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IE42180B1 - Preparation of -6-deoxytetracyclines - Google Patents

Preparation of -6-deoxytetracyclines

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Publication number
IE42180B1
IE42180B1 IE2514/75A IE251475A IE42180B1 IE 42180 B1 IE42180 B1 IE 42180B1 IE 2514/75 A IE2514/75 A IE 2514/75A IE 251475 A IE251475 A IE 251475A IE 42180 B1 IE42180 B1 IE 42180B1
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Ireland
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rhodium
process according
triphenylphosphine
group
compound
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IE2514/75A
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IE42180L (en
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Pfizer
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Publication of IE42180B1 publication Critical patent/IE42180B1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0073—Rhodium compounds
    • C07F15/008—Rhodium compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/5045—Complexes or chelates of phosphines with metallic compounds or metals
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F41—WEAPONS
    • F41A—FUNCTIONAL FEATURES OR DETAILS COMMON TO BOTH SMALLARMS AND ORDNANCE, e.g. CANNONS; MOUNTINGS FOR SMALLARMS OR ORDNANCE
    • F41A9/00—Feeding or loading of ammunition; Magazines; Guiding means for the extracting of cartridges
    • F41A9/01—Feeding of unbelted ammunition
    • F41A9/24—Feeding of unbelted ammunition using a movable magazine or clip as feeding element
    • F41A9/26—Feeding of unbelted ammunition using a movable magazine or clip as feeding element using a revolving drum magazine
    • F41A9/27—Feeding of unbelted ammunition using a movable magazine or clip as feeding element using a revolving drum magazine in revolver-type guns
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F41—WEAPONS
    • F41A—FUNCTIONAL FEATURES OR DETAILS COMMON TO BOTH SMALLARMS AND ORDNANCE, e.g. CANNONS; MOUNTINGS FOR SMALLARMS OR ORDNANCE
    • F41A9/00—Feeding or loading of ammunition; Magazines; Guiding means for the extracting of cartridges
    • F41A9/29—Feeding of belted ammunition
    • F41A9/30—Sprocket-type belt transporters
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/822—Rhodium

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  • Chemical & Material Sciences (AREA)
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  • Inorganic Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Hydrogenation of the exocyclic methylene gp. of a 6-deoxy-6-demethyl-6-methylene-tetracycline (I), or its acid addition salt, in a stereoselective manner giving the alpha-isomer in preference to the beta-isomer, is carried out at 20-100 degrees C and 1-100 atmos. under neutral conditions, or using a weakly acidic acid addn. salt, in the presence of a catalytic amt. of a cpd. of formula Rh(OCOR)2(P C6H5 3) (II) (where R = H, 1-6C alkyl, ClCH2, Cl2CH, Cl3C, FCH2, F2CH, F3C, phenyl, chlorphenyl, tolyl, anisyl). The ratio of alpha-isomer to beta-isomer is >=9:1. Known methods give a less favourable ratio e.g. 1:1.

Description

This invention relates to the preparation of a - 6 - deoxytetracyclines. More particularly, the invention is concerned with a process for the preparation of an a - 6 - deoxytetracycline which involves hydrogenation of a mixture of a 6 - deoxy - 6 - demethyl5 6 - methylene - tetracycline compound and a catalytic amount of a dicarboxylato(triphenylphosphine)-rhodiumdl) or dicarboxylato(substituted triphenylphosphine)rhodium(II) compound, in a reactioninert solvent. The hydrogenation takes place with a stereoselectivity which favours the 6a - isomer over the 6β - isomer.
The products>are known antibacterial agents.
British Patent Specification No. 995,032 discloses the production of a - 6 - deoxytetracycline derivatives by a process which involves hydrogenation of certain 6 - deoxy - 6 - demethyl6 - methylenetetracyclines in the presence of a catalytic amount of a noble metal catalyst such as rhodium or palladium. The process results in the production of β - 6 - deoxytetracyclines as well as a - 6 - deoxytetracyclines. The present invention improves upon that process by providing a higher a - isomer to β - isomer ratio.
Xt has now been found that a higher ratio of a - isomer to βisomer may be achieved by hydrogenating a mixture of a 6 - deoxy6 - demethyl -6.- methylenetetracycline compound and a specific, soluble rhodium(II) compound, as herein described, in a reactioninert solvent.
West German Offenlegungsschrift No. 2,308,227 broadly discloses the use of soluble rhodium compounds for the stereoselective reduction of 6 - deoxy - 6 - demethyl - 6 - methylenetetracyclines. However, the said Offenlegungsschrift exemplifies only the use of rhodium(I) compounds. Hui et al, Inorganic Chemistry, 12, 757 (1973), and Journal of the Chemical Society (London), Part D, 1196 (1970), report that rhodium(II) diacetate is an effective hydrogenation catalyst. However, the use of rhodium(II) diacetate in the hydrogenation of 6 - deoxy - 6 - demethyl - 6 methylenetetracyclines does not lead to a favourable a to β ratio, approximately equal amounts of the a- and β-isomers being formed.
It has been found, according to the present invention, that the presence of the triphenylphosphine or substituted triphenylphosphine ligand is essential to obtain a stereoselective reduction. Although Legzdins et al, Journal of the Chemical Society (London), Part D,825, (1969) have reported the use of rhodium diacetate in the presence of triphenylphosphine as a hydrogenation catalyst, their experiments were run in the presence of a very strong acid.
The process of the present invention is carried out under neutral conditions, or on a weakly-acidic tetracycline acid-addition salt.
In accordance with the present invention there is provided a process for the preparation of an a - 6 - deoxytetracycline of the general formula: which comprises mixing a catalytic amount of a compound of the formula Rh(OCDR)2Q with a tetracycline compound of the general formula:- or or an acid-addition salt thereof, in a reaction-inert solvent, and maintaining hydrogen in contact with the reaction mixture thus formed, at a temperature of from 20° to 100°C, and at a pressure from 1 to 100 atmospheres until reaction of from 1 to 2 moles of hydrogen per mole of tetracycline compound occurs, the reaction - 4 42180 being conducted in the absence of a strong acid, wherein R is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or a chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, chlorophenyl, tolyl or anisyl group, Q is an unsubstituted triphenylphosphine group of the formula ΡίΟ^Η^)^ or a triphenylphosphine group substituted on one or more of the phenyl rings by one or more substituents, each of which is an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms or a fluorine, chlorine or bromine atom, X is a hydrogen or chlorine atom and Ϋ is a hydrogen atom or a hydroxy group or an alkanoyloxy group having from 2 to 7 carbon atoms.
The process of the present invention results in hydrogenation of the exocyclic methylene group, and proceeds with a stereoselectivity which favours the a - isomers over the β - isomers by a factor of at least 9:1. The specific rhodium compound used in the present invention is a compound of the formula: Rh(OCOR)2Q wherein R and Q are as defined above. However, the preferred catalysts are those wherein the triphenylphosphine group is unsubstituted, i i.e., compounds of the formula Rh(0C0R)2P[C6H5]3).
Especially preferred catalysts are those wherein the triphenylphosphine group is unsubstituted and R is an alkyl group, particularly methyl.
The starting materials used in the process of the present invention are tetracycline compounds of the formula (I) and (II) above and the acid addition salts thereof.
The preparation of these starting materials is disclosed in British Patent Specification No. 995,032 . in general, the - 5 42180 preparation involves treatment of an 11a - chloro - 6,12 - hemiketal derivative of the appropriate tetracycline compound with a strong acid of the dehydrating type such as sulphuric, trifluoroacetic, polyphosphoric or perchloric acid or hydrogen fluoride.
Of these, the preferred acid is hydrogen fluoride. Optimum conditions are readily determined by routine experimentation. Generally, the selected 11a - chloroketal is merely added to the selected acid and allowed to react, most appropriately at a temperature within the range of from 0° to 50°C and for a time of up to several hours. After reaction is complete, the product is I recovered in an appropriate manner, e.g., in the case of volatile acids by evaporation of the same to obtain the residual product, and in Other cases by standard procedures such as stirring with a non-solvent, e.g., diethyl ether, to precipitate the product.
These 6 - methylene compounds may be converted to acid addition salts or polyvalent metal salt complexes by standard procedures prior to hydrogenation.
Example XXXVII of British Patent Specification No. 995,032 illustrates hydrogenation of an 11a - chloro - 6 - deoxy - 620 demethyl - 6 - methylenetetracycline hydrochloride to obtain the corresponding 11a - deschloro compound.
When Y of the starting compound for the present invention is an alkanoyloxy group having from 2 to 7 carbon atoms, it is appropriate to use the method disclosed in British Patent Specification No. 995,032 f°r the preparation thereof. According to that method,, the appropriate 11a - chloro - 6 - demethyl - 6 - deoxy6 - methylene - 5 - hydroxytetracycline in the form of the free base or a poly-addition salt is treated with a carboxylic acid having from 2 to 7 carbon atoms in the molecule in the presence - 6 42180 of methanesulphonic, ethanesulphonic or hydrofluoric acid, preferably at a temperature of from 20° to 70°C for a period of time generally ranging from 2 to 20 hours. The resulting product may then be reduced to the 11a - deschloro compound by the procedure described above.
The rhodium compounds of the formula Rh(OCOR)2Q are either known in the art, or they are simple analogues or homologues of compounds known in the art, and they may be prepared by methods such as those discussed by Stephenson et al. Journal of the Chemical Society (London), 3632 (1965). According to these procedures, rhodium carboxylates are prepared by refluxing rhodium hydrous oxide in, for example, an excess of formic, acetic or propionic acid and ethanol. The yellow solutions gradually turn amber and then green. The resulting solutions are cooled and the dark green powders which precipitate are filtered off and recrystallized from methanol or water. These products are found to be stable at temperatures up to 24O°C. The final catalyst complex is prepared by the addition of triphenylphosphine, or the appropriately substituted triphenylphosphine, and diethyl ether to a cold ethanolic solution of the rhodium carboxylate.
Appropriate reaction-inert solvents for the process of the present invention include those which serve to substantially dissolve the starting materials or the product. Examples of such solvents include ethers such as diethyl ether, tetrahydrofuran, dioxan, 1,2 - dimethoxyethane; lower aliphatic ketones such as acetone and methyl ethyl ketone; low molecular weight esters such as ethyl acetate and butyl acetate; mono- and polyhydric lower alcohols such as methanol, ethanol, isopropanol, ethylene glycol, propylene glycol and diethylene glycol; lower alkoxy - substituted alkanols such as 2 - methoxyethanol and 2-(2- ethoxyethoxy)ethanol; lower alkanoic acids such as acetic acid and propionic acid; tertiary amides such as N,N - dimethylformamide, N,N - dimethylacetamide and N - methyl - 2 - pyrrolidone and mixtures thereof.
Introduction of the hydrogen gas into the reaction-inert solvent medium containing the rhodium compound and the tetracycline compound is generally accomplished by carrying out the reaction in a sealed vessel under an atmosphere of hydrogen or of hydrogen IO mixed with an inert diluent such as nitrogen or argon. The pressure inside the reaction vessel may vary from 1 to 100 atmospheres. The preferred pressure range, when the atmosphere in the reaction vessel is substantially pure hydrogen, is from 10 to 100 psig.
The hydrogenation is conducted at a temperature of from 20° to 100°C, and preferably from 40° to 70°C. Utilizing the preferred temperature and pressure values, hydrogenation generally takes place in a few hours, e.g., from 2 to hours to 10 hours.
On hydrogenating a 7 - halo - substituted 6 - methylene - 6deOXy - 6 - demethyl tetracycline starting material in the process of this invention, the 7 - halo substituent remains substantially intact. On the other hand, an 11a - chloro substituent is removed.
The expression catalytic amount as used herein is well understood by those skilled in the art of known tetracycline hydrogenations. Generally, this amount ranges from 0.1 to 100 mol%, based on the tetracycline compound. The preferred amount is from 1 to 10 mol%.
The reaction product of the present invention may be isolated from the reaction medium by standard methods. For example, the product often may be precipitated by the addition of a non-solvent such as hexane -or water or by the addition of certain agents which form insoluble salts with the product. Alternatively, the crude product may be .isolated by evaporation of the solvent or by dilution of the reaction mixture with a large excess of water, followed by extraction of the product into a water-immiscible organic solvent and subsequent evaporation of the’ water-immiscible solvent.
The following Examples illustrate the present invention and the manner in which it may be performed.
EXAMPLE 1 Reduction of 6 - Methylene - 6 - demethyl - 6 - deoxy - 5 - hydroxytetracycline using Diacetato(triphenylphosphine)rhodium(II) A solution Of 2.0 g. (4.18 mmol) of 6 - methylene - 6 - demethyl - 6 - deoxy - 5 - hydroxytetracycline hydrochloride and 0.088 g. (4.4 mol-percent) of diacetato(triphenylphosphine)rhodium(II) in 30 ml. of degassed methanol was shaken under an atmosphere of hydrogen, in a sealed vessel, at 60—70°C., for 5.75 hours. The hydrogen pressure in the reaction vessel was 66—71 psig. The vessel was then opened and the reaction solution was filtered. The filtrate was examined by high-pressure liquid chromatography, which indicated that it contained the required a - 6 - deoxy - 5 hydroxytetracycline, contaminated by 2—3% of its C-6 epimer.
To the filtrate was then added a mixture of 20 ml. of water and 30 ml. of 10% aqueous sulfosalicyclic acid, with stirring. Stirring was continued overnight, and then the precipitate was filtered off, giving 2.62 g. (95% yield) of a - 6 - deoxy - 5hydroxytetracycline as its sulfosalicylate salt. The product was shown to be 93% pure by ultraviolet spectroscopy.
EXAMPLE 2 The procedure of Example 1 is repeated, except that the 69 4318 0 methylene - 6 - demethyl - 6 - deoxy - 5 - hydroxytetracycline used therein is replaced by an equimolar amount of: - methylene - 6 - demethyl -6.- deoxy - tetracycline, - methylene - 6 - demethyl - 6 - deoxy - 5 - acetoxytetra5 cycline, - methylene - 6 - demethyl - 6 - deoxy - 5 - propionyloxytetracycline, - methylene - 6 - demethyl - 6 - deoxy - 5 - butyryloxytetracycline, 6 - methylene - 6 - demethyi - 6 - deoxy - Ila - chlorotetracycline, - methylene - 6 - demethyl - 6 - deoxy - 5 - hexanoyloxytetracycline, - methylene - 6 - demethyl - 6 - deoxy - 7 - chlorotetra15 cycline, - methylene - 6 - demethyl - 6 - deoxy - 7 - chloro - 5hydroxytetracycline, - methylene - 6 - demethyl - 6 - deoxy - 7 - chloro - 5acetoxytetracycline, 6 - methyl®e - 6 - demethyl - 6 - deoxy - 7 - chloro - 5isobutyryloxytetracycline, - methylene - 6 - demethyl - 6 - deoxy - 7 - chloro - 5isovaleryloxytetracycline, and - methylene - 6 - demethyl - 6 - deoxy - 7 - chloro - 525 heptanoyloxytetracycline, respectively, and the diacetato(triphenylphosphine)rhodium-(II) used therein is replaced by an equimolar amount of; dipropionato(triphenylphosphine)rhodium(II) dibenzoa ta'( triphenylphosphine) rhodium(II) - 10 42180 dibutyrato(triphenylphosphine)rhodium(II) di(p - chlorobenzoato) (triphenylphosphine)rhodium(II), dibenzoata(triphenylphosphine)rhodium (II) diformato(triphenylphosphine)rhodium(II) diacetato(triphenylphosphine)rhodium(II) dibenzoata(triphenylphosphine) rhodium(II), di(m - toluato) (triphenylphosphine)rhodium(II), dihexanoato(triphenylphosphine)rhodium(II), diheptanoato(triphenylphosphine)rhodium(II), and di(p - methoxybenzoato) (triphenylphosphine)rhodium(II), respectively.
This affords the following compounds, respectively: a - 6 - deoxytetracycline, a - 6 - deoxy - 5 - aeetoxytetracycline, a - 6 - deoxy - 5 - propionyloxytetracycline, a - 6 - deoxy - 5 - butyryloxytetraeycline, a - 6 - deoxytetracycline, a - 6 - deoxy - 5 - hexanoyloxytetracycline, a - 6 - deoxy -7- chlorotetracycline, a - 6 - deoxy - 7 - chloro - 5 - hydroxytetracycline, a - 6 - deoxy - 7 - chloro - 5 - aeetoxytetracycline, a - 6 - deoxy - 7 - chloro - 5 - isobutyryloxytetracycline, ά - 6 - deoxy - 7 - chloro - 5 - isovaleryloxytetracycline, and a - 6 - deoxy - 7 - chloro - 5 - heptanoyloxytetracycline. The following Preparations illustrate the preparation of rhodium compounds used as catalysts in the process of the present invention.
PREPARATION A Rhodium(II) Acetate A mixture of 1.72 g. of rhodium hydrous oxide (Rh[0H]^.H^O), ml. of glacial acetic acid and 15 ml. of ethanol is heated under reflux for 24 hours. The reaction mixture is cooled, and the volatile components are removed by evaporation in vacuo to give the crude product. The crude product is purified by dissolving it in acetone, allowing the solvent to evaporate slowly and then filtering off the solid which precipitates.
PREPARATION B Reaction Of rhodium hydrous oxide with the appropriate carboxylic acid, according to the procedure of Preparation A, produces the'following rhodium(II) carboxylates; rhodium(II) propionate, rhodium(II) benzoate. rhodium(II) butyrate. rhodiumdl) £ - chlorobenzoate. rhodoim(II) formate, rhodiumdl) m - toluate, rhodium(II) hexanoate. rhodium(II) heptanoate, rhodium(II) £ - methoxybenzoate. rhodiim(II) chloroacetate. rhodium(II) dichloroacetate, rhodium(TI) trichloroacetate. rhodium(II) fluoroacetate. rhodium(II) difluoroacetate, and rhodium(II) trifluoroacetate.
PREPARATION C Diacetato)tr iphenylphosphine) Rhodium(II) A mixture of 110 mg. of rhodium(Il) acetate and 100 ml. of methanol is cooled to 17°C. and a solution of 131 mg. of triphenylphosphine in 5 ml. of ether is added with stirring. Stirring is continued at ambient temperature for 2 hours and then the precipitate is removed by filtration. This affords 219 mg. of the title compound, m.p. 203°—204°C, PREPARATION D The procedure of Preparation C is repeated, except that the rhodium(II) acetate is replaced by the appropriate rhodium(II) carboxylate, to produce the following congeners: dipropionato(triphenylphosphine) rhodium(II), dibenzoato(triphenylphosphine)rhodium(ll), dibutyrato(triphenylphosphine)rhodium(Il), di(p - chlorobenzoata) (triphenylphosphine)rhodium(II), diformato(triphenylphosphine)rhodium(II), di(m - toluato) (triphenylphosphine)rhodium(II), dihexanato(triphenylphosphine)rhodium(II), diheptanato(triphenylphosphine) rhodium(II), di(p - methoxybenzoato) (triphenylphosphine)rhodium(Il), di(chloroacetato) (triphenylphosphine)rhodium(II), di (dichloroacetato) (triphenylphosphine) rhodium (II) di(trichloroacetato) (triphenylphosphine)rhodium(Il), di(fluoroacetato) (triphenylphosphine)rhodium(II), di(difluoroacetato) (triphenylphosphine)rhodium(II), and di(trifluoroacetato) (triphenylphosphine)rhodium(II).
The following Comparative Example is included to show thatj the hydrogenation process does not proceed with stereoselectivity if the rhodium compound catalyst does not contain the triphenylphosphine ligand.
COMPARATIVE EXAMPLE Reduction of 6 - Deoxy - 6 - demethyl - 6 - methylene - 5 - hydroxy5 tetracycline using Rhodium(II) Diacetate A solution of 2.0 g. (4.18 mmol.) of 6 - deoxy - 6 - demethyl6 - methylene -· 5 - hydroxytetracycline hydrochloride and 46 mg. (5 mol-percent) of rhodium(II) diacetate in 30 ml. of de-gassed methanol was shaken under an atmosphere of hydrogen at 65—70°C. for .25 hours. The hydrogen pressure in the reaction vessel was 65— psig. The cooled reaction vessel was then opened and the contents were filtered. The filtrate was examined by high-pressure liquid chromatography. This indicated that it contained a - 6deoxy - 5 - hydroxytetracycline and β - 6 - deoxy - 5 - hydroxy15 tetracycline, in a ratio of about ^3, together with a small amount of unreduced starting material.

Claims (13)

1. A process for the preparation of an a - 6 - deoxytetracycline of the general formulas (I) which comprises mixing a catalytic amount of a compound of the formula Rh(OCOR) 2 Q with a tetracycline compound of the general formula :- (il) or OH CONH. (ill.) or an acid-addition salt thereof, in a reaction-inert solvent, and maintaining hydrogen in contact with the reaction mixture thus formed, at a temperature of from 20° to 100°C, and at a pressure - 15 42180 from 1 to 1OO atmospheres until reaction of from 1 to 2 moles of hydrogen per mole of tetracycline compound occurs, the reaction being conducted in the absence of a strong acid, wherein R is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or a chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,'trifluoromethyl, phenyl, chlorophenyl, tolyl or anisyl group, Q is an unsubstituted triphenylphosphine group of the formula P(C or a triphenylphosphine group substituted on one or more of the phenyl rings by one or more substituents, each of which is an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms or a fluorine, chlorine or bromine atom, X is a hydrogen Or chlorine atom and Y is a hydrogen atom or a hydroxy group or an alkanoyloxy group having from 2 to 7 carbon atoms.
2. A process according to-claim 1, wherein the starting tetracycline compound is 6 - methylene - 6 - demethyl - 6 - deoxy5 - hydroxytetracycline or an acid addition salt thereof.
3. A process according to claim 1, wherein the starting tetracycline compound is 6 - methylene - 6 - demethyl - 6 - deoxyIla - chlorotetracycline or an addition salt thereof.
4. A process according to any one of claims 1 or 3, wherein the catalyst is a rhodium compound of the formula Rh(OCOR) 2 P[C 6 H 5 J 3 wherein R is as defined in claim 1.
5. A process according to claim 4, wherein R is an alkyl group having from 1 to 6 carbon atoms.
6. A process according to claim 5, wherein R is methyl.
7. A process according to any one of claims 1 to 6 wherein the temperature employed is from 40° to 7O°c. 16 42180
8. A process according to any one of the preceding claims, wherein the catalytic amount of the rhodium compound is 0.1 to 100 mol-percent, based on the tetracycline compound.
9. A process according to claim 8, wherein the said catalytic 5 amount is 1 to 10 mol-percent, based on the tetracycline compound.
10. A process according to any one of the preceding claims wherein the reaction-inert solvent medium is diethyl ether, tetrahydrofuran, dioxan, 1,2 - dimethoxyethane, acetone, methyl ethyl ketone, ethyl acetate, butyl acetate, methanol, ethanol, isopropanol 10 ethylene glycol, propylene glycol, diethylene glycol, 2 - methoxyethanol, 2-(2- ethoxyethoxy) - ethanol, acetic acid, propionic acid, N,N - dimethylformamide, N,N - dimethylacetamide, N - methyl2 - pyrrolidone or a mixture thereof.
11. A process according to any one of the preceding claims 15 wherein the pressure is 10 to 100 psig.
12. A process for the preparation of an a - 6 - deoxytetracycline according to claim 1 and substantially as hereinbefore described with reference to Examples 1 and 2.
13. An a - 6- deoxytetracycline whenever prepared by a process 20 according to any one of the preceding claims.
IE2514/75A 1974-12-19 1975-11-18 Preparation of -6-deoxytetracyclines IE42180B1 (en)

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SE435619C (en) * 1973-02-01 1985-11-18 Pfizer PROCEDURE FOR PREPARING A 6ALFA DEOXYTETRACYCLINE
DK386784A (en) * 1983-08-17 1985-02-18 Hovione Int Ltd PROCEDURE FOR PREPARING ALFA-6-DESOXY-TETRACYCLINES

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GB1368431A (en) * 1970-07-22 1974-09-25 Johnson Matthey Co Ltd Rhodium complex and methods of preparing the complex
SE435619C (en) * 1973-02-01 1985-11-18 Pfizer PROCEDURE FOR PREPARING A 6ALFA DEOXYTETRACYCLINE

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YU39474B (en) 1984-12-31
AT344320B (en) 1978-07-10
CH609042A5 (en) 1979-02-15
SE426587B (en) 1983-01-31
YU305075A (en) 1982-05-31
DE2554564A1 (en) 1976-07-01
NO754085L (en) 1976-06-22
FR2295014A1 (en) 1976-07-16
ZA757902B (en) 1976-12-29
HU173508B (en) 1979-05-28
FI59395B (en) 1981-04-30
AR208347A1 (en) 1976-12-20
BG24798A3 (en) 1978-05-12
CS203099B2 (en) 1981-02-27
AU8766875A (en) 1976-09-23
NO146236B (en) 1982-05-18
DK151224C (en) 1988-05-16
BE836775A (en) 1976-06-18
PH13795A (en) 1980-10-01
ES443626A1 (en) 1977-05-01
NL7514840A (en) 1976-06-22
DK151224B (en) 1987-11-16
FI59395C (en) 1981-08-10
JPS5186457A (en) 1976-07-29
NL164849B (en) 1980-09-15
RO72846A (en) 1982-04-12
DD123600A5 (en) 1977-01-05
SU799650A3 (en) 1981-01-23
FR2295014B1 (en) 1978-10-06
IE42180L (en) 1976-06-19
FI753459A (en) 1976-06-20
SE7513091L (en) 1976-06-21
PL105946B1 (en) 1979-11-30
ATA937675A (en) 1977-11-15
DK576575A (en) 1976-06-20
LU74054A1 (en) 1976-11-11
NO146236C (en) 1982-08-25
AU476488B2 (en) 1976-09-23
JPS5324944B2 (en) 1978-07-24

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