DE1238898B - Process for the preparation of styrylethanolamines - Google Patents

Description

GERMAN

PATENT OFFICE

• z)

'EDITORIAL

238 898 German KL: 12 ο -19/03

Number: 1 238 898

File number: N 26997 IV b / 12 ο

Filing date: July 7, 1965

Open date: April 20, 1967

The invention relates to a process for the preparation of styrylethanol oils of the formula I.

Ch = CH-CHOH-CH ₂ -NH-R

and their salts, where Y ₁ and / or Y _{2 can be} identical or different and represent hydrogen, halogen or an alkyl, alkoxy or an alkylthio radical having 1 to 4 carbon atoms and R is hydrogen, an optionally branched alkyl radical and / or denotes a cycloalkyl radical or an aralkyl or phenoxyalkyl radical, the phenyl radical can be substituted by one or two alkyl, alkoxy or hydroxy radicals, which is characterized in that it is carried out in a manner known per se
a) a compound of the general formula ao

Y ₁ ■ / - V-CH = CH-Z

where Z

-CH-CH ₂ , -CHOH-CH ₂ -halogen, .0

-CHOHC '

or

—Co — c:

Process for the production of
Styrylethanolamines

Applicant:

NV Philips' Gloeilampenfabrieken,
Eindhoven (Netherlands)

Representative:

Dipl.-Ing. H. Zoepke, patent attorney,

Munich 5, Erhardtstr. 11

Named as inventor:

Hendrik Durk Moed,

Volkert Ciaassen,

Gerard Bernard Paerels, Weesp (Netherlands)

Claimed priority:

Netherlands of July 11, 1964 (6407 943)

where Z

and

C-CH ₂ -NHR, CH (OH) CN,
O

—COCN, —COCNOH
-CHOH-C = NOH

means reduced; if R has the meaning H, the alkylation is carried out in a manner known per se.

means, reacts with an amine of the general formula RNH ₂ and reduces the optionally obtained Schiff base;

b) a compound of the general formula

Y ₁ - €

-CH = CH-Z

It has been found that the compounds obtained by the process according to the invention are of interest have pharmacological effects. It was found, among other things, that the compounds a sympathicolytic effect, especially a beneficial cardiac effect, and an effect on the Central nervous system, in particular have an analgesic effect.

In particular, it has been found that the compounds obtained according to the invention have a pronounced beta-sympathicolytic Have an effect. Accordingly

709 550/362

can do the same after putting them into a suitable administration form have been brought into remedies for treating patients with cardiac arrhythmias and are used in tachycardia, even if these cardiac regulation disorders are the result the use of another remedy, e.g. B. a uterine spasmolytic, as well as diseases, z. B. Angina and hypertension. Also the decrease in blood pressure as a result of the Use of a uterine spasmolytic can be prevented by previously using one of the according to the invention compounds obtained is administered.

The beta sympathicolytic effects of the compounds According to the invention, in investigations on an isolated caviarium preparation which was found in suspended in a Ringer's solution and connected to a frequency counter. By addition of N-isopropyl noradrenaline can be used in this preparation a frequency increase can be caused. It was now examined to what extent one This increase in frequency can be counteracted by taking N-isypropylnoradrenaline before the administration adding a compound obtained by the process according to the invention.

The table below shows the results of comparative experiments in which, in the manner described above, the activity of four compounds according to the invention was compared with the activity of a compound known under the trade name "Inderal". "Inderal" has the following chemical structural formula:
/ '^; - O - CH ₂ - CHOH-CH ₂ - NIC ₃ H ₇

Y ₁ Y ₂ R. activity o-OCHg
0-OC ₂ H ₅
0-OC ₃ H ₇
0-SCH3
Inderal KKKK I i-propyl
i-propyl
i-propyl
i-propyl 1.1
1.9
1.4
2.3
1

The above test results clearly show the superior action of the compounds according to the invention. It has also been found that in particular compounds of the formula I in which Y _{1 is} an ortho-alkyl- or ortho-S-alkyl with 1 to 3 carbon atoms, Y _{2 is} hydrogen and R is a branched alkyl group with 3 or 4 carbon atoms have a particularly good effect.

Furthermore, in particular those compounds of the formula I for which R is optionally in The phenoxyalkyl or aralkyl group substituted for the phenyl group is a very strong and sustainable one beta-sympathicolytic effect.

It was z. B. found that the connection of the

Formula II

- CH = CH - CHOH - CH ₂ - NH - CHCH ₃ - CH ₂ - CH _?

has a longer lasting effect than that of the well-known beta-sympathicolytic a- (isopropylaminomethyl) -2-naphthalenemethanol. If z. B. in the mentioned experiment with a certain dosage of the / 5-naphthylethanolamine an ^{effect lasting I 1} Za hours was achieved, an effect lasting longer than 6 hours was found with the same dosage of the compound of the formula II.

The compounds of the invention can be prepared according to those used for the preparation of similar compounds known and similar processes are produced.

Particularly suitable salts of the compounds are acid addition salts which, for. B. from the Amine with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, tartaric acid, Citric acid, ascorbic acid, benzoic acid, p-aminobenzoic acid, mandelic acid or salicylic acid are formed.

According to the invention, the new compounds and their salts are prepared by processes known per se brought into a suitable administration form, the usual pharmaceutical Processes and materials are used. For example, for the preparation of injection liquids, aqueous solutions of salts of the new Amines at a concentration of 1 to 50 mg / ml made isotonic with blood with the help of table salt. Mixtures of water and alcohols, e.g. B. glycerol or benzyl alcohol, as a liquid diluent to be used.

Solid pharmaceutical molded pieces are produced in the usual way in that the active ingredient in solid pharmaceutical carrier materials, e.g. B. milk sugar, powdered sugar, potato starch, talc, Magnesium stearate, gum arabic, gelatin, calcium phosphate and / or titanium dioxide, added and the mixture is processed into tablets or coated tablets.

example 1
1-amino-4-phenyl-3-buten-2-ol

A solution of 40 g (0.25 mol) of 2-hydroxy-4-phenyl-3-butenenitrile in 200 ml of absolute ether, while stirring, a solution of 24 g (0.625 mol) of lithium aluminum hydride in 400 ml of absolute Ether added dropwise. The mixture was refluxed for IV2 hours and then with decomposed a mixture of 75 ml of water and 150 ml of tetrahydrofuran. The reaction mixture was left to stand one night at room temperature, after which the solid material was suctioned off. This was stirred three times with warm chloroform and suctioned off each time. The chloroform extracts were added to the filtrate and the whole thing dried with sodium sulfate, filtered and evaporated dry in vacuo. The residue (38 g) was in 200 ml

Benzene dissolved, after which 200 ml of petroleum ether (boiling point 40 to 60 ° C) were added to the solution. The mixture was overnight at +5 ⁰ C allowed to stand, after which the crystallized substance sucked off, with

Benzene-petroleum ether (1: 2) washed and on the Air dried. Yield 12.2 g (30%); the substance sintered at 75 ° C and melted from 91 to 94.5 ° C. After recrystallization from 100 ml of benzene, yield 10.1 g (25%), m.p. = 95.5 to 97.5 ° C.

A sample recrystallized twice from benzene had a melting point of 97 to 99 ° C Equivalent weight of 166 (calculated 163); an iodine number of 155.8 (calculated 155.8); and UV absorption maxima at 251, 282 and 291 πΐμ, where s was 17300, 1270 and 890, respectively.

Example 2

1-Isopropylamino-4-phenyl-3-buten-2-ol-HCl

2 ml of 2 normal aqueous sodium hydroxide solution, 3 ml (2.4 g; 0.04 Mol) acetone and carefully added 3.04 g (0.08 mol) sodium borohydride while cooling with cold water. After the vigorous reaction subsided, the mixture was boiled for 2 hours. The methanol was evaporated in vacuo and the residue was shaken with 50 ml of water and 50 ml of benzene. The layers were separated and the aqueous layer was shaken twice more with 25 ml of benzene. The combined benzene extracts were extracted with 10 ml of 2η hydrochloric acid plus 20 ml of water and then with 5 ml of 2η hydrochloric acid plus 10 ml of water. The hydrochloric acid extracts were made alkaline with aqueous alkali and extracted once with 50 ml and twice with 25 ml of benzene. The combined benzene layers were _{dried over MgSO 4} and evaporated dry in vacuo. The remaining oil (1.9 g) was dissolved in a small amount of absolute alcohol, the solution was filtered off, and 3.5 ml of 2.85 normal alcoholic HCl was added to the filtrate. The solution was evaporated dry and the residue from a mixture of

3 ml of alcohol and 30 ml of acetone crystallized. The result was 1.3 g (26.8%), m.p. = 160 to 163 ° C.

1.84 g of the product thus obtained were removed

4 ml of absolute alcohol plus 35 ml of acetone recrystallized; this gave 1.45 g of substance with a melting point of 163 to 164 ° C. Cl * found 15.1% (calculated 14.7%). Equivalent weight from bromine addition 267.5 (calculated 241.5). UV absorption maxima 251, 282 and 291 πΐμ, ε 19500, 1480 and 1100, respectively.

Example 3

1- (1-Methyl-3-phenylpropylamino) -4-phenyl-3-buten-2-ol-HCl

A solution of 2.3 g (0.0145 mol) of 1-amino-4-phenyl-3-buten-2-ol in 45 ml of methanol were successively 4.5 g (0.03 mol) of benzyl acetone, 5 ml of 2N aqueous sodium hydroxide and 2.3 g 91Voiges (0.055 moles) of sodium borohydride were added. The mixture was boiled for 2 hours, after which the Methanol was evaporated in vacuo. 25 ml of water was added to the residue, followed by was poured out three times with 25 ml of ether. The collected ether extracts were mixed with 20 ml of water plus 10 ml 2 η-hydrochloric acid shaken. There was immediately a solid substance that was sucked off with Ether washed and dried; Weight 1.13 g (23Vo), F. = 164.5, 172, 174.5 ° C (decomposition), Cl 11.4% (calculated 10.7%).

Recrystallization from 20 ml of water gave 0.84 g, mp = 164, 174, 181 ° C. (decomposition). The substance was recrystallized from 34 ml of isopropyl alcohol and gave 0.65 g, m.p. = 188 to 190 ^° C. Cl ¹ 11.1% (calculated 10.7%>). UV absorption maxima 251.5, 281 and 290.5 πΐμ, «20000, 1500 and 1030, respectively.

Example 4
1-Amino-4- (4-methoxyphenyl) -4-buten-2-ol-HQ

a) 2-Hydroxy-4- (4-methoxyphenyl) -3-butenenitrile

86 g of the bisulfite addition product of p-methoxycimetaldehyde were _{suspended in a solution of 12 g of Na 2} S ₂ O ₅ in 220 ml of water. The mixture

ao was cooled to 5 to 10 ° C. in an ice bath, after which 500 ml of diethyl ether were added. An ice-cold solution of 41 g of NaCN in 100 ml of water was then added all at once with vigorous stirring. After stirring for Va hour (in an ice bath), 5 g of Na ₂ S ₂ O _{5 were} added, followed by stirring for 1 hour. The liquid layers were separated. The water layer was extracted twice with 130 ml of diethyl ether, after which the collected organic liquid was _{washed twice with 130 ml of a 20% Na 2} S ₂ O ₅ solution in water and then twice with 130 ml of water. The liquid was dried _{with Na 2} SO _4. The solvent was removed under reduced pressure and the residue was taken up in 100 ml of benzene. The product was evaporated dry under reduced pressure and taken up in 200 ml of benzene. Evaporation of the benzene gave an oily residue (55 g) which was crystallized from a mixture of 110 ml of benzene and 45 ml of petroleum ether (40:60). The cyanohydrin obtained had a melting point of 73 to 78 ° C.

b) 15.12 g of the cyanohydrin obtained according to a) were dissolved in 75 ml of acetic anhydride. The mixture was left at room temperature for 16 hours and then heated on the steam bath for ½ hour. Excess acetic anhydride was distilled off under reduced pressure to obtain an oily residue (19.0 g). This oil was dissolved in 100 ml of dry diethyl ether, and this solution was added dropwise to a solution of 12 g of LiAlH ₄ in 300 ml of dry ether ^{in 3 hours.} The mixture was then refluxed for 3 hours. The reaction mixture was decomposed by adding 36 ml of water. The hydroxide precipitate formed, on which it was found that the greater part of the desired reaction product had been absorbed, was suctioned off. This precipitate was boiled with 150 ml of chloroform, filtered hot, boiled again with 150 ml of chloroform and then washed with warm chloroform. The solvent was removed from the collected chloroform extracts under reduced pressure, leaving a residue of 9.0 g of solid matter. After crystallization from 100 ml of benzene and washing with 40 ml of a 1: 1 benzene-petroleum ether mixture and 40 ml of petroleum ether, the result was 7.65 g of white substance, m.p. = 114 to 116 ° C.

Example 5

1-Isopropylamino-4- (4-methoxyphenyl) -3-buten-2-ol hydrochloride

3.86 g of the amine prepared according to Example 4 and 3.0 ml of acetone were dissolved in 60 ml of methanol, after which 0.25 ml of 2.3 normal alcoholic HCl were added. After the mixture ^{had stood at room temperature for 1} second hour, 1.2 g of about 90% NaBH _{4 was} added, followed by boiling for 1 hour. After cooling, 4.0 nal of acetone were added, and after the mixture had stood again for half an hour at room temperature, 1.6 g of 90% NaBH _{4 were} added and the mixture was then boiled for 1 hour. After removing the solvent under reduced pressure, the oily residue was dissolved in a mixture of 50 ml of water and 50 ml of diethyl ether. The liquid layers were separated. The water layer was extracted twice with 25 ml of diethyl ether. After drying with the aid of Na ₂ SO ₄ , the solvent was removed from the combined ether extracts under reduced pressure. The residue was taken up a few times in chloroform, which was then removed again by evaporation. The solid substance obtained (4.6 g) was dissolved in 25 ml of absolute ethanol, after which 8.7 ml of 2.3 normal alcoholic HCl was added. After adding 75 ml of dry diethyl ether, a substance began to crystallize, which was ^{filtered off after 1} hour and dried in the air. This resulted in 4.2 g of the amine salt mentioned. M.p. = 153 to 154 ° C (decomposition).

Example 6

1-Amino-4- (2-methylphenyl) -3-buten-2-ol-oxalic acid

14 g of o-methylcinnamaldehyde were shaken with a solution of 20 g of Na ₂ SgO ₆ in 40 ml of water. A precipitate was formed which, after suctioning off, was washed with water and ether. _{A solution of 3.4 g of Na 2} S ₂ O ₅ in 50 ml of water and 150 ml of ether was added to an amount of 23.6 g (0.09 mol) of this disulfite adduct. The mixture was cooled in ice. An ice-cold solution of 11.9 g (0.24 mol) of NiaCN in 30 ml of water was quickly added to the mixture with vigorous stirring. After stirring for half an hour, a further 1.5 g of Na ₂ S ₂ O _{5 were} added, after which the mixture was stirred for another half hours while cooling with ice. The layers were separated, the water layer was shaken out twice with 40 ml of ether, and the collected ether layers were washed twice with 40 ml of 20% Na _{2 SO 5} solution and twice with 40 ml of water. The solution was dried _{over MgSO 4.} After filtration, a mixture of 20 ml of pyridine and 50 ml of acetic anhydride was added to the ethereal solution while cooling with ice. After 2 hours the temperature was allowed to rise to room temperature. After standing at room temperature overnight, the solvent was evaporated. The residue was taken up in 100 ml of dry ether.

_{The solution obtained was added dropwise to a solution of 15 g (0.4 mol) of LiAlH 4} in 650 ml of dry ether at -10 ° C. over a period of 2 hours, while stirring. The mixture was then stirred at -10 ° C. for a further 1 hour. Then 80 ml of ethyl acetate and then 80 ml of water were added while cooling with ice. The ether was poured off; the residue was extracted four times with warm chloroform and removed

S sucked. The chloroform and ether solutions were washed with water and saturated sodium chloride solution and dried _{with MgSO 4.} After filtering, the solvents were removed. The residue was taken up in ether, and this solution

ίο was extracted with 2N HCl. The HCl solution was made alkaline and extracted with ether. The ether solution was dried _{with MgSO 4.} After filtering, a solution of 4 g of oxalic acid in 18 ml of ethanol was added to the concentrated solution. A precipitate resulted which was washed with ether. M.p. = 160 ° C with decomposition.

Example 7

ao 4- (4-chlorophenyl) -1-isopropylamino-3-buten-2-ol hydrochloride

a) 4- (4-chlorophenyl) -2-hydroxy-3-butenenitrile

_{A solution of 7.70 g (0.041 mol) of Na 2} S ₂ O ₆ in 30 ml of water was added to a solution of 9.84 g (0.059 mol) of p-chlorocinnamaldehyde in 100 ml of ether. After this mixture had been stirred for 1 hour, it was cooled to 5 "C. in an ice bath, after which a solution of 7.3 g (0.15 mol) of sodium cyanide in 20 ml of water was added all at once with stirring stirred for an hour at 0 to 5 ⁰ C, then 1.0 g of Na ₂ S ₂ O ₅ were added and finally stirred for I ¹ Za hours at 0 to 5 ° C. the layers were separated and the water layer was extracted twice with 25 ml of benzene The collected organic liquid was washed twice with 25 ml of a 20 ° Zoi.gen Na ₂ S., O _s solution and twice with 25 ml of water and finally dried with sodium sulfate.After filtration and evaporation of the solvents in vacuo, the residue became evaporated dry with 200 ml of benzene in vacuo and finally dissolved in 25 ml of benzene. After dilution with 25 ml of petroleum ether 40:60, 10.1 g (88 ⁰ Zo) of a substance crystallized,

F. = 60 to 64 ° C, off.

b) 1-Amino-4- (4-chlorophenyl) -3-butol-2-ol

A solution of 8.16 g (0.042 mol) of the compound obtained according to Example 7, a in 140 ml of dry ether was added dropwise with stirring to a solution of 6 g of lithium aluminum hydride in 200 ml of dry ether. The temperature of the reaction mixture was maintained with the aid of an ice-salt bath to -5 ⁰ C. The mixture was stirred at this temperature for 5 hours, after which the reaction mixture was decomposed with 18 ml of water at such a rate that the temperature did not rise above 10.degree. The mixture was then stirred for 1/2 hour at room temperature, after which the hydroxides formed, on which, as it turned out, almost all of the reaction product had been absorbed, were filtered off with suction. The hydroxides were extracted three times with 200 ml of warm chloroform and the collected filtrates were evaporated dry in vacuo. There were 5.5 g of solid substance. This was dissolved in 55 ml of benzene. After dilution with 28 ml of petroleum ether 40: 60 crystallized 4.37 g (52 ° / o), mp = 115 to 117 ⁰ C, of.

9 10

c) 4- (4-ΟΜοφ ^ ηγ1) -1-ίδορΓθργΐ3ΐηΐηο-3 ^ υΙβη- with stirring and cooling with such a

2-ol hydrochloride rate that the temperature of the reaction

mixture ^{did not exceed 10 0} C, a solution of

A solution of 3.95 g (0.020 mol) of the substance obtained after 33 g of lithium aluminum hydride in 11 dry ether game 7, b in 60 ml of methanol 5 was added dropwise. 0.16 ml of 3.8 normal alcoholic hydrochloric acid were then stirred at 5 ° C. for 3 1/2 hours. The reaction mixture was (g 2 ₇ 37, 0.041 mol) with 100 ml of water and then 3.0 ml of acetone added. added at such a rate. After half an hour, 1.2 g of sodium boron _? that the temperature did not exceed 15 ° C. The hydride was added and the mixture was boiled for 1 hour. The hydroxides formed were filtered off with suction. The filtrate The reaction mixture was then delivered to room temperature, after evaporation of the ether was cooled in vacuo and temperature, after which 4.0 ml (3.16 g, repeated evaporation of dryness in vacuo with 100 ml 0.055 mol) of acetone were added became. After 1 hour of benzene, 22 g of oil obtained from a mixture of 70 ml, 1.6 g of sodium borohydride were added, after which benzene and 130 ml of 40:60 petroleum ether, crystallized, were boiled again for 1 hour. The reaction was, yield 9.15 g, mp = 79 to 83 ° C. The mixture was evaporated dry in vacuo and the sucked hydroxides were extracted three times with 300 ml of residue in a mixture of 50 ml of ether and chloroform. The collected extracts dissolved in 50 ml of water. The layers were separated and evaporated dry in vacuo. This gave the water layer twice with 25 ml of 21.5 g of oil, which was extracted from a mixture of 55 ml of benzene ether. The collected ethereal solution and 100 ml petroleum ether 40:60 was crystallized, after drying over sodium sulfate ao yield 12.56 g, mp = 78 to 84 ° C. evaporated together with in a vacuum. After 100 ml of benzene had been added to the already obtained amount of 9.15 g, the residue was again substance by dissolving in 57 ml of benzene and evaporated dry in vacuo. The resulting re-dilution with 60 ml of petroleum ether 40:60 recrystallized (4.64 g). It was ablated in 15 ml. After washing with a mixture of 20 ml of solute alcohol, 8 ml of normal aiko-25 benzene and 30 ml of petroleum ether 40:60 and 50 ml of holic hydrochloric acid were added. The hydro-petroleum ether 40:60 became the product obtained on chloride began to crystallize immediately. After air drying, yield 20.5 g (35% in total 150 ml of dry ether had been diluted, became all), m.p. = 79 to 83 ° C.
the white substance sucked off and exposed to air.

dries, yield 4.87 g (88%), ^{m.p. = 198 to 30 b} ) l-isopropylamino ^ -p-tolyl-S-butene

205 ° C (decomposition). The substance eventually became 2-ol hydrochloride

recrystallized from 250 ml of isopropyl alcohol, from a solution of 5.31 g (0.030 mol) of the after

booty 4.34 g, m.p. 205 to 206 ° C (decomposition). Example 8, a substance prepared in 90 ml of metha

nol were 4.5 ml (3.56 g, 0.062 mol) of acetone and

Example 8 35 0.25 ml of 3.8 normal alcoholic hydrochloric acid were added.

After the solution obtained has been in the room for two and a half hours

l-Isopropylamino ^ -p-tolyl-S-butene temperature, 1.8 g of sodium

2-ol hydrochloride added borohydride and the mixture for 1 hour

\ ιλ ™ · _λ / ι * ι ι iu * ι ι is boiling. Then 6.0 ml (4.74 g, 0.082 mol)

a) l-Ammo-4-p-tolyl-3-buten-2-ol _{to 40 AfMoa? replaces them Nac? 1 emer semi} ^v _{s Stu} ^B _{was ligands} ^

A solution of 49 g (0.34 mol) of p-methylcinnamic 2.4 g of sodium borohydride was added, after which dehydration in 50 ml of ether was boiled for 2 hours. The reaction mixture was evaporated dry in a solution of 44 g (0.23 mol) Na ₂ S ₂ O ₅ in 250 ml vacuum, and the residue was stirred with water. 450 ml of ether were added in a mixture of 75 ml of water and 75 ml and the resulting reaction mixture was dissolved in 45 ether with stirring. The layers were separated and the ice bath cooled. When the temperature of the 5 ° C water layer was twice extra with 30 ml of ether, an ice cold one was here in one go. After dissolving 41 g (0.84 mol) of sodium cyanide in 100 ml, the collected ether layers were added to dryness over sodium sulfate in vacuo and water; in the process, the temperature rose to evaporated, and the residue obtained rose to 15 ° C, but then quickly fell again to 5 ° C. _{50 250 ml of benzene evaporated dry in vacuo, off-After stirring for 2} hours, 5 g of 6.38 g were obtained, these were added in 20 ml of absolute Na 2 S ₂ O ₅ , after which alcohol was still dissolved in an ice bath and the solution 15 ml of 3normal alcohol IV was stirred for 2 hours. Then the holic hydrochloric acid and then 250 ml of ether were added. Layers separated, after which the water layer was still The resulting crystalline substance was suctioned off and extracted twice with 100 ml of ether. The ether layers collected and dried in the air, yield 6.36 g (86%) were washed twice with 100 ml of F. = 158 to 162 ° C., after recrystallization from 20% Na ₂ S ₂ O ₅ -LoSUOg and then washed twice with 100 ml 40 ml isopropyl alcohol 5.92 g, F. = 158 to 162 ° C. water. After drying over sodium sulfate and after evaporation of the ether in Example 9
Vacuum resulted in an oil that with 100 ml of benzene 60

and twice 100 ml of methylene chloride very carefully 4- (2-butoxyphenyl) -l-isopropylamino-3-butene

kn vacuum was evaporated dry to still pre-2-ol hydrochloride

to remove existing water. The oil obtained. _n "^,,. . ., ...,,

(49 g) was dissolved in 250 ml of acetic anhydride. ^a ) 2-butoxybenzaldehyde diethyl acetate

After 20 hours, the reaction ^{mixture was heated on the steam bath for 1} 1/2 hours and then evaporated dry in benzaldehyde in a mixture of 30.4 ml of ortho-vacuum. The oily residue of ethyl formate and 18.2 ml of absolute Atha was dissolved in 250 ml of dry ether and then nol, to which 60 mg of p-toluenesulfonic acid was added,

was kept overnight at room temperature. Then 1.5 ml of 0.5 normal alcoholic potassium hydroxide solution were added, after which the reaction mixture was evaporated dry in vacuo. Finally, the residue obtained was distilled in vacuo, bp. _O09 80 to 82 ⁰ C, yield 38.33 g (= 100 "/").

b) 3- (2-butoxyphenyl) -3-ethoxypropionaldehyde diethyl acetate

An amount of 1.5 ml of a lOVoijgen solution of anhydrous zinc chloride in glacial acetic acid and 38.2 g (0.151 mol) according to Example 9, a produced substance was added with stirring and at such a rate that the temperature of the reaction mixture 5O ⁰ C not exceeded, 15.4 ml (11.6 g, 0.161 mol) of ethyl vinyl ether was added dropwise. The mixture was stirred at 50 ° C. for 1 hour. Then 30 ml of ether and 30 ml of 2η sodium hydroxide solution were added, the layers were separated and the water layer was extracted again with 15 ml of ether. The collected ether layers were dried over anhydrous potassium carbonate. After filtering and evaporation of the ether in vacuo, a residue which was distilled in vacuo 45.3 g (= 98%), bp. _{O 0, 5125-127} ° C, yield.

c) 2-butoxycinnamaldehyde

A solution of 45.3 g (0.147 mol) of the substance prepared according to Example 9, b, 2.5 ml of water and 3.76 g of anhydrous sodium acetate in 62 ml of glacial acetic acid was boiled under nitrogen for 3 hours. After cooling down a solution of 70 g of anhydrous sodium carbonate in 250 ml of water was added. That the resulting oil crystallized almost immediately. After suctioning off, washing six times with 50 ml of water and Drying in air gave 26.74 g of light yellow substance. This was recrystallized from 150 ml of ligroin, Yield 22.7 g (= 76 Vo), m.p. = 53.5 to 55 ° C.

d) 4-2- (Butoxyphenyl) -24iydroxy-3-butennirilacetaite

A mixture of 20.4 g (0.100 mol) of the substance prepared according to Example 9, c in 50 ml of ether and 26.6 g (0.140 mol) of Na ₂ S ₂ O ₅ in 100 ml of water was shaken vigorously at room temperature in a vacuum evaporated until the greater part of the ether was removed. A clear solution resulted from which the disulfite adduct began to crystallize after a few moments. 200 ml of ether were added, after which the reaction mixture was cooled to 0 ° C. with stirring. A solution of 26.3 g of sodium cyanide in 50 ml of water was then gradually added with stirring, at such a rate that the temperature of the reaction mixture did not exceed 10.degree. The mixture was stirred at 0 to 5 ° C. for 2 hours, after which the layers were separated. The water layer was extracted twice with 50 ml of ether. The collected ethereal solutions were washed twice with 50 ml of water each time and then dried at 0 ° C. over sodium sulfate. After filtering, a solution of 10 ml of dry pyridine in 25 ml of acetic anhydride was added all at once to the still cold solution. The reaction mixture was stored at 0 ° C. for 20 hours and then at room temperature for a weekend. It was then evaporated dry in vacuo, giving 21.8 g (80%) of a light brown clear oil which was used for the following reaction without further purification.

e) l-amino-4- (2-butoxyphenyl) -3-buten-

2-ol hydrochloride

A solution of 12 g of lithium aluminum hydride in 500 ml of absolute ether became a solution of 21.8 g of the substance prepared according to Example 9, d

ίο in 100 ml of absolute ether while stirring and cooling is added dropwise at such a rate that the temperature of the reaction mixture is not -5 ° C exceeded. The mixture was then stirred at -5 to -10 ° C for 5 hours. The reaction mixture was 66 ml Water decomposes taking care that the temperature does not exceed 0 ° C. After suction and washing twice with 50 ml of ether, the filtrate was evaporated dry in vacuo. The residue (13.5 g of yellow oil) was dissolved in 80 ml of benzene and the solution was diluted with 200 ml of petroleum ether 40:60 was extracted with 30 ml of 2N hydrochloric acid. This extract was washed with 20 ml of ether, then made alkaline with 20 ml of 50% potassium hydroxide solution and finally extracted three times with 20 ml of ether.

After drying over sodium sulfate and evaporation of the ether in vacuo, the residue obtained was evaporated dry a few times with benzene in vacuo until all the water had been removed. This gave 8.93 g of oil. This oil was dissolved in 25 ml of absolute ethanol, after which 3 normal alcoholic hydrochloric acid was added until the solution was just acidic. After dilution with 400 ml of absolute ether, 6.55 g of hydrochloride with a melting point of 137 to 138 ° C crystallized out; l _max - 253 ηιμ, t _max = 14000.

f) 4- (2-Butoxyphenyl) -1 -isopropylamino-3-buten-2-ol hydrochloride

A solution of 0.475 g (20.6 m. At.) Sodium

+0 in 60 ml of methanol were 5.94 g (21.8 mol) of the after Example 9, e prepared substance and then added 3.0 ml of acetone. After half an hour were 1.2 g of sodium borohydride were added and the reaction mixture was boiled for 1 hour. After cooling down 4.0 ml of acetone was added. After half an hour, 1.6 g of sodium borohydride was added, followed by the reaction mixture was boiled for 1 hour. Then it was evaporated dry in vacuo, and the residue was dissolved in 50 ml of water and 25 ml of ether. The layers were separated and the Water layer extracted with 30 and 15 ml of ether. The collected essential solutions were over Sodium sulfate dried and then evaporated dry in vacuo. The residue was in vacuo evaporated dry with benzene until all water was removed and then in 10 ml absolute Dissolved ethanol. 3Normal alcoholic hydrochloric acid was added to this solution until the reaction just occurred was acidic, after which it was diluted with 220 ml of absolute ether, yield 5.0 g, m.p. = 129 to 131 ° C.

Example 10

4- (2,6-Dimethoxyphenyl) -1-isopropylamino-3-buten-2-ol hydrochloride

a) 2,6-dimethoxybenzaldehyde diethyl acetate

This substance was prepared by the same method as described in Example 9, a

13 14

has been. Yield 92%, bp. _Os 103 to 104 ⁰ C, Example 11

F. = 42 to 44 ° C.

. ,,.,. "J. , λ "... j. . 4- (2,5-dimethoxyphenyl) -l-isopropylamino-

b) 3- (2,6-Dimethoxypheny) -3-athoxypropion-3-buten-2-ol hydrochloride

aldehyde diethyl acetate -

^. "..". τ,. ·, _Λ , 2,5-dimethoxybenzaldehyde diethyl acetate

This substance was according to the method in Example 9, b jj

described method produced. Yield 85%, a solution of 20 g (0.12 mol) 2., 5-dimethoxy-

Bp. _{0> 5} 134 to 136 ° C. Benzaldehyde in 125 ml of absolute ethanol were

25 ml of ethyl orthoformate and 50 mg

c) 2,6-dimethoxycinnamaldehyde ¹⁰ p-toluenesulfonic acid was added. After the Reak

had stood for one night, it became

This substance was cooked for the hour in Example 9. After cooling, 1 ml of the procedure described was prepared. It was made up of 0,5normale alcoholic potassium hydroxide zuBenzol-petroleum ether 40 to 6O ⁰ C and tetrachloride. The reaction mixture was then in Vakohlenstoff-petroleum ether 40 to 6O ⁰ C umkristalli- trockengedampft 15 uum and the residue in Siert. Yield 83 »/ o, m.p. = 77 to 80 ° C. Vacuum distilled.

Fraction: 98 to 100 ° C / 0.25 mm. Yield 23.4 g of d) 4- (2,6-dimethoxyphenyl) -2-hydroxy- (81%).

3-butenenitrile acetate

A mixture of 12.73 g (0.0070 mol) of the substance prepared according to 20 ^b ) 3- (2,5-dimethoxyphenyl) -3-ethoxypropion-Example 10, c in 120 ml of ether aldehyde diethyl acetate

and 18.2 g (0.096 mol) Na ₂ S ₂ O ₅ in 40 ml of water This substance was according to the method in Example 9, b

was stirred vigorously until the disulfite adduct prepared according to the procedure described, yield 80%, began to crystallize. The reaction mixture had _{a boiling point of} 122 to 123 ° C.
cooled to D ⁰ C with stirring, after which in a 25

Draw a solution of 17.4 g of sodium cyanide in 50 ml of ^c ) 2,5-dimethoxycinnamaldehyde

Water and then 50 ml of chloroform was added. This substance was according to the method in Example 9, c

the. The process described was then stirred at 0 to 5 ° C. for 2 hours. It was made from whereupon the layers were separated. After the ligroin recrystallized. Yield 92%, m.p. 84.5 water layer diluted with 50 ml water 30 to 86.5 ° C.
it was extracted twice with 50 ml of benzene each time. The collected organic solutions wur- ^d) 4- (2,5-dimethoxyphenyl) -2-hydroxides at 0 ⁰ C over sodium sulfate. After 3 ^ butenmyl acetate
Filtration and evaporation of the solvent at 13.96 g (72.6 mmol) of the substance prepared according to Example 11, c room temperature in vacuo resulted in a red 35 substance was 9 hours with an oil, which was immediately dissolved in 100 ml of acetic anhydride solution of 19, 3 g (102 mmol) Na ₂ S ₂ O ₅ in 60 ml was. This solution was shaken with room water and 35 ml of alcohol for 20 hours. The Reaktemperatur allowed to stand and then for 1 hour at tion mixture was heated overnight at 0 ⁰ C stehengedem steam bath. After evaporation to dryness, after which the greater part of the alcohol in vacuo gave 13.5 g of oil, which was evaporated off at room temperature without a further 40 vacuum. Purification used for the subsequent reaction. Then 70 ml of ether and 70 ml of benzene were added. sets, after which the reaction mixture is stirred

tiyarocruorm _{45, the temperature of the} reaction mixture 10 ⁰ C is not a solution of 13.5 g of according to Example 10, d exceeded, a solution of 19 g of sodium cyanide in substance prepared in 100 ml of absolute ether, 35 ml of water. The mixture was then stirred for 4 hours at 0 to 5 ° C. to 5.0 g of lithium aluminum hydride in 200 ml. The layers were dripped into absolute ether. The reaction mixture separates, and the water layer, after being boiled for IV2 hours and then diluted with 15 ml of water with 100 ml of water, was decomposed three times. After suctioning off, the filtrate was evaporated dry with a mixture of 20 ml of benzene and 20 ml of vacuum. The residue obtained was extracted from petroleum ether 40:60. The collected organs were evaporated dry with benzene in vacuo until niche fluids were removed four times with 50 ml of any water. This gave water and washed ^{7.8 g of oil at 0} ° C. over sodium sulfate. The oil was dried in 10 ml of absolute alcohol. After filtration, the still cold solution was dissolved, after which 6.5 ml of 2.2 normal solution were added all at once to a solution of 10 ml of dry alcoholic hydrochloric acid and 55 ml of absolute ether to pyridine in 25 ml of acetic anhydride. The white substance, which was crystallized for a few hours at 0 ° C., was filtered off with suction, washed three times with 25 ml of ether then left to stand one night at room temperature and dried in the air. Finally it was dried in vacuo. Yield 2.75 g, F. = 153 to 155 ^° C. (decomposition). steams. The remaining oil (15.0 g, 79%)

was used without further purification at the following

f) 4- (2,6-Dimethoxyphenyl) -l-isopropylamino reaction used.

3-buten-2-ol hydrochloride _e) L

This substance was according to the method in Example 9, f
described method produced. Yield 85%, 15.0 g (57.5 mmol) of the according to Example 11, d

M.p. = 149 to 155 ° C (decomposition). put substance in 100 ml of absolute ether was

the stirring and cooling at such a rate that the temperature of the reaction mixture - added dropwise did not exceed 5 ⁰ C, a solution of 8.6 g of lithium aluminum hydride in 360 ml absolute ether. The mixture was stirred for 4 hours at a temperature between -5 and -1O ⁰ C. The reaction mixture was decomposed with 26 ml, the temperature being kept below 10 ^° C. The hydroxides formed were filtered off with suction and extracted three times with 150 ml of warm chloroform each time. The combined filtrates were washed with petroleum ether 40: 60 diluted until they were just turbid and then allowed to stand overnight at O ⁰ C, yield 7.27 g (57%), white crystals, mp = 109 to 111 ^C C.

f) 4- (2,5-Dimethoxyphenyl) -1 -isopropylamino-3-buten-2-ol hydrochloride

This substance was prepared according to the method described in Example 8, b.

Example 12

4- (2-methoxyphenyl) -1-isopropylamino-3-buten-2-ol hydrochloride

a) 4- (2-methoxyphenyl) -2-hydroxy-3-butenenitrile

_{A solution of 32.3 g (0.17 mol) of Na 2} S ₈ O ₆ in 130 ml of water was added to a solution of 41.34 g (0.25 mol) of o-methoxy cinnamaldehyde in 400 ml of ether. This mixture was stirred until the disulfite compound formed, which took place after about 10 minutes, after which the mixture was stirred for 1 hour. The mixture was then ^{cooled to 5 °} C. in an ice bath, after which a solution, cooled in ice, of 31 g of sodium cyanide in 75 ml of water was added all at once with stirring. Stirring was continued for 1 hour at 0 "to 5 ° C., after which 3.6 g of Na ₈ S ₂ O _{5 were} added and finally stirring was continued for another 2 hours at 0 to 5 ° C. The layers were then separated, after which the water layer was added twice was extracted with 100 ml. The collected ether extracts were washed twice with 100 ml of a 20 "/ own Na ₂ S ₂ O ₅ solution and twice with 100 ml of water each time and then dried with sodium sulfate. After filtering and evaporation of the solvents in vacuo, the residue was evaporated dry with 200 ml of benzene in vacuo. The residue, an orange-yellow oil, weight 41 g, was used in the subsequent reaction without further purification.

b) 1-amino-4- (2-methoxyphenyl) -3-buten-2-ol-

Hydrochloride

A solution of 27.1 g (0.196 mol) of the substance prepared according to Example 12, a in 140 ml of dry ether was added dropwise with stirring to a solution of 23 g of lithium aluminum hydride in 700 ml of dry ether. The temperature of the reaction mixture was kept between 0 and -5 ° C. by means of an ice-salt bath. It was stirred for 4 hours, during which the temperature rose slowly to room temperature, after which it was decomposed with cooling with 70 ml of water at such a rate that the temperature did not exceed ^{15 ° C.} The mixture was then stirred for 1/2 hour at room temperature, after which the hydroxides formed were filtered off with suction. The hydroxides were extracted three times with 500 ml of hot chloroform each time. The collected filtrates were evaporated dry in vacuo. A light yellow oil resulted. The calculated amount of alcoholic hydrochloric acid and then ether were added to this until the whole thing just began to become cloudy. The hydrochloric acid salt then crystallized out relatively quickly, yield 14.7 g, mp = 130.5 to 133 ° C (decomposition), after recrystallization from a mixture of absolute alcohol and absolute ether, yield 11.6 g, mp = 134.5 to 135.5 ⁰ C.

c) 4- (2-methoxyphenyl) -1-isopropylamino-3-buten-2-ol hydrochloride

»5 4.5 g of the substance prepared according to Example 12, b were dissolved in 50 ml of water, 40 ml of 2N sodium hydroxide solution were added to the solution, and then three times was extracted with 100 ml of ether. The ether extracts were dried with sodium sulfate. To Filtering off and evaporating dry in vacuo gave a white substance which was dissolved in 60 ml of methanol after which 0.25 ml of 2.22 normal alcoholic acid and 3 ml of acetone (2.37 g; 41 mmol) were added. After half an hour, 1.2 g of sodium borohydride were added and the mixture was boiled for 1 hour. The reaction mixture was then cooled to room temperature whereupon 4.0 ml (3.16 g; 55 mmol) of acetone were added. After half an hour, 1.6 g of sodium borohydride were added

sets and cooked 1 hour. The reaction mixture was evaporated dry in vacuo and the residue was dissolved in a mixture of 50 ml of water and 50 ml of ether. After the layers separated the water layer was extracted twice with 25 ml of ether each time. The collected Ether extracts were dried with sodium sulfate and evaporated dry in vacuo. The residue was again evaporated dry in vacuo after 100 ml of chloroform had been added.

The residue obtained (4.7 g) crystallized. The crystals were dissolved in 25 ml of absolute alcohol, after which 9 ml of 2.22 normal alcoholic hydrochloric acid and then 75 ml of absolute ether were added. The hydrochloride began to crystallize almost immediately, yield 4.05 g (74.6%), mp = 167.5 to 168.5 ⁰ C (decomposition). After recrystallization from Isopronal yield 3.21 g, mp = 169-170 ⁰ C.

Example 13

In-octylamino-4-phenyl-3-buten-2-ol-oxalic acid

A solution of 1.0 g (6.1 mmol) of 1-amino-4-phenyl-3-buten-2-ol in 40 ml of ethanol was successively added 1.8 g (14 mmol) of n-octanal, a crystal of p- Toluenesulfonic acid and 25 ml of benzene were added. The solvents were distilled off as completely as possible, finally in vacuo.
The residue was taken up in 25 ml of methanol, and 1.8 g (47 mmol) of NaBH ₄ were added in small amounts while cooling with ice. The mixture was boiled for 1 hour. The methanol was evaporated off in vacuo and the residue was shaken with 30 ml of water and 60 ml of ether. The layers were separated and the water layer extracted twice with 30 ml of ether.

The collected ether extracts were washed with 25 ml of water and dried _{over MgSO 4.}

17 18

After filtering, the concentrated (0.026MoI) NaBH _{4 was} added. The mixture was boiled solution of a solution of 0.6 g of oxalic acid in 8 ml for ¹ hour, after which 3.5 ml (2.8 g = 0.048 mol) of ethanol was added. A precipitate resulted and acetone was added. . The mixture was filtered off with suction and washed with ether. After two and a half hours, 1.4 g of recrystallization from ethanol, yield 1.4 g (62%), 5 (0.037 mol) of NaBH _{4 were} carefully added and then ge-F. - 170 to 172 ° C. were cooked. The reaction mixture was in Va

evaporated dry, and the residue were

Example 14 50 ml of water and 50 ml of ether added. After this

all solid matter was dissolved, 1-phenoxyisopropylamino-4-phenyl-3-buten-2-ol _{10 the} layers were separated, followed by the water layer

A solution of 1.5 g (0.009 mol) of 1-amino was washed twice with 25 ml of ether each time. The 4-phenyl-3-buten-2-ol in 60 ml of ethanol were ether extracts were _{dried over Na 2} SO ₄ , and successively 3.2 g (0.02 mol) of phenoxyacetone, one of the ethers was distilled off in vacuo. It gave crystals of p-toluenesulphonic acid and 40 ml of benzene in addition to a residue of 3.89 g, which was dissolved in 10 ml. The solvents were dissolved as completely as possible, after which 7 ml of absolute were distilled off, finally in vacuo. alcoholic hydrochloric acid was added. According to V.

The residue was diluted in 40 ml of methanol, 3.74 g of crystallized ether was taken with 100 ml of ether, after which 2.5 g (0.06 mol) (0.0138 mol), m.p. = 124.5 to 126, were taken while cooling with ice. 5 ⁰ C, off.
NaBH. were added in small amounts. The Ge, _{s Λ} . . . , " ,.,,,. ", _X

The mixture was then boiled for 1 hour. The methanol ao ^b ) l-Ammo-4- (3-methoxyphenyl) -3-butene was evaporated in vacuo and the residue ^ -oi-hydrocmond

shaken with 40 ml of water and 55 ml of ether. A solution of 5.5 g (0.144 mol) LiAlH ₄ in

Layers were separated and the water layer 150 ml of absolute ether was shaken a solution of twice with 20 ml of ether each time. The total of 9.17 g (0.49 mol) of crude 2-hydroxy-4- (3-methoxymelt ether extracts were washed with 25 ml of water, phenyl) -3-butenenitrile in 50 ml of absolute ether and washed with MgSO ₄ dried. After the fiI- The temperature of the reaction mixture was tration, dry HCl was passed into the ether. was kept at about -10 ° C. It was 5 stun There was a precipitate in water up to the -1O ⁰ C stirred at -15. The mixture was taken. The water layer was then decomposed with 16.5 ml of water, the NaOH being made 2N alkaline and extracted three times at 30 temperature by cooling with an ice-salt ether (80 ml). The ether extract was kept below 10 ° C with mixing. The hydroxides 20 ml of water and saturated NaCl solution were filtered off with suction and washed with a little ether, washed and dried _{with MgSO 4.} After filtration, the ethereal solutions were removed in vacuo and the ether removed in vacuo. The evaporated back, with 4.09 g of residue from a mixture of 20 ml of benzene 35 equivalent weight of 224 remained. The hydro- and 20 ml petroleum ether 40:60 crystallized, yield xide were boiled four times with 50 ml chloroform each 169 g (59%), m.p. = 77 to 78.5 ° C. The chloroform was evaporated, whereby

3.58 g of residue with an equivalent weight of

Example 15 148 remained. The residue of 4.09 g was in

" _T,. . , "^,,,, \", 40 dissolved 50 ml of absolute ethanol and 7 ml

l-isopropylamino - ^^ _{S-methylphenyO-buten-2,} 2normaler acidified alcoholic hydrochloric acid.

Z-ol-Hydrocnlond ^ after the _{addition of} J _{30 M absolute ether} k _r i _st alli-

From 2.5 g (9.3 mmol) of 1-amino-4- (2-methylated 2.76 g with a melting range from 133 to phenyl) -3-buten-2-ol-oxalic acid was isopropyl-162 ⁰ C. The residue, weighing 3.58 g, was compound prepared according to a procedure which is converted into the hydrochloride in the same manner analogous to the synthesis of 1-isopropylamino-. It crystallized from 1.86 g with a melting-4- (2,6-dimethoxyphenyl) -3-buten-2-ol hydrochloride range of 138 to 16O ⁰ C.
was, F. = 175 to 177 ° C (after recrystallization. _{Λ TT} , _. "

from isopropanol). ^c ) 2-Hydroxy-4- (3-methoxyphenyl) -3-butenmtnl

50 A solution of 8.21 g (0.051 mol) of m-methoxy-

Example 16 cinnamaldehyde in 80 ml of ether was a solution of

a) l-Isopropylamino-4- (3-methoxyphenyl) - ⁶ >? f (0.035 mol) Na ₂ SO ₅ in 25 ml of water

3-buien-2-ol hydrochloride i ^e . ^tzt · DasGeimsch was stirred for ₂ hours and m

^J ice chilled, after which a cold solution of 6.3 g

A solution of 4.25 g (0.0186 mol) of 1-amino-55 NaCN in 15 ml of water was added. The Rea-

4- (3-methoxyphenyl) -3-buten-2-ol hydrochloride was mixed with ice for 2 hours while cooling with ice.

15 ml of water were added 10 ml of 2N NaOH. stirred, after half an hour 0.75 g of NaS ₂ O ₅

The mixture was extracted by shaking with chloroform, added. The layers were separated that

once with 50 ml and once with 20 ml. After the water layer is washed twice with 15 ml of ether each time

Chloroform extracts washed with water and washed over 60 and the collected ether layers twice with

Na ₂ SO ₄ had been dried, the 15 ml of 20% Na, S ₂ O ₆ solution and twice with each

The solvent was distilled off in vacuo, and 15 ml of water remained washed. The essential solution

3.33 g (0.0173 moles = 93%) of the amine. It was _{dried with Na 2} SO ₄ and a vacuum

The residue was dissolved in 55 ml of methanol and then evaporated. The residue was dried by

2.6 ml (2.0 g = 0.36 mol) of acetone and 0.25 ml of 65 that the remaining water with benzene im

2.2 normal alcoholic hydrochloric acid was added. Vacuum was azeotropically distilled off. It resulted

After the mixture has been kept for one hour at room temperature, a residue of 9.17 g, which does not crystallize

rature, 1.0 g was cautiously wanted and further processed raw.

J9 20

B e s ρ i e 117 mixture was stirred for 2 hours with ice cooling,

ν. , "._ ,,, ui \ ι · ι · with 0.5 g of Na ₂ S ₂ O ₁₁ added after half an hour

a) 4- (2-Chlorophenyl) -l- _1S opropylammo- _{sets threw} _ _{The layers} ^ _{Γαεη a} bgltrWnt, the

S-buten ^ -ol-Hydrochlond water layer twice with 10 ml of ether each and the

3.66 g (0.0156 mol) of 1-amino-4- (2-chlorophenyl) -5 collected ether layers twice with 10 ml of 3-butene-2-hydrochloride were added to a solution of 20% Na ₂ S ₂ O ₅ Solution and washed twice with 10 ml each of 0.35 g (0.015 mol) of sodium in 50 ml of methanol to water. The ethereal solution was added, after which 2.35 ml (1.85 g = 0.032 mol) of Ace-Na ₂ SO _{4 were} dried and evaporated in vacuo. The clay were added. The mixture was <fr hour residue was dried by the left to stand still at room temperature, after which forward "· water present with benzene in vacuo azeotrosichtig 0.94 g (0.025 mol) of NaBH were added. ₄ pisch was distilled off. After 1 hour on the steam bath, a residue of 7.39 g remained, which was further processed raw.
The reflux condenser had been boiled, were 3.0 ml

(2.4 g = 0.041 mol) acetone added. The mixture example 18

was again Vs hour at room temperature 15. , _T ·, <»/ * t 1.«

left to stand, after which 1.26 g (0.033MoI) NaBH ₄ ^a ) l-Isopropylamino-4- (2-propylo _X yphenyl) -

were added. The solution again became 3-buten-2-ol hydrochloride for 1 hour

cooked and then evaporated dry in vacuo. The 4.00 g (0.0181 mol) of l-amino-4- (2-propyloxyphe-

The residue was dissolved in 45 ml of water and 45 ml of ether (nyl) -3-buten-2-ol was dissolved in 60 ml of methanol, the layers were separated and the water was then 2.7 ml (2.14 g = 0.037 Mol) acetone and serschicht washed three times with 25 ml of ether. The 0.25 ml of about 2 normal alcoholic hydrochloric acid collected in the ether extracts were added with Na ₂ SO ₄ . The reaction mixture was dried for half an hour and the ether was evaporated in vacuo. The left to stand at room temperature, after which pre-residue was dissolved in 10 ml of absolute ethanol, 1.1 g (0.029MoI) of NaBH _{4 was} added, and with 7.8 ml of about 2 normal alcoholic salt after 1 hour on the steam bath in an acid acidified. After the hydrochloride had been boiled, 3.7 ml of acetone, yield 3.59 g (0.013 mol = 83%), m.p. 185.5 ° C. UV spectrum: E _max = 7180 later, at room temperature, 1.5 g λ = 249 πΐμ. (0.039 mol) NaBH ₄ added. The solution was

30 boiled again for 1 hour and then dried in a vacuum

b) l-Amino ^ - ^ - chlorphenyO-S-buten ^ -ol- vaporized. The residue was dissolved in 50 ml of water

Hydrochloride ^and 50 ml of ether dissolved, the layers were removed

separates, and the water layer was twice with each

Washed to a solution of 5.0 g (0.13 mol) of LiAlH ₄ in 25 ml of ether. The collected ether-150 ml of absolute ether became a solution of 35 extracts were _{dried with Na 2} SO ₄ and the 7.39 g (0.036 mol) of crude 4- (2-chlorophenyl) -2-hy ether was evaporated in vacuo. The residue hydroxy-3-butenenitrile in 100 ml of absolute ether was dissolved in 20 ml of absolute ethanol and added dropwise. The temperature of the reaction mixture about 2ncrmaler alcoholic hydrochloric acid was kept under careful -5 ⁰ C. It was acidified for 5 hours. After diluting the alcoholic Löbei stirred -5 ⁰ C. The mixture was then dissolved with 75 ml of ether, the hydrochloride was decomposed with 15 ml of water, the temperature increasing, yield 4.46 g (0.015 mol = 82%), m.p. = 170 by cooling with an ice-salt mixture below 5 ° C to 172 ° C. UV spectrum E _roM = 15,800 was maintained. 500 ml of ether were added,; = 253 πΐμ.

after which the reaction mixture overnight at Zim-. .

mertemperature was left to stand. The hydroxides 45 ^b ) l-Ammo-4- (2-propyloxyphenyl) -

were sucked off and washed with a little ether. 3-buten-2-ol

The ethereal solution was dried in vacuo to a solution of 15.0 g (0.39 mol) LiAlH ₄ in

evaporated to leave a residue of 5.3 g. 500 ml of absolute ether became a solution of The hydroxides were boiled three times with 150 ml of chloro- 16.0 g (0.060 mol) of crude 2-acetoxy-4- (2-propyl form. The chloroform was evaporated, 50 oxyphenyl) -3-butenenitrile added dropwise to 200 ml of ether, which resulted in a residue of 1.5 g. The 5.3 g The temperature of the reaction mixture was predominant residue was dissolved in 25 ml of absolute Ätha- - 6 ⁰ C. Then, 4 hours at -10 was dissolved to nol and stirred with 10 ml of about -5 ⁰ C 2normaler alcoholic. The mixture was then acidified with high hydrochloric acid. Decomposed after dilution with 45 ml of water, whereby the temperature crystallized from solid ether 3.86 g (0.165 mol 55 cooling with an ice-salt mixture below 10 ⁰ C ge = 46%) melting range from 99 to 196 ⁰ C the end. was holding. After the mixture was recrystallized for one night from alcohol — ether changed and left to stand, the hydroxides were suctioned off. Melting point did not. From the back weighing 1.5 g and washed with a little ether. The ethereal solution was prepared in the same way. 0.51 g of substance solution was evaporated dry in vacuo to obtain. 60 9.3 g of residue with an equivalent weight of

\ λ π / IUi u η - ■> ι, j ^ u ₄ · * · ι 411 remained. The hydroxides were three times

c) 4- (2-chlorophenyl) -2-hydroxy-3-butenn ₁ tnl _{mM with chloroform g 'ekocht. The} chloroform

A solution of 6.06 g (0.036 mol) of o-chlorine was evaporated, with 3.7 g of residue with a cinnamaldehyde in 60 ml of ether becoming a solution of equivalent weight of 412. The 4.7 g (0.25 mol) of Na ₂ S ₂ O ₅ in 20 ml of water were added. 65 residues were processed further together. The mixture was stirred for 1 hour and poured in ice. For this purpose, the oil was cooled in chloroform, after which a cold solution of 4.4 g of NaCN was dissolved in, extracted with 16 ml of 2N HCl and twice 11 ml of water was added. The reaction washed with water. The layers of water were

21 22

washed with ether and washed with 16 ml of 2N NaOH per 15 ml of water. The essential solution

made alkaline. The alkaline water _{layer was dried with Na 2} SO ₄ and the ether was removed.

was shaken out with ether and the ether steamed with it. The residue was distilled, and the

Na ₂ SO ₄ dried. After distilling off the ether fraction with a boiling point 0.35 from 124 to

5.95 g of residue remained in vacuo. He 5 130 ⁰ C was collected. The yield was

was dissolved in 35 ml of benzene and with 20 ml of petroleum - 30.91 g (0.10 mol = 92%).
ether diluted. Crystallized from this solution

4.51g (0.0205 mole = 34%), m.p. 69-71 ° C, f) 2-propyloxybenzaldehyde diethyl acetal

Equivalent weight 222, from. 19.2 g (0.117 mol) of 2-propoxybenzaldehyde were added

_{λ n} . . _{/ n} ι ι i \ ^lo with 23.5 ml (21 g = 0.14 mol) orthoformic acid

c) 2-Acetoxy-4- (2-propylo _X yphenyl) - ethyl ester and 24 ml of absolute ethanol mixed.

3-butemutnl _Eg W _11n Each _n q.05 g of p-toluenesulfonic acid was added, where-

A solution of 14.26 g (0.075 mol) of 2-propyl- after the mixture was left to stand one night,

oxycinnamaldehyde in 20 ml of ether became a solution. The acid was

neutralized by 28.5 g (0.150 mol) of Na ₂ S ₂ O ₅ in 100 ml of water 15 painterly alcoholic lye. The mixture

added. The ether was evaporated in vacuo without heating and the residue

men evaporated. The formed suspension of Al distilled, yield 25.77 g (0.108MoI = 93%),

dehyds reacted quickly to form the disulfite compound. The Kp. _{O 35} 97 to 99 ° C.
Mass was ^{cooled to -10 0} C, after which a

Solution of 19.5 g (D, 26 mol) KCN in 35 ml water 20 Example 9

was added dropwise. The temperature was below. . , ".... .., _x ... ,.

-5 ⁰ C held. After adding 50 ml of ether ^a > 4- (2-AthoxyphenyO-l-isopropylamino-

was stirred for 3 hours with ice cooling until all of the 3-buten-2-ol hydrochloride

had been resolved. The ether and water layers 8.66 g (0.0355 mol) l-amino-4- (2-ethoxyphenyl) -

have now been disconnected. The water layer was 25 3-buten-2-ol hydrochloride were a solution of

three times with 60 ml of ether and the ether layers add 1.12 g (0.0350 mol) of sodium in 120 ml of methanol

washed twice with water. The essential solution, after which 5.5 ml (4.3 g = 0.075 mol) of acetone

The solution was _{dried with Na 2} SO ₄ at 0 ^° C. and added. After half an hour

then filtered, after which a mixture is carefully added to the 2.15 g (0.057 mol) NaBH ₄ while cooling with ice,

from 7.5 ml of pyridine and 18.7 ml of acetic anhydride 30, after which the reaction mixture for 1 hour on the

was added dropwise. After the solution has been boiled over a steam bath on a reflux condenser.

Was left to stand at the weekend, it was placed in the va- There were (5.5 g = 0.095 mol) acetone and, after-

kuum dry-steamed. The result was a residue which the mixture ^{had stood for 1} hour, 3.0 g

of 16.0 g, which was further processed raw. (0.078 mol) NaBH ₄ added. The mixture was

. 35 then again for 1 hour on the steam bath

d) 2-Propyloxyzimtaldehyd _{warms D} j _e solution was then in vacuo single

30.91 g (0.10 mol) of 3 ethoxy-3- (2-propyloxyphe- evaporated, after which the residue was dissolved in 100 ml of water nyl) -propanaldiethyl acetate in 42 ml of acetic acid and 100 ml of ether. The layers were dissolved, after which 2.5 g of anhydrous sodium acetate were separated off and the water layer was applied twice. The mixture was then washed for 3 hours with 40 ml of ether each time. The collected ethers in a heating mantle on a reflux condenser into extracts were evaporated dry in vacuo, boiling under a nitrogen atmosphere. After that there was a residue of 7.4 g. The residue solution was cooled, it was dissolved in 30 ml of absolute ethanol, _{acidified with a 10.6 ml solution of 44 g (anhydrous) Na 2} CO ₃ in 170 ml of 2.8 normal alcoholic hydrochloric acid and water neutralized. The precipitated aldehyde was diluted with 50 ml of ether, yield 8.69 g was taken up in ether and the water layer was shaken out with two (0.030Mol = 85%) hydrochloride, F. = 182 to times with ether. The ether was at 183 ⁰ C.

Na ₂ SO ₄ dried and evaporated in vacuo. There UV spectrum E _mas = 16,000 at λ = 253 πιμ.

a residue of 18.90 g resulted. This return,. ,. . . , ...,,,. . ,

was dissolved in 50 ml of ligroin by heating. 5 ° ^b > l-Ammo-4- (athoxyphenyl) -3-buten-

The solution was cooled in the refrigerator 2-ol-hydrochloride

and, after standing one night, To a solution of 11.0 g (0.29 mol) LiAlH ₄ in

suctioned off, yield 15-41 g (0.081 mol = 81%), 350 ml of absolute ether became a solution of F. = 38 to 40 ° C. 17.0 g (0.07 mol) of crude 2-acetoxy-4- (2-ethoxyphe-

. "..., ...,, w 55 nyl) -3-butenenitrile in 200 ml of absolute ether.

e) 3-Athoxy-3- (2 _: propyloxyphenyl) - _tr ^ _{ft The temperature of the} reaction mixture

propanaldiathylacetal _{wnnle UQter 5} _ o _{c geha} i _{th. Then wuide} 4 hours

An amount of 25.72 g (0.108 mol) of 2-propyloxy- at -10 to -5 ° C was then stirred. The mixture of benzaldehyde diethyl acetal was 1.1 ml of which was then decomposed with 33 ml of water, the 10% strength zinc chloride solution in acetic acid being added 0.120 mol) was mixed held below 10 ^0C. After the vinyl ethyl ether had stood at such a rate for one night, the hyzues were added so that the temperature of the reac- droxide was sucked off and stayed at 50 ° C. five times with 100 ml of chlorotion mixture each time. It was cooked at form for 1 hour. The ether and the Chloroformfraketwa 50 ⁰ C stirred, after which 50 ml of ether and 65 were combined functions and the complementary and 9.5 ml 2-N NaOH was added. After the tel distilled off in vacuo. The result was a return mixture. Had been shaken well, the 14.4 g equivalent weight of layers were separated and the ether layer was separated twice with 301. The residue was dissolved in 50 ml! Normal salt

23 24

Acid and extracted twice with 50 ml of ether each time _{. Aether layer was dried with K 2} COj. Of the

shakes. The ether extracts were with 25 ml of water, ether was distilled off in vacuo, and the back

ser washed. The water layer and wash stand (56.4 g) were distilled in vacuo, with

water were mixed alcoholically with 25 ml of 2N NaOH a main fraction of 47.63 g (0.171 mol = 85%)

and was collected with two portions of 50 ml _{CHCl 0} 5 each, boiling point _O45 118 to 122 ° C.

shaken out. The chloroform extracts were marked with _Λ "., ..., ... ,, - .. _x,,

Washed with water and dried _{over Na 2} SO _4. The ^f ) 2-ethoxybenzaldehyde diethyl acetate

Solvent was then distilled off in vacuo, 116.44 g (0.77 mol) of 2-ethoxybenzaldehyde became

a residue of 10.7 g resulted. After using 154 ml (136 g = 0.91 mol) of orthoformic acid

Acidification of a solution of this residue mixed with 16 ml of io ethyl ester and 160 ml of absolute ethanol.

2.8 normal 6T alcoholic hydrochloric acid, yield 0.30 g of p-toluenesulfonic acid were added, where-

8.66 g (0.035MoI = 50%) hydrochloride, F. = 160 after the mixture has been left to stand one night,

up to 162 ° C. After the solution has been boiled for ¹ 1/2 hour,

. ". ,, ". ,,, X ". ., 6.2 ml of 0.5 normal alcoholic

c) 2-Acetoxy-4- (2-athoxyphenyl) -3-butennitnl ,,. _{Lical lye added} . The mixture was

A solution of 17.60 g (0.100MoI) of 2-ethoxy- kuum evaporated and the residue in vacuo cinnamaldehyde in 25 ml of ether was distilled from a solution of, yield 164.4 g (0.73 mol = 95%), 38, 0g (0,200Mol) Na ₂ S ₂ O ₆ in 130ml water züge- Kp. _oll 130 to 133 ° C.
puts. The ether was evaporated cold in a vacuum. B ice die 1 20
Initially, a suspension of the aldehyde 20 ^{p resulted}
and then, by forming the disulfite compound, an a) l-isopropylamino-4- (2-methylthiophenyl) -clear solution, from which the disulfite compound is extracted from 3-buten-2-ol hydrochloride
stalled. 50 ml of ether were added. The one solution of 0.48 g (0.023 mol) of 1-amino mass was ^{cooled to -5 0} C, after which a Lö- 4- (2-methylthiophenyl) -3-buten-2 ~ ol in 10 ml methase of 26 , 0 g (0.35 mol) of KCN in 45 ml of water were 45 nol, after the addition of one drop of 2normal drops. The temperature was kept at about 1 alcoholic hydrochloric acid, 0.37 ml (0.28 g 3 ° C., then acetone was added for a further 3 hours = 0.005 mol). After stirring the ice cooler. The ether layers had been mixed '/ 2 hour, 0.15 g and the water layer were separated, the water (0.0040 mol) NaBH _{4 was} added, after which 1 hour layer was four times with 5D ml of ether and the 30 was boiled . Then 0.5 ml of acetone and, after the ether layer, were washed twice with water. The ethereal solution to which the mixture had stood for V2 hour again was added at ⁰ ° C. with Na ₂ SO ₄ , after which 0.2 g of NaBH _{4 was} added, after which it was again dried for 1 hour and filtered, after which it was boiled with ice cooling. The mixture was evaporated in a vacuum dry mixture of 10 ml of pyridine and 25 ml of acetic acid, and the residue was added dropwise in 10 ml of anhydride. After the mixture has dissolved 35 water and 10 ml ether. The layers were left standing for one night, the ether and the ether were separated, the water layer was washed twice with the excess reactants in a vacuum of 5 ml of ether each time. The ether layers were evaporated, yield 17.0 g (0.07 mol = 70%). dried with Na ₂ SO ₄ , after which the ether is removed, _{N. v,.} ,,,, was steamed. The residue (0.55 g) was _dissolved in 2 ml _yma d) _2-abso Athoxyzimtaldehyd ^ f _{UTEM Äthano} i calculated _{with% T}

36.5 g (0.116MoI) 3-ethoxy-3- (2-ethoxyphenyl) - amount of 2 normal alcoholic hydrochloric acid

Propanal diethylacetal was acidified in 49 ml of acetic acid. The solution was made with 10 ml of absolute ether

dissolves, after which 2.9 g of anhydrous sodium acetate is diluted, after which the salt crystallized, yield

were set. The mixture was 3 hours in 0.27 g (0,0098MoI = 86%, bp. 170-174 ⁰ C.

a heating mantle in a nitrogen atmosphere 45

heated to reflux. The solution was cooled ^b ) l-Ammo-4- (2-metiiy thiophenyl) -

and then with a solution of 51 g (anhydrous) 3-buten-2-ol

Na ₂ CO ₃ neutralized in 200 ml of water. To a solution of 3.0 g (0.078 mol) LiALH ₄ in

precipitated aldehyde was taken up in some ether 100 ml of absolute ether became a solution of

and the water layer twice with ether 50 4.57 g (0.019 mol) of crude 2-acetoxy-r- (2-methylthio-

shakes. The ether was _{dried on Na 2} SO _{4 (} phenyl) -3-butenenitrile in 50 ml of absolute ether.

and evaporated in vacuo. The received back drops. The temperature of the reaction mixture

was dissolved in 50 ml ligroin, and the solution was maintained at -10 to -5 ⁰ C. It was

was placed in the refrigerator, yield 17.79 g for 4 hours at -10 to -5 ⁰ C was stirred. The GE-

(0.101 mol = 87%), m.p. = 34 to 36 ° C. 55 was then mixed with 9 ml of water while cooling with ice

\ -> * ι. -> /.-. - ^. ι. i \ decomposed. The hydroxides were sucked off and three-

e) S-Athoxy - ^ - athoxyphenyl) - _ma , _{mh 2Q mJ} ^ washed. InI filters crystalline

propanol _{diethyl acetate αύα ms Das mtnt} ^^ _with p _etro j_

An amount of 45.0 g (0.20 mol) of 2-ethoxybenz ether diluted until it began to become cloudy. It is critical

aldehyddiäthylacetat were 2 ml of a 10% iGeo 60 stallisierte 0.48 g of to 83 ⁰ C and the melting point 78th

Zinc chloride solution in acetic acid was added, after which a second amount of amine could be isolated by

with stirring 23 ml (17.5 g = 0.24 mol) of vinyl ethyl that the hydroxides are washed with chloroform and

ether was added dropwise at such a rate the extracts were dried and evaporated,

were that the temperature of the reaction mixture _x . . ,, ", ,,. , ,,

50 ° C remained. After 1 hour to about 50 ° C after- 65 ^c > 2-acetoxy-4- (2-methylthiophenyl) -

had been stirred, 50 ml of ether and 40 ml of 3-butennitnl

2 n-KOH added. After the mixture worked out well, a solution of 5.48 g (0.031 mol) of 2-methylthio-

was shaken, the layers were separated, and the cinnamaldehyde in 30 ml of ether became a solution of

12 g of Na ₂ S ₂ O ₅ in 40 ml of water were added. The ether was evaporated in vacuo without heating. The disulfite solution crystallized out. 30 ml of ether were added to the suspension of the disulfite solution. The mixture was ^{cooled to 0 °} C. and a solution of 8.0 g (0.108 mol) of KCN in 14 ml of water was added dropwise. The temperature was kept below 5 ^° C. The mixture was stirred for 3 hours while cooling with ice, after which the layers were separated off. The water layer was extracted four times with 15 ml of ether. The ether layers were washed twice with water and then dried ^{at 0} ° C. with Na ₂ SO _4. The solution was filtered, after which a mixture of 3 ml of pyridine and 8 ml of acetic anhydride was added dropwise while cooling with ice. After the mixture was left to stand at room temperature for several days, the solution was evaporated dry in vacuo to give a residue of 4.57 g, which was processed without further purification.

20 d) 2-methylthiocinnamaldehyde

11.55 g (0.0387 mol) of 3-ethoxy-3- (2-methylthiophenyl) propanol diethyl acetate was dissolved in 16 ml of acetic acid, after which 0.97 g of anhydrous sodium acetate was added. The mixture was refluxed in a heating mantle in a nitrogen atmosphere for 3 hours. The solution was cooled and then neutralized with a solution of 17 g (anhydrous) Na ₂ CO ₃ in 65 ml of water. The aldehyde was taken up in 100 ml of ether and the water layer was washed with 50 ml of ether. The ether was _{dried over Na 2} SO ₄ and evaporated in vacuo. A residue of 6.94 g resulted, which was recrystallized from 50 ml of ligroin, yield 5.48 g (0.031 mol = 80%), mp = 73 to 76 ° C.

e) 3-Ethoxy-3- (2-methylthiopheny)) propanol diethyl acetate

An amount of 3.87 g (0.039 mol) of 2-methylthiobenzaldehyde ^{diethyl acetate were 0.3 ml of a 10 0} / oigen ZnCl ₂ solution in glacial acetic acid and then 4.2 ml (3.2 g = 0.044 mol) of vinyl ethyl ether with a stirring added at such a rate that the temperature of the reaction mixture remained 50 ^0C . The mixture was subsequently stirred to about 50 ^° C. for 1 hour, then 20 ml of ether and 3.5 ml of 2N NaOH were added. After vigorously shaking the mixture, the layers were separated and the ether layer was washed twice with 5 ml of water each time. The ether was dried and evaporated, yield 11.55 g (0.038 mol = 99%).

f) 2-methylthiobenzaldehyde diethyl acetate

7.0 g (0.046 mol) of 2-methylthiobenzaldehyde were mixed with 9 ml (8 g = 0.05 mol) of ethyl orthoacetate, 9.5 ml of absolute ethanol and 0.02 g of p-toluenesulfonic acid, and the mixture was allowed to stand overnight at room temperature ditched. After adding 0.2 ml of 0.5 normal alcoholic liquor, the excess of ethanol and ethyl orthoformate was evaporated off in vacuo. The residue was distilled. The main fraction with a boiling point of 88 to 91 ^° C. at 0.15 mm weighed 9.07 g (0.040 mol - 87%).

Claims (1)

Claim: Process for the preparation of styrylethanolamines of the general formula -CH = CH-CHOH CH ₂ -NH -R and via salts, where Y ₁ and / or Y _{2 can be} identical or different and represent hydrogen, halogen or an alkyl, alkoxy or an alkylthio radical having 1 to 4 carbon atoms and R is hydrogen, an optionally branched alkyl radical and / or a cycloalkyl radical or denotes an aralkyl or phenoxyalkyl radical, the phenyl radical can be substituted by one or two alkyl, alkoxy or hydroxy radicals, characterized in that one is carried out in a manner known per se a) a compound of the general formula Y ₁ - / V-CH = CH-Z where Z -CH-CH ₂ , -CHOH-CH ₂ -halogen, ,O - CHOHC: or —Co — c; means, reacts with an amine of the general formula RNH ₂ and reduces the optionally obtained Schiff base; b) a compound of the general formula CH = CH-Z where Z C-CH ₂ -NHR, Il ο CH (OH) CN, - COCN, - COCNOH and -CHOH-C = NOH means reduced; if R has the meaning H, the alkylation is carried out in a manner known per se.