DE1793040A1 - Process for the preparation of 1- (3,5-dimethoxy-4-hydroxyphenyl) -2-monomethylaminoethanol - Google Patents

Description

PATENT LAWYERS

DR. ING. A. VAN DER WERTH DR. FRANZ LEDERER

21 HAMBURG 90 1793040 8 MUNICH 80

Wl LSTORFER STR. 3 2 - TEL. 134 111 77 08 61 LUCILe-GR «iHN-S TR. 22-TEL. C08III 440846

.Munich, July 25th Br

Registration Dr "L ^o Zam" beletti 3 _ο ρ · Λ _ο , Hailand / Italy, Via Zambeletti, 14.

PAIUiEK 2UR THE PRODUCTION OF 1 »(3, 5-DIMLTIIoXY-4-IiYDROXYPHElIY 1 / -2 1.10IiOM ^ THiIuUnNOATiIANOL "

(Ziiotvjss aur- German patent application i ^; T) 43 57O ₀ 4 from 9.3, -i 967)

In the German main registration P 16 43 570.4 of 9 * 0.1967 v / earth a new drug with blu fcd r ticker-increasing effect, tui'l av / ar das 1 «- (3i5 '- dimethoxy-4-' hydroxyphenyl) -2 ~ monomethyl- · - arainoethanol, as well as a method for its division described *

In further elaboration of the lli'i'Lndun ^ vmrdü now found that the 1 - ■ · (3 s 5 ~ dimethoxy-4-hydroxyphenyl) - '2 -iii'morne k> »ylam Lnoa ethanol (7T; j by the synthesis shown schematically below

/ er ^: eiLhaj't hoi '^ estellt v; _t ; f: lon *

OH OiOClU

- ■. OCH-, Η-, ΠΟν ^ : -K ../00H,

J U

"r"' T " ^q

ΙΙ ^ Ί ^ _ / Α) \ · τ H ₅ OOv ... -'- .. OCH,

■ 'if' («ΠJtO) ₂ ". Ίί Br,

ί Il LV

Π98 3 2/1179 BAD'ORIGINAL

OCOCH,

L r

(HCi)

COCH ₂ Br

COCH

₂ MCH,

ο HCl

CH ₂ NHCH ₅ .HCl
VII

As can be seen from the reaction scheme, the 1 -, - 3-dimethylpyrogallol (I) is acetylated with acetic anhydride and the acetyl derivative (II) prepared in this way is subjected to a rearrangement according to Fries with AlCl, whereby 4 "IIydroxy-3» 5 ⁱ " dimethoxyaceto ~ phenone (III) is obtained from this latter pent to the corresponding acetyl derivative (IV), which by bromination gave the 4-acetoxy-3, ii-dimethoxy-CO-bromoacetophenone (V)

This compound is made with monomethylamine (in aqueous-alcoholic Medium) in 4 "hydroxy-3,5-dimethoxy-Q-methylarainoacetophenone converted and isolated as the hydrochloride (VI) j is noteworthy that in the transition from (V) to (VI), except for the Hubatitution of the bromine atom with the NHCH, group, also the hydrolysis of the acetoxy group takes place. From (VI) one finally arrives to the final product by means of catalytic hydrogenation «,

The following example serves to explain the invention * » moderate procedure without restricting it.

example

153 g of 1,3-dimethylpyrogallol (I) are heated with 205 ml of acetic anhydride and left to react for 3 1/2 hours; then the anhydride is first distilled off and then the 2 = acetyl-1,3-dimethylpyrogallol (IT.), which has a boiling point of 160 ° G (10 mm) has »Yield: 217 g»

217 g of 2-acetyl-1 »3 ~ dimethylpyro £ allol (II) v / earth in 1060 ml dissolved anhydrous nitrobenzene; after cooling to 0 ° one gives 147 g of anhydrous aluminum chloride in small doses with stirring. When the addition of aluminum chloride is complete, he ~ the mass is warmed to 50 ° G for 15 hours. Finally, it is cooled to room temperature and treated with dilute hydrochloric acid until a clearly acidic reaction; the 4 ~ hydroxy-3 »5-dimethoxyacetophenone (III) is separated off by cooling and is filtered, dried and crystallized from a benzene-hexane mixture becomes ο Yield: 95 6 of the compound III with melting point = 118 ~ 120 ° Go

95 g of the product (III) are added to 160 ml of acetic anhydride, heated and allowed to react for 4 hours. By cooling the 4 ~ acetoxy ~ 3 is separated »5-dimethoxy acetophenone (IV) and precipitated is washed with hexane and obtained 110 g of 4-acetoxy ~ 3» 5-dimethoxy acetophenone (IV) with melting point at 159 ° C ₀ ^

110 g of the product (IV) are dissolved in 300 ml of anhydrous benzene; the solution is warmed slightly and 26 _f 3 ml of bromine. added at such a rate that a gentle reflux is maintained. When all of the bromine added has reacted, it is distilled to dryness and the residue is washed with hexane. Yield: 137 g of CO ~ Brorao «4-acetoxy-3,5-dimethoxyacetophenone (V), which, crystallized from hexane, has a melting point of 122 °. 125 ° C.

209832/1 179

137 g of the product (V) are in 300 ml of ethyl alcohol 95 ° C and dissolved with 750 ml of 35 'Mger monomethylamine solution Treated for 3 hours at 80 ° C. Then it is distilled at reduced pressure to almost dryness; as a residue remains a kind of pulp, which is filtered and made of pure alcohol is crystallized ο yield? 45 g of product with melting point from 162 ° G,

The product obtained is in gaseous form! Hydrogen chloride saturated methyl alcohol is dissolved and the solution is after previous Addition of activated charcoal filtered By adding water · = From free ether one separates the 03 - ^ ethylamino-3 ~ 5 ~ dimethoxy ~ 4 ~ hydroxy-acetophenone ^ hydrochloride (VI) from »Yield: 45 g with Melting point of 235 ° - 238 ° C.

The solution of 45 g of CO ~ methy1- 'amino-3 »5-" dimethoxy-4-hydroxy-acetophenone hydrochloride (VI) in a mixture consisting of 120 ml of water and 120 ml of methanol is added to a suitable vessel Hydrogen at room temperature in the presence of 3p5 g ΡΪΟ20 As soon as the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the filtered solution is dried in a water bath; the residue is an oil that is dissolved in methanol and filtered warm .. By adding Ether is separated from the 1 (3 _f 5-dimethoxy-4-hydroxy-phenyl) -2-monomethylnminoethanol hydrochloride (VII), which has a melting point of 173 ° -178 ° C. ". Yield: 43 g"

P The product (VII) obtained shows dior <Iben chemical-physical characteristics and the same pH-ecological features in the German patent application T ¹ .6 43 57Oo 4 dam ·: \ <?. han werdenο

2 nights 9 8 3 2 / ■ 1 1 7 H.
BAD OBIQtNAL

Claims (1)

Munich, July 2, 1968 Br PATEHY CLAIM Process for the preparation of 1- (3,5 ~ dimethoxy- ^ hydroxyphenyl · 2-monomethylaminoätlianol, characterized in that 4 "hydroxy ~ 3,5- = dimethoxybenHol (I) is acetylated, the acetyl derivative thus obtained is treated with AlCl, as a result of which a rearrangement takes place in 4-Hydroxy ~ 3,5 ™ dimethoxyacetophenone (III), which converts the latter with acetic anhydride to 4-acetoxy ~ 3t5- ^> dimethoxyaceto- * f phenone (IV), this compound with bromine to 4-acetoxy-3 »5-dimethoxy-co-bromoacetophenone (V) is brominated, this latter compound reacts with monomethylamine in an aqueous-alcoholic medium, whereby the bromine atom is substituted by a SHCH group and the acetoxy group is hydrolytically split off at the same time, whereupon the 4-hydroxy -3t5-dimethoxy »GO-methylamino ~ acetophenone is catalytically hydrogenated as the hydrochloride ο (^ 7 3