Synthesis of new β-lactams

Abstract

The object of the present invention is the development of new chiral auxiliaries for improved β-lactam formation that control both the diastereoselectivity of β-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, such as paclitaxel. Further, the object of the present invention is enantiomerically pure (S)-(−)-1-(p-methoxy-phenyl)propyl-1-amine.

Description

BACKGROUND OF THE INVENTION

The present invention is directed to a novel process for the convenient preparation of β-lactams which can be used for the preparation β-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, β-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 β-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 β-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 β-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 β-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 β-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 β-lactam formation that control both the diastereoselectivity of β-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 β-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 β-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 β-lactams of formulae 8a and 8b, to obtain an enantiomerically pure β-lactam of formula 8a, followed by treatment of said β-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 β-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 β-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 β-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 β-lactam, used previously as a precursor to the side chain of paclitaxel is exemplified below.

The diastereomeric β-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 β-lactam intact.

The preparation of the enantiomerically pure β-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)-(−)-14] gave a 73:27 mixture (78%) of enantiomerically pure (−)-11 and 12 upon reaction with acetoxyacetyl chloride 2. Fortunately the required major diastereoisomer (−)-11 could be isolated free of 12 by recrystallisation from ethyl acetate/hexane [52% from (S)-10]. Treatment of the now pure (−)-11 with ceric ammonium nitrate gave the known azetidinone (−)-13. We were able to isolate the by-product p-methoxypropiophenone in 77% yield, which in principle can be recycled in the synthesis of further (S)-(−)-(p-methoxyphenyl)propyl-1-amine.

The invention will be explained further in the following examples.

EXAMPLE 1

Preparation of the Oxime of P-methoxypropiophenone

4-Methoxypropiophenone (100 g, 0.61 mol) and hydroxylamine hydrochloride (61 g, 0.88 mol) were dissolved in ethanol (375 cm 3 ) and water (120 cm 3 ). This solution was added to a solution of potassium hydroxide (93 g, 1.65 mol) in water (95 cm 3 ) and the resultant mixture refluxed for 2.5 hours. After addition of water (1200 cm 3 ) and cooling, the pH of the solution was adjusted to 7 with aqueous hydrochloric acid (1 M). The solution was extracted with chloroform (3×500 cm 3 ) and the organic extracts dried (magnesium sulfate), filtered and concentrated in vacuo to give the oxime as a white powder (109 g, 100%) which was used without purification in the next stage; m.p. 63-64 C.; ν max (KBr Disc)/cm −1 3281, 3235, 3127, 3071, 2965, 2935, 1606, 1513, 1462, 1300, 1252, 1241, 1181, 1034, 1026, 971, 910, 837, 831, 597; δ 1 H (300 MHz, CDCl 3 ) 1.16 (3H, t, J 7.6 Hz, 3-H), 2.79 (2H, q, J 7.6 Hz, 2-H), 3.83 (3H, s, OMe), 6.90 (2H, d, J 8.9 Hz, 3′-H), 7.56 (2H, d, J 8.9 Hz, 2′-H), 7.99 (1H, br s, OH), δ 13 C (75 MHz, CDCl 3 ) 10.9 (CH 3 ); 19.6 (CH 2 ), 55.1 (CH 3 ), 113.9 (CH), 127.6 (CH), 129.7 (C), 160.1 (Cq), 160.4 (C); (CI: Found: [M] + 179.0948. C 10 H 13 NO 2 requires 179.0946 m/z (CI) 180 ([M+H] + , 100%), 164 (30).

Preparation of Racemic Amine (±)-14

p-Methoxypropiophenone oxime (109 g, 0.61 mol) was dissolved in ethanol (600 cm 3 ) and the solution heated to reflux. Under a nitrogen blanket, sodium metal (120 g, 5.2 mol was added in small pieces over 90 minutes. After a further 2.5 hours heating at reflux, additional ethanol (800 cm 3 ) was slowly added over 30 minutes, followed by the slow addition of aqueous ethanol (10% water, v/v, 400 cm 3 ) until all the sodium metal residues had been destroyed. Most of the ethanol was evaporated and then water (400 cm 3 ) was added. Extraction of the mixture with diethyl ether (3×350 cm 3 ), drying (magnesium sulfate) and concentration in vacuo gave a crude product, which was further purified by distillation under reduced pressure to give the amine as a colourless oil (81.7 g, 81%); b.p. 107-108° C. (5 mm Hg); ν max (thin film on CsI plates)/cm −1 2962, 2931, 1612, 1513, 1302, 1248, 1176, 1037, 832; δ 1 H (300 MHz, CDCl 3 ) 0.81 (3H, t, J 7.3 Hz, 3-H), 1.60 (2H, dq, J 6.9 Hz, 7.3 Hz, 2-H), 3.71 (1H, t, J 6.9 Hz, 1-H), 3.74 (3H, s, OMe), 6.82 (2H, d, J 8.6 Hz, 3′-H), 7.18 (2H, d, J 8.6 Hz, 2′-H); m/z (FAB) 166 ([M+H] + , 80%), 149 (70), 136 (100).

Preparation of Racemic Imine (±)-10

Benzaldehyde (0.67 g, 6.31 mmol) and the amine (±)-14 (0.80 g, 4.85 mmol) were stirred in dry dichloromethane (15 cm 3 ) in the presence of 4 Å molecular sieves, at room temperature overnight, under a nitrogen atmosphere. Filtration and concentration in vacuo gave the imine (±)-10 as a yellow oil (1.09 g, 90%) which was used in the next stage without purification: ν max (thin film on CsI plates)/cm −1 2964, 2933, 2873, 1644, 1612, 1582, 1512, 1464, 1452, 1379, 1303, 1247, 1174, 1037, 832, 694; δ 1 H (300 MHz, CDCl 3 ) 0.87 (3H, t, J 7.3 Hz, 3-H), 1.93 (2H, m, 2-H), 3.79 (3H, s, OMe), 4.14 (1H, t, J 6.9 Hz, 1-H), 6.88 (2H, d, J 4.6 Hz, 3′-H), 7.35 (2H, d, J 4.6 Hz, 2′-H), 7.40 (3H, m, 4″-H and 5″-H), 7.78 (2H, 3″-H), 8.31 (1H, s, 1″-H); m/z (FAB) 254 ([M+H] + , 80%), 224 (40), 149 (90), 121 (55).

Preparation of β-lactams (±)-11 and (±)-12

The azetidinones were prepared using the general procedure developed by Holton (EP-A-0 400 971). The imine (±)-10 (0.10 g, 0.395 mmol) and triethylamine (0.16 g, 1.68 mmol) in dry dichloromethane (1 cm 3 ) were slowly added acetoxyacetyl chloride (53.9 mg, 0.395 mmol) in dry dichloromethane (1 cm 3 ) at 0° C. The mixture was stirred at 0° C. for 1.5 h and then at room temperature for a further 3 h. The solution was poured into dichloromethane (10 cm 3 , and washed successively with hydrochloric acid (1 M, 2×5 cm 3 ), water (5 cm 3 ) and saturated sodium bicarbonate solution (5 cm 3 ). The organic extract was dried (magnesium sulfate), filtered and evaporated in vacuo to give the azetidinones [78 mg, 56%; (±)-11:(±)-12 67:33] as cream powders: ν max (K Br Disc)/cm −1 2971, 2933, 1754, 1514, 1369, 1226, 1181, 1035, 702; δ 1 H (300 MHz, CDCl 3 ) 0.84 (3H, t, J 7.2 Hz, major 3′-H), 0.86 (3H, t, J 7.2 Hz, minor 3′-H), 1.64 (3H, s, minor Ac), 1.66 (3H, s, major Ac), 1.85 (2H, m, major 2′-H), 2.05 (2H, m, minor 2′-H), 3.78 (3H, s, minor OMe), 3.80 (3H, s, major OMe), 4.01 (1H, t, J 9.3 Hz, minor 1′-H), 4.57 (1H, m, major 3-H), 4.60 (1H, m, minor 3-H), 4.62 (1H, t, J 9.3 Hz, major 1′-H), 5.62 (1H, d, J 4.8 Hz, major 4-H), 5.66 (1H, d, J 4.8 Hz, minor 4-H), 6.77 (2H, d, J 8.2 Hz, minor 3″-H), 6.83 (2H, d, J 8.2 Hz, major 3″-H), 7.03 (2H, d, J 8.2 Hz, minor 2″-H), 7.08 (2H, d, J 8.2 Hz, major 2″-H), 7.27 (10 H, m, Ar); m/z (FAB) 376 ([M+Na] + , 10%), 354 ([M+H] + , 50), 307 (20), 149 (100).

Preparation of Racemic β-Lactam (±)-13

The azetidinones (±)-11 and (±)-12 (0.01 g, 0.28 mmol) were dissolved in acetonitrile (3 cm 3 ), cooled to 0° C. and slowly added to a cooled (0° C.) solution of ceric ammonium nitrate (0.46 g, 0.85 mmol) in distilled water (5 cm 3 ). After stirring at 0° C. for one hour, the mixture was then diluted with distilled water (15 cm 3 ), and extracted with ethyl acetate (3×15 cm 3 ). The organic extracts were washed with saturated sodium bicarbonate solution (10 cm 3 ). These aqueous washings extracted with ethyl acetate (15 cm 3 ). The combined organic phases were washed with sodium sulfite solution (10% w/v) until the aqueous layer remained colourless, then with saturated sodium bicarbonate solution (10 cm 3 ), and brine (10 cm 3 ). Drying (magnesium sulfate), filtration and concentration in vacuo, followed by recrystallisation from acetone and hexane gave the azetidinone (±)-13 as white crystals (0.05 g, 85%); m.p. 150-151° C.; Found C, 64.5; H, 5.1; N, 6.7. C 11 H 11 NO 3 requires C, 64.4; H, 5.4; N, 6.8%; R f 0.59 (silica, ethyl acetate); ν max (KBr disc)/cm −1 3200, 1755, 1720, 1500, 1460, 1370, 1225, 1210, 1165, 1125, 820, 760, 700, 500; δ 1 H (300 MHz, CDCl 3 ) 1.56 (3H, s, Ac), 4.92 (1H, d, J 4.6 Hz, 3-H), 5.75 (1H, dd, J 4.6 Hz, 2.6 Hz, 4-H), 6.75 (1H, br s, NH), 7.21 (5H, m, Ph): δ 13 C (75 MHz, CDCl 3 ) 19.7 (CH), 57.8 (CH), 78.1 (CH 3 ), 127.4 (CH), 128.2 (CH), 128.5 (CH), 134.4 (C), 165.7 (C), 169.1 (C); m/z (FAB) 206 ([M+H] + , 40%), 165 (60), 160 (70), 152 (90), 128 (40), 115 (45), 106 (100), 89 (75).

Preparation of Enantiomerically Pure Amine (−)-14

The amine (±)-14 (40 g, 0.25 mmol) and N-acetyl-(L)-leucine (44 g, 0.25 mol) in water (ca. 1600 cm 3 ) were heated until dissolution occurred. Upon cooling to ambient temperature, the amine salt precipitated as white crystals, which were filtered from the mother liquors and washed well with water. A second recyrstallisation from water (ca. 600 cm 3 ) gave the salt as translucent needles. These were filtered, washed well with cold water and added with stirring to sodium hydroxide solution (5 M, 200 cm 3 ). Extraction with diethyl ether (3×150 cm 3 ), drying (magnesium, sulfate), filtration and concentration in vacuo gave the (S)-amine (−)-14 as a colourless oil [11.8 g, 30%, 99% e.e. by chiral G.C. (see below)]: b.p. 107-108° C. (5 mm Hg); [α] D 20 −1.25 (c 4.0, methanol); ν max (thin film on CsI plates)/cm −1 2964, 2933, 2873, 1644, 1612, 1582, 1512, 1464, 1452, 1379, 1303, 1247, 1174, 1037, 832, 694; δ 1 H (300 MHz, CDCl 3 ) 0.81 (3H, t, J 7.3 Hz, 3-H), 1.60 (2H, dq, J 6.9 Hz and 7.3 Hz, 2-H) 3.71 (1H, t, J 6.9 Hz, 1-H), 3.74 (3H, s, OMe), 6.82 (2H, d, J 8.6 Hz, 2′-H), 7.18 (2H, d, J 8.6 Hz, 3′-H): δ 13 C (75 MHz, CDCl 3 ) 10.9 (CH 3 ), 32.5 (CH 2 ), 55.1 (CH), 57.1 (CH 3 ), 113.6 (CH), 127.3 (CH), 138.6 (C), 158.4 (C); (EI: found: [M] + 165.1158. C 10 H 15 NO requires [M] + 165.1154): m/z (FAB) 166 ([M+H] + , 80%), 149 (70), 136 (100). The enantiomers of the N-trifluoroacetyl derivative of 14 were clearly resolved by G.C. using a Chiraldex trifluoroacetyl-γ-cyclodextrin column. The N-trifluoroacetyl derivative of (R)-14 was 24.4 minutes whilst that of the (S)-14 derivative was 24.9 minutes [temperature 120→160° C. at 2° C. minute −1 and 10 minutes at 160° C.].

Preparation of Enantiomerically Pure Imine (+)-10

The amine (−)-14 (8.0 g, 7.0 cm 3 , 48.5 mmol) and benzaldehyde (5.17 g, 4.95 cm 3 , 48.5 mmol) were dissolved in toluene (100 cm 3 ) with a catalytic amount of Amerlyst 15 resin (H + form) and heated to reflux in a flask equipped with Dean-Stark apparatus. After two hours, the solution was filtered and concentrated in vacuo to give the imine (+)-10 as a pale brown oil (12.3 g, 100%); [α] D 20 +37.2° (c 0.4, chloroform): ν max (KBr Disc)/cm −1 2964, 2933, 2873, 1644, 1612, 1582, 1512, 1464, 1452, 1379, 1303, 1247, 1174, 1037, 832, 694: δ 1 H (300 MHz, CDCl 3 ) 0.87 (3H, t, J 7.3 Hz, 3-H), 1.93 (2H, m, 2-H), 3.79 (3H, s, OMe), 4.14 (1H, t, J 6.9 Hz, 1-H), 6.88 (2H, d, J 4.6 Hz, 3′-H), 7.35 (2H, d, J 4.6 Hz, 2′-H), 7.40 (3H, m, 4″-H and 5″-H), 7.78 (2H, m, 3″-H), 8.31 (1H, s, 1″-H): δ 13 C (75 MHz, CDCl 3 ) 11.2 (CH 3 ), 31.6 (CH 2 ), 55.3 (CH), 76.5 (CH 3 ), 113.8 (CH), 128.1 (CH), 128.3 (CH), 128.5 (CH), 130.5 (CH 3 ), 136.5 (C), 136.7 (C), 158.5 (C), 159.5 (CH); (EI: found: [M] + 253.1463. C 17 H 18 NO requires 253.1466); m/z (FAB) 254 ([M+H] + , 80%), 224 (40), 149 (90), 121 (55), 91 (100).

Preparation of Enantiomerically Pure β-Lactam (−)-11

To a cold (0° C.) stirred solution of the imine (+)-10 (9.00 g, 35.5 mmol) and triethylamine (5.40 g, 7.44 cm 3 , 53.4 mmol) in dry benzene (120 cm 3 ) was added acetoxyacetyl chloride (4.86 g, 3.83 cm 3 , 35.6 mmol) and the solution stirred at 0° C. for one hour, then at ambient temperature overnight. After this time, dichloromethane (200 cm 3 ) was added and the solution washed with hydrochloric acid (1 M, 2×65 cm 3 ), saturated sodium bicarbonate solution (2×50 cm 3 ) and water (2×50 cm 3 ). The organic fraction was dried (magnesium sulfate) filtered and concentrated in vacuo to give the azetidinone as a 2.7:1 ratio of diastereoisomers (9.9 g, 78%). Recrystallisation from ethyl acetate/hexane gave the β-lactam (−)-11 as white rod-shaped crystals (6.5 g, 52%): m.p. 117-8° C.; Found C, 71.4; H, 6.7; N, 3.9. C 21 H 23 NO 4 requires C, 71.3; H, 6.6; N, 3.9%; [α] D 20 −11.8° (c 0.3, chloroform): ν max (KBr Disc)/cm −1 2971, 2933, 1754, 1514, 1369, 1226, 1181, 1035, 702: δ 1 H (300 MHz, CDCl 3 ) 0.84 (3H, t, J 7.2 Hz, 3′-H), 1.66 (3H, s, Ac), 1.85 (2H, m, 2′-H), 3.80 (3H, s, OMe), 4.57 (1H, d, J 4.8 Hz, 3-H), 4.62 (1H, t, J 9.3 Hz, 1′-H), 5.62 (1H, d, J 4.8 Hz, 4-H), 6.83 (2H, d, J 8.2 Hz, 3″-H), 7.03 7.08 (2H, d, J 8.2 Hz, 2″-H), 7.27 (5 H, m, Ar): δ 13 C (75 MHz, CDCl 3 ) 7.7 (CH 3 ), 11.2 (CH), 26.5 (CH 2 ), 55.3 (CH 3 ), 59.3 (CH), 61.4 (CH), 76.2 (CH), 114.1 (CH), 128.0 (CH), 128.7 (CH), 128.8 (CH), 129.2 (CH), 129.7 (C), 134.0 (C), 159.2 (C), 164.9 (C), 169.1 (C); (CI: found: [M+H] + 354.1708. C 21 H 23 NO 4 requires 354.1705): m/z (FAB) 376 ([M+Na] + , 10%), 354 ([M+H] + , 50), 307 (20), 149 (100).

Preparation of Enantiomerically Pure β-Lactam (−)-13

The azetidinone was prepared in a similar manner to the synthesis of (±)-13, using the azetidinone (−)-11 (6.4 g, 18.1 mmol) with other reagents scaled accordingly. Recrystallisation from ethyl acetate/hexane gave the azetidinone (−)-13 as a white powder (3.24 g, 87%) with identical spectroscopic properties to (±)-13; m.p. 151-52° C.; [α] D 20 −45.7° (c 0.4, chloroform).

References

1 Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C. M.; Brigaud, T. Tetrahedron., 1992, 48, 6985-7012.

2 R. A. Holton, European patent application, 1990, EP 0 400 971 A2.

3 Bourzat, J. D.; Commerçon, A. Tetrahedron Lett., 1993, 34, 6049-6052.

4 Farina, V.; Hauck, S. I.; Walker, D. G. Synlett, 1992, 761-763.

Claims

1. A process of preparation a β-lactam of formula 9 wherein R2 is aryl, substituted aryl, C1-C5 alkyl, C1-C5 alkenyl or C1-C5 alkynyl, and R5 is aryl, substituted aryl or C1-C5 alkyl, comprising the steps of:a) reaction of an S-amine of formula 5 whereinR1 is C1-C5 alkyl, R3 is hydrogen, C1-C5 alkyl, C1-C5 alkoxy or aryloxy, and R4 is C1-C5 alkoxyl or aryloxy, with a aldehyde of formula R2CHO, wherein R2 is as defined above; to obtain a compound of formula 6 wherein R1, R2, R3 and R4 are as defined above,b) reaction of the compound of formula 6 with an acyl chloride R5CO2CH2COCl of formula 7, wherein R5 is as defined above, in the presence of triethylamine, to obtain a mixture of diastereo-isomeric β-lactams of the formulae 8a and 8b: wherein R1, R2, R3, R4 and R5 are as defined above, andc) separation of the β-lactams of formulae 8a and 8b, to obtain an enantiomerically pure β-lactam of formula 8a, followed by treatment of said β-lactam of formula 8a with cerium ammoniumnitrate [Ce(NH4)2(NO3)6] in the presence of acetonitrile and water, to obtain the β-lactam having formula 9.

2. A process according to claim 1, wherein said β-lactams of formulae 8a and 8b are separated by recrystallisation from an ethyl acetate/hexane mixture.

3. A process according to claim 1, wherein step b) is effected in hexane, benzene or in DMF, preferably DMF, as reaction solvent.

4. A process according to claim 1, wherein compounds are used wherein:R1 is C1-C5 alkyl, R2 is aryl, substituted or not, R3 is hydrogen, R4 is C1-C5 alkoxyl or aryloxy, and R5 is C1-C5 alkyl.

5. Enantiomerically pure (S)-(−)-1-(p-methoxyphenyl)propyl-1-amine.

6. A process for the preparation of enantiomerically pure (S)-(−)-1-(p-methoxy-phenyl)propyl-1-amine from a racemic mixture of said amine, by resolution with an optically active amino acid, wherein a racemic mixture of 1-(p-methoxyphenyl)propyl-1-amine having formula (14) is reacted with N-acetyl-L-leucine having formula (15) to provide the diastereoisomeric salts having formula (16), followed by fractional crystallisation from water to obtain the (S)-amine-N-acetyl-L-leucine salt having formula (16), which salt (16) is thereafter treated with sodium hydroxide to give the desired (S)-(−)-1-(p-methoxyphenyl)propyl-1-amine having formula (14) and N-acetyl-L-leucine, which may, if desired, be recycled:

7. A process for the preparation of pactitaxel by reaction of 10-deacetylbaccatin III with a β-lactam,wherein a β-lactam of formula 9, obtained according to a process according to claim 1 is used.

8. A pharmaceutical composition containing paclitaxel, wherein said paclitaxel is obtained from a β-lactam prepared according to claim 7.

9. A process for preparation a beta-lactam according to claim 1 comprising reacting enantiomerically pure (S)-(−)-1-(p-methoxyphenyl)propyl-1-amine and acetoxyacetyl chloride to obtain the (−)-azetidinone of formula (13), wherein Ac represents the acetyl residue and Ph represents a phenyl group: