Process for preparing adrenaline

Details Process for preparing adrenaline Process for preparing adrenaline

2000-07-26

2001-04-17

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S304000

Reexamination Certificate

active

06218575

ABSTRACT:

The present invention relates to an improved process for preparing adrenaline, or an addition salt thereof, on an industrial scale, with asymmetric hydrogenation as a key step and a special sequence of successive steps, using [Rh(COD)Cl]
2
as catalyst and a chiral, bidentate phosphine ligand such as (2R,4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphinomethyl)-N-methylaminocarbonylpyrrolidine as the catalyst system.
BACKGROUND OF THE INVENTION
Adrenaline is a hormone and neurotransmitter which belongs to the catecholamines. In the human body, it is formed from tyrosine when the latter is reacted via dihydroxyphenylalanine, dopamine, and noradrenaline, finally producing adrenaline. Adrenaline, being a sympathetic agent, stimulates the adrenergic receptors of the sympathetic nervous system, increasing the pulse rate, cardiac output, and systolic blood pressure, reducing intestinal peristalsis, relaxing the bronchial muscles and dilating the bronchi, dilating the pupils, increasing the basal metabolic rate by promoting O
2
consumption, hyperglycemia and glycosuria by mobilizing the glycogen reserves in the liver and increasing lipolysis, inter alia, thereby increasing the free fatty acids in the blood. Because of its wide range of activities adrenaline is of considerable commercial interest in the treatment of anaphylactic shock, inter alia, or as an addition to local anesthetics.
Chemically, adrenaline is L-1-(3′,4′-dihydroxyphenyl)-2-methylaminoethan-1-ol with the following structure (Formula I):
PRIOR ART
Industrially, adrenaline is usually manufactured by non-stereoselective hydrogenation of 3′,4′-dihydroxy-2-N-methylaminoacetophenone or a derivative thereof with protected OH functions or amino function and subsequent racemate separation.
Enantioselective methods of synthesis are also known. One of these is described, for example, in Tetrahedron Letters 5 (1979), 425-428. According to this method, 3′,4′-dihydroxy-2-N-methylaminoacetophenone is reacted to produce adrenaline by hydrogenation under a hydrogen pressure of about 50 bar using a chiral hydroxyalkylferrocenylphosphine as catalyst. The amount of catalyst to substrate is about 1:100, based on the molar ratio. Under these conditions, L-1-(3′,4′-dihydroxyphenyl)-2-methylaminoethan-1-ol (adrenaline) is obtained in an enantiomeric excess over the S-enantiomer of 60% ee after about 2 to 4 days reaction.
This process, however, is unsuitable for producing adrenaline on an industrial scale for a number of reasons: in spite of the use of large amounts of catalyst in the asymmetric reaction step, the product cannot be produced in sufficiently pure form for pharmaceutical purposes except by the use of expensive purification procedures, as this reaction produces adrenaline only as a mixture containing a relatively high proportion of the opposite enantiomer as a contaminant. The relatively long reaction time of the asymmetric hydrogenation step, i.e., 2 to 4 days, also constitutes a reaction step which is very equipment-intensive and expensive for industrial purposes, with not inconsiderable safety risks.
Achiwa et al., writing in Tetrahedron Letters 30 (1989), 367-370 and Chem. Pharm. Bull. 43 (5) (1995) 738-747, describe an asymmetric rhodium catalyst which was used in the manufacture of L-phenylephrine. Using asymmetric hydrogenation, 3′-benzyloxy-2-(N-benzyl-N-methyl)aminoacetophenone hydrochloride is reduced within 20 hours with hydrogen in the presence of [Rh(COD)Cl]
2
/(2R,4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphinomethyl)-N-methylaminopyrrolidine as catalyst. After filtration, concentration of the reaction mixture and cleaving of the benzyl nitrogen protecting group, phenylephrine is obtained as the product. In addition to the L-enantiomer, the D-enantiomer is also obtained in an amount of at least 7.5% as a contaminant (85% ee). The precise mechanism of rhodium-catalyzed asymmetric hydrogenation is not known at present.
The main disadvantage of this process is that the L-phenylephrine obtained cannot be purified economically on an industrial scale to the level of purity essential for its use as a pharmaceutical. Moreover, the hydrogenation reaction is relatively long, taking more than 20 hours, which is associated with the disadvantages described above.
It is not known to produce adrenaline by this method.
SUMMARY OF THE INVENTION
The present invention relates to a new process for preparing adrenaline by asymmetric hydrogenation which overcomes the problems and drawbacks known from the prior art or described above.
One of the essential objectives of the present invention is to develop a process by mean., of which adrenaline can be produced with high optical and chemical purity. Thus, for example, the risk of the unwanted enantiomer contaminating pharmaceutical preparations which contain adrenaline as active ingredient should be minimized.
Another objective of the invention is to develop a process by means of which substantially enantiomerically pure adrenaline can be produced easily, i.e., without complicated purification procedures.
A further aim of the invention is to produce adrenaline by means of a stereoselective process in order to avoid reaction steps in which chiral intermediate compounds or the chiral end product adrenaline is obtained as a racemate together with its opposite enantiomer in a similar amount.
The process according to the invention also sets out to keep the hydrogenation times needed for adrenaline production as short as possible in order to reduce the costs and risks involved in using hydrogen under high pressure, inter alia.
Another aim of the present invention is to provide the skilled person with a process for manufacturing adrenaline by which this substance, which is needed in large quantities, can be produced cheaply from readily available educts.
Surprisingly, it has now been found that adrenaline or the sulphate thereof can be obtained in exceptionally high optical purity from 3′,4′-dihydroxy-2-N-benzyl]-N-methylaminoacetophenone 1 using asymmetric hydrogenation with [Rh(COD)Cl]
2
/(2R,4R)-4-dicyclohexylphosphino)-2-(diphenylphosphinomethyl)-N-methylaminocarbonylpyrrolidine (RR-MCCPM) as the catalyst system and a special sequence of subsequent steps. The abbreviation COD used in the general formula denotes cyclooctadiene.
DETAILED DESCRIPTION OF THE INVENTION
With a molar ratio of catalyst to substrate of about 1:1500 (see Example), adrenaline sulphate 3 can be obtained by the process according to the invention, starting from benzyladrenalone (3′,4′-dihydroxy-2-N-benzyl-N-methylaminoacetophenone) 1, with an optical purity of 98% ee or more (HPLC) (reaction diagram 1).
Reaction diagram 1:
According to reaction diagram 1, first of all 3′,4′-dihydroxy-2-N-benzyl-N-methylaminoacetophenone 1 is reacted by asymmetric hydrogenation, using [RH(COD)Cl]
2
/(2R,4R)4-(dicyclohexylphosphino)-2-(diphenylphosphinomethyl)-N-methylaminopyrrolidine as catalyst, to form the optically active benzyladrenaline base (R-1-(3′,4′-dihydroxyphenyl)-2-N-benzyl-N-methylaminoethan-1-ol) 2 (reaction step 1). This is then precipitated in the basic range by the addition of ammonia (reaction step 2). In a 3rd reaction step the benzyl protecting group is then eliminated by hydrogenation with hydrogen and palladium, preferably palladium on charcoal, in a sulfuric acid solution, so as to obtain the adrenaline sulphate 3.
For easy production of almost optically pure adrenaline or its sulphate 3, another important step, in addition to asymmetric hydrogenation with the rhodium catalyst described above, is precipitation of the N-benzyladrenaline 2. By means of these two steps taken together, asymmetric hydrogenation plus precipitation of the benzyladrenaline in the basic range, an intermediate compound with high optical purity is readily obtained, from which adrenaline or the acid addition salts thereof can be obtained with high optical purity in another simple reaction step.

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