JPS6139306B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel carbostyril compounds. More specifically, the present invention relates to the general formula (In the formula, R ¹ , R ⁴ and R ⁵ are each a hydrogen atom,
or represents an alkyl group having 1 to 4 carbon atoms, at least one of R ⁴ and R ⁵ is a hydrogen atom, and R ² and R ³ may be the same or different. , represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenylalkyl group containing a straight-chain or branched alkyl group having 1 to 4 carbon atoms in the alkyl moiety, and R ² and
R ³ may be taken together with the nitrogen atom to which they are bonded to form a piperidino group or a morpholino group, with the formula The carbostyril skeleton represented by the formula

[Formula] or

[expression]). This invention relates to a novel carbostyril compound represented by: It is well known that certain carbostyril derivatives exhibit potent pharmacological activity. Typical compounds of this type are listed in Journal of Medical Chemistry, Vol. 15, No. 3, pp. 260-266 (1972), Japanese Patent Publication No. 38789/1978, and Chemical Abstracts, Vol. 62, pp. 16212e (1965), etc. Disclosed. However, these references regarding prior art indicate that compounds having a (1-hydroxy-2-substituted amino) alkyl group at the 5-position of the carbostyril structure or 3,4-dihydrocarbostyryl structure have excellent β-adrenergic receptor stimulating activity. does not indicate that it has. We use carbostyryl having a 5-(1-hydroxy-2-substituted amino)-alkyl group at the 5-position of the carbostyril structure or 3,4-dihydro structure and a substituent at the 1-position and/or the 8-position. The derivatives or 3,4-dihydrocarbostyryl derivatives and their pharmacologically acceptable acid addition salts have β-adrenergic receptor stimulating activity and are therefore useful as bronchodilators, peripheral vasodilators, and antihypertensive agents. It has been found to be effective as a therapeutic agent, such as a drug and similar agents, particularly as a drug for the treatment of bronchial asthma. The object of the present invention is to satisfy the following general formula (a) A novel 5-(1-hydroxy-2-substituted amino)alkyl-8-substituted carbostyryl compound represented by and the following general formula (b) Novel 5-(1-hydroxy-2-substituted amino)alkyl-8-substituted-3,4 represented by
-An object of the present invention is to provide a novel carbostyril derivative represented by the general formula () that is useful as an intermediate for a dihydrocarbostyryl compound. (In the formula, R ¹ , R ⁴ and R ⁵ are each a hydrogen atom,
or represents an alkyl group having 1 to 4 carbon atoms, at least one of R ¹ and R ⁵ is a hydrogen atom, and R ² and R ³ may be the same or different. , represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenylalkyl group containing a straight-chain or branched alkyl group having 1 to 4 carbon atoms in the alkyl moiety, and R ² and ^R3
may form a piperidino group or a morpholino group together with the nitrogen atom to which they are attached). The 5-(1-hydroxy-2-substituted amino)alkyl-8-substituted carbostyryl derivatives and -3,4-dihydrocarbostyryl derivatives of formula (a) and formula (b) and their acid addition salts are β- exhibits adrenoceptor stimulating activity, and therefore
It is effective as a bronchodilator, peripheral vasodilator or antihypertensive agent. The term "alkyl" as used herein with respect to ^R1 , ^R2 , and ^R3 refers to a straight or branched alkyl group having 1 to 4 carbon atoms;
Examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tertiary-butyl group, and the like. “Phenylalkyl” as used herein
The phrase refers to phenylalkyl groups containing straight-chain or branched alkyl groups having 1 to 4 carbon atoms in the alkyl moiety, such as benzyl group, α-methylbenzyl group, α+α-dimethylbenzyl group, phenethyl group. group, α,α-dimethylphenethyl group, etc. The term "halogen" as used herein means fluorine, chlorine, bromic acid and iodine, preferably chlorine and bromine. The compounds represented by the formulas (a) and (b) can be produced from the starting carbostyryl compound of the general formula () according to the following reaction schemes. Here, (A) represents a catalytic reaction and (B) represents a reduction using a reducing agent. In the diagram, R ₄ and R ⁵ each represent a hydrogen atom or an alkyl group, and Y represents a hydrogen atom or

[Formula] Group or

[Formula] represents a group, and X' has the same meaning as X and may be the same as or different from X. In the chemical structure shown in the above diagram and throughout this specification and claims,
The dotted lines at the 3- and 6-positions of the carbostyril moiety represent an incidental single bond between the 3- and 4-positions or two hydrogen atoms bonded to the 3- and 4-positions. . i.e. chemical structure

【formula】 is the chemical structure

[Formula] or

Carbostyryl moiety having [Formula] or 3,4-dihydryl
Showing the dolocarbostyril moiety. As shown in the above reaction scheme, in the present invention
It is one intermediate. 1 - Substitution - expressed by the formula
5-Haloacetyl-8-substituted-carbostyryl or
is the corresponding 3,4-dihydrocarbostyryl
1-substituted-8-substituted-carbostyryl or -3,
4-dihydrocarbostyryl in the presence of a solvent or
is carried out in the presence of a well-known Lewis acid catalyst without the use of a solvent.
by reacting with haloacetyl halide
It can be produced in one step (route A). R ^Four is a hydrogen atom, the compound of the formula R ^Four is water
8-Hydroxycarbostiri of the formula which is an elementary atom
or 8-hydroxy-3,4-dihydrocarbo
Alternative routes starting from Styril (B) + (B′) and
It can be produced similarly using either (C) + (C′).
can. In route (B) + (B'), 8-hydro
Xycarbostyryl or 8-hydroxy-3,4
-dihydrocarbostyryl () and α of formula ()
-The reaction between haloalkanoic acid halide is expressed by the formula
(a) A novel 8-haloalkali in which X is a halogen atom
Noylcarbostyryl or -3,4-dihydroca
resulting in luvostyril, which in turn halo
The acetyl group is rearranged to form an intermediate.
Ru. In route (C) + (C′), starting material ()
The reaction between and α-haloalkanoic acid halide is
Formula (b) A new 5- where X is the same as defined above.
Haloalkanoyl-8-haloalkanoyloxy
Carbostyril or 3,4-dihydrocarbosti
This results in a lyle product, which is then 8-halo
The alkanoyl group is hydrolyzed to form an intermediate.
Form. In fact, 8-hydroxy-3,4-dihydro
Carbostyryl and α-haloalkanoic acid halide
The reactions between the above three reaction routes, namely:
Proceed with the combinations of (A), (B) + (B′) and (C) + (C′)
Ru. Therefore, the reaction products are the compounds (), (
Obtained as a mixture of a) and (b). general
However, if the reaction is carried out at a relatively low temperature,
The resulting product contains compounds (), (a) and a small amount of
would be a mixture of compound (b), while relatively
If the reaction is carried out at high temperature, the resulting product
The substances are compounds () and (b) and a small amount of the compound
It would be a mixture of (b). Compound (), (a) or from the reaction product
The separation of (b) can be carried out using well-known operations such as fractional crystallization.
This can be advantageously carried out by In one preferred embodiment for separation
The solvent used is removed by distillation and the residue is
or pour the reaction mixture onto crushed ice blocks to freeze.
Precipitate crystals. The residue or the crystals are soaked in hot water or cold.
Wash with methanol. Insoluble substances in methanol
to recombine to form 5-haloalkanoyl-8-substituted-
Carbostyryl or -3,4-dihydrocarbos
get chiril(). Remove remaining methanolic mother liquor
Concentrate to dryness under reduced pressure and recrystallize the residue from acetone.
8-halo-alkanoyl-carbostyryl
-3,4-dihydrocarbostyryl (a)
obtain. The resulting acetone mother liquor is then concentrated under reduced pressure.
Dry and dissolve the residue in acetone or ethyl acetate.
Recrystallized from 5-haloalkanoyl-8-halo
Alkanoyloxycarbostyryl or -3,4
-obtain dihydrocarbostyril (b). Compounds having formulas (a) and (b) are
5-(α-halo) of the formula () obtained as follows.
Alkanoyl)-8-hydroxycarbostyryl
Or -3,4-dihydrocarbostyryl derivative is expressed as
() (R in the formula ² and R ³ is the same as defined above
) as shown in the reaction scheme.
, the expression () (R in the formula ¹ ,R ² ,R ³ ,R ^Four and R ^Five is defined above
A novel carbostyryl or 3,4-dihydride having
By obtaining locarbostyril, 5-halo
Alkanoyl-8-substituted-carbostyryl or-
Manufactured from 3,4-dihydrocarbostyryl ()
can do. The method of the invention will be explained in more detail below. 1- or 8-position used as starting material for the present invention
Substituted-3,4-dihydrocarbostyryl () is a publicly available
It is a known compound, and is also known, for example, as described by George R.
Rettit et al., J.Org, Chem. vol. 33, p. 1089
(1968).
can be built. α-haloa that can be used in the present invention
Lucanoic acid halide () contains α-chloropropyl
chloride, α-bromopropionic acid chloride
α-Chlorobutylic acid chloride, α-bromob
Thylic acid chloride, α-bromobutylic acid brolide,
Includes α-chlorovaleric acid chloride, etc. Catalysts that can be used in reaction route (A)
is the usual Lewis acid, e.g. aluminum bromide,
Aluminum chloride, zinc chloride, ferric chloride, star
Iron nitrate, boron trifluoride, etc., preferably chloride
It is aluminum. These catalysts are
Approximately 2 to 10 per mole of bostyril compound ()
Amounts of molar, preferably about 3 to 6 molar are used. This reaction can be carried out without using a solvent.
However, this reaction is carried out in an inert organic solvent.
Go straight inside more smoothly. What to use in this reaction
Examples of suitable solvents that can
Nitrobenzene, ether, dioxane, etc.
Carbon disulfide is preferred. These reaction solvents are
Usually 0.5 to 20 times the volume of the reaction reagent, preferably
Used in 2 to 10 times the amount. Reaction (A) is an equimolar amount to a large excess of α-haloal
Canonic acid halide, preferably the starting carboxylic acid halide
Approximately 2 to 20 mol per mol of lyle compound (), maximum
Also preferably about 2 to 10 moles of α-haloalkanone
It is carried out using acid halides. The reaction takes place at room temperature to approx.
Proceed at 150°C, preferably from room temperature to about 80°C. anti
However, the reaction time varies depending on the reaction temperature used.
generally for about 1 to 20 hours, preferably for about 1 to 20 hours.
It is 10 hours. Reaction (B) is carried out using the same catalyst used in reaction (A).
in the same solvent used in reaction (A) using
can be accomplished without the use of solvents.
This reaction takes place from an equimolar amount to an excess amount of α-haloa
lucanoic acid halide, preferably the starting carboxylic acid halide
About 2 to 20 moles per mole of lyle compound, preferably
Approximately 2 to 10 moles of α-haloalkanoic acid halide is used.
for about 1 to 20 hours, preferably about 1 to 10 hours, approximately
From room temperature to about 150℃, preferably from about room temperature to about 80℃
It can be carried out at any temperature. 8-haloalkali obtained in reaction (B) as above
Noyloxy(-3,4-dihydro)carbosti
5-haloalkanoyl-8-substituted from ryl
To obtain (3,4-dihydro)carbostyril
The reaction (B′) is generally known as the Fries rearrangement.
in the same solvent as in reaction (A).
or the catalyst in reaction (A) without using a solvent.
This can be accomplished using the same catalyst. temperature
from room temperature to about 150℃, preferably from room temperature to about 80℃
The reaction time is about 1 to 20 hours, preferably
The average time is about 1 to 10 hours. This reaction is similar to the previous reaction
α-haloalkanoic acid remaining unreacted in system (B)
Can be carried out in the presence of a halide. like this
In such a case, the presence of the α-haloalkanoic acid halide
is the product, 5-haloalkanoyl-8-substituted-
Yield of (3,4-hydro)carbostyryl ()
was found to improve. Reaction (C) is carried out in the same solvent used in reaction (A).
or the catalyst used in reaction (A) without using a solvent
can be carried out using the same amount of the same catalyst as
Ru. α-Haloalkanoic acid halide from equimolar amount
In large excess, but preferably 8-substituted-
(3,4-dihydro)carbostyryl () 1
from about 2 to about 20 moles per mole, most preferably from about 3 to about 20 moles per mole.
6 moles are used. Reaction temperature ranges from room temperature to approx.
°C, preferably room temperature to about 80 °C, and the reaction temperature is
The time is about 1 hour to 20 hours, preferably about 1 hour to 20 hours.
Approximately 10 hours. The obtained 5-(α-haloalkanoyl)-8-
Haloalkanoyloxy-(3,4-dihydro)
Reaction to obtain compound () from carbostyril
The reaction (C′) is a solvent such as water, methanol, ethanol, etc.
Lower alkanols such as alcohol and isopropanol
in the presence of a catalyst such as an alkali metal hydroxide
or basic substances such as carbonates, e.g. sodium hydroxide.
potassium hydroxide, sodium carbonate, carbonic acid
potassium, etc., or inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid
etc. can be used to do this. The amount of catalyst is
Varies depending on the type of catalyst present. For example, hydrochloric acid
Or sodium hydroxide is a 5-(α-haloalkaline
Noyl)-8-haloalkanoyloxy-(3,
1 to 5 per mole of carbostyril (4-hydro)
Used in molar amounts. The reaction is generally about
Proceed for 0.5 to 5 hours at a temperature of approximately 0°C to 150°C
However, if a basic substance is used as a catalyst,
If the temperature is 0°C to 40°C, the catalyst
and when inorganic acids are used, at 70°C to 100°C.
carried out at temperature. The above obtained 5-(α-haloalkanoyl)-
1-(and/or -8-substituted-(3,4-dihydro
b) Used in the reaction with carbostyril ()
Examples of amines that can be used include alkyl amines.
Methylamine, ethylamine, n-propylamine
amine, isopropylamine, n-butylamine,
2-Butylamine, 3-butylamine, Siku
Loalkylamines such as cyclobutylamine,
Clopentylamine, cyclohexylamine, a
Ralkylamines e.g. benzylamine, α-methylene
Rubenzylamine, α,α-dimethylbenzyl
Amine, phenethylamine, α,α-dimethyl fluoride
enethylamine, etc., and substituted or unsubstituted heterocyclic atom
Mines such as piperidine, morpholine, 2-methyl
- Contains piperidine, 3-methylpiperidine, etc.
It can be done. Amine () and 5-(α-haloalkanoyl)
-1- and -8-substituted-(3,4-dihydro)ka
This reaction between Luvostyril () is approximately atmospheric
in a suitable solvent or amine at pressures of up to about 10 atm.
Using itself as a solvent, the temperature rises from room temperature to the reflux temperature of the reaction system.
temperature, preferably between 40°C and 100°C.
carried out using a large excess of the amine from the amount of
-(α-substituted-aminoalkanoyl)-8-substituted
-(3,4-dihydro)carbostyryl (),
5-(α-substituted-aminoalkanoyl)-8-a
Lukoxy-(3,4-dihydro)carbostyryl
(a) or 5-(α-substituted-aminoalkanois)
)-8-hydroxy-(3,4-dihydro)ka
Luvostyril (b) can be obtained. Instead, R ^Four represents an alkyl group
Riru compound or 3,4-dihydrocarbostyryl
Compound (a) is decomposed with hydrogen halide before reduction.
alkylating to obtain a compound of formula (b);
Or R ^Four represents a hydroxyl group
compound or 3,4-dihydrocarbostyrylation
The compound is alkylated before reduction to give formula (a)
This can be done as shown in the reaction scheme. Halogen used in the above dealkylation
Hydrogen chlorides include hydrogen bromide, hydrogen chloride, hydrogen iodide, etc.
Preferably, hydrogen bromide is included. These halogenated
Hydrogen, preferably methanol, ethanol, isopropyl
Lopanol, preferably in a solvent such as water, for about 10
~50% solution, preferably 47% water of hydrogen halide
Can be used in solution. This dealkylation reaction generally takes about 5 to 20 hours.
preferably for about 5 to 10 hours at a temperature of about 100 to 150°C
hydrogen halide, preferably heated to reflux temperature.
from an equimolar amount to compound (a), in large excess
This can be accomplished using a large excess amount, preferably a large excess amount.
Ru. Alkylation of the compound of formula (b) is basification
with alkylating agents well known in the art in the presence of compounds.
This can be accomplished by reacting. a
Suitable examples of alkylating agents include alkyl iodides, chlorides,
Alkyl, alkyl halides such as alkyl bromide
dia, such as dimethyl sulfate, dimethyl sulfate,
Examples include lukyl sulfate. A suitable example of a basic substance
are alkaline metals such as sodium metal and potassium metal.
Potash metals and their hydroxides, carbonates, and bicarbonates
Salts and alcoholates, and pyridine, piperidine
There are aromatic amines such as The alkylation is advantageously carried out in an equimolar amount to a large excess of
of an alkylating agent, preferably a compound of formula (b)
With 5 to 10 moles of alkylating agent per mole,
water, methanol, ethanol, isopropanol
alcohol, lower alkanols such as n-butanol, acetic acid
Solubility of ketones such as ton, methyl ethyl ketone, etc.
It progresses in the drug. The alkylation is generally carried out at room temperature.
proceed. 5-(α-position of formula (), (a) or (b)
Formula from carbostyryl (aminoalkanoyl)
Reduction to the compound (), (a) or (b) is
respectively, lithium aluminum hydride,
Reducing agents such as sodium borohydride etc.
Conventional reduction used, or palladium black, palladium
Mu carbon, Raney nickel, platinum black, acidic platinum, etc.
by conventional catalytic reduction in the presence of a catalyst and hydrogen.
It can be done by The above reducing agent is preferably heated at about 0°C to 100°C under atmospheric pressure.
Preferably, the solvent is cooled to a temperature of about 20℃ to 50℃.
Among them, 1 mole of carbostyryl compound of formula (a)
An amount of about 2 to 10 moles per mol, preferably about 2 to 5 moles
can be used. Sodium as reducing agent
If borohydride is used, the solvent is
Water or alkanols such as methanol and ethanol
Lithium aluminum is preferred as the reducing agent.
If polyhydride is used, no solvent is used.
water diethyl ether, ethyl acetate, tetrahydro
Non-aqueous solvents such as furan and the like are preferred. Catalytic reduction is performed at room temperature to about 150°C, preferably at room temperature.
Temperature from warm to about 120℃, atmospheric pressure to about 100 atm,
Water preferably at a pressure of from atmospheric pressure to about 50 atmospheres.
A solvent such as water or methanol under an elementary atmosphere,
Alkali such as ethanol or isopropanol
carbostyril compound of formula (a) in alcohol
from about 0.05 to about 1 mole per mole of, preferably about
Advantageously, using the abovementioned catalysts in amounts of 0.1 mol to 0.5 mol
can be carried out while stirring the reduction system.
Ru. The above catalytic reduction is carried out at atmospheric pressure and above about 50℃.
Accomplished at temperatures above room temperature or under pressure.
It is advantageous to do so. Catalytic reduction that can be used in the method of the present invention
Reduction with a reducing agent is shown in more detail in reaction scheme V.
shown. These reactions are expressed by formulas (), (a) and
and (b) as described above for the reduction of the compounds of
It can be carried out in the same way as described above. 3-
A formula () having a double bond between the position and the 4-position,
Catalytic reduction of the compound (a) or (b)
Generally, formula (), (a) or
is the corresponding 3,4-dihydrocarbos of (b)
Generates each chiril, however, contact
Reduction is possible if the conditions of reduction are carefully controlled.
is a carbosuti of formula (), (a) or (b)
By reducing only the 5-position of the lyle compound, the 3- and 4-
The remaining formula (), (a) of the double bond between
or to the corresponding carbostyril compound of (b)
It should be noted that it can be used to
be. However, the 5-
For the reduction of only
It is preferable to use of a compound of formula (a) to a compound of formula (b)
conversion or inverse conversion, i.e. alkylation or dealkylation
Alization of a compound of formula (a) or (b)
The methods described for kylation or dealkylation and
It can be done by the same method. As shown in the reaction scheme, 3,4-dihydro
The locarbostyryl compound may be used in any of the methods of the present invention.
The corresponding carbostyryl compound also at the stage of
can be converted to . of the compound of formula (b) to the compound of formula (a)
The conversion or dehydrogenation is the 3-
By releasing hydrogen atoms from the 4- and 4-positions,
Forming a double bond between the 3- and 4-positions
This can be carried out by any known method.
This dehydrogenation is performed using (1) a dehydrogenating agent such as chloranie;
(tetrachloro-1,4-benzoquinone), di
Using chlorodicyano-1,4-benzoquinone etc.
(2) Using dehydrogenating agents such as sulfur and selenium dioxide.
This can be achieved depending on the method used, and advantageously
This can be accomplished using method (1) or (2) above.
Both dehydrogenations are carried out in solvents such as benzene and toluene.
xylene, phenetol, chlorobenzene, etc.
aromatic hydrocarbons, methanol, ethanol,
Lower alcohols such as sopropanol and tert-butanol
canol, ether e.g. dioxane, acetone
Can be carried out in solvents such as ketones, water, acetic acid, etc.
Wear. The dehydrogenation is advantageously carried out at room temperature.
Reflux temperature of the reaction system, preferably reflux temperature or reflux temperature
It can be accomplished at close range. Compounds of formula () obtained as above and
Both compounds of formula () are basic substances.
Forms acid addition salts with various organic or inorganic acids
can. Particularly useful such salts are hydrochloric acid, sulfuric acid,
acid, inorganic acids such as phosphoric acid, hydrobromic acid, etc.
Acid, maleic acid, fumaric acid, malic acid, citric acid
acid, organic acids such as tartaric acid, ascorbic acid, etc.
With pharmacologically acceptable oxidized salts formed by
be. These acid addition salts can be prepared by well-known methods such as
Tanol, ethanol, isopropanol, acetic acid
The compound dissolved in a suitable organic solvent such as
By adding an equivalent to excess amount of acid to a solution of
It can be easily manufactured. Free bases of compounds of formula () and acid addition salts thereof
Both stimulate β-adrenergic receptors.
It is highly active and therefore causes diseases such as bronchial asthma.
It is very effective as a drug for the treatment of Qi. As will be clear to those skilled in the art, embodiments of the present invention
The compound contains two asymmetric centers and therefore four
Optically active forms may be provided. By referring to the following reference examples and working examples:
The present invention will be explained in more detail, but these
Examples are given for illustrative purposes only.
be construed as limiting the scope of the invention.
It shouldn't be done. All unless otherwise noted
Parts, percentages, proportions, etc. are by weight.
represents the weight percentage, weight percentage, etc. Reference example 1 8-hydroxycarbostyril 27g, Chlorua
37ml of cetyl chloride to 250ml of nitrobenzene
After dissolving and gradually adding 85g of aluminum chloride
Stirred at 70°C for 20 hours. Added 500ml of 10% hydrochloric acid
Nitrobenzene was removed by post-steam distillation.
After cooling, the precipitated crystals were collected and washed with 300 ml of hot water.
Then recrystallize from methanol to a melting point of 285-287℃ (minutes).
solution) of pale yellow crystals of 5-chloroacetyl-8-h
14.0 g of droxycarbostill was obtained. Reference example 2 5.0g of 8-hydroxycarbostyril and acetic acid chloride
Add 20g of aluminum, mix well, then cool with ice water.
Gradually add 10g of chloroacetyl chloride to the bottom.
Ta. 8-chlor by heating reaction at 40-45℃ for 2 hours
Acetoxycarbostyryl was produced. then
After stirring at 70℃ for 3 hours and cooling, remove the precipitated crystals and add water.
After washing with 300ml, recrystallize from methanol.
Pale yellow crystalline 5-chlorine with a melting point of 285-287℃ (decomposition)
Ruacetyl-8-hydroxycarbostyryl 2.6
I got g. In addition, the 8-chloroacetate formed in the intermediate
Cicarbostyril takes out a part of the reactant and
Recrystallize from acetone to obtain pale yellow crystals,
When I checked the temperature, it was 248-250℃ (decomposition).
Ta. Reference example 3 Chlorol in 0.5g of 8-hydroxycarbostyril
1.5 g of acetyl chloride and 20 ml of carbon disulfide.
Add 2g of aluminum chloride gradually under ice water cooling.
added. After mixing thoroughly, gradually warm up for 30 minutes.
It refluxed. Excess chloroacetyl chloride after cooling
and carbon disulfide, and crushed ice is added to the residue to solidify it.
crystallized. After washing with water, recrystallize from acetone to melting point.
8-Chlorua as pale yellow crystals at 248-251℃ (decomposition)
0.45 g of setoxycarbostyril was obtained. Reference example 4 8-chloroacetoxycarbos obtained in reference example 3
Chiril 1.0g, aluminum chloride 20g, Chlorua
Add 10g of cetyl chloride and heat at 75-85℃ for 1 hour.
Heated. Pour into crushed ice while hot to remove precipitated crystals.
After washing with water, recrystallize from methanol with a melting point of 285-287℃.
(decomposition) of pale yellow crystals of 5-chloroacetyl-8
-3.7g of hydroxycarbostyril was obtained. Reference example 5 7.3g of 8-hydroxycarbostyril and
12.5g of loracetyl chloride in nitrobenzene
70ml, add 30g of aluminum chloride while stirring on ice.
Add gradually. Stirring was performed at 50-55℃ for 6 hours.
Then place in ice water. Take the precipitated crystals and add methanol
After washing with
5-Chloroacetyl as light yellow crystals at 241℃ (decomposition)
Leu-8-chloroacetoxycarbostyril 3.5g
get. Reference example 6 5-chloroacetyl-8-chloro obtained in reference example 5
Ruacetoxycarbostyril 1.7g in 10% hydrochloric acid 50%
ml and stir at 95-100°C for 2 hours. Precipitation after cooling
Take the results, wash them with water, and reconsolidate them with methanol.
Pale yellow crystals with a melting point of 285-286℃ (decomposition) 5
-Chloroacetyl-8-hydroxy-carbosti
Obtain 1.1 g of Lil. Reference example 7 5-chloroacetyl-8-chloroacetate obtained in 5
Toxicarbostyril 2.5g with 5% potassium hydroxide
Add to 30ml of aqueous solution and stir at 20-25℃ for 30 minutes.
Ru. While cooling, add dilute hydrochloric acid to adjust the pH to 2 to 3, and precipitate.
After removing the crystals and washing them with water, they were rehydrated using methanol.
Crystals form pale yellow crystals with a melting point of 285-287℃ (decomposition).
5-Chloroacetyl-8-hydroxycarbostili
Obtained 1.7g of chlorine. Reference example 8 4.5g of 8-hydroxycarbostyril and
Chloride in 10g of loracetyl chloride under ice-cooling and stirring.
Gradually add 20g of aluminum. then 55-60
5-Chloroacetyl-8 was stirred at ℃ for 8 hours.
-Produces chloracetoxycarbostyryl
Then, add 40ml of 5% potassium hydroxide and stir at room temperature.
Stir for 30 minutes. Then add 10% hydrochloric acid to make the acidic solution
Then remove the precipitated crystals. From methanol after washing with water
Recrystallized into pale yellow crystals with a melting point of 285-286℃ (decomposition)
5-chloroacetyl-8-hydroxy-carbo
Obtain 2.3 g of styril. In addition, as mentioned above, 5% aqueous
Before adding potassium hydroxide, remove one portion from the reaction system.
Take out a portion and pour it into ice water to remove the precipitated crystals.
After washing with methanol, recrystallize from ethyl acetate.
A pale yellow crystal with a melting point of 238-241℃ (decomposed).
Chloracetyl-8-chloroacetoxycarbos
Got Chiril. Example 1 5-chloroacetyl obtained in Reference Example 4 or 8
8-Hydroxycarbostyril 12.6g
Suspend in 130 ml of panol and add isopropylene while stirring.
Add 25.5 g of Ruamine dropwise. Stir at 55-60℃ for 3 hours
Stir. After cooling, add concentrated hydrochloric acid to adjust the pH to 2-3.
Take the precipitated crystals, wash them with acetone, and then wash them with methanol.
From lu-dimethylformamide (volume ratio 1:1)
Recrystallized into pale yellow crystals with a melting point of 286-288℃ (decomposed)
5-isopropylaminoacetyl-8-hydro
6.5 g of xycarbostyril hydrochloride is obtained. Example 2 5-chloroacetyl obtained in Reference Example 4 or 8
8.0g of 8-hydroxycarbostyril in ethanol
Suspend in 100 ml of tert-butyl amine and stir.
Drop 10g of water. Stir at 55-60°C for 5 hours.
After concentrating to about half the volume, add concentrated hydrochloric acid to adjust the pH to 2 to 3.
shall be. After taking the precipitated crystals and washing them with acetone
Regenerated from methanol-ethanol (volume ratio 1:1)
Crystallizes into pale yellow crystals with a melting point of 291-293℃ (decomposition).
5-tert-butylaminoacetyl-8-hydroxy
4.1 g of cicarbostyril hydrochloride is obtained. Example 3 5-chloroacetyl obtained in Reference Example 4 or 8
4.3g of 8-hydroxycarbostyril in ethanol
Suspend in 50 ml of sec-butylamine and stir.
Add 5g dropwise. Stir at 60-65°C for 5 hours. cold
Then add concentrated hydrochloric acid to adjust the pH to 3. Precipitated crystals
Separately, methanol-ethanol (volume ratio 1:1)
It recrystallizes to form a pale yellow crystal with a melting point of 289-291℃ (decomposition).
Crystal 5-sec-butylaminoacetyl-8-hydro
2.9 g of roxycarbostyril hydrochloride is obtained. Example 4 5-chloroacetyl produced in Reference Example 4 or 8
-8-Hydroxycarbostyril 10g in benzene
Pyridine to this suspension suspended in 50 ml
1.0 ml was added and the mixture was then heated to reflux with stirring.
The reaction was continued for 6 hours. Strain the reaction mixture
Obtain the reaction product and then add it to benzene and then
Washed with 50 ml of isopropanol. The resulting insoluble
The substance was dissolved in 150 ml of 2% hydrochloric acid. solution
Concentrate and dry under reduced pressure, and dissolve the resulting residue in ethanol.
It has a melting point of 239-241℃ (decomposition) after recrystallization from
White amorphous 5-piperidinoacetyl-8-hydro
Obtained 7.5g of Roxycarbostyril Hydrochloride Hemihydrate
Ta. Example 5 5-chloroacetyl produced in Reference Example 4 or 8
-8-Hydroxycarbostyril 10g in benzene
Add morpholin to this suspension by suspending it in 60 ml.
9 ml of water were added and the mixture was stirred at reflux for 4 hours.
Made it react. The reaction mixture was cooled and the resulting precipitate was
I took it. Dissolve this precipitate in 60 ml of isopropanol.
The dissolved solution was adjusted to pH 2-3 with concentrated hydrochloric acid. obtained
Cool the acidic solution with ice and remove the formed precipitate.
and then recrystallized from ethanol. This precipitate
Dissolve the solution in 20ml of water with sodium bicarbonate to pH 7.5
The temperature was adjusted to ~8.0 and cooled in an ice bath. formed by cooling
Take the precipitate and recrystallize it from ethanol to obtain a melting point of 238.
White amorphous 5-monocarbon with ~239.5°C (decomposition)
Luphorinoacetyl-8-hydroxycarbostili
Obtained 4.2 g. The product thus obtained
is IR spectral analysis, NMR spectral analysis and
This was confirmed by elemental analysis. Example 6 5-chloroacetyl produced in Reference Example 4 or 8
-8-Hydroxycarbostyril 15g and benzyl
Add 120 ml of amine and stir the mixture for 1 hour at room temperature.
did. Adding petroleum ether to the reaction mixture
By adding dilute hydrochloric acid to the precipitate thus formed,
Dissolve and remove the remaining insoluble material.
Separated. Next, the hydrochloric acid layer was concentrated and dried, and the residue was
Melting point: 274-279℃ (color decomposition)
16.4 g of material with . obtained in this way
The resulting product was subjected to NMR spectroscopy and IR spectroscopy.
5-benzylamino by tor analysis and elemental analysis.
Acetyl-8-hydroxycarbostyryl hydrochloride
It was confirmed that Example 7 40ml of 2,2-dimethylphenethylamine was added to 5-
Chloroacetyl-8-hydroxycarbostyryl
5 g and the mixture was kept in the dark at room temperature for 5 hours.
Stirred. Adding petroleum ether to the reaction mixture
Wash the precipitate formed with diethyl ether.
and dissolve the inert substance in a methanol solution of hydrochloric acid.
was removed. Distill the methanol and remove the residue.
Recrystallized from tanol, melting point 246-247℃ (color content
6.1 g of a substance having the following solution was obtained. In this way
The obtained product was subjected to NMR spectroscopy and IR spectrum analysis.
Spectral analysis revealed that 5-(2,2-dimethylphenylene)
Nethylaminoacetyl)-8-hydroxycarbo
Confirmed that it is styryl hydrochloride hemihydrate.
Ta. Reference example 9 8-hydroxy-3,4-dihydrocarbosti
Ril 24.3g and chloroacetyl chloride, 68
Add g to 130 ml of carbon disulfide, add salt while cooling with ice water and stirring.
Gradually add 200g of aluminum chloride. 60~70℃
After stirring for 6 hours, carbon disulfide was distilled off. Residue
Pour the distillate into 500 ml of ice water. Precipitated crystals
After washing with water, recrystallize twice from methanol.
5-Chlorua, a pale yellow crystal with a melting point of 189-191℃
Cetyl-8-hydroxy-3,4-dihydrocal
Obtain 8.0g of Bostyril. Reference example 10 8-hydroxy-3,4-dihydrocarbosti
13g of rill, 20g of chloroacetyl chloride
Lobenzene dissolved in 100ml aluminum chloride 40
After gradually adding g, the mixture was stirred at 70-75°C for 15 hours.
Nitrobenzene is removed by steam distillation. cold
After removing the precipitated crystals and washing them with hot water,
Pale yellow crystals with a melting point of 189-190°C are recrystallized from a
5-chloroacetyl-8-hydroxy-3,4
- Obtain 7.2 g of dihydrocarbostyril. Reference example 11 78-Mexy-3,4-hydrocarbostyryl
17g, 66g of chloroacetyl chloride, nitrobe
Added 30 ml of water. Aluminum chloride under ice cooling
100 g was gradually added and stirred at room temperature for 30 minutes. 30
After standing for a minute, it was poured into 70 ml of ice water. precipitate
then washed with ethanol and re-washed with methanol.
20 g of a crystalline white needle-like substance with a melting point of 187-188°C
I got it. This has been determined by NMR, IR and elemental analysis.
From the analysis results, 5-chloroacetyl-8-methoxy
Must be C-3,4-dihydrocarbostyryl
was confirmed. Reference example 12 8-methoxy-3,4-dihydrocarbostiri
8.5g of chloroacetyl chloride, 33g of chloroacetyl chloride, disulfuric acid
30 ml of carbon dioxide was added. Aluminum chloride 50 under ice cooling
g was gradually added, and the mixture was stirred at room temperature for 2 hours. disulfide
After removing the carbon layer at an angle, crushed ice is added to crystallize it.
I let it happen. The generated precipitated crystals are taken, and then ethanol is added.
Wash with water and recrystallize from methanol to determine the melting point.
11 g of a white needle-like substance having a temperature of 187-188°C was obtained. this
Are the results of NMR, IR, and elemental analysis?
5-chloroacetyl-8-methoxy-3,4-
It was confirmed that it is dihydrocarbostyryl.
Ta. Reference example 13 8-hydroxy-3,4-dihydrocarbosti
24.3g of rill and 68g of chloroacetyl chloride
was added to 130 ml of carbon disulfide and mixed with acetic acid chloride while cooling with ice water and stirring.
Gradually add 200g of aluminum. 4 o'clock under ice cold
8-chloroacetoxy-3,4-di
Generates hydrocarbostyril. Then 60～
After stirring at 70℃ for 2 hours, carbon disulfide is distilled off.
Ru. Pour the residue into 500ml of ice water and collect the precipitated crystals.
Separate the crystals, wash with water, and recrystallize twice from methanol.
5-chlor, pale yellow crystals with a melting point of 189-191℃
Acetyl-8-hydroxy-3,4-dihydroca
Obtain 8.0 g of Luvostyril. 8 generated in the middle
-Chloracetoxy-3,4-dihydrocarbos
Chiril takes out a part of the reactant and recrystallizes it.
When its melting point was confirmed, it was 183-186°C. Reference example 14 8-hydroxy-3,4-dihydrocarbosti
Add 40g of aluminum chloride to 11.5g of rill.
After mixing, add chloracetyl chloride under ice water cooling.
Gradually add 21g of do. Heat and stir at 35-40℃ for 2 hours
After stirring, excess chloroacetyl chloride is distilled off.
leave Pour the residue into crushed ice to remove the precipitated crystals.
After washing with water, recrystallize from acetone to obtain MP・182～
8-Chloroacetoxy in pale yellow crystals at 184℃
5.6 g of 3,4-dihydrocarbostyryl are obtained. Reference example 15 8-hydroxy-3,4-dihydrocarbosti
nitrate 13g of rill and 20g of chloroacetyl chloride.
Lobenzene dissolved in 100ml aluminum chloride 40
After gradually adding g, the mixture was stirred at 70-75°C for 15 hours.
Nitrobenzene is removed by steam distillation. cold
After removing the precipitated crystals and washing them with hot water,
Recrystallized from a pale yellow crystal with a temperature of 189 to 190℃.
Crystal 5-chloroacetyl-8-hydroxy-3,
7.2 g of 4-dihydrocarbostyryl are obtained. Reference example 16 8-hydroxy-3,4-dihydrocarbosti
Ril 6.0g and chloroacetyl chloride 15.0
30 g of aluminum chloride was added to the g while stirring on ice.
I can do it. Next, stir at 55 to 60°C for 6 hours.
-Chloroacetyl-8-chloroacetoxy-3,
4-dihydrocarbostyryl is produced, and its
Add 50ml of 10% hydrochloric acid aqueous solution and incubate at 95-100℃ for 3 hours.
Stir in between. After cooling, remove the precipitated crystals and wash with water.
Afterwards, it was recrystallized from methanol and the melting point was 189.
~190℃ pale yellow crystals of 5-chloroacetyl-8
-Hydroxy-3,4-dihydrocarbostyryl
Obtain 2.7g. In addition, before hydrolysis, the reaction system
A part of it was taken out and poured into ice water to precipitate it.
After taking the crystals and washing them with hot methanol, dimethyl
From formamide-methanol (volume ratio 1:1)
Recrystallized to produce pale yellow crystals with a melting point of 206-207℃.
Loracetyl-8-chloroacetoxy-3,4-
Dihydrocarbostyril was obtained. Example 8 5-chloroacetyl-8- obtained in Reference Example 16
Hydroxy-3,4-dihydrocarbostyryl 4
Dissolve g in 50 ml of isopropanol, add isopropyl
20 g of ruamine was added, and the mixture was stirred at 60°C for 3 hours. After concentrating the reaction solution to 1/3 to 1/4 volume, add dry hydrochloric acid gas.
saturate the space. After cooling, remove the precipitate and add it to ethanol.
A colorless amorphous substance with a melting point of 274-275℃ after recrystallization.
3.5g was obtained. This one is NMF, IR and elemental analysis
From the analysis results, 5-isopropylaminoacetate
Chil-8-hydroxy-3,4-dihydrocarbo
It was confirmed to be styryl hydrochloride. Example 9 5-chloroacetyl-8- obtained in Reference Example 16
Hydroxy-3,4-dihydrocarbostyryl 3
Dissolve g in 40 ml of isopropanol and add methylamine.
3 g of chlorine was added dropwise over 30 minutes while stirring at 60°C. End of dripping
After completion of the reaction, the mixture was further heated and stirred for 1 hour. Reduce the liquid volume to 1/3
Concentrate and then add concentrated hydrochloric acid to adjust the pH to 1-2.
Ta. Collect the precipitate and recrystallize it from ethanol.
Obtained 1.5 g of a colorless amorphous substance with a melting point of 254-256°C.
Ta. This material can be separated by NMR, IR and elemental analysis.
From the analytical results, 5-methylaminoacetyl-8-hydro
Roxy-3,4-dihydrocarbostyril hydrochloride
It was confirmed that Example 10 5-chloroacetyl-8- obtained in Reference Example 16
Hydroxy-3,4-dihydrocarbostyryl
Dissolve 2.54g in 30ml of isopropanol and add ethyl
2.7 g of amine was added dropwise over 20 minutes while stirring at 60°C.
After the dropwise addition was completed, the mixture was heated and stirred for an additional 40 minutes. Reduce the liquid volume by 1/3
Concentrate to double volume and add concentrated hydrochloric acid to adjust pH to 1-2.
did. Collect the precipitate and recrystallize it from ethanol.
1.9 g of a colorless amorphous substance with a melting point of 258-260℃ was obtained.
Ta. This material can be separated by NMR, IR and elemental analysis.
From the analysis results, 5-ethylaminoacetyl-8-hydro
Roxy-3,4-dihydrocarbostyril hydrochloride
It was confirmed that Example 11 5-chloroacetyl-8- obtained in Reference Example 16
Hydroxy-3,4-dihydrocarbostyryl 4
Dissolve g in 60 ml of isopropanol and add tert-butyl
20 g of amine was added dropwise to the mixture over 20 minutes while stirring at 60°C.
After the dropwise addition was completed, the mixture was heated and stirred for an additional 40 minutes. Reduce the liquid volume by 1/2
Concentrate to double volume and add concentrated hydrochloric acid to adjust pH to 1-2.
did. Collect the precipitate and add ethanol-acetone (by volume).
Repeat recrystallization with a mixed solvent (quantity ratio 1:1)
Obtained 2.0 g of a colorless amorphous substance with a melting point of 253-255°C.
Ta. This material can be separated by NMR, IR and elemental analysis.
From the analytical results, 5-tert-butylaminoacetyl-8
-Hydroxy-3,4-dihydrocarbostyryl
It was confirmed that it was a hydrochloride. Example 12 5-chloroacetyl-8- obtained in Reference Example 16
Hydroxy-3,4-dihydrocarbostyryl 3
Dissolve g in 40 ml of isopropanol and add sec-butylene
10 g of ruamine was added dropwise to the mixture over 20 minutes while stirring at 60°C. drop
After the completion of the reaction, the mixture was further heated and stirred for 2.5 hours. Increase liquid volume by 1/3
After concentrating to a volume, it was saturated with dry hydrochloric acid gas. analysis
The extracted product is recrystallized from ethanol to determine the melting point.
1.8 g of a colorless amorphous substance with a temperature of 269-271°C was obtained. child
The results are based on NMR, IR, and elemental analysis.
to 5-sec-butylaminoacetyl-8-hydro
Roxy-3,4-dihydrocarbostyril hydrochloride
It was confirmed that Example 13 5-chloroacetate obtained in Reference Examples 11 and 12
Ru-8-methoxy-3,4-dihydrocarbosti
Dissolve 4g of Ril in 50ml of isopropanol and add
Add 20g of propylamine and stir at 60℃ for 3 hours.
Ta. After concentrating the reaction solution to 1/3 to 1/4 volume, dry hydrochloric acid
Saturated gas. After cooling, remove the precipitate and add ethanol
Recrystallized from colorless needle crystals with a melting point of 208-209℃
3.5 g of quality was obtained. This item includes NMR, IR and elemental content.
From the analysis results, 5-isopropylaminoa
Cetyl-8-methoxy-3,4-dihydrocarbo
It was confirmed to be styryl hydrochloride. Example 14 5-chloroacetate obtained in Reference Examples 11 and 12
Ru-8-methoxy-3,4-dihydrocarbosti
Dissolve 3 g of Ril in 40 ml of isopropanol and add methyl
3 g of Ruamine was added dropwise over 30 minutes while stirring at 60°C.
After the dropwise addition was completed, the mixture was heated and stirred for an additional hour. Reduce the liquid volume by 1/3
Concentrate to double volume, then add concentrated hydrochloric acid to adjust the pH to 1-2.
I arranged it. Remove the precipitate and recrystallize it from ethanol.
and 1.5 g of a colorless needle-like substance with a melting point of 232-234°C.
Obtained. This is determined by NMR, IR and elemental analysis.
From the analysis results, 5-methylaminoacetyl-8-methyl
Toxi-3,4-dihydrocarbostyril hydrochloride
It was confirmed that Example 15 5-chloroacetate obtained in Reference Examples 11 and 12
Ru-8-methoxy-3,4-dihydrocarbosti
Dissolve 2.54g of Ril in 30ml of isopropanol and add
Add 2.7g of thylamine dropwise over 20 minutes while stirring at 60℃.
Ta. After the dropwise addition was completed, the mixture was heated and stirred for an additional 40 minutes. liquid volume
Concentrate to 1/3 volume and add concentrated hydrochloric acid to adjust the pH to 1-2.
It was adjusted. Remove the precipitate and reconsolidate with ethanol.
1.9 g of colorless needle crystal substance with a melting point of 224-227°C
I got it. This has been determined by NMR, IR and elemental analysis.
From the analysis results, 5-ethylaminoacetyl-8-
Methoxy-3,4-dihydrocarbostyryl hydrochloride
It was confirmed that it was salt. Example 16 5-chloroacetate obtained in Reference Examples 11 and 12
Ru-8-methoxy-3,4-dihydrocarbosti
Dissolve 4g of Ril in 60ml of isopropanol,
- Add 20g of butylamine dropwise over 20 minutes while stirring at 60℃.
did. After the dropwise addition was completed, the mixture was heated and stirred for an additional 40 minutes. liquid amount
was concentrated to 1/2 volume, and concentrated hydrochloric acid was added to adjust the pH to 1-2. Remove the precipitate and ethanol-acetone
(Volume ratio 1:1) Repeated recrystallization with mixed solvent
2.0g of a colorless amorphous substance with a melting point of 208-210℃
I got it. This has been determined by NMR, IR and elemental analysis.
From the analysis results, 5-tert-butylaminoacetyl
-8-methoxy-3,4 dihydrocarbostyryl
It was confirmed that it was a hydrochloride. Example 17 5-chloroacetate obtained in Reference Examples 11 and 12
Ru-8-methoxy-3,4-dihydrocarbosti
Dissolve 3g of Ril in 40ml of isopropanol, sec
-Drop 10g of butylamine over 20 minutes while stirring at 60℃
Ta. After the dropwise addition was completed, the mixture was further heated and stirred for 2.5 hours. liquid amount
After concentrating to 1/3 volume, it was saturated with dry hydrochloric acid gas. Collect the precipitate and recrystallize it from ethanol.
Obtained 1.8 g of a colorless needle-like substance with a melting point of 212-244°C.
Ta. This material can be separated by NMR, IR and elemental analysis.
From the analysis results, 5-sec-butylaminoacetyl-8
-Methoxy-3,4-dihydrocarbostyryl salt
It was confirmed that it was an acid salt. Example 18 5-chloroacetyl-8- obtained in Example 13
Methoxy-3,4-dihydrocarbostyryl hydrochloride
Dissolve 1 g of salt in 10 ml of 47% hydrogen bromide aqueous solution, and
The mixture was heated under reflux at 120-130°C for 2.5 hours. ethanol
10 ml and 5 ml of water were added and concentrated. Add another 20ml of water.
Well, add sodium bicarbonate to adjust the pH to 6.5-7.5.
It was adjusted. The precipitated crystals were collected, washed with water, dried, and then
Dissolve in propanol and saturate with dry hydrochloric acid gas.
Ta. Take the precipitate, recrystallize it from ethanol and melt it.
Obtained 0.5 g of a colorless amorphous crystal substance with a temperature of 274-275℃.
Ta. This material can be separated by NMR, IR and elemental analysis.
From the analysis results, 5-isopropylaminoacetyl-8
-Hydroxy-3,4-dihydrocarbostyryl
It was confirmed that it was a hydrochloride. Example 19 5-chloroacetyl-8- obtained in Example 14
Methoxy-3,4-dihydrocarbostyryl hydrochloride
Dissolve 0.7 g of salt in 10 ml of 47% hydrogen bromide solution and
The mixture was heated under reflux at a temperature of 120 to 130°C for 4 hours. Examples below
Colorless amorphous with a melting point of 254-256°C obtained by the same procedure as 14.
0.5g of material was obtained. This item includes NMR, IR and original
Based on the results of elementary analysis, 5-methylaminoacetate
Chil-8-hydroxy-3,4-dihydrocarbo
It was confirmed to be styryl hydrochloride. Example 20 5-tert-butylaminoacetyl-8-methoxy
C-3,4-dihydrocarbostyryl hydrochloride 0.9
Dissolve g in 10ml of 47% hydrogen bromide aqueous solution and carry out the following procedure.
Proceed as in Example 18 to obtain a pale yellow color with a melting point of 252-255℃.
0.2 g of a solid substance was obtained. This item is NMR, IR and
From the analysis results of 5-tert-butyl
Aminoacetyl-8-hydroxy-3,4-dihi
It was confirmed that it was dolocarbostyril hydrochloride.
Ta. Example 21 5-sec-butylaminol obtained in Example 17
Cetyl-8-methoxy-3,4-dihydrocarbo
Styryl hydrochloride 0.5g in 47% hydrogen bromide aqueous solution 10ml
The melting point was determined by the same procedure as in Example 18.
0.24 g of a colorless amorphous substance with a temperature of 269-271°C was obtained. child
The results are based on NMR, IR, and elemental analysis.
to 5-sec-butylaminoacetyl-8-hydro
Roxy-3,4-dihydrocarbostyril hydrochloride
It was confirmed that Reference example 17 20g of 8-hydroxycarbostyril and α-bro
Mobutyric acid bromide 50g, anhydrous aluminum chloride 50g
g, add 400ml of carbon disulfide and heat at 50℃ for 13 hours.
The carbon disulfide layer is then removed at an angle and crushed into a residue.
After adding ice and crystallizing it, take it and wash it with water.
Ru. Furthermore, it is recrystallized from methanol and 5-(α
-bromobutyryl)-8-hydroxycarbosti
Obtain 27g of Lil. Melting point 218-219℃ (color decomposition). Reference example 18 1g of 8-hydroxycarbostyril and α-bro
Mobutyric acid chloride 25g, anhydrous aluminum chloride 25g
Add g and heat at 70℃ for 4 hours while mixing thoroughly.
Afterwards, add crushed ice to crystallize it, then remove it.
Wash with water. Furthermore, it is recrystallized from methanol and 5-
(α-bromobutyryl)-8-hydroxycarbo
Obtain 12.6 g of styril. Melting point 218-219℃ (color content
solution). Reference example 19 10g of 8-hydroxycarbostyril and α-bro
25g of mobutyric acid bromide, 100ml of nitrobenzene
Add 25g of anhydrous aluminum chloride while cooling.
Ru. After heating at 70℃ for 10 hours, pour into crushed ice.
Take the precipitation results, wash them with water, and then remove them from methanol.
After recrystallization, 5-(α-bromobutyryl)-8
- Obtain 11.2 g of hydroxycarbostyril. melting point
217-218.5℃ (color decomposition). Example 22 5-(α-bromobutylene) obtained in Reference Examples 17 to 19
10g of Ril)-8-hydroxycarbostyril
Add 200ml of dibutylamine and heat at 60℃ for 20 hours.
This is then concentrated to dryness, and water is added to precipitate it.
After taking the crystals and dissolving them in 50ml of ethanol,
Add concentrated hydrochloric acid to adjust the pH to 1. Crystals that then precipitate
was recrystallized from methanol to give a melting point of 212 ~
5-(α-sec-butylamine) at 214℃ (color decomposition)
Nobutyril)-8-hydroxycarbostyryl salt
8.3 g of the acid salt are obtained. Example 23 5-(α-bromobutylene) obtained in Reference Examples 17 to 19
Ril)-8-hydroxycarbostyril 5g
Add 10ml of sopropylamine and 50ml of methanol.
After heating under reflux for 6 hours, it was concentrated to dryness, and the following Example 1 was prepared.
In the same manner as above, 8-
Hydroxy-5-(α-isopropylamine butylene)
Ril) carbostyryl-methanol solvate 4.2
get g. Example 24 20g of 8-hydroxycarbostyril and α-bromine
Mobutyric acid bromide 5g, anhydrous aluminum chloride 50
g, add 400ml of carbon disulfide and heat at 50℃ for 13 hours.
The carbon disulfide layer is then removed at an angle and crushed ice is added to the residue.
In addition, crystals are precipitated. Take this crystal and wash it with water.
and further recrystallized from methanol to obtain 5-(α-
Bromobutyryl)-8-hydroxycarbostiri
Obtained 27g of gel [melting point 218-219℃ (colored decomposition)].
5-(α-bromobutyryl)-8-hydroxy
5g of carbostyril and 100ml of isopropylamine
was added, heated at 50℃ for 4 hours, concentrated to dryness, and added water.
The crystals that precipitate are washed with water and removed from methanol.
Recrystallize to form 8-hydroxy-5-(α-isopropylene)
pyraminobutyryl) carbostyryl-methanol
4.6 g of the alcohol solvate are obtained. Melting point 136-137℃ (foaming
Disassembly). Example 25 25g of β-phenethylamine was added to Example 38, 39 or
5-(α-bromobutyryl)-8- produced in 40
Add 5g of hydroxycarbostyril and mix
Stirred at a temperature of 30°C for 8 hours. diethyl ether
and petroleum ether to the reaction mixture to precipitate
Dissolve the stagnant material in dilute hydrochloric acid to remove insoluble materials
did. Concentrate the hydrochloric acid layer, remove the precipitate, and add ethanol.
Recrystallize from the liquid to a melting point of 200-201℃ (color decomposition).
Obtained 5.3 g of material with obtained in this way
The substances were analyzed by NMR spectrum and IR spectrum.
Analysis and elemental analysis revealed that 5-[α-(β-phene
tylamino)]butyryl-8-hydroxycarbo
It was confirmed that it was styryl hydrochloride dihydrate. Example 26 Morpholine 5ml 5- produced in Reference Examples 17 to 19
(α-bromobutyryl)-8-hydroxycarbo
Add 5g of styryl and heat the mixture to 40°C while stirring.
The reaction was carried out at a temperature of 4 hours. Then reduce the reaction mixture.
It was concentrated under pressure, and 100 ml of water was added to the resulting residue. Mixed
The mixture was stirred, filtered, and the mother liquor was concentrated under reduced pressure.
Ta. Dissolve the residue in acetone and filter this solution.
Insoluble material was removed. Then concentrate the liquid under reduced pressure
Then adjust the pH to 2-3 with concentrated hydrochloric acid, and cool in an ice bath.
The precipitate formed is recrystallized from ethanol to determine the melting point.
White amorphous 5- with a temperature of 179-182℃ (decomposition)
(α-morpholinobutyryl)-8-hydroxyca
2.1 g of rubostyril hydrochloride monohydrate was obtained. this
The product obtained in this way was analyzed by NMR spectroscopy.
Confirmed by analysis, IR spectrum analysis and elemental analysis.
Approved. Reference example 20 α-bromopropionyl chloride 17.1g, anhydrous
27g of aluminum chloride and 8ml of nitrobenzene
8-methoxy-3,4-dihydrocarbostyryl
8g and heat the mixture at 50°C for 1 hour while stirring.
Heated to a temperature of 60°C. The reaction mixture is then poured into ice-water.
Pour onto 200ml, remove the formed precipitate and wash with water.
Purified. This precipitate was then recrystallized from ethanol.
11.5 g of material having a melting point of 154°C to 155°C was obtained.
The product thus obtained has an NMR spectrum
by IR spectrum analysis and elemental analysis.
5-(α-bromopropionyl)-8-methoxy
Must be C-3,4-dihydrocarbostyryl
It was confirmed. Reference example 21 α-bromobutyryl bromide 26.4g, anhydrous salt
17.5 g of aluminum chloride and 5 ml of nitrobenzene
8-methoxy-3,4-dihydrocarbostyryl
Add 5g to 50-60 g for 1 hour while stirring the mixture.
heated to a temperature of °C. Next, mix the reaction mixture with ice-water.
Pour into 100ml, remove the formed precipitate and wash with water.
Purified. The precipitate was then recrystallized from ethanol and melted.
5 g of material having a temperature of 151 DEG -152 DEG C. was obtained. In this way
The obtained product was subjected to NMR spectroscopy and IR spectrum analysis.
Spectral analysis and elemental analysis revealed that 5-(α-bromine)
Mobutyryl)-8-methoxy-3,4-dihydro
It was confirmed that it was carbostyril. Example 27 5-(α-bromopropiopropyl) produced in Reference Example 20
Nyl)-8-methoxy-3,4-dihydrocarbos
Suspend 2 g of Tyril in 50 ml of isopropanol,
This suspension was stirred at a temperature of 60°C for 2 hours.
Ta. The solvent is then distilled off and the resulting residue is
Dissolved in 50ml of propanol. This solution is then concentrated.
The pH was adjusted to 2-3 with hydrochloric acid. Remove the formed precipitate
and add a mixture of acetone and diethyl ether to the liquid.
added to. Collect the formed precipitate and add isopropanol
It has a melting point of 172-174℃ (decomposition) when recrystallized from a
1.5 g of a white amorphous material was obtained. in this way
The product obtained was analyzed by NMR spectroscopy and
By IR spectrum analysis and elemental analysis, 5-(α
-isopropylaminopropionyl)-8-meth
xy-3,4-dihydrocarbostyryl hydrochloride di
It was confirmed that it was a hydrate. Example 28 5-(α-bromopropio) obtained in Reference Example 20
)-8-methoxy-3,4-dihydrocarbo
5g of styryl was suspended in 50ml of isopropanol.
Then add 10g of tert-butylamine and heat at 60℃ for 15 hours.
Stir. Distill the solvent and dilute the residue with isopropanol.
After dissolving in 10ml, add concentrated hydrochloric acid to adjust the pH to 2-3. Analysis
Separate the output, add acetone to the liquid, and then
The precipitates are further separated. Add ether to the liquid
Remove the precipitate. Isopropanol-ether
It is colorless and has a melting point of 207-210℃ (decomposition) when recrystallized from
2.1 g of solid material is obtained. This item is NMR, IR and
From the analysis results by elemental analysis and
butylaminopropionyl)-8-methoxy-
3,4-dihydrocarbostyryl hydrochloride monohydrate
I confirm. Example 29 5-(α-bromobutyl) obtained in Reference Example 21
)-8-methoxy-3,4-dihydrocarbos
After suspending 2g of Tyril in 50ml of isopropanol
Add 5g of isopropylamine and stir at 60℃ for 4 hours.
Stir. The solvent was distilled off and the residue was diluted with isopropanol 5
After dissolving in ml, add concentrated hydrochloric acid to adjust the pH to 2-3. precipitation
Remove the material and reconstitute with isopropanol-acetone.
A colorless amorphous substance with a crystalline melting point of 204-206℃ (decomposition)
Obtain 1.7g of quality. This item includes NMR, IR and elemental content.
From the analysis results, 5-(α-isopropyla
minobutyryl)-8-methoxy-3,4-dihyde
Confirmed as locarbostyril hydrochloride monohydrate. Example 30 5-(α-bromobutylene obtained in Reference Example 21)
)-8-methoxy-3,4-dihydrocarbos
After suspending 3g of Tyril in 50ml of isopropanol
Add 9g of tert-butylamine and stir at 60℃ for 19 hours.
Stir. The solvent was distilled off and the residue was diluted with isopropanol 5
After dissolving in ml, add concentrated hydrochloric acid to adjust the pH to 2-3. precipitation
Separate the liquid, add acetone to the liquid, and then
The precipitates are further separated. Add ether to the liquid
Well, remove the precipitate. Reproduced from isopropanol
Colorless amorphous substance with crystalline melting point of 160-162℃ (decomposition)
Obtain 1.6g of quality. This item includes NMR, IR and elemental content.
From the analysis results, 5-(α-tert-butyl acetate)
minobutyryl)-8-methoxy-3,4-dihyde
Confirmed as locarbostyril hydrochloride monohydrate. Example 31 The 5-(α-isopropyl alcohol obtained in Example 27)
(minopropionyl)-8-methoxy-3,4-di
Hydrocarbostyril 1.5g 47% hydrobromic acid 15
ml and heated under reflux at 130-140°C for 15 hours. anti
Concentrate the reaction solution and add acetone to crystallize it. workman
Recrystallized from tanol-acetone, melting point 223-226
Obtain 1.1 g of substance at °C (decomposition). This thing is
Based on the analysis results of NMR, IR and elemental analysis, 5-
(α-isopropylaminopropionyl)-8-
Hydroxy-3,4-dihydrocarbostyryl odor
Confirm with hydrochloride. Example 32 5-(α-isopropylaminobutyryl)-8
-Methoxy-3,4-dihydrocarbostyryl
Dissolve 1.5g in 15ml of 47% hydrobromic acid and heat to 130-140℃
Heat under reflux for 15 hours. Concentrate the reaction solution and add acetone.
Add and crystallize. Ethanol-acetone
Recrystallize to obtain 1.0g of a substance with a melting point of 165-168℃.
Ru. This material can be separated by NMR, IR and elemental analysis.
From the analytical results, 5-(α-isopropylaminobutyryl)
)-8-hydroxy-3,4-dihydrocarbo
Confirmed as styryl hydrobromide hemihydrate. Example 33 Hydrochloride hydrate made as described in Example 28
5-(α-tert-butylaminopropyl) obtained from
onyl)-8-methoxy-3,4-dihydrocal
Dissolve 1 g of Bostyril in 15 ml of 47% hydrobromic acid.
Heat under reflux at 140-150°C for 15 hours. Concentrate the reaction solution
Add acetone to crystallize. ethanol-
Recrystallized from acetone with a melting point of 224-227℃ (decomposition)
Obtain 0.7 g of substance. This one includes NMR, IR and elemental
From the analysis results, 5-(α-tert-butyl
Aminopropionyl)-8-hydroxy-3,4
-Dihydrocarbostyryl hydrobromide monohydrate
I confirm. Example 34 Hydrochloride 1 water made as described in Example 30
5-(α-tert-butylaminobutyl
Ryl)-8-methoxy-3,4-dihydrocarbo
Dissolve 1.5 g of styryl in 15 ml of 47% hydrobromic acid and add 140
Heat to reflux at ~150°C for 19 hours. Concentrate the reaction solution
Add acetone to crystallize. Ethanol-a
Recrystallized from setone with a melting point of 144-146℃ (decomposition)
Obtain 1.1g of quality. This item includes NMR, IR and elemental content.
From the analysis results, 5-(α-tert-butyl acetate)
minbutyryl)-8-hydroxy-3,4-dihi
Confirmed as dolocarbostyryl hydrobromide dihydrate
do. Example 35 5-(αbromopropionyl)-8-hydroxy
5 g of C-3,4-dihydrocarbostyril was added to the
Suspend in 30 ml of Zen and add mol to this suspension.
Add 4.2 ml of Holin and then heat the mixture under reflux
The reaction was continued for 4 hours. Filter the reaction mixture.
Then, wash the liquid with water and concentrate under reduced pressure to remove the remaining water.
Removed. Pour the resulting residue into 50 ml of isopropanol.
and adjust the solution to pH 2-3 with concentrated hydrochloric acid.
Ta. A viscous precipitate formed by cooling in an ice bath.
The lees were separated and dissolved in acetone by heating. Cool the solution
After cooling, the formed precipitate was dissolved in 30 ml of water and diluted with sodium bicarbonate.
The pH was adjusted to 7.5-8 with lime. By ice bath cooling
Take the formed precipitate and add 10ml of 47% hydrogen bromide aqueous solution.
and then concentrated under reduced pressure. obtained in this way
Wash the residue with 10 ml of ethanol, and
It has a melting point of 235-236℃ (decomposed) when recrystallized from
White amorphous 5-(α-morpholino)-propio
Nyl-8-hydroxy-3,4-dihydrocarbo
2.6 g of styryl hydrobromide monohydrate was obtained. Reference example 22 30ml of nitrobenzene and chloroacetyl chloride
70ml of 1-methyl-8-methoxycarbostyryl
40g and add to this while cooling the mixture in an ice bath.
Gradually add 130g of aluminum chloride and then mix
The mixture was reacted at a temperature of 60° C. for 4 hours with stirring.
Next, the reaction mixture was poured into 1 ice water to obtain the product.
was precipitated. Collect the precipitate and dilute it with diethyl ether.
Wash with chloroform and ethanol (2:5 volume).
Recrystallized from a mixture of
white amorphous 1-methyl-5-chloroa with
Obtained 32g of cetyl-8-methoxycarbostyril.
Ta. The product thus obtained was subjected to elemental analysis.
By IR spectral analysis and NMR spectral analysis
I confirmed it. Reference example 23 40ml of nitrobenzene and monochloroacetylchloride
12ml of Lido to 1-methyl-8-hydroxycarbos
Add 7.4 g of Chiril and cool the mixture with ice water.
Gradually add 20g of aluminum chloride to this, and then
React at a temperature of 60 °C for 18 h while stirring the mixture to
I let it happen. Next, pour the reaction mixture into 500ml of ice water.
The product was precipitated. Take the precipitate and dilute it with diethyl
Wash with ether, ethanol and dimethylform
Recrystallized from a mixture of amides (1:1 volume ratio)
White amorphous 1 with melting point 287-289℃ (decomposition)
-Methyl-5-chloroacetyl-8-hydroxy
2.8 g of carbostyril was obtained. This way you get
The resulting product was subjected to elemental analysis and IR spectrum analysis.
This was confirmed by NMR spectrum analysis. Example 36 1-methyl-5-chloroa produced in Reference Example 22
Inject 2.7 g of cetyl-8-methoxycarbostyryl.
Dissolve in 40 ml of sopropanol and leave the solution for 1.5 hours.
Pour into this while heating to a temperature of 55-60℃.
9 g of soproamine was added. After adding, mix
The mixture was allowed to react for 1 hour with stirring. reaction mixture
was concentrated under reduced pressure, and the resulting residue was diluted with isopropanol.
Dissolved in 40ml. Then pass through the solution to remove the insoluble matter.
Remove the substances and adjust the pH of the liquid to 2 to 3 with concentrated hydrochloric acid.
Ta. Cool the mixture in an ice bath and remove the precipitate that has formed.
and recrystallized from ethanol to obtain white amorphous 1-
Methyl-5-isoproaminoacetyl-8-meth
Xycarbostyril hydrochloride was obtained. Do it like this
The product obtained was subjected to morphological analysis and IR spectrum analysis.
This was confirmed by analysis. Example 37 10 ml of isoproamine was prepared in Example 59.
Methyl-5-chloroacetyl-8-hydroxyka
Add 1.6g of Luvostyril, stirring the mixture
The reaction was then carried out at a temperature of 35°C for 2 hours. reaction mixture
Concentrate under reduced pressure and dry by azeotropic distillation with ethanol.
Ta. Dissolve the obtained residue in 20 ml of ethanol and
The liquid is filtered to remove insoluble substances, which are then subjected to heat evaporation.
Dissolve in tanol. Adjust the solution to PH2-3 with concentrated hydrochloric acid.
and cooled in an ice bath. Remove the formed precipitate
It was dissolved in 20ml of water. Solution with sodium bicarbonate
Adjust the pH to 6.5 to 7.5 and remove the formed precipitate with ethanol.
Recrystallized from white powder with a melting point of 136-138℃ (decomposition)
Regular form of 1-methyl-5-isopropylaminoacetate
Obtained 1.1g of thyl-8-hydroxycarbostyril.
Ta. Example 38 -Methyl-5-isopropyl produced in Example 36
Ruaminoacetyl-8-methoxycarbostyryl
Dissolve 2.0 g of hydrochloride in 30 ml of 47% hydrobromic acid aqueous solution.
The solution was refluxed for 8 hours at a temperature of 120-130°C.
Heated in an oil bath. Add 10ml of water to the reaction mixture.
Then, it was concentrated by distillation. Add 10ml of water to the mixture again.
It was then concentrated. After cooling the mixture, formed
The precipitate was collected and dissolved under heating in 60 ml of water. obtained
Adjust the pH of the solution to 6.5-7.5 with sodium bicarbonate.
Then, the formed precipitate was collected. Precipitate with ethanol
white with a melting point of 136-138℃ (decomposition)
Colorless amorphous 1-methyl-5-isopropylamino
Acetyl-8-hydroxycarbostyryl 0.45g
I got it. Reference example 24 5-isopropylaminoacetyl-8-hydro
Dissolve 1.0 g of xycarbostyril hydrochloride in 40 ml of water.
Dissolved, add 0.5g of palladium on carbon as a catalyst,
Heat to ~40°C and absorb hydrogen while stirring. reduction
At the end of the process, separate the catalyst and concentrate the liquid under reduced pressure.
Reduce to dryness. Add more ethanol and concentrate to dryness
After completely removing the water, add acetate to the residue.
and crystallize it. Dilute the residue with ethanol
Recrystallized from setone (volume ratio 1:1), melting point 210
~212℃ (decomposition) pale yellow amorphous 5-(2-i)
Sopropylamino-1-hydroxy)ethyl-8
- Obtained 0.4g of hydroxycarbostyril hydrochloride
Ru. Reference example 25 5-sec-butylaminoacetyl-8-hydro
Dissolve 2.0g of xycarbostyril in 100ml of methanol.
Dissolve and add 0.8 ml of sodium boron hydride while stirring on ice.
Gradually add g. Stirring was carried out at the same temperature for 15 minutes.
Afterwards, stirring is continued for an additional hour at room temperature. Add concentrated hydrochloric acid
After adjusting the pH to 1.5 to 2, the solvent is distilled off under reduced pressure. residue
Add 300 ml of ethanol to the solution and dry under reduced pressure again to remove moisture.
Remove. Add 50ml of absolute ethanol to the residue and dissolve.
Add a solution of sodium hydroxide in ethanol.
Well, adjust the pH to 7-8.5. Separate the precipitate,
Dry the liquid under reduced pressure. Add 50ml of absolute ethanol to the residue.
and pass hydrogen chloride gas through the extract. Decompression
After concentrating to dryness, the residue was dissolved in isopropyl alcohol.
Pale yellow with a melting point of 143-144℃ (decomposition) after recrystallization from
Colorless amorphous 5-(1-hydroxy-2-sec-b)
thylamino)ethyl-8-hydroxycarbosti
1.3 g of ril dihydrochloride monohydrate are obtained. Reference example 26 5-tert-butylaminoacetate obtained in Example 2
1.5g of Ru-8-hydroxycarbostyril in meth
Dissolve in 100 ml of sodium hydride and stir under ice-cooling.
Gradually add 0.7 thorium boron. Same temperature for 15 minutes
Stir at room temperature for an additional 1 hour.
cormorant. Below, the same treatment as in Example 2 was carried out to produce ethanol.
Recrystallized from pale yellow with a melting point of 242-244℃ (decomposition)
Amorphous 5-(1-hydroxy-2-tert-butylene)
Ruamino)ethyl-8-hydroxycarbostili
Obtain 0.9 g of Ru hydrochloride. Reference example 27 5-piperidinoacetyl produced in Example 4
8-Hydroxycarbostyril hydrochloride 2.0g
Dissolve in 200ml of tanol and cool the solution in an ice bath.
Add 2.0g of sodium borohydride and then
The mixture was stirred for 2 hours. The mixture was adjusted to pH2 with concentrated hydrochloric acid.
~3 and let the mixture stand at room temperature for 1 hour and then
passed. The filtered reaction mixture was concentrated under reduced pressure to remove the residue.
The residue was dissolved in 30 ml of ethanol. Strain the solution
Insoluble materials were removed and the liquid was concentrated under reduced pressure. this
(dissolution in ethanol, filtration and concentration)
was repeated three times. Add the obtained residue to acetone.
Dissolve with heat, remove the precipitate formed by cooling, and
Recrystallized from propanol, melting point 146-148℃ (min.
white amorphous 5-(1-hydroxy
-2-piperidino)ethyl-8-hydroxycal
Bostyril hydrochloride 11/2 hydrate was obtained. like this
The product obtained was subjected to IR spectroscopy and
Confirmed by NMR spectroscopy and elemental analysis
Ta. Reference example 28 5-morpholinoacetyl produced in Example 5
8-Hydroxycarbostyril 1.0g with methanol
Dissolve sodium borohydride in 100 ml of this solution.
Add 1.2g of hydride and then stir the mixture.
The reaction was continued for 2 hours. PH the reaction mixture with concentrated hydrochloric acid
2-3 and leave the mixture at room temperature for 1 hour.
Ta. Next, the reaction mixture was filtered and the liquid was concentrated under reduced pressure.
Ta. Dissolve the residue in 20ml of ethanol and add this solution.
The insoluble substances were removed by filtration, and the solution was concentrated under reduced pressure.
Ta. This operation (dissolving in ethanol, super and concentrated
) was repeated three times, and the residue thus obtained was
The residue was recrystallized from acetone. the precipitated crystals
Take it and mash it with 20ml of sodium bicarbonate aqueous solution.
Remove the soluble substances by filtration and remove the insoluble substances with water.
Wash with water and heat dissolve in ethanol. obtained
Adjust the pH of the solution to 2-3 with concentrated hydrochloric acid and cool.
The precipitate formed by
White amorphous 5-(1
-Hydroxy-2-morpholino)ethyl-8-
Hydroxycarbostyril hydrochloride 11/2 hydrate
Obtained. The product thus obtained is an IR spectrometer.
vector analysis, NMR spectrum analysis and elemental analysis
Confirmed by. Reference example 29 50 ml of methanol was mixed with 5-ben produced in Example 14.
Dylaminoacetyl-8-hydroxycarbosti
Add 5 g of Ryl's free base and cool the solution in an ice bath.
and sodium borohydride to this under stirring
3g was added slowly and the mixture was stirred at room temperature for 1 hour.
did. The resulting mixture was adjusted to PH1 with concentrated hydrochloric acid,
The precipitate formed was separated. Concentrate and dry the liquid.
Crystallized from setone, the resulting crystals are hydroxylated
Precipitate formed by adjusting pH to 8 with sodium aqueous solution
and washed with water. Adjust the precipitate to PH1 with dilute hydrochloric acid.
The mixture was adjusted and concentrated to dryness. obtained in this way
Recrystallize the residue from a mixture of methanol and acetone
4.2g of a white amorphous substance with a melting point of 120-121℃
Obtained. The product thus obtained is
Spectral analysis, IR spectral analysis and elemental analysis
5-(1-hydroxy-2-benzyl)
Mino)ethyl-8-hydroxycarbostyryl salt
It was confirmed that it was an acid salt dihydrate. Reference example 30 5-(1-phenethylamine produced in Example 6)
noacetyl)-8-hydroxycarbostyryl salt
Dissolve 1 g of the acid salt in 50 ml of methanol, and add this solution to
Weakly alkaline with methanol solution of sodium hydroxide
changed to Then add water to this mixture while cooling in an ice bath.
Add 0.5g of thorium borohydride and then bring to room temperature.
The mixture was stirred for 1 hour at . Concentrated salt until PH3
Separate the precipitate formed by adding acid;
The liquid was concentrated and dried. The resulting residue is converted into pure ethanol.
Dissolve the solution in sodium hydroxide in ethanol.
The pH was adjusted to 9 with a solution of water. The precipitate separates and the liquid
was concentrated and dried. Crystallize the residue from acetone
and washed with water. The obtained crystals are diluted with isopropano
This solution was saturated with hydrochloric acid gas and then cooled.
Rejected. Remove the formed precipitate with isopropanol.
A white amorphous substance with a melting point of 162-164℃ after recrystallization from
Obtained 0.77 g of shaped material. obtained in this way
The product was analyzed by NMR spectroscopy and IR spectroscopy.
Analysis and elemental analysis revealed that 5-[1-hydroxy-2
-(1-phenethylamino)]-ethyl-8-h
Droxycarbostyril hydrochloride dihydrate
I confirmed that. Reference Example 31 0.1 g of platinum oxide and 50 ml of water were produced in Example 14.
5-benzylaminoacetyl-8-hydroxy
In addition to 0.5 g of carbostyril hydrochloride monohydrate, mix
The mixture was exposed to air in a hydrogen atmosphere for 24 h with stirring.
Reduced under pressure at room temperature. After the return is completed, please touch
The medium was separated, and the aqueous layer was concentrated and dried. Residue is methano
Recrystallized from a mixture of alcohol and acetone, melting point 261.
White amorphous 5-(1) with ~262°C (decomposition)
-Hydroxy-2-amino)ethyl-8-hydro
0.25 g of xicarbostyril hydrochloride was obtained. This way
The product obtained in this way was analyzed by IR spectroscopy and
Confirmed by NMR spectroscopy and elemental analysis
did. Reference example 32 5-(2,2-dimethylphenethylaminoacetate)
Chill)-8-hydroxycarbostyril 1.5g
Dissolve in 5 ml of methanol and stir while cooling with ice water.
Add 1 part of sodium borohydride to this solution.
g and then continued stirring at room temperature for an additional hour.
Ta. The resulting mixture was then adjusted to pH 1 with concentrated hydrochloric acid.
The mixture was concentrated to dryness. Convert residue into ethanol
Insoluble material was removed by dissolution and separation. Etano
Concentrate and dry the solid layer and dissolve the residue in isopropanol.
Dissolved. This isopropanol layer is concentrated and acetate
The product was crystallized. The product is meta
Recrystallized from nor-acetone, melting point 167-168℃
Obtained 1.4 g of a white amorphous substance with (color decomposition)
Ta. NMR spectrum of the substance obtained in this way
by IR spectrum analysis, IR spectrum analysis, and elemental analysis.
5-[2-(2,2-dimethylphenethylamine
-1-hydroxy]ethyl-8-hydroxy
Confirmed to be carbostyril hydrochloride dihydrate
did. Reference example 33 Add 2.5 g of chloranil and 20 ml of xylene to 5-(1
-Hydroxy-2-amino)ethyl-8-hydro
2.2g of xy-3,4-dihydrocarbostyryl
and the mixture was heated under reflux for 24 hours. reaction mixture
The mixture was then concentrated to dryness and the residue was quenched with carbon tetrachloride.
Crab washed. The residue was then dissolved in 30 ml of methanol.
The solution is dissolved by introducing hydrochloric acid gas into the solution.
The pH of the solution was adjusted to 1. Remove the precipitated crystals and
Recrystallized from nol to a melting point of 261-262℃ (decomposed)
1.5 g of material was obtained. obtained in this way
The resulting product was analyzed by NMR spectroscopy and IR spectroscopy.
Analysis and elemental analysis revealed that 5-(1-hydroxy-
2-amino)ethyl-8-hydroxycarbosti
It was confirmed that it was ril hydrochloride. Reference example 34 200ml of water, 0.9g of sodium hydroxide and Raneni
5-[2-(2,2-dimethyl fluoride)
enethylamino-1-hydroxy]ethyl-8-
Hydroxy-3,4-dihydrocarbostyryl salt
Add 4.3 g of the acid salt dihydrate and bring the mixture under reflux for 15 min.
Heated to a temperature of 80°C for an hour. Then the reaction mixture
The catalyst was removed by filtration and the liquid was concentrated. obtained
Recrystallize the crystal precipitate from water to obtain a melting point of 167-168℃.
2.6 g of material with (decomposition) was obtained. Do it like this
The product obtained was subjected to NMR spectroscopy and IR spectrum analysis.
Spectral analysis and elemental analysis revealed that 5-[1-hydro]
Roxy-2-(2,2-dimethylphenethylamine)
c)] Ethyl-8-hydroxycarbostyryl salt
It was confirmed that it was an acid salt monohydrate. Reference example 35 5-isopropylaminol obtained in Example 18
Cetyl-8-hydroxy-3,4-dihydrocal
Dissolve 2.0 g of bostyril hydrochloride in 40 ml of water and add
Add 0.5g of Dium Black as a catalyst and heat to 70-75℃.
Stirring was performed at room temperature and under normal pressure to absorb hydrogen. return
When the gas is finished, separate the catalyst and concentrate the liquid under reduced pressure.
It was evaporated to dryness. Further water completely using ethanol.
After removing the residue, add acetone to crystallize it.
I set it. Ethanol-azetone (volume ratio 1:1)
Colorless amorphous crystal with a melting point of 199-201℃ after recrystallization.
1.1 g of quality was obtained. This item includes NMR, IR and elemental content.
From the analysis results, 5-(2-isopropyl acetate)
mino-1-hydroxy)ethyl-8-hydroxy
-3,4-dihydrocarbostyryl hydrochloride
This was confirmed. Reference example 36 5-tert-butylaminoa obtained in Example 20
Cetyl-8-hydroxy-3,4-dihydrocal
Dissolve 1.5 g of bostyril hydrochloride in 35 ml of water and add
Add 1.0g of dium carbon as a catalyst, 50-60℃, 4
Shaking was performed under ~5 atmospheres to absorb hydrogen. return
When the original is finished, separate the palladium on carbon,
The liquid was concentrated to dryness under reduced pressure. Add acetone to the residue
Crystallize, methanol-acetone (volume ratio 1:
1) Recrystallized to form colorless crystals with a melting point of 240-241℃
0.8g of substance was obtained. This item includes NMR, IR and original
From the analysis results of elementary analysis, 5-(2-tert-buti)
Ruamino-1-hydroxy)ethyl-8-hydro
xy-3,4-dihydrocarbostyril hydrochloride
It was confirmed that there is. Reference example 37 5-sec-butylaminol obtained in Example 12
Cetyl-8-hydroxy-3,4-dihydrocal
Dissolve 2.0g of Bostyril in 100ml of methanol and add to ice.
Gradually add 0.8 g of sodium boron hydride under cold stirring.
added to. After stirring at the same temperature for 15 minutes,
Stirring was carried out at room temperature for an hour. PH with concentrated hydrochloric acid
After adjusting the concentration to 1.5 to 2, the solvent was distilled off under reduced pressure. on the residue
Add 30ml of tanol and dry under reduced pressure again to remove water.
Ta. Add 50ml of absolute ethanol to the residue and dissolve it.
Add ethanolic solution of sodium hydroxide to adjust the pH.
Adjusted to 7-8.5. Separate the precipitate and reduce the liquid.
It was dried under pressure. Extract the residue with 50ml of absolute ethanol
Then, hydrogen chloride gas was passed through the extract. Vacuum concentration drying
After solidifying, the residue was mixed with methanol-acetone (volume ratio
1:1) Recrystallized from mixed solvent, melting point 183-184℃
1.3 g of a colorless amorphous substance was obtained. This thing is
Based on the analysis results of NMR, IR and elemental analysis, 5-
(2-sec-butylamino-1-hydroxy)ethyl
Ru-8-hydroxy-3,4-dihydrocarbos
It was confirmed to be tyryl hydrochloride. Reference example 38 Add 0.7 g of palladium black and 130 ml of water to 8-hydroxy
-5-(α-methylbenzylaminoacetyl)ka
Add 1.5 g of Luvostyril Hydrochloride and shake the mixture.
The reaction was carried out under a hydrogen pressure of 4 atm at a temperature of 60°C.
The catalyst was separated and the aqueous layer was concentrated to dryness. residue
Acetone was added to the solution to crystallize the product. product
Next, wash with 100ml of ethanol, and mix with methanol.
Recrystallized from a mixture of ethyl acetate to give a white amorphous
5-(1-hydroxy-2-2-methylbenzyl
amino) ether-8-hydroxy-3,4-dihi
0.8 g of dolocarbostyril hydrochloride was obtained. This way
The product obtained in this way was analyzed by IR spectroscopy.
Confirmed by NMR spectroscopy and elemental analysis
Ta. Reference example 39 Mix 0.1 g of palladium black and 50 ml of water with 5-[(1-hyde)
Roxy-2-benzylamino)ethyl]-8-h
In addition to droxycarbostyril hydrochloride dihydrate,
The mixture was exposed to air for 8 hours under a hydrogen atmosphere while stirring.
The reaction was carried out at room temperature under pressure. reaction has finished
Afterwards, the catalyst is separated and the aqueous layer is concentrated to dryness. this
The residue obtained in this way was mixed with methanol and acetone.
Recrystallized from a mixture of 5-(1-
Hydroxy-2-amino)ethyl-8-hydroxy
0.2 g of cicarbostyril hydrochloride was obtained. like this
The product obtained was subjected to IR spectroscopy and
Confirmed by NMR spectroscopy and elemental analysis
Ta. Reference example 40 Add 0.7g of palladium black and 100ml of water to 5-(α-base).
ndylaminoacetyl)-8-hydroxy-3,
Added to 1.4g of 4-dihydrocarbostyril hydrochloride
Then, the mixture was heated to 60°C under 4 atmospheres of hydrogen pressure.
Refund with. After the reduction is complete, separate the catalyst and collect the
The aqueous solution was concentrated and dried. Add acetone to the residue
The added product crystallized. obtained in this way
Wash the collected crystals with 100ml of ethanol, and
Recrystallized from a mixture of chloride and ethyl acetate to form a white amorphous
5-(1-hydroxy-2-amino)ethyl of the form
-8-hydroxy-3,4-dihydrocarbosti
0.7 g of ril hydrochloride was obtained. obtained in this way
The resulting product was analyzed by IR spectroscopy and NMR spectroscopy.
Confirmed by analysis and elemental analysis. Reference example 41 0.05 g of platinum black and 100 ml of water were mixed with 5-[(1-hydro
xy-2-amino)ethyl]-8-hydroxyca
Add 1g of Luvostyril Hydrochloride and shake the mixture.
while at 50℃ for 10 hours at 2 atmospheres of hydrogen pressure.
I gave back. After the reduction is complete, separate the catalyst and remove the aqueous layer.
was concentrated and dried. The precipitate obtained in this way
Recrystallize and melt from a mixture of methanol and acetone.
White amorphous 5-[(1-
Hydroxy-2-amino)ethyl]-8-hydro
xy-3,4-dihydrocarbostyril hydrochloride
0.9g was obtained. The product thus obtained is
IR spectral analysis and NMR spectral analysis and
Confirmed by elementary analysis. Reference example 42 Add 0.5 g of palladium black and 50 ml of water to 5-(1-hi)
Droxy-2-isopropylamino)ethyl-8
-2g of hydroxycarbostyril plus the mixture
hydrogen atmosphere at a temperature of 70 °C with shaking.
It was reduced to below atmospheric pressure. After the reduction is complete, remove the catalyst.
The aqueous layer was separated and concentrated to dryness. obtained in this way
The precipitate was recovered from a mixture of methanol and acetone.
Crystalline white amorphous 5-(1-hydroxy-2
-isopropylamino)ethyl-8-hydroxy
-3,4-dihydrocarbostyril hydrochloride 1.7g
I got it. The product thus obtained is
Spectral analysis and NMR spectral analysis and elemental content
This was confirmed by analysis. Reference example 43 Add 0.1 g of palladium black and 30 ml of water to 5- [(1-
Droxy-2-sec-butylamino)ethyl]-8
- Add 1 g of hydroxycarbostyril and mix
3 atmospheres at a temperature of 60℃ for 10 hours with shaking.
It was reduced with hydrogen pressure. After the reduction is complete, remove the catalyst.
The aqueous layer was separated and concentrated to dryness. obtained in this way
The precipitate was recovered from a mixture of methanol and acetone.
Crystallized to 5-(1-hydroxy-2-sec-butyl
amino)ethyl-8-hydroxy-3,4-dihy
0.6 g of dolocarbostyril hydrochloride was obtained. This way
The product obtained in this way was analyzed by IR spectrum analysis.
Confirmed by NMR spectroscopy and elemental analysis
Ta. Reference example 44 0.5g of 10% palladium on carbon and 50ml of water
[(1-hydroxy-2-tert-butylamino)ethyl
]-8-hydroxycarbostyril hydrochloride 1.5
g and the mixture was incubated at 75 °C for 16 h with shaking.
It was reduced at a temperature of 5 atmospheres of hydrogen pressure. of reduction
After completion, the catalyst was separated and the aqueous layer was concentrated and dried. child
The precipitate obtained as above was mixed with methanol and acetate.
It has a melting point of 240-241℃ when recrystallized from a mixture of
white amorphous 5-(1-hydroxy-2-tertiary)
butylamino)ethyl-8-hydroxy-3,4
-Dihydrocarbostyril 1.1 was obtained. like this
The product obtained was subjected to IR spectroscopy and
Confirmed by NMR spectroscopy and elemental analysis
Ta. Reference example 45 100 mg of palladium black and 50 ml of water were mixed with 5-[1-hyde
Roxy-2-(2,2-dimethylphenethylamine)
c)] Ethyl-8-hydroxycarbostyryl salt
Add 300 mg of acid salt monohydrate and store the mixture at 45-50℃.
Reduced at 2.5 atm hydrogen pressure for 8 hours at temperature
Ta. The catalyst was separated and the liquid was concentrated and dried. water the residue
A white amorphous substance with a melting point of 120-121℃ after recrystallization from
Obtained 260 mg. The product thus obtained is
NMR spectral analysis and IR spectral analysis and original
By elementary analysis, 5-1-hydroxy-2-(2,2
-dimethylphenethylamino)ethyl-8-hydro
Roxy-3,4-dihydrocarbostyril hydrochloride
It was confirmed that it was a dihydrate. Reference example 46 Add 0.2 g of platinum oxide and 50 ml of water to 5-(1,1-di
methylphenethylaminoacetyl)-8-hydro
Added to 1.0g of xycarbostyril hydrochloride 1/2 hydrate
Then, the mixture was heated to 5 atm hydrogen pressure for 20 hours at a temperature of 80°C.
It was returned in Concentrate the liquid after removing the catalyst
Dry. The obtained residue was recrystallized from water to determine the melting point.
Obtained 0.8g of white amorphous material with temperature of 120-121℃
Ta. The product thus obtained is an NMR spectrometer.
For spectrum analysis, IR spectrum analysis, and elemental analysis
5-1-hydroxy-2-(1,1-dimethy
ruphenethylamino)ethyl-3,4-dihydro
Confirmed to be carbostyril hydrochloride dihydrate
did. Reference example 47 5-piperidinoacetyl-8-hydroxycal
Dissolve 1.5 g of bostyril hydrochloride in 100 ml of water and add
0.5g of dium carbon and 0.2g of palladium black in their solution
Then add the resulting mixture to 70 ml while shaking.
Under atmospheric pressure in a hydrogen atmosphere for 4 days at a temperature of °C.
It was catalytically reduced. After the end of the reduction, the reaction mixture is
The catalyst was removed separately by filtration, and the liquid was concentrated and dried under reduced pressure.
did. The obtained residue was heated and dissolved in acetone, and then
The solution was cooled. The precipitate formed by cooling
Recrystallized from isopropanol, melting point 136-139℃
white amorphous 5-(2-piperi) with (decomposition)
Dino-1-hydroxy)ethyl-8-hydroxy
-3,4-dihydrocarbostyril hydrochloride 1/2 water
0.8 g of the compound was obtained. The generation thus obtained
The material is analyzed by IR spectrum analysis, NMR spectrum analysis and
This was confirmed by elemental analysis. Reference example 48 10ml of 47% bromic acid aqueous solution was mixed with 5-(1-hydroxy
C-2-isopropylamino)ethyl-8-meth
In addition to 1 g of xycarbostyril hydrochloride monohydrate,
The mixture was heated under reflux for 15 hours and then concentrated to dryness.
Ta. Add acetone to the resulting residue to solidify the product.
crystallize, then add this to dilute aqueous sodium hydroxide solution
The pH was adjusted to 8. Take the precipitated crystals and add water
Washed and dissolved in ethanol. Solution with concentrated hydrochloric acid
The pH was adjusted to 1 and concentrated to dryness. In this way
Mix the obtained residue with ethanol and diethyl ether
It has a melting point of 210-212℃ (decomposition) when recrystallized from a substance.
0.7g of the substance was obtained. The raw material obtained in this way
The composition was analyzed by NMR spectrum analysis and IR spectrum analysis.
and elemental analysis revealed that 5-(1-hydroxy-2-
isopropylamino)ethyl-8-hydroxyca
It was confirmed that it was rubostyril hydrochloride. Using the same method as described in Reference Example 48, the corresponding
The following compounds were obtained from the 8-methoxy compound
Ta. 5-(1-hydroxy) with a melting point of 203-204℃ (decomposition)
C-2-isopropylamino)ethyl-8-hydro
Roxy-3,4-dihydrocarbostyryl hydrochloride
salt. 5-(1-hydroxy) with a melting point of 244-246℃ (decomposition)
C-2-tert-butylamino)ethyl-8-hydro
Xycarbostyril hydrochloride hemihydrate. White amorphous 5-(1-hydride) with a melting point of 120-121°C.
Roxy-2-benzylamino)ethyl-8-hydro
Roxycarbostyril hydrochloride dihydrate. 5-[1-hydroxy] with a melting point of 167-168℃ (decomposition)
C-2-(1,1-dimethylphenethylamine
c)] Ethyl-8-hydroxycarbostyryl salt
Acid acid monohydrate. 5-(1-
Hydroxy-2-amino)ethyl-8-hydroxy
C-3,4-dihydrocarbostyril hydrochloride. Reference Example 49 40ml of methanol was obtained in the same manner as Example 23 or 24.
5-(α-isopropylaminobutyryl)-8-
In addition to 2 g of hydroxycarbostyril, the obtained
Add sodium to the solution while stirring while cooling in an ice bath.
Add 25g of Mborohydride and continue for 1 hour.
Stirring was continued at room temperature. Add concentrated hydrochloric acid to the reaction mixture
to adjust the pH to 1, and then concentrate the mixture to dryness.
Ta. The precipitate was washed with acetone, dissolved in water and
Adjust the pH to 8 with aqueous sodium hydroxide solution and crystallize.
was precipitated. Take the obtained crystals and add ethanol
5 with a melting point of 141-142℃ (colored decomposition) after recrystallization from
-(1-hydroxy-2-isopropylamino)
Butyl-8-hydroxycarbostyryl monohydrate
1.8g was obtained. Reference Example 50 5-(α-2nd butane) produced in the same manner as Example 22
Ruaminobutyryl)-8-hydroxycarbosti
Add 30 ml of methanol to 1.5 g of rill, and add the resulting solution.
Add sodium to the solution while stirring in an ice bath.
1.5 g of borohydride was added in small portions. room temperature
Stirring was continued for 1 hour. then react
The mixture was adjusted to pH 1 with concentrated hydrochloric acid and then concentrated to dryness.
Ta. Take the precipitate, wash it with acetone, and dissolve it in water.
Then adjust the pH to 8 with an aqueous sodium hydroxide solution.
Ta. Take the precipitated crystals, wash them with water and re-
Dissolved in dilute hydrochloric acid. Concentrate and dry the obtained solution
Then, the precipitate was recrystallized from ethanol to a melting point of 182 ~
5-(1-hydroxy) with a temperature of 183℃ (foam decomposition)
C-2-sec-butylamino)butyl-8-hydro
Obtained 1.3g of xycarbostyril hydrochloride monohydrate
Ta. Reference Example 51 5-(α
-isopropylaminobutyl)-8-hydrokica
20% tetrahydrofuran per 1g of rubostyril hydrochloride
ml and the resulting mixture was diluted with tetrahydrofurane.
Lithium aluminum hydride in 10ml
Into the suspension containing 0.12 g, add
Dropped warm. After the end of the addition, add a small amount to the reaction mixture.
Add excess lithium aluminum hydride to water
I took the ride apart. Then pour the reaction mixture into 50ml of ice water.
The aqueous layer of the resulting solvent is separated and concentrated.
It was condensed to dryness. Take the precipitated crystals and wash them with acetone.
Cleaned and dissolved in water. Sodium hydroxide solution
Adjust the pH to 8 with a solution to precipitate the crystals, then
and recrystallized from ethanol to give a melting point of 141-142.
5-(1-hydroxy-) with °C (color decomposition)
2-isopropylamino)butyl-8-hydroxy
0.8 g of cicarbostyril monohydrate was obtained. Reference Example 52 5-α-(β-Fe produced in the same manner as Example 25)
netylamino)butyl-8-hydroxycarbonylate
Dissolve 1.5 g of free base in 150 ml of methanol.
Then, while stirring the solution under ice-water cooling, add sodium chloride to the solution.
Gradually add 2g of aluminum borohydride and then
Stirring was continued for an additional hour at room temperature. obtained next
Adjust the mixture to PH1 with concentrated hydrochloric acid and filter the mixture.
The precipitate formed was removed. Concentrate and dry the liquid,
Acetone was added to crystallize the residue. Then this
Add sodium hydroxide solution to the crystals until the pH is 8.
The precipitate formed was collected and re-evaporated from ethanol.
Crystalline white with a melting point of 147-148℃ (foaming decomposition)
13 g of colored amorphous material was obtained. obtained in this way
The substances were analyzed by NMR spectrum analysis and IR spectrum analysis.
Based on analysis and elemental analysis, 5-1-hydroxy-2-
(β-phenethylamino)butyl-8-hydroxy
Confirmed that it is cicarbostyryl trihydrate.
Ta. Reference example 53 Mix 25 g of chloranil and 20 ml of xylene in 5-(1-hyperoxygen)
Droxy-2-isopropylamino)propyl-
8-Hydroxy-3,4-dihydrocarbostili
and heat the mixture under reflux for 24 hours.
Ta. The reaction mixture was concentrated to dryness and the residue was dissolved in carbon tetrachloride 50
Wash gently with ml. Then dissolve the residue in methanol 30
ml and add hydrochloric acid gas to this solution until the pH becomes 1.
was introduced and then cooled. the precipitated crystals
Recrystallized from methanol, melting point 164-166℃
1.5 g of material with (decomposition) was obtained. Do it like this
The product obtained was subjected to NMR spectroscopy and IR spectrum analysis.
Spectral analysis and elemental analysis revealed that 5-(1-hydride
Roxy-2-isopropylamino)propyl-8
-Hydroxycarbostyril hydrochloride monohydrate
I was sure that. Compatible with the same method as described in Reference Example 53 above.
3,4-dihydrocarbostyryl compound
The following compounds were also produced. 5-(1-hydroxy) with a melting point of 182-183℃ (decomposition)
C-2-sec-butylamino)butyl-8-hydro
Xycarbostyril hydrochloride monohydrate. 5-(1-hydro) with a melting point of 174-177.5℃ (decomposition)
xy-2-ethylamino)butyl-8-hydroxy
Cicarbostyril hydrochloride. Reference example 54 5-[(1-hydroxy-2-isopropyla
Mino)propyl]-8-methoxycarbostyryl
10ml of 47% hydrobromic acid aqueous solution for 1g of hydrochloride monohydrate
was added and the mixture was heated under reflux for 15 h and then concentrated.
Dry. Produced by adding acetone to the resulting residue
crystallize the substance, then add this to dilute sodium hydroxide
The pH was adjusted to 8 with an aqueous solution. Take the precipitated crystals
washed with water and dissolved in ethanol.
This solution was adjusted to pH 1 with concentrated hydrochloric acid, concentrated and dried.
Ta. The residue thus obtained was mixed with ethanol.
Recrystallized from a mixture of diethyl ether and melting point
0.7 g of material with a temperature of 164-166°C (decomposed) was obtained.
The product thus obtained has an NMR spectrum
by IR spectrum analysis, IR spectrum analysis, and elemental analysis.
5-(1-hydroxy-2-isopropylamide
c) Propyl-8-hydroxycarbostyryl salt
It was confirmed that it was an acid salt. Using the same method as in Reference Example 54, create the corresponding structure.
The following compound was obtained from the 8-methoxy compound. 5-(1-hydroxy) with a melting point of 213-214℃ (decomposition)
C-2-isopropylamino)butyl-8-hydro
Roxycarbostyril hydrochloride. Reference Example 55 Hydrobromide prepared as described in Example
5-(α-isopropylamine obtained from hemihydrate)
(nopropionyl)-8-hydroxy-3,4-di
Hydrocarbostyril 1.0g in methanol 50ml
Dissolve and cool on ice 0.3 g of sodium boron hydride
was gradually added and stirred at room temperature for 1 hour. Chlorinated water
Add methanol saturated with elementary gas to pH 1-2
shall be. Separate the precipitate and concentrate the liquid to dryness.
Add 1N aqueous sodium hydroxide solution to adjust pH to 7.5-8.
After that, remove the precipitate. Dissolve the precipitate in ethanol.
Then, hydrogen chloride gas is blown in. remove the precipitate
and recrystallized from ethanol, with a melting point of 211-213℃.
Obtain 0.8 g of substance. This one includes NMR, IR and elemental
From the analysis results, 5-(2-isopropyl
Amino-1-hydroxy)propyl-8-hydro
xy-3,4-dihydrocarbostyryl hydrochloride 1/
Confirm that it is a dihydrate. Reference example 56 5-(α-isopropylaminobutyryl)-8
-Hydroxy-3,4-dihydrocarbostyryl
Add 20ml of ethanol and 0.05g of platinum oxide to 1.0g.
Then, reduce at 60℃ under 2 atmospheres of hydrogen pressure for 10 hours. reaction
After separating the catalyst, add concentrated hydrochloric acid to the liquid to adjust the pH to 1.
After that, concentrate to dryness. Reconsolidate the residue with ethanol
0.9 g of crystallized material with a melting point of 196-198°C is obtained. This too
Based on the analysis results of NMR, IR and elemental analysis
5-(2-isopropylamino-1-hydroxy
c) Butyl-8-hydroxy-3,4-dihydro
Confirmed to be carbostyril hydrochloride monohydrate. Reference example 57 5 obtained from the corresponding monohydrate prepared in Example 33
-(α-tert-butylaminopropionyl)-8
-Hydroxy-3,4-dihydrocarbostyryl
Hydrobromide 1.0g, water 50ml and palladium black 0.2
g and reduced at 60°C under normal pressure for 20 hours. After reaction
The catalyst is separated and the liquid is concentrated to dryness. Empty the residue
Recrystallized from tanol with a melting point of 198-199℃ (decomposition)
Obtain 0.75 g of substance. This item includes NMR, IR and original
From the elementary analysis results, 5-(1-hydroxy
-2-tert-butylamino)propyl-8-hydro
Roxy-3,4-dihydrocarbostyryl bromide water
Confirm that it is oxalate monohydrate. Reference example 58 5 obtained from the corresponding dihydrate prepared in Example 34
-(α-tert-butylaminobutyryl)-8-hi
Droxy-3,4-dihydrocarbostyryl bromide
Add 50 ml of water and 0.2 g of palladium black to 1.0 g of hydrogen salt.
Then, reduce at 80°C under normal pressure for 10 days. Post-reaction catalyst
Separate and concentrate the liquid to dryness. Ethanol residue
A substance with a melting point of 164-166℃ (decomposition) that is recrystallized from a
Obtain 0.7g. This item is NMR, IR and elemental analysis
From the analysis results, 5-(1-hydroxy-2-
tert-butylamino)butyl-8-hydroxy-
3,4-dihydrocarbostyryl hydrobromide
(ethanol solvate). Reference example 59 5-(α-isopropylaminobutyryl)-8
-2g of hydroxycarbostyril and palladium black
Add 0.1 g and 50 ml of ethanol, hydrogen pressure 35 atm,
Perform the reduction reaction by stirring at 75°C for 15 hours. reaction
After separating the catalyst, add concentrated hydrochloric acid and concentrate to PH1.
Dry. The resulting precipitate was reconsolidated from ethanol.
5-(1-hydroxy-
2-isopropylamino)butyl-8-hydroxy
C-3,4-dihydrocarbostyryl hydrochloride hydration
Obtain 1.7g of substance. Reference example 60 5-(α-isopropylaminobutyryl)-8
-1g of hydroxycarbostyril hydrochloride plus platinum black
Add 0.05g and 100ml of water, hydrogen pressure 40atm, and at 60℃.
Mix and react for 18 hours. After the reaction is complete, remove the catalyst.
The precipitate obtained by concentrating and drying the
Recrystallize the substance from isopropanol to a melting point of 196~
5-(1-hydroxy-2-isopropyl) at 198℃
butyl-8-hydroxy-3,4-di
Obtained 0.85g of hydrocarbostyril hydrochloride monohydrate
Ru. Reference example 61 5-(α-sec-butylaminoptyryl)-8
-Hydroxycarbostyril 0.5g plus palladium
Add 0.025g of black and 15ml of ethanol, and add hydrogen.
Mix and react at 50 atm and 80°C for 15 hours.
After the reaction is complete, remove the catalyst and add the resulting reaction solution to concentrated hydrochloric acid.
After adjusting the pH to 1, concentrate to dryness. Then the precipitate
5- with a melting point of 205-207℃ after recrystallization from ethanol.
(1-hydroxy-2-sec-butylamino)buty
Ru-8-hydroxy-3,4-dihydrocarbos
0.45 g of Tyryl hydrochloride hydrate is obtained. Reference example 62 5-(1-hydroxy-2-tert-butylamide
c) Propyl-8-methoxy-3,4-dihydro
Add 15 ml of 47% hydrobromic acid to 1.5 g of carbostyril.
After heating under reflux for 15 hours, concentrate to dryness and add acetone.
Add and crystallize. The crystals were dissolved in ethanol-a
Recrystallized from setone with a melting point of 198-199℃ (decomposition)
Obtain 1.4g of quality. This item includes NMR, IR and elemental content.
From the analysis results, 5-(1-hydroxy-2
-tert-butylamino)propyl-8-hydroxy
C-3,4-dihydrocarbostyryl hydrobromide
Confirm that it is salt monohydrate. The present invention obtained by the same operation as in Reference Example 62 below
The target compound is shown. 5-[1-hydroxy] with a melting point of 127-129℃ (decomposition)
C-2-morpholinobutyl-8-hydroxy-
3,4-dihydrocarbostyril hydrochloride. 5-1-hydroxy with a melting point of 183-185℃ (decomposition)
-2-morpholinobutyl-8-hydroxy-3,
4-dihydrocarbostyryl hydrobromide. Reference example 63 5-(α-tert-butylaminobutyryl)-8-
Hydroxy-3,4-dihydrocarbostyryl
Add 50ml of water and 0.2g of palladium black to 1.0g and mix
The substance is reduced at atmospheric pressure for 10 days at a temperature of 80°C.
Ta. After completion of reduction, separate the catalyst and concentrate and dry the liquid.
did. The obtained residue was recrystallized from ethanol.
0.7 g of material with a melting point of 164-166°C (decomposed) was obtained. child
NMR spectrum of the product obtained as follows
5 by analysis, IR spectrum analysis and elemental analysis.
-(Hydroxy-2-tert-butylamino)butyl
-8-hydroxy-3,4-dihydrocarbosti
Lyruhydrobromide (as ethanol sorbate)
It was confirmed that Reference example 64 5-(2-morpholinobutyryl)-8-hydro
xy-3,4-dihydrocarbostyryl hydrogen bromide
Dissolve 1.0 g of the acid salt in 70 ml of water and add paralysis to this solution.
Add 0.2g of Dium Carbon and 0.3g of Palladium Black, then
Hydrogenate the mixture for 10 days at a temperature of 70 °C with shaking.
Catalytic reduction was carried out under atmospheric pressure.
After the reduction is completed, the reaction mixture is filtered to remove the catalyst.
The solution was concentrated and dried under reduced pressure. The obtained residue
Heat dissolved in acetone and then cooled the solution.
Recrystallize the precipitate formed by cooling from ethanol.
White amorphous with melting point 183-185℃ (decomposed)
5-(1-hydroxy-2-morpholino)buty
Ru-8-hydroxy-3,4-dihydrocarbos
0.7 g of tyryl hydrobromide 1/2 hydrate was obtained. this
The product obtained in this way was analyzed by NMR spectroscopy.
Confirmed by analysis, IR spectrum analysis, and elemental analysis
did. Reference Example 65 1-Methyl-5-isopropropylene produced in Example 37
Pyraminoacetyl-8-hydroxycarbosti
Dissolve 0.45 g of Lil's free base in 50 ml of methanol.
and add this solution to it while stirring while cooling in an ice bath.
Gradually add 0.2g of sodium borohydride.
Ta. Stirring was continued for an additional hour and the resulting reaction mixture
The mixture was adjusted to pH 2-3 with concentrated hydrochloric acid. The formed sediment
The lees was then removed separately, the liquid was concentrated under reduced pressure, and
The residue was dissolved in 20 ml of ethanol. Pass the solution
to remove insoluble materials, concentrate the liquid under reduced pressure, and
Add 20 ml of ethanol to this, and then strain and evaporate.
Soluble substances were removed. Concentrate the liquid under reduced pressure to make ethanol.
Add 40 ml of ethanol to this residue to remove the remaining ether.
Nol-soluble substances were removed. ethanol insoluble
The material was washed twice with 20 ml of cold water and reconsolidated from ethanol.
White amorphous crystal with a melting point of 202-203.5℃ (decomposition)
1-methyl-5-[(1-hydroxy-2-iso
propylamino)ethyl]-8-hydroxycal
0.3 g of bostyril hydrochloride was obtained. In this way
The obtained product was analyzed by IR spectroscopy and NMR spectroscopy.
Confirmed by vector analysis and elemental analysis. Reference example 66 1-methyl-5-isopropylaminoacetyl
- 1g of 8-hydroxycarbostyril hydrochloride in water
Suspend in 100 ml and add paradi to this suspension.
Add 0.1g of aluminum carbon and then heat the mixture to 60-70℃.
Catalytic reduction with hydrogen at atmospheric pressure for 25 h at
Ta. After the reduction is complete, strain the reaction mixture and reduce the liquid.
It was concentrated and dried under pressure. The resulting residue is reconstituted from acetone.
Crystallized and then recrystallized from ethanol to a melting point of 196 ~
White amorphous 1-methyl-5- at 197℃ (decomposition)
[(1-Hydroxy-2-isopropylamino)et
Chil]-8-hydroxy-3,4-dihydrocal
0.3 g of Bostyril was obtained. obtained in this way
The resulting product was analyzed by IR spectroscopy and NMR spectroscopy.
Confirmed by analysis and elemental analysis. Reference example 67 5-isopropylaminoacetyl-8-methoxy
Dissolve 1.0 g of cicarbostyril in 50 ml of methanol.
Dissolve and add the solution to the solution while stirring in an ice bath.
Gradually add 0.6g of thorium borohydride and then
The mixture was stirred at room temperature for 1 hour. reaction mixture
Adjust the pH to 2-3 with concentrated hydrochloric acid and separate the formed precipitate.
did. Concentrate and dry the liquid, and mix the obtained crystals with acetone or
was crystallized. Recrystallize the product from ethanol
to obtain 0.8g of a substance with a melting point of 230-231℃ (decomposition).
Ta. The product thus obtained is an NMR spectrometer.
For spectrum analysis, IR spectrum analysis, and elemental analysis
5-(1-hydroxy-2-isopropyla)
Mino)ethyl-8-methoxycarbostyryl hydrochloride
It was confirmed that it was a salt monohydrate. Reference example 68 5-isopropylaminoacetyl-8-methoxy
2 g of C-3,4-dihydrocarbostyryl in meth
Dissolve in 70 ml of alcohol and cool the solution with ice water.
Gradually add 1g of sodium borohydride to this.
was added and then stirred for an additional hour at room temperature. reaction mixture
The mixture was adjusted to pH 1 with concentrated hydrochloric acid, and the precipitate formed was
Separated. Concentrate and dry the liquid, and evaporate the resulting residue.
Recrystallized from alcohol with a melting point of 206-208℃ (decomposition)
1.5 g of material was obtained. The generation thus obtained
The material is analyzed by NMR spectral analysis, IR spectral analysis and
5-(1-hydroxy-2-i) was determined by
sopropylamino)ethyl-8-methoxy-3,
4-dihydrocarbostyril hydrochloride
confirmed. Reference example 69 5-(2-isopropylamino-1-hydroxy
c) Ethyl-8-hydroxycarbostyryl hydrochloride
Dissolve 3 g of salt in 20 ml of water and add sodium hydroxide to this solution.
0.9g of thorium was added. The solution was then cooled in an ice bath.
1.3 g of dimethyl sulfate was added dropwise while stirring, and for 1 hour
Stir for a while. Stir the mixture for 2 hours at a temperature of 40-50℃
The reaction mixture was stirred and extracted with chloroform. nine
The loloform extract was washed with water, dried, and
Introducing hydrochloric acid gas into this chloroform extract
Ta. Mix the precipitated crystals with ethanol and acetone
Substances that crystallize from objects and have a melting point of 235-237℃ (decomposition)
2.3g was obtained. The product thus obtained is
NMR spectral analysis and IR spectral analysis and original
By elementary analysis, 5-(1-hydroxy-2-isopropylene)
(ropylamino)ethyl-8-methoxycarbosuti
It was confirmed that it was ril hydrochloride monohydrate. Reference example 70 5-(1-hydroxy-2-isopropylamine
c) Ethyl-8-hydroxy-3,4-dihydro
Dissolve 2.6g of carbostyril in 30ml of water and add this
0.45 g of sodium hydroxide was added to the solution. solution
Add 1.3 g of dimethyl sulfate to this while cooling in a water bath.
The mixture was lowered and stirred for 1 hour. The reaction mixture was heated to 40-50 °C.
The mixture was stirred at room temperature for 2 hours and extracted with chloroform. child
The chloroform extract of
Introducing hydrochloric acid gas into this chloroform extract by
did. The precipitated crystals were recrystallized from ethanol.
Obtained 2.2 g of a substance with a melting point of 206-208 °C (decomposition)
Ta. The product thus obtained is an NMR spectrometer.
For spectrum analysis, IR spectrum analysis, and elemental analysis
5-(1-hydroxy-2-isopropyla)
mino)ethyl-8-methoxy-3,4-dihydro
It was confirmed that it was carbostyril hydrochloride. Reference example 71 10ml of 47% hydrobromic acid aqueous solution was mixed with 1-methyl-5-
(1-hydroxy-2-isopropylamino)et
Chill-8-methoxy-3,4-dihydrocarbos
Add 1 g of tyryl hydrochloride monohydrate and reflux the mixture.
The mixture was heated for 15 hours and then concentrated to dryness. the residue obtained
Add acetone to the residue to crystallize the product, and then
Adjust the pH to 8 with dilute sodium hydroxide solution.
Ta. Take the precipitated crystals, wash them with water and evaporate them.
Dissolved in ethanol. Adjust the solution to pH 1 with concentrated hydrochloric acid.
It was chopped and concentrated to dryness. obtained in this way
Mix the resulting residue with ethanol and diethyl ether.
A substance recrystallized from a substance with a melting point of 198-200℃ (decomposition)
I got it. The product thus obtained is NMR
Spectral analysis IR spectral analysis and elemental analysis
1-methyl-5-(1-hydroxy-2-
isopropylamino)ethyl-8-hydroxy-
3,4-dihydrocarbostyril hydrochloride
I confirmed that. The novel intermediate according to the present invention was determined by the following pharmacological tests.
The excellent pharmacological action of compound (1) obtained from
Explain. Pharmacological testing Application of the present invention to β-adrenergic receptors
The stimulating activity of the compound was measured as follows. 10~15Kg
A mixed-breed adult male dog weighing 30mg/kg body weight was
Intravenous administration of barbital sodium can induce hemp
Treated with drunkenness. Each anesthetized dog has its back immobilized.
A canicol tube was inserted into the trachea. concept
-Retzler method [Konzett H. & Roessler R.,
“Versuchsanordnug zn Utersuchungen an
der Bronchial Moskalatur”，Arch.Exp.Path.，
Pharmack, 195 , 71-74, 27-40 (1940)]
Artificial respiration was performed using a device. Air during inhalation
Flow is measured through a pulmonary velocimeter to determine bronchial resistance.
Measure and record the obtained value on the heart rate recorder.
Ta. In the above test, histamine was used to induce bronchoconstriction.
used as a drug at a dosage level of 10mg/Kg body weight, and
Each test compound and control shown in Table 1
1 minute before administration of histamine, administer the following aqueous solution:
femoral vein at various dosing levels as shown in
The drug was administered to each anesthetized dog through. exam period
Suppress spontaneous breathing and maintain anesthesia throughout the procedure
Currently being tested at a dose level of 4mg/Kg body weight to
Sodium bentobarbital was injected. No pitching
Increased bronchial resistance due to histamine administration in the case of drugs
Bronchial resistance after compound administration
The inhibition rate is shown in the table below.

【table】

[Table] In addition, 10 male rats (DD species, body weight 18-20 g) each were fasted for 12 hours before the test.
Six groups were used to test acute toxicity for the test compounds shown in the table below. Salbutamol and isoproterenol were used as controls. The results of LD ₅₀ (50% lethal dose) were as follows.

Table: Compounds of the present invention can be prepared in tablets, powders, granules, capsules, preferably in combination with pharmacologically acceptable carriers or excipients well known in the art, at dosage levels of 100 g to 50 mg/Kg/day. They can be administered by oral, intravenous, intramuscular or inhalation routes of administration in pharmaceutically customary dosage forms such as syrups, solutions, suspensions, inhalants and the like. Compounds of the invention and dosage forms containing at least one of the compounds of the invention can be administered in single or multiple doses. Formulation Example Prescription of Pharmaceutical Composition Lactose 55g Corn starch 22g Crystalline cellulose 22g Methyl cellulose 0.8g Active ingredient 0.1g The above ingredients were mixed in a conventional manner and press-molded into tablets to make 1000 tablets. Although the present invention has been described in detail with reference to specific reference examples, examples, pharmacological tests, and formulation examples thereof, those skilled in the art will recognize that the present invention can be changed or modified in various ways without departing from the spirit and scope of the invention. It should be obvious.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ , R ⁴ and R ⁵ are each a hydrogen atom,
or represents an alkyl group having 1 to 4 carbon atoms, at least one of R ⁴ and R ⁵ is a hydrogen atom, and R ² and R ³ may be the same or different. , represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenylalkyl group containing a straight-chain or branched alkyl group having 1 to 4 carbon atoms in the alkyl moiety, and R ² and ^R3
may be taken together with the nitrogen atom to which they are bonded to form a piperidino group or a morpholino group,
formula The carbostyryl skeleton represented by the formula [Formula] or [Formula]] A novel carbostyryl derivative represented by the following.