FI58629B - FOERFARANDE FOER FRAMSTAELLNING AV EN HYPOKOLESTEROLEMISKT OCH HYPOTRIGLYSERIDEMISKT ACTIVE FOERENING - Google Patents

Description

ESr * l γβΊ «« ADVERTISEMENT Juice cqx0q U (') UTLÄCC NI NGSSKRI FT 5 8 629 (S1) Kv.ik.Va1 C 07 C 59/72, 69/712 FINLAND —FINLAND (21) ^ «« »Λ ^ - ^ βηβηΛΜΝιι 2675/73 (22) HakantapUv · —AM5kning (4 «g 28.08.73 '' (23) Alkupllvt — GUtlghtttdkg 28.08.73 (41) Tullut JulklMlul - Bltvlt offmtllg 01.03.7 ^

Patent and Registration Office .... __________ .

___ ', (44) Date of issue. - oQ -, -, on

Patent · och registarstyrelsen 'AmMcm uttagd oeh uti.skrHUn pubiicund 28.11.80 (32) (33) (31) • toluiku.-augird prior » 90 Park Avenue, New York, NY, USA (72) Donald Kenney Phillips, East Greenbush, New York, USA (7! +) Oy Kolster Ab $ (5IO Method for Blood Cholesterol and Triglyceride Lowering Compound - Förfarande för frams t alin in g av en hypokolesterolemiskt och hypotriglyserideuiskt Aktiv förening

The invention relates to a process for the preparation of a blood cholesterol and triglyceride lowering compound of the formula _ CHq

"\\ _ 0 - C - C00R I

y '2 n R1'-R1 wherein R is hydrogen or alkyl of 1 to 6 carbon atoms, Q is hydrogen or chlorine, R1 2 2' is hydrogen, alkyl of 1 to 3 carbon atoms or phenyl, R and R are each ... ..

fluorine, chlorine or bromine, R is hydrogen, alkyl or phenyl having 1 to 3 carbon atoms, 2 58629 3 '..3.

R is hydrogen, n is 0 or 1, or R and Q may together form an ethylene bridge when (CH-) is a direct bond attached to the benzene ring at the ortho position to Q, wherein Q and R form a 6-membered ring, or R being hydrogen to prepare a base salt of this compound.

Preferred pharmacologically acceptable salts are the sodium, calcium, magnesium and ammonium salts, as well as the salts of low-toxicity organic amines, for example the diethanolamine and N-methylglucamine salts.

The compounds of formula I can be prepared by:

a) a compound of formula X.

R3 '^ X

& ή — O-C-COOR

T 083

Q

2 21 wherein R is lower alkyl is treated with a carbene group-producing compound of formula (CR) R, such as chloroform or bromoform, or

b) a compound of formula IV

2 2 '

R R

'3'

Q

is reacted with a mixture of chloroform, acetone and alkali hydroxide or with an O <bromoisobutyric acid ester of the formula (CH 2 ClBiCOOROR in the presence of a base) and, if desired, the compound of formula I in which R is lower alkyl is hydrolysed to a compound in which R is hydrogen, and if desired the compound in which R is hydrogen is converted into a base salt.

The above formulas are used in the following descriptions, which show private reaction sequences within the general procedure above.

3,58629 τ> 31

^ Method A

- OC- (CH 2) p 2 R 1 '(R 1) - O-lower alkyl +: C 1 H 2 R 2.

Q

II

R R ^

y-n

r ^ R ^ β-O-lower alkyl -y

Q

III

R2 R2 'r3' -r ^ —— (0Vn 3.1 ν “\ I 3 n Λ Λ / V OH + BrCCO„ -al emp i-alkyl 1 i -> \ l / '- CH3

Q

IV \ CHCl 3, CH 2 CO-CH, OH-I (R is lower alkyl) - * I (R is H) 11,58629

In Method A described above, an alkenyl-substituted 1 3 3 '

phenol-lower alkyl ether of formula II (wherein R, R, R and Q

mean the same as described above and the lower alkyl has 1-1 + carbon atoms), to react with the medium which generates the carbene, 22 '. 2 2 ': CR R (where R and R have the same meaning as above).

... 2 2 '.

Carbenes,: CR R, can be formed from several halogenated organic compounds. Particularly useful media for this purpose are haloforms in the presence of a strong base such as potassium tert-butoxide. The haloforms used are, for example, chloroform (which produces: 001 ^), bromoform (iCBrg), iodoform (: 01 ^ ^), chlorodifluoromethane (: CF1) and the like. Other sources of carbenes include chlorodiazomethane (CHCl 3), FClgCCOCCl 2 F (: CFCl), ethyl trichloroacetate (iCCl 2), phenyl (trichloromethyl) mercury (iCCl 2), phenyl (bromodichloromethyl) mercury (: CBr 2) sodium fluoride, sodium chloride, sodium chloride, sodium chloride; (?

The second step of Method A is the cleavage of a cyclopropyl-substituted phenol ether III prepared by the preceding carbene reaction. Cleavage of the ether is performed in the presence of a strong acid. The strong acid may be a protic acid such as hydrobromic acid or hydroiodic acid, or a Levris acid such as boron tribromide. Examples of reagents used to cleave phenol ethers include boron tribromide, boron trichloride, boron trifluoride etherate (in the presence of acetic anhydride and lithium bromide), aluminum bromide, aluminum chloride and aluminum chloride, hydrobromic acid, in the presence of hydroiodic acid, phosphorus and acetic anhydride (phosphorus and acetic anhydride).

The ether cleavage product, a cyclopropyl-substituted phenol of formula IV, is then treated with either a lower alkyl ester of 4-bromo-aminobutyric acid / ("(CH 2) g Cl 2 Br) CO 2 R 4 base; or a mixture of chloroform, acetone and alkali metal hydroxide). The above reaction yields a compound of formula I wherein R is lower alkyl and the reaction is carried out at a temperature between about 50 and 150 ° C in the presence of a basic substance such as potassium carbonate, the latter reaction being carried out at a temperature between about 50 and 100 ° C , suitably at reflux temperature, affords a compound of formula I wherein R is hydrogen If desired, a compound of formula I wherein R is lower alkyl may be hydrolyzed by conventional methods such as dilute alkali to give a compound wherein R is hydrogen.

3 5 58629

In the case where Q and R together form an ethylene bridge and (CHgJn is a direct bond to the benzene ring in the ortho position to the symbol Q, dihydronaphthalene lower alkyl ether of the formula: R1 R3 '- ^

I j -l-0-ai empi-ai kyy li V

1.3 *.

wherein R and R are as defined above, which starting material treated with the intermediate 2 2 'to give the carbene m: CR R yields a compound of formula 2 2' R 1 R 1 J 1 Tb 2 Ya 5

I — I-O-lower alkyl VI

s having a 2,3-dihydro-1H-cyclopropaZa7naphthalene ring system numbered as shown in the figure (Revised Ring Index No. 2119). The ether linkage of the latter is then cleaved and the resulting phenolic compound (Via) is treated with either an alkyl ester of Q (bromoisobutyric acid) or a mixture of chloroform, acetone and alkali metal hydroxide to give a compound of formula I wherein Q and R 3 are joined to form 2.3 -dihydro-1H-cyclo-propa / naphthalene ring system, a 6-membered non-aromatic ring, namely: 2 2 'R .Ά.

kx, ,,

I -) - O-C-COOR

ch3 6 58629

Method B

3 * 0

E «1) CHCl, CH-CO-CH, OH

N. CH-C _ 5 J 3 h5 ^ 2) ROH (H +) t / 011 _ * ft

VII

I ®3

I BrC-COOR

f CH

R 2 -O-C-COOR MBH 4> R 2 -Mg-halophenide or 'R 2 -Li H "7 or 3 (R is lower alkyl)

H5 'M

a3> <»- iv = v ^ ch3

R V Vo-C-COOR

V / ^. · Ε2 ° CH3 7 ft IX (H is lower alkyl) R3 'CC2' Γ ^ / ^ λ f3 Λ RC ^ “OC-COOR iC \ fi2 '1 (a is lower alkyl) ch3 - ^ ft X (R is lower alkyl) 58629

In Method B, an alkonoyl of formula VII is treated with a substituent 3 '.

the introduced phenol (R, R and Q are as defined above) either with an alkyl ester of P (bromoisobutyric acid in the presence of a base or with a mixture of chloroform, acetone and alkali metal hydroxide, followed by esterification of the resulting compound of formula VIII wherein R is hydrogen, with a lower alkanol.

This gives a compound of formula VIII in which R is lower alkyl.

In the next step of Method B, an alkanoyl-substituted phenoxy isobutyric acid ester of formula VIII is treated with an alkali metal borohydride, R 1 magnesium halide or R 1 lithium, wherein R 1 is alkyl of 1 to 3 carbon atoms, or phenyl. The reaction takes place in an inert solvent at or below ambient temperature. Reaction with adkali metal borohydride (MBH., Where M is an alkali metal, preferably lithium or sodium) 4. 1 yields a carbinol of formula IX wherein R is hydrogen and R is lower alkyl. Reaction with R 1 magnesium halide or R 1 lithium gives a carbinol of formula IX wherein R 1 is lower alkyl or phenyl and R is lower alkyl.

The carbinol of formula IX is then dehydrated to form the alkenyl-substituted phenoxy isobutyric acid ester of formula X. The dehydration is carried out by heating the carbinol in an inert solvent with a dehydrating agent such as p-toluenesulfonic acid, p-toluenesulfonyl chloride, naphthalene-4-sulfonic acid, methanesulfonyl chloride-sulfur dioxide, methyl chlorosulfite, boron trifluoride or boron trifluoride. The reaction is conveniently carried out at the reflux temperature of the solvent using means for removing water formed in the reaction.

The final step is the treatment of an olefinic ester of formula X with a 2 2 '2 medium to give a carbene of the formula: CR R (R and 2 f R are as defined above), as described in more detail above in connection with Method A, to give a compound of Formula I wherein R is lower alkyl. Method B is also suitable for use in the preparation of compounds in which Q and R together form an ethylene bridge and a (CH 2) 2 O direct siO moiety in the ortho ring to the benzene ring relative to the symbol Q.

Compounds of formula VIII in which Q is H and the substituents are in the para position can be prepared by carrying out a Friedel-Crafts-type reaction between reactants of the formulas: 58629 θ CK y OC-COOR and '^ TCH-COCl b3 ^ (R is lower alkyl)

The acyl group becomes para to the ether bond and the reaction is performed in the presence of a Lewis acid such as aluminum chloride.

An alternative to this method involves carrying out a Friedel-Crafts reaction between a phenoxyalkanoic acid ester and dichloroacetyl chloride to form a dichloroacetophenone derivative of the formula: / -?? H3 ci9chco _ / V O-C-COOR VIII c \ = / ffl3

Following steps analogous to Method B, the latter compound can be converted to a carbinol of the formula: ci 2ch-c -P y-oc-coor R2 ch3 ac and an olefin of the formula:, _ CH-, ΓΛ · 3 ci2c-cc y— oc-coor R1 CH3 X c

Finally, the latter is treated with a medium which generates unsubstituted carbene (CH 2) or substituted carbene (CH 2 R 2), wherein R and Hr are as defined above. Suitable sources of such carbenes are diethylzinc methylene iodide, Simmons- Smith's reagent, e.g., a pair of zinc copper (or zinc powder and cupro halide with iodine tax ethyl.] O-methyl-zinc; and ethyl.l.-ene iodide-d 1 ethyl-zinc. Penylcarbene (CHCl 3 / H 2) can be generated by reduction of zinc with 9256 This gives a compound of formula:

Cl Cl n3 '/ y- 0-0-0008 I c H3 H1 CH3

Method C

0 tr ΕΧ-0 / == rv *) CHCl 3 »CH 3 -CO-CH 3, oh" ° H 2) ROH (H +) 1 "7 - ^

Q

XI

CH3

BRC-COOR

I- r1'c'V = \ - '"3 \ ^“ O-C-COOR (C6H5) 3-P-CH (R5) (R5') Br I <* 3 ->

Q

XII (R is lower alkyl) R5

CmC _ CH_ 2

C "V \ / = \ t 3 R

R1 A-O-C-COOR sC \ 2 'v v' I (R is lower alkyl) CH3 -> X (R is lower alkyl) 0 10 58629

In Method C, an alkanoyl-substituted phenol of formula XI (R * 'is as defined above) is treated with either an alkyl ester of N-bromoisobutyric acid in the presence of a base or a mixture of chloroform, acetone and alkali metal hydroxide, followed by esterification of the resulting compound of formula XII. , where R is hydrogen, with a lower alkanol. This gives a compound of formula XII wherein R is lower alkyl.

In the next step of process C, an alkanoyl-substituted phenoxyalkanoic acid ester of formula XII is treated with Wittig's reagent, 3 ', e.g. triphenylphosphonium bromide derivative (C 1 H) -P-CH (R) (R) Br (R and R are as defined above). shown) in the presence of a strong base such as sodium hydride while heating to 50-100 ° C in an inert anhydrous solvent. This gives an alkenyl-substituted phenoxy isobutyric acid ester of the formula X, which, as described above in connection with method B, can be converted by a carbene reaction into a compound of the formula I in which R is lower alkyl.

Method D

C1 C1 NaUO2, H SO2 ^ ^ XIII Cl Xl /.-Λ CHCl1, CH COCH, 0H “->

XIV

ch3 \

Br-C-C00R

* N / «3 C1 _ CH3

0-C-C00R

XV

11,58629

Method D is another process step for preparing a preferred product starting from commercially available p- (2,2-dichlorocyclopropyl) -aniline (XIII). The latter is subjected to diazotization and hydrolysis to give p- (2,2-dichlorocyclopropyl) phenol (XIV), which is then treated as described above with either lower alkyl O-bromoisobutyrate or a mixture of chloroform, acetone and alkali metal hydroxide to give lower alkyl 2- [p- (2,2-dichlorocyclopropyl) phenoxy] isobutyrate (XV, R is lower alkyl) or 2- [p- (2,2-dichlorocyclopropyl) phenoxy] isobutyric acid (XV, R is hydrogen, respectively) are obtained, respectively. ).

Alternatively, in Methods A, B, C and D, the CH 2 Cl 2 COOR reactant can be replaced by BrCH 2 CN or BrCH 2 COOR and then the methyl residues can be coupled by methylation with methyl iodide in the presence of a base. In the presence of a nitrile group, it can be hydrolyzed to the carboxyl group by means of an aqueous alkali solution, for example, in the last step of method A, substituting BrCHgCN for lower alkyl - <* bromoisobutyrate gives a compound of formula r2 \ X «V * R3

XVI

which can then be methylated with methyl iodide and hydrolysed to give a compound of formula I. Correspondingly, replacement of the lower alkyl o (-bromoisobutyrate with BrCHgCOOR) gives a compound of formula

r2 Ά \ _OCH COOR

X * 2 / UQ

R3

XVII

12,58629 which can be methylated with methyl iodide to give a compound of formula I.

Analogous transformations can be performed for the cyclopropa / 4-naphthalene intermediate Via: 2 2 'e3'— ^ | ^ _oh

Analogous substitutions in methods B and C yield compounds of the formulas: 3 'R \ c = c R1 N \ - OCH2CN Xa

"Y

Q

3 '

R

R R1 0CH2C00R Xb

Q

The compounds of formulas Xa and Xb may then be reacted 22 '. . . . .

carbenem: CR R to give compounds of formulas XVI and XVII.

Biological evaluation of the compounds of the invention has shown that they have a cholesterol- and triglyceride-lowering effect and are therefore useful in the treatment of arterial embrittlement conditions caused by elevated blood cholesterol and triglyceride levels.

Compounds lowering blood cholesterol and triglyceride levels similar in structure to those prepared according to the invention have been reported e.g. U.S. Patent Nos. 3,598,866 and 3,598,862. The compounds disclosed in these publications, which are close in structure to both the compounds of the invention and commercially produced clofibrate, ethyl 2- (p-chlorophenoxy) -2-methylpropionate, have not been marketed commercially. as medicinal products, so that their therapeutic efficacy and / or toxicity can be expected to be 13 58629 inferior to clofibrate. ('Comparative experiments between them and clfibrate have also not been published). For this reason, the compounds of the invention have been compared below to established drug clofibrate.

The cholesterol- and triglyceride-lowering effect was measured by administering the compounds orally to rats / Turner et al., Scand. J. Clin. Lab. Investigation 9, 210 (19 ^ 9) »Arnold et al., J. of Atherosclerosis Research 7j 111-115 (1967) _ / · Male rats are fasted for five days, the drug is administered by gavage, and then the rats are fed either normal food or with fatty foods. This diet is continued for h days. On the fifth day, blood is taken by cardiac puncture. Blood samples are analyzed for cholesterol and triglycerides and values are expressed in mmol of cholesterol or triglyceride per 100 ml of blood. The activities of the compounds are evaluated by the ED 2 values, which are the calculated doses at which a 33% reduction in blood cholesterol or triglyceride value occurs. The compounds of the invention were found to have cholesterol-lowering ED 1 values ranging from 15 mg / kg to 250 mg / kg of triglyceride-lowering ED 2 values from 2 mg / kg to 250 mg / kg in rats fed a normal diet. Rats fed a high fat diet had lower ED 2 -® · 1 ^ 0 ^ lower.

The following table shows the results of experiments with some of the preferred compounds of the invention using the five-day experimental protocol set forth above for rats.

Effect on lipid levels

Normal food Fatty food

Example Cholesterol Triglyceride Cholesterol Triglyceride

Er> 33 (rcg / k6) ED33 (mg / kg) ED ^ (mg / kg ED ^ (mg / kg 1 (d) 15 <6 7 1 2 (c) 96 <12 15 15 3 (c)> 96 <12 8 (c)> 96 <2 2 2 10 (c)> U8 <6 12 (e) 15 <k 1 3 13 30 <12 15 (e) 35 2 1 2 16 (b) 12 <12 18 ( c) 160 8 2U (b) 15-20 2 2.5-5 2 clofibrate * lUo-150 U60 125 lk 5 8 6 2 9 x commercially available reference substance, ethyl 2- (p-chlorophenoxy) -2-methylpropionate top.

In clinical trials, the compound prepared in Example 2Mb), 2- [p- (2,2-dichlorocyclopropyl) -phenoxy] -2-methylpropionic acid, caused a significant decrease in cholesterol content (lipoprotein fraction) at a daily dose of 80 mg.

Advantages over clofibrate were observed as follows: a) greater effect on low density lipoproteins, b) one daily treatment and lower doses (clofibrate must be administered three or four times daily) and c) possible side effects due to clofibrate are as in Example 24 (b). compound.

The structures of the compounds of the invention were confirmed by synthetic methods, elemental analysis and IR and NMR spectra.

The following examples further illustrate the invention.

Method A

Example 1 (a) p-Isopropenylanisole

A solution of 150 g (1.0 mol) of p-methoxyacetophenone in 1,500 ml of anhydrous ether was added dropwise over 90 minutes to a solution of 22 g (1.0 mol) of methyllithium (1.66 molar in ether). and which had been cooled in an ice bath. The reaction mixture was stirred for 30 minutes at 0 °, 30 minutes at room temperature and one hour at reflux temperature. Two more 0.1 molar portions of methyllithium were then added to the heated mixture at 1/2 hour intervals. The reaction mixture was added to an aqueous solution of ammonium chloride, and the aqueous layer was separated and extracted with ether. The combined ether solutions were washed with aqueous sodium bisulfite, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was distilled and boiling in the range of 75-91 ° C (1.2 mm) gave 120.4 g of p-isopropenylanisole.

(b) p- (2,2-dichloro-1-methylcyclopropyl) anisole.

228 g (2.04 moles) of potassium t-butoxide were added portionwise over 2 1/2 hours to a stirred solution of 120 g of p-isopropenylanisole in 750 g of chloroform and 3500 ml of pentane, which solution was kept at -4 ° C. :in. The reaction mixture was stirred at -40 ° C for one hour, then the cooling bath was removed and stirring was continued for 3 hours. The reaction mixture was cooled in ice-water, the layers were separated, and the aqueous layer was extracted with pentane. The combined pentane solutions were washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give 190 g of p- (2,2-dichloro-1-methyl-cyclopropyl) anisole as an oil.

15,58629 (c) p- (2,2-dichloro-1-methylcyclopropyl) phenol

A solution of 6.1 g (0.021 + 2 moles) of boron tribromide in 25 mL of methylene dichloride was added dropwise to a stirred solution of 6.1 g (0.026H moles) of p- (2,2-dichloro-1-methylcyclopropyl) anisole in 25 ml of methylene chloride and cooled in an ice bath. The reaction mixture was stirred at 0 ° C for one hour, then the ice bath was removed and the mixture was stirred for another hour. The reaction mixture was cooled in ice-water and the layers were separated. The aqueous layer was extracted with methylene chloride and the combined methylene dichloride solutions were washed with water and dilute sodium hydroxide solution. The sodium salt of p- (2,2-dichloro-1-methyl-cyclopropyl) phenol separated and was collected by filtration. The filter cake was combined with the original aqueous layer and acidified with concentrated hydrochloric acid. The acidified solution was extracted with ether and the ether was dried over anhydrous sodium sulfate and concentrated in vacuo.

The residue was recrystallized from carbon tetrachloride to give p- (2,2-dichloro-1-methylcyclopropyl) phenol, m.p. 125-126 ° C.

(d) 2- [p- (2,2-dichloro-1-methylcyclopropyl) phenoxy] -2-methylpropionic acid 1 RR '2 2' / 1: R is CH 2, R, R, R and Q are H, R and R is Cl and n is O; para-orientation /.

5.1+ chloroform was added to a mixture which was heated to reflux and stirred and containing 9.1 g of p- (2,2-dichloro-1-methylcyclopropyl) phenol and 7 * 2 g of sodium hydroxide in 200 ml of acetone.

After the addition of chloroform was completed, the mixture was heated under reflux for 3 hours and then cooled in an ice bath. The solid sodium salt was collected by filtration, washed with cold acetone and dissolved in water. The latter solution was acidified with concentrated hydrochloric acid and the acidified mixture was extracted with ether and the ether was dried over anhydrous sodium sulfate and concentrated in vacuo. The residual oil was crystallized by trituration with hexane and then recrystallized from hexane to give 8.5 g of 2- [p- (2,2-dichloro-1-methylcyclopropyl) phenoxy] -2-methylpropionic acid as a pale cream solid. , sp. 108-111 ° C.

16 58629

Example 2 (a) p- (2,2-Difluoro-1-methylcyclopropyl) anisole.

A warm solution of 91.5 S sodium chlorodifluoroacetate (pre-dried at 50 ° C under vacuum) in 175 ml of diglyme (diglycol dimethyl ether) was added dropwise over 90 minutes to a stirred and refluxed solution containing 74 g of p-isopropenylanisole in 500 ml: porcine diglyme containing a small amount of trinitrobenzene and 4-t-butylpyrocatechol as stabilizers. The reaction mixture was stirred at reflux for 5 minutes, then cooled and filtered to remove sodium chloride. The sodium chloride was washed with a small amount of diglyme and then with pentane, and the combined washings and filtrate were mixed with 3 liters of water and extracted three times with pentane. The pentane solution was washed with aqueous potassium hydroxide solution, then with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give 96.5 g of p- (2,2-difluoro-1-methylcyclopropyl) anisole as a straw-colored oil.

(b) p- (2,2-Difluoro-1-methylcyclopropyl) phenol was prepared from 9.9 g of p- (2,2-difluoro-1-methylcyclopropyl) anisole and 20 g of boron tribromide in 200 ml of ethylene dichloride in Example 1 above. , according to the method described in (c), to give 9 g of a pink oil which solidified on standing.

(c) 2- [p- (2,2-difluoro-1-methylcyclopropyl) phenoxy] -2-methylpropionic acid 1 * 3 51 p p po po / 1; R is (¾, R. R, RJ and Q are H, R and R * are, F and n is 0} para-orientation] 9 g of p- (2,2-difluoro-1-ethylcyclopropyl) phenol were prepared , 10.9 g of sodium hydroxide and 8.1 g of chloroform in 200 ml of acetone according to the procedure described in Example 1 (d) above, the product was recrystallized from hexane to give 8.3 g of 2- [p- (2,2-difluoro- 1-methylcyclopropyl) phenoxy] -2-methylpropionic acid as a pale cream solid, mp 110-111 ° C.

Example 3 (a) p- (2,2-Dibromo-1-methylcyclopropyl) anisole @ 4 g (0.75 moles) of potassium t-butoxide was added portionwise over two hours to a stirred mixture of 45 g (0.3 moles) of ) p-isopropenylanisole and 480 g (1.9 moles) of bromoform in 1350 ml of pentane and the mixture was cooled in a dry ice bath. For the first 90 minutes, the addition was performed at -40 ° C, then for 30 minutes at -10 ° C. The reaction mixture was stirred for 1 hour at -10 ° C, then the cooling bath was removed and stirring was continued for 3 hours. The mixture was cooled in ice-water, the layers separated and the organic layer washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give 58.529 g of p- (2,2-dibromo-1-methylcyclopropyl) anisole as a red-brown oil.

(b) p- (2,2-Dibromo-1-methylcyclopropyl) phenol was prepared from 10 g of p- (2,2-dibromo-1-methylcyclopropyl) anisole, 7.5 g of boron tribromide and 100 ml of methylene dichloride according to the method described in Example 1, (c) above. This gave 6 g of p- (2,2-dibromo-1-methylcyclopropyl) phenol as an off-white solid.

(c) 2- [p- (2,2-dibromo-1-methylcyclopropyl) phenoxy] -2-methylpropionic acid R 1 is CH 2, R, R, E and Q are H, R and R is Br and n is 0; para-orientation? prepared from 11.7 g of p- (2,2-dibromo-1-methylcyclopropyl) phenol, 15.2 g of sodium hydroxide, 11.3 g of chloroform and 250 ml of acetone in Example 1 above ( (d) according to the method described. There was thus obtained 10.2 g of 2- [β- (2,2-dibromo-1-methylcyclopropyl) -phenoxy] -2-methylpropionic acid as a pale cream solid, m.p. 130-131.5 ° C recrystallized from ether / hexane.

Example 1+ (a) p- (1,2-Dimethylvinyl) anisole.

A mixture of 150 g of 2- (p-methoxyphenyl) -2-butanol and 360 ml of acetic anhydride was heated under reflux for 2 1/2 hours. The solvent was removed by distillation, and the residue was subjected to fractional distillation. The final fraction obtained above 11 ° C + (10 mm) gave 27.0 g of p- (1,2-dimethylvinyl) anisole, which was mainly the cis isomer.

(b) p- (2,2-Dichloro-1,3-dimethylcyclopropyl) anisole was prepared from 61+, 6 g of p- (1,2-dimethylvinyl) anisole, 101 g of potassium t-butoxide, 258 g chloroform and 1,800 ml of pentane according to the procedure described in Example 1 (b) above. The product distilled between 90-98 ° C (0.07-0.09 mm) to give 79.1 g of p- (2,2-dichloro-1,3-dimethylcyclopropyl) anisole with 80% cis isomer.

(c) p- (2,2-dichloro-1,3-dimethylcyclopropyl) phenol was prepared from 79.1 g of p- (2,2-dichloro-1,3-dimethylcyclopropyl) anisole, 1 + 6.9 g: boron tribromide and 520 ml of methylene dichloride according to the method described in Example 1 (c) above. The product was recrystallized from benzene / hexane to give 1 + 3.7 g of p- (2,2-dichloro-1,3-dimethylcyclopropyl) -phenol cis-isomer as colorless needles, m.p. 79 "O2 ° C.

(d) 2- [p- (2,2-dichloro-1,3-dimethylcyclopropyl) phenoxy] -2-methylpropionic acid / J: R and R are CH 2, R 2 and Q are H, R and R are Cl and n is 0; para-orientation 7 was prepared from 39.1 g of p- (2,2-dichloro-1,3-dimethylcyclopropyl) phenol, 1 + 0.6 g of sodium hydroxide, 30.2 g of chloroform and 1,275 ml of: acetone according to the method described in Example 1 (d) above. The product precipitated as the sodium salt, m.p. 200-202 ° C. The salt was poured into the free acid and recrystallized from aqueous ethanol to give k2t5 g of 2- [2- (2,2-dichloro-1,3-dimethylcyclopropyl) phenoxy] -2-methylpropionic acid, m.p. 133.5-131 +, 5 ° C, cis orientation of 1- and 3-methyl groups.

Example 5 (a) o- (2,2-dichlorocyclopropyl) anisole was prepared from ho, 2 g of o-vinyl anisole, 8 g of potassium t-butoxide and 21 g of chloroform in 1,500 ml of pentane above according to the method described in Example 1, point (b).

The product distilled between 80-85 ° C (0.1 mm) to give 7.9 g of o- (2,2-dichlorocyclopropyl) anisole.

(b) o- (2,2-dichlorocyclopropyl) phenol was prepared from 7.8 g of o- (2,2-dichlorocyclopropyl) anisole and 5.3 g of boron tribromide according to the procedure described in Example 1, (c) above, to give 7.1 g of an oil which was used directly in the next reaction.

(c) Ethyl 2- [o- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionate / 1: R is, R, R, R and Q are H, R and R are Cl and n is 0; ortho-orientation / prepared from 6.6 g of o- (2,2-dichlorocyclopropyl) phenol, 12.7 g of ethyl E (bromoisobutyrate and 13.5 g of anhydrous potassium carbonate in 30 ml of dimethylformamide according to the procedure described in Example 10 (a) below, the product was distilled between 98 and 100 ° C (0.05 mm) to give * +, 78 g of ethyl 2- [3- (2,2-dichlorocyclopropyl) phenoxy]. -2-methylpropionate as a very pale yellow oil, bp 98-100 ° C (0.05 mm).

Example 6 (a) p- (2,2-Difluorocyclopropyl) anisole was prepared from 129 g of p-vinyl anisole and 170 g of sodium chlorodifluoroacetate in 1,500 ml of diglyme according to the procedure described in Example 2 (a) above. This gave 122 g of p- (2,2-difluorocyclopropyl) anisole as a yellow oil.

(b) p- (2,2-difluorocyclopropyl) phenol was prepared from 120 g of p- (2,2-difluorocyclopropyl) anisole and 81 g of boron tribromide according to the procedure described in Example 1, (c) above to give 72 g the oil used directly in the next reaction.

(c) 2- [N- (2,2-difluorocyclopropyl) phenoxy] -2-methylpropionic acid; R, R, R, R and Q are H, R and R are F and n is 0; para-orientation 7 was prepared from 25.5 g of p- (2,2-difluorocyclopropyl) phenol, 36.0 g of sodium hydroxide, 26.8 g of chloroform and 1100 ml of acetone in Example 1 above. (d) according to the method described. The product was recrystallized from benzene / hexane to give 22 g of 2- [β- (2,2-difluorocyclopropyl) phenoxy] -2-methylpropionic acid as cream needles, m.p. 97 ~ 99 ° C.

58629 19

Example 7 (a) p- (2,2-Dichlorocyclopropylmethyl) anisole.

A mixture of 81.5 g of p- (2-propenyl) anisole and 80.9 g of phenyldichlorobromomethylmercury (C 9 H 2 Cl 2 Cl 2) in 200 ml of benzene was heated under reflux for 5 1/2 hours. The product was separated and distilled to remove unchanged starting material and then chromatographed on 1200 g of silica gel eluting with pentane and pentane containing 1-1% ether. This gave 28 g of p- (2,2-dichlorocyclopropylmethyl) anisole as a yellow oil.

(b) p- (2,2-Dichlorocyclopropylmethyl) phenol was prepared from 28 g of stap- (2,2-dichlorocyclopropylmethyl) anisole and 20 g of boron tribromide according to the procedure described in Example 1, (c) above. The product was recrystallized from benzene / cyclohexane to give 17-3 g of p- (2,2-dichlorocyclopropylmethyl) phenol as a beige solid, m.p. 57-62 ° C.

(c) Ethyl 2- [p- (2,2-dichlorocyclopropylmethyl) phenoxy] -2-methylpropionate] R is C 1 H, R 2 and R 2 are H, R and R are Cl and n is 1: para-orientation 7 was prepared from 17 * 8 g of p- (2,2-dichlorocyclopropylmethyl) phenol, 56 g of ethyl O (bromoisobutyrate and 51.3 g of potassium carbonate in Example 10 below). , according to the procedure described in (a), to give 20.6 g of ethyl 2- [p- (2,2-dichlorocyclopropylmethyl) phenoxy] -2-methylpropionate as a yellow oil.

(d) 2- [p- (2,2-dichlorocyclopropylmethyl) phenoxy] -2-methylpropionic acid; 133 '. 2.2 'R. R, R, R and Q are H, R and R are Cl and n is 1; para-orientation? ·

A mixture of 19 g of ethyl 2- [β- (2,2-dichlorocyclopropylmethyl) phenoxy] -2-methylpropionate, 25 ml of 10 ml of aqueous sodium hydroxide solution and 25 ml of ethanol was stirred for 3 hours at room temperature. The reaction mixture was acidified and the resulting product was collected and recrystallized twice from hexane to give 10.0 g of 2- [2- (2,2-dichlorocyclopropylmethyl) phenoxy] -2'-methylpropionic acid, m.p. 78-80 ° C.

Example 8 (a) 1,1-Dichloro-2,3-dihydro-5-methoxy-1H-cyclopropa [a] naphthalene / VI; R 1 and 31 2 2 'R are H, R and R are Cl, lower alkyl is CH 2 7 was prepared from 6 g of 6-methoxy-3,3-dihydro-naphthalene, 8 g of potassium t-butoxide and 227 g of g of chloroform in 1,350 ml of pentane according to the procedure described in Example 1 (b) above to give 76 g of product as a red-brown oil.

(b) 1,1-Dichloro-2,3-dihydro-1H-cyclopropa [a] -5-naphthol was prepared from 2h, 3 g of 1,1-dichloro-2,3-dihydro-5-methoxy-1H-cyclopropa /? 7-naphthalene and 25.0 g of boron tribromide according to the procedure described in Example 1, (c) above, to give 21.4 g of a red-brown oil which was used directly in the next reaction.

20 58629 (c) 2- (1,1-dichloro-2,3-dihydro-1H-cyclopropa [a] -5-naphthyloxy) -2-propio-1,3 ', 2.2' nitric acid [1; R, R and R are H, R and R are Cl, Q and together are CH 2 CH 2, and n is o] prepared from 21.4 g of 1,1-dichloro-2,3-dihydro-1H-cyclopropa [a] -5-naphthol, 22, 4 g of sodium hydroxide, 16.1 g of chloroform and 350 ml of acetone according to the procedure described in Example 1 (d) above. This gave 3.5 g of 2- (1,1-dichloro-2,3-dihydro-1H-6-cyclopropa [a] -5-naphthyloxy) -2-propionic acid as an olive gray powder, m.p. 104-106.5 ° C recrystallized from cyclohexane.

Method £

Example 9 (a) 2- (p-Propionylphenoxy) -2-methylpropionic acid was prepared from 374 g of p-hydroxypropiophenone, 600 g of sodium hydroxide, 390 g of chloroform and 7 liters of acetone according to the procedure described in Example 1 (d) above. by. 321 g of 2- (p-propionylphenoxy) -2-methylpropionic acid were obtained.

(b) Methyl 2- (p-propionylphenoxy) -2-methylpropionate

A mixture of 118 g of 2- (p-propionylphenocene) -2-methylpropionic acid, 48 g of methanol, 3-5 ml of concentrated sulfuric acid and 150 ml of ethylene dichloride was stirred and refluxed for 22 hours. The reaction mixture was cooled, the layers separated and the organic layer washed successively with water, sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue distilled between 122-127 ° C (0.08 mm) to give 114.5 g of methyl 2- (p-propionylphenoxy) -2-methylpropionate, m.p. 47-49 ° C.

(c) Methyl 2- [p- (1-hydroxypropyl) phenoxy] -2-methylpropionate 10.6 g (0.279 moles) of sodium borohydride was added to a stirred solution containing 114 x 5 g (0.458 moles) of methyl 2- (p- -propionylphenoxy) -2-methylpropionate in 500 ml of methanol while maintaining the temperature of the solution at 5 ° 0 with an ice bath. After the exothermic reaction was slowed down, the ice bath was removed and the reaction mixture was stirred for one hour at room temperature. The solvent was removed in vacuo and the residue partitioned between ether and water containing slightly more acetic acid than was required to acidify the aqueous layer. The ether layer was separated, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. 113 g of methyl 2- [p- (1-hydroxypropylphenoxy] -2-methylpropionate were obtained as a pale straw-yellow oil.

(d) Methyl 2- [p- (1-propenyl) phenoxy] -2-methylpropionate

A solution of 113 g of methyl 2- [p- (1-hydroxypropyl) -phenoxy] -2,82929 2-methylpropionate and 1.5 g of p-toluenesulfonic acid in 1000 ml of toluene was heated under reflux using a dewatering trap for one hour. The reaction mixture was cooled, washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue distilled between 95-100 ° C (0.05-0.08 mm) to give 33 g of methyl 2- [p- (1-propenyl) phenoxy] -2-methylpropionate, m.p. 1.5281.

(e) Methyl 2- [p- (2,2-dichloro-3-methylcyclopropyl) phenoxy] -2-methylpropionate [I; R is CH 2, R, R and Q are H, R and K 'are Cl and n is 0? para-orientation] was prepared from 37.5 g of methyl 2- [p- (1-propenyl) phenoxy] -2-methylpropionate, 45 g of potassium t-butoxide and 120 mg of chloroform in 750 ml of pentane above in Example 1, according to the method described in (b). The product was chromatographed twice using a column of 2 kg of silica gel and the column was eluted with pentane / ether (3 * 1) to give 41.3 g of methyl 2- [p- (2,2-dichloro-3-29 methylcyclopropyl). ) phenoxy] -2-methylpropionate, n = 1.5252.

Example 10 (a) Ethyl 2- (4-acetyl-2-chlorophenoxy) -2-methylpropionate.

A solution of 204 g (1 * 2 moles) of 3-chloro-4-hydroxyacetophenone, 497 g (3 * 6 moles) of potassium carbonate and 1140 ml of dimethylformamide was heated to 80 ° C with stirring. 230 g of ethyl 2-bromo-2-methylpropionate were then added over 5 minutes and the reaction mixture was stirred and heated for one hour. An additional 230 g of ethyl 2-bromo-2-methylpropionate was then added, the mixture was stirred for one hour, then a further 68 g of ethyl 2-bromo-2-methylpropionate was added and the mixture was finally stirred for 2 l / 2 hours. The reaction mixture was filtered, the anodizing cake was washed with ether, and the combined ether washes and dimethylformamide solution were concentrated in vacuo. The residue was partitioned between dilute sodium chloride solution and ether, and the ether solution was washed with 10% sodium hydroxide solution, water and 10% sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo.

The residue was distilled at 146 ° C (0.02 mm) to give 176.5 g of ethyl 2- (4-acetyl-2-chlorophenoxy) -2-methylpropionate.

(b) 2- (4-acetyl-2-chlorophenoxy) -2-methylpropionic acid.

A mixture of 10 g of ethyl 2- (4-acetyl-2-chlorophenoxy) -2-methylpropionate, 15 ml of 35 ml of aqueous sodium hydroxide solution, 25 ml of 95 ml of ethanol and 100 ml of water was stirred for 15 minutes. The mixture was then acidified with hydrochloric acid, cooled and the solid product collected and recrystallized from aqueous ethanol to give 8.35 g of 2- (4-acetyl-2-chlorophenoxy) -2-methylpropionic acid, m.p. 123-125 ° C.

22,58629 (c) Ethyl 2- [4- (1-hydroxyethyl) -2-chlorophenoxy] -2-methylpropionate was prepared from 28.4 g of ethyl 2- (4-acetyl-2-chlorophenoxy) -2 methyl propionate and 1.9 g of sodium borohydride according to the procedure described in Example 9 (c) above. 30.0 g of ethyl 2- [4- (1-hydroxyethyl) -2-chlorophenoxy] -2-methylpropionate were obtained.

(d) Ethyl 2- (4-vinyl-2-chlorophenoxy) -2-methylpropionate was prepared from 28.6 g of ethyl 2- [4- (1-hydroxyethyl) -2-chlorophenoxy] -2-methylpropionate and well from p-toluenesulphonic acid in 150 ml of toluene according to the procedure described in Example 9 (d) above. The product distilled between 110-114 ° C (0.05 mm) to give 12.96 g of ethyl 2- (4-vinyl-2-chlorophenoxy) -2-methylpropionate.

(e) Ethyl 2- [2-chloro-4- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionate [I; R is C H r 1, r 3 and R 3 'are H, Q is 2-Cl, R and R are Cl and n is 0; para-orientation] was prepared from 26.8 g of ethyl 2- (4-vinyl-2-chlorophenoxy) -2-methylpropionate, 28 g of potassium t-butoxide and 50 ml of chloroform in 500 ml of pentane in Example 1 above. , according to the method described in (b). The product distilled between 135-137 ° C (0.08 mm) to give 19.22 g of ethyl 2- [2-chloro-4- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionate.

Example 11

Ethyl 2- [2-chloro-4- (2,2-difluorocyclopropyl) phenoxy] -2-methyl-

Γ 1 “3 * 3 I

propionate [I; H is C H, R, R and R are H, Q is 2 21 ^ 2-Cl, R and R are P and n is 0; para-orientation] was prepared from 40.3 g of ethyl 2- (4-vinyl-2-chlorophenoxy) -2-methylpropionate and 32.9 g of sodium chlorodifluoroacetate in 190 ml of diglyme according to the procedure described in Example 2 (a) above. The product distilled between 112 ° C and 114 ° C (0.01 mm) to give 26.39 g of ethyl 2- [2-chloro-4- (2,2-difluorocyclopropyl) phenoxy] -2-methylpropionate.

Example 12 (a) Ethyl 2- (3-acetylphenoxy) -2-methylpropionate was prepared from 177 g of m-hydroxyacetophenone, 632 g of ethyl 2-bromo-2-methylpropionate, 537 g of anhydrous potassium carbonate and 1200 ml. dimethylformamide according to the method described in Example 10 »(a) above. The product distilled between 121 and 128.5 ° C (0.04 mm) to give 227.3 g of ethyl 2- (3-acetylphenoxy) -2-methylpropionate.

(b) Ethyl 2- [3- (1-hydroxyethyl) phenoxy] -2-methylpropionate was prepared from 125 g of ethyl 2- (3-acetylphenoxy) -2-methylpropionate and 9.45 g of sodium borohydride in Example 9 above under ( c) according to the procedure described and thereby obtained 125.6 g of ethyl 2- [3- (1-hydroxyethyl) phenoxy] -2-methylpropionate as an oil.

23 5 8 6 2 9 (c) Ethyl 2- (3-vinylphenoxy) -2-methylpropionate was prepared from 125.6 g of ethyl 2- (T3-hydroxyethyl) phenoxy] -2-methylpropionate and 1.5 g of p-toluenesulfonic acid in 1,500 ml of toluene according to the procedure described in Example 9, (d) above, to give 115.9 g of ethyl 2- (3-vinylphenoxy) -2-methylpropionate as an oil.

(d) 2- [m- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionic acid f1; 133 '. 2.2 'R, R, R, R and Q are H, R and R are Cl and n is 0; meta-orientation / prepared from 35.1 g of ethyl 2- (3-vinylphenoxy) -2-methylpropionate, 1 + 2.0 g of potassium t-butoxide, 107 g of chloroform and 750 ml of pentane according to the method described in Example 1, point (b) above. The product distilled between 123-125 ° C (0.08 mm) and was chromatographed on a column of 500 g of silica gel. The column was eluted with pentane and pentane / ether mixtures, and the obtained purified ethyl 2- [m- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionate was hydrolyzed with 10 ml of a solution of sodium hydroxide 35 in 100 ml of 95 μl. ethanol. After standing for 20 minutes at room temperature, the reaction mixture was diluted and acidified and the acidified solution was extracted with ether. The ether solution was concentrated in vacuo and the residue was crystallized from hexane to give 8.77 g of 2- [2- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionic acid, m.p. 81-86 ° C.

Example 13 (a) 2- (p-Acetylphenoxy) -2-methylpropionic acid was prepared from 5 * + 5 g of p-hydroxyacetophenone, 960 g of sodium hydroxide and 715 g of chloroform in 11 liters of acetone in Example 1 (d) above. according to the method described. The product was recrystallized from carbon tetrachloride and isopropyl acetate to give 2- (p-acetylphenoxy) -2-methylpropionic acid as a pale cream solid, m.p. 108-110 ° C.

(b) Ethyl 2- [p- (1-hydroxyethyl) phenoxy] -2-methylpropionate was prepared from 141 g of ethyl 2- (p-acetylphenoxy) -2-methylpropionate / prepared by esterification of the acid prepared in (a) according to Example 16 (a) and 10.7 g of sodium borohydride according to the procedure described in Example 9, (c) above, to give 10 g of ethyl 2- [p- (1-hydroxyethyl) phenoxy] -2-methylpropionate as a pale yellow liquid.

(c) Ethyl 2- (p-vinylphenoxy) -2-methylpropionate

A mixture of 116 g of ethyl 2- [N- (1-hydroxyethyl) phenoxy] -2-methylpropionate and 92 g of p-toluenesulfonyl chloride in 500 ml of pyridine was heated under reflux for 3 hours, kept at room temperature for about 16 hours and then heated to reflux again for 6 hours. The reaction mixture was poured into ice water and extracted with hexane. The hexane solution was washed successively with dilute sulfuric acid, 10% potassium bicarbonate solution, water and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate for 2k '58629

And concentrated in vacuo. The residue distilled between 104-111 ° C (0.03-0.08 mm).

And 60 g of ethyl 2- (p-vinylphenoxy) -2-methylpropionate were obtained.

(d) Ethyl 2- [p- (2,2-dibromocyclopropyl) phenoxy] -2-methylpropionate was prepared from 23-4 g of ethyl 2- (p-vinylphenoxy) -2-methylpropionate, 39, 2 g of potassium t-butoxide and 198 g of chromoform according to the method described in Example 1 (b) above. The product was separated and hydrolyzed without further purification.

(e) 2- [p- (2,2-dibromocyclopropyl) phenoxy] -2-methylpropionic acid [I; R, R 1, R 3, R 3 and Q are H, R 1 and R 2 are Br and n is 0; the para orientation was hydrolyzed with sodium hydroxide in aqueous ethanol for 5 hours at room temperature. The acid fraction was separated and recrystallized from aqueous ethanol and benzene / hexane (1: 1) to give 18 g of 2- [p- (2,2-dibromocyclopropyl) phenoxy] -2-methylpropionic acid, m.p. 129-131 ° C '

Example 1 k (a) Ethyl 2- [p- (2-chloro-2-fluorocyclopropyl) phenoxy] -2-methylpropionate.

A mixture of 13.6 g of ethyl 2- (4-vinylphenoxy) -2-methylpropionate and 33 g of phenyldichlorodluoromethylmercury (C 9 H 8 -HgClCl 3) in 120 ml of benzene was heated under reflux for 48 hours. The reaction mixture was allowed to stand at room temperature for 2 hours, then filtered and the filtrate evaporated in vacuo. The residue was stirred with pentane, filtered and concentrated in vacuo to give ethyl 2- [p- (2-chloro-2-fluorocyclopropyl) phenoxy] -2-methylpropionate as an orange oil which was hydrolyzed as described below.

(b) 2- [p- (2-chloro-2-fluorocyclopropyl) phenoxy] -2-diethylpropionic acid [i; R, R1, R3, R3 and Q are H, R2 is Cl, R2 'is F and n is 0; para-orientation] was prepared by hydrolyzing ethyl 2 * - [p- (2-chloro-2-fluorocyclopropyl) phenoxy] -2-methylpropionate in an aqueous ethanolic solution of trihydroxide. There were thus obtained 14.4 e of 2- [p- (2-chloro-2-fluorocyclopropyl) phenoxy] -2-methylpropionic acid as beige needles, m.p. 97-102 ° C after recrystallization from benzene / hexane.

Example 19 (a) Ethyl 2- (p-phenylacetylphenoxy) -2-methylpropionate was prepared from 100 g of p-phenylacetylphenol, 230 g of ethyl 2-bromo-2-methylpropionate and 228 g of potassium carbonate in Example 10 above. , according to the method described in (a). This gave 70 g of ethyl 2- (p-phenylethylphenoxy) -2-methylpropionate, m.p. 110-113 ° C.

58629 (b) Ethyl 2- [p- (1-hydroxy-2-phenethyl) phenoxy] -2-methylpropionate was prepared from 101 g of ethyl 2- (p-phenylacetylphenoxy) -2-methylpropionate and 11.4 g sodium borohydride to give 97.8 g of ethyl 2- [p- (1-hydroxy-2-phenethyl) phenoxy] -2-methylpropionate as a yellow oil.

(c) Ethyl 2- [p- (2-phenylvinyl) phenoxy] -2-methylpropionate was prepared from 94.5 g of ethyl 2- [p- (1-hydroxy-2-phenethyl) phenoxy ] -2-methyl propionate and 1.3 g of p-toluenesulfonic acid in toluene according to the procedure described in Example 9, (d) above. The product was recrystallized from 95 g of ethanol to give 53.5 g of ethyl 2- [p- (2-phenyl-vinyl) phenoxy] -2-methylpropionate, m.p. 55 'at 65 ° C.

(d) Ethyl 2- [p- (2,2-dichloro-3-phenylcyclopropyl) phenoxy] -2-methylpropionate.

A mixture of 25 g of ethyl 2- [p- (2-phenylvinyl) phenoxy] -2-methylpropionate and 39 g of phenyldichlorone bromomethylmercury in 100 ml of benzene was gently heated under reflux for 3 hours. An additional 5 g of phenyldichlorobromomethylmercury was then added and the mixture was heated to reflux for a further 3 hours. The reaction mixture was kept at room temperature for 2 days, then filtered and the filtrate was evaporated in vacuo. The residue was taken up in hexane, filtered and concentrated in vacuo to give 34.2 g of ethyl 2- [p- (2,2-dichloro-3-phenylcyclopropyl) phenoxy] -2-methylpropionate as a brown oil which was hydrolyzed without further purification.

(e) 2- [p- (2,2-dichloro-3-phenylcyclopropyl) phenoxy] -2-methylpropionic acid [I; R, R 1, R 3 and Q are H, R 3 is C 1 H, R 2 and R 2 'are Cl and n is O 1 para orientation] was prepared by hydrolysis of ethyl 2- [p- (2,2-dichloro-3-phenylcyclopropyl) phenoxy] -2-methylpropionate with aqueous ethanolic sodium hydroxide solution. The product was chromatographed twice using a silica gel column and eluted with pentane / ether (1: 1) and then recrystallized from hexane / benzene (2: 1) to give 15 g of 2- [p- (2,2-dichloro). 3-phenylcyclopropyl) phenoxy] -2-methylpropionic acid, m.p. 129-132 ° C.

Method C Example 16 (a) Methyl 2- (p-acetylphenoxy) -2-methylpropionate was prepared by esterifying 222 g of 2- (p-acetylphenoxy) -2-methylpropionic acid [Example (a)] by heating said acid with 96 g methanol and 7 ml of concentrated sulfuric acid in 300 ml of chloroform. The product was separated and distilled at 114 ° C (θ, θ6 mm) to give 206.6 g of methyl 2- (p-acetylphenoxy) -2-methylpropionate, m.p. 62-63 ° C.

(b) Methyl 2- [p- (1,2-dimethylvinyl) phenoxy] -2-methylpropionate.

15.1 g (0.36 mol, 57% oil dispersion) of sodium hydride was placed in a 2 L flask and rinsed three times with pentane to remove oil. Anhydrous dimethyl sulfoxide (240 mL) was then added and the flask was evacuated and purged with nitrogen. The mixture was heated between 75-80 ° C for 45 minutes, then cooled in an ice bath. A solution of 155.2 g of ethyl triphenylphosphonium chromide in 720 ml of dimethyl sulfoxide was then added, the mixture was stirred for 15 minutes and then treated with a solution of 70.8 g (0.50 moles) of methyl 2- (p-acetylphenoxy). ) -2-methylpropionate in 120 ml of dimethyl sulfoxide. The reaction mixture was stirred for 5 hours at room temperature and then poured into water. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate to give 81.8 g of methyl 2- [p- (1,2-dimethylvinyl) phenoxy] -2-methylpropionate as an oil (mixture of geometric isomers). ).

(c) 2- [p- (2,2-dichloro-1,5-dimethylcyclopropyl) phenoxy] -2-methylpropionic acid [I; R and R are CH 2, R, R and Q are H, R and R are Cl and n is Of para orientation] was prepared from 24.8 g of methyl 2- [p- (1,2-dimethylvinyl) phenoxy] - 2-methylpropionate, 28 g of potassium t-butoxide and 50 ml of chloroform in 500 ml of pentane according to the procedure described in Example 1 (h) above. The methyl ester thus obtained was hydrolyzed in the usual manner with sodium hydroxide 95 in methanol. The acid fraction thus obtained was recrystallized from benzene / hexane to give 12.5 S of 2- [p- (2,2-dichloro-1,5-dimethylcyclopropyl) phenoxy] -2-methylpropionic acid, m.p. 158-145 ° C, (mixture of geometric isomers).

Example 17 2- [p- (2,2-Dibromo-1,5-dimethylcyclopropyl) phenoxy] -2-methylpropionic acid [I; R 1 and R 3 are CH, R, R 3 and Q are H, R 2 and R 2 'are Br and n is 0; para-orientation] was prepared from 24.8 g of methyl 2- [p- (1,2-dimethylvinyl) phenoxy] -2-methylpropionate, 55 g of potassium t-butoxide and 152 g of bromoform in 500 ml of pentane in Example 1 above ( (b) as described. The resulting methyl ester was hydrolyzed in the usual manner with sodium hydroxide in $ 95 ethanol, and the acid product was separated and recrystallized from benzene / hexane to give 12.9 g of 2- [p- (2,2-dibromo-1,5-dimethylcyclopropyl) phenoxy] -2 -methylpropionic acid in the form of light brown rosettes, m.p. 141-142.5 ° C (decomposes) (more than 90 i-trans isomers).

Example 16 (a) Ethyl 2- (p-benzoylphenocol) -2-methylpropionate was prepared from 198 g of p-hydroxybenzophenone, 490 g of ethyl 2-bromo-2-methylpropionate and 485 g of potassium carbonate in Example 10 above. according to the method described in (a). The neutral fraction was separated and the resulting 208 g of a beige solid was recrystallized from benzene / hexane to give 180 g of ethyl 2- (p-benzoylphenoxy) -2-methylpropionate, m.p. 82-85 ° C.

(b) Ethyl 2- [p- (1-phenylvinyl) phenoxy] -2-methylpropionate was prepared from 31.2 g of ethyl 2- (p-benzoylphenoxy) -2-methylpropionate, 42.8 g of methyltriphenylphosphonium bromide and 5.05 g of sodium hydride in dimethyl sulfoxide according to the procedure described in Example 16, (b) above, to give $ 1.6 g of ethyl 2- [p- (1-phenylvinyl) phenoxy] -2-methylpropionate as a yellow liquid.

(c) 2- [β- (2,2-dichloro-1-phenylcyclopropyl) phenoxy] -2-methylpropionic acid [1; r "'is C 9 H 8, R, R 3, R 3, R 3 and q are H, R 2 and R 2 are Cl and n is 0; para-orientation] was prepared from 31.6 g of ethyl 2- [p- (1-phenylvinyl) phenoxy] -2-methylpropionate, 28 g of potassium t-butoxide and 30 ml of chloroform according to the procedure described in Example 1 (b) above, The ethyl ester obtained is hydrolyzed in the usual manner with sodium hydroxide in 95% ethanol and the acid product obtained separated and recrystallized from benzene / hexane to give 20 g of 2- [p- (2,2-dichloro-1-phenylcyclopropyl) phenoxy] -2-methylpropionic acid as colorless needles, mp 171-173 ° C.

Example 19 2- [p- (2,2-Dibromo-1-phenylcyclopropyl) phenoxy] -2-methylpropionic acid [Ij R1 is CgH, R, R3, R3 and Q are H, R2 and R2 'are Br and n is 0? para-orientation] was prepared from 31.0 g of ethyl 2- [p- (1-phenylvinyl) phenoxy] -2-methylpropionate [Example 18 (b)], 35 g of potassium t-butoxide and 152 g of bromoform. according to the method described in Example 1, point (b) above. The resulting ethyl ester was hydrolyzed in the usual manner with sodium hydroxide 95 in another ethanol, and the acid product was separated and recrystallized several times from benzene / hexane to give 11.5 g of 2- [p- (2,2-dibromo-1-phenylcyclopropyl) phenoxy] - 2-methylpropionic acid as colorless needles, m.p. 1? 6-178 ° C. (At the same time gas evolves).

Example 20 2- [p- (2,2-Difluoro-1-phenylcyclopropyl) phenoxy] -2-methylpropionic acid [i * R1 is CgH, R, R3, R3 'and q are H, R2 and R2' are F and n is 0; para-orientation] was prepared from 62 g of ethyl 2- [p- (1-phenylvinyl) phenoxy] -2-methylpropionate [Example 20, step (b)] and βΟ of sodium chlorodifluoroacetate in aglyme according to the method described in Example 2, point (a) above. . The resulting ethyl ester was hydrolyzed in the usual manner with sodium hydroxide in 95% ethanol, and the resulting acid product was recrystallized from benzene / hexane to give 28,58629 31.3 g of 2-βη (2,2-difluoro-1-phenylcyclopropyl) phenoxy-7'-2- methylpropionic acid, m.p. 9 T-99 ° C.

Example 21 (a) Methyl 2- [p- (1-ethylvinyl) phenoxy] -2-methylpropionate was prepared from 52.5 g of methyl 2- (p-propionylphenoxy) -2-methylpropionate / Example 9, item (b) 7, 107 g of methyl biphenylphosphonium bromide and 12.6 g of sodium hydride in dimethyl sulfoxide according to the procedure described in Example 16, (b) above. The product distilled between 93-95 ° C (0.1 mm) to give 37.5 g of methyl 2- [p- (1-ethylvinyl) phenoxy] -2-methylpropionate.

(b) Methyl 2- [p- (2,2-dichloro-1-ethylcyclopropyl) phenoxy] -2-methylpropionate / 1; R is CH 2, R is C 1 H 2, R, R and Q are H, R and R are

Cl and n are 0; para-orientation / was prepared from 18.5 g of methyl 2- [p- (1-ethylvinyl) phenoxy] -2-methylpropionate, 21 g of potassium t-butoxide and 56 g of chloroform in Example 1 above, according to the method described in (b) and was obtained as a pale straw yellow oil, b.p. 131-133 ° C. (0.09 mm) (18.5 g). Method D Example 22 (a) p- (2,2-Dichlorocyclopropyl) phenol.

A solution of 50 g (0.2-8 moles) of p- (2,2-dichlorocyclopropyl) aniline in 185 ml of glacial acetic acid was cooled to about 10 ° C and a solution containing 18 was added dropwise with stirring. 9 g (0.273 mol) of sodium nitrile in 185 ml of water. A thick slurry formed and was added portionwise to a stirred solution of 160 ml of concentrated sulfuric acid in 320 ml of water, the temperature of which was maintained between 100 and 105 ° C. The reaction mixture was stirred at 100-5 ° C for 10 minutes, then cooled and diluted with water. The resulting product was collected by filtration, dissolved in ether and washed with sodium bicarbonate solution. The ether solution was then extracted with sodium hydroxide solution 29,58629 and the sodium hydroxide solution was acidified and extracted with ether. The ether solution was dried and concentrated in vacuo, and the residue (18 g) was subjected to water-steam distillation to give 9 g of a yellow resin which crystallized on trituration with ether. This gave 8 g of p- (2,2-dichlorocyclopropyl) phenol, m.p. 54 »5-56 ° C.

(b) 2- [p- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionic acid [1, R, R, R, R and Q are H, R and R are Cl and are 0; para-orientation].

At 0 ° C, a mixture of 8 g (0.0356 moles) of p- (2,2-dichlorocyclopropyl) phenol, 11.2 g (0.28 moles) of sodium hydroxide tablets, 11.2 g of chloroform and 350 g of ml of acetone. The cooling bath was removed, the mixture was stirred for one minute and then heated to reflux with a steam bath. The reaction mixture was stirred under reflux for 3 hours and then concentrated in vacuo. The remaining resin was partitioned between dilute hydrochloric acid and ether and the ether layer was separated, dried and concentrated in vacuo. The residual oil (14 g) was partitioned between dilute aqueous sodium bicarbonate and ether. The sodium bicarbonate solution was acidified with concentrated hydrochloric acid and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated. The residue (9.5 g of a yellow oil) was crystallized twice from hexane to give 6.0 g of 2- [p- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionic acid as a pale cream solid, m.p. 114-116 ° C.

Example 23

Methyl -2- [p- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionate [i; R is CH 2, R, Pvbj R 1 and q are H, R 2 and R 2 are Cl and n is 0; para-orientation].

A mixture of 10 g (0.0346 moles) of 2- [p- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionic acid [Example 22 (b)], 3, 33 β (0.1038 moles) of methanol and 0.5 ml of concentrated sulfuric acid in 100 ml of methylene chloride were stirred at reflux for 4 hours. The reaction mixture was cooled, washed with water and sodium bicarbonate solution, dried and concentrated in vacuo. The residue was distilled to give 8.5 g of methyl 2- [p- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionate as a colorless oil, b.p. 115 ° C (0.05 mm) ·

Alternatively, ethyl 2- [p- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionate was prepared from 20 g of p- (2,2-dichlorocyclopropyl) phenol [Example 22 (a)], 38 g of ethyl 2-bromo-2-methylpropionate and 42 g of potassium carbonate in 100 ml of acetonitrile. Ethyl 2-bromo-2-methylpropionate was added in two equal portions, with a second dose of 30,58629 added after 7 hours of refluxing. The reaction mixture was heated to reflux for about 3 days and the product was isolated to give 32 g of ethyl 2- [β- (2,2-dichlorocyclopropyl) phenoxy] -2-ylpropionate. The latter was hydrolyzed in the usual manner with ethanolic sodium hydroxide solution to give 2- [p- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionic acid, which was identical to the compound formed in Example 22 (b).

Claims (2)

58629 31 1. A process for preparing a blood cholesterol and triglyceride lowering compound of the formula CH. rv OC-COOR I (“Λ« ™ 3 r3'_ R3 where R is hydrogen or alkyl of 1 to 6 carbon atoms, Q is hydrogen or chlorine, 1.2 2 'R is hydrogen, alkyl of 1 to 3 carbon atoms or phenyl , R and R are ... each fluorine, chlorine or bromine, R is hydrogen, 3 to 3 alkyl or phenyl having 1 to 3 carbon atoms, R is hydrogen, n is 0 or 1, or R and Q may together form an ethylene bridge when (CH) is a direct bond attached to the benzene ring at the ortho position to Q, where Q and RJ form a 6-membered ring, or when R is hydrogen to form a base salt of this compound, known that a) a compound of formula X R 3 "- r_r CH r 3 v 'Nrr · x„ 1 Λ V-O-C-COOR v Q 2 21 wherein R is lower alkyl is treated with a compound producing a carbene group of formula ^ CR R , such as chloroform or bromophone, or b) reacting a compound of formula IV 2 'R 2 R 3 - f * ^ (CH 0) n / · R 3 R 1 With a (λ-bromoisobutyric acid ester of (CH 2 Cl 2) Br in the presence of a base, and if desired the compound of formula I in which R is lower alkyl is hydrolyzed to a compound in which R is hydrogen and, if desired, a compound in which R is hydrogen , is converted to the base salt. Process for the preparation of 2- [p- (2,2-dichlorocyclopropyl) -phenoxy] -2-methylpropionic acid according to Claim 1, characterized in that the p- (2,2-dichlorocyclopropyl) phenol is treated with a mixture of chloroform, acetone and an alkali metal hydroxide or. with a compound of formula (CH 2 gCiBriCOOR wherein R is alkyl of 1 to 6 carbon atoms in the presence of a strong base, and in the latter case the lower alkyl ester obtained is hydrolyzed to the free acid i. 33 58629 1. A process for the preparation of hypocholesterolemic and hypotriglycolic active compounds of formula I CH ^ 3 '/ \ -OC-COOR R, 0,3 R3 color R is the value of alkyl with 1-6 cholaters, Q is the value of chlorine , R1 is a derivative, 2 2 'alkyl with 1-3 cholaters or phenyl, R and R r is a fluorine, chlorine or chromium, 3 3' is a derivative, alkyl with 1-3 cholaters or phenyl, R is 0 or 1, or R and Q are the same as in ethylene, and (CH) is not directly 2 n3. binding to benzene and orthostalling to Q colors Q and R to the ring with 6 atomers, or to R is not possible from the base to the bass. kännetecknat därav, att a) man behandlar en förening med formeln X \ -jO-C-COOR V «3 Q color R är lägre alkyl, med en förening, ur vilken bildas en Karben med formuleln CR2R2 \ säsom med chloroform or bromoform, eller b) man omsätter en förening med formeln IV 2 2 'R R (CH 2 Cl 2 R 1 V 1 H ° C;