CA1265148A - Process for the manufacture of fluorinated recorcinol ethers - Google Patents

Abstract

Abstract 4-Arylresorcinol ethers of the formula (I) in which R1 is lower alkyl, R2 is fluorinated lower alkyl, R3 is hydrogen, lower alkoxy, trifluoromethyl or halogen, alk is an alkylene or hydroxyalkylene radical which is un-interrupted or interrupted by oxygen, one of the radicals R4, R5 and R7 is a group of the formula -NH-C(=O)-R8, a radical R4 or R5 which differs from this is a radical R9 and a radical R7 which differs from this is a radical R10, R6 is hydrogen, lower alkyl, trifluoromethyl, halogen, carboxyl which is free, esteritied or amidated, cyano or lower alkanoyl, R8 is carboxyl which is free, esterified or amidated or 5-tetrazolyl, R9 is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and R10 is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, cyano or carboxyl which is free, esterified or amidated, and their salts have antiallergic and antiinflammatory properties.
They are prepared, for example, by reacting compounds of the formulae in which one of the radicals X5 and X6 is hydroxyl which is free or in salt form and the other is a radical -O-alkH
substituted by reactive esterified hydroxyl or epoxy.

Description

-1- 214~9-6851 Process for the manu~actur~ of fluorinated reso~cinol ethers The invention r~lates ~o a process for the manufacture of l-fluoroalkylated 4-acylresorcinol ethers of ~he formula O~alk-0 ~ ~5 (I) in which R1 is lower alkyl, R2 is fluorinated lower alkyl, R3 is hydrogen, lower alkoxy, trifluoromethyl or halogen, alk is an alkylene or hydroxYalkylene radical which is ~Ininterrupted or 1nterrupted by oxygen, one of the radlcals R4, R5 and R7 is a group of the for~ula -N~-C(~0)-R8, a radical R4 or R5 which differs from this is a radical Rg and a radical R7 which differs from this is a radical R1or R6 is hydrogen, lower alXyl, trifluoromethyl, halogen, carboxyl which ls free, esterified or amidated, cyano or lower al~anoyl,~ is carboxyl which is free, esterified or amidated or 5~tetrazolyl, Rg is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and R1o is hydroqen, lower alkyl, lower alko~y, halogen, trifluoromethyl, cyano or carboxyl which is free, esterified or amidated, and salts thereof r to said compounds and salts per se, to pharmaceutical products containing said compounds and salts and to a process for the manufacture oE said products.
Alkylene radicals alk can have not more than 9 chain members and are, :Eor example, straight-chain alkylene radicals of the formula

2)m (Ia) ~3 6~

- 2 - 214~9-6~51 in which m is an integer from 2 to not more than 9, but can also be alkylene rad;ca~s which are branched, in part;cular in POsitions uhich are higher than the ~-position and lower than the ~position, and are preferably lower alkylene radi-cals (straight-chain ancl branched) of the type mentioned.
Alkylene radicals interrupted by oxygen are, for example, mono-, d;- or trioxaalkylene radicals, for example of the formula -(CH2)n,----~O-(CH2)n~ (Ib) ;n wh;ch n and n ;ndependently of one another are 2, 3 or 4 and k ;s 1, 2 or 3, and are, in particular, oxa- or dioxa-lower alkylene radicals, for example of the formula Ib in which n and n is 2 and k is 1 or 2.
Hydroxyalkylene radicals ~h;ch are ~ninterrupted or interrupted by oxygen are, for example, hydroxyalkylene, hydroxy~oxa3alkylene or hydroxy~dioxa)aLkylene radicals in which the hydroxyl group is bonded in a position higher than the ~-position and louer than the ~-posi~ion, for example radicals of the formula --~(C}I2)l, ~ CH2cH(oH)cH2-~c-(cH2)l~ ~Ic) in which l and l independently of one another are Z or 3 and o and p independenely of one another are O or 1, and are, in particular, corresponding hydroxy-lower alkylene radicals, and furthermore hydroxy~oxa)-lower alkylene radicals.
Esterified carboxyl is, for example, lower alkoxy-carbonyl, but in the case of Rô~ can also be N,N-di-lower alkylamino-lower alkoxycarbonyl, N,N-lower alkyleneamino-lower alkoxycarbonyl, substituted or unsubstituted N,N-(aza)-lower alkyleneamino-lo~er alkoxycarbonyl, N,N-(oxa)-lower alkyleneamino-lower alkoxycarbonYl or N,N-(thia~-lower alkyleneamino-lower alkoxycarbonyl.
Amidated carboxyl is~ for example, carbamyl, N-mono-or N,N-di lower alkylcarbamy', and furthermore N,N-lower ~LZ6~

alkylene-, N,N-~aza)-lower alkylene-, N,N-(oxa)-lower alkylene- or N,N-(thia)-lower alkylene-carbamyl.
"Lower" organic compounds above and below and groups derived therefrom are to be understood, for example, as those which contain not more than 7, in particular not more than 4, carbon atoms (C a~oms~.
Fluorinated lower alkyl has, ~or example, not more than 3, in particular terminally bonded, fluorine atoms and is, for example, mono-, di- or trifluoro-c1-c4-alkyl~ such as trifluoromethyl, 3-Fluoropropyl, 3,3-difluoropropyl or

3,3,3-tri~luoropropyl.
Lower alkyl is, for example, C1-C4-alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, and furthermore secondary or tertiary butyl.
Lower alkoxy is, for example, C1-C4-alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy.
Halogen hasO for example, an atomic number of not more than 53, in par~icular 17 to no~ more than 53, and ;s, for example, fluor;ne, chlorine, bromine or iodine.
Lower alkanoyl ;s, for example, C1-C7-alkanoyloxy, such as formyl, acetyl, propionyl, butyryl, valeroyl or pivaloyl Straight-cha;n lower alkylene is, for example, straight-chain c2-c~-alkYlene, such as ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene or 1,7-heptylene, but can also be 1,2-propylene, 1,3-butylene or Z,4-pentylene.
Branched lower alkylene is~ -For example, branched C4 C6-alkylene~ such as 1,3-~2-methyl~-propylene or 1,3-(2,2-di methyl)propylene.
Oxa-lower alkylene is, for example, 3- or 4-oxa-C5-C7-alkylene, such as 1,5-(3-oxa)pentylene or 1,7-t4-oxa)-heptylene; d;oxa-lower alkylene is, for example, 1,7-(3,5-dioxa)heptylene.
Hydroxy-lower alkylene is, for example, 2-, 3- or 4-hydroxy-C3~C7~alkYlene~ such as 1~3-(2 hydroxy)propylene, 1,4-~2-hydroxy)butylene, 1,5-(3-hydroxy)pentylene, ~,6-~2-., ~s~

4 --hydroxy)hexylene or 1,7-(4-hydroxy)heptylene. Hydroxy(oxa)-lower alkylene is, for example, 2-hydroxy-4-oxa-C6-C7~
alkylene, such as 1,6-(2-hydroxy-~t-oxa)hexylene or 1,7-(2-hydroxy-4-oxa)heptylene.
Lower alkoxycarbonyl is, for example, C~-c4-alkoxy-carbonyl, such as methoxy-, ethoxy-, propoxy-, isopropoxy-or butoxycarbonyl.
N~N-Di-lower alkylamino-lower alkoxycarbonyl is, for example, N~N-di-c1-c4-alkylamino-c2-c~-alkoxycarbonyl~
such as 2-(dimethylamino)ethoxycarbonyl, 2-(d;ethylamino)-ethoxycarbonyl or 3-(dimethylamino)propoxycarbonyl.
N,N-Lower alkyleneamino-lower alkoxycarbonyl is, for example, 5-membered to 7-membered N,N-alkyleneamino-C2-~4-alkoxycarbonyl, such as 2 (pyrrolidino)-, 2-(piperidino~- or 2-(tetrahydroazepino~ethoxycarbonyl.
Substituted or unsubstituted N,N-(aza)-lower alkylene-amino-lower alkoxycarbonyl is, for example, 5-membered to 7-membered N,N-(aza)alkYleneam;no-~z-C4-alkoxycarbonyl, such as 2-(piperazino)ethoxycarbonyl or 2-(4-methylpiperaz-;no)ethoxycarbonyl.
N,N-(Oxa)- or N,N-tthia)-lower alkylamino-lower alkoxycarbonyl is, for example, 5-membered to 7-membered N,N-(oxa)- or N,N-(thia)-alkyleneamino-C2-C4-alkoxycarbonyl, such as 2-tmorpholino)- or 2 (thiomorpholino)ethoxycarbonyl.
N-Mono- or N,N-di-lower alkylcarbamyl is, for exa~ple, N-C1-C7-alkyl- or N,N-di-C1-C~-alkylcarbamyl, such as N-methyl-~ N-ethyl- or N,N-d;methylcarbamyl.
N,N-Lower alkylenecarbamyl or N,N-(aza)-, N,N-(oxa)~
or N,N-(thia)-lower alkylenecarbamYl is, for example~ ~-membered to 7-membered N,N-alkylene-, N,N-~aza)alkylene-, N,N-(oxa)alkylene- or N,N-(thia)alkylenecarbamyl, such as pyrrolidino-, piperidino-, pyridazino-, (4-methyl)piperazino-, morpholino- or thiomorpholinocarbonyl.
Preferred salts of compounds of the formula I are pharmaceutically acceptable salts, such as metal salts, ammonium salts or salts with organic bases. Metal salts are, For example, correspond;ng alkal; metal and alkaline earth ~s~

metal salts, ~or example lithium, sodium, potass;um, magnes-ium or calcium salts, and furthermore pharmaceutically accept-able transition metal salts, such as zinc or copper salts.
Salts with organic bases are formed, ~or example, from com-pounds of the formula I in which R6 and/or R7 is carboxyl and/or R8 is carboxyl or 5-tetrazolyl with mono-, di- or trisubstituted organic amines, such as corresponding alkyl-amines, hydroxyal~ylamines, suitable heterocyclic compounds containing at least one N atom, such as morpholine, thio-morpholine, piperidine or pyrrolidine, amino-saccharides which may or may not be N-substituted~ for example with N-methyl-D-glucamine, or basic amino acids, such as lysine, arginine, histidine or ornithine, those with the L-configura-tion being preferred. Alkylam;nes are, for example, mono-, di- or tri-lower alkylamines~ such as ethyl-~ tert.-butyl-, diethyl-, diisopropyl-, trimethyl- or triethylamine.
~ydroxyalkylamines are, for example, mono-, di- or tri-hydroxyalkylamines~ such as mono-, di- or triethanolamine or diisopropanolamine, or hydroxy-lower alkyl-Lo~er alkylamines, such as N~N-dimethyl- or NpN-diethylamino-ethanol or tri-(hydroxymethyl)methylamine.
Other salts are pharmaceutically acceptable acid addition salts, such as hydrohalides~ methanesulfonates, N-cyclohexylsulfamates, maleinates, fumarates, maleates or tartrates of compounds of the formula I in which the radical R8 is capable of form;ng corresponding salts.
The compounds of the formula I with chiral C atoms can, depending on the number thereof, be present in forms wh;ch are enantiomeric or diastereomer;c with respect to one another or as mixtures thereof, such as diastereomer mixtures, racemates or racemate mixtures.
The novel compounds are distinguished by useful pharmacological properties.
Thus, they have an antiallergic action based on a pronounced LTD4-(leucotriene-D4)~ and PAF-(PAF-aceto-ether~~antagonism. The LTD4-antagonist;c proper~ies of the compounds according to the ;nvention can be demonstrated, for ~L26~

example, in vitro by means of their inhibiting ef-fect, detectable in concentrations from about 0.03 to about 0.10 ~mol/l, on contractions triggered off on the ;solated guinea-pig ;leum by LTD4, and in vivo by means of their ;nhib;-ting effect, detectable on intravenous treatment in doses from about 0.08 mg/kg or on aerosol treatment from an active ingredient content of about 0.025% by weight, on bronchospasms in gu;nea-pigs triggered of~ by LTD~. They furthermore have a pronounced inh;bition on LTDlt synthesis, which can be demonstrated in vitro by means of the ;nh;b;-tion of aggregation of per;toneal PMN in rats.
In compar;son with antiallergic compounds of similar structure, the compounds according to the invention are dis-tinguished by a longer durat;on of action and, in addition to the above LTD4-antagonistic action, exhibit phospho-lipase-;nhib;t;ng propert;es which are novel for this class of compound and a pronounced anti-inflammatory and dermato-phlogistat;c action as ~ell as a pronounced inhibiting effect on leucotr;ene-B4 b;osynthes;s9 such as can be demonstrated ;n vitro in concentrat;ons from about 0.5 ~mol/l, these propert;es already themselves being very useful and also supplementing the antialler~ic action ;n a des;rable manner.
The phospholipase-;nh;biting properties can be demonstrated, for example, ;n vitro by means of the inhibition, detect-able ;n concentrations from about 10 ~mol/l, of the activ;ty of phospholipases A2 ~from human leucocytes) and C (from human platelets), and the ant;inflammatory or dermatophlogis-t;c propert;es can be demonstrated in vivo by means of the ;nhibiting effect, in concentrations from about 10 mg/ml, on experimental croton o;l ear oedema ;n rats.
The compounds accord;ng to the invention can accord-;ngly be used as antiallergics, for example for the treatment of asthma, hayfever, rhinitis and skin allergies, but in particular as ant;;nflammator;es, espec;ally for the treat-ment of inflammatory rheumatic diseases, and as skin and mucous membrane phlogistatics, for the treatment of inflam-matory dermatoses of the most d;verse origins, but especially of allerg;c origin, for exa~ple for the treatment af inflam matory skin irritations, contact dermatitis, exanthema, burns and inflammations of the mucosa of the eyes, l;ps, mouth and gen;tal or ana~ region.
The inh;bi~ing effect on experimenta~ ear oedema in rats can be achieved in accordance with the method of G~ Tonelli and L. Thibault, Endocr;nology 77, 625 ~1965).
The follouing experimental des;gns, for example, can be us~d to determine the other properties mentioned.
Inh;b;t;ng effect on_LTD4-induced contract;ons of the . . _ . . _ .
guinea-pig ileum Contractions are tr;gg~r~d off by synthet;c LTD4 tleucotr;ene D4, potassium salt) on îleum segments ~hich have been taken from ~uinea-pigs ~ith a body weight of 300 to 400 9, fixed in an orsan bath in Tyrode solut;on ~38C~
gassing uith 95X of 2 and 5% of C02) and loaded with 1p, and the degree of the contract;ons ;s recorded. The degree of inhib;tion of these contractions to be attributed to the LTD4-antagonist;c action of the test substance is m~asured.
The concentration, designated the IC50, of the test substance which reduces LTD4-induced contractions to SOX of the start-ing value is determined. In this experimental design, for examp(e, an IC50 value of O.DB7 ~mol/1 uas obtained for the sodium salt of N-~3-C3-~4-ace~y~ hydroYy-2-propy~-phenoxy) 2-hydroxy-propoxy]-2-cyano-phenyl~ oxamic acid according to U.S. Pa-tent Specification No. 4,448,7291and an IC50 value of 0.012 ~moL/1 was obtained for the sodium salt of N- ~13- ~3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy~ -4-bromo-6-methyl-phenyl~ -1H-tetrazole-5-carboxamide according to the invention.
In vitro test for the determination of the inhibition of phospholipase A2 from human leucocytes Neutrophilic polymorphonuclear human leucocytes are isolated, starting from "buffy coats" by multi-stage frac-tional sedimentation and are deep-froæen. The phospholipase A2 is extracted from the cell suspension by homogen-isation with the addition of ice-cold 0.36N H2SO4 in 2 M NaCL, 1~6S~f~f~

and the supernatant obtaineb after centr;fugation at 10,000 9 is dialysed against sodium acetate buffer, pH 4.5.
To determine the enzyme activity, the enzyme (10-30 ~9 of protein) is incubated in 0.1 M ~ris/HCl buffer, pH 7, w;th the addition of 1 mM CaCl2 and substrate consisting of phospholipids (2 ~M), rad;oactively labelled biosynthetically with 14C-oleic acid, of Escherichia coli, at 37C for 1 hour. The reaction is stopped by add;tion of Dole reagent ~;sopropanol/heptane/IN H2S0~ 40:10:1, volume/volume~ and the 1~C-ole;c acid rel~ased s~lectively by phospholipase A2 is extrac~ed. The substrate also co-extracted is removed completely by f;ltration of the extract through 3 sil;ca gel column. The 14C-oleic acid in the eluate ;s determined by radiometry~
To determine an inhibit;ng effsct of test substances on the phosphol;pase A2, these are added to the incubation batch as solutions in ~ater, dimethylsulfoxide ~f;nal concen-trat;on in the batch up to S vol X~ or ethanol tfinal concen-tration in the batch up to 2.5 vol X). The action potency of the test substances ;s expressed by the IC50, ;.e. the concentrat;on ~h;ch causes an inhibition of 50% o~ the con-trol activ;ty. The IC50 is determined graph;cally by plotting the percentage inhibition on the ordinate against the logarithm of the concentration t~M) on the abscissa.
In th;s experimental design, for example, an IC~o value of 1Z ~mol/l was obtained for the sodium salt of N-~
¦3-~3-C4-acetyl-3-hydroxy-2-t3,3,3-trifluoropropyl)-phenoxy~-propoxy3-4-bromo-6-methyl-phenyl~-1H- tetrazole-5-carboxamide and an IC50 value of 13 ~moltl ~as obtained for N-~3-~3-~4-acetyl-3-hydroxy-2-~3,3,3-tr; f luoropropyl)-phenoxy~-propoxy~-4-chloro-6-methyl-phenyl3~-1H- tetrazole

-5-carboxamideJ wh;lst the sod;um salt of N-~3-C3-~4-acetyl-3-hydroxy-2-propyl-pheroxy)-2-hydroxy-propoxy~-2-cyano-phenyl~-oxamic ac;d according to U.S~ Patent Spetifica-tion No. 4,448,729 st;ll showed no action even at 100 ~mol/l.

~, :P ~6~
- 9 _ 21489-685l Calcium ionophore-induced synthesis of LT~4 Peritoneal exudate tneutrophiles) of Wistar rats (RA 25, male) are obtained 24 hours after intraperitoneal inject;on of 12% sodium caseinate. Cells (1 x 107/ml~ are stimulated by Ca ionophore A 23187 t1 x 10 6 M) for 4 minu-tes. Supernatants are investigated for their ability to ~rigger off PMN aggregation in vitro. Inhibiting substances in dimethylsulfoxide are added S minutes before the addition of the ionophore.
The results are ~iver, in % inhibition of the control twithout an ;nhibitor) and as the ICso.
The in~ention particularly relates to compounds of the formula I in wh;ch R1 is lower alkyl, R2 is fluorinated lower alkyl having not more than 3 fluorine atoms~ R3 is hydrogen, lower alkoxy, tr;fluoromethyl or halo~
gen, alk is lower alkylene or hydroxy-lower alkylene wh;ch ;s un;nterrupted or ;nterrupted by oxygen~ ;n part;cular a radi-cal of the formula -(CH2) - (Ia), -~CH2) ,-[0-(CHz) ]-k (Ib~
or --~(CH2)l ~ CH2 CH(OH)-CH2-k~CH2)l~ tIc~, in which k is 1, 2 or 3, L and l independently of one another are 2 or 3, m is an ;nteger from 2 to not more than 9, n and n independently of one another are 2, 3 or 4 and o and p inde-pendently of one another are 0 or 1, one of the radicals R4, Rs and R7 is a group of the formula -NH-(C=0)-R8~ a radical R4 or Rs which d;fters ~rom eh;s is a radical R9 and a radical R7 which differs from this ;s ~ radical R10, R6 is hydrog~n, lower alkyl, trifluoromethyl, halogen, lower alkanoyl, carboxyl, lower alkoxycarbonyl, cyano, carbamyl or N-mono- or N~N-di-lower alkylcarbamyl, R8 is on the one hand carboxyl, lower alkoxycarbonyl, N,N-di-lower alkylam;no-lower alkoxycarbonyl, N,N-lower alkyleneamino-lower alkoxycarbonyl, carbamyl, N-mono- or N,N-di-lower alkyl-carbamyl or N~N-lo~er alkylene- or N,N-taza)-lower alkylene-, N,N-(oxa)-lower alkylene- or N,N-tthia~-lower alkylene-carbamyl, or on the other hand 5-tetra~olyl, Rg is hydrogen, lower alkyl, lower alkoxy~ halogen or trifluoromethyl is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, carboxyl, lo~er -10- 21489-6~51 alko~ycarbonyl, cyano, carhamyl or N-mono- or N,N-di.-lower alkylcarbamyl, and their salts, in particular pharmaceutically acceptable salts.
The inventlon preferably relates to compounds of ~he formula I in which Rl is lower alkyl haviny not more than 4 C
a~oms, such as me~hyl, R2 is ~--fluoro,~-difluoro- or ~,~,~-trifluoro-lower alkyl having not more than 4 C atoms, such as trifluoromethyl or 3,3,3-trifluoropropyl, or furthermore 3-fluoropropyl or 3,3-difluoropropyl, R3 is hydrogen, R4 is hydrogen t lower alkyl having no mare than 4 C atoms, such as methyl, trifluoromethyl or halogen with an atomic nurnber of not more than 35, such as chlorine or bromine, R5 is oxaloamino, lower alkoxyoxalylamino with 3 to not more than 6 C atoms, such as methoxy- or ethoxyoxalylamino, or 5-tetrazolylcarbonylamino, R6 is hydrogen, lower alkyl having not more than 4 C atoms, such a~
methyl, halogen with an atomic number of not more than 35, such as chlorine or bromine, tri~luorome~hyl, lower alkoxycarbonyl having not more than 5 C atoms, such as ethoxycarbonyl, cyano or carbamyl, R7 is hydrogen, lower alkyl having not more than 4 C
atoms, sueh as methyl, halogen with an atomic number of not more than 35 r such as chlorine, earbamyl or cyano and alk is strai~ht-chain, terminally bonded lower alkylene having 2 to not more than 5C atoms, such as 1,3-propylene, or hydroxy-lower alkylene having 3 to not more than 7 C atoms, in which the hydroxyl group is bonded in a position higher than the ~-position and lower than the position, such as 1,3-(2-hydroxy)propylene, and their salts, in particular pharmaceutically acceptable salts, with bases.

, ~ .,.,r) -lOa- 214~9-6~51 The invention particularly relates to compounds of the formula I ln whi~h R1 is lower alkyl hav:Lng not more than 4 C
atoms, such as meth~l, R2 is ~-fluoro-,~ ,~,-difluoro- or~,~,~-trifluoro-lower alkyl hav.ing not more than 4 C atoms, such as 3,3,3-trifluoropropyl, or fur-thermore 3~1uoropropyl or 3,3-difluoropropyl, R3 is hydroyen, R~ is hydrogen, lower alkyl, having no more than 4 C atoms such as methyl, trifluoromethyl or halogen wlth an atomi~ number of not more than 35, such as .~

~2~S~

~ 1489-6851 chlorine or bromine, R5 is oxa~oamino, lower alkoxyoxalyl-amino having 3 to not more than 6 C atoms, such as methoxy-or ethoxyoxalylamino, or 5 tetrazolylcarbonylamino~ Ro is hydrogen, lo~er alkyl having not more than 4 C atoms, such as methyl, halogen with an atomic number of not more than 35, such as chlorine or bromine, trifluoromethYl or cyano, R7 ;s hydrogen, lower alkyl having not more than 4 C atoms, such as methyl, cyano or halogen with an atomic numbe.r of not more than 35~ such as chlorine or bromine, and alk is straight-chain, term;nally bonded lo~er alkylene having 2 to not more than S C atoms, such as 1,3-propylene, or hydroxy-lower a~kylene having 3 ~o not more than 7 C atoms, in which the hydroxyl group is bonded in a position higher than the ~-position and lo~er than the ~-position, such as 1,3-(2-hydroxy)propylene, and their salts, in particular pharma-ceutically acceptable salts, with bases.
The invention relates very particularly tocompounds of the formula I in which R1 is lower a~-kyl hav;ng not more than 4 C atoms, such as methyl, 2z ;s ~, ~,~-trifluoro-lower alkyl hav;ng not more than 3 C atoms, such as 3,3,3-tr;fluoropropyl, R3 is hydrogen and R5 is oxaloami no~ lower alkoxyoxalylam;no hav;ng 3 to not more than 6 C
atoms, such as methoxy- or ethoxyoxalylamino, or 5-tetra~olyl-carbonylamino~ R4 is lower alkyl havina not more than 4 C atoms,such as methyl, R6 is halogen with an atomic number of not more than 35, such as chlorine or bromine, or cyano and R7 is hydrogen and alk is strai~ht-chain, term;nally bonded lower alkylene hav;ng 2 to not more than 5 C atoms, such 2S
1,3-propylene~ or furthermore hydroxy-lower alkylene ha~ing 3 to not more ~han 7 C atoms9 in which ~he hydroxyl group is bonded in a position higher than the ~-position and lower than the ~-pos;tion, such as 1,3-(2-hydroxy)propylene, and their salts, ;n particular pharmaceutically acceptable salts, with bases.
The invention above all relates to compounds of the formula I ;n wh;ch R1 is lower alkyl having not more than 4 G atoms, sùch as methyl, R2;s~-fluoro-,~ ,~-difluoro-,, ^~

~Z~

- 12 - 2148g-6851 or ~,~-trifluoro-lower alkyl having not more than 3 C
atoms, such as 3,3,3-trifluoropropyl, R3 and R7 are hydrogen, one of the radica~s R4 and R6 is lower alkyl having not more than 4 C atoms, such as methyl, and the other is halogen with an atomic number of not more than 35, such as fluorine, chlorine or bromine, R5 is oxaloamino or S-tetrazolyl-carbonylamino and alk is s~raight-chain, terminally bonded lower alkylene having Z to not more than 5 C atoms, such as 1,3-propylene, or furthermore ~lydroxy-lower alkylene havin~
3 to not more than 7 C aeoms, ;n ~hich the hydroxyl group is bonded in a position higher thar, the K-posltion and lower than the ~pos;tion~ such as 1,3-(2-hydroxy)propy~ene, and their salts, in particular pharmaceutically acceptable salts, w;th bases.
In particular, the invention rela-tes to the compounds of the formula I mentioned in the examples and their salts, in particular pharmaceutically acceptable salts, with bases.
The process for the m~nufacture of the compounds according to the invention is based on methods which are known per se, any comprises a) rearran~ing a compound Of ~ne ~ormu~a ~-~ /R3 R6~

R~-C(=O)~ G-alk-O~ ~ R ~II) ~2 ~7 or b) reacting a compound of the formula ~ 3 R6~

X ~ ~ ~ \O~alk-O~ 5 (III) in ~h~ch X1 is free or etherified hydroxyl, with a compound of the formula R1-xz tIV), in ~hich X2 is free or func-tionally modified carboxyl, orc~ converting X3 in a compound of the formula ~26S~

~ 13 - 21489-6~51 R~ ,,~ ~.5 R6\ ~

HO ~ allc--O ~ Rl t V ) in ~hich X3 is a radical whlch can be converted ;nto the fluorinated lower alkyl radical R2, or in a salt thereof, ;nto fluorina~ed lower alkyl R~, or d) converting X~ in a compound of the formula R~ t~
X~ ~ O-alk-O~ (VI) in ~hich X4 is a radical which can be converted into hydro~yl, into hydroxyl, or e) reacting compounds of the formulae R~ ,R3 R~ R4 Q ~1 ( V I I ~ and 1~ ( V I I I ) 2 ~7 in which one of the radicals X5 and X6 ;s hydroxyl whi ch is free or in salt form and the other ;s a radical -O-alkH
substituted by reactive esterified hydroxyl or epoxy, i.e.
an alkoxy radical corresponding to alk and subst~tuted by reactive esterified hydroxyl, a mono-~ di- or trioxaaLkyl radiral corresponding to alk or an alkoxy or mono- or dioxa-alkylene radical corresPonding to alk and substituted by epoxy, wi th one another, or f) reacting a compound of the formula R~ t~R3 HO~ \-~ ~O-alk-O \-~ ~s' (IX) ~2 ~71 in which one of the radicals R4', R5' and R7~ ~s the amino 1 ':' `~

~5~

group, a radical R4' or R5' which differs from this is a radical R9 and a radical R7' which differs from this is a radical R10, or a sa~t thereof, with a compound of the formula X7 - Rô~ (X~

in wh;ch R~' is a carboxyl group which is free, esterified or amidated or 5-tetrazolyl which is protected, if approp-riate, in the 1-posit;on and X7 is a carboxyl group which is free, esterified, amidated, converted into an anhydride or, if R8' is 5-tetrazolyl protected in the 1-position, in salt form, and, if appropriate, detaching the protective group in the 1-position of a tetrazolyl group R8, or g) converting X8 in a co0psund of the formula R, ,.~ ,~3 ~ R4"

HO/ \,s~ \O-alk-O 1~ Rs (XI) in which one of the radicals R4", Rs" and R7" is a radical Xg, a radical R4" or Rs" which differs from this is a radical R9 and a radical R7" ~hich differs froM this is a radical R1o and X8 is a radical which can be converted into the desired group of the formula -NH-C~=O)-R8, into this group, or h) converting alk' in a compoun~ of the formula HO/ 'A~ ~o-alk~~O A ~S tI') in which alk' is a radical which can be converted into a group alk, into a group alk, and, if desired, in each case converting a compound obtainable according to the process into another compound of the formula I, separating an isomer mixture obtainable according to the process and isolating the ~LZ6S~

desired isomer(s), and/or converting a free compound obtain-able according to the process înto a salt or salt obtainable according to the process into the free compound or into another salt.
Free or etheriFied hydroxyl X1 in formula III is, for example, lower alkoxy, such as methoxy.
free or functionally modified carboxyl X2 in formula IV is, for example, carboxyl which is free, esterified or converted into an anhydride, such as carboxyl, lower aLkoxy-carbonyl, for example methoxy- or ethoxycarbonyl, halogeno-carbonyl, for example chlorocarbonyl, or carboxyl converted into an anhydride~ of the formula -C(=O)-O C(=O)-R1 (Iva).
Radicals X3 in formula V which can be converted into fluorinated lower alkyl radicals R2 are, for exampLe, fluorinated lower alkenyl radicals, such as 3-fluoro-, 3,3-difluoro- or 3,3,3-trifluoro-prop-1-enyl or 3-fluoro- or 3,3-difluoro-prop-2-enyl, fluorinated lower alkinyl radicals, such as 3-fluoro-, 3~ difluoro- or 3,3,3~trifluoro-prop-1-ynyl, and furthermore fluorinated hydroxy lower alkyl radi-cals, such as 3~fluoro-, 3,3-difluoro- or 3,3,3-trifluoro-1-hydroxy-propyl, and furthermore halogen with an atomic number of 19 to not more than 53, such as bromine or iodine, and furthermore chlorine.
Radicals X~ in formula VI which can be converted ;nto hydroxyl are, for example, etherified or esterified hydroxyl groups. Etherified hydroxyl X4 is, for example, aliphatically etherified hydroxyl, ~or example lower alkoxy, such as methoxy, or lower alkenyloxy~ such as allyloxy, phenyl-lower alkoxy, in particular subst;tuted or unsubsti-tuted phenyl-lower alkoxy, such as benzyloxy, and furthermore tetrahydropyran-2-yloxy or silyloxy, in particular tri-lower alkylsilyloxy, for example trimethylsilyloxy. Ester;fied hydroxyl X4 is, for example, hydroxyl ester;fied with a carboxylic acid, such as an aliphatic or aromatic carboxylic acid~ or with an aliphatic or aromatic half-ester of carbonic acid, such as lower alkanoyloxy, for example acetoxy, sub-stituted or ur,substituted benzoyloxy, for example of the ~L~S~

fo~rnula R1-Ct=O)-O-~ halogenated or non-halogenated louer alkoxycarbonyl, ~or example methoxy-, ethoxy- or tert;ary butoxycarbonyl, 2,2,2-triiodoethoxy- or 2,2,2-trichloro-ethoxycarbonyl, substituted or unsubstituted phenyl-lower alkoxycarbonyl, in particular 1-phenyl-lo~er alkoxycarbonyl, for example benzyloxycarbonyl, or substituted or unsubstitu-ted phenoxycarbonyl.
Hydroxyl Xs in the formula VII or X6 in formula VIII
or carboxyl in formula X, in salt form, is, in particular, in the form of an al~ali metal salt, for example as the sodium or potassium salt.
Alkoxy radicals X5 in formula VII and X6 in formula VIII which are substituted by reactive esterified hydro~yl or epoxy are, for example, radicals Qf the formulae -o-(~H2)mX, ~ ~ ~)~}k (~)n' ~ (Cl~2)~C~2C}~(011) C112--tO-tCH2 ~ OX, ~ ~)~ ~--X', in w~ich X is reactive esterified hydroxyl and X' is 1,2-epoxyethyl. Reactive esterified hydroxyl here is, for example, halogen, such as chlorine, bromine or iodine, or organic sulfonyloxy, such as lower alklanesulfonyloxy, for example methanesulfonyloxy, or substituted or unsubstituted benzenesulfonyloxy, for example benzene-, p-bromobenzene- or p-toluenesulfonyloxy.
Carboxyl X7 in formula X which is free, esterified, amidated or converted into an anhydride is, for example, free carboxyl, esterified carboxyl R8 or carboxyl esterified ~ith a substituted or unsubst;tuted phenol, such as pheno~y-, 4-nitrophenoxy- or 2,4-dinitrophenoxycarbonyl~ amidated carboxyl R8 or activated carbamyl, such as 1-imidazolyl- or 1-(Z,5-d;methylimidazolyl)-carbonyl, or carboxyl converted into an anhydride with a hydrogen halide acid~ such as halogeno-carbonyl, for example of the formula Hal-Ct=O)-, in ~hich Hal is chlorine, bromine or iodine, in particular chlorine.
Starting substances X are, in particular, those of the formulae R8"-R8" (Xa)~ in ~hich R8" is free or esterified carboxyl, and Hal-C~=O)-Rg' tXb). 5-Tetra~olyl radicals Ra~ in protected form are, for example, 1-(K-~ 17 -aralkyl)-tetr~zol-5-yl radicals which are unsubstituted or substituted in the aryl part, such as 1-benzylt~trazol-5-yl or 1-tp-methoxybenzyl)-tetrazol-S-yl.
A radical X~ in formula XI which can be converted into the group of the formula -NH-C~=O)-Rg ;s, for example, a radical which can be converted ;nto th;s group by solvolysis, i.e. hydrolysis, alcoholysis ~reac~ion with the alcohol corresponding to the desired esterified carboxyl group R~) and/or aminolysis treaction with ammonia or an amine corres-pondins to the desired amidated carboxyl group R8), for example a group of the formula -NH-XA, in which XA is a functionally modified oxalo group which is other than a free, esterified or amidated oxalo group and can be converted into this. Such functionally mod;f;ed oxalo groups are preferably those wh;ch contain, as the functionally modified ~-carbonyl grouping, thioxomethylene~ iminomethylene or an esterified and/or etherified dihydroxymethylene grouping, and/or, as the functionally modified carboxyl group, a functionally modified carboxyl group other than an esterified or amidated carboxyl group. Esterified and/or etherified dihydroxymethylene groupings are, for example, dihydroxymethylene groupings esterified with a hydrogen halide ac;d, such as hydrochloric ac;d, and/or ether;fied with a lower alkanol, such as methanol or ethanol. Examples are, in particular, dihalo-genomethylene groupings, such as dichloromethylene, lower alkoxyhalogenomethylene groupings, such as methoxy- or ethoxychloromethylene~ or di-lower alkoxymethylene groupings, such as dimethoxy- or diethoxymethylene~ Func~ionaLly modi-fied carboxyl groupings other than est~rified or amidated carboxy! groups are, ~or example, the cyano group, carboxyl groups converted ;nto anhydrides, such as halogenocarbonyl, ~or example chlorocarbonyl, imino ester groupings, such as imide- or amine halide groupirlgs, for example iminochloro-or aminod;chloromethyl, iminoether groupings, such as lower alkyl- or lower alkyleneiminoether groupings, for example methoxy- or ethoxyiminomethylenes 4,4- or 5~5-dimethyloxazo-lin-2-yl or 4,~,6-trimethyl-dihydro-oxazin-2-yl, amidino ~2~;if~
~ 18 -groups, such as amidino or lower alkylamidino, for example methylamidino, orthoacid groupings esterified with a hydrogen halide aci~, such as hydrochloric acid, and/or etherified w;th a lower alkanol, such as tri-lower alkoxy-, lower alkoxyhalogeno- or trihalogenomethyl groups, in particular trimethoxy- or tr;ethoxymethyl, ethoxydichloromethyl or tri-chloromethyl, or free or es~erified thiocarboxyl groups, such as lower alkylthiocarbonyl groups, for example ethylthio-carbonyl~
A radical X~ which can be converted ;nto the group of the formula -NH-C(=O~-R8, in which R8 is 5-tetrazolyl, is, for example, the group of the formula Nl~-C(=O)-CN or a group of the formula -NH-C(=O)-R~', ;n which R8' ;s 5-tetrazolyl protected in the 1-position. 5-Tetrazolyl radicals R8' in the protected form are, for example, 1-(~-aralkyL)-tetrazol-5-yl radicals which are unsubstituted or substituted in the aryl part, such as 1-benzyltetrazol-5-yl or 1-(p-methoxyben~yl)-tetrazol-5-yl.
Other radicals Y8 which can be converted ;nto groups of the formula -NH-C(=O)-R8 are, for example, groups of the formula -NH-XB which can be converted ox;datively into these, in wh;ch XB is the hydrated or non-hydrated glyoxyl group which can be converted oxidatively into the oxalo group of the formula -C~=0)-~, in which R~ is carboxyl. This can advantageously be formed ;n s;tu in the course of the ox;dation reaction, for example from the acyl group of an aliphatic or araliphatic carboxylic acid, which may be d,~-unsaturated or ~,~-dihydroxylated, a gLycoloyl group which is free or ester;fied on the hydroxyl group or the glycyl yroup, or l;berated from one of ;ts functional deriva~ives, for example one of its acetals or imines. Acyl groups of carboxylic ac;ds wh;ch may be ~,p-unsaturated or dihydroxylated are, for example, alkanoyl groups, such as lower alkanoyl, for example acetyl, acyl groups of K,~-un-saturated al;phat;c mono- or d;carboxylic acids, for example acryloyl or crotonyl, or the acyl group of free or function-ally modified fumar;c or male;c acid, acyl groups of ~,~-~L26S~l~8 unsaturated araliphatic carboxylic ac;ds, for example sub-stituted or unsubstituted cinnamoyl, or acyl groups of ali-phatic ~,~~d;hydroxydicarboxylic acids~ such as tartaric acid, or monoFunctional carboxyl derivatives, such as esters or amides, thereo~. Esteri~ied glycoloyl groups are, for example, glycoloyl groups esterified on the hydroxyl group with a mineral acid, such as a hydrogen halide acid, for example with hydrochloric or hydrobromic acid, or ~ith a carboxylic acid, for example with acet;c acid or substituted or unsubstituted benzoic acid. Acetalised glyoxyloyl groups are, for example, glyoxyloyl groups acetalised with lo~er alkanols or a lower alkanediol, such as d;methoxy-, diethoxy-or ethylenedioxyacetyl. Imines of glyoxyloyl groups are, for example, substituted or unsubstituted N-benzylimines or ~-tZ-benzothiazolyl)~imines thereof or imines with 3,4-di-tert~-butyl~o-quinone. Other radicals which can be converted oxidatively into the oxalo group are, for example, 2-furoy~
groups which are substituted or unsubstituted, such as those containing an acetalised formyl group, such as diethoxymethyl, in the 5-position. Groups which can be oxidised to esteri-fied oxalo groups of the formula -C~=O)-Rg in which R8 is esterified carboxyl are etherified glycoloyl groups, such as lower alkoxyacetyl. Radicals XB which can be oxidised to free, esterified or amidated oxaloamino groups are, further-more, free, hydrated or acetalised formylmethylamino groups or free or functionally modified carboxymethylamino groups or carboxymethyleneimino groups~ for example of the formula -NH-CH2-CH=0, -NH-CH2-R8 or -N=CH-R8.
Groups which can be converted into radicals alk are, for example, radicals alk substituted by oxo or etherified or esterified hydroxyl, such as oxoalkylene, oxo(oxa)alkylene or oxo(dioxa)alkylene radicals, for example of the formula t(CHz) ~ C~zC( 80) CHz - k~( CH2 ~ 1~ ( I b I ) or etherified or esteriFied hydroxyalkylene, hydroxy(oxa)-alkylene or hydroxy(dioxa~3lkYlene radicals of the formula ~t35~

--~(c}~z)l~ ~ c~l2c~l(x~`)cll2~o-(c~l2)l~ ~Ib") ;n which X" is etherified or esterified hydroxyl~
EtheriFied hydroxyl X" here is, for example, hydroxyl etheri~ied with an ~-aralkanol or a silanol, such as sub-stituted or unsubstituted benzyloxy or tr;-lower alkylsilyl-oxy, for example trimethyls;lyloxy.
Esterified hydroxyl X" is, for example, hydroxyl es~erified with a carboxylic acid, such as a lower alkanoic acid, or a half-ester o~ carbonic acid, such as lower alkanoyloxy, for example acetoxy or pivaloyloxy, lower alkoxycarbonyloxy, for example tertiary butoxycarbonyloxy, or substituted or unsubstituted benzyloxycarbonyl, for example carbobenzoxy.
The reactions according to the process and the pre-paration of novel starting substances and intermediates are carried out by procedures analogous to those for the reaction and formation of known starting substances and intermediates.
The particular customary auxiliaries~ such as cataLysts, condensing and solvolysis a~ents and/or solvents or diluents, and reaction conditions, such as temperature and pressure condit;ons, and, if appropriate, protective gases are used here, even i~ this is not expressly mentioned below.
The rearrangement of compounds II according to process variant a) is carried out, for example, photochemic--ally or in the presence of an acid condensing agent. Suit-able acid condensing agents are, for example, Lewis acids, in particular compLex metal halides of the formula Mnyn (XIX~, in which M is an n-valent, coordinatively unsaturated metal atom of group IIbo IIIa, IIIb, Iva, Ivb, Va or VIIIb of the periodic table of the elements, for example a zincII, boron~ aluminiumIII, ga~iumIII~ ~ jnIV t jtan jUmIV
antimonyV or ironlII atom, and Y is a halogen atom, in particular with an atomic number of not more than 35, such as fluorine, chlorine or bromine. Boron trifluoride, aluminium trichloride, gallium chloride, tin tetrachloride or, in par-ticular, zinc chloride is preferably used. Other suitable ~6~

~ 21 ~ 21A89 6851 acid condens1ng agents are complex oxygen acids, in particular of sulfur or phosphorus, such 3S sulfur;c acid, pyrosuLfuric acid, phosphoric acid, pyrophosphoric acid or polyphosphoric acid. Suitable inert solvents are, for example, carbon tetrachloride, tetrachloroethane, ~richloroethylene, carbon disulfide and nitrobenzene. If necessary, the reaction is carried out with cooling or warming, for example at about -10 to about 40C, in par~icular at ~5 to ~30C.
Starting substances II can be prepared, for example, by reacting compounds of the formulae R5~ $~o~ (VIII) HO~ ~-/ \OH X6 ~- \Rs ~2 1~7 ;n which X6 is an alkoxy radica~ substieuted by reactive esterif;ed hydro~yl or epoxy, for e~ample of the formuLa -O- ( CH 2 ~--X ~ 2)~ X~
(CH2) ~ ;CH2CH(OH)CH2 ~ (CHt)l,]oX clr ~ t(CH2) ~ CH2 X , ;n which X is reactive esterified hydroxyl, for example halogen, and X' is 1,2~epoxye~hyl, ~ith one another in the cus~omary manner and 0-acylating the reaction produc~ of the formula R3 R6\ ,~s-~ /R~

HO~ al3c--O ~-~ \Rs (XIII) ~z R7 in the customary manner, for example by reaction ~ith a com-pound R1-X1 ~IY), in which X1 is, for example, haLogeno-carbonyl or carboxyl converted into an anhydride, of the formula -C~=0)-0-C(aO)-R1.
Compounds XII are obtained, for example, by reacting compounds of the formulae - ~2 - 21~89-6851 R3~
l il IXIV) and X1~-R~ (XV) in ~hich the radicals R ~re identical or different etherified hydroxyl yroups, R3' is hydrogen, lower alkoxy, trifluoro-methyl, fluorine or nitro and one of the groùps X9 and X10 ;s a metallic radical, such as an alkali metal atom, for example sodium or lithium, or furthermore copper, or a halo-genoalkaline earth metal group, for example of the formula ~Mg-Hal, and the other is a group -Hal, which is halogen, for example brom;ne or iodine, with one another, for example in a di-lower alkyl or lower alkylene ether, such as diethyl ether, tertiary butoxymethane, d;oxane or tetrahydrofuran, reducing n;tro R3' to am;no and converting this into halogen R3 by treatment with sodium nitrite and a hydrogen halide acid, and splitting the groups R~ for example by treatment with hydrogen bromide in methylene chloride, to give hydroxyl.
In a modification of this process, the organometallic component can be formed in situ by using the corresponding halogen compound as the starting substance and carrying ou~
the reaction~ preferably with warming, in the presence of the corresponding metal in finely divided form, for example in the form of copper powder. In another modification of this process, cor[~ounds XII are obtained by reactin~ a compound XIV in which X9 is one of the metallic radi Cd ls mentioned~ preferably an alkali metal atom or a group -Mg Hal, with a fluorinatèd lower alkanal or lower alkanone, hydrogenating the hydroxy-lower alkyl group in the compound formed, of ~he formula ~ 3 ~I ~! ~ tXVI) in ~hich X3 is fluorinated hydroxy-lo~er alkyl, ;f approp-~''.',1 ~ ~ ....

21489-6~51 - 2~ -riate after detachment of water, for example by acetylation and subsequent treatment with zinc and ammonium chloride, to the corresponding fluorinated lower alkenYl group, to give the desired fluorinated radical R2, converting nitro into halogen and splitting R to give hydroxyl.
In another modifica~ion of this process, it is also po~sible to react the compound XIV~ in ~hich X9 is bromine or ;odine, ~ith trifluoroiodomethane in ~he presence of copper po~der to give the corresponding compound of the ~ormula ll R / ~ (XVII) and subsequently, ;f appropriate, to convert nitro into halogen and the radic21s R into hydroxyl.
Compounds XI~ in which R2 is 3-fluoro- or 3,3-di--- fluoropropyl are obtained in a particularly elegant manner by subjecting a compound of the formula ~ ~.~R3 S X Y I I I ) X3-O~
in ~hich X1 is free or etherified hydroxyl and X3 is a 1-fluoro- or 1,1-difluoroprop-2-enyl radical, which in turn is obtainable by reaction of the corresponding R3-resorcinol or resorcinol monoeeher ~ith a 1-fluoro- or 1~1-difluoro-prop-2-enyl-1-bromide, to allyL rearrangement, for example by heaeing to about 150 to 250C, preferably to about 190 to 220C, advantageously in a solvent, such ~s diphenyl ether or N,rl-d;methyl- or W,N-diethylaniline, and hydrogenating the 3-fluoro- or 3,3-difluoroprop-2-enyl group formed in the reaction product of the formula . ~

~/ ~ (XIX) X:~
into 3-fluoro- or 3,3-difluoro-propyl ar.d, if necessary, splitting etherified hydroxyl X1 to give hydroxyl.
Compounds XII` in which R2 is 3,3,3-trifluoropropyl are obtained ;n a particularly elegant manner according to a novel procedure by reacting an aldehyde of the formula ~. ~R3 ,!~ ,'!~ (xx) CH=O
in ~hich R is, for example, methoxy, with the compound of the formula CF3CCl2ZnCl(CzHs)20 (XXI), for example in the presence of dimethylformamide~ to give the corresponding compound of the formula R~ / \R ( X X I I ) HO~ H-CClzCF3 acylating this in the side chain, for example by react;on with acetic anhydride in the presence of pyridine, converting the reaction product of the formula R~ ~/ ~ ( XxIIa~
Ac-O-~H-C(Cl2)-CF3 in which Ac is acylt for example acetyl, into the correspond-ing compound of the formula ~;265~

11 (XXIII) R ~
kH--C( Cl ) -CF3 by treatment with a metallic reducing agent, for example with activated ~inc dus-t in the presence of ammonium chloride, detaching hydrogen chloride from this product, for example by treatmen~ ~ith potassium tertiary butanolate, hydrogenat-ing the side chain in the resulting compound of the formula ~ 3 il R ~-/ ~ (XXIV) ~C-CF3 for example in the presence of palladium-on~charcoal, and liberating the hydroxyl groups in the resulting compound of the formula il R ~ XV) ~z for example by treatment with hydrobromic acid in methylene chlor;de.
The preparation of compounds VIII is described under process variant e).
The reaction of compounds III and IV of which those in which X2 is carbo~yl are particularly suitable, according to process variant b) is usually carried out in the presence of an ac;d condensing agent, advantageously in an inert solvent, if necessasry with cooling or heating, for example at about ~80 to ~140C, in particular at about 80 to about 120C. Acid condensing agents are, for example, those mentioned for process variant a).
Starting substances III can be prepared, for e~ample, by reacting compounds of the Formulae ~265~
- 2 6 - 2148~6851 R6~ /R~
'! ~XII) and ! i! (VIII) HO/ ~. \0~ X6~ ~- ~Rs ~2 ~7 with one another~ it also be;ng poss;ble for the compound XIl to be in monoether and/or in salt form, and X6 being a r~dical -0-alkH substituted by reactive esterified hydroxyl, i.e. a reac~ive esterified hydroxyalkoxy radical or an epoxy-alkoxy rad;cal, for example a group of the formula -O- t CH 2 ) mX ~ )n }~ ~H2 )~
{}~(cH2)l ~ cH2cH(oH)cH2-k}~H2 ~ x or ~( C~12 ) 10~;C~2_X ~
in which X is reactive esterified hydroxyl, such as halogen, and X' is 1,2-epoxyethyl. The reaction is carried out, for example, analogously to that ;n process variant e~.
The conversion of the above radicals X3 containing fluorine to groups R2 according to process variant c) is carried out, for example, by reduction. The reducing agent ;s, for example, hydrogen in the presence of a hydrogeration catalyst, such as a platinum, palladium or rhodium catalyst, for example platinum oxide. The treatment ~ith cataly~ically act;vated hydrogen ~hydrogenation) is carried out under normal or at most slightly increased pressure and temperature conditions, for example wnder an increased pres~ure of about 0 to 5 bar and/or in the temperature range from about 20 to about 80C. The conversion o~ halogen ;nto, for example~
trifluoromethyl, is carried out, for example, by heating uith tr;fluoro;odomethane and copper powder.
Starting subseances V in which X3 is a mono- or di-fluorinated lower alkenyl rad;cal are obtained, for example, by subjecting a compound of the formula .~

~Z65~

R~ t~
X3-0 ~- O-alk-0/ ~ s (XXVI) to allyl rearrangement, for example by heating to about 150 to 25ûC, preferably to about 190 to 220C~ advantag~ously in a solvent, such as diphenyl ether or N,N-dimethyl- or N,N-diethylaniline.
Compounds XXVI are in turn obtair,ed by reacting a corresponding compound of the formula R . ~3 Rlo\ ~\ ~4 Rl t li ~ il (XXVII~
}10 ~:~ O-alk--0/ ~/ \Rs with a fluorinated lower alkene of the formula X3-H (XXVIII) substituted by chlorine, bromine or iodine in the allyl posit;on relative to the double bond, for example in the presence of a basic condensing agent, such as potassium carbonate.
The conversion of groups X4 into hydroxyl according to process variant d) is carried out in the customary manner~
for example by treatment with a complex metal halide of the formula MnYn (XIX), in which M is an n-valent, coordina-tively unsaturated metal cation of group IIa, IIb, IIIa, IIIb, Iva, Ivb~ Va or YIIIb of the periodic table of the elements, for example a magnesium, zincII, boronIII alumi 1 III
galliumIII, tinIV, titaniumIV, antimonyV or ironIII or iron ion, and Y is a halogen atom with an atomic number or not more than 35~ such as fluorine or chlorine, for example aluminium trichloride, or with a tertiary organic ammonium salt, such as a pyrid;nium or tr;-lower alkylammonium halide, for example with pyridinium chloride or bromide or triethyl-ammon;um chloride, but can also be carried out by solvolysis, in particular by hydrolysis, if necessary in the presence of a, preferably acid, hydrolys;ng agent. In addition to - 2~ -customary basic hydrolys;ng agents, such as alkali metal hydroxides, hydrolysing agents are, as acid hydrolysing agents, for examp~e, mineral ac;ds, for example hydrochloric, hydrobromic or hydr;od;c ac;d, sulfur;c acid, phosphoric acid or polyphosphoric acid, and also complex metal acids, for example hexachloroantimonic acid, tetrafluoboric acid and the like, and in the case of hydroxyl groups X4 esterified with organic carboxylic acids~ furthermore lower alkanecarboxylic acids, such as acetic acid. Solvents in the hydrolysis are, for example, ~ater-miscible organic solvents~ The reaction is in each case preferably carried out in the presence of a solvent or d;luent or a solubilising agent, with cooling or warming, for example in the temperature range from about 0 to 120C, and/or under an inert gas.
In compounds VI wh;ch conta;n, as group X4, a sub-st;tuted or unsubstituted ~-phenyl-lower alkoxy group or another customary protected hydroxyl grou~ which can be split by reduction, the hydroxyl group can advantageously be liberated by reduction. Thus, for example, it is possibLe to carry out hydrogenation, i.e. reduction with hydrogen in the presence of a hydrogenation catalyst, for example a palladium, plat;num, nickel or rhodium catalyst, for example palladium-on-charcoal or Raney nickel.
Furthermore, starting from compounds VI in which X4 is hydroxyl esterified with an organic carboxylic acid, the hydroxyl group can be liberated by transesterification, i.e.
by treatment w;th an alcohol, for example a lower alkanol, in the presence of an ac;d or basic agent, such as a mineral acid, for example sulfuric acid, or an alkali metal hydroxide or alcoholate, for example sod;um hydrox;de or a sodium lower alkanolate~
Starting substances VI are prepared, for example, by reacting compounds of the formulae Rl 1l i (XXIX) 11 1 (VIII~, X~ \X5 X;~ 5 ~2 1~7 1~65~

in ~hich one of the radicals X5 and X~ is hydroxyl which is free or in salt form and ~he other is a radical -O-alkH
which is subst;tuted by reactive esterified hydroxyl or epoxy, tor example a group of the formula -O-~CI!2)mX, ~F(~2)-nJk(cH2)n' X, ~-~(CI~2) ~ CH2C~I(O}~)C~12--~(CH2 ~ or ~ -~(C~I2) ~pCtl2-X , in which X is reactive esterified hydroxyl, for example halogen, and X' is 1,2-epoxyethyl, with one another.
The react;on of compounds VII and VIII according to process variant e? is carried out in the customary manner, for example in ~he presence of a basic condensing agent, such as a hydroxide or carbonate of an alkali metal or aLkaline earth metal, such as sodium hydroxide or potassium hydroxide or poeass;um carbonate or calc;um carbonate, advantageously in a lower alkanol, for example methanol or amyl alcohol, di-lower alkyl ketone, for example in acetone or die~hyl ketone, or N~N-di-lower aLkyl-lower alkano;c ac;d amide or N-lo~er alkyl~Lower alkanoic acid lactam, for example in dimethylformamide or N-methylpyrrolidinone.
The s~arting substances YII are prepared, for e~ample, by reacting a compound of the formula '! ! tXII~
HO~ OH

~ith a compound of the formula R1-X2 CIV; X~ = carboxyl~
in the presence of a Le~is acid, for example zinc chloride, and, if desired, converting the hydroxyl group in the p-position relative to R1-C(=O)- in the resulting compound VII, in which X5 is hydroxyl, into an alkoxy radical sub-stituted by halogen or hydroxyl by reaction ~ith a dihalogeno-alkane, epoxyalkane or halogenoalkanol and, if appropriate, reactively ester1Fying hydroxyalko~y, for example by treat-ment ~ith thionyl chloride~ phosphorus tribromide or a ` 2 ~%6~

sulfonic acid chloride.
Compounds VIII can be obtained, for example, by reducing the nitro group in a compound of the formula ~ ~ \ /R~
X6/ ~'~ \Rsl" (XXX) 1~7" 1 in which one of the radicals R4"', R5"' and R7"' is the nitro group, a radicaL R~"' or R5"' which differs from this ;s a radical R9 and a radical R7"' which differs from this is a radical R1o, to amino, for example with hydrogen in the presence of Raney nickel, and reacting the compound of the formula X6 ~'/ \Rs ' ( X X X I ) ~71 ' ' ' `
in which one of the radicals R4', R5' and R7' ;s the amino group, a radical R~' or R5' which differs from this is a group Rg and a radical R7~ which differs from this is a radical R10, with a compound of the formula Hal-C(=O)-R~g (Xb; Hal = halogen) in the presence of a base, for example triethylamine or pyridine, and, if d~sired, converting the hydroxyl group in the resulting compound VIII, in which X6 is hydroxyl, ;nto an alkoxy radical substituted by halogen, epoxy or hydroxyl by reaction with a dihalogenoalkane, epoxy-alkane or halogenoalkanol, dihalogeno(hydroxy)alkane, halo-geno(epoxy)aLkane or halogenoalkanediol~ and, if appropriate, reactively monoesterifying hydroxyalkoxy or dihydroxyalkoxy, for example by treatment with thionyl chloride, phosphorus tribromide or a sulfonic acid chloride.
The reaction of compounds IX and X according to pro-cess_variant_f) can be carried out in the customary manner, in particular in the manner known from the literature for analogous react;ons, if n~cessary in the presence of a ~5~

- 31 - 214~9 6851 condensing agent, in the case of reaction with an ester-halide or amide-ha~ide of oxalic acid, for example, a basic condens-ing agen~, such as a tertiary organic nitrogen base, for example triethylamine or pyridine, or an alkal; metal hydrox-ide or carbonate, for example sodium hydroxide or potassium hydroxide, or in the case of the reaction with oxalic acid, for example, a condensing agent which effects dehydration of the ammonium salt primarily formed, such as a water-binding agent, for example dicyclohexylcarbodiimide or an isonitrile, such as tertiary butylisonitrile, or a mineral acid, for example hydrochloric acid, or an acid anhydride, for example phosphorus pentoxide, in each case in an inert solYent, such as a halogenoalkane, for example in methylene chloride, or an ~,N-dialkylamide, for exaMple in N,N-dimethylformamide or -acetamide.
The 1-pro~ective group of 5-tetrazolyl radicals R'8 can then be detached, for example~ by acidolysis, i.e. treat-ment ~ith an acid, for example with`trifLuoroacetic acid/
anisole, or hydrogenolytically, in particular by means of hydrogen and palladium-on-charcoal.
Starting substances IX can be prepared, for example, by reacting compounds of the formulae ~ (Vll) and ~ ~ (X~ ) in which one of the radicals R~"', Rs"~ and R7"' is the nitro group, a radical R4"' or Rs"' which differs from this is a radical Rg and a radical R7"' ~hich differs from this ;s a rad;cal Rlo, and in which one of the radicals X5 and X6 is hydroxyl which is free or in salt form and the other is a radical -O-alkH substituted by reactive esterified hydroxyl or epoxy, for example a group of the for~ula O (CH2)m-X~ -O-(CII2)mX, ~ (~)~ ~ (OE~), X, ~(cH2)~cll2cll(oH)cH2{~(cH2~x C~ ~(CH2)--O~CH2--X', ;n whtch X ls reactive esterified hydroxyl, for example ~i5~

halogen, and X' is 1,2-epoxyethyl~ with one another, and reducing the nitro group in the resulting compound of the formula ,Q ,-~ ~3 ~ 4 (Ixa) HO -~ O-alk-O ~ ~5"' 1~2 ~7"1 to amino, for example by reaction with hydrogen in the pre-sence of a hydrogenation catalyst, such as palladium-on-charcoal or, in particular~ Raney nickel, for example in tetrahydrofuran.
Conversion of the group X8 in compounds XI into those of the formula -NH-C(=O)-R8 according to process var;ant 9~ is carried out, for example, by solvolysis or oxidation or~ star~ing from groups X8 of the formula -~H~Ct=O)-CN, by reaction with hydra~oic acid, or, starting from groups Xg of the formula -NHC(=O)-Rg', in which R8' ;s 5-tetrazolyl protected in the 1-position, by detachment of the protective group. Thus, the groups XA mentioned in radicals Xg of the formula -NH-XA can be converted hydro-lytically ;nto the oxalo group. A group XA containing, as a functionally modified carboxyl group, an iminoether, ortho-ester or ester-halide grouping and/or, as a functionally modified ~-carbonyl group, thioxo- or iminomethylene or an ester;fied or etherified dihydroxymethylene group can further-more be hydrolysed to esteriFied oxalo groups -C(=O)-Rg. A
group XA containin~, as a funct;onally modified carboxyl group, the cyano group or an amid;no or ;mide- or amide-hal;de grouping and/or, as a functionally modified ~-carbonyl group, thioxo- or ;minomethylene or an etherified or esterified di-hydroxymethylene group, can likewise be hydrolysed to amidated oxalo groups -C(=O)~Rg. The hydrolysis can be carr;ed out in the customary manner~ if necessary in the presence of a basic or, preferably, acid hydrolysing agent, such as an alkali metal hydrox;de~ such as sodium or potassium hydroxide~

~ .

or, preferabLy, a proton acid, preferably a mineral acid, for example a hydrogen halide acid, such as hydrochloric acid, or an organic carboxyl-ic or sulfonic acid, for example acetic acid or p-toluenesulfonic acid~
A functionaLly modified oxalo group XA containing, as a functionally modified carboxyl group, a carboxyl group converted into an anhydride, such as halogenocarbonyl, for example chlorocarbony(, or cyanocarbonyl, or a lower alkyl-eneimino-ether grouping, for example ~,4- or 5,5-dimethyl-oxazolin-2-yl, or 4,4,6-trimethyl-dihydro-oxazin-2-yl, can furthermore be converted into esterified oxalo groups -Ct=O)-R~ by customary alcoholysis, i.e. react;on ~ith the corresponding alcohol. Alcoholysis of carboxyl groups con-verted into anhydrides is advantageously carried out in the presence o~ a basic condensing agent, for example pyridine or triethylamine, whilst alcoholys;s of carboxyl or a lower alkyleneiminoether grouping is preferably carried out under acid conditions, for example in the presence of hydrochloric acid, p-toluenesulfonic acid or acetic acid. A functionally modified oxalo group containing a carboxyl group converted into an anhydride can also be converted into an amidated oxalo group -C(=O)-Rg in an analogous manner by ammonolysis or aminolysis, i.e. reaction with ammonia or a corresponding primary or secondary amine, preferably in the presence of a basic condensing agent, for example sodium hydroxide, pyri-dine or triethylamine.
The groups XB men~ioned are converted into those of the formula -NH-Ct=O)~R8, for example, by oxidation.
The oxidation can be carried out in the customary manner by reaction with a suitable oxidising agent~ Suitable oxidising agents are, in particular, oxidising heavy metal compounds, such as silver compounds, for example silver nitrate or silver picolinate, oxygen acids of heavy metals, for example of manganese-IV, manganese-VII, chromium-VI and iron-III, or of halogens or anhydrides or salts thereof, such as chromic acid, chromium dioxide, potassium dichromate, potassium per-manganate, manganese dioxide, potassium hexacyanoferrate, ~s~

- 3~ -sodium chlorite in the presence of sulfamic acid, sodium hypocl1lorite in the presence of nickel chloride or sodium iodate, sodium periodate or lead tetraacetate. The reaction with these oxidising agents is carried out in the customary manner, for example ;n an inert solvent, such as acetone, acetic acid, pyridine or water, or in a, preferably aqueous, inert solvent mixture, at normal temperature or, if necessary, with cooling or warming, for example at about û to about 100C. The oxidation of free or etherified glycoloyl groups to free or esterified oxalo groups is advantageously carried out, for example~ with potassium permanganate in aqueous pyridine or acetone at room temperature~ Acetalised glyoxyl groups and iminoacetyl groups are preferably oxidised under acid conditions, for example with potassium dichromate in sulfuric acid~ acyl groups of ~,~-dihydroxylated aliphatic carboxylic acids, such as the acyl radical of tartaric acid, are advantageously ox;d;sed with periodic acid, whilst potassium ferrate in an alkaline medium, for example at pH
10-13~ for example 11.5O or organic silver salts, such as silver picolinate, are preferably used for the oxidation of the glycyl group. Groups of the formula -N=CH-Rg are prefer ably oxidised with an organic peracid, for example with per-acetic acid or m-chloroperbenzoic acid, in an inert solvent, for example methylene chloride, chloroform or benzene.
The reaction of grouPs X8 of the formula -NH-Ct=0)-CN
with hydrazoic acid is preferably carried out with formation of the acid in situ by treatment of an alkali metal azide with an acid, such as hydrochloric acid, preferably in tolu-ene or similar solventsJ
Detachment of the protective group from groups ~8 of the formula -NH-CS=0)-R~', in which R8' ;s 5-tetrazolyl protected in the 1-position, is carried out in the customary manner, ;n particular by acidolysis, i.e. treatment with an acid, for example with trifluoroacetic acid, in an ether~
such as anisole, or by cataLytic hydro~enat;on, for example in the presence of palladium.
The starting substances XI are prepared, for e~ample~

~Z6S~f~

by reacting a compound of the formula ,Q ,-~ /R3 ~ /R4' (IX) HO \-~ O-all;-O/ \-~ Rs~
~2 1~7' ;n which one of the radicals R4', R5' and R7' is the amino group, a radical R4' or R5' which d;ffers from this is a radical R~ and a rad;cal R7' wh;ch differs from this ;s a radical R1o, or an acid addition salt thereof, with a corresponding acid, for example of the formula XA-OH (XXXIIa) or XB-OH tXXXIIb) or R8'-COOH (XXXIIc) or a functional derivat;ve thereof~ F-lnctional derivatives of acids XXXIIa to XXXIIc are, in particular~ acid derivatives containing a carboxyl group which is esterified, amidated or converted into an anhydride, such as lo~er alkoxycarbonyl, substituted or unsubstituted carbamyl, for example carbamyl or imidazol-1-yl-carbonyl, or halogenocarbonyl, for example chloro- or bromocar~onyl, or a group of the formuLa -CON3 or -CON2~ Hal~. Examples of acids XXXIIa to XXXIIc and functional derivatives thereof are, in particular: as func-tional derivatives of acids XXXIIa, oxalyl halides, such as oxalyl chloride or oxalyl bromide, tri-lower alkoxy- and di-halogeno-lower alkoxyacet;c ac;d lower alkyl esters, such as tetraethyl oxalate or diethyl dichlorooxalate, oxalic acid iminod;alkyl estersO such as mono- or diiminodiethyl oxalate, oxalic acid amidines, such as N-lower alkyloxalic acid ester-amidines~ oxalic ac;d dith;o-lower alkyl esters, such as di~ethyl ester, cyanoformyl chloride or cyanogen, and, as acids XXXIIb and functional derivatives thereof, glycolic acids and their lower alkyl esters and the correspond;ng lactide, mono- or di-lower alkoxyacetic acid lower alkyl esters, such as ethyl esters~ for example ethyl ethoxy- or diethoxyacetate, halogenoacetic anhydrides~ such as chloro-acetic anhydride or chloroacetyl chloride and tartaric acid~
or 2~3-diacetoxysuccinic anhydride, and fur~hermore cinnamoyl :IL26S~

~ 36 chloride, acetyl chloride and glycine. Funct;onal deriva-t;ves of acids XXXIIc are, in particular, chlorides thereof.
The reaction of compounds IX and XXXIIa to XXXIIc or their derivatives can be carried out in the customary manner, for example in the presence of a water-binding agent, such as an acid anhydride, for example phosphorus pentoxide, or dicyclohexylcarbodiimide, or, for example, an acid or basic condensing agent, such as a mineral acid, for example hydro-chloric acid, or an alkali metal hydroxide or carbonate, for example sodium or potassium hydroxide, or an organic nitrogen base, for example triethylamine or pyridine. In the case of the reaction with an acid anhydride, such as an acid chlor-ide, an organic nitrogen base is preferabLy used as condens-ing agent 1. The reaction ~ith carboxylic acids is prefer-ably carried out in the presence of a water-bind;ng agent.
If necessary, the reaction is ;n each case carried out ;n an ;nert solvent, at normal temperature or with cooling or warm;ng, for example in a temperature range from about 0 to about 100C, in a closed vessel and/or under an inert gas, for example nitrogenn Compounds XI in which X8 is a group R8-CH=N- can be prepared analogousLy by condensation o-F compounds IX with free, esterified or am;dated glyoxylic acid.
Compounds XI in which Xg ;s a group -NH-Xa and XB
is glyoxyloyL can furthermore be prepared by heating a correspond;ng halogenoacetyl, such as bromoacetyl, compound with hexamethylenetetramine, preferably in an aqueous alcohol, or ox;d;sing the starting compound ~;th s;lver tetrafluoborate in dimethylsulfoxide. A chloroacety~ compound can also be oxidised analogously with potassium dichromate in hexamethyl-phosphoric acid triamide in the presence of dicyclohexyl-18-crown-6 ether. Compounds XI in which X8 is a group -NH-XB
and XB is an iminoace~yl group, for example subst;tuted or unsubstituted benzyliminoacetyl, can be prepared starting from the corresponding glycyl compounds, by reacting these with the corresponding carbonyl compound, for example with benzaldehyde, and rearranging the intermediate ~hus obtain-fl~

- ~7 -able, for example an N~benzylideneglycyl compound, preferably under the reaction cond;tions.
Functionally modified oxalo groups containing, as a functionally modiFied carboxyl group, an iminoether grouping can be prepared starting from the corresponding cyanocarbonyl compound by reaction with the corresponding alcohol, for example a lower alkane(di)ol or amino-lower alkanol.
Conversion o~ the radical alk' of a compound I' according to ~rocess variant h~ is carried out in the cus-tomary manner, ~or example reductively, starting from com-pounds I' in which alk' is a radical alk substituted by oxo or hydroxyl etherified with an K-alkanol or esterified with a carbonic acid mono-~-aralkyl radical, and solvolytically, starting from compounds IX in which alk' is a radical alk substituted by etherified or esterified hydroxyl groups other than those mentioned above.
Reducing agents ~or the reduction of radicals alk' substituted by oxo to the corresponding radicals alk sub-sti~uted by hydroxyl are, for example, alkali metal boro-hydrides, such as lith;um borohydride, sodium borohydride or sodium cyanoborohydride, or secondary alcohols, such as secondary lower alkanols or cyclo-lower alkanols, for example isopropanol or cyclohexanol, in the presence of an aluminium alcoholate, in particular isopropanol in the presence of aluminium isopropanolate. The reaction with the alkali metal borohydrides mentioned is advantageously carried out in a lower alkanol, a di-lower alkyl ether or a lo~er alkylene ether or mixtures of ~hese solvents, for example in ethanol.
The reaction with alcohols in the presence of an aluminium alcoholate is advantageously carried out in an excess of the alcohol used as the reducing agent.
Radicals alk' substituted by oxo can, however, also be reduced to the corresponding unsubstituted radicals alk' by replacing the oxo group by 2 hydrogen atoms, by reaction with hydrazine or semicarbazide and a base, for example an alkali metal lower alkanolate, such as sodium methanolate, or in a high-boiling alcohol, for example di- or triethylene :LZC~S~L4~

- 3~ -glycol or diethylene glycol monomethyl ether~ with hydraz-ine and an alkali metal hydroxide, such as potassium hydrox-ide, preferably with heating, for example at the boiling point. The corresponding hydrazones or semicarbazones are thereby intermediately formed. ~lowever, the reaction can also be carried out with a sulfonic acid hydrazide, for example with p-toluenesulfonic acid hydrazide, to give the corresponding N'-sulfonylhydrazones, for example N'-(p-toluenesulfonyl)-hydrazones, and these can be reduced with an alkali metal borohydride, for example with lithium or sodium borohydride.
Reductive splitting of ~-aralkoxy or ~-aralkoxy-carbonyloxy to hydroxyl is preferably carried out by hydro-genolysis, i.e. the action of hydrogen in the presence of a hydrogenation catalyst, such as a palladium, platinum, iridium or nickel catalyst, for example palladium-on-charcoal, platinum oxide or Raney nickel, advantageously in a lower alkano;, for example in methanolic solution, if necessary under increased pressure and/or w;th warming, for example under about 1 ~o 10 bar and at 2û to 60C.
The solvolytic liberation of hydroxyl from etherif;ed or esterified hydroxyl groups other than those mentioned, such as from silyloxy, lower alkanoyloxy or lower alkoxy-carbonyloxy, is carried out, for example, by hydrolysis (reaction with water), alcoholysis (reaction with an alcohol) or ammonolysis or aminolysis ~reaction wieh ammonia or an amine which contains at least one free hydrogen)~ if neces-sary in the presence of an acid or basic agent and/or ~ith warming, for example at about 20 to 100C. Suitable acid agen~s are, for example~ mineral acids, such as hydrogen halide acids, for example hydrochloric acid, or oxygen acids of sulfur or phosphorus, for example sulfuric or phosphoric acid, or organic sulfonic or carboxylic acids, such as lower alkanesulfonic acids or substituted or unsubstituted benzene-sulfonic acids or lower alkanoic ac;ds, for example p-toluene-sulfonic ac;d or acet;c ac;dn Basic hydrolysing agents are, for example, hydroxides or carbonates of alkali metals, For ~.2~ C3 example potassium carbonate, sodium hydroxide or potassium hydroxjde, and ~or alcoholysis, furthermore, corresponding alcohol2tes, such as a~kali metal lower alkanolates, for example sodium methanolate.
Starting substances I' can be obtained, for example, by reacting compounds of the formulae ~i~ and X~ Rs in ~hich one of the radicals Xs and X6 is hydroxyl in the free form or in salt form and the other is a radical -O-a(k~-X~ i.e. a radical -O-alk-X substituted by oxo or etherified or esterified hydroxyl, such as an oxoalkylene, oxotoxa)alkylene, oxo~d;oxa)alkylene or etherified or esteri-fied hydroxy~oxa)alkylene or hydroxy(dioxa)alkylene radical substltuted by X, for example of the tormula -o--t(C~2)l, ~ cH2C(-o)c~2-k~-(cH2)~px ~Ib ) ~r ~t(CH2)~cll~cH~x")cH2~(cHz)~ X (IigY ) in which X is reactive esterified hydroxyl, for example halogen, with one another.
A compound of the general formula I accord-ing to the inven~ion can be converted into another ro~pound of the general formwla I in a manner ~hich is known per se.
Thus, for example, a free carboxyl group R6, R7 and/or R3 can be converted in the customary manner, for example by treatment with a diazo-lower alkane or tri-lower alkyLoxonium, tri-lower alkylcarboxonium or di-lower alkyl-carbon;um salt, such as a hexachloroantimonate or hexafluoro-phosphate, or, in particular, by reactlon with the corres-ponding alcohol or a reactive derivative, such as a carboxy-lic, phosphorous, sulfurous or carbonic acid ester thereof, for example a lower alkanol~ N,N-di-lower alkylamino-lower alkanol, N,N-lower alkyleneamino-lower alkanol, substituted ,~ .

6S~

~ 40 or unsubstituted N,N-(aza)-lower alkyleneamino~lower alkanol, ~,N-(oxa~-lower alkyleneamino-lower alkanol or N,N-(thia)-lower alkyleneamino lower alkanol or with a lower alkane-carboxylic acid ester, tri-lower alkyl phosph;te or di-lower alkyl sulFite, to give co~pounds of the general formula I in ~hich Ro~ R7 and/or R~ is esterified carboxyl. The reaction ~ith the corresPonding alcohol itself can advantage-ously be carried out in the presence of an acid catalyst, such as a pro~on acid~ for example hydrochloric or hydro-bromic, sulfuric, phosphoric, boric, benzenesulfonic and/or toluenesulfonic acid, in an inert solvent, in particular an excess of the alcohol employed, and if necessary in the pre-sence of a water-binding agent and/or with distillative, for example azeotropic, removal of the water of reaction anp/or at elevated temperature. The reaction with a reactive derivative of the corresponding aLcohol can be carried out in the customary manner, starting from a carboxylic, phos-phorous, sulfurous or carbonic acid ester, for example in the presence of an acid catalyst, such as one of those mentioned above, in an inert solvent, for example ;n toluene, or an excess of the alcohol derivative employed or of the corres-ponding alcohol, if necessary with removal of the water of reaction by distillation, for example azeotropic removal by distillation. Starting from a mineral acid ester or sulfonic acid ester, the acid to be esterified is advantageously empLoyed in the form of a salt, for example the so~ium or potassium salt, and the reaction is carried out, if neces-sary, in the presence of a basic condensing agent, such as an inorganic base, for exampLe sodium hydroxide or carbonate, potassium hydroxide or carbonate or-calcium hydroxide or carbonate, or a tertiary organic nitrogen base, for example triethylam;ne or pyridine, and/or in an inert solvent, such as one of the above tertiary nitrogen bases or a polar sol-~ent~ for exampLe in dimethylformamide, and/or at elevated temperature. The reaction with an olefine can be carried out, for example, in the presence of an acid catalyst, for example a ~ewis acid, for example boron trifLuoride, a 51~3 ~ 41 -sulfonic acid~ for example p-toluenesulfonic acid, or, in par-~icular, a basic cataLyst, for example sodium hydroxide or potassium hydroxide, advantageously in an inert solvent, such as an ether, ~or example in diethyl ether or tetrahydrofuran.
A free carboxyl group R6, R7 and/or R8 can further-more be converted in~o an amidated carboxyl group by reaction with ammonia or an amine con~aining at least one hydrogen atom in the customary manner, with dehydrat;on of the ammon-ium salt intermediately formed, for example by aze~tropic distillation with benzene or toluene or dry heating.
The above conversions of carboxyl into esterified or amidated carboxyl groups can, however, also be carried out by first converting a compound of the fQrmula I in which R6, R7 and~or R8 iS carboxyl into a reactive derivative in the customary manner~ for example into an acid halide by means of a halide of phosphorus or sulfur, for example by means of phosphorus trichloride or -bromide, phosphorus pentachloride or thionyL chloride, or into a reactive ester, i.e. esters with electron-attracting structures, such as the ester with phenol, thiophenol, p-nitrophenol or cyanomethyl alcohol, or a reactive amide, for example the amide derived from imidazole or 3,5-dimethylpyrazole, by reaction ~ith a corresponding alcohol or amine, and then reacting the result-ing reactive derivative with a corresponding alcohol, ammonia or the corresponding amine containing at least one hydrogen atom in the customary manner, for example as described below for the transes~eri~ication, transamidation or reciprocal conversion of esterified and amidated carboxyl groups, to give the desired group R4, R6 and/or Rg.
An esteri~ied carboxyl group R6~ R7 and/or R8 and cyano R6 andtor R7 can be hydrolysed in the customary manner, for example by hydrolysis in the presence of a catalyst, for example a basic or acid agent, such as a strong base, for example sodium hydroxide or potassium hydroxide, or a mineral acid, for example hydrochloric acid, sulfuric acid or phos-phoric ac;d, to give the free carboxyl group, cyano R6 and/or R7 and furthermore carbamyl~ Esterified carboxyl R6, R7 ~26~

- ~2 ~ 9-6~51 and/or R8 can likewise be converted into an amidated carho~yl group~ ~or example hy reaction with ammonia or the corresponding amine con~aining at least one hydrogen atom.
An esterified carboxyl group R6, R7 and/or R8 can furthermore be transesterified in the customary manner, for example by r~action with a metal salt, such as the sodium or potassium salt, of a corresponding alcohol or with the alco-hol itself in the presence of a catalyst, for example a strong base, for example sodium hydrox;de or potassium hydrox-;de, or a strong acid, such as a mineraL acid, for e~ample hydrochloric acid~ sulfuric ac;d or phosphoric acid, or an organic sulfonic ac;d, for example p-toluenesu~fonic acid, or a Le~is acid, for examp~e boron tr;f~uoride-etherate, to give another esterified carboxyl group.
An amidated carboxyl group R6, R7 and/or R8 can be converted ;nto the free carboxyl group ;n the customary manner~ for example by hydrolysis in the presence of a cata-lyst, for example a strong base, such as an alkali meta~
hydroxide or carbonate or alkaline earth metal hydro~ide or carbonate, for example sodium hydroxide or carbonate or potassium hydroxide or carbonate, or a strong acid, such as a mineral acid, for example hydrochloric ac;d, sulfuric acid or phosphoric aci do Subs~ituents can furthermore be introduced into one or both ph~nyl rings ;n a compound obta;nable according to the invention and/or existing substituents can be converted into other substituents. Thus, lower alkyl or lower alkanoyl, respectively, can be introduced by reaction with a lower alkyl halide or lower alkene or a lower alkanoic acid halide or anhydride, in each case in the presence of a Lewis acid, such as aluminium trichloride. Halogen can furthermore be introduced, ~or example by treatment with a halogen in the presence of a Lewis acid, such as iron-III chloride, or by reactionwi-th N -chlorosuccinimide. ~loreover,halogen, in particular iodine, can be replaced by trifluoromethyl by reaction with trifluoroiodomethane in the presence of copper.
As mentioned, depending on the choice of the star-ting . ~ , . .

6S;~

substances and procedures, the novel compounds can be in the form of one of the possible isomers or as mixtures thereof, for example, depending on the number of asymmetr;c carbon atoms, as pure optical isomers, such as antipodes, or as isomer mixtures, such as racemates, diastereoisomer mixtures or racemate mixtures.
Resulting diastereomer mixtures and racemate mixtures can be resolved into the pure isomers, diastereomers or race-mates by means of the physico-chemical differences of their constituents in a known manner, for exampLe by chromato-graphy and/or fractional crystallisation.
Resulting racemates can furthermore be resolYed into the optical antipodes by known methods, for example by re-crystallisation from an opt;cally active solvent, w;th the aid of microorganisms, or by`reaction of an acid end product with an optically active base which forms salts with the racemic acid and separation of the salts obtained in this manner, for example by means of their different solubilities, ;nto the diastereomers, from which the antipodes can be liberated by the action of suitable agents. The more active of the two antipodes is advantageously isolated.
Resulting free compounds of the formula I, for example those in which R6 and/or R7 is carboxyl and/or R8 is carboxyl or S-tetra20lyl, can be converted into salts in a manner which is known pér se, for example by treatment with a base or with a suitable salt of a carboxylic acid, uswally ;n the presence of a solvent or diluent.
Resulting salts can be converted into the free com-pounds or resulting free compounds in which R8 is capable of forming acid addition salts can be converted into ac;d addi-t;on salts thereof in a manner which is known per se~ for example by treatment with an acid reagent~ such as a mineral acid, or one of the sal~-forming acids mentioned.
The compounds~ including their salts, can also be obtained in the form of their hydrates or can incLude the solvent used ~or the crystallisation.
As a result of the close relationship bet~een the -44/50- ~ 21489-6851 novel compounds in the free form and in the form of their salts, the free compounds or their salts, where appropriate, are correspondingly and appropriately also to be understood as the corresponding salts or, respectively, free compounds above and belo~.
The invention also relates to those embodiments of the process in which a compound obtainable as an intermediate at any stage of the process is used as the starting substance and the missing steps are carried out, or a starting sub-stance is used in the form of, or, in part;cular, forms under the reaction conditions, a salt and/or racemate or antipode.
The invention like~ise relates to the novel starting substances and intermediates arising in the processes accord-ing to the invention and their preliminary stages and to processes for their preparation.
Preferably, starting substances are used and the reaction condi~ions are chosen such ~hat the compounds men-tioned above as particularly preferred are obtained.
In this connection, particular reference is made to compounds of ehe formulae VII, i n which X5 is hydroxyl, and XII and their salts, ~hich have been developed specifically as starting substances for compounds of the formula $.

g~3 'LZ~iSif~

The present invention also relates to pharmaceutical products which contain one of the compounds of the formula I
according to the invention or a pharmaceut;cally acceptable salt thereof~ ~he pharmaceutical products according to the invention are those which are intended for topical and local as well as enteral, such as oral or rectal, and parenteral administration to and for inhalation by warm-blooded organisms and contain the pharmacolvg;cal active ingredient by itself or together w;th a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the species of warm-blooded organism, the age and individual condition and the mode of adminis~ration.
The novel pharmaceutical products contain, for example, from about 10X to about 95%, preferably from about 20X to about 90%, of the active ingredient. Pharmaceutical products according to the invention are, for example, those in aerosol or spray form or in dosage unit forms, such as sugar-coated tablets, tablets~ capsules or suppositories, and furthermore ampoules.
The pharmaceutical products of the present invent;on are prepared in a manner which is known per se, for exampLe by means of conventional m;xing, granulation, coating, dis-solving or lyophil;sing prscesses. Thus, pharmaceutical products for oral use can be obtained by combining the active ingredient with solid carriers, a resulting mixture can be granulated~ if appropriate~ and the mixture or granules, if des;red or necessary, can be processed to tablets or sugar-coated tablet cores, after addition of suitable adjuncts.
Suitable carriers are, in particular, fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose products and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes, for example mai~e, wheat, rice or potato starch paste, gelatine, tragacanth~ methyl-~3 ~Z~;51~

cellulose and~or polyvinylpyrrolidone~ and/or, if desired, disintegrators, such as the abovementioned starches, and furthermore carboxymethyl starch, crosslinked polyvinyl-pyrrolidone, agar and alginic acid or a salt thereof, such as sodium alginate. Adjuncts are~ in particular, glidants and lubricants, for example silicic acid~ talc, stearic acid or sal~s thereof~ such as magnesium stearate or calcium stearate, and~or polyethylene glycol. Sugar-coated tablet cores are provided ~ith suitable coatings, which may be res;stant to gastric juice, using, inter alia, concentrated sugar solutions, which contain, if appropriate, gum arabic, talc, polyvinylpyrrolidones, polyethylene glycol and/or titanium dioxide, shellac solutions in suitable organic solvents or solvent mixtures or~ for the preparation of coa~ings which are resistant to gastric juice, solutions of suitable cellulose products, such as acetylcellulose phthal-ate or hydroxypropylmethylcellulose phthalate. Dyes or pig-ments may be added to the tablets or coatings of sugar-coated tablets, ~or example to identify or ind;cate dif-ferent doses of active ingredient.
Further phar0aceutical products for oral use are dry-filled capsules of gelatine, and also soft, sealed capsules made of gelatine and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules can contain the active ingredient in the form of granules, for example mixed with ~illers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, if appropriate, stabil;sers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid poly-ethylene glycols, to which stabilisers can like~ise be added.
Pharmaceutical products for rectal administration are, for example, suppositories, which consist of a combina-t;on of the active ingredient and a suppository base. Suit-able suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Rectal gelatine capsules containing a ~LZ~;5~8 combination of the active ingredien~ with a base can further-more also be used; base substances are, for example, liquid triglycerides~ polyethylene glycols or paraffin hydrocarbons.
Aqueous solutions of an active ingredient in water-soluble form, ~or example of a water-soluble salt, and furthermore suspensions of the active ingredient, such as corresponding oily injection suspensions, using suitable lipoph;lic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increas;ng substances, for example sodium carboxymethylcellulose~ sorbitol and/or dextran and, if appropriate, also stabitisers, are chiefty suitable for parenteral administration.
Inhalation products for treatment of the respiratory tract by nasal or bucal administration are, for example, aerosols or sprays which can disperse the pharmacological active ingredient in the form of a powder or in the form of drops of a solution or suspension. Products with powder-dispersing properties usually contain~ in addition to the active ingredient, a liquid propetlant with a boiling point below room tempera~ure and, if desired, adjuncts, such as liquid or solid non-ionic or anionic surfactants and/or diluents. Products in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant, and furthermore, if necessary, an addi-t;onal solvent and/or a stabiliser~ Instead of the propel-lant, compressed air can also be used, it being possible for this to be produced as required by means of a suitable com-pression and expansion device.
Pharmaceutical products for topical and local use are, for example, for the treatment of skin, lotions and creams containing a l;quid or semi-solid oil-in-water or water-in-oil emulsion, and ointments (these preferably con-taining a preservative~ and, for the treatment of eyes, eye drops containing the active compound in aqueous or oily solution and eye ointments, which are preferably prepared in ~L~65:1~B

-- s~, sterile form, and, for the ~reatment of the nose, powders, aerosols and sprays (similar to those described above for the treatment o-f ~he respiratory tract) and coarse powders which are administered by rapid inhalation through the nostrils, and nose drops containing the active compound in aqueous or oily solution, or, for local treatment of the mouth, s~eets for sucking, containing the active cornpound in a mass gener-ally formed from sugar and gum arabic or tragacanth, to which flavouring agents may be added, and pastilles containing the active substance in an inert mass, for example of gelatine and glycerol or su~ar and gum arabic.
The invention also relates to the use of the novel compounds of the formula I and of their salts as pharmaco-logically active compounds, for example as antiallergics or, in particular, antiinflammatories, preferabLy in the form of pharmaceutical products. The daily dose administered to a warm-blooded organism weighing about 70 kg is from about ZûO mg to about 1,200 mg.
The follo~ing examples illustrate the invention des-cribed above without in any way restricting the scope thereof.
Temperatures are given in degrees Celsius.
Example 1: A solution of 3 g (4.5 mmol) of N-~3-~3-C4-acetyl-3-hydroxy-2-t3~3,3-trifluoropropyl)-phenoxy]-propoxy3-4-chloro-6-methyl-phenyl~-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 90 ml of trifluoroacetic acid and 9 ml of anisole is refluxed for 60 minutes. The reaction mixture is concentrated under reduced pressure, about 150 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off~ The N~~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-triFluoropropyl)-phenoxy3-propoxy~-4-chloro-6-methyl-phenyl ~-1H-tetrazoLe-S-carboxamide thus obtained, of melting point 236-238 (decomposition) is dissolved ;n 50 ml of tetra-hydrofuran, and one equivalent of sodium, dissolved in S ml of methanol, ;s added. After addition of ether, crystallisa-tion starts. The sodium salt of N-~3-~3-C4-acetyL-3-hydroxy-Z-(3,3,3-trifluoropropyl)-phenoxy]-Propoxy~-4-chloro-6-methyl-phenyl~-1H-tetrazole-5-carboxamide of melting point 9û

.,, 12~

tdecomposition) is thus obtained.
N-~3-~3-~4-Acetyl-3-hydroxy~2-~3,3~3-trifluoropropyl)-phenoxy]-propoxy3-4-bromo-6-methyl-phenyl3~-1H-tetrazole-5 carboxamide of melting point 245-248 (decomposition) and its sodium salt of melting poin~ 120-130C are obtained in an analogous manner starting from N-~3-~3-~4-acetyl-3-hydro~y-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy~-4~bromo~6-methyl~
phenyl~-1-(4-methoxybenzyl)-tetrazole-5-carboxamide.
The starting material can be prepared~ for example, as follows:
S~age A~ Dichloro-2~2~2-tri~luoro-ethyl-zinc chloride diethyl etherate, CF3CCl2ZnCl(C2H5)0 65.~t g (1 mole) of zinc dust tactiYated according to Fieser ~ Fieser) are suspended in 800 ml of diethyl ether in a 1 l three-necked round-bottomed flask and 188 9 (1 mole) of CF3CCl3 are slowly added under a blanket of argon. The mixture is subsequentlystirred at room temperature for Z0 hours~ ~he reaction mixture is then filtered over "Selecta"
filter flocculant material, ~he complex precipitating in crystalline form after cooling the filtrate or after it has cooled down. The complex is recrystallised from diethyl ether, for further purification. The excess diethyL ether is decanted off and the colourless crystalline residue is dried in vacuo. 1,1-Dichloro-2,2,2-trifluoro-ethyl-zinc chloride diethyl etherate of melting point 105 is obtained, yield 80%.
Stage B: 1,3-Dimethoxy-2~ hydroxy 2,2-dichloro-3,3,3-tri-fluoropropyl)-benzene 130.1 9 (0.40 mole~ of 1,1-dichloro-2,2,Z-trifluoro-ethyl~zinc chloride diethyl etherate in 700 mL of absolute dime~hylformamide are introduced into a three-necked round-bottomed flask (1,000 ml) with a thermometer, bubble counter and argon connectionO after evacuating/flushing with argon 3 times. 51.0 9 tO.32 mole) of Z,o-dimethoxybenzaldehyde are then added all at once. The yellow clear react;on solution is stirred at room temperature for 72 hours and then poured onto a m;xture of S00 9 of ice and 600 ml of 10% hydrochloric ., .

~L~6S~8 acid. After extraction with ether, washing with 2X hydro-chloric acid and brine, drying over magnesium sulfate and concentration, a dark red oil is obtained, from which red-brown crystals of 1,3-dimethoxy-2~ hydroxy-2,2~dichLoro-3,3,3-trifluoro-propyl)-benzene precipitate, y~ld 99~. This does not have to be subsequently purified for further pro-cessing.
C: 1,3-Dimethoxy-2~ acetoxy-2,2-dichloro-3,3,3-tri-fluoropropyl)-benzene 31 ml (0.33 mole) of acetic anhydride are added to 97.6 9 (0.30 mole) of 1,3-dimethoxy-2~(1-hydroxy-2,2-di-chloro-3,3,3-trifluoro-propyl)-benzene in a 500 ml pear-shaped flask at room temperature. 3~ ml (0.36 mole) of pyridine are then added to the dark red solution (weakly exo-thermic). The reaction solution is stirred at room tempera-ture for 3 days. The reaction mixture is then poured onto ice and acidified with 10~ hydrochloric acid. It is extrac-ted with ether and the extract is washed with wa~er and brine, dried over magnesium sulfate and evaporated to dryness.
The 1,3-dimethoxy-2-(1-acetoxy-2,2 dichloro-3,3,3-trifluoro-propyl)-benzene which remains (yield 87%) is employed for stage D without further purification.
Sta~e D: 1,3-Dimethoxy-2-(2-chloro-3,3,3-trifluoroprop-1-enyL~-benzene 96~5 9 (0.266 mole) of 1,3-dimethoxy-2-(1-hydroxy-2,2-dichloro-3,3,3-trifluoro-propyl)-benzene are dissolved in 1,000 ml of ethanol in a 1.5 l sulfonating flask with a thermometer, condenser and bubble counter, and 30 9 (0.5b mole3 of ammonium chloride are added. Zinc activated accord-ing to Fieser æ Fieser (36.9 9 = D.564 mole) is added in portions to the resulting brownish suspension, the reaction temperature rising to 42. Stirr;ng is continued overnight and the grey-yellow reaction mixture is then poured onto ice-water and extracted with ether and the extract is washed with water (3x) and brine, dried over magnesium sul~ate and evaporated. 1,3-Dimethoxy-Z-~Z-chloro-3,3,3-trifluoroprop-1-enyl)-benzene ( ~ : 94%~ is obtained as a reddish oil.

,.

12~

Zinc dust is activated as follo~s: suspension in 5%
HCl and decanting (exothermic) twice, suspension ;n UzO and decanting 3 ~imes, suspension in methanol and decanting twice, suspension with ether and decanting 3 times; drying under greaely reduced pressure and storage under argon.
Sta~e E: 1,3-Dimethoxy~2-(3,3,3-trifluoroprop~1-ynyl)-benzene 30.7 g of po~assium ter~iary butanolate in 900 ml of tertiary butanol are introduced into a 1.5 l sulfonating flask with a thermometer, condenser, bubble counter and dropping funnel. 63.7 g (0.25 mole) of 1,3-dimethoxy-2-(Z-chloro-3,3,3-trifluoroprop-1-enyl)-benzene in 100 ml of tertiary butanol are added dropwise to this clear, colourless solution (weakly exothermic) and the reac~ion is brought to completion by stirring at room temperature ~or 24 hours. The orange suspension is poured onto ice and extracted with ether and the extract is washed with water, N bicarbonate solution and brine~ dried over magnesium sulfate and concentrated until crystals precipitate. The crystal mass is cooled, filtered cold and washed with a l;ttle ice-cold petroleum ether. 103-Dimethoxy-2-(3,3,3-trifluoroprop-1-ynyl)-benzene is obtained in the form of pale beige, fine crystals of melting point 110-111 (yield 73X).
Sta~e F. 1,3-Dimethoxy~2-(3,3,3-trifluoropropyl)-benzene 41.5 ~ (0.18 mole~ of 1,3-dimethoxy-2-~3,3,3-tri-fluoroprop-1-ynyl)-benzene are dissolved in tetrahydrofuran and hydrogenated in the presence of palladium-on-charcoal at room temperature under normal pressure. The catalyst is filtered off over diatomaceous earth and washed with tetra-hydrofuran and the filtrate is concentrated. Drying under reduced pressure gives crys~alline 1,3-dimethoxy-2-(3,3,3-trifluoropropyl)-benzene ( ~ 87%)~
Sta~e_G: 2-(3~3,3-Trifluoropropyl)-resorcinol 30.5 9 (0.13 mole) of 1,3-dimethoxy-2-~3,3,3-tri-fluoropropyl)-benzene in 275 ml of methylene chloride are introduced into a 1~5 l sulfonating flask with a thermometer, bubble counter, dropping funnel with cooling jacket and argon connection and cooled to ~75O 340 ml of a precooled 1 molar solution of boron tribromide in methylene chloride are now added dropwise such that the reaction temperature does not rise above -70 (about 90 minutes). Af~er subsequently stirring at room temperature for 6 hours, the red reaction solution is poured onto 800 ml of ice-water. The organic base is separated off, the aqueous phase is extracted again ~ith ether and the combined organic phases are washed with brine, dried over magnesium suLfate and evaporated. 2-(3,3,3-Trifluoropropyl)-resorcinol is obtained in the form of red crystals of meLting point 82-84 ty~ 100%~.
~: 2~4-Dihydroxy-3-t3~3~3-trif luoroproPyl)-acetophenone 21~0 9 (0.154 mole) o~ zinc chLoride in 27 ml of glacial acetic acid are introduced into a 100 ml three-necked round-bottomed flask with a condenser, bubble counter and thermometer and heated to 120, a clear, colourless solu-tion forming. 27.0 9 (0.13 mole) of 2-(3~3,3-trifluoro-propyl)-resorcinol are added at this temperature, whereupon the temperature falls to 82. The red, clear solution is refluxed (132) for a further 4 hours and allowed to cool.
A red suspension is obta;ned; this ;s poured onto 440 ml of half-concentra~ed hydrochloric acid and extracted 3 times with ether. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to a high degree.
The reddish crystals obtained are suspended in pentane, filtered off with suction and washed with pentane. 2,4-Di-hydroxy-3-(3,3,3-trifluoropropyl)-acetophenone is obtai-ned~
yield: Z6.5 9 of yellow crystals of 0elting point 18û-184;
82%
Stage I: 4-(3-Bromopropoxy)-2-hydroxy-3-(3,3,3-trifluoro-propyl)-acetophenone 3.32 9 of potassium carbonate and 0.5 g of potassium iodide are added to a solution of 2~45 ml of 1,3-dibromo-propane in 30 ml of acetone and the mixture is refluxed. A
solution of 1.98 9 of 2,4-dihydroxy-3-(3,3,3-trifluoropropyl)-acetophenone in 10 ml of àcetone is added dropwise in the course of 2 hours and the mixture is refluxed for a further 3 hours. The reaction mixture is filtered and the filtrate ;5il~

5~, is evaporated in vacuo~ The resi~ue is dissolved in 50 ml of methylene ~hloride and the solution is washed w;th 10 ml of water. The organic phase is dried over sodium sulfate and evaporat~d in vacuo and the residue is chromatographed on 100 9 of silica gel with methylene chloride as the mobile phase. 4-(3-Bromopropoxy)-2-hydroxy-3-(3,3,3-trifluoro-propyl~-acetophenone is eluted in the first fraction, and, after evaporation, is obtained in the form of colourless crystals of melting point 70-72C.
Stage J: 3-~3-~4-Ace~yl-3-hydroxy-2-~3,3,3-trifluoropropyl)--phenoxy~-propoxy~-4-chloro- or -bromo-6-methyl-nitrobenzene A spatula-tip oF potassium iodide and 3.5 9 t9.5 mmol) of 4-(3-bromopropoxy)-2-hydroxy-3-(3~3,3-trifluoropropyl)-acetophenone are added to a suspension of 1.87 g t10 mmol) of 2-chloro-4-methyl-5-nitrophenol and 1.5 9 (10.5 mmol) oF
calcined potassium carbonate in 30 ml of ethyl methyl ke~one and the mixture is refluxed for 10 hours~ The reaction mix-ture is cooled, poured onto water and extracted three times with methylene chloride~ The organic phases are combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. Crystallisation of the residue from ether/petroleum ether gives 3-{3 C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyL)-phenoxy]-propoxy~-4-chloro-

6-methyl-nitrobenzene of melting point 11~-120 3-~3-C4-Acetyl-3 hydroxy-2-(3,3,3 trifluoropropyl)-phenoxy]-propoxy3-4-bromo-6-methyl-nitrobenzene of melting point 106-109 are obtained in an analogous manner starting from 2-bromo-4-methyl 5-nitrophenol.
Stage_K: 3-~3 ~4-Acetyl 3 hydroxy 2-(3~3,3-triFluoropropyl)-phenoxy~-propoxy~-4-chloro- or -bromo-6-methyl-aniline 1.0 g of Raney nickel is added to a solution of 3.7 9 of 3-C3-t~t-acetyl-3-hydroxy 2-(3,3~3-trifluoropropyl)-phenoxy)-propoxy~-4~chloro-6~methyl-nitrobenzene in 40 ml of tetrahydrofuran and the starting substance is hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. Thé filtrate is evaporated to dryness under reduced pressure and the residue ;s crystallised from ~s~

- ~o -ether/petroleum ether. 3-~3-C4-Acetyl-3-hydroxy Z-(3,3,3-tri fluoropropyl)-phenOxy~-propoxy~-4-chloro-6~methyl-aniline o~ m~ti~g point 111-~13 is thus obtained~
3-[3-C4-Acetyl-3~hydroxy-2~(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-bromO-6-methy~-aniline of melting point 124-126 is obtained in an analogous manner starting from 3-~3-C4-acety~-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy~-4-bromo-6-methyl-~i~robenzene.
Sta~e L: N-l~3-~3-C4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy~-4-chloro- or -bromo-6-methyl-phenyl3~-1-(p-methoxy-benzyl)-tetrazole-5-carboxamide 0.66 ml ~7.7 mmol) of oxalyl chloride is added to a suspènsion of 2.07 9 ~7.7 mmol) of potassium~1-(4-methoxy-benzyl)-tetrazole]-S-çarboxylate in 30 ml of benzene and 0.5 ml of pyridine at 0-5 and the mix~ure is stirred at room temperature for 30 minutes. The reaction mixture is concen-trated under reduced pressure, the residue is taken up in benzene and the mixture is evaporated again under reduced pressure~ The residue is suspended in 200 ml of methylene chloride and the suspension is added dropwise to a solution of 2.6 9 (5.8 mmol) o~ 3-~3-C4-acetyl-3-hydroxy-2-(3~3,3-tri-fluoropropyl~-phenoxy]-propoxy~-4-chloro-6-methyl-aniline and 0.61 ml of pyridine in 30 ml Of methylene chloride at û-5 in the course of 10 minutes. The mixture is then stirred at room temperature for 3 hours. The reaction mixture is diluted with methylene chloride and washed twice ~ith water.
The organic phase is dried over sodium sulfate and evaporated under reduced pressure. Crystall;sation of the residue from ether gives N-~3-~3-C4-acetyl-3-hydroxy-2-~3~3,3-trifluoro-propyl)-phenoxy~-propoxy7-4-chloro-6-methyl-phenyl~-1-t4-methoxybenzyl)-tetrazole-5-carboxamide Of melting point 148-150.
N-~f3-~3 C4-Acetyl-3 hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy~-4-bromo-6-methyl-phenyl~-1-(4-methoxy-benzyl~-tetrazole-5-carboxamide of melting point 140-142C ;s obtained in an analogous manner starting from 3-~3 C4-acetyl-3~hydroxy~2~(3,3,3~trifluoropropyl)-phenoxy]-propoxy -4-bronQ-6-methyl-aniline.
Example 2: A solution of 0.36 ml (3.57 mmol) of methyl chlorooxalate in S ml of methylene chloride is added dropwise to a solut;on, cooled ~o 0, of 1.75 9 t3.57 mmol) of 3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-bro~o-6-methyl-an;l;ne (~xample 1) and û.55 ml (3.57 mmol) of triethylamine ;n 15 ml of methylene chlor;de ;n the course of 5 minutes~ The reaction mixture is subse-quently stirred at room temperature for 90 minutes and poured onto ice-water and ~he organic phase is separated off. The organic phase is ~ashed with water, dried over sod;um sulfate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether gives methyl N-~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-bromo-6-methyl-phenyl~-oxamate of melting point 1 39-1 40 a Example 3: A suspens;on of 1.75 9 (3 mmol~ of methyl N- ~3-{3-~4-acetyl-3-hydroxy-2-~3,3,3-trifluoropropyl)-phenoxy]-propoxy3-4-brono-6-methyl-phenyl~ -oxamate (Example 2) in 30 ml of methanol and 3.2 ml of N sodium hydroxide solution is refluxed for 60 m;nutes. The reaction mixture is concen-trated under reduced pressure, the residue ;s dissolved in acetone and dilute sodium hydroxide solution and the solution is acidified with dilute hydrochlor;c acid. The product which has precipitated is filtered off and washed neutral with water. N-~3-~3-~4-Acetyl-3-hydroxy-2-t3,3,3-trifluoro-propyl)-phenoxy]-propoxy3-4-bromo-6-methyl-phenyl7~-oxamic acid of melting point 207-Z09 is thus obtained~
Example 4: 1.55 ~ (2.76 mmol) of N-~3-~3-C4-acetyl-3-hydroxy-2-~3,3,3-tr;fluoropropyl)-phenoxy]-propoxy~-4-bromo-6-methyl-phenyl~ -oxamic acid ~Example 3) are dissolved hot in 300 ml o~ acetone, and a solut;on of 411 m~ ~2.8 mmol) of tri-ethanolamine in 10 ml of acetone is added~ The reaction solution is concentrated to 50 ml under reduced pressure.
After addition of ether, crystallisation starts~ The product which has prec;pitated out is f;ltered off and washed with ethera The triethanolammonium salt of N-{~3-{3-C4-acetyl-3-~L2~

hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~~propoXy~~4~bromo-6-methyl-phenyl~-oxamic acid is thus obtained; melting point 133-135~.
Example 5: A solution of 1.9 ml (21 mmol) of methyl chloro-oxalate in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0, ot 7.5 9 of 3 ~3-[4~acetyl-3-hydroxy-2-(3r3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methyl-aniline and 3.0 9 of triethylamine in 60 ml of methylene chloride in the course of about 5 minutes. The reaction mixture is subsequently stirred at room temperature for 90 minutes and poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water~ dried over sodium sulfate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether gives methyl N-~3-~3-[4-acetyL-3-hydroxy-2 (3,3,3-trifluoropropyl~-phenoxy~-propoxy7-6-methyl-phenyl~-oxamate.
Methyl N-{~3-¦3-C4-acetyl 3-hydroxy-2-(3,3,3-tri-fluoropropyl~-phenoxy]-propoxy~-phenyl~-oxamate is obtained in an analogous manner starting from 3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-aniline.
The s~arting material can be prepared, for example, as follows.
A spatula-tip of potassium iodide and 9.5 9 of 4-(3-bromopropoxy)-2-hydroxy-3-~3,3,3-trifluoropropyl)-acetophen-one are added ~o 3 suspension of 5.1 9 of 4-methyl-3-nitro-phenol and 4.6 g of calcined potassium carbonate in 100 ml of ethyl methyl ketone and the mixture is refluxed for 14 hours.
The reaction mixture is cooled, poured onto water and extrac-ted three times with ether. The organic phases are washed with water, combined, dried over sodium sulfate and concen-trated to dryness under reduced pressure. Crystallisation of the residue gives 3-{3-C4-acetyl-3-hydroxy-2-(3,3,3-tri-fluoropropyl)-phenoxy]~propoxy~-o-methyl-nitrobenzene.
3-I3-C4-Acetyl-3-hydroxy-2~~3,3,3-trifluoropropyl~-phenoxy]-propoxy~-nitrobenzene is obtained in an analogous manner starting from m~nitrophenol.

~2~

1.0 9 of Raney nickel is added to a solution of 9.1 9 (23.5 mmol) of 3-C3-(4-acetyl-3-hydroxy-Z~n~proPyL~Phenoxy) propoxy~-6-methyl-ni~roben2ene in 90 ml of tetrahydrofuran and the starting substance is hydro~enated at room tempera-ture. The catalyst is filtered off and washed with tetrahydro-furan. The filtrate is evaporated to dryness under reduced pressure. 3-~3-C4-Acetyl-3~hydroxy-2~(3,3~3-trifluoropropyl)-phenoxy]-propoxy~-6-methyl-aniline is thus obtained.
3~~3-C4-Ace~yl-3-hydroxy-2-(3,3,3-tri~luoropropyl)-phenoxy3-propoxy3-aniline (ether/petroleum ether) is obtained in an analogous manner starting from 3-~3-C4-acetyl-3-hydroxy-Z-t3,3,3-trifluoropropyl)-phenoxy~-propoxy}-nitrobenzene.
Example 6: 20 ml of lN sodium hydroxide solution are added to a suspension of 8.60 9 (19.4 mmol) of methyl N-~3-~3-C4-acetyl-3-hydroxy-Z-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-6-methyl-phenyl~-oxamate in 60 ml of methanol and 2~ ml of water and the mixture is re~luxed for 10 minutes. The reac-tion mixture is cooled and the product which has precipi~ated out is fiLtered off. The sodium salt of N-~{3-~3-C4-acetyl-3-hydroxy-2-(3,3,3 trifluoropropyl)-phenoxy~-propoxy}-6-methyl-phenyl~-oxamic acid is thus obtained.
The sodium salt of N-~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-phenyl7~-oxamic acid can be prepared in an analogous manner.
Example 7: The following compounds are obtained in a manner analogous to that described in Example Z: methyl N-~3-~3-Cl~acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy~-2-methyl-phenyl~?-oxamate; methyl N-~{3-~5-C~-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-pentoxy~-phenyl~-oxamate; methyl N-~4-~3-C4-acetyl-3-hydroxy-Z~
(3,3,3-trifluoropropyl)-phenoxy]-propoxy~3-methoxy-phenyl~-oxamate; methyl N-~¦4-~3~C4-acetyl-3-hydroxy-2-(3,3,3-tri-fluoropropyl)-phenoxy]-propoxy~-2 methyl-phenyl~ -oxamate;
methyl N-f~2-~3-C4-acetyl-3-hydroxy-2-~3,3,3-trifluoropropyl)-phenoxy~-propoxy~-phenyl~~oxamate; methyl N-~4-~3-~4-acetyl~3-hydroxy-Z-~3,3,3-trifLuoropropyl)-phenoxy~-propoxy~-phenyl~-oxamate; methyl N-~3-~3-C4-acetyl-3-hydroxy-Z-~2~i51~

(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-chloro-6-tri-fluoromethyl-phenyl~-oxamate; methyl N-~3-~3-~4-acetyl-3-hydroxy-2-~3,3,3-trjfluoropropyl)-phenoxy~-propoxy~-2,4,6-trichloro-phenyl~-oxamate as an oil and methyl N-~3-~3-C4-acetyl-3-hydroxy-2-(3~3~3-trifluoropropyl)-phenoxy]-pr 4,6-dimethyl-phenyl~-oxamate.
The starting materials can be prepared, for example, in a manner analogous to that described in Example 1:
~xample 8: N-~3-~3-~4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy~-2-methyl-phenyl3~-oxamic acid and the triethanolammonium salt thereof, and N-~3 {5-~4-acetyl-3-hydroxy-2-(3,3~3-trifluoropropyl~-phenoxy~-pentoxy~-phenyl~-oxamic acid and the triethanolammonium salt thereof; N-~3-~3-[4-acetyl~3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-trifluoromethyl-phenyl~-oxamic acid and the tr-iethanolammonium salt thereof; N-~3-~3-~4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy~-Z,4,b-trichloro phenyl~-oxamic acid and the triethanolammonium salt thereof and N-~3-~3-C4-acetyl-3-hydroxy-3-(3,3,3-tri-~luoropropyl)-phenoxy]~propoxy~-4,6-dimethyl-phenyl~-oxamic acid and the triethanolammonium salt thereof are obtained in a manner analogous to that described in Example 3.
Example 9: 1~ ml of N sodium hydroxide solution are added to a solution of 7.95 g of methyl N-~4-~3-~4-acetyl-3-hydroxy-Z-~3,3,3 trifluoropropyl)-phenoxy]-propoxy}-3-methoxy-phenyl~}-oxamate in 100 ml of methanol and the mix-ture is refluxed for 1 hour. The hot solution is then poured into ~00 ml of 0.1 N hydrochloric acid. The product which has precipitated out is filtered off, washed ~ith water and dried over phosphorus pentoxide in a dry;ng cabinet. The N-; ~4-~3-C4-acetyl-3 hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]- propoxy~-3-methoxy- phenyl~-oxamic acid thus obtained is dissolved hot a~ain in 100 ml of methanol, and one equivalent of triethanolamine in 10 ml of methanol is added. After addition of 400 ml of ether, crystallisation starts. The triethanolammonium salt of N-~4-~3-~4-acetyl-3-hydroxy-2-; ~3,3,3-trifluoropropyl)-phenoxy]-propoxy~-3-methoxy-phenyl~-~2~ 4~.~

oxamic acid is thus obtained.
The follo~ing compounds are obtained in an analo~ous manner: N-~4-~3-t4-ace~yl-3-hydroxy~2-~3,3,3 trifluoro-propyl)-phenoxy]-propoxy~-2-methyl-phenyl~-oxamic acid and the triethanolammonium salt thereof; ~ 2-~3-~4-acetyl-3-hydroxy-2-(3,3,3-trif~uoropropyl) phenoxy]-propoxy~-phenyl~-o~amic acid and the triethanolammonium salt thereof; and N-~4-~3-C4-acetyl-3-hydroxy-Z-~3,3,3-trifluoropropyl)-phenoxy~-propoxy~-phenyl~-oxamic acid and the triethanolammonium salt thereof.
Example 10: The following compound is obtained in a manner analogous to that described in Example 1: N-{~3-~3-C4-acetyl-3-hydroxy-2-(3,3~-trifluoropropyl~-phenoxy~-propoxy~-phenyl~-lH-tetrazole-5-carboxamide and the triethanolammon-ium salt thereof.
A solution of 12.3 ml of ethyl chlorooxalate in 30 ml of methylene chloride is added dropwise to a solution, cooled to 0C~ of 43.6 9 of 3-f3-~4-acetyl-3-hydroxy-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-aniline and 15.3 ml of triethylamine in 400 ml of methylene chloride in the course of ~bout S minutes and the mixture is then stirred a~ room temperature for a further 90 minutes.
The reaction mixture is poured onto ice-water and the organic phase is separated off, washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystal-lisation from ethyl acetate/ether/petroleum ether gives ethyl N-{~3-~3-C4-acetyl-3-hydroxy-2-~3,3,3-tritluoropropyl)-phenoxy~-propoxy~-4-bromo-6-methyl-phenyl~?-oxamate.
Example 1?: 44~ mg (7.5 mmol~ of potassium hydroxide are added to a suspension of 4.û ~ of ethyl N-~3-~3-~3-(4-acetyl^3-hydroxy-2-(3,3~3-trifluoropropyl)-phenoxy~-propoxy~-4-bromo-6-methyl-phenyl~-oxamate in 40û ml of ethanol and ~he mixture 7S refluxed for 4 hours. The reaction mixture is cooled and the product which has precipitated out is filtered off. The potassium salt of N-~3-~3-C4-acetyl-3-hydroxy-2-(3,3~3-~rifluoropropyl)-phenoxy]-propoxy~-4-bromo-6-me~hyl-phenyl~}-oxamic acid is thus obtained.

~2~S~

- ~6 -The sodium salt of N-{{3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy~-4-bromo-6-methyl-phenyl~-oxamic acid can also be prepared in an analogous manner.
Example 13: 4.06 g of N-~3- ~-C4-acetyl~3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy~-4-bromo-6-methyl-phenyl7~-oxamic acid are dissolved in 40 ml of acetone, and a solution of 840 mg o~ diethanoLamine in 5 ml of acetone is added.
After addition of e~her, crystallisation starts~ The product which has precipitated out is filtered off and ~ashed with ether. The diethanolammonium salt of N-~3-~3-~4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-bromo-6-methyl-phenyl~?-oxamic ac;d is thus obta;ned.
The tristhydroxymethyl)-methylammonium salt of N-~3-~3-C4-acetyl-3-hydroxy-2-n-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~ 4 bromo-6-methyl-phenyl7?-oxamic acid can also be prepared in an analogous rnannerO
le 14: A solution of 7.05 9 of N-~¦3-~3-C4-asetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-2-cyano-phenyl~-1-(4-methoxybenzyl) tetrazole-5-carboxamide in 150 mL
of trifluoroacetic acid and 15 ml of anisole is refluxed for 30 minutes. The reaction mixture is concentrated under redwced pressure, about 200 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off.
The N-~3-~3-C4-acetyl 3-hydroxy-2-(3,3,3-tr;fluoropropyl~-phenoxy]-propoxy~-Z-cyano-phenyl~-1H-tetrazole-5-carboxamide thus obtained, of melting point 206-208, is dissolved hot in 50 ml of acetone, and the calculated amount of triethanol-amine ;n 30 ml of acetone is added. After addition of ether, crystallisation star~s. The triethanolammonium salt of N-~3-~3-~4-acetyl-3-hydroxy-2-t3,3,3-tri~luoropropyl)phenoxy]-propoxy~-2-cyano-phenyl~?-1H-tetrazole-5-carboxamide is thus obtained.
The following compounds can be prepared in an analo-gous manner: N-~3-~3-C4-acetyl-3-hydroxy-2-(3~3,3-tri-fluoropropyl)-phenoxy]-propoxy~-4-cyano-6-methyl-phenyl~
H-tetrazole-5-carboxamide and N-~3-¦3-C4-acetyl-3-hydroxy-~26~

2-t3~3,3~tri~luoropropyl)-phenoxy~-propoxy~-4-Fluoro-6~methyl-pheny~ -1-H-tetrazole-5-carboxamide.
The starting material can be prepared, for example, as follo~s:
A spatula-tip of potassium iodide and 3105 9 of 4 (3-bromopropoxy) 2-hydroxy-3-(3,3,3-trifluoropropyl)-acetophen-one are added to a sùspension of 13.1 g of 2-cyano-3-nitro-phenol and 13.8 9 of calcined potass;um carbona~e in 100 ml of ethyl methyl ketone and the mixture is refluxed for 20 hours. The reaction mixture is cooled, poured onto ~ater and extracted three times with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated to dryness under reduced pressure.
Crystallisation of the residue from ether/hexane gives 2-~3-~4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-6-nitro-benzonitrile.
2.5 9 of 10% Pd-on-charcoal are added to a solution of 10 9 of 2-f3-C~-acetyl-3-hydroxy--2-(3,3,3-trifluoropropyl~-phenoxy]-propoxy~ nitro-benzonitrile and 10 9 of cyclo-hexene in 500 ml of ethanol and the mixture is refluxed for 30 minutes. After cooling to room temperature, it is filtered and ~reed from the solvent. Ether is added to the residue and the crystals which have separated out are fil-tered off. 2~Amino-6-~3-C4-acetyl-3-hydroxy-Z-(3,3,3-tri-fluoropropyl)-phenoxy~-propoxy}-benzonitrile is obtained.
1.84 ml t21.5 mmol) of oxalyl chloride are added to a suspension of 5.8 9 of potassium 1-(4-methoxybenzyl)-tetrazole~5-carboxylate in 110 ml of benzene and 1.0 ml of pyrid;ne at 0-5 and the m;xture is stirred at room tem-perature for 30 minutes. The reaction mixture is concentra-ted under reduced pressure~ the residue ;s taken up ;n ben~
zene and the m;xture ;s evaporated again under reduced pres-sure. The residue ;s d;ssolved ;n 80 ml of methylene chlor;de and the solution is added dropwise to a solution of 6.3 9 of 2-amino-6-~3-~4-acetyl~3~hydroxy-2~(3,3,3-trifluoropropyl~-phenoxy]-propoxy~-benzonitr;le and 1.72 ml of pyridine ;n 40 ml of methylene chlor;de at 0-5 in the course of about ~2~:iS~

- 6~ -10 minutes. The mixture is then stirred at room temperature for 3 hours. The reaction mixture is diluted with methylene chloride and washed three times with water. The organic phases are combined, dried over sodium sulfate and evaporated under reduced pressure. Crystall;sat;on of the residue from ethyl acetate/hexane gives N-~3-~3-~4-acetyl~3-hydroxy-2~
(3,3,3-triFLuoropropyl)-phenoxy]-propoxy~-2-cyano-phenyl~-1-(4-methoxybenzyl)-tetrazole-5-carboxamide.
Example 15: The following compounds are furthermore obtained in a manner analogous to that described in Examples 1-14:
methyl N ~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy~-4-methyl-6-chloro-pheny~-oxamate; methyl N-~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phen-oxy~-propoxy~-4-methyl-6-bromo-phenyl~7-oxamate; N-~3-{3-t4-acetyl 3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-methyl-6-chloro-phenyl~-oxamic acid and the tri-ethanolammonium salt thereof; N-~{3-~3-L4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy~-4-methyl-6-chloro phenyl~-1H-tetrazole-5-carboxamide and the tri-ethanolammonium salt thereof; N-~l3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl~phenoxy]-propoxy}-4-methyl-6-bromo-phenyl~ -tetrazole-5-carboxamide and the triethanolammon-ium salt thereof; ethyl N-~3-{3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy~ 2-cyano-phenyl~-oxamate; and N-~3-{3-~4-acetyl~3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy~-propoxy~-2-cyano~phenyl~-oxamic acid and the triethanolammonium salt thereof~
Example 16: 3.0 9 of boron tribromide are added dropwise to a solution, cooled to -78C~ of 2.2 g of methyl N-{~3-{3-[4-acetyl-3-methoxy-2-(393,3 trifluoropropyl) phenoxy)-propoxy3-phenyl~-oxamate in 2~ ml of methylene chloride in the course of 5 minutes. The mixture is then stirred at room temperature for 6 hours. 5 ml of water are added, with cooling, and the organic phase is separated off and evaporated under reduced pressure. Recrystallisation from methylene chloride/ether gives methyl N-~3-~3-~4-acetyl-3-hydroxy-2-~3,3,3-trifluoro-propyl)-phenoxy]-Propoxy~-phenyl7}-oxamate.

1;~6~

The starting material can be prepared, for example, as -follows:
5,530 mg o~ sodium hydride are added to a solution of 7~46 9 of 3-~3-C4-acetyl-3 hydroxy-2-(3,3~3-trifluoro-propyl~-phenoxy]-propoxy~ -nitrobenzene in 75 ml of dimethyl-formamide and the reaction mixture is warmed to 40. 5.7 9 of methyl iodide are added dropwise in the course of 15 minutes. Thereafter, the reaction mixture is kept at 40C
-for a fur~her hour. After cooling, it is poured onto dilute hydrochloric acid and extracted with methylene chloride and the extract is evaporated. Recrystallisation from ether/
hexane gives 3-{3-C4-acetyl-3-methoxy-Z-(3,3,3-trifluoro-propyl)-phenoxy~-propoxy~-nitrobenzene.
2.0 9 of ~aney nickel are added to a solution of 10 9 of 3-~3-C4 acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-nitrobenzene in 100 ml of tetrahydrofuran and the star~ing subs~ance is hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran.
Evaporation of the filtrate under reduced pressure gives 3-~3 C4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phen~xy]-propoxy} aniline as a colourless oil~
A solution of 3.45 ml of methyl chlorooxalate in 1U ml of methylene chloride is added dropwise to a solution of 9.2 9 of 3-~3-C4-acetyl-3-methoxy-2-(3,3,3-trifluoro-propyl~-phenoxy]-propoxy}-aniline and 4.3 ml of triethanol-amine in 90 ml of methylene chloride in the course of 10 m;nutes. After stirring at room temperature for S hours, the mixture is poured onto water and extracted with methylene chloride. Evaporation of the extracts and recrystallisation of the residue from ether gives methyl N ~3 ~3-C4-acetyl-3-methoxy-2-~3,3,3-trifluoropropyl~-phenoxy]-propoxy3-phenyl~3-oxamate.
Example 17: A spatula-tip of potassium iodide and 3.2 9 of methyl N-C3-(3-bromopropoxy)-phenyl]-oxamate are added to a suspension of 2.3 9 of 2,4-dihydroxy-3-~3,3,3-trifluoro-propyl)-acetophenone and 1.6 9 of calcined potassium carbon-ate in 40 ml of ethyl methyl ketone and the mixture is ~;~6~

refluxed for 8 hours. The reaction mixture is cooled, poured onto water and extracted three -times with methylene chLoride.
The combined extracts are washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. Crystallisation of the residue from ether gives methyl N-~3-~3-C4-acetyl-3-hydroxy-2-t3,3,3-trifluoropropyl)-phenoxy)-propoxy~-phenyl~-oxamate.
The star~ing material can be prepared, for example, as follows:
43 ml of 1,3-dibromopropane are added to a suspension of 29 9 of potassium carbonate and 0.5 9 of potassium iodide in 170 ml of acetone and the mixture is refluxed. A solution of 19.4 9 of 3-nîtrophenol is then added dropwise in the course of 2 hours and the mixture is refluxed for a further 15 hours. The reaction mixture is filtered hot and evaporated.
Chromatography of the residue on silica gel ~ith toluene gives 3-(3-bromopropoxy)-nitrobenzene as a pale yellow oil.
1 g of Raney nickel is added to a solution of 4 9 of 3-(3-bromopropoxy)-nitrobenzene in 40 ml of tetrahydrofuran and the starting substance is hydrogenated at room tempera-ture. The catalyst is filtered off and washed with tetra-hydrofuran. Evaporation of the filtrate gives 3-(3-bromo-propoxy)-aniline as a colourless oil.
A solution of 1.5 ml of oxalic acid monomethyl ester chloride ;n 1a ml o~ methylene chloride is added dropwise to a solution of 3.5 9 of 3-t3-bromopropoxy)-aniline and 1.3 ml of pyridine in 40 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for Z hours, the mixture is poured onto water and extracted with methylene chloride. The combined extracts are evaporated and the residue is chromatographed on silica gel with methylene chloride/ethyl acetate (1~:1), The eluate is evaporated and the residue is crystallised from ether/hexane. Methyl N-C3-t3-bromopropoxy)-phenyl]-oxamate of melting point 90-91 is obtained.
Exam ~ : A spatula-tip of potassium iodide and 3.15 9 of 4-~3-bromopropoxy)-2-hydroxy-3-(3,3,3-trifluoropropyl~-aceto-~2651~

phenone are a~ded ~o a suspension of 1.8 9 o~ methyl N-~3-hydroxyphenyl)-oxamate and 1.38 g of calcined potassium carbonate in 20 ml of e-thyl methyl ketone and the mixture is refluxed for 12 hours~ The reaction mixture is cooled, poured onto water and extracted three ~imes wi~h methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. Crystallisation of the residue from methylene chloride/ether gives methyl N-~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy3-phenyl~-oxamate.
The starting material is obtained, for example as follows:
A solution of 1.9 ml of methyl chlorooxalate in 10 ml of methylene chloride is added dropwise to a solution of 2.5 9 of 3-aminoanisole and 1.5 ml o~ pyridine in 40 ml of methylene chloride in the course of 10 minutes. After stirr-ing at room temperature for 3 hours, the mixture is poured onto water and extracted with methylene chloride~ The extracts are dried over sodium sul~ate and evaporated and the residue is crystallised trom ether/hexane. Methyl N-(3-methoxyphenyl)-oxamate is obtained.
5 9 of boron tribromide are added dropwise to a solution, cooled to -78C, of Z g of methyl N-(3-methoxy-phenyl)-oxamate in 20 ml of methylene chloride ;n the course of 5 minutes. The mixture is stirre~ at room temperature for 5 hours, 5 ml of water are added, with cooling, and the organic phase is s~parated off~ Drying over sodium sulfate and evaporation gives methyl N-(3-hydroxyphenyl)-oxamate.
Example_19: The following compounds are furthermore obtained in a manner analogous to that described in Examples 1 to 14 and 16 to 1~: N-~3-~3-C4~acetyl-3-hydroxy-(3,3,3-trifluoro-propyl)-phenoxy~-propoxy~-4-methoxycarbonyl-pheny~-oxamic acid and the triethanolammonium salt thereof and N-~3-~3-C4-acetyl-3-hydroxy-2-~3,3,3-trifluoropropyl)-phenoxy~-propoxy~-carboxy-phenyl3~-oxamic acid and the mono- and disodium salt thereof.
: A suspension of 10.0 g of methyl N-~3-~3-C4-~Z6~

acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-Z-acet-oxy-propoxy~-6-methyl-phenyl~-oxamatè in 60 ml of methanol and 100 ml of N sodium hydrox;de solution is reFluxed for 1 hour. The re~c-tion mixture is cooled and acidified with dilute hydrochloric acid and the N-~3-~3 ~4-acetyl-3-hydroxy-2-t3,3~3-trjfluoropropyl)-phenoxy] 2-hydroxy-propoxy~-6-methyl-phenyl~-oxamic acid whi ch has precipitated out is filtered off and washed with water. For purification, the product is dissolved in 200 ml of boiling methanol, 22 ml of N sodium hydroxide solution are added and the mixture is concentrated to about 100 ml under reduced pressure. After addition of acetone and ether, crystallisation starts. The product is filtered off and washed with ether. The sodium salt of N-{~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy~-2-hydroxy-propoxy3-6-methyl-phenyl~-oxamic acid is thus obtainedn N-~4-~3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-2-hydroxy-Propoxy}-3-methoxy-phenyl~-oxamic acid can be prepared in an analo~ous manner starting from methyl N-~4-{3-~4 acetyl-3-hydroxy-2~~3,3,3 trifluoropropyl)-phenoxy~-2-acetoxy-propoxy~-3-methoxy-phenyl~-oxamate.
The starting materials are obtained, for example, as follows:
440 mg of a 55% sodium hydride suspension in mineral oil are added to a solution of 18.4 9 of 4-methyl-3-nitro-phenol in 1~0 ml of ethanol. A solution of ZS.0 9 of 4-t2,3-epoxypropoxy)-2-hydroxy-3-(3,3,3-trifluoropropyl)-acetophen-one, obtainable by reaction of 2,4-dihydroxy-3-(3,3,3-tri-f~uoropropyl)-acetophenone and epichlorohydrin, in 150 ml of ethanol is then added dropwise under reflux in the course of 1 hour and the mixture is subsequently stirred under reflux for 6 hours. The reaction mixture is cooled and concentrated to about 150 ml under reduced pressure and the concentrate is poured onto ;ce. The aqueous phase is acidified with d;lute hydrochloric acid and extracted three times with methylene chloride~ The organic phases are washed with water, combined, dried over sodium sulfate and concentrated under 12~ f-~

- 73 - 214~9-6~51 reduced pressure. Crystall;sation of the residue from ether gives 3-¦3-tb-acetyl-3-hydroxy-2-(3~3,3-trifluoropropyl-phenoxy]-2-hydroxy-propoxy~-6-methyl-nitrobenzene.
4-~3-C~-Acetyl 3-hydroxy-2-(3,3,3-trifluoropropyL)-phenoxy]-2-hydroxy propoxy~-3-methoxy-nitrobenzene is obta;ned in an analogous manner starting from 4-hydroxy-3-methoxy-nitrobenzene and 4-(2,3-epoxypropcxy)-Z-hydroxy-3-t3,3,3-trifluoropropyl)-acetophenone.
A suspension of 10.0 9 of 3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-tr;fluoropropyl)-phenoxy~~2-hydroxy~propoxy~-6-methyl-nitrobenzene in 100 ml of acetic anhydride and 1 ml of pyri-dine is stirred a~ 60 for 1 hour. The reaction mixture is then evaporated ~o dryness under reduced pressure and the crude 3-~3-~4-acetyl-3-hydroxy-2-t3,3,3-trifLuoropropyl-phenoxy]-2-acetoxy-propoxy~-6-me~hyl-nitrobenzene thus obtained is hydrogenated with Raney nickel in tetrahydrofuran. 3-~3-C4-Acetyl-3-hydroxy-2-(3,3,3-trifluoroprGpyl)-phenoxy]-2-acetoxy-propoxy~-6-methyl-aniline is obta;ned.
4-{3-C4-Acetyl-3-hydroxy-2-53,3,3-trifluoropropyl)-phenoxy]-2-a~etoxy-propoxy~-3-methoxy~aniline is obtained as an oi~ of Rf value = 0.10 ~silica gel; toluene/ethyl acetate = 6:1) in an analo~ous manner starting from 4-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy3-2-hydroxy-propoxy-~3~methoxy-nitrobenzeneO
A solution of 1.9 ml of methyl chlorooxalate in 8 ml of methylene chlorid~ is added dropwise to a solution, cooled to 0, of 8.3 9 of 3-{3-~4-acetyl-3-hydroxy-2-(3,3,3-tri-fluoropropyl)-phenoxy~-2-acetoxy-propoxy~-6-methyl-aniline and 2~9 ml of triethylamine in 70 ml of methylene chloride in the course of about S minutes and the mixture is then stirred at room tempera~ure ~or a further 2 hours. The reac-tion mixture is poured onto ice-water and the organic phase is separated Offn The methylene chloride phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. MethylN-~3-~3-C4~acetyl-3-hydroxy-Z-(3,3~3-trifluoropropyl)-phenoxy]-2-acetoxy-propoxy}-6-methyl-phenyl~-oxamate is thus obtained as an oil with an Rf value ~S3~

= 0.13 (silica gel; toluene/ethyl acetate = 6~
Methyl N-~4-~3-C4-acetyl-3 hydroxy-2-(3~3,3-tri-fluoropropyl)-phenoxy~-2-acetoxy-propoxy~-3-methoxy-phenyl 7 -oxamate is obtained in an analogous manner starting from 4-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl~-phenoxy]-2-acetoxy-propoxy~-3-methoxy-aniline.
: 1.45 ml of ethyl chlorooxalate are added drop-wise to a solution, cooled to 0, of 5.5 9 of 3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]~2-hydroxy-prop-oxy~-4-bromo-6-methyl-aniline in 60 ml of methylene chloride, with rapid stirring. The reaction mixture is subsequently stirred at 0 for 40 minutes and at room temperature for 5 hours and poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed three times with 10 ml of water each time, dried over sodium sulfate and evaporated under reduced pressure. The residue is crystallised from ether/petroleum ether. ~thyl N-~3-~3-~4-acetyl-3-hydroxy-2-(3,3~3-trifluoropropyl)-phenoxy~-2-hydroxy-propo~y~-4-bromo-6-methyl-phenyl~-oxamate has a meltinQ point of 113-115.
The starting material can be prepared as follows:
A mixture of 10.0 9 of 2,4-dihydroxy-3-(3,3,3-tri-fluoropropyl)-acetophenone and 16.4 g of epibromohydrin in 20 ml of ethanol is refluxed and a solution of 2.46 9 of potassium hydroxide in Z0 ml of ethanol and 0.5 ml of water ;s added dropwise. The suspension is refluxed for 2 hours, cooled, diluted with 150 ml of water and extracted with 20n ml of methylene chloride. The methylene chloride phase is washed with 40 ml of water, dried over sodium sulfate and concentrated to dryness under reduced pressure. 4-(Z,3-Epoxypropoxy)-Z-hydroxy~3-~3,3,3-trifluoropropyl)-acetophen-one is obtained as a yellow oil.
0.1 9 of a dispersion of sodium hydride in mineral oil (55~ is added to a solution of 3.8 9 of Z-bromo-4-methyl-5-nitro-phenol in 50 ml of anhydrous ethanol. The red solution is refluxed and a solution of 5.0 y o~ 4-(2,3-epoxy-propoxy)-2-hydroxy-3~(3,3~3-trifluoropropyl)-acetophenone in ~:6~

50 ml of anhydrous ethanol is added dropwise in ~he course of two hours~ while passing in 3rgon~ The mixture is refluxed for 7 hours and cooled, 200 ml of water and Z00 ml of methyl-ene chloride are added and the mixture is acidified with Z N
hydrochloric acid. The methylene chloride phase is separated off and the aqueous suspension is extracted again with 100 ml of methylene chloride. The combined methylene chloride phases are washed ~ith 50 ml of water, dried over sodium sulfate and evapora~ed -to dryness under reduced pressure.
Grystallisation of the residue from ether/petroleum ether gives 3-~3~C4-acetyl-3-hydroxy-2-~3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propoxy~-4-bromo-6-methyl-nitrobenzene as pale yellow crystals of melting point 127-129.
1.0 9 of Raney nickel is added to a solu~ion of 6.5 9 of 3-~3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phen-oxy]-2-hydroxy-propoxy~-4-bromo-6-methyl-nitrobenzene in 65 ml of tetrahydrofuran and the starting substance is hydro-genated at room temperature. The catalyst is -Filtered off and washed witn tetrahydrofuran. The filtrate is evaporated to dryness under reduced pressure and the residue is crystaL-lised from ether/petroleum ether. 3-~3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-2-hydroxy-propoxy3-4-bromo-6-methyl-aniline has a melting point of 118-120.
Example 22: A mixture of 3.3 9 of ethyl N-{~3-~3-[4-acetyl-3-hydroxy-2~(3,3,3-tri~luoropropyl)-phenoxy3-2-hydroxy-propoxy~-4-bromo-6-methyl-phenyl~-oxamate in 40 ml of ethanol and 1Z.5 ml of N sod;um hydroxide soLution is refluxed for 2 hours. The reaction mixture is concentrated under reduced pressure, 50 ml o~ water are added and the mixture is acidi~ied with 2 N hydrochloric acid. The suspen-sion is extracted ~ith 100 ml of ethyl acetate. The ethyl acetate solution is separated off, washed with 20 ml of water dried with sodium sulfate and concentrated under reduced pressure. The residue is crystallised ~rom ethyl acetate~
petroleum ether. N-~{3-~3-~4-Acetyl-3-nydroxy-2-~3,3,3-tri-fluoropropyl)-phenoxy]-2-hydroxy-propoxy~-4-bromo-6-methyl-phenyl~-oxamic acid has a melting point of 195-196.

~6~

: 2.6 9 of N-~3-~3-~4-acetyl-3 hydroxy~Z-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propoxy~-4-bromo-6-methyl-phenyl~-oxamic acid are dissolved in ZS0 ml of ace-tone, and a solution of 1 ml of diethylamine in 10 ml of acetone is added. ~he reaction solution is concentrated to 30 ml under reduced pressure and ether is added, whereupon the diethylammonium salt of N-{~3~{3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-2-hydroxy-propoxy~-4-bromo-6-methyl-phenyl~-oxamic acid crystallises out. Melting point 160-162~
Example Z4: A solution of 6.2 g of N-~{3-~3-~4-acetyl-3-hydroxy-Z-(3,3,3-trifluoropropyl) phenoxy]-Z-hydroxy-propoxy~-4-bromo-6-methyl-phenyl~ (4-methoxybenzyl)-tetrazole-5-carboxamide in 130 ml of trifluoroacetic acid and 14 ml of anisole is refluxed for 30 minutes. The reaction mixture is concentrated under reduced pressure, about Z00 ml of ether and 300 ml of petroleum ether are added and the crystaLs are filtered off. N-~{3-~3-~4-Ace~yl-3-hydroxy-2-(3,3,3-tri-fluoropropyl)-phenoxy]-Z-hydroxy-propoxy~-4-bromo-b-methyL-phenyl~-lH-tetrazole-5-carboxamide is obtained.
The starting material can be prepared, for example, as follows:
1.0 ml of oxalyl chloride is added to a suspension of 3.0 g of potassium 1-(4-methoxy-benzyl)-tetrazole-S-carboxylate in 40 ml of benzene and 0.~ ml of pyridine at 0-5 and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, the residue is taken up in benzene and the mixture is evaporated again wnder reduced pressure. The residue is suspended in 300 ml of methylene chloride and the suspension is added dropwise to a solution of 4.2 g of 3-~3-~4-acetyl-3-hydroxy-2-~3,303-trifluoropropyl)-phenoxy]-2-hydroxy-propoxy3-4-brorno-5-methyl-anil;ne and 0.92 ml of pyridine in 4D ml of methylene chloride at 0-5 in the course of 10 minutes. The mixture is then stirred for 3 hours at room temperature. The reaction mixture is diluted with methylene chloride and washed twice with water. The organic phase is ~2~55~

dried over sodium sulfate and evaporated under reduced pres-sure. N~ {~-C4-Acetyl 3-hydroxy-Z-~3,3,3-trifluoropropyl)-phenoxy~-2-hydroxy-propoxy~-4-bromo-6-methyl-phènyl~-1-t4-methoxy-benzyl)-tetrazole-5-carboxamide is in the form of a yellow oil.
The following compounds can be prepared analogously:
N-~3~ 3-C4-acetyl-3-hydroxy-2-t3,3,3-trifluoropropyl)-phenoxy~-2-hydroxy-propoxy~-4-chloro-6-methyl-phenyl~}-1H-tetrazole-5-carboxamide, N-~3-~3-C4-acetyl-3-hydroxy-2-t3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propoxy}-4-cyano-6-methyl-phenyl~ -tetrazole-5-carboxamide, N-~{3-~3-C4-acetyl-3-hydraxy-2-(3,3,3-trifluoropropyl)-phenoxy~-2-hydroxy-propoxy~-4-fluoro-6-methyl-phenyl~-1H-tetrazole-5-carbox-amide.
: The following compounds are obtained in a manner analogous to that described in Example 2 by reaction of 3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-chloro-6-methyL-aniLine, 3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy~-4-fLuoro-6-methyl-aniline or 2-~3-[4-acetyl-3-hydroxy-2-(3,3,3-tri-fluoropropyl)-phenoxy~-propoxy~-4-amino-5-methyl-benzonitrile with methyL chlorooxalate or ethyl chlorooxalate: methyl N-~3-{3-C4-acetyl-3-hydroxy-Z-(3,3,3-trifluoropropyl~-phenoxy~-propoxy~-4-chLoro-6-methyl-phenyl3~-oxamate, ethyl N-~3-~3-C4-acetyl-3-hydroxy-2-t3,3,3-trifluoropropyl)-phenoxy]-pro-poxy~-4-chloro-6-methyl-phenyl~-oxamate, methyl N-~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-~-fluoro-6-methyl-phenyl~}-oxamate, ethyl N-~3-~3-[4~acetyl-3-hydroxy-2-~3,3,3-trifluoropropyla-phenoxy~-propoxy~-4-fluoro-6-methyl-phenyl~-oxamate~ methyl N-~3-~3-C4-acetyl-3-hydroxy-2-t3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-cyano-6-methyl-phenyl~-oxamate and ethyl N-~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-cyano-6-methyl-phenyl~-oxamate.
Example 26: The following compounds are ob~a;ned in a manner :
analogous to that described in Example 3, 6 or ~2 by hydro-lysis of methyl or ethyl N-~3-~3-~4-acetyl 3-hydroxy-2-~2&~5~

~ 7~ -(3,3,3-trifluoropropyl) phenoxy~-propoxy~ chloro-6-methyl-phenyl~-oxamate, methyl or ethyl N-~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy3-propoxy~-4-fluoro-6-methyl-phenyl~-oxamate or me~hyl or ethyl N-~3-~3 C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-cyano-6-methyl-phenyl~}-oxamate: N-~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~-propoxy~-4-chloro-6-methyl-phenyl~-oxamic acid and the sodium and potassium salt thereof, N-~3-~3-~4-acetyl 3-hydroxy-2 (3,3,3-tri-fluoropropyl)-phenoxy~-propoxy~ 4-fluoro-6-methyl-phenyl~}-oxamic acid and the sodium and potassium salt thereof and N-~3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-cyano-6-methyl-phenyl~-oxamic acid and the sodium and potassium salt thereof.
Example Z7: Another of the oxamic acid or 5-tetrazolecarbox-amide compounds mentioned in the above examples can be con-verted into its diethanolammonium, tris(hydroxymethyl)methyl-ammonium or diethylammonium salt in a manner analogous to that described in Examples 13 and 2~.
Example 28: Tablets containing 25 mg of active ingredien~, for example the triethanolammonium salt of N-~{3-~3-C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-methyl-phenyl~-oxamic acid, can be prepared as 'F O l l O W S D
Constituents (for 1,000 tablets):
Active ingredient25.0 9 Lactose 100.7 9 Wheat starch 7.5 9 Polyethylene glycol 6000 5.0 9 Talc 5.0 9 Magnesium stearate1~8 9 demineralised waterq.s~
Preparation: All the solid ingredients are first forced ___ through a sieve of 0.6 mm mesh width. The active ingredient~
the lactose, the talc, the magnesium stearate and half of the starch are ~hen mi~ed~ The other half of the starch is sus-pended in 40 ml o~ water, this suspension is added to a ~2~

boiling solution of the polye~hylene glycol in 100 ml of water and the mixture is granula~ed, if necessary with the addition of water. The granules are driecl overnight at 35, forced through a sieve of 1.2 mm mesh width and compressed to tablets, concave on both sides, of about 6 mm diameter Tablets containing in each case 25 mg of another of the compounds of the formula I mentioned in Examples 1 to 27 can also be prepared in an analo~ous manner, it being pos-sible for compounds in which R3 is carboxyl or 5-tetrazolyl to be in the form of salts with bases, for example as the sodium salt or triethanolammonium salt, or in the free form.
Example 29: Tablets for chewing~ containing 30 mg of active ingredient, for example the triethanolammonium salt of N-~3-~3 C4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy~-4-chloro-6-methyl-phenyl~-oxam;c acid, can be pre-pared, for example, as follows:
Composition (for 1,000 tablets):
Active ingred;ent30.0 9 Mannitol 267.0 9 Lactose 179.5 9 Talc 20.0 9 Glycine 12.5 9 Stearic acid 10.0 9 Saccharin 1.0 9 5% gelatine solution q.s.
on: All the solid ingredients are first forced through a sieve of 0.25 mm mesh width. The mannitol and the lactose are mixed, the mixture is granulated, with the addi-tion of gelatine solution, and the granules are forced through a sieve of 2 mm mesh width, dried at 50 and again forced through a sieve of 1.7 mm mesh width. The active ingredient, the glycine and the saccharin are mixed thoroughly, the mannitol, the lactose granules, the stearic acid and the talc are added and the entire mass is mixed thoroughly and compressed to tablets concave on both sides and of 10 mm diameter, with a breaking notch on the upper side.
.

~2~3 Tablets containing in each case 30 mg of another of the compounds of the formula I mentioned in Examples 1 to 27 can also be prepared in an analogous manner~ it being pos-sible for compounds in whic~l R~ is carboxyl or 5-tetrazolyl to be in the free form or in the form of salts with bases, for example as the sodium salt or triethanolammonium salt.
Example 30: ~ablets containing 100 mg of active ingredient, for example the triethanolammonium salt of N- ~3-~3-~4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy~propoxy~-4-chloro-6-methyl phenyl} -oxamic acid, can be prepared as follows:
~omposition (for 1,000 tablets):
Act;ve ingredient100.0 9 Lactose 248.5 9 Maize starch 17.5 9 Polyethylene glycol 6000 5.0 Talc 15.0 9 Magnesium stearate~.0 9 demineralised waterq.s.
Preparation: The solid ingredients are first forced through a sieve of 0.6 mm mesh width. The active ingredient, lactose, talc, magnesium stearate and half of the starch are then intimately mixed. The other half of the starch is suspended in 65 ml of water and this suspens;on is added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting paste is added to the powdered substances and the entire mass ;s mixed and granulated, if necessary with the addition of water. The granules are dried overnight at 35 forced through a sieve of 1.2 mm mesh width and compressed to tablets concave on both sides and about 10 mm in diameter, with a breaking notch on the upper side.
Tablets containing 100 mg of another compound of the ~ormuLa I according to Examples 1 to 27 can also be prepared in an analogous manner, it being possible for compounds in which R8 is carboxyl or 5-tetrazolyl to be in the free form or in the form of salts with bases, for example as the sodium salt or ~riethanolammonium salt.

~2~

- 81 ~
Example 31; A propellant-containing inhalation suspension which forms a solid aerosol and contains 0.1% by weight of methyl N- ~3-~3-C4 acetyl-3-hydroxy-2-(3,3,3~trifluoropropyl)-phenoxy~-propoxy~-4-chloro-6-methyl-phenyl~ oxamate (active ingredien~) can he prepared, for example, as follows:
Composition:
Active ingredient, micronised 0.1% by weight "Sorbitan trioleate" 0.5% by weight Propellant A (trichlorotrifluoroethane) 4.4% by weight Propellant B (mixture of 15 parts of dichlorodifluoromethane and 80 parts o~
symmetric dichlorotetrafluoroethane) q.s.
Preparation: The active ingredient is suspended in the tri-chlorotrifluoroethane with exclusion of moisture, with the aid of a cus~omary homogeniser and with the addition of the sorbitan trioleate, the suspension is introduced into a metered aerosol container and this is sealed and filled with the dichlorodifluoromethane/dichlorotetratluoroethane mixture under pressure.
Inhalation suspénsions containing another compound of the formula I according to Examples 1 to 27 can also be prepared ;n an analogous manner, it being possible for com-pounds ;n which R8 i~ carboxyl or 5-tetrazolyl to be in the free form or in the form of salts w;th bases~ for example as the sodium saLt or triethanolammonium salt~
~ : An approximately Z% aqueous solution of the tri-ethanolammonium salt of N-~ 3-~3-~4-acetyl-3-hydroxy-Z-t3,3,3 trifluoropropyl)-phenoxy]-propoxy3-4-chloro-6-methyl-phenyl 3-oxamir acid as the active ingredient, which is suit-able for inhalation,can be prepared, for example, in the following composition:
~3~1~
Active ingredient 2,000 mg Stabiliser~ for example disodium ethylenediaminetetraacetate 10 mg Preservative, for example benzalkonium chloricle 10 mg 5~4~

- ~2 Water, fresh~y distilled to 10a ml Preparation: The active ingredient is dissolved in freshly distilled waterO The stabiliser and the preservative are then added. A-fter complete solution of all the cornponents, the resulting solution is made up to 100 Ml and introduced into bott(es and these are sealed gas-tight.
2~o In~alation solutions containing another active ingredient of one of Examples 1 to 27 can also be prepared in an analogous manner.
Example 33: Capsules which are suitable for insufflation and contain about 25 mg of methyl N-~ 3-~3-[4-acetyl 3-hydroxy-2-(3,3~3-trifluoropropyl)-phenoxy]-propoxy3-4-chloro-6-methyl-phenyl~ -oxamate as the active ingredient can be pre-pared, for example, in the following composition:
Composition Active ingredient 25 y Lactose, finely ground Z5 9 Preparation: The active ingredient and the lactose are intimately mixed. The resulting powder is then sieved and introduced into 1,000 gelatine capsules in portions of in each case 50 mg.
Insufflation capsules containing in each case another active ingredient according to one of Examples 1 to 27 can also be prepared in an analogous manner.

Claims (32)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A 2-fluoroalkylated 4-acylresorcinol ether of the formula (I) in which R1 is lower alkyl, R2 is fluorinated lower alkyl, R3 is hydrogen, lower alkoxy, trifluoromethyl or halogen, alk is an alkylene or hydroxyalkylene radical which is uninterrupted or interrupted by oxygen, one of the radicals R4, R5 and R7 is a group of the formula -NH-C(=O)-R8, a radical R4 or R5 which differs from this is a radical R9 and a radical R7 which differs from this is a radical R10, R6 is hydrogen, lower alkyl, trifluoromethyl, halogen, lower alkanoyl, carboxyl, lower alkoxycarbonyl, cyano, carbamoyl or N-mono- or N,N-di-lower alkylcarbamyl, R8 is on the one hand carboxyl, lower alkoxycarbonyl, N,N-di-lower alkylamino-lower alkoxycarbonyl, N,N-lower alkyleneamino-lower alkoxycarbonyl, N,N-(aza)-, N,N-(oxa)- or N,N-(thia)-lower alkyleneamino-lower alkoxycarbonyl, carbamyl, N-mono- or N,N-di-lower alkyl- carbamyl or N,N-lower alkylene- or N,N-(aza)-lower alkylene-, N,N-(oxa)-lower alkylene-or N,N-(thia)-lower alkylene-carbamyl, or on the other hand 5-tetrazolyol, R9 is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and R10 is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, carboxyl, lower alkoxycarbonyl, cyano, carbamyl, of N-mono- or N,N-di-lower alkylcarbamyl, or a salt thereof.

2. A compound according to claim 1, in which R1 is lower alkyl, R2 is fluorinated lower alkyl having not more than 3 fluorine atoms, R3 is hydrogen, lowex alkoxy, trifluoromethyl or halogen, alk is a radical of the formula -(CH2)m- (Ia), -(CH2)n,-[O-(CH2)n)k (Ib) or [(CH2)1,-O]oCH2-CH(OH)-CH2 [O-(CH2)1]p (Ic), in which k is 1, 2 or 3, 1 and 1' independently of one another are 2 or 3, m is an integer from 2 to not more than 9, n and n' independently of one another are 2, 3 or 4 and o and p independently of one another are 0 or 1, one of the radicals R4, R5 and R7 is a group of the formula -NH-C(=O)-R8, a radical R4 or R5 which differs from this is a radical R9 and a radical R7 which differs from this is a radical R10, R6 is hydrogen, lower alkyl, trifluoromethyl, halogen, lower alkanoyl, carboxyl, lower alkoxycarbonyl, cyano, carbamyl or N-mono- or N,N-di-lower alkylcarbamyl, R8 is on the one hand carboxyl, lower alkoxycarbonyl, N,N-di-lower alkylamino-lower alkoxycarbonyl, N,N-lower alkyleneamino-lower alkoxycarbonyl, carbamyl, N-mono- or N,N-di-lower alkylcarbamyl or N,N-lower alkylene- or N,N-(aza)-lower alkylene-, N,N-(oxa)-lower alkylene- or N,N-(thia)-lower alkylene- carbamyl, or on the other hand 5-tetrazolyl, R9 is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and R10 is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, carboxyl, lower alkoxycarbonyl, cyano, carbamyl or N-mono- or N,N di-lower alkylcarbamyl, or a salt thereof.

3. A compound according to claim 1, in which R1 is lower alkyl having not more than 4 C atoms, R2 is .omega.-fluoro-, .omega.,.omega.-difluoro- or .omega.,.omega.,.omega.-trifluoro-lower alkyl having not more than 4 C atoms, R3 is hydrogen, R4 is hydrogen, lower alkyl having not more than 4 C atoms, trifluoromethyl or halogen with an atomic number of not more than 35, R5 is oxaloamino, lower alkoxyoxalylamino with 3 to not more than 6 C atoms, or 5-tetrazolylcarbonylamino, R6 is hydrogen, lower alkyl having not more than 4 C atoms, halogen with an atomic number of not more than 35, trifluoromethyl, lower alkoxycarbonyl having not more than 5 C atoms, cyano or carbamyl, R7 is hydrogen, lower alkyl having not more than 4 C atoms, halogen with an atomic number of not more than 35, carbamyl or cyano and alk is straight-chain lower alkylene having 2 to not more than 5 C atoms, or hydroxy-lower alkylene having 3 to not more than 7 C atoms, in which the hydroxyl group is bonded in a position higher than the .alpha.-position and lower than the .omega.-position, or a salt thereof.

4. A compound according to claim 1, in which R1 is lower alkyl having not more than 4 C atoms, R2 is .omega.-fluoro-, .omega.,.omega.-difluoro- or .omega.,.omega.,.omega.-trifluoro-lower alkyl having not more than 4 C atoms, R3 is hydrogen, R4 is hydrogen, lower alkyl having not more than 4 C atoms, trifluoromethyl or halogen with an atomic number of not more than 35, R5 is oxaloamino, lower alkoxyoxalylamino having 3 to not more than 6 C atoms, or tetrazolylcarbonylamino, R6 is hydrogen, lower alkyl having not more than 4 C atoms, halogen with an atomic number of not more than 35, trifluoromethyl or cyano, R7 is hydrogen, lower alkyl having not more than 4 C atoms, cyano or halogen with an atomic number of not more than 35, and alk is straight-chain lower alkylene having 2 to not more than 5 C atoms, or hydroxy-lower alkylene having 3 to not more than 7 C atoms, in which the hydroxyl group is bonded in a position higher than the .alpha.-position and lower than the .omega.-position, or a salt thereof.

5. A compound according to claim 1, in which R1 is lower alkyl having not more than 4 C atoms, R2 is .omega.,.omega.,.omega.-trifluoro-lower alkyl having not more than 3 C atoms, R3 is hydrogen, R5 is oxaloamino, lower alkoxyoxalylamino having 3 to not more than 6 C
atoms, or 5-tetrazolylcarbonyl- amino, R4 is lower alkyl having not more than 4 C atoms, R6 is halogen with an atomic number of not more than 35, or cyano R7 is hydrogen, and alk is straight-chain lower alkylene having 2 to not more than 5 C atoms, or hydroxy-lower alkylene having 3 to not more than 7 C atoms, in which the hydroxyl group is bonded in a position higher than the .alpha.-position and lower than the .omega.-position, or a salt thereof.

6. A compound according to claim 1, in which R1 is lower alkyl having not more than 4 C atoms, R2 is .omega.-fluoro-, .omega.,.omega.-difluoro- or .omega.,.omega.,.omega.-trifluoro-lower alkyl having not more than 3 C atoms, R3 and R7 are hydrogen, one of the radicals R4 and R6 is lower alkyl having not more than 4 C atoms, and the other is halogen with an atomic number of not more than 35, R5 is oxaloamino or 5-tetrazolylcarbonylamino and alk is straight-chain lower alkylene having 2 to not more than 5 C atoms, or hydroxy-lower alkylene having 3 to not more than 7 C atoms, in which the hydroxyl group is bonded in a position higher than the .alpha.-position and lower than the .omega.-position, or a salt thereof.

7. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy}-4-chloro-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide or a salt thereof.

8. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phellyl}}-1H-tetrazole-5-carboxamide or a salt thereof.

9. Methyl N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamate.

10. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamic acid or a salt thereof.

11. Ethyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamate.

12. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro propyl)-phenoxy]-propoxy}-4-fluoro-6-methyl-phenyl}}-1-H-tetrazole-5-carboxamide or a salt thereof.

13. Ethyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-2-hydroxy-propoxy}-4-bromo-6-methyl-phenyl}}-oxamate.

14. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-2-hydroxy-propoxy}-4-bromo-6-methyl-phenyl}}-oxamic acid or a salt theraof.

15. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-2-hydroxy-propoxy}-4-bromo-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide or a salt thereof.

16. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-2-hydroxy-propoxy}-4-chloro-6-methyl-phenyl}}-1H-tetrazola-5-carboxamide or a salt thereof.

17. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-2-hydroxy-propoxy}-4-cyano-6-methyl-phenyl}}-1H-tetrazola-5-carboxamide or a salt thereof.

18. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-2-hydroxy-propoxy}-4-fluoro-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide or a salt thereof.

19. Methyl N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-methyl-phenyl}}-oxamate.

20. Methyl N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-fluoro-6-methyl-phenyl}}-oxamate.

21. Ethyl N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy}-4-chloro-6-methyl-phenyl}}-oxamate.

22. Ethyl N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy}-4-fluoro-6-methyl-phenyl}}-oxamate.

23. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy}-4-chloro-6-methyl-phenyl}}-oxamic acid or a salt thereof.

24. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy}-4-fluoro-6-methyl-phenyl}}-oxamic acid or a salt thereof.

25. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-propoxy)-4-cyano-6-methyl-phenyl}}-oxamic acid or a salt thereof.

26. A salt-forming compound according to any one of claims 1 to 3 in the form of the sodium, potassium, triethanolammonium, diethanolammonium, tris(hydroxymethyl)-methylammonium or diethylammonium salt.

27. A pharmaceutical product containing as active ingredient a compound according to claim 1 together with customary pharmaceutical adjuncts and carriers.

28. An antiallergic pharmaceutical product according to claim 27, characterized in that an antiallergically active ingredient is selected.

29. A process for the preparation of a 2-fluoroalkylated 4-acylresorcinol ether of the formula (I) in which R1 is lower alkyl, R2 is fluorinated lower alkyl, R3 is hydrogen, lower alkoxy, trifluoromethyl or halogen, alk is an alkylene or hydroxyalkylene radical which is uninterrupted or interrupted by oxygen, one of the radicals R4, R5 and R7 is a group of the formula -NH-C(=O)-R8, a radical R4 or R5 which differs from this is a radical R9 and a radical R7 which differs from this is a radical R10, R6 is hydrogen, lower alkyl, trifluoromethyl, halogen, lower alkanoyl, carboxyl, lower alkoxycarbonyl, cyano, carbamyl or N-mono- or N,N-di-lower alkylcarbamyl, R8 is on the one hand carboxyl, lower alkoxycarbonyl, N,N-di-lower alkylamino-lower alkoxycarbonyl, N,N-lower alkyleneamino-lower alkoxycarbonyl, N,N-(aza)-, N,N-(oxa)- or N,N-(thia)- lower alkyleneamino-lower alkoxycarbonyl, carbamyl, N-mono- or N,N-di-lower alkyl-carbamyl or N,N-lower alkylene- or N,N-(aza)-lower alkylene-, N,N-(oxa)-lower alkylene- or N,N-(thia)-lower alkylene-carbamyl, or on the other hand 5-tetrazolyl, R9 is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and R10 is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, carboxyl, lower alkoxycarbonyl, cyano, carbamyl or N-mono- or N,N-di-lower alkylcarbamyl, or a salt thereof, which comprises a) rearranging a compound of the formula (II) or b) reacting a compound of the formula (III) in which X1 is hydroxy or lower alkoxy, with a compound of the formula R1-X2 (IV), in which X2 is carboxyl, lower alkoxycarbonyl, halogen-carbonyl or carboxyl in the form of the anhydride having the formula -C(=O)-O-C(=O)-R1, or c) converting X3 in a compound of the formula (V) in which X3 is fluorinated lower alkenyl, fluorinated lower alkinyl, fluorinated hydroxy-lower alkyl or halogen, or in a salt thereof, into R2, or d) converting X4 in a compound of the formula (VI) in which X4 is lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, tetrahydropyran-2-yloxy, tri-lower alkylsilyloxy, lower alkanoyloxy, benzoyloxy, a group of the formula R1-C(=O)-O-, lower alkoxycarbonyloxy which can be halogenated, phenyl-lower alkoxycarbonyloxy or phenoxycarbonyloxy, into hydroxyl, or e) reacting compounds of the formulae (VII) and (VIII) in which one of the radicals X5 and X6 is hydroxyl which is free or in salt form and the other is a radical of the formula -O-alkH
which is substituted at the carbon atom in .omega.-position relative to the oxygen atom shown in the formula -O-alkH by halogen, lower alkanesulfonyloxy, benzenesulfonyloxy, halogenobenzenesulfonyloxy or lower alkylbenzenesulfonyloxy or is substituted at the carbon atoms in .omega.- and (.omega.-1)-position relative to the oxygen atom shown in the formula -O-alkH by epoxy, the carbon atom in .omega.-position relative to the oxygen atom shown in the formula -O-alkH being the carbon atom of the radical alk which, in the end product of the formula I, is bonded to that oxygen atom shown in the partial structure -O-alk-O- depicted in said formula I that is different from the oxygen atom shown in the formula -O-alkH, and the carbon atom in (.omega.-1)-position relative to the oxygen atom shown in the formula -O-alkH being the carbon atom of the radical alk which is adjacent to said carbon atom in .omega.-position relative to the oxygen atom shown in the formula -O-alkH and which, in the end product of the formula I, is bearing the hydroxy group of the hydroxyalkylene radical alk which is uninterrupted or interrupted by oxygen, wlth one another or f) reacting a compound of the formula (IX) in which one of the radicals R4', R5' and R7' is the amino gxoup, a radical R4' or R5' which differs from this is a radical R9 and a radical R7' which differs from this is a radical R10, or a salt thereof, with a compound of the formula X7 - R8' (X) in which R8' is a group R8 or 5-tetrazolyl which is protected in the 1-position and X7 is carboxyl, esterified carboxyl R8 as defined for the formula I, amidated carboxyl X8 as defined for the formula I, carboxyl esterified with a phenol which is unsubstituted or mono- or di-substituted by nitro, 1-imidazolylcarbonyl, 1-(2,5-dimethylimidazolyl)- carbonyl, halogencarbonyl or, if R8' is 5-tetrazolyl protected in the 1-position, carboxyl in salt form, and, if appropriate, detaching the protective group in the 1-position of a 5-tetrazolyl group R8, or g) converting X8 in a compound of the formula (XI) in which one of the radicals R4", R5" and R7" is a radical X8, a radical R4" or R5" which differs from this is a radical R9 and a radical R7" which differs from this is a radical R10 and X8 is a radical which can be solvolysed or oxidised to a group of the formula -NH-C(=O)-R8 wherein R8 is carboxyl, esterified carboxyl R8 as defined for the formula I or amidated carboxyl R8 as defined for the formula I, or X8 is, in the case that a compound of the formula I, wherein R8 is 5-tetrazolyl, is to be prepared, a group of the formula -NH-C(=O)-CN or a group of the formula -NH-CI-O)-R8', wherein R8' is 5-tetrazolyl protected in the 1-position, into the group of the formula -NH-C(=O)-R8, or h) converting alk' in a compound of the formula (I') in which alk' is a group which is identical to the group alk in the desired end product of the formula I, wherein alk is hydroxyalkylene which is uninterrupted or interrupted by oxygen, except that the radical of the formula -?-(OH)-, which forms a part of the group alk in the desired end product of the formula I, wherein alk is hydroxyalkylene which is uninterrupted or interrupted by oxygen, is replaced by the radical of the formula -?(X")-, or alk' is a group which is identical to the group alk in the desired end product of the formula I, wherein alk is hydroxyalkylene which is uninterrupted or interrupted by oxygen, except that the radical of the formula -CH(OH)-, which forms a part of the group alk in the desired end product of the formula I, wherein alk is hydroxyalkylene which is uninterrupted or interrupted by oxygen, is replaced by the radical of the formula -C(=O)-, or alk' is a group which is identical to the group alk in the desired end product of the formula I, wherein alk is alkylene which is uninterrupted or interrupted by oxygen, except that a radical of the formula CH2-, which forms a part of the group alk in the desired end product of the formula I, wherein alk is alkylene which is uninterrupted or interrupted by oxygen, is replaced by the radical of the formula -C(-O)-, X" being hydroxyl etherified with an .alpha.-aryl-lower alkanol, tri-lower alkylsilyloxy, lower alkanoyloxy, lower alkoxycarbonyloxy or benzyloxycarbonyloxy, into alk, and, if desired, in each case converting a compound obtainable according to the process into another compound of the formula I, separating an isomer mixture obtainable according to the process and isolating the desired isomer(s), and/or converting a free compound obtainable according to the process into a salt or a salt obtainable according to the process into the free compound or into another salt.

30. A process according to claim 29, which comprises using as the starting material a compound obtainable at any stage of the process as an intermediate and carrying out the missing stages or using a starting material in the form of a salt and/or racemate or antipodes or, in particular, forming a starting material under the conditions of the reaction.

31. A process for the preparation of a pharmaceutical product according to claim 27, characterized in that the active ingredient is processed to form a pharmaceutical product together with customary pharmaceutical adjuncts and carriers.

32. A process according to claim 31 for the preparation of an antiallergic pharmaceutical product according to claim 28, characterized in that an antiallergically active ingredient is selected.