C0 ~ 00 CH2cH20-n C3H7 3 14 . ~ H3 ~ H20-CON H2 10 90 (3) ~ ~2 r~-c3H7ocH2cH2oo~coo~cH2cH2o-n-c3H7 1 512 C6~15-1CIl2 ~ ~2 I 3 C H2C H200C ~ COOC H2C HzO-n C3~7 1 45 3 H ~ C H2C~-CON H 2 10 88 (5) ~ ~2 i-C3H700C ~ COOc2Il5 1 338 CH3 H CH2o-coN~l ~ CQ10 86 . .

_~ 124~9~1 - 19 -.
Table I-2: (cont'd) FA~ BP HR
No. % increase% decrease % increase Nifedipine 10 10 0. 6 (1) 17 120 ,(2) (4) 13 14 0 tS) 385 2 0 Thus, the compounds of the general formula I obtained by the process of the present invention are expected to be useful as vasodi-lators as well as hypotensive drugs. The mode of administration of the compounds may be optionally chosen for such a purpose, and 20 it may be e.g. parenteral administration such as intravenous, hypodermic or intramascular injection or rectal administration, or oral administration in a form of tablets, powders, granules, capsules, sublingual tablets or syrups. The dose may vary depending upon the diseased condition, age and weight of the patient and the mode of the administration, but is usually from 0.1 to 1,000 mg per day, preferably from 1 to 100 mg per day, for an adult. The above-mentioned formulations may be prepared by conventional methods which are commonly employed.

1240~91 - ~o -Now, the preparation of the novel enamine compounds of the general formula II and acetylene compounds of the general formula VI
which are useful as intermediates of the compounds of the general formula I, will be described in detail.
Referring firstly to the process for the preparation of the enamine compounds, the 3-amino- 3-carbamoyloxyalkylacrylic acid derivatives of the the general formula II (i.e. the enamine compounds~
are prepared by reacting a 3-carbamoyloxyalkylpropiolic acid deriva-tive represented by the general formula:
10 ~ ~NCOO--A--C -- CCoOR3 (VI) where R3, R5, R6 and A are as defined above, with ammonia or its salt.
The salt of ammonia may be an inorganic ammonium salt such as ammonium carbonate, bicarbonate or borate, or an organic ammonium 15 salt such as ammonium formate, acetate, propionate, butyrate, tartrate, citrate, glutarate, oxalate, benzoate, phenylacetate, salicylate,-phthalate or nicotinate.
In this process, ammonia or its salt is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles, per mole of the 20 starting material of the general formula Vl.
The rea(:tion is carried out at room temperature or a slightly elevntecl temperature.
The solvent for the reaction may be selected from a lower alcohol such as methanol, ethanol, propanol, isopropanol, butyl alcohol, 25 isobutyl alcohol, secondary butyl alcohol, tertiary butyl alcohol or 12~

amyl alcohol, ethylene glycol, propylene glycol, glycerol, methyl-cellusolve, ethylene glycol dimethyl ether, dimethylsulfoxide, dimethyl-formamide, acetone, tetrahydrofuran and acetonitrile. Further, as the solvent for the reaction, a solvent mixture of water with an inert 5 organic solvent such as benzene, ethylacetate, chloroform or diethyl ether may a~so be used other than the above-mentioned organic solvents.
The reaction time is usually from 1 to 10 hours, preferably from 1 to 5 hours.
In a preferred embodiment, R3 is methyl, ethyl, propyl, iso-10 propyl, butyl, isobutyl, ~-chloroethyl, allyl, propargyl, benzyl, phenyl, B-methoxyethyl, ,~-propoxyethyl, ~-isopropoxyethyl, ~-allyloxy-ethyl, ~-benzyloxyethyl, ~-phenoxyethyl, ,~-N-methylbenzylaminoethyl, B - piperidi noethyl, ~ - ( 4- m ethylpiperazino ) ethyl, or B - morpholinoethyl, each of R5 and R is hydrogen, methyl, ethyl, propyl, isopropyl, 15 butyl, isobutyl, tertiary butyl, ~-chloroethyl, benzyl, phenyl, ~-chlorophenyl, ~-hydroxyethyl or cyclohexyl, or R5 and R6 form, together with the adjacent nitrogen atom a heterocyclic group selected from the group consisting of piperidino, 4- methylpiperazino and morp}lolino and A is methylene, ethylene, methyl methylene or 20 dimethyl methylene.
Amorlg the enamine compounds of the general formula II thus obtain-able, preferred are ~-rnethoxyethyl 3-amino-4-carbamoyloxycrotonate, methyl 3-amino-4-N-methylcarbamoyloxycrotonate, ethyl 3-amino-4-N-methylcarbamoyloxycrotonate, ~-methoxyethyl 3-amino-4-N-methyl-25 carbamoyloxycrotonate, ethyl 3-amino- 4-N -ethylcarbamoyloxycrotonate, `` :lZ40991 ethyl 3-amino-4-N-propylcarbamoyloxycrotonate, ethyl 3-amino-4-N-t-butylcarbamoyloxycrotonate, ethyl 3-amino-4-N-eyclohexylcarbamoyloxy-erotonate, ethyl 3-amino-4-N-phenylcarbamoyloxycrotonate, methyl 3- amino- 4-N - (p-chlorophenyl)carbamoyloxyerotonate, ~ -propoxyethyl 3-amino-4-N,N-dimethylcarbamoyloxycrotonate, ethyl 3-amino-4-N ,N-dicyclohexylcarbamoyloxycrotonate, ethyl 3-amino-4-N,N-diphenyl-earbamoyloxycrotonate, ethyl 3-amino- 4-piperidinoearbonyloxycrotonate, ethyl 3-amino-4-(4-methylpiperazino)carbonyloxycrotonate, ethyl 3-amino-4-morpholinoearbonyloxycrotonate, ethyl 3-amino-4-N,N-bis(~ -10 chloroethyl)carbamoyloxycrotonate, ethyl 3-amino-4-N-benzyl-N-methylearbamoyloxyerotonate, ethyl 3-amino-4-earbamoyloxycrotonate, isobutyl 3- amino- 4-carbamoyloxyerotonate, ~-propoxyethyl 3- amino - 4-carbamoyloxycrotonate, ~-propoxyethyl 3-amino-4-N-methylcarba-moyloxycrotonate, methyl 3-amino-4-carbamoyloxycrotonate 15 and isopropyl 3-amino-4-earbamoyloxycrotonate. Most preferred are methyl 3-amino-4-carbamoyloxycrotonate and isopropyl 3-amino-4-carbamoyloxycrotonate .
Referring now to the process for the preparation of the acetylene compounds of the present invention, the 3-carbamoyloxyalkylpropiolic 20 acid clerivatives of the general formula Vl (i.e. the acetylene compounds) are prepared by:

.
~24099~

(a) reacting an acetylene compound represented by the general formula:
HO--A--C -- CCoOR3 (VII ) where R and A are as defined above, with an isocyanate represented 5 by the general formula:
R9NCo where R9 is chlorosulfonyl, dichlorophosphoryl, trichloroacetyl, hydrogen, lower allcyl, cycloalkyl, lower alkenyl, aralkyl or aryl, or a compound capable of forming the isocyanate under the reaction 10 condition, followed by hydrolysis, if necessary, or with a carbamic acid chloride represented by the general formula:
R6 >NCOCQ

where n5 and R6 are as defined above but excluding hydrogen;

15 (b) reacting the acetylene compound of the general formula VII
with phosgene or trichloromethylchloroformate to form a chloroformic acid ester derivative represented by the general formula:
C QCOO--A--C -- CCoOR3 (VIII ) where R3 and A are as defined above, which is then reacted with 20 an amine compound represented by the gcneral fornlula:

R 6 ~
where RS and R6 are as defined above; or (c) reacting an acetylene compound represented by the general formula:

HO--A--C _ Cl-l (lX) lZ40991 where A is as defined above, with phosgene or trichloromethylchloro-formate to form a chloroformic acid ester derivative represented by the general formula:
CQCOO--A--C g CH (X) 5 where A is as defined above, which is then reacted with an amine compound represented by the general formula:
R6~NH

where R 5 and R 6 are as defined above, to form a carbamate derivative 10 represented by the general formula:

R6 ~NCOO--A--C -- CH (XI) where R5, }t6 and A are as defined above, which is in turn reacted with a metalli zing reagent to form an organic metal compound, which is in turn reacted with a chloroformate represented by the general 15 formula:
c QcooR3 where R 3 is as defined above .

~24~9g~

The reaction process of the method (a) may be illustrated by the following reaction scheme in a case where ethyl 4-hydroxy- 2-butynoate and methyl isocyanate are used as starting materials:

Hocll2c--ccooc2H5 CH3~NCOOcH2c-ccOOC2H5 The reaction process of the method (b) may be illustrated by the following reaction scheme in a case where ethyl 4-hydroxy-2-butynoate, phosgene and dimethylamine are used as starting materials:

ElocH2c-ccooc2H5 ~ CQCOOCH C~CCOOC H

C ~1 3 ~ N H

CH3 > NCOOCH2C--CCOOC2H5 1~40~9~

The reaction process of the method (c) may be illustrated by the following reaction scheme in a case where propargyl alcohol, phosgene, dimethylamine, butyl lithium and ethylchloroformate are used as starting materials.

~OCH2C--CH ) CQCOOCH2C--CH
CH

C ll 3 1) BuLi CH3> NCOOCH C~CCOOC H5 2) C QCOOC 2H 5 3 The starting acetylene compounds of the general formulas VII and IX are known compounds or may readily be prepared by known methods if not disclosed in literatures. (M. Mark Midland; a. Org. Chem., 40, 2250- 2252 ( 1975), Henne Greenlee; J . Am . Chem . Soc ., 67, 484 (1945)) The method (a) is concerned with the preparation of the compound of the formula VI by reacting the acetylene compound of the general t formula VII with an isocyanate or a carbamic acid chloride.
As the isocyanate of the general formula R9NCo (where R9 is as defined al~ove), there may be mentioned chlorosulfonyl isocyanate, dichlorophosphoryl isocyanate, trichloroacetyl isocyanate, isocyanic acid, methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate, butyl isocyanate, isobutyl isocyanate, tert.-butyl isocyanate, allyl isocyanate, cyclohexyl isocyanate, cyclopentyl isocyanate, phenyl isocyanate, o-, m- or p-chlorophenyl isocyanate, o-, m- or p-nitro-2S phenyl isocyanate, m,p-dichlorophenyl isocyanate, p-fluorophenyl lZ4099~

isocyanate, p-methoxyphenyl isocyanate, p-tolyl isocyana$e, p-dimethylaminophenyl isocyanate, benzyl isocyanate, diphenylmethyl isocyanate, phenethyl isocyanate or ,B-dimethylaminoethyl isocyanate.
As the carbamic acid chloride of the general formula RG>NCOCQ
5 (where R5 and R6 are as defined above) to be used in this method, there may be mentioned dimethylcarbamylchloride, diethylcarbamyl-chloride, dipropylcarbamylchloride, diisopropylcarbamylchloride, methylethylcarbamylchloride, methylbenzylcarbamylchloride and methylphenylcarbamylchloride .
In this reaction, instead of the isocyanate of the general formula R9NCo, a compound capable of forming such an isocyanate under the reaction condition as mentioned below may be used. As such a com-pound, there may be mentioned an acid azide represented by the general formula R9CON3 (where R9 is as defined above) under a 15 heating condition, or a thiocarbamate represented by the general formula R9NHCoSR (where R9 is as defined above, and R is lower alkyl) under a heating condition or in the presence of a trialkylamine and a heavy metal (for instance, silver nitrate or mercury chloride).
The reaction condition for the method (a) for the preparation of 20 the compound of the general formula VI is suitably selected depending upon the particular types of the starting materials to be used. In general, the isocyanate of the general formula R9NCo (where R9 is as defined above) or the carbamic acid chloride of the general formula R6>NCOC~ (where R5 and R6 are as defined above) are used in 25 an amount of from 1 to 2 moles per mole of the acetylene compound of the gelleral formula VlI. The molar ratio of the starting materials may be varied within a wide range without adversely affecting the 124099i reaction. The reaction is usually carried out under cooling, at room tempcrature or under warming or heating.
In the case where the carbamic acid chloride is employed, a base such as pyridine, triethylamine or dimethylaniline is used in an equi-5 molar amount or in an excess amount relative to the carbamic acidchloride. As the solvent for the reaction, an inert organic solvent such as dichloromethane, chloroform, diethyl ether, tetrahydrofuran or benzene is usually used. The reaction is usually carried out for 1 to 24 hours under stirring.
When chlorosulfonyl isocyanate, dichlorophosphoryl isocyanate or trichloroacetyl isocyanate is used as the isocyanate, it will be necessary to conduct hydrolysis treatment of the reaction mixture by adding water thereto after the completion of the reaction.
Referring now to the method (b), firstly the compound of the 15 gencral formula VIII is synthesized by the reaction of the acetylene compound of the general formula VII with phosgene or trichloro-methylformate, and then the compound of the general formula VI is prepared by the reaction of the compound of the general formula VIII
with an amine compound of the general formula RRB~NH (where R5 B ~ ;/oror~efhy~Joro~orm~i 20 and $1 are as defined above). The ~hylformatc to be used in this reaction is contacted with a very small amount of pyridine or nctive carbon, whereupon the generated phosgene gas is absorbed in an inert or~anic solvent such as benzene, or is dropwise added to a solution of an inert organic solvent such as benzene to obtain a 25 phosgene solution, as a pretreating operation before the reaction with the acetylene compound of the general formula VII. As the amine compound of the general formula RG>NH (where R5 and R6 are as defined nbove) to be used in this reaction, there may be mentioned ~2409~

ammonia, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, tertiary-butylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diiso-butylamine, methylethylamine, diethanolamine, cyclohexylamine, 5 dicyclohexylamine, ally~amine, benzylamine, a-methylbenzylamine, phenethylamine, aniline, diphenylamine, c~-pyridylamine, cl-naphthyl-amine, N-methylbenzylamine, N-methylaniline, pyperidine, 4-methyl-pyperazine, 4-methylhomopyperazine, morpholine, homomorpholine, pyrrolidine, imidazolidine, imidazoline, pyrazolidine, indoline and 10 isoindoline.
In the method (b), the reaction condition for the reaction of the acet-,~lene compound VII with phosgene or trichloromethylchloro-formate is usually such that phosgene or trichloromethylchloroformate is used in an amount of from 1 to 2 moles per mole of the acetylene 15 compound of the general formula VII.
In the method (b), the reaction condition for the reaction of the compound of the general formula VIII with the amine compound is usually such that relative to one mole of the compound of the general formula VIII, the amine compound of the general formula 20 nG>NI3 (where R5 and R6 are as defined above) is used in an amount of from 2 to 3 moles, or the amine compound in an amount of from l to 2 moles is used in combination with from 1 to 2 moles of a tertiary amine such as triethylamine, dimethylaniline or pyridine.
The molar ratio of the reactants may be varied within a wide 25 range without adversely affecting the reactions. In each ase, the reaction is carried out under cooling with ice or at room temperature.

lZ~99~

In each reaction, an inert organic solvent such as diethyl ether, tetrahydrofuran, benzene, toluene, dichloromethane or chloroform is usually used as the solvent. With respect to the reaction time, each reaction is carried out under stirring for 30 minutes to 3 hours, 5 followed by stirring for one night at room temperature for completion.
The method (c) is a continuous or successive process for the preparation of the compound of the general formula VI in which firstly the compound of the general formula X is prepared by the reaction of the acetylene compound of the general formula IX with phosgene or 10 trichloromethylchloroformate, then the compound of the general formula XI is prepared by the reaction of the compound of the general formula X with the amine compound of the general formula RR6>NH (where R5 and R~ are as defined above, but excluding hydrogen), further a metallizing reagent is reacted to the compound of the general formula Xl 15 to form an organic metal compound and then a chloroformate of the general formula CQCoOR3 (where R3 is as defined above) is reacted thereto. As the amine compound of the general formula RR6>~H (where R5 and R6 are as defined above, but excluding hydrogen), there may be mentioned the amine compounds mentioned in the above method (b), 20 except for ammonia and primary amines such as methylamine and benzylamine. As the chloroformate of the general formula CQCOOR
(where R is as defined above) to be used in the reaction of the method (c), there may be mentioned, methylchloroformate, ethylchloro-formate, propylchloroformate, isopropylchloroformate, ~ - chloroethyl-25 chloroformate, allylchloroformate, propargylchloroformate, benzyl-chloroformate, phenylchloroformate, ~-methoxyethylchloroformate, ~z4099~

~-ethoxyethylchloroformate, ~-propoxyethylchloroformate, 3-isopropoxy-ethylchloroformate, B-butoxyethylchloroformate, ~-propoxypropyl-chloroformate, ~-allyloxyethylchloroformate, ,~-benzyloxyethylchloro-formate, B-phenoxyethylchloroformate, ~-dimethylaminoethylchloro-5 formate, ~-diethylaminoethylchloroformate, ~-N-methylbenzylaminoethyl-chloroformate, ~-N-methylbenzylaminopropylchloroformate, ~-piperidino-ethylchloroformate, ~- ( 4-methylpiperazino)ethylchloroformate, ~-morpholinoethylchloroformate, and y- ( 4-methylhomopiperazino)propyl-chloroformate .
As the metallizing reagent to be used for the reaction of the method (c), there may be mentioned methyl lithium, ethyl lithium, n-propyl lithium, n-butyl lithium, s-butyl lithium, t-butyl lithium, cyclopropyl lithium, vinyl lithium, cis-propenyl lithium, phenyl lithium, triphenylmethyl lithium, lithium diisopropylamide, lithium diethylamide, 15 lithium di-trimethylsilylamide, lithium benzylamide, lithium cyclohexyl-amide, sodium, potassium, lithium, sodium amide, potassium amide, lithium amide, magnesium methyliodide, magnesium ethyliodide, magnesium methylbromide, magnesium ethylbromide and magnesium phenylchloride .
In the method (c), the reactions of the first two steps, i.e.
the reaction of the acethylene compound of the general formula IX
with phosgene or trichloromethylchloroformate and the reaction of the compound of the general formula X with the amine compound, are conducted in the same manner, with respect to the reaction conditions, 25 reaction temperatures, solvents and reaction times as the correspond-ing reactions in the above-mentioned method (b).

~40g9~

The reaction of the compound of the general formula Xl with the metallizing reagent in the method (c) is usually conducted under such a condition that the metallizing reagent is used in an equtmolar arnount or a slightly excess amount relative to the compound for the general 5 formula XI, and the chloroformate is used in an amount of from 1 to 2 moles per mole of the compound. The reaction with the metallizing reagent is conducted under cooling with ice or at a lower temperature to -120C, preferably from -60 to -80C, and the reaction with the chloroformate is conducted under cooling with ice or at a lower temper-10 ature to -80C, preferably from -60 to -80C. As the solvent for the reactions, an inert organic solvent such as diethyl ether or tetra-hydrofuran is used. With respect to the reaction time, the reaction with the metallizing reagent is conducted for from 10 to 30 minutes, followed immediately by the reaction with the chloroformate for from 15 30 to 60 minutes.
In a preferred embodiment, R3 is methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, ~-chloroethyl, allyl, propargyl, benzyl, phenyl, ~-methoxyethyl, ,~-propoxyethyl, ~-isopropoxyethyl, 3-allyloxy-ethyl, ~-benzyloxyethyl, ~-phenoxyethyl, ~-N-methylbenzylaminoethyl, 20 ~ -pipcridinoethyl, ~-(4-methylpiperazino)ethyl, or ~-morpholinoethyl, each of R5 and R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, ~-chloroethyl, benzyl, phenyl, ~-chlorophenyl, 13-hydroxyethyl or cyclohexyl, or R5 and R6 form, together with the adjacent nitrogen atom a heterocyclic group selected 25 from the group consisting of piperidino, 4- methylpiperazino and morpholino and A is methylene, ethylene, methyl methylene or dimethyl methylene.

124099~

Among the 3-carbamoyloxyalkylpropiolic acid derivatives of the general formula Vl thus obtainable, preferred are methyl 4-carba-moyloxy-2-butynoate, ethyl 4-carbamoyloxy-2-butynoa~e, isopropyl 4-carbamoyloxy-2-butynoate, isobutyl 4-carbamoyloxy-2-butynoate, ~-methoxyethyl 4-carbamoyloxy- 2-butynoate, B -propoxyethyl 4-carbamoyloxy-2-butynoate, methyl 4-N-methylcarbamoyloxy-2-butynoate, ethyl 4-N-methylcarbamoyloxy-2-butynoate, ~-methoxyethyl 4-N-methylcarbamoyloxy-2-butynoate, ~-propoxyethyl 4-N-methylcarba-moyloxy-2-butynoate, ethyl 4-N-ethylcarbamoyloxy-2-butynoate, ethyl 4-N-propylcarbamoyloxy-2-butynoate, ethyl 4-N-t-butylcarba-moyloxy - 2-butynoate, ethyl 4-N -cyclohexylcarbamoyloxy- 2-butynoate, ethyl 4-N-phenylcarbamoyloxy-2-butynoate, methyl 4-N - (p-chloro-phenyl) carbamoyloxy- 2-butynoate, ~ -propoxyethyl 4-N, N - dimethyl-carbamoyloxy-2-butynoate, ethyl 4-N ,N-dicyclohexylcarbamoyloxy-2-butynoate, ethyl 4-N ,N-diphenylcarbamoyloxy-2-butynoate, ethyl 4-piperidinocarbonyloxy-2-butynoate, ethyl 4-(4-methylpiperaæino) carbonyloxy-2-butynoate, ethyl 4-morpholinocarbonyloxy-2-butynoate, ba~ ~
ethyl 4-N ,N-bis( ,~-chloroethyl)e~ 2-butynoate and ethyl 4-N-benzyl-N -methylcarbamoyloxy- 2-butynoate . Particularly preferred are methyl 4-carbamoyloxy- 2-butynoate, ethyl 4-carbamoyloxy- 2-butynoate, isopropyl 4-carbamoyloxy-2-butynoate, isobutyl 4-curbalnoyloxy-2-butynoate, ~-propoxyethyl 4-carbamoyloxy-2-butynoate and ~-propoxyethyl 4-N-methylcarbamoyloxy-2-butynoate. Most preferred are methyl 4-carbamoyloxy- 2-butynoate and isopropyl 4-carbamoyloxy- 2-butynoate .

1240gg~

Now, the present invention will be described in further detail with reference with Examples. However, it should be understood that the present invention is by no means restricted by these specific Examples .
Firstly, Examples for the preparation of 3-carbamoyloxyalkyl-propiolic acid derivatives of the general formula Vl of the present invention will be given. These Examples are identified by symbol "VI" .

~o99~

EXAMPLE Vl-1: Preparation of methyl 4-carbamoyloxy-2-butynoate H2NCOOCHzc CCOOCH3 22.8 g (0.2 mole) of Methyl 4-hydroxy-2-butynoate was dissolved in 200 ml of dichloromethane, and 17.5 ml (0.2 mole) of chlorosulfonyl 5 isocyanate was added thereto at a temperature of -20C. The mixture was stirred for 30 minutes at a temperature of from -10 to -20C.
To the reaction mixture, 20 ml of water was added, and hydrolysis treatmerIt was carried out for 30 minutes at a temperature of about 0C.
Crystals formed in the r0action mixture were collected by filtration 10 to obtain 18 g of primary crystals. The filtrate was subjected to phase separation. The dichloromethane phase obtained by the phase separa-tion and the dichloromethane extraction solutions obtained by extraction treatment of the aqueous phase with dichloromethane, were put together, washed with water and then concentrated under reduced pressure, 15 and the crystals thereby formed we~re collected to obtain 10 g of secondary crystals. The primary and secondary crystals were put together and recrystallized from ethylacetate, whereby 25.1 g (yield:
80g~) of methyl 4-carbamoyloxy-2-butynoate in crystal form was obtained.
mp: 113 - 114C
IR (I~Br), cm 1 3410, 3350, 3300, 3220, 2250, 1750, 1700, 1620, 1440, 1320, 1295, 1090, 1050, 930, 750.
H NMR (90 MHz, DMSO-d6), ~: 3.77 (s, 3~1), 4.82 (s, 2~1), 6.8 (broad s, 2H) i24099~

EX~MPLE VI-2 to Vl-8:
In the same manner as in Example VI-l, the compounds identified in Table VI-1 were obtained.
Table VI-l Example Compounds (VI ) Yields ~ Melting VI-2 H NCOOCH C~CCOOC H 14 2 g 86-87 VI-3 H2NcoocH2c-ccooc3H7 (n) 13 9 g 134-136 VI-4 I~2NcoocH2c-ccoocH2cH2oc3H7 (n) 185%5 g Oily sub-10 Vl-5 H2HcoocH2c-ccoocH2cH2ocH2cH=cH2 16 g Oily sub-*: The yields of the compounds (VI) obtained by the reaction of 0. l mole of the respective starting materials of the general formula VII.

1~099~

Table VI-1 ExLlrnple 1 R ( X B r ) l H--NMR (9 OMH z ) Nos. cm ~ ~ i n ppm 3480,3350, 3290, 2250, CDMSO--d~ ); 1.2 4 (t,3 Vl 2 1755,1720,1600, 1410, J=7.5Hz),4.21(q,2H,J=
1325,1250.1050 705Hz),4.82( s,2H), 6.80 ( br . s , 2H) _ 3475,3420,3350. 3300, (cDce~ ); 0.98 ( t,3H, J=
2980,2250,1740, 1710, 7Hz), L74 ~n 2H), 4.19( t, Vl-3 1690,lG10,1405, 1390, 2H, J=7Hz ), 4.85 ( s,2H), 1320,1300,1270, 1250, 4.6~5.6(br . c ,2 1240, 1090, 10457 950 925, 780, 745 3500,3380,2980, 2900, (CDC~ ; 0.92( t,3H, J=
2250,1720,1650, 1600, 7.5Hz), 1.6 (jn,2H), 3.45 ( t, Vl-4 1430,1390,1330, 1260, 2~ J=7Hz), 3.66(t ,2H,J=
1150,1130,1090, 1055, 5Hz), 4.35(t,2H,J=5Hz), 985,780, 750 4.82 ( s ,2 H ) . 4.9~5.4 ( b r . ~ , (Licluic- film) 2H) 3500, 3400, 2990, 2900, (CDC~.g );
2250, 1720, 1650, 1605, 3.66 ( t, 2H, J=fiHz) 1430, 139(), 1330, lZ60, 3.9 (d,2H, J=SHz ) Vl-5 1130, 1050, 990, 910, 4.35 (t ,2H,J=6Hz) 750. 4.B 2 ( s ,2 H ) (Li~lui(l film) 5.2 ( broad s,2H) 5.2 td,2H,I=llIlz) 5.4~5.9 ( m,1H) . ~ _ ~24099~

Table VI-l Example Compounds (VI) Yields * point (C2 VI-6 H2NcoocH2c-ccoocH2cH2ocH2c5H5 729~ stance VI-7 H2~coocH2c-ccoocH2cH2oc6Hs 17 2 g Oily sub-. _ _ Vl - 8 H2NcoocH2c--ccoocH2cH2N~ 3 ~ e ~z4C~99~

Table VI- 1 (cont'd~

E~mpl~I R ( K B r ) l'H - N~R ( g oMH z ) Nos .c m ~l ~ i n ppm 3480,3400, 3000, (CDC~3 );
2sno ~ 2250, 1720, 3.66 ( t,2H, J=S.SHz ) 1645,1600, 1435, 4.35( t,2H, J=5.5Hz) VI-61390,1325, 1255, 4.52 ( ~,2H) 1125,1090, 1055, 4.82( 9, 2H) 780, 740, 5.2 ( ~road s,2H) (Liqi~id film) 7.35 ( s,5H) _ 3480,3420, 2250, (CDC~
1720,1650, 1610, 3.65 ( t,2H, J=6Hz) 1600,1440, 1390, 4.35 ( t,2H, J=6~z) Vl-71330,l2fiO, 1150, 4.8 (s,2H) 1130,1090, 1060, 5.2 ( broad s ,2H) 780, 755 6.9~ 7.5 (m , S H ) (Liquid film) .
3500 ,3400, 2980, ~CDC~
2230,1720, 1650, 2.15 ( ~,3~1) 16()5,1435, 1390, 2.52( t,3H, J=6Hz) Vl-81325,12fiO, 1130, 3.48( ~,21~) 1USo, 780, 735 4.12 ( t,2H, J=6~z ) (Liquid ~llm) 4.8 ( s, H ) 5.2 ( bro~d s,2~) 7.34 ( 9, .~

~z4099~

EXAMI~LE Vl-9: Preparation of ethyl ~-propycarbamoyloxy-2-butynoate H ~NcoocE~2c--ccooc2H5 To 40 ml of a benzene solution of phosgene (containing 6.2 g (62.5 millimoles) of phosgene), 6.~ g (50 millimoles) of ethyl 4-hydroxy-5 2-butynoate was rapidly added under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. The reaction mixture was returned to room temperature and left to stand for one night. Then, the reaction mixture was concentrated under reduced pressure to distil off benzene, whereby 8.1 g (yield: 85%) of oily ethyl 10 4-(chlorocarbonyloxy)-2-butynoate was obtained as the residue.
IR (liquid film), cm 1 2250, 1785, 1720 11 NMR (90 MHz, CDCQ3), ~: 1.3g (t, 3H0, 4-28 (q, 2H)~
5.02 (s, 2H) 2.85 g (15 millimoles) of ethyl 4-(chlorocarbonyloxy)-2-butynoate 15 was dissolved in 30 ml of benzene, and 12 ml of a benzene solution of propylamine (containing 2.22 ml (27 millimoles) of propylamine) was rapidly added thereto under cooling with ice. The mixture was stirred for 30 minutes under cooling with ice. The reaction mixture was poured into ice water and adjusted to pH 2 with dilute hydrochloric 20 acid. To this mixture, 100 ml of ethyl acetate was added and stirred for extraction treatment. The ethyl acetate extraction solution was dried over sodium sulfate and concentrated under reduced pressure, whereby 3.08 g (yield: 96.296) of oily ethyl N-propylcarbamoyloxy-2-butynoate was obtained.

99~

IR (liquid film), cm 1 2250, 1785, 1720, 1250 H NMR (90 MHz, CDCQ3), ~: 0.95 (t, 3H, J=7Hz), 1. 35 (t, 3H, J=7Hz), 1. 62 (m, 2H, ), 3. 20 (m, 2H, ), 4.29 (q, 2H,), 4.86 (s, 2H,), 8.40 (broad, lH) EXAMPLE Vl-10 to VI-21:
In the same manner as in Example VI-9, the compounds identified in Table VI-2 were prepared.

. ., ~24099~

Table VI-2 . Melting I
ExaNmospl ¦ Compounds (VI ) Yields * point l -v ~ ;NCO CU~C-Vl-1l CH>NCOOCH2C--CCOOCH2CH2C~ 84% ;71--72 VI-12 C~?NCOOCH2C----CCOOCH2CH--CH2 7 5% sstuabn-ce I

Vl-13 c~NCOOCH2 C--CCOOCH2C----CH 6.8f souly-7 oo/O stance *: The yields of the compounds (VI) obtained by the reaction of 50 millimoles of the respective starting materials of the general formula VII.

124099~

Table VI - 2 (~ont'd) .
E~ I R I H - NM R ( 9 n MH z ) Nos . cm~l ~ i n ppm .
400,3000,2950,2240, ( CDC P,3 ) ; L37 ( t ,3 H , J =75 l720,1710,1530,1365, Hz), 4.3 ( q,2H, J=7.5Hz), VI-10 1245,1130,1070,1010, 4.88 ( s,2H), 4.8~5.2 (m, lH), 990, 770, 750 2.88(d,3H,J=4.5Hz) (Liquid film) .
3350,2950,2250,1710, ( CDC~.~ ); 2.85 ( d, 3H, J=4.5 17()0,1575,1455,1310, Hz), 3.75(t,2H,J=7.5Hz), Vl-11 1290,1280,1260,1250, 4.47(t ,2H,J=7.5Hz), 4.87 1160,1100,1010, 775, ( ~ , 2 H ) , 4.7~ 5.3 ( m ,1 H ) 750 (KBr) 34t)U,2970,2250,1715, ( CDC~3 ); 2.83 ( d,3H, J=6 1530,1450,1425,1365, Hz), 4.7(d ,2H,J=t~Hz), Vl-12 1240,1135,1070, 995, 4.83( s,2H), 4.6~5.1 (m, lH), 940, 775, 75n 5.2~5.6(m,2H), 5.7~6.3(m, (Liquid film ) 1 H ) i 344(),3370,3300,2960, ( cDce~ );
225U,2140,1720,1530, æ55 ( t, lII,1=3~1Z) 1440,1420,1370,1240, 2.83 (d,311,J=SHz) Vl-13 1130,1070, 995, 775, 4.79 ( d,2H, J - 3Hz ) 750 4.7 - 5.05 (m, lH) (Liquid film ) 4.83 ( ~,2 H ) :

924099~

Table V1-2 (cont'd) ~ . M eltir~
ExNampsl.e Compounds (VI) Yields * point ¦
. .

IVI 1 ~ C H > NC O CHz C----CCOOCH2 CHz OC ~ H ~ 9 5 7 ~ sub -VI- 15 C H >N C O O C H2 C----C C O O C H2 C~ Hs 7 0O/O stance .

Vl - lG > ~ICOOCH2C--C C O O Co H5 7.7 ~ souly-C ~3 6 6U,'o stance IC~O~ `--CCOOC2~is ~ 7.8~ ~subY

124099~L
- g5 -Table VI - 2 (cont'd) ExampleI R I'H--NMPc ( q o~IHz ) Nos. cm~l ~ in opm 3380,2980,2890,2250, (CDC~, ),0.93( t,3H, J=
1720,1530,145~),1365, 7l~z~, 1.63(m,2H), ".~4((1, Vl-141245,1130,1070,1015, 3H,J=5Hz), 3.45(t ,2H,J=
990, 770, 750 7Hz). 3.68( t ,2h,J=4.5Hz), (Liquid film) 4.35 ( t,2H,3=4.5Hz ), 4.85 ( s,2H), 4.8--5.3 (m, lH) 3400 ,2970,2250, ~ 720, ( CDCf~ ); 2.8 ( d .3H, J=5Hz ) 1530 ,1455,1420,1375, 4.81 ( s,2}1), 4.7~5.1 (m, lH), VI-15124û ,113n, lU7U, 995, 5.22 ( s,2H), 7.4 ( s,5H) 750, 700.
(Liquid ~llm) .

3~50 ,~:~80,2970; 225(), (~l)C~
173() ,1530,14~5,123n, 2.8(d,3H, J=5Hz), VI-lGI l 9Q, ] 13(), 990, 7~() 4.87 ( s,2H), (Liquid film) 4.7--5.2 ( m,1 H ), 7.0--7.~ (m,5H) 3370,30U0,22~0,172(), ( cDcr~ );
153U,1450,1370,1250, 1.18 ( t ,3H, J=7.5Hz), 1140,1075,1 ()25, 770, 1.34 ( t, ?sH, J=7Hz ) .
VI-17 750 3.28 ( quintet ,2H, J=7-7.5Hz ) (Liquid film) 4.3 ( q ,21~, J = 7 ~1 z ) 4.84 (s,2~O
4.8~5.1 ( m,1 H ) lZ4099~

Table Vl-2 (cont'd) Ex~npk Meltin g Nos. Compounds (Vl~ Yields* poing Vl- 18 C H > N C O O C H2C--C C O O C H:s 3 0 6/o st~bnce Vl -1~ T{ > NCOOCH2 C~ C 00 Cz ~156.8 ~ sOily t-C~ H~ 6 0% stance , Vl-~O C ~ NCOOCH2C--CCOOC2Hs 745/0 67--68 _ VI-21 C 1~ >~JCOOCH2C--CCOOC~12CHzOCJH7W 6.5~ soilb-6 L5~o stance .

~2409~1 Table Vl-2 (cont'd) I I!H--i~lMR ( 9 0 M H Z ) Example I R
Nos . c m~l ~ i n p pm 3400,2970, 2250, ( CDC~, );
1720,1535, 1435, æ82 (d,3H, J=6Hz) VI-18 1250,1130, 1070, 3.8 ( 5, 3H) 990, 940, 770, 4.82 ( 9, 2H) 750 (Liquid film) 5.13(m, lH) 3400,2250, 1780 (CDC~3 );
1720,1520, 1255 L32( t,3H, J=7.5Hz) Vl-19(Liquid film) 426(q 2H, J=7.5Hz) 4.79 ( s,2H) i 3350,2970, 2250, (CDC~
1715,1695, 1530, 1.34( t, 3H, J=7.5Hz) 1450,1320, 1265, 1.2~2.2 (m,1 OH) Vl-201250 ,1235, 1145, 3.3~3.8(m, lH) 1085,1050, 750 428 ( q,2H, J=7.5Hz ) ( KB r ) 4.7~5.1 (m, lH) 4.83(s,2~1) 3360,2950, 2870, (CDC~3 ) ;0.92( t ,3H,J=
225011720, 1530, 8H z ), 1.65 ( m, 2H ) 1450,1365, 1250, 33~3.8 (m, lH) Vl-211230,1130, 1075, 3.44(t ,2H,J=8Hz) }0~5, 985, 970, 3.65 ( t,21~, J=4.5~1z) 890, 770, 75(1 4.35 ( t,211, J=4.5Hz ) ~Liquid film) 4.6~ 5.1 ( m, 1 H ), 4.8 ( ~,2 H ) :1.24099~

EXAMPLE Vl- 22: Preparation of ethyl 4-N -phenylcarbamoyloxy-2-butynoate 6.4 g (0.05 mole) of ethyl 4-hydroxy-2-butynoate was dissolved in 100 ml of dichloromethane, and 6 ml (0.055 mole) of phenyl iso-5 cyanate and 0.5 ml of triethylamine were added thereto at a temperatureof - 20C . The mixture was reacted for 1 hour under stir~ing. The reaction mixture was washed with 10 ml of 1 N hydrochloric acid and water successively, then dried over magnesium sulfate and concentrated . under reduced pressure. The residue was separated and puri~led by 10 means of a liquid chromatography apparatus (System 500 A manufactured by Waters Co.) by using a silica gel column (Pre PAK-500(~) and ethylacetate-hexane (1: 3) as the developer solvent. Useful fractions were collected and concentrated under reduced pressure, whereby 10.6 g (yield: 85.8Q6) of oily ethyl 4-N-phenylcarbamoy]oxy-2-butynoate 15 was obtained.
IR (liquid film), cm 1 3350, 2250, 1720, 1540, 1255, 1210, 1050, 750 H NMR (90 MHz, CDCQ3), ô (ppm): 1.33 (5, 3H, J=8.5Hz), 4,3 (q, 2H, J=8.5Hz), 4.92 (s, 2H), 6. 9 - 7.2 (br. s), 7.3- 7.6 (br. s, 5H) EXAMPL~: VI-23: Preparation of ~-propoxyethyl 4-N ,N-diethyl-carbamoyloxy- 2-butynoate >NcoocH2c-ccoocH2cH2oc3H7(n) To 800 ml of a diethyl ether solution of phosgene (containing 298 g (2.5 moles) of phosgene), 112.1 g (2 moles) of propargyl alcohol was rapidly added under cooling with ice. The mixture was reacted for 2 hours under stirring and cooling with ice. The r eaction mixture was returned to room temperature and left to stand one night. Then, the ether was distilled off. The residue was purified by vacuum distillation, whereby 194 g (yield: 81.8~6) of colorless propargylchloroformate was obtained from the fraction distilled at a temperature of 47C/40 mmHg to 44C/34 mmHg.
Boiling point: 44C/34 mmHg-47C/40 mmElg 111 NMR (90 MHz, CDCQ3), ~: 2.68 (t, lH, J=3Hz), 4.88 (d, 2H, J=3Hz) To 200 ml of a benzene solution of diethylamine (containing 26 ml (249 millimoles) of diethylamine), 11.8 g (99.6 millimoles) of the proparg~yl chloroformate obtained as above, was added under cooling with ice. The mixture was reacted for 3~ minutes under stirring and 20 cooling with ice. The reaction mixture was poured into ice water and extracted with benzene. The benzene extraction solution was clriecl over sodium sulfate and then concentrated under reduced prcssure. The residue was purified by vacuum distillation, whereby 14.7 g (yield: 95gO) of colorless oily propargyl N ,N-diethylcarbamate 25 was obtained from the fraction distilled at a temperature of from 71 to 73C/8 mmHg.

9gl - Boiling point: 71-73C/8 mm Hg IR (liquid film), cm 1 3320, 3270, 3000, 2140, 1700 Il NMR (90 MHz, CDCQ3), ~: 1.16 (t, 6H, J=7.5 llz), 2.~8 (t, lH, J=3Hz), 3.33 (q, 41~, ~=7.5H~), 4.73 (d, 2H, J=3Hz) To 60 ml of a tetrahydrofran solution containing 14.7 g ( 9g. 7 millimoles) of propargyl N ,N -diethylcarbamate thus obtained, 57.4 ml (1.65 moles) of a hexane solution of butyl lithium (contain-ing 94. 7 millimoles of butyl lithium) was dropwise added at a temperature of from -65 to -75C (dryice, acetone cooling bath), and then 16. 6 g ( 99, 5 millimoles) of ,~-propoxyethylchloroformate was added at a temperature of from -60 to -70C. The mixture was reacted -for 30 minutes at a temperature of from -60 to -70C under stirring. Then, the cooling bath was removed, and when the liquid temperature reached room temperature, the reaction mixture was poured into ice water and extracted with ethylacetate. The ethyl-acetate extraction solution was dried and then concentrated under reduced pressure. The oily residue thereby obtained was purified by silica gel column chromatography (with use of 150 g silica gel).
The desired fraction eluted by benzene was collected and concentrated under reduced pressure, whereby 12. 65 g (yield: 46. 8~) of colorless oily ~-propoxyethyl 4-N ,N-diethylcarbamoyloxy- 2-butynoate was obtained .

`` ~240991 IR (liquid film), cm 1 2250, 1750, 1710, 1430, 1255, 1165 ll NMR (90 MHz, CDCQ3), ~: 0.93 (t, 3H, J=7E3z), 1.16 (t, 6H, J=7.5Hz), 1.62 (m, 2H), 3.33 (q, 4H, J=7.5Hz), 3.45 (t, 2H, J=7. 5Hz), 3. 67 (t, 2H, J=7. 5Hz), 4.33 (t, 2H, J=7.5Hz), 4.86 (s, 2H) EXAMPLE VI-24 to VI-35:
In the same manner as in Example VI-23, the compounds identified in Table VI-3 were prepared.

Table VI-3 xample M eltin g .
Nos Compounds (VI ) Yields t C

VI-24 C ~NC~OCH2C--CCOOCII2CH~OC3H~(n) 9.8~q SstiaYnce 1- 2 5 ~ i -C' H > N COOCHz C Z C C O O C H2 C H2 OC3 d. (n~ I g ~ Oily ~Vl-2(; ¦ ~ Cc~1l NCOOC'dzCZ COOCilz CH20C~ (nl ¦ 15 3g ~ sub- ¦

__ VI - 27 ce C~Z ~ 2>I`~ C O () C H2 C----C C O O Cz H5 3 1~ SstUabYnce I

*: The yields of the compounds (VI) obtained by the reaction of 0.1 mole of the respective starting materials of the general formula IX.

l.Z4099~

Table VI-3 (cont'd) Excun~le I R tH - NMR ( g OMH z ) Nos. cm~~ ~ i n ppm 2250,1715,1250. ( CDC~ ) 1175 - 0.93 ( t,3H, J=7.5Hz ) (Liquid film) 1.62 ( m,2H, ) 296 ( s ,6 H , ) VI-24 3.45 ( t,2H, J=7Hz) 3.6fi ( t,2H, J=4.7IIz) . 4.35( t,2H,J=4.7Hz) 4.84 ( s ,2H ) 2250,1705,1440, ( CDC~
1250,1050 0.92 ( t,3H, J=7.5Hz) 1.14 ( d,12H, J=7Hz ) Vl-25 (Liquid film) 1.61 (m,2H), 3.44 ( t,2H), 3.67 ( t,2H, J=4.7~z), 3.93(m ,2~, 4.35 ( t ,2H , J=4.7Hz), 4.85 ( s,2H) 2250,1710,1425, (CDC~3 );
1250 0.94 ( t,9H, J - 7.5Hz ) (Liquid ~llm) 1.1~ 1.8 (m,10H). 3.24 ( t, ~H, Vl - 26 J = 0.8 H ~ ) , 3.45 ( t ,2 H , J=6.8 Hz ), 3.66 ( t,2H, J=4.7Hz ), .35 ( t, 2~1, J=4.7~}z ), 4.84( ~,2H) (Licluid lïlm): ( CDC~ );
171U,1465,1420, 1.33(t ,3H,J=7.5I~z) Vl - 27 1370,13 0,1240, 3.5~4.0 ( m ,8 H ) 1150,1000, 880, 4.25 ( q,211, J=7.5Hz ) 765, 675 4.90 ( s,2~O

124099~

Table VI-3 (cont'd) ~;XNosPl ¦ Compounds (VI) Yieldsi MpeiOnct VI-28 C~H >~COOC~2C--CCOOC2H5 13.8s~ stlYncSeub~
r- -~

VI-29 c~ 1~5 >N C OOCH2 C----CCOOC2Hs 1 7.8 ~ Oily sub-Vl-30 ¦ ~lCOOCH2C--CCOOCzHs 10.~ Oily sub- .
/ 4 6% stance Oily sub-VI-31 C~COCH2C--CCOOC2H5 12.7~ stance _ 53% i ~.240~g~

Table VI - 3 (cont'd) Exarnple I R ~H--NMR ( 9 0 ~III z ) Nos. cm I ~ in ppm (Liquid film) : ( CDC~3 );
2250, 1785 ,1705, 1.1~2.0 (m, 23H) VI-28 1440,1240,1025 3.2~3.7 (m, 2H) 4.25 ( q, 2H, J=i.sHz ) 483( s, 2H) (Liquid film): ( CDC~3 );
2250,1720,1600, 1.30( t, 3H, J=7.5Hz) VI-2~ 1SOO,1380,1260, 4.25(q, 2H, J=7.5IIz) 1210 ,1055, 765, 4.9 0 ( s, 2H) 755, 700 7.3 4 ( s, 1 OH) (Liquid film) : ( CDC~3 );
1710,1435,1180, 1.3U(t ,3H,J=7.5Hz) Vl-30 1~)30, 860 1.9 0 (m, 4H) 3.44 (m, 4H) 4.23 ( q, 2H, J=7.5Hz) (Liquid film): ( CDC~, );
170r,14~10,1235~ 1.30( t ,3H,J~7.5Hz) Vl-31 l 150, lO30 1.62 (m, 6H) 3.5 3 (m, ~H) 4.2 3 ( q , 2~ , J=7.51-lz ) 4.77(s,2~) .

~z~o99~

Table VI-3 (cont'd) ~xarnplei ¦ j Melting ¦
Nos Compounds (Vl ) Yields*¦ point VI - 32 O~N C O O C H2 C--CCOOC 2 H~. 1 4.0 ~ sub-Tl - 33 CH~ I~ N C O O C H~ C CCOOC 2 H~ I 1 6. U 9 s ~ b Vl - 34 7rl0Cll-Z Cl-l >NCOOCH2 cac C O O C 2 Hs 9.1 ~ Oily ¦V~ ~5 ¦ I o~u ( ~1 ~NCOOCII, C a CCOOCH2 Clf20C~ a9'9 Isu Y-~~ -~240991.

Table VI-3 (cont~d) .
Ex~)le I R ~ H--NM R ( 9 o MI-I z ) Nos. cm~l ~ in ppm (Liquid film): ( CDC~.~ );
2250 ,17] 0 ,1~35, 1.3 4 ( t, 3H . J=7.5Hz ) VI-32 ] 241) 3.5 3 ( m, ~H) 3.71 (m, 4H) 4.2 9 ( q, 2H, J--i.5Hz ) 4.88( s ,2H) (Liquid film): ( CDC~a );
2250 ,1710 ,1435, 1.3 3( t, 3H, J=7.5~z ) 1365 2.34( s, 3H ) VI-33 2.41 (m, 4H ) 3.55(m. 4H ) 4.2 8 ( q, ~, J=7.51-{z ) 4.86 ( s, 2H) (Liquid ~lm): ( cDce~ );
3420 ,1700 ,1470, 1.29 ( t, 3H, J=7.5I-lz ) 1 4 0 , 1 3 7 0 , 1 3 2 0 , 3.5 4 ( m , 4 H ) VI-34 1260,1225,1145, 3.83 (m, 4H) 1050, 8fiO, 770 ~ 3.7~4.3 ( broad, 2H) 4.23( q, 2H, J=7.5Hz) 4.86 ( s, 2H) (Li~luid film): ( CDC~
34-20,17l)0,1475, 0.93~ t, 3I~, J=7.511z) 1 4 20 ,12fiO ,1 2"0, 1.6 2 (m , 211) VI - 35 I 1 2 5 , I 0 5 0 , 8 6 0 , 3.3 5~ 4.0 ( m , 1 2II ) 7 7 n 4.ll 8 ( broad 9, 2H ) 4.32( t, 2H, J=4.:311z) 4.84 ( 9, 2H) 99~

EXAMPLE VI- 36: Preparation of ethyl 4- (N-benzyl-N-methyl-carbamoyloxy)-2-butynoate C6H5CH2 >NcoocH2c-ccooc2H5 2.85 g (15 millimoles) of ethyl 4-(chlorocarbonyloxy)-2-butynoate obtained in the first step of Example VI- 9 was dissolved in 20 ml of dichloromethane, and 9 ml of a dichloromethane solution containing 3.1 ml (24 millimoles) of N-methylbenzylamine was rapidly added under cooling with ice. The mixture was reacted for 1 hour under stirring and cooling with ice. The reaction mixture was poured into ice water, 10 adjusted to pH 2 with dilute hydrochloride acid and subjected to extraction treatment. The dichloromethane extraction solution was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (with use of 30 g of silica gel). The desired fraction eluted by 15 llexane-benzene (1 : O ~ 3 : 1), was collected and concentrated under reduced pressure, whereby 1.18 g (yield: 28.5%) of colorless oily ethyl 4- (N -benzyl-N-methylcarbamoyloxy) - 2-butynoate was obtained.
Il~ (liquid ~llm), cm 1 2250, 1720, 1255, 1140 lH NMR (90 MHz, CDCQ3), ô: 1.30 (t, 3H, J=7Hz), 2.87 (s, 3H), 4.24 (q, 2H, J=7Hz), 4.49 (s, 2H), 4.87 (s, 2H), 7.31 (s, 5H) ~a.Z~09g~

l~XAMPLE VI-37: Preparation of ethyl 4-N-methylcarbamoyloxy-2-pentynoate H ~ NCooCHC- CCOOC2~5 To 90 ml of a benzene solution containing 3.8 g (26.7 millimoles) 5of ethyl 4-hydroxy-2-pentynoate, 1. 8 ml (30.5 millimoles) of methyl-isocyanate and 4.2 ml (30 millimoles) of polyethylamine were added, and the mixture was reacted for 1.5 hours at room temperature under stirring. The reaction mixture was washed with S0 ml of 1-N hydro-chloric acid and water successively, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel (Prep PAK 500/silica) column chromatography by means of a liquid chromatography apparatus (System 500 A manufactured by ~Vaters Co. ) . The desired fraction eluted by hexane-ethylacetate (3: 1) was collected and concentrated under reduced pressure, whereby 3.6 g (yield: 67%) of colorless oily ethyl 9-N-methylcarbamoy-oxy- 2-pentynoate was obtained.
IR (liquid film), cm 1 3360, 3000, 2850, 2250, 1710, 1530, 1470, 1450, 1420, 1370, 1240, 1130, 1095, 1050, 1020, 980, 940, 860, 775, H NMR (90 MHx, CDC~3), ~: 1.3 (t, 3H, 3=7.5i~
1.53 (d, 3H, J=GHz), 1.82 (d, 31-1, J=5.5Hz), 4.25 (q, 2H, J=7.511z), 4.6-5.1 (broad s, lH), 5.54 (q, lH, 6Hz) lZ4C~9~

EXAMPLE VI-38: ~par~tion of ethyl 4-carbamoyloxy-4-methyl-2-pentynoate >NCOOCC-- CCOOC2H5 To 100 ml of a dichloromethane solution containing 4. 9 g (31.4 millimoles) of ethyl 4-hydroxy-4-methyl-2-pentynoa.e, 3 ml (34.5 millimoles) of chlorosulfonyl isocyanate was added at a temperature of - 10C . The mixture was reacted for 30 minutes at -10C under stirring. The reaction mixture was returned to room temperature, and 20 ml of water was added thereto. The mixture 10 was stirred for 15 minutes for hydrolysis treatment. The dichloro-methane phase was separated by phase separation, washed with a10% barium chloride solution and water successively, dried over sodium sulfate and then concentrated under reduced pressure, whereby 2.1 g (yield: 33%) of ethyl 4-carbamoyloxy-4-methyl-2-15 pentynoate in crystal form was obtained.

mp: 111 - 113.5C
IR (KBr), cm 1 3580, 3360, 3300, 3220, 3020, 2240, 1710, 1605, 1380, 1370, 1265, 1230, 1145, 1050, 1035, 865, 785, 755 lH NMR (90 MHz, CDCQ3), ~: 1.24 (t, 3H, J=7.5I-lz) 1.64 (s, 6H), 4.2 (q, 2H, J=7.5Hz), 6.57 (s, 2H) --` ~z40~

EXAMPLl~ VI-39: Preparntion of ethyl 5-N-methylcarbamoyloxy-2-pentynoate CH?NcoocH2cH2c-c 2 5 To 50 ml of a benzene solution containing 2.85 g (20 millimoles) of ethyl 5-hydroxy-2-pentynoate, 1.2 ml (2û millimoles) of methyl isocyanate and 2.8 ml (20 millimoles) of triethylamine were added, and the mixture was reacted for 1 hour at room temperature under stirring.
The reaction mixture was purified in the same manner as in 10 Example VI-37, whereby 3.6 g (yield: 90.5g~) of colorless oily ethyl 5-N-methylcarbamoyloxy-2-pentynoate was obtained.
lR (liquid film), cm : 3400, 2970, 2240, 1710, 1530, 1470, 1370, 1250, 1140, 1075, 1010, 860, 775, 750 15 lH NMR (90 MHz, CDCQ3), ô in ppm: 1.33 (t, 3H, J=7Hz), 2.63 (t, 2H, J=6Hz), 2.83 (d, 3H, J=5Hz), 4.25 (t~ 2H, J=6Hz), 4.27 (q, 2H, J=7Hz,), 4.7-5.1 (m, lH) EXAMPLE VI- 40: Preparation of ethyl 4-carbamoyloxy- 4-phenyl-20 2 -butynoate H NCOOqHC- CCOOC H

To 100 ml of a dichloromethane solution containing 8 g t39.2 millimoles) of ethyl 4-hydroxy-4-phenyl-2-butynoate, 3.5 ml 25 (40.2 millimoles) of chlorosulfonyl isocyanate was added at a temperature of -20C, and the mixture was reacted for 30 minutes tll - 1()"(, ullclcr stirring. Tllen, llydrolysis ~nd purirlc~l~ioll tre~tll~ellt wel~c ~ollductecl in tlle same manner as in Example VI- 38, wl~ereby '1.5 g (yicl(l: ~8~G) of ethyl 4-carbamoyloxy-9-phenyl-2-butylloate in CI yst<ll forlll was obt~ined.
~ 32C
11~ (l~13r), cm 1 3~1G0, 3350, 32~0, 3010, 2950, 2250, 1730, 1705, 1~05, 1500, 1~G5, 13G5, 128(), 12G0, 1195, 1090, 1015, 780, 760, 750, 700 Il NMI~ (90 Mllz, CDCQ3), ~in ppm: 1.32 (t, 3H) J=711z), ;l o 4.2G (q, 21-3, J=711z), 5.05 (broad s, 211), G.51 (s, 11l ), 7.4G (broad s, 511) Now, J~'xamples for the preparation of the novcl 3-an~ o- 3-c~ )allloyloxyllltyl acrylic acid clcrivatives of t~le general fOI mlIla II
Or I llc pl cscnl invcnlioJl will be given.
l,~ 11'L.Ii' II-1: Preparation of et]lyl 3-amino-4-metllylcarl~alnoyloxy-crotonate ~ NCoocll2c=cl-lcooc2ll5 5 Ir (10 millillloles) of etllyl 4-N-Illetllylcarbalnoyloxy-2-l~ulyll07llc ull(l 3. ~34 g (50 millimoles) of ammorlium acetale were dissol.~l in 20 ml af ~] ar~l r~Lted at 60C f~r 4 h~rs UTX;~ st-i~:rirr~.
'l'llc r cslclion mixture wns concerltrate(l under reducecl prcssure.
To ll~(' l'CSi(lUC, 50 ml of etllylacetate nllcl 10 ITIl of a 20~7O so(li cll]ori(lc a(lucolls soluLion were added for extraction treatlllellt.
'I`llc clllylacctate extraction solution was dlied over magncsiulll sulfatc and concentrated under reduced pressure. The r csidue ~vas p~niriccl by silica gel (Prep P/~l~ 500/silica) column cllromntogr.lplly \\

` ~24~gg~

by means of a liquid chromatography apparatus (System 500 A
manufactured by Waters Co.). The desired fraction eluted by hexane-ethylacetate (5 : 4) was collected and concentrated under reduced pressure, whereby 0.88 g (yield: 44%) of ethyl 3-amino-4-N-methylcarbamoyloxycrotonate in crystal form was obtained.
mp: 60- 61C
UV ~lMmeaH 274 nm (E 14000) IR(KBr), cm 1 3950, 3350, 3000, 2950, 1720, 1660, 1620, 1590, 1540, 1445, 1370, 1280, 1190, 1170, 1055, 1040, 955, 790 H NMR (90 MHz, CDCQ3), ~ in ppm: 127 (t, 3H, J=75Hz), 283 (d, 3H, J=6Hz), 4.6 (s, 2H), 4.66 (s, lH), 4.75-5.1 (m, 111), 6.1-6.8 (broad, 2H) 15 EXAMPLE 11-2 to II-27:
ln the same manner as in Example II-1, the compounds indentified in Table II-1 were prepared.

, .

- 64~ -Table II- 1 R >NCOOCH2C=CHCOOR

. Example Compounds (II) * Melting ~ U V

tF r =~
II-2 H H CH3 0.94~ 9~92 %7 54/o .

II-3 H H C;~H5 ~98,~ 42--44 ;~74 . 52~; . . .
_ Il - 4 H H n--C~ H7 Q8 3~ Oily sub- 2 7 4 ~1~ stance __ . _ II- 5 ~I H CH~CH~OC~I7 (n) 145% stlaYr~cSeub~ 2 7 4 *: The yields of the compounds (II) obtained by the reaction of 10 millimoles of the respective starting materials of the generul formula VI.

124~ 91.

Table II-l (conttd) ~xample I R 1 H--N~/lR ( 9 O~,~HZ ) Nos. --1 ~ in ppm j ( ~Br ) : ( : D C l 3):
. 3 5 00, 3370, 3220, 564 ( ~,3H) 1730,16 ~ 0, 162 09 4.5 8 ( B, 2H) II-2 1570,1440, 1400, 4.6 3 ( a, l~) 1335,1280, 1170, 59 ( broad s,2H ) 1070, 950,920, 64~7.2( broad,2H) 800, 785 ( K ~ r ) : ( D M S 0--d 6) ;
3520,3 370, 3250, L17 ( t,3H, J=7.5HZ ) 1730,1660, 1625, 4.0 5 ( q, 2H, J=7.5~Z ) II-3 1565,13 ~ 0, 1335, 4.5 ( ~,2II ) 1290,1170, 1110, 4.5 ?J ( ~, lH) 1040,950, 780 ~76 ( a,2H) 7.2 ( broad 8, ''H) (Liquid fiimj: ( DMS0~6);
3480,3360, 2990, (19 ( t,3H, J=7HZ ) . 172 S, 1660, 1625, 16 ( m,2H) II-4 1570,1440, 1385, 4.0 ( t,2H, J=7HZ ) 1335,1330, 1285, 4.52 (8,2H) 1170,1070, 790 4- 55 (8, lH ) 6.73 ( broad 6, 2H ) ~g~7.6( broad, ZH 1 (Liquid film~: ( C D C .C 3), o.g(t,3~ J=7.
~s 460, 3350, 2970, L6 ( m,2H) . 2880,17 Z 0, 1660, ~44 ( t,2H, J=7.5HZ ) 1625,1570, 1440, :365 ( t,2H, J=6HZ ) II-5 138 ~,1330, 1280, 4.24 ~ t,2H, J=6HZ ) 1165,1040, 785 ~.6 (9, 2H), 50~6(8,2~) 61--6.9 ( broad 9, 2H) I
_ ~z~99~

Table 1.l-1 (cont'd) Example Compounds (II ) . Yields ~
Nos . _ ~ 6 C m a :~.

II - 6 H H C H2 CH2 0 C~2 C~ Q8 5 ~ stance 2 7 4 Il - 7 Il H C H2 CH, O C ~ CG ~5~ 11 oæ stance 2 7 g 11 - 8 H H C H C ~I ~1/ C ~3 12 4 ,~ sulbY- 2 7 4 2 6 5 4 ~5% stance _ II-'J IIC~13 C~3 a 48~o 14~147 273 _ .

~2~099~.

Table II-l (cont~d) ;
Example I R 1 H--~,IR ( 9 O~IHZ ) Nos. ~1 . ~ i n ppm .
3 g 5 0,3 3 5 0, 2 9 7 0, (CDC~3):565(t, 2~, J=
2 8 8 0,l 7 Z 0, l 6 5 0, 3.5HZ), ~.O(d, 2H, J=9~Z),~
1 6 3 0,1 5 7 0, 1 4~L0, 9.25(t, 2~, J~HZ), 4.6 11~6l 3 8 0,l 3 3 0,l 2 8 0, (s, 2H), 4.7(8, lH), 5l~
1 1 6 0,1 0 4 0, 1 0 0 0, ~5(m, 4H), 56~62(~, l~), 4 0, 87 0, 78 5, 6.3--G9(broad, 2 (Liquid film3 3 4 5 0,3 3 5 0, 2 9 8 0, (CDC'3);~64(t, 2H, J=
2 8 9 0,1 q 2 5, 1 6 6 5, ~EZ), d.20(t, 2~;, J=~~iZ), l 6 2 0,l 5 6 0, l 4 _ 0, _.52(s, 2H), 4-6(6, 2~)--l 3 7 5~l 2 8 0~ l 2 6 0, g~7(s, lH), 5~o~~4(brGzd~
II-7l 0 6 0,lO 4 0,l 0 0 0, 2H), 62~69(broad,

9 8 5, 9 4 0, 6 9 5 7.4(a, 5~) (Liquid film) _ I
3460, 3350. 2970, (CDC~3);~.20(s, 3 1 q 2 0,l 6 6 0, l 6 2 5, 2.62(t, 2H, J=~hZ), S5(s, 15 7 0, 144 0, 13 8 5, 2H), 4.17(t, 2H, J=6XZ), 11-8l 3 3 0,l 2 8 0,l l 6 0, 4.~(s, 2H), ~.7(s, lH), 51P~
l O 4 0, 7 8 0, 7 4 0, ( b r o aG s, 2~ ~69 (Liquid film) (broad, 2H), 7.27(s, 5H) j ( ~3r ); (D~S0~6);
3 ~ 5 0,3 3 5 0, l q l 0, 2~6 (d, 3~, J=45~Z) 16 8 0,1 6 2 0, l 5 9 0, :354( 8, 3H) 11-~l 5 3 5,l 4 2 5,l 3 8 0, 4.52(s, 5H) l 2 9 0,l ~ 5 5, 1 l 7 5, 6.~~7.7 (broad, 3H) ll~0, 980, qgo 1;2~0991 Table II- 1 (cont'd) Ex flmple ~ Com ~ounds (II ) ~ M elting l!'if3 x m I I - 10 H C H3 C Hz C H, C ~ L3 ~ ,~ sulby 2 ~ ~r . 5 8~o stance II - 11 H CH3 CHz C H=C H;~ 1.0 ,~ sub- 2 7 ~1 4 ~ stance Il- 12 H CH3 CH;~ C--CH ~ stuabnce 27 3 i . . ,.

Il- 13 II CH3 CH;,~ CH;~ O C3 H7 (n) 111;~ sub- 27 4 4~ 57'o stancf~

. .

Table II-1 (cont'd) Exnmple I R ~N~,IR(9Oh5Hz) Nos. --1 ~ in ppm 3 4 5 0, 3 3 5 0, 2 9 5 0, ( C D C .C 3 );
1 7 2 0, 16 6 5, 1 6 2 0, 2.85 t d, 3H, J=6nz ) 1 5 6 0, 1 S 4 0, 1 4 5 0, 3.7 ( t, 2H, J=6Hz ) Il-101 4 2 0, 1 3 8 0, 12 8 0, 4~5 ( t, 2X, J=6Hz ) 1 2 5 5, 11 6 0, 114 0, 4.63 ( 8, 2H), 4.7 ( ~, lH), 1 1 0 0 , 1 0 4 0 , 1 0 2 0 , 4.8--~3 ( m, lH ) 9 0 0 , q 8 0 6 1~~9 (~, 2H) ( Liqui d film ) 3 4 5 0 , 3 3 5 0 , 2 9 5 0 , ( CDCL3 ) ;
17 2 0, 1 6 S 5, 16 0 0, 2~5 (d, 3~I, J=6Hz ), 4~6 (d, 1 5 6 5, 1 4 4 0, 1 4 2 0, 2~I, J=4.5~z ), 4.62 ( 8, 2~1), 11-111370, 1260, 1165, 4.ô9(6, lH), ~0~55(m, 2H) 11 4 0, 1 0 4 O, 9 9 0, , 5.7~~2 (n~, lH), ~q~~7 ( 9 3 S, 7 9 0 broad~ 2H j, (Liquid fi1m) 62~9 ( br 0 a d,. lH ) .
3 4 4 0, 3 3 5 0, 2 9 5 0, ( CDC~3 );
21S0, 1720, 16qO, 2.~4(t, l~L J=3HZ) 1 6 2 0 , 1 5 6 0 , 1 5 4 0 , 2.8 2 ( d , 3 H, J=55 ~1 z ) 11-12 1440, 1420, 13qO, 4.6 (6, lII) 1 2 8 0, 1 2 6 0 1 1 6 0, 4.68 (d, 2H, J=3~z) 1100, 1040, 1000, 4.69(a, 2H), 4.9~~13(m, 1 940, 900, 785 HJ, 6.3~68(braad~ 2H) (Liqui~ film) 3 4 5 0, 3 3 5 0, 2 9 7 0, ( OD0~3 );
2 8 8 0, 1 7 2 0, 1 6 6 5, 0.92 ( t, 3H, J=7.SHz ), ~6 ( 1625, 1570, 1440, m, 2H), 2.82(d, 3H, J--GUæ) 11-13lS~0, 1330, 1280, , 3.44(t, 2H, J=7.5Hz),~63 1 2 G 0, 1 1 6 5, 1 1 3 0, ( t, 2H, J=45Hz ), 4.~3 ( t, 2 1045, 790 H, J=~.5Hz), 4.6(a, 2H),4-9 (Liquid film) --5.4 ( m, lH), Gl~69 ~brad, 2 ~240991 ~ 70 -Table II-l (cont'd) Example Compounds (II) Meltir.g UV
Yields point ,t ~l e OH r~
Nos. R5 R6 R3 ~ C ma x .
. .

11-14 H c~3CH2 C~H5 Q8q~soul~y- 2 7 3 3y~ stance _ 11-15 H CH3C6H5 Q9 O,~ sub- 2 7 4 . . 3 6% stance 11-16 HC~ H 5C~H5 Q9 1,~7 soilby- 27 4 4 7.5~ stance 1 l - l7 Ht~ll~ C :1~ S 7 S~ 9tubnce 2 7 _ lZ409gl.

Table II- 1 (cont~d) _ Example I R 1 H--NMR ( 9 03~HZ ) Nos. --I ~ in ppm _ 3450, 3350, 2~50, (D1l~0~6l;
17 2 5,16 6 ~ 2 0, 2~3(d, 3H, J=5H~; ) 1560, 1~L50, 1370, 455(E, 2H) Il-14 1 2 8 0, 1 2 6 0~ 1 0 6 0. 4.6 ( 8, lH) q 8 5 q 4 0 6 9 5 ~0 8 ( 6, 2H ) . 7.1~~:6 ( b r o a d, 311 ) (Liquid film) 7.4 ( 6, 5H ) 3 4 5 0, 3 3 5 0, 2 5~ 5 0, (D.~S0--d 6 );
17 2 0, 1 6 7 0, 1 6 2 5, 2.6 S ( d, 3H, J--5H:~ ) 15 7 0, 13 7 0, 12 6 0, 454( 8, 2H) II-15 1200, 1135. 1040, 4.64(Ei, lX) 102 0, 9 6 0, 7 9 0, 6q--7.8(m, 8H) (Liquid film) __ 3 9 6 0 , 3 3 6 0 , 3 0 o o , ( C D C ~ 3 ) ;
17 2 0, 16 6 5, 16 3 0, 1.16 ( t, 3H, J=~.5HZ ) 1 5 7 5 ,1 5 3 5 , 1 ~ 5 0 , L2 7 ( t , 3 ~, J--7 H Z ) -16 1370, 1290, 1250, 527(~11, 2~) 1 0 q 0, 1 0 9 5, 1 0 3 0, 4.15 ( ~, 2H, J=7HZ ) 7 9 0 4.6 ( i3, 2H ), 4.6 6 ( i--i, lH ) (Liquid film) 5~0 8 ( m, 1H ) 5.9~6.9 ( e, 2H ) S ~ 5 O, 3 3 5 0, 2 9 8 0, ( CDC ' ~ ); .
1 7 2 0, 1 6 6 0, 1 6 2 0, L3 3 ( Fl 91I ) 1 5 7 0, 15 2 5, 1 4 5 5, 4.13 ( q, 2H, J=8HZ ) 11-17 1365, 1285, 1265, ~.53(~, 2~1) 1210, 1165, 1085, 4.65(8, 1~)

10 ~ 0, 9 10, 7 8 0 4-76--~03(broad, lH) (Liquid film) 6.1~.7 6 ( b r o ~d, 2H ) 24099~

Table II-l (cont'd) Example Compounds (II ) Melting UlV OTI
_ _ I Yields pointA v ~ nm No~ R R6 R3 C ma ~

I1- 18 H /3 C2 H5 Q 6 8~2 sllb - 2 7 4 2 5% stance _ _ I1- l9 H ~ . CH2 CH.~ O C3 H7 ( n ) Q8.45~o sub - 2 7 .L

11- 2 0 H ~ C2 Hs Q9 151 su~b - 2 7 g 3 45~o stance II - 21 H n C~ C~ H5 Q8 9 ~;7 s01il1b 2 7 4 stence Table Il-1 (cont'd) ,;Examp1e I :R 1 H--N~ R ( 9 O~I3 ) ¦ l~OS. C,?Z 1 ~ ~ n ppm 3 4 6 0 ,3 3 6 0 ,2 9 5 0 , ( CDC ~ 3 ) ;
1 7 1 5,1 6 6 5,1 6 2 5, 1.2 5 ( t, 31~ J=r~ 11 z ) L~--. l 5 7 0, l 5 3 0, l ~ 5 0, 2.Z(m, lOH), ~3.7 (m, lH), II-18 l 3 6 5, l 2 8 0, l 2 5 0, *15 ( q, 2H, J=7HZ ), 4~8(9, l 2 3 0, ll7 0, l 0 4 0, 2H), 4.66( 6, lH), ~--51(m, 7 9 0 lH ), 6~69 ( b r o ad, 2X ) (Liquid film~
3 4 7 0, 3 S 6 0, 2 9 6 0, ( CDC~3 ); 0.9 2 ( t, 3~, J=7 2 8 8 0, l 7 l 5, l 6 7 0, HZ ), L65 (~, 2H), l.~2.2(;!1, 1 6 3 0, l 5 7 5, 1 5 3 0, lOF, ), 3.3--~7 ( m, lH ), ~45 Il-l9l 4 5 5, l 3 8 5, l 5 7 0, ( t 2H, J=7HZ ), 6 ( t, 2 l 2 ~3 0,l Z 6 0, l % 3 5, , 4~9 ( G, 2H), 4.7 ( B, l~I ), l l 7 0, l l 3 0, l 0 6 0, 4.o~~1 ( m, lH ), 61~69 l 0 5 0, 8 9 0, 7 9 0 ( br, 2H ) (Liquqd film) 4 6 0, 3 3 5 0, 3 0 0 0, ( CDC~3 );
1 q l 0, l 6 4 0, l 6 0 0, L25 ( t, 3~I, J--8HZ ) 1 5 7 0, 1 5 4 0, 1 ~ ~ 5, 4.13 ( q, 2H, J=8HZ ) 11-20 13 7 0, l 2 8 0, l 2 6 0, ~.6 ( ~, 2H), 4.6~ ( 6, lH) 1 2 l 0, l 0 5 0, 9 0 0, Gl~7.3(broad, l~I) 8~5, 750 7.41(~, 5~) . (Liquid film) 3 ~ 6 0, 3 3 6 0, 3 0 0 0, ( CDC ~ 3 3; Q9 3 ( t, 3H, J=q.5 l 7 2 0, l 6 6 5, 1 6 3 0, HZ ), l26( t, 311, J--7.5HZ ), 1575, 1535, 1460, l56(m, 2H), 5l8(q, 2H, J--11-21 l ~ 5 0, 13 7 0, l 2 9 0, 75HZ ), 4l~ ( q, 2H, J--7.5H
1275, 12~0, 1170, 4s_s3(m, l~), 61--ti9 1 15 O, 110 O, 1 0 4 O, ( broad, 2H) 7 9 0 (Liquid fi~m) _ I

- ~l,z4099l Table 11-1 tcont'd) ¦~ RS Compounds (Il) ~ 1~ ~ ¦

_ 11. 9 ¦ Gily sub- 274 11- 2 2 H ~3C C 2H 5 3 9 75 I st ance

12. 7 ¦ Oily sub- 274 II-23 H ~CQ CH3 44. 6% stan _ 10 . 5 ~ Oily sub- 2 7 4 11-24 H H CH2CH2ocH3 48.1% stance I 11.9 ~ jOily sub- 274 11-25 H ~) CH2CH20CH 3 ¦~ ~ stan _ 11. 2 ¦ Oily sub- 27 4 11 _ 2 6 H ¦~ CH 2CH 20C 3H7 34 8~ stance CQ 14.7 g Oily sub- 274 11 27 H 1~ CH2CH20C3H7 1~ stance ~.Z4099'1.

Table II- 1 (cont'd) Example -1 lH NMR (90 MHz) Nos. cm ~ in ppm (Liquid film): (CDC Q3) 3450, 3350, 1720, 1665, 1.25 (t, 3H, J=7.5Hz), 4.15 (q, 2H, 11-22 1625, 1290, 1175, 830, J=7.5Hz), 4.6 (s, lH), 4.67 (s, 2H), 770, 74û 5.9-7.0 (broad, 2H), 7.45 (d, 2H, J=8.5Hz), 7.63 (d, 2H, ~=8.5Hz) (Liquid film): I (DMSO-d6):
3460, 3350, 1710, 1670, 3.54 (s, 3H), 4.52 (s, 3H), 6.5-7.7 11-23 1630, 1290, 1170, 1145, (broad, 3H), 7.48 (d, 2H, J=8~0Hz) 830, 790, 740 7.65 (d, 2H, J=8. OHz) _ (1iquid film): I (CDCQ3) 3460, 3350, 2970, 1720, 3.42 (s, 3H), 3.65 (t, 2H, J=4Hz), II-24 1660, 1625, 1330, 1280, 4.23 (t, 2H, v=4Hz), 4.6 (s, 2H), 1160, 1035, 785 4.69 (s, lH), 5.27 (broad, s, 2H), 6.1-6.9 (broad, 2H) (Liquid film): (CDC Q3):
3470, 3360, 2950, 1710, 0.9-2.2 (m, lOH), 3.4 (s, 3H), 3.3-11-25 1665, 1625, 1280, 1165, 3.7 (m, lH), 3.64 (t, 2H, J=4Hz), 1040, 700 4.23 (t, 2~ ,=4~1z), 4.58 (s, 2~1), 4.65 (s, lH), 4.6-5.1 (m, lH), 6.0- 6. 9 (broad, 2H ) _ (Liquid film): (CDC Q3):
3440, 3340, 2970, 1720, 0.94 (t, 3H, J=7Hz), 1.3- l.9(m, 2H) 1665, 1625, 1570, 1255, 3.45 (t, 2H, J=7Hz), 3.67 (t, 2H, 11-26 1165, 1130, 830, 770, a=5Hz), 4.35 (t, 2H, J=5Hz), 4.59 740 (s, 2H), 4.68 (s, lH), 4.9-5.45 (broad, lH), 6.0-7.0 (broad, 2H), 7.45 (d, 2H, J=8Hz), 7.65 (d, 2H, J=8HZ) ( Liquid film ): I (CD C Q 3) 3440, 3340, 2970, 1720, 0.92 (t, 3H, J=8.5Hz), 1.3- 1.9 (m, II 2 1660, 1620, 1570, 1530, 2H), 3.44 (t, 3H, J=8.5Hz), 3.63 7 1280, 1260, 1165, 1130, (t, 2H, J=4.5Hz), 4.22 (t, 2H, 810, 750 J=4.5Hz), 4.62 (s, 2H), 4.71 (s, lH), 4.9-5.5 (broad, lH), 6.1-6.9 (broad, 2H), 7.4 (d, lH, J=8Hz), 7.52 (d, lH, J=8Hz), 7.7 (s, lH) - .
1 2409~3~

EXAMPLE II-28: Preparation of ~-propoxyethyl 3-an~ino-4-N,N-diethylcarbamoyloxycrotonate CH3cH2~NcoocH2c=cHcoocH2cH2oc3H7(n) 12.5 g (43. 8 millimoles) of ~-propoxyethyl 4-N ,N-diethylcarbamoyl-S oxy-2-butynoate was dissolved in 180 ml of isGpropyl alcohol, and 11 ml of 28% aqueous ammonia was added. The mixture was reacted at 60C for 1 hour under stirring. The reaction mixture was concen-trated under reduced pressure. The residue was extracted with ethylacetate. The ethylacetate extraction solution was subjected to water-removal treatment and then concentrated under reduced pressure.
The residue was purified by silica gel (Prep PAK 500/silica) column chromatography by means of a chromatography apparatus (System S00 A
manufactured by Waters Co.). The desired fraction eluted by hexane-ethylacetate (2: 1) was collected and concentrated under reduced pressure, whereby 8.6 g (yield: 65~6) of colorless oily ,B-propoxyethyl 3-amino-4-N,N-diethylcarbarl10yloxycrotonate was obtained.
UV: ~MmealI 275nm (e 13500) IR (Liquid film), cm 1 3450, 3350, 2980, 1695, 1625, 1575, 1480, 1430, 1380, 1365, 1275, 1160, 201120, 1095, 1070, 1005, 790, 765 H NMR (9n MHz, CDCQ3), ô in ppm:
0. ~2 (t, 3~1, J=8~-lz), 1.15 (t, 611, J=7.5Hz), 1.62 (m, 2H), 3.32 (q, 4H, J=7. SHz), 3.45 (t, 2H, J=8Hz), 3.65 (t, 2H, J=4.5Hz), 4.25 (t, 2H, J=4.5Hz), 4.62 (s, 2H), 4.71 (s, 1H), 6.0-7.0 ( broad, s, 2H ) -:12~C)99~

EXAMPLE 11- 29 to Il - 40:
In the same manner as in Example II-28, the compounds identified in Table Il-2 were prepared.

1:~4099~.

Table II-2 R-CooCH2C=CHCooR3 _ Example I Compc nds (II) ¦Me.?ting U V
Nos. R R3 C mæ x.

11 ~.~ j _ II-30 i C~H7/ CH~CH;~OC~H7(n) 1.495% sstuabn-ce 2 7 ~L

l ~ r--11-31 n--C4H~\N-- CH~C~;2OC3H7 (n) ~A7,~ sOul,~y 2 7 5 n--C4 H~/ 4 l~o/ stance .

Il-32 C CH;~CH~ C2H5 1'65% SstUabnce 2 7 5 *: The yields of the compounds (II) obtained by the reaction of 10 millimoles of the respective starting materials of the general formula VI.

- ~ 2a~099~

Table II-2 (cont'd) Ex~mple I R 1 H--NMR ( 9 0 ~HZ ) Nos . cm I ~ i n pp~
3460, 3350, 2970, (CI)C.~3):
2 9 0 0, 1 5~ 1 0 ~1 6 7 5, 0.9 3 ( t, 3H, J=8H3 ) 1 6 3 0 , 1 5 7 5 ,1 4 0 ~ 1.6 3 ( m, 2II ) , 2.9 8 ( 9 , 6 H ) I I - 2 9 1 3 6 0, 1 2 8 0, 1 1 ~ O, 54 6 ( t 2~ z ) ~ 2 5 ( t, ZH.
116 5, 112 O, 10 6 O, J=5HZ ), 4.6:Z( a, 2H), 4.74 7 9 0, 7 q O ( 8, lH), ~2~69 (brGad, ZH) (Liquid film ) 3 4 5 0~ 3 3 5 O, 2 9 9 o, ( CDC~3 );
2 9 0 O, 16 8 O, 16 3 O, tl92( t, 3H, J--8HZ ), 125(d, 1 5 7 0, 1 4 6 S, 1 4 4 O, 2~, J--8HZ ) . 1~18 _(m, 2 11-3013 q 0,1 3 1 O, 1 2 ~ O, ( t, 2H, J=6HZ ), 598 ( q, Z~I, 1 2 2 0, 1 1 6 0, 1 1 3 5, J=8HZ ), 4.2S ( t, 2H, J=6HZ ) 10 6 O, 9 9 5, 7 9 O, 4.62( 8, 2H), 4.73 ( æ, lH) 7 7 (Liquid fi1m) 62~6.8 ( b r o a d, 2H ) 3 4 5 O, 2 9 7 O, 2 ~ 9 O, ( CDC~ 3 );
1700, 1(~30~ 15qO~ ~93(t, 9H, J=7HZ), 105--1470, 1420, 1370, 18(m, lOH), ~25(t, 4H~ J
Il-31 1 2 9 0, 1 2 2 0, 1 1 6 0, ---7H Z ) 3.4~ ( t, 2H, J--7 HZ ) 1110, q a 0, q q o 4.25 ( t, 2~, J=4.5HZ ), (Liquid film) 4.61 ( B, 2H ), 4.7 1 ( ~, lH ), 6:~9 ( broad, 2H ) 3 4 6 O, 3 3 5 O, 3 0 0 0, ( CDCL3 );
29 q 0, 1710, 16 7 O, L38( t, 311, J--75HZ ) 1630, 1575, 1a qO, 3,qq(t, 21I, J=35~Z) 1410, 13~;5, 12~O, 593(t, 2H, J~5H':) 11-32 1 2 6 0, 1 2 0 S, 1 1 7 0, g,.16 ( q, 2H, J--7.5H:~ ) 114S, lO7S, 1005, 4.68(a, 2H), 4~73(a, lH) 990, 880, 79~ 61--6~(broad~ 2H) . 7 7 0 (Liquid film) :1.2409~

Table II-2 (cont'd) _ ._ Ex~mple Compounds (Il ) M ~lting UV
_ _ Yields* poi~t ,~ Ir~D
Nos . R R C ma ~

I 1- 3 3C 6 Hll N-- C .2 Ha 1.1 ~ ~ 8 7. 5 2 7 4 11-34Cl;H5 \N-- C2H5LQ58% ll~allq 2q33, Il - 35~N-- c;c E~51.52 1~SstUabnce 2 7 4 _ . _ 11 3G CN-- C~ ~I5 ~ 5~7 S0U1Y ~ 7 L
5 2 5~o stance ~2~09~1.

Table 11-2 (cont'd~

Ex~mpieI R j I~I--NI~R ( 90M~Z ) l~os. cm 8 i n ppm .
3 4 2 0, 3 3 3 0,2 9 5 O, t ODC~ ~ );
2860, 1690, 1660, 12~(t, 3~, J=7~z) 1630, 1565, 14g5, L4,--~l(m, 2()H) II-331 3 5 0, 1 2 9 0,1 Z 6 5, 52~58 ( m, 2H ) 12 3 ~, 117 0, 1 1 6 0, ~.15 ( q, 2H, J--7.5~
1090, 1030, 895, ~6(s, 2X), 4.~8(E3, 1~) 79 0, 7 6 5 ( ~Br ) 61--7.0(broad, 2II?
3 4 5 0, 3 3 5 0,3 0 0 0, ( CDC t 3 ) , 1 ~ 7 0, 16 3 0,1 5 8 5, 125 ( -t, 3H, J--7H~ ) .
14 9 0, 1 4 1 0,1 3 5 0, 4.1'3 ( q, 2 H, J--7H~ ) II-3413 1 0, 1 2 ~ 0, 1 17 5, 4.6 ( ~, lH) 10 ~ 5, 1 0 5 0, 9 7 (), 4~8( s, 2H) 7 9 5, 7 5 0, 7 0 () 5.8~~7 ( broad, ~ ) ( K B r ) 7.1~7.6 ( m, 5H ) .
3460, 3~60, 30()0, (C~:)C~3); ~- .
2 9 0 0, 17 0 0, 1 6 q 0, 1.26 ( t, 3H, J=71IZ ) 16 2 5, 15 7 5, 14 4 0~ 189 (m, 4H), 3,4 ' ( m, 4H) II- 351 2 0, 13 7 0, 13 5 0, 4.15 ( q, 2H, J--7HZ ) 1 3 4 0, 1 2 9 0, 1 1 ~ 5, ~L.t; ~, ( 8, 2H ) 1 1 3 0, 1 1 0 0, 1 0 5 O, 4~6 r~ ( 9 ~ 1~ ) 7 ~ 0, 7 7 0 ~O~~.o ( bro~d, 2H) (Liquid 911m) , ,~
3~-~0, 33S0, 295(:~, ~C~ ,3J,, 2 8 7 0, 17 O 0, 1 ~ 7 0, L2~3 ( t, 3H, J--~H~ ) 16 'S, 1570, 1440, 1~2(broad, B, ~H) II-~G1365, 12~35, 1260, ~3(broad, ~, 4H) 1 ?. 3 S, 1 1 f3 0,1 1 5 0, ~.17 ( q, 21I, J--'~H~ ) 10 9 0, 10 2 5, 7 9 0 4.6~ ( 6, 2H ), 4(j~ ( ~, lH) (Liquid film) 60~--7.0 ( broad, 211 J
. ~

lZ4099~

Table II-2 (cont'd~
_ , Example Compounds (II) l~qelting ¦ IJV
Yields* point ~ 0-.
Nos. R R3 C '(;3a~

II - 37 ~/-- C2 H s ll 2~ soulb - 2 7 4 4 ~5/o stance II - 3 8 C H3--N N-- C 2 H 5 15 62% sstuabn-ce 2 ~ 3 . .

CEI3 \ C2 H5 LO 5 ,,$1 sub - 2 7 3 II - 39 C 6 H5 CH2/N S 6% stance ~ ~ l II-40 llOCH~C~2\N_ C~H5 Q83,~7 sulb- 27 4 l !oc~I2cH2/ 3 0~ ~

~240~91 Table 11- 2 (cont'd) Example --1 j 1 H--N MR ( 9 0 MH Z ) Nos . cm ~ i n ppm 3450, 3350, 2980, I ( cnc~3);
2 8 6 0, 17 0 0, 16 7 0, L28 ( t, 3H, J=7.5HZ
.1 6 2 5,1 5 7 0,1 4 6 0, ~53 ( t, 4H, J=&~Z ) II- 37 1 4 3 0,1 3 6 5, 1 2 8 0, 3.71 ( t, 4H, J=4.o~Z ) 1 2 4 0,1 1 6 5, 1 1 15, 4.18 ( q, 2H, J=7.5Hz ) 1090, 1070, 1040, 4~65(a, 2H), 4.7(~, lH) 9 7 0, 8 5 0, 7 9 0, 60~7.0(broad, 2H) q 6 o (Liquid film) 3 4 6 0, 3 3 5 0, 2 9 6 o, ( CDCL3 );
2 8 Z 0, 1 q 1 0, 1 6 q 5, 12 6 ( t, 3~, J=7.5HZ ) 1 6 3 0 , 1 ~ 7 5 , 1 4 6 5 , 2.33 ( 8, 3~ ) II- 381 ~ ~ 0, 1 3 7 0, 1 2 9 5, 2~2 ( t, ~H, J=4HZ ) 1 2 B 0, 1 2 4 0, 11 7 0, 5ss ( t, 4:~, J=4HZ ) 1 1 5 0, 1 1 10, 1 0 7 5, ~6 2 ( 6, 2H ), ~.~ q ( F;, lH ) 1050, 1010, 790, 6.0~7.0 ( broad s, 2H) 7 ~ 5 (Liquid fiIm) 3 4 ~ 0 , 3 3 5 0 ,3 0 0 0 , ( C D C ' 3 ) ;
2 9 5 0, 17 10, 1 6 7 0, L27( t, S~, J=~.5HZ ) 1 6 3 0, 1 5 7 0, 1 4 8 o, 4.15 ( q, 2~, J=7.5HZ ) 1455, 1405, 1370, 4.5 (6, 2J~) II-391 2 9 0, 1 2 3 0, 1 1 7 0, 4.6q ( 6, 3H ) 11 4 5, 10 4 0, 7 9 0, 60~7.0 ( broad, 2H ) 77o, 700 7.1~7.~(bro ad, "H) (Liquid film) 3 4 5 0 , 3 3 5 0 ,2 9 6 o , ( CDC~ 3 ) ;
16 9 0, 16 3 0, 15 7 0, Lz4 ( t, 3tI, J=7~Z ) 1 4 q 0, 1 4 2 0, 13 7 0, 3.51 ( t, 4H, J=~-5HZ ) Il-~o1290, 1220, 1170, ~ (t, ~I, J=4~s~z) 11 4 0, 1 0 7 0, 1 0 4 5, 4.1 ( q, 2H, J=7HZ ) 8 6 0, 7 9 0, q 7 o ~26 ( ~, 2H), 4.63 ( 8, 3E~ ) (Liquid film) ti5~69 ( broad. 2~ ) .

-` ~2~099~

E;XAMPLE II-41: Preparation of ethyl 3-amino-4-N-methylcarbamoyl-oxycrotonate 1. 85 g ( 10 millimoles) of ethyl 4-N -methylcarbamoyloxy- 2-butynoate and 3.95 g (50 millimoles) of ammonium bicarbonate were dissolved in 20 ml of methyl cellosolve and reacted at 60C for 4 hours. The subsequent treatmentswere conducted in the same manner as in Example Il-1, whereby 0.8 g tyield: 40%) of ethyl 3-amino-~-N-methylcarbamoyloxycrotonate in crystal form was obtained.
mp: 60- 61C
The analytical results by IR(KBr), UV and 1H-NMR agreed very well to the results obtained with respect to the compound of Example II-1.
EXAMPLE II-42: Preparation of ethyl 3-amino-4-N-methylcarbamoyl-oxycrotonate 1. 85 g (10 millimoles) of ethyl 4-N-methylcarbamoyloxy-2-butynoate and 1.73 g (12.5 millimoles) of ammonium benzoate were dissolved in 20 ml of dimethylformamide and reacted at 60C for 1 hour under stirring. The subsequent treatmentswere conducted in the same manner as in Example 11-1, whereby 1.1 g (yield: 55%) of ethyl 3-amino-4-N-0 methylcarbamoyloxycrotonate was obtained.
mp: 60- 61C
The analytical results by IR(KBr), UV and l~-NMR agreed very well to the results obtained with respect to the compound of Example II-1.

124099~

EXAMPLE Il- 43: Preparation of ethyl 3-amino-4-N-methylcarbamoyloxy-2-pentenoate 3.6 g (18 millimoles) of ethyl 4-N-methylcarbamoyloxy-2-pentynoate and 1.5 g (19.5 millimoles) of ammonium acetate were dissolved in 20 ml of dimethylformamide and reacted at 60C for 2 hours under stirring .
The reaction mixture was concentrated under reduced pressure.
The residue was dissolved in 8 mixed solution of 50 ml of ethyl-acetate and water and stirred for mixing. The ethylacetate extraction solution was washed with water, then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel (Prep PAK 500/silica) column chromatography by means of a liquid chromatography apparatus (System 500 A manufactured by Waters Co. ) . The desired fraction eluted by hexane-ethylacetate (2: l) was collected and concentrated under reduced pressure, w hereby 2 g (9.3 millimoles, yield: 52~6) of oily ethyl 3- amino- 4-N -methylcarbamoyloxy- 2-pentenoate was obtained .
UV: ~MeaH 274nm IR (liquid film), cm ': 3440, 3350, 3000, 1710, 1660, 1620, 1580, 1445, 1360, 1310, 1260, 1165, 1140, 1090, 1030, 955, 7gO
H-NMR (90 MHz, CDCQ3), ~ in ppm:
1.25 (t, 3H, J=7Hz), 1.43 (d, 3H, J=7.5Hz), 2.8 (d, 3H, J=6Hz), 4.13 (q, 2H, J=7Hz), 4.66 (s, lH), 4.7-5.16 (broad, lH), 5.23 (q, lH, J=7flz), 5. 9-6. 9 (broad, 2H) - EX~MPLE II-44: Preparation of ethyl 3-amino-4-carbamoyloxy-4-methyl- 2- pentenoate H NCOOC--C = CHCOOC2H5 (~H3 N 2 The reaction and purification treatment were conducted in the same manner as in Example II-43 except that 2.1 g (10.5 millimoles) of ethyl 4-carbamoyloxy-4-methyl-2-pentynoate w~s used asthe starting material, whereby 0. 47 g (2. 1 millimoles, yield: 20~o~ of ethyl 3-amino-4-carbamoyloxy- 4-methyl- 2-pentenoate in crystal form was obtained .
mp: 109- 111C
UV ~ MeOH 277nm max .
In(KBr), cm 1 3460, 3350, 3290, 3220, 3000, 1735, 1650, 1630, 1610, 1555, 1360, 1295, 1200, 1160, 1140, 1100, 1025, 1000, 790 lH-NME~ (9OMHz, CDCQ3), ~ in ppm:
1.26 (t, 3H, J=7.5Hz), 1.62 (s, 6H), 4.15 (q, 2H, J=7.5Hz), 4.7 (s, lH), 5.06 (s, 2H), 6.3- 6.9 (broad, 2H) EXAMPLE Il-45: Preparation of ethyl 3-amino-5-N-methylcarbamoyloxy-_pentenoate CH ~NcoocH2c~l2 lc--cHcooc2H5 The reaction and purification treatment were conducted in the same manner as in Example II-43 except that 3.6 g (18 millimoles) 25 of ethyl 5-N-methylcarbamoyloxy-2-pentynoate was used as the starting material, whereby 0.48 g (2.2 millimoles, yield: 12.2Q6) of oily ethyl 3-amino-5-N-methylcarbamoyloxy-2-pentenoate was obtained.

,. :

,; .

UV ~ MeOH 276nm max.
IR (liquid film), cm 1 3475, 3360, 3000, 1730, 1660, 1615, 1430, 1385, 1350, 1270, 1170, 1100, - 1~40, 790 1H-NMR (9OMHz, CDCQ3), ~ in ppm:
1.32 (t, 3H, J=8Hz), 3.83 (t, 2H, J=7.5Hz), 4.06 (t, 2H, J=7.5Hz), 4.25 (q, 2H, J=8Hz), 4.83 (s, lH), 5.2-5.4 (broad s, 2H), 6.3-7.0 (broad, 2H) EXAMPLE II-46: Preparation of ethyl 3-amino-4-carbamoylo~y-4-phenylcrotonat e H2NCOO ICH - C = CHCOOEt i5 The reaction and purificiation treatments were conducted in the same manner as in Example II-37 except that 4.95 g (20 millimoles) of ethyl 4-carbamoyloxy-4-phenyl-2-butynoate was used as the starting material, whereby 1.9 g (yield: 26.1%) of oily ethyl 3-amino-4-carbamoyloxy- 4-phenylcroronate was obtained.
UV: ~Mmeall 274nm IR (liquid film), cm 1 3450, 3350, 3200, 3000, 1740, 1660, 1630, 1570, 1500, 1450, 1370, 1320, 1305, 1280, 1260, 1200, 1170, 1060, 1025, 965, 755, 695 lH-NMR (9OMHz, CDCQ3), ~ in ppm:
1.34 (t, 3H, J=7Hz), 4.28 (q, 2H, J=7Hz), 4.83 (s, lH), 5.1-5.3 (broad s, 2H), 6.1-6.8 (broad, 21-l), 7.5 (broad s, 511) ~ 8~3L
Now, the process for the preparation of 2-carbamoyloxyalkyl-1,4-dihydropyridine derivatives according to the present invention will be specifically described.
EXAMPLE I-1: Preparation of 2-carbamoyloxymethyl-6-methyl-4-(o-nitrophenyl) - 3,5-diethoxycarbonyl- 1,4-dihydropyridine 9.4 g (50 millimoles) of ethyl 4-carbamoyloxy-3-aminocrotonate and 13.2 g (50 millimoles) of ethyl 2-(o-nitrobenzylidene)acetoacetate were dissolved in 200 ml of ethanol and reacted at a temperature of from 10 60 to 70C for 16 hours under stirring. The reaction mixture was con-centrated under reduced pressure. The residue was crystallized from ethylacetate-hexane, whereby 12.6 g (yield: 58%) of 2-carbamoyloxy-methyl-6-methyl-4-(o-nitrophenyl)-3,5-diethoxycarbonyl-1,4-dihydro-pyridine in crystal form was obtained.
mp: 128- 132C
UV: AMeaOxH 235, 350nm IR (KBr): 3540, 3400, 3000, 1710, 1690, 1535, 1495, 1340, 1205, 1120, 1100, 1095, 780, 755, 715 cm 1 NMR (9OMHz, CDCQ3): ~ 1.18 (t, J=7Hz, 6H), 2.35 (s, 3H), 4.15 (m, 4H), 5.38 (broad s, 4H), 5.96 (s, lH), 7. 1-8. 0 (m, 5H) EX~MPLE I - 2 to 1 - 6:
In the same manner as in Example I-1, the compounds identified in Table 1-3 were prepared.

--` ~240~9~

Table I- 3 _ l Exa Yield l~lelting UV
mpleCompounds (I) Point ~MeOHnm 12 2 g ¦ 110 ¦ 35 I-2CH300C~COOCH3 60 % - 114 355 CH3 H CH2o--CNH2 r ~,NO 2 ~ ~ ~
I-3 C2H500~CoOC2H5 13637%g 1441483355 --j [~3~N 2 ~ _ CH 9. 4 g 130 235 I-4 CH3,~CI-IOOC~ ~COOC2H5 42 % - 132 355 CH3 H CH2o--CNH2 r ~ NO 2 ~ _ 11.8 g 166 236 1-5 Cl-cH2cH2ooc~ ~COOCH3 52 g6 - 168 355 ,1 _ ~ _ _ 1-6 Cl CI12CH200C~CoOc~2CH20c3H712486%g 323565 C 1~ 3 H C H 2--CON H 2 ~240~391 Table I- 3 (cont'd) Exa- IR(KBr): cm 1 ¦ H NMR (9OMHz,CDCl3):~in ppm 3540,3360,2980,1715, 2.38(s,3H),3.72(s,6H) ,5.2(s,1H), 1690,1495,1355,1340, 5.35(s,2H), 5.4(s,2H),7.3 - 8.25(m,5H) 1-2 1210,1105,1090,830, 805, 790, 755, 710 3540,3380,3000,1710, 1.23(t,J=7Hz,6H),2.4(s,3H~,4.18(q,J
1690,1490,1355,1335, =7Hz,4H),5.2(s,1H),5.3(s,2H),5.4(s,2H), I - 31210,1105,1090,790, 7.2 - 8.2(m,5H) 760, 720 3450,3350,2980,1705, 1.14(t,J=8Hz,3H) ,1.27(d,J=6Hz, 1685,1530,1485,1350, 6H),1.42(s,3H),4.15(q,J=8Hz,2H), I-4 1205,1100,1080,780, 5.0(sep,J=6Hz,lH),5.14(s,1H),5.3 715 (s,2H),6.1(m,2H),7.5 - 8.4(m,5H) r 3420,2960,1740,1710, 2.44(s,3H) ,3.7(s,3H) ,3.7(t,J=
1685,1645,1600,1530, 6Hz,2H),4.36(t,J=6Hz,2H),5.1 - 5.8 1-5 1475,1350,1320,1205, (br.s,2H),5.2(s,1H),5.33(s,2H), 1070,900, 830, 755 7.45 - 8.3(m,5H) 3500,3900,3000,1710 0.8, (t .J=7Hz,3H), 1.4G(q ,J=7Hz,2H) lG90,lG40,lG00,1530, 2.35(s,3H),3.3(t.J=7Hz,2H),3.5(t,J
I-G 1990,1350,1210,1100, =6Hz,2H),3.75(t,J=5Hz,2H),4.1(t,a 900, 780, 760, 720 =6Hz,2H),4.24(t,J=5Hz,2H),4.92(d,J
=12Hz,lH) ,5.05(s,1H) ,5.06(d,J=12Hz, lH) ,6.6(broad-s,2H) ,7.3 - 8.1(m,4H), 9.0( s , lH) 12~099~

EXAMPLE I-7: Pre aration of 2-N-meth lcarbamo lox meth l-6-P Y Y Y Y

methyl- 4- (o-nitrophenyl) - 3,5- diethoxycarbonyl-1,4-dihydropyridine 10.1 g (50 millimoles) of ethyl 4-N-methylcarbamoyloxy -3-amino-5crotonate and 13.2 g (50 millimoles) of ethyl 2-(o-nitrobenzylidene)-acetoacetate were dissolved in 200 ml of ethanol and reacted at a temperature of from 60 to 70C for 16 hours under stirring. The reaction mixture was concentrated under reduced pressure. The residue was crystallized from diisopropylether-hexane, whereby 10 12.4 g (yield: 55.5%) of 2-N-methylcarbamoyloxymethyl-6-methyl-4- (o- nitrophenyl) - 3,5- diethoxycarbonyl- 1,4-dihydropyridine in crystal form was obtained.
mp: 165- 169C
UV: A Mea~l 235, 350nm i5 lR (KBr): 3380, 3000, 1690, 1680, 1535, 1495, 1355, 1280, 1205, 1100, 785, 760, 715 cm 1 NMR (90Mllz, CDCQ3): ~ 1.2 (t, J=7Hz, 6H), 2.38 (s, 3H), 2.91 (d, J=6Hz, 3H), 4.18 (m, 4H), 5.15 (m, lH), 5.38 (s, 2H), 5.98 (s, lH), 7.2-8.0 (m, 5H) 20 EXAMPLE I-8 to 1-17:

In the same manner as in Example I-7, the compounds identi~led in Table 1- 4 were prepared.

~24099~

Table 1-4 Exn Y ield ~leltin ~ UV
mpleCompounds (I ) C ~ ex Hnm _ ~N 2 ~ ~1 I-8C2~'5C~COOC2H5 14 3 g 192193 2355 CH3 ~ CH2o-coNH - cH3 r I ~N02 ~ _ 1-9 CH300C~COOCH3 ' 12 4 g 151153 3555 CH3 H CH2~CNH~CH3 ~3,N0 2 C H I 10 6 g 194 235 I-10 cH3~CHoOC~OO~C2H5 46 % - 196 355 CH~ H CH20-CONH - CH3 r ~NO2 _~
l 14 5 g 194 236 I - 11 Cl-C H 2C H 200C~OOCH3 62 ~ - 195 355 CH3 HN CH2o-coNH-cH3 _ _ ~N02 c~3 T 11 1 g 153 235 1-12 cH3~CHOOC~COOC2H5 48 % - 154. ¦ 355 _ ~Z4099~

Table 1-4 (cont'd) ENmXPoal.e IR(I~Br): cm 1 lH NMR(90 MHz)*: ôin ppm .
3400, 3300,3000,1690, (b); 1.18(t,J=7Hz,6H),2.38(s,3H), 1685, 1480,1355,1280, 2.67(d,J=5Hz,3H),4.12(q,J=7Hz,4H) I - 8 1205, 1105,790, 760, 5.13( s,3H),7.22(m, lH),7.5 - 8 ~ 3(m,9H), 720, 9.13(s, lH) 3350, 2950,1700,1685, (a); 2.38(s,3H),2.88(d,J=SHz,3H), 1530, 1480,1350,1210, 3.72(s,6H),5.2(s,2H),5.4(s,2H), I - 9 1095, 780, 705 7.35 - 8.3(m,5H) 3380, 3290,2980,1680, (b); 1.0 - 1.3(m,9H),2.38(s,3H),2.67 1525, 1480,1350,1275, (m,3H),4.1(q,J=7Hz,2H),4.93(sep,J
I-10 1250, 1205,1100,780, =6Hz,lH),5.1(s,3H),7.2(m,1H), 715 7.4 - 8.2(m,4H),9.1(s,lH) , _ _ 3400, 3300, 2960, 1690, (a); 2.47(s,3H),2.85(d,J=5Hz,3H), 1640, 1610, 1530, 1480, 3.73(s,3H),3.75(t,J=6Hz,2H), I-ll 1350, 1280, 1260, 1210, 4.4(t,J=6Hz,2H),5.22(s,1H),5.34 1110, 905, 830, 780, (s,2H),6.7(q,J=5Hz,lH),7.45 - 8.5 760, 715 (m,5H) I

_ 3350, 2980,lG85, 1530, (b); 0.9 - 1.3(m,12H),2.34(s,3H),3.07 1480, 1350,1275, 1250, (q,J=7Hz,2H),4.07(q,J=8Hz,2H), I-12 1205, 1095,780, 715 4.9(m,1H),5.06(s,3H),7.28(t,J=7Hz, lH),7.5 - 8.2(m,4H),9.05(br . s, lH) *; (a): CDC13, (b): Dl~SO-d6 i ` 12~0991 Table 1-4 (cont'd) Exa- Y icld Mel tin g UV
mple Compounds (1~ C ~l~qaxHnlr _ I ~N 2 ~ --CH3 I 9 5 g 150.5235 I-13 CH >CHOOC~OOC2H5 40 % - 152 355 ~NO 2 ~-14 cH3>CHooC~COOC2H5 1428%g 15759.53555 ~N02 1-15 CH3~CHooC~ooc2H5 104i7%g 1341363356 CH3 HN CH2O - coNH~
I

CH3 ~ 11.2 g 113 235 1-16 C~l ~CHOOC~OOC2H5 40 % - 116.5355 CH3 HN CH2O - CON~' _ i I-17 ~NO2 C1-CH2CH2OOC~OOCH3 12457~g 34535 CH3 HN H2o - CONH~Cl _ ~24099~

Table 1-4 (cont'd) mple IR (KBr): cm 1 lH NMR (90 MHz) *: ~ ~n ppm _ _ 3350,2980,1685,1530, (b); 0.88(t,J=8Hz,3H) ,1.0 - 1.3(m,9H), 1480,1355,1270,1240, 1.48(m,2H),2.38(s,3H),3.04(q ,3=7Hz, I 131207,1100,780, 715 2H),4.12(q,J=8Hz,2H),4.14(m,1H), 5.1(s,3H),7.36(t,J=7Hz,lH),7.6 -8.3(m,4H),9.1( s, lH) 3350,2940,1680,1530, (b); 1.0 - 1.4(m,9H),1.4 - 2.0(m,10H), I-14 1480,1350,1275,1207, 2.37(s,3H),3.35(br.s,2H),4.1(q,J=
1095,780, 710 8Hz,2H),4.93(m,1H),5.1(s,3H) ~ . .

3350,2980,1685,1530, (b); 1.0 - 1.4(m,9H),2.4(s,3H),4.12(q,J
I 151480,1350,1205,1100, =8Hz,2H),4.93(m,1H),5.1(s,lH~, 740, 710, 690 5.25(s,2H),7.0 - 8.3(m,9H),9.27(s,1H), 9.86(s,1H) L
3380,2980,1695,1530, (b); 0.95 - 1.35(m,9H),2.37(s,3H), 1350,1220,1100,825, 4~08(q,J=8Hz,2H),4.93(m,1H),5.1(s,1H), I 16740, 705 5.36,(s,2H),7.3 - 8.3(m,8H),9.27 (s,lH),10.0(s,lH) 3400, 3000, 1750, 1690, 1670,1600,1530,1480, T-17 1350,1220,llOO,900, . 805, 750, 700 _ *; (a): CDC13, (b): D~]SO-d6 ~24099~L

EXAMPLE 1-18: Preparation of 2-carbamoyloxymethyl-6-methyl-4-(m -nitrophenyl) - 3-ethoxycarbonyl- 5- ( ~-ethoxy-ethoxy)carbonyl- 1,4-dihydropyridine 9. 4 g (50 millimoles) of ethyl 4-carbamoyloxy-3-aminocrotonate and 15.4 g (50 millimoles) of ~-ethoxyethyl 2-(m-nitrobenzylidene)-acetoacetate were dissolved in 200 ml of isopropyl alcohol and reacted at a temperature of from 60 to 70C for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was crystallized from diisopropylether-hexane, whereby 12.9 g (yield:
10 54%) of 2-carbamoyloxymethyl-6-methyl-4-(m-nitrophenyl)-3-ethoxy-cnrbonyl- 5- ( ~-ethoxyethoxy)carbonyl- 1,4-dihydropyridine in crystal form was obtained.
mp: 135- 138C
UV: ~MeaH 236, 355nm 15IR (KBr): 3520, 3360, 1990, 1705, 1690, 1645, 1610, 1525, 1485, 1350, 1205, 1120, 1105, 1055, 905, 830, 780, 755, 720 cm 1 NMR (9OMHz~ DMSO-d6): ô 1.07 (t, J=8Hz, 3H), 1.15 (t, J=3E~z, 3H), 2.37 (s, 3H), 3.45 (q, J=8Hz, 2H), 3.62 (t, J=4Hz, 2H), 4.08 (q, J-8Hz, 2H), 4.12 (t, J=4Hz, 2H), 4.97 (d, J=12Hz, lH), 5.1 (s, lH), 5.13 (d, J=12Hz, lH), 6.7 (br. s, 2EI), 7.6-8.2 (m, 4H), 9.11 (s, lH) EXAMPLE I-l9 to I-32:
In the same manner as in Example I-18, the compounds identified in Table I-5 were prepared.

`

iz4099~

Table 1-5 Exn- Yield ~lelting UV
mple Compounds (I) Point I MexOHnm [~N2 I- 19 C3T17OCH2CH2OO(~OOC2H5 15;5%g147149 323565 C H 3 H ~ H 2 2 ~NO 2 r -20 i-c3H7OCH2cH2O ~OOC2H5 1456%g 139142 33s5 CH3 H H2o-coNH2 ~N02 - 21 C 2l~5ooc~coocH2cH2ocH3 427~g 121125 33565 _ ~N02 -22 C2l~5ooc~oocH2cH2oc3H7 10448%g 1-36138. 33565 _ ~,NO 2 r 11.7 g 135 236 1-23 Cll2=c~cl~2ocl-l2cH2 )oc~ooc2~l5 48 % - 139 355 _ 12~099~

Table 1- 5 (cont'd) Exa-mple IR(KBr): cm 1lH NMR(go MHZ, DMS d6) No .
3520, 3350, 2950, 1700, 0.85(t.J=8Hz,3H),1.18(t,J=8Hz, 1645, 1610, 1520, 1480, 3H),1.5(m,2H),2.39(s,3H),3.36(t,J
1350, 1330, 1270, 1200, =8Hz,2H),3.57(t,J=5Hz,2H),4.12 I-l91120, 1100, 1080, 90S, (q,J=8Hz,2H),4.15(t,J=SHz,2H),5.0 830, 780, 755, 720 (d,J=13Hz,lH),5.12(s,1H),5.15(d,J
=13Hz, lH),6.68(br . s,2H),7.5 - 8.3 (m,4H),9.05(s, lH) 3520, 3360, 2980, 1702, 1.06(d,J=6Hz,6H),1.16(t,J=7Hz, 1685, 1645, 1610, 1525, 3H),2.37(s,3H),3.55(m,1H),3.62 1485, 1350, 1330, 1270, (t,J=6Hz,2H),4.09(q,J=7Hz,2H), 1-201200, 1120, 1080, 900, 4.12(t,J=6Hz,2H),4.97(d,J=12Hz, 825, 780, 755, 720 lH),S.l(s,lH),5.13(d,J=12Hz,lH) 6.65(br.s,2H),7.5 - 8.3(m,4H), 9. lO(s, lH) 3480, 3380, 2990, 1690, 1.16(t,J=8Hz,3H),2.38(s,3H),3.28 1645, 1610, 1530, 1490, (s,3H),3.53(t,J=5Hz,2H),4.0S(q,J=
1350, 1275, 1210, 1110, 8Hz,2H),4.18(t,J=5Hz,2H),5.0(d,J=
I-al1095, 1080, 905, 830, 13Hz,lH),5.11(s,1H),5.13(d,J=13Hz, 780, 755, 720 lH) ,6.7(br.s,2H),7.5 - 8.3(m,4H), 9.07(s,1H) 3500, 3380, 2980, 1710, 0.83(t,J=7Hz,3H),1.15(t,J=7Hz,3H), 1680, 1640, 1600, 1525, 1.5(m,2H),2.37(s,3H),3.35(t,J=7Hz, 1-221490, 1350, 1275, 1210, 2H),3.56(t,J=3Hz,2H3,4.08(q,J=7Hz,2H), 1095, 905, 830, 780, 4.16(t,J=3Hz,2H),5.0(d,J=13Hz,lH), 760, 715 5.1(s,1H),5.15(d,J=13Hz,lH),6.72(s,2H), 7.5 - 8.3(m,4H),9.07(s, lH) i _ 3520,3360, 2990, 1705, 1.16(t,J=8Hz,3H),2.38(s,3H),3.58 1685,lG40, 1610, 1520, (t,J=SHz,2H),3.98(d,J=9Hz,2H),4.1 1485,1350, 1330, 1270, (q,J=8Hz,2H),4.15(t,J=5Hz,2H),5.08 1200,1120, 1100, 1080, (d,J=lOHz,lH),5.1(s,1H),5.1 - 5.4 1-23 1000,920, 900, 825, (m,2H),5.15(d,J=lOHz,lH),5.6 - 6.2 780, 755, 720 (m, lH ),6.71( s,2H),7.5 - 8.3 ( m,4H), L 9.11( s,1H) ..

~240991 Table I-5 (cont'd) Exn - Y ield ~leltin g UV
NOple Compounds (I ) Point~Mmax nn -- ~N0 I-24 ~CH2CH~OO2C2cHosN~2 3j7~g 89 933235 _ ~2 12 4 g 58.5 236 I-25 C6H5cH2ocH2cH2ooc~ ~COOC2H5 46 % - 62 355 CH3 HN CH2 - CNH2 .
. .
~N02 I-26 C3H7ocH2cH2oo~oocH2cH2oc3H7 127 38 %g 91 33565 CH3 HN H2~CONH2 I .
~N02 I - 27 CH3OCH2CH2OOC~OOCH2CH2OCH3 15368%g 1111533565 _ _ ~NO2 11 1 ~ 120 234 I-28 C3~7Oc~i2c~2o ~C2H5 95 % - 126 340 _ CH3 H CH2 C~H2 ' .

i24099~

TableI-5 (cont'd) Exa- IR(KBr): cm 1 lH NMR(90 MHz, DMSO-d6~:~in ppm _ _ 3480, 3920, 3360, 2950, 1.16(t,~=9Hz,3H),2.4(s,3H),3.64 1710, 1690, 1615, 1600, (t,J=7Hz,2H),4.1(q,J=9Hz,2H),4.25 1530, 1490 1350, 1335, (t,J=7Hz,2H),5.0(d,J=13Hz,lH),S.ll 1250, 1200 1125, 1080, (s,lH),5.16(d,J=13Hz,lH),6.73(br.s, 1-24930, 915, 780, 755, 2H),6.9 - 7.5(m,5H),7.4 - 8.3(m,4H), 720, 690 9.16(s,lH) 3500, 3360, 2950, 1720, 1.15(t,J=7Hz,3H),2.37~s,3H),3.63 1700, 1685, 1640, 1610, (t,J=5Hz,2H),4.1(q,J=7Hz,2H),4.2 1530, 1485, 1350, 1330, (t,J-5Hz,2H),~52(s,2H),4.98(d,J=
I-251280, 1210, 1120, 1095, 12Hz,lH),5.13(d,J=12Hz,lH),5.13 1085, 905, 830, 780, (s,lH),6.72(s,2H),7.4(s,5H),7.5 -740, 700 8.3(m,4H),9.11(s,lH) I_ 3510, 3400, 3330, 2960, 0.82(t,J=7Hz,6H),1.46(m,4H), 2870, 1740, 1695, 1665, 2.34(s,3H),3.28(t,J=7Hz,4H),3.5 1525, 1475, 1345, 1325, (t,J=5Hz,4H),4.08(t,J=5Hz,4H), 1-261275, 1220, 1200, 1120, 4.9(d,J=12Hz,lH),5.1(d,J=12Hz,lH), 1090, 1070, 1015, 905, 5.12(s,1H),6.6(s,2H),7.35 - 8.2 830, 785, 755, 710 (m,4H),8.95(s,1H) 3500, 3400, 3000, 1690, 2.38(s,3H),3.3(s,6H),3.53(t,J
1640, 1610, 1530, 1485, =5Hz,4H),4.12(t,J=5Hz,4H),5.05(d,J
1350, 1330, 1280, 1210, =13Hz,lH),5.1(s,1H),5.15(d,J=13Hz, I-271110, 1095, 905, 830, lH),6.7(s,2H),7.5 - 8.3(m,4H), 780, 755, 720 9.1(s,lH) 3400, 2970, 1710, 1690, 0.78(t,J=7Hz,3H),1.08(t,J=8Hz, 1640, 1605, 1530, 1490, 3H),1.4(m,2H),2.28(s,3H),3.23(t,J=7Hz, 1335, 1320, 1280, 1205, 2H),3.47(t,J=8Hz,2H),4.02(q,J=8Hz, 1 281110, 1100, 1080, 860, 2H),4.05(t,J=8Hz,2H),4.83(d,J=13Hz, 830, 780, 755, 710 lH),5.0(d,J=13Hz,lH),5.63(s,1H), 6.6(br.s,2H),7.2 - 7.9(m,4H),8.86 (s,lH) 124~99~

Table I-5 (cont'd) _ Exa Yield ~elting UV
No. ¦ Compounds (I) Pcint ~max nm _ I ~ ~ ~ 222 . . 11 6 g 117 280 1-2 ¦C3H7OCH2CH2OO(~;¢ ~OOC2H5 4i ~ - 121 370 CH3 N H2~CONH2 ; D C H 2C H 2 ~OO C H 2C H 2OC N 3 3 s 3 96g ~ 16 6 3 6 6 CH3 HN CH2--CNH2 .

~OCH3 1-31 CH3OCH2CH2OO~COOCH2CH2OCH3 1524%g 33s5s C~1~C 200C,~OOCH2CH2OCH ~ 14 0 g ~ 122 ~ 237 -!

~z4~99~

TableI-5 (cont'd) ENmXpaI.e IR(KBr): cm 1 lH NMR (90 MHz, DMSO-d6):~ ~ ppm _ , 3500, 3400, 3000, 1690, 0.85(t,J=8Hz,3H),1.15(t,J=8Hz, 1640, 1610, 1530, 1485, 3H),1.5(m,2H),2.38(s,3H),3.36(t,J
1350, 1330, 1280, 1210, =8Hz,2H),3.55(t,J=4Hz,2H),4.03 I 2 1110, 1095, 905, 830, (q,J=8Hz,2H),4.15(t,J=4Hz,2H),4.9 9 780, 755, 720 (d,J=12Hz,lH),5.02(s,1H),5.05 (d,J=12Hz,lH),6.6(s,2H),7.42(d,J=9Hz, 2H),8.1(d,J=9Hz,2H),8.94(s,lH) 3540, 3380, 3000, 2230, 2.36,(s,3H),3.28(s,6H),3.53(t,J
1710, 1690, 1640, 1605, =4Hz,4H),4.18(t,J=4Hz,4H),4.97(d,J
1490, 1390, 1335, 1275, =13Hz,lH),5.13(d,J=13Hz,lH),5.25 1-30 1200, 1120, 1090, 1040, (s,lH),6.73(br. 9, 2H),7.3 - 7.9(m,5H), 940, 840, 775 8.97(s,lH) _ 3420, 3350, 2980, 1720, 2.26(s,3H),3.27(s,6H),3.5(t,J
1680, 1605, 1490, 1380, =4Hz,4H),3.7(s,3H),4.08(t,J=4Hz, 1320, 1280, 1210, 1110, 4H),4.88(d,J=12Hz,lH),5.02(d,J
I 31 1095, 860, 750 =12Hz,lH),5.2(s,1H),6.58(s,2H), 6.7 - 7.3(m,5H),8.57(s,1H) _ 3420, 2980, 1705, 1685, 2.31(s,3H),3.28(s,6H),3.52(t,J
1640, 1605, 1490, 1385, =4Hz,4H),4.13(t,J=4Hz,4H),4.9 1370, 1330, 1280, 1205, (d,J=13Hz,lH),5.1(d,J=13Hz,lH), 1~32 1110, 1100, 1080, 1040, 5.38(s,1H),6.7(br.s,2H),7.1 - 7.6 830, 755 (m,5H),8.85(s,1H) _ ~240gg~

EXAMPLE 1-33: P~paration of 2-N-methylcarbamoyloxymethyl-6- methyl- 4- (m-nitrophenyl) - 3-ethoxycarbonyl- 5-( ~ - ethoxyetho~y) carbonyl- 1,4- dihydropyridine 10.1 g (50 millimoles3 of ethyl 4-N-methylcarbamoyloxy-3-amino-crotonate and 15.4 g (50 millimoles) of ~-ethoxyethyl 2-(m-nitro-benzylidene)acetoacetate were dissolved in 200 ml of n-propanol and reacted at a temperature of from 65 to 75C for 20 hours under stirring. The reaction mixture was concentrated under reduced pressure. The residue was crystallized from diisopropylether-hexane, whereby 11.1 g (yield: 45%) of 2-N-methylcarbamoyloxymethyl-6-methyl- 4- ( m -nitrophenyl) - 3- ethoxycarbonyl - 5- ( ~ -ethoxyethoxy) -carbonyl-1,4-dihydropyridine in crystal form was obtained.
mp: 148- 149C
UV: ~Mmeax~l 236, 355nm i5 IR (KBr): 3390, 3280, 2980, 1680, 1640, 1610, 1535, 1480, 1355, 1280, 1205, 1120, 1095, 905, 830, 780, 760, 715 cm 1 NMR (9OMHz, DMSO-d6): ~ 1.11 (t, J=8Hz, 3H), 1.19 (t, J=7H, 3H), 2.39 (s, 3H~, 2.67 (d, J=4.5Hz, 3H), 3.48 (q, J-8Hz, 2H), 3.65 (t, a=5Hz~ 2H), 4.12 (q, J=7Hz, 2H), 4.15 (t, J=5Hz, 2H), 5.06 (d, J=12Hz, lH), 5.14 (s, lH), 5.18 (d, J=12Hz, lH), 7.22 (m, lH), 7.6-8.25 (m, 4H), 9.18 (s, lH) EXAMPLE I-34 to I-42:
In the same manner as in Example 1-33, the compounds identified in Table I - 6 were prepared.

`\ ~24099~

Table I - 6 _ Exa Yield Meltin g UV
Nmpl,eCompounds lI ) Point ~ exOHn~

. ~2 1-34C3H7ocH2cH2~ooc2H5 6j8 g 136137 33565 CH3 H H2O--CON~CH3 ~,NO 2 1-35~,-C3H7OcH2cH2~ooc2H5 1154%g 12122 33555 _ ~,NO 2 1-36C2H500C~oO.CH2CH2OCH3 11509%g 152156 3355 CH3 H H2o-coNH-cH3 _ ~
~N02 1-37C2H5ooc~oocH2cH2oc3H7 15i9%g 1-52155.5 233565 CH3 H H2o-coNH-cH3 _ ~N 2 1-38 C3H7ocH2cH2 C~oocH2cH2oc3H7 176i2,~,g 11912o 33565 CH3 N H2o-coNH--CH3 .

1~4099~

Table1-6 (cont'd) Exa- -1 mple IR(KBr): cm lH NMR (90 MHZ, DMSO-d6) No.
3380, 3290, 2970, 1680, 0.82,(t,J=8Hz,3H),1.13(t,J=8Hz, 1640, 1610, 1530, 1480, 3H),1.48(m,2H),2.35(s,3H),2.63 1350, 1275, 1200, 1120, (d,J=6Hz,3H),3.33(t,J=8Hz,2H), I-34 1100, 905, 830, 780, 3.54(t,J=5Hz,2H),4.07(q,J=8Hz, 760, 715 2H),4.11(t,J=5Hz,2H),5.0(d,J=13Hz, lH),5.09(s,lH),5.13(d,J=13Hz,lH), 7.15(m,1H),7.5 - 8.3(m,4H),9.10 _ (s,lH) 3370, 2980, 1680, 1640, 1.06(d,J=7Hz,6H),1.16(t,J=8Hz, 1610, 1530, 1480, 1350, 3H),2.37(s,3H),2.65(d,J=6Hz,3H), 1275, 1205, 1120, 1095, 3.56(m,1H),3.60(t,J=7Hz,2H),4.09(q,J
1-35905, 830, 780, 760, =8Hz,2H),4.10(t,J=7Hz,2H),5.03(d,J
710 =13Hz,lH),5.11(s,1H),5,14~d,J=13Hz, lH),7.16(m,1H),7.5- 8.3(m,4H),9.12 (s,lH) 3370, 3280, 2980, 1680, 1.17(t,J=7Hz,3H),2.37(s,3H), 1640, 1610, 1530, 1480, 2.65(d,J=5Hz,3H),3.27(s,3H),3.52 1350, 1275, 1205, 1100, (t,J=5Hz,2H),4.10(q,J=7Hz,2H), 1-36905, 830, 780, 760, 4.16(t,J=5Hz,2H),5.06(d,J=14Hz,lH), 715 5.1(s,1H),5.14(t,J=14Hz,lH),7.18 (m,lH),7.5 - 8.3(m,4H),9.12(s,1H) 3380, 2980, 1680, 1640, 0.86,(t,J=7Hz,3H),1.2(t,J=7Hz, 1610, 1530, 1485, 1355, 3H),1.52(m,2H),2.4(s,3H),2.68(d,J
1280j 1205, 1100, 910, =6Hz,3H),3.38(t,J=7Hz,2H),3.58 I-37830, 780, 760, 715 (t,J=4Hz,2H),4.1(q,J=7Hz,2H), 4.18(t,J=4Hz,2H),5.09(d,J=13Hz,lH), 5.13(s,lH),5.18(d,J=13Hz,lH),7.2 (m,lH),7.4 - 8.4(m,4H),9.12(s,1H) 3350, 3300, 2960, 2870, 0.83(t,J=7Hz,6H),1.5(m,4H), 1685, 1635, 1600, 1530, 2.35(s,3H),2.62(d,J=5Hz,3H),3.3 1480, 1350, 1275, 1250, (t,J=7Hz,4H),3.52(t,J=4Hz,4H),4.12 1-381200, 1130, 1100, 1015, ~t,J=4Hz,4H),5.0(d,J=13Hz,lH),5.1 990, 900, 830, 780, (d,J=13Hz,lH),5.14(s,lH),7.1(m,lH), 760, 750, 710 7.4 - 8.3(m,4H),9.0(s,lH) ; ? ~2~099~

Table I-6 ~cont'd) Exa Yield r.lelting UV
mpleCompounds (I) C )`~laxoHnlr .
. ~2 .

I-3C2H500C~COOCH2CH20CH3 6i % 148152 3255 C H 3 H ~C H 2--CON H~>
_ ~N02 1-4C2HsOCH2CH2OOC~COOC2H5 13 6 g 13814232536 CH3 HN~CH20-coN;~3 _ _ ~2 I gC3H7OCH2CH2OO~COOCH2CH2OC3H7 154j5%g 140145 32452 .CH3 HN~CH2O-CON~1 _ ~NO2 1-4C3~l7OCH2CH2OOC~cooCH2CH2OC3H7 14309%g 128135 23535 . 3 H C Il 20--CON H~Cl 1;~40991 Table1-6 (cont'd) ENXPoal.eIR(~Br): cm 1 lH NMR (90 MHz, DMSO d6) 3350, 2950, 1680, 1640, 1.18(t,J=8Hz,3H),1.7(br.s,10H), 1610, 1530, 1480, 1350, 2.37(s,3H),3.25(s,3H),3.35(m,1H), 1310, 1210, 1095, 1060, 3.5(t,J=4Hz,2H),~.08(q,J=8Hz,2H), I-39900, 830, 780, 740, 4.15(t,J=4Hz,2H),5.05(d,J=13Hz,lH), 710 5.1(s,1H),5.15(d,J=13Hz,lH),7.25(d,J
=7Hz,lH),7.5 - 8.3(m,9H),9.1(s,lH) 3350, 3000, 1585, 1645, l.l(t,J=7Hz,3H),1.2(t,J=7Hz,3H), 1600, 1530, 1480, 1350, 2.4(s,3H),3.5(q,J=7Hz,2H),3.65(t,J
1310, 1205, 1100, 1080, =5Hz,2H),4.1(q,J=7Hz,2H),4.15(t,J
1-401070, 905, 850, 825, =5Hz,2H),5.05(d,J=12Hz,lH),5.15(s,1H), 770, 740, 710, 690 5.2,(d,J=12Hz,lH),7.0 - 8.3(m,9H), 9.27(s,1H),9.86(s,1H~

3400, 3000, 1700, 1600, 0.85(t,J=7Hz,6~),1.5(m,4H),2.4 1530, 1490, 1480, 1350, (s,3H),3,37(t,~=7Hz,4H),3.6(t,J=4Hz, 1280, 1220, 1100, 1070, 4H),4.18(t,J=4Hz,4H),5.15(s,1H),5.15 1-911030, 900, 825, 770, (d,J=12Hz,lH),5.34(d,J=12Hz,lH),7.43 740, 705 (d,J=9Hz,2H),7.63(d,J=9Hz,2H),7.5 - 8.3(m,5H),9.15(s,lH) 3420, 3300, 3100, 3000, 0.85(t,J=7Hz,6H),1.5(m,4H),2.4 1750, 1690, 1670, 1610, (s,3H),3.38(t,J=7Hz,4H),3.58(t,J
1595, 1530, 1480, 1350, =4Hz,4H),4.18(t,J=4Hz,4H),5.04 1290, 1220, 1120, 1100, (~,lH),5.05(d,J=12Hz,lH),5.25(d,J
1-42 910, 810, 755, 710 -12Hz,lH),7.3 - 8.2(m,8H),9.2(s,1H) - 108 ~
EXAMPLE I-43: Preparation of 2-carbamoyloxymethyl-6-methyl-- 4- (m-nitrophenyl) - 3-methoxycarbonyl- 5- [ ~-(N -methylbenzylamino) ethoxy] carbonyl- 1,4-dihydropyridine 8.7 g (50 millimoles) of methyl ~-carbamoyloxy-3-aminocrotonate and 19.1 g (50 millimoles) of ~-(N methylbenzylamino)ethyl 2-(m-nitrobenzylidene)acetoacetate were dissolved in 300 ml of ethanol and reacted at a temperature of from 60 to 70C for 20 hours under stirring. The reaction mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography. ~y using ethylacetate as the developer solvent, the desired fraction was collected and concentrated under reduced pressure. The residue was dissolved in acetone. A
hydrochloric acid-ethanol solution was added thereto. The precipitates tllereby formed were collected and recrystallized from acetone-ethyl-acetate, whereby 9.2 g (yield: 32%) of 2-carbamoyloxymethyl-6-methyl-4- (m -nitrophenyl) - 3-methoxy-carbonyl- 5- [ ~- (N -methylbenzylamino) -ethoxy]carbonyl-1,4-dihydropyridine hydrochloride in crystal form was obtained .
Illp: 117.5 - 121C
UV: ~ Mmea~ 236, 355nm IR (I~Br): 3400, 2950, 1720, lG90, 1640, 1610, 1525, 1475, 1350, 1320, 1210, 1010, 900, 825, 780, 740, 700 cm 1 lZ4099~

NMR (90MHz, DMSO-d6): ô 2.37 (s, 3H), 2.57 (s, 3H), 3.36 (m, 2H), 3.68 (s, 3H), 4.25 (s, 2H), 4.43 (m, 2H), 4. 88 (d, J=14Hz, lH), 5. 03 (d, J=14Hz, lH), . ~
5.03 (s, lH), 6.73 (br. s, 2H), 7.42 (s, 5H), 7.5-8.2 (m, 4H), 9.2 (s, lH) EXAMPLE I-44 to I-50:
In the same manner as in Example.I-43, the compounds identified in T able I - 7 w ere prepared .

Ç~ ` 124~99~

Table 1-7 Ex~- Yield Melting UV
Nmpl.e Compounds (I) Polnt ;~leOH
_ ~ _ f ~ HCl 8 8 g 77 236 1-44 CH3~CH2cH2Ooc~ 3 30 ~ - 82 353 CH3 HN CH2o-coNH--CH3 _ N 2 _ C 6H 5 IC 2 ~ HCl 1-45 CH3--NC~2CH2OOC~COOCH3 1347%g 33563 CH3 HN CH2O--CONH~Cl _ ~3,N0 2 I - 46 CN C H 2C H 200C~ OO C H 3 10 8 g 75 80 324282 _ , ~3,N0 2 - 47 CH3-N~JNCH2CH200C~OOCH3 1366%g 163168 323415 ~ ~ . HCl 11 6 g 68 235 -48 O\~NCH2CH2OO~OOCH3 43 % - 75 355 j CH3 N H2O CONH2 ~ ~z4099~

Table 1-7 (cont'd) ENmxpOale IR(KBr): cm 1 lH NMR (90 MHz, DMSO d6) ~

3380,3330,2960, 1690, 2.13(s,3H),2.36(s,3H),2.6(t,J
1640,1605,1530, 1480, =6Hz,2H),2.65(d,J=5Hz,3H),3.5(s,2H), 1350,1280,1250, 1210, 3.62(s,3H),4.16(t,J=6Hz,2H~, I-44 1105,1050,905, 830, 5.1(d,J=13Hz, lH),5.13(s, lH),5.16 780, 740, 700 (d, J=13Hz, lH),7.2(m, lH),7.33(s,5~il), 7.4 - 8.3(m,4H),9.16(s,1H) _ 3400,3320,2960, 1740 2.13(s,3H),2.36(s,3H),2.6(t,3 1690,1640,1605, 1530, =6Hz,2H),3.5(s,2H),3.62(s,3H), 1480,1350,1280, 1250, 4.16(t,J=6Hz,2H) ,5.13(s,1H) ,5.13 1210,1100,905, 830, (d,J=12Hz, lH),5.33(d,J=12Hz, lH), 1-45 780, 750, 720 7.3 - 8.3(m,9H),7.33(s,5H),9.2(s,1H) 3400,2950,1740, 1685, 1.7(br . s,6H),2.46( s,3H),2.8 1525,1500,1350, 1245, (br.s,4H),3.3(s,3H),3.3(m,2H),4.35 1200,1190,1090, 1020, (m,2H),4.9(s,2H),5.05(s,1H), 1010,975, 900, 825, 5.25(br.s,2H),7.5 - 8.3(m,4H), I-~6 800, 760, 730, 690 9.35(s,1H) 3420,1690,1525, 1500, 2.48(s,3H) ,2.9(s,3H) ,3.3 - 4.0 1350,1210,1095, 1010, (br.s,lOH~ ,3.7(s,3H) ,4.5(m,2H), 975, 900, 830, 800, 5.02(d,J=12Hz,lH) ,5.15(s,1H) ,5.2 780, 760, 740(d,J=12Hz,lH~ ,6.8(br.s,2H) ,7.6 - 8.3 1-47 (m,4H) ,9.38(s,1H) __ 3450,2960,1690, 1640, 2.45,(s,3H),2.9 - 4.1(m,10H), 1610,1530,1480, 1350, 3.68(s,3H),4.5(m,2H),4.97(d,J
1330,1280,1210, 1100, =13Hz,lH),5.12(s,1H),5.14(d,J
1070,1020,910, 830, =13Hz,lH),6.73(br.s,2H),7.5 - 8.3 1-48 780, 760, 710 (m,4H),9.35(s,1H) ~ .

o99~

T able 1- 7 (cont'd~
. Yield Meltin g W
Exa- I Compounds (I ) . ¦ Point I_ ~

C 2H 5 ~ HCl . 230 1- 49 >NCH2C~2~OC ~COOC H3 ~37~g 345 l I
C H C H ~ 2 HCl 6 51 2 ~r 13.3 g 71 235 1-50 CH3 hCH2 2 ~oocH2cH2oc3H7 41 % - 72 355 L I CH3 H C~CONH2 1 f~
~Z~099~

Table 1-7 (cont'd) ENmXPoal.e IR(KBr): cm 1 lH NMR (90 HZ, DMS d6) I .
3420, 2950, 1735,1685, l.l9(m,6H) ,2.45(s,3H) ,3.06(m,~H), 1525, 1500, 1350,1240, 3.25(t ,J=7Hz,2H),3.55(s,3H),4.36 I - 49 1200, 1190, 1090,1020, (t ,J=7Hz,2H),4.93(s,2H),5.08( s, lH), 975, 900, 825, 800, 6.75(br.s,2H) ,7.5 - 8.3(m,4H), 760, 730, 690 9.4(br.s,lH) ~ , , 3420, 2960, 1690,1640, 0.8(t,J=8Hz,3H),1.46(m,2H), 1610, 1530, 1480,1350, 2.4(s,3H),2.6(s,3H),3.48(t,J=8Hz,2H), 1320, 1280, 1210,1080, 3.52(m,2H),3.68(m,2H),4.12(m,2H), I 50 900, 830, 810, 780, 4.26(br . s,2H),4.44(m,2H),4.88 _ 740, 700 (d,J=13Hz,lH),5.03(s,1H),5.08 (d,J=13Hz,lH) ,6.65(br.s,2H), 7.43(s,5H),7.5 - 8.2(m,4H~,9.2(s,1H) ,.

09~

XAMPLE I-51: Preparation of 2-N-methylcarbomoyloxymethyl-6-methyl- 4- (m-nitrophenyl) - 3,5-diethoxycarbonyl-1,4-dihydropyridine 10.1 g (50 millimoles) of ethyl 4-N-methylcarbamoyloxy-3-amino-crotonate, 7.6 g (50 millimoes) of m-nitrobenzaldehyde and 6.5 g (50 millimoles) of ethyl acetoacetate were dissolved in 200 ml of ethanol and reacted at a temperature of from 60 to 70C for 16 hours under stirring. The reaction mixture was concentrated under reduced pressure. The residue was crystallized from diisopropylether, whereby 7.6 g (yield: 34%) of 2-N-methylcarbamoyloxymethyl-6-methyl-4-(m-nitrophenyl)-3,5-diethoxycarbonyl-1,4-dihydropyridine irl crystal form was obtained.
mp: 192- 193C
The analytical data of this product by UV, IR and NMR agreed i5 very well to the data obtained with respect to the product of Example I-8.
EXAMPLE I-52: Preparation of 2-N-methylcarbamoyloxymethyl-6-methyl- 4- (m-nitrophenyl) - 3,5-diethoxycarbonyl-1,4-dihydropyridine 9.2 g (S0 millimoles) of ethyl 4-N-methylcarbamoyloxy-2-butynoate,

13.2 g (50 millimoles) of ethyl 2-(m-nitrobenzylidene)acetoacetate and 10 g (125 millimoles) of ammonium acetate were dissolved in 200 ml of ethanol and reacted at a temperature of from 60 to 70C for 16 hours.
The reaction mixture was concentrated under reduced pressure.
The oily residue was extracted with 200 ml of ethylacetate. The ethylacetate extraction solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.

1.240991 The residue was separated and purif;ed by means of a liquid chromatography apparatus (System 500 A manufactured by Waters Co.) by using a Prep PAK-500/silica column and ethylacetate-hexane (2: 1) as the developer solvent. The desired fraction was collected and concentrated under reduced pressure. The residue was crystallized from diisopropylether, whereby 4.8 g (yield: 21.5%) of 2-N -methyl-carbamoyloxymethyl- 6-methyl- 4- (m-nitrophenyl) - 3,5-diethoxycarbonyl-1,4-dihydropyridine in crystal form was obtained.
mp: 192- 193C
The analytical data of this product by UV, IR and ~MR agreed very well to the data with respect to the product of Example I -8.
EXAMPLE I-53: Preparation of 2-N-methylcarbamoyloxymethyl-6-methyl- 4- (m-nitrophenyl) - 3,5-diethoxycarbonyl-i5 1,4-dihydropyridine 9.2 g (50 millimoles) of ethyl 4-N-methylcarbamoyloxy-2-butynoate, 7.5 g (50 millimoles) of m-nitrobenzaldehyde, 6.4 g (50 millimoles) of ethvlacetoacetate and 10 g (125 millimoles) of ammoniumacetate were dissolved in 200 ml of ethanol and reacted at a temperature of from 60 to 70C for 16 hours under stirring. The reaction mixture was concentrated under reduced pressure. The residue was extracted with 200 ml of ethylacetate. The extraction solution was dried over anhydrous maKnesium sulfate and then concentrated under reduced pressure. The residue was separated and purified by means of a liquid chromatography apparatus (System 500 A manufactured by Waters Co.) by using a Prep PAK-500/silica column and ethylacetate-hexane (2: 2) as the developer solvent. The desired fraction was collected and concentrated under reduced pressure.

0991.

The residue thereby obtained was crystalli zed from diisopropylether, whereby 5. 0 g (yield: 22. 3%) of 2-N-methylcarbamoyloxymethyl-6-methyl-4-(m-nitrophenyl)-3,5-diethoxycarbonyl-1,4-dihydropyridine in cryst al form w as obtained .
mp: 192-193C
The analytical data of this product by UV, IR and NMR agreed very well to the data obtained with respect to the product of Example 1-8.

, . . .

Claims (28)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a 3-amino-3-carbamoyloxalky-lacrylic acid derivative represented by the general formula:
(II) where R3 is lower alkyl, haloalkyl, lower alkenyl, lower alkynyl, arakyl, arlyl, hydroxyalkyl, lower alkoxyalkyl, lower alkeny-loxyalkyl, aralkyloxyalkyl, aryloxyalkyl or (where B is straight-chained or branched alkylene, and each of R7 and R8 is lower alkyl, aralkyl or aryl, or R7 and R8 form, together with the adjacent nitrogen atom, a heterocyclic group), A is alkylene, and each of R5 and R6 is hydrogen, lower alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aralkyl or aryl, or R5 and R8 form, together with the adjacent nitrogen atom, a heterocyclic group, which comprises reacting a 3-carbamoyloxyalkylpropiolic acid derivative represented by the general formula:

(VI) where R3, R5, R6 and A are as defined above, with ammonia or its salt.

2. The process according to claim 1, in which R3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, .beta.-chloroethyl, .beta.-bromoethyl, .beta.-chloro-with the adjacent nitrogen atom, a heterocyclic group selected from the group consisting of piperidino, 4-methylpiperazino, 4-ethylpiperazino, 4-propylpiperazino, 4-methylhomopiperazino, morpholino, homo-morpholino, l-pyrrolidinyl, l-imidazolidinyl, 1-pyrazolidinyl, l-indolinyl and 2-isoindolinyl.

3. A process according to claim 1, in which R3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .beta.-chloro-ethyl, allyl, propargyl, benzyl, phenyl, .beta.-methoxyethyl, .beta.-propoxyethyl, .beta.-isopropoxyethyl, .beta.-allyloxyethyl, .beta.-benzy-loxyethyl, .beta.-phenoxyethyl, .beta.-N-methylbenzylaminoethyl, .beta.-piperidinoethyl, .beta.-(4-methylpiperazino)ethyl or .beta.-morpholi-noethyl, each of R5 and R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, .beta.-chloroethyl, benzyl, phenyl, .beta.-chlorophenyl, .beta.-hydroxyethyl or cyclohexyl, or R5 and R6 form, together with the adjacent nitrogen atom a heterocyclic group selected from the group consisting of piperidino, 4-methylpiperazino and morpholino and A is methylene, ethylene, methyl methylene or dimethyl methylene.

4. A process according to claim 1, in which .beta.-methoxyethyl 3-amino-4-carbamoyloxycrotonate, methyl 3-amino-4-N-methylcarbamoyloxycrotonate, ethyl 3-amino-4-N-methylcarbamoy-loxycrotonate, .beta.-methoxyethyl 3-amino-4-N-methyicarbamoyloxycro-tonate, ethyl 3-amino-4-N-ethylcarbamoyloxycrotonate, ethyl 3-amino-4-N-propylcarbamoyloxycrotonate, ethyl 3-amino-4-N-t-butyl-carbamoyloxycrotonate, ethyl 3-amino-4-N-cyclohexylcarbamoyl-oxycrotonate, ethyl 3-amino-4-N-phenylcarbarnoyloxycrotonate, methyl 3-amino-4-N-(p-chlorophenyl)carbamoyloxycrotonate, .beta.-propoxyethyl 3-amino-4-N,N-dimethylcarbamoyloxycrotonate, ethyl 3-amino-4-N,N-dicyclohexylcarbamoyloxycrotonate, ethyl 3-amino-4-N,N-diphenylcarbamoyloxycrotonate, ethyl 3-amino-4-piperidinocar-bamoyloxycrotonate, ethyl 3-amino-4-(4-methylpiperazino)carbamoy-loxycrotonate, ethyl-3-amino-4-morpholinocarbamoyloxycrotonate, 3-amino-4-N-benzyl-N-methylcarbamoyloxycrotonate ethyl 3-amino-4-N,N-bis(.beta.-chloroethyl)carbamoyloxycrotonate is produced.

5. A 3-amlno-3-carbamoyloxyalkylacryllc acld derlva-tlve represented by the general formula:

,; > N COO--A--C -- C IICC)Ol~ (11 ) where R3 Is lower alkyl, haloalkyl, lower alkenyl, lower al~ynyl, aralkyl, aryl, hydroxyalkyl, lower alkoxyalkyl, lower alkeny-loxyalkyl, aralkyloxyalkyl, aryloxyalkyl or B-N < n7 (where B Is stralght-chalned or branched alkylene, and each of R7 and R8 Is lower alkyl, aralkyl or aryl, or R7 and R8 form, together wlth the adJacent nltrogen atom, a heterocycllc group), Is alkylene, and each of R5 and R6 Is hydrogen, lower alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aralkyl or aryl, or R5 and R6 form, together wlth the adJacent nltrogen atom, a heterocycllc ~roup.

6. The 3-amlno-3-carbamoyloxyalkylacryllc acld derlva--tlve accordlng to ClaIm 5, whereln R3 Is methyl, ethyl, propyl, Isopropyl, butyl, Isobutyl, tertlary butyl, pentyl, hexyl, ~ -chloroethyl, ~-bromoethyl, ~ -chloropropyl, r-chloropropyl, chlorobutyl, ~ ~ dlchloroethyl, trlfluoromethyl, ~ ~, ~
trlchloroethyl, vlnyl, allyl, 3-butenyl , Isopropenyl, propargyl, 2-butynyl, benzyl, ~ -methylbenzyl, phenethyl, phenyl, pyrldyl, naphthyl, qulnolyl, ~-hydroxyethyl, ~ hydroxypropyl, hydroxybutyl, r-hydroxypropyl, ~-hydroxybutyl, ~ ~ -dlhydroxypropyl, ~ - methoxyethyl, ~-ethoxyethyl, ~ -propoxyethyl, ~ -Isopropoxyethyl, ~-butoxyethyl, ~ Isobut-oxyethyl, ~ -tertlarybutoxyethyl, ~-methoxypropyl, ~ -ethoxypropyl, ~ -propoxypropyl, ~ Isopropoxypropyl, butoxypropyl, r-methoxypropyl, ~-ethoxypropyl, r-propoxypropyl, r -butoxypropyl, ~J-propoxybutyl, ~-vlnyloxyethyl, ~ -alIyloxyethyl, ~-(3-butenyloxy)ethyl, ~-lso-// ~

propenyloxyethyl, .beta.-allyoxypropyl, .beta.-benzyloxyethyl, .beta.-phenethyloxyethyl, .beta.-(?-methylbenzyloxy)ethyl, .beta.-phenoxyethyl, .beta.-pyridyoxyethyl, .beta.-phenoxypropyl, .beta.-phenoxybutyl, .beta.-dimethy-laminoethyl, .beta.-diethylaminoethyl, .beta.-methylethylaminoethyl, .beta.-dimethylaminopropyl, ?-dimethylaminopropyl, .omega.-dimethylamino-butyl, .beta.-N-methylbenzylaminoethyl, .beta.-N-methylbenzylaminopropyl, .beta.-N-methylbenzylaminobutyl, ?-N-methylbenzylaminopropyl, .omega.-N-methylbenzylaminobutyl, .beta.-piperidinoethyl, .beta.-(4-methylpiper-azino)ethyl, .beta.-(4-ethylpiperazino)ethyl, .beta.-(4-propylpiper-azino)ethyl, .beta.-(4-methylhomopiperazino)ethyl, .beta.-morpholino-ethyl,?-morpholinopropyl, .omega.-morpholinobutyl, .beta.-homomorpho-linoethyl, .beta.-(1-pyrrolidinyl)ethyl, .beta.-(1-imidazolidinyl)ethyl, .beta.-(1-pyrazolidinyl)-ethyl, .beta.-(1-indolinyl)ethyl, .beta.-(2-isoindolinyl)ethyl, or .beta.-N-methylanliino-ethyl; A is methylene, methylmethylene, phenylemethylene, dimethylmethylene, ethylene, trimethylene or tetramethylene; and each of R5 and R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, .beta.-chloroethyl, .beta.-bromoethyl, .beta.-chloropropyl, ?-chloroproyl, .omega.-chlorobutyl, .beta.,.beta.-dichloro-ethyl,.beta.,.beta.,.beta.-trichloroethyl, trifluoromethyl, .beta.-hydroxyethyl, .beta.-hydroxypropyl, ?-hydroxypropyl,.omega.-hydroxybutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, ?-methylbenzyl, phenethyl, phenyl, 4-chlorophenyl, 3,4-dichloro-phenyl, pyridyl or naphthyl, or R5 and R6 form, together with the adjacent nitrogen atom, a heterocyclic group selected from the group consisting of piperidino, 4-methylpiperazino, 4-ethyl-piperazino, 4-propylpiperazino, 4-methylhomopiperazino, mor-pholino, homomorpholino, i-pyrrolidinyl, i-imidazolidinyl, i-imidazolinyl, i-pyrazolidinyl, i-indolinyl and 2-isoindoilnyl.

7. The 3-amino-3-carbamoyloxyalkylacrylic acid deriva-tive according to Claim 5, wherein R3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .beta.-chloroethyl, allyl, propargyl, benzyl, phenyl, .beta.-methoxyethyl, .beta.-propoxyethyl, .beta.-isoprop-oxyethyl, .beta.-allyloxyethyl, .beta.-benzyloxyethyl, .beta.-phenoxyethyl, .beta.-N-methylbenzylaminoethyl,.beta.-piperidinoethyl, .beta.-(4-methylpiperazino)ethyl or .beta.-morpholinoethyl, each of R5 and R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl tertiary butyl, .beta.-chloroethyl, benzyl, phenyl .beta.-chlorophenyl, .beta.-hydroxyethyl or cyclohexyl, or R5 and R6 form, together with the adjacent nitrogen atom a heterocyclic group selected from the group consisting of piperidino, 4-methylpiperazino and morpholino and A is methylene, ethylene or dimethyl methylene.

8. The 3-amino-3-carbamoyloxyalkylacrylic acid deriva-tive according to Claim 5, which is .beta.-methoxyethyl 3-amino-4-car-bamoyloxycrotonate, methyl 3-amino-4-N-methylcarbamoyloxycroto-nate, ethyl 3-amino-4-N-methylcarbamoyloxycrotonate, .beta.-methoxyethyl 3-amino-4-N-methylcarbamoyloxycrotonate, ethyl 3-amino-4-N-ethylcarbamoyloxycrotonate, ethyl 3-amino-4-N-propyl-carbamoyloxycrotonate, ethyl 3-amino-4-N-t-butylcarbamoyloxycro-tonate, ethyl 3-amino-4-N-cyclohexylcarbamoyloxycrotonate, ethyl 3-amino-4-N-phenylcarbamoyloxycrotonate, methyl 3-amino-4-N-(p-chlorophenyl)carbamoyloxycrotonate, .beta.-propoxyethyl 3-amino-4-N, N-dimethylcarbamoyloxycrotonate, ethyl 3-amino-4-N,N-dicyclo-hexylcarbamoyloxycrotonate, ethyl 3-amino-4-N,N-diphenylcarbamoy-loxycrotonate, ethyl 3-amino-4-piperidinocarbamoyloxycrotonate, ethyl 3-amino-4-(4-methylpiperazino)carbamoyloxycrotonate, ethyl 3-amino-4-morpholinocarbamoyloxycrotonate, 3-amino-4-N-benzyl-N-methylcarbamoyloxycrotonate, ethyl 3-amino-4-N,N-bis(.beta.-chloro-ethyl)carbamoyloxycrotonate.

9. A process according to claim 1 in which R5 and R6 are hydrogen.

10. A 3-amino-3 carbamoyloxalklacrylic acid derivative according to claim 1 in which R3 is as in claim 1 and R6 and R6 are hydrogen.

11. A process according to claim 9 in which R3 is ethyl.

12. A process according to claim 1 which comprises reacting ethyl-4-carbamoyoxy-2-butynoate in ethanol at elevated temperature with ammonium acetate.

13. Ethyl 3-amino-4-carbamoyloxycrotonate.

14. A process according to claim 9 in which R3 is isobutyl.

15. A process according to claim 1 which comprises reacting isobutyl-4-carbamoyloxy-2-butynoate in ethanol at ele-vated temperature with ammonium acetate.

16. Isobutyl 3-amino-4-carbamoyloxycrotonate.

17. A process according to claim 9 in which R3 is .beta.-propoxyethyl.

18. A process according to claim 1 which comprises reacting .beta.-propoxyethyl-4-carbamoyloxy-2-butynoate in ethanol at elevated temperature with ammonium acetate.

19. .beta.-propoxyethyl 3-amino-4-carbamoyloxycrotonate.

20. A process according to claim 1 in which R5 is hydrogen, R6 is methyl and R3 is .beta.-propoxyethyl.

21. A process according to claim 1 which comprises reacting .beta.-propoxyethyl-4-N-methylcarbamoyloxy-2-butynoate in ethanol at elevated temperature with ammonium acetate.

22. .beta.-propoxyethyl 3-amino-4-N-methylcarbamoyloxycro-tonate.

23. A process according to claim 9 in which R3 is methyl.

24. A process according to claim 1 which comprises reacting methyl-4-carbamoyloxy-2-butynoate in ethanol at elevated temperature with ammonium acetate.

25. Methyl 3-amino-4-carbamoyloxycrotonate.

26. A process according to claim 9 in which R3 is iso-propyl.

27. A process according to claim 1 which comprises reacting isopropyl-4-carbamoyloxy-2-butynoate in ethanol at ele-vated temperature with ammonium acetate.

28. Isopropyl 3-amino-4-carbamoyloxycrotonate.