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WO2009094462A1 - Intermédiaire synthétique cristallin pour des pyrrolidin-3-yl-glycylaminoalkylboronates - Google Patents

Intermédiaire synthétique cristallin pour des pyrrolidin-3-yl-glycylaminoalkylboronates Download PDF

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Publication number
WO2009094462A1
WO2009094462A1 PCT/US2009/031709 US2009031709W WO2009094462A1 WO 2009094462 A1 WO2009094462 A1 WO 2009094462A1 US 2009031709 W US2009031709 W US 2009031709W WO 2009094462 A1 WO2009094462 A1 WO 2009094462A1
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Prior art keywords
formula
compound
crystalline form
solution
nmr spectrum
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PCT/US2009/031709
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English (en)
Inventor
Peng Wang
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Phenomix Corp
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Phenomix Corp
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Publication of WO2009094462A1 publication Critical patent/WO2009094462A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the field of the invention is a composition of matter of a synthetic intermediate, the intermediate being useful in the preparation of pyrrolidin-3- ylglycylamino-alkylboronates that are known inhibitors of the enzyme DPP-IV, and a crystalline form of the intermediate prepared by a process of the invention; methods of preparing the crystalline form of the intermediate, and methods of using the crystalline form of the intermediate in the preparation of the pyrrolidin- 3-ylglycyl aminoboronic acid enzyme inhibitors.
  • DPP-IV dipeptidyl peptidase IV
  • GLP-I insulotropic peptide I
  • GIP gastric inhibitory protein
  • DPP-VII DPP-VIII
  • DPP-IX DPP-IX
  • FAP fibroblast activation protein
  • R a and R b are OH providing a boronic acid, or its salt or a protected form, is disclosed.
  • the compound is referred to as a pyrrolidin-3-yl-glycyl- ⁇ oro-proline, or more generally, a pyrrolidin-3-ylglycylaminoalkylboronate.
  • IV such as diabetes
  • boro-proline derivative an analog of proline wherein the carboxylic acid moiety of the aminoacid has been replaced by a boronic acid moiety or a protected form thereof, such as a boronic ester.
  • R a and R b are protected hydroxyl groups, which can be deprotected to yield N- (pyrrolidin-3-ylglycyl) ⁇ oro-proline or a salt thereof.
  • the 1- carbobenzyloxypyrrolidin-3-yl-N-carbobenzyloxyglycine is therefore a key intermediate in the preparation of the selective DPP-IV inhibitor N-(pyrrolidin- 3 -ylglycyl)£or ⁇ -proline.
  • the present invention is directed to a compound of the formula (I)
  • An embodiment of the present invention is directed to the molecular structure and compound of formula (I), which the inventors herein believe to be an unknown and unreported structure never before described in the literature or known or used by others.
  • the compound can be referred to as dicyclohexylammonium 1 -benzyloxycarbonylpyrrolidin-3-yl-N- benzyloxycarbonylglycinate.
  • the compound contains a single chiral center, at the pyrrolidine 3 -position, which can be either (R) or (S), or any mixture thereof.
  • An embodiment of the invention further provides the R-stereoisomer of the compound of formula (I), that is, a compound of formula (II)
  • An embodiment of the invention further provides a crystalline form of the compound of formula (II).
  • the crystalline form of the invention is readily purified by crystallization to provide a synthetic intermediate suitable for the preparation of DPP-IV inhibitors.
  • the crystalline form is also easily handled as a solid on a relatively large scale.
  • An embodiment of the invention is directed to a crystalline form of the compound of formula (II) wherein the X-ray Powder Diffraction pattern and Differential Scanning Calorimetry trace are substantially as shown herein.
  • An embodiment of the invention further provides a method of preparation of a compound of formula (I) or of formula (II), comprising crystallization of the compound to yield a stable, solid, and readily handled physical form of the substance.
  • the solid, crystalline form is readily purified by recrystallization, can be stored under suitable conditions for prolonged periods of time, and can be converted to a known DPP-IV inhibitor.
  • embodiments of the invention further provides a method for using the compound of formula (I) or formula (II) as a synthetic intermediate in the preparation of a selective DPP-IV inhibitor, for example, the preparation of a compound of formula (VIII) or (IX) via its bis-Cbz protected derivative of formula (VI) or (VII) respectively.
  • the method comprises coupling the compound of formula (I) or (II) with the boro-proline derivative of formula (V), to provide a compound of formula (VI) or (VII).
  • the bis-Cbz protected derivative of formula (VI) or (VII) is then readily converted a DPP-IV inhibitory compound of formula (VIII) or (IX), respectively, by hydrogenolysis of the Cbz groups.
  • the invention further provides a method of use for a compound of formula (I) prepared from a compound of formula (II) or a crystalline form of formula (II), the method comprising administering the compound of formula (I) to a patient for treatment of a malcondition wherein selective inhibition of DPP- IV is indicated, or wherein the malcondition comprises diabetes or a disorder of glucose metabolism.
  • Scheme 1
  • Figure 1 shows a differential scanning calorimetry (DSC) trace of a sample of the crystalline form of the compound of formula (II).
  • Figure 2 shows a powder X-ray diffraction pattern of a sample of the crystalline form of the compound of formula (II).
  • Figure 3 shows a solution 1 H-NMR spectrum of the crystalline form of the compound of formula (II) dissolved in deuterochloroform.
  • Figure 4 shows a solution 13 C-NMR spectrum of the crystalline form of the compound of formula (II) dissolved in deuterochloroform.
  • An embodiment of the present invention provides a compound of formula (I),
  • the XPD pattern includes maxima at 2theta values as shown in Figure 2, selected maxima having approximate values of 6.16, 7.47, 8.52, 10.51, 14.24, 16.79, 17.13, 17.81, 18.30, 19.03, 20.51, 20.78, 22.43, 23.69, 25.18, 27.07, and 28.1084 degrees.
  • NMR spectra, proton and carbon- 13 respectively, are provided for the crystalline form of the compound of formula (II), dissolved in CDCl 3 .
  • the proton and carbon-13 NMR spectra are characteristic of the inventive crystalline form of the compound of formula (II), which is also a crystalline form of a compound of formula (I).
  • the crystalline form of the compound of formula (II) has a carbon-13 NMR spectrum taken in CDCl 3 solution substantially conforming to the following description ( ⁇ : 174.0, 156.4, 154.9, 154.5, 133.8, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.6, 127.1, 67.1, 66.7, 66.6, 55.6, 55.3, 54.8, 54.5, 52.4, 48.0, 47.7, 47.3, 44.4, 44.2, 29.1, 29.0, 28.4, 27.9, 25.1, 24.7.
  • a method of preparation of a compound of formula (I) and a compound of formula (II) is provided.
  • the dicyclohexylamine (DCHA) salt can be prepared by crystallization from an organic solution of the free acid combined with dicyclohexylamine.
  • the organic solution can comprise isopropyl acetate.
  • the organic solution can further comprise tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the compound of formula (I) or (II), respectively is contacted the pinanediol-protected boro-proline (V) under conditions suitable for formation of an amide bond.
  • Such conditions include but are not limited to mixed anhydrides such as formed with isobutylchloroformate, activated esters and dehydrating reagents such as N-hydroxytriazole / EDAC, Schotten Bauman conditions using acyl halides, as well as other reaction conditions known in the art.
  • a previously prepared solution of 20% sodium hydroxide (2.5 kg 2.1 L) in water (9.5 L) was added to the reaction mixture from the previous reaction while maintaining the temperature at 15-45 0 C.
  • the pH of the aqueous phase should be about 6.
  • the mixture was heated to reflux for 30 min, then cooled to 15-25 0 C.
  • the reaction mixture was allowed to stand for 30 min, and phase separation occurred.
  • the lower (aqueous) phase was separated and retained, and the organic (upper) phase was discarded.
  • An apparent third layer can be present which should be drawn off with the lower (aqueous) phase.
  • the aqueous phase was washed three times each with MTBE (2.0 L), each time retaining the aqueous (lower) layer with any apparent third, or emulsion, layer, while discarding the organic (upper) layer.
  • the retained solution or suspension was used directly in the next step.
  • the aqueous (lower) phase was again adjusted to pH 0.7-1.3 with concentrated hydrochloric acid, if necessary, and again extracted with isopropyl acetate (7.0 L) was added, the mixture stirred 30 min at 15-25 0 C, and allowed to stand for 30 min.
  • the organic (upper) phase was again separated and combined with the previous organic phase.
  • the concentration (C) of the free carboxylic acid in the isopropyl acetate solution was determined by HPLC, and the total weight (W) of the solution was determined.
  • the volume of the combined organic phases was adjusted with additional isopropyl acetate to 18 L, then tetrahydrofuran (1.0 L) and dicyclohexylamine (0.615 x C x W kg) were added with stirring.
  • Dicyclohexylammonium 1-Cbz-pyrrolidinyl-N-Cbz-glycinate 1.0 kg on a free acid basis
  • 1 -hydroxybenztriazole 0.454 kg
  • pinanediol-protected boro- proline 0.765 kg
  • N,N-dimethylformamide 3.0 L
  • EDAC 0.519 kg
  • ethyl acetate (7.0 L) and deionized water (10.0 L) were added to the reaction mixture, maintaining the reaction temperature at 15-25 0 C.
  • the mixture was stirred for 20 min, the phases allowed to separate, and the aqueous (lower) layer drawn off and discarded.
  • An additional 10.0 L of deionized water was added and the extraction repeated.
  • a previously prepared solution of sodium bicarbonate (0.37 kg) in deionized water (5.2 L) was added and the mixture stirred at 15-25 0 C, the phases allowed to separate, and the aqueous (lower) phase drawn off and discarded.
  • the concentrated solution from the previous reaction was diluted with methanol (7.0 L) at a temperature of 15-25 0 C, then palladium on carbon (5% Pd, 0.04 kg) was added and the mixture stirred. Then, hydrogen gas under a pressure of about 3 to about 9 bar (about 45 to about 135 psi) was introduced and the mixture stirred until the content of starting material was less than 0.4% (GC analysis).
  • the reaction mixture was filtered through a bed of cellulose (10.0) kg) and anhydrous sodium sulfate (0.4-1.7 kg) supported on a 0.45 micron filter, then the filter bed rinsed with methanol (1.3 L).
  • the methanol solution was concentrated under vacuum at a temperature of no more than 35°C to a final volume of about 2.0 L.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur des composés et sur des formes cristallines 1-benzyloxycarbonylpyrrolidin-3-yl-N-benzyloxycarbonylglycinate de dicyclohexylammonium, utiles comme d'un intermédiaire de synthèse dans la préparation de certains inhibiteurs sélectifs à base de boroproline de l'enzyme DPP-IV. L'invention porte également sur des procédés de préparation des composés et des formes cristallines, et sur des procédés d'utilisation des composés et des formes cristallines dans la préparation de certains inhibiteurs de DPP-IV.
PCT/US2009/031709 2008-01-25 2009-01-22 Intermédiaire synthétique cristallin pour des pyrrolidin-3-yl-glycylaminoalkylboronates Ceased WO2009094462A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2348708P 2008-01-25 2008-01-25
US61/023,487 2008-01-25

Publications (1)

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WO2009094462A1 true WO2009094462A1 (fr) 2009-07-30

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3496163A (en) * 1965-02-08 1970-02-17 Upjohn Co 7-halo-7-deoxylincomycins and process for preparing the same
US20070299036A1 (en) * 2003-11-12 2007-12-27 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-iv

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3496163A (en) * 1965-02-08 1970-02-17 Upjohn Co 7-halo-7-deoxylincomycins and process for preparing the same
US20070299036A1 (en) * 2003-11-12 2007-12-27 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-iv

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