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WO2016181313A1 - Procédé pour la préparation d'intermédiaires sofosbuvir et leur forme polymorphe - Google Patents

Procédé pour la préparation d'intermédiaires sofosbuvir et leur forme polymorphe Download PDF

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Publication number
WO2016181313A1
WO2016181313A1 PCT/IB2016/052684 IB2016052684W WO2016181313A1 WO 2016181313 A1 WO2016181313 A1 WO 2016181313A1 IB 2016052684 W IB2016052684 W IB 2016052684W WO 2016181313 A1 WO2016181313 A1 WO 2016181313A1
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WO
WIPO (PCT)
Prior art keywords
formula
process according
preparation
compound
base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2016/052684
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English (en)
Inventor
Girij Pal Singh
Dhananjai Srivastava
Kishor Gulabrao Mehare
Vineet Malik
Sharad Chandrabhan Deokar
Abhijeet Avinash DANGE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lupin Ltd
Original Assignee
Lupin Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lupin Ltd filed Critical Lupin Ltd
Publication of WO2016181313A1 publication Critical patent/WO2016181313A1/fr
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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/242—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of hydroxyaryl compounds
    • 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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines

Definitions

  • the present invention pertains to process for preparing N-[(2,3,4,5,6- Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester (formula 2) and resolving the formula 2 in the presence base to form N-[(S)-(2,3,4,5,6- Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester (formula 2').
  • the present invention also relates to a novel crystalline form of N-[(S)-(2, 3, 4, 5, 6- Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester.
  • Sofosbuvir is chemically named as (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4- dioxo3,4- dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran- 2yl)methoxy)- (phenoxy)phosphorylamino)propanoate and is represented by the following chemical structure:
  • PCT publications WO2011123645 and WO2010135569 describes process for preparation of compound of formula 2' by reacting isopropyl (chloro(phenoxy)phosphoryl)-L-alaninate and pentaflurophenol in the presence of base.
  • Figure 1 illustrates Infra-red spectrograph of compound of formula 4.
  • Figure 2 illustrates X-ray powder diffraction pattern of crystalline form of formula 2'.
  • Figure 3 illustrates Nuclear magnetic resonance spectrograph of compound of formula 2'.
  • the present invention relates to a process for preparation of compound of formula 2 in the absence of base.
  • the present invention provides a resolution of compound of formula 2 in the presence of base.
  • the present invention relates to a novel crystalline form of compound of formula 2' and process for the preparation thereof.
  • Formula 2 comprising: i) reaction of compound of formula 3 or pharmaceutically acceptable salts thereof with compound of formula 4 or pharmaceutically acceptable salts thereof in the absence of base.
  • M + is a metal ion which can be selected from but not limited to sodium, Potassium, Magnesium.
  • Compound of formula 4 is prepared by treating pentaflurophenol with metal ion precursor such as sodium hydroxide, sodium methoxide, sodium hydride, potassium hydroxide.
  • metal ion precursor such as sodium hydroxide, sodium methoxide, sodium hydride, potassium hydroxide.
  • the solvent for the above reaction can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t- butyl methyl ether, 1 ,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; and acetonitrile or mixtures thereof.
  • the solvent is methylene dichloride, 1, 2- dimethoxy ether (DME), 1,4-dioxane and tetrahydrofuran or mixtures thereof.
  • the invention provides process for preparation of specific stereo isomer of formula 2':
  • Formula 2' comprising treating of compound of formula 2 with a base to obtain a desired specific stereo isomer of formula 2'.
  • the base can be selected from organic bases selected from tertiary and secondary amines for example triethylamine; inorganic bases such as sodium hydroxide, Potassium carbonate (K 2 CO 3 ), sodium carbonate (Na 2 C0 3 ), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K 3 PO 4 ).
  • organic bases selected from tertiary and secondary amines for example triethylamine
  • inorganic bases such as sodium hydroxide, Potassium carbonate (K 2 CO 3 ), sodium carbonate (Na 2 C0 3 ), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K 3 PO 4 ).
  • the compound of formula 2 used in the above reaction obtaining an existing solution from a previous processing step.
  • the present invention provides novel crystalline form of Formula 2' characterized by XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2 ⁇ at 7.9, 8.3, 9.4,11.0, 14.9,16.5 and 31.72 ⁇ 0.2 degrees.
  • XRPD X-ray powder diffractogram
  • the invention provides a process for preparation of novel crystalline forms of compound of formula 2' comprising the steps of:
  • the organic solvent used in step-(i) is selected from but not limited to water, methanol, ethanol, isopropyl alcohol, n-butanol, tert-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, n-heptane, cyclohexane, toluene, methylene chloride, Di-isopropyl ether and mixtures thereof. Instrument settings for XRPD
  • XRPD X-ray powder diffraction spectrum
  • reaction mass was stripped with n- hepatane to get crude product.
  • Crude product was dissolved in Methyl tert-butyl ether and n- heptane (1 : 1 ratio).
  • the pH of reaction mass was adjusted to pH 8 by using triethylamine.
  • Reaction mass was stirred overnight. Solid mass was filtered and washed with a mixture of methyl tertiary-butyl ether: n-heptane (1 : 1).
  • the obtained product was dissolved in ethyl- acetate and washed with water and 20% brine solution. Ethyl acetate layer was separated; solvent was distilled off under reduced pressure. Reaction mass was stripped with diisopropyl ether.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation de N- [(2,3,4,5,6-Pentafluorophénoxy) phénoxyphosphinyl]-L-alanine 1-méthyléthyle ester (formule2) et la résolution de la formule 2 en présence d'une base pour former le N- [(S)- (2,3,4,5,6-Pentafluorophénoxy) phénoxyphosphinyl]-L-alanine 1-méthyléthyle ester (formule 2').
PCT/IB2016/052684 2015-05-11 2016-05-11 Procédé pour la préparation d'intermédiaires sofosbuvir et leur forme polymorphe Ceased WO2016181313A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1857/MUM/2015 2015-05-11
IN1857MU2015 2015-05-11

Publications (1)

Publication Number Publication Date
WO2016181313A1 true WO2016181313A1 (fr) 2016-11-17

Family

ID=56098295

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/052684 Ceased WO2016181313A1 (fr) 2015-05-11 2016-05-11 Procédé pour la préparation d'intermédiaires sofosbuvir et leur forme polymorphe

Country Status (1)

Country Link
WO (1) WO2016181313A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111087421A (zh) * 2019-12-24 2020-05-01 南京正大天晴制药有限公司 一种用于手性药物合成的磷酰胺化合物的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010135569A1 (fr) 2009-05-20 2010-11-25 Pharmasset, Inc. Ester de n-[(2 ' r) -2' -désoxy-2' -fluoro-2' -méthyl-p-phényl-5' -uridylyl]-l-alanine 1-méthyléthyle et son procédé de production
WO2011123645A2 (fr) 2010-03-31 2011-10-06 Pharmasset, Inc. Phosphoramidates de nucléosides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010135569A1 (fr) 2009-05-20 2010-11-25 Pharmasset, Inc. Ester de n-[(2 ' r) -2' -désoxy-2' -fluoro-2' -méthyl-p-phényl-5' -uridylyl]-l-alanine 1-méthyléthyle et son procédé de production
WO2011123645A2 (fr) 2010-03-31 2011-10-06 Pharmasset, Inc. Phosphoramidates de nucléosides

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111087421A (zh) * 2019-12-24 2020-05-01 南京正大天晴制药有限公司 一种用于手性药物合成的磷酰胺化合物的制备方法

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