JPS6361297B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for removing a carboxylic acid protecting group, in which carboxylic acid amide derivatives derived from 5,6-dihydrophenanthridine are deprotected by treatment with an oxidizing agent to produce carboxylic acids. Protection of carboxylic acids is an important issue in organic synthesis reactions, and is an indispensable issue to overcome in order to complete the synthesis of molecules having a variety of functional groups. Conventionally, regarding the protection and deprotection of carboxylic acids, the literature "E. Haslam, Chemistry and Industry"
and industry), 610 (1979); E. Haslam, Tetrahedron (E.Haslam, Tetrahedron), 36 ,
2409 (1980), research is being conducted from multiple directions. The typical protection method is to convert it into an ester, but the protection and deprotection reactions are carried out under acidic or basic conditions. It cannot be used in unstable and complex molecules. The present inventors have overcome these drawbacks, discovered a very unique protecting group that can be oxidatively deprotected, and is stable under acidic or basic conditions, and have arrived at the present invention. That is, the present invention has the following formula [], [In the formula, R is C ₁ to C ₁₀ which may have a substituent
represents an alkyl group or phenyl group. ] Characterized by reacting a carboxylic acid amide derivative represented by the following with an oxidizing agent, the following formula [], RCOOH...[] [wherein R is the same as defined above]. ] This is a method for producing carboxylic acids represented by the following. The carboxylic acid amide derivative represented by the above formula [], which is a raw material of the present invention, can be produced by a dehydration condensation reaction between the corresponding carboxylic acid represented by the above formula [] and 5,6-dihydrophenanthridine. I can do it. In the carboxylic acids represented by the formula [],
R represents a C ₁ -C ₁₀ alkyl group or phenyl group which may have a substituent. Such substituents include halogen atoms such as fluorine, chlorine, bromine, and iodine; aliphatic or alicyclic hydrocarbon groups such as methyl, ethyl, and cyclohexyl; methoxy, Alkoxy groups such as ethoxy, phenoxy, etc.; organothio groups such as methylthio, phenylthio, benzylthio, etc.; dimethylamino,
Alkylamino groups such as diethylamino group, piperidino group, etc.; Carbonyl group such as formyl group, acetyl group, benzoyl group, etc.; Alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group, etc.; Acetoxy group , acyloxy groups such as benzoyloxy groups; hydroxyl groups, t-butyldimethylsilyloxy groups, trimethylsilyloxy groups, tetrahydropyranyloxy groups, carboxyl groups, or phenyl groups substituted with at least one of these substituents or steroid rings; Examples include alicyclic hydrocarbon groups such as Examples of _C1 to _C10 alkyl groups which may be substituted with such substituents include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group,
Examples include Sec-butyl group, t-butyl group, pentyl group, hexyl group, octyl group, and decyl group. Specific examples of such carboxylic acids include acetic acid, phenyl acetic acid, 4-phenyl-n-butyric acid,
-phenyl-n-butyric acid, 11-bromoundecanoic acid, 5-benzoyl-n-valeric acid, 5-acetyl-n-valeric acid, p-formylbenzoic acid, 3α-acetoxycholanic acid, 3-oxocholanic acid, etc. It can be mentioned as a part. In addition, 5,6-dihydrophenanthridine is described in the literature "EC Taylor 5, Journal of the American Chemical Society (E.
C. Taylor et al., Journal of American
Chemical Society), 76 , 1699 (1954). ” or “Double You.C.Utten, R.L.
Mitski, Journal of American Chemical Society (WCWooten and RL)
Mckee, Journal of American Chemical
Society), 71 , 2946 (1949). It can be easily obtained by the method described in ``. The dehydration condensation reaction is achieved by subjecting it to a conventional amidation reaction known per se using a dehydration condensation agent. Examples of such dehydration condensation agents include, for example, New Experimental Chemistry Course (edited by the Chemical Society of Japan), Volume 14;
They are introduced in detail on pages 1136 to 1147, and any of them are preferably used, but a particularly preferred one is the literature ``E. Baldo, K. Saigo, T. Mukaiyama, Chemistry Letters (E.
Blad, K. Saigo, and T. Mukaiyama,
Chemistry Letters), 1163 (1975); Mukaiyama, wai. Aikawa, S. Kobayashi, Chemistry Letters (T.Mukaiyama, Y.
Aikawa, and S. Kobayashi, Chemistry
Letters), 57 (1976); Mukaiyama, wai. Aikawa, S. Kobayashi, Heterocycles (T.Mukaiyama, Y.Aikawa, and S.
Kobayashi, Chemistry Letters), 4 , 1707
(1976), a dehydration condensation reaction using a 2-halopinidinium salt. Dehydration condensation reaction used in the presence of a catalytic amount of 4-dimethylaminopyridine (Reference: K. Narasaka, K. Maruyama, T. Mukayama, Chemistry Letters)
K. Maruyama, and T. Mukaiyama, Chemistry
Letters, 885 (1978). The embodiment of the dehydration condensation reaction when 2-chloro-6-methyl-1,3-diphenylpyridinium tetrafluoroborate is used as the dehydration condensation agent is as specifically described as a reference example. The thus obtained carboxylic acid amide derivative represented by the formula [] is a compound that is stable under acidic or basic conditions, such as under acidic conditions with hydrochloric acid or potassium hydroxide solution (methanol-
There is almost no change under the conditions of 10 hours at 70°C in a THF aqueous solution. Therefore, utilizing such stability of carboxylic acid amide derivatives, various functional group conversion reactions or carbon bond formation reactions can be carried out.
It is also possible to obtain carboxylic acids by subsequent oxidative deprotection reaction, which is a major feature of the present invention. In other words, the following formula []' [In the formula, R' is C ₁ - substituted with a hydroxyl group, a protected hydroxyl group, a formyl group, an acyl group, an alkoxycarbonyl group, an acyloxy group, or a carboxyl group.
Represents a C ₁₀ alkyl group or phenyl group. ] A carboxylic acid amide derivative represented by the following formula []′ R″COOH …[]′ [wherein, R″ represents a C ₁ to C ₁₀ alkyl group or phenyl group in which at least one of the substituents of R′ in the formula []′ is substituted with a group that has undergone functional group conversion or carbon bond formation. ] This is a method for producing carboxylic acids represented by the following. The functional group conversion reaction or carbon bond forming reaction naturally differs depending on the nature of the substituent of R' in formula []'. That is, when the substituent of R′ is an alkoxycarbonyl group or an acyloxy group, a hydrolysis reaction is possible, when it is a hydroxyl group or a carboxyl group, an esterification reaction is possible, and when it is a formyl group or an acyl group. In the case of a hydroxyl group, it is a Grignard reaction, in the case of a hydroxyl group, it is a protection reaction of the hydroxyl group, and in the case of a protected hydroxyl group, it is a deprotection reaction of the hydroxyl group. In some cases, it is also possible to employ a combination of two or more of these reactions. The formula [] or formula []′ obtained in this way
The carboxylic acid amide derivative represented by is deprotected by reacting with an oxidizing agent to produce the desired carboxylic acid represented by formula [] or formula []'. Examples of the oxidizing agent used in the above reaction include divalent palladium compounds, divalent mercury compounds, trivalent cobalt compounds, hexavalent chromium compounds, and tetravalent cerium compounds. Particularly preferred are cerium compounds. Examples of such tetravalent cerium compounds include ceric ammonium nitrate (CAN), ceric ammonium sulfate (dihydrate), ceric hydroxide, ceric oxide, and ceric sulfate. Among them, ceric ammonium nitrate is particularly preferred. Although the carboxylic acid amide derivative and the oxidizing agent undergo a stoichiometrically equivalent reaction, the oxidizing agent is usually used in slightly excess in order to allow the reaction to proceed smoothly and to obtain the desired product in a high yield. That is, the oxidizing agent is used in an amount of 0.8 to 10 equivalents, preferably 1.0 to 5 equivalents, particularly preferably 1.0 equivalents, per equivalent of the carboxylic acid amide derivative.
Performed using ~2.0 equivalents. The reaction is carried out in the presence of a solvent. As such a solvent, acetonitrile, benzene, toluene, tetrahydrofuran, dioxane, etc. are used, and the reaction is usually carried out in the presence of water. Depending on the amount of solvent and water used, the reaction may be a homogeneous system or a heterogeneous system, but it is better to carry out the reaction in a homogeneous system. The amount of solvent including water is usually 1 to 1,000 times the amount of raw materials.
Double amounts, preferably 10 to 100 times, are used. The reaction temperature is -20°C to 50°C, particularly preferably 0°C.
The range is ~30℃, and the reaction time varies depending on the reaction temperature, but for example, at room temperature (20℃~30℃)
The reaction is completed within 15 minutes, even within several hours at 0°C. After the reaction, the resulting product can be isolated as follows. After distilling off the solvent used in some cases under reduced pressure, an ordinary extraction operation is performed, followed by washing (usually using an aqueous hydrochloric acid solution and a saline solution), drying, and concentration to obtain almost pure carboxylic acids, but further purification is required. If necessary, the target carboxylic acids can be obtained with even higher purity by purification using means such as recrystallization, chromatography, and distillation. As explained above, the amide derivative derived from carboxylic acids and 5,6-dihydrophenanthridine provided by the present invention is a stable derivative under acidic or basic conditions, and moreover, it can be used under mild oxidation conditions. It has the characteristic that it is selectively eliminated at the bottom to give carboxylic acids. Due to its advantages, in complex molecules with various functional groups, carboxylic acids can be protected by the method of the present invention, followed by acidic or basic reactions as described above, followed by oxidative deprotection to form carboxyl groups. A series of reactions becomes possible, and the effects on organic synthesis reactions are immeasurable. Hereinafter, the present invention will be explained in more detail with reference to Examples. Reference example 2-chloro-6-methyl-1,3-diphenylpyridinium tetrafluoroborate containing a catalytic amount of 4-dimethylaminopyridine (220 mg,
0.60 mmol) in acetonitrile (2.5 ml),
4-phenyl-n-butyric acid (82 mg, 0.5 mmol) and proton sponge (259
A solution of 5,6-dihydrophenanthridine (101 mg, 0.56 mmol) in acetonitrile (9.0 ml) was added. 1.5 ml of reaction mixture at room temperature
After stirring for an hour, the mixture was further heated under reflux for 5.5 hours. After the reaction, water was added and ether extraction was performed, and the separated ether layer was washed with an aqueous sodium hydrogen carbonate solution, then a 1N aqueous hydrochloric acid solution, and brine in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the The concentrate was subjected to silica gel column chromatography to obtain the desired amide derived from 4-phenyl-n-butyric acid and 5,6-dihydrophenanthridine (160 mg, 98%). The following carboxylic acid amide derivatives were synthesized in a similar manner. Starting materials, solvents, reaction conditions, and yields are summarized in Table 1.

【table】

[Table] Example 1 5,6-dihydrophenanthridinamide of 4-phenyl-n-butyric acid (245 mg, 0.749 mmol)
Acetonitrile solution containing 20% water (7.5ml)
904 mg of cerium () ammonium nitrate (hereinafter abbreviated as CAN),
1.65 mmol) was added. After stirring at room temperature for 15 minutes, ether was added to the reaction mixture for extraction, and the separated ether layer was washed with 1N hydrochloric acid and then with brine.
After drying over anhydrous sodium sulfate and concentrating under reduced pressure, almost pure 4-phenyl-n-butyric acid (119 mg,
0.726 mmol, 97%) was obtained. The following carboxylic acid amide derivatives were treated with CAN in a similar manner to obtain deprotected carboxylic acids. The raw material amide, reaction solvent, reaction conditions, and yield are summarized in Table 2.

【table】

[Table] Reference example Amide derived from 3α-acetoxycholanic acid and 5,6-dihydrophenanthridine (99 mg,
0.170mmol) in THF (4.5ml) and methanol (0.5ml)
ml) and water (1.0 ml), and lithium hydroxide (21 mg, 0.50 mmol) was added. at room temperature
After stirring for 18 hours, post-process and separate using conventional methods.
Amide derived from 3α-hydroxycholanic acid and 5,6-dihydrophenanthridine (87mg,
0.162 mmol, 95%) was obtained. Reference example Amide derived from p-formylbenzoic acid and 5,6-dihydrophenanthridine (154 mg,
A solution of 0.492 mmol) in THF (10 ml) was added dropwise to an ether solution (2.0 ml) of methylmagnesium iodide (1.58 mmol) at -78°C, and after raising the temperature to -20°C, stirring was continued for 1 hour. Ta. The amide derived from p-(1-hydroxy-1-pentyl)benzoic acid and 5,6-dihydrophenanthridine (156 mg, 0.472 mmol,
96%).

Claims (1)

[Claims] 1. The following formula [] [In the formula, R is C ₁ to C ₁₀ which may have a substituent
represents an alkyl group or phenyl group. ] A carboxylic acid amide derivative represented by the following formula [] RCOOH ...[] [wherein R is the same as defined above]. ] A method for producing carboxylic acids represented by: 2. The method for producing carboxylic acids according to claim 1, wherein the oxidizing agent is a tetravalent cerium compound.