JPS588066A - Preparation of optically active(s)-(-)-carbostyril derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as a remedy for stenocardia, etc., in high yield, only by hydrolyzing an optically active[5S]-(+)-5-(3, 4- dihydrocarbostyril-5-yl)oxymethyl-3-alkyloxazolidin-2-one. CONSTITUTION:The[ 2S ]-(-)-alkylamino-3-( 3, 4-dihydrocarbostyril-5-yl )oxy-2- propanol of formyla 2 is prepared by the hydrolysis of an optically active[5S]- (+)-5-(3, 4-dihydrocarbostyril-5-yl)oxymethyl-3-alkyl-oxazolidin-2-one of formulaI (R is lower alkyl), preferably in the presence of a basic compound. The compound of formula 1 can be prepared, e.g. by a series of reactions shown in the reaction formula. USE:It has beta-adrenergic neuronal blocking activity and is useful as a remedy for arrhythmia, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing optically active [S]-←)-carbostyryl derivatives. More specifically, the present invention provides an optically active [5S]-(t)-5-(3,4-disocarbostyryl) represented by the general formula I (wherein R represents a lower alkyl group). -5-yl)o+dimethyl-(2S)-, which is an optically active compound represented by the formula (R is the same as above), which is characterized by hydrolyzing 2-one in 3-alcohol. ←)-1-altolylamino-3-(3,4-,; human O carbostyryl 5
The present invention relates to a method for producing 2-yl)oxy-2-panol. The compound of the general formula ρ) obtained by the method of the present invention is a known compound, which has a β-adrenergic nerve blocking action and is useful as a therapeutic agent for, for example, angina pectoris and arrhythmia.

In this specification, the lower alkyl group represented by R includes, for example, methyl, ethyl, pyl, isopropyl, butyl, tart-butyl, and the like.

The compound of general formula (1)C) which is a starting material in invention F14 is produced, for example, by the method shown in reaction scheme-1 below.

Reaction formula-1 (B) (4)(6)
False) (9)
(am) (In the formula, or the same as above. R1 is a lower alkyl group, X is a halogen atom, Yl is an alkyl sulfonyl group or an arylsulfonyl group, Y is a halogen atom, an arylsulfonyl group (or aryl, sulfonyl, and oxy groups, respectively.) In Reaction Scheme-1, the lower alkyl group represented by xl includes, for example, the lower alkyl group shown in JjK above. Examples of the halogen atom represented by X and Y include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the arylsulfonyl group represented by Yl include methanesulfonyl and ethanesulfonyl groups, and examples of the arylsulfonyl group include benzenesulfonyl and toluenesulfonyl groups.

According to Reaction Scheme-1, compound (3) can be led to cyclyl compound (4) by cyclyl cleavage using a conventional method. The nuclear reaction easily proceeds in the presence of an oxidizing cleavage agent such as lead tetraacetate or a periodate salt such as sodium periodate or potassium periodate in about 1 to 20 hours under ice cooling to room temperature. . Nuclear reactions are usually carried out in the presence of a suitable solvent. Examples of the solvent used include water, methanol, ethanol, acetic acid, ethyl acetate, dimethylformamide (DH), dimethylsulfonamide (DMSO),
Examples include carbon dioxide and mixed solvents thereof.

The amount of the oxidative cleavage agent to be used is usually at least twice the molar amount of compound (3), and in the case of cleavage with periodate, a weakly basic compound such as hydrogen carbonate is used. It is desirable to carry out the reaction by adding sodium, sodium carbonate, potassium carbonate, etc. to the reaction system.

The compound (4) thus obtained is subjected to a reaction with a compound of the following general formula (5) as a reaction mixture after isolation or without isolation. The reaction is carried out in the presence of a reducing agent such as sodium borohydride, and if necessary, the above-mentioned weakly basic compound may be added to the reaction system as a dissolution agent. The amount of the compound of general formula (5) to be used is the compound (
The amount of sodium borohydride used is usually equal to or more than the amount of compound (4), preferably about 1.5 to 3 times the molar amount of the compound (4). , preferably about 1 to 5 times equivalent. The reaction is carried out under water cooling to about room temperature, and is generally completed in about several hours to about 20 hours.

Compound (6) can also be obtained by catalytic reduction of compound (4) in the presence of compound (5) according to a conventional method.

The reaction may be carried out in the presence of a basic compound in a solvent. Examples of the solvent used include water, acetone, pyridine, dichloroform, methylene chloride, tetrahydrofuran,
Examples of basic compounds include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and potassium hydrogen carbonate, and tertiary amines such as triethylamine. can. The compound of general formula (7) and the basic compound are usually used in an amount of 7 molar or more, preferably about t-11-2 times the molar amount of the compound of general formula (6). It is usually carried out under water cooling at about 50° C., preferably at 0 to room temperature, and is generally completed in about 10 minutes to several hours.

The compound of general formula (9) can be led to the compound of general formula (9) by cleaving it and then ring-closing it.

The cleavage reaction is carried out without a solvent or in the presence of an acid in a conventional appropriate solvent. Examples of the solvent include water, methanol, ethanol, and acetic acid. Also, as an acid,
Examples include hydrochloric acid, acetic acid, trifluoroacetic acid, trifluoroacetic acid, and perchloric acid. The amount of acid to be used is not particularly limited as long as it is at least a catalytic amount, but it is usually preferable to use a large amount to also serve as a linear solvent. The reaction is usually carried out under water cooling at ~150°C.
The process is carried out at a temperature of approximately 0.degree. C., and is generally completed within several minutes to approximately 6 hours. Furthermore, the ring-closing reaction is carried out without a solvent or in the presence of a basic compound in a suitable solvent. As a solvent, for example, DMF
%DMSO, benzene, dioxin, tetrahydrobrush, etc., and basic compounds such as gold bullion alcolade such as sodium methylate, sodium ethylate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. Examples include inorganic carbonates and tertiary amici such as triethylamine. The amount of the basic compound to be used is not particularly limited, but it is usually a catalytic amount or more, preferably an equimole-2 times the amount of the starting compound.

The reaction is usually carried out at about 80 to 150°C and is generally completed in about 4 to 10 hours. Moreover, even better results can be expected if the reaction is carried out in a stream of ordinary inert gas such as nitrogen gas or alkoxy gas.

The compound of general formula (9) thus obtained can be easily converted into a compound of general formula 〇〇 by reacting it with a compound of general formula (2) or a suitable halogenating agent. For the reaction between the compound of general formula (9) and the compound of the general formula member, the same reaction conditions as for the reaction between the compound of general formula (6) and the compound of general formula (7) can be adopted. Also, the general formula (
In the reaction of the compound of 9) with a halogenating agent, examples of the halogenating agent include oxychloride, phosphorus trichloride, ricyl pentachloride, phosphorus tribromide, sulfuryl chloride, and thionyl chloride.

The amount of the halogenating agent used is not limited to %, but
Generally, an equimolar amount or more based on the compound of general formula (9),
Preferably, the amount used is about 3 times the molar amount at the same temperature. The above reaction is carried out in the absence of a solvent or in a suitable solvent such as methylene chloride, diOOform, pyridine, diochusashi, tetrashidofurashi and the like. The above reaction starts at room temperature
The temperature is raised to 70°C, and the reaction is generally completed in 30 minutes to 6 hours.

A compound of general formula (1) 0, which is a starting material, can be obtained by reacting the thus obtained compound of general formula 〇〇 with a compound (goods). The reaction is carried out in a suitable solvent in the presence of a basic compound. Examples of solvents include water, lower alcohols such as methanol and ethanol, ethers such as diosaccharide and natohydrofuran, aromatic hydrocarbons such as benzene, tornidi, and silica, DMF, DMSO, etc.
Examples include aprotic polar solvents such as samethyl phosphoric acid triazide, and mixed solvents thereof. As the basic compound, a wide range of ordinary basic compounds can be used, such as inorganic basic compounds such as potassium hydroxide, sodium hydroxide, aluminum hydroxide, sodium carbonate, potassium carbonate, and sodium hydride, sodium ethylate, and sodium methane. Examples include sodium alcoholades such as triethylamine, pyridine, tertiary amici such as diazabicyclononene and diazabicyclononene.

The amount of compound (2) used is not particularly limited, but
It is usually used in an amount of 7 moles or more, preferably 1 to 2 times the mole of the compound of general formula 〇〇. The reaction is usually carried out at room temperature to 200°C, preferably about 70 to 150°C, and is generally completed in about 30 minutes to 10 hours.

In the present invention, in the above reaction, it is preferable to introduce the hydroxyl group at the 5-position of the carbostyril skeleton of compound (2) into an alkali metal salt, and then react the mosquito metal salt with the compound of general formula 〇〇 in the same manner as above. The reaction leading to the alkali gold maple salt is a compound (good) such as sodium hydride, potassium hydride, sodium amide, potassium amide, metallic potassium,
This can be achieved by reacting with sodium metal, sodium chloride, sodium chloride, potassium chloride, sodium hydroxide, potassium hydroxide, lithium hydroxide, methyllithium, and the like.

In the present invention, the hydrolysis of the compound of general formula (1) is usually carried out in a suitable solvent or in the presence of a basic compound, preferably a basic compound. Examples of acids include hydrochloric acid,
Examples of the basic compound include inorganic acids such as sulfuric acid and nitric acid, and inorganic basic compounds such as potassium hydroxide, sodium hydroxide, calcium hydroxide, and barium hydroxide. Examples of good solvents include water, lower alcohols such as methanol, ethanol, and ethylene glycol, non-zero polar polar solvents such as DMF and DMSO,
Examples include ethers such as dioxane and tetrahydroflag, aromatic hydrocarbons such as benzene and toluene, and mixed solvents thereof. The reaction temperature for this reaction varies depending on the solvent used, etc., but cannot be generalized.
The reaction normally proceeds suitably at about 50 to 200°C, preferably 70 to 120°C, and is generally completed in about 0.5 to 24 hours.

According to the method of the present invention, [2S] is represented by the general formula @)
-←) -1-Ramino-3-(3,4-disocarbostyryl-5-yl)oxy-2-propanol can be produced under mild conditions with simple operations and with good yield. .

Reference examples and examples are given below.

Reference example 1 1.2; 5,6-diO-isozu0viride:, 1-
Add D-manitol 16F to 200wLt of ethyl vinegar, stir well, and gradually add 36t of lead tetraacetate. After stirring overnight at room temperature, excess lead tetraacetate is decomposed by adding 3-4111 ethylene glycol. Transfer the reaction solution to a silica gel column (
5-5X B3; 00 form) and concentrated to [2
R) -2,3-isopropylidene diopionaldehyde is obtained. Add this to 50m/ethanol,
While stirring at 0°C, tart -
Drop f. After stirring for 30 minutes, 2.91 ml of sodium borohydride is added in portions while cooling with water. After leaving it for 12 hours,
Add 00 hol 6150ml/ and add silica gel column (
4-5X5oRyriOO form). After concentration, purification (by distillation under reduced pressure) yields [25)-〇-isozu0viride, /
-3-tart-dithylamino-1,2-diloba:
J,! ; All obtained 14.8F.

Colorless oil, boiling point 53°C/1waHf IRC liquid film): 1667cWI' NMR: J = 1.10 (9H,t), 1.3
5 (3H, JF) 1.41 (3H, s ), 2.62
-2.72 (2H), 3.56-3.71 (1),
3.93-4.24 (2H) ppw+ Reference Example 2 1.2 ; 5,6- , ; -0-IsodzO hiritizi D-mannitol 18t methanol 100-solution, sodium periodic acid 2!2 water 100-fIII fluid and 5
Mix 22.5 m of sodium bicarbonate aqueous solution,
Stir at 0°C for 1 hour. Tart-butylamine in this?
Add 5.35y and stir for an additional hour. Add 5.33 f of sodium borohydride and stir at room temperature overnight. Add methanol 5Qsu to the high flow suit (Hy
fro-51LpgrcgL) (sold by Wako Tsumugi Pharmaceutical Co., Ltd.). After concentrating the p liquid, benzene is added and water is removed by azeotropic distillation. The residue was dissolved in ether, dried, concentrated, and purified by vacuum distillation to obtain C2S]-0
-isozu0pyrithi,y-3-tart-butylatriano1.2-dioxypandiol llf is obtained.

Colorless oil, boiling point 60℃/5w H9IRC liquid film)
: 1667 cm-”NMR: δ= 1.10 (9f
f, JP), 1.35 (1, JF), 1.41 (3
N, #), 2.62-2.72 (2H), 3.5
6-3.71 (Iff), 3.93-4.24<2H
)PP'- Reference example 3 ■ C2S]-0-IsojOviride:/-3-ta
rt-dutyl-a-san-no 1.2-d-o-hashidiol 4.6
To a solution of 6 iu of acetocytate in water (1:1) of ethyl chloroformate, 2-95 f of ethyl chloroformate and then 5 i of potassium carbonate in water was added to a solution of 5 i of acetate (1:1) at 5°C. The reaction solution was stirred vigorously for 30 minutes and then extracted with ether (50 dx
3). After washing with saturated brine and then with water, dry and concentrate. Purification by vacuum distillation gives 5.49F of [25)-〇-isozylidene-3-(N-ethodocodicarbonyl-N-tart-dutyl)amino-1,2-dohashidiol.

Colorless oil, boiling point 120℃/2K Hf IR (ClIC1-,) ” 1680 cm-” NM
R: δ = 1.24 (3ff, t, J = 7Hz
), 1.33 (3H, JF ), 1.39 (3f
F,! ) 1.40 ('l, #), 4-07 (2H1
q.

/=7#z), 3.20-4.30 (5H)■ (25)-□-isozu0pylidene-3-(N-
A solution of 3.24 t of ethodeca-dicarbonyl-N-tart-butyl)amino-1,2-propanediol in 3 ml of ethanol is added all at once to a 50° C. solution of 5 d of aqueous 1-thihydrochloric acid solution and 5 ml of ethanol.

After stirring the reaction solution for 5 minutes, Amberlite (Anher-r
Neutralize the pH to about 7 with IRA-400C (manufactured by Munich & Haas, USA). Acipalite IRA-
400 ml and washed with ethanol. Concentrate the p solution, add benzene, and remove water by azeotropic distillation to obtain colorless oily (2S)-3-(N-ethodocodicarbonyl-jV
-tart-butyl)amino-1,2-dimethyl 2.34F is obtained.

IR (CHCl3): 3350.1680 tx-
”NMR: J=1.27 (3H,t, J=
7H1) 1.40 (9H,j), 3-30-4.4
0 (5H), 4-12 (2f, q, /=7fz) prx
t ■ 2.3 of the (2S)-3-(#-ethoxaldicarbonyl-H-tεrt-butyl)amino-1,2-dicarbonate obtained in the above (■) and 2.3 of the potassium carbonate. Of DMF
In addition to 5QMt, react at K120°C for 8 hours under alkoxy gas flow. After cooling, it is filtered and the V solution is concentrated and applied to a silica gel column, and eluted with chloroform and methanol=10:l. The product is recrystallized from ether to give colorless scaly crystals of [5S)-5-dimethyl-3-tart-butylene salilidision-2-one of 1.032%.

Melting point 83-84℃ [α], = +47.8° (C-1, Ri00 form)
IR: 3400.1725 (Ay)m-1#MR:
δ=1.3 (9#, JP), 3.43-3.94 (4#
) 4.36-4.56 <1#) PP elemental analysis value (as C8I□5NO3) HN calculated value (%) 55.47 8.77 8.07
Analysis value (%) 55. Now 8 8.73 8-09
■ Obtained in the above (■) (5S1-5-t nido 0 + dimethyl-
3-tart-Petit Luo Shisu Jiriginoshi 2-on 2
52■ and para-toluenesulfonyl chloride 2291
1v Pisodishi 5- and dichlormethashiro + afo1
Add to solution g and stir overnight at room temperature. Pour the reaction solution into ice water and extract 100ml. The 00 form layer is washed with 10 aqueous sodium bicarbonate solution and then with water, dried and concentrated. The residue was applied to a FLoritil column (manufactured by D-Lysine Co.) to obtain 351w of mono-tosyl-dimethyl-saziridin-2-one.

Melting point 97-98℃ [α), -+27.5° (C=1.ri00form) IR
', 1742.1725.1595QII-'NMR:
δ= 1.36 (9H2I), 2.46 (3H,
I') 3.38-3.77 (2H), 4.09-4
．． 12 (2H), 4.30-4.70 (IH), 7
-36 (2H2d, J=8.3Hz), 7.8
0 (2H, cl, J=8.3Hz) ppra
-Elemental analysis value (as C engineering, H2□N05S) CHN Calculated value (%) 55.04 6.47 4.2
8 analysis value (vomit) 54.90 6.52 4.
09 ■ [5-5] -3-tart obtained in above ■
-Butyl-5-tosyl-dimethyl-saziridine-
351w of 2-one and 286q of the sodium salt of 3,4-dihydrocarbostyril in DMF5-
and stirred at 110°C for 5 hours. The reaction solution is concentrated to dryness, and the residue is dissolved in 00 form, washed with a 1N aqueous sodium hydroxide solution and then with water, dried, and concentrated. The residue was recrystallized from ether to give [55] -5-(3,4-dididrocarbostyryl-5-yl)o+dimethyl-3-ta.
rt-zuchiluo+saliridin-2-osi 193q is obtained.

Colorless needle crystals, melting point 199-200°C [α]″D’=+12.2° (C=1, ri00 form)
IR:1738.1672.1601511-”NMR
: δ engineering 1.42 ('l, I), 2.46-2-68 (
2H), 2.84-3.04 (27), 3.48-3.
88 (2H), 4.06-4.16 (2N), 4.5
2-4.90 (Iff), 6.45 (11t, z
=8. oHz), 6.54 (lid.

J = 8.0 Hz), 7.13 (IH,t,
J -8,0Hz) ppwt Elemental analysis value (C engineering, as H22NO4) CHN Calculated value (%) 64.13 6.97 8.8
0 analysis value (%) 64.05 6.98 8.
C 5 S obtained in Example 71 Reference Example -5-(3,4-dihydrocarnestyryl-5-yl)o+dimethyl-3-tgr
Mix 190~ and 0.5f of sodium hydroxide in water-ethanol (2:1) 6N
1 and refluxed for 7 hours. Ethanol is distilled off and 0
0 form extraction. After washing the 00 form with water, drying and concentrating, a gum-like [2S]-1tgrt-dithylamino-3-
(3,4-dihydrocarbostyryl-5-yl) 120"lF of 2-dihydropanol is obtained.

JR: 3350.3210%l 670. 1601
61M-'NMR: δ = 1.13 (9, W,
j) ppm Furthermore, C2', 5) -1-tgr, which was recrystallized from hydrochloride, was recrystallized from wave-di-panol to form colorless needle-like crystals.
t-Butylamino-3-(3,4-dishidrocarbostyryl-5-yl)oxalic acid 2-dipanol/1 salt is obtained.

Melting point 242-244°C [a]:' = -14,3° (C-!, H2O) NMR
(100MHz, Z)2() ) ”δ=1.46
(9ff.

#), 2.26-2.66 (2f), 2.74-3.0
8 (2H), 3.10-3.46<2N), 4.04
-4.46 (5H), 6.48-6.84 (2K), 7
．． 08-7.32 (IH) (or more)

Claims (1)

[Claims] ■ General formula [In the formula, R represents a lower alkyl group. )-5-(3,4-, ;cyto0carbostyryl-5-yl)-dimethyl-3-aluminyl-dimethyl-3-alkyl-2-one is hydrolyzed to the optically active [5S]- represented by [In the formula, R is the same as above.] ] Optical activity represented by [2S]-←)-1-arylamino-3-(3,4-,;
A method for producing panol.