DE1620192A1 - Process for the preparation of optically active or racemic 2,3-dimethoxy-10-dimethylamino-berbin - Google Patents

Description

Dr. F. Zumstein sen, ■ * Dr. E. Assmann

Dr. R. Koeiiigsberger - Dipl. Phys. R. Holzbauer

Dr. F, Zumstein jun.

Patent attorney β

8 M ü η c h β η 2, eräuhausstraßa 4 / JII

90 / Mon -

Caa 960 D al · ■ <

HOUäSEL-UOLÄI ¹ , Paris / France

Process for the production of optically active or racemic 2,3-dimethoxy-iO-dimethylamino-berbin '

(Removal from patent -, ... ... (patent application

P 16 20 172.2)

The present invention relates to a method of manufacture of optically active or racemic 2,3-bimethoxy-10-dimethylamino-berbin of formula I -

OIL

and of its salts "

009 823/1863

ΝβΙΙΘ Documents (Art? | L Ab8.2Nr.1 Sab? 3

J. v. 4. 9. iaS7J

620 192

DLestj compounds are distinguished by werbvoll υ tranquil ize.v- and anaigetisehe Properties.

liaeh a preferred embodiment there is;) inventive method for the preparation of the compound en de.-r formula E,
whose reaction sequence is given in the attached scheme, in that inari the 4-nitro-holnophthalic anhydride, II, with
3,4-Diinethoxy-phenethylamine condenses, the acidic function, the / obtained 2-carboxy-4-nitro-E- [ß- (3 '»4' -dime tho. '. Y -phenyl) -äthylJ-phenylacetamide, III, mainly esterified to the methyient, 17, the esterified product cyclized with the aid of phosphorus oxychloride to give 2,3-di-methoxy-8-oxo-10 ~ nitro-13-dehydro-berbin, V, to the compound obtained Libhlum- Lithium hydride in the form of an aluminum halide, such as aluminum chloride
or -brornide, allowed to act, 2,3-dimethoxy-10-aniino-13-dehydro-berbin, VI, obtained, the 13-Doppelbli: Ldurig is reduced with the help of an alkali borohydride, and the obtained
2, 'i-Dimethoxy-IO-amirio-yberbiri with formaldehyde in Cfegeuwart of acetic acid to convert 2, 3-Dimethoxy-10-dimethylamino-b he bin.

Another embodiment of the process described above is that 2-Garbomethoxy-4-nitro-W- _L ß- (3 '>4'-dimethoxyphenyl) ethyl] -phenylacetamide, IV, ^ eltü.tiv on the . Ester function with the help of an alkali borohydride in the presence
a lithium salt reduced, the resulting 2-hydroxy-methyl-4-nitro-N- [ß- (3 '>4'-dimethoxyphenyl) -äthylj-phenyI acetamide,
VII, treated with phosphorus oxychloride and then with an alkali borohydride, giving 2,3-dimethox: y- la-nitr-oberbiri, VIII, which is reduced to the IU-amino derivative with the help of zinc or bison in an acidic medium, which one with
Formaldehyde in the presence of acetic acid autn 2, 'i -Dlmethoxy-IO -
converts dimethylamino-berbin.

The production of 2,3-I) imethoxy-10-amino-berb i mü Ui ι. Lm

ötammpatenb (patent application P 16 20 |. ';'. ■, »).

beach drive en.

0 0 9 8 2 3/1868
BATH ORIGINAL

Your connection is measured according to the method according to the invention with. Formaldehyde in the presence of zinc in acetic acid for room

1 a ρ or a door aura; ⁵ , ^ -Dimeffaoxy-IO-dimethylaTnino-berbin implemented,

The appropriate procedure is not restricted to the forms of management described above, but also includes the technical equivalents. As examples of such equivalent IUK management forms, the case may be mentioned that the movement of the desired grouping into the later 10-position also occurs at the beginning of the synthesis instead of via the above conversion; ¹ ! (ions can be brought about at the end of the synthesis. For example, the synthesis can be carried out with a homophthalic anhydride as a substance which has a dimethyl amino group in the 4-position

The following example explains the invention, suspects it is limiting.

Example: E ers t el 1 and d es 2 , 3-Diroet hOxy-10r-dlmethvl amino- b erb ins

With stirring at room temperature, O, P & g Γ, 3-dimethoxy-10-amino-berbiii, which according to the parent patent. ... ... (patent application P Ib TO 172.2) described process can be prepared, £ ru TO cm 4O? I'igem Pormaldehyd, mixed with

2 g cini dust, 10 cm * acetic acid and set. the stirring

3 1/2 hours away. ,

It is filtered off with suction, washed with acetic acid and water and neutralized then the filtrate. by adding sodium hydroxide solution to pH = 10 and extracted with methylene chloride. -

The organic phase is washed with; left, dried and distilled to dryness under vacuum.

Dor residue is ized from isopropyl ^ kj rsta] 1 to give 0.6 g ^c J, corresponding to a yield of 66? I, 2,3-dimethoxy-i0-dimethylamino-berbin, I, P = 90 to 92 OJ ⁰

009823/1868 _L

BATH

The product arises in the form of rods which are insoluble are in water, slightly soluble in ether and soluble in alcohol, - / icetone, benzene and chloroform.

Analysis: ° 2ί ^Η 26 ° 2 ^Ν 2 ⁼

Calculated: C 74.52 II 7.74 IJ $ 8.28

found: 74.7 7.9 8.3

The connection has not yet been described in the literature.

As mentioned above, the Berbinderivate of Formula I are with valuable pharmacological properties. In particular they have an important tranquilizer and analgesic marriage Effect.

They can be used to treat manic arousal, acute psychosis, syndromes of confusio mental is, Over-excitability, restlessness and anxiety, functional en organic disorders caused by mental tension or intensified, heuralgia and various ochrr.erzen.

The?, 3-Dimethoxy-berbinverbindungen dei ¹ formula I are used tuccal, trunsKutan or reiital.

You .grains in different. pharmacy provide forms] i ep en, such as drinkable or injectable solutions or suspensions, conditioned as ampoules, vials of various capacities, Tablets, coated tablets, lozenges, gelcaps, granules, syrups, drops and suppositories.

The useful Pos og il ie moves ζ wipe 0.05 g and 1 "50 g per day in Abhängigkei t of the jirt- of administration.

In particular, the usable Josierung moves between 100 mg and 1.50 g] ^ o day for the 2,3 -!) Im < thoxy-10-dimethyl

.0 0 9823/1868
BATH

amino-berbin per day in adults depending on the Mode of administration, -.

The pharmaceutical forms of application, such as solutions or drinkable or injectable suspensions, tablets, coated Tablets, pastilles, G-ellcapsein, granules, syrups, drops and suppositories, are made according to the usual methods,

009823/1868 BAD O & IJ3JNAL

Claims (1)

P a t e η t a η a ρ r ü c h e 1. Process for the production of optically ak L Lvein or racem Luch em ? , 3-LUmethoxy-10-dimethylamino-boron Lu el er Forme L and from its balances, characterized in that 4-nitro-homophthalic anhydride is then used with 3,4-dimethoxy-phenethyl amine to form 2-CJarboxy-4-nitro-H- [ß- (3 ', 4' - dimethoxy-pheny 1) ~ ethy 1.] ■ -phenylacetamide condenses, its acidification esterifies, the esterified product with the help of phosphorusoxychloride to 'S ,; 5-dimethoxy-8-oxo-10-nitro-13- dehydro-Berb in cyolisiert, the latter to the action of Iithium-Aluminiumhydri.d in the presence of aluminum halides such as aluminum chloride _r odor bromide, linterwirf t, to obtain the 2, 3-Dimöthoxy IO ami.io-I i-dfihydrobeirbin , whose Ho ρ ρ el bond, in ri-3 I e i 1 ua _; .; reduced with-FIiIfO of alkali borohydride and the ao erulte; iv ', -Ί-Dimethoicy-10-amine-o-berbLn with formal deii, y ei in the presence of van -.', na i ,. .iii 'c , 3- Whore thoxy- 10 -diine fchy'l am irio-berbin um-se ti .; t. ?. ivVi-'i tide tion des Verfulirentj after .msprucrl. I-, π 'zeiohiittt that one daii 2-Oarbui'iethoxy- -tn L t. ro I- 11 ^.: · ί ', 4'-d iiiit, · thoicy-pheny I j-uLhyL [--ph einyl acetamid' ίΐοΐο :! iv M ₁ noil er · Es terfiink tion with Hi 1 le from <llkal.iborhytlr Ld ■> .- Gt. , ■ uwar t, "iriti-i Li thiuiii., - U x-titi reiiiiK I. er t, dan erhai feen-e J - Hydro:, / ■, ι -; t hyl · ι -ι, it ru N ~ [U- (i ', 4' - 1 iHu; tlioxy-phenyL) -athyi] -pheny lao.'Lanti.i with Π Π Q- fi 9 1/1 fi fi C documents ΙαΛ. AS I ABa, 2 fir. I SaU 3, ^ BATH ORIGINAL . ν. 4-!), \ Ϊ́, ΛΆ Phonplioroxychl oxide and then treated with Alltaliborhydrid, whereby you get the?, 5-Dimethoxy-1 ü-nitro-berhin, the with the help of ink or iron in an acidic medium 1ü-Amlt; oc erivat reduced, which one with formaldehyde- 'in the presence of kssignic acid to 2,3-dimethoxy-iO-dimetl) ylamino-berbin umoot st,. ".'-.-" 3. The method according to claim 1 and 2, characterized gekennzeichnot that formaldehyde is allowed to act on the 2,3-dimethoxy-iO-amino-berbin in the presence of! '".' Sigsaure and zinc and the ?, 3-Dimethuxy- I ^ '- dimethyl amino-berbin receives., 4. The method according to claim t to 3, characterized in that ·. ' . mil on the Methylieruüg Stickstoif the inogruppe to the "3 ~ Vin) 6:?. thoxy-10-airino berbins with formaldehyde in Gerenwart of" in. carried out in acetic acid at room temperature, [). Optically active or racemic 2,3-DiniethOXy-1ö-dimethylamino-berbiiv; ^r eriäJi claim 1, characterized by the formula and de «iien ÜmIbo. 0 0 9 8 7 3/1 8 B 8 BATH ORIGINAL Blank page