Application of Organometallic Catalysis to the Commercial Production of L-DOPA W. S. Knowles Monsanto Agricultural Products Company, Research Division, St. Louis, MO 63167 The discovery in the mid-'sixties that 1-3,4-dihydroxyphenylalanine (L-DOPA) was effective in the treatment of Parkinson's disease created a sudden demand for this rather rare amino acid. Even though the original clinical work was performed with the racemic mixture, it was soon recognized that only the S or (1) isomer was active, and to minimize side reactions, particularly with the large doses required, the unwanted R or (d) isomer had to be removed. These findings follow the general pattern that whenever racemic compounds are used in living systems only one form is effective. Almost simultaneous with this L-DOPA demand a technique for asymmetric hydrogenation emerged which offered a unique approach toward the desired molecule. I t is rare that a new discovery is so beautifully timed with the need for its use. This paper describes the application of this novel technology to the commercial preparation of L-DOPA. Resolutions A great deal of ingenuity has been applied to the resolution problem, hut it remains so severe that for the most part when there is a commercial need for a chiralmolecule, industry resorts to a biochemical route where the desired isomer is made directly. Here the dilute solutions, difficult separations, and sensitivity encountered in fermentation processes, is preferred over running a resolution. Thus, almost all a amino acids are manufactured by biochemical routes even though in many cases very efficient chemistry is available for the racemic mixture. A big improvement for industrial resolutions is called directed crystallization, where the desired isomer is selectively seeded out of the racemate. This technique, which avoids use of a resolving agent, is applicable only on dl mixtures that form a conglomerate crystal which is actually an equal mixture of d and 1crystals. I t has been applied commercially in a number of cases, and an excellent description appears in the literature in its application to 1-a-methyl-DOPA (1,2).It is described generally in a recent text 13). Even use of this directed crystallization to MSG (monosodium glutamate) still has not tipped the balance in favor of the chemical route. Actually, for most compounds, the racemate has a crystalline form different from the pure isomer, and the simplified method is not applicable.
Asymmetric hydrogenation, which was in its infancy in the late 'sixties, offered a chance to get a real advantage. The use of rhodium, complexed with a chiral phosphine, was giving modest ee*sl on a-phenylacrylic acid (4). At the time
Figure 1. me LDOPA synthesis. a) series R, = CsHs.Rn = H; b) series R, = CH,. RI = Ac.
L-DOPA Problem
The need to make L-DOPA immediately available generated considerable effort t o find an efficient manufacturing process. Even though a numher of alternates were considered, including natural product sources like velvet beans, most really serious effort comprised making the racemic mixture by classical chemistry and then devising a good resolution. Since the emphasis in the pharmaceutical industry was on getting the product out t o the patient, it is not surprising that only an outsider not under this extreme urgency could develop a truly novel approach, since for him entry into the field depended only on devising a superior process.
' ee = enantiomeric efficiency = % R - % S. 222
Journal of Chemical Education
Figure 2. Asymmetric reductions of lllb.
L-DOPA was being manufactured usine the Erlenmeyer azlactune synthesis (3,61comhincd with a resolulion. Figure I, series a, compounds la, lln, llla. lVa, Va, and VI. Surprisingly, it was found that whenasymmetric hydrogenation was applied to the unsaturnted intermediate llla or Illh. it actuallv worked hetter than on simnle nlefins and the resulting ee's obtained were a very sensitive function of ligand structure. An efficient solution was discovered with only limited synthetic effort as shown in Figure 2 depicting the steowise oroeress . .. toward imoroved ohosohines. was shown by t'he fact that the ~ v i d n c for e rapid first commercial candidate CAMP (VIIJ was the sixth phosphine prrpnred and the improwd rrrsion Dil'AMP (VTTI) the 15th. Over the past 15 years a considerable number of highly efficient phosphines have been discovered that are applicable to enamides related to I11 and to little else (7). . . Other prochiral systems like hydrogenation of a-phenyl acrylic or hvdroformvlation of olefins havenot turned out to be easv to optimize by varying ligand structure, and, even to this day, do not eive commerciallv useful efficiencies (8). One ihing that was established early was that the efficiencv of the asvmmetric hvdroeenation did not vaw much with the ~ - ~ r o u on p sthe en"amiie and thus one couid consider a varietv of routes to L-DOPA all incoroorating the advantages bf a resolution free process. able 1shows the almost complete invariability with different R groups using CAMP and DiPAMP ligands. The catalysis worked poorly with E isomers, hut this limitation was not serious since the base condensations used gave the desirable 2-olefin (7). The optimum L-DOPA process follows the sequence in Figure 1,b series, making maximum use of known chemistry. Filtrations are minimized by not isolating I1 as well as suhstitutine.. acetvl . for the benzovl used in a series. The racemic iorrn olIVhis a conglomerale that enables easy quantitative rerovrries. and the, deblockinr! of the nlethoxvl and aretsls are combined in onestep. o he only important new element is the unique asymmetric hydrogenation. ~
~~~
~~
~~~~
~
Asymmetrlc Hydrogenatlon The hydrogenation turns out to be the simplest step in the sequence. The catalyst can be prepared in situ from two eauivalents of ohosohine . . and one eauivalent of Rh(CODK1 dimer or other RhU) complex or best as the air-stable sdlid [Rh(Bis-Ligandl-(diene)lf BFa-. Usual conditions are lOOOn mol ratio of substrate to catalyst and about 3 atm orensure. 50 "C. and one-hour reaction time. Since this cataiyst is comiderably more expensive than typical noble met-
Table 1. Hydrogenations wlth CAMP (VII) and DiPAMP (VIII) Substrate H
Best
/COOR4
\c=c
'NHco,, RB 3Me0-60UC8Hs 3MeO-4-AcOG& Ph Ph
Ph
Ph 3 MeO-4AcMsH3 Ph H H H *Run
see
als on carriers and since reaction rates in a poison free system are proportional t o the amount of catalyst, a balance must be achieved between catalyst usage and productivity. For large scale this means 24-hour cycles and much smaller amounts of catalyst. For these very large turnovers poisons must be avoided. Unlike heterogeneous hydrogenation catalysts, these complexes do not convert traces of oxygen in the hydrogen or peroxides in the solvent t o harmless water, hut these impurities remain to oxidize the rhodium complex to inactive materials. Thus, prior to introduction of catalyst, the batch must he thoroughly purged by venting and filling with nitrogen and finally with hydrogen, and only peroxide-free solvents can be used. On the olus side these soluble catalvsts are not ovroohoric .. . and are murh less hazardous Lo use with flammable solvents. The L-DOPA ororess also takes advantage of the fact that with the catalyst in solution one can hydrogenate slurries. Thus. usine a suitable water-isoorooanol mix one can start with slurry of reactant, hydrogenate, and obtain a slurry of product. The hatch is cooled and the 1-isomer suitable for deblocking is filtered leaving the dl that is made as well as the spent catalyst in solution. This mother liquor can then be further treated for recovery of rhodium metal. Slurries, which do not work well with heterogeneous catalysts because of coating problems, are a very effective way to increase payloads of sparingly soluble materials. In the literature auite a lot of work has been done outtine chiral rhodium complexes on carriers for easy recycle (9). In the L-DOPA case a homogeneous catalyst is a decided advantage since separation of product from spent catalyst is easy. In addition such intangibles as uniformity, high activity, and reliability are strong pluses for the soluble systems, and it would be desirable to have many other reactions that would be run in such a simple straightforward manner. There are manv variables in the use of these catalvsts that can he put to guod use fa,r optimization as shown in Tahle 2. When redurina the free arid the liaands show ooorer oerformance a t high'pressures, but n o t k u c h variahce with temperature. When the anion of the free carhoxylic acid is used the system is only slightly variant with pressure but,particularly with CAMP, quite sensitive to temperature. Thus, ee's approaching 90%can be achieved with amonophosphine but only at prohibitively slow rates a t either low pressures or low temoeratures. One advautaee of DiPAMP is that i t can achieve high ee's under conlitions which give fast rates. In the balance none of the newer lieands that have aooeared in .. the literature are superior (9).
a
-
Catalyst The key to asymmetric hydrogenation is the structure of the chiral ligand. The phosphines are prepared by a multistep route and are quite expensive, but fortunately one mole will make many thousands of moles of product. Even so, the ligand must be made from cheap starting materials. Some
of RZCH~-C-H /COOR4
\NHcoRs R4 H H H H H
H H CH1 H
H H
R6 Ph
CAMP
CH, Ph
CH1 CHI CHI CH3 CH3 CHS H CHXI
Table 2.
Ligand
DiPAMP
" e
"
90 88 85 85 93 95. 94 96 90 94 97
Hydrogenatlon of 2-Acetamldocbnamlc Actd ~emp.
Free Acid
Anion
"
25 25 25 50 50 25 0
Press. iatm)
CAMP
% ee DIPAMP
27 3 0.7 3 3 3
54 80 87 79 56
78 94
79
96
3
88
...
... 94 95
r i m 0.95 equlvalsng of N~OH.
Volume 63 Number 3 March 1986
223
economy of scale is achieved by making a 10-year supply in a few olant-size hatches. At first CAMP was oreoared from . . phenyl dichlorophosphine via Mislt,w'~menthyl ester (10). intr(ducinc the u-anisvl erouo last. Unfortunntelv. .. the desired isomer was i n k i n o r amount and, to correct this situation, i t was necessary to reverse the order of addition of aryl groups. The sequence starting with trirnethylphosphite is outlined in Figure 3. A large excess of trimethylphosphite was needed to get good yields of mono-substitution product IX. In the sequence, IX-X-XI, only the nicely crystalline phosphinic acid XI was isolated. The fact that the acid chloride XI1 can he converted to an 80120 mix of (S)p and (R)p isomers means that the menthol oreferentiallv reacts with one form while the other isomer rap~dlyracemizes.'l'hus, the catalyst preparation was greatIv facilitated hv an asvmmetric synthesis of its own directed by 1-menthol. Another advantage of the sequence in Figure 6 was that CAMP and DiPAMP were prepared from a common intermediate XIV and no new resolution orocedure needed to he worked out.Thus, thechange toan improved ligand could he donr with minimum di;location both at the synthesis and the utilization end. I t is a clear advantage of catalytic processes that it is often easy to shift from the old to the new. CAMP was prepared by a selective hydrogenation of XIV using a rhodium on carbon heterogeneous catalyst. I t was important to monitor the reaction closely and stop before the anisyl ring started to hydrogenate. Reduction with trichlorosilane and TEA gave R-CAMP VII with inversion. The (R)p rnenthyl ester XIV could also have been used in this sequence if the last step was run with pure HSiC13 which goes with retention (10,ll). In the case of DiPAMP the copper coupling step run with lithium diisopropyl arnide (12) and CuClz did not not affect the stereochemistry. However, only the base promoted trichlorosilane t o give a double inversion was applicable. In this case an empirical study showed that use of tributyl amine minimized meso formation. In principle, the menthol recovered in Figure 4 could be recycled, make the usage of chiral agent derived from nature truly minimal, but in practice it has not been worth the effort. More useful is the recovery by hydrolysis of the phos-
phinic acid XI from the (R)p menthyl ester XIV. In contrast to CAMP, DiPAMP is a stable solid melting at 102 "C. Heated a t 100 "C i t has a half-life of 3-5 h. This racemization was somewhat faster than Mislow's phosphines (lo), which did not invert appreciably until 1W15 'C hieher. The rate was reasonable if one considers that inversign a t either end destroys chirality. Use of DiPAMP comolexed with rhodium must invert much more slowlv because kfficient asymmetric hydrogenations have been obtained a t 95-100 OC. For the sake of convenience, particularly on a large scale, a solid complex was made by reacting two equivalents of phosphiue with one equivalent of [Rh(COD)CI]z in alcohol (12). This air-stable orange solid Rh (Bis-Ligand) (COD)+ BLmade a most suitable catalyst precursor. Mechanism I t should he pointed out that this process was operatedfor several vears without much knowledee of the mechanism or much of a feel for the complexes involved. From the heginninr it wasestablished that the catalvst rewired exactlv two eqGvalents of phosphine, which is consistent with the-high ee's obtained with a number of chelating his ligands. Even so, it is remarkable that these systems worked so well using such simple structures since the job they are doing is usually reserved for enzymes. The hasic reason for this result is the ability of substrate I11 to chelate with the metal by means of both the double bond and the amide oxygen. The olefin comes in to hind as a hidentatespecies andleavesas a weakly attached oroduct. The orocess facilitates ranid catalvsis as well as a rigid intermediate favorable for high xeric control. Such a cwnplex has heen isolated and characterized (13) and
-
0 Men
I
CI
OW,
w
O=p888tjCH,
O=P8m,CH,, CH, XI1
A
O Men 20% ( R ) p
XIV Flgure 3. Preparation of CAMP and DiPAMP imermediate.
224
Journal of Chemical Education
80% (SIP XI11 Figure 4. Preparation of CAMP and DIPAMP:
I
XIX
L = phosphine
XX
XXI
Iv to the minor form. The dihvdride XX where the structure cas changed from square-plakar t o octahedral has not been detected. but a monohvdride adduct XXI can be observed by low-Lmperature NMR. The true nature of the transition state where the stereochemistrv is determined remains elusive, but i t is postulated that H chiral array of aryl groups around the metal center is the determining factor (12).In a relatively short time this hydrogenation has become one of the best understood catalytic reactions. In addition, its successful application ~OL-DOPA has been a strong motivating factor for working out mechanistic details as well as elahorating structure-efficiency relationships for a large number of ligands. Literature Cited
Figure 5. Catalytic sequence in production of DiPAMP.
(11 Reinhold, D. F.;Fim%tone.R.A.: Gaines, W. A ; Chemerde. J. M.: Sletzinger, M. J. ~~
the catalytic sequence goes much as is shown in Figure 5, where the catalyst precursor is hydrogenated to a solvated ligand metal complex containing no hydrogen. This product rapidly adds enamide to form XIX. When the phosphine ligand is cbiral the complex XIX forms two diastereoisomers and hydrogen adds preferential-
.
Or- C b m IJRII..?.?~,1Pm ....
(2 K~.PLII,K.H:LWJ..I .Hnntuck..I.A U S P a m - 4415 459. 196.1 131 Jacques. I Collrr. A w ~ l r n .S II ' Enanttomem n a ~ ~ n , s uand s nesulutinna": H ~ l r y l n v r s r ~ e n rNlw r York. 1981 111 K ~ ~ ~ w I b~ s ~\ k ,, J. ~~..SmtI.J \1 S , n l n s i l . IY7X. 119 19) Csplar, V.; Comiaao, G.: Sunjie, V. Synthesis 1981,85. J.;Mislow, K. J.Amw.Chem.Soc. L968,90,4842. 1101 Korpian,O.;Lnuin,R.A.;Chiekos, 111) Knovles. W.S.:Ssbaekv.M.J.:Vinevard.B. D.Adu. Chem.Ssr. 1974.132.274. J.;Bsehman, G.L.; ~ e i " k a u f f . D . J J . 1121 ~ i ~ e ~ a r d , B . ~ . ~ ~ nW. a ls:;sab&kv,M. vl&, Amer Chem. Soe. 1917.99.5946. (131 Chs",A. S.C.;Pluth, J. J.;Halpern.J.J.Amer. Chem.Soc. 1980.10Z.5952.
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Number 3
March 1986
225
