WO2004035538A1 - Procede de fabrication de l'acide azetidine-3-carboxylique - Google Patents

Procede de fabrication de l'acide azetidine-3-carboxylique Download PDF

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WO2004035538A1
WO2004035538A1 PCT/US2003/032074 US0332074W WO2004035538A1 WO 2004035538 A1 WO2004035538 A1 WO 2004035538A1 US 0332074 W US0332074 W US 0332074W WO 2004035538 A1 WO2004035538 A1 WO 2004035538A1
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group
halo
compound
optionally substituted
formula
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PCT/US2003/032074
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Ross Miller
Fengrui Lang
Zhiguo Jake Song
Daniel Zewge
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Merck & Co., Inc.
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Priority to AU2003279915A priority Critical patent/AU2003279915A1/en
Publication of WO2004035538A1 publication Critical patent/WO2004035538A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • 3-carboxylic acid which is an intermediate useful for making certain SlPi/Edgl agonists.
  • Compounds that are SlPi/Edgl receptor agonists have immunosuppressive activities by producing lymphocyte sequestration in secondary lymphoid tissues.
  • SlPi/Edgl agonists are disclosed, for example, in WO 03/061567, WO 03/062248 and WO 03/062252, all of which published on July 31 , 2003.
  • Immunosuppressive agents have been shown to be useful in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis and asthma. They have also proved useful as part of chemotherapeutic regimens for the treatment of cancers, lymphomas and leukemias.
  • each of these conditions may be quite different, they have in common the appearance of a variety of autoantibodies and/or self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates.
  • the host lymphocytes recognize the foreign tissue antigens and begin to produce both cellular and humoral responses including antibodies, cytokines and cytotoxic lymphocytes which lead to graft rejection.
  • tissue destruction caused by inflammatory cells and the mediators they release.
  • Anti-inflammatory agents such as NS AIDs act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease.
  • cytotoxic agents such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb to infection as they are to their autoimmune disease.
  • Cyclosporin A is a drug used to prevent rejection of transplanted organs.
  • FK-506 is another drug approved for the prevention of transplant organ rejection, and in particular, liver transplantation. Cyclosporin A and FK-506 act by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. Cyclosporin A was approved for the treatment of severe psoriasis and has been approved by
  • Cyclosporin A and FK-506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort. Therefore, an immunosuppressant without these side effects still remains to be developed and would be highly desirable.
  • the immunosuppressive compound FTY720 is a lymphocyte sequestration agent currently in clinical trials.
  • FTY720 is metabolized in mammals to a compound that is a potent agonist of sphingosine 1 -phosphate receptors.
  • Agonism of sphingosine 1 -phosphate receptors induces the sequestration of lymphocytes (T-cells and B-cells) in lymph nodes and Peyer's patches without lymphodepletion.
  • lymphocytes T-cells and B-cells
  • Such immunosuppression is desirable to prevent rejection after organ transplantation and in the treatment of autoimmune disorders.
  • Sphingosine 1 -phosphate is a bioactive sphingolipid metabolite that is secreted by hematopoietic cells and stored and released from activated platelets.
  • Chem. 274:4626-4632 and inhibits chemotaxis by blocking Rac activation, see Okamoto, H., ⁇ . Takuwa, T. Yokomizo, ⁇ . Sugimoto, S. Sakurada, H. Shigematsu, and Y. Takuwa. 2000. Mol. Cell. Biol. 20:9247-9261.
  • SIP4 is localized to hematopoietic cells and tissues, see Graeler, M.H., G. Bernhardt, and M. Lipp. 1999. Curr. Top. Microbiol. Immunol. 246:131-6, whereas SIP5 is primarily a neuronal receptor with some expression in lymphoid tissue, see Im, D.S., C.E.
  • sphingosine 1-phosphate also has cardiovascular and bronchoconstrictor effects that limit its utility as a therapeutic agent.
  • Intravenous administration of sphingosine 1-phosphate decreases the heart rate, ventricular contraction and blood pressure in rats, see Sugiyama, A., N.N. Aye, Y. Yatomi, Y. Ozaki, and K. Hashimoto. 2000. Jpn. J. Pharmacol. 82:338-342.
  • hi human airway smooth muscle cells sphingosine 1-phosphate modulates contraction, cell growth and cytokine production that promote bronchoconstriction, airway inflammation and remodeling in asthma, see Ammit, A.J., A.T. Hastie, L. C.
  • An SlPi/Edgl receptor selective agonist has advantages over current therapies and extends the therapeutic window of lymphocytes sequestration agents, allowing better tolerability with higher dosing and thus improving efficacy as monotherapy.
  • immunosuppressants is in treating bone marrow, organ and transplant rejection
  • other uses for such compounds include the treatment of arthritis, in particular, rheumatoid arthritis, insulin and non-insulin dependent diabetes, multiple sclerosis, psoriasis, inflammatory bowel disease, Crohn's disease, lupus erythematosis and the like.
  • Azetidine-3-carboxylic acid is an intermediate useful in the preparation of certain SlPi/Edgl receptor agonists described in the above patent applications.
  • Known methods for making azetidine-3-carboxylic acid and related compounds are described in Anderson, et. al., J. Org. Chem., 1972, 3953, JP 62081367, EP 0165636, EP 0199413, EP 0190786 and EP 0169603.
  • the productivity of these known processes are not high and rely on the use of highly toxic reagents, it was impractical for large scale preparation of this compound.
  • the present invention provides for an improved process for synthesizing azetidine-3- carboxylic acid, which avoids the use of toxic chemicals, such as cyanide and epi chlorohydrin.
  • the improved process is also shorter in length, operationally more simple and uses readily- available reagents that are economically viable as compared to the processes known described in the art.
  • the present invention is directed to an improved process for synthesizing azetidine-3-carboxylic acid, comprising triflating diethylbis(hydroxymethyl)malonate followed by azetidine ring-formation by intramolecular cyclization using an amine, decarboxylation to give the mono acid azetidine and hydrogenation to give the title compound.
  • Azetidine-3- carboxylic acid is useful as an intermediate for making certain SlPj/Edgl receptor agonists, which are immunosupressive agents.
  • the present invention encompasses a method for making a compound of formula A
  • Ra and Rb are each independently selected from the group consisting of:
  • items (1) to (4) above are each optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, cyano, C3_6cycloalkyl, phenyl, naphthyl, HET2 and Cj ⁇ alkoxy, said C3_6cycloalkyl, phenyl, naphthyl, HET2 and C ⁇ alkoxy groups optionally substituted with 1-3 substituents independently selected from halo, hydroxy, nitro, cyano, C ⁇ _4alkoxy and C ⁇ _4alkylthio, said phenyl, naphthyl and HET2 further optionally substituted with C i _4alkyl ;
  • HETl and HET2 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl
  • R-NH2 D wherein R is selected from the group consisting of: allyl or benzyl, the phenyl portion of benzyl being optionally substituted with 1-5 substituents independently selected from the group consiting of: C ⁇ _4alkyl, haloC ⁇ _4alkyl, halo, hydroxy, cyano, nitro, Ci_4alkoxy, and Ci-4alkylthio,
  • halogen or halo includes F, CI, Br, and I.
  • alkyl means linear or branched structures and combinations thereof, having the indicated number of carbon atoms.
  • Ci- ⁇ alkyl includes methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • haloalkyl means alkyl defined as above with one or more hydrogen atoms substituted with a halo group as defined above. The halo groups can be the same or different.
  • alkoxy means alkoxy groups of a straight, branched or cyclic configuration having the indicated number of carbon atoms.
  • Ci- ⁇ alkoxy for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • alkylthio means alkylthio groups having the indicated number of carbon atoms of a straight, branched or cyclic configuration.
  • C ⁇ _6alkylthio for example, includes methylthio, propylthio, isopropylthio, and the like.
  • alkenyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon double bond, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond.
  • C2-6alkenyl for example, includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.
  • alkynyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon triple bond.
  • C3- galkynyl' f° r example includes, propenyl, 1-methylethenyl, butenyl and the like.
  • cycloalkyl means mono-, bi- or tri-cyclic structures, optionally combined with linear or branched structures, the indicated number of carbon atoms.
  • cycloalkyl groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-l- bicyclo[4.4.0]decyl, and the like.
  • the terms "acidic condition,” “neutral condition” and “basic condition” mean that the pH during the reaction is adjusted accordingly by adding, for example, an acid or a base. The selection of the appropriate acid or base is well within the skill of one having ordinary skill in the art and exemplified in the example below. For example, in step 2) basic conditions can be achieved by adding N,N-disopropylethylamine.
  • step 1) the compound of formula B is commercially available or can be made by procedures known in the art.
  • bis(hydroxymethyl)malonate is commercially available or easily made from diethylmalonate.
  • Compounds of formula B can also be prepared by following the procedures in museumseau, et al., Synthesis, 1987, 1281.
  • the terms "chloronating agent”, “bromonating agent” and “iodonating agent” mean compounds that are capable of providing chlorine, bromine or iodine to replace the hydroxy group in the compound of formula B. Examples of these agents are hydrogen halides or phosphorous halides.
  • alkyl halides from alcohols. Such techniques are disclosed, for example, in Larock, R.C., Comprehensive Organic Transformations, 2nd ed., 1999, pp. 689-701.
  • the compounds RC-S(O)2-halo or R c -S(O)2-O-S(O)2-R c are also commercially available or can be readily made by utilizing procedures known in the art. Examples include p- tolunesulfonyl chloride or trifluoromethanesulfonic acid anhydride. Methods for making the compounds RC-S(O)2-halo or RC-S(O)2-O-S(O)2-R c are described in, for example, Stang, P.J. et al., Synthesis, 1982, pp. 82-126.
  • R-NH2 for example benzylamine
  • R-NH2 are also either commercially available or can be made by procedures known in the art, as described in, for example, Larock, R.C., Comprehensive Organic Transformations, 2nd ed., 1999, pp. 753-880.
  • elevated temperature means above about 50 °C, preferably in the range of about 50 °C to about 200 °C, more preferably in the range of about 90 °C to about 100 °C. , _____
  • hydrohalogenating agent in the presence of a catalyst is well understood by one having skill in the art for replacing the group R in the compound of formula H with hydrogen.
  • examples include molecular hydrogen in the presence of Pd(OH)2 or formic acid in the presence of palladium.
  • Other techniques for hydrogenation that can be utilized in the present invention are described in Rylander, P.N., Catalytic Hydrogenation in Organic Syntheses, 1979, pp. 271-285.
  • An embodiment of the invention encompasses the above method wherein the compound of formula B is reacted with RC-S(O)2-O-S(O)2-R c in step 1) to yield a compound of formula C wherein l is -O-S(O)2-R c -
  • R c is selected from -toluene, /?-bromophenyl, methyl or trifluoromethyl.
  • step 1) wherein the compound of formula B is reacted with R c -S(O)2-O-S(O)2-R c in step 1) in a first polar aprotic solvent selected from the group consisitng of: acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, N,N- dimethylacetamide and N-methylpyrrolidone, or a mixture thereof, to yield a compound of formula C.
  • a first polar aprotic solvent selected from the group consisitng of: acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, N,N- dimethylacetamide and N-methylpyrrolidone, or a mixture thereof, to yield a compound of formula C.
  • step 2) is reacted with a compound of formula D in in a second polar aprotic solvent selected from the group consisitng of: acetonitrile, dimethylsulfoxide, N,N- dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, or a mixture thereof, to yield a compound of formula E.
  • a second polar aprotic solvent selected from the group consisitng of: acetonitrile, dimethylsulfoxide, N,N- dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, or a mixture thereof, to yield a compound of formula E.
  • the first polar aprotic solvent and second polar aprotic solvent are acetonitrile.
  • step 1) and step 2) are conducted at a low temperature in the range of about -20 °C to about 0 °C.
  • R is benzyl.
  • R a and Rb are each independently Ci-6alkyl.
  • Z as the "corresponding cation of the inorganic base" is well understood by the ordinarily skilled artisan, typically meaning the alkali metal or alkaline earth metal portion of the inorganic base. For example, if the inorganic base is NaOH, then Z is Na. If the inorganic base is KOH, Z is K.
  • the inorganic base can be a basic salt of an alkali metal or an alkaline earth metal.
  • the inorganic base can be selected from the group consisting of alkali metal hydroxides, oxides, carbonates, and bicarbonates.
  • Exemplary bases include LiOH, NaOH, KOH, L1HCO3, NaHCO3, KHCO3, Na2 ⁇ , K2O, Li2CO3, Na2CO3, and K2CO3.
  • the inorganic base can be in the form of a hydrate or it can be anhydrous (e.g., anhydrous LiOH).
  • the inorganic base is selected from the group consisting of: LiOH, NaOH, KOH, LiHCO3, NaHCO3, KHCO3, Na2 ⁇ , K2O, Li2CO3, Na2CO3, and K2CO3. Also within this embodiment is encompassed the above method wherein the inorganic base is NaOH and is reacted with the compound of formula E in an alcohol solvent. Also within this embodiment is encompassed the above method wherein the alcohol solvent is methanol.
  • the invention also encompasses the above method wherein the acid reacted with the compound of formula F is selected from the group consisting of: acetic acid, formic acid, hydriodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, nitric acid, hypochlorous acid, chlorous acid chloric acid, perchloric acid, phosphoric acid, sulfuric acid and sulfurous acid.
  • the acid is hydrochloric acid.
  • Another embodiment of the invention encompasses the above method wherein the elevated temperature is in the range of about 50 °C to about 200 °C. Another embodiment of the invention encompasses the above method wherein the elevated temperature is in the range of about 90 °C to about 100 °C. Another embodiment of the invention encompasses the above method wherein the hydrogenating agent is molecular hydrogen and the catalyst is Pd(OH)2-
  • Another embodiment of the invention encompasses the above method wherein the hydrogenating agent is formic acid and the catalyst is palladium.
  • the invention also encompasses a method for making azetidine-3-carboxylic acid comprising
  • Another embodiment of the invention encompasses a process for making a compound of formula ⁇
  • n O;
  • Y is a bond, -O- or -S(O)k-, wherein k is 0, 1 or 2;
  • each R3 is independently selected from the group consisting of: hydrogen and C ⁇ _4alkyl, said Ci-4alkyl optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Ci-4alkoxy and carboxy;
  • each R4 is independently selected from the group consisting of: halo, hydroxy, C ⁇ _4alkyl and Cj ⁇ alkoxy, said C ⁇ alkyl and Ci ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;
  • each R is independently selected from the group consisting of:
  • items (e) to (j) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy and Cj ⁇ alkoxy, said Cj ⁇ alkoxy group optionally substituted from one up to the maximum number of substitutable positions with halo, and
  • items (k) and (1) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Ci ⁇ alkyl and C ⁇ alkoxy, said Cj ⁇ alkyl and Cj ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;
  • R6 is selected from the group consisting of: (1) hydrogen
  • items (4) to (6) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C3_6cycloalkyl, phenyl, HET3 and Cj ⁇ alkoxy, said C3_ ⁇ cycloalkyl, phenyl, HET3 and Cj ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,
  • item (7) above is optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, phenyl, HET4 and C ⁇ _3alkoxy, said phenyl, HET4 and Ci ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo, and
  • items (8) and (9) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C ⁇ _4alkyl and Cj ⁇ alkoxy, said C]i -4alkyl and Cj ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,
  • R6 is not halo or cyano when Y is -O- or -S(O)k ⁇ ; or R6 and one R5 group or two R5 groups may be joined together to form a five or six-membered monocyclic ring optionally containing 1 or 2 heteroatoms selected from the group consisting of: O, S, or N(R7),
  • each R7 is independently hydrogen or Cl-4alkyl, said C ⁇ _4alkyl optionally substituted substituted from one up to the maximum number of substitutable positions with halo;
  • HETl, HET2, HET3 and HET4 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl
  • azetidine-3-carboxylic acid made according to any of the above processes and a reducing agent in a compatible solvent to yield a compound of Formula H
  • the reducing agent is selected from the group consisiting of: sodium cyanoborohydride, sodium triacetoxyborohydride and sodium borohydride
  • the compatible solvent is selected from the group consisitng of: methanol, ethanol, acetonitrile and methylene chloride.
  • Another embodiment of the invention encompasses a process for making a compound of Formula II
  • n 0;
  • Y is a bond, -O- or -S(O)k-, wherein k is 0, 1 or 2;
  • each R3 is independently selected from the group consisting of: hydrogen and C ⁇ _4alkyl, said C ⁇ _4alkyl optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Ci_4alkoxy and carboxy;
  • each R4 is independently selected from the group consisting of: halo, hydroxy, Cj ⁇ alkyl and C ⁇ _3alkoxy, said C ⁇ alkyl and C ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;
  • each R5 is independently selected from the group consisting of:
  • items (e) to (j) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy and Cj ⁇ alkoxy, said C ⁇ alkoxy group optionally substituted from one up to the maximum number of substitutable positions with halo, and
  • items (k) and (1) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cj ⁇ alkyl and Cj ⁇ alkoxy, said Cj ⁇ alkyl and Cj ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;
  • R6 is selected from the group consisting of: (1) hydrogen
  • items (4) to (6) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C3_6cycloalkyl, phenyl, HET3 and Cj ⁇ alkoxy, said C3- ⁇ cycloalkyl, phenyl, HET3 and Cj ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,
  • item (7) above is optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, phenyl, HET4 and Cj ⁇ alkoxy, said phenyl, HET4 and Cj ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo, and
  • items (8) and (9) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, Cj ⁇ alkyl and Cj ⁇ alkoxy, said Cj ⁇ alkyl and C ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,
  • R6 is not halo or cyano when Y is -O- or -S(O)k-; or
  • R6 and one R5 group or two R groups may be joined together to form a five or six-membered monocyclic ring optionally containing 1 or 2 heteroatoms selected from the group consisting of: O, S, or N(R7),
  • each R7 is independently hydrogen or C ⁇ _4alkyl, said C ⁇ _4alkyl optionally substituted substituted from one up to the maximum number of substitutable positions with halo;
  • HETl, HET2, HET and HET4 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,
  • azetidine-3-carboxylic acid made according to any of the above processes and a weak base in a compatible solvent at or above about room temperature to yield a compound of Formula II.
  • the weak base is selected from the group consisting of: sodium carbonate, potassium carbonate, triethylamine, and N,N- diisopropylethylamine
  • the compatible solvent is selected from the group consisting of: methanol, ethanol and acetonitrile.
  • Another embodiemnt of the invention encompasses a process for making a compound of Formula I
  • Ar is phenyl or naphthyl
  • n 0;
  • A is -CO2H; Rl and R2 are each hydrogen;
  • R is selected from the group consisting of: hydrogen and C ⁇ _4alkyl, optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo and hydroxy;
  • each R4 is independently selected from the group consisting of: halo, C j ⁇ alkyl and C j ⁇ alkoxy, said C ⁇ 4alkyl and C 1-3 alkoxy optionally substituted from one up to the maximum number of substitutable positions with halo,
  • C is selected from the group consisting of:
  • Ci-8alkyl, C__8alkoxy, -(C O)-C ⁇ .galkyl or -CHOH-C ⁇ _6alkyl, said Ci_
  • B is selected from the group consisting of: phenyl, C5- ⁇ galkyl, C5-
  • R6 and R7 are independently selected from the group consisting of: hydrogen, Ci-9alkyl and - (CH2)p-phenyl, wherein p is 1 to 5 and phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: Ci-3alkyl and Ci_3alkoxy, each optionally substituted with 1-3 halo groups,
  • azetidine-3-carboxylic acid made according to any of the above processes and a reducing agent in a compatible solvent to yield a compound of Fomiula I.
  • the reducing agent is selected from the group consisiting of: sodium cyanoborohydride, sodium triacetoxyborohydride and sodium borohydride
  • the compatible solvent is selected from the group consisitng of: methanol, ethanol, acetonitrile and methylene chloride.
  • Another embodiment of the invention encompasses a process for making a compound of Formula I
  • Ar is phenyl or naphthyl
  • n 0;
  • A is -CO2H
  • Rl and R2 are each hydrogen
  • R3 is selected from the group consisting of: hydrogen and C ⁇ _4alkyl, optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo and hydroxy;
  • each R4 is independently selected from the group consisting of: halo, Ci ⁇ alkyl and Cj ⁇ alkoxy, said Cj ⁇ alkyl and Cj ⁇ alkoxy optionally substituted from one up to the maximum number of substitutable positions with halo,
  • C is selected from the group consisting of:
  • B is selected from the group consisting of: phenyl, C5-i6alkyl, C5- I ⁇ alkenyl, Cs-igalkynyl, -CHOH-C 4 - 1 5alkyl, -CHOH-C 4 -i5alkenyl, -CHOH-C - 15 alkynyl, C4-15alkoxy, -O-C4_i5alkenyl, -O-C4_i5alkynyl, C4_ ⁇ 5alkylthio, -S-C4_ 15 alkenyl, -S-G ⁇ .
  • R6 and R7 are independently selected from the group consisting of: hydrogen, Ci-9alkyl and - (CH2)p-phenyl, wherein p is 1 to 5 and phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: C ⁇ -3alkyl and C ⁇ _3alkoxy, each optionally substituted with 1-3 halo groups,
  • X is selected from the group consisting of: Br, CI, I, -O-Rd, wherein Rd is tosyl, brosyl, mesyl or trifyl,
  • azetidine-3-carboxylic acid made according to any of the above methods and a weak base in a compatible solvent at or above about room temperature to yield a compound of Formula I.
  • the invention also encompasses the above process wherein wherein the weak base is selected from the group consisting of: sodium carbonate, potassium carbonate, triethylamine, and N,N- diisopropylethylamine and the compatible solvent is selected from the group consisting of: methanol, ethanol and acetonitrile.
  • Quantitative assay of the toluene layer gave a yield of 86% (AR). pH of aqueous layer was 9-10, loss in aqueous layers was less than 2%. Organic layer was concentrated to 20 % of its original volume at 45 °C under reduced pressure, and 3 x 20 L of MeOH used for solvent switch. Batch final volume was 40 L. Amount of toluene at the end of solvent switch was determined to be 6 v % by GC (AR). The methanol solution of diester 5 was directly used in the subsequent step.
  • the wet solid was mixed with 28 L methanol and stirred overnight at room temperature.
  • the solid was filtered and washed with 2x12L methanol.
  • the solid was dried in vacuum oven at room temperature overnight, giving 3.61 kg (approx 90wt% pure, 3.25 kg pure basis) disodium salt 6 as an off- white solid.
  • the azetidine malonate was not sufficiently crystalline to isolate, therefore the malonate was hydrolyzed directly to the highly crystalline bis sodium salt using methanolic sodium hydroxide in 74% overall yield from (1). Acidification with HC1 gave the crystalline diacid in 61% isolated yield from diethyl (bis)hydroxymethylmalonate.
  • Ar is phenyl or naphthyl
  • n 0 or 1;
  • A is selected from the group consisting of: -CO2H, -PO3H2, -PO2H, -SO3H, -PO(C!-3alkyl)OH and lH-tetrazol-5-yl;
  • Rl and R2 are each independently selected from the group consisting of: hydrogen, halo, hydroxy, -CO2 ⁇ and Ci-4alkyl, optionally substituted from one up to the maximum number of substitutable positions with halo;
  • R3 is selected from the group consisting of: hydrogen and Ci-4alkyl, optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo and hydroxy;
  • each R is independently selected from the group consisting of: halo, C ⁇ alkyl and C j ⁇ alkoxy, said Cj ⁇ alkyl and C 1-3 alkoxy optionally substituted from one up to the maximum number of substitutable positions with halo,
  • C is selected from the group consisting of: (1) C salkyi, C ⁇ _8alkoxy, or -CHOH-C ⁇ _6alkyl, said C ⁇ _
  • phenyl or HET each optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, phenyl, C j - 4alkyl and C ⁇ alkoxy, said Cj ⁇ alkyl and Cj ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from halo and hydroxy, and said phenyl optionally substituted with 1 to 5 groups independently selected from the group consisting of : halo and Ci-4alkyl, optionally substituted with 1-3 halo groups, or C is not present;
  • B is selected from the group consisting of: phenyl, C5- ⁇ galkyl, C5- 16 alkenyl, Cs-igalkynyl, -CHOH-C 4 -i5alkyl, -CHOH-C4-i5alkenyl, -CHOH ⁇ -j ⁇ alkynyl, C4_i5alkoxy, -O-C4_ ⁇ alkenyl, -O-C4_i5alkynyl, 04.
  • R6 and R7 are independently selected from the group consisting of: hydrogen, C ⁇ alkyl and - (CH2)p-phenyl, wherein p is 1 to 5 and phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: Ci ⁇ 3alkyl and C ⁇ _3alkoxy, each optionally substituted with 1-3 halo groups.
  • n 0 or 1 ;
  • Y is a bond, -O- or -S(O)k-, wherein k is 0, 1 or 2;
  • each R3 is independently selected from the group consisting of: hydrogen and C ⁇ _4alkyl, said Ci-4alkyl optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C ⁇ _4alkoxy and carboxy;
  • each R4 is independently selected from the group consisting of: halo, hydroxy, C j ⁇ alkyl and C ⁇ alkoxy, said C ⁇ alkyl and Cj ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;
  • each R5 is independently selected from the group consisting of:
  • Ci_6alkyl-S(O)k- wherein k is 0, 1 or 2
  • items (e) to (j) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy and C ⁇ alkoxy, said C ⁇ alkoxy group optionally substituted from one up to the maximum number of substitutable positions with halo, and
  • items (k) and (1) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C ⁇ alkyl and C ⁇ alkoxy, said C ⁇ alkyl and Cj ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo;
  • R6 is selected from the group consisting of:
  • items (4) to (6) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C3_6cycloalkyl, phenyl, HET3 and Cj ⁇ alkoxy, said C3- ⁇ cycloalkyl, phenyl, HET3 and Cj ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,
  • item (7) above is optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, phenyl, HET4 and Cj ⁇ alkoxy, said phenyl, HET4 and Cj ⁇ alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo, and
  • items (8) and (9) above are each optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: halo, hydroxy, C ⁇ alkyl and C ⁇ alkoxy, said C ⁇ alkyl and Cj_3alkoxy groups optionally substituted from one up to the maximum number of substitutable positions with halo,
  • R6 is not halo or cyano when Y is -O- or -S(O)k-;
  • R6 and one R5 group or two R5 groups may be joined together to form a five or six-membered monocyclic ring optionally containing 1 or 2 heteroatoms selected from the group consisting of: O, S, or N(R7),
  • each R7 is independently hydrogen or C ⁇ _4alkyl, said Ci_4alkyl optionally substituted substituted from one up to the maximum number of substitutable positions with halo;
  • HETl, HET2, HET3 and HET4 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl
  • the compounds of Formula ⁇ can be synthesized by the following synthetic routes:
  • intermediates A-i can be combined with a benzyl halide or sulfonate ester A-iv in the presence of an appropriate base (e.g., sodium carbonate, potassium carbonate, triethylamine, N,N-diisopropylethylamine) in a compatible solvent solvent (e.g., methanol, ethanol, acetonitrile) at or above room temperature to give compounds of Formula II.
  • an appropriate base e.g., sodium carbonate, potassium carbonate, triethylamine, N,N-diisopropylethylamine
  • a compatible solvent solvent e.g., methanol, ethanol, acetonitrile
  • the individual stereoisomers of Formula II can obtained by methods known to those skilled in the art which include (but are not limited to): stereospecific synthesis, resolution of salts of Formula II or any of the intermediates used in its preparation with enantiopure acids or bases, resolution of Formula II or any of the intermediates used in its preparation by HPLC employing enantiopure stationary phases.
  • solvent X -CI, -Br, -I, or -OS0 2 R
  • An alternative method to activate the benzoic acid A-vii would be to convert it to the corresponding benzoyl chloride (e.g., by warming A-vii in the presence of thionyl chloride or by treating A-vii with oxalyl chloride and catalytic N,N-dimethyl formamide in a suitable solvent).
  • benzoic acids A-vii that can be used to prepare intermediates A-ii are available from commercial sources. Some methods that can be employed to prepare benzoic acids A-vii are depicted in Scheme 3. In cases where R is alkyl and Y is -O-, phenol A-ix can be treated with an alkyl halide or alkyl sulfonate ester in the presence of base (e.g., triethylamine, sodium bicarbonate, potassium carbonate) in a suitable solvent (e.g., THF, acetonitrile, methanol, ethanol) at or above room temperature to afford ether A-x.
  • base e.g., triethylamine, sodium bicarbonate, potassium carbonate
  • a suitable solvent e.g., THF, acetonitrile, methanol, ethanol
  • A-ix in which the carboxylate is masked as B (e.g., B could be a carboxylate ester, aldehyde, nitrile, etc.) which would then be subsequently transformed to a carboxylic acid using methods known to those skilled in the art (see Larock, "Comprehensive Organic Transformations, A Guide to Functional Group Preparations", VCH Publishers, Inc.).
  • Alternative methods to prepare A-x could involve treating A-ix with an alcohol, triphenylphosphine and a dialkyl azodicarboxylate (e.g., diethyl azodicarboxylate or diisopropyl azodicarboxylate) in a suitable solvent (THF, CH 2 C1 2 , toluene) to give A-x.
  • a dialkyl azodicarboxylate e.g., diethyl azodicarboxylate or diisopropyl azodicarboxylate
  • THF a suitable solvent
  • Another method to prepare A-x could be to treat aryl fluoride A- xii with an alcohol and a strong base (NaH, KH, lithium diisopropylamide) in a suitable solvent (THF, 1,2-dimethoxyethane) to give A-x.
  • A-ix in which the carboxylate is masked as B (e.g., B could be nitrile, vinyl, aldehyde acetal, etc.) which would then be subsequently transformed to a carboxylic acid using methods known to those skilled in the art (see Larock, "Comprehensive Organic Transformations, A Guide to Functional Group Preparations", VCH Publishers, Inc.).
  • R 6 is alkyl and Y is -O-
  • R 6 is alkyl and Y is a bond
  • Aldehyde A-l 4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde
  • Step B 4-(5-(4-(2-Methylpropyl)phenyl)-1.2.4-oxadiazol-3-yl)phenylmethanol
  • Step C 4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde
  • Aldehyde A-3 4-(5-(4-Hexylphenyl)- 1 ,2,4-oxadiazol-3-yl)benzaldehyde
  • Aldehyde A-7 4-(5-( 1 , 1 -Biphen-4-yl)- 1 ,2,4-oxadiazol-3-yl)benzaldehyde
  • Aldehyde A-8 4-(5-(4-(2-Furyl) ⁇ henyl)-l,2,4-oxadiazol-3-yl)benzaldehyde
  • Aldehyde A-10 ( ⁇ )-4-(5-(4-(l-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde
  • Aldehyde A-11 4-(5-(4-( 1 , 1 -Dimethylpropyl)phenyl)- 1 ,2,4-oxadiazol-3-yl)benzaldehyde
  • Aldehyde A-12 4-(5-(4-(l,l-Dimethylethyl)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde
  • Step C 4-(5-(4-(2,2-Dimethylpropyl)phenyl)-l,2,4-oxadiazol-3- vDbenzaldehvde
  • the title compound was prepared using a procedure analogous to Aldehyde A-l substituting 4-(2,2-dimethylpropyl)benzoic acid (from Step B above) for 4-(2- methylpropyl)benzoic acid in Aldehyde A-l, Step B: ESI-MS 321 (M+H); LC-1: 4.7 min.
  • Aldehyde A- 16 4-(5-(4-(3,3,3-Trifluoropropyl)phenyl)-l,2,4-oxadiazol-3-y)benzaldehyde
  • the title compound was prepared using procedures analogous to those described for Aldehyde A-15 substituting l-bromo-3,3,3-trifiuoropropane for l-bromo-2,2-dimethylpropane in Step A: ESI-MS 347 (M+H); LC-1: 4.0 min.
  • Aldehyde A-17 4-(5-(4-(3,3,3-Trifluorobutyl)phenyl)-l,2,4-oxadiazol-3-y)benzaldehyde
  • Step A 3-(4-Bromo-2-methylphenyl)-5-(4-(2-methylpropyl)phenyl)-l ,2,4- xadiazole
  • Step B 4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)-3-methyl benzonitrile
  • Step C 4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)-3- methyl benzaldehvde
  • Aldehyde A-21 4-(5-(4-(2-(S)-Butoxy)-3-trifluoromethylphenyl)- 1 ,2,4-oxadiazol-3-yl) benzaldehyde
  • Step C 4-(5-(4-(2-(S)-Butoxy)-3-trifluoromethylphenyl)- 1,2,4- oxadiazol-3-yl)phenylmethanol
  • Step D 4-(5-(4-(2-(S)-Butoxy)-3-trifluoromethylphenyl)-l,2,4-oxadiazol-3- vPbenzaldehyde
  • Step B 3-Fluoro-4-(2-(S)-butoxy)benzoic acid
  • Step C 4-(5-(4-(2-(S)-Butoxv)-3-fluoro ⁇ henyl)-l,2.4-oxadiazol-3-vl) benzaldehvde
  • Step A) 106 mg (0.9 mmol) of zinc cyanide, 69 mg of tris(dibenzylideneacetone)dipalladium(0) and 100 mg (0.18 mmol) of l,l'-bis(diphenylphosino)ferrocene in 3 mL of DMF and 30 ⁇ L of water. The resulting solution was heated to 80 °C for 1 h and then cooled and concentrated.
  • Step C 3 ,5-Difluoro-4-(2-(S)-butoxy)benzoic acid
  • Step D 4-(5-(4-(2-(S)-Butoxy)-3,5-di-fluorophenyl)-l,2,4-oxadiazol-3-yl) benzaldehvde
  • Step C 4-(5-(4-(2-(S)-Butoxy)phenyl)-1.2.4-oxadiazol-3-yl)benzaldehvde
  • Aldehyde A-26 4-(5-(4-(Cyclobutoxy)phenyl)-l,2,4-oxadiazol-3-yl)benzaldehyde
  • Step A ( ⁇ )-4-(5-(4-(2-Methylpropyl)phenyl)-l,2,4-oxadiazol-3-yl)-l-(l- hvdroxyethvDbenzene
  • Step B 4-(5-(4-(2-Methylpropyl)phenyl)-1.2,4-oxadiazol-3-yl)acetophenone
  • the title compound was prepared using a procedure analogous to that described in
  • Step C aVl- ⁇ -r4-(5-(4-(l.l-Dimethvlethvl)phenvlV1.2.4-oxadiazol-3-yl)phenyl)ethvD azetidine-3-carboxylic acid
  • aryl is defined as a mono- or bi-cyclic aromatic ring system and includes, for example, phenyl, naphthyl, and the like.
  • aralkyl means an alkyl group as defined above of 1 to 6 carbon atoms with an aryl group as defined above substituted for one of the alkyl hydrogen atoms, for example, benzyl and the like.
  • aryloxy means an aryl group as defined above attached to a molecule by an oxygen atom (aryl-O) and includes, for example, phenoxy, naphthoxy and the like.
  • aralkoxy means an aralkyl group as defined above attached to a molecule by an oxygen atom (aralkyl-O) and includes, for example, benzyloxy, and the like.
  • arylthio is defined as an aryl group as defined above attached to a molecule by an sulfur atom (aryl-S) and includes, for example, thiophenyoxy, thionaphthoxy and the like.
  • aroyl means an aryl group as defined above attached to a molecule by an carbonyl group (aryl-C(O)-) and includes, for example, benzoyl, naphthoyl and the like.
  • aroyloxy means an aroyl group as defined above attached to a molecule by an oxygen atom (aroyl-O) and includes, for example, benzoyloxy or benzoxy, naphthoyloxy and the like.
  • HET is defined as a 5- to 10-membered aromatic, partially aromatic or non-aromatic mono- or bicyclic ring, containing 1-5 heteroatoms selected from O, S and N, and optionally substituted with 1-2 oxo groups.
  • HET is a 5- or 6-membered aromatic or non-aromatic monocyclic ring containing 1-3 heteroatoms selected from O, S and N, for example, pyridine, pyrimidine, pyridazine, furan, thiophene, thiazole, oxazole, isooxazole and the like, or heterocycle is a 9- or 10-membered aromatic or partially aromatic bicyclic ring containing 1-3 heteroatoms selected from O, S, and N, for example, benzofuran, benzothiophene, indole, pyranopyrrole, benzopyran, quionoline, benzocyclohexyl, naphtyridine and the like.
  • HAT also includes the following: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thien
  • a preferred group of HET is as follows:

Abstract

La présente invention porte sur un procédé amélioré visant à synthétiser l'acide azétidine-3-carboxylique, ce procédé consistant à triflater un diéthylbis(hydroxyméthyl)malonate, puis à former un noyau d'azétidine par cyclisation intramoléculaire en utilisant un amine, par décarboxylation pour obtenir un mono acide azétidine et par hydrogénation pour obtenir le composé précité. L'acide azétidine-3-carboxylique est utile comme intermédiaire dans la fabrication de certains agonistes du récepteur S1P1/Edg1 qui sont des agents immunosuppresseurs.
PCT/US2003/032074 2002-10-15 2003-10-10 Procede de fabrication de l'acide azetidine-3-carboxylique WO2004035538A1 (fr)

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