JPS5811423B2 - Method for producing α-6-deoxycycline - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing α-6-cyoxytetracycline represented by general formula (I): (wherein, X represents a hydrogen atom or OH, and Y represents a hydrogen atom).

The compound represented by the general formula (I) is known to have excellent antibacterial activity and is widely used in the treatment of many infectious diseases in humans and animals.

One of the best known of these is 6-cyoxy-6-α-methyl-5-hydroxytetracycline, which has been given the internationally accepted name "doxycycline."

The method for producing the compound represented by general formula (I) has various problems.

One of the most serious problems is that a large amount of the β-isomer of the target substance is produced during the reaction unless special techniques are used.

The reaction is similar to most natural products such as tetracyclines,
For example, chlortetracycline, tetracycline,
6-Methyl-6, which includes oxytetracycline, etc.
- This occurs especially when hydroxytetracyclines are directly hydrogenated.

Since the antibacterial activity of the β-isomer is extremely limited,
The therapeutic interest of the β-isomer has been lost.

Methods for obtaining a large amount of the desired (6-α-methyl) isomer have already been disclosed in several patent documents.

For example, 6-cyoxy-13-yl buttetracyclines are first prepared and then treated with a trialkyl phosphite (UK Patent No. 1,117,407) or destreamed by Raney nickel (US Pat. No. 3.1).
65,531)).

Furthermore, a method has already been disclosed in which a noble metal such as rhodium or palladium is used as a catalyst for hydrogenation of 6-deoxy-6-bumethyl-6-methylenetetracyclines (US Pat. No. 3,200,149).

However, the final product thus obtained is a mixture of isomers and contains a high percentage of the unwanted β-isomer, usually more than 30%.

Moreover, the catalyst is partially deactivated due to these reactions (US Pat. No. 3,444.19'8).

Moreover, since the unnecessary β-isomer must be removed from the final product, and some of the desired isomer is naturally lost during the removal of the β-isomer, the final yield will inevitably be reduced. becomes lower.

More recently, the use of rhodium-tris-(triphenyl-phosphine) as a catalyst (DE 2,308,227) and the use of rhodium(■)-diacetate-(triphenylphosphine) GB 1,476.123) has substantially improved hydrogenation in homogeneous systems.

However, when using these methods, although the ratio of α-isomer to β-isomer is increased, the unwanted β-isomer is still present in the final product from 5 to 10%.

The final product referred to here is one that is used for human treatment and therefore must comply with the pharmacopeia regulations.

For example, the British Pharmacopoeia specifies a maximum permissible concentration of the β-isomer in doxycycline of 2 parts, so that the final product containing a high proportion of the β-isomer obtained by conventional catalytic hydrogenation methods is The product must be further refined to meet pharmacopoeial specifications.

As a result of intensive research to overcome the problem of slanting, the present inventors have found that diene type complexes such as 2,5-norbornadiene and 1,5-hexadiene and chiral complexes such as camphanyl-diphenyl-phosphine have been developed. 6-6 in a homogeneous system using a novel catalyst consisting of a noble metal complex with a ligand
The present inventors discovered a method for hydrogenating deoxy-6-bumethyl-6-methylenetetracyclines and completed the present invention.

That is, the present invention uses 6-deoxy-6-bumethyl-6-methylenetetracyclines represented by the general formula (■): (wherein X and Y are the same as above) or their acid addition salts as starting materials; (general formula QV): [(camphanyl-diphenyl-phosph (wherein, M is a rhodium atom, R is 1,5-hexadiene or 2,5-norbornadiene, A is ClO4, Cl
or Br) at a temperature of 20 to 100° C. under a hydrogen pressure of 1 to 100 atm in a solvent or mixed solvent in which both the starting material and the catalyst are soluble.
The general formula (I) is characterized in that it is hydrogenated with
The present invention relates to a method for producing α-6-cyoxytetracycline shown in the following.

The novel complex catalyst represented by the general formula (IV) used in the present invention exhibits extremely high selectivity when hydrogenating various prochiral double bonds in an asymmetric enantioselective manner, It is particularly effective when used in the hydrogenation of 6-methylenetetracycline.

The complex catalyst represented by the general formula (IV) is, for example, a complex catalyst represented by the formula (■
) (wherein R' is a methyl group) and camphanyl-diphenyl-phosphine having the general formula (VI): M-C
It can be obtained by reacting a metal complex having 1R2(Vl) (wherein M and R are the same as above) and a compound that generates the anion A when ionized.

It is one of the complex catalysts represented by the general formula (■).

[(camphanyl-diphenyl-phosphine)2-Rh
-2,5-norbornadiene)].ClO4 is considered to have the following structural formula in terms of Q as far as analysis using current analytical means is concerned.

(In the formula, R' is a methyl group.

) those complex catalysts act highly regioselective and diastereoselective in the hydrogenation of exocyclic methylene groups of 6-methylenetetracyclines;
As a result, 6-cyoxytetracycline containing an extremely high ratio of α-isomer of 99% is produced.

As a hydrogenation method, a known general method is employed using an inert solvent or a solvent mixture in which both the starting material and the complex catalyst are soluble.

Preferred solvents include, for example, methanol and methanol-benzene.

The hydrogen pressure in the hydrogenation reaction is preferably 1 to 100 atm, particularly 2 to 30 atm, and more preferably 8 to 15 atm.

The reaction temperature is preferably 20 to 100°C, particularly 30 to 100°C, and more preferably 60 to 100°C.

Under such suitable reaction pressure and temperature conditions, hydrogenation of the starting materials is complete in 2 to 5 hours.

The complex catalyst may be added to the reaction solution in the form of a crystalline, stable organometallic complex, but it is preferred and convenient to form it in situ in the hydrogenation reaction solution.

After completion of hydrogenation, a known and simple method can be used to isolate the final product from the reaction solution.

Next, the manufacturing method of the present invention will be explained in detail with reference to manufacturing examples and examples, but the present invention is not limited to these actual processes.

Production example ([(camphanyl-diphenyl-phosphine) 2-R
Production of h-2,5-/rubornacien] barchlorate) Add 0.7 ml of 2,5-norbornadiene to a solution of 0.25 g of rhodium chloride (chemical formula Rh013.H2O) dissolved in 4 ml of ethanol-water (5:1). The resulting reaction solution was kept at room temperature for 48 hours to obtain 0.176 mg of yellow crystals, which were collected in a furnace.

To a solution of 0.137 g (0.3 mmol) of this crystal dissolved in 6 ml of methylene chloride, 0.055 g (0.6 mmol) of 2,5-norbornadiene and then silver perchlorate monohydrate were added under a nitrogen atmosphere. .

The resulting suspension was kept stirring at room temperature for 1 hour, and silver chloride precipitated.

The filtrate from which silver chloride was filtered off was evaporated to dryness under vacuum.

The obtained residue was recrystallized by adding 6 ml of tetrahydrofuran to obtain pure (Rh-(2,
0.130 g of yellowish crystals of 5-norbornadiene)2].ClO4 were obtained.

The results of this analysis are shown below.

NMR spectrum (CDC13, δ value ppm): 1.5
5 (broad s, CH2), 4. ．． 20 (broad 52
-CH), 5.40 (Broad S, 4-CH) Next, prepare a solution of 0.421 g of camphanyl-diphenyl-phosphine dissolved in 10 ml of degassed anhydrous tetrahydrofuran, and add (Rh-2°5-norbornadiene) to this solution.
2] 0.233 g of ClO4 was added.

The resulting reaction solution was continuously stirred at room temperature for 1 hour, then 20 ml of degassed n-hexane was added and cooled to 0°C.
Furthermore, stirring was continued at C0.

The reaction solution was filtered, washed with n-hexane, and then dried to obtain 0.6 g of the crystalline target product.

This material had a melting point of about 182° C. and changed its crystal form upon heating.

The results of this analysis are shown below.

NMR spectrum (CDC13, δ value ppm): 0.8
8 (s, CH3), 0.91 (s, CH3), 1.0
9 (S, CH3), 1.2o to 2.30 (m, CH2-
CH2), 2. f'i 0 (Broad 51P-CH2
), 3.85 (broad a, CH), 4.45 and 4
．． 65 (CH in 2 broads) Elemental analysis value; C51H62O8CIP2Rh-C4H,
0 (THF) Calculated value (%) C61,66H6,21 Actual value (%) C61,35H6,22 Example 1 5 g (10.44 mmol) of 6-deoxy-6-bumethyl-6-methylene-tetracycline was degassed in advance 10 g (0,0
93 mmol) was added to the reactor.

Next, hydrogenation was carried out while the reactor was maintained at a hydrogen pressure of 14 atm and a reaction humidity of 100°C.

Sampling was performed in 4-hour stages and analysis by thin layer chromatography (TLC) confirmed that repulsion was complete.

TLC used cellulose treated with 0.1M EDTA-Na as an adsorbent and EDTA-Na as a developing solvent.
CH (13-butanol) saturated with CH was used.

Detection of spots was performed under a Shiba line after exposing the plate to ammonia.

The filtrate obtained by filtering the reaction solution was evaporated to 15 mA, and 5 g of sulfosalicylic acid was added with 10 methanol of methanol.
A solution dissolved in m1 was added.

After cooling in an ice bath, the resulting product was filtered, washed with methanol, and then dried in vacuo.

Crystalline doxycyclin sulfate, fosalicylate 6.3
G is Eka.

. . Compound. λ-349nm. E1%1cm was 247.

Quantitative analysis by chromatography revealed that β-
The content of isomers was less than 2%.

Example 2 [Rh-C1 (1,5-hexadiene) 2] 50 mg and camphanyl-diphenyl-phosphine 160 mg
were added to 5 ml of separately degassed benzene to prepare two solutions, and then the phosphine solution was added to the rhodium complex solution, and the mixture was stirred for 15 minutes.

A solution of 5 g of 6-deoxy-6-bumethyl-6-methylene-5-hydroxytetracycline dissolved in 50 TL of methanol was added to the mixture.

Hydrogenation was carried out in an autoclave under conditions of a hydrogen pressure of 8 atm and a reaction humidity of 60°C, and was completed in 5 hours.

The target substance was precipitated in the form of sulfosalicylate from the resulting reaction solution, collected by filtration, and dried.

The obtained sulfosarinalate was suspended in an aqueous methanol solution, the pH was lowered to 50 by adding caustic soda, and the mixture was stirred at 0° C. for 5 hours to precipitate doxycycline base.

The obtained doxycycline base monohydrate 4.3
g was suspended in 5 times the volume of ethanol and then made into a solution by adding the minimum required amount of hydrochloric acid.

The resulting solution was immediately treated with activated carbon and filtered.

After adding 0.8 ml of concentrated hydrochloric acid to the filtrate, it was heated at 60°C for 3 hours, and then slowly cooled to 0°C with stirring over 8 hours.

The resulting product was recovered by filtration, washed with ethanol and dried to give a crystalline form of doxycycline bicrate (doxycycline), which met all specifications of the British Pharmacopoeia.
(Yeline hyclate) 4.1g was obtained.

Claims (1)

[Claims] 1. 6-deoxy-6-bumethyl-6-menalentetracyclines represented by the general formula (■): (wherein, Acid addition salts are used as starting materials, and these are expressed by the general formula %): () (where M is a rhodium atom, R is 1,5-hexadiene or 2,5-norbornadiene, A is C10-4, C
1- or Br-) in a solvent or mixed solvent in which both the starting material and the catalyst are soluble, under a hydrogen pressure of 1 to 100 atmospheres at a temperature of 20 to 1
General formula (■
): α- represented by (wherein, X and Y are the same as above)
Method for producing 6-cyoxytetracycline. 2. The manufacturing method according to claim 1, wherein the solvent is methanol, the hydrogen pressure is 8 to 15 atm, and the temperature is 60 to 100°C. 3 The complex catalyst is [[camphanyl-diphenyl-phosphine)2-Rh-2,5-norbornadiene].C
The manufacturing method according to claim 1 or 2, wherein 1O4 is used. 4. Claim No. 4, wherein the complex melting medium is obtained by reacting camphanyl-diphenyl-phosphine and (Rh.Ci(1,5-hexadiene)2) in situ in a hydrogenation reaction system. 5. The manufacturing method according to claim 1 or 2. 5. Claims 1 and 2, in which 6-deoxy-6-bumethyl-6-methylene-5-hydroxytetracycline or an acid addition salt thereof is used as the starting material.
The manufacturing method according to item 3 or 4.