Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-01-19
2001-02-13
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
Reexamination Certificate
active
06187956
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an improved process for preparing L-phenylephrine hydrochloride by means of rhodium-catalysed asymmetric hydrogenation on an industrial scale.
TECHNOLOGICAL BACKGROUND TO THE INVENTION
L-phenylephrine is one of the analogues of adrenaline frequently used for pharmaceutical purposes and is of great commercial interest. L-phenylephrine is used pharmaceutically in the form of L-phenylephrine hydrochloride and acts as a sympathomimetic in the treatment of hypotonia and as a vasoconstrictor in ophthalmology and rhinology. The chemical structure of the chiral &agr;-aminoalcohol L-phenylephrine is shown in formula I.
Formula I:
PRIOR ART
The methods of preparing L-phenylephrine hydrochloride known from the prior art include the asymmetric hydrogenation of the prochiral N-benzyl-N-methyl-2-amino-m-benzyloxyacetophenone hydrochloride (formula II) according to Tetrahedron Letters 30 (1989), 367-370, or Chem. Pharm. Bull. 43 (5) (1995) 738-747.
Formula II:
Achiwa et al. writing in Tetrahedron Letters 30 (1989), 367-370 describe the asymmetric hydrogenation of 3-benzyloxy-2-(N-benzyl-N-methyl)-aminoacetophenone hydrochloride as a substrate with hydrogen in the presence of [Rh(COD)Cl]
2
/(2R,4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphino-methyl)-N-methyl-aminopyrrolidine as catalyst. Immediately after filtration and concentration of the reaction mixture the benzylic nitrogen protecting group is cleaved and phenylephrine is obtained as the product. In addition to the L-enantiomer, the D-enantiomer is obtained in a proportion of at least 7.5% as an impurity (85% ee). For the reaction, the catalyst has to be used in a molar ratio of 1:2000 based on the substrate. The main disadvantage of the process is that the L-phenylephrine obtained cannot be purified economically to a degree of purity of at least 98% ee which is essential if it is to be used as a pharmaceutical composition.
In Chem. Pharm. Bull. 43 (5) (1995) 738-747 a molar ratio of substrate to catalyst of about 1,000:1 is given as the preferred ratio for asymmetric hydrogenation.
However, the process described in the prior art is unsuitable for the production of L-phenylephrine on an industrial scale on account of a number of disadvantages: In spite of the use of large amounts of catalyst in the asymmetric reaction step the product cannot be prepared as the L-enantiomer with sufficient purity for pharmaceutical purposes without expensive purification procedures, but is only obtainable as a mixture containing a relatively large amount of D-enantiomer as a contaminant.
In addition, the relatively long reaction time of the step of asymmetric hydrogenation of about 20 hours constitutes a very equipment-intensive and expensive reaction step precisely for the production of L-phenylephrine on an industrial scale, with a by no means negligible safety risk.
DESCRIPTION OF THE INVENTION
The present invention relates to a new method of producing L-phenylephrine hydrochloride by asymmetric hydrogenation which overcomes the difficulties and drawbacks known from the prior art or mentioned above.
One of the essential goals of the present invention is to develop a process by means of which L-phenylephrine hydrochloride can be prepared with high optical and chemical purity. At the same time, the risk of contamination of drug preparations containing L-phenylephrine hydrochloride as active substance with the unwanted D-enantiomer should be minimised.
Another objective of the invention is to develop a process by means of which largely enantiomerically pure L-phenylephrine can easily be prepared.
A further goal of the invention is to prepare L-phenylephrine by a stereoselective process in order to avoid reaction steps in which chiral intermediate compounds or the chiral end product L-phenylephrine is obtained as a racemate in a similar amount to the corresponding antipode.
The process according to the invention further sets out to shorten significantly the hydrogenation times required for the preparation of L-phenylephrine hydrochloride, in order to reduce the costs and dangers involved in the use of hydrogen under high pressure, inter alia.
Another aim of the present invention is to provide the skilled person with a process for preparing L-phenylephrine by which this active substance which is needed in large quantities is cheaply obtainable starting from readily available educts.
Surprisingly, it has now been found that L-phenylephrine hydrochloride can be obtained with exceptionally high optical purity from N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone hydrochloride 1 by asymmetric hydrogenation with [Rh(COD)Cl]
2
/(2R,4R)-4-dicyclohexylphosphino)-2-(diphenylphosphino-methyl)-N-methyl-aminocarbonylpyrrolidine as the catalyst system and a special sequence of steps. The abbreviation COD used in the overall formula stands for cyclooctadiene.
With a molar ratio of catalyst to substrate of about 1:1000, starting from benzyladrianone (N-benzyl-N-methyl-2-amino-m-hydroxy-acetophenone-hydrochloride) 1, benzyladrianol hydrochloride 2 is obtained by the process according to the invention with an optical purity of 92% ee (reaction plan 1). By converting the benzyladrianol hydrochloride 2 into the free base and then precipitating it from an ammonia/methanol/water mixture, the optical purity can easily and remarkably be improved even to >99% ee. This intermediate compound which is sufficiently pure for pharmaceutical purposes is then converted into L-phenylephrine hydrochloride 3 in a subsequent reaction step.
The precise mechanism of the rhodium-catalysed asymmetric hydrogenation is not presently known. This is particularly true of the reaction of N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone hydrochloride 1 with hydrogen catalysed by [Rh(COD)Cl]
2
and (2R,4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphino-methyl)-N-methyl-aminocarbonylpyrrolidine as the catalyst system.
Reaction plan 1:
It has also been found that, contrary to the prevailing opinion, a molar ratio of catalyst to substrate of about 1:1000 is not necessary for the asymmetric hydrogenation step in order to achieve good yields or high optical purity, as indicated by the prior art. In the process according to the invention, this ratio can be dramatically lowered by a factor of 10 to 100. In spite of this significant reduction in the amount of catalyst the intermediate product 2 resulting from the asymmetric hydrogenation—and hence eventually L-phenylephrine—is still obtained with a significantly higher optical yield than in the process known from the prior art. Thus, for example, L-phenylephrine is still obtained in an optical yield of 88% ee with a catalyst concentration of only 1:10,000. Reducing the amount of catalyst makes the purification of the product considerably easier.
By reducing the amount of catalyst and using the commercially favourable N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone 1 as educt, the costs of preparing L-phenylephrine can be reduced substantially by the new process.
In addition, the new process reduces the reaction time for asymmetric hydrogenation by up to 75% compared with the prior art. It is particularly advantageous for the production of L-phenylephrine on an industrial scale precisely from the point of view of costs and safety.
Finally, with the process according to the invention, it is possible to omit the protection of the phenolic hydroxy group in the 2-aminoketone 1 and still successfully react 1 to form the chiral 2-aminoalcohol 2 by asymmetric hydrogenation with one of the catalyst systems according to the invention.
Moreover, by purification at the benzyladrianol stage 2 the process according to the invention makes it possible to obtain L-phenylephrine with high optical purity.
According to reaction plan 1 the commercially favourable N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone 1 is reacted with hydrogen in a first reaction step in the presence of a chiral rhodium catalyst under a pressure in the range from 10 to 100 bar, preferably 10 to 50 bar and most pre
Dietrich Wolfgang
Klinger Franz Dietrich
Wolter Lienhard
Barts Samuel
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen
Raymond Robert P.
Witkowski Timothy X.
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