DE2308187A1 - PROCESS FOR THE PREPARATION OF 4METHYL-5,7-BIS- (BETA-MORPHOLINOAETHOXY) CUMARIN - Google Patents

Description

DR. STEPHAN G. BESZEDES PATENT ADVOCATE

Ö06 DACHAU near MUNICH

BOX 1168

AM HEIDEWEG 2

TELEPHONE: DACHAU «71 Postal checking account Munich 1360 71 Bank account no.GO C37 Lei of the district and city

Sparkasse Dachüu-Indersdorf

P 555

Describe !; η

for patent application

RECOßDATI SA CHEIUICAL AKD PH-iRKaCEUTICAL COUPMlI

Lugano, Switzerland

concerning

N proceed to He r position of ^z 4 - RJ et hyl-5 // - bis - (ß-ni orpholinoätho xv) -c uiaarjn

^ -Methyl-5,7-t> is- (ß-morpholinoothoxy) -coumarin int a known Connection with therapeutic efficacy. Its structural formula is as follows:

CH ₂ O - C - C - N J ^Η 2 ^Η 2 ^Ν

^ J η _ ο _ _σ _ _Ν

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The known processes for the preparation of this compound, however, have the significant disadvantage that by this The yields achieved are only moderate.

Surprisingly, a new process for Production of 4-methyl-5,7-bis ;-( ß-: norpholirioäthox.y) -curaarin, which is characterized by excellent yields.

The invention relates to a process for the preparation of ^ -L1ethyl-5> 7-his- (ß-morpholinoathox _t y) -cuinarine, which is characterized in that a lower allyl ester of ß-aminocrotonic acid in the presence of a strong acid or a metal salt is condensed as a catalyst with phloroglucinol and then the 4-Lethyl-5,7-dioxycoumarin obtained is reacted with an acid addition salt of a β-IIorpholinoäthylhalogenide in the presence of an acid-binding agent. "Lower alkyl esters" are to be understood as meaning those with alkyl radicals having 1 to 4 carbon atoms.

First, then, ^ -üethyl- ^ jV-dioxycoumarin, a well-known compound, is produced. The usual process for the production of these is the classic Pechmann process for the production of gunarines, in which phloroglucinol and ethyl acetoacetate are reacted. The preparation according to the invention consists in the reaction of phloroglucinol with a lower alkyl ester of ß-aniinocrotonic acid, in particular ß-aminocrotonic acid ethyloGter, in the presence of a strong acid, preferably sulfuric acid, orthophosphoric acid or trifluoroacetic acid, or a lower alkyl ester, preferably tin tetrachloride (tin tetrachloride). Sr) GlO or titanium tetrachloride (TiCl ₁ ,), as a catalyst, optionally in a polar solution. t; ol, preferably Λ "ethanol, or in the absence of solvents, advantageously with a duration of 20 to 10%) ⁰ G.

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D. This reaction can in the case of ß-aminocrotonic acid ethyl ester as starting material can be illustrated by the following reaction scheme:

G - NH

G - II

G-O-G.

CH, OH

catalyst

So the 4-methyl-5,7-dioxycoumarin is almost theoretical Yield obtained.

According to the invention, 4-methyl-5 »7-bis (ß-morpholinoethoxy) coumarin is then used by condensation of 4— Methy1-5.7- -dioxycoumarin with an acid addition salt of a ß-Morpholinoäthylhalogenides obtained in counterv / kind of an acid-binding agent. In the preferred embodiments of the invention the 4-I.! ethyl-5,7-dioxycoumarin with a hydrohalide, preferably hydrochloride, a ß-morpholinoethyl halide, preferably of ß-morpholinoethyl chloride respectively ß-Morpholinoäthylbromid, condensed. As an acid-binding Agent is preferably used potassium carbonate and the reaction is advantageously carried out in a polar solvent, in particular isopropanol carried out. This reaction can be illustrated by the following reaction scheme will:

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O O

HC

* £ 5

OJ

OW

OJ

ow

I r4

OJ

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By using an acid addition salt of the resktionsf rihi-ren ß -:.: orpholinoäthylhalo ^ eni ior> in place of the, ß-l'.orpholino? r.thylhalo?; eniäes in Fern der Bu. '. e vvird dio formation a quaternary Spirovarbindur: -, where; lche from -? ί, 'οΐ' küien the base easily forms according to the following Regletionsr.c.her.a, avoided:

2 0

N-C-C-Eq

2 cl

.Probably this adverse reaction is for those with the known processes obtained moderate yields ye rant. '/ locally. In contrast, the inventive method allows the achievement of the desired product in excellent yields and in a no lower degree of purity than that of the product obtained in a known manner.

The invention is not intended to be limiting in light of the following Examples to be understood are explained in more detail.

example 1

16.2 g (0.1 I.:ol) of phloroglucin dihydrate and 12.9 g (0.1!.! Oil) of ß-aminocrotonic acid ethyl ester were introduced into 50% 99.9% ethanol. It v.oirde obtained a clear solution. Subsequently, while stirring or shaking the mixture, 37.6 g (0.35 mol) of sulfuric acid with a density of 1.82 were added dropwise over a period of about 60 minutes. During the dropping, it was found that the temperature rose to 40 ⁰ C and a precipitate formed, !!

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_BATH

Completion of the dropwise addition. The I.:i3chunr with stirring or shaking 5 hours. Hold Ι ^ πζ on ? .O to 3C ⁰ O g and then in V / assor a joros?.: · ';.' :. The au / ^ eschJ oion solid substance vmr: lü by filtering: j ::. cr.neri ut.I mit., water washed. The yield was ~ 21 r (1C0 / 5 ' l theory)

uiiiarinmr.ohydrate r.it; a cutting point

of 29O ° G.

There were added to 16.2 g (0.1: were u:;:; he lead cezi ohurigs.v ·· -ise shaking during a period of time vcn etv / a ^ O minutes 12.9 (0.1 I. '. ol) fi-äsinocrotor.Gäuroäth.yl ^ stcr ^ he; ei; zt. ! I "ischung was still stirring or shaking 5 hours Lana; 50 ^O 3 irhi: zt and then poured into '.Yasser The resulting precipitate ^^; rde by filtration rev / cnnen and V / asrior GeV /. ^. ^ oner .. Di = * expansion was 21 g (IOC ?? of theory) ^ -L! ethyl-s,? - iic> :. ycurriarir.:::or.oh:/-drat with a, ochrnolzpunkt from 285 to 29 :. '?.

Example 5

There are 1G, 2 g (0.1 i.'ol)? Hlcro-; 2ucind.i: y'li'at uni ^ 5.9 g (0.1 I.'ol) ß-Aninocrotcr'GV .urs'rithy] ester in 3C ct / '99j9 / 5-iges ethanol. Ss v.urao a -: clear reading; obtain. This / rare while stirring b i'Ziehunrjs'veise shaking during a period of time of 30 minutes 26, C % (0.1 "oil) tin tetrachloride ku ^ etronft. The Lischun-x was always ^{heated to ICO 0} C for 5 hours while stirring or pouring, and then poured into V / acr

BATHROOM ^?

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Bit 7 / ater washed. The goal for was 21, O g ^/ L + eth.yl-5 '7-dioxycu ^r narinn (1CO S ^theory?): Cnchydrat nit a * DchnolzpunVrt of 295> ° Si

BelST) iel

Eg 16.2 g (0.1 L: ol) phloroglucin dihydrate and 12.9% (0.1% oil) ß-amino-protonic acid ethyl ester were introduced into 50% 99.97-3% ^es / ethanol. A clear reading was obtained. Then were wahrocd. a period of time 23 of about 30 VA slots 66, ^ g (0.55 I.'ol) of lithium tetrachloride zuretroj; ft. During the dropping in, the reaction was detected, which became dark in color and formed a blackish precipitate. Before the end of the dropping, the liquid was left with stirring or shaking for 5 hours

Heated to 50 ° C for a long time and then soak in water. The retired solid matter was collected by filtration and washed with water. The yield was 21.0 g (100% of the Theory) 4 -!.: Iithyl-5 »7-dioxycur: arin morchydrate n-it a Schuelzpunkt from? 85 to 290 ° G.

There were 1 ^C - ,? a (0.1!.: ol) phloro ^ lucine dihydrate and 12 »9 Z (0.1 l'c3) ß-Ar-inocrotonfiliurööthyloster in 50 er / 99.9 ^ -iee.i ethanol. Ii) A clear solution was obtained. Then under · I? I; hrcn rel. dripping in minutes. V. 'during the Zutroyjfena v.-urde fc :: -; tr; o3tellt, that £ the temperature up to 40 ° C r: tic £. After the r ^ cniirrun ^ dos Zutrorfens the i'itchun ^, from '.velchor a plentiful Iliääorschlag was ruled out, under fortiauerrj: i:; r: liühr'm bezjchur.r ^. ^ Ine Schütteln 20 3tur. -

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heated to 100 ° C for a long time and then poured into water. The precipitated solid was collected by filtration and washed with rasser. The yield was 19 »0 g (about 9O? s of theory) 4 ~ ll

with a melting point of 290 ° C

Example 6

Ee became a stirred or shaken Mixture of 21 g (0.1 mol) ^ -Methyl - ^. Y-dioxycoumarin monohydrate, 52.2 g anhydrous potassium carbonate and 130 cnr isopropyl alcohol during a time period of 15 to 20 minutes ^ 3.5 B (0.23'hol) ß-LIorpholinoäthylchloridhydrochlorid added and the quench was refluxed for 8 hours heated to boiling, cooled to room temperature and filtered.

The solid matter thus obtained was washed several times with water to remove the alkalinity, and then with 60 to 65 ° C dried in a stream of air So were 35 6 (83% of theory) 4-methyl-5,7-bis (ß-morpholinoethoxy) - -coumarin with a melting point of 133 to 13 ^ ° C.

Claims - 9 -

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Claims (10)

Claims Process for the preparation of 4-methyl-5j7-bis- - (ß-morpholinoethoxy) -cuicarin, characterized in that that a lower alkyl ester of ß-aminocrotonic acid in the presence of a strong acid, respectively condensed a metal salt as a catalyst with phloroglucinol and then the 4-methyl- -5 »7-dioxycoumarin with an acid addition salt of a ß- ^ llorpholinoäthylhalogenides in the presence of an acid-binding Implemented means. 2.) Process according to claim 1, characterized in that the catalyst used is Sch.vef el acid, orthophosphoric acid or trifluoroacetic acid is used. 3.) Process according to claim 1, characterized in that the catalyst used is tin tetrachloride or Titanium tetrachloride is used. 4.) Method according to claim 1 to 3 »characterized in that that is used as the lower alkyl ester of ß-aminocrotonic acid ß-aminocrotonic acid ethyl ester. 5.) Process according to claim 1 to 4, characterized in that the condensation of the lower alkyl ester is carried out of ß-aminocrotonic acid with phloroglucinol at a temperature of 20 to 100 ° C. 6.) Method according to claim 1 to 5> characterized in that the condensation of the lower alkyl ester of ß-aminocrotonic acid with phloroglucinol in a polar Solvent, preferably ethanol, carries out. - 10 - 309838/1273 7.) Method according to claim 1 to 6, characterized in that that as ß- ^ orpholinoäthylhalorenid ß-iorpholinoäthylchlorid used. 8.) Process according to claim 1 to 7> characterized in that the acid addition salt of ß-Iv! Orpholinoäthylhalogenides a hydrohnlo-enide, preferably that Hydrochloride, is used. 9.) Method according to claim 1 to 8, characterized in that that one uses 1 potassium carbonate as the acid-binding medium. 10.) Method according to claim 1 to 9 »characterized in that that the implementation dos 4-methyl ~ 5 »7-dioxycumarines with the acid addition salt of ß-Morpholinoäthylhalogenides in a polar solvent, preferably isopropanol, carried out. 309838/1273