CA1120492A - Process for the preparation of 1-(3-trifluoromethylphenyl)-2- (2-benzoyloxyethylamino)-propane - Google Patents
Process for the preparation of 1-(3-trifluoromethylphenyl)-2- (2-benzoyloxyethylamino)-propaneInfo
- Publication number
- CA1120492A CA1120492A CA000313312A CA313312A CA1120492A CA 1120492 A CA1120492 A CA 1120492A CA 000313312 A CA000313312 A CA 000313312A CA 313312 A CA313312 A CA 313312A CA 1120492 A CA1120492 A CA 1120492A
- Authority
- CA
- Canada
- Prior art keywords
- propane
- trifluoromethylphenyl
- benzoyloxyethylamino
- vii
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
TITLE OF THE INVENTION
"PROCESS FOR THE PREPARATION OF 1-(3-TRIFLUOROMETHYLPHENYL)-2-(2-BENZOYLOXYETHYLAMINO)-PROPANE"
ABSTRACT OF THE DISCLOSURE
The invention relates to a process for preparing 1-(3-tri-fluoromethylphenyl)-2-(2-benzoyloxyethylamino)propane by cata-lytic debenzylation of 1-(3-trifluoromethylphenyl)-2-[N-(2-benzoyloxyethyl)-N-benzylamino]propane.
"PROCESS FOR THE PREPARATION OF 1-(3-TRIFLUOROMETHYLPHENYL)-2-(2-BENZOYLOXYETHYLAMINO)-PROPANE"
ABSTRACT OF THE DISCLOSURE
The invention relates to a process for preparing 1-(3-tri-fluoromethylphenyl)-2-(2-benzoyloxyethylamino)propane by cata-lytic debenzylation of 1-(3-trifluoromethylphenyl)-2-[N-(2-benzoyloxyethyl)-N-benzylamino]propane.
Description
This invention relates to a new process for the synthe~is of 1-(3-trifluoromet.hylphenyl)-2-(2-benzoyloxyethylamina~pro-pane, of -the ~ormula (I) Ar-CH2-CH-NH-CH2-CH2-O-C-C6H5 (I) O
where Ar ,represents a 3-tri~luoromethylphenyl re~idue.
Compound (I) is well-know *or its interesting hypolipaemi-zing activity.
¦ According to the prior art (F2P 1517 587) said substance is preparod~by a benzoylation reaction of 1-(3-trifluoromethylphe ¦ nyl)-2-(2-hydroxyethyl-amino~propane, as shown in the -~ollowin~
scheme: CH
3 C H -COCl Ar-CH2-CH-NH-CH2-CH20H 6 5 _ ~ (I) ` (II) where Ar has the same meaning as aboveO
~hi~ reaction is characterized by a low y~d~owing to the l competitive benzoylation at the N-atomO Moreo~er, the starting ¦ compound (II) can be obtained only through the reaction of the co~re~ponding primary amine (III) with ethylene oxide-CH3 C ~ ~ /CH2 CH3 Ar-CH2-CH-NH2 -- ~ Ar-CH2-CH-NH-CH2-CH20H
(III) (II) 4~
where Ar has the same meaning as above.
This reaction shows a highly unsatisfactory course hecause, even in the presence of an understoichiometric of ethylene oxide, a great amount of the bis-hydroxyethyl derivative is produced.
This by-product must be separated from (II) by a distil-lation under reduced pressure which is accompanied by some drawbacks.
The amine (III) itself is prepared from (3-trifluoro-. methylphenyl)acetone, for example through the oxime, whichis reduced catalytically. Only poor yields are obtained.
The low transformation yield in the final steps of the synthesis greatly affect the economy of the process leading to (I)-This is particularly true because the above side reactionsdestroy the trifluoromethyl-substituted moiety of the mole-cule, that is of the more expensive component.
It has been found that the above described drawbacks can be overcome by employing for the preparation of ~I) a new synthesis procedure, characterized in that 1-(3-trifluoro-methylphenyl)-2-[N-(2-benzoyloxyethyl)-N-benzylamino]-propane, of the formula VII, is catalytically debenzylated according to the following ireaction scheme:
I ~2 Ar-cH2-cH-N-cH2-cH2-o U C6 5 (I) CH~2-C~H.5 0 (VII) where Ar has the same meaning as aboveO
The reaction scheme can be more specifically set out as follows:
CH CH
1 3 C6H5-~12NH2 1 3 NaB H
Ar~CH2~C= ~ Ar-CH2-C=N~CH2-C6H5 ~ ?
(IV) f H3 C ~ - CH2 f H3 Ar~cH2-cH-NH-c~I2-c6H5 Q ~ Ar-CH2-CH~I-CH2-CH20H
(V) CH2-C~H5 l (~1) ¦ C6H5~ cl ~aH2 cH I~ ~H2 cH2 0 e C6 5 ~ (I) l (VII) ~where Ar has the same meaning as above.
I The preparation of the ~ohif~ base (IV) can be acoomplished Ireadily and the expected product is obtained in nearly quanti-¦tative yield. The same applies for the reduction of the N-be_ ¦zylderivati~e (~ In practi~e, it is suitable to bring about ~:
¦the reduction of (IV) ~ith a boro~ydride withou~b isolation of ¦the said Schiff base, ¦ ~he h~ro~-;yethylation rsaction of 1-(3-trifluoromethylphe-¦nyl)-2-(2-N benzylamin~-propane (V) occurs smoothly and affo~s ¦high yields of compound ~VI) which is practically free from ¦by-products~ Owing to the lack of hydrogen atoms on the amine ¦nitrogen the~ subs~quent benzoylation step i5 also univocal and ¦can be brought about directly with benzoyl chloride? without ¦any addition of acid acceptors~ Finally, the catalytic debenzy~
gz lation of compound (VI-L) affords the expected product (I) in high yield and great purity.
Accordingly9 the new process has to be considered a great improvement with re~pect to the prior art.
The following example i~ illustrative rather than limitati-ve of the present invention, E~AMP~E
a) 1-(3-TrifluoromethylphenYl)-2-b~n~ a=~g~LLL~
A solution of 101 g (0.5 mole) of (3-trifluoromethylphenyl`
acetone and 53 g (0 5 mole) of benzylamine in 500 ml of benze-ne i~ refluxed in an apparatus which allow~ ~ continuosly re-move the reaction water (a suitable apparatu~ is for example a Marcu~son'~ device).
When no more water is evolved~ the benzene is e~aporated un der diminished pressure, at last ~ith a rotating evaporator.
~ he residue? w~ich is formed mainly by the Schiff base (IV), weigh~ !147 g; it is dissolved in ethanol (500 ml) and the resulting solution is 910wly added with stirring to a suspensi n f 7 5 g (0.2 mole) of NaB~4 in 200 ml o.f ethanol. During the addition the temperature iæ kept at 15~20C by external coolin .
When the addition is complete~ the mi~ture is stirred for 10 hours at room temperature and then most of the ethanol is distilled (finally under diminished pressure), After diluition with 400 ml of ~ater, the reaction mixture is acidified with 2N EIC The emall a ount of unreaoted Xe-tone ia extracted with llZ~9,~
CH cl2, the aqueous ~eyer is basified with 15~0 NaOH and the ¦organic base is extracted with CH2C12, After drying of the ¦organic layer with K2C03, the solvent is removed and the resi-¦due is distilled under diminished pressure. The yield of the !product is 129 g9 bop. 0 5 = 130-133C. The yield on the star-¦ting ketone is 88%.
¦AnalYSis for C17 18 3 reg~ ~ C=69.62; H-6.14; N=4~77 l found ~o C=69.83; H=6~11; N=4.64 ¦ ~he spectral data (IR and NMR) are in agreement with the ¦expected structure.
b) 1-(3-~rifluorometh~lphenyl)-2- ~ ?-h~drox~ethyl)-~-benæ~
amino7-pro~e.
I
~o 58.6 g (0.2 mole) of the prod~ct obtained as described ~in a) is added 1 ml of water and the mixture is cooled -to 1-10C in an autoclave. 16 g (0.36 mole) of liqui-fied ethylene ¦oxide (-10C) are then added.
l The reaction mixture is heated to 100-115C ~or 8 hours, ¦cooled down and taken up with 300 ml of toluene~ It is washed ¦with 2 x 200 ml of water and dried on Na2SQ4~ ~he solvent is ¦eliminated under diminished pressure. 60~6 g (90~o of the theo ¦retical amount) of the product are obtained as a colourless ~ uid~ b.p. 0 5= 140-~4C.
¦Analysis for ClgH220NF3 rei.~ C=67.65; H=6.52; N=4.15 C1 4~Z
il - 6 -found % C=67.81; H=6.54; N=4.23 The IR and NMR spectra are in agreement with the expected structure.
c) 1-(3-Trifl rometh~phenyl)-2-/N-(2-benzoyloxye~-z,ylaminQ7~propaneO
A mixture of 50.5 g(0.15 mole) of 1-(3-trifluoromethylphe-nyl)-2-~(2-hydroxyethyl)-N-benzylamin~7-propane and 22,4 g (0.16 mole) oE benzoyl chloride in 200 ml of anhydrous toluene are heated f`or 6 hours under stirring at 70-80C.After cooling the hydrochloride of the benzoylation product separates out an~
is filtered with suc tion, thoroughly washed with toluene a~d dried.M.p. 141C.Yield 58.6 g(82% of the theoretical amount), Analy~iS for C26H26N2F3Cl req.~ C=65.40; H~5.66; Cl=7,44;N=2.93 found 7~o C=65.52~ H=5.68; Cl=7,63;N=2.98 The spectral data(IR and NMR~are in agreement with the ex-pected ones, d)1-(3-Trifluoromethylphenyl)-2-(2-benzoyloxyeth~lamino)proparE
A solution of 47.7 g (0,1 mole) OI -the hydrochloride descri bed under c) in 400 ml of ethanol is hydrogenated in the pre-~ence of 2~5 g of 510 palladium on carbon, at room temperature and pressure. During 1.5 hour 0.1 mole oE hydrogen are consu-med. The catalyst is Eiltered out and the solvent removed un-der diminished pressure. The residue is -taken up in 150 ml of ethy scetate, filtered with suction snd the crystalline pro-duct is washed with a little-ethyl acetate.
The hydrochloride o~ 1-(3-trifluoromethylphenyl)-2-(2-ben zoyloxyethylamino)-propane obtained shows a m.p. of 160-161C.
A mi~ture with a product prepared according to Fr.P. 1.517.587 : does not show any lowering o~ the m.p.
~he yield o~ the debenzylation 9tep is o~er 951~.
where Ar ,represents a 3-tri~luoromethylphenyl re~idue.
Compound (I) is well-know *or its interesting hypolipaemi-zing activity.
¦ According to the prior art (F2P 1517 587) said substance is preparod~by a benzoylation reaction of 1-(3-trifluoromethylphe ¦ nyl)-2-(2-hydroxyethyl-amino~propane, as shown in the -~ollowin~
scheme: CH
3 C H -COCl Ar-CH2-CH-NH-CH2-CH20H 6 5 _ ~ (I) ` (II) where Ar has the same meaning as aboveO
~hi~ reaction is characterized by a low y~d~owing to the l competitive benzoylation at the N-atomO Moreo~er, the starting ¦ compound (II) can be obtained only through the reaction of the co~re~ponding primary amine (III) with ethylene oxide-CH3 C ~ ~ /CH2 CH3 Ar-CH2-CH-NH2 -- ~ Ar-CH2-CH-NH-CH2-CH20H
(III) (II) 4~
where Ar has the same meaning as above.
This reaction shows a highly unsatisfactory course hecause, even in the presence of an understoichiometric of ethylene oxide, a great amount of the bis-hydroxyethyl derivative is produced.
This by-product must be separated from (II) by a distil-lation under reduced pressure which is accompanied by some drawbacks.
The amine (III) itself is prepared from (3-trifluoro-. methylphenyl)acetone, for example through the oxime, whichis reduced catalytically. Only poor yields are obtained.
The low transformation yield in the final steps of the synthesis greatly affect the economy of the process leading to (I)-This is particularly true because the above side reactionsdestroy the trifluoromethyl-substituted moiety of the mole-cule, that is of the more expensive component.
It has been found that the above described drawbacks can be overcome by employing for the preparation of ~I) a new synthesis procedure, characterized in that 1-(3-trifluoro-methylphenyl)-2-[N-(2-benzoyloxyethyl)-N-benzylamino]-propane, of the formula VII, is catalytically debenzylated according to the following ireaction scheme:
I ~2 Ar-cH2-cH-N-cH2-cH2-o U C6 5 (I) CH~2-C~H.5 0 (VII) where Ar has the same meaning as aboveO
The reaction scheme can be more specifically set out as follows:
CH CH
1 3 C6H5-~12NH2 1 3 NaB H
Ar~CH2~C= ~ Ar-CH2-C=N~CH2-C6H5 ~ ?
(IV) f H3 C ~ - CH2 f H3 Ar~cH2-cH-NH-c~I2-c6H5 Q ~ Ar-CH2-CH~I-CH2-CH20H
(V) CH2-C~H5 l (~1) ¦ C6H5~ cl ~aH2 cH I~ ~H2 cH2 0 e C6 5 ~ (I) l (VII) ~where Ar has the same meaning as above.
I The preparation of the ~ohif~ base (IV) can be acoomplished Ireadily and the expected product is obtained in nearly quanti-¦tative yield. The same applies for the reduction of the N-be_ ¦zylderivati~e (~ In practi~e, it is suitable to bring about ~:
¦the reduction of (IV) ~ith a boro~ydride withou~b isolation of ¦the said Schiff base, ¦ ~he h~ro~-;yethylation rsaction of 1-(3-trifluoromethylphe-¦nyl)-2-(2-N benzylamin~-propane (V) occurs smoothly and affo~s ¦high yields of compound ~VI) which is practically free from ¦by-products~ Owing to the lack of hydrogen atoms on the amine ¦nitrogen the~ subs~quent benzoylation step i5 also univocal and ¦can be brought about directly with benzoyl chloride? without ¦any addition of acid acceptors~ Finally, the catalytic debenzy~
gz lation of compound (VI-L) affords the expected product (I) in high yield and great purity.
Accordingly9 the new process has to be considered a great improvement with re~pect to the prior art.
The following example i~ illustrative rather than limitati-ve of the present invention, E~AMP~E
a) 1-(3-TrifluoromethylphenYl)-2-b~n~ a=~g~LLL~
A solution of 101 g (0.5 mole) of (3-trifluoromethylphenyl`
acetone and 53 g (0 5 mole) of benzylamine in 500 ml of benze-ne i~ refluxed in an apparatus which allow~ ~ continuosly re-move the reaction water (a suitable apparatu~ is for example a Marcu~son'~ device).
When no more water is evolved~ the benzene is e~aporated un der diminished pressure, at last ~ith a rotating evaporator.
~ he residue? w~ich is formed mainly by the Schiff base (IV), weigh~ !147 g; it is dissolved in ethanol (500 ml) and the resulting solution is 910wly added with stirring to a suspensi n f 7 5 g (0.2 mole) of NaB~4 in 200 ml o.f ethanol. During the addition the temperature iæ kept at 15~20C by external coolin .
When the addition is complete~ the mi~ture is stirred for 10 hours at room temperature and then most of the ethanol is distilled (finally under diminished pressure), After diluition with 400 ml of ~ater, the reaction mixture is acidified with 2N EIC The emall a ount of unreaoted Xe-tone ia extracted with llZ~9,~
CH cl2, the aqueous ~eyer is basified with 15~0 NaOH and the ¦organic base is extracted with CH2C12, After drying of the ¦organic layer with K2C03, the solvent is removed and the resi-¦due is distilled under diminished pressure. The yield of the !product is 129 g9 bop. 0 5 = 130-133C. The yield on the star-¦ting ketone is 88%.
¦AnalYSis for C17 18 3 reg~ ~ C=69.62; H-6.14; N=4~77 l found ~o C=69.83; H=6~11; N=4.64 ¦ ~he spectral data (IR and NMR) are in agreement with the ¦expected structure.
b) 1-(3-~rifluorometh~lphenyl)-2- ~ ?-h~drox~ethyl)-~-benæ~
amino7-pro~e.
I
~o 58.6 g (0.2 mole) of the prod~ct obtained as described ~in a) is added 1 ml of water and the mixture is cooled -to 1-10C in an autoclave. 16 g (0.36 mole) of liqui-fied ethylene ¦oxide (-10C) are then added.
l The reaction mixture is heated to 100-115C ~or 8 hours, ¦cooled down and taken up with 300 ml of toluene~ It is washed ¦with 2 x 200 ml of water and dried on Na2SQ4~ ~he solvent is ¦eliminated under diminished pressure. 60~6 g (90~o of the theo ¦retical amount) of the product are obtained as a colourless ~ uid~ b.p. 0 5= 140-~4C.
¦Analysis for ClgH220NF3 rei.~ C=67.65; H=6.52; N=4.15 C1 4~Z
il - 6 -found % C=67.81; H=6.54; N=4.23 The IR and NMR spectra are in agreement with the expected structure.
c) 1-(3-Trifl rometh~phenyl)-2-/N-(2-benzoyloxye~-z,ylaminQ7~propaneO
A mixture of 50.5 g(0.15 mole) of 1-(3-trifluoromethylphe-nyl)-2-~(2-hydroxyethyl)-N-benzylamin~7-propane and 22,4 g (0.16 mole) oE benzoyl chloride in 200 ml of anhydrous toluene are heated f`or 6 hours under stirring at 70-80C.After cooling the hydrochloride of the benzoylation product separates out an~
is filtered with suc tion, thoroughly washed with toluene a~d dried.M.p. 141C.Yield 58.6 g(82% of the theoretical amount), Analy~iS for C26H26N2F3Cl req.~ C=65.40; H~5.66; Cl=7,44;N=2.93 found 7~o C=65.52~ H=5.68; Cl=7,63;N=2.98 The spectral data(IR and NMR~are in agreement with the ex-pected ones, d)1-(3-Trifluoromethylphenyl)-2-(2-benzoyloxyeth~lamino)proparE
A solution of 47.7 g (0,1 mole) OI -the hydrochloride descri bed under c) in 400 ml of ethanol is hydrogenated in the pre-~ence of 2~5 g of 510 palladium on carbon, at room temperature and pressure. During 1.5 hour 0.1 mole oE hydrogen are consu-med. The catalyst is Eiltered out and the solvent removed un-der diminished pressure. The residue is -taken up in 150 ml of ethy scetate, filtered with suction snd the crystalline pro-duct is washed with a little-ethyl acetate.
The hydrochloride o~ 1-(3-trifluoromethylphenyl)-2-(2-ben zoyloxyethylamino)-propane obtained shows a m.p. of 160-161C.
A mi~ture with a product prepared according to Fr.P. 1.517.587 : does not show any lowering o~ the m.p.
~he yield o~ the debenzylation 9tep is o~er 951~.
Claims (4)
1. A process for the preparation of 1(3-trifluoromethyl-phenyl)-2-(2-benzoyloxyethylamino)propane, the formula of which is CH3 (I) where Ar represents a 3-trifluoromethylphenyl residue, characterized in that l-(3-trifluoro-methylphenyl)-2-[N-(2-benzoyloxyethyl)-N-benzylamino]-propane, of the formula VII, is catalytically debenzylated according to the following reaction scheme:
(I) (VII) where Ar has the same meaning as above.
(I) (VII) where Ar has the same meaning as above.
2. A process as claimed in claim 1, characterized in that the debenzylation reaction is catalyzed by palladium.
3. A process as claimed in claim 1, characterized in that l-(3-trifluoromethylphenyl)-2-[N-(2-benzoyloxyethyl)-N-benzylamino]-propane is prepared according to the following synthetic pathway:
(VI) (V) (VI) (VII) where Ar has the same meaning as above.
(VI) (V) (VI) (VII) where Ar has the same meaning as above.
4. A process as claimed in claim 3 characterized in that the reduction with NaBH4 is performed directly on the crude reaction product from (3-trifluoromethylphenyl)acetone and benzylamine, without isolation of the Schiff base (IV).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT29.071A/77 | 1977-10-28 | ||
| IT2907177A IT1089009B (en) | 1977-10-28 | 1977-10-28 | PROCESS FOR THE PREPARATION OF 1- (3-TRIFLUOROMETILFENIL) -2- (2-BENZOYLOXYETHYLAMIN) -PROPANE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1120492A true CA1120492A (en) | 1982-03-23 |
Family
ID=11226107
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000313312A Expired CA1120492A (en) | 1977-10-28 | 1978-10-12 | Process for the preparation of 1-(3-trifluoromethylphenyl)-2- (2-benzoyloxyethylamino)-propane |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS5835499B2 (en) |
| CA (1) | CA1120492A (en) |
| ES (1) | ES474498A1 (en) |
| IT (1) | IT1089009B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20012597A1 (en) * | 2001-12-11 | 2003-06-11 | Synteco Spa | SYNTHESIS OF 1- (3-TRIFLUOROMETILFENIL) -2 - (- 2-BENZOYLOXYETHYLAMIN) -PROPANE |
| CN101880238B (en) * | 2010-07-06 | 2014-05-21 | 沈阳药科大学 | Preparation method of benzoic acid-2-((1-methyl-2-[3-(trifluoromethyl)-phenyl] ethyl) amino) ethyl ester hydrochloride |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1175516A (en) * | 1966-04-15 | 1969-12-23 | Science Union & Cie | New Phenyl-Aminopropane Derivatives and Preparations Containing them |
-
1977
- 1977-10-28 IT IT2907177A patent/IT1089009B/en active
-
1978
- 1978-10-12 CA CA000313312A patent/CA1120492A/en not_active Expired
- 1978-10-23 JP JP53130940A patent/JPS5835499B2/en not_active Expired
- 1978-10-25 ES ES474498A patent/ES474498A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5470238A (en) | 1979-06-05 |
| IT1089009B (en) | 1985-06-10 |
| JPS5835499B2 (en) | 1983-08-03 |
| ES474498A1 (en) | 1979-04-16 |
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| MKEX | Expiry |