JPS6041668B2 - α-thio-α-(2-fluoro-4-biphenylyl)carboxylic acid derivative - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula h■□ -COOR2-(I) (wherein R is hydrogen or a methyl group, R'' is an alkyl group or an aryl group, and R'' is hydrogen or It is an alkyl group.

) It relates to an α-thio α-(2-fluoro-4-biphenylyl)carboxylic acid derivative represented by: A compound represented by the above general formula (I) in which R is hydrogen can be easily converted into a compound of general formula (I) in which R is a methyl group by treatment with a methylating agent in the presence of a base.

The compound of general formula (I) in which R is a methyl group can be hydrolyzed if desired, and then subjected to reductive desulfurization to obtain
α-(2-fluoro-4-biphenylyl)propionic acid can be obtained. This compound, known as flupiprofen, has significant anti-inflammatory, analgesic, and antipyretic effects (S, S, Adams, F, McCu
Ilough, J.S.

Nicholson9Ar2neim, -Forsch
, DragRes), ) Giant, 1786 (1975)). The following method has been proposed as a method for producing α-(2-fluoro-4-biphenylyl)propionic acid (flupiprofen). The Ullmann reaction between 4-bromo-3-nitroacetophenone and iodobenzene produces 4
, -acetyl-2-nitrobiphenyl is obtained, this nitro group is reduced to an amino group, and this amino group is converted to fluorine by a Seeman reaction to obtain 4-
Acetyl-2-fluorobiphenyl is produced.

Further, this 4-acetyl-2-fluorobiphenyl is heated with morpholine and sulfur to form a thiomorpholide through the so-called Wilgerrodt reaction, and then hydrolyzed in a sulfuric acid-acetic acid system to lead to 2-fluoro-4-biphenyliacetic acid. This was converted to ethyl ester with ethanol sulfuric acid, then converted to α-ethoxycarbonyl-(2-fluoro-4-biphenylyl)ethyl acetate with diethyl sodium carbonate ethoxide, and this was further methylated with dimethyl sulfate to give the corresponding α-methyl ester. Obtain an incarnation. The ester group of this α-methylated product is hydrolyzed with sodium hydroxide to form a dicarboxylic acid, and then decarboxylated at a high temperature of 180 to 200°C, the desired α-(2-fluoro-4-biphenylyl)propion is obtained. Acid is obtained [USP 3,755,4
27 (1973)]. However, this conventional method requires seven steps from the intermediate raw material 4-acetyl-2-fluorobiphenyl, and also requires reactions under harsh conditions such as the Will-Gerott reaction, and high-temperature reactions such as the final step decarboxylation. This method is not suitable as an industrial manufacturing method. The inventors of the present invention have made extensive studies to overcome such difficulties, and have developed a completely new method in which the number of steps is short and each step proceeds under mild conditions by using the compound of the present invention. This has led to the completion of the present invention.

The compounds of the present invention can be prepared according to the following formula.

This step is carried out by combining 3-fluoro-4-phenylbenzaldehyde (■) with the general formula (wherein R1 is an alkyl group or an aryl group).

) with formaldehyde mercaptal S-oxide in the presence of a base. In this reaction, common organic solvents such as dimethylformamide, tetrahydrofuran, dioxane, methanol, ethanol, and benzene can be used as the reaction solvent. When formaldehyde mercaptal S-oxide used as a raw material is a liquid substance, the reaction proceeds smoothly even without the use of a solvent. Further, as the base, relatively strong bases such as sodium hydroxide, potassium hydride, Triton B1 sodium hydroxide, potassium hydroxide, etc. are preferable. The reaction temperature is room temperature to 150°C, but 50 to 110°C is particularly suitable. Under the above reaction conditions, ketene mercaptal S-oxide represented by the general formula (■) can be formed. Step B This step involves reacting the compound of general formula (■) with an acid chloride.

Examples of acid chlorides include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, acetyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, etc.; Thionyl chloride and phosphorus oxychloride are preferred from the viewpoint of high yield.

In carrying out this step B, the raw materials are used in approximately S equimolar amounts, and the reaction is preferably carried out in an aprotic solvent such as methylene chloride, chloroform, tetrahydrofuran, ether, or benzene. The reaction is carried out smoothly at a temperature of -100°C to room temperature, but from the viewpoint of ease of operation, the temperature is preferably -80°C to room temperature. Further, it is preferable that a base be present in order to supplement hydrogen chloride produced as a by-product in step B. As the base, organic bases such as diethylamine, dicyclohexylamine, pyridine, and triethylamine can be suitably used. The compound formed in step B is chloroketene mercaptal represented by the above general formula (■), but this compound is isolated or subjected to step C as a crude product without being completely isolated. be able to.

Step C In Step C, a compound represented by the above general formula (■) is combined with the general formula R2OH (wherein R2 is an alkyl group).

) in the presence of an acid is an essential requirement. As the acid, inorganic acids such as sulfuric acid, perchloric acid, hydrogen chloride, and hydrogen bromide, and organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, and trichloroacetic acid can be suitably used. The amount of acid used is sufficient to be the so-called contact amount. In carrying out this step, there is no problem in using a solvent that does not participate in the reaction, but an excess amount of alcohol used as a reaction reagent can be used as a solvent.

Although the reaction proceeds smoothly at a temperature of room temperature to 150° C., it is preferable to carry out the reaction at the reflux temperature of the reaction system from the viewpoint of ease of joining.

By the above operation, it is expressed by the general formula (1″), and R2
can form ester compounds where is an alkyl group. If desired, the ester can be converted into the corresponding carboxylic acid (1'', R2=hydrogen) by alkaline hydrolysis.Step D This step involves adding a methylating agent to the compound of general formula (1'') in the presence of a base. It causes a reaction.

Examples of the base used include metal hydrides such as sodium hydroxide and potassium hydride, organic thio compounds such as methyllithium, butyllithium, and lithium diethylamide, alkali metal amides such as sodium amide, naphthalene-sodium, and the like. Further, as the methylating agent, methyl halides such as methyl iodide, or active methyl esters such as dimethyl sulfate, trimethyl phosphoric acid, and methyl fluorosulfonate can be used. In the general formula (1''), when R2 is an alkyl group, the base and methylating agent are used in an amount equivalent to S equivalent to the starting compound, and when R2 is hydrogen, it is sufficient to use 2 equivalents of the base. be.

In carrying out the reaction, it is preferable to use an aprotic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, or 1,2-dimethoxyethane, and the reaction proceeds smoothly at 0 to 100°C. The above reaction forms an α-thio α-(2-fluoro-4-biphenylyl)propionic acid derivative (pi), but if desired, the ester can be converted to the corresponding carboxylic acid by alkaline hydrolysis. can.

Alkaline hydrolysis in steps C and D can be easily carried out by using potassium carbonate or sodium hydroxide in an equivalent molar amount or more based on the raw material compound, and using water, alcohol, water-1,2-dimethoxyethane or water-tetrahydrofuran as the solvent. can be achieved.

Under the above conditions, a desired α-thio α-(2-fluoro-4-biphenylyl)carboxylic acid derivative represented by general formula (1) can be formed. The present invention will be explained in more detail below with reference to Reference Examples and Examples.

Example 1 Under an argon atmosphere, 133 mg of 3-fluoro-4-phenyl bezaldehyde was dissolved in 1 mt of t-butanol,
109 mg of formaldehyde dimethyl mercaptal S-oxide was added.

Potassium t-butoxide solution in t-butanol (a).
51) at room temperature for 6 hours, then at 50°C.
Stir in between. 0.5 ml of water and 50 ml of methylene chloride were added, and the mixture was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, it was separated by column chromatography (Florisil, ethyl acetate) and 1-methylsulfinyl-1
-Methylthio 2-(2-fluoro-4-biphenylyl)ethylene 119 mg was obtained. Yield 59%. Pale yellow oily substance IR (Neat): 3030, 2900, 1481
,1413,1127,1060,764,695cm
-1. NMR (CDCl3): δ2.30 (S, 3H)
,2.72(S,3l(),7.16~7.90(M,
9l(). MS: m/E29O (M+-16,50%)
, 243 (25%), 229 (18%), 228 (reference peak), 18.3 (20%), 114 (22%) Cl
Calculated value as 6Hl5S2OF: C, 62.72; H, 4.93%. Actual value: C
,62.38:H4.83%,C,62.36:H,4
．． 86%. Example 2 Chloroform was cooled to 0°C under an argon atmosphere. 1m
1, 1-methylsulfinyl-1-methylthio2-
(2-fluoro-4-biphenylyl)ethylene 225m
9 and 0.14 ml of triethylamine were dissolved.

107 mg of thionyl chloride was added dropwise, and the solution was heated on ice for 60 minutes.
Then, the mixture was stirred at room temperature. Chloroform was added to the reaction solution, washed with water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the product was separated by column chromatography (Florisil, benzene) to obtain 168 m9 of 1,1-(bis(methylthio)-2-chloro-2-(2-fluoro-4-biphenylyl)ethylene). Yield: 70 %. Pale yellow oily substance (please leave this in the refrigerator to solidify,
Melting point 68.5-69. Light brown crystals were obtained at ℃. )IR(
Treat). 3048, 2910, 1553, 14
86, 1410, 1277, 1159, 1128, 80
7,698,5630-1. NMR (CDCl3): δ
2.15 (S, 3H), 2.41 (S, 3H), 7.0
4-7.59(M, 8l().MS:m/E326(M
++2, 38%), 324 (M+, 90%), 264 (
38%), 262 (reference peak), 228 (23%),
227 (52%), 226 (31%), 185 (24%
), 183 (71%), 47 (22%), 45 (31%
). Calculated value as Cl6Hl4S2FCI: C, 59. l6:H, 4.34%. Actual value: C
, 59.38:H, 4.37%. Example 3 1-Methylsulfinyl-1-methylthio-2-(2-fluoro-4
-Biphenylyl)ethylene 119m9 to chloroform 11
．． 5 mt, 0.1 mL of triethylamine and 84 mg of thionyl chloride were added under ice cooling under an argon atmosphere, and the mixture was stirred for 1 hour.

After adding 30ml of chloroform to the reaction solution, add 10ml of water.
Washed twice with After drying the reaction solution over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 165 mg of an oily substance. After confirming by NMR that this was 1,1-bis(methylthio)-2-chloro-2-(2-fluoro-4-biphenylyl)ethylene, anhydrous methanol 5
0.1 mt of methanol saturated with hydrogen chloride was added, and the mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, and the residue was separated by column chromatography (silica gel, 1:1 mixed solvent of n-hexane and benzene) to obtain 89 mg of methyl α-methylthio(2-fluoro-4-biphenylyl)acetate. Yield 79%. Colorless oily substance (This was allowed to stand in the refrigerator to solidify to obtain colorless crystals with a melting point of 50 to 51°C.

)IR (Neat) 3045, 3020, 2940,
2910, 1740, 1483, 1418, 1268,
1153,1010,767,69F3Cm-1. N.M.
R(CDCl3): δ2.23(S,3FI), 3.8
6 (S, 3ll), 4.59 (S, lH), 7.10~
7.80 (M, 8H), MS: m/E29O (M+, 1
8%), 244 (21%), 243 (24%), 231
(Reference peak), 215 (53%), 185 (47%)
, 183 (47%). Calculated value as Cl6Hl5O2SF: C, 66. l9:H, 5.2l%. Actual value: C, 6
5.64:H,5. l2%. Example 4 168 m9 of 1,1-bis(methylthio)-2-chloro-2-(2-fluoro-4-biphenylyl)ethylene was dissolved in 2 m of anhydrous methanol.
1, 0.1 ml of methanol saturated with hydrogen chloride was added, and the mixture was heated under reflux for 4 hours.

After the solvent was distilled off under reduced pressure, 50 mt of methylene chloride was added and the mixture was dried over anhydrous magnesium sulfate. After distilling off the solvent, 129 mg of an oily substance was obtained. This was subjected to column chromatography (silica gel, n-hexane and benzene).
:1 mixed solvent) to obtain 86 mg of methyl α-methylthio(2-fluoro-4-biphenylyl)acetate. Yield 57%. Example 5 α-Methylthio (2-fluoro-4-biphenylyl)
89 mg of methyl acetate to 1 ml of anhydrous dimethyl sulfoxide
Soaked, 18 mg of sodium hydride under argon atmosphere
(containing 55%) was added under ice cooling and stirred at room temperature for 3 minutes.

0.1 mL of methyl iodide was added and reacted at room temperature for 40 minutes. Ammonium chloride aqueous solution (200mg in 30mt water)
After adding the solution (dissolved in water), extraction was performed four times with 20 mL of ether, and the organic layer was washed three times with 10 mL of water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was separated by column chromatography (silica gel, 1.1 mixed solvent of n-hexane and benzene) to obtain 69 m9 of methyl α-methylthio α-(2-fluoro-4-biphenylyl)propionate. Yield 74%. Colorless oily substance (this should be left in the refrigerator to solidify, with a melting point of 6
Colorless crystals with a temperature of 4.5 to 66.5°C were obtained.

IR (Neat): 2980, 2948, 2911, 1
732, 1487, 1410, 1242, 1103, 7
68,700 crft-1. NMR (CDCl3): δ
1.80 (S, 3H), 2.00 (S, 3ll), 3.
75 (S, 3H) 7.00-7.62 (M, 8] 1).
MS: m/E3O4 (M+, 6%), 257 (56%)
, 245 (52%), 229 (44%), 199 (25
%), 198 (36%), 197 (reference peak), 19
6 (33%), 170 (23%), 43 (27%),
15 (46%). Calculated value as Cl7Hl7O2SF: C, 67. O8:H, 5.63%. Actual value: C, 6
7.27:H, 5.63%. Example 6 58 mg of methyl α-methylthio α-(2-fluoro-4-biphenylyl)propionate was dissolved in 1.0 mt of methanol, and 0.0 mt of water was dissolved.
．． 5 ml and 547,719 potassium hydroxide were added.

After reacting at 60° C. for 3 hours, 30 ml of water was added and washed with 10 ml of methylene chloride.

Add 2.5 ml of concentrated hydrochloric acid to the aqueous layer, and add 20 ml of ether to
Extracted twice. The organic layer was dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, α-methylthio α-
(2-Fluoro-4-biphenylyl)propionic acid was obtained almost quantitatively. Colorless crystal melting point: 141.5-143.

C (from n-hexane and benzene). 1R (Nune 1)
:1688,1274,767.721,699α-1
．． NMR (CDCl3): δ1.82 (S, 3H),
2.07 (S, 3H), 6.97-7.68 (M, 8H
), 10.53 (Bs, lH). MS:2901T1/
e (M+, 22.6), 245 (31.8), 243 (
89.1), 198 (24.8), 197 (89.2)
, 196 (26.8), 43 (93.7). Cl6Hl
Calculated value as 5O2RS: C, 66. l9:H, 5.2l%. Actual value: C, 66.4O:H, 5.2l%. Reference Example 57 m9 of α-methylthio α-(2-fluoro-4-biphenylyl)propionic acid was dissolved in 1 Tr11 of acetic acid, 6 m9 of anhydrous copper sulfate and 32 m9 of zinc powder were added, and the mixture was heated under reflux for 1 hour.

Claims (1)

[Claims] 1 α-thio-α-(2-fluoro-4-biphenylyl)carboxylic acid derivative represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is hydrogen or a methyl group] , R^1 is an alkyl group or an aryl group, and R^2 is hydrogen or an alkyl group. ].