JPS5874633A - Preparation of carboxylic acid - Google Patents

Abstract

PURPOSE:To obtain a carboxylic acid, by removing the protecting group from an amide derivative derived from a carboxylic acid stable under acidio or basic conditions and 5,6-dihydrophenanthridine oxidatively with an oxidizing agent, e.g. a tetravalent cerium compound, etc. under mild conditions. CONSTITUTION:A carboxylic acid amide derivative of formulaI(R is 1-10C alkyl or phenyl which may have a substituent group), e.g. 5,6-dihydrophenanthridine amide of 4-phenyl-n-butyric acid, is reacted with an oxidizing agent, preferably a tetravalent cerium compound, e.g. ammonium ceric sulfate, to give a carboxylic acid of formula II. A carboxylic acid amide derivative of formula III (R' is OH, protected OH, formyl, etc.) is subjected to the functional group converting or carbon bond forming reaction, and then reacted with an oxidizing agent to afford a carboxylic acid of formula IV (R'' is an alkyl, etc. in which at least one of the substituents in R' is substituted by a group subjected to the functional group conversion or carbon bond formation).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a method for deprotection of a novel carboxylic acid protecting group in which a carboxylic acid amide conductor derived from -6-dihydrophenanthridine is deprotected by treating with an oxidizing agent to produce carboxylic acids. Regarding the separation method.

In organic synthesis reactions, the protection of carboxylic acids is an important issue and is an essential issue to overcome in order to complete the synthesis of molecules with various functional groups. Disengagement lIK! Ill also refer to the literature ``E, Haslam, Chemistry and Industry (Haslam*Ch@mlstry mad In
industry), s t o (I S?I);
Yi, Haslam, Tetrahedron (1, Hasta Peng!
Tetrahedron), 36.24011 (1
980) Research is being conducted from multiple directions, as shown in J.

The typical protection method is to convert it into an ester, but the protection 111# and deprotection reactions are carried out under acidic or basic conditions. For complex molecules that are unstable under conditions-
It cannot be used if The inventors of the present invention overcame these drawbacks and discovered a very unique protecting group that can be oxidatively deprotected and is stable under acidic or basic conditions, thereby achieving the present invention.

That is, the present invention is characterized in that a carboxylic acid amide derivative represented by the following formula CI) is reacted with an oxidizing agent, and the following formula (II), RCOOH
This is a method for producing carboxylic acids represented by -(I[) (wherein the wings are as defined above).

The carboxylic acid amide derivative represented by the formula (I), which is a raw material of the present invention, can be produced by a dehydration condensation reaction of a carboxylic acid represented by the corresponding formula [phantom] and 5,6-dihydrophenanthridine. can.

In the carboxylic acids represented by formula CII), 8 represents a furkyl group or phenyl group of 01 to Cjl which may have a substituent. Such substituents include fluorine atom, chlorine atom, and bromine atom.

5/%P atom of iodine atom: methyl group.

Aliphatic or cycloaliphatic hydrocarbon groups such as ethyl group, Schiff-hexyl group, etc.; methoxy group.

Alpoxy groups such as ethoxy groups, 7eth/oxy groups, etc.;
Organothio groups such as methylthio group, phenylthio group, benzylthio group, etc. Alkylamino groups such as dimethylamino group, diethylamino group, pipedino group;
Hol ξ group.

7 Carbonyl groups such as cetyl group, benzoyl group, etc.;
aluminoxycarbonyl group such as meth, oxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group; acetoxy group;

Acyloxy groups such as benzoyloxy groups; hydroxyl groups, t-butyldimethylsilyloxy groups, trimethylsilyloxy groups, tetrahydropyranyloxy groups, carboxyl groups, or 7-enyl groups substituted with at least one of these substituents or steroids Examples include alicyclic hydrocarbon groups such as rings. Examples of C8-C1 alkyl groups which may be substituted with such substituents include methyl group, ethyl group, bupyl group, impulpyl group, butyl group, isobutyl group, g@e-butyl group, and t-butyl group. , pentyl group, hexyl group, octyl group, decyl group, etc. □ Specific examples of such carboxylic acids include acetic acid, phenylacetic acid, 4-phenyl-n-11alt2-phenyl-n W1r acid e 11 7' romoundecanoic acid,
6-benzoyl-n-jeractic acid,! I-7 Cetyl-n-valeric acid, p-formylbenzoic acid.

Some examples include 3-=7 setoxycholanic acid and 3-oxocholanic acid.

In addition, s,6-dihydrophenanthridine is described in the literature “E. C. Tiller 5. Journal of American
Chemical Society (G, C, Taylor)
@tal, tJournal of Amer
icanChemical 8oci*ty),'ys
, 16119 (111!!4), J or [Meprini-
, See, Utsuten, Earl.

L, Mitski, Journal Op Φ American and Chemical Society (W, C, Woot@nand
R, L, Mckes, Jotzrnal of Am@
rican Chemica18oei@ty),?
1.21148 (11411), J.

The dehydration condensation reaction is achieved by subjecting it to a conventional amidation reaction known to Homare itself using a deicing condensation agent. Examples of such dehydration condensation agents include, for example, New Experimental Chemistry Course (Nippon Kagaku Yoon), Volume 14 ■, Shin 1136-114? All of them are introduced in detail in ``I, Pardo.'' All of them are preferably used, but the most preferred one is the document ``I, Pardo.''

K, Saigo, T, Mukaiyama, Chemistry 9 Letters (E*Ba1d, Ni, Saigo, and
T, Muk-aiyamae Ch@m1stry L
@tt@rs), 111i 3 (lays);-
vp-z (T, Mma-Peng w Y, Alkava, and 8. Kobayashit
Cchemimtry L@tt@rs).

ay(xs)6): Tei, mukaiyama, wai, a,
Payashi, Haete I+1! -Ickles (T, Mtlkalyama, Y, Alkavava
nd 8. KebayashI 嘗Chemlstr
y L@tt@rs), 4, 1 'I @fu(
19? @) It is a dehydration condensation reaction using a 1%-vinidinium salt as shown in J, and 1% is preferable.
Dehydration condensation reaction used in the presence of monopyridinium tetrafluoriborate and puto-dimethylaminopyridine
Mukalyamat Chsmistry L@-t
t@rl, 881(111]S)").

, -6-methyl-1,S-diphenylpyridinium tetrafluoroborate dehydration condensation The embodiment of the dehydration reaction of gold is as specifically described as a reference example.

The thus obtained carboxylic acid amide derivative represented by formula (I) is a compound that is stable under acidic or basic conditions. For example, hydrochloric acid acidic 1 is a potassium hydroxide solution 11
! Under the conditions of (7·' CIO time in methanol-TIP aqueous solution), it does not change at all. Therefore, it is also possible to utilize such stability of carboxylic acid amide derivatives to perform various functional group conversion reactions or carbon bond formation reactions, and then subject them to oxidative disengagement reactions to obtain carboxylic acids. The main features of the present invention are:
The following formula [■]'R'C0OH-, which is characterized by subjecting the carboxylic acid amide derivative represented by the following formula [I]' to a functional group conversion reaction or longitudinal bond formation reaction, and then reacting with an oxidizing agent. This is a method for producing carboxylic acids represented by (u)'.

The functional group conversion reaction or carbon bond forming reaction varies greatly depending on the nature of the substituent of R' in formula [■]'. That is, when the substituent of R' is a fulpoxycarbonyl group or an acy-oxy group, a hydrolysis reaction is possible,
When it is a hydroxyl group or a carboxyl group, an esterification reaction is possible, when it is a formyl group or an acyl group, it is a gamma diary reaction, and when it is a hydroxyl group, it is a retention reaction of the hydroxyl group. If the reaction is a protected hydroxyl group, this 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 thus obtained carboxylic acid amide derivative represented by formula CI) or formula [I]' is deprotected by reacting with an oxidizing agent to produce the desired formula.

The oxidizing agents used in the above reaction include divalent palladium compounds, divalent mercury compounds, trivalent cobalt compounds, 6
Among them, 414-valent cerium compounds are particularly preferred.

An example of such a tetravalent cerium compound is ceric nitrate (CAM).

Licumammonium 27th sulfate (dica salt).

Serium hydroxide.

Liium 27 oxide.

Among them, sericum ammonium nitrate is particularly preferred.

Although the carboxylic acid 7ξ-do derivative and the oxidizing agent undergo a stoichiometric reaction, the oxidizing agent is usually used in a slightly excessive amount in order to make the reaction proceed smoothly and obtain the desired product in a high yield. . That is, the oxidizing agent is used in an amount of 1.8 to 10 equivalents, preferably L6 to 5 equivalents, and preferably 10 to zO weight per 1 weight of the carboxylic acid amide derivative.

The reaction is carried out in the presence of *medium. 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 homogeneous or heterogeneous, but it is better to conduct it homogeneously.

The amount of *S including water is usually 1 to too many times the amount of raw materials,
Preferably an amount of 10-1 ounces is used.

The reaction temperature is 0°C to SO°C, particularly preferably 0°C to 3°C.
Although the reaction time varies depending on the reaction temperature, for example, the reaction is completed within 15 minutes at room temperature (20°C to 30°C), and within several hours even 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, a conventional extraction operation is performed, followed by washing (usually using an aqueous hydrochloric acid solution and a saline solution), drying, and concentration to obtain roughly pure carboxylic acids, but further purification is necessary. If the desired carboxylic acid is required, it is possible to obtain the target carboxylic acid with even higher purity by purifying it using means such as i-crystal, p-maturography, and distillation.

As explained above, the amide derivatives derived from carboxylic acids and he-6-cyhydrophenanthridine provided by the present invention are stable derivatives under acidic or basic conditions, and moreover, under mild oxidation conditions. It has 5411 mold which can be selectively eliminated to give carboxylic acids.

Due to its advantages, in complex molecules with a variety of 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 disassociation to form the carboxylic acid in the carboxylic acid. This makes it possible to perform a series of reactions based on the base, 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-L3-diphenylpyridine containing a catalytic amount of 4-dimethylaminopyridine? Muchidola fluoscipora) (200mg, o, s Omm
el )'s 77tonitorik(!!Iaj) solui! 2,
4-7 product run n-butyric acid (8
2Ijp, a S mmol), Bouton sponge (269111F, 141 mmol) and 5,6-
Cyhydrophenanthridine (1 oswg, oss ol
) in 7 setonitrile (t o d ) was added. After stirring the reaction maple compound at room temperature for 1 S hour, further! The mixture was heated to reflux for Li hours. After the reaction, water is added, ether extraction is performed, and the separated ether layer is added to an aqueous sodium bicarbonate solution, and then! After washing with normal aqueous hydrochloric acid solution and brine in this order, followed by drying with anhydrous sulfuric acid solution, it was concentrated under reduced pressure, and the resulting condensate was subjected to silica gel column chromatography to obtain the desired 4-7 enyl group. - 7mid derived from butyric acid and 6-cyhydrophenanthridine (tsosf, 91
11G) was obtained.

The following carboxylic acid Al)' derivatives were synthesized in a similar manner. Starting materials, solvent 2 reaction conditions, and yields are summarized in Table IK.
show.

(4-Dimethylaminopyridine) Table 1 Example 1 4-phenyl-n-butyric acid he-6-dihydrophenanthridine 7mide (!4Sjl!P, a74smmol) was added to an acetonitrile solution containing 20% water (T, !i
sd) K, and cerium (mV) ammonium nitrate (hereinafter abbreviated as CAN) is dissolved in it.

1104 da, L61 round o1) 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 1 normal hydrochloric acid and then with brine.
After drying over anhydrous sodium sulfate and concentrating under reduced pressure, pure 4-phenyl-n-butyric acid (11 sq, o, t 26
mmo1.97%) was obtained.

Using a similar method, the following carboxylic acid amide derivatives were prepared by CA.
The mixture was treated with N to obtain disarticulated carboxylic acids. Raw material amide, reaction solvent 1 reaction conditions.

Table 2 shows the collection of vehicles.

Table 2 **Example 2 Amide derived from sa-acetoxycholanic acid and 5,6-cyhydro7-enanthuridine (99 Da, a 17
0 mmol) was poured into a mixed solvent of THF (4.5 m), methanol (65 m), and water (1.0 mm), and hydroxide (2 s wg, as Omm
ol) was added. After stirring at room temperature for 18 hours, the bales were separated by a conventional method to obtain 74-d (87 m
1% J, 0162 mmol, s 5 h) was obtained.

Back 1 Example 3 p-formylbenzoic acid! An amide derived from I,6-dihydrophenanthridine (ls4q.

A THF (tomJ) solution of 4*@mmol) was added to methylmagnesium iodide (L!I@m
Add 4c of ether solution (toil) of -7
The mixture was added dropwise at a°C, and after the temperature was raised to -20°C, stirring was continued for 1 hour. The amide (1869,04) derived from p-(1-hydroxy-1-pentyl)benzoic acid and 6-dihy)'-7enaneF lysine was separated by post-treatment using a conventional method.
zmmot, 5ad) was obtained.

Claims (1)

[Claims] 1. The following formula () % formula % () [wherein 8 is a The same as the above definition.] The legality of the carboxylic acid represented by. 1. A method for producing carboxylic acids according to claim 1, wherein the oxidizing agent is a tetravalent metal ceriumide. ! The following formula [■]'R'C0OH..・[■]′ ・Production method of carboxylic acids represented by . Also, carboxylic acids of the formula [・1]' odor CR' are a flukoxycarboel group or an acy-oxy group, and the functional group conversion reaction is a hydrolysis reaction. manufacturing method. 5. The method for producing carboxylic acids according to claim 3, wherein the substituent of R' in formula (I)' is a hydroxyl group or a carboxyl group, and the functional group conversion reaction is an esterification reaction. 4. The method for producing carboxylic acids according to claim 3, wherein the substituent of R' in French formula (I)' is a formyl group or an acyl group, and the carbon bond y# forming reaction is a Dalignard reaction. 7. The method for producing carboxylic acids according to claim 1IwEs, wherein the substituent of R' in formula (I)' is a hydroxyl group, and the blind functional group envying reaction is a protection reaction of the hydroxyl group. 1 Formula [!] ', the substituent of R' is a protected hydroxyl group, and the functional group conversion reaction is a deprotection reaction of the hydroxyl group. 9. The method for producing carboxylic acids according to any one of claims 3 to 8, which is a cerium compound of valence.