NO317356B1 - 4,10beta-diacetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [G] tax-11-en-13 <alpha> -yl (2R, 3S) - 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, and preparation thereof - Google Patents
4,10beta-diacetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [G] tax-11-en-13 <alpha> -yl (2R, 3S) - 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, and preparation thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 4
- AMDOWEDYDFGDJI-IREPQIBFSA-N (2r,3s)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid;dihydrate Chemical compound O.O.CC(C)(C)OC(=O)N[C@H]([C@@H](O)C(O)=O)C1=CC=CC=C1 AMDOWEDYDFGDJI-IREPQIBFSA-N 0.000 title description 5
- ZVAFCKLQJCZGAP-WDEREUQCSA-N (2r,3s)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H]([C@@H](O)C(O)=O)C1=CC=CC=C1 ZVAFCKLQJCZGAP-WDEREUQCSA-N 0.000 claims abstract description 18
- 150000004683 dihydrates Chemical class 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 238000003860 storage Methods 0.000 claims description 2
- -1 (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate carboxylate Chemical class 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract 1
- 230000008025 crystallization Effects 0.000 abstract 1
- 238000010586 diagram Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 4
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ZVAFCKLQJCZGAP-UHFFFAOYSA-N 2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)C(O)=O)C1=CC=CC=C1 ZVAFCKLQJCZGAP-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
Dihydratet av 4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-1 -hydroksy-9-okso- 19-nor-cyklopropa[G]tax-l l-en-13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat og dets fremstilling ved krystallisering fra en vann-alkohol- eller vann-keton-oppløsning.The dihydrate of 4,10B-diacetoxy-2a-benzoyloxy-5B, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [G] tax-11-en-13a-yl (2R, 3S) - 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and its preparation by crystallization from a water-alcohol or water-ketone solution.
Description
Foreliggende oppfinnelse angår 4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-l-hydroksy-9-okso-19-nor-cyklopropa[G]tax-l 1 -en-13a-yl (2R,3S)-3-tert-butoksy-karbonylamino-2-hydroksy-3-fenylpropionat dihydrat, samt dets fremstilling. The present invention relates to 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-1 1 -en-13a-yl (2R,3S) -3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate dihydrate, as well as its preparation.
4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-l -hydroksy-9-okso-19-nor-cyklo-propa[G]tax-11 -en-13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat dihydrat oppviser bemerkelsesverdige anticancerøse og anti-leukemiske egen-skaper. 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclo-propa[G]tax-11-en-13a-yl (2R,3S)-3 -tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate exhibits remarkable anti-cancerous and anti-leukemic properties.
4,10B-diacetoksy-2o>benzoyloksy-5B,20-epoksy-1 -hydroksy-9-okso-19-nor-cyklopropa[G]tax-l 1 -en-13ct-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat fremstilles i henhold til den fremgangsmåte som mer spesielt er beskrevet i WO 94/13654. 4,10B-diacetoxy-2o>benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-1 1 -en-13ct-yl (2R,3S)-3- tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is prepared according to the method which is more particularly described in WO 94/13654.
Som beskrevet ovenfor er oppfinnelsen rettet mot en forbindelse som karakteriseres ved at den er 4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-l-hydroksy-9-okso-19-nor-cyklopropa[G]tax-l 1-en-l 3ct-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionatdihydrat. As described above, the invention is directed to a compound which is characterized in that it is 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-l-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-l 1-en-1 3ct-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate.
Oppfinnelsen er også rettet mot en fremgangsmåte for fremstilling av denne forbindelse og denne fremgangsmåte karakteriseres ved at man krystalliserer 4,10B-diacetoksy-2ct-benzoyloksy-5B,20-epoksy-1 -hydroksy-9-okso-19-nor-cyklopropa[G]tax-11 -en-13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat eller dets hydrat i en blanding av vann og en alifatisk Cu-alkohol eller i en blanding av vann og et C3- 4-keton, tørker det oppnådde produkt under redusert trykk og eventuelt oppbevarer det under betingelser med relativ fuktighet lik større enn 40 % eller at man tørker produktet direkte under betingelser med relativ fuktighet lik større enn 40 %. The invention is also directed to a method for producing this compound and this method is characterized by crystallizing 4,10B-diacetoxy-2ct-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[ G]tax-11 -en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or its hydrate in a mixture of water and an aliphatic Cu alcohol or in a mixture of water and a C3-4 ketone, drying the obtained product under reduced pressure and possibly storing it under conditions with relative humidity greater than 40% or drying the product directly under conditions with relative humidity greater than 40%.
For gjennomføring av fremgangsmåten ifølge oppfinnelsen kan det være fordelaktig For carrying out the method according to the invention, it can be advantageous
å bringe det angjeldende 4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-1 - to bring the relevant 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1 -
hydroksy-9-okso-19-nor-cyklopropa[G]tax-l l-en-13a-yl (2R,3S)-3-tert- butok-sykarbonylamino-2-hydroksy-3-fenylpropionat eller dets hydrat i oppløsning i en alifatisk alkohol inneholdende 1 til 3 karbonatomer eller i et keton inneholdende 3-4 karbonatomer, hydroxy-9-oxo-19-nor-cyclopropa[G]tax-1 l-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or its hydrate in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or in a ketone containing 3-4 carbon atoms,
å behandle oppløsningen med vann, to treat the solution with water,
å ympe oppløsningen med dihydratet og derefter å behandle den på ny med vann, inoculating the solution with the dihydrate and then retreating it with water,
å separere de oppnådde produkter, og to separate the products obtained, and
å tørke produktet under redusert trykk og derefter eventuelt å oppbevare det i en atmosfære hvis relative fuktighet er lik større enn 40 %, det vil si for eksempel for en relativ fuktighet på 40 %, en tørking under et rest-trykk på rundt 1,33 kPa for en temperatur av 25°C og under et rest-trykk på rundt 3,86 kPa for en temperatur rundt 45°C, eller to dry the product under reduced pressure and then optionally to store it in an atmosphere whose relative humidity is greater than 40%, i.e. for example for a relative humidity of 40%, a drying under a residual pressure of around 1.33 kPa for a temperature of 25°C and under a residual pressure of around 3.86 kPa for a temperature around 45°C, or
å tørke de oppnådde krystaller direkte i en atmosfære hvis relative fuktighet er lik større enn 40 %, det vil si for eksempel for en relativ fuktighet på 40 %, en tørking under et rest-trykk på rundt 1,33 kPa for en temperatur av 25°C og under et rest-trykk rundt 3,86 kPa for en temperatur rundt 45°C. drying the obtained crystals directly in an atmosphere whose relative humidity is equal to greater than 40%, that is, for example, for a relative humidity of 40%, a drying under a residual pressure of about 1.33 kPa for a temperature of 25 °C and under a residual pressure of around 3.86 kPa for a temperature of around 45°C.
Generelt blir 4,106-diacetoksy-2a-benzo<y>loks<y>-5B,20-e<p>oks<y>-l -hydroksy-9-okso-19-nor-cyklopropa[G]tax-l 1-en-l 3a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat eller dets hydrat oppløst i et overskudd av den alifatiske alkohol, fortrinnsvis etanol, et rent overskudd av ketonet, fortrinnsvis aceton. Fortrinnsvis ligger mengden alkohol eller keton mellom 4 og 16 volum-deler i forhold til vekten av det anvendte 4,10B-diacetoksy-2a-benzoyloksy-58,20-epoksy-1 -hydroksy-9-okso-19-nor-cyklopropa[G]tax-l 1 -en-13ct-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat. In general, 4,106-diacetoxy-2a-benzo<y>lox<y>-5B,20-e<p>ox<y>-l -hydroxy-9-oxo-19-nor-cyclopropa[G]tax-l becomes 1 -en-1 3a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or its hydrate dissolved in an excess of the aliphatic alcohol, preferably ethanol, a pure excess of the ketone, preferably acetone. Preferably, the amount of alcohol or ketone is between 4 and 16 parts by volume in relation to the weight of the 4,10B-diacetoxy-2a-benzoyloxy-58,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[ G]tax-1 1 -en-13ct-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
Generelt blir vann tilsatt på en slik måte at forholdet for slutt-volumene vann:alkohol eller vann:keton ligger mellom 1:3 og 3:1. In general, water is added in such a way that the ratio of the final volumes of water:alcohol or water:ketone is between 1:3 and 3:1.
Dihydratet av 4,10B-diacetoksy-2cc-benzoyloksy-5B,20-epoksy-l -hydroksy-9-okso-19-nor-cyklopropa[G]tax-l 1-en-l3a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat som krystalliseres ut separeres, fortrinnsvis ved filtrering eller sentri-fugering. Tørkingen eller den eventuelle oppbevaring i en atmosfære hvis relative fuktighet er lik større enn 40 % gjennomføres under redusert trykk, generelt mellom 0,5 og 30 kPa og fortrinnsvis nær 5 kPa ved en temperatur mellom 10 og 70°C og fortrinnsvis nær 40°C. The dihydrate of 4,10B-diacetoxy-2cc-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-1 1-en-13a-yl (2R,3S)- The 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate which crystallizes out is separated, preferably by filtration or centrifugation. The drying or the possible storage in an atmosphere whose relative humidity is greater than 40% is carried out under reduced pressure, generally between 0.5 and 30 kPa and preferably close to 5 kPa at a temperature between 10 and 70°C and preferably close to 40°C .
Isotermen for vannaktiviteten i produktet er studert. Således ble prøver av 4.10B-diacetoksy-2oc-benzoyloksy-5B,20-epoksy-1 -hydroksy-9-okso-19-nor-cyklopropa[G]tax-1 l-en-13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat dihydrat dehydratisert ved kraftig tørking, holdt i en atmosfære med kontrollert relativ fuktighet (RF) ved 25°C. Vannmengdene, bestemt ved TGA, viser at produktene stabili-serer seg ved mengder nær 4 % (mellom 3 og 5 %) når den relative fuktighet er lik stør-re enn 40 % (teoretisk vannmengde for et dihydrat er 4,15 %). The isotherm for the water activity in the product has been studied. Thus, samples of 4,10B-diacetoxy-2oc-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-1 l-en-13a-yl (2R,3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate dehydrated by vigorous drying, maintained in a controlled relative humidity (RH) atmosphere at 25°C. The amounts of water, determined by TGA, show that the products stabilize at amounts close to 4% (between 3 and 5%) when the relative humidity is greater than 40% (theoretical amount of water for a dihydrate is 4.15%).
For å gjennomføre fremgangsmåten ifølge oppfinnelsen er det mulig å arbeide direkte på en etanolisk oppløsning av 4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-l-hydroksy-9-okso-19-nor-cyklopropa[G]tax-11 -en-13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat, oppnådd efter debeskyttelse i surt medium av 4,106-diacetoksy-2a-benzoyloksy-5B,20-epoksy-l-hydroksy-9-okso-19-nor-cyklopropa[G]tax-11-en-l 3a-yl (2R,3S,5R)-3-tert-butoksykarbonyl-2-(4-metoksyfenyl)-4-fenyl-oksazolidin-5-karboksylat. In order to carry out the method according to the invention, it is possible to work directly on an ethanolic solution of 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax -11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, obtained after deprotection in acidic medium of 4,106-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1 -hydroxy-9-oxo-19-nor-cyclopropa[G]tax-11-en-1 3a-yl (2R,3S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl -oxazolidine-5-carboxylate.
De følgende eksempler skal illustrere oppfinnelsen. The following examples shall illustrate the invention.
Eksempel 1 Example 1
Til en trehalskolbe innføres 2 g 4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-l-hydroksy-9-okso-l 9-nor-cyklopropa[G]tax-11 -en-13a-yl (2R,3S)-3-tert-butoksy-karbonylamino-2-hydroksy-3-fenylpropionat i uren tilstand og 20 cm<3> absolutt etanol. Til oppløsningen, omrørt ved 50°C, settes i løpet av 45 minutter, ca. 20 cm<3> vann hvor-efler den oppnådde suspensjon avkjøles til en temperatur nær 20°C. Efter filtreringen blir produktet vasket på filteret med 20 cm<3> absolutt etanol:vann 1:1 på volumbasis, hvorefter produktet tørkes ved 40°C under et redusert trykk på 5,3 kPa. Man oppnår 1,64 g dihydrat av 4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-l-hydroksy-9-okso-19-nor-cyklopropa[G]tax-l 1 -en-13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat inneholdende 3,8 % vann (bestemt ved TGA) (den teoretiske verdi for vannmengden i dihydratet er 4,15 %). Det oppnådde utbyttet er rundt 80 %. Pulver-røntgen-analysediagrammet viser at det således oppnådde produkt oppviser dihydratets karakteristika. Pulverdiagrammet for røntgenstråler oppnås ved hjelp av en Philips PW 1700® apparatur med et kobolt anti-katode-rør ( X = 1,7889 Å), idet sveipingen gjennomføres i en initialsveipevinkel på 5" 2-0 og sluttsveipingen ved 40° 2-0, med et skritt på 0,02" 2-9 i en hastighet på 1 sekund pr. skritt idet man bruker en silisiumtablett. 2 g of 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-11-en-13a-yl (2R ,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate in the impure state and 20 cm<3> of absolute ethanol. To the solution, stirred at 50°C, add within 45 minutes, approx. 20 cm<3> of water where the resulting suspension is cooled to a temperature close to 20°C. After filtration, the product is washed on the filter with 20 cm<3> of absolute ethanol:water 1:1 on a volume basis, after which the product is dried at 40°C under a reduced pressure of 5.3 kPa. 1.64 g of dihydrate of 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-1 1 -en-13a-yl is obtained (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate containing 3.8% water (determined by TGA) (the theoretical value for the amount of water in the dihydrate is 4.15%). The yield achieved is around 80%. The powder X-ray analysis diagram shows that the product thus obtained exhibits the characteristics of the dihydrate. The X-ray powder diagram is obtained using a Philips PW 1700® apparatus with a cobalt anti-cathode tube ( X = 1.7889 Å), the sweep being carried out at an initial sweep angle of 5" 2-0 and the final sweep at 40° 2-0 , with a step of 0.02" 2-9 at a rate of 1 second per steps while using a silicon tablet.
Den termogravimetriske analyse, TGA, gjennomføres ved hjelp av en Perkin-Elmer TGA 7® termovekt ved en initial-temperatur på 25°C og en slutt-temperatur på 300°C med en temperatur-gradient på 10°C pr. minutt. The thermogravimetric analysis, TGA, is carried out using a Perkin-Elmer TGA 7® thermobalance at an initial temperature of 25°C and a final temperature of 300°C with a temperature gradient of 10°C per minute.
Eksempel 2 Example 2
Til en nitrogenspylt reaktor settes 515 g urent dihydrat av 4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-1 -hydroksy-9-okso-19-nor-cyklopropa[G]tax-11 -en-13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat og 41 absolutt etanol. Man oppvarmer suspensjonen til 35 til 40°C inntil oppløsning og reaksjonen settes under et redusert trykk på 8 kPa. Man destillerer av ca. 8 1 oppløsningsmiddel til kons-tant volum ved kontinuerlig å mate reaktoren med 8 1 etanol. Efter å ha bragt reaktoren til atmosfærisk trykk ble oppløsningen gjort klar ved føring gjennom et filter med et filternivå på 0,45 um. Efter vasking av filteret med 1 1 absolutt etanol tilsettes i løpet av 1 time og ved 40°C, til totaliteten av oppløsningen, ca. 1,8 1 vann. Efter ymping med 8 g dihydrat av 4,10B-diacetoksy-2a-benzoyloksy-5lf,20-epoksy-1 -hydroksy-9-okso-19-nor-cyklopropa[G]tax-l 1 -en-13ct-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat blir blandingen avkjølt til en temperatur nær 20°C i 15 timer. Suspensjonen oppvarmes så til 40°C hvoretter man i løpet av 4 timer tilsetter 1,661 vann. Blandingen avkjøles til en temperatur nær 20°C og settes hen under omrøring i 17 timer. Suspensjonen filtreres på en glassfritte og det avhelte produkt vaskes med 1,25 1 alko-hohvann 50:50 på volumbasis. Produktet tørkes i en ovn ved 35°C under 5,3 kPa trykk i 72 timer i nærvær av en vannreserve og derefter ved 35°C under 2,7 kPa i 8 timer uten vannreserve og på ny ved 35°C under 5,3 kPa i 16 timer i nærvær av en vannreserve. Man oppnår på denne måte 491 g dihydrat av 4,10B-diacetoksy-2a-benzoyloksy-5fi,20-epoksy-1 -hydroksy-9-okso-19-nor-cyklopropa[G]tax-11 -en-13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat inneholdende 4,0 % vann (Karl Fischer). Røntgenpulverdiagrammet viser at det således oppnådde produkt foreligger i form av et dihydrat (den teoretiske mengde for vannet i dihydratet av 4,106-diacetoksy-2ct-benzoyloksy-5B,20-epoksy-1 -hydroksy-9-okso-19-nor-cyklopropa[G]tax-11 -en- 13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat er 4,15 %. 515 g of impure dihydrate of 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-11-en-13a- are added to a nitrogen-flushed reactor yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and 41 absolute ethanol. The suspension is heated to 35 to 40°C until dissolution and the reaction is placed under a reduced pressure of 8 kPa. It is distilled from approx. 8 1 solvent to constant volume by continuously feeding the reactor with 8 1 ethanol. After bringing the reactor to atmospheric pressure, the solution was made ready by passing through a filter with a filter level of 0.45 µm. After washing the filter with 1 1 of absolute ethanol, add approx. 1.8 1 water. After inoculation with 8 g dihydrate of 4,10B-diacetoxy-2a-benzoyloxy-5lf,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-1 1 -en-13ct-yl ( 2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, the mixture is cooled to a temperature close to 20°C for 15 hours. The suspension is then heated to 40°C, after which 1.661 of water is added over the course of 4 hours. The mixture is cooled to a temperature close to 20°C and left under stirring for 17 hours. The suspension is filtered on a glass frit and the decanted product is washed with 1.25 1 alcohol-hohwater 50:50 by volume. The product is dried in an oven at 35°C under 5.3 kPa pressure for 72 hours in the presence of a water reserve and then at 35°C under 2.7 kPa for 8 hours without a water reserve and again at 35°C under 5.3 kPa for 16 hours in the presence of a water reserve. 491 g of dihydrate of 4,10B-diacetoxy-2a-benzoyloxy-5′,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-11-en-13a-yl is obtained in this way (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate containing 4.0% water (Karl Fischer). The X-ray powder diagram shows that the product thus obtained exists in the form of a dihydrate (the theoretical amount of water in the dihydrate of 4,106-diacetoxy-2ct-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[ G]tax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is 4.15%.
Røntgenpulverdiagrammet oppnås under de betingelser som er beskrevet i eksempel 1. The X-ray powder diagram is obtained under the conditions described in Example 1.
Eksempel 3 Example 3
Til en trehalskolbe settes 2 g urent 4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-l-hydroksy-9-okso-l9-nor-cyklopropa[G]tax-l l-en-13a-yl (2R,3S)-3-tert-butoksy-karbonylamino-2-hydroksy-3-fenylpropionat og 20 cm<3> aceton. Til den oppnådde opp-løsning som omrøres ved en temperatur nær 20°C settes i løpet av 35 minutter ca. 20 cm<3> vann. Den oppnådde suspensjon omrøres i ca. 15 minutter. Efter filtrering blir produktet vasket 2 ganger på filteret med 20 cm<3> aceton:vann 1:1 på volumbasis hvorefter produktet tørkes ved 40°C under et redusert trykk på 5,3 kPa. Man oppnår på denne måte 1,28 g dihydrat av4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-l-hydroksy-9-okso-19-nor-cyklopropa[G]tax-l 1 -en-13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat. Utbyttet er rundt 75 %. Røntgenpulverdiagrammet viser at det således oppnådde produkt oppviser dihydratets karakteristika. 2 g of impure 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-1 l-en-13a-yl ( 2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate and 20 cm<3> acetone. To the obtained solution, which is stirred at a temperature close to 20°C, add approx. 20 cm<3> of water. The obtained suspension is stirred for approx. 15 minutes. After filtration, the product is washed twice on the filter with 20 cm<3> acetone:water 1:1 on a volume basis, after which the product is dried at 40°C under a reduced pressure of 5.3 kPa. In this way, 1.28 g of dihydrate of 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-1 1 -ene-13a is obtained -yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. The yield is around 75%. The X-ray powder diagram shows that the product thus obtained exhibits the characteristics of the dihydrate.
Røntgenpulverdiagrammet oppnås under de betingelser som er beskrevet i eksempel 1. The X-ray powder diagram is obtained under the conditions described in Example 1.
Eksempel 4 Example 4
Til en reaktor spylt med nitrogen settes 120 g 4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-1 -hydroksy-9-okso-19-nor-cyklopropa[G]tax-11 -en-13a-yl (2R,3S,5R)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat og 1,08 1 etylacetat. Suspensjonen omrøres ved en temperatur nær 20°C og derefter tilsettes en oppløsning av 3,25 cm<3> 36 %-ig saltsyre i 17,6 cm<3> vann. Efter henstand i 3 timer og 30 minutter setter man til reaktoren en oppløsning av 3,5 g natriumhydrogenkarbonat i 350 cm<3> vann hvorefter det hele omrøres i 15 minutter. Efter dekantering og avtrekking av den vandige fase vasker man to ganger med 350 cm<3> vann. Den organiske fase konsentreres under redusert trykk ved rundt 25°C til et restvolum på 350 cm<3> og derefter innføres 350 cm<3> absolutt etanol. Destillasjonen under redusert trykk gjentas ved rundt 30°C inntil etylacetatet er forbrukt, idet det mates til 1,5 1 absolutt alkohol. Oppløsningen oppvarmes til 40°C og derefter tilsettes i løpet av 15 minutter 470 cm<3> vann. Oppløsningen ympes med en suspensjon av 1 g dihydrat av 4,10B-diacetoksy-2a-benzoyloksy-5B,20-epoksy-l-hydroksy-9-okso-19-nor-cyklopropa[G]tax-11 -en-13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat i en blanding av 40 cm<3> vann og 40 cm<3> absolutt etanol. Efter henstand i 15 timer ved rundt 40°C tilsettes i løpet av 4-5 timer 410 cm3 vann og derefter avkjøles suspensjonen til 20°C. Efter filtrering og vasking av produktet på filteret blir produktet tørket i 15 timer under et redusert trykk på 2,7 kPa ved 25°C, så i 24 timer ved 35°C. Man oppnår på denne måte 102 g dihydrat av 4,10fl-diacetoksy-2a-benzoyloksy-56,20-epoksy-1 -hydroksy-9-okso-19-nor-cyklopropa[G]tax-11 -en-13a-yl (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylpropionat inneholdende 4,3 % vann (Karl Fischer), noe som tilsvarer et utbytte på rundt 93 %. Røntgenpulverdiagrammet viser at det således oppnådde produkt oppviser dihydratets karakteristika. 120 g of 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-11-en-13a-yl are added to a reactor flushed with nitrogen (2R,3S,5R)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and 1.08 L of ethyl acetate. The suspension is stirred at a temperature close to 20°C and then a solution of 3.25 cm<3> of 36% hydrochloric acid in 17.6 cm<3> of water is added. After standing for 3 hours and 30 minutes, a solution of 3.5 g of sodium bicarbonate in 350 cm<3> of water is added to the reactor, after which the whole is stirred for 15 minutes. After decanting and drawing off the aqueous phase, wash twice with 350 cm<3> of water. The organic phase is concentrated under reduced pressure at around 25°C to a residual volume of 350 cm<3> and then 350 cm<3> of absolute ethanol is introduced. The distillation under reduced pressure is repeated at around 30°C until the ethyl acetate is consumed, feeding it to 1.5 1 of absolute alcohol. The solution is heated to 40°C and then 470 cm<3> of water is added over 15 minutes. The solution is inoculated with a suspension of 1 g of dihydrate of 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-11 -ene-13a- yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in a mixture of 40 cm<3> water and 40 cm<3> absolute ethanol. After standing for 15 hours at around 40°C, 410 cm3 of water are added over 4-5 hours and the suspension is then cooled to 20°C. After filtering and washing the product on the filter, the product is dried for 15 hours under a reduced pressure of 2.7 kPa at 25°C, then for 24 hours at 35°C. 102 g of dihydrate of 4,10fl-diacetoxy-2a-benzoyloxy-56,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[G]tax-11-en-13a-yl is obtained in this way (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate containing 4.3% water (Karl Fischer), which corresponds to a yield of about 93%. The X-ray powder diagram shows that the product thus obtained exhibits the characteristics of the dihydrate.
Røntgenpulverdiagrammet oppnås under de betingelser som er beskrevet i eksempel 1. The X-ray powder diagram is obtained under the conditions described in Example 1.
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9514841A FR2742438B1 (en) | 1995-12-14 | 1995-12-14 | (2R, 3S) DIHYDRATE -3-TERT-BUTOXYCARBONYLAMINO-2-HYDROXY- 3-PHENYLPROPIONATE OF 4,10BETA-DIACETOXY-2ALPHA-BENZOYLOXY- 5BETA, 2O-EPOXY-1-HYDROX CYCLOPROPA (G) TAX-11- ENE-13ALPHA-YLE, AND PREPARATION METHOD THEREOF |
| PCT/FR1996/001957 WO1997021695A1 (en) | 1995-12-14 | 1996-12-09 | 4,10β-DIACETOXY-2α-BENZOYLOXY-5β,20-EPOXY-1-HYDROXY-9-OXO-19-NOR-CYCLOPROPA[G]TAX-11-ENE-13α-YL (2R,3S)-TERT-BUTOXYCARBONYLAMINO-2-HYDROXY-3-PHENYLPROPIONATE DIHYDRATE, AND METHOD FOR PREPARING SAME |
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| Publication Number | Publication Date |
|---|---|
| NO982561D0 NO982561D0 (en) | 1998-06-04 |
| NO982561L NO982561L (en) | 1998-06-04 |
| NO317356B1 true NO317356B1 (en) | 2004-10-18 |
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| NO19982561A NO317356B1 (en) | 1995-12-14 | 1998-06-04 | 4,10beta-diacetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [G] tax-11-en-13 <alpha> -yl (2R, 3S) - 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, and preparation thereof |
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