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WO2011156355A1 - Procédé de production de sels de phénylguanidine et de leurs intermédiaires - Google Patents

Procédé de production de sels de phénylguanidine et de leurs intermédiaires Download PDF

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Publication number
WO2011156355A1
WO2011156355A1 PCT/US2011/039420 US2011039420W WO2011156355A1 WO 2011156355 A1 WO2011156355 A1 WO 2011156355A1 US 2011039420 W US2011039420 W US 2011039420W WO 2011156355 A1 WO2011156355 A1 WO 2011156355A1
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Prior art keywords
compound
formula
represented
treating
reaction
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PCT/US2011/039420
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English (en)
Inventor
Michael Ross Johnson
Myung-Chol Kang
Brian L. Bray
Stephen Schneider
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Kainos Medicine Inc
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Kainos Medicine Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms

Definitions

  • the present invention relates to novel methods for producing phenyl guanidine salts having pharmacological activity, as well as compounds useful as intermediates for producing various compounds having pharmacological activity.
  • a compound of Formula I is under development for multiple indications, including chronic bronchitis, cystic fibrosis, dry eye, and dry mouth (xerostomia) associated with Sjogren's syndrome. This compound is a new chemical entity that belongs to a family of compounds referred to as
  • pyrazinoylguanidines Several regions of a compound of Formula I confer binding specificity to the epithelial sodium channel. These regions include the 6-chloro and 5- amino substituents on the pyrazine ring, and the guanidine group which retains a positive charge at physiological pH and exhibits a pKa that is equal to 8.4 at 37°C.
  • the compounds of Formula I are capable of forming a wide variety of different salts, and thus, can be in the form of a pharmaceutically acceptable salt.
  • the compound of Formula I is present as the mesylate salt and has a molecular weight of 548.01 daltons and the empirical formula C 3 oH 3 oCIN 7 0 7 S. SUMMARY OF THE INVENTION
  • this invention in one aspect, relates to robust and scaleable methods for the synthesis of compounds of Formula I (individually or together referred to hereinafter as "active compounds").
  • active compounds compounds which are useful as intermediates for producing compounds having pharmacological activity.
  • the active compounds are synthesized using a convergent route strategy. The inventors discovered that the active compounds can be synthesized using, as a key intermediate, compound 5.
  • the present invention provides the following.
  • Solvents useful in producing compounds having pharmacological activity include, but are not limited to, water, acetates (e.g., ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate), ethers (e.g., diethyl, methyl-tert-butyl), acetonitrile, tetrahydrofuran (THF), /V,/V-dimethylformamide (DMF), acetone, an alcohol (e.g., methanol, ethanol, isopropyl alcohol), dioxane, heptane, toluene, and the like.
  • Reducing agents useful in producing compounds having pharmacological activity include, but are not limited to, lithium aluminum hydride, boranes, and
  • PG protecting group
  • Cbz carbobenzyloxyl protecting group
  • Fmoc 9H-fluoren-9-yl)methyloxycarbonyl
  • tBoc tert- butyloxycarbonyl
  • the active compounds may be described as forming a variety of different salts with various inorganic or organic acids. Salts of the base form of the active compounds are readily prepared by treating the base compound with an amount of the chosen acid, such as in a solvent or suitable medium, to obtain the desired solid salt.
  • Suitable acids are those which can be used to form non-toxic acid addition salts (e.g., salts containing pharmacologically acceptable anions, including but not limited to acetate, ascorbate, aspartate, benzoate, citrate, glutamate, halide, lactate, maleate, mesylate, nitrate, phosphate, succinate, sulfate, sulfonate, tartrate, and the like).
  • non-toxic acid addition salts e.g., salts containing pharmacologically acceptable anions, including but not limited to acetate, ascorbate, aspartate, benzoate, citrate, glutamate, halide, lactate, maleate, mesylate, nitrate, phosphate, succinate, sulfate, sulfonate, tartrate, and the like).
  • Scheme 1 depicts the synthesis of compound 5a, an important intermediate for the synthesis of the active compounds using the methods of the present invention.
  • the carboxylic acid group in commercial compound 1 4-methoxyphenylbutyric acid, was activated by reaction with iso-butylchloroformate, the product of which was treated in situ with methanolic ammonia to afford amide, compound 2.
  • the amide group in compound 2 was reduced to its corresponding amine by borane-THF complex or lithium aluminum hydride (LAH), the product of which, without purification, was subsequently subject to hydrolysis by hydrobromic acid to afford compound 3 as an HBr salt.
  • the amino group in compound 3 was protected by the carbobenzyloxyl protecting group affording compound 4a.
  • the diol side chain in the structure of compound 5a was then established by the reaction of the phenol hydroxyl group in compound 4a with an epoxide (e.g., glycidol, either in chiral or racemic form, or similar functionally substituted aliphatic epoxide as known in the art).
  • an epoxide e.g., glycidol, either in chiral or racemic form, or similar functionally substituted aliphatic epoxide as known in the art.
  • the amino group in compound 3 may be protected with another suitable amine protecting group.
  • the resulting protected amine compound 4 may be carried forward in synthesizing compound 5 via an analogous process, as apparent to one skilled in the art from Scheme 1 and chemical methods known in the art.
  • Scheme 1 Synthesis of compound 5
  • the present invention provides methods that synthesize the active compounds in a robust process which (a) avoids tedious work-up and chromatographic purifications in each step, and (b) can be easily scaled up to any desired production scale desired for commercializing the active compounds.
  • compound 3 may be used as a starting material.
  • the inventors have discovered a method for the synthesis of compound 3 as follows.
  • Compound 2, 4-(4- methoxyphenyl)butyramide was prepared via the reaction with ammonia of a mixed anhydride which was prepared in situ by the reaction of the commercially available 4- methoxyphenyl butyric acid, compound 1 , with iso-butylchloroformate. It should be noted that the mixed anhydride is not stable in aqueous medium and under elevated
  • reaction proceeded smoothly and the product, after extraction with diethyl ether, concentration and subsequent crystallization from heptane, was isolated in a good yield (65-70%).
  • Reduction of compound 2 was realized by either borane/THF complex, or by lithium aluminum hydride (LAH, either solid or 2.5M solution in THF).
  • LAH lithium aluminum hydride
  • compound 2 was charged as a solid into the reaction vessel containing the reducing agent (1 M solution). The reaction mixture was then heated to reflux for 5-7 hours, and the completion of the reaction was monitored by TLC. The batch, after cooling down to low temperature ( ⁇ 5 °C), was quenched by the careful addition of methanol.
  • the reducing agent was added into the reaction vessel containing THF, followed by the addition of the amide, compound 2, portionwise. If an LAH/THF solution was used, the reducing agent was added slowly into a mixture containing the amide and solvent THF. However, in both cases, the reduction by LAH was conducted for 15-20 hours, and quenched by the addition of a saturated aqueous sodium sulfate solution.
  • the reduction product amine either obtained by borane/THF or by LAH, was stabilized as an HBr salt by the addition of a 48% aqueous HBr solution (1-2 equiv) into a concentrated product solution after work-up, and used directly (without purification) in the following
  • Compound 5 was then synthesized in 55-65% yield by the reaction of compound 4a with glycidol in refluxing ethanol in the presence of a catalytic amount of triethylamine (0.005-0.1 equiv). Formation of oligomers of either glycidol or the product may be observed due to the possible polymerization of glycidol under the reaction conditions or over-reaction of the desired product with excess glycidol. These by-products can be removed by filtering the reaction mixture, after concentration and taking up in ethyl acetate, through a short silica gel pad eluting with the straight ethyl acetate or by crystallization from I PA.
  • Methanesulfonic acid (one equiv) was added dropwise into the suspension. Any undissolved solid was filtered off before the solution was added to ether (such as methyl iert-butyl ether, MTBE) for precipitation. The final product, an active compound herein, was isolated in 75-80% yield by vacuum filtration.
  • An alternate route to making an active compound herein involves the use of the commercially available 2-Methyl-2-thiopseudourea hemisulfate in order to avoid the need for the toxic substance cyanamide, methyl iodide, and the noxious gas hydrogen sulfide, in the synthetic process.
  • amide bond forming reagents including, but not limited to, TBTU (O-(Benzotriazol-l-yl)- /V,/V,/V,/V-tetramethyluronium tetrafluoroborate), BOP (Benzotriazole-1 -yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate), pyBop (benzotriazol-1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate), and EDC (1-ethyl-3-(3- dimethylaminopropyl) carbodiimide), may be used for this transformation. Condensation with compound 11 in a manner analogous to that discussed above, produced the Boc- protected analogue of a compound represented by Formula I (e.g., compound 15).
  • BOP Benzotriazole-1 -yl-oxy-tris- (dimethylamino)-phosphon
  • the slurry was transferred to a 72-L, unjacketed reactor, aqueous hydrobromic acid (48 wt%, 9.0 L, 80 mol) was added and the slurry was heated to 95 to 1 15 for 13 hours. Progress of the reaction was monitored by HPLC analysis [f R of 3: 8.7 min; f R of 4: 6.5 and 6.8 min. The reaction mixture was cooled to 0-5 and transferred to a 100-L, jacketed reactor where it was stirred for 2 hours.
  • the product mixture was then evaporated to approximately 500 mL and transferred to a 2 L separatory funnel with ethyl acetate while decanting away from the solids.
  • the aqueous layer was extracted with ethyl acetate (3 x 1 L).
  • the extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to afford 265 g of the crude product.
  • the crude material was crystallized from a mixture of toluene/heptane (1 :1 , v/v).
  • the crystallized product was suction filtered and washed with toluene/heptane (1 :1 , v/v).
  • Compound 12 can be prepared by adding compound 10 (24 g, 61.8 mmol), purified compound 11 (17.0 g, 61.8 mmol), and DIEA (21.4 ml_, 129.7 mmol) to DMF (7 vol, 170 mL). The mixture was warmed to 65 °C with stirring and the resulting solution was stirred until judged complete by HPLC ( ⁇ 6 hours). Water was slowly added to the 65 °C solution. The heat source was removed and stirring continued while allowing the solution to slowly cool to ambient temperature. Once crystals formed the mixture was cooled to 0-5 °C and the solids were collected by vacuum filtration. The solids were washed with water and partially dried on the filter.
  • a purer product of compound 17 can be obtained by the following method: the above crude product (10.8 g) was stirred in a mixture of MTBE and 2-propanol (400 mL, 1/4 v/v) at room temperature overnight.
  • 6-Chloro-3,5-diaminopyrazine-2-carboxylic acid (compound 13, CAS# 4878-36-8, 100 mg, 1 .0 eq), tert-butyl amino(methylthio)methylenecarbamate (compound 16; 1 1 1 mg, 1.1 eq), and BOP (Benzotriazole-l -yl-oxy-tris-(dimethylamino)-phosphonium

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention porte sur des procédés pour la production de sels de phénylguanidine ayant une activité pharmacologique, ainsi que sur l'identification et la synthèse de composés utiles comme intermédiaires pour la production de sels de phénylguanidine ayant une activité pharmacologique.
PCT/US2011/039420 2010-06-09 2011-06-07 Procédé de production de sels de phénylguanidine et de leurs intermédiaires Ceased WO2011156355A1 (fr)

Applications Claiming Priority (2)

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US35290110P 2010-06-09 2010-06-09
US61/352,901 2010-06-09

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WO2011156355A1 true WO2011156355A1 (fr) 2011-12-15

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8669262B2 (en) 2011-06-27 2014-03-11 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide
US9586911B2 (en) 2013-12-13 2017-03-07 Parion Sciences, Inc. Arylalkyl- and aryloxyalkyl-substituted epthelial sodium channel blocking compounds
US9593084B2 (en) 2012-12-17 2017-03-14 Parion Sciences, Inc. Chloro-pyrazine carboxamide derivatives with epithelial sodium channel blocking activity
US9695134B2 (en) 2012-12-17 2017-07-04 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(n-(4-phenylbutyl)carbamimidoyl)pyrazine-2-carboxamide compounds
US10167266B2 (en) 2002-02-19 2019-01-01 Parion Sciences, Inc. Sodium channel blockers

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4013659A (en) * 1973-07-13 1977-03-22 Smith Kline & French Laboratories Limited Certain n,n'-disubstituted guanidine compounds and their use
US6858615B2 (en) * 2002-02-19 2005-02-22 Parion Sciences, Inc. Phenyl guanidine sodium channel blockers
US20070232581A1 (en) * 2006-04-03 2007-10-04 Bristol-Myers Squibb Company Oxime-Containing Acyl Guanidines as Beta-Secretase Inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4013659A (en) * 1973-07-13 1977-03-22 Smith Kline & French Laboratories Limited Certain n,n'-disubstituted guanidine compounds and their use
US6858615B2 (en) * 2002-02-19 2005-02-22 Parion Sciences, Inc. Phenyl guanidine sodium channel blockers
US7189719B2 (en) * 2002-02-19 2007-03-13 Parion Sciences, Inc. Sodium channel blockers
US7192960B2 (en) * 2002-02-19 2007-03-20 Parion Sciences, Inc. Sodium channel blockers
US7332496B2 (en) * 2002-02-19 2008-02-19 Parion Sciences, Inc. Methods of using sodium channel blockers
US20070232581A1 (en) * 2006-04-03 2007-10-04 Bristol-Myers Squibb Company Oxime-Containing Acyl Guanidines as Beta-Secretase Inhibitors

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10167266B2 (en) 2002-02-19 2019-01-01 Parion Sciences, Inc. Sodium channel blockers
US8669262B2 (en) 2011-06-27 2014-03-11 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide
US9586910B2 (en) 2011-06-27 2017-03-07 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide
US10752597B2 (en) 2011-06-27 2020-08-25 Parion Sciences, Inc. 3,5-diamino-6-chloro-N—(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide
US11578042B2 (en) 2011-06-27 2023-02-14 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide
US9593084B2 (en) 2012-12-17 2017-03-14 Parion Sciences, Inc. Chloro-pyrazine carboxamide derivatives with epithelial sodium channel blocking activity
US9695134B2 (en) 2012-12-17 2017-07-04 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(n-(4-phenylbutyl)carbamimidoyl)pyrazine-2-carboxamide compounds
US10071970B2 (en) 2012-12-17 2018-09-11 Parion Sciences, Inc. Chloro-pyrazine carboxamide derivatives with epithelial sodium channel blocking activity
US10246425B2 (en) 2012-12-17 2019-04-02 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(N-(4-phenylbutyl)carbamimidoyl) pyrazine-2-carboxamide compounds
US9586911B2 (en) 2013-12-13 2017-03-07 Parion Sciences, Inc. Arylalkyl- and aryloxyalkyl-substituted epthelial sodium channel blocking compounds
US9957238B2 (en) 2013-12-13 2018-05-01 Parion Sciences, Inc. Arylalkyl-and aryloxyalkyl-substituted epithelial sodium channel blocking compounds
US10233158B2 (en) 2013-12-13 2019-03-19 Parion Sciences, Inc. Arylalkyl- and aryloxyalkyl-substituted epithelial sodium channel blocking compounds

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