Illllllllllll
`
`US007241907B2
`US007241907B2
`
`(12) United States Patent
`(12) United States Patent
`Didier et al.
`Didier et a].
`
`(io) Patent No.:
`(10) Patent N0.:
`(45) Date of Patent:
`(45) Date of Patent:
`
`US 7,241,907 B2
`US 7,241,907 B2
`Jul. 10, 2007
`Jul. 10, 2007
`
`(56)
`(56)
`
`CO71) 407/00
`(2006.01)
`(2006.01)
`C07D 407/00
`(2006.01)
`C07D 493/00
`(2006.01)
`C07D 493/00
`(52) U.S. CI
`549/510
`(52) US. Cl. ...................................... ..
`549/510
`(58) Field of Classiflcation Search
`549/510
`(58) Field of Classi?cation Search ............... .. 549/510
`See application
`file for complete search history.
`See application ?le for complete search history.
`References Cited
`References Cited
`FOREIGN PATENT DOCUMENTS
`FOREIGN PATENT DOCUMENTS
`this
`0982027
`0982027
`WO 96/30355
`WO 96/30355
`WO 97/32869
`WO 97/32869
`
`(54) ACETONE SOLVATE OF DIMETHOXY
`(54) ACETONE SOLVATE OF DIMETHOXY
`DOCETAXEL AND
`ITS PROCESS OF
`DOCETAXEL AND ITS PROCESS OF
`PREPARATION
`PREPARATION
`
`Inventors: Eric Didier, Paris (FR); Marc-Antoine
`(75)
`(75) Inventors: Eric Didier, Paris (FR); Marc-Antoine
`Perrin, Jouy en Josas (FR)
`Perrin, Jouy en Josas (FR)
`
`(73) Assignee: Aventis Pharma S.A., Antony (FR)
`(73) Assignee: Aventis Pharma S.A., Antony (FR)
`
`( * ) Notice:
`( * ) Notice:
`
`Subject to any disclaimer,
`the
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 449 days.
`U.S.C. 154(b) by 449 days.
`
`(21) Appl. No.: 10/944,254
`(21) App1.No.: 10/944,254
`
`(22) Filed:
`(22) Filed:
`
`Sep. 17, 2004
`Sep. 17, 2004
`
`(65)
`(65)
`
`Prior Publication Data
`Prior Publication Data
`US 2005/0065138 Al Mar. 24, 2005
`US 2005/0065138 A1
`Mar. 24, 2005
`
`Related U.S. Application Data
`Related US. Application Data
`(60) Provisional application No.
`60/519,895,
`(60) Provisional application No. 60/519,895, ?led on Nov.
`14, 2003.
`14, 2003.
`
`Foreign Application Priority Data
`(30)
`Foreign Application Priority Data
`(30)
`Sep. 19, 2003
`(FR)
`03 11016
`Sep. 19, 2003
`(FR) ................................. .. 03 11016
`
`(51) Int. CI.
`(51) Int. Cl.
`C07D 305/00
`C07D 305/00
`
`(2006.01)
`(2006.01)
`
`of
`
`term
`EP
`EP
`WO
`W0
`WO
`W0
`
`* 3/2000
`* 3/2000
`* 10/1996
`* 10/1996
`* 9/1997
`* 9/1997
`
`* cited by examiner
`* cited by examiner
`Primary Examiner—Margaret D. Seaman
`Primary ExamineriMargaret D. Seaman
`Assistant Examiner—Niloofar Rahmani
`Assistant ExamineriNiloofar Rahmani
`(74) Attorney, Agent, or Firm—Balaram Gupta; Paul R.
`(74) Attorney, Agent, or FirmiBalaram Gupta; Paul R.
`Darkes
`Darkes
`
`(57)
`(57)
`
`ABSTRACT
`ABSTRACT
`
`filed on
`Nov.
`This invention discloses and claims an acetone solvate of
`This invention discloses and claims an acetone solvate of
`dimethoxydocetaxel or
`4-acetoxy-2a-benzoyloxy-5p,20-ep-
`dimethoxydocetaxel or 4-acetoxy-20t-benZoyloXy-5 [3,20-ep
`oXy-1-hydroXy-7[3,10[3-dimethoXy-9-oXotaX-11-en-13a-yl
`oxy-1 -hydroxy-7 (3,10p-dimethoxy-9-oxotax-11 -en-13a-yl
`(2R,3S)-3-tert-butoxycarbonylamino-2-hydroXy-3-phenyl
`(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-
`propionate and its preparation by crystallization from an
`propionate and its preparation by crystallization from an
`solution.
`aqueous/acetone
`aqueous/acetone solution.
`
`16 Claims, 1 Drawing Sheet
`16 Claims, 1 Drawing Sheet
`
`MYLAN - EXHIBIT 1011
`
`

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`US 7,241,907 B2
`
`FIG. 1
`
`H .05
`
`Operations: Import
`
`
`
`.bnE. “25.230
`
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`
`US 7,241,907 B2
`US 7,241,907 B2
`
`1
`1
`ACETONE SOLVATE OF DIMETHOXY
`ACETONE SOLVATE OF DIMETHOXY
`DOCETAXEL AND ITS PROCESS OF
`DOCETAXEL AND ITS PROCESS OF
`PREPARATION
`PREPARATION
`
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`
`This application claims the benefit of U.S. Provisional 5
`This application claims the bene?t of US. Provisional
`Application No. 60/519,895, filed Nov. 14, 2003 and benefit
`Application No. 60/ 519,895, ?led Nov. 14, 2003 and bene?t
`of priority of French Patent Application No. 03/11,016, filed
`of priority of French Patent Application No. 03/11,016, ?led
`Sep. 19, 2003, both of which are incorporated herein by
`Sep. 19, 2003, both of Which are incorporated herein by
`reference in their entirety.
`reference in their entirety.
`
`2
`2
`to seed the solution with a suspension of said product in an
`to seed the solution With a suspension of said product in an
`acetone/water mixture and then to again treat with water,
`acetone/Water mixture and then to again treat With Water,
`to separate the crystals obtained, then
`to separate the crystals obtained, then
`to dry them under reduced pressure.
`to dry them under reduced pressure.
`Generally, 4-acetoxy-20t-benzoyloxy-5[3,20-epoxy-1-hy
`Generally, 4-acetoxy-2a-benzoyloxy-5p,20-epoxy-l-hy-
`droxy-7[3,10[3-dimethoxy-9-oxotax-11-en-130t-yl (2R,3S)
`droxy-7p,10p-dimethoxy-9-oxotax-ll-en-13a-yl (2R,3S)-
`3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
`3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
`is dissolved in acetone. Preferably, the amount of acetone is
`is dissolved in acetone. Preferably, the amount of acetone is
`between 5 and 20 parts by volume (ml) with respect to the
`betWeen 5 and 20 parts by volume (ml) With respect to the
`Weight (in grams) of 4-acetoxy-20t-benzoyloxy-5[3,20-ep
`10 weight (in grams) of 4-acetoxy-2a-benzoyloxy-5p,20-ep-
`oxy-1-hydroxy-7[3,10[3-dimethoxy-9-oxotax-11-en-130t-yl
`oxy-1 -hydroxy-7 (3,10p-dimethoxy-9-oxotax-11 -en-13a-yl
`(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl
`(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-
`1. Field of the Invention
`propionate employed (ideally 10).
`propionate employed (ideally 10).
`1. Field of the Invention
`The present invention relates to the acetone solvate of
`The preferred seeding is carried out at a concentration of
`The present invention relates to the acetone solvate of
`The preferred seeding is carried out at a concentration of
`dimethoxydocetaxel or 4-acetoxy-20t-benzoyloxy-5 [3,20-ep
`dimethoxydocetaxel or4-acetoxy-2a-benzoyloxy-5p,20-ep- 15 60 to 80 g (ideally 68 g) per liter of mixture comprising an
`60 to 80 g (ideally 68 g) per liter of mixture comprising an
`oxy-1-hydroxy-7[3,10[3-dimethoxy-9-oxotax-11-en-130t-yl
`oxy-1-hydroxy-7 (3,10p-dimethoxy-9-oxotax-l 1 -en-13a-yl
`acetone/water ratio by volume of from about 65/35 to about
`acetone/Water ratio by volume of from about 65/35 to about
`(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl
`(2R,3S)-3 -tert-butoxycarbony lamino -2 -hydroxy-3 -phenyl -
`75/25 and preferably of approximately about 68/32. The
`75/25 and preferably of approximately about 68/32. The
`propionate and to its process of preparation.
`propionate and to its process of preparation.
`acetone/water mixture by volume at the end of precipitation
`acetone/Water mixture by volume at the end of precipitation
`2. Description of the Art
`is between 70/30 minimum and 30/70 maximum (ideally
`2. Description of the Art
`is betWeen 70/30 minimum and 30/70 maximum (ideally
`4-Acetoxy-20t-benzoyloxy-5 [3 ,20-epoxy-1 -hydroxy-7 [3,
`4-Acetoxy-2a-benzoyloxy-5p,20-epoxy-l -hydroxy-7p,
`20 45/55). The entire crystallization process takes place,
`45/55). The entire crystallization process takes place,
`20
`10p-dimethoxy-9-oxotax-ll-en-13a-yl
`(2R,3S)-3-tert-bu-
`10[3-dimethoxy-9-oxotax-11-en-130t-yl (2R,3S)-3 -tert-bu
`according to a better way of implementing the invention, at
`according to a better Way of implementing the invention, at
`toxycarbonylamino-2-hydroxy-3-phenylpropionate exhibits
`20±5° C. (ideally 20° C.).
`toxycarbonylamino-2-hydroxy-3-phenylpropionate exhibits
`2015° C. (ideally 20° C.).
`noteworthy anticancer and antileukemic properties.
`noteWorthy anticancer and antileukemic properties.
`The acetone solvate of 4-acetoxy-2a-benzoyloxy-5p,20-
`The acetone solvate of 4-acetoxy-20t-benzoyloxy-5[3,20
`4-Acetoxy-20t-benzoyloxy-5 [3 ,20-epoxy-1 -hydroxy-7 [3,
`4-Acetoxy-2a-benzoyloxy-5p,20-epoxy-l -hydroxy-7p,
`epoxy-1 -hydroxy-7 (3,10(3 -dimethoxy-9-oxotax-11 -en- 13 a-
`epoxy-1-hydroxy-7[3,10[3-dimethoxy-9-oxotax-1 1-en-130t
`10[3-dimethoxy-9-oxotax-11-en-130t-yl (2R,3S)-3 -tert-bu
`10p-dimethoxy-9-oxotax-ll-en-13a-yl
`(2R,3S)-3-tert-bu- 25 yl
`(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phe-
`yl (2R,3 S)-3 -tert-butoxycarbonylamino -2 -hydroxy-3 -phe
`25
`toxycarbonylamino-2-hydroxy-3-phenylpropionate is pre­
`nylpropionate Which crystallizes is separated, preferably by
`nylpropionate which crystallizes is separated, preferably by
`toxycarbonylamino-2-hydroxy-3-phenylpropionate is pre
`pared according to the process which is disclosed more
`filtration or centrifuging. Drying is carried out under a
`pared according to the process Which is disclosed more
`?ltration or centrifuging. Drying is carried out under a
`particularly in international application PCT WO 96/30355
`particularly in international application PCT WO 96/30355
`reduced pressure generally of between 0.5 and 30 kPa,
`reduced pressure generally of betWeen 0.5 and 30 kPa,
`or international application PCT WO 99/25704; according to
`preferably in the region of 0.7 kPa, at a temperature of
`or international application PCT WO 99/25704; according to
`preferably in the region of 0.7 kPa, at a temperature of
`the process disclosed in these applications, the product is not 30 between 30 and 60° C., preferably in the region of 40° C.
`the process disclosed in these applications, the product is not
`betWeen 30 and 60° C., preferably in the region of 40° C.
`30
`crystallized and is not characterized.
`The drying of the product was studied. Thus, samples of
`crystallized and is not characterized.
`The drying of the product Was studied. Thus, samples of
`All of the references described herein are incorporated
`acetone solvate of 4-acetoxy-2a-benzoyloxy-5|3,20-epoxy-
`All of the references described herein are incorporated
`acetone solvate of 4-acetoxy-20t-benzoyloxy-5[3,20-epoxy
`herein by reference in their entirety.
`1-hydroxy-7[3,10[3-dimethoxy-9-oxotax-11-en-130t-yl (2R,
`herein by reference in their entirety.
`1 -hydroxy-7 (3,10(3 -dimethoxy-9-oxotax-11 -en-13a-yl (2R,
`3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropi
`3 S)-3 -tert-butoxycarbonylamino-2-hydroxy-3 -phenylpropi-
`35 onate deliberately treated at a temperature above 70° C. (70
`onate deliberately treated at a temperature above 70° C. (70
`35
`to 100° C.) shows an increasing loss in the content of
`to 100° C.) shoWs an increasing loss in the content of
`It has been found that the acetone solvate of 4-acetoxy-
`It has been found that the acetone solvate of 4-acetoxy
`acetone with the increase in the temperature. For the drying,
`acetone With the increase in the temperature. For the drying,
`20t-benzoyloxy-5[3,20-epoxy-1-hydroxy-7[3,10[3
`2a-benzoyloxy-5 (3,20-epoxy-l -hydroxy-7|3,10(3-
`the preferred temperature is thus between 30 and 60° C. and
`the preferred temperature is thus betWeen 30 and 60° C. and
`dimethoxy-9-oxotax-11-en-130t-yl (2R,3S)-3 -tert-butoxy
`dimethoxy-9-oxotax-11 -en-13a-yl
`(2R,3 S)-3 -tert-butoxy-
`more preferably still is in the region of 40° C. A mean value
`more preferably still is in the region of 40° C. A mean value
`carbonylamino-2-hydroxy-3-phenylpropionate
`is
`carbonylamino-2-hydroxy-3-phenylpropionate
`is
`fully
`fully 40 of the content of acetone is 7%, which represents approxi­
`of the content of acetone is 7%, Which represents approxi
`40
`characterized from a chemical viewpoint.
`mately the acetone stoichiometry, which is 6.5%, for a
`characterized from a chemical vieWpoint.
`mately the acetone stoichiometry, Which is 6.5%, for a
`solvate comprising one molecule of acetone.
`solvate comprising one molecule of acetone.
`The present invention will be more fully described using
`The present invention Will be more fully described using
`the following examples, which should not be regarded as
`the folloWing examples, Which should not be regarded as
`FIG. 1 is a powder x-ray diffraction (PXRD) diagram of 45 limiting the invention,
`FIG. 1 is a poWder x-ray diffraction (PXRD) diagram of
`limiting the invention.
`45
`the acetone solvate form of the product of Example 1.
`the acetone solvate form of the product of Example 1.
`
`SUMMARY OF THE INVENTION
`SUMMARY OF THE INVENTION
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`EXAMPLE 1
`EXAMPLE 1
`
`DETAILED DESCRIPTION OF THE
`DETAILED DESCRIPTION OF THE
`INVENTION
`INVENTION
`
`940 ml of purified water are added at 20±5° C. ambient
`940 ml of puri?ed Water are added at 20:5° C. ambient
`50 temperature to a solution of 207 g of approximately 92% by
`temperature to a solution of 207 g of approximately 92% by
`50
`According to the invention, the acetone solvate of 4-ac-
`weight 4-acetoxy-2a-benzoyloxy-5(3,20-epoxy-l-hydroxy-
`Weight 4-acetoxy-20t-benzoyloxy-5 [3 ,20-epoxy- 1 -hydroxy
`According to the invention, the acetone solvate of 4-ac
`etoxy-2a-benzoyloxy-5 (3,20-epoxy-1 -hydroxy-7 (3,10(3 -
`7|3,10|3-dimethoxy-9-oxotax-ll-en-13a-yl in approximately
`7[3,10[3-dimethoxy-9-oxotax-11-en-130t-yl in approximately
`etoxy-20t-benzoyloxy-5 [3 ,20-epoxy- 1 -hydroxy-7 [3 , 1 0[3 -
`dimethoxy-9-oxotax-11-en-130t-yl (2R,3S)-3 -tert-butoxy
`dimethoxy-9-oxotax-11 -en-13a-yl
`(2R,3 S)-3 -tert-butoxy-
`2 liters of acetone and then seeding is carried out with a
`2 liters of acetone and then seeding is carried out With a
`carbonylamino-2-hydroxy-3-phenylpropionate
`can
`be
`suspension of 2 g of 4-acetoxy-2a-benzoyloxy-5|3,20-ep-
`carbonylamino-2-hydroxy-3-phenylpropionate
`can
`be
`suspension of 2 g of 4-acetoxy-20t-benzoyloxy-5[3,20-ep
`obtained by crystallization of 4-acetoxy-20t-benzoyloxy-5[3,
`obtained by crystallization of 4-acetoxy-2a-benzoyloxy-5|3, 55 oxy-l-hydroxy-7|3,10|3-dimethoxy-9-oxotax-ll-en-13a-yl
`oxy-1-hydroxy-7[3,10[3-dimethoxy-9-oxotax-11-en-130t-yl
`55
`20-epoxy-1 -hydroxy-7 (3,10(3 -dimethoxy-9-oxotax-11 -en-
`20-epoxy-1-hydroxy-7[3,10[3-dimethoxy-9-oxotax-1 1-en
`(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl
`(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-
`130t-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3
`13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-
`propionate, isolated from acetone/water, in a mixture of 20
`propionate, isolated from acetone/Water, in a mixture of 20
`phenylpropionate from a mixture of water and of acetone,
`mi of water and 20 ml of acetone. The mixture is left stirring
`phenylpropionate from a mixture of Water and of acetone,
`ml of Water and 20 ml of acetone. The mixture is left stirring
`followed by drying the isolated product under reduced for
`approximately 10 to 22 hours and 1.5 liters of purified
`folloWed by drying the isolated product under reduced
`for approximately 10 to 22 hours and 1.5 liters of puri?ed
`pressure.
`60 water are added over 4 to 5 hours. The mixture is left stirring
`pressure.
`Water are added over 4 to 5 hours. The mixture is left stirring
`60
`For the implementation of the process according to the
`for 60 to 90 minutes and then the suspension is filtered under
`For the implementation of the process according to the
`for 60 to 90 minutes and then the suspension is ?ltered under
`invention, it can be particularly advantageous
`reduced pressure. The cake is washed on the filter with a
`invention, it can be particularly advantageous
`reduced pressure. The cake is Washed on the ?lter With a
`to dissolve 4-acetoxy-2a-benzoyloxy-5|3,20-epoxy-l-hy-
`solution prepared from 450 ml of acetone and 550 ml of
`to dissolve 4-acetoxy-20t-benzoyloxy-5[3,20-epoxy-1-hy
`solution prepared from 450 ml of acetone and 550 ml of
`droxy-7[3,10[3-dimethoxy-9-oxotax-11-en-130t-yl
`(2R,
`droxy-7|3,10|3-dimethoxy-9-oxotax-ll-en-13a-yl
`(2R,
`purified water and is then dried in an oven at 55° C. under
`puri?ed Water and is then dried in an oven at 55° C. under
`3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl
`3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-
`65 reduced pressure (0.7 kPa) for 4 hours. 197 g of 4-acetoxy-
`reduced pressure (0.7 kPa) for 4 hours. 197 g of 4-acetoxy
`65
`20t-benzoyloxy-5[3,20-epoxy-1-hydroxy-7[3,10[3
`propionate in acetone,
`2a-benzoyloxy-5 (3,20-epoxy-1 -hydroxy-7 (3,10(3-
`propionate in acetone,
`dimethoxy-9-oxotax-11-en-130t-yl (2R,3S)-3 -tert-butoxy
`to treat the solution with water,
`dimethoxy-9-oxotax-ll-en-13a-yl
`(2R,3S)-3-tert-butoxy-
`to treat the solution With Water,
`
`

`
`US 7,241,907 B2
`US 7,241,907 B2
`
`15
`
`4
`3
`3
`4
`carbonylamino-2-hydroxy-3 -phenyl-propionate.acetone,
`2. An acetone solvate of 4-acetoxy-2a-benzoyloxy-5p,
`carbonylamino-2-hydroxy-3-phenyl-propionate.acetone,
`2. An acetone solvate of 4-acetoxy-20t-benzoyloxy-5[3,
`20-epoxy-1-hydroxy-7[3,10[3-dimethoxy-9-oxotax-11-en
`20-epoxy-l-hydroxy-7 (3, lOfS-dimethoxy-Q-oxotax-l 1 -en-
`comprising 0.1% of water and 7.2% of acetone (theoretically
`comprising 0.1% of Water and 7.2% of acetone (theoretically
`130t-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3
`13a-yl (2R,3 S)-3 -tert-butoxycarbonylamino-2-hydroxy-3 -
`6.5% for a stoichiometric solvate), are obtained.
`6.5% for a stoichiometric solvate), are obtained.
`phenylpropionate comprising from about 5 to about 7
`phenylpropionate comprising from about 5 to about 7
`Drying Study
`Drying Study
`5 percent by weight of acetone.
`percent by Weight of acetone.
`The product is again placed in an oven and successively
`The product is again placed in an oven and successively
`3. A process for the preparation of the acetone solvate of
`3. A process for the preparation of the acetone solvate of
`dried for 18 hours at 60° C. under a reduced pressure of 0.7
`dried for 18 hours at 60° C. under a reduced pressure of 0.7
`4-acetoxy-2a-benzoyloxy-5p, 20-epoxy-l-hydroxy-7 (3,10(3-
`4-acetoxy-20t-benzoyloxy-5 [3 ,20-epoxy-1 -hydroxy-7 [3 , 1 0[3
`kPa, for 3 hours at 60° C. under a relative humidity of
`kPa, for 3 hours at 60° C. under a relative humidity of
`dimethoxy-9-oxotax-11-en-130t-yl (2R,3S)-3 -tert-butoxy
`dimethoxy-9-oxotax-ll-en-13a-yl
`(2R,3S)-3-tert-butoxy-
`approximately 80% (reduced pressure of 160 mmHg) and
`approximately 80% (reduced pressure of 160 mmHg) and
`carbonylamino-2-hydroxy-3-phenylpropionate, which com-
`carbonylamino-2-hydroxy-3-phenylpropionate, Which com
`for 18 hours at 70° C. under a relative humidity of approxi­
`for 18 hours at 70° C. under a relative humidity of approxi
`prises:
`10 prises:
`mately 80% (reduced pressure of 200 mmHg). At this stage,
`mately 80% (reduced pressure of 200 mmHg). At this stage,
`crystallizing 4-acetoxy-20t-benzoyloxy-5[3,20-epoxy-1
`crystallizing
`4-acetoxy-2a-benzoyloxy-5 (3,20-epoxy-1 -
`the content of water is 0.2% and the content of acetone is
`the content of Water is 0.2% and the content of acetone is
`hydroxy-7[3,10[3-dimethoxy-9-oxotax-11-en-130t-yl
`hydroxy-7 (3,10|3-dimethoxy-9-oxotax-l 1 -en-13a-yl
`4.7% (194 g). At this same stage, 1 aliquot of 1 g of the batch
`4.7% (194 g). At this same stage, 1 aliquot of 1 g of the batch
`(2R,3S)-3-ter‘t-butoxycarbonylamino-2-hydroxy-3
`(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-
`is dried under a reduced pressure of 5 mmHg successively
`is dried under a reduced pressure of 5 mmHg successively
`phenylpropionate from a mixture of water and acetone,
`phenylpropionate from a mixture of Water and acetone,
`for 18 hours at 80° C. (residual acetone content of 0.5%) and
`for 18 hours at 80° C. (residual acetone content of 0.5%) and
`which comprises seeding the solution with a suspen­
`Which comprises seeding the solution With a suspen
`then for 21 hours at 100° C. (residual acetone content of
`then for 21 hours at 100° C. (residual acetone content of
`sion of said product in an acetone/water mixture and
`sion of said product in an acetone/Water mixture and
`0.02%). The remainder is dried at 80° C. under a reduced
`0.02%). The remainder is dried at 80° C. under a reduced
`then subsequently treating with water, and which com­
`then subsequently treating With Water, and Which com
`pressure of 5 mmHg for 31 hours (acetone 1.7%, water
`pressure of 5 mmHg for 31 hours (acetone 1.7%, Water
`prises drying the product obtained under reduced pres­
`prises drying the product obtained under reduced pres
`0.3%, assay with regard to such of 96.5%, purity of greater
`0.3%, assay With regard to such of 96.5%, purity of greater
`sure.
`sure.
`than 99%).
`than 99%).
`4. The process as set forth in claim 3, wherein the seeding
`20
`4. The process as set forth in claim 3, Wherein the seeding
`20
`Operating Conditions Used for the Acquisition of the PXRD
`Operating Conditions Used for the Acquisition of the PXRD
`is carried out at a concentration of from about 60 to about 80
`is carried out at a concentration of from about 60 to about 80
`Diagram (FIG. 1)
`Diagram (FIG. 1)
`g per liter of a mixture comprising an acetone/water ratio by
`g per liter of a mixture comprising an acetone/Water ratio by
`The analyses are carried out on the Bruker D5000 dif-
`volume of from about 65/35 to about 75/25.
`The analyses are carried out on the Bruker D5000 dif
`volume of from about 65/35 to about 75/25.
`fractometer equipped with an Anton Paar TTK temperature
`fractometer equipped With an Anton Paar TTK temperature
`5. The process as set forth in claim 4, wherein the seeding
`5. The process as set forth in claim 4, Wherein the seeding
`chamber. The set-up in reflection possesses focusing geom- 25 is carried out in a mixture comprising an acetone/water ratio
`chamber. The set-up in re?ection possesses focusing geom
`25
`is carried out in a mixture comprising an acetone/Water ratio
`etry of Bragg-Brentano type (0—0). The powder is depos­
`etry of Bragg-Brentano type (040). The poWder is depos
`by volume of about 68/32.
`by volume of about 68/32.
`ited on a hollow aluminum sample holder. A cobalt anti-
`ited on a holloW aluminum sample holder. A cobalt anti
`6. The process as set forth in claim 3, wherein the
`6. The process as set forth in claim 3, Wherein the
`cathode tube (40 kV/30 mA) supplies iron-filtered incident
`cathode tube (40 kV/30 mA) supplies iron-?ltered incident
`acetone/water mixture by volume at the end of precipitation
`acetone/Water mixture by volume at the end of precipitation
`radiation. Radiation is emitted at two wavelengths: Co Kcq
`radiation. Radiation is emitted at tWo Wavelengths: Co Kotl
`is from about 70/30 to about 30/70.
`is from about 70/30 to about 30/70.
`(X=1.7890 A) and Co Ka2 (X=1.7929 A). Filtering by iron 30
`(7t:1.7890 A) and Co Kot2 (7»:17929 A). Filtering by iron
`7. The process as set forth in claim 6, wherein the
`30
`7. The process as set forth in claim 6, Wherein the
`does not completely remove the K|3 radiation (X=1.6208 A
`does not completely remove the K[3 radiation (7»:16208 A
`acetone/water mixture by volume at the end of precipitation
`acetone/Water mixture by volume at the end of precipitation
`for cobalt), which still participates in the incident radiation
`for cobalt), Which still participates in the incident radiation
`is about 45/55.
`is about 45/55.
`at a level of 1% (manufacturer's data) of the intensity of the
`at a level of 1% (manufacturer’s data) of the intensity of the
`8. The process as set forth in claim 3, wherein the
`8. The process as set forth in claim 3, Wherein the
`Ka doublet.
`KO. doublet.
`crystallization process takes place at about 20±5° C.
`crystallization process takes place at about 2015° C.
`Soller slits improve the parallelism of the beam. Variable 35
`Soller slits improve the parallelism of the beam. Variable
`35
`9. The process as set forth in claim 4, wherein the
`9. The process as set forth in claim 4, Wherein the
`front slits make it possible to retain a constant illumination
`front slits make it possible to retain a constant illumination
`crystallization process takes place at about 20±5° C.
`crystallization process takes place at about 2015° C.
`area of the sample. A 1 mm collimator limits the scattering
`area of the sample. A 1 mm collimator limits the scattering
`10. The process as set forth in claim 5, wherein the
`10. The process as set forth in claim 5, Wherein the
`between the tube and the measuring chamber. A Braun 50 M
`betWeen the tube and the measuring chamber. A Braun 50 M
`crystallization process takes place at about 20±5° C.
`crystallization process takes place at about 2015° C.
`multichannel linear detector is used. It exhibits a detection
`multichannel linear detector is used. It exhibits a detection
`11. The process as set forth in claim 6, wherein the
`11. The process as set forth in claim 6, Wherein the
`window with a width of 10° of 20 angle. The conditions for 40
`WindoW With a Width of 10° of 20 angle. The conditions for
`40
`crystallization process takes place at about 20±5° C.
`crystallization process takes place at about 2015° C.
`recording the diagrams are as follows: scanning from 1.5 to
`recording the diagrams are as folloWs: scanning from 1.5 to
`12. The process as set forth in claim 7, wherein the
`12. The process as set forth in claim 7, Wherein the
`50° in 20, counting time of 30 seconds per degree in 20,
`50° in 20, counting time of 30 seconds per degree in 20,
`crystallization process takes place at about 20±5° C.
`crystallization process takes place at about 2015° C.
`under ambient conditions of temperature, pressure and rela­
`under ambient conditions of temperature, pressure and rela
`13. The process as set forth in claim 3, wherein drying is
`13. The process as set forth in claim 3, Wherein drying is
`tive humidity.
`tive humidity.
`carried out at a temperature in the range of from about 30
`carried out at a temperature in the range of from about 30
`FIG. 1 represents the reference PXRD diagram of the 45
`FIG. 1 represents the reference PXRD diagram of the
`45
`and about 60° C.
`and about 60° C.
`solvate form comprising acetone (form A) of the product of
`solvate form comprising acetone (form A) of the product of
`14. The process as set forth in claim 13, wherein drying
`14. The process as set forth in claim 13, Wherein drying
`example 1.
`example 1.
`is further carried out under a pressure in the region of 0.7
`is further carried out under a pressure in the region of 0.7
`NMR Spectrum of the Product of Example 1
`NMR Spectrum of the Product of Example 1
`kPa.
`kPa.
`1H NMR spectrum (400 MHz, CDC13, 8 in ppm): 1.20 (s,
`1H NMR spectrum (400 MHZ, CDCl3, 6 in ppm): 1.20 (s,
`15. The process as set forth in claim 3, wherein drying is
`15. The process as set forth in claim 3, Wherein drying is
`3H), 1.22 (s, 3H), 1.37 (s, 9H), 1.67 (s, 1H), 1.72 (s, 3H), 50
`3H), 1.22 (s, 3H), 1.37 (s, 9H), 1.67 (s, 1H), 1.72 (s, 3H),
`50
`carried out at a temperature of about 40° C. under a pressure
`1.80 (mt, 1H), 1.88 (s, 3H), 2.17 (s, 6H), from 2.20 to 2.40
`carried out at a temperature of about 40° C. under a pressure
`1.80 (mt, 1H), 1.88 (s, 3H), 2.17 (s, 6H), from 2.20 to 2.40
`in the region of 0.7 kPa.
`in the region of 0.7 kPa.
`(mt, 2H), 2.36 (s, 3H), 2.70 (mt, 1H), 3.30 (s, 3H), 3.46 (s,
`(mt, 2H), 2.36 (s, 3H), 2.70 (mt, 1H), 3.30 (s, 3H), 3.46 (s,
`16. The process as set forth in claim 3, wherein the
`3H), 3.47 (mt, 1H), 3.82 (d, J=7.5 Hz, 1H), 3.86 (dd, J=ll
`16. The process as set forth in claim 3, Wherein the
`3H), 3.47 (mt, 1H), 3.82 (d, 1:75 Hz, 1H), 3.86 (dd, 1:11
`preparation is carried out directly starting from the acetone
`and 6.5 Hz, 1H), 4.17 (d, J=8.5 Hz, 1H), 4.30 (d,J=8.5 Hz,
`preparation is carried out directly starting from the acetone
`and 6.5 Hz, 1H), 4.17 (d, 1:85 Hz, 1H), 4.30 (d,J:8.5 Hz,
`1H), 4.63 (mt, 1H), 4.80 (s, 1H), 4.97 (broad d, J=10 Hz, 55 solution of 4-acetoxy-2a-benzoyloxy-5|3,20-epoxy-l-hy-
`solution of 4-acetoxy-20t-benzoyloxy-5[3,20-epoxy-1-hy
`1H), 4.63 (mt, 1H), 4.80 (s, 1H), 4.97 (broad d, 1:10 Hz,
`55
`droxy-7[3,10[3-dimethoxy-9-oxotax-11-en-130t-yl (2R,3S)
`droxy-7|3,10|3-dimethoxy-9-oxotax-11 -en-13a-yl
`(2R,3S)-
`1H), 5.27 (broad d, J=10 Hz, 1H), 5.44 (d, J=10 Hz, 1H),
`1H), 5.27 (broad d, 1:10 Hz, 1H), 5.44 (d, 1:10 Hz, 1H),
`3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
`3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
`5.64 (d, J=7.5 Hz, 1H), 6.21 (t, J=9 Hz, 1H), from 7.25 to
`5.64 (d, 1:75 Hz, 1H), 6.21 (t, 1:9 Hz, 1H), from 7.25 to
`obtained by deprotection in an acid medium of the ester
`7.45 (mt, 5H), 7.49 (t, J=7.5 Hz, 2H), 7.60 (broad t, J=7.5
`obtained by deprotection in an acid medium of the ester
`7.45 (mt, 5H), 7.49 (t, 1:75 Hz, 2H), 7.60 (broad t, 1:75
`4-acetoxy-2a-benzoyloxy-5(3,20-epoxy-l-hydroxy-7(3,10(3-
`Hz, 1H), 8.09 (d, J=7.5 Hz, 2H).
`4-acetoxy-20t-benzoyloxy-5 [3 ,20-epoxy-1 -hydroxy-7 [3 , 1 0[3
`Hz, 1H), 8.09 (d, 1:75 Hz, 2H).
`60 dimethoxy-9-oxotax-ll-en-13a-yl
`(2R,4S,5R)-3-tert-bu-
`dimethoxy-9-oxotax-11-en-130t-yl
`(2R,4S,5R)-3 -ter‘t-bu
`What is claimed is:
`What is claimed is:
`60
`toxycarbonyl-2-(4-methoxyphenyl)-4-phenyloxazolidine-5
`toxycarbonyl-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-
`1. An acetone solvate of 4-acetoxy-2a-benzoyloxy-5|3,
`1. An acetone solvate of 4-acetoxy-20t-benzoyloxy-5[3,
`carboxylate.
`carboxylate.
`20-epoxy-1 -hydroxy-7 (3,10(3 -dimethoxy-9-oxotax-11 -en-
`20-epoxy-1-hydroxy-7[3,10[3-dimethoxy-9-oxotax-1 1-en
`130t-yl (2R,3S)-3-ter‘t-butoxycarbonylamino-2-hydroxy-3
`13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-
`phenylpropionate.
`phenylpropionate.