WO2020001812A1 - Nouveau procédé de préparation d'inhibiteurs de sglt-2 - Google Patents

Nouveau procédé de préparation d'inhibiteurs de sglt-2 Download PDF

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Publication number
WO2020001812A1
WO2020001812A1 PCT/EP2019/025192 EP2019025192W WO2020001812A1 WO 2020001812 A1 WO2020001812 A1 WO 2020001812A1 EP 2019025192 W EP2019025192 W EP 2019025192W WO 2020001812 A1 WO2020001812 A1 WO 2020001812A1
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WIPO (PCT)
Prior art keywords
compound
formula
iii
compounds
cyclic
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Application number
PCT/EP2019/025192
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English (en)
Inventor
V. Theocharis KOFTIS
Thanos Andreou
Ioanna Georgopoulou
Efstratios Neokosmidis
Original Assignee
Pharmathen S.A.
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.)
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Application filed by Pharmathen S.A. filed Critical Pharmathen S.A.
Priority to EP19742290.0A priority Critical patent/EP3810623A1/fr
Publication of WO2020001812A1 publication Critical patent/WO2020001812A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals

Definitions

  • the present invention relates to a novel process for the preparation of SGLT-2 inhibitors. Such compounds have attracted a continuously growing interest, owed to their use in the treatment of diabetes.
  • SGLT-2 inhibitors are a new and promising class of drugs utilized in diabetes treatment. Their distinguishing feature from previously known antidiabetic drugs is the biological pathway they are involved into. In particular, the sodium glucose transport proteins regulate the reabsorption of glucose from the nephron. Inhibition of SGLT proteins results in the excretion of glucose in the urine, leading in a reduction of blood glucose levels.
  • Patent application W02010023594A1 discloses the synthesis of such a SGLT-2 inhibitor, Ertugliflozin (Formula la), according to the scheme shown below.
  • the starting material is prepared from D-glucose in 4 steps with 57% yield.
  • This process features the introduction of the required hydroxymethyl group at the first steps of the synthetic route with the use of formaldehyde.
  • the two-step transformation suffers from low yield (53%).
  • the given process also employs the use of reagents unsuitable for industrial production, such as n-butyl lithium and trimethylaluminium.
  • the process further requires the deprotection of three benzyl groups via catalytic hydrogenation with precious metals, raising the overall cost of the process.
  • the method is hindered by the epimerization which occurs under the influence of n-butyl lithium, making tedious purifications unavoidable.
  • Patent application WO2014159151A1 discloses another process for the preparation of compound of formula I.
  • the starting material is tetra-O-benzyl-D-glucose.
  • This process not only employs expensive reagents for the hydroxymethylene group introduction, but it further uses benzyl protecting groups, which requires the use of palladium catalyst. Overall this route suffers from the use of costly reagents.
  • the present invention discloses a novel process for the preparation of compound of Formula I, comprising the introduction of a hydroxymethyl group into compound of formula II, thereby producing compound of formula III.
  • Ar represents the moiety shown below, protecting groups PG1 and PG2 together form a first cyclic protecting group and protecting groups PG3 and PG4 form a second cyclic protecting group.
  • hydroxyl protecting groups refers to protecting groups suitable for the protection of the hydroxyl moiety, which is then defined as“protected hydroxyl group”.
  • the definition includes both simple and cyclic protecting groups. Such groups are known in the art and are exemplified such as in Greene’s Protective Groups on Organic Synthesis 4 th Edition, John Wiley & Son, Peter G. M. Wuts, Theodora W. Greene, Print ISBN: 9780471697541.
  • Preferred protecting groups are trltyl, benzyl, naphthyl, methoxybenzyl, p-nitrobenzyl, benzoyl, a substituted benzoyl, acetyl, a substituted acetyl, pivaloyl,trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, thexyldimethylsilyl, allyl, methoxymethyl, (2-methoxyethoxy)methyl, tetrahydropyranyl.
  • Preferred cyclic hydroxyl protecting groups are ethylidene, isopropylidene, pentylidene, hexylidene, benzyline, p- methoxybenzylidene, naphthylidene, 4-phenylbenzylidene, methoxymethylene, ethoxymethylene, cyclic carbonate, l,3-(l,l,3,3-tetraisopropyl)disiloxanediyl, di-tert- butylsilylenediyl.
  • Stereoisomers are ethylidene, isopropylidene, pentylidene, hexylidene, benzyline, p- methoxybenzylidene, naphthylidene, 4-phenylbenzylidene, methoxymethylene, ethoxymethylene, cyclic carbonate, l,3-(l,l,3,3-tetrais
  • stereoisomers Some compounds prepared according to the present invention exist as stereoisomers.
  • the scope of the present invention involves the preparation of such compounds either as mixtures of stereoisomers, or as single stereoisomers.
  • Optimal purification according to standard techniques, known to the skilled person, can afford each stereoisomer in a pure form, whenever this is preferred.
  • Base when used herein includes hydroxides or alkoxides, hydrides, or compounds such as amine and its derivatives, that accept protons in water or solvent.
  • exemplary bases include, but are not limited to, alkali metal hydroxides and alkoxides (i.e., MOR, wherein M is an alkali metal such as potassium, lithium, or sodium, and R is hydrogen or alkyl, as defined above, more preferably where R is straight or branched chain Cl -5 alkyl, thus including, without limitation, potassium hydroxide, potassium tert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodium tert- butoxide, lithium hydroxide, etc.); other hydroxides such as magnesium hydroxide (Mg(OH) 2 ) or calcium hydroxide (Ca(OH) 2 ), barium hydroxide (Ba(OH) 2 ); alkali metal hydrides (i.e., MH, wherein M is as defined above, thus including, without
  • Aqueous bases include metal hydroxides, for example, hydroxides of Group l/Group 2 metals such as Li, Na, K, Mg, Ca, etc. (e.g., aqueous LiOH, NaOH, KOH, etc.), alkyl ammonium hydroxides, and aqueous carbonates.
  • metal hydroxides for example, hydroxides of Group l/Group 2 metals such as Li, Na, K, Mg, Ca, etc. (e.g., aqueous LiOH, NaOH, KOH, etc.), alkyl ammonium hydroxides, and aqueous carbonates.
  • Non-aqueous bases include but not limited to, amines and their derivatives, for example, trialkyl amine (e.g., Et 3 N, diisopropylethyl amine, etc.), and aromatic amine (e.g., Ph-NH 2 , PhN(Me)H, etc.); alkali metal alkoxides; alkali metal hydrides; alkylated disilazides; and non-aqueous carbonates.
  • A“strong base” is a base that is completely dissociated in an aqueous solution.
  • the present invention discloses a novel process for the preparation of compound of formula I, comprising: a) conversion of compound of formula II to compound of formula III, wherein Ar represents the moiety shown below, protecting groups PG1 and PG2 together form a first cyclic protecting group and protecting groups PG3 and PG4 together form a second cyclic protecting group, said cyclic protecting groups selected from cyclic acetals, cyclic ketals, cyclic ortho esters, cyclic carbonates and silyl derivatives and PG5 is a hydroxyl protecting group selected from alkyl and aryl ethers, silyl ethers, esters, carbonates, sulfonates; and
  • formaldehyde source may conveniently be achieved in the presence of a formaldehyde source.
  • the source of formaldehyde may be any source available to the skilled person either commercially or by using his common general knowledge and standard laboratory techniques. For example, p-formaldehyde or a solution of aldehyde, such as aqueous solution, may be used.
  • the amount of formaldehyde should be excessive. Excess of formaldehyde promotes the reduction of the aldehyde carbon which leads to compound of formula III, in a Cannizzaro-type fashion.
  • the temperature of the reaction may be such that drives the reaction to completion.
  • the reaction is performed at a temperature range from 25 °C to the boiling point of the solvent used in the reaction. More preferably, the reaction is performed at a temperature between 40 and 100 °C.
  • the reaction is performed in polar protic solvents, such as methanol and by using strong bases.
  • Compound of formula II may be isolated pursuant to standard techniques or it may be prepared shortly before and used without isolation in the reaction towards compound III. In a preferred embodiment compound II is not isolated.
  • Each pair of protecting groups PG1/PG2 and PG3/PG4 represents a cyclic protecting group. Accordingly, there are two cyclic protecting groups which are protecting 4 hydroxyl groups.
  • the cyclic protecting groups are selected from: ethylidene, isopropylidene, pentylidene, hexylidene, benzyline, p- methoxybenzylidene, naphthylidene, 4-phenylbenzylidene, methoxymethylene, ethoxymethylene, cyclic carbonate, l,3-(l,l,3,3-tetraisopropyl)disiloxanediyl, di-tert- butylsilylenediyl.
  • the cyclic protecting groups are selected from: ethylidene, isopropylidene, pentylidene, hexylidene, benzyline, p- methoxybenzylidene, 4-phenylbenzylidene. Even more preferably, the cyclic protecting groups are isopropylidene groups.
  • the present invention discloses a process for the preparation of compound of formula I as described above, wherein step b comprises: i) selectively deprotecting PG5 from compound of formula III to form compound of formula IV ;
  • protecting group PG5 may be performed in accordance with the nature of the group.
  • Protecting group PG5 should be selected such that it can be removed in the presence of cyclic groups PG1/PG2 and PG3/PG4.
  • Preferred hydroxyl protecting groups are alkyl and aryl ethers, silyl ethers, esters, carbonates, sulfonates.
  • protecting group PG5 is a silyl protecting group. Appropriate deprotection techniques are well known to the skilled person and can be found in textbooks as mentioned above.
  • step b-ii The conversion of compound of formula IV to compound of formula V according to step b-ii is performed by selective oxidation of the secondary (benzylic) hydroxyl group in the presence of two unprotected primary hydroxyls groups.
  • a number of available techniques are disclosed in textbooks, such as March’s Advanced Organic Chemistry, M. B. Smith & J. March, John Wiley & Sons, 6 th edition, ISBN 13:978-0- 471-72091-1, Chapter 19-3.
  • the selective oxidation is performed with manganese (II) oxide.
  • the solvents of the reaction can be aprotic polar solvents, such as dichloromethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, ethyl acetate, acetone, N,N- dimethylformamide, acetonitrile, dimethyl sulfoxide, or non-polar solvents, such as pentane, hexane, cyclohexane, benzene, toluene, chloroform, diethyl ether, chloroform, l,4-dioxane .
  • aprotic polar solvents such as dichloromethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, ethyl acetate, acetone, N,N- dimethylformamide, acetonitrile, dimethyl sulfoxide, or non-polar solvents, such as pent
  • excess of manganese (II) oxide is used, most preferably 10 equivalents.
  • the deprotection of protecting groups PG1-PG4 according to step b-iii may be performed in accordance with the nature of the group.
  • the conditions employed for deprotection may also bring about the simultaneous cyclization of the deprotected intermediate towards compound of formula I. For example, when acidic conditions are used, this may lead to the deprotection of acid-labile protecting groups with simultaneous cyclization.
  • Other conditions, suitable for the deprotection of protecting groups PG1-PG4 may also be employed, followed by the use of an appropriate reagent to promote the cyclization, as exemplified in prior art.
  • Suitable reagents are trifluoroacetic acid, acetic acid, pyridinium p-toluenesulfonate (PPTS), hydrogen halides and their solutions, preferable, hydrogen chloride and its solutions, sulfuric acid and its solutions, acidic resins such as Amberlyst and Dowex resins.
  • PPTS pyridinium p-toluenesulfonate
  • hydrogen halides and their solutions preferable, hydrogen chloride and its solutions, sulfuric acid and its solutions, acidic resins such as Amberlyst and Dowex resins.
  • Suitable conditions for this step can be also found in widely used textbooks, such as Greene’s Protective Groups on Organic Synthesis 4 th Edition, John Wiley & Son, Peter G. M. Wuts, Theodora W. Greene, Print ISBN: 9780471697541.
  • the present invention discloses a process for the preparation of compound of formula I as described in the previous embodiments, further comprising preparing compound of formula II by oxidation of compound of formula VI.
  • Several methods for the oxidation of primary hydroxyl groups to aldehydes are available in prior art and exemplified in common textbooks (March’s Advanced Organic Chemistry, M. B. Smith & J. March, John Wiley & Sons, 6th edition, ISBN 13:978-0-471-72091-1, Chapter 19-3).
  • Compound of formula II may be isolated or directly used in the next step of the process, as described in previous embodiments.
  • the oxidation is performed under Swem conditions.
  • Swem conditions involve the use of dimethysulfoxide and oxalyl chloride and are well described in textbooks as mentioned above.
  • Compound of formula VIII is prepared from compound of formula VII by reaction with ArMgBr under standard Grigrard conditions. This reaction creates a new stereocenter and the product of the reaction may be a mixture of two diastereomers with respect to this stereocenter. Both of them, however, are equally useful within the process described herein, as this hydroxyl group is intended to be oxidized in the last steps of the process (see scheme 5). Therefore no separation of the diastereomers is required.
  • protecting group PG5 The benzylic hydroxyl group of compound of formula VIII is protected with protecting group PG5 to provide compound of formula IX under standard techniques available in textbook mentioned above.
  • protecting group PG5 has been discussed above. It should be added that protecting group PG5 should be stable enough under conditions that remove protecting group PG6.
  • protecting group PG5 is a silyl protecting group. Thereafter, deprotection from PG6, performed according to the nature of the protecting group, converts compound of formula IX to compound of formula VI.
  • Protecting group PG6 should be selected such that it can be removed in the presence of protecting groups PG1/PG2, PG3/PG4 and PG5.
  • PG5 is an ester protecting group.
  • a process for the preparation of compound of formula V comprising the conversion of compound of formula II to compound of formula III as described in the previous embodiments.
  • novel compounds of formulae II, III, IV and V are provided.
  • protecting groups PG1/PG2 and PG3/PG4 are isopropylidene protecting groups and compounds of formulae III, IV and V are compounds of formulae Ilia’, IVa, Va.
  • protecting groups PG1/PG2 and PG3/PG4 are isopropylidene protecting groups and protecting group PG5 is a silyl protecting group. More preferably, PG5 is a TBS group and compounds of formulae II, III are respectively Ila and Ilia.
  • Oxalyl chloride (0.095 ml; 1.14 mmol) was dissolved in dry DCM (2 ml) in a dry 25 ml round-bottomed flask, and cooled at -65 °C.
  • dry DMSO (0.1 ml) was dissolved in dry DCM( 0.6 ml) and the DMSO solution was added dropwise to the solution of oxalyl chloride at -65 °C, followed by stirring at this temperature for 10 min.

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Abstract

La présente invention concerne un nouveau procédé pour la préparation d'inhibiteurs de SGLT-2 par addition d'un groupe hydroxyméthylène dans un intermédiaire à chaîne ouverte, facile à obtenir à partir de D-glucose.
PCT/EP2019/025192 2018-06-25 2019-06-21 Nouveau procédé de préparation d'inhibiteurs de sglt-2 WO2020001812A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP19742290.0A EP3810623A1 (fr) 2018-06-25 2019-06-21 Nouveau procédé de préparation d'inhibiteurs de sglt-2

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EPPCT/EP2018/025170 2018-06-25
EP2018025170 2018-06-25

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WO2020001812A1 true WO2020001812A1 (fr) 2020-01-02

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020137903A1 (en) 1999-10-12 2002-09-26 Bruce Ellsworth C-aryl glucoside SGLT2 inhibitors and method
WO2010023594A1 (fr) 2008-08-28 2010-03-04 Pfizer Inc. Dérivés de dioxa-bicyclo[3.2.1.]octane-2,3,4-triol
WO2014159151A1 (fr) 2013-03-14 2014-10-02 Msd International Gmbh Procédés de préparation d'inhibiteurs de sglt2

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020137903A1 (en) 1999-10-12 2002-09-26 Bruce Ellsworth C-aryl glucoside SGLT2 inhibitors and method
WO2010023594A1 (fr) 2008-08-28 2010-03-04 Pfizer Inc. Dérivés de dioxa-bicyclo[3.2.1.]octane-2,3,4-triol
WO2014159151A1 (fr) 2013-03-14 2014-10-02 Msd International Gmbh Procédés de préparation d'inhibiteurs de sglt2

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BERNHARDSON D. ET AL.: "Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin", OPRD, vol. 18, no. 57, 2014, pages 57 - 65, XP055212312, DOI: doi:10.1021/op400289z
BOWLES P. ET AL.: "Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin", OPRD, vol. 18, no. 57, 2014, pages 66 - 81, XP055283061, DOI: doi:10.1021/op4002802
DAVID BERNHARDSON ET AL: "Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 18, no. 1, 17 January 2014 (2014-01-17), pages 57 - 65, XP055212312, ISSN: 1083-6160, DOI: 10.1021/op400289z *
PAUL BOWLES ET AL: "Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 18, no. 1, 17 January 2014 (2014-01-17), US, pages 66 - 81, XP055283061, ISSN: 1083-6160, DOI: 10.1021/op4002802 *
PETER G. M. WUTSTHEODORA W. GREENE: "Greene's Protective Groups on Organic Synthesis", JOHN WILEY & SONS

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