AU651669B2

AU651669B2 - Beta-phenylisoserine-(2R,3S), salts, preparation and use thereof

Info

Publication number: AU651669B2
Application number: AU12237/92A
Authority: AU
Inventors: Jean-Pierre Duchesne; Max Ferraro
Original assignee: Rhone Poulenc Rorer SA
Current assignee: Aventis Pharma SA
Priority date: 1991-01-17
Filing date: 1992-01-16
Publication date: 1994-07-28
Anticipated expiration: 2012-01-16
Also published as: JPH06504549A; FI113641B; AU1223792A; EP0603176A4; YU5492A; EP0603176B2; HUT64939A; ATE157081T1; CA2099783C; KR930703240A; FR2671799A1; FR2671799B1; NO932458L; KR100235372B1; EP0603176B1; WO1992012958A1; ZA92317B; JP3233632B2; CZ139093A3; NO303539B1

Abstract

(2R,3S)- beta -Phenylisoserine, its salts and its preparation by the action of ammonia on (2R,3R)- beta -phenylglycidic acid, and its use for the preparation of taxane derivatives of general formula: <IMAGE> (R = H, COCH3; R1 = C6H5, (CH3)3C-O-).t

Description

OPI DATE 27/08/92 AOJP DATE 01/10/92 APPLN, D 12237 I9? PCT NUMBER PCT/FRq2/0oo32

DEMANDE

RE DE BREVETS (PCT) (51) Classification internationale des brevets 5 (11) Numno de publication internationale: WVO 92/12958 C07C 229/34, C07D 305/14 All (43) Date de publication internationale: 6 aoat 1992 (06.08.92) (21) Numtiro, dc [a demnande internationale: PCT/FR92/00032 (81) Etats d~signis: AT (brevet europ~en), AU, BE (brevet europ~en), CA, CH (brevet europ~en), CS, DE (brevet euro- (22) Date de di~p6t international: 16janvier 1992 (16.01.92) p~en), DK (brevet europ~en), ES (brevet curop~en), Fl, FR (brevet europ~en), GB (brevet europ~en), GR (brevet europ~en), HU, IT (brevet europ~en), JP, KR, LU (bre- Donn~es relatives i la priorit vet europ~en), MC (brevet europ~en), NL (brevet euro- 91/00491 I7janvier 1991 (17.01,91) FR p~en), NO, PL, RU, SE (brevet europ~en), US.

(71) Diposant (pour tous les Etats d~signu~s sa:(f US): RHONE- Publi~e POULENC RORER S.A. [FR/FR]; 20, avenue Ray- Aw'c rapport de recherche imternationale.

mond-Aron, F-92 160 Antony (FR).

(72) Inventeurs; et ~h lnventeurs/D36posants (US sealemnent) DUCH ESN E, Jean- Pierre [FR/FR]; 160, rue Marcel-MWrieux, F-69007 Lyon FERRARO, Max [FR/FR]; 1, chemnin Beauregard, F-69320 Feyzin (FR), (74)i Mandataire: PILARD, Jacques; Rh6ne-Poulenc Rorer Direction Brevets, 20, avenue Rayrnond-Aron, F- 92 165 Antony C~dex (FR).

(54)Title: ll-1'FENYLISOSERINE.(2R,3S), SALTS, PREPARATION AND USE THEREOF (54)Titre: LA 11-PHENYLISOSERINE-(211,3S), SES SELS, SA PREPARATION ET SON EMPLOI

RICO-NH

3S C0- CH, 2R

OH

OCOC

6

H

(57) Abstract P-phenylisoserine.(2R,3S), salts and preparation theve-of through the action or ammonia on P-phenylglycidic.(2R,3R) acid and its use in the p,.,paration of taxane derivatives of general fornmula: (R H, COCH 3

R

1

C

6 1 1 5

(CH

3 3 (57) Abr~gi La f-ph~nylisos~rine-(2Rk.3S), ses sels et sa preparation par action de l'ammoniac sur I'acide I)-ph~nylglycidic-(2R1,311) et son emrploi pour la preparation de d~riv~s du taxane de formule g~n~rale (R H, COCH.1; R, CAH, (CH 3 3 WO 92/12958 PCT/FR92/00032 (2R,3S)-P-PHENYLISOSERINE, ITS SALTS, ITS PREPARATION AND ITS USE The present invention relates to (2R,3S)- P-phenylisoserine of formula: H2N ,OOH 2R

C

6 H OH

(I)

as well as its alkali metal or alkaline earth metal salts and its salts with nitrogenous bases, to its preparation and to its use for the preparation of therapeutically active products.

Whereas the (2R,3R), (2S,3S) and (2S,3R) isomers of P-phenylisoserine are known in the scientific literature, e.g. in the papers by E. Kamandi et al., Arch. Pharmaz., 307, 871-878 (1974) by E. Kamandi et al., Arch. Pharmaz., 308, 135-141 (1975) or by K. Harada and Y. Nakajima, Bull. Chem. Soc.

Japan, 47, 2911-2912 (1974), (2R,3S)-P-phenylisoserine does not yet appear to have been described other than in ester form H6nig et al., Tetrahedron, 46, (11) 3841-3850 (1990)].

According to the invention, (2R,3g)- P-phenylisoserine, optionally in salt form, may be obtained by the action of ammonia solution on (2R,3R)-p-phenylglycidic acid, preferably in the form 2 of an alkali metal or alkaline earth metal (sodium, potassium, calcium) salt, of an ammonium salt or of a salt with a nitrogenous base (a-methylbenzylamine, pyridine).

Generally, the process is carried out in water, optionally mixed with an organic solvent such as methanol. It is preferable to work in water.

To carry out the process, it is necessary to use an excess of ammonia relative to (2R,3R)l 10 p-phenylglycidic acid. Generally, from 10 to 100 moles of ammonia, and preferably from 50 to 80 moles, are used per mole of (2R,3R)-P-phenylglycidic acid.

The ammonia is preferably used in the form of a concentrated aqueous solution such as a solution whose concentration .is between 20 and 32% at a temperature in the region of 25 0

C.

The process being carried out at a temperature of between 0 and 100°C, and preferably between 40 and 60"C. Generally, it is performed at atmospheric pressure or alternatively under an autogenous pressure which is in the region of 2.5 bars at 60 0

C.

In order to speed up the reaction, it is especially advantageous to work in the presence of an ammonium salt such as ammonium chloride or ammonium hydrogen carbonate. It is preferable to use ammonium hydrogen carbonate which enables the reaction rate to be increased while retaining the selectivity.

3 Generally, a stoichiometric amount of ammonium salt is used relative to the P-phenylglycidic acid employed.

Generally, the process is carried out using the salt of (2R,3R)-P-phenylglycidic acid with a-methylbenzylamine.

However, it is also possible to use an alkali metal (sodium, potassium) salt which is obtained by the action of a base (sodium hydroxide, potassium hydroxide) in a stoichiometric amount on the salt of (2R,3R)-P-phenylglycidic acid with a-methylbenzylamine, or the ammonium salt which is obtained by displacement of the salt of (2R,3R)-P-phenylglycidic acid with a-methylbenzylamine by an excess of ammonia solution.

In the latter case, it is possible to favour the displacement by continuous or semi-continuous extraction of the a-methylbenzylamine by means of a suitable organic solvent such as toluene.

It is especially advantageous to use the ammonium salt of (2R,3R)-P-phenylglycidic acid, which enables the ring-opening by means of ammonia to be rendered both regioselective and stereoselective.

Irrespective of the manner in which the action of ammonia on (2R,3R)-P-phenylglycidic acid is carried out, the (2R,3S)-P-phenylisoserine may be isolated according to one of the following methods: 1) the excess aramonia may be removed under reduced pressure so as to obtain the ammonium salt of (2R,3S)- P-phenylglycidic acid in aqueous solution. After the 4 addition of a strong mineral acid, the (2R,3S)- P-phenylisoserine precipitates and is separated by filtration, or alternatively 2) before, during or after the removal of the ammonia under reduced pressure, it is possible to add an alkali metal base (sodium hydroxide, potassium hydroxide) or alkaline earth metal base (quicklime or slaked lime); the salt formed precipitates after the addition, where appropriate, of an organic solvent such as acetone. The alkali metal or alkaline earth metal salt thereby obtained is separated by filtration. In order to facilitate salting-out of the salt, especially of the sodium salt, of (2R,3S)-P-phenylisoserine, and to improve the yield, it may be advantageous to saturate the water present in the reaction mixture by adding sodium chloride.

(2R,3R)-p-Phenylglycidic acid may be prepared under the conditions described by J-N. Denis et al., J.

Org. Chem., 51, 46-50 (1986).

The (2R,3S)-p-phenylisoserine obtained by carrying out the process according to the invention is especially useful for performing the synthesis of therapeutically active products such as the taxane derivatives of general formula:

L.

I Ii i R- O O OH R CO-NH 3S CO-0---

C

6

H

5 2R I I

H

OH OH OCOCH3

OCOC

6

H

in which R represents a hydrogen atom or an acetyl radical and R, represents a phenyl or t-butoxy radical.

By the action of a benzoylating agent (benzoyl chloride) or of a t-butoxycarbonylating agent (t-butyl dicarbonate) and then of an agent for protection of the hydroxyl function, P-phenylisoserine yields the product of general formula:

R

1

CO-NH

3S

COOH

C

6

H

5 2R O-Zi in which R, represents a phenyl or t-butoxy radical and Z represents a group of the hydroxyl function (l-ethoxyethyl).

By condensation of the acid of general formula (III) with baccatine III or 10-deacetylbaccatine III in which the hydroxyl functions at the 7-position and, where appropriate, at the 10-position are protected by protective groups (silyl, 2,2,2-trichloroethoxycarbonyl radicals), followed by replacement of the protective groups with M6- c 6 hydrogen atoms, the product of general formula (II) is obtained.

The condensation of the acid of general I formula (III) with protected baccatine III or protected 5 10-deacetylbaccatine III, as well as the replacement of the protective groups with hydrogen atoms, may be carried out under the conditions described in European Patent EP-0,336,840 OR EP-0,336,841.

The example which follows, given without implied limitation, shows how the invention may be put into practice.

EXAMPLE 1 3 kg of a-methylbenzylamine (2R,3R)- P-phenylglycidate, assaying at 98% and the enantiomeric excess of which is greater than 98.5%, and 15 litres of 32% ammonia solution are introduced into a column. At the bottom of the column, toluene is introduced by means of a metering pump at a flow rate of 3 to 5 litres/hour. The toluene solution which separates out at the column head is removed by overflowing. After 18 litres of toluene have been introduced, a-methylbenzylamine is no longer detected in the toluene extract.

The ammonium p-phenylglycidate solution obtained above and 30 litres of 32% ammonia solution (30 litres) are introduced into a 150-litre autoclave. The autoclave is closed and then heated in the course of 1 hour to 60"C with stirring. The i 7 pressure is in the region of 2.5 bars. Stirring is continued at 60°C for 5 hours and the autoclave is then allowed to cool to 18 0 C. The ammonia is removed by distillation under reduced pressure (100-700 mm of mercury; 13.3-93 kPa) at 24°C after the addition of 9 kg of sodium chloride and 0.42 kg of sodium hydroxide pellets in 2.5 litres of water. When the pressure in the apparatus reaches 45 mm of mercury (6 kPa), the reaction mixture is heated to 48 0 C in order to dissolve the salts and is then cooled to a temperature of between -5 and -8°C for 3 hours.

The white crystals obtained are separated by filtration and then dried at 40 0 C under reduced pressure (1 mm of mercury; 0.13 kPa). (2R,3S)p-Phenylisoserine sodium salt (1932 melting point 218°C, is thereby obtained.

The 1C nuclear magnetic resonance spectrum of the (2R,3S)--phenylisoserine sodium salt, determined in deuterated water at 90 MHz, is characterised by the following chemical shifts 60.2 (IJCH=140 Hz); 80.0 ('JCH=147 Hz; 2 J=2.6 Hz); 129.6; 130.2; 131.5; 144.4 and 181.6 ppm.

EXAMPLE 2 kg of a-methylbenzylamine (2R,3R)p-phenylglycidate (35.08 mol), 15 litres of water and litres of toluene are introduced into a 250-litre reactor, and 10 litres of 4N sodium hydroxide are then added in the course of 10 minutes at a temperature in 8 the region of 20*C. The mixture is stirred for 1 hour.

The aqueous phase i. -parated after settling has taken place. The toluene phase, which contains amethylbenzylamine, is retained. The aqueous phase is washed with 2 times 10 litres of toluene to remove all of the a-methylbenzylamine. From the combined toluene phases, the a-methylbenzylamine may be isolated.

1.860 kg of ammonium chloride and 162 litres of 20% ammonia solution are added to the aqueous phase placed in a 250-litre reactor. The mixture is heated to 50 0 C and then kept stirring for 17 hours.

After cooling to 35"C, 35 kg of sodium chloride are added and the mixture is then maintained at this temperature for 30 minutes. It is allowed to cool slowly (2 hours) to a temperature of between 0 and and is then maintained for 1 hour at this temperature.

The precipitate is separated by filtration and then dried under reduced pressure at 50 0 C. 7 kg of dry product are thereby obtained, which product contains approximately 25% of sodium chloride and approximately 5.300 kg of pure (2R,3S)-P-phenylisoserine sodium salt.

The yield is 72%.

The product thereby obtained may be used in the subsequent synthesis operations without further treatment.

c

Claims

1. (2R,3S)-P-Phenylisoserine as well as its alkali metal or alkaline earth metal salts and its salts with nitrogenous bases.

2. Process for preparing (2R,3S)- P-phenylisoserine, optionally in salt form, characterised in that ammonia is reacted with (2R,3R)- P-phenylglycidic acid or one of its salts, and (2R,3S)- P-phenylisoserine is isolated, where appropriate in salt form.

3. Process according to claim 1, characterised in that from 10 to 100 moles of ammonia are used per mole of (2R,3R)-P-phenylglycidic acid.

4. Process according to one of claims 1 and 2, characterised in that the reaction is performed in water or in an organic solvent.

Process according to claim 4, characterised in that the solvent is chosen from aliphatic alcohols containing 1 to 4 carbon atoms.

6. Process according to one of claims 1 to characterised in that the reaction is performed, in addition, in the presence of an ammonium salt.

7. Process according to claim 6, characterised in that the ammonium salt is chosen from ammonium chloride and ammonium hydrogen carbonate.

8. Process according to one of claims 6 and 7, characterised in that one mole of ammonium salt is used per mole of (2R,3R)-p-phenylglycidic acid I employed.

9. Process according to one of claims 1 to 8, characterised in that the reaction is performed at a temperature of between 0 and 100"C.

10. Use of the (2R,3S)-p-phenylisoserine according to claim 1 for the preparation of taxane derivatives of general formula: R-O O R 1 CO-NH 3S COo- C 6 H 5 2R O H OH OH OCOCH 3 OCOC 6 H in which R represents a hydrogen atom or an acetyl radical and R, represents a phenyl or t-butoxy radical, characterised in that a benzoylating or t- butoxycarbonylating agnt and then an agent for protection of the hydroxyl function are reacted with (2R,3S)-P-phenylisoserine, the product obtained is then condensed with baccatine III or III in which the hydroxyl functions at the 7- and, where appropriate, the 10-position(s) are protected, and then, after replacement of the groups protecting the hydroxyl functions with hydrogen atoms, the product obtained is isolated. i i L I- L INTERNATIONAL SEAR~CH REPORT IriatnOAl APOucation No PC±/E-iR ?2/00032 1. CLASSIFICATbON OF XUitJ '-71ATTER ut~,'Iclasslificatior Tyfybolo wooly, Indicate alia Accoroing to International Pistant Cia.oi' cation (IPC) or to path National C-.helfication and IPC Int. CJ. C'O7C229/34; C07D305/14

11, FIELDS SEARCHED Mintrw-' Documentation Searched 7 Documntation S.avrched other than Minimum Docume~ntation te ttwLcIaft thtat luen DocumtsI1t are Included Int the Fields Searche.d I 11l. DOCUMENTS CONSIDERED TO ME RELEVAHT' Category Citation of Docum~on: 11 with Indication. Whre~r approonate, ot the relevant passag., Is !--ant to Cialm No 13 A AR=~l DER PHARMAZIE. 1-9 Vol. 308, No. 2, February 1975, WETNHEfl' DE pages 135 141; E. KAMANDI Er' AL: 'DIE SII=ES VON BEl'A-PHENYL- IS0SEPR21aN DUPRCH AM~CNOLYSE VON BErA-PHENYLGLYCIDESTE-RN. II.' cited in the aj,)lication see the whole document A ARCHIV DER PHAkRMAZIE. 1-9 vol. 307, ND. I I, Novc-nzer 1974, WEINHEI DE pages 871 878; E. KAMANDI FT~ AL: OYNTHESE VON BETA-PHENYL ISOSERIN DURCH ANW*'OLYSE VCN' B~L'-PHFE'YL-TLYCTDESTERN. P cited in the applicatio-n see the whole drocument Specie' categories of cited documents 1t later documon', Published afiter th. i-io-ational filing oate dA ocument defining trhi o gn*'a 01ji of In$ am whli. is not or Priority date and not in conflic t -me apolication but cons~ redto b of eruciat &-,rPncecited to unoratand tePninciole or inorY underlying the concere tO e o pef~cufi? ~~'ncCinvention E" estiie document but publishec on or sfhor the interitt.onal document of Particular reiseriant trio claimed invention film dn.etc cannot be considered novel or c.,,mot be considered to ocument whfich may throwr C.'Its on prioirit t) or invove an inventive stop whicri is cited to etablish Iho Doli'cation date o' inoinar "Y document of Parttcular reIvericelo the claimed invention c~itation or other apecial re~aao I it becified) cannot be considered to invoive an tflensivs st wnen ithe "0 oocumont rnterring to an oWc ciscio0ure, USe, ethitition or document is combined with one o! mots Other such ooCu. other means mania, Such combination being oov'ive 10 a parson skitled documnent published prior to tire initernational filing cile but inl the art. later than the tinority cate cialmvc cocument member of the &ame ioabjtfamly IV. CERTIFICATION 00te of the Actual completion of the initietional Searc' D atea of Meling of this international soar:! zaeaof 3 April 1992 (03.04 .92) 6 May 1992 (06.05.92) International Searching Authority JSiOnAtute Of AUthoriled Officer -EUREAN PATENT OFF'ICE Form PCT/tSA/21o (second Shaet lJwvuary characterised in that a benzoylating or t- butoxycarbonylating agent and then an agent for /12 InternationlI Ap~o."bon No. POPC/FR 92/00032 Ill. DOCUMCKTIS COkXID JF TO BE RELEVANT (CONTINUED tROM THP ;.-OWD SHEZ. Calooory Citawn me~ witfl roiatnior, wn azoronst, of m" ri.po a s Aej.,ant to Clim No 2 A BULLET'I OF THE CHEMICAL sozmr OF JAPAN, 1-9 vol. 47, November 19 74, 7-0KYO JP pages 2911-2912; H. HARADA ET AL: 'OPTICAL RESOLUTrION AND (X)NFIGMJRTION OF CIS-BETrA-PHEYLGYCIDIC ACID' cited in the application see the whole document A JOURNAL OF ORGANIC CHEWISTRY. vol. 55, No. 6, 16 March 1990, WASHINGMOXN US pages 12S57 1959; DENIS ET AL: 'AN 10,'1PROVED SYNTH{ESIS OF TE TAXOL SIDE CHAIN AND OF 11,56976, see the whole document A CHEMICAL As CTS,, No. 115, 1-9 28 ctober 1991, Colurnb4s, Ohiio, ,US; abstract No. 183831G, page 985 see abstract AMINO ACIDS- CHEM. ,BIOL. MED. IT. CCNJGR. AMINO ACID RES.) Vol. 1989, 1990, pages 134 142; H HOENTIG ET AL: 'CHEMOEZYMIC SY~IIIESIS OF- ENANTIOICERICALLY PURE HYDIROXY AMINO ACIDS' P,X JOUJRNAL OF ORGANIC CHEAMIS-RY. .1,10 vol. 56, No. 5, 1 March 199l, WASH LNGIY US pages 1681 1683; I. OJI1MA ET AL: 'EFFICIENT AND PRACTICAL ASYME~TIC SYNTHESIS OF THE TAXOC, C-13 SIDE CHAIN, NQ-BENZOYU--(ZR, 3S)-3-PHYLISOSERnt4, AND ITS ANALOGUE-S VIA C1HkAL ESTER EOLATE-IMLNE L CYCLOCONDENSATIOtN' see the whole document Form PCTIISAt210 laxra an..u1 fJAvy 19S) M.-Modo RAPP'ORT DE RECHE RCHE IN1TERNATIONALE DCMande In Z~t)a..e NO PCT/F, 32/00032 1C ASSENYXNT DE L1NWVL NflON (si piuseurssyi e F~~ce cJ-rr~:r stavapu.aWCS, Its incjaue tolus) 50013 12±nt~O C~~i'01LtSek,00jJC fs b.-e (CIB ou a Ix foi, "Job h. Ifiaeoa 1111aOaauel cia CIE CIB 5 C07C229,'34; C070305/14. OAINES SUR. LESQUELS LA REQiXP.4 A P'ORTE Docueumica =im. consune Sysleme Ge cat01fun def ciasafi(atio CIB S C07C Documentaton coosultee aiia ci-t mia0atnalaie cans La mci-ur Dud is ia en ~ts foot PaniC Su "U el c~~12 recber-.ne a Por4 M. £00=1v4ENTS C0NSmIE'S COMME PEYUVTiENT'u Caoeicntificanon let dc-cuments cites, 21tc &I atecc~san, No. 4?-rediai Ct-oedci V25=jci PtMrin-t: 14 A ARCHIV DE-R PHARKAZIE. 1-a vol. 309, no. 2, F~vrier 1975, WEINHEIM DE pages 235 141; E. KAMANDI ET AL: 'DIE SYNTHESE VOIN BETA-PHENYL- ISOSERl.IEN DURCH A~vMQNLYSE VON BETA-PHENYLGLYCIDESTERN. II,' cltd cans la dlemance voir document en entier A ARCHIV :ER PHARMAZIE. 1-9 vol, 307, no.

12, Novenibre 1974, 't'EINHEIM E Dage~c 971 878; KAMAYDI ET AL: 'DIE SYNTHESE VON BETA-PHENYL SOSERP'',E-N- DURCH AMMONOLYSE 1 DN BETA-PH ENYL-GLYCIDESTERN. T ct da-s la aemande Yoir le cocument en entier Categones t*cales de do.,j~.nts cis: t t 'T it uhibseu pubUt posleneiatment a Ix late it et tz.tIoattnIUCIJ au U 3a1 data do Pnociti 4K D ;PLrteLt t43S A'.ocument difirtaat Ileat Mena de 11 tec:. DIRUC, DOA cut dIta tecaique ptmerunt, misls c~t pour com>nrvr cotaDiet comme p~uut-C ii et Pemet~ It -nncIF ou 12 theon. coasvtuana 11 do l'lyeoo E d>cumwt antenetur, roaia p~bllk i la date de deDt tnterna* 4o-.zmat Pa~ildaro*mt pennotzt ~Uf e'O' atonal 00 lares cente date -we* be Pout *atnoe r combae esouvc ou come -L document pouyint leter unt :aute sur unt rcodicanon de Imtpliqttant Ube aCtivtte inlenave pnone 00 cite pour detem~.'er 1a late 4 Pubucauor, d'uae lo ~cumet Pa&roaiIeet parusena: Vi'aemnon revven- 2utre citation ou pour Lint jsa spe.to~ tAle qu'lnhlquee) ci:aee at pei etre cosite cmme kmit'uint une docuiment se et-akilt I VLt dtIYItt3D oraLI, a n sa tta, 2 id:Ktt& Inventive Iotique It document tsi zssoce a UMa Di unle exM on ou tolds i:J:C mraovs putiuti auv iocaments i memo aLiue. cmte cob documentt pualle avanst 11 all eI ddkpt 11teataOala, mall WIson e~t evtlento pour une pemotte tu meter. poinumn A date dt priorni tevcmliqUet 'V documtmt qui W-at pamoe it Ix mine famE!] e,4e brevv= TV. CERTh1CATlON Date a ia~gud]e La rtmercneroltML-MLIC a Cit dlecnVteeae atCnevt t lexteItion tu present rtpport de r-s-Mb~e into-aUOnLaie 03 AVIRIL 1992 05 05.2 92 Atmjnatyamuon czarlt" at Is recte--,,e Intennatiocaie -itrt du foocaoaiar imtonmt.§ OFFICE EVROPEEN DES BREVETS SANCHEZ Y GARCIA I- "PerILW21a a-II I.ULA4I 9M)l PCT/FR 92/C: D32 Dermazat Intemnzwruje (SUIT DES kENSEJCNDF6.4lr LNDIQUES SL-k LA W. DOCUM(ENTh CONSIDERES CO'ME FERTINL-NTS" DEUXIENIE FEUlI-E) catevone 4 te Boa omeats alm, .1avec Lgos 51 ov"=a,,e iNC. 4r =-'uons ces IaszlDm wt 1 BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN. vol. 47, Noyembre 1974, TOKYO JP pages 2911 2912; H. HARADA T AL: 'OPTICAL RESOLUTION AND CONFIGURAT:JNll OF CIS-BETA-PHENYLGLYCIDIC ACID' citd dans !a dernandle voir le ozument en entier JOURNAL OF ORGANIC CHEMISTRY. vol. 55, no, 6, 16 Mars 1990, WASHINGTON US pages 1957 !i959; DENIS ET AL: 'AN IMPROVED SYNTHESIS OF THE TAXOL SIDE CHAIN AND OF RP56976' voir le ocurent en entler CHEMICAL ASSTR.ACTS, no. 115, 28 Octo~re 1991, Columous, Ohio, US; aostract no. 183831G, page 985; voir abr~ad AMINO ACDS- CHEM,BIOL. MED.,(PAPINT.CONGR. AMINO ACID RES.) vol. 1989, 1990, pages 134 142; H HOENIG ET AL: 'CHEMOENZYMIC SYNTHESIS OF' ENANTIOMERICALLY PURE HYDROXY AMINO ACIDS' JOURNAL OF ORGANIC CHEMISTRY. vol. 56, nc. 5, 1 Mars 1991, WASHINGTON US pages 1681 1683; I. OJIMA ET1 AL: 'EFFICIENT AND PRACTICAL ASYMMETRIC SYNTHESIS OF THE TAXOL C-13 SIDE CHAIN, N-B--NZOYL-(2R,3S)-3-PHENYLISOSERINE, AND ITS ANALOGUES VIA CHIRAL ESTER ENOLATE-IMINE CYCLOCONDENSATION' voir le document en entier PCT;LWll0 beiama..Us I I 0awn 1"11 L offifid