CH626881A5 - Process for the preparation of new octahydrobenzo[c]quinolines - Google Patents

Description

626,981

2

PATENTANSPRÜCHE

1. Verfahren zum Behandeln von feuchtem Holz, bei welchem das in eine geschlossene Kammer bei Atmosphärendruck eingebrachte feuchte Holz im wesentlichen durch Kontakt mit Heizelementen zur Verdampfung des wassers erhitzt wird und aus dem Holz , dadurch gekennzeichnet, dass vor der Dampfbildung im feuchten Holz der Kammerdruck auf 2 bis 45 bar erhöht und anschliessend während eines Zeitraumes von 10 bis 180 Minuten durch Ablassen von Luft aus der Kammer auf Atmosphärendruck reduzier west und red das Holz ein konstanter mechanischer Druck von 1 bis 150 bar wenigstens bis zum Ab-schluss des Schrumpfens des Holzes ausgeübt wird.

2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass als zusätzliches Heizmittel die Luft in der Kammer auf 70 bis 200 ° C erhitzt wird.

3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass das Holz durch den mechanischen Druck verformt wird.

4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass nach der Reduzierung des Kammerdrucks der mechanische Druck auf das Holz erhöht wird.

5. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass das Holz nachfolgend einem Vakuum ausgesetzt und anschliessend daran mit mit Wasser unverträglichen Substanzen behandelt wird.

6. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass das Holz entweder bis 60 ° C ohne mechanische Druckbelastung oder bis 80 ° C bei einer mechanischen Druckbelastung von 1 bis 5 bar vorerhitzt wird.

7. Verfahren nach Anspruch 6, dadurch gekennzeichnet, dass vor dem Erhitzen das Holz einem Vakuum ausgesetzt wird.

8. Verfahren nach Anspruch 7, dadurch gekennzeichnet, dass unter dem Vakuum das Holz mit einer Spülflüssigkeit zum Entfernen schädlicher Stoffe aus dem Holz kontaktiert wird.

9. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass das Holz vor dem Erhitzen einer Beize, einem Färbe- oder Imprägniermittel, die Mittel auf Alkohol-, Öl- oder Wasserbasis sein können, oder Polyurethan, Phenolharchenyl, Polyester oder Ammoniumchlorid ausgesetzt wird.

10. Vorrichtung zur Durchführung des Verfahrens nach Anspruch 1, gekennzeichnet durch eine wärmeisolierte Kammer (20), die beheizbar und mit einem Überdruck und einem Vakuum beaufschlagbar ist, durch wenigstens zwei inbarebareare, 20) , 30), zwischen denen das zu behandelnde Holz (W) anzuordnen bestimmt ist, und durch wenigstens eine am Kolben eines Hydraulikzylinders (P) sitzende Kolbenstange (27), die an einer Platte (26) angreift.

11. Vorrichtung nach Anspruch 10, gekennzeichnet durch mehrere jeweils an wenigstens einer der Platten (26,30) angreifende Kolbenstangen (98a, 97a) von Hydraulikzylindern (98, 97).

12. Vorrichtung nach Anspruch 10, dadurch gekennzeichnet, dass wenigstens an einer Platte (30) dem Holz (W) zugewandte Vorsprünge (32) vorgesehen sind.

13. Vorrichtung nach Anspruch 10, gekennzeichnet durch die Platten (26, 30) vertikal durchsetzende Bohrungen (67).

14. Vorrichtung nach Anspruch 11, dadurch gekennzeichnet, dass die einander gegenüberliegenden Plattenflächen als Formgebungsstücke zur Formgebung des behandelnden Holzes ausgebildet sind.

15. Vorrichtung nach Anspruch 11, gekennzeichnet durch Einrichtungen (36) zum Zuführen von trockener Heissluft ins

Kammerinnere und zum Abführen von mit Feuchte beladener Heissluft aus der Kammer (20).

Die Erfindung betrifft ein Verfahren zum Behandeln von feuchtem Holz, bei welchem das in eine geschlossene Kammer bei Atmosphärendruck eingebrachte feuchte Holz im wesentlichen durch Kontakt mit Heizelement und zer Verdampfung des io Wasszammer Kammerdruckreduzierung abgeführt wird.

Es ist bereits bekannt, Holz mittels Heissluft zu trocknen. Dabei wird das Holz so gestapelt, dass Kanäle für den Durch-15 ström der Trocknungsluft freibleiben. Der Holzstapel wird in einer Kammer angeordnet, in der die für das Trocknen erhitzte Luft zugeführt wird, durch die Kanäle im Stapel strömt, dabei das Holz erwärmt und aus dem Holz entweichende nach eichtungtungtungtungtungtungtungin ist (US-PS 3,940,860).

Bei diesem Verfahren werden zunächst die äusseren Holzschichten getrocknet. Anschliessend muss dann der weiter im Inneren des Holzes gebildete Dampf durch die bereits getrock-25 neten äusseren Bereiche hindurchgehen, was zu einer Rissbildung, zum Splittern und zu einer Formveränderung des Holzes führt.

Zur Herstellung von formbeständigem Holz ist es bekannt, das Holz, das einen Feuchtegehalt von 15 bis 30% hat, in einem 30 Autoklaven bei einem Überdruck von bis zu 6.5 bar 15 Stunden lang einer Temperatur von 160 ° C auszusetzen (DE-AS 22 63 758). Dies erfordert eine sehr lange Behandlungszeit des Holzes unter Zuhilfenahme einer aufwendigen Vorrichtung.

Bei einem anderen bekannten Verfahren zum gleichzeitigen 3S Stabilisieren und Trocknen von Holz in einer Warmpresse wird das Holz, das einen Wassergehalt von 15 bis 30% hat, in einem Zeitraum von 15 Minuten bis 5 Stunden senkrecht zur Faserrichtung einem einer Temperatur von 110 bis 200 ° C ausgesetzt. Dabei soll das Holz soweit 40 getrocknet werden, dass der Wassergehalt nach der Behandlung weniger als 12% beträgt (AT-PS 247 590). Mit dieser Presstrocknung wird die Bildung von Flecken am Holz vermieden. Das Holz wird dabei nur senkrecht zur Pressrichtung, nicht jedoch in der Pressrichtung stabiliert.

45 Zum Stand der Technik gehört schliesslich noch ein Verfahren zum Trocknen von Holzbrettern und Holzleisten, die in einem Stapel angeordnet werden, in welchem die Bretter durch flache thermostatgeregelte Heizelemente getrennt sind. Mittels der Heizelemente wird die Temperatur im Inneren der Bretter auf den gewünschten Wert gebracht. Dabei wird das Holz einem Unterdruck ausgesetzt, der kleiner ist als der Dampfdruck des Sattdampfs in dem erhitzten Holz (DE-OS 17 79 223). Dieses Verfahren erfordert ein genaues Einhalten nach Erfahrung gewonnener Betriebsparameter. Trotzdem lässt sich bei bestimm-55 ten Hölzern ein Splittern manchmal nicht ausschliessen.

Alle bekannten Verfahren haben insgesamt den Nachteil, dass die in der beschriebenen Weise behandelten Hölzer ihre Eigenschaften dann, wenn sie extremen Bedingungen über längere Zeit ausgesetzt sind, nicht beibehalten.

60 Die der Erfindung zugrundeliegende Aufgabe besteht deshalb darin, das Verfahren der eingangs genannten Art so auszubilden, dass sich mit ihm ein trockenes formbeständiges Holz herstellen lässt, dessen Eigenschaftsbild bei lang andauernnd extrem.

65

Diese Aufgabe wird bei dem Verfahren der eingangs genannten Art dadurch gelöst, dass vor der Dampfbildung im feuchten Holz der Kammerdruck auf 2 bis 45 bar erhöht und

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anschliessend während eines Zeitraums von 10 bis 180 Minuten durch Ablassen von Luft aus der Kammer auf Atmosphärendruck reduziert wird und dass spätestens zu Beginn dieser Reduzierung des Kammerdrucks auf das Holz ein konstanter mechanischer Druck von 1 bis 150 bar wen Schum Holzes ausgeübt wird.

Das erfindungsgemässe Verfahren hat den Vorteil, dass sich mit ihm die verschiedensten Hölzer unter Anwendung sehr hoher Temperaturen sehr schnell trocknen lassen. Diese hohen Temperaturen ergeben einen sehr hohen Dampfdruck im Holz, der an sich zu einer sofortigen Zerstörung der Holzstruktur führen würde, wenn diesem Druck nicht in der erfindungsgemässen Weise entgegengewirkt würde. Erst dadurch ist es möglich, den Dampf aus dem Inneren des Holzes zu entfernen, ohne dass Strukturschäden am Holz auftreten. Es können somit in äusserst günstiger Weise Hölzer in Grossproduktion, insbesondere geformte Schafthölzer für Gewehre und dergleichen hergestellt werden, die sich in ihrem Eigenschaftsbild auch dann, wenn sie extremsten Umweltbedingungen.

Damit von dem Holz keine Wärme an es umgebende Luft in der Kammer abgeführt werden kann, kann vorteilhaft als zusätzliches Heizmittel die Luft in der Kammer auf 70 bis 200 ° C erhitzt werden.

Da sich das Holz in einem elastischen Zustand befindet, kann es durch den mechanischen Druck verformt werden.

Die Dichte des Holzes und somit seine Festigkeit, Oberflächenhärte und Elastizität können dadurch verbessert werden, dass nach der Reduzierung des Kammerdrucks der mechanische Druck auf das Holz erhöht wird.

Das Holz kann nachfolgend einem Vakuum ausgesetzt und anschliessend daran mit mit Wasser unverträglichen Substanzen behandelt werden. Mit dieser Massnahme kann eine noch vorhandene Restfeuchte vollständig entfernt werden, wobei der mechanische Druck und die Kammertemperatur aufrechterhalten werden können. Das vollständig getrocknete Holz kann dann mit den genannten, mit Wasser nicht verträglichen imprägnierenden Gemischen behandelt werden.

Um eine Vortrocknung des Holzes zu erreichen, kann es entweder bei 60 ° C ohne mechanische Druckbelastung oder bis 80 ° C bei einer mechanischen Druckbelastung von 1 bis 5 bar vorerhitzt werden. Dabei kann vor dem Erhitzen das Holz einem Vakuum ausgesetzt werden. Dadurch, dass unter diesem Vakuum das Holz mit einer Spülflüssigkeit zum Entfernen schädlicher Stoffe aus dem Holz kontaktiert werden kann, kann beispielsweise Salz aus dem Holz entfernt werden, das bei der späteren Verwendung des Rüzen. Es lassen sich auch andere Stoffe, wie Säuren aus dem Holz entziehen. Der Spülvorgang kann mehrfach ausgeführt werden.

Um dem Fertigprodukt spezielle Eigenschaften zu geben, kann das Holz vor dem Erhitzen einer Beize, einem Färbe- oder Imprägniermittel, die Mittel auf Alkohol-, Öl- oder Wasserbasis sein können, oder Polyurethan, Phenolharchen, Polyester ausgesetzt werden.

Auf diese Weise können trockene Hölzer bzw. Schichthölzer in der gewünschten Form hergestellt werden, wobei als Ausgangsmaterial entsprechendes Frischholz verwendet wird, das auch in Form von Brettern oder Schichten eingesetzt werden kann, die miteinander verleimt sind. Man erhält formstabile Hölzer, die gebeizt sind, deren Oberfläche behandelt ist, die durch Imprägnierung feuerfest und termitensicher gemacht sind und die in der gewünschten Form eine hohe Zugfestigkeit, eine hohe Dichte, eine hohe Oberflächenhärte.

Die zur Durchführung des erfindungsgemässen Verfahrens verwendete Vorrichtung hat eine wärmeisolierte Kammer, die beheizbar ist und mit einem Überdruck und einem Vakuum beaufschlagbar ist, wenigstens zwei in der Kammer annordbareiken, 5 am Kolben eines Hydraulikzylinders sitzende Kolbenstange, die an einer Platte angreift. Es können auch mehrere, jeweils an einer der Platten angreifende Kolbenstangen von Hydraulikzylindern vorgesehen werden.

Zweckmässigerweise hat wenigstens eine der Platten dem io Holz zugewandte Vorsprünge. Damit lässt sich einerseits ein Muster in die Oberfläche des Holzes prägen, andererseits ist es möglich, dass zwischen den Vorsprüngen aus dem Holz austretender Dampf abgeführt werden kann. Dieser Dampf kann auch durch die Platten vertikal durchsetzende Bohrungen entwei-15 chen.

Wenn das Holz verformt werden soll, können die einander gegenüberliegenden Plattenflächen der durch Verformen zu erzielenden Gestalt des Holzes (W) angepasst werden.

Für das Zuführen von Heissluft ins Kammerinnere und für 20 das Abführen von mit Feuchte beladener Heissluft aus der Kammer können Einrichtungen in Form entsprechender Leitungen und Ventile vorgesehen sein.

Anhand der Zeichnungen wird die Erfindung beispielsweise näher erläutert. Es zeigt 25 Fig. 1 eine erste Ausführungsform einer Kammer zur Durchführung des erfindungsgemässen Verfahrens im Längsschnitt,

Fig. 2 eine Draufsicht auf einen Teil einer Platte der Vorrichtung von Fig. 1,

30 Fig. 3 eine zweite Ausführungsform der Vorrichtung teilweise im Längsschnitt,

Fig. 4 eine Einzelheit einer Platte der Vorrichtung von Fig. 3

und

Fig. 5 eine dritte Ausführungsform einer Vorrichtung sche-35 matisch in einer Seitenansicht.

Die in Fig. 1 gezeigte Kammer 20 ist mit einer Isolierung 23 zur Reduzierung der Wärmeverluste im Kammerinneren versehen. Die Kammer ist fahrbar und hat eine Tür 21 zum Einbringen und Entfernen des Holzes W. Durch die Oberseite der 40 Kammer 20 erstreckt sich eine Büchse 28, in der abdichtend eine Kolbenstange 27 eines Hydraulikzylinders P geführt ist. An dem kammerseitigen Ende der Kolbenstange 27 ist eine Platte

26 befestigt, die sich im wesentlichen über den ganzen Kammerquerschnitt erstreckt und vertikal durch Bewegung der Kolben-

45 stange 27 verschiebbar ist. Auf dem Boden 31 der Kammer 20 liegt eine Platte 30 mit pyramidenstumpfförmigen Vorsprüngen 32, deren Oberseiten 33 in einer Ebene liegen. Auf den Oberseiten 33 der Vorsprünge 32 liegt das Holz W in Form eines Blocks auf. Auf der Oberseite des Holzes W liegen die pyrami-50 denstumpfförmigen Vorsprünge 32 einer weiteren Platte 30 auf, an der die Platte 26 anliegt.

Wie aus Fig. 2 zu ersehen ist, haben die Platten 30 Heizleiter 35 zum Erhitzen der Platten mittels elektrischer Energie, Hochfrequenzenergie oder mittels eines Fluids.

55 In den Kammerwänden sind Sichtöffnungen 22 und Rohranschlüsse 36 vorgesehen, mit denen eine Verbindung mit einer Vakuumquelle, mit einer Zuführung für Heissluft oder Dampf oder mit einer Zuführung für Chemikalien hergestellt werden kann.

60 Durch den Hydraulikzylinder P kann über die Kolbenstange

27 und die Platte 26 auf das zwischen den Vorsprüngen 32 liegende Holz W ein mechanischer Druck ausgeübt werden, wobei dem Holz W durch den Kontakt mit den Vorsprüngen 32 Wärme zugeführt wird, die in den Platten 30 mittels der Heizlei-

65 ter 35 erzeugt wird.

Die in Fig. 3 gezeigte Ausführungsform entspricht dem wesentlichen Aufbau der Vorrichtung von Fig. 1, wobei anstelle eines einzigen Blocks mehrere Balken in Schichten angeordnet

626,881

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the main structural changes in the t-trahydrocannabinol molecule appear to give significant reductions in analgesic activity.

Paton in Annual Review of Pharmacology, 15,192 (1975) presents generalizations on structure-action relationships among cannabinoid derivatives. The presence of the gem-dimethyl group on the pyran ring is crucial for cannabinoid-type activity and the substitution of N for O in the pyran ring removes activity.

We have now found that certain benzo [c] quinolines, in particular the l, 9-dihydroxyoctahydro-6H-benzo [c] quino-léines (I), are effective as agents acting on the central nervous system, in particular as analgesics and transquil - binders, as hypotensive agents, which are not narcotic and which are addictive, as agents for the treatment of glaucoma and as diuretic agents. Also included in this invention is the preparation of various derivatives of said compounds which can be used as dosage forms. The above-mentioned compounds and their derivatives have the formula I. The compounds of formulas II, III and IV are precursors of the compounds of formula I.

z-w

6 (II)

y.-w

6 (m)

In these formulas:

R is chosen from the group comprising hydroxy, alkanoyloxy groups having from one to five carbon atoms and hydroxymethyl.

Rj is chosen from the group comprising hydrogen atoms and benzyl, benzoyl, alkanoyl groups having from one to five carbon atoms and -CO- (CH2) p-NR2R3 where p is 0 or an integer from 1 to 4; each of R2 and R3, taken individually, is chosen from the group comprising hydrogen atoms and alkyl groups having from one to four carbon atoms; or R2 and R3 taken with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring chosen from the group comprising the piperidino, pyrrolo, pyr-rolidino, morpholino and N-alkylpiperazino groups, the alkyl group of which has from one to four carbon atoms;

R4 is chosen from the group comprising hydrogen atoms and alkyl groups having from 1 to 6 carbon atoms and - (CH2) z-C6H5 where z is an integer from 1 to 4;

Rs is chosen from the group comprising hydrogen atoms and methyl and ethyl groups;

R () is chosen from the group comprising hydrogen atoms and - (CH2) y-carbalkoxy groups having from one to four carbon atoms in the alkoxy group and y is 0 or an integer from 1 to 4; carbobenzyloxy, formyl, alkanoyl having two to five carbon atoms, alkyl having one to six carbon atoms; - (CTL) X-C6H5 where x is an integer from 1 to 4 and -CO (CH2) x _, - C6H5;

Ru is chosen from the group comprising oxo, methylene and alkylenedioxy groups having from two to four carbon atoms;

R 'is selected from the group consisting of R and Ro;

s Z is chosen from the group comprising:

(a) alkylene groups having from one to nine carbon atoms;

(b) - (alk ^ n, —X— (alk2) n— where each of (alkt) and (alk2) is an alkylene group having from one to nine carbon atoms,

provided that the sum of the carbon atoms in (alkj) plus (alk2) is not more than nine; each of m and n is 0 or 1; X is selected from the group consisting of O, S, SO and SO2; and

W is chosen from the group comprising hydrogen atoms and methyl, pyridyl, piperidyl,

15

, W! where Wi is chosen from the group comprising hydrogen, fluorine or chlorine atoms; and

20. (CH2)

-CH / CH-W2 where Wi is chosen in

\ (CH2) r the group comprising the hydrogen atoms and

25

W | ; a is an integer from 1 to 5 and b is 0 or an integer from

1 to 5; provided that the sum of a and b does not exceed 5; and ketals of the compounds of formulas II, III and IV in which the ketal part has from two to four carbon atoms.

Also included in this invention is the preparation of the pharmaceutically acceptable acid addition salts of the compounds of formula I. Examples of these salts are the salts of mineral acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; the salts of organic acids such as citrate, acetate, sulfosalicylate, tartrate, gly-colate, malonate, maleate, fumarate, malate, 2-hydroxy-3-naphthoate, pamoate, salicylate, stearate, phthalate, succinate, gluconate, mandelate, lactate and methanesulfonate.

The compounds of formulas I, II and III above have asymmetric centers at positions 6a and / or 10a. There may be additional asymmetric centers in the substituent at position 3 (-ZW) and at positions 5,6 and 9. Diastereoisers having the 9β configuration are generally preferred to 9a isomers because of their biological activity above the point of quantitative view. For the same reason, the trans (6a, 10a) diastereoisomers of the compounds of formula I are generally preferred to the cis (6a, 10a) diastereoisomers. n / a With regard to the compounds of formula II where one of R4 and R5 is other than a hydrogen atom, diastereoisomers are preferred because of their greater biological activity. As regards the compounds of formula IV, asymmetric centers exist in position 9 and in the substituents in position. 55 3. Among the enantiometers of a given compound, one will generally be preferred compared to the other and to the racemic because of its greater activity. The preferred enantiomer is determined by the procedures described herein. For example, the 1-enantiomer of 5, 6, 6aß, 7, 8, 9,10, 1 Oaa-octahydro-1-acetoxy-60 9ß-hydroxy-6ßmethyl-3- (5-phenyl-2-pentyloxy) benzo [c] -qui-noline is preferred to the d enantiomer and the racemic, because of its greater analgesic activity. For reasons of convenience, the above formulas describe the racemic compounds. However, the foregoing formulas are considered to be general and to include the various racemic possibilities of the compounds of this invention, diastereoisomeric mixtures, pure enantiomers and their diastereoisomers. The usefulness of racemic mixtures, diastere mixtures

5

626,881

reoisomers as well as enantiomers and pure diastereoisomers is determined by the bioassays described below.

In addition, various intermediates which can be used in the preparation of the compounds of formulas I, II, III and IV will also be described here. Intermediaries have the formulas in which R4, R5, R6 and Z-W are as defined above;

R7 is chosen from the group comprising hydrogen atoms and formyl groups; and

Yj is chosen from the group comprising hydrogen atoms and protecting groups for the hydroxy group, in particular methyl, ethyl and benzyl groups.

Asymmetric centers can exist in intermediates V, VI and VII in position 2 in the substituent in position 7 (-ZW) and obviously at other positions, for example in the substituent in position 1. Positions 2 and 7 of the formulas V to VII correspond respectively to positions 6 and 3 of the compounds of formulas I, II, III and IV.

Due to their greater biological activity compared to that of other compounds described here, the compounds of formulas I and II are preferred in which R and Rq are as defined above;

R [is a hydrogen atom or an alkanoyl group;

R5 is a hydrogen atom or a methyl or ethyl group.

and each of R4 and R6 is a hydrogen atom or an alkyl group;

Z and W have the meanings indicated below:

Z m n W

alkylene having 5 to 9 carbon atoms alkylene having 2 to 5 carbon atoms - (alki) m-0- (alk2) n-

- (alk!) M-0- (alk2) n-

here

1 day

î î î

0 1

1 0

H or CH3

C6Hs, 4-FC6H4,4-C1C6H4,4-pyridyle Cf, H5,4-FC6H4,4— C1C6H4,4-pyridyle

{HouCH {H or CH (HouCH

The preferred compounds of formula I are the preferred compounds described above where R represents a hydroxy group and which have the trans configuration. The preferred compounds of formula II are those in which R0 is an oxo group.

Particularly preferred are the preferred compounds of formulas I and II in which:

R is a hydroxy group (formula I only);

Ri is a hydrogen atom or an acetyl group; s R5 is a hydrogen atom;

R4 is a methyl or pyropyl group;

R6 is a hydrogen atom or a methyl or ethyl group;

when Z is an alkylene group having 2 to 5 carbon atoms, W is a phenyl or 4-pyridyl group;

when Z is a group - (alk ^ -O-Çal ^) ,, - where m is 0 and n is 1, (alk2) n is an alkylene group having from four to nine carbon atoms, W is an atom hydrogen or a phenyl group; and when Z is an alkylene group having five to nine carbon atoms, W is a hydrogen atom.

In addition, the preferred categories of intermediates of formulas III, IV, V, VI and VII include the compounds having said formulas which serve as intermediates for preparing the preferred compounds of formulas I and II.

The compounds of formulas I and II in which R6 is other than a hydrogen atom, an alkyl group and a group - (CH2) X-C6H5, also serve as intermediates for the compounds of formulas I and II in which R6 is a hydrogen atom or an alkyl group or - (CH2) X-C6H5.

The compounds of formula V can be prepared from suitably substituted anilines, for example 3-hydroxy-5- (ZW -) - anilines (VIII) or their derivatives in which the 3-hydroxy group is protected by a group. 30 (Yt) easily removable to regenerate the hydroxy group. Suitable protecting groups are those which do not interfere with the subsequent reactions of said substituted and protected anilines in position 3, and which can be removed under conditions which do not cause undesirable reactions at other sites of said compound (s) obtained from aniline. The typical protective groups (Yi) are the methyl, ethyl, benzyl and substituted benzyl groups, the substituent of which is, for example, an alkyl group having from 1 to 4 carbon atoms, a halogen atom (Cl, Br, F, I) or 40 alkoxy having from one to four carbon atoms.

The exact chemical structure of the protective group is not decisive vis-à-vis the invention because its importance lies in its ability to play the role described above.

The selection and identification of the appropriate protective group can easily and quickly be made by those skilled in the art. The suitability and effectiveness of a group as a protecting group for the hydroxy group is determined using such a group in the reaction sequence described above. It must therefore be a group which is easily removed to allow the recovery of the hydroxy groups. The methyl group is preferred as a protective alkyl group because it is easily removed by treatment with pyridine hydrochloride. The ben-55 zyle group, which is also a preferred protective group, is eliminated by catalytic hydrogenolysis or acid hydrolysis.

When Z is a group - (alk1) m-X- (alk2) n-, Y! is preferably a benzyl or substituted benzyl group since it can then be eliminated without harming the Z group. The protected aniline derivative VIII can then be transformed into a compound of formula IX by known methods, as described here.

An abbreviated reaction scheme (Scheme A) of the preparation of representative compounds of formula V, 65 is given below starting from a 3- (hydroxy-protected) -5- (ZW-) aniline of formula VIII or - ZW is OCH ,:

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Diagram A

0CU3 °

ra-c-cn, cgo r

OC!

CH30

o

(VXII)

OCH

30

(GO)

cooc2h5

HBr-HOAc

HOAc

EYELASH

„I9U

ccor

V Ra

(ix)

r, r.c = ch-ccor a 5

OR

r ^ -coch-jcoor0 NaCNBH ^

och,

(1) c1c00c2h5 [3

Game

CH30

eoo R-r.

cr5 = k)

(X)

OH 0

Br- (alk-) -W

JL n oh o

W- (alk-) -0 '

XI

O

.N ^ R.

I

he ot-c)

R ° in the previous diagram represents a group of effective solvents when the reaction is carried out at kyle temperature having from one to six carbon atoms (R5 for reflux purposes, since they allow the azeotropic elimination of water the illustration in the overall diagram is shown as being formed as a by-product 40. Other means of removing a hydrogen atom. However, in reaction VIII - X water - or the actual removal of water - like sieves or VIII - »VB, R5 can be a hydrogen atom or a molecular one can be used, as well as other solvents which group methyl or ethyl). allow azeotropic elimination of water.

The substituent in position 5 of the compounds of formula VIII The preferred protective groups for the 3-hy-

may be the —Z — W group desired in the droxy-aniline-5-substituted compounds are the methyl, ethyl groups formulas II or I, or a group easily convertible into and benzyl since the ethers are easily prepared, provide this compound . When the Z part of the —Z-W group is satisfactory yields of the compounds of formulas IX and V

- (allcj) m — X- (alk2) n— where X is O or S and each of m and n is 0, and are easily eliminated.

the substituent in position 5 when W is a hydrogen atom. An excess of the alkyl P-ketoester is generally used,

is -XH (that is to say OH or SH) or a group -XH pro 50 preferably one in which the alkyl group has from one to six tegees of formula -X-Yi where Yj is as defined above . carbon atoms, to ensure maximum transformation When obviously -ZW is - (alkj) ,,, - X- (alk2) n — W where m is aniline reagent in ß-anilino-ß- (R4) -acrylate alkyl corres-1, n is 0 and W is hydrogen, substituting it in position 5 laying (IX). A ten to twenty percent excess of the p-keto ester becomes - (alkj) m — X-H. The -XH group is advantageous- alkyl is generally sufficient to obtain protected transforms as described above. 55 satisfactory mations. Acetic acid is used in quantities

The catalytic 5-substituted 3-hydroxy-anilines are then reacted to facilitate the reaction.

suitable as described above, preferably in the form. The alkyl p-anilino-p- (R4) -acrylate is then reduced to derivatives in which the 3-hydroxy group (and the group- (IX) in 3 - [(3- hydroxy-protected) -5-substituted-anilino] -3- (R4) -ment 5-hydroxy if present) is protected as mentioned corresponding alkyl propionate (X) using for example the above to obtain satisfactory reactions, with a mixture of sodium acetic borohydride and an alkyl hydrogen-P-ketoester, for example an alkyl acetoacetate, in catalytic tion. A preferred catalyst is platinum dioxide in the presence of acetic acid to form ß - [(3-hydroxy-pro- because it allows the reaction to be carried out conveniently at low teg) -anilino-5-substituted -] - p - (R4) -acrylate corresponding pressures, that is to say pressures below 3.5 kg / cm2.

(IX). The reaction is generally carried out in a solvent. Other catalysts such as noble metals, for example the inert with respect to the reaction, such as benzene or toluene, with 65 platinum, palladium, rhodium, on a support or not. , can temperatures ranging from about 50 ° C to the temperature to be used with hydrogen pressures ranging from the reflux pressure of the solvent under conditions which cause atmospheric elimination at higher pressures, for example 140 kg / d as a by-product. Benzene and toluene are cm2. In addition to these catalysts which are hetero-

7

626,881

genes, this step can be carried out using homogeneous catalysts such as Wilkinson's catalyst, tris- (triphé-nylphosphine) chlororhodium (I).

Obviously, when the protective group or groups are a benzyl or substituted benzyl group, the catalytic hydrogenation will lead to their elimination. For this reason, ethyl or methyl groups are preferred as protecting groups for 3- and / or 5-hydroxy groups of the reagents of formula VIII.

Alternatively, the compounds of formula X can be prepared directly from the compounds of formula VIII by reacting the compounds of formula VIII with an alkyl 3,3-R4R5-acrylate in acetic acid. The reaction is conveniently carried out by reacting equimolar amounts of the 3,3-R4R5-alkyl acrylate and the disubstituted aniline (VIII) in 0.1 to 2 equivalents of glacial acetic acid at temperatures between 0 ° C and the reflux temperature.

Alternatively, the compounds of formula V-B can be prepared directly by condensing equimolar amounts of VIII with appropriately substituted acrylic acid (R4R5C = CH-COOH) in pyridine hydrochloride at 150 ° -200 ° C.

In addition, when the groups R4 and R5 are both alkyl groups, the treatment with mercuric acetate of the compound of formula VIII and of the R4, R5-alkyl acrylate in a solvent inert towards the reaction , for example tetrahy-drofuran, then reduction with sodium borohydride give compound X.

The direct transformation of the compound of formula VIII into the compound of formula X is also conveniently carried out by treating a hydrochloride of 3,5- (protected dihydroxy) -aniline with an excess of an alkyl acetoacetate, for example acetoacetate ethyl, in the presence of sodium cyanoborohydride in a solvent such as methanol.

Then the 3-anilino-3- (R4) -alkylpropionate (X) is cyclized to the corresponding 2- (R4) -quinoline-4-one (formula VA or VB) using a cyclization agent suitable as polyphosphoric acid (PPA), hydrogen bromide-acetic acid mixture, sulfuric acid, oleum (fuming sulfuric acid), hydrogen fluoride, trifluoroacetic acid, phosphoric acid-acid mixture formic, and other cyclizing agents known to those of skill in the art. In a modification of this transformation, it is possible to transform the alkyl 3-anilino-3- (R4) -propionate of formula (X) into the corresponding acid, for example by saponification of the ester followed by acidification, before cyclization .

The ether protecting groups are the 3- (and 5-) hydroxy groups can be removed at the time of cyclization using hydrobromic acid in acetic acid as cyclization agent and unblocking agent. 48% aqueous hydrobromic acid is generally used because it provides satisfactory cyclization and unblocking. The reaction is carried out at elevated temperatures and preferably at reflux temperature. However, when Z is - (alk ^ -X- (alk2) n-, cyclization conditions using polyphosphoric acid or trifluoroacetic acid should be used to avoid cleavage of the ether or thioether bond.

Alternatively, the protective group (s) can be removed after the cyclization reaction. The bromhydri-that-acetic acid mixture is also a favorite agent for unblocking at this stage of the overall synthesis. The reaction is carried out as described above.

Other reagents such as hydroiodic acid, hydrochloride or pyridine hydrobromide can be used to remove the protective ether groups such as the methyl and ethyl groups. When the protective groups are the benzyl or substituted benzyl groups, or can remove them by catalytic hydrogenolysis. Suitable catalysts are palladium or platinum, in particular on a carbon support. Alternatively, they can be removed by solvolysis using trifluoroacetic acid. Obviously, when the group -Zr-W contains sulfur, acid debenzylation is used instead of catalytic debenzylation.

A preferred method for the transformation of the compounds of formula X into compounds of formula V, which provides satisfactory yields and allows the use of relatively moderate conditions, involves the transformation of the compounds of formula X into N-carbalkoxy derivatives in which the group N-carbalkoxy has from two to five carbon atoms, by reaction with suitable alkyl or benzyl chloroformate. The N-carbalcoxy or N-carbobenzyloxy derivative of formula X is then cyclized using a polyphosphoric acid to the corresponding N-carbalcoxy or carbobenzyloxy derivative of the compounds of formula V. The N-substituted derivatives of the compounds of formula X can if desired, be hydrolyzed to the corresponding 3 - [(N-substituted) -3- (protected hydroxy) -anilino] -3- (R4) -propionic acid before cyclization. Polyphos-20 phoric acid generally gives maximum cyclization and is a preferred cyclizing agent.

The hydrobromic acid-acetic acid mixture is treated to obtain the compounds of formula V-A, the compounds of formula V in which the hydroxy group or groups are protected and in which the nitrogen atom is substituted by a carbalkoxy group. When the protective group or groups of the hydroxy group are benzyl or substituted benzyl groups, the regeneration of the hydroxy groups is carried out by catalytic hydrogenolysis. A carb-30 alkoxy group, if it is present on the nitrogen atom, is not modified by this reaction. It can if desired be subsequently removed by treatment with the hydrobromic acid-acetic acid mixture or with any of various acids or bases. Removal of the benzyl protecting group by treatment with trifluoroacetic acid also eliminates any N-carbalkoxy group present.

When the substituent -ZW of the compounds of formula V is -XH (X = 0 or S) and it is desired that this substituent zZ-W represents in the compounds of formula II or I a group 40 _x_ (alk2) nW where X is O, S, SO or S02 and that W is as defined above, the group -XH is transformed into the group -X- (alk2) nW, conveniently and advantageously at this time in the overall reaction sequence . Thus, the group 7-XH of formula 45 VB above is transformed (which was shown by way of illustration by -OH) using the Williamson reaction with the bromide [Br- (alk2) nW], the appropriate mesylate or tosylate, in a group -Ó- (alk2) nW (formula VC).

Similarly, when the group -Zr-W of formula V is 50- (alkj) -XH, its transformation into a group - (aUq) -X- (alk2) n — W where n is 0 or 1 and W is other that a hydrogen atom is conveniently carried out at this stage of the reaction sequence, via the Williamson reaction.

Various groups, such as those included in definition 55 of R6, can be used in place of the carbalkoxy or carbobenzyloxy groups in this preferred process for protecting nitrogen from protonation.

The group R6 if it is not already present in the compounds of formula VA, VB or VC, can be introduced before its formation of the derivative with hydroxymethylene group (formula VI) by reaction with the reagent Cl-R6 or Br-R6 appropriate, according to known procedures. Obviously, when an acyl, for example acetyl, R6 group is desired in the products of formulas I or II, these groups can generally be introduced at this moment in the reaction sequence (scheme B) after formation of the compounds of formula II in which R6 is a hydrogen atom, for example by acylation with the appropriate acyl halide according to known procedures.

626,881

The compounds of formula V and obviously of formula V-A, V-B and V-C, can be transformed by the following representative scheme (scheme B) into representative compounds of formulas II and I (R5 = H in the representation).

Scheme B

OH 0

Z-W

ai3-CO-CK = CH „Base, CK„ OK

Z-W

(VII) £ + derivative 1,3-1) 13-formylated (VII — A) T__

(II) [+ eis isomer]

(The transformation III - »II -» I and II -s-1 is the subject of the invention). 40

The quinolines of formula V can be transformed into hydroxymethylene derivatives of formula V by reaction with ethyl formate and sodium hydride. This reaction, a formylation reaction, provides the bis-formylated derivative of formula (VI) with an excellent yield. Treatment of the bis-formylated derivative with methylvinyletone gives a mixture of the corresponding mono-N-formylated Michael adduct (VII) and the 1,3-bis-formylated Michael adduct. The two products are conveniently separated by column chromatography on silica gel.

The compounds of formula VII can be transformed into compounds of formula III in an aldolic condensation of the mono-N-formylated compound of formula VII. The Michael 1,3-bis-formylated adduct, when subjected to aldolic condensation, gives a spiranic cyclization product (III-A) as the main product. However, VII-A can be transformed into VII by treatment with one equivalent of potassium carbonate in methanol.

H.

0 OH

II

XGK

TO!

z-w

* kb

CH „GH

(VII-A)

(III-A)

In addition to the spirannic cyclization product, small amounts of the desired enone (formula III) and of compound (V) are also obtained.

The enone of formula III can be converted by Birch reduction to the compound of formula II. We obtain the isis and trans isomers. This reduction is conveniently carried out using lithium as the metal. Sodium or potassium can also be used. The reaction is carried out at a temperature of from about 65 ron - 35 ° C to about - 80 ° C. Birch reduction is preferred because it allows stereo-selectivity resulting in the formation of the desired trans-ketone of formula II as the main product. Catalytic reduction on noble metal is preferred

9

626,881

when the cis-diastereoisomers are the main product.

The hydroxy ketones of formula II (compounds in which R0 is an oxo group and R (is a hydrogen atom) and the dihydroxylated compounds of formula I (R = OR, = OH) seem to be rather unstable. oxidation as shown in purple to red color formation. Colored byproduct formation occurs even when hydroxy ketone is reduced by sodium borohydride. It has been found that formation can be prevented colored by-products by acylation, and in particular acetylation, of the 1-hydroxy group (ORJ by acetic anhydride in pyridine, and by formation of acid addition salts, for example hydrochlorides. Acetylated derivatives are stable at rest and even when they are subjected to a subsequent reaction.

It is believed that the above-mentioned colored by-products have a quinonoid structure originating from the oxidation of the 1-hydroxy group (OR,) to the oxo group and the introduction of a second oxo group in position 2 or 4. The by-products by themselves have activity on the central nervous system, in particular, as analgesics and tranquilizers and as hypotensive agents, and are used in the same manner and at the same doses as are the compounds of formulas I and II.

The reduction of the 9-oxo group of the compounds of formula II, and preferably for the reasons of the stability mentioned above of the acetylated derivative of formula II, by reduction with a metal hydride provides compounds of formula I in which the grouping hydroxy in position 1 is present in the form of the acetylated derivative. Sodium borohydride is preferred as a reducing agent in this step because not only does it provide satisfactory product yields but it keeps the acetoxy group in position 1 and reacts slowly enough with the hydroxylated solvents (methanol, ethanol, water) to allow their use as solvents. Generally a temperature of about 0 ° C to about 30 ° C is used. Lower temperatures even up to about -70 ° C can be used to improve the selectivity of the reduction. Higher temperatures cause the sodium borohydride to react with the hydroxylated solvent and deacetylation. If higher temperatures are desired or are necessary for a given reduction, isopropyl alcohol or dimethyl ether of diethylene glycol is used as the solvent. A preferred reducing agent is sodium tri-s-butyl borohydride because it promotes the stereoselective formation of the 9a-hydroxy group. The reduction is carried out in dry tetrahydrofuran at a temperature below about -50 ° C using equimolar amounts of the 9-oxo compound and a reducing agent.

Reducing agents such as lithium borohydride or double lithium aluminum hydride require anhydrous conditions and non-hydroxylated solvents, such as 1,2-dimethoxyethane, tetrahydrofuran, ether, dimethyl ether ethylene glycol.

Or, and preferably, the compounds of formula III, in particular those in which the 1-hydroxy group is protected by a benzyl ester or ether, are transformed into compounds of formula I by catalytic hydrogenation. A convenient procedure comprises catalytic hydrogenation on palladium, for example palladium-on-charcoal or on another noble metal, supported or not.

The acetylated derivatives of formula I thus obtained are transformed into corresponding hydroxylated derivatives by cutting the acetylated group according to conventional methods.

The isomeric compounds 9a and 9β-hydroxy of formula I are obtained in the reduction steps described above. Treatment of ketone compounds of the formulas II-IV with the appropriate al-kylene glycol or akylenedithiol having two to four carbon atoms in the presence of a dehydrating agent such as p-toluenesulfonic acid, or another acid used in ketalization (oxalic, adipic), provides the corresponding ketals or thiocetals (Fahrenholtz et al., J. Am Chem. s Soc., 89, 5934 1967).

Another procedure allowing the introduction of alkyl groups in position 6, with final production of the compounds of formulas I and II, is that of scheme D.

Scheme D

40

The 6-oxohexahydrobenzo [c] quinooleins of formulas IV-C and IV-E can be prepared from compounds of formulas IV-45 A and IV-D, by reacting them with sodium or potassium hydroxide at temperatures high, for example around 200 300 ° C. The transformation into quaternary derivatives of nitrogen of compound IV-A, by reaction of compound IV-A with methyl or ethyl iodide, benzyl bromide or another aralkyl halide, makes it possible to carry out reaction with sodium or potassium hydroxide under more moderate conditions. The intermediate adduct formed is easily oxidized by moderate oxidizing agents, including air, to the oxo compound of formula IV-E but which obviously, as a result of the reaction for the formation of quaternary derivatives, carries a substituent (methyl, ethyl, aralkyl) on the nitrogen atom.

Another procedure consists in treating compound IV-A with a peracid, for example m-chloroperbenzoic acid, peracetic acid, to form the corresponding N-oxide which is then reacted with acetic anhydride in a transposition of N-oxide to give the compound of formula IV-C (Boekelheide transposition). Other methods known in the art can be used for the transformation of N-oxides into lactams.

The compounds of formula IV-C or IV-E are then treated with an excess of a suitable Grignard reagent, for example methyl or ethylmagnesium bromide, to form the corresponding 6,6-dialkylated compound II-B.

626 881 10

The 3-hydroxy-5- (Z-W) anines can be prepared from (disubstituted phenyl) -ketone (Y2 = alkyl). When the 5- (ZW) -resorcinols are used by the Bucherer reaction, which methyl methyl, the resulting acetophenone derivative is treated to react the appropriate 5- (ZW) resorcinol with sulfite a Grignard reagent (W — Z'-MgBr). The aqueous ammonium bisulfite or product is hydrolyzed. The intermediate alcohol addition reaction is carried out which is hy-

in an autoclave at elevated temperatures, for example envidrogenolysis thereafter to replace the hydroxy group with ron 150 at about 230 ° C. The aniline obtained is isolated in acidi- a hydrogen atom. This procedure is particularly trusting the cooled reaction mixture and extracting the mixture useful for the compounds in which Z is an alkyl-acid group with, for example, ethyl acetate. We neutralize the lene.

acid solution and it is extracted with an appropriate solvent, by unlocking the ether groups by the following means:

example chloroform, to collect the aniline obtained. Either treatment with pyridine hydrochloride (Y, = methyl) or else the aniline obtained is isolated by extracting the catalytic reachydrogenolysis mixture (Y, = benzyl), or treatment with a mixture cooled by an appropriate solvent and then carrying out an acid such as trifluoroacetic acid, hydrochloric acid, bromhy-column chromatography of the crude product. dric or sulfuric. Acid debenzylation is obviously

If the 5- (Z-W) resorcinols are not known, they can be used when the group -Z-W contains sulfur.

prepare from 3,5-dihydroxybenzoic acid. Mode 15 Another process for the transformation of the compounds of operative consists in esterifying 3,5-dihydroxybenzoic acid mule XII into those of formula XIV comprises the reaction of one in which the hydroxy groups are protected (for example ketone of formula XII (Y2 = alkyl) with the appropriate pie derivative in the form of methyl, ethyl or benzyl ether); or +

well to effect the amidation of 3,5- [di (hydroxy-triphenylphosphonium bromide [(C6H5) 3p-Z-W] Br in pre-ge)] benzoic acid. 20 sence of a base, for example sodium hydride. The reaction

The abbreviated overall sequence is illustrated below (diagram is done via an alkene which is then hydrogenated catalytically to the corresponding alkane (ZW) and which is released to obtain the dihydroxy compound XIV. Obviously , when -Z- is (alk1) mX- (alk2) n and Y [is a benzyl group, catalytic hydrogenation also results in cleavage of the benzyl ethers.

Alternatively, the compounds of formula XII can be transformed into those of formula XIV by the sequence XII -> XIII - »XIV. In this sequence, the twice protected benzamide 30 (XII, Y2 = NH2) is transformed into ketone (XII, Z '= Z minus a CH2 group) by reaction with the appropriate Grignard reagent (BrMg-Z'— W) and then reaction with methyl- or ethyl-magnesium halide to form the corresponding alcohol. Dehydration of the alcohol, for example with p-toluenesulfonic acid, provides the corresponding alkene which is then hydrogenated catalytically (Pd / C) to obtain Falcane (XIV). The ethers are unblocked (transformed into a hydroxy group) as described above.

• »o When Z is an alkylene group, Yj is preferably an alkyl group having from one to four carbon or benzyl atoms. The role of the group Y1 is to protect the hydroxyl groups during the subsequent reactions. It is its ability to perform a particular role, that is to say the protection of hydroxy groups, rather than its structure which is important. The selection and identification of suitable protective groups can easily and quickly be carried out by those skilled in the art. The suitability and effectiveness of a group as a protecting group for the 50 hydroxy group are determined using such a group in the reaction sequence described above. It must therefore be a group which is easily removed to allow the restoration of the hydroxy groups. The methyl group is preferred as a protective alkyl group because it is easily removed by treatment with pyridine hydrochloride. The benzyl group, if used as a protec group. The starting substance, I 3,5-dihydrator acid, is converted, is removed by catalytic hydrogenolysis or oxy-benzoic hydrolysis XI, into a compound of formula XII in which acid

Y2 represents an alkoxy group, preferably a group - When z is a group - (alk,) mX- (alk2) n, Y, is methoxy or ethoxy for reasons of ease of preparation preferably a benzyl group or substituted benzyl because it tion, or an amino group; and Y] is a protected group can then be eliminated without harming the group Z.

Hydroxy group, according to methods described in the Compounds of formula VIII-A can also be literature. prepared from 3-amino-5-hydroxybenzoic acids by the

The diprotected benzoic acid derivative is then transformed into the procedure of scheme F below.

of formula XII into a compound of formula XIV by methods es The compounds of formula VIII-A in which -Z-W is known. In a procedure, compound XII is hydrolyzed an alkylene-W group or - (alk:) - X '- (alk2) nW where (alk,), to the corresponding acid (Y2 = OH) or its lithium salt, and on (alk2), W and n are as defined above and X 'is O or reacted with the appropriate alkyl lithium to produce the alkyl - S) are obtained by the following scheme (scheme F):

E).

Diagram E

V

OH

11

626,881

Scheme F

(Ac-acetyl) J 1 (c, Ht.), P-CHCOOC „H [. '1

b o 3 l d

AcNlJ \ / \ r ^ 0

Z

XOOC-H

R "

(R1 - H, alkyl)

2 5

fYl

AcKH •

M,

Gl CH2OH

AT \

CjHjN / chloride \ ®r3

'_de ^ tòsyle \ i

OY,

OY,

~ OI £ H_ lOi, ch ,,

AcNir \ ^ \ ai ^ CH2 ~ OTs AcKIÎ ^ - ^ Ol "CH2Br

V- (alk_) -X'H Z n

R "

(c6h5) 3P

AcNH

r "-c- (ch2) v-w

OY,

AcKH

o

JSL.

2s

CH CH = C- (CH2> V-W

R "

R "

The first step of the previous sequence (Wittig reaction) provides the possibility, by choosing the appropriate reagents, of obtaining compounds having straight or branched alkylene groups. The amino group is protected by acety-lation according to conventional procedures. In the representation given, if R "is a methyl or ethyl group, there is the formation of a compound having an alkyl substitution on the carbon atom (a) adjacent to the phenyl group. The substitution of a methyl or ethyl group at other sites, for example on the ß carbon atoms of the alkylene group, is obtained by choosing the appropriate triphé-nylphosphorane carboalkoxyalkylidene, for example (C6H5) 3P = C (R ") ~ COOC2H5. The unsaturated ester thus obtained is reduced to the corresponding saturated alcohol by reaction with lithium aluminum hydride. The presence of a small amount of aluminum chloride sometimes accelerates this reaction. Or, when Y j is other than a benzyl group (for example methyl), the alcohol is produced by catalytic reduction of the unsaturated ester using palladium on carbon, then by treating the saturated ester thus obtained with l lithium and aluminum hydride. The transformation of the alcohol into the corresponding tosylate or mesylate and then the alkylation of the tosylate or of the mesylate with an alkali metal salt of the reagent HX '- (alk2) n-W and the final elimination of the protective groups Y] provide the desired compound

45 of formula VIII-A. When X 'is sulfur, the protective group Y [is a methyl group.

A variant of the previous sequence involves the bromination of the alcohol rather than its transformation into tosylate or mesylate. Phosphorus tribromide is a suitable brominating agent. The brominated derivative is then reacted with the appropriate HX '- (alk2) n-W reagent in the presence of an appropriate base (Williamson reaction).

The brominated compounds also serve as interesting intermediates making it possible to increase the length of the chain of the alkylene part in the preceding sequence to obtain compounds in which Z is an -alkylene-W group. The process involves treating the brominated derivative with triphenylphosphine to form the corresponding triphenylphosphonium bromide. The reaction of triphenylphosphonium 60 bromide with the appropriate aldehyde or ketone in the presence of a base such as sodium hydride or n-butyl lithium, provides an unsaturated derivative which is catalytically hydrogenated to the saturated compound. corresponding.

In this variant, the acidification of the protector group 65 chosen Yj depends on the particular sequence followed. When using the vertical sequence on the right, the benzyl group is the preferred protective group due to the catalytic hydrogenation step. The methyl group is the

626,881

12

preferred protective group when following the vertical sequence on the left, since it is conveniently removed by treatment with an acid as described here.

The compounds of formula II are obtained in which -Z-W is - (alk1) Itl-X- (alk2) n-W and X is -SO- or -SO2-, by oxidation of the corresponding compounds in which X is -S-. Hydrogen peroxide is a convenient agent for the oxidation of thioethers to sulfoxides. The oxidation of thioethers to corresponding sul-fones is conveniently carried out using a peracid such as perbenzoic, perphthalic or m-chlo-roperbenzoic acid. The latter peracid is particularly useful because the by-product, m-chlorobenzoic acid, is easily eliminated.

The esters of the compounds of formula II to IV in which Rj is an alkanoyl group or -CO- (CH2) p-NR2R3 can be easily prepared by reacting the compounds of formulas II to IV with the appropriate alkanoic acid or the acid of formula HOOC- (CH2) p — NR2R3, in the presence of a condensing agent such as dicyclohexylcarbodiimide. Alternatively, they are prepared by reacting a compound of formula II-IV with the appropriate alkanoic acid chloride or anhydride, for example acetyl chloride or acetic anhydride, in the presence of a base like pyridine.

The esters of the compounds of formula I can be prepared in which each of the groups R and Ri is esterified, by acylation according to the procedures described above. The compounds in which only the 9-hydroxy group is acylated are obtained by moderate hydrolysis of the corresponding 1,9-diacylated derivative, using the greatest ease of hydrolysis of the phenolic acyl group. The compounds of formula I are obtained in which only the 1-hydroxy group is esterified by reduction by the borohydride of the corresponding ketone of formula II esterified in position 1. The compounds of formula I thus obtained carrying an l-acyl-9- substitution hydroxy or a 1-hydroxy-9-acyl substitution can then be acylated using a different acylating agent to form a diesterified compound of formula I in which the ester groups in positions 1 and 9 are different.

The presence of a basic group in the ester part (ORO of the compounds of this invention allows the formation of acid addition salts involving the said basic group. When the basic esters described here are prepared by condensation of the amino hydrochloride - appropriate acid (or another acid addition salt) with the appropriate compound of formula I-IV in the presence of a condensing agent, the hydrochloride of the basic ester is obtained. Careful neutralization provides the free base The free base can then be transformed into other acid addition salts by known procedures.

It is obviously for those skilled in the art that the acid addition salts can be formed with the nitrogen of the benzo [c] quinoline system. These salts are prepared by conventional procedures. The basic ester derivatives can obviously form mono- or di-salts of acid addition, because of their basic double function.

The analgesic properties of the compounds obtained according to this invention are determined by tests using thermal nociceptive stimuli, such as the procedure for wincing the tail of a mouse, or chemical nociceptive stimuli, for example by measuring the ability of a compound to suppress convulsions induced by an irritant agent which is phenylbenzoquinone, in mice. These and other tests are described below.

Tests using thermal nociceptive stimuli a) Analgesic hot plate test in mice

The method used is modified from Woolfe and McDonald, J. Pharmacol. Exp. Ther., 80,300-307 (1944). A specific thermal stimulus is applied to the legs of the mice on an aluminum plate 3.2 mm thick. A 250 watt reflective infrared heat lamp is placed under the bottom of the aluminum plate. A thermal regulator, connected to thermistors on the surface of the plate, programs the heating lamp to maintain a constant temperature of 57 ° C. Each mouse is placed in a glass cylinder (165 mm in diameter) resting on the hot plate, and timing is started when the animal's legs touch the plate. Half an hour and two hours after treatment with the test compound, the mouse is observed to determine the first "thrill" movements of one or both of the hind legs, or until 10 seconds have elapsed. flow without the appearance of these movements. For mor-15 phine, MPE50 = 4—5.6 mg / kg subcutaneously.

b) Analgesic wiggle test of the tail of a mouse

The tail wincing test in mice is modified from D'Amour and Smith, J. Pharmacol. Exp. Ther., 72, 20 74—79 (1941), using determined high intensity heat applied to the tail. Each mouse is placed in a narrow metal cylinder, the tail protruding at one end. This cylinder is placed so that the tail lies flat on a hidden heat lamp. At the start of the test, an aluminum cover is removed from the lamp, allowing the light beam to pass through the slit and focus on the end of the tail. A stopwatch is activated simultaneously. The waiting time for a sudden twitch of the tail is determined. Untreated mice usually respond within 3 to 4 seconds after exposure to the lamp. The end point for protection is 10 seconds. Each mouse is tested half an hour and 2 hours after treatment with morphine and the test compound. For morphine, MPE50 is 3.2-5.6 mg / kg subcutaneously.

35

Test using chemical nociceptive stimuli Suppression of phenylbenzoquinone-induced convulsions

Groups of 5 Carworth Farms CF-1 mice are treated beforehand, subcutaneously or orally with a saline solution, morphine, codeine or with the test compound. Twenty minutes after (if treated subcutaneously) or fifty minutes after (if treated orally), each group is treated by intraperitoneal injection of phenylbenzoquinone, an irritant that produces abdominal contractions. The mice are observed for 5 minutes to determine the presence or absence of the convulsions starting 5 minutes after the injection of the irritant. The MPE5 () which is given by the pretreatment with the drug with regard to the blocking of convulsions are determined.

50

The results of the previous tests are recorded as the percentage of the maximum possible effect (% MPE). The% MPE of each group is statistically compared to the% MPE of the reference product and the pre-drug control. The% 55 MPE is calculated as follows:

„Duration of test - duration of witness

% MPE = - ^ ———; : - X 100

stop time - duration of witness

In the tables below, the analgesic activity is given as 60-MPE5 values (1, dose at which half of the maximum possible analgesic effect is observed in a given test.

The compounds of formula I are active analgesics by oral and parenteral administration and are conveniently administered in the form of a composition. Such com-65 compositions take a pharmaceutical carrier chosen according to the intended route of administration and conventional pharmaceutical use. For example, they can be administered in the form of tablets, pills, powders or granules containing excipients such as

13

626,881

starch, lactose, certain types of clay, etc. ... They can be administered in capsules, in mixtures with the same or equivalent excipients. They can also be administered in the form of suspensions, solutions, emulsions, syrups and elixirs intended for the oral route, which may contain flavoring and coloring agents. For oral administration of these therapeutic agents, tablets or capsules containing from about 0.01 to about 100 mg are suitable for most applications.

The attending physician will determine the dose that will best suit the particular patient, and this dose will vary with the age, weight and reaction of the particular patient and the route of administration. However, in general, the initial analgesic dose in adults can range from 0.01 to 500 mg / day, in a single dose or in several separate doses. In most cases, it is not necessary to exceed 100 mg / day. The preferred oral dose range is about 0.01 to about 300 mg / day; the preferred dose is from about 0.10 to about 50 mg / day. The preferred parenteral dose is from about 0.01 to about 100 mg / day, the preferred range is from about 0.01 to about 20 mg / day.

The analgesic activity of several compounds obtained according to the invention and of certain compounds of the prior art has been determined using the preceding procedures.

The following abbreviations are used in the tables:

PBQ = phenylbenzoquinone-induced convulsion; TQ = wincing of the tail; PC = hot plate.

Table I

Analgesic activity (MPES0-mg / kg, s.c.) x = hydrochloride + = 9cc-OH

r

Ri r4

R5

Rfi z-w

6a, 10a bpq tq pc h

h ch3

h h

-0-ch (ch3) c5hn cis / trans

1.05

1.32

10-32

h

COCH3

ch3

h h

-0-ch (ch3) c5hn trans

1.0-1.76

1.0

5.6

h

COCH3

ch3

h h

-0-ch (ch3) c5hn trans *

100 to 10

5.6

5.6

h h

ch3

h h

-0-ch (ch3) c5h1!

trans

0.5

3.2

10

cochj

COCH3

ch3

h h

-0-ch (CH3) c5hh trans

1.78-3.2

10

> 10

coch3

COCH3

ch3

h h

-och (CH3) c5hh trans *

<10

5.6-10

> 10

h h

ch3

h

COCH3

-0-ch (CH3) c5hu trans

> 10

> 10

> 10

COCH3

COCH3

ch3

h ch,

-0-ch (CH3) c5hh trans

100 to 10

1-3.2

3.2-5.6

h h

ch3

h h

-0-ch (ch3) (ch2) 3c6h5

trans

0.1-0.56

1-3.2

1-3.2

h

COCH3

ch3

h h

-0-ch (ch3) (ch2) 3c6h5

trans*

0.25

0.42

1-3.2

h

COCH3

ch3

h h

-0-ch (ch3) (ch2) 3c6h5

eis

0.56-1.0

1-3.2

3.2-10

h h

ch3

h qh5

-och (CH3) c5hu trans

0.09

h

COCH3

h h

h

-och (CH3) csh! !

trans

10

> 10

> 10

h

COCH3

ch3

h ch3

-och (ch3) (ch2) 3c6h5

trans*

0.05

h

COCH3

h h

h

-och (ch3) (ch2) 3c6h5

trans

0.83

h coch-j h

h ch3

-och (ch3) (ch2) 3c6h5

trans

0.1

0.32-0.56

0.56-1.1

h

COCH3

h h

ch3

-och (CH3) c5hu trans

100 to 3.2

100 to 10

<10

morphine

0.8

3.2-5.6

4.0-5.6

h

COCH3

n-C3H7

h h

-0-ch (ch3) (ch2) 3c6h5

trans*

0.14

0.34

h coch3

n-C3H7

h h

-0-ch (ch3) (ch2) 3c6h5

eis *

0.12

0.44

0.61

h coch3

ch3

h

H

-0-ch (ch3) (ch2) 3c6h5

trans (a)

0.14

0.26

h

COCH3

ch3

h h

-0-ch (ch3) (ch2) 3c6h5

trans (b)

7.40

h oh ch3

h c2h5

-0-ch (ch3) (ch2) 3c6h5

trans*

0.21

1.47

3.64

h oh ch3

h

(ch2) 2c6h5

-0-ch (ch3) (ch2) 3 c6h5

trans

14.33

h oh ch3

h

(ch2) 3c6h5

-o-ch (ch3) (ch2) 3c6h5

trans

29 to 10

a) 6S, 6aR, 9R, IOaR b) 6R, 6aS, 9S, lOaS

626,881

14

Table H

Inhibition of the binding of 3H-dihydromorphine to opiate receptors by benzo [c] quinolines of the following formula at a concentration of 10 "4:

MP-M

•HA

r ri r4

r5

r6

rH

z-w

HA

Inhib

ß-OH

coch3

ch3

H

H

a-h

at

HCl

31

ß-OH

coch3

ch3

H

H

ß-H

at

HCl

59

ß-OH

h ch3

H

h a-H

at

HCl

20

ß-OH

coch3

ch3

h ch3

a-h

at

HCl

12

ß-OH

coch3

H

h h

a-h

at

-

9

ß-OH

coch3

ch3

h h

a-h

b

HCl

19

ß-OH

coch3

ch3

h ch3

a-h

b

-

11

a-OH

coch3

H

h ch3

a-h

at

HCl

44

ß-OH

co (c2) 3-piperidino ch3

h h

a-h

at

2hc1

78

ß-OH

coch3

h ch3

h a-H

at

HCl

19

a-OH

coch3

ch3

h h

ß-H

at

HCl

35

ß-OH

coch3

n-C3H7

H

H

a-h

at

HCl

28

ß-OH

coch3

n-C3H7

H

H

ß-H

at

HCl

23

ß-OH

H

ch3

H

(ch2) 3c6h5

a-h

at

HCl

-3

ß-OH

H

ch3

H

n-C3H7

a-h

at hcl

19

ß-OH

H

ch3

H

n-C6Hi3

a-h

at

HCl

4

ß-OH

H

ch3

H

n-C5Hn a-H

at

HCl

19

ß-OH

H

ch "3

H

(CH2) 4C6H5

a-h

at

HCl

-4

ß-OH

H

ch3

H

n — CjHy a-H

at

HCl

7

ß-OH

H

ch3

H

CH3

a-h

at

HCl

8

ß-OH

coch3

c2h5

h

H

a-h

at

HCl

53

ß-OH

coch3

n-C6Hi3

H

H

a-h

at

HCl

9

a-OH

coch3

ch3

H

CH3

a-h

at

HCl

52

ß-OH

coch3

ch3

H

ch3

ß-H

at

HCl

39

ß-OH

coch3

(ch2) 2c6h5

H

H

a-h

at

HCl

3

ß-OH

COCH2) 2COOH

ch3

H

H

a-h

at

HCl

17

ß-OH

coch3

ch3

H

H

a-h

vs

HCl

9

ß-COCH3

coch3

ch3

H

H

~ H

vs

-

-5

ß-CH2OH

H

ch3

H

QH5

a-h

at

HCl

23

a-CH2OH

H

ch3

H

W

a-h

at

HCl

27

a-CH2OH

H

ch3

H

COCH3

a-h

at

-

44

ß-CH2OH

H

ch3

H

COCH3

a-h

at

-

89

a-CHiOH

H

ch3

H

COCH3

ß-H

at

-

89

ß-CH2OH

H

ch3

H

coch3

ß-H

at

-

88

ß-OH

coch3

n — C5Hh

H

H

a-h

at

HCl

21

ß-OH

coch3

n-C4H9

H

H

a-h

at

HCl

25

a-CH2OH

coch3

ch3

H

c2h5

ß-H

at

HCl

45

ß-OH

coch3

H

n-C4H9

H

a-h

at

18

-OH

COCHJ

ch3

H

H

-H

ai i in

38

-OH

COCH,

ch3

H

H

-H

a2

HCl

40

-coch3

H

ch3

H

COCH3

-H

at

-

66

-OH

H

ch3

H

COCH3

-H

at

-

70

morphine sulfate

92 *

levorphenol tartrate

100 *

a = Z-W = -OCH (CH3) (CH2) 3-CftH5; b = Z-W = -0 (CH2) 4-C6H5; c = Z-W = —0 (CH2) 3-C6H5; a, = "A" diastereomer of Z — W = a; a2 = diastereomer "B" of Z-W = a; * concentration = 10 ~ 3

15

626,881

Ri

R4

RÄ

Rfi

Z-W

6a, 10a pbq tq pc h

ch,

h h

-0 ~ ch (ch3) c5h ,,

cis / trans

3.2

coch,

chì

h h

-0 ~ ch (ch3) c5h1!

eis

100 to 10

coch,

ch3

h h

-0-ch (ch3) c5hn trans

10

> 10

> 10

coch,

ch3

h

COCH3

-0-ch (ch3) c5hn trans

> 10

> 10

> 10

h ch3

h ch3

-0-ch (ch3) c5hu trans

100 to 10

-10

-10

coch3

ch3

h h

-0-ch (ch3) (ch2) 3c6h5

eis

0.1-0.56

3.2-5.6

10

coch,

ch3

h h

-0-ch (ch3) (ch2) 3c6h5

trans

1.78

2.4

<10

COCH3

h h

ch3

-0-ch (ch3) c5h1,

trans

100 to 10

coch,

h h

h

-0-ch (ch3) (ch2) 3c6hs trans

100 to 10

1.0-3.2

> 10

COCH3

h h

h

-0-ch (ch3) (ch2) 3c6h5

eis

100 to 28

coch,

ch,

h h

-0-ch (ch3) (ch2) 3c6h5

eis *

0.31

3.9

h ch3

h

COCH3

-0-ch (CH3) c5hu trans

> 10

> 10

coch,

h h

h

-0-ch (CH3) c5hu trans

> 10, -56

> 10

COCH3

ch3

h coc6h5

-0-ch (ch3) c5h [i trans

> 10

h ch,

h coc6h5

-och (ch3) c5hn trans

> 10

COCH3

ch3

H

ch3

-0-ch (ch3) (ch2) 3c6h5

trans*

0.17

coch,

H

h ch,

-0 ~ ch (ch3) (ch2) 3c6h5

trans

2.07

<5.6

coch,

n-c3H7

H

h '

-0-ch (ch3) (ch2) 3c6h5

trans*

0.38

2.37

83 to

COCH3

n-c3H7

h h

-0-ch (ch3) (ch2) 3c6h5

eis *

0.16

1.76

COCH3

ch3

h h

-0-ch (ch3) (ch2) 3c6h5

cis * (a>

25 to 10

COCH3

ch3

H

h

-0-ch (ch3) (ch2) 3c6h5

CÌs * (b)

0.62

COCH3

ch3

h h

-0-ch (ch3) (ch2) 3c6h5

trans * (a '

2.11

COCH3

ch3

H

H

-0-ch (ch3) (ch2) 3c6h5

trans * (b)

7.28

COCH3

c2h5

h

H

-0-ch (ch3) (ch2) 3c6h5

eis

0.17

0.78

1.62

COCH3

c6h, 3

H

h

-0-ch (ch3) (ch2) 3c5h5

trans

35 to 10

COCH3

c2h5

H

H

-0-ch (CH3) (ch2) 3c6hs trans *

1.60

COCH3

c6h, 3

H

H

-0-ch (ch3) (ch2) 3c5h5

eis

21 to 10

COCH3

(CH2) 2h6hs h

H

-o-ch (ch3) (ch2) 3c6h5

trans

100 to 10

COCH3

(ch2) 2c6h5 h h

-0-ch (ch3) (ch2) 3c6h5

eis

34 to 10

COCH3

ch3

h h

-0 (ch2) 3c6h5

trans

22 to 56

COCH3

ch3

h

H

-o (ch2) 3c6h5

eis

12 to 56

coch,

c5h „

h h

-o-ch (ch3) (ch2) 3c6h5

trans

14 to 10

COCH3

C5Hu h

H

-o-ch (ch3) (ch2) 3c6h5

eis

14 to 10

COCH3

c4h9

h h

-o-ch (ch3) (ch2) 3c6h5

trans

4.36

COCH3

c4h9

h h

-o-ch (ch3) (ch2) 3c6h5

eis

16 to 10

(a) = 6S, 6aR, 9R, IOaR

(b) = 6R, 6aS, 9S, lOaS

Their antihypertension usefulness is determined by their ability to lower the blood pressure of conscious hypertensive rats and dogs to a statistically significant degree when administered orally to hosts at the above doses.

Their tranquilizing activity is demonstrated by oral administration to rats at doses of about 0.01 to 50 mg / kg, with subsequent decreases in spontaneous motor activity. The daily dose for mammals is approximately 0.01 to approximately 100 mg.

The usefulness of these compounds for the treatment of glaucoma is believed to be due to their ability to reduce intraocular pressure. Their effects on intraocular pressure are determined

55 by tests on dogs. The test drug is instilled into a dog's eye as a solution or is given generally at various times, after which the eye is anesthetized by instillation of tetracaine hydrochloride, 0.5 %, 2 drops. A few minutes after this lo-60 wedge anesthesia, intraocular pressure measurements are made with a mechanical Schiotz tonometer, and after administration of fluorescein with a tonometer with manual Holberg application. The test drug is conveniently used in a solution like the following: test drug (1 mg), ethanol 65 (0.05 ml), Tween 80 (polyoxyalkylene derivative of sorbitan mono-oleate, available from Atlas Powder Co., Wil-mington, Delaware 19 899, USA) (50 mg) and saline (to make 1 ml), or in a more concentrated solution where

626,881

16

the ingredients are present in the respective proportions of 10 mg, 0.10 ml, 100 mg and 1 ml. For use in humans, drug concentrations of 0.01 mg / kg to 10 mg / kg can be used.

Their activity as diuretic agents is determined by the procedure of Lipschitz et al., J. Pharmacol., 79.97 (1943) which uses rats as test animals. The dose interval for this use is the same as that indicated above for the use of the compounds described here as analgesic agents.

Preparation A

dl-3- (3,5-dimethoxyaniline) ethyl butyrate

A mixture of 95.7 g (0.624 mole) of 3,5-dimethoxy-aniline, 87.2 ml (0.670 mole) of 535 ml ethyl acetoacetate is heated at reflux for 15 hours under a nitrogen atmosphere. and 3.3 ml of glacial acetic acid, and the water is collected using a Dean-Stark trap. The reaction mixture is cooled to room temperature, it is discolored with activated carbon, it is filtered and then it is concentrated under reduced pressure, which gives the product, 3- [3,4-dimethoxy) anilino] - Ethyl 2-butenoate, in the form of an eight (168.7 g).

A mixture of ethyl 3- (3,5-dimethoxyanilino) -2-buté-noate (5.0 g, 18.7 mmol) is hydrogenated in a Parr stirrer at 3.5 kg / cm 2 for 1.5 hours. ) in 42 ml of glacial acetic acid and 250 mg of platinum oxide. The reaction mixture is filtered through a filter aid, 50 ml of benzene are added and the solution is concentrated under reduced pressure to an oil. The oil is taken up in chloroform, the solution is washed successively with a saturated sodium bicarbonate solution (2 × 50 ml) and a saturated sodium chloride solution. Then it is dried over MgSO 4, filtered and concentrated under reduced pressure, which gives the product in the form of an oil (5.1 g).

The repetition of the previous procedure but using 168.7 g of ethyl 3- (3,5-dimethoxyanilino) -2-butenoate, 320 ml of glacial acetic acid and 2.15 g of platinum oxide gives 160 , 8 g of product.

Preparation B

dl-3- (3,5-dimethoxyanilino) ethyl butyrate

To a solution of 370 g (1.45 mole) of 3,5-dimethoxyaniline hydrochloride, 4.51 of reactive methanol and 286.3 g (2.64 moles) of ethyl acetoacetate in a flask 12-liter round bottom, with 3 tubes, equipped with a mechanical stirrer and a reflux condenser, 54 g (0.76 mole) of sodium cyanoborohydride are added at once. Once reflux has resumed (10 min), the mixture is heated on a steam bath for an additional 20 minutes. To the cooled reaction mixture, 5.4 g (0.07 mole) of additional sodium cyanoborohydride and 28.6 g (0.26 mole) of ethyl acetoacetate are added and the mixture is refluxed for 30 minutes. This last operation is repeated once more.

The reaction mixture is isolated in portions by pouring approximately 500 ml into 1 liter of ice water mixed with 500 ml of methylene chloride, separating the layers and washing the aqueous phase in return with an additional 100 ml of methylene chloride. This process is repeated using 500 ml portions until the entire reaction mixture is processed.

The methylene chloride layers are combined and dried over MgSO4, they are discolored with charcoal, filtered and evaporated to give a yellow oil.

The excess ethyl acetoacetate is distilled at an oil bath temperature of 130 ° C. and a pressure of 1-5 mm, which leaves 376 g (72% yield) of 3- (3.5 -dimethoxyanilino) crude ethyl butyrate which is a viscous oil of amber color which is used without further purification.

The compound has the following spectral characteristics:

1 H NMR (60 MHz (ppm): 5.82-6.0 (m, 3H, aromatics), 4.20 (q, 2H, methylene ester), 3.80-4.00 ( m, 2H, -NH and N-CH-CHj), 3.78 (s, 6H, -OCH3), 2.40-2.55 (m, 2H, 5 -CH2COOEt), 1.78 (d, 3H , methyl) and 1.29 (t, 3H, methyl).

Preparation C

dl-3- (3,5-dimethoxyanilino) ethyl hexanoate

Following the procedure of preparation B, the conio densation of 3,5-dimethoxyaniline hydrochloride and ethyl buty-rylacetate gives ethyl d, l-3- (3,5-dimethoxyanilino) hexa-noate . It is converted into the hydrochloride by addition of hydrogen chloride to a solution of this compound in methylene chloride; m.p. 127-129.5 ° C. Recrystallization from a 5: 1 mixture of cyclohexane and benzene gives the analytical sample, m.p. 126-128.5 ° C.

Analysis: Calculated for C16H2504N.HC1:

C, 57.91; H, 7.90; N, 4.22%

20Found: C, 57.89; H, 7.74; N, 4.40%

m / e-295 (m +)

'H NMR (60 MHz) ôgfë ,, (ppm): 10.76-11.48 (wide, variable, 2H, NH2 +), 6.77 (d, J = 2Hz, 2H, H in meta), 6, 49, 25 6.45 (d of d, J = 2Hz, 1H, H in meta), 4.08 (q, 2H, OCH2), 3.77, (s, 6H, [OCH3] 2), about 3 , 5-4.8 (m, 1H, CH-N), 2.90 (t, 2H, CH2-C = 0), about 1.4-2.2 (m, 4H, [CH2] 2), 1.21 (t, 3H, 0-C-CH3), 0.84 (t, 3H, -C-CH3).

30 Preparation D

d, 1-3- [3,5-dimethoxy-N-ethoxycarbonyl) anilino] ethyl butyrate

Method A -

71.4 ml (0.75 mole) of ethyl chloroformate are added dropwise over 45 min to a mixture of 159.8 g (0.598 mole) of ethyl 3- (3,5-dimethoxyanilino) butyrate , 100 ml of methylene chloride and 5 ml (1.24 mole) of pyridine at 0 ° C. under a nitrogen atmosphere. The mixture is stirred for 40 min after the addition of ethyl chloroformate and then poured into a mixture of 750 ml of chloroform and 500 ml of ice water. The chloroform layer is separated, washed successively with 10% hydrochloric acid (3 X 500 ml), a saturated solution of sodium bicarbonate (1 X 300 ml) and an aqueous saturated solution of sodium chloride (IX 400 ml) and then dried over MgS04. It is then discolored with activated charcoal and concentrated under reduced pressure to an oil (215 g). We use the product as is.

Method B

50 Under a positive nitrogen atmosphere, a mixture of 376 g (1.4 mole) of ethyl 3- (3,5-dimethoxyanilino) butyrate is stirred and cooled in an ice bath at 0-5 ° C. 1.41 methylene chloride and 388.8 g (2.81 moles) anhydrous potassium carbonate. 153 g (1.41 mole) of 55 ethyl chloroformate are added all at once. The mixture is allowed to warm to room temperature in one hour, another 153 g (1.41 mole) of ethyl chloroformate is added and the mixture is heated at reflux in a steam bath for 1 hour. Then allowed to cool to room temperature and the potassium carbonate is removed by filtration. The red filtrate is successively washed with water (2 X 1000 ml), brine (IX 500 ml), dried over MgSO 4 then it is discolored and evaporated under reduced pressure, which gives 439 g of crude product which is used without further purification. 65 'H NMR (60 MHz) (ppm): 6.2-6.42 (m, 3H, aromatic), 4.65 (sextet, 1H, -N-CH-, CH3), 4.10-4, 15 (2 quarts, 4H, methylene ester), 3.70 (s, 6H, -OCH3), 2.30-2.60 (m, 2H, -CH, COOEt), 1.00- 1.40 (m, 9H, 3 methyls).

17

626,881

Preparation E

Acid d, 1-3 [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] butyri-que

Method A -

202 g (0.595 mol) of ethyl 3 - [(3,5-dimethoxy-N-ethoxy-carbonyl) anilino] butyrate, 595 ml of aqueous sodium hydroxide are combined and stirred at room temperature overnight. IN and 595 ml of ethanol. The reaction mixture is concentrated to a volume of approximately 600 ml under reduced pressure, the concentrate is diluted with water to a volume of 1200 ml and extracted with ethyl acetate (3 X 750 ml ). Then the aqueous layer is acidified with 10% hydrochloric acid to pH 2 and extracted again with ethyl acetate (3 X 750 ml). These latter extracts are combined, washed with brine, dried over MgSO 4, filtered and concentrated in vacuo, which gives the title product in the form of an oil (163.5 g, 88 , 2%).

Analysis: Calculated for C25H3607N2:

C, 63.00; H, 7.61; N, 5.88%

Found: C, 62.87; H, 7.64; N, 5.88%

s MD = - 43.5 ° (c = 1.0, CHCy.

The J_-ephedrine salt of the _1 isomer is stirred in a mixture of 1000 ml of ethyl acetate and 4001 of 10% hydrochloric acid for 10 minutes. The organic phase is separated, washed with 10% hydrochloric acid (2 X 400 ml), dried and concentrated under reduced pressure to an oil. Crystallization of the oil in 400 ml of a 1: 1 mixture of ethyl acetate and hexane provides 34.6 g of l_-3 - [(3,5-dimethoxy-N-ethoxycarbonyl acid) ) anilino] butyric, pf 96-97 ° C.

15

Analysis: Calculated for C15H2106N:

C, 57.86; H, 6.80; N, 4.50%

Found: C, 57.90; H, 6.66; N, 4.45%

Method B -

Is introduced into a round bottom flask with three tubes, 5 liters, equipped with a mechanical stirrer and a reflux condenser, a solution of 439 g (1.41 mole) of 3 - [(3,5- ethyl dimethoxy-N-ethoxycarbonyl) anilino] butyrate in 21 ethanol. 21 IN sodium hydroxide is added and the mixture is heated to reflux on a steam bath for 3 hours. The reaction mixture is poured into ice-cold water and extracted in portions of 11 with diethyl ether (500 ml per portion). The aqueous layer is cooled by adding approximately 11 ice and then acidifying with concentrated hydrochloric acid (1.75 ml, 2.1 moles). It is extracted in portions of 11 with methylene chloride (250 ml per serving). The methylene chloride layers are combined and dried over magnesium sulfate, discolored with charcoal and evaporated to dryness, giving a viscous yellow oil. Crystallization from a 1: 2 mixture of ether and cyclohexane provides 224 g (55.3%) of the crystalline product, m.p. 78-80 ° C. This substance is used without further purification in the next step.

'H NMR (60 MHz) ô $ ^ i, (ppm): 6.24-6.53 (m, 3H, aromatic), 4.65 (sextet, 1H, —N (COOC2H5) CH (CH3) CH2COO, H5), 4.10 (quartet, 2H, methylene ester), 3.78 (s, 6H, -OCH3), 2.40-2.60 (m, 2H, -CH2COOH), 1.18 ( t), 1.28 (d, 6H, methyl), 10.8 (broad s, variable, 1H, COOH).

MS (molecular ion) m / e - 311.

An analytical sample obtained by recrystallization from a 1: 5 mixture of ethyl acetate and hexane melts at 89-91 ° C.

Analysis: Calculated for C | 5H2106H:

C, 57.86; H, 6.80; N, 4.50%

Found: C, 58.08; H, 6.65; N, 4.46%

Preparation F

D- and 1—3 [(3,5-dimethoxy-4-N-ethoxycarbonyl) anilino] -butyric acids

Dissolve in 500 ml of methylene chloride a mixture of d, l-3-f (3,5-dimethoxy-N-ethoxycarbonyl) anili-no] butyric acid (136.6 g, 0.44 mole) and 1 ^ -ephedrine (72.5 g, 0.44 mole). Then the methylene chloride is removed in vacuo to obtain the l_-ephedrine salt of d, l-3 - [(3,5-di-methoxy-N-ethoxycarbonyl) -anilino] butyric acid as a oil, [0J55 = - 20.0 0 (c = 1.0, CHC13). The addition of 1500 ml of ether causes the crystallization of a white solid which is separated by filtration and which is dried, 102 g, m.p. 114 ° - 116 ° C. Recrystallization from a 1: 1 mixture of ethyl acetate and hexane provides 71.1 g (34%) of the L-ephedrine salt of IL-3 - [(3,5-dimethoxy-N -ethoxycarbonyl) -anilino] bu-tyric; m.p. 126-127 ° C.

20 [a] o = - 25.4 0 (c = 1.0, CHC13).

The remaining mother liquor of the recrystallization of the 1-ephedrine salt of the isomer 1 is treated with hydrochloric acid as described above, to obtain d-3 - [(3,5-dimethoxy-N- ethoxycarbonyl) crude butyric. Treatment of the crude acid with d-ephedrine gives, after crystallization from ether, the d-ephedrine salt of the d isomer, m.p. 124-125 ° C.

Analysis: Calculated for C25H3607N2:

C, 63.00; H, 7.61; N, 5.88%

Found: C, 62.82; H, 7.47; N, 5.97%

[aß5 = +44.0 0 (c = 1.0, CHCI3).

The salt of d-ephedrine is converted into d-3 - [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] butyric acid in the same manner as described above for the transformation of the salt of 1-ephedrine into free acid, pf 96-97 ° C after recrystallization from a 3: 5 mixture of ethyl acetate and hexane.

Analysis: Calculated for C15H2106N: 40 C, 57.86; H, 6.80; N, 4.50%

Found: C, 57.95; H, 6.57; N, 4.35%

[cxF = +25.3 0 (c = 1.0, CHCIj).

45 Preparation G

3- (3,5-dimethoxyanilino) methyl propionate

A mixture of 3,5-dimethoxyaniline (114.9 g, 0.75 mole), methyl acrylate (69.73 g, 0.81 mole) and 2 ml of acid is heated at reflux for 20 hours. glacial acetic. The reflux is stopped and the reaction mixture is concentrated and then distilled under vacuum, which gives 106.8 g (73.9%) of the title product, mp 174-179 ° C (0.7 mm).

'H NMR (60 MHz ôj ^ / ppm): 5.62-5.95 (m, 3H, aromatic), 4.1 (variable, s broad, 1H, -NH), 3.74 (s, 6H , 55 -OCH3), 3.68 (s, 3H, COOCH3), 3.41 and 2.59 (two triples of 2H, -NCH2CH2CO2).

Preparation H

rf, 7-J - {[3-hydroxy-5- (5-phenyl-2-pentyl)] anilino} methyl propionate 60

Heated to 106-110 ° C overnight a mixture of 1.0 g of 3-hydroxy-5- (5-phenyl-2-pentyl) aniline, 345 mg of methyl acrylate and 0.1 ml acetic acid. The cooled residue is dissolved in 100 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution. The organic phase is then dried over MgSO 4 and evaporated to a crude residue which is chromatographed on 130 g of silica gel using a 2: 1 mixture of benzene and

626,881

18

ether as eluent. After elution of the less polar impurities, 540 mg (40%) of d, l-3 - {[3-hydroxy-5- (5-phenyl-2-pentyl)] anilino} propionate are collected. This product has the following spectral characteristics:

'H NMR (60 MHz) òj ™, (ppm): 7.14 (s, 5H, aromatic), 5.83-6.13 (m, 3H, aromatic), 3.66 (s, 3H, -CO -OCH3), 3.37 (t, 2H, -NCH2), 2.16-2.78 (m, 5H, -CH2COO and benzyl), 1.28-1.69 (m, 4H, - (CH2) 2-), 1.11 (d, 3H, X'HO, 4.4-5.2 and 1.28-2.78 (variable, IH, NH, OH), m / e - 341 (m +)

Preparation Gl a) 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] methyl propionate

2.0 g (8.4 mmol) of ethyl chloroformate is added dropwise over 10 minutes to a mixture of 1.0 ml (10.5 mmol) of 3- (3.5- dimethoxyanilino) methyl propionate, 5 ml of methylene chloride and 5 ml of pyridine at 0 ° C. under a nitrogen atmosphere. The mixture is stirred at 0 ° C for 20 min after the addition of ethyl chloroformate and then at room temperature for an additional 20 min, and is then poured into a mixture of 75 ml of methylene chloride and 50 ml of ice water. The methylene chloride layer is separated, washed successively with 10% hydrochloric acid (2 X 50 ml), a saturated aqueous solution of sodium bicarbonate (1 X 30 ml) and an aqueous solution saturated with sodium chloride (1 X 40 ml) and dried over MgSO4.

Then it is discolored with activated charcoal and concentrated under reduced pressure to an oil (2.72 g). We use the product as is. 30

b) 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] -propionic acid

2.72 g (8.36 mmol) of 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) aniino] methyl propionate, 8.4 ml of IN aqueous sodium hydroxide and 8.4 ml of ethanol and stirred overnight under nitrogen at room temperature. Then the reaction mixture is concentrated under reduced pressure to half volume, diluted with 35 ml of water and extracted with ethyl acetate. The aqueous phase is acidified to pH 2 with 10% hydrochloric acid and extracted with methylene chloride (3 X 50 ml). The combined extracts are washed with brine, dried over MgSO4 and concentrated, giving the product in the form of an oil (2.47 g) which is used as it is.

c) l-carbethoxy-5,7-dimethoxy-4-oxo-1,2,3,4-tetrahydroquino-45 leine

Heated at 65 ° C for 45 minutes under a nitrogen atmosphere a mixture of 1.10 g (3.7 mmol) of 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] propionic acid and 4 g of polyphosphoric acid and then cooled to 0 ° C. It is then taken up 50 in 200 ml of a 1: 1 mixture of methylene chloride and water. The organic layer is separated and the aqueous phase is extracted again with methylene chloride (2 X 100 ml). The combined extracts are washed with saturated sodium bicarbonate solution (3 X 100 ml), brine (1 X 100 ml) and then dried over MgSO 4. The concentration of the dried extract gives the product in the form of an oil which crystallizes from benzene. 645 mg are obtained, m.p. 109—111 ° C.

to a dark oil. The oil is dissolved in 50 ml of water and the aqueous solution is neutralized to pH 6-7 with IN sodium hydroxide. 50 ml of a saturated salt solution in water are added and the resulting mixture is extracted with ethyl acetate (3 X 150 ml). The extracts are combined, dried over MgSO4 and concentrated under reduced pressure to an oil. The oil is taken up in a 1: 1 mixture of benzene and ethyl acetate and the solution is loaded into a column of silica gel. The column is eluted with a volume of benzene equal to 10 volume of the column and then with 250 ml of a 4: 1 mixture of benzene and ethyl acetate then 250 ml of a 2: 1 mixture of benzene and d 'ethyl acetate. 75 ml fractions are collected. Fractions 4 to 9 are combined and evaporated under reduced pressure. The oily residue is crystallized from a 1:10 mixture of ethanol and hexane. 1.86 g, m.p. 166-169 ° C.

Subsequent recrystallization raises the melting point to 171-172.5 ° C.

m / e -179 (m +)

Analysis: Calculated for C9H9O3N:

C, 60.33; H, 5.06; N, 7.82%

Found: C, 60.25; H, 4.94; N, 7.55%

Preparation I

d, l-l-carbethoxy-5,7-dimethoxy-2-methyl-4-oxo-l, 2,3,4-tetra-hydroquinoline

A solution of 4.0 g (12.8 mmol) of 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] -butyric acid in 2 ml of 5.0 chloroform is added dropwise with stirring. g of polyphosphoric acid heated to 60 ° C on a steam bath. The reaction mixture is kept at 60-65 ° C for 2 hours and then poured into a mixture of 100 g of ice and 100 ml of ethyl acetate. The aqueous layer is then extracted with ethyl acetate (2 X 100 ml) and the combined organic extracts are washed successively with saturated sodium bicarbonate solution (3 X 100 ml), brine (1 X 100 ml ) then it is dried over anhydrous magnesium sulfate. The concentration under reduced pressure of the dried extract gives 2.6 g of crude product.

The purification is carried out by column chromatography of a benzene solution of 2.5 g of the product, on 95 g of silica gel. The column is eluted with a volume of benzene equal to half the volume of the column, then with a 1: 1 mixture of benzene and ethyl acetate. 40 ml fractions are collected. The fractions are combined 9:18 and evaporated under vacuum, which gives 1.55 g of the product which is then purified by recrystallization from petroleum ether, 1.33 g, m.p. 92.5-94 ° C.

Recrystallization of this product from a hot 1: 1 mixture of ethyl acetate and hexane provides an analytical sample; m.p. 94-95 ° C.

55

Analysis: Calculated for C15H1905N:

C, 61.42; H, 6.53; Found: C, 61.54; H, 6.55;

m / e-293 (m +)

IR (KBr) - 5.85.5.95 ^ - () = 0)

N, 4.78% N, 4.94%

Analysis: Calculated for C14H1705N:

C, 60.21; H, 6.14; N, 5.02%

Found: C, 60.11; H, 6.14; N, 4.80%

a) 5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline

A mixture of 60 ml of glacial acetic acid, 60 ml of 48% hydrobromic acid and 4.0 g (14.3 mmol) of l-carbethoxy-5,7-dimethoxy is heated at reflux overnight. -4-oxo-1,2,3,4-tetrahydroquinoline then concentrated in vacuo

60

65

Preparation J

d, 1-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquino-leine

Method A -

A mixture of 240 ml of glacial acetic acid, 240 ml of 48% hydrobromic acid and 16.0 g (55 mmol) of 1-carbethoxy-5,7-dimethoxy-2 is heated at reflux overnight. -methyl-4-oxo-1,2,3,4-tetrahydroquinoline then concentrated in vacuo to a dark oil. The oil is dissolved in 200 ml of water and the aqueous solution is neutralized to pH 6-7 with IN sodium hydroxide. Add a saturated solution

19

626,881

salt in water (200 ml) and the resulting mixture is extracted with ethyl acetate (3 X 500 ml). The extracts are combined, dried over MgSO 4 and concentrated under reduced pressure to a dark oil (12.8 g). A 10: 1 mixture of hexane and ethyl acetate is added to the oil and the resulting crystals are collected by filtration, 3.8 g, m.p. 158-165 ° C. Trituration of the crystals in ethyl acetate gives 1.65 g of product, m.p. 165-168 ° C.

Additional material separates from the mother liquors by standing (2.9 g, mp 168-170 ° C). Chromatography of the filtrate on a silica gel column using a 1: 1 mixture of benzene and ether as solvent gives an additional 4.6 g of product, m.p. 167—169 ° C.

Further purification is obtained by recrystallizing the product from ethyl acetate; m.p. 173—174 ° C.

Analysis: Calculated for C10HnO3N:

C, 62.16; H, 5.74; N, 7.25%

Found: C, 62.00; H, 5.83; N, 7.14%

m / e -193 (m +)

Method B -

Heated in an oil bath at 110 ° C for 2 hours a mixture of 100 g (0.32 mole) of d, 1-3-f (3,5-dimeth-oxy-N-ethoxycarbonyl) anilino acid ] butyric acid, 500 ml of 48% hydrobromic acid and 300 ml of glacial acetic acid. Then the temperature of the oil bath is raised to 145 ° C. and the heating is continued for an additional 2 hours. During this last heating period, an azeotropic mixture distills (boiling point 42 -> 110 ° C, about 200-300 ml) and the homogeneous dark red solution is allowed to cool to room temperature. The mixture is poured onto water and ice (3 liters) and ether (2 liters), the layers are separated and the aqueous solution is washed with ether (2 X 1000 ml). The ethereal layers are combined and washed successively with water (2 X 1000 ml), brine (1 X 500 ml), saturated NaHCO3 solution (4 X 250 ml) and brine (1 X 500 ml ) and then dried (MgS04). Discoloration with charcoal and evaporation of the ether provides a yellow foam which is recrystallized from approximately 300 ml of methylene chloride, which gives 31.3 g (50.4%) of 5,7-dihydroxy. -2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline pure. More product can be isolated from the mother liquor by silica gel chromatography.

1H NMR (60 MHz) ô ™ s (100 mg of sample / 0.3 ml of CDCl3 / 0.2 ml of CD3SOCD3) (ppm): 12.40 (s, 1H, C5-OH), 5.72 (d, 2H, H in meta), 5.38-5.60 (s, large, 1H, C7-OH), 3.50-4.00 (m IH, C2H), 2.38-2.60 (m, 2H, Qr-H3), 1.12 (d, 3H, methyl).

m / e -193 (m +)

Analysis: Calculated for C10HnO3N:

C, 62.16; H, 5.74; N, 7.25%

Found: C, 62.01; H, 5.85; N, 7.02%

Similarly, the d, 1 -3- {[3-hydroxy-5- (5-phe-nyl-2-pentyl] anilino} propionate is transformed into d, l-5-hydroxy-7- (5-phe- nyl-2-pentyl) -4-oxo-1,2,3,4-tetrahydroquinoline which is purified by column chromatography using silica gel and a 5: 1 mixture of benzene and ether as eluent.

m / e-309 (m +)

'H NMR (60 MHz ôj ^ / ppm): 12.22 (s, IH, OH in 5), 7.14 (s, 5H, C6H5), 6.04 (d, J = 2.5Hz, 1H , H in meta), 5.87 (d, J = 2.5Hz, 1H, H in emta), 4.19 ^, 60 (broad, 1H, NH), 3.48 (t, 2H, CH2H), 2.18-2.89 (m, 5H, ArCH, ArCH2, CH2-C = 0), 1.38-1.86 (m, 4H, - [CH2] 2 -), 1.13 (d, 3H , CH3).

and transform d, l-3- (3,5-dimethoxy-) hydrochloride

anilino) ethyl hexanoate in d, 1 -5,7-dihydroxy-2-propyl-4-oxo-l, 2,3,4-tetrahydroquinoIéine, m.p. 117 ° —119 ° C (in methylene chloride).

m / e —221 (m +), 135 (base peak, m + -propyle).

s and converting l-3 - [(3,5-dimethoxy- (N-ethoxycar-bonyl) anilino) butyric acid into d-5,7-dihydroxy-2-methyl-4-oxo-1,2, 3,4-tetrahydroquinoline, mp 167—168 ° C.

[a] o = +167.8 ° (c = 1.0, CH3OH).

m / e -193 (m +)

10

Analysis: Calculated for Ci0HnO3N:

C, 62.16; H, 5.74; N, 7.25%

Found: C, 61.87; H, 5.62; N, 6.96%

15 and transform d-3- [3,5-dimethoxy-N-ethoxycar-bonyl) -anilino] butyric acid into l_-5,7-dihydroxy-2-methyl-4-oxo-1,2,3 , 4-tetrahydroquinoline; m.p. 166 ° —168 ° C. [a] ß5 = - 168.5 ° (c = 1.0, CH3OH).

m / e _ 193 (m +)

20

Analysis: Calculated for C10HnO3N:

C, 62.16; H, 5.74; N, 7.25%

Found C, 61.82; H, 5.83; N, 7.22%

25 Preparation K

a) d, 1 -5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquino-leine

A) A mixture of 230 g (1.5 mole) of 3,5-dimethoxyaniline, of 150 (1.5 mole) of

30 methyl crotonate and 90 g (1.5 mole) of galcial acetic acid. An additional 90 g of glacial acetic acid is added and the mixture is heated under reflux overnight. 1000 ml of a 48% hydrobromic acid solution and 850 ml of glacial acetic acid are added to the reaction mixture which is heated

35 at reflux for 4 h V2. The title product is isolated and purified according to the procedure of Example 12. 36 g, m.p. 166-170 ° C.

B) A mixture of 4.6 g (0.03 mole) of 3,5-dimethoxyaniline, of 2.54 g is heated at 185-200 ° C. for 45 minutes.

40 (0.03 mole) crotonic acid and 3.0 g (1.26 mole) pyridine hydrochloride. The cooled reaction mixture is suspended in 500 ml of water (pH about 3) and the pH is adjusted to 7 and the resulting mixture is stirred for 10 minutes. The organic layer is separated, dried over MgS04 and washed

45 concentrates up to 3.2 g of a yellow oil.

A mixture of 110 ml of glacial acetic acid, 110 ml of 48% hydrobromic acid and yellow oil is heated for 1 hour and then concentrated in vacuo to a dark oil. Dissolve the oil in water and neutralize the

50 aqueous solution at pH 6-7 with IN sodium hydroxide. A saturated salt solution in water is added and the resulting mixture is extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated under reduced pressure to a dark oil (2.8 g). Chromatography

55 on a silica gel column of the crude residue using a 4: 1 mixture of benzene and ether as eluent gives an additional 510 mg of product, m.p. 168-170 ° C.

Additional purification is obtained by recrystallizing the product from ethyl acetate, m.p. 173-174 ° C.

60

Analysis: Calculated for C10H1IO3N:

C, 62.16; H, 5.74; N, 7.25%

Found: C, 62.00; H, 5.83; N, 7.14%

65 m / e -193 (m +), 178 (m + -methyl, base peak)

Similarly, 3,3-dimethylacrylic acid and 3,5-dimethoxyaniline give, after purification, by chromatography on silica gel (1: 1 mixture of benzene and ether

626,881

20

as eluent), 5,7-dihydroxy-2,2-dimethyl-4-oxo-1,2,3,4-tetrahydroquinoline in the form of a yellow oil.

Analysis (SM) Parent peak (m +)

Base peak (mH

Calculated for CuH [303N: 207.0895 Found: 207.0895

• 15)

Calculated for CinH10O3N: 192.0661 Found: 192.0655

Likewise, styrylacetic acid and 3,5-dimethoxyaniline condense giving the d, 1 -5,7-dihydroxy-2-benzyl-4-oxo-1,2,3,4-tetrahydroquinoline as an oil after purification using a 3: 1 mixture of benzene and ether as eluent.

m / e = 269 (m +) and 178 (m + -benzyl-base base) NMR (CDCl3) ô (ppm): 8.76 (s, 1H, 5-OH], 7.18-7.6 (m, 5H, CfiHs, 5.84 (d, J = 3Hz, 1H) and 5.62 (d, J = 3Hz, 1H) for aromatics coupled in meta, and 2.14 - 4.82 (4m, 7H), for the remaining protons (7-OH, CH — N, CN? -C = Q, -CH2-C6H5 and NH.

b) d, l-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetra-hydroquinoline

325 mg (52 mmol) of potassium hydroxide pellets are added to a solution of 1.0 g (52 mmol) of d, l-5,7-dihydroxy-2-methyl-4-oxo-1,2, 3,4-tetrahydroquinoline in 10 ml of N, N-dimethylformamide. The mixture is heated to 100 ° C and to the resulting solution is added all at once with good stirring 1.08 g (60 mmol) of d, 1 -2-bromoheptane. After 10 minutes, an additional 160 mg of potassium hydroxide is added, followed by an additional 500 mg of d, 1-2-bromoheptane. The addition of potassium hydroxide and d, 1-2-bromoheptane is repeated two more times, using 80 ml of potassium hydroxide and 250 mg of d, 1-2-bromoheptane each time. The reaction mixture is stirred for an additional 10 minutes and then cooled. 50 ml of chloroform and 25 ml of IN aqueous sodium hydroxide are added, the mixture is stirred for 10 minutes and the layers are separated. The extraction with chloroform is repeated, the extracts are combined, they are dried over MgSO4 and they are concentrated under reduced pressure until a dark oil is obtained. The oil is chromatographed on 120 g of silica gel using benzene as solvent. 30 ml fractions are collected each. The fractions 12-18 are combined and concentrated under reduced pressure to a light yellow oil (850 mg) which crystallizes on standing. The desired product is filtered off and recrystallized from hot hexane, m.p. 76-77 ° C.

The previous procedure is repeated on a scale 20 times larger but using as chromatographic solvent a 9: 1 mixture of benzene and ethyl acetate. 750 ml fractions are collected each. The combination of fractions 2-6 provides 32 g of oil which partially crystallizes in hexane by standing and cooling to give 18.2 g of product. An additional 3.2 g of product is obtained by concentrating the mother liquor and allowing it to crystallize by standing in the cold. A total of 21.4 g is obtained.

Analysis: Calculated for Q7H25O3H:

C, 70.07; H, 8.65; N, 4.81%

Found: C, 69.82; H, 8.67; N, 4.93%

-NH), 4.1-4.6 (m, IH, -0-CH-), 3.3 (t, 2H, J = 7Hz, -CH2-), 2.6 (t, 2H, J = 7Hz, -CH2-), 2.0-0.7 (m, remaining protons).

5 Preparation L a) d, l-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline

A) A mixture of 16.4 g (5 mmol) of 5-phenyl-2- (R, S) -pentanol, 28 ml (200 mmol) of triethylamine is cooled in an ice-water bath. 80 ml of tetrahydrofuran under a nitrogen atmosphere. 8.5 ml (110 mmol) of methanesulfonyl chloride in 20 ml of dry tetrahydrofuran are added dropwise at a rate such that the temperature remains essentially constant. The mixture is allowed to warm to room temperature and then filtered to remove the triethylamine hydrochloride. The filter cake is washed with dry tetrahydrofuran and the combined washing liquid and filtrate are evaporated under reduced pressure to obtain the product in the form of an oil. The oil is dissolved in 100 ml of chloroform and the solution is washed with water (2 X 100 ml) then with saturated brine (1 X 20 ml). Evaporation of the solvent provides 21.7 g (89.7%) of the d, l-5-phenyl-2-pentanol mesylate which is used in the next step without further purification.

25 Heated to 80-82 ° C in an oil bath for 1 h 7-t a mixture of 1.0 g (5.2 mmol) of d, 1 -5,7-dihydroxy-2-methyl -4-oxo-1,2,3,4-tetrahyquinoline, and 14.35 g (0.104 mole) of potassium carbonate, 60 ml of N, N-dimethylformamide and 13.68 g (57 mmol) of d, l-5-phenyl-2-30 pentanol mesylate, under a nitrogen atmosphere. The mixture is cooled to room temperature and then poured into 300 ml of ice and water. The aqueous solution is extracted with ethyl acetate (2 X 50 ml) and the combined extracts are washed successively with water (3 X 50 ml) and saturated brine (1 X 50 ml). Then the extract is dried over MgSO4, decolorized with charcoal and evaporated to obtain the product.

m / e-339 (m +)

The previous procedure is repeated, but using 114.8 g (0.594 mole) of d, 1-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3 , 4-tetrahydroquinoline, 612 ml of N, N-dimethylformamide, 174.8 g (1.265 mole) of potassium carbonate and 165.5 g (0.638 mole) of d, 1-5-phenyl-2-pentanol mesylate. The reaction mixture is cooled and poured into 41 ice water and the aqueous solution is extracted into ethyl acetate (2X41). The combined extract is washed with water (4 × 21), brine (1 × 21) and dried over MgSO 4. Evaporation provides 196 g of the title product. It is used without further purification.

'HRMN (60MHz) ô "^ scli (ppm): 12.73 (s, IH, OH), 7.22 50 (s, 5H, aromatic), 5.80 (d, J = 33Hz, 1H, H in meta), 5.58 (d, J = 3Hz, 1H, H in meta), 1.25 (d, 6H, CH3-CH-N and CHj-CH-O-), 1.41-4.81 ( m, 11H, protons remaining). d, 1-5-hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetra-hydroquinoline 55 B. Repeating mode above but using 5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline in place of 5,7-diyhdroxy-2-methyl-4-oxo-1,2, 3,4-tetrahydro-quinoline provides d, l-5-hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline as an oil with 60 a 74% increase.

m / e -325 (m +)

m / e - 291 (m +) IR (KBr): 6.01 jx (= 0) Analysis: Calculated for CjoH ^ NO ,:

In the same way, the 5,7-dihydroxy-4 C, 73.70 is transformed; H, 7.12; N, 4.31%

oxo-1,2,3,4-tetrahydroquinoline d, l-5-hydroxy-7- (2-hep- 65 Found: C, 73.69; H, 7.15; N, 4.08% tyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline, which is an oil.

'H NMR (60 MHz)) ppm): 13.3 (s, 1H, phenoli-' H NMR (60 MHz) ôjî &, (ppm): 12.6 (s wide, 1H, pheno-que), 5, 5 and 5.7 (d, 2H, J = 2Hz, aromatic), 4.6 (s broad, 1H, lique), 7.3 (s, 5H, aromatic, 5.8 (d, 1H, aromatic, J =

21

626,881

2Hz), 5.6 (d, IH, aromatic, J = 2Hz), 4.7-4.1 (m, 2H, NH and O-CH), 3.5 (t, 2H, CH2, J = 7Hz ), 3.1-2.1 (m, 4H, 2-CH2-), 2.1-1.5 (m, 4H, 2-CH2), 1.3 (d, 3H, -CH-CH3, J = 6Hz).

Similarly, 27 g (0.14 mol) of the d, l-5,7-dihydr-oxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline are alkylated with 35.2 g ( 0.154 mol) of 4-phenylbutyl methanesulfonate, which gives 41.1 g (90%) of d, l-5-hydroxy-2-methyl-7- (4-phe-nylbutyloxy) -4-oxo-1 , 2,3,4-tetrahydroquinoline desired, mp 88-90 ° C. Recrystallization from a 1: 2 mixture of ethyl acetate and hexane gives the analytical sample, m.p. 90-91 ° C.

Calculated for C29H2303N:

C, 73.82; H, 7.12; N, 4.30%

Found: C, 73.60; H, 7.09; N, 4.26%

m / e-235 (m +)

'' NMR (60 MHz) ôj ^ ,, (ppm): 12.58 (s, 1H, -OH), 7.21 (s, 5H, C6HS), 5.74 d, J = 2.5 Hz, 1H , H in meta), 5.5 (d, J = 2.5 Hz, 1H, H in meta, 4.36 (broad s, IH, NH), 3.33-4.08 (m, 3H, - 0-CH2, -CH-N), 2.29-2.83 (m, 4H, -CH2-C = 0, QHj-CH,), 1.51-1.92 (m, 4H, - [CH2 ] 2), 1.23 (d, 3H, CH3-).

Similarly, alkylation of d-5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline with d-2-octyl methanesulfonate provides d-5-hydroxy-2- methyl-7- (2- (R) -octyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline, mp 64-68 ° C.

g5 = +110.2 ° (c = 1.0, CHC13),

and the alkylation of d, l-5,7-dihydroxy-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline with d, l-5-phenyl-2-pentanol mesylate gives the d, 1-5-hydroxy-7 (5-phenyl-2-pentyIoxy) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline; m / e - 367 (m +).

b) d, 1-l-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline

A solution of 195 g (about 0.58 mole) of d, l-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyl-oxy) -4-oxo-1 is added dropwise. 2,3,4-tetrahydroquinoline in 1140 g (14.6 moles) of ethyl formate with 72 g of sodium hydride (3.0 moles), obtained by washing 140 g of a 50% solution of sodium hydride with 3 times 500 ml of hexane, stirring well. After about 1 hour when adding the ethyl formate solution, the addition is stopped to allow the substantial foam which has formed to dissipate. 600 ml of ether are added. diethyl and the mixture is stirred for 15 minutes before adding the remainder of the ethyl formate solution. When the addition is complete, 600 ml of diethyl ether are added, the reaction mixture is stirred for a further 10 minutes and then poured into ice water. Acidified to pH 1 with 10% HCl and the phase is separated which is extracted with ethyl acetate (2 X 21). The combined organic solutions are washed successively with water (2 × 21), brine (1 × 11) and dried over MgSO 4. The concentration gives 231 g of a red brown oil which is used without further purification.

Rf = 0.1-0.5 (stretched) on thin layer chromatography silica gel plate, benzene / ether 1: 1.

Similarly, the d, 1 -5-hydroxy-7- (5-phenyl-2-pentyloxy) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline is converted into d, 1 - l- formyl-5-hydroxy-3-hydroxymethylene-7- (5-phenyl-2-pentyloxy) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline. It is used in the following examples as is.

Preparation M

d, l-l-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline

To 18.2 g (0.38 mole) of sodium hydride obtained by washing with pentane a dispersion at 50% of sodium hydride in a mineral oil, a dropwise addition is added at 11.1 g (0.038 mole) solution of d, 1 -5-hydroxy-2-me-thyl-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline in

110 g (1.48 mole) of ethyl formate. An exothermic reaction takes place with vigorous evolution of hydrogen and formation of a yellow precipitate. The reaction mixture is cooled, 150 ml of ether are added and the resulting mixture is heated to reflux and stirred for 3 hours. It is then cooled to 0 ° C. and neutralized by adding 400 ml of IN hydrochloric acid. The ethereal layer is separated and the aqueous phase is extracted with ether (2 X 150 ml). The ethereal extracts are combined, washed successively with a saturated solution of sodium bicarbonate (2 × 100 ml) and brine (1 × 150 ml) and then dried over MgSO 4. The concentration of the dried extract provides an orange foam (10.8 g). An additional 2.3 g is obtained by acidifying the sodium bicarbonate wash solutions with concentrated hydrochloric acid and then extracting the acid solution with ether (2 X 100 ml). The concentration of the combined ethereal extracts, after drying, gives 2.3 g of product (in total 13.1 g). We use the product as is.

'H NMR (60 MHz) ô ^ ci3 (ppm): 12.27 (broad s, 1H, phenolic OH 20), 8.8-11.9 (m, 1H, variable, = COH), 8.73 ( s, 1H, N-CHO), 7.41 (s, 1H, = CH), 6.32 (s, 2H, aromatics), 5.52 (q, 1H -CH-N), 4.18-4 , 77 (m, 1H, -0-CH), 0.6-2.08 (m, 17H, CH3-C-C5HU and CH3-CN).

In the same way, the d, l-5-hydroxy-2-25 methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroqui-noline is converted into d , ll-formyl-5-hydroxy-5-hydroxymethylene-2-mes-thyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquino-leine.

'H NMR: (60 MHz) (60 MHz) ô ^ ci3 (ppm): 12.22 30 (broad s, 1H, ArOH), 8.8-11.6 (variable, 1H, = COH), 8, 64 (s. 1H, -CHO), 7.21 (broad s, shoulder at 7.30.6 h, aromatic and = CH), 6.23 and 6.17 two doublets of IH, J = 2 Hz, meta), 5.42 (wide q, 1H, N-CH), 4.18-4.70 (m, 1H, -OCH), 2.4-3.0 (m 2H, Ar-CH2), 1.53- 2.0 (m, 4H, - (CH2) 2-), 1.29 (overlapping doublets, 6H, CH3-C — N and CH3-CO).

We transform d, 1 -5-hydroxy-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline to d, 1 -1 -formyl-5-hydroxy-3-hydroxymethylene-7 - (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline, which is an oil.

40 1 NMR (60 MHz), q ™ q, (PPm): 12.1 (broad s, 1H, phenolic), 8.8 (s, 1H, -N-CHO); 8.1 (s, 1H), 7.3 (s, 1H), 6.1 (s, 2H aromatic), 4.5 (s broad, 2H, -CH2-), 4.2-4.8 ( m, -0-CH2-), 2.0-0.7 (remaining protons).

The d, 1 -5 -hydroxy-7- (5 -pentyl-2-pentyloxy) -45 4-oxo-1,2,3,4-tetrahydroquinoline is transformed into d, l-formyl-5-hydroxy-3- hydroxymethylene-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline.

'H NMR (60 MHz) ô ™ ci3 (PPm): 12.4 (broad, 1H, phenolic), 8.5 (s, 1H, CHO), 7.2 (m, 6H, aromatic and = CH ~ ), so 6.2 (m, 2H, aromatics), 4.5 (s, 2H, -CH2-), 4.4 (m, 1H, -CH-CH3), 2.6 (bt, 2H, - CH2-), 1.7 (m, 5H, remaining protons, 1.3 (d, 3H, -CH-CH3, J = 6Hz).

and converting d, 1 -5-hydroxy-2-methyl-7- (4-phenylbu-tyloxy) -4-oxo-1,2,3,4-tetrahydroquinoolein to d, ll-formyI-5-55 hydroxymethylene -2-methyl-7- (4-phenylbutyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline, pf 132-135 ° C (in hexane). Recrystallization from hot methanol gives the analytical sample, m.p. 131-132 ° C.

60 Calculated for C2iH2305N:

C, 69.27; H, 6.08; N, 3.67%

Found: C, 69.25; H, 5.88; N, 3.88%

m / e-381 (m +)

65 'H NMR (60 MHz) (ppm): 12.4-13.6 (m, H, = OH), 12.26 (s, IH, 5-OH), 8 ^ 62 (s, IH, - C (= 0) -H), ~ 7.18-7.48 (m, 1H, = H), 7.27 (s, 5H, C6H5), 6.26 (wide s, 2H, H in meta) , 5.46 (q, 1H, CH-N), 3.82-4.23 (m, 3H, -CHn-O),

626,881

22

2.49-2.80 (m, 3H, ArCH2), 1.67-2.02 (m, 4H, -CH2 2-), 1.27 (d, 3H, CH3).

Preparation N

d., 1-1 -formyl-5-hydroxy-2-methyl- 7- (5 -phenyl-2-pentyloxy) -4-oxo-3 - (3-oxobutyl) -l, 2,3,4-tetrahydroquinoline

To a solution of d, 1 -1 -formyI-3 -hydroxymethylene-5 -hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tet trahydroquinoline (229 g, approximately 0.58 mole) in 880 ml of methanol under a nitrogen atmosphere, 27.2 ml of triethylamine is added with stirring. Then 97.0 ml of methylvinyl acetone is added and the mixture is stirred overnight at room temperature.

The reaction is complete at this time and comprises a mixture of the title compound and d, 1 -3-diformyl-5-hydr-oxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4 -oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline. The following steps are necessary to transform the diformylated compound into the desired title compound.

The reaction mixture is diluted with 61 ether and then washed successively with 10% aqueous sodium carbonate (4 X 1700 ml), brine (1 X 21) and then dried over MgSO 4. Concentration of the solution provides 238 g of a red-brown oil. The oil is dissolved in 1920 ml of methanol and the solution is cooled to 0 ° C. 21.2 g of potassium carbonate are added, the mixture is stirred for 3 hours at 0 ° C. and then treated with 18.7 g of acetic acid. The methanol is removed under reduced pressure and the resulting oil is stirred with 21 of water and 21 of ethyl acetate for 10 minutes. The aqueous phase is separated, extracted with ethyl acetate (1 × 21) and the combined ethyl acetate solutions are washed with water (2 × 2 1), brine (1 × 21) and are dried on MgS04. Concentration under reduced pressure and chromatography of the concentrate on silica gel (1.8 kg) gives 159 g of the title product.

m / e —437 (m +)

'H NMR (60 MHz) (ppm): 12.7 (s, 1H, OH), 8.78 (broad s, 1H, -CHO), 7.22 (s, 5H, aromatic), 6.22 ( s broad, 2H, H in meta), 2.12.2.07 (s, 3H, -CH3-CO-), 1.31 (d, 3H, -CH3-CO-), and 1.57-5 , 23 (m, 13H, remaining protons).

Similar treatment of 35 g (0.09 mole) ded, ll-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (4-phenylbutyl-oxy) -4-oxo-1,2,3, 4-tetrahydroquinoline gives 22.7 g (60%) of d, l-1-formyl-5-hydroxy-2-methyl-7- (4-phenylbutyIoxy) -4-oxo-3- (3-oxobutyl) -l , 2,3,4-tetrahydroquinoline, mp 101-103 ° C. The analytical sample is obtained by recrystallization from methanol, m.p. 104-105 ° C.

Calculated for C25H2905N:

C, 70.90; H, 6.90; N, 3.31%

Found: C, 70.77; H, 6.81; N, 3.46%

'H NMR (60 MHz) ôj ^ ci, (ppm): 12.88 (s, 1H, -OH), 9.08 (wide s, 1H, -CHO), 7.29 (s, 5H, C6H5) , 6.25 (broad s, 2H, H in meta), 4.88-5.43 (m, 1H, -CHN), 3.86-4.21 (m, 2H, -CH2-0-), about 2.49-3.02 [m, 7H, ArCH2) - (CH2, - (CH2) 2-C (= O) -, —CH-C (= 0)], 2.18 [s, 3H, CH3-C (= 0)], 1.68-2.03 [m, 4H, - (CH2) 2-], 1.13 (d, 3H, CH3).

m / e-423 (m +);

and d, 1 -1-formyl-5-hydroxy-3-hydroxymethylene-7- (5-phenyl-2-pentyloxy) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline provides d , 1 -1 -formyl-5-hydroxy-7- (5-phenyl-2-pentyl-oxy) -4-oxo-3- (3-oxobutyl) -l, 2,3,4-tetrahydroquinoline which is use it as is.

Preparation O

d, ll-formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline and d, 1-1, 3-diformyl-5 -

hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) ~ 1,2,3,4-tetrahydroquinoline

To a solution of 13.1 g (37.7 mmol) of d, 1-5-hydroxy-3-hydroxymethylene-2-methyl-7- (2-heptyloxy) -4-oxo-1,2,3,4 -tetrahydroquinoline in 56 ml of methanol and 5.52 mg (68 mmol) of methylvinyl ketone, 1.3 ml (9.3 mmol) of triethylamine are added. The mixture is stirred for 18 hours under a nitrogen atmosphere at room temperature and then diluted with 550 ml of ether. The solution is washed with a 10% aqueous solution of sodium bicarbonate (4 X 60 ml), then with brine (1 X 100 ml) and dried over MgSO 4. Removal of the ether by evaporation gives a dark oil (16 g). The oil is dissolved in a minimum volume of benzene and the solution is loaded onto a column of 500 g of silica gel. Then the column is eluted with a volume of benzene equal to the volume of the column. A mixture of benzene containing 15% ether is then used as the eluting solvent, and fractions of 100 ml are collected when the first colored strip begins to elute from the column. Fractions 5 to 13 are combined and concentrated under reduced pressure, giving d, ll, 3-difor-myl-5 -hydroxy-2-methyl-7 - (2-heptyloxy) -4-oxo-3 - (3 -oxobu-tyl) -1,2,3,4-tetrahydroquinoline in the form of a yellow oil

(8.7 g).

The column is then eluted with a mixture of 15% ether and benzene. Fractions 19 to 37 are combined and concentrated under reduced pressure, giving d, 1 -1 -formyl-5-hydroxy-

2-methyl-7- (2-heptyloxy) -3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline as an oil (4.6 g). Additional monoformylated product is obtained in the following manner.

1 g of the diformylated product is stirred with 200 mg of post potassium carbonate in 25 ml of methanol for 2 hours at 0 ° C. Then the solvent is evaporated in vacuo and the residue is suspended in ether and filtered. The filtrate is concentrated and the residue is distributed between ether and water. The organic layer is separated, the aqueous phase is acidified with 10% hydrochloric acid and extracted with ether. The combined ethereal extracts are washed successively with a saturated sodium bicarbonate solution and a saline solution, then they are dried over MgSO 4, they are filtered and concentrated to obtain additional monoformylated product.

The monoformylated derivative has the following NMR spectrum:

XH NMR (60 MHz) (ppm): 12.73 (S, 1H, phenolic OH), 8.87 (S, 1H, N-CHO), 6.12 (S, 2H, Aromatics), 4, 78-5.50 (M, 1H, N-CH), 4.11-4.72 (M, 1H, -O-CH), 2.21 (S, 3H, CH3-CC (= 0), 0 , 63-3.12 (M, 22H, other hydrogens.)

Likewise, the following compounds are prepared from the appropriate reagents:

d, l-l-formyl-5-hydroxy-7- (2-heptyloxy) -4-oxo-3- (3-oxo-butyl) -1,2,3,4-tetrahydroquinoline, which is an oil,

! H NMR (60 MHz) ô $ ^ i, (ppm): 12.8 (S, 1H, phenolic), 8.7 (S, 1H, N-CHO), 6.1 (S, 2H, aromatic), 4.1-4.6 (m, 1H, -O-CH), 4.1 (d, 2H, J = 5H2, -CH2-), 2.3-3.0 (m, 3H, CH2 and CH-C (= 0)), 2.2 (S, 3H, -C (= 0) -CH3), 2.3-0.7 (remaining protons),

d, l-1-formyl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyI-oxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline.

1 H NMR (60 MHz) (PPm): 12.68 (S, IH, -OH), 8.82 (wide s, 1H, -C (0) H), 7.20 (wide s, 5H, C6H5 ), 6.18 (broad s, 2H, aromatic), 4.78-5.34 (m, 1H, -N-CH), 4.18-4.68 (m, 1H, -O-CH), 2.17 (S, 3H, -C (0) CH3), 1.30 (d, 3H, -0-C-CH3), 1.12 (d, 3H, -NC-CH3), 1.4- 3.1 (m, 11H, other protons).

d, l-l-formyl-5-hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-

3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline.

m / e —423 (m +)

The corresponding 1,3-diformylated derivative is also obtained as a by-product in each of these preparations.

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626,881

Preparation P

d, 1-5,6,6a, 7-tetrahydro-1-hydroxy-6ji-methyl-3 - (5-phenyl-1 -pentyloxy) benzo [cjquinoline-9 (8H) -one

A solution of 174 g (0.398 mole) of d, ll-formyl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) is stirred and refluxed for 1 night under nitrogen. -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoIine in 5.91 of 2N methanolic potassium hydroxide and 5.9 liters of methanol. To the cooled solution, 708 g of acetic acid are added dropwise with stirring, over 15 minutes. The resulting solution is concentrated in a rotary evaporator (under vacuum, water pump) to a semi-solid which is filtered and washed first with water to remove the potassium acetate and then with ethyl acetate until the black tar is removed. 68 g (44%) of yellow solids are obtained, m.p. 188-190 ° C. Recrystallization from hot ethyl acetate provides the pure product, m.p. 194-195 ° C.

m / e -391 (m +)

Analysis: Calculated for C25H29O3N:

C, 76.09; H, 7.47; N, 3.58%

Found: C, 76.43; H, 7.48; N, 3.58%

'H NMR (60 MHz) ô ™ s (100 mg dissolved in 0.3 ml of CD3OD and 0.3 ml of CD3S (0) CD3) (ppm): 7.21 (s, 5H, aromatic), 5, 80 (s, 2H, H in meta), 1.20 (d, 6H, CH3-CHO and CH3-CH-N. ~~

From the mother liquors, a small amount of the corresponding axial methyl derivative is obtained by evaporation. It is purified by column chromatography on silica gel using a 1: 1 mixture of benzene and ether as eluents. Evaporation of the eluate and recrystallization of the residue from a 1: 1 mixture of ether and hexane provides an analytically pure substance, m.p. 225-228 ° C.

Its Rf by thin layer chromatography on silica gel using 2.5% methanol in ether as eluent and a demonstration with solid blue is 0.34. The 6β-methyl derivative has an Rf of 0.41.

m / e-391 (m +)

'H NMR (60 MHz) ô ™ s (100 mg dissolved in 0.3 ml of CD3OD of 0.3 ml of CD3S (0) CD3) (ppm): 7.19 (s, 5H, aromatic), 5, 75 (s, 2H, H in meta), 1.21 (d, 3H, CH3-CHO-), and 0.95 (d, 3H, CH3-CH-N).

The similar treatment of 22 g of d, 1 -1-formyl-5-hydr-oxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-3- (3-oxobutyl) -1,2, 3,4-tetrahydroquinoline gives 17.1 g (87%) of d, l-5,6,6a, 7-tetrahydro-l-hydroxy-6P-methyl-3- (4-phenylbutyl-oxy) benzo [c ] quinoline-9 (8H) -one, pf 222-224 ° C. The analytical sample is obtained by recrystallization from methanol, m.p. 224-225 ° C.

Calculated for C24H2703H:

C, 76.36; H, 7.21; N, 3.71%

Found: C, 76.03; H, 7.08; H, 3.68%

1 H NMR (60 MHz) [1: 1 mixture of (CD3), SO and DC3OD]: 1.24 (d, 3H, 6β-CH3.

m / e-377 (m +)

Evaporation of the mother liquor gives 2.8 g (mp 185-195 ° C) of product whose NMR shows that it is a mixture of the 6ß-nrethylö derivative (about 40%), and the d, l- 5,6,6a, 6-tetra-hydro-1-hydroxy-6a-methyl-3- (4-phenyl butyloxy) -benzo [c] -quinoline-9 (8H) -one.

! H NMR (60 MHz) [1: 1 mixture of (CD3) 2SO and CD3OD]: 1.24 (d, 1.2H, 6ß-CH3 and 0.95 (d, 1.8H, 6a-CH3.)

Preparation Q

d, l-5,6,6a, 7-tetrahydro-l-hydroxy-6fi-methyl-3- (2-heptyloxy) benzo- [c] -quinoline-9 (8H) -one

A solution of 4.5 g (11.5 mmol) of d, ll-formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxo-butyl) is treated. ) -1,2,3,4-tetrahydroquinoline in 150 ml of methanol with 150 ml of a 2N methanolic potassium hydroxide solution. This mixture is stirred for one hour at room temperature and then heated to reflux under a nitrogen atmosphere for 20 hours. The dark red mixture is allowed to cool to room temperature, neutralized with acetic acid and concentrated under pressure to about 100 ml. The concentrate is diluted with 400 ml of water and the reddish brown solid is filtered off, washed with water and dried (about 6 g). It is first triturated in ether and then in methanol, filtered and dried (1.96 g); m.p. 223-229 ° C. Recrystallization from hot methanol provides crystals melting at 235-237 ° C.

Analysis: Calculated for C2iH2903H:

C, 73.43; H, 8.51; N, 4.08%

Found: C, 73.22; H, 8.30; H, 4.11%

Additional material is collected by evaporating all the mother liquors and extracting the aqueous solution from which the crude red-brown product was obtained with chloroform and then evaporating the extract. The combined residues are purified by chromatography on silica gel using ether as the eluent.

In the same way, the following compounds are prepared from the appropriate reagents:

d, l-5,6,6a, 7-tetrahydro-l-hydroxy-3- (5-phenyl-2-pentyl-oxy) -benzo [c] -quinoline-9 (8H) -one; m.p. 170-173 ° C. (recrystallized from chloroform).

m / e-377 (m +)

Analysis: Calculated for C24H2703N:

C, 76.36; H, 7.21; N, 3.71%

Found: C, 76.38; H, 7.21; N, 3.85%

d, l-5,6,6a, 7-tetrahydro-l-hydroxy-3- (2-heptyloxy) benzo [-c] -quinoline-9 (8H) -one; m.p. 208-209 ° C.

m / e-329 (m +)

Analysis: Calculated for C2oH2703H:

C, 72.92; H, 8.26; N, 4.25%

Found: C, 72.92; H, 8.31; N, 4.42%

d, l-5,6,6a, 7-tetrahydro-l-hydroxy-3- (5-phenyl-2-pentyl-oxy) -6P-propylbenzo [c] quinoline-9 (8H) -one; m.p. 164-166 ° C.

Analysis: Calculated for C27H3303N:

C, 77.29; H, 7.93; N, 3.34%

Found: C, 76.97; H, 7.98; N, 3.41%

1-5,6,6 a, 7-tetrahydro-1-hydroxy-3 - (5-phenyl-2-penty 1-oxy) -6ß-methylthenzo [c] quinoline-9) 8H) -one; m.p. 176-178 ° C.

[<*] £ = - 416.0 0 (c = 0.33, CH3OH)

m / e-391 (m +)

Analysis: Calculated for C2sH2903N:

C, 76.69; H, 7.47; N, 3.58%

Found: C, 76.32; H, 7.36; N, 3.33%

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626,881

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d-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyl- Analysis: Calculated for C25H29O3N: oxy) -6ß-methylthenzo [c] quinoline-9 (8H) -one ; m.p. 172-C, 76.69; H, 7.47; N, 3.58%

174 ° C. Found: C, 76.40; H, 7.39; N, 3.51%

[a] f / = 412.9 0 (c = 1.0, CH3OH)

m / e -391 (m +) 5 Other compounds according to the following table were prepared by this method:

ZW R4 R5

-0-ch (ch3) (ch2) 3c5h5 c2hs h

-0-ch (ch3) (ch2) 3c6hs c6h13 h m / e (° C) Wedge. Find

R (i (m +) m.p. Formula C, H, N C, H, N

c-77.00 c-76.86 h 405 155-6 c26h3103n h-7.71 h-7.62

n-3.45 n-3.45 c-78.05 c-78.16 h 461 139-141 c3üh3903n h-8.52 h-8.53

n-3.08 n-3.09

-0-ch (ch3) (ch2) 3c6h5 c5hu h

-0-ch (ch3) (ch2) 3c6h5 c4h9 h

-0-ch (ch3) (ch2) 3c6h5 - (ch2) 2-c6h5 h

-0-ch (ch3) (ch2) 3c6h5 ch3 h c-77.81 c-77.78

h 477 150-3 c29h3703n h-8.33 h-8.19

n-3.13 n-3.13

c-77.56 c-77.28

h 433 160-2 qiftsojn h-8.14 h-7.92

n-3.23 n-3.18

c-79.80 c-79.64

h 481 200-201 c32h3503n h-7.33 h-7.34

n-2.91 n-2.93

c-76.00 c-76.19

h 363 246-7 c, 3h2503n h-6.93 h-7.14

n-3.85 n-3.89

c-77.70 c-77.94

-c (ch3) 2-c6h3 ch3 h h 355 261-2 c ^ h ^ c ^ n h-9.36 h-9.36

n-3.94 n-3.99

c-75.62 c-75.26

-0 (ch2) 2c6h5 ch3 h h 349 248-250 c22h2303n h-6.63 h-6.66

n-4.01 n-3.93

c-77.56 c-77.86

-0-ch (ch3) (ch2) 3c6h5 h c4h9 h 433 95-98 c ^ h ^ c ^ n h-8.14 h-8.37

n-3.23 n-3.17

(a) l_-enantiomer; [a] f, 5 = - 416.0 0 (C = 0.33, CH3OH) liquid moniac (distilled through hydroxide pellets

(b) d-enantiomer; [a] p = +412.9 0 (C = 1.0, CH3OH) potassium). The dropping funnel is rinsed with 10 ml of tetrahy drofuran. The mixture was stirred for 10 minutes and then solid ammonium chloride was added to remove the blue Example 1 color. The excess ammonia is allowed to evaporate and the d, 1 -5,6,6a, 7,10,10a-hexahydro-1-hydroxy-6ß-methyl-3- (2- residue in 100 ml) is taken up again. of water and 50 ml of ethyl acetate. The heptyloxy) -benzofc] quinoline-9 (8H) -one is separated from the ethyl acetate layer and the aqueous phase is extracted with

Ethyl acetate (2 X 50 ml) is added dropwise through an ampoule. The combined extracts are washed with bromine a solution of 1.0 g (2.91 mmol) of d, 1-5.6.6a, 7-65 brine, dried over MgSO4 and concentrated under tetrahydro- 1-hydroxy-6ß-methyl-3 (2-hepty! Oxy) benzo [c] which- reduced pressure to a brown semisolid (1.35 g). Tritura-noline-9 (8H) -one in 20 ml of tetrahydrofuran, at a solution of the semi-solid in a 1: 1 mixture of pentane and ether rapidly stirred solution of 0.1 g of lithium in 75 ml of ammoon a light brown solid (0.884 g); m.p. 130-138 ° C.

25

626,881

The previous procedure is repeated, but using 1.84 g (5.36 mmol) of benzo [c] quinoline-9-one, 0.184 g of lithium, 140 ml of liquid ammonia and 45 ml of tetrahydrofuran. The residue (2.1 g) remaining after evaporation of the ammonia is dissolved in benzene and it is introduced on a chromatographic column (3.8 × 61 cm) containing 250 g of silica gel. The column is eluted with a volume of degassed benzene equal to the volume of the column and then with 1700 ml of a 9: 1 mixture of degassed benzene and ether. Continuous elution (1100 ml) gives a brilliant red eluate which is concentrated to 580 mg of a brilliant purple solid under reduced pressure which is triturated in a 1: 1 mixture of benzene and ether, which gives 370 mg of solid; mp 154-156 ° C. It is stored under nitrogen and in the dark. The isolated solids are mixtures of the cis and trans forms of the title product.

m / e - 345 (m +)

'H NMR (100 MHz) ô $ fë, 3 (ppm): 6.85 and 7.49 (1H, large variable, OH), 5.67.5.71.5.85.5.93 (d, J = 2Hz, 2H in total, aromatic hydrogens from the cis / trans mixture), 0.90 (t, 3H, terminal CH3), 1.12-4.43 (m, H remaining).

Example 2

5,6,6a, 7,10,10a-Hexahydro-l-acetoxy-6fi-methyl-3- (2-heptyl-oxy) benzo [c] quinoline-9 (8H) -one isomers.

2.2 ml of pyridine are added to a 222 mg (0.642 mmol) suspension of 5.6,6a, 7,10,10a-hexahydro-1-hydroxy-6ß-methyl-3- (2-heptyloxy) benzo [ c] quinoline-9 (8H) -one in 2.2 ml of acetic anhydride under nitrogen. The mixture is stirred for an hour and a half at room temperature and then poured onto 50 ml of ice. The gum which separates is extracted with ether (3 X 50 ml) and the combined extracts are washed first with water (4 X 50 ml) then with brine (1X 60 ml). The extract is dried over MgSO4 and then evaporated under reduced pressure to a red oil (250 mg).

The oil is dissolved in a minimum of hot ether and loaded onto a column of 45 g of silica gel, packed and eluted with a 3: 1 mixture of pentane and ether. The column is eluted with 200 ml of a 3: 1 mixture of pentane and ether. The elution is continued and the 10 ml fractions are collected. Fractions 22-32 are combined and concentrated to a foam (113.5 mg) which crystallizes from petroleum ether in the form of white crystals; mp 112-114 ° C.

The fractions 33-50 are combined and concentrated to a foam (89.7 mg) which is recrystallized from petroleum ether in the form of white crystals; mp 78-82 ° C.

The products are the isomeric monoacethylated components.

Example 3

d, l-5,6,6a-10,10a-Hexahydro-l -acétoxy-6fi-methyl-3- (2-hep-tyloxy) -benzo [c] quinoline-9 (8H) -one

The procedure of Example 1 is repeated, but using double the quantities of reagents. The product is then directly acylated (2.22 g) according to the procedure of Example 10, which gives 2.35 g of the acetylated product. This product is triturated in a 3: 1 mixture of pentane and ether until a yellow brown solid (905 mg) is obtained which, when recrystallized from ethanol, gives 404 mg of light brown yellow crystals; mp 112-113.5 ° C.

The mother liquors are combined and concentrated from which each of the preceding solids has been separated. The residue is dissolved in a minimum of a 1: 1: 1 mixture of benzene, ether, and methylene chloride and it is introduced into a column of 275 g of silica gel (packed and eluted with a mixture 3: 1 petroleum ether). The column is first eluted with 2 l of a 3: 1 mixture of petroleum ether and ether, then with 1.5 l of a 2: 1 mixture of petroleum ether and ether, then with 2 l of a 1: 1 mixture of petroleum ether and ether. Fractions 2-11 (50 ml each) of the eluate from the solvent system 1: 1 are combined and concentrated under reduced pressure to a foam (496 mg). Crystallization from petroleum ether provides white crystals, mp 100-113 ° C (410 mg). Recrystallization from a 1: 1 mixture of ethanol and s of water gives d, 1 -trans-5,6,6aß-7,10,1 Oaa-hexahydro-1-acetoxy ^ -methyl-3- (2 -heptyloxy) benzo [c] quinoIein-9 (8H) -one melting at 111-112 ° C.

m / e-387 (m +)

io Calculated Analysis for C23H34N:

C, 71.29; H, 8.58; N, 3.61%

Found: C, 70.95; H, 8.64; N, 3.58%

Fractions 12 to 18 and 19 to 27 (50 ml each) are collected and concentrated, giving 273 mg and 208 mg of the acetylated product, respectively. The crystallization of the residue of fractions 19-27 in petroleum ether gives 119 mg of white crystals, mp 84-88 ° C. Recrystallization from a 1:10 mixture of ethyl acetate and hexane gives d, l-cis-5,6,6aß, 7,10,10aa-hexahydro-l -ac0toxy-3- (2- heptyloxy) -6ß-m0thyI-benzo [c] quinoline-9 (8H) -one, mp 84-86 ° C.

Analysis: Calculated for C23H3304N:

C, 71.29; H, 8.58; N, 3.61%

Found: C, 71.05; H, 8.48; N, 3.56%

Likewise, the following compounds are prepared from the appropriate reagents:

d, 1 -trans-5,6,6aß, 7,10,1 Oaa-hexahydro-1 -acétoxy-30 6ß-methyl-3- (5-ph0nyl-2-pentyloxy) benzo [c] quinol0ine-9- (8H) -one, mp 80-82 ° C.

m / e-435m +)

Analysis: Calculated for C27H3304N:

C, 74.45; H, 7.64; N, 3.22%

35 Found: C, 74.43; H, 7.73; N, 3.28%

ladjl-cis-5,6,6aß, 7,10,10aß-hexahydro-l-ac0toxy-6ß-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline-9 (8H) -one, mp 172-176 ° C as hydrochloride in acetone-40 ether (1: 1).

Analysis: Calculated for C27H3304.HC1:

C, 68.71; H, 7.26; N, 2.97%

Found: C, 68.86; H, 7.16; N, 2.97%

45

d, l-trans-5,6,6aP, 7,10,10aa-hexahydro-l-acetoxy-3- (5-ph6nyl-2-pentyIoxy) -6ß-propylbenzo [c] quinoI0ine-9 (8H) - one; mp 79-80 ° C.

m / e-463 (m +) 50 la d1l-cis-5,6,6aß, 7,10,10aß-hexahydro-l-ac0toxy-3- (5-ph0nyl-2-pentyloxy) -6ß-propylbenzo [c] quinolin-9 (8H) -one; mp 144-146 ° C. as hydrochloride, m / e -463 (m +).

dJ-cis-5,6,6aß, 7,10,10aß-hexahydro-l-ac0toxy-3- (5-55 phnnyl-2-pentyloxy) -6ß-nwthylbenzo [c] quinoline-9 (8H) -one , mp 90-94 ° C in the form of the hydrochloride.

[ajg5 = +22.8 0 (c = 0.31, CH3OH)

m / e -435 (m +)

60 Analysis: Calculated for C27H3304N.HC1:

C, 68.71; H, 7.26; N, 2.97%

Found: C, 69.24; H, 7.30; N, 3.01%

Iad1l-trans-5,6,6aß, 7,10,10aß-hexahydro-l-ac0toxy-3-65 (5-phenyI-2-pentyloxy) ^ - methylbenzo [c] quinoline-9- (8H) -one; mp 90-95 ° C in the form of the hydrochloride. [a] b5 = +78.46 ° (c-0.13, CH3OH)

m / e —435 (m +)

626,881

26

Analysis: Calculated for C27H33O4N.HCI: 5.6 g (23.4%) of the trans isomer of the title product. We

C, 68.71; H, 7.26; N, 2.97% combines the fractions 21—27 and 7.6 g are obtained (yield

Found: C, 70.20; H, 7.23; N, 3.07% 31.8%) of a mixture of the trans and eis isomers, and the fractions 28-32 are combined to give 2.5 g (10.4%) of the isis eis of the d , l-cis-5,6,6aß, 7,10,1 Oaß-hexahydro-l-acetoxy-3- (5- 5 title product. phnnyl-2-pentyIoxy) -6ß-methylbenzo [c] quino [ 0ine-9 (8H) - The trans isomer has the following characteristics:

one, mp 90-92 ° C, as the hydrochloride. m / e - 435 (m +)

[a] n = - 20.5 0 (c = 0.19, CH3OH) 'H NMR (60 MHz) (ppm) 7.24 (s, 5H, aromati-

m / e - 435 (m +) ques), 5.97 (2.2H, H in meta), 2.28 (s, 3H, CH3-COO), 1.23

ic (d, 3H, CH3-CH-O-), 1.20 (d, 3H, Œ3-, CH-N), 1.3-4.5 (m, Analysis: Calculated for C27H3304N.HC1: 17H, remaining protons), mp - 81-83 ° C.

C, 68.71; H, 7.26; N, 2.97%

Found: C, 68.92; H, 7.23; N, 3.09% Analysis: Calculated for C27H33O4N:

C, 74.45; H, 7.64; N, 3.22%

d, 1 -trans-5,6,6aß, 7,10,1 Oaß-hexahydro-1-acetoxy-3-found: C, 74.15; H, 7.68; N, 3.18%

(5-ph0nyl-2-pentyloxy) -6ß-m0thylbenzo [c] quinoline-9 (8H) -

one; mp 92-96 ° C in the form of the hydrochloride. The eis isomer has the following characteristics:

[cx] d = - 79.0 0 (c = 0.10, CH3OH) m / e - 435 (m +)

m / e - 435 (m +) m.p. of hydrochloride —172—176 ° C (dec.) (in acetone-

20 ether)

Analysis: Calculated for C27H33O4N.HCI:

C, 68.71; H, 7.26; N, 2.97% Analysis: Calculated for C27H3304N.HC1:

Found: C, 68.67; H, 7.23; N, 3.02% C, 68.71; H, 7.26; N, 2.97%

Found: C, 68.86; H, 7.16; N, 2.97%

Example 4 25

d, l-5,6,6a, 7,10,1 Oa-Hexahydro-1 -acétoxy-6ß-mithyl-3 - (5- Example 5

phenyl-2-pentyloxy) benzo [c] quinoline-9 (8H) -one, isomers eis d, l-5,6,6a, 7,10,1 Oa-Hexahydro-1 -acétoxy-6 (i-methyl- 3- (4-and trans phenylbutyloxy) benzo [c] quinoline-9 (8Hà) -one, trans isomers

1150 ml of ammonia are condensed directly under atmospheric pressure.

nitrogen sphere, in a 3 1-flask flask, 3 1, dried at 30 Following the procedure of Example 3, the flame is reduced and equipped with a mechanical stirrer, first with a bulb d, l-5,6,6a, 7- ^ trahydro-l-hydroxy-6ß-ir ^ thyl-3-bromine of 500 ml and cooling by dry ice / (4-phenylbutyloxy) benzo [c] quinoline-9 (8H) -one with li-acetone, (approximately - 75 ° C). Lithium wire (2.2 g, thium and ammonia is added, then acylated to obtain the isomers cut into 8 mm pieces) and a desired hexahydrogenated is immediately formed. Separation by characteristic blue color chromatography. To the blue solution stirred under a silica gel column using ether as eluent provides 78 ° C., is added 21.5 g (0.055 mole) of d, l-5,6,6a, 7-tetrahy- first d, l-trans-5,6,6aß-7,10,1 Oaa-hexahydro-1-acét-dro-l-hydroxy-6P-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] - oxy ^ -methyl-3- (4-phenylbutyloxy) benzo [c] quinoline-quinoline-9 (8H) -one dissolved in 250 ml of tetrahydrofu- 9 (8H) -one, mp 155-156 ° C, after recrystallization in a me-ranne, drop by drop in 10 minutes. After 5 min additional 1: 5 of ethyl acetate and pentane.

stirring plates at -78 ° C., the reaction is stopped by adding 40

20 g of dry ammonium chloride. Then the cooling is stopped - Analysis: Calculated for C26H3104N:

ment and the reaction mixture is slowly reheated on a C, 74.08; H, 7.41; N, 3.32%

steam bath to evaporate the ammonia. When almost found: C, 74.00; H, 7.47; N, 3.22%

dry, add 21 ethyl acetate, and 11 water and stir the mixture for 10 minutes. We then separate the layers and 45 m / e - 421 (m +)

the aqueous phase is extracted once more with 500 ml of acé. Further purification of the last columns with ethyl tate. The combined organic extracts are washed once with additional column chromatography on silica gel in water (11), dried over MgSO4 and concentrated until using a 1: 1 mixture of cyclohexane and a semi - solid brown (about 28 g). Ether is immediately dissolved, d, l-cis-5,6,6aß, 7,10,1 Oaß-hexahydro-1-this residue is provided in 200 ml of methylene chloride, 7.5 g 50 acetoxy are added. -6ß-methyl-3- (4-phenylbutyloxy) benzo [c] quinoline- (0.061 mole) of 4-dimethylaminopyridine and 6.1 g (0.061 mole) 9 (8H) -one isomer, mp 95-96 ° C, after recrystallization from triethylamine and the stirred solution is cooled to 0 ° C (1: 5 cooling mixture of ethyl acetate and hexane.

ice / water distribution) under a nitrogen atmosphere. Then we add m / e - 421 (m +)

drip in 5 minutes with good agitation 6.1 g (0.061 mole)

acetic anhydride. After an additional 30 minutes of agitation 55 Analysis: Calculated for C26H3104N:

tation at 0 ° C, dilute the reaction mixture with 21 acetate C, 74.08; H, 7.41; N, 3.32%

ethyl and water and stirred for 10 minutes. Extract Found: C, 73.95; H, 7.51; N, 3.31%

once more with water and the combined organic phases are washed successively with water (four times 1 liter) Example 6

saturated sodium bicarbonate solution (1X11), 60 d solution, l-5,6,6aß, 7,10,10aß-hexahydro-l-acetoxy-3- (2-heptyloxy) -saline (1X11); dried over MgSO4 and concentrated benzo [c] -quinoline-9 (8H) -one to a light brown oil (about 27 g). Chromatography A solution of 9.0 g of d, l-the residue is added dropwise onto 1.8 g of silica gel, using as solvent 5,6,6a, 7-tetrahydro-1-hydroxy-3 - (2-heptyloxy) benzo [c] quino-elution of benzene 15 / ethyl acetate. Fraclein-9 (8H) -one is collected in 100 ml of tetrahydrofuran, to a one liter solution. 65 quickly stirred 0.1 g of lithium in 750 ml of aramo-

After elution of the non-polar impurities, the liquid fracini are combined. An additional 0.1 g of 16-20 ions is added in portions and evaporated to a residue which crystallizes lithium during the addition, to maintain a blue color, in a mixture of ether and ether of petroleum, which gives the mixture is stirred for 10 minutes and then the

27

626,881

blue color by addition of an excess of ammonium chloride. The excess ammonia is allowed to evaporate and the residue is taken up in a mixture of water and ethyl acetate. The organic layer is separated and the aqueous phase is extracted two more times with ethyl acetate. The combined extracts are washed with water, with brine, dried over MgSO4 and evaporated, which gives 8.45 g of the crude product in the form of a brown solid.

8.0 g of the crude product are suspended in 48 ml of methylene chloride at 0 ° C. and treated with 3.24 g of N, N-dimethyl-4-aminopyridine and 3.72 ml of triethylamine. Then added to the mixture 2.52 ml of acetic anhydrous and then stirred for 30 minutes at 0 ° C. Dilute with 300 ml of methylene chloride and separate the layer of methylene chloride which is washed with water (3 X 150 ml), with saturated sodium bicarbonate (1 X 100 ml), brine (1 X 100 ml) and dried over MgS04. Evaporation of the methylene chloride gives 13.7 g of a dark oil which is chromatographed on a column of 450 g of silica gel. The column is eluted successively with a 1: 1 mixture of ether and hexane, a 2: 1 mixture of ether and hexane, and ether. The fractions of 18 ml each are collected. The fractions 176-224 are combined and concentrated to an oil which is crystallized from hexane, which gives 3.24 g (32%) of the trans isomer of the title compound, in the form of light yellow crystals, mp 65.5 ° -68 ° C.

m / e - 373 (m +)

IR (KBr): 5.82 (ketone C = 0), 5.75 (ester C = 0), 295 (NH) n.

The fractions 246-290 are combined and concentrated, giving 0.55 g (5%) of the crude isomer of the title compound as an oil. It is then purified by column chromatography as described above, to obtain the pure isomer as an oil.

m / e - 373 (m +)

IR (CHCI3): 5.82 (ketone C = 0), 5.67 (ester = C = 0), 2.92 (NH) n.

Analysis: Calculated for C22H31O4N:

C, 70.75; H, 8.37; N, 3.75%

Found: C, 70.90; H, 8.54; N, 3.79%

from lad, 1-5.6, 6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyloxy) -benzo [c] quinoline-9 (8H) -one.

d, l-trans-5,6,6aP, 7,10,10aa-hexahydro-l-acetoxy-3- (5-phenyI-2-penty! oxy) -benzo [c] quinoIein-9 (8H) -one , which is an oil.

m / e -421 (m +)

Analysis: Calculated for C26H3104N:

C, 74.08; H, 7.41; N, 3.32%

Found: C, 74.16; H, 7.59; N, 3.20%

d, l-cis-5,6,6aß, 7,10,10a /? - hexahydro-l-acetoxy-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline-9 (8H) -one, which is an oil.

15 m / e-421 (m +)

Analysis: Calculated for C26H3104N:

C, 74.08; H, 7.41; N, 3.32%

Found: C, 74.04; H, 7.49; N, 3.54%

20

and transforming d, l-5,6,6a, 7-tetrahydro-l-hydroxy-6a-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline-9 (8H) -oneen d , l-trans-5,6,6aß, 7,10,10aa-hexahydro-l-acétóxy-6a-

Methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline-9 (8H) -one,

and d, l-cis-5,6,6aß, 7,10,1 Oaß-hexahydro-1-acetoxy-6a-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline-9 (8H ) -one.

The isomeric products are converted to their hydrochlorides as described in the general salt formation procedure. The characteristics of the salts are given below:

35 hydrochloride isomer P.F (° C.)

m / e Rf (m +)

(a) Analysis (b) C H N

trans eis

107-110 94-102

435 0.74 68.92 435 0.72 68.74

7.17 2.86 6.93 3.12

40

The fractions 225-245 are combined and evaporated, which gives 2.69 g (26%) of a mixture of the isis and trans isomers which are separated by the procedure described above. The following compounds are prepared in a similar manner:

(a) Thin layer chromatography in benzene: ether 1: 1

(b) calculated for C27H3304N.CH1: C, 68.71; H, 7.26; N, 2.96 According to the method described above, the compounds of the following table were obtained:

(° c.)

me

Hold.

Find

ZW

r4

r5

r9

m.p.

(m +)

Formula

C, H, N

C, H, N

C-69.18

C-68.89

-0-CH (CH3) (CH2) 3C6H5

c2h5

H

<H

125-130

449

CÄO.KHCl

H-7.47 N-2.88

C-69.18

H-7.45 N-2.90

C-69.18

-o-ch (ch3) (ch2) 3c6h5

c2h5

H

"'h

153-155

449

c28h35o4n.hci

H-7.47 N-2.88

H-7.47 N-2.93

626,881

28

(° C.) M / e Hold. Find

ZW R4 Rs R9 m.p. (m +) Formula C, H, N C, H, N

C-76.00 C-75.88

-0-ch (ch3 (ch2) 3c6h5 c6h13 h '"h 103-104 505 c32h4304n h-8,57 h-8,47

N-2.77 N-2.84

C-76.00 C-75.62

-0-ch (ch3) (ch2) 3c6h5 c6h13 h 100-101 505 c32h4304n h-8.57 h-8.39

N-2.77 N-2.63

C-77.68 C-77.54

-0-ch (ch3) (ch,) 3c6h5 ch2ch2 h '"h 100-105 525 c34h3904n h-7.48 h-7.40

I N-2.66 N-2.65

c6h5

c-77.68 c-77.62

-0-ch (ch3) (ch,) 3c6h5 ch2ch2 h 118-119 525 c34h3904n h-7.48 h-7.61

I N-2.66 N-2.64

c6h5

C-75.73 C-75.82

-0-ch (ch3) (ch2) 3c5h5 c5hn h '"h 99-100 491 c31h4104n h-8.41 h-8.31

N-2.85 N-3.12

C-75.73 C-75.68

-0-ch (ch3) (ch2) 3c6hs c5h „h ^ h 129-130 491 c31h4104n h-8.41 h-8.26

N-2.85 N-2.95

C-75.44 C-75.50

-0-ch (ch3) (ch2) 3c6h5 c4h9 h '"h 86-88 477 c, 0h39o4n h-8,23 h-8,12

N-2.93 N-2.91

c-75.44 c-75.76

—0-ch (ch3) (ch2) 3c6h5 c4h9h h <«h 104-106 477 c3„ h3904n h-8,23 h-8,26

N-2.93 N-3.02

C-73.68 C-73.93

-0- (ch2) 3c6h, ch3 h '"h 132-134 407 c2sh2904n h-7.17 h-7.05

N-3.44 N-3.41

C-73.68 C-73.45

—0- (ch2) 3c6hs ch3 h '"h 110-112 407 c25ho904n h-7.17 h-7.23

N-3.44 N-3.39

(a) and (b): Transformed into the hydrochloride by the general salt formation procedure. Thin layer chromatography in benzene / ether (1: 1) gave Rf of (a) = 0.74 and Rf of (b) = 0.72.

Example 7 NMR (60 MHz) here, presents a singlet characteristic of, l-Trans-5,6,6aß, 7,8,9,10,1 Oaa-octahydro-l-acetoxy-9- at 2.82 ppm for methyl acetate.

hydroxy-6fi-methyl-3- (2-heptyloxy) benzo [c] quinoline 50 The main and minor isomers are separated, as

To a stirred solution of 150 mg (0.39 mmol) of d, l-trans- as follows: 180 mg of the alcohols of d, l-trans-5,6,6aß, 7,10,10aa-hexahydro- are introduced l-ac0toxy-6ß-methyl-3- (2- 5,6,6aß-7,8,9,10,10aa-octahydro-l-ac0toxy-9-hydroxy-6ß-heptyloxy) -benzo [c] quinoline- 9 (8H) -one in 10 ml of ethanol methyl-3- (2-heptyloxy) benzo [c] quinoline in a column at 0 ° C, 40 mg of sodium borohydride are added. After containing 15 g of silica gel and eluting with a sol-half hour mixture, the reaction mixture is poured into a mixture made up of 3 parts of benzene and 1 part of ether. 50 ml of 5% acetic acid and 75 ml of ether are collected at 15 ml temperatures. Fractions 6-8 are pooled, concentrated with ice. After separation of the ethereal layer, the reaction is carried out under reduced pressure, which gives 13 mg of the dj.-again extracts the aqueous phase with ether (2 × 50 ml). 5,6,6aß, 7,8,9,10,10aa-octahydro-l-ac0toxy-9a-hydroxy-The ethereal extracts are washed successively with water 6ß-möthyl-3- (2-heptyloxy) benzo [c] quinoline.

(2 X 50 ml), saturated sodium bicarbonate (1 X 50 ml), a 60 The fractions 11-16 are combined and concentrated, which brines (1 X 75 ml), they are dried over MgSO 4, they are filtered and 83 mg of d, l-trans-5,6,6aß, 7,8,9,10,1 Oaa-octahy- are given

Ies concentrated under reduced pressure, which gives 156 mg of a dro-1-ac0toxy-9ß-hydroxy-6ß-methyl-3- (2-hepty! Oxy) ben-

white foam containing a mixture of axial alcohol (low zo [c] quinoline.

quantity) and equatorial alcohol (predominant quantity) of other compounds prepared from the appropriate reagents d4-trans-5,6,6aß, 7,8,9,10,10aa-octahydro-l-ac0toxy- 9-65 according to the previous procedure include the following:

hydroxy-6ß-methyl-3- (2-heptyloxy) benzo [c] quinoföne. d, l -trans-5,6,6aß, 7,8,9,10,1 Oaa-octahydro-l-acetoxy-9-

m / e - 389 (m +) hydroxy-6P-methyl-3 (5-phenyl-2-pentyloxy) benzo [c] quino-

IR (CHCl3 5.72 | x (carbonyl of the ester) lein.

29

626

m / e-437 (m +)

IR (CHC13) - 5.70 [x (ester carbonate)

The transformation into hydrochloride provides a solid, mp 188-190 ° C. Recrystallization from a 25: 1: 100 mixture of acetone, methanol and ether provides an analytical sample of 9β-alcohol, mp 193-194 ° C.

Analysis: Calculated for C27H3504N, HC1:

C, 68.42; H, 7.66; N, 2.96%

Found: C, 68.48; H, 7.70; N, 2.89%

The conversion to methane sulfonate (with me-thanesulfonic acid in dichloromethane) gives a solid which is recrystallized from ethyl acetate, obtaining white crystals, mp 110-114 ° C. 1

IR (CHCI3). 2.95, 3.70, 3.95, 5.60, 6.06, 6.19 and 6.27 fi.

Analysis: Calculated for C27H3504N.CH403S:

C, 63.02; H, 7.37; N, 2.63%

Found: C, 62.90; H, 7.31; N, 2.74%;

d, l-cis-5,6,6aP, 7,8,9,10,10aP-octahydro-l-acetoxy-9-hydroxy-6P-methyl-3- (5-phenyl-2-pentyloxy) benzo [c ] quino-leine.

m / e-437 (m +)

IR (CHCI3) - 5.71 [i (carbonyl of the ester). j_-trans-5,6,6aß-7,8,9,10,10aa-octahydro-l-ac0toxy-9ß-hydroxy-6ß-methyl-3- (5-ph0nyl-2-pentyIoxy) benzo [c] quino -line; mp 120-125 ° C. (dec.) as hydrochloride. ["Iß5 -98.57 0 (c = 0.351, CH3OH)

m / e-437 (m +)

Analysis: Calculated for C27H3504N.HC1:

C, 68.42; H, 7.66; N, 2.96%

Found: C, 68.24; H, 7.68; N, 3.00% 35

U

25

30

U

a +

U

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d-trans-5,6,6aß, 7,8,9,10,10aa-octahydro-l-ac0toxy-9ß-hydroxy-6ß-methyl-3- (5-plwnyl-2-pentyloxy) -benzo [c] quino-leine; mp 120-125 ° C (dec.) in the form of the hydrochloride.

[a] o = + 99.33 0 (c = 0.30, CH3OH) 40

m / e-437 (m +)

Analysis: Calculated for C27H35O4H.HCI:

C, 68.42; H, 7.66; N, 2.96%

Found: C, 68.41; H, 7.54; N, 2.95% 45

In the same way, the compounds given in the table below are prepared from the appropriate reagents.

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626 881 30

Similarly, the following compounds were prepared: OH

0-COCH-

0-ÇH- (CÎ! 2) 3-C6H5 C1U

HCl 3

Configuration

(° C)

m.p.

m / e (b) Analysis (m +) C H

NOT

25 (d) D

(-) 2'R, 6S, 6aR, 9R, 10aR 145-154 437 68.41 7.66

(dee.)

(-) 2'S, 6S, 6aR, 9R, 10aR 224-225 437 68.09 7.47

(dee.)

+ 2 ', 6R, 6aS, 9S, 1 OaS

135-140 437 67.29 7.56 (dee.)

+ 2'R, 6R, 6aS, 9S, l OaS 218-220 437 67.75 7.58

(dee.)

(b) 100%

(c) Wedge, for C27H3504N.HC1: C: 68.41; H: 7.66; N: 2.95

(d) C = 1.0, CH3OH

2.95 2.94 3.02 2.89

-100

-118

+ 110

+ 110

ZW

-C (CH3) 2C6H, 3

(° C)

R4 R5 Rfi m.p.

me

(m +) Formula

CH3 H H 108-112 397 Ç ^ NC ^

-OCH (CH3) (CH2) 3C6H5 H CH3 H 125-130 433 C27H3i04N [6R, 6aR]

-OCH (CH3) (CH2) 3C6H5 CH3 H H 145-146 433 C27H3104N [6S, 6aR]

-OCH (CH3) (CH2) 3C6H5 CH3 H H 167-168 433 C27H3104N [2'S, 6S, 6aR]

Hold. Found C, H, N C, H, N

C-75.53 C-75.62 H- 8.87 H- 8.73 N- 3.52 N- 3.52

C-74.80 C-74.96 H- 7.21 H- 7.11 N- 3.23 N- 3.19

C-74.80 C-74.91 H- 7.21 H- 7.20 N- 3.23 N- 3.24

C-74.80 C-74.66 H- 7.21 H- 7.20 N- 3.23 N- 3.33

31,626,881

(° C.) M / e Hold. Find

ZW R4 R5 Rf) m.p. (m +) Formula C, H, N C, H, N

C-74.80 C-74.58

-OCH (CH,) (CH2), C6H,) CH3 H H 120-121 433 C27H3104N H- 7.21 H- 7.19 [2'R, 6S, 6aR] N- 3.23 N- 3.27

C-73.63 C-73.38

-OCH2CH2C6H3 CH3 H H 159-160 391 C24H2504N H- 6.44 H- 6.41

N- 3.58 N- 3.59

Example 8

The following compounds are prepared in a similar manner from the appropriate reagents:

ZW

Rj

-0-ch (ch3) (ch2), c6h5 cshn

-0-ch (ch3) (ch2) 3c6h5 c4h9

-0-ch (ch3) (ch2) 3c6h5 ch3

(° C.) M / e Rs R6 m.p. (m +)

H H 209-210 493

H H 159-160 479

H H 130-138 409

Formula

Hold. Found C, H, N C, H, N

-0-ch (ch3) (ch2) 3c6h5 c3h7

-0-CH (CH3) (CH2) 3C6H5 C2H5

-0-ch (ch3) (ch2) 3c6h5 c6h1:

-0-ch (ch3) (ch2) 3c6h5 c3h7

-o- (ch2) 2c6h5

CH,

H H 193-195 465

H H 154-157 451

H H 196-199 507

H CH, 154-156 479

H H 210-212 395

C (CH3) 2- (CH2) 5CH3 CH3 H H 114-115 401

(a) = eis 6a, 10a c31h43o4h.hci

C, nH4i04N-HCl

C ^ H ^ O.N.HCI

-0-CH (CH3) (CH2) 3C6H5 (CH2) 2C6H5 H H 199-200 527 C34H4104N.HC1

c29h39o4n.hci c28h37o4n.hci

C „H4 <i04N.HCl

C30H41O4N.HCl c, 4h, 9o4n.hci c25h39o3n

C-70.23 C-70.04 H- 8.37 H- 8.15 N- 2.64 N- 2.30

C-69.82 C-70.05 H- 8.20 H- 8.44 N- 2.71 N- 2.66

C-67.33 C-67.60 H- 7.23 H- 7.22 N- 3.14 N- 3.06

C-72.39 C-72.33 H- 7.51 H- 7.38 N- 2.48 N- 2.50

C-69.35 C-69.89 H- 8.03 H- 8.36 N- 2.79 N- 3.05

C-68.88 C-68.58 H- 7.85 H- 7.52 N- 2.87 N- 2.79

C-70.61 C-69.75 H- 8.53 H- 8.19 N- 2.58 N- 2.51

C-69.79 C-69.76 H- 8.21 H- 8.16 N- 2.72 N- 2.74

C-66.73 C-66.37 H- 7.00 H- 6.93 N- 3.24 N- 3.18

C-74.77 C-74.47 H- 9.79 H- 9.24 N- 3.49 N- 3.24

626,881

32

Example 9

dl-trans-5,6,6aß, 7,10,1 Oaa-hexahydro-1-acetoxy-5-acetyl-6ß-nwthyl-3- (5-phenyl-2-pentyloxy) -benzo [cjquinoline-9 (8H ) -one

3.49 g (8 mmol) of dl-trans-5,6,6aß, 7,8,9,10,10aa-octahy-dro-l-acetoxy-6P are dissolved in 20 ml of alcohol-free chloroform -methyl- (5-phenyl-2-pentyloxy) -benzo [c] -quinoline-9 (8H) -one, the solution is cooled in an ice bath, and 14 ml of pyridine are first added ( dried on KOH pellets) then a solution of 0.95 ml (13 mmol) of acetyl chloride in 5 ml of chloroform. The homogeneous solution is stirred for 18 hours at room temperature, the mixture is poured into 50 ml of ice water, and it is extracted with twice 25 ml of chloroform. The combined organic phases are successively washed with 25 ml of saturated NaHCO3, 25 ml of water and 25 ml of NaCl solution, dried over MgSO4, filtered and evaporated to dryness at reduced pressure. Purification is carried out by chromatography (200 g of Brinkman silica gel; solvent: 3 p. Cyclohexane, 1 p. Ether), and 2.20 g (yield 83.8%) of the title compound are obtained.

Analysis: Calculated for Ç29H35O5N:

C, 72.90; H, 7.39; N, 2.80 Found: C, 72.69; H, 7.48; N, 2.49%

IR (KBr): 2.90 jx (m), 3.38 | x (s), 3.48 (x (s), 5.62 [x (s), 5.78 y. (S), 6 .00 n (s), 6.15 fi (s), 6.30 ji (s), m / e: 477 (m +)

1 H NMR (60 MHz); $ 0} ^ (ppm): 7.20 (m, 5H, aroma), 6.53 (d, 1H, C_4), 4.71-4.08 (m, 2H, methines), 2.29 ( s, 3H, acetate -CH3), 2.02 and 2.04 (2s, 3H, amide -CH3), 1.25 and 1.23 (2d, 3H, C_ 6 CH), 1.12 (d, 3H , CH3 of the side chain), 3.20-1.36 (other remaining protons).

Similarly, dl-cis-5,6,6aß, 7,10aß-hexahy-dro-l-ac0toxy-6ß-möthyl-3- (5-ph0nyl-2-pentyloxy) benzo [c] -quinoline- 9 (8H) one is transformed into dl-cis-5,6,6aß-7,10aß-hexahydro-l-ac0toxy-5-ac0tyl-6ß-m0thyl-3- (5-plre-nyl-2-pentyloxy) benzo [c] quinoline-9 (8H) -one.

m.p. 125-128 ° C, 82% yield.

Analysis: Calculated for C29H3505N:

C, 72.90; H, 7.39; N, 2.80%.

Found: C, 72.80; H, 7.35; N, 2.70%.

'H NMR (60 MHz) 0 $ ^,: 7.22 (m, 5H, arom.), 6.55 (2d,

2H, C2 and C4), 5.02-4.62 (m, 1H, C_ 6 methine), 4.52-4.12 (m, 1H, methine in side chain), 2.28 (s, 3H, Acetate CH3, 2.11 and 2.13 (3H, amide CH3), 1.26 and 1.28 (3H, C6 CH3), 1.22 (d, 3H, CH3 of side chain), 3.42-1.65 5 (variable remaining protons).

IR (KBr): 2.95 \ i (w), 3.43 [x (s), 5.65 | x (s), 5.81 [x (s), 6.02 jx (s), 6 , 16 dx, 6.32 p. (s), 6.70 [x (s).

m / e: 477 (m +).

10 Example 10

dJ-cis-5,6,6aß, 7,8,9,10,10aß-octahydro-l-acitoxy-9a-hydr-oxy-6fi-methyl-3- (5-phenyl-2-pentyloxy) benzo [c ] quinoline

To a solution of 1.0 g (2.296 mmol) of d, l-cis 5,6,6aß, 7,10,1 Oaß-hexahydro-1-acetoxy-6ß-methyl-3- (5-15 phenyl-2 -pentyloxy) benzo [c] quinoline-9 (8H) -one in 100 ml of dry tetrahydrofuran at -78 ° C, 4.6 ml of a 0.5 M solution of tri-s-butylborohydride of potassium (2.296 mmol) drop by drop in 5 minutes. The reaction mixture is stirred for an additional 30 minutes at 20 - 78 ° C and then poured, with stirring, into a solution of 250 ml of 5% acetic acid and 500 ml of ether, previously cooled to 0 ° C . The layers are separated and the aqueous layer is extracted with an additional 250 ml of ether. The combined ethereal extracts are washed successively with water (2 × 250 25 ml); saturated sodium bicarbonate solution (1 X 250 ml), and brine (IX 250 ml), dried over MgSO4 and concentrated in vacuo to give a yellow oil (1.4 g). The crude oil is chromatographed on 100 g of silica gel using a 3: 1 mixture of benzene and ether as the eluent. After elution of the less polar impurities, the title compound is isolated as a clear oil (700 mg). The oil is dissolved in 35 ml of ether and treated with ether saturated with HCl gas to obtain the hydrochloride of the title compound (448 mg), mp 115-124 ° C after recrystallization from a mixture 35 ether and chloroform.

SM (molecular ion)

IR (KBr) 5.58 (> C = 0 of the ester)

Analysis: Calculated for C-, 7H3504N.HC1: 40 C, 68.41; H, 7.66; N, 2.96%

Found: C, 68.52; H, 7.91; N, 2.73%

The following compounds are prepared in the same way from the appropriate reagents:

PF SM

-Z-W R4 R, Rf) Rs (° C) mol ion.

5-phenyI-2-pentyloxy CH, H CH, '"H 159-162"' 451

H CH, H "H oil

* 'hydrochloride.

Analysis: Calculated for C2KH3704N.HCI: C, 68.88; H, 7.85; N, 2.87%

Found: C, 68.42; H, 7.78; N, 2.75%

Example 11

d, 1 -5,6,6aß, 7,8,9,10,1 Oa-octahydro-1,9-diacetoxy-6fi-mé-thyl-3- (2-heptyloxy) benzo [c] quinoline

1.2 g of the non-chromatographed reduction product of d, l-trans-5,6,6aP, 7,10,10aa-hexahydro-l-acetoxy-6P-methyl-3- (2-heptyloxy) benzo are stirred [c] quinoline-9 (8H) -on of Example 3, with an excess of acetic anhydride and pyridine overnight at room temperature. The mixture is poured onto ice water, the aqueous mixture is extracted with ether (3 X 100 ml), and the combined extracts are washed with water, brine and then dried over MgSO4 and they are dried. evaporates. The residue is subjected to column chromatography (40 g of silica gel, benzene: ether 9: 1 as eluting solvent), which gives 680 mg of d, l-trans-5,6,6aß -7,8,9,10,10aa-octahydro-l, 9-diacetoxy-6p-methyl-3- (2-heptyloxy) -benzo [c] quinoline desired, which crystallizes by addition of hexane and acetate d 'ethyl, mp. 86-87 ° C.

m / e -431 (m +)

IR (KBr) - 5.73 | x (carbonyl of esters)

'H NMR (60 MHz) ô ^, 3 (ppm): 5.88 (broad s, H2, H4 -2H), 2.28 and 2.05 [2 singlets of 3 protons, CH3-C (= 0) -] and about 0.8-5.0 (multiplets, remaining protons);

Analysis: Calculated for C25H3705N:

C, 69.57; H, 8.64; N, 3.25%

Found: C, 69.51; H, 8.54; N, 3.14%

Similar treatment of 60 mg of d, l-trans-5,6,6aß, 7,8,9,10,10aa-octahydro-l-ac0toxy-9ß-hydroxy-6ß-m0thyl-3- (4-phenylbutyloxy ) benzo [c] quinoline in 1 ml of pyridine and 1 ml of acetic anhydride for one hour at room temperature, provides d, l-trans-5,6,6aß! = t:! 7,8,9, 10.10aa-octahydro-1 ^ -diacetoxy-6p-methyl-3- (4-phenylbutyloxy) -benzo [c] quinoline desired mp 146-147 ° C after recrystallization from a 1: 1 mixture of ethyl acetate and of hexane. m / e -465 (m +)

Analysis: Calculated for C28H35O5N:

C, 72.23; H, 7.58; N, 3.01%

Found: C, 72.17; H, 7.61; N, 3.08%

Preparation R

d, l-trans-5,6,6aß, 7,8,9,10,10aa-octahydro-l, 9-dihydroxy-6fi-methyl-3- (2-heptyloxy) benzo [c] quinoline

A solution of 130 mg of dil-trans-5,6,6aß, 7,8,9,10,10aa-octahydro-l-ac0toxy-9-hydroxy-6P-methyl-3- (2) is stirred at room temperature. -heptyloxy) benzo [c] quinoline and 46 mg of potassium carbonate in 35 ml of methanol.

After 30 minutes, the reaction mixture is neutralized with acetic acid and concentrated under reduced pressure. The residue is dissolved in 100 ml of ether, washed successively with 2 times 35 ml of water, 1 time 35 ml of sodium bicarbonate, 1 time 40 ml of brine, dried over MgSO 4 and concentrated under reduced pressure, which gives 96 mg of d, l-trans-5,6,6aß, 7,8,9,10,10aa-octahydro-l, 9-dihydroxy-6ß-m0thyl-3- (2-heptyloxy ) benzo [c] quinoline, in the form of an amorphous solid, mp 80-100 ° C with decomposition.

m / e - 347 (m +)

The NMR spectrum (CDCl3, 60 MHz), does not show the absorption for acetate methyl and the IR spectrum (CHCl3) does not show an absorption for a carbonyl in the ester.

In the same way, the following compound is prepared starting from the corresponding 1-acetoxy derivative of Example 7.

d, l-trans-5,6,6aß, 7,8,9,10,10aa-octahydro-l, 9-dihydr-oxy-6ß-m0thyl-3- (5-ph0nyl-2-pentyloxy) benzo [c ] quinoline. m / e —395 (m +)

The transformation into hydrochloride gives a powder, mp 151-156 ° C.

33 626 881

IR (KBr): 3.00.4.00 (H $ =); 6.10 and 6.25 jx.

Similarly, the d, l-trans-5,6,6aß-7,10,10aa-hexahydro-l-acetoxy-5-methyl-6P-methyl-3- (2-heptyloxy) benzo [c] quinoline is hydrolyzed. -9 (8H) -one in compound 1-hydroxy corres-5 laying, mp 157-160 ° C.

m / e-359 (m +)

Analysis: Calculated for C22H3303N:

C, 73.50; H, 9.25; N, 3.90%

10Found: C, 73.16; H, 9.14; N, 3.85%

Example 12

d, 1 -trans-5,6,6aß, 7,10,1 Oaa-hexahydro-1 -acétoxy-3- (2-hep-tyloxy) -5-benzoyl-6fi-methylbenzo [c] quinoline- 9 (8H ) -one 15 To a stirred solution of the product of Example 3, 812 mg of d1l-trans-5,6,6aß, 7,10,10aa-hexahydro-l-ac0toxy-6ß-m0-thyl-3- ( 2-heptyloxy) benzo [c] quinoline-9 (8H) -one in 2.5 ml of pyridine, 421 mg of benzoyl chloride in 5 ml of chloroform is added. After 2 hours, the reaction mixture is poured onto galee and extracted twice with ether. The combined ethereal extracts are washed with water and a sodium bicarbonate solution, dried over MgSO 4 and filtered, which gives, after concentration and crystallization in a mixture of ether and petroleum ether, the d, l-trans-25 5,6,6aß-7,10,10aa-hexahydro-l-acetoxy-3- (2-heptyloxy-5-benzoyI-6P-methylbenzo [c] quinoline-9 (8H) -one mp 108-110 ° C.

m / e —491 (m +).

The repetition of the previous procedure but using an equivalent amount of acetyl chloride in place of benzoyl chloride, and the appropriate benzo [c] quinoline, provides the following compound:

cy.-trans-5,6,6aß, 7, 10,10aa-hexahydro-1-acetoxy-3- (2-heptyloxy) -5-acetyl-6p-methylbenzo [c] luinoline-9 (8H) -one. 35 m / e - 433 (m +)

Example 13

d, l-trans-5,6,6aß, 7,10,1 Oaa-hexahydro-1-acetoxy-5-methyl-40 6ß-methyl-3- (2-heptyloxy) -benzo [c] quinoline-9 ( 8H) -one To a stirred solution of 387 mg of d, l-trans-5,6,6aß, 7, 10,1 Oa-hexahydro-1-acetoxy-6 ß-methyl-3- (2-heptyloxy) benzo [c] quinoline-9 (8H) -one in 3 ml of acetonitrile, cooled to 15 ° C., 0.5 ml of 37% aqueous formaldehyde is added 45 then 100 mg of sodium cyanoborohydride. Acetic acid is added to maintain a neutral pH until the reaction is complete, as evidenced by the absence of starting materials in thin layer chromatography. The product is isolated as follows. Ice water and ether are added to the reaction mixture, the ethereal layer is separated and the aqueous phase is extracted once more with ether. The ethereal layers are combined, dried and evaporated, giving d, l-trans-5,6,6aP, 7,10,10aa-hexahydro-l-acetoxy-5-methyl-6P-55 methyl -3- (2-heptyloxy) -benzo [c] quinoline-9 (8H) -one desired in the form of an oil.

The H NMR spectrum, (60 MHz, CDCl3) exhibits a characteristic absorption at 2.85 ppm for 5 5N-CH3.

In the same way, the following compounds are prepared from the appropriate reagents:

d, l-trans-5,6,6a | 3,7,10,10aa-hexahydro-l-acetoxy-5-me-thyl-3- (2-heptyloxy) benzo [c] quinoline-9- (8H) -one, an oil.

d, l-trans-5,6,6aß, 7,8,9,10ct, 10a -octaydro-l, 9-diacetoxy-5-methyl ^ -methyl-3- (2-heptyloxy) benzo [c] quinoline, a 65 oil.

m / e - 445 (m +)

In addition, the following compounds are prepared in the same way:

626,881

34

5 r o-c-ch.

Z-W

-z-w

R4 R5 Rfî Rg pf m / e (m +)

CH,

-0-ch- (ch2) 3c6h5

ch3

CH, H

CH,

'H

-0-ch- (ch2) 3c6h5 ch3 h ch, -4 h

94-97 ° C

oil2

449

449

-0- (CH2) 4C6H5 CH3 H

'' in hydrochloride form

CH,

"H

102-103 ° C. 3435

Analysis: Calculated for C28H35N • CHI: C, 69.19; H, 7.47; C, 68.72; H, 7.18; ;: Calculated for C28H3504N: C, 74.80; H, 7.85; C, 74.66; H, 8.05; ;: Calculated for C27H3304N: C, 74.45; H, 7.64; C, 73.89; H, 7.51;

Found: 2 Analysis:

Found: 'Analysis:

Found:

N, 2.88% N, 2.74%

N, 3.12% N, 2.66%

N, 3.22% N, 3.04%

Example 14

d, l-trans-5,6,6aß, 7,8,9,10,10aa-octahydro-l, 9-dihydroxy-5-ethyl-6P-methyl-3- (2-heptyloxy) benzo [c] quinoline .

To a solution of 100 mg of lithium aluminum hydride in 5 ml of dry tetrahydrofuran (cooled in an ice and water bath), a solution of 90 mg of d, 1 -trans is added dropwise. -5,6,6aß, 7,8,9,10,10aa-octahydro-1,9, di-hydroxy-5-acetyl-6p-methyl-3- (2-heptyloxy) benzo [c] quino-leine in 3 ml of tetrahydrofuran. When the addition is complete, the reaction mixture is heated to reflux for one hour and then allowed to cool to room temperature. Equivalent amounts of water and then 3N potassium hydroxide are added, the resulting precipitate is filtered and the filtrate is concentrated in vacuo, giving the desired N-ethyl derivative as an oil.

m / e-375 (m +)

Example 15

d, l-trans, 5,6,6aß, 7,8,9,10,1 Oaa-octahydro-1-acetoxy-9-hydr-oxy-5-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline

1.1 ml of a 7% aqueous solution of formaldehyde are added to a solution of d, l-trans-5,6,6aß, 7,10,10aa-hexahy-dro-l-acetoxy-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline-9- (8H) -one in 15 ml of acetonitrile at room temperature, then 0.262 g of sodium cyanoborohydride. The reaction mixture is stirred for one hour, during which time the pH is kept neutral by the addition of acetic acid as necessary. 0.262 g of additional cyanoborohydride and 15 ml of methanol are added to the reaction mixture which is then acidified to pH 3, which is stirred for 2 hours and which is concentrated under reduced pressure to an oil. The oil is diluted with 50 ml of water, then the pH is adjusted to 9-10 at

25 using an aqueous solution of sodium hydroxide and the alkaline mixture is extracted with ether (sometimes 200 ml). The combined ether extracts are washed with brine, dried over Na2SO4 and concentrated under reduced pressure to a clear oil. Then the oil is dissolved in a 50% mixture of ether and hexane and introduced onto a column of silica gel. The column is eluted first with a 50% ether-hexane mixture and then with 60%, 70% and 75% ether-hexane mixtures. The eluate is checked by thin layer chromatography (ether / hexane 10: 1). The first product collected is 35 d, l-trans-5,6,6a, 7,10,10a-hexahydro-l-acetoxy-5-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline-9- (8H) -one (0.125 g).

m / e — 435 (m +)

40 Analysis: Calculated for C27H3304N:

C, 74.45; H, 7.64; N, 3.22%

Found: C, 74.06; H, 7.77; N, 3.31%

The second product is the 9a-hydroxy diastereomer of the title compound 45 (25 mg).

m / e —437 (m +)

Analysis: Calculated for C27H3504N:

C, 74.11; H, 8.06; N, 3.20%

50 Found: C, 73.96; H, 8.34; N, 3.00%.

The third product is the re-9β-hydroxy diastereon of the title compound (0.7 g)

m / e-437 (m +)

55

Analysis: Calculated for C27H3504N:

C, 74.11; H, 8.06; N, 3.20%

Found: C, 73.56; H, 7.86; N, 3.21%

60

Similarly, the d, 1 -trans, 5,6,6aß, 7,10,1 Oaa-hexa-hydro-l-acetoxy-3- (2-heptyloxy) benzo [c] quinoline-9 (8H) is treated. one with sodium cyanoborohydride to obtain:

d, 1 -trans-5,6,6aß, 7,10, 10aa-hexahydro-1-acetoxy-5-me-65 thyl-3- (2-heptyloxy) benzo [c] quinoline-9- (8H) - one as an oil.

m / e-387 (m +)

IR (CHC13): 5.80 (C = 0 ketone), 5.65 (C = 0 of the ester),

35

626,881

Analysis: Calculated for: ^ 23 ^ 33 ^ 4 ^:

C, 71.29; H, 8.58; N, 3.61%

Found: C, 70.78; H, 8.71; N, 3.27%

d, 1 -trans-5,6,6aß, 7,8,9,10,1 Oaa-octahydro-1-acetoxy-9P-hydroxy-5-methyl-3- (2-heptyIoxy) benzo [c] quinoIéine, an oil.

m / e-389 (m +)

IR (CHClj): 2.80 (O-H); 5.70 (C = 0 of the ester).

Analysis: Calculated for C23H35O4N:

C, 70.92; H, 9.06; N, 3.60%

Found: C, 70.56; H, 8.95; N, 3.56%

and the d, 1 -trans-5,6,6aß, 7,10,1 Oaa-hexahy-dro-l-acetoxy ^ -methyl-3- (5-phenyl-2-pentyloxy) benzo [c] - quinoline-9 (8H) -one in:

cU-trans-5,6,6aß, 7,10,1 Oaa-hexahydro-1-acetoxy-5-methyl-6ß-methyl-3- (5-ph6nyl-2-pentyIoxy) benzo [c] quinoMine- 9 (8H) -one;

d, 1 -trans-5,6,6aß, 7,8,9,10,1 Oaa-octahydro-1-acetoxy-9ß-hydroxy-5-m0thyI-6ß-m0thyI-3- (5-phönyl-2- pentyloxy) -benzo [c] -quinoline, which is isolated in the form of the hydrochloride, mp 163-165 ° C.

m / e-451 (m +)

Example 16

d, l-trans-5,6,6aß, 7,10,1 Oaa-hexahydro-l-acetoxy-5-ìsobuty-ryl-3 - (5-phenyl-2 -pentyloxy) benzo [c] quinoline-9 ( 8H) -one

A solution of 114 mg (1.07 mmol) of isobutyryl chloride in 20 ml of chloroform is added slowly, with stirring, to a solution of 450 mg (1.07 mmol) of d, l-trans-5,6 , 6aß, 7,10,10aa-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline-9 (8H) -one in 1,5 ml of dry pyridine at 0 ° C and under a nitrogen atmosphere. The reaction mixture is stirred for 5 hours and then poured into 50 ml of ice and water. The chloroform layer is separated and the aqueous layer is extracted with chloroform (2 times 20 ml). The chloroform extracts are combined and washed with 10% hydrochloric acid (2 times 10 ml) then with brine (1 time 10 ml) and dried over MgSO 4. The concentration of the chloroform solution under vacuum gives a yellow oil which solidifies on standing. Trituration of the solid with hexane gives a white crystalline solid which is collected by filtration and which is dried (400 mg), mp 128-129 ° C.

The concentration of the hexane filtrate gives 121 mg of oil.

Example 17

d, l-trans-5,6,6aß, 7,8,9,10,10a-octahydro-l -acetoxy-9ß-hy-droxy-5-isobutyryl-3 - (5-phenyl-2 -pentyloxy) benzo [c] quino-leine

38 mg (1.0 mmol) of sodium borohydride is added slowly to a solution of 260 mg (0.529 mmol) of d, l-trans-5,6,6aß, 7,10, l Oaa-hexahydro-1-acetoxy -5 -isobutyryl-3- (5 -phenyl-2-pentyloxy) -benzo [c] quinoline-9 (8H) -one (260 mg, 0.529 mmol) in 20 ml of absolute ethanol, at 5-10 ° C under a nitrogen atmosphere. The reaction mixture is stirred for one hour and acidified with 10% hydrochloric acid. The ethanol is removed by concentration under reduced pressure. 10 ml of water are added to the resulting solution which is then extracted with ethyl acetate (2 times 50 ml). The extracts are combined, washed with brine and then dried, (MgS04). Concentration in vacuo provides the title compound as an amorphous solid (213 mg) which is used without further purification.

Example 18

d, l-trans-5,6,6aß, 7,8,9,10,1 Oaa-octahydro-1,9ß-diacitoxy-5-isobutyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline.

Under a nitrogen atmosphere, a solution of d, l-5trans-5,6,6aß, 7,8,9,10,10aa-octahydro-l-ac0toxy-9ß-hydr-oxy-5-isobutyryl-3 is added. - (5-phenyl-2-pentyloxy) -benzo [c] quinoline (213 mg, 0.432 mmol) in 5 ml of tetrahydrofuran to a suspension of 100 mg (2.6 mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran at am-10 biante temperature. The mixture is stirred overnight and then 0.1 ml of water, 0.1 ml of a 15% sodium hydroxide solution and 0.3 ml of water are added. Then filtered under nitrogen and the filter cake is washed with tetrahydrofuran (2 times 5 ml). The combined filtrate and washing solution are concentrated until a reddish oil (0.174 g) is obtained.

The oil is dissolved under nitrogen in 1 ml of pyridine and the solution is cooled to 0 ° C. To the pyridine solution is added with stirring 1 ml of acetic anhydride and the reaction mixture is stirred for 30 minutes at 0 ° C. It is then poured into 20 ml of water and extracted with ethyl acetate (3 times 25 ml). The extracts are combined, washed with brine, dried over MgSO4 and concentrated to a crude oil (184 mg). The oil is purged with nitrogen and chromatographed on silica gel (40 g) using a 9: 1 mixture of ben-zene and ether as the eluent. Fractions of 10 ml each are collected. Fractions 2:10 are combined and concentrated to an oil (109 mg).

m / e —521 (m +)

30 Analysis: Calculated for C32H4305N:

C, 73.67; H, 8.31; N, 2.68%

Found: C, 74.33; H, 8.89; N, 2.23%

'H NMR (60 MHz) ô $$ ci, (PPm): 7> 22 (s. 5H, aromatics), 6.05 (d, 1H, aromatic), 5.90 (d, 1H, aromatic ), 4.90 (wide, 1H) 4.30 (wide, 1H), 3.10 (d, 2H, N-CH2), 2.90 (d, 2H, N-CH2), 2.70 (s broad, 2H), 2.40 and 2.15 (s, 6H, 2-CH3-COO-), 1.85 (s broad, 2H, H7 and H8), 1.5 (m), 1, 05

40 (d, 6H—> 1.0-3.0 (variable, remaining protons).

The following preparations give illustrations of the possible transformations of the compounds obtained.

45 SI Preparation

dl-trans-5,6,6aß4, 1,10,10aa-hexahydro-5-acetyl-l -hydroxy-6fi-methyl-9-methylene-3 - (5-phenyl-2 -pentyloxy) -benzo [c] -quinoline.

A dispersion of 0.94 g (39 mmol) of sodium hydride 50, obtained by washing 1.87 g of 50% sodium hydride in a dispersion of a mineral oil with dry pentane, is heated in 75 ml of dimethyl sulfoxide for 2 '/? hours at 50 ° C. After addition of 15.32 g (43 mmol) of triphenyl-methylphosphonium bromide, the reaction mixture is heated for 2 hours at 60 ° C. A solution of 1.86 g (4 mmol) of dl-trans-5,6,6aß, 7,10,10aa-hexahydro-1-acetoxy-5-acé-tyI-6P-methyl-3- (5 is added. -phenyl-2-pentyloxy) -benzo [c] quinoline-9 (8H) -one in 57 ml of dimethylsulfoxide, and the mixture is further heated for 30 minutes at 60 ° C. The refroi-60 di mixture is then poured into a mixture of water and ice (200 ml) containing 20 g of sodium bicarbonate. The whole is extracted with 2 × 50 ml of ethyl acetate, the combined organic phases are washed with 50 ml of water and 50 ml of brine, dried over mangesium sulphate, filtered and the mixture is evaporated. solvent 65 to obtain an orange oil (contains triphenylphosphine oxide, detected by thin layer chromatography). Purification is carried out by chromatography (125 g of silica gel according to Brink-man; solvent: 3 p. Of cyclohexane and 1 p. Of ether) to obtain

626,881

36

1.251 g of the title compound, yield: 74%; m.p. 174-176 ° C.

Analysis: Calculated for C ^ 8H3503N:

C, 77.56; H, 8.14; N, 3.23%

Found: C, 77.29; H, 7.96; N, 3.22%

IR (KBr): 2.98 | x (s), 3.34 n (m), 3.38 (x (m), 3.44 | x (m), 6.10 [x (s), 6 , 24 | x (s), 6.58 (x (s), 6.90 | x (s).

m / e: 433 (m +).

'' HNMR (60 MHz): 8.80 (s, 1H, phenol), 7.16 (m, 5H, aroma), 6.32 (d, 1H, C_2H), 6.09 (d, 1H, C_4H ), 4.64 (broad s, 2H, vinyl), 1.96 and 1.93 (2s, 3H, CH3 amide), 1.27 and 1.25 (2d, 3H, C6-CH3), 1.02 , d, 3H (CH3 side chain), 0.9-4.5 (variable remaining protons).

The following compound is prepared from the appropriate starting product:

dl-cis-5,6,6aß, 7,10,1 Oaß- hexahydro-5-acetyl-1-hydroxy-

6P-methyl-9-methylene-3- (5-phenyl-2-pentyloxy) -benzo [c] -

quinoline.

mp 168-169.5, yield: 88%.

Analysis: Calculated for C28H3503N:

C, 77.56; H, 8.14; N, 3.23%

Found: C, 77.25; H, 8.14; N, 3.12%.

1HNMr (60 MHz) Sgg ,: 8.82 (s, 1H, phenol), 7.16 (m, 5H, aroma), 6.36 (d, 1H, C_ 2H), 6.12 (d, 1H , C_4H), 4.68 (broad s, 2H, vinyl), 2.08 and 2.06 (2s, 3H, CH3 amide), 1.22 and 1.20 (2d, 3H, C_6CH3), 1.10 (d, 3H, CH3 side chain), 1.50 - 4.50 (variable remaining protons).

IR (KBr): 2.95 | X (m), 3.36 jx (s), 6.10 (X (s), 6.33 fx (s), 6.88 (i (s), 7, 20 [x (s), 7.35 | x (s), 8.50 u (s).

m / e: 433 (m +).

Preparation S2

(2 R, 6S, 6aR, 9R, 10aR) - (-) - l-Acetoxy-5,6,6a, 7,8,9,10,10a-octahydro-9-hydrOxy-5,6-dimethyl-3 - (5-phenyl-2-pentyloxy) -benzo [c] quinoline.

To a stirred solution of 1.0 g (2.1 mmol) is added hydrochloride from (2'R, 6S, 6aR, 9R, 10aR) - (-) -l-acetoxy-5,6,6a, 7, 8,9,10,10a-octahydro-9-hydroxy-6-methyl-3- (5-phe-nyl-2-pentyloxy) -benzo [c] quinoline in 30 ml of CHCl3, 30 ml of a saturated solution NaHCO3, and stirred for 5 minutes at room temperature. The layers are separated and the aqueous layer is extracted with 20 ml of CHCl3. The combined chloroformed layers are dried over MgSO 4, filtered and the solvent is removed in vacuo to obtain the free base in the form of a colorless foam.

This foam is dissolved in 4 ml of tetrahydrofuran, and 1.0 g of 5% Pd / C, 1.05 ml (18 mmol = 8.7 equiv.) Of glacial acetic acid and 15.8 are added. ml (0.20 mole = 100 equiv.) 37% aqueous formaldehyde. The mixture is placed in a Parr apparatus and hydrogenated for 50 minutes at 3.5 atmospheres. The catalyst is filtered on diatomaceous earth, and washed with ethyl acetate. The filtrate is diluted to 50 ml with ethyl acetate and this solution is washed successively with 3 × 100 ml of saturated NaHCO 3 solution, 3 × 75 ml of H20.1 × 75 ml of brine and dried over MgS04. The solvent is filtered and removed in vacuo to give a yellow viscous oil which is chromatographed on 50 g of silica gel (0.04 to 0.63 mm) and eluted with toluene / diethyl ether (1: 1). Similar fractions are combined which are dried under vacuum to provide a colorless oil which is redissolved in 50 ml of diethyl ether; dry HCl is bubbled under a nitrogen atmosphere and with stirring through this solution. The solid white precipitate is filtered under a nitrogen atmosphere and dried under vacuum (0.1 mm) for 24 hours at room temperature, and finally 0.45 g (rendt. 44%) of the title product is obtained with a pf from 90 to 95 ° C (decomposition).

NMR (CDC13) -2.73 ppm, singlet, 3H (N-CH3).

O

I

1R (KBr) - 4.25 [X [-N H <+> Cl (->] 5.61 (-O-Ç -CH3)

I

CH3

Wedge, for C28H3704N.HCI:

C, 68.90; H, 7.85; N, 2.87%

Found C, 68.60; H, 7.92; N, 2.77%.

[a] g = - 73 ° (C, 1.0, methanol).

Mass spectrum m / c = 451 (m +).

The following compounds are prepared in a similar manner: dl-1-ac0toxy-5,6,6aß hydrochloride, 7,8,9,10,10aa-octahy-dro-9p-hydroxy-5,6P-dimethyl-3- (1,1-dimethylheptyl) -ben-zo [c] quinoline,

mp 129-130 ° C (decomp.)

m / e = 415 (m +, 100%).

O

II

IR (KBr) - 5.67 (X (-C -CH3),

and dl-l-ac0toxy-5,6,6aß, 7,8,9, l0,10aa-octahydro-9ß-hydroxy-5-methyl-6ß-n-butyl-3- (5-ph0nyl-2-) hydrochloride pentyloxy) -benzo [c] quinoline.

mp106-108 ° C.

m / e = 493.

C31H4304N.HC1: Wedge.

C, 70.21; H, 8.37; N, 2.6%

Found: C, 71.02; H, 8.43; N, 2.6%

Preparation S3

dl-5,6,6aß, 7,8,9a, 10,1 Oaa-octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6fi-methyl-3- (1-methyl-4-phenylbutoxy) -benzò [c] -quinoline.

A stirred suspension of 47.4 g (0.10 mole) of dl-5,6,6aß, 7,8,9a, 10,10a "-octahydro-6ß-methyl-3- (1-methyl) hydrochloride is cooled. -4-phenylbutoxy) -benzo [c] quinoline in 500 ml of CHCl3 under an atmosphere of N2 at 0 ° C, and this suspension is treated with 250 ml of pyridine, then with 58 ml (0.50 mole) of chloride chloride benzoyl in 500 ml of chloroform. The homogeneous solution which forms at reflux is heated on a steam bath for one hour. The reaction-nel mixture is then poured onto crushed ice and the mixture formed is extracted with chloroform. The organic extracts are combined, washed successively with 2 × 500 ml of water, 10% hydrochloric acid, 500 ml of a saturated solution of sodium bicarbonate and 500 ml of saturated brine, dried over MgS04, filtered and concentrated to obtain 119 g of a light yellow oil. Chromatography on 2000 g of silica gel (eluted with 20% ethyl acetate in eyelohexane) gives 50.5 g (78%) of dl -5.6.6aß, 7,8,9ct, 10, lOaa-octahy-dro-l-acetoxy-5 ~ benzoyl-9-benzoyloxy ^ -methyl-3- (l-me-thyl-4-phenyibutoxy) -benzo [c] quinoline, mp 125 at 130 ° C.

Analysis: Calculated for C4IH4306N:

C, 76.24; H, 6.72; N, 2.17%

Found C, 76.35; H, 6.92; N, 2.19%

Separation of dl-5,6,6aß, 7,8,9a, 10, 10aa-octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6P-methyl-3- (la-methyl-4-phenylbutoxy) - benzo [c] quinoIin and dl-5,6,6aß, 7,8,9a, 10,1 Oaa-octahydro-l-acetoxy-i5-benzoyl-9-benzoyloxy-6p-methyl-3- (lp-methyl -4-phenylbutoxy) -benzo [c] quinoline

Recrystallization of 5.5 g of dl-5,6,6aß, 7,8,9a, 10,10aa-octoahydro-l-acetoxy-5-benzoyI-9-benzoyloxy-6P-methyl-3-

5

10

15

20

25

30

35

40

45

50

55

60

65

37

626,881

(1-methyl-4-phenylbutoxy) -benzo [c] quinoline from 21 of 2-propanol gave 23.8 g of a white solid, mp 136 at 138 ° C, and after two more recrystallizations from 2-propanol and one from acetonitrile, 5.7 g of the same compound la were finally obtained with a mp of 148 to 149 ° C. s

The filtrate of the first crystallization from 2-propanol of the above compound was evaporated to give a white foam which was triturated with 500 ml of ether to give 12.9 g of a white solid, mp 129 to 132 ° C. This solid was triturated two more times with ether, and 3.8 g of compound 10b having a mp of 139-141 ° C were obtained.

Preparation of dl-5,6,6aß, 7,8,9a hydrochloride,

10,10aa -octahydro-l-ac6toxy-9-hydroxy-6ß-methyl-3- (lß-methyl-4-phenylbutoxy) -benzo [c] quinoline

To a solution of 2.0 g (5.3 mmol) in 150 ml of hydrofuran tetra- is added, under a nitrogen atmosphere, a solution of 5.7 g (8.8 mmol) of dl-5, 6.6aß, 7.8.9a, 10.10aa-octahydro-1-acetoxy-5-benzoyl-9-benzoyloxy-6P-methyl] -3- (1 P-methyl-4-phenylbutoxy) -benzo [c] quinoline in 112 ml of tetrahydrofuran dropwise over 5 minutes. The mixture is heated for 45 minutes at reflux, cooled and carefully poured onto an ice-cold mixture of 1125 ml of 5% acetic acid in water and 2250 ml of ether. This two-phase mixture is stirred for ten minutes and the layers are allowed to separate. The aqueous layer is extracted with 500 ml of ether, and the combined ethereal phases are washed successively with 3 × 500 ml of water, 2 × 500 ml of saturated sodium bicarbonate solution, and 1 × 500 ml of solution. saturated with NaCl, dried over MgS04, filtered and evaporated to give 5.4 g of d 1 -5-benzyl-5,6,6aß, 7,8,9a, 10, 10aa-octahydro-1,9- dihydr-oxy-6ß-methyl-3- (1-methyl-4-phenylbutoxy) -benzo [c] qui-nolein as a slightly purple oil.

This product is immediately taken up in 450 ml of methanol and hydrogenated at atmospheric pressure on 4.27 g of Pd / C for 3 hours to give dl-5,6,6aß, 7,8,9a, 35

10.1 Oaa-octahydro-1,9-dihydroxy-6ß-methyl-3- (l ß-nre-thyl-4-phenylbutoxy) -benzo [c] quinoline after filtration of the catalyst and evaporation of methanol.

This compound is immediately dissolved in 210 ml of methylene chloride, the solution is cooled to 0 ° C. under a nitrogen atmosphere and treated successively with 1.35 ml of triethylamine, 1.19 g (9.7 mmol) of 4-dimethylaminopyridine and finally with 0.834 ml (8.8 mmol) of acetic anhydride. After stirring for 30 minutes, the reaction mixture is poured into 250 ml of water and the organic layer is separated. The aqueous layer is extracted with methylene chloride, and the combined methylene chloride layers are washed successively with 2 X 150 ml of saturated sodium bicarbonate solution, 150 ml of water and saturated NaCl solution , dried over MgSO4, filtered and evaporated and finally chromatographed on 300 g of silica gel using toluene containing 33% ether as eluent to obtain 1.4 g of dl-5,6,6aß, 7,8,9, a, 10,10aa-octahydro-l-ac0toxy-9-hydroxy-6ß-m0thyl-3- (lß-m0thyI-4-phenylbutoxy) -benzo [c] quino-leine in free base form . Treatment of this product in ethereal solution with gaseous HCl gives 795 mg of dl-5,6,6aß, 7,8,9a, 10,10aa-octahydro-l-acetoxy-9-hydroxy-6ß-methyl-3- (lß-möthyl-4ph0nylbutoxy) -benzo [c] quinoMine in hydrochloride form, mp 213 at 215 ° C after filtration and trituration with acetone, m / e = 437 (m + 100%). 60

Analysis: Calculated for C27H3504N.HC1:

C, 68.42; H, 7.66; N, 2.96 Found C, 68.48; H, 7.63; N, 3.05

55

65

Similarly, 1.1 g of dl-5,6,6aß hydrochloride, 7,8,9a, 10,1 Oaa-octahydro-1-acetoxy-9-hydroxy-6ß-methyl-3- (lß) are prepared. -nrethyI-4-ph0nylbutoxy) -benzo [c] quino-

lein from 3.8 g dl-5,6,6aß, 7,8,9a, 10,1 Oaa-octahydro-l-ac6toxy-5-benzoyl-9-benzoyloxy-6ß-methyl-3- (lß- methyl-4-phenylbutoxy) -benzo [c] quinoolein, mp 202-205 0 (dec.), m / e = 437 (100%, m +).

Analysis: Calculated for C27H3504N.HC1:

C, 68.42; H, 7.66; N, 2.96 Found C, 68.20; H, 7.56; N, 3.04.

Preparation S4

d, l-5,6,6a / ?, 7,10,1 Oaa-Hexahyd.ro-1-hydroxy-6ß-methyl-3- (2-heptylsulfinyl) benzo [cjquinoline-9 (8H) -one

Equimolar amounts of m-chloroper-benzoic acid and d, 1-5,6,6aß-7,10,1 Oaa-hexahydro-1-hydroxy-6ß-methyl-3- (2-heptyIthio) are added [ c] quinoI0ine-9 (8H) -one to a mixture of chloroform and acetic acid (2: 1) and the reaction mixture is stirred for one hour at room temperature. The organic phase is then separated, washed with water, dried over MgSO4 and evaporated to dryness to obtain the title product.

Preparation S 5

d, l-trans-5,6,6a, 7,10,1 Oa-Hexahydro-1-hydroxy-6fi-methyl-3- (2-heptylsulfonyl) benzol [c] quinoline-9 (8H) -one

The procedure for preparation S 4 is repeated, but using 2 equivalents of m-chloroperbenzoic acid of oxidizing agent per mole of thioether reagent, to obtain the title compound.

Preparation S 6

d, l-5,6,6a, 7-tetrahydro-l- (4-morpholinobutyryioxy) -6fi-mé-thyl-3- (2-heptyloxy) benzo [c] quinoline-9 (8H) -one

To a solution of 0.51 g (1.5 mmol) of d, l-5,6,6a, 7-tetra-hydro-l-hydroxy-6p-methyl-3- (2-heptyloxy) benzo [c] quino -9-line (8H) -one in 25 ml of dry methylene, 0.315 g (1.5 mmol) of 4-morpholinobutyric acid hydrochloride is added and the mixture is stirred at room temperature under a nitrogen atmosphere. A 0.1N solution of dicyclohexylcarbodiimide in methylene chloride (12.5 ml, 1.5 mmol) is added dropwise and the mixture is stirred for 24 hours. It is then filtered and evaporated to obtain the title compound which is purified by column chromatography on silica gel.

Preparation S 7

D, l-trans-5,6,6aß, 7,8,9,10,1 hydrochloride Oaa-octahydro-1 - (4-N-piperidyl-butyryloxy) -9-hydroxy-6fi-methyl-3 - ( 5-phe-nyl-2-pentyloxy) benzo- [c] quinoline

To a 25 ° C solution of 1.0 g (2.53 mmol) of d, l-trans, 5,6,6aß, 7,8,9,10,10aa-octahydro-l, 9-dihydroxy-6ß- ntethyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline in 20 ml of methylene chloride, 0.524 g (2.53 mmol) of 4-N-piperidylbutyric acid hydrochloride and 0.573 g are added (2.78 mmol) of dicyclohexylcarbodiimide. The reaction mixture is stirred at 25 ° C for 6 hours and then cooled for 12 hours and filtered. Evaporation of the filtrate and trituration of the residue with ether gives 1.3 g of solid which is the monohydrochloride.

IR (KBr): 2.95, 3.70, 5.65 (C = 0 of the ester), 6.13 and 6.27 [x. Preparative thin layer chromatography of a portion of this solid on 0.5 mm thick silica gel and elution with a 10% mixture of methanol in methylene dichloride provides the free base, the d , l-trans-5,6,6aß, 7,8,9,10,10aa-octahydro-l- (4-N-pip0ridylbutyryl-oxy) -9-hydroxy-6P-methyl-3- (5-phenyl- 2-pentyIoxy) benzo [c] quinoline.

»H NMR (60 MHz) (ppm): 1.12 (d, J = Hz, me-

626,881

38

thyle of the side chain at C3), 1.25 (d, J = 6 Hz, methyl at C-6), 5.84 (s, 2H aromatics) and 7.16 (s, 5H).

Treatment of this free base with an excess of hydrogen chloride in ether provides the dihydrochloride in the form of a hygroscopic powder.

Preparation S 8

Dj-5,6,6a, 7-tetrahydro-1- (4-N-piperidylbuty-ryloxy) -6§-methyl-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] -quinoline hydrochloride -9 (8H) -one

10

To a solution at 25 ° C of 550 mg (1.41 mmol) of d, l.-5,6,6a, 7-tetrahydro-l-hydroxy-6P-methyl-3- (5-phenyl-2-pen -tyloxy) benzo [c] quinoline-9 (8H) -one in 26 ml of methylene chloride, 291 mg (1.41 mmol) of 4-N-piperidybutyric acid hydrochloride and 319 mg (1, 55 mmol) of dicyclohexylcarbodiimide. This reaction mixture is stirred for 18 hours then cooled to 0 ° C and filtered. Evaporation of the filtrate and trituration of the residue with ether gives 800 mg of the hydrochloride of d, 1 -5,6,6a, 7-tetrahydro-1 - (4-N-piperidylbutyryloxy) -6P -methyl-3- (5-phenyl-2-pentyloxy) benzo [-c] quinoline-9 (8H) -one in the form of a hygroscopic yellow powder. ©

IR (CHCI3): 2.92; 4.14 (HN =), 4.69 (ester), 6.00, 6.20 and 6.40. 25

In the same way, the hydrochloride of d, l-trans-5,6,6aß, 7,8,9,10,1 Oaa-octahydro-1 - (4-N-morpholino-butyryloxy) -9- is prepared. hydroxy-6p-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline from 4-N-morpholinobutyric acid and d, l-trans-5,6,6aß, 7, 8,9,10,10aa-octahydro-1,9-dihy-droxy-6P-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quino-leine.

IR (KBr): 3,00,3,75,5,67 (ester), 6,15 and 6,30 [x.

Preparation S 9 35

dJ_-7,10-Dihydro-1-hydroxy-3- (2-heptyloxy) -6-methylbenzo-

[c] -quinoline-9 (8H) -one-ethylene ketal

A solution of 371 mg (1.0 mmol) of d, 1,10-dihydro-1-hydroxy-3- (2-heptyloxy) benzo [c] quino-leine-9 (8H) -one-ethylene ketal is added slowly in 50 ml of ether at an ice temperature solution of 44 mg (2.0 mmol) of methyl lithium in 25 ml of ether. The 5-lithio-6-methylated derivative thus obtained is dissolved in dry ether and treated with dry oxygen to obtain the title compound, after filtration and evaporation of the solvent. 45

General formation of hydrochlorides

An excess of hydrogen chloride is passed through a solution of the appropriate benzo [c] quinoline of formula I or II and the resulting precipitate is separated which is recrystallized from a suitable solvent, for example a mixture 1: 10 methanol and ether.

In this way, the following salt is prepared: d, l-trans-5,6,6aß, 7,8,9,10,1 Oaa-octahydro-1-acetoxy-9ß-hydroxy-6ß-methyl-3- ( 5-ph0nyl-2-pentyloxy) benzo [c] -quinoline, mp 191-193 ° C.

m / e —437 (m +)

55

Analysis: Calculated for C27H3604NC1:

C, 68.48; H, 7.70; N, 2.89% Found: C, 68.42; H, 7.66; N, 2.96%

60

Preparation T1 2-Bromo-5-phenylpentante

812 g of phosphorus pentabromide, prepared by adding 65 9.0 g of bromine in 10 ml of methylene chloride to 15.0 g of phosphorus tribromide in 15 ml of methylene chloride at 0 ° C. 5-phenyl-2-pentanol in methylene chloride at 0 ° C. The mixture is stirred for 2.5 hours at 0 ° C and then allowed to warm to room temperature. 50 ml of water are added, the mixture is stirred for one hour and the layer of methylene chloride is separated. The extraction is repeated and the combined extracts are washed with water, saturated sodium bicarbonate solution and brine and then dried over magnesium sulfate. The concentration of the dried extracts gives 12.4 g of the title product in the form of a light yellow oil.

NMR 1.6 (D, 3, methyl, J = 7 Hz), 1.6-2.0

(M, 4, ethylene), 2.3-3.0 (Broad T, 2, benzyl methylene), 3.7 ^ 4.2 (M, 1, methine), 6.9-7.4 (M, 5, aromatic).

T2 preparation

2- (3,5-Dimethoxyphenyl) -5 -phenylpentane

A solution of 51.7 g of 1-bropropopropylbenzene in 234 ml of ether is added dropwise over two hours to a reflux mixture of 7.32 g of magnesium in 78 ml of ether. The reaction mixture is heated to reflux for an additional 30 minutes, then a solution of 50 g of 3,5-dimethoxy-acetophenone in 78 ml of ether is added dropwise and the mixture is heated to reflux for one and a half hours. The reaction is stopped by adding 234 ml of saturated ammonium chloride, the ethereal layer is separated and the aqueous phase is extracted with ether (3 times 200 ml). The combined ether extracts are dried over magnesium sulfate and concentrated in vacuo to give 81g of an oil. 40 g of the oil are hydrogenated in a mixture containing 300 ml of ethanol, 2 ml of concentrated hydrochloric acid and 5 g of 5% palladium on carbon. The catalyst is filtered and the ethanol is removed in vacuo. The residue is distilled under vacuum, which gives 28 g of 2- (3,5-dimethoxyphenyl) -5-phenylpen-tane, pe at 0.125 mm, 154—159 "C.

NMR: ô ™ c! 3 1.25 (d, 3, a-CH3), 1.3-2.1 (M, 4, ethylene), 2.2-2.9 (M, 3, methylene benzyl, methinyl), 3.45 (S, 6, methoxy), 6.2-6.7 (M, 3 aromatics), 7.2 (S, 5, aromatics).

Preparation T 3

2- (3,5-Dihydroxyphenyl) -5 -phenylpentane

A mixture of 22 g of 2- (3,5-dimethoxyphenyl) -5-phe-nylpentane and 94 g of pyridine hydrochloride under nitrogen is heated at 190 ° C. for 2 hours with vigorous stirring. The reaction mixture is cooled and dissolved in 200 ml of 6N hydrochloric acid. and diluted with water to 600 ml. The aqueous solution is extracted with 4 times 100 ml of ethyl acetate, the ethyl acetate extracts are dried over sodium sulphate and concentrated in vacuo, which gives 24 g of crude product. The product is purified by chromatography on silica gel to give 19.2 g of 2- (3,5-dihydroxyphenyl) -5-phenylpentane as an oil.

NMR: "" ^ sc, 3 1.1 (d, 2, a-methyl), 1.35-1.65 (M, 4, ethylene), 2.2-2.8 (M, 3, methylene benzyl , methinyl), 6.1-6.5 (M, 3, aromatics) 6.65 (broad S, 2, hydroxyl), 7-7.4 (M, 5, aromatics).

Following the procedures for preparations T2 and T3, the compounds indicated below are prepared by substituting the appropriate 1-bromoalkylbenzene for 1-bromopropylbenzene: 2- (3,5-dihydroxyphenyl) -6-phenylhexane.

NMR: "" gJsCIi 1.1 (D, 3, a-methyl, J = 7 Hz), 1.0-1.9 [M, 6.0CH2 (CH2) 3-CH (CH3) —Ar], 2 , 2-2.8 (M, 3, methylene benzyl, methinyl), 6.0 (broad s, 2 phenolic OH), 6.2-6.4 (M, 3, aromatic), 7.1-7, 4 (M, 5, aromatic).

1- (3,5-dihydroxyphenyl) -2-phenylethane mp: 76-77 ° C

2- (3,5-dihydroxyphenyl-4-phenylbutane (oil)

NMR 1,1,1,25 (d, 2, methyl), 1,45-2,0 (M, 2, methylene), 2,15-2,7 (M, 3, methylene benzyl, methinyl], 6 , 3 (S, 3, aromatics), 6.85 (S, 2, DzO-OH overlay), 7.1 (S, 5, aromatics).

39

626,881

Preparation T4

l- (3,5-Dihydroxyphenyl) -2-methyl-4-phenylbutane

29 ml of a 2.2M solution of n-butyl lithium are added dropwise to 31.5 g of 3,5-dimethoxybenzyl triphenyl phosphonium bromide in 200 ml of tetrahydrofuran, with stirring, and the mixture is stirred for half an hour the resulting dark red solution. 9.4 g of benzylaceous tone are added dropwise and the reaction mixture is stirred for 12 hours. Then the pH is adjusted to 7 by addition of acetic acid and the mixture is concentrated under reduced pressure. The residue is extracted with methylene chloride and the extract is evaporated, which gives the

1- (3,5-dimethoxyphenyl) -2-methyl-4-phenyl-1-butene crude in the form of an oil. It is purified by chromatography of 400 g on silica gel and by elution with benzene. 10 g are obtained in the form of an oil.

NMR: 1.95 (S, 3), 2.3-3.1 (M, 4), 3.8 (S, 6), 6.15-6.6 (M, 3), 7.1- 7.5 (M, 6).

9.4 g of l- (3,5-dimeth-oxy-phenyl) -2-methyl-4-phenyl-1-butene thus prepared are dissolved in 250 ml of ethanol and the mixture is catalytically hydrogenated at 3.15 kg / cm2 in the presence of 1 g of 10% palladium on carbon and 1 ml of concentrated hydrochloric acid. 9.4 g of 1- (3,5-dimethoxyphenyl-2-methyl-4-phenylbutane) are obtained in the form of an oil.

NMR: 0.9 (d, 3), 1.35-1.95 (M, 3), 2.2-2.9 (M, 4), 3.75 (S, 6), 6.35 ( S, 3), 7.25 (S, 5).

It is demethylated according to the procedure of the preparation to obtain 1- (3,5-dihydroxyphenyl) -2-methyl-4-phenylbu-tane.

3,5-Dimethoxybenzyltriphenylphosphonium bromide is prepared by refluxing a mixture of 12 g of 3,5-dimethoxybenzyl bromide and 14.2 g of triphenylphosphine in 200 ml of acetonitrile for one hour. Then the reaction mixture is cooled and the crystalline product is collected by filtration, washed with ether and dried, 20 g, mp 269-270 ° C.

Preparation T 5

2-Methyl-2- (3,5-dihydroxyphenyl) -5-phenylpentane

To a solution of snack reagent prepared from 5.5 g of 2-phenylbromoethane of 0.8 g of magnesium and 60 ml of dry ether, a solution of 2.75 g of 2-methyl-2 is added. -2 C3,5-dimethoxyphenyl) propionitrile in 20 ml of ether. The ether is distilled and replaced with 50 ml of dry benzene and the mixture is heated to reflux for 48 hours. It is then broken down by careful treatment with dilute sulfuric acid and heated on a steam bath for one hour. The mixture is then extracted with ether, the extract is dried over MgSO4 and concentrated to an oil. The distillation of the oil under vacuum provides 2-methyl-2- (3,5-di-methoxyphenyl) -5-phenyl-3-pentanol, mp 168 ° C / 0.2 mm, 2.32 g (60 %).

58 g of the pentanone thus obtained are dissolved in 400 ml of ether and treated with 10 g of sodium borohydride at room temperature. The reaction mixture is stirred for 12 hours and then cooled and neutralized with 6N hydrochloric acid. The ethanol is removed under reduced pressure and the residue is extracted with ether. The extract is dried over MgSO4 and concentrated, giving 52 g (88% yield) of 2-methyl-2 (3,5-dimethoxyphenyl) -5-3-pentanoI as an oil.

16 g of the potassium powder in 100 ml of ether are taken up and reacted with 2.5 g of potassium powder in 200 ml of ether. An equimolar amount of carbon disulfide relative to potassium is added and the mixture is stirred for half an hour. Then 9.0 g of methyl iodide are added and the reaction mixture is stirred for 6 hours. The resulting suspension is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in 150 ml of ether, 25 g of Raney nickel are added and the mixture is heated at reflux for 18 hours. Evaporation of the alcohol and distillation of the residue gives 2-methyl-2 (3,5-dimethoxyphenyl) -5-5 phenyl-3-pentene.

The pentene derivative is hydrogenated catalytically according to the procedure of preparation T4 and the methylene is demethylated.

2-methyl-2- (3,5-dimethoxyphenyl) -5-phenyl-3-pentane resulting according to the procedure of preparation T3 to obtain the product.

Preparation T6

Over an hour and a half, 531 ml of a 2M solution of methyl-lithim (1.06 mole) under nitrogen atmosphere are added to a rapidly stirred solution of 175 g (0.531 mole) of 3.5 acid -dibenzyloxybenzoic acid in 250 ml of ether and 1400 ml of tetrahydrofuran, maintained at 15-20 ° C. After stirring for a further three quarters at 10-15 ° C, 600 ml of water are added slowly, keeping the reaction below 20 ° C. 2o The aqueous layer is separated and extracted with ether (3 X 250 ml). The organic phases are combined, washed with saturated sodium chloride solution (4 times 300 ml), dried over sodium sulfate and concentrated in vacuo, which gives an oil which slowly crystallizes from ether isopropyl-25 that. The crude product is recrystallized from ether-hexane, which gives 104.7 g (59%) of product, mp 59-61 ° C. ,

Preparation T7

3- (3,5-Dbenzyloxyphenyl) ethyl crotonate (30 Wittig reaction)

A mixture of 43.2 g (0.13 mole) of 3,5-dibenzyloxy-acetophenone and 90.5 g (0.26 mole) of carbethoxymethy- is heated under a nitrogen atmosphere at 170 ° C. for 4 hours. lenetriphenylphosphorane. The clear melt is cooled to room temperature, triturated with ether, and the precipitate of triphenylphosphine oxide is removed by filtration. The filtrate is concentrated under vacuum to an oily residue which is chromatographed on 1500 g of silica gel, eluting with solutions of benzene and hexane, the concentration of benzene of which increases from 40:60 and ending with 100% benzene. The concentration of the appropriate fractions gives an oily residue which is crystallized from hexane. 40.2 g (77%) are obtained, mp 73-75 ° C.

45 Analysis: Calculated for C26H2604:

C, 77.58; H, 6.51%

Found: C, 77.72; H, 6.60%

Similarly, ethyl 3- (3,5-dimethoxyphé-50 nyI) -crotonate is prepared from 3,5-dimethoxyacétophé-none (51,7 g) and carbéthoxyméhtylènipénylphosphorane (200 g). 61.8 g, 86% are obtained, eg 146-162 ° C at 0.3 mm.

Preparation T8 55 3- (3,5-dibenzyloxyphenyl) -l-butanol

A solution of 24.1 g (60 mmol) of 3- (3,5-dibenzyloxyphenyl) crotonate in 250 ml of ether is added to a mixture of 3.42 g (90 mmol) of lithium hydride and aluminum and 250 ml of ether. 0.18 g (1.35 mmol) 60 of aluminum chloride is added and the mixture is heated to reflux for 2 hours and then cooled. Then 3.4 ml of water, 3.4 ml of 6N sodium hydroxide and 10 ml of water are successively added to the reaction mixture. The precipitating mineral salts are filtered and then the filtrate is concentrated under vacuum, which gives the desired alcohol in the form of an oil, 2.4 g (98%).

Rf = 0.25 [on silica gel / benzene (18): ethyl acetate

(1)]

m / e-362 (m +)

626,881

40

Analysis: Calculated for ^ - '24 ^ 26 ^ 3 *

C, 79.53; H, 7.23%

Found: C, 79.37; H, 7.11%

Similarly, ethyl 3- (3,5-dimethoxyphenyl) crotonate (60.4 g) is reduced to 3- (3,5-dimethoxyphenyl) butanol (48.0 g, 90%).

Preparation T9

3- (3,5-dibenzyloxyphenyl) butyl tosylate

11.1 g (58.1 mmol) of tosyl chloride are added to a solution of 20.7 g (57 mmol) of 3- (3,5-dibenzyloxyphenyl) -1-butanol in 90 ml of pyridine at -45 ° C. The reaction mixture is kept at - 35 ° C for 18 hours then diluted with 1500 ml of cold 2N hydrochloric acid and extracted with ether (5 times 250 ml). The combined extracts are washed with a saturated sodium chloride solution (4 times 250 ml) and then licked over Na2SO4. The concentration of the dried extract provides the product as an oil. It is crystallized by treatment with a mixture of ether and hexane. 24.63 g (84%) are obtained.

Analysis: Calculated for Q1H32O5S:

C, 72.06; H, 6.24%

Found: C, 72.05; H, 6.29%

TIO preparation

3- (3-Dibenzyloxyphenyl) -1-phenoxybutane

A solution of 4.56 g (48.6 mmol) of phenol in 40 ml of dimethylformamide is added, under a nitrogen atmosphere, to a suspension of 2.32 g of sodium hydride (48.6 mmol of a 50% product previously washed with pentane) in 70 ml of dimethylformamide at 60 ° C. The reaction mixture is stirred for one hour at 60-70 ° C after which a solution of 23.93 g (46.3 mmol) of 3- (3,5-dibenzyloxyphé-nyl) butyl tosylate in 80 ml of solution is added. dimethylformamide. The reaction mixture is stirred at 80 ° C for half an hour and then cooled to room temperature, diluted with 500 ml of cold water and extracted with ether (4 times 400 ml ). The combined extracts are washed successively with cold 2N hydrochloric acid (2 times 300 ml) and a saturated sodium chloride solution (3 times 300 ml) and then dried over Na2SO4. Removal of the solvent under reduced pressure provides the product as an oil. The oily residue is dissolved in benzene and filtered through silica gel (100 g). Concentration of the filtrate under reduced pressure gives a product in the form of an oil 14.86 g (73%).

Rf = 0.7 (silica gel, benzene)

m / e-438 (m +)

Analysis: Calculated for C3UH30O3:

C, 82.16; H, 6.89%

Found: C, 82.07; H, 6.48%

Preparation Tll

3- (3,5-Dihydroxyphenyl) -1-phenoxybutane

Hydrogenated for 2 hours under 4.2 kg / cm2 of hydrogen in the presence of 1.5 g of 10% palladium on carbon a solution of 14.7 g (133.5 mmol) of 3- (3.5- dibenzyloxyphé-nyl) -l-phenoxybutane in a mixture of 110 ml of ethyl acetate, 110 ml of ethanol and 0.7 ml of concentrated hydrochloric acid. Removal of the catalyst by filtration and concentration of the filtrate gives an oil. The oil is purified by chormatography on 100 g of silica gel, eluting with a mixture of benzene and ethyl acetate comprising from 0 to 10% ethyl acetate. The medium fractions are combined and concentrated to obtain the title product: 7.8 g (80%) in the form of an oil.

Rf = 0.25 [silica gel, benzene (4), methanol (1)] m / e-258 (m +)

118 ° 3:

Analysis: Calculated for C ^ Hf 5 C, 74.39; H, 7.02%

Found: C, 74.13; H, 7.00%

Preparation T12

1-Bromo-3- (3,5-dimethoxyphenyl) butane 10 A solution of 5.7 ml (0.06 mole) of phosphorus tribromide in 30 ml of héhter is added to a solution of 30.0 g (0.143 mol) of 3- (3,5-dimethoxyphenyl) -1-butanol in 20 ml of ether at a temperature of -5 ° C to -10 ° C, and the reaction mixture is stirred at this temperature for 2 hours and 15 half. Then it is warmed to room temperature and stirred for an additional 30 minutes. The mixture is poured onto 200 g of ice, and the resulting mixture is extracted with ether (3 times 50 ml). The combined extracts are washed with a 5% solution of sodium hydroxide (3 times 50 ml), a saturated solution of sodium chloride (1 time 50 ml) and dried over Na2SO4. Removal of ether and vacuum distillation of the residue provides the title product; 25 g (55%), e.g. 125-132 ° C at 0.4 mm.

25 Preparation T13

4- (3,5Dihydroxyphenyl) -1- (4-pyridyl) pentane

A mixture of 19.0 g (35.4 mmol) of 3- (3,5-dimethoxyphenyl) butyltriphenylphosphonium bromide in 50 ml of dimethyl sulfoxide is added to 3.79 g (35.4 mmol) of 4-pyridi-30 necarboxaldehyde in 40 ml of tetrahydrofuran. Then the resulting mixture is added dropwise to a suspension of 1.87 g (39 mmol) of 50% sodium hydride in 20 ml of tetrahydrofuran under a nitrogen atmosphere at 0-5 ° C. After the addition is complete, the mixture is stirred for one hour at 0-5 ° C and then concentrated under reduced pressure. The concentrate is diluted with 200 ml of water and then acidified with 6N HCl. The aqueous acid solution is extracted with benzene (4 times 50 ml). Then it is made alkaline and extracted with ethyl acetate (3 times 50 ml). Evaporation of the combined extracts after drying 40 (MgSO4) provides Ie4- (3,5-dimethoxyphenyl) -1-4- (pyridyl) -1-pentene, 7.1 g, 70%, as an oil.

The catalytic hydrogenation of the pentene derivative thus obtained according to the procedure of preparation T4, provides 45 4- (3,5-dimethoxy-phenyl) -1- (4-pyridyl) pentene in quantitative yield; mp 131-133 ° C.

The pentane derivative thus obtained is demethylated by heating a mixture of 7.15 g (25 mmol) of the compound and 105 g of pyridine hydrochloride under a nitrogen atmosphere at 210 ° C. for 8 hours. The hot mixture is poured into 40 ml of water and the resulting solution is alkalinized with 6N sodium hydroxide. Water and pyridine are removed by vacuum distillation. 50 ml of ethanol are added to the residue and the precipitating mineral salts are filtered. The filtrate is concentrated in vacuo and the residue is chromatographed under 150 g of silica gel using as eluent 4 liters of 5% ethanol in benzene, one liter of 10% ethanol in benzene 11 of 13% ethanol in benzene and 5 l of 16% ethanol in benzene. The product is isolated in the form of a glassy solid, by concentration of the appropriate fractions of the eluate. 5.0 g (78%) are obtained.

3- (3,5-dimethoxyphenyl) butyl-triphenyl-phosphonium bromide is prepared by refluxing a mixture of l-bromo-3- (3,5-dimethoxyphenyl) butane (21.5 g, 78.5 65 mmol) and triphenylphosphine (20.5 g, 78.5 mmol) in 60 ml of xylene for 18 hours. Then the reaction mixture is cooled to room temperature and filtered. The filter cake is washed with ether and dried in a

41

626,881

vacuum desiccator which gives 36.4 g (86%) of product, mp 190-200 ° C.

Preparation T14

3,5-Dimethoxy-a-methylstyrene oxide

To a solution of 69.4 mm of dimethyl sulfoxonium methylide in 65 ml of dimethyl sulfoxide at room temperature, 10 g (55.5 mmol) of solid 3,5-dimethoxyaceous tophenone are added. The reaction mixture is stirred for one hour at 25 ° C, for half an hour at 50 ° C, then cooled. The mixture is diluted with 50 ml of water and added to a mixture of 200 ml of ice water, 250 ml of ether and 25 ml of low boiling oil ether. The organic extract is washed twice with water (250 ml, dried over MgSO4 and evaporated to an oil. The fractional distillation of the oil provides 8.0 g (75%) of 3,5-di-methoxy-a-methylstyrene oxide, mp 93-97 ° C, 0.2 mm.

IR (CCU): 2780,1595,1196,1151,1058 cm "1 UV (95% ethanol) * .max = 279 nm (e = 2068) m / e-194 (m +)

RMP (CDCI3) (60 MHz): ô 1.70 (S, CH3-), 2.76 (d, O O

J = 6 Hz, / \ H) 2.95 (d, J = 6 Hz), / \ H), 3.81 (S, CH3O-), 6.41 (t, J = 2 Hz, ArH) and 6.58 (d, J = 2 Hz, ArH).

Analysis: Calculated for CnHi403:

C, 68.02; H, 7.27%

Found: C, 67.96; H, 7.28%

Preparation T15

2- (3,5-dimethoxyphenyl) -2-hydroxypropyl and 2-phenylethyl oxide

A mixture of 30 ml (251 mmol) of dry 2-phenylethanol and 690 mg (30 mmol) of metallic sodium is heated at 110 ° C. for 30 minutes. The resulting 1M solution of sodium 2-phenylethylate is cooled to 60 ° C., 2 g (10.3 mmol) of 3,5-dimethoxy-a-methylstyrene oxide are added and the reaction mixture is heated for 15 hours to 60 ° C. The reaction mixture is cooled and added to a mixture of ether and water. The ether extract is dried over magnesium sulfate and evaporated. The excess 2-phenylethanol is removed by vacuum distillation (eg about - 65 ° C, 0.1 mm), which leaves a residue of 3.5 g. The residue is purified by column chromatography on silk gel 60 from Merck (330 g) and eluted in 15 ml fractions with a mixture of 60% ether in pentane. Fractions 52-88 provide 2.9 g (89%) of 2- (3,5-di-methoxyphenyl-2-hydroxypropyl and 2-phenylethyl ether oxide. IR (CC14): 3534,1595,1202,1153 cm "1 UV (95% ethanol): 278 (e = 1830), 273 (e =

1860).

m / e-316 (m +)

RMP (CDC12, 50 MHz): ô 1.46 (S, CH3-), 2.86 (S, OH), 2.86 (t, J = 7 Hz, -CH2-Ph), 3.53 (S , CH20), 3.71 (t, J = 7 Hz, -CH20), 3.80 (S, OCH3), 6.38 (t, J = 2 Hz, ArH), 6.61 (d, J = 2 Hz, ArH) and 7.23 (S, PhH).

Analysis: Calculated for C19H2404:

C, 72.12; H, 7.65%

Found: C, 71.92; H, 7.63%

Preparation T16

2- (3,5-dimethoxyphenyl) propyl and 2-phenylethyl oxide To a 0 ° C solution of 2- (3,5-dimethoxyphenyl) -2-hydroxypropyl and 2-phenylethyl oxide (550 mg, 1.74 mmol), in 2 ml of pyridine, 477 ml (5.22 mmol) of phosphorus oxychloride are added dropwise. This reaction mixture is allowed to warm to 20 ° C over an hour and a half. Then stirred for an hour and a half at 20 ° C and added to 150 ml of ether and 100 ml of 5% sodium carbonate. The organic phase is separated and washed with 15% sodium carbonate (3 times 50 ml), dried over mangesium sulfate and evaporated to an oil. The oil is dissolved in 15 ml of absolute ethanol, 100 mg of 10% palladium on carbon are added and the mixture is stirred under an atmosphere of hydrogen gas. When the hydrogen intake ceases (26.5 ml, 20 minutes), the reaction mixture is filtered on diatomaceous earth and the filtrate is evaporated to an oil. The oil is purified by preparative thin layer chromatography on a silica gel plate, eluted twice with a 10: 1 mixture of pentane and ether to give 211 mg (40%) of l 2- (3,5-dimethoxyphenyl) propyl and 2-phenyl-ethyl oxide.

15 IR (CC14): 1600,1205,1155,1109 cm "'.

m / e-300 (m +)

RMP (CDC13, 60 MHz) ô 1.22 (d, J = 7 Hz, CH3-), 2.82 (t, J = 7 Hz, CH2Ph), 2.8 (HC-Me), -3.6 (-CH2-0-CH2-), 3.75 (S, OCH3), 6.35 (m, ArH) and 7.18 (S, PhH).

20

Preparation T17

2- (3,5-dihydrophenyl) -propyl and 2-phenylethyl oxide A mixture of 195 mg (0.65 mmol) of 2- (3,5-dimethoxyphenyl oxide) is heated at 190 ° C. for 6 hours ) pro-pyle and 2-phenylethyl, 0.4 ml (4.96 mmol) of pyridine and 4 g (34.6 mmol) of dry pyridine hydrochloride. The reaction mixture is cooled and added to a mixture of 100 ml of water and 150 ml of ether. The ether extract is washed once with water (50 ml) and then with a second ether extract (50 ml) from the aqueous phase, dried over magnesium sulphate and evaporated to an oil . The oil is purified by preparative thin layer chromatography on silica gel plates, eluted 6 times with a 30% ether mixture in pentane to give 65.8 mg (37%) of the 2- (3,5-dihydroxyphenyl) propyl and 2-phenylethyl oxide.

IR (CHCI3); 3559.3279.1605.1147.1105 cm "1 m / e-272 (m +)

RMP (CDCIj, 60 MHz), ô 1.18 (d, J = 7 Hz, CH3-), 2.80 (t, J = 7 Hz, -CH2Ph), 2.80 (HC-Me), 3, 4-3.8 (-CH2OCH2-), 6.08 (t, J = 2 Hz, ArH), 6.21 (d, J = 2 Hz, ArH) and 7.16 (S,

PhH).

Preparation T18 45 4- (3,5-Dihydroxyphenyl) -l-phenoxypentane

Under a nitrogen atmosphere, a mixture of 50.0 g (0.15 mole) of 3,5-dibenzyloxyacetophenone in 175 ml of tetrahydrofuran and 7.18 g (0.15) is added dropwise over one hour three quarters. mole) of 3-phenoxypropylItriphé-50 nylphosphonium bromide in 450 ml of dimethylsulfoxide, to a suspension of 50% sodium hydride (7.89 g, 0.165 mole) (previously washed with pentane) in 75 ml of tetrahydrofuran, maintained at 0.5 ° C. After 4 hours of stirring at 0 ° C-5 ° C, the reaction mixture is allowed to warm to room temperature, then it is stirred carefully in 2000 ml of ice water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate (5 times 400 ml). The combined organic phases are washed with a saturated sodium chloride solution (3 times 300 ml), dried over sodium sulfate 60 and concentrated in vacuo, which gives an oil which is triturated with ether to precipitate triphenyiphosphine oxide. Filtration then concentration of the filtrate gives an oily residue which is chromatographed on 1300 g of silica gel, eluting with a mixture of benzene and hexane ranging from 65 to 100% benzene. From the medium fractions, 51 g (75%) of 4- (3,5-dibenzyloxyphé-nyl) -l-phenoxypentene-3, Rf 0.8 (silica gel, benzene) are isolated in the form of an oil. : hexane 2: 1); m / e 450 (m +)

626,881

42

Analysis: Calculated for C31H3 () C> 3:

C, 82.63; H, 6.71%

Found: C, 82.90; H, 6.69%

Hydrogenation is carried out for 12 hours under 3.85 kg / cm 2 of hydrogen in the presence of Pd / C at 10%, a solution of 51 g (0.113 mole) of 4- (3,5-dibenzyloxyphenyl) -1-phenoxypen-tene -3 in a mixture of 160 ml of absolute ethanol, 160 ml of ethyl acetate and 0.2 ml of concentrated hydrochloric acid. Removal of the catalyst by filtration and concentration of the filtrate in vacuo provides 30.8 g (100%) of the product as a viscous oil.

Analysis: Calculated for Cl7H, nO- ,:

C, 74.97; H, 7.40%

Found: C, 74.54; H, 7.45%

Preparation T19 3-Hydroxy-5-pentylaniline

1.8 g (0.01 mole) of olivetol, 2.65 g (0.05 M) of ammonium chloride, 5.2 g (0.05 mole) of sodium bisulfite and 12.5 are combined. ml of ammonium hydroxide and heated in a steel bomb at 230 ° C for half an hour. Then the bomb is cooled and the content is dissolved in 350 ml of ethyl acetate. 300 ml of 10% hydrochloric acid are added, the mixture is stirred and the organic layer is separated. The extraction is repeated two more times. The aqueous acid solution is neutralized with 6N sodium hydroxide and extracted with chloroform (3 times 300 ml). The combined chloroform extracts are dried and concentrated. The residue is taken up in ethyl acetate, discolored with charcoal and concentrated. The addition of hexane to the residue causes it to crystallize: 270 mg; mp 88-91 ° C. When recrystallized from a hot 1: 1 mixture of ethyl acetate and hexane, it melts at 95-96 ° C. Analysis: Calculated for CnH17ON:

C, 73.70; H, 9.56; N, 7.81%

Found: C, 73.64; H, 9.62; N, 7.91%

Preparation T20

d, 1 -N-Acetyl-3-hydroxy-5- (5-phenyl-2 -pentyl) aniline

Stirred at room temperature for 45 minutes, a solution of 2.4 g (9.5 mmol) of d, l-3-hydroxy-5- (5-phe-nyl-2-pentyl) aniline in 24 ml of pyridine and 24 ml of acetic anhydride. The reaction mixture is poured onto 200 ml of water and 200 ml of ethyl acetate. After 10 minutes of stirring, the organic phase is separated and washed successively with water (4 times 100 ml), brine (once 100 ml), dried over MgSO 4, filtered and filtered. concentrates which gives 3.5 g of crude d, lN-acetyl-3-acetoxy-5- (5-phenyl-2-pentyl) aniline. A solution of d, lN-acetyl-3-acetoxy-5- (5-phenyl-2-pentyl) aniline and 1 g of potassium carbonate in 100 ml of methanol is stirred at room temperature for one hour, the filter, it is concentrated and it is dissolved in ethyl acetate. The organic solution is washed with water, dried over MgSO4 and concentrated to an oil which crystallizes from hexane to give 1.5 g of d, 1N-acetyl-3-hydroxy-5- (5-phenyl-2-pentyl) aniline, mp 128-130 ° C m / e-297 (m +)

'H NMR (60 Hz) ô ^ i, (ppm): 8.64 (broad s, 1H, -NH), 7.12,6.58 and 6.45 (broad s, variable ÌH, ArOH), 2 , 19-2.78 (m, 3H, Ar-CH, and Ar-CH2), 2.05 (s, 3H, CH3-C) (= 0) -), 1.3-1.78 (m, 4H, (CH2) 2.12 (d, 3H, -C-CH3).

Preparation T21

d, l-3-Benzyloxy-5- (5-phenyl-2-pentyl) -aniline

To a stirred solution of 1.2 g (4.03 mmol) of d, lN-acetyl-3-hydroxy-5- (5-phenyl-2-pentyl) aniline in 50 ml of tetrahydrofuran, 193 mg (4 , 03 mmol) of 50% sodium hydride. After 30 minutes of stirring, 1.38 g (8.06 mmol) of alpha-bromotoluene is added and stirring is continued for 16 hours. Then the reaction mixture is filtered, 1 ml of acetic acid is added to the filtrate which is then concentrated and which is chromatographed (silica gel, benzene / ether 2: 1 as eluent) which gives 1.43 g of d, lN-acetyl-3-benzyloxy-5- (5-phenyl-2-pentyl) aniline in the form of an oil.

5 m / e - 387 (m +)

! H NMR (60 MHz) (ppm): 7.88 (broad s, 1H, NH), 7.38,7,20,6,84,6,59 (broad s, 5H, 6H, 1H, 1H, aromatic), 5.0 (s, 2H, -0-CH2Ar), 2.21-2.98 (m, 3H, Ar-CH and Ar-CH2), 2.07 (s, 3H, CH3-C ( = 0) -N), 1.30-1.69 (m, 4H, io I

- (CH2) 2), 1.15 (d, 3H, CHj-C -Ar).

A solution of 1.4 g of d, lN-acetyl-3-benzyloxy-5- (5-phenyl-2-pentyl) -aniline, of 14 ml of hydroxide is heated at reflux on a steam bath for 4 days. of 20% potassium, 15 of 14 ml of methanol and 10 ml of 2-propanol. After cooling, water and ethyl acetate are added and the mixture is stirred for 10 minutes. The organic phase is separated and the aqueous phase is again extracted with ethyl acetate. The organic solutions are combined, dried over 20 MgSO 4, concentrated in vacuo, and chromatographed on 35 g of silica gel using a 3: 1 mixture of benzene and ether as eluent, and obtains d, l-3-benzyloxy-5- (5-phenyl-2-pentyl) aniline in the form of an oil, m / e-345 (m +)

25! H NMR (60 Hz) here, (ppm): 7.32 (broad s, 5H, aromatic) 7.13 (broad s, 5H, aromatic), 6.01-6.33 (m, 3H , aromatic), 4.95 (s, 2H, ArCHzO), 3.48 (broad s, 2H, variable, NH2), 2.17-2.88 (m, 3H, Ar-CH and Ar-CH,) , 1.32-1.76 (m, 4H, (CH2) 2), 1.14 (d, 3H, -C-CH3).

30

Preparation T22

Dyl-5-phenyl-2-pentanol mesylate

To a stirred solution of 482 g (2.94 moles) of 5-phenyl-2-pentanol in 2250 ml of tetrahydrofuran at 0 ° C., 35,300 ml of methanesulfonyl chloride are added, at a speed such that the internal temperature does not does not rise above 10 ° C (total addition time 4.5 hours). Once the addition is complete; the reaction mixture is allowed to warm to room temperature, and stirring is continued for an additional hour. The reaction mixture is filtered and the supernatant liquor is concentrated to a light yellow oil (2800 g) which is dissolved in 2 l of chloroform and washed with brine (4 times 1 liter). (1 liter), which is treated with 50 g of charcoal, which is dried over MgS04, which is filtered through 45 diatomaceous earth, and which is concentrated to an orange oil clear (687 g, 95% yield). This material can be used without further purification.

'H NMR (60 Hz) ô ™ q. : (ppm) 7.23 (s, 5H, aromatic), 4.53-5.13 (m, 1H, -CH-0-), 2.93 (s, 3H, 0-S02-CH3), so 2.42-2.93 (m, 2H, -CH, C6H5), 1.50-1.92 (m, 4H, - (CH2) 2-), 1.23 (s, 3H, O-CH- CH3).

Likewise, the following mesylates are prepared from the appropriate alcohols:

4-phenylbutanol mesylate, yellow oil 55 m / e —228 (m +)

'H NMR (60 MHz) (ppm) 7.22 (broad s, 5H, aromatic), 4.08-4.34 (m, 2H, -CH2-0-), 3.93 (s, 3H, S02CH3 ), 2.40-2.82 (m, 2H, -CH2C6H5), 1.51-1.93 (m, 4H, - (CH2) 2-). ^ -2-OctanoI mesylate, colorless oil "o [a] 25 = _ 9) 695" (c _ 2.6, CHCI3)

'H NMR (60 Hz) ppm: 4.79 (wide q, 1H, -CH-O), 2.97 (s, 3H, S, CH3), 1.40 (d, 3H, CH3-CH), 0.87 (t, 3H, CH3-che-), 1.0-2.0 (m, 10H, - (CH2) 5-).

Mesylated d-2-octanol 65 Mb5 = +9.238 0 (C = 2.8, CHCI3)

'H NMR, identical to form 1.

An overview of some compounds obtained by the process of the invention is given below.

6a, 10a = trans (1): hydrochloride (d): decomposition

R *

R,

R "

Z-W

Calculated C H

c2h5

h ho>

OCH (CH3) (CH2) 3C6H5

68.88

7.85

n-C4H9

H

rf »

OCH (CH3) (CH2) 3C6H5

69.82

8.20

n — C5Hi!

H

H <'>

OCH (CH3) (CH2) 3C6H5

70.23

8.37

n_CéH13

h hd)

OCH (CH3) (CH2) 3C6H5

70.61

8.53

(CH2) 2

c6h5

H

H <">

OCH (CH3) (CH2) 3C6H5

72.39

7.51

n-C3H7

H

ch3 (1)

OCH (CH3) (CH2) 3C6Hs

69.79

8.21

n-C4H9

h ch3 <"

OCH (CH3) (CH2) 3C6H5

70.21

8.37

ch3

h

CH3 (,)

C (CH3) 2 (CH2) sCH3

69.06

9.37

ch3

h h

C (CH3) 2 (CH2) sCH3

74.77

9.79

ch3

h h <"

OCH2CH2C6Hs

66.73

7.00

ch3

h ch3 ("

OCH (CH3) (CH2) 3C6H5

68.90

7.85

ch3

h h '”

OCH (CH3) (CH2) 3C6H5

68.42

7.66

ch3

h ho

OCH (CH3) (CH2) 3c6H5

68.42

7.66

ch3

h h0)

OCH (CH3) (CH2) 3C6Hs

68.42

7.66

ch3

h h0>

OCH (CH3) (CH2) 3C6Hs

68.42

7.66

h ch3

n-C4H9 H

h ho

OCH (CH3) (CH2) 3C6H5

0 (ch2) 3c6h5

67.33

7.23

Compounds prepared by the methods of

Examples 4—11,14,15,17 and 18

(a): 2A = one of the two diastereomers;

2B: the other of the two diastereomers of the -Z-W chain.

Analysis

Find

NOT

VS

H

NOT

me

P.F.

Z-W (a »

(m +)

(° C)

2.87

67.58

7.52

2.87

451

154-

157

2.71

70.05

8.44

2.66

479

195-

196

2.64

70.04

8.16

2.59

493

209-

210

2.58

68.75

8.19

2.51

507

196-

199

2.48

72.33

7.38

2.50

527

199-

200

2.72

69.76

8.16

2.74

479

154-

156

2.64

71.02

8.43

2.66

493

106-

108

3.10

67.27

8.97

2.88

415

129-

130 (d)

3.49

70.47

9.24

3.24

401

114-

115

3.24

66.27

6.93

3.18

395

210-

212

2.87

68.60

7.92

2.77

152-

2A, levo

154 (d)

2.96

68.18

7.61

2.96

145-

2 A, levo

154 (d)

2.96

68.09

7.47

2.94

224-

2B, levo

225 (d)

2.96

68.48

7.63

3.05

437

213-

2B

2i5 (d>

2.96

68.20

7.66

3.04

437

202-

2A

205 (d)

479

oil

3.14

67.60

7.22

3.06

409

138-

140 (d)

R.

r6

R

Z-W

Calculated C H

COCH3

ch3o)

a-OH

OCH (CH3) (CH2) 3C6H5

68.88

7.85

coœ3

CH, <»

ß-OH *)

OCH (CH3) (CH2) 3C6H5

68.88

7.85

COCH3

COQHj

ß-OCOC6H5

OCH (CH3) (CH2) 3C6H5

COCH3

coc6h5

ß-OCOC6H5

NOCH (CH3) (CH23C6H5

76.24

6.72

H

COCH3

ß-OH

OCH (CH3) (CH2) 3C6H5

74.11

8.06

H

COCH3

ß-OCOCH,

OCH (CH3) (CH2) 3C6H5

72.62

7.78

H

H (1)

ß-OH

OCH (CH3) (CH2) 3C6H5

69.49

7.94

H

H <"

ß-OH

OCH (CH3) (CH2) 3C6H5

69.49

7.94

COCH3

h (i)

ß-OCOC6H5

OCH (CH3) (CH2) 3C6H5

75.37

7.26

h ch3o

ß-OH

OCH (CH3) (CH2) 3C6H5

69.99

8.14

h n-CA "»

ß-OH

och (ch;) (ch2) 3c6h5

71.34

8.84

coch3

h

COC3 H7 (CH2) 2

c6h5o

ß-OCOC3H7 ß-OH

OCH (CH3) (CH2) 3C6H5 OCH (CH3) (CH2) 3CftH5

74.49

8.22

H

n-C5H „<”

ß-OH

OCH (CH3) (CH2) 3C6H5

71.74

8.84

6a, 10a = trans *) 6a, 10a = eis

(1), (a): see p. 43

Analysis

Find

NOT

VS

H

NOT

me

P.F.

(m +)

(° C)

2.87

68.42

7.78

2.74

451

159-

162

2.87

68.55

7.77

2.86

451

114-

148-

149

2.17

76.02

6.90

2.30

139-

141

3.20

74.11

7.84

3.28

437

195-

196

2.92

72.26

7.72

2.94

479

158-

161

3.25

64.69

7.46

3.02

395

178-

183 (d)

3.25

67.07

7.45

3.16

395

17-

183 (d)

2.59

75.75

7.19

2.68

541

131—

133

3.14

70.11

8.21

3.14

409

238-

240

2.79

70.33

8.36

2.91

451

238-

240 (d)

89-91

2.48

73.37

8.04

2.24

527

207-

210

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224

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