KR910005749B1 - Process for the preparation of 3-carbamoyl oxyalkyl propiolic acid derivitives - Google Patents

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Description

Method for preparing 3-carbamoyloxyalkyl propiolic acid derivative

The present invention relates to a process for the preparation of 3-carbamoyloxyalkyl propiolic acid derivatives. In particular, the present invention relates to a process for the preparation of novel 3-carbamoyloxyalkyl propiolic acid derivatives useful as intermediates for the preparation of 2-carbamoyloxy alkyl-1,4-dihydropyridine derivatives having pharmacological activity. It is about.

2-carbamoyloxy alkyl-1,4-didropyridine derivatives having substituents in the asymmetric structure on the 2- and 6- of the dihydropyridine ring are disclosed in Japanese Unexamined Patent Publication Nos. 118,565 / 1982 and 175,166 / It is described in 1982. This dihydropyridine derivative has coronary vasodilating activity or hypotension activity and is expected to be useful as a medicine for treating diseases of the circulatory organs.

The preparation method of such asymmetric 1,4-dihydropyridine derivative is 4-substituted acetic acid ester, 4-substituted-2-ylidene aceto acetic acid ester or 4-substituted 2-ylidene aceto acetic acid ester or 4-substituted-3 Aminocrotonic acid esters have been proposed to be used as starting materials (Japanese Unexamined Patent Publication Nos. 5777/1977 and 79873/1978). However, these methods are not effective because they involve multiple steps to prepare the final product, i.e., asymmetric 4-dihydropyridine derivative, from each reactant.

As a result of extensive research, we have found novel 3-amino-3-carbamoyloxyalkyl acrylic acid derivatives and 3-carbamoyloxy useful as intermediates or starting materials for the preparation of asymmetric 1,4-dihydropyridine derivatives. It has been found that alkyl propiolic acid derivatives can be readily prepared in one step reaction.

Therefore, the present invention is (a) reacting a 3-amino-3-carbamoyloxyalkyl acrylic acid derivative represented by the following general formula (II) with a benzylidene compound represented by the following general formula (III), or (b The 3-amino-3-carbamoaloxyalkyl acrylic acid derivative of the general formula (II) is reacted with an aldehyde compound represented by the following general formula (IV) and a β-ketoester compound represented by the following general formula (V) Or (c) reacting a 3-carbamoyloxyalkyl propiolic acid derivative represented by the following general formula (VI) with a benzylidene compound of alban formula (III) and ammonia or a salt thereof: or (d) A 3-carbamoyloxyalkyl propiolic acid derivative of (VI) is reacted with an aldehyde compound of formula (IV), a β-keto-ester compound of formula (V) and ammonia or a salt thereof 2-carbamoyloxyalkyl-1,4-dihydropy represented by general formula (I) It provides a process for the preparation of derivatives:

[Wherein, R ¹ is halogen, cyano, nitro or lower alkoxy, R ² and R ³ are lower alkyl, haloalkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, lower alkoxyalkyl, lower al, respectively Kenyloxyalkyl, aralkyloxyalkyl, aryloxyalkyl or Wherein B is straight or branched alkylene and R ⁷ and R ⁸ are lower alkyl or aralkyl, or R ⁷ and R ⁸ together form a heterocyclic group with adjacent nitrogen atoms, and R ⁴ is lower alkyl A is alkylene R ⁵ and R ⁶ are each hydrogen, lower alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aralkyl or aryl, or R ⁵ and R ⁶ together with adjacent nitrogen atoms form a heterocyclic group.]

3-amino-3-carbamoyloxyalkyl acrylic acid derivatives of general formula (II) and 3-carbamoyloxyalkyl propiolic acid derivatives of general formula (VI) used as starting materials in the above process are novel Compound.

The 3-amino-3-carbamoyloxyalkyl acrylic acid derivatives of formula (II) can be prepared by reacting the 3-carbamoyloxyalkyl propiolic acid derivatives of formula (VI) with ammonia or salts thereof.

3-carbamoyloxyalkyl propiolic acid derivatives of general formula (VI) are formulas of (a) an acetylene compound represented by the following general formula (VII)

Reacted with an isocyanate represented by, or a compound capable of producing an isocyanate under reaction conditions, and then hydrolyzed if necessary, or formula

Wherein R ⁵ and R ⁶ are as previously defined except for hydrogen

Or (b) reacting the acetylene compound of formula (VII) with phosgene or trichloromethylchloroformate to produce a chloroformic acid ester derivative represented by the following alban formula (VII): Then, expression

A chloroformic acid ester derivative represented by the following general formula (X) by reacting with an amine compound represented by the formula (c) or (c) reacting an acetylene compound represented by the following general formula (IX) with phosgene or trichloromethylchloroformate. After generating the following formula

Reacted with an amine compound represented by to form a carbamate derivative represented by the following general formula (XI), and then reacted with a metalizing agent to produce an organometallic compound, followed by general formula

It can be prepared by reacting with chloroformate represented by:

Wherein A, R ³ , R ⁵ , and R ⁶ are as previously defined, and R ⁹ is chlorosulfony, dichlorophosphoryl, trichloroacetyl, hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl Or aryl).

The present invention will now be described in more detail with reference to preferred embodiments.

R ¹ is a halogen such as fluorine, chlorine, bromine or iodine: di-substituted amino such as cyano: nitro: hydroxyl: dimethylamino, diethylamino or dipropylamino: lower such as methoxy, ethoxy, propoxy or butoxy Alkoxy.

Each of R ² and R ³ is lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl: β-chloroethyl, β-bromoethyl, β-chloropropyl, γ Haloalkyl such as chloropropyl, ω-chlorobutyl, β, β-dichloroethyl, trifluoromethyl or β, β, β-trichloroethyl: lower alkenyl such as vinyl, allyl, 3-butenyl or isopropenyl : Lower alkynyl, such as propargyl or 2-butynyl: Aralkyl, such as benzyl, α-methylbenzyl or phenethyl: Aryl, such as phenyl, pyridyl, niphthyl or quinolyl: β-methoxyethyl, β-ethoxyethyl , β-propoxyethyl, β-isopropoxyethyl, β-butoxyethyl, β-isobutoxyethyl, β-tert-butoxyethyl, β-methoxypropyl, γ-ethoxypropyl, γ-prop Lower alkoxyalkyls such as oxypropyl, γ-butoxypropyl or ω-propoxybutyl: β-vinyloxyethyl, β-allyloxyethyl, β- (3-butenyl Lower alkenyloxyalkyl such as ethyl, β-isopropenyloxyethyl or β-allyloxypropyl; aralkyl such as β-benzyloxyethyl, β-phenethyloxyethyl or β- (α-methylbenzyloxy) ethyl Oxyalkyl: aryloxyalkyl such as β-phenoxyethyl, β-pyridyloxyethyl, β-phenoxypropyl or β-phenoxybutyl: β-dimethylaminoethyl, β-diethylaminoethyl, β-methylethylamino Ethyl, β-dimethylaminopropyl, γ-dimethylaminopropyl, ω-dimethylaminobutyl, β-N-methylbenzylaminoethyl, β-N-methylbenzylaminopropyl, β-N-methylbenzylaminobutyl, γ-N -Methylbenzylaminopropyl, ω-N-methylbenzylaminobutyl, β-piperidinoethyl, β- (4-methylpiperazino) ethyl, β- (4-ethylpiperazino) ethyl, β- (4 -Propyl piperazino) ethyl, β- (4-methylhomopiperazino) ethyl, β-morpholinoethyl, γ-morpholinopropyl, ω-morpholinobutyl, β-homomorpholi Ethyl, β- (1-pyrrolidinyl) ethyl, β- (1-imidazolidinyl) ethyl, β- (1-imidazolidinyl) ethyl, β- (1-pyrazolidinyl) ethyl, β Such as-(1-pyrazolidinyl) ethyl, β- (1-pyrazolidinyl) ethyl, β- (2-isoindolinyl) ethyl or β-N-methylanilinoethyl to be.

R ⁴ is lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.

A is alkylene such as methylene, methylmethylene, ethylmethylene, phenylmethylene, dimethylmethylene, methylethylmethylene, methylisobutylene, phenylmethylene, ethylene, methylethylene, ethylethylene, ethylethylene, trimethylene or tetramethylene.

R ⁵ and R ⁶ are each lower hydrogen such as hydrogen: methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl: β-chloroethyl, β-bromoethyl, β-chloropropyl, γ-chloro Haloalkyl such as propyl, ω-chlorobutyl, β, β-dichloroethyl, β, β, β-trichloroethyl or trifluoromethyl: β-hydroxyethyl, β-hydroxypropyl, γ-hydroxypropyl or hydroxyalkyl such as ω-hydroxy butyl: cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl: lower alkenyl such as vinyl, allyl, 3-butenyl or isopropenyl; benzyl, α-methyl Aralkyl such as benzene or phenethyl; Aryl, such as phenyl, pyridyl, or naphthyl, or R ⁵ and R ⁶ together with the adjoining nitrogen atom, piperidino, 4-methylpiperazino, 4-ethylpiperazino, 4-propylpiperazino, 4-methyl homopiperazino, morpholino, homomorpholino, 1-pyrrolidinyl, 1-imidazolidinyl, 1-imidazolinyl, 1-piperazolidinyl, 1-indolinyl or 2 To form heterocyclic groups such as isoindolinyl.

The aromatic ring contained in aralkyl, aryl, aralkyloxyalkyl and aryloxyalkyl of R ² -R ⁸ may be substituted by 1 to 3 substituents. As such substituents, di-substituted aminos such as halogen: cyano: nitro: hydroxyl: dimethylamino, diethylamino or diisopropylamino such as fluorine, chlorine, bromine or iodine: methoxy, ethoxy, propoxy or minor Lower alkoxy such as oxy; lower alkyl such as methyl, ethyl, propyl or butyl; and trifluoromethyl.

From now on, the process for preparing 2-carbamoyloxyalkyl-1,4-dihydropyridine derivatives of general formula (I) will be described in particular.

In a preferred embodiment of the invention, R ⁵ is hydrogen and R ⁶ is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl or aryl, and R ¹ to R ⁴ and A are related to general formula (I) As defined. In particular, R ¹ is O-nitro, m-nitro, O-chloro, O-cyano or O-methoxy, R ² and R ³ are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, β Chloroethyl, allyl, propargyl, benzyl, phenyl, β-methoxyethyl, β-ethoxyethyl, β-propoxyethyl, β-isopropoxyethyl, β-allyloxyethyl, β-benzyloxyethyl, β-phenoxyethyl, β-N-methylbenzyl aminoethyl, β-piperidinoethyl, β- (4-methylliprazino) ethyl or β-morpholinoethyl, R ⁴ is methyl or ethyl and A Is methylene or ethylene, R ⁵ is hydrogen, R ⁶ is hydrogen, methyl, ethyl, propyl, cyclohexyl, phenyl p-chlorophenyl or m, p-dichlorophenyl.

Of the four methods of (a), (b), (c) and (d), the methods of (a) and (c) are particularly preferred.

With respect to methods (a) and (b), the compound of general formula (I) is referred to as 3-amino-3-carbamoyloxyalkyl acrylic acid derivative of general formula (II) (hereinafter sometimes simply referred to as "enamine compound") ) Is reacted with a benzylidene compound of formula (III) (method (a) or an aldehyde compound of formula (V) and a β-keto-ester compound of formula (V) (method (b)) .

The reaction conditions of methods (a) and (b) are appropriately selected depending on the type of starting material used. In general, the benzylidene compound of formula (III), or the aldehyde compound of formula (IV) and the β-keto-ester compound of formula (V) are actually stoichiometric with respect to the enamine compound of formula (II) Amount, ie equimolar amount. The molar ratio of the reactants can be varied within a range that does not adversely affect the reaction.

The reaction is usually carried out under cooling, at room temperature or under heating.

As a solvent for the reaction, water, an inert organic solvent or a solvent mixture of water and an inert organic solvent can be used. As inert organic solvents, alcohols such as methanol, ethanol, propanol, isopropanol or butanol, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, acetone, dimethylformamide, ethyl acetate. Benzene or chloroform can be used.

The reaction can be carried out using a catalyst such as an acid such as acetic acid, a base such as piperidine or a salt of acid and base.

In connection with the methods (c) and (d), the compound of formula (I) is a compound of formula (IV), wherein the 3-carbamoyloxyalkyl propiolic acid derivative (hereinafter simply referred to as "acetylene compound") It is prepared by reacting a benzylidene compound of III) and ammonia or a salt thereof, or with an aldehyde compound of the general formula (IV), a β-keto-ester compound of the general formula (V) and ammonia or a salt thereof.

The reaction conditions of methods (c) and (d) can be arbitrarily selected depending on the type of starting material used. In general, the acetylene compounds of formula (VI), the benzylidene compounds of formula (III), the aldehyde compounds of formula (IV) and the β-keto-esters of formula (V) are actually stoichiometric in each reaction. Amounts, ie equimolar amounts, and ammonia or salts thereof are used stoichiometrically. The molar ratio of the reactants can be varied within a range that does not adversely affect the reaction.

As the salt of ammonia, ammonium salts of organic acids such as acetic acid, formic acid, citric acid, benzoic acid or phenylacetic acid or ammonium salts of inorganic acids such as carbonic acid, bicarbonate or boric acid can be used.

The reaction is usually carried out under cooling, at room temperature or under heating or heating.

The solvent for the reaction may be water, an inert organic solvent or a solvent mixture of water and an inert organic solvent.

As inert organic solvents, alcohols such as methanol, ethanol, propanol, isopropanol, or butanol, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, acetone, dimethylformamide. Ethyl acetate. Benzene or chloroform can be used.

The reaction can be carried out using a catalyst such as an acid, a base or a salt of an acid with a base.

Compounds of formula (I) prepared by the process of the present invention may be purified by conventional methods such as extraction by organic solvents, separation by chromatography with a carrier such as silica gel or alumina and purification or crystallization. Can be isolated or collected. Also, if the compounds thus prepared are capable of forming salts, they can be converted to the respective salts using inorganic acids such as hydrochloric acid or organic acids such as citric acid.

The compound of general formula (I) obtained by the present invention has vasodilating activity and hypotension activity. In particular, since they have strong coronary vasodilation activity and extremely weak toxicity, they are expected to be very useful drugs for the treatment of circulatory diseases such as hypertension, heart failure, angina spectose, myocardial infarction or cerebral vascular disease.

Pharmacology:

Pharmacology and toxicity tests were performed on 2-carbamoyloxyalkyl-1, 4-dihydropyridine derivatives obtained by the method of the present invention.

1. Test Method

a) coronary vasodilation

O. Langendorff (Pfl) ers arch. ges. According to phisiol., 61 291-332 (1895)), the rabbit's isolated heart is tested for coronary vasodilation effects. The strength of coronary vasodilation is measured by the amount of sample required to increase the coronary outflow by 50%, ie ICD ₅₀ (g / ml).

b) acute toxicity

Samples are administered intravenously to DM male mice (18-22 g) and ₅₀ LD values are obtained according to the up-and-down method.

c) ornamental effects on dogs

Beagle dogs (13-16 kg, male) underwent thoracotomy under anesthesia with sodium petobarbital, the probe is attached to the left coronary ventral descending artery of each animal, and coronary blood flow (CF) is measured with an electromagnetic flowmeter. . On the other hand, the probe is attached to the exposed artery and the femoral arterial blood flow (FAF) is measured by an electron flow gauge. The drainage tube is inserted into the left femoral artery and the systemic blood pressure (BP) is measured by a transducer.

Heart rate (HR) is measured by electrocardiogram.

Sample solution is injected intravenously into the right femoral vein.

Coronary blood flow (CF), femoral artery blood flow (FAF), and heart rate (HR) are expressed as percent increase at each sample injection compared to each control at physiological saline injection. It is expressed as percent reduction compared to the control of systemic blood pressure (BP).

2. Results

Coronary vasodilation effects and isolated acute toxicity on mice are shown in the isolated heart of rabbits in Tables 1a and 1b. The compounds obtained by the present invention are considered to have a strong coronary vasodilation effect on coronary vessels. Acute toxicity is better than 1/6 to 1/17 of the acute toxicity of nifedipine.

The ornamental effect on Beagle dogs is shown in Table 2. The five representative compounds obtained by the present invention increase coronary blood flow (CF) with increasing dosage of them and their efficacy is equal to or greater than nifedipine. It is also contemplated that the coronary effect can be obtained without actually decreasing the pretrial blood pressure (BP) or actually without affecting the heart rate (HR). Therefore, no heavy burden will be placed on the heart and the compounds obtained by the present invention in connection with minimal toxicity make very useful vasodilators.

In addition, compounds 1 to 10 µg / kg of Examples 1-3, 1-26, and 1-38 increased 40 to 50% of cerebral blood and peripheral blood flow from the results of separate pharmacological tests administered intravenously. It can be seen that the compounds of the present invention are also useful as cerebral vasodilators and peripheral vasodilators.

TABLE 1-1a

Coronary vasodilation and acute toxicity

TABLE 1-1b

Coronary vasodilation and acute toxicity

TABLE 1-2

Therefore, the compounds of formula (I) obtained by the method of the present invention are expected to be useful as vasodilators and hypotensive drugs. The dosage form of this compound may be arbitrarily selected for such purposes and may be parenteral, such as intravenous, subcutaneous or intramuscular injection or rectal administration, or as a tablet, powder, granule, capsule, sublingual or syrup. The same oral administration may be used. The dosage may vary depending on the condition, age and weight of the patient and the mode of administration, usually from 0.1 to 1000 mg, preferably 1 to 100 mg per day for adults. The above-described formulations can be prepared by conventional methods commonly used.

The preparation of the acetylene compounds of formula (VI) and the new enamine compounds of formula (II), which will now be useful as intermediates of compounds of formula (I), will be described in detail.

First, about the manufacturing method of an enamine compound, the 3-amino-3- carbamoyloxyalkyl acrylic acid derivative of general formula (II) (that is, an enamine compound) is 3-carba represented by the following general formula (VI). It is prepared by reacting a barmoyloxyalkyl propiolic acid derivative with ammonia or a salt thereof:

(Wherein R ³ , R ⁵ , R ⁶ and A are as previously defined.)

Salts of ammonia can be inorganic ammonium salts such as carbonic acid, bicarbonate or boric acid or ammonium, or ammonium salts such as formic acid, acetic acid, propionic acid, butyric acid, tartaric acid, citric acid, glutaric acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, phthalic acid or ammonium nicotinic acid. .

In this process, ammonia or a salt thereof is usually used in an amount of 1 to 10 moles, preferably 1 to 5 moles per mole of starting material of general formula (VI).

The reaction is carried out at room temperature or at slightly elevated temperature.

Solvents for the reaction include lower alcohols such as methanol, ethanol, propanol, isopropanol, butyl alcohol, isobutyl alcohol, secondary-butyl alcohol, tert-butyl alcohol, or amyl alcohol, ethylene glycol, propylene glycol, glycerol, methylcellulose , Ethylene glycol diethyl ether, dimethyl sulfoxide, dimethylformamide, acetone, tetrahydrofuran and acetonitrile. Also as a solvent for the reaction, a solvent mixture of water and an inert organic solvent such as benzene, ethyl acetate, chloroform or diethyl ether may be used in addition to the above-mentioned organic solvents.

The reaction time is usually 1 to 10 hours, preferably 1 to 5 hours.

In a preferred embodiment, R ³ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, β-chloroethyl, allyl, propargyl, benzyl, phenyl, β-methoxyethyl, β-propoxyethyl, β- Isopropoxyethyl, β-allyloxyethyl, β-benzyloxyethyl, β-phenoxyethyl, β-N-methylbenzylaminoethyl, β-piperidinoethyl, β- (4-methylpiperazino) ethyl Or β-morpholinoethyl, R ⁵ and R ⁶ are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, β-chloroethyl, benzyl, phenyl, β-chlorophenyl, β-hydroxyethyl or cyclohexyl, or R ⁵ and R ⁶ together with adjacent nitrogen atoms form a heterocyclic group selected from the group consisting of piperidino, 4-methylpiperazino and morpholino and A is methylene, ethylene , Methyl methylene or dimethyl methylene.

Among the enamine compounds of the general formula (II) thus obtained, β-methoxyethyl 3-amino-4-carbamoyloxy crotonate, methyl 3-amino-4-N-methylcarbamoyloxy Crotonate, ethyl 3-amino-4-N-methylcarbamoyloxy crotonate, β-methoxyethyl 3-amino-4-N-methylgarbamoyloxy crotonate, ethyl 3-4-N -Ethylcarbamoyloxy crotonate, ethyl3-amino-4-N-propylcarbamoyloxy crotonate, ethyl 3-amino-4-Nt-butylcarbamoyloxy crotonate, ethyl 3-amino 4-N-cyclohexylcarbamoyloxy crotonate, ethyl 3-amino-4-N-phenylcarbamoyloxy crotonate, ethyl 3-amino-4-N- (p-chlorophenyl) carba Moyloxy crotonate, β-propoxyethyl 3-amino-4-N, N-dimethylcarbamoyloxy crotonate, ethyl 3-amino-4-N, N-dicyclohexylcarbamoyloxy croto Nate, Ethyl 3-amino-4-N, N-diphenylcarbamoyloxy crotonate, ethyl 3-amino-4-pyridinocarbamoyloxy crotonate, ethyl 3-amino-4- (4-methyl Piperazino) carbonyloxy crotonate, ethyl-3-4-morpholinocarbamoyloxy crotonate, ethyl 3-amino-4-N, N-bis (β-chloroethyl) carbamoyloxy Crotonate, ethyl 3-amino-4-N-benzyl-N-methylcarbamoyloxy crotonate, ethyl 3-amino-4-carbamoyloxy crotonate, isobutyl 3-amino-4-car Barmoyloxy crotonate, β-propoxyethyl 3-amino-4-carbamoyloxy crotonate, β-propoxyethyl 3-amino-4-N-methylcarbamoyloxycrotonate methyl 3- Preferred are amino-4-carbamoyloxy crotonate and isopropyl 3-amino-4-carbamoyloxy crotonate. Most preferred are methyl 3-amino-4-carbamoyloxy crotonate and isopropyl 3-amino-4-carbamoyloxy crotonate.

Regarding the method for preparing the acetylene compound of the present invention, the 3-carbamoyloxyalkyl propiolic acid derivative of the general formula (VI) (ie, the acetylene compound) may be (a) an acetylene compound represented by the following general formula (VII). expression

R ⁹ NCO

After reacting with an isocyanate represented by (wherein R ⁹ is chlorosulfonyl, dichlorophosphoryl, trichloroacetyl, hydrogen, lower alkenyl, aralkyl or aryl), or a compound capable of forming an isocyanate under reaction conditions Or, if necessary, hydrolyze or formula

Or (b) reacting an acetylene compound of formula (VII) with phosgene or trichloromethylchloroformate, wherein R ⁵ and R ⁶ are as defined above except for hydrogen. Reacting to produce a chloroform acid ester derivative represented by the following general formula (VIII), and then

Or (c) reacting an acetylene compound of the general formula (IX) with phosgene or trichloromethylchloroformate, wherein R ⁵ and R ⁶ are as defined above. To produce a chloroform acid ester derivative represented by (X),

(R ⁵ and R ⁶ are as previously defined)

The reaction rate is indicated by the reaction with an amine compound to produce a carbamate derivative represented by the following general formula (XI), followed by reaction with a metallizing agent to produce an organometallic compound, and then the general formula

ClCOOR ³

Prepared by reacting with chloroformate represented by (R ³ is as defined above):

(Wherein R³, R⁵, R⁶And A is as previously defined.)

In the case where ethyl 4-hydroxy-2-butinoate and methyl isocyanate are used as starting materials, the reaction process of method (a) can be described by the following scheme:

In the case where ethyl 4-hydroxy-2-butinoate, phosgene and dimethylamine are used as starting materials, the reaction process of the method (b) can be described by the following scheme:

The reaction process of process (c) can be illustrated by the following reaction scheme when propargyl alcohol, phosgene, dimethylamine, butyllithium and ethylfluoroformate are used as starting materials.

Starting acetylene compounds of formulas (VII) and (IX) are known compounds or, if not described in the literature, known methods (M. Mark Midland: J. Org. Chem., 40, 2250-2225 (1975), Henne Greenlee: J. Am. Chem. Soc., 67, 484 (1945)).

Process (a) relates to the preparation of compounds of formula (VI) by reacting an acetylene compound of formula (VII) with an isocyanate or carbamic acid chloride.

Isocyanates of the general formula R ⁹ NCO (R ⁹ is as previously defined) include 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-nitrophenyl isocyanate , m, p-dichlorophenyl isocyanate, p-fluorophenyl isocyanate, p-methoxyphenyl isocyanate, p-tolyl isocyanate, p-dimethyl isocyanate, benzyl isocyanate, diphenylmethyl isocyanate, pen There may be mentioned an isocyanate or β- dimethylaminoethyl isocyanate.

General formula to be used for this method Carbamic acid chloride, wherein R ⁵ and R ⁶ are as defined previously, wherein dimethylcarbamyl chloride, diethylcarbamyl chloride, dipropylcarbamyl chloride, diisopropylcarbamyl chloride, methylethylcarbamyl chloride, methyl Benzylcarbamyl chloride and methylphenylcarbamyl chloride.

In this reaction, a compound capable of forming such isocyanate under the reaction conditions described below in place of the isocyanate of the general formula R ⁹ NCO may be used. As such compounds, they are either acid azide represented by the general formula R ⁹ CON ₃ (wherein R ⁹ is as defined above) under heating conditions, or under heating conditions or in the presence of trialkylamines and heavy metals (e.g., silver nitrate or mercuric chloride) And thiocarbamates represented by the general formula R ⁹ NHCOSR (R ⁹ is as defined above and R is lower alkyl).

The reaction conditions of the method (a) for preparing the compound of formula (VI) may be appropriately selected depending on the type of starting material used. In general, isocyanates or general formula R ⁹ NCO wherein R ⁹ is as defined above Carbamic acid chlorides (R ⁵ and R ⁶ as previously defined) are used in amounts of 1-2 moles per mole of acetylene compound of formula (VII). The molar ratio of starting material can be varied within a range that does not adversely affect the reaction. The reaction is usually carried out at room temperature under cooling or under heating or heating.

If carbamic acid chloride is used, a base such as pyridine, triethylamine or dimethylaniline is used in equimolar or excess relative to carbamic acid chloride. As the solvent for the reaction, an inert organic solvent such as dichloromethane, chloroform, diethyl ether, tetrahydrofuran or benzene is 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 is necessary to hydrolyze the reaction mixture by adding water thereto after completion of the reaction.

For method (b), a acetylene compound of formula (VII) is reacted with phosgene or trichloromethylformate to synthesize a compound of formula (VIII), and then a compound of formula (VIII) and a formula A compound of formula (VI) is prepared by reaction with an amine compound of formula (R ⁵ and R ⁶ as previously defined). The trichloromethyl formate to be used in this reaction is contacted with a very small amount of pyridine or activated carbon and the phosgene gas generated is absorbed into an inert organic solvent such as benzene, or added drop wise to an inert organic solvent solution such as benzene. A phosgene solution is obtained as a pretreatment operation before the reaction with the acetylene compound of VII). General formula to be used in this reaction Amine compounds, wherein R ⁵ and R ⁶ are as defined above; ammonia, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, tert-butylamine, dimethylamine, di Ethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, methylethylamine, diethanolamine, cyclohexylamine, dicyclohexylamine, allylamine, benzylamine, α-methylbenzylamine, Phenethylamine, aniline, diphenylamine, α-pyridylamine, α-naphthylamine, N-methylbenzylamine, N-methylaniline, piperidine, 4-methylpiperazine, 4-methylhomopiperazine, Morpholine, homomorpholine, pyrrolidine, imidazolidine, imidazoline, pyrazolidine, indolin and isoindolin.

In method (b), the reaction conditions for the reaction of the acetylene compound (VII) with phosgene or trichloromethylchloroformate are usually phosgene or trichloromethylchloroformate, the acetylene compound of formula (VII) It is used in an amount of 1 to 2 moles per mole.

In process (b), the reaction conditions for the reaction of the compound of formula (VII) with the amine compound are usually represented by 1 mole of the compound of formula (VII). The amine compound (R ⁵ and R ⁶ are the same as the former) is used in an amount of 2 to 3 moles, or 1 to 2 moles of the amine compound is 1 to 2 moles of a tertiary amine such as triethylamine, dimethylaniline or pyridine It is used in combination with.

The molar ratio of the reactants can be used over a wide range without adversely affecting the reaction. In each case, the reaction is carried out under ice cooling or at room temperature. In each reaction, an inert organic solvent such as diethyl ether, tetrahydrofuran, benzene, toluene, dichloromethane or chloroform is usually used as the solvent. For the reaction time, each reaction is carried out under stirring for 30 minutes to 3 hours and then stirred overnight at room temperature to complete.

Method (c) is prepared by first reacting an acetylene compound of general formula (IX) with phosgene or trichloromethylchloroformate to prepare a compound of general formula (X), and then converting the compound of general formula (X) (R ⁵ and R ⁶ are as defined above except for hydrogen) as an amine compound to produce a compound of formula (XI) by reacting with an amine compound to react the compound of formula (XI) with a metallizing agent It is a continuous or powered process for preparing compounds of formula (VI) by forming organometallic compounds and then reacting them with chloroformates of the general formula ClCOOR ³ (R ³ is as defined above). General formula As amine compounds of R ⁵ and R ⁶ as previously defined except for hydrogen, the amine compounds listed in the above method (b) except for ammonia and primary amines such as methylamine and benzylamine can be mentioned. Chloroformate of the general formula CICOOR ³ to be used in the reaction of process (c), wherein R ³ is as previously defined, methylgloformate, allylchloroformate, propylchloroformate, isopropylchloroform Mate, β-chloroethylchloroformate, allylchloroformate, propargylchloroformate, benzylchloroformate, phenylchloroformate, β-methoxyethylchloroformate, β-ethoxyethylchloroformate, β Propoxyethylchloroformate, β-isopropoxycycloformate, β-butoxyethylchloroformate, β-propoxypropylchloroformate, β-allyloxyethylchloroformate, β-benzyloxyethylchloro Formate, β-phenoxyethylchloroformate, β-dimethylaminoethylchloroformate, β-diethylaminoethylchloroformate, β-N-methylbenzyl Minoethylchloroformate, β-N-methylbenzylaminopropylchloroformate, β-piperidinoethylchloroformate, β- (4-methylpiperazino) ethylchloroformate, β-morpholinoethylchloro Formate and γ- (4-methylhomopiperazino) prochloroformate.

As metallurgical agents to be used in the reaction of the method (c), methyllithium, ethyllithium, n-propyllithium, n-butyllithium, s-butyllithium, t-butyllithium, cyclopropyllithium, vinyllithium, cis-propenyllithium , Phenyl lithium, lithium diisopropyl amine, lithium diethylamide, lithium di-trimethylsilylamide, lithium benzylamide, lithium cyclohexylamide, sodium, potassium, lithium, sodium amide, potassium amide, lithium amide, magnesium methyl Iodide, magnesium ethyl iodide, magnesium methyl bromide, magnesium ethyl bromide and magnesium phenyl chloride.

In method (c), the reaction of the first two steps, namely, the reaction of the acetylene compound of formula (XI) with phosgene or trichloromethylchloroformate and the reaction of the alban formula (X) with the amine compound muroga It is carried out with the same reaction conditions, reaction temperature, solvent and reaction time as in one method (b).

The reaction of the compound of general formula (XI) with the metallizing agent of method (c) is usually carried out in an equimolar amount or slightly excess with respect to the compound of general formula (XI), and the chloroformate is used in the amount of 1 to per mole of this compound. It is carried out under the conditions used in the amount of 2 moles.

The reaction with the metallizing agent is carried out under ice-cooling or lower temperature to -120 ° C, preferably -60 to -80 ° C, and the reaction with chloroformate is under ice-cooling or lower temperature to -80 ° C preferably- It is carried out at 60 ℃ to -80 ℃. As the solvent for the reaction, an inert organic solvent such as diethyl ether or tetrahydrofuran is used. For the reaction time, the reaction with the metallizing agent is carried out for 10 to 30 minutes, and then immediately for 30 to 60 minutes with the chloroformate.

In a preferred embodiment, R ³ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, β-chloroethyl, allyl, propargyl, benzyl, phenyl, β-methoxyethyl, β-propoxyethyl, β- Isopropylethyl, β-allyloxyethyl, β-benzyloxyethyl, β-phenoxyethyl, β-N-methylbenzylaminoethyl, β-piperidinoethyl, β- (4-methylpiperazino) ethyl, Or β-morpholinoethyl, R ⁵ and R ⁶ are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, β-chloroethyl, benzyl, phenyl, β-chlorophenyl, β-hydroxyethyl or cyclohexyl, or R ⁵ and R ⁶ together with adjacent nitrogen atoms form a heterocyclic group selected from the group consisting of piperidino, 4-methylpiperazino and morpholino and A is methylene, ethylene , Methylmethylene or dimethylmethylene.

Among the 3-carbamoyloxyalkyl propiolic acid derivatives of the general formula (VI) which can thus be obtained, methyl 4-carbamoyloxy-2-butinoate, ethyl 4-carbamoyloxy-2-part Tinoate, isopropyl 4-carbamoyloxy-2-butinoate, isobutyl 4-carbamoyloxy-2-butinoate, β-methoxy ethyl 4-carbamoyloxy-2-butinoate , β-propoxyethyl 4-carbamoyloxy-2-butinoate, methyl 4-N-methylcarbamoyloxy-2-butinoate, β-methoxyethyl-4-N-methylcarbamoyl jade 2-butinoate, β-propoxyethyl 4-N-methylcarbamoyloxy-2-butinoate, ethyl 4-N-ethylcarbamoyloxy-2-butinoate, ethyl 4-N-propyl Carmabamoyloxy-2-butinoate, ethyl 4-Nt-butylcarbamoyloxy-2-butinoate, ethyl 4-N-cyclohexylcarbamoyloxy-2-butinoate, ethyl 4-N -Phenylcarbamoyloxy-2-butino , 4-N- (P-chlorophenyl) carbamoyloxy-2-butinoate, β-propoxyethyl 4-N, N-diphenylcarbamoyloxy-2-butinoate, ethyl 4- N, N-dicyclohexylcarbamoyloxy-2-butinoate, ethyl 4-N, N-diphenylcarbamoyloxy-2-butinoate, ethyl 4-piperidinocarbonyloxy-2- Butinoate, ethyl 4- (4-methylpiperazino) carbonyloxy-2-butinoate, ethyl 4-morpholinocarbonyloxy-2-butinoate, ethyl 4-N, N-bis ( β-chloroethyl) carbonyloxy-2-butinoate and ethyl 4-N-benzyl-N-methylcarbamoyloxy-2-butinoate are preferred. Particularly preferably methyl 4-carbamoyloxy-2-butinoate, ethyl 4-carbamoyloxy-2-butinoate, isopropyl 4-carbamoyloxy-2-butinoate, isopropyl 4 Carbamoyloxy-2-butinoate isobutyl 4-carbamoyloxy-2-butinoate, β-propoxyethyl 4-carbamoyloxy-2-butinoate and β-propoxyethyl 4 -N-methylcarbamoyloxy-2-butinoate. Most preferably methyl 4-carbamoaloxy-2-butinoate and isopropyl 4-carbamoyloxy-2-butinoate.

From now on, the present invention will be explained in more detail with reference to examples. However, the present invention is not limited by these examples.

First, the present invention will be given examples of preparation of 3-carbamoyloxyalkyl propiolic acid derivatives of general formula (VI). These embodiments are indicated by the symbol '6'.

Example 6-1

Preparation of Methyl 4-carbamoyloxy-2-butinoate

H ₂ NCOOCH ₂ C≡CCOOCH ₃

22.8 g (0.2 moles) of methyl 4-hydroxy-2-butynate are dissolved in 200 ml of dichloromethane, and 17.5 ml (0.2 moles) of chlorosulfonyl isocyanate is added thereto at a temperature of -20 ° C. The mixture is stirred for 30 minutes at a temperature of -10-20 ° C. 20 ml of water is added to the reaction mixture, and hydrolysis is performed for 30 minutes at a temperature of about 0 deg. Crystals formed in the reaction mixture are collected by filtration to obtain 18 g of primary crystals. Phase separate the filtrate. The dichloromethane phase obtained by phase separation and the dichloromethane extract solution obtained by extracting the aqueous phase with dichloromethane are combined, washed with water, concentrated under reduced pressure, and the crystals thus formed are collected to obtain 10 g of secondary crystals. The primary and secondary crystals combined and recrystallized with ethyl acetate yielded 5.1 g (80% yield) of methyl 4-carbamoyloxy-2-butinoate in crystalline phase.

mp: 113 ~ 114 ℃

IR (KBr), cm­¹: 3410,3350,3300,3220,2250,1750,1700,1620,1140,1320,1295,1090,1050,930,750.

¹ H NMR (90`MHz, DMSO-d ₆ ), δ: 3.77 (s, 3H), 4.82 (s, 2H), 6.8 (brood s, 2H)

[Examples 6-2 to 6-8]

In the same manner as in Example 6-1, the compound shown in Table 3a is obtained.

Table 6-1

*: Compound (VI) yield is obtained by reaction of 0.1 mole of each starting material (VII) of formula (VII).

Example 6-9

Preparation of Ethyl N-propylcarbamoyloxy-2-butinoate

To 40 ml of a benzene solution of phosgene (containing 6.2 g (62.5 mmol) of phosgene) was quenched, and 6.4 g (50 mmol) of ethyl 4-hydroxy-2-butinoate were added rapidly, and the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture is allowed to come to room temperature and then left overnight. The reaction mixture is then concentrated under reduced pressure and benzene is distilled off to yield 8.1 g (yield 85%) of oily ethyl 4- (chlorocarbonyloxy) -2-butynate as a residue.

IR (liquid film), cm ¹ : 2250,1785,1720

¹ H NMR (90 MHz, CDCl ₃ ), δ: 1.34 (t, 3H), 4,28 (q, 2H), 5.02 (s, 2H)

2.85 g (15 mmol) of ethyl 4- (chlorocarbonyloxy) -2-butinoate is dissolved in 30 ml of benzene, and 12 ml of a benzene solution of propyl amine [containing 2.22 ml (27 mmol) of propylamine] Cool quickly under ice. The mixture is stirred for 30 minutes under ice-cooling. Pour the reaction mixture into ice water and adjust the pH to 2 with dilute hydrochloric acid. 100 ml of ethyl acetate is added to the mixture and stirred for extraction. The ethyl acetate extract was dried over sodium sulfate and concentrated under reduced pressure to yield 3.08 g (yield: 96.2%) of oily ethyl N-propyl carbamoyloxy-2-butinoate.

IR (liquid film), cm-¹: 2250, 1785, 1720, 1250

¹ H NMR (90 MHz, CDCl ₃ ), δ: 0.95 (t, 3H, J = 7 Hz), 1.35 (t, 3H, J = 7 Hz), 1.62 (m, 2H), 3.20 (m, 2H), 4.29 ( q, 2H), 4.86 (s, 2H), 8.40 (Brode, 1H)

[Examples 6-10 to 6-21]

In the same manner as in Example 6-9, the compounds of Table 3b are prepared.

Table 6-2

*: The yield of compound (VI) is obtained by the reaction of 50 mmol of each starting material of the general formula (VII).

Example 6-22

Preparation of Ethyl 4-N-phenylcarbamoyloxy-2-butinoate

6.4 g (0.05 mole) of ethyl 4-hydroxy-2-butynate was dissolved in 100 ml of dichloromethane, and 6 mm (0.055 mole) of phenyl isocyanate and 0.5 ml of triethylamine were temperatured at -20 ° C. Add from The mixture is reacted for 1 hour under stirring. The reaction mixture is washed continuously with 10 ml of IN hydrochloric acid and water, then dried over magnesium sulfate and concentrated under reduced pressure. The residue is separated and purified by a silica gel column (Pre PAK-500R) and a liquid chromatography apparatus (System 500A) using ethyl acetate-hexane (1: 3) as the developing solvent. Concentration under 10.6 g (85.8% yield) of oily ethyl 4-N-phenylcarbamoyloxy-1-butinoate was obtained.

IR (liquid film), cm ^-1 : 3350,2250,1720,1540,1255,1210,1050,750

¹ H NMR (90 MHz, CDCl ₃ ), δ (ppm): 1.33 (t, 3H, J = 7 Hz), 4.3 (q, 2H, 5 Hz), 7.92 (s, 2H), 6.9 to 7.2 (br, s), 7.3 to 7.6 (br, s, 5H)

Example 6-23

Preparation of α-propoxyethyl 4-N, N-diethyl gartbamoyloxy-2-butinoate

To 800 ml of a diethyl ether solution of phosgene (containing 248 g (2.5 moles) of phosgene) is rapidly added 112.1 g (2 moles) of propargyl alcohol under ice-cooling. The mixture is allowed to react for 2 hours under ice cooling and stirring. The reaction mixture is left at room temperature overnight. Then, the ether is distilled off. Purification of the residue by vacuum distillation yields 194 g (yield (81.8%) of colorless propargyl chloroformate from fractions distilled at temperatures between 47 ° C./40 mm Hg and 44 ° C./34 mm Hg).

Boiling Point: 44 ℃ / 34mmHg ~ 47 ℃ / 40mmHg

NMR (90 MHz, CDCI ₃ ), δ: 2.68 (t, 1H, J = 3 Hz), 4.88 (d, 2H, J = 3 Hz)

To 200 ml of a benzene solution of diethylamine (containing 26 ml (249 mmol) of diethylamine), 11.8 g (99.6 mmol) of propargyl chloroformate obtained above was added under ice-cooling. The mixture is allowed to react for 30 minutes under ice-cooling and stirring. The reaction mixture is poured into ice water and extracted with benzene. The benzene extraction solution is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by vacuum distillation gave 14.7 g (yield 95%) of colorless oily propargyl N, N-diethylcarbamate from the fraction distilled at a temperature of 71-73 ° C / 8mmHg.

Boiling Point: 71 ~ 73 ℃ / 8mmHg

IR (liquid film), cm ^-1 : 3320,3270,3000,2140,1700

¹ H NMR (90 MHz, CDCI ₃ ), δ: 1.16 (t, 6H, J = 7.5 Hz), 2.48 (t, 1H, J = 3 Hz), 3.33 (q, 4H, J = 7.5 Hz), 4.73 ( d, 2H, J = 3 Hz)

57.4 ml (1.65 mol) of hexane solution of butyl lithium (containing 94.7 mmol of butyl lithium) in 60 ml of tetrahydrofuran solution containing 14.7 g (94.7 mmol) of propargyl N, N-diethylcarbamate thus obtained Is added dropwise at a temperature of -65 to -75 ° C (triice, acetone cooling bath), and then 16.6 g (99.5 mmol) of β-propoxyethylchloroformate is added at a temperature of -60 to -70 ° C. The mixture was stirred for 30 minutes at a temperature of -60 to -70 ° C, then the cooling bath was removed, and when the temperature of the liquid reached room temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate extract solution is dried and then concentrated under reduced pressure. The oily residue thus obtained is purified by silica gel column chromatography (using 150 g of silica gel). After collecting the desired fraction eluted with benzene and concentrating under reduced pressure, 12.65 g (46.8% yield) of colorless oily β-propoxyethyl 4-N, N-diethylgarbamoyloxy-2-butinoate Obtained.

IR (liquid film), cm ^-1 : 2250,1750,1710,1430,1255,1165

¹ H (90 MHz, CDCl ₃ ), δ: 0.93 (t, 3H, J = 7 Hz), 1.16 (t, 6H, J = 7.5 Hz), 1.62 (m, 2H), 3.33 (q, 4H, J = 7.5 ㎐), 3.45 (t, 2H, J = 7.5 ㎐), 3.67 (t, 2H, J = 7.5 ㎐), 4.33 (t, 2H, J = 7.5 ㎐), 4.86 (s, 2H)

[Examples 6-24 to 6-35]

In the same manner as in Example 6-23, the compounds of Table 3c are prepared.

Table 6-3

*: The yield of compound (VI) is obtained by the reaction of 0.1 mole of each starting material of the general formula (VII).

Example 6-36

Preparation of ethyl 4- (N-benzyl-N-methylcarbamoyloxy) -2-butinoate

2.85 g (15 mmol) of ethyl 4-2 (chlorocarbonyloxy) -2-butinoate obtained in the first step of Example 6-9 were dissolved in 20 ml of dichloromethane, and 3.1 ml (24 mmol) of 9 ml of dichloromethane solution containing N-methylbenzeneamine is added rapidly under ice cooling. The mixture is allowed to react for 1 hour under ice-cooling and stirring. The reaction mixture is poured into ice water and extracted by adjusting the pH to 2 with dilute hydrochloric acid. The dichloromethane extract solution is dried over sodium sulfate and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (using 30 g of silica gel). Collect the desired fraction eluted with hexane-benzene (1: 0 → 3: 1) and concentrate under reduced pressure to give colorless oily ethyl 4- (N-benzyl-N-methylcarbamoyloxy) -2-part. 1.18 g (yield: 28.5%) of tynoate are obtained.

IR (liquid film), cm ^-1 : 2250,1750,1255,1140

¹ H NMR (90 MHz, CDCl ₃ ), δ: 1.30 (t, 3H, J = 7 Hz), 2.87 (s, 3H), 4.24 (q, 2H, J = 7 Hz), 4.49 (s, 2H), 4387 (s, 2H), 7.31 (s, 5H)

Example 6-37

Preparation of ethyl-4-N-methylcarbamoyloxy-2-pentinoate

To 40 ml of a benzene solution containing 3.8 g (26.7 mmol) of ethyl 4-hydroxy-2-pentinoate, 1.8 ml (30.5 mmol) of methyl isocyanate and 4.2 ml (30 mmol) of polyethylamine were added and the mixture was The reaction is carried out at room temperature under stirring for 1.5 hours. The reaction mixture is subsequently washed with 50 ml of 1N hydrochloric acid and water, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by silica gel (Prep PAK 500 / silica) column chromatography by liquid chromatography apparatus (Water 500 manufactured by Water Company). Collect the desired fraction eluted with hexane-ethyl acetate (3: 1) and concentrate under reduced pressure to give 3.6 g (yield 67%) of colorless oily ethyl 4-N-methyl-carbamoyloxy-2-pentino. Eight is obtained.

IR (liquid film), cm ^-1 : 3360,3000,2850,2250,1710,1530,1470,1450, 1420,130,1240,1130,1095,1050,1020,980,940,860,775,750

775,750

¹ H NMR (90 MHz, CDCl ₃ ), δ: 1.3 (t, 3H, J = 7.5 Hz), 1.53 (d, 3H, J = 6 Hz), 1.82 (d, 3H, J = 5.5 Hz), 4.25 ( q, 2H, J = 7.5 kV), 4.6 to 5.1 (brood s, 1H), 5.54 (q, 1H, 6 kPa)

Example 6-38

Preparation of ethyl 4-carbamoyloxy-4-methyl-2-pentinoate

To 100 ml of dichloromethane solution containing 4.9 g (31.4 mmol) of ethyl 4-hydroxy-methyl-2-pentinoate, 3 ml (34.5 mmol) of chlorosulfonyl isocyanate are added at -10 ° C. The mixture is reacted at −10 ° C. for 30 minutes with stirring. The reaction mixture is brought to room temperature and 20 ml of water is added thereto. The mixture is stirred for 15 minutes for hydrolysis treatment. The dichloromethane phases were separated by phase separation, washed successively with 10% barium chloride solution and water, dried over sodium sulfate and concentrated under reduced pressure to afford crystalline ethyl-4-carbamoyloxy-4-methyl-2-pentinoate 2.1. g (yield 33%) is obtained.

mp: 111-13.5 ° C

IR (KBr), cm ^-1 : 3580,3360,3300,3220,3020,2240,1710,1605,1380,1370,1265,1230,1145,1050,1035,865,785,755

¹ H NMR (90 MHz, DMSO-d ₆ ), δ: 1.24 (t, 3H, J = 7.5 Hz), 1.64 (s, 6H), 4.2 (q, 2H, J = 7.5 Hz), 6.57 (s, 2H )

Example 6-39

Preparation of ethyl 5-N-methylcarbamoyloxy-2-pentinoate

To 50 ml of benzene solution containing 2.85 g (20 mmol) of ethyl 5-hydroxy-2-pentinoate was added 1.2 ml (20 mmol) of methyl isocyanate and 2.8 ml (20 mmol) of triethylamine, and the mixture The reaction is stirred for 1 hour at room temperature under stirring.

Purification of the reaction mixture in the same manner as in Example 6-37 yielded 3.6 g of a colorless oil of ethyl 5-N-methylcarbamoyloxy-2-pentinoate (yield: 90.5%).

IR (KBr), cm ^-1 : 3400,2970,2240,1710,1530,1470,1370,1140,1075,1010,860,775,750

¹ H NMR (90 MHz, CDCl ₃ ), δ: 1.33 (t, 3H, J = 7.5 Hz), 2.6 (t, 2H, J = 6 Hz), 4.2 (d, 3H, J = 5 Hz), 4.25 ( t, 2H, J = 6 Hz), 4.2 (q, 2H, J = 7 Hz), 4.7 to 5.1 (m, 1H)

Example 6-40

Preparation of ethyl 4-carbamoyloxy-4-phenyl-2-butinoate

To 100 ml of dichloromethane solution containing 8 g (39.2 mmol of ethyl 4-hydroxy-4-phenyl-2-butynate) 3.5 ml (40.2 mmol) of chlorosulfonyl isocyanate was added at a temperature of -20 ° C and the mixture After reacting for 30 minutes at -10 ° C, hydrolysis and purification were carried out in the same manner as in Example VI-38, and 9.5 g of crystalline ethyl 4-carbamoyloxy-4-phenyl-2-butinoate ( Yield 98%) is obtained.

Melting point 82 ℃

IR (KBr), cm ^-1 : 3460,3350,3290,3010,2950,2250,1730,1705,1605,1500,1465,1365,1280,1260,1195,1090,1015,780,760,750,700

¹ H NMR (90 MHz, CDCl ₃ ), δ in ppm: 1.32 (t, 3H, J = 7 Hz), 4.26 (q, 2H, J = 7 Hz), 5.05 (brood s, 2H), 6.51 (s , 1H), 7.46 (brood s, 5H)

Examples will now be given for the preparation of novel 3-amino-3-carbamoyloxyalkyl acrylic acid derivatives of general formula (II) of the present invention.

Example 2-1

Preparation of ethyl 3-amino-4-methylcarbamoyloxy crotonate

1.85 g (10 mmol) of ethyl 4-N-methylcarbamoyloxy-2-butinoate and 3.84 g (50 mmol) of ammonium acetate are dissolved in 20 ml of ethanol and reacted at 60 ° C. for 4 hours under stirring. . The reaction mixture is concentrated under reduced pressure. 50 ml of ethyl acetate and 10 ml of 20% aqueous sodium chloride solution are added to the residue for extraction. The ethyl acetate extract is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel (Prep PAK 500 / silica) column chromatography using a liquid chromatography apparatus (Water Corp. System 500A). Collect the desired fractions eluted with hexane-ethyl acetate (5: 4) and concentrate under reduced pressure to give 0.88 g (44% yield) of crystalline ethyl 3-amino-4-N-methyl carbamoyloxy crotonate. do.

Melting Point: 60 ~ 61 ℃

IR (KBr), cm ^-1 : 3450,3350,3000,2950,1720,1660,1620,1590,1540,1445,1370,1280,1190,1170,1055,1040,955,790

¹ H NMR (90 MHz, CDCl ₃ ), δ in ppm: 1.27 (t, 3H, J = 7.5 μs), 2.83 (d, 3H, J = 6 μs), 4.6 (s, 2H), 4.66 (s, 1H ), 4.75 to 5.1 (m, 1H), 6.1 to 6.8 (brood, 2H)

[Examples 2-2 to II-27]

In the same manner as in Example 2-1, the compounds of Tables 4a, 4b, and 4c were prepared.

TABLE 2-1

Example 2-28

Preparation of β-Prooxyethyl 3-amino-4-N, N-diethylcarbamoyloxycrotonate

12.5 g (43.8 mmol) of g-propoxyethyl 4-N, N-diethylcarbamoyloxy-2-butyate are dissolved in 180 ml of isopropyl alcohol and 11 ml of 28% ammonia water is added. The mixture is reacted at 60 ° C. for 1 hour while stirring. The reaction mixture is concentrated under reduced pressure. The residue is extracted with ethyl acetate. This ethyl acetate extract was subjected to a water removal treatment and then concentrated under reduced pressure. The residue is purified by silica gel (Prep PAK 500 / silica) column chromatography by chromatography apparatus (Water 500 manufactured by Water Company). Collect the desired fractions eluted with hexane-ethyl acetate (2: 1) and concentrate under reduced pressure to give 8.6 g (yield 65%) of erosive oily g-propoxyethyl 3-amino-4-N, N-di. Ethylcarbamoyloxycrotonate is obtained.

UV: 275 nm (ε14000)

IR (liquid film), cm ^-1 : 3450,3350,2980,1695,1625,1575,1480,1430,1380,1365,1275,1160,1120,1095,1070,1005,790,765

¹ H NMR (90 MHz, CDCl ₃ ), δ in ppm: 0.92 (t, 3H, J = 8 μs), 1.15 (t, 6H, J = 7.5 μs), 1.62 (m, 2H), 3.32 (q, 4H , J = 7.5 ㎐, 3.45 (t, 2H, J = 8 ㎐), 3.65 (t, 2H, J = 4.5 ㎐), 4.25 (t, 2H, J = 4.5 ㎐), 4.62 (s, 2H), 4.71 (s, 1HO), 6.0 to 7.0 (brood, s, 2H)

[Example 2-29 to 2-40]

In the same manner as in Example 2-28, the compounds of Table 5 were prepared.

Table 2-2

*: The yield of compound (II) is obtained by the reaction of 10 mmol of each starting material of the general formula (VI).

Example 2-41

Preparation of ethyl 3-amino-4-N-methylcarbamoyloxycrotonate

1.85 g (10 mmol) of ethyl 4-N-methylcarbamoyloxy-2-butinoate and 3.95 g (50 mmol) of ammonium bicarbonate are dissolved in 20 ml of methyl cellosolve and reacted at 60 ° C. for 4 hours. . Subsequent treatment in the same manner as in Example 2-1 yielded 0.8 g (40% yield) of ethyl 3-amino-4-N-methylcarbamoyloxycrotonate in crystalline form.

Melting Point: 60 ~ 61 ℃

The analytical results by IR (KBr), UN and ¹ H-NMR are completely consistent with the results for the compound of Example 2-1.

Example 2-42

Preparation of ethyl 3-amino-4-N-methylcarbamoyloxycrotonate

1.85 g (10 mmol) of ethyl 4-N-methylcarbamoyloxy-2-butinoate and 1.73 g (12.5 mmol) of ammonium bicarbonate are dissolved in 20 ml of methyl cellosolve and reacted at 60 ° C. for 1 hour. . Subsequent treatment in the same manner as in Example 2-1 gave 1.1 g (yield 55%) of ethyl 3-amino-4-N-methylcarbamoyloxycrotonate.

Melting Point: 60 ~ 61 ℃

The analytical results by IR (KBr), UN and ¹ H-NMR are completely consistent with the results for the compound of Example 2-1.

Example 2-43

Preparation of ethyl 3-amino-4-N-methylcarbamoyloxy-pentinoate

3.6 g (18 mmol) of ethyl 4-N-methyl carbamoyloxy-2-pentinoate and 1.5 g (19.5 mmol) of ammonium acetate were dissolved in 20 ml of dimethylformamide and stirred at 60 ° C. for 2 hours. React.

The reaction mixture is concentrated under reduced pressure. The residue is dissolved in 5 ml of a mixed solution of ethyl acetate and water and stirred to mix. The ethyl acetate extract solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel (Prep PAK 500 / silica) column chromatography by liquid chromatography apparatus (Water 500 manufactured by Water Company). The desired fractions eluted under reduced pressure with hexane-ethyl acetate (2: 1) were collected and concentrated to give 2 g (9.3 mmol, yield 52%) of oily ethyl 3-amino-4-N-methylcarbamoyloxy-. 2-pentenoate is obtained.

UV: 274 nm

IR (liquid film), cm- ¹ : 3440,3350,3000,1710,1660, 1620, 1580,1445,1360,1310,1260,1165,1140,1090,1030,955,790

¹ H NMR (90 MHz, CDCl ₃ ), δ in ppm: 1.25 (t, 3H, J = 7 Hz), 1.43 (d, 3H, J = 7.5 Hz), 3.32 (d, 3H, J = 6 Hz), 4.13 (q, 2H, J = 7 Hz), 4.66 (s, 1H), 4.7 to 5.16 (brood, 1H), 5.23 (q, 1H, J = 7 Hz), 5.9 to 6.9 (brood, 2H)

Example 2-44

Preparation of ethyl 3-amino-4-carbamoyloxy-4-methyl-2-pentenoate

The reaction and purification were carried out in the same manner as in Example 2-43 except that 2.1 g (10.5 mmol) of ethyl 4-carbamoyloxy-4-methyl-2-pentinoate was used as a starting material. 0.47 g (2.1 mmol, 20% yield) of ethyl 3-amino-4-carbamoyloxy-4-methyl-2-pentenoate is obtained.

Melting Point: 109 ~ 111 ℃

UV: 277 nm

IR (KBr), cm ^-1 : 3460,3350,3290,3220,3000,1735,1650,1630,1610,1555,1360,1295,1200,1160,1140,1100,1025,1000,790

¹ H NMR (90 MHz, CDCl ₃ ), δ in ppm: 1.26 (t, 2H, J = 7.5 Hz), 1.62 (s, 6H), 4.15 (q, 2H, J = 7.5 Hz), 4.7 (s, 1H ), 5.06 (s, 2H), 6.3 to 6.9 (brood, 2H)

Example 2-45

Preparation of ethyl 3-amino-5-methylcarbamoyloxy-2-pentenoate

0.48 g (18 mmol) of ethyl 5-N-methylcarbamoyloxy-2-pentinoate was used in the same manner as in Example II-43 except that 0.48 g ( 2.2 mmol, yield 12.2%) of oil ethyl 3-amino-5-N-methylcarbamoyloxy-2-pentenoate is obtained.

UV: 276 nm

IR (liquid film), cm ^-1 : 3475,3360,3000,1730,1660,1615,1430,1385,1350,1270,1170,1100,1040,790

¹ H NMR (90 MHz, CDCl ₃ ), δ in ppm: 1.32 (t, 3H, J = 8 Hz), 3.83 (t, 2H, J = 7.5 Hz), 4.06 (t, 2H, J = 7.5 Hz), 4.25 (q, 2H, J = 8 Hz), 4.83 (s, 1H), 5.2 to 5.4 (brood s, 2H), 6.3 to 7.0 (brood, 2H)

Example 2-46

Preparation of ethyl 3-amino-4-carbamoyloxy-4-phenylcrotonate

The reaction and purification were carried out in the same manner as in Example II-377 except that 4.95 g (20 mmol) of ethyl 4-N-carbamoyloxy-4-phenyl-2-butinoate was used as starting material. 1.9 g (yield 26.1%) of oil ethyl 3-amino-4-carbamoyloxy-4-phenylcrotonate are obtained.

UV: 274 nm

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

¹ H NMR (90 MHz, CDCl ₃ ), δ in ppm: 1.34 (t, 3H, J = 7 Hz), 4.28 (q, 2H, J = 7 Hz), 4.83 (s, 1H), 5.1 to 5.3 (brood s 2H), 6.1 to 6.8 (brood 2H), 7.5 (brood s, 5H)

Now, the preparation method of another 2-carbamoyloxyalkyl-1,4-dihydropyridine derivative according to the present invention will be described in particular.

Example 1-1

Preparation of 2-carbamoyloxymethyl-6-methyl-4- (O-nitrophenyl) -3,5-diethoxycarbonyl-1,4-dihydropyridine

9.4 g (50 mmol) of ethyl 4-N-carbamoyloxy-3-aminocrotonate and 13.2 g (50 mmol) of ethyl 2- (O-nitrobenzylidene) acetoacetate are dissolved in 200 ml of ethanol The reaction is carried out for 16 hours at a temperature of 60-70 ° C. under stirring. The reaction mixture is concentrated under reduced pressure. Crystallization of the residue with ethyl acetate-hexane afforded crystalline 2-carbamoyloxymethyl-6-methyl-4- (O-nitrophenyl) -3, 5-dimethoxycarbonyl-1, 4-dihydropyridine 12.6 g (yield 58%) is obtained.

Melting Point: 128 ~ 132 ℃

UV: 235,350 nm

IR (KBr), cm ^-1 : 3540,3400,3000,1710,1690,1535,1495,1340,1205,1120,1100,1095,780,755,715cm ^-1

¹ H-NMR (90 MHz, CDCl ₃ ), δ in ppm: 1.18 (t, J = 7 Hz, 6H), 2.35 (s, 3H), 4.15 (m, 4H), 5.38 (brood s, 4H), 5.96 (s, 1H), 7.1 to 8.0 (m, 5H)

[Examples 1-1 to 1-6]

In the same manner as in Example 1-1, the compounds of Table 6 were prepared.

Table 1-3

Example 1-7

Preparation of 2-N-methylcarbamoyloxymethyl-6-methyl-4- (O-nitrophenyl) -3,5-diethoxycarbonyl-1,4-dihydropyridine

10.1 g (50 mmol) of ethyl 4-N-methylcarbamoyloxy-3-aminocrotonate and 13.2 g (50 mmol) of ethyl 2- (O-nitrobenzylidene) acetoacetate in 200 ml of ethanol It is dissolved and reacted for 16 hours at the temperature of 60-70 degreeC under stirring. The reaction mixture is concentrated under reduced pressure. Crystallization of the residue with diisopropylether-hexane gave the crystal form 2-N-methylcarbamoyloxymethyl-6-meth-4- (O-nitrophenyl) -3, 5-diethoxycarbonyl-1, 12.4 g (5-5.5% yield) of 4-dihydropyridine are obtained.

Melting Point: 165 ~ 169 ℃

UV: 235,350 nm

IR (KBr), cm ^-1 : 3380,3000,1690,1680,1535,1495,1355,1280,1205,1100,785,760,715 cm ^-1

NMR (90MHz, CDCl ₃ ): δ1.2 (t, J = 7Hz, 6H), 2.38 (s, 3H), 2.91 (d, J = 6Hz, 3H), 4.18 (m, 4H), 5.15 (m, 1H), 5.38 (s, 2H), 5.98 (s, 1H), 7.2 to 8.0 (m, 5H)

[Examples 1-8 to 1-17]

In the same manner as in Example 1-7, the compounds of Table 7 were prepared.

Table 1-4

*: (a): CDCl ₃ , (b): DMSO-d ₆

[Example 1-18]

Preparation of 2-carbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3-ethoxycarbonyl-5- (β-ethoxyethoxy) carbonyl-1,4-dihydropyridine

200 ml of 9.4 g (50 mmol) ethyl 4-N-carbamoyloxy-3-aminocrotonate and 15.4 g (50 mmol) β-ethoxyethyl 2- (m-nitrobenzylidene) acetoacetate Isopropyl alcohol and reacted for 18 hours at a temperature of 60 ~ 70 ℃. The reaction mixture is concentrated under reduced pressure. Crystallization of the residue with diisopropylether-hexane gave crystalline 2-carbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3-ethoxycarbonyl-5- (β-ethoxye). 12.9 g (54% yield) of oxy) carbonyl-1,4-dihydropyridine are obtained.

Melting Point: 135 ~ 138 ℃

UV: 236,355nm

IR (KBr), cm ^-1 : 3520,3360,1990,1705,1690,1645,1610,1525,1485,1350,1205,1120,1105,1055,905,830,780,755,720cm ^-1

NMR (90MHz, DMSO-d ₆ ): δ1.07 (t, J = 8Hz, 3H), 1.15 (t, J = 3Hz, 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, 1H), 5.1 (s, 1H), 5.13 (d, J = 12 Hz, 1H), 6.7 (br.s, 2H), 7.6 to 8.2 (m, 4H), 9.11 (s, 1H)

[Examples 1-19 to 1-32]

In the same manner as in Example 1-18, the compounds of Table 8 were prepared.

TABLE 8a

Table 1-5

Example 1-33

2-N-methylcarbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3-ethoxycarbonyl-5- (β-ethoxyethoxy) carbonyl-1,4-dihydro Preparation of Pyridine

10.1 g (50 mmol) ethyl 4-N-methylcarbamoyloxy-3-aminocrotonate and 15.4 g (50 mmol) β-ethoxyethoxy 2- (m-nitrobenzylidene) acetoacetate Is dissolved in 200 ml of n-propanol and reacted at a temperature of 65-75 ° C. for 20 hours. The reaction mixture is concentrated under reduced pressure. Crystallization of the residue with diisopropylether-hexane afforded 11.1 g (45% yield) of 2-N-carbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3-ethoxycarb in crystalline phase. Carbonyl-5- (m-ethoxyethoxy) carbonyl-1,4-dihydropyridine is obtained.

Melting Point: 148 ~ 149 ℃

UV: 236,355nm

IR (KBr) : 3390,3280,2980,1680,1640,1610,1535,1480,1355,1280,1205,1120,1095,905,830,780,760,715cm^-One

NMR (90MHz, DMSO-d ₆ ): δ1.11 (t, J = 8Hz, 3H), 1.19 (t, J = 7Hz, 3H), 2.39 (s, 3H), 2.67 (d, J = 4.5Hz, 3H), 3.48 (q, J = 8 Hz, 2H), 3.65 (t, J = 5 Hz, 2H), 4.12 (q, J = 7 Hz, 2H), 4.15 (t, J = 5 Hz, 2H), 5.06 (d , J = 12 Hz, 1H), 5.14 (s, 1H), 5.18 (d, J = 12 Hz, 1H), 7.22 (m, 1H), 7.6-8.25 (m, 4H), 9.18 (s, 1H)

[Examples 1-34 to 1-42]

In the same manner as in Example 1-33, the compounds of Table 9 were prepared.

Table 1-6

[Example 1-43]

2-carbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3-ethoxycarbonyl-5- [β- (N-methylbenzylamino) ethoxy] carbonyl-1,4- Preparation of Dihydropyridine

8.7 g (50 mmol) ethyl 4-carbamoyloxy-3-aminocrotonate and 19.1 g (50 mmol) β- (N-methylbenzylamino) ethyl 2- (m-nitrobenzylidene) aceto Acetate is dissolved in 300 ml of isopropyl alcohol and reacted for 20 hours at a temperature of 60-70 ° C. The reaction mixture is concentrated under reduced pressure. Crystallization of the residue with diisopropylether-hexane gave 2-carbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3-ethoxycarbonyl-5- (m- (N- 9.2 g (34% yield) of methylbenzylamino) ethoxy] carbonyl-1,4-dihydropyridinehydrochloride are obtained.

Melting Point: 117.5 ~ 121 ℃

UV: 236,355nm

IR (KBr) : 3400,2950,1720,1690,1640,1610,1525,1475,1350,1320,1210,1010,900,825,780,740,700cm^-One

NMR (90MHz, DMSO-d ₆ ): δ2.37 (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 = 14 Hz, 1H), 5.03 (d, J = 14 Hz, 1H), 5.03 (s, 1H), 6.73 (br.s, 2H), 7.42 (s, 5H), 7.5 -8.2 (m, 4H), 9.2 (s, 1H)

[Examples 1-44 to 1-50]

In the same manner as in Example 1-43, the compounds of Table 10 were prepared.

Table 1-7

[Example 1-51]

Preparation of 2-N-methylcarbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3,5-diethoxycarbonyl-1,4-dihydropyridine

10.1 g (50 mmol) of ethyl 4-N-methyl carbamoyloxy-3-aminocrotonate was charged with 7.6 g (50 mmol) of m-nitrobenzaldehyde and 6.5 g (50 mmol) of ethylacetoacetate in 200 ml of ethanol. Dissolved in the reaction and reacted for 16 hours at a temperature of 60-70 캜. The reaction mixture is concentrated under reduced pressure. Crystallization of the residue with diisopropylether-hexane afforded crystalline 2-N-methylcarbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3, 5-diethoxycarbonyl-1, 4 7.6 g (34% yield) of dihydropyridine are obtained.

Melting Point: 192 ~ 193 ℃

The analytical data of this product by UV, IR and NMR are consistent with the data obtained from the product of Example I-8.

[Example 1-52]

2-N-methylcarbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3,5-diethoxycarbonyl-1,4-dihydropyridine

9.2 g (50 mmol) ethyl 4-N-methylcarbamoyloxy-2-butinoate, 13.2 g (50 mmol) ethyl 2- (m-nitrobenzylidene) acetoacetate and 10 g (125 mmol) Ammonium acetate was dissolved in 200 ml of ethanol and reacted at a temperature of 60 to 70 ° C. for 16 hours. The reaction mixture is concentrated under reduced pressure. The oily residue is extracted with 200 ml ethyl acetate. The ethyl acetate extract solution is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was sorted and purified by liquid chromatography apparatus (System 500A manufactured by Water Company) using Prep PAK-500 / silica column and ethyl acetate-hexane (2: 1) as the developing solvent. Collect desired fractions and concentrate under reduced pressure. Crystallization of the residue with diisopropyl ether gave crystalline 2-N-methylcarbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3, 5-diethoxycarbonyl-1, 4-di 4.8 g (21.5% yield) of hydropyridine are obtained.

Melting Point: 192 ~ 193 ℃

Analytical data of this product by UV, IR and NMR are consistent with that of the product of Example I-8.

[Example 1-53]

Preparation of 2-N-methylcarbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3,5-diethoxycarbonyl-1,4-dihydropyridine

9.2 g (50 mmol) ethyl 4-N-methylcarbamoyloxy-2-butinoate, 7.5 g (50 mmol) m-nitrobenzaldehyde and 6.4 g (50 mmol) ethylacetate and 10 g (125) Mmol) ammonium acetate is dissolved in 200 ml of ethanol and reacted for 16 hours at a temperature of 60-70 ° C. The reaction mixture is concentrated under reduced pressure. The residue is extracted with 200 ml ethyl acetate. The extract solution is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is sorted and purified by liquid chromatography apparatus (System 500A from Water) using Prep PAK-500 / silica column and ethylacetate-hexane (2: 2) as developing solvent. Collect desired fractions and concentrate under reduced pressure. The residue thus obtained was crystallized with diisopropyl ether to give 2-N-methylcarbamoyloxymethyl-6-methyl-4- (m-nitrophenyl) -3, 5-diethoxycarbonyl-1 in the crystalline phase. 5.0 g (yield 22.3%) of 4-dihydropyridine are obtained.

Melting Point: 192 ~ 193 ℃

Analytical data of this product by UV, IR and NMR are consistent with the data obtained from the product of Examples 1-8.

Claims (4)

The acetylene compound represented by the following general formula (VII) is represented by general formula In which R ⁹ is chlorosulfonyl, dichlorophosphoryl, trichloroacetyl, lower alkyl, cycloalkyl, aralkyl or aryl) or a compound capable of forming an isocyanate under reaction conditions A method for producing a 3-carbamoyloxyalkylpropioic acid derivative represented by the following general formula (VI), which is characterized in that it can be hydrolyzed. [Wherein R ³ is lower alkyl, haloalkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, lower alkoxyalkyl, lower alkenyloxyalkyl, aralkyloxyalkyl, aryloxyalkyl or Wherein B is straight or branched alkylene, R ⁷ and R ⁸ are lower alkyl or aralkyl, or R ⁷ and R ⁸ together form a heterocyclic group with adjacent nitrogen atoms, and A is alkylene R ⁵ and R ⁶ are each hydrogen, lower alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aralkyl or aryl, or R ⁵ and R ⁶ together with the adjacent nitrogen atom form a heterocyclic group.] The acetylene compound represented by the following general formula (VII) is represented by general formula A process for producing a 3-carbamoyloxy alkyl propiolic acid derivative represented by the following general formula (VI), wherein the compound is reacted with carbamic acid chloride represented by [wherein R ⁵ and R ⁶ are as defined below]. [Wherein R ³ is lower alkyl, haloalkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, lower alkoxyalkyl, lower alkenyloxyalkyl, aralkyloxyalkyl, aryloxyalkyl or Wherein B is straight or branched alkylene, R ⁷ and R ⁸ are lower alkyl or aralkyl, or R ⁷ and R ⁸ together form a heterocyclic group with adjacent nitrogen atoms, and A is alkylene R ⁵ and R ⁶ are each hydrogen, lower alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aralkyl or aryl, or R ⁵ and R ⁶ together with the adjacent nitrogen atom form a heterocyclic group.] The acetylene compound of the following general formula (VII) is reacted with phosgene or trichloromethyl chloroformate to form a chloroformic acid ester derivative represented by the following general formula (VIII), which is then general formula A method for producing a 3-carbamoyloxyalkyl propiolic acid derivative represented by the following general formula (VI), which is reacted with an amine compound represented by [wherein R ⁵ and R ⁶ are as defined below]. [Wherein R ³ is lower alkyl, haloalkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, lower alkoxyalkyl, lower alkenyloxyalkyl, aralkyloxyalkyl, aryloxyalkyl or Wherein B is straight or branched alkylene, R ⁷ and R ⁸ are lower alkyl or aralkyl, or R ⁷ and R ⁸ together form a heterocyclic group with adjacent nitrogen atoms, and A is alkylene R ⁵ and R ⁶ are each hydrogen, lower alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aralkyl or aryl, or R ⁵ and R ⁶ together with the adjacent nitrogen atom form a heterocyclic group.] The acetylene compound represented by the following general formula (VII) is reacted with phosgene or trichloromethyl chloroformate to form a chloroformic acid ester derivative represented by the following general formula (VII), which is then represented by the following general formula Wherein R ⁵ and R ⁶ are as defined below to react with an amine compound to form a carbamate derivative represented by the general formula (XI), and then react with a metalizing agent to form an organometallic compound. Continue with the following formula A process for preparing a 3-carbamoyloxyalkyl propiolic acid derivative according to the following general formula (VI), characterized in that it reacts with chloroformate represented by [wherein, R ³ is as defined below]. [Wherein R ³ is lower alkyl, haloalkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, lower alkoxyalkyl, lower alkenyloxyalkyl, aralkyloxyalkyl, aryloxyalkyl or Wherein B is straight or branched alkylene, R ⁷ and R ⁸ are lower alkyl or aralkyl, or R ⁷ and R ⁸ together form a heterocyclic group with adjacent nitrogen atoms, and A is alkylene R ⁵ and R ⁶ are each hydrogen, lower alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aralkyl or aryl, or R ⁵ and R ⁶ together with the adjacent nitrogen atom form a heterocyclic group.]