JPS5913508B2 - Method for producing acyloxy-substituted carbostyril derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing acyloxy-substituted carbostyryl derivatives.

``5 Conventionally, acyloxy-substituted carbostyryl is produced using a method in which oxyquinoline is N-oxidized using a peracid, then acylated with acetic anhydride, and then the acyl group is rearranged, i.e., Journal of Organismochemistry 1968
The method by Petty, Fleming and Paul [GeorgeR.
^, Pettit, Wayne C_.

FlemingandKennethD,Paul,
J, Org. C_hem,, 33, L089-1092
(1968)]. However, this production method is accompanied by various adverse conditions, such as difficulty in obtaining oxyquinoline as a raw material, the risk of using peracid, and the risk of melting the raw material with alkali, and the reaction conditions are too strong, resulting in decomposition reactions. This results in poor product purity and low yield. The present inventors have made various efforts to overcome the above-mentioned drawbacks, and as a result, we have found that acyloxy-substituted 3 and 4
The inventors have completed the present invention by discovering that the target substance can be obtained under mild conditions with high purity and high yield by oxidizing -dihydrocarbostyryl derivatives. 35 In the present invention, the acyloxy-substituted 3,4-dihydrocarbostyryl derivative is prepared in the presence of a radical initiator or under radical reaction conditions by the general formula [wherein R1 is a C1 to C4 halogen-substituted or unsubstituted lower alkyl group or The aryl group and R2 represent a hydrogen atom.

It is produced by reacting an acyloxy-substituted 3,4-dihydrocarbostyryl derivative represented by the following with a halogen-based oxidizing agent. According to the present invention, the compound represented by formula (1) is used as a raw material, and since this compound can be easily obtained, the difficulty in obtaining raw materials can be solved. In addition, the danger of using peracids for reactions with halogen-based oxidizing agents and the danger of reacting by melting raw materials with alkali is eliminated, and it is now possible to easily obtain the target substance under mild reaction conditions. . In addition, in the conventional method, the reaction conditions are harsh, which causes decomposition reactions and the purity and yield are not satisfactory.However, the method of the present invention conducts the reaction under mild conditions, which reduces side reactions and provides high purity. The compound can now be obtained in high yield. The starting material, the compound represented by formula (1), is a known compound that is extremely easily obtained, 56-, 7- or 8-hydroxy-3,4-dihydrocacarbostyryl (hydroxy-substituted 3,4-dihydrocarbostyryl). Styril), for example, as follows.

That is, 5-hydroxy-3,4-dihydrocarbostyryl is produced by Mr. Tamura's production method (Yasumitsu Tamura, Mitsuhiko Mano, Special Publication 1972-
39694), and 6-, 7- and 8-hydroxy-3,4-dihydrocarbostyryl are p- and m, respectively.
-0-anisidine and β-chloropropionic acid chloride are reacted to acylate and then to Friedel-Crafts cyclization.
et. al. ) can be easily obtained by the production method. This hydroxy-substituted 3,4-dihydrocarbostyryl is acylated using an acid chloride or acid anhydride by a conventional method. Acid chlorides include all acid chlorides such as acetic acid chloride, propionic acid chloride, butyric acid chloride, isobutyric acid chloride, benzoyl chloride, α-bromobutyric acid bromide, and butyric acid bromide, and acid anhydrides include acetic anhydride and propionic anhydride. Any anhydride such as an acid can be used, but acetic anhydride is preferably used in consideration of handling and economic efficiency. As mentioned above, the starting raw material formula (1
) is manufactured using the compound represented by Details of the production of the compound of formula (1) are as shown in Reference Examples below. In the present invention...logeno-based oxidizing agents include N-chlorsuccinimide, N-bromsuccinimide, chlorine, bromine, iodine, pyridinium bromide perbromide, phenyltrimethylammonium perbromide, trichloromethanesulfonyl chloride, 1,2- Dibromo-tetrachloroethane is used in the presence of a radical initiator or under radical reaction conditions. When chlorine, bromine, or iodine is used as an oxidizing agent, the oxidation reaction proceeds even under radical reaction conditions, but it is most advantageous to use bromine in the coexistence of benzoyl peroxide. Formula (1) which is the starting material
The ratio of the compound represented by the formula and the oxidizing agent used is usually from an equimolar amount to an excess molar amount of the latter relative to the former, preferably from about an equimolar amount to about twice the molar amount. As the radical initiator, peroxides such as benzoyl peroxide, m-chloroperbenzoic acid, and ditertiary butylperoxy, and azo radical initiators such as dd''-azobisisobutyronitrile are used, and preferably Perbenzoic acid, m-chloroperbenzoic acid is used.

Alternatively, the radical reaction may be initiated by irradiation with light or the like. The solvent used in the present invention is a nonpolar halogenated hydrocarbon such as carbon tetrachloride or tetrachlorethylene, but carbon tetrachloride is preferably used.

The reaction should be carried out under mild conditions and the reaction temperature is usually 50 to 50℃.
180°C, preferably about 70-90°C. The reaction time is appropriately selected depending on the raw materials, reaction temperature, catalyst, etc., but the reaction is usually completed in 2 to 24 hours, resulting in high purity and low side reactions.
The target product can be obtained in high yield. In the reaction of the present invention, 5-acyloxy-3,4-dihydrocarbostyryl derivatives are oxidized to produce 8-halogen-5-acyloxycarbostyryl derivatives.

In the oxidation of 7-acyloxy-3,4-dihydrocarbostyryl derivatives, 6-halogen-J-[acyloxycarbostyryl derivatives] are produced together with 7-acyloxycarbostyryl derivatives. It can be easily separated by recrystallization or the like.

In the oxidation of 8-acyloxy-3,4-dihydroxycarbostyryl derivatives, 8-
Only acyloxycarbostyryl derivatives are produced.

The halogeno-substituted acyloxycarbostyryl derivative obtained here can be easily de-logenized by catalytic reduction and converted into an acyloxycarbostyryl derivative. The acyloxy-substituted carbostyril derivatives obtained by the present invention can exhibit anti-inflammatory effects, platelet aggregation inhibiting effects, and antilipemic effects by themselves, and can be used as pharmaceuticals utilizing these pharmacological effects, as well as β-adrenergic blockers. It is also a useful compound as an intermediate for pharmaceuticals such as stimulants.

When used as the above-mentioned intermediate, the compound obtained by the present invention is subjected to a reaction according to, for example, the following reaction scheme. Reaction Scheme-1> [In the formula, R1 represents a halogen-substituted lower alkyl group, R1'' represents a lower alkylene group, and R4 and R5 each represent a hydrogen atom or an alkyl group.

Moreover, R2 and R3 are the same as above. ] The compound of the above general formula () is obtained by preparing a corresponding compound in which R1 represents an unsubstituted lower alkyl group in a solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc., logenated hydrocarbons, etc. It can be obtained by reacting with a halogenating agent such as a halogen molecule or N-halogenosuccinimide.

Details of the reaction shown in the above reaction scheme-1 will be explained in Reference Examples below.

Examples will be given to specifically explain the present invention.

Example 1 8-acetyloxy-3,4-dihydrocarbostyryl 615η (0.003 mol), N
- 530 η (0.003 mol) of bromsuccinimide and 10 η of m-chloroperbenzoic acid were added, and the mixture was heated under reflux for 3 hours with stirring.

After cooling the reaction solution, it is concentrated under reduced pressure to remove carbon tetrachloride. After adding 50 d of water to the residue and stirring at room temperature for 1 hour, insoluble matter was removed and dried under reduced pressure to obtain crude 8-acetyloxycarbostyryl 556Tf in the form of a colorless powder with a melting point of 243-250°C.
Get 9. The substance obtained here and 8-oxyquinoline were combined with N-
The melting point of the mixture with the compound obtained by oxidation and further acetylation rearrangement was 241 to 250°C, and the IR chart of the mixture also matched the IR chart of 8-acetyloxylcarbostyryl. Further, the melting point of 8-acetyloxycarbostyryl obtained by recrystallization with methanol was 248 to 250°C. In the above reaction, 560 η of 8-acetyloxycarbostyryl is obtained in the same manner even when the reaction is carried out in the same manner as above except that tetrachloroethane is used as a solvent instead of carbon tetrachloride. Example 2 Carbon tetrachloride 20 ml 615~(0.003 mol) of 8-acetyloxy-3,4-dihydrocarbostyryl and 5η of benzoyl peroxide were added to the mixture, and the mixture was heated under reflux for 3 hours with stirring.

Add bromine 600 to (0.0038 mono(ha)) to this reaction solution.
, 5η of perbenzoic acid and 10 ml of carbon tetrachloride are added dropwise over a period of 1 hour. After the completion of the dropwise addition, continue heating under reflux for 1 hour, then cool, collect the precipitate, wash with water, and dry to obtain a solution with a melting point of 240~
590 η of crude 8-acetyloxycarbostyryl is obtained as a colorless powder at 246°C. Further, it is recrystallized from methanol to obtain colorless powder 8-acetyloxycarbostyryl having a melting point of 248 to 250°C. Example 3 In 30 ml of carbon tetrachloride, 410 w (0.002 mol) of 8-acetyloxy-3,4-dihydrocarbostyryl and 700 η (0.0 mol) of 1,2-dipromtetrachloroethane were added.
0215 mol) was added and irradiated with a 500W sun lamp for 8 hours while stirring.

The reaction solution was cooled, the precipitate was removed, and the melting point was 237-240°C.
Crude 8-acetyloxycarbostyryl 3 as a colorless powder
Get 80 TV. The 8-acetyloxycarbostyryl obtained here is not of high purity, and when recrystallized from methanol, it becomes a colorless powder with a melting point of 248-250°C.
Acetyloxycarbostyryl is obtained. Example 4 410 8-acetyloxy-3,4-dihydrocarbostyryl in 50 ml of 1,1,2,2-tetrachloroethane
Tn9 (0.002 mol), benzoyl peroxide 10mf
7 and trichloromethylsulfonyl chloride (0.0021 mol) were added, and the mixture was heated under reflux for 5 hours with stirring.

After cooling the reaction solution, remove insoluble matter, wash with water, and dry until the melting point is 24.
360 η of crude 8-acetyloxycarbostyryl is obtained as a colorless powder at 6-248°C (recrystallized from methanol, melting point: 248-25’C). Example 5 8-acetyloxy-3,4-dihydrocarbostyryl 410111f (0.002 mol), pyridinium bromide perbromide 620η (
0.002 mol) and 10η of benzoyl peroxide were added, and the mixture was heated under reflux for 3 hours while stirring.

After cooling the reaction solution, remove the insoluble matter, wash with water, and dry until the melting point is 24.
Crude 8-acetyloxycarbostyryl 320 is obtained as a colorless powder with a temperature of 0 to 245°C. Example 6 8-(α-promobutyryloxy)-3,4-dihydrocarbostyryl 312 w (0.
001 mol), N-bromsuccinimide 190ヮ(0
．． 001 mol) and 10η of benzoyl peroxide were added, and the mixture was heated under reflux for 7 hours.

After cooling the reaction solution, collect the precipitate, wash with water, and dry to obtain crude crystals 2.
Get 90 instant. Then, it is recrystallized from methanol to a melting point of 2.
Colorless needle-like crystals of 8-(α-promobutyryloxy) carbostyryl 210W of 59-26 "C" are obtained. IR: 176
0? -1 (-COO-), 1655c! n-1(-C
ON) NMR: δ8.1 (1H,.d, 9.5Hz3
position CH) δ6,65(1H,.d19.5Hz 4th position CH
) δ5.15 (1H,.m,.BrCH) δ2.25
(2H..m.CH2) δ1,18 (3H.t, 7H
zCH3) Example 7 1.0y (0.0049 mol) of 5-acetyloxy-3,4-dihydrocarbostyryl in 50ml of carbon tetrachloride,
1,57 (0.0086 mol) of N-bromsuccinimide and 0.3f7 of benzoyl peroxide are added, and the mixture is heated under reflux for 3 hours.

After adding 100 ml of water to the reaction solution and concentrating under reduced pressure to remove carbon tetrachloride, 100 ml of water was added to the residue. 11 was added and stirred at room temperature for 30 minutes, and then a lot of insoluble material was collected, washed with water, and dried. The obtained crude crystals were added to hot methanol 1007!1j to remove methanol-insoluble matter, washed with methanol, and recrystallized from chloroform-methanol (3:1) to obtain white needle-like crystals 5- with a melting point of 264-266°C. acetyloxy
0.57 of 8-bromocarbostyryl is obtained. Example 8
1.07 (0.0049 mol) of 7-acetyloxy-13,4-dihydrocarbostyryl in 50 ml of carbon tetrachloride,
1.5 t (0.0086 mol) of N-bromsuccinimide and 0.37 mol of benzoyl peroxide are added, and the mixture is heated under reflux for 30 minutes.

100 ml of water was added to the reaction solution, and carbon tetrachloride was removed under reduced pressure. 100 ml of hot methanol was added to the residue, and the mixture was heated to reflux. The methanol-insoluble material is collected, washed with methanol, and dried to obtain a white powder substance 7-acetyloxycarbostyryl 0.68f7 with a melting point of 245-248°C. The methanol-soluble portion is concentrated and cooled to obtain white needle-like crystals of 7-acetyloxy-6-bromocarbostyryl 0.42y with a melting point of 251-252°C. Below, reference examples 1 to 3 are examples of the production of the starting material compounds used in each of the above examples, and examples of the production of active ingredient compounds of β-adrenergic blockers and stimulants from the compounds obtained in the examples are reference examples. 4, and further list pharmacological tests of the compounds obtained according to the present invention. Reference example 1 5-hydroxy-3,4-dihydrocarbostyryl 70
t was suspended in 400 ml of chloroform, 52.8 ml of acetic anhydride and 71.8 ml of triethylamine were added thereto, and the mixture was stirred at room temperature.

After 3 hours, the solvent is distilled off, and the resulting residue is washed with dilute aqueous sodium hydroxide solution and ether.

Recrystallize from ethanol to obtain 5-acetyloxy-3,4
-dihydrocarbostyril 66.9y is obtained. Mpl8
9-190°C Elemental analysis device (as CllH, lNO3) Reference Example 2 In the same manner as in Reference Example 1 above, the following compounds are obtained from appropriate starting materials.

08-acetyloxy-3,4-dihydrocarbostyryl Mp2l6℃ (methanol) 07-acetyloxy-3,4-dihydrocarbostyryl Mpl6O-162℃ (isopropyl alcohol) Reference example 3 8-hydroxy-3,4-dihydrocarbo Styril Jmo
V was suspended in 400 ml of chloroform, 12.8 f of d-promobutyryl bromide and 7.2 ml of triethylamine were added thereto, and the mixture was stirred at room temperature for 5 hours.

The residue obtained by distilling off the solvent is washed with dilute aqueous sodium hydroxide solution and ether. When dried, white crystalline 8-
(α-promobutyryloxy)-3,4-dihydrocarbostyryl 9.3fi! get. IRλ; 1650, 1
720C7! l-1 elemental analysis value (Cl3Hl4NO3B
Reference Example 4(1) Production of 5-(α-promobutyryl)-8-hydroxycarbostyryl 8-(α-
8,4y of aluminum chloride and 8,47 of α-promobutyryl bromide were added to 5.57 g of carbostyril (promobutyryloxy), and then stirred at 70°C for 3 hours. After washing, recrystallization from methanol yields 3.47 5-(α-promobutyryl)-8-hydroxycarbostyryl.

Mp2l8-219°C (color decomposition) (2) Production of 8-hydroxy-5-(α-isopropylaminobutyryl)carbostyryl-methanolate 5
-(α-promobutyryl)-8-hydroxycarbostyryl 5V was added with 100ml of isopropylamine, and 50
After heating at ℃ for 4 hours, it was concentrated to dryness, water was added, the precipitated crystals were collected, washed with water, and recrystallized from methanol to obtain 8-hydroxy-55-(α-isopropylaminobutyryl)carbostyryl-methanolate. We get 4.67.

Mpl36-137°C (foam decomposition). (3) Production of 8-hydroxy-5-[(1-hydroxy-2-isopropylamino)butyl]carbostyril monohydrate 8-hydroxy-5-(α-isopropylaminobutyryl)carbostyril 27 and methanol 40ml Add 2.5 y of sodium boron hydride little by little while stirring under ice-cooling, and stir at room temperature for an additional hour.

Next, concentrated hydrochloric acid is added to this reaction solution to obtain PHL, which is concentrated to dryness, and the precipitate is washed with acetone, then dissolved in water, and an aqueous sodium hydroxide solution is added to adjust the pH to 8 to precipitate crystals. The precipitated crystals were collected and recrystallized from ethanol to give 1.8 y of 8-hydroxy-5-[(1-hydroxy-2-isopropylamino)butyl nicarbostyryl monohydrate with a Mpl of 4 l to 142°C (colored decomposition). get.
[Pharmacological test method] Pharmacological tests were conducted according to the principle described in Natya I, pp. 927-929 (1962).

That is, the platelet aggregation inhibiting effect was measured using a platelet aggregation meter (Platelet A blank Reg) manufactured by Niko Bioscience Co., Ltd.
It was measured using atiOnTracerMOdelPAT-6M). A swing-type rotor was used to prepare a blood sample by adding 3.8% trisodium citrate solution [the mixing ratio of trisodium citrate solution and blood is 1:9 (volume ratio)] to the blood collected from a rabbit. Centrifugation was performed for 10 minutes at room temperature in a centrifuge.

After separating the platelet-rich supernatant of the separated blood, the precipitate was further centrifuged for 2000y for 15 minutes, and the supernatant was collected to obtain platelet-free plasma (PlateletpOOOrplasma). ) (hereinafter abbreviated as "PPP") was obtained. 3.3 μl of the platelet-rich plasma was diluted with 10 ml of commercially available physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd., Japanese Pharmacopoeia physiological saline), and the number of platelets in this mixture was measured using a coal tar counter (Caul tar counter).
terElectrOnicss Inc. Hialea
Ch. The platelet concentration of the same plasma is calculated by diluting the same plasma appropriately with PPP to obtain platelet-rich plasma (P) with a constant platelet count (500,000//!Ld).
lateretrichplasmal, this is referred to as “P
RP) was obtained.

The PRP prepared as described above and the current PPP were used as materials for the following tests. Test 1: A solution containing the compound to be tested at a predetermined concentration (solvents are described separately), or as a blank test, 20μl of the solvent alone and 0.2ml of PRP.
1 was placed in a glass cuvette of a platelet aggregometer, mixed thoroughly, and an iron rotor was inserted, and this cuvette was inserted into the cuvette insertion part of the platelet aggregometer (the cuvette was
The iron rotor is maintained at 7°C and is rotated at a constant speed by electromagnetic induction.)

Three minutes after the insertion, 20 μl of adenosine diphosphate (hereinafter abbreviated as “ADP”) solution or collagen suspension was injected into the liquid inside the cuvette using a microsyringe to induce platelet aggregation.ADP was manufactured by Sigma Corporation. 7.
A 5 μM physiological saline solution was stored frozen at -20°C and thawed before use for testing (the ADP solution once thawed was not reused). Collagen suspension is COllag
enreagentHOln(HOROMN-CHEM
IEMUNCHENGMBH) was used and diluted to 200 μ7/ml with physiological saline before use and used for the test. The platelet aggregation inhibiting effect was expressed as the inhibition rate relative to the aggregation rate of platelet aggregation in a blank test.

Here, the aggregation rate and inhibition rate were calculated according to the following formula. a = Permeability of PRP containing test compound solution (or only its solvent) b = Permeability of PPP c = PRP containing test compound solution (or only its solvent)
Maximum permeability A of the mixture after addition of VCADP solution or collagen suspension = aggregation rate B of blank test - aggregation rate results obtained for PRP containing the test compound are shown in Table 1.

Test compound black

Claims (1)

[Claims] 1 General formula under radical reaction conditions ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 represents a halogen-substituted or unsubstituted lower alkyl group or aryl group of C_1 to C_4. R^2 represents a hydrogen atom. General formula ▲ characterized by reacting an acyloxy-substituted 3,4-dihydrocarbostyryl derivative represented by ] with a halogen-based oxidizing agent,
There are chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same as above. R^3 represents a hydrogen atom or a halogen atom. ] A method for producing an acyloxy-substituted carbostyryl derivative.