GB1579230A - Quinoline compounds useful intermediates in the preparation of hexahydrobenzo(c)quinolines - Google Patents

Description

PATENT SPECIFICATION ( 11) 1579230

( 21) Application No 35906/79 ( 22) Filed 16 May 1977 ( 19) Oa ( 62) Divided out of No 1 579 228 ( 31) Convention Application No 687 332 ( 32) Filed 17 May 1976 If 3 ( 31) Convention Application No 777 928 ( 32) Filed 15 March 1977 in ( 33) United States of America (US) ( 44) Complete Specification published 12 Nov 1980 ( 51) INT CL 3 C 07 D 215/22 ( 52) Index at accepance C 2 C 1173 1174 1175 1177 1530 1532 1534 213 215 220 221 225 226 22 Y 246 247 248 250 251 258 25 Y 28 X 304 30 Y 311 313 31 Y 338 350 351 352 355 35 Y 360 361 364 365 366 367 36 Y 373 37 Y 388 389 397 40 Y 43 X 462 463 464 612 613 614 623 624 628 635 652 655 658 662 672 697 699 760 771 775 AA QS QT QU TA TY ( 54) NOVEL QUINOLINE COMPOUNDS, INTERMEDIATES IN THE PREPARATION OF HEXAHYDRO BENZO lCl QUINOLINES ( 71) We, PFIZER, INC, a Corporation organized under the laws of the State of Delaware, United States of America, of 235, East 42nd Street, New York, State of New York, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to

be performed, to be particularly described in and by the following statement: 5

This invention relates to certain novel quinolines which are intermediates in the preparation of 1,9-dihydroxyoctahydrobenzolclquinolines, Ihydroxyhexahydrobenzolclquinoline-9 ( 8 H)-ones and l-hydroxytetrahydrobenzolclquinolines and derivatives thereof useful as CNS agents, especially as analgesics and tranquilizers, as hypotensives in mammals, including man, as agents for the 10 treatment of glaucoma and as diuretics.

In our co-pending Application No 20521/77 (Serial No 1,579,228) certain benzolclquinolines; namely, 1,9-dihydroxyoctahydro-6 H-benzolclquinolines (I), 1 hydroxyhexahydro-6 H-benzolclquinoline-9 ( 8 H)-ones (II) and l-hydroxy515 tetrahydroquinolines (IV) have been found to be effective as CNS agents, especially 15 as analgesics and tranquilizers, as hypotensives, which are non-narcotic and free of addiction liability, as agents for the treatment of glaucoma and as diuretics Also included in our co-pending Application No 20521/77 (Serial No 1,579,228) are various derivatives of said compounds which are useful as dosage forms and precursors therefor The above-named compounds and their derivatives have the 20 formulae I, II and IV Compounds of formulae III and IV are precursors to compounds of formulae II and I.

1,579,230 Am R N Z-W PN -W l RG R R X andz z 4-w R 6 (I Ii) (IV) wherein R is selected from hydroxy, alkanoyloxy having from one to five carbon atoms and hydroxymethyl; R is selected from hydrogen, benzyl, benzoyl, alkanoyl having from one to five carbon atoms and -CO (CH 2) NR 2 R 3 wherein p is 0 or an integer from 1 5 to 4; each of R 2 and R 3 when taken individually is selected from hydrogen and alkyl having from one to four carbon atoms; or R 2 and R 3 when taken together with the nitrogen to which they are attached form a 5 or 6-membered heterocyclic ring selected from piperidino, pyrrolo, pyrrolidino, morpholino and Nalkylpiperazino having from one to four carbon atoms in the alkyl group; 10 R 4 is selected from hydrogen, alkyl having from I to 6 carbon atoms and -(CH 2)z-C,,H 5 wherein z is an integer from I to 4; R 5 is selected from hydrogen, methyl and ethyl; R is selected from hydrogen, -(CH 2),-carbalkoxy having from one to four carbon atoms in the alkoxy group and y is 0 or an integer from I to 4; carbo 15 benzyloxy, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to six carbon atoms; (CH 2)x CH 5; and -CO(CH 2)x,-C^H 5; wherein x is an integer from 1 to 4; Ro is selected from oxo, methylene and alkylenedioxy having from two to four carbon atoms; 20 R' is selected from R and R; Z is selected from:

(a) alkylene having from one to nine carbon atoms; (b) -(alkk)m-X (alk 2)n wherein each of (alk,) and (alk 2) is alkylene having from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alk,) plus (alk 2) is not greater than nine; each of m and N is 0 or 1; X is selected from 0, S, SO and SO 2; and W is selected from hydrogen, methyl, pyridyl, piperidyl, W -W 1 5 wherein W, is selected from hydrogen, fluoro and chloro; and / (CH 2)a -CH CH-W 2 (CH 2)b J wherein W 2 is selected from hydrogen and W 1;W a is an integer from I to 5 and b is O or an integer from I to 5; with the proviso that 10 the sum of a and b is not greater than 5; and the ketals of compounds of formulae II, III and IV wherein the ketal moiety has from two to four carbon atoms.

Also included in the invention described in co-pending Application No.

20521/77 (Serial No 1,579,228) are pharmaceutically acceptable acid addition salts of compounds of formulae I and II Representative of such salts are mineral acid 15 salts such as the hydrochloride, hydrobromide, sulfate, nitrate, phosphate; organic acid salts such as the citrate, acetate, sulfosalicylate, tartrate, glycolate, malonate, maleate, fumarate, malate, 2-hydroxy-3-naphthoate, pamoate, salicylate, stearate, phthalate, succinate, gluconate, mandelate, lactate and methane sulfonate.

Compounds having the formulae I, II and III above contain asymmetric 20 centers at the 6 a and/or 10 a-positions There may be additional asymmetric centers in the 3-position substituent (-Z-W), and 5-, 6 and 9-positions.

Diastereomers with the 9/1-configuration are generally favored over the 9 a-isomers because of greater (quantitatively) biological activity For the same reason, the trans( 6 a,10 a)diastereomers of compounds of formula I are generally favored over 25 the cis ( 6 a,10 a)diastereomers As regards compounds of formula II, when one of R 4 and Rs is other than hydrogen, the cis-diastereomers are preferred because of their greater biological activity As regards formula IV compounds, asymmetric centers exist at the 9-position and in the 3-position substituents Among the enantiomers of a given compound, one will generally be favored over the other and the racemate 30 because of its greater activity The enantiomer favored is determined by the procedures described herein For example, the l-enantiomer of 5,6,6 a/p,7,8,9,10,10 aa octahydro I acetoxy 9/3 hydroxy 6/p methyl 3 ( 5phenyl 2 pentyloxy)benzolclquinoline is favored over the d-enantiomer and the racemate because of its greater analgesic activity For convenience, the above 35 formulae depict the racemic compounds However, the above formulae are considered to be generic to and embracive of the racemic modifications of the compounds of this invention, the diastereomeric mixtures, the pure enantiomers and diastereomers thereof The utility of the racemic mixtures, the diastereomeric mixtures as well as of the pure enantiomers and diastereomers is determined by the 40 biological evaluations described below.

Our co-pending Application No 35905/79 (Serial No 1,579,229) relates to intermediates of the formula (V) useful in the preparation of compounds of formulae I, II, III and IV.

The present invention is to intermediates of the formula (VII) which are useful 45 in the preparation of compounds of the formulae I, II, III and IV and which may be 1,579,230 prepared from the intermediates of the formula (V) The intermediates of our copending Application No have the formula:Z-WI (V) R 6 and the intermediates of the present invention have the formula:@Y 1 (VII) R 4 ' Z-W wherein R 4, R 5, R, and Z-W are as defined above; R 7 is selected from hydrogen and formyl; and Y, is selected from hydrogen, methyl, ethyl and benzyl.

Asymmetric centers may exist in intermediates V, VI and VII at the 2position and in the 7-position substituent (-Z-W) and, of course, at other positions, e g in the l-position substituent The 2 and 7-positions in formulae V-VII correspond to the 6 and the 3-positions, respectively, of compounds having formulae I, II, III and IV.

Favored, because of their greater biological activity relative to that of other compounds described herein, are compounds of formulae I and II where R and Ro are as defined above; R, is hydrogen or alkanoyl; Rs is hydrogen, methyl or ethyl; and each of R 4 and R, is hydrogen or alkyl; Z and W have the values shown below:

z m n W alkylene having from 5 to 9 H or CH 3 carbon atoms alkylene having from 2 to 5 Ci H 5, 4-FC 6,, 4carbon atoms CIC 8 H 4, 4-pyridyl (alk,)m O-(alk 2)n I I C H ' 4-FCH,, 40 1 Icc 5, 1 6 Cl CH 4, 4-pyridyl I O -(alk,)m-O-(alk 2)n I I I H or CH 3 0 1 {H or CH 3 I O {H or CH 3 1,579,230 Preferred compounds of formula I are those favored compounds described above wherein R represents hydroxy and which have the trans-configuration.

Preferred compounds of formula II are those wherein R O is oxo.

Especially preferred are those preferred compounds of formulae I and II wherein: 5 R is hydroxy (formula I only); R, is hydrogen or acetyl; R 5 is hydrogen; R 4 is methyl or propyl; R 6 is hydrogen, methyl or ethyl; 10 when Z is alkylene having from 2 to 5 carbon atoms W is phenyl or 4pyridyl; when Z is -(alk,)m-O (alk 2)n wherein m is 0 and N is 1, (alk 2)n is alkylene having from four to nine carbon atoms, W is hydrogen or phenyl; and when Z is alkylene having from five to nine carbon atoms, W is hydrogen.

Additionally, the favored and preferred classes of intermediates of formula VII 15 are those compounds having formulae which serve as intermediates for the favored and preferred compounds of formulae I and II.

The compounds of this invention of formula V are prepared from appropriately substituted anilines, e g, 3-hydroxy-5-(Z-W-substituted)anilines (VIII) or derivatives thereof in which the 3-hydroxy group is protected by a group 20 (Y.) easily removable to regenerate the hydroxy group Suitable protective groups are those which do not interfere with subsequent reactions of said 3(protected hydroxy)-5-substituted anilines and which can be removed under conditions which do not cause undesired reactions at other sites of said compound or of products produced therefrom Representative protective groups (Y) are methyl, ethyl, 25 benzyl, substituted benzyl wherein the substituent is, for example, alkyl having from I to 4 carbon atoms, halo (Cl, Br, F, I), and alkoxy having from one to four carbon atoms.

The exact chemical structure of the protecting group is not critical to this invention since its importance resides in its ability to perform in the manner 30 described above.

The selection and identification of appropriate protecting groups can easily and readily be made by one skilled in the art The suitability and effectiveness of a group as a hydroxy protecting group are determined by employing such a group in the above-illustrated reaction sequence It should, therefore, be a group which is 35 easily removed to permit restoration of the hydroxy groups Methyl is favored as a protecting alkyl group since it is easily removed by treatment with pyridine hydrochloride The benzyl group, also a favored protecting group, is removed by catalytic hydrogenolysis or acid hydrolysis.

When Z is -(alk,)m-X-(alk 2)n-, Y 1 is preferably benzyl or a substituted 40 benzyl group since it can subsequently be removed without detriment to the Z group.

The protected aniline derivative (VIII) is then converted to a compound of formula IX by known technology as described herein.

An abbreviated reaction sequence (Flow Sheet A) for preparing representative 45 compounds of formula V beginning with a 3-(protected hydroxy)-5-(Z-Wsubstituted)aniline (VIII) wherein -Z-W is OCH 3 is given below:

1,579,230 1,579,230 0 CH 3 Flow Sheet A 0 II R 4-C-CH 2 C 00 R O NH HOA c NH 2 ( (VIII) COOR N R 4 H (IX) R 4 R 5 C=CH-COOR O or R 4-COCH 2 COOR O \+ Na CNBH 4 Ct COOC 2 H 5 0/ PPA (x) (V-A) H BrHO Ac H BrHOA c Br (a) k 2)n W KOH R 4 W/-(,al 12),-0 ' H H ( V) (V-_C) R in the above flow sheet represents alkyl having from one to six carbon atoms (R 5, for the purpose of illustration in the overall Flow Sheet, is represented as hydrogen However, in the sequence VIII -e X or VIII 'V-B, R can be hydrogen, methyl or ethyl) The 5-substituent of formula VIII compounds can be group -Z-W desired in compounds of formulae II or I, or a group readily convertible to said group When the Z moiety of group -Z-W is (alk,)m-X (alk 2)n, wherein X is O or S and each of m and N is 0, the 5-substituent, when W is hydrogen, is -XH (i e, OH or SH) or a protected -XH group of the formula -X-Y, wherein Y is as defined (Rs,= H) H 2 ( 1) ( 2) ( 3) COO R Adz -n above When, of course, -Z-W is (alk,)m-X (alk 2)n-W wherein m is I, N is 0 and W is hydrogen, the 5-substituent becomes (alk,)m-X-H The -XH group is advantageously protected in the manner described above.

The appropriate 3-hydroxy-5-substituted anilines discussed above are reacted, preferably in the form of derivatives in which the 3-hydroxy group (and 5hydroxy 5 group if one is present) is protected as mentioned above in order to achieve satisfactory reactions, with an alkyl 3-ketoester, e g, an alkyl acetoacetate, in the presence of acetic acid to provide the corresponding p 3-l( 3-protected hydroxy)-5substituted anilinol-/-(R 4)-acrylate (IX) The reaction is generally conducted in a reaction-inert solvent such as benzene or toluene at temperatures of from about 10 C to the reflux temperature of the solvent under conditions which result in removal of by-product water Benzene and toluene are efficient solvents when the reaction is conducted at the reflux temperature, since they permit azeotropic removal of by-product water Other means of water removal or effective removal of water such as molecular sieves can be employed, as can other 15 solvents which permit azeotropic removal of water.

Favored protecting groups for the 3-hydroxy-5-substituted aniline reactants are methyl, ethyl and benzyl groups since the ethers are easily prepared, afford satisfactory yields of compounds of formulae IX and X and are conveniently removed 20 The alkyl /3-ketoester, preferably one in which the alkyl group has from one to six carbon atoms, is generally used in excess to insure maximum conversion of the aniline reactant to the corresponding alkyl p 3-anilino-/3-(R 4)-acrylate (IX) Ten to twenty percent excess of alkyl 3-ketoester is usually sufficient to achieve satisfactory conversions Acetic acid is used in catalytic amounts to facilitate 25 reaction.

The alkyl /3-anilino-/-(R 4)-acrylate (IX) is then reduced to the corresponding alkyl-3-l( 3-protected hydroxy)-5-substituted anilinol-3-(R 4)-propionate (X) by, for example, sodium borohydride-acetic acid and catalytic hydrogenation A preferred catalyst is platinum dioxide since it conveniently permits the reaction to be carried 30 out at low pressures, i e, at pressures under 50 p s i Other catalysts such as noble metals, e g, platinum, palladium, rhodium, supported or unsupported, can be used along with pressures of hydrogen ranging from about atmospheric to superatmospheric, e g, 2000 p s i In addition to such catalysts which are heterogeneous catalysts, this step can be carried out using homogeneous catalysts such as 35 Wilkinson's catalyst, tris(triphenylphosphine)chlororhodium(I).

Of course, when the protecting group or groups are benzyl or substituted benzyl, catalytic hydrogenation will result in their removal For this reason, methyl or ethyl groups are preferred as protecting groups for the 3 and/or 5hydroxy groups of formula VIII reactants 40 Alternatively, compounds of formula X can be prepared directly from compounds of formula VIII by reaction of formula VIII compounds with an alkyl 3,3-R 4 Rs-acrylate in acetic acid The reaction is conveniently carried out by reacting equimolar quantities of the alkyl 3,3-R 4 R 5-acrylate and disubstituted aniline (VIII) in from 0 1 to 2 equivalents of glacial acetic acid at temperatures 45 ranging from O C to the reflux temperature.

Alternatively, compounds of formula V-B may be prepared directly by condensation of equimolar quantities of VIII with the appropriate substituted acrylic acid (R 4 Rs C=CH-COOH) in pyridine hydrochloride at 150 -200 C.

In addition, when the R 4,Rs groups are both alkyl, treatment of VIII and the 50 alkyl R 4,Rs acrylate in a reaction-inert solvent, e g tetrahydrofuran, with mercuric acetate followed by reduction with sodium borohydride gives X.

Direct conversion of compounds of formula VIII to compounds of formula X is also conveniently achieved by treating a 3,5-(diprotected hydroxy) aniline hydrochloride with an excess of an alkyl acetoacetate, e g ethyl acetoacetate, in the 55 presence of sodium cyanoborohydride in a solvent such as methanol.

The alkyl 3-anilino-3-(R 4)-propionate (X) is then cyclized to the corresponding 2-(R 4)-quinolin-4-one (formula V-A or -B) by means of a suitable cyclizing agent such as polyphosphoric acid (PPA), hydrogen bromide-acetic acid, sulfuric acid, oleum (fuming sulfuric acid), hydrogen fluoride, trifluoroacetic acid, phosphoric 60 acid-formic acid and others known to those skilled in the art In a modification of this conversion, the alkyl 3-anilino-3-(R 4)-propionate (X) can be converted to the corresponding acid by, for example, saponification of the ester followed by acidification, prior to cyclization.

The ether protecting, or blocking, groups on the 3-(and 5-)hydroxy groups can 65 1,579,230 be removed at the time of cyclization through the use of hydrobromic acid in acetic acid as cyclizing agent and deblocking agent Hydrobromic acid, 48 % aqueous, is generally used since it affords satisfactory cyclization and deblocking The reaction is conducted at elevated temperatures and desirably at the reflux temperature.

However, when Z is -(alk,)m-X-(alk 2)n cyclization conditions such as 5 polyphosphoric acid or trifluoroacetic acid must be used to avoid cleavage of the ether or thioether linkage.

Alternatively, the protecting group (or groups) can be removed subsequent to the cyclization reaction Hydrobromic acid-acetic acid is also a favored agent for deblocking at this stage of the overall synthesis The reaction is carried out as 10 described above.

Other reagents such as hydriodic acid, pyridine hydrochloride or hydrobromide can be used to remove protecting ether groups such as methyl and ethyl groups When the protecting groups are benzyl or substituted benzyl groups, they can be removed by catalytic hydrogenolysis Suitable catalysts are palladium or 15 platinum, especially when supported on carbon Alternatively, they can be removed by solvolysis using trifluoroacetic acid Of course, when group -ZW contains sulfur, acid debenzylation is used rather than catalytic debenzylation.

A favored method for the transformation of compounds of formula X to compounds of formula V which affords satisfactory yields and permits use of 20 relatively mild conditions comprises conversion of formula X compounds to Ncarbalkoxy derivatives wherein the N-carbalkoxy group has from two to five carbon atoms by reaction with the appropriate alkyl or benzyl chloroformate The N-carbalkoxy or carbobenzyloxy derivative of formula X is then cyclized by means of a polyphosphoric acid to the corresponding N-carbalkoxy or carbobenzyloxy 25 derivative of formula V compounds The N-substituted derivatives of formula X compounds can, if desired, be hydrolyzed to the corresponding 3-l(Nsubstituted)3-(protected hydroxy)-5-substituted anilinol-3-(R 4)-propionic acid prior to cyclization Polyphosphoric acid generally produces maximum cyclization and is a preferred cyclizing agent 30 Compounds of formula V in which the hydroxy group or groups are protected and in which the nitrogen atom is substituted with carbalkoxy are treated with hydrobromic acid-acetic acid to give compounds of formula V-B When the hydroxy protecting group or groups are benzyl or substituted benzyl, regeneration of the hydroxy groups is accomplished by catalytic hydrogenolysis A carbalkoxy 35 group if present on the nitrogen atom is unchanged by this reaction It can, if desired, be subsequently removed by treatment with hydrobromic acidacetic acid or any of a variety of acids or bases Removal of the benzyl protecting group by treatment with trifluoroacetic acid also removes any N-carbalkoxy group present.

When the -Z-W substituent of formula V compounds is -XH (X = O or S), 40 and it is desired to have said -Z-W substituent represent, in compounds of formulae 11 or I, a group -X-(alk 2) W wherein X is 0, S, SO or SO 2, and W is as previously defined, conversion of group -XH to group -X-(alk 2)n-W is conveniently and advantageously undertaken at this point in the overall reaction sequence Thus, the 7-XH group of formula V-B above represented, for the 45 purposes of illustration, as -OH, is transformed by the Williamson reaction with the appropriate bromide lBr-(alk 2)n-Wl, mesylate or tosylate, to group -O-(alk 2),-W (formula V-C).

Similarly, when group -Z-W of formula V is (alk,)-X-H, its conversion to -(alk,) X-(alk 2)n-W wherein N is 0 or I and W is other than hydrogen is 50 conveniently undertaken at this stage of the reaction sequence via the Williamson reaction.

A variety of groups, such as those included within the definition of R 6, can be used in place of carbalkoxy or carbobenzyloxy in this favored method to mask the nitrogen against protonation 55 Group R 6, if not already present in compounds of formulae V-A, V-B or V-C, can be introduced prior to formation of the hydroxymethylene derivative (formula V 1) by reaction with the appropriate C Il-R 6 or Br-R 8 reactant according to known procedures.

Compounds of formula V and, of course, of formulae V-A, V-B and V-C, 60 are converted by the following illustrative sequence (Flow Sheet B) to representative tompounds of the formula VII (Rs= H in the illustration).

1,579,230 0 7 3 Flow Shee L B w-z OH O 0 H 11-CH -CNai M R 4 H (v) OH OC 2 H 5 N Z-W CHO (VI) CH 3-CO-CH= CH 2 Base, CH 30 H OH R Cio l+ 1,3-bisformy) derivative (EI-A)l (VII) The quinolines of formula V are converted to hydroxymethylene derivatives of formula V 1 by reaction with ethyl formate and sodium hydride This reaction, a formylation reaction, produces the bis-formylated derivative (VI) in excellent yield.

Treatment of the bis-formylated derivative with methyl vinyl ketone gives a mixture of the corresponding mono-N-formylated Michael adduct (VII) and 1, 3bis-formylated Michael adduct (VII-A) The two products are conveniently separated by column chromatography on silica gel.

Compounds of the formula VII-A can be converted to VII by treatment with an equivalent of n 0 OH (VII-A) -W potassium carbonate in methanol.

1,579230 a The 3-hydroxy-5-(Z-W-substituted)anilines are prepared from corresponding 5-(Z-W-substituted)resorcinols via the Bucherer Reaction which comprises reacing the appropriate 5-(Z-W-substituted)resorcinol with aqueous ammonium sulfite or bisulfite The reaction is conducted in an autoclave at elevated temperatures, e g from about 150 to about 230 C The aniline product is isolated 5 by acidifying the cooled reaction mixture and extracting the acid mixture with, for example, ethyl acetate The acid solution is neutralized and extracted with a suitable solvent, e g chloroform, to recover the aniline product Alternatively, the aniline product is isolated by extracting the cooled reaction mixture with an appropriate solvent followed by column chromatography of the crude product 10 The 5-(Z-W-substituted)resorcinols, if not known are prepared from 3,5dihydroxybenzoic acid The procedure comprises esterifying 3,5-dihydroxybenzoic acid in which the hydroxy groups are protected (e g, as methyl, ethyl or benzyl ethers); or alternatively, amidating the 3,5-ldi(protected hydroxy) lbenzoic acid 15 The overall abbreviated sequence is illustrated below (Flow Sheet E):

Flow Sheet E OH OY 1 H 4 O, Ya OCO CO-Y 2 (Xl) OH OYI 0 oij H W Y 1 J (XIV) (XIII) OH iq Z-W (VIII-A) 1,579,230 The starting material, 3,5-dihydroxybenzoic acid XI is converted to a compound of formula XII wherein Y 2 represents an alkoxy group, desirably methoxy or ethoxy for ease of preparation, or an amino group; and Y 1 is a hydroxy protecting group, by methods described in the literature.

The diprotected benzoic acid derivative XII is then converted to a compound 5 of formula XIV by known technology In one procedure XII is hydrolyzed to the corresponding acid (Y 2 =OH), or lithium salt, and reacted with the appropriate alkyl lithium to produce an alkyl disubstituted phenyl ketone (Y 2 = alkyl) When methyl lithium is used, the resulting acetophenone derivative is treated with a Grignard Reagent (W-Z'-Mg B r) The intermediate adduct is hydrolyzed to the 10 corresponding alcohol which is then hydrogenolyzed to replace the hydroxy group with hydrogen This procedure is especially useful for those compounds wherein Z is alkylene.

The ether groups are deblocked by suitable means: treatmept with pyridine hydrochloride (Y = methyl) or catalytic hydrogenolysis (Y = benzyl), or by 15 treatment with an acid such as trifluoroacetic acid, hydrochloric, hydrobromic or sulfuric acids Acid debenzylation is, of course, used when the group -Z-W contains sulfur.

A further method for converting compounds of formula XII to those of formula XIV comprises reaction of a ketone of formula XII (Y 2 = alkyl) with the 20 + appropriate triphenyl phosphonium bromide derivative l(CH 5)3 P-Z-WlBr in the presence of a base (e g, sodium hydride) The reaction proceeds via an alkene which is subsequently catalytically hydrogenated to the corresponding alkane (Z-W) and deblocked to the dihydroxy compound XIV Of course, when -Z is 25 (alk,)m-X (alk 2)n and Y 1 is benzyl, the catalytic hydrogenation also results in cleavage of the benzyl ethers.

Alternatively, conversion of structure XII compounds to those of structure XIV can be achieved by the sequence XII XIII 'XIV In this sequence, the diprotected benzamide (XII, Y 2 = NH 2) is converted to the ketone (XIII, Z' = Z less 30 one CH 2 group) by reaction with the appropriate Grignard reagent (Br Mg-Z'-W) followed by reaction with methyl or ethyl-magnesium halide to form the corresponding carbinol Dehydration of the carbinol, e'g, with ptoluenesulfonic acid, affords the corresponding alkene which is then catalytically hydrogenated (Pd/C) to the alkane (XIV) The ether groups are deblocked 35 (converted to hydroxy) as described above.

When Z is alkylene, Y 1 is desirably alkyl having from one to four carbon atoms or benzyl The function of group Y is to protect the hydroxy groups during subsequent reactions It is its ability to perform a specific function; i e, protection of the hydroxy groups, rather than its structure which is important The selection 40 and identification of appropriate protecting groups can easily and readily be made by one skilled in the art The suitability and effectiveness of a group as a hydroxy protecting group are determined by employing such a group in the aboveillustrated reaction sequence It should, therefore, be a group which is easily removed to permit restoration of the hydroxy groups Methyl is favored as a 45 protecting alkyl group since it is easily removed by treatment with pyridine hydrochloride The benzyl group, if used as a protecting group, is removed by catalytic hydrogenolysis or acid hydrolysis.

When Z is -(alk,)m-X (alk 2)n, Y is preferably benzyl or a substituted benzyl group since it can subsequently be removed without detriment to the Z 50 group.

Formula VIII-A compounds can, alternatively, be prepared from 3-amino-5hydroxybenzoic acids via the procedure of Flow Sheet F below.

Compounds of formula VIII-A wherein -Z-W is -alkylene-W or (alk,)-X' (alk 2), W wherein (alk,), (alk 2), W and N are as defined above and 55 X' is O or S, are obtained by the following sequence (Flow Sheet F):

1,579,230 111 F low Ghte E V ( 4 c = a c e Ey 1) (C 6 H 5)3 P=CHCOC 1 2 1,579,230 1 2 oyl )CAS CH 2 ACNH 1 H CO O C 2 H 5 I/ RA 01,11,' (R'=H 7 alkyi) Ac W C 5 W 5 N/TOSY 1 RI' Pbi Oyl Al' Chloride CH 2 Ac NH Ac W CH CH 2-OTS Ill R OY 1 OY 1 CH 2 CH 2 G) 1 1") ACW ACN CH CH 2 X H c 111 1 H 2P (CGH 5)3 R (a,) k 2)o R 11 Br O 1 n(1 A W O 1 OM H 2 Pd-C H + CH 2 CH =C -(CR 2) -W' 1 V \ j CH 1 ll R Z-W Ac NH 111 R (V 111-A) W (a 1 k A,1-X 1 M A 11 (C 6 H 5) 3 P 11 DY 1 R 11-C H 2)-WThe first step in the above sequence (the Wittig reaction) provides opportunity, by choice of appropriate reactants, to produce compounds having straight or branched alkylene groups The amino group is protected by acetylation according to standard procedures In the given illustration, the value of R" as methyl or ethyl permits formation of a compound having alkyl substitution on the 5 carbon atom (a) adjacent to the phenyl group Substitution of a methyl or ethyl group at other sites, e g, the 3-carbon atoms of the alkylene group, is achieved by choice of the appropriate carboalkoxy alkylidene triphenylphosphorane, e g.

(C 6 Hs)3 P=C(R")-COOC 2 H 5 The unsaturated ester thus produced is reduced to the corresponding saturated alcohol by reaction with lithium aluminum hydride 10 The presence of a small amount of aluminum chloride sometimes accelerates this reaction Alternatively, when Y is other than benzyl (e g methyl), the alcohol is produced by catalytic reduction of the unsaturated ester using palladiumcarbon, followed by treatment of the saturated ester thus produced with lithium aluminum s 15 hydride Conversion of the alcohol to the corresponding tosylate or mesylate 15 followed by alkylation of the tosylate or mesylate with an alkali metal salt of the appropriate HX'-(alk 2)n-W reactant, and finally removal of the protecting groups (Y) affords the desired compound VIII-A When X' is sulfur, the protecting group Y 1 is methyl.

A variation of the above sequence comprises bromination of the alcohol rather 20 than converting it to a tosylate or mesylate Phosphorous tribromide is a convenient brominating agent The bromo derivative is then reacted with the appropriate HX'-(alk 2) W in the presence of a suitable base (Williamson reaction).

The bromo compounds also serve as valuable intermediates for increasing the 25 chain length of the alkylene moiety in the above sequence to give compounds wherein Z is -alkylene-W The process comprises treating the bromo derivative with triphenyl phosphine to produce the corresponding triphenylphosphonium bromide Reaction of the triphenylphosphonium bromide with the appropriate aldehyde or ketone in the presence of a base such as sodium hydride or nbutyl 30 lithium affords an unsaturated derivative which is then catalytically hydrogenated to the corresponding saturated compound.

In this variation, the value of the protecting group (Y) selected depends upon the particular sequence followed When the vertical sequence on the right is used, benzyl is the preferred protecting group by reason of the catalytic hydrogenation 35 step Methyl is the preferred protecting group when the left vertical sequence is followed, since it is conveniently removed by treatment with acid as described herein.

Example I.

Ethyl dl-3-( 3,5-Dimethoxyanilino)butyrate 40 A mixture of 3,5-dimethoxyaniline ( 95 7 g, 0 624 mole), ethyl acetoacetate ( 87 2 ml, 0 670 mole), benzene ( 535 ml) and glacial acetic acid ( 3 3 ml) is refluxed for 15 hours under an atmosphere of nitrogen and water collected by means of a Dean-Stark trap The reaction mixture is cooled to room temperature, decolorized with activated charcoal, filtered, and then concentrated under reduced pressure to 45 give the product, ethyl 3-l 3,4-dimethoxy)anilinol-2-butenoate, as an oil ( 168 7 g).

A mixture of ethyl 3-( 3,5-dimethoxyanilino)-2-butenoate ( 5 0 g, 18 7 mmole) in glacial acetic acid ( 42 ml) and platinum oxide ( 250 mg) is hydrogenated in a Parr shaker at 50 p s i for 1 5 hours The reaction mixture is filtered through filteraid, benzene ( 50 ml) added and the solution concentrated under reduced pressure 50 to an oil The oil is taken up in chloroform, the solution washed successively with saturated sodium bicarbonate solution ( 2 x 50 ml) and saturated sodium chloride solution It is then dried (Mg SO 4), filtered and concentrated under reduced pressure to give the product as an oil ( 5 1 g).

Repetition of the above procedure but using 168 7 g of ethyl 3-( 3,5-di 55 methoxyanilino)-2-butenoate, glacial acetic acid ( 320 ml) and platinum oxide ( 2 15 g.) gives 160 8 g of product.

Example 2.

Ethyl dl-3-( 3,5-Dimethoxyanilino)butyrate.

To a solution of 3,5-dimethoxyaniline hydrochloride ( 370 g, 1 45 mole), reagent grade methanol ( 4 5 1) and ethyl acetoacetate ( 286 3 g, 2 64 mole) in a 12 60 liter round bottom, 3 neck flask fitted with mechanical stirrer and reflux condenser is added sodium cyanoborohydride ( 54 g, 0 73 mole) in one portion After the refluxing subsides ( 10 minutes) the mixture is heated on a steam bath for an 1,579,230 additional 20 minutes To the cooled reaction mixture is added additional sodium cyanoborohydride ( 5 4 g, 0 07 mole) and ethyl acetoacetate ( 28 6 g, 0 26 mole) and the mixture refluxed for 30 minutes This latter process is repeated once more.

The reaction mixture is isolated in portions by pouring ca 500 ml onto I liter of ice-water/500 ml methylene chloride, separating the layers and backwashing the, 5 aqueous phase with additional methylene chloride ( 100 ml) (This process is repeated using 500 ml portions until the entire reaction mixture is worked up).

The methylene chloride layers are combined and dried (Mg SO 4), decolorized with charcoal, filtered and evaporated to yield a yellow colored oil.

The excess ethyl acetoacetate is distilled (at 130 C oil bath temperature and 10 1-5 mm pressure) leaving the crude ethyl 3-( 3,5-dimethoxyanilino) butyrate (an amber colored viscous oil): 376 g ( 72 % yield) which is used without further purification.

It has the following spectral characteristics:

TMS H NMR ( 60 M Hz) o CDC, (ppm): 5 82-6 0 (m,3 H,aromatic), 4 20 (q,2 H, 'ester methylene), 3 80-4 00 (m,2 H,-NH and N-CH-CH 3), 3 78 (s, 6 H, 15 -OC He), 2 40-2 55 (m,2 H,-CH 2 COO Et), 1 78 (d,3 H,methyl) and 1 29 (t, 3 H, methyl).

Example 3.

dl-Ethyl 3-( 3,5-Dimethoxyanilino)hexanoate.

Following the procedure of Example 2, condensation of 3,5dimethoxyaniline 20 hydrochloride and ethyl butyrylacetate gives ethyl d,l-3-( 3,5dimethoxyanilino)hexanoate It is converted to the hydrochloride salt by addition of hydrogen chloride to a methylene chloride solution thereof; m p 127 -129 5 C.

Recrystallization from cyclohexane/benzene ( 5:1) gives the analytical sample, m p.

126 0-128 5 C 25 Analysis: Calc'd for C,,,H 2,04 N HCI: C, 57 91; H, 7 90; N,4 22 % Found: C, 57 89; H, 7 74; N, 4 40 % m/e 295 (m+) H NMR ( 60 M Hz) CDMC (ppm): 10 76-11 48 (b, variable, 2 H, NH 2 +), 6 77 (d, J= 2 Hz, 2 H, meta H's), 6 49, 6 45 (d of d, J= 2 Hz, 1 H, meta H), 4 08 (q, 2 H, 30 OCH 2), 3 77 (s, 6 H, lOCH 312), ca 3 5-4 8 (m, IH, CH-N), 2 90 (t, 2 H, CH 2-C=O), ca 1 4-2 2 (m, 4 H, lCH 2 l 2), 1 21 (t, 3 H, O-C-CH 3), 0 84 (t, 3 H, -C-CH 3).

Example 4.

d,l-Ethyl 3-l( 3,S-Dimethoxy-N-ethoxycarbonyl)anilinolbutyrate 35 Method A Ethyl chloroformate ( 71 4 ml 0 75 mole) is added dropwise over a 45 minute period to a mixture of ethyl 3-( 3,5-dimethoxyanilino)butyrate ( 159 8 g, 0 598 mole), methylene chloride ( 100 ml), and pyridine ( 100 ml, 1 24 moles) at O C under a nitrogen atmosphere The mixture is stirred for 40 minutes following addition of the 40 ethyl chloroformate and is then poured into a mixture of chloroform ( 750 ml) and ice-water ( 500 ml) The chloroform layer is separated, washed successively with % hydrochloric acid ( 3 x 500 ml), saturated aqueous sodium bicarbonate (I x 300 ml) and saturated aqueous sodium chloride (I x 400 ml) and then dried (Mg SO 4) It is then decolorized with activated charcoal and concentrated under 45 reduced pressure to an oil ( 215 g) The product is used as is.

Method B Under a positive nitrogen atmosphere a mixture of ethyl 3-( 3,5-dimethoxyanilino)butyrate ( 376 g, 1 4 mole), methylene chloride ( 1 4 liters) and anhydrous potassium carbonate ( 388 8 g, 2 81 mole) is stirred and cooled in an ice bath to 0 O 50 C Ethyl chloroformate ( 153 g, 1 41 mole) is added in one portion The mixture is allowed to warm to room temperature over a period of one hour, ethyl chloroformate ( 153 g, 1 41 mole) is added once more and the mixture is refluxed on a steam bath for one hour It is then allowed to cool to room temperature and the potassium carbonate removed by filtration The red colored filtrate is washed 55 successively with water ( 2 x 1000 ml), brine (I x 500 ml), dried (Mg SO 4), and then decolorized and evaporated under reduced pressure to afford 439 g of crude product which is used without further purification.

1,579,230 1 i 4 1,579,230 15 1 H MR( 60 M) TMS 1 H NMR ( 60 M Hz) CDCI 3 (ppm): 6 2-6 42 (m, 3 H, aromatic), 4 65 (sextet, IH, -N-CH-, CH 3), 4 10-4 15 ( 2 quartets, 4 H, ester methylenes), 3 70 (s, 6 H, -OCH 3), 2 30-2 60 (m, 2 H, -CH 2 COO Et), 1 00-1 40 (m, 9 H, 3 methyl).

Example 5.

d,l-3-l( 3,5-Dimethoxy-N-ethoxycarbonyl)anilinolbutyric Acid 5 Method A Ethyl 3-l( 3,5-dimethoxy-N-ethoxycarbonyl)anilinolbutyrate ( 202 g, 0 595 mole), aqueous sodium hydroxide ( 595 ml of IN) and ethanol ( 595 ml) are combined and stirred at room temperature overnight The reaction mixture is concentrated to about 600 ml volume under reduced pressure, the concentrate 10 diluted with water to 1200 ml volume and extracted with ethyl acetate ( 3 x 750 ml.) The aqueous layer is then acidified with 10 %/ hydrochloric acid to p H 2 and extracted again with ethyl acetate ( 3 x 750 ml) These latter extracts are combined, washed with brine, dried (Mg SO 4), filtered and concentrated in vacuo to yield the s 15 title product as an oil ( 163 5 g, 88 2 %) 15 Method B A 5 liter 3 neck, round bottom flask equipped with mechanical stirrer and reflux condensor is charged with a solution of ethyl 3-l( 3,5-dimethoxy-Nethoxycarbonyl)anilinol-butyrate ( 439 g, 1 41 moles) in ethanol ( 2 liters) Sodium hydroxide ( 2 liters of IN) is added and the mixture refluxed on a steam bath for 3 20 hours The reaction mixture is poured onto 5 liters of ice-water and extracted in one liter portions with diethyl ether ( 500 ml /portion) The aqueous layer is cooled by adding ca one liter of ice and then acidified with concentrated hydrochloric acid ( 1 75 ml, 2 1 moles) It is extracted in portions of one liter with methylene chloride ( 250 ml /portion) The methylene chloride layers are combined and dried 25 over magnesium sulfate, decolorized with charcoal and evaporated to dryness to yield a viscous yellow oil Crystallization from ether/cyclohexane ( 1:2) affords 224 g ( 55 3 %) of crystalline product, m p 78 0-80 C This material is used without further purifications in the following step.

'H NMR ( 60 M Hz) CD Ci (ppm): 6 24-6 53 (m, 3 H, aromatic), 4 65 (sextet, 30 IH, -N(COOC 2 Hs)CH(CH 3)CH 2 COOC 2 Hs), 4 10 (quartet, 2 H, ester methylene), 3.78 (s, 6 H, -OCH 3), 2 40-2 60 (m, 2 H, -CH 2 COOH), 1 18 (t), 1 28 (d, 6 H,methyl), 10 8 (bs, variable, IH, COOH).

MS (mol ion) m/e -311.

An analytical sample, obtained by recrystallization from ethyl acetate/hexane 35 ( 1:5), melted at 89 0-91 C.

Analysis: Calc'd for Cs H 2106 N: C, 57 86; H, 6 80; N, 4 50 % Found: C, 58 08; H, 6 65; N, 4 46 % Example 6.

d and l-3 l( 3,5-Dimethoxy-4-N-ethoxycarbonyl)anilinolbutyric Acids 40 A mixture of d,l-3-l( 3,5-dimethoxy-N-ethoxycarbonyl)anilinolbutyric acid ( 136 6 g, 0 44 mole) and 1-ephedrine ( 72 5 g, 0 44 mole) is dissolved in methylene chloride ( 500 ml) The methylene chloride is then removed in vacuo to yield the Iephedrine salt of d,l-3-l( 3,5-dimethoxy-N-ethoxycarbonyl)anilinolbutyric acid as an oil, lalD 5 = -20 0 (c=l 0, CHCI 3) Addition of ether ( 1500 ml) causes 45 crystallization of a white solid which is separated by filtration and dried ( 102 g), m.p 114 -116 C Recrystallization from ethyl acetate/hexane ( 1:1) affords 71 1 g.

( 34 %) of the l-ephedrine salt of 1-3-l( 3,5-dimethoxy-N-ethoxycarbonyl) anilinolbutyric acid; m p 126 -127 C.

Analysis: Calc'd for C 25 H 3607 N 2: C, 63 00; H, 7 61; N, 5 88 % 50 Found: C, 62 87; H, 7 64; N, 5 88 % lal 25 = -43 50 (c=l 0, CHCI 3).

The l-ephedrine salt of the l-isomer is stirred in a mixture of ethyl acetate ( 1000 ml.) and 10 % hydrochloric acid ( 400 ml) for ten minutes The organic phase is separated, washed with 10 % hydrochloric acid ( 2 x 400 ml), dried and 55 concentrated under reduced pressure to an oil Crystallization of the oil from ethyl acetate/hexane ( 400 ml of 1:1) affords 34 6 g of 1-3-l( 3,5-dimethoxy-Nethoxycarbonyl)anilinolbutyric acid, m p 96 -97 C.

Analysis: Calc'd for C,,H 2,O O N: C, 57 86; H, 6 80; N, 4 50 % Found: C, 57 90; H, 6 66; N, 4 45 % la 15 = -25 4 (c= 11 0, CHCI 3).

The mother liquor remaining from recrystallization of the l-ephedrine salt of the l-isomer is treated with hydrochloric acid as described above to give crude d-3l( 3,5-dimethoxy-N-ethoxycarbonyl)anilinolbutyric acid Treatment of the crude acid with d-ephedrine affords, after crystallization from ether, the dephedrine salt of the d-isomer, m p 124 -125 C.

Analysis: Calc'd for C 25 H 3,O 7 N 2: C, 63 00; H, 7 61; N, 5 88 % Found: C, 62 82; H, 7 47; N, 5 97 % 10 1 al 2 i= + 44 0 (c= 1 0, CHCI 3).

The d-ephedrine salt is converted to d-3-l( 3,5-dimethoxy-Nethoxycarbonyl)anilinolbutyric acid in the same manner as described above for conversion of the 1ephedrine salt to the free acid M p 96 0-97 C after recrystallization from ethyl acetate/hexane ( 3:5) Analysis: Calc'd for C,5 H 21 ON: C, 57 86; H, 6 80; N, 4 50 % Found: C, 57 95; H, 6 57; N, 435 % lal 25 = + 25 3 (c= 11 0, CHCI 3).

Example 7

Methyl 3-( 3,5-Dimethoxyanilino)propionate A mixture of 3,5-dimethoxyaniline ( 114 9 g, 0 75 mole), methyl acrylate ( 69 73 g., 0 81 mole) and glacial acetic acid ( 2 ml) is refluxed for 20 hours Reflux is discontinued and the reaction mixture is concentrated and then distilled in vacuo, to yield 106 8 g ( 73 9 %) of the title product, b p 174 0-179 C ( 0 7 mm).

'H NMR ( 60 M Hz) CD Mi (ppm): 5 62-5 95 (m, 3 H, aromatic),4 1 (variable, 25 bs, IH, -NH), 3 74 (s, 6 H, -OCH 3), 3 68 (s, 3 H, COOCH 3), 3 41 and 2 59 (two 2 H triplets, -NCH 2 CH 2 CO 2).

Repetition of this procedure but using the appropriate aniline reactant in place of 3,5-dimethoxyaniline affords the following compounds.

OY 1 /COOCH 3 CH 2 Q 30 W-ZN H Y 1 Z-W C 2 H 5 OC 2 H 5 C 7 H 7 OC 7 H 5 C 7 H 7 SCH 3 CH 3 SCH 3 C 2 H 5 SCH 3 Example 8.

Methyl 3-( 3,5-Dimnethoxyanilino)alkanoates.

The procedure of Example 7 is repeated but using the appropriate ester R 4 Rs C=CH-COOCH 3 in place of methyl acrylate and the appropriate protected aniline reactant to give the following compounds.

1,579,230 17 1,579,230 17 When R, is hydrogen, the same products are obtained by the procedure of Examples I and 2 but using methyl acetoacetate and methyl propionylacetate in place of ethyl acetoacetate and the appropriate protected aniline reactant.

0 Y 1 / CO O CH 3 CH 2 W-Z N"KR 4Y Z-W R, RB 5 CH 3 OCH 3 CH 3 H CH, OCH 5, CH 3 CH 3 CH 3 SCH 3 CH, H CH:, SCH 3 CH, H 10 CH, SCH 3 C 2 H 5 H C^H OCH, C^H CH 3 CH, OCH, CH 3 H CH, O C 7 H 7C 2 H 5 H Is C^H SCH 3 CH 3 CH 3 15 CH, SCH 3 CH 3 H CH,3 OCH 3 C^H C^H CH 3 SCH, CH 5, CH 3 CIT 3 OCH, CH, CIT 3 CIT 3 OCH 3 n-CAH H CIT 3OCH 3n-C 4 H 9H 2 CH 3 OCH 3 n-C 6 H 13 H CIT 3 SCH 3 n-CAH H CIT 3 SCH, n-CH 11 CIT 3 C^H OC 7 IH,i-CAH H 25 CIT 3 OCH 3 n-C 4 H, CIT 3 CIT 3 OC^H n-CH 13 CH 3 CIT 3 OCH 3 CHC^H H Y, Z-W R 4 Rs CH 3 OCH 3 CH 2 CH 5 CH 3 CH 3 OCH 3 (CH 2)4 C Hs CH 3 CH 3 SCH 3 CH 2 C 1 H 5 CH 3 CH 3 OCH 3 (CH 2)3 C 8 Hs CH 3 5 CH 3 SCH 3 (CH 2)2 C^Hs C 2 Hs CH 3 SCH 3 CH 2 C 6 H 5 H C 2 H 5 O C 2 Hs C C 2 HC 2 H 5 C 7 H 7 SCH 3 (CH 2)4 C H 5 C 2 H 5 C 7 H 7 OC 7 H 7 CH 3 CH 3 10 C 2 Hs OC 2 Hs (CH 2)2 Ce H 5 CH 3 Example 9.

d,l-Methyl 3-1 l 3-hydroxy-5-( 5-phenyl-2-pentyl)lanilinolpropionate.

A mixture of 3-hydroxy-5-( 5-phenyl-2-pentyl)-aniline ( 1 0 g), methyl acrylate ( 345 mg), and acetic acid ( 0 1 ml) is heated at 106 -110 C overnight The cooled 15 residue is dissolved in 100 ml ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution The organic phase is then dried (Mg SO 4) and evaporated to a crude residue which is chromatographed on 130 g of silica gel using benzene-ether ( 2:1) as the eluant After elution of less polar impurities, 540 mg ( 40 %), d,l-methyl 3-1 l 3-hydroxy-5-( 5-phenyl-2-pentyl) lanilinolpropionate is 20 collected It has the following spectral characteristics:

H NMR ( 60 M Hz) CDCI (ppm): 7 14 (s, 5 H, aromatic), 5 83-6 13 (m, 3 H, SC 3 aromatic), 3 66 (s, 3 H, -COOCH 3), 3 37 (t, 2 H, -NCH 2), 2 16-2 78 (m, 5 H, -CH 2 COO and benzylic), 1 28-1 69 (m, 4 H, -(CH 2)2-), 1 11 (d, 3 H, > CH 3), 4 4-5 2 and 1 28-2 78 (variable, I H, NH, OH) 25 m/e 341 (m+).

Example 10.

Methyl 3 l( 3,5-Dimlethoxy-N-ethoxycarbonyl)anilinolpropionate.

Ethyl chloroformate ( 2 0 g, 8 4 mmole) is added dropwise over a 10 minute period to a mixture of methyl 3-( 3,5-dimethoxyanilino)propionate ( 1 0 ml, 10 5 30 mmole), methylene chloride ( 5 ml) and pyridine ( 5 ml) at 0 C under a nitrogen atmosphere The mixture is stirred at O C for 20 minutes following addition of the ethyl chloroformate and then at room temperature for an additional 20 minutes, and is then poured into a mixture of methylene chloride ( 75 ml) and icewater ( 50 ml) The methylene chloride layer is separated, washed successively with 10 %,' 35 hydrochloric acid ( 2 x 50 ml), saturated aqueous sodium bicarbonate ( 1 x 30 ml) and saturated aqueous sodium chloride (I x 40 ml) and dried (Mg SO 4) It is then decolorized with activated charcoal and concentrated under reduced pressure to an oil ( 2 72 g) The product is used as is.

Similarly, d,l-methyl-3-l 3-hydroxy-5-( 5-phenyl-2-pentyl) anilinolpropionate is 40 converted to d,l-methyl-3-{ l 3-hydroxy-5-( 5-phenyl-2-pentyl)-Nethoxycarbonyllanilinolpropionate and the following compounds are prepared from compounds of Examples 7 and 8 by reaction with the appropriate alkyl chloroformate or other reactant of formula R 6 Br where R 6 is other than hydrogen:

1,579,230 oyl CO 0 CM 3 CH 2 l.'R 4 w-Z N R Y, Z-W R, R, RS CH 3 OCH, H COO-n-C^ H C^ OC^ H CHC O OC^ H C 7 H, OCH, H COOCH, H C^ SCH, H CO O C^ H CH 3 SCH, H COO-n-C ^ H C^ SCH, H (C Hj C O OCH, H CH OCH 3 CH 3 CHC O OC^ H CH, OCH 3 C^ COOCH, H 10 C Hr, SCH 3 CH, COOCH, H CH 3 SCH, CH 3 COOCH,' H C Hr, OC^ C^ CHC 00-n-C^ H C^ OCH, C^ CO O C^ H is C^ OCH, CH 3 COOCH 3 H 1 5 C^ SCH 3 C^ CO O C^ H C^ OC^ C^ COOCH 3 H C^ SCH 3 CH 3 ' Coo-'-CA H C^ SCH 3 CH 3 (CHI)3 CO O CH, H CH 3 OCH, H CO O C^ H 20 CH 3 OCH 3 CH 3 COOCH, H CH 3 OCH 3 CH, CH, H CH 3 OCH 3 CH 3 C^ H CH 3 OCH 3 CH, n-CH, H C^ SCH 3 H '-CA H 25 C Hr, OCH 3 CH 3 CHC,% H CH 3 OC^ CH 3 (CH,),C H, H CH, OCH 3 CH 3 (CH,) C H H 1,579,230 1 ( 1,579,230 Y, Z-W R, C^ CH 3 CH 3 CH 3 CH CH, CH 3 C^ CH, CH 3 CH 3 CH, CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH, CH 3 CH, CH, CH 3 CH 3 CH 3 CH 3 CH, CH 3 CH 3 CH 3 CH 3 SCH 3 OCH 3 OCH 3 SCH 3 OCH 3 OCH 3 OCH 3 SCH 3 OCH, SCH 3 OCH 3 OCH 3 OCH 3 OCH, OCH 3 OCH 3 OCH 3 OCH, SCH, OCH, OCH, SCH 3 OCH 3 OCH 3 OCH 3 SCH 3 OCH, OCH 3 OCH 3 SCH 3 SCH, H CH, CH, C^ CH 3 CH 3 C^ CH 3 CH 3 CH, CH 3 CH 3 CH 3 CH 3 n-CA n-CH,, n-CH,3 n-CH, n-C Hl CH 2 C 6 H 5 (CH 1)2 C H, (CH 2) C H,, (CH 2),CH,, CH 2 C H.

CH 3 (CH 2),CH, CH 3 CH 3 CH 3 H H CH 3 H CHC^ H CH 3 H (CH 2)3 C,,H, H CO O C 2 H, CH 3 COOCH 3 C^ CO O C 2 H, CH, CO O C 2 H, CH 3 CH 3 CH 3 CO O C 2 H, CH 3 CO O CH 2 C(CHI CH, CH 2 CO O CHI H (CH 2),COOCH 3 H n-CH 13 H COOCH 3 H COOCH 3 H CO 0 CH 3 H CH 3 CH 3 CH 2 C,H, CH 3 (CH 2),CH, CH 3 C 2 H 1 CH 3 n-C Hl C 2 H, CO O C 2 H, CH, CH 3 CH 3 COCH 3 CH 3 CHO CH 3 COCH 11 CH 3 COCH Cffi, CH 3 CO(CHICIA H COCH 3 H n-CH 3 H is is Y, Z-W R 4 R 6 Rs CH 3 SCH 3 n-C 3 H 7 n-C 4 H 9 H CH 3 OCH 3 CH 2 C,H 5 COOCH 3 H C 7 H 7 OC 7 H 7 i-C 3 H 7 COOC 2 H, H CH 3 OC 2 Hs n-CH 1,3 i-C 3 H 7 CH 3 5 CH, SCH 3 CH 2 C 8 H 5 COOC 7 H 7 CH, CH 3 OCH 3 (CH 2)3 C 6 Hs COCH 2 C 8 Hs CH 3 CH 3 SCH 3 CH 2 Cs Hs COO-n-C 4 H 9 H C 2 H 5 OC 2 H 5 CH 3 COOC 7 H 7 CH 3 Example I 1 10 3-l( 3,5-Dimethoxy-N-ethoxycarbonyl)anilinolpropionic Acid.

Methyl 3-l( 3,5-dimethoxy-N-ethoxycarbonyl)anilinolpropionate ( 2 72 g, 8 36 mmoles), aqueous sodium hydroxide ( 8 4 ml of IN) and ethanol ( 8 4 ml) are combined and stirred overnight under nitrogen at room temperature The reaction mixture is then concentrated under reduced pressure to half-volume, diluted with 15 water ( 35 ml) and then extracted with ethyl acetate The aqueous phase is acidified to p H 2 with 10 % hydrochloric acid and extracted with methylene chloride ( 3 x 50 ml.) The combined extracts are washed with brine, dried (Mg SO 4) and concentrated to give the product as an oil ( 2 47 g) which is used as is.

In like manner, the remaining compounds of Example 10 are hydrolyzed to 20 their corresponding alkanoic acids having the formula COOH OY 1 / CH 2 R W-ZN I " 5 R 6 Example 12.

I-Carbethoxy-S, 7-dimethoxy-4-oxo-I,2,3,4-tetrahydroquinoline.

A mixture of 3-l( 3,5-dimethoxy-N-ethoxycarbonyl)anilinolpropionic acid ( 1 10 25 g., 3 7 mmole) and polyphosphoric acid ( 4 g) is heated at 65 C for 45 minutes under an atmosphere of nitrogen and is then cooled to O C It is then taken up in a mixture of methylene chloride-water ( 200 ml of 1:1) The organic layer is separated and the aqueous phase extracted again with methylene chloride ( 2 x 100 ml) The combined extracts are washed with saturated sodium bicarbonate ( 3 x 100 ml), 30 brine (I x 100 ml) and then dried (Mg SO 4) Concentration of the dried extract gives the product as an oil which crystallizes from benzene Yield = 645 mg, m p.

109 -11 i C.

Analysis: Calc'd for C 4 H,7 Os O N: C, 60 21; H,6 14; N, 5 02 % Found: C, 60 11; H,6 14; N,4 80 % 35 Example 13.

5,7-Dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline.

A mixture of glacial acetic acid ( 60 ml), 48 % hydrobromic acid ( 60 ml) and Icarbethoxy-5,7-dimethoxy-4-oxo 1,2,3,4-tetrahydroquinoline ( 4 0 g, 14 3 mmole) is refluxed overnight and is then concentrated in vacuo to a dark oil The oil is 40 1,579,230 dissolved in water ( 50 ml) and the aqueous solution neutralized to p H 67 with IN sodium hydroxide A saturated solution of salt water ( 50 ml) is added and the resulting mixture extracted with ethyl acetate ( 3 x 150 ml) The extracts are combined, dried (Mg SO 4) and concentrated under reduced pressure to an oil The oil is taken up in benzene-ethyl acetate ( 1:1) and the solution charged to a silica gel column The column is eluted with a volume of benzene equal to the volume of the column and then with benzene-ethyl acetate ( 250 ml of 4:1) and benzeneethyl acetate ( 250 ml of 1:1) Fractions ( 75 ml) are collected Fractions 4-9 are combined and evaporated under reduced pressure The oily residue is crystallized from ethanol-hexane ( 1:10) Yield= 1 86 g, m p 166 -169 C.

Further recrystallization raises the melting point to 171 -172 5 C.

m/e 179 (m+) Analysis: Calc'd for Cg H 903 N: C, 60 33; H, 5 06; N, 7 82 % Found: C, 60 25; H,4 94; N,7 55 % By means of the procedure of Example 12 and this procedure, 3-{l 3hydroxy-5( 5-phenyl-2-pentyl)-N-ethoxycarbonyllanilinolpropionic acid is transformed to 5hydroxy-7-( 5-phenyl-2-pentyl)-4-oxo- 11,2,3,4-tetrahydroquinoline, and the following compounds are prepared from compounds of Example 11:

0 OH R 8 H H H H CH 3 C 2 H 5 H CH 3 C 2 H 5 H X-H R 5 OH H SH H SH H SH H OH H CH 3 C 2 Hs n-C 4 H, CH 3 CH 3 CH 3 H CH 2 C H 5 CH 3 (CH 2)2 C 6 H 5 CH 3 (CH 2)4 CH 5 CH 3 CH 3 H CH 3 C 2 H 5 CH 2 C 8 Hs CH 3 OH H OH H OH H SH H OH H OH H OH H SH H OH H SH H 35 (CH 2)3 CAH, C 2 H^ SH H 1,579,230 23 1,579,230 23 R, R 4 X-H R C^H H OH H CH 3 CH, SH H H CH, OH CH, H CH, OH C^H H CH 3 OH C 2 H 5 n-C 8,H 13CH 3 OH H H CH 3 SH CH 3 H C^H SH C 2 H, CHCOOH H OH H 10 CHCOOH CH 5 OH H CHCOOH CH 3 OH H (CH 2)2 COOH H SH H (CHI)COOH CH 3 SH H i 5 (C Hj)COOH CH 3 OH H 15 H n-C 3 H,OH H H n-C 4 H,SH H H n-C H 13OH H H CH 3 OH CH 43 H n-CH, OH CH 3 20 H n-C 4,H 9OH C 2 H, H n-CH 13 OH CH 3 H CHC 6 H, OH CH 3 H (CH 2)2 CH, OHCH 3 H (CH 2)4 C 6 H, OHCH 3 25 H CH Ch H, SH CH 3 H (CHI)C 6 Hh SHC^H CH 3 CH 3 OH CH 3 n-C 3 H 7CH 3 OH CH 3 n-CAH 3 CH 3 OH CH 3 30 n-CH, CHC^H OH CH, CH 3 n-CH, OH CH, 24 1,579,230 24 Re R, X-H Re CHCH, CH, OH CH 3 (CH 2) CH, CH 3 OH CH 3 CH Ce H, (CH 2),CH, OH CH 3 CHCOOHCH, OH CH 3 (CH,),COOH CH, OH CH 3 (CH,),COOH CH, OH CH 3 CH 3 CH 3 OH CH 3 CHCOOH CH, OH CH 3 CHC 8 H, CH, SH CH 3 10 (CHI)CH, CH, SH CH 3 CH, CH 3 SH CH 3 CH 3 CH 2 C 6 H,SH CH 3 i-C 3 H, n-CH, SH CH, CH 2 COOH (CHI)C 6 H, SH C^H 15 n-CH 11 CH 3 SH CH 3 (CHI)COOH CH, SH CH 3 CH 2 CH, (CHI)CH, SH CH 3 H n-CH 1, SH CH 3 CHC 6 H, CH, OH H 20 n-CH, CH, OH H CHCH, H OH H (CH 2)2 COOH CH 3 SH H (CH 2)4 COOH H OH H H CHCH, SH H 25 i-CAH CH 3 SH CH 3 (CH 2)3 C 6 HCH 3 SH CH 3 Example 14.

d,l-I -Carbet hoxy, 7-dimethoxy-2-methyl-4-oxo-1, 2,3,4tetrahydroquinoline.

A solution of 3-l( 3,5-dimethoxy-N-ethoxycarbonyl)anilinolbutyric acid ( 4 0 g, 30 12.8 mmole) in chloroform ( 2 ml) is added dropwise with stirring to polyphosphoric acid ( 5 0 g) heated to 600 C on a steam bath The reaction mixture is held at 60 o 1-65 o 1 C for two hours and is then poured into a mixture of ice ( 100 g) and ethyl acetate ( 100 ml) The aqueous layer is further extracted with ethyl acetate ( 2 x 100 ml) and the combined organic extracts washed successively with 35 saturated sodium bicarbonate solution ( 3 x 100 ml), brine (I x 100 ml), and then dried over anhydrous magnesium sulfate Concentration of the dried extract under reduced pressure gives 2 6 g of crude product.

Purification is accomplished by column chromatography of a benzene solution of the crude product ( 2 5 g) on silica gel ( 95 g) The column is eluted with a 5 volume of benzene equal to one-half the volume of the column, followed by benzene/ethyl acetate ( 1:1) Fractions ( 40 ml) are collected Fractions 918 are combined and evaporated in vacuo to give 1 55 g of product which is purified further by recrystallization from petroleum ether 1 33 g, m p 92 5 -94 C.

Recrystallization of this product from hot ethyl acetate/hexane ( 1:1) affords an 10 analytical sample; m p 94 0-95 C.

Analysis: Calc'd for C 1 H 190 s N: C, 61 42; H, 6 53; N, 4 78 % Found: C, 61 54; H,6 55; N, 4 94 % m/e 293 (m+) IR (K Br) 5 85, 5 95 pu (≥O) 15 Example 15.

d,l-5, 7-Dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline.

Method A A mixture of glacial acetic acid ( 240 ml), 48 % hydrobromic acid ( 240 ml) and 1-carbethoxy-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline ( 16 0 g, 20 mmole) is refluxed overnight and is then concentrated in vacuo to a dark oil The oil is dissolved in water ( 200 ml) and the aqueous solution neutralized to p H 6-7 with IN sodium hydroxide A saturated solution of salt water ( 200 ml) is added and the resulting mixture extracted with ethyl acetate ( 3 x 500 ml) The extracts are combined, dried (Mg SO 4) and concentrated under reduced pressure to a dark oil 25 ( 12 8 g) Hexane-ethyl acetate ( 10:1) is added to the oil and the resulting crystals recovered by filtration ( 3 8 g); m p 158-165 C Trituration of the crystals in ethyl acetate gives 1 65 g of product; m p 165 -168 C.

Additional material separates from the mother liquors on standing ( 2 9 g) m p.

168 -170 C Column chromatography of the filtrate on silica gel using benzene 30 ether ( 1:1) as solvent gives an additional 4 6 g of product, m p 167 169 C.

Further purification is achieved by recrystallizing the product from ethyl acetate; m p 173 -174 C.

Analysis: Calc'd for Co Ha 103 N: C, 62 16; H, 5 74; N, 7 25 % Found: C, 62 00; H, 5 83; N, 7 14 % 35 m/e 193 (m+) Method B A mixture of d,1-3-l( 3,5-dimethoxy-N-ethoxycarbonyl)anilinolbutyric acid ( 100 g., 0 32 mole) and 48 % hydrobromic acid ( 500 ml)/glacial acetic acid ( 300 ml) is heated in an oil bath at 110 C for 2 hours The oil-bath temperature is then 40 increased to 145 C and heating is continued for an additional 2 hours During this last heating period an azeotropic mixture distills (boiling point 42 O 110 C.

-200-300 ml) and the deep-red homogeneous solution is allowed to cool to room temperature The mixture is poured onto ice-water ( 3 liters) and ether ( 2 liters), thelayers are separated and the aqueous solution is washed with ether ( 2 x 1000 ml) 45 The ether layers are combined and washed successively with water ( 2 x 1000 ml), brine ( 1 x 500 ml), saturated Na HCO 3 solution ( 4 x 250 ml) and brine ( 1 x 500 ml) and then dried Mg SO 4) Decolorization with charcoal and evaporation of the ether affords a yellow foam which is crystallized from ca 300 methylene chloride to give 31 3 g ( 50 4 %) of pure 5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4tetrahydroquinoline 50 Additional product can be isolated from the mother liquor by silica gel chromatography.

H NMR ( 60 M Hz) STMS ( 100 mg sample/0 3 ml CDCI/0 2 ml CD 35 OCD 3) (ppm): 12 40 (s,IH,Cs-OH), 5 72 (d,2 H,meta H), 5 38-5 60 (bs,IH,C 7-OH), 3 50-4 00 (m,IH,C 2 H), 2 38-2 60 (m,2 H,C 3-H 2), 1 12 (d,3 H,methyl) 55 m/e 193 (m+) Analysis: Calc'dfor CCH,103 N: C,62 16; H, 5 74; N,7 25 % Found: C 62 01: H 5 85: N, 7 02 % Similarly, methyl dl-3-113-hydroxy-5-( 5-phenyl-2-pentyl) lanilinolpropionate is converted to d,I-5-hydroxy-7-( 5-phenyl-2-pentyl)-4-oxo 1,2,3,4tetrahydro1,579,230 quinoline which is purified by column chromatography using silica gel and benzene/ether ( 5:1) as eluant.

m/e 309 (m+) TM H NMR ( 60 M Hz) 8 CD Ci 3 (ppm): 12 22 (s, IH, 50 H), 7 14 (s, 5 H, C 8, H 5), 6 04 (d, J= 2 5 Hz, IH meta H), 5 87 (d, J= 2 5 Hz, IH meta H), 4 19-4 60 (b, IH, 5 NH), 3 48 (t, 2 H, CH 2 N), 2 18-2 89 (min, 5 H, Ar CH, Ar CH 2, CH 2-C=O) , 1.38-1 86 (m, 4 H, -lCH 212-), 1 13 (d, 3 H, CH 3).

and ethyl d,l-3-( 3,5-dimethoxyanilino)hexanoate hydrocholride is converted to d,l-5,7-dihydroxy-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline; m p 117 119 C.

(from methylene chloride) 10 m/e 221 (m+), 135 (base peak, m+ propyl).

and 1-3-l( 3,5-dimethoxy-(N-ethoxy carbonyl)anilinolbutyric acid is converted to d-5,7-dihydroxy-2-methyl-4-oxo 1,2,3,4-tetrahydroquinoline, m p 167 168 C.

lal 25 = + 167 8 (c=l 0, CH 3 OH).

m/e 193 (m+) 15 Analysis: Calc'd for Co H,103 N: C, 62 16; H, 5 74; N, 7 25 % Found: C, 61 87; H, 5 62; N, 6 96 % and ethyl d,l-3-( 3,5-dimethoxyanilino)hexanoate hydrochloride is converted to 1-5,7-dihydroxy-2-methyl-4-oxo 1,2,3,4-tetrahydroquinoline; m p 166 -168 O C.

lal 5 = -168 5 (c=l 0, CH 3 OH) 20 m/e 193 (m+) Analysis: Calc'd for C 10 H 1 03 N: C, 62 16; H, 5 74; N, 7 25 % Found: C,61 82; H, 5 83; N, 7 22 % Example 16.

d,l-5,7-Dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline 25 A mixture of 3,5-dimethoxyaniline ( 230 g, 1 5 moles), methyl crotonate ( 150 g., 1 5 moles) and glacial acetic acid ( 90 g, 1 5 moles) is heated at reflux for 6 hours.

Additional glacial acetic acid ( 90 g, 1 5 moles) is added and the mixture refluxed overnight Hydrobromic acid ( 1000 ml of 48 % solution) and glacial acetic acid ( 850 ml) are added to the reaction mixture which is heated at reflux for 4 5 hours The 30 title product is isolated and purified according to the procedure of Example 13.

Yield = 36 g, m p 166 0-170 C.

Repetition of this procedure but replacing methyl crotonate with methyl acrylate, methyl 3-ethyl acrylate or methyl 3,3-dimethylacrylate affords 5,7dihydroxy-4-oxo 1,2,3,4-tetrahydroquinoline, 5,7-dihydroxy-2-ethyl-4-oxo1,2,3,4 35 tetrahydroquinoline, and 5,7-dihydroxy-2,2,-dimethyl-4-oxo-1,2,3,4tetrahydroquinoline, respectively.

Example 17.

d,l-5, 7-Dihydroxy-2-methyl-4-oxo-1,2 3,4-tetrahydroquinoline.

A mixture of 3,5-dimethoxyaniline ( 4,6 g, 0 03 mole), crotonic acid ( 2 54 g, 40 0.03 mole) and pyridine hydrochloride ( 3 0 g, 1 26 moles) is heated at -200 C for 45 minutes The cooled reaction mixture is suspended in water ( 500 ml) (p H -3) and the p H adjusted to 7 and the resultant mixture stirred for 10 minutes The organic layer is separated, dried (Mg SO 4) and concentrated to 3 2 g.

of a yellow oil 45 A mixture of glacial acetic acid ( 110 ml), 48 % hydrobromic acid ( 110 ml) and the yellow oil is refluxed for one hour and is then concentrated in vacuo to a dark oil The oil is dissolved in water and the aqueous solution neutralized to p H 6-7 with IN sodium hydroxide A saturated solution of salt water is added and the resulting mixture extracted with ethyl acetate The extracts are combined, dried 50 (Mg SO 4) and concentrated under reduced pressure to a dark oil ( 2 8 _g) Column chromatography of the crude'residue on silica gel using benzene-ether ( 4:1) as eluant gives an additional 510 mg of product, m p 168 -170 C.

Further purification is achieved by recrystallizing the product from ethyl acetate; m p 173 -174 C 55 Analysis: Calc'd for C 10 HO 3 N: 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).

In a similar manner, 3,3-dimethyl acrylic acid and 3,5-dimethoxyaniline gives after purification by silica gel chromatography (benzene/ether 1:1 as eluant) 5,7 60 dihydroxy-2,2-dimethyl-4-oxo-1,2,3,4-tetrahydroquinoline as a yellow oil.

1,579,230 Analysis (MS) Parent peak (m+) Calc'd for C,1 H 1303 N: 207 0895 Found: 207 0895 Base peak (m+ 15) Calc'd for Co H,003 N: 192 0661 Found: 192 0655 Similarly, styryl acetic acid and 3,5-dimethoxyaniline are condensed to yield d,l-5,7-dihydroxy-2-benzyl-4-oxo 1,2,3,4-tetrahydroquinoline as an oil after purification using benzene/ether ( 3:1) as eluant.

m/e = 269 (m+) and 178 (m±benzyl, base peak) NMR (CDCI 3) 8 (ppm): 8 76 (s, IH, 5-OH), 7 18-7 6 (m, 5 H, C Hls), 5 84 (d, J= 3 Hz, IH) and 5 62 (d, J= 3 Hz, IH) for the metal coupled aromatics, and 2.14-4 82 ( 4 m, 7 H), for the remaining protons ( 7-OH, CH-N, CH 2-C=O, -CH 2-Ce H 6 and N-H).

Example 18.

Following the procedures of Examples 9-15, the compounds tabulated below are prepared from appropriate 3-hydroxy-5-(Z-W)anilines and appropriate esters of the formula R 4 R 5 C=CH-COOCH 3 wherein each of R 4,R 6 is hydrogen, methyl or ethyl.

0 OH R 5 z w H H H CH 3 H C 2 Hs H CH 3 H H H H H H H C 2 H 5 H H H CH 3 H H H CH 3 H H H H CH 3 H CH(CH 3)(CH 2)3 CH(CH 3)(CH 2)3 CH(CH 3)(CH 2)3 CH(CH 3)(CH 2)4 CH(CH 3)(CH 2)3 (CH 2)3 (CH 2)4 (CH 2)4 (CH 2)2 CH(C 2 Hs) CH(C 2 Hs)(CH 2)3 C(CH 3)2 C(CH 3)2 (CH 2)3 (CH 2)6 (CH 2)8 CH(CH 3)(CH 2)7 2015 C 8 H 6 CH, C 6 Hs C 6 He C 6 H C 6 H 5 C 6 H, Ce H, C 66 C 6 H 6 C 6 H 5 C 6 H 5 C 6 H, C 6 H 5 Ce 15 C 6 H 5 C Hll Cel 15 1,579,230 1,579,230 H H H H H H H H 11 CH 3 H H H is H H H H H H H H H H H H H H H H H H R, H H CH 3 H CH, C^ H CH 3 H CH 3 CH 3 H H H H C 2 H, H CH, H H C 2 H, H CH, H CH 3 H H H CH 3 CH, CH 3 z W CH 2 CH(CHYCHI CH(CHYCHI CH(CH 3 WH 2 CH(CH 3)CH 2 CH(CH 3)(CHI CH(CH 3)(CH 2)2 CH(CH 3) CH 2 (CH 2)3 CH(CHYCHI CH(CH,)CH 2 CH(CH,)(CHI CH(CHYCH,), CH(CH,)CH 2 CH(CH 3 WH(CH,) CH(CH,)CH(CH 3) CH(CH,,)(CH,), CH(CH,,)(CH,), (CH 2), (CH 2)l (CH 2)l (CH 2)3 CH(CH 3) CH(CHYCH 2)l CH(CH,)(CHICH(CH 3) CH(CH 3)CH(CH 1 WH 2 (CH 2)3 (CHI (CH,), (CH 211 (CH 2)l CHCH(CH,)CH, C,,H, 4-FC 6 H 4 4-FCH,, 4-FC 8 H, 4-FCH 4 4-CICH 4 C,H, C^ CH C,Hl; C^ C^ C^ CH, C 6 H 11 C 6 H 11 Ce HI, CA 1 C 3 H, C 6 H 11 COH 11 C 6 H 11 C 6 H 11 C 6 H 11 COH 11 2-pyridyl 4-pyridyl 2-pyridyl 4-pyridyl 3-pyridyl 4-pyridyl is 1,579,230 R, R 4 z W CH(CH,)(CH 2)2 CH(CH,)CH(C Hj CH 2 CH(CH)(CHA, CH 2 CH(CA)CH, CH(CH)(CH 2)2 CH(C 2 H,)(CH 2)2 CH(CH,)(CHICH(C Hj CH(CH)(CHI CH(CHYCH 2)2 CH(CH 3)CH,-0 CH 2)2 (CH 2)4 CH(CH 3)CH(CHYCH 2)l CH(CH 3)CH(CHYCH 2)l CH, CH 2 (CH 11 (CH 2).

(CH 2).

CH(CH 3) (CH 2)3 CH(CH 3) CH(CHYCHI (CH 2)3-0(CH 2)3-0(CH 2)3-0(CH,)2 f-0(CHI-0(CH 2)3-0(CH 2)3-0-(CH,)2 (CH 2),-0 (CH 2)2 (CH 2)3-0-CH(CH 3) 3-pyridyl 4-pyridyl 3-pyridyl 3-pyridyl 4-piperidyl 2-piperidyl 4-piperidyl C 7 H 13 C 7 H 13 CH, CH 3 H H H CH 3 CH 3 CH 3 CH 3 CH, H C 6 H 11 CH 3 C^ 4-FC,H, C 6 H 11 CA CH 3 4-( 4-FC^)CH 1, 4-CIC H, C.H, 4-piperidyl H C 2 H, H CH 3 H H H H H H H CH 3 H CH 3 H CH 3 H H H CH 3 H H H CH 3 H H is H H H CH 3 H H H H H CH, H H H CH 3 H H H C 2 H, H H H CH 3 H CH 3 H C^ H H H CH 3 H C 2 H, H H H CH 3 is 1,579,230 z W H CH 3 H H H H H CH 3 H CH 3 H CH 3 H H H CH 3 H H H C^ H CH, H H H CH 3 is H C^ H H H CH 3 H H H CH 3 H CH 3 H H H H H CH, H CH 3 H C^ H H H CH 3 H CH 3 H CH, H CH 3 H C,,H H CH 3 (CHI)3-0-CH(CH,)(CHI)2 (CH 2),-0-CH(CH 3)(CH,), CH(CHYCH 2)2-0CH(CH,)(CH,),-O-CH 2 CH(CHYCHI-0 (CH 2), CH(CHYC Hj,-O-CH(C Hj CH(CH,)(CH,),-0-CH 2 CH C 2 H,) (C H 1-0(CHI-O-CH(CH 3)CH 2 (CH 2),-0 CH,),,(CHI-O-CH 2 CH(CHYCH 2)3-0CH(CHYCHI-0 XCH 2), CH(CH 3)(CH 2)3-0 (CH 2)2 CH(C^)(CHA-0-(CH 2).

CH(C 2 H)(CHI-O-CH(CH,) CH(C 2 HXCH,)2-0-(CH 2)2-CH(CH 3) CH(CH 3)-O-CH 2 CH(CM)(CH,),-0CH(CM)(CH 2),-0(CH 2)3-S(CH 2)3-S-CH 2 (CH 2)3-S(CH 2)3-S (CH 2)2 (CH 2)3-S (CH 2),, CH(CHYCHI-SCH(CH,)(CHI-SC H (C H,)(C H A-S ( C H 2)11 CH(CH,)(CHI-S-WH,),, CH(C 2 H,)(CH 2)2-SC.H, CH 3 C,H, CH 3 CH, C 7 H 13 CH 3 C,H, 3-piperidyl 4-pyridyl 4-FC^ 2-( 4-FC Hj CH, C^ CH, C Hr, 4-piperidyl C 7 H 13 C^ C 3 H 5 2-( 4-FCH,1 K 7 H 12 C^ 4-FCH 4 CH.

CH 3 CH, 4-piperidyl 4-(C H)CH,.

4-pyridyl C,,H, C 6 H 11 to Is CH(C 2 H,)(CH 2)-S CH 2),-CH(CH 3) CH 3 1,579,230 3 1 3 1 R, R, z W H H H H H H H H H H H H H is H H H H H H CH, C 2 H, C 2 H, CH 3 H H CH 3 H CH, CH, C 2 H, CH 3 H H CH 3 H CH 3 H H CH, C^ CH 3 CH 3 H H CH, CH, CH 3 H CH 3 CH, CH 3 C 2 H, CH, CH 3 CH 2 C H.

n-CH 13 C^ (CH,) C,,H,, CH 3 CH 3 C 2 H 5 CH 3 CH(CH)(C Hj,-S-CH(CH,) CH(CH 3)(CH 2)3-S CH,).

CH(CH 3)(CH 2)3-S (CH,).

CH(CH,)CH,-0-(CH,), CH(CH,)CH 2-0 (CH,), CH(C Hj CH,-0-(CH,), CH(C Hj CH,-O-CH(CH 3)CH, CH(C Hj CH 2-(-CH(CH 3)CH, CH(CH 3)CH 2-0-CH(CH 3)CH 2 CH(CH 3)CH,-O-CH 2 CH(CH)CH,-0-(CHI CH(C Hj CH 2-0-CH(CH 3) CHCH(CH 3)-O-CH 2 CH 2 CH(CH 3)-O-CH 2 CHCH(CH 3)-O-TH 2)11 CH 2 CH(CH 3)-O-CH(CH 3)CH 2 CHCH(CH 3)-0 CH,), C(CH 3 MCH 2), C(CHI(CH 2).

CH(CH,)(CHI CH(CH)(CHI CH(CH)(CHA, CH(CH)(CHI (CHAI (CH 2)4 (CH 2)4 (CH 2)2 CH(C 2 H,) C(CHI C(CHI(CHI (CH 2).

(CH 2).

4-CIC,H 4 4 TC H,, 4-pyridyl CH 3 COHS CH 3 C^ COH 5 COH 5 4-FCH, 4-pyridyl CH 3 CH 3 CH 3 CH 3 C 6 H 5 4 TC H, H H COHS C,,H, Co HS C 6 H, C 6 H 5 C 6 H 5 C,,H, C 6 H 5 Ca Hr, C 6 H 5 C 6 H 5 C 6 H 5 Is t.i L^ Un n N N n X X 1 z W X J n N N n = X -X z W O W n N N n = X z z n n X z W = z r) (_) X z W J, L r) r) X z r) r) X N N N X = N N N N N N N N = N N N = = = N n X = = = -= = = X = z = = r) X X N r) n n:? r) N N -, '= N N N N N N r) r) r) r)n r) ? n = A = X = N h = r = X z A = N = z = = = N N = W W = W A = W = n: N:E: r) r) 0 1 O O In -) 11 n n X n-n XX n X W n 1 (i 1 n n n r) n n X tr) z (is 1,579,230 W z H CH 3 CH 3 H CH, CH 3 CH 3 C,H, H CH 3 CH, CH 3 H is CH 3 CH 3 CH 3 CH, CH 3 C^ CH, H CH 3 CH, CH 3 CH 3 CH 3 CH, CH 3 CH, CH 3 CH 3 n-CHU (CRICAS CH 3 n-CH, CH 3 CH 3 CH 3 CH, CH 2 C H.

CH 3 CH, CH 3 n-CH,, CH 3 CH 3 CH 3 CH 3 CH 3 C 2 Hr, CH, n-CA CH 3 CH 3 CH 3 CH 3 CH 3 CH, CH 3 CHH,H, CH, CH 3 (CHI CH(CH 3) WHI CH(CH 3) (CH 2)3-0(CH 2)3-0(CH 2)37-0(CH 2)3-0(CH 2)3-0(CH 2)3-0(CH 2)3-0 (CH 2)2 (CH 2)3-0-CH(CH 3) CH(CH 3 XCHI-0CH(CHIXCHI-O-CH 2 CH(CH 3 XCHI-0-(CHJ, CH(CH 3)(CH 2)2-0-CH CH 3) CH(CH 3)(CH 2)2-0-CH,-CH(C 2 H,) (CH 2)4-0(CHI-O-CH(CH 3)CH 2 (CHI-O-CH 2 CH(CH 3 XCHI-0CH(CH 3)(CH 2)3-0 (CHI)2 CH(C 2 H 5)(CH 2)2-0-CH(CH 3) CH(C 2 H)(CHI-0CH(C 2 H 5)(CH 2)2-0(CHI-S ' (CH 2)3-S-CH 2 (CH 2)3-S(CH 2)3-S-(CH 2).

CH(CH 3 XCHI-SCH(CH 3)(C Hj,-S-(CHI CH 3 CH 3 H COH 11 C,H, 4-FC,H, COH 11 CA CH, 4-( 4-FCH,)C H,, 4-CIC,H, 4-piperidyl CH, CH 3 C 7 H 13 CH 3 C^ 3-piperidyl 4-FC,H, 2-( 4-FC Hj C^ C^ 4-piperidyl C^ 2-( 4-FC,H,,)CH 12 C,H, 4-FC H 4 cHg C 11 H 5 4-piperidyl 4-pyridyl is R 5 R, Z W CH 3 CH 3 CH(CH 3)(CH 2)2-S (CH 2)4 C 8 Hs C 2 Hs C 2 Hs CH(C 2 H 5)(CH 2)2-SO Ce H 11 H n-Ce H,3 CH(C 2 H)(CH 2)2-S-CH(CH 3) 4-CICH 4 CH 3 n-C 4 H 9 CH(CH 3)(CH 2)3-S (CH 2), 4-FC 6 H 4 5 CH 3 CH 3 CH(CH 3)(CH 2)3-S (CH 2)4 4-pyridyl CH 3 CH 3 CH(CH 3)CH 2-O-(CH 2) CH 5 CH 3 CH 3 C(CH 3)2 (CH 2)s H C 2 H 5 C 2 H 5 C(CH 3)2 (CH 2)e H Of course, when Z contains an ether or thioether linkage, the procedure of 10 Example 14 is used for the cyclization step.

Example 19.

d,l-S-Hydroxy-2-methyl-7-( 2-heptyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline.

Potassium hydroxide pellets ( 325 mg, 52 mmole) is added to a solution of d,l5,7-dihydroxy-2-methyl-4-oxo-l,2,3,4-tetrahydroquinoline ( 1 0 g, 52 mmole) in 15 N,N-dimethylformamide ( 10 ml) The mixture is slowly heated to 100 C and to the resulting solution d,l-2-bromoheptane ( 1 08 g, 60 mmole) is added all at once with good stirring After 10 minutes additional potassium hydroxide ( 160 mg) is added followed by additional d,/-2-bromoheptane ( 500 mg) The addition of potassium hydroxide and d,l-2-bromoheptane was repeated two more times using 80 mg 20 potassium hydroxide and 250 mg d,/-2-bromoheptane each time The reaction mixture is stirred an additional 10 minutes and is then cooled Chloroform ( 50 ml) and aqueous sodium hydroxide ( 25 ml of IN) are added, the mixture stirred for 10 minutes and the layers separated The chloroform extraction is repeated, the extracts combined, dried (Mg SO 4) and concentrated under reduced pressure to a 25 dark oil The oil is chromatographed on silica gel ( 120 g) using benzene as solvent.

Fractions of 30 ml each are collected The 12th-18th fractions are combined and concentrated under reduced pressure to a light yellow oil ( 850 mg) which crystallizes upon standing The desired product is separated by filtration and recrystallized from hot hexane, m p; 76 -77 C 30 The above procedure is repeated on a 20-fold scale but using benzeneethyl acetate ( 9:1) as chromatographic solvent Fractions of 750 ml each are collected.

Combination of the 2nd-6th fractions affords 32 g of oil which partially crystallizes from hexane upon standing and cooling to give 18 2 g of product An additional 3 2 g is obtained by concentrating the mother liquor and allowing it to crystallize by 35 standing in the cold Total yield= 21 4 g.

Analysis: Calc'd for C,,H 2 s O 3 N: C, 70 07; H, 8 65; N,4 81 % Found: C,69 82; H,8 67; N,4 93 % m/e 291 (m+) IR (K Br): 6 01 a (= 0) 40 In like manner, 5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline converted to d,l-5-hydroxy-7-( 2-heptyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline, an oil.

H NMR ( 60 M Hz) TMS H NMR ( 60 M Hz) CDCI 3 (ppm): 13 3 (s, IH, phenolic), 5 5 and 5 7 (d, 2 H, J = 2 Hz, aromatic, 4 6 (bs, IH, -NH), 4 1-4 6 (m, IH, -O-CH-), 3 3 (t, 2 H, J = 7 Hz, -CH 2), 2 6 (t, 2 H, J = 7 Hz, -CH 2-), 2 0-0 7 (m, remaining protons) 45 Example 20.

The following compounds are prepared according to the procedure of Example 19 but using the appropriate Br (alk 2)n-W reactant and the appropriate 3,7-dihydroxy-2-R 4 R 5-4-oxo-1,2,3,4-tetrahydroquinoline or 5-hydroxy-7thiol-2R 4 R 5-4-oxo-1,2,3,4-tetrahydroquinoline 50 1,579,230 1,579,230 0 on (al k 2) W R, H H H H H H H H H H H H Is H H H H H H H H H H H H H H R, H CH 3 CH 3 H CH 3 CH 3 H CH 3 H C He H CH 3 CH, H CH, H CH 3 C^ H H CH 3 C Hr, CH 3 H CH 3 CH 3 X -alk 2CH, CH 2 (CH 2)2 (CH 2)4 (CH 2).

(CH 2).

CH(CH)3 CH 2 CH(CH 3)(CHI CH(CH 3)(CHI CH 2 (CH 2)2 (CH 2)4 CH 2 CH 2 CH(CH 3)CH 2 CH(CHYCHI CH(CHYCHI (CH 2)l CH(CH 3)CH(CHYCHI (CHI (CHI (CH 2)3 CH(CH,)CH 2 CH 2.

CH 2 CH(CH 3) W H H H H H H H H CH 3 C.Hr, CH, C,H, 4-CI Ce H 4 4-FC H 4 Ce H, Ce H, C,H, Ce H, CH 4-pyridyl 4-pyridyl 3-pyridyl 2-pyridyl C 3 H, C 3 H, C 4 H, Re H H H CH 3 H H C 2 H, CH 3 H CH 2 C^ CH 2 COOH CH 2 COOH H H CH 3 CH 3 H H H C^ H n-CA H H H H is 36 1,579,230 3 R 5 R, X -alk,W Re H CH, H CH 3 H CH 3 H C 2 H, H CH 3 H H H CH 3 H H H H H C 2 H, H H H C^H H CH 3 H H H H H C 2 H, H C^H H H H H H CH 3 H C 2 H, H CH 3 H CH, H H H CH 3 H H H CH 3 H H H CH 3 H C 2 H, H H S cl S cl S (C S (C S (C S (C S (C S (C (CH 2)2 CH, (CH 2)l (CH 2)3 (CH) C^H C^" 4-FC 6 H.

4-CICH, C^H C 7 H 13 2-(C 6 H 5)CAH 2-(C H 5)CAH 4-(C 6 H)C 8 H 1.

3-(Ce H 5)C 7 H 12 4-pyridyl 4-pyridyl 4-piperidyl 2-pyridyl 3-piperidyl H H H H H H H H H 2)3 H 2)3 H 2)5, H 2)4 H 2)9 H H H H 5 H H CH 3 H (CH 2)2 C 6 Hr, 10 H H H H H 15 H CH 3 H H C 2 H 5, 20 H H H H H 25 H (CHI)COOH (CH 2)2 COOH H H H H R, R, X -alk, W R, H CH 3 S CH(CH 3)(CHI) H (CHI)COOH H H S CH(CH 3)(CHI) H H H CH 3 S CH, C^H H H H S CH, C 8 H 11 H 5 H CH 3 S (CHI) COH 11 H H C^H S (CH 2)4 CRH 3 H H H S CH(CH 3) C^H H H H S CH(CH 3)CH(CH 3)(CHI)CH 3 H H CH 3 S CH(CH 3)CH(CH)(CHI) CH 3 H 10 H H S C(CHI)(CHJ)5 CH 3 H H CH 3 S C(CHI)(CH), CH, H H CH 3 S CH, C 6 H, H H CH 3 S (CHI) C 6 H, H H H S CH(CH 3)(CH 2)2 C^H H Is H CH 3 S CH(CH 3)(CH 2), C 6 H 5 CH 3 H CH 3 S CH 2 4-FC^H H H H S CH, 4-CICH 4 H H CH 3 S (CHI) 4-pyridyl H H C 2 H 5,S CH(C Hj)CH, 2-pyridyl H 20 H H S C^H H H CH 3 S 4-FC 6 H, H H C 2 H 5, S C 5 H, H H CH 3 S COH 11 H H H S 4-pyridyl H 25 H CH 3 S 4-piperidylCHC 6 H, H CH,, S C 7 H 13 H H CH 3 S 2-(CH 5)C 3 H 4 H H CH 3 S 4-(C H)C H 1, H H H S 4-CIC 8 H 4H 30 H H S CH(CH 3)(CH 2)4 CH, CH 3 H CH, S CH(CH 3)(CHI) C^H CH,, 1,579,230 1,579,230 -alk, R, R, X W R, i-C 3 H, (CH,),CH, (CH,) C H.

n-CH, CHCOOH CHCOOH (CH,),COOH H CH 3 H H H H H H CH 3 n-C 3 H, n-C,,H 13 CHCOOH (CH,),,COOH CH Cffi, H H CHCH, (CH,) C H,, H H H CH 3 H H (CHICOOH H H H H H H H CH 3 C Hs CH 3 CH, CH, CH 3 CH, CH, H CH 3 H H H CH, CH, CH, CH 3 CH 3 CH 3 C^ H CH 3 CH 3 CH 3 CH H C 2 H, CH, CH, CH, H H CH, CH 3 CH 3 CH 3 CH 3 n-CH,3 CH, CH 3 n-CH,3 CH 3 CH 3 C 2 H, CH 3 CH, CH 2 C^ n-CH, (CH 2),Co Hs CH, CH 3 C 2 H.

C 2 H, CH 3 CH, CH 3 CH 3 S S C(CH 3 MCH 2)5 (CH 2)4 CH(CH 3)(CHI CH(CH 3)(CH 2), CH(CHYCH 2), CH(CHYCHI CH(CH 3)(CHI CH 2 (CH 2)4 (CH 2).

CH(CHYCHI CH(CHYCH,), CH(CH 3)CH(CHYCH,), C(CHI(CH 2).

CH(CHYCHI CH(CH)(CHJ, CH(CHYCHI CH(CHYCHJ, CH(CHYCHI CH(CHYCH,), (CH 2)3 CH(CHYCH 11 CH 2 (CHI CH 3 CH, CH 3 CH, C Hr, CH, CH, H H H CH 3 CH 3 CH 3 CH 3 C.H, CH 3 4-FCH, CH 3 CH 3 4-CICH, 4-pyridyl 3-pyridyl C.H 5 4-FCH, 4-pyridyl CH.

C 7 H 13 3-piperidyl 2-(C H X 3 H 4 3-(CHX 7 H 12 C 3 H 5 COH 11 is 1,579,230 -alk,R 5 CH, CH, CH, CH, CH 3 H CH, CH, C^ CH 3 CH, CH:, C 1 H 5 is CH, CH, CH, CH, CH 3 C 1 H 5 H CH 3 H CH, CH, C 2 H 5 CH, CH, CH 3 CH, X W R,, C^ CH 3 CH, CH 3 CH 3 n-CH, (CH,),,C^ CH 2 Cffi, (CH 2)2 CH, CH 3 n-C,,H 13 CH 2 C H, C 2 H 5 CH 3 CH 3 CH 3 CH 3 CH 3 n-CH, CH 2 C H.

(CH 2)2 CH, n-CA n-C,,H, (CH 2),C H.

(CH 2)3 CH 5 CH 3 CH 2 C H 5 n-CH, CH 3 S S S S S S S S S S S S S S S S S S S S 0 ' S (CHI CH 2 (CH 2)r, (CH 2)g C(CH 3 MCH 2).

CH(CH 3)(CHA, CH(CH 3)(CHI CH(CHYCHI C(CH 3 MCH 2)l 2-(C H KA C(CHI(CH 2).

CH 2 (CHI CH 2, (CHI CH(CHYCH 2).

C(CHJACH 2), C 7 H 13 C^ 4-CIC 11 H 4 C 7 H 13 4-(C H,,)C Hl.

C,H, 4-pyridyl Ce HI, 4-F Cffi, 4-(C,H)CH,.

C^ C,,H, H H H H CH 3 C,^ COH 11 H H H 4-pyridyl CH 3 C,Hr, C,H, 4-FC,H, H CH 3 (CH 2 WOOH n-C 5 Hl H H H H CH 2 C H, CH 3 CHCOOH (CHICOOH H H H CH 3 -C 3 H, (CH 2),C,,H.

CH 2 CH, H -C 3 H 7 H H H H H H n-CH 13 n-CA CH 3 CH 2 COOH is Example 21.

d,1-5-Hydroxy-2-methyl-7-( 5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4tetrahydroquinoline.

A mixture of 5-phenyl-2-(R,S)-pentanol ( 16 4 g, 100 mmole), triethylamine ( 28 ml., 200 mmole) and dry tetrahydrofuran ( 80 ml) under a nitrogen atmosphere is cooled in an ice/water bath Methanesulfonyl chloride ( 8 5 ml, 110 m M) in dry 5 tetrahydrofuran ( 20 ml) is added dropwise at such a rate that the temperature holds essentially constant The mixture is allowed to warm to room temperature and is then filtered to remove triethylamine hydrochloride The filter cake is washed with dry tetrahydrofuran and the combined wash and filtrate evaporated under reduced pressure to give the product as an oil The oil is dissolved in 10 chloroform ( 100 ml) and the solution washed with water ( 2 x 100 ml) and then with saturated brine (I x 20 ml) Evaporation of the solvent affords 21 7 g ( 89 7 %) yield of the mesylate of d,l-5-phenyl-2-pentanol which is used in the next step without further purification.

A mixture of d,l-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline 15 ( 1.0 g, 5 2 mmole), potassium carbonate ( 14 35 g, 0 104 mole), N,Ndimethylformamide ( 60 ml) and dl-5-phenyl-2-pentanol mesylate ( 13 68 g, 57 mmole), under a nitrogen atmosphere, is heated to 80 -82 C in an oil bath for 1 75 hours.

The mixture is cooled to room temperature and then poured in to ice/water ( 300 ml) The aqueous solution is extracted with ethyl acetate ( 2 x 50 ml) and the 20 combined extracts washed successively with water ( 3 x 50 ml) and saturated brine (I x 50 ml) The extract is then dried (Mg SO 4), decolorized with charcoal and evaporated to give the product.

m/e 339 (m+) The above procedure is repeated but using 114 8 g ( 0 594 mole) of d,1-5, 7-di 25 hydroxy-2-methyl-4-oxo 1,2,3,4-tetrahydroquinoline, 612 ml of N,Ndimethylformamide, 174 8 g ( 1 265 moles) of potassium carbonate and 165 5 g ( 0 638 mole) of d,l-5-phenyl-2-pentanol mesylate The reaction mixture is cooled and poured onto ice water ( 4 liters) and the aqueous solution extracted with ethyl acetate ( 2 x 4 liters) The combined extract is washed with water ( 4 x 2 liters), brine ( 1 x 2 liters) 30 and dried (Mg SO 4) Evaporation affords 196 g of the title product It is used without further purification.

H NMR ( 60 M Hz) SCDCI (ppm): 12 73 (s, IH, OH), 7,22 (s, 5 H, aromatic), 5.80 (d, J= 3 Ha, IH, meta H), 5 58 (d, J= 3 H 3, IH, meta H), 1 25 (d, 6 H, CH 3-CH-N and CH 3-CH-O-), 1 41-4 81 (m, 1 1 H, remaining protons) 35 Example 22.

d,l-5-Hydroxy-7-( 5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline Repetition of the procedure of Example 21 but using 5,7-dihydroxy-4-oxo1,2,3,4-tetrahydroquinoline in place of the 5,7-dihydroxy-2-methyl-4-oxol,2,3,4tetrahydroquminoline affords d,l-5-hydroxy-7-( 5-phenyl-2-pentyloxy)-4oxo-1,2,3,4 40 tetrahydroquinoline as an oil in 74 % yield.

m/e 325 (m+) Analysis:Calc'dfor C 20 H 23 NO 3: C, 73 70; H,7 12; N,4 31 % Found: C, 73 69; H,7 15; N,4 08 % I NMR( 60 z) TMS 4 'H NMR ( 60 M Hz) MCDCI 3 (ppm): 12 6 (bs, IH, phenolic), 7 3 (s, 5 H, 45 aromatic), 5 8 (d, IH, aromatic, J = 2 Hz), 5 6 (d, IH, aromatic, J = 2 Hz), 4 7-4 1 (m, 2 H, NH and O-CH), 3 5 (t, 2 H, CH 2, J = 7 Hz), 3 1-2 1 (min, 4 H, 2CH 2-), 2.1-1 5 (min, 4 H, 2-CH 2), 1 3 (d, 3 H, -CH-CH 3, J = 6 Hz).

Similarly, d,l-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline ( 27 g, 0 14 mole) is alkylated with 4-phenylbutyl methanesulfonate ( 35 2 g, 0 154 mole) 50 to yield 41 1 g ( 90 %) of the desired d,l-5-hydroxy-2-methyl-7-( 4phenylbutyloxy)4-oxo-1,2,3,4-tetrahydroquinoline, m p 88 -90 C Recrystallization from ethyl aetate-hexane ( 1:2) gives the analytical sample, m p 90 -91 C.

Calc'd for C 20 H 2303 N: C, 73 82; H, 7 12; N, 4 30 % Found: C, 73 60; H, 7 09; N, 4 26 % 55 m/e 325 (m+) 1,579,230 H NMR ( 60 M Hz) STS(ppm): 12 58 (s, I H, -OH), 7 21 (s, 5 H, CH,), 5.74 (d, J = 2 5 Hz, IRH, meta H-), 5 5 (d, J = 2 5 Hz, i RH, meta H), 4 36 (bs, IRH, NH), 3.33-4 08 (in, 3 H, -O-CH,, -CH N), 2 29-2 83 (in, 4 H, -CH 2-C=O, CH,-CH 2), 1 51-1 92 (in, 4 H, -lCH,l,l), 1 23 (d, 31 H, CH,-).

In like manner, alkylation of d-5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydro 5 quinoline with d-2-octylmethanesulfonate gives d-5-hydroxy-2-methyl-7-( 2(R)octyloxy)-4-oxo-1 I,2,3,4-tetrahydroquinoline, m p 64-680 C.

lall' = + 110 20 (c= 11 0, CHCI 3).

and alkylation of d,1-5,7-dihydroxy-2-propyl-4-oxo I 1,2,3,4-tetrahydroquinoline with d,1-5-phenyl-2-pentanol inesylate gives d,1-5-hydroxy-7-( 5-phenyl-2 10 pentyloxy)-2-propyl-4-oxo-1 I,2,3,4-tetrahydroquinoline, m/e 367 (m').

Example 23.

The following compounds are prepared from appropriate reactants by the procedure of Example 21 The necessary alkanol reactants not previously described in the literature are prepared from appropriate aldehydes or ketones by 15 the procedures of Preparations G and H.

0 OH R,5 O -(ak 2)-W Rr, R, alk, W H CR, CH 2 C(CH 3)2 CH 2)4 CH, H CH 3 CH 2 CH(CH 3)(CHI)CH(CH 3)CH 12 CR 3 2 H CH 3 CH(CH,)CH 2 CH(CH 3)CH 2 CH(CH 3) CH, H H CH(CHY)CHI)C(CH 1) CH 3 H C 2 H, CH 2 CH(C 211) C 6 H, H CR, CH 2 CH 2 CH(CH 3) C 8 H 5, H CH 3 (CH 2)7 C^H 25 H H CH(CHY)CH 2) 5 C 8 H, H CH, (CH 2)g C 8 H 5 H H (CH 2)l CR 3 H H CH(CH 3)CH 2 2-pyridyl H C 2 H, (CRH)2 2-pyridyl 30 H CH, (CH 2) 2-pyridyl H H (CH 2)3 2-piperidyl H CR 3 (CR 2)3 4-piperidyl H CR 3 (CR 2)3 4 FC 6 H, 1,579,230 H H (CH 1 4-CIC 6 H 4 35 C= 0 eq Ln Ln rq e e l z z m 0 O >, U U U o -a>, E: -0 c U z z z 0 O >, L, Cl In L) U (_) 1 z 4 4 f 4 A U I?4 4 4 4 c ->, ->, X O O j r r Ll >, >, I I.

c ( 14 m 0 en C 14 cr rn et 2 U 0 O O m O X =:z = = = = = = = = = X U U U U U U U U U U U U = 0 m U U 0 2 N tn N 0 m U 1 1 1 i 1 1 1 1 1 1 1 1 i 1 1 1 1 1 1 43 1,579,230 43 alk, W H H H H H H H H CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 H H CH 3 H H C 2 H C^H H H H CH,, CH,, CH 3 CH 3 CH, CH,, H C^H CH 3 CH 3 CH 3 CH 3 CH 3 CH, CH 3 CH 3 CH 3 CHCH, CHCH, CH.CH, (CH 2)3 C H.

(CHI)CH, C 2 H 5 CH 3 i-C 3 H, n-CH, n-C 6,H 13 n-CH 13 CH 3 CH 3 -(CH 2)3-C(CH 3)2 (C 2)5 -C(CH 3)2 (H 2-CH(CH 3)C(H)C 24 -CH(CH 3),(CH 2),3-C(CH 3)2 (CH 2)6 -CH(CH 3)CH(CH 3)(CH-CH(CH)(CH 2)3(CH 2)8 -C(CH 3 M)24-CH(CH)(CHI)-CH(CH 3)CH(CI(C 25 -C(CH 3)2 CH 2)8 -(CH 2)cCH 3 CH 3 CU 3 CU 3 CH 3 CH 3 CH 3 CU 3 CH, C 6 H 5 i H C^H 4-CICH, 2-pyridyl H H 4-FC^H C^H CH, C 8 H 5 i 4-FCH 5, 4-piperidyl H H CH 3 C^H 4-(C H)C 8 H,, Example 24.

d,l 1 Formyl 5 hydroxy 3 hydroxymethylene2 methyl 7 (S phenyl 2 pentyloxy) -4 oxo 1,2,3,4 tetrahydroquinoline.

A solution of d,l-5-hydroxy-2-methyl-7-( 5-phenyl-2-pentyloxy)-4-oxo 1,2, 3,4tetrahydroquinoline ( 195 g, ca 0 58 mole) in ethyl formate ( 1140 g, 14 6 moles) is added dropwise to sodium hydride ( 72 g, 3 0 moles, obtained by washing 144 g of 50 %? sodium hydride with hexane, 3 x 500 ml), with good stirring After about 1 5 1,579,230 hours when 2/3 of the ethyl formate solution is added, the addition is discontinued to allow the vigorous foaming to subside Diethyl ether ( 600 ml) is added and the mixture stirred for 15 minutes before adding the remainder of the ethyl formate solution When addition is complete diethyl ether ( 600 ml) is added, the reaction mixture stirred for an additional 10 minutes and then poured onto ice water ( 2 5 liters) It is acidified to p H 1 with 10 % HCI and the phase separated and extracted with ethyl acetate ( 2 x 2 liters) The combined organic solutions are washed successively with water ( 2 x 2 liters), brine (I x one liter) and dried (Mg SO 4).

Concentration gives 231 g of red-brown oil which is used without further purification 10 Rf = 0 1- 5 (stretched) on thin layer chromatography, silica gel plates, benzene/ether ( 1:1).

Similarly, d,l5 hydroxy 7 ( 5 phenyl 2 pentyloxy) 2 propyl 4 oxo 1,2,3,4 tetrahydroquinoline is converted to d,l I formyl 5 hydroxy 3 hydroxy methylene 7 ( 5 phenyl 2 pentyloxy) 2 propyl 4 oxo 1,2,3,4 15 tetrahydroquinoline.

Example 25.

d,l I Formnyl 5 hidroxv 3 hvdroxymethylene 2 methyl 7 ( 2heptyloxy) 4 oxo 1,2,3,4 tetrahydroquinoline.

To sodium hydride ( 18 2 g, 0 38 mol) obtained by washing 50 % sodium 20 hydride in mineral oil dispersion with pentane is added dropwise, over a half-hour period, a solution of d,l-5-hydroxy-2-methyl-7-( 2-heptyloxy)-4-oxo-1,2,3, 4,-tetrahydroquinoline ( 11 1 g, 0 038 mole) in ethyl formate ( 110 g, 1 48 moles) .

Exothermic reaction occurs with vigorous evolution of hydrogen and formation of a yellow precipitate The reaction mixture is cooled, ether ( 750 ml) added and the 25 resulting mixture then heated at reflux and stirred for 3 hours It is then cooled to 0 C and neutralized by addition of IN hydrochloric acid ( 400 ml) The ether layer is separated and the aqueous phase extracted with ether ( 2 x 150 ml) The ether extracts are combined, washed successively with saturated sodium bicarbonate solution ( 2 x 100 ml) and brine ( 1 x 150 ml) and then dried (Mg SO 4) 30 Concentration of the dried extract affords an orange foam ( 10 8 g) An additional 2.3 g is obtained by acidifying the sodium bicarbonate wash solutions with concentrated hydrochloric acid followed by extraction of the acid solution with ether ( 2 x 100 ml) Concentration of the combined ethereal extracts after drying gives 2 3 g of product (Total= 13 1 g) The product is used as is 35 1 H MR( 60 M) TMS H NMR ( 60 M Hz) TCDCM 3 (ppm): 12 27 (bs, IH, Ar OH), 8 8-11 9 (m, IH, variable, =COH), 8 73 (s, IH, N-CHO), 7 41 (s, 1 H, =CH), 6 32 (s, 2 H, aromatic), 5.52 (q, IH, -CH-N), 4 18-4 77 (m, IH, -O-CH), 0 6-2 08 (m, 17 H, CH 3-C-CH,, and CH 3-C-N) 40 In like manner, d,l5 hydroxy 2 methyl 7 ( 5phenyl 2 pentyloxy) 4 oxo 1,2,3,4 tetrahydroquinoline is converted to d,l I formyl 5 hydroxy 3 hydroxymethylene 2 methyl 7 ( 5 phenyl 2 pentyloxy) 4 oxo 1,2,3,4 tetrahydroquinoline.H NMR: ( 60 M Hz) TMS ( 6 Mz TMS

* DC 3 H NMR: ( 60 M Hz) Mz) CDCI (ppm): 12 22 (bs, IH, Ar OH), 8 8-11 6 (variable, IH, =COH), 8 64 (s, IH, -CHO), 7 21 (bs, shoulder at 7 30, 45 6 H, aromatic and = CH), 6 23 and 6 17 (two IH doublets, J = 2 Hz, meta), 5 42 (bq, I H, N-CH), 4 18-4 70 (m, I H,-OCH), 2 4-3 O (m, 2 H, Ar-CH 2), 1 53-2 0 (m, 4 H, -(CH 2)2-), 1 29 (overlapping doublets, 6 H, CH 3-C-N and CH 3-C-O).

d,l 5 hydroxy 7 ( 2 heptyloxy) 4 oxo 1,2,3,4tetrahydroquinoline is converted to d,l I formyl 5 hydroxy 3 hydroxymethylene 7 ( 2heptyl 50 oxy) 4 oxo 1,2,3,4 tetrahydroquinoline, an oil.

H NMR ( 60 M Hz) TCDMC (ppm): 12 1 (bs, IH, phenolic), 8 8 (s, IH, -N-CHO), 8 1 (s, IH), 7 3 (s, IH), 6 1 (s, 2 H, aromatic), 4 5 (bs, 2 H, CH 2-), 55 4.2-4 8 (m, -O-CH 2-), 2 0-0 7 (remaining protons).

d,l 5 hydroxy 7 ( 5phenyl 2 pentyloxy) 4 oxo 1,2,3,4tetrahydro quinoline is converted to d,l I formyl 5 hydroxy 3 hydroxymethylene 7 ( 5 phenyl 2 pentyloxy) 4 oxo 1,2,3,4 tetrahydroquinoline.

1,579,230 H MR( 60 M) TMS H NMR ( 60 M Hz) MCDC 1 a (ppm): 12 4 (bs, IH, phenolic), 8 5 (s, IH, CHO) , 7.2 (m, 6 H, aromatic and =CH-), 6 2 (m, 2 H, aromatic), 4 5 (s; 2 H, -CH 2-), 4 4 (m, IH, -CH-CH 3), 2 6 (bt, 2 H, -CH 2-), 1 7 (m, 5 H, remaining protons), 1 3 (d, 3 H, -CH-CH 3, J = 6 Hz).

and d,l 5 hydroxy 2 methyl 7 ( 4 phenylbutyloxy) 4 oxo 1,2,3,4 5 tetrahydroquinoline is converted to d,l I formyl 5 hydroxy 3 hydroxy methylene 2 methyl 7 ( 4 phenylbutyloxy) 4 oxo 1,2,3,4 tetrahydro quinoline, m p 132 0-135 C (from hexane) Recrystallization from hot methanol provides the analytical sample, m p 131 -132 C.

Calc'd for C 22 H 2305 N: C, 69 27; H, 6 08; N, 3 67 % 10 Found: C, 69 25; H, 5 88; N, 3 88 % m/e 381 (m+) OH H MR( 60 M) TMS H NMR ( 60 M Hz) CDC 13 (ppm): 12 4-13 6 (m, H,), 12 26 (s, 1 H, H 5-OH), 8 62 (s, IH, -C(=O)-H), ca 7 18-7 48 (m, IH,), 7 27 (s, 5 H C^Hs), 6 26 (bs, 2 H, meta H's), 5 46 (q, IH, CH-N), 3 82-4 23 (m, 3 H, 15 -CH 2-O), 2 49-2 80 (m, 3 H, Ar CH 2), 1 67-2 02 (m, 4 H, -lCH 2 l 2-), 1 27 (d, 3 H, CH 3).

Example 26.

d,l 1 Formyl 5 hydroxy 2 methyl 7 ( 5 -phenyl2 pentyloxy)4 oxo 3 ( 3 oxobutyl) 1,2,3,4 tetrahydroquinoline 20 To a solution of d,l-l-formyl-3-hydroxymethylene-5-hydroxy-2-methyl-7-( 5phenyl-2-pentyloxy)-4-oxo-l,2,3,4-tetrahydroquinoline ( 229 g, ca 0 58 mole) in methanol ( 880 ml) under a nitrogen atmosphere is added triethylamine ( 27 2 ml) with stirring Methyl vinyl ketone ( 97 0 ml) is then added and the mixture stirred overnight at room temperature 25 The reaction is complete at this point and comprises a mixture of the title compound and d,l-1,3-diformyl-5-hydroxy-2-methyl-7-( 5-phenyl-2-pentyloxy) -4oxo-3-( 3-oxobutyl)-1,2,3,4-tetrahydroquinoline The following steps are required to convert the diformyl compound to the desired title compound.

The reaction mixture is diluted with ether ( 6 liters) and then washed 30 successively with 10 % aqueous sodium carbonate ( 4 x 1700 ml), brine ( 1 x 2 liters) and then dried (Mg SO 4) Concentration of the solution affords 238 g of a redbrown oil The oil is dissolved in methanol ( 1920 ml) and the solution cooled to 0 C Potassium carbonate ( 21 2 g) is added, the mixture stirred for 3 hours at O C.

and then treated with acetic acid ( 18 7 g) The methanol is removed under reduced 35 pressure and the resultant oil stirred with water ( 2 liters) and ethyl acetate ( 2 liters) for 10 minutes The aqueous phase is separated, extracted with ethyl acetate (I x 2 liters) and the combined ethyl acetate solutions washed with water ( 2 x 2 liters), brine ( 1 x 2 liters) and dried (Mg SO 4) Concentration under reduced pressure and chromatography of the concentrate on silica gel ( 1 8 kg) gives 159 g of the title 40 product.

m/e 437 (m+) H MR( 60 M) TMS H NMR ( 60 M Hz) TCDCI 3 (ppm); 12 7 (s, 1 H, OH), 8 78 (bs, IH, -CHO), 7.22 (s, 5 H, aromatic), 6 22 (bs, 2 H, meta H's), 2 12, 2 07 (s, 3 H, CH 3-CO-), 1 31 (d, 3 H, -CH 3-C-O-), and 1 57-5 23 (m, 13 H, remaining protons) 45 Similar treatment of 35 g ( 0 09 mole) of dl-l-formyl-5-hydroxy-3-hydroxymethylene 2 methyl 7 ( 4 phenylbutyloxy) 4 oxo 1,2,3,4 tetrahydro quinoline gives 22 7 g( 60 %) of dlIformyl 5 hydroxy 2 methyl 7 ( 4 phenylbutyloxy) 4 oxo 3 ( 3 oxobutyl) 1,2,3,4 tetrahydroquinoline, m p.

101 -103 C The analytical sample is obtained by recrystallization from 50 metehanol, m p 104 -105 C.

Calc'd for C 2 s H 29 Os N C, 70 90; H, 6 90; N, 3 31 % Found: C,70 77; H,6 81; N, 3 46 % H NMR ( 60 M Hz) TMS 6 CD Ci 3 (ppm): 12 88 (s, IH, -OH), 9 08 (bs, IH, -CHO), 1,579,230 7.29 (s, SH, Cl Hl), 6 25 (bs, 2 H, meta H's), 4 88-5 43 (m, IH, -CHN), 3 86-4 21 (m, 2 H, -CH 2-O-), ca 2 49-3 02 lm, 7 H, Ar CH 2, (CH 2)2-C(=O)-, -CH-C(=O)l, 2 18 Is, 3 H, CH 3-C(=O)l, 1 68-2 03 lm, 4 H, -(CH 2)2-l, 1 13 (d, 3 H, CH 3).

m/e 423 (m+); 5 and d,l I formyl 5 hydroxy 3 hydroxymethylene 7 ( 5 phenyl 2 pentyloxy) 2 propyl 4 oxo 1,2,3,4 tetrahydroquinoline affords d,I I formyl 5 hydroxy 7 ( 5phenyl 2 pentyloxy) 4 oxo 3 ( 3 oxobutyl) 1,2,3,4 tetrahydroquinoline which is used as is.

Example 27 10 d,I 1 Formnyl 5 hydroxy 2 methyl 7 ( 2 heptyloxy)4 oxo 3 ( 3 oxobutyl) 1,2,3,4tetrahydroquinoline and d,l1,3 Diformyl 5 hydroxy 2 methyl 7 ( 2 heptyloxy) 4 oxo 3 ( 3 oxobutyl) 1,2,3,4 tetrahydroquinoline.

To a solution of d,l-5-hydroxy-3-hydroxymethylene-2-methyl-7-( 2heptyloxy)4-oxo-l,2,3,4-tetrahydroquinoline ( 13 1 g, 37 7 mmol), in methanol ( 56 ml) and 15 methyl vinyl ketone ( 5 52 mg, 68 mmol) is added triethylamine ( 1 3 ml, 9 3 mmol) The mixture is stirred for 18 hours under a nitrogen atmosphere at room temperature and is then diluted with ether ( 550 m l The solution is washed with % aqueous sodium bicarbonate solution ( 4 x 60 ml) followed by brine ( 1 x 100 ml) and dried (Mg SO 4) Removal of the ether by evaporation gives a dark oil 20 ( 16 g) The oil is dissolved in a minimum volume of benzene and the solution charged to a column of silica gel ( 500 g) The column is then eluted with a volume of benzene equal to the volume of the column The eluting solvent is then changed to 15 % ether-benzene and 100 ml fractions collected when the first color band begins to elute off the column Fractions 5-13 are combined and con 25 centrated under reduced pressure to give d,l 1,3 diformyl 5 hydroxy 2 methyl 7 ( 2 heptyloxy) 4 oxo 3 ( 3 oxobutyl) 1,2,3,4,tetrahydroquinoline as a yellow oil ( 8 7 g).

The column is eluted further with 15 % ether-benzene Fractions 19-37 are combined and concentrated under reduced pressure to give d,l I formyl 5 30 hydroxy 2 methyl 7 ( 2heptyloxy) 3 ( 3 oxobutyl) 1,2,3,4 tetrahydro quinoline as an oil ( 4 6 g) Additional monoformyl product is obtained in the following manner:

I g of diformyl product is stirred with 200 mg potassium carbonate in methanol ( 25 ml) for two hours at O C The solvent is then evaporated in vacuo and 35 the residue suspended in ether and filtered The filtrate is concentrated and the residue partitioned between ether and water The organic layer is separated, the aqueous phase acidified with 10 % hydrochloric acid and extracted with ether The combined ether extracts are washed successively with saturated sodium bicarbonate and brine, and then dried (Mg SO 4), filtered and concentrated to yield 40 additional monoformyl product.

The monoformyl derivative has the following NMR spectrum:

H NMR ( 60 MH 2),CDCI (ppm): 12 73 (S, IH, Ar OH), 8 87 (S, IH, N-CHO), 6 12 (S, 2 H, Aromatic), 4 78-5 50 (M, IH, N-CH), 4 11-4 72 (M, IH, -O-CH), 2 21 (S, 3 H, CH 3-C(=O)), 0 63-3 12 (M, 22 H, remaining 45 hydrogens).

Similarly, the following compounds are prepared from appropriate reactants:

d,l I formyl 5 hydroxy 7 ( 2heptyloxy) 4 oxo 3 ( 3 oxobutyl) 1,2,3,4, tetrahydroquinoline, an oil.

'H NMR ( 60 MH 2) CD Ci (ppm): 12 8 (S, IH, phenolic), 8 7 (S, IH, 50 N-CHO), 6 1 (S, 2 H, aromatic), 4 1-4 6 (m, IH, -O-CH), 4 1 (d, 2 H, J= 5 H 2, -CH 2-), 2 3-3 0 (m, 3 H, CH 2 and CH-C(=O)), 2 2 (S, 3 H, -C(=O)-CH 3), 2.3 O 7 (remaining protons).

d,l I formyl 5 hydroxy 2 methyl 7 ( 5phenyl 2 pentyloxy) 4 55 oxo 3 ( 3 oxobutyl) 1,2,3,4 tetrahydroquinoline.

H NMR ( 60 MH 2) MCD SC (ppm): 12 68 (S, IH, -OH), 8 82 (b, s, IH, -C(O)H), 7 20 (b, s, 5 H, CHJ), 6 18 (b, s, 2 H, aromatic), 4 78-5 34 (m, IH, -N-CH), 4 18-4 68 (m, IH, -O-CH), 2 17 (S, 3 H, -C(O)CH 3), 1 30 (d, 3 H, 1,579,230 -O-C-CH 3), 1 12 (d, 3 H, -N-C-CH 3), 1 4-3 1 (m, 1 IH, remaining H's).

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

m/e 423 (m+) Also produced as by-product in each of the preparations is the corre 5 sponding, 1,3-diformyl derivative.

Example 28.

Following the procedures of Examples 25 and 27, the 5-hydroxy-2-R 4-7(Z-W)-4-oxo-l,2,3,4-tetrahydroquinolines of Examples 18, 20 and 23 are converted to compounds having the formula below wherein R 4, R 5, Z and W are as 10 defined in Examples 18, 20 and 23 When R 8 of the tetrahydroquinoline reactants is hydrogen, it is converted to formyl (CHO).

PREPARATION A.

2-Bromo-5-phenylpentane 15 To phosphorus pentabromide, prepared by addition of bromine ( 9 0 g) in methylene chloride ( 10 ml) to phosphorus tribromide ( 15 0 g) in methylene chloride ( 15 ml) at O C, is added 5-phenyl-2-pentanol ( 812 g) in methylene chloride at 0 C The mixture is stirred for 2 5 hours at O C and is then allowed to warm to room temperature Water ( 50 ml) is added, the mixture stirred for one 20 hour and the methylene chloride layer separated The extraction is repeated and the combined extracts washed with water, saturated sodium bicarbonate solution, brine and then dried over magnesium sulfate Concentration of the dried extracts gives 12 4 g of title product as a light yellow oil.

NMR: TMS 1 6 (D,3,methyl,J= 7 Hz), 1 6-2 0 (M,4,ethylene), 2 3-3 0 25 8 CDC 13 (bd,T,2,benzylic-methylene), 3 7-4 2 (M,l,methine), 6 9-7 4 (M,5,aromatic) .

PREPARATION B. 2-( 3,5-Dimethoxyphenyl)-5-phenylpentane A solution of l-bromopropylbenzene ( 51 7 g) in ether ( 234 ml) is added dropwise over a 2-hour period to a refluxing mixture of magnesium ( 7 32 g) in 30 ether ( 78 ml) The reaction mixture is refluxed for 30 minutes longer and then a solution of 3,5-dimethoxy-acetophenone ( 50 g) in ether ( 78 ml) is added dropwise and heated to reflux for 1 5 hours The reaction is quenched by addition of saturated ammonium chloride ( 234 ml), the ether layer is separated and the aqueous phase extracted with ether ( 3 x 200 ml) The combined ether extracts are 35 dried over magnesium sulfate and concentrated under vacuum to yield 81 g of an oil Forty grams of the oil is hydrogenated in a mixture containing ethanol ( 300 ml.), concentrated hydrochloric acid ( 2 ml) and 5 % palladium-on-carbon ( 5 g).

The catalyst is filtered off and the ethanol removed under vacuum The residue is distilled under vacuum yielding 28 g of 2-( 3,5-dimethoxyphenyl)-5phenylpentane 40 (b.p 0 125 mm, 154 0-159 C) NM: TMS 125 d 3, NMR: CD Ci 3 1 25 (d,3,a-CH 3), 1 3-2 1 (M,4,ethylene), 2 2-2 9 (M,3,benzylic-methylene,methinyl), 3 45 (S,6,methoxyl), 6 2-6 7 (M,3, aromatic), 7.2 (S,5,aromatic).

1,579,230 4,,,,J 1 7,JU 48 PREPARATION C.

2-( 3,5-Dihydrox)phenyl)-S-phenylpentane A mixture of 2-( 3,5-dimethoxyphenyl)-5-phenylpentane ( 22 g) and pyridine hydrochloride ( 94 g) under nitrogen is heated to 190 C for 2 hours with vigorous stirring The reaction mixture is cooled, dissolved in 6 N hydrochloric acid ( 200 ml) 5 and diluted with water to 600 ml The aqueous solution is extracted with ethyl acetate ( 4 x 100 ml), the ethyl acetate extracts dried over sodium sulfate and concentrated under vacuum to yield 24 g of crude product The product is purified by silica gel chromatography to yield 19 2 g of 2-( 3,5-dihydroxyphenyl)5-phenylpentane as an oil 10 NM: TMS NMR: STCD Cia 1 1 (d,3,a-methyl), 1 35-1 65 (M,4,ethylene), 2 2-2 8 (M,3,benzylic-methylene,methinyl), 6 1 6 5 (M,3,aromatic), 6 65 (bd S, 2, hydroxyl), 7-7 4 (M,5,aromatic).

Following the procedures of Preparations B and C, the compounds listed 15 below are prepared by substituting the appropriate l-bromoalkylbenzene for 1bromopropylbenzene:

2-( 3,5-dihydroxyphenyl)-6-phenylhexane.

NMR: C DCI 1 1 (D,3,a-methyl, J-7 cps), 1 0-1 9 CDC 1 a lM,6,0 CH 2 (CH 2)3-CH(CH 3)-Arl, 2 2-2 8 (M,3,benzylic methylene, methinyl), 20 6.0 (bd S, 2,phenolic OH), 6 2-6 4 (M,3,aromatic), 7 1-7 4 (M,5,aromatic).

I -( 3,5-dihydroxyphenyl)-2-phenylethane.

m.p: 76 -77 C.

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

NMR: 8 TM 51 NMR: SCDC 3 1 1, 1 25 (d,2,methyl), 1 45-2 0 (M,2,methylene), 2 15-2 7 25 (M,3,benzylic-methylene,methinyl), 6 3 (S,3,aromatic), 6 85 (S,2, hydroxyl-D 20 overlay), 7 1 (S,5,aromatic).

The following compounds are prepared in like manner from the appropriate alcohol and 3,5-dimethoxybenzaldehyde or 3,5-dimethoxyacetophenone by the methods of Preparations A, B and C: 30 OH 00Z m HO)Z-W z W CH(CH 3)CH 2 C 5 H 9 CH(CH 3)(CH 2)2 Cs H 9 CH(CH 3)CH 2 C 3 Hs 35 CH(CH 3)CH(CH 3) Coi, CH(CH 3)(CH 2)3 Cs H 1, CH(CH 3)(CH 2)4 Cs H 9 CH(CH 3)(CH 2)s C 6 HCH(C 2 Hs)(CH 2)2 C 6 H 11 40 (CH 2)3 Cs H 9 CH(C 2 Hs)(CH 2)3 C 6 H 5 C(CH 3)2 C 6 HS (CH 2)4 C 65 (CH 2)2 CH(C 2 Hs) C 6 Hs 45 CH(CH 3)CH 2 CH(C 2 Hs) C 6 H 5 I Z 7 o raln PREPARATION D.

-( 3,5-Dihydroxyphenyl)-2-methyl-4-phenylbutane A solution of n-butyl lithium ( 29 ml of 2 2 M) is added dropwise to 3,5dimethoxybenzyl triphenylphosphonium bromide ( 31 5 g) in tetrahydrofuran ( 200 5 ml) with stirring and the resulting deep red solution is stirred for onehalf hour.

Benzyl acetone ( 9 4 g) is added dropwise and the reaction mixture stirred for 12 hours It is then adjusted to p H 7 by addition of acetic acid and concentrated under reduced pressure The residue is extracted with methylene chloride and the extract evaporated to give crude 1-( 3,5-dimethoxyphenyl)-2-methyl-4-phenyl-1butene as 10 an oil It is purified by chromatography on silica gel ( 400 g) and elution with benzene Yield: 10 g as an oil.

NMRTMS 15 (,) NMR: SCD Cl 1 95 (S,3), 23-3 1 (M,4), 3 8 (S,6), 6 15-6 6 (M,3), 7 1-7 5 S(M,6).

The l-( 3,5-dimethoxyphenyl)-2-methyl-4-phenyl-l-butene ( 9 4 g) thus 15 prepared is dissolved in ethanol ( 250 ml) and catalytically hydrogenated at 45 p s i.

in the presence of palladium-on-charcoal (I g of 10 %o) and concentrated hydrochloric acid (I ml) Yield: 9 4 g of 1-( 3,5-dimethoxyphenyl)-2methyl-4phenylbutane as an oil.

NMR: SICD Ci 0 9 (d,3), 1 35-1 95 (M,3), 2 2-2 9 (M,4), 3 75 (S,6), 6 35 (S,3), 7 25 8 (S,5) 20 It is demethylated according to the procedure of Preparation C to give l( 3,5dihydroxyphenyl)-2-methyl-4-phenylbutane.

The 3,5-dimethoxybenzyl triphenylphosphonium bromide is prepared by refluxing a mixture of 3,5-dimethoxybenzyl bromide ( 12 g) and triphenylphosphine ( 14 2 g) in acetonitrile ( 200 ml) for one hour The reaction mixture is 25 then cooled and the crystalline product recovered by filtration, washed with ether and dried ( 20 g); m p 269 -270 C.

PREPARATION E.

2-Methyl-2-( 3,5-dihydroxyphenyl)-5-phenylpentane To a solution of the Grignard reagent prepared from 2-phenylbromoethane 30 ( 5.5 g), magnesium ( 0 8 g) and dry ether ( 60 ml) is added a solution of 2-methyl-2( 3,5-dimethoxyphenyl)propionitrile ( 2 75 g) in dry ether ( 20 ml) The ether is distilled off and replaced by dry benzene ( 50 ml) and the mixture refluxed for 48 hours It is then decomposed by careful treatment with dilute sulfuric acid and heated on a steam bath for one hour The mixture is then extracted with ether, the 35 extract dried (Mg SO 4) and concentrated to an oil Distillation of the oil in vacuo affords 2-methyl-2-( 3,5-dimethoxyphenyl)-5-phenyl-3-pentanone; b p 168 C /0 2 mm (Yield: 2 32 g, 60 %).

The thus-produced pentanone ( 58 g) is dissolved in ethanol ( 400 ml) and treated with sodium borohydride ( 10 g) at room temperature The reaction mixture 40 is stirred for 12 hours and is then cooled and neutralized with 6 N hydrochloric acid.

The ethanol is removed under reduced pressure and the residue extracted with ether The extract is dried (Mg SO 4) and concentrated to give 2-methyl-2( 3,5dimethoxyphenyl)-5-phenyl-3-pentanol as an oil ( 52 g, 88 % yield).

' The pentanol ( 16 g) is taken up in ether ( 100 ml) and reacted with powdered 45 potassium ( 2 5 g) in ether ( 200 ml) Carbon disulfide (equimolar to the potassium) is added and the mixture stirred for a half-hour Methyl iodide ( 9 0 g) is then added and the reaction mixture stirred for 6 hours The resulting suspension is filtered and the filtrate concentrated under reduced pressure The residue is taken up in ethanol ( 150 ml), Raney nickel added ( 25 g) and the mixture refluxed for 18 hours 50 Evaporation of the alcohol and distillation of the residue gives 2-methyl2-( 3,5dimethoxyphenyl)-5-phenyl-3-pentene.

The pentene derivative is catalytically hydrogenated according to the procedure of Preparation D and the resulting 2-methyl-2-( 3,5dimethoxyphenyl)-5phenylpentane demethylated via the procedure of Preparation C to give the 55 product.

PREPARATION F.

3,5-Dibenzyloxyacetophenone Over a period of 1 5 hours, methyl lithium ( 531 ml of a 2 molar solution, 1 06 M) is added under a nitrogen atmosphere to a rapidly stirring solution of 3,5 60 dibenzyloxybenzoic acid ( 175 g, 0 532 M) in ether ( 250 ml)tetrahydrofuran ( 1400 1,579,230 ml.) maintained at 15 0-20 C After stirring an additional 0 75 hour at 10 -15 C, water ( 600 ml) is slowly added keeping 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 x 300 ml), dried over sodium sulfate, and concentrated under vacuum to give an oil which slowly crystallized from isopropyl ether The crude product is recrystallized from ether-hexane to yield 104 7 g ( 59 %) of product; m p 59 0-61 C.

PREPARATION G.

Ethyl 3-( 3,S-dibenzyloxyphenyl)crotonate (Wiltig Reaction) A mixture of 3,5-dibenzyloxyacetophenone ( 43 2 g, 0 13 mole) and 10 carbethoxymethylenetriphenylphosphorane ( 90 5 g, 0 26 mole) is heated under a nitrogen atmosphere at 170 C for 4 hours The clear melt is cooled to room temperature, triturated with ether and the precipitate of triphenyl phosphine oxide removed by filtration The filtrate is concentrated under vacuum to an oily residue s 15 which is chromatographed over silica gel ( 1500 g) and eluted with benzene:hexane 15 solutions of increasing benzene concentration beginning with 40:60 and ending with 100 % benzene Concentration of appropriate fractions gives an oily residue which is crystallized from hexane Yield: 40 2 g ( 77 %); m p 73 -75 C.

Analysis: Calc'd for C 2,H,O 4: C, 77 58; H, 6 51 % Found: C, 77 72; H, 6 60 % 20 In like manner, ethyl 3-( 3,5-dimethoxyphenyl)crotonate is prepared from 3,5dimethoxyacetophenone ( 51 7 g) and carbethoxymethylene triphenylphosphorane ( 200 g) Yield = 61 8 g, 86 %, b p 146 -162 C at 0 3 mm.

PREPARATION H.

3-( 3,5-Dibenzyloxyphenyl)-l-butanol 25 A solution of ethyl 3-( 3,5-dibenzyloxyphenyl)crotonate ( 24 1 g, 60 mr M) in ether ( 250 ml) is added to a mixture of lithium aluminum hydride ( 3 42 g, 90 m M) and ether ( 250 ml) Aluminum chloride ( 0 18 g, 1 35 m M) is added and the mixture refluxed for 12 hours and then cooled Water ( 3 4 ml), sodium hydroxide ( 3 4 ml of 6 N) and water ( 10 ml) are then added successively to the reaction mixture The 30 inorganic salts which precipitate are filtered off and the filtrate is then concentrated in vacuo to give the desired alcohol as an oil 2 4 g ( 98 %).

Rf = 0 25 lsilica gel:benzene( 18):ethyl acetate(l)l.

m/e 362 (m+) Analysis: Calc'd for CH 242,O 3: C, 79 53; H, 7 23 % 35 Found: C, 79 37; H 7 11 % In like manner, ethyl 3-( 3,5-dimethoxyphenyl)crotonate ( 60 4 g) is reduced to 3-( 3,5-dimethoxyphenyl)butanol ( 48 0 g, 90 %).

PREPARATION I.

3-( 3,S-Dibenzyloxyphenyl)butyl Tosylate Tosyl chloride ( 11 1 g, 58 1 m M) is added to a solution of 3-( 3,5dibenzyloxyphenyl)-l-butanol ( 20 7 g, 57 m M) in pyridine ( 90 ml) at -45 C The reaction mixture is held at -35 C for 18 hours and is then diluted with cold 2 N hydrochloric acid ( 1500 ml) and extracted with ether ( 5 x 250 ml) The combined extracts are washed with saturated sodium chloride solution ( 4 x 250 ml) and then dried (Na 2 SO 4) Concentration of the dried extract affords the product as an oil It is crystallized by treatment with ether-hexane Yield: 24 63 g ( 84 %).

Analysis: Calc'd for C 3,H 3205 S: C, 72 06; H, 6 24 % Found: C, 72 05; H, 6 29 % PREPARATION J 50 3-( 3,S-Dibenzyloxyphenyl)l-phenoxybutane A solution of phenol ( 4 56 g, 48 6 m M) in dimethylformamide ( 40 ml) is added under a nitrogen atmosphere to a suspension of sodium hydride ( 2 32 g, 48 6 m M of 50 % previously washed with pentane) in dimethylformamide ( 70 ml) at 60 C.

The reaction mixture is stirred for one hour at 60 0-70 C, after which a solution of 55 3-( 3,5-dibenzyloxyphenyl)butyl tosylate ( 23 93 g, 46 3 m M) in dimethylformamide 1,579,230 51,7,3 51 ( 80 ml) is added The reaction mixture is stirred at 80 C for a halfhour and is then cooled to room temperature, diluted with cold water ( 2500 ml) and extracted with ether ( 4 x 400 ml) The combined extracts are washed successively with cold 2 N hydrochloric acid ( 2 x 300 ml) and saturated sodium chloride solution ( 3 x 300 ml) and then dried (Na 2 SO 4) Removal of the solvent under reduced pressure affords 5 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 the product as an oil Yield: 14 86 g ( 73 %).

Rf = 0 7 (silica gel, benzene).

m/e 438 (m+) 10 Analysis: Calc'd for C 30 H,003: C, 82 16; H, 6 89 % Found: C, 82 07; H, 6 84 % Repetition of Procedures G through J, but using the 3,5-dibenzyloxy derivatives of benzaldehyde, acetophenone or propiophenone, the appropriate carbethoxy (or carbomethoxy) alkylidene triphenyl phosphorane; and the 15 appropriate alcohol, phenol, thiophenol, hydroxypyridine or hydroxypiperidine as reactants affords the following compounds:

OCH 2 C 6 H 5 H 5 C 6 CH 20 Q( 3 kl)-X-(all k 2) w For convenience, the various values of W for given values of -(alk 1) X (alk 2)n are collectively tabulated 20 1,579,230 alki (CH,):, (CHI (CHI (CHI (CH,)3 CH(CH,)(CH 2)2 CH(CH,)(CH 2)l CH(CH,)(CHJ 2 CH(CH 3)(CHI CH(CH,)(CHI CH(CH 3)(CHI CH(CH)(CHI CH(C Hj(CHI CH(C 2 H,)(CH 2)2 CH(C Hj(CHI CH(C 2 Hj(CH,), CH(C 2 Hj(CHI (CH 2).

(CH,),, (CH,).

X alk 2 0 W n C^, 4-FCH,, CH,, 4-CIC,^, CH,,, 4-pyridyl, 3-pyridyl, 4-(CH,)C,,H,,,, 4-piperidyl, CH 3, 4-( 4-FCH,)C,,H,,.

Cffi,, 4-FCH,, CH,,, 4-piperidyl, CH,.

CH,, CH 3, 4-CICH 4, 4-pyridyl.

C,^, 4-FCH,, CH 3, 4-piperidyl, 2-pyridyl.

CH,, 4-pyridyl, CH,.

C^, 4-FCH,, C H,,, CA, 4-pyridyl, CH 13, 3-piperidyl, CH 3, 4-(C Hj CH,,, 2-( 4-CICH,)C^.

C^, 4-FC^, 4-pyridyl, 2-piperidyl, CH,.

C.H, 4-FC^, 4-pyridyl, 4-piperidyl, CH,, C^.

C,^, 4-pyridyl, 2-piperidyl, CH,, 4-(C^)CH,,.

C^, 4-FC^, CH 3, C^.

C^, 4-CIC^, CH 3, 3-piperidyl, CH 13.

COH,, CH 3, C Hl.

C,%, 4-F Cffi,, 2-pyridyl, CH 3, 4-piperidyl, CA, 2-( 4-FCH,)CH,,.

C^, 4-FCH,, 4-pyridyl, CH 11, 2-piperidyl, CH 3.

C,^, 4-FCH,, 4-pyridyl, C %, C^.

C,^, 4-FC^, CH,, 2-pyridyl, 4-piperidyl, C H 11.

C,^, 4-FC^, CH 13.

C^, 4-FC^, 4-CIC^, 4-pyridyl, CH,, 2-piperidyl, CH,.

C,^, 4-FC^, 4-pyridyl, 3-pyridyl, 4-piperidyl, CH 3, CH,,.

C,H,, 4-FCH,, 4-(C^)CH, CH, (CHI CH(CH,) CH(C Hj(CH 2)l CH 2 (CH 2)l (CH 2)4 (CH 2)2 CH(CH 3) CH(C Hj CH 2 CH(CA) (CHI (CHI CH(CH 3) (CH 2)2 CH(CH 3) CH 2 CHCH(CH 3) .A o hi 'i X S S S S S alk 2 CH(CH,)CH 2 (CHJ, CH 2 (CH 2)2 (CHI alki (CH 2)l (CHI (CH 2)l (CH 2), (CH 2)l (CH 2)l CH(CH)(CHI CH(C Hj(CHI CH(CH 3 XCHI CH(CH,)(CHI CH(C 2 H,)(CH 2)2 CH(C 2 H,)(CH 2)2 CH(C 2 H,)(CH 2)1.

CH(CH 3)(CH 2), CH(CH 3 XCH 1 CH(C Hj(CHJ, CH(CH 3)(CH 2).

n W 1 C^, CH,, 2-pyridyl, 3-piperidyl, 4-piperidyl, 4-FCH 4.

1 C^,, 4-pyridyl, 3-piperidyl, 4-CIC^.

0 CH,, 4-FCH,, 4-CICH 4, 4-pyridyl, 2-pyridyl, 2-piperidyl, 4-piperidyl, CH 3, C 3 H, C H, Ch HI 19 4-(C 1 COH 4)C 6 H 10.

1 C^, 4-KH,,, CH 3, 2-pyridyl, 4-pyridyl, 3-piperidyl, C^.

1 CH 5, 4-CICH 4, 4-pyridyl, CH 3, C^.

1 CH, 4-FCH,, 4-pyridyl, CH,, 4-piperidyl, C H,,.

0 CH,,, 4-FC,,H,, C H,,, CH,, 4-pyridyl, 3-pyridyl, 4-piperidyl, CH,, 4-(Ce Hj C,H, 1 C^,4-K^, CH 3, 2-pyridyl.

1 C Hs, 4-CICH,, CH,, 4-pyridyl, 3-piperidyl.

1 CH,,, CH 3, 4-pyridyl.

0 C^, 4-FCH,, 4-(CH JCH,,, 4-pyridyl, 3-pyridyl, 2-piperidyl, COH 11, 1 C^, 47 ,C 1 CIH 4, CH 3, 4-piperidyl.

1 C^, CH,, 4-pyridyl.

0 CH,, CH,, 4-KH 4, 4-pyridyl, CA, CH,, 2-( 4-FC,,,4,,)CH,.

1 C^, CH,, 3-pyridyl, 4-piperidyl, CH 1,.

0 C^, CH,, 4-CIC H,,, 2-pyridyl, CH 3-( 4-CICH,)CH,,,.

1 CH,, C^, 4-FC,, 4-pyridyl.

k-h -3 o m 14 S CH 2 S (CHI S (CH 2).

S S S S S CH(CH 3) (CH 2)2 CH(CH) (CH 2)2 (CH).

54 1,579,230 54 PREPARATION K.

3-( 3,5-Dihydroxyyphenyl)-l-phenoxybutane A solution of 3-( 3,5-dibenzyloxyphenyl)-1-phenoxybutane ( 14 7 g, 133 5 m M) in a mixture of ethyl acetate ( 110 ml), ethanol ( 110 ml) and concentrated hydrochloric acid ( 0 7 ml) is hydrogenated for 2 hours under 60 p s i hydrogen in 5 the presence of 10 % palladium-on-carbon ( 1 5 g) Removal of the catalyst by filtration and concentration of the filtrate gives an oil The oil is purified by chromatography on silica gel ( 100 g) and eluting with benzene-ethyl acetate consisting of 0-10 % ethyl acetate The middle fractions are combined and concentrated to give the title product: 7 8 g( 80 %), as an oil 10 R, = 0 25 lsilica gel, benzene( 4), methanol(l)l.

m/c 258 (m+) Analysis: Calc'd for C,6 H,803: C, 74 39; H, 7 02 % Found: C, 74 13; H, 7 00 % In like manner, the remaining ethers (X = O) of Preparation J are 15 debenzylated to afford the corresponding 3,5-dihydroxy derivatives.

The thio ethers are debenzylated by treatment with trifluoroacetic acid The procedure comprises stirring a solution of the dibenzyl ether (X = S) in trifluoroacetic acid at room temperature for two hours The reaction mixture is evaporated to dryness and the residue taken up in ether The ether solution is washed with 20 water, dried (Mg SO 4) and evaporated to give the debenzylated compound.

PREPARATION L.

I -Bromo-3-( 3,5-dimethoxyphenyl)butane A solution of phosphorus tribromide ( 5 7 ml 0 06 mole) in ether ( 30 ml) is added to a solution of 3-( 3,5-dimethoxyphenyl)-l-butanol ( 30 0 g, 0 143 mole) in 25 ether ( 20 ml) at -5 C to -10 C and the reaction mixture stirred at -5 C to -10 C for 2 5 hours It is then warmed to room temperature and stirred for an additional 30 minutes The mixture is poured over ice ( 200 g) and the resulting mixture extracted with ether ( 3 x 50 ml) The combined extracts are washed with 5 % sodium hydroxide solution ( 3 x 50 ml), saturated sodium chloride solution 30 (I x 50 ml) and dried (Na 2 SO 4) Removal of the ether and vacuum distillation of the residue affords the title product; 25 g ( 55 % 4 yield); b p 125 0132 C at 0 4 mm.

The following compounds are prepared from 3,5-dimethoxybenzaldehyde, 3,5dimethoxyacetophenone and 3,5-dimethoxypropiophenone and the appropriate 35 carbethoxyalkylidene triphenylphosphorane by the procedures of Preparations G, H and L.

o CH 3 0 CM 3 H 3 CO Z r Z (CH 2)3 40 (CH 2)4 C(C 2 H 5)CH 2 PREPARATION M.

4-( 3,5-Dihydroxvphenyl) I -( 4-pyridyl)pentane A mixture of 3-( 3,5-dimethoxyphenyl)butyl triphenylphosphonium bromide 45 ( 19 0 g, 35 4 mmoles) in dimethylsulfoxide ( 50 ml) is added to 4pyridinecarboxaldehyde ( 3 79 g, 35 4 mmoles) in tetrahydrofuran ( 40 ml) The resulting mixture is then added dropwise to a slurry of 50 % sodium hydride ( 1 87 g, 39 mmoles) in tetrahydrofuran ( 20 ml) under a nitrogen atmosphere at 0 -5 C.

Following completion of addition, the mixture is stirred for one hour at 0 0-5 C.

and then concentrated under reduced pressure The concentrate is diluted withwater ( 200 ml) and then acidified with 6 N HCI The aqueous acid solution is extracted with benzene ( 4 x 50 ml) It is then made basic and extracted with ethyl acetate ( 3 x 50 ml) Evaporation of the combined extracts after drying (Mg SO 4) 5 affords 4-( 3,5-dimethoxyphenyl)-l-( 4-pyridyl)-1-pentene ( 7 1 g, 70 %) as an oil.

Catalytic hydrogenation of the thus-produced pentene derivative according to the procedure given in Preparation D gives 4-( 3,5-dimethoxyphenyl)-1-( 4pyridyl)pentane in quantitative yield; m p 131 -133 C.

The pentane derivative thus obtained is demethylated by heating a mixture of 10 the compound ( 7 15 g, 25 mmoles) and pyridine hydrochloride ( 35 g) under a nitrogen atmosphere at 210 C for 8 hours The hot mixture is poured into water ( 40 ml) and the resulting solution made basic with 6 N sodium hydroxide Water and pyridine are removed by distillation in vacuo Ethanol ( 50 ml) is added to the residue and the inorganic salts which precipitate are filtered off The filtrate is 15 concentrated in vacuo and the residue chromatographed on silica gel ( 150 g) using an eluting agents 5 % ethanol/benzene ( 4 liters), 10 % ethanol/benzene (I liter), 13 % ethanol/benzene (I liter) and 16 % ethanol-benzene ( 5 liters) The product is isolated as a glassy solid by concentration of appropriate fractions of the eluate.

Yield = 5 0 g ( 78 %) 20 The 3-( 3,5-dimethoxyphenyl)butyltriphenylphosphonium bromide is prepared by refluxing a mixture of l-bromo-3-( 3,5-dimethoxyphenyl)butane ( 21 5 g, 78 5 mmoles) and triphenyl phosphine ( 20 5 g, 78 5 mmoles) in xylene ( 60 ml) for 18 hours The reaction mixture is then cooled to room temperature and filtered The filter cake is washed with ether and dried in a vacuum desicator to give 36 4 g 25 ( 86 %o) yield of product; m p 190 -200 C.

Repetition of this procedure but using the appropriate bromo-( 3,5dimethoxyphenyl)alkane and the appropriate aldehyde or ketone affords the following compounds.

OH 30 O HO Z-W Z W (CH 2)3 2-pyridyl (CH 2)3 3-pyridyl (CH 2)3 4-pyridyl (CH 2)3 2-piperidyl 35 (CH 2)3 4-piperidyl (CH 2)4 2-pyridyl (CH 2)4 4-pyridyl (CH 2)4 3-piperidyl (CH 2)4 4-piperidyl 40 CH 2 CH(CH 3)CH 2 2-pyridyl CH 2 CH(CH 3)CH 2 4-piperidyl CH(CH 3)CH(CH 3)CH 2 3-pyridyl CH(CH 3)CH(CH 3)CH 2 4-pyridyl 45vutrru tt 4 \flu 45 ,, t 3l,13 2 3-plpcriuy I 1,579,230 _ 1,579,230 z W 2-pyridyl 3-pyridyl 4-piperidyl 3-pyridyl 4-piperidyl 4-pyridyl 4-pyridyl 2-piperidyl 4-piperidyl 3-pyridyl 3-pyridyl 4-piperidyl 2-pyridyl 4-pyridyl 2-piperidyl COH 11 C#H 11 C.^ C^ C^ C 7 H 13 COHI, CH, C^ C^ C^ C^ 4-FC,,H,, C^ 4-CIC H, 4-CICH, 4-CIC^ CH(CH,)(CH,), CH(CH 3 XCHI CH(CH)(CHI CH(CH,)(CH 2)l CH(CHYCH 2)l CH(CH 3)CH(CA)CH 2 CH(C 2 He XCHI CH(C 2 H)(CHI CH(C 2 H)(CHI CH 2 CH(CA)CH 2 CH(CA)(CHI CH(C 2 H)(CH 2)21 CH(CA)CH(CH 3)CH 2 CH(C 2 H,)CH(C 2 H,)CH 2 CH(C 2 H)CH(CA)CH 2 (CH 2)l CH(CHYCH 2), (CH 2).

(CH 2)2 CH 2 CH(CH,)CH 2 CH(CH)(CHI CH(CH 3)CH(CH,)CH, (CH 2).

(CH 2)l (CH 2)g CH(CH 3)(CH 2), CH(CHXCH 2)l CH(CHYCHI C(CH,),(CHI CH(CHYCH 2)l CH(CH 3 XCH 2)l CH(CH,)(CH,) is is Z W CH(CH 3)(CH 2) 4-FCH 4 CH(CH 3)(CH 2)2 4-FCH 4 CH(CH 3)(CH 2)2 4-CIC 6 H 4 (CH 2)3 CH(CH 3) C 6 H 1 5 CH(CH 3)(CH 2)2 CH(CH 3) Co Hs CH(CH 3)(CH 2)2 CH(CH 3) CH, CH(CH 3)(CH 2)2 CH(CH 3) 4-piperidyl CH(CH 3)(CH 2)3 C 61 H, CH(CH 3)(CH 2)2 CH(CH 3) C 6 H 1, 10 (CH 2)3 CH, (CH 2)4 C 6 H,, (CH 2)8 C 1 H 1, PREPARATION N.

3,5-Dimethoxy-a-methylstyrene Oxide 15 To a solution of dimethylsulfoxonium methylide ( 69 4 m M) in dimethylsulfoxide ( 65 ml) at room temperature is added solid 3,5dimethoxy acetophenone ( 10 g, 55 5 m M) The reaction mixture is stirred for one hourat C, for one-half hour at 50 C and is then cooled The mixture is dilutedwith water ( 50 ml) and added to a mixture of ice water ( 200 ml) ether ( 25) ml) -low 20 boiling petroleum ether ( 25 ml) The organic extract is washed twice withwater ( 250 ml), dried (Mg SO 4) and evaporated to an oil Fractional distillation of theoil yields 8 0 g ( 75 %) of 3,5-dimethoxy-a-methylstyrene oxide, b p 93 097 C,0,2 mm.

IR (CCI 4): 2780, 1595, 1196, 1151, 1058 cm-' 25 UV ( 95 % ethanol): A,,max = 279 nm (E = 2068).

m/e 194 (m+) PMR (CDCI 3) ( 60 M Hz):, 1 70 (S,CH 3-), 2 76 (d,J = 6 Hz, 0 O / \ H), 2 95 (d,J = 6 Hz, /) 3 81 (S,CH 3 O-), 6 41 (t,J = 2 Hz, Ar H) and 6 58 (d,J = 2 Hz, Ar H) 30 Analysis: Calc'd for C 11,H 403:C, 68 02; H, 7 27 % Found:C, 67 96; H, 7 28 % PREPARATION O.

2-( 3,5-Dimethoxyphenyl)-2-hydroxypropyl-2-phenylethyl Ether A mixture of dry 2-phenylethanol ( 30 ml, 251 m M) and sodium metal ( 690 35 mg 30 m M) is heated at 110 C for 30 minutes The resulting IM solution of sodium 2-phenylethoxide is cooled to 60 C, 3,5-dimethoxy-a-methylstyrene oxide ( 2 g, 10 3 m M) added and the reaction heated 15 hours at 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 Excess 2-phenylethanol is removed 40 by vacuum distillation (b p -65 C, 0 1 mm) leaving a 3 5 g residue The residue is purified via column chromatography on Merck silica gel 60 ( 300 g) and eluted in 15 ml fractions with 60 % ether-pentane Fractions 52-88 yielded 2 9 g ( 89 %/) of 2( 3,5-dimethoxyphenyl)-2-hydroxypropyl 2-phenylethyl ether.

1,579,230 IR (CDCI 4): 3534, 1595, 1202, 1153 cm-'.

UV ( 95 % ethanol): Am-x = 278 (E = 1830), 273 (e = 1860).

m/e 316 (m+) PMR (CDCI 3, 60 M Hz): 8 1 46 (S,CH 3-), 2 86 (S,OH), 2 86 (t,J = 7 Hz, -CH 2-Ph), 3 53 (S,-CH 2 O), 3 71 (t,J = 7 Hz,-CH 2 O), 3 80 (S,OCH 3), 6 38 (t,J = 5 2 Hz, Ar H), 6 61 (d,J = 2 Hz, Ar H) and 7 23 (S,Ph H).

Analysis: Calc'd for C 1 H 2404: C, 72 12; H, 7 65 % Found: C, 71 92; H, 7 63 % PREPARATION P.

2-( 3,5-Dimethoxyphenyl)propyl 2-Phenylethyl Ether 10 To a 0 C solution of 2-( 3,5-dimethoxyphenyl)-2-hydroxypropyl 2phenylethyl ether ( 550 mg, 1 74 m M) in pyridine ( 2 ml) is added dropwise phosphorous oxychloride ( 477 ml 5 22 m M) The reaction is allowed to warm to 20 C over a 1 5 hour period It is then stirred for 1 5 hours at 20 C and then added to ether ( 150 ml) and 15 % sodium carbonate ( 100 ml) The organic phase is separated and 15 washed with 15 % sodium carbonate ( 3 x 50 ml), dried over magnesium sulfate and evaporated to an oil The oil is dissolved in absolute ethanol ( 15 ml), 10 % palladium-on-carbon ( 100 mrg) added and the mixture stirred under one atmosphere of hydrogen gas When hydrogen uptake ceases ( 26 5 ml, 20 min), the reaction is filtered through diatomaceous earth and the filtrate evaporated to an 20 oil The oil is purified via preparalive layer chromatography on silica gel plates, eluted twice with 6:1 pentane:ether to yield 211 mg ( 40 %) of 2-( 3,5dimethoxyphenyl)propyl 2-phenylethyl ether.

IR (CCI 4): 1600, 1205, 1155, 1109 cm-'.

m/e 300 (m+) 25 PMR (CDCI 3, 60 M Hz) 8 1 22 (d,J = 7 Hz, CH 3-), 2 82 (t,J = 7 Hz, CH 2 Ph), -2.8 (H-C-Me), -3 6 (-CH 2-O-CH 2-), 3 75 (S,OCH 3), 6 35 (m,Ar H) and 7.18 (S,Ph H).

PREPARATION Q.

2-( 3,5-Dihydroxyphenyl)propyl 2-Phenylethyl Ether 30 A mixture of 2-( 3,5-dimethoxyphenyl)propyl 2-phenylethyl ether ( 195 mg, 0.65 m M), pyridine ( 0 4 ml, 4 96 m M) and dry pyridine hydrochloride ( 4 g, 34 6 m M) is heated at 190 C for 6 hours The reaction mixture is cooled and added to a mixture of water ( 100 ml) and ether ( 150 ml) The ether extract is washed once with water ( 50 ml) and, along with a second ether extract ( 50 ml) of the aqueous 35 phase, is dried over magnesium sulfate and evaporated to an oil The oil is purified via preparative layer chromatography on silica gel plates, eluted six times with 30 % ether-pentane to yield 65 8 mrg ( 37 %) of 2-( 3,5-dihydroxyphenyl)propyl 2-phenylethyl ether.

IR (CHCI 3): 3559, 3279, 1605, 1147, 1105 cm-' 40 m/e 272 (m+) PMR (CDCI 3, 60 M Hz) 8 1 18 (d,J = 7 Hz, CH 3-), 2 80 (t,J = 7 Hz, -CH 2 Ph), 2 80 (H-C-Me), 3 4-3 8 (-CH 2 OCH 2), 6 08 (t,J = 2 Hz, Ar H), 6 21 (d,J = 2 Hz, Ar H) and 7 16 (S,Ph H).

The following compounds are prepared from appropriate alkanols by the 45 methods of Procedures O and P.

1,579,230 OH 0/4 CH 2 (ak 2)-W I, CH 3 (alk 2) W (CH 2)6 CH 3 À-(CH 2)6- C 6 H 5 -(CH 2)4 CH 3 5 -CH(CH 3)CH 2 CH 3 -CH(CH 3)(CH 2)4 CH 3 (CH 2) 4-F Ce H 4 (CH 2)2 4-pyridyl (CH 2)2 2-piperidyl 10 -CH(CH 3)CH 2 4-piperidyl (CH 2)2 CH(CH 3)(CH 2)2 CH 3 -CH(CH 3) CH 3 -C(C Ha)2 CH 3 s 5 PREPARATION R 15 4-( 3,S-Dihydroxyphenyl)- 11-phenoxypentane.

Under a nitrogen atmosphere a mixture of 3,5-dibenzyloxyacetophenone ( 50 0 g., 0 15 M) in tetrahydrofuran ( 175 ml) and 3-phenoxypropyltriphenylphosphonium bromide ( 7 18 g, 0 15 M) in dimethylsulfoxide ( 450 ml) is added dropwise over 1 75 hours to a suspension of 50 % sodium hydride ( 7 89 g, 0 165 M),0 (previously washed with pentane) in tetrahydrofuran ( 75 ml) maintained at 0 0-5 C After stirring for 4 hours at O -5 C the reaction is allowed to warm to room temperature and is then carefully stirred into ice water ( 2000 ml), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate ( 5 x 400 ml).

The combined organic phases are washed with saturated sodium chloride solution 25 ( 3 x 300 ml), dried over sodium sulfate and concentrated under vacuum to yield an oil which is triturated with ether to precipitate triphenylphosphine oxide.

Filtration, followed by concentration of the filtrate, gives an oily residue which is chromatographed over silica gel ( 1300 g) eluting with benzene-hexane consisting of 30 % to 100 % benzene From the middle fractions 51 g ( 75 %) of 4-( 3, 5-dibenzyl 30 oxyphenyl)-l-phenoxypent-3-ene is isolated as an oil; R,= 0 8 (silica gel, 2benzene:l-hexane); m/e 450 (m+).

Analysis: Calc'd for C 3,H 300: C, 82 63; H, 6 71 % Found: C, 82 90; H, 6 69 % A solution of 4-( 3,5-dibenzyloxyphenyl)-1 l-phenoxypent-3-ene ( 51 g, 0 113 M) 35 in a mixture of absolute ethanol ( 160 ml), ethyl acetate ( 160 ml) and concentrated hydrochloric acid ( 0 2 ml) is hydrogenated for 12 hours under 55 lbs hydrogen in the presence of 10 % Pd/C Removal of the catalyst by filtration and concentration of the filtrate under vacuum yields 30 8 g ( 100 %) of product as a viscous oil.

Analysis: Calc'd for C,7 H 20 O: C, 74 97; H, 7 40 % 40 Found: C, 74 54; H, 7 45 % 1,579,230 1,579230 6 flU PREPARATION S.

3,5-Dimethoxy-/3-mnethvlstyrene oxide.

To a -78 C solution of diphenylsulfonium ethylide ( 1 0 mole) in tetrahydrofuran (one liter) is slowly added 3,5-dimethoxybenzaldehyde ( 1 0 mole).

The reaction mixture is stirred at -78 C for 3 hours and then allowed to warm to 5 room temperature It is then added to ether-water and the ether phase separated.

The ether phase is washed with water, dried (Mg SO 4) and evaporated Fractional distillation of the residue gives the title product.

PREPARATION T.

3-( 3,5-Dihydroxyphenyl)-2-propylbutyl Ether 10 To a solution of sodium butoxide min butanol ( 0 5 liters of IM) is added 3,5dimethoxy-p-methylstyrene oxide ( 6 33 M) The mixture is heated for 18 hours at C and is then cooled and added to a mixture of ether-water The ether solution is separated, dried (Mg SO 4) and evaporated to give 3-( 3,5dimethoxyphenyl)-3hydroxy-2-propyl butyl ether It is purified by column chromatography on silica gel 15 with ether-pentane elution.

By means of the procedure of Preparation P the title product is produced.

Similarly, the following are prepared from appropriate alcohols.

OH C H 3 o 7 CH % A /c 2Ho-(ak 2)-W 2 (alk 2) W 20 CH 2 CH 3 (CH 2)8 CH 3 (CHJ, C 6 Hs (CH 2)2 4-FC 8 H 4 (CH 2)2 4-pyridyl 25 CH(CH 3)CH 2 CH 3 CH(C 2 Hs)-(CH 2)2 CH 3 CH(CH 3)CH 2 C 6 Hs PREPARATION U.

Alkylation of 3,5-Dihydroxyphenylmercaptan 30 A solution of 3,5-dihydroxyphenylmercaptan ( 3 5 g, 0 01 mole) in absolute ethanol ( 50 ml) is made just alkaline with sodium ethoxide The appropriate bromide of formula Br (alk 2)n-W ( 0 01 mole) is added and the mixture refluxed for 3 hours It is then concentrated under reduced pressure and the residue extracted with ether Evaporation of the ether affords the product 35 The following compounds are thus prepared:

1,579,230 An OH HO (a)k 2) W n (alk,) W 1 -CH(CH)(CH 2)ti CH 3 -CH(CHI)CH(CHI)(CH 2)1 CHI -C(CH 3)2 (CHI)5 CH 3 5 -(CH 2) CH 3 c H ' 1 -CH 2 C,,H, 1 -(CH 2)2 C'^ -CH(CH)(CH 2):3 C^ 10.

-CH 2 C^ 1 -CH 2 C',H, 1 -CH 2 COH 11 1 (CH 2)2 C^ 1 5 1 (CH 2)1 C'H, 1 5 1 (CH 2)r, COH 11 (CH 2)4 C'H, -(CH 2)ICH(C 2 Hr,) C 6 Hil (CH)7 C^ 1 (CH 2)4 C 7 H 13 20 1 (CH 2)2 C 7 H 13 1 -(CH 2)5 C 1 H 7 C 3 H 5 (CH 2) 2-piperidyl -(CH 2)3 4-piperidyl 25 1 (CH 2) 2-pyridyl 1 (CH 2)1 3-pyridyl 1 (CH 2)4 2-pyridyl 1 -CH(CH 3)(CH 2)1 2-pyridyl 1,579,230 n (alk 2) W -CH(CH 3)(CH 2)3i -CH(C 2 H 5)(CH 2)2I -H-(CH 2)4I -CH(CH 3)(CH 2)2I -CH(CH 3)(CH 2)34-pyridyl 4-piperidyl 4-FC 6 H 4 4-CIC 6 H 4 4-FCH 4 C 6 H 5 4-FC 6 H 4 4-CIC 6 H 4 C 3 H 5 C 5 H 9 C 6 Hll C 7 H 13 4-pyridyl 2-piperidyl 2-pyridyl 2-(C Hs)C 3 H 4 4-(C Hj)C 6 H 1 o 3-(C 6 Hs)C 7 H 12 CH 3 PREPARATION V.

3-Hydroxy-5-pentylaniline.

Olivetol ( 1 8 g, 0 01 M), ammonium chloride ( 2 65 g, 0 05 M), sodium bisulfite ( 5.2 g, 0 05 M) and ammonium hydroxide ( 12 5 ml) are combined and heated in a steel bomb at 230 C for a half-hour The bomb is then cooled, the contents dissolved in ethyl acetate ( 350 ml) Hydrochloric acid ( 300 ml of 10 %) is added, the mixture stirred and then the organic layer separated The extraction is repeated two more times The aqueous acid solution is neutralized with 6 N sodium hydroxide and then extracted with chloroform ( 3 x 300 ml) The combined chloroform extracts are dried and concentrated The residue is taken up in ethyl acetate, decolorized 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 hot ethyl acetate-hexane ( 1-I) it melts at 95 -96 C.

Analysis: Calc'dfor C 1,H 17 ON: C,73 70; H,9 56; N,7 81 o Found: C, 73 64; H,9 62; N,7 91 % In like manner, the compounds of Preparations C, D, E, K, M, Q, R, T, U and CC are converted to the corresponding aniline derivatives having the formula wherein Z and W are as defined in said Preparations.

PREPARATION W.

d,I-N-Acetyl-3-hydroxy-5-( 5-phenyl-2-pentyl)aniline.

A solution of 2 4 g ( 9 5 mmole) d,l-3-hydroxy-5-( 5-phenyl-2-pentyl) aniline in 5 24 ml pyridine and 24 ml acetic anhydride is stirred at room temperature for 45 minutes The reaction mixture is poured onto 200 ml each of water and ethyl acetate After stirring for 10 minutes, the organic layer is separated and washed successively with water ( 4 x 100 ml), brine ( 1 x 100 ml), dried (Mg SO 4), filtered and concentrated to yield 3 5 g of crude d,l-N-acetyl-3-acetoxy-5-( 5phenyl-2 10 pentyl)aniline A solution of d,l-N-acetyl-3-acetoxy-5-( 5-phenyl-2-pentyl) aniline and I g potassium carbonate in 100 ml methanol is stirred at room temperature for one hour, filtered, concentrated and dissolved in ethyl acetate The organic solution is washed with water, dried (Mg SO 4) and concentrated to an oil which is crystallized from hexane to yield 1 5 g d,l-N-acetyl-3-hydroxy-5-( 5phenyl-2 15 pentyl)aniline, m p 128 -130 C.

m/e 297 (m+) TMS H NMR ( 60 M Hz) 8 CDC 13 (ppm): 8 64 (bs, IH, -NH), 7 12, 6 58 and 6 45 (bs, IH variable, Ar OH), 2 19-2 78 (m, 3 H, Ar-CH and Ar-CH 2), 2 05 (s, 3 H, CH 3-C(=O)-), 1 3-1 78 (m, 4 H, (CH 2)2), 1 12 (d, 3 H, -C-CH 3) 20 PREPARATION X.

d,l-3-Benzyloxy-5-( 5-phenyl-2-pentyl)aniline.

To a stirred solution of 1 2 g d,l-N-acetyl-3-hydroxy-5-( 5-phenyl-2pentyl)aniline ( 4 03 mmole) in 50 ml tetrahydrofuran is added 193 mg of 50 % sodium hydride ( 4 03 mmole) After 30 minutes of stirring, 1 38 g ( 8 06 mmole) of 25 a-bromotoluene is added and stirring continued for 16 hours The reaction mixture is then filtered, I ml of acetic acid added to the filtrate which is then concentrated and chromatographed (silica gel, benzene/ether l 2:1 l as eluant) to yield 1 43 g d,lN-acetyl-3-benzyloxy-5-( 5-phenyl-2-pentyl)aniline as an oil.

m/e 387 (m+) 30 HNM ( O z;TMS H NMR ( 60 M Hz) MCD CI (ppm): 7 88 (bs, IH, N-H), 7 38, 7 20, 6 84, 6 59 (bs, 5 H, 6 H, IH, IH, aromatic), 5 0 (s, 2 H, -O-CH 2 Ar), 2 21-2 98 (m, 3 H, Ar-CH and Ar-CH 2), 2 07 (s, 3 H, CH 3-C(=O)-N), 1 30-1 69 (m, 4 H, -(CH 2)2), 1 15 (d, 3 H, CH 3-C-Ar).

A solution of 1 4 g d,l-N-acetyl-3-benzyloxy-5-( 5-phenyl-2-pentyl) aniline, 14 35 ml 20 % potassium hydroxide, 14 ml methanol and 10 ml 2-propanol is heated at reflux on a steam bath for 4 days After cooling, water and ethyl acetate are added and the mixture stirred for 10 minutes The organic phase is separated and the aqueous phase extracted again with ethyl acetate The organic solutions are combined, dried (Mg SO 4), concentrated in vacuo and chromatographed ( 35 g silica 40 gel, benzene/ether l 3:1 l as eluant) to yield d,l-3-benzyloxy-5-( 5phenyl-2-pentyl)aniline as an oil.

m/e 345 (m+) H NMR ( 60 M Hz), SCDCI (ppm): 7 32 (bs, 5 H, aromatic), 7 13 (bs, 5 H, aromatic), 6 01-6 33 (m, 3 H, aromatic), 4 95 (s, 2 H, Ar CH 2 O), 3 48 (bs, 2 H 45 variable, NH 2), 2 17-2 88 (m, 3 H, Ar-CH and Ar-CH 2), 1 32-1 76 (m, 4 H, (CH 2)2), 1 14 (d, 3 H, -C-CH 3).

1,579,230 Following the procedures of Preparations W and X, the 3-hydroxy-5-(Z-W)anilines of Preparation V are converted to 3-benzyloxy-5-(Z-W)anilines wherein Z and W are as defined in Preparation V.

PREPARATION Y.

d,l-3-Metho xy-5-( 5-pheny 11-2-pentyl)aniline 5 The procedures of Preparations W and X are repeated but using methyl bromide in place of a-bromotoluene to give the title product.

Similarly, the compounds of Preparation V are reacted with methyl bromide or ethyl bromide to give compounds having the formula 9 Yt 10 M Z-X 4 wherein Z and W are as defined in Preparation V and Y is methyl or ethyl.

PREPARATION Z.

3,5-Diethoxvaniline.

A mixture of 3-ethoxy-5-hydroxynitrobenzene ( 8 7 g), diethyl sulfate ( 9 1 g), potassium carbonate ( 7 4 g) and toluene ( 200 ml) is heated at reflux for four hours 15 The toluene is removed by steam distillation and the residue cooled The solid product 3,5-diethoxy nitrobenzene is recovered by filtration and dried.

The solid ( 11 g) is dissolved in glacial acetic acid ( 100 ml) and water ( 100 ml).

Tin (I g) is added, followed by a solution of stannous chloride ( 7 g) in concentrated hydrochloric acid ( 70 ml) The mixture is stirred vigorously and held 20 at 40 C for six hours It is then made alkaline with sodium hydroxide and extracted with ether ( 3 x 100 ml) The combined extracts are dried (Na 2 SO 4) and evaporated to give the product It is purified by vacuum distillation.

PREPARATION AA.

( 2-Halophenyl)cycloalkanols 25 The procedure of Huitric et al, J Org Chem, 23, 715-9 ( 1962) is employed but using the appropriate cycloalkylene oxide and p-halo (Cl or F) phenyl lithium reactants to produce the following compounds.

H OH H\ o H /-"-c/ __ (XH),a \C HX a X a X 30 2 Cl 2 F 3 Cl 3 F Cl 5 F PREPARATION BB.

( 4-Halophenyl)cyclohexanols 35 A 3 and 4-( 4-Fluorophenyl)cclohexanolh.

A benzene solution containing equimolar amounts of 4-fluorostyrene and 2methoxybutadiene and hydroquinone ( 1 % by weight based on diene) is heated in a sealed tube at 150 C for 10 hours The reaction vessel is cooled, the contents 1,579,230 removed and concentrated to give l-methoxy-4 (and 5)-4-(fluorophenyl) cycloheptene which are separated by distillation in vacuo Hydrolysis of the ether with 3 % hydrochloric acid affords 3 and 4-( 4-fluorophenyl)cyclohexanones.

Sodium borohydride reduction of the ketones according to the procedure of Example 31 affords the hydroxy compounds 5 In like manner, the corresponding 3 and 4-( 4-chlorophenyl)cyclohexanols are prepared from 4-chlorostyrene.

B 2-( 4-Fluorophenyl)cyclohexanol.

This compound is prepared from cyclohexane oxide and p-fluorophenyl lithium according to the procedure of Huitric et al, J Org Chem, 27, 7159 10 ( 1962), for preparing 2-( 4-chlorophenyl)cyclohexanol.

PREPARATION CC.

Alkylation of 3,S-Dihydroxyphenylmercaptan.

A solution of 3,5-dihydroxyphenylmercaptan ( 3 5 g, 0 01 mole) in absolute ethanol ( 50 ml) is made just alkaline with sodium ethoxide The appropriate 15 bromide of formula Br-(alk 2)n-W ( 0 01 mole) is added and the mixture refluxed for 3 hours It is then concentrated under reduced pressure and the residue extracted with ether Evaporation of the ether affords the product.

The following compounds are thus prepared:

OH 20 HO S (alk 2) -W n (alk 2) W I -CH(CH 3)(CH 2)B H I -CH(CH 3)CH(CH 3)(CH 2)4 CH 3 1 -C(CH 3)2 (CH 2)5 CH 3 1 (CH 2)8 CH 3 25 i -(CH 2) CH 3 I -CH 2 C 8 H 5 i -(CH 2)2 C 6 H 5 I -CH(CH 3)(CH 2)3 C 6 Hs I -CH 2 C 3 Hs 30 I CH 2 Cs H^ I -CH 2 Call,' I (CH 2)2 C 5 H 9 l (CH 2)5 Cell.

1 -(CH 2)4 Cs H 9 35 I -(CH 2)3 CH(C 2 Hs) C 6 H 11 I -(CH 2), Cs H 9 1,579,230 1,579,230 n (alk,) W 0 -(CH,),(CH 2)2(CH 2)5-(CH 2)5(CH 2)(CH 2)z,(CH 2)(CH 2)1(CH,), -CH(CH)(CHI-CH(C Hj(CHI-CH(C 2 H,)(CH 2)2(CH 2) _ -CH(CH,)(CHI-CH(CHYCHIC 7 H 13 C 7 H 13 CH 7 C^ 2-piperidyl 4-piperidyl 2-pyridyl 3-pyridyl 2-pyridyl 2-pyridyl 4-pyridyl 4-piperidyl 4-FC,H, 4-CIC,H, 4-FC^ CH, 4-FC,H, 4-CICH, CH, CH COH 11 C 7 H 13 4-pyridyl 2-piperidyl 2-pyridyl 2-(C H X 3 H.

4-(C,Hj C H 1.

3-(C H 5 K 7 H 12 CH 3 is is PREPARATION DD.

d,l-5-Phenyl-2-Pentanol Mesylate.

To a stirred solution of 5-phenyl-2-pentanol ( 482 g; 2 94 moles) in tetrahydrofuran ( 2250 ml) at O C is added methanesuffonyl chloride ( 300 ml) at such a rate that the internal temperature does not rise above 10 C (total addition time 4 5 5 hours) After 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 supernate concentrated to a light yellow oil ( 2800 g) which is dissolved in chloroform ( 2 1) and washed with water ( 4 x I I), brine (I x I 1), charcoal treated ( 50 g) dried (Mg SO 4), filtered through diatomaceous earth and 10 concentrated to a light orange oil ( 687 g, 95 % yield) This material is suitable for use without further purification.

H MR( 60 M) TMS H NMR ( 60 MH Iz) TSCDCI (ppm): 7 23 (s, 5 H, aromatic), 4 53-5 13 (m, IH, -CH-O-), 2 93 (s, 3 H, O-SO 2-CH 3), 2 42-2 93 (m, 2 H, -CH 2 C^H 5), 1 50-1 92 (m, 4 H, (CH 2)2-), 1 23 (s, 3 H, O-CH CH 3) 15 Similarly, the following mesylates are prepared from appropriate alcohols:

4-phenylbutanol mesylate, a yellow oil.

m/e 228 (m+) H NMR ( 60 M Hz) SCDC (ppm): 7 22 (bs, 5 H, aromatic), 4 08-4 34 (m, 2 H, -CH 2-O-), 3 93 (s, 3 H, SO 2 CH 3), 2 40-2 82 (m, 2 H, -CH 2 CH 6), 20 1.51-1 93 (m, 4 H, -(CH 2)2-).

1-2-octanol mesylate, a colorless oil.

latl 25 = -9 695 (C 2 6, CHCI 3) H NMR ( 60 M Hz) MCD Ci (ppm): 4 79 (bg, IH, -CH-O-), 2 97 (s, 3 H, S-CH 3), 1 40 (d, 3 H, CH 3-CH), 0 87 (t, 3 H, CH 3-CH 2), 1 0-2 0 (m, 10 H, 25 (CH 2)5).

d-2-octanol mesylate.

lal 25 = + 9 238 (C = 2 8, CHCI 3) H NMR, identical to the 1-form.

Claims (1)

1. WHAT WE CLAIM IS: 30

   I A compound having the formula:

   0 1 R 4/ Nz-W R 5 R 6 wherein Y is selected from hydrogen, benzyl, methyl and ethyl; R 4 is selected from hydrogen, alkyl having from I to 6 carbon atoms and 35 (CH 2),-CH 5 wherein z is an integer from I to 4; R 5 is selected from hydrogen, methyl and ethyl; R, is selected from hydrogen and formyl; Re is selected from hydrogen, (CH 2)v-carbalkoxy having from one to four carbon atoms in the alkoxy group and wherein y is 0 or an integer from I to 4, 40 carbobenzyloxy, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to six carbon atoms, (CH 2)x-C 6 H 5 and -CO(CH 2)x_ 1-C 6 Hs; wherein x is an integer from I to 4; Z is selected from (a) alkylene having from one to nine carbon atoms; 45 (b) (alk,)m-X (alk 2)n wherein each of (alk 1) and (alk 2) is alkylene having 1,579,230 from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alk,) plus (alk 2) is not greater than nine; each of m and N is O or 1; X is selected from 0, S, SO and SO 2; and W is selected from hydrogen, methyl, pyridyl, piperidyl, wherein W 1 is selected from hydrogen, fluoro and chloro; and K (CH 2)a' -CH CH-W 2 (c H 2)bj wherein W 2 is selected from hydrogen and W 1}W Q a is an integer from I to 5 and b is 0 or an integer from I to 5; with the proviso that 10 the sum of a and b is not greater than 5.

   STEVENS, HEWLETT & PERKINS, Chartered Patent Agents, Quality Court, Chancery Lane, London, W C 2.

   Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1980.

   Published by the Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.

   1.579230 O R