CA1050985A

CA1050985A - Substituted-phenyl substituted-alkyl ethers and the preparation thereof

Info

Publication number: CA1050985A
Application number: CA228,557A
Authority: CA
Inventors: Takashi Kamiya; Yoshihisa Saito
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1974-06-04
Filing date: 1975-06-04
Publication date: 1979-03-20
Also published as: AU8185575A; CH613940A5; DE2524865A1; DK248875A; FR2273518A1; FR2273518B1; GB1503953A

Abstract

ABSTRACT OF THE DISCLOSURE
The disclosure relates to substituted-phenyl substituted-alkyl ethers of the formula:

wherein R1 is lower alkyl, cycloalkyl, aryl, ar(lower) alkyl, a heterocyclic group or a group represented by the formula:

wherein R3 and R4 are each hydrogen or lower alkyl, R5 is carboxy, esterified carboxy or hydroxymethyl and A
is lower alkylene:
R2 is hydrogen, lower alkyl, cycloalkyl, aryl, ar(lower)alkyl, a heterocyclic group or a group represented by the formula:
wherein R3, R4, R5 and A are each as defined above:
R3, R4, R5 and A are each as defined above; and R6 is hydrogen, hydroxy or lower alkoxy; in which the aryl or the ar(lower)alkyl for R1 and R2 may be substituted with halogen, hydroxy or lower alkoxy, and when R1 and R2 are both lower alkyl, R1 and R2 may be linked together; and pharmaceutically acceptable salts thereof. These ethers have hypolipidemic activity.
Processes for preparing these compounds are also disclosed.

Description

:~05~98S
The preqent invention relates to new substituted-phenyl substituted-alkyl ethers and pharmaceutically acceptable ~alts thereof, which have hypolipidemic activity, and to processes for the preparation thereof.
The new sub~tituted-phenyl substituted-alkyl ethers of the present invention are represented by t.he formula:

N-A ~ 0_¦3R5

2 ~ R4 (I) wherein Rl is lower alkyl, cycloalkyl, aryl, ar(lower)alkyl, a heterocyclic group or a group represented by the formula:

0 -A ~ I R5 wherein R3 and R4 are each hydrogen or lower alkyl, RS i9 carboxy, esterified carboxy or hydroxymethyl and A
i9 lower alkyle~e, R~ is hydrogen, lower alkyl, cycloalkyl, aryl, ar(lower)alkyl, a heterocyclic group or a group represented :
by the formula: ~:

-A ~ 1 5 wherein R3, R4, R5 and A are each as defined abo~e, R3, R4, R5 and A are each as defined above: and R~ is hydrogen, hydroxy or lower alkoxy: in which the aryl or the ar~lower)alkyl for Rl and R2 may be substituted with halogen, hydroxy or lower alkQxy: or Rl and R2 may be linked together, and pharmaceutically acceptable salts thereof.
The invention is especially concerned with ethers of formula (I), in which Rl i~ (Cl-C4)-alkyl, (C5-C7)cycloalkyl, phenyl, benzyl, pyridyl, benzothiazolyl or a group represented by the formula:

-A- ~ O-C-R5 wherein R3 and R4 are each hydrogen or (Cl-C4)-~S~9~35 alkyl, R5 is carboxy, (Cl-C4~alkoxy-carbonyl or hydroxymethyl and A i~ (Cl-C4)alkylene, R2 is hydrogen, (C1-C4)alkyl, (C5-C7)-cycloalkyl, phenyl or benzyl, R3, R4, R5 and A are each as defined above; and R6 is hydrogen, hydroxy or (Cl-C4)alkoxy, in which the phenyl for Rl and R2 may be ~ubstituted with (Cl-C4)-alkyl, halogen, hydroxy or SCl-C4)alkoxy, or Rl and R2 are linXed together with the nitrogen atom to which they are connected to form a pyrrolidinyl group.
In another aspect the invention is concerned with a process for producing the ethers of formula (I) and especially with the preparation of the above particularly defined group of ethers, compri3ing processes A to J, as described in greater detail hereinafter.
In this ~pecification, it i~ to be understood that the la -.

~ 8 5 term "lower" used in connection with the moieties derived from alkane such as alkyl or alkylene is intended to mean a g~oup having 1 to 6 carbon atom(s) unless otherwise indicated.

The switable example of lower alkyl may be one having 1 to 6 carbon atom~s) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, and preferably one having 1 to 4 carbon atom~s).

The suitable example of cycloalkyl may be one having 3 ;
to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopenty:L, cyclohexyl, cycloheptyl or the like, and preferably one having 4 to 6 carbon atoms.
:-The suitable example of aryl may be one having 6 to 10 carbon atoms such as phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl or the like, and preferably one having 6 to 8 carbon atoms.

The suitable example of ar(lower)alkyl may be one having 7 to 10 carbon atoms such as benzyl, phenethyl, talylmethyl, xylylmethyl, mesitylmethylJ cumenylmethyl or the like~ and preferably one having 7 to 8 carbon atoms~

The aryl or ar~lower)alkyl mentioned above may be optionally substituted with halogen ~e.g., chlorine, bromine, fluorine or iodine),hydroxy or lower alkoxy, wherein such substituents may be same or dlfferent ones more than 2.

.
The suitable example of lower alkoxy may be one having .. . .... . . - , 9~5 :, 1 to ~ carbon atom(s), such as methoxy, ethoxy, propoxy, isopYopoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, and preferably one having 1 to 4 carbon atom(s), and more preferably one having 1 to 2 carbon atom(s).

The heterocyclic group includes mono- or polycyclic heterocyclic groups which contain at least one hetero atom selected from the group consisting of oxygen, sulfur, nitrogen and the like.
The suitable example of the heterocyclic groups may be 3 to 8-membered heteromonocycle containing a sulfur atom ~e.g. thienyl, ~tc.), a condensed-heteroc~cle containing a sulfur atom (e.g.
benzothienyl, etc.~, a 3 to 8-membered heteromonocycle containing an oxygen atom (e.g. furyl, pyranyl, etc.), a condensed-heterocycle containing an oxygen atom (e.g. isobenzofuranyl, chromenyl9 xanthenyl, etc.), a 3 to 8-membered heteromonocycle containing 1 to ~ nitrogen atom(s) (e.g. 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, etc.), a condensed-heterocycle containing 1 to 3 nitrogen atomts) (e.g. indolyl, iso-indolyl, indazolyl, quinolyl, isoquinolyl, benzotriazolyl, benzimidazolyl, etc.), a 3 to 8-membered heteromonocycle con-taining an oxygen atom and 1 to 3 nitrogen atom(s) (e.g. oxazolyl, isoxazolyl, oxadiazolyl, etc.), a condensed-heterocycle containing an oxygen atom and 1 to 2 nitrogen atom~s) (e.g. benzoxazolyl, benzoxadiazolyl, etc.), a 3 to 8-membered heteromonocycle i containing a sulfur atom and 1 to 3 nitrogen atom~s) ~e.g.
thiazolyl, isothiazolyl, thiadiazolyl, etc.), a condensed-heterocycle containing a sulfur atom and 1 to 2 nitrogen atom(s) (e.g. ~enz~thiazolyl, benzothiadiazolyl, etc.~, and the like.

' '

- 3 -~ O ~ 9 ~ ~
The suitable example of esterified carboxy may be, -for example, lower alkoxycarbonyl having 2 to 7 carbon atoms such as methoxycarbonyl, ethoxycarbonyl~ propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl or the like, and preferably one having 2 to 4 carbon atoms; cycloalkoxycarbonyl having 6 to 8 carbon atoms such as cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl or the like; lower alkenyloxycarbonyl having 3 to 6 carbon atoms such as vinyloxy-carbonyl, l-propenyloxycarbonyl, allyloxycarbonyl, l,l-dimethyl-2-propenyloxycarbonyl, 3-butenyloxycarbonyl or the like; lower alkynyloxycarbonyl having 4 to ~ carbon atoms such as 2-propynyl-oxycarbonyl, l,l-dimethyl-2-propynyloxycarbonyl or the like;
aryloxycarbonyl having 7 to 11 carbon atoms such as phenoxycarbonyl, tolyloxycarbonyl, xylyloxycarbonyl, naphthyloxycarbonyl or the like; ar~lower)alkoxycarbonyl having 8 to 10 carbon atoms such as ~ - ;
benzyloxycarbonyl, phenethyloxycarbonyl, tolylmethoxycarbonyl, xylylmethoxycarbonyl or the like; lower alkoxy(lower)alkoxycarbonyl having 3 to 5 carbon atoms such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, ethoxyethoxycarbonyl or the like; ~.
lower alkylthio(lower)alkoxycarbonyl having 3 to 5 carbon atoms .~ :
such as methylthiomethoxycarbonyl, methylthioethoxycarbonyl, ethylthioethoxycarbonyl or the like; di(lower)alkylamino(lower)-alkoxycarbonyl having 4 to 7 carbon atoms such as dimethylamino- . .
methoxycarbonyl, dimethylaminoethoxycarbonyl, diethylaminoethoxy-carbonyl or the like; aryloxy~lower)alkoxycarbonyl having 8 to 9 :
carbon atoms such as phenoxymethoxycarbonyl, phenoxyethoxycarbonyl ~ -or the like; arylthio(lower)alkoxycarbonyl having 8 to 9 carbon atoms such as phenylthiomethoxycarbonyl, phenylthioethoxycarbonyl :
or the like; aroyl~lower)alkoxycarbonyl having 9 to 10 carbon :
atoms such as benzoylmethoxycarbonyl, toluoylmethoxycarbonyl or .

- 4 --, .
. .

~ ~ ~ 9 ~ S
the like; lower alkaneamido(loweT)alkoxycarbonyl having 4 to 5 carbon atoms such as acetamidomethoxycarbonyl, acetamidoethoxy-carbonyl or the like; or esters -formed by the reaction of carboxy group with 3-hydroxypyridine, 3-hydroxymethylpyridine, 2-hydroxy-methylpyridine-l-oxide, l-methyl-4-hydroxypiperidine, 1~3-propanediol or the like.

The suitable example of lower alkylene may be one having 1 to 4 carbon atom~s) such as methylene, ethylene, methyl-ethylene9 propylene, trimethylene, 2-methyltrimethylene or the like, and preferably one having 1 to 2 carbon atom(s).

In the above definition, when Rl and R2 are both lower alkyl, Rl and R2 may be linked together to form a ring containing a nitrogen atom such as pyrrolidinyl, piperidino, homopiperidino or the like.

The suitable example of pharmaceutically acceptable salts may be salts with an acid such as an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) 9 an organic acid (e.g., acetic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, toluenesul~onic acid, etc.) or the like; and salts with a base, i.e. an inorganic base, ~or example, an alkali metal salt ~e.g., sodium salt7 potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), a salt with an organic base ~e.g., triethylamine~
pyridine, N,N dimethylaniline, etc.) or the like.

The object compound ~I) of the present invention may be prepared by various methods and these methods are illustrated ~5~985 as follows:
(1) Process A: R3 IR3 2a R' R4 , lb~N-A ~/ ~ O-C-R5 (II) (III) (Ia) (2) Process B: IR3 IR3 Rlc~NH + y Ar~O-C-R5 ~ 1C`N-A4~o-C,-R5 R2c ~ R4 R2c ~ R4 R6 R6 :
(IV) (V) (Ib) ~3) Process C: ~R3 13 .
Rld-N=A' ~ O-R4R5 ~ Rld-NH-A ~ O-CI R5 (VI) a) R3 OH(Ic) / C or (4) Process D: R~ CX3 IR3 lf ~ ~ b) R { ~ R
R2d R6 C~IX3 R3 CO R~ 2d R6 (IIa) (VIII) (IX) (Id)

(5) Process E: R3 IR3 e,N-A~,~O-C;COOH ~ Rlf`N-A~o-C~ ;cooR7

6 .
( e) (I~) .:
' .......

'~, ., .. . . ' . .

~13S~985 (6) Proces s F: R3 R3 R6; R2d ~ R4 (Ig) (Ih)

(7) Process G: R3 IR3 R28 ~ R4 R6 (Ii) ~Ij) :

(8)Proc~ss H: R3 R3 13 ;
Rld'-NH2 + Y-A~ O-C-R5 -~ R5- I O ~A N A ~3j O-C-R

(X) (V) ( Ik) :

(9)Process I: R3 13 R . -NH-A~ O C R5 ~ N A~ O -C - R5 (IQ) (Im)

(10) Process J: R3 Rl 3 , N-A~O-C;R5 1l~`N-A~ O C;R5 ( In) ( Io) in which Rl~ R2, R39 R~,R5, R6 and A are each as defined above;
Rla is lower alkyl, cycloalkyl, aryl, ar(lower)alkyl, a heterocyclic . ~ . ~ . , . ' 9~s group or a group represented by the formula: -A ~ OH wherein A
is as defined above;
R2a is hydrogen, lower alkyl, cycloalkyl, aryl, ar(lower)alkyl, a heterocyclic group or a group represented by the formula:- `
-A ~ OH wherein A is as defined above, in which the aryl or the ~
ar(lower)alkyl for Rla and R2a may be substituted with halogen or .
lower alkoxy, and when Rla and R2a are both lower alkyl, Rla and R2a may be linked together, R6 is hydrogen or lower alkoxy;
Y is an acid residue;
R5 is carboxy or esterified carboxy;
Rlb is lower alkyl, cycloalkyl, aryl, ar(lower)alkyl,~ heterocyclic group or a group represented by the formula: -A ~ -,-Rs wherein R3, R4, R5 and A are each as defined above; R~
R2b is hydrogen, lower alkyl, cycloalkyl, aryl, ar(lower)alkyl~ a heterocyclic group or a group represented by the formula:
-AJ~ ~R~R5 wherein R3, R~, R5 and A are each as defined above, . in which the aryl or the ar~lower)alkyl for Rlb and R2b may be substituted with halogen or lower alkoxy, and when Rlb and R2b are both lower alkyl, Rlb and R2b may be linked together; :
RlC is lower alkyl, cycloalkyl, aryl, ar(lower)alkyl or a heterocyclic group;
R2C is hydrogen, lower alkyl, cycloalkyl, aryl, ar~lower)alkyl or a heterocyclic group, in which the aryl or the ar(lower)alkyl for RlC and R2C may be substituted with halogen, hydroxy or lower .
alkoxy, and when RlC and R2C are both lower alkyl, RlC and R2C
may be linked together;
A' is a trivalent residue of saturated aliphatic hydrocarbon group, ~R~d is lower alkyl, cycloalkyl, aryl or ar(lower)alkyl, in which .
the aryl or ~he ar~lower)alkyl for Rld may be substituted with ' : ~ - 8 -~50985 halogen, hydroxy or lower alkoxy;
Rld' is lower alkyl, cycloalkyl, aryl or ar(lower)alkyl;
R2d' is hydrogen, lower alkyl, cycloalkyl, aryl or ar~lower)alkyl, in which the aryl or the ar(lower)alkyl for Rld' and R2d' may be substituted with halogen or lower alkoxy, and when Rld' and R2d' are both lower alkyl, Rld' and R2d' may be linked together;
X is halogen;
Rle is lower alkyl, cycloalkyl, aryl, ar~lower)alkyl or a group represented by the formula: A ~ O-Ç-COOH wherein R3, R4 and A are each as defined above;
R2e is hydrogen, lower alkyl, cycloalkyl, aryl, ar(lower)alkyl or a group represented by the formula: -A ~ O-~-COO~I wherein R3, R4 and A are each as de~ined abore, in which the aryl or the ar~lower)-alkyl for Rle and R2e may be substituted with halogen, hydroxy or lower alkoxy, and when Rle and R2e are both lower alkyl, Rle and R2e may be linked together;
Rlf is lower alkyl, cycloalkyl, aryl, ar~lower)alkyl or a group represented by the formula: A ~ O-C-COOR7 wherein R3~ R4 and A
are each as defined above and R7 is lower alkyl;
R2f is hydrogen, lower alkyl, cycloalkyl, aryl ar(lower)alkyl or a group represented by the formula: -A ~ O-Ç-COOR7 wherein R3~ R
R7 and A are each as defined above, in which the aryl or the ar(lower)alkyl for Rlf and R2f may be substituted with halogen, hydroxy or lower alkoxy, and when Rlf and R2f are both lower alkyl, Rlf and R2f may be linked together;
R2d is hydrogen, lower alkyl, cycloalkyl, aryl or ar~lower)alkyl;
in which the aryl or the ar~lower)alkyl for R2d may be substituted with halogen, hydroxy or lower alkoxy, and.when Rld and R2d are both lower alkyl, Rld and R2d may be linked together;
R8 is a group convertible into carboxy group;

, . .

~ S~9~5 ~:
Rlg is lower alkyl, cycloalkyl, aryl, ar~lower)alkyl, a heterocyclic group or a group represented by the formula: ~A- ~ O-~;R5 wherein~ .
R3, R4, R5 and A are each as defined above, R2g is hydrogen, lower alkyl, cycloalkyl, aryl, ar(lower)alkyl, a heterocyclic group or a group represented by the formula:

A~ O c Rt wherein R3, R4, R5'and A are each as defined above, in which the aryl or the ar(lower)alkyl for Rlg and R2g may be substituted with halogen, hydroxy or lower alkoxy, and when Rlg and R2g are both lower alkyl, Rlg and R2g may be linked together;~:
Rlh is lower alkyl, cycloalkyl, aryl, ar(lower)alkyl,Ra heterocyclic group or a group represented by the formula: -A ~ O-C-CH20H .
wherein R3, R4 and A are each as defined above; 4 R2h is hydrogen, lower alkyl, cycloalkyl, aryl, ar~lower)alkyl, a:
heterocyclic group or a group represented by the formula: .
A ~ -O C CH OH wherein R3, R4 and A are each as defined above, in which the aryl or the ar(lower)alkyl for Rlh and R2h may be :
substituted with halogen9 hydroxy or lower alkoxy, and when Rlh and R2h are both lower alkyl, Rlh and R2h may be linked together;.
Rli is lower alkyl~ cycloalkyl, aryl, ar(lower?alkyl or a group . .
represented by the formula: -A ~ O-C-Rs wherein R3, R4, R5 and A are each as defined above, in whichR4 the aryl or the ar(lower)-alkyl or Rli may be substituted with halogen or lower alkoxy;
Rg is lower alkyl or ar(lower)alkyl;
R6' is lower alkoxy;
Rlj is lower alkyl, cycloalkyl, aryl or ar(lower)alkyl;
R2j is hydrogen, lower alkyl, cycloalkyl, aryl or ar(lower)alkyl, in which the aryl or the ar(lower)alkyl for Rlj and R2i may be substituted with halogen or hydroxy, and when Rlj and R2j are both lower alkyl, Rlj and R2j may be linked together, and R5 is carboxy or esterified carboxy.

- 10 ~
... .. . .

~1) Process A: This process comprises reacting a compound (II) or salts thereof with a compound (III) or salts thereof.

Suitable salts of the compound (II) may be alkali metal salt (e.g., sodium salt, potassium salt, etcO), alkaline earth metal salt (e.g., calcium salt, magn~sium salt, etc.); a salt with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.); a salt with an organic acid (e.g., acetic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, etc.) or the like.

rrhe suitable salts of the compound (III) may be aforementioned alkali metal salt, alkaline earth metal salt~ a salt with an organic base (e.g., trimethylamine, triethylamine, N,N-dimethylaniline, pyridine~ picoline, N~N-dibenzylethylenediamine, etc.) or the like.

The suitable acid residue for Y may be halogen (e.g., chlorine, bromine, fluorine or iodine), alkanesulfonyloxy (e.g., mesyloxy, ethanesulfonyloxy, etc.), arenesulfonyloxy ~e.g., benzene-sul~onyloxy, tosyloxy, 4-bromobenzenesulfonyloxy, ~-chlorobenzene-sulfonyloxy, etc.) or the like.

The present reaction is ~sually carried out in a solvent such as water, ethanol, acetone, methylisobutylketone, dimethylformamide 9 ether, benzene or any other solvent which does not give bad influence to the reaction.

The reaction is preferably carried out in the presence of a base such as an inorganic base, for example, alkali metal , ':

hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide ~e.g., calcium hycLroxide, magnesium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate ~e.g., calcium carbonate, magnesium carbonate, etc.), a]kali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.) or alkali metal hydride (e.g., sodium hydride, potassium hydride, etc.) or the like, or an organic base, for example, alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, e~c.), trialkylamine (e.g., trimethylamine, triethylamine, etc.), triethanolamine, N,N-dimethylamiline~ N,N-dimethylbenzylamine, N-methylmorpholineJ N,N'-dimethylpiperazine, pyridine, quinoline or the like, These bases may be usecl alone or in combination and a liquid base can serve as a solvent as well.

The reaction temperature is not restrictive and the reaction can be carried out at any temperature of room temperature to under heating.

(2) Process B: This process comprises reacting a compound ~IV) with a compound (V) or salts thereof The suitable salts of the compound (V) can be also referred to the ones exemplified for the compound ~III).

The present reaction is usually caTried out in a solvent such as water, ethanol, acetone, ether, d~methylformamide or any other solvent which does not give bad influence to the reaction.

g~5 The reaction is preferably carried out in the presence of a base such as an inorganic base, for example, alkali metal hydride (e.g., sodium hydride, potassium hydride, etc.), alkali m~tal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate~
potassium bicarbonate, etc.), or an organic base, for example, trialkylamine (e.g., trimethylamine9 triethy~amine, etc.) or the like. The compound (IV) can serve as a base as well and a liquid base can serve as a solvent as well.

The reac.tion temperature is not restictive and preEerably carried out under cooling or at room temperature.

The starting compound (V) of the present reaction is novel compound and can be prepared by reacting a compound of the formula:

Z-h~ o- 11 -R5 (XI) R6 RD, wherein R3, R4, R5', R6 and A are each as defined above, Z is hydrogen or hydroxy, or salts thereo-E with a regent which can make Z change into the acid residue.

t3) Process C: This process comprises reducing a compound (VI) or salts thereof.

The suitable salts of the compound (VI) can be also referred to the ones exemplified for the compound (III) ~ ~ 5~ 9 The suitable example of ~rivalent residue of saturated aliphatic hydrocarbon group ~or A' may be lower alkylidyne (e g., methylidyne, ethylidyne, etc.), lower alkanylylidene (e.g. 3 l-ethanyl-2-ylidene, 1-propanyl-2-ylidene, 1-propanyl-3-ylidene, 2-methyl-1-propanyl-3-ylidene, etc.) or the like.

The suitable example o~ reduction used in the present reaction is a reduction with a reducing agent such as alkali metal borohydride (e.g., lithium borohydride~ sodium borohydride, potassium borohydride, etc.), alkali metal aluminum hydridé (e.g., lithium aluminum hydride, etc.), dialkoxyaluminumlithium hydride ~e.g., di-tert-butox~aluminumlithium hydride, dipentyloxyaluminum-lithium hydride, etc ), a catalytic reduction or the like.

The suitable catalys~s used in the catalytic reduction may be platinum catalyst (e.g., platinum wire, platinum plate, platinum spongy, platinum black, platinum oxide, platinum eolloid, etc.), palladium catalyst (e.g., palladîum spongy, palladium blac~, palladium oxide, palladium on barium sulfate, palladium on barium carbonate, palladium on charcoal, palladium on silica gel, palladium colloid, etc.), platinum group metal catalyst (e.g., rhodium on asbestos, iridium, rhodium colloid, luthenium oxide, iridium colloid, etc.), nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel, Urushibara nickel, nickel catalyst formed by decomposition of nickel formate, nickel borate, etc.), cobalt catalyst (e.g., reduced cobalb, Raney cobalt, Urushibara cobalt, etc.), iron catalyst (e.g., reduced iron, Raney iron, etc.), copper catalyst (e.g., reduced copper, Raney eopper,ullmann eopper ete.), zinG eatalyst or the like.

:: . ' ;:,, ' :
..:

~ O S~ 9 ~ 5 The present reaction can be carried out in any solvent which does not give bad influence to the reaction, and, for example9 when the catalylic reduction is employed in the present reaction, the present reaction is preferably carried ou~ in a solvent such as methanol, ethanol, or the like.

The reaction temperature is not restrictive, and the reaction is preferably carried out under cooling or at room temperature.

The starting compound (VI) of the present reaction is novel compound and can be prepared by (a) reacting a compound of the formula:
Rld-N=A' ~ OH (XII) wherein Rld, R~ and A are each as defined aboveg with a compound of the formula:
l3 Y -C - R5' (III) :
. R4 wherein R3, R4, R5 and Y are each as defined above or salts ~ -thereoe, or (b) reacting a compound o the formula:

O=A ~ o- C- R5' (XIII) : 6 ~

wherein R3, R4, R5 , R6 and A' are each as defined above or salts thereof, with a compound of the formula: :
~ Rld-NH2 (X? . :

.; :

~ 8 5 wherein Rld is as defined above.

In the present reaction, when alkali metal aluminum hydride is used as reducing agent, the carboxy or the esterified carboxy group for R5' is changed into hydroxymethyl group in the course of the reaction, and this is also included in the scope of the present reaction.

(4) Process D: This process comprises a) reacting a compound (II ) or salts ~hereof with a compound (VII) in the presence of a a strong base, or b) reacting a compound ~IIa) or salts thereo:E with a compound (VIII) and a compound (IX) in the presence of a strong base.

The suitable example of halogen for X may be chlorine, bromine, fluorine or iodine.
,:
The suitable salts of the compound (IIa) may be alkali metal salt (e.g., sodium salt, potassium sal~, etc.3, acid salt (e.g., hydrochloride, hydrobromide, etc.) or the like.
.
The reaction of the process D-a) is carried out by reacting the compound (IIa) or salts thereof with the compound (VII) in the presence of a strong base.
' '' The present reaction [process D-a] is carried out in `~
the presence of strong base such as alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc ), alkali metal alXoxide, for example, sodium alkoxide ~e.g., sodium methoxide, sodium ethoxide, etc.), po*assium alkoxide (e~g., potassium ~ 16 -. . .. ~ . .. .

~ g85 methoxide, potassium ethoxide, etc.) or the like.

The present reaction is usually carried out in a solvent such as water, methanol, ethanol, acetone3 dioxane, ether, benzene or any other solvent which does not give bad influence to the reaction.

The reaction temperature is not restrictive, and the reaction is preferably carried out at room temperature, under warming or heating. The reaction product is isolated by con~entional methods.

Ihe reaction of the process D-b) is carried out by reacting a compound ~IIa) or salts thereof with a compound ~VIII) and a com~ound ~IX) in the presence o-f a strong base.

The suitable example of strong base can be also referred to the ones exemplified in the process D-a).

The present reaction is usually carried out in a solvent such as water, methanol, ethanol, dioxane, ether, benzene or any other solvent which does not give bad influence to the reaction.
And when the starting compound (IX) is in liquid, the compound (IX) can ser~e as a solvent as well.

The reaction temperature is not restrictive and the reaction is preferably carried out at room temperature, under warming or under heating. The reaction product is isolated by conventional methods.

~ S~985 In the present reaction, the compound ~VIII) is firstly reacted with the compound (IX) to give the compound (VII) and then said compound (VII) ~acts with compound (IIa) to give the object compound (Id) (5) Process E: This process comprises subjectirlg a compound ~Ie) or reactive equivalents thereof to esterification.

The suitable reactive equi~alent of the compound (Ie) may be salt such as acid salt (e.g., hydrochloride, hydrobromide, sulfuric acid salt, etc.), salt with base, for example, salt with organic base (e.g., trimethylamine salt, triethylamine salt, N,N-dimethylaniline salt, pyridine salt, picoline salt, N,N'-dibenzylethylenediamine salt, etc.), salt with inorganic base ~e.g., sodium salt, potassium salt, calcium salt, magnesium salt, etc.), nitrile, acid azide, acid halide, acid anhydride, activated amide, activated ester or the like, and a suitable reactive equivalent ;-can be optionally selected according to the kind of the compound (Ie) to be used practically.

The suitable example of lower alkyl or R7 can be also referred to the ones exemplified for ~he compound (I).

The suitable esterifying agent used in the present reaction may be alcohol of the formula:
R7 - OH ~XIV) wher~in R7 is as defined above, or a compound of the formulao R7-OCQON=C~ (XV) Rll . :

. . .. ... ., .. . .,, ,. . ~ .. , , , . , ., , , . . , . ~ .

~L05~985 wherein R7 is as defined above, Rlo and Rll are each electron withdrawing group.

The suitable electron withdra~ing group may be cyano, carbamoyl, lower alkoxycarbonyl ~e.g., methoxycarbonyl, ethoxy-carbonyl, propoxycarbonyl, butoxycarbonyl, etc.) or the like.

Further lower alkyl halide, di(lower)alkyl sulfate, diazo(lower)alkane, lower alkyl p-toluenesulfonate or the like which has lower alkyl group of R7 as lower alkyl moiety of it can be used as an esterifying agent in the present reaction.

The present reaction is usually carried out in a solvent which does not give bad influence to the reaction. When the alcohol (XIV) is used as an esterifying agent it is convenient to use the alcohol (XIV) serving as a solvent as well.
~ ..
The reaction temperature is not restricti~e and the reaction is preferably carried ou~ at a ~emperature of room temperature to boiling point of a solvent.

In the present reaction when the compound (Ie) is used in a form of free acid, it is preferable to carry out the reaction in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, boron trifluoride, benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, ferric chloride, aluminum chloride, zinc chloride or the like, or a condensing agent such as N,N'-dicyclohexylcarbodiimide, pentamethylene~etene-N-cyclohexylimine, l-alkoxy-l-chloroethylene, tetraalkyl pyrophosphite, 2-ethyl-5-(m-sulfophenyl)lsoxazolium hydroxide intramolecular salt, - 1 9 - ~ . :
. ~ .

5131~85 2-ethyl-7-hydroxybenzisoxazolium salt, ethyl polyphosphate, isopropyl polyphosphate, phosphorous oxychloride 9 phosphorous trichloride, thionyl chloride, oxalyl chloride, L-(4-chlorobenzene-sulfonyloxy)-6-chloro-lH-benzotriazole, strongly acidic ion exchange resin, molecular sieve or the like.

The reaction product is isolated by conventional methods.

The starting compound (Ig) is novel compound and can be prepared by some processes mentioned in this speci~ication.

(6) Process F: This process comprises treating a compound (Ig) by conventional methods.

The suitable group convertible into carboxy group for ~8 includes all groups which can be convertible into carboxy group, the example of which may be ester, acid amide, acid anhydride, nitrile, acid halide, acid azide, or a group formed by reaction of carboxy group with silyl compound [e.g., dimekhyldichlorosilane, bis(trimethylsilyl)ace~amide, etc.] or nonmetal compound ~e.g., titanium tetrachloride, etc.), or the like.

Suitable esters may include, aliphatic esters and esters containing an aromatic or heterocyclic ring.
The suitable aliphatic esters may include saturated or unsaturated, lower or higher alkyl esters which may be branched or which may contain a cyclic ring, such as lower or higher aliphatic esters9 for example, lower alkyl ~e.g., methyl, ethyl, propyl, isopropyl, l-cyclopropylethyl, butyl, tert-butyl, pentyl, tert-pentyl, hexyl, etc ) esters, lower alkenyl (e.g., vinyl, l-propenyly allyl, .

1,1-dimethyl-2-propenyl, 3-butenyl, etc.) esters, lower alkynyl (e.g., e~hynyl, 1,1-dimethyl-2-propynyl, 3-butynyl, ~-pentynyl, etc.~ esters, cycloalkyl ~e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) esters, etc., and lower or higher aliphatic esters containing a nitrogen, sulfur or oxygen atom, for example, lower alkoxy(lower)alkyl(e~g., methoxymethyl, ethoxyethyl, methoxyethyl, etc~ esters, lower alkylthio(lower)alkyl (e.g., methylthiomethyl, methylthioethyl, ethylthioethyl, methylthiopropyl, etc.) esters, di(lower)alkylamino(lower)alkyl (e.g., dimethylamino-ethyl, diethylaminoethyl, dipropylaminomethyl, etc.) esters, lower alkylsulfinyl(lower)alkyl (e.g., methylsulfinylmethyl, ethyl-sulfinylmethyl, etc.) esters, lower alkaneamido(lower)alkyl (e.g., acetoamidomethyl, acetoamidoethyl, etc.) esters, etc.

The suitable esters containing an aromatic ring may include, for example, aryl (e.g. 9 phenyl, xylyl, tolyl, naphthyl, etc.) esters, ar(lower)alkyl (e.g., benzyl, phenethyl, trityl, diphenylmethyl, etc.) esters, aryloxy(lower)alkyl ~e.g., phenoxy-methyl, phenoxyethyl, phenoxypropyl, etc) esters, arylthio(lower~-alkyl (e.g., phenylthiomethyl, phenylthioethyl, phenylthiopropyl, etc.) esters, arylsulinyl~10wer)alkyl (e g., phenylsul~inylmethyl, phenylsul~inylethyl, etc.) esters, aroyl~lower)alkyl (e.g.
benzoylmethyl, toluoylethyl, etc.) esters, etc.

The aliphatic esters and the esters containing an aromatic ring as mentioned above may have 1 to 5 appropriate substituent(s) such as lower alkoxy (e.g., methoxy, ethoxy~propoxy, isopropoxy, butoxy, tert-butoxy, etc.), lower alkanesul~onyl (e.g., mesyl~ ethanesulfonyl, etc.), phenylazo, halogen (e.g., chlorine, bromine, fluorine, etc.), cyano, nitro, hydroxy, etc., exarnples of ..

, . ; . . , ~ : ,, ~ . .' s which are illustrated by mono(or di or tri)halo(lower)alkyl (e.g., chloromethyl, bromoethyl, dichloromethyl, 2,2,2 trichloroethyl, 2,2,2-~ribromoethyl, etc.) es~ers, cyano(lower)alkyl (e.~., cyanomethyl, cyanoethyl, 2-cyano-1,1-dimethylethyl, e~c.) esters, mono~or di or tri or tetra or penta)halophenyl ~e.g., 4-chlorohenyl, 3,5-dibromophenyl, 2,4,5-trichlorophenyl, 2~4,6-trichlorophenyl, pentachlorophenyl, etc.) esters, lower al~anesu:Lfonylphenyl ~e.g. 5 ~-mesylphenyl, 2-ethanesulfonylphenyl, etc.) esters, 2-(or 3- or 4-)phenylazophenyl esters, mono(or di or tri)nitrophenyl (e.g., 4-nitrophenyl, 2,4-dinitrophenyl, 3,4-5-trinitrophenyl, etc.) esters, mono(or di or tri or tetra or penta)halophenyl(lower)-alkyl (e.g., 4-chlorobenzyl, 2,4-dibromobenzyl, 3,4,5-trichloro-benzyl, pentachlorobenzyl, etc.) esters, mono(or di or tri)nitro-phenyl(lower)alkyl (e.g., 2-nitrobenzyl, 4-nitrobenzyl, 3,~,5-trinitrobenzyl, etc.) esters, mono(or di or tri)(lower)alkoxy-phenyl~lower~alkyl ~e.g., 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, etc.)esters,hydroxy and di(lower)alkyl-phenyl(lower)alkyl (e.g., 3,5-dimethyl-4-hydroxybenzyl, 3,5-ditert-butyl-4-hydroxybenzyl, etc.) esters, mono (or di or tri)-nitrophenylthio(lower)alkyl (e.g., 4-nitrophenylthiomethyl, 2,4-dinitrophenylthiomethyl, etc.) esters, mono(or di or tri)halophenyl-thio(lower)alkyl (e.g., 4-chlorophenylthiomethyl, 3,4,5-trichloro-phenylthiomethyl, etc.) esters, mono(or di or tri)nitroaroyl(lower)-alkyl (e.g., 4-nitrobenzoylmethyl, 2,4-dinitrobenzoylmethyl, etc.) esters, mono~or di or tri)haloaroyl(lower)alkyl (e g., 4-chlorobenzoylmethyl, 3,4,5-trichlorobenzoylmethyl, etc.) esters, etc.

And suitable esters may further include esters formed by the reaction of carboxy group with substituted or unsubstituted : . '; : . : , . , , ' ~ ~ ~ 9 8 S
thioalcohol, N-hydroxysuccinimide, N-hydroxyphthalimide, tetra-hydropyranol, 1,3-propanediol, 1-phenyl-3-methyl-5-pyrazolone, 3-hydroxypyridine, 3-hydroxymethylpyTidine, 2-hydroxymethylpyridine-l-oxide, l-hydroxypiperidine, l-methyl-4-hydroxypiperidine, l-hydroxy-2(1~l)-pyridone, dimethylhydroxylamine, diethylhydroxylamine, glycolamide, 8-hydroxyquinoline, oxime, 2-hydroxymethylquinoline-l-oxide, methoxyacetylene, ethoxyacetylene, N,N-dimethyl-393-dimethyl-l-butynylamine, N,N-diethyl-3,3-dimethyl-1-butynylamine, N,N-diethyl-l-butynylamine, 2-ethyl-5-~3-sulfophenyl)isoxazolium hydroxide intramolecular salt, halogeno-9,10-dihydroanthracene (e.g., 1,5,9,9,10-pentachloro-9,lO-dihydroanthracene, 9,9,10-trichloro-9,10-dihydroanthracene, 1,8,9,10,10-pentachloro-9,10-dihydroanthracene, etc.) or the like.

The suitable acid amides may include, for example, N-lower alkyl acid amide (e,g., N-methyl acid amide, N-ethyl acid amide, etc.), N,N-di~lower)alkyl acid amide ~e.g., N,N-dimethyl acid amide, N,N-diethyl acid amide, N-methyl-N-ethyl acid amide, etc.), N-phenyl acid amide, or an acid amide with pyrazole, imidazole, triazol, tetrazol, 4-lower alkylimidazole (e.g., 4-methylimidazole, 4-ethylimidazole, etc,), etc.

The suitable acid anhydricles include, or example, a so-called mixed anhydride with a ~lowerjalkyl phosphate ~e.g., methyl phosphate, ethyl phosphate~ etc.), phosphoric acid halide (e.g., phosphoric acid chloride, phosphoric acid bromide~ etc.), ~
di~lower)alkyl phosphite (e.g., dimethyl phosphite9 diethyl -phosphite, etc.), sulfurous acid, thiosulfuric acid, sulfuric acid, lower alkyl carbonate (e.g., methyl carbonate, ethyl carbonate etc.), hydrazoic acid, saturated or unsaturated lower aliphatic carboxylic ;~

'' , ~,,,", , ", , ", " , "~" , " " , , " ~ , " ,,,, , ,, , , , ~ .. . .. :~ ' -s acid ~e.g., pivalic acid~ pentanoic acid9 isopentanoic acid, ~-ethylbutanoic acid, crotonic acid, valeric acid, propionic acid, etc.), saturated or unsaturate~ halo(lower)aliphatic carboxylic acid (e.g., chloroacetic acid, trifluoroacetic acid9 3-chloro-2-pentenoic acid, 3-bromo-2-butenoic acid, etc.)y substituted lower aliphatic carboxylic acid (e.g., phenylacetic acid, diphenylacetic acid, phenoxyacetic acid9 furanacetic acid, thiopheneacetic acid, etc.), or a symmetric acid anhydride, etc.

As the conventional methods which comprise converting the group R8 of the compound (Ig) into a carboxy group to provide the compound (Ih), there may be included, for example, reduction~
hydrolysis, a method by Usi]lg anhydrous basic catalyst, e~c.

The hydrolysis is carried out by using an acid or a base The suitable acid may be an inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, an organic acid such as formic acid, trihaloacetic acid (e.g., trichlor~acetic acid, tri~luoroacetic acid, etc.), acetic acid, p-toluenesul~onic acid, tri1uoromethanesulfonic acid~ a mixture of hydrochloric acid and acetic acid, acidic ion exchange resin or the like.
In the hydrolysis using acid, when solvent is used, the reaction is usually carried out in hydrophilic organic solvent, water o~ a mixture of water and hydrophilic organic solvent.

The suitable base may be inorganic base, for example, alkaline metal hydroxide such as alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal . .... ~ ' :. . ....

~ 8 5 hydroxide (e.g., magnesium hydroxide9 calcium hydroxide, etc.), alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, etc., an organic base such as trialkylamine (e.g., trimethylamine9 tri-ethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine9 etc., or basic ion exchange resin, etc. The reaction using base is usually carried out in water, hydrophilic sol~ent or a mixture thereof.

In case that the group convertible into carboxy group is activated ester, activated amide, acid anhydride, acid hal;de, acid azide or the like, the hydrolysis reaction is carried out not only under usual conditions, but also milder conditions such as contacting with water.

In case that the group convertible into carboxy group is 2-iodoethyl ester~2,2,2-trichloroethyl ester~ benzyl ester, the reduction is suitably employed in the reaction, and in case that the group convertible into carboxy group is ethynyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester or the like, the reduction may be suitably carried out by using a basic catalyst in an anhydrous condition.

The reduction is carried out by using a combination of metal (e.g., zinc, zinc amalgam, tin, etc.) or chrome salt of acid (e.g., chromium chloTide; chromium aceta~e, etc.~ and acid (e.g., hydrochloric acid, formic acid9 acetic acid, propionic acid, etc.) ~
or by using catalytic reduction or the like. ;~-: ., The suitable catalyst used in the catalytic reduction ' ,.,~
, ... . ....

~ 9 8 S
may be platinum catalyst (e.g., platinum wire~ platinum spongy, platinum black9 platinum oxide9 platinum colloid, etc.~, palladium catalyst ~e.g., palladium spongy, palladium black, palladium oxide, palladium on barium sulfate, palladium on barium carbonate, palladium on charcoal, palladiwn on silica gel, palladium colloid, etc.), nickel catalyst ~e.g., reduced nickel, nickel oxide, Raney nickel, Urushibara nickel etc.) or the like.

The suitable basic catalyst using in an anhydrous condition may be sodium benzenethiolate, ~CH3)2LiCu or the like.

The reaction temperature is not restrictive and optionally selected according to the kind of starting compounds (Ig), reagents,solvents, etc., to be used.

The starting compound ~Ig) is novel compound and can be prepared by some processes mentioned in this specification.

(7) Process G: This process comprises reducing a compound ~Ii).

The present reaction is carried out by reduction with a reducing agent such as alkaline metal aluminum hydride, for example, alkali metal aluminum hydride ~e.g., lithium aluminum hydride, sodium aluminum hydride~ etc.), a~kaline ear~h metal aluminum hydride ~e.g., calcium aluminum hydride, magnesium aluminum hydride, etc.) 9 or by reduction using a combination of an alcohol ~e.g., methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, etc.) and sodium or the like.

The reduction with an alkaline metal aluminum hydride , . ~ . , . ~ i -~ 9 ~ S
is carried out according to a conventional manner in a solvent such as ether, dibutyl ether, tetrahydrofuran, dioxane or the like.

The reduction with an alcohol and sodium is carried out according to a conventional manner.

The starting compound (Ii) is novel compound and can be prepared by some processes mentioned in this specification.

(8) Process H: This process comprises reacting a compound (X) : :
with a compound (V) or salts thereof.

The suitable salts of the compound (V) and reaction conditions are similar to those mentioned in Process B, In the present reaction, it is preferable to use more than 2 molar equivalents of the compound (~) or salts thereof to the compound (X).

In the present reactian the intermediate of the formula:

R dt-NH-A ~ R4 (Ip) wherein Rld 9 R3, R~,,R5 and A are each as defined above, may be obtained in the course of the reaction and the compound (Ip) can be further reacted with the compound (V) or salts thereof to .
produce the object compound (Ik).
. . .

(9) Process I: This process comprises reacting a compound (I~) : . , ,, . .. .~ .

l~S~g~
or salts thereof with a re~gent which is able to introduce a substituent into nitrogen atom of the compound (I~).

The suitable salts of the compound (XQ) can be also referred to the ones exemplified for the compound (II).

The suitable lower alkyl or ar(lower~alkyl for R9 can be also referred to the ones exemplified for Rl and R2 of the compound (I).

The suitable reagent which is able to introduce a substituent into nitrogen atom which can be used in the present reaction may be a compound of the formula:
Rg - Y ~XVI) wherein Rg and Y are each as defined above; a compound of the :
formula: .
Rg - C~10 (XVII) wherein Rg is hydrogen, lower alkyl, aryl or ar~lower)alkyl;
di(lower)alkyl sulfate which has lower alkyl group of Rg as lower alkyl moiety thereo-f, or the like.
More particularly9 the reactions as stated above can be explained as follows. That is, the compound (IQ) is reacted with the compound tXYI) according to a conventional manner so that the substituent, Rg- is introduced to the nitrogen a~om thereof to provide the compound (Im) wherein Rg is as defined above. The compound (I~) is reacted with the compound (XVII) under reductive condition according to a conventional manner so that the substituent, Rg -CH2- is introduced to the nitrogen atom to provide . ;

- . . ,. .

~ ~ ~ 9 ~ 5 the compound (Im) wherein Rg is as defined above.

And, the compound (IQ) is reacted with di(lower)alkyl sulfate according to a conventional manner so that the substituent~
lower alkyl is introduced into the nitrogen atom thereof to provide the co~pound (Im) wherein Rg is lower alkyl.

The starting compound (IQ) is novel compound and can be prepared by some processes mentioned in this specification.

~10) Process J: This process comprises subjecting a compound (In) to dealkylation.

The suitable example of dealkylating agent used in the present reaction may be lower alkanethiol (e.g., methanethlol, ethanethiol, propanethiol, etc.) or alkali metal salts (e.g., sodium salt, potassium salt, etc.) thereof, metal halide (e.g., boron tribromide, boron trichloride,aluminum chloride, aluminum bromide, lithium iodide, etc.) or the like.

The present reaction is usually carried out in a solvent such as dimethyl~ormamide, dimethylsulfoxide, or any other solvent which does not give bad influence to the reaction.

The reaction temperature is not restrictive and the reaction is preferably carried out under warming or heating.

The starting compound (In) of the present reaction is novel compound and can be prepared by some processes mentioned in this speci~ication.

., ,, . -:, ",, ',,. ';' ~ '''','' .,'~.''i` ,'. ,' .. ::'' .',.

~ ~ 5~ 9 ~ S
In the present reaction, when R5 of the compound ~In) is esterified carboxy, the esterified carboxy group may be changed into carboxy group in the course of the reaction, and this is also included in the scope of the present reaction.

In case that, in the processes B, C, E,F or J mentioned above, are obtained the object compounds having a moiety o the formula:

O- I - R5 (XVIII) wherein R3, R4 and R5 are each as defined above and the hydroxy group is in the ortho position of -O-C-Rs group, these group may be linked together, for example, in courses of conventional post-treatment of the reaction mixtures to form a moiety of the formula:

O- C- R4 (XIX) O CO
wherein R3 and R4 are each as defined above, and this conversion and the product therein are also included in the scope of the present invention. Thus obtained product having a moiety of the formula (XIX) also shows a similar pharmacological activity to that of the compound (I). And~ in this case, said product may be treated with a base to give salts of a compound having a moiety of the formula:

~/ ~ O - C- COOH (XX) .

. . . . . . :

wherein R3 and R4 are each as defined above, and this process is also included in the scope of the present invention.

Thus obtained compounds may be converted into pharmaceutically acceptable salt thereof by the conventional methods, if desired.

The substituted-phenyl substituted-a~kyl ethers (I) and pharmaceutically acceptable salts thereof are useful as the therapeutic agents in the treatment of hyperlipemia.

The compounds (I) and pharmaceutically acceptable salts thereof can be administered by the conventional methods, the conventional types of unit dosages or with the conventional pharma-ceutical carriers to produce a hypolipidemic activity ln human beings Thus, they can be used in the form of pharmaceutical ~ - -preparation, which contain them in admixture with a pharmaceutical -~
organic or inorganic carrier material suitable for enteral or parenteral applications. Oral administration by the use of tablets, capsules or in liquid form such as suspensions, solutions or emulsions, or injectional application is particularly advanta-geous. When ~ormed into tablets, the conventional binding and disintegrating agents used in therapeutic unit dosages can be employed. Illustrative of binding agents there can be mentioned glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilica~e and talc. Illustrative o disintegrating agents there can be mentioned corn starch, keratin, colloidal silica and potato starch. When administered as liquids the conventional liquid carriers can be used.
' -. :, .

- 31 - ~

. . . . ..
.. , . . . , . . . ~. . .... . .
, .: . . , . : , . .

9~s The dosage or therapeutically effective quantity of the compounds (I) and their salts for human beings can vary over wide limits such as that of about 10 to 1000 milligrams/day for adult.
The upper limit is limited only bythe de~ree Of effect desired and economic considerations. For oral administration it is to employ from about 5 to 30 milligrams of the therapeutic agent per unit dosage. For injectional use, ~he active ingredient may be employed from 1 to 10 mg per unit dosage. Of course, the dosage of the particular therapeutic agent used can vary considerably, such as the age of the patient and the degree of therapeutic effect desired. By the term pharmaceutical carrier it is intended to include non-therapeutic materials which are conventionally used with unit dosage and includes fillers, diluents, binders, lubricants, disintegrating agents and solvents. Of course, it is possible to administer the novel therapeutics, i.e. the pure compounds, without the use of a pharmaceutical carrier.

Practical and presently-preferred embodiments of this invention are illustratively shown in the following Examples.

~xample 1 ~Process A~
(A) A mixture of 500 mg of 4-(4-chloroanilinomethyl~phenol, 632 mg of ethyl 2-bromo-2-methylpropionate 9 7.5 mQ of methyl isobutyl ketone and 448 mg of potassium carbonate is refluxed under heating for 6 hours. The insolubles are filtered off from the reaction mixture, and the filtrate is washed with water, dried and concentrated. The residue (730 mg) is purified by column chromatography, using 22 g of silica gel and chloroform as a developer to give 410 mg of ethyl2-[4-(4-chloroanilinomethyl)-phenoxy]-2-methylpropionate, mp 58 to 60C.

, ' . . .
(B) To a solution of 0.256 g of sodium in 30 mQ of ethanol is added 2 g of 4-(4-chloroanilinomethyl)phenol, and 2.02 ~ o~
ethyl 2-bromopropionate is further added dropwise at room temperature. The mixture is thereafter refluxed under heating for 5.5 hours. The ethanol is distilled off from the reaction mixture, 20 mQ of wa~er is added to the r~sidue, and the dilu~ed residue is extracted with ether. The extract is washed twice with a saturated aqueous solution of sodium chloride and then dried. After distilling off the solvent from the dried extract, the residue (2.9 g) is puri~ied by column chromatography, using 60 g of silica gel and chloroorm as a developer, to giV3 2.1 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxylpropionate as ~n oily product.
N.M.R. spectrum ~CDCQ3, ~ ) ppm 6.4 - 7.5 (8H, m) 4.77 (lH, q, J=7Hz) 4.23 ~2H, q, J=7Hz) 4.20 (~H, s) 4.1 ~lH, broad s) p, , , ;. - . .
;, 1.57 (3H, d, J=7Hz) 1.22 (3H, t, J=7Hz) (C) A mixture of 1.9 g of 4-(4~chloroanilinomethyl)~2-methoxyphenol, 2.11 g of ethyl 2-bromo-2-methylpropionate 1.5 g of potassium carbonate and 29 ml of methyl isobutyl ketone is refluxed for 2~ hours. To the mixture is further added 705 mg of ethyl 2-bromo-2-methylpropionate and the resulting mixture is further refluxed for 3 hours. The insolubles are ~iltered off and the filtrate is washed with water, dried and concentrated under reduced pressure. The residual oil is purified by column chromatography, using 60 g of silica yel and benzene as a develoFer, to give 1.1 g o~ ethyl 2-[4~(4-chloroanilinomethyl)-2 methoxyphenoxyl -2-methylpropionate, mp 73 to 74C. Infrared absorption spectrum (nujol) 3400, 1735 cm 1. N.M.R.spectrllm (CDC13,~ ) ppm 6.45 - 7.33 (7H, m), 4.25 (2~, q, J=7Hz), 4.20 (2H, s) 3.79 (3H, s), l.S9 (6H, s), 1.30 (3H, t, J=7~1z) (D) The following compounds are obtained by using the similar procedures as those of the above Examples.
~1) Ethyl 2-t4-eth~laminomethylphenoxy)-2-methylpropionate hydrochloride, mp 117 to 119C.
~2) Ethyl 2-[4-(1-pyrrolidinylmethyl)pheTloxy]-2-methyl-- propionate, colorless oil. Infrared absorption spectrum ~liquid film) 1725, 1280, 1230~ 1175, 1135~ 1020 cm 1 -~

(3) Fthyl 2-~4-anilinomethylphenoxy)-2-methylpropionate, ~p 45 to 46C.
(4} Ethyl 2-(4-anilinomethylphenoxy)-2-methylpropionate hydrochloride, mp 158 to 163C.

~ ~ S~ 9 ~ 5 (5) Ethyl 2-[~-~p-anisidinomethyl)phenoxy3-2-methylpropionate hydrochloride, mp 119 to 120C.
(6) Ethyl 2-[4-(4-chloroanilinomethyl)pllenoxy]-2-methyl-propionate hydrochloride, mp 143 to 145C.
(7) Ethyl 2-(4-cyclohexylaminomethylphenoxy)-2-methyl-propionate hydrochloride, mp 140 to 142C.
(8) Ethyl 2-(4-i.sobutylaminomethylphenoxy)-2-methylpropionate hydrochlori.de, mp 118 to 119C.
(9) Ethyl 2-(4-benzylaminomethylphenoxy)-2-methylpropionate hydrochloride, mp 138 to 139C.
(10~ Ethyl 2-[4-(p-toluidinomethyl)phenoxy~-2-methylpropionate hydrochioride, mp 133 to 135C.
tll) Ethyl 2-~4-(3-chloroanilinomethyl)~phenoxy]-2-meth propionate hydrochloride, mp 146 to 148C.
(12) Ethyl 2-[4-{N-(4-chlorophenyl)-N-methylaminomethyl}-phenoxy]-2-methylpropionate, oil.

~ ~ ~ 9 ~ 5 Infrared absorption spectrum (liquid film) 1730, 1280, 1235, 1175, 1140, 1020 cm~l.
(13) 2-[4-(4-Chloroanilinome~hyl)phenoxy]-Z-methylpropionic acid, mp 155 to 158C.
(14) N,N-bis[4-(1-methyl-1-ethoxycarbonylethoxy)benzyl]-ethylamine hydrochloride, mp 164 to 1~5~.
(15) Ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methyl-butyrate hydrochlorode, mp 135 to 137C.
(16) Ethyl 2-[4-{N-benzyl-N-~4-chlorophenyl)aminomethyl}-phenoxy]-2-methylpropionate hydrochloride, mp 137 to 141C.
(17) 2-[4-~4-Chloroanilinomethyl)phenoxy]propionic acid, mp 148 to 149C.
(18) 2-~4-(~-Chloroanilinomethyl)phenoxy]-2-methylbutyr:ic acid, mp 152 to 153C.
(19) 2-[4-{N-Methyl-N-(4-chlorophenyl)aminomethyl}phenoxy~-2-methylpropionic acid, mp 63 to 65C.
(20) 2-~4-{N-Benzyl-N-(4-chlorophenyl)aminomethyl}phenoxy}-2-methylpropionic acid, mp 65 to 67C.
(21) Ethyl 2-[4-(2-benzothiazolylaminomethyl)phenoxy3-2-methylpropionate hydrochloride, mp 219 to 220C.
(22) ~thyl 2-[4-(2-pyridylaminomethyl)phenoxy~-2-methyl-propionate, mp 78 to 79C.

Example 2 (Process B) ~A) (a) A mixture of 20 g of ethyl 2-(p-tolyloxy)-2-methyl-propionate, 17.7 g o N-bromosuccinimide, 0.2 g o benzoyl peroxide and 140 mQ of anhydrous carbon tetrachloride is re-fluxed under heating for 4 hours. After the reaction, the reaction mixture is left to stand for cooling and washed with water.

_ 36 -.. . :,, , ; , . ~ ~, . . :

8~i The carbon tetrachloride layer is dried and then concentrated.
The resul~ing oily product (28 g) is distilled under reduced pressure to give 18.3 g of ethyl 2-(4-bromomethylphenoxy)-2-methyl-propionate, bp 146 to 148C/1-2 mmHg.
(b) 50 mQ of 40% ethanol solution of ethylamine and 4.58 g of potassium carbonate are suspended in 50 mQ of absolute ethanol. Over a period of 1.25 hours, a solution of 10 g of ethyl 2-(4-bromomethylphenoxy)-2-methylpropionate in 20 mQ of absolute ethanol is added dropwise to the suspension with ice-cooling and stirring, and the mixture is stirred for 1 day while being cooled with water. After the reaction, the ethanol is distilled off, water is added to the residue and the diluted residue is extracted three times with benzene. The extract is washed twice with a saturated aqueoussolution of sodium chlori~e ~n~ clried over magnesium sulfate, and the solvent is distilled off.
The resulting 8.87 g of pale yellow oil is subjected to column chromatography with 88 g of silica gel, using 2% methanol-benzene solution first and then 5% methanol-benzene solution for elution.
The solvent is distilled off from the 5% methanol-benzene eluate to give 3.93 g of an oil product, which is then converted to its hydrochloride by using a mixture o~ hydrochloric acid and ethanol, namely 4.1~ g of ethyl 2-(~-ethylaminomethylphenoxy)-2-~ethyl-propionate hydrochloride, mp 117 to 119C.

(B) To 15 mQ of pyrrolidine being ice-cooled and stirred is added dropwise 5.0 ~ of ethyl 2-(4-bromomethylphenoxy)-2-methyl-propionate prepared in the similar manner as in Example 2 (A~ (a), and the mixture is thereafter stirred at room temperature for 30 minutes. An aqueous solution of sodium bicarbonate and ether are added to the reaction mixture for extraction,and the extract is ~ ~ S~ 9 ~ 5 thoroughly washed with water seven to eight times and further extracted twice with dilute hydrochloric acid. The dilute hydrochloric acid extract is washed with ether three times and thereafter basified with an aqueous solution of sodium bicarbonate.
The resulting extract is further extracted twice with ether, and the extract is washed with water twice and then dried over magnesium sulfate. The solvent is distilled off from the extract to give 2.9 g of an oily prod~ct, which is then caused to be adsorbed by 15 g of alumina and is thereafter eluted with benzene.
The solvent is distilled off from the eluate under highly reduced pressure to give 2.63 g of e~hyl 2-[4-(1-pyrrolidinylmethyl)-phenoxy]-2-methylpropionate as a colorless oil. Infrared absorption spectrum ~liquid film) 172S~ 1280, 1230, 1175, 1135, 1020 cm~l.
I

(C) 4.98 g of 2-benzothiazolamine is dissolved in 49 mQ of dimethylformamide, and 1.76 g of 50% sodium hydride is gradually added to the solution with ice-cooling and stirring. The mixture is s~irred at the same temperature for 1.5 hours. To the result-ing solution is added dropwise, with ice-cooling and stirring, a solution of 10.0 g of ethyl 2-(4-bromomethylphenoxy)-2-me~hyl-propionate in 10 mQ of dimethylormamide. The mixture is stirred at the same temperature for 1.5 hours. To the reaction mixture are added 30 mQ of methanol and then water, and the mixture is extrac*ed four times with ekher. The extract is washed with water four times and then dried over magnesium sulfate.
The solvent is distilled off, and the resulting 10.84 g of oily product is purified by column chromatography, using 100 g of silica gel and 2~ methanol-benzene solution as a developer, to give 3.92 g of an oily product. In conventional manner, the oily .. . . ~
. ~. : : . .: . : ~ . . .

9~S

product is converted, with a hydrochloric acid-ethanol solution, to its hydrochloTide, i.e. 2.04 g of ethyl 2-[4-(2-benzothiazolyl-aminomethyl)phenoxy]-2-methylpropionate hydrochloride, mp 193 to 198C. The crystals are recrystallized from 24 mQ of ethanol and collected by filtration to give 1.3 g of a pure product, mp 219 to 220C. On the other hand, the solvent is distilled off from the filtrate. Recrystallization of the residue from 5 mQ
of ethanol, followed by treatment with ac~ivated carbon, gives 0.2 g of a pure product similarly melting at 219 to 220C.

(D) In 62 mQ of dimethylformamide are suspended 6.25 g of 2-pyridinamine and 9.18 g of powdery potassium carbonate. Over a period of 30 minutes, a solution of 20.0 g of ethyl 2-(~-bromomethylphenoxy)-2-methylpropionate in 20 mQ of dimethyl-formamide is added dropwise to the suspension with ice-cooling and stirring. The mixture is stirred at the same temperature for 2 hours. ~ater is added to the reaction mixture, and the resulting mixture is extracted three times with ether. The extract is washed with water and is further subjected to extraction three times with dilute hydrochloric acid. The dilute hydrochloric acid layer is washed with ether, then basified with sodium carbonate and extracted three times with ether. The extract is washed with water twice, thereafter dried over magnesium sulfate and the solvent is distilled off. The resulting 10 g of orange oil is purified by column chromatography with 100 g of silica gel, using chloroform first and then 3% methanol-chloroform as developers, to give 2.3 g of an oily product. After addition of 3 mQ of ether and n-hexane to the oily product, the product is pulverized and then collected by filtration to give 1.52 g of ethyl 2- L4- (2-pyridylaminomethyl)phenoxy]-2-methylpropionate, mp 78 to 7~C.

i, .
" ~ .. . .

~s~9~
An additional 0.07 g of the product is obtained from the mother liquor. Total yield: 1.59 g.

(E) The following compounds are obtained by using the similar procedures as those of the Examples 2 (A) to 2 (~
(1) Ethyl 2-(4-anilinomethylphenoxy)-2-methylpropionate, mp 45 to 46C.
(2) Ethyl 2-(4-anilinomethylphenoxy)-2-methylpropionate hydrochloride~ mp 158 to 163C.
(3) Ethyl 2-~4-tp-anisidinomethyl)phenoxy]-2-methylpropionate hydrochloride, mp 119 to 120C.
(4) Ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methyl-propionate hydrochloride, mp 143 to 145C.
(5) ~thy:l 2-[4-~4-chloroanilinom~thyl)phenoxy]--2-methyl-propionate, oil.
(6) Ethyl 2-(4-cyclohexylaminomethylphenoxy)-2-methyl-propionate hydrochloride, mp 140 to 142C.
(7) Ethyl 2-(4-isobutylaminomethylphenoxy)-2-methylpropionate hydrochloride, mp 118 to 119C.
(8) Bthyl 2-(4-benzylaminomethylphenoxy)-2-methylpropionate hydrochloride, mp 138 to 139C.
(9) Ethyl 2-[4-(p-~oluidinomethyl)phenoxyl 2-methylpropionate hydrochloride, mp 133 to 135C.
(10) Ethyl 2-[4-~3-chloroa.nilinomethyl)phenoxy]-2-methyl-propionate hydrochloride, mp 146 to 148C.

(11) Ethyl 2-[4-{N-t4-chlorophenyl)-N-mekhylaminomethyl}-phenoxy~-2-methylpropionate, oil. Infrared absorption spectrum (liquid film) 1730, 1280, 1235, 11759 1140, 1020 cm 1. ~

(12) 2-[4-~4-Chloroanilinomethyl)phenoxr~-2-methylpropionic :~ :

: 40 .. . . . . ..
. . . , :: :
acid, mp 155 to 158C.

(13) Ethyl 2-14-(4-chloroanilinomethyl)phenoxy]-2~methyl-butyrate hydrochloride, mp 135 to 137C.
~14) 2-[4-~4-Chloroanilinomethyl)phenoxy]-2 methylbutyric acid, mp 152 to 153C.
~15) Ethyl 2-~4-~4-chloroanilinomethyl)phenoxy]propionate, oil. Infrared absorption spectrum (liquid film) 3410, 1740 ~m 1 N.M.R. spectrum ~CDCQ3,~) ;
ppm 6.3 - 7.3 ~8H, m) 4.65 (lH, q, J=7Hz) .15 ~2~, q, J=7~1z) 4.13 ~2~-l, s) 3.6 - 4.0 (lH, broad s) 1.55 ~3~1, d, J=7Hz) 1.20 (3H, t, J~7Hz) tl6) 2-~4-(4-Chloroanilinomethyl)phenoxy~propionic acid, mp 148 to 149C.
(17) Ethyl 2-[4-{N-~4-ch~orophenyl)-N-benzylaminomethyl}-phenoxy~-2-methylpropionate hydrochloride, mp 137 to 1~1C .
~18) 2-[4-{N-~4-Chlorophenyl)-N-benzylaminomethyl}phenoxy]-2-methylpropionic acid, mp 65 to 67C.
~19) 2-[4-{N-(4-Chlorophenyl)-N-methylaminamethyl}phenoxy]-2-methylpropionic acid, mp 63 to 65C.
(20) Ethyl 2-[4-(4-chloroanilinomethyl~-2-methoxyphenoxy~
-2-methylpropionate, mp 73 to 74C.
~21) Sodium 2-[4-(4-chloroanilinomethyl)-2-hydroxyphenoxy]
-2-methylpropionate, mp 121 to 125C.
(22) 3,3-Dimethyl-7-(4-chloroanilinomethyl)-1,4-benzo--. . .
.

1~5~9~5 di.oxan-2-one, mp 97 to 98C.

Example 3 (Process C) _ _ ~A) (a) To 170 mQ of absolute ethanol is added 1.48 g of sodium, and 8.4 g of 4-(N-phenylformimidoyl)phenol is added to the mixture at room temperature with stirring to prepare a solution.

~ 5~185 12.5 g of ethyl 2-bromo-2~methylpropionate is added to the solution, and the mixture is refluxed under heating for 5 hours. After the reac~ion, the e~hanol is distilled off. The residue is dissolved in ether and thereafter washed with 5~ aqueous solution of sodium hydroxide and then with water. After drying the resulting mixture, the ether is distilled off to give 9.2 g of ethyl 2-[4-~N-phenyl-formimidoyl)phenoxy]-2-methylpropionate. Infrared absorption spectrum (liquid film) 1735, 1280, 1245, 1170~ 1140, 1020 cm~l.
(b) In 90 mQ of methanol is dissolved 9.0 g of ethyl 2-[4-tN-phenylformimidoyl)phenoxy]-2-methylpropionate. Over a period of 1.5 hours, 1.1 g of sodium borohydride is added to the solution at 15 to 20C with cooling and stirring, and the mixture is stirred at room temperature for 1 hour. After the reaction, the methanol is distilled o~f under reduced pressure, the residue i5 dissolved in ether, and the ethereal solution is washed with water and dried. Removal of the ether by distillation gives an oily residue (7.7 g~, which partially solidifies when left to stand. The residue is washed with a mixture of benzene and petroleum e~her, and the crystals are collected by filtration to gi~e 1.2 g of ethyl 2-(4-anilinomethylphenoxy)-2-methylpropionate, mp 45 to 46C. The filtrate is concentrated, and the residue is dissolved in ether. Addition of a mixture of hydrochloric acid and ethanol to the solution yields crystals, which are collected by filtration and washed with ether to give 5.2 g of ethyl 2-(4-anilinomethylphenoxy)-2-methylpropionate hydrochloride, mp 158 to 163C. The product is recrystallized twice from isopropanol to give 3.9 g of a pure product, mp 167 to 168C.
Elemen~ary analysis : ClgH23NO3-HCQ
Calcd. C 65.23; H 6.91; N 3.890 Found C 65.05; H 6.90; N 3.90.
:

- : , . :;. - - . . .
. ., . , ~ ~ S~ 9 ~ S
(B) (a) 2.38 g of 50% sodium hydride is suspended in 75 mQ
of anhydrous dimethylformamide, and 7.5 g of ~-[N-(q-methoxyphenyl)-formimidoyl]phenol is added in four portions to the suspension at room temperature with stirring. Subsequently, 9.65 g of ethyl 2-bromo-2-methylpropionate is added dropwise to the resulting mixture at 20 to 25C over a period o~ about 40 minutes. The mixture is stirred at room temperature for 1 hour and then at 50 to 5~C for 2 hours. The reaction mixture is poured into cold water, extracted with ether, and the extract is washed with 5%
aqueous solution of sodium hydroxide until disappearance of the color of the aqueous layer, then washed with water and dried.
After drying, the ether is distilled off to give 7.5 g of ethyl 2-[4-~N-(4-methoxyphenyl)formimidoyl}phenoxy~-2-methylpropionate in the form o an oil.
Inrared absorption spectrum ~liquid film) 1735, 1285, lZ~5, 1170, 1140, 1020 cm~l.
(b) In 75 mQ of methanol is dissolved 7~5 g of ethyl 2-[~-{N-(4-methoxyphenyl)formimidoyl}phenoxy]-2-methylpropionate.
Over a period of 1.5 hours, 0.84 g of sodium borohydride is added to the solution at 15 to 20C with cooling and stirring. After stirring the mixture at room temperature or 1 hour, the methanol is distilled off, and the residue is dissolved in ether. The ethereal solution was washed with water and dried. The ether is distilled off, and the resulting oily residue ~6.3 g) is dissolved in 50 DIQ of ether. A mixture of hydrochloric acid and ethanol is added in excess to the solution. The ether is removed from the resulting mixture until crystals start to precipitate out.
The mixture is left to stand with coollng, and the crystalline precipitate is collected by filtration to give 4.9 g of ethyl 2-[4-(p-anisidinoDIethyl)phenoxy]-2-methylpropionate hydrochloride.

F. - 12 l(~S~ S
The product is recrystallized ~wice from a mixture of isopropanol and isopropyl ether to gi~e 3.6 g of a pure product, mp 119 to 120C.
Elementary analysis : C20H25NO4-HCQ
Calcd. C 63.23; H 6.90; N 3.69.
Found C 63.49; H 7.10; N 3.64.

~C) ~a) 0.312 g of 50% sodium hydride is suspended in 10 mQ
of anhydrous dimethylformamide, and 1.16 g of 4-lN-(4-chlorophenyl)-formimidoyl]phenol is added to the suspension at 20 to 25C with stirring. Subsequently over a period of 15 minutes, 1.27 g of ethyl 2-bromo-2-methylpropionate is added dropwise to the resulting mixture at the same temperature with stirring. The mixture is stirred at the same temperature for 30 minutes, then at 50 to 55C
~or 2 hours and thereafter at 80C for 3 hours. The reaction mixture is poured into cold water, extracted with ether, and the extract is washed with 5~ aqueous solution of sodium hydroxide and then with water. Ater drying, the solvent is distilled off to give 1.5 g of ethyl 2-[4-{N-(4-chlorophenyl)formimidoyl}phenoxy]-2-methylpropionate.
Infrared absorption spectrum (liquid film~
1735, 1280, 1245, 1170, 1140, 1020 cm~l.
(b) In 40 mQ of methanol is dissolved 5.3 g of ethyl 2-~4-{N-~4-chlorophenyl)formimidoyl}phenoxy~-2-methylpropionate.
Over a period of about 1 hour, 0.58 g of sodium borohydride is added to the solution at 20 to 25C with stirring. After stirring the mixture at room temperature for 1 hour, the methanol i5 distilled off, and the residual oil is dissolved in ether. The solution is washed with water and dried, and the ether is there- -;
after distilled off. The resulting oily residue (4.2 g) is .

~ D~ 8 5 dissolved in 20 mQ of ether. A mixture of hydrochloric acid and ethanol is added to the solution. The resulting precipitate is collected by filtration and washed with ether to give 3.9 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionate hydrochloride, mp 139 to 141C. Recrystallization of the crystals from a mixture o-f methanol and ether gives 3.1 g of crystals, mp 143 to 145C. The crystals are suspended in a mixture of ether and water, and the suspension is adjusted ~o pH 8 to 9 by addition of 28% ammonia water. The ether layer is theTeafter separated, washed with water and dried. After drying, removal of the ether by distillation gives 2.9 g of ethyl 2-[4-t4-chloroanilinomethyl)phenoxy]-2-methylpropionate as an oil.
- . '.
~D) (a) To 70 mQ of absolute ethanol is added 872 mg of sodium, and 7 g of 4-~N-cyclohexylformimidoyl)phenol is added to ;
the solution. Subsequently, 7.4 g of ethyl 2-bromo-2-methyl-propionate is further added. The mixture is refluxed under heating and with stirring ~or 15 hours. After distilling off the ethanol from the reaction mixture, water is added to the residue, ;
and the solution is extracted three times with benzene. The extract is washed with water twice, with cooled dilute aqueous solution o sodium hydroxicle three times andthen with water twice.
~fter drying the resulting solution over magnesium sulfate, the solvent is distilled off to give 5.54 g of ethyl 2-[4-(N-cyclohexyl-formimidoyl)phenoxy]-2-methylpropionate as an oil.
Inf~a~ed absorption spectrum (liquid film) 1740, 1280, 1235, 1170, 1020 cm~~
~ b) In 50 mQ of methanol is dissolved 5.54 g of ethyl 2-[4-~N-cyclohexylformimidoyl)phenoxy]-2-methylpropionate, and O.S g of sodium borohydride is gradually added to the solution '''' .' . ." , . .

~ 8 S

with stirring and cooling with water. The mixture is stirred at the same temperature for 1 hour. After the reaction~ the methanol is distilled off, water is added to the residue, and the solution is extracted twice with benzene. The extract is washed with water, then with cooled dilute aqueous solution of sodium hydroxide and thereafter with water, twice respectively. After drying the ;
extract over magnesium sulfate, the solvent is distilled off.
The resulting oily product (6.0 g) is purified by column chromato-graphy with 60 g of silica gel, using chloroform first and then a mixture of 100 mQ of chloroform and 5 mQ o methanol as deve:Lopers.
4.67 g of the resulting oily product is then dissolved in ether.
A mixture of hydrochloric acid and ethanol is added to the solution, and the resultant precipitate is collected by f;ltration to give 4.6 g of ethyl 2-(4-cyclohexylaminomethylphenoxy)-2-methylpropionate hydrochloride,mp 140 to 1~2C. Recrystallization of the crystals from a mixture of 5 mQ of isopropanol and 80 mQ of ether gives 4.0 g of colorless needles, mp 140 to 142C.

(E) (a) To 100 mQ of absolute ethanol is added 0.80 g of sodium, and 5.5 g of 4-(N-isobutylformimidoyl)phenol is added to the solution. Subsequently, 6.78 g of ethyl 2-bromo-2-methyl-propionate is further added. The mixture is refluxed under heating and with stirring for 10 hours. After distilling of-f the ethanol from the TeaCtiOn mixture, water is added to the residue, which is then extracted three times with benzene. The extract is washed with water twice and dried, and the solvent is removed therefrom to give 5.61 g of ethyl 2-[4-(N-isobutylformimidoyl)-phenoxy3-2-methylpropionate in *he form of a pale orange oil.
Infrared absorption spectrum (liquid film) 1741, 1650 cm (b) In 56 mQ of methanol is dissolved 5.61 g of ethyl 2-[4-(N-isobutylformimidoyl)phenoxy]-2-methylpropionate, and 0.6 g of sodium boTohydride is gradually added to the solution with stirring ana cooling with water. After the reaction, the methanol is distilled off under reduced pressure, water is added to the residue, and the diluted residue is extracted three times with ;
benzene. The extract is washed with water twice, then with cooled dilute aqueous solution of sodium hydroxide three times and thereafter with water twice. After drying the resulting solution over magnesium sulfate, the solvent is distilled off. The result-ing oily product ~4.25 g) is dissolved in ether. Addition of a ;
mixture of hydrochloric acid and ethanol to the ethereal solution produces crystals, which are collected by filtration and washed with ether to give 3.6 g of ethyl 2-~4-isobutylaminomethylphenoxy)-2-methy1propionate hydrochloride, 1~ llS to 117C. The product is recrystallized from a mixture of isopropanol and ether to give 2.3 g of a purified product, mp 118 to 119C.
' '' "

(P) (a~ To 50 mQ of absolute ethanol is added 0.573 g of sodium, and S g of 4-(N-benzylformimidoyl)pheDol and then 5.54 g of ethyl 2-bromo-2-methylpropionate are added to the solution under cooling with water. The mixture is refluxed under heating and with stirring for 22 hours. The ethanol is distilled off from the reaction mixture under reduced pressure. After dissolv-ing the residue in 30 mQ of benzene, the insolubles are filtered off. The benzene filtrate is washed with water twice, then dried over magnesium sulfate and thereafter the solvent is distilled off.
6.12 g of the resulting oily product is dissolved in ether. After removing the insolubles from the ethereal solution by filtration, the filtrate is concentrated to give 5.06 g of ethyl 2-~4-(N-' 9~s benzylformimidoyl)phenoxy]-2-methylpropionate in the form of a pale brown oil.
Infrared absorption spectrum (liquid film) 1740, 1285, 1240, 1175, 1140 cm 1.
~ b) In 90 mQ of methanol is dissolved 4.76 g of ethyl 2-[4-~N-benzylformimidoyl)phenoxy~-2-methylpropionate, and 0.4 g of sodium borohydride is gradually added to the solution with stirring and cooling with water. After the reaction, the methanol is distilled off under reduced pressure, water is added to the residue, and the diluted residue is extracted three times with ether. The extract is washed with water twice, then with ice-cooled dilute aqueous solution of sodium hydroxide three times and thereafter with water twice. After drying the resulting solution over magnesium sulfate, the solvent is distilled off. The resulting pale yellow oily product t4.12 g) is dissolved in ether. Addition o~ a mixture of hydrochloric acid and ethanol to the ethereal solution with cooling produces crystals, which are collected by filtration and washed with ether to give 4.14 g of ethyl 2-t4-benzylaminomethylphenoxy)-2-methylpropionate hydrochloride, mp 136 to 138C. The crystals aTe dissolved in 20 mQ of isopropanol, and the solution is treated with activated carbon. Addition of 50 mQ of ether to the resulting solution gi~es 2.9 g of colorless needles, mp 138 to 139C.

~G) ta~ To 50 m~ of absolute ethanol i5 added 0.58 g of sodium, and 4.2 g of 4-~N-(p-tolyl)formimidoyl]phenol and then 7.84 g of ethyl 2^bromo-2-methylpropionate are added to the solution ~ room tempera~ure with stirring. The mixture is refluxed under heating and with stirring for 5 hours on an oil bath. After d~stilling off th~ ethanol from the reaction mixture, the residue . '~ ' ~ .

~ , ~ .~ , . . . . ...
I . . . . . . .. .

1~5~35 is dissolved in ether. The solution is washed with 5% aqueous solution of sodium hydroxide and then with water. After drying the solution, the ether is distilled off, and the residue is further concentrated under reduced pressure on an oil bath at 100C to give 4.0 g of ethyl 2-[4-{N-~p-tolyl)formimidoyl}phenoxy]-2-methyl-propionate as an oily product.
Infrared absorption spectrum (liquid ~ilm) 1735, 1285, 1240, 1160, 1140, 1020 cm~~
(b) In 36 mQ of me~hanol is dissolved 3.6 g of ethyl 2-[4-{N-(p-tolyl)formimidoyl}phenoxy]-2-methylpropionate. Over a period of 40 minutes, 0.42 g of sodium borohydride is added to the solution at 15 to 20C with cooling and stirring, and the mixture is stirred at the same temperature for 1 hour. After the reaction, the methanol is distilled off, and the residue is dissolved in ether. The solution is washed with water and dried. After drying, the ether is distilled of. The resulting oily residue ... ..... .. .
~3.4 g) is dissolved in 30 mQ of ether. A mixture of hydrochloric acid and ethanol is added dropwise to the solution with cooling.
The precipitated crystals are collected by filtration ~nd washed with ether to give 2.6 g of ethyl 2-[4-(p-toluidinomethyl)phenoxy]-2-methylpropionate hydrochloride, mp 126 to 130C.
Recrystallization of the crystals from a mixture of ethanol and isopropyl ether gives 1.7 g of crystals, mp 133 to 135C.

(H) (a~ To 60 mQ of absolute ethanol is added 0.58 g of sodium, and 4.6 g of 4-[N-(3-chlorophenyI)formimidoyl]phenol and then 5.84 g of ethyl 2-bromo-2-methylpropionate are added to the solution at room temperature with stirring. The mixture is refluxed under heating and with stirring for 5 hours. After ~istilling off the ethanol from the reaction mixture, the residue .. . - . . : : .

~ 05~5~85 is dissolved in ether. The solution is washed with 5% aqueous solution of sodi~m hydroxide until disappearance of the color of the aqueous layer, then washed with water and dried. After drying, the solvent is distilled off to give 4.1 g of ethyl 2-[4-{N-(3-chlorophenyl)formimidoyl}phenoxy]-2-methylpropionate.
Infrared absorption spectrum ~liquid film) 1730, 1300, 1280, 1240, 1160, 1140, 1020 cm l.
(b) In 40 mQ of methanol is dissolved 4.0 g of ethyl 2-[4-{N-(3-chlorophenyl)formimidoyl}phenoxy]-2-methylpropionate.
Over a period of 1 hour, 0.44 g of sodiu~ borohydride is added to the solution at 15 to 20C with cooling and stirring, and the mixture is stirred at the same temperatUTe for 1 hour. After the reaction, the methanol is distilled off, and the residue is dissolved in ether. The solution is wash~d with water ancl dried.
A~tor drying, the ether is distilled o-ff, and the resulting oily residue (3.8 g) is dissolved in 30 mQ o ether. A mixture of hydrochloric acid and ethanol is added to the solution, and the resulting mix~ure is left to stand. The precipitated crystals are filtered off and washed with ether to give 3.0 g of ethyl 2-~4-(3-chloroanilinomethyl)phenoxy]-2-methylpropionate hydro-chloride~ mp 138 to 142C. Recrystallization of the crys~als from a mixture of ethanol and ether gives 1.6 g of crystals, mp 146 to 148C.

~I) In 50 mQ of ethanol is dissolved 33.15 g of ethyl 2-[4-{N-~4-chlorophenyl)formimidoyl}phenoxy]propionate prepared from 4-[N-~4-chlorophenyl)formimidoyl~phenol and ethyl 2-bromopropionate -by using the similar manner as that of Example 3 ~C) ~a). With ice-cooling and stirring, the ethanol solution is added dropwise to a solution prepared by adding 3.79 g o~ sodium borohydride to .

. - I
.. . . .. . .. .
. . . .

1~5~8S
150 mQ of ethanol with stirring. The mixture is thereafter stirred a~ room temperature for 1 hour. The reaction mixture is poured into 1.5 Q of water and then extracted with ether. The extract is washed with water and dried over magnesium sulfate. After drying, the solvent is distilled off, and the resulting oily residue (32.50 g) is subjected to silica gel column chromatography for purification, using benzene as a developer. This gives 13.5 g of ethyl 2-~4-(4-chloroanilinomethyl)phenoxy]propionate.
Infrared absorption spectrum ~liquid film) 3410, 1740 cm 1.
N.M.R. spectrum (CDCQ3,~) ppm 6.3 - 7.3 (8H,m) 4.65 (lH, q, J=7Hz) 4.15 (2H, q, J=7Hz) 4.13 (2H, s~
3.6 - 4.0 (lH, broad s) 1.55 (3H, d, J-7Hz) 1.20 (3H, t, J=7Hz) (J) In 600 mQ of methanol is dissolved 20 g of ethyl 2-(4-formylphenoxy)-2-methylpropionate, and 10.8 g of 4-chloroaniline is added to the solution. The mixture is stirred at 50C for 5 hours. Subsequently, 3.2 g of sodium borohydride is added ~t room temperature to the resulting solution containing e~hyl 2-[4-{N-~4-chlorophenyl)formimidoyl}phenoxy]-2-methylpropisnate.
The mixture is stirred for 1.5 hours. The reac~ion mixture is concentrated, and water is added to the residue. The diluted residue is extracted with ethyl acetate, and the extract is washed with water and dried. Distillation of the dried extract to remsve the solvent gives an oily product (22 gj, 2 g of which is .. . .. .
.

1(~5~)985 subjected to column chromatography wi~h 60 g of silica gel, using chloroform as a developer, to give 1.12 g of ethyl 2-[4-~4-chloroanilinomethyl)phenoxy]-2-methylpropionate, mp 58 to 60C.
1.12 g of the crystals are dissolved in 20 mQ of ether, and a mixture of hydrochloric acid and ethanol is add~3d to the solution.
The resulting precipitate is collected by filtration and washed with ether to give 1.05 g of ethyl 2-[4-~4-chloroanilinomethyl)-phenoxy]-2-methylpropionate hydrochloride, mp 139 to 141C. The crystals are recrystallized from a methanol-ether mixture to obtain a purified product, mp 143 to 145C.

(K) ta~ In 100 mQ of dried benzene are dissolved 17.0 g of ethyl 2-(4-~ormylphenoxy)propionate and 9.73 g of 4-chloroaniline, and the mixture is refluxed under heating and with stirring or 6 hours. Concentration of the reaction mixture gives 24.0 g of ethyl 2-~4-{N-~4-chlorophenyl)formimidoyl}phenoxy3propionate as an oily product.
Infrared absorption spectrum (liquid film) 1750, 1630, 1605 cm~l. -~;
N.M.R. spectrum (CDCQ3,~) ppm 8.32 (lH, s) 6.7 - 8.0 (8H, m) 4.82 (lH, q, J=7Hz) -4.22 (2H, q, J=7Hz) 1.65 (3H, d, J=7Hz) 1.27 (3H, t, J=7Hz) ~ b) 1.9 g of sodium borohydride is added to 75 mQ of ethanol with stirring, and to the solution is added dropwise, with cooling with water, a solution of 16.58 g of ethyl 2-[4-{N-. -~ (4-chlorophenyl)formimidoyl}phenoxy]propionate in 25 mQ of ethanol.
, .:

' ~

~C)5~9~5 The mixture is then stirred at room temperature for 2 hours.
The reaction mixture is poured into 0.75 Q of water and is extracted with ether. The extract is washed with water and then dried over magnesium sulfate. Removal of the solvent by distillation gives a pale yellow residual oil ~16.25 g), which is purified by column chromatography with silica gel, using benzene as a developer to give 6.75 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]propionate as an oily product.
Infrared absorption spectrum (liquid film) 3410, 1740 cm~l N.M.R. spectrum (CDCQ3,~) ppm 6.3 - 7.3 (8H, m) 4.65 (lH, q, J=7Hz) 4.15 (2~1, q, J=7~1z) 4.13 ~2~1~ s) 3.6 - 4.0 (lH, broad s) 1.55 (3H, d, J=7Hz) 1.20 (3H, t, J=7Hz) (L) The following compoun~s are obtained by using the similar procedures as those of the Examples 3 (A) to 3 (K).
~1) Ethyl 2-~4-ethylaminomethylphenoxy)-2-methylpropionate hydrochloride, mp 117 to 118C.
(2) 2-[4-~4-Chloroanilinomethyl)phenoxy]-2-methylpropionic acld, mp 155 to 158C.
(3) Bthyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylbutyrate hydrochloride, mp 135 to 137C.
(4) 2-[4-(4-Chloroanilinomethyl)phenoxy]-2-methylbutyric acid~
mp 152 to 153C.
(5) 2-[4-(4-Chloroanilinomethyl~phenoxy]propionic acid, mp 148 to 149C~

: . ,;, ~ . . . ...

~L05`()9~35 (6) 2-[4-(4-Chloroanilinomethyl)phenoxy]prOpanO1r mp 81 to 83C.
(7) 2-[4-(4--Chloroanilinomethyl)phenoxy]-2-methyl-propanol, mp 92 to 93C.
(8~ Ethyl 2- E4- (4-chloroanilinomethyl)-2-methoxyphenoxy~-2-methylpropionate, mp 73 to 74C.
(9) Sodium 2-- E4- (4-chloroanilinomethyl)-2-hydroxy-phenoxy]-2-methylpropionate, mp 121 to 125C.
(10) 3,3-Dimethyl-7-(4-chloroanilinomethyl)-1,4-benzodioxan-2-one, mp 97 to 98C.

:

:

Example 4 (Process D) (A) 11.7 g of 4-(4-chloroanilinomethyl)phenol and 16.8 g of powdery potassium hydroxide are suspended in 176 mQ of acetone.
To the suspension is added dropwise a solution of 10.7 g of 1-trichloromethyl-l-methylethanol in 8 mQ of acetone, and the mixture is refluxed under heating for 5.5 hours. The reaction mixture is filtered and washed with acetone. The filtrate and washed liquor are combined together and distilled under reduced pressure to remove the acetone. 100 mQ of water is added to the residue, and the ~:
aqueous solution is washed twice with 50 mQ of diisopropyl ether.
Over the aqueous solution is placed 150 mQ of ethyl acetate, and the mixture is adjusted to pH 4 with 10% hydrochloric acid. The ethyl acetate layer is separated, whilst the aqueous layer is extracted with 50 mQ of ethyl acetate. The extract is combined with the previously separated e~hyl acetate solution, and the mixture is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. To 15.6 g of the resulting residue is added 130 mQ of 5~ aqueous solution of sodium bicarbonate.
The mixture is heated at 50 to 55C to dissolve the residue. The solution obtained is left to stand for cooling and then washed three times with 50 mQ of ethyl acetate. Over the aqueous solution is placed 100 mQ of ethyl acetate, the mixture is adjus~ed to pH 4, and the ethyl acetate layer is separated. The aqueous layer is extracted with 50 mQ of ethyl acetate, and the extract and the separated ethyl acetate layer combined together are washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then distilled under reduced pressure to remove the solvent to give 12.6 g of 2-[4-~4-chloroanilinomethyl)phenoxyl-2-methylpropionic acid, mp 160 to 162C.

:: .
~E - 24 lq)S~)9i~S
(B~ In 10 mQ of acetone are suspended 1 g of 4-(~-chloro-anilinomethyl)phenol a~d 1.44 g of powdery potassium hydroxide, and 0.54 m~ of chloroform is added dropwise to the suspension at room temperature. The mixture is stirred at 55C for 5,5 hours.
The acetone is distilled off from the reaction mixtuTe, water is added to the residue, and the aqueous solution obtained is washed wi~h ether, adjusted to pH 4 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is back-extracted with a saturated aqueous solution of sodium bicarbonate, and the extract is adjusted to pH 4 with 10% hydrochloric acid and thereafter ex-tracted with ethyl acetate again. The resulting extract is washed with water, dried and distilled under reduced pressure to remove the solvent. The residue is recrystallized from ethanol to give 0.8 g o~ 2-[4-(4-chloroanilinomethyl~phenoxyl-2-methylpropionic acid, mp 161 to 162C.

(C) In 80 mQ of dioxane is dissolved 2 g of 4-~4- -chloroanilinomethyl)phenol, and 4.8 g of powdery potassium hydroxide is added to the solution with stirring. 3.04 g of l-trichloro-methyl-l-methylethanol is gradually added to the resulting solution.
The mixture is stirred at 55C for 3 hours. The reaction mixture is distilled under reduced pressure to remove dioxane, and to the - ;
resulting residue is added water. The aqueous solution is washed with ether, then adjusted to p~l 4 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is back-ex~racted with 5% aqueous solution of sodium carbonate. The resultant extract is adjusted to pH 4 with 10% hydrochloric acid and extracted again with ethyl acetate. The ethyl acetate extract is washed with water, dried and distilled under reduced pressure to remove the sol~ent. The residue is washed with ethanol to give 0.74 g of ~ ~ ' - 57 ~

1~09~5 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionic acid, mp 158 to 161C.

~D) At room temperature, 18.6 g of tribromomethane is added dropwise to a solution of 10 g of 4-(4-chloroani;Linomethyl)phenolg 50 mQ of methyl ethyl ketone, 13.8 g of powdery potassium hydroxide in 100 mQ of dioxane. The mixture is refluxed under heating for 5 hours and then distilled under reduced pressure to remove the solvent, and water is added to the residue. The solution is washed with ether, thereafter adjusted to pH 4 with 10% hyclro-chloric acid and extracted with ethyl acetate. The extract is washed with water and dried. The solvent is distilled off from the dried extract under reduced pressure, and the resulting residue is dissolved in an aqueous solution of 2.83 g o sodium bicarbonate in 100 m~ of water at 50C. The solution is washed twice with ethyl acetate. The aqueous layer is separated and adjusted to pH 4 with 10% hydrochloric acid and extracted twice with ethyl ~;
acetate. The extract is washed with water and dried. After distilling off the solvent from the dried extract, the residue is washed with diisopropyl ether. The precipitated crystals are collected by filtration to give 4.2 g of 2-{4-t4-chloroanilino-methyl)phenoxy}-2-methylbutyric acid, mp 152 to 153C.

(E) The following compounds are obtained by using the similar procedures as those of the Exampl~ 4 (A) to 4 ~D).
~1) 2-{4-(4-Chloroanilinomethyl)phenoxy}propionic acid, mp 1~8 to 149C. --(2) 2-~4-~N-~4-Chlorophenyl~-N-methylaminomethyl}phenoxyl-2-m~thylpropionic acid~ mp 63 to 65C.
~3) 2-~4-{N-~4-Chlorophenyl)-N-benzylaminomethyl}phenoxy]-2- ~ -methylpropionic acid, mp 65 to 67C.

, . , :, ~. :

..

~6 3S~9~5 Process E) (A) A mixture of 6.27 g of 2-[4-(4-chloroanilinomethyl)-phenoxy3-2-methylpropionic acid, 120 mQ of absolute ethanol and 2.2 g o~ concentrated sulfuric acid is refluxed under heating for 3 hours and 40 minutes. The ethanol is distilled off -from the reaction mixture under reduced pressure. The residue is basified with a dilute aqueous solution of sodium bicarbonate, and the resulting solution is extracted three times with ether. The extract is washed with water once, then with a dilute aqueous solution of sodium bicarbonate twice and thereafter wi~h water twice and is subsequently dried over magnesium sulfate. The dried extract is concentrated under reduced pressure, and the resulting oily concentrate is dis,solved in ether. Ethanol and hydrochloric acid are added to the solution~ and the precipitated crystals are collected by -filtration, washed with ether and recrystallized from isopropyl alcohol to give 4.8 g of ethyl 2-[4-(4-chloroanilino-methyl)phenoxyl-2-methylpropionate hydrochloride in the form of colorless flakes, mp 143 to 146C.
Elementary analysis: ClgH23N03CQ2 Calcd. C 59.38; H 6.03; N 3.68; CQ 18.45.
Found C 59.29; H 6.00; N 3.80; CQ 18.57.

(B) In 100 mQ of ethanol is dissolved 5.6 g of 2-[4-~4-chloroanilinomethyl)phenoxy]-2-methylbutyric acid, and 5.6 g of concentrated sulfuric acid is added to the solution. The mixture is refluxed under heating for 6 hours. After distilling off ethanol from the reaction mixture under reduced pressure, diisopropyl ether is added to the residue, and 20 mQ of water and 22 mQ of 20~
aqueous solution of sodium carbonate are further added thereto with ice-cooling. The diisopropyl ether layer is separated from the ~ .

, ., . , . ,, :. , ~, . .

1~5`1~98S
mixture, and the aqueous layer is extracted with diisopropyl ether.
The extract is combined wikh the previously separated diisopropyl ether solution, and the solution is wasked with a saturated aqueous solution of sodium chloride, dried and the solvent is distilled off under reduced pressure. The oily residue is su'bjected to silica gel column chromatography by using benzene as develo~er. Concen-tration of the eluate under reduced pressure gi~es 2.3 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylbutyrate as a residue.
The product is dissolved in ether, and 15% ethanol solution of hydrochloric acid is added to the solution. The precipitated crystals are collected by filtration to give 2 g of ethyl 2-l4-r4- ~
chloroanilinomethyl)phenoxy]-2-methylbutyrate hydrochloride, mp 135 ~-to 137C.

(C~ The ~ollowing compounds are obtained by using the similar procedures as those o the Examples 5 (A) to 5 (B).
(1) Ethyl 2-(4-anilinomethylphenoxy)-2-methylpropionate, mp 45 to 46C.
(2) Ethyl 2-(4-anilînomethylphenoxy)-2-methylpropionate hydrochloride, mp 158 to 163C.
~3) Ethyl 2-[4-(p-anisidinomethyl)phenoxy~-2-methylpropionate hydrochloride, mp ll9 to 120C.
~4) Ethyl 2-(4-cyclohexylaminomethylphenoxy)-2-methylpropionate hydrochloride, mp 140 to 142C.
(5) Ethyl 2-(4-isobutylaminomethylphenoxy)-2-methylpropionate hydrochloride, mp 118 to 119C.
~6) Ethyl 2-(4-benzylaminomethylphenoxy)-2-methylpropionate hydrochloride, mp 138 to 139C.
(7) Ethyl 2-[4-(p-toluidinomethyl)phenoxy]-2-methylpropionate hydrochloride, mp 133 to 135C.

- 60 ~

~5~5 ~8) E~hyl 2-l4-~3-chloroanilinomethyl)phenoxy~-2-me~hyl-propionate hydrochloride, mp 146 to 148C.
~9) Ethyl 2-~4-{N-(4-chlorophenyl)-N-methylaminomethyl}-phenoxy]-2-methylpropi.onate, oil.
Infrared absorption spectrum (liquid fi:Lm) 1730, 1280, 1235, 1175, 11409 1020 cm 1 (10) Ethyl 2-(4-ethylaminomethylphenoxy)-2-methylpropionate hydrochloride, mp 117 to 118C.
(11) Ethyl 2-[4-{N-benzyl-N-(4-chlorophenyl)aminomethyl}-phenoxy]-2-methylpropionate hydrochloride, mp 137 to 141C.
~12~ Ethyl 2-{4-~4-chloroanilinomethyl)phenoxy}propionatev oil.
Infrared absorption sectrum (liquid film) 3410, 1740 cm 1.
(13) N,N-bis~4-(1-methyl-1-ethoxycarbonylethoxy)benzyl~-ethylami.ne hydrochloride "np 164 to 165C.

(14) Ethyl 2-[4-~1-pyrrolid.inylmethyl)phenoxy]-2-methylpropionate, colorless oil.
Infrared absorption spectrum (liquid film) 1725, 1280, 1230, 1175, 1135, 1020 cm 1.

(15) Ethyl 2-[4-(4 chloroanilinomethyl)-2-methoxyphenoxy]-2-methylprop.ionate, mp 73 to 74~C.

~xample 6 (Process F) (A) A mixture of 6.14 g of ethyl 2-~4-(4-chloroanilinomethyl)-phenoxy]-2-methylpropionate, 130 mQ of 95% ethanol and 52 mQ of lN aqueous solution of sodium hydroxide is stirred at 70C for 50 minutes. After concentrating the reaction mixture under reduced pressure, the residue is dissolved in water and the solution is washed with ether five times. To the aqueous solution is added 55 m~ of lN hydrochloric acid with cooling, and the precipitated crystals are extracted twice with etherO The extract is washed Wit}l wat.er twice, then dri.ed over magnesium sulfate and thereafter .- ;. , ,. ................ .' ..... . .: ~
, .

s~85 the solvent is distilled off to give 5.6 g o-f 2-[4-~4-chloro-anilinomethyl)phenoxy~-2-methylpropionic acid1 colorless crystals, mp 155 to 158C.

~B) In 50 mQ of dried methanol are dissolved 10.0 g of ethyl 2-[4-~4-chloroanilinomethyl)phenoxylpropionate and 1.68 g of potassium hydroxide. The mixture is stirred at room temperature for 5 hours. After concentrating the reaction mixture, wa~er is added to the residue, and the resulting solution is washed with ether. The aqueous layer is acidified with hydrochloric acid and extracted with ether. The extract is washed with water, then dried over magnesium sulfate and thereafter the solvent is distilled off.
The resulting crystalline residue is recrystallized from benzene to give 8.0 g of 2-[4-t4-chloroanilinomethyl)phenoxy]propionic acid, mp 148 to 149C.

(C) In 20 mQ of ethanol is dissolved 1.2 g of ethyl 2-~4-{N-~4-chlorophenyl)-N-methylaminomethyl}phenoxy]-2-methylpropionate.
Subsequently, 15 mQ of lN aqueous solution of sodium hydroxide is added to the solution, and the mixture is stirred at room temperature for 4 hours. After dlstilling off the ethanol from the reaction mixture under reduced pressure, the residue is dissolved in water.
. .
The solution is adjusted to p~l 4 with 10% hydrochloric acid, and the precipitated crystals are collected by filtration and dried to giue 0.94 g of 2-[4-{N-(4-chlorophenyl)-N-methylaminomethyl}-phenoxy]-2-methylpropionic acid, mp 63 to 65C.

~D) In 40 mQ of ethanol lS dissolved 2.3 g of ethyl 2-[4-{N-~4-chlorophenyl)-N-benzylaminomethyl}phenoxyl-2-methylpropionate, - -and 25 mQ of lN aqueous solution of sodium hydroxide is added to ' ~L05~5 the solution. The mixture is refluxed under heating for 2 hours.
ALtcr col~ccntratillg the reactio]l mixtur~ under reduced pressure, the resldue is dissolved in water. The solut;on is adjusted to pH 4 with 10% hydrochloric acid. The resulting crystals are collected by filtration and dried to give 1.9 g of 2-[4-{N-(4-chlorophenyl)-N-benzylaminomethyl}phenoxy]-2-methylpropionic acid9 mp 65 to 67C.

(E) The following compounds are obtained by using the similar procedures as those of the ~xamples 6 (A) to 6 ~D).
(1) 2-[4-(4-chloroanilinomethyl)phenoxy~-2-methylbutyric acid, mp 152 to 153C.
(2) Sodium 2-[~-(9-chloroanilinomethyl)-2-hydroxy-phenoxy]-2-methylpropionate, mp 121 to 125C.
(3) 3,3-Dimethyl 7-(4-chloroanilinomethyl)-1,4-benzodioxan-2 one, mp 97 to 98~C.

~ ~5~D9 ~ 5 Example 7 (Process G) (A) A solution of 2.0 g of cthyl 2-[4-~4-chloroanilinolnethyl)-phenoxy]propionate in 20 mQ of ether is dropwise added to a suspension of 324 mg of lithium aluminum hydride in 20 m~ of anhydrous ether over a period of 10 minutes under 10C. The mixture is stirred for 20 minutes at room temperature and cooled under 10C, and to the mixture is dropwise added 25 m~ o-f 10~
ammonium chloride aqueous solution. An insolub:Le material is filtered off and the ether layer is separated. The aqueous layer is extracted with ether and both of the e~her layers are combined. The extrac~ is washed with a saturated sodium chloride aqueous solution and dried, after which the solvent is distilled off. The residue is collected by filtration, washed w;th a mixture oE n-hexane and diisopropyl ether and dried to give L.~2 g o~ 2~ -chloroanilinomethyl)phenoxy]propanol, mp 81 to 83C.
Infrared absorption spectrum (nujol) 3250 cm s ~B) A solution of 5 g of ethyl 2-[4-~4-çhloroanilinomethyl)-phenoxy]-2-methylpropionate in 50 mQ of ether is dropwise added to a suspension of 775 mg of lithium aluminum hydride in 50 mQ of anhydrous ether under 10C with stirring and the mixture is stirred for 2 hours at the same temperature. To the resultant mixture is dropwise added 60 mQ of 10% ammonium chloride aqueous solution at 5 to 10C. An insoluble material is filtered off and the ether layer is separated. The aqueous layer is f~rther extracted with ether and both of the ether layers are combined. The combined ether solution is washed with a saturated sodium chloride aqueous solution and dried. The solvent is distilled off and the residue is washed with diisopropyl ether and dried to give 3.5 g of 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropanQl, mp 84 to 91C.
This mater:ial is recrystallized from diisopropyl ether to give pure compound, mp 92 to 93C.
Infrared absorption spectrum (nujol) 3250 cm~l.
N.M R. spectrum ~CDCQ3,~) ppm 6.40 - 7.33 (8H, m~
4.22 (2H, s) 3.56 (2H, s) 2.33 (lH, broads) 1.24 (6H, s) Example 8 (Process H) A mixture of 1.25 g of 40% ethanol solution of ethylamine, 3.06 g of powdery potassium carbonate and 20 mQ of absolute ethanol is cooled to 5 to 10C with stirring, and a solution of 6.68 g of ethyl 2-(4-bromomethylphenoxy)-2-methyl-propionate in 7 mQ of absolute ethanol is added dropwise to the ~ - 33 _ 65 -~5~985 resulting soiution over a period of about 30 minutes. The mixture is stirred at room temperature for 2 hours, and 0.3 mQ of 40%
ethanol solution of ethylamine is added to the mixture. After stirring the mixture for 1 hour, the insolubles are removed by filtration and the filtrate is concentrated. The oily residue is dissolved in ether, and the ethereal solution is washed with water, dried and distilled to remove the ether. The residual oil ~5.4 g) is dissolved in 30 mQ of ether, and a mixture of hydrochloric acid and ethanol is added to the solu~ion. After distilling off the solvent, a small amount of ether is added to the oily residue, which is solidified by triturating it with cooling. The solid ;
is washed with ether and then collected by filtration to give 3.0 g of N,N-bis[4-(1-methyl-1-ethoxycarbonylethoxy)benzyl]ethy:Lamine hydrochloride, mp 163 to 165C. Recrystallization of the product from a mixture of ethanol and ether gives 2.0 g of a pure product, mp 164 to 165C. On the other hand, the ethér is distilled off from the filtrate previously prepared to obtain an oily product, which is solidified in an ether-isopropyl ether mixture and filtered to give 2.5 g of the object compound, mp 153 to 157C. The crystals are recrystallized from a mixture of ethanol and ether to give crystals (1.9 g~, which are further recrystallized to give 1.5 g of the object compound, mp 161 to 163C.
Blementary analysis: C28H39NO6 HCQ
Calcd. C 64.42; H 7.72; N 2.68; CQ 6.79 Found C 64.37; H 7.69; N 2.85; CQ 6.89 ,:~
Bxample 9 ~Process I~ -:
~A) To 2.9 g of ethyl 2-[4-(4-chloroanilinomethyl~phenoxy]-2-methylpropionate are added 10 mQ of formaldehyde and 20 mQ of formic acid to prepare a solution, which is stirred at room ~ ~ 9 ~ 5 temperature -for 30 minutes and then at 50C for 1 hour. The ~ormaldehyde and formic acid are distilled off from the reaction mixture under reduced pressure, and ethanol is added to the residue. After filtering of-~ the insolubles from the resulting solution, the ethanol is distilled off from the filtrate. The resulting oily residue is dissolved in ether, washed with water and dried. The ether is distilled off from the dried solution to give an oily residue ~2.8 g), which is purified by silica gel column chroma~ography, using chloroform as an eluen~ to give 2.3 g of ethyl 2-[4-{N-~4-chlorophenyl)-N-methylaminomethyl}phenoxy]-2-methylpropionate, an oily product.
Infrared absorption spectrum (liquid film) 1730, 1280, 1235, 1175, 1140, 1020 cm N.M.R. spectrum (CDCQ3,~) ppm 6.5 - 7.3 ~8H, m) 4~40 (2H, s) 4.21 (2H, q, J=7Hz) 2.93 ~3H, s) 1.56 (6~, s) 1.23 (3~1, t, J=7~1z) (B) 3.47 g of benzyl bromide is added dropwise to a mixture of 6 g of ethyl 2-[4-(4-chloroanilinomethyl)phencxy]-2-methyl-propionate hydrochloride, 3.24 g of potassium carbonate and 90 mQ ~-of- dimethylformamide, and the resulting mixture is stirred at 60C
for 3 hours. The reaction mixture is poured into 300 mQ of ice-water and is extracted three times with 100 mQ of ethyl acetate and twice with 50 mQ of the same. The extract is washed with a saturated aqueous solution of sodium chloride and then dried.
The solvent is distilled off from the dried extract, and the '', ., ~ . , ' . , , . , ;

~ 5~91~3~
residue ~7.5 g} is purified by column chromatography with 150 g of silica gel, using chloroorm as a developer, to give 5.7 g of ethyl 2-~4-{N-(4-chlorophenyl)-N-benzylaminomethyl}phenoxy] 2-methylpropionate. The product is dissolved in :L00 mQ o-f ether, and dried hydrogen chloride gas is introduced into the solvtion.
The resulting crystals are collected by filtration and recrystal-lized from isopropyl alcohl to give 4.3 g of ethyl 2-~4-{N~4-chlorophenyl)-N-benzylaminomethyl}phenoxy]-2-methylpropionate hydrochloride, mp 137 to 141C.

(C) The following compounds are obtained by using the similar procedures as those o the Examples 9 (A) to 9 ~B).
(1~ 2-[4-{N-~4~Chlorophenyl~-N-benzylaminomethyl}phenoxy]-2-methylpropionic acid, mp 65 to 67C.
(2) 2-~4-{N-(4-Chlorophenyl)-N-methylaminomethyl}phenoxy]-2-methylpropionic acid, mp 63 to 65C.
(3) N,N-bis~4-(1-Methyl-l-ethoxycarbonylethoxy)benzyl]-ethylamine hydrochloride, mp 164 to 165C.
Example 10 (Process J) A mixture of 500 mg of ethyl 2-[4-(4-chloroanilino-meth~ 2-methoxyphenoxy~-2-methylpropionate, 206 mg of ethane-thiol, 159 mg of 50~ sodium hydride and 10 ml of dimethyl-formamide is heated at 100C for 3 hours. The reaction mixture is poured into ice-water and washed with ether. The aqueous layer is adjusted to pH 2 with 10% hydrochIoric acid and extracted with ether. The extract is washed with water, dried and concentrated. The residue is pulverized with a mixtureof diisopropyl ether and n-hexane and the crystals are collected by filtration to give 250 mg of 3,3-dimethyl-7~
(4-chloroanilinomethyl)-1,4-benzodioxan-2~one, mp 97 to 98C.

~05~85 From the mother liquor 60 mg of the same compound is further obtained.
Infrared absorption spectrum (nujol) :
3400, 1760 cm 1 N. M. R. spectrum (CDC13,~) - -ppm 6.40 - 7.17 (7H, m) 4.23 (2H, s) 1.53 (6~I, s) To a solution of 158.7 mg of 3,3-dimethyl-7-(4-chloroanilinomethyl)-1,4-benzodioxan-2-one in 10 ml of ethanol is added 5 ml of a l/lON sodium hydroxide aqueous solution and the mixture is warmed to give clear solution.
The solution is concentrated and the precipitated crystals are collected by ~iltration, washed with water and ether, and dried to give 140 mg of sodium 2-~4-(4-chloroanilino-methyl)-2-hydroxyphenoxy]-2-methylpropionate, mp 121 to 125C.
Infrared absorption spectrum (nujol) . .
3500, 3400, 2650 2400, 1560 cm .
, ~ . . . . .

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for preparing substituted-phenyl sub-stituted-alkyl ethers of the formula:

wherein R1 is (C1-C4)- alkyl, (C5-C7)cycloalkyl, phenyl, benzyl, pyridyl, benzothiazolyl or a group represented by the formula:
wherein R3 and R4 are each hydrogen or (C1-C4)-alkyl, R5 is carboxy, (Cl-C4)alkoxy-carbonyl or hydroxymethyl and A is (C1-C4)alkylene;
R2 is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl;
R3, R4, R5 and A are each as defined above; and R6 is hydrogen, hydroxy or (C1-C4)alkoxy; in which the phenyl for R1 and R2 may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)alkoxy, or R1 and R2 are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; or pharmaceutically acceptable salts thereof which comprises (a) reacting a compound of the formula:

wherein R1a is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl, pyridyl, benzothiazolyl or a group represented by t:he formula:
wherein A is as defined above;

R2a is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl; in which -the phenyl for R1a and R2a may be substituted with (C1-C4)alkyl, halogen or (C1-C4)alkoxy, or R1a and R2a are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group;
R'6 is hydrogen or (C1-C4)alkoxy; and A is (C1-C4)alkylene; or salts thereof with a compound of the formula:

wherein R3 and R4 are each as defined above;
R'5 is carboxy or (C1-C4)alkoxy-carbonyl; and Y is an acid residue; or salts thereof, to give a compound of the formula:

wherein R3, R4, R5, R'6 and A are each as defined above;
R1b is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl, pyridyl, benzothiazolyl or a group represented by the formula:
wherein R3, R4, R5 and A are each as defined above; and R2b is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl;
in which the phenyl for R1b and R2b may be substituted with (C1-C4)alkyl, halogen or (C1-C4)alkoxy, or R1b and R2b are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; or (b) reacting a compound of the formula:

wherein R1c is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl pyridyl or benzothiazolyl, and R2c is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl; in which the phenyl for R1C
and R2c may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)alkoxy, or R1C and R2c are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; with a compound of the formula:

wherein R3, R4, R'5, R6, A and Y are each as defined above or salts thereof, to give a compound of the formula:

wherein R1c, R2c, R3, R4, R'5, R6 and A are each as defined above or (c) reducing a compound of the formula:

wherein R3, R4, R'5 and R6 are each as defined above;

R1d is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl;
in which the phenyl for R1d may be substituted with (C1-C4)-alkyl, halogen, hydroxy or (C1-C4)alkoxy; and A' is (C1-C4)-alkylidyne or (C1-C4)alkanylylidene; or salts thereof, to give a compound of the formula:

wherein R1d, R3, R4, R5, R6 and A are each as defined above; or (d) reacting a compound of the formula:

wherein R6' and A are each as defined above;
R1d' is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl;
and R2d' is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl; in which the phenyl for R1d' and R2d' may be substituted with (C1-C4)alkyl, halogen or (C1-C4)alkoxy, or R1d' and R2d' are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; or salts thereof (i) with a compound of the formula:

wherein R3 and R4 are each as defined above; and X is halogen;
or (ii) with a compound of the formula:

wherein X is as defined above, and a compound of the formula:

wherein R3 and R4 are each as defined above; in the presence of a strong base, to give a compound of the formula:

wherein R1d', R2d', R3, R4, R6' and A are each as defined above;
or (e) subjecting a compound of the formula:

wherein R3, R4, R6 and A are each as defined above;
R1e is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl or a group represented by the formula: wherein R3, R4 and A are each as defined above; and R2e is hydrogen, (C1-C4)alkyl, (C5-c7)cycloalkyl, phenyl or benzyl; in which the phenyl for R1e and R2e may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)alkoxy, or Rle and R2e are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; or reactive equivalents thereof, to esterification, to give a compound of the formula:

wherein R3, R4, R6 and A are each as defined above;
R1f is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl or a group represented by the formula:
wherein R3, R4 and A are each as defined above, R7 is (C1-C4)alkyl;
R2f is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl; and R7 is as defined above; in which the phenyl for Rlf and R2f may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)alkoxy, or R1f and R2f are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; or (f) subjecting a compound of the formula:

wherein R1d, R3, R4, R6 and A are each as defined above;
R2d is hydrogen, (C1-C4)alkyl, (C5-C7)cycloakyl phenyl or benzyl; and R8 us a group convertible into carboxy group;
in which the phenyl for R1d and R2d may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)alkoxy, or R1d and R2d are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; to convertion reaction of said group R8 into a carboxy group, to give a compound of the formula:

wherein R1d, R2d, R3, R4, R6 and A are each as defined above;
or (g) reducing a compound of the formula:

wherein R3, R4, R5', R6 and A are each as defined above;
R1g is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl, pyridyl, benzothiazolyl or a group represented by the formula:
wherein R3, R4, R5' and A are each as defined above;
R2g is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalky, phenyl or benzyl; in which the phenyl for R1g and R2g may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)alkoxy, or R1g and R2g are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group;
to give a compound of the formula:

wherein R3, R4, R6 and A are each as defined above;
R1h is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl, pyridyl, benzothiazolyl or a group represented by the formula:

wherein R3, R4 and A are each as defined above; and R2h is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl; in which the phenyl for R1h and R2h may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)alkoxy, or R1h and R2h are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; or (h) subjecting a compound of the formula:

wherein R1d, R2d, R3, R4, R5 and A are each as defined above;
and R6" is (C1-C4)alkoxy; to dealkylation, to give a compound of the formula:

wherein R3, R4 and A are each as defined above;
R1j is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl;
R2j is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl; in which the phenyl for R1j and R2j may be substituted with (C1-C4)alkyl, halogen or hydroxy, or R1j and R2j are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; and R5" is carboxy or (C1-C4)alkoxy-carbonyl; and, if necessary, converting the resulting compounds into pharmaceutically acceptable salts thereof.

2. A process for preparing substituted-phenyl sub-stituted-alkyl ethers of the formula wherein R1b is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl, pyridyl, benzothiazolyl or a group represented by the formula:

wherein R3 and R4 are each hydrogen or (C1-C4)alkyl, R5, is carboxy or (C1-C4)alkoxycarbonyl and A
is (C1-C4)alkylene, R2b is hydrogen, (C1-C4)alkyl, (C5-C7)-cycloalkyl, phenyl or benzyl, R3, R4, R5, and A are each as defined above; and R6, is hydrogen or (C1-C4)alkoxy, in which the phenyl for R1b and R2b may be substituted with (C1-C4)-alkyl, halogen or (C1-C4)alkoxy, or R1b and R2b are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group, or pharmaceutically acceptable salts thereof which comprises reacting a compound of the formula:

wherein R1a is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl pyridyl, benzothiazolyl or a group represented by the formula: wherein A is as defined above;
R2a is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl;
R6, and A are each as defined above; in which the phenyl for R1a and R2a may be substituted with (C1-C4)alkyl, halogen or (C1-C4)alkoxy, or R1a and R2a are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; or a salt thereof with a compound of the formula:

wherein R3, R4 and R5, are each as defined above; and Y is an acid residue; or a salt thereof.

3. A process according to claim 2, wherein R1a and R1b are the same and are ethyl, isobutyl, cyclohexyl, phenyl, p-tolyl, 3-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, benzyl, 2-pyridyl, 2-benzothiazolyl or 4-(1-methyl-1-ethoxycarbonylethoxy)-benzyl, R2a and R2b are the same and are hydrogen, methyl, ethyl or benzyl or both of R1a and R2a, and R1b and R2b together with the nitrogen atom to which they are connected to form l-pyrrolidinyl, R3 is methyl, R4 is hydrogen, methyl or ethyl, R5, is carboxy or ethoxycarbonyl, R6, is hydrogen or methoxy, A is methylene and Y is bromo.

4. A process according to claim 3, wherein R1a and R1b are ethyl, R2a and R2b are hydrogen, R4 is methyl, R5, is ethoxy-carbonyl and R6 is hydrogen.

5. A process according to claim 3, wherein R1a and R1b are isobutyl, R2a and R2b are hydrogen, R4 is methyl, R5, is ethoxy-carbonyl and R6' is hydrogen.

6. A process according to claim 3, wherein R1a and R1b are cyclohexyl, R2a and R2b are hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6 is hydrogen.

7. A process according to claim 3, wherein R1a and R1b are phenyl, R2a and R2b are hydrogen, R4 is methyl, R5. is ethoxycarbonyl and R6, is hydrogen.

8. A process according to claim 3, wherein R1a and R1b are p-tolyl, R2a and R2b are hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6 is hydrogen.

9. A process according to claim 3, wherein R1a and R1b are 3-chlorophenyl, R2a and R2b are hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6 is hydrogen.

10. A process according to claim 3, wherein R1a and R1b are 4-chlorophenyl, R2a and R2b and R4 are hydrogen, R5 is carboxy and R6, is hydrogen.

11. A process according to claim 3, wherein R1a and R1b are 4-chlorophenyl, R2a, R2b and R4 are hydrogen, R5, is ethoxycarbonyl and R6, is hydrogen.

12, A process according to claim 3, wherein R1a and R1b are 4-chlorophenyl, R2a and R2b are hydrogen, R4 is methyl, R5, is carboxy and R6, is hydrogen.

13. A process according to claim 3, wherein R1a and R1b are 4-chlorophenyl, R2a and R2b are hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6, is hydrogen.

14. A process according to claim 3, wherein R1a and R1b are 4-chlorophenyl, R2a and R2b are hydrogen, R4 is methyl, R5. is ethoxycarbonyl and R6, is methoxy.

15. A process according to claim 3, wherein R1a and R1b are 4-chlorophenyl, R2a and R2b are hydrogen, R4 is ethyl, R5, is carboxy and R6, is hydrogen.

16. A process according to claim 3, wherein R1a and R1b are 4-chlorophenyl, R2a and R2b are hydrogen, R4 is ethyl, R5, is ethoxycarbonyl and R6. is hydrogen.

17. A process according to claim 3, wherein R1a and R1b are 4-chlorophenyl, R2a, R2b and R4 are methyl, R5, is carboxy and R6, is hydrogen.

18. A process according to claim 3, wherein R1a and R1b are 4-chlorophenyl, R2a, R2b and R4 are methyl, R5, is ethoxycarbonyl and R6. is hydrogen.

19. A process according to claim 3, wherein R1a and R1b are 4-chlorophenyl, R2a and R2b are benzyl, R4 is methyl, R5, is ethoxycarbonyl and R6, is hydrogen.

20. A process according to claim 3, wherein R1a and R1b are p-methoxyphenyl, R2a and R2b are hydrogen, R4 is methyl, R5 is ethoxycarbonyl and R6, is hydrogen.

21. A process according to claim 3, wherein R1a and R1b are benzyl, R2a and R2b are hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6, is hydrogen.

22. A process according to claim 3, wherein R1a and R1b are 2-pyridyl, R2a and R2b are hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6, is hydrogen.

23. A process according to claim 3, wherein R1a and R1b are 2-benzothiazolyl, R2a and R2b are hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6, is hydrogen.

24. A process according to claim 3, wherein R1a and R1b are 4-(1-methyl-1-ethoxycarbonylethoxy)benzyl, R2a and R2b are ethyl, R4 is methyl, R5, is ethoxycarbonyl and R6, is hydrogen.

25. A process according to claim 3, wherein both of R1a and R2a, and R1b and R2b are linked together with the nitrogen atom to which they connect to form 1-pyrrolidinyl, R4 is methyl, R5, is ethoxycarbonyl and R6, is hydrogen.

26. A process for preparing substituted-pheynyl substituted-alkyl ethers of the formula:

wherein R1c is (C1-C4)alkyl, (C5-C7)cycloalky1, phenyl, benzyl, pyridyl or benzothiazolyl; R2c is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl, R3 and R4 are each hydrogen or (C1-C4)alkyl; R5, is carboxy or (C1-C4)alkoxy-carbonyl; R6 is hydrogen, hydroxy or (C1-C4)alkoxy; and A is (C1-C4)alkylene; in which the phenyl for R1C and R2C may be substitued with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)-alkoxy, or R1c and R2c are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group;

or pharmaceutically acceptable salts thereof which comprises reacting a compound of the formula wherein R1c and R2C are each as defined above, with a compound of the formula:

wherein R3, R4, R5 " R6 and A are each as defined above, and Y is an acid residue; or salt thereof.

27. A process according to claim 26, wherein R1c is ethyl, isobutyl, cyclohexyl, phenyl, p-tolyl, 3-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, benzyl, 2-pyridyl or 2-benzo-thiazolyl, R2c is hydrogen, methyl or benzyl, or R1c and R2c are linked together with the nitrogen atom to which they are connected to form 1-pyrrolidinyl, R3 is methyl, R4 is hydrogen, methyl or ethyl, R5, is carboxy or ethoxycarbonyl, R6 is hydrogen, hydroxy or methoxy, A is methylene and Y is bromo.

28. A process according to claim 27, wherein R1c is ethyl, R2c is hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6 is hydrogen.

29. A process according to claim 27, wherein R1c is isobutyl, R2c is hydrogen, R4 is methyl, R5 is ethoxycarbonyl and R6 is hydrogen.

30. A process according to claim 27, wherein R1c is cyclo-hexyl, R2c is hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6 is hydrogen.

31. A process according to claim 27, wherein R1c is phenyl, R2c is hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6 is hydrogen.

32. A process according to claim 27, wherein R1c is p-tolyl, R2c is hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6 is hydrogen.

33. A process according to claim 27, wherein R1c is 3-chlorophenyl, R2c is hydrogen, R4 is methyl, R5, is ethoxy-carbonyl and R6 is hydrogen.

34. A process according to claim 27, wherein R1c is 4-chlorophenyl, R2c and R4 are hydrogen, R5, is carboxy and R6 is hydrogen.

35. A process according to claim 27, wherein R1c is 4-chlorophenyl, R2c and R4 are hydrogen, R5, is ethoxycarbonyl and R6 is hydrogen.

36. A process according to claim 27, wherein R1c is 4-chlorophenyl, R2c is hydrogen, R4 is methyl, R5, is carboxy and R6 is hydrogen.

37. A process according to claim 27, wherein R1c is 4-chlorophenyl, R2c is hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6 is hydrogen.

38. A process according to claim 27, wherein R1c is 4-chlorophenyl, R2c is hydrogen R4 is methyl, R5, is carboxy and R6 is hydroxy.

39. A process according to claim 27, wherein R1c is 4-chlorophenyl, R2c is hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6 is methoxy.

40. A process according to claim 27, wherein R1c is 4-chlorophenyl, R2c is hydrogen, R4 is ethyl, R5, is carboxy and R6 is hydrogen.

41. A process according to claim 27, wherein R1c is 4-chlorophenyl, R2c is hydrogen, R4 is ethyl, R5, is ethoxycarbonyl and R6 is hydrogen.

42. A process according to claim 27, wherein R1c is 4-chlorophenyl, R2c and R4 are methyl, R5, is carboxy and R6 is hydrogen.

43. A process according to claim 27, wherein R1c is 4-chlorophenyl, R2c is benzyl, R4 is methyl, R5, is carboxy and R6 is hydrogen.

44. A process according to claim 27, wherein R1c is 4-chlorophenyl, R2c is benzyl, R4 is methyl, R5, is ethoxycarbonyl and R6 is hydrogen.

45. A process according to claim 27, wherein R1c is 4-methoxyphenyl, R2c is hydrogen, R4 is methyl, R5, is ethoxy-carbonyl and R6 is hydrogen.

46. A process according to claim 27, wherein R1c is benzyl, R2c is hydrogen, R4 is methyl, R5, is ethoxy-carbonyl and R6 is hydrogen.

47. A process according to claim 27, wherein R1c is 2-pyridyl, R2c is hydrogen, R4 is methyl, R5, is ethoxycarbonyl and R6 is hydrogen.

48. A process according to claim 27, wherein R1c is 2-benzothiazolyl, R2c is hydrogen, R4 is methyl, R5, is ethoxy-carbonyl and R6 is hydrogen.

49. A process according to claim 27, wherein R1c and R2c are linked together with the nitrogen atom to which they are connected to form 1-pyrrolidinyl, R4 is methyl, R5, is ethoxy-carbonyl and R6 is hydrogen.

50. A process for preparing substituted-phenyl substituted-alkyl ethers of the formula:

wherein R1d is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl: R3 and R4 are each hydrogen or (C1-C4)alkyl; R5 is carboxy, (C1-C4)alkoxycarbonyl or hydroxymethyl, R6 is hydrogen, hydroxy or (C1-C4)alkoxy; and A is (C1-c4)alkylene; in which the phenyl for R1d may be substituted with (C1-C4)alkyl, halo-gen, hydroxy or (C1-C4)alkoxy; or pharmaceutically acceptable salts thereof which comprises reducing a compound of the formula:

wherein R1d, R3, R4 and R6 are each as defined above, and R5, is carboxy or (C1-C4)alkoxycarbonyl, and A' is (C1-C4)alkylidyne or (C1-C4)alkanylydene, or a salt thereof.

51. A process according to claim 50, wherein R1d is ethyl, isobutyl, cyclohexyl, phenyl, p-tolyl, 3-chloro-phenyl, 4-chlorophenyl, 4-methoxyphenyl or benzyl, R3 is methyl, R4 is hydrogen, methyl or ethyl, R5 is carboxy, ethoxycarbonyl or hydroxymethyl, R5, is carboxy or ethoxy-carbonyl, R6 is hydrogen, hydroxy or methoxy, A is methylene and A' is methylidyne.

52. A process according to claim 51, wherein R1d is ethyl, R4 is methyl, R5 and R5, are ethoxycarbonyl and R6 is hydrogen.

53. A process according to claim 51, wherein R1d is isobutyl, R4 is methyl, R5 and R5, are ethoxycarbonyl and R6 is hydrogen.

54. A process according to claim 51, wherein R1d is cyclohexyl, R4 is methyl, R5 and R5, are ethoxycarbonyl and R6 is hydrogen.

55. A process according to claim 51, wherein R1d is phenyl, R4 is methyl, R5 and R5, are ethoxycarbonyl and R6 is hydrogen.

56. A process according to claim 51, wherein R1d is p-tolyl, R4 is methyl, R5 and R5, are ethoxycarbonyl and R6 is hydrogen.

57. A process according to claim 51, wherein R1d is 3-chlorophenyl, X4 is methyl, R5 and R5, are ethoxycarbonyl and R6 is hydroge.

58. A process according to claim 51, wherein R1d is 4-chlorophenyl, R4 is hydrogen, R5 and R5, are carboxy and R6 is hydrogen.

59. A process according to claim 51, wherein R1d is 4-chlorophenyl, R4 is hydrogen, R5 and R5, are ethoxycarbonyl and R6 is hydrogen.

60. A process according to claim 51, wherein R1d is 4-chlorophenyl, R4 is hydrogen, R5 is hydroxymethyl, R5, is carboxy and R6 is hydrogen.

61. A process according to claim 51, wherein R1d is 4-chlorophenyl, R4 is methyl, R5 and R5, are carboxy and R6 is hydrogen.

62. A process according to claim 51, wherein R1d is 4-chlorophenyl, R4 is methyl, R5 and R5, are carboxy and R6 is hydroxy.

63. A process according to claim 51, wherein R1d is 4-chlorophenyl, R4 is methyl, R5 and R5, are ethoxycarbonyl and R6 is hydrogen.

64. A process according to claim 51, wherein R1d is 4-chlorophenyl, R4 is methyl, R5 and R5, are ethoxycarbonyl and R6 is methoxy.

65. A process according to claim 51, wherein R1d is 4-chlorophenyl, R4 is ethyl, R5 and R5, are carboxy and R6 is hydrogen.

66. A process according to claim 51, wherein R1d is 4-chlorophenyl, R4 is ethyl, R5 and R5, are ethoxycarbonyl and R6 is hydrogen.

67. A process according to claim 51, wherein R1d is 4-methoxyphenyl, R4 is methyl, R5 and R5, are ethoxycarbonyl and R6 is hydrogen.

68. A process according to claim 51, wherein R1d is benzyl, R4 is methyl, R5 and R5, are ethoxycarbonyl and R6 is hydrogen.

69. A process for preparing substituted-phenyl substituted-alkyl ethers of the formula:

wherein R1d, is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl; R2d, is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl, R3 and R4 are each hydrogen or (C1-C4)-alkyl R6. is hydrogen or (C1-C4)alkoxy, and A is (C1-C4)-alkylene; in which the phenyl for R1d, and R2d, may be sub-stituted with (C1-C4)alkyl, halogen or (C1-C4)alkoxy, or R1d, and R2d, are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group: or pharma-ceutically acceptable salts thereof which comprises reacting a compound of the formula:

wherein R1d', R2d', R6, and A are each as defined above;
or a salt thereof (i) with a compound of the formula:

wherein R3 and R4 are each as defined above, and X is halogen;
or (ii) with a compound of the formula: CHX3 wherein X is as defined above, and a compound of the formula:

wherein R3 and R4 are each as defined above; in the presence of a strong base.

70. A process according to claim 69, wherein R1d, is 4-chlorophenyl, R2d, is hydrogen, methyl or ethyl, R3 is methyl, R4 is hydrogen, methyl or ethyl, R6, is hydrogen, A is methylene and X is bromo or chloro.

71. A process according to claim 70, wherein R2d, is hydrogen, R4 is hydrogen and X is chloro.

72. A process according to claim 70, wherein R2d, is hydrogen, R4 is methyl and X is chloro.

73. A process according to claim 70, wherein R2d, is hydrogen, R4 is ethyl and X is bromo.

74. A process according to claim 70, wherein R2d, is methyl, R4 is methyl and X is chloro.

75. A process according to claim 70, wherein R2d, is benzyl, R4 is methyl and X is chloro.

76. A process for preparing substituted-phenyl substituted-alkyl ethers of the formula:

wherein R1f is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl or a group represented by the formula:

wherein R3 and R4 are each hydrogen or (C1-C4)alkyl and A is (C1-C4)alkylene, R2f is hydrogen, (C1-C4)-alkyl, (C5-C7)cycloalkyl, phenyl or benzyl, R3, R4, R7 and A
are each as defined above, and R6 is hydrogen, hydroxy or (C1-C4)alkoxy; in which the phenyl for R1f and R2f may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)-alkoxy, or R1f and R2f are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; or pharmaceutically acceptable salts thereof which comprises subjecting a compound of the formula:

wherein R3, R4, R6 and A are each as defined above;

R1e is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl or a group represented by the formula: wherein R3, R4 and A are each as defined above; and R2e is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl;
in which the phenyl for R1e and R2e may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)alkoxy, or R1e and R2e are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; or reactive equivalents thereof, to esterification.

77. A process according to claim 76, wherein R1e and R1f are each ethyl, isopropyl, cyclohexyl, phenyl, p-tolyl, 2-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, benzyl or 4-(1-methyl-1-ethoxycarbonyl)benzyl, R2e and R2f are each hydrogen, methyl, ethyl or benzyl, or both of R1e and R2e, and R1f and R2f are linked together with the nitrogen atom to which they connected to form 1-pyrrolidinyl, R3 is methyl, R4 is hydrogen, methyl or ethyl, R6 is hydrogen or methoxy, R7 is methyl and A is methylene.

78. A process according to claim 77, wherein R1e and R1f are ethyl, R2e and R2f are hydrogen, R4 is methyl and R6 is hydrogen.

79. A process according to claim 77, wherein R1e and R1f are isobutyl, R2e and R2f are hydrogen, R4 is methyl and R6 is hydrogen.

80. A process according to claim 77, wherein R1e and R1f are cyclohexyl, R2e and R2f are hydrogen, R4 is methyl and R6 is hydrogen.

81. A process according to claim 77, wherein R1e and R1f are phenyl, R2e and R2f are hydrogen, R4 is methyl and R6 is hydrogen.

82. A process according to claim 77, wherein R1e and R1f are p-tolyl, R2e and R2f are hydrogen, R4 is methyl and R6 is hydrogen.

83. A process according to claim 77, wherein R1e and R1f are 3-chlorophenyl, R2e and R2f are hydrogen, R4 is methyl and R6 is hydrogen.

84. A process according to claim 779 wherein R1e and R1f are 4-chlorophenyl, R2e, R2f, R4 and R6 are hydrogen.

85. A process according to claim 77, wherein R1e and R1f are 4-chlorophenyl, R2e and R2f are hydrogen, R4 is methyl and R6 is hydrogen.

86. A process according to claim 77, wherein R1e and R1f are 4-chlorophenyl, R2e and R2f are hydrogen, R4 is methyl and R6 is methoxy.

87. A process according to claim 77, wherein R1e and R1f are 4-chlorophenyl, R2e and R2f are hydrogen, R4 is ethyl and R6 is hydrogen.

88. A process according to claim 77, wherein R1e and R1f are 4-chlorophenyl, R2e, R2f and R4 are methyl and R6 is hydrogen.

89. A process according to claim 77, wherein R1e and R1f are 4-chlorophenyl, R2e and R2f are benzyl, R4 is methyl and R6 is hydrogen.

90. A process according to claim 77, wherein R1e and R1f are 4-methoxyphenyl, R2e and R2f are hydrogen, R4 is methyl and R6 is hydrogen.

91. A process according to claim 77, wherein R1e and R1f are benzyl, R2e and R2f are hydrogen, R4 is methyl and R6 is hydrogen.

92. A process according to claim 77, wherein R1e and R1f are 4-(1-methyl-1-ethoxycarbonylethoxy)benzyl, R2e and R2f are ethyl, R4 is methyl and R6 is hydrogen.

93. A process according to claim 77, wherein both of R1e and R2e, and R1f and R2f are linked together with the nitrogen atom to which they connected to form 1-pyrrolidinyl, R4 is methyl and R6 is hydrogen.

94. A process for preparing substituted-phenyl substituted alkyl ethers of the formula:

wherein R1d is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl;
R2d is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl; R3 and R4 are each hydrogen or (C1-C4)alkyl; R6 is hydrogen, hydroxy or (C1-C4)alkoxy; and A is (C1-C4)alkylene;
in which the phenyl for R1d and R2d may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)alkoxy, or R1d and R2d are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group; or pharmaceutically acceptable salts thereof which comprises subjecting a compound of the formula:

wherein R1d, R2d, R3, R4, R6 and A are each as defined above;
and R8 is a group convertible into carboxy group; to convertion reaction of said group R8 into a carboxy group.

95. A process according to claim 94, wherein R1d is 4-chlorophenyl, R2d is hydrogen, methyl or benzyl, R3 is methyl, R4 is hydrogen, methyl or ethyl, R6 is hydrogen or hydroxy, R8 is ethoxycarbonyl and A is methylene.

96. A process according to claim 95, wherein R1d is 4-chlorophenyl and R2d, R4 and R6 are hydrogen.

97. A process according to claim 95, wherein R1d is 4-chlorophenyl, R2d is hydrogen, R4 is methyl and R6 is hydrogen.

98. A process according to claim 95, wherein R1d is 4-chlorophenyl, R2d is hydrogen, R4 is methyl and R6 is hydroxy.

99. A process according to claim 95, wherein R1d is 4-chlorophenyl, R2d is hydrogen, R4 is ethyl and R6 is hydrogen.

100. A process according to claim 95, wherein R1d is 4-chlorophenyl, R2d and R4 are methyl and R6 is hydrogen.

101. A process according to claim 95, wherein R1d is 4-chlorophenyl, R2d is benzyl, R4 is methyl and R6 is hydrogen.

102. A process for preparing substituted-phenyl substituted-alkyl ethers of the formula:

wherein R1h is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl, pyridyl, benzothiazolyl or a group represented by the formula:

wherein R3 and R4 are each hydrogen or (C1-C4)alkyl and A is (C1-C4)alkylene, R2h is hydrogen, (C1-C4)-alkyl, (C5-C7)cycloalkyl, phenyl or benzyl, R3, R4 and A are each as defined above; and R6 is hydrogen, hydroxy or (C1-C4)-alkoxys; in which the phenyl for R1h and R2h may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)alkoxy, or R1h and R2h are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group, or pharma-ceutically acceptable salts thereof which comprises reducing a compound of the formula:

wherein R3, R4, R6 and A are each as defined above, R1g is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl, benzyl, pyridyl, benzo-thiazolyl or a group represented by the formula:
wherein R3, R4 and A are each as defined above, and R5, is carboxy or (C1-C4)alkoxycarbonyl; and R2g is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl; in which the phenyl for R1g and R2g may be substituted with (C1-C4)alkyl, halogen, hydroxy or (C1-C4)alkoxy, or R1g and R2g are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group,

103. A process according to claim 102, wherein R1g and R1h are 4-chlorophenyl, R2g and R2h are hydrogen, R3 is methyl, R4 is hydrogen or methyl, R5, is ethoxycarbonyl, R6 is hydrogen and A is methylene.

104. A process according to claim 103, wherein R4 is hydrogen.

105. A process according to claim 103, wherein R4 is methyl.

106. A process for preparing substituted-phenyl substituted-alkyl ethers of the formula:

wherein R1j is (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl: R2j is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl, R3 and R4 are each hydrogen or (C1-C4)-alkyl; R5" iS carboxy or (C1-C4)alkoxycarbonyl; and A iS (C1-C4)alkylene; in which the phenyl for R1j and R2j may be substituted with (C1-C4)alkyl, halogen or hydroxy, or R1j and R2j are linked together with the nitrogen atom to which they are connected to form a pyrrolidinyl group;
and pharmaceutically acceptable salts thereof which comprises subjecting a compound of the formula:

wherein R3, R4 and A are each as defined above;
R1d is (C1-C4)alkyl, (C5-a7)cycloalkyl, phenyl or benzyl;
R2d is hydrogen, (C1-C4)alkyl, (C5-C7)cycloalkyl, phenyl or benzyl;
R5, is carboxy or (Cl-C4)alkoxycarbonyl; and R6" is (C1-C4)alkoxy; in which the phenyl for R1d and R2d may be substituted with (C1-C4)alkyl, halogen, hydroxy or (Cl-C4)alkoxy, or R1d and R2d are linked toeether with the nitrogen atom to which they are connected to form a pyrrolidinyl group;
to dealkylation.

107. A process according to claim 106, wherein R1d and R1j are 4-chlorophenyl, R2d and R2j are hydrogen, R3 and R4 is methyl, R5, is ethoxycarbonyl, R5" is carboxy, R6" is methoxy and A is methylene.

108. A compound of the formula:

wherein R1, R2, R3, R4, R5, R6 and A are each as defined in claim 1 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

109. A compound of the formula:

wherein R1b, R2b, R3, R4, R5', R6, and A are each as defined in claim 2 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

110. A compound of the formula:

wherein R1c, R2c, R3, R4, R5', R6 and A are each as defined in claim 26 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 26 or by an obvious chemical equivalent thereof.

111. A compound of the formula:

wherein R1d, R3, R4, R5, R6 and A are each as defined in claim 50 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 50 or by an obvious chemical equivalent thereof.

112. A compound of the formula:

R1d', R2d', R3, R4, R6, and A are each as defined in claim 69 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 69 or by an obvious chemical equivalent thereof.

113. A compound of the formula:

wherein R1f, R2f, R3, R4, R6, R7 and A are each as defined in claim 76 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 76 or by an obvious chemical eqivalent thereof.

114. A compound of the formula:

wherein R1d, R2d, R3, R4, R6 and A are each as defined in claim 94 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 94 or by an obvious chemical equivalent thereof.

115. A compound of the formula:

R1h, R2h, R3, R4, R6 and A are each as defined in claim 102 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 102 or by an obvious chemical equivalent thereof.

116. A compound of the formula:

wherein R1j, R2j, R3, R4, R5" and A are each as defined in claim 106 or pharmaceutically acceptable salt thereof whenever prepared by the process of claim 106 or by an obvious chemical equivalent thereof.

117. 2-[4-(4-Chloroanilinomethyl)phenoxy]propionic acid or pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 10, or by an obvious chemical equivalent thereof.

118. Ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methyl-propionate or pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 13, or by an obvious chemical equivalent thereof.

119. 2-[4-(4-Chloroanilinomethyl)phenoxy]propionic acid or pharmaceutically acceptable salts thereof whenever prepared by the process of claim 34, or by an obvious chemical equivalent thereof.

120. Ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methyl-propionate or pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 37, or by an obvious chemical equivalent thereof.

121. 2-[4-(4-Chloroanilinomethyl)phenoxy]propionic acid or pharmaceutically acceptable salts thereof whenever prepared by the process of claim 58, or by an obvious chemical equivalent thereof.

122. Ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methyl-propionate or pharmaceutically acceptable salts thereof when-ever prepared by the process of claim 63, or by an obvious chemdcal equivalent thereof.

123. 2-[4-(4-Chloroanilinomethyl)phenoxy]propionic acid or pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 71, or by an obvious chemical equivalent thereof.

124. Ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methyl-propionate or pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 85, or by an obvious chemical equivalent thereof.

125. 2-[4-(4-Chloroanilinomethyl)pheno]cy]propionic acid or pharmaceutically acceptable salts thereof whenever prepared by the process of claim 96, or by an obvious chemical equivalent thereof.