Claims
- 1. A compound selected from the group consisting of 3-formylamino-4-hydroxy-.alpha.-[N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl]benzyl alcohol of the formula: ##SPC24##
- and the pharmacologically acceptable non-toxic acid addition salts thereof.
- 2. A compound according to claim 1 which is 3-formylamino-4-hydroxy-.alpha.-[N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl]benzyl alcohol 1/2 fumarate.
- 3. A compound according to claim 1 which is 3-formylamino-4-hydroxy-.alpha.-[N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl]benzyl alcohol 1/2 fumarate showing melting point (decomposition) of 138.degree.-140.degree. C.
- 4. A compound according to claim 1 which is 3-formylamino-4-hydroxy-.alpha.-[N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl]-benzyl alcohol of 1/2 fumarate showing melting point (decomposition) of 154.degree.-155.degree. C.
Priority Claims (4)
| Number |
Date |
Country |
Kind |
| 47-13121 |
Feb 1972 |
JA |
|
| 47-39416 |
Apr 1972 |
JA |
|
| 47-51013 |
May 1972 |
JA |
|
| 47-52925 |
May 1972 |
JA |
|
DETAILED DESCRIPTION OF THE INVENTION
This application is a Continuation-in-Part of pending application Ser. No. 325,596 filed Jan. 22, 1973 now abandoned.
The present invention relates generally to novel .alpha.-aminomethylbenzyl alcohol derivatives and more particularly, it relates to novel .alpha.-aminomethylbenzyl alcohol derivatives represented by the general formula I ##SPC1##
The compounds of this invention have utility as .beta.-adrenergic stimulants and thus have great activity on respiratory smooth muscle and are suitable as bronchodilating agents.
As a compound having bronchodilating effects, there are known hitherto various compounds and especially, Isoproterenol and Trimetoquinol, these compounds being well known among the bronchodilating drugs and being widely sold since they have strong effects. Further a bronchlodilating agent should not have any ill-effects on the heart that is, it should have high selectivity, and Salbutamol satisfies this requirement and is also widely sold.
Further, compounds having a similar structure to the present compounds are the known 3-amino-4-hydroxy-.alpha.-isopropylaminomethylbenzyl alcohol (see Dutch Patent No. 85197: "Chemical Abstract", 52 11121d (1958)), 3-ethoxycarbonylamino-4-hydroxy-.alpha.-isopropylaminomethylbenzyl alcohol (see Belgian Patent No. 765,986), .alpha.-(isopropylaminomethyl)-4-hydroxy-3-ureido benzyl alcohol (see Japanese Patent Application Public Open No. 2676/1971).
As a result of various investigations in this area, the present inventors have discovered that the novel .alpha.-aminomethylbenzyl alcohols represented by the formula (I) supra have superior bronchodilating effects and are superior bronchodilating agents having a high selectivity.
In formula I representing the compounds of this invention, examples of R.sup.1 are a hydrogen atom, an alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, a tert butyl group, a 1, 3-dimethylbutyl group, a 1, 3-dimethylpentyl group, a 2, 3-dimethylbutyl group, a 2, 3, 3-tributyl group, etc.; examples of R.sup.4 are a hydrogen atom, a hydroxyalkyl group such as a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, etc., an alkanoylaminoalkyl group such as a formamidemethyl group, an acetylaminomethyl group, an acetylaminoethyl group, an acetylaminopropyl group, a butyrylaminoethyl group, etc. Examples of an alkyl group of R.sup.3 are a propyl group, an isopropyl group, a n-butyl group, a tert-butyl group, a 1, 3-dimethylbutyl group, a 1, 3-dimethylpentyl group, a 2, 3-dimethylbutyl group, a 2, 3, 3-trimethylbutyl group, etc.; examples of the cycloalkyl group of R.sup.3 are a cyclopentylmethyl group, a 2-cycloethyl group, a cyclohexylmethyl group, a 2-cyclohexylethyl group, a 3-cyclohexyl-1-methylpropyl group, etc. Examples of Alk are an alkylene group such as methylene group, an ethylene group, a propylene group, a butylene group, a 1-methylethylene group, a 1-ethylethylene group, a 1-methylpropylene group, a 1-ethylpropylene group, a 2-methylpropylene group, a 3-methylbutylene group, a 2-ethylbutylene group, etc. The examples of X, Y and Z are a hydrogen atom, a hydroxy group, al alkanoylamino group such as a formamide group, an acetylamino group, a propionylamino group, a butyrylamino group, etc., an alkyl group such as a methyl group, an ethyl group, a propionyl group, an isopropyl group, an isobutyl group, a tert-butyl group, etc., or an alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, etc.
The particularly useful compounds of this invention are 3-formamido-4-hydroxy-.alpha.-[N-(1-methyl-2-p-hydroxyphenylethyl) amino-methyl] benzyl alcohol, 3-formamido-4-hydroxy-.alpha.-[N-(1-methyl-2-p-methoxyphenylethyl) aminomethyl]benzyl alcohol, 4-hydroxy-3-methylamino-.alpha.-(N-tert-butylaminomethyl) benzyl alcohol, etc.
When A of the formula I representing the compounds of this invention is a hydroxyl group and B is the ##STR2## group, the compounds of this invention are shown by the formula I' ##SPC3##
As the starting materials for preparing the products of this invention, there are used those compounds wherein one or more of hydrogen atoms of the mono-substituted amino group and the hydroxyl group thereof have been protected by a group capable of being easily released by reduction, such as a benzyl group, a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, etc.
Furthermore, the starting materials for the products of this invention which have a hydroxyl group bonded to the benzene ring through a =CH-group, i.e., a secondary hydroxyl group, may be a compound having a carbonyl group at the position ##SPC5##
The compounds of this invention may be prepared by catalytic reduction, e.g., the starting materials or salts thereof in a solvent such as ethanol, isopropanol, ethyl acetate, and the like, at normal temperature or an elevated temperature, under a normal pressure or a high pressure, in the presence of a catalyst such as palladium, platinum, and the like, according to conventional procedures.
Suitable starting materials for the compounds of this invention are as follows:
When the hydroxyl groups of the groups R.sup.3 and R.sup.4 of those starting materials for the compounds of this invention have been substituted by benzyl groups, benzyloxycarbonyl groups, etc., the substituents of the hydroxyl groups are released to give the hydroxyl groups at the practice of the aforesaid reduction.
The desired products of formula I thus obtained can be isolated and purified by an ordinary chemical operation. Furthermore, because the compounds represented by formula I of this invention have at least one asymmetric carbon atom, the compounds of this invention include all the possible optical active forms and racemic mixtures. The racemic mixture may be resolved by such a known method as, for example, forming optically active acid addition salts and then separating them by fractional crystallization.
The pharmacological effects of the compounds of this invention will be illustrated in the following experiments and results while comparing these of known compounds.
The trachea of a guinea pig was cut spirally and the isolated bronchial preparation was suspended in Magnus bath. Tyrode's solution was filled in a 50 ml bath and kept at 37.degree. C. Then, 10-.sup.5 g/ml of histamine dihydrochloride or methacholine chloride was added to a bath as spasmogen. After the contraction of the trachea reached a plateau, a test substance shown in the below-showing table was added to the preparation, cumulatively. The concentration producing 50% relaxation of the contracted bronchial muscle was designated as ED.sub.50. The results are shown in the Table I.
Known compounds used above are as follows:
A guinea pig was placed in a 11 liter glass chamber and exposed to the spasmogen by means of a nebulizer. Thus, when 0.01% histamine dihydrochloride or methacholine chloride solution was sprayed into a chamber for 10 seconds, the guinea pigs showed the symptoms of dyspnea. Drugs were administered subcutaneously to animals 30 minutes before application of the spasmogen. If a guinea pig showed no asthmatic dyspnoic symptoms, the drug was evaluated to be effective. ED.sub.50 was calculated by the method of Litchfield-Wilcoxon [J. Pharmacol. Exptl. Therap, 96, 99-113 (1949)]. The results are shown in Table II.
Mongrel dogs of either sex weighing about 10 Kg were anesthetized with pentobarbital Na, 35 mg/Kg intravenously, and prepared for measurement of bronchial resistance (Konzett & Roessler; Arch exp. Path. Pharmakol, 195, 71-74 (1940)). Temporary increases in bronchial resistance, measured with a low pressure transducer connected to a penrecorder, were produced by histamine dihydrochloride 10 .mu.g/Kg injected intravenously at intervals of 10 minutes. The test samples were injected intravenously 5 minutes before injection of histamine, cumulatively. In all experiments, the drugs were injected intravenously through a cannula in a femoral vein. ED.sub.50 values of .beta.-agonists were obtained from the dose-response (inhibition) curves. (.beta..sub.2. action).
Mongrel dogs of either sex weighing about 10 Kg were anesthetized with pentobarbital Na, 30 mg/Kg intravenously. Arterial blood pressure was measured from a cannula in the right femoral artery and the pulse pressure used to trigger a ratemeter for a record of heart rate. (.beta..sub.1.action). Intravenous injections were made through a cannula in a femoral vein, and ED.sub.50bpm values were obtained from the does-response (.DELTA.HR) curves. ED.sub.50bpm vs. ED.sub.50 ratios mean its own selectivity.
As shown in Table I, the activity on bronchial smooth muscle of the present products is greater than that of the compounds A, B or C each having the similar structure to the instant compound, or Trimetoquinol (E) or Isoproterenol (F), since ED.sub.50 values of the present compounds are smaller than that of said each compounds.
As shown in Table II, the antiasthmatic action of the present compounds in vitro is greater than that of Trimetoquinol (E) or Isoproterenol (F) each being well known for their strong effects among the bronchodilating drugs being widely sold, since ED.sub.50 of the present compounds are less than that of compounds E or F.
As shown in Table III, the present products are more selective than that of Salbutamol (D) having high selectivity, since the ratio of .beta..sub.1 /.beta..sub.2 of the present compounds is greater than that of Salbutamol (D).
For the above reasons, it is clear that the present products have superior bronchodilating activity and further they are superior bronchodilating agents having a high selectivity as compared with known bronchodilators.
The products of this invention may be used in various forms and in general they are used in the form of the salts of pharmacologically useful nontoxic acids. For example, they are used as the salts of such inorganic acids as hydrochloric acid, sulfuric acid, phosphoric acid, and the like, or such organic acids as fumaric acid, maleic acid, acetic acid, lactic acid, citric acid, and the like.
The compounds of this invention may be administered orally or parenterally. In the case of oral administration, they may be in the form of sugar-coated tablets, buccals, or capsules. They may also be in the form of aerosols as inhalations. Furthermore, they may be injected subcutaneously, intramuscularly, or intravenously as injections.
The dosage of the compounds of this invention depends upon the condition of the patients, their ages, and administration form but the suitable oral dosage range for an adult is 0.3-1.5 mg./day.
a. In 60 ml. of chloroform was dissolved 5.4 g. of 4-benzyloxy-3-nitroacetophenone and after dropwise to the solution a mixture of 3.2 g. of bromine and 5 ml. of chloroform with stirring, the mixture was stirred further for 30 minutes. The reaction product was concentrated under a reduced pressure and the crystalline residue obtained was washed with 20 ml. of benzene and dried to give 5.5 g. of 4-benzyloxy-3-nitro-.alpha.-bromoacetophenone. The product, when recrystallized from chloroform, melted at 135.degree.-136.degree. C.
b. In 60 ml. of tetrahydrofuran was dissolved 5.3 g. of 4-benzyloxy-3-nitro-.alpha.-bromoacetophenone and after adding to the solution 4.5 g. of N-benzyl-N-isopropylamine, the mixture was stirred overnight at room temperature. Then, after filtering off the precipitates thus formed, the filtrate was concentrated under a reduced pressure and the crystalline residue obtained was washed with ethanol to provide 5.5 g. of the yellow crystal line 4-benzyloxy-3-nitro-.alpha.-(N-benzyl-N-isopropylamino) acetophenone. The product, when recrystallized from ethanol, melted at 92.degree.-93.degree. C.
c. In 35 ml. of ethanol was suspended 3.5 g. of 4-benzyl-oxy-3-nitro-.alpha.-(N-benzyl-N-isopropylamino)acetophenone and after adding to the suspension 0.4 g. of sodium borohydride, the mixture was stirred for 3 hours at room temperature. After distilling off ethanol from the reaction product under a reduced pressure and adding water to the residue, the product was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure to provide 3.4 g. of faint-yellow crystals of 4-benzyloxy-3-nitro-.alpha.-(n-benzyl-N-isopropylaminomethyl)benzyl alcohol. The product, when recrystallized from ethanol, melted at 97.degree. C.
d. In 30 ml. of 50% aqueous acetic acid solution was dissolved 3 g. of 4-bensyloxy-3-nitro-.alpha.-(N-benzyl-N-isopropylaminomethyl) benzyl alcohol and after adding to the solution 1.5 g. or iron powder, the mixture was refluxed for 30 minutes under heating. After filtering off the insoluble materials from the reaction product, the filtrate was concentrated under a reduced pressure. To the residue thus obtained was added 20 ml. of 5% aqueous sodium carbonate solution and the product was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to provide the brownish crystal of 3-amino-4-benzyloxy-.alpha.(N-benxyl-N-isopropylaminomethyl)-benzyl alcohol.
The product, when recrystallized from 2:5 benzene-n-hexane, melted at 63.degree.-65.degree. C. The amount of the product obtained was 2.2 g.
e. In 5 ml. of a mixture of acetic anhydride and formic acid was dissolved 1.9 g. of 3-amino-4-benzyloxy-.alpha.-(N-benzyl-N-isopropylaminomethyl) benzyl alcohol and after allowing this mixture to stand overnight, the solution was concentrated under a reduced pressure. After adding to the residue thus obtained 20 ml. of 5% aqueous sodium carbonate solution, the product was extracted with 30 ml. of benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to provide 1.9 g. of a brownish oily 4-benzyloxy-3-formylamino-.alpha.-(N-benzyl-N-isopropylaminomethyl) benzyl alcohol.
The product was dissolved in 10 ml. of 90% methanol and after adding to the solution 0.5 g. of sodium carbonate, the mixture was stirred for 30 minutes at room temperature. Then, the solvent was distilled off under a reduced pressure and the residue obtained was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to provide 1.9 g. of a brownish oily 4-benzyloxy-3-formylamino- -(N-benzyl-N-isopropylaminomethyl)benzyl alcohol.
a. In 30 ml. of pyridine was dissolved 5 g. of 3-amino-4-benzyloxyacetophenone and after adding to the solution 3.9 g of benzyloxyacetyl chloride under cooling, the mixture was stirred overnight at room temperature. The solvent was distilled off from the reaction product under a reduced pressure, the residue formed was dissolved in 50 ml. of chloroform, and then the solution was washed twice each time with 20 ml. of water. Then, the solution was dried over anhydrous sodium sulfate and chloroform was distilled off under a reduced pressure. By recrystallizing the yellow crystals thus obtained from ethanol, 7.5 g. of 4-benzyloxy-3-benzyloxyacetylamino-acetophenone melting at 104.degree.-105.degree. C was obtained.
b. In 50 ml. of chloroform was dissolved 1.9 g. of 4-benzyloxy-3-benzyloxyacetylaminoacetophenone and after adding to the solution 0.78 g. of bromine, the mixture was stirred for 30 minutes at room temperature. Then, chloroform and hydrogen bromide were distilled off from the reaction mixture under a reduced pressure and the crystal material thus obtained was recrystallized from chloroform-n-hexane to provide 1.85 g. of 4-benzyloxy-3-benzyloxy-acetylamino-.alpha.-bromoacetophenone melting at 155.degree.-157.degree. C.
c. In 100 ml. of tetrahydrofuran was dissolved 4 g. of 4-benzyloxy-3-benzyloxyacetylamino-.alpha.-bromoacetophenone at 40.degree.-50.degree. C. and after adding to the solution 2.68 g. of N-benzyl-N-sopropylamine, the mixture was stirred overnight at the same temperature as above. The reaction product was cooled, N-benzyl-N-isopropylamine hydrochloride formed was filtered off and then the solvent was distilled off under a reduced pressure. After dissolving the yellow oily material (5 g.) thus obtained in 100 ml. of ethanol, 0.5 g. of sodium borohydride was added to the solution and the mixture was stirred for 4 hours at room temperature. Then, the solvent was distilled off from the reaction product under a reduced pressure and the white crystals thus obtained were recrystallized from ethanol to give 2.3 g. of 4-benzyloxy-3-benzyloxyacetylamino-.alpha.-(N-benzyl-J-isopropylaminomethyl) benzyl alcohol melting at 93.degree.-95.degree. C.
a. In 50 ml. of chloroform was dissolved 5.4 g. of 4-hydroxy-3-nitroacetophenone and then 5 ml. of chloroform solution of 4.8 g. of bromine was added dropwise to the solution gradually. Thereafter, the mixture was stirred for 15 minutes and concentrated under a reduced pressure to form yellow crystals. By recrystallizing the product from benzene-n-hexane, 6.3 g. of the crystals of .alpha.-bromo-4-hydroxy-3-nitroacetophenone melting at 69.degree.-71.degree. C. were obtained.
b. In 50 ml. of methyl ethyl ketone was dissolved 5.2 g. of .alpha.-bromo-4-hydroxy-3-nitroacetophenone and after adding to the solution 9 g. of N-benzylisopropylamine, the mixture was stirred overnight at room temperature. After filtering off the hydrobromide of N-benzylisopropylamine thus precipitated, the filtrate was concentrated to provide a crude yellowish brown oily 4-hydroxy-3-nitro-.alpha.-(N-benzyl-N-isopropylamino) acetophenone.
c. In 50 ml. of ethanol was dissolved the crude 4-hydroxy-3-nitro-.alpha.-(N-benzyl-N-isopropylamino) acetophenone prepared above and after adding to the solution 1.5 g. of sodium borohydride, the mixture was stirred overnight at room temperature. The reaction product was concentrated under a reduced pressure and after adding water to the residue thus obtained, the product was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to give a yellow-brown oily material. The oily product was subjected to a silica gel column chromatography, the product was then recovered therefrom using benzene as an eluting agent, and from the effluents collected there was obtained 4 g. of 4-hydroxy-3-nitro-.alpha.-(N-benzyl-N-isopropylamino-methyl) benzyl alcohol.
d. In 30 ml. of methanol was dissolved 2.7 g. of the 4-hydroxy-3-nitro-.alpha.-(N-benzyl-N-isopropylaminoethyl) benzyl alcohol prepared above and after adding to the solution 1 g. of Raney nickel catalyst, the catalytic reduction of the compound was conducted at normal temperature and normal pressure. When 600 ml. of hydrogen was absorbed, the reaction was stopped. After filtering off the catalyst and adding 8.2 ml of 1 normal hydrogen chloride-ethanol solution to the filtrate, the reaction product was concentrated under a reduced pressure to provide 2.7 g. of a yellow-brown powder of 3-amino-4-hydroxy-.alpha.-(N-benzyl-N-isopropylaminomethyl) - benzyl alcohol hydrochloride.
e. In 20 ml. of pyridine was dissolved 1.2 g. of the 3-amino-4-hydroxy-.alpha.-(N-benzyl-N-isopropylaminomethyl) benzyl alcohol hydrochloride prepared above and after adding to the solution 0.20 g. of formic acid and 0.85 g. of dicyclohexylcarbodiimide under cooling below 0.degree. C., the mixture was stirred overnight at room temperature. The dicyclohexyl urea thus precipitated was filtered off, the filtrate was concentrated, and after adding water to the residue, the mixture was washed with ethyl acetate. The aqueous solution formed was neutralized by the addition of sodium carbonate and then extracted with ethyl acetate. The extract was dried and concentrated to give a brown residue. The residue was subjected to a silica gel column chromatography, the product was recovered using a 5 : 1 chloroform-acetone mixture as an eluting agent, and then from the effluents there was obtained 0.5 g. of a yellow powder of 3-formylamino-4-hydroxy-.alpha.-(N-benzyl-N-isopropylaminomethyl) benzyl alcohol.
a. In 60 ml of chloroform there was dissolved 5.4 g of 4-benzyloxy-3-nitroacetophenone and after adding dropwise to the solution a mixture of 3.2 g of bromine and 5 ml. of chloroform, with stirring, the mixture was further stirred for 30 minutes. The reaction product was concentrated under a reduced pressure and the crystalline residue thus obtained was washed with 20 ml. of benzene and dried to give 5.5 g of 4-benzyloxy-3-nitro-.alpha.-bromoacetophenone melting at 135.degree.-136.degree. C.
b. A mixture of 4.6 g of 4-benzyloxy-3-nitro-.alpha.-bromoacetophenone and 6.4 g of N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl) amine was heated together with 50 ml. of methyl ethyl ketone to 70.degree.-80.degree. C for 30 minutes.
After cooling the reaction product, the precipitates formed were filtered off and the filtrate was concentrated under a reduced pressure. When ethanol was added to the residue obtained, the product was crystallized. The crystalline material was recovered by filtration and recrystallized from ethanol to provide 5.5 g of 4-benzyloxy-3-nitro-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)amino]-acetophenone melting at 84.degree.-85.degree. C.
c. In 100 ml. of ethanol there was suspended 4.5 g of 4-benzyloxy-3-nitro-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)-amino] acetophenone and after adding to the suspension 0.5 g of sodium borohydride, the mixture was stirred for one hour at room temperature. Then, ethanol was distilled off from the reaction product under reduced pressure and after adding water to the residue, the product was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give the 4.4 g of a yellowish crystalline powder of 4-benzyloxy-3-nitro-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol.
d. In 40 ml. of a 60% aqueous acetic acid solution there was dissolved 4.3 g. of 4-benzyloxy-3-nitro-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)aminomethyl] benzyl alcohol and after adding to the solution 1.5 g. of iron powder, the mixture was refluxed for 30 minutes under heating. After filtering off the insoluble material from the reaction product, the product was concentrated under a reduced pressure. To the residue obtained there was added a 10% aqueous sodium carbonate solution and the product was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to give 3.7 g. of a brownish crystalline powder of 3-amino-4-benzyloxy-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol.
e. In 10 ml. of a 5 : 3 acetic anhydride formic acid mixture was dissolved 3.3 g. of 3-amino-4-benzyloxy-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)aminomethyl] benzyl alcohol and after allowing the mixture to stand overnight at room temperature, the mixture was concentrated under reduced pressure. The residue thus obtained was dissolved in 50 ml. of methanol and after adding to the solution 3 ml. of water and 3 g. of sodium carbonate, the mixture was stirred for one hour at room temperature. Methaol was distilled off under reduced pressure from the mixture and the residue was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off from the extract to give 3.4 g. of a faint-brown powder of 4-benzyloxy-3-formylamino-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl) amino-methyl] benzyl alcohol. In 30 ml. of benzene there was dissolved 2.5 g. of the faint brown powder obtained above and on allowing the solution to stand overnight at room temperature, crystals were formed. The crystals were separated and recrystallized from ethyl acetate-benzene to give 1.2 g. of a white crystalline material melting at 135.degree.-137.degree. C.
Nuclear magnetic resonance spectra: (CDCl.sub.3)
.delta.: 4.50 ppm. (m, 1H, CH at the root of hydroxyl group), 3.46, 3.87 ppm. (AB pattern, q, 2H,CH.sub.2 at the root of N).
This product is called 4-benzyloxy-3-formylamino-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)aminomethyl] benzyl alcohol [A].
Furthermore, the solvent was distilled off from the mother liquor left in the above step and the residue thus obtained was subjected to a silica gel column chromatography. Then, by using 10 : 2 benzene ethyl acetate mixture, 0.8 g. of a white crystalline powder was obtained.
Nuclear magnetic resonance spectra: (CDCl.sub.3)
.delta.: 4.34 ppm (m, 1H, CH at the root of hydroxyl group), 3.76 ppm. (S, 2H, CH.sub.2 at the root of N).
This product is called 4-benzyloxy-3-formylamino-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenyl)aminomethyl] benzyl alcohol [B].
a. In 270 ml. of chloroform there was dissolved 27 g. of 4-benzyloxy-3-nitroacetophenone and after adding dropwise to the solution a mixture of 16 g. of bromine and 10 ml. of chloroform gradually, with stirring, the mixture was further stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and the crystalline residue obtained was washed with a mixture of 50 ml. of benzene and 50 ml. of n-hexane and dried to give 31 g. of 4-benzyloxy-3-nitro-.alpha.-bromoacetophenone melting at 135.degree.-136.degree. C.
b. A mixture of 30.5 g. of 4-benzyloxy-3-nitro-.alpha.-bromoacetophenone and 28.5 g. of N-benzyl-N-tert-butylamine was refluxed together with 300 ml. of methyl ethyl ketone for 3 hours under heating. After cooling, the precipitates thus formed were filtered off. The filtrate was concentrated under a reduced pressure and the crystals thus formed were recovered and recrystallized from ethanol to give 30 g. of 4-benzyloxy-3-nitro-.alpha.-(N-benzyl-N-tert-butylamino)-acetophenone melting at 99.degree.-100.degree. C.
c. In a mixture of 200 ml. of ethanol and 150 ml. of tetrahydrofuran there was dissolved 30 g. of 4-benzyloxy-3-nitro-.alpha.-(N-benzyl-N-tert-butylamino)acetophenone and after adding to the solution 3 g. of sodium borohydride, the mixture was stirred for 3 hours at room temperature. The reaction product was concentrated under reduced pressure and after adding water to the residue, the product was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to give 30 g. of 4-benzyloxy-3-nitro-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol in the form of an oil.
d. In 150 ml. of a 50% aqueous acetic acid solution there was dissolved 30 g. of 4-benzyloxy-3-nitro-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol and after adding to the solution 12 g. of iron powder, the mixture was refluxed for 25 minutes, accompanied by heating. While the reaction mixture was still hot, it was filtered and the filtrate was concentrated under a reduced pressure. Then, after adding to the residue 50 ml. of a 10% aqueous sodium carbonate solution, the product was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crystalline residue. By recrystallizing the product from a mixture of 40 ml. of benzene and 60 ml. of n-hexane, 23 g. of 3-amino-4-benzyloxy-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol melting at 68.degree.-69.degree. C was obtained.
e. In 50 ml. of 5 : 3 acetic anhydride-formic acid there was dissolved 20 g. of 3-amino-4-benzyloxy-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol and after allowing the solution to stand overnight, the solution was concentrated under a reduced pressure. The residue thus obtained was dissolved in 120 ml. of methanol and after adding to the solution 5 ml. of water and 7.5 g. of sodium carbonate, the mixture was stirred for one hour at room temperature. Then, the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to give 20.5 g. of 4-benzyloxy-3-formylamino-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol in the form of an oil.
f. In 30 ml. of anhydrous tertrahydrofuran there was dissolved 5 g. of 4-benzyloxy-3-formylamino-.alpha.-(N-benzyl-N-tort-butylaminomethyl) benzyl alcohol and the resultant solution was added dropwise, with stirring, to a solution of 20 ml. of tetrahydrofuran and 20 ml. of ether to which there had been added 3 g. of lithium aluminum hydride. Thereafter, the resultant mixture was refluxed for one hour, accompanied by heating. Then, after adding dropwise 20 ml. of water to the reaction mixture gradually followed by stirring for one hour, the reaction mixture was filtered and the filtrate was concentrated under a reduced pressure. The residue was extracted with benzene and the extract was washed with water, dried, and concentrated under reduced pressure. The residue was subjected to a silica gel (70 ml.) column chromatography, the 3rd-8th fractions (each fraction 40 ml.) were collected by using chloroform as an eluting agent and concentrated under reduced pressure to provide 2.8 g. of a faint-yellow oily 4-benzyloxy-3-methylamino-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol.
g. In 5 ml. of 5 : 3 acetic anhydride-formic acid mixture there was dissolved 1.5 g. of 4-benzyloxy-3-methylamino-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol and the solution was allowed to stand overnight. The mixture was then concentrated under reduced pressure, the residue formed was dissolved in 50 ml. of methanol, and after adding to the solution 3 ml. of chilled water and 2 g. of sodium carbonate, the resultant mixture was stirred for one hour. The reaction product was concentrated under reduced pressure and the residue obtained was extracted with benzene. After washing the extract with water followed by drying over magnesium sulfate, the solvent was distilled off under reduced pressure to give 1.5 g. of a brownish oily 4-benzyloxy-3-(N-methyl-N-formylamino)-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol.
a. In 100 ml. of chloroform there was dissolved 16.5g. of p-nitroacetophenone and after adding dropwise to the solution 16 g. of bromine at room temperature, the mixture was stirred for 30 minutes. When the solvent was distilled off from the mixture under reduced pressure, a yellow crystalline material was obtained. By recrystallizing the crystals from benzene-n-hexane, 18.8 g. of 4-nitro-.alpha.-bromoacetophenone melting at 100.degree.-101.degree. C was obtained. The yield was 77%.______________________________________Elemental analysis for C.sub.8 H.sub.6 NO.sub.3 Br: C(%) H(%) N(%) Br(%)______________________________________Calculated: 39.37 2.48 5.74 32.74Found: 39.22 2.30 5.41 32.33______________________________________
b. In 50 ml. of anhydrous acetonitrile there was dissolved 10 g. of .alpha.-bromo-4-nitroacetophenone and after adding to the solution 13.7 g. of N-benzyl-N-tert-butylamine at normal temperature, the mixture was stirred for 2 hours. After distilling off the solvent under reduced pressure from the mixture, 100 ml. of benzene was added to the residue and after filtering off the hydrobromide of N-benzyl-N-tert-butylamine which had formed, benzene was distilled off under reduced pressure to give a red-black liquid. When 10 ml. of ethanol was added to the liquid, a crystalline material was formed, which was recovered by filtering and recrystallizing from ethanol to provide 3.5 g. of yellow acicular crystals of 4-nitro-.alpha.-(N-benzyl-N-tert-butylamino)-acetophenone melting at 88.degree.-90.degree. C.______________________________________Elemental analysis for C.sub.19 H.sub.22 N.sub.2 O.sub.3 : C(%) H(%) N(%)______________________________________Calculated: 69.92 6.79 8.58Found: 69.73 6.81 8.71______________________________________
c. In 200 ml. of ethanol there was dispersed 5 g. of 4-nitro-.alpha.-(N-benzyl-N-tert-butylamino)acetophenone and after adding to the dispersion 1 g. of sodium borohydride, the mixture was stirred at room temperature, whereby the acetophenone dissolved gradually. When the compound dissolved completely, the solution was stirred for 30 minutes and then the solvent was distilled off under reduced pressure to give yellow crystals. By recrystallizing these crystals from ethanol, 4 g. of yellow acicular crystals of 4-nitro-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol melting at 111.degree.-112.degree. C were obtained.______________________________________Elemental analysis for C.sub.19 H.sub.24 N.sub.2 O.sub.3 : C(%) H(%) N(%)______________________________________Calculated: 69.49 7.37 8.53Found: 69.19 7.49 8.72______________________________________
d. In 100 ml. of anhydrous methanol there was dissolved 4 g. of 4-nitro-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol and after adding to the solution 1 g. of Raney nickel, the catalytic reduction was conducted at normal temperature and pressure until 1080 ml. of hydrogen was absorbed. After filtering off the catalyst, the solvent was distilled off under a reduced pressure to provide an oily material. By purifying the oily material by means of a 100 ml. silica gel column and using benzene as a developing solvent, a yellow liquid was obtained. When the liquid was allowed to stand at room temperature, a crystalline material was formed, which was recovered by filtration and recrystallized from ethanol-n-hexane to provide 2.13 g. of yellow acicular crystals of 4-amino-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol metling at 88.degree.-90.degree. C.______________________________________Elemental analysis for C.sub.19 H.sub.26 N.sub.2: C(%) H(%) N(%)______________________________________Calculated: 76.47 8.78 9.39Found: 76.59 9.11 9.53______________________________________
e. In 10.6 ml. of 5 : 3 acetic anhydride-formic acid mixture there was dissolved 2.13 g. of 4-amino-.alpha.-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol and the solution was stirred overnight at room temperature. Then, when the excessive acetic anhydride and formic acid were distilled off under reduced pressure, an oily material was obtained. The product was dissolved in 30 ml. of methanol and after adding to the solution 5 ml. of water and an excessive amount of sodium carbonate, the resultant mixture was stirred for one hour at room temperature. The solvent was then distilled off from the reaction mixture under reduced pressure, the oily material thus obtained was dissolved in 50 ml. of benzene, and the solution was washed with water until the washing became neutral. After drying the solution over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 2 g. of caramel-like 4-formylamino-.alpha.-(N-benzyl-N-tert-butylaminomethyl)-benzyl alcohol.
The nuclear magnetic resonance spectra and infrared absorption spectra of the product coincided with those of the presumed structure.
a. In 200 ml. of methanol there was dissolved 16.0 g. of 4-benzyloxy-3-formylamino-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] prepared in Reference Example 4 and after adding to the solution 30 ml. of 4.8 normal hydrochloric acid, the mixture was refluxed for one hour and 30 minutes under heating. After the reaction was completed, the reaction product was cooled and after adding thereto 10 g. of potassium hydroxide and 50 ml. of water, the resultant mixture was stirred for one hour. The solvent was distilled off from from the reaction product under reduced pressure and the residue obtained was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to provide 14.5 g. of a crystalline powder of 3-amino-4-benzyloxy-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A].
b. In 20 ml. of acetic anhydride there was dissolved 4.0 g. of 3-amino-4-benzyloxy-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)aminomethyl] benzyl alcohol [A] prepared above and after heating the mixture to 65.degree.-80.degree. C for one hour and 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of 15 ml. of methanol and 2.0 g. of potassium hydroxide and the solution was stirred for one hour at room temperature. Then, methanol was distilled off under reduced pressure and after water was added to the residue, the residue was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and dried. Thereafter, by distilling off the solvent, 3.8 g. of a crystalline powder of 4-benzyloxy-3-acetylamino-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)aminomethyl] benzyl alcohol [A] was obtained. By recrystallizing 2.0 g. of the product thus obtained from 20 ml. of ethanol 1.6 g. of the crystalline pure product was obtained, melting at 141.degree.-143.degree. C.______________________________________Elemental analysis for C.sub.32 H.sub.36 N.sub.2 O.sub.4 : C(%) H(%) N(%)______________________________________Calculated: 75.55 6.92 5.34Found: 75.62 7.03 5.21______________________________________
In 20 ml. of anhydrous pyridine there was dissolved 2 g. of 3-amino-4-benzyloxy-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)-aminomethyl]benzyl alcohol (prepared in the aforesaid Reference Example 7-a) and the solution was cooled to temperatures from -20.degree. to -30.degree. C. A solution of 2.28 g. of benzyloxyacetyl chloride in 5 ml. of toluene was added dropwise to the solution thus cooled and while stirring the mixture, the temperature of the mixture was elevated slowly to room temperature. After stirring the mixture overnight, the solvent was distilled off under reduced pressure and the residue was mixed with 50 ml. of water. After washing the benzene solution thus obtained with water, benzene was distilled off from the reaction mixture under reduced pressure to provide a red oily material. The product was dissolved in 50 ml. of ethanol and after adding to the solution 5 ml. of water and 10 ml. of 4N sodium hydroxide solution, the resultant mixture was stirred for two hours. After adjusting the pH of the reaction mixture to 3 by adding 1N hydrochloric acid, an excessive amount of sodium carbonate was added thereto. Then, ethanol was distilled off under reduced pressure and the residue was extracted with benzene. The extract was washed three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a yellow oily material. The product was then subjected to a silica gel column chromatography (65 ml.). The product was eluted using 9 : 1 benzene-acetone mixture and the effluent was concentrated under reduced pressure to provide 3-benzyloxyacetylamino-4-benzyloxy-.alpha.-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)aminomethyl]benzyl alcohol.
Nuclear magnetic resonance spectra (CDCl.sub.3):
.delta.: 1.00 ppm. (d, 3H, CH--CH.sub.3), 4.08 ppm. ##STR3##
US Referenced Citations (2)
| Number |
Name |
Date |
Kind |
|
2393820 |
Schnider |
Jan 1946 |
|
|
3644520 |
Hartley et al. |
Feb 1972 |
|
Non-Patent Literature Citations (2)
| Entry |
| Larsen et al., J. Med. Chem., vol. 10, pp. 462-472 (May 1967). |
| Burger, Medicinal Chem., 3rd Ed., Pt. II, pp. 1235-1286 (1970). |
Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
325596 |
Jan 1973 |
|
Patent Grant
3994974
