CA1282077C - Process for producing substituted-phenethylamine derivatives - Google Patents
Process for producing substituted-phenethylamine derivativesInfo
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- CA1282077C CA1282077C CA000515041A CA515041A CA1282077C CA 1282077 C CA1282077 C CA 1282077C CA 000515041 A CA000515041 A CA 000515041A CA 515041 A CA515041 A CA 515041A CA 1282077 C CA1282077 C CA 1282077C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract
ABSTRACT OF THE DISCLOSURE
A novel process is disclosed for the production of substituted phenethylamine derivatives of the formula:
A novel process is disclosed for the production of substituted phenethylamine derivatives of the formula:
Description
311~132~
SPECIFICATION
-Title of ~he invention:
A novel process for producing substituted phenethyl-amine derivatives Detailed ex~lanation f the invention This invention relates to a process or producing a compound of the following formula (I) and a salt thereof Rl ~ C~2CIXN~CH2C 2 ~
wherein Rl represents a lower alkyl group, a lower alkoxy group, or a hyroxyl group; R2 represents a hydrogen atom, or a lower alkyl group; R3 represents a hydrogen atom or a lower alkyl group; and R4 represents a hydrogen ato~, a lower alkyl group, a lower alkoxy group, or a hydroxyl group (hereinafter, these means the same signifLcances).
U.S. Patent 4,373,106 discloses that the above formula (I) compounds exhibit ~-adrenergic bloc~ing ac~icn and are useful as an antihypertensive agent and an agent for the treatment of congestive heart failure.
So far, ~e formula (I) compounds have been produced by a process disclosed in U.S. Patent No. 4,217,305 or ~,373~ 106. This prior art process is as follows:
;~
~ \
SPECIFICATION
-Title of ~he invention:
A novel process for producing substituted phenethyl-amine derivatives Detailed ex~lanation f the invention This invention relates to a process or producing a compound of the following formula (I) and a salt thereof Rl ~ C~2CIXN~CH2C 2 ~
wherein Rl represents a lower alkyl group, a lower alkoxy group, or a hyroxyl group; R2 represents a hydrogen atom, or a lower alkyl group; R3 represents a hydrogen atom or a lower alkyl group; and R4 represents a hydrogen ato~, a lower alkyl group, a lower alkoxy group, or a hydroxyl group (hereinafter, these means the same signifLcances).
U.S. Patent 4,373,106 discloses that the above formula (I) compounds exhibit ~-adrenergic bloc~ing ac~icn and are useful as an antihypertensive agent and an agent for the treatment of congestive heart failure.
So far, ~e formula (I) compounds have been produced by a process disclosed in U.S. Patent No. 4,217,305 or ~,373~ 106. This prior art process is as follows:
;~
~ \
2~
SO~NH~ . SO~NH ~3 0 R~ 4 or R ~3 CH--CH ¦
o~q R2 ( b ) 5~Z
1 H~NCH2 C~ O--~ U . S . Pat . 4 ,217,305 So~NH R3 Rl ~CEI CEINH CH7 CH~0 ~ _ o~R2 R~
ogenation S07~
.s~ P~. 4j373,106 R~ CH~ ICEzCE~0 R2 R~
.1, Reduction ( I ) - - (I~ the above formulae, A represe~ts a halogen atom, and Rl, R2, R3 and R4 are as defined above. ) An object of the invention of this applica,ion is to provide a novel process for producing the formula (I) compounds which process is easy and suitable for industrial production of the compounds (I).
... . ,--. - - ~
~%~
That is, this invention relates to a process for producing a compound of the formula (I) or a salt therof which comprises reacting a compound of the formula R~ CH CXN / 1 (II) (wherein Rl, R2, and R3 are as defined above; and Xl and X2 represent a hydrogen atom or a protective group for an amino group) or a salt thereof with a sub~tituted phenoxy compound ~- ~ 2 (III) .
~wherein R4 is as defined above; and Y represents an aldehyde gr~p which may be protected, or -CH2-Z- (Z
represents a remov ~g group)~ and then, if Y is an aldehyde group which may be pro~ected, reducing the for~ed compound.
The compounds (I) contain an asymmetric carbon atom if R2 is a lower-alkyl group, and the aimed co~pounds (I) of the process of this invention include the racemic compounds thereof, a mixture of the racemic compounds .and each optically active substance . Each optically active substance or the recemic co~pounds o~ the compo~ds (I) can be produced by using an optically active or : racemic compound of- the s~arting material (II~
SO~NH~ . SO~NH ~3 0 R~ 4 or R ~3 CH--CH ¦
o~q R2 ( b ) 5~Z
1 H~NCH2 C~ O--~ U . S . Pat . 4 ,217,305 So~NH R3 Rl ~CEI CEINH CH7 CH~0 ~ _ o~R2 R~
ogenation S07~
.s~ P~. 4j373,106 R~ CH~ ICEzCE~0 R2 R~
.1, Reduction ( I ) - - (I~ the above formulae, A represe~ts a halogen atom, and Rl, R2, R3 and R4 are as defined above. ) An object of the invention of this applica,ion is to provide a novel process for producing the formula (I) compounds which process is easy and suitable for industrial production of the compounds (I).
... . ,--. - - ~
~%~
That is, this invention relates to a process for producing a compound of the formula (I) or a salt therof which comprises reacting a compound of the formula R~ CH CXN / 1 (II) (wherein Rl, R2, and R3 are as defined above; and Xl and X2 represent a hydrogen atom or a protective group for an amino group) or a salt thereof with a sub~tituted phenoxy compound ~- ~ 2 (III) .
~wherein R4 is as defined above; and Y represents an aldehyde gr~p which may be protected, or -CH2-Z- (Z
represents a remov ~g group)~ and then, if Y is an aldehyde group which may be pro~ected, reducing the for~ed compound.
The compounds (I) contain an asymmetric carbon atom if R2 is a lower-alkyl group, and the aimed co~pounds (I) of the process of this invention include the racemic compounds thereof, a mixture of the racemic compounds .and each optically active substance . Each optically active substance or the recemic co~pounds o~ the compo~ds (I) can be produced by using an optically active or : racemic compound of- the s~arting material (II~
3-- .
.
~2~2~1~7 The term "lower" used in the above forumla means a straight or branched chain having 1 to 5 carbon atoms.
Therefore, for example, a lower alkyl group includes methyl grcup, ethyl group, propyl group, butyl group, pen~yl group, isobutyl group, etc., anda lower alkoxy group includes methoxy group, ethoxy group, propoxy group, bu~oxy group, etc. The term l'halogen" in ~he formula means chlorine, bromine, iodine or fluorine.
As a protec~ive group for ~n amino group for Xl or X2, there are, or ~e~ple, trityl, substituted-trityl, kenzyl, substituted-t~ityl, benzyl, substit ~ d-benzyl, benzvlo~y~e~T~l, subs~tuted ~ nzyloxy, t~ethylsilyl, metho~thyl, etc.; as a prote ~ ve grouD fo~ an_loehydeE group for Y, there are, ~or e~Dle, dia~laoetals (e.g., ~ lacetale, diethylaoet21e, etc.), ring stn~lre aoet~les (e.g., et~leneaoetale, etc.), acylales (e.g., diaoetvl, etc.), which pn~ctive groups do not af~ect ~ reacticns and can be easily r;eleased. As a re~ovin~
gxoup which Z m~, there are, for ~le, a h310sen atom, or an or~c sulfonic acid residue such as tosvl, neth ~ sulfonyl, The compounds (I) or the starting compounds (II) can orm salts thereofte g. a salt with an inor~c add 5uch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, or with an organic acid such as formic acid, acetic acid, citric acid, succinic acid, fumaric acid, maleic acid/ tartaric acid, methanesulfonic acid, ethanesuIfonic acid, etc. These salts can be produced by an ordinary manner for producing such salts.
- ~2~32~
The processes of the invention are further described in more detail.
Firs~ly, a phenethylamine compound ~) or its salt is reacted with an reactive equivalent amount of a substituted phenoxy compound (III) in an organic sol~ent suitable for the reaction (Process I), and then, if Y is an aldehyde group which may be protected, the formed compound is subjected to a reducing reaction (Process II).
These processes are schematically shown below.
S02N~IR3 Rl~_C~ CHN/ + ~OC~I Y
212\x2 \j=( 2 tor its salt) R R4 (III) (II) _ ~
- Process I Process II
( in the case o f Y being an aldehyde - group whi ch may be prote cted ) . R~ 3cx2c~N=cxcx2o~
r ~ (V) reduction Rl--~ \~CH2fl~N~C~2 2 R .4 (I) R
~2~2~
Process I
This process ~that is, the reaction of a phenethylamine compound (II) or its salt with a substituted phenoxy compound (III)) can be performed in a solvent (which is inert to the reaction) such as alcohols(e.g.,me~ol, ethanol, iso-proDanol,etc.) ethers(e.g.,dioxane,tetrahydrofura~, acetonitrile, dimethyl-formamide, dimethylsulfoxide, etc. ~n equimolar or excess amount of the o~ounds is usedfor the reactIon.
It may be preferred to use an equimolar amou~t of Compounds if there eY~ist inorganic base (for example, potassium carbona~e, sodium carbonete, sodium hydrogen carbonate, etc.) or an organic ~ase (for example, triethylamine~ pyridine, picoline, N,N-dimethylaniline, N-methylmorpholine, etc.).
In the case of the o~ound (II) ~eing used, it may be preferred to perform the rea~icns in the preseneoe of an inorganic or orqanic base~
The reaction temperature or time may be changed suitably, considering the kind of Compound (II) or (III), or of sol-~ent.
The reaction is preferably performed in usual at room temperature or under heating such as under reflux.
Process II
.
The reactioll of a phenethylamine compound (II) or its salt with a substituted phenoxy compound in case of Y being an aldehyde group which may be protected,is usuallv ~rfo ~ d in a sol~ent which is inert to the reaction and can solubilize the reaction oom-pounds (e.g., alcohols such as methanol, eth2nol, iso-pro~anoli ethers such as tetrahydrofuran, dioxanei acetonitrile, d ~ thyl-fon~de, diemthylsulfo~lde~ at ~x~ tem¢erature or un~er heating.
, .
. .
''-''' The reaction can be finished in about 1 hour. The formed compound (IV) (in the reaction solution or after isolating) is then reduced. In this process, an acetal compound may be used instead of the formula (III) compound (in this case, the acetal compound is firstly hydroly~ed by using an inorganic acid (e.g., hydrochloric acid) t an organic acid (e.g., acetic acid, formic acid, toluenesulfonic acid, methanesulfonic acid), an organic acid salt (e.g., pyridine-toluenesulfonic acid salt), etc., and then, is subjected to the following reaction). The reduction can be accomplished in alcohols (e.g., methanol, ethanol, iso-propanol) or ethers (e.g., dioxane, tetrahydrofuran by adopting catalytic reduction using platinum oxide, palladium catalyst, Baney nickel,* or by using metal hydride such as sodium borvhydride, sodium borocyanohydride, lithium borohydride, lithium alminum hydride, etc.
*Trade Mark . ' .
1 32~
The desired compounds of this invention thus prepared is obtaiRed as free base or its salt. The free ~ase compound may be subjected to a salt forming reaction by a usual method,and the salt may be isolated and ourified by usual ma.~ner.The isolation and purification of the compounds can be ac~omplished by usual chemical procedures ~uch as filtratior~, extraction, recrystalli-zation, reprecipitation, various chromatagraphies, etc.
(Effects of the invention) In the case of the prior art methods for producing the compounds of this invention, there are needed ~anv steps of reaction, and so there is a difficulty in ~ ~rior art __ _ _ methods- for its mdustri~l ap~lication. In the case or ~ s invention, there is ne~ded on_~ an ext~_y fewer steps than the prior art methods,sincethe reaction procedures are simple; and the deslred compounds can be obtained in high yield. Accordingly, the method or this invention is very suitable for the industrial aDp~cation.
Purther, the reac~ns of this invention never accompany racemisation. Hence, each optical i:~rof the formula (I) com~ound Qn ~eselectively produced by using ~orresponding optical isomer of the starting material ~II) which is ' , . . '' ' . ~ '' :
' ~.
easily produced.
In order to explain the invention in more detail, there are set out below Reference Examples and Examples.
The formula (III) compounds which are starting materials for the processes of this invention, are novel compounds, and Reference Examples below show the production thereof.
Further, optical isomers of the phenethylamine derivatives of the formul~ (II) and their production are shown in Reference Examples 2 and 3.
Reference Example 1 Sodium hy~ri~e-(-in oil,-60%;--4.6g) was stirred in dry diemthylformami~e (100 ml), and after adding ~.~owly there-to 13.8 g of o-ethoxyphenol ,'the resultant mixture was x O
stirred under heatin~ at 60 C for l hour~ Then, under ice-cooling, 19.7 g of bromoacetaldehyde diethyl ac~tal ~was added drop~ise to the reaction mixture over a period of 1 hour. The reaction mixture was stirred at room temperature overnight, was heated while tirring at 60 C
for 2 hours, and then was poured into 500 ml of ice-water.
After extracting with ethyl acetate, the extract was wa~hed with water, and dryed over anhydrous sodium sulfate.
The solvents were distilled away to give oily residu~. The residue was distilled under reduced pressure to give oily material of 2-(0-ethoxyphenoxy)acetaldehyde diethyl acetal (12 g).
Boiling point: 113-116 C (0.5 mmHg) . .. ..... --q_ .... .. . .. .. . . .. . .. .
. . . . . - . .
'; ~' ' ., -P-N~IR ( CDCl3) o: 1.2~L ( 6~I, t, J=
~z, -CE7 C~I3 X 2 ), 1.~ 2 ( 3E? tr J=~Ez, -~E~
CH3), 3.4~ 3.9 ( 4H~ ~.. -OC~z CH3 X 2 ), 3.C~ 402 ( ~lF~, m, -OCl~I7 C~:3~ ~OCE7 C~ < ), A.8 6 ( l H, t, J=
5~z, -OCH7 CE< ), 6.8 8 (4E, s, aromatic ring) Referenoe Exam~le 2 (Prepara~ion of R(-) ~ound) a) In 6 ml of pyridine was dissol.ved 1.5 ~ ofR(-~-2-~p-methoxyphenyl)-l-methylethylamlne ( ~ ~23:-30.1 (c-1..2,--ne-~ha~ol)j~--arld after-addin~ there o 3 ml of .._ .. ..._ ... . _ .. . . . .
acetic cnhydride, the mix.ure was allowea to stand at~
room tem~e~ature for 1 hour. After distilling o~~ the solvent, the residue ~as extrzcted with e~:~yl acet~te:
The ethyl acetate ex,rac, was washed with water, ana dried over annYarous sodium sulrate,ancthesolvent as aistilled orf 2nd the c_ude c,vstals formed were recrys .cllized from z mi:~ture or n-hexane and ~enzene to provide 1.8 g of (R)(.)-~-acetyl-2-(p-me_hoxv?renYl)-l-methyle '~hylamine.
elting point: 92-93C
~ic-.-entcl anaivsis ~or C12~17~-02:
C(%) H~%) N(~) C~lc! ~ . 69.54 8.27 6.76 Found: 69 41 8.19 6 66 ]24:1~.8 (c=l.O9, methanol) ....
. - - ,~- , , " .
b) In 60 g of chlorosulfonic acid was added 6 g of (R) (T)-N-acetyl-2-~p-methoxyphenyl)-1-methylethylamine, under cooling at 0 to -10C. The mixture was stirred for 1 hour at 0 to 5C, and the reaction solution was poured into 600 g of ice-water. The oily material precipitated was extracted with ethyl acetate, and the ethyl acetate extract was washed by a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After distilling off the solvent, the formed residue (without purification) was dissolved in 120 ml of tetrahydrofuran.
After adding dropwise thereto 180 ml of a concentrated aqueous ammonia solution, the mixture was stirred for 1 hour at room temperature. The crystals precipitated were collected by filtration, washed with water, and recrystallized from methanol to provide 6 g of (R)~ N-acetyl-5-[(2-amino-2-methyl)-ethyl]-2-methoxybenzenesulfonamide; another name: R(~)-5-~2-acetylamino)propyl]-2-methoxybenzenesulfonamide.
Melting point: 197-198C
Elemental analysis for C12H18N2O4S:
(C%) H~%~ N(%) Calcd.: 50.34 6.34 9.78 Found: 50.28 6.41 9.69 ~]24:14.7 (c=1.0, methanol) ac~9 ~ O ~
c) 5 g of (Rj (I)-N-acetyl 5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide was dissol~ed in 125 ml of 5%
hydrochloric acid, and the solution was refluxed under heating for 16 hours. After distilling off the solvent, the crude crystals formed were recrystallized from isopropanol to provide 4.5 g of (R) (-)-5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide; namely, R(-~-5-(2-aminopropyl) 2-methoxybenzenesulfonamide (HCl salt).
Melting point: 273-277 C (decomposition) Elemental analysis for C10H17C1N2O3S:
C(%) H(%) N(%) Calcd.: 42.78 6.10 9.98 Found: 42.68 6.00 9.93 [a]24: -6.3~ (c=1.03, methanol) D
Reference Example 3 (Preparation of S(+) compound) a) By following the same procedure as in Reference Example 2(a), (S) (-)-N-acetyl-2-(p-methoxyphenyl)-1-methylethylamine was obtained by using S(~)-2-(p-methoxyphenyl)-1-methylethylamine.
Melting point: 94-96C
Elemental analysis for C12H17N2:
C(%) H(%) N(~) Calcd........ 69.54 8.27 6.76 Found: 69.~7 8.31 6.69 [a]2~: -15.3 (c=1.25, methanol) ~82~7~
b) ~y following the same procedure as in Reference Example 2(b), (S)(-)-N-acetyl-5-[(2-2mino-Z-methyl)-ethyl]-2-methoxybenzenesulonamide ~another name:
5(-)-5-[2-(acetylan.ino)propyl]-2-methoxybenzene-sulfonamide)was obtained by using ~S)(-)-N-acetyl-2-(p-methoxyphenyl)-1-methylethYlamine as the starting material.
Melting point: 196-198C
Ysls ~or C12X18N20 S
C(%) ~(%) N(%) Calcd.: 50.34 6.34 9.78 Found: 50.31- 6.24 9~73 ~]D -:-14.2 (c=l.01, me_;~anol) c) By following the same procedure as in Reference Ex.
2(c), (S) (T) -5-[(2-amino-2-methyl)ethyl]-2-methoxybenzene-sulfonamide was obtained by using (S)(-)-N-acetyl-5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide as the starting material.
Melting point: 273-276C (decomposition Elemental analysis for ClOH17~lN2O3S:
C(%) H(%) N(%) Calcd.: 42.78 6.10 9.98 Found: 42.65 6.03 9.89 [~]24: 6.0 (c=l.01, methanol) '~ .
3LZ8Zq:~7 Example 1 2.8 g of 2-(o-ethoxyphenoxy)acetaldehyde diethyl acetal was dissolved in 20 ml of acet~ne, and after adding thereto 3 ml of 6N-hydrochloric acid, the mixture was stirred~for 1.5 hour at room temperature.
The solvent was distiled away and after adding water~to the residue, the precipitated oily material was extracted with ether. The ether extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled away to give oily residue. The residue was dissolved in 100 ml of methanol and fter adding ~~~ theretb R~ 5-(2-aminopropyl)-2-methoxybenzensulfonamide (2.4 g~, the mixture was refluxed under heating for 1 hour. After coo~ing, 0.25 g of platinum oxide catalyst was added, and the reaction mixtuxe was subjected ~o re~uction reaction by a usual manner. The catalyst was remove~ by filtration and after acidifying the filtxate with ~Cl-ethanol, the solvent was distilled away. The residue was recrystallized from methanol to give R(-)-5~[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzensulfonamide ~Cl salt.
Melting point 228-230 C [~¦D -4.1 (methanol) 5~
:~
', Example 2 ~ y following the same procédure as in Example 1, by using S(+)-5-(2-aminopropyl-2-methoxybenzenesulfon-amide (instead of R(-)-5-(2waminopropyl)-2-methoxy benzenesulfonamide), 5(+)-5-[2-[~2-(o-ethoxyphenoxy)-ethyl]amino]propyl]-2-methcxybenze~esulfonamide HCl salt.
Melting point: 228-230C ~]24 +4 1 ~methanol) Example 3 By following the same procedure as in Example 1, by using racemic compound of 5-(2-aminopropyl)-2-methoxy-benzenesulfonamide (instead of R(-)-5-(2-aminopropyl)-2-methoxybenzenesulfon~lide), racemic compound of 5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyi]-2-methoxybenzene-sulfonamide RCl salt.
Melting point: 254-256~C
Examp~le 4 2.8 g of 2-(o ethoxyphenoxy)acetaldehyde diethyl acstal was dissolved in 20 ml of acetone, and after adding thereto 3 ml of 6N-hydrochloric acid, the resultant mixture was stirred at room temperature for 1.5 hour. The solvent was distilled away, and after adding water to the residue, the precipitated oily material was extracted with ether. The ether extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was distiled awav to give oily residue. The residue was dissolved in 10~ ml of me~hanol and after adding thereto 2.4 g of R(~ (2-aminopropyl)-~'~8~
-2-methoxybenzenesulfonamide, the mixture was refluxed under heating for 1 hour. Then, sodium borohydride (0.42 g) was added to the mixture at 5-10C over a period of 1 hour, the mixture was allowed to stand overnight. The solvent ~as distilled away, and the residue was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled away, a~d the residue was treated with HC1-ethanol, and recrystallized from methanol to give R(-)-5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide HC1 salt.
Melting point: 228 230 C
[~]24 +4.1 tmethanol) D
Example 5 By following the same procedure as in Example 4, by using S(~)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide (instead of R(-)-5-(2-aminopropyl)-2-methoxybenzene-sulfonamide), S(~)-5-[2-[[2-(o-ethoxyphenoxy)-ethyl]propyl]-2-methoxybenzenesulfonamide HC1 salt.
Melting point: 228 230C
[~]24 ~g.l (methanol) D
Example 6 By following the same procedure as in Example 4, by using racemic compound of 5 (2-aminopropyl)-2-methoxy-benzenesulfonamide (instead of R(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide), racemic compound of 5-[2-[~2-~o-ethoxyphenoxy)ethyl]propyl]-2-methoxybenzene-sulfonamide HC1 salt. Melting point: i55_156 C.
Example 7 In 120 ml of ethanol were dissolved 2.4 g of (R)(-)~5-(2-aminopropyl)-2-methoxybenzenesulfonamide and 1.2 g of 2-~o-ethoxyphenoxy)ethyl bromide, and the mixture was refluxed for 16 hours under heating. The solvent was distilled away, and after alkalifing the residue by the addition of 10% sodium hydroxide, and the oily material precipitated was extraced with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled away, and the residue was subjected to column chromatography. The product was eluted with CHC13-methanol (9 5) to provide 1.5 g of the crude crystals of (R)(-)-5-[2-~[2-(o-ethoxyphenoxy)-ethyl]amino]-2-methylethyl]-2-methoxybenzenesulfonamide, which was treated with HC1-ethanol to give a hydrochloric acid salt of (R) ~ 5-[2-[[2-(o-ethoxyphenoxy)ethyl]-amino]propyl]-2-methoxybenzenesulfonamide.
Melting point: 228-230C
Elemental analysis for C~oH2gClN2OsS:
C~%) H(%) N(%) Calcd.: 53.99 6.57 6.30 Found: 53.90 6.64 6.27 [a]24: -4.0 (c=0.35, methanol) ~2~
Exzmple 8 By followina the same proced~re Jas in ExamDle 7 (S)( )-5-[2-[~2-(o-ethoxvphenoxv)ethvl]amino]-propyl]-2-methXyDenzenesulfcnamide HC1 salt was obtained by using (S)( )-5-[(2-aminopropyl) -- 2-methoxy-benzenesulfon2mide as the star~inc mzt~zl.
~elting point: 228-230C (met~anol~
Element~l analysis ~or C20-~29ClN2O5S:
C(~) H(%) N(~) Cacld.: 53.~9 6.57 6.30 Faund: 5:3-g2 6.57 6.~5 [~ 24 4 2 (c=0.36, methanol~
~ l 9 _ : --, .
137~
Example 9 3 ~ ~2CH HCH2CH2o ~
HCl 1) In 40 ml of water was dissolved R(-)-5-(2-amino-propyl)-2-methoxybenzenesulfonamide HCl salt (4 g) by heating, and after adding thereto 14 ml of a saturated aqueous potassium carbonate solution, the mixture was stirred at 5C for 2 hours. The precipitated crystals were collected by filtration,-and the crystals obtained weré recrystallized from ethanol to give 2.6 g of R(-~-5~(2-aminopropyl)-2-methaxybenzenesulfonamide.
Melting point: 166-167C
[~ ~23 -17.3 (c=1.07, methanol) 2) In 5 ml of N,N-dimelthylformamide were dissolved 976 mg of R(-)-5-(2-aminopropyl)-2-methoxybenzenesulfon-amide and 245 mg of 2-(o-ethoxyphenoxy)ethyl ~romide, and after heating the solution at 60C for 5-7 hours, the solvent was distilled away. To the residue was add-ed 28 ml of water, and the mixture was refluxed under heating for 30 minutes. The mixture was stirred at 5C for 1 hour, and the crystals precipita~ed during .he stirring were collected by filtration. The crystals collected were recrystalized from iso propanol to give 320 mg of R(~ [2-[[2-(o-ethoxyphenoxy)ethyl]amino]-: ;~. . _ .
, 32~7~7 propyl]-2-methoxybenzenesulfonamide. This product was dissolved in 9.6 ml of methanol while heati~g, and after acidifying the solution by addition of conc.
hydrochloric acid under heating, the mixture was stirred at 5C overnight. The orystals precipitated were collected by flltration to give 270 mg of R(-)-5-[2-1~2-(o-ethoxyphenoxy)ethyl]amino~propyl]-2-methoxybenzenesulfonamide HC1 salt.
Melting point: 227-230C
Elemental analysis for C20H29clN2o5s C(~ H~) N(~
Cacld. 53.98 6.57 6.30 Found: 54.01 6.35 6.27 [~ ]22 _4,~o (c=0.35, methanol) Example 10 S02N~I2 CH30~EI2CHNHCH2CH20 c~3 C2H5 HCl 3y following the same procedure as in Example 9, by using the corresponding S(~)-isomer instead of R(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, S(~)-5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino~propyl]-2-methoxybenzenesulfonamide HCl salt was obtained.
Melting point: 228-230C
,, , , _ ~2~
Elemental analysis for C~0~29ClN205S
C(~) H(~) N(%) Cacld.: 53.98 6.57 6.30 Found: 53 90 6.55 6.29 [~]234.2 (c=0.36, methanol) --2~--. .
.
.
.
~2~2~1~7 The term "lower" used in the above forumla means a straight or branched chain having 1 to 5 carbon atoms.
Therefore, for example, a lower alkyl group includes methyl grcup, ethyl group, propyl group, butyl group, pen~yl group, isobutyl group, etc., anda lower alkoxy group includes methoxy group, ethoxy group, propoxy group, bu~oxy group, etc. The term l'halogen" in ~he formula means chlorine, bromine, iodine or fluorine.
As a protec~ive group for ~n amino group for Xl or X2, there are, or ~e~ple, trityl, substituted-trityl, kenzyl, substituted-t~ityl, benzyl, substit ~ d-benzyl, benzvlo~y~e~T~l, subs~tuted ~ nzyloxy, t~ethylsilyl, metho~thyl, etc.; as a prote ~ ve grouD fo~ an_loehydeE group for Y, there are, ~or e~Dle, dia~laoetals (e.g., ~ lacetale, diethylaoet21e, etc.), ring stn~lre aoet~les (e.g., et~leneaoetale, etc.), acylales (e.g., diaoetvl, etc.), which pn~ctive groups do not af~ect ~ reacticns and can be easily r;eleased. As a re~ovin~
gxoup which Z m~, there are, for ~le, a h310sen atom, or an or~c sulfonic acid residue such as tosvl, neth ~ sulfonyl, The compounds (I) or the starting compounds (II) can orm salts thereofte g. a salt with an inor~c add 5uch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, or with an organic acid such as formic acid, acetic acid, citric acid, succinic acid, fumaric acid, maleic acid/ tartaric acid, methanesulfonic acid, ethanesuIfonic acid, etc. These salts can be produced by an ordinary manner for producing such salts.
- ~2~32~
The processes of the invention are further described in more detail.
Firs~ly, a phenethylamine compound ~) or its salt is reacted with an reactive equivalent amount of a substituted phenoxy compound (III) in an organic sol~ent suitable for the reaction (Process I), and then, if Y is an aldehyde group which may be protected, the formed compound is subjected to a reducing reaction (Process II).
These processes are schematically shown below.
S02N~IR3 Rl~_C~ CHN/ + ~OC~I Y
212\x2 \j=( 2 tor its salt) R R4 (III) (II) _ ~
- Process I Process II
( in the case o f Y being an aldehyde - group whi ch may be prote cted ) . R~ 3cx2c~N=cxcx2o~
r ~ (V) reduction Rl--~ \~CH2fl~N~C~2 2 R .4 (I) R
~2~2~
Process I
This process ~that is, the reaction of a phenethylamine compound (II) or its salt with a substituted phenoxy compound (III)) can be performed in a solvent (which is inert to the reaction) such as alcohols(e.g.,me~ol, ethanol, iso-proDanol,etc.) ethers(e.g.,dioxane,tetrahydrofura~, acetonitrile, dimethyl-formamide, dimethylsulfoxide, etc. ~n equimolar or excess amount of the o~ounds is usedfor the reactIon.
It may be preferred to use an equimolar amou~t of Compounds if there eY~ist inorganic base (for example, potassium carbona~e, sodium carbonete, sodium hydrogen carbonate, etc.) or an organic ~ase (for example, triethylamine~ pyridine, picoline, N,N-dimethylaniline, N-methylmorpholine, etc.).
In the case of the o~ound (II) ~eing used, it may be preferred to perform the rea~icns in the preseneoe of an inorganic or orqanic base~
The reaction temperature or time may be changed suitably, considering the kind of Compound (II) or (III), or of sol-~ent.
The reaction is preferably performed in usual at room temperature or under heating such as under reflux.
Process II
.
The reactioll of a phenethylamine compound (II) or its salt with a substituted phenoxy compound in case of Y being an aldehyde group which may be protected,is usuallv ~rfo ~ d in a sol~ent which is inert to the reaction and can solubilize the reaction oom-pounds (e.g., alcohols such as methanol, eth2nol, iso-pro~anoli ethers such as tetrahydrofuran, dioxanei acetonitrile, d ~ thyl-fon~de, diemthylsulfo~lde~ at ~x~ tem¢erature or un~er heating.
, .
. .
''-''' The reaction can be finished in about 1 hour. The formed compound (IV) (in the reaction solution or after isolating) is then reduced. In this process, an acetal compound may be used instead of the formula (III) compound (in this case, the acetal compound is firstly hydroly~ed by using an inorganic acid (e.g., hydrochloric acid) t an organic acid (e.g., acetic acid, formic acid, toluenesulfonic acid, methanesulfonic acid), an organic acid salt (e.g., pyridine-toluenesulfonic acid salt), etc., and then, is subjected to the following reaction). The reduction can be accomplished in alcohols (e.g., methanol, ethanol, iso-propanol) or ethers (e.g., dioxane, tetrahydrofuran by adopting catalytic reduction using platinum oxide, palladium catalyst, Baney nickel,* or by using metal hydride such as sodium borvhydride, sodium borocyanohydride, lithium borohydride, lithium alminum hydride, etc.
*Trade Mark . ' .
1 32~
The desired compounds of this invention thus prepared is obtaiRed as free base or its salt. The free ~ase compound may be subjected to a salt forming reaction by a usual method,and the salt may be isolated and ourified by usual ma.~ner.The isolation and purification of the compounds can be ac~omplished by usual chemical procedures ~uch as filtratior~, extraction, recrystalli-zation, reprecipitation, various chromatagraphies, etc.
(Effects of the invention) In the case of the prior art methods for producing the compounds of this invention, there are needed ~anv steps of reaction, and so there is a difficulty in ~ ~rior art __ _ _ methods- for its mdustri~l ap~lication. In the case or ~ s invention, there is ne~ded on_~ an ext~_y fewer steps than the prior art methods,sincethe reaction procedures are simple; and the deslred compounds can be obtained in high yield. Accordingly, the method or this invention is very suitable for the industrial aDp~cation.
Purther, the reac~ns of this invention never accompany racemisation. Hence, each optical i:~rof the formula (I) com~ound Qn ~eselectively produced by using ~orresponding optical isomer of the starting material ~II) which is ' , . . '' ' . ~ '' :
' ~.
easily produced.
In order to explain the invention in more detail, there are set out below Reference Examples and Examples.
The formula (III) compounds which are starting materials for the processes of this invention, are novel compounds, and Reference Examples below show the production thereof.
Further, optical isomers of the phenethylamine derivatives of the formul~ (II) and their production are shown in Reference Examples 2 and 3.
Reference Example 1 Sodium hy~ri~e-(-in oil,-60%;--4.6g) was stirred in dry diemthylformami~e (100 ml), and after adding ~.~owly there-to 13.8 g of o-ethoxyphenol ,'the resultant mixture was x O
stirred under heatin~ at 60 C for l hour~ Then, under ice-cooling, 19.7 g of bromoacetaldehyde diethyl ac~tal ~was added drop~ise to the reaction mixture over a period of 1 hour. The reaction mixture was stirred at room temperature overnight, was heated while tirring at 60 C
for 2 hours, and then was poured into 500 ml of ice-water.
After extracting with ethyl acetate, the extract was wa~hed with water, and dryed over anhydrous sodium sulfate.
The solvents were distilled away to give oily residu~. The residue was distilled under reduced pressure to give oily material of 2-(0-ethoxyphenoxy)acetaldehyde diethyl acetal (12 g).
Boiling point: 113-116 C (0.5 mmHg) . .. ..... --q_ .... .. . .. .. . . .. . .. .
. . . . . - . .
'; ~' ' ., -P-N~IR ( CDCl3) o: 1.2~L ( 6~I, t, J=
~z, -CE7 C~I3 X 2 ), 1.~ 2 ( 3E? tr J=~Ez, -~E~
CH3), 3.4~ 3.9 ( 4H~ ~.. -OC~z CH3 X 2 ), 3.C~ 402 ( ~lF~, m, -OCl~I7 C~:3~ ~OCE7 C~ < ), A.8 6 ( l H, t, J=
5~z, -OCH7 CE< ), 6.8 8 (4E, s, aromatic ring) Referenoe Exam~le 2 (Prepara~ion of R(-) ~ound) a) In 6 ml of pyridine was dissol.ved 1.5 ~ ofR(-~-2-~p-methoxyphenyl)-l-methylethylamlne ( ~ ~23:-30.1 (c-1..2,--ne-~ha~ol)j~--arld after-addin~ there o 3 ml of .._ .. ..._ ... . _ .. . . . .
acetic cnhydride, the mix.ure was allowea to stand at~
room tem~e~ature for 1 hour. After distilling o~~ the solvent, the residue ~as extrzcted with e~:~yl acet~te:
The ethyl acetate ex,rac, was washed with water, ana dried over annYarous sodium sulrate,ancthesolvent as aistilled orf 2nd the c_ude c,vstals formed were recrys .cllized from z mi:~ture or n-hexane and ~enzene to provide 1.8 g of (R)(.)-~-acetyl-2-(p-me_hoxv?renYl)-l-methyle '~hylamine.
elting point: 92-93C
~ic-.-entcl anaivsis ~or C12~17~-02:
C(%) H~%) N(~) C~lc! ~ . 69.54 8.27 6.76 Found: 69 41 8.19 6 66 ]24:1~.8 (c=l.O9, methanol) ....
. - - ,~- , , " .
b) In 60 g of chlorosulfonic acid was added 6 g of (R) (T)-N-acetyl-2-~p-methoxyphenyl)-1-methylethylamine, under cooling at 0 to -10C. The mixture was stirred for 1 hour at 0 to 5C, and the reaction solution was poured into 600 g of ice-water. The oily material precipitated was extracted with ethyl acetate, and the ethyl acetate extract was washed by a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After distilling off the solvent, the formed residue (without purification) was dissolved in 120 ml of tetrahydrofuran.
After adding dropwise thereto 180 ml of a concentrated aqueous ammonia solution, the mixture was stirred for 1 hour at room temperature. The crystals precipitated were collected by filtration, washed with water, and recrystallized from methanol to provide 6 g of (R)~ N-acetyl-5-[(2-amino-2-methyl)-ethyl]-2-methoxybenzenesulfonamide; another name: R(~)-5-~2-acetylamino)propyl]-2-methoxybenzenesulfonamide.
Melting point: 197-198C
Elemental analysis for C12H18N2O4S:
(C%) H~%~ N(%) Calcd.: 50.34 6.34 9.78 Found: 50.28 6.41 9.69 ~]24:14.7 (c=1.0, methanol) ac~9 ~ O ~
c) 5 g of (Rj (I)-N-acetyl 5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide was dissol~ed in 125 ml of 5%
hydrochloric acid, and the solution was refluxed under heating for 16 hours. After distilling off the solvent, the crude crystals formed were recrystallized from isopropanol to provide 4.5 g of (R) (-)-5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide; namely, R(-~-5-(2-aminopropyl) 2-methoxybenzenesulfonamide (HCl salt).
Melting point: 273-277 C (decomposition) Elemental analysis for C10H17C1N2O3S:
C(%) H(%) N(%) Calcd.: 42.78 6.10 9.98 Found: 42.68 6.00 9.93 [a]24: -6.3~ (c=1.03, methanol) D
Reference Example 3 (Preparation of S(+) compound) a) By following the same procedure as in Reference Example 2(a), (S) (-)-N-acetyl-2-(p-methoxyphenyl)-1-methylethylamine was obtained by using S(~)-2-(p-methoxyphenyl)-1-methylethylamine.
Melting point: 94-96C
Elemental analysis for C12H17N2:
C(%) H(%) N(~) Calcd........ 69.54 8.27 6.76 Found: 69.~7 8.31 6.69 [a]2~: -15.3 (c=1.25, methanol) ~82~7~
b) ~y following the same procedure as in Reference Example 2(b), (S)(-)-N-acetyl-5-[(2-2mino-Z-methyl)-ethyl]-2-methoxybenzenesulonamide ~another name:
5(-)-5-[2-(acetylan.ino)propyl]-2-methoxybenzene-sulfonamide)was obtained by using ~S)(-)-N-acetyl-2-(p-methoxyphenyl)-1-methylethYlamine as the starting material.
Melting point: 196-198C
Ysls ~or C12X18N20 S
C(%) ~(%) N(%) Calcd.: 50.34 6.34 9.78 Found: 50.31- 6.24 9~73 ~]D -:-14.2 (c=l.01, me_;~anol) c) By following the same procedure as in Reference Ex.
2(c), (S) (T) -5-[(2-amino-2-methyl)ethyl]-2-methoxybenzene-sulfonamide was obtained by using (S)(-)-N-acetyl-5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide as the starting material.
Melting point: 273-276C (decomposition Elemental analysis for ClOH17~lN2O3S:
C(%) H(%) N(%) Calcd.: 42.78 6.10 9.98 Found: 42.65 6.03 9.89 [~]24: 6.0 (c=l.01, methanol) '~ .
3LZ8Zq:~7 Example 1 2.8 g of 2-(o-ethoxyphenoxy)acetaldehyde diethyl acetal was dissolved in 20 ml of acet~ne, and after adding thereto 3 ml of 6N-hydrochloric acid, the mixture was stirred~for 1.5 hour at room temperature.
The solvent was distiled away and after adding water~to the residue, the precipitated oily material was extracted with ether. The ether extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled away to give oily residue. The residue was dissolved in 100 ml of methanol and fter adding ~~~ theretb R~ 5-(2-aminopropyl)-2-methoxybenzensulfonamide (2.4 g~, the mixture was refluxed under heating for 1 hour. After coo~ing, 0.25 g of platinum oxide catalyst was added, and the reaction mixtuxe was subjected ~o re~uction reaction by a usual manner. The catalyst was remove~ by filtration and after acidifying the filtxate with ~Cl-ethanol, the solvent was distilled away. The residue was recrystallized from methanol to give R(-)-5~[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzensulfonamide ~Cl salt.
Melting point 228-230 C [~¦D -4.1 (methanol) 5~
:~
', Example 2 ~ y following the same procédure as in Example 1, by using S(+)-5-(2-aminopropyl-2-methoxybenzenesulfon-amide (instead of R(-)-5-(2waminopropyl)-2-methoxy benzenesulfonamide), 5(+)-5-[2-[~2-(o-ethoxyphenoxy)-ethyl]amino]propyl]-2-methcxybenze~esulfonamide HCl salt.
Melting point: 228-230C ~]24 +4 1 ~methanol) Example 3 By following the same procedure as in Example 1, by using racemic compound of 5-(2-aminopropyl)-2-methoxy-benzenesulfonamide (instead of R(-)-5-(2-aminopropyl)-2-methoxybenzenesulfon~lide), racemic compound of 5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyi]-2-methoxybenzene-sulfonamide RCl salt.
Melting point: 254-256~C
Examp~le 4 2.8 g of 2-(o ethoxyphenoxy)acetaldehyde diethyl acstal was dissolved in 20 ml of acetone, and after adding thereto 3 ml of 6N-hydrochloric acid, the resultant mixture was stirred at room temperature for 1.5 hour. The solvent was distilled away, and after adding water to the residue, the precipitated oily material was extracted with ether. The ether extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was distiled awav to give oily residue. The residue was dissolved in 10~ ml of me~hanol and after adding thereto 2.4 g of R(~ (2-aminopropyl)-~'~8~
-2-methoxybenzenesulfonamide, the mixture was refluxed under heating for 1 hour. Then, sodium borohydride (0.42 g) was added to the mixture at 5-10C over a period of 1 hour, the mixture was allowed to stand overnight. The solvent ~as distilled away, and the residue was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled away, a~d the residue was treated with HC1-ethanol, and recrystallized from methanol to give R(-)-5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide HC1 salt.
Melting point: 228 230 C
[~]24 +4.1 tmethanol) D
Example 5 By following the same procedure as in Example 4, by using S(~)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide (instead of R(-)-5-(2-aminopropyl)-2-methoxybenzene-sulfonamide), S(~)-5-[2-[[2-(o-ethoxyphenoxy)-ethyl]propyl]-2-methoxybenzenesulfonamide HC1 salt.
Melting point: 228 230C
[~]24 ~g.l (methanol) D
Example 6 By following the same procedure as in Example 4, by using racemic compound of 5 (2-aminopropyl)-2-methoxy-benzenesulfonamide (instead of R(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide), racemic compound of 5-[2-[~2-~o-ethoxyphenoxy)ethyl]propyl]-2-methoxybenzene-sulfonamide HC1 salt. Melting point: i55_156 C.
Example 7 In 120 ml of ethanol were dissolved 2.4 g of (R)(-)~5-(2-aminopropyl)-2-methoxybenzenesulfonamide and 1.2 g of 2-~o-ethoxyphenoxy)ethyl bromide, and the mixture was refluxed for 16 hours under heating. The solvent was distilled away, and after alkalifing the residue by the addition of 10% sodium hydroxide, and the oily material precipitated was extraced with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled away, and the residue was subjected to column chromatography. The product was eluted with CHC13-methanol (9 5) to provide 1.5 g of the crude crystals of (R)(-)-5-[2-~[2-(o-ethoxyphenoxy)-ethyl]amino]-2-methylethyl]-2-methoxybenzenesulfonamide, which was treated with HC1-ethanol to give a hydrochloric acid salt of (R) ~ 5-[2-[[2-(o-ethoxyphenoxy)ethyl]-amino]propyl]-2-methoxybenzenesulfonamide.
Melting point: 228-230C
Elemental analysis for C~oH2gClN2OsS:
C~%) H(%) N(%) Calcd.: 53.99 6.57 6.30 Found: 53.90 6.64 6.27 [a]24: -4.0 (c=0.35, methanol) ~2~
Exzmple 8 By followina the same proced~re Jas in ExamDle 7 (S)( )-5-[2-[~2-(o-ethoxvphenoxv)ethvl]amino]-propyl]-2-methXyDenzenesulfcnamide HC1 salt was obtained by using (S)( )-5-[(2-aminopropyl) -- 2-methoxy-benzenesulfon2mide as the star~inc mzt~zl.
~elting point: 228-230C (met~anol~
Element~l analysis ~or C20-~29ClN2O5S:
C(~) H(%) N(~) Cacld.: 53.~9 6.57 6.30 Faund: 5:3-g2 6.57 6.~5 [~ 24 4 2 (c=0.36, methanol~
~ l 9 _ : --, .
137~
Example 9 3 ~ ~2CH HCH2CH2o ~
HCl 1) In 40 ml of water was dissolved R(-)-5-(2-amino-propyl)-2-methoxybenzenesulfonamide HCl salt (4 g) by heating, and after adding thereto 14 ml of a saturated aqueous potassium carbonate solution, the mixture was stirred at 5C for 2 hours. The precipitated crystals were collected by filtration,-and the crystals obtained weré recrystallized from ethanol to give 2.6 g of R(-~-5~(2-aminopropyl)-2-methaxybenzenesulfonamide.
Melting point: 166-167C
[~ ~23 -17.3 (c=1.07, methanol) 2) In 5 ml of N,N-dimelthylformamide were dissolved 976 mg of R(-)-5-(2-aminopropyl)-2-methoxybenzenesulfon-amide and 245 mg of 2-(o-ethoxyphenoxy)ethyl ~romide, and after heating the solution at 60C for 5-7 hours, the solvent was distilled away. To the residue was add-ed 28 ml of water, and the mixture was refluxed under heating for 30 minutes. The mixture was stirred at 5C for 1 hour, and the crystals precipita~ed during .he stirring were collected by filtration. The crystals collected were recrystalized from iso propanol to give 320 mg of R(~ [2-[[2-(o-ethoxyphenoxy)ethyl]amino]-: ;~. . _ .
, 32~7~7 propyl]-2-methoxybenzenesulfonamide. This product was dissolved in 9.6 ml of methanol while heati~g, and after acidifying the solution by addition of conc.
hydrochloric acid under heating, the mixture was stirred at 5C overnight. The orystals precipitated were collected by flltration to give 270 mg of R(-)-5-[2-1~2-(o-ethoxyphenoxy)ethyl]amino~propyl]-2-methoxybenzenesulfonamide HC1 salt.
Melting point: 227-230C
Elemental analysis for C20H29clN2o5s C(~ H~) N(~
Cacld. 53.98 6.57 6.30 Found: 54.01 6.35 6.27 [~ ]22 _4,~o (c=0.35, methanol) Example 10 S02N~I2 CH30~EI2CHNHCH2CH20 c~3 C2H5 HCl 3y following the same procedure as in Example 9, by using the corresponding S(~)-isomer instead of R(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, S(~)-5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino~propyl]-2-methoxybenzenesulfonamide HCl salt was obtained.
Melting point: 228-230C
,, , , _ ~2~
Elemental analysis for C~0~29ClN205S
C(~) H(~) N(%) Cacld.: 53.98 6.57 6.30 Found: 53 90 6.55 6.29 [~]234.2 (c=0.36, methanol) --2~--. .
.
.
Claims (5)
1. A process for producing a compound of the following general formula (I) or a salt thereof (I) wherein R1 represents a lower alkyl group, a lower alkoxy group, or a hydroxyl group; R2 represents a hydrogen atom, or a lower alkyl group; R3 represents a hydrogen atom or z Lower alkyl group; and R4 represents a hydrogen atom, a lower alkyl group; a lower alkoxy group, or a hydroxyl group, which comprises reacting a compounf of the following formula (II) (II) (wherein R1, R2, and R3 are as defined above; and X1 and X2 represent a hydrogen atom or a protective group for an amino group) or a salt thereof with a substituted phenoxy compound (III) [wherein R4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group; and Y represents an aldehyde group which may be protected, or -CH2-Z- (Z
represents a removing group)] and then, if Y is an aldehyde group which may be protected, reducing the formed compound.
represents a removing group)] and then, if Y is an aldehyde group which may be protected, reducing the formed compound.
2. A process according to claim 1 wherein R1 is a lower alkoxy group, R2 is a lower alkyl group, R3 is a hydrogen atom, and R4 is a lower alkoxy group.
3. A process according to claim 1 or 2 for producing 5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzensulfonamide or its salt which comprises reacting 5- (2-aminopropyl)-2-methoxybenzene-sulfonamide or its salt with a substituted phenoxy compound of the formula (IV) (wherein Ya represents a halogenomethyl group or an aldehyde group which may be protected), and then, if Y represents an aldehyde group which may be protected, reducing the formed compound.
4. A process according to claim 1 or 2 for producing R-(-)-5-[2-[[2-(o-ethoxyphenoxy)ethyl]aminol-propyl ]-2-methoxybenzenesulfonamide or its salt which comprises reacting R-(-)-5-(2-aminopropyl)- 2-methoxybenzenesulfonamide or its salt with a phenoxy compound of the formula (IV) (wherein Ya represents a halogenomethyl group or an aldehyde group which may be protected), and then, if Ya represents an aldehyde group which may be protected, reducing the formed compound,
5. A process according to claim 1 for producing each optically active compound of the formula (I) compound which comprises reacting each corresponding optically active compound of the formula (II) compound with the formula (III) compound.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP254,326 | 1985-11-13 | ||
| JP60254326A JPS62114952A (en) | 1985-11-13 | 1985-11-13 | Production of substituted phenethylamine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1282077C true CA1282077C (en) | 1991-03-26 |
Family
ID=17263445
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000515041A Expired - Lifetime CA1282077C (en) | 1985-11-13 | 1986-07-31 | Process for producing substituted-phenethylamine derivatives |
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| Country | Link |
|---|---|
| JP (1) | JPS62114952A (en) |
| KR (1) | KR940007746B1 (en) |
| AT (1) | AT397960B (en) |
| CA (1) | CA1282077C (en) |
| ES (1) | ES2000382A6 (en) |
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| WO2004016582A1 (en) * | 2002-08-14 | 2004-02-26 | Natco Pharma Limited | An improved process for the preparation of tamsulosin hydrochloride |
| KR100503639B1 (en) | 2003-02-12 | 2005-07-26 | 보령제약 주식회사 | A purification process of Tamsulosin |
| SI21655A (en) * | 2003-12-29 | 2005-06-30 | LEK farmacevtska dru�ba d.d. | Synthesis of optically pure (r)-5-(2-aminopropyl)-methoxybenzene sulphonamide |
| CZ295583B6 (en) * | 2004-02-05 | 2005-08-17 | Zentiva, A. S. | Process for preparing (R)-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide |
| WO2006004093A1 (en) * | 2004-07-07 | 2006-01-12 | Hamari Chemicals, Ltd. | Process for producing optically active phenylpropylamine derivative |
| SI2394648T1 (en) | 2009-02-04 | 2017-02-28 | Astellas Pharma Inc. | Pharmaceutical composition for oral administration |
| EP2255793A1 (en) | 2009-05-28 | 2010-12-01 | Krka Tovarna Zdravil, D.D., Novo Mesto | Pharmaceutical composition comprising tamsulosin |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1147342A (en) * | 1977-10-12 | 1983-05-31 | Kazuo Imai | Process of producing novel phenylethanolamine derivatives |
| US4558156A (en) * | 1980-02-08 | 1985-12-10 | Yamanouchi Pharmaceutical Co., Ltd. | Sulfamoyl-substituted phenethylamine derivatives |
| JPS56110665A (en) * | 1980-02-08 | 1981-09-01 | Yamanouchi Pharmaceut Co Ltd | Sulfamoyl-substituted phenetylamine derivative and its preparation |
-
1985
- 1985-11-13 JP JP60254326A patent/JPS62114952A/en active Granted
-
1986
- 1986-07-07 KR KR1019860005460A patent/KR940007746B1/en not_active IP Right Cessation
- 1986-07-28 AT AT0203286A patent/AT397960B/en not_active IP Right Cessation
- 1986-07-29 ES ES8600685A patent/ES2000382A6/en not_active Expired
- 1986-07-31 CA CA000515041A patent/CA1282077C/en not_active Expired - Lifetime
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7329780B2 (en) | 2003-12-09 | 2008-02-12 | Cj Corporation | Method of preparing optically pure phenethylamine derivatives |
| RU2456269C2 (en) * | 2003-12-29 | 2012-07-20 | Лек Фармасьютикалз Д.Д. | Synthesis of r-5-(2-(2-(2-ethoxyphenoxyethylamino)propyl)-2-methoxybenzene sulphonamide hydrochloride of high chemical purity |
| WO2005080323A1 (en) * | 2004-02-23 | 2005-09-01 | Cadila Healthcare Limited | Process for manufacturing optically pure (r) or (s)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide |
| EP1786764A2 (en) | 2004-08-16 | 2007-05-23 | Scinopharm Singapore Pte Ltd. | Process for preparing tamsulosin |
| EP1786764B1 (en) * | 2004-08-16 | 2017-03-15 | Scinopharm Singapore Pte Ltd. | Process for preparing tamsulosin |
| WO2007031823A1 (en) * | 2005-09-12 | 2007-03-22 | Aurobindo Pharma Limited | An improved process for preparing tamsulosin hydrochloride |
| US8273918B2 (en) | 2005-09-12 | 2012-09-25 | Avrobindo Pharma Ltd. | Process for preparing tamsulosin hydrochloride |
| WO2008152653A2 (en) * | 2007-06-11 | 2008-12-18 | Matrix Laboratories Ltd | An improved process for the preparation of tamsulosin hydrochloride |
| WO2008152653A3 (en) * | 2007-06-11 | 2010-04-29 | Matrix Laboratories Ltd | An improved process for the preparation of tamsulosin hydrochloride |
| JP2013504563A (en) * | 2009-09-12 | 2013-02-07 | サンド・アクチエンゲゼルシヤフト | Process for the preparation of indoline derivatives and intermediates thereof |
| DE202023102187U1 (en) | 2023-04-25 | 2023-05-02 | Nusrath Anjum | Derivative formulation based on tamsulosin |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0137391B2 (en) | 1989-08-07 |
| KR940007746B1 (en) | 1994-08-24 |
| KR870004949A (en) | 1987-06-02 |
| ATA203286A (en) | 1993-12-15 |
| JPS62114952A (en) | 1987-05-26 |
| AT397960B (en) | 1994-08-25 |
| ES2000382A6 (en) | 1988-02-16 |
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