Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1998-12-15
2001-05-01
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S354000, C549S510000, C549S511000, C564S304000, C564S389000
Reexamination Certificate
active
06225463
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to a novel process for the convenient preparation of &bgr;-lactams which can be used for the preparation &bgr;-lactams which serve as precursors of the paclitaxel side-chain.
Paclitaxel (Taxol™), isolated in minute quantities from the bark of the pacific yew
Taxus brevifolia
, is a potent anticancer agent used clinically to treat advanced ovarian and breast cancers. Paclitaxel is a member of the taxane natural products having the following structure:
The difficulties in meeting the growing demand for large quantities of paclitaxel has been circumvented by its semi-synthesis from 10-deacetylbaccatin-III, a taxane isolated from the needles of the English yew
Taxus baccata
. The structure of 10-deacetylbaccatin-III is shown below:
Semi-synthetic paclitaxel is made from derivatives of 10-deacetylbaccatin-III by coupling a suitable side chain precursor to the free hydroxyl group at position 13. In addition all the total syntheses reported to date the side-chain has been installed in a similar way as one of the late steps.
1
The current interest in paclitaxel has therefore created a need for good synthetic routes to such precursors of the C-13 side chain. The side-chain is also a very important structural feature that is, in part, responsible for paclitaxel's impressive ability to stabilise microtubules. As a consequence, many analogues of paclitaxel possessing a modified C-13 side chain have been made by semi-synthesis.
Of the numerous synthetic routes to the side-chain, &bgr;-lactams constitute one of the most important type of side-chain precursor and can be made via the Staudinger reaction between an imine and a ketone.
2
The &bgr;-lactam 3 has previously been made by the Staudinger reaction between the imine 1 and the ketene derived in situ from acetoxyacetyl chloride 2 (3:4, 75:25, 74%).
3
However, the &bgr;-lactam was ring-opened in the next step of what constituted a synthesis of the phenylisoserine side-chain: the auxiliary was removed by hydrogenolysis.
Farina and co-workers have also used a similar chiral auxiliary based approach to the synthesis of the C-13 side chain.
4
They used a derivative of L-threonine as the auxiliary, as shown below. Although the diastereoselectivity of &bgr;-lactam formation is good (10:1), four reactions are required to remove the auxiliary via treatment with fluoride ion, methanesulfonyl chloride and triethylamine, ozone, and sodium bicarbonate in 66% overall yield. These steps necessarily increase the costs of a process and severely limit the number of possible compatible functional groups present in any side chain analogue. Additionally, the L-threonine derivative is not commercially available and would be expensive to make.
A new auxiliary to control the diastereoselectivity in the ringforming reaction which could be made inexpensively and also be removed without destruction of the &bgr;-lactam ring in a single step is therefore needed. This could be obtained by the use of p-methoxyphenyl substituted amines. We have now developed a new stereocontrolled route to the paclitaxel &bgr;-lactam side-chain precursor using a chiral auxiliary that is cleaved oxidatively from the lactam nitrogen atom.
SUMMARY OF THE INVENTION
The object of the present invention is the development of new chiral auxiliaries for improved &bgr;-lactam formation that control both the diastereoselectivity of &bgr;-lactam formation and which can be removed without destruction of the sensitive azetidinone ring, providing valuable intermediates for coupling to the C-13 hydroxyl group of anti-tumor taxanes.
The present invention is therefore directed to a process of preparing a &bgr;-lactam of formula 9
wherein R
2
is aryl, substituted aryl, C
1
-C
5
alkyl, C
1
-C
5
alkenyl or C
1
-C
5
alkynyl, and R
5
is aryl, substituted aryl or C
1
-C
5
alkyl, comprising the steps of:
a) reaction of an S-amine of formula 5
wherein
R
1
is C
1
-C
5
alkyl,
R
3
is hydrogen, C
1
-C
5
alkyl, C
1
-C
5
alkoxyl or aryloxy, and
R
4
is C
1
-C
5
alkoxyl or aryloxy, with a aldehyde of formula R
2
CHO, wherein R
2
is as defined above;
to obtain a compound of formula 6
wherein R
1
, R
2
, R
3
and R
4
are as defined above,
b) reaction of the compound of formula 6 with an acylchloride R
5
CO
2
CH
2
COCl of formula 7, wherein R
5
is as defined above, in the presence of triethylamine, to obtain a mixture of diastereo-isomeric &bgr;-lactams of the formulae 8a and 8b:
wherein R
1
, R
2
, R
3
, R
4
and R
5
are as defined above, and
c) separation of the &bgr;-lactams of formulae 8a and 8b, to obtain an enantiomerically pure &bgr;-lactam of formula 8a, followed by treatment of said &bgr;-lactam of formula 8a with cerium ammonium nitrate [Ce(NH
4
)
2
(NO
3
)
6
] in the presence of acetonitrile and water, to obtain the &bgr;-lactam having formula 9.
According to the above process, the required diastereoisomer (−)-8a could be isolated free of the isomer 8b in a high yield.
Expediently, the &bgr;-lactams of formulae 8a and 8b are separated by recrystallisation from an ethyl acetate/hexane mixture.
Preferrably, the abovementioned step (b) of the process according to the invention is effected in hexane, benzene or in DMF, for the selectivity of the &bgr;-lactams (±)-8a and (±)-8b appeared to be somewhat dependent upon the reaction solvent, as will be explained below.
Expediently, compounds are used in the present process wherein
R
1
is C
1
-C
5
alkyl,
R
2
is aryl, substituted or not,
R
3
is hydrogen,
R
4
is C
1
-C
5
alkoxyl or aryloxy, and
R
5
is C
1
-C
5
alkyl.
A further object of the present invention is enantiomerically pure (S)-(−)-1-(p-methoxy-phenyl)propyl-1-amine. This compound could be prepared in a 89% overall yield by the sodium/ethanol reduction of the oxime p-methoxypropiophenone.
The enantiomerically pure chiral auxiliary S-(−)-1-(p-methoxyphenyl)-propyl-1-amine is required for the production of a single diastereoisomer of paclitaxel upon coupling with 10-deacetylbaccatin-III, and represents thus a valuable intermediate in a production process of paclitaxel.
The use of this invention for the synthesis of a &bgr;-lactam, used previously as a precursor to the side chain of paclitaxel is exemplified below.
The diastereomeric &bgr;-lactams (±)-11 and (±)-12 were prepared by the Staudinger reaction between the imine (±)-10 [derived from 1-(p-methoxyphenyl)propyl-1-amine; see below] and acetoxyacetyl chloride 2 in the usual way. The selectivity was somewhat dependent upon the reaction solvent; in hexane, (±)-11:(±)-12 67:33, 54%, in benzene, (±)-11: (±)-12 74:26, 78%; and in DMF (±)-11:(±)-12 70:30, 85%. When the mixture of (±)-11 and (±)-12 was treated with ceric ammonium nitrate in a mixture of water and acetonitrile (3:5) for 1 h at 0° C. the reaction proceeded cleanly to give the azetidinone (±)-13 (85%) and p-methoxypropiophenone. This is therefore a key feature of the invention as the auxiliary group is easily removed to reveal the &bgr;-lactam intact.
The preparation of the enantiomerically pure &bgr;-lactam is possible by the use of an enantiomerically pure chiral auxiliary.
The preparation of enantiomerically pure (S)-(−)-1-(p-methoxyphenyl)propyl-1-amine (−)-14 is achieved by resolution of its salt with N-acetyl-L-leucine 15. The 1-(p-methoxyphenyl)propyl-1-amine (±)-14 is in turn prepared in 89% overall yield by the sodium/ethanol reduction of the oxime p-methoxypropiophenone. Reaction of the amine with N-acetyl-L-leucine 15 gave the expected diastereoisomeric salts. The less soluble (S)-amine N-acetyl-L-leucine salt 16 was obtained (30%) by fractional crystallisation of the mixture from water. Treatment of the salt 16 with sodium hyroxide solution gave the amine (S)-(−)-1-(p-methoxyphenyl)propyl-1-amine (−)-14 (quant.) and recovered N-acetyl-L-leucine 15 (88%).
The imine (S)-(−)-10 [quantitatively obtained from (S)-(&
Brown Stephen
de Vos Dick
Jordan Allan M.
Lawrence Nicholas J.
McGown Alan Th.
Browdy and Neimark
Pharmachemie B.V.
Trinh Ba K.
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