DK141366B - Analogous process for the preparation of 2- (p-cyclopropylphenoxy) -2-methylpropionic acid compounds or salts thereof with bases. - Google Patents

Description

(11) PUBLICATION 141366 \ Ra / DENMARK "" 'nta'8 of c ei / rn' (21) Application No 4717/73 (22) Filed on 28 Slig · 1975 (23) Running day 28 Aug 1973 ( 44) The application submitted and q «the submission thesis published on 5 · mST · 1 9 ^ v DIRECTORATE FOR out.

PATENT AND TRADEMARKET (30> Priority requested from it

Aug. 29-Aug. 1972, 284577, US

(71) STERLING DRUG INC., 90 Park Avenue, New York, N.Y., US.

(72) Inventor: Donald Kenney Phillips, 12 Columbia Drive, East Greenbush,

New York, US.

(74) Plenipotentiary in the proceedings:

Hofman-Bang & Boutard Engineering Company. __ (54) Analogous process for the preparation of 2- (p-cyclopropylphenoxy) -2-methylproplonic acid compounds or salts thereof with bases.

The present invention relates to an analogous process for the preparation of novel 2- (p-cyclopropylphenoxy) -2-methylpropionic acid compounds having the general formula I or salts with the bases of the compounds wherein R is hydrogen.

Preferred pharmacologically acceptable salts are the sodium, calcium, magnesium and ammonium salts and salts of low toxicity organic amines, e.g. the diethanolamine and N-methylglucamine salts.

Biological studies of these compounds have shown that they have hypocholesteremic and hypotriglyceridemia effects and are therefore useful in treating atherosclerotic diseases caused by elevated serum cholesterol and triglyceride levels.

Danish Patent Application No. 3884/70 discloses related phenoxy-alkane carboxylic acid derivatives having the same direction of action, but by a closer comparison of the data set out in the above application and the data set forth in the following description, in which case both are compared with the commercially widely used compound clofibrate, it is seen that the compounds described in the above application have an activity of the same magnitude or in a single case up to 6 times the activity of clofibrate, while the compounds of the present invention are 7-100 times as active. as clofibrate.

The process according to the invention is characterized by the characterizing part of the claim.

The process of the invention is illustrated by the following reaction schemes, which also include various reaction pathways to obtain the starting compounds. In Scheme A, the final steps of Compound IV show process (a) of claim 1 with reactants (i) and (ii). In Schemes B and C, the final steps of compound X show process (b) according to the claim. In Scheme D, the final steps of Compound XIV show process (a) of claim 1 with reactants (i) and (ii) to prepare a preferred compound.

Schedule A

3 = 13 C = p - \\ / \ - O- (C1-C4 alkyl) +: Οχ 2, - »

R1 V in // R

Q

II

r2 r2 * - / ^ Yo-tC - ^ - alkyl)> 'H R1 \\. i //

Q

III

R2 R2 '

Q

/ IT \ fi / \ (ii) Br-C-COORf, / OH "(i) ΚΠίΚΠ.,., CH ^ COCH ^, OH"

50-150 ° C / 50-100 ° C

In (R 5 C 1 -C 8 alkyl) -Mdrolysis> I (R = H) in which formulas Q, R "1", R 2, R 2 and R 1 have the meaning given in the claim.

In Scheme A above, an alkenyl-substituted phenylalkyl ether of formula II is reacted with a carbene-producing medium: CR

The carbenes of the above formula can be prepared from a wide variety of halogenated organic compounds. Particularly useful media for this purpose are trihalomethanes in the presence of a strong base such as potassium tert-butoxide. The trihalogen methanes used include chloroform (yielding: CC12), bromo form (: CBr2), iodoform (: CI2), chlorodifluoromethane (: CF2). Other sources of carbene include FCl2CCOClClF (: CFCl), ethyl trichloroacetate (: CC12), phenyl (trichloromethyl) mercury (: CC12), phenyl (bromodichloromethyl) mercury (: CBr2), sodium chlorodifluoroacetate (: CF2), sodium trichloro (CC2), sodium , bis (tribromomethyl) mercury (: CBr2), bromine trifluoromethane (: CF2), methyldichlorofluoroacetate (: CFC1) and (CH2) ^ SnCF2 (: CF2). The reaction usually takes place at anhydrous conditions at room temperature or at a lower temperature.

The second step of Scheme A is a cleavage of the cyclopropyl-substituted phenol ether III produced by the previous carbene reaction. The ether cleavage is carried out in the presence of a strong acid. The strong acid may be a protonic acid such as hydrogen bromic acid or hydrogen iodide acid or a Lewis acid such as boron tribromide. Examples of phenol ether cleavage reagents include boron tribromide, boron trichloride, boron trifluoride etherate (in the presence of acetic anhydride and lithium bromide), aluminum bromide, aluminum chloride, hydrogen iodide acid (in the presence of phosphorus and acetic acid anhydride), hydrogen bromide anhydride, hydrogen bromide and dioxide.

The product of the ether cleavage, the cyclopropyl-substituted phenol of formula IV, is then reacted either with a 2-bromo-2-methylpropionic ester in the presence of a base or a mixture of chloroform, acetone and an alkali metal hydroxide. The former reaction gives a compound of formula I wherein R is alkyl of 1-6 carbon atoms and is carried out at a temperature of 50-150 ° C in the presence of a base such as potassium carbonate. The latter reaction is carried out at a temperature of 50-100 ° C, usually at the reflux temperature, to give a compound of formula I wherein R is hydrogen. If desired, the compound of formula I wherein R is alkyl of 1-6 carbon atoms may be hydrolyzed by conventional methods, e.g. with base, to form the compound wherein R is hydrogen.

Schedule B

6 U1366 o i-v i) chci3> ch3coch3, OH “H3C-C - <^ ° H 2) R'OH (H +)

Q

WE YOU

GH, i 3

Br-C-COOR 't CH3 Ψ O / = x ch3 H3C-C Λ- O-C-COOR' MBH4, R1Mg halide. or R 1 Li - *

Q

VIII

0H / -v CH3 H, C-C-Λ-O-C-COOR '-H "0 3; V / i ,, _! _

Q

IX? / -v CH 3: C \ 2 '/ - \ «5 ^ R ^ H, C = C_L OC-COOR' - ^ I (R = C -, - C ^ -alkyl) ITXaV k / q 0 / Hydrolysis XI ( R = H) 12 2 'in which formulas Q, R, R, R and R' have the meaning set forth in the claim.

In Scheme B, a p-acetylphenol of formula VII is treated either with a 2-bromo-2-methylproionic acid ester in the presence of a base or with a mixture of chloroform, acetone and an alkali metal hydroxide followed by esterification of the compound formed with an alkanol.

The next step in Scheme B consists of treating the 2- (p-acetylphenoxy) -2-methylpropionic acid ester of formula VIII with an alkali metal- 1 »11 1» borohydride, R-magnesium halide or R-lithium where R is alkyl of 1-3 carbon atoms. The reaction takes place in an inert solvent at room temperature or below. The reaction with alkali metal borohydride (MBH +, where M is alkali metal, preferably lithium or sodium) gives a carbinol of formula IX wherein R 1 is hydrogen. The reaction with the R-magnesium halide or R-lithium gives a carbinol of formula IX wherein R 1 is alkyl of 1-3 carbon atoms.

The carbinol of formula IX is then dehydrated to give an alkenyl-substituted 2-phenoxy-2-methylpropionic 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 -sulfonic acid, methanesulfonyl chloride sulfur dioxide, methyl chlorosulfite, boron trifluoride etherate or the like. The reaction is conveniently carried out at the reflux temperature of the solvent with means for removing the water produced by the reaction.

The final step is the treatment of the alkenic ester of Formula X with a medium which produces a carbene of Formula: CR R as fully described in connection with Scheme A above, thereby forming a compound of Formula I, wherein R is alkyl. This compound may, if desired, be hydrolyzed to the corresponding compound wherein R is hydrogen by conventional methods.

Alternatively, the compounds of formula VIII wherein Q is H may be prepared by a Friedel-Crafts reaction between the reactants of formulas 8

Him - ch3 // \ Vo -C-COOR 'and H ^ CCOCl ch3

The acyl group enters the para position of the ether bond and the reaction is carried out in the presence of a Lewis acid such as aluminum chloride.

Schedule C

9 141366 C -, i "/ - \ 1) CHCl, CH, COCH, OH" 2) Hk® *) XI Q -> CH, »ί

BrC-COOR '®3 O .__ CH, i "/ ^ Λ * 3 + R-C- /. Λ — O-C-COOR' (CÆ), - P-CH, Br i, g" '.

XII Q

/ - \ ^ 3: C \ 2 '/ = \ * 5 ^ H "C = C - / Λ-O-C-COOR". t * / t ~ \ / ~ in "2 '<*, -V16 I 5 / Hydrolysis Q 1 XI (R = H) 12 2' in which formulas Q, R, R, R and R 'have the claim set forth in the claim importance.

In Scheme C, a p-acetylphenol of formula XX is treated either with a 2-bromo-2-methylpropionic ester in the presence of a base or with a mixture of chloroform, acetone and an alkali metal hydroxide followed by esterification of the resulting compound with a lower alkanol. Thus, a compound of formula XII is obtained.

The next step in Scheme C consists of treating the 2- (p-acetylphenoxy) - 2-methylpropionic acid ester of formula XII with a Wittig reagent, i. triphenylmethylphosphonium bromide, in the presence of a strong base such as sodium hydride, heated to between 50 and 100 ° C in an inert anhydrous solvent. Thereby, an alkenyl-substituted 2-phenoxy-2-methylpropionic acid ester of Formula X is formed, which as described wins Scheme B can be converted by a carbene reaction to a compound of Formula I wherein R is alkyl of 1-6 carbon atoms.

1Λ13 6 6 11

Scheme D Cl Cl NH2 NaN02, H2S04

XIII

C1 Cl OH (i) CHCl3, CH3COCH3, OH-

XIV

ςπ. ci

Z - * “V V-O-c-COOH

CH, Ά 3 i 3 / (ii) Br-C-COOR ', OH' / '' Ί ^, '/ Hydrolysis CH, / Ψ 3 /

Cl Cl X?> / \ // \\ _ O-C-COOR '

XV

wherein R 'has the meaning set forth in the claim.

141366 12

The method of Scheme D is a process modification to produce a preferred compound using the commercially available β- (2,2-dichlorocyclopropyl) aniline (VIII). The latter is subjected to diazotization and hydrolysis to form p- (2,2-dichlorocyclopropyl) phenol (XXV), which is then treated as described above either with a 2-bromo-2-methylpropionic acid ester or with a mixture of chloroform, acetone and alkali metal hydroxide, forming alkyl 2- [p- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionate (XV hydrolyzed to the corresponding free acid) or 2- [p- (2,2-dichlorocyclopropyl) - phenoxy] -2-methylpropionic acid (XV ') ·

For example, the hypocholesteremic and hypotriglyceridemic effects of the compounds prepared by the process of the invention were measured. by oral administration to rats [Turnet et al.,

Scan. J. Clin. Lab. Investigation 9, 210 (1949); Arnold et al., J. of Atherosclerosis Research 7, 111-115 (1967)] · Female rats, fasted for 5 hours, were given the drug via the digestive tract and then fed either with a normal diet or with a high fat diet. This feeding was carried out for 4 days. Blood was drawn from a vein on the 5th day. Serum samples were analyzed for cholesterol and triglycerides, and the values are given in mg cholesterol or triglyceride per day. 100 ml of serum. The effect of the compounds was evaluated as ED ED values, which is the calculated dose at which 33% reduction of serum cholesterol or triglyceride content is obtained. The compounds of the invention were found to have hypocholesteremic ED 2 values of 15-20 mg / kg and hypotriglyceridemic ED 2 values of 2-250 mg / kg in rats maintained on normal diets. In rats fed on high-fat diets, ED values were lower.

33

Below is shown in tabular form a comparison between a compound of the invention of Example 10 and the compound clofibrate [ethyl 2- (p-chlorophenoxy) -2-methylpropionate] which is a known and commonly used antihypercholesteremic agent, cf. British Patent Specification No. 860,303. It is seen that the subject compound has a number of advantages over clofibrate in the form of much lower effective dose (ED ED) for rats on both normal and high-fat diets, greater efficacy over hypercholesterolemic monkeys, no inhibition of hormone-sensitive lipase as well as a serum half-life greater than twice as long in rats.

,, 141366. 13

Parameter Compound of Example 10 Clofibrat CEj

Cl2 A - ^^ - Oy-GOQH Op-COOEt CH ^ CH ^

Relative hypocholesterolemic and hypotriglyceridemic (rat) laboratory cost, 5-day test Hypocholest. ED ,, Hypocholest. ED, ·, 10 and 20 mg / kg 55 140 and 150 mg / kg5

Hypotriglyc. ED, 3 mg / kg 55

Relative cardiac cholesterolemia and hypotriglyceridemic (rat) high-fat diet, 5-day trial of Hypocholest. ED ,, Hypocholest. ED, 4.7 and 6.5 mg / kg5 90, 135 and 180 55 mg / kg

Hypotriglyc. ED ,, Hypotriglyc. ED, 0.44 and 0.55 55 133, 180 and 3005 mg / kg mg / kg

Relative hypocholesterolemic and hypotriglyceridemic effect (rat) high-fat diet, 2-week trial Hypocholest. ED ,, Hypocholest. ED, 1.5 and 3 mg / kg 55 350 and 400 mg / kg5

Hypotriglyc. ED ,, Hypotriglyc. ED, 1 and 1 mg / kg 55 120 and 175 mg / kg 14-dose oral toxicity, 400 mg / kg / day x 14 1200 (1000-1400) (LDcq) rats (on the 8th day following mg / kg / day x 14 14. treatment) on the 8th day after 14. treatment) 141366 14

Hormone Sensitive Lipase Not Inhibited by Inhibited by the 150 Compound at 15 mg / kg x 3 (cholesterol-mg / kg x 3 (cholesterol sterol decreased from role decreased from 70 to 70 to 35. 56 40, 42 mg / 100 ml) mg / 100 ml)

Hypolipidemic effect Hypocholesterolemic - Not hypocholic - on monkeys in a group of sterolemic in one of 4 monkeys in 90 group of 6 monkeys mg / kg / day x 14, but at a dose of not at 30 or 200 mg / kg / day 10 mg / hg / day x 14

Tritonized Hyperlipidemia- The Compound Protected- Clofibrate Protective Rats tended to be almost complete at 180, but you at 10 or 22.5 not at 90 mg / kg / mg / kg / day x 4 versus day x 4 rats from the hyperlipidemic hyperlipidic effect of triton mical effects of triton

Hyperlipidemic monkeys (8 At 30 mg / kg / day in up-clofibrate, monkeys per group in divided doses for 2 weeks by static signic cross-examination suppressed compound protection than significant serum (200 mg / kg / cholesterol dose) day x 14), although in monkeys. The beneficial suppression effect of the compound clearly went in the same tendon was in the serum β-lipo direction as seen in the protein fraction previously

Hyperlipidemic Compound Sub-Clofibrat Submarine Effectively Depressed the Increase Increase in Serum Cholesterol- Serum Cholesterol Sterol in Guinea Pigs Feed in Hypercholestero- with Cholesterol-containing Lemic Guinea Pigs Diet (1 mg / kg / day x 14 (13 mg / kg / day x 14 suppressed the increase) 33% calculated) with 33% calculated)

Half-life Rats: 2.5 hours approx. 12 hours

Monkeys: ca. 5 hours 4-6 hours

The mechanism of the Hypocholesterolemia Clofibrate-induced hypocholesterolemic accompanied by the increase brings about a specific specific serum, liver-increased specific se and adrenal cholesterol rum cholesterol activity, which pre-activity, thus, significantly impairs its hypocholesterolemia. - sterolemic action biosynthesis or inhibition may be the increased mobilization same as the action of tissue cholesterol by the compound depots from Example 10

In the aforementioned 5-day test in rats, the lipid-lowering activity of a variety of compounds prepared according to the following examples was determined.

141366

Lipid-lowering activity (rat, 5-day trials)

Normal diet Fed diet

Cholesterol friglyceride Cholesterol Triglyceride

Example ED ^ (mg / kg) ED ^ (mg / kg) ED ^ (mg / kg) ED ^ («tg / kg) _HT 9__ _____ '_; __ \ 1 15 <6 7 1 2 96 <12 15 15 3> 96 <12 4> 96 <2 2 2 5 15 <4 13 6 30 <12 7 35 2 1 2 8 12 ~ 12 10 15-20 2 2 , 5-5 2 ^ clofibrate 140-150 460 125 ^ Commercial standard; ethyl-2- (p-chlorophenoxy) -2-methylpropionate

In clinical studies, the compound of Example 10, 2- [p- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionic acid, produced a significant lowering of cholesterol (β-11poproteln fraction) at 80 mg / day. Benefits over chlorofibrate are: a) a greater effect on low density lipoproteins, b) once-a-day administration pattern as well as lower doses (clofibrate is given three or four times a day) and c) possible side effects of clofibrate show say to be less with the compound of Example 10.

The structural structure of the subject compounds was found by synthesis methods, by elemental analysis and by infrared and NMR spectral determinations.

The following examples further illustrate the process of the invention.

EXAMPLE 1,. 1A13 6 6 16 (a) p-Isopropenylanisole

A solution of 150 g (1.0 mol) of p-methoxyacetophenone in 1500 ml of anhydrous ether was added dropwise over 90 minutes to a solution of 22 g (1.0 mol) of methyl lithium (1.66 molar) in ether cooled in a ishad. The reaction mixture was stirred for 30 minutes at 0 ° C, 30 minutes at room temperature and 1 hour at reflux. Clay added two additional portions of 0.1 mole of methyl lithium to the boiling mixture at half-hour intervals. The reaction mixture was added to aqueous ammonium chloride solution and the aqueous phase was separated and extracted with ether. Le combined ethereal solutions were washed with aqueous sodium bisulfite solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was distilled, boiling point 75 - 81 ° C (1.2 mm) to give 120.4 g of the desired compound.

(b) p- (2,2-dichloro-1-methylcyclopropyl) anisole 228 g (2.04 mol) of potassium t-butoxide was added portionwise over 2.5 hours to a stirred solution of 120 g of p-isopropenylanisole in 750 g chloroform and 3500 ml of pentane cooled to -40 ° C. The reaction mixture was stirred at -40 ° C for 1 hour, then the cooling bath was removed and stirring was continued for 3 hours. The reaction mixture was poured into ice water, the phases separated and the aqueous phase extracted with pentane. Le 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-methylcyclopropyl) anisole as an oil.

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

A solution of 6.1 g (0.0242 mol) of boron tribromide in 25 ml of methylene chloride was added dropwise to a stirred solution of 6.1 g (0.0264 mol) of p- (2,2-dichloro-1-methylcyelopropyl) anisole in 25 ml of methylenedichloride cooled in an ice bath. The reaction mixture was stirred at 0 ° C for 1 hour, then the ice bath was removed and the mixture stirred for an additional 1 hour. The reaction mixture was poured into ice water and the phases separated. The aqueous phase was extracted with methylene dichloride and the combined methylene dichloride solutions were washed with water and with dilute sodium hydroxide solution. At this time, the sodium salt of p- (2,2-dichloro-1-methylcyclopropyl) phenol was precipitated and this was collected by filtration. The filter cake was combined with the original aqueous phase and acidified with concentrated hydrochloric acid. The acidic solution is extracted with ether and the ether phase is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from carbon tetrachloride to give p- (2,2-dichloro-1-methylcyclo-propyl) phenol, mp 125 -126 ° C.

(d) S - ^ - ^ g ^ g-dichloro-1-methylcyclopropylphenoxyJ-g-methyl ;; propionic acid [I; is CH 2, R and Q are H, R 2 and R 2 T are Cl

5.4 g of chloroform was added dropwise to a mixture of 9.1 g of p- (2,2-dichloro-1-methylcyclopropyl) phenol and 7.2 g of sodium hydroxide in 200 ml of acetone stirred at boiling point. After the chloroform addition was complete, the mixture was heated to boiling for 5 hours and 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 acidic mixture extracted with ether. The ether phase was dried over anhydrous sodium sulfate and concentrated in vacuo.

The residual oil was crystallized by crystallization with hexane and then it was recrystallized from hexane to give 8.5 g of 2- [p- (2,2-dichloro-1-methylcyclopropyl) phenoxy] -2-methyl-propionic acid as a pale, cream colored, solid, m.p. 108 -1119 o.

EXAMPLE 2 (a) Elimin-difluoro-1-methylcyclopropyl-anisole

A hot solution of 91.5 g of sodium chlorodifluoroacetate (pre-dried at 50 ° C in vacuo) in 150 ml of diethylene glycol dimethyl ether was added dropwise over 90 minutes to a stirred and boiling solution of 74 g of p-isopropylene anisole in 500 ml of diethylene glycol. dimethyl ether containing traces of trinitrobenzene and 4-t-butylpyrocathol as stabilizers. The reaction mixture was stirred under boiling for 5 minutes, cooled and filtered to remove sodium chloride. This was washed with a small amount of diethylene glycol dimethyl ether and then with penane, and the combined washings and filtrate were mixed with 3 liters of water and extracted three times but pentane. The pentane solution was washed with 10% aqueous potassium hydroxide, then with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give 96.5 g of p- (2,2-difluoro-1-methyl-cyclopropyl) anisole as a straw yellow oil.

(b) g- (2A2 = difluoro-1-methylcyclo2ropyl) 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 dihydrochloride analogous to the procedure described above in Example 1, part (c), yielding 9 g of pink oil which solidified on standing.

(c) §; 1Eil2i2 = difluoro-1-methylcyclopropyl22henoxy _] - 2-methyl2 propionic acid [I; R ^ is CH₂, R and Q are H, R ^ and R ^ are F] prepared from 9.0 g of β- (2,2-difluoro-1-methylcyclopropyl) phenol, 10.9 g of sodium hydroxide and 8 1 g of chloroform in 200 ml of acetone, analogous to the procedure described above in Example 1, part (d).

The product was recrystallized from hexane to give 8.5 g of 2- [p- (2,2-difluoro-1-methylcyclopropyl) phenoxy] -2-methylpropionic acid as a light cream colored solid, mp 110-111 ° C.

EXAMPLE 5 (a) β- (2,2-Dibromo-1-methylcyclopropyl) anisole 84 g, 0.75 mol, potassium t-butoxide was added portionwise over a period of 2 hours to a stirred mixture of 45 g. (0.3 mole) of p-iso-propenylanisole and 480 g (1.9 mole) of bromoform in 1350 ml of pentane, cooled in a dry ice bath. For the first 90 minutes the addition was carried out at -40 ° C, for the next 30 minutes at -10 ° G. 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 poured into ice water, the phases separated, and the organic phase washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give 95.5 g of p- (2,2-dibromo-1-methylcyclopropyl) anisole as a reddish brown oil. .

(B) g- (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 dihydrochloride analogously to the procedure described above in Example 1, part (c). There was thus obtained 6 g of p- (2,2-dibromo-1-methylcyclopropyl) phenol as a white solid.

(c) S- ^ p- ^ g ^^ dibromo-1-methylcyclopropyl ^ henoxyJ ^ g-methyl-ΕΓ2Ε ^ 23®ΥΕ®. [1 »R 2 is CII 3» R and Q are H, and R 2 'is Br] were 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 analogous to the procedure described above in Example 1, part (d). There was thus obtained 10.2 g of 2- [p- (2,2-dibromo-1-methylcyclopropyl) phenoxy] -2-methylpropionic acid as a light, cream colored solid, m.p. 130-131.5 ° C. it was recrystallized from an ether-hexane mixture.

Example 4 (a) p- (2,2-difluoroyclopropyl) anisole was prepared from 129 g of p-vinylanisole and 170 g of sodium chlorodifluoroacetate in 1500 ml of diethylene glycol dimethyl ether analogous to the procedure described above in Example 2, part (a). Thus, 122 g of p- (2,2-difluorocyclopropyl) anisole was obtained 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 analogous to the procedure described above in Example 1, part (c), giving 72 g of an oil used directly in the following reaction.

(c) 2- [p- (2,2-difluorocyclopropyl) phenoxy] -2-methyl-propionic acid [I; R, R and Q are H, R 4 and R 2 analogous to the procedure described above in Example 1, part (d) The product was recrystallized from benzene-hexane to give 22 g of 2- [p- (2,2-difluorocylopropyl) phenoxy] -2-methylpropionic acid as cream needles, m.p. 99 ° C.

EXAMPLE 5 (a) Ethyl 2,4-acetyl-2-chloro-phenoxy) -2-methylpropionate

A solution of 204 g (1.2 mole) of 3-chloro-4-hydroxy xyacetophenone, 497 g (3.6 mole) of potassium carbonate and 1140 ml of dimethylformamide was heated to 80 ° C with stirring. Then clay was added 230 g of ethyl 2-bromo-2-methylpropionate over 5 minutes and the reaction mixture was stirred and heated for 1 hour. Clay was added an additional 230 g of etbyl-2-bromo-2-methylpropionate and the mixture was stirred for one hour. An additional 68 g of ethyl 2-bromo-2-methylpropionate was added and the mixture was stirred for 2.5 hours. The reaction mixture was filtered, the filter cake washed with ether, and the combined ether washings and dime thylphamide 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 µl sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was distilled at 146 ° G (0.02 mm) to give 176.5 g of ethyl 2- (4-acetyl-2-chloro-phenoxy) -2-methylpropionate.

(b) gthyl 2- [4- (1-hydroxyethyl) -2-chlorophenoxyl-2-methylpropionate 1.9 g (0.05 mole) of sodium borohydride was added to a stirred solution of 28.4 g (0.1 mole) ethyl 2- (4-acetyl-2-chlorophenoxy) -2-methyl-propionate in 50 ml of dry ethanol kept at 5 ° C in an ice bath. After the exothermic reaction had died, the ice bath was removed and the reaction stirred for one hour at room temperature. The reaction mixture was acidified with acetic acid, poured into 300 ml of ice water and extracted with ethyl acetate. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give 30.0 g of ethyl 2- [4- (1-hydroxyethyl) -2-chlorophenoxy] -2-methylpropionate as an oil , which was used directly in the next reaction without further rising.

(c) Ethyl 2- [4- = yinyl-2-chlorophenoxy} -2-methylpropionate

A solution of 28.6 g of ethyl 2- [4- (1-hydroxyethyl) -2-chlorophenoxy] -2-methylpropionate and a trace of p-toluenesulfonic acid in 150 ml of toluene heated to reflux, a water trap is obtained in 6 hours. The reaction mixture was neutralized with pyridine (10 drops) and evaporated. The residue was distilled at 110-114 ° C (0.05 mg Hg) to give 12.96 g of ethyl 2- (4-vinyl-2-chlorophenoxy) -2-methylpropionate in the form of an oil used directly. in the next reaction without further purification.

(d) Ethyl = 2- [2-ceMor-4- {2,2-dichlorocyclo-chloro] 2-yl] henoxyJ-2-methylproplonate [I; R is CR 2 is H, Q is 2-C 1, R 2 and R 2 T are Cl] 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, analogous to the method described in Example 1, part (b). The product was distilled at 135 - 137 ° C (0.08 mm) to give 19.22 g of ethyl 2- [2-chloro-4- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionate.

ext 6 yl 2 Yl; 2 = J [2 = chloro-4- (2A2 = difluoroCYClO2ro2yl2ghenoxyJ-2-methyl: ΕΕ2Εΐ222ί C1 »R is C2H5 'is 0 is 2-C1, R ^ and R ^ are F] were 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 diethylene glycol dimethyl ether analogous to the method of Example 2, part (a). 112 - 114 ° C (0.01 mm) to give 26.39 g of ethyl 2- [2-chloro-4- (2,2-difluorocyclopropyl) phenoxy] -2-methylpropionate.

EXAMPLE 7 (a) 2- (p-Acetylphenoxy) -2-methylpropionic acid was prepared from 545 g of p-hydroxyacetophenone, 960 g of sodium hydroxide and 715 g of chloroform in 11 liters of acetone, analogous to the method described in Example 1, part (d). The product was recrystallized from carbon tetrachloride and from isopropyl acetate to give 2- (p-ethylethylphenoxy) -2-methylpropionic acid as a light, cream colored solid, m.p. 108-110 ° C.

(B) EthgI-2 - [] |) - (1-hydroxyethyl) phenoxy] -2-methylpropionate was prepared from 141 g of ethyl 2- (p-acetylphenoxy) -2-methylpropionate [prepared by esterification of the acid of part (a) with methanol and concentrated sulfuric acid in chloroform] and 10.7 g of sodium borohydride analogous to the method described in Example 5, part (c) to give 140 g of ethyl 2- [p- (1-hydroxyethyl) phenoxy ] - 2-methylpropionate as a light yellow liquid.

(c) Ethyl 1-2- (p-vinylphenoxy) -2-methylgrogionate

A mixture of 116 g of ethyl 2- [4- (1-hydroxyethyl) phenoxy] -2-methyl propionate and 92 g of p-toluenesulfonyl chloride in 500 ml of pyridine was heated to reflux for 5 hours, kept at room temperature for 16 hours. The mixture was then heated to boiling 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, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was distilled at 104 - 111 ° C (0.03 - 0.08 mm) to give 60 g of ethyl 2- (p-vinylphenoxy) -2-methylpropionate.

(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 bromoform analogous to the method described in Example 1, part (b). The product was isolated and hydrolyzed without further purification.

(e) 2- [β- (2 ± 2-dibromocyclopropyl) -henoxy2-2-methoxy] prionic acid [I; And R is H and is Br]

The product of step d was hydrolyzed with sodium hydroxide in aqueous ethanol for 5 hours at room temperature. The alkaline hydrolysis medium was acidified with hydrochloric acid and extracted with an organic solvent. The acid product thus obtained was isolated and recrystallized from aqueous ethanol and from benzene-hexane 1: 2 to give 18 g of 2- / p- (2,2-dibromocyclopropyl) phenoxy7-2-methylpropionic acid, mp 129-131 ° C.

EXAMPLE 8 (a) Ethyl 2- [p- (2-chloro-2-fluorocyclopropyl) phenoxy] -2-methyl-chloroionate _______________________

A mixture of 13.6 g of ethyl 2- (4-vinylphenoxy) -2-methylpropionate and 33 g of phenyl-dichlorofluoromethyl mercury (OgH The residue was mixed with hexane, filtered and concentrated in vacuo to give ethyl 2- [p- (2-ehlo: i-2-fluorocyclopropyl) phenoxy] -2-methylpropionate as a orange oil hydrolyzed as described below.

(b) 2- [p- (2-chloro-2-fluorocyclopropyl) phenoxy] -2-methylpropionic acid [I; R, R 1 and Q are H, R 2 is Cl and R 2 'is F] prepared by hydrolysis of ethyl 2- [p- (2-chloro-2-fluoro-cyclopropyl) phenoxy] -2-methylpropionate in aqueous ethanol solution of sodium hydroxide. Thus, clay was obtained 14.4 g of 2- [p- (2-chloro-2-fluorocyclopropyl) phenoxy] -2-methylpropionic acid in the form of beige needles, m.p. 97 - 102 ° C, when recrystallized from a benzene-hexane mixture .

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 l of acetone analogous to the procedure described above in Example, part (d). Thus, 321 g of 2- (p-propionylphenoxy) -2-methylpropionic acid were obtained.

(b) 5-ethyl-2β-propionylpheno3,2Z2-methylpropionate

A mixture of 118 g of 2- (p-propionylphenoxy) -2-methylpropionic acid, 48 g of methanol, 3.5 ml of concentrated sulfuric acid and 150 ml of ethylene dichloride was stirred and heated to reflux for 22 hours. The reaction mixture was cooled, the phases separated and the organic phase washed successively with water, sodium carbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was distilled at 122 - 127 ° C (0.08 mm) to give 114.5 g of methyl 2- (p-propionylphenoxy) -2-methylpropionate, mp 47-49 ° C.

(C) Methyl 2- [p- (1-ethyllyinyl) ghenoxy] -2-methylpropoxonate 12.6 g (0.3 mol) of sodium hydride, 57% in oil dispersion was placed in a flask and rinsed three times with pentane to remove the oil. Then 210 ml of anhydrous dimethyl sulfoxide was added and the flask was pumped out and rinsed with nitrogen. The mixture was heated to 75 - 80 ° C for 45 minutes and then cooled in an ice bath. Then a solution of 10.7 g of methyltriphenylphosphonium bromide in 600 ml of dimethylsulfoxide was added over 30 minutes, the mixture was stirred for 15 minutes and then treated with a solution of 52.5 g of methyl 2- (p-propionylphenoxy) -2 -methyl propionate in 80 ml of dimethyl sulfoxide over 20 minutes. The reaction mixture was stirred for three hours at room temperature and then poured into water. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was distilled at 93 - 95 ° C (0.1 mmHg) to give 37.5 g of methyl 2- [p- (1-ethylvinyl) phenoxy] -2-methylpropionate, nQ '= 1 , 5,182th

(d) Methyl -: - 2- [g- (2,2-dichloro-1: ethylcyclopropyl) phenoxy] -2-methylpropionate [I; R is CH 2, R is C 2 H 2, Q is H, R 2 and R is Cl] were prepared from 18.5 g of methyl 2- [p- (1-ethylvinyl) phenoxy] -2-methyl propionate, 21 g potassium t-butoxide and 56 g of chloroform analogous to the method described in Example 1, part (b) and obtained in the form of a light, straw colored oil, bp 131 - 133 ° C (0.09 mmHg) (18.5 g) .

Example 10 (a) g- (2,2-dichlorocyclopropyl) phenol

A solution of 50 g (0.248 mol) of β- (2,2-dichlorocyclopropyl) -aniline in 185 ml of glacial acetic acid was cooled to ca. And a solution of 18.9 g (0.273 mole) of sodium nitrite in 185 ml of water was added dropwise to the stirred mixture. A thick slurry was formed and added portionwise to a stirred solution of 160 ml of concentrated sulfuric acid in 320 ml of water at 100 -105 ° C. The reaction mixture was stirred at 100-5 ° C for 10 minutes, cooled and diluted with water. The resulting product was collected on a filter, dissolved in ether and washed with sodium bicarbonate solution. The ether solution was extracted with sodium hydroxide solution and the sodium hydroxide solution acidified and extracted with ether. The ether solution was dried and concentrated in vacuo and the residue (18 g) evaporated to give 9 g of a yellow gum which crystallized when dissolved in ether. 8 g of p- (2,2-dichlorocyclopropyl) phenol were obtained, mp 54.4-56 ° C.

(b) 2- [g- (2,2-dichlorocyclopropyl)]] -heno: xy] -2-methylproponic acid [I; And Q are H, R * and R are Cl]

A mixture of 8 g (0.0356 mole) of p- (2,2-dichlorocyclopropyl) phenol, 11.2 g (0.28 mole) of sodium hydroxide, 11 g of chloroform and 350 ml of acetone was prepared at 0 ° C. The cooling bath was removed and the mixture was stirred for 1 minute and heated on a steam bath for boiling. The reaction mixture was stirred at boiling point for 3 hours and concentrated in vacuo. The remaining rubber was dissolved in dilute hydrochloric acid and ether, and the ether phase was separated, dried and concentrated in vacuo. The remaining oil (14 g) was dissolved in dilute aqueous sodium hydrogen carbonate solution and ether. The sodium hydrogen carbonate 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 in the form of a light, cream-colored , solid, mp 114 - 116 ° C.

Alternatively, ethyl 2- [p- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionate was prepared from 20 g of p- (2,2-dichlorocyclopropyl) phenol / bromo-2-methylpropionate and 42 g of potassium carbonate in 100 ml of acetonitrile. Ethyl 2-bromo-2-methylpropionate was added in 2 equal portions, the second portion added after seven hours of heating at the boiling temperature. The reaction mixture was heated to boiling for 3 days and the product isolated to give 32 g of ethyl 2- [p- (2,2-dichlorocyclopropyl) phenoxy] -2-methylpropionate. The latter was hydrolyzed in the usual manner

Claims (1)

26 U1366 to give 2- [p- (2,2-dichlorocyclopropyl) pheno: xy] -2-methyl-propionic acid. This product was identical to the compound formed above under (b). Patent claim: Analogous process for the preparation of 2- (p-cyclopr opylphenoxy) -2-methylpropionic acid compounds of the general formula? pt ΪΓ k AQ ch 3 - ^> - OC-COOR IH R1 CH 2 wherein R means hydrogen or alkyl of 1-6 carbon atoms, Q means hydrogen or chlorine, R1 means hydrogen or alkyl of 2 '1-3 carbon atoms, and R and R are the same or different and mean fluorine, chlorine or bromine, or salts with bases of the compounds wherein R is hydrogen, characterized in (a) that a compound of formula 2 H in which R, R, R and Q have the above meaning are reacted with either (i) a mixture of chloroform, acetone and an alkali metal hydroxide at a temperature of 50-100 ° C to form a a compound of formula I wherein R is hydrogen, or (ii) a compound of formula CH, Br - C - C00R 'CH3 wherein R * is alkyl of 1-6 carbon atoms, in the presence of a base at a temperature of 50-150 ° C to form a compound of formula I wherein R is alkyl of 1-6 carbon atoms which, if desired, is hydrolyzed to give the corresponding free acid wherein R is hydrogen, or (b) a compound of the formula ~ r0 ~ -F- R