WO2013052094A2 - Methods for preparing anti-viral nucleotide analogs - Google Patents

Methods for preparing anti-viral nucleotide analogs Download PDF

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Publication number
WO2013052094A2
WO2013052094A2 PCT/US2012/000441 US2012000441W WO2013052094A2 WO 2013052094 A2 WO2013052094 A2 WO 2013052094A2 US 2012000441 W US2012000441 W US 2012000441W WO 2013052094 A2 WO2013052094 A2 WO 2013052094A2
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WO
WIPO (PCT)
Prior art keywords
compound
ethyl
propyl
diastereomerically pure
treated
Prior art date
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Ceased
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PCT/US2012/000441
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English (en)
French (fr)
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WO2013052094A3 (en
Inventor
Denise A. COLBY
Andrew Anthony MARTINS
Benjamin James Roberts
Robert William Scott
Nicole S. SOLOMON
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Gilead Sciences Inc
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Gilead Sciences Inc
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Priority to EA201490753A priority Critical patent/EA027086B1/ru
Priority to JP2014534535A priority patent/JP6190372B2/ja
Priority to AU2012319172A priority patent/AU2012319172B2/en
Priority to MX2014003952A priority patent/MX353064B/es
Priority to NZ624513A priority patent/NZ624513B2/en
Priority to CN201710365515.5A priority patent/CN107266498B/zh
Priority to CN202311252160.0A priority patent/CN117343101A/zh
Priority to KR1020197019875A priority patent/KR102139440B1/ko
Priority to KR1020207021316A priority patent/KR20200090975A/ko
Priority to HK15101331.9A priority patent/HK1200834B/en
Priority to CN201280048965.7A priority patent/CN103842366B/zh
Priority to BR112014011340A priority patent/BR112014011340A2/pt
Priority to EP18153951.1A priority patent/EP3333173B1/en
Priority to CA2850466A priority patent/CA2850466C/en
Priority to ES12798029.0T priority patent/ES2661705T3/es
Priority to EP12798029.0A priority patent/EP2764002B1/en
Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Priority to KR1020147011619A priority patent/KR102033802B1/ko
Priority to PL18153951T priority patent/PL3333173T3/pl
Publication of WO2013052094A2 publication Critical patent/WO2013052094A2/en
Publication of WO2013052094A3 publication Critical patent/WO2013052094A3/en
Priority to IL23187914A priority patent/IL231879B/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • U.S. Patent Nos. 7,390,791 and 7,803,788 (the content of each bf which is incorporated by reference herein in its entirety) describe certain prodrugs of phosphonate nucleotide analogs that are useful in therapy.
  • One such prodrug is 9- ⁇ (R)-2-[((S)- ⁇ [(S)-l -
  • Compound 15 is depicted as a mixture of diastereomers at the phosphorus center. The two diastereomers that make up the mixture of compound 15 are shown here as compounds 15a and 15b. Isomer 15a is identical in structure to compound 16.
  • a method comprising subjecting a solution comprising: a) a suitable solvent; b) a suitable base; c) the diastereomeric mixture 9- ⁇ (R)-2-[((R,S)- ⁇ [(S)-l-
  • the method comprises subjecting a solution comprising: a) a suitable solvent; b) a suitable base; c) 9- ⁇ (R)-2-[((R,S)- ⁇ [(S)-l - (isopropoxycarbonyl)ethyl]amino ⁇ phenoxyphosphinyl)methoxy]propyl ⁇ adenine; and, optionally, d) one or more seed crystals of 9- ⁇ (R)-2-[((S)- ⁇ [(S)-l - (isopropoxycarbonyl)ethyl]amino ⁇ phenoxyphosphinyl)methoxy]propyl ⁇ adenine, to conditions that provide for the epimerization of the phosphorus center, under conditions that also provide selective crystallization of 9- ⁇ (R)-2-[((S)- ⁇ [(S)- ⁇ [(S)- ⁇ [(S)- ⁇ [(S)- ⁇ [(S)- ⁇ [(S)- ⁇ [(S)- ⁇ [(
  • the crystallization can be carried out in any suitable solvent.
  • it can be carried out in an aprotic organic solvent, or in a mixture thereof.
  • the aprotic organic solvent may comprise ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, acetone, methyl ethyl ketone, methyl ter/-butylether, toluene, or acetonitrile, or a mixture thereof.
  • the solvent comprises acetonitrile.
  • the resolution can be carried out in the presence of any suitable base.
  • the resolution can be carried out in the presence of a base selected from l ,5-diazobicyclo[4.3.0]non-5-ene (DBN), l ,8-diazabicyclo[5.4.0]undec- 7-ene (DBU), 7-methyl-l ,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), tetramethylguanidine, a Verkade base (e.g., 2,8,9-triisopropyl-2,5,8,9-tetraaza- l -phosphabicyclo[3.3.3]undecane, and 2,8,9-triisobutyl-2,5,8,9-tetraaza- l -phosphabicyclo[3.3.3]undecane), a metal carbonate (e.g., M X C0 3 ), a metal phenoxide (M + OPh
  • the resolution can also be carried out at any suitable temperature, for example, a temperature in the range of from about 0 °C to about 50 °C. In one specific embodiment, the resolution is carried out at a temperature of about 20 °C.
  • the resolution is carried out in the presence of phenol.
  • the percentage of compound 16 in the starting diastereomeric mixture can be anywhere in the range from about 0% to about 99%. In one embodiment of the invention, the percentage of compound 16 in the starting diastereomeric mixture is in the range from about 0% to about 20%. In one embodiment, the percentage of compound 16 in the starting diastereomeric mixture is in the range from about 20% to about 99%. In one embodiment, the percentage of compound 16 in the starting diastereomeric mixture is in the range from about 50% to about 99%. In one embodiment, the final compound 16 is at least about 90%, about 95%, about 97%, or about 99% diastereomerically pure. In one embodiment, the final compound 16 contains less than 1 % of any diastereomeric impurities. In one embodiment, the final compound 16 is free of any detectable diastereomeric impurities.
  • compound 12 can be prepared by treating compound 12 with a suitable halogenating agent.
  • compound 13 can be prepared by treating compound 12 with a halogenating agent such as, for example, thionyl chloride (SOCl 2 ), oxalyl chloride (C 2 0 2 C1 2 ), phosphorus trichloride (PC1 3 ), a
  • a halogenating agent such as, for example, thionyl chloride (SOCl 2 ), oxalyl chloride (C 2 0 2 C1 2 ), phosphorus trichloride (PC1 3 ), a
  • chlorotriphenylphosphorane salt thionyl bromide (SOBr 2 ), oxalyl bromide (C 2 0 2 Br 2 ), phosphorus tribromide (PBr 3 ), or a bromotriphenylphosphorane salt.
  • the reaction can be carried out in a suitable organic solvent at a suitable temperature (e.g., a temperature in the range from about -20 °C to about 100 °C).
  • suitable solvents include tetrahydrofuran, 2-methyltetrahydrofuran,
  • dichloromethane acetonitrile, toluene, chlorobenzene, 1 ,2-dichloroethane, 1 ,4-dioxane, sulfolane, and trichloroethylene, and mixtures thereof.
  • compound 12 is treated with thionyl chloride in toluene at a temperature of from about 22 °C to about 1 10 °C to provide compound 13a: that is at least about 90% diastereomerically pure.
  • the final compound 13a is at least about 90%, about 95%, about 97%, or about 99% diastereomerically pure.
  • the final compound 13a contains less than 1 % of any diastereomeric impurities.
  • the final compound 13a is free of any detectable diastereomeric impurities.
  • Compound 15 can be prepared by treating compound 13 (wherein X is halo) that is at least about 90% diastereomerically pure with amine 11 under conditions that provide compound 15 that is at least about 90%
  • compound 15 can be prepared by treating compound 13 with amine 11 in a suitable organic solvent at a suitable
  • Suitable solvents include organic solvents such as tetrahydrofuran,
  • reaction conveniently can be carried out in the presence of a suitable base, such as, for example, triethylamine ( ⁇ Hs ⁇ N), N,N-diisopropylethylamine ([(CH 3 )2CH]2NC2H 5 ), or l ,8-bis(dimethylamino)- naphthalene (proton sponge, CuHigNi).
  • a suitable base such as, for example, triethylamine ( ⁇ Hs ⁇ N), N,N-diisopropylethylamine ([(CH 3 )2CH]2NC2H 5 ), or l ,8-bis(dimethylamino)- naphthalene (proton sponge, CuHigNi).
  • the resulting material can be washed with an aqueous solution containing a suitable wash reagent, such as, for example, sodium phosphate monobasic (NaH 2 P0 4 ), potassium bicarbonate ( HCO3), citric acid (CeHsO ? ), or sodium bicarbonate (NaHCCb).
  • a suitable wash reagent such as, for example, sodium phosphate monobasic (NaH 2 P0 4 ), potassium bicarbonate ( HCO3), citric acid (CeHsO ? ), or sodium bicarbonate (NaHCCb).
  • a suitable drying agent for example, sodium sulfate, magnesium sulfate, or calcium chloride to provide compound 15 that is at least about 90% diastereomerically pure compound 16.
  • compound 13 that is at least about 90%
  • diastereomerically pure (wherein X is chloro) is treated with amine 11 in dichloromethane at a temperature of -25 °C to 25 °C in the presence of triethylamine.
  • the resulting reaction mixture is then washed with an aqueous solution containing sodium phosphate monobasic (NaH 2 P0 4 ) and potassium bicarbonate ( HCO3) and dried over sodium sulfate to provide compound 15 that is at least about 90% diastereomerically pure compound 16.
  • the starting compound 13 and resulting compound 15 are at least about 95% or 97% diastereomerically pure.
  • the final compound 15 contains at least about 90%, about 95%, about 97%, or about 99%
  • compound 15 contains less than 1 % of any diastereomeric impurities.
  • Compound 12 can be prepared as described in, e.g., U.S. Patent
  • a method for preparing compound 12 comprising treating PMPA with triphenylphosphite in the presence of a suitable base to provide compound 12.
  • the reaction conveniently can be carried out in a suitable solvent, such as, for example, acetonitrile, N-methylpyrrolidone (NMP), dichloroethane, ⁇ pyridine, an alkyl acetate (e.g., ethyl acetate), or a dialkyl ether (e.g., diethyl ether), or a mixture thereof.
  • a suitable solvent such as, for example, acetonitrile, N-methylpyrrolidone (NMP), dichloroethane, ⁇ pyridine, an alkyl acetate (e.g., ethyl acetate), or a dialkyl ether (e.g., diethyl ether), or a mixture thereof.
  • the reaction conveniently also can be carried out in the presence of a suitable base, such as, for example, a trialkylamine (e.g., triethylamine), 2-methylimidazole, dimethylaminopyridine (DMAP), l ,5-diazobicyclo[4.3.0]non-5-ene (DBN), l ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or pyridine, or a mixture thereof.
  • a suitable temperature such as, for example, a temperature from about 20 °C to about 120 °C (e.g., from about 20 °C to about 82 °C).
  • PMPA is treated with tripheny lphosphite in the presence of triethylamine and dimethylaminopyridine in acetonitrile at about 80 °C to provide compound 12.
  • a solution of sodium phosphate monobasic (2.2 kg, 18 mol, 6.90 equiv) in water (16 kg) was prepared. Half of the sodium phosphate monobasic solution was charged to the phosphonamidate reactor, and vigorously stirred. The layers were settled and partitioned. The organic layer was washed again with the remaining half of sodium phosphate monobasic solution.
  • a solution of potassium bicarbonate ( 1 .1 kg, 1 1 mol, 4.22 equiv) in water (5.5 kg) was prepared. Half of the potassium bicarbonate solution was charged to the organic phase, and vigorously stirred. The layers were settled and partitioned.
  • the organic layer was washed again with the remaining half of the potassium bicarbonate solution, followed by a final water (3.3 kg) wash. The organic phase was then retained and distilled to a volume of approximately 6 L. The resultant solution was analyzed for water content. If the water content was > 1.0%, DCM could be charged and the distillation to approximately 6 L repeated.
  • the pot temperature was adjusted to 19 °C to 25 °C prior to discharge of the stock solution in DCM to provide the diastereomeric mixture 9- ⁇ (R)-2-[((R,S)- ⁇ [(S)-l - (isopropoxycarbonyl)ethyl]amino ⁇ phenoxyphosphinyl)methoxy]propyl ⁇ adenine (compound 15).
  • Example 2 Crystallization-induced Dynamic Resolution of Diastereomeric Mixture 9- ⁇ (R)-2-[((R,S)- ⁇ [(S)- 1 -
  • Phenol (9.9 g, 0.1 1 mol, 0.1 equiv) and DBU (16 g, 0.1 1 mol, 0.1 equiv) were added and the mixture was stirred for an additional 24 hours, or until the weight percent of compound 16 remaining in solution was less than 12%.
  • the slurry was then cooled to 0 °C and stirred for an additional 18 hours at 0 °C.
  • the slurry was filtered and washed with a 1 : 1 solution of isopropyl acetate:acetonitrile (1 .5 L) at 0 °C.
  • the solids were dried in a vacuum oven at 50 °C to give 0.40 kg of compound 16

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PCT/US2012/000441 2011-10-07 2012-10-03 Methods for preparing anti-viral nucleotide analogs Ceased WO2013052094A2 (en)

Priority Applications (19)

Application Number Priority Date Filing Date Title
CN201280048965.7A CN103842366B (zh) 2011-10-07 2012-10-03 制备抗病毒核苷酸类似物的方法
AU2012319172A AU2012319172B2 (en) 2011-10-07 2012-10-03 Methods for preparing anti-viral nucleotide analogs
MX2014003952A MX353064B (es) 2012-10-03 2012-10-03 Metodos para preparar analogos nucleotidicos antivirales.
NZ624513A NZ624513B2 (en) 2011-10-07 2012-10-03 Methods for preparing anti-viral nucleotide analogs
CN201710365515.5A CN107266498B (zh) 2011-10-07 2012-10-03 制备抗病毒核苷酸类似物的方法
JP2014534535A JP6190372B2 (ja) 2011-10-07 2012-10-03 抗ウイルスヌクレオチド類似体を調製する方法
KR1020197019875A KR102139440B1 (ko) 2011-10-07 2012-10-03 항-바이러스 뉴클레오티드 유사체의 제조 방법
KR1020207021316A KR20200090975A (ko) 2011-10-07 2012-10-03 항-바이러스 뉴클레오티드 유사체의 제조 방법
HK15101331.9A HK1200834B (en) 2011-10-07 2012-10-03 Methods for preparing anti-viral nucleotide analogs
BR112014011340A BR112014011340A2 (pt) 2012-10-03 2012-10-03 métodos para a preparação de análogos de nucleotídeos antivirais
CN202311252160.0A CN117343101A (zh) 2011-10-07 2012-10-03 制备抗病毒核苷酸类似物的方法
EA201490753A EA027086B1 (ru) 2012-10-03 2012-10-03 Способы получения обладающих противовирусным действием аналогов нуклеотидов
CA2850466A CA2850466C (en) 2011-10-07 2012-10-03 Methods for preparing anti-viral nucleotide analogs
ES12798029.0T ES2661705T3 (es) 2011-10-07 2012-10-03 Métodos para la preparación de análogos de nucleótidos antivirales
EP12798029.0A EP2764002B1 (en) 2012-10-03 2012-10-03 Methods for preparing anti-viral nucleotide analogs
EP18153951.1A EP3333173B1 (en) 2012-10-03 2012-10-03 Methods for preparing anti-viral nucleotide analogs
KR1020147011619A KR102033802B1 (ko) 2011-10-07 2012-10-03 항-바이러스 뉴클레오티드 유사체의 제조 방법
PL18153951T PL3333173T3 (pl) 2012-10-03 2012-10-03 Sposoby wytwarzania przeciwwirusowych analogów nukleotydów
IL23187914A IL231879B (en) 2012-10-03 2014-04-02 Methods for preparing anti-viral nucleotide analogs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US61/544,950 2011-10-07
US201161544950P 2014-04-11 2014-04-11

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WO2013052094A2 true WO2013052094A2 (en) 2013-04-11
WO2013052094A3 WO2013052094A3 (en) 2013-06-20

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PCT/US2012/000441 Ceased WO2013052094A2 (en) 2011-10-07 2012-10-03 Methods for preparing anti-viral nucleotide analogs

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US (4) US8664386B2 (enExample)
EP (2) EP2764002B1 (enExample)
JP (2) JP6190372B2 (enExample)
KR (3) KR20200090975A (enExample)
CN (4) CN113264959A (enExample)
AR (1) AR088109A1 (enExample)
AU (3) AU2012319172B2 (enExample)
BR (2) BR112014011340A2 (enExample)
CA (2) CA2850466C (enExample)
CL (1) CL2014000827A1 (enExample)
CO (1) CO6940431A2 (enExample)
CR (1) CR20140204A (enExample)
EA (1) EA027086B1 (enExample)
EC (1) ECSP14000074A (enExample)
ES (2) ES2661705T3 (enExample)
HK (1) HK1255222B (enExample)
IL (1) IL231879B (enExample)
MX (1) MX353064B (enExample)
PE (1) PE20141160A1 (enExample)
PL (1) PL3333173T3 (enExample)
PT (2) PT2764002T (enExample)
SI (1) SI3333173T1 (enExample)
TW (4) TWI613211B (enExample)
UY (1) UY34361A (enExample)
WO (1) WO2013052094A2 (enExample)

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WO2014195724A1 (en) * 2013-06-07 2014-12-11 Cipla Limited An efficient process for separation of diastereomers of 9-[(r)-2-[[(r,s)-[[(s)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl] methoxy]propyl]adenine
CN104628773A (zh) * 2013-11-06 2015-05-20 杭州和泽医药科技有限公司 (r)-9-[2-(磷酰苯酚基甲氧基)丙基]腺嘌呤的制备方法
WO2015107451A2 (en) 2014-01-14 2015-07-23 Mylan Laboratories Ltd. Purification of tenofovir alafenamide and its intermediates
CN104817593A (zh) * 2015-04-27 2015-08-05 广州同隽医药科技有限公司 半富马酸替诺福韦艾拉酚胺关键中间体的合成工艺
WO2015079455A3 (en) * 2013-11-27 2015-08-27 Laurus Labs Private Limited A recycling process for preparing tenofovir alafenamide diastereomers
WO2015161781A1 (zh) * 2014-04-21 2015-10-29 四川海思科制药有限公司 一种核苷类似物及其中间体的制备方法
US9676804B2 (en) 2012-10-03 2017-06-13 Gilead Sciences, Inc. Methods for preparing anti-viral nucleotide analogs
WO2017118928A1 (en) 2016-01-06 2017-07-13 Lupin Limited Process for the separation of diastereomers of tenofovir alafenamide
WO2017157352A1 (en) 2016-03-17 2017-09-21 Zentiva, K.S. A preparation method of diastereomerically pure tenofovir alafenamide or its salts
US9840525B2 (en) 2014-07-21 2017-12-12 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Crystal form of tenofovir prodrug, preparation method thereof, and method of use thereof
TWI616452B (zh) * 2015-08-26 2018-03-01 Preparation method of nucleoside analog and intermediate thereof
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
CN108148094A (zh) * 2014-11-12 2018-06-12 四川海思科制药有限公司 一种替诺福韦艾拉酚胺富马酸盐晶型c及其制备方法和用途
KR20210125298A (ko) 2020-04-08 2021-10-18 주식회사 파마코스텍 테노포비어 알라펜아미드 헤미타르트레이트의 신규한 제조방법

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TWI516499B (zh) 2011-08-16 2016-01-11 吉李德科學股份有限公司 泰諾福韋（ｔｅｎｏｆｏｖｉｒ）亞拉芬醯胺（ａｌａｆｅｎａｍｉｄｅ）之半反式丁烯二酸鹽
TWI660965B (zh) 2014-01-15 2019-06-01 美商基利科學股份有限公司 泰諾福韋之固體形式
WO2015197006A1 (zh) * 2014-06-25 2015-12-30 四川海思科制药有限公司 一种取代的氨基酸硫酯类化合物、其组合物及应用
MA44209B1 (fr) 2015-08-05 2022-03-31 Eisai R&D Man Co Ltd Procede de preparation d'un oligomere phosphorodiamidate substantiellement diastereomeriquement pure, un oligomere phosphorodiamidate faite par un tel procede et une composition pharmaceutique comprenant un tel oligomere phosphorodiamidate
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