CH628034A5 - Process for the preparation of new benzo[c]quinol-9-(8H)-ones - Google Patents

Abstract

The compounds of formula III, the symbols of which are defined in Claim 1, are obtained by reacting a compound of formula VI with methyl vinyl ketone in the presence of a base; the intermediate from this aldol condensation is then cyclised using KOH. The compound of formula VI can be obtained from the corresponding 1,2,3,4-tetrahydroquinol-4-one by reacting with ethyl formate in the presence of NaH. The compounds of formula III can be used as intermediate chemical products, in particular as starting materials for the manufacture of medicaments. <IMAGE>

Description

This invention relates to the preparation of certain new l-hydroxyhexahydrobenzo [c] quinoline-9 (8H) -ones and their derivatives, which can be used as agents acting on the central nervous system, in particular as analgesics and tranquilizers, as hypotensive agents in mammals. and humans, as agents for treating glaucoma and as diuretics; and this invention also relates to the preparation of certain starting materials for obtaining the above-mentioned compounds.

The subject of the invention is methods of preparing a compound of formula

10

GOLD

R,

'6

in which

Ri = H, benzyl, benzoyl, C ^ -alkanoyl or -CO- (CHi) p — NR2R3 (p = 0; 1 to 4) where R2 and R3 taken separately, identical or not, are hydrogen or groups C1-alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a piperidino, pyrrolo, pyrrolidino, morpholino or N- (Cj ^, - alkyl) -piperazino nucleus;

R4 = H, C1_fi-alkyl or - (CH2) Z-C6H5 (z = 1 to 4);

R5 = H, CH3, C2H5;

R6 = H; - (CH2) y-COO (C1_Jalkyle) (y = 0; 1 to 4);

- (CH2) y-carbobenzyloxy, formyl, C, _5-alkanoyl, C ^ -al-kyle; - (CH2) W-C6H5 or - ^ 0 (CH2), „- C6H5;

Z = C ^ tj-alkylene or - (alk1) mX- (alk2) n where (alkj) and (alk2) are the same or different and are a group C1_9-alky-lene the sum of the carbon atoms of (alkj) + (alk2) not being greater than 9; each of n and m is 0 or 1; and X is O, S, SO or SO2; and

5

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628,034

W is a hydrogen atom or a methyl, pyridyl, piperidyl group,

"O"

W! where W, is a hydrogen, fluorine, or chlorine atom, or a group

-CH

\

(CH2) b

CH-W2 where W2 is a hydrogen atom or

Wj; a = 1 to 5 and b = 0 to 5, the sum of a and b not being greater than 5.

Another possibility of nomenclature for the compounds described here is based on the replacement of the root "benzofc] -quinoline" by "phenanthridine". Thus, d, l-trans-5,6,6aß, 7,8,9,10aa-octahydro-l-acetoxy-9ß-hydroxy-6ß-methyl-3 (5-phenyl-2-pentyloxy) benzo [c ] quinoline becomes d, l-trans-5,6,6aß, 7,8,9,10, 10aa-octahydro-l-acetoxy-9P-hydroxy-6ß-methyl-3- (5-phenyl-2-pentyIoxy ) phenanthridine.

Despite the current availability of a number of analgesic agents, the search for new and improved agents continues, highlighting the absence of an agent that can be used to combat high pain with minimal side effects. The most commonly used agent, aspirin, is not of practical interest in combating severe pain and is known to have various undesirable side effects. Other more potent analgesic agents like d-propoxyphene, codeine and morphine have addictive properties. The need for improved and potent analgesic agents is therefore evident.

The analgesic properties of 9-nor-9ß-hydroxyhexahy-drocannabinol and other compounds with cannabinoid structures, such as A8-tetrahydrocannabinol (A8-THC) and its primary metabolite, 1 l-hydroxy-As-THC, have been described by Wilson and May, Absts. Papers, Am. Chem. Soc., 168 Meet., MEDI 11 (1974), J. Med. Chem. 17,475-476 (1974), and J. Med. Chem., 18,700-703 (1975).

U.S. patents Nos 3 507 885 and 3 636 058 issued respectively on April 21, 1970 and January 18, 1972, describe various l-hydroxy-3-alkyl-6H-dibenzo [b, djpyrannes having in position 9 substituents like the groups oxo, hydro- carbyl, and hydroxy or chloro, hydrocarbylidene, and their appropriate intermediates.

The U.S. Patent No. 3,649,650 issued March 14, 1972 describes a series of tetrahydro-6,6,9-trialkyl-6H-di-benzo [b, d] pyran derivatives having in position 1 a group u) -di-alkyl- aminoalkoxy, active as psychotherapeutic agents.

German patent application No. 2,451,934 published on May 7, 1975 describes l, 9-dihydroxyhexahydrodibenzo [b, djpyrannes and certain 1-acylated derivatives having in position 3 an alkyl or alkylene group, as hypotensive, psychotropic, sedative and pain relievers. The hexahydro-9H-diben-zo [b, d] pyran-9-ones used as precursors in their preparation and which it is indicated that they have the same utility as the corresponding 9-hydroxylated compounds, are described in the application for German Patent No. 2,451,932 published May 7, 1975.

The U.S. Patent N ° 3 856 821 issued on December 24, 1974 describes a series of 3-alkoxy-dibenzo [b, d] pyrannes having an anti-arthritic, anti-inflammatory activity and an activity on the central nervous system.

Bergel et al., J. Chem. Soc., 286-287 (1943) studied the replacement of the pentyl group in position 3 of 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b,

d] pyran-l-ol by an alkoxy group (butoxy, pentyloxy, hexyloxy and octyloxy) and have found that it leads to biological inactivity. It is indicated that the hexyloxy derivative exhibits a low activity of the hashish type at 10-20 mg / kg. The other ethers do not show activity at doses up to 20 mg / kg.

In a more recent study, Loev et al., J. Med. Chem., 16, 1200-1206 (1973) describe a comparison of 7,8,9,3 0-t-trahydro-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-l-ols substituted in position 3 by groups -OCH (CH3) C =; H1 .. io -CH2CH (CH3) C5Hn or -CH (CH3) -C5Hn. The compound having an ether side chain is half as active, as regards the activity on the central nervous system, than the corresponding compound in which the alkyl side chain is attached directly to the aromatic cycle instead of being attached by 15 l 'intermediary of an oxygen atom; and 5 times more active than the compound in which the oxygen is replaced by a methylene group.

Hoops et al., J. Org. Chem., 33.2995-2996 (1968) describe the preparation of the 5-aza homolog of A6a (10a) -tetrahy-20 drocannabinol called here 7,8,9,10-tetrahydro-1-hydroxy-

5.6.6.9-tetramethyl-3-n-pentylphenanthridine, but indicate no utility for the compound. Beil in "Psychomimetic Drugs", edited by Efron, Raven Press, New York, 1970, page 336, indicates that the compound is "totally inert in pharma-

25 animal ecology ”.

Hardman et al., Proc. West. Pharmacol. Soc., 14,14-20 (1971) indicates a certain pharmacological activity for the

7.8.9.10-tetrahydro-1-hydroxy-6,6,9-trimethyl-3-n-pentyl phenanthridine, a 5-aza-A6a (10) a-tetrahydrocannabinol.

30 Mechoulam and Edery in “Marijuana” edited by Mecou-lam, Academic Press, New York, 1973, page 127, observe that the main structural changes in the molecule of t-trahydrocannabinol seem to give significant reductions in analgesic activity.

35 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 40 in the pyran ring removes activity.

We have now found that certain benzo [c] quinooleins, in particular the l, 9-dihydroxyoctahydro-6H-benzo [c] quino-leins (I), the l-hydroxyhexahydro-6H-benzo [c] quinoline-9 (8H) -ones (II) and 1-hydroxy-tetrahydroquinolines (IV) 45 are effective as agents acting on the central nervous system, in particular as analgesics and tranquilizers, as hypotensive agents, which are not narcotic and which are addictive , as agents for the treatment of glaucoma and as diuretic agents. The above-mentioned compounds and their derivatives have the formulas I, II and IV. The compounds of formulas III and IV are precursors of the compounds of formulas II and I.

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4

alkylene having 5 to 9 carbon atoms alkylene having 2 to 5 5 carbon atoms - (alk!) m-0- (aIk2) n-

- (alkOm-O-Calkz) ,, -

m n E - - HouCHj

(iv)

In these formulas:

R is chosen from hydroxy, alkanoyloxy groups having from one to five carbon atoms and hydroxymethyl;

R0 is chosen from oxo, methylene and alkyenedioxy groups having from two to four carbon atoms; and R 'is chosen from R and R0; the other symbols having the meanings given above.

The compounds of formula 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. Diastereoisomers with the 9ß configuration are generally preferred over 9a isomers because of their higher quantitative biological activity . Among the enantiomers of a given compound, one will generally be preferred over the other and racemic because of its greater activity.

The preferred enantiomer is determined by the procedures described herein. For convenience, the foregoing formulas describe the racemic compounds. However, the above formulas are considered to be general and to include the various racemic possibilities of the compounds obtained according to this invention, the diastereoisomeric mixtures, the pure enantiomers and their diastereoisomers. The usefulness of racemic mixtures, diastereoisomeric mixtures as well as enantiomers and pure diastereoisomers is determined by the bioassays described below.

Due to the greater biological activity compared to that of other final compounds described here, the preparation of the compounds of formula III in which R is as defined above is preferred:

Ri 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:

1 1

0 1

1 0 1 1

0 1

1 0

C6H5,4-FC6H4,4-C1C6H4,4-pyridyle C5H5,4 — FC6H4,4— C1C6H4j 4-pyridyle

{H or CH3 {H or CH3 {Hou CH3

Particularly preferred are the compounds of formula III in which:

R 1 is a hydrogen atom or an acetyl group; R5 is a hydrogen atom;

R4 is a methyl or propyl 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 - (alk1) m-0- (alk2) n- where m is 0 is n is 1, (alk2) n is an alkylene group having from four to nine carbon atoms, W is an atom of hydrogen or a phenyl group; and when Z is an alkylene group having five to nine carbon atoms, W is a hydrogen atom.

The compounds of formula III in which R6 is four that a hydrogen atom that an alkyl group and that a group- (CH2) X-C6H5, can also serve as intermediates for the compounds of formulas III in which R6 is a hydrogen atom or an alkyl group or - (CH2) x-C6H5.

The process according to the invention for preparing the compounds of formula III in which R 1 = H and R 6 = H is characterized in that a compound of formula is reacted

40

45

(vi)

cho alkylene having 5 to 9 carbon atoms alkylene having 2 to 5 carbon atoms - (alkOm-O-CalkJn—

- (alk i) m — O— (alk2) rl—

m n W - - HouCH3

1 1

0 1

1 0 1 1

0 1

1 0

C6H5, 4-FQH4,4-CIQH4,4-pyridyle C6H5, 4-FC6H4,4-

C1C6H4,4-pyridyle

{H or CH3 {H or CH3 {H or CH3

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

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

Z and W have the meanings indicated below:

with methyl vinyl ketone in the presence of a base and then with KOH.

The preferred preparation of the starting compound of formula VI is described below; or indeed it is generally obtained from a compound of formula V, see scheme A below.

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 55 (Yi) 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. Typical protective groups (Y!) Are methyl, ethyl, benzyl, 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 65 alkoxy having one to four carbon atoms.

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

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The choice 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 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 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 benzyl 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 substituted benzyl or bnezyl group because it can then be eliminated without harming the group Z.

The protected aniline derivative VIII is then transformed into a compound of formula IX by known methods, as described herein.

An abbreviated reaction scheme (Scheme io A) of the preparation of representative compounds of formula V is given below, starting from a 3- (hydroxy protected) -5- (Z — W—) aniline of formula VIII or -ZW is OCH3:

Diagram A

oc11.

0 11

OCiI.

i j r, -c-cfl_cc0 r

U £

jox

- (Vtu)

och

30

COOC2H5

(go)

HBr-HOAc

OH 0

HOAc

Eyelash.

J & Ji

C00R R,

I

H

(I *)

R # R_c = n »-ccoa * èu

R ^, - CO CH., C00 ?.

H.

(1) cicooc2h5

(2) 0H ~

(3)? Pa och eoo,

CH30

R,

Br- (alk2) n-W

KÖH '

V- (alk_) -0 'z n cr5 = H)

(X)

OH 0

.AT. R,

IV-C)

R ° in the previous diagram represents an alkyl group having from one to six carbon atoms (R5 for the purposes of illustration in the global diagram is represented as being a hydrogen atom. However, in eraction VIII X or VIII - * VB, R5 can be a hydrogen atom or a methyl or ethyl group).

The substituent in position 5 of the compounds of formula VIII can be the group -Z-W desired in the compounds of 65 formulas II or I, or a group easily convertible into this compound. When the Z part of the group -Z — W is - (alkj) ,,, - X- (alk2) m- where X is O or S and each of m and n is 0, substituting it in position 5 when W is a hydrogen atom

is -XH (ie GI I or SH) or a protected —XH group of formula —X-Y, where Y, is as defined above. When obviously -ZW is - (alki) m — X— (alk2) n — W where m is 1, n is 0 and W is hydrogen, the substituent in position 5 becomes - (alk ^ -XH. XH is advantageously protected in the manner described above.

The appropriate 5-substituted 3-hydroxy-anilines described above are reacted, preferably in the form of derivatives in which the 3-hydroxy group (and the 5-hydroxy group if it is present) is protected as mentioned above in order to obtain the satisfactory reactions with a lakyl p-ketoester, for example an allcyl acetoacetate, in the presence of acetic acid to form ß - [(3-hydroxy pro-tegej-anilino-5-substituted] -p- (R4) - corresponding acrylate (IX) The reaction is generally carried out in a solvent inert to the reaction, such as benzene or toluene, at temperatures ranging from approximately 50 ° C. to the reflux temperature of the solvent in the conditions which lead to the elimination of water as a by-product. Benzene and toluene are effective solvents when the reaction is carried out at reflux temperature, because they allow the azeotropic elimination of the water formed as a by-product. Other means of removing water - or eliminating it effective water - as molecular sieves can be used, as well as other solvents that allow azeotropic removal from water.

The preferred protective groups for the 5-substituted 3-hydr-oxv-aniline reagents are the methyl, ethyl and benzyl groups since the ethers are easily prepared, provide satisfactory yields of the compounds of formulas IX and V and are easily eliminated.

An excess of the alkyl P-ketoester, preferably one in which the alkyl group has from one to six carbon atoms, is generally used to ensure maximum conversion of the aniline reagent to ß-anilino-ß- (R4) -acrylate. corresponding alkyl (IX). A ten to twenty percent excess of the alkyl P-keto ester is generally sufficient to obtain satisfactory transformations. Acetic acid is used in catalytic amounts to facilitate the reaction.

The alkyl ß-anilino-ß- (R4) -acrylate (IX) is then reduced to 3 - [(3-hydroxy protected) -5-substituted anilino] -3- (R4) ~ corresponding alkyl propionate (X) using for example the sodium borohydride-acetic mixture and a catalytic hydrogenation. A preferred catalyst is platinum dioxide because it allows the reaction to be carried out conveniently at low pressures, that is to say pressures below 3.5 kg / cm 2. Other catalysts such as noble metals, for example platinum, palladium, rhodium, on a support or not, can be used with hydrogen pressures ranging from atmospheric pressure to higher pressures, for example 140 kg / cm 2. In addition to these catalysts which are heterogeneous catalysts, this step can be carried out using homogeneous catalysts such as the Wilkinson 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.

Furthermore, when the groups R4 and Rs 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 diyhdroxy) -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 eliminated at the time of cyclization by tulifying 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 - (alk1) m-X- (alk2) n-, cyclization conditions using polyphosphoric acid or trifluoroacetic acid should be used to avoid ether or thioether linkage cleavage.

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 golbal 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, they can be removed by catalytic hadrogenolysis. 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 -Z-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 -carbalcoxy 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 it is desired to be hydrolyzed to acid 3 - [(N-substituted) -3- (protected hydroxy) -anilino 5-substituted] -3- (R4) -

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corresponding propionics before cyclization. Polyphosphoric 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 carbalkoxy group, if it is present on the nitrogen atom, is not modified by this reaction. It can, if desired, then be 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 = O or S) and it is desired that this substituent zZ-W represents in the compounds of formula II or I a group -X- (alk2) nW where X is O, S, SO or S02 and W is as defined above, the group -XH is transformed into the group -X- (alk2) nW, conveniently and advantageously at this time in the global sequence of reaction. Thus, the group 7-XH of formula V-B above is transformed (which was shown by way of illustration by -OH) using the Williamson reaction with bromide [Br-

Sch6ma B

(alk2) n-W), the appropriate mesylate or tosylate, in the group -0- (alk2) n — W (formula V-C).

Similarly, when the group -ZW of the formula V is - (alkj-XH, its transformation into a group - (alkj) —X— s (alk2) nW where n is 0 or 1 and W is other than an atom d Hydrogen is conveniently carried out at this stage of the reaction sequence, via the Williamson reaction.

Various groups, such as those included in the definition of R6, can be used in place of the carbalc-oxy 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 formation of the derivative with hydroxymethylene group (formula 15 VI) by reaction with the reagent Cl-R6 or Br-R6 appropriate, according to known procedures. Obviously, when an acyl group R6, for example acetyl, is desired in the products of formulas I or II, these groups are generally introduced at this time of 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.

The compounds of formula V and obviously of formula V-A, V-B and V-C, can be transformed according to the following representative scheme (scheme B) first into compounds of formula VI. These will in turn be transformed, according to the invention into compounds of formula III which can finally give the representative compounds of formulas II and I (R5 = H in the representation).

W-Z

(V3Ï) £ + 1,3-bis-formylated derivative (VII-A) l

£ + cisj isomer

(I)

628,034

The quinolines of formula V are transformed into hydroxy-methylene 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 methylvinyl ketone gives a mixture of the corresponding Michael mono-N-formylated adduct (VII) and of the Michael 1,3-bis-formylated adduct. The two products are conveniently separated by column chromatography on silica gel.

The compounds of formula VII are transformed into compounds of formula III in an aldolic condensation of the mono-N-formylated compound of formula VII. The 1,3-bis-formylated Micheal adduct product, when subjected to aldolic condensation, gives a spirannic 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.

10

Oh

II

Nün ck-ck o ^ ci TO!

kb

(vii-a)

(iii-a)

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

The enone of formula III can be transformed by Birch reduction into a 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 - 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 when the cis-diastereoisomers are the main product.

The hydroxy ketones of formula II (compounds in which R0 is an oxo group and Rj is a hydrogen atom) and the dihydroxy compounds of formula I (R = ORj = OH) seem to be rather unstable. At rest, they undergo an oxidation as shown by the formation of purple to red colorations. The formation of colored by-products occurs even when the hydroxy ketone is subjected to reduction by sodium borohydride. It has been found that the formation of colored by-products can be prevented by acylation, and in particular acetylation, of the 1-hydroxy group (ORj) by acetic anhydride in pyridine, and by formation of addition salts. acid, for example hydrochlorides. The 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 (ORs) to the oxo group and the introduction of a second oxo group in position 2 or 4.

The compounds of formulas I and II, including those in which each of R4 and R5 is an alkyl group, can also be prepared by the reactions of Scheme C below.

628,034

10

The 3-hydroxy-5- (ZW) anilines can be prepared from the 5- (ZW) -resorcinols by the Bucherer reaction which consists of reacting the appropriate 5- (Z-W) resorcinol with the sulfite or bisulfite aqueous ammonium. The reaction is carried out in an autoclave at elevated temperatures, for example from about 150 to about 230 ° C. The aniline obtained is isolated by acidifying the cooled reaction mixture and extracting the acid mixture with, for example, ethyl acetate. The acid solution is neutralized and extracted with an appropriate solvent, for example chloroform, to collect the aniline obtained. Alternatively, the obtained aniline is isolated by extracting the cooled reaction mixture with an appropriate solvent and then performing column chromatography of the crude product.

If the 5- (Z-W) resorcinols are not known, they can be prepared from 3,5-dihydroxybenzoic acid. The procedure consists in esterifying 3,5-dihydroxybenzoic acid in which the hydroxy groups are protected (for example in the form of methyl, ethyl or benzyl ether); or else to effect the amidation of 3,5- [di (protected hydroxy)] benzoic acid.

10 The abbreviated global sequence is illustrated below (diagram E).

Diagram E

HO ~ COD H (XI)

oy.

O

(XII)

co-Y.

The starting material, 3,5-dihydr acid, which is particularly useful for compounds in which Z is an oxybenzoic agent XI, is transformed into a compound of formula XII in which alkylene group.

Y2 represents an alkoxy group, preferably a methoxy or ethoxy group for reasons of ease of preparation, unblocks the ether groups by the following means: tion, or an amino group; and Y! is a group protected by treatment with pyridine hydrochloride (Yj-methyl) or killer of the hydroxy group, according to methods described in catalytic hydrogenolysis (Yj benzyl), or treatment by literature. The diprotected derivative of acid acid such as 1 trifluoroacetic acid, hydrochloric acid, bromhy-benzoic acid of formula XII is then transformed into a compound of formula XIV by driclue or sulfuric. Acid debenzylation is obviously known methods. In a procedure, the 60 used is hydrolyzed when the —Z-W group contains sulfur.

compound XII into the corresponding acid (Y2 = OH) or its salt Another process for transforming compounds of form

lithium, and reacted with the appropriate alkyl lithium to promote them. Formula XIV comprises reacting an alkyl- (disubstituted phenyl) ketone (Y2 = alkyl). When ketone of formula xn (Y2 = alkyl) with the appropriate derivative of methyl lithium is used the derivative resulting from acetophenone triphenylphosphonium bromide [(C6H5) 3P -ZW] Br is pre-treated with a reagent of Grignard (W-Z'-MgBr). A base is hydrated, for example sodium hydride. The reaction lyses the intermediate adduct to the corresponding alcohol takes place via an alkene which is hydrogenated and which is then hydrogenolized to replace the group subsequently catalytically to the corresponding alkane (Z — W ) and that hydroxy by a hydrogen atom. This procedure is unlocked to obtain the dihydroxy compound XIV. Evi-

9,628,034

N I

h

11

628,034

demment, when -Z- is (alk1) m-X- (alk2) n and Y [is a benzyl group, the catalytic hydrogenation also causes the 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 (XII, Y2 = NH2) is transformed into a ketone (XII, Z '= Z minus a CH 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.

When Z is an alkylene group, Y] is preferably an alkyl group having from one to four carbon atoms or benzyl. The role of the group Y, 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 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 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 protective group, is removed by catalytic hadrogenolysis or acid hydrolysis.

When Z is a group - (alki) m-X- (alk2) n, Y! is preferably a benzyl or substituted benzyl group since it can then be removed without harming the Z group.

The compounds of formula VIII-A can also be prepared from 3-amino-5-hydroxybenzoic acids by the procedure of scheme F below.

The compounds of formula VIII-A in which -ZW is an alkylene group -W or- (alk1) -X '- (alk2) „- W where (alkj, (alk2), W and n are as defined above and X 'is O or S, are obtained by the following diagram (diagram F):

Diagram F

OY,

(Ac = acetyl) I 1

OY

(c6h5) 3p-chcooc2h5 1 a

R "

(R * - B, ulkyl)

CH,

CH X00C "H

I

R *

2 5

CH20H

Cite Âôsyle f1

fol ai ^ CH0-OTs AcN

I ”••

W- (alk0) -X'E x n

(<V5> /

628,034

12

AcNH

_Ol ^ CH JOj

CH -X »AcliiT ^ TTE

I

; (alk2) n R "

w I S

OY,

, CR ©

œ2 - * "W3

Br

G

r "-c- (ch0) -w 1 2 v

° v

AcKH

JL

^ CH.

ck Vh "= c ™ (gyv-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 grouping, 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 Yt is other than a benzyl group (for example methyl), 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, then the alkylation of the tosylate or of the mesylate with an alkali metal salt of the appropriate reagent HX '- (alk2) „- W and the final elimination of the protective groups Y! provide the desired compound 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 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 corresponding saturated compound.

In this variant, the acidification of the protective group Yj chosen 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 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 III can be obtained in which -Z-W is - (alk1) m-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 sulfones is conveniently carried out using a peracid such as perbenzoic acid, perphthalic acid or m-chloroperbenzoic acid. The latter peracid is particularly useful because the by-product, m-chlorobenzoic acid, is easily eliminated.

The esters of the compounds of formula III in which Ri is an alkanoyl group or —CO- (CH2) p-NR2R3, are easily prepared by reacting the compounds of formula III with the appropriate alkaconic acid or the acid of formula HOQC - (CH2) p-NR2R3, in the presence of a condensing agent such as dicy-clohexylcarbodiimide. Alternatively, they are prepared by reacting a compound of formula III with the appropriate alkanoic acid chloride or anhydride, for example ethyl chloride or acetic anhydride, in the presence of a base such as pyridine.

The presence of a basic group in the ester part (ORi) of the compounds of formula III allows the formation of acid addition salts 55 implying said basic group. When the basic esters described here are prepared by condensing the hydrochloride of the appropriate amino acid (or another acid addition salt) with the appropriate compound of formula III in the presence of a condensing agent, the hydrochloride 60 of the basic ester. Careful neutralization provides the free basis. The free base can then be transformed into other acid addition salts by known procedures.

It is obvious to those skilled in the art that the acid addition salts can be formed with the nitrogen of the benzo [c] 65 quinoline system. These salts are prepared by conventional procedures. The basic ester derivatives can obviously form mono- or di-salt additives of acid, because of their basic double function.

30

35

40

45

50

13

628,034

The analgesic properties of the compounds of formulas I and II 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 for suppressing convulsions induced by an irritant agent which is phenylben-zoquinone, in mice.

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.

Preparation Al d, 1-3 - (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 ethyl acetoacetate, 535 is heated at reflux for 15 hours under a nitrogen atmosphere. ml and 3.3 ml glacial acetic acid, and the water is collected using a Dean-Stark trap. The reaction mixture is cooled to ambient temperature, it is discolored with active carbon, it is filtered and then it is concentrated under reduced pressure, which gives the product, 3- [3,4- (dimethoxy) anilino] -2 - ethyl 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 until

500 ml portions until the entire reaction mixture is processed.

The methylene chloride layers are combined and dried over MgSO 4, 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) $ $ ^ i3 (ppm): 5.82-6.0 (m, 3H, aromatics), 4.20 (q, 2H, methylene ester), 3.80-4 .00 (m,

I

2H, -NH and N-CH-CH3), 3.78 (s, 6H, -OCH3), 2.40-2.55 (m, 2H, -CH2COOEt), 1.78 (d, 3H, methyl ) and 1.29 (t, 3H, methyl).

Preparation A3 20 d, l-3- (3,5-dimethoxyanilino) ethyl hexanoate

Following the procedure of Preparation A2, the condensation of 3,5-dimethoxyaniline hydrochloride and ethyl buty-rylacetate gives ethyl d, l-3- (3,5-dimethoxyanilino) hexanoate. 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.

30 Analysis: Calculated for Ci6H2504N ■ HCl:

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

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

m / e-295 (m +)

35 'H NMR (60 MHz) ô "gjsa (ppm): 10.76-11.48 (wide, variable, 2H, NH2 +), 6.77 (d, J = 2Hz, 2H, H in meta), 6 , 49, 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,

gives 160.8 g of product.

than an oil. The oil is taken up in chloroform, the solution is washed successively with a saturated solution of bicarbo-40 O-C-CH3), 0.84 (t, 3H, -C-CH3).

sodium nate (2X50 ml) and a saturated solution of sodium chloride. Then it is dried over MgS04, filtered and Preparation B1

concentrated under reduced pressure, which gives the product under I. d, l-3- [3,5-dimethoxy-N-ethoxycarbonyl) anilino] butyrate as an oil (5.1 g). ethyl

The repetition of the preceding procedure but using 45 Method A being 168.7 g of ethyl 3- (3,5-dimethoxyanilino) -2-butenoate, is added dropwise over 45 min. 71.4 ml (0, 75 mole) of 320 ml of glacial acetic acid and 2.15 g of platinum oxide ethyl chloroformate 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 50 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 sodium bicarbonate solution (1X 300 ml) and an aqueous saturated sodium chloride solution (1X400 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.

Preparation A2

d, l -3- (3,5-dimethoxyanilino) ethyl butyrate

To a solution of 370 g (1.45 mole) of 3,5-dimethoxyaniline hydrochloride, 4.5 I of reactive methanol and 286.3 g (2.64 moles) of ethyl acetoacetate in a flask with a 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 nm), 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. We repeat this process using

60

Method B

Under a positive nitrogen atmosphere, stirred and cooled in an ice bath at 0-5 ° C a mixture of 376 g (1.4 mole) of 3- (3,5-dimethoxyanilino) ethyl butyrare, 1.41 of methylene chlo-65 and 388.8 g (2.81 moles) of anhydrous potassium carbonate. 153 g (1.41 mole) of ethyl chloroformate are added all at once. The mixture is allowed to warm up to room temperature in one hour, added once

628,034

14

another 153 g (1.41 mole) of ethyl chloroformate and the mixture is heated to reflux in a steam bath for 1 hour. Then it is allowed to cool to room temperature and the potassium carbonate is removed by filtration. The red filtrate is successively washed with water (2 × 1000 ml), brine (1 × 500 ml), it is dried over MgSO 4 then it is discolored and evaporated under reduced pressure, which gives 439 g of product crude which is used without further purification.

'H NMR (60 MHz) ôjjf, 3 (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, -CH2COOEt), 1.00- 1.40 (m, 9H, 3 methyls).

methoxy-N-ethoxycarbonyl) -anilino] butyric in the form of an oil, [a] ^ = - 20.0 ° (c = 1.0, CHCl3). 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. 114-5116 ° C. Recrystallization from a 1: 1 mixture of ethyl acetate and hexane provides 71.1 g (34%) of the l_-ephedrine salt of acid 1—3 - [(3,5-dimethoxy-N -ethoxycarbonyl) -anilino] butyri-que; m.p. 126-127 ° C.

io Analysis: Calculated for C25H3607N2:

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

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

II. D, l — 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) anili-nojbutyric acid

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 ). The aqueous layer is then 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%).

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- dimethoxy-N-ethoxycarbonyl) ethyl anilinoj-butyrate in 2 l of 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 5 l of ice water and extracted in 1 l portions 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'Sf ,, (ppm): 6,24-6,53 (m, 3H, aromatic), 4.65 (sextet, 1H, -N (COOC2H5) CH (CH3) CTLC002H5) , 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 C15H2] 06H:

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

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

III. D- and l_-3 f (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 under vacuum to obtain the 1-ephedrine salt of the acid d, l-3-f (3,5-di-

["] □ = - 43.5 ° (c = 1.0, CHCI3).

The 1-ephedrine salt of the 1-isomer is stirred in a mixture of 1000 ml of ethyl acetate and 400 ml 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] butyri-que, pf 96-97 ° C.

, 5 Analysis: Calculated for C: 5H2i06N: C, 57.86; H, 6.80;

Found:

C, 57.90; H, 6.66;

N, 4.50% N, 4.45%

[cx] d = - 25.4 ° (c = 1.0, CHC13).

3Q The remaining mother liquor is treated with the recrystallization of the 1-ephedrine salt of the J_ isomer, with hydrochloric acid as described above, to obtain the acid d-3 - [(3,5-dimethoxy-N -ethoxycarbonyl) anilino] raw butyric. The 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.

40

Analysis: Calculated for C25H3607N2: C, 63.00; H, 7.61;

Found:

C, 62.82; H, 7.47;

N, 5.88% N, 5.97%

[aß5 = +44.0 ° (c = 1.0, CHC13).

The salt of d-ephedrine is transformed 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, m.p. 96-97 ° C after recrystallization from a 3: 5 mixture of ethyl acetate and hexane.

50

Analysis: Calculated for C15H2i06N:

Found:

C, 57 ,: C, 57.95;

H, 6.80; H, 6.57;

N, 4.50% N, 4.35%

[aß5 = +25.3 ° (c = 1.0, CHC13).

55

Preparation C

3- (3,5-dimethoxyanilino) methyl propionate

A mixture of 3.5-60 dimethoxyaniline (114.9 g, 0.75 mole), methyl acrylate (69.73 g, 0.81 mole) and 2 ml of is heated at reflux for 20 hours. glacial acetic acid. The reflux is stopped and the reaction mixture is concentrated and then it is 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) ô ™!, 3 (ppm): 5.62-5.95 (m, 3H, aromatic), 4.1 (variable, large s, 1H, -NH), 3.74 (s, 6H, -OCH3), 3.68 (s, 3H, COOCH3), 3.41 and 2.59 (two triples of 2H, —NCH2CH2CO2).

15

628,034

Preparation D

d, l-3 - {[3-hydroxy-5- (5-phenyl-2-pentyl)] anilino} methyl propionate

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 a saturated solution of sodium bicarbonate. Then the organic phase is dried over MgSO .; and evaporated to a crude residue which is chromatographed on 130 g of silica gel using a 2: 1 mixture of benzene and ether as eluent. After elution of the less polar impurities, 540 mg (40%) of d, l-3 - {[3-hydroxy-5- (5-phenyl-2-pentyI)] ani! Ino} methyl propionate are collected. This product has the following spectral characteristics:

'H NMR (60 MHz) ôj ^ i5 (ppm): 7.14 (s, 5H, aromatic), 5.83-6.13 (m, 3H, aromatic), 3.66 (s, 3H, -CO -OCH3), 3.37 (t, 2H, -NCH,), 2.16-2.78 (m, 5H, -CH2COO and benzyl), 1.28-1.69 (m, 4H, - (CH2 ) 2-), 1.11 (d, 3H,> -CH3), 4.4-5.2 and 1.28-2.78 (variable, 1H, NH, OH).

m / e-341 (m +)

Preparation B2

I. 3 - Methyl [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] 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) propionate of methyl of 5 ml of methylene chloride and of 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 a further 20 min, and is then poured into a mixture of 75 ml of methylene chloride and 50 ml of frozen water. The methylene chloride layer is separated, washed successively with 10% hydrochloric acid (2 × 50 ml), a saturated aqueous solution of sodium bicarbonate (1 × 30 ml) and a saturated aqueous solution of chloride of sodium (1x40 ml) and dried over MgS04. Then it is discolored with activated charcoal and concentrated under reduced pressure to an oil (2.72 g). We use the product as is.

sodium nate (3 X 100 ml), brine (1 X 100 ml) and then dried over MgS04. 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.

Analysis: Calculated for C14HnOsN:

C, 60.21; H, 6.14; N, 5.02% Found: C, 60.11; H, 6.14; N, 4.80%

II. 5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline Heated at reflux overnight a mixture of 60 ml of glacial acetic acid, 60 ml of 48% hydrobromic acid and 4 , 0 g (14.3 mmol) of 1-carbethoxy-5,7-dimethoxy-4-15 oxo-1,2,3,4-tetrahydroquinoline then concentrated in vacuo 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 the 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 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%

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

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

2.72 g (8.36 mmol) of 3 - [(3,5-dimethoxy-N-45 ethoxycarbonyl) anilino] methyl propionate, 8.4 ml of 1N aqueous sodium hydroxide and 8.4 are combined. 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 as an oil (2.47 g) which is used as it is.

Preparation E

I. 1-carbethoxy-5,7-dimethoxy-4-oxo-1,2,3,4-tetrahydro-quinoline 60

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 in 200 ml of a 1: 1 mixture of methylene chloride 65 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 a saturated bicarbo solution.

Preparation F

d, 1-1 -carbethoxy-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetra-hydroquinoline

A solution of 4.0 g (12.8 mmol) of 3 - [(3,5-dimethoxy-N-ethoxycarbonyI) anilino] butyric acid in 2 ml of 5.0 g chloroform is added dropwise with stirring. 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 a saturated sodium bicarbonate solution (3 X 100 ml), brine (1 X 100 ml) and then washed. dry 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.

628,034

16

Analysis: Calculated for C15H1905N: Analysis: Calculated for C10HuO3 N:

C, 61.42; H, 6.53; N, 4.78% C, 61.16; H, 5.74; N, 7.25%

Found: C, 61.54; H, 6.55; N, 4.94% Found: C, 62.01; H, 5.85; N, 7.02%

m / e-293 (m +) 5 Similarly, we transform the d, l-3 - {[3-hydroxy-5- (5-phe-

IR (KBr) - 5.85, 5.95 | x (> = 0) nyl-2-pentyl)] anilino} propionate in d, l-5-hydroxy-7- (5-phe

nyl-2-pentyl) -4-oxo-1,2,3,4-tetrahydroquinoline which can be prepared by Preparation G by column chromatography using d, 1-5,7-dihydroxy-2- gel methyl-4-oxo-1,2,3,4-tetrahydro-silica and a 5: 1 mixture of benzene and ether as eluent.

quinoline io m / e - 309 (m +)

NMR method (60 MHz) ô $ ^ 3 (ppm): 12.22 (s, IH, OH in 5),

A mixture of 240 ml is heated at reflux overnight 7.14 (s, 5H, QH5), 6.04 (d, J = 2.5 Hz, 1H, H in meta), 5.87 (d, d glacial acetic acid, 240 ml 48% hydrobromic acid J = 2.5 Hz, 1H, H in meta), 4.19 ^ 1.60 (wide, 1H, NH), 3.48 (t, and 16.0 g (55 mmol) l-carbethoxy-5,7-dimethoxy-2H, CH2N), 2.18-2.89 (m, 5H, ArCH, ArCH2, CH2-C = 0), methyl -4-oxo-1,2,3,4-tetrahydroquinoline then it is concentrated 1.38 - 1.86 (m, 4H, - [Ct2] 2-), 1.13 (d, 3H, CH3) .

be under vacuum until dark oil. Dissolve the oil in And transform the hydrochloride of d, l-3- (3,5-dimethoxy-

200 ml of water and the aqueous solution is neutralized to pH 6-7 anilino) ethyl hexanoate in d, 1 -5,7-dihydroxy-2-propyl-4-with IN sodium hydroxide. A satu-oxo-1,2,3,4-tetrahydroquinoline solution is added; m.p. 117-119 ° C (in the salt level in water (200 ml) and the resulting mixture of methylene chloride is extracted).

with ethyl acetate (3X500 ml). The extracts are combined, 20 m / e-221 (m +), 135 (base peak, m + -propyle).

dried over MgS04 and concentrated under reduced pressure And the acid L-3 - [(3,5-dimethoxy- (N-ehtoxy-

to a dark oil (12.8 g). A d-5,7-dihydroxy-2-methyl-4- d-5,7-dihydroxy-butyric iscarbonyl) is added to the oil.

10: 1 mixture of hexane and ethyl acetate and collected by oxo-1,2,3,4-tetrahydroquinoline, m.p. 167—168 ° C.

filtration of the resulting crystals, 3.8 g, m.p. 158 ° -165 ° C. [Aß5 = +167.8 ° (c = 1.0, CH3OH).

trituration of the crystals in ethyl acetate gives 1.65 g 25 m / e -193 (m +)

of product, m.p. 165-168 ° C.

Additional material separates from mother liquors Analysis: Calculated for C10HnO3N:

by standing (2.9 g, mp 168-170 ° C). Yarn chromatography - C, 62.16; H, 5.74; N, 7.25%

trat on silica gel column using a solvent Found: C, 61.87; H, 5.62; N, 6.96%

1: 1 mixture of benzene and ether gives an additional 4.6 g 30

of product, m.p. 167-169 ° C. and transform the acid d-3- [3,5-dimethoxy-N-ethoxycar-

Further purification is obtained by recrystallizing the bonyl) -anilino] butyric in 1: -5,7-dihydroxy-2-methyl-4-oxo-product in ethyl acetate; m.p. 173-174 ° C. 1,2,3,4-tetrahydroquinoline; m.p. 166-168 ° C.

[aß5 = - 168.5 0 (c —1.0, CH3OH).

Analysis: Calculated for C10HnO3N: 35 m / e _ 193 (m +)

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

Found: C, 62.00; H, 5.83; N, 7.14% Analysis: Calculated for C10HnO3N:

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

m / e-193 (m +) Found: C, 61.82; H, 5.83; N, 7.22%

40

Mé'tf> ° deB. ,, naked Preparation H

Heat in an oil barn at 110 C for 2 hours, 7 ~ 0 aioqa a mixture of 100 g (0.32 mole) of acid çU-3 - [(3,5-dimeth- ^ J ^ dn »cy .2-n ^ l ^^ l ^, 4 ^ m ^ droq ^ oxy-N-ethoxycarbonyl) anilmo] butyrique, 500 ml of acid Qn heated at reflux for 6 hours a mé, 230

hydrobromic at 48% and 300 ml of glacial acetic acid. Then 4s (1 5 mole) of 3) 5_dimethoxyanilinej of 150 (1.5 mole) of croto-on the temperature of the oil bath is raised to 145 C and 1 is followed by methylate and 90 (15 mole) with glacial acetic acid. heating for 2 additional hours. During this Qn add an additional 9Q of glacial acetic acid and a heating azeotropic mixture distilled, heated, to the dermere of heating; overnight Qn added (boiling point 42 - 110 C, about 200-300 ml) and on 10Q0 m, d, 48% hydrobromic acid solution and 850 ml leaves the homogeneous dark red solution to cool down to 50 acéti, adal au mé, reactional which ron heats room temperature. We pour the mixture on 1 water and reflux for 4h ^ Qn isolated I duit dté title and we, e ice (3 liters) and 1 ether (2 liters) ^ P ^ 'layers and rify is [on lg EII preparation procedure. The aqueous solution is washed with 1 ether (2 X 1000 ml). The ethereal layers are combined to obtain 36 e o f 166-170 ° C and washed successively with water.

(2 X 1000 ml), brine (1 X 500 ml), saturated solution 55 p - r t- j fe Na »CS (4 X 250 ml) and brine (1 X 500 ml) then dZ5J-daiydroxy-2-methyl-4 -oXo-l, 2,3A-tetrahydwquino-

dries them (MgS04). Discoloration with charcoal and evaporation of the ether provide a yellow foam which is recrystallized.

,. . . ,, ,, ,,. . ,? ., Heated at 185-200 C for 45 minutes a mixture read in about 300 ml of methylene chloride which gives mole) of 3,5-dimethoxyaniline, 2.54 g (0.03

31.3 g (50.4% 5,7-dihydroxy-2-methyl-4-oxo-l 2,3,4-te- 6Q mo] e) toni and 3 0 {126 mole) of chlorh trahydroqu .nole.ne pure. More dreaded product can be isolated from the cooled reaction mixture from the mother liquor by chromatography on silica gel. suspension in 500 ml of water (pH about 3) and the pH is adjusted

1 H NMR (60 MHz) ô ™ s (100 mg of sample / 0.3 ml of to 7 and the resulting mixture is stirred for 10 minutes.

CDCl3 / 0.2 ml of CD3SOCD3) (ppm): 12.40 (s, 1H, C5-OH), separates the organic layer, it is dried over MgS04 and it is

5.72 (d, 2H, H in meta), 5.38-5.60 (s, broad, 1H, C7-OH), 65 concentrates up to 3.2 g of a yellow oil.

3.50-4.00 (m, 1H, C2H), 2.38-2.60 (m, 2H, C3-H2), 1.12 (d, 110 ml mixture of glacial acetic acid is heated ,

3H, methyl). 110 ml 48% hydrobromic acid and yellow oil

m / e - 193 (m4 ^) for 1 hour then concentrated in vacuo to an oil

17

628,034

dark. The oil is dissolved in water and the aqueous solution is neutralized to 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 MgSQ4 and concentrated under reduced pressure to a dark oil (2.8 g). Silica gel column chromatography of the crude residue using a 4: 1 mixture of benzene and ether as the 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.

Analysis: Calculated for CioHn03N:

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

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

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 as eluent), la5,7-dihydroxy -2,2, -dimethyl-4-oxo-1,2,3,4-tetrahydroquinoline in the form of a yellow oil.

Analysis (SM)

Parent woodpecker (m +)

Calculated for C1 jH ^ OjN: 207.0895

Found: 207.0895 Base peak (m + -15)

Calculated for C10H10O3N: 192.0661

Found: 192.0655

by filtration the desired product and it is recrystallized from hot hexane, m.p. 76-77 ° C.

The previous procedure is repeated on a scale 20 times larger but using as a 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 an 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 Q7H25O3N:

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

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

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

m / e - 269 (m +) and 178 (m + -benzyl, base peak) NMR (CDCI3) Ô (ppm): 8.76 (s, 1H, 5-OH), 7.18-7.6 (m , 5H. QH5.5.84 (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, CH2-C = 0, -CH2-C6H5 and NH).

Preparation J

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-dihy-droxy-2-methyl-4-oxo-l, 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. Fractions 12-18 are combined and concentrated under reduced pressure to a light yellow oil (850 mg) which crystallizes on standing. We separate m / e-291 (m +)

IR (KBr): 6.01 [t (= 0)

Similarly, 5,7-dihydroxy-4-20 oxo-1,2,3,4-tetrahydroquinoline is transformed into d, l-5-hydroxy-7- (2-hep-tyloxy) -4-oxo -1,2,3,4-tetrahydroquinoline, which is an oil.

'H NMR (60 MHz) ô ™ ci3 (PPm): 13.3 (s, 1H, phenolic), 5.5 and 5.7 (d, 2H, J = 2Hz, aromatic), 4.6 (s , 1H, -NH), 4.1—4.6 (m, 1H, -0-CH-), 3.3 (t, 2H, J = 7 Hz, 25 -CH2-), 2.6 (t , 2H, J = 7 Hz, -CH2-), 2.0-0.7 (m, remaining protons).

Preparation K

d, l-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-30 1,2,3,4-tetrahydroquinoline

A mixture of 16.4 g (5 mmol) of 5-phenyl-2- (R, S) -pentanol, 28 ml (200 mmol) of triethylamine and 80 ml are cooled in an ice-water bath. of tetrahydrofuran under a nitrogen atmosphere. 8.5 ml (110 35 mmol) of methanesulfonyl chloride are added dropwise to 20 ml of dry tetrahydrofuran 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 40 is washed with dry tetrahydrofuran and the washing liquid is evaporated from the combined filtrate 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 × 100 ml) then with saturated brine (1 × 20 ml). Evaporation of the solvent 45 provides 21.7 g (89.7%) of the d, 1 -5-phenyl-2-pentanol mesylate which is used in the next step without further purification.

Heated to 80-82 ° C in an oil bath for 1 h Vi a mixture of 1.0 g (5.2 mmol) of d, l-5,7-dihydroxy-2-mé-thyl-4- oxo-1,2,3,4-tetrahydroquinoline, and 14.35 g (0.104 50 mole) of potassium carbonate, 60 ml of N, N-dimethylfor-mamide and 13.68 g (57 mmol) of mesylate of d, l-5-phe-nyl-2-pentanol, 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 55 (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, discolored with charcoal and evaporated to obtain the product.

m / e -339 (m +)

60 The preceding procedure is repeated but using 114.8 g (0.594 mole) of d, 1 -5-hydroxy-2-methyl-7-phenyl-2-pentyloxy) -4-oxo-1,2 3,4-tetrahydroquinoline, 612 ml of N, N-diméhtyIformamide, 174.8 g (1.265 mole) of potassium carbonate and 165.5 g (0.638 mole) of 65 d, 1-5-phenyl-2- mesylate pentanol. The reaction mixture is cooled and poured into ice water and the aqueous solution is extracted into ethyl acetate (2 X 4 1). The combined extract is washed with water (4 × 21), brine (1 × 2 1) and dried over MgSO 4.

628,034

18

Evaporation provides 196 g of the title product. It is used without further purification.

'H NMR (60 MHz) ö ^ fis (ppm): 12.73 (s, 1H, OH), 7.22 (s, 5H, aromatic), 5.80 (d, J = 3 Hz, 1H, H in meta), 5.58 (d, J = 3 Hz, ÎH, H in meta), 1.25 (d, 6H, CHj-CH-N and CH3-CH-0-), 1.41-4, 81 (m, 11 H, remaining protons).

Preparation Kl d, l -5-hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetra-hydroquinoline

The repetition of the procedure for preparation K but using 5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquino-leine in place of 5,7-dihydroxy-2-methyl-4 -oxo-1,2,3,4-tererahydroquinoline provides d, 1 -5-hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline under form of an oil with a yield of 74%.

miss-

lS (m +)

Analysis: Calculated for C20H23NO3:

C, 73.70; H, 7.12; N, 4.31%

Found: C, 73.69; H, 7.15; N, 4.08%

'H NMR (60 MHz) ô ™ ci3 (PPm): 12> 6 (broad s, 1H, phenolic), 7.3 (s, 5H, aromatic), 5.8 (d, 1H, aromatic, J = 2Hz), 5.6 (d, 1H, 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, 1 -5-hydroxy-2-methyl-7- (4-phe-nylbutyloxy) -4-oxo-1 , 2,3,4-tetraquinoline 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 C29 H2303N:

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

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

m / e —235 (m +)

'H NMR (60 MHz ôj ^ i / ppm): 12.58 (s, IH, -OH), 7.21 (s, 5H, C6H5), 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, 1H, NH), 3.33 - 4.08 (m, 3H , -0-CH2, -CH-N), 2.29-2.83 (m, 4H, -CH2-C = 0, C6H5-CH2), 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. D - 5 + 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-pentyloxy) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline; m / e - 367 (m +).

Preparation L

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

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 h1 /: when we added the 7? of the ethyl formate solution, the addition is stopped to allow the substantial foam which has formed to be absorbed. 600 ml of diethyl ether are added and the mixture is stirred for 15 minutes before adding the rest 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. Acidification to pH 1 s with 10% HCl and the phase is separated which is extracted with ethyl acetate (2X2 1). The combined organic solutions are washed successively with water (2X2 1), brine (1X11) and dried over MgSO4. The concentration gives 231 g of a red brown oil which is used without further purification.

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

Similarly, the d, l-5-hydroxy-7- (5-phenyl-2-pentyloxy) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline is transformed into d, 1 -1 - formyl-5-hydroxy-3-hydroxymethylene-7- (5-phenyl-2-15 pentyloxy) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline. It is used in the following examples as is.

Example 1

A) d, l-l-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-20 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 is added dropwise, in V2 hour, a solution of 11 , 1 g (0.038 mole) of d, 1 -5-hydroxy-2-me-25 thyl-7- (2-heptyloxy) -4-oxo-1,2,3,4, -tetrahydroquinoline in 110 g (1 , 48 moles) 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 the addition of 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 X 100 ml) and brine (1 X 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 washing solutions with sodium bicarbonate with concentrated hydrochloric acid 40 and then extracting the acid solution with ether (2 X 100 ml). The concentration of the ethereal extracts combined, after drying, gives 2.3 g of product (in total 13.1 g). We use the product as is.

'H NMR (60 MHz) ô ^, 3 (ppm): 12.27 (broad s, IH, OH 45 phenolic), 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, -O-CH), 0.6-2.08 (m, 17H, CH3-C-C5Hu and CH3-CN).

In the same way; the d, l-5-hydroxy-2-50 methyl-7- (5-phenyl-2-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-t-trahydroquinoline is transformed into d, 1 -1 -formyl-5-hydroxy-3-hydroxymé-thylène-2-methyl-7- (5 -phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tee-trahydroquinoline.

! H NMR: (60 MHz) ôgfë, 3 (60 MHz) ôj ^ h (ppm): 12.22 (s ss large, IH, Ar OH), 8.8-11.6 (variable, 1H, = COH ), 8.64 (s, 1H, -CHO), 7.21 (s wide, shoulder at 7.30.6H, aromatic and = CH), 6.23 and 6.17 (two doublets of 1H, J = 2Hz, meta), 5.42 (q wide, IH, 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 60, 6H, CH3-CN and CH3-CO).

The d, l-5-hydroxv-7- (2-heptyIoxy) -4-oxo-1,2,3,4-tetrahydroquinoline is transformed into d, 1 -1 -formyl-5-hydroxy-3-hydroxymethylene-7 - (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline, which is an oil.

65 iH NMR (60 MHz), 0 ^ -, / ppm): 12.1 (wide, 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, —O-CH2- ), 2.0-0.7 (remaining protons).

19

628,034

We transform d, 1 -5-hydroxy-7- (5-pentyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline to d, 1 -1 -formyl-5-hydr-oxy -3-hydroxymethyl lene-7 - (5-phenyl -2-penty loxy) -4-oxo-1,2,3,4-tetrahydroquinoline.

'H NMR (60 MHz) 6 ™ (S;. (Ppm): 12.4 (broad, 1H, phenolic), 8.5 (s, 1H, CHO), 7.2 (m, 6H, aromatic and = CH ~),

6.2 (m, 2H, aromatic "), 4.5 (s, 2H, -CH ;-), 4.4 (m. 1H, -CH-CH3), 2.6 (bt, 2H. -CH2-) , 1.7 (m, 5H, remaining protons),

1.3 (d, 3H, -CH-ŒL, J = 6Hz).

and the d, 1 -5-hydroxy-2-methvl-7- (4-phenylbu-tyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline is transformed into d, ll-formyl-5-hydroxy- methylene-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.

Calculated for C22H23O5N:

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

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

m / e-381 (m +)

■ H NMR (60 MHz) ^f ^ ci (ppm): 12.4-13.6 (m, H,

V

103 ° C. The analytical sample is obtained by recrystallization from methanol, m.p. 104-105 ° C.

Calculated for C5H-, 905N: s "C 70.90;

Found: C, 70.77;

H, 6.90; N, 3.31% H, 6.81; N, 3.46%

.OH

), 12.26 (s, 1H, 5-OH), 8.62 (s, 1H, -C (= 0) -H),

.H

), 7.27 (s, 5H, C6H5), 6.26 (broad s, 2H, H in meta), 5.46 (q, 1H, CH-N), 3.82-4.23 (m, 3H, -CHi-O), 2.49-2.80 (m, 3H, ArCIL), 1.67-2.02 (m, 4H, -CH, 1.27 (d, 3H, CH3).

7.18-7.48 (m, 1H,

B) d, ll-formyl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyl-oxy) -4-oxo-3- (3-oxobutyl) -l, 2,3,4- tetrahydroquinoline

To a solution of d, 1 -1 -formy 1-3-hydroxymethylene-5-hy-droxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4 -tetra-hydroquinoline (229 g, about 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 methyl vinyl ketone 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 -1,3-diformyl-5-hy-droxy-2-methyl-7- (5-pheny] -2-pentyloxy ) -4-oxo-3- (3-oxobu-tyl) -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 6 l of ether and then washed successively with 10% aqueous sodium carbonate (4X1700 ml), brine (1X21) and then dried over MgSO4. 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 2 L of water and 2 L of ethyl acetate for 10 minutes. The aqueous phase is separated, extracted with ethyl acetate (1X 21) and the combined ethyl acetate solutions are washed with water (2X2 1), brine (1X 2 1 ) and they are dried over 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) ^j ^, 3 (ppm): 12.7 (s, 1H, OH), 8.78 (broad s, 1H, -CHO), 7.22 (s, 5H, aromatic), 6.22 (broad s, 2H, H in meta), 2.12, 2.07 (s, 3H, -CH3-CO-), 1.31 (d, 3H, -CH3-C-0), and 1.57-5.23 (m, 13H, remaining protons).

The similar treatment of 35 g (0.09 mole) of d, 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, ll-formyl-5-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-3- (3-oxobutyl) -l, 2,3,4-tetrahydroquinoline, mp 101-

<H NMR (60 MHz) 0 ™ ^ (ppm): 12.88 (s, 1H, -OH) 9.08 10 (broad 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-O-), approximately 2.49-3.02 [m, 7H, ArCHz, - (CH2, - (CH2), - C (= 0) -, -CH-C (= 0)], 2.18 [s, 3H, CH3 -C (= 0)], 1.68-2.03 [m, 4H, - (CH2) 2-], 1.13 (d, 3H, CH3). 15 m / e-423 (m +)

and d, ll -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) -1,2,3,4-tetrahydroquinoline which is used as is.

C) d, ll-formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -l, 2,3,4-tetrahydroquinoline and d, ll, 3-di-formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxo-25 butyl) -1,2,3,4,4-tetrahydroquinoline

To a solution of 13.1 g (37.7 mmol) of d, l-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 × 60 ml), then with brine (1 × 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 15% ether mixture of benzene with 40% ether is then used as the elution solvent, and 100 ml fractions are collected when the first colored band begins to elute from the column. Fractions 5 to 13 are combined and concentrated under reduced pressure, giving d, 1 -1,3-diformyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3 - (3-oxobutyl) -1,2,3,4-tetrahy-45 droquinoline 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 to give d, ll-formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -3 - (3-oxobutyl) -l , 2,3,4-tetrahydro-50 quinoline in the form of 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 potassium carbonate in 25 ml of methanol for 2 hours at 0 ° C. The solvent is then 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 60 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:

'H NMR (60 MHz) (ppm): 12.73 (S, 1H, OH phe-65 nolic), 8.87 (S, 1H, N-CHÖ), 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).

628,034

20

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

d, l-1 -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) JJ ^ i3 (PPm): 12.8 (S, 1H, phenolic), 8.7 (S, 1H, N-CHO), 6.1 (S, 2H, aromatics), 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-l-formyi-5-hydroxy-2-methyl-7- (5-phenyi-2-pentyl-oxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline.

'H NMR (60 MHz) ôjîf, 3 (ppm): 12.68 (S, 1H, -OH), 8.82 (wide s, 1H, -C (O) 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, -OC-CHj), 1.12 (d, 3H, -NC-CH3), 1.4 -3.1 (m, 11H, other protons).

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

m / e-423 (m +)

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

D) d, 1—5,6,6a, 7-tetrahydro-l -hydroxy-6ß-mithyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline-9 (8H) -one

A solution of 174 g (0.398 mol) of d, ll-formyl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) is stirred and refluxed for 1 night under a nitrogen atmosphere. -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline 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 (C) CD3) (ppm): 7.21 (s, 5H, aromatic), 5, 80 (s, 2H, H in meta), 1.20 (d, 6H, CH3-CHO and CHj-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. The 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 6p-methyl derivative has an Rf of 0.41.

m / e-391 (m +)

'H NMR (60 MHz) 0 ™ s (100 mg dissolved in 0.3 ml of CD3OD 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). ~

Similar treatment of 22 g of d, 1 -1 -formy 1-5-hy-droxy-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-phenyIbutyl-oxy ) benzo [c] quinoline-9 (8H) -one, pf 222-224 ° C. The analytical sample is obtained by recrystallization from methanol, 5 m.p. 224-225 ° C.

Calculated for C24H2703N:

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

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

10

'H NMR (60 MHz) [1: 1 mixture of (CD3) 2SO and DC3OD]: 1.24 (d, 3H, 6ß-CH3)

m / e - 377 (m +)

Evaporation of the mother liquor gives 2.8 g (mp 185-15 195 ° C) of product, the NMR of which shows that it is a mixture of the 6P-methylated derivative (about 40%), and of the d, l -5,6,6a, 7-tetra-hydro-1-hydroxy-6a-methyl-3- (4-phenylbutyloxy) -benzo [c] -quinoline-9 (8H) -one.

HRMN (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).

Example 2

d, 1—5,6,6a, 7-tetrahydro-1-hydroxy-6ß-methyl-3- (2-heptyl-oxy-) 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) -l, 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 under 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 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 235-40,237 ° C.

Analysis: Calculated for C2iH2903N:

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

Found: C, 73.22; H, 8.30; N, 4, ll%

Additional material is collected by evaporating all the mother liquors and extracting with chloroform the aqueous solution from which the crude red-brown product was obtained 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, 1 -5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyl-oxy) benzo [c] quinoline-9 (8H) -one; m.p. 170 ° —173 ° C. (recrystal-55 read in chloroform).

m / e-377 (m +)

Analysis: Calculated for C24H2703N:

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

6o Found: C, 76.38; H, 7.21; N, 3.85%

d, 1 -5,6,6a, 7-tetrahydro-1-hydroxy-3- (2-heptyloxy) benzo [c] quinoline-9 (8H) -one; m.p. 208 ° —209 ° C.

m / e - 329 (m +)

65

Analysis: Calculated for C2 () H2703N:

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

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

21

628,034

d, l-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyl-oxy) -6ß-propylbenzo [c] quinol6in-9 (8H) -one; m.p. 164 ° —166 ° C.

Analysis: Calculated for C25H29O3N:

C, 76.69; H, 7.47; N, 3.58% Found: C, 76.32; H, 7.36; N, 3.33%

Analysis: Calculated for C27H33O3N:

C, 77.29; H, 7.93; N, 3.34% Found: C, 76.97; H, 7.98; N, 3.41%

1-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyI-2-pentyI-oxy) -6p-methylbenzo [c] quinoIein-9 (8H) -one; m.p. 176 ° -178 ° C.

[aß5 = - 416.0 ° C (c = 0.33, CH3OH)

m / e-391 (m +)

5 d-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyl-oxy) -6P-methylIbenzo [c] quinoline-9 (8H) -one; m.p.

172 ° -174 ° C.

[aß5 = + 412.9 ° (c = 1.0, CH3OH)

m / e- 391 (m +)

10

Analysis: Calculated for C25H29O3N:

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

Found: C, 76.40; H, 7.39; N, 3.51%

Other compounds according to the following table were prepared by this method:

C-77.00 C-76.86

-0-CH (CH3) (CH2) 3C6H5 C2Hs H H 405 155-6 C26H3103N H-7.71 H-7.62

N-3.45 N-3.45

-0-CH (CH3) (CH2) 3C6H5 C6Hi

H H

461 139-141 C30H39O3N

C-78.05

H-8.52

N-3.08

C-78.16

H-8.53

N-3.09

-0-CH (CH3) (CH2) 3C6H5 C5H!

H H

447 150-3

C29H3703N

C-77.81

H-8.33

N-3.13

C-77.78

H-8.19

N-3.13

C-77.56 C-77.28

-0-CH (CH3) (CH2) 3C6HS C4H9 H H 433 160-2 C28H3503N H-8.14 H-7.92

N-3.23 N-3.18

C-79.80 C-79.64

-0-CH (CH3) (CH2) 3C6Hs - (CH2) 2-C6H5 H H 481 200-201 C32H3503N H-7.33 H-7.34

N-2.91 N-2.93

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

H H 363 246-7 C23H2503N

C-76.00

H-6.93

N-3.85

C-76.19

H-7.14

N-3.89

-C (CH3) 2-C5H3

CH,

H H 355 261-2 C23H3302N

C-77.70

H-9.36

N-3.94

C-77.94

H-9.36

N-3.99

-0 (CH2) 2C6H5

CH,

H H 349 248-250 C22H2303N

C-75.72

H-6.63

N-4.01

C-75.26

H-6.66

N-3.93

C-77.56 C-77.86

-0-CH (CH3) (CH2) 3C6H5 H C4H9 H 433 95-98 C28H3503N H-8.14 H-8.37

N-3.23 N-3.17

(a) i-enantiomer; [aß = - 416.0 ° (C = 0.33, CH3OH)

(b) d-enantiomer; [aß = + 412.9 ° (C = 1.0, CH3OH)

22

Example 3

d, 1-5,6,6a, 7,10,1 Oa-hexahydro-1-hydroxy-6ß-mithyl-3- (2-hepyloxy) benzo [c] quinoline-9 (8H) -one

A solution of 1.0 g (2.91 mmol) of d, 1-5,6,6a, 7-tetrahydro-1-hydroxy-6p-methyl is added dropwise via a dropping funnel. -3 (2heptyloxy) benzo [c] qui-noléin-9 (8H) -one in 20 ml of tetrahydrofuran, to a rapidly stirred solution of 0.1 g of lithium in 75 ml of liquid ammonia (distilled through pellets potassium hydroxide.) The dropping funnel is rinsed with 10 ml of tetrahydrofuran. The mixture is stirred for 10 minutes and then solid ammonium chloride is added to remove the blue color. The excess ammonia is allowed to evaporate and the residue is taken up in 100 ml of water and 50 ml of ethyl acetate. The ethyl acetate layer is separated and the aqueous phase is extracted with ethyl acetate (2 x 50 ml). The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to a brown semi-solid (1.35 g). Trituration of the semi-solid in a 1: 1 mixture of pentane and ether gives a light brown solid (0.884 g); m.p. 130-138 ° C.

The previous procedure is repeated, but using 1.84 g (5.36 mmol) of the 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) (ppm): 6.85 and 7.49 (1H, wide 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 5

d, l-5,6,6a, 7,10,10a-hexahydro-l-acetoxy-6fi-methyl-3- (2hep-tyloxy) benzo [c] quinoline-9 (8H) -one

The procedure of Example 3 is repeated, but using double the quantities of reagents. The product is then directly acylated (2.22 g) according to the procedure of Example 4, which gives 2.35 g of the acetylated product. This product is triturated in a 3: 1 mixture of pentane and ether until a brown yellow solid is obtained (905 mg) which, when recrystallized in ethanol, gives 404 mg of yellow brown crystals clear; m.p. 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, isotherm, and methylene chloride and it is introduced into a column of 275 g of silica gel (packed and eluted with a 3: 1 mixture of petroleum ether and ether). The column is first eluted with 21 of a 3: 1 mixture of petroleum ether and ether, then with 1.5 l of a 2: 1 mixture of petroleum ether, 20 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 1: 1 solvent system are combined and concentrated under reduced pressure to a foam (496 mg). Crystallization from petroleum ether provides white crystals, m.p. 100-113 ° C 25 (410 mg). Recrystallization from a 1: 1 mixture of ethanol and water gives d, l-trans-5,6,6aß-7,10,10aa-hexahydro-l-acetoxy-6P-methyl-3- (2- heptyloxy) benzo [c] quinoIein-9 (8H) -one melting at 111-112 ° C.

m / e-387 (m +)

30

Analysis calculated for C23H34N:

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

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

35

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 40, m.p. 84-88 ° C. Recrystallization from a 1:10 mixture of ethyl acetate and hexane gives d, l-cis-5,6,6ap, 7,10,10aa-hexahydro-l-acetoxy-3- (2-heptyloxy ) -6p-methyl-benzo [c] quinoline-9 (8H) -one, pf 84-86 ° C.

Example 4

5,6,6a, 7,10,1 Oa-hexahydro-l -acétoxy-6fi-méthyi-3- (2-heptyl-45 oxy) benzo- [c] quinoline-9 (8H) -one isomers.

2.2 ml of pydridine 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) -on in 2.2 ml of acetic anhydride under nitrogen atmosphere. The mixture is then stirred for one and a half hours 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; m.p. 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; m.p. 78-82 ° C.

The products are the isomeric monoacetylated components.

Analysis calculated for C23H3304N:

€, 71.29; H, 8.58; N, 3.61%

Found: €, 71.05; H, 8.48; N, 3.56%

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

d, l-trans-5,6,6aß-7, l 0,10aa-hexahydro-l-acetoxy-6P-methyl-3- (5-phenyl-2-pentyIoxy) benzo [c] quinoline-9- ( 8H) -one, pf 80-82 ° C.

m / e-435 (m +)

Analysis calculated for C27H3304N:

€, 74.45; H, 7.64; N, 3.22%

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

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

Analysis calculated for C27H3304N • HCl:

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

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

23

628,034

d, 1 -trans-5,6,6aß-7,10,1 Oaa-hexahydro-1 -acétoxy-3- (5-phenyl-2-pentyloxy) -6p-propylbenzo [c] quinoIéine-9 (8H> -one; ft. 79-80 ° C.

m / e -463 (m +)

d, l-cis, 5,6,6apap-7,10,1 Oaß-hexahydro-l-acetoxy-3- (5-phenyl-2-pentyloxy) -6p-propyIbenzo [c] quinoline-9 (8H) -one; m.p. 144-146 ° C, as hydrochloride, m / e-463 (m +)

d, 1 -cis-5,6,6aß, 7,10,1 Oaß-hexahydro-1 -acétoxy-3- (5-phenyl-2-pentyIoxyj-6p-methylbenzo [c] quinoIéine-9 (8H) - one, mp 90-94 ° C. as hydrochloride.

[aß5 = + 22.8 ° (c = 0.31, CH3OH)

m / e-435 (m +)

Analysis calculated for C27H3304N • HCl:

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

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

d, 1 -trans-5,6,6aß-7,10,10ap-hexahydro-1-acetoxy-3- (5-phenyl-2-pentyloxy) -6P-methylIbenzo [c] quinoline-9- (8H) -one; m.p. 90-95 ° C, in the form of the hydrochloride. [cx] p = + 78.46 ° (c = 0.13, CH3OH)

m / e-435 (m +)

Analysis calculated for C27H3304N • HCl:

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

Found: C, 70.20; H, 7.23; N, 3.07%

5 dJ-cis-5,6,6aß-7,10,1 Oaß-hexahydro-l-acetoxy-3- (5-phenyl-2-pentyloxy) ^ - methylbenzo [c] -quinoin-9 (8H) - one, pf 90-92 ° C, in the form of the hydrochloride. [a] & 5 = - 20.5 ° (c = 0.19, CH3OH)

m / e -435 (m +)

io Analysis calculated for C27H3304N • HCl:

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

Found: C, 68.92; H, 7.23; N, 3.09%

d, 1 -trans-5,6,6aß-7,10,1 Oaß-hexahydro-1 -acétoxy-3- (5-ph0nyl-2-pentyloxy) -6ß-m0thylbenzo [c] quinoMine-9 (8H) -15 one; m.p. 92-96 ° C, in the form of the hydrochloride. [a] p = - 79.0 ° (c = 0.10, CH3OH)

m / e -435 (m +)

Analysis calculated for C27H3304N • HCl: 20 C, 68.71; H, 7.26; N, 2.97%

Found: C, 68.67; H, 7.23; N, 3.02%

Similarly, the following compounds were prepared:

ZW

-C (CH3) 2C6H13

R4 R5 Rfi

CH, H H

-OCH (CH3) (CH2) 3C6H5 H CH3 H [6R, 6aR]

-OCH (CH3) (CH2) 3C6Hs CH3 H H [6S, 6aR]

-OCH (CH3) (CH2) 3C6H5 CH3 H H [2'S, 6S, 6aR)

-OCH (CH3) (CH2) 3C6H5 CH3 H H [2'R, 6S, 6aR]

-OCH2CH2C6H5

CH, H H

(° C) m.p.

m / e (m +)

108-112 397

145-146,433

167-168,433

159-160,391

Formula c25h35no3

125-130 433 C27H3104N

C27H310 <N

c27h31o4n

120-121 433 C27H3104N

Q4H23O4N

Hold.

Find

C, H, N

C, H, N

C-75.53

C-75.62

H-8.87

H-8.83

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

C-74.80

C-74.58

H-7.21

H-7.19

N-3.23

N-3.27

C-73.63

C-73.38

H-6.44

H-6.41

N-3.58

N-3.59

Example 6

d, l-trans-5,6,6aß- 7,10,1 Oaa-hexahydro-1 -acétoxy-5-

acetyl-6fi-methyl-3- (5-phenyl-2-pentyloxy) -benzo [c] quino-

lein-9 (8H) -one

63 3.49 g (8 mmol) of d, l-trans-5,6,6aß, 7,10,10aa-hexahydro-l-acetoxy-6P-methyl- are dissolved in 20 ml of alcohol-free chloroform 3- (5-phenyl-2-pentyloxy) -benzo [c] -qui-nolein-9 (8H) -one, the solution is cooled in a

628,034

24

ice, and first add 14 ml of pyridine (dried on KOH tablets) 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 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 C29H35O5N:

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

Found: C, 72.69; H, 7.48; N, 2.49%

I.R. (KBr): 2.90 n (m), 3.38 (s), 3.48 (s), 5.62 [x (s),

5.78 fi (s), 6.00 (.t (s), 6.15 jx (s), 6.30 fx (s).

crumb — Garlic (m +)

'HRMN (60 MHz); (PPm): 7.20 (m, 5H, aroma),

6.53 (d, IH, CU), 4.71-4.08 (m, 2H, methines), 2.29 (s, 3H,

r? Hî, xw? fis p- * ™

(2d, 3H, C_ „CH), 1.12 (d, 3H, CH3 of the side chain), 3.20 acetic acid to maintain a neutral pH until the

'T ^ a ftreS Prot ° ns restfnts)'. 25 reaction is complete, as evidenced by the absence of

Analogously of the ^ -as-5; 6,6aß, 7,10aß-hexahy- starting substances in a chromatography on layer dro-î-acetoxy-6p-methyI-3- (5-phenyl-2-pentyloxy) -benzo [c] - thin. The product is isolated as follows.

ff, ^ f; (or) 0nte? tra, nsformee e "ii-f", u,, To the reaction mixture are added ice water and e-

/ '' ^ aP '' 10aß-hexahy ^ ol-acetoxy-5-acetyl-6ß-methyl-3- ^ Qn & the ethereal layer and we extract the hase ae l5;? Î1! 7 ^ enty XjSfnZ0 [c] qUm0 eme "9 ()" 0ne'Pi-125 30 once more with ether. The layers are combined at _8 C,% yield. ethereal, they are dried and evaporated, which gives the d, l-

. ,. _ TT XT trans-5,6,6aß, 7,10,10aa-hexahydro-l-acetoxy-5-methyl-6p-

Analysis ca eu ee for Q9H35Os: methyl-3- (2-heptyloxy) -benzo [c] quinoline-9 (8H) -one desired

Found: C, 72.80; H, 7.35; N, 2.70% 35 s ^ i ^^^ Sh1 (60 MHz, CDCI3) has an absorb-

2H, C2 and C4) 5.02-4.62 m, 1H C ^ methine), 4 ^ 2-4.12 (m, ir of reagents

1H mettane in side chain), 2.28 (s 3H, CH, ace ^ M-5,6,6afr7,10,10aa-hexahydro-l-acetoxy-5-methyl-3-

tate), 2.11 and 2.13 (3H, CH3 of I amide), 1.26 and 1.28 (3H, CH3 40 (2-heptyloxy) benzo [c] quinoline-9- (8H) -one, one oil, C,), 1.22 (d, 3H, CH3 of the side chain), 3.42-1.65 çU-trans-5,6,63 ^ 7,8,9, lO ^ lOa-octahydro -l, 9-diacét-

WSÎ W? 3.43 L (s), 5.65, 1 (s), 5.81 [X (s),

6.02 u (s), 6.16 fi (s), 6.32 ^ (s), 6.70 [x (s). m / _ 445 (m +)

m / e - 477 (m). In addition, the following compounds are prepared in the same way:

they are filtered, which gives, after concentration and crystallization from a mixture of ether and petroleum ether, the d, l-trans-5,6,6aP-7,10,10aa-hexahydro-l-acetoxy-3 - (2-heptyloxy-5-benzoyl-6P-methylbenzo [c] quinoline-9 (8H) -one, mp 108- s 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:

d, l-trans-5,6,6ap, 7,10,10aa-hexahydro-l-acetoxy-3- (2-heptyloxy) -5-acetyl-6P-methylbenzo [c] quinoline-9 (8H) -one . m / e-433 (m +)

15 Example 8

d, l-trans-5,6,6aß, 7,10,1 Oaa-hexahydro-l-acetoxy-5-

methyl-6fi-methyl-3- (2-heptyloxy) -benzo [c] quinoline-

9 (8H) -one

To a stirred solution of 387 mg of d, ltrans-5,6,6aß, 7, 10, lQaa-hexahydro-l-ac0toxy-6ß-methyl-3- (2-heptyloxy) benzo [c] quinoline-9 ( 8H) -one in 3 ml of acetonitrile, cooled

Hip at 1 S ° P nn aimitp. H 5 ml Hp. fnrmalHp.lwrte arniftiiY at 37%

Example 7

d, 1 -trans-5,6,6aß, 7,10,1 Oaa-hexahydro-1 -acétoxy-3 - (2-hep-tyloxy) -5- (benzoyl-6ß-mithylbenzo [c] quinoMine-9 ( 8H) -one 50

To a stirred solution of the product of Example 5.812 mg of dj-trans-5,6,6aß-7,10,1 Oaa-hexahydro-l-acetoxy-6ß-mes-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 ice and extracted twice with ether. The combined ethereal extracts are washed with water and a sodium bicarbonate solution, dried over MgSO4 and

0-c-CH

3

H jf jÇX <i \

5 Rg

-z-w ch,

I

-0-ch- (ch2) 3c6h5

ch3

r.

CH,

H

Ra

CH,

r "

m.p.

m / e (m +)

"" H 94-97 "C1 449

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

-0- (ch2) 4c6h5 ch3 h ch3

-H oil2 449

"" H 102 ° —103 ° C3 435

25

628,034

1 in hydrochloride form Analysis

Calculated for: C28H35N- CHI:

C, 69.19; H, 7.47; N, 2.88%

Found: C, 68.72; H, 7.18; N, 2.74%

2 Analysis Calculated for: C28H35O4N:

C, 74.80; H, 7.85; N, 3.12%

Found: C, 74.66; H, 8.05; N, 2.66% 10

3Analysis Calculated for: CU7H33O4N:

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

Found * C, 73.89; H, 7.51; N, 3.04% 15

25

30

Example 9

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

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, 6aß7,10,10aa-hexahydro-1-acetoxy-3- (5-phenyI-2-pen-tyloxy) 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), m.p. 128-129 ° C.

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

Example 10

d, l - 5,6,6aß7,10,10aa-hexahydro-1-hydroxy-6ß-mithyl-3- <* o (2-heptyl-sulfinyl) benzo [c] quinoline-9 (8H) -one

Equimolar amounts of m-chloroper-benzoic acid and d, 1 - 5,6,6aß, 7,10,1 Oaa-hexahydro-1-hydroxy-6p-methyl-3- (2heptylthio) benzo are added [c] quinoIine-9 (8H) -one to a mixture of chloroform and acetic acid (2: 1) and the reaction mixture was 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.

50

Example 11

d, l-trans-5,6,6a, 7,10,10a-hexahydro-l -hydroxy-6ft-methyl-3- (2-heptylsulfonyl) benzo [c] quinoline-9 (8H) -one

The procedure of Example 10 is repeated, but using 2 equivalents of m-chloroperbenzoic acid of oxidizing agent per mole of thioether reagent, to obtain the title compound.

Preparation M — l

2-Bromo-5-phenylpentane 60

812 g of 5 are added to phosphorus pentabromide, prepared by adding 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. -phenyl-2-pentanol in methylene chloride at 0 ° C. The mixture is stirred for 2 ½ 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, a 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: ÔJKci,! '6 (D> 3 methyl, J = 7 Hz), 1.6-2.0 (M, 4, ethylene), 2.3-3.0 (Broad T, 2, methylene benzyl) , 3.7-4.2 (M, 1, methine), 6.9-7.4 (M, 5, aromatics).

Preparation M — 2

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

A solution of 51.7 g of 1-bromopropylbenzene 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 in vacuo to give 28 g of 2- (3,5-dimethoxyphenyl) -5-phenylpenetane, mp 0.125 mm, 154-159 ° C.

NMR: ô £ Kci, 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 M-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, 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: ô ™ ci3 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, aromatic), 6.65 (broad S, 2, hyroxyl), 7-7.4 (M, 5, aromatic).

Following the procedures of preparations B and C, the compounds indicated below are prepared by substituting the appropriate 1-bromoalkylbenzene for 1-bromopropylbenzene: 2- (3,5-dihydroxyphenyl) -6-phenylhexane. NMR: 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 benzyls, methinyl), 6.0 (broad s, 1 OH phenolics), 6 , 2-6.4 (M, 3, aromatic), 7.1-7.4 (M, 5, aromatic).

1- (3,5-dihydroxyphenyl) -2-phenylethane m.p .: 76-77 ° C

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

NMR: i, 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).

Preparation M-4

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

29 ml of a 2.2 M solution of

628,034

26

n-butyl lithium at 31.5 g of 3,5-dimethoxybenzyl triphenyl phosphonium bromide in 200 ml of tetrahydrofuran, with stirring, and the resulting dark red solution is stirred for half an hour. 9.4 g of benzylaceous tone are added dropwise and the reaction mixture is stirred for 12 hours. Then if 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, giving the crude 1 - (3,5-dimethoxyphenyl) -2-methyl-4-phenyl-1-butene as an oil. It is purified by chromography of io 400 g on silica gel and by elution with benzene. 10 g are obtained in the form of an oil.

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

9.4 g of l- (3,5-dimeth- isoxy-phenyl) -2-methyl-4-phenyl-1-butene thus prepared are dissolved in 250 ml of ethanol and hydrogenated catalytically to 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: ôj ^ i3 O-9 (A, 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 Preparation C to obtain 1- (3,5-dihydroxyphenyl) -2-methyl-4-phenyl-butane. 25

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. The reaction mixture is then cooled and the crystalline product is collected by filtration, washed with ether and dried, 20 g, m.p. 269-270 ° C.

Preparation M — 5

2-Methyl-2 - (3,5-dihydroxyphenyl) -5-phenylpentane 35

To a solution of snack reagent prepared from 5.5 g of 2-phenylbromoethane, 0.8 g of magnesium and 60 ml of dry ether, a solution of 2.75 g of 2-methyl- is added. 2- (3-5-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 MgSO 4 and concentrated, which gives 52 g (88% yield) of ss 2-methyl-2 (3,5-dimethoxyphenyl) -5-3-pentanol in the form of an oil.

16 g of the pentanol are taken up in 100 ml of ether 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-phenyl-3-pen-tene.

The pentene derivative is hydrogenated catalytically according to the procedure of preparation M-4 and the resulting 2-methyl-2- (3,5-dimethoxyphenyl) -5-phenyl-3-pentane is demethylated according to the mode procedure of preparation C to obtain the product.

Preparation M-6

Over an hour and a half, 531 ml of a 2 M solution of methyl lithium (1.06 mole) are added under a nitrogen atmosphere 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 slowly added while maintaining the reaction temperature below 20 ° C. 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 crystallizes slowly in isopropyl ether, the crude product is recrystallized from ether-hexane, which gives 104.7 g (59%) of product, mp 59-61 ° C.

Preparation M — 7

3- (3,5-Dibenzyloxyphenyl) ethyl crotonate (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 benzene concentration of which increases from 40:60 onwards. 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, m.p. 73-75 ° C.

Analysis calculated for C26H2604:

C, 77.58; H, 6.51%

Found: C, 77.72; H, 6.60%

Similarly, ethyl 3- (3,5-dimethoxyphé-nyl) -crotonate is prepared from 3,5-dimethoxyacétophé-none (51.7 g) and carbethoxymethylenetriphenylphosphorane (200 g). 61.8 g, 86% are obtained, eg 146-162 ° C at 0.3 mm.

Preparation M-8

3- (3,5-Dibenzyloxyphenyl) -1 -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) of aluminum chloride is added and the mixture is heated to reflux for 2 hours and then cooled. Then 3.4 ml of water are successively added to the reaction mixture. 3.4 ml of 6N sodium hydroxide and 10 ml of water. The mineral salts which precipitate 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 +)

27

628,034

Analysis calculated for C24H2f) 03:

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 M-9

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 ° vs. 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 dried 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 C31H3205S:

C, 72.06; H, 6.24%

Found: C, 72.05; H, 6.29%

Preparation M-10

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-dibenzyloxy-phenyl) 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 C30H3üO3:

C, 82.16; H, 6.89%

Found: C, 82.07; H, 6.84%

Preparation M — 11

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) -1-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 chromatography on 100 g of silica gel, eluting with a mixture of benzene and ethyl acetate comprising from 0 to 10% ethyl acetate. The fractions of the medium 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 +)

Analysis calculated for CIf) H1803:

Found:

C, 74.39; H, 7.02% C, 74.13; H, 7.00%

15

Preparation M — 12 5 l-Bromo-3- (3,5-dimethoxyphenyl) butane

A solution of 5.7 ml (0.06 mole) of phosphorus tribromide in 30 ml of ether is added to a solution of 30.0 g (0.143 mole) of 3- (3,5-dimethoxyphenyl) -l- 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 2.5 hours. 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.

20

Preparation M-13

4- (3,5-Dihydroxyphenyl) -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- 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. Once 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 alkalized and extracted with ethyl acetate (3

35 times 50 ml). Evaporation of the combined extracts after drying (MgSO 4) provides 4- (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 D provides 40 4- (3,5-dimethoxy-phenyl) -1- (4-pyridyl) pentane in quantitative yield; m.p. 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 eluting agent 4 liters of 5% ethanol in benzene, one liter of 10% ethanol in benzene, 11% 13% ethanol in benzene and 5% 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.

The 3- (3,5-dimethoxyphenyl) butyl-triphenylphosphonium bromide is prepared by refluxing a mixture of

1-bromo-3- (3,5-dimethoxyphenyl) butane (21.5 g, 78.5

60 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 vacuum desiccator to give 36.4 g (86%) of product, m.p. 65 190-200 ° C.

Preparation M — 14

3,5-Dimethoxy-amethylstyrene oxide

To a solution of 69.4 mmol of dimethyl methylide

628,034

28

sulfoxonium, in 65 ml of dimethyl sulfoxide at room temperature, 10 g (55.5 mmol) of solid 3,5-dimethoxy-acetophenone 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 petroleum 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 (CC14): 2780,1595,1196,1151,1058 cm "1 UV (95% ethanol) Xmax = 279 nm (e = 2068) m / e-194 (m" * ")

RMP (CDCI3) (60 MHz): ô 1.70 (S, CH3-), 2.76 (d, J = 6 15

O O

Hz, ZA.H) 2.95 (d, J = 6 Hz, ZA.H), 3.81 (S, CH3O-), 6.41 (t, J = 2 Hz, ArH) and 6.58 ( d, J = 2 Hz, ArH).

Analysis calculated for CuHi403:

C, 68.02; H, 7.27% Found: C, 67.96; H, 7.28%

20

25

Preparation M-15 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. 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. The 40 fractions 52-88 provide 2.9 g (89%) of 2- (3,5-di-methoxyphenyl) -2-hydroxypropyl and 2-phenylethyl ether. IR (CC14): 3534,1595,1202,1153 cm "1 UV (95% ethanol): Xmax 278 (e = 1830), 273 (e = 1860)."

m / e-316 (m +)

RMP (CDC12, 60 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, -CH1O), 3.80 (S, OCH3), 6.38 (t, J = 2 Hz, ArH), 6.61 (d, so J = 2Hz, ArH) and 7.23 (S, PhH).

Analysis calculated for ClgH2404:

C, 72.12; H, 7.65%

Found: C, 71.92; H, 7.63% 55

Preparation M-16

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), 60 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 in 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 magnesium sulfate and evaporated to an oil. We dissolve the oil 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 the oxide. 2- (3,5-dimethoxyphenyl) propyl and 2-phenyl-ethyl.

IR (CC14): 1600,1205,1155,1109 cm "1.

m / - 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).

Preparation M — l 7

2- (3,5-dihydrophenyl) propyl and 2-phenylethyl oxide

A mixture of 195 mg (0.65 mmol) of 2- (3,5-dimethoxyphenyl) propyl and 2-phenylethyl ether, 0.4 ml (4, 4) is heated at 190 ° C. for 6 hours. 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) then with a second ether extract (50 ml) from the aqueous phase, dried over magnesium sulfate and evaporated to an oil. The oil is purified by preparative thin layer chromatography on silica gel plates, eluted 6 times with a mixture of 30% ether in pentane, which gives 65.8 mg (37%) of the oxide. 2- (3,5-dihydroxyphenyl) propyl and 2-phenylethyl.

IR (CHC13); 3559.3279,1605,1147,1105 cm "-1.

crumb —212 (m +)

RMP (CDClj, 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 M — 18

4- (3,5-Dihydroxyphenyl) -l-phenoxypentane

Under a nitrogen atmosphere, three quarters of 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. mole) of 3-phenoxypropyltriphé-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 up to room temperature, then it is carefully stirred 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 solution of sodium chloride (3 times 300 ml), dried over sodium sulfate and concentrated in vacuo, which gives an oil which is triturated with ether to make precipitate triphenylphosphine oxide. Filtration and then concentration of the filtrate give an oily residue which is chromatographed on 1300 g of silica gel, eluting with a mixture of benzene and hexane ranging from 30 to 100% benzene. From the medium fractions, 51 g (75%) of 4- (3,5-dibenzyloxy-phenyl) -l-phenoxypentene-3, Rf 0.8 (silica gel, ben -zene: hexane2: 1); m / e-450 (m +)

Analysis calculated for C31H30O3:

C, 82.63; H, 6.71%

Found: C, 82.90; H, 6.69%

29

628,034

Hydrogenation is carried out for 12 hours under 3.85 kg / cm 2 of hydrogen in the presence of 10% Pd / C, a solution of 51 g (0.113 mole) of 4- (3,5-dibenzyloxyphenyl) -1-phenoxypentene-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 C17H20O3:

C, 74.97; H, 7.40%

Found: C, 74.54; H, 7.45%

Preparation M — l 9 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 are combined. 5 ml of ammonium hydroxide and they are 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; m.p. 88-91 ° C. When recrystallized from a hot 1: 1 mixture of ethyl acetate and hexane, it melts at 95-96 ° C.

30

35

Analysis calculated for CuH17ON:

C, 73.70; H, 9.56; N, 7.81%

Found: C, 73.64; H, 9.62; N, 7.91%

Preparation M-20

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 (9.4 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,

it is dried over MgSO4 and concentrated to an oil which crystallizes from hexane, giving 1.5 g of d, l-acetyl-3-hy-droxy-5- (5-phenyl-2-pentyl) aniline, pf 128-130 ° C.

m / e-297 (m +) 55

'H NMR (60 Hz) Ôfka, (ppm): 8.64 (wide s, 1H, -NH), 7.12,6.58 and 6.45 (wide s, variable H, 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 M — 21 60

d, 1 -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, 65 1.38 g (8.06 mmol) of alpha-bromotoluene is added and the a45 is continued.

50

gitation 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, m / e-387 (m +)

'H NMR (60 MHz) (ppm): 7.88 (broad s, IH, NH), 7.38,7,20,6,84,6,59 (broad s, 5H, 6H, IH, 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,

I

- (CH2) 2), 1.15 (d, 3H, CH3-c-Ar).

A solution of 1.4 g of 14 ml of d, 1 -N-acetyl-3-benzyloxy-5- (5-phenyl-2-pentyl) -aniline is heated at reflux on a steam bath for 4 days. potassium hydroxide 20%, 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 MgSO4, concentrated in vacuo, and chromatographed on 35 g of silica gel using a 3: 1 mixture of benzene and ether as the eluent, to obtain d, 1 -3-benzyloxy-5- (5-phenyl-2-pentyl) aniline in the form of an oil, m / e -345 (m +)

! HRMN (60 Hz) ô ™ q3 (ppm): 7.32 (broad s, 5H, aromatic), 7.13 (broad s, 5H, aromatic), 6.01-6.33 (m, 3H, aromatic ), 4.95 (s, 2H, ArCH20), 3.48 (broad s, 2H, variable NH2), 2.17-2.88 (m, 3H, Ar-CH and Ar-CH2), 1.32 -1.76 (m, 4H, (CH2) 2), 1.14 (d, 3H, -C-CH3).

Preparation M-22

D, 1 -5-phenyl-2-pentanol mesylate

To a stirred solution of 482 g (2.94 moles) of 5-phenyl-2-pentanol in 2250 ml of tetrahyrofuran at 0 ° C, 300 ml of methanesulfonyl chloride are added, at a speed such that the internal temperature is not do not raise 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 on diatomaceous earth, and which is concentrated to a light orange oil ( 687 g, 95% yield). This material can be used without further purification.

'H NMR (60 Hz) ôj ^ i,: (PPm) = 7.23 (s, 5H, aromatic), 4.53-5.13 (m, 1H, -CH-O), 2.93 (s , 3H, 0-S02-CH3), 2.42-2.93 (m, 2H, -CH2C6H5), 1.50-1.92 (m, 4H, - (CH2) 2-), 1.23 ( s, 3H, 0-CH-CH3).

Likewise, the following mesylates are prepared from the appropriate alcohols:

4-phenylbutanol mesylate, yellow oil m / e-228 (m +)

'H NMR (60 MHz) ô £ Kci, (PPm): 7.22 (broad s, 5H, aromatic), 4.08-4.34 (m, 2H, -CH2-0-), 3.93 ( s, 3H, SO2CH3), 2.40-2.82 (m, 2H, -CH2C6H5), 1.51-1.93 (m, 4H, - (CH2) 2-). 1-2-octanol mesylate, colorless oil [a] gs = - 9.695 ° (C-2.6, CHClj)

! H NMR (60 Hz) ppm: 4.79 (q wide, 1H, -CH-O), 2.97 (s, 3H, S, CH3), 1.40 (d, 3H, CH3-CH), 0.87 (t, 3H, CH3-ché), 1.0-2.0 (m, 10H, - (CH2) 5-).

D-2-octanol mesylate [a] p = + 89.238 ° (C = 2.8, CHCl3)

'H NMR, identical to form 1 ..

VS

Claims (7)

628,034 2. Method according to claim 1, characterized in that a starting compound is used in which: R4 = H or alkyl, R5 = H, CH3orC2H5, Z = C5 to C9 alkylene and W = H or CH3, or Z = C2 to C5 alkylene and W = phenyl, p-fluorophenyl, p-chlorophenyl or 4-pyridyl, or Z = - (alk]) in -O- (alk2) n - where alk ,, alk2, m and n have the meaning given to claim 1, and W = H, CH3, p-fluorophenyl, 4-chlorphenyl or pyridyle . 2 CLAIMS 1. Process for the preparation of a compound of formula GOLD, R, 3. Process for the preparation of a compound of formula III in which R6 is an alkyl radical in Q to C6 or a group of formula - (CH ^^ CgHs, characterized in that the process of claim 1 is carried out and subjecting the compound obtained to alkylation or aralkylation, respectively. 4. Process for the preparation of a compound of formula III in which R6 is a Q to C6 alkyl radical or a group of formula - (CH2) 1_tC6H5, characterized in that the process of claim 1 is carried out and that the compound obtained is subjected to a corresponding acylation followed by reduction of the carbonyl group. 5. Method according to claim 4, characterized in that the compound of formula III is reacted with formaldehyde then with the borohydride of an alkali metal to prepare the corresponding compound where R6 is methyl. 6. Process for the preparation of a compound of formula III in which R6 is a radical -CO (CH2) o_3-C6H5 or C ^ -alkanoyl, characterized in that the process according to claim 1 is carried out and that reacts the compound obtained with a corresponding acid halide. 6 in which Ri = H; R4 = H, Cj __6-aIkyle or - (CH2) Z-C6H5 (z = 1 to 4); R5 = H, CH3, C2H5; R6 = H; Z = Ci-çralkylèneou-Calki ^ -X-Ca ^ nOÙCalk ^ and (alk2) are the same or different and are a group C ^ Q-akylene, the sum of the carbon atoms of (alkj) + (alk2) not being greater than 9; each of n and m is 0 or 1; and X is O, S, SO or SO2; and W is a hydrogen atom or a methyl, pyridyl, piperidyl group, where Wj is a hydrogen, fluorine, or chlorine atom, or a group (CH2) a \ -CH îf CH — W-> where W2 is a hydrogen atom or N (CH2) r " Wj; a = 1 to 5 and b = 0 to 5, the sum of a and b not being greater than 5; characterized in that a compound of formula i-W is reacted CHO with methyl vinyl ketone in the presence of a base and then with KOH. 7. Process for the preparation of a compound of formula III in which Ri is a benzoyl radical, C1 to C5 alkanoyl or -CO (CH2) pNR2R3 in which p = 0 where 1 to 4, where R2 and R3, taken separately , are identical or not and are hydrogen or alkyl groups in Q to C4; or R2 and R3 together form and with the nitrogen atom to which they are attached, a piperidino, pyrrolo, pyrrolidino, morpholino or N-C ^ ^ -alkyl) -piperazino nucleus, characterized in that the process of claim 1 and that the compound obtained is esterified.