[1]The present invention relates to a process for the preparation of acid amide compounds suitable for mass production.
[2]
This application claims the benefit of priority based on the June 30 Korea Patent Application No. 10-2015-0092704, and in May 2016, May 31, Korea Patent Application No. 10-2016-0067409, 2015, and of the Korea Patent Application everything described in the literature comprises a part of this specification.
[3]
BACKGROUND
[4]
Adamantane O (adamantane) group, one of compounds having a 5-substituted adamantan-1-yl -N- (2,4- dihydroxy-benzyl) -2,4-dimethoxy-benzoic acid amides of human skin by inhibiting the melanin present in the skin layer get the excellent whitening effect has been proposed as an effective ingredient of the cosmetic composition.
[5]
In relation to the production of the compounds it is manufactured according to the Republic of Korea Patent Publication No. 2013-0015954 No. Scheme.
[6]
[7]
Specifically, 5-adamantane-1-yl -N- (2,4- dihydroxy-benzyl) -2,4-dimethoxy-benzoic acid amide is (i) 2 in the presence of acetic acid and sulfuric acid catalyst in the dichloromethane solvent , 4-hydroxy benzoic acid is reacted with 1-adamantanol at room temperature 5-Ada manta synthesizing the carbonyl-2,4-dihydroxy benzoic acid; (Ii) synthesizing a 5-Ada manta carbonyl-2,4-dihydroxydiphenyl by reacting hydroxybenzoic acid with dimethyl sulfate 5-Ada manta carbonyl-2,4-dimethoxybenzoic acid in the presence of sodium hydroxide or potassium hydroxide; And (iii) and producing the 5-Ada manta carbonyl-2,4-dimethoxy-benzoic acid N- hydroxy-succinimide, N, N'- dicyclohexyl carbodiimide under the presence benzylamine to yield.
[8]
This 5-Ada the production method (i) manta carbonyl-2,4-dihydroxybenzoic acid is acetic acid and the solvent used in the manufacture and consumption respectively, at least 8-fold and 2-fold compared to the reaction, and the reaction time is also required for at least five hours and, that has a yield of 80 to 85%.
[9]
Further, (iii) steps are N- hydroxysuccinimide / 1, 3-dicyclohexyl carbodiimide (HOSu / DCC) under high water / dioxane solvent. Dichloromethane in SOCl 2 or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC). MeCN in cyanuric chloride, toluene within the B (OH) 3 used in the coupling agent for coupling the like, whereby the solvent is limited according to Fig required. The yield of the obtained compound is very low as 30%, the end product is in a complex mixture (complex mixture) remaining purity and also causes low problem.
[10]
Especially, dihydroxy benzylamine used as a reactant in the step of (iii) is prepared by the following procedure.
[11]
[12]
In this reaction, after the dihydroxy benzaldehyde as starting material by using sodium carbonate in methanol or ethanol is carried out for 5 hours the reaction to activate, and after performing a further reaction by adding an in hydrochloric acid methanol or ethanol production of the oxime compound do.
[13]
Then, by using the hydrogen gas of the high-pressure performs a reduction reaction in the carbon support in the presence of Pd-supported catalyst to produce a di-hydroxy-benzylamine. The reaction is required for a long period of time of about 5 hours, however, even if represents about 50% of the yield. Moreover, this reaction are to be use expensive Pd, 50psi of hydrogen gas pressure in the reaction is used, there is a problem in which the process is complicated and increases the process cost.
[14]
In the fall or the like with the yield becomes irregular production patterns are formed inseparably mixtures according to the size of the step increases, various problems not suitable for mass production was observed.
[15]
Thus, the acid amide compound, despite excellent effectiveness with respect to whitening and there are many restrictions in industrially utilized, it was necessary circumstances, the development of a novel process for preparing a production efficiency is improved.
[16]
[Prior art document]
[17]
Patent Document 1: Republic of Korea Patent Application Publication No. 2013-0015954 call, "New benzoic acid amide compound."
[18]
Detailed Description of the Invention
SUMMARY
[19]
According to the present invention it is not was carried out a study to suggest a new method of manufacturing the acid amide compound, by specifying the reaction conditions at each step, as well as to shorten the process time required for the entire manufacturing use expensive materials and the catalyst was securing economic advantages, it was possible that benzoic acid amide compound in a high yield.
[20]
Furthermore, producing the dihydroxy benzylamine used as reactants to 90% or more high yield for a short period of time in an aqueous solution without using an organic solvent, which was used in the preparation of the acid amide compound.
[21]
Accordingly, it is an object of the invention to provide a method of producing easy-to-acid amide compound applied to the mass production process.
[22]
It is another object of the present invention is to provide a method of manufacturing a benzylamine compound that can be used as reactants in the production of the benzoic acid amide compound.
Problem solving means
[23]
In order to achieve the above object, the present invention is to be represented by the reaction formula 1, wherein performing the formula (2) of benzyl amine and amide coupling reaction of Ada manta carbonyl benzoyl anhydride of formula (3) under a basic catalyst; formula (I) via the It is the provide a method for producing benzoic acid derivatives:
[24]
[Reaction Scheme 1]
[25]
[26]
(In the above scheme 1, R 1 to R 5 are as described in the specification)
[27]
In this case, as to the benzylamine compound of the formula (2) shown by Reaction Scheme 2,
[28]
T1) the method comprising reacting a benzaldehyde compound with a hydroxylamine of the formula (4) producing the benzaldehyde oxime compounds of formula (5) in the basic aqueous solution; And
[29]
T2) in the acidic aqueous solution treating the benzaldehyde oxime compounds of formula 5 with a reducing agent; manufactured through:
[30]
[Reaction Scheme 2]
[31]
[32]
(In the above scheme 2, R 3 and R 4 are as described in the specification)
Effects of the Invention
[33]
Production method of acid amide compounds presented in this invention is not only to reduce costs by reducing the overall reaction time, and it is possible to manufacture with high yield.
[34]
In addition, it proposed a key intermediate, the benzylamine derivative is available as a method for producing an organic solvent in high yields of 90% or more within a short period of time without the use of an aqueous solution.
[35]
Therefore, within a short time and by the present invention can implement the mass production of the benzoic acid amide compound in a high yield.
[36]
Best Mode for Carrying Out the Invention
[37]
Will now be described in more detail the present invention.
[38]
The present invention proposes a new method for producing the benzoic acid derivatives having an excellent whitening effect through, in particular, inhibit melanin such as organic chemistry, cosmetic field.
[39]
Specifically, the acid amide derivative is represented by the following general formula (1):
[40]
Formula 1
[41]
[42]
(In the formula 1,
[43]
R 1 to R 4 is different from or equal to each other, and each independently hydrogen, hydroxy, C1-alkoxy group of C5, a haloalkoxy group of C3 to cycloalkoxy group, C6 to aryloxy C20 of C6, or C1 to C5 )
[44]
May be straight alkoxy groups are straight or branched as referred to in this specification, it is preferable that the carbon number is 1 to 5. Specific examples are methoxy, ethoxy, n- propoxy, isopropoxy, i- propyloxy, n- butoxy, isobutoxy, tert- butoxy, sec- butoxy, or 1,2-dimethyl-butoxy, etc. this however, is not limited to these
[45]
Cycloalkoxy referred to herein is preferably a chain ring, the carbon number is 3 to 6. Specific examples thereof include cycloalkyl propoxy, cycloalkyl-butoxy, pentoxy cycloalkyl or cycloalkyl H. butoxy, but are not limited to these.
[46]
Aryloxy groups referred to herein, it is preferable that the carbon number is 6 to 20. Specific examples thereof include phenoxy, p- tolyl oxy, m- tolyl-oxy, 3,5-dimethyl-phenoxy, 2,4,6-trimethyl-phenoxy, p-tert- butylphenoxy, 3-phenyloxy, 4 non-phenyloxy, 1-naphthyloxy, 2-naphthyloxy, 4-methyl-1-naphthyloxy, 5-methyl-2-naphthyloxy, 1-oxy-anthryl, 2-anthryl-oxy, 9 -anthryl-oxy, 1-oxy-phenanthryl, 3-phenanthryl, etc., but is oxy, 9-phenanthryl-oxy, but is not limited to these.
[47]
Haloalkoxy groups referred to herein, means a substituted alkoxy group halogen (-F, -Cl, -Br or -I).
[48]
Alkyl groups referred to herein may be straight linear or branched and preferably has 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n- propyl, isopropyl, butyl, n- butyl, isobutyl, tert- butyl, sec- butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n- pentyl , isopentyl, neopentyl, tert- pentyl, hexyl, n- hexyl, 1-methylpentyl, 2-methylpentyl, and the like, but is not limited to these.
[49]
Preferably, the R 1 , R 3 and R 4 is one member selected from the group consisting of the same or different, respectively hydrogen, hydroxy and C1 to C3 alkoxy each other.
[50]
In more preferred, acid amide derivatives of formula (I) may be selected from: (1) 5-adamantane-1-yl-2,4-hydroxy -N- [2- (4- hydroxy hydroxyphenyl) ethyl] benzoic acid amide; (2) 5-adamantane-1-yl-2-hydroxy -N- [2- (4- hydroxy-phenyl) -ethyl] -4-methoxy-benzoic acid amide; (3) 5-adamantane-1-yl -N- [2- (4- hydroxy-phenyl) -ethyl] -2,4-dimethoxy-benzoic acid amide; (4) 5-adamantane-1-yl -N- (2,4- dihydroxy-benzyl) -2,4-dihydroxy-benzoic acid amide; (5) 5-adamantane-1-yl -N- (2,4- dihydroxy-benzyl) -2-hydroxy-4-methoxy-benzoic acid amide; (6) 5-adamantane-1-yl -N- (2,4- dihydroxy-benzyl) -2,4-dimethoxy-benzoic acid amide; (7) 3-adamantan-l-yl-4-hydroxy -N- [2- (4- hydroxyphenyl) ethyl] benzoic acid amide; (8) 3-adamantan-1-yl -N- [2- (4- hydroxy-phenyl) -ethyl] -4-methoxy-benzoic acid amide; (9) 3-adamantan-1-yl -N- (2,4- dihydroxy-benzyl) -4-hydroxy-benzoic acid amide; 10 using 3-adamantan-1-yl -N- (2,4- dihydroxy-benzyl) -4-methoxy-benzoic acid amide.
[51]
Among them, 5-adamantane-1-yl -N- (2,4- dihydroxy-benzyl) -2,4-dimethoxy-to preferred - the acid amide.
[52]
Acid amide derivatives of formula (I) is an adamantyl improves the absorption due to the increased lipophilic group having carbon shows an excellent melanogenesis inhibitory effect and the tyrosinase activity inhibition effect. In addition there may be a variety of different effects.
[53]
More specifically, the step of performing the formula (2) of benzyl amine and amide coupling reaction of Ada manta carbonyl benzoyl anhydride of formula (3) under a basic catalyst as described for the acid amide derivative of formula (1) shown in Scheme 1; prepared including do:
[54]
[Reaction Scheme 1]
[55]
[56]
(In the above scheme 1, R 1 to R 4 are as stated above, R 5 is an alkyl group of C1 to C6)
[57]
According to Scheme 1, amide coupling reaction is carried out in a solvent under a basic catalyst.
[58]
The base catalyst used is not particularly limited in the present invention, if a base catalyst of the known bar in the art can be used either. Specifically, the base catalysts include triethylamine, pyridine, N, N- ethyldiisopropylamine, N- methyl morpholine, and any one may be used selected from the group consisting of and mixtures thereof, preferably triethylamine to and amine.
[59]
The solvent may be one selected from dichloromethane, chloroform, 1,2-dichloroethane, ethane, chlorobenzene and the group consisting of a 1,1,2-trichloroethane.
[60]
This reaction is carried out a reaction for 2 to 3 hours to 0 to 40 degrees, more preferably to, and performed at room temperature for 30 minutes to 4 hours to a preferred, more preferred.
[61]
As already mentioned, the amide coupling reaction of Reaction Scheme 3 can be carried out without the use of separate coupling reagent. In the prior art reaction disclosed in the Republic of Korea Patent Publication No. 2013-0015954 ㅎho, and using a specific coupling agent, and a combination of solvents coupling reagent. This method is not easy to remove the product, as well as to the final resultant low as about 30% final yield. In addition, since the price of using expensive reagents are unsuitable for mass production.
[62]
However, without the use of formula (3) of the Ada manta carbonyl benzoyl anhydride and by this reaction, the reaction easy benzylamine compound of the formula (2) a coupling agent and hence the specific solvent according having a coupling reaction of the present invention exits the conventional 30% and perching more than 75-90% to 75-95% to yield a stable, preferably may be prepared acid amide compounds of formula (I) in high yield. In addition, it also facilitates separation of the acid amide compound in the final product, it is possible through the process of low-cost reagents, the greater the effectiveness of the cost reduction and mass production process advantage.
[63]
In particular, the benzylamine compound of the formula (2) used as reactants in the scheme 1 are difficult to manufacture, expensive, and the price of the raw material itself, less significantly the stability of the material itself. Therefore great care is required to apply to the reaction of the compound material. In particular, R as shown in the above formula (2) 3 and R 4 3,4 or 2,5 position of the compound is not a 2,4 is relatively higher than that of the compound is low and the stability of the substance 2,4 price.
[64]
In addition, the conventional benzyl for preparing an organic solvent a benzaldehyde derivative of the amine compound, i.e., the sodium acetate is added under an ethanol solvent were reacted for more than five hours long period of time producing the oxime compound, prepared by this re-use of costly Pd catalyst, such method can not be found to be suitable for mass production in terms of time, cost and yield.
[65]
The present invention proposes a new method for a benzylamine compound of the formula (2) to solve the problem (i.e., stability, price, time and yield) of the above 2,4-substituted compounds.
[66]
Preferably, the benzyl amine compound of formula (II) can be manufactured according to the following scheme 2:
[67]
[Reaction Scheme 2]
[68]
[69]
(In the above scheme 2, R 3 and R 4 the same as those mentioned above)
[70]
Specifically, according to the scheme 2, benzylamine compound of the formula (II)
[71]
T1) the method comprising reacting a benzaldehyde compound with a hydroxylamine of the formula (4) producing the benzaldehyde oxime compounds of formula (5) in the basic aqueous solution; And
[72]
T2) in the acidic aqueous solution treating the benzaldehyde oxime compounds of formula 5 with a reducing agent; prepared via the.
[73]
Benzaldehyde compound of formula (IV) used as starting materials in the above T1) phase, R 3 and R 4, which is as far as it satisfies all possible uses, can be a 2,4-dihydroxy benzaldehyde used as an example. These compounds are purchased to be manufactured or marketed directly. The benzaldehyde compounds in water but soluble, is in progress it is possible to facilitate the reaction under basic conditions.
[74]
The T1) step is to carry out the reaction in an aqueous solution in the presence of a base.
[75]
At this time, the base is sodium carbonate, it can be one selected from the group consisting of sodium hydrogen carbonate, potassium carbonate and potassium hydrogen carbonate, and sodium carbonate is used to preferably. The amount of the base is the starting material, prepare the content 1 of formula (8): are used so that a molar ratio of 1: 0.01 to 1.
[76]
The reaction is carried out a reaction for 1 to 2 hours to preferably 0 to 40 degrees, more preferably to, and performed at room temperature, for 30 minutes to 3 hours to preferably. When the crystals were precipitated after the reaction through filtration to obtain the benzaldehyde oxime compounds of formula (5).
[77]
Preparation of the benzaldehyde oxime compounds prior to the organic solvent, using sodium acetate with ethanol as compared to react for at least 5 hours for a long time, the time as well as greatly reduced as 1 to 2 hours, the reaction yield also 95% or more high yield it is possible to obtain the benzaldehyde oxime compounds of formula (5).
[78]
Next, the T2) step the reaction is conducted in an aqueous solution under acid and reducing agent present.
[79]
The acid is hydrochloric acid, sulfuric acid, and a possible one member selected from the group consisting of and mixtures thereof, and preferably using hydrochloric acid to. The amount of the acid is of formula (V) content over one of the starting material - used to a molar ratio of 1 to 1:10.
[80]
The reducing agent used in step T2) is the zinc powder can be used to zinc, preferably, the conversion of the oxime to the amine.
[81]
The zinc powder may be to facilitate the purchase price, as well as less expensive, lower cost-effective mass production of benzylamine compound. The zinc powder and the purchase on the market, compared to the compound of formula 51: used in an amount of from 1 to 1:10.
[82]
The reaction is performed at -4 to 40 degrees, and, preferably, and to perform the 30 minutes to 4 hours, 2 to 3 hours for a reaction to more preferably, it is possible to manufacture the benzylamine compound of the formula (2) in a high yield.
[83]
The T2) phase was used as the precious metal catalyst is Pd with a conventional reducing agent, in this case, there is a problem, and a problem yield less reproducible failure to schedule up to 50 to 95%, such as increased production costs and excessive reaction times. In particular, there occurs particularly a lot of by-products during the mass production process yield was difficult to separate the problem of the reduction or complete hydrochloride or acetate form to 50% or less.
[84]
In the present invention, as already mentioned, as well as use of low-cost zinc powder as the reducing agent, reduce costs, and also greatly shorten the reaction time, a stable, even when applied to a mass production process, the yield of about 90 to 95% It can be secured. In addition, it is possible to proceed with the reaction in an aqueous solution, the working environment is improved compared to a method using a conventional organic solvent.
[85]
The final resulting benzylamine compound of the formula (2) is made of a salt state by the addition of acid, for use after washing or has to remove the simple filtration the solvent without further purification hydrochloride state can be applied to the reactants in scheme 1.
[86]
Further, Ada manta carbonyl benzoyl anhydride of formula (III) to react with benzylamine compound of the formula (2) in Scheme 1 can be manufactured on the basis of the following scheme 3:
[87]
[Reaction Scheme 3]
[88]
[89]
(In the above scheme 2, R 1 , R 2, R 4 , R 5 and X are as mentioned above)
[90]
, Producing a manta Ada carbonyl benzoyl anhydride of formula (III) according to Scheme 3
[91]
S1) the step of adamantane by performing tilhwa reaction of 1-adamantanol of benzoic acid compounds of Formula 6 and Formula 7 to prepare a manta Ada carbonyl benzoic acid compound of formula (8) the presence of an acid catalyst; And
[92]
S2) are prepared by reacting the acid Ada manta carbonyl compound and an alkyl halo formate of formula 9 of the formula (8) under a basic catalyst:
[93]
First, S1) step is reacted with 1-adamantanol of the formula and acid compounds of formula 67.
[94]
Benzoic acid compound of formula (VI) used as starting material is a benzoic acid derivative carboxylic acids are substituted at the benzene ring, and specific compounds are an R mentioned in the compounds of the formula 1 , and R 2 is a compound that satisfies it is possible either which one. In one example, the benzoic acid compound of formula (VI) is 2,4-dihydroxy benzoic acid, 2-hydroxy-4-methoxybenzoic acid, 2,4-dimethoxybenzoic acid, 4-hydroxybenzoic acid, 4-methoxy-benzoic acid yl and it can be purchased to be manufactured or marketed directly.
[95]
1-adamantanol of Formula 7 can be purchased to be manufactured or marketed directly.
[96]
1-adamantanol of the acid compound of formula (VI) and formula (7) it may be reacted in consideration of the stoichiometric equivalent ratio, wherein the reaction is 1: used in a molar ratio of 1.2: 1 to 1. If there is a molar ratio of 1-adamantanol it can be reacted in the undesired positions when used in excess.
[97]
This reaction is carried out in a solvent in the presence of an acid catalyst.
[98]
The acid catalyst is for increasing the rate of the reaction, hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, and mixtures thereof can be one selected from the group consisting of a, and is used as a trifluoroacetic Preferably a mixture of acetic acid and sulfuric acid.
[99]
The solvent used is dichloromethane.
[100]
The content of the solvent to be used is in about which can sufficiently proceed the reaction, but not limited to the content, in the optimum in the range of for cost reduction such as according to the used solvent, and the reaction to preferably: 1 solvent: 1 to 1:50, preferably 1, to: use a volume ratio of 1 to 1:30. At this time, the reaction means that the sum of the benzoic acid compound with 1-adamantanol.
[101]
The reaction temperature and the reaction time is adjusted so that the reaction can sufficiently shorten the time taking place as possible the production of compounds in high yield, from a starting material to the production of end-benzoic acid amide compound.
[102]
Specifically, S1) the reaction of step is carried out a reaction for 30 minutes to 2 hours to perform and in the reflux temperature of the solvent, preferably, 1 to 1.5 hours to more preferred. At this time, the reaction temperature is low, the reaction rate will slow down, there is a possibility to happen if the decomposition is too high. Further, the reaction time is because it may be extended for a total process time required to manufacture the overall acid amide compound if it exceeds the time as a time that can occur sufficiently in the reaction scheme 2, is carried out within the time.
[103]
In particular, the S1) for the step in the conventional method performs the excess of sulfuric acid and reaction was performed for 5 hours or more for a long time in the presence of acetic acid with an excess of an organic solvent, the yield is low in the reaction of such a long period of time while there is a problem
[104]
However, in the present invention to reduce the content of the organic solvent to less than 1/2, the acid can be conducted on-line, even if the content of the reaction (e. G., Acetic acid) to less than 1/8, and the reaction time of up to 2 hours, the existing time compared to the advantage of big savings. The content and processing time savings of using these solvents has the advantage of increasing the productivity of the entire process, process costs are also lower. In particular, it is possible to obtain an about 90% yield in the face, in the reaction efficiency and ensure the excellent advantages superior.
[105]
Next, S2) step is to prepare a manta Ada carbonyl benzoyl anhydride of formula (3) to carry out the reaction with an alkyl halo formate of formula and Ada manta carbonyl benzoic acid compound of formula 89.
[106]
It used a leaving group is an alkyl halo formate of formula (9), since the reaction of Ada manta carbonyl benzoic acid compound with a benzylamine compound of the formula (2) of formula (8) does not occur directly, responsive to Ada manta carbonyl benzoic acid compound of formula (VIII) for the reaction activation switch to superior anhydride.
[107]
The anhydride has the advantage that as a mixed anhydride (mixed anhydride) form, the benzyl amine compound and easy reaction of the above formula (2) proceeds.
[108]
Alkyl halo formate for anhydride produced is a R mentioned above 5 is a compound satisfying and X which may be all be possible, preferably, ethyl chloroformate, isobutyl chloroformate supposed to, which is produced directly, or a commercially available It is purchased to be.
[109]
Ada manta carbonyl benzoic acid derivative with an alkyl halo formate of formula (8) is possible is produced in consideration of the stoichiometric equivalent ratio, 1: used in a molar ratio of 1.2: 1 to 1. If there is a molar ratio of alkyl halo formate it can be reacted in the undesired positions when used in excess.
[110]
This reaction is carried out in a solvent under a basic catalyst.
[111]
It decided to free base catalyst may be triethylamine, pyridine, N, N- ethyldiisopropylamine, N- methyl morpholine, and any one selected from the group consisting of a mixture thereof, preferably using triethylamine .
[112]
The solvent used is dichloromethane to preferable.
[113]
The reaction is carried out a reaction for 10 minutes to 2 hours to preferably, performing -4 to 0 degree to a low temperature, preferably.
[114]
Steps in the foregoing is summarized in the following scheme 6.
[115]
[Reaction Scheme 4]
[116]
[117]
(In the Scheme 4, R 1 to R 5 and X are as mentioned above)
[118]
Production method of acid amide of formula I according to the invention based on the above reaction scheme 4, a compound with the process conditions necessary for the reaction of Ada manta carbonyl benzoyl anhydride of formula with benzylamine compound of the formula 23, represented by the above formula (2) of a method suitable for mass production by providing new production conditions.
[119]
First, as follows are the benefits of the new manufacturing process of the benzylamine compound of the formula (2).
[120]
First, it is the compound prepared of the formula (4) proceeds in an aqueous solution, and the reaction time is shorter it is also possible, up to a maximum of 2 hours made of a high yield of over 95%. In this way, even if the conventional over 5 hours of reaction in an organic solvent, it can be seen that an improved method compared to methods which produced a lower yield.
[121]
Then, the production is possible in a high yield of up to 95% after a reaction within a maximum of 3 hours to the price in the manufacture of a compound of formula (2) using a cheap zinc powder. These methods, even if using a conventional Pd expensive reducing agent it is possible to solve the problem of an unstable yield of 50-95% with a reaction time required for a long period of time.
[122]
As a result, it can be seen the manufacturing method of the benzylamine compound of the formula (2) is a conventional process compared to the process time and process cost such that the process efficiency is greatly improved.
[123]
In addition, shortening the process time by up to two hours before the compound of formula 8 with a compound of the formula (6) in relation to the production of Ada manta carbonyl benzoyl anhydride of formula (3), the starting material is greatly reducing the amount of solvent and the acid required in the manufacture even when it is possible to ensure a 90% yield.
[124]
Furthermore, the separation also cheap reagents is possible, and after the reaction the desired compound benzoic acid amide compound of formula I in the form of the compound of formula 3 in the production reaction of the formula (1) or more easily can take place, and 75% as the roughness and yield easily it can be removed. This method can be seen that use of expensive reagents and catalyst, and 30% of is made of a low yield, a highly improved process when the separation of the desired compound In comparison to the conventional way of holding the challenge.
[125]
As a result, manufacture of benzoic acid derivatives of the general formula (I) of the present invention the bar presented in Scheme 4 is the preparation of a compound of interest in a short time in a high yield can be possible, and replace the reagent used in each step at a lower reagent In addition, there may also reduce its usage. In addition, there is an advantage that because of the high reproducibility and reliability can be produced in the reaction of the desired compound.
[126]
Accordingly, the production process according to the present invention can be preferably applied to a mass production process of a benzoic acid derivative of the formula (I).
[127]
Benzoic acid amide compound of the formula I prepared in this way can be used in the cosmetic composition take the whitening effect, and is also applicable to other areas in addition.
[128]
For example, because of the skin whitening effect and is useful as a component of cosmetics for skin external preparations, in particular bleaching. The final product contained in the external preparation for skin may be used as a compound, an isomer thereof, a pharmaceutically acceptable salt, prodrug thereof (pro-drug), any one or more form of a hydrate and solvate thereof.
[129]
Mode for the Invention
[130]
The described embodiments to assist in understanding of the present invention below. The following examples are not only applicable to an embodiment of the effect of the present invention, the scope and effects of the present invention it is not limited thereto.
[131]
Preparation 1: Preparation of 2,4-dihydroxy hydroxy-benzylamine
[132]
[Reaction Scheme 5]
[133]
[134]
2,4-Dihydroxy-benzaldehyde with mixing (50g) and water (600mL) and stirred was added dropwise to hydroxylamine hydrochloride (32.7g). Slow dropwise addition of 0.23M sodium carbonate solution (200mL) and the resulting mixture was stirred at room temperature for 1 hour. After all the starting material disappeared filtering the resulting solid in a reaction solution and washed with water to give the 2,4-dihydroxy-benzaldehyde oxime (54g, 97% yield).
[135]
1H-NMR(300MHz, DMSO-d6) 10.9(brs, 1H), 10.05(brs, 1H), 9.76(brs, 1H), 8.19(s, 1H), 7.23 (d, 1H), 6.30(s, 1H), 6.28(s, 1H)
[136]
Into the 2,4-hydroxy-benzaldehyde oxime (5.5g) prepared above in a new flask with stirring under ice-cooling was added to 6M hydrochloric acid solution (48ml) was added dropwise zinc powder (9.42g) slowly. A first temperature within the reaction vessel exerts little by little and stirred to maintain a less than 40. After adding all of the zinc stirred for 2 hours at room temperature and the excess zinc After confirming the disappearance of starting material was removed by filtration and the filtrate was concentrated under reduced pressure to remove water to give the 2,4-hydroxy benzylamine hydrochloride in condition.
[137]
Prepared 2,4-dihydroxy-benzyl amine (5.5g, 90% yield) is obtained as a hydrochloride form in the solid state, was used for the next reaction without further purification.
[138]
Example 1: 5 - adamantane -1-yl -N- (2,4- dihydroxy- benzyl ) -2,4 -dimethoxy -benzoic acid O Preparation of imide
[139]
The title compound was prepared in accordance with the following reaction.
[140]
[Scheme 6]
[141]
[142]
(1) 5-adamantane-1-one Preparation of 2,4-dimethoxybenzoic acid
[143]
2 hours 2,4-dimethoxy-benzoic acid (10g) and 1-adamantanol (9.2g) and then added dropwise acetic acid (4mL) and concentrated sulfuric acid (6.7mL) trifluoroacetate while stirring was dissolved in dichloromethane (120mL) It was refluxed for. After distillation under reduced pressure to a stirring solution of the residue dissolved in ethanol (100mL) and water (100mL) and stirring it was adjusted to a pH of 6 using a solution of potassium hydroxide solution 50%. The resulting solid was filtered and placed in ethanol (30mL) and 1N hydrochloric acid solution (120mL) to the solids were filtered the resulting solid and stirred for 1 hour, 5-adamantane-1-yl-2,4-dimethoxybenzoic acid to give the (17g, 97% yield).
[144]
1H-NMR(300MHz, DMSO-d6) 12.07(brs, 1H), 7.57 (s, 1H), 6.63(s, 1H), 3.89(s, 3H), 3.84(s, 3H), 1.99(s, 9H), 1.71(s, 6H).
[145]
[146]
(2) 5- adamantane -1-yl-2,4- dimethoxy-benzoic acid Preparation of the non-whiskers
[147]
(1) 5-adamantane-1-yl-2,4-dimethoxybenzoic acid (9.1 g) was dissolved in dichloromethane (50mL) to process a mixed anhydride form under ice-cooling triethylamine (4.8 manufactured by It was added to ml) was added dropwise ethyl chloroformate (3.3mL) and stirred for 30 minutes. Later the hydrochloride was used only after the removal of the filtered solution produced when using.
[148]
[149]
(3) 5- adamantane -1-yl -N (2,4- dihydroxy- benzyl ) -2,4 -dimethoxy -benzoic acid amides prepared
[150]
Was added triethylamine (4.8ml) were dissolved in a 2,4-di-hydroxy-benzylamine hydrochloride obtained in Preparation Example 1 in N, N'- dimethylformamide (50ml) was stirred for 5 minutes.
[151]
The solution of 5-adamantan-1-yl-2,4-dimethoxybenzoic acid anhydride solution obtained in the above (2) was added dropwise with stirring. The temperature of the reaction vessel is maintained at or below 25 degrees and stirred for 2 hours at room temperature after.
[152]
After completion of the reaction diluted in dichloromethane (50mL) and extracted with water (100ml). The organic layer was washed again with 1N hydrochloric acid aqueous solution and a saturated sodium bicarbonate solution and an excess of brine and the organic layer collected and dried over activated clay and anhydrous magnesium sulfate. The solution mixture was filtered and recrystallized using dichloromethane and hexane was concentrated under reduced pressure after the target compound O as a white solid 5-adamantan-1-yl -N (2,4- dihydroxy-benzyl) -2,4- dimethoxy-benzoic acid amide (9.45g, yield 75%) was obtained.
[153]
1H-NMR(300MHz, DMSO-d6) 9.67(s, 1H), 9.13(s, 1H), 8.51(m,1H), 7.78 (m, 1H), 6.92(d, 1H, J=8.1Hz), 6.66(s, 1H), 6.27(s, 1H), 6.16(d, 1H, J=8.1Hz), 4.30(d, 2H, J=5.4Hz), 3.93(s,3H), 3.88(s,3H), 1.98(s, 9H), 1.71(s, 6H).
[154]
[155]
Comparative Example 1: 5 - adamantane -1-yl -N (2,4- dihydroxy- benzyl ) -2,4 -dimethoxy -benzoic acid O Preparation of imide
[156]
Republic of Korea by the method of the bar according to claim 2013-00159954 Patent Publication, it was prepared the same as in Example 1, the title compound.
[157]
[158]
Example 2: 5 - adamantane -1-yl -N- (2,4- dihydroxy-benzyl ) -2,4-dihydroxy-benzoic acid Preparation of amides
[159]
Except the starting material 2,4-dimethoxy-benzoic acid was used to form 2,4-dihydroxy benzoic acid, and instead, performed in the same manner as in Example 1, the title compound was prepared.
[160]
[Scheme 7]
[161]
[162]
1H-NMR(300MHz, DMSO-d6) 12.41(s, 1H), 9.91(s,1H), 9.40(s,1H), 9.09(s,1H), 8.83 (m, 1H), 7.47 (s,1H), 6.89(d, 1H, J=8.1Hz), 6.26(s, 2H), 6.16(d, 1H, J=8.1Hz), 4.29(m, 2H), 2.02(s, 9H), 1.70(s, 6H).
[163]
[164]
Example 3: 5 - adamantane -1-yl -N- (2,4- dihydroxy-benzyl ) -2-hydroxy-4- methoxy -ben producing a premature infant imide
[165]
Except the starting material 2,4-dimethoxy-benzoic acid was used to form 2-hydroxy-4-methoxybenzoic acid instead, performed in the same manner as in Example 1, the title compound was prepared.
[166]
[Reaction Scheme 8;
[167]
[168]
1H-NMR(300MHz, DMSO-d6) 12.73(s, 1H), 9.40(s,1H), 9.11(s,1H), 8.95 (m,1H), 7.52 (s,1H), 6.90(d, 1H,J=8.4Hz), 6.43(s, 1H), 6.28(s, 1H), 6.17(d, 1H, J=8.4Hz), 4.31(d, 2H, J=5.4Hz), 3.79(s,3H), 2.00(s,9H), 1.71(s, 6H).
[169]
[170]
Experimental Example 1: Comparison of yield and reaction time
[171]
To to to Example 1 and Comparative Example 1, measurement of the reaction time and yield required for the preparation of compounds shown in Table 1 below. The reaction time was, except for the time, such as after-treatment, and to calculate only the time required for the reaction.
[172]
TABLE 1
Comparative Example 1 Example 1
The total reaction time (hr) 24 hours 4.5 hours
yield(%) 45% 75%

[173]
The comparison in Table 1 The results of Example 1 and Example 1, was the time required for manufacturing the same compound significantly reduced in the case of Example 1, the number is found to be significantly increased in yulmyeon.
[174]
With this result, the production method of the amide acid presented in the present invention and simultaneously reduce the total process time and to allow the compound prepared in yield, it can be seen that preferably applicable to the mass production process.

WE Claims

[Claim 1]To be represented by the reaction formula 1, wherein performing the formula (2) of benzyl amine and amide coupling reaction of Ada manta carbonyl benzoyl anhydride of formula (3) under a basic catalyst; method for producing a benzoic acid derivative represented by the general formula (1), comprising: [Reaction Scheme 1] (in the above scheme 1, R 1 to R 4 is different from or equal to each other, each independently represent a hydrogen, a hydroxy group, a C1 to C5 alkoxy group, C3 to cycloalkoxy group, C6 to aryloxy C20 of C6 , or a C1 to C5 haloalkoxy group, and R a 5 is an alkyl group of C1 to C6)
[Claim 2]
2. The method of claim 1, wherein R 1 and R 2 is a methoxy group, R 3 and R 4 is a process for producing a benzoic acid derivative wherein the hydroxy group.
[Claim 3]
The method of claim 1 wherein the base catalyst, triethylamine, pyridine, N, N- ethyldiisopropylamine, N- methyl morpholine, and benzoic acid derivatives, characterized in that any one of selected from the group consisting of a mixture thereof the method of manufacture.
[Claim 4]
The method of claim 1, wherein the process for producing a benzoic acid derivative benzylamine compound of the formula (II) characterized in that used as the hydrochloride in the form of a solid.
[Claim 5]
According to claim 1, Ada manta carbonyl benzoyl anhydride of the formula (3) The method for producing the benzoic acid derivatives, characterized in that the form of mixed anhydride (mixed anhydride).
[Claim 6]
The method of claim 1 wherein the amide coupling reaction of one member selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, ethane, chlorobenzene, 1,1,2-trichloroethane and mixed solvents thereof with process for producing a benzoic acid derivative according to claim which is carried out in the presence of a solvent.
[Claim 7]
To be represented by the reaction formula 2, T1) by reacting a benzaldehyde compound with a hydroxylamine of the formula (4) in a basic aqueous solution to prepare a benzaldehyde oxime compounds of formula (5); And T2) the acidic aqueous solution in the step of processing the benzaldehyde oxime compounds of formula 5 with a reducing agent; method for producing a benzyl represented by the formula (2), characterized in that for manufacturing, including the amine compound: [Reaction Scheme 2] (Scheme 2 in, R 3 and R 4 are different or equal to each other, and each independently hydrogen, hydroxy, C1-alkoxy, C3 to cycloalkoxy group, C6 to aryloxy C20 of C6 of C5, or a C1 to C5 of haloalkoxy group a)
[Claim 8]
Claim 7, wherein T1) a basic aqueous solution in step is sodium carbonate, and benzyl, characterized in that the aqueous solution containing the base of one member selected from sodium hydrogen carbonate, the group consisting of potassium carbonate, a mixture of potassium bicarbonate, and their amine a process for the preparation of a compound.
[Claim 9]
The method of claim 7, wherein the T2) of the reducing agent step process for producing a benzylamine compound, characterized in that zinc.
[Claim 10]
The method of claim 7, wherein the T2) the acidic aqueous solution of step is a process for producing a benzylamine compound, characterized in that an aqueous solution containing hydrochloric acid.
[Claim 11]
The claim 7 to claim 10, wherein the Ada manta carbonyl benzoyl anhydride of formula (II) of the benzyl amine compound, formula (3) prepared according to any one of the steps for performing the amide coupling reaction under a basic catalyst; by formula (1) containing a process for producing a benzoic acid derivative represented: [reaction formula 1] (in the above scheme 1, R 1 to R 4 is different from or equal to each other, each independently represent a hydrogen, a hydroxy group, an alkoxy group of C1 to C5, a C3 to C6 cycloalkoxy groups, C6 to C20 aryloxy group, or a C1 to C5 haloalkoxy group, and R a 5 is an alkyl group of C1 to C6)