Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-01-14
2002-10-22
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S304000, C564S438000, C564S443000
Reexamination Certificate
active
06469213
ABSTRACT:
The invention relates to a new, stable and pure Tramadol derivative, a specific process for preparing it and its use. The invention also relates to a process for producing Tramadol and salts thereof, especially Tramadol hydrochloride using the derivative.
Tramadol is the compound cis(+/−)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl) cyclohexanol which, in the form of the hydrochloride salt is widely used as an analgesic.
Tramadol hydrochloride assumes a special position among centrally acting ;s analgesics since this active ingredient acts as a strong inhibitor of pain without the side effects which are known for opioids (T. Phannacol. Exptl. Ther. 267,331 (1993)).
The compound per se is described in U.S. Pat. No. 3,652,589 and UK 997,399. Tramadol is obtained in the cis-racemate form as the major synthetic product. In known processes, the trans-racemate is present as a minor component of the reaction mixture. U.S. Pat. No. 3,652,589 describes an isolation process for the pure cis-racemate-isomer in which a complex Grignard reaction mixture is distilled and the crude mixture of the isomers is precipitated and filtered. However, there is still a relatively high level of the trans-racemate-isomer present in the final product.
U.S. Pat. No. 5,414,129 describes a process for the purification and separation of cis(+/−)-2-[(dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol-hydrochloride from a reaction mixture containing the cis-racemate-isomer, the trans-racemate-isomer and Grignard reaction side products In that process, the reaction mixture is combined with a solution of hydrochloric acid in a C
2
-C
3
alcohol or with gaseous hydrogen chloride in the presence of specific solvents. The process is said to effect the selective precipitation of cis(+/−)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol-hydrochloride. A specific example using isopranol is given and the process is also said to have been successful using one of the following solvents as an alternative: butyl acetate, MIBK, 1-butanol, 1-pentanol,PAA (primary amyl alcohol mixture), 1-hexanol, cyclohexanol, 1-octanol, 2-ethylhexanol, anisole.
However, the yield of the cis(+/−)-isomer is still relatively low and the content of the trans(+/−)-isomer is relatively high in most cases.
There is therefore a need for an improved process for preparing the pure cis form of Tramadol without several further purification steps.
Tramadol can exist in either its cis or trans isomer forms. In this specification cis-Tramadol means the racemic mixture of cis-Tramadol as shown by the following chemical structures:
STATEMENTS OF INVENTION
According to the invention, there is provided the base hydrate of cis-Tramadol as herein defined.
The invention also provides the use of the base hydrate of cis-Tramadol as an intermediate in a process for preparing Tramadol Hydrochloride.
The invention further provides the use of the base hydrate of cis-Tramadol as a medicament.
In addition, the invention provides a pharmaceutical composition including the base hydrate of cis-Tramadol. The composition may be in a form for oral, buccal, topical and parenteral or of rectal administration, especially parenteral administration.
In another aspect, the invention provides a process for preparing pure cis-Tramadol hydrochloride comprising the steps of:
reacting a Mannich base with a Grignard reagent to form a base hydrate of cis-Tramadol; and
forming cis-Tramadol hydrochloride from the base hydrate of cis-Tramadol.
In a preferred embodiment of the invention the Mannich base is formed by forming a Mannich hydrochloride and liberating the Mannich base. Preferably, the Mannich hydrochloride is formed by reaction of cyclohexanone with paraformaldehyde and diethylamine hydrochloride to form dimethylaminomethyl-cyclohexanone hydrochloride. In one embodiment of the invention, the Mannich base is liberated by treating the Mannich hydrochloride with a base such as sodium hydroxide in a solvent system which may comprise a mixture of toluene, methyl t-butylether and water.
In a preferred embodiment of the invention, the cis-Tramadol hydrochloride is formed from the cis-Tramadol base hydrate by acidification with hydrochloric acid.
The invention also provides Tramadol and salts thereof whenever prepared by the process of the invention.
We have found that pure cis-2[(dimethylamino)methyl]-1-(3-dimethoxyphenyl) cyclohexanol forms very selectively with equimolar amount of water a monohydrate which solidifies in a crystalline form.
In comparison cis-Tramadol base in anhydrous form at room temperature is an oil. Surprisingly it was found that cis-Tramadol base monohydrate is a stable derivative, which can be crystallised very easily, purified and can be used to produce pure cis-Tramadol hydrochloride.
The base monohydrate of cis-Tramadol can also be formulated in different forms. The invention therefore includes therapeutical drugs, which can be used in human or veterinarian medicines. Such drugs can be formulated with the usual pharmaceuticals ingredients.
The base hydrate of cis-Tramadol can be formulated for oral, buccal, topical, parenteral or rectal use. For example, for the oral application the base monohydrate of cis-Tramadol can be formulated as tablets, in capsules, powder. in solution, as a syrup or in suspension, which can be stabilised and produced with emulsion of oily ingredients.
DETAILED DESCRIPTION OF THE INVENTION
The invention will be more clearly understood from the following description thereof given by way of example only.
In the improved process of the invention, the first step is the reaction of cyclohexanone with paraformaldehyde and dimethylamine hydrochloride to form the Mannich hydrochloride, dimethylaminomethylcyclohexanone hydrochloride, which is recovered from acetone.
The Mannich hydrochloride formed in Step 1 is treated with sodium hydroxide in a mixture of toluene, methyl t-butyl ether and water to liberate the Mannich base.
The Mannich base is then reacted with a Grignard reagent to form a crude cis-Tramadol base hydrate.
The cis-Tramadol base hydrate is then purified by recrystallisation from ethyl acetate.
Finally, cis-Tramadol hydrochloride is formed from the cis-Tramadol base hydrate by acidification with hydrochloric acid.
In general, the reaction scheme may be illustrated as follows.
In this scheme only the (RR)-enantiomer of the Tramadol Base Hydrate is illustrated. It will be appreciated that both the (RR) and (SS) enantiomers are present in the same way as cis-Tramadol as defined above.
REFERENCES:
patent: 3652589 (1972-03-01), Flick et al.
patent: 5223541 (1993-06-01), Maryanoff et al.
patent: 5336691 (1994-08-01), Raffa et al.
patent: 5414129 (1995-05-01), Cherkez et al.
patent: 5516803 (1996-05-01), Raffa
patent: 0534628 (1993-03-01), None
patent: 0778262 (1997-06-01), None
patent: 0787715 (1997-08-01), None
patent: 0831082 (1998-03-01), None
patent: 997399 (1965-07-01), None
Raffa et al, Journal of Pharacology . . . , vol. 267, No. 1, 1993, “Complementary and Synergistic . . . ”, pp. 331-342.
Chemical Abstracts, vol. 126, No. 26, Jun. 30, 1997, & IL 1030 096 A (Chemagis Ltd), Dec. 5, 1996.
Chemical Abstracts, vol. 127, No. 20, Nov. 17, 1997, Ben-Zhi et al, “Synthesis and structure of . . . ”.
Nikolopoulos Aggelos
Schickaneder Helmut
Barts Samuel
Jacobson & Holman PLLC
Russinsky Limited
LandOfFree
Tramadol, salts thereof and process for their preparation does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Tramadol, salts thereof and process for their preparation, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tramadol, salts thereof and process for their preparation will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2932228