Process for the production of alpha-6-deoxytetracyclines

A process for the hydrogenation of a 6-methylenetetracycline in the production of alpha-6-deoxytetracyclines, particularly the antibiotic doxycycline, in the presence of hydriodotetrakis (triphenylphosphine) rhodium (I) as a homogenous hydrogenation catalyst. The desired alpha-6-deoxy product is produced in high yields and stereospecificities, the process requiring the use of minimal quantities of rhodium metal in the hydrogenation catalyst per mole of the 6-methylenetetracycline hydrogenated.

This invention relates to a process for the preparation of 
alpha-6-deoxytetracyclines, and more particularly to such a process for 
the production of the antibiotic doxycycline, viz., 
alpha-6-deoxy-5-oxytetracycline. 
BACKGROUND OF THE INVENTION 
The preparation of doxycycline and other alpha-6-deoxytetracyclines was 
first described in Blackwood et al. U.S. Pat. No. 3,200,149 granted Aug. 
10, 1965. That patent described their preparation by the catalytic 
hydrogenation of a corresponding 6-methylene intermediate, e.g., in the 
case of doxycycline, 
11a-chloro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline (11a-chloro 
methacycline) or 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline 
(methacycline), in the presence of a heterogeneous noble metal catalyst, 
e.g. palladium on carbon. The Blackwood patent disclosed the production, 
in yields of up to about 50%, of equimolar proportions of the 
diastereoisomers (epimers) of the 6-deoxytetracyclines. In the case of 
doxycycline, the patent disclosed the co-production of the corresponding 
beta epimer, beta-6-deoxy-5-oxytetracycline. 
Subsequent efforts have been directed to the development of syntheses for 
producing the 6-deoxytetracyclines in greater yields and with greater 
stereoselectivity of formation of the desired alpha epimers, e.g., 
doxycycline. Thus, Korst U.S. Pat. No. 3,444,198 granted May 13, 1969, 
disclosed that the stereoselectivity of formation of the alpha epimers may 
be increased when the noble metal hydrogenation catalyst is poisoned. The 
Korst patent described the formation of epimeric mixtures of the 
6-deoxytetracyclines in total yields of up to about 60%, with the 
stereoselective production of the alpha epimers in amounts of up to about 
90% of the epimeric product mixtures. The use of other noble metal or 
noble metal salt compositions as heterogeneous hydrogenation catalysts in 
the production of doxycycline has also been disclosed in the literature. 
See, for example, Morris U.S. Pat. No. 3,954,862 granted May 4, 1976 and 
Faubl et al U.S. Pat. No. 3,962,131 granted June 8, 1976. 
The use of rhodium halide complexes containing tertiary phosphine ligands, 
e.g., tris (triphenylphosphine) chloro rhodium (I), as homogeneous 
hydrogenation catalysts was first described by Wilkinson et al. in 1966. 
J. Chem. Soc. 1711-32. Subsequently, a number of soluble complexes of 
platinum metals, particularly rhodium, with halides and tertiary 
phosphines or the like, have been described as useful in a variety of 
regiospecific, stereoselective and asymmetric reduction reactions. See 
Knowles et al., Chem. Communs. 1445 (1968); Horner et al., Angew Chem. 
Int. Ed. 7, 942 (1968); Vol Pin et al., Russian Chemical Reviews, 38, 
273-289 (1969); Augustine et al., Ann. N.Y. Sci., 158, 482-91 (1969); 
Ruesch et al., Tetrahedron, 25, 807-11 (1969); Piers et al., Chem. 
Communs. 1069-70 (1969); "Aspects Of Homogeneous Catalysis", Vol I, pp. 
5-75 (1970), Carlo Manfredi, Milan, Italy; "Homogeneous Catalysis, 
Industrial Applications And Implications," Vol. 70, Advances in Chemistry 
Series, American Chemical Society; Grubbs et al., J. Am. Chem. Soc., 93, 
3062 (1971); Kagan et al., J. Am. Chem. Soc., 94, 6429 (1972); Knowles et 
al., Chem. Communs. 10 (1972); and Harmon et al., Chem. Rev. 73, 21-52 
(1973). Similar disclosures have been made in the patent literature. See, 
for example, U.S. Pat. Nos. 3,489,786; 3,549,780; and 3,639,439; and 
British Pat. Nos. 1,121,642; 1,121,643; 1,138,601; and 1,219,763. 
The use of rhodium chloride/triphenylphosphine and similar complexes as 
homogeneous, stereospecific hydrogenation catalysts in the production of 
doxycycline and other alpha-6-deoxy-5-oxytetracyclines has also been 
extensively discussed in the patent literature. See, for example, U.S. 
Pat. Nos. 3,907,890; 3,962,331; 4,001,321; 4,207,258; 4,550,096; 
4,743,699; and French Pat. No. 2,216,268. 
The present invention is directed to an improved process for the production 
of doxycycline and other alpha-6-deoxytetracyclines, wherein the desired 
alpha epimer is produced in both high yield and stereospecificity, and the 
noble metal constituent of the hydrogenation catalyst is utilized in 
smaller proportions than heretofore required and is readily recoverable 
from the reaction mixture for re-use. Other objects and advantages of this 
invention will be apparent from the following description of preferred 
embodiments thereof. 
SUMMARY OF THE INVENTION 
This invention comprises an improved process for the preparation of 
alpha-6-deoxy-tetracyclines by the hydrogenation of the corresponding 
6-methylenetetracyclines, in the presence of 
hydridotetrakis(triphenylphosphine) rhodium (I) in a homogeneous medium. 
It has been found that when an appropriate 6-methylenetetracycline 
substrate is hydrogenated in the presence of such a homogeneous catalyst, 
the corresponding alpha-6-deoxytetracycline is produced in greater than 
about 95% yield and without the co-production of substantial amounts of 
the corresponding beta-6-deoxytetracycline epimer. Further, the 
hydrogenation may be carried out in the presence of substantially smaller 
quantities of rhodium than required in previously described homogeneous 
catalyses for the production of doxycycline or other 
alpha-6-deoxytetracyclines. Increased economies are thus achieved, both 
because of the decreased quantities of rhodium required for catalysis and 
because of the elimination of expensive purification operations heretofore 
required for separation of the undesired beta epimers.

PREFERRED EMBODIMENTS OF THE INVENTION 
The process of this invention may be utilized in the production of any of 
the known alpha-6-deoxytetracyclines, preferably those having the formula: 
##STR1## 
wherein 
R and R.sub.2 are each hydrogen or chloro, and R.sub.1 is hydrogen or 
hydroxyl. 
The preceding compounds are produced by hydrogenation of the corresponding 
6-methylenetetracycline compounds of the formula: 
##STR2## 
wherein R, R.sub.1 and R.sub.2 are as defined above. 
6-methylenetetracyclines which are thus reacted may be prepared in the 
manner known in the art, e.g., as described in Blackwood U.S. Pat. No. 
2,984,986 granted May 16, 1961 or Villax U.S. Pat. No. 3,848,491 granted 
Nov. 19, 1974. 
Preferably, the catalytic hydrogenation is utilized to prepare doxycycline 
(wherein R is hydrogen and R.sub.1 is hydroxyl) from 11a-chloro 
methacycline (wherein R is hydrogen, R.sub.1 is hydroxyl, and R.sub.2 is 
chloro). 
The homogeneous catalyst used in the hydrogenation, 
hydridotetrakis(triphenylphosphine) rhodium (I) possesses excellent 
catalytic hydrogenation properties and greater stereospecificity than 
exhibited by previously proposed catalytic materials. It is produced by 
reacting a rhodium salt, preferably rhodium chloride; an alkali metal 
hydroxide, preferably potassium hydroxide; and a tertiary phosphine, 
preferably triphenylphosphine, at a temperature of about 78.degree. C. for 
about 5 minutes in lower alcohols such as methanol, ethanol etc., 
essentially according to the method described by S. D. Robinson et al. in 
J.Chem. Soc. 843-47 (1972). Numerous other publications have described the 
preparation and applications of hydridotetrakis(triphenylphosphine) 
rhodium (I), e.g., J. Orgmetal. Chem. 46(1) 159-65 (1972); 59 161-66 
(1973); Chem. Ind. (London) 42 1514 (1969); Naturwissenschaften 56(8) 
415-16 (1969); Inorg. Chem. 7(3) 546-51 (1968); J. Organic Chem. 39, 1622 
(1974); Can. J. Chem. 52, 776 (1974); J. Chem. Soc., Chem. Commun. (3), 
114- 15 (Eng.) (1978); Inorg. Chem. 17(11), 3069-74 (1978); J. Mol. Catal. 
7(4), 454-68 (Eng.) (1980). The use of this material as a hydrogenation 
catalyst in the reduction of ketones to alcohol [J. Organomet. Chem. 175 
222-232 (1979)], in the selective hydrogenation of dienes to mono-enes [J. 
Organomet. Chem. 70 89 (1974), Italy 912,648 (1972)], in the selective 
reduction of unsaturated esters and nitriles to corresponding saturated 
esters and nitriles, and in the hydrogenation of cyclohexene [U.S. 
3,480,659 (1969), Yakagaku 32 726 (1983)] has also been described. It has 
not previously been described as useful in the hydrogenation of the 
6-methylenetetracyclines. 
The hydrogenation reaction is carried out in the manner known in the art, 
with the stereospecific formation of the desired alpha epimer in yields in 
excess of 95%. HPLC analyses of the hydrogenation products indicate 
beta-epimer contents of less than 0.5%. The hydrogenation is effected in 
the presence of from about 0.4 to 1.5 millimoles of catalyst per mole of 
6-methylenetetracycline reacted. The amount of rhodium required for the 
reduction varies from about 1/4 to 1/150th. of that required in previously 
described processes. Accordingly, the catalytic hydrogenation of the 
present invention provides superior yields and purities of the desired 
alpha-6-deoxytetracyclines, with substantially improved efficiencies in 
the operation. 
The reaction is suitably carried out in a lower alkanolic solvent, 
preferably methanol, ethanol, propan-1-ol, propan-2-ol, or butanol. The 
solvents are degassed with nitrogen prior to use. 
The reaction time depends on the amount of catalyst and the type of 
autoclave used for hydrogenation. Normally, to obtain high yields and 
purities, reaction times of from about 3 to 16 hours are utilized. It is 
preferred, but not critical, to carry out the reaction under pressures 
ranging from about 4 to 12 kg/cm.sup.2, and at temperatures of from about 
50.degree. to 90.degree. C. At temperatures lower than about 50.degree. C. 
the reaction is too slow, and at higher temperatures decomposition occurs. 
A small amount of triphenylphosphine, e.g., from about 30 to 60 millimoles 
per mole of the 6-methylenetetracycline substrate, when added to the 
reaction mixture prior to hydrogenation, acts as a promoter and 
accelerates the rate of hydrogen absorption, thus facilitating completion 
of the reaction. The optimum quantity of triphenylphosphine is determined 
empirically. 
The doxycycline or other alpha-epimer is crystallized as an acid addition 
salt from the reaction mixture, preferably in the form of the 
sulfosalicylate salt (by adding excess sulfosalicylic acid). The purity is 
more than 99.5% by HPLC. The doxycycline sulfosalicylate is thereafter 
converted directly to doxycycline hyclate (the hemiethanolate hemihydrate) 
in stoichiometric yield by procedures known in the art. 
The catalytic hydrogenation may be utilized in a single step to effect both 
the reductive dehalogenation and reduction of the 6-methylene group of an 
11a-halo-6-deoxy-6-demethyl-6-methylenetetracycline, e.g., 11a-chloro 
methacycline. The corresponding alpha-6-deoxytetracycline, e.g., 
doxycycline, is directly produced in improved yield and purity, and with 
decreased rhodium consumption. 
In a preferred embodiment, a mixture containing an 
11a-halo-6-deoxy-6-demethyl-6-methylenetetracycline, preferably the 
p-toluene sulfonate of 11a-chloro methacycline; 
hydridotetrakis(triphenylphosphine) rhodium (I); and a tertiary phosphine, 
preferably triphenylphosphine, in methanol is subjected to agitation in a 
stainless steel autoclave, and hydrogenated at about 50.degree. to 
90.degree. C. under a pressure between about 4 and 12 kg/cm.sup.2, prior 
to the termination of the reaction. Sulfosalicylic acid is added and the 
reaction mixture is cooled to about 10.degree. C. for 2-4 hours. The 
alpha-6-deoxy-5-oxytetracyline sulfosalicylate, preferably doxycyline 
sulfosalicylate (or toluene sulfonate) thus obtained is filtered and 
washed with methanol. 
Alternatively, the reductive dehalogenation and hydrogenation can be 
carried out with a two-step process initially effecting 11a-dehalogenation 
with a conventional catalyst, e.g., 5% Rh/C or 5% Pd/C in methanol. The 
initial catalyst is then removed by filtration, and the solution is again 
subjected to hydrogenation in the presence of the above catalyst. 
In the following examples, particularly preferred embodiments of the 
hydrogenation catalyst and the process for the preparation of 
alpha-6-deoxytetracyclines therewith are described. In the examples, all 
temperatures are given in Degrees Celsius and all parts and percentages by 
weight, unless otherwise specified. 
EXAMPLE 1 
Preparation of Hydridotetrakis(triphenylohosphine) Rhodium (I) Catalyst 
Solutions of hydrated rhodium trichloride (0.26 g. 1.0 mM) in warm ethanol 
(20 ml), and potassium hydroxide (0.4 g., 7.1 mM) in warm ethanol (20 ml) 
were added in rapid succession to a vigorously stirred solution of 
triphenylphosphine (2.62 g. 10 mM) in boiling ethanol (80 ml). The mixture 
was heated under reflux for 5 minutes, cooled to 30.degree. C., filtered 
and the solid washed with ethanol, water, ethanol and finally n-hexane. It 
was dried under vacuum to give a yellow microcrystalline solid (0.88 g., 
77.4%); m. pt. 142.degree.-47.degree. C. (Found: C 75.3, H 5.2, Rh 8.7, 
Calc. C 75.0, H 5.35, Rh 8.9%). 
EXAMPLE 2 
Production of Doxycyline from Methacycline Hydrochloride with 
Hydridotetrakis (Triphenylohosphine) Rhodium (I) Catalyst 
Methacycline hydrochloride (20 g., 0.042 mole), 0.03 g of the catalyst 
prepared in Example 1 and methanol (240 ml) were charged to a stainless 
steel hydrogenation vessel. The reactants were hydrogenated at 
80.degree.-85.degree. C. and at a pressure of 85-90 psi for 6 hours. 
Sulfosalicylic acid (32 g, 0.127 mole) was added to the reaction mixture, 
and the mixture was stirred for 3 hrs. at room temperature. Doxycycline 
sulfosalicylate (SSA) separated out immediately and was then filtered, 
washed first with water (100 ml), and then with methanol:water (1:1) (100 
ml), and dried at 55.degree.-60.degree. C. The product weighed 27.2 g 
(98.3%). HPLC analysis indicated: alpha epimer 99.8%, beta epimer 0.07%, 
methacycline none, and others less than 0.1%. 
The doxycycline SSA product was dissolved in hot 20% ethanolic-HCl (250 ml) 
and treated with activated charcoal (1.25 g) for 15 minutes. The reaction 
mixture was filtered through a G-4 sintered funnel. To the filtrate was 
added conc. hydrochloric acid (20 ml), and the mixture was agitated at 
55.degree.-60.degree. C. for 3 hours. It was cooled to 40.degree. C., 
filtered, washed with acetone (100 ml), and dried. The resulting 
doxycycline hyclate weighed 16.1 g (76.4%). A second crop was obtained as 
doxycycline SSA (3.6 g) by the addition of sulfosalicylic acid to the 
mother liquor. 
The p-toluene sulfonate (PTS) salt of doxycycline was obtained when 
sulfosalicylic acid was replaced by p-toluene sulfonic acid. 
The yield, stereospecificity, and purity of the product obtained in Example 
2 are compared with those claimed in corresponding examples of various 
prior art doxycycline synthesis patents in the following tabulation: 
TABLE - I 
__________________________________________________________________________ 
Comparison of Doxycycline Produced in Example 2 
With Prior Art Products 
Rhodium used 
per kg of Content (%) Purity 
Patent No. MOT.HCl Alpha 
Beta of isolated 
MOT Example 
(mg) Yield.sup.d (%) 
Isomer 
Isomer 
MOT product (%) 
__________________________________________________________________________ 
US 4,207,258 
2 19540 78.0 NS NS NS 99.3.sup.b 
French 2,216,268 
3 21252 90.6 NS NS NS NS 
US 3,954,862 
3 1962 80.0 81.0* 
1.6* 
NS NS.sup.a 
US 4,001,321 
1 9369 95.0 93.0 
2.0- 
NS 93.0.sup.b 
3.0* 
US 3,962,131 
2 less than 
98.8 NS NS NS 99.7.sup.b 
3332.4 
US 3,907,890 
5 0 75.2 98.0 
2.0 0 98.0.sup.a 
Re. 32,535 
4 620.6 99.1 99.89 
0 0 99.89.sup.c 
Present 2 133.5 98.3 99.8 
0.07 
None 
99.8.sup.a 
Invention 
__________________________________________________________________________ 
*Values in the reaction mixture 
NS: Not stated 
MOT: 6deoxy-6-demethyl-6-methylene-5-oxytetracycline (methacycline). 
.sup.a HPLC analysis 
.sup.b UV analysis 
.sup.c Paper chromatography 
.sup.d Examples with highest yields considered for comparison purposes. 
1200 G 
From the preceding table it will be seen that the only prior art processes 
which resulted in the formation of doxycycline products in yields, 
stereospecificities, and purtities which even approached those obtained in 
Example 2 (the processes of U.S. Pat. Nos. 3,962,131 and Re. 32,535), 
required from five to as much as twenty-five times the amount of rhodium 
utilized in Example 2. Use of the procedure of Example 2 thus provides 
substantially and unexpectedly superior economies relative to each of the 
noted prior art procedures. 
EXAMPLE 3 
Example 2, when repeated with 0.040 g of the catalyst prepared as described 
in Example 1, yielded doxycycline SSA (26.8 g, 96.8%). The quality of the 
product was comparable to that obtained in Example 2. 
EXAMPLE 4 
Example 2 was repeated in the presence of triphenylphosphine (0.5 g). In 
this case the reaction was completed in 5 hrs. The yield of doxycycline 
SSA was 27.0 g (99.83%, beta epimer 0.05%, methacycline 0.05%, and other 
impurities less than 0.1%. 
EXAMPLE 5 
Production of Doxycycline from 11a-Chloro Methacycline PTS Salt with 
Hydridotetrakis (Triphenylphosphine) Rhodium (I) Catalyst 
11a-chloromethacycline PTS salt (50 g, 0.076 mole), triphenylphosphine (23 
g, 0.087 mole), and 0.055 g of the catalyst of Example 1 were mixed in 
methanol (300 ml) in a stainless steel pressure vessel. The reactor was 
thoroughly flushed with nitrogen. The reaction mixture was thereafter 
hydrogenated for 7 hrs at 80.degree.-85.degree. C. and under a pressure of 
90-95 psi for 6.5 hrs. Doxycycline SSA was isolated in the manner 
described in Example 2 (47 g, 92.3%), and converted to its hyclate, 
yielding 28.2 g (77.52%) of product. No beta epimer or methacycline was 
detectable by thin layer chromatography. From the mother liquor, a second 
crop of doxycycline SSA was obtained, weighing 6.0 g. HPLC analysis: alpha 
epimer 99.8%, beta epimer 0.19%, methacycline none and other less than 
0.1%. 
The yield, stereospecificity, and purity of the product obtained in Example 
5 are compared with those claimed in corresponding examples of various 
prior art doxycycline synthesis patents in the following tabulation: 
TABLE - II 
__________________________________________________________________________ 
Comparison of Doxycycline Produced in Example 5 
With Prior Art Products 
Rhodium used 
per kg of Content (%) Purity 
11a-Cl MOT alpha 
beta of isolated 
U.S. Pat. No. 
Example 
(mg) Yield.sup.d (%) 
isomer 
isomer 
MOT product (%).sup.d 
__________________________________________________________________________ 
US 3,962,331 
1 4889 70.1 95.0* 
5.0* 
Slight 
98.9 
traces 
US 3,954,862 
17 2140 86.7 59.9 
1.33 
0.8 59.0.sup.a 
Re. 32,535 
13 378.4 90.7 99.6 
0.3 0 99.6.sup.a 
Present 
5 133.5 92.3 99.8 
0.19 
NIL 99.8.sup.a 
Invention 
__________________________________________________________________________ 
.sup.a HPLC analysis; .sup.b UV analysis; .sup.c Paper chromatography; 
.sup.d Examples with highest yields considered for comparison purposes. 
MOT: 6deoxy-6-demethyl-6-methylene-5-oxytetracycline (methacycline). 
*In reaction mixture. 
1200G 
From the preceding table it will be seen that the only prior art process 
which resulted in the formation of a doxycycline product in a yield, 
stereospecificity, and purity which even approached the values obtained in 
Example 5 (the process of reissue patent Re. 32,535), required almost 
three times more rhodium than employed in Example 5. Use of the procedure 
of Example 5 thus provides substantially and unexpectedly superior 
economies relative to the noted prior art process. 
EXAMPLE 6 
Example 5 was repeated except that doxycycline was isolated as its PTS salt 
(42.9 g, 90.6%). Thin layer chromatography of the product showed only 
traces of methacycline and beta epimer. 
EXAMPLE 7 
Example 5 was repeated using ethanol (300 ml) as the solvent instead of 
methanol. Thin layer chromatography showed principally doxycycline 
contaminated with only a negligible amount of methacycline and beta 
epimer. 
EXAMPLE 8 
Example 5 was repeated at 65.degree.-70.degree. C., maintaining the other 
conditions constant. In this case, the product yield was low (35 g, 68%). 
Thin layer chromatography of the product showed the presence of 3-4% 
methacycline. 
EXAMPLE 9 
Example 5 was repeated using 0.10 g of the Example 1 catalyst. The yield of 
doxycycline SSA was 46.5 g (91.39%). The purity of the product was 
comparable to that of the product obtained in Example 5. 
EXAMPLE 10 
11a-chloro methacycline PTS salt (40 g, 0.062 mole) and (50wet) 5% Rh/C 
(1.0 g) in methanol (240 ml) were charged to the hydrogenation vessel. The 
contents were hydrogenated at room temperature under a pressure of 0.5 
kg/cm.sup.2 until hydrogen absorption ceased (1 hour). Thin layer 
chromatography of the reaction mixture showed almost pure methacycline. 
The Rh/C catalyst was filtered off and the filtrate was charged back to 
the hydrogenator, followed by the addition of 0.07 g of the catalyst of 
Example 1 and triphenylphosphine (8.0 g, 0.03 mole). Hydrogenation was 
carried out under the conditions of temperature and pressure employed in 
Example 2. Doxycycline SSA (30.5 g, 74.9%) was obtained. 
EXAMPLE 11 
Preparation of Hydridotetrakis (Triphenyluphosphine) Rhodium (I) Catalyst, 
and Production of Doxycycline from 11a-Chloro Methacycline Therewith 
To a refluxing solution of triphenylphosphine (0.35 g, 1.34 mmol) in 
ethanol (15 ml) was added a hot solution of rhodium chloride (0.05g, 0.189 
mmol) quickly followed by a hot solution of potassium hydroxide (0.077 g, 
1.37 mmol). Almost immediately a yellow solid separated out. Refluxing was 
continued for 5 minutes. All operations were done under a nitrogen 
atmosphere. 
The catalyst thus prepared was used without isolation, in the hydrogenation 
of 11a-chloro methacycline PTS (100 g, 0.154 mole). The reaction was 
carried out as described in Example 5, giving 92.2 g (90.6%) of 
doxycycline SSA after addition of sulfosalicylic acid. Thin layer 
chromatography showed a negligible amount of methacycline and no beta 
epimer. 
It will be understood that various changes may be made in the procedures 
for preparing and utilizing the preferred catalyst embodiments described 
hereinabove without departing from the scope of the present invention. 
Accordingly, it is intended that the invention is not limited to the 
preceding description but should be construed in the light of the 
following claims: