JPH052679B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to novel quinazoline derivatives. More particularly, the present invention relates to novel quinazoline derivatives, processes for their preparation, pharmaceutical compositions containing quinazoline derivatives as active ingredients, and methods of using quinazoline derivatives in the treatment of allergic diseases, such as allergic asthma. That is, an object of the present invention is to provide quinazoline derivatives that are effective as anti-allergic drugs. Another object of this invention is to provide a method for producing quinazoline derivatives. A further object of the invention is to provide a pharmaceutical composition containing a quinazoline derivative as an active ingredient. The quinazoline derivative of this invention has the general formula [In the formula, R ¹ is hydrogen, a carboxy group or an esterified carboxy group, and A ² is the general formula

【formula】

[expression] or

[Formula] (wherein R ⁴ _a is hydrogen, an alkyl group, a hydroxy group, an alkoxy group or an alkenyloxy group,
R ⁶ is an esterified carboxy group, R ⁵
is an alkyl group or an alkenyl group), and R ² and R ³ are hydrogen, an alkyl group, a halogen, a nitro group, an alkoxy group, an aryloxy group, an alkylthio group, an alkylpiperazinyl group, an acylamino group. or dialkylamino group]. Next, in the description of this specification, definitions of various terms to be included within the scope of this invention will be explained in detail. The term "lower" in this specification means 1 to 6 carbon atoms, unless otherwise specified. Suitable esterified carboxy groups for R ¹ , R ¹ _a , R ¹ _b and R ⁶ include lower alkoxycarbonyl groups having 2 to 7 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl). , butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl), and the like. Preferred alkyl groups for R ² , R ³ , R ⁴ , R ⁴ _a and R ⁵ include linear or branched lower alkyl groups (e.g. methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl). Halogens in R ² and R ³ include fluorine, chlorine, bromine and iodine. Preferred alkoxy groups for R ² , R ³ , R ⁴ and R ⁴ _a include linear or branched lower alkoxy groups (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyl oxy, hexyloxy). Suitable aryloxy groups for R ² and R ³ include phenoxy, naphthyloxy, tolyloxy, and the like. Suitable alkylthio groups for R ² and R ³ include linear or branched lower alkylthio groups (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, t-butylthio, pentylthio, hexylthio). It will be done. Suitable dialkylamino groups for R ² and R ³ include lower dialkylamino groups such as
dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino)
can be mentioned. Suitable alkylpiperazinyl groups for R ² and R ³ include 4-lower alkylpiperazinyl groups (e.g. 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-propylpiperazinyl,
-isopropylpiperazinyl, 4-t-butylpiperazinyl, 4-pentylpiperazinyl, 4-hexylpiperazinyl). The acylamino group in R ² and R ³ includes a monoacylamino group and a diacylamino group. The acyl portion of the acylamino group includes organic carboxylic acid residues and organic sulfonic acid residues.
Preferred acyls include lower alkanoyl groups (e.g., formyl, acetyl, propionyl,
butyryl, isobutyryl, 3,3-dimethylbutyryl, valeryl, isovaleryl, pivaloyl) and higher alkanoyl groups having 7 to 18 carbon atoms (e.g. heptanoyl, 2,3-dimethylpentanoyl, lauroyl, myristoyl, palmitoyl,
Alkanoyl group containing stearoyl), carbon number 3
~9 lower alkoxalyl groups (e.g. methoxalyl, ethoxalyl, propoxalyl), lower cycloalkanecarbonyl groups having 4 to 8 carbon atoms (e.g. cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), lower (C3 _{to C7} ) cycloalkyl(lower)alkanoyl group (e.g. 3-cyclopentylpropionyl),
Aroyl groups (e.g. benzoyl, naphthoyl,
toluoyl, xyloyl, phthaloyl), lower aralkanoyl groups (e.g., phenylacetyl),
Examples include lower alkanesulfonyl groups (eg, mesyl, ethanesulfonyl, propanesulfonyl), and the like. Suitable alkenyloxy groups for R ⁴ and R ⁴ _a include alkenyloxy groups having 2 to 6 carbon atoms (eg, vinyloxy, allyloxy, 1-propenyloxy, 3-butenyloxy). Suitable alkenyl groups for R ⁵ include lower alkenyl groups having 2 to 6 carbon atoms (e.g., vinyl, allyl, 2-propenyl, 3-butenyl, 3
-pentenyl, 5-hexenyl, etc.). The quinazoline derivatives of this invention are produced by various methods detailed below. [In the formula, R ² , R ³ and A ² are each as defined above, R ¹ _a and R ¹ _b are esterified carboxy groups, and A ¹ is the general formula

【formula】 or

[Formula] (In the formula, R ⁴ is hydrogen, an alkyl group, a hydroxy group, an alkoxy group, or an alkenyloxy group, and R ⁵ is an alkyl group or an alkenyl group)
is a group represented by, R ² _a is an acyl group,
R ⁷ is an alkoxy group] The above method will be described in further detail below. Method for producing raw material 1 The target compound () is produced by reacting the compound () or a salt thereof with the compound (). Preferred examples of the alkoxy group in R ⁷ of compound () include lower alkoxy groups (e.g.
methoxy, ethoxy, propoxy, etc.). Examples of the salts of the compound () include salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, toluenesulfonic acid, and the like. The raw material compounds () include known compounds and novel compounds. Known compounds such as 4-
Aminoquinazoline, 2-chloro-4-aminoquinazoline, 2-hydroxy-4-aminoquinazoline and 2-methoxy-4-aminoquinazoline are
Journal of the Chemical Society (C)1284
(1969), Chemical Abstracts
Abstracts) 54, 24778b and 9939C (1960), and the novel compound () can be produced by a method similar to this. The method for producing this new compound will be described in detail in the following production examples of raw material compounds. The reaction in this method is typically carried out in an inert solvent such as N,N-dimethylformamide, ethanol, propanol, isobutyl alcohol, tetrahydrofuran, diphenyl ether, chloroform, toluene, or xylene at temperatures ranging from cooled to heated conditions. It will be held in This reaction also applies to alkali metal hydrides (e.g., sodium hydride), alkali metal amides (e.g., sodium amide), alkali metal alkoxides (e.g., potassium t-butoxide),
It may be carried out in the presence of a base such as a diazabicyclo compound (for example, 1,5-diazabicyclo[3,4,0]nonene-5, 1,5-diazabicyclo[5,4,0]undecene-5, etc.) . If this reaction is carried out at relatively high temperatures, a closed ring compound, ie, a pyrimidoquinazoline compound (), may be produced. Method for producing raw material 2 Target compound (b) is produced by reducing compound (a). This reduction reaction is preferably carried out by catalytic reduction. This catalytic reduction is usually carried out at room temperature or under cooling.
Inert solvents (e.g. N,N-dimethylformamide, ethanol, propanol, isobutyl,
The catalytic reduction is carried out in alcohol, tetrahydrofuran, chloroform, ethyl acetate, acetic acid, etc.) using a catalyst for catalytic reduction such as Raney nickel or palladium-carbon. Method for producing raw material 3 Target compound (c) is produced by reacting compound (b) with an acylating agent. Acylating agents used in this reaction include organic acids (ie, compounds of the general formula R ² _a OH, where R ² _a is as defined above) and reactive derivatives thereof. Here, suitable examples of the organic acid include organic acids having the acyl moiety of the acylamino group in R ² of the above-mentioned compound () as R ² _a . Suitable reactive derivatives include acid halides (e.g. acid chlorides, acid bromides, etc.), acid azides,
Examples include acid anhydrides, activated amides, and activated esters. When a free acid is used as the acylating agent,
The acylation reaction is preferably carried out in the presence of a condensing agent. This reaction is usually carried out in the presence of an inert solvent such as N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, chloroform, pyridine or a mixture thereof. This reaction preferably also includes alkali metals (e.g. sodium), alkaline earth metals (e.g.
calcium), alkali metal hydrides or alkaline earth metal hydrides (e.g. sodium hydride,
alkali metal hydroxides or alkaline earth metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.); alkali metal or alkaline earth metal carbonates or bicarbonates (e.g. , sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.),
Alkali metal or alkaline earth metal alkoxides (e.g. sodium ethoxide, lithium methoxide, agnesium methoxide), trialkylamines (e.g. triethylamine), pyridine, bicyclodiaza compounds (e.g. 1,5-
diazabicyclo[3,4,0]nonene-5,1,
5-diazabicyclo[5,4,0]undecene-
5 etc.) in the presence of an organic or inorganic base. This reaction is usually preferably carried out at room temperature or under cooling. Further, when an excessive amount of acylating agent is used in this acylation reaction, an N,N-diacyl compound may be simultaneously produced, and such a case is also included within the scope of this method. Method for producing target substance 1 Target compound (a) is produced by heating compound (d). This reaction is usually carried out under heating, preferably between 160 and
N,N-dimethylformamide at 270°C,
It is carried out in the presence of an inert, high-boiling solvent such as diphenyl ether, biphenyl, paraffin, etc., or without a solvent. Preferred reaction conditions are selected from the above reaction conditions depending on the type of raw material compound. Method for producing target substance 2 Target compound (b) can be produced by subjecting compound (a) to selective hydrolysis of ester. This reaction is usually carried out by heating compound (a) in the presence of lithium iodide in an inert solvent such as N,N-dimethylformamide, collidine, lutidine, pyridine, etc., and then treating the product with water. Manufactured by The target compounds produced by each of the above methods can be isolated and purified by known methods. The target compound, a quinazoline derivative (), is
It has strong anti-allergic and anti-inflammatory activity. That is, the object compound of this invention is suitable for allergic asthma, allergic rhinitis, hives, hay fever, allergic conjunctivitis, atopic dermatitis, ulcerative colitis, dietary allergies (eg, milk allergy), and bird lovers. It is effective in treating symptoms related to allergic diseases such as canker sores, aphthous stomatitis, etc. Next, the antiallergic effects and acute toxicity of representative compounds among the target compounds (2012) will be explained using test examples. Test [PCA (passive cutaneous anaphylaxis)
Reaction inhibitory effect] (1) Test compound

【table】

【table】

(2) Test method (a) Preparation of antiserum An emulsion was prepared by mixing a solution of ovalbumin (2 mg) in pertussis-diphtheria-tetanus combined vaccine (1 ml) with Freund's incomplete adjuvant (1 ml). This emulsion was applied to the four paws of an 8-week-old male SD (Sprague Dawly) rat weighing approximately 300 g, and a 1 ml dose was divided into 4 equal doses (0.25 g).
ml) and administered subcutaneously. Immunization 10
A day later, blood was collected from the rat's femoral artery and left undisturbed on ice for 5 hours. The separated supernatant was centrifuged at 4°C (10,000 revolutions x 1 hour). The antiserum thus obtained was stored at -80°C until use. (b) PCA reaction inhibitory effect A PCA reaction was carried out using SD male rats, 8 weeks old and weighing 290 to 330 g, using the allogeneic sensitized antibody antiserum prepared as described above. 0.1 ml of each 64-fold diluted antiserum was injected intradermally into separate sites on the backs of completely shaved rats, and 48 hours later,
Aqueous solution 1 containing 5 mg each of ovalbumin and Evans Blue to induce a PCA reaction
ml was injected intravenously. Test compounds were administered orally 60 minutes or intravenously 5 minutes before antigen challenge. The control group received vehicle. There were 5 animals in each administration group. Antigen induction 1
After hours, the animals were sacrificed and skinned. The size of spots stained on the back side of the skin with the antiserum was examined. The results were expressed as a ratio of the inhibition value calculated from the average value of the longest and shortest diameters of each spot compared to the control group. (3) Test results The test results are shown in the table below.

【table】

[Table] Note *: Not tested.
Test [PCA (passive cutaneous anaphylaxis)
Reaction inhibitory effect] (1) Test compound Structural formula of test compound

[Table] (2) Test method This test was conducted in substantially the same manner as the test, except that instead of a 64-fold dilution of the antiserum used for passive sensitization, a 32-fold dilution was used in this test. A diluted solution was used. (3) Test results The test results are shown in the table below.

[Table] Note *: Not tested.
Test (acute toxicity) The above test compound No. 38 was administered to each group of 10 male and female rats.
Results observed for 14 days after oral administration of up to 3200 mg/Kg to
As a result, no abnormality was observed. The quinazoline derivative () of this invention is an antiallergenic
in free form or as an inorganic acid.
or salts with organic acids, inorganic bases or organic bases.
as pharmaceuticals such as salts of amino acids and salts with amino acids, etc.
It can also be used in the form of acceptable salts. target compound () or pharmaceutically acceptable
The salts are typically administered to mammals, including humans, e.g.
For example, capsules, microcapsules, tablets, and granules.
Granules, powders, lozenges, syrups, aerosols
inhalants, solutions, injections, suspensions, emulsions
Administer in dosage forms such as pills, suppositories, ointments, etc.
I can do it. The antiallergic agent of this invention has a conventional pharmaceutical use.
Contains various organic or inorganic carrier materials used.
Examples include excipients (e.g.
sugar, starch, mannitrate, sorbitol, lactose,
Glucose, cellulose, talc, calcium phosphate
calcium carbonate, etc.), binders (e.g.
Lulose, methylcellulose, hydroxypropylene
cellulose, polypropylpyrrolidone, gelati
gum arabic, polyethylene glycol, silicone
sucrose, starch, etc.), disintegrants (e.g., starch)
Carboxymethyl cellulose, carboxymethyl cellulose
Calcium salt of chillulose, hydroxypro
Pill starch, sodium glycol-starch
Sodium bicarbonate, calcium phosphate, que
(e.g. calcium phosphate), lubricants (e.g. stearyl
magnesium phosphate, aerosil, talc, lauri
flavoring agents (e.g. sodium sulfate), flavoring agents (e.g.
ammonium of phosphoric acid, menthol, glycyrrhizin
salt, glycine, orange powder, etc.), preservatives (e.g.
For example, sodium benzoate, sodium bisulfite
(mu, methylparaben, propylparazine, etc.),
Stabilizers (e.g. citric acid, sodium citrate,
acetic acid), suspending agents (e.g. methylcellulose,
Polyvinylpyrrolidone, aluminum stearate
), dispersants [e.g. polysorbate 80,
Emulgen 408, Emazol (both surface active
agent), aqueous diluent (e.g. water), wax base
(For example, cocoa butter, polyethylene glycol,
Uitepsol, white petrolatum, etc.)
Ru. Use of active compounds in antiallergic agents of this invention
The amount depends on the weight and/or age of the patient and
(or) the extent of the allergic disease, and even the administration
Varies depending on various factors such as route, but effective
The dosage is usually about 20-2000mg/oral administration.
Approximately 2.5 to 250 days for intramuscular or intravenous injection
mg/day, approximately 10-1000 mg/day for subcutaneous injection, rectal
For the route, select from the range of approximately 120 to 2000 mg/day.
selected. The total daily dose above is 6 to 6 per day.
Patients may be given divided doses 12 hours apart.
stomach. A single dose of the active compound of this invention is preferably
For example, as a tablet or capsule, about 10
~500mg, approx. 1.25 as a vial or ampoule
~250mg, approximately 60-500mg as a suppository, etc.
In addition, external dosage forms include ointments, solutions, and
is approximately 1 to 10% as an emulsion. The starting material used in the production of the quinazoline derivative of the present invention
The production method of the starting compound and target compound is carried out as follows.
This will be explained specifically by using an example. Example 1 O-aminobenzonitrile (22.58g) and phor
A mixture of Muamide (96 ml) was refluxed at 220°C for 2 hours.
did. After cooling the reaction solution to room temperature, the precipitated crystals were
The crystals were collected by filtration, washed twice with a small amount of water, and dried under reduced pressure.
to obtain crystals of 4-aminoquinazoline (17.0g).
Ta. mp: 265-268℃ IR (nujiol) νmax: 3100, 1690, 1615, 1585cm ^-1 NMRδppm (DMSO _Four −d ₆ ): 7.4-8.0 (5H, m), 8.30 (1H, broad d, J = 8.0Hz), 8.50 (1H,
s) By a method substantially similar to Example 1, the following chemical
I got a compound. (1) 4-Amino-6-chloroquinazoline mp: ＞270℃ IR (Nudiyol) νmax: 3100, 1680, 1570, 1548cm ^-1 (2) 4-Amino-7-chloroquinazoline IR (Nudiyol) νmax: 3275, 3100, 1685,
1605. 1575cm ^-1 NMRδppm (DMSO−d ₆ ): 7.52 (1H, dd, J=
2.0 and 8.0Hz), 7.70 (1H, d, J = 2.0Hz), 7.90 (2H, broad s), 8.33 (1H, d, J =
8.0Hz), 8.40 (1H, s) (3) 4-amino-6-methylquinazoline mp: 266-269℃ IR (Nudyol) νmax: 3400-3100, 1680,
1580, 1555cm ^-1 NMR, δppm (DMSO−d ₆ ):2.44(3H,s),
7.56 (4H, m), 8.05 (1H, broad s), 8.30 (1H,
broad s) (4) 4-Amino-6-phenoxyquinazoline mp: 97-99℃ IR (Nudyol) νmax: 1664, 1642, 1590cm ^-1 NMR, δppm (DMSO−d ₆ ): 6.4−7.8 (7H,
m), 7.93 (1H, d, J = 9.0Hz), 8.43 (1H, s),
10.4 (2H,s) (5) 4-amino-6-N,N-dimethylaminoki
Nazolin mp: ＞270℃ IR (nujiol) νmax: 3400−3100, 1662,
1612, 1565cm ^-1 NMRδppm (DMSO−d ₆ ): 2.96 (6H, s), 7.12 (1H, d, J=3.0Hz), 7.36 (4H, m), 8.12
(1H, s) (6) 4-amino-6-ethylthioquinazoline mp: 158-164℃ IR (Nudiyol) νmax: 3300, 3100, 1670, 1600cm ^-1 NMRδppm (DMSO−d ₆ ): 1.26 (3H, t, J = 8.0Hz), 3.1 (2H, quartet, J = 8.0Hz),
7.6 −8.0 (4H, m), 8.2 (1H, d, J = 2.0Hz),
8.40 (1H, s) (7) 4-Amino-7-methoxyquinazoline IR (Nudiyol) νmax: 3330, 3130, 1670,
1620, 1578, 1560cm ^-1 NMRδppm (DMSO−d ₆ ): 3.86 (3H, s), 7.1 (2H, m), 7.56 (2H, broad, s), 8.13 (1H,
d, J=10.0Hz), 8.30 (1H, s) (8) 4-amino-7-acetamidoquinazoline mp: ＞300℃ IR (Nudiyol) νmax: 1675, 1628, 1570cm ^-1 NMRδppm (DMSO−d ₆ ): 2.16 (3H, s), 7.6 (3H, broad s), 7.9-8.3 (2H, m), 8.36
(1H, s), 10.23 (1H, broad s) (9) 4-amino-6-ethylquinazoline mp: 224-227℃ IR (Nudiyol) νmax: 3300, 3100, 1665,
1575, 1540cm ^-1 NMRδppm (CDCl ₃ ): 1.30 (3H, t, J = 7.0Hz), 1.83 (2H, s), 2.77 (2H, quartet, J = 7.0Hz), 7.4-8.0 (3H, m), 8.26 (1H, s) (10 ) 4-Amino-6-butyl quinazoline mp: 209-210℃ IR (Nudiyol) νmax: 3050, 1680, 1570, 1540cm ^-1 NMRδppm (DMSO−d ₆ ): 0.7-1.8 (7H, m), 2.7 (2H, t, J = 7.0Hz), 7.63 (4H, broad
s), 8.07 (1H, s), 8.37 (1H, s) (11) 4-amino-8-methylquinazoline mp: 200-214°C IR (Nudiyol) νmax: 3350, 3120, 1670,
1612, 1588cm ^-1 NMRδppm (DMSO−d ₆ ): 2.66 (3H, s), 7.3
- 8.0 (4H, m), 8.16 (1H, d, J = 9.0Hz), 8.56 (1H, s) (12) 4-amino-6-propylquinazoline mp: 194-198℃ IR (Nujiol) νmax: 3320 ,3100,1660,
1570, 1550, 1500cm ^-1 NMRδppm (DMSO−d ₆ ): 0.93 (3H, t, J = 7.0Hz), 1.3-2.1 (2H, m), 2.73 (2H, t, J = 7.0Hz), 7.70 (2H, s), 7.75 (2H, m), 8.13 (1H, s), 8.46 (1H, s) (13) 4-Amino-6,7-dimethylquinazoline mp: ＞360℃ IR (Nudiyol) νmax: 3270, 3070, 1680,
1620, 1560cm ^-1 (14) 4-Amino-7-methylquinazoline mp: 278-279°C IR (Nudiyol) νmax: 3330, 3150, 1670,
1620 900, 790cm ^-1 NMRδppm (DMSO−d ₆ ): 2.43 (3H, s), 7.3 (1H, d, J=8.0Hz), 7.45 (1H, s), 7.6
(2H, s), 8.1 (1H, d, J = 8.0Hz), 8.33 (1H, s) (15) 4-Amino-6-(4-methylpiperazine
) Quinazoline mp: 229-234℃ IR (nujiol) νmax: 3170, 3050, 1670,
1640, 1620cm ^-1 NMRδppm (DMSO−d ₆ ): 2.23 (3H, s), 2.5 (4H, m), 3.26 (4H, m), 3.45 (2H, s),
7.3− 7.6 (3H, m), 8.2 (1H, s) (16) 4-Amino-6,7-dimethoxyquinazoli
mp: 204-206℃ IR (nujiol) νmax: 3320, 1672, 1612, 1580cm ^-1 NMRδppm (DMSO−d ₆ ): 3.90 (6H, s), 7.1 (1H, s), 7.40 (2H, s), 7.6 (1H, s),
8.27 (1H, s) (17) 4-Amino-7-pivalamide quinazoline mp: 305-307°C Example 2 2-amino-5-nitrobenzonitrile (48.9
g), anhydrous potassium carbonate (45.6g), formamide
(240ml) and N,N-dimethylformamide
After stirring the mixture (200ml) at 150℃ for 50 minutes,
Cooled to room temperature. Add a small amount of water to this reaction solution while stirring.
added. The precipitated crystals were collected by filtration, washed three times with water,
Dry under reduced pressure to obtain 4-amino-6-nitroquinazoli.
(50.1 g) was obtained. mp:＞360℃ IR (nujiol) νmax: 3350, 3200, 1680, 1620cm ^-1 NMRδppm (DMSO−d ₆ ): 7.76 (1H, d, J = 9.0Hz), 8.43 (1H, dd, J = 3.0 and 9.0Hz), 9.26 (1H, d, J = 3.0Hz), 8.30 (2H, m) Example 3 ( a) 2,4-quinazolinedione (20g), tri-
n-propylamine (38g) and phosphorus oxychloride
(200ml) was stirred at 120°C for 40 minutes.
The solid residue obtained by concentrating the reaction mixture under reduced pressure was 2%
Tri-n-propylamine-heptane warm solution
(250 ml) and further extracted with 2% tri-n-
2 with propylamine-ether solution (250ml)
Extracted twice. Add a small amount of beer to the combined extract.
The precipitated crystals were dissolved by adding Zhenzene. Add this solution to 0.5N sodium hydroxide aqueous solution.
Washed three times with water and then saturated sodium chloride
Washed with an aqueous solution of lium. The resulting solution is dried
Dry with magnesium sulfate and concentrate under reduced pressure.
Obtain crystals of 4-dichloroquinazoline (20g)
Ta. Dissolve the crystals in dioxane (140ml)
After that, ammonia was blown in for 40 minutes.
I left it undisturbed at night. Filter the precipitate and wash it twice with water.
and dried under reduced pressure to give 2-chloro-4-amino
Crystals of quinazoline (12.4 g) were obtained. (b) Dry allylalyl of metallic sodium (0.7 g)
4-amino-2-chloro in kohl (90ml) solution
Quinazoline (35g) was added and the mixture was heated to 100℃.
Stirred for 5 hours. Concentrate the reaction solution under reduced pressure and remove the residue.
Added a small amount of water. This aqueous reaction solution was diluted with acetic acid.
Extracted twice with chill. The organic layer is saturated with water.
Wash with sodium chloride solution and anhydrous sulfuric acid mug
Dry with nesium and further concentrate under reduced pressure.
The crystalline residue obtained was mixed with ethyl acetate and hexane.
2-allylic acid is recrystallized from a mixed solvent with
Crystals of xy-4-aminoquinazoline (2.8g)
I got it. mp: 105-110℃ IR (nujiol) νmax: 3300, 3100, 1670,
1635, 1615cm ^-1 NMR. δppm (DMSO−d ₆ ): 4.88 (2H, d, J = 4.0Hz), 5.2-5.5 (2H, m), 6.1 (1H, m), 7.2-8.3 (6H, m) Example 4 (a) 1-Methylquinazoline-2 ,4-dione
(8.88g), tri-n-propylamine (8.6g)
and a mixture of phosphorus oxychloride (80ml) at 110~
The mixture was stirred at 120°C for 1 hour. The obtained reaction solution was
Cool to room temperature and concentrate under reduced pressure to reduce the resulting residue to 2%
Tri-n-propylamine-chloroform solution
dissolved in. Add this solution to 2N sodium hydroxide
and ice mixture under alkaline pH. water
The layers were separated and extracted twice with chloroform. nine
Combine the loloform layers and add water then saturated sodium chloride.
Anhydrous magnesium sulfate
and concentrated under reduced pressure to give 4-chloro-1-
Crystals of methyl-1H-quinazolin-2-one
Obtained. (b) 4-chloro-1-methyl-1H- obtained above
Quinazolin-2-one with methanol (50ml)
It was dissolved in dioxane (70ml) and cooled on ice. Bubble ammonia into this solution for 16 minutes.
After that, it was allowed to stand overnight at room temperature. Filter out insoluble matter
Separate and wash with methanol. Combine the filtrate and washing liquid.
The residue was dissolved in methanol and concentrated under reduced pressure.
I understand. When ether was added dropwise to this solution, the resulting
Filter the precipitate and mix with methanol and ether.
Washed with solvent. By the above operation, 4-amino
Nor-1-methyl-1H-quinazolin-2-one
(4.05 g) of crystals were obtained. Crystals of the above compound (0.7g) were prepared in the same manner as above.
and recovered from the mother liquor. mp: 252-262℃ IR (nujiol) νmax: 3350, 3160, 1708,
1652, 1590, 1530cm ^-1 NMRδppm (DMSO−d ₆ ): 3.48 (3H, s), 3.50 (2H, broad s), 7.12-7.40 (2H, m), 7.72 (1H, t, J = 8.0Hz), 8.16 (1H, d, J = 8.0Hz) Implementation Example 5 (a) 2-bromo-4-ethylaniline (29.2g)
and cuprous cyanide (14.4 g).
Stir in pyridine (25.4g) at 160℃ for 16 hours.
Ta. After cooling to 60°C, the reaction mixture was poured into concentrated ammonia.
In a (1:1) mixture of near water and water (250ml)
poured into. Add ethyl acetate (300ml) to this mixture.
was added under stirring. Insoluble matter was filtered off. organic layer
Wash three times with water and then with saturated aqueous sodium chloride solution.
After cleaning and drying with anhydrous magnesium sulfate,
Concentration under pressure gave an oily residue. This residue
Zhenzene was added thereto, and the mixture was concentrated under reduced pressure. remove pyridine
This operation was repeated twice to achieve this. residual oily
silica gel column chromatography
(Eluent: benzene-hexane mixed solvent, 3:
1) and 2-amino-4-ethylbenzoni
Tolyl (16.4g) was obtained. IR (thin film) νmax: 3460, 3370, 3225, 2200, 1620cm ^-1 NMRδppm (CCl _Four ): 1.16 (3H, t, J = 7.0Hz) 2.5 (2H, quartet, J = 7.0Hz), 4.36 (2H, s),
6.5 (1H, d, J = 10.0Hz), 7-7.4 (2H, m) (b) 2-amino-4-ethylbenzonitrile
(39.9g) in acetic acid (200ml).
Potassium annate (24.4g) was cooled on ice for 15 minutes.
The mixture was stirred overnight in a water bath. reaction mixture
Add water to the solution, collect the precipitate by filtration, and wash with water.
Dry at room temperature. The obtained crude crystals are dissolved in ethanol.
Recrystallized from (2-cyano-4-ethyl phthalate)
Crystals of enyl)urea (29.0 g) were obtained. mp:＞360℃ IR (nujiol) νmax: 3450, 3350, 3250,
3200, 2220, 1660, 1620cm ^-1 NMRδppm (DMSO−d ₆ ): 1.2 (3H, t, J = 7.0Hz), 2.6 (2H, quartet, J = 7.0Hz), 6.40 (2H, broad s), 7.40-7.73 (2H, m), 8.0 (1H, d, J =8.0Hz)、8.50(1H、broad
s) (c) Sodium metal (0.365g) in dry methanol
(2-cyano-
Add 4-ethylphenyl)urea (10g) and incubate.
The reaction mixture was heated to reflux for 5.5 hours. reaction mixture
Water was added to the residue obtained by concentrating under reduced pressure.
The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure.
4-amino-6-ethyl-2-hydroxyquina
Crystals of Zolin (9.35 g) were obtained. mp:＞350℃ IR (nujiol) νmax: 3360, 3100, 1670,
1635, 1600cm ^-1 NMRδppm (DMSO−d ₆ ): 1.2 (3H, t, J = 8.0Hz), 2.6 (2H, quartet, J = 8.0Hz), 7.06 (1H, d, J = 8.0Hz), 7.46 (1H, dd,
J = 2.0 and 8.0Hz), 7.6-8.0 (3H, m), 11.2 (1H, s) Example 6 (a) 2-Amino-5-ethylbenzoic acid (20.28g)
and ethyl chlorocarbonate (53.5g)
After heating to 100°C for 50 minutes, it was cooled to 90°C.
Add acetyl chloride (13.81 g) to this reaction mixture.
was added dropwise over 15 minutes and the reaction mixture was heated at 100℃.
Stirred for 2 hours. Cool the reaction mixture to room temperature
After that, add hexane to the reaction mixture and let it cool to room temperature.
The precipitated crystals were collected by filtration and washed with hexane.
and dried under reduced pressure to give 6-ethyl-2H-3,1
-benzoxazine-2,4-(1H)-dione
(19.55 g) of crystals were obtained. mp: 178-181℃ IR (nujiol) νmax: 3230, 1760, 1690,
1615, 1605cm ^-1 NMRδppm (CDCl ₃ ): 1.23 (3H, t, J = 8.0Hz), 2.7 (2H, quartet, J = 8.0Hz), 7.0−8.0 (3H, m), 9.3 (1H, s) (b) 6-ethyl-2H- 3,1-benzoxadi
2,4-(1H)-dione (19.55g) and urea
(6.18 g) of dry N,N-dimethyl
Heat reflux in formamide (98 ml) for 3 hours 40 minutes.
It flowed. After cooling the reaction solution to room temperature,
Add water to the solution while stirring to precipitate crystals.
After filtering, washing with water, and drying under reduced pressure, 6-ethyl
-1H,3H-quinazoline-2,4-dione
(11.74 g) of crystals were obtained. mp: 271-274℃ IR (nujiol) νmax: 3310, 3160, 3030,
1720, 1685, 1620cm ^-1 NMRδppm (DMSO−d ₆ ): 1.2 (3H, t, J = 8.0Hz), 2.65 (2H, quartet, J = 8.0
Hz), 7.18 (1H, d, J = 8.0Hz), 7.56 (1H, dd,
J = 2.0 and 8.0Hz), 7.8 (1H, d, J = 2.0Hz),
12.0 (2H,s) (c) 6-ethyl-1H,3H-quinazoline-2,4
-dione (37.8g), tri-n-propylamide
(5.72g) and phosphorus oxychloride (38ml).
The mixture was stirred at 120°C for 40 minutes and then allowed to cool to room temperature.
It was cooled down. Residue obtained by concentrating the reaction solution under reduced pressure
Then, heat (50-60℃) 2% tri-n-propyl
While stirring the amine-heptane solution (50 ml)
added. Separate and remove the supernatant and remove substantially all of the residue.
was treated three times in the same manner as before. heptane layer
At the same time, benzene was added to this. This mixture
Dilute the material with 5% aqueous sodium hydroxide solution (50ml).
After washing twice and three times with water, saturated sodium chloride
Washed with an aqueous solution. Mix the mixture with anhydrous sulfuric acid
After drying with sodium chloride and concentrating under reduced pressure,
Crystals of lolo-6-ethylquinazoline (4.07g)
I got it. mp: 80-83℃ IR (nujiol) νmax: 1530, 1480, 1450,
1410, 1160, 1110cm ^-1 NMRδppm (CDCl ₃ ): 1.4 (3H, t, J = 8.0
Hz), 2.93 (2H, quartet, J = 8.0Hz), 7.96 (2H, broad s), 8.1 (1H, s) (d) 2,4-dichloro-6-ethylquinazoline
(10.8g) in a mixture of methanol and chloroform.
It was dissolved in a combined solvent (70 ml) and cooled in ice. anti
Bubble ammonia gas through the reaction mixture for 20 minutes and mix.
The material was left at room temperature for 18 hours. Concentrate the mixture under reduced pressure
Add water to the residue and heat to 50-60℃ while stirring.
heated to. The precipitate was collected by filtration and washed with hot water.
After that, it was recrystallized from dioxane to give 4-amino-
2-chloro-6-ethylquinazoline (8.3g)
crystals were obtained. The mother liquor was treated in the same way as above.
Crystals (0.7 g) of the same compound were obtained. mp: 244-246℃ IR (nujiol) νmax: 3380, 3340, 3120,
1660, 1570, 1540cm ^-1 NMR. δppm (DMSO−d ₆ ): 1.3 (3H, t, J = 8.0Hz), 2.8 (2H, quartet, J = 8.0Hz), 7.5-7.9 (2H, m), 8.16 (1H, s), 8.3 (2H, broad s) ( e) Sodium metal (1.19g) in methanol
(270ml) solution of 4-amino-2-chloro-6-
Ethylquinazoline (9.01g) was added. reaction mixture
The mixture was heated to reflux for 7 hours and then heated to 60°C for 38 hours.
Heated. Residue obtained by concentrating the reaction mixture under reduced pressure
Water was added to the mixture while stirring while heating. precipitation
The product was collected by filtration and dried under reduced pressure to give 4-amino-6-
Ethyl-2-methoxyquinazoline (6.77g)
Obtained crystals. mp: 168-170℃ IR (nujiol) νmax: 3300, 1630, 1580cm ^-1 NMRδppm (DMSO−d ₆ ): 1.3 (3H, t, J = 7.0Hz), 2.76 (2H, quartet, J = 7.0
Hz), 4.06 (3H, s), 7.70 (2H, m), 8.36 (1H, broad s), 9.20 (2H, m) Example 7 Iron (113.9g), concentrated hydrochloric acid (57ml) and water (2.3
) mixture was stirred at 95°C for 20 minutes. This mixture
4-amino-6-nitroquinazoline (114.1
g) was added over 10 minutes. Reaction mixture at 95℃
Stirred for 1.5 hours and then filtered. Heat the filter residue
Washed with water. Combine the filtrate and washing liquid and concentrate under reduced pressure.
and add a small amount of ethanol to the residue to form a precipitate.
I let it happen. The precipitate was collected by filtration and dried to give 4,6-diamide.
Noquinazoline hydrochloride (94.8g) was obtained. Same as above
The same compound (4.3 g) was recovered from the mother liquor using the same method.
Ta. IR (nujiyoru) νmax: 3310, 1665, 1610, 1560cm ^-1 Example 8 4,6-diaminoquinazoline hydrochloride (1.97g),
Sodium bicarbonate (6.72g) and pyridine
(20 ml) was stirred under ice-cooling. This mixture
Cool methanesulfonic acid chloride (4.58g) on ice.
It was added dropwise over a period of 30 minutes. Cool the reaction mixture on ice.
The mixture was stirred for 1 hour, and further stirred for 4 hours at room temperature.
After adding ice water to this mixture and stirring for 5 minutes,
It was concentrated under pressure. Chloroform and methanol are added to the residue.
A mixture of these was added and stirred while heating. Filter out insoluble matter
The filtrate was then concentrated under reduced pressure to obtain crude crystals.
After that, the crystals are mixed with chloroform and methanol.
A mixed solvent (4:1) was added. Stir the mixture under heat.
The crystals precipitated by stirring were collected by filtration to give 4-amino-6
- methanesulfonamide quinazoline (1.45g)
Obtained crystals. mp: 287-290℃ IR (nujiol) νmax: 3350, 3150, 1660, 1615cm ^-1 NMRδppm (DMSO−d ₆ ): 3.3 (3H, s), 7.7 -8.33 (4H, m), 8.83 (1H, s), 9.8 (2H, s) Example 9 4,6-diaminoquinazoline hydrochloride (10.0 g),
Tripropylamine (17.61g) and dried piri
3,3-dimethylbutylene in a mixture of gin (100ml)
Pour luchloride (10.34g) on ice for 35 minutes.
dripped. The reaction mixture was stirred at the same temperature for 2 hours.
Ta. Add ice water to this mixture and stir for 5 minutes.
It was then concentrated under reduced pressure. water and sodium bicarbonate in the residue
Add lium (13.0g) little by little to form a precipitate.
The precipitate was collected by filtration, washed with water, and dried. like this
The crude crystals obtained were mixed with chloroform and methanol.
was heated and dissolved in a mixed solvent of Filter out insoluble matter and filter
The residue obtained by concentrating the liquid under reduced pressure was diluted with 5% methanol.
It was suspended in chloroform solution (70ml). heating stirring
After that, the suspension was filtered to give 4-amino-6-(3,3
-dimethylbutyramide)quinazoline (8.5g)
crystals were obtained. mp: 273-274℃ IR (nujiol) νmax: 3330, 3220, 1685, 1650cm ^-1 NMRδppm (DMSO−d ₆ ): 1.06 (9H, s), 2.26 (2H, s), 7.6 (2H, s), 7.63 (1H, d, J
= 8.0Hz), 7.83 (1H, dd, J = 2.0 and 8.0Hz), 8.4 (1H, s), 8.4 (1H, d, J = 2.0Hz), 10.03 (1H,
s) Example 10 The following reaction was carried out in substantially the same manner as in Example 9.
I got a compound. (1) 4-amino-6-pivalamide quinazoline mp: 269-273°C IR (Nudyol) νmax: 3325, 3175, 1670,
1580, 1560, 1525cm ^-1 N.M. R. δppm (DMSO−d ₆ ): 1.23 (9H, s),
7.5 (2H, s), 7.56 (1H, d, J=9.0Hz),
7.80 (1H, dd, J = 2.0 and 9.0Hz), 8.3 (1H, s), 8.35 (1H, s), 9.4 (1H, s) (2) 4-Amino-6-(2,3-dimethylpenta
(amide) quinazoline mp: 240-243°C Example 11 4,6-diaminoquinazoline hydrochloride (1.97g),
Tripropylamine (2.60g) and dry pyridine
(20 ml) was added with 2-ethylbutylene in an ice bath.
Luchloride (1.75 g) was added dropwise over 10 minutes.
After stirring this mixture at the same temperature for 3 hours, the reaction
Crushed ice was added to the mixture. The mixture was stirred for 5 minutes.
After that, it was concentrated under reduced pressure. Water (50ml) was added to the residue
After that, add sodium hydrogen carbonate (3.6g) little by little.
The precipitate is collected by filtration, washed with water and dried.
It was dry. This crude crystal is mixed with chloroform and methanol.
It was heated and dissolved in a mixed solvent with Insoluble matter was filtered out
After that, the filtrate was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate.
suspended in. After heating and stirring, the suspension was collected by filtration and added to 4-A.
Mino-6-(2-ethylbutyramide)quinazoli
(1.20 g) of crystals were obtained. mp: 248-250℃ IR (nujiol) νmax: 3320, 3100, 1660,
1570, 1535cm ^-1 NMRδppm (DMSO−d ₆ ):9.2(6H,t,J=
6.0Hz), 1.34-1.88 (4H, m), 2.08-2.44 (1H, m),
7.2 (2H, s), 7.6 (1H, d, J=10.0Hz), 7.8
(1H, dd, J=3.0, 10.0Hz), 8.34 (1H, s), 8.38 (1H,
d, J = 3.0Hz), 10.02 (1H, s) Example 12 4,6-diaminoquinazoline hydrochloride (10g) and
Dry mixture with tripropylamine (17.6g)
Stirred in pyridine (100ml) in an ice bath for 1 hour.
Add isobutyric anhydride (8.85g) to this mixture for 40 minutes.
It dripped. The mixture was stirred at 5°C for 1 hour.
Add crushed ice to the reaction mixture, stir for 5 minutes, then reduce
The residue obtained by pressure concentration was dissolved in water. insoluble matter
After filtration, the filtrate was diluted with an aqueous sodium hydrogen carbonate solution.
The pH was adjusted to 8 to 9, and the residue obtained by concentration under reduced pressure was chloroformed.
It was dissolved in a mixed solvent of form and methanol. melt
The liquid was filtered and the crystalline residue obtained by concentrating under reduced pressure was dissolved in vinegar.
Suspended in ethyl acid. Filter the suspension to remove 4-amino
No-6-(2-methylpropionamide)quinazo
Phosphorus (5.05g) was obtained. mp: 280-283℃ IR (nujiol) νmax: 3260, 3120, 1655,
1575, 1510cm ^-1 NMRδppm (DMSO−d ₆ ): 1.12 (6H, d, J=7.0Hz), 2.5-2.8 (1H, m), 7.5 (2H, s),
7.5 (1H, d, J = 9.0Hz), 7.86 (1H, dd, J =
2.0, 9.0Hz), 8.3 (1H, s), 8.4 (1H, d, J=2.0
Hz), 10.03 (1H, s) Example 13 4,6-diaminoquinazoline hydrochloride (12 g)
Dry mixture with tripropylamine (31.7g)
Stirred in pyridine (120ml) in an ice bath for 1 hour.
Add cyclohexane carbonyl chloride to this mixture.
(12.1 g) was added dropwise at 70°C over 4 hours and 20 minutes.
The mixture was further stirred at 5°C for 1 hour, then crushed ice
added. The mixture was stirred for 1 hour and concentrated under reduced pressure.
After adding water, PH the mixture with sodium bicarbonate.
Adjust to 8 and collect the generated precipitate by filtration, wash with water and dry.
did. Mix the precipitate with chloroform and methanol.
It was dissolved in a combined solvent and heated. Filter out insoluble matter and filter
Concentrate the liquid under reduced pressure to obtain 4-amino-6-cyclohexane.
Crystals of carboxamide quinazoline (9.25g)
Obtained. mp: 301-303℃ IR (nujiol) νmax: 3700-3100, 1650,
1585, 1560, 1510cm ^-1 NMRδppm (DMSO−d ₆ ): 1.0-2.0 (10H, m), 2.4-2.8 (1H, m), 7.53 (2H, s), 7.6 (1H,
d, J=8.0Hz), 7.78 (1H, dd, J=2.0, 8.0
Hz), 8.3 (1H, s), 8.43 (1H, d, J=2.0Hz),
10.0 (1H, s) Example 14 4,6-diaminoquinazoline hydrochloride (10g)
Dry the mixture with tripropylamine (26.4g)
Stirred in pyridine (100ml) in an ice bath for 20 minutes.
Add 3-cyclopentylpropionyl to this mixture.
Loride (12.2 g) was added dropwise over 1.5 hours. Mixed
The mixture was stirred in an ice bath for 1.5 hours. into the reaction mixture
Add crushed ice and stir for 5 minutes, then concentrate under reduced pressure.
Ta. After adding water to the reaction mixture, sodium bicarbonate
Add a small amount of aluminum, collect the formed precipitate by filtration, and add water.
Washed and dried. The crude crystals were mixed with chloroform.
Filter out impurities by heating and dissolving in a mixed solvent with tanol.
The filtrate was treated with activated carbon and then concentrated under reduced pressure.
The obtained residue was suspended in ethyl acetate and heated for 1 hour.
After hot stirring, 4-amino-6-(3-
cyclopentylpropionamide) quinazoline
(7.2 g) of crystals were obtained. mp: 279-283℃ IR (nujiol) νmax: 3280, 3120, 1660,
1565, 1510cm ^-1 NMRδppm (DMSO−d ₆ ): 0.7−2.16 (11H,
m), 2.46 (1H, t, J=6.0Hz), 7.6 (2H, m),
7.66 (1H, d, J=9.0Hz), 7.93 (1H, d, J=
9.0Hz), 8.33 (1H, s), 8.50 (1H, s), 10.40 (1H, s) Example 15 4-Aminoquinazoline (11.6g) and diethyl ethyl
Toximethylene propanedioate (19.0g)
The mixture was diluted with N,N-dimethylformamide (40ml).
Stir at 160°C for 1 hour and 20 minutes, then warm to room temperature.
It was cooled to precipitate crystals. Stir into this mixture
Added a small amount of water at the bottom. After filtering the crystals and washing with water,
It was dried under reduced pressure overnight and dissolved in ethyl acetate. obtained
The solution was dried with anhydrous magnesium sulfate and diluted with acetic acid ethyl chloride.
Recrystallize diethyl from a mixed solvent of chill and hexane.
[(4-quinazolinylamino)methylene]pro
Crystals of pandioate (22.7 g) were obtained. mp: 115-117℃ IR (nujiol) νmax: 1735, 1660, 1628cm ^-1 NMRδppm (CDCl ₃ ): 1.36 (3H, t, J = 7.0
Hz), 1.40 (3H, t, J=7.0Hz), 4.36 (4H, m),
7.5−8.2 (4H, m), 8.96 (1H, s), 9.40 (1H, d, J=12.0Hz), 12.3 (1H, broad d, J=12
Hz) Example 16 The following compound was prepared by substantially the same method as Example 15.
I got something. (1) Diethyl [(6-phenoxy-4-quinazoli
nylamino)methylene]propanedioate mp: 121-123℃ (recrystallized from a mixed solvent of chloroform, ethyl acetate and hexane) IR (Nudiol) νmax: 1720, 1625, 1617,
1608, 1580cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (6H, t, J = 8.0Hz), 4.33 (2H, quartet, J = 8.0
Hz), 4.37 (2H, quartet, J=8.0Hz), 7.0−7.6
(7H, m), 8.06 (1H, d, J = 9.0Hz), 8.90 (1H,
s), 9.33 (1H, d, J = 12.0Hz), 12.16 (1H, d, J = 12.0Hz) (2) Diethyl [(6-dimethylamino-4-quina
zolinylamino)methylene] propanedioether
mp: 156-158℃ (recrystallized from a mixed solvent of chloroform and hexane) IR (nudyl) νmax: 1720, 1652, 1628, 1600cm ^-1 NMRδppm (CDCl ₃ ): 1.36 (6H, m), 3.04 (6H, s), 4.34 (4H, m), 6.50 (1H, d, J = 3.0Hz), 7.34 (1H, dd, J = 3.0 and 9.0Hz), 7.72 (1H, d, J = 9.0Hz), 8.60
(1H, s), 9.24 (1H, d, J=11.0Hz), 11.90
(1H, d, J=11.0Hz) (3) Diethyl [(6-ethylthio-4-quinazoli
Nylamino)methylene]propanedioate mp: 103-106℃ (recrystallized from a mixed solvent of ethyl acetate and hexane) IR (Nudiol) νmax: 1722, 1650, 1624, 1600cm ^-1 NMRδppm (CDCl ₃ ): 1.3-1.8 (9H, m), 3.14 (2H, quartet, J = 8.0Hz), 4.2-4.7
(4H, m), 7.7-8.1 (3H, m), 8.90 (1H, s), 9.3 (1H, d, J = 12.0Hz), 12.4 (1H, d, J
=12.0Hz) (4) Diethyl [(7-methoxy-4-quinazolini)
(ruamino) methylene] propanedioate mp: 134-138℃ (recrystallized from a mixed solvent of chloroform and hexane) IR (Nudiol) νmax: 1736, 1630, 1572 cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (3H, t, J = 7.0Hz), 1.43 (3H, t, J = 7.0Hz), 3.96
(3H, s), 4.36 (4H, m), 7.1−7.4 (2H, m),
7.83 (1H, d, J=9.0Hz), 8.87 (1H, s),
9.30 (1H, d, J = 12.0Hz), 12.2 (1H, d, J = 12.0
Hz) (5) Diethyl [(7-acetamido-4-quinazo
linylamino)methylene]propanedioate IR (nudiol) νmax: 3420, 1720, 1695,
1655, 1630, 1585cm ^-1 NMRδppm (CDCl ₃ −DMSO−d ₆ ): 1.36 (3H,
t, J = 7.0Hz), 1.43 (3H, t, J = 7.0Hz),
2.23 (3H, s), 4.30 (4H, m), 7.93 (2H, m),
8.34 (1H, m), 8.90 (1H, s), 9.30 (1H, d, J = 12Hz), 10.27 (1H, s), 12.2 (1H, d, J = 12Hz) (6) Diethyl [(2- Hydroxy-4-quinazoli
nylamino)methylene]propanedioate mp: 265-268°C (recrystallized from a mixed solvent of N,N-dimethylformamide and water) IR (Nudiyol) νmax: 1702, 1660, 1630,
1585, 1575cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (6H, m), 4.40 (4H, m), 7.3-8.0 (4H, m), 9.24 (1H,
d, J=11.0Hz), 12.3 (1H, d, J=11.0Hz),
12.90 (1H, s) (7) Diethyl [(2-methoxy-4-quinazolini
methylene] propanedioate mp: 129-135°C (recrystallized from a mixed solvent of ethyl acetate and hexane) IR (nudiol) νmax: 1692, 1645, 1630,
1608, 1568cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (3H, t, J = 7.0Hz), 1.46 (3H, t, J = 7.0Hz), 4.16 (3H, s), 4.32 (4H, m), 7.3-8.0 (4H,
m), 9.30 (1H, d, J = 11.0Hz), 12.3 (1H, d, J = 11.0Hz), (8) Diethyl [(2-allyloxy-4-quinazo
linylamino)methylene]propanedioate mp: 117-119℃ (recrystallized from a mixed solvent of ethyl acetate and hexane) IR (Nudiyol) νmax: 1672, 1640, 1620, 1560cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (3H, t, J = 7.0Hz), 1.45 (3H, t, J = 7.0Hz), 4.40 (4H, m), 5.0-6.5 (5H, m), 7.3-8.0
(4H, m), 9.30 (1H, d, J = 12.0Hz), 12.3 (1H, d, J = 12.0Hz) (9) Dimethyl [(2-methyl-4-quinazolinyl
Amino)methylene]propanedioate IR (Nudiyol) νmax: 1680, 1640, 1620,
1600, 1550cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (6H, m), 2.76 (3H, s), 4.33 (4H, m), 7.44-8.0 (4H,
m), 9.34 (1H, d, J = 12.0Hz), 12.14 (1H, d, J = 12.0Hz) (10) Diethyl [(2-hydroxy-6-ethyl-
4-quinazolinylamino)methylene]propane
Geoate mp: 267-270℃ (recrystallized from a mixed solvent of chloroform and methanol) IR (Nujiol) νmax: 1720, 1665, 1615, 1588cm ^-1 NMR. δppm (CDCl ₃ ): 1.16−1.76 (9H, m), 2.83 (2H, quartet, J = 8.0Hz), 4.30 (4H,
m), 7.56 (3H, broad s), 9.26 (1H, d, J=11.5Hz), 12.26 (1H, d, J=11.5Hz),
12.90 (1H, s) Example 17 4-amino-6-ethylquinazoline (6.35g)
and diethyl ethoxymethylene propanedioate
(9.52g) was mixed with N,N-dimethylforma
Stir at 110°C for 3 hours in 25ml of
Cooled to room temperature. Add a little water to the resulting mixture
The crystals were collected by filtration and washed with water.
did. Dissolve the crystals in chloroform and add saturated sodium chloride.
Wash with thorium aqueous solution and anhydrous magnesium sulfate.
After drying with a vacuum cleaner, the mixture was concentrated under reduced pressure to obtain a crystalline residue.
This was reprocessed from a mixed solvent of ethyl acetate and hexane.
It crystallizes into diethyl [(6-ethyl-4-quinazo
linylamino)methylene]propanedioate
(8.40 g) of crystals were obtained. Furthermore, the same person as above
Crystals (2.75 g) of the same compound were recovered from the mother liquor using the method
did. mp: 104-106℃ IR (nujiol) νmax: 3250, 1700, 1645,
1610, 1560cm ^-1 NMRδppm (CDCl ₃ ): 1.2-1.5 (9H, m), 2.96 (2H, quartet, J=7.0Hz), 4.1-4.7 (4H,
m), 7.7 -8.1 (3H, m), 8.95 (1H, s), 9.4 (1H,
d, J = 12.0Hz), 12.3 (1H, d, J = 12.0Hz) Example 18 Using substantially the same method as Example 17, the following chemical
I got a compound. (1) Diethyl [(6-methyl-4-quinazolinyl
Amino)methylene]propanedioate mp: 137-139℃ (recrystallized from a mixed solvent of chloroform and hexane) IR (Nujiol) νmax: 1735, 1655, 1630, 1615cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (3H, t, J = 8.0Hz), 1.46 (3H, t, J = 8.0Hz), 2.63 (3H, s), 4.33 (2H, quartet, J = 8.0
Hz), 4.46 2H, quartet, J = 8.0Hz), 7.8-8.1 (3H,
m), 8.93 (1H, s), 9.4 (1H, d, J = 12.0Hz),
12.16 (1H, d, J=12.0Hz) (2) Diethyl [(6-butyl-4-quinazolinyl
Amino)methylene]propanedioate mp: 83-85℃ (recrystallized from a mixed solvent of ethyl acetate and hexane) IR (Nujiol) νmax: 3220, 1730, 1650,
1630, 1610, 1560cm ^-1 NMRδppm (CCl _Four ): 0.7-2.1 (13H, m), 2.86 (2H, t, J = 7.0Hz), 4.26 (2H,
quartet, J=7.0Hz), 4.36(2H, quartet, J=7.0
Hz), 7.6-8.0 (3H, m), 8.76 (1H, s), 9.23
(1H, d, J=12.0Hz), 12.2 (1H, d, J=12.0
Hz) (3) Diethyl [(8-methyl-4-quinazolinyl
Amino)methylene]propanedioate mp: 121-123℃ (recrystallized from a mixed solvent of ethyl acetate and hexane) IR (Nudiol) νmax: 1705, 1650, 1618,
1605, 1580cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (3H, t, J = 7.0Hz), 1.43 (3H, t, J = 7.0Hz), 2.73 (3H, s), 4.37 (4H, m), 7.4-7.9 (3H,
m), 8.97 (1H, s), 9.33 (1H, d, J = 12.0Hz), 12.26 (1H, d, J = 12.0Hz) (4) Diethyl [(6-propyl-4-quinazolini)
methylene] propanedioate mp: 96-99°C (recrystallized from a mixed solvent of ethyl acetate and hexane) IR (Nudiol) νmax: 3200, 1690, 1640,
1630, 1600, 1550cm ^-1 NMRδppm (CCl _Four ): 0.8-2.2 (11H, m), 2.9 (2H, t, J = 8.0Hz), 4.0-4.7 (4H,
m), 7.5 -8.0 (3H, m), 8.8 (1H, s), 9.23 (1H,
d, J = 12Hz), 12.23 (1H, d, J = 12.0Hz) (5) Diethyl [(7-methyl-4-quinazolinyl
Amino)methylene]propanedioate mp: 118-120℃ (recrystallized from a mixed solvent of chloroform and hexane) IR (Nudiol) νmax: 3250, 1685, 1640,
1620, 1605, 1560cm ^-1 NMRδppm (DMSO−d ₆ ): 1.2 (3H, t, J = 7.0Hz), 1.26 (3H, t, J = 7.0Hz), 3.2
(3H, s), 4.15 (2H, quartet, J = 7.0Hz), 4.26 (2H, quartet, J = 7.0Hz), 7.4-8.0 (3H,
m), 8.8 (1H, s), 9.06 (1H, d, J = 12.0Hz),
11.53 (1H, d, J = 12.0Hz) Example 19 4-amino-6-(4-methylpiperazinyl)
Quinazoline (2.19g) and diethyl ethoxime
A mixture of tyrene propanedioate (2.13g)
2 hours at 100℃ in isobutyl alcohol (9 ml)
The mixture was stirred for 25 minutes and then cooled to room temperature. reaction solution
was concentrated under reduced pressure, and the residue was recrystallized from ethanol.
diethyl [{6-(4-methylpiperazinyl)-
4-quinazolinylamino}methylene]propane
Crystals of oeate (1.58 g) were obtained. mp: 154-159℃ IR (nujiol) νmax: 3300, 1760, 1740,
1690, 1650, 1630, 1600cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (3H, t, J = 7.0Hz), 1.43 (3H, t, J = 7.0Hz), 2.40
(3H, s), 2.63 (4H, m), 3.43 (4H, m), 4.33
(4H, m), 7.0 (1H, d, J=3.0Hz), 7.56 (1H,
dd, J = 3.0 and 9.0Hz), 7.86 (1H, d, J = 9.0Hz),
8.76 (1H, s), 9.39 (1H, d, J = 12.0Hz) Example 20 The following formula was prepared using substantially the same method as in Example 19.
I got a compound. diethyl [(6,7-dimethoxy-4-quinazo
linylamino)methylene]propanedioate mp: 226-229℃ (recrystallized from a mixed solvent of chloroform and hexane) IR (Nudiol) νmax: 1675, 1636, 1620,
1608, 1550cm ^-1 NMRδppm (CDCl ₃ ): 1.37 (3H, t, J = 7.0Hz), 1.40 (3H, t, J = 7.0Hz), 4.03
(3H, s), 4.06 (3H, s), 4.33 (4H, m), 7.03
(1H, s), 7.23 (1H, s), 8.76 (1H, s), 9.30
(1H, d, J = 12.0Hz), 12.0 (1H, d, J = 12.0Hz) Example 21 2,4-diaminoquinazoline (3g), diethyl
L-ethoxymethylene propanedioate (8.5g)
and N,N-dimethylformamide (15
ml) at 150°C for 2 hours and 45 minutes, then cooled to room temperature.
Cooled to . Add a small amount of water to this mixture to form a
After forming crystals, filtering them, washing them with water, and drying them under reduced pressure.
It was dry. The crude crystals were collected using silica gel column chromatography.
(eluent: chloroform-ethyl acetate)
tetraethyl 2,2'-
[2,4-quinazolinediylbis(iminomethyl)
gin)] crystals of bispropanedioate (1.8g)
I got it. mp: 146-148℃ IR (nujiol) νmax: 3250, 1700, 1680,
1650, 1640, 1630, 1600, 1545cm ^-1 NMRδppm (CDCl ₃ ): 1.43 (12H, m), 4.40 (8H, m), 7.33-8.00 (4H, m), 9.23 (1H,
d, J=12.0Hz), 9.25 (1H, d, J=13.0Hz),
11.0 (1H, d, J = 13.0Hz), 12.30 (1H, d, J
=12.0Hz) Example 22 4-amino-6-nitroquinazoline (57.0g)
and diethyl ethoxymethylenepropanedioether
(130g) of anhydrous N,N-dimethyl
Add to formamide (570ml) and cool to 5°C.
Ta. Add sodium hydride (in mineral oil) to this reaction mixture.
65.5%) (13.2g) over 30 minutes, then
The mixture was stirred for 1 hour and 40 minutes under ice cooling. chloride in the reaction mixture
Add ammonium (47.2g) and stir for 20 minutes.
Add ice water (1) while stirring and leave to crystallize.
was precipitated. The crystals were filtered, washed with water, and kept at room temperature.
Dry overnight. Heating this crude crystal in chloroform
Dissolved. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure.
Precipitate the crystals and add the crystals to methanol (300ml).
The mixture was heated to dissolve and allowed to stand at room temperature. The precipitated crystals
Collected by filtration, washed with methanol, dried under reduced pressure and
Chil [(6-nitro-4-quinazolinylamino)
methylene] propanedioate (64.9g) in yellow
Obtained as crystals. mp: 228-230℃ IR (nujiol) νmax: 1715, 1640, 1618cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (3H, t, J = 7.0Hz), 1.46 (3H, t, J = 7.0Hz), 4.33
(2H, q, J=7.0Hz), 4.46 (2H, q, J=7.0Hz),
8.18 (1H, d, J = 9.0Hz), 8.7 (1H, dd, J =
2.0 and 9.0Hz), 8.98 (1H, d, J = 2.0Hz), 9.06
(1H, s), 9.3 (1H, s, J = 12.0Hz), 12.55 (1H, d, J = 12.0Hz) Example 23 4-Amino-6-chloroquinazoline (8.7g)
and diethyl ethoxymethylenepropanedioether
(11.53g) of N,N-dimethylphosate.
Stir in Lumamide (25ml) at 150℃ for 2 hours and 40 minutes.
did. After cooling the reaction mixture to room temperature, under stirring
Add water to precipitate crystals, and wash these crystals with water.
The residue was dried under reduced pressure and dissolved in ethyl acetate under heating. No
After filtering the solution, add hexane to the filtrate and cool to room temperature.
The mixture was left to stand to precipitate crystals. Filter out these crystals
and washed with a mixed solvent of ethyl acetate and hexane.
diethyl [(6-chloro-4-quinazolinyl
amino) methylene] propanedioate and ethyl
10-chloro-4-oxo-4H-pyrimide [1,
2-c] with quinazoline-3-carboxylate
Crystals of the mixture (13.48 g) were obtained. (a) Diethyl [(6-chloro-4-quinazolinyl
Amino)methylene]propanedioate NMRδppm (CDCl ₃ ): 1.3−1.6 (6H, m), 4,
2 -4.6 (4H, m), 7.7 - 8.2 (3H, m), 8.9
(1H, s), 9.26 (1H, d, J=11.0Hz), 12.16
(1H, broad d, J=11.0Hz) (b) Ethyl 10-chloro-4-oxo-4H-pi
limido[1,2-c]quinazoline-3-carbo
Xylate NMRδppm (CDCl ₃ ): 1.43 (3H, t, J = 7.0Hz), 4.40 (2H, q, J = 7.0Hz), 7.88 (2H, broad s), 8.70 (1H, m), 8.93
(1H, s), 9.54 (1H, s) Example 24 4-amino-7-chloroquinazoline (1.3g)
and diethyl ethoxymethylenepropanedioether
(1.72g) in N,N-dimethylform.
The mixture was stirred in Muamide (6 ml) at 150°C for 2 hours.
The reaction mixture was cooled to room temperature and poured into ice water.
Precipitate the crystals, collect the crystals by filtration, wash with water, and add ethanol.
Recrystallized from diethyl [(7-chloro-4-
quinazolinylamino)methylene] propanedioe
and ethyl 9-chloro-4-oxo-4H-
pyrimido[1,2-c]quinazoline-3-carbo
A mixture with xylate (1.65 g) was obtained. blend
silica gel-column chromatography (elution
Agent: benzene-hexane mixed solvent, 10:1)
Purified crystals were obtained. (a) Diethyl [(7-chloro-4-quinazolinyl
Amino)methylene]propanedioate NMRδppm (CDCl ₃ ): 1.42 (6H, m), 4.35 (4H, m), 7.56 (1H, dd, J = 2.0 and 8.0
Hz), 7.90 (1H, d, J = 8.0Hz), 7.97 (1H, broad
s), 8.90 (1H, s), 9.27 (1H, d, J = 12.0Hz), 12.26 (1H, d, J = 12.0Hz) (b) Ethyl 9-chloro-4-oxo-4H-pi
limido[1,2-c]quinazoline-3-carbo
Xylate NMRδppm (CDCl ₃ ): 1.43 (3H, t, J = 7.5Hz), 4.46 (2H, q, J = 7.5Hz), 7.72 (1H, dd, J = 2.0 and 9.0Hz), 8.02 (1H, d, J = 2Hz) , 8.80 (1H, d, J = 9.0Hz),
9.03 (1H, s), 9.66 (1H, s) Example 25 4-Aminoquinazoline (7.27g) and dimethylmethane
Toximethylene propanedioate (9.6g) and
A mixture of N,N-dimethylformamide (35
ml) at 15°C for 2 hours. Bring the reaction mixture to the chamber
Cool to room temperature, pour into ice water to precipitate crystals,
The crystals were collected by filtration, washed with water, dried at room temperature, and
Chil[(4-quinazolinylamino)methylene]propylene
Ropandioate and methyl 4-oxo-4H-
pyrimido[1,2-c]quinazoline-3-carbo
A mixture with xylate (13.3 g) was obtained. (a) Dimethyl [(4-quinazolinylamino)methy
] Propanedioate NMRδppm (CDCl ₃ ): 3.87 (6H, s), 7.5-8.2 (4H, m), 9.07 (1H, s), 9.37 (1H, d, J = 12.0Hz), 12.3 (1H, d, J = 12.0Hz) (b ) Methyl 4-oxo-4H-pyrimide [1,
2-c] Quinazoline-3-carboxylate NMRδppm (CDCl ₃ ): 4.03 (3H, s), 7.6- 8.12 (3H, m), 8.88 (1H, d, J = 8.0Hz),
9.10 (1H, s), 9.73 (1H, s) Example 26 Diethyl [(6-amino-4-quinazolinyl
mino)methylene] propanedioate (2.5 g),
Pyridine (1.2g) and dichloromethane (55ml)
The mixture was stirred under ice cooling. In this reaction mixture
Isobutyryl chloride (1.06g) was added dropwise. anti
The reaction mixture was stirred for 30 minutes under ice-cooling, then at room temperature.
Stir for 20 minutes. After adding ice water to the reaction mixture,
The mixture was stirred and extracted with chloroform. extraction
Insoluble matter was filtered off from the liquid. Wash the extract three times with water,
After washing with saturated aqueous sodium chloride solution,
It was dried over magnesium and concentrated under reduced pressure. Sift the residue
Lyca gel-column chromatography (eluent:
chloroform) and purified with chloroform.
Diethyl is recrystallized from a mixed solvent with hexane.
[(6-isobutyramide-4-quinazolinylamide
methylene] propanedioate (1.28g)
Obtained crystals. by substantially the same recrystallization method as described above.
Crystals (0.67 g) of the same compound were collected from the mother liquor.
Ta. mp: 190-193℃ IR (nujiol) νmax: 3530, 1775, 1710,
1700, 1678, 1660, 1615cm ^-1 NMRδppm (CDCl ₃ ): 1.2 − 1.5 (12H, m), 2.2 − 2.8 (1H, m), 4.25 (2H, quartet, J = 6
Hz), 4.39 (2H, quartet, J=6Hz), 7.4−8.2
(4H, m), 8.8 (1H, s), 9.15 (1H, d, J=12Hz),
12.06 (1H, d, J = 12Hz), Example 27 The following compound was prepared by substantially the same method as Example 26.
manufactured something. (1) Diethyl [(6-acetamido-4-quinazo
linylamino)methylene]propanedioate mp: 178-180℃ (recrystallized from a mixed solvent of tetrahydrofuran and hexane) IR (Nudiyol) νmax: 3380, 1695, 1660,
1630, 1610cm ^-1 NMRδppm (CDCl ₃ ): 1.32 (3H, t, J=6
Hz), 1.36 (3H, t, J=6Hz), 2.08 (3H, s),
4.3 (4H, quartet, J=6Hz), 7.7−8.1 (2H,
m), 8.44 (1H, s), 8.83 (1H, s), 9.28 (1H, s),
9.28 (1H, d, J = 12Hz), 11.98 (1H, d, J
= 12Hz) (2) Diethyl [(6-propionamide-4-ki
Nazolinylamino)methylene] propanedioe
mp: 190-193℃ (recrystallized from a mixed solvent of ethyl acetate and hexane) IR (nudylol) νmax: 3340, 1736, 1670,
1660, 1635, 1572cm ^-1 NMRδppm (CDCl ₃ ): 1.2-1.6 (9H, m), 2.50 (2H, quartet, J = 7.0Hz), 4.34 (2H, quartet, J = 7.0Hz), 4.40 (2H, quartet, J = 7.0Hz), 8.0 (2H , m), 8.40 (1H, broad s), 8.56 (1H, s), 8.90 (1H, s), 9.36 (1H, d, J = 12Hz), 12.1 (1H, d, J
=12Hz) (3) Diethyl [(6-butylamide-4-quinazo
linylamino)methylene]propanedioate mp: 187-190℃ (recrystallized from methanol) IR (Nudiol) νmax: 3380, 1748, 1680,
1625, 1580, 1554cm ^-1 NMRδppm (CDCl ₃ ): 0.98 (3H, t, J = 7.0Hz), 1.27 (3H, t, J = 6.8Hz), 1.33 (3H, t, J = 6.8Hz), 1.80 (2H, m),
2.43 (2H, t, J=7Hz), 4.33 (4H, m), 8.0 (2H,
m), 8.43 (1H, broad s), 8.90 (2H, s), 9.40 (1H, d, J = 12Hz), 12.1 (1H, d, J =
12Hz) (4) Diethyl [(6-hexaneamide-4-quina
zolinylamino)methylene] propanedioether
mp: 157-162℃ (recrystallized from a mixed solvent of chloroform, ethyl acetate and hexane) IR (nudyl) νmax: 1686, 1640, 1620,
1600, 1550cm ^-1 NMRδppm (CDCl ₃ ): 0.6-1.2 (3H, m), 1.2 -2.2 (12H, m), 2.80 (2H, broad t, J = 7.0Hz), 4.36 (4H, m), 7.83 (1H, d, J = 9.0Hz) ), 8.1−8.5 (2H, m), 8.76 (1H,
s), 9.16 (1H, d, J=12Hz), 10.2 (1H, s),
12.3 (1H, d, J=12Hz) (5) Diethyl [(6-ethoxysalamide-4-
quinazolinylamino)methylene] propanedio
Etate mp: 191-192℃ (recrystallized from a mixed solvent of chloroform, ethyl acetate and hexane) IR (nudylol) νmax: 3300, 1720, 1685,
1650, 1630, 1610cm ^-1 NMRδppm (CDCl ₃ ): 1.27-1.66 (9H, m), 4.17-4.66 (6H, m), 7.9-8.27 (2H, m),
8.50 (1H, broad s), 8.93 (1H, s), 9.33
(1H, d, J=12.0Hz), 9.43 (1H, s), 12.23 (1H,
d, J=12.0Hz) (6) Diethyl [(6-cyclohexanamide-4
-quinazolinylamino)methylene]propane
Oate mp: 202-208℃ (recrystallized from a mixed solvent of chloroform and methanol) IR (Nudyol) νmax: 3340, 1728, 1660,
1634, 1615, 1570cm ^-1 NMRδppm (CDCl ₃ ): 1.37 (6H, t, J=7.0Hz), 1.0-2.6 (11H, m), 4.37 (4H,
m) 7.8−8.2 (3H, m), 8.33 (1H, broad s),
8.90 (1H, s), 9.37 (1H, d, J=12.0Hz),
12.1 (1H, d, J = 12.0Hz) (7) Diethyl [(6-benzamide-4-quinazo
linylamino)methylene]propanedioate mp: 164-165℃ (recrystallized from a mixed solvent of chloroform and hexane) IR (Nudiol) νmax: 3400, 1715, 1710,
1660, 1640, 1610cm ^-1 NMRδppm (CDCl ₃ ): 1.33 (6H, t, J = 8.0Hz), 4.3 (2H, quartet, J = 8.0Hz) 4.33 (2H, quartet, J = 8.0Hz), 7.4-8.8
(7H, m), 8.46 (1H, s), 8.7 (1H, s), 8.90
(1H, s), 9.33 (1H, d, J=12.0Hz), 12.1
(1H, d, J=12Hz) (8) Dimethyl [(6-phenylacetamide-4
-quinazolinylamino)methylene]propane
Oate mp: 113-117℃ (recrystallized from a mixed solvent of ether and hexane) IR (Nujiol) νmax: 3600, 1748, 1710,
1690, 1660, 1632, 1620cm ^-1 NMRδppm (CDCl ₃ ): 1.33 (3H, t, J = 7.0Hz), 1.37 (3H, t, J = 7.0Hz), 3.80 (2H, s), 4.33 (4H, m), 7.33 (5H, S),
7.83 (2H, broad s), 8.43 (2H, broad s),
8.83 (1H, s), 9.33 (1H, d, J=12Hz), 12.0
(1H, d, J=12Hz) (9) Diethyl [(6-pivalamide-4-quinazo
linylamino)methylene]propanedioate mp: 141-142℃ (recrystallized from a mixed solvent of ether and ethyl acetate) IR (Nudiol) νmax: 3380, 1720, 1672,
1652, 1628, 1610cm ^-1 NMRδppm (CDCl ₃ ): 1.2-1.7 (15H, m), 4.2-4.7 (4H, m), 7.7-8.16 (3H, m), 8.33 (1H, s), 8.83 (1H, s), 9.33 (1H, d, J = 12Hz), 12.0 (1H, d, J = 12Hz) Example 28 Diethyl [(6-amino-4-quinazolinyl
mino)methylene]propanedioate (3.03g),
Pyridine (3.63g) and dichloromethane (93g)
ml) was cooled on ice, then acetic anhydride (1.88
g) was added. The reaction solution was stirred for 30 minutes under ice cooling, and then
The mixture was further stirred at room temperature for 2 hours and 15 minutes. Add ice water to the mixture
and the resulting mixture was extracted with chloroform.
Ta. The organic layer was washed three times with water and further washed with saturated sodium chloride.
Wash with thorium aqueous solution, then anhydrous magnesium sulfate.
dried in a humidifier. Residue obtained by concentration under reduced pressure
silica gel-column chromatography (solvent
Purify with chloroform,
Recrystallized from a mixed solvent of ethyl acetate and hexane
and diethyl [(6-acetamido-4-quina
Zolinylamino)methylene]propanedioate
(2.2 g) of crystals were obtained. N, M, R, δppm (CDCl ₃ ): 1.32 (3H, t, J=
6Hz), 1.36 (3H, t, J=6Hz), 2.08 (3H, s), 4.3
(4H, quartet, J=6Hz), 7.7-8.1 (2H, m), 8.44
(1H, s), 8.83 (1H, s), 9.28 (1H, s), 9.28 (1H,
d, J = 12Hz), 11.98 (1H, d, J = 12Hz) Example 29 Diethyl [(6-nitro-4-quinazolinyl
Mino)methylene]propanedioate (10.8g)
was suspended in N,N-dimethylformamide (380 ml).
Cloudy 10% palladium on carbon in a stream of hydrogen at room temperature.
(3.6g) as a catalyst and the amount of hydrogen absorbed reaches 2030ml.
Stir until mixed. Filter off the catalyst and add a small amount of N,N
- Washed with dimethylformamide. Filtrate and washing liquid
Add pyridine (17ml) to this and mix.
The mixture was cooled in an ice bath. Chloryl pivalate in solution
After adding dropwise (6.33 g) over 20 minutes, the reaction solution
The mixture was stirred at room temperature for 2 hours and 40 minutes. Add this solution under stirring.
Ice water was added and the mixture was concentrated under reduced pressure. Chlorophor in the residue
and saturated aqueous sodium bicarbonate solution.
Washed with water. Filter out insoluble matter from the chloroform layer
did. The filtrate was washed with saturated aqueous sodium chloride solution.
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. mosquito
The resulting oil was chromatographed on silica gel.
Roughy (eluent: dichloromethane)
One fraction A and a second fraction B were obtained. Concentrate fraction A under reduced pressure.
By condensation, diethyl [(6-pivalami
do-4-quinazolinylamino)methylene]propa
Crystals of undioate (4.6 g) were obtained. this purpose
The NMR spectrum of the compound is the same as that of Example 27(9).
Agreed. Example 30 Diethyl [(4-quinazolinylamino)methylene
] Propanedioate (16.0g) was preheated to 250℃.
Add damply heated diphenyl ether (70ml).
Ta. The reaction mixture was heated to 250-260 °C for 20 min.
After that, it was cooled to room temperature. Add hexane to this mixture.
The mixture was stirred to precipitate crystals. Take this crystal
Washed with sun and dried. The crude crystals were dissolved in ethyl acetate.
The mixture was heated and dissolved in a glass bottle. After filtering out insoluble matter, the filtrate is
It was concentrated under reduced pressure to a volume of 200ml. Add to concentrate
Add San and leave it at room temperature to precipitate crystals.
Filter the crystals and add a mixed solvent of ethyl acetate and hexane.
Wash with ethyl 4-oxo-4H-pi
limido[1,2-c]quinazoline-3-carboxy
Crystals of sylate (12.4 g) were obtained. mp: 171-172℃ IR (nujiol) νmax: 1725, 1702, 1620cm ^-1 NMRδppm (CDCl ₃ ): 1.43 (3H, t, J = 7.0
Hz), 4.40 (2H, quartet, J=7.0Hz), 7.6−8.2
(3H, m), 8.84 (1H, broad d, J=7.0Hz), 9.03
(1H, s,), 9.66 (1H, s) Example 31 The following compound was prepared in substantially the same manner as in Example 30.
Manufactured. (1) Methyl 4-oxo-4H-pyrimide [1,
2-c] Quinazoline-3-carboxylate mp: 203-205°C (recrystallized from chloroform) NMRδppm (CDCl ₃ ): 4.03 (3H, s), 7.6- 8.12 (3H, m), 8.88 (1H, d, J = 8.0Hz),
9.10 (1H, s), 9.73 (1H, s) (2) Ethyl 4-oxo-10-chloro-4H-pi
limido[1,2-c]quinazoline-3-carbo
Xylate mp: 161-163℃ (recrystallized from a mixed solvent of chloroform and hexane) IR (Nujiol) νmax: 1752, 1700, 1621, 1584cm ^-1 NMRδppm (CDCl ₃ ): 1.43 (3H, t, J = 7.0Hz), 4.40 (2H, quartet, J = 7.0
Hz), 7.88 (2H, broad s), 8.70 (1H, m), 8.93 (1H, s), 9.54 (1H, s) (3) Ethyl 4-oxo-9-chloro-4H-py
limido[1,2-c]quinazoline-3-carbo
Xylate mp: 192.5-193.5℃ (recrystallized from a mixed solvent of diphenyl ether and hexane) IR (nudyl) νmax: 1755, 1710, 1610,
1603, 1580cm ^-1 NMRδppm (CDCl ₃ ): 1.43 (3H, t, J = 7.5Hz), 4.46 (2H, quartet, J = 7.5
Hz), 7.72 (1H, dd, J = 2.0 and 9.0Hz), 8.02 (1H, d, J = 2Hz), 8.80 (1H, d, J =
9.0Hz), 9.03 (1H, s), 9.66 (1H, s) (4) Ethyl 4-oxo-10-methyl-4H-pi
limido[1,2-c]quinazoline-3-carbo
Xylate mp: 182-183℃ (recrystallized from a mixed solvent of chloroform, ethyl acetate, and hexane) IR (Nudiyol) νmax: 1752, 1690, 1614 cm ^-1 NMRδppm (CDCl ₃ ): 1.42 (3H, t, J = 7.8Hz), 2.56 (3H, s), 4.40 (2H, quartet, J = 7.8Hz), 7.76 (2H, m), 8.56 (1H, broad s), 8.92 ( 1H, s), 9.50
(1H,s) (5) Ethyl 4-oxo-10-nitro-4H-pi
limido[1,2-c]quinazoline-3-carbo
Xylate mp: 171-174℃ (recrystallized from a mixed solvent of chloroform and hexane) IR (Nujiol) νmax: 1720, 1700, 1625, 1585cm ^-1 NMRδppm (CDCl ₃ ): 1.43 (3H, t, J = 6.0Hz), 4.36 (2H, quartet, J = 6.0
Hz), 8.16 (1H, d, J = 9.0Hz), 8.73 (1H, dd, J = 3.0 and 9.0Hz), 9.03 (1H, s), 9.66 (1H, d, J = 3.0Hz), 9.73 ( 1H,s) (6) Ethyl 4-oxo-10-phenoxy-4H
-pyrimido[1,2-c]quinazoline-3-ka
Ruboxylate mp: 210-213℃ (recrystallized from a mixed solvent of chloroform, ethyl acetate and hexane) IR (nudylol) νmax: 1750, 1680, 1618, 1593cm ^-1 NMRδppm (CDCl ₃ ): 1.43 (3H, t, J = 7.0Hz), 4.43 (2H, d, J = 7Hz), 7.0
−8.4 (7H, m), 8.0 (1H, d, J=8.0Hz), 9.0
(1H, s), 9.63 (1H, s) (7) Ethyl 4-oxo-10-(dimethylamino)
-4H-pyrimido[1,2-c]quinazoline-
3-carboxylate mp: 240-242℃ (recrystallized from tetrahydrofuran) IR (Nudiyol) νmax: 1745, 1685, 1612, 1595cm ^-1 NMRδppm (CDCl ₃ ): 1.44 (3H, t, J = 7.5Hz), 3.16 (6H, s), 4.4 (2H, quartet, J = 7.5Hz), 7.3-7.5 (2H, m),
7.80 (1H, m), 8.98 (1H, s), 9.44 (1H, s) (8) Ethyl 4-oxo-10-ethylthio-4H
-pyrimido[1,2-c]quinazoline-3-ka
Ruboxylate mp: 168-170℃ (recrystallized from a mixed solvent of chloroform and hexane) IR (Nujiol) νmax: 1750, 1695, 1610, 1495cm ^-1 NMRδppm (CDCl ₃ ): 1.45 (6H, t, J = 8.0Hz), 3.16 (2H, quartet, J = 8.0
Hz), 4.47 (2H, quartet, J=8.0Hz), 7.8−8.0
(2H, m), 8.6 (1H, m), 9.03 (1H, s), 9.60 (1H, s) (9) Ethyl 4-oxo-9-methoxy-4H-
pyrimido[1,2-c]quinazoline-3-cal
Boxylate mp: 202-206℃ (recrystallized from a mixed solvent of chloroform and hexane) IR (Nujiol) νmax: 1740, 1680, 1615, 1585cm ^-1 NMRδppm (CDCl ₃ ): 1.43 (3H, t, J = 7.0Hz), 4.40 (3H, s), 4.43 (2H, quartet, J = 7.0Hz), 7.40 (2H, m), 8.77 (1H, d, J = 10.0Hz ), 9.00 (1H, s),
9.67 (1H,s) (10) Ethyl 4-oxo-10-acetamido-
4H-pyrimido[1,2-c]quinazoline-3
-Carboxylate mp: 294-295℃ (N,N-dimethylformamide
(recrystallized from de) IR (nujiol) νmax: 3360, 1740, 1720,
1675, 1615cm ^-1 NMRδppm (DMSO−d ₆ ): 1.3 (3H, t, J=6.0Hz), 2.1 (3H, s), 4.30 (2H,
quartet, J=6.0Hz), 7.83 (1H, d, J=9.0Hz), 8.1
(1H, dd, J = 2.0 and 9.0Hz), 8.87 (1H, s), 9.03 (1H, d, J = 2.0Hz), 9.36 (1H, s),
10.46 (1H,s) (11) Ethyl 4-oxo-9-acetamide-
4H-pyrimido[1,2-c]quinazoline-3
-Carboxylate mp: 281-285°C (recrystallized from a mixture of N,N-dimethylformamide and water) IR (Nudiyol) νmax: 3560, 3400, 1742,
1616, 1588cm ^-1 (12) Ethyl 4-oxo-10-propionamide
-4H-pyrimido[1,2-c]quinazoline-
3-carboxylate mp: 274-276°C (recrystallized from a mixed solvent of chloroform and methanol) IR (Nudyol) νmax: 3360, 1740, 1720,
1670, 1618cm ^-1 NMRδppm (DMSO−d ₆ ): 1.13 (3H, t, J = 7.0Hz), 1.30 (3H, t, J = 7.0Hz), 2.43 (2H, quartet, J = 7.0Hz), 4.30 (2H,
quartet, J=7. 0Hz) 7.90 (1H, d, J=10.0
Hz), 8.16 (1H, dd, J=2.0 and 10.0Hz), 8.90
(1H, s), 9.10 (1H, d, J = 2.0Hz), 9.40 (1H,
s), 10.43(1H,s) (13) Ethyl 4-oxo-10-butylamide-
4H-pyrimido[1,2-c]quinazoline-3
-Carboxylate mp: 278-282℃ (recrystallized from a mixed solvent of chloroform and methanol) IR (Nujiol) νmax: 3410, 1745, 1712,
1680, 1615cm ^-1 NMRδppm (CDCI ₃ ): 1.30 (3H, t, J = 7.0Hz), 1.43 (3H, t, J = 7.0Hz), 1.76 (2H, m), 2.46 (2H, t, J = 7.0Hz),
4.46 (2H, quartet, J = 7.0Hz) 8.0 (1H, d, J
= 9.0Hz), 8.43 (1H, dd, J = 2.0 and 9.0Hz), 8.97 (1H, d, J = 2.0Hz), 9.05 (1H, s),
9.63 (1H,s) (14) Ethyl 4-oxo-10-isobutylamide
Do-4H-pyrimido[1,2-c]quinazoline
-3-carboxylate mp: 245-247℃ (recrystallized from a mixed solvent of chloroform and hexane) IR (nudylol) νmax: 3400, 1730, 1710,
1690, 1625, 1410cm ^-1 NMR. δppm (DMSO−d ₆ ): 1.2−1.8 (9H,
m), 2.3-2.9 (1H, m), 4.46 (2H, quartet, J=7.0Hz), 7.8-8.1 (2H, m), 8.43 (1H,
dd, J=2 and 10Hz), 8.92 (1H, d, J=2
Hz), 9.05 (1H, s), 9.63 (1H, s) (15) Ethyl 4-oxo-10-hexanamide
-4H-pyrimido[1,2-c]quinazoline-
3-carboxylate mp: 231-234°C (recrystallized from a mixed solvent of chloroform and methanol) IR (Nudiyol) νmax: 3400, 3100, 1745,
1720, 1680, 1610cm ^-1 NMRδppm (DMSO _Four −d ₆ ): 0.6−2.0 (10H,
m), 2.1-2.6 (4H, m), 4.30 (2H, quartet, J = 7.0Hz), 7.9 (1H, d, J = 9.0Hz), 8.16
(1H, dd, J = 2.0 and 9.0Hz), 8.90 (1H, s), 10.55 (1H, s) (16) Ethyl 4-oxo-10-ethoxalami
Do-4H-pyrimido[1,2-c]quinazoline
-3-carboxylate mp: 263-264℃ (recrystallized from a mixed solvent of chloroform and methanol) IR (nudylol) νmax: 3400, 1745, 1725, 1610cm ^-1 NMRδppm (DMSO−d ₆ ): 1.26 (3H, t, J = 6Hz), 1.30 (3H, t, J = 6Hz), 4.3
(2H, quartet, J=6Hz), 4.36 (2H, quartet, J=6Hz) 7.96 (1H, d, J=9.0Hz), 8.33
(1H, dd, J=2 and 9Hz), 8.9 (1H, s),
9.27 (1H, d, J=2Hz), 9.43 (1H, s), 11.4
(1H,s) (17) Ethyl 4-oxo-10-cyclohexane
Carboxamide-4H-pyrimide [1,2-c]
Quinazoline-3-carboxylate mp: 262-266°C (recrystallized from a mixed solvent of chloroform and hexane) IR (Nujiol) νmax: 3400, 3100, 1730,
1692, 1672, 1612cm ^-1 NMRδppm (CDCI ₃ ): 1.40 (3H, t, J = 7.0Hz), 1.0-2.6 (11H, m), 4.46 (2H, quartet, J = 7.0Hz) 7.90 (1H, s),
8.0 (1H, d, J = 9.0Hz), 8.43 (1H, dd, J = 3.0 and
and 9.0Hz), 8.93 (1H, d, J = 3.0Hz), 9.1 (1H, s), 9.66 (1H, s) (18) Ethyl 4-oxo-10-benzamide-
4H-pyrimido[1,2-c]quinazoline-3
-Carboxylate mp: 237-239℃ (recrystallized from a mixed solvent of chloroform and methanol) IR (Nujiol) νmax: 3400, 1730, 1680, 1620cm ^-1 NMRδppm (DMSO−d ₆ ): 1.40 (3H, t, J = 7.0Hz), 4.40 (2H, quartet, J = 7.0
Hz), 7.5-8.3 (6H, m), 8.55 (1H, dd, J = 2.0 and 10.0Hz), 9.0 (1H, s), 9.40 (1H,
d, J=2.0Hz), 9.53 (1H, s), 10.86 (1H, s) (19) Ethyl 4-oxo-10-phenylaceto
Amido-4H-pyrimido[1,2-c]quinazo
Phosphorus-3-carboxylate mp: 230-235°C (recrystallized from a mixed solvent of methanol and chloroform) IR (Nujiol) νmax: 3370, 1735, 1720,
1670, 1618cm ^-1 NMRδppm (DMSO−d ₆ ): 1.3 (3H, t, J = 7.0Hz), 3.75 (2H, s), 4.33 (2H, quartet, J = 7.0Hz), 7.33 (5H, s), 7.8-
8.3 (2H, m), 8.90 (1H, s), 9.12 (1H, dd,
J=2Hz), 9.40 (1H, s), 10.76 (1H, s) (20) Ethyl 4-oxo-10-ethyl-4H-
pyrimido[1,2-c]quinazoline-3-cal
Boxylate mp: 168-170℃ (recrystallized from a mixed solvent of ethyl acetate and hexane) IR (Nujiol) νmax: 1720, 1700, 1620, 1500cm ^-1 NMRδppm (CDCI ₃ ): 1.4 (3H, t, J = 8.0
Hz), 1.46 (3H, t, J=8.0Hz), 2.95 (2H,
(21) ) Ethyl 4-oxo-10-butyl-4H-
pyrimido[1,2-c]quinazoline-3-cal
Boxylate mp: 151-154℃ (recrystallized from a mixed solvent of ethyl acetate and hexane) IR (Nujiol) νmax: 1720, 1690, 1610, 800cm ^-1 NMRδppm (CCl _Four ): 0.8-2.1 (10H, m), 2.9 (2H, t, J=8.0Hz), 4.43 (2H,
quartet, J=7.0Hz), 7.7-8.0 (2H, m), 8.63 (1H,
s), 8.9 (1H, s), 9.53 (1H, s) (22) Ethyl 4-oxo-8-methyl-4H-
pyrimido[1,2-c]quinazoline-3-cal
Boxylate mp: 166-172℃ (recrystallized from a mixed solvent of chloroform, ethyl acetate, and hexane) IR (Nudyol) νmax: 1750, 1692, 1622, 1600cm ^-1 NMRδppm (CDCl ₃ ): 1.46 (3H, t, J = 7.0Hz), 2.73 (3H, s), 4.46 (2H, quartet, J = 7.0Hz), 7.4-7.9 (2H, m),
8.60 (1H, broad d, J=8.0Hz) 8.93 (1H,
s), 9.56 (1H, s) (23) Ethyl 4-oxo-10-bropyl-4H
-pyrimido[1,2-c]quinazoline-3-ka
Ruboxylate mp: 161-163℃ (recrystallized from benzene) IR (Nudiyol) νmax: 1700, 1620, 1610,,
1500 1150cm ^-1 NMRδppm (CDCl ₃ ): 1.0 (3H, t, J = 7.0
Hz), 1.3-2.2 (5H, m), 2.9 (2H, t, J = 7.0
Hz), 4.43 (2H, quartet, J=7.0Hz), 7.8−8.1
(2H, m), 8.63 (1H, s), 9.0 (1H, s), 9.6 (1H,
s) (24) Ethyl 4-oxo-9-methyl-4H-
pyrimido[1,2-c]quinazoline-3-cal
Boxylate mp: 186-188℃ (recrystallized from tetrahydrofuran) IR (Nudiyol) νmax: 1705, 1680, 1300, 800cm ^-1 NMRδppm (CDCl ₃ ): 1.4 (3H, t, J = 8.0
Hz), 2.6 (3H, s), 4.33 (2H, quartet, J=8.0
Hz), 7.56 (1H, d, J = 8.0Hz), 7.76 (1H, s),
8.7 (1H, d, J=8.0Hz), 9.0 (1H, s), 9.63
(1H,s) (25) Ethyl 4-oxo-10-(4-methylpi
perazinyl)-4H-pyrimido[1,2-c]
Nazoline-3-carboxylate mp: 203-206°C (recrystallized from a mixed solvent of ethanol and chloroform) IR (Nujiol) νmax: 1740, 1680, 1608 cm ^-1 NMRδppm (CDCl ₃ ): 1.43 (3H, t, J = 7.0Hz), 2.36 (3H, s), 2.60 (4H, m), 3.46 (4H, m), 4.43 (2H, quartet, J = 7.0
Hz), 7.50 (1H, dd, J = 3.0 and 8.5Hz), 7.80 (1H, d, J = 8.5Hz), 8.03 (1H, d, J =
3.0Hz), 8.96 (1H, s), 9.46 (1H, s) (26) Ethyl 4-oxo-9,10-dimethoxy
-4H-pyrimido[1,2-c]quinazoline-
3-carboxylate mp: 262-264℃ (recrystallized from chloroform) IR (Nudiyol) νmax: 1705, 1675, 1595cm ^-1 NMRδppm (CDCl ₃ ): 1.43 (3H, t, J = 7.0Hz), 4.13 (6H, s), 4.46 (2H, quartet, J = 7.0Hz), 7.40 (1H, s) 8.16 (1H, s), 9.05 (1H, s), 9.67 (1H, s) (27) Ethyl 4-oxo-10-pivalamide-
4H-pyrimido[1,2-c]quinazoline-3
-Carboxylate mp: 247-250℃ (recrystallized from a mixed solvent of chloroform and methanol) IR (Nujiol) νmax: 3370, 1712, 1672, 1610cm ^-1 NMRδppm (CDCl ₃ ): 1.45 (3H, t, J = 7.0Hz), 1.37 (9H, s), 4.46 (2H, quartet, J = 7.0Hz), 7.96 (1H, d, J =
9.5Hz), 8.41 (1H, dd, J=3 and 9.5Hz), 9.13 (2H, broad s), 9.63 (1H, s), 12.1
(1H,s) (28) Ethyl 4-oxo-6-hydroxy-
4H-pyrimido[1,2-c]quinazoline-3
-Carboxylate mp: >270°C (recrystallized from a mixed solvent of chloroform and methanol) IR (Nudiyol) νmax: 1770, 1742, 1705,
1638, 1615, 1602cm ^-1 NMRδppm (DMSO−d ₆ ): 1.32 (3H, t, J = 6.0Hz), 4.30 (2H, quartet, J = 6.0
Hz), 7.2-7.6 (2H, m), 7.74 (1H, t, J = 8.0
Hz), 8.26 (1H, d, J = 8.0Hz), 8.92 (1H,
s), 12.5 (1H, broad s) (29) Ethyl 4-oxo-6-methyl-4H-
pyrimido[1,2-c]quinazoline-3-cal
Boxylate mp: 167-168℃ (recrystallized from benzene) IR (Nudiyol) νmax: 1735, 1700, 1615, 1590cm ^-1 NMRδppm (CDCl ₃ ): 1.43 (3H, t, J = 7.0Hz), 3.20 (3H, s), 4.47 (2H, quartet, J = 7.0Hz), 7.6-8.0 (3H, m),
8.73 −8.93 (1H, m), 8.93 (1H, s) (30) Ethyl 4-oxo-6-hydroxy-10
-ethyl-4H-pyrimido[1,2-c]quina
Zolin-3-carboxylate mp: 315-318°C (recrystallized from a mixed solvent of chloroform and methanol) IR (Nudiyol) νmax: 1748, 1630, 1595 cm ^-1 Example 32 Diethyl [(2-allyloxy-4-quinazoli
nylamino)methylene]propanedioate
(6.0g) was added to diphenyl ether (14ml).
The mixture was stirred at 260 °C for 15 min, then allowed to reach room temperature.
Cooled. Add hexane to this mixture to precipitate
This precipitate was collected by filtration and washed with hexane.
Crude crystals were obtained. Coat the crude crystals with a silica gel column.
Attached to chromatography (eluent: chloroform)
A first fraction A and a second fraction B were obtained. Fraction A
The crystals precipitated by concentration under reduced pressure were mixed with chloroform,
Recrystallized from a mixed solvent of ethyl acetate and hexane
and ethyl 4-oxo-6-allyloxy-
4H-pyrimido[1,2-c]quinazoline-3-
Crystals of carboxylate (1.8 g) were obtained. mp: 191−195℃ IR (nujiol) νmax: 1775, 1725, 1690, 1608cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (3H, t, J = 7.0Hz), 4.43 (2H, quartet, J = 7.0
Hz), 4.90 (2H, m), 5.40 (2H, m), 6.0 (1H, m),
7.30 (2H, m), 7.80 (1H, t, J=7.0Hz),
8.56 (1H, d, J = 7.0Hz), 8.66 (1H, s) On the other hand, the crystals precipitated by concentrating fraction B under reduced pressure are
Recrystallized from a mixed solvent of ethyl acetate and hexane.
ethyl 4,6-dioxo-7-allyl-4H
-6,7-dihydropyrimide[1,2-c]quina
Crystals of zolin-3-carboxylate (1.5g)
I got it. mp: 163−166℃ IR (nujiol) νmax: 1740, 1710, 1682,
1645, 1615, 1600cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (3H, t, J = 7.0Hz), 4.40 (2H, quartet, J = 7.0
Hz), 4.88 (2H, m), 5.24 (2H, m), 6.92 (1H, m),
7.34 (2H, m), 7.74 (1H, t, J=8.0Hz),
8.60 (1H, d, J = 7.0Hz), 9.14 (1H, s) Example 33 Diethyl [(2-methoxy-4-quinazolini
methylene] propanedioate (8.0
g) in diphenyl ether (30ml).
The mixture was stirred at 260°C for 32 minutes. Bring the reaction mixture to room temperature
Let stand overnight to precipitate crystals, collect by filtration and add hexane
Crude crystals A were obtained. In addition, a large amount is added to the filtrate.
of hexane was added and left at room temperature overnight to precipitate.
The crystals were recovered from a mixed solvent of ethyl acetate and hexane.
Crude crystals B and mother liquor A were obtained by crystallization. Crude crystal A
Combine B and silica gel column chromatography.
Fiery (eluent; ethyl acetate: chloroform =
1:9). Obtained by concentrating one fraction under reduced pressure.
The crystals were collected in a mixed solvent of chloroform and hexane.
was recrystallized to give ethyl 4,6-dioxo-7-methane.
Chil-4H,6H,-6,7-dihydropyrimide
[1,2-c]quinazoline-3-carboxylate
(0.7 g) of crystals were obtained. mp: 265-271℃ IR (nujiol) νmax: 1732, 1642, 1610cm ^-1 NMRδppm (CDCl ₃ ):． 40 (3H, t, J=7.8Hz), 3.80 (3H, s), 4.45 (2H,
quartet, J=7.8Hz), 7.30-8.00 (3H, m), 8.73 (1H,
d, J = 8.0Hz), 9.22 (1H, s) Further, mother liquor A was concentrated under reduced pressure and poured into a silica gel column.
Mucochromatography (eluent: chloroform)
It was attached to. Concentrate the eluate under reduced pressure and collect the resulting crystals.
Recrystallization from a mixed solvent of chloroform and hexane
and ethyl 4-oxo-6-methoxy-4H
-pyrimido[1,2-c]quinazoline-3-cal
Crystals of boxylate (0.45 g) were obtained. mp: 180-183℃ IR (nujiol) νmax: 1765, 1708, 1625,
1610, 1590cm ^-1 NMR. δppm (CDCl ₃ ): 1.46 (3H, t, J=7.0Hz), 4.33 (3H, s), 4.46 (2H,
quartet, J=7.0Hz), 7.3-8.0 (3H, m), 8.70 (1H,
d, J=7.0Hz), 8.86 (1H, s) Example 34 Tetraethyl 2,2'-[2,4-quinazoline
Diylbis (iminomethylidine)] Bispropane
Geoate (2.2g) was dissolved in diphenyl ether (11
ml) was stirred at 260 °C for 35 min, then
The mixture was cooled to room temperature. Add hexane to the reaction mixture
In addition, crystals are precipitated, collected by filtration, and dried to obtain crude crystals.
(1.3g) was obtained. Re-crystallize these crystals from ethanol.
Crystallize diethyl 4,9-dioxo-4H,9H
-pyrimido[1,2-c]pyrimide[1,2-
a] Quinazoline-3.8-carboxylate (0.9
g) was obtained. mp: 193-195℃ IR (nujiol) νmax: 1760, 1720, 1680,
1640, 1600cm ^-1 NMRδppm (CDCl ₃ ): 1.43 (6H, t, J = 8.0Hz), 4.40 (4H, quartet, J = 8.0
Hz), 7.5 - 8.0 (2H, m), 8.67 (1H, s), 8.67 - 9.16
(2H, m), 9.73 (1H, s) Example 35 2,2-dimethyl-5-[(4-quinazolinyl)
Amino]methylene-1,3-dioxane-4,6
-dione (3.5g) in diphenyl ether (15ml)
The mixture was stirred at 250-260℃ for 10 minutes, then
The mixture was cooled to room temperature. Add hexane to the reaction mixture
Add it, leave it at room temperature, collect the precipitated crystals by filtration, and store it in a container.
Crude crystals (3 g) were obtained by washing with xane. coarse crystal
silica gel-column chromatography (elution
agent; ethyl acetate:hexane=3:7).
The eluate was concentrated under reduced pressure and the precipitated crystals were dissolved in chloroform.
4H-
Pyrimido[1,2-c]quinazolin-4-one
(1.6g) was obtained. mp: 181-183℃ IR (nujiol) νmax: 1700, 1625, 1610, 1582cm ^-1 NMRδppm (CDCl ₃ ): 6.57 (1H, d, J = 7.0
Hz), 7.86 (3H, m), 8.27 (1H, d, J = 7.0Hz),
8.76 (1H, broad d, J=8.0Hz), 9.53 (1H,
s) Example 36 Methyl 4-oxo-4H-pyrimide [1,2
-c] Quinazoline-3-carboxylate (6.3
g) and lithium iodide (15.8g).
Add to N,N-dimethylformamide (100ml)
Stir at 150°C for 2.5 hours, then cool to room temperature.
Rejected. Add water to the reaction mixture and collect by filtration.
(600 ml), dried and 4-oxo-
4H-pyrimido[1,2-c]quinazoline-3-
Crystals of carboxylic acid (0.9 g) were obtained. mp:＞270℃ IR (nujiol) νmax: 1720, 1620cm ^-1 NMRδppm (CF ₃ COOH): 8.10−8.66 (3H,
m), 8.9-9.2 (1H, m), 9.53 (1H, s), 10.16
(1H,s) Example 37 4-amino-6-(3,3-dimethylbutyla
quinazoline (8.5g), dimethyl methoxy
Methylene propanedioate (12.75g) and
Mixture of N,N-dimethylformamide (34g)
The mixture was stirred at 100°C for 1 hour. After cooling to room temperature,
Add water to the mixture and collect the resulting precipitate by filtration and wash with water.
dimethyl [{6-(3,3-dimethyl)
(Tylbutyramide)-4-quinazolinylamino}
Crystals of methylene]propanedioate (10.9g)
I got it. mp: 196-198℃ IR (nujiol) νmax: 3540, 3350, 3250,
1705, 1680, 1660, 1650 1610cm ^-1 NMRδppm (CDCl ₃ ): 1.10 (9H, s), 2.3 (2H, s), 4.83 (3H, s), 4.9 (3H, s), 7.93
(2H, s), 8.3 (2H, m), 8.8 (1H, s), 9.3 (1H, d, J = 12.0Hz), 11.9 (1H, d, J = 12.0Hz) Example 38 4-Amino- 6-(3,3-dimethylbutylacetate)
quinazoline (12.2g), diethyl ethoxylate
Simethylene propanedioate (15.3g) and
Mixture of N,N-dimethylformamide (50ml)
The mixture was stirred at 150°C for 2 hours. The reaction mixture was kept at room temperature or
After cooling with water and adding water, extract with chloroform.
Ta. The chloroform layer was washed twice with water, and saturated sodium chloride was added.
After washing once with an aqueous solution of aluminum, anhydrous sulfuric acid
The residue was dried with sodium hydroxide and concentrated under reduced pressure, and the residue was added with ethyl acetate.
Added ru. Filter the insoluble matter, dry it, and check the melting point.
Ethyl 4-oxo-10-(3,3
-dimethylbutyramide)-4H-pyrimide [1,
2-c] Quinazoline-3-carboxylate
(4.7g) was obtained. The residue obtained by further concentrating the filtrate under reduced pressure
reconsolidate the substance from a mixed solvent of ethyl acetate and hexane.
crystallizes, diethyl [{6-(3,3-dimethylbutylene)
tylamido)-4-quinazolinylamino}methylene
]Propanedioate (10.1g) crystals were obtained.
Ta. mp: 133-135℃ IR (nujiol) νmax: 3350, 1695, 1640,
1625, 1610cm ^-1 NMRδppm (CDCl ₃ ): 1.15 (9H, s), 1.38 (3H, t, J = 6.0Hz), 1.40 (3H, t, J =
6.0Hz), 2.35 (2H, s), 4.33 (2H, q, J=6.0Hz),
4.43 (2H, q, J=6.0Hz), 7.80 (1H, s), 7.9−8.1 (2H,
m), 8.20 (1H, s), 8.86 (1H, s), 9.33 (1H,
d, J=12.0Hz), 12.0 (1H, d, J=12.0Hz) Elemental analysis C _{twenty two} H ₂₈ N _Four O _Five Calculated value as: C 61.66 ; H 6.54 ; N 13.08 Experimental value: C 61.51 ; H 6.49 ; N 13.19 Example 39 4-Amino-6-pivalamide quinazoline
(2.44g), dimethyl methoxymethylenepropane
dioate (2.61 g) and N,N-dimethylphosate
Stir the mixture of Lumamide (10ml) at 100℃ for 1 hour.
Stirred. After cooling to room temperature, add water to the mixture
Ta. Stir the mixture to precipitate crystals, collect by filtration, and sieve.
Lyca gel-column chromatography (eluent: vinegar
Purified by ethyl acid:chloroform=1:2)
Crystals (3.48 g) were obtained. Chlorophore
Dissolve the liquid in the filtrate, add activated charcoal, filter, and reduce the filtrate.
The crystals obtained by pressure concentration were recrystallized from ethyl acetate.
Dimethyl [(6-pivalamide-4-quinazoli
nylamino)methylene]propanedioate
(2.3 g) of crystals were obtained. mp: 189-190℃ IR (nujiol) νmax: 3400, 3350, 1750,
1690, 1630, 1615cm ^-1 NMRδppm (CDCl ₃ ): 1.4 (9H, s), 3.8 (3H, s), 3.93 (3H, s), 7.85 (1H, s), 8.00
(2H, m), 8.45 (1H, s), 8.9 (1H, s), 9.4 (1H,
d, J=12.0Hz) Elemental analysis C ₁₉ H _{twenty two} N _Four O _Five Calculated value as: C 59.06 ; H 5.74 ; N 14.50 Experimental value: C 58.99 ; H 5.53 ; N 14.21 Example 40 4-Amino-6-methanesulfonamide quinazo
Phosphorus (2.0g), diethyl ethoxymethylenepro
Pandioate (3.15g) and N,N-dimethy
A mixture of formamide (16 ml) was heated to 140°C for 1 hour.
Stir for half an hour. The reaction mixture was diluted with diethyl ethoxymethane.
Added tyrene propanedioate (1.57g).
The reaction mixture was stirred for 1 hour and then cooled to room temperature.
Ta. Add water to this mixture to precipitate crystals, and filter
and diluted with a mixed solvent of chloroform and methanol.
Dissolved. Dry this solution with anhydrous magnesium acetate.
Add chloroform to the dried and concentrated residue under reduced pressure.
Ta. Heat the mixture, filter out the insoluble matter, and reduce the melting point to 310.
Ethyl 4-oxo-10-methanesulfate at ~312°C
Honamide-4H-pyrimido[1,2-c]quina
Zolin-3-carboxylate (0.12g) was obtained.
Ta. Further, the filtrate was concentrated under reduced pressure and left at room temperature for analysis.
The crystals (1.63g) were mixed with silica gel (60g).
Lamb chromatography (eluent: 3% methanol)
(chloroform solution). Obtained
Dissolve the crystals in 10% methanol-chloroform solution.
I understand. The solution was treated with activated carbon and concentrated under reduced pressure.
The residue was recrystallized from chloroform and diethyl
[(6-methanesulfonamide-4-quinazoni
methylene] propanedioate (1.45
Crystals of g) were obtained. mp: 200-202℃ IR (nujiol) νmax: 3500, 3210, 1720,
1690, 1675, 1640, 1625, 1600cm ^-1 NMRδ.ppm (DMSO−d ₆ ): 1.3 (3H, t, J=
7.0Hz), 1.35 (2H, t, J=7.0Hz), 3.16 (3H, s),
4.25 (2H, q, J=7.0Hz), 4.38 (2H, q, J=
7.0Hz), 7.8 -8.1 (3H, m), 8.9 (1H, s), 9.2 (1H, d, J = 12.0Hz), 10.53 (1H, s), 11.55 (1H,
d, J=12.0Hz) Example 41 4-amino-6-methanesulfonamide quinazo
Phosphorus (6.89g), diethyl ethoxymethylenep
Ropandioate (15.5g) and N,N-dimethane
A mixture of chloroformamide (55 ml) was heated at 155 °C for 2.5 min.
Stir for hours. Cool the reaction mixture to room temperature and add water
was added to form a precipitate, which was collected by filtration and washed with water. meta
Mixed solvent of alcohol and chloroform (1:4)
(400ml) was added to the crystals. Insoluble after heating and stirring
The substance (6.95 g) was collected by filtration and diluted with N,N-dimethylform.
Recrystallized from amide to give ethyl 4-oxo-10
-methanesulfonamide-4H-pyrimide [1,
2-c] Quinazoline-3-carboxylate
(5.76 g) of crystals were obtained. mp: 310-312℃ IR (nujiol) νmax: 3200, 3050, 1725,
1665, 1610cm ^-1 NMRδppm (DMSO−d ₆ ): 1.3 (3H, t, J=
7.0Hz), 3.1 (3H, s), 4.3 (2H, q, J = 7.0Hz), 7.7
−8.1 (2H, m), 8.56 (1H, d, J=2.0Hz), 8.9
(1H, s), 9.4 (1H, s), 10.5 (1H, m) Elemental analysis C ₁₅ H ₁₄ N _Four O _Five Calculated value as S: C 49.72; H 3.89; N
15.46; S 8.85 Experimental value: C 49.88; H 3.96; N
15.52; S 8.71 Example 42 4-Amino-6-methanesulfonamide quinazo
Phosphorus (6.68g), dimethyl methoxymethylenep
Ropandioate (6.35g) and N,N-dimethane
A mixture of chloroformamide (27 ml) was heated to 100°C.
Stir for hours. Cool the reaction mixture to room temperature and add water
was added to precipitate crystals, collected by filtration, and N,N-dimethyl
Recrystallized from chloroformamide and dimethyl [(6
-Methanesulfonamide-4-quinazolinylamide
methylene] propanedioate (7.20g)
Obtained crystals. mp: 284-287℃ IR (nujiol) νmax: 3230, 3130, 1730,
1690, 1650, 1625, 1600cm ^-1 NMRδppm (DMSO−d ₆ ): 3.12 (3H, s), 3.76 (3H, s), 3.90 (3H, s), 7.7-8.1 (4H,
m), 8.86 (1H, s), 9.26 (1H, m) Example 43 (1) Diethyl [(6-nitro-4-quinazolini
(ruamino) methylene] propanedioate
(10.8g) of N,N-dimethylformamide
(325 ml) solution of palladium-carbon (3.6 g)
The mixture was shaken in a stream of hydrogen at room temperature. hydrogen
After the absorption of the catalyst was completed, the catalyst was filtered off. filtrate
It was concentrated under reduced pressure, and benzene was added to the residue. mixture
The product was concentrated under reduced pressure to obtain diethyl [(6-amino
-4-quinazolinylamino)methylene]propa
Crude crystals of undioate were obtained. (2) Diethyl obtained as above [(6
-amino-4-quinazolinylamino)methylene
] Propanedioate, pyridine (3.32g)
and dry methylene chloride (200ml).
Stir the mixture under ice-cooling, and add 3,3-di
Methyl butyryl chloride (4.8g)
chloride (10 ml) solution was cooled on ice for 50 minutes.
The reaction mixture was further cooled on ice for 3 hours.
Stir for 10 minutes. Add ice water to the reaction mixture and stir
After that, the mixture was extracted with methylene chloride.
Ta. Wash the organic layer with water and add saturated sodium chloride solution
After washing with liquid, dry with anhydrous magnesium sulfate.
and concentrated the residue under reduced pressure to silica gel (200g).
- Column chromatography (eluent: methylene
fraction A and fraction B were obtained.
Ta. Crystals obtained by concentrating fraction A under reduced pressure (4.28 g)
Dissolved in ethyl acetate and treated with activated carbon to recrystallize
By doing, diethyl [{6-(3,3
-dimethylbutyramide)-4-quinazolinyl
Amino}methylene]propanedioate (2.29
Crystals of g) were obtained. mp: 133-135℃ IR (nujiol) νmax: 3350, 1695, 1640,
1625, 1610cm ^-1 NMRδppm (CDCl ₃ ): 1.15 (9H, s), 1.38 (3H, t, J = 6.0Hz), 1.40 (3H, t, J =
6.0Hz), 2.35 (2H, s), 4.33 (2H, q, J=6.0Hz),
4.43 (2H, q, J=6.0Hz), 7.80 (1H, s), 7.9
−8.1 (2H, m), 8.2 (1H, s), 8.86 (1H, s),
9.33 (1H, d, J = 12.0Hz), 12.0 (1H, d, J
=12.0Hz) Elemental analysis C _{twenty two} H ₂₈ N _Four O _Five Calculated value as: C 61.66 ; H 6.54 ; N 13.08 Experimental value: C 61.51 ; H 6.49 ; N 13.19 Example 44 Dimethyl [(6-pivalamide-4-quinazo
linylamino)methylene]propanedioate
(24.5g) and diphenyl ether (150ml).
The mixture was heated to 260°C for 20 minutes and then cooled to room temperature.
Ta. Add hexane to the reaction mixture to precipitate crystals
filtered, washed with hexane, and washed with chloroform.
(400 ml) was heated and dissolved. Insoluble matter is filtered out and the filtrate is
The mixture was concentrated under reduced pressure to 200 ml and left under cooling.
The precipitated crystals were collected by filtration and washed with chloroform.
Methyl 4-oxo-10-pivalamide-4H-
pyrimido[1,2-c]quinazoline-3-carbo
Crystals of xylate (18.29 g) were obtained. Reduce mother liquor
The crystals precipitated by pressure concentration were collected from silica gel (50 g).
Column chromatography (eluent: 5% methane)
purify with chloroform solution) and purify with chloroform
The same target compound (3.2 g) was obtained by recrystallizing from
Ta. mp: 239-240℃ IR (nujiol) νmax: 3380, 1715, 1685, 1610cm ^-1 NMR. δppm (CDCl ₃ ): 1.4 (9H, s), 3.96
(3H, s), 7.85 (1H, s), 8.0 (1H, d, J=9.0
Hz), 8.4 (1H, dd, J = 3.0 and 9.0Hz), 8.9 (1H,
d, J=3.0Hz), 9.05 (1H, s), 9.63 (1H, s) Example 45 Dimethyl [(6-methanesulfonamide-4
-quinazolinylamino)methylene] propanedio
ate (7.2g) and diphenyl ether (43ml)
The mixture was stirred at 250 °C for 15 min and then brought to room temperature.
The crystals precipitated by cooling to
Wash with a mixed solvent of lume and methanol, and
4-oxo-10-methanesulfonamide-
4H-pyrimido[1,2-c]quinazoline-3-
Crystals of carboxylate (4.72 g) were obtained. mp: 293-296℃ IR (nujiol) νmax: 3220, 1725, 1670, 1608cm ^-1 Example 46 Diethyl [{6-(3,3-dimethylbutyla
-4H-quinazolinylamino}methylene]
Ropandioate (13.1g) and diphenyl ether
Stir the mixture at 250°C for 15 minutes, then room temperature.
Cooled to warm temperature. Add hexane to this mixture,
The precipitate formed by stirring is collected by filtration and mixed with chloroform.
It was dissolved in a mixed solvent with methanol. in this solution
Activated carbon was added, stirred, and filtered. Concentrate the filtrate under reduced pressure.
The crystals that were condensed and precipitated were mixed with chloroform and hexane.
Recrystallized from a mixed solvent of ethyl 4-oxo-
10-(3,3-dimethylbutyramide)4H-pyri
mido[1,2-c]quinazoline-3-carboxy
A crystal of Rate (9.15 g) was obtained. mp: 253-254℃ IR (nujiol) νmax: 3350, 1715, 1680,
1615, 1585, 1565, 1505cm ^-1 N. M. R.δppm (DMSO−d ₆ ): 1.1 (9H, s),
1.3 (3H, t, J=8.0Hz), 2.26 (2H, s), 4.3
(2H, q, J = 8.0Hz), 7.9 (1H, d, J = 9.0Hz), 8.16
(1H, dd, J = 2.0 and 9.0Hz), 8.9 (1H, s),
9.15 (1H, d, J=2.0Hz), 9.4 (1H, s),
10.36 (1H, s) Elemental analysis C ₂₀ H _{twenty two} N _Four O _Four Calculated value: C 62.81 ; H 5.80 ; N 14.65 Experimental value: C 62.69 ; H 5.77 ; N 14.67 Example 47 Dimethyl [{6-(3,3-dimethylbutyla
(mid)-4-quinazolinylamino}methylene]
Ropandioate (7.30g) and diphenyl ether
(44 ml) was stirred at 260°C for 10 minutes,
Cooled to room temperature. Add hexane to this mixture
Crystals were precipitated, collected by filtration, and washed with hexane.
, methyl 4-oxo-10-(3,3-dimethyl
(rubutyramide)-4H-pyrimide [1,2-c]
Quinazoline-3-carboxylate (6.28g)
Obtained crystals. mp: 247-249℃ IR (nujiol) νmax: 3350, 1740, 1720,
1685, 1610cm ^-1 NMR. δppm (DMSO−d ₆ ): 1.1 (9H, s),
2.33 (2H, s), 3.9 (3H, s), 7.96 (1H, d,
J = 9.0Hz), 8.23 (1H, dd, J = 2.0 and 9.0Hz), 9.00 (1H, s), 9.22 (1H, s), 9.46 (1H, s),
10.43 (1H, s) Example 48 Methyl 4-oxo-10-pivalamide-4H
-pyrimido[1,2-c]quinazoline-3-cal
Boxylate (1.27g), anhydrous lithium iodide
(3.18g) and dry pyridine (13ml)
was stirred at 120°C for 3 hours and then concentrated under reduced pressure to obtain the
The residue was dissolved in water. Insoluble matter is filtered out and the filtrate is
Adjust the pH to 1 with concentrated hydrochloric acid to precipitate crystals, and filter.
I took it out and washed it with water. Add methanol to this crude crystal
Stir and filter the crystals (1.0g) into chloroform.
Wash with a mixed solvent of 4-oxo and methanol.
-10-pivalamide-4H-pyrimide [1,2-
c] Condensation of quinazoline-3-carboxylic acid (0.65g)
I got crystal. mp: 330-332℃ IR (nujiol) νmax: 3340, 1720, 1680,
1660, 1610cm ^-1 N. M. R.δppm (DMSO−d ₆ ): 1.25 (9H, s),
7.9 (1H, d, J = 9.0Hz), 8.35 (1H, dd, J =
2.0 and 9.0Hz), 8.93 (1H, s), 9.13 (1H, d, J=
2.0Hz), 9.4 (1H, s), 9.75 (1H, s) Elemental analysis C ₁₇ H ₁₆ N _Four O _Four Calculated value as: C 59.99 ; H 4.74 ; N 16.46 Experimental value: C 59.49 ; H 4.60 ; N 16.39 Example 49 Methyl 4-oxo-10-methanesulfonamide
do-4H-pyrimido[1,2-c]quinazoline-
3-carboxylate (4.32 g), anhydrous phosphorus iodide
of tium (10.8g) and dry pyridine (43ml).
The mixture was stirred at 120°C for 2 hours. reaction mixture
Dissolve the residue obtained by concentration under reduced pressure in water (900 ml).
Ta. Insoluble matter was filtered out, and the filtrate was adjusted to pH5 with concentrated hydrochloric acid.
The precipitated crystals were collected by filtration and mixed with chloroform and meth.
Suspend in a mixed solvent with alcohol, stir, and filter the crystals.
Remove, dry, and give 4-oxo-10-methanesulfone.
Amido-4H-pyrimido[1,2-c]quinazoli
Crystals of 3-carboxylic acid (2.8 g) were obtained. mp: 319-322℃ IR (nujiol) νmax: 3550, 3450, 1695,
1680, 1605cm ^-1 NMRδppm (DMSO−d ₆ ): 3.20 (3H, s), 7.8
- 8.2 (2H, m), 8.65 (1H, d, J = 2.0Hz),
9.0 (1H, s), 9.5 (1H, s), 10.56 (1H, s) Example 50 Methyl 4-oxo-10-(3,3-dimethyl
butylamide)-4H-pyrimide[1,2-c]ki
Nazoline-3-carboxylate (6.0g), anhydrous
Lithium iodide (15.0g) and dry pyridine
(60ml) was stirred at 120°C for 2 hours. reaction mixture
Water was added to the residue obtained by concentration under reduced pressure. mixture
The crystals obtained by filtration were suspended in water (100 ml) and concentrated.
Adjust the pH to 1-2 with hydrochloric acid, collect the crystals by filtration, and dry.
4-oxo-10-(3,3-dimethylbutylene)
-4H-pyrimido[1,2-c]quinazo
Crystals of phosphorus-3-carboxylic acid (2.5 g) were obtained. mp: 304-306℃ IR (nujiol) νmax: 3330, 1730, 1690,
1660, 1610cm ^-1 NMRδppm (DMSO−d ₆ ): 1.00 (9H, s), 2.26 (2H, s), 7.93 (1H, d, J = 9.0Hz),
8.16 (1H, dd, , J = 2.0 and 9.0Hz), 8.96 (1H, s), 9.20 (1H, d, J = 2.0Hz), 9.43 (1H, s),
10.40 (1H, s) Example 51 4-amino-6-(2-ethylbutyramide)
Quinazoline (5.58g), dimethyl methoxymethi
Renpropanedioate (5.62g) and N,N
-Dimethylformamide (22ml) at 100℃ for 1.5 hours
Stir for a while. After cooling to room temperature, add water (90ml).
The resulting solid was collected by filtration, washed with water, and dried.
Dimethyl [(6-(2-ethylbutyramide)-
4-quinazolinylamino)methylene]propane
Oate (4.85g) was obtained. mp: 221-225℃ IR (nujiol) νmax: 3280, 1725, 1660,
1630, 1610, 1570, 1525cm ^-1 NMRδppm (DMSO−d ₆ ): 0.92 (6H, t, J=7.0Hz), 1.3-1.8 (4H, m), 2.0-2.5
(1H, m), 3.76 (3H, s), 3.92 (1H, s), 7.9 (1H, d, J = 10.0Hz), 8.2 (1H, dd, J = 2.0, 10.0
Hz), 8.56 (1H, d, J=2.0Hz), 8.83 (1H, s),
9.23 (1H, d, J=12.0Hz), 10.5 (1H, s),
11.52 (1H, d, J = 12.0Hz) Example 52 4-Amino-6-isobutylamidoquinazoline
(6.2g) and dimethyl methoxymethylenepro
Pandioate (7.01g) was added to N,N-dimethylphosate.
The mixture in Lumamide (25 ml) was heated to 100℃.
Stirred for 1.5 hours, then cooled to room temperature. reaction
Add water to the mixture and collect the solid produced by filtration and wash with water.
dimethyl [(6-isobutyl acetate)].
Mido-4-quinazolinylamino)methylene]pro
Pandioate (8.9g) was obtained. Ethyl acetate?
Recrystallization was performed to obtain purified crystals with a melting point of 212-214°C. IR (nujiol) νmax: 3270, 1710, 1660,
1630, 1610, 1560, 1530cm ^-1 N.M. R.δppm (DMSO−d ₆ ): 1.20 (6H, d, J=7.0Hz), 2.40−2.66 (1H, m), 3.76 (1H,
s), 3.90 (3H, s), 7.93 (1H, d, J=9.0Hz),
8.08 (1H, d, J=9.0Hz), 8.4 (1H, s), 8.73
(1H, s), 9.13 (1H, d, J=12.0Hz), 10.4 (1H, s),
11.13 (1H, d, J=12.0Hz) Elemental analysis C ₁₈ H ₂₀ N _Four O _Five Calculated value as: C 58.06 ; H 5.41 ; N 15.03 Experimental value: C 58.14 ; H 5.39 ; N 15.19 Example 53 4-Amino-6-cyclohexanecarboxamide
Doquinazoline (8.85g) and dimethyl methoxime
Tyrene propanedioate (8.55g) and N,N
- mixture added to dimethylformamide (35 ml)
The mixture was stirred at 100°C for 1 hour. After cooling to room temperature,
The solid produced by adding water is collected by filtration, washed with water, and dried.
Ta. This solid was dissolved in 1% methanol-chloroform.
Silica gel chromatography using liquid
and recrystallized from chloroform to obtain a crystalline solid.
(6.13g) was obtained. This solid is dimethyl
Clohexanecarboxamide-4-quinazonylua
mino)methylene]propanedioate and methyl
4-Oxo-10-cyclohexanecarboxami
do-4H-pyrimido[1,2-c]quinazoline-
3-carboxylate in a ratio of approximately 2:1.
It is a compound. Chromatograph the mixture on silica gel
Methyl 4-oxo-10 obtained by fractionation with E
-Cyclohexanecarboxamide-4H-pyrimi
do[1,2-c]quinazoline-3-carboxylene
The NMR spectrum of the raw material obtained in Example 57 is
It matched that of the finished product. Dimethyl [(6-cyclohexanecarboxa
Mido-4-quinazolinylamino)methylene]
Physical properties of lopandioate mp: 235-237°C (recrystallized from chloroform and ethyl acetate) Example 54 4-Amino-6-(3-cyclopentylpropylene)
onamide) quinazoline (7.05g) and dimethylmethane
Toximethylene propanedioate (6.48g) and
was added to N,N-dimethylformamide (28 ml).
The mixture was stirred at 100°C for 1 hour and 10 minutes. Room temperature
After cooling at , water was added to the reaction mixture to produce
The solid was washed with water and dried. This crude crystal is
Activated carbon is dissolved in a mixed solvent of lume and methanol.
After the treatment, the mixture was concentrated under reduced pressure until crystal formation started. cold
After cooling, the generated solid was collected by filtration and mixed with methanol and
Washed with dichloromethane. In this way,
4-oxo-10-(3-cyclopentyl)
ropionamide)-4H-pyrimide [1,2-c]
Quinazoline-3-carboxylate (2.16g)
Crystals were obtained. NMR spectrum of this product
is consistent with that of the target compound obtained in Example 58.
Ta. The residue obtained by concentrating the filtrate under reduced pressure was diluted with 1% methanol.
silica gel using dichloromethane solution
-subjected to chromatography. The first fraction is methi
4-oxo-10-(3-cyclopentylpro
pionamide)-4H-pyrimide[1,2-c]ki
Contains Nazoline-3-carboxylate (1.9g)
I was reading. NMR spectra of this product were performed
It was consistent with that of the target compound obtained in Example 58. No.
The second fraction is dimethyl [{6-(3-cyclopentyl
propionamide)-4-quinazolinylamino}
Contains methylene] propanedioate (5.16g)
It was. Physical properties of the product obtained from the second section mp: 193-197℃ IR (Nujiol) νmax: 3340, 1745, 1708,
1690, 1660, 1630, 1620cm ^-1 NMRδppm (DMSO−d ₆ ): 0.8-2.1 (11H, m), 2.23 (2H, t, J=7.0Hz), 3.75 (3H, s),
3.90 (3H, s), 7.78 (1H, d, J=9.0Hz),
8.05 (1H, d, J=9.0Hz), 8.36 (1H, s), 8.73 (1H, s),
9.11 (1H, d, J=12.0Hz), 10.40 (1H, s),
11.40 (1H, d, J=12.0Hz) Example 55 Dimethyl [{6-(2-ethylbutyramide)
-4-quinazolinylamino}methylene]propane
Geoate (5.3g) and diphenyl ether (32g)
ml) and heated to 255 °C for 15 min then room temperature.
Cooled to . Add hexane to the reaction mixture
The resulting crystals were collected by filtration, washed with hexane, and dried.
Ta. This crude crystal was mixed with chloroform-methanol.
(10:1) Dissolved in a mixed solvent by heating. Filter out insoluble matter
The filtrate was concentrated under reduced pressure, and the precipitated crystals were chloroformed.
Recrystallize from a mixed solvent of form and hexane,
Methyl 4-oxo-10-(2-ethylbutyl acetate)
(mido)-4H-pyrimido[1,2-c]quinazoline
-3-carboxylate (3.81 g) was obtained. mp: 239-240℃ IR (nujiol) νmax: 3350, 1730, 1690,
1665, 1610, 1490cm ^-1 NMRδppm (DMSO−d ₆ ): 0.92 (6H, t, J=8.0Hz), 1.24−1.84 (4H, m), 2.12−
2.42 (1H, m), 3.84 (3H, s), 7.92 (1H, d,
J = 8.0Hz), 8.18 (1H, dd, J = 2.0, 8.0Hz), 8.88 (1H,
s), 9.12 (1H, d, J=2.0Hz), 9.38 (1H, s),
10.4 (1H, s) Elemental analysis C ₁₉ H ₂₀ N _Four O _Four Calculated value as: C 61.94 ; H 5.47 ; N 15.21 Experimental value: C 61.71 ; H 5.55 ; N 15.38 Example 56 Dimethyl [{6-(2-methylpropionamide)
(d)-4-quinazolinylamino}methylene]pro
Pandioate (8.4g) to diphenyl ether
(42ml) and stirred the mixture at 255℃ for 15 minutes.
Ta. Cool the reaction mixture to room temperature to precipitate crystals.
filtered, washed with hexane, dried and coarsely
6.9 g of crystals were obtained. The crude crystals were dissolved in chloroform-meth
The mixture was heated and dissolved in a mixed solvent of alcohol (4:1). No
The solution was filtered off, and the filtrate was concentrated under reduced pressure to about 150 ml.
After cooling, methyl 4-oxo-10-(2-methyl
propylonamide)-4H-pyrimide [1,2-
c] Quinazoline-3-carboxylate (5.85
Crystals of g) were obtained. mp: 275-277℃ IR (nujiol) νmax: 3345, 1700, 1670,
1610, 1580, 1560cm ^-1 NMRδppm (DMSO−d ₆ ): 1.16 (6H, d, J=
7Hz), 2.4-2.8 (1H, m), 3.86 (1H, s), 7.93
(1H, d, J=9Hz), 8.22 (1H, dd, J=2.9Hz), 8.93
(1H, s), 9.2 (1H, d, J=2Hz), 9.43 (1H,
s), 10.43 (1H, s) Elemental analysis C ₁₇ H ₁₆ N _Four O _Four Calculated value: C 59.99 ; H 4.74 ; N 16.46 Experimental value: C 59.73 ; H 4.58 ; N 16.37 Example 57 Dimethyl [{6-Cyclohexanecarboxa
Mido-4-quinazolinylamino}methylene]pro
Pandioate (4g) and diphenyl ether
(31ml) was stirred at 260°C for 15 minutes. room
After cooling to room temperature, the solid formed was collected by filtration and
It was washed with sun and dried. In this way,
Chil 4-oxo-10-cyclohexanecarboxy
Samido-4H-pyrimido[1,2-c]quinazoli
Ne-3-carboxylate (3.6g) was obtained. mp: 250−251℃ NMRδppm (DMSO−d ₆ ): 1.1-2.1 (10H, m), 2.2-2.8 (1H, m), 3.86 (3H, s), 7.9 (1H,
d, J=9.0Hz), 8.18 (1H, dd, J=2.0, 9.0
Hz), 8.9 (1H, s), 9.13 (1H, d, J=2.0Hz), 9.4
(1H, s), 10.36 (1H, s) Elemental analysis C ₂₀ H ₂₀ N _Four O _Four Calculated value: C 63.15 ; H 5.30 ; N 14.73 Experimental value: C 63.12 ; H 5.24 ; N 14.78 Example 58 Dimethyl [{6-(3-cyclopentylpropylene)
onamido)-4-quinazolinylamino}methylene
] propanedioate (6.9g) and diphenyl
The mixture in ether (53 ml) was heated to 255°C for 15 minutes.
After stirring for a while, the mixture was cooled to room temperature. solid produced
was collected by filtration, washed with hexane, dried, and
4-oxo-10-(3-cyclopentyl)
ropionamide)-4H-pyrimide [1,2-c]
Quinazoline-3-carboxylate (4.5g)
Obtained. mp: 244-247℃ IR (nujiol) νmax: 3350, 1712, 1682, 1612cm ^-1 NMRδppm (DMSO−d ₆ ): 1.0-2.0 (11H, m), 2.3 (2H, m), 3.85 (3H, s), 7.8-8.2 (2H,
m), 8.93 (1H, s), 9.20 (1H, s), 9.43 (1H,
s), 10.50 (1H, s) Example 59 Methyl 4-oxo-10-(2-ethylbutyl
amide)-4H-pyrimido[1,2-c]quinazoli
N-3-carboxylate (3.2g), anhydrous iodide
Lithium (8.0g) and dry pyridine (32ml)
The mixture was stirred at 120°C for 1.5 hours. reaction mixture
Concentrate under reduced pressure, dissolve the residue in water, and filter out the insoluble matter.
Separated. Adjust the filtrate to pH 1-2 with concentrated hydrochloric acid and precipitate.
The resulting crystals were collected by filtration and dried. This crude crystal is
After washing three times with alcohol, re-wash from acetonitrile.
It crystallizes into 4-oxo-10-(2-ethylbutyl
amide)-4H-pyrimido[1,2-c]quinazoli
3-carboxylic acid (0.7 g) was obtained. mp: 295−298℃ NMRδppm (DMSO−d ₆ ): 0.96 (6H, t, J=7.0Hz), 1.3-1.9 (4H, m), 2.0-2.6
(1H, m), 8.0 (1H, d, J = 9.0Hz), 8.26 (1H, dd, J
= 2.0, 9.0Hz), 9.0 (1H, s), 9.26 (1H, d, J =
2.0Hz), 9.5 (1H, s), 10.5 (1H, s) Example 60 Methyl 4-oxo-10-isobutyramide-
4H-pyrimido[1,2-c]quinazoline-3-
Carboxylate (5.42g) and anhydrous lithium iodide
The mixture was heated in dry pyridine (54 ml) at 100 °C.
The mixture was stirred for 1.5 hours. Cool the reaction mixture to crystallize
was precipitated, collected by filtration, and washed with pyridine. crystal
Suspended in water (200ml) and adjusted to pH2.5-3.0 with concentrated hydrochloric acid.
The yellow crystals obtained were filtered, washed with water, and dried.
Ta. The crude crystals were mixed with chloroform-methanol.
Washed twice with a mixed solvent of (1:1), dried,
4-oxo-10-isobutyramide-4H-pyri
Mido[1,2-c]quinazoline-3-carboxylic acid
(3.80 g) of crystals were obtained. mp: 312-314℃ IR (nujiol) νmax: 3350, 1730, 1698,
1655, 1620cm ^-1 NMRδppm (DMSO−d ₆ ): 1.15 (6H, d, J=7.0Hz), 2.4-2.8 (1H, m), 7.9 (1H,
d, J=9.0Hz), 8.2 (1H, dd, J=2.0, 9.0Hz),
8.93 (1H, s), 9.15 (1H, d, J=2.0Hz),
9.36 (1H, s), 10.4 (1H, s) Elemental analysis C ₁₆ H ₁₄ N _Four O _Four Calculated value as: C 58.89 ; H 4.32 ; N 17.17 Experimental value: C 58.73 ; H 4.36 ; N 17.22 Example 61 Methyl 4-oxo-10-cyclohexanecal
Boxamide-4H-pyrimide [1,2-c]quina
Zolin-3-carboxylate (4.7g) and anhydrous
Mixture with lithium iodide in dry pyridine,
Stir at 100°C for 1 hour, then cool to room temperature.
Ta. The generated solid was collected by filtration and washed with ethanol.
Ta. Suspend the solid in water (100ml) and pH it with concentrated hydrochloric acid.
Adjust to 1 to 2 and collect the generated yellow crystals by filtration and wash with water.
and dried. This crude crystal was mixed with chloroform and methane.
After washing with a mixed solvent of alcohol and drying, 4-
Oxo-10-cyclohexanecarboxamide
4H-pyrimido[1,2-c]quinazoline-3-
Carboxylic acid (2.75g) was obtained. mp: 311-314℃ IR (nujiol) νmax: 3330, 3020, 1740,
1710, 1660, 1610, 1580cm ^-1 NMRδppm (DMSO−d ₆ ): 1.0-2.2 (10H, m), 2.23-2.8 (1H, m), 7.93 (1H, d, J = 9.0
Hz), 8.2 (1H, dd, J=9.0, 2.0Hz), 8.96 (1H,
s), 9.2 (1H, d, J=2.0Hz), 9.45 (1H, s),
10.4 (1H, s) Elemental analysis C ₁₉ H ₁₈ N _Four O _Four Calculated value: C 62.28 ; H 4.95 ; N 15.29 Experimental value: C 61.59 ; H 4.91 ; N 15.20 Example 62 Methyl 4-oxo-10-(3-cyclopentyl
(propionamide)-4H-pyrimide [1,2-
c] Quinazoline-3-carboxylate (5.42
g) and anhydrous lithium iodide (14.3g)
was stirred in dry pyridine (59 ml) at 120°C for 1.5 hours.
did. The reaction mixture was concentrated under reduced pressure and the precipitated crystals were collected.
Suspended in water (100ml). PH the suspension with concentrated hydrochloric acid
Adjust the temperature to 1.7, filter out the yellow crystals produced, and wash with water.
and dried. From N,N-dimethylformamide
Recrystallize to give 4-oxo-10-(3-cyclopentyl
(propionamide)-4H-pyrimide [1,2-
c] Condensation of quinazoline-3-carboxylic acid (4.4 g)
I got crystal. mp: 279-283℃ IR (nujiol) νmax: 3350, 1730, 1690,
1668, 1610, 1600, 1580cm ^-1 NMRδppm (DMSO−d ₆ ): 0.7-2.1 (11H, m), 2.4 (2H, m), 7.90 (2H, d, J = 8Hz),
8.16 (1H, dd, J=8.0, 2.0Hz), 8.93 (1H, s), 9.13
(1H, d, J=2.0Hz), 9.23 (1H, s), 10.41 (1H,
s) Example 63 4-amino-6-(2-ethylbutyramide)
Quinazoline (0.9g) and diethyl ethoxymethylene
mixture with propanedioate (0.95g)
100 in N,N-dimethylformamide (4 ml)
The mixture was stirred at ℃ for 2 hours and 40 minutes. Add water to the reaction mixture
The precipitated crystals were collected by filtration, washed with water, and dried. this
Crude crystals were collected using 20% ethyl acetate-chloroform solution.
Then, silica gel chromatography was carried out and vinegar was applied.
Consisting of ethyl acid, chloroform and hexane
Recrystallization from a mixed solvent yields diethyl [{6-(2
-ethylbutyramide)-4-quinazolinylamide
of methylene]propanedioate (11g)
I got crystal. mp: 191-194℃ IR (nujiol) νmax: 3280, 1720, 1658,
1628, 1610, 1570cm ^-1 NMRδppm (DMSO−d ₆ ): 0.92 (6H, t, J=
7Hz), 12.8 (3H, t, J = 7Hz), 1.32 (3H, t, J
=7Hz), 1.56 (4H, m), 2.36 (1H, m), 4.2 (2H, q, J = 7Hz), 4.36 (2H, q, J = 7Hz), 7.88
(1H, d, J=9Hz), 8.16 (1H, d, J=9Hz), 8.48'
(1H, s), 8.8 (1H, s), 9.16 (1H, d, J=12Hz),
10.44 (1H, s), 11.4 (1H, d, J = 12Hz) Example 64 Diethyl [{6-(2-ethylbutyramide)
-4-quinazolinylamino}methylene]propane
Geoate (0.6g) was mixed with diphenyl ether (3
ml) was stirred at 250°C for 15 minutes and brought to room temperature.
Cooled to warm temperature. The formed crystals were collected by filtration and diluted with acetic acid.
Washed with chill, dried, ethyl 4-oxo-10
-(2-ethylbutyramide)-4H-pyrimide
[1,2-c]quinazoline-3-carboxylate
(0.5 g) was obtained. mp: 220-222℃ IR (nujiol) νmax: 3340, 1715, 1700, 1668cm ^-1 NMRδppm (DMSO−d ₆ ): 0.88 (6H, t, J=
7Hz), 1.32 (3H, t, J=7Hz), 1.56 (4H, m),
2.35 (1H, m), 4.3 (2H, q, J=7Hz), 7.92 (1H,
d, J=9Hz), 8.16 (1H, d, J=9Hz), 8.88 (1H, s),
9.16 (1H, broad s), 9.38 (1H, s), 10.4 (1H, s) Example 65 4-Amino-6-(3-cyclopentylpropylene)
onamide) quinazoline (4.4g) and diethyl ethyl ether
Toximethylene propanedioate (5.5g) and
A mixture of N,N-dimethylformamide (20
ml) at 100°C for 3 hours. into the reaction mixture
Add water and collect the precipitated crystals by filtration, wash with water, and dichloromethane.
Suspended in lomethane and heated. Bring the suspension to room temperature.
After cooling, the crystals were collected by filtration and diluted with dichloromethane.
Wash and add ethyl 4-oxo-10-(3-cyclo
Lopentylpropionamide)-4H-pyrimide
[1,2-c]quinazoline-3-carboxylate
(2.4 g) was obtained. Reduce the filtrate to 1/4 of the original volume.
Concentrate and cool to 0°C to obtain more of the same substance (0.37
g) was obtained. The crude crystal obtained as above (2.77
g) using 2% methanol-dichloromethane
and subjected to silica gel chromatography. Living
The product was dissolved in a mixed solvent of methanol and dichloromethane.
A crystalline purified product (2.45 g) was obtained by recrystallizing from
Ta. mp: 241-246℃ IR (nujiol) νmax: 3350, 1725, 1685,
1672, 1615, 1582, 1560cm ^-1 Dilute the mother liquor with 1.5% methanol-chloroform solution
silica gel chromatography using
The obtained oil (1.15g) was mixed with ethyl acetate and hexane.
Diethyl [{6
-(3-cyclopentylpropionamide)-4-
quinazolinylamino}methylene] propanedioe
(0.82 g) was obtained. mp: 155-158℃ IR (nujiol) νmax: 3280, 1730, 1660,
1615, 1608, 1568, 1540cm ^-1 N.M. R. δppm (DMSO−d ₆ ): 1.30 (3H, t,
J = 7Hz), 1.32 (3H, t, J = 7Hz), 0.9-2.0 (11H,
m), 2.36 (2H, m), 4.20 (2H, q, J=7Hz), 4.33
(2H, q, J=7Hz), 7.80 (1H, d, J=9Hz), 8.06
(1H, d, J=9Hz), 8.36 (1H, br s), 8.73 (1H,
s), 9.10 (1H, d, J=12Hz), 10.36 (1H, s),
11.5 (1H, d, J = 12Hz) Example 66 4-Amino-6-(2,3-dimethylpentane
amide) quinazoline (6.75g) and dimethyl meth
xymethylene propanedioate (6.48g)
100 in N,N-dimethylformamide (20ml)
Stirred for 1 hour at <RTIgt;C,</RTI> then cooled to room temperature. anti
Add water to the reaction mixture and collect the resulting solid by filtration and wash with water.
dimethyl [{6-(2,3-dimethyl)
(tylpentanamide)-4-quinazolinylamino}
methylene]propanedioate (6.58g) was obtained.
Ta. A portion of this crude product was dissolved in chloroform-acetic acid ester.
Silica gel using a mixed solvent of chill (3:1)
- Chromatography and reconsolidation with ethyl acetate
Crystallized and analytically pure dimethyl [6-(2,3
-dimethylpentanamide)-4-quinazolinyl
Amino}methylene}propanedioate (0.45
g) was obtained. mp: 216-217℃ IR (nujiol) νmax: 3270, 1725, 1660,
1630, 1610, 1565, 1540, 1500cm ^-1 NMRδppm (DMSO−d ₆ ): 0.7-2.0 (12H, m), 2.2-2.8 (1H, m), 3.8 (3H, s), 3.93 (3H,
s), 7.93 (1H, d, J = 9Hz), 8.2 (1H, dd, J
= 2,9Hz), 8.55 (1H, d, J = 2Hz), 8.85 (1H, s),
9.23 (1H, d, J = 12Hz), 10.43 (1H, s), 11.6 (1H,
d, J=12Hz) Elemental analysis C _{twenty one} H ₂₆ N _Four O _Five Calculated value as: C 60.85 ; H 6.32 ; N 13.52 Experimental value: C 61.16 ; H 6.15 ; N 13.56 Example 67 Dimethyl [{6-(2,3-dimethylpentane
(amide)-4-quinazolinylamino}methylene]
Propanedioate (5.75g) to diphenyl ether
The mixture was stirred at 225℃ for 15 minutes.
Stir and cool to room temperature. Filter the generated solid
It was then washed with hexane and dried. This coarse crystal
Syringe using 4% methanol-chloroform solution.
It was subjected to licage gel chromatography. the product
Reconsolidation from a mixed solvent of methanol and chloroform
methyl 4-oxo-10-(2,3-dimethyl)
(tylpentanamide)-4H-pyrimide [1,2-
c] Quinazoline-3-carboxylate (0.4g)
I got it. The crystalline residue obtained by concentrating the mother liquor was chromatographed.
Recrystallized from a mixture solvent of loform and hexane.
An additional 4.25 g of the same product was obtained. mp: 220-221℃ IR (nujiol) νmax: 3350, 1715, 1690,
1620, 1585, 1565, 1510cm ^-1 NMRδppm (DMSO−d ₆ ): 0.7-2.0 (12H, m), 2.2-2.7 (1H, m), 3.83 (3H, s), 7.9 (1H,
d, J=9Hz), 8.2 (1H, dd, J=2,9Hz),
8.9 (1H, s), 9.33 (1H, d, J=2Hz), 9.4 (1H, s),
10.36 (1H, s) Elemental analysis C ₂₀ H _{twenty two} N _Four O _Four Calculated value: C 62.81 ; H 5.80 ; N 14.65 Experimental value: C 62.80 ; H 5.55 ; N 14.66 Example 68 Methyl 4-oxo-10-(2,3-dimethyl
pentanamide)-4H-pyrimide [1,2-c]
Quinazoline-3-carboxylate (3.4g) and
Dry pili mixture with lithium iodide (8.5g)
The mixture was stirred in gin (34 ml) at 100°C for 1 hour and 20 minutes.
The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water.
The formed precipitate was collected by filtration and washed with water. this crystal
Produced by suspending it in water and adjusting the pH to 1-2 with concentrated hydrochloric acid.
The resulting yellow crystals were collected by filtration, washed with water, and dried. This coarse
Crystals in a mixed solvent of chloroform and methanol
The mixture was heated and dissolved, and insoluble matter was filtered off. Up to 40ml of filtrate
It was concentrated under reduced pressure and cooled in an ice bath. The precipitated crystals
Collected by filtration, mixed solvent of chloroform and methanol
suspended in water and heated. Cool the suspension to room temperature
After that, the crystals were collected by filtration and dried to give 4-oxo-10-
(2,3-dimethylpentanamide)-4H-pyri
Mido[1,2-c]quinazoline-3-carboxylic acid
(1.0g) was obtained. mp: 286-288℃ IR (nujiol) νmax: 3330, 1740, 1700,
1660, 1610, 1580, 1520cm ^-1 NMRδppm (DMSO−d ₆ ): 0.7-1.9 (12H, m), 2.2-2.7 (1H, m), 7.9 (1H, d, J = 9
Hz), 8.18 (1H, dd, J=2,9Hz), 8.93 (1H, s),
9.16 (1H, d, J=2Hz), 9.4 (1H, s), 10.33 (1H,
s), 12.3 -13.1 (1H, broad s) Example 69 4-Amino-7-pivalamide quinazoline
(10.5g) and dimethyl methoxymethylene propane
mixture with N,N-dioate (10.9g)
1 hour at 100°C in methylformamide (32ml)
Stirred for 25 minutes. The reaction mixture was cooled to room temperature.
After that, add water and collect the formed solid by filtration, wash with water and dry.
It was dry. This crystal is mixed with ethyl acetate and ethanol.
Recrystallized from a mixed solvent to obtain dimethyl [(7-dimethyl
Valamido-4-quinazolinylamino)methylene
Crystals of propanedioate (13.7g) were obtained.
Ta. mp: 183-184℃ IR (nujiol) νmax: 3470, 3250, 1705,
1680, 1650, 1620, 1540cm ^-1 NMRδppm (DMSO−d ₆ ): 1.32 (9H, s), 3.72 (3H, s), 3.82 (3H, s), 7.72 (1H, d,
J = 10Hz), 7.92 (1H, dd, J = 2, 10Hz), 7.35 (1H,
d, J=2Hz), 8.72 (1H, s), 9.02 (1H, d,
J=12Hz), 9.66 (1H, s), 11.36 (1H, d, J=12Hz) Example 70 Dimethyl [(7-pivalamide-4-quinazo
linylamino)methylene]propanedioate
(11.7g) to diphenyl ether (58ml)
The mixture was stirred at 250°C for 15 minutes and then allowed to warm to room temperature.
It was cooled down. Add hexane to the reaction mixture to precipitate
The resulting crystals were collected by filtration, washed with hexane, and dried.
Ta. These crystals are mixed with chloroform and methanol.
The mixture was heated and dissolved in a combined solvent, and insoluble matter was filtered off. filtrate
The mixture was concentrated under reduced pressure until crystal precipitation began. Bring the solution to room temperature
After cooling to
4-oxo-9-pivalamide-4H-pyri
mido[1,2-c]quinazoline-3-carboxy
A rate (5.1 g) was obtained. Concentrate the mother liquor and further
Crystals of the same compound (3.4 g) were obtained. mp: 260−262℃ IR (nujiol) νmax: 3340, 1725, 1680,
1610, 1580, 1560, 1525cm ^-1 NMRδppm (DMSO−d ₆ ): 1.3 (9H, s), 3.8 (3H, s), 8.06 (1H, d, J = 9Hz), 8.36
(1H, s) 8.64 (1H, d, J=9Hz), 8.84 (1H, s),
9.24 (1H, s), 9.80 (1H, s) Example 71 Methyl 4-oxo-9-pivalamide-4H
-pyrimido[1,2-c]quinazoline-3-cal
Boxylate (6.5g) and anhydrous lithium iodide
(16.25 g) in dry pyridine at 100°C.
Stir for 1 hour and 30 minutes at
did. Oily residue obtained by concentrating the reaction mixture under reduced pressure
was dissolved in water. Adjust this solution to PH1 with concentrated hydrochloric acid.
The yellow crystals precipitated were collected by filtration, washed with water, and dried.
Ta. This crude crystal is mixed with chloroform and methanol.
The mixture was heated and dissolved in a mixed solvent, and insoluble matter was filtered off. solution
Concentrate under reduced pressure until crystal precipitation begins, cool and analyze.
The resulting crystals were collected by filtration and dried. Do it like this
4-oxo-9-pivalamide-4H-pyri
Mido[1,2-c]quinazoline-3-carboxylic acid
(2.9g) was obtained. mp: 252-256℃ IR (nujiol) νmax: 3370, 3250, 1735,
1690, 1650, 1615, 1550cm ^-1 NMRδppm (DMSO−d ₆ ): 1.30 (9H, s), 8.08 (1H, dd, J=2,9Hz), 8.38 (1H, d,
J=2Hz), 8.64 (1H, d, J=9Hz), 8.86 (1H, s), 9.44
(1H, s), 9.82 (1H, s)

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is hydrogen, a carboxy group or an esterified carboxy group, and A ² is the general formula [Formula] [Formula] or [Formula] (wherein, R ⁴ _a is hydrogen, an alkyl group, a hydroxy group, alkoxy group or alkenyloxy group, R ⁶ is an esterified carboxy group,
R ⁵ is an alkyl group or an alkenyl group), and R ² and R ³ are hydrogen, alkyl group, halogen, nitro group, alkoxy group, aryloxy group, alkylthio group, and alkylpiperazinyl group, respectively. , an acylamino group or a dialkylamino group] and pharmaceutically acceptable salts thereof. 2 General formula (wherein R ¹ , R ² , R ³ and R ⁴ _a are each as defined above) or a pharmaceutically acceptable salt thereof; . 3 Methyl 4-oxo-10-pivalamide-
4H-pyrimido[1,2-c]quinazoline-3-
2. A compound according to claim 2 which is a carboxylate. 4. The compound according to claim 2, which is 4-oxo-10-pivalamide-4H-pyrimido[1,2-c]quinazoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 5 4-oxo-10-(3,3-dimethylbutyramide)-4H-pyrimido[1,2-c]quinazoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof Claim 2 Compounds described in. 6 4-oxo-10-isobutyramide-4H-
The compound according to claim 2, which is pyrimido[1,2-c]quinazoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 7 4-oxo-10-(2-ethylbutyramide)
-4H-pyrimido[1,2-c]quinazoline-3
- The compound according to claim 2, which is a carboxylic acid or a pharmaceutically acceptable salt thereof. 8 General formula (wherein R ¹ and R ⁵ are each as defined above) The compound according to claim 1, which is a compound represented by the following or a pharmaceutically acceptable salt thereof. 9 General formula (wherein R ¹ and R ⁶ are each as defined above) The compound according to claim 1, which is a compound represented by the following or a pharmaceutically acceptable salt thereof. 10 General formula [In the formula, R ¹ is hydrogen, a carboxy group or an esterified carboxy group, and R ² and R ³
is hydrogen, alkyl group, halogen, nitro group, alkoxy group, aryloxy group, alkylthio group,
A 2 is an alkylpiperazinyl group, an acylamino group, or a dialkylamino group, and A ² is a general formula [Formula] [Formula] or [Formula] (wherein R ⁴ _a is hydrogen, an alkyl group, a hydroxy group, an alkoxy group, or is an alkenyloxy group, R ⁶ is an esterified carboxy group,
R ⁵ is a group represented by an alkyl group or an alkenyl group] In producing a pyrimidoquinazoline compound represented by the following and a pharmaceutically acceptable salt thereof, the general formula [In the formula, R ¹ _a and R ¹ _b are esterified carboxy groups, R ² and R ³ are each as defined above, and A ¹ is the general formula [Formula] or [Formula] (in the formula , R ⁴ is hydrogen, an alkyl group, a hydroxy group, an alkoxy group, an alkenyloxy group, a dialkylamino group or a 2,2-dialkoxycarbonylvinylamino group, and R ⁵ is as defined above) is] by heating the compound represented by the general formula (wherein R ¹ _a , R ² , R ³ and A ² are each as defined above) A method for producing a pyrimidoquinazoline compound and a pharmaceutically acceptable salt thereof, which is characterized by obtaining a compound represented by the following. 11 General formula [In the formula, R ¹ is a carboxy group or an esterified carboxy group, and A ² is a general formula [Formula] [Formula] or [Formula] (wherein, R ⁴ _a is hydrogen, an alkyl group, a hydroxy group, an alkoxy group or an alkenyloxy group, R ⁶ is an esterified carboxy group,
R ⁵ is as defined above), and R ² and R ³ are each hydrogen, alkyl group, halogen, nitro group, alkoxy group, alkylpiperazinyl group, acylamino group, or dialkylamino group. The active ingredient is one or more of the pyrimidoquinazoline compounds or their salts represented by
An anti-allergic agent characterized by containing a pharmaceutically acceptable carrier.