JPS5888381A - Imidazopyrimidine compound - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI[R<1> is H, 1-4C alkyl, phenyl, 2- 5C alkoxycarbonyl, benzoyl, etc.; R<2> and R<3> are H, 1-10C alkyl, allyl, cyclohexyl, benzyl, or group of formula V (R<4> is 1-4C alkyl, 1-4C alkoxy, etc.; n is 0, 1 or 2)]. EXAMPLE:2-Cyclohexyl-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo-[1, 5-C]pyrimidine. USE:Pharmaceuticals, agricultural chemicals, and their intermediates. PROCESS:The objective compound of e.g. formula IV can be prepared by reacting the orotic acid ester of formula II (R<5> is 1-4C alkyl) with the isocyanate of formula III (R<6> is 1-10C alkyl, allyl, etc.) in the presence of a tertiary amine, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to new compounds, imidazopyrimidines. More specifically, this invention is based on the formula [wherein R1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
phenyl group, alkoxycarbonyl group having 2 to 5 carbon atoms,
An aliphatic acyl group having 2 to 5 carbon atoms, a benzoyl group, or a cyano group represents a halogen atom, and R2 and R3 are a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an allyl group, a cyclohexyl group, or a benzyl group, respectively. , or -(y(R
” (R' is an alkyl group having 1 to 4 carbon atoms, 1 to 4 carbon atoms
represents an alkoxy group or a halogen atom, n is 0,
1 or 2. ) represents a group. ] is an imidazopyrimidine M represented by

The imidazopyrimidines of the present invention are useful as medicines, agricultural chemicals, and intermediates thereof, and can be synthesized, for example, by the method shown below.

(A) Formula [wherein R1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
phenyl group, alkoxy7carbonyl group having 2 to 5 carbon atoms,
Represents an aliphatic anru group having 2 to 5 carbon atoms, a benzoyl group, a cyano group, or a halogen atom, R2 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an allyl group, a cyclohexyl group,
benzyl (R')n group, or -Q''(R' represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogen atom, and n is 0.1 or 2) ), and R5 represents an alkyl group having 1 to 4 carbon atoms. ] and the orotate ester represented by the formula R6-N=C=0
[:] [wherein R6 is an alkyl group having 1 to 1 carbon atoms, an allyl group, a cyclohexyl group, a benzyl group, t or -a
(R'"" (R4 represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogen atom, and 1
．． n is 0.1 or 2. ) represents a group. ] in the presence of a tertiary amine and/or a quaternary ammonium fluoride (hereinafter referred to as reaction A).

This reaction A is thought to proceed as shown in the following formula.

R'8. C,,R' C CI) CI+]1 Specific examples of the orotate ester represented by the formula [D include ethyl orotate, ethyl 1-phenylorotate, ethyl 5-methylorotate, 5-methyl-1- Ethyl phenyl orotate, ethyl 1-butyl-5-7enyl orotate, ethyl 5-(ethoxycarbonyl) ocitate, ethyl 5-ethoxycarbonyl-1-propylorotate, 1-butyl-5-(ethoxycarbonyl)
Ethyl orotate, l-cyclohexyl-5-(ethoxycarbonyl)ethyl orotate, 5-ethoxycarbonyl-1-phenyl orotate, 5-ethoxycarbo-1-)IJ ethyl orotate, 5-ethoxy Ethyl carbonyl-1-(methoxyphenyl)orotate, ethyl 1-dichlorophenyl-5-(ethoxycarbonyl)orotate, ethyl 5-acetyl-1-ethyl orotate, ethyl 5-acetyl-1-cyclohexyl orotate, 5- Ethyl acetyl-1-tolyrotate, ethyl 5-acetyl-1-(methoxyphenyl)orotate, ethyl 5-acetyl-1-chlorophenylorotate, ethyl 5-benzoyl-1-ethyl orotate, 5-benzoyl-1- ethyl butylorotate,
Ethyl 5-benzoyl-1-cyclohexylorotate, ethyl 5-pensoyl-1-phenylorotate, 5
-ethyl benzoyl-1-(methoxyphenyl)orotate, ethyl 5-benzoyl-1-dichlorophenylorotate, ethyl 5-cyano-1-ethyl orotate,
Ethyl l-butyl-5-cyanoorotate, ethyl 5-cyano-1-7chlorohexylorotate, 1-allyl-
Ethyl 5-cyanoorotate, ethyl 1-benzyl-5-cyanoorotate, ethyl 5-cyano-1-phenylorotate, ethyl 5-fluoroorotate, ethyl 5-fluoro-1-methylorotate, l-allyl-5 −
Fluoroo. Ethyl tinate, ■-Ethyl benzyl-5-fluoroorotate, ethyl 5-fluoro-1-phenylorotate, ethyl 5-chloroorotate, ethyl 5-bromoorotate, ethyl 5-bromo-1-propylorotate, 5- Ethyl bromo-1-phenylorotate can be mentioned.

Specific examples of incyanato represented by formula C11[] and 1
7. Methylisocyanate, ethyl incyanate, globylisocyanate, butyl incyanate, hexyl incyanate, allyl inocyanate, cyclohexyl inocyanate, benzyl inocyanate, phenyl isocyanate, tolylyl inocyanate , methoxyphenylinocyanate, chlorophenylincyanate, dichlorophenylincyanate, and the like.

Specific examples of the tertiary amine include aliphatic tertiary amines such as trimethylamine, triethylamine, tripropylamine, and tributylamine.

Quaternary ammonium fluoride is a compound represented by the formula: Specific examples include hensyltrimethylammonium fluoride, methyltributylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride,
Examples include tetramethylammonium fluoride.

Reaction A can be carried out using inert organic solvents, such as aromatic hydrocarbons such as benzene, toluene, chlorobenzene, dichlorobenzene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, acetonitrile, globionitrile, It is carried out in the presence of nitriles such as benzonitrile. However, in the orotate ester represented by the formula Cl0), when the substituent R2 is a hydrogen atom, using a halogenated hydrocarbon as a solvent means that the orotate ester is alkylated by the halogenated hydrocarbon as a solvent. In some cases,
It's not very nice.

The reaction method is to react orotate, incyanate and tertiary amine and/or under substantially anhydrous conditions.
Alternatively, any method of contacting with quaternary ammonium fluoride can be adopted, and there is no particular restriction on the order of addition.

The amount of incyanate used is preferably 2 moles or more per mole of orotate ester.

The amount of tertiary amine and quaternary ammonium 70lide used is 1 to 3%, respectively, per mole of orotate ester.
mol, and preferably 0.1 to 1 mol. In this reaction, the tertiary amine and quaternary ammonium fluoride have the effect of promoting the reaction. When aromatic incyanates are used, tertiary amine and quaternary ammonium fluoride are usually used alone, but when using aliphatic incynates with low reactivity, in order to further speed up the reaction, Tertiary amine and quaternary ammonium 7
It is preferred to use 0rid in combination.

The reaction is generally carried out at temperatures ranging from 20 to 150C and from 1 to
It will be held for 50 hours.

11 (wherein, R11 is a λ axoxycarboxylic acid having 2 to 5 carbon atoms)
R12 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a phenyl group;
'3 represents an alkyl group having 1 to 4 carbon atoms. ) and hydantoins represented by

A method of reacting phenyl isocyanate represented by the following in the presence of a tertiary amine and/or a quaternary ammonium 70lide (hereinafter referred to as reaction B).

Reaction B is believed to proceed as shown in the following formula.

1 [■] [■] 1 A specific example of hydantoin represented by the formula [■] is:
Examples include 5-bis(ethoxycarbonyl)methylene-3-phenylhydantoin, 5-bis(ethoxycarbonyl)methylene-3-propylhydantoin, and 5-(ethoxycarbonyl)fluoromethylene dantoin.

Specific examples of the tertiary amine and quaternary ammonium 70lide include the compounds exemplified in Reaction A.

This reaction B is carried out in the presence of the inert organic solvent exemplified in 5 Reaction A.

As for the reaction method, hydantoin, phenyl isocyanate, and tertiary amine and/or quaternary ammonium 7 are reacted under substantially anhydrous conditions as in reaction A.
Any method of contacting the 0 lid can be employed,
There is no particular restriction on the order of these additions.

The amount of phenyl incyanate used is preferably 2 mol or more per 1 mol of hydantoin.

The amounts of the tertiary amine and quaternary ammonium furide used are preferably 1 to 3 mol and 0.1 to 1 mol, respectively, per 1 mol of hydantoin. In this reaction, tertiary amine and quaternary ammonium fluoride have the effect of accelerating the reaction, and are usually used individually, but if their accelerating effect is small, they can be used in combination. preferable.

The reaction is generally carried out at temperatures ranging from 20 to 150C and from 1 to
It will be held for 50 hours.

The target product is imidazopyrimidine.

Since it is a crystal, by utilizing the difference in solubility,
It can be isolated from the product mixture of reactions A and B.

Specific examples of imidazopyrimidines represented by formula [l] and their melting points are shown below.

Next, an example of synthesis of imidazopyrimidines by reaction A will be shown.

Example 1 (Chemical substance number 1) Tetraethylammonium fluoride dihydrate 2.89
13-0 ml of ethylene chloride containing 9 was heated, and 80 ml of the solvent was distilled off under normal pressure to remove water from the mixture.

After cooling, add 1.529 g of triethylamine to the mixture at room temperature.
70 ml of benzene containing 2,769 ml of cyclohexyl incyanate were added dropwise, followed by 2,769 ml of ethyl orotate, and then 20 rnl of benzene containing 3,769 cyclohexyl incyanate. The mixture was heated and reacted under reflux for 14 hours.

After the reaction, the resulting reaction product mixture was filtered.

Fi was concentrated under reduced pressure. Add 79,750 ml of water and 50 mJ of water to the residue, filter it, and add 2-cyclohexyl-1,2
,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C)pyrimidine crystal 1
．． 47g was obtained.

This was recrystallized from ethylene chloride, with a melting point of 269-271
Colorless crystals of C were obtained. The elemental analysis values are shown below.

HN Analysis value 54,67 5.00 16.09 Calculated value
54,75 4.98 15.96 (CI2 Hl
:l N304) Example 2 (Compound No. 2) Ethyl orotate 2829 and triethylamine 1.55
In 120 ml of ethylene chloride containing 9, ethylene chloride 3 containing 3.659 tephenyl incyanate at room temperature Q
ml was added dropwise. Heat the mixture to reflux for 4
Allowed time to react.

After the reaction, the resulting reaction product mixture was filtered to obtain 2-phenyl-1,2,3,5,6,71-hexahydro-1
,3,5,7-tetraoxoimidazo[1,5-Ca1
2.599 pyrimidine crystals were obtained. This was recrystallized with acetonitrile to obtain colorless petal-like crystals with a decomposition point of 288-290C. The elemental analysis values are shown below.

CHN Analysis value 56,18 2.80 16.56 Calculated value 56.04. 2.7j, 16.34 (C
1°H, N30. Example 3 (Compound No. 4) 20 ml of ethylene chloride containing 1.51 g of phenyl isocyanate was added dropwise at room temperature to ml of ethylene chloride containing 1.659 ethyl 1-phenylorotate and 0.649 triethylamine. added.

The mixture was heated and reacted under reflux for 3.5 hours.

After the reaction, the resulting reaction product mixture was filtered to give 2.6-
diphenyl-1,2,3,5,6,7-hexahydro-
1,3,5,7-tetraoquinimidazo (1,5-C)
1.219 crystals of pyrimidine were obtained. This was recrystallized from Improvil alcohol to obtain colorless needle crystals with a melting point of 274C. The elemental analysis values are shown below.

CI, N Analysis value 64,83 3.30 12.50 Calculated value 64,87 3.33 12.61 (Cl8
H1lN304) Example 4 (Compound No. 5) To 20 ml of ethylene chloride containing 043 g of ethyl 5-methylorotate and 0229 of triethylamine, 1 l of ethylene chloride containing 0.529 phenyl isocyanate at room temperature.
Q'ml was added dropwise.

The mixture was heated and reacted under reflux for 3 hours.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

Add ethylene chloride l□+++/ to the residue and filter 17.8
-Methyl-2-phenyl-1,2°3.5,6.7-hexahydro-1,3,5°7-tetraoquinimidazo[1,5-C]pyrimidine crystals 0.1'99 were obtained. Ta. This was recrystallized with chlorobenbin, and the decomposition point was 287 ~
Colorless needle-like crystals of 289C were obtained. The elemental analysis values are shown below.

CHN analysis fii 57.81 3.52 15.3
7 Calculated value 57,57 3.34 15.49 (
C,3H9N304) Example 5 (Compound No. 6) Ethyl 5-methyl-1-phenylorotate 1.349
and 30 m of ethylene chloride containing 049 g of triethylamine
1 was added dropwise at room temperature with 20 ml of ethylene chloride containing 130 g of I)-) lyliso7anate. The mixture was heated and reacted under reflux for 65 hours.

After the reaction, the resulting reaction product mixture was filtered.

The p solution was concentrated under reduced pressure, 5 Q ml of Improvil alcohol was added to the residue, and filtered to give 8-methyl-6-phenyl-2-(p-)lyl)-1,2°3.5,6. 7-hexahydro-1,3,5゜7-tetraoxoimidazo[
0.509 crystals of 1,5-Ca1 pyrimidine were obtained. This was recrystallized from isopropyl alcohol and had a melting point of 246.
Colorless crystals of tZ'(7) were obtained. The elemental analysis values are shown below.

CF (N Analysis value 66.40 4.15 11.39 Calculated value 66.48 4.18 11.63 (C20
H1! Example 6 (Compound No. 7) Ethyl x-(n-butyl)-5-phenylorotate 1
679 and 0.5.3 g of triethylamine at room temperature.
20 ml of ethylene chloride containing 0 g were added dropwise. The mixture was allowed to react for 21 hours with stirring at room temperature.

After the reaction, the resulting reaction product mixture was filtered and the lachrymal fluid was concentrated under reduced pressure. The residue was washed with silica gel (Wakogel C-2
00,809) through a column (diameter 25 fans),
Eluted with benzene. After elution with 1800 ml of benzene, the solution obtained by elution with 2500 ml of benzene was concentrated under reduced pressure F, and 6-(n-butyl)-8-phenyl-2
-(p-Tolyl)-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo(1,5
-c) 2.00 g of pyrimidine crystals were obtained. This was recrystallized from Improvil alcohol, with a melting point of 158-160.
Colorless microacicular crystals of C were obtained. The elemental analysis values are shown below.

CHN Analysis value 68,38 5.26 10.39 Calculated value 68,47 5.25 10.42 (C29
1'121N304) Example 7 (Compound No. 8) Ethyl 5-(ethoxycarbonyl)orotate 0599
Benzene 2 Q containing triethylamine and 0.479
10 ml of benzene containing 0.829 phenyl incyanate were added dropwise at room temperature. The mixture was heated and reacted under reflux for 7 hours.

After the reaction, the resulting reaction product mixture was filtered, and the lachrymal fluid was concentrated under reduced pressure. Add 5 ml of ethanol to the residue and filter it to obtain 8-ethoxycarbonyl-2-phenyl-1,2,3
,5,6,7-hexahydro-1,3,5,7-tetraoquinimidazo(1,5-C)pyrimidine crystal 0.3
3g was obtained. This was recrystallized from acetonitrile to obtain colorless crystals with a decomposition point of 288C. The elemental analysis values are shown below.

CHN Analysis value 54,29 3.36 12.53 Calculated value 54.72 3.37 12.76 (C+5
(as HuNsOa) Example 8 (Compound No. 9) 7-enyl incyanate 1 was added to 20 ml of benzene containing 1079 ethyl 5-ethoxycarbonyl-1-inpropylorotate and 0.499 triethylamine at room temperature.
．． 10 ml of benzene containing 019 was added dropwise. The mixture was heated and reacted under reflux for 5 hours.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

Add 20ml of Improvil ether to the residue and strain.
8-ethoxycarbonyl-6-isobroby-2-phenyl-1,2,3゜5.6.7-hexahydro-1,3
, 1.18 g of crystals of 5,7-tetraoxoimidazo[1,5-C)pyrimidine were obtained. This was recrystallized with carbon tetrachloride to obtain colorless crystals with a melting point of 186-188C. The elemental analysis values are shown below.

CHN Analysis value 57.56 4.64 11.35 Calculated value 58.22 4.61 11.32 (Cl8
017N306) Example 9 (Compound No. 12) 14 m of ethylene chloride containing 1.51 mmol of tetraethylammonium fluoride and 0.31 g of triethylamine
1K, at room temperature 0.519 ethyl 1-cyclohexyl-5-(ethoxycarbonyl)orotate was added, followed by 20 ml of ethylene chloride containing 0.17 g methyl incyanate.
ml was added dropwise. The mixture was heated and reacted under reflux for 8.5 hours.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

Add 30% ethylene chloride to the residue. ml and 20 ml of water were added, and the layers were separated into an organic layer and an aqueous layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Add 10 ml of Improvil ether to the residue and add 6-cyclohexyl-8
-ethoxycarbonyl-2-methyl-1,2,3,5,
040 g of crystals of 6°7-hexahydro-1,3,5,7-tetraoquinimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from ethylene chloride to obtain colorless needle crystals with a melting point of 265C. The first round of elemental analysis is shown below.

CHN Analysis value 55,23 5.40 11.94 Calculated value 55,01 5.48 12.03 (C16
(as HIQN306) Example 10 (Compound No. 15) Ethylene chloride 30m containing 0.839 triethylamine
To 1, 1.379 nityl 5-ethoxycarbonyl-1-phenylorotate was added at room temperature, and then ethylene chloride lome containing 1-0.98 g of phenyl incyaner was added.
was added dropwise. The mixture was heated and reacted under reflux for 2 hours.

After the reaction, the resulting reaction product mixture was filtered to give 2.6-
Sipheny-8-ethoxycarbonyl-1,2,3,5
,6,7-hexahydro-1゜3.5.7-tetraoquinimidazo[1,5-C]pyrimidine crystal 0.879
I got it. This was recrystallized from toluene and had a melting point of 336-3.
Colorless needle-like crystals of 38C were obtained. The elemental analysis values are shown below.

CHN Analysis value 62.49 3.88 10.15 Calculated value 62.22 3.73 10.37 (C21
(as HI5N306) Example 11 (Compound No. 16) 17 m of ethylene chloride containing 2.75 mmol of tetraethylammonium fluoride and 0.569 mmol of triethylamine
1 was added with 1.009 ml of ethyl 5-ethoxycarbonyl-1-(p-methoxyphenyl)orotate at room temperature, and then 20 ml of ethylene chloride containing 0.399 ethyl isocyaner) was added dropwise. The mixture was heated and reacted under reflux for 7.5 hours.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

20 ml of chloroform and 30 me of water were added to the residue, and the layers were separated into an organic layer and an aqueous layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Toluene 5 to the residue
8-ethoxycarbonyl-2-
Ethyl-6-(p-methoxyphenyl)-1,2+3+
5s6.7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C)pyrimidine crystals 0.36
I got a 9. This is recrystallized from benzene and has a melting point of 239~
Colorless needle-like crystals of 240C were obtained. The elemental analysis values are shown below.

CHN Analysis value 56,07 4.41 10.63 Calculated value 55.81 4.42 1085 (C, 8H
,7N30)) Example i2 (Compound No. 20) Ethylene chloride 40 containing 3.13 mmol of tetraethelammonium fluoride and 0.559 mmol of triethylamine
rnl, 1-(p-chlorophenyl)-5- at room temperature.
1.009 of ethyl (ethoxycarbonyl)orotate was added, followed by dropwise addition of 10 ml of ethylene chloride containing 0.549 of n-butyl isocyaner. The mixture was heated and reacted under reflux for 12.5 hours. After the reaction, the resulting reaction product mixture was washed with 50 ml of water,
After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure. Add 5Qml of Improvil ether to the residue, and add 2-(
lobutyl)-6-(p-chlorophenyl)-8-ethoxycarbonyl-1,2,3,5,6,7-hexahydro-1,3,s + 7-tetraoquinimidazo[1°5-C] Crystals of pyrimidine 031 were obtained. This was recrystallized with benzene to obtain colorless needle crystals with a melting point of 247-250C. The elemental analysis values are shown below.

CHN Analysis value 54,72 4.38 10.01 Calculated value 54.36 4.32 10.00 (C,,
H,8C! N 30 ) Example 13. (Compound No. 22) Ethyl 5-acetyl-1-ethylorotate 0.76 g
To 20 ml of ethylene chloride containing 0.60 g of triethylamine was added dropwise at room temperature, and then 10 ml of ethylene chloride containing 1.009 g of p-) lyluinanate was added dropwise. The mixture was heated and reacted under reflux for 18 hours.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

15 mt of benzene and 15 ml of water were added to the residue and filtered.
8-acetyl-6-nityl-2-(p-)lyl)-1
,2,3,5,6,7-hexahydro-1,3,5,7
-Tetraoxoimidazo[:1,5-C,1 pyrimidine crystals of 0.27 ml were obtained. This was recrystallized from ethylene chloride to obtain pale yellow crystals with a decomposition point of 270-273C.

The elemental analysis values are shown below.

CHN Analysis value 59,79 4.70 12.16 Calculated value 59,82 4.43 12.31 (CI?
H,,N30. ) Example 14 (Compound No. 23) 5-acetyl-1-cyclohexylorotic acid xfk
20ml of benzene containing 1.009 1K, 5m7 of benzene containing 0.66% of triethylamine at room temperature! was added dropwise, followed by dropwise addition of 10 ml of benzene containing 1.089 p-MJ lysocyanate. The mixture was heated and reacted under reflux for 15 hours.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

Add 20 ml of Improvil alcohol to the residue and filter it to give 8-acetyl-6-cyclohexyl-2-(p-)lyl)-1,2,3°5.6.7-hexahydro-1,3
, 1.08 g of crystals of 5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from acetonitrile to obtain colorless crystals with a decomposition point of 290-292c. The elemental analysis values are shown below OCHN Analysis value 63,92 5.38 10.90 Calculated value 63.79 5.35 10.63 (C2+
H2tN30s) Example 15 (Compound No. 25) 5-acety)cy 1-(p-)lyl)ethyl orotate 1. T) Benzene 15 mt containing 09,
Tetraethylammonium fluoro at room temperature! J 1.54
4 ml of t-crystallized ethylene containing mmol, 5 ml of benzene containing 0649 of t +
were added dropwise in this order. The mixture was heated and reacted under reflux for 17.5 hours.

After the reaction, the obtained reaction product mixture is FAl=B-7
-t-tyl-2-(p-1'rollophenyl)-6-(p-
h Lil)-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,
0.419 crystals of 5-C]pyrimidine were obtained. This was recrystallized from acetonitrile to obtain colorless crystals with a decomposition point of 343'C. The elemental analysis values are shown below.

CI-I N C1 Analysis value 59,49 3,51 9,54 8.40
Calculated value 5951 3.33 991 8. :U7(C
21H14CIN305) Fruit #1Ko16 (Compound No. 26) In 20 ml of ethylene chloride containing 0.859 ethyl 5-acetyl-1-(p-)7phenyl)orotate,
Ethylene chloride 5 containing triethylamine 052q at room temperature
ml was added dropwise, followed by 10 ml of ethylene chloride containing p-methoxyphenylinocyanate 0959.

The mixture was heated and reacted under reflux for 14.5 hours.

After the reaction, the resulting reaction product mixture was filtered and 8-acetyl-2,6-di(p-methoxyphenyl)-1,2,3
, 5,6,7-hekizahydro rl-1.3,5.7-titraoquinimidazo[1,5-'C']pyrimidine crystals of 0.619 were obtained.

This was recrystallized from acetonitrile to obtain pale yellow sword-shaped crystals with a decomposition point of 325C. The first shift of elemental analysis will be carried out next.

(SitoIN analysis value 60,77 4,02 9.37 total nasal value 60,69 3,94 9.65 (C22"
17 (as N307) Example 17 (Compound No. 27) 5-7 Benzene containing 1-(p-10 lophenyl)ethyl orotate 1009 26 ml K, benzene containing triethylamine 0609 at room temperature 5 ml p
- benzene l (Jml) containing chlorophenylisocyanate 1.149, and tetraethylammonium 70
4 ml of ethylene chloride containing 1.54 mmol of lido were added dropwise in this order. Heat the mixture under reflux for 35 min.
Allowed time to react.

After the reaction, the resulting reaction product mixture was filtered and mixed with 20 m of water.
8-acetyl-2,6-di(p-chlorophenyl)-1,2,3,5,6゜7-hexahydro-1
, 0.769 crystals of 3,5,7-tetraoxoimidazo[l,5-C]pyrimidine were obtained. This was recrystallized from dimethyl sulfoxide to obtain colorless crystals with a decomposition point of 365C. The elemental analysis values are shown below.

CHNC analysis value 536t 2,66 9.15 15.60
Calculated value 54,07 2.50 -9.46 15.
96 (as C20H11C)2N 305) Example 18 (Compound No. 30) 15 ml of benzene containing 100 g of ethyl 5-benzoyl-1-(n-butyl)orotate contains 295 mmol of tetraethyl ammonium fluoride at room temperature. Ethylene chloride 7.5mA! ,) 5 ml of benzene containing 0.599 ml of ethylamine and 7.5 ml of benzene containing 0.91 ml of cyclohexyl isocyanate were added dropwise in this order. The mixture was heated and reacted under reflux for 8 hours.

After the reaction, the resulting reaction product mixture was washed with 30 rnl of water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Add 20ml of isopropyl ether to the residue, and add 8-
Benzoyl-5-(n-butyl)-2-cyclohexyl-1,2,3゜5.6.7-hexahydro-1,3,5
, 0.919 crystals of 7-tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized with benzene to obtain colorless crystals with a decomposition point of 246-248C. The elemental analysis values are shown below.

CHN Analysis value 65,03 6.02 9.92 Calculated value 65,24 5,95 9.92 (C23H2
5Ns O! Example 19 (Compound No. 33) 12.5 ml of ethylene chloride containing 492 mmol of tetraethelammonium fluoride at room temperature in 30 m/of ethylene chloride containing 2009 ethyl 5-benzoyl-1-7 chlorohexafluorotate , triethylamine 1.099
10 ml of ethylene chloride containing 1. and 15 mg of ethylene chloride containing 1,499% of cyclohexyl isocyanate were added dropwise in this order. The mixture was heated and reacted under reflux for 3 hours.

After the reaction, 5 ml of ethanol was added to the resulting reaction product mixture at room temperature and filtered. Concentrate the P solution under reduced pressure,
Add 15 liters of ethanol to the residue and filter it to obtain 8-benzoyl-2,6-dicyclohexyl-1,2,3,5,6
, 7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C)pyrimidine crystal 0989 was obtained. This was recrystallized from 1,4-dioxane and the decomposition point was 33.
Colorless crystals of 2-334C were obtained. The elemental analysis values are shown below.

CHN Analysis value 66.92 6,02 9.51 Calculated value 66.80 6.05 9.35 (C25H,
as N, o) Example 20 (Compound No. 33) Ethyl 5-pensoyl-1-phenylorotate 100
Ethylene chloride containing 9+++A! 5 ml of ethylene chloride containing 0.569% of triethylamine was added dropwise at room temperature, followed by p-) IJ ruin cyanate 0.
．． 10 ml of ethylene chloride containing 809 were added dropwise. The mixture was heated and reacted under reflux for 25 hours.

After the reaction, the resulting reaction product mixture was filtered to give 8-benzoyl-6-phenyl-2-(p-)lyl)-1,2,
Crystals of 3,5,6,7-hexahydro-1,3,5,7-tetraoquinimidazo[1,5-C:]pyrimidine 0
．． I got 449.

This was recrystallized from acetonitrile to obtain colorless crystals with a decomposition point of 355C. The elemental analysis values are shown below.

CHN Analysis value 69.26 3,86 9.15 Calculated value 69.18 3,79 9.31 (026H1
7N305) Example 21 (Compound No. 37) To 25 ml of ethylene chloride containing 1.009 ethyl 5-benzoyl-1-(p-methoxyphenyl) orotate,
At room temperature, 0.519 ions of triethylamine in ethylene chloride was added dropwise, followed by 1.199 of 3,5-dichlorophenylinocyanate. The mixture was allowed to react for one day with stirring at room temperature.

After the reaction, the reaction product mixture obtained was filtered I7.

8-benzoyl-2-(3,5-dichlorophenyl)-
6-(p-methoxyphenyl)-1゜2.3,5,6,
0.479 crystals of 7-hexahydro-1,3°5.7-tetraoquinimidazo[1,5-C:]pyrimidine were obtained. This is recrystallized with ethylene chloride, and the decomposition point is 312~
Yellow crystals of 320C were obtained. The elemental analysis values are shown below.

CHNC analysis value 58.24 2.73 7.86 1
3.06 calculated value 58.23 2.82 7.8
3 13.22 (as C26HI5C)2N306) Example 22 (Compound No. 38) Ethyl 5-benzoyl-1-(3,5-dichlorophenyl)orotate], OO9 containing b-benzene 20 ml
5 ml of benzene containing 0.479 triethylamine was added dropwise to the solution at room temperature, and then p-1 lyliso7anate-
10 ml of benzene containing 0,779 was added dropwise.

The mixture was heated and reacted under reflux for 10 hours.

After the reaction, the resulting reaction product mixture was filtered to obtain 8-pensoyl-6-(3,5-dichlorophenyl)-2-(p
-)-1,2,3,5゜6.7-hexahydro-
1,3,5,7-tetraoxoimidazo[1,57C:
] 078 g of pyrimidine crystals were obtained. This was recrystallized from ethylene chloride to obtain pale yellow crystals with a decomposition point of 335C.

The elemental analysis values are shown below.

CHNC analysis value 60,52 3,09 7.84 13.64
Calculated value 60,02 2.91 8.0B 1
3.63 (as C26HI5C)2N305) Example 23 (Compound No. 40) Ethyl 1-(n-)ethyl)-5-cyanoorotate 1
．． To 30 ml of ethylene chloride containing 589 and 0.669 of triethylamine was added dropwise at room temperature 20 ml of ethylene chloride containing 1.599 of p-) IJ Ruincyanate. The mixture was allowed to react for 8 hours while stirring at room temperature.

After the reaction, the resulting reaction product mixture was filtered to obtain 6-(
n-butyl)-8-cyano-2-(p-tolyl)-1
,2,3,5,6,7-hexahydro-1,3,5,7
0.369 crystals of -tetraoquinimidazo[1,5-C) bilimin were obtained. This was recrystallized with ethylene chloride to obtain colorless bulk crystals with a decomposition point of 276C. The elemental analysis values are shown below.

CHN Analysis value 61.07 4.59 15.11 Calculated value 61,36 4.58 15.90 (CuH
+aN40+ and l-) Example 24 (Compound No. 41) Ethylene chloride 30m containing 1179 ethyl 5-cyano-1-phenylorotate and 0.469 triethylamine
1 was added dropwise at room temperature with 20 rnl of ethylene chloride containing 1.089 phenyl ynnanate. The mixture was heated and reacted under reflux for 11 hours.

After the reaction, the resulting reaction product mixture was filtered.

8-cyano-2,6-diphenyl-1,2,3°5,.
6,7-hexahydro-1,3,5,7-tetraoquinimigzo[1,5-C]pyrimidine crystal 0.249
I got it. This was recrystallized with acetonitrile and the decomposition point was 3.
Colorless acicular crystals of 25C were obtained. The elemental analysis values are shown below.

CHN analysis value 63,79 2. ．． 95 15.95 Calculated value 63.69 2・81 15.64 (Cl
0HION404) Example 25 (Compound No. 42) Ethyl 5-fluorotate 1°009 and tetraethylammonium fluoro! 5 ml of acetonitrile containing 157 g of n-hexyl isocyanate and 0.509 of triethylamine were added dropwise to 45 ml of acetonitrile containing 2.16 mmol of IJ).

The mixture was heated and reacted under reflux for 5.5 hours.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

Add 100 ml of isopropyl ether and 20 ml of water to the residue.
and filtered, 8-fluoro-2-(n-hexyl)
-1,2,3,5,6゜7-hexahydro-1,3,5
1.299 crystals of ,7-tetraoquinimidazo(1,5-C]pyrimidine were obtained. This was recrystallized from acetonitrile to obtain yellow granular crystals with a melting point of 278-284C.

The elemental analysis values are shown below.

CHN Analysis value 51.04 4.97 14.78 Calculated value 50.88 4.98 14.83 (Cl2
1414FN304) Example 26 (Compound No. 44) To 30 ml of acetonitrile containing 085 g of ethyl 5-fluoroorotate and 0.859 of triethylamine, 10 ml of acetonitrile containing 1.409 of penzylisocyaner) was added dropwise at room temperature. . Heat the mixture and
The reaction was carried out under reflux for 1 hour.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

Add isopropyl ether Some and 30 ml of water to the residue, filter it, and give 2-benzyl-8-fluoro-1,2,
3,5,6,7-hexahydro-1,3,5,7-tetraoquinimidazo[:1.5-C]pyrimidine crystal 1
．． 06g was obtained. This was recrystallized with acetonitrile and
Colorless plate-like crystals with a melting point of 292-296C were obtained. The elemental analysis values are shown below.

CF (N Analyzed value 54.07 2.86 14.71 Calculated value 53,99 2.79 14.53 (Cl5
H, FN, 04) Example 27 (Compound No. 46) Acetonitrile 30 mA containing 0.759 ethyl 5-fluoroorotate! To the solution, 10 m/ml of acetonitrile containing 1.609 g of p-)') lysocyanate and 075 g of triethylamine was added dropwise at room temperature. The mixture was allowed to react for 17 hours with stirring at room temperature.

After the reaction, the resulting reaction product mixture was filtered, and the P solution was concentrated under reduced pressure F. Ethylene chloride 10mA on the residue! Add 30 ysl of isopropyl ether and filter, 8-fluoro-2-(p-tolyl)=1.2,3,5,6.7
One crystal of -hexahydro-1゜3.5.7-tetraoquinimidazo(1,5-C]pyrimidine (0.839 g) was obtained. This was recrystallized from acetonitrile, melting point 332-3.
Colorless needle-like crystals of 38C were obtained. The elemental analysis values are shown below.

CHN Analysis value 5.4,40 2.78 15.05 Calculated value 53,99 2.79 14.53 (Cl
5H8FN304) Example 28 (Compound No. 50) Ethyl 1-benzyl-5-fluoroorotate 0.78
Ethylene chloride 3 containing 9 and triethylamine 0.549
0 ml of p = nitrile isocyanate 0 f1 at room temperature.
100 tnl of ethylene chloride containing was added dropwise. The mixture was allowed to react for one day with stirring at room temperature.

After the reaction, the resulting reaction product mixture was filtered and 6-benzyl-8-fluoro-2-(p-tolyl)-1,2,3,
Crystals of 5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1°5-C]pyrimidi/0.54
I got a 9. This is recrystallized with ethylene chloride, and the decomposition point is 1.
Colorless microcrystals with a size of 40 to 142 tl' were obtained. The elemental analysis values are shown below.

Analytical value 11.18 Calculated value 11.08 (as C20H14PN, 0.) Example 29 (Compound No. 53) Ethyl 5-fluoro-1-phenylorotate 1.15
Ethylene chloride 5 containing 9 and 0.84 g of triethylamine
1.559 of 3.5-dichlorophenylinocyanate was added to 0 ml at room temperature.

The mixture was allowed to react for one day with stirring at room temperature.

After the reaction, the resulting reaction product mixture was filtered to obtain 2-(3
,5-dichlorophenyl)-8-fluoro-6-phenyl-1,2,3,5,6,7-hexahydro-1,3,
0.64 g of crystals of 5-+ 7-tetraoquinimidazo(1,5-C]pyrimidine were obtained. This was recrystallized from ethylene chloride to obtain colorless microneedle crystals with a decomposition point of 326C.

The elemental analysis values are shown below.

C) (N Analysis value 51.75 1.99 10.11 Calculated value 51.45 1.92 10.00 (CI8
H8C], FN30. ) Example 30 (Compound No. 54) To 40 ml of acetonitrile containing 2.00 g of ethyl 5-chloroorotate and 9.01 mmol of tetraethylammonium fluoride, 0.999 of triethylamine was added, followed by 1.0 g of inflovir incyanate. 20 ml of acetonitrile containing 989 were added dropwise. The mixture was heated and reacted under reflux for 5 hours.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

30 ml of ethylene chloride and 30 ml of water were added to the residue, filtered, and 8-chloro-2-inpropyl-1,2,3,5,
1.629 crystals of 6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C)pyrimidine were obtained.

This was recrystallized from ethylene chloride and had a melting point of 268-270.
Colorless crystals of C were obtained. The elemental analysis values are shown below.

CHN Analysis value 41,67 3.18 16.27 Calculated value 41,96 3.13 16.31 (C,H
8C1N,;04) Example 31 (Compound No. 56) To 20 ml of acetonitrile containing 200 g of ethyl 5-chloroorotate and 96 mmol of tetraethylammonium 70lide was added 1.839 of triethylamine at room temperature, and then allyl inanor) 2. 20 m/l of acetonitrile containing '159 were added dropwise. The mixture was heated and reacted under reflux for 6 hours.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

Add 30 ml of ethylene chloride and 30 ml of water to the residue and filter it to obtain 2-allyl-8-chloro-1,2,3,5,6,7
-Hexahydro-1゜3.5.7-Tetraoquinimidazo(1,5-C]pyrimidine crystal 1.6!IM' was obtained. This was recrystallized from ethylene chloride, and the decomposition point was 239~
Colorless needle-like crystals of 240C were obtained. The elemental analysis values are shown below.

CHN Analysis value 41.65 2.51 16.20 Calculated value 42,29 2.37 16.44 (C,H
6C1N304) Example 32 (Compound No. 61) 1.969 ethyl 5-bromoorotate +) To 40 ml of ethylene chloride containing 0.85 g of ethylamine,
20 ml of ethylene chloride containing 1.78 g of phenylisonanate were added dropwise at room temperature.

The mixture was allowed to react for one day with stirring at room temperature.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

Add 40 ml of benzene to the residue and 10 ml of N hydrochloric acid.
and 20 ml of water were added and filtered to give 8-bromo-2-phenyl-1,2,3,5,6,7-hexahydro-1,3,
2.402 crystals of 5,7-tetraoquinimidazo(l,5-C)pyrimidine were obtained. This was recrystallized from ethylene chloride to obtain pale yellow crystals with a decomposition point of 284-285C.

The elemental analysis values are shown below.

CHN Br Analysis value 43.01 1.81 12.49 2
4.01 Calculated value 42,88 1.80 12.50
23.77 (as C, □H, aBrN304) Example 33 (Compound No. 62) Ethyl 5-bromo-1-isopropylorotate 1.1
Benzene 20 containing 0.09 and triethylamine 0.739
rtrl, phenyl isocyanate 0.86 at room temperature
Benzene 1 (Jnl) containing g was added dropwise. The mixture was allowed to react for 1 day with stirring at room temperature.

After the reaction, the resulting reaction product mixture was filtered to give 8-furomo6-1 nogrovir-2-phenyl-1,2,3,
Crystals of 5,6,7-hexahydro-1,3,5,7-tetraoquinimidazo[1,5-C)pyrimidine 0.59
I got it. This was recrystallized from ethylene chloride, with a melting point of 30
Colorless crystals of 1C were obtained. The elemental analysis values are shown below.

CHN Br Analysis value 47,84 3.20 11.15 20.9
1 calculated value 47.64 3.20 11.11
21.13 (as C,,H,2BrN304) Example 34 (Compound No. 64) Ethylene chloride 401 containing ethyl 5-bromo-1-phenylorotate 2719 and triethylamine 1.629
10 ml of ethylene chloride containing 1.909 g of phenyl isocyanate were added dropwise at nlK and room temperature. The mixture was allowed to react for one day with stirring at room temperature.

After the reaction, the resulting reaction product mixture was filtered to give 8-bromo-2,6-diphenyl-1,2,3°5.6.7-
285 g of crystals of hexahydro-1,3,5,7-tetraoquinimidazo[1,5-C)pyrimidine were obtained. This was recrystallized with ethylene chloride to obtain colorless needle crystals with a decomposition point of 373C. The elemental analysis values are shown below.

CHN Analysis value 49.63 2.61 8.63 Calculated value 49,43 2.62 9.10 (C, 8H,
oBrN30. (as) Next, an example of synthesis of imidazopyrimidines by reaction B will be shown.

Example 35 (Compound No. 14) 45 m of ethylene chloride containing 5.02 mmol of tetraethylammonium fluoride and 1.269 mmol of triethylamine
(To !, add 1.499 of 5-bis(ethquincarbonyl)methylene-3-isopropylhydantoin at room temperature,
Then 20 rnl of ethylene chloride containing 2969/phenyl incyanate were added dropwise. The mixture was heated and reacted under reflux for 10.5 hours.

After the reaction, the resulting reaction product mixture was added with 30 m of water at room temperature.
The lachrymal fluid was separated into an organic layer and an aqueous layer. After drying the moriki layer over anhydrous sodium sulfate, it was concentrated under reduced pressure. Add 10 ml of ethanol to the residue and filter it.
8-Ethoxycarbonyl-2-improbyl-6-phenyl-1,2,3,5,6,7-hexahydro-1,3
, 5,7-tetraoquinimidazo CI, 5-C) 0.44 g of pyrimidine crystals were obtained. This was recrystallized from toluene to obtain colorless needle crystals with a melting point of 256-258C. The elemental analysis values are shown below. O CHN Analysis value 58,53 4.69 11.21 Calculated value 58,22 4.61 11.32 (Cl8
817N306) Example 36 (Compound No. 15) 4 j) ml of ethylene chloride containing 332 g of 5-bis(ethoxycarbonyl)ethylene-3-phenylhydantoin and 202 g of triethylamine was added with 1.98 ml of tetraethylammonium fluoride at room temperature. 5 ml of ethylene chloride containing No. 1 was added dropwise, followed by dropwise addition of ethylene chloride IQm/ containing 2.389 phenyl isocyanate. The mixture was heated and reacted under reflux for 5.5 hours.

After the reaction? 2.6.
-diphenyl-8-ethoxycarbonyl-1,2,3,
Crystals of 5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C)pyrimidine 0.28
I got a 9.

Example 37 (Compound No. 51) To 40 ml of acetonitrile containing 1.389 5-(ethquincarbonyl)fluoromethylenehydantoin, 1.389 triethylamine was added at room temperature, and then 20 ml of acetonitrile containing 3.22 g of phenyl isocyanate was added.
ml was added dropwise.

The mixture was allowed to react for one day with stirring at room temperature.

After the reaction, the resulting reaction product mixture was concentrated under reduced pressure.

50 ml of ethylene chloride and 50 ml of water were added to the residue to separate it into an aqueous layer and an organic layer. The aqueous layer was concentrated to a reduced volume, and 15 ml of 1N hydrochloric acid was added to the residue. 35ml of water and 50ml of ethylene chloride
8-fluoro-6-phenyl-1,2
,3,5,6,7-hexahydro-1,3,5,7-tetraoquinimidazo(1,5-C)pyrimidine J%
0.73 g was obtained. This was recrystallized with a mixed solvent of tetrahydrofuran and inflovir ether in a volume ratio of 1:1 to obtain colorless crystals with a decomposition point of 245C. The elemental analysis values are shown below CCJ (N Analysis value 51,60 2.62 15.77 Calculated value 52.37 2.20 15.27 (C+z
As HaFN30+) Patent issued and filed by Ube Kotei Co., Ltd.

Claims (1)

[Scope of Claims] Formula [wherein R1 is a hydrogen atom, a purkyl group having 1 to 4 carbon atoms,
Phenyl group, alkoxycarbonyl group having carbon i''1lk2-5, aliphatic acyl group having 2-5 carbon atoms, benzoyl group,
Represents a cyano group or a halogen atom, R2 and R3 are each a hydrogen atom, an alkyl group having 1 to 10 carbon atoms,
Allyl group and cyclo represent an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogen atom, and n
is 0.1 or 2. ) represents a group. ]
Imidazopyrimidines represented by