SK16482002A3 - Process for preparation of substituted 2-aryl alkane acids derivatives - Google Patents

Abstract

The invention relates to a new preparation method of derivatives of substituted 2-­arylaikanoic acids. The compounds are used for the preparation of histaminically active compounds and antiphlogistics. The compounds are prepared by reaction of suitably substituted a-halogen acetophenones with orthoformates with catalysis by mineral and Lewis acids.

Description

A process for the preparation of substituted 2-aryl alkanoic acid derivatives

Technical field

The invention relates to a novel process for the preparation of substituted 2-aryl alkanoic acid derivatives. The compounds are used in particular for the preparation of histamines and anti-inflammatory drugs.

BACKGROUND OF THE INVENTION

The invention relates to a process for the preparation of 2-aryl alkanoic acid derivatives of the general formula I,

wherein R ^{1 =} represents hydrogen, C ¹ to C ⁸ straight or branched alkyl, cyclopropyl, cyclopropanecarbamoyl, hydroxymethyl, formyl, carboxy, alkoxycarbonyl, 2-oxocyclopentylmethyl, halogen, OH, OQ wherein Q are hydroxyl protecting groups, phenyl, phenyl independently substituted with halogen in the 2- and / or 4, alkoxy C ¹ to C ⁴ at position 3 and / or 5, phenoxy, benzoyl, 2-thiophenoyl, 3-thienyl, R ² = H, C ¹ to C ⁴ straight or branched alkyl, benzhydryl, benzyl, R ⁴ , R ³ independently represent hydrogen or C ¹ -C ⁴ straight or branched alkyl, cyclopropyl, cyclopentyl and salts thereof

The classical reaction of alpha halo acetophenones in alcohols with Ag ⁺ salts e.g. with silver nitrate in ethanol to prepare 2-phenyl propionic acid esters (Cope, Graham; J.Amer.Chem.Soc .; 73; 1951; 4702, 4706. or Kimpe, Norbert De; Stevens, Christian; Tetrahedron; 46; 19; 1990; 6753-6770. An analogous reaction for the catalysis of mercury salts is described in dioxane (Larramona; CR Hebd. Seances Acad. Sci .; 237; 1953; 190, 192.) or in water (House, HO et al .; J. Org. Chem .: 41; 19; 1976; 3067-3076. Another method of catalysis is with AgSbF 6 and Ag ₂ CO ₃ (Kimpe, Norbert De; Buyck, Laurent De; Verhe, Roland; Schamp, Niceas; Chem.Ber .; 116; 11; 1983; 3631-3636.) Or zinc bromide in methanol at 115 ° C (Giacomo, Barbara Di; Coletta, Donato; Natalini, Benedetto; Ni, Ming-Hong; Pellicciari, Roberto; Farmaco; 54; 9; 1999; 600-610., Giordano, Claudio; Castaldi, Graziano; Uggeri , Fulvio; Gurzoni, Francesco; Synthesis; 4; 1985; 436-437.).

Other preparation methods are described in Piccolo, Oreste; Spreafico, Franca; Visentin, Giuseppina; Valoti, Ermanno .: J. Org. Chem .: 52; 1; 1987 10-14. Reaction of the α-chloropropiophenone acetal with catalysis of the Zn ²⁺ salts afforded the corresponding 2-arylpropionic acid. Thus, the preparation of optically active aryl propionic acids by rearrangement of optically active acetals to esters is also described. The method is limited to the preparation of alpha-aryl propionic acid derivatives. U.S. Pat. 4736061 is again necessary in the preparation of Naproxen for the ketalization step before the rearrangement. Optically active alpha-substituted aryl ketones need to be converted to the corresponding ketals prior to the switch to alpha-arylalkanoic acids also in EP 0081993.

The use of orthoformates in the catalysis of Tl ³⁺ salts to transform acetophenone derivatives is described by Higgins, Stanley D .; Thomas, Barry, CJ Chem. Soc. Perkin Trans. 1; 1982 235-242., Which transformed α-iodoacetophenone to 2-phenylpropionic ester in the presence of perchloric acid. The use of alkyl orthoformates and thallium trinitrate, catalysed by 70% perchloric acid for the rearrangement of haloketones, is also described: Yamauchi, Takayoshi; Nakao, Kenji; Fujii, z

Kyoichi; J. Chem. Soc. Perkin Trans. 1; 1987 1255-1258., Fujii, Kyoichi; Nakao, Kenji; Yamauchi, Takayoshi; Synthesis, 6; 1983 444-445. The thesis states that to achieve the required effect, it is necessary to use all components. The process for preparing alpha-arylalkanoic acids by rearrangement of alpha-sulfonyl acetals is described in Tet. Lett .: 22, 4305 (1981).

The starting alpha haloacetophenones applied in the processes are well known and in many cases commercially available, or the process for their preparation is widely documented. They may be prepared e.g. Friedel-Crafts reaction of suitable benzene derivatives with an acylating agent such as e.g. acid chlorides and are known as e.g. haloacetophenone derivatives. The selection of the alpha haloacetophenone protecting group is well known and is described e.g. in "Protective Groups in Organic Syntheses", T.W. Greene, Wiley (1981). Similarly, the cleavage of these protective groups, e.g. mineral acids, strong inorganic hydroxides and the like. In many cases, the orthoformates are commercially available or the methods for their preparation are generally known.

A disadvantage of the processes known to date (e.g., Synthesis, 6; 1983; 444.) is that minimal molar amounts of highly toxic Hg ²⁺ or Tl ³⁺ salts are used with the need to remove them from the product. This is particularly disadvantageous in the case of pharmaceutical intermediates. Other processes also employ expensive silver salts for production. The reactions described below (e.g., Synthesis; 4; 1985; 436.) are limited to the para-unsubstituted acetophenones, since subsequent reactions give rise to dealkylated products or cannot be used in the case of substitution with tert. alkyl. Thus, the processes described are limited to the preparation of unbranched arylalkanoic acids.

SUMMARY OF THE INVENTION

We have found that by the process according to the invention, by applying the orthoformate of the formula II to the haloacetophenone rearrangement under Lewis acid catalysis, these disadvantages of the prior art can be eliminated.

A process for the preparation of substituted 2-arylalkanoic acid derivatives of the general formula I,

wherein R 1 = represents hydrogen, C ¹ to C ⁸ straight or branched alkyl, cyclopropyl, cyclopropanecarbamoyl, hydroxymethyl, formyl, carboxy, alkoxycarbonyl, 2-oxocyclopentylmethyl, halogen, OH, OQ wherein Q are hydroxyl protecting groups, phenyl, phenyl independently substituted with halogen in the 2- and / or 4, alkoxy C ¹ to C ⁴ at position 3 and / or 5, phenoxy, benzoyl, 2-thiophenoyl, 3-thienyl, R ² = H, C ¹ to C ⁴ straight or branched alkyl, benzhydryl, benzyl, R ⁴ , R ³ is independently hydrogen or C ¹ -C ⁴ straight or branched alkyl, cyclopropyl, cyclopentyl and salts thereof based on the reaction of compounds of formula II,

II, /

wherein R ^{1 =} represents hydrogen, C ¹ to C ⁸ straight or branched alkyl, cyclopropyl, cyclopropanecarbamoyl, hydroxymethyl, formyl, carboxy, alkoxycarbonyl, 2-oxocyclopentylmethyl, halogen, OH, OQ where Q are hydroxyl protecting groups, phenyl, phenyl independently substituted with halogen in position 2 and / or 4, the alkoxy group C ¹ to C ⁴ in position 3 and / or 5, phenoxy, benzoyl, 2-thiophenoyl, 3-thienyl, R ⁴ , R ³ is independently hydrogen or C ¹ -C ⁴ or branched alkyl, cyclopropyl, cyclopentyl and X = halogen, hydroxy, OQ where Q are hydroxyl protecting groups, OSO ₂ R 'wherein R' is methyl, phenyl, tolyl with orthoformates of formula ΠΙ,

R ⁶ O

V-OR ⁵

T 5

R'O

III, wherein R ⁵ , R ⁶ , R ⁷ is independently C ¹ -C ⁸ straight or branched alkyl, C ¹ -C ⁴ alkyl substituted with an alkyloxy group wherein the alkyl comprises C ¹ -C ⁴ , vinyl, allyl, phenyl, benzyl with Lewis acids of formula IV,

MX

IV, wherein M represents hydrogen, lithium, zinc, magnesium, calcium, aluminum, boron, titanium, tin, manganese, iron, lanthanum, cerium, and X represents fluoro, chloro, bromo, iodo, CIO4 ', HSO4 *, SO4 ² ', OSO ₂ R' wherein R 'is methyl, trifluoromethyl, phenyl, tolyl.

The compounds of formula I are prepared for the purposes of the invention by reacting the compounds of formula ΠΙ and compounds II in anhydrous organic solvents. It will be appreciated that the reaction is carried out with at least a molequivalent ratio of compounds H and III. For the purposes of the invention, it is preferred that the reaction of the compounds H with the compounds ΙΠ is carried out without solvent in an excess of the compound IH. The excess použitΠ orthoformate used can be easily recovered by distillation. The reaction is carried out with 0.01 to 1.5 mol. Lewis acid equivalent of formula IV. Preferably, however, a catalytic amount of Lewis acid is used. After completion of the reaction, the Lewis acid is simply separated by filtration or washing with water or an alkali solution such as sodium hydroxide, sodium bicarbonate. When using solvents, they are selected from the group of solvents such as methanol, ethanol, propanol, toluene, dioxane, tetrahydrofuran or mixtures thereof. These reactions are carried out at temperatures from 50 ° C to the boiling point of the solvent, preferably at the boiling point of the solvent, and the reaction time ranges from 2 to 48 hours. Temperatures allowing control of the formation of the undesired product are preferred. Such a reaction allows the product to be isolated without increased purification requirements. Purification of the product may be accomplished by distillation under reduced pressure or by crystallization. Column "flash" chromatography is preferred.

The advantage of the process of the invention over the prior art is that it is simple to carry out using readily available haloacetophenones, avoiding toxic or expensive salts, without the need to prepare and isolate the acetals of the starting haloacetophenones. Another advantage is the high purity of the intermediates and the product, with the possibility to also prepare alpha-aryl tert. alkyl acids (e.g.: 2-aryl-2-alkylalkanoic acids) having an active compound content of above

98%, which is sufficient for the preparation of a medicinal substance with the corresponding quality declared in pharmacopoeias and easy industrial feasibility of the mentioned reaction (with the possibility of process control, automation, etc.)

Hereinafter, the patent is described in the examples without being limited thereto.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2- (4-Ethylphenyl) -2-methylpropionic acid methyl ester

5.25g (20.57mmol, 1mol eq) of 2-bromo-1- (4-ethylphenyl) -2-methylpropan-1-one was dissolved in 16.3ml (159.1mmol, 7.7mol eq) of trimethyl orthoformate. After addition of 153.2mg (0.68mmol, 3mol%) of zinc bromide (anhydrous), the mixture was heated to reflux for 36 h under stirring under an inert Ar atmosphere. The reaction mixture was concentrated by evaporation of the volatiles, diluted with 50 ml of diethyl ether, filtered and freed from solvents by vacuum distillation. The obtained 4.08g of crude product was a yellow oil. The product was purified by vacuum distillation (bp: 85 ° C / 3Pa). After distillation, 3.84g (91%) of 2- (4-ethylphenyl) -2-methylpropionic acid methyl ester was obtained as a colorless oil.

1 H-NMR (CDCl ₃ ) 7.25 (m, 2H, HC _Ar ); 7.15 (m, 2H, HC _Ar ); 3.64 (s, 3H; MeOOC-); 2.63 (q, 2H, J = 7.7, -CH ₂ -C _Ar ); 1.57 (s, 6H, 2 * Me-); 1.23 (t, 3H, J = 7.7, Me -).

Example 2

2-Cyclopropyl-2- (4-ethyl-phenyl) -propionic acid methyl ester

Using a procedure analogous to Example 1 except that 4.1 g (14.6 mmol) of 2-bromo-2-cyclopropyl-1- (4-ethylphenyl) propan-1-one was used, 3.2g (13.8 mmol, 95%) of 2-cyclopropyl acid methyl ester was obtained 2- (4-ethylphenyl) propionic acid.

Example 3

2- (4-Ethylphenyl) -2-methylpropionic acid methyl ester

1.7g (8.8mmol) of 1- (4-ethylphenyl) -2-hydroxy-2-methylpropan-1-one was dissolved in 5.2ml trimethyl orthoformate. After adding 0.1 ml of horse. perchloric acid, the mixture was heated to reflux for 48 h under stirring under an inert Ar atmosphere. The reaction mixture was extracted with 2 x 1 mL NaHCO ₃ sat. aqueous solution, dried on standing over Na ₂ SO 4, filtered and concentrated by evaporation of the volatiles by vacuum distillation. The obtained 1.3g of crude product was purified by vacuum distillation. After distillation, 1.8g (8.7mmol, 99%) of 2- (4-ethylphenyl) -2-methylpropionic acid methyl ester was obtained.

Example 4

2- (4-Chloro-phenyl) -2-methyl-propionic acid ethyl ester

Using a procedure analogous to Example 3 except that 1.10 g (5.2 mmol) of 1- (4-chlorophenyl) -2-methoxy-2-methylpropan-1-one and 5.4 ml of triethyl orthoformate were obtained, yielding 1.0 g (4.46 mmol, 86%) of the ethyl ester. 2- (4-chlorophenyl) -2-methylpropionic acid.

Example 5

2- (3-Phenoxyphenyl) -2-methylpropionic acid butyl ester

1.8g (5.8mmol) of 2-bromo-1- (3-phenoxyphenyl) -2-methylpropan-1-one was dissolved in 5.5ml of tributylorthoformate and 15ml of butanol. 0.15 ml of boron trifluoride etherate was added and the mixture was heated to 50 ° C for 48 hours with stirring and under an inert Ar atmosphere. The reaction mixture was concentrated by evaporation of the volatiles in vacuo, diluted with 50 mL of diethyl ether, and washed with 2 x 15 mL of 10% sodium bicarbonate solution. The organic layer was dried by standing over sodium sulfate. After filtration and removal of solvent by vacuum distillation, 1.9 g of crude product was obtained. The product was purified by column chromatography on silica gel eluting with diethyl ether-isohexane 1.0: 2.5. 1.2g (3.8mmol, 66%) of 2- (3-phenoxyphenyl) -2-methylpropionic acid butyl ester was obtained.

Example 6

2- (4-Isobutylphenyl) -2-propionic acid methyl ester

Using a procedure analogous to Example 1 except that 3.2g (11.9mmol) of 2-bromo-1- (4-isobutylphenyl) propan-1-one was used, 2.5g (11.3mmol, 95%) of 2- (4-isobutylphenyl) -2-methyl ester was obtained propionate.

Example 7 α, α-dimethyl-4-hydroxyphenethyl benzyl ether

Using a procedure analogous to Example 1 except that 1.8 g (5.2 mmol) of 2-bromo-2-benzyloxymethyl-1- (4-hydroxyphenyl) propan-1-one was used, 0.7 g of α, α-dimethyl-4-hydroxyphenethyl benzyl ether was obtained.

Industrial usability

The invention is useful in the preparation of pharmaceutical substances, in particular in the preparation of substituted 2-arylalkanoic acid derivatives which are used in the preparation of active compounds and anti-inflammatory drugs.

Claims (4)

s PATENT CLAIMS A process for the preparation of substituted 2-arylalkanoic acid derivatives of the general formula I wherein R 1 = hydrogen, C ¹ to C ⁸ straight or branched alkyl, cyclopropyl, cyclopropanecarbamoyl, hydroxymethyl, formyl, carboxy, alkoxycarbonyl, 2-oxocyclopentylmethyl, halogen, OH , an OQ group wherein Q are hydroxyl protecting groups, phenyl, phenyl independently substituted with halogen in the 2- and / or 4, alkoxy C ¹ to C ⁴ at position 3 and / or 5, phenoxy, benzoyl, 2-thiophenoyl, 3-thienyl R ² = hydrogen, C ¹ -C ⁴ straight or branched alkyl, benzhydryl, benzyl, R ⁴ , R ³ independently represent hydrogen or C ¹ -C ⁴ straight or branched alkyl, cyclopropyl, cyclopentyl and salts thereof, characterized in that: the compounds of formula Π are reacted, Wherein R ^{1 =} hydrogen, C ¹ to C ⁸ straight or branched alkyl, cyclopropyl, cyclopropanecarbamoyl, hydroxymethyl, formyl, carboxy, alkoxycarbonyl, 2-oxocyclopentylmethyl, halogen, OH, OQ wherein Q are hydroxyl protecting groups, phenyl, phenyl independently by halogen in the 2- and / or 4, alkoxy C ¹ to C ⁴ at position 3 and / or 5, phenoxy, benzoyl, 2-thiophenoyl, 3-thiophenyl, R ^4, R ³ is independently hydrogen or C ¹ to C ^{4 is a} straight or branched alkyl, cyclopropyl, cyclopentyl and X - represents halogen, hydroxy, OQ where Q is hydroxyl protecting groups, a group of the formula OSO2R 'wherein R' is methyl, phenyl, tolyl with orthoformates of the formula ΙΠ, R ⁶ O Vor ⁵ R ⁷ OM wherein R ^5, R ^6, R ⁷ are independently C ¹ to C ⁸ straight or branched alkyl, C ¹ to C ⁴ alkyl group substituted with an alkyloxy group wherein the alkyl group comprises ^C1 to ^C4, vinyl, allyl, phenyl , benzyl with Lewis acids of formula IV, MX IV where M represents hydrogen, lithium, zinc, magnesium, calcium, aluminum, boron, titanium, tin, manganese, iron, lanthanum, cerium and X represents fluorine, chlorine, bromine, iodine, ClOT, HSO ₄ ', SO4 ² ', a group of the formula OSO ₂ R' wherein R 'is methyl, trifluoromethyl, phenyl, tolyl. A process for the preparation of compounds of formula I according to claim 1, characterized in that R ¹ is preferably ethyl and R ² , R ³ , R ⁴ is preferably methyl. A process for the preparation of compounds of formula I according to claim 1, characterized in that R ⁴ is preferably hydrogen, R ¹ is preferably 2-methylpropyl and R ³ , R ² is preferably methyl. 4. A process for the preparation of compounds of the formula I as claimed in claim 1, characterized in that the reaction mixture is heated to 50 DEG C. up to the boiling point.