JPH069522A - Production of 4-dedimethylamino-12a-deoxytetracycline - Google Patents

Abstract

PURPOSE:To obtain 4-dedimethylamino-12a-deoxytetracycline useful for nodose rheumatism, periodontal diseases, etc., by hydrolyzing a specific 4- dedimethylaminotetracyclin-12a-ester derivative in a solvent in the presence of a metal catalyst. CONSTITUTION:A 4-dedimethylaminotetracyclin-12a-ester derivative of formula I (R is H, alkyl, aryl or aralkyl) (e.g. 4-dedimethylamino-12a-formyltetracycline) is hydrolyzed in a solvent such as tetrahydrofuran in the presence of a metal catalyst (preferably palladium carbon or Raney nickel) to give 4- dedimethylamino-12a-deoxytetracycline of formula II and formula III. 4- Dedimethylamino-12a-deoxytetracycline is useful for treating diseases characterized by excessive destruction of collagen such as nodose rheumatism, periodontal diseases, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 4-dedimethylamino-
It relates to a method for producing 12a-deoxytetracycline. 4-dedimethylamino-12 obtained by the present invention
a-deoxytetracycline is associated with rheumatoid arthritis,
It is useful for the treatment of diseases characterized by excessive collagen destruction such as periodontal disease (JP-A-61-243023).
(See the official gazette).

[0002]

2. Description of the Related Art Tetracycline antibiotics or salts thereof such as hydrochlorides (hereinafter, these are abbreviated as tetracyclines) are widely used as antibiotics having a wide antibacterial spectrum. 198
In the third year, the anti-collagenase action of minocycline in periodontal disease was reported [see J. Periodontal Res., Vol. 18, p. 516]. Since then, along with the results of studies on various diseases characterized by the destruction of collagen, the clinical application of tetracyclines for the treatment of these diseases has been studied. On the other hand, attention has been paid to the collagenase inhibitory action of tetracyclines, and the synthesis of various derivatives having the skeleton thereof has been studied. For example, 4
-Compounds obtained by chemically modifying the tetracycline skeleton such as dedimethylaminotetracycline do not have antibacterial activity and have anti-collagen-destroying enzyme activity or anti-collagenase activity, so long-term administration of drugs cannot be avoided. It is known to be useful for the treatment of diseases characterized by excessive collagen destruction, such as arthritis and periodontal disease (see JP-A-61-243023). 4-dedimethylamino-12a-deoxytetracycline having a structure similar to the above 4-dedimethylaminotetracycline is tetracycline in an acetic acid aqueous solution,
It has been reported to be obtained by reduction with zinc [A. Green et al., Journal of the American Chemical Society (J. Amer. Chem. Soc.), No. 82].
Vol., Page 3946 (1960)].

[0003]

According to the method described in the above document, it is not possible to obtain 4-dedimethylamino-12a-deoxytetracycline with high yield and high purity. That is, the synthesis of 4-dedimethylamino-12a-deoxytetracycline was attempted by the method described in the above literature, and the isolated product was analyzed by high performance liquid chromatography (hereinafter sometimes referred to as HPLC), The main product is 4-dedimethylaminotetracycline (content 59%), and the other products are 4-dedimethylamino-12a-deoxytetracycline (content 13%) and 4-dedimethylaminoanhydrotetracycline (content 13%). The content was 23%) (see Comparative Example described later). Further, according to the method described in the literature, an attempt was made to purify the crude product by recrystallization, but 4-dedimethylamino-12a-deoxytetracycline could not be obtained in high purity. Therefore, an object of the present invention is to provide a method for producing 4-dedimethylamino-12a-deoxytetracycline in high yield and high purity.

[0004]

According to the present invention, the above-mentioned object is achieved by the following general formula (I):

[0005]

[Chemical 2]

[In the formula, R represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group.] 4-dedimethylaminotetracycline-12a-ester derivative (hereinafter, this is abbreviated as ester derivative (I)) Do)
It is achieved by providing a method for producing 4-dedimethylamino-12a-deoxytetracycline, which comprises hydrolyzing hydrogen peroxide in a solvent in the presence of a metal catalyst.

Examples of the alkyl group represented by R in the above general formula (I) include a methyl group, an ethyl group, a propyl group, a butyl group and a pentyl group. Examples of the aryl group include a phenyl group, tolyl group, naphthyl group, p-methoxyphenyl group, p-chlorophenyl group and the like, and examples of the aralkyl group include a benzyl group, a methylbenzyl group, a methoxybenzyl group, Examples thereof include a phenethyl group.

Specific examples of the ester derivative (I) include:
For example, 4-dedimethylamino-12a-formyltetracycline, 4-dedimethylamino-12a-acetyltetracycline, 4-dedimethylamino-12a-
Propionyl tetracycline, 4-dedimethylamino-12a-benzoyl tetracycline, 4-dedimethylamino-12a-toluoyl tetracycline and the like can be mentioned.

Examples of the metal catalyst used in the present invention include palladium carbon and Raney nickel.
Mention may be made of metal catalysts usually used for hydrogenolysis of organic compounds, but palladium carbon or Raney-nickel is preferred. The metal catalyst is preferably used in the range of 0.5 to 100% by weight, more preferably 10 to 40% by weight, based on the ester derivative (I) as a raw material.

As the reaction solvent, ester derivative (I) is used.
Is preferably a solvent which does not hinder the progress of the reaction, and examples thereof include ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, and dimethyl. Formamide and the like are used. The amount of the solvent used is preferably in the range of 1 to 500 ml, and more preferably in the range of 5 to 200 ml, per 1 g of the ester derivative (I) as a raw material.

The reaction is preferably carried out under a hydrogen pressure of 1 to 200 atm in absolute pressure, more preferably 1 to 100 atm. Further, the reaction is usually preferably carried out at a temperature in the range of room temperature to 200 ° C, more preferably at a temperature in the range of room temperature to 120 ° C.

Isolation and purification of 4-dedimethylamino-12a-deoxytetracycline thus obtained from the reaction mixture can be carried out, for example, as follows. That is, the reaction mixture was filtered and the filtrate was concentrated to give a crude product of 4-dedimethylamino-12a-deoxytetracycline, which crude product was purified by reprecipitation, column chromatography, HPLC, recrystallization and the like. , 4-dedimethylamino-12a-deoxytetracycline is obtained.

The 4-dedimethylamino-12a-deoxytetracycline obtained according to the present invention has the following structural formula:

[0014]

[Chemical 3]

And

[0016]

[Chemical 4]

It is a mixture of two isomers represented by:

The ester derivative (I) as a raw material can be obtained by esterifying a known substance, 4-dedimethylaminotetracycline. The esterification of 4-dedimethylaminotetracycline is carried out under the reaction conditions usually employed for esterification of organic compounds. For example, 4-dedimethylaminotetracycline in an inert solvent such as methylene chloride or chloroform in the presence of a condensing agent such as dicyclohexylcarbodiimide,
It can be obtained by condensing with a carboxylic acid such as formic acid, acetic acid or benzoic acid.

[0019]

EXAMPLES The present invention will be specifically described below with reference to examples. The present invention is not limited to these examples. In Examples, 4-dedimethylamino-12a
-Deoxytetracycline purity was determined by HPLC.

Reference Example 1 1110 g of dicyclohexylcarbodiimide was dissolved in 30 kg of methylene chloride, and 162 ml of acetic acid was added to the resulting solution.
Was added and the mixture was stirred at room temperature for 1 hour, and then 3.3 g of 4-dimethylaminopyridine was added. The obtained suspension was ice-cooled, and a solution obtained by dissolving 1080 g of 4-dedimethylaminotetracycline in 4 l of 1,4-dioxane was slowly added dropwise to this suspension. After the dropping was completed, the temperature was returned to room temperature and then the mixture was stirred at the same temperature for 90 hours. The reaction solution obtained was filtered, the filtrate was concentrated under reduced pressure, dicyclohexylurea was removed from the obtained crude product by reprecipitation, and then recrystallized from ethanol.
375 g of 4-dedimethylamino-12a-acetyltetracycline having the following physical properties was obtained (yield 31
%). ↑ 1 H-NMR (270 MHz, CDCl ↓ 3) δ:
1.50 (3H, s), 1.83 to 1.92 (1H,
m), 2.05 (1H, m), 2.12 (3H, s),
2.43 to 2.50 (1H, m), 2.77 to 2.81
(1H, m), 3.14 to 3.19 (2H, m), 4.
95 (1H, bs), 6.89 to 6.94 (1H,
m), 7.08 to 7.12 (1H, m), 7.50 to
7.57 (1H, m), 8.99 (2H, bs), 1
1.72 (1H, bs) FD mass spectrum: [M] ↑ + 443

Reference Example 2 12.4 g of dicyclohexylcarbodiimide was dissolved in 480 ml of methylene chloride, and 1.13 of formic acid was added to the resulting solution.
After adding ml, and stirring at room temperature for 1 hour, 30.7 mg of 4-dimethylamino pyridines were added. The obtained suspension was ice-cooled, and a solution obtained by dissolving 12.0 g of 4-dedimethylaminotetracycline in 120 ml of 1,4-dioxane was slowly added dropwise to this suspension. End of dripping 1
After 0 minutes, the temperature was returned to room temperature, then 13.5 at the same temperature.
Stir for hours. The reaction solution obtained was filtered, the filtrate was concentrated under reduced pressure, and dicyclohexylurea was removed from the obtained crude product by reprecipitation to give 4-dedimethylamino-12a-formyl having the following physical properties. 7.5 g of tetracycline was obtained (yield 58%). FD mass spectrum: [M] ↑ + 429

Reference Example 3 1.03 g of dicyclohexylcarbodiimide was dissolved in 20 ml of methylene chloride and benzoic acid 319 was added to the resulting solution.
After adding mg and stirring at room temperature for 1 hour, 3 mg of 4-dimethylamino pyridines were added. The obtained suspension was ice-cooled and 4-dedimethylaminotetracycline 1.00 g
Was dissolved in 5 ml of 1,4-dioxane, and the resulting solution was slowly added dropwise. Ten minutes after the completion of the dropping, the temperature was returned to room temperature, and then the mixture was stirred at the same temperature for 10 hours. The reaction solution obtained was filtered, the filtrate was concentrated under reduced pressure, and dicyclohexylurea was removed from the obtained crude product by reprecipitation to give 4-dedimethylamino-12a-benzoyl having the following physical properties. 604 mg of tetracycline
Obtained (yield 48%). FD mass spectrum: [M] ↑ + 505

Example 1 200 mg of 4-dedimethylamino-12a-acetyltetracycline was dissolved in 20 ml of tetrahydrofuran, the resulting solution was transferred to an autoclave, 40 mg of 5% palladium carbon was added, and the inside of the reaction vessel was replaced with hydrogen. The hydrogen pressure was adjusted to 50 atm while stirring the reaction mixture, and the reaction was carried out at 120 ° C. for 2 hours. After confirming almost disappearance of the raw materials by HPLC, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was reprecipitated from n-hexane-ethyl acetate. 153 mg of 4-dedimethylamino-12a-deoxytetracycline was obtained (yield 88%, purity 98% or more). The resulting 4-dedimethylamino-12a-deoxytetracycline is a mixture of two isomers,
Two isomers were separated by HPLC. The respective physical property values are shown below. Isomer 1: ↑ 1 H-NMR (500 MHz, CDCl ↓ 3) δ:
1.02 (1H, dd, J = 24.5 Hz and 12.
0Hz), 1.66 (3H, s), 2.20 (1H,
m), 2.27 (1H, dd, J = 16.1 Hz and 14.3 Hz), 2.39 (1H, m), 2.47 (1
H, dd, J = 16.1 Hz and 4.5 Hz), 2.
73 (1H, m), 3.67 (1H, d, J = 4.0H
z), 5.87 (1H, s), 6.87 (1H, d, J
= 8.0 Hz), 7.14 (1H, d, J = 8.0H)
z), 7.53 (1H, t, J = 8.0 Hz), 9.2
8 (1H, s), 12.23 (1H, s), 14.85
(1H, s), 17.94 (1H, s) ↑ 13 C-NMR (500 MHz, CDCl ↓ 3) δ:
27.6, 30.6, 32.0, 38.6, 45.7,
51.1, 71.3, 100.1, 105.1, 11
3.4, 115.6, 117.4, 138.0, 14
8.1, 163.0, 167.6, 173.4, 19
0.0, 194.8, 199.0 Isomer 2: ↑ 1 H-NMR (500 MHz, CDCl ↓ 3) δ:
1.56 (3H, s), 1.90 (1H, m), 1.9
5 (1H, dd, J = 25.0Hz and 11.5H
z), 2.49 (1H, m), 2.59 (1H, dd,
J = 18.6 Hz and 1.7 Hz), 2.89 (1
H, dd, J = 11.5 Hz and 6.5 Hz), 3.
07 (1H, dd, J = 18.6Hz and 6.2H
z), 3.44 (1H, d, J = 5.0 Hz), 5.8
2 (1H, s), 6.93 (1H, d, J = 8.0H
z), 7.06 (1H, d, J = 8.0 Hz), 7.4
5 (1H, t, J = 8.0 Hz), 9.22 (1H,
s), 12.12 (1H, s), 15.05 (1H,
s), 18.00 (1H, s) ↑ 13 C-NMR (500 MHz, CDCl ↓ 3) δ:
22.2, 25.6, 29.3, 37.4, 43.0,
51.1, 69.5, 100.8, 104.2, 11
4.2, 115.0, 118.3, 136.6, 14
6.6, 163.0, 173.4, 176.3, 19
1.7, 193.1, 193.8

Example 2 7.5 g of 4-dedimethylamino-12a-formyltetracycline was dissolved in 60 ml of tetrahydrofuran,
The resulting solution was transferred to an autoclave, 1.5 g of 5% palladium carbon was added, and the inside of the reaction vessel was replaced with hydrogen.
While stirring the reaction mixture, the hydrogen pressure was adjusted to 30 atm,
The reaction was carried out at 55 ° C. for 84 hours. After confirming the disappearance of the raw materials by HPLC, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to give 4-dedimethylamino-12.
2.3 g of a-deoxytetracycline was obtained (yield 3
3%, purity 98% or more).

Example 3 200 mg of 4-dedimethylamino-12a-benzoyltetracycline was dissolved in 20 ml of tetrahydrofuran, the resulting solution was transferred to an autoclave, 40 mg of 5% palladium carbon was added, and the inside of the reaction vessel was replaced with hydrogen. The hydrogen pressure was adjusted to 50 atm while stirring the reaction mixture, and the reaction was carried out at 120 ° C. for 2 hours. The resulting reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to give 66 mg of 4-dedimethylamino-12a-deoxytetracycline.
Obtained (yield 43%, purity 98% or more).

Example 4 200 mg of 4-dedimethylamino-12a-acetyltetracycline was dissolved in 20 ml of tetrahydrofuran, the resulting solution was transferred to an autoclave, 40 mg of 5% palladium carbon was added, and the inside of the reaction vessel was replaced with hydrogen. The hydrogen pressure was adjusted to 30 atm while stirring the reaction mixture, and the reaction was carried out at 55 ° C for 12 days. After confirming almost disappearance of the raw materials by HPLC, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 54 mg of 4-dedimethylamino-12a-deoxytetracycline (yield 31%, purity 98% or more).

Example 5 200 mg of 4-dedimethylamino-12a-acetyltetracycline was dissolved in 20 ml of tetrahydrofuran, the resulting solution was transferred to an autoclave, 40 mg of 5% palladium carbon was added, and the inside of the reaction vessel was replaced with hydrogen. The hydrogen pressure was adjusted to 50 atm while stirring the reaction mixture, and the reaction was carried out at 120 ° C. for 2.0 hours. After confirming almost disappearance of the raw materials by HPLC, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. By reprecipitating the obtained crude product from n-hexane-ethyl acetate, 142 mg of 4-dedimethylamino-12a-deoxytetracycline was obtained (yield 82%, purity 98% or more).

Comparative Example 5 g of tetracycline was added to 70 ml of acetic acid and 30 ml of water.
Dissolved in a mixed solvent of. 3.3 g of zinc powder in the obtained solution
Was added, and the mixture was stirred at 25 ° C. under a nitrogen atmosphere. Reaction start 2
After 4 hours and 48 hours after the start of the reaction, zinc powder 3.3 g
Was added. 72 hours after the start of the reaction, the reaction mixture was filtered,
The filtrate was added to 355 ml of 0.5% dilute hydrochloric acid under ice cooling and allowed to stand for 1 hour. The deposited precipitate was collected by filtration and dried to obtain 2.8 g of a crude product. The crude product was 4-dedimethylaminotetracycline (content 59%), 4-dedimethylaminoanhydrotetracycline (content 23%) and 4-dedimethylamino-12a-deoxytetracycline (content 13%). Was a mixture of.

[0029]

According to the present invention, 4-dedimethylamino-12a-deoxytetracycline can be produced in high yield and high purity.

Claims (1)

[Claims] 1. The following general formula: (Wherein R represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group), and hydrogenolysis of the 4-dedimethylaminotetracycline-12a-ester derivative in a solvent in the presence of a metal catalyst. A method for producing 4-dedimethylamino-12a-deoxytetracycline, which comprises: