WO2016029216A2 - Method for producing amidine derivatives - Google Patents

Method for producing amidine derivatives Download PDF

Info

Publication number
WO2016029216A2
WO2016029216A2 PCT/US2015/046582 US2015046582W WO2016029216A2 WO 2016029216 A2 WO2016029216 A2 WO 2016029216A2 US 2015046582 W US2015046582 W US 2015046582W WO 2016029216 A2 WO2016029216 A2 WO 2016029216A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
bis
alkyl
defined above
Prior art date
Application number
PCT/US2015/046582
Other languages
French (fr)
Other versions
WO2016029216A3 (en
Inventor
Pravin L. Kotian
Vivekanand P. Kamath
Venkat R. CHINTAREDDY
Ahmed Abdel-Magid
Pooran Chand
Original Assignee
Biocryst Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biocryst Pharmaceuticals, Inc. filed Critical Biocryst Pharmaceuticals, Inc.
Publication of WO2016029216A2 publication Critical patent/WO2016029216A2/en
Publication of WO2016029216A3 publication Critical patent/WO2016029216A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/61—Halogen atoms or nitro radicals

Definitions

  • the present invention relates to an improved method for preparing certain amidine derivatives.
  • the invention also relates to intermediates useful in the method, and to methods for preparing such intermediates.
  • the original synthesis described above suffers from multiple drawbacks that made it unsuitable for large-scale preparations.
  • the synthesis is very long - it includes five steps to produce the compound 1f (total yield 10.9%) and seven to produce the compound of formula 2h (total yield 23%).
  • the remaining synthesis, beginning with the coupling step of the compounds 1f and 2h, takes nine steps to reach the final product, so a total of 21 chemical steps are involved in the total synthesis.
  • the invention comprises a method of producing a compound of formula (I):
  • X is CH or ;
  • Y is CH or N
  • Ri is hydrogen, C ⁇ 6 alkyl, C 3 . 8 cycloalkyl, C -6 alkoxy or C 3 . 8 cycloalkoxy, C 1-6 alkylthio, aryl, aryloxy, heteroaryl or heteroaryloxy;
  • R 2 is hydrogen, C 1-6 alkyl, C 3 . 6 cycloalkyl or (C 3 . 6 cycloalkyl)-C -6 alkyl, each optionally substituted by 1 or 2 hydroxyl groups;
  • R 3a and R 3b are each independently hydrogen or C 1-6 alkyl
  • n 0, 1 or 2;
  • n 0, 1 , 2, 3 or 4;
  • R 4a and R 4b are each independently hydrogen, C 1-6 alkyl, C 3 _ 8 cycloalkyl, C 1-6 alkoxy or C 3-8 cycloalkoxy, aryl, heteroaryl, or aralkyl;
  • R 5a and R 5b are each independently hydrogen or C 1-6 alkyl
  • the invention provides a method of producing a compound of formula (VI):
  • Ri is as defined above, and
  • R 6a and R 6 b are each independently C 1-6 alkyl; or R 6a and R 6 together with the boron and oxygen atoms to which they are attached form an optionally substituted 5-7-membered ring;
  • Hal is a halogen atom
  • R 6a and R 6b are as defined above;
  • the invention comprises a method of producing a compound of formula (XI):
  • Y, Hal, R 2 and R 3b are as defined above;
  • R 7 is C 1 -8 alkyl (optionally substituted with one or more of the following: chlorine, fluorine, C-i.6 alkoxy, C 3-8 cycloalkoxy, C 3-8 cycloalkyl, heterocycloalkyl, heterocycloalkoxy, aryl or heteroaryl), C 2-6 alkenyl; C 2-6 alkynyl; C 3-8 cycloalkyl, aryl or heteroaryl;
  • the invention provides a method of producing a compound of
  • R c is a halogen atom (preferably fluorine) or a C 1-6 alkoxy group
  • R d is hydrogen or a boronate ester residue
  • M is an alkali metal atom (preferably lithium, sodium or potassium, more preferably potassium);
  • a suitable coupling catalyst in the presence of a suitable coupling catalyst and, optionally a ligand and/or a base.
  • the invention provides a method of producing a compound of formula
  • a base of which the pK a of the conjugate acid ranges from 4 to 10 in the presence of a base of which the pK a of the conjugate acid ranges from 4 to 10, and optionally a suitable amide coupling agent and/or an amide coupling additive.
  • the invention provides a method of producing a compound of formula (I), in which X, Y, m, n, R f R 2 , R3a, R3 b , R4a, 4b, Rs a and R 5b are as defined above;
  • the invention provides a method of producing a compound of formula (I) as defined above; comprising the steps of:
  • the invention provides a method of producing a compound of formula (VI), as defined above, using the following steps:
  • the invention provides a method of producing a compound of formula (XV), as defined above, using the following steps:
  • the method steps enable the compounds of formula (I) to be produced in much larger quantities than was possible in the prior art.
  • the method steps permit the compounds of formula (I) to be produced on scales exceeding 100, such as more than 1 kg, such as more than 10 kg.
  • the method of the present invention is a much shorter synthesis (a total of 13 chemical steps) than the prior method. In particular, it involves only six steps beginning with the coupling of the boron compound and the halogenated arylamide.
  • the reagents are commercially available on large scale; the procedure is safer and suitable for scale up; and the compatibility of various functional groups minimizes undesirable side reactions and improves isolated yields; the steps used avoid protection and deprotection of functional groups; and the cost of manufacturing and production time are both reduced significantly. Definitions
  • alkyl means a straight or branched, saturated aliphatic radical having a chain of carbon atoms.
  • (Ci_ 6 )alkyl means alkyl groups that have a chain of between 1 and 6 carbons such as methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, isobutyl, ferf-butyl, n-pentyl and n-hexyl.
  • the alkyl group may be a (C 1-4 ), (C 1-3 ) or (C 1-2 ) alkyl.
  • Cycloalkyl means a saturated monocyclic ring of carbon atoms. (C 3 .
  • cycloalkyl includes cyclopropyl, cyclobiityl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. .
  • the cycloalkyl group may be a (C 3-6 ) or (C 3 . 4 ) cycloalkyl.
  • (Cycloalkyl)-alkyl means alkyl, as defined above (either in its broadest aspect or a preferred aspect), which is substituted by cycloalkyl, as defined above (either in its broadest aspect or a preferred aspect).
  • Examples of (cycloalkyl)-alkyl groups include (C 3-8 cycloalkyl)methyl groups such as cyclopropylmethyl, cyclobutylmethyl,
  • the (cycloalkyl)alkyl group may be a (C 3 . 4 )cycloalkyl(C 1-2 ) alkyl group, and in particular cyclopropylmethyl.
  • Alkoxy means an oxygen atom bonded to an alkyl group, wherein alkyl is as defined above(either in its broadest aspect or a preferred aspect).
  • (C 1-6 )alkoxy means alkoxy groups that have a chain of between 1 and 6 carbons such as methoxy, 1-ethoxy, 2- ethoxy, 1-propyloxy, 2-propyloxy, 3-propyloxy, isopropoxy, 1-butyloxy, 2-butyloxy, 3- butyloxy, 4-butyloxy, sec-butyloxy, isobutyloxy, ferf-butyloxy, 1-pentyloxy and 1- hexyloxy.
  • alkenyl means a straight or branched, aliphatic radical having a chain of carbon atoms and one or more double bonds.
  • (C 2-6 )alkenyl means alkenyl groups that have a chain of between 2 and 6 carbons such as vinyl, 1-propenyl, 1-butenyl, 2-butenyl, isobutenyl, 1- pentenyl and 1-hexenyl.
  • the alkenyl group may be a (C 2-3 ) alkenyl.
  • Alkynyl means a straight or branched, aliphatic radical having a chain of carbon atoms and one or more triple bonds.
  • (C 2-6 )alkynyl means alkynyl groups that have a chain of between 2 and 6 carbons such as ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl and 1-hexynyl.
  • the alkynyl group may be a (C 2- 3) alkynyl.
  • Alkyl means alkyl, as defined above (either in its broadest aspect or a preferred aspect), which is substituted by 1 to 3 aryl groups, as defined below (either in its broadest aspect or a preferred aspect).
  • the aryl group may be substituted as defined below.
  • Examples of aralkyl groups include benzyl, phenethyl, benzhydryl and trityl.
  • Alkylthio means a sulfur atom bonded to an alkyl group, wherein alkyl is as defined above(either in its broadest aspect or a preferred aspect).
  • (C -6 )alkylthio means alkylthio groups that have a chain of between 1 and 6 carbons such as methylthio, 1-ethylthio, 2- ethylthio, 1-propylthio, 2-propylthio, 3-propylthio, isopropylthio, 1-butylthio, 2-butylthio, 3- butylthio, 4-butylthio, sec-butylthio, isobutylthio, te/f-butylthio, 1-pentylthio and 1- hexylthio.
  • Cycloalkoxy means an oxygen atom bonded to a cycloalkyl group, wherein cycloalkyl is as defined above (either in its broadest aspect or a preferred aspect).
  • (C 3-8 )cycloalkoxy includes cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
  • the cycloalkoxy group may be a (C 3 . 6 ) or (C 3 . 4 ) cycloalkoxy.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Haldroxyl means the group -OH.
  • Alkylene unless indicated otherwise, means a straight or branched, saturated, aliphatic, divalent radical.
  • (C 1-6 )alkylene means an alkylene groups that has a chain of between 1 and 6 carbons such as includes methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), trimethylene (-CH 2 CH 2 CH 2 -), tetramethylene (-CH 2 CH 2 CH 2 CH 2 -),
  • Alkoxy means an oxygen atom bonded to an alkyl group, wherein alkyl is as defined above (either in its broadest aspect or a preferred aspect).
  • (C 1-6 )alkoxy means alkoxy groups that have a chain of between 1 and 6 carbons such as methoxy, 1-ethoxy, 2- ethoxy, 1-propyloxy, 2-propyloxy, 3-propyloxy, isopropoxy, 1-butyloxy, 2-butyloxy, 3- butyloxy, 4-butyloxy, sec-butyloxy, isobutyloxy, terf-butyloxy, 1-pentyloxy and 1- hexyloxy.
  • Heterocycloalkyi means a saturated 3 to 8 membered ring, wherein at least one (preferably 1 to 3, such as 1 or 2) of the atoms forming the ring is a heteroatom selected, independently from N, O, or S.
  • heterocycloalkyi include azetidinyl, piperidyl, morpholyl, piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1 ,4- diazaperhydroepinyl, tetrahyrofuranyl, 1 ,3-dioxanyl and 1 ,4-dioxanyl.
  • Heterocycloalkoxy means an oxygen atom bonded to a heterocycloalkyi group, wherein heterocycloalkyi is as defined above (either in its broadest aspect or a preferred aspect).
  • Aryl means phenyl or naphthyl.
  • the aryl group may be optionally substituted with a number (preferably 1 to 5, such as 1 , 2 or 3) substituents selected from halogen, hydroxy, (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 1-6 )alkylthio, (C 3 . 8 )cycloalkyl, (C 3-8 )cycloalkoxy, aryl and nitro.
  • Aryloxy means an oxygen atom bonded to an aryl group, wherein aryl is as defined above (either in its broadest aspect or a preferred aspect).
  • the aryl group may be optionally substituted with a number (preferably 1 to 5, such as 1 , 2 or 3) substituents selected from halogen, hydroxy, (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 1-6 )alkylthio, (C 3 . 8 )cycloalkyl, (C 3-8 )cycloalkoxy, cyano and nitro.
  • Heteroaryl means a monocyclic or bicyclic or polycyclic aromatic group wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are carbon.
  • Monocyclic heteroaryl groups include, but are not limited to, cyclic aromatic groups having five or six ring atoms, wherein at least one (preferably 1 to 4, such as 1 , 2 or 3) ring atom is a heteroatom and the remaining ring atoms are carbon.
  • heteroaryl groups of this invention include furanyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, 1 ,2,3-oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, thiazolyl, 1 ,3,4-thiadiazolyl, triazolyl and tetrazolyl.
  • the heteroaryl group may be optionally substituted with a number (preferably 1 to 5, such as 1 , 2 or 3) substituents selected from halogen, hydroxy, (C -6 )alkyl, (C 1-6 )alkoxy,
  • Heteroaryloxy means an oxygen atom bonded to a heteroaryl group, wherein heteroaryl is as defined above (either in its broadest aspect or a preferred aspect).
  • the heteroaryl group may be optionally substituted with a number (preferably 1 to 5, such as 1 , 2 or 3) substituents selected from halogen, hydroxy, (C 1-6 )alkyl, (C 1-6 )alkoxy,
  • Niro means the group -N0 2 .
  • Cyano means the group -CN.
  • X is CH. In another embodiment, X is N.
  • Y is CH. In another embodiment, Y is N.
  • R- is hydrogen. In one embodiment, R-, is a C 1-6 alkyl group. In one embodiment, R-, is a C -6 alkoxy group. In one embodiment, is a methoxy group.
  • the group Ri is present at the 4-position of the phenyl ring (the carbon attached to the amide group being the 1-position).
  • R 2 is C 1-6 alkyl, C 3-6 cycloalkyl or (Cs-ecycloalky -C ⁇ e alkyl, each optionally substituted by 1 or 2 hydroxyl groups. In one embodiment, R 2 is a
  • R 2 is a cyclopropylmethyl group.
  • R 3a is hydrogen or methyl. In one embodiment, R 3a is hydrogen. In one embodiment, R 3b is hydrogen or methyl. In one embodiment, R 3b is hydrogen. In one embodiment, m is 0 (i.e. R 4a is absent and there are no additional substituents on the ring).
  • n is 0 (i.e. R 4b is absent and there are no additional substituents on the ring).
  • R 5a is hydrogen or methyl. In one embodiment, R 5a is hydrogen.
  • each R 5b is independently hydrogen or methyl. In one embodiment, each R 5b is hydrogen.
  • R 7 is C 1-6 alkyl, C 3 . 8 cycloalkyl or benzyl. In one embodiment, R 7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, cyclohexyl or benzyl.
  • the compounds used in the present invention are compounds of formula (I), as defined above, provided that when X is N, Y is CH, RT is 4-methoxy, m is 0, n is 0, and R 3a , R 3b , Rs a and R 5b are all hydrogen, R 2 is other than isobutyl. Such compounds are referred to herein as compounds of formula ( ).
  • X is CH
  • Y N
  • Ri is hydrogen or methoxy
  • R 2 is a
  • X is CH
  • Y is N
  • R 2 is a cyclopropylmethyl group
  • m is 0,
  • n is 0, and
  • R 3a , R 3b , R 5a and R 5b are all hydrogen.
  • the methods of the present invention relate to the production of a compound of formula (XVIII):
  • Figure 1 depicts a flow chart of the procedure of Step 1 of Example 1.
  • Figure 2 depicts a flow chart of the procedure of Step 2 of Example 1.
  • Figure 3 depicts a flow chart of the procedure of Step 3 of Example 1.
  • Figure 4 depicts a flow chart of the procedure of Step 4 of Example 1.
  • Figure 5 depicts a flow chart of the procedure of Step 5 of Example 1.
  • Figure 6 depicts a flow chart of the procedure of Step 6 of Example 1.
  • Figure 7 depicts a flow chart of the procedure of Step 7 of Example 1.
  • Figure 8 depicts a flow chart of the procedure of Step 8 of Example 1.
  • Figure 9 depicts a flow chart of the procedure of Step 9 of Example 1.
  • Figure 10 depicts a flow chart of the procedure of Step 10 of Example 1.
  • Figure 1 1 depicts a flow chart of the procedure of Step 11 of Example 1.
  • Figure 12 depicts a flow chart of the procedure of Step 12 of Example 1.
  • Figure 13 depicts a flow chart of the procedure of Step 13 of Example 1.
  • Figure 14 depicts a flow chart of the procedure of Step 14 of Example 1.
  • Figure 15 depicts a powder X-ray diffraction pattern (PXRD) of Compound XIX in
  • Figure 16 depicts a differential scanning calorimetry (DSC) thermogram of Compound XIX in Example 5.
  • Figure 17 depicts a thermogravimetric (TG) thermogram of Compound XIX in Example 5.
  • Figure 18 depicts a crystal structure as determined by scanning electron microscopy (SEM) of Compound XIX in Example 5.
  • Figure 19 depicts a powder X-ray diffraction pattern (PXRD) of Compound XX in
  • Figure 20 depicts a differential scanning calorimetry (DSC) thermogram of Compound XX in Example 4.
  • Figure 21 depicts a thermogravimetric (TG) thermogram of Compound XX in Example 4.
  • the boronate esters of Formula (VI) which are used to form one moiety of the compound of formula (I) may be produced in a three step synthesis according to Scheme 1 below. This synthesis is advantageous over the prior art synthesis in which five steps were needed to produce the corresponding intermediate.
  • the first step of the method is the production of a compound of formula (III) by halogenation of a compound of formula (II) by procedures known in the literature.
  • Suitable halogenating reagents include, bromine, N-bromosuccinimide; 1 ,3-dibromo-5,5- dimethylhydantoin and the like, more preferably bromine or N-bromosuccinimide; most preferably bromine.
  • the reaction is carried out in the presence of an acid.
  • the acid may be a Bnzmsted acid, examples of which include a hydrohalic acid such as hydrochloric acid and hydrobromic acid, a carboxylic acid such as acetic acid, propionic acid, oxalic acid, formic acid, and mandelic acid; a sulfonic acid such as p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid or camphor-sulfonic acid, or a mineral acid such as sulfuric acid or nitric acid; or a Lewis acid such as AICI 3 or FeCI 3 . (which may be in catalytic amounts).
  • a hydrohalic acid such as hydrochloric acid and hydrobromic acid
  • a carboxylic acid such as acetic acid, propionic acid, oxalic acid, formic acid, and mandelic acid
  • a sulfonic acid such as p-to
  • a catalytic amount of iodine and Fe can also be used in the reaction.
  • Selective monobromination of electron-rich arenes can also be carried out using CuBr 2 or alkali metal bromides in the presence of concentrated H 2 S0 4 or various oxidants in the presence of acids and/or catalysts.
  • the reaction is normally and preferably carried out in a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, halogenated hydrocarbons such as carbon tetrachloride, chloroform, or
  • dichloromethane ethers such as diethyl ether, dioxane, or tetrahydrofuran; carbon disulfide; alcohols such as methanol or ethanol; and carboxylic acids and anhydrides thereof such as acetic acid or acetic anhydride.
  • the solvent is a carboxylic acid, most preferably the solvent is acetic acid.
  • the reaction temperature typically ranges from 0°C to 50°C, and preferably room temperature to 40°C.
  • the reaction time typically ranges from 1 to 72 hours, and preferably 12 to 48 hours.
  • the compound of formula (III) is isolated from the reaction mixture by conventional methods.
  • the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • the product may further be purified by conventional methods such as crystallization or column chromatography.
  • the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography purify the product.
  • the second step of the method is the production of a compound of formula (IV).
  • group R ⁇ is alkoxy, aryloxy or heteroaryloxy
  • this process involves base-catalysed alcoholysis of a compound of formula (III) using an alcohol of formula R-, ⁇ . This process can be carried out by methods similar to General Method Z of US 6,699,994.
  • the reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • a solvent the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • Polar solvents are preferred.
  • suitable solvents include alcohols such as methanol, ethanol, isopropanol and terf-butanol; ketones such as acetone; sulfoxides such as dimethyl sulfoxide; and amides such as ⁇ , ⁇ -dimethylformamide and hexamethylphosphoramide; and mixtures thereof.
  • group R-i is alkoxy
  • the alcohol of formula R ⁇ H additionally acts as the solvent, either wholly or partially.
  • a mixture of the alcohol of formula R ⁇ and dimethyl sulfoxide is preferred.
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from room temperature to 70°C, and preferably 40 to 60°C.
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 10 minutes to 12 hours, and preferably 30 minutes to 6 hours.
  • the compound of formula (IV) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water, sodium chloride or sodium hydroxide in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • the product may further be purified by conventional methods such as crystallisation or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
  • the third step of the method is the production of a compound of formula (VI) by reaction of the compound of formula (IV) with a bis-boronate ester of formula (V). This step has not been previously described in the art.
  • the invention provides a method of producing a compound of formula (VI):
  • Ri is as defined above, either in its broadest aspect or a preferred aspect
  • Hal is a halogen atom, preferably bromine
  • R 6a and R 6b are each independently C 1-6 alkyl; or R 6a and R 6b together with the boron and oxygen atoms to which they are attached form an optionally substituted 5-7-membered ring, the substituents on the ring being defined by those on the starting diboron compound of formula (V) below;
  • R-i and Hal are defined above, either in its broadest aspect or a preferred aspect
  • R 6a and R 6b are as defined above;
  • bis-boronate esters usable in this step include 4,4,5,5-tetramethyl-l ,3,2- dioxaborolane; bis(pinacolato)diboron; bis(diethyl-l-tartrate glycolato)diboron; 4,4,5,5- tetramethyl-l ,3,2-dioxaborolane; bis(hexyleneglycolato)diboron; bis(diisopropyl-d-tartrate glycolato)-diboron; bis(catecholato)diboron; bis(diisopropyl-l-tartrate glycolato)diboron; bis[(+)-pinanediolato]diboron; bis(A/,/V,W ⁇ W'-tetramethyl-d-tartaramide glycolato)diboron; catecholborane; bis[(-)-pinanediolato]diboron; bis(N,A/,/V ⁇
  • the residue corresponds to the ring formed by R 6a and R 6b together with the boron and oxygen atoms to which they are attached; for example, the ring formed in
  • bis(pinacolato)diboron is a 5-membered ring formed by the boron and oxygen atoms and the 1 ,1 ,2,2-tetramethylethylene residue.
  • R 6a and R 6b are each independently C 1-4 alkyl; or R 6a and R 6 b together form a 1 ,1 ,2,2-tetramethylethylene group.
  • a preferred reagent of formula (V) is bis(pinacololato)diboron, in which the groups R 6a and R 6b on each oxygen attached to boron together form a 1 ,1 ,2,2-tetramethylethylene group. It has surprisingly been found by the present inventors that use of the boronate esters of formula (V) enables the reaction to proceed in good yield, while avoiding the formation of significant side products, and without the need to first protect the alcohol aldehyde functional groups on the compound of formula (IV).
  • the reaction is carried out in the presence of a suitable catalyst, the nature of which is not especially critical provided it is capable of catalysing the coupling reaction of a boronate ester with an aryl halide.
  • Suitable catalysts include palladium (II) and palladium (0) complexes, particularly those palladium (II) or palladium (0) complexes having one or more (preferably 2 or 4) nitrogen or phosphorus ligands bonded to the palladium.
  • Ligand free catalytic systems can also be used in this type of reaction.
  • Suitable palladium catalysts include palladium acetate;
  • the reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, aromatic hydrocarbons such as benzene, toluene and xylenes; symmetrical or unsymmetrical ethers such as tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether, alcohols like tert-butanol, n-butanol; water; nitriles such as acetonitrile; and mixtures thereof.
  • the use of a suitable amount of cosolvents in water or the use of pure water as the solvent are used in the ligand-free catalytic systems. It is preferred that the
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 50°C to the boiling point of the solvent, and preferably 70°C to 1 10°C.
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from preferably from 30 minutes to 24 hours, and more preferably 6 to 18 hours.
  • the compound of formula (VI) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • the product may further be purified by conventional methods such as crystallisation or column chromatography.
  • the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
  • the amides of Formula (XI) which are used to form one moiety of the compound of formula (I) may be produced in a four step synthesis according to Scheme 2 below.
  • R 8 is (Ci -6 ) alkyl (preferably methyl), and Hal is a halogen atom (preferably bromine);
  • R 8 is as defined above.
  • Suitable halogenating reagents include bromine, N-bromosuccinimide, 1 ,3-dibromo-5,5- dimethylhydantoin, and the like, more preferably bromine or N-bromosuccinimide; most preferably bromine.
  • the reaction is carried out in the presence of a strong acid.
  • Suitable acids include Bronsted acids such as those described and exemplified above, particularly nitric acid, sulphuric acid and oleum (sulphuric acid containing dissolved sulphur trioxide) and Lewis acids such as AICI 3 or AIBr 3 . Oleum is preferred.
  • the reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. It is preferred that the acid also acts as the solvent.
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 20°C to 200°C, and preferably 100 to 150°C.
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 2 to 96 hours, and preferably 24 to 80 hours.
  • the compound of formula (VIII) is isolated from the reaction mixture by conventional methods.
  • the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water, sodium chloride or sodium hydroxide in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • the product may further be purified by conventional methods such as distillation or column chromatography.
  • the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
  • the second step of the method is the production of a compound of formula (IX).
  • This process involves treating the compound of formula (VIII), as defined above with an oxidizing agent to oxidize the alkyl side chains of the compound of formula (VIII) to carboxylic acids.
  • This process can be carried out by methods well known to those skilled in the art.
  • This oxidation can be carried out by any other oxidizing agents well known to those skilled in the art.
  • suitable oxidizing agents include manganese (VII) compounds such as sodium permanganate or potassium permanganate. Potassium permanganate is preferred.
  • This method is known in the literature, for example in N. Zimmermann et al; Bioorganic Chemistry, 32(1), 13-25; 2004; and E. Meggers et al; Journal of the American Chemical Society, 122(43), 10714-10715; 2000.
  • the reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • a solvent the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • Polar solvents are preferred and water is especially preferred.
  • This oxidation can be facilitated by the addition of an organic co-solvent such as dioxane, pyridine, acetone or teAi-butanol.
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 40 to 120°C, and preferably 60 to 100°C.
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 1 to 48 hours, and preferably 6 to 24 hours.
  • the compound of formula (IX) is isolated from the reaction mixture by conventional methods.
  • the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • the product may further be purified by conventional methods such as crystallisation or column chromatography.
  • the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
  • the third step of the method is the production of a bis-ester compound of formula (X).
  • This process involves treating the bis-carboxylic acid of formula (IX) with an alcohol of formula R 7 OH (in which R 7 is as defined herein) to esterify both the carboxylic acid functional groups.
  • This process can be carried out by esterification methods well known to those skilled in the art.
  • the reaction is carried out in the presence of an acid catalyst, the nature of which is not especially critical provided it is capable of catalysing an esterification reaction.
  • suitable acid catalysts include Bransted acids, examples of which include hydrohalic acids such as hydrofluoric, hydrochloric or hydrobromic acids, carboxylic acids such as acetic acid, propionic acid, oxalic acid, formic acid, mandelic acid, and the like; sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid,
  • trifluoromethanesulfonic acid camphor-sulfonic acid
  • mineral acids such as sulfuric acid or nitric acid.
  • the preferred catalyst is sulphuric acid.
  • the reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, aromatic hydrocarbons such as benzene, toluene and xylenes; alcohols such as methanol, ethanol, isopropanol and tert-butanol; and mixtures thereof.
  • the alcohol of formula R 7 OH (wherein R 7 is as defined above, either in its broadest aspect or a preferred aspect) also acts as the solvent.
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 40°C to 100°C, and preferably 50°C to 80°C.
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 10 minutes to 48 hours, and more preferably 4 to 24 hours.
  • the compound of formula (X) is isolated from the reaction mixture by conventional methods.
  • the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • the product may further be purified by conventional methods such as crystallisation or column chromatography.
  • the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
  • the fourth step of this part of the method is the amination of the bis-ester compound of formula (X) to produce the amide of formula (XI).
  • this reaction can be controlled by carrying out the reaction in suitable solvents at particular dilutions to reduce the production of the bis-amide and the alternative amide.
  • the invention comprises a method of producing a compound of formula (XI):
  • the reaction is carried out in a suitable solvent. It has unexpectedly been found that the choice of solvent enables the compound of formula (XI) in a manner which avoids the production of the by-products illustrated above.
  • suitable solvents include tetrahydrofuran, acetonitrile, ⁇ , ⁇ -dimethylformamide, isopropanol and tert-butanol; and mixtures thereof, of which tert-butanol is preferred.
  • the reaction is carried out at a dilution of 0.5 to 1.0 moles per litre. It has unexpectedly been found that carrying out the reaction at this level of dilution enables the compound of formula (XI) in a manner which reduces the production of the by-products illustrated above. Preferably, the reaction is carried out at a dilution of 0.7 to 0.8 moles per litre. By “dilution” is meant the concentration of the compound of formula (X) in the reaction mixture.
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 40°C to 100°C, and preferably 50°C to
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from preferably from 2 to 48 hours, and more preferably 12 to 24 hours.
  • the compound of formula (XI) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • the product may further be purified by conventional methods such as crystallisation or column chromatography.
  • the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
  • the invention provides a method of producing a compound of formula (XII):
  • R-, R 6a and R 6b are as defined above;
  • a suitable catalyst in the presence of a suitable catalyst and, optionally, a ligand and/or a base.
  • Suitable catalysts include palladium (II) and palladium (0) complexes, particularly those palladium (II) or palladium (0) complexes having one or more (preferably 2 or 4) nitrogen or phosphorus ligands bonded to the palladium.
  • suitable palladium catalysts include those described and exemplified above with respect to catalysts for the coupling reaction of the compounds of formulae (IV) and (V) to produce the compound of formula (VI).
  • the preferred catalyst is bis(triphenylphosphine)palladium (II) chloride.
  • the reaction is normally and preferably carried out in the presence of a ligand, the nature of which is not especially critical provided it is capable of coordinating to the catalyst used in the reaction.
  • a ligand is preferably a nitrogen- or phosphorus-based ligand, examples of suitable ligands of which are well known to those skilled in the art and include the following:
  • di-t-butylmethylphosphine di-t-butylmethylphosphonium tetrafluoroborate
  • triphenylphosphine is preferred.
  • the reaction is normally and preferably carried out in the presence of a base, the nature of which is not especially critical provided it is capable of acting as such.
  • suitable bases include metal hydroxides, especially alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide; and thallium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate and caesium carbonate, alkali metal
  • hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogen carbonate
  • alkali metal fluorides such as potassium fluoride and caesium fluoride
  • alkali metal alkoxides such as sodium methoxide, sodium tert-butoxide and potassium t- butoxide
  • alkali metal phosphates such as potassium phosphate
  • alkali metal acetates such as sodium acetate, potassium acetate, and organic bases such as triethylamine or lithium hexamethyldisilazane, of which sodium carbonate is preferred.
  • the reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, aromatic hydrocarbons such as benzene, toluene and xylenes, and ethers such as diethyl ether, tert-butyl methyl ether, dimethoxyethane and tetrahydrofuran; alcohols like tert-butanol, n-butanol; or water.
  • the solvent is an ether, in particular tetrahydrofuran.
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 40°C to the boiling point of the solvent, and preferably 50°C to 70°C.
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 30 minutes to 24 hours, and preferably 4 to 12 hours.
  • the compound of formula (XII) is isolated from the reaction mixture by conventional methods.
  • the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • an aqueous solution such as water or sodium chloride
  • the product may further be purified by conventional methods such as crystallisation or column chromatography.
  • the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
  • the second step of this part of the method is the production of a compound of formula (XIII).
  • This process involves treating the compound of formula (XII) with an agent capable of converting a hydroxyl group into a leaving group LG. This process can be carried out by methods well known to those skilled in the art.
  • the leaving group LG may be a halogen atom, a sulfonyloxy group (such as C 1-4 alkylsulfonate, benzenesulfonate, para-toluenesulfonate or trifluoromethanesulfonate), or a diazonium moiety (-N 2 + ).
  • a sulfonyloxy group such as C 1-4 alkylsulfonate, benzenesulfonate, para-toluenesulfonate or trifluoromethanesulfonate
  • a diazonium moiety (-N 2 + ).
  • the reaction can be carried out by reacting with a sulfonating agent of formula R a S0 2 LG 1 wherein R a is a hydrocarbon or halogenated hydrocarbon moiety (such as d -4 alkyl, phenyl, p-tolyl or trifluoromethyl) and LG ! is a leaving group (which may be a halogen, or may be another sulfonyloxy group).
  • a sulfonyloxy group such as C 1-4 alkylsulfonate, benzenesulfonate, para-toluenesulfonate or trifluoromethanesulfonate
  • the reagent is either a sulfonic anhydride of formula (R a S0 2 ) 2 0 or a bis-sulfonylamide of formula (R a S0 2 ) 2 NR b (wherein R is a hydrocarbon or halogenated hydrocarbon moiety such as C -4 alkyl, phenyl, p-tolyl or trifluoromethyl).
  • R is a hydrocarbon or halogenated hydrocarbon moiety such as C -4 alkyl, phenyl, p-tolyl or trifluoromethyl.
  • a particularly preferred reagent is trifluoromethanesulfonic anhydride.
  • the reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, aromatic hydrocarbons such as benzene, toluene and xylenes, and symmetrical and unsymmetrical ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane and dioxane, acetonitrile, halogenated hydrocarbons such as dichloromethane or chloroform; and mixtures thereof.
  • the solvent is a halogenated hydrocarbon, preferably dichloromethane or chloroform.
  • the reaction is normally and preferably carried out in the presence of a base, the nature of which is not especially critical provided it is capable of acting as such.
  • bases include organic amines such as triethylamine, diisopropylethyamine or pyridine; of which pyridine is preferred.
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from -50°C to 20°C, and preferably -20 to 10°C.
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 1 to 24 hours, and preferably 2 to 8 hours.
  • the compound of formula (XIII) is isolated from the reaction mixture by conventional methods.
  • the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • the product may further be purified by conventional methods such as crystallisation or column chromatography.
  • the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
  • the third step of this part of the method is the production of a compound of formula (XIV) by reaction of the compound of formula (XIII) with a vinylating agent.
  • This step has not been previously described in the art, and confers significant advantages over the prior art for the reasons set out below. Therefore, in one aspect, the invention provides a method of producing a compound of formula (XIV):
  • R c is a halogen atom (preferably fluorine)
  • R d is hydrogen or an ester residue
  • M is an alkali metal atom (preferably lithium, sodium or potassium, more preferably potassium);
  • R d is an ester residue
  • examples include those residues include C 1-6 alkyl (optionally substituted with one or combination of the following: chlorine, fluorine, C 1-6 alkoxy, C 3 . 8 cycloalkoxy, C 3 . 8 cycloalkyl, heterocycloalkyl, heterocycloalkoxy, aryl or heteroaryl), C 2-6 alkenyl; C 2-6 alkynyl; C 3-8 cycloalkyl, aryl or heteroaryl.
  • Suitable catalysts include palladium (II) and palladium (0) complexes, particularly those palladium (II) or palladium (0) complexes having one or more (preferably 2 or 4) nitrogen or phosphorus ligands bonded to the palladium.
  • suitable palladium catalysts include those described and exemplified above with respect to catalysts for the coupling reaction of the compounds of formulae (IV) and (V) to produce the compound of formula (VI).
  • the preferred catalyst is bis(triphenylphosphine)palladium (II) chloride.
  • the reaction is normally and preferably carried out in the presence of a base, the nature of which is not especially critical provided it is capable of acting as such.
  • a base such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide; and thallium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate and caesium carbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogen carbonate, alkali metal or ammonium fluorides such as potassium fluoride, caesium fluoride and (tetra-n-butyl)ammomiun fluoride, alkali metal alkoxides such as sodium methoxide, sodium tert-butoxide and potassium t-butoxide, alkali metal phosphates such as potassium phosphate; alkali metal acetates such as sodium acetate
  • the reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, aromatic hydrocarbons such as benzene, toluene and xylenes, and ethers such as diethyl ether, dioxane, tertbutylmethyl ether, dimethoxyethane and
  • tetrahydrofuran tetrahydrofuran
  • alcohols such as tert-butanol or n-butanol
  • water water
  • mixtures thereof It is preferred that the solvent is an ether, in particular dimethoxyethane.
  • the use of a suitable amount of cosolvents in water or the use of pure water as the solvent are used in the ligand-free catalytic systems.
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 40°C to the boiling point of the solvent, and preferably 50°C to 70°C.
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 30 minutes to 24 hours, and preferably 4 to 12 hours.
  • the compound of formula (XIV) is isolated from the reaction mixture by conventional methods.
  • the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • an aqueous solution such as water or sodium chloride
  • the product may further be purified by conventional methods such as crystallisation or column chromatography.
  • the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
  • the fourth step of this part of the method is the production of a compound of formula (XV).
  • This process involves treating the compound of formula (XIV) with an oxidizing agent capable of oxidizing the aldehyde moiety of the compound of formula (XIV) to a carboxylic acid. This process can be carried out by methods well known to those skilled in the art.
  • Suitable oxidizing agents include chlorine (III) compounds such as sodium chlorite; chromium (VI) compounds such as sodium chromate or potassium dichromate; managanese (VII) compounds such as sodium permanganate or potassium
  • reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • a solvent the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. Polar solvents are preferred.
  • suitable solvents include alcohols such as methanol, ethanol, isopropanol and tert-butanol; ethers such as diethyl ether, dioxane, tertbutylmethyl ether, dimethoxyethane and tetrahydrofuran; ketones such as acetone; nitriles such as acetonitrile; water; and mixtures thereof of which a mixture of tert-butanol, water and acetonitrile is preferred.
  • alcohols such as methanol, ethanol, isopropanol and tert-butanol
  • ethers such as diethyl ether, dioxane, tertbutylmethyl ether, dimethoxyethane and tetrahydrofuran
  • ketones such as acetone
  • nitriles such as acetonitrile
  • water and mixtures thereof of which a mixture of tert-butanol, water and ace
  • a positive chlorine species i.e. a species including chlorine in a positive oxidation state
  • the reaction is preferably carried out in the presence of a chlorine scavenging agent.
  • a chlorine scavenging agent prevents the chlorine from adding to the vinyl group on the compound of formula (XIV) and avoids the production of side products.
  • suitable chlorine scavenging agents include alkenes such as 1-pentene, 2-pentene and 2-methyl-2-butene, and sulphur compounds such as dimethyl sulfoxide and sulfamic acid, of which 2-methyl-2-butene is preferred.
  • this reagent is also used in the corresponding step of the synthesis generally described in US 6,699,994, the starting material in that step of the synthesis lacks a vinyl group. It is considered unexpected that the use of this reagent allows the reaction to proceed without giving rise to side products caused by oxidation of the vinyl group.
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from -20°C to room temperature, and preferably -10 to 20°C.
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 10 minutes to 6 hours, and preferably 20 minutes to 4 hours.
  • the compound of formula (XV) is isolated from the reaction mixture by conventional methods.
  • the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • the product may further be purified by conventional methods such as crystallisation or column chromatography.
  • the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
  • the compounds of formula (I) may be produced in two step synthesis from the carboxylic acids of formula (XV) according to Scheme 4 below, including an optional third step to produce the compound of formula (I) in salt form. This is advantageous over the prior art synthesis for the further reasons described herein.
  • the first step of this part of the method is the production of a compound of formula (XVII) by coupling the carboxylic acid of formula (XV) with the amine of formula (XVI).
  • This process can be carried out by methods similar to General Method J of US 6,699,994.
  • carrying out this step as described below confers significant advantages over the prior art for the reasons set out below.
  • the invention provides a method of producing a compound of formula (XVII):
  • X, n, R 3a , R 4b , R 5a and R 5b are as defined above; in the presence of a base of which the pK a of the conjugate acid ranges from 4 to 10 and optionally a suitable amide coupling agent.
  • the amine of formula (XVI) is typically supplied to the reaction in the form of a bis-acid addition salt, such as a dihydrochloride salt. It will be appreciated that the amine of formula (XVI) has both an arylamine and an amidine functional group, either of which is capable of reacting with the carboxylic acid of formula (XV) depending on the conditions under which the reaction is carried out. It has surprisingly been found by the present inventors that using a base of which the pK a of the conjugate acid ranges from 4 to 10 in the above reaction allows much greater selectively for the arylamine functional group, allowing the reaction to proceed in good yield, while avoiding the formation of significant side products. This conveys a significant advantage compared with the synthetic methods of the prior art.
  • amide coupling agent examples include but are not limited to: dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N- ethoxycarbonyl-2-ethoxy-1 ,2-dihydroquinoline (EEDQ), O-benzotriazole- ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethyl-uronium-hexafluoro -phosphate (HBTU)), 2-(5-norborene-2,3- dicar
  • the reaction is preferably carried out in the presence of a suitable amide coupling additive, the nature of which is not especially critical provided it is capable of promoting the coupling reaction of an amine with a carboxylic acid.
  • suitable amide coupling additives include but are not limited to hydroxybenzotriazole (HOBt), N- Hydroxysuccinimide (HOSu) and 1-hydroxy-7-azabenzotriazole (HOAt).
  • the reaction is carried out in the presence of a base of which the pK a of the conjugate acid ranges from 4 to 10. This allows much greater selectively for the arylamine functional group, allowing the reaction to proceed in good yield, while avoiding the formation of significant side products.
  • the reaction is preferably carried out in the presence of a base of which the pK a of the conjugate acid ranges from 4.5 to 6.5, such as 4.6 to 6.1 , such as 5 to 5.5, such as 5.2 to 5.4.
  • the reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent.
  • suitable solvents include alcohols such as methanol, ethanol, isopropanol and tert-butanol, and symmetrical and unsymmetrical ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, tert- butylmethylether and dioxane, amines such as pyridine, acetonitrile, sulfoxides such as dimethyl sulfoxide, amides such as DMF, and HMPA, or ketones such as acetone.
  • the solvent is an alcohol, in particular isopropanol.
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from -20°C to 50°C, and preferably -10°C to room temperature.
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 30 minutes to 48 hours, and preferably 1 to 24 hours.
  • the compound of formula (XVII) is isolated from the reaction mixture by conventional methods.
  • the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • an aqueous solution such as water or sodium chloride
  • methanesulfonic acid it has been found particularly advantageous according to the present invention to add methanesulfonic acid during the reaction workup.
  • the methanesulfonic acid salt isolated is crystalline and particularly easy to handle. This avoids the need to use column chromatography to purify the product.
  • the product can be precipitated from the reaction mixture, for example as the hydrochloride salt, and directly taken forward to the next step.
  • a bis-acid addition salt such as a dihydrochloride salt
  • the amide coupling agent is supplied to the reaction in the form of an acid addition salt, such as a hydrochloride salt
  • the product can be precipitated from the reaction mixture, for example as the hydrochloride salt, and directly taken forward to the next step.
  • the second step of this part of the method is the production of a compound of formula (I) by hydrolysis of the carboxylic ester functionality of the compound of formula (XVII).
  • This process can be carried out by a number of methods well known to those skilled in the art, including those similar to General Method 1-2 of US 6,699,994.
  • carrying out this step according to the conditions below confers significant advantages over the prior art for the reasons set out below.
  • the invention provides a method of producing a compound of formula (I), in which X, Y, m, n, R 2 , R 3a , Rsb, R 4a , R 4 b, Rsa, Rsb and R 7 are as defined above;
  • X, Y, m, n, R 2 , R3ai Rsbi R4ai R ⁇ tbi Rsai Rsb Sind R7 are as defined above, to ester hydrolysis conditions in the presence of acetonitrile as solvent.
  • the reaction is carried out in the presence of a base, the nature of which is not especially critical provided it is capable of promoting ester hydrolysis.
  • a base is preferred as the hydrolysis reaction is rendered irreversible by deprotonation of the carboxylic acid.
  • suitable bases include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, of which sodium hydroxide is preferred.
  • reaction is carried out in the presence of an acid, the nature of which is not especially critical provided it is capable of neutralizing the base.
  • Suitable acid catalysts include Bronsted acids, particularly strong mineral acids such as sulphuric acid, nitric acid, hydrochloric acid, methanesulfonic acid, acetic acid and formic acid of which acetic acid is preferred.
  • the reaction is normally and preferably carried out in the presence of a solvent.
  • the reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from -20°C to 50°C, and preferably -5°C to 20°C.
  • the reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from preferably from 10 minutes to 12 hours, and more preferably 1 to 12 hours.
  • the compound of formula (X) is isolated from the reaction mixture by conventional methods.
  • the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
  • the product may further be purified by conventional methods such as crystallization or column chromatography.
  • the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
  • the final step of the synthesis is optional and comprises one or more of the following: treating the compound of formula (I) with a base to produce a cationic salt of the compound of formula (I); and/or treating the compound of formula (I) with an acid to produce an acid addition salt of the compound of formula (I).
  • the base used to treat the compound of formula (I) is not particularly limited; examples of such bases include alkali metal hydroxides such as potassium, sodium and lithium hydroxides or alkali metal alkoxides, such as potassium ethanolate and sodium propanolate; alkaline earth metal hydroxides such as calcium hydroxide; ammonia; salts of primary, secondary and tertiary amines including, as primary amines, methylamine, ethylamine, propylamine, benzylamine, aniline and butylamine, as secondary amines dimethylamine, and diethylamine, and as tertiary amines trimethylamine and
  • triethylamine substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, ⁇ , ⁇ '-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso- propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine,
  • triethanolamine triethylamine, trimethylamine, tripropylamine and tris-(hydroxymethyl)- methylamine (tromethamine).
  • Alkali metal hydroxides especially sodium hydroxide, are preferred.
  • the acid used to treat the compound of formula (I) is not particularly limited; examples of such acids include hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid; other mineral acids such as sulfuric, nitric or phosphoric acid, etc.; alkyl and monoarylsulfonic acids such as methanesulfonic, ethanesulfonic, toluenesulfonic and benzenesulfonic acids; and other organic acids and their corresponding salts such as acetic, tartaric, maleic, succinic, citric, benzoic, salicylic and ascorbic acid.
  • hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid
  • other mineral acids such as sulfuric, nitric or phosphoric acid, etc.
  • alkyl and monoarylsulfonic acids such as methanesulfonic, ethanesulfonic, toluenesulfonic and benzenesulfonic acids
  • Further acid addition salts of the compound of formula (I) that can be produced according to the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, butyrate, camphorate, camphorsulfonate, caprylate, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, 1 ,2-ethanedisulfonate (edisylate), fumarate, galacterate (from mucic acid), galacturonate, gentisate, glucoheptonate, gluconate, glutamate,
  • glycerophosphate glycolate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesulfonate, isethionate, iso-butyrate, lactate, lactobionate, malate, malonate, mandelate, metaphosphate, methylbenzoate,
  • the acid is hydrochloric acid, sulfuric acid or
  • methanesulfonic acid The preferred salt is hydrochloride.
  • the compounds of formula (I) used in the present invention also possess a free acid form, and may be present as free acids.
  • a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • Hydrochloride salt of the compounds of formula (I) are especially preferred. Therefore in one aspect the present invention provides a hydrochloride salt of a compound of formula (I), as defined above.
  • the present invention provides a hydrochloride salt of a compound of formula (XVIII):
  • the present disclosure provides 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5- methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride and pharmaceutical compositions thereof.
  • the present disclosure also provides for novel crystalline forms of 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride and pharmaceutical compositions thereof.
  • a crystal form may be referred to herein to be characterized "as depicted in" a Figure.
  • Such data include powder X-ray diffractograms (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and scanning electron microscopy.
  • PXRD powder X-ray diffractograms
  • DSC differential scanning calorimetry
  • TG thermogravimetric analysis
  • scanning electron microscopy The skilled person will understand that the data as depicted in the Figures may be subject to variations (for example, variations in peak intensity and/or exact peak positions) due to variations on instrument parameters, sample concentration, and sample purity.
  • the skilled person will be able to compare the Figures herein and the data for an unknown crystalline form and determine whether the data characterize the crystalline form (s) disclosed or different crystalline forms.
  • a crystalline form (polymorph) may be referred to herein as substantially free of any other crystalline (polymorphic) forms.
  • the expressions "substantially free of any other forms” means that the crystalline form contains, 20% or less (w/w), 10% or less (w/w), 5% or less (w/w), 2% or less (w/w), or 1 % or less (w/w) of other crystalline (polymorphic) forms of the subject compound as measured, for example, by PXRD.
  • a crystalline form of 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2- carboxylic acid hydrochloride contains greater than 80% (w/w), greater than 90% (w/w), greater than 95% (w/w), greater than 98% (w/w), or greater than 99% (w/w) of the subject polymorphic form of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride.
  • the present disclosure provides two crystalline 3-[2-(4-carbamimidoyl-phenylcarbamoyl)- 5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride, namely form A (also referred to as compound XIX) and form C (also referred to as compound XX).
  • the present disclosure provides crystalline form A of 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride.
  • form A (compound XIX) is characterized by data selected from a group consisting of: i) a powder XRD (PXRD) pattern having peaks at 7.3, 9.5, 18.5 and 21.9 2 ⁇ 0.2 °2 ⁇ ; ii) a powder XRD pattern having peaks at 7.31 , 9.52, 18.54 and 21.85 2 ⁇ 0.2 °2 ⁇ ; iii) a PXRD pattern as depicted in FIG. 15; and iv) any combination thereof.
  • PXRD powder XRD
  • form A is characterized by data selected from a group consisting of: i) a powder XRD pattern having peaks at 14.7, 20.3, 22.5, 22.7, 26.1 , and 26.7 2 ⁇ 0.2 0 2 ⁇ ; ii) a powder XRD pattern having peaks at 14.65, 20.28, 22.51 , 22.96, 26.14, and 26.72 2 ⁇ 0.2 0 2 ⁇ ; iii) a differential scanning calorimetry (DSC) thermogram as depicted in FIG. 16; iv) a thermogravimetric (TG) thermogram as depicted in FIG. 17; v) a crystal structure as determined by scanning electron
  • form A is characterized by data selected from a group consisting of: i) a powder XRD (PXRD) pattern having peaks at 7.3, 9.5, 18.5 and 21.9 2 ⁇ 0.2 °2 ⁇ ; ii) a powder XRD pattern having peaks at 7.31 , 9.52, 18.54 and 21.85 2 ⁇ 0.2 °2 ⁇ ; iii) a PXRD pattern as depicted in FIG.
  • PXRD powder XRD
  • variable hydrate in relation to crystalline 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride means that the water content is dependent on relative humidity ("RH") conditions. At about room temperature and 30% RH, Form A shows water content consistent with a monohydrate (estimated at about 1.2 mole of water per mole of crystalline form A).
  • the compound of formula (XIX) is present as a hydrochloride salt, wherein the chloride content of the salt is greater than or equal to 0.65 and less than or equal to 1.4 (molar ratio of chloride to compound XVIII) or greater than or equal to 0.65 and less than or equal to 1 (molar ratio of chloride to compound XVIII).
  • form A has the advantageous property of superior solubility in pharmaceutical compositions, in particular oral pharmaceutical compositions.
  • pharmaceutical compositions of form A (compound XIX), in particular oral pharmaceutical compositions, when administered to a subject provide for increased bioavailability of the compound as compared to amorphous 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid and salts thereof and other crystalline forms.
  • form A (compound XIX) has the advantageous property of stability to polymorphic conversion.
  • Form A of crystalline 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride is substantially free of any other polymorphic forms.
  • Methods for the manufacture of form A are disclosed herein.
  • Form A may be obtainable by treatment of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy- 4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid in aqueous acetonitrile with base followed by hydrochloric acid, precipitation of 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride, and washing of the 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride with methyl terf-butyl ether.
  • the present disclosure provides crystalline form C of 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride.
  • form C is characterized by data selected from a group consisting of: i) a powder XRD (PXRD) pattern having peaks at 4.2, 7.9, and 10.8 2 ⁇ 0.2 °2 ⁇ ; ii) a powder XRD pattern having peaks 4.15, 7.94, and 10.79 2 ⁇ 0.2 °2 ⁇ ; iii) a PXRD pattern as depicted in FIG. 19; and iv) any combination thereof.
  • PXRD powder XRD
  • form C is characterized by data selected from a group consisting of: i) a powder XRD pattern having peaks at 12.6, 20.9, 21.3, 23.8, 24.5, 27.0, and 28.4 2 ⁇ 0.2° 2 ⁇ ; ii) a powder XRD pattern having peaks at 12.57, 20.90, 21.31 , 23.97, 24.45, 27.02, and 28.36 2 ⁇ 0.2° 2 ⁇ ; iii) a differential scanning calorimetry (DSC) thermogram as depicted in FIG. 20; iv) a thermogravimetric (TG) thermogram as depicted in FIG. 21 ; and v) any combination of the foregoing.
  • DSC differential scanning calorimetry
  • form C is characterized by data selected from a group consisting of: i) a powder XRD (PXRD) pattern having peaks at 4.2, 7.9, and 10.8 2 ⁇ 0.2 °2 ⁇ ; ii) a powder XRD pattern having peaks 4.15, 7.94, and 10.79 2 ⁇ 0.2 °2 ⁇ ; iii) a PXRD pattern as depicted in FIG.
  • PXRD powder XRD
  • Form C means that the water content is dependent on relative humidity ("RH") conditions. At about room temperature and 34% RH, Form C shows water content close to a monohydrate (estimated at about 1.4 mole of water per mole of crystalline Form C).
  • the crystalline 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride Form C of the invention is substantially free of any other polymorph forms.
  • Form C may be obtainable by treatment of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6- (cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid in aqueous acetonitrile with base followed by hydrochloric acid, precipitation of 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2- carboxylic acid hydrochloride, and washing of the 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2- carboxylic acid hydrochloride with
  • the compounds used in the present invention may exist in the form of solvates. Such solvates include solvent molecules in their crystal structure. Therefore, in a further aspect, the invention provides a pharmaceutically acceptable solvate of a compound of formula (I) as defined herein, either in its broadest aspect or a preferred aspect, and a method of producing it.
  • the invention provides a pharmaceutically acceptable solvate of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl- phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid and a method of producing it.
  • solvates include hydrates and alcoholates.
  • solvates include hydrates and alcoholates.
  • Prodrug derivatives of the compounds of Formula (I) produced in the present invention can be prepared by modifying substituents of compounds of the present invention that are then converted in vivo to a different substituent.
  • the invention includes in the step of producing a compound of Formula (I) or pharmaceutically acceptable salt, solvate, ester or prodrug thereof, methods of converting the compound of formula (I) into a salt or solvate thereof, or into an ester or other prodrug thereof, or into a salt or solvate of an ester or other prodrug thereof.
  • Esters of the compounds of Formula (I) produced in the present invention can be formed by reacting the compounds with a suitable compound containing a hydroxyl group. Therefore, in a further aspect, the invention includes in the step of producing a compound of Formula (I) or pharmaceutically acceptable salt, solvate, ester or prodrug thereof, methods of producing a pharmaceutically acceptable ester of a compound of formula (I) as defined herein, either in its broadest aspect or a preferred aspect.
  • the invention provides a method of producing a pharmaceutically acceptable ester of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]- 6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid.
  • suitable esters include alkyl esters, in particular C -4 alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl esters, and longer-chain alkyl esters such as C 5 .
  • alkyl esters including pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadceyl, heptadecyl, octadecyl, nonadecyl, icosyl, henicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl and triacontyl esters.
  • esters include substituted Ci -4 alkyl esters (preferably substituted methyl or ethyl esters) wherein the substituent is selected from the group consisting of:
  • hydroxyl group examples include 2-hydroxyethyl
  • alkoxy group in particular Ci -4 alkoxy
  • substituted groups include methoxymethyl or 2-ethoxyethyl
  • RO-C( 0)-0- wherein R is C 1-6 alkyl; examples of such substituted groups include isopropyl methyl carbonate wherein the ester moiety has the formula
  • amino acid residue including but not limited to Gly (glycine), Ala (alanine;
  • Glu glutamic acid
  • His histidine
  • lie isoleucine
  • Leu leucine
  • amino acid residue may be attached via its amine terminus, its carboxylic acid terminus or a side chain; examples of such substituted groups include valinemethyl, 2-
  • substituted groups examples include 2-(morpholino)ethyl.
  • Amide prodrugs of the compounds of formula (I) can be formed by reacting the compounds with a suitable compound containing a primary or secondary amine group, such that the carboxylic acid group forms an amide bond with the amine, eliminating a molecule of water. Therefore, in a further aspect, the invention includes in the step of producing a compound of Formula (I) or pharmaceutically acceptable salt, solvate, ester or prodrug thereof, methods of producing a pharmaceutically acceptable amide prodrug of a compound of formula (I) as defined herein, either in its broadest aspect or a preferred aspect.
  • the invention provides a method of producing a pharmaceutically acceptable amide prodrug of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)- 5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid.
  • amide prodrugs include those formed by reaction with the following: ammonia; alkylamines, in particular C 1-4 alkyl amines such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamines, sec-butylamine and tert-butyl amine;
  • dialkylamines in particular di(C 1-4 alkyl) amines such as dimethylamine, diethylamine, N- methylethylamine, dipropylamine, N-methylpropylamine, N-methylisopropylamine, N- ethylisopropylamine, diisopropylamine, dibutylamine, diisobutylamine, di(sec-butyl)amine and di(tert-butyl)amine;
  • di(C 1-4 alkyl) amines such as dimethylamine, diethylamine, N- methylethylamine, dipropylamine, N-methylpropylamine, N-methylisopropylamine, N- ethylisopropylamine, diisopropylamine, dibutylamine, diisobutylamine, di(sec-butyl)amine and di(tert-butyl)amine;
  • arylalkylamines and diarylalkylamines such as benzylamine and benzhydrylamine
  • amino acid residues such as those defined and exemplified above in relation to amino acid substituted alkyl esters
  • saturated nitrogen-containing heterocyclic amines having 3-8 ring atoms, of which at least one ring atom is a nitrogen atom and other heteroatoms are selected from nitrogen, oxygen and sulphur; including but not limited to aziridine; azetidine; pyrrolidine;
  • Amidine prodrugs of the compounds produced in the present invention can be formed by reacting the compounds with a compound capable of reacting with an amidine functional group. Therefore, in a further aspect, the invention includes in the step of producing a compound of Formula (I) or pharmaceutically acceptable salt, solvate, ester or prodrug thereof, methods of producing a pharmaceutically acceptable amidine prodrug of a compound of formula (I) as defined herein, either in its broadest aspect or a preferred aspect. In one embodiment, the invention provides method of producing a
  • amidine prodrugs include the following:
  • prodrugs wherein the amidine is bonded to a hydroxyl group
  • prodrugs wherein the amidine is bonded to an alkyl group; such as those defined and exemplified above;
  • prodrugs with amino acid residues where the amino acid residue is as defined and exemplified above in relation to amino acid substituted alkyl esters; examples of such prodrugs include valine amides; and
  • carbamates in particular alkyl carbamates, such as C 1-6 alkyl carbamates such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl carbamates.
  • alkyl carbamates such as C 1-6 alkyl carbamates such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl carbamates.
  • the prodrugs may themselves form salts and solvates.
  • suitable salts and solvates include as those listed above in relation to pharmaceutically acceptable salts and solvates of the compounds of formula (I).
  • prodrugs of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy- 4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid, including salts thereof, that can be produced according to the present invention include those listed in Table 1 below.
  • Example-1 Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid hydrochloride (7b)
  • the mixture was allowed to settle and most of the supernatant liquid was decanted to a waste container using nitrogen pressure.
  • Water (600 L) was added to the solid, stirred, mixture was allowed to settle and then most of the supernatant liquid was decanted to a waste container using nitrogen pressure.
  • Water (100 L) was added to the decanted mixture, stirred for 15 min and the solid obtained was collected by filtration using a centrifuge. The solid was washed with water (2 x 100 L) and air-dried in a tray drier for 3.75 h to afford the crude product 1 b (52 kg).
  • Average yield of isolated 1 b from step-1 is 78 - 88%.
  • Step (3) 5-Hydroxy-4-methoxy-2-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- y benzaldehyde (4a)
  • the mixed filtrate was washed with water (17.5 L), brine (17.5 L), dried over Na 2 S0 4 , filtered and the solution was passed through a pad of silica gel (2 kg, mesh size 230-400). The silica gel pad was washed with toluene. The combined filtrate and washing was concentrated under reduced pressure and the residual crude product was stirred with n-hexane (23 L) for 1 h to obtain a solid product.
  • step (3) The average yield of 5-hydroxy-4-methoxy-2-(4,4,5,5-tetramethyl-[1 ,3,2]dioxa-borolan-2- yl)benzaldehyde (4a) from step (3) is 78 - 90%.
  • 2,6-lutidine (5a) (115 kg, 1073.3 mol) was added into pre-chilled oleum (20-23%, 1015 kg, 2276.7 mol) at 0 °C over a period of 4.5 h (temperature r6ached 14 °C during the addition).
  • Bromine (88.18 kg, 1103.6 mol) was then added at 5-10 °C over a period of 1 h.
  • the reaction mixture was slowly heated to 150 °C over a period of 12h. TLC analysis indicated about 40-50% conversion to product and the formation of a dimer by-product (5%).
  • the reaction mixture was cooled to room temperature and then additional bromine (88.18 kg, 1103.6 mol) was added slowly.
  • the reaction mixture was slowly heated to maintain a temperature of 65-75 °C over a period of 15h. TLC analysis indicated a 65-70 % conversion to product and the formation of 5% dimer by product.
  • the reaction mixture was quenched by addition of water (500L) while maintaining the reaction temperature below 20 °C.
  • the mixture was basified with 6.6 M NaOH (3800 L) while maintain the temperature at ⁇ 40 °C.
  • EtOAc (220 L) was added and the mixture was stirred for 1 h then allowed to settle over a period of 2 h. The layers were separated and the aqueous layer was treated with NaOH (10 kg) in water (10 L) and extracted with EtOAc (160 L).
  • the average isolated yield for step (7) is 50% to 60%.
  • Step (8) Preparation of methyl 6-((cyclopropylmethyl)carbamoyl)-3-(2-formyl-4-hydroxy- 5-methoxyphenyl)picolinate (6a) 2
  • the reaction mixture was degassed again two times by applying alternate vacuum and nitrogen.
  • the reaction mixture was heated at reflux for 6.5 h, cooled to room temperature and filtered through a Celite bed. Water (75 L) was added to the filtrate and the product was extracted with ethyl acetate (75 L). The aqueous layer was back extracted with ethyl acetate (2 ⁇ 60 L). The combined ethyl acetate extract was divided into two equal portions and each portion was washed with brine (37 L), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give crude methyl 6-
  • Step (9) Preparation of methyl 6-((cyclopropylmethyl)carbamoyl)-3-(2-formyl-5-methoxy- 4-(((trifluoromethyl)sulfonyl)oxy)phenyl)picolinate (6b)
  • the reaction mixture was stirred at -5°C for 1.3 h, quenched with saturated aqueous NaHCO 3 (10.4 L) and stirred for 30 mins.
  • the organic layer was separated, washed successively with saturated aqueous NaHC0 3 (10.4 L), 1 HCI (2 x 16.6 L), water (13.2 L), brine (13.2 L), dried over MgS0 4 , filtered and concentrated under reduced pressure to give the crude product.
  • the crude product was stirred with 15% ethyl acetate in n-hexane (7.0 L) for 1 h.
  • the solid obtained was collected by filtration washed with 15% ethyl acetate in n- hexane (3.0 L).
  • the solid was stirred again with 15% ethyl acetate in n-hexane (7.0 L) for 1 h, was collected by filtration and washed with 15% ethyl acetate in n-hexane (3.0 L).
  • the solid was stirred again with 15% ethyl acetate in n-hexane (8.0 L) for 1 h, collected by filtration washed with 15% ethyl acetate in n-hexane (3.0 L).
  • the reaction mixture was cooled to room temperature and then filtered through a Celite bed. Demineralized water (118 L) was added to the filtrate followed by ethyl acetate (124 L). The mixture was stirred for 20 min and then the organic layer was separated. The aqueous layer was back-extracted with ethyl acetate (2 x 95 L). The combined organic extract was washed with brine (95 L), dried over Na 2 S0 4 , and filtered. The solvent was evaporated under reduced pressure to give the crude product.
  • the crude product was purified by column chromatography (silica gel, 120 kg, 230-400 mesh size, eluting with ethyl acetate in n-hexane) to obtain methyl 6- ((cyclopropylmethyl)carbamoyl)-3-(2-formyl-5-methoxy-4-vinylphenyl)picolinate (6c) (6 kg, 72%).
  • Step (1 1) Preparation of 2-(6-((cyclopropylmethyl)carbamoyl)-2-
  • the reaction mixture was stirred at 0 °C for 2 h, diluted with water (40 L) and ethyl acetate (24 L). After stirring the mixture, it was allowed to settle and the organic layer was separated. The aqueous layer was back-extracted with ethyl acetate (2 x 20 L) then acidified with 5.9 % aqueous acetic acid (2 L) and extracted once with ethyl acetate (10 L).
  • Step (13) Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-rnethoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid hydrate
  • this material can be crystallized from a mixture of acetone and water.
  • Step 14 Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid hydrochloride (7b
  • a pre-cooled (5-8 °C) aqueous NaOH solution prepared from solid NaOH (1.97 kg, 49.25 mol) in demineralized water (41 L) was added to a pre-cooled (0-5 °C) suspension of (3i) (13.8 kg, 26.9 mol) in acetonitrile (41 L).
  • the reaction mixture was stirred at 0-5 °C for 30 min (until the reaction mixture becomes homogeneous).
  • the reaction mixture was filtered through a sparkler filter washed with 50% acetonitrile in demineralized water (4.4 L). The filtrate was charged into a reactor and cooled to 0-5 °C.
  • Aqueous HCI prepared from cone.
  • Average isolated yield for this step varies from 63% to 80%.
  • Example-2 Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid sulfate salt (8b)
  • Step-2 preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid sulfate salt (8b)
  • reaction mixture was neutralized with a solution of sulfuric acid (0.483 ml, 9.00 mmol) in water (5 mL) and stirred for 10 min at room temperature. To this cold water (5 ml) was added and stirred at room temperature until product crystallized out. Cold water (5 mL) was added to the slurry and stir for additional 20 min, additional cold water (5 mL) was added prior to filtration of solid.
  • Example-3 Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid methane s

Landscapes

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

Abstract

The invention provides methods and intermediates useful in the synthesis of a compound of formula (I): or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; wherein the variables are as defined herein.

Description

METHOD FOR PRODUCING AMIDINE DERIVATIVES
Field of the Invention The present invention relates to an improved method for preparing certain amidine derivatives. The invention also relates to intermediates useful in the method, and to methods for preparing such intermediates.
Background to the Invention
A synthesis of the compound 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4- vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid (Compound 3i) is described in Schemes A-C.
O y OHCk n Br^ ^OCH3
B Brr22,, AAccOOHH Y^ V"" \ \ tt--BBuuOOKK
OHC^^^O " Br^\^0 MeOH " OHC
1a 1b 66%
Figure imgf000003_0001
1d 95% 1 e
Figure imgf000003_0002
1f
Scheme A
Figure imgf000004_0001
Figure imgf000005_0001
3h 31
Scheme C
A synthetic scheme for similar compounds, including some reactions similar to those set out in Schemes A-C, is described in US 6,699,994,
The original synthesis described above suffers from multiple drawbacks that made it unsuitable for large-scale preparations. In particular, the synthesis is very long - it includes five steps to produce the compound 1f (total yield 10.9%) and seven to produce the compound of formula 2h (total yield 23%). The remaining synthesis, beginning with the coupling step of the compounds 1f and 2h, takes nine steps to reach the final product, so a total of 21 chemical steps are involved in the total synthesis.
In addition, the isolation of the products of this synthesis is done by column
chromatography, which is unsuitable for large scale processes. Furthermore, many of the reagents used are expensive or unavailable for large scale and several reagents and solvents are unsafe for scale up. Many of the steps are impractical and unsafe, and not suitable for scale up. This would lead to a high cost of manufacturing the product.
Summary of the Invention
In one aspect, the invention comprises a method of producing a compound of formula (I):
Figure imgf000006_0001
(I)
wherein:
X is CH or ;
Y is CH or N;
Ri is hydrogen, C^6 alkyl, C3.8 cycloalkyl, C -6 alkoxy or C3.8 cycloalkoxy, C1-6 alkylthio, aryl, aryloxy, heteroaryl or heteroaryloxy;
R2 is hydrogen, C1-6 alkyl, C3.6 cycloalkyl or (C3.6cycloalkyl)-C -6 alkyl, each optionally substituted by 1 or 2 hydroxyl groups;
R3a and R3b are each independently hydrogen or C1-6 alkyl;
m is 0, 1 or 2;
n is 0, 1 , 2, 3 or 4; R4a and R4b are each independently hydrogen, C1-6 alkyl, C3_8 cycloalkyl, C1-6 alkoxy or C3-8 cycloalkoxy, aryl, heteroaryl, or aralkyl; and
R5a and R5b are each independently hydrogen or C1-6 alkyl;
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof;
according to the method steps described herein.
In one aspect, the invention provides a method of producing a compound of formula (VI):
Figure imgf000007_0001
VI
wherein:
Ri is as defined above, and
R6a and R6b are each independently C1-6 alkyl; or R6a and R6 together with the boron and oxygen atoms to which they are attached form an optionally substituted 5-7-membered ring;
the method comprising reacting a compound of formula (IV):
Figure imgf000007_0002
IV
wherein is as defined above, and
Hal is a halogen atom;
with a compound of formula (V):
Figure imgf000007_0003
V
wherein R6a and R6b are as defined above;
in the presence of a suitable catalyst.
In another aspect, the invention comprises a method of producing a compound of formula (XI):
Figure imgf000008_0001
XI in which:
Y, Hal, R2 and R3b are as defined above; and
R7 is C1-8 alkyl (optionally substituted with one or more of the following: chlorine, fluorine, C-i.6 alkoxy, C3-8 cycloalkoxy, C3-8 cycloalkyl, heterocycloalkyl, heterocycloalkoxy, aryl or heteroaryl), C2-6 alkenyl; C2-6 alkynyl; C3-8 cycloalkyl, aryl or heteroaryl;
treating a compound of formula (X):
Figure imgf000008_0002
X in which Y, Hal and R7 are as defined above;
with an amine of formula NHR2R3b (in which R2 and R3b are as defined above);
in a suitable solvent at a dilution of 0.5 to 1.0 moles per litre.
In a yet further aspect, the invention provides a method of producing a compound of
Figure imgf000008_0003
XIV in which Y, Ri , R2 and R3b, R4a, R7 and m are as defined above;
the method comprising reacting a compound of formula (XIII):
Figure imgf000009_0001
XIII in which Y, R-i, R2 and R3b, R4a, R7 and m are as defined above and LG is a leaving group;
with a vinylating agent of formula
[CH2=CHB(RC)3]- M+ or [CH2=CHB(ORd)2]
in which Rc is a halogen atom (preferably fluorine) or a C1-6 alkoxy group,
Rd is hydrogen or a boronate ester residue; and
M is an alkali metal atom (preferably lithium, sodium or potassium, more preferably potassium);
in the presence of a suitable coupling catalyst and, optionally a ligand and/or a base.
In another aspect, the invention provides a method of producing a compound of formula
Figure imgf000009_0002
XVII in which Y, Ri, R2, R3a, R3b, R4a, R4b, Rsa, Rsb, R7, m and n are as defined above;
the method comprising reacting a carboxylic acid of formula (XV):
Figure imgf000010_0001
XV wherein Y, R2, R3b, a, rn and R7 are as defined above;
with an amine of formula (XVI):
Figure imgf000010_0002
XVI wherein X, n, R3a, R4b, R5a and R5b are as defined above
in the presence of a base of which the pKa of the conjugate acid ranges from 4 to 10, and optionally a suitable amide coupling agent and/or an amide coupling additive.
In a still further aspect, the invention provides a method of producing a compound of formula (I), in which X, Y, m, n, R f R2, R3a, R3b, R4a, 4b, Rsa and R5b are as defined above;
the method comprising subjecting a carboxylic ester of formula (XVII):
Figure imgf000010_0003
XVII wherein X, Y, m, n, R1 t R2, R3ai R3bi R4ai R4b> Rsai Rsb ^nd R7 are as defined above, to ester hydrolysis conditions in the presence of acetonitrile as solvent.
In a still further aspect, the invention provides a method of producing a compound of formula (I) as defined above; comprising the steps of:
(a) producing a carboxylic ester of formula (XVII), as defined above, by reacting a carboxylic acid of formula (XV) with an amine of formula (XVI), as defined above, in the presence of a base of which the pKa of the conjugate acid ranges from 4 to 10, and optionally a suitable amide coupling agent and/or an amide coupling additive; and (b) subjecting said carboxylic ester of formula (XVII) to ester hydrolysis conditions in the presence of a strong alkali metal hydroxide (such as NaOH, KOH or LiOH) in a suitable solvent such as acetonitrile, methanol or ethanol, and the like, preferably acetonitrile.
In another aspect, the invention provides a method of producing a compound of formula (VI), as defined above, using the following steps:
(a) halogenation of a compound of formula (II):
Figure imgf000011_0001
(N)
using a suitable halogenating agent, to produce a compound of formula (III):
Figure imgf000011_0002
(HI)
(b) conversion of the compound of formula (III) to a compound of formula (IV), as defined above; and
(c) conversion of the compound of formula (IV) to a compound of formula (VI) by reacting said compound of formula (IV) with a compound of formula (V) as defined above.
In another aspect, the invention provides a method of producing a compound of formula (XV), as defined above, using the following steps:
(a) treating a compound of formula (XI), as defined above, with a compound of formula (VI) as defined above to produce a compound of formula (XII)
Figure imgf000012_0001
(XII)
in which Y, m, Ri, R2, R3b, R4a and R7 are as defined above
(b) treating the compound of formula (XII) with a compound capable of converting an alcohol into a leaving group to produce a compound of formula (XIII) as defined above;
(c) reacting the compound of formula (XIII) with a vinylating agent as defined above in the presence of a coupling catalyst and a base, to produce a compound of formula (XIV); and
(d) oxidation of the aldehyde function of the compound of formula (XIV) with an oxidizing agent to produce a compound of formula (XV) .
Advantages and Surprising Findings
The method steps enable the compounds of formula (I) to be produced in much larger quantities than was possible in the prior art. In particular, the method steps permit the compounds of formula (I) to be produced on scales exceeding 100, such as more than 1 kg, such as more than 10 kg.
The method of the present invention is a much shorter synthesis (a total of 13 chemical steps) than the prior method. In particular, it involves only six steps beginning with the coupling of the boron compound and the halogenated arylamide. In addition, the reagents are commercially available on large scale; the procedure is safer and suitable for scale up; and the compatibility of various functional groups minimizes undesirable side reactions and improves isolated yields; the steps used avoid protection and deprotection of functional groups; and the cost of manufacturing and production time are both reduced significantly. Definitions
In this specification "alkyl" means a straight or branched, saturated aliphatic radical having a chain of carbon atoms. (Ci_6)alkyl means alkyl groups that have a chain of between 1 and 6 carbons such as methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, isobutyl, ferf-butyl, n-pentyl and n-hexyl. In some embodiments, the alkyl group may be a (C1-4), (C1-3) or (C1-2) alkyl. "Cycloalkyl" means a saturated monocyclic ring of carbon atoms. (C3.8)cycloalkyl includes cyclopropyl, cyclobiityl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. . In some embodiments, the cycloalkyl group may be a (C3-6) or (C3.4) cycloalkyl.
"(Cycloalkyl)-alkyl" means alkyl, as defined above (either in its broadest aspect or a preferred aspect), which is substituted by cycloalkyl, as defined above (either in its broadest aspect or a preferred aspect). Examples of (cycloalkyl)-alkyl groups include (C3-8cycloalkyl)methyl groups such as cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl cyclohexylmethyl, cycloheptylmethyl and cyclooctylmethyl. . In some embodiments, the (cycloalkyl)alkyl group may be a (C3.4)cycloalkyl(C1-2) alkyl group, and in particular cyclopropylmethyl.
"Alkoxy" means an oxygen atom bonded to an alkyl group, wherein alkyl is as defined above(either in its broadest aspect or a preferred aspect). (C1-6)alkoxy means alkoxy groups that have a chain of between 1 and 6 carbons such as methoxy, 1-ethoxy, 2- ethoxy, 1-propyloxy, 2-propyloxy, 3-propyloxy, isopropoxy, 1-butyloxy, 2-butyloxy, 3- butyloxy, 4-butyloxy, sec-butyloxy, isobutyloxy, ferf-butyloxy, 1-pentyloxy and 1- hexyloxy.
"Alkenyl" means a straight or branched, aliphatic radical having a chain of carbon atoms and one or more double bonds. (C2-6)alkenyl means alkenyl groups that have a chain of between 2 and 6 carbons such as vinyl, 1-propenyl, 1-butenyl, 2-butenyl, isobutenyl, 1- pentenyl and 1-hexenyl. In some embodiments, the alkenyl group may be a (C2-3) alkenyl. "Alkynyl" means a straight or branched, aliphatic radical having a chain of carbon atoms and one or more triple bonds. (C2-6)alkynyl means alkynyl groups that have a chain of between 2 and 6 carbons such as ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl and 1-hexynyl. In some embodiments, the alkynyl group may be a (C2-3) alkynyl.
"Aralkyl" means alkyl, as defined above (either in its broadest aspect or a preferred aspect), which is substituted by 1 to 3 aryl groups, as defined below (either in its broadest aspect or a preferred aspect). The aryl group may be substituted as defined below. Examples of aralkyl groups include benzyl, phenethyl, benzhydryl and trityl.
"Alkylthio" means a sulfur atom bonded to an alkyl group, wherein alkyl is as defined above(either in its broadest aspect or a preferred aspect). (C -6)alkylthio means alkylthio groups that have a chain of between 1 and 6 carbons such as methylthio, 1-ethylthio, 2- ethylthio, 1-propylthio, 2-propylthio, 3-propylthio, isopropylthio, 1-butylthio, 2-butylthio, 3- butylthio, 4-butylthio, sec-butylthio, isobutylthio, te/f-butylthio, 1-pentylthio and 1- hexylthio.
"Cycloalkoxy" means an oxygen atom bonded to a cycloalkyl group, wherein cycloalkyl is as defined above (either in its broadest aspect or a preferred aspect). (C3-8)cycloalkoxy includes cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. In some embodiments, the cycloalkoxy group may be a (C3.6) or (C3.4) cycloalkoxy.
"Halogen" means fluorine, chlorine, bromine or iodine.
"Hydroxyl" means the group -OH.
"Alkylene", unless indicated otherwise, means a straight or branched, saturated, aliphatic, divalent radical. (C1-6)alkylene means an alkylene groups that has a chain of between 1 and 6 carbons such as includes methylene (-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2-), tetramethylene (-CH2CH2CH2CH2-),
2-methyltetramethylene (-CH2CH(CH3)CH2CH2-), pentamethylene
(-CH2CH2CH2CH2CH2-), hexamethylene (-CH2CH2CH2CH2CH2CH2-) and 1 ,1 ,2,2- tetramethylethylene (-C(CH3)2C(CH3)2-)and the like. "Alkoxy" means an oxygen atom bonded to an alkyl group, wherein alkyl is as defined above (either in its broadest aspect or a preferred aspect). (C1-6)alkoxy means alkoxy groups that have a chain of between 1 and 6 carbons such as methoxy, 1-ethoxy, 2- ethoxy, 1-propyloxy, 2-propyloxy, 3-propyloxy, isopropoxy, 1-butyloxy, 2-butyloxy, 3- butyloxy, 4-butyloxy, sec-butyloxy, isobutyloxy, terf-butyloxy, 1-pentyloxy and 1- hexyloxy.
"Heterocycloalkyi" means a saturated 3 to 8 membered ring, wherein at least one (preferably 1 to 3, such as 1 or 2) of the atoms forming the ring is a heteroatom selected, independently from N, O, or S. Examples of heterocycloalkyi include azetidinyl, piperidyl, morpholyl, piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1 ,4- diazaperhydroepinyl, tetrahyrofuranyl, 1 ,3-dioxanyl and 1 ,4-dioxanyl. "Heterocycloalkoxy" means an oxygen atom bonded to a heterocycloalkyi group, wherein heterocycloalkyi is as defined above (either in its broadest aspect or a preferred aspect).
"Aryl" means phenyl or naphthyl. The aryl group may be optionally substituted with a number (preferably 1 to 5, such as 1 , 2 or 3) substituents selected from halogen, hydroxy, (C1-6)alkyl, (C1-6)alkoxy, (C1-6)alkylthio, (C3.8)cycloalkyl, (C3-8)cycloalkoxy, aryl and nitro.
"Aryloxy" means an oxygen atom bonded to an aryl group, wherein aryl is as defined above (either in its broadest aspect or a preferred aspect). The aryl group may be optionally substituted with a number (preferably 1 to 5, such as 1 , 2 or 3) substituents selected from halogen, hydroxy, (C1-6)alkyl, (C1-6)alkoxy, (C1-6)alkylthio, (C3.8)cycloalkyl, (C3-8)cycloalkoxy, cyano and nitro.
"Heteroaryl" means a monocyclic or bicyclic or polycyclic aromatic group wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are carbon. Monocyclic heteroaryl groups include, but are not limited to, cyclic aromatic groups having five or six ring atoms, wherein at least one (preferably 1 to 4, such as 1 , 2 or 3) ring atom is a heteroatom and the remaining ring atoms are carbon. Examples of heteroaryl groups of this invention include furanyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, 1 ,2,3-oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, thiazolyl, 1 ,3,4-thiadiazolyl, triazolyl and tetrazolyl. The heteroaryl group may be optionally substituted with a number (preferably 1 to 5, such as 1 , 2 or 3) substituents selected from halogen, hydroxy, (C -6)alkyl, (C1-6)alkoxy,
(C^alkylthio, (C3.8)cycloalkyl, (C3-8)cycloalkoxy, cyano and nitro.
"Heteroaryloxy" means an oxygen atom bonded to a heteroaryl group, wherein heteroaryl is as defined above (either in its broadest aspect or a preferred aspect). The heteroaryl group may be optionally substituted with a number (preferably 1 to 5, such as 1 , 2 or 3) substituents selected from halogen, hydroxy, (C1-6)alkyl, (C1-6)alkoxy,
(C1-6)alkylthio, (C3.8)cycloalkyl, (C3-8)cycloalkoxy, cyano and nitro.
"Nitro" means the group -N02. "Cyano" means the group -CN.
In one embodiment, X is CH. In another embodiment, X is N.
In one embodiment, Y is CH. In another embodiment, Y is N.
In one embodiment, is hydrogen. In one embodiment, R-, is a C1-6 alkyl group. In one embodiment, R-, is a C -6 alkoxy group. In one embodiment, is a methoxy group.
In one embodiment, the group Ri is present at the 4-position of the phenyl ring (the carbon attached to the amide group being the 1-position).
In one embodiment, R2 is C1-6 alkyl, C3-6 cycloalkyl or (Cs-ecycloalky -C^e alkyl, each optionally substituted by 1 or 2 hydroxyl groups. In one embodiment, R2 is a
(C3-4)cycloalkyl(C1-2) alkyl group. In one embodiment, R2 is a cyclopropylmethyl group.
In one embodiment, R3a is hydrogen or methyl. In one embodiment, R3a is hydrogen. In one embodiment, R3b is hydrogen or methyl. In one embodiment, R3b is hydrogen. In one embodiment, m is 0 (i.e. R4a is absent and there are no additional substituents on the ring).
In one embodiment, n is 0 (i.e. R4b is absent and there are no additional substituents on the ring).
In one embodiment, R5a is hydrogen or methyl. In one embodiment, R5a is hydrogen.
In one embodiment, each R5b is independently hydrogen or methyl. In one embodiment, each R5b is hydrogen.
In one embodiment, R7 is C1-6 alkyl, C3.8 cycloalkyl or benzyl. In one embodiment, R7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, cyclohexyl or benzyl. In one embodiment, the compounds used in the present invention are compounds of formula (I), as defined above, provided that when X is N, Y is CH, RT is 4-methoxy, m is 0, n is 0, and R3a, R3b, Rsa and R5b are all hydrogen, R2 is other than isobutyl. Such compounds are referred to herein as compounds of formula ( ). In one embodiment, X is CH, Y is N, Ri is hydrogen or methoxy, R2 is a
(C3-4)cycloalkyl(C1-2) alkyl group, m is 0, n is 0, and R3a, R3b, R5a and R5b are all hydrogen.
In one embodiment, X is CH, Y is N, is 4-methoxy, R2 is a cyclopropylmethyl group, m is 0, n is 0, and R3a, R3b, R5a and R5b are all hydrogen.
In particular, the methods of the present invention relate to the production of a compound of formula (XVIII):
Figure imgf000018_0001
XVIII
and to crystalline Form A and crystalline Form C thereof, as described in more detail below.
Brief description of the Drawings
Figure 1 depicts a flow chart of the procedure of Step 1 of Example 1.
Figure 2 depicts a flow chart of the procedure of Step 2 of Example 1.
Figure 3 depicts a flow chart of the procedure of Step 3 of Example 1.
Figure 4 depicts a flow chart of the procedure of Step 4 of Example 1.
Figure 5 depicts a flow chart of the procedure of Step 5 of Example 1.
Figure 6 depicts a flow chart of the procedure of Step 6 of Example 1.
Figure 7 depicts a flow chart of the procedure of Step 7 of Example 1.
Figure 8 depicts a flow chart of the procedure of Step 8 of Example 1.
Figure 9 depicts a flow chart of the procedure of Step 9 of Example 1.
Figure 10 depicts a flow chart of the procedure of Step 10 of Example 1.
Figure 1 1 depicts a flow chart of the procedure of Step 11 of Example 1.
Figure 12 depicts a flow chart of the procedure of Step 12 of Example 1.
Figure 13 depicts a flow chart of the procedure of Step 13 of Example 1.
Figure 14 depicts a flow chart of the procedure of Step 14 of Example 1.
Figure 15 depicts a powder X-ray diffraction pattern (PXRD) of Compound XIX in
Example 5.
Figure 16 depicts a differential scanning calorimetry (DSC) thermogram of Compound XIX in Example 5. Figure 17 depicts a thermogravimetric (TG) thermogram of Compound XIX in Example 5. Figure 18 depicts a crystal structure as determined by scanning electron microscopy (SEM) of Compound XIX in Example 5.
Figure 19 depicts a powder X-ray diffraction pattern (PXRD) of Compound XX in
Example 4.
Figure 20 depicts a differential scanning calorimetry (DSC) thermogram of Compound XX in Example 4.
Figure 21 depicts a thermogravimetric (TG) thermogram of Compound XX in Example 4. Method Steps
Particular features of the method of the present invention are as follows.
Production of Boronate Esters of Formula (VI)
The boronate esters of Formula (VI) which are used to form one moiety of the compound of formula (I) may be produced in a three step synthesis according to Scheme 1 below. This synthesis is advantageous over the prior art synthesis in which five steps were needed to produce the corresponding intermediate.
OHC. ^ HO- ^^CHO
OHC ^ υ Hal^^O
(ll) (III)
(IV)
Figure imgf000019_0001
Scheme 1
The first step of the method is the production of a compound of formula (III) by halogenation of a compound of formula (II) by procedures known in the literature.
Examples of such procedures are described in the following references: A.E.
Haakansson et al; Chemistry - A European Journal, 12(12), 3243-3253; 2006; G. Poli and G. Giambastiani, J. Org. Chem., 67(26), 9456-9459; 2002; R.H. Furneaux, et al; J. Org. Chem., 69(22), 7665-7671 ; 2004; Lin, Ming-Yuan et al; J. Am. Chem. Soc, 128(29), 9340-9341 ; 2006; B.D. Chapsal, and I. Ojima, Iwao; Organic Letters, 8(7), 1395-1398; 2006; P.C. Conrad, et al; J. Org Chem., 52(4), 586-91 ; 1987; S.A Baechler et al; Bioorg. Med. Chem. , 21 (3), 814-823; 2013; B.D. Chapsal, et al; Tetrahedron: Asymmetry, 17(4), 642-657; 2006; S.P.; Khanapure, et al; J. Med. Chem., 46(25), 5484-5504; 2003; S.P. Khanapure and E.R.Biehl, J. Org. Chem, 55(5), 1471-5; 1990; P.C. Stanislawski et al; Organic Letters, 8(10), 2143-2146; 2006; G. Cahiez et al; Organic Letters, 7(10), 1943- 1946; 2005; G. Cahiez et al; Organic Letters, 7(10), 1943-1946; 2005; A.I. Meyers et al; J. Am. Chem. Soc, 109(18), 5446-52; 1987; S. Mitra, et al; J. Org. Chem, 72(23), 8724- 8736; 2007.
Suitable halogenating reagents include, bromine, N-bromosuccinimide; 1 ,3-dibromo-5,5- dimethylhydantoin and the like, more preferably bromine or N-bromosuccinimide; most preferably bromine.
The reaction is carried out in the presence of an acid. The acid may be a Bnzmsted acid, examples of which include a hydrohalic acid such as hydrochloric acid and hydrobromic acid, a carboxylic acid such as acetic acid, propionic acid, oxalic acid, formic acid, and mandelic acid; a sulfonic acid such as p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid or camphor-sulfonic acid, or a mineral acid such as sulfuric acid or nitric acid; or a Lewis acid such as AICI3 or FeCI3. (which may be in catalytic amounts). A catalytic amount of iodine and Fe can also be used in the reaction. Selective monobromination of electron-rich arenes can also be carried out using CuBr2 or alkali metal bromides in the presence of concentrated H2S04 or various oxidants in the presence of acids and/or catalysts.
The reaction is normally and preferably carried out in a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. Examples of suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, halogenated hydrocarbons such as carbon tetrachloride, chloroform, or
dichloromethane; ethers such as diethyl ether, dioxane, or tetrahydrofuran; carbon disulfide; alcohols such as methanol or ethanol; and carboxylic acids and anhydrides thereof such as acetic acid or acetic anhydride. Preferably the solvent is a carboxylic acid, most preferably the solvent is acetic acid.
The reaction temperature typically ranges from 0°C to 50°C, and preferably room temperature to 40°C.
The reaction time typically ranges from 1 to 72 hours, and preferably 12 to 48 hours.
After completion of the reaction, the compound of formula (III) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent. The product may further be purified by conventional methods such as crystallization or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography purify the product.
The second step of the method is the production of a compound of formula (IV). When the group R^ is alkoxy, aryloxy or heteroaryloxy, this process involves base-catalysed alcoholysis of a compound of formula (III) using an alcohol of formula R-,Η. This process can be carried out by methods similar to General Method Z of US 6,699,994.
When the group R-i is alkoxy, aryloxy or heteroaryloxy, the reaction is carried out in the presence of an alcohol of formula R^ .
The reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. Polar solvents are preferred.
Examples of suitable solvents include alcohols such as methanol, ethanol, isopropanol and terf-butanol; ketones such as acetone; sulfoxides such as dimethyl sulfoxide; and amides such as Ν,Ν-dimethylformamide and hexamethylphosphoramide; and mixtures thereof. When the group R-i is alkoxy, it is preferred that the alcohol of formula R^H additionally acts as the solvent, either wholly or partially. A mixture of the alcohol of formula R^ and dimethyl sulfoxide is preferred.
The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from room temperature to 70°C, and preferably 40 to 60°C.
The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 10 minutes to 12 hours, and preferably 30 minutes to 6 hours. After completion of the reaction, the compound of formula (IV) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water, sodium chloride or sodium hydroxide in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent. The product may further be purified by conventional methods such as crystallisation or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product. The third step of the method is the production of a compound of formula (VI) by reaction of the compound of formula (IV) with a bis-boronate ester of formula (V). This step has not been previously described in the art.
Therefore, in one aspect, the invention provides a method of producing a compound of formula (VI):
Figure imgf000022_0001
VI
wherein:
Ri is as defined above, either in its broadest aspect or a preferred aspect
Hal is a halogen atom, preferably bromine; and
R6a and R6b are each independently C1-6 alkyl; or R6a and R6b together with the boron and oxygen atoms to which they are attached form an optionally substituted 5-7-membered ring, the substituents on the ring being defined by those on the starting diboron compound of formula (V) below;
the method comprising reacting a compound of formula (IV):
Figure imgf000023_0001
IV
wherein R-i and Hal are defined above, either in its broadest aspect or a preferred aspect;
with a compound of formula (V):
Figure imgf000023_0002
b
V
wherein R6a and R6b are as defined above;
in the presence of a suitable catalyst.
Examples of bis-boronate esters usable in this step include 4,4,5,5-tetramethyl-l ,3,2- dioxaborolane; bis(pinacolato)diboron; bis(diethyl-l-tartrate glycolato)diboron; 4,4,5,5- tetramethyl-l ,3,2-dioxaborolane; bis(hexyleneglycolato)diboron; bis(diisopropyl-d-tartrate glycolato)-diboron; bis(catecholato)diboron; bis(diisopropyl-l-tartrate glycolato)diboron; bis[(+)-pinanediolato]diboron; bis(A/,/V,W\W'-tetramethyl-d-tartaramide glycolato)diboron; catecholborane; bis[(-)-pinanediolato]diboron; bis(N,A/,/V\N'-tetramethyl-l-tartaramide glycolato)diboron; bis(neopentylglycolato)-diboron; bis(diethyl-d-tartrate
glycolato)diboron; bis(/V,A/,/V\A/'-tetramethyl-l-tartaramide glycolato)diboron; and 2- isopropoxy-4,4,5,5-tetramethyl[1 ,3,2]dioxa-borolane. For each of the above reagents, the residue corresponds to the ring formed by R6a and R6b together with the boron and oxygen atoms to which they are attached; for example, the ring formed in
bis(pinacolato)diboron is a 5-membered ring formed by the boron and oxygen atoms and the 1 ,1 ,2,2-tetramethylethylene residue.
In one embodiment, R6a and R6b are each independently C1-4 alkyl; or R6a and R6b together form a 1 ,1 ,2,2-tetramethylethylene group. A preferred reagent of formula (V) is bis(pinacololato)diboron, in which the groups R6a and R6b on each oxygen attached to boron together form a 1 ,1 ,2,2-tetramethylethylene group. It has surprisingly been found by the present inventors that use of the boronate esters of formula (V) enables the reaction to proceed in good yield, while avoiding the formation of significant side products, and without the need to first protect the alcohol aldehyde functional groups on the compound of formula (IV). This conveys a significant advantage compared with the synthetic methods of the prior art, which required the use of an alkyllithium reagent to attach the boron moiety for this step: such reagents are known to react with alcohols and aldehydes. Avoiding the need to protect these groups enables the boron compounds of formula (VI) to be produced in two fewer steps than was possible in the prior art.
The reaction is carried out in the presence of a suitable catalyst, the nature of which is not especially critical provided it is capable of catalysing the coupling reaction of a boronate ester with an aryl halide. Suitable catalysts include palladium (II) and palladium (0) complexes, particularly those palladium (II) or palladium (0) complexes having one or more (preferably 2 or 4) nitrogen or phosphorus ligands bonded to the palladium. Ligand free catalytic systems can also be used in this type of reaction.
Examples of suitable palladium catalysts include palladium acetate;
tetrakis(triphenylphosphine)palladium(0); bis(triphenylphosphine)palladium(ll) dichloride;
[1 , 1'-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride; allylchloro[1 ,3-bis(2,4,6- trimethylphenyl)imidazol-2-ylidene]palladium(ll); bis(dibenzylideneacetone)palladium(0); N,N'-[bis(2,6-dimethylphenyl)-1 ,3-dimethyM ,3- propanediylidene](methyl)(triethylphosphine)palladium(ll); 1 ,3-bis(2,6-di-i- propylphenyl)imidazol-2-ylidene(1 ,4-naphthoquinone)palladium(0) dimer; [P,P'-1 ,3- bis(di-i-propylphosphino)propane][P-1 ,3-bis(di-i-propylphosphino)propane]-palladium(0); bis(tri-t-butylphosphine)palladium(0); 1 ,2-bis(phenylsulfinyl)ethane-palladium(ll) acetate; 1 ,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene(1 ,4-naphthoquinone) palladium(O); bis(tri-o-tolylphosphine)palladium(0); chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1 ,1'- biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll);
chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1 , 1 '-biphenyl)(2'-amino-1 , 1 '-biphenyl-2- yl) palladium(ll); chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1 ,1'-biphenyl)[2-(2- aminoethylphenyl)]palladium(ll) methyl-t-butylether adduct; chloro(2- dicyclohexylphosphino-3,6-dimethoxy-2l,4',6'-tri-i-propyl-1 ,1 '-biphenyl)(2'-amino-1 ,1'- biphenyl-2-yl)palladium(ll); chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-tri-i- propyl-1 ,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll); chloro(2- dicyclohexylphosphino-2',6'-di-i-propoxy-1 , 1 '-biphenyl)(2-amino-1 , 1 '-biphenyl-2- yl)palladium(ll); chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1 ,1'-biphenyl)[2-( 2-aminoethylphenyl)]palladium(ll) methyl-t-butylether adduct; chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1 , 1 '-biphenyl)(2'-amino-1 , 1 -biphenyl-2-yl) palladium(ll), chloro(2-dicyclohexylphosphino-2',4',6,-tri-i-propyl-1 l1'-biphenyl)[2-( 2-aminoethyl)phenyl] palladium(ll) methyl-t-butylether adduct; chloro(di-2- norbornylphosphino)(2'-dimethylarnino-1 ,1'-biphenyl-2-yl)palladium(ll), chloro(di-2- norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladiurn(ll), chloro[(1 ,2,3-r))- 3-phenyl-2-propenyl][1 ,3-bis(2,6-di-i-propylphenyl)-4l5-dihydroimidazol-2- ylidene]palladium(ll), chloro[(1 ,2,3-r|)-3-phenyl-2-propenyl][1 ,3-bis(2,6-di-i- propylphenyl)imidazol-2-ylidene]palladium(ll), trans-di( -acetato)bis[o-(di-o- tolylphosphino)benzyl]dipalladium(ll), di- -bromobis(tri-t-butylphosphino)-dipalladium(l); dichlorobis(acetonitrile)palladium(ll), dichlorobis(benzonitrile)-palladium(ll), dichloro[1 ,1'- bis(dicyclohexylphosphino)ferrocene]palladium(ll), dichloromethane adduct,
dichlorobis{[4-(N,N-dimethylamino)phenyl]di-t-butylphosphino}palladiurn(ll); dichloro[(R)- (+)-2,2,-bis(diphenylphosphino)-1 ,1'-binaphthyl]palladium(ll); dichloro[(S)-(-)-2,2'- bis(diphenylphosphino)-1 , 1 '-binaphthyl]palladium(ll); dichloro[1 , 1 - bis(diphenylphosphino)ferrocene]palladium(ll) dichloromethane adduct; dichloro[1 ,1'- bis(di-i-propylphosphino)ferrocene]-palladium(ll), trans- dichlorobis(triphenylphosphine)palladium(ll); dichloro(di-p-chloro)bis[1 ,3-bis(2,6-di-i- propylphenyl)imidazol-2-ylidene]dipalladium(ll); dichloro[9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene]palladium(ll); dichloro(norbomadiene)palladium(ll), methanesulfonato[2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',4',6'- tri-i-propyl-1 ,1'-biphenyl](2'-amino-1,1,-biphenyl-2-yl)palladium(ll), methanesulfonato(2- di-t-butylphosphino-2\4',6'-tri-i-propyl-1 ,1'-biphenyl)(2,-amino-1 ,1'-biphenyl-2- yl)palladium(ll), methanesulfonato(2-dicyclohexylphosphino-2',6'-dimethoxy-1 ,1'- biphenyl)(2'-amino-1 ,1'-biphenyl-2-yl)palladium(ll) dichloromethane adduct;
methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1 ,1'- biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(ll); methanesulfonato(2- dicyclohexylphosphino-2',6'-di-i-propoxy-1 , 1 '-biphenyl)(2-amino-1 , 1 '-biphenyl-2- yl)palladium(ll), methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1 , 1'-biphenyl)(2'-amino-1 ,1'-biphenyl-2-yl)palladium(ll); palladium(ll) chloride Tris[di(4-acetoxybenzylidene)acetone]dipalladium(0) di(4 acetoxybenzylidene)-acetone adduct; tris(dibenzylideneacetone)dipalladium(0) chloroform adduct;
and tris(dibenzylideneacetone)dipalladium (0). The preferred catalyst is
tetrakis(triphenylphosphine)palladium (0).
The reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. Examples of suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, aromatic hydrocarbons such as benzene, toluene and xylenes; symmetrical or unsymmetrical ethers such as tetrahydrofuran, dioxane, dimethoxyethane or tert-butyl methyl ether, alcohols like tert-butanol, n-butanol; water; nitriles such as acetonitrile; and mixtures thereof. The use of a suitable amount of cosolvents in water or the use of pure water as the solvent are used in the ligand-free catalytic systems. It is preferred that the solvent is an aromatic hydrocarbon, in particular toluene.
The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 50°C to the boiling point of the solvent, and preferably 70°C to 1 10°C.
The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from preferably from 30 minutes to 24 hours, and more preferably 6 to 18 hours. After completion of the reaction, the compound of formula (VI) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
The product may further be purified by conventional methods such as crystallisation or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product. Production of Amides of Formula (XI)
The amides of Formula (XI) which are used to form one moiety of the compound of formula (I) may be produced in a four step synthesis according to Scheme 2 below.
Figure imgf000027_0001
(VII) (VIII) (IX)
Figure imgf000027_0002
Scheme 2
This synthesis is advantageous over the prior art synthesis for the reasons described herein. f this part of the method is the production of a compound of formula (VIII):
Figure imgf000027_0003
VIII
in which R8 is (Ci-6) alkyl (preferably methyl), and Hal is a halogen atom (preferably bromine);
n of a compound of formula (VII):
Figure imgf000027_0004
(VII)
in which R8 is as defined above.
This method is known in the literature, for example in N. Zimmermann et al; Bioorganic Chemistry, 32(1), 13-25; 2004; and A.D. Dunn and S. Guillermic, Zeitschrift fiir Chemie, 28(2), 59-60; 1988. Suitable halogenating reagents include bromine, N-bromosuccinimide, 1 ,3-dibromo-5,5- dimethylhydantoin, and the like, more preferably bromine or N-bromosuccinimide; most preferably bromine. The reaction is carried out in the presence of a strong acid. Examples of suitable acids include Bronsted acids such as those described and exemplified above, particularly nitric acid, sulphuric acid and oleum (sulphuric acid containing dissolved sulphur trioxide) and Lewis acids such as AICI3 or AIBr3. Oleum is preferred. The reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. It is preferred that the acid also acts as the solvent. The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 20°C to 200°C, and preferably 100 to 150°C.
The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 2 to 96 hours, and preferably 24 to 80 hours.
After completion of the reaction, the compound of formula (VIII) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water, sodium chloride or sodium hydroxide in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent. The product may further be purified by conventional methods such as distillation or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
The second step of the method is the production of a compound of formula (IX). This process involves treating the compound of formula (VIII), as defined above with an oxidizing agent to oxidize the alkyl side chains of the compound of formula (VIII) to carboxylic acids. This process can be carried out by methods well known to those skilled in the art. This oxidation can be carried out by any other oxidizing agents well known to those skilled in the art. Examples of suitable oxidizing agents include manganese (VII) compounds such as sodium permanganate or potassium permanganate. Potassium permanganate is preferred. This method is known in the literature, for example in N. Zimmermann et al; Bioorganic Chemistry, 32(1), 13-25; 2004; and E. Meggers et al; Journal of the American Chemical Society, 122(43), 10714-10715; 2000.
The reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. Polar solvents are preferred and water is especially preferred. This oxidation can be facilitated by the addition of an organic co-solvent such as dioxane, pyridine, acetone or teAi-butanol.
The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 40 to 120°C, and preferably 60 to 100°C. The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 1 to 48 hours, and preferably 6 to 24 hours.
After completion of the reaction, the compound of formula (IX) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent. The product may further be purified by conventional methods such as crystallisation or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product. The third step of the method is the production of a bis-ester compound of formula (X). This process involves treating the bis-carboxylic acid of formula (IX) with an alcohol of formula R7OH (in which R7 is as defined herein) to esterify both the carboxylic acid functional groups. This process can be carried out by esterification methods well known to those skilled in the art.
The reaction is carried out in the presence of an acid catalyst, the nature of which is not especially critical provided it is capable of catalysing an esterification reaction.
Examples of suitable acid catalysts include Bransted acids, examples of which include hydrohalic acids such as hydrofluoric, hydrochloric or hydrobromic acids, carboxylic acids such as acetic acid, propionic acid, oxalic acid, formic acid, mandelic acid, and the like; sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid,
trifluoromethanesulfonic acid, camphor-sulfonic acid, and mineral acids such as sulfuric acid or nitric acid. The preferred catalyst is sulphuric acid.
The reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. Examples of suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, aromatic hydrocarbons such as benzene, toluene and xylenes; alcohols such as methanol, ethanol, isopropanol and tert-butanol; and mixtures thereof. It is preferred that the alcohol of formula R7OH (wherein R7 is as defined above, either in its broadest aspect or a preferred aspect) also acts as the solvent. The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 40°C to 100°C, and preferably 50°C to 80°C.
The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 10 minutes to 48 hours, and more preferably 4 to 24 hours.
After completion of the reaction, the compound of formula (X) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent. The product may further be purified by conventional methods such as crystallisation or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product. The fourth step of this part of the method is the amination of the bis-ester compound of formula (X) to produce the amide of formula (XI). This process involves treating the bis- ester of formula (X) with an amine of formula NHR2R3 (in which R2 and R3b are as defined herein). However, depending on the conditions under which the reaction is carried out, the product can be contaminated with the alternative amide and bis-amide the structures of which are shown below:
Figure imgf000031_0001
It has been unexpectedly found by the present inventors that this reaction can be controlled by carrying out the reaction in suitable solvents at particular dilutions to reduce the production of the bis-amide and the alternative amide.
Therefore, in another aspect, the invention comprises a method of producing a compound of formula (XI):
Figure imgf000031_0002
XI 2015/046582
in which Y, R2l R3t>, Hal and R7 are as defined above, either in its broadest aspect or a preferred aspect;
the method comprising treating a compound of formula (X):
Figure imgf000032_0001
X
in which Y, Hal and R7 are as defined above, either in its broadest aspect or a preferred aspect;
with an amine of formula NHR2R3 (in which R2 and R3b are as defined above);
in a suitable solvent at a dilution of 0.5 to 1.0 moles per litre.
The reaction is carried out in a suitable solvent. It has unexpectedly been found that the choice of solvent enables the compound of formula (XI) in a manner which avoids the production of the by-products illustrated above. Examples of suitable solvents include tetrahydrofuran, acetonitrile, Ν,Ν-dimethylformamide, isopropanol and tert-butanol; and mixtures thereof, of which tert-butanol is preferred.
The reaction is carried out at a dilution of 0.5 to 1.0 moles per litre. It has unexpectedly been found that carrying out the reaction at this level of dilution enables the compound of formula (XI) in a manner which reduces the production of the by-products illustrated above. Preferably, the reaction is carried out at a dilution of 0.7 to 0.8 moles per litre. By "dilution" is meant the concentration of the compound of formula (X) in the reaction mixture.
The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 40°C to 100°C, and preferably 50°C to
80°C.
The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from preferably from 2 to 48 hours, and more preferably 12 to 24 hours. After completion of the reaction, the compound of formula (XI) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
The product may further be purified by conventional methods such as crystallisation or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
Coupling of Boronate esters of Formula (VI) with Amides of Formula (XI) and subsequent processing to carboxylic acids of formula (XV) The carboxylic acids of formula (XV) which are used to form one moiety of the compound of formula (I) may be produced in a four step synthesis according to Scheme 3 below. This is advantageous over the prior art synthesis in that two fewer steps are used compared with the prior art and for the further reasons described herein.
Figure imgf000033_0001
Scheme 3 The first step of this part of the method is the production of a compound of formula (XII) by reaction of the amide of formula (XI) with the boronate ester of formula (VI). This step has not been previously described in the art, and confers significant advantages over the prior art for the reasons set out below.
Therefore, in one aspect, the invention provides a method of producing a compound of formula (XII):
Figure imgf000034_0001
(XII)
in which Y, n, R2, R3b, a and R7 are as defined above;
the method comprising reacting a compound of formula (XI)
Figure imgf000034_0002
(XI)
in which Y, R2, R3b, Hal and R7 are as defined above
with a compound of formula (VI):
Figure imgf000034_0003
(VI)
wherein R-,, R6a and R6b are as defined above;
in the presence of a suitable catalyst and, optionally, a ligand and/or a base.
It has surprisingly been found by the present inventors that the above reaction proceeds in good yield, while avoiding the formation of significant side products, and without the need to first protect the alcohol or aldehyde functional groups on the compound of formula (VI). This conveys a significant advantage compared with the synthetic methods of the prior art, which required the protection of these groups. Avoiding the need to protect these groups enables the compounds of formula (XII) to be produced in two fewer steps than was possible in the prior art.
The reaction is carried out in the presence of a suitable catalyst, the nature of which is not especially critical provided it is capable of catalysing the coupling reaction of a boronate ester with an aryl alide. Suitable catalysts include palladium (II) and palladium (0) complexes, particularly those palladium (II) or palladium (0) complexes having one or more (preferably 2 or 4) nitrogen or phosphorus ligands bonded to the palladium. Examples of suitable palladium catalysts include those described and exemplified above with respect to catalysts for the coupling reaction of the compounds of formulae (IV) and (V) to produce the compound of formula (VI). . The preferred catalyst is bis(triphenylphosphine)palladium (II) chloride.
The reaction is normally and preferably carried out in the presence of a ligand, the nature of which is not especially critical provided it is capable of coordinating to the catalyst used in the reaction. When the catalyst is a palladium complex, the ligand is preferably a nitrogen- or phosphorus-based ligand, examples of suitable ligands of which are well known to those skilled in the art and include the following:
(S)-1-amino-8-(diphenylphosphino)-1 ,2,3,4-tetrahydronaphthalene;
(1 R,2R)-2-amino-1-phenylpropyldiphenylphosphine;
(1 S,2S)-2-amino-1 -phenylpropyldiphenylphosphine;
(2-ammonioethyl)di-t-butylphosphonium bis(tetrafluoroborate);
(3-ammoniopropyl)di-t-butylphosphonium bis(tetrafluoroborate);
benzyldi-1 -adamantylphosphine;
1-benzyl-3-{(1 R,2R)-2-[(11 bS)-dinaphtho[2,1-d:1\2,-q[1 I3,2]dioxaphosphepin-4- ylamino]cyclohexyl}urea;
benzyldiphenylphosphine;
1-benzyl-3-[(1S,2S)-2-(di-o-tolylphosphinoamino)cyclohexyl]urea;
(R)-(+)-7-[4(S)-(benzyl)oxazol-2-yl]-7-di(3,5-di-t-butylphenyl)phosphino-2,2,3,3- tetrahydro-1 ,1-spirobiindane; (S)-(-)-7-[4(S)-(benzyl)oxazol-2-yl]-7-di(3,5-di-t-butylphenyl)phosphino-2,2,3,3- tetrahydro-1 ,1-spirobiindane;
(R)-(+)-7-[4(S)-(benzyl)oxazol-2-yl]-7'-diphenylphosphino-2,2,3,3-tetrahydro-1 ,1- spirobiindane;
(S)-(-)-7-[4(S)-(benzyl)oxazol-2-yl]-7-diphenylphosphino-2,2,3,3-tetrahydro-1 ,1'- spiroiindane;
(R.RX-J-e.e'-Kl .r-biphenyl^^'-diylJbisioxyMbis^.e-di-t-butyl-l ,2,10,11- tetramethyl]dibenzo[d,f][1 ,3,2]dioxaphosphepin bisacetonitrile adduct;
(S.SJ-i+J-e.e'-KI .I '-biphenyl^.Z-diylJbisioxy)] bis[4,8-di-t-butyl-1 ,2,10,1 1
tetramethyl]dibenzo[d,f][1 ,3,2]dioxaphosphepin bisacetonitrile adduct;
(1 R,2R)-N,N-bis{2-[bis(3,5-dimethylphenyl)phosphino]benzyl}cyclohexane-1 ,2-diami (1 S,2S)-N,N-bis{2-[bis(3,5-dimethylphenyl)phosphino]benzyl}cyclohexane-1 ,2-diamine^ (R)-2,2'-bis[bis(3,5-dimethylphenyl)phosphino]-4,4\6,6'-tetramethoxybiphenyl;
(S)-,2'-bis[bis(3,5-dimethylphenyl)phosphino]-4,4 6,6,-tetrarnethoxybiphenyl;
(R)-2,2'-bis[bis(4-methoxy-3,5-di-t-butylphenyl)phosphino]-4,4\6,6'-tetramethoxy- biphenyl;
(S)-2,2'-Bis[bis(4-methoxy-3,5-di-t-butylphenyl)phosphino]-4,4\6,6'-tetramethoxy- biphenyl;
(R)-2,2'-Bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-4,4\6,6'-tetramethoxy^ biphenyl;
(S)-2,2'-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-4,4\6,6'-tetramethoxybi
(R)-2,2'-bis[bis(3,5-trifluoromethylphenyl)phosphino]-4,4\6,6'-tetramethoxybiph (S)-
2,2'-bis[bis(3,5-trifluoromethylphenyl)phosphino]-4,4\6,6^etramethoxybiphen (R,R)-(-
)-2,3-bis(t-butylmethylphosphino)quinoxaline;
(S,S)-(+)-2,3-bis(t-butylmethylphosphino)quinoxaline;
bis(2-cyanoethyl)phenylphosphine;
bis[2-(di-1-adamantylphosphino)ethyl]amine;
2-[bis(3,5-di-t-butyl-4-methoxyphenyl)phosphino]benzaldehyde;
(R,R)-(+)-1 ,2-bis(t-butylmethylphosphino)benzene; (S,S)-(-)-1 ,2-Bis(t- butylmethylphosphino)benzene;
bis[2-(di-t-butylphosphino)ethyl]amine;
1 ,3-bis(di-t-butylphosphinomethyl)benzene;
2,6-bis(di-t-butylphosphinomethyl)pyridine;
1 ,5-bis(di-t-butylphosphino)pentane; a,a'-bis(di-t-butylphosphino)-o-xylene;
1 ,4-bis(di-t-butylphosphonium)butane bis(tetrafluoroborate);
1.2- bis(dichlorophosphino)-1 ,2-dimethylhydrazine;
2, 2'-bis(dicyclohexylphosphino)-1 ,1 '-biphenyl;
1 ,2-bis(dicyclohexylphosphino)ethane;
bis[2-(dicyclohexylphosphino)ethyl]amine;
bis(dicyclohexylphosphino)methane;
bis(2-dicyclohexylphosphinophenyl)ether;
1 ,4-bis(dicyclohexylphosphonium)butane bis(tetrafluoroborate);
1 ,2-bis(dicyclohexylphosphonium)ethane bis(tetrafluoroborate);
1.3- bis(dicyclohexylphosphonium)propane bis(tetrafluoroborate);
1.3- bis(dicyclopentylphosphinomethyl)benzene;
1.4- bis(dicyclopentylphosphonium)butane bis(tetrafluoroborate);
1 ,2-bis(dicyclopentylphosphonium)ethane bis(tetrafluoroborate);
1 ,3-bis(dicyclopentylphosphonium)propane bis(tetrafluoroborate);
(R)-(-)-5,5'-bis[di(3,5-di-t-butyl-4-meth^
(S)-(+)-5,5'-bis[di(3,5-di-t-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1 ,3-benzodioxole;
(R)-(-)-2,2'-bis[di(3,5-di-t-butyl-4-methoxyphenyl)phosphino]-6,6,-dimethoxy-1 ,1l- biphenyl;
(S)-(+)-2,2'-bis[di(3l5-di-t-butyl-4-methoxyphenyl)phosphino]-6,6'-dimethoxy-1 , 1 '- biphenyl;
(R)-(+)-2,2'-bis[di(3,5-di-t-butylp.henyl)phosphino]-6,6'-dimethoxy-1 ,1 '-biphenyl;
(SJ-^^^'-BisIdiiS.S-di-t-but lpheny phosphino^e.e'-dimethoxy-l .l '-biphenyl;
racemic-trans-1 ,2-Bis[di(3,5-dimethylphenyl)phosphinomethyl]cyclobutane;
(R)-(+)-7J'-bis[di(3,5-dimethylphenyl)phosphino]-2,2',3,3,-tetrahydro-1 l1'-spirobiindane; (S)-(-)-7,7,-bis[di(3,5-dimethylphenyl)phosphino]-2,2',3,3'-tetrahydro-1 ,1'-spirobiindane; (RJ-^^^'-bisIdiiS^-di-i-propyl^-dimethylaminopheny phosphinoj-e.e'-dimethoxy-l , 1 '- biphenyl;
(S)-(+)-2,2'-bis[di(3,5-di-i-propyl-4-dimethylaminophenyl)phosphino]-6,6'-dimethoxy-1 ,1'- biphenyl;
1 ,2-bis(diethylphosphino)ethane;
(-)-1 ,2-bis((2R,5R)-2,5-diethylphospholano)benzene;
(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene;
(+)-1 ,2-bis((2R,5R)-2,5-diethylphospholano)ethane; (-)-1 ,2-bis((2S,5S)-2,5-diethylphospholano)ethane;
(R)-(+)-2,2'-bis(di-2-furanylphosphino)-6,6'-dimethoxy-1 , 1 '-biphenyl;
(SJ- ^^'-bisidi^-furanylphosphinoJ-e.B'-dimethoxy-l , 1 '-biphenyl;
bis{2-[(1 1 bR)-3,5-dihydro-4H-dinaphtho[2 -c:1 \2'-e]phosphepin-4-yl]ethyl}amine; bis{2- [(11 bS)-3,5-dihydro-4H-dinaphtho[2,1-c:1 ',2,-e]phosphepin-4-yl]ethyl}amine; (+)-1 ,2- bis[(2S,5S)-2,5-dimethyl-(3S,4S)-3,4-dihydroxyphospholano]benzene
bis(trifluoromethanesulfonate)salt;
bis(3,5-dimethylphenyl)phosphine;
2-[bis(3,5-dimethylphenyl)phosphino]benzaldehyde;
(R)-(+)-7,7'-bis[di(4-methylphenyl)phosphino]-2,2,,3,3'-tetrahydro-1 ,1 '-spirobiindane; (S)-
(-)-7,7'-bis[di(4-methylphenyl)phosphino]-2,2',3,3'-tetrahydro-1 , 1 '-spirobiindane; 1 ,2- bis(dimethylphosphino)ethane;
bis(dimethylphosphino)methane;
(-)-1 ,2-bis((2R,5R)-2,5-dimethylphospholano)benzene;
(+)-1 ,2-bis((2S,5S)-2,5-dimethylphospholano)benzene;
(+)-1 ,2-bis((2R,5R)-2,5-dimethylphospholano)ethane;
(-)-1 ,2-bis((2S,5S)-2,5-dimethylphospholano)ethane;
(-)-2,3-bis[(2R,5R)-2,5-dimethylphospholanyl]-1-[3,5-bis(trifluoromethyl)phenyl]-1 H- pyrrole-2,5-dione;
(-)-2,3-bis[(2R,5R)-2,5-dimethylphospholanyl]-1-(3,5-dimethylphenyl)-1 H-pyrrole-2,5- dione;
(-)-2,3-bis[(2R,5R)-2,5-dimethylphospholanyl]maleic anhydride;
bis(4,6-dimethyl-3-sulfonatophenyl)(2,4-dimethylphenyl)phosphine, disodium salt hydrate;
1 ,2-bis(dipentafluorophenylphosphino)ethane;
bis(diphenylphosphino)acetylene;
N,N-bis(diphenylphosphino)amine;
(RJ-C+J^^'-bisCN-diphenylphosphinoaminoJ-S.S'.e.e'JJ'.S.S'-octahydro-l .r-binaphthyl; (SJ-C-^^'-bisiN-diphenylphosphinoaminoJ-S.S'.e.e'JJ'.e.S'-octahydro-l .r-binaphthyl; 1 ,2-bis(diphenylphosphino)benzene;
(1 R,2R)-N,N-bis[2-(diphenylphosphino)benzyl]cyclohexane-1 ,2-diamine;
(1 S,2S)-N,N-bis[2-(diphenylphosphino)benzyl]cyclohexane-1 ,2-diamine;
(R)-(+)-5,5'-bis(diphenylphosphino)-4,4'-bi-1 ,3-benzodioxole;
(S)-(-)-5,5'-bis(diphenylphosphino)-4,4'-bi-1 ,3-benzodioxole; (2R,3R)-(-)-2,3-bis(diphenylphosphino)-bicyclo[2.2,1]hept-5-ene;
(2S,3S)-(+)-2,3-Bis(diphenylphosphino)-bicyclo[2.2.1]hept-5-ene;
racemic-2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthyl;
(R)-(+)-2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthyl;
(S)-(-)-2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthyl;
2,2'-bis(diphenylphosphino)-1 , 1 '-biphenyl;
(2S,3S)-(-)-bis(diphenylphosphino)butane;
1.4- bis(diphenylphosphino)butane;
(R)-(-)-1 ,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1 ,5]dioxonin;
(S)-(+)-1 ,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1 ,5]dioxonin;
(R)-(+)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1 ,1 '-biphenyl;
(S)-(-)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1 ,1 '-biphenyl;
1 ,2-bis(diphenylphosphino)ethane;
1.2- bis(diphenylphosphino)ethane monoxide;
bis[(2-diphenylphosphino)ethyl]ammonium chloride;
cis-1 ,2-bis(diphenylphosphino)ethylene;
bis(2-diphenylphosphinoethyl)phenylphosphine;
bis(diphenylphosphino)methane;
bis(diphenylphosphino)methane monoxide;
(4R,5R)-(-)-4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1 ,3-dioxolane;
(4S,5S)-(+)-4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1 ,3-dioxolane;
S.S'-bisCdiphenylphosphinoJ-S.S'.e.e'jy.e.S'-octahydrop^'jbinaphthalene chloroform adduct;
(RJ-C+^^'-bisidiphenylphosphinoJ-S.S'.e.e'JJ'.S.S'-octahydro-l .r-binaphthyl; (SJ-^^^'-BisCdiphenylphosphino^S.S'.e.e'jy.e.e'-octahydro-l .l '-binaphthyl; 1 ,8-bis(diphenylphosphino)octane;
(R)-(-)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane;
(S)-(+)-4, 12-bis(diphenylphosphino)-[2.2]-paracyclophane;
1.5- bis(diphenylphosphino)pentane;
(2R,4R)-(+)-2,4-bis(diphenylphosphino)pentane;
(2S,4S)-(-)-2,4-bis(diphenylphosphino)pentane;
4.6- bis(diphenylphosphino)phenoxazine;
bis(2-diphenylphosphinophenyl)ether;
1.3- bis(diphenylphosphino)propane; (R)-(+)-1 ,2-bis(diphenylphosphino)propane;
1 ,3-bis(diphenylphosphino)propane monoxide;
(^-(-^S.S'-bisCdiphenylphosphino^^^'^'-tetrafluoro^^'-bi-I .S-benzodioxole, dichloromethane adduct;
(S)-(+)-5,5'-bis(diphenylphosphino)-2,2,2',2,-tetrafluoro-4,4'-bi-1 ,3-benzodioxole, dichloromethane adduct;
R-i+J-e.e'-bisidiphenylphosphino^^'.S.S'-tetrahydro-S.S'-bi-l ^-benzodioxin;
S-i-J-e.G'-bisidiphenylphosphino^^'.S.S'-tetrahydro-S.S'-bi-l ^-benzodioxin;
12, 12'-bis(diphenylphosphino)-9,9', 10, 10 -tetrahydro-1 1 , 1 1 '-bi-9, 10-ethenoanthracene; e.e'-bisCdiphenylphosphinoJ-l .l '.S.S'-tetrahydrofS.S'lbiisobenzofuran;
racemic-S.S'-bisidiphenylphosphinoJ-S.S'^^'-tetrahydro^^^'^'.e^'-hexamethyl^^'- spirobi[2H-1 -benzopyran];
(R)-(+)-7,7'-bis(diphenylphosphino)-2,2',3,3'-tetrahydro-1 , 1 -spirobiindane;
(SJ-i- J'-bisidiphenylphosphino^^'.S.S'-tetrahydro-l , 1 '-spirobiindane;
(R^^'-bisidiphenylphosphinoH^'.e.e'-tetramethoxybiphenyl;
(S)-2,2'-bis(diphenylphosphino)-4,4',6,6'-tetramethoxybiphenyl;
(1 Z,3Z)-1 ,4-bis(diphenylphosphino)-1 ,2,3,4-tetraphenyl-1 ,3-butadiene;
(-)-1 ,2-bis((2R,5R)-2,5-diphenylphospholano)ethane;
(+)-1 ,2-bis((2S,5S)-2,5-diphenylphospholano)ethane;
1 ,4-bis(di-i-propylphosphino)butane;
(R)-(+)-2,2'-bis(di-i-propylphosphino)-6,6'-dimethoxy-1 ,1 '-biphenyl;
(SJ-i-^^'-bisidi-i-propylphosphinoVe.e'-dimethoxy-l , 1 '-biphenyl;
1.2- bis(di-i-propylphosphino)ethane;
bis[(2-di-i-propylphosphino)ethyl]amine;
4,5-bis-(di-i-propylphosphinomethyl)acridine;
1.3- bis(di-i-propylphosphino)propane;
(+)-1 ,2-bis((2R,5R)-2,5-di-i-propylphospholano)benzene;
(-)-1 ,2-bis((2S,5S)-2,5-di-i-propylphospholano)benzene;
1 ,2-bis((2R,5R)-2,5-di-i-propylphospholano)ethane;
1 ,2-bis((2S,5S)-2,5-di-i-propylphospholano)ethane;
1 ,2-bis(di-2-pyridylphosphino)ethane;
1 ,2-bis(di-4-sulfonatophenylphosphino)benzene tetrasodium salt DMSO adduct;
(1 R,2R)-N,N-bis[2-(di-p-tolylphosphino)benzyl]cyclohexane-1 ,2-diamine;
(1 S,2S)-N,N-bis[2-(di-p-tolylphosphino)benzyl]cyclohexane-1 ,2-diamine; (R)-(+)-2,2'-bis(di-p-tolylphosphino)-1 , 1 '-binaphthyl;
(S)-(-)-2,2'-bis(di-p-tolylphosphino)-1 , 1 '-binaphthyl;
(RJ-C+^^'-bisidi-p-tolylphosphinoJ-S.e'-dimethoxy-l .r-biphenyl;
(S)-(-)-2,2'-bis(di-p-tolylphosphino)-6,6'-dimethoxy-1 ,1'-biphenyl;
(R)-2,2'-bis(di-p-tolylphosphino)-4,4',6,6'-tetramethoxybiphenyl;
(S^^'-bisidi-p-tolylphosphino^^'.e.e'-tetramethoxybiphenyl;
(R)-(+)-2,2'-bis[di(3,4,5-trimethoxyphenyl)phosphino]-6,6'-dimethoxy-1 , 1 '-biphenyl;
(S)-(-)-2,2'-bis[di(3,4,5-trimethoxyphenyl)phosphino]-6,6'-dimethoxy-1 , 1 '-biphenyl;
(R)-(+)-5,5'-bis[di(3,5-xylyl)phosphino]-4,4'-bi-1 ,3-benzodioxole;
(S)-(-)-5,5'-bis[di(3,5-xylyl)phosphino]-4,4'-bi-1 ,3-benzodioxole;
(R)-(+)-2,2'-bis[di(3,5-xylyl)phosphino]-1 , 1 '-binaphthyl;
(S)-(-)-2,2'-bis[di(3l5-xylyl)phosphino]-1 ,1,-binaphthyl;
(R)-(+)-2,2'-bis[di(3,5-xylyl)phosphino]-6,6'-dimethoxy-1 ,1'-biphenyl;
(S^C-^^'-bistdiCS.S-xyly phosphinol-e.e'-dimethoxy-l .l '-biphenyl;
(R)-(-)-4, 12-bis(di(3,5-xylyl)phosphino)-[2.2]-paracyclophane;
(S)-(+)-4,12-bis(di(3,5-xylyl)phosphino)-[2.2]-paracyclophane;
(11 bR)-N,N-bis[(R)-(-)-1-(2-methoxyphenyl)ethyl]dinaphtho[2,1-d:1'l2'-f][1 ,3,2]dioxa- phosphepin-4-amine;
(11bS)-N,N-bis[(S)-(+)-1-(2-methoxyphenyl)ethyl]dinaphtho[2,1-d:1',2'-f][1 ,3,2]dioxa- phosphepin-4-amine;
(R)-4, 12-bis(4-methoxyphenyl)-[2.2]-paracyclophane;
bis(2-methoxyphenyl)phenylphosphine;
(R,R)-(-)-1,2-bis[(2-methoxyphenyl)(phenyl)phosphino]ethane;
(S,S)-(+)-1 ,2-bis[(2-methoxyphenyl)(phenyl)phosphino]ethane;
N,N-bis[(1 R)-(+)-phenylethyl]dibenzo[d,f][1 ,3,2]dioxaphosphepin-6-amine;
N,N-bis[(1S)-(-)-phenylethyl]dibenzo[d,f][1 ,3,2]dioxaphosphepin-6-amine;
1.2- bis(phenylphoshino)ethane;
1.3- bis(phenylphosphino)propane;
1 ,2-bis(phosphino)benzene;
1 ,2-bis(phosphino)ethane;
bis(3-sulfonatophenyl)(3,5-di-trifluoromethylphenyl)phosphine, disodium salt monohydrate;
bis(p-sulfonatophenyl)phenylphosphine dihydrate dipotassium salt;
bis(3-sulfonatophenyl)(4-trifluoromethylphenyl)phosphine disodium dehydrate; 1 -{2S)-1 -[(11 bR)-2,6-bis(trimethylsilyl)dinaphtho[2, 1 -d: 1 ',2'-f][1 ,3,2]dioxaphosphepin-4- yloxy]propan-2-yl}-3-phenylurea;
bis(triphenylphosphine)iminium chloride;
2-bromophenyldiphenylphosphine;
butyldi-1-adamantylphosphine;
n-butyl-di-(1-adamantyl)phosphonium iodide;
t-butyldicyclohexylphosphine;
4-butyl-N-[(11 bR)-dinaphtho[2>1-d:1',2'-f][1 ,3,2]dioxaphosphepin-4-yl]benzene- sulfonamide triethylamine adduct;
4-butyl-N-(diphenylphosphino)benzenesulfonamide;
t-Butylphosphine;
2-cyanoethyl N,N,N',N'-tetra(i-propyl)phosphorodiamidite;
cyclohexyldi-t-butylphosphine;
cyclohexyldiphenylphosphine;
cyclohexylphosphine;
(I R.I'R^S^'SH+J^^'-di-t-butyl^.S^'.S'-tetrahydro-l .r-bi-IH-isophosphindole;
(2-cyanophenyl)diphenylphosphine;
di-1-adamantylchlorophosphine;
di-1 -adamantylphosphine;
2-(di-1-adamantylphosphino)dimethylaminobenzene;
2-(di-1-adamantylphosphino)-3,6-dimethoxy-2\4',6'-tri-i-propyl-1 ,1'-biphenyl;
N-[2-(di-1-adamantylphosphino)phenyl]morpholine;
(1 R,2R)-(+)-1 ,2-diaminocyclohexane-N,N'-bis(2,-diphenylphosphinobenzoyl);
(1S,2S)-(-)-1 ,2-diaminocyclohexane-N,N'-bis(2'-diphenylphosphinobenzoyl);
(1 R,2R)-(+)-1 ,2-diaminocyclohexane-N,N,-bis(2-diphenylphosphino-1-naphthoyl); (1S,2S)-(-)-1 ,2-diaminocyclohexane-N,N'-bis(2-diphenylphosphino-1-naphthoyl);
2-di[3,5-bis(trifluoromethyl)phenylphosphino]-3,6-dimethoxy-2\4 6'-tri-h
biphenyl;
e.e'- .S'-di-t-butyl-S.S'-dimethoxy-l .r-biphenyl^^'-diy bisioxy)]- bis(dibenzo[d,f][1 ,3,2]dioxaphosphepin) hemi ethyl acetate adduct;
di-t-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine;
di-t-butyl(2,2-diphenyl-1-methylvinyl)phosphine;
(1S,rS,2R,2'R)-(+)-1 ,1'-di-t-butyl-f2,2']-diphospholane;
di-t-butylmethylphosphine; di-t-butylmethylphosphonium tetrafluoroborate;
di-t-butylneopentylphosphine;
di-t-butylneopentylphosphonium tetrafluoroborate;
di-t-butylphenylphosphonium tetrafluoroborate;
di-t-butylphosphine;
racemic-2-di-t-butylphosphino-1 ,1'-binaphthyl;
2-(di-t-butylphosphino)biphenyl;
2-(di-t-butylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl-1 , 1 '-biphenyl;
2-di-t-butylphosphino-2'-(N,N-dimethylamino)biphenyl;
2-(di-t-butylphosphino)ethylamine;
2-(di-t-butylphosphino)-3-methoxy-6-methyl-2',4',6,-tri-i-propyl-1 , 1 '-biphenyl;
2-di-t-butylphosphino-4-methoxy-3,5,6-trimethyl-2',4',6'-tri-i-propylbiphenyl];
2-di-t-butylphosphino-2'-methylbiphenyl;
2-(di-t-butylphosphinomethyl)-6-(diethylaminomethyl)pyridine;
3-(di-t-butylphosphino)propylamine;
2-di-t-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-tri-i-propylbiphenyl;
5-(di-t-butylphosphino)-1 ',3',5'-triphenyl-1 ,4'-bi-1 H-pyrazole;
2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1 , 1 '-biphenyl;
di-t-butyl(i-propyl)phosphine;
di-t-butyl(3-sulfonatopropyl)phosphine;
(SS.S'S^S^'S.1 1 bS,1 1'bSX+H^'-di-t-but M^'.S.S'-tetrahydro-a.S'-bi-SH- dinaphfho[2, 1 -c: 1 ',2'-e]phosphepin;
(R)-(+)-5,5'-dichloro-6,6'-dimethoxy-2,2'-bis(diphenylphosphino)-1 ,1 '-biphenyl;
(S)-(-)-5,5'-dichloro-6,6'-dimethoxy-2,2'-bis(diphenylphosphino)-1 ,1 '-biphenyl;
dicyclohexyl(9-benzylfluoren-9-yl)phosphonium tetrafluoroborate;
dicyclohexyl(9-butylfluoren-9-yl)phosphonium tetrafluoroborate;
dicyclohexyl(2,2-diphenyl-1-methylcyclopropyl)phosphine;
dicyclohexyl(2,2-diphenyl-1-methylvinyl)phosphine;
dicyclohexyl[9-(3-phenylpropyl)fluoren-9-yl]phosphonium tetrafluoroborate;
dicyclohexylphosphine;
2-(dicyclohexylphosphino)biphenyl;
2-(dicyclohexylphosphino)-N,N-bis(1-methylethyl)-1 H-indole-1-carboxamide;
2-dicyclohexylphosphino-2',6'-dimethoxy-1 ,1 '-biphenyl;
2'-dicyclohexylphosphino-2,6-dimethoxy-3-sulfonato-1,r-biphenyl hydrate sodium salt; 2-(dicyclohexylphosphino)-3,6-dirnethoxy-2',4',6'-tri-i-propyl-1 , 1 '-biphenyl;
2-(dicyclohexylphosphino)-2'-(N,N-dimethylamino)biphenyl;
2-dicyclohexylphosphino-2',6'-di-i-propoxy-1 ,1'-biphenyl;
2'-dicyclohexylphosphino-2,6-di-i-propyl-4-sulfonato-1 ,1 '-biphenyl hydrate sodium salt;
[2-(dicyclohexylphosphino)ethyl]trimethylammonium chloride;
11 -dicyclohexylphosphino-12-(2-methoxyphenyl)-9, 10-ethenoanthracene
dichloromethane adduct;
1 -(dicyclohexylphosphino)-2-(2-methoxyphenyl)-1 H-indole;
2-dicyclohexylphosphino-2'-methylbiphenyl;
9-[2-(dicyclohexylphosphino)phenyl]-9H-carbazole;
11 -dicyclohexylphosphino-12-phenyl-9,10-ethenoanthracene dichloromethane adduct;
1 -(dicyclohexylphosphino)-2-phenyl-1 H-indole;
2-[2-(dicyclohexylphosphino)phenyl]-1 -methyl-1 H-indole;
S-idicyclohexylphosphinoJ-l'.S'.S'-triphenyl-fl ^'l-bi-I H-pyrazole;
2-(dicyclohexylphosphino)-2',4',6'-tri-i-propyl-1 ,1 '-biphenyl;
dicyclohexyl-{9-[3-(4-sulfonylphenyl)propyl]-2-sulfonylfluoren-9-yl}phosphonium hydrogen sulfate;
dicyclopentylphosphine;
diethylphosphine;
2-{2-[(2R,5R)-2,5-diethyl-1 -phospholano]phenyl}1 ,3-dioxolane;
2-{2-[(2S,5S)-2,5-diethyl-1-phospholano]phenyl}1 ,3-dioxolane;
[1-(2R,5R)-2,5-diethylphospholanyl]-[2-(2R,5R)-2,5-diethylphospholanyl-1- oxide]benzene;
[1-(2S,5S)-2,5-diethylphospholanyl]-[2-(2S,5S)-2,5-diethylphospholanyl-1- oxide]benzene;
9-[2-(diethylphosphino)phenyl]-9H-carbazole;
(1 R,2R)-2-[(4S, 11 bR)-3,5-dihydro-4H-dinaphtho[2, 1 -c; 1 ',2'-e]phosphepin-4-yl]-1 ,2- diphenylethanamine;
(1 S,2S)-2-[(4R,1 1 bS)-3,5-dihydro-4H-dinaphtho[2>1-c:1 ',2'-e]phosphepin-4-yl]-1 ,2- diphenylethanamine;
2-[(1 1 bS)-3,5-dihydro-4H-dinaphtho[2, 1 -c: 1 ',2'-e]phosphepin-4-yl]ethyl]amine;
2-[(1 1 bR)-3,5-dihydro-4H-dinaphtho[2,1-c:1 ',2'-e]phosphepin-4-yl]ethaminium tetrafluoroborate; 2-[(11bS)-3,5-dihydro-4H-dinaphtho[2 -c:1 2'-e]phosphepin-4-yl]ethaminium tetrafluoroborate;
(1 R,2R)-2-[(4S 1bR)-3,5-dihydro^H-dinaphtho[2 -c:1\2,-e]phosphepin-4-yI]-1- phenylpropan-2-amine;
(1 S,2S)-2-[(4R, 11 bS)-3,5-dihydro-4H-dinaphtho[2, 1 -c: 1 ',2'-e]phosphepin-4-yl]-1 - phenylpropan-2-amine;
(1 R,2R)-2-[(4S, 11 bR)-3,5-dihydro-4H-dinaphtho[2, 1 -c: 1 ',2'-e]phosphepin-4-yl]-1 - phenylpropan-2-aminium tetrafluoroborate;
(1 S,2S)-2-[(4R, 11 bS)-3,5-dihydro-4H-dinaphtho[2, 1 -c: 1 ',2'-e]phosphepin-4-yl]-1 - phenylpropan-2-aminium tetrafluoroborate;
[4-(N,N-dimethylarnino)phenyl]di-t-butylphosphine;
9,9-dimethyl-4,5-bis(di-t-butylphosphino)xanthene;
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthenes;
1 -{(1 S,2R)-1 -[(11 bR)-2,6-dimethyldinaphtho[2, 1-d: 1 ',2'-f][1 ,3,2]dioxaphosphepin-4- yloxy]-1-phenylpropan-2-yl}-3-phenylurea;
1- ^SJ-l-Kl lbS^.e-dimethyldinaphtho^.l-dil'^'-flll .S^ldioxaphosphepin^- yloxy]propan-2-yl}-3-phenylurea;
(S)-(+)-(2,6-dimethyl-3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphtrialen-4- yl)dimethylamine;
dimethylphenylphosphine;
2- {2-[(2R,5R)-2,5-dimethyl-1-phospholano]phenyl}1 ,3-dioxolane;
2-{2-[(2S,5S)-2,5-dimethyl-1-phospholano]phenyl}1 ,3-dioxolane;
[1-(2R,5R)-2,5-dirnethylpriospholanylH2-(2R,5R)-2,5-dimethylphospholanyl-1- oxide]benzene;
[1-(2S,5S)-2,5-dimethylphospholanyl]-[2-(2S,5S)-2,5-dirnethylphospholanyl-1- oxide]benzene;
(+)-6,6'-{[(1R,3R)-1 ,3-dimethyl-1 l3-propanediyl]bis(oxy)}bis[4,8-bis(t-butyl)-2,10- dimethoxy-bibenzo[d,f][1 ,3,2]dioxaphosphepin];
(-)-6,6'-{[(1S,3S)-1 ,3-dimethyl-1 ,3-propanediyl]bis(oxy)}bis[4,8-bis(t-butyl)-2,10- dimethoxy-bibenzo[d,f][1 ,3,2]dioxaphosphepin];
(3aR,8aR)-(-)-(2,2-dimethyl-4,4,8,8-tetraphenyl-tetrahydro-t1 ,3]dioxolo[4,5- e][1 ,3,2]dioxaphosphepin-6-yl)dimethylamine;
Figure imgf000045_0001
phenylpropan-2-yl}-3-phenylurea; 1 -{(2R)-1 -[(1 1 bR)-dinaphtho[2, 1 -d: 1 ',2'-f][1 ,3,2]dioxaphosphepin-4-yloxy]propan-2-yl}-3- phenylurea;
Figure imgf000046_0001
phenylurea;
N-Kl l bSJ-dinaphthop.l-di l'^'-flll .S.qdioxaphosphepin^-yll-l .l .l- trifluoromethanesulfonamide triethylamine adduct;
di-2-norbornylphosphine;
(S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)- benzyl(methyl)amine;
(SJ-i+J-CS.S-dioxa^-phosphacyclohepta^.l-aiS^-a'ldinaphthalen^-y bisKI RJ-l-il- naphthalenyl)ethyl]amine;
(S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)bis[(1 R)-1- phenylethyl]amine, dichloromethane adduct;
(S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)bis[(1 S)-1- phenylethyl]amine;
Figure imgf000046_0002
diphenylethanaminium tetrafluoroborate;
(S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)diethylamine; (RJ-^-iS.S-dioxa^-phospha-cyclohepta^.l-ajS^-a'ldinaphthalen^-ylJdimethyl-amine; (1 S,2S)-2-((4R,1 1bS)-3H-dinaphtho[2l1-c:1 ',2,-e]phosphepin-4(5H)-yl)-1 ,2- diphenylethanaminium tetrafluoroborate;
(S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)dimethylamine; (S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2 -a;3,4-a']dinaphthalen-4-yl)morpholine; (S)- (+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)[(1 R)-1- phenylethyl]amine;
(S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)piperidine; diphenylphosphine
(1 R,2R)-2-(diphenylphosphino)-1 -aminocyclohexane;
(1S,2S)-2-(diphenylphosphino)-1-aminocyclohexane;
(R)-1 -(diphenylphosphino)-2-amino-3,3-dimethylbutane;
(S)-1-(diphenylphosphino)-2-amino-3,3-dimethylbutane;
(R)-1 -(diphenylphosphino)-2-amino-3-methylbutane;
(S)-1-(diphenylphosphino)-2-amino-3-methylbutane;
2- (diphenylphosphino)benzaldehyde; 2-(iphenylphosphino)benzoic acid;
(1 R,2R)-2-(diphenylphosphino)cyclohexanaminium tetrafluoroborate;
(1 S,2S)-2-(diphenylphosphino)cyclohexanaminium tetrafluoroborate;
(1 R,2R)-2-(diphenylphosphino)-2,3-dihydro-1 H-inden-1-amine;
(1 S,2S)-2-(diphenylphosphino)-2,3-dihydro-1 H-inden-1-amine;
(1 R,2R)-2-(diphenylphosphino)-2,3-dihydro-1 H-inden-1-aminium tetrafluoroborate; (1 S,2S)-2-(diphenylphosphino)-2,3-dihydro-1 H-inden-1-aminium tetrafluoroborate; 2-diphenylphosphino-2'-(N,N-dirnethylamino)biphenyl;
1- diphenylphosphino-2-(N,N-dimethylamino)-1 H-indene;
(R)-1-(diphenylphosphino)-3,3-dimethylbutan-2-aminiurn tetrafluoroborate;
(S)-1-(diphenylphosphino)-3,3-dimethylbutan-2-aminiurn tetrafluoroborate;
(+)-{(1 S,4R)-3-[4-(diphenylphosphino)-2,5-dimethyl-3-thienyl]-4,7,7- trimethylbicyclo[2 .1]hept-2-en-2-yl}bis(3,5-dimethylphenylphosphine;
(+)-{(1 S,4R)-3-[4-(diphenylphosphino)-2,5-dimethyl-3-thienyl)-4,7,7- trimethylbicyclo[2.2.1]hept-2-en-2-yl}diphenylphosphine;
(1 R,2R)-2-(diphenylphosphino)-1 ,2-diphenylethylamine;
(1 S,2S)-2-(diphenylphosphino)-1 ,2-diphenylethylamine;
(1 R,2R)-2-(diphenylphosphino)-1 ,2-diphenylethylaminium tetrafluoroborate;
(1 S,2S)-2-(diphenylphosphino)-1 ,2-diphenylethylaminium tetrafluoroborate;
2-(diphenylphosphino)ethanaminium tetrafluoroborate;
2- (diphenylphosphino)ethylamine;
2-[2-(diphenylphosphino)ethyl]pyridine;
(R)-(+)-2-(diphenylphosphino)-2'-methoxy-1 , 1 '-binaphthyl;
(S)-(-)-2-(diphenylphosphino)-2'-methoxy-1 , 1 '-binaphthyl;
(R)-1-(diphenylphosphino)-3-methylbutan-2-aminium tetrafluoroborate;
(S)-1-(diphenylphosphino)-3-methylbutan-2-aminium tetrafluoroborate;
(2R,4R)-(+)-2-(diphenylphosphinomethyl)-4-(dicyclohexylphosphino)-N-(t- butoxycarbonyl)pyrrolidine;
(2R,4R)-(+)-2-(diphenylphosphinomethyl)-4-(dicyclohexylphosphino)-N-methyl-1- pyrrolidinecarboxamide;
(2S,4S)-(-)-2-(diphenylphosphinomethyl)-4-(dicyclohexylphosphino)-N-methyl-1- pyrrolidinecarboxamide;
(2R,4R)-(+)-2-(diphenylphosphinomethyl)-4-(diphenylphosphino)-N-(t- butoxycarbonyl)pyrrolidine; (2S,4S)-(-)-2-(diphenylphosphinomethyl)-4-(diphenylphosphino)-N-(t- butoxycarbonyl)pyrrolidine;
(2R,4R)-(+)-2-(diphenylphosphinomethyl)-4-(diphenylphosphino)pyrrolidine;
(2S,4S)-(-)-2-(diphenylphosphinomethyl)-4-(diphenylphosphino)pyrrolidine;
2-diphenylphosphino-6-methylpyridine;
(S)-2-[(diphenylphosphino)methyl]pyrrolidine;
(R)-2-[(diphenylphosphino)methyl]pyrrolidine;
(S)-2-[(diphenylphosphino)methyl]pyrrolidinium tetrafluoroborate;
(R)-(+)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline;
(S)-(-)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline;
9-[2-(diphenylphosphino)phenyl]-9H-carbazole;
(S)-1-[2-(diphenylphosphino)phenyl]ethanaminium tetrafluoroborate;
(R)-1-[2-(diphenylphosphino)phenyl]ethylamine;
(R)-2-(diphenylphosphino)-1-phenylethylamine;
(S)-2-(diphenylphosphino)-1-phenylethylamine;
(R)-(+)-2-[2-(diphenylphosphino)phenyl]-4-(1-methylethyl)-4,5-dihydrooxazole;
(S)-(-)-2-[2-(diphenylphosphino)phenyl]-4-(1-methylethyl)-4,5-dihydrooxazole;
(1 R,2R)-1 -(diphenylphosphino)-l -phenylpropan-2-aminium tetrafluoroborate;
(R)-2-[(diphenylphosphino)methyl]pyrrolidinium tetrafluoroborate;
3-(diphenylphosphino)propylamine;
3-(diphenylphosphino)propylammonium tetrafluoroborate;
(RJ-e-idiphenylphosphinoJ-I ^.S^-tetrahydronaphthalen-l-aminium tetrafluoroborate; (+)-{4-[(1 R,4S)-3-(diphenylphosphino)-1 ,7 ,7-trimethylbicyclo[2.2.1 ]hept-2-en-2-yl]-2,5- dimethyl-3-thien-3-yl}bis(3,5-dirnethylphenyl)phosphine;
diphenyl(m-sulfonatophenyl)phosphine dihydrate sodium salt;
diphenyl(p-sulfonatophenyl)phosphine monohydrate dimethylsulfoxide adduct, potassium salt;
diphenyl[3-(triethoxysilyl)propyl]phosphine;
(R)-1-[2-(diphenylphosphino)phenyl]ethanaminium tetrafluoroborate;
di-i-propylchlorophosphine;
di-i-propylphosphine;
1- di-i-propylphosphino-2-(N,N-dimethylamino)-1 H-indene;
2- (di-i-propylphosphino)ethylamine;
9-[2-(di-i-propylphosphino)phenyl]-9H-carbazole; (R)-2-(diphenylphosphino)-1-phenylethanarninium tetrafluoroborate;
3-(di-i-propylphosphino)propylamine;
(S)-2-(diphenylph9sphino)-1-phenylethanaminium tetrafluoroborate;
(S)-1-[2-(diphenylphosphino)phenyl]ethylamine;
2-(di-i-propylphosphonium)ethylammonium bis(tetrafluoroborate);
3-(di-i-propylphosphonium)propylammonium bis(tetrafluoroborate);
di-p-tolylphosphine;
2-(di-p-tolylphosphino)benzaldehyde;
2,2'-(di-o-tolylphosphino)diphenyl ether;
1-[(1 R,2S)-1-(di-o-tolylphosphinooxy)-1-phenylpropan-2-yl]-3-phenylurea;
1-[(2S)-1-(di-o-tolylphosphinooxy)propan-2-yl]-3-phenylurea;
(1 S,2S)-1-(diphenylphosphino)-1-phenylpropan-2-aminium tetrafluoroborate;
(S)-8-(diphenylphosphino)-1 ,2,3,4-tetrahydronaphthalen-1 -aminium tetrafluoroborate; ethyldiphenylphosphine;
(1 1 aR)-(+)-5,6, 10,1 1 , 12,13-hexahydro-5-phenyl-4H-diindeno[7, 1 -cd: 1 ,7-ef]-phosphocine;
N-(2-methoxyphenyl)-2-(di-t-butylphosphino)pyrrole;
1- (2-methoxyphenyl)-2-(dicyclohexylphosphino)pyrrole;
2- (2-methoxyphenyl)-1 -methyl-3-diphenylphosphino)-1 H-indole;
methyldiphenylphosphine;
{2-methyl-3-[polyisobutyl(20)]propyl}diphenylphosphine (50% in
heptane/polyisobutylene) ;
(S)-2-(1-naphthyl)-8-diphenylphosphino-1-[(R)-3,5-dioxa-4-phospha-cyclohepta[2,1- a;3,4-a']dinaphthalen-4-yl]-1 ,2-dihydroquinoline toluene adduct;
(R)-2-(1-naphthyl)-8-diphenylphosphino-1-[(S)-3,5-dioxa-4-phospha-cyclohepta[2, 1- a;3,4-a']dinaphthalen-4-yl]-1 ,2-dihydroquinoline toluene adduct;
(S)-(+)-neomenthyldiphenylphosphine;
(S)-(+)-(8,9, 10,1 1 ,12, 13,14,15-octahydro-3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4- a']dinaphthalen-4-yl)dimethylamine;
1-{(1 S,2R)-1-[(11 bR)-8,9,10,11 ,12,13,14,15-octahydrodinaphtho[2,1-d:1 ',2'- f][1 ,3,2]dioxaphosphepin-4-yloxy]-1-phenylpropan-2-yl}-3-phenylurea;
1-{(2R)-1-[(1 1 bR)-8,9,10,11 l12,13l14, 15-octahydrodinaphtho[2,1-d:1 ',2,- f][1 ,3,2]dioxaphosphepin-4-yloxy]propan-2-yl}-3-phenylurea;
N-phenyl-2-(di-t-butylphosphino)indole;
N-phenyl-2-(di-t-butylphosphino)pyrrole; N-phenyl-2-(dicyclohexylphosphino)indole;
N-phenyl-2-(dicyclohexylphosphino)pyrrole;
phenyldimethoxyphosphine;
(1 1 aR)-(+)-10,1 1 ,12,13-tetrahydrodiindeno[7, 1 -de: 1 ',7'-fg][1 ,3,2]dioxaphosphocin-5- bis[(R)-1-phenylethyl]amine;
(1 1 aS)-(-)-10,11 ,12,13-tetrahydrodiindeno[7, 1 -de: 1 ',7'-fg][1 ,3,2]dioxaphosphocin-5- bis[(R)-1-phenylethyl]amine;
(1 1 aR)-(+)-10,1 1 , 12,13-tetrahydrodiindeno[7, 1 -de: 1 \7'-fg][1 ,3,2]dioxaphosphocin-5- dimethylamine;
(1 1 aS)-(-)-10,1 1 ,12,13-tetrahydrodiindeno[7,1-de:1 \ 7'-fg][1 , 3,2]dioxaphosphocin-5- dimethylamine;
(1 1 aR)-(+)-10, 1 1 ,12,13-tetrahydrodiindeno[7, 1 -de: 1 ',7'-fg][1 ,3,2]dioxaphosphocin-5- phenoxy;
(1 1aS)-(-)-10,11 ,12,13-tetrahydrodiindeno[7, 1-de:1 ',7'-fg][1 , 3,2]dioxaphosphocin-5- phenoxy;
(3aR,8aR)-(-)-4,4,8,8-tetrakis(3,5-diethylphenyl)tetrahydro-2,2-dimethyl-6-phenyl-1 ,^ dioxolo[4,5-e]dioxaphosphepin;
(3aS,8aS)-(+)-4,4,8,8-tetrakis(3,5-diethylphenyl)tetrahydro-2,2-dimethyl-6-phenyl-1 ,3- dioxolo[4,5-e]dioxaphosphepin;
(3aR,8aR)-(-)-4,4,8,8-tetrakis(3,5-dimethylphenyl)tetrahydro-2,2-dimethyl-6-phenyl-1 ,3- dioxolo[4,5-e]dioxaphosphepin;
(3aS,8aS)-(+)-4,4,8,8-tetrakis(3,5-dimethylphenyl)tetrahydro-2,2-dimethyl-6-phenyl-1 ,3- dioxolo[4,5-e]dioxaphosphepin;
(R)-(+)-2,2\6,6'-tetrarnethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine;
(S)-(-)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine;
(R)-(+)-2,2\6,6'-tetratTiethoxy-4,4'-bis(di(3,5-xylyl)phosphino)-3,3'-bipyridine;
(S)-(-)-2,2\6,6'-tetramethoxy-4,4'-bis(di(3,5-xylyl)phosphino)-3,3'-bipyridine;
tetramethyl 6,6'-bis(diphenylphosphino)-1 ,1 ',3,3'-tetrahydro[5,5']biindenyl-2,2',2,2'- tetracarboxylate;
1 ,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane;
p-tolyldiphenylphosphine;
triallylphosphine;
1 ,3,5-triaza-7-phosphaadamantane;
tribenzylphosphine; tri-t-butylphosphine;
tri-t-butylphosphonium tetrafluoroborate;
tri-t-butylphosphonium trifluoromethanesulfonate;
2,8,9-tri-i-butyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; tri(m-chlorophenyl)phosphine;
tri(p-chlorophenyl)phosphine;
tricyclohexylphosphine;
tricyclohexylphosphonium tetrafluoroborate;
tricyclohexylphosphonium trifluoromethanesulfonate;
tricyclopentylphosphine;
tricyclopentylphosphine;
triethylphosphine;
triethylphosphonium tetrafluoroborate;
tri-2-furylphosphine;
2 ,4,4-trimethylpentylphosphine;
1-(2,4,6-trimethylphenyl)-2-(dicyclohexylphosphino)imidazole;
trimethylphosphine;
trimethylphosphonium tetrafluoroborate;
2,8,9-trimethyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; tri(1-naphthyl)phosphine;
tri-n-octylphosphine;
triphenylphosphine;
tri-n-propylphosphine;
2,8,9-tri-isopropyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; tris(2-carboxyethyl)phosphine hydrochloride;
tris(2-cyanoethyl)phosphine;
tris(dimethylamino)phosphine;
tris(2,4-dimethylphenyl)phosphine;
tris(3,5-dimethylphenyl)phosphine;
tris(4,6-dimethyl-3-sulfonatophenyl)phosphine trisodium salt hydrate;
1 , 1 , 1 -tris(diphenylphosphino)methane;
1 ,1 ,1-tris(diphenylphosphinomethyl)ethane;
tris(p-fluorophenyl)phosphine;
tris(hydroxymethyl)phosphine; tris(3-hydroxypropyl)phosphine;
tris(4-methoxy-3,5-dimethylphenyl)phosphine;
tris(o-methoxyphenyl)phosphine;
tris(m-methoxyphenyl)phosphine;
tris(p-methoxyphenyl)phosphine;
tris(pentafluorophenyl)phosphine;
tris(3-sulfonatophenyl)phosphine hydrate, sodium salt;
tris(p-trifluoromethylphenyl)phosphine;
trls(2,4,6-trimethoxyphenyl)phosphine;
tris(2,4,6-trimethylphenyl)phosphine;
tris(trimethylsilyl)phosphine;
tris(trimethylsilyl)phosphine;
tri-o-tolylphosphine;
tri-m-tolylphosphine;
tri-p-tolylphosphine; and
vinyldiphenylphosphine;
of which triphenylphosphine is preferred.
The reaction is normally and preferably carried out in the presence of a base, the nature of which is not especially critical provided it is capable of acting as such. Examples of suitable bases include metal hydroxides, especially alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide; and thallium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate and caesium carbonate, alkali metal
hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogen carbonate, alkali metal fluorides such as potassium fluoride and caesium fluoride, alkali metal alkoxides such as sodium methoxide, sodium tert-butoxide and potassium t- butoxide, alkali metal phosphates such as potassium phosphate; alkali metal acetates such as sodium acetate, potassium acetate, and organic bases such as triethylamine or lithium hexamethyldisilazane, of which sodium carbonate is preferred.
The reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. Examples of suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, aromatic hydrocarbons such as benzene, toluene and xylenes, and ethers such as diethyl ether, tert-butyl methyl ether, dimethoxyethane and tetrahydrofuran; alcohols like tert-butanol, n-butanol; or water. It is preferred that the solvent is an ether, in particular tetrahydrofuran. The use of a suitable amount of cosolvents in water or the use of pure water as the solvent are used in the ligand-free catalytic systems.
The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 40°C to the boiling point of the solvent, and preferably 50°C to 70°C.
The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 30 minutes to 24 hours, and preferably 4 to 12 hours.
After completion of the reaction, the compound of formula (XII) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
The product may further be purified by conventional methods such as crystallisation or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
The second step of this part of the method is the production of a compound of formula (XIII). This process involves treating the compound of formula (XII) with an agent capable of converting a hydroxyl group into a leaving group LG. This process can be carried out by methods well known to those skilled in the art.
The leaving group LG may be a halogen atom, a sulfonyloxy group (such as C1-4 alkylsulfonate, benzenesulfonate, para-toluenesulfonate or trifluoromethanesulfonate), or a diazonium moiety (-N2 +). When the leaving group LG is a sulfonyloxy group (such as C1-4 alkylsulfonate, benzenesulfonate, para-toluenesulfonate or trifluoromethanesulfonate) the reaction can be carried out by reacting with a sulfonating agent of formula RaS02LG1 wherein Ra is a hydrocarbon or halogenated hydrocarbon moiety (such as d-4 alkyl, phenyl, p-tolyl or trifluoromethyl) and LG! is a leaving group (which may be a halogen, or may be another sulfonyloxy group). It is preferred that the reagent is either a sulfonic anhydride of formula (RaS02)20 or a bis-sulfonylamide of formula (RaS02)2NRb (wherein R is a hydrocarbon or halogenated hydrocarbon moiety such as C -4 alkyl, phenyl, p-tolyl or trifluoromethyl). A particularly preferred reagent is trifluoromethanesulfonic anhydride.
Procedures for conversion of a phenolic -OH group to a halide are well known in the literature, and include the following:
1. A process for preparing organochlorides; Li, Jian; Faming Zhuanli Shenqing, 102372594, 14 Mar 2012.
2. Preparation of aryl chlorides from phenols; Bay, Elliott et al; Journal of Organic ' Chemistry, 55(10), 3415-17; 1990.
3. Deoxygenative chlorination of alcohols catalyzed by ferric chloride; Sheng, Chunqi et al; Huaxue Yanjiu Yu Yingyong, 20(4), 503-506; 2008.
4. Triphenylphosphine Dichloride; Dormoy, Jean-Robert and Castro, Bertrand; e- EROS Encyclopedia of Reagents for Organic Synthesis, No pp. given; 2001.
5. Transchlorination of polychlorobenzenes and benzene into chlorobenzene;
Shinoda, Kiyonori and Yasuda, Kensei; Nippon Kagaku Kaishi, (12), 1999-2005; 1989.
6. Preparation and X-ray structures of 2-[(aryl)iodonio]benzenesulfonates: novel diaryliodonium betaines; Justik, Michael W. et al; Tetrahedron Letters, 50(44), 6072-6075; 2009.
7. The conversion of phenols to the corresponding aryl halides under mild
conditions; Thompson, Alicia L. S. et al; Synthesis, (4), 547-550; 2005
The reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. Examples of suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, aromatic hydrocarbons such as benzene, toluene and xylenes, and symmetrical and unsymmetrical ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane and dioxane, acetonitrile, halogenated hydrocarbons such as dichloromethane or chloroform; and mixtures thereof. It is preferred that the solvent is a halogenated hydrocarbon, preferably dichloromethane or chloroform.
The reaction is normally and preferably carried out in the presence of a base, the nature of which is not especially critical provided it is capable of acting as such. Examples of suitable bases are well known to those skilled in the art, include organic amines such as triethylamine, diisopropylethyamine or pyridine; of which pyridine is preferred.
The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from -50°C to 20°C, and preferably -20 to 10°C.
The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 1 to 24 hours, and preferably 2 to 8 hours. After completion of the reaction, the compound of formula (XIII) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent. The product may further be purified by conventional methods such as crystallisation or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product. The third step of this part of the method is the production of a compound of formula (XIV) by reaction of the compound of formula (XIII) with a vinylating agent. This step has not been previously described in the art, and confers significant advantages over the prior art for the reasons set out below. Therefore, in one aspect, the invention provides a method of producing a compound of formula (XIV):
Figure imgf000056_0001
XIV
in which Y, m, R1 f R2, R4a, R7 and R3b are as defined above;
the method comprising reacting a compound of formula (XIII):
Figure imgf000056_0002
XIII
in which Y, m, Ri, R2, R4a, R7, R3b and LG are as defined above;
with a vinylating agent of formula
[CH2=CHB(Rc)3r M+ or [CH2=CHB(ORd)2]
in which Rc is a halogen atom (preferably fluorine),
Rd is hydrogen or an ester residue, and
M is an alkali metal atom (preferably lithium, sodium or potassium, more preferably potassium);
in the presence of a coupling catalyst and a base.
When Rd is an ester residue, examples include those residues include C1-6 alkyl (optionally substituted with one or combination of the following: chlorine, fluorine, C1-6 alkoxy, C3.8 cycloalkoxy, C3.8 cycloalkyl, heterocycloalkyl, heterocycloalkoxy, aryl or heteroaryl), C2-6 alkenyl; C2-6 alkynyl; C3-8 cycloalkyl, aryl or heteroaryl. It has surprisingly been found by the present inventors that the above reaction proceeds in good yield, while avoiding the formation of significant side products, and This conveys a significant advantage compared with the synthetic methods of the prior art, in that the use of toxic vinyl tin reagents used in the prior art can be avoided.
The reaction is carried out in the presence of a suitable catalyst, the nature of which is not especially critical provided it is capable of catalysing the coupling reaction of a vinyl boron compound with an aryl halide or sulfonate. Suitable catalysts include palladium (II) and palladium (0) complexes, particularly those palladium (II) or palladium (0) complexes having one or more (preferably 2 or 4) nitrogen or phosphorus ligands bonded to the palladium., Examples of suitable palladium catalysts include those described and exemplified above with respect to catalysts for the coupling reaction of the compounds of formulae (IV) and (V) to produce the compound of formula (VI). . The preferred catalyst is bis(triphenylphosphine)palladium (II) chloride.
The reaction is normally and preferably carried out in the presence of a base, the nature of which is not especially critical provided it is capable of acting as such. The presence of the base allows the catalyst to be regenerated. Examples of suitable bases include metal hydroxides, especially alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide; and thallium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate and caesium carbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogen carbonate, alkali metal or ammonium fluorides such as potassium fluoride, caesium fluoride and (tetra-n-butyl)ammomiun fluoride, alkali metal alkoxides such as sodium methoxide, sodium tert-butoxide and potassium t-butoxide, alkali metal phosphates such as potassium phosphate; alkali metal acetates such as sodium acetate, potassium acetate, and organic bases such as triethylamine or lithium hexamethyldisilazane of which potassium hydrogencarbonate is preferred as it results in a cleaner reaction and the product to be produced in a purity exceeding 90%.
The reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. Examples of suitable solvents include aliphatic hydrocarbons such as pentanes, hexanes, heptanes, octanes, nonanes, or decanes, aromatic hydrocarbons such as benzene, toluene and xylenes, and ethers such as diethyl ether, dioxane, tertbutylmethyl ether, dimethoxyethane and
tetrahydrofuran; alcohols such as tert-butanol or n-butanol; water; and mixtures thereof. It is preferred that the solvent is an ether, in particular dimethoxyethane. . The use of a suitable amount of cosolvents in water or the use of pure water as the solvent are used in the ligand-free catalytic systems.
The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from 40°C to the boiling point of the solvent, and preferably 50°C to 70°C.
The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 30 minutes to 24 hours, and preferably 4 to 12 hours.
After completion of the reaction, the compound of formula (XIV) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent.
The product may further be purified by conventional methods such as crystallisation or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
The fourth step of this part of the method is the production of a compound of formula (XV). This process involves treating the compound of formula (XIV) with an oxidizing agent capable of oxidizing the aldehyde moiety of the compound of formula (XIV) to a carboxylic acid. This process can be carried out by methods well known to those skilled in the art.
Examples of suitable oxidizing agents include chlorine (III) compounds such as sodium chlorite; chromium (VI) compounds such as sodium chromate or potassium dichromate; managanese (VII) compounds such as sodium permanganate or potassium
permanganate; oxone; or silver oxide (Pearl, I. A. Org. Synth. /V 1963, 972-978.) of which sodium chlorite is preferred. The reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. Polar solvents are preferred.
Examples of suitable solvents include alcohols such as methanol, ethanol, isopropanol and tert-butanol; ethers such as diethyl ether, dioxane, tertbutylmethyl ether, dimethoxyethane and tetrahydrofuran; ketones such as acetone; nitriles such as acetonitrile; water; and mixtures thereof of which a mixture of tert-butanol, water and acetonitrile is preferred.
When a positive chlorine species (i.e. a species including chlorine in a positive oxidation state) is used as the oxidizing agent, the reaction is preferably carried out in the presence of a chlorine scavenging agent. It has been unexpectedly found by the present inventors that the presence of a chlorine scavenging agent prevents the chlorine from adding to the vinyl group on the compound of formula (XIV) and avoids the production of side products. Examples of suitable chlorine scavenging agents include alkenes such as 1-pentene, 2-pentene and 2-methyl-2-butene, and sulphur compounds such as dimethyl sulfoxide and sulfamic acid, of which 2-methyl-2-butene is preferred. Although this reagent is also used in the corresponding step of the synthesis generally described in US 6,699,994, the starting material in that step of the synthesis lacks a vinyl group. It is considered unexpected that the use of this reagent allows the reaction to proceed without giving rise to side products caused by oxidation of the vinyl group.
The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from -20°C to room temperature, and preferably -10 to 20°C.
The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 10 minutes to 6 hours, and preferably 20 minutes to 4 hours. After completion of the reaction, the compound of formula (XV) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent. The product may further be purified by conventional methods such as crystallisation or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product.
Coupling of carboxylic acids of formula (XV) with amines of Formula (XVI) and subsequent processing to form compounds of formula (I)
In the final stage of the synthesis, the compounds of formula (I) may be produced in two step synthesis from the carboxylic acids of formula (XV) according to Scheme 4 below, including an optional third step to produce the compound of formula (I) in salt form. This is advantageous over the prior art synthesis for the further reasons described herein.
Figure imgf000060_0001
The first step of this part of the method is the production of a compound of formula (XVII) by coupling the carboxylic acid of formula (XV) with the amine of formula (XVI). This process can be carried out by methods similar to General Method J of US 6,699,994. However, carrying out this step as described below confers significant advantages over the prior art for the reasons set out below.
Therefore, in one aspect, the invention provides a method of producing a compound of formula (XVII):
Figure imgf000061_0001
XVII
in which X, Y, n, m, R2, R3a, 3t>, R4a, R4t>, Rsa, R7 and R5b are as defined above;
g reacting a carboxylic acid of formula (XV):
Figure imgf000061_0002
XV
wherein Y, R^ R2, R3b R4a, m and R7 are as defined above;
(XVI):
Figure imgf000061_0003
XVI
wherein X, n, R3a, R4b, R5a and R5b are as defined above; in the presence of a base of which the pKa of the conjugate acid ranges from 4 to 10 and optionally a suitable amide coupling agent.
The amine of formula (XVI) is typically supplied to the reaction in the form of a bis-acid addition salt, such as a dihydrochloride salt. It will be appreciated that the amine of formula (XVI) has both an arylamine and an amidine functional group, either of which is capable of reacting with the carboxylic acid of formula (XV) depending on the conditions under which the reaction is carried out. It has surprisingly been found by the present inventors that using a base of which the pKa of the conjugate acid ranges from 4 to 10 in the above reaction allows much greater selectively for the arylamine functional group, allowing the reaction to proceed in good yield, while avoiding the formation of significant side products. This conveys a significant advantage compared with the synthetic methods of the prior art. The reaction is preferably carried out in the presence of a suitable amide coupling agent, the nature of which is not especially critical provided it is capable of promoting the coupling reaction of an amine with a carboxylic acid. Examples of suitable amide coupling agents include but are not limited to: dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N- ethoxycarbonyl-2-ethoxy-1 ,2-dihydroquinoline (EEDQ), O-benzotriazole-Ν,Ν,Ν',Ν'- tetramethyl-uronium-hexafluoro -phosphate (HBTU)), 2-(5-norborene-2,3- dicarboximido)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate TNTU, 2-Succinimide- 1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TSTU), (0-(7-azabenzotriazol-1-yl)- Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate (HATU), benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate BOP, Phosphoric acid bis(2-oxooxazolidide) chloride (BOP-CI), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) and bromotripyrrolidinophosphonium
hexafluorophosphate (PyBroP), of which 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) is preferred.
The reaction is preferably carried out in the presence of a suitable amide coupling additive, the nature of which is not especially critical provided it is capable of promoting the coupling reaction of an amine with a carboxylic acid. Examples of common amide coupling additives include but are not limited to hydroxybenzotriazole (HOBt), N- Hydroxysuccinimide (HOSu) and 1-hydroxy-7-azabenzotriazole (HOAt).
The reaction is carried out in the presence of a base of which the pKa of the conjugate acid ranges from 4 to 10. This allows much greater selectively for the arylamine functional group, allowing the reaction to proceed in good yield, while avoiding the formation of significant side products. The reaction is preferably carried out in the presence of a base of which the pKa of the conjugate acid ranges from 4.5 to 6.5, such as 4.6 to 6.1 , such as 5 to 5.5, such as 5.2 to 5.4. Examples of suitable bases include pyridine (pKa = 5.25); hydroxylamine (pKa = 5.97); methoxyamine (pKa = 4.60); Ν,Ο- dimethylhydroxylamine (pKa = 4.75); N-methylmethoxyamine (pKa = 4.75); N- methylhydroxylamine (pKa =5.96); N-dimethylhydroxylamine (pKa = 5.2); N- (cyanomethyl)piperidine (pKa = 4.55); (cyanomethyl)amine (aminoacetonitrile) pKa = 5.34); N-norcodeine-(CH2)2CN (pKa = 5.68); 2-amino-2-cyanopropane (pKa = 5.3) di(cyanoethyl)amine (pKa = 5.26); CF3CH2NHCH3 (pKa =6.05); CF3CH2NH2 (pKa = 5.7); CF3CH2N(CH3)2 (pKa =4.75); dimeoone (pKa = 5.23); p-methoxyaniline (pKa = 5.29); p- hydroxyaniline (pKa = 5.50); p-ethoxy aniline (pKa = 5.25); Ν,Ν-dimethyl-aniline (pKa = 5.07); N-isobutylmethylaniline (pKa = 5.20); N-cyclopentylaniline (pKa = 5.30;
hexamethylenetetramine (pKa = 5.13); isoquinoline (pKa = 5.14) and 5,6-benzoquinoline (pKa = 5.15), of which pyridine is preferred.
The reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not especially critical provided it is inert to the reaction and is capable of dissolving the reactants at least to some extent. Examples of suitable solvents include alcohols such as methanol, ethanol, isopropanol and tert-butanol, and symmetrical and unsymmetrical ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, tert- butylmethylether and dioxane, amines such as pyridine, acetonitrile, sulfoxides such as dimethyl sulfoxide, amides such as DMF, and HMPA, or ketones such as acetone. It is preferred that the solvent is an alcohol, in particular isopropanol. The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from -20°C to 50°C, and preferably -10°C to room temperature.
The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from 30 minutes to 48 hours, and preferably 1 to 24 hours.
After completion of the reaction, the compound of formula (XVII) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent. It has been found particularly advantageous according to the present invention to add methanesulfonic acid during the reaction workup. The methanesulfonic acid salt isolated is crystalline and particularly easy to handle. This avoids the need to use column chromatography to purify the product. Alternatively, in particular when the amine of formula (XVI) is supplied to the reaction in the form of a bis-acid addition salt, such as a dihydrochloride salt, and the amide coupling agent is supplied to the reaction in the form of an acid addition salt, such as a hydrochloride salt, the product can be precipitated from the reaction mixture, for example as the hydrochloride salt, and directly taken forward to the next step.
The second step of this part of the method is the production of a compound of formula (I) by hydrolysis of the carboxylic ester functionality of the compound of formula (XVII). This process can be carried out by a number of methods well known to those skilled in the art, including those similar to General Method 1-2 of US 6,699,994. However, carrying out this step according to the conditions below confers significant advantages over the prior art for the reasons set out below.
Therefore, in one aspect, the invention provides a method of producing a compound of formula (I), in which X, Y, m, n, R2, R3a, Rsb, R4a, R4b, Rsa, Rsb and R7 are as defined above;
the method comprising subjecting a carboxylic ester of formula (XVII):
Figure imgf000065_0001
wherein X, Y, m, n, R2, R3ai Rsbi R4ai R<tbi Rsai Rsb sind R7 are as defined above, to ester hydrolysis conditions in the presence of acetonitrile as solvent. In one embodiment, the reaction is carried out in the presence of a base, the nature of which is not especially critical provided it is capable of promoting ester hydrolysis. A base is preferred as the hydrolysis reaction is rendered irreversible by deprotonation of the carboxylic acid. Examples of suitable bases include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, of which sodium hydroxide is preferred.
In another embodiment, the reaction is carried out in the presence of an acid, the nature of which is not especially critical provided it is capable of neutralizing the base.
Examples of suitable acid catalysts include Bronsted acids, particularly strong mineral acids such as sulphuric acid, nitric acid, hydrochloric acid, methanesulfonic acid, acetic acid and formic acid of which acetic acid is preferred.
The reaction is normally and preferably carried out in the presence of a solvent.
However, it has been found by the present inventors that carrying out the reaction in acetonitrile as solvent enables the base to remain dissolved and allows the reaction to proceed in good yield.
The reaction temperature depends on various factors such as the nature of the reagents and the solvent. However, it is typically from -20°C to 50°C, and preferably -5°C to 20°C.
The reaction time depends on various factors such as the nature of the reagents, the solvent and the temperature. However, it is typically from preferably from 10 minutes to 12 hours, and more preferably 1 to 12 hours.
After completion of the reaction, the compound of formula (X) is isolated from the reaction mixture by conventional methods. For example, the compound may be extracted using an organic solvent, the organic layer may be washed with an aqueous solution such as water or sodium chloride in order to remove any ionic species present, filtered to remove any solid matter, and concentrated to remove the solvent. The product may further be purified by conventional methods such as crystallization or column chromatography. However, the method step described herein is capable of producing the product in sufficient purity such that it is generally not necessary to use column chromatography to purify the product. The final step of the synthesis is optional and comprises one or more of the following: treating the compound of formula (I) with a base to produce a cationic salt of the compound of formula (I); and/or treating the compound of formula (I) with an acid to produce an acid addition salt of the compound of formula (I). The base used to treat the compound of formula (I) is not particularly limited; examples of such bases include alkali metal hydroxides such as potassium, sodium and lithium hydroxides or alkali metal alkoxides, such as potassium ethanolate and sodium propanolate; alkaline earth metal hydroxides such as calcium hydroxide; ammonia; salts of primary, secondary and tertiary amines including, as primary amines, methylamine, ethylamine, propylamine, benzylamine, aniline and butylamine, as secondary amines dimethylamine, and diethylamine, and as tertiary amines trimethylamine and
triethylamine, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, Ν,Ν'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso- propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine,
triethanolamine, triethylamine, trimethylamine, tripropylamine and tris-(hydroxymethyl)- methylamine (tromethamine). Alkali metal hydroxides, especially sodium hydroxide, are preferred.
Similarly, the acid used to treat the compound of formula (I) is not particularly limited; examples of such acids include hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid; other mineral acids such as sulfuric, nitric or phosphoric acid, etc.; alkyl and monoarylsulfonic acids such as methanesulfonic, ethanesulfonic, toluenesulfonic and benzenesulfonic acids; and other organic acids and their corresponding salts such as acetic, tartaric, maleic, succinic, citric, benzoic, salicylic and ascorbic acid. Further acid addition salts of the compound of formula (I) that can be produced according to the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, butyrate, camphorate, camphorsulfonate, caprylate, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, 1 ,2-ethanedisulfonate (edisylate), fumarate, galacterate (from mucic acid), galacturonate, gentisate, glucoheptonate, gluconate, glutamate,
glycerophosphate, glycolate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesulfonate, isethionate, iso-butyrate, lactate, lactobionate, malate, malonate, mandelate, metaphosphate, methylbenzoate,
monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphonate, phthalate, and vanillate. In one embodiment, the acid is hydrochloric acid, sulfuric acid or
methanesulfonic acid. The preferred salt is hydrochloride.
The compounds of formula (I) used in the present invention also possess a free acid form, and may be present as free acids. Alternatively a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
Hydrochloride salt of the compounds of formula (I) are especially preferred. Therefore in one aspect the present invention provides a hydrochloride salt of a compound of formula (I), as defined above.
In particular, the present invention provides a hydrochloride salt of a compound of formula (XVIII):
Thus, the present disclosure provides 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5- methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride and pharmaceutical compositions thereof.
The present disclosure also provides for novel crystalline forms of 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride and pharmaceutical compositions thereof.
A crystal form may be referred to herein to be characterized "as depicted in" a Figure. Such data include powder X-ray diffractograms (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and scanning electron microscopy. The skilled person will understand that the data as depicted in the Figures may be subject to variations (for example, variations in peak intensity and/or exact peak positions) due to variations on instrument parameters, sample concentration, and sample purity. The skilled person will be able to compare the Figures herein and the data for an unknown crystalline form and determine whether the data characterize the crystalline form (s) disclosed or different crystalline forms.
A crystalline form (polymorph) may be referred to herein as substantially free of any other crystalline (polymorphic) forms. As used herein in this context, the expressions "substantially free of any other forms" means that the crystalline form contains, 20% or less (w/w), 10% or less (w/w), 5% or less (w/w), 2% or less (w/w), or 1 % or less (w/w) of other crystalline (polymorphic) forms of the subject compound as measured, for example, by PXRD. Furthermore, a crystalline form of 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2- carboxylic acid hydrochloride contains greater than 80% (w/w), greater than 90% (w/w), greater than 95% (w/w), greater than 98% (w/w), or greater than 99% (w/w) of the subject polymorphic form of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride.
The present disclosure provides two crystalline 3-[2-(4-carbamimidoyl-phenylcarbamoyl)- 5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride, namely form A (also referred to as compound XIX) and form C (also referred to as compound XX).
In one embodiment, the present disclosure provides crystalline form A of 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride. In one embodiment, form A (compound XIX) is characterized by data selected from a group consisting of: i) a powder XRD (PXRD) pattern having peaks at 7.3, 9.5, 18.5 and 21.9 2Θ±0.2 °2Θ; ii) a powder XRD pattern having peaks at 7.31 , 9.52, 18.54 and 21.85 2Θ±0.2 °2Θ; iii) a PXRD pattern as depicted in FIG. 15; and iv) any combination thereof.
In still another embodiment, form A (compound XIX) is characterized by data selected from a group consisting of: i) a powder XRD pattern having peaks at 14.7, 20.3, 22.5, 22.7, 26.1 , and 26.7 2Θ±0.2 0 2Θ; ii) a powder XRD pattern having peaks at 14.65, 20.28, 22.51 , 22.96, 26.14, and 26.72 2Θ±0.2 0 2Θ; iii) a differential scanning calorimetry (DSC) thermogram as depicted in FIG. 16; iv) a thermogravimetric (TG) thermogram as depicted in FIG. 17; v) a crystal structure as determined by scanning electron
microscopy (SEM) as depicted in FIG. 18; and vi) any combination of the foregoing.
In still another embodiment, form A (compound XIX) is characterized by data selected from a group consisting of: i) a powder XRD (PXRD) pattern having peaks at 7.3, 9.5, 18.5 and 21.9 2Θ±0.2 °2Θ; ii) a powder XRD pattern having peaks at 7.31 , 9.52, 18.54 and 21.85 2Θ±0.2 °2Θ; iii) a PXRD pattern as depicted in FIG. 15; iv) a powder XRD pattern having peaks at 14.7, 20.3, 22.5, 22.7, 26.1 , and 26.7 2Θ±0.2 0 2Θ; v) a powder XRD pattern having peaks at 14.65, 20.28, 22.51 , 22.96, 26.14, and 26.72 2Θ±0.2 0 2Θ; vi) a differential scanning calorimetry (DSC) thermogram as depicted in FIG. 16; vii) a thermogravimetric (TG) thermogram as depicted in FIG. 17; viii) a crystal structure as determined by scanning electron microscopy (SEM) as depicted in FIG. 18; and ix) any combination of the foregoing.
The above crystalline Form A as described above is a variable hydrate. As used herein, and unless stated otherwise, the term "variable hydrate" in relation to crystalline 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride means that the water content is dependent on relative humidity ("RH") conditions. At about room temperature and 30% RH, Form A shows water content consistent with a monohydrate (estimated at about 1.2 mole of water per mole of crystalline form A).
In another embodiment, the compound of formula (XIX) is present as a hydrochloride salt, wherein the chloride content of the salt is greater than or equal to 0.65 and less than or equal to 1.4 (molar ratio of chloride to compound XVIII) or greater than or equal to 0.65 and less than or equal to 1 (molar ratio of chloride to compound XVIII).
In one embodiment, form A (compound XIX) has the advantageous property of superior solubility in pharmaceutical compositions, in particular oral pharmaceutical compositions. In another embodiment, pharmaceutical compositions of form A (compound XIX), in particular oral pharmaceutical compositions, when administered to a subject provide for increased bioavailability of the compound as compared to amorphous 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid and salts thereof and other crystalline forms. In another embodiment, form A (compound XIX) has the advantageous property of stability to polymorphic conversion. In particular, conversion to other polymorphic forms was not observed for form A in RH conditions of 43%, 75%, and 100%, at room temperature. Preferably, Form A of crystalline 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride is substantially free of any other polymorphic forms. Methods for the manufacture of form A (compound XIX) are disclosed herein. Form A may be obtainable by treatment of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy- 4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid in aqueous acetonitrile with base followed by hydrochloric acid, precipitation of 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride, and washing of the 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride with methyl terf-butyl ether. Thus there is provided 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6- (cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride in the form obtainable by this method.
In one embodiment, the present disclosure provides crystalline form C of 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride. In one embodiment, form C (compound XX) is characterized by data selected from a group consisting of: i) a powder XRD (PXRD) pattern having peaks at 4.2, 7.9, and 10.8 2Θ±0.2 °2Θ; ii) a powder XRD pattern having peaks 4.15, 7.94, and 10.79 2Θ±0.2 °2Θ; iii) a PXRD pattern as depicted in FIG. 19; and iv) any combination thereof. In still another embodiment, form C (compound XX) is characterized by data selected from a group consisting of: i) a powder XRD pattern having peaks at 12.6, 20.9, 21.3, 23.8, 24.5, 27.0, and 28.4 2Θ±0.2° 2Θ; ii) a powder XRD pattern having peaks at 12.57, 20.90, 21.31 , 23.97, 24.45, 27.02, and 28.36 2Θ±0.2° 2Θ; iii) a differential scanning calorimetry (DSC) thermogram as depicted in FIG. 20; iv) a thermogravimetric (TG) thermogram as depicted in FIG. 21 ; and v) any combination of the foregoing.
In still another embodiment, form C (compound XX) is characterized by data selected from a group consisting of: i) a powder XRD (PXRD) pattern having peaks at 4.2, 7.9, and 10.8 2Θ±0.2 °2Θ; ii) a powder XRD pattern having peaks 4.15, 7.94, and 10.79 2Θ±0.2 °2Θ; iii) a PXRD pattern as depicted in FIG. 19; iv) a powder XRD pattern having peaks at 12.6, 20.9, 21.3, 23.8, 24.5, 27.0, and 28.4 2Θ±0.2° 2Θ; v) a powder XRD pattern having peaks at 12.57, 20.90, 21.31 , 23.97, 24.45, 27.02, and 28.36 2Θ±0.2° 2Θ; vi) a differential scanning calorimetry (DSC) thermogram as depicted in FIG. 20; vii) a thermogravimetric (TG) thermogram as depicted in FIG. 21 ; and viii) any combination of the foregoing.
The above 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6- (cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride crystalline Form C is a variable hydrate.
As used herein, the term "variable hydrate" in relation to crystalline 3-[2-(4- carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)-pyridine-2-carboxylic acid hydrochloride Form C means that the water content is dependent on relative humidity ("RH") conditions. At about room temperature and 34% RH, Form C shows water content close to a monohydrate (estimated at about 1.4 mole of water per mole of crystalline Form C).
Preferably, the crystalline 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid hydrochloride Form C of the invention is substantially free of any other polymorph forms.
Methods for the manufacture of form C are described herein. Form C may be obtainable by treatment of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6- (cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid in aqueous acetonitrile with base followed by hydrochloric acid, precipitation of 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2- carboxylic acid hydrochloride, and washing of the 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2- carboxylic acid hydrochloride with water. Thus there is provided 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2- carboxylic acid hydrochloride in the form obtainable by this method. The compounds used in the present invention may exist in the form of solvates. Such solvates include solvent molecules in their crystal structure. Therefore, in a further aspect, the invention provides a pharmaceutically acceptable solvate of a compound of formula (I) as defined herein, either in its broadest aspect or a preferred aspect, and a method of producing it. In one embodiment, the invention provides a pharmaceutically acceptable solvate of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl- phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid and a method of producing it. Examples of solvates include hydrates and alcoholates. In further embodiments of the present invention there are provided solvates of the intermediate compounds of formulae (VI), (XI), (XII), (XIII), (XIV), (XV), and (XVII) as defined herein, either in their broadest aspects or in preferred aspects, and methods of producing them. Examples of solvates include hydrates and alcoholates. Prodrug derivatives of the compounds of Formula (I) produced in the present invention can be prepared by modifying substituents of compounds of the present invention that are then converted in vivo to a different substituent. In particular, the compounds of Formula (I) produced in the present invention possess a carboxylic acid (-C02H) group and may possess amidine (-C(=NH)NH2) functional groups, either of which can be derivatised to form prodrugs of the compounds of the invention. Therefore, in one aspect, the invention includes in the step of producing a compound of Formula (I) or pharmaceutically acceptable salt, solvate, ester or prodrug thereof, methods of converting the compound of formula (I) into a salt or solvate thereof, or into an ester or other prodrug thereof, or into a salt or solvate of an ester or other prodrug thereof.
Esters of the compounds of Formula (I) produced in the present invention can be formed by reacting the compounds with a suitable compound containing a hydroxyl group. Therefore, in a further aspect, the invention includes in the step of producing a compound of Formula (I) or pharmaceutically acceptable salt, solvate, ester or prodrug thereof, methods of producing a pharmaceutically acceptable ester of a compound of formula (I) as defined herein, either in its broadest aspect or a preferred aspect. In one embodiment, the invention provides a method of producing a pharmaceutically acceptable ester of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]- 6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid. Examples of suitable esters include alkyl esters, in particular C -4 alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl esters, and longer-chain alkyl esters such as C5.30 alkyl esters including pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadceyl, heptadecyl, octadecyl, nonadecyl, icosyl, henicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl and triacontyl esters.
Other examples of suitable esters include substituted Ci-4 alkyl esters (preferably substituted methyl or ethyl esters) wherein the substituent is selected from the group consisting of:
a hydroxyl group; examples of such substituted groups include 2-hydroxyethyl;
an alkoxy group, in particular Ci-4 alkoxy; examples of such substituted groups include methoxymethyl or 2-ethoxyethyl;
an acyloxy group, wherein the acyl moiety is a group R-C(=0)- wherein R is a hydrocarbon group, including but not limited to an alkyl group (such as a Ci_4 or C5-30 alkyl group as defined and exemplified above) or a benzyl group; examples of such substituted groups include acetyloxyethyl, pivaloyloxymethyl, 2-(pivaloyloxy)ethyl and 2- methyl-1 -(pivaloyloxy)propyl;
a carbonate group, wherein the carbonate group attached is a moiety of formula
RO-C(=0)-0- wherein R is C1-6 alkyl; examples of such substituted groups include isopropyl methyl carbonate wherein the ester moiety has the formula
(CH3)2CH-0-C(=0)-0-CH2-;
a 5-methyl-2-oxo-1 ,3-dioxolene-4-yl group; examples of such substituted groups include (5-methyl-2-oxo-1 ,3-dioxolene-4-yl)methyl;
an amino acid residue, including but not limited to Gly (glycine), Ala (alanine;
CH3CH(NH2)CO-), Arg (arginine), Asn (asparagine), Asp (aspartic acid), Cys (cysteine),
Glu (glutamic acid), His (histidine), lie (isoleucine), Leu (leucine;
(CH3)2CHCH2CH(NH2)CO-), Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val (valine), The amino acid residue may be attached via its amine terminus, its carboxylic acid terminus or a side chain; examples of such substituted groups include valinemethyl, 2-
(valine)ethyl, 2-(valine)propyl, 2-(phenylalanine)ethyl, 2-(isoleucine)ethyl; a saturated heterocyclic group having 3-8 ring atoms, of which at least one ring atom (preferably 1 , 2 or 3; more preferably 1 or 2) is a heteroatom selected from nitrogen, oxygen and sulphur; including but not limited to aziridinyl; azetidinyl; piperidyl, morpholinyl, piperazinyl, pyrrolidinyl, azepinyl, azocinyl,1 ,3-dioxanyl, 1 ,4-dioxanyl;
examples of such substituted groups include 2-(morpholino)ethyl.
Amide prodrugs of the compounds of formula (I) can be formed by reacting the compounds with a suitable compound containing a primary or secondary amine group, such that the carboxylic acid group forms an amide bond with the amine, eliminating a molecule of water. Therefore, in a further aspect, the invention includes in the step of producing a compound of Formula (I) or pharmaceutically acceptable salt, solvate, ester or prodrug thereof, methods of producing a pharmaceutically acceptable amide prodrug of a compound of formula (I) as defined herein, either in its broadest aspect or a preferred aspect. In one embodiment, the invention provides a method of producing a pharmaceutically acceptable amide prodrug of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)- 5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid.
Examples of such amide prodrugs include those formed by reaction with the following: ammonia; alkylamines, in particular C1-4 alkyl amines such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamines, sec-butylamine and tert-butyl amine;
dialkylamines, in particular di(C1-4 alkyl) amines such as dimethylamine, diethylamine, N- methylethylamine, dipropylamine, N-methylpropylamine, N-methylisopropylamine, N- ethylisopropylamine, diisopropylamine, dibutylamine, diisobutylamine, di(sec-butyl)amine and di(tert-butyl)amine;
arylalkylamines and diarylalkylamines, such as benzylamine and benzhydrylamine; amino acid residues, such as those defined and exemplified above in relation to amino acid substituted alkyl esters;
saturated nitrogen-containing heterocyclic amines having 3-8 ring atoms, of which at least one ring atom is a nitrogen atom and other heteroatoms are selected from nitrogen, oxygen and sulphur; including but not limited to aziridine; azetidine; pyrrolidine;
piperidine, morpholine, piperazine, azepine and azocine. 2
Amidine prodrugs of the compounds produced in the present invention can be formed by reacting the compounds with a compound capable of reacting with an amidine functional group. Therefore, in a further aspect, the invention includes in the step of producing a compound of Formula (I) or pharmaceutically acceptable salt, solvate, ester or prodrug thereof, methods of producing a pharmaceutically acceptable amidine prodrug of a compound of formula (I) as defined herein, either in its broadest aspect or a preferred aspect. In one embodiment, the invention provides method of producing a
pharmaceutically acceptable amidine prodrug of 3-[2-(4-carbamimidoyl- phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine- 2-carboxylic acid.
Examples of amidine prodrugs include the following:
prodrugs wherein the amidine is bonded to a hydroxyl group;
prodrugs wherein the amidine is bonded to an alkyl group; such as those defined and exemplified above;
prodrugs with amino acid residues, where the amino acid residue is as defined and exemplified above in relation to amino acid substituted alkyl esters; examples of such prodrugs include valine amides; and
carbamates, in particular alkyl carbamates, such as C1-6 alkyl carbamates such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl carbamates.
The prodrugs may themselves form salts and solvates. Examples of suitable salts and solvates include as those listed above in relation to pharmaceutically acceptable salts and solvates of the compounds of formula (I).
Particular examples of prodrugs of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy- 4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid, including salts thereof, that can be produced according to the present invention, include those listed in Table 1 below.
Figure imgf000077_0001
Figure imgf000078_0001
lsoprc >pyl methyl carbonate
Figure imgf000079_0001
Figure imgf000080_0001
Table 1
Examples
A particularly preferred synthesis is set out in Schemes 1a through 4a below and described in detail in the Examples. In this section, the following abbreviations are used:
Figure imgf000080_0002
Figure imgf000081_0001
Figure imgf000082_0001
Example-1 : Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid hydrochloride (7b)
Figure imgf000082_0002
7b
Step (1): Preparation of 6-Bromobenzo 1 ,3]dioxole-5-carbaldehyde (1 b):
Figure imgf000082_0003
1b
A solution of bromine (33.0 kg, 206.49 mol) in acetic acid (27.5 L) was added slowly to a solution of piperonal (1a) (29.9 kg, 199.16 mol) in acetic acid (105 L) at room temperature over a period of 50 min and the reaction mixture was stirred at room temperature for 14.2 h. Additional solution of bromine (33 kg, 206.49 mol) in acetic acid (27.5 L) was added slowly to the reaction mixture over a period of 2 h and the reaction mixture was stirred for 22 h. The reaction mixture was quenched by addition of ice water (500 L) with stirring over a period of 6 h and continued stirring for additional 1.25 h. The mixture was allowed to settle and most of the supernatant liquid was decanted to a waste container using nitrogen pressure. Water (600 L) was added to the solid, stirred, mixture was allowed to settle and then most of the supernatant liquid was decanted to a waste container using nitrogen pressure. Water (100 L) was added to the decanted mixture, stirred for 15 min and the solid obtained was collected by filtration using a centrifuge. The solid was washed with water (2 x 100 L) and air-dried in a tray drier for 3.75 h to afford the crude product 1 b (52 kg). The crude product (51.2 kg) was stirred in n-hexane (178 L) for 3 h, collected by filtration, washed with n-hexane (25 L) and dried to afford 6-bromobenzo[1 ,3]dioxole-5-carbaldehyde (1b) (40.1 1 kg, 87.9%) as a light brown solid. MP: 109-112°C. 1H NMR (300 MHz, CDCI3) δ 10.21 (s, 1 H), 7.37 (s, 1 H), 7.07 (s, 1 H), 6.10 (s, 2H); HNMR (DMSO-cf6): δ 10.06 (s, 1 H), 7.42 (s, 1 H), 7.29 (s, 1 H), 6.20 (d, J =12.3 Hz, 2H)
The process is also illustrated in Fig. 1.
Average yield of isolated 1 b from step-1 is 78 - 88%.
Step (2): Preparation of 2-Bromo-5-hydroxy-4-methoxy-benzaldehyde (1c)
Figure imgf000083_0001
A solution of potassium terf-butoxide (10.7 kg, 95.36 mol) in DMSO (49 L) was stirred at 50 °C for 30 min. Methanol (49 L) was added slowly over a period of 4.25 h and stirred at 50 °C for 30 min. 6-Bromobenzo[1 ,3]dioxole-5-carbaldehyde (1 b) (9.91 kg, 43.27 mol) was added to the reaction mixture in small portions over a period of 45 min and stirred at 50 °C for 1 h. The reaction mixture was cooled to room temperature and split into two equal portions. Each portion was quenched with water (50.9 L) and basified with 50% aqueous NaOH solution (2.4 L). Each portion was extracted with MTBE (4 x 36 L) to remove impurities. The aqueous layer was acidified with cone. HCI to pH ~ 3 to obtain product as a yellow solid. The solid was collected by filtration using a centrifuge, washed with water (2 x 35 L) and air-dried to afford 2-Bromo-5-hydroxy-4-methoxy-benzaldehyde (1c) (4.37 kg, 40.7%, contains 7 % water); Mp: 100-102°C; 1HNMR (300MHz, DMSO-d6): δ 10.00 (s, 1 H), 9.92 (s,1 H), 7.27 (s, 1 H), 7.26 (s, 1 H), 3.93 (s, 3H).
The process is also illustrated in Fig. 2.
Average yield of isolated product 2-Bromo-5-hydroxy-4-methoxy-benzaldehyde (1c) from step-2 is 40-50%. Step (3): 5-Hydroxy-4-methoxy-2-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- y benzaldehyde (4a)
Figure imgf000084_0001
2-Bromo-5-hydroxy-4-methoxy-benzaldehyde (1c) [1.3 kg (93%, 7% water content), 5.25 mol] was dissolved in toluene (13 L) in a reaction flask equipped with a Dean Stark apparatus. The solution was heated at reflux with stirring to distil off about 25% of the toluene along with water (90 ml_). The solution was cooled to 90 °C then
bis(pinacolato)diboron (1.5 kg, 5.82 mol), KOAc (772.6 g, 7.87 mol) and Pd(PPh3) (24.3 g, 0.02 mol) were added and the reaction mixture was heated at reflux for 10h. After confirming the completion of reaction by TLC (mobile phase: 100% DCM), the reaction mixture was cooled to room temperature and was kept standing overnight. The reaction mixture was filtered through celite and the celite cake was washed with toluene (4 L). The filtrate of this batch was mixed with the filtrate of another batch (batch size 1.3 kg obtained from an identical reaction). The mixed filtrate was washed with water (17.5 L), brine (17.5 L), dried over Na2S04, filtered and the solution was passed through a pad of silica gel (2 kg, mesh size 230-400). The silica gel pad was washed with toluene. The combined filtrate and washing was concentrated under reduced pressure and the residual crude product was stirred with n-hexane (23 L) for 1 h to obtain a solid product. The solid was collected by filtration, washed with n-hexane (5 L) and dried to afford 5- hydroxy-4-methoxy-2-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)benzaldehyde (4a) (2.47 kg, 84.6%). H NMR (300 MHz, CDCI3) δ 10.54 (s, 1 H), 7.57 (s, 1 H), 7.33 (s, 1 H), 5.89 (s, 1 H), 4.01 (s, 3H), 1.37 (s, 12H); 1H NMR (300 MHz, DMSO-d6) δ 10.35 (s, 1 H), 9.95 (s, 1 H), 7.33 (s, 1 H), 7.23 (s, 1 H), 3.87 (s, 3H), 1.33 (s, 12H); MS (ES+) 301.1 (M+Na); 579.1 (2M+Na); Analysis calculated for C14H19B05: C, 60.46; H, 6.89; Found: C, 60.60; H, 6.87
The average yield of 5-hydroxy-4-methoxy-2-(4,4,5,5-tetramethyl-[1 ,3,2]dioxa-borolan-2- yl)benzaldehyde (4a) from step (3) is 78 - 90%.
The process is also illustrated in Fig. 3.
Step (4): Preparation of 3-Bromo-2,6-dimethylpyridine (5b)
Figure imgf000085_0001
2,6-lutidine (5a) (115 kg, 1073.3 mol) was added into pre-chilled oleum (20-23%, 1015 kg, 2276.7 mol) at 0 °C over a period of 4.5 h (temperature r6ached 14 °C during the addition). Bromine (88.18 kg, 1103.6 mol) was then added at 5-10 °C over a period of 1 h. The reaction mixture was slowly heated to 150 °C over a period of 12h. TLC analysis indicated about 40-50% conversion to product and the formation of a dimer by-product (5%). The reaction mixture was cooled to room temperature and then additional bromine (88.18 kg, 1103.6 mol) was added slowly. The reaction mixture was slowly heated to maintain a temperature of 65-75 °C over a period of 15h. TLC analysis indicated a 65-70 % conversion to product and the formation of 5% dimer by product. The reaction mixture was quenched by addition of water (500L) while maintaining the reaction temperature below 20 °C. The mixture was basified with 6.6 M NaOH (3800 L) while maintain the temperature at < 40 °C. EtOAc (220 L) was added and the mixture was stirred for 1 h then allowed to settle over a period of 2 h. The layers were separated and the aqueous layer was treated with NaOH (10 kg) in water (10 L) and extracted with EtOAc (160 L). The organic extracts were combined washed with brine (100 L), dried over Na2S04 (50.0 kg), filtered and the solvent was evaporated under atmospheric pressure. The residue was vacuum distilled and the desired product 3-bromo-2,6-dimethylpyridine (5b) was collected at 58-60 °C, 2 mmHg (98.45 kg, 49.2 %) as a colorless liquid.
The process is also illustrated in Fig. 4. Step (5): Preparation of 3-Bromopyridine-2,6-dicarboxylic acid (5c)
Figure imgf000086_0001
5b 5c
To a stirred solution of 3-bromo-2,6-dimethylpyridine (5b) (98 kg, 5326 mol) in water (1310 L) was added KMn0 (225 kg, 1423.6 mol) in 5 equal portions in 1 h intervals at 70 °C. After stirring for 1 h at 70 °C, additional KMn04 (225 Kg, 1423.6 mol) was added in 5 equal portion in 1 h intervals at 90 °C. The reaction mixture was stirred for 12 h at 90 °C. The suspension was filtered hot through celite to obtain a clear solution. The solvent was distilled off to remove about 30% of the total volume. The remaining concentrated solution was chilled to 0 °C and made acidic (to pH 3-4) by the addition of cone. HCI (120 L). The white precipitate obtained was collected by filtration and dried at 70 °C to afford 3-bromopyridine-2,6-dicarboxylic acid (5c) as a white solid (109 kg, 84%).
The process is also illustrated in Fig. 5.
Step (6): Preparation of Dimethyl 3-Bromopyridine-2,6-dicarboxylate (5d)
Figure imgf000086_0002
To a stirred solution of 3-bromopyridine-2,6-dicarboxylic acid (5c) (20.0 kg, 81.29 mol) in methanol (100 L) was added cone. H2S04 (4.4 L) over a period of 30 min. The reaction mixture was heated to 65 °C and maintained at that temperature for 5 h (the reaction was monitored by TLC analysis to determine completion of reaction). The reaction mixture was cooled to room temperature basified by careful addition of aqueous NaHC03 solution (prepared from 10 kg NaHC03 in 120 L of water) and further diluted with water (120 L). The white solid obtained was collected by filtration, washed with plenty of water and then oven-dried at 40 °C to obtain dimethyl 3-bromopyridine-2,6- dicarboxylate (5d) (9.2 kg, 41.3%) as a white solid; 1HNMR (300 MHz, DMSO-cf6) δ 8.47 (d, J = 8.4, 1 H), 8.08 (dd, J = 4.5, 8.4, 1 H), 3.95 (s, 3H), 3.91 (s, 3H); MS (ES+) 570.6 (2M+Na); Analysis calculated for C9H8BrN04: C, 39.44; H, 2.94; Br, 29.15 N, 5. 1 ;
Found: C, 39.52; H, 2.92; Br, 29.28; N, 5.03.
The process is also illustrated in Fig. 6. 6582
Step (7): Preparation of Methyl 3-bromo-6-(cyclopropylmethylcarbamoyl)pyridine-2- carboxylate (
Figure imgf000087_0001
To a stirred solution of dimethyl 3-bromopyridine-2,6-dicarboxylate (5d) (27 kg, 98.52 mol) in ierf-butanol (135 L) was added at room temperature cyclopropylmethanamine (7.83 kg, 110.1 mol). The reaction mixture was heated at 65 °C for 17 h. The progress of reaction was monitored by TLC and HPLC (HPLC analysis showed the formation of 74% of the product 5e after 17 h. The reaction mixture was cooled to room temperature and then cone. HCI (2.7 L) was added slowly and the mixture was stirred for 15 min. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in hot /-PrOH (54 L) filtered through a celite pad. The filtrate was cooled with stirring to 10 °C to obtain a white precipitate. The solid obtained was collected by filtration, washed with cold
i-PrOH (13 kg), n-hexane (15 L) and dried to provide pure methyl 3-bromo-6- (cyclopropylmethylcarbamoyl)pyridine-2-carboxylate (5e) (15.7 kg, 50.9%). The filtrate was concentrated under reduced pressure and the crude product can be purified by silica gel column chromatography eluting with tert-butanol in hexanes to furnish additional 10% methyl 3-bromo-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylate (5e). HNMR (300 MHz, DMSO-cf6) δ 8.83 (t, J = 5.9, 1 H), 8.47 - 8.41 (m, 1 H), 8.06 (d, J = 8.4, 1 H), 3.96 (s, 3H), 3.16 (t, J = 6.5, 2H), 1.14 - 0.99 (m, 1 H), 0.42 (m, 2H), 0.30 - 0.19 (m, 2H); MS (ES+) 337.0 (M+23), 650.8 (2M+23); Analysis calculated for
C12H13BrN203: C, 46.03; H, 4.18; N, 8.95; Br, 25.52; Found: C, 46.15; H, 4.17; N, 8.72; Br, 25.26.
The average isolated yield for step (7) is 50% to 60%.
The process is also illustrated in Fig. 7.
Step (8): Preparation of methyl 6-((cyclopropylmethyl)carbamoyl)-3-(2-formyl-4-hydroxy- 5-methoxyphenyl)picolinate (6a) 2
Figure imgf000088_0001
6a
THF (37.5 L) was charged to a 100 L reactor followed by ethyl 3-bromo-6-
(cyclopropylmethyl-carbamoyl)pyridine-2-carboxylate (5e) (2.5 kg, 7.98 mol) under a nitrogen atmosphere. The reaction mixture was degassed twice by applying alternate vacuum and nitrogen. 5-Hydroxy-4-methoxy-2-(4,4,5,5-tetramethyl-[1 ,3,2]dioxa-borolan- 2-yl)benzaldehyde (4a) (2.88 kg, 10.36 mol) was added, followed by the addition of PPh3 (53.13 g, 0.20 mol), PdCI2(PPh3)2 (120.4 g, 0.17 mol) and a solution of Na2C03 (2.12 kg, 20.00 mol) in demineralized water (10.0 L) under nitrogen atmosphere. The reaction mixture was degassed again two times by applying alternate vacuum and nitrogen. The reaction mixture was heated at reflux for 6.5 h, cooled to room temperature and filtered through a Celite bed. Water (75 L) was added to the filtrate and the product was extracted with ethyl acetate (75 L). The aqueous layer was back extracted with ethyl acetate (2 χ 60 L). The combined ethyl acetate extract was divided into two equal portions and each portion was washed with brine (37 L), dried over Na2S04, filtered and concentrated under reduced pressure to give crude methyl 6-
((cyclopropylmethyl)carbamoyl)-3-(2-formyl-4-hydroxy-5-methoxyphenyl)picolinate (6a) as a reddish viscous material (-4.5 Kg) which was used as such for the next step without further purification. An analytical sample was prepared by purification of a small sample by flash column chromatography (silica gel, eluting with 0-100% ethyl acetate in hexane) to furnish methyl 6-((cyclopropylmethyl)carbamoyl)-3-(2-formyl-4-hydroxy-5- methoxyphenyl)-picolinate (6a) as an off-white solid; HNMR (300 MHz, DMSO-d6) δ 9.89 (s, 1 H), 9.52 (s, 1 H), 8.79 (t, J = 6.1 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 7.34 (s, 1 H), 6.90 (s, 1 H), 3.85 (s, 3H), 3.62 (s, 3H), 3.22 (m, 2H), 1.16 - 1.02 (m, 1 H), 0.49 - 0.38 (m, 2H), 0.32 - 0.22 (m, 2H); MS (ES+) 791.0 (2M+Na), (ES-) 382.7 (M-1), 767.3 (2M-1); Analysis calculated for C20H20N2O6.0.25 H20: C, 61.77; H, 5.31 ; N, 7.20; Found: C, 61.54; H, 5.13; N, 7.05.
The process is also illustrated in Fig. 8. 46582
Step (9): Preparation of methyl 6-((cyclopropylmethyl)carbamoyl)-3-(2-formyl-5-methoxy- 4-(((trifluoromethyl)sulfonyl)oxy)phenyl)picolinate (6b)
Figure imgf000089_0001
6a 6b
A solution of methyl 6-((cyclopropylmethyl)carbamoyl)-3-(2-formyl-4-hydroxy-5- methoxyphenyl)picolinate (6a) (2.11 kg, estimated about 3.83 mol from step-8) in dichloromethane (16.0 L) and pyridine (1.4 L, 17.4 mol) cooled to -10°C and maintained at that temperature for 1 h was added a solution of triflic anhydride (980.0 ml_, 5.8 mol) in dichloromethane (6.0 L) drop wise over a period of 3 h at -10 °C. The reaction mixture was stirred at -5°C for 1.3 h, quenched with saturated aqueous NaHCO3 (10.4 L) and stirred for 30 mins. The organic layer was separated, washed successively with saturated aqueous NaHC03 (10.4 L), 1 HCI (2 x 16.6 L), water (13.2 L), brine (13.2 L), dried over MgS04, filtered and concentrated under reduced pressure to give the crude product. The crude product was stirred with 15% ethyl acetate in n-hexane (7.0 L) for 1 h. The solid obtained was collected by filtration washed with 15% ethyl acetate in n- hexane (3.0 L). The solid was stirred again with 15% ethyl acetate in n-hexane (7.0 L) for 1 h, was collected by filtration and washed with 15% ethyl acetate in n-hexane (3.0 L). The solid was stirred again with 15% ethyl acetate in n-hexane (8.0 L) for 1 h, collected by filtration washed with 15% ethyl acetate in n-hexane (3.0 L). The solid was dried to afford methyl 6-((cyclopropylmethyl)carbamoyl)-3-(2-formyl-5-methoxy-4- (((trifluoromethyl)sulfonyl)-oxy)phenyl)picolinate (6b) as a light brown solid (1.7 kg, 86% yield, for combined steps 8 & 9). Average isolated yield for combined steps 8 and 9 was 70% to 86%; Ή NMR (300 MHz, DMSO-cf6): δ 9.64 (s, 1 H), 8.78 (t, J = 6.1 , 1 H), 8.29 (d, J = 8.0, 1 H), 8.16 (d, J = 8.0, 1 H), 8.03 (s, 1H), 7.39 (s, 1 H), 4.00 (s, 3H), 3.63 (s, 3H), 3.22 (m, 2H), 1.11 (m, 1 H), 0.52 - 0.39 (m, 2H), 0.28 (m, 2H); MS (ES+) 538.9 (M+Na). The process is also illustrated in Fig. 9. Step (10): Preparation of methyl 6-((cyclopropylmethyl)carbamoyl)-3-(2-formyl-5- methoxy-4-vinylphenyl)picolinate (6c)
Figure imgf000090_0001
A solution of methyl 6-((cyclopropylmethyl)carbamoyl)-3-(2-formyl-5-methoxy-4-
(((trifluoromethyl)sulfonyl)oxy)phenyl)picolinate (6b) (12 kg, 23.24 mol) in DME (106 L) was charged into reactor under nitrogen. The reaction mixture was degassed twice by applying alternate vacuum and nitrogen. Potassium trifluoro(vinyl)borate (3.9 kg, 29.1 1 mol), PdCI2(PPh3)2 (815 g, 1.13 mol), KHC03 (4.65 g, 46.44 mol) and demineralized water (12 L) was then added under a N2 atmosphere. The reaction mixture was degassed by applying alternate vacuum and nitrogen. The reaction mixture was heated at reflux for 5 h. The reaction mixture was cooled to room temperature and then filtered through a Celite bed. Demineralized water (118 L) was added to the filtrate followed by ethyl acetate (124 L). The mixture was stirred for 20 min and then the organic layer was separated. The aqueous layer was back-extracted with ethyl acetate (2 x 95 L). The combined organic extract was washed with brine (95 L), dried over Na2S04, and filtered. The solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, 120 kg, 230-400 mesh size, eluting with ethyl acetate in n-hexane) to obtain methyl 6- ((cyclopropylmethyl)carbamoyl)-3-(2-formyl-5-methoxy-4-vinylphenyl)picolinate (6c) (6 kg, 72%). 1H NMR (300 MHz, CDCI3): δ (ppm) 9.64 (s, 1 H), 8.35 (d, J = 7.8 Hz, 1 H), 8.06-8.03 (m, 2H), 7.78(d, J = 7.8 Hz, 1 H), 7.02-6.92 (m, 1 H), 6.61 (s, 1 H), 5.86 (d, J = 17.7 Hz, 1 H), 5.38 (d, J = 1 1.4 Hz, 1 H), 3.84 (s, 3H), 3.67 (s, 3H), 3.35-3.29 (m, 2H),1.08-1.03 (m, 1H), 0.55-0.49 (m, 2H), 0.29-0.2 4(m, 2H). 1HNMR (300 MHz, DMSO- d6) 6 9.68 (s, 1 H), 8.77 (t, J = 6.1 , 1 H), 8.35 - 8.21 (m, 1 H), 8.16 - 8.01 (m, 2H), 7.14 - 6.87 (m, 2H), 6.01 (dd, J = 1.2, 17.8, 1 H), 5.45 (dd, J = 1.1 , 1 1.3, 1 H), 3.91 (s, 3H), 3.64 (s, 3H), 3.23 (m, 2H), 1.21 - 1.01 (m, 1H), 0.51 - 0.40 (m, 2H), 0.34 - 0.20 (m, 2H). MS (ES+) 417.0 (M+Na); Analysis calculated for C22H22N205: C, 66.99; H, 5.62; N, 7.10;
Found: C, 66.75; H, 5.52; N, 7.06.
The process is also illustrated in Fig. 10. Step (1 1): Preparation of 2-(6-((cyclopropylmethyl)carbamoyl)-2-
(methoxycarbonyl)pyridin-3-yl)-4-methoxy-5-vinylbenzoic acid (6d)
Figure imgf000091_0001
To a stirred solution of methyl 6-((cyclopropylmethyl)carbamoyl)-3-(2-formyl-5- methoxy-4-vinylphenyl)picolinate (6c) (1.57 kg, 3.80 mol) in acetonitrile (15.4 L) was added ferf-butyl alcohol (22.2 L), demineralized water (3.2 L) and sodium dihydrogen phosphate monohydrate (323.74 g, 2.346 mol). The reaction mixture was cooled to 0 °C and added 2-methyl-2-butene (5.3 L, 50.0 mol) and stirred at 0 °C for 30 min. A solution of 80% sodium chlorite (1.36 kg, 12.0 mol) in demineralized water (5.2 L) was added to the reaction mixture over a period of 2.5 h at 0 °C [temperature rises to 7 °C during the addition]. The reaction mixture was stirred at 0 °C for 2 h, diluted with water (40 L) and ethyl acetate (24 L). After stirring the mixture, it was allowed to settle and the organic layer was separated. The aqueous layer was back-extracted with ethyl acetate (2 x 20 L) then acidified with 5.9 % aqueous acetic acid (2 L) and extracted once with ethyl acetate (10 L). The organic extracts were combined washed with water (2 x 20 L), a solution of acetic acid (125 mL) in water (20.0 L), brine (2 χ 20 L), dried over Na2S04, filtered and concentrated under reduced pressure (vapor temperature below 40 °C). The residue obtained was dissolved in acetone (7 L) (residue didn't dissolve completely). The solution was poured slowly into a reactor containing stirred n-hexane (70.0 L) to precipitate the solid product and the mixture was stirred for 2 h. The solid obtained was collected by filtration, washed with 10% acetone in n-hexane (6.3 L), AJ-hexane (6.3 L), dried to afford 2-(6-((cyclopropylmethyl)carbamoyl)-2-(methoxycarbonyl)pyridin-3-yl)-4- methoxy-5-vinylbenzoic acid (6d) as an off-white solid (1.29 Kg, yield: 79.0%). Average isolated yield for step 1 1 is 74% to 84%. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 12.50 (brs, 1 H), 8.69(t, J= 6.0 Hz, 1 H, NH), 8.20 (d, J= 7.9 Hz, 1 H), 8.09 (s, 1 H), 7.95 (d, J= 8.1 Hz, 1 H), 6.97 (dd, J= 18.0, 1 1.3 Hz, 1 H), 6.88 (s, 1 H), 5.92 (d, J= 7.9 Hz, 1 H), 5.38 (d, J= 1 1.1 Hz, 1 H), 3.85 (s, 3H), 3.63 (s, 3H), 3.27-3.17 (m, 2H), 1.15-1.05 (m, 1 H), 0.48-0.40 (m, 2H), 0.31-0.24 (m, 2H); MS (ES+) 433.26, (M+Na); (ES-) 409.28 (M-1). The process is also illustrated in Fig. 1 1.
Step (12): Preparation of Methyl 3-[2-(4-carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylate methanesulfonate (7a
Figure imgf000092_0001
Pyridine (3.8 L, 47.17 mol) and EDCI (5.31 kg, 27.66 mol) were sequentially added to a cooled solution (0 °C) of 2-(6-((cyclopropylmethyl)carbamoyl)-2-(methoxycarbonyl)- pyridin-3-yl)-4-methoxy-5-vinylbenzoic acid (6d) (9 kg, 21.92 mol) and 4- aminobenzamidine dihydrochloride (5.13 kg, 24.65 mol) in /-PrOH (90 L). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. TLC analysis indicated incomplete reaction. Additional EDCI (1.08 kg, 5.6 mol) was added and the reaction mixture was stirred for 8 h. The reaction was still incomplete as indicated by TLC analysis, additional EDCI (0.54 kg, 2.8 mol) was added and the reaction mixture was stirred for 5 h. TLC analysis indicated there was trace amount of unreacted starting material remaining. The reaction mixture was cooled to 0 °C and a solution of
methanesulfonic acid (MSA) (9.13 kg, 95 mol) in MeOH (38.7 L) was added to the cooled mixture over a period of 4 h. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. The product was collected by filtration, washed with a mixture of /'-PrOH and MeOH (4:1 , 45 L). The wet cake was slurried in a mixture of /- PrOH and MeOH (2:1 , 135 L) stirred for 1 h and the product was collected by filtration and washed with a mixture of /'-PrOH and MeOH (4:1 , 46.8 L). The product was dried in 2015/046582
a vacuum oven at 45 °C to afford methyl 3-[2-(4-carbamimidoylphenylcarbamoyl)-5- methoxy-4-vinylphenyl]-6-(cyclopropylmethyl-carbamoyl)pyridine-2-carboxylate methanesulfonate (7a) as a pink-colored solid (12.71 kg, 93%). Average isolated yield for this step: >90%.
1H NMR (300 MHz, DMSO-c/6) δ 10.71 (s, 1 H), 9.16 (s, 2H), 8.80 (s, 2H), 8.68 (t, J = 6.1 Hz, 1 H), 8.22 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1 H), 7.93 (s, 1H), 7.84 - 7.72 (m, 4H), 7.12 - 6.97 (m, 2H), 6.04 (dd, J = 17.8, 1.3 Hz, 1 H), 5.45 (d, J = 12.6 Hz, 1H), 3.91 (s, 3H), 3.60 (s, 3H), 3.25 - 3.16 (m, 2H), 2.32 (s, 3H), 1.10 - 1.01 (m, 1 H), 0.48 - 0.37 (m, 2H), 0.30 - 0.22 (m, 2H); MS (ES+) 528.0 (M+1); Analysis calculated for
C29H29N5O5.CH3SO3H.2H2O. C, 54.62; H, 5.65; N, 10.62; S, 4.86; Found: C, 54.95; H, 5.55; N, 10.61 ; S, 4.87.
The process is also illustrated in Fig. 12.
Step (13): Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-rnethoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid hydrate
Figure imgf000093_0001
(3i) ,a 3i
A pre-cooled (0-5 °C) aq. NaOH solution [prepared from solid NaOH (4 kg, 100 mol) in water (86 L)] was added to a suspension of methyl 3-[2-(4- carbamimidoylphenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-(cyclopropylmethyl- carbamoyl)pyridine-2-carboxylate methanesulfonate (7a) (28.7 kg, 46 mol) in acetonitrile (86 L) cooled to 0 to 5 °C over a period of 25 mins. The reaction mixture was stirred at 0 to 5 °C for 2.5 h (TLC analysis showed the reaction was complete). The reaction mixture was filtered through a sparkler filter, washed with a mixture of 1 :1 CH3CN / H20 ( 57.4 L). Acetic acid (3.2 L, 55.9 mol) in water (56 L) was added to the filtrate at room temperature over a period of 25 mins and the resulting mixture was stirred at room temperature for 2.5 h. The solid product obtained was collected by filtration, washed with a 1 :4 mixture of CH3CN / H20 (57.5 L). The solid was dried at 45°C in a vacuum oven to afford 3-[2-(4- Carbamimidoylphenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-
(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid hydrate (3i) as an off-white solid (12,77 kg, 54.1%). Average yield for this step is 50% to 75%. Mp: >200°C; H NMR (300 MHz, DMSO-d6): δ 13.49 (s, 1 H), 8.94 (bs, 4H), 8.56 (t, 1 H), 7.82 - 7.71 (m, 2H), 7.67 - 7.56 (m, 4H), 7.51 (d, J = 7.8, 1 H), 6.98 (dd, J = 11.3, 17.8, 1 H), 6.68 (s, 1 H), 5.92 (d, J = 16.6, 1 H), 5.36 (d, J = 12.4, 1 H), 3.80 (s, 3H), 3.16 (m, 2H), 1.05 (m, 1 H), 0.43 (m, 2H), 0.24 (m, 2H); MS (ES+) 514.1 (M+1), 536.1 (M+Na), (ES-) 512.1 ; Analysis calculated for C28H27N5O5.3H2O: C, 59.25; H, 5.86; N, 12.34; Found C, 59.50; H,
5.75; N, 12.05. If needed this material can be crystallized from a mixture of acetone and water.
The process is also illustrated in Fig. 13.
Step 14: Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid hydrochloride (7b
Figure imgf000094_0001
A pre-cooled (5-8 °C) aqueous NaOH solution (prepared from solid NaOH (1.97 kg, 49.25 mol) in demineralized water (41 L) was added to a pre-cooled (0-5 °C) suspension of (3i) (13.8 kg, 26.9 mol) in acetonitrile (41 L). The reaction mixture was stirred at 0-5 °C for 30 min (until the reaction mixture becomes homogeneous). The reaction mixture was filtered through a sparkler filter washed with 50% acetonitrile in demineralized water (4.4 L). The filtrate was charged into a reactor and cooled to 0-5 °C. Aqueous HCI [prepared from cone. HCI (9.3 L) in demineralized water (36 L)] was added slowly with stirring to keep the reaction temperature at or below 15 °C, the resulting mixture was stirred at 10- 15 °C for 13 h. The reaction mixture was cooled to 0-5 °C and stirred for 1 h. The solid obtained was collected by filtration and washed with demineralized water (36 L). The solid product was suspended in water (69 L) stirred for 30 mins and collected by filtration washed twice with water (20 L each). The solid product was dried in a vacuum oven at 45°C to afford 3-[2-(4-carbamimidoylphenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6- (cyclopropylmethyl carbamoyl)pyridine-2-carboxylic acid hydrochloride (7b) (1 1.21 Kg, 75.77%). Mp: >200°C; 1H NMR (300 MHz, DMSO-ci6): δ 12.98 (br s, 1 H), 10.86 (s, 1 H), 9.24 (s, 3H), 9.04 (s, 2H), 8.22 (d, J = 7.8 Hz, 1 H), 7.96 (d, J = 5.7 Hz, 2H), 7.78 (s, 4H), 7.09-6.99 (m, 2H), 6.07 (d, J = 17.7 Hz, 1 H), 5.45(d, J = 11.4 Hz, 1 H), 3.88 (s, 3H), 3.26- 3.24 (m, 2H), 1.09 (m, 1 H), 0.47 (m, 2H), 0.28 (m, 2H).
Average isolated yield for this step varies from 63% to 80%.
The process is also illustrated in Fig. 14.
Example-2: Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid sulfate salt (8b)
Figure imgf000095_0001
6d 8a
To a solution of 2-(6-((cyclopropylmethyl)carbamoyl)-2-(methoxycarbonyl)pyridin-3-yl)-4- methoxy-5-vinylbenzoic acid (6d) (2.35 g, 5.7 mmol) and 4-aminobenzamidine dihydrochloride (1.79 g, 8.6 mmol) in DMF (20 mL) and pyridine (30 ml_) at 0 °C was added EDCI (1.65 g, 8.6 mmol) and allowed to warm to room temperature overnight. The reaction mixture was quenched with 6N HCI (60 mL) and extracted with chloroform (3 x 60 mL). The organic layer was dried over MgS04, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel, 110 g, eluting with 0 to 100% chloroform in CMA 80 and 0-100% chloroform in CMA 50) to furnish methyl 3-(2-((4-carbamimidoylphenyl)carbamoyl)-5-methoxy-4-vinylphenyl)-6- ((cyclopropylmethyl)-carbamoyl)picolinate hydrochloride (8a) (2.2 g, 65%) as a white solid; MP 266 °C; 1HNMR (300 MHz, DMSO-d6) δ 10.78 (s, 1 H), 9.26 (s, 2H), 9.03 (s, 2H), 8.67 (t, J = 6.1 , 1 H), 8.22 (d, J = 8.0, 1 H), 8.06 (d, J = 8.0, 1 H), 7.96 (s, 1 H), 7.89 - 7.74 (m, 4H), 7.13 - 6.96 (m, 2H), 6.07 (d, J = 17.7, 1 H), 5.45 (d, J = 12.4, 1 H), 3.91 (s, 3H), 3.61 (s, 3H), 3.20 (s, 2H), 1.09 (dd, J = 4.7, 8.2, 1 H), 0.43 (dt, J = 4.9, 5.4, 2H), 0.34 - 0.21 (m, 2H); MS (ES+) 528.1 (M+1); Analysis calculated for C29H29N505 (H20)1 5 (HCI): C, 58.93; H, 5.63; N, 1 1.85; Found: C, 58.75; H, 5.65; N, 1 1.92.
Step-2: preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid sulfate salt (8b)
Figure imgf000096_0001
8a 8b j0 a solution of methyl 3-(2-((4-carbamimidoylphenyl)carbamoyl)-5-methoxy-4-vinylphenyl)- 6-((cyclopropylmethyl)carbamoyl)picolinate hydrochloride (8a) (1.128 g, 2 mmol) in acetonitrile (5 ml), was added 1 N aqueous sodium hydroxide (5.00 ml, 5.00 mmol) and stirred at room temperature for 2 h, TLC [CMA80/CMA50 (7/3)] shows reaction was complete. The reaction mixture was neutralized with a solution of sulfuric acid (0.483 ml, 9.00 mmol) in water (5 mL) and stirred for 10 min at room temperature. To this cold water (5 ml) was added and stirred at room temperature until product crystallized out. Cold water (5 mL) was added to the slurry and stir for additional 20 min, additional cold water (5 mL) was added prior to filtration of solid. The solid obtained was collected by filtration washed with water (5 mL and 2.5 mL), dried under vacuum overnight to afford 3-[2-(4-carbamimidoylphenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6- (cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid sulfate salt (8b) (1.103 g, 90 % yield) as a white solid; MP 221.7 °C; H NMR (300 MHz, DMSO-d6) δ 12.30 - 10.91 (bs, 1 H, D20 exchangeable), 10.69 (bs, 1 H, D20 exchangeable), 9.24 (t, J = 6.0 Hz, 1 H), 9.16 (s, 2H, D2O exchangeable), 8.78 (s, 2H, D2O exchangeable), 8.24 (d, J = 8.0 Hz, 1 H), 8.04 - 7.91 (m, 2H), 7.84 - 7.67 (m, 4H), 7.13 - 6.94 (m, 2H), 6.03 (dd, J = 17.8, 1 .4 Hz, 1 H), 5.51 - 5.37 (m, 1 H), 3.88 (s, 3H), 3.24 (t, J = 6.4 Hz, 2H), 1.16 - 1.01 (m, 1 H), 0.52 - 0.41 (m, 2H), 0.32 - 0.22 (m, 2H); MS (ES+) 514.0 (M+1); Analysis calculated for: C28H27N605 1.0H2SO4 1.5H20: C, 52.66; H, 5.05; N, 10.97; S, 5.02; Found: C, 52.81 ; H, 4.95; N, 10.94; S, 4.64.
Example-3: Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid methane s
Figure imgf000097_0001
To a solution of methyl 3-(2-((4-carbamimidoylphenyl)carbamoyl)-5-methoxy-4- vinylphenyl)-6-((cyclopropylmethyl)carbamoyl)picolinate hydrochloride (8a) (1.128 g, 2 mmol) in acetonitrile (5 ml) was added 1 N aqueous sodium hydroxide (5.00 ml, 5.00 mmol) and stirred at room temperature for 2 h, TLC [CMA80/CMA50 (7/3)] shows reaction was complete. The reaction mixture was neutralized with methanesulfonic acid (0.584 ml, 9.00 mmol) and stirred for 1 h at room temperature. Cold water (5.00 ml) was added to the reaction mixture and stirred at room temperature until product crystallized out. To the slurry was added water (5 ml) of water stirred for additional 20 min, followed by the addition of water (5 ml) prior to filtration. The solid obtained was collected by filtration washed with water (5 ml and 2.5 ml), dried under vacuum to afford 3-[2-(4- Carbamimidoylphenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6-
(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid methane sulfonate salt (8c)
(1 .138 g, 1.867 mmol, 93 % yield) as a white solid; MP 221.2 °C; 1 H NMR (300 MHz, DMSO-d6) δ 12.89 (s, 1 H, D2O exchangeable), 10.69 (s, 1 H, D2O exchangeable), 9.24
(t, J = 6.0 Hz, 1 H), 9.16 (s, 2H,), 8.85 (s, 2H), 8.24 (d, J = 8.0 Hz, 1 H), 8.06 - 7.91 (m, 2H), 7.86 - 7.70 (m, 4H), 7.15 - 6.96 (m, 2H), 6.03 (dd, J = 17.8, 1.4 Hz, 1 H), 5.52 - 5.35 (m, 1 H), 3.88 (s, 3H), 3.25 (t, J = 6.3 Hz, 2H), 2.34 (s, 3H), 1.17 - 1.01 (m, 1 H), 0.53 - 0.43 (m, 2H), 0.32 - 0.23 (m, 2H); MS (ES+) 514.0 (M+1); Analysis calculated for:
CzeH^NsOsCHsSOsH 1.5H20: C, 54.71 ; H, 5.38; N, 11.00; S, 5.04; Found: C, 54.80; H, 5.14; N, 10.94; S, 4.90.
Example-4: Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid hydrochloride (7b) in Form C (Compound XX)
Figure imgf000098_0001
The jacket of a 10 L glass reactor was set to -5 °C. To the reactor was charged 2-(6- ((cyclopropylmethyl)carbamoyl)-2-(methoxycarbonyl)-pyridin-3-yl)-4-methoxy-5- vinylbenzoic acid (6d) prepared in Step (11) of Example 1 (500 g, 1.22 mol), 4-amino- benzamidine-2HCI (280 g, 1.34 mol), and 2-propanol (4.05 kg). The mixture was cooled 46582
to 0.3 °C, and pyridine (210 g, 2.62 mol) followed by EDCI HCI (310 g, 1.61 mol) was added. The mixture was stirred at -1.1 - -0.3 °C for 22 hrs followed by addition of the second portion of EDCI HCI (58 g, 0.30 mol). The temperature of jacket was set to 14.0 °C, and the mixture was stirred for 89 hrs. The precipitate was filtered, and washed with 1.32 kg of 2-propanol.
The wet product (8a) was recharged to the reactor followed by addition of acetonitrile (1 .6 kg) and 0.57 kg water. The mixture was heated to 46 °C. 21 g of Smopex-234 and 10 g Acticarbone 2SW were added and the mixture was stirred at this temperature for 1 hr. The solution was filtered, and filtrate was returned back to the reactor. The jacket of the reactor was set to -5 °C, and the mixture was cooled to -0.2 °C. NaOH solution (256 g 46% NaOH, 2.95 mol, in 960 g water) was added in 25 min keeping the temperature <3 °C. The mixture was stirred at 0.2-2.0 °C for 1 hr 40 min and then quenched with cone, acetic acid (40 g, 0.66 mol). Diluted acetic acid (80 g, 1.33 mol AcOH in 1000 g water) was added during 1 hr 20 min (temperature 1.7-3.0 °C), followed by 1250 g water (30 min). The suspension was stirred at 0-3.0 °for 1 hr, and filtered at 0-5 °C (ice mantle around the filter). The reactor and product (8d) was rinsed with 3.5 kg water.
The wet product (8d) was recharged to the reactor followed by 0.65 kg water and 1.69 kg acetonitrile. The mixture was heated to 57-60 °C, and stirred at this temperature for 14.5 hrs. The mixture was cooled to -2.2 °C (Tjacke,= -5 °C), and a solution of NaOH (163 g 46%, 1.87 mol, in 580 g water) was added during 15 min. The temperature rose to -0.4 °C. Hydrochloric acid (407 g 37% HCI, 4 mol) was added in 10 min, the temperature rose to 7.5 °C. The suspension was agitated at -3 - 0 °C for 19 hrs. The product was filtered and the filter cake was rinsed with 2.87 kg water, compressed and pulled dry. The wet product (1.30 kg) was dried at 40-43 °C and 50 mbar for 1 17 hrs to furnish 3-[2- (4-carbamimidoylphenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6- (cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid hydrochloride (7b) (484 g) as Form C (Compound XX).
A powder X-ray diffraction pattern (PXRD) of Compound XX is depicted in Figure 19; a differential scanning calorimetry (DSC) thermogram of Compound XX is depicted in Figure 20; and a thermogravimetric (TG) thermogram of Compound XX is depicted in Figure 21. Example-5: Preparation of 3-[2-(4-Carbamimidoylphenylcarbamoyl)-5-methoxy-4- vinylphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid hydrochloride (7b) in Form A (Compound XIX)
The procedure was carried out in an identical manner to Example 4, with the exception that after the final filtration the filter cake was rinsed with 2.87 kg methyl terf-butyl ether instead of 2.87 kg water, and pulled dry. The product was dried at 40-43 °C and 50 mbar to furnish 3-[2-(4-carbamimidoylphenylcarbamoyl)-5-methoxy-4-vinylphenyl]-6- (cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid hydrochloride (7b) as Form A (Compound XIX).
A powder X-ray diffraction pattern (PXRD) of Compound XIX is depicted in Figure 15; a differential scanning calorimetry (DSC) thermogram of Compound XIX is depicted in Figure 16; a thermogravimetric (TG) thermogram of Compound XIX is depicted in Figure 17; and a crystal structure as determined by scanning electron microscopy (SEM) of Compound XIX is depicted in Figure 18.
All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments.
Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in chemistry or related fields are intended to be within the scope of the following claims.

Claims

Claims
1. A method of producing a compound of formula (VI):
Figure imgf000101_0001
wherein:
R-i is hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, C3.8 cycloalkoxy, C1-6 alkylthio, aryl, aryloxy, heteroaryl or heteroaryloxy; and
R6a and R6b are each independently C1-6 alkyl; or R6a and R6b together with the boron atom to which they are attached form an optionally substituted 5-7 membered ring;
the method comprising reacting a compound of formula (IV):
Figure imgf000101_0002
wherein Ri is as defined above; and Hal is a halogen atom;
with a compound of formula (V):
R6aO OR6a
B-B
R6bO R6b (V)
wherein R6a and R6b are as defined above;
in the presence of a suitable catalyst.
2. A method of producing a compound of formula (XI):
Figure imgf000101_0003
in which:
Hal is a halogen atom;
Y is CH or N;
R2 is hydrogen, Ci-6 alkyl, C3-6 cycloalkyl or (Cs-ecycloalky -C^ alkyl, each optionally substituted by 1 or 2 hydroxyl groups;
R3b is hydrogen or C -6 alkyl; and R7 is C1-6 alkyl (optionally substituted with one or combination of the following: chlorine, fluorine, C1-6 alkoxy, C3.8 cycloalkoxy, C3-8 cycloalkyl, heterocycloalkyl,
heterocycloalkoxy, aryl or heteroaryl), C2_6 alkenyl; C2-6 alkynyl; C3.8 cycloalkyl, aryl or heteroaryl;
ating a compound of formula (X):
Figure imgf000102_0001
in which Y, Hal and R7 are as defined above;
with an amine of formula NHR2R3b in which R2 and R3b are as defined above;
in a suitable solvent at a dilution of 0.5 to 1.0 moles per litre. ucing a compound of formula (XIV):
Figure imgf000102_0002
(XIV)
in which:
Ri is as defined in claim 1 ;
Y, R7, R2 and R3b are as defined in claim 2;
m is 0, 1 or 2; and
R a is C -6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy or C3-8 cycloalkoxy;
the method comprising reacting a compound of formula (XIII):
Figure imgf000102_0003
(XIII) in which Y, m, R^ R2 and R3b, R4a and R7 are as defined above and LG is a leaving group;
with a vinylating agent of formula
[CH2=CHB(RC)3]~ M+ or [CH2=CHB(ORd)2]
in which Rc is a halogen atom (preferably fluorine) ;
Rd is hydrogen or a boronate ester residue, and
M is an alkali metal atom (preferably lithium, sodium or potassium, more preferably potassium);
in the presence of a suitable coupling catalyst and, optionally, a ligand and/or a base.
4. A method of producing a compound of formula (XVII):
Figure imgf000103_0001
(XVII)
in which:
X is CH or ;
RT is as defined in claim 1 ;
Y, R7, R2 and R3B are as defined in claim 2;
R3A is hydrogen or C1-6 alkyl;
m is 0, 1 or 2;
n is 0, 1 , 2, 3 or 4;
R4A and R4B are each independently Ci-6 alkyl, C3_8 cycloalkyl, C-,-6 alkoxy or C3.8 cycloalkoxy; and
R5A and R5B are each independently hydrogen or C1-6 alkyl;
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof;
the method comprising reacting a carboxylic acid of formula (XV):
Figure imgf000104_0001
(XV)
wherein Y, m, R2, R3b, R4a and R7 are as defined above;
with an amine of formula (XVI):
Figure imgf000104_0002
wherein X, n, R3a, R4b, R5a and R5b are as defined above;
in the presence of a base of which the pKa of the conjugate acid ranges from 4 to 10, and optionally a suitable amide coupling agent.
5. A method of producing a compound of formula (I):
Figure imgf000104_0003
(I)
wherein:
X is CH or ;
Y is CH or N;
RT is hydrogen, C1-6 alkyl, C3.8 cycloalkyl, C1-6 alkoxy, C3.8 cycloalkoxy, C1-6 alkylthio, aryl, aryloxy, heteroaryl or heteroaryloxy R2 is hydrogen, d.6 alkyl, C3.6 cycloalkyl or (C3.6cycloalkyl)-C1-6 alkyl, each optionally substituted by 1 or 2 hydroxyl groups;
R3a and R3b are each independently hydrogen or C1-6 alkyl;
m is 0, 1 or 2;
n is 0, 1 , 2, 3 or 4;
R4a and R4b are each independently C1-6 alkyf, C3.8 cycloalkyl, C1-6 alkoxy or C3.8 cycloalkoxy; and
R5a and R5b are each independently hydrogen or d_6 alkyl;
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof;
the method comprising subjecting a carboxylic ester of formula (XVII):
Figure imgf000105_0001
wherein X, Y, m, n, R^ R2, R3a, R3b. 4a> R4b. Rsa, Rsb and R7 are as defined above, to ester hydrolysis conditions in the presence of acetonitrile as solvent. 6. A method of producing a compound of formula (I) as defined in claim 5;
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof;
comprising the steps of:
(a) producing a carboxylic ester of formula (XVII), as defined above, by reacting a carboxylic acid of formula (XV) with an amine of formula (XVI), according to the method of claim 4; and
(b) subjecting said carboxylic ester of formula (XVII) to ester hydrolysis conditions according to the method of claim 5.
7. A method of producing a compound of formula (VI) as defined in claim 1 , using the following steps:
(a) halogenation of a compound of formula (II):
Figure imgf000106_0001
using a suitable halogenating agent, to produce a compound of formula (III)
Figure imgf000106_0002
(III)
wherein Hal is a halogen atom
conversion of the compound of formula (III) to a compound of formula (IV), defined above; and
(c) conversion of the compound of formula (IV) to a compound of formula (VI) using the method of claim 1.
A method of producing a compound of formula (I) as defined above; comprising the steps of:
(a) producing a carboxylic ester of formula (XVII), as defined above, by reacting a carboxylic acid of formula (XV) with an amine of formula (XVI), as defined above, in the presence of a base of which the pKa of the conjugate acid ranges from 4 to 10, and optionally a suitable amide coupling agent; and
(b) subjecting said carboxylic ester of formula (XVII) to ester hydrolysis conditions in the presence of acetonitrile as solvent.
9. A method of producing a compound of formula (XV), as defined above, comprising the following steps:
(e) treating a compound of formula (XI), as defined in claim 2, with a compound of formula (VI) as defined in claim 1 to produce a compound of formula (XII)
Figure imgf000107_0001
(XII)
in which Y, m, Ri, R2, R3b, R4a and R7 are as defined above;
(f) treating the compound of formula (XII) with a compound capable of converting an alcohol into a leaving group to produce a compound of formula (XIII) as defined above;
(g) reacting the compound of formula (XIII) with a vinylating agent of formula
[CH2=CHB(RC)3]" M+ according to the method of claim 3 to produce a compound of formula (XIV); and
(h) oxidation of the aldehyde function of the compound of formula (XIV) to produce a compound of formula (XV).
10. The method of any one of claims 1 to 5, wherein R-i is methoxy.
1 1 . The method of claim 10, wherein RT is methoxy at the 4-position (the carbon bearing the aldehyde group being the 1 -position).
12. The method of any one of claims 1 to 5, wherein Y is N.
13. The method of any one of claims 1 to 5, wherein X is CH.
14. The method of any one of claims 1 to 5, wherein R2 is a cyclopropylmethyl group.
15. The method of any one of claims 1 to 5, wherein R3a is hydrogen.
16. The method of any one of claims 1 to 5, wherein R3b is hydrogen.
17. The method of any one of claims 1 to 5, wherein m is 0.
18. The method of any one of claims 1 to 5, wherein n is 0.
19. The method of any one of claims 1 to 5, wherein R5a is hydrogen.
20. The method of any one of claims 1 to 5, wherein each R5b is hydrogen.
21. A compound of formula (VI):
Figure imgf000108_0001
wherein Ri, R6a and R6b are defined in claim 1.
22. A compound of formula (XI):
Figure imgf000108_0002
in which: Hal, Y, R2 , R3b and R7 are as defined in claim 2.
23. A compound of formula (XII):
Figure imgf000108_0003
(XII)
in which Y, m, R^ R2, R3t>, R4a and R7 are as defined in claim 3.
24. A compound of formula (XIII):
Figure imgf000109_0001
in which: LG, Y, m, R2, R3b, F?4a and R7 are as defined in claim 3. 25. A compound of formula (XIV):
Figure imgf000109_0002
in which Y, m, R-,, R2, R3t>, R a, and R7 are as defined in claim 3.
26. A compound of formula (XV):
Figure imgf000109_0003
wherein Y, m, R-i , R2, R3b, R4aand R7 are as defined in claim 3. 27. A compound of formula (XVII):
Figure imgf000110_0001
whereii X, Y, m, n, Ri, R2, R3a, R3b, 4a, R4b, Rsa. sb and R7 are as defined in claim 5,
28. A hydrochloride salt of a compound of formula (I), wherein X, Y, m, n, Ri, R2, R3a, R3b, R4a, R4bi sa, Rsb are as defined in claim 5.
29. The compound of any one of claims 21 to 28, wherein Ri is methoxy.
30. The compound of claim 29, wherein is methoxy at the 4-position (the carbon bearing the carbonyl group being the 1 -position).
31. The compound of any one of claims 21 to 28, wherein Y is N.
32. The compound of any one of claims 21 to 28, wherein X is CH.
33. The compound of any one of claims 21 to 28, wherein R2 is a cyclopropylmethyl group.
34. The compound of any one of claims 21 to 28, wherein R3a is hydrogen.
35. The compound of any one of claims 21 to 28, wherein R3b is hydrogen.
36. The compound of any one of claims 21 to 28, wherein m is 0.
37. The compound of any one of claims 21 to 28, wherein n is 0.
38. The compound of any one of claims 21 to 28, wherein RSa is hydrogen.
39. The compound of any one of claims 21 to 28, wherein each R5b is hydrogen.
40. A hydrochloride salt of a compound of formula (XVIII):
Figure imgf000111_0001
XVIII
41. A compound according to claim 40, in crystalline Form A. 42. A compound according to claim 40, in crystalline Form C.
43. A method according to claim 5 or claim 6, which includes the step or steps of
converting the compound of formula (I) into a salt or solvate thereof, or into an ester or other prodrug thereof, or into a salt or solvate of an ester or other prodrug thereof.
PCT/US2015/046582 2014-08-22 2015-08-24 Method for producing amidine derivatives WO2016029216A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462040818P 2014-08-22 2014-08-22
US62/040,818 2014-08-22

Publications (2)

Publication Number Publication Date
WO2016029216A2 true WO2016029216A2 (en) 2016-02-25
WO2016029216A3 WO2016029216A3 (en) 2016-05-12

Family

ID=54012342

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2015/046582 WO2016029216A2 (en) 2014-08-22 2015-08-24 Method for producing amidine derivatives

Country Status (1)

Country Link
WO (1) WO2016029216A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106749358A (en) * 2016-11-22 2017-05-31 雅本化学股份有限公司 A kind of method for synthesizing the aldehyde radical phenyl boric acid pinacol ester of 5 methoxyl group, 4 hydroxyl 2
WO2018081513A1 (en) * 2016-10-31 2018-05-03 Biocryst Pharmaceuticals, Inc. Prodrugs of kallikrein inhibitors
WO2023160509A1 (en) * 2022-02-25 2023-08-31 中国科学院上海药物研究所 Amidine derivative compound, and preparation method therefor and use thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6699994B1 (en) 2001-04-06 2004-03-02 Biocryst Pharmaceuticals, Inc. Biaryl compounds as serine protease inhibitors

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1332131A2 (en) * 2000-11-07 2003-08-06 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
TW200628153A (en) * 2004-10-05 2006-08-16 Smithkline Beecham Corp Novel compounds
SA08280783B1 (en) * 2007-01-11 2011-04-24 استرازينيكا ايه بي Pyridopyrimidine Derivatives as PDE4 Inhibitors
US8716478B2 (en) * 2010-01-27 2014-05-06 Anacor Pharmaceuticals, Inc. Boron-containing small molecules

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6699994B1 (en) 2001-04-06 2004-03-02 Biocryst Pharmaceuticals, Inc. Biaryl compounds as serine protease inhibitors

Non-Patent Citations (24)

* Cited by examiner, † Cited by third party
Title
A.D. DUNN; S. GUILLERMIC, ZEITSCHRIFT FUR CHEMIE, vol. 28, no. 2, 1988, pages 59 - 60
A.E. HAAKANSSON ET AL., CHEMISTRY-A EUROPEAN JOURNAL, vol. 12, no. 12, 2006, pages 3243 - 3253
A.I. MEYERS ET AL., J. AM. CHEM. SOC, vol. 109, no. 18, 1987, pages 5446 - 52
B.D. CHAPSAL ET AL., TETRAHEDRON: ASYMMETRY, vol. 17, no. 4, 2006, pages 642 - 657
B.D. CHAPSAL; OJIMA, IWAO, ORGANIC LETTERS, vol. 8, no. 7, 2006, pages 1395 - 1398
BAY, ELLIOTT ET AL.: "Preparation of aryl chlorides from phenols", JOURNAL OF ORGANIC CHEMISTRY, vol. 55, no. 10, 1990, pages 3415 - 17
E. MEGGERS ET AL., JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 122, no. 43, 2000, pages 10714 - 10715
G. CAHIEZ ET AL., ORGANIC LETTERS, vol. 7, no. 10, 2005, pages 1943 - 1946
G. POLI; G. GIAMBASTIANI, J. ORG. CHEM., vol. 67, no. 26, 2002, pages 9456 - 9459
JEAN-ROBERT; CASTRO, BERTRAND: "Triphenylphosphine Dichloride; Dormoy", E-EROS ENCYCLOPEDIA OF REAGENTS FOR ORGANIC SYNTHESIS, 2001
JUSTIK, MICHAEL W. ET AL.: "Preparation and X-ray structures of 2-[(aryl)iodonio]benzenesulfonates: novel diaryliodonium betaines", TETRAHEDRON LETTERS, vol. 50, no. 44, 2009, pages 6072 - 6075, XP026602578, DOI: doi:10.1016/j.tetlet.2009.08.067
LI, JIAN: "A process for preparing organochlorides", FAMING ZHUANLI SHENQING, 14 March 2012 (2012-03-14)
LIN, MING-YUAN ET AL., J. AM. CHEM. SOC, vol. 128, no. 29, 2006, pages 9340 - 9341
N. ZIMMERMANN ET AL., BIOORGANIC CHEMISTRY, vol. 32, no. 1, 2004, pages 13 - 25
P.C. CONRAD ET AL., J. ORG CHEM., vol. 52, no. 4, 1987, pages 586 - 91
P.C. STANISLAWSKI ET AL., ORGANIC LETTERS, vol. 8, no. 10, 2006, pages 2143 - 2146
R.H. FURNEAUX ET AL., J. ORG. CHEM., vol. 69, no. 22, 2004, pages 7665 - 7671
S. MITRA ET AL., J. ORG. CHEM, vol. 72, no. 23, 2007, pages 8724 - 8736
S.A BAECHLER ET AL., BIOORG. MED. CHEM., vol. 21, no. 3, 2013, pages 814 - 823
S.P. KHANAPURE; E.R.BIEHL, J. ORG. CHEM, vol. 55, no. 5, 1990, pages 1471 - 5
S.P.; KHANAPURE ET AL., J. MED. CHEM., vol. 46, no. 25, 2003, pages 5484 - 5504
SHENG, CHUNQI ET AL.: "Deoxygenative chlorination of alcohols catalyzed by ferric chloride", HUAXUE YANJIU YU YINGYONG, vol. 20, no. 4, 2008, pages 503 - 506
SHINODA, KIYONORI; YASUDA, KENSEI: "Transchlorination of polychlorobenzenes and benzene into chlorobenzene", NIPPON KAGAKU KAISHI, no. 12, 1989
THOMPSON, ALICIA L. S. ET AL.: "The conversion of phenols to the corresponding aryl halides under mild conditions", SYNTHESIS, vol. 50, 2005, pages 547 - 5

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018081513A1 (en) * 2016-10-31 2018-05-03 Biocryst Pharmaceuticals, Inc. Prodrugs of kallikrein inhibitors
US10759759B2 (en) 2016-10-31 2020-09-01 Biocryst Pharmaceuticals, Inc. Prodrugs of kallikrein inhibitors
US11618731B2 (en) 2016-10-31 2023-04-04 Biocryst Pharmaceuticals, Inc. Prodrugs of kallikrein inhibitors
CN106749358A (en) * 2016-11-22 2017-05-31 雅本化学股份有限公司 A kind of method for synthesizing the aldehyde radical phenyl boric acid pinacol ester of 5 methoxyl group, 4 hydroxyl 2
CN106749358B (en) * 2016-11-22 2019-05-10 雅本化学股份有限公司 A method of synthesis 5- methoxyl group -4- hydroxyl -2- aldehyde radical phenyl boric acid pinacol ester
WO2023160509A1 (en) * 2022-02-25 2023-08-31 中国科学院上海药物研究所 Amidine derivative compound, and preparation method therefor and use thereof

Also Published As

Publication number Publication date
WO2016029216A3 (en) 2016-05-12

Similar Documents

Publication Publication Date Title
AU2022202535B2 (en) Methods and intermediates for preparing a therapeutic compound useful in the treatment of retroviridae viral infection
AU2013203283B2 (en) Processes for the preparation of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine
TWI766176B (en) Process for preparing btk inhibitors
CA3129096A1 (en) Process for preparing enantiomerically enriched jak inhibitors
CN107721851B (en) Method for preparing apoptosis inducer
KR20180005248A (en) Synthesis of heterocyclic compounds
RU2553990C2 (en) Preparation of substituted 2-fluoroacrylic acid derivatives
WO2016029216A2 (en) Method for producing amidine derivatives
KR20170122807A (en) Chemical methods for preparing pyrimidine derivatives and intermediates thereof
AU2022214735A1 (en) Biphenyl compound as immunomodulator, preparation method therefor and use thereof
ES2748324T3 (en) Method for producing an indole compound
ES2902874T3 (en) Chemical process for preparing imidazopyrrolidinone derivatives and their intermediates
KR20080099865A (en) Method for producing aminoacetylpyrrolidinecarbonitrile derivative and production intermediate thereof
AU2014220865A1 (en) Asymmetric synthesis of a substituted pyrrolidine-2-carboxamide
KR20210080373A (en) Methods for preparing solid forms of BET bromodomain inhibitors
ES2802815A1 (en) SALT 3- [2 (R) -AMINO-2-PHENYLETHYL] -5- (2-FLUORO-3-METOXIFENIL) -1- [2-FLUORO-6- (TRIFLUOROMETIL) BENZYL] -6-METHYL-1H -PYRIMIDIN-2,4 (1H, 3H) -DIONA (I) IN SOLID FORM, PROCEDURE FOR ITS PREPARATION AND USE OF THE SAME IN THE SYNTHESIS OF ELAGOLIX (Machine-translation by Google Translate, not legally binding)
Font et al. Synthesis of pyrimidinyl arylglycines through subsequent Mitsunobu and Petasis reactions
JP2024524246A (en) Methods for preparing EGFR inhibitors
KR20200142529A (en) Method for producing substituted pyridinone-containing tricyclic compound
US20080108830A1 (en) Production method of optically active 2-[(N-benzylprolyl)amino]benzo-phenone compound
AU2007212756A1 (en) Preparation of 7-alkenyl-3 quinolinecarbonitriles via a palladium mediated coupling reaction
US6573384B1 (en) Process for production of indole derivatives and intermediates therefor
KR100594339B1 (en) Process for producing 2-aminobenzophenone compound
JP6267221B2 (en) Process for the preparation of 2-trifluoromethylisonicotinic acid and esters
EP2994472A1 (en) Process for the preparation of boronic acid intermediates

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15756792

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15756792

Country of ref document: EP

Kind code of ref document: A2