JPS5942355A - 3-carbamoyloxyalkylpropiolic acid derivative and preparation thereof - Google Patents

Abstract

NEW MATERIAL:A derivative of formula I (R<1> and R<2> are H, lower alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, etc.; A is straight or branched chain alkylene which may be substituted by aryl; R<3> is lower alkyl, haloalkyl, lower alkenyl, lower alkynyl, etc.). EXAMPLE:Methyl 4-carbamoyloxytetrolate. USE:An intermediate for preparing medicines, useful for treating cardiovascular diseases, and useful as an intermediate for preparing 2-carbamoyloxyalkyl-1,4- dihydropyridine derivatives having calcium antagonistic, vasodilator and hypotensive action. PROCESS:An acetylenic compound of formula II is reacted with an isocyanate of the formula R<6>NCO (R<6> is chlorosulfonyl, dichlorophosphoryl or H, etc.) or a compound capable of producing the compound under the reaction conditions, etc. to afford the aimed compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 3-carbamoyloxyalkylpropiolic acid derivative and a method for producing the same.

More specifically, the present invention refers to a group of the general formula (Tl, lower alkyl group, cycloalkyl group, lower alkenyl group, aralkyl group or aryl group, provided that R1 and R2 together with the nitrogen atom (diheterocyclic may form a group, A means a linear or branched alkylene group, provided that A may be substituted with an aryl group, R3 is a lower alkyl group, a haloalkyl group, a lower alkenyl group, lower alkynyl group, aralkyl group, aryl group, hydroxyalkyl group, lower alkoxyalkyl group, lower alkenyloxy 6-alkyl group, aralkyloxyalkyl group, aliR4-1-ruoxyalkyl group or -B-N(R, (B is a straight chain or a branched alkylene group, where R4 and R5 are the same or different and mean a lower alkyl group, an aralkyl group, or an aryl group, respectively.However, R4R5 may form a heterocyclic group together with a nitrogen atom). The present invention relates to a 3-carbamoyloxyalkylpropiolic acid derivative represented by the following meanings, respectively, and a method for producing the same.

The present invention compound CI) was prepared by the present inventors (-Related patent applications, Japanese Patent Application No. 56-003..250 and Japanese Patent Application No. 56-060)
．． ．． It is a useful intermediate in producing the 2-carbamoyloxyalkyl-1,4-dihydropyridine derivatives described in the 677 specification.

2-Carbamoyloxyalkyl-1+4-dihydropyridine derivatives have an asymmetric structure in which the substituents at the 2- and 6-positions of the dihydropyridine ring have a strong calcium antagonistic effect, vasodilatory effect, and antihypertensive effect, and are associated with cardiovascular diseases. It is a useful drug for the treatment of.

7- In synthesizing the asymmetric 1,4-dihydropyridine derivative, 4-substituted acetoacetate as a synthetic intermediate,
4-substituted-2-ylideneacetoacetate or 4-
Methods using substituted 3-aminocrotonic acid esters have been described so far (Japanese Patent Application Laid-Open No. 52-5777).
, Japanese Unexamined Patent Publication No. 53-. 79873).

However, 4-carbamoyloxy-3-, which is considered as a synthetic intermediate for asymmetric 1,4-dihydropyridine derivatives,
Aminocrotonic acid ester or 4-carbamoyloxytetrolic acid ester has not been synthesized so far and is a compound that has not been described in any literature.

As a result of intensive research, the present inventors discovered a new synthesis method for 3-carbamoyloxyalkylpropiolic acid derivatives, which are intermediates for the synthesis of 2-carbamoyloxyalkyl-1,4-dihydropyridine derivatives, and completed the present invention. .

Specific example 8 contained in the 3-carbamoyloxyalkylpropiolic acid derivative of the compound (1) of the present invention will be described below.

R1 and R2 are the same or different, 1 hydrogen atom 1 lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl 1 cyclo group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl Alkyl groups, vinyl, allyl, alkenyl groups such as 3-butenyl and isopropenyl; aralkyl groups such as benzyl, α-methylbenzyl and 7-enethyl; aryl groups such as phenyl, pyridyl and naphthyl; or piperidino, 4 -Methylpiperazino, 4-ethylpiperazino, 4-
Heterocyclic groups such as propylpiperazino, 4-methylhomopiperazino, morpholino, homomorpholino, l-pyrrolidinyl, 1-imidazolidinyl, 1-imidazolinyl, 1-pyrazolidinyl, ■-indolinyl, and 2-isoindolinyl, etc. .

A is an alkylene group such as methylene, methylmethylene, ethylmethylene, phenylmethylene, dimethylmethylene, methylethylmethylene, methylisobutylmethylene, phenylmethylmethylene, ethylene, methylethylene, ethylethylene, trimethylene, and tetramethylene. Can be mentioned.

Examples of the lower alkyl group of R3 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl, and examples of the haloalkyl group include β-chloroethyl, β-bromoethyl, β-chloropropyl, and γ-chloro. Propyl, ω-chlorobutyl, β
, β-dichloroethyl, trifluoromethyl, and β
, β, β-trichloroethyl, etc., lower alkenyl groups and sitehavinyl, allyl, 3-butenyl, isopropenyl, etc., lower alkynyl groups include propargyl and 2-butynyl, and aralkyl groups include benzyl, α-methylbenzyl, etc. and phenethyl, etc., phenyl, pyridyl, naphthyl, quinonyl, etc. as ryoryl groups, and β as lower alkoxyalkyl groups.
-methoxyethyl, β-ethoxyethyl, β-proboxyethyl, β-isopropoxyethyl, β-butoxyethinobe β-isobutoxyethyl, β-~sweat, tertiary butoxyethyl, β-methoxypropyl, β -ethogicipropyl, β-propoxypropyl, β-isopropoquinepropyl, β-butquinpropyl, γ-methginpropyl, γ
-Ethoxypropyl, γ-propoxypropyl, γ-butoxypropyl and ω-propoxybutyl, etc., and lower alkenyloxyalkyl groups include β-vinyloxyethyl, β-allyloxyethyl, β-(3-butenyloxy)ethyl, etc. , β-isopropenyloxyethyl and β-allyloquinbrovir.

Examples of the aralkyloxyalkyl group include β-benzyloxyethyl, β-7enethyloxyethyl, and β-(α
-methylbenzyloxy)ethyl, etc., and the aryloxyalkyl groups include β-phenoxyethyl, β-pyridyloxyethyl, β-phenoxypropyl and β-
7-dimethylaminoethyl, β-diethylaminoethyl, β-methylethylaminoethyl, β-dimethylminopropyl, γ- Dimethylamine propyl, ω-dimethylaminobutyl, β-N-methylbenzylaminoethyl, β-N-methylbenzylaminoglopyl, β-N-
Methylbenzylaminobutyl, γ-N-methylbenzylaminopropyl, ω-N-methylbenzylaminobutyl, β-piperidinoethyl, β-(4-methylpiperazino)ethyl, β-(4-ethylpiperazino)ethyl, β-
(4-propylpiperazino)ethyl, β-(4-methylhomopiperazino)ethyl, β-morpholinoethyl, γ-
Morpholinopropyl, ω-morpholinobutyl, β-homomorpholinoethyl, β-B-pyrrolidinyl)ethyl, β
-(], -imidazolidinyl)ethyl, β-(1-imidazolinyl)ethyl, β-(1-hira7” 'J cynyl)ethyl, β-(1-indolinyl)ethyl, β-(
Examples thereof include 2-isoindolinyl)ethyl and β-N-methyl(isoindolinyl)ethyl.

R1 to R5 are aralkyl groups, aryl groups, aralkyloxyalkyl groups, and aryloxyalkyl groups (the aromatic rings contained in the two may be substituted with 1 to 3 substituent groups, and the substituents I'' include fluorine, a salt group, etc.). , halogen atoms such as bromine and iodine; cyano groups; di], 0 and 1 hydroxyl groups; 2-substituted amine groups such as dimethylamino, diethylamine and diisoglobylamino; lower alkoxy such as methoxy, ethoxy, propoquine and butoxy. groups; lower alkyl groups such as methyl, ethyl and propyl; and trifluoromethyl groups.

The compounds of the present invention can be prepared by the following methods.

The present invention provides an acetylene compound represented by the general formula (lI) HO-A-C:CC0OR" (1) [wherein Ao"; and R3 have the same meanings as above] NGO (wherein R6 is a chlorosulfonyl group, dichlorophosphoryl group, trichloroacetyl group, hydrogen atom, lower alkyl group, cycloalkyl group,
isocyanate represented by 13- (meaning a lower alkenyl group, aralkyl group or aryl group) or a compound that produces the isocyanate under reaction conditions, and then optionally hydrolyzed, or R'z〉NC0C
71, (wherein R1 and R2 have the same meanings as above. No acyl hydrogen atom is included) or react with an acetylene compound represented by the general formula (■) (01). By reacting with phosgene or trichloromethyl chloroformate, a chloroformate derivative represented by the general formula (Ill) C1,C0O-A-CICCOOR3 (Ill) [wherein A and R3 have the same meanings as above] is obtained. , this (2 general formula):>
An amine compound represented by NH (in the formula, R1 and R2 have the same meanings as above) is reacted, or (c) the general formula side HO-A-CECH (IV) [in the formula, A is The same meaning as above] is reacted with phosgene or trichloromethylchloropormate to form the general formula (V) L4COO-AC3CH(V) [wherein A is the same as above] )
By reacting the amine compound represented by the general formula (■1) 1 R2>NC00-A, -CmiCH('t/l) [in the formula,
R1, R2 and A have the same meanings as above], and then this is treated with a metallizing reagent to form an organometallic compound, and then the general formula CVICO
General formula (I) characterized by reacting a chloroformate represented by OR3 (in the formula, R3 means the same as above) 1>NC0O-A-C=CCOOR'' (1)2 [in the formula , R', R2, A and R3 have the same meanings as above].

The reaction step of method (a) can be expressed by the following reaction formula (2) when ethyl 4-hydroxytetrolate and methyl isocyanate are used as raw materials.

The reaction step of method (b) can be expressed by the following reaction formula (2) when ethyl 4-hydroxytetrolate, phosgene, and dimethylamine are used as raw materials.

oC12 nocH2e=ccooc,,H,-1→ClC00C
I-T2C==CCOOC2r:T.

The reaction step of method (c) can be represented by the following reaction formula when propargyl alcohol, phosgene, dimethylamine, butyl lithium, and ethyl chloroformate are used as raw materials.

0C12 r]0cI (2C1l=CH--) ClC00CH
2C=CI method for producing the compound (1) of the present invention (two methods will be explained in detail below).

The raw materials used in the present invention (1) are already known compounds, or even if they are unpublished in literature, they can be synthesized according to known methods.

(M, Mark MidlandiJ, Org,
Chem-, 40,225'O-2252<1975)
, Henne 0reenleeiJ, Am, C
hemSoc-+67,. 484 (19,45)] Method G) relates to the preparation of compound (1) by reaction of an acetylene compound with incyanate or carbamic acid chloride.

-17~ This reaction (1) The isocyanates represented by the general formula R6NC0 (R6 means the same as above) used include chlorosulfonyl isocyanate, dichlorophosphoryl isocyanate, trichloroacetyl isocyanate, isocyanic acid, Methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate, butyl isocyanate, isobutyl isocyanate, tertiary butyl isocyanate, okori isocyanate, cyclohexyl isocyanate, cyclopentyl isocyanate, phenyl isocyanate, 0 −%
m- or p-nitrophenyl isocyanate, o-l
m- or p-chlorophenyliso T-j---),
m, p-dichlorophenyl isocyanate, p-fluorophenyl isocyanate, p-methoxyphenyl isocyanate, p-)lylisocyanate% p-dimethylaminophenyl isocyanate, benzyl isocyanate, diphenylmethyl isocyanate, phenethyl isocyanate, Examples include 18-dimethylaminoethyl isocyanate. In addition, as the carbamic acid chloride represented by this reaction (-R1 general formula used, 2') NCOC6 (R1 and R2 have the same meanings as above), dimethyl carbamyl chloride, diethyl carbamyl chloride, dipropyl Examples include carbamyl chloride, diisopropyl carbamyl chloride, methyl ethyl carbamyl chloride, methylbenzyl carbamyl chloride, methyl-p-chlorobenzyl carbamyl chloride, methylphenyl carbamyl chloride, and the like.

In place of the incyanate of R'NGO (R' means the same as above) in this reaction (in II), compounds capable of producing it under the following reaction conditions, such as under heating (with the formula R' in II) CON5 (R' means the same as above)
An acid azide of the formula R6NI(CO8R(R'
has the same meaning as above, and R means a lower alkyl group) It is also possible to use thiol carbon-1.

The reaction conditions for producing the compound in method (a) (ii) are appropriately selected depending on the type of raw material used, but generally 1 mol of the acetylene compound (■) (2 to R
'NGO (R6 means the same as above) I1 Socyanato or R2>N (-0(-l(R' and R
The carbamic acid chloride (2 has the same meaning as above) is preferably used in a proportion of 1 to 2 mol. Molification can be varied over a wide range without adverse effects.The reaction temperature is usually carried out under cooling, at room temperature, or at elevated temperatures.

When using carbamic acid chloride (- means use pyridine, triethylamine, dimethylaniline, etc. as a base in an amount equivalent to or more than the excess amount of carbamic acid chloride.As a reaction solvent, dichloromethane, chloroform, diethyl ether, tetrahydro7) is used. run,
An inert organic solvent such as benzene is used. The reaction is 1
The mixture is stirred for 24 hours to 24 hours.

When using chlorosulfonyl isocyanate, dichlorophosphoryl isocyanate, and trichloroacetylisocyanate as the incyanate, it is necessary to add the two to the reaction mixture and perform a hydrolysis treatment after the completion of the reaction.

Method (b) first synthesizes compound (IIl) by reacting an acetylene compound (■) with phosgene or trichloromethyl chloroformate, and then synthesizes compound G11l with the formula, 2) NH (R+ and R2 are (means the same as)
This invention relates to a method for producing compound (I) by reaction with an amine compound represented by: The trichloromethyl chloroformate used in this reaction is brought into contact with a trace amount of pyridine or activated carbon, and the generated phosgene gas is absorbed into an inert organic solvent such as benzene, or it contains a trace amount of pyridine or activated carbon. It is added dropwise to a solution of an inert organic solvent such as benzene to form a phosgene solution, and then reacted with acetylene compound (II).Also, the compound (R2) NH (R1 and R2 are the same as above) used in this reaction is reacted with acetylene compound (II). (meaning)) Examples of the leramine compounds include ammonia, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine,
21- Tertiary butylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, methylethylamine, jetanolamine, cyclohexylamine, dicyclohexylamine, allylamine, benzylamine, α-methylbenzylamine, phenethylamine , aniline, diphenylamine, α-pi4-methylbiperazine, 4-methylhomopiperazine, morpholine, homomorpholine, pyrrolidine, imidazolidine, imidacilline, pyrazolidine, indoline, and isoindoline.

In method (b), the reaction conditions of the acetylene compound (11) and phosgene or trichloromethyl chloroformate are general (= 1 mole of acetylene compound (preferably 1 to 2 moles of phosgene or trichloromethyl chloroformate to 2 moles) In addition, in method (b) (2), the reaction conditions for the compound (fill) and the amine compound are generally as follows: R2:>N H
(R1 and R2 mean the same as in the previous =22-).
A molar ratio or a ratio of 1 to 2 moles of the amine compound and 1 to 2 moles of the tertiary amine such as triethylamine, dimethyl chloride, and pyridine is used. The molar ratio can be varied over a wide range without adversely affecting the results. All reactions are carried out under water cooling or at room temperature. The reaction bath medium used in all reactions is an inert organic solvent such as diethyl ether, tetrahydrofuran, benzene, toluene, dichloromethane, or chloroform. The reaction time is as follows: In either reaction, the reaction mixture is stirred for 30 minutes to 3 hours under water cooling, and then stirred overnight at room temperature.

Method (c) first synthesizes the reaction of an acetylene compound with phosgene or trichloromethyl chloroformate (compound ■) from 1, and then synthesizes compound ■) with the formula R2>N
Reaction with an amine compound represented by 1 ((R1 and R2 mean the same as above. However, hydrogen atoms are not included) (:
Compound III is synthesized from C: Compound II is reacted with a metallizing reagent to form an organometallic compound, and this is then synthesized with the formula C/C.
Compound (
1) Regarding the manufacturing method of 1. This reaction (binary formula R2) N
Examples of the amine compound represented by IT (R' and R2 have the same meanings as above. However, hydrogen atoms are not included) include the amine compounds listed in (b) C2 above; however, ammonia and Primary amines such as methylamine and benzylamine are not included.

Method (Formula CJCOO'R3(R
3 means the same as above), methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, β-taloloethyl chloroformate, allyl chloroformate , propargyl chloroformate, benzyl chloroformate, 7enyl chloroformate, β-methoxyethyl chloroformate, β-ethoxyethyl chloroformate, β-propoxyethyl chloroformate, β-impropoxyethyl Chloroformate, β-butoxyethyl chloroformate, β
-propoxyglopyl chloroformate, β-allyloxyethyl chloroformate, β-benzyloxyethyl chloroformate β-phenoxyethyl chloroformate, β-dimethylaminoethyl chloroformate,
β-diethylaminoethyl chloroformate, β-N-
Methylbenzylaminoethyl chloroformate, β-N
- methylbenzylaminopropyl chloroformate,
β-piperidinoethyl chloroformate, β-(4-methylpiperazino)ethyl chloroformate.

, I/-morpholinoethyl chloroformate, and γ
-(4-methylhomopiperazino)propyl chloroformate and the like.

The metallization reagents used in the reaction of method (c) include methyllithium, ethyllithium 4 n-propyllithium,
n-butyllithium, S-butyllithium, t-butyllithium, cyclopropyllithium, vinyllithium,
cis-propenyl lithium, phenyl lithium, triphenyl methyl lithium, lithium diisogubiruamide, lithium diethylamide, lithium ditrimethylsilylamide, 25-thium benzylamide, lithium cyclohexylamide, sodium, potassium, lithium, sodium amide, potassium amide, lithium Examples include ryomedo, methylmagnesium iodide, ethylmagnesium iodide, methylmagnesium bromide, ethylmagnesium bromide, and phenylmagnesium chloride.

Reaction sequence (1) The reaction in the first 2゛ step of the reaction between compound (V) and an amine compound is based on the reaction conditions, reaction temperature, and reaction solvent sequence (same as the reaction time for 2) of the corresponding method (b).
It will be carried out in two steps.

In method (c), the reaction conditions of the compound (Vl) and the metallizing reagent chloroformate represented by the following formula CICOOR3 (R3 means the same as above) are general (1 compound (■) 1 mol (di On the other hand, the metallizing reagent is used in an equimolar or slightly excess amount, and the chloroformate is used in a ratio of 1 to 2 molar.The reaction temperature is between water cooling and -120°C in the reaction with the metallizing reagent. The reaction with chloroformate is carried out at a temperature of -60 to -8000° C. (260°C to 180°C, preferably b4. -60°C to -8000° C.). The reaction bath medium is diethyl ether. , tetrahydro7rane, etc. The reaction time is determined by
Immediately after the reaction between ll) and the metallizing reagent is carried out for 10 to 30 minutes, the reaction with chloroformate is carried out for 30 to 60 minutes.

Compound (I) is 3 which is a raw material for 2-carbamoyloxyalkyl-1,4-dihydropyridine derivatives.
-It is a useful intermediate in producing carbamoyloxyalkyl-3-aminoacrylic acid ester.

The 2-carbamoyloxyalkyl-1,4-dihydropyridine derivative has the compound (■) of the present invention and the formula R'-CO-C.
β-ketoester compound represented by H2-COOR3 (R means a hydrogen atom or lower alkyl group, R3 means the same as above), R"CτHO (・'R" means a substituted phenyl group) It is synthesized by reacting an aldehyde compound represented by (-) with ammonia or a salt thereof, or by reacting a β-keto ester compound (1) with a benzylidene compound and ammonia or a salt thereof.

Alternatively, the compound (I) of the present invention may be reacted with ammonia or a salt thereof to form a 3-carbamoyloxyalkyl compound.
A carbamoyloxyalkyl-1,7I=dihydropyridine derivative is synthesized.

The method for synthesizing 2-carbamoyloxyalkyl-1,4-dihydropyridine derivatives is described in detail in the patent application filed by the present inventors (1) and Japanese Patent Application No. 136343/1982 (2).

2-Carbamoyloxyalkyl-1,4-dihydropyridine derivatives have vasodilatory and antihypertensive effects, and are particularly effective against hypertension, cardiac dysfunction, angina pectoris, It is a drug that is expected to treat circulatory system diseases such as myocardial infarction (1) and cerebrovascular disorders.

Next, the manufacturing method of the present invention will be explained in detail with reference to Examples, but the present invention is not limited to this.

Methyl 4-hydroxytetrolate 22.8g (02
Dissolve mol) in dichloromethane (2007ne), add chlorosulfonyl in cyanide (17.5m610.2 mol) at 20°C, and -
Stir for 30 minutes at 10 to -20°C. Add water (20°C) to the reaction solution and perform hydrolysis treatment at around 0°C for 30 minutes. Obtain 18 g of crystalline P primary crystals. Collect the dichloromethane layer obtained by branching P# and the aqueous dichloromethane (dichloromethane extract obtained by second extraction process).
After washing with water, 115 crystals produced by concentration under reduced pressure are collected to obtain secondary crystals 10F. -Secondary crystal arrangement (Secondary crystals are collected and recrystallized from ethyl acetate to obtain crystalline methyl 4-carbamoyloxytetrolate 25.1.9 (yield 80%).

mpil13 114°C IR (KBr), cm-'; 341o, 3350. :
3300°3220.2250,1750,1700,
1,620°1440, 1320.1295.1,09
0.1050°930.750°'HNMR (90MHz, DMSOd6), δ; 377
(s, 3H), 4.82 (s, 2H),
6.8 (broad s.

2]) Examples 2 to 8 According to the method described in Example 1 (2), the compounds described in Table 1 (1) were obtained.

30- Table 1 Yield and yield of each compound obtained by reacting 0.1 mol of raw material (Ill).

Table 1 (continued) Example 9 Synthesis of N-propylcarbamoyloxytetrolic acid ethyl c3I (7>NC00CH2C:==CCOOC
2H.

40 ml of phosgene in benzene solution (phosgene 6.
2. ! i'.

Containing 625 mmol) (- Under water cooling, 6.4.9 (50 mmol) of ethyl 4-hydroxytetrolate was distilled off, and the residue was an oily ethyl 4-(chlorocarbonyloxy)tetrolate sl&c. 720'r(-NMR(90MHz, CDCl!3)
, δ; 1.34 (t.

3H), 4.28. (q, 2H), 5.0
2 (s, 2Hl) 2.85.9 (15 mmol) of ethyl 4-(chlorocarbonyloxy)tetrolate obtained above was dissolved in 1 m of benzene (30 m), and 12 m of benzene a of water-cooled efrohiramine (propylamine 22 m) was dissolved in 1 m of benzene (30 m).
2F (containing 11.27 mmol) was added immediately, and the mixture was stirred for 30 minutes under water cooling. Pour the reaction solution into ice water (twice) and adjust the pH to 2f with diluted hydrochloric acid (twice).
Add d) and stir to extract. The ethyl acetate extract was dehydrated using Glauber's salt (secondary dehydration treatment 1,7) and concentrated under reduced pressure to obtain oily ethyl N-propylcarbamoyloxytetrolate 3.08F (yield 962%).

IR (liquid film), cm=12250,1785
゜1720.1250"H-NMR (90MHz, CDCl,), δ; 0
．． 95 (t, 3H, J=7Hz) 1.35 (t,
3H, J=7Hz) 1.62 (m, 2 H,) 3.20 (m, 2 H,) 4.29 (q+ 2 H2) 4.86 (s, 2H) 8.40 (broad l I H )Example lO
~21 According to the method f2 described in Example 9 (2), the compounds described in Table 2 (2) are obtained.

Middle: Yield and yield of each compound obtained by reacting raw material + 150 mol.

, Ij-2/God) Back-') (m) Table-2 (Continued) Table-2 (Continued) Example I R1'H-NMR (90 MI
(z) Number cm”” δin p
pm3400.2970. 2250. (C
DC7?3) ;1720.1535,1435.
2.82 (d, 3H, J=6Hz) 18 125
0.1130,1070. 3.8 (s, 3
H)990.940. 770. 4.82 (s
, 2H) 750 (liquid film) 5.13
(m, IH) 3400.2250. 1780
(CDC/3);1720.1520,1255
1.32 (t, 3H, J=7.5Hz) 19
(Liquid film) 1.37 (s,
9H) 4.26 (q, 2H, J=7.5Hz) 4.79
(s, 21() 3350.2970. 2250. (CDC
7?3);1715.1695,1530. 1
．． 34 (t, 3H, J=7.5Hz) 20 1450
．． 1320.1265. 1.2-2.2 (m,
l0H) 1250.1235.1145. 3.3
~3.8 (m, LM) 1085.105 (+, 75
0 4.28 (q, 2H, J=7.5Hz) (K
B r ) 4.7-5.1 (m,
IH) 4.83 (s, 2H) 3360.2950.2870, (CDC7?3)
i 0.92 (t, 3 H, J-2250, 17
20,1530,8Hz), 1.65(m, 2H)1
450.1365,1250. 1.5-2.1 (m
, l0H) 33-3.8 (m, I T() Example 22 Ethyl 4-hydroxytetrolate 6.4 g (0,0
5 moles) in dichloromethane 100m7! 1.6 ml of phenyl isocyanate was dissolved at -20°C.
(0,055 mol) and triethylamine 05g were added, and the reaction was carried out with stirring for 1 hour.

The reaction mixture was washed sequentially with 1N hydrochloric acid (107Ie) and water, and then dehydrated with magnesium sulfate.
For use, ethyl acetate-hexane (1"') was used as a developing solvent.
: 3) - Separate and purify from the second step. 4. Collect the effective fractions and concentrate them under K pressure to obtain a liquid state. - Ethyl N-phenylcarlebamoyloxytetrolate 10.6.9 (yield 8
5.8%).

IR (liquid film), cm' 13350, 2250
゜1720.1540,1255,1210,1050
゜50''H-NMR (90MHz, CDCl3), δ(
ppm) il, 33 (1,3H, J=8.5l-T
z), 4.3 (q, 2I-].

J = 8.5Hz), 4.92 (s, 2
H16, 9-7, 2(f)r.

s) 7.3-7.6 (1) r, s, 5l-
T) Example 23 Diethyl ether of phosgene'flJ7 (1800me
The pro-liquid was added to a solution containing 248 g (248 g, 25 mol) of Lt sugen under water cooling at room temperature (-) and allowed to stand overnight, then the ether was distilled off. The residue was purified by vacuum distillation, resulting in a distilled fraction of 47.
°C/40mmH7-44°C/34mm
l-I g (dicolorless propargyl chloroformate 1
9/Ml (yield 818%) is obtained.

Boiling point; 44 °C734mm) 1.9-47 °C/4
0 mm l-T,! i''HNMR (90MHz
, CDCl5), δ; 2.68 (t, 1■1.
J=3Hz) 4.88 (d, 2f(, J=3F
-1z) Benzene solution of diethylamine 7i200 yn
e (Contains 26 tne of ethylamine, 249 mmol) (Extraction treatment is carried out with the propargyl chloroforme benzene obtained in Section 1-1 under ice cooling. The benzene extract was heated to 73 °C/8 mmH!! to form a colorless oil. Propargi/l/N.

N-diethyl alcohol) 1.4.7.9 (yield 95%)
) is obtained.

Boiling point 171-73°C/8 mm H,! i'ding R
(liquid film), cm'; 3320, 32703
0'OO, 2140, 1700"HNMR (90MHz, CDCl5), δ
;1.16 (t, 6H, J=7.5)Iz)2.4
8 (t, IH, J=3Hz) 3.33 (q, 4H, J=7.5Hz) 45-4.73 (d, 2H, J=3Hz)''2H self-obtained propargyl carbamate 14. 7 g (94.7 mmol)
Tetrahydrofuran solution (60 WeiA) (=-65~-
16 at 7500 (dry ice, acetone cold bath)
574 ml of hexane solution of 5 mole butyl lithium (containing 947 mmol of butyl lithium) was added dropwise, followed by -
60~-70°C (200°C)
Extraction processing is performed from the second step. After dehydration, the ethyl acetate extract was concentrated under reduced pressure, and the curved residue was purified by silica gel column chromatography (using silica gel 150.!i'). Concentration under reduced pressure gives colorless oily 4-N,N-diethylcarbamoyloxytetrolic acid β-propoxyethyl ester 12,65!j (yield: 468%).

-46=IR (liquid film), cm' 12250, 1750
゜17] 0. 1430. 1255. 1165'I
-T-NMR (90MHz, CDCIJ3), δ
.

0.93 (t, 3H, J near Hz) 1.1 6
(t, 61-1, J=7.5Hz
)1,. 62 (m, 2 I-J) 3.33
(q, 41], J=7.5Hz) 3.45 (t,
2H, J = 7.5Hz) 3.67 (t, 2H, J
=7.5 Hz, )4.33 (t, 211.J
=7.5Hz) 4.86 (s, 21-() Examples 24-35 Based on the method described in Example 23 (2), the compounds described in Table 3 (2) are obtained.

Table 3: Yield and yield of each compound obtained by reacting raw materials (■ > 0.1 mol).

Table-3 (continued) Table-3 (continued) Table-3 (continued) Table-3 (continued) Table-3 (continued) Example 36 CH3:>NC00CH2C; CC00C,, 11°C
6H,C)12 Ethyl 4-(chlorocarbonyloxy)tetrolate obtained in the upper part of Example 9 2.85. ! 17 (15 ml) N-methylbenzylamine 3.111 d (24 ml) was poured into ice water, and the pH was adjusted to dilute hydrochloric acid (p'H2) for extraction. After the treatment, it is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (silica gel 30&).

The target fraction eluted with hexane-benzene (1:0→3:1) was collected and concentrated under reduced pressure to form a colorless oily 4-(N-
Ethyl benzyl-N-methylcarbamoyloxy)tetrolate t18.9 (yield 285%) is obtained.

54-IR (liquid film), cm'; 2250
．． 1720°1255. 1140'Ii-NMR (90MHz, CDCl5),
δ; 1.30 (t, 3H, J=7Hz)2.
87 (s, 3H) 4.24 (q, 2I(, J=7Hz) 4.49
(s, 2H) 4.87 (s, 2H) 7.31 (s, 5H) Example 37 A solution of 3.8 g (2 mmol) of ethyl 4-hydroxy-2-pentate in benzene 1 (40 ffil/l dimethyl Triethylamine was added to 1.811" (30.5 mmol) of isocyanate, and the mixture was stirred at room temperature for 15 hours to react.

The reaction solution was sequentially dehydrated using 1N hydrochloric acid (50++e) and water over 6 L of sodium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel (prep P) using a preparative liquid chromatograph (Waters Corporation, System 500A)
AK500/s mountain ca) column chromatography E! : Yosu refining process. Hexane-ethyl acetate (3
: The target fractions eluted in step 1) were collected and concentrated under reduced pressure to give a colorless curved 4-N-methylcarbamoyloxy-2-
Pe1450, 1420, 1370, 1240, 1130
.

1095, 1050, 1020, 980, 940.

860, 775, 750.

'H NlvIR (9 0 MHz, CDC I
Is) δ: 1, 3 (t, 3H, J=7.5Hz
)1, 53 (d, 3H, J=6Hz)2,
82 (d, 3H, J=5.51-Tz)4, 25
(q, 2) 1, J=7.5Hz) 4, 6-5.1
(broad s, l H)5, 54 (q,
IH, J = 6 Hz) Example 38 Texture solution of ethyl 4-carbamoyloxy-4-methyl-2-pentate (100-) in 10 °C (chlorosulfonyl isocyaner) 3 m (34. 5 mmol) and stir for 30 minutes at -10°C (20°C) to react.The reaction solution is heated to room temperature (20°C) and stirred for 15 minutes to carry out hydrolysis treatment. Separate and sequentially add 10% barium chloride solution, water (double washing,
Glauber's salt (crystalline 4 when concentrated under reduced pressure after dehydration)
21 g of ethyl -carbamoyloxy-4-methyl-2-pentate (yield: 57, yield: 33%) is obtained.

mp: 111=113.5°C I R (K B r), cm' i3580
, 3360, 3300.

3220, 3020, 2240, 1710, 1605.

1380, 1370, 1265, 1230, 1145.

1050, 1035, 865, 785, 755
'H-NMR (90MHz, CDC13), δ; 1,
24 (t, 3H, J=7.5Hz)1, 64 (
s, 6H) 4, 2 (q, 2H, J=7.5Hz) 6, 57
(s, 2H) Example 39 cH. :>NC00CH2Cl-12C=CCOOC2
H.

Ethyl 5-hydroxy-2-pentate 2.8! V(2
A benzene solution (50 mmol) of 1.2 m (20 mmol) of dimethyl isocyanate and 58% of triethylamine were stirred and reacted at room temperature for 1 hour.

The reaction solution was purified according to the method described in Example 37 (2) to give ethyl 5-N-methylcarbamoyloxy-2-pentate 36!j (yield 90.5%) as a colorless oil.
is obtained.

IR (liquid film), cm'i 3400
．． 2970°2240.1.7]0,1,530,14
70,1370°1250.1140,1075,10
10,860,775.750'H-NMR (90MHz, CDCl!s), δIn
ppm i], 33 (t, 3 I'', J = 7
11z) 2.63 (t, 2H, J=6Hz) 2.8
3 (d, 3H, J=5Hz) 4.25 (t, 2
I-1, J=6Hz)4.27 (q, 21-1.
J=7Hz)4.7~5.1 (m, ], H)
Example 40 H2NCOOCHC3CC00C2H.

C6H.

4-Hydroxy-4-phenyltetrolic acid 8.9
(39.2 mmol) in dichloromethane 1 (1007
I71) Chlorosulfonyl incyaner at 20°C) 357#l! (40.2 mmol) Add 3
Stir and react at −10° C. for 0 min.

Following hydrolysis treatment and purification treatment according to the method described in Example 38 (2), crystalline 4-carbamoyl
-4-phenyltetrolate ethyl 9.5.9 (yield 9
8%) is obtained.

m p i 82°C IR (KBr), cmS 13460, 3350, 32
90,3010,2950.2250.1730.17
05°1605.1500,14.65,1365,1
280°1260.1195,1090,1015,7
80°760.750,700 - NMR (90MI (z, CDCl3), δi
nppmi1.32 ft, :3I-]',
J=7H2C4,26 (q, 2H, J=7Hz) 5.05 (broad s, 2H) 6.51
(s, IH,) 7.46 (broad s, 5H) patent applicant
Banyu Pharmaceutical Co., Ltd. 61- Procedural amendment (method) % formula % 1 Display of case 1981 Patent Application No. 151'70
No. 6 No. 2 Title of the invention 3-Carbamoyloxyalkylpropiolic acid derivatives and their manufacturing method 3 Relationship with the case of the person making the amendment Patent applicant Tun Date of amendment order November 12, 1980 (Shipping date November 1980) 30th of May) 5 Subject of amendment "Table frames in the specification" G Contents of the amendment As per the attached sheet (Contents) The table frames of each member shown below should be clearly described using paperbacks and attached. I got 1.

(]) Page 33...Table-1 (2) Page 32...Table-1 (continued) (3) Part 3
Page 3...Table-1 (continued) (4) Page 34...Table-1 (
(continued) (5) Page 37...Table-2 (6) Page 38...Table-2 (continued) (7) Part 3
Page 9...Table-2 (continued) (8) Page 40...Table-
2 (Continued) (9) Page 41...Table-2 (Continued) (10
) Page 42...Table-2 (continued) (11) Page 48...
...Table-3 (12) Page 49...Table-3 (continued) (13)
Page 50...Table-3 (continued) (14) Page 51...
・Table-3 (continued) (15) Page 52...Table-3 (continued) (16) Page 53...Table-3 (continued) Table-] Raw material (Ill 0.1 mol Compound and yield of each compound obtained by reacting.

31- Table-1 (Continued) Table-1 (Continued) Table-1 (Continued) Fist; Yield and yield of each compound obtained by reacting raw material '1i(2)5 (19 moles).

Table 2 (gun) Further examples 'RrH-NMR (!l nMHz
) number cm-' δjn ppm:
'1400, 3000, 2950, 2240. (CDC
/3)il, 37(t, 3H, J=7.51720.
1710.153 c), 1365. z),
4.3(q, 21(j=7.5Hz).

10 1245.1130, 1070.1014+
, 8(s, 211), 48-5.2(m, 1)0
゜99t1,770,750 2.88 (d,
30. J=4.5+1z) (liquid film) 3350.2950,2250,1710. (CDC/
, ); 2.85 (d, 3TI, J=4.517110
．． 157F1, 1455, 1310. ), 3.7
5(t, 2HJ=7.5Hz).

11 1290.1280,1260,1250.
47 (t, 28.J=7.5Hz), 4.87116
0.1100,1010.775. (s, 2l-I
), 4.7-5.3(m, If()75(1, (KB
r) 34 (10,297G, 2250.1715 (CD
C/,');2.83(d,311.J-61530,
1450, 1425, 1365, z), 4.7 (d, 2
14. J=6Hz).

I! 1240, 1135, 1070, 995,
4.83 (s, 2) f), 4.6-5.1 (m, IH)
.

940.775,750. 5.2-5.6 (m
, 2) D, 5.7-6.3 (m.

(Liquid film) IH) 3440.3370,3300,2960. (CDCI
! ,) ;2250.2140.1720,1530,
2.55 (t, IH, J=3Hz) 1440.1
42G, 1370, 1240, 2.83 (d, 3
1(, J=5Hz)13 1130.1070,9
95.7'15,4.79 (d, 2H, I=3H
z>750 4.7-5.05
(m, IH) Table-2 (system) Table-2 (continued) Table-2 (u) 41- Table-2 (system) Example TR"H-NMR (90MHz
) number cm-' δ+n ppm
3400.2970.2250. (CDC/
, ) ;1720.1535,1435. 2
．． 82(d,3H,,1=flz)18 1250.
1130.1070. 3.8 (s, 3) ()9
90.940. 770. 4.82(s, 2H
) 750 (liquid film > 5.13 (m,
II) 3400.2250. 1780 (
CDCIs) ;1720.1520,1255
1.32 (t, 3H, J=7.5Hz) 19
(Liquid film) 1.37 (s,
9H) 4.26 (q, 2H, J=7.511z) 4.7
9 (s, 2H) 3350.2970,2250. (CDCI
! s);1715.1695.153G,
1.34 (t, 3H, J = 7.5) + z) 20 14
50.1320,1265. 1.49-2.2
(m, 1 (IH) 1250.1235, 1145.
3.3-3.8 (m, IM) 1085.105+1
．． 75 (14, 28 (q, 2H, J = 7.5Hz) (
K B r ) 4.7-5.1 (m
, IH) 4.83(s, 2H) 3360.2950,2870. (CDC/
! 3): (1,92(t, 3T(, J -225(L1
720.1530. 8Hz), 1.65(m,
2H) 1450.1365.125G, IJ~
11 (m, l0H) 21 1230.1130,107
5. ”3-3.8 (m・111)ri 7m/Anv
tvh Dinghui＼ Table 3 1: Yield and yield of each compound obtained by reacting 0.1 mol of raw material (IV).

Back-3 (continued) Table-3 (continued) Table-3 (continued) 51- Table-3 (continued) 52- Table-3 (continued) -53- 617-

Claims (1)

[Claims] ■) General formula (1) [In the formula, R1 and R2 are the same or different, and include a hydrogen atom, a lower alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a lower alkenyl group, It means an aralkyl group or an aryl group, provided that R1 and R2 may form a heterocyclic group together with a nitrogen atom, and A means a linear or branched alkylene group, provided that A is an aryl group. R3 may be substituted with a lower alkyl group, a haloalkyl group, a lower alkenyl group, a lower alkynyl group, an aralkyl group, an aryl group, a lower alkoxyalkyl group, a lower alkyloxyalkyl group, or an aralkyloxy group. Alkyl group, aryloxyalkyl group, or -B-N(□, (B represents a linear or branched alkylene group, R4 and R5 are the same or different and represent a lower alkyl group, aralkyl group, or aryl group, respectively) (However, R4 and R5 may form a heterocyclic group together with the nitrogen atom. 〉Ncoo-A-c=ccooRs (1)
2 [In the formula, R1 and R2 are the same or different and are hydrogen atoms,
means a lower alkyl group, cycloalkyl group, lower alkenyl group, aralkyl group, or aryl group, provided that R
1 and R2 may form a heterocyclic group together with the nitrogen atom, A means a linear or branched alkylene group, provided that A may be substituted with an aryl group, and 2- R3 is a lower alkyl group, haloalkyl group, lower alkenyl! , (l alkynyl group, aralkyl group, aryl group,
Hydroxyalkyl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or -B4-N(,,(B is a linear or branched alkylene group,
R4 and R5 are the same or different and each represents a lower alkyl group, an aralkyl group or an aryl group. However, in producing the 3-carbamoyloxyalkylpropiolic acid derivative represented by the general formula (II) HO- A -CyoCCOOR3(1) [In the formula, A and R3 have the same meanings as above] An acetylene compound represented by the general formula R6NC0 (in the formula,
R' hachlorosulfonyl group, dichlorophosphoryl group,
It means a trichloroacetyl group, three hydrogen atoms, a lower alkyl group, a cycloalkyl group, a lower alkenyl group, an aralkyl group, or an aryl group. ] or a compound that produces the isocyanate under reaction conditions, and then hydrolyzed as desired, or with the general formula R2>NCO
Cl [wherein R1 and R2 have the same meanings as above. However, hydrogen atoms are not included] or (b) an acetylene compound represented by the general formula flT) is reacted with phosgene or trichloromethyl chloroformate to form a compound of the general formula (I) CICOO. A chloroformic acid ester derivative represented by -A-C3CCOOR3 (1) [wherein A and R3 have the same meanings as above], 1 and the general formula R2>NH (R1 and R2 are the same as above). or -4~ (c) general formula (IV) HO-A, -C 壬CI ((IV) [wherein A means the same as above ] The acetylene compound represented by the formula (V) is reacted with phosgene or trichloromethyl chloroformate to form a chloroform compound represented by the general formula (V) clcoo-AC3CH(V) [wherein A means the same as above]. formic acid ester derivative, and the general formula R2) NH[R
1 and R2 have the same meanings as @] to form the general formula (VT) I R2>NC0O-A-CEECH(Vl) [in the formula R
1, R2 and A have the same meanings as above], and then treated with a metallizing reagent to form an organometallic compound, and then a carbamate derivative of the general formula C71ICOO
A method for producing a 3-carbamoyloxyalkylpropiolic acid derivative represented by the general formula (11), which comprises reacting a chloroformate represented by R3 (R' has the same meaning as above).