Method For Preparing Substituted Phenylacetic Acid Derivative

Abstract

The invention belongs to the pharmaceutical manufacturing field, which relates to a novel process for the preparation of substituted phenylacetic acids derivatives, especially relates to the preparation of 2-(4-(2-oxocyclopentyl)phenyl)propanoic acid. The process for the preparation of the precursor form of loxoprofen which use 1,4-di-halobenzyl compounds or disubstituted benzyl compounds as starting material, is through the substitution reaction of cyclopentanone groups or its precursor compounds.

##STR00001##

Wherein X is halogen, L.sub.1 is a suitable leaving group selected from halogen, OH, OMs, OTs, OTf and the like; L.sub.2 is a suitable leaving group selected from halogen, CN, OH, CH.sub.2OH, CHO, CH.sub.3NO.sub.2, ester group, NR.sub.4R.sub.5, OTf, OTs, OMs, CCR.sub.6, CCR.sub.7 and the like, wherein R.sub.4, R.sub.5, R.sub.6, R.sub.7 are short chain alkyl groups; Z is cyclopentanone group and its precursor form selected from

##STR00002##

and the like; R.sub.3 is short chain alkyl groups. L.sub.3 is a suitable leaving group selected from halogen, OH, OMs, OTs, OT.sub.f and the like, or organometallic groups. The invention also include the detailed procedure to convert the precursor compounds of cyclopentanone group to cyclopentanone, followed by the transformation of the precursor compounds of loxoprofen to loxoprofen.

Claims

1. A compounds of formula G and formula G.sub.1: ##STR00038## wherein R.sub.1 is hydrogen or short chain alkyl groups; R.sub.2 is halogen, CN, OH, CH.sub.2OH, CHO, CH.sub.3NO.sub.2, ester group, NR.sub.4R.sub.5, OTf, OTs, OMs, CCR.sub.6, or CCR.sub.7, wherein R.sub.4, R.sub.5, R.sub.6, R.sub.7 are short chain alkyl groups; Z is cyclopentanone group and its precursor form selected from ##STR00039## R.sub.3 is short chain alkyl groups; The definition of L.sub.2 is same with R.sub.2. L.sub.3 is a suitable leaving group selected from halogen, OH, OMs, OTs, OT.sub.f and the like, or organometallic groups.

2. A compound of formula III: ##STR00040## wherein R.sub.1 is hydrogen or short chain alkyl groups; R.sub.2 is the group selected from halogen, CN, OH, CH.sub.2OH, CHO, CH.sub.3NO.sub.2, ester group, NR.sub.4R.sub.5, OTf, OTs, OMs, CCR.sub.6, CCR.sub.7 and the like, wherein R.sub.4, R.sub.5, R.sub.6, R.sub.7 are short chain alkyl groups; R.sub.3 is short chain alkyl groups.

3. The compound refer to claim 2 with the formula as III-1, III-2 and III-3: ##STR00041## wherein X is halogen; R.sub.1 and R.sub.3 is short chain alkyl groups.

4. A preparation method of formula G and formula G1 refer to claim 1. Wherein by the reaction of 1,4-di-halobenzyl compounds or disubstituted benzyl compounds with the precursor of cyclopentanone group. The reaction scheme is shown as follows: ##STR00042## wherein X is halogen, L.sub.1 is halogen, OH, OMs, OTs, OTf; L.sub.2 is same with the definition of R.sub.2 in claim 1; The definition of Z is same with above in claim 1.

5. The preparing method refer to claim 4. Wherein the disubstituted benzyl compounds is prepared from 1,4-di-halobenzyl compounds or 1,4-dihydroxylbenzyl alcohol. The reaction scheme is shown as follows: ##STR00043## wherein X is halogen, R.sub.3 is short chain alkyl groups, L.sub.1 or L.sub.2 is OMs, OTs, OTf, CH.sub.3NO.sub.2, CN, CC or ##STR00044##

6. Formula G and formula G.sub.1 of claim 1. Wherein the preparation method of loxoprofen include the decarboxylation step.

7. According to claim 6, the sequence of decarboxylation is from the first step to the second step and the third step.

8. A preparation method of formula III-1 of claim 3. Wherein the reaction between the 1,4-bishalobenzyl compounds and alkyl 2-oxocyclopentanecarboxylate. The reaction scheme is shown as follows: ##STR00045## wherein X is halogen, R.sub.3 is short chain alkyl groups.

9. A preparation method of formula III-2 of claim 3 is prepared by cyanation reaction with formula III-1. The reaction scheme is shown as follows: ##STR00046## wherein X is halogen, R.sub.3 is short chain alkyl groups.

10. A preparation method of formula III-3 of claim 3 is prepared by alkylation of formula III-2. The reaction scheme is shown as follows: ##STR00047## wherein R.sub.1 and R.sub.3 are short chain alkyl groups.

11. A preparation method of formula III-3 of claim 3. Wherein formula III-3 is prepared by the substitution, cyanation and alkylation reaction in any order. The reaction scheme is shown as follows: ##STR00048## ##STR00049## wherein X is halogen, R.sub.1 and R.sub.3 are short chain alkyl groups.

12. (canceled)

13. (canceled)

14. A method for preparing loxoprofen or its derivatives can be proceeded by substitution, decarboxylation, cyanation, alkylation and hydroxylation reactions. The reaction scheme is shown as follows: ##STR00050## wherein X is halogen, R.sub.1 and R.sub.3 are short chain alkyl groups.

Description

DETAILED DESCRIPTION

[0042] ##STR00030##

Example 1

[0043] 1,4-bis(chloromethyl)benzene (30 g, 0.17 mol), DMF (150 g, 4.74 vol) and sodium carbonate (19.8 g, 0.19 mol) were added to a 250 mL round bottom flask. The reaction mixture was stirred and heated to 60 C. Then methyl 2-oxocyclopentanecarboxylate (22.1 g, 0.16 mol) was added to the reaction mixture dropwise in one hour, afterwards maintain the reaction temperature for 30 minutes. Then the reaction mixture was cooled to 25 C., filtrated and mixed the mother liquor with water. The solid is separated. The mother liquor was extracted with EtOAc. Concentrate the organic phase to give the compound of Formula III-1 (47.0 g) with a yield of 83.3% (HPLC purity of 83.3%) (wherein R.sub.1 is H, R.sub.2 is Cl, R.sub.3 is methyl).

##STR00031##

Example 2

[0044] The compound of Formula III-1 (wherein R.sub.1 is H, R.sub.2 is Cl, R.sub.3 is methyl) (10 g, 0.036 mol), acetonitrile (50 g, 5 vol), NaCN (1.9 g, 0.039 mol) were added to a 100 mL round bottom flask. The reaction mixture was refluxed. When starting material disappeared, the reaction mixture was cooled to 25 C. After filtration and evaporation, adding EtOAc and water while stirring. The organic layer was separated and evaporated to give the compound of Formula III-2 (9.8 g) with the yield of 94.7% (HPLC purity of 93.7%) (wherein R.sub.1 is H, R.sub.2 is CN, R.sub.3 is methyl).

##STR00032##

Example 3

[0045] The compound of Formula III-2 (wherein R.sub.1 is H, R.sub.2 is CN, R.sub.3 is methyl) (30 g, 0.11 mol), dimethyl carbonate (24.8 g, 0.28 mol), K.sub.2CO.sub.3 (1.5 g, 0.011 mol), and tetrabutylammonium bromide (1.8 g, 0.006 mol) were added to an autoclave. The reaction mixture was stirred under 130-140 C. for 10 h. The pressure of the autoclave is approximately 0.3 Mpa. Then the reaction mixture was cooled to 28 C., quenched by adding small amount of benzaldehyde. Filtration and the filter cake was washed by EtOAc, 1 N HCl and water. The organic layer was separated and evaporated to give the compound of Formula III-3 (32.6 g) with the yield of 80.5% (HPLC purity of 78.1%) (wherein R.sub.1 is methyl, R.sub.2 is CN, R.sub.3 is methyl).

##STR00033##

Example 4

[0046] The compound of Formula III-3 (wherein R.sub.1 is methyl, R.sub.2 is CN, R.sub.3 is methyl) (18.5 g, 0.065 mol) and H.sub.2SO.sub.4 (80 wt. % solution in water, 16 g, 0.13 mol) were added to a 100 mL round bottom flask. The reaction mixture was stirred under 80-90 C. for 5 h. When the starting material disappeared, the reaction mixture was cooled to 25 C., adding EtOAc to extract. The organic layer was washed by water and evaporated to give loxoprofen with a yield of 96.2% (HPLC purity of 93.7%).

##STR00034##

Example 5

[0047] The compound of Formula III-1 (wherein X is Cl, R.sub.3 is methyl) (21 g, 0.075 mol), AcOH (37 mL, 2 vol) and HCl (35 wt. % solution in water, 63 mL, 3 vol) were added to a 100 mL round bottom flask. The reaction mixture was stirred under 90-95 C. for 2.5-3.5 h. When starting material disappeared, the reaction mixture was cooled to 15-25 C. afterwards added water and EtOAc. The organic layer was washed with 5% NaHCO.sub.3 solution, saturated NaCl solution and water. The organic layer was separated and evaporated to give the compound of Formula IV (19.7 g) with the yield of 96.1% (HPLC purity of 81.4%) (wherein X is Cl).

##STR00035##

Example 6

[0048] The compound of Formula IV (wherein X is Cl) (10 g, 0.045 mol), acetonitrile (50 g, 5 vol), NaCN (2.4 g, 0.049 mol) were added to a 100 mL round bottom flask. The reaction mixture was refluxed. When starting material disappeared, the reaction mixture was cooled to 25 C. After filtration and evaporation, adding EtOAc and water to stir. The organic layer was washed by saturated NaCl solution and water; Then the organic layer was separated and evaporated to give the compound of Formula V (9.68 g) with the yield of 94.7% (HPLC purity of 93.7%).

##STR00036##

Example 7

[0049] The compound of Formula V (30 g, 0.14 mol), dimethyl carbonate (31.5 g, 0.35 mol), K.sub.2CO.sub.3 (1.5 g, 0.011 mol), and tetrabutylammonium bromide (1.8 g, 0.006 mol) were added to a 100 mL autoclave. The reaction mixture was stirred under 130-140 C. for 10 h. The pressure of autoclave is approximately 0.3 Mpa. Then the reaction mixture was cooled to 28 C., and quenched by adding small amount of benzaldehyde. Filtration and the filter cake was washed by EtOAc, 1 N HCl and water. The organic layer was separated and evaporated to give the compound of Formula VI (31.7 g) with a yield of 80.4% (HPLC purity of 81.1%) (wherein R.sub.1 is H).

##STR00037##

Example 8

[0050] The compound of Formula VI (wherein R.sub.1H) (18.5 g, 0.081 mol) and AcOH (37 mL, 2 vol) and HCl (35 wt. % solution in water, 55.5 mL, 3 vol) were added to a 100 mL round bottom flask. The reaction mixture was stirred under 90-95 C. for 2.5-3.5 h. When starting material was disappeared, the reaction mixture was cooled to 15-25 C. and was added water and EtOAc. The organic layer was washed with saturated NaCl solution and water; The organic layer was separated and evaporated to give loxoprofen (20.5 g) with the yield of 96.2% (HPLC purity of 93.7%).