TW200900376A - Method for producing 4-aminomethylbenzoic acid - Google Patents

Abstract

Disclosed is a method for efficiently producing 4-aminomethylbenzoic acid, which is a production intermediate for tranexamic acid or cetraxate at low cost. Specifically disclosed is a method for producing a compound represented by the formula (3) below, which is characterized in that a compound represented by the formula (2) below (wherein R represents a C1-C6 alkyl group) is obtained by heating a compound represented by the formula (1) below in a C1-C6 alcohol, and the thus-obtained compound is subjected to catalytic reduction in an aqueous ammonia solution or a mixture of an aqueous ammonia solution and an organic solvent in the presence of a metal catalyst. (1) (2) (3)

Description

200900376 IX. OBJECTS OF THE INVENTION: TECHNICAL FIELD The present invention relates to a method for producing a heart amine methylbenzoic acid which can be used as a manufacturing intermediate of pharmaceuticals and the like. [Prior Art]

Tranexamic acid is known as an antiplasmin having a chemical structure of trans-4-aminononylcyclohexane-1-carboxylic acid, which is useful for inhibiting bleeding and inhibiting wetness. A medicinal product such as rash such as rash or suppression of congestion or swelling such as tonsillitis. There are various methods for producing tranexamic acid, and examples thereof include the following methods. [Chemical 1] CH0

C00H

COOH : COOH tranexamic acid ch2nh2 h2 / metal catalyst _ H2 / metal catalyst NH 〆 organic solvent

COOH In the above production method, 'contact 4-reductive benzoic acid in ammonia. methanol to produce 4-aminomethylbenzoic acid', followed by contact reduction of the benzene ring to obtain cis and trans-4- After amidino-cyclohexane_1-carboxylic acid, isomerized by treatment with a base or oxygen, thereby selectively producing trans-4-aminomethylcyclohexane-1-decanoic acid Acid) (Patent Document ^3). In the above step of subjecting 4-mercaptobenzoic acid to contact reduction in ammonia sterol, the Schiff base formed by the reaction of the aldehyde group with ammonia is reduced to produce 4-aminomethylbenzoic acid. In this step, 'Schiff base is not produced, 4_曱醯 129658.doc 200900376-based benzoic acid is reduced to produce 4-hydroxymethylbenzoic acid by-product. Further, the resulting 4-aminomercaptobenzoic acid and 4-methylmercaptobenzoic acid-forming test were reduced in the following manner to produce a secondary amine. [Chemical 2]

Therefore, a method in which a solution of 4-methylmercaptobenzoic acid and ammonia is heated to sufficiently form a Schiff base and then subjected to contact reduction is also employed. In this case, there is also a case where the following trimer is produced as a by-product. The desired effect cannot be obtained (Patent Document 1). [Chemical 3]

As described above, there have been various improvements in the method for producing 4-aminomethylbenzoic acid from 4-mercaptobenzoic acid, but it is not a satisfactory production method, so that a more preferable production method is desired. [Patent Document 1] Japanese Patent Laid-Open Publication No. SHO-54-41839 [Patent Document 2] Japanese Patent Publication No. Sho 34-421 [Patent Document 3] Japanese Patent Publication No. Sho 54-7784 No. 129658.doc 200900376 [Invention] [Invention] Problem to be Solved] A method of producing a system of the present invention (Cetraxate). It is in the manufacture of intermediates that provide a kind of tranexamic acid and sulphuric acid ester, ie, 4-aminomethylbenzoic acid, which is cheap and efficient. [Technical means to solve the problem]

The method for the manufacture of i-methyl benzoic acid was carried out. 7 The research was carried out. The results were obtained from the method of "defective" and the production of 4' methyl-formic acid. invention. That is, the present invention provides a method of producing a compound represented by the following formula (3丨 &# _, and the needle (the formula (3) is characterized in that the compound represented by the following Λ 1 is

Heating in CcCV% to obtain a compound represented by the following fly (2), and in a mixture of a cyanide aqueous solution or an aqueous ammonia solution, in the presence of a genus of a genus Contact reduction, [Chem. 4] 129658.doc CH0

C00H 20U9UU376 [Chemical 5]

/OR HC—〇R

(2)

COOH (6-yard base) (where R is C.

[Chemical 6]

(3)

COOH is also a method for producing a compound represented by the formula (5), and the following is a special test for:

Heating in a Cl~C6_alcohol to obtain a compound in the mixture of the following formula (2) and a compound in the presence of a metal catalyst or an aqueous ammonia solution in the presence of a metal catalyst; The obtained compound; = the compound represented by the formula (4) represented by the formula (7), which is subjected to contact reduction to obtain a treatment by the lower or ammonia, and the obtained compound (4) is a base 129658.doc 200900376

[Chemical 7] CHO

COOH

[化8]

/OR HC-OR

COOH (where R is C! [Chemical 9]

(3) COOH

[化10]

COOH 129658.doc (4) 200900376 [Chem. 11]

C00H • [Effects of the Invention] The present invention is capable of producing an amine-based benzoic acid at a low cost and with high efficiency (the 'method' can therefore produce tranexamic acid (5) and citric acid inexpensively and efficiently, It also contributes to the medical field. [Embodiment] Hereinafter, 4-aminomercaptobenzoquinone is produced from 4-mercaptobenzoic acid (1) via 4_dialkoxymethylbenzoic acid (2). The conditions of the acid (3) are described in detail. In the production method of the present invention, the compound (1) is heated in a c-c6-alcohol to prepare a compound (2) in ammonia or a mixture of ammonia water and an organic solvent. In this case, the compound (2) is contact-reduced with a metal catalyst to produce a compound ti 0). . The Ci~C6-alcohol used in the above reaction may, for example, be a linear or branched alcohol, preferably a linear or branched alcohol, more preferably methanol, ethanol, n-propanol or isopropanol. Especially good is methanol. When the compound (1) is suspended in a Ci~CO-alcohol and heated to reflux for a specific period of time, the compound (2) is produced. The degree of formation or formation of the compound (2) "T was confirmed by HPLC (high performance liquid chromatography) or SIMR (nuclear magnetic resonance). Compound P) is preferably formed as close as possible to 129658.doc -11 - 200900376 100%. When the C-C6_alcohol suspension of the compound (1) is heated, it is not necessary to heat to the boiling point of the alcohol, (4) the reaction time is shortened and the temperature is easily controlled, and it is preferred to heat to the point of the alcohol. The compound (7) can be isolated, but does not have to be isolated, and it is preferably produced in the industrial process for the purpose of not being isolated and used in the lower-reduction reaction. When the compound (7) is not isolated, the alcohol to be used may be distilled off under reduced pressure or normal pressure for use in the next step, or may be used in the next step in the presence of an alcohol. The obtained compound (2) is preferably prepared by adding an appropriate amount of an aqueous sodium hydroxide solution to prepare a clear solution, which is cooled and used in the next step. The reduction S of the compound (7) should be carried out in a mixture of an aqueous ammonia solution and an organic solvent. The organic solvent used herein may, for example, be methanol, ethanol, n-propanol or isopropanol. The preferred ratio of aqueous ammonia to organic solvent in the mixed solution is i: 2 to 丨0: 1, more preferably i i. Of these, it is preferred to use ammonia water. 〃 Also, if the ammonia water is ammonia water at a concentration of 20% or more, it is more preferably μ% ammonia water. ° As the metal catalyst used in the contact reduction, Pd (# bar), RU (pair), Rh (money), and pt (inscription) which are usually used, preferably h and Rh, are preferred. It is a relatively cheap Ru in the platinum group catalyst. It is also preferable to use Ru to adsorb or adhere to a carrier such as activated carbon, alumina, diatomaceous earth or strontium gel, and to mention Hankou Ru and Ru-A12〇3. Wait as a representative example. The amount of the metal catalyst is not particularly positive. If the amount of the catalyst is small, the reaction time is prolonged. Therefore, for example, when 5% Ru-C is used, it is preferably used in comparison with the compound (2) to the ratio of 129658.doc 12· 200900376 1 to 10% of the amount of 5% iRu_c, more preferably 3 to 6%. The hydrogen pressure at the time of contact reduction is the pressure (initial pressure) at the time when hydrogen is sealed in the high pressure dad, and may be in the range of 5 to 100 kg/cm 2 , more preferably 1 〇 3 〇 kg/cm 2 ° and In the contact reduction, the high (four) is heated from the outside, and the external temperature may be in the range of m 2 m 2 : preferably, it is just ~ 17 passages, more preferably 145 to 165 ° C. The production method of the compound (7) of the present invention has two remarkable characteristics as compared with the production method (hereinafter, referred to as a conventional method) described in Japanese Laid-Open Patent Publication No. SHO-54-41839, and the like. That is, the production method of the present invention has the step of heating 4, methylmercaptobenzoic acid (1) with an alcohol to form 4-dimethoxymethylbenzoic acid (7), and dissolving the 4-diethoxymethylbenzoic acid (7). A remarkable feature of contact reduction in aqueous ammonia. In the conventional method, 4-methylmercaptobenzoic acid (1) is subjected to contact reduction directly in the presence of ammonia to produce 4-aminomethylbenzoic acid (3), but as described above, a large amount of by-products are reported. Actually, as described in the comparative examples described later, a large amount of 4-hydroxymethylbenzoic acid was produced in the conventional method. On the other hand, in the production method of the present invention via decantamoxymethylbenzoic acid (2), the yield of 4-aminomethylbenzoic acid (3) is improved by the formation of '4_-methylbenzoic acid The rate is also reduced. Further, in the conventional method, in the contact reduction of 4-methylmercaptobenzoic acid (1), ammonia is dissolved in an organic solvent such as methanol, and this production condition has a large disadvantage. That is, since the amount of ammonia which can be dissolved in an organic solvent such as methanol is very small as compared with the case of dissolving in water, it is related to the case of using ammonia water 129658.doc • 13- 200900376 Indium ▲: Toluene ammonia The solution, only from this point of view, also requires a large autoclave. Therefore, the equipment that is used to the earth is expensive and economically disadvantageous. High-grade I: In the production method of the present invention using ammonia water, since a -虱7' is used, a small autoclave can be utilized as compared with the conventional method. ^I know that the towel has been contact-reduced with ammonia relative to 4m-based benzoyl (1), so the gas must be removed after the reaction is completed. Nitrogen or air is bubbled in the reaction solution to remove ammonia from the reaction liquid. At this time, 1 releases ammonia into the human atmosphere, which not only causes a direct recruitment to the operator. It also causes air pollution problems, so it is necessary to recover the wind, which is usually absorbed into the water to recover ammonia. In the conventional method, since an ammonia/methanol solution is used, it is difficult to reuse ammonia, i.e., ammonia water, which is absorbed in human water. Therefore, in the conventional method, it is necessary to neutralize the aqueous solution of the recovered ammonia, which is not only economically unsatisfactory, but also produces waste. In the production method of the present invention, 4•dimethoxymethylbenzoic acid (7) is also subjected to contact reduction in aqueous ammonia. Therefore, it is necessary to recover excess ammonia after completion of the reaction. However, unlike the conventional method, since the production method of the present invention uses ammonia water, the ammonia recovered by absorption into water can be reused, which not only contributes to reduction in manufacturing cost but also contributes to the environment. As described above, the production method of the present invention produces 4-aminomethylbenzoic acid (3) via 4-dioxymethylbenzoic acid (2), so that the number of steps is increased as compared with the conventional method, but not only The formation of by-product, 4-hydroxymethylbenzoic acid, can be reduced, and the recovered ammonia can be reused due to the use of ammonia water, which is economically and environmentally preferable. 129658.doc -14· 200900376 Further, the reaction liquid containing 4:aminomethyl benzoic acid (3) obtained by the method can be used to remove excess ammonia by bubbling with nitrogen or the like, and can be directly used in the following In the lower benzene ring reduction step. The step of producing the acid (5) from the compound (3) produced by the above method will be described. Contact with 4-aminomethylbenzoic acid (3) obtained by the above method using a metal catalyst such as Ru-C or Pt in the same manner as the method described in JP-A-49-62443 or the like. Reduction, preparation of cis and trans-4-aminomethylcyclohexane calcined small formic acid (4), and then isomerized by treatment or ammonia treatment, thereby selectively producing trans-4_aminomethyl Cyclohexane-benzoic acid (5) (tranexamic acid). Further, regarding the method of introducing cis 4-aminomethylcyclohexane decanoic acid (4) into trans 4-aminononylcyclohexanecarboxylic acid (5), Japanese Patent Publication No. Sho 41_14830, Japan is used. The method described in Japanese Patent Publication No. Sho 42-237, Japanese Patent Publication No. Sho 54-3867, and Japanese Patent Publication No. Sho 54-7784 may be used. [Examples] Hereinafter, the present invention will be specifically described by way of examples. However, the examples do not limit the invention. [Example 1] 1.00 g of (Ald' Lot. 12928MC) 4-methylmercaptobenzoic acid (1) and 5_00 mL (5 v/w) of methanol were added to a reaction vessel, and heated to an external temperature of 80 on an oil bath. ~90. (:, reflux for 3 hours. The reaction solution was left to cool to about 30 ° C. 129658.doc 15- 200900376 One part of the sample reaction solution was 'concentrated and dried,' and the concentrated residue was dissolved in D2 , and confirmed by NMR. Formation of 4-dialkyloxymercaptobenzoic acid (2) and completion of its formation reaction NMR (D20) δ: 7.59 (2Η, d), 7.19 (2H, d), 5.15 (1H, s), 3.10 (6H, s). Add 0.27 g (l equivalent) of sodium hydroxide, 4.5 mL of 28% ammonia water, and 50 mg of 5% Ru-C to the above reaction solution, and inject into the autoclave and blow in. Hydrogen at 10 kg/cm2 (initial pressure) was reacted for 9 hours at a temperature of 150 to 16 (rc (pressure at the time of heating at 21 kg/cm2). Removal of the catalyst by filtration'. The reaction solution was concentrated and dried, and then utilized. The residue was analyzed by Hplc (column carrier, octadecyl group; ε 烧), and it was confirmed that 0.95 g (yield 93.6%) of 4-aminomethylbenzoic acid (3) was produced. Further, as a by-product, 3.6 〇/〇 of 4-hydroxymethylbenzoic acid and 25% of 4-methylbenzoic acid were formed. Further, one of the above residues was partially dissolved in D2 ,, and nmr was measured. NMR (D2〇) δ: 7.64 ( 2Η, d), 7.20 (2H, d), 3.62 (2H, s).

[Comparative Example 1] The method described in Japanese Patent Laid-Open No. SHO34-42 No. 0.25 g of ruthenium 4-methylmercaptobenzoate was added to a 5 Torr autoclave at 3 Torr. 7.5 Add 7.5 mL of 2.0 N-ammonia·methanol solution to the following internal temperature, add 0.07 g of sodium hydroxide and 〇〇3 mgw^Ru_c, and the pressure of chlorine is 5〇 (four) force initial pressure) 12〇. The reaction was carried out for 1 hour under the conditions of (the analysis was carried out by HPLC (f column carrier: analysis of the reaction liquid of the octagonal basestone) to confirm the formation of _·22 g (yield 89.2%) of 4-aminomethylbenzoic acid ( 3). As a product of 4, 6 3% of 4-methylbenzoic acid was produced. 129658.doc 200900376 [Comparative Example 2] 专利本专利公开昭5"1839, 曰本专利特听听49 132031 The method described in the method. Add 30.30 g of 4_Yin-based benzene-f-acid T ester to 50 mL of high-frequency bismuth, add 7.5 mL·2.0 N_ ammonia. methanol solution and 50 sponge catalyst (Kawasei The manufactured NDT-9(R) was reacted for 1 hour under the conditions of a hydrogen pressure of 1 〇kg/cm2 (initial pressure) and an external bath of 120 C. The catalyst was removed by filtration, and the reaction solution was concentrated to dryness, and then HPLC was used. Column column carrier: octadecyl decane) analysis of the residue 'Results confirmed the formation of 4-·24 g (yield 79.6%) of methyl 4-aminomercaptobenzoate. 129658.doc 17-

Claims (1)

200900376 X. Patent application: A method for producing a compound represented by the following formula (3), characterized in that a compound represented by the following formula (1) is bitten in a CpC6-alcohol- a compound represented by the following formula 1, followed by an ammonia aqueous solution, a mixture of an aqueous emulsion solution and an organic solvent, and a contact reduction under a metal catalyst; C00H [Chemical 2] (2) (wherein 'R denotes C丨~C:6-alkyl) [Chemical 3] 』_2 y) ο) C〇〇H ο 129658.doc 1 ·If the request method is manufactured, the metal touch The media is Ru_c or as 200900376 AI2O3. 3. The method of manufacturing of claim 1 or 2, wherein the metal catalyst is Ru-c. 4. The manufacturing method according to claim 1 or 2, wherein the hydrogen pressure used in the contact reduction is 5 to 30 kg/cm2. 5. The manufacturing method according to claim 1 or 2, wherein the contact reduction temperature is 50 to 250. . . 6. A method for producing a compound represented by the following formula (5), characterized in that: a compound represented by the following formula (1) is added to a c-g &alcohol; (2) A compound such as _main _ -u ^ ^), followed by contact reduction with an aqueous solution of ammonia or hydrazine in the presence of an organic solvent, in the presence of a metal catalyst, in the presence of a metal catalyst. The compound A f is a compound represented by the following formula (3), and the sputum (3) represented by (4) is subjected to contact reduction to obtain a sputum of the following formula, which is treated by _ / , and then obtained. Compound (4) with test or ammonia addition [Chemical 4] (1) C00H 129658.doc 200900376 [Chemical 5] (wherein R represents Q [6] C6-alkyl) (3) C00H [Chemistry 7] (4) C00H [Chem. 8] C00H 129658.doc (5) 200900376 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best Chemical formula showing the characteristics of the invention: (none) 1 129658.doc