Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
  • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Definitions

• This invention relates to synthetic processes used to make substituted phenylalanine- based compounds.
• the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] is involved in multiple central nervous facets of mood control and in regulating sleep, anxiety, alcoholism, drug abuse, food intake, and sexual behavior. In peripheral tissues, serotonin is reportedly implicated in the regulation of vascular tone, gut motility, primary hemostasis, and cell- mediated immune responses. Walther, D. J., et ah, Science 299:76 (2003).
• TPH tryptophan hydroxylase
• mice genetically deficient for the tphl gene
• the mice reportedly expressed normal amounts of serotonin in classical serotonergic brain regions, but largely lacked serotonin in the periphery. Id.
• the knockout mice exhibited abnormal cardiac activity, which was attributed to a lack of peripheral serotonin. Cote, F., et al, PNAS 100(23): 13525-13530 (2003).
• TPH ⁇ e.g., TPHl
• preferred compounds of this formula inhibit TPH ⁇ e.g., TPHl), and may be useful in the treatment of various diseases and disorders.
• This invention is also directed to various intermediates that are useful in the synthesis of compounds of formula I .
• This invention is based on the discovery of a novel process that can be used to efficiently prepare compounds of formula I.
• preferred compounds of formula I When administered to mammals, preferred compounds of formula I inhibit peripheral TPH, and may be used in the treatment of various diseases and disorders, including disorders of the GI tract. See generally, U.S. patent application no. 11/638,677, filed December 12, 2008.
• alkenyl means a straight chain, branched and/or cyclic hydrocarbon having from 2 to 20 ⁇ e.g., 2 to 10 or 2 to 6) carbon atoms, and including at least one carbon-carbon double bond.
• alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2- heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1- decenyl, 2-decenyl and 3-decenyl.
• alkyl means a straight chain, branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20 ⁇ e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to 4 carbons are referred to as "lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.
• Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Additional examples of alkyl moieties have linear, branched and/or cyclic portions (e.g., 1- ethyl-4-methyl-cyclohexyl).
• alkyl includes saturated hydrocarbons as well as alkenyl and alkynyl moieties.
• alkylaryl or “alkyl-aryl” means an alkyl moiety bound to an aryl moiety.
• alkylheteroaryl or “alkyl-heteroaryl” means an alkyl moiety bound to a heteroaryl moiety.
• alkylheterocycle or “alkyl-heterocycle” means an alkyl moiety bound to a heterocycle moiety.
• alkynyl means a straight chain, branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2 to 6) carbon atoms, and including at least one carbon-carbon triple bond.
• alkynyl moieties include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-l-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.
• alkoxy means an -O-alkyl group.
• alkoxy groups include, but are not limited to, -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -O(CH 2 ) 3 CH 3 , -O(CH 2 ) 4 CH 3 , and -O(CH 2 ) 5 CH 3 .
• aryl means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms.
• An aryl moiety may comprise multiple rings bound or fused together.
• aryl moieties include, but are not limited to, anthracenyl, azulenyl, biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydro-naphthalene, and to IyI.
• arylalkyl or "aryl-alkyl” means an aryl moiety bound to an alkyl moiety.
• halogen and halo encompass fluorine, chlorine, bromine, and iodine.
• heteroalkyl refers to an alkyl moiety in which at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, O or S).
• heteroaryl means an aryl moiety wherein at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, O or S).
• heteroatom e.g., N, O or S.
• examples include, but are not limited to, acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl,
• heteroarylalkyl or “heteroaryl-alkyl” means a heteroaryl moiety bound to an alkyl moiety.
• heterocycle refers to an aromatic, partially aromatic or non-aromatic monocyclic or polycyclic ring or ring system comprised of carbon, hydrogen and at least one heteroatom (e.g., N, O or S).
• a heterocycle may comprise multiple (i.e., two or more) rings fused or bound together.
• Heterocycles include heteroaryls.
• Examples include, but are not limited to, benzo[l,3]dioxolyl, 2,3-dihydro-benzo[l,4]dioxinyl, cinnolinyl, furanyl, hydantoinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and valerolactamyl.
• heterocyclealkyl or “heterocycle-alkyl” refers to a heterocycle moiety bound to an alkyl moiety.
• heterocycloalkyl refers to a non-aromatic heterocycle.
• heterocycloalkylalkyl or “heterocycloalkyl- alkyl” refers to a heterocycloalkyl moiety bound to an alkyl moiety.
• pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
• suitable pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N 5 N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
• Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p- toluenesulfonic acid.
• inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic
• Non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids.
• Examples of specific salts thus include hydrochloride and mesylate salts.
• Others are well known in the art. See, e.g., Remington ' s Pharmaceutical Sciences (18th ed., Mack Publishing, Easton PA: 1990) and Remington: The Science and Practice of Pharmacy (19th ed., Mack Publishing, Easton PA: 1995).
• the term "protecting group” or “protective group,” when used to refer to part of a molecule subjected to a chemical reaction means a chemical moiety that is not reactive under the conditions of that chemical reaction, and which may be removed to provide a moiety that is reactive under those conditions.
• pseudohalogen refers to a polyatomic anion that resembles a halide ion in its acid-base, substitution, and redox chemistry, generally has low basicity, and forms a free radical under atom transfer radical polymerization conditions.
• pseudohalogens include azide ions, cyanide, cyanate, thiocyanate, thiosulfate, sulfonates, and sulfonyl halides.
• stereomerically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
• a stereomerically pure composition of a compound having one stereocenter will be substantially free of the opposite stereoisomer of the compound.
• a stereomerically pure composition of a compound having two stereocenters will be substantially free of other diastereomers of the compound.
• a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
• substituted when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with a chemical moiety or functional group such as, but not limited to, alcohol, aldehylde, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-OC(O)alkyl), amide (-C(O)NH- alkyl- or -alkylNHC(O)alkyl), amidinyl (-C(NH)NH-alkyl or -C(NR)NH 2 ), amine (primary, secondary and tertiary such as alkylamino, arylamino, arylalkylamino), aroyl, aryl, ary
• the term “include” has the same meaning as “include, but are not limited to,” and the term “includes” has the same meaning as “includes, but is not limited to.” Similarly, the term “such as” has the same meaning as the term “such as, but not limited to.” Unless otherwise indicated, one or more adjectives immediately preceding a series of nouns is to be construed as applying to each of the nouns.
• a structure or name of a compound or genus of compounds encompasses all forms of that compound or genus of compounds, and all compositions comprising that compound or genus of compounds.
• a chemical moiety that forms part of a larger compound may be described herein using a name commonly accorded it when it exists as a single molecule or a name commonly accorded its radical.
• the terms “pyridine” and “pyridyl” are accorded the same meaning when used to describe a moiety attached to other chemical moieties.
• the two phrases “XOH, wherein X is pyridyl” and “XOH, wherein X is pyridine” are accorded the same meaning, and encompass the compounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.
• any atom shown in a drawing with unsatisfied valences is assumed to be attached to enough hydrogen atoms to satisfy the valences.
• chemical bonds depicted with one solid line parallel to one dashed line encompass both single and double (e.g., aromatic) bonds, if valences permit.
• One embodiment of the invention encompasses a method of preparing a compound of formula I(a), which comprises contacting a compound of formula II:
• A is optionally substituted cycloalkyl, aryl, or heterocycle
• X is O, S, or NR 6
• Yi is halogen or pseudohalogen
• one of Zi, Z 2 , Z 3 , and Z 4 is a carbon atom attached to the adjacent optionally substituted phenyl moiety, and the others are each independently CR 7 or N
• Pi is Ri or a protecting group
• P 2 is a protecting group
• P 3 is OR 2 , SR 2 , NR 9 Ri 0 , NHNHR 9 , or a protecting group
• Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
• R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
• R 3 is hydrogen, cyano, or optionally substituted alkyl or aryl
• P 3 is OR 2 .
• R 2 is hydrogen.
• Zi is CR 7 .
• R 7 is NR 9 Ri O .
• R 9 is hydrogen.
• Ri 0 is hydrogen.
• Z 2 is N.
• Z 3 is a carbon atom attached to the adjacent optionally substituted phenyl moiety.
• Z 4 is CR 7 .
• R 7 is hydrogen.
• n is 1.
• R 5 is hydrogen.
• X is O.
• R 3 is hydrogen.
• R 4 is optionally substituted alkyl.
• R 4 is -CF 3 .
• A is optionally substituted biphenyl.
• the compound of formula II is of formula II(a):
• Rn is independently hydrogen, cyano, nitro, halogen, OR 8 , NR 9 Ri 0 , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ri 2 is independently hydrogen, cyano, nitro, halogen, ORg, NR 9 RiO, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; m is 1-5; and p is 1-4.
• the compound of formula II (a) is of formula II (b):
• the compound of formula III is of formula III (a):
• the compound of formula II is prepared by contacting a compound of formula IV:
• Ai is optionally substituted cycloalkyl, aryl, or heterocycle
• a 2 is optionally substituted cycloalkyl, aryl, or heterocycle
• Y 2 is halogen or pseudohalogen
• each R is independently hydrogen, optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane.
• Ai is optionally substituted phenyl.
• Ai is anisole.
• a 2 is optionally substituted phenyl.
• a 2 is phenyl.
• R 3 is hydrogen.
• R 4 is optionally substituted alkyl.
• R 4 is -CF 3 .
• X is O.
• the compound of formula IV is of formula IV(a) :
• each Rn is independently hydrogen, cyano, nitro, halogen, ORs, NR9R10, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and m is 1-5.
• the compound of formula I V(a) is of formula IV(b) :
• each Ri 2 is independently hydrogen, cyano, nitro, halogen, ORg, NR9R10, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and p is 1-4.
• the compound of formula V(a) is of formula V(b):
• the compound of formula I ⁇ I(a) is prepared by contacting a compound of formula VI:
• Y 3 is halogen or pseudohalogen; and each R' is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane.
• n is 1.
• R 5 is hydrogen.
• Zi is CR 7 .
• R 7 is NR 9 R 10 .
• R 9 is hydrogen.
• Ri 0 is hydrogen.
• Z 2 is N.
• Z 3 is a carbon atom attached to the adjacent optionally substituted phenyl moiety.
• Z 4 is CR 7 .
• R 7 is hydrogen.
• the compound of formula VI is of formula VI (a):
• One embodiment of the invention comprises deprotecting the compound of formula I(a) to provide a compound of formula I:
• Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle.
• the compound of formula I is of formula I(b):
• each Rn is independently hydrogen, cyano, nitro, halogen, ORg, NR9R10, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R12 is independently hydrogen, cyano, nitro, halogen, OR 8 , NR 9 Ri 0 , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; m is 1-5; and p is 1-4.
• the compound of formula I(b) is of formula I(c), I(d) or I(e):
• compounds of general formulae VI and VII are coupled under conditions suitable for the formation of a compound of formula III (e.g. , contact with a transition metal catalyst, a base, and a solvent or solvent mixture with water), moieties of which may be deprotected if appropriate.
• the compound of formula III is then coupled with a compound of formula II under conditions sufficient to provide a compound of formula I(a) (e.g., nucleophilic substitution conditions), which is deprotected (e.g., by hydrolysis under acidic or basic conditions) to afford the compound of general formula I.
• Scheme 2(a) shows the preparation of two intermediate compounds:
• Conditions sufficient for the formation of the compound of formula II(a) include the use of a transition metal catalyst, a base, and a solvent or solvent mixture with water.
• the intermediate compounds are coupled as shown below in Scheme 2(b), to provide a compound that is deprotected to provide the final product:
• reaction conditions may be used in this approach to obtain the desired product. As those skilled in the art will immediately recognize, preferred reaction conditions may depend on the specific compounds involved.
• Yi is Cl.
• Y 2 is Br.
• Y 3 is Cl.
• R is hydrogen.
• R' is hydrogen.
• both R are taken together with the oxygen atoms to which they are attached to provide 4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl.
• each protecting group is independently aryl-alkyl, heteroaryl- alkyl, or -C(O)Ri 3 , wherein Ri 3 is alkyl, aryl-alkyl, aryl, heterocycle, alkoxy, aryloxy, or aryl-alkoxy.
• protecting groups include benzyl, diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl, and pthalimido.
• this invention encompasses novel compounds that can be used to prepare compounds of formula I.
• Examples include compounds of the formula: and salts and solvates thereof, wherein: Pi is R 1 , -C(O)Ri3, or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; P 2 is -C(O)Ri3 or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; and each Ri 3 is independently alkyl, aryl-alkyl, aryl, heterocycle, alkoxy, aryloxy, or aryl-alkoxy.
• Pi is hydrogen.
• P 2 is benzyl, diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl, or pthalimido.
• a particular compound is of the formula:
• the invention also encompasses compounds of the formula:
• Pi is R 1 , -C(O)Ri 3 , or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
• P 2 is -C(O)Ri 3 or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
• Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
• each Ri 3 is independently alkyl, aryl-alkyl, aryl, heterocycle, alkoxy, aryloxy, or aryl-alkoxy.
• Pi is hydrogen.
• P 2 is benzyl, diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl, or pthalimido.
• a particular compound is of the formula:
• This invention also encompasses compounds of the formula:
• the mixture was dissolved in anhydrous 2-propanol (175 ml) and the entire vessel was purged with argon by 3 vacuum-thaw cycles. The reaction mixture was then purged with hydrogen by 3 vacuum-thaw cycles. The reaction was carried out under 60 psi hydrogen atmosphere. After 24 hours of stirring and no more hydrogen consumption, the reaction was deemed complete by GC-MS analysis (no more starting ketone). The contents of the reaction vessel were transferred to a round bottom flask with MeOH rinsing (3 x 20 ml), and concentrated under reduced pressure until no more solvent was distilling off.
• the titled compound was prepared using catalyst [(tra «s r )-RuCl 2 [(iS)-Xyl-P- Phos] [(S)-DIAPEN].
• reaction mixture was cooled to 40 0 C, it was filtered through a pad of Celite, washed with methanol (3x100 ml). The filtrate was diluted with 100 ml of water and concentrated. The resulting syrup was dissolved in 700 ml of ethyl acetate and washed with 1 N sodium hydroxide (2x100 ml), water (2x100 ml) and brine (1x100 ml). The organic layer was heated with activated carbon (14 g) and Hyflo Super CeI (14 g) at 60 0 C for 1 hours. This mixture was filtered hot and washed with ethyl acetate (100 ml ) and then concentrated to a syrup.
• the reaction mixture was then filtered at 50 0 C through a pad of celite (Celpure P300, 0.15 wt., Sigma) and the filter cake was washed with methanol (2 x 2.5 vol). The filtrate was concentrated under reduced pressure at 40-45 0 C to 5 vol. The slurry was then transferred to a separatory funnel and MTBE (10 vol) was added. The mixture was then washed with a 50% solution of sodium hydroxide (0.6 vol). After stirring, the layers were separated and the aqueous phase was extracted with MTBE (1.5 vol). The organic extracts were combined and washed with water (1 vol) followed by 20% aqueous sodium chloride (1 vol) to provide 11.9 volumes of organic product solution.
• the solution was transferred to a reactor, treated with a slurry of Darco G-60 (0.3 wt) in MTBE (1 vol) and heated to 50 0 C. After 90 minutes, the mixture was filtered through a pad of Celpure P300 (0.15 wt) and washed with MTBE (2 x 3 vol).
• the filtrate (14.8 vol) was transferred to a reactor and distilled under vacuum at 45°C to remove MTBE.
• the filtrate was reduced to 6.7 volumes over 2.5 hours and then heptane (3.15 vol) was added.
• the solution was further distilled at 50 0 C to 6.7 vol over 1 hours and then additional heptane (3.15 vol) was added.
• the solution was concentrated to 6.7 vol at 55°C over 1.5 hours and then heptane was added (3.15 vol). Precipitation was observed immediately and the distillation was continued under vacuum at 60 0 C. After 2.5 hours, the distillation was stopped (7 vol remaining), the heat was switched off and the batch was cooled overnight to ambient temperature.
• the batch was filtered at 24°C and washed with heptane (1.5 vol).
• the solids were dried at room temperature under vacuum over the weekend to provide 799.7 g of 3 as a white solid [72% yield, >99% (AUC)].
• This ester compound 6 was prepared based on a literature procedure (Firooznia, et al, Tetrahedron Lett., 1999, 40, 213-216). Bis(pinacolato)diboron (90 g, 1.1 eq), potassium acetate (63 g, 2 eq), tricyclohexylphosphine (2.3 g, 2.5% mol), and palladium acetate (0.72 g, 1 mol%) were mixed in acetonitrile (950 ml) and the resulting mixture stirred at room temperature for 5 minutes. The above triflate (5) solution (190 g, 0.32 mol) was added and the resulting mixture was heated at 80 0 C for 1 hours and cooled.
• Acetonitrile was removed from the filtrate under reduced pressure to give an aqueous slurry (950 ml, additional water was added during distillation).
• the slurry was filtered through a pad of 20 ⁇ cellulose and washed with water (200 ml).
• the filtrate was washed with MTBE (500 ml) and rediluted with 700 ml MTBE.
• the mixture was acidified to pH about 4.5 with 6 N hydrochloric acid.
• the organic layer was washed with water (500 ml) and concentrated under reduced pressure to the titled product (7) as a brown oil (206 g, 95% yield based on estimated purity by NMR).
• the crude product was used directly in the following step.
• Compound 7 can optionally isolated by crystallization.
• the above MTBE solution of 7 can be dried with anhydrous Na 2 SO 4 and concentrated to about 1.0 vol under vacuum.
• Heptane (2.5 vol) was added and concentrated to about 1.5 vol under vacuum.
• Heptane (4.2 vol) was added slowly at 36 ⁇ 42°C followed by cooling slowly to 5 ⁇ 10°C.
• the resulting slurry is filtered, washed by heptane, and dried under vacuum at 20-30 0 C to give the product 7 in about 76% yield.
• a l L jacketed three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe, and gas bubbler was charged with 100ml of an ethanol solution containing 50.88 g 7.
• the solution was set stirring under nitrogen, diluted with 35ml ethanol, then with 50ml 2-propanol, and was heated to ⁇ 60°C.
• 250ml water were added to reach the cloudy point and the turbid solution was held at ⁇ 60°C for 75 minutes followed by cooling to ⁇ 10°C over ⁇ 1.5hrs.
• the mixture was biphasic and was diluted with an additional 30ml 2-propanol.
• the mixture was stirred under nitrogen at 10 0 C overnight and the resulting white fine suspension was filtered.
• the filtrate was washed with ethyl acetate (400 ml) and diluted with 3:1 THF/MTBE (600 ml). The mixture was acidified to pH about 3.5. The organic layer was washed with brine (300 ml) and concentrated to give the crude product 8 as a red oil (180 g). This oil was redissolved in THF (300 ml), polish-filtered, and washed with THF (100 ml). The filtrate was diluted with isopropanol (400 ml) and the mixture was distilled atmospherically to about 300 ml. More isopropanol (400 ml) was added and distillation continued until the volume reached about 500 ml.
• the batch was then distilled under reduced pressure at 45°C over a period of 15 hours to afford 4-5 L of a yellow slurry.
• the batch was then allowed to cool overnight. Water was added (3 vol) and after heating to 45°C, distillation was continued for 1 hours until no more distillate was collected. The vacuum was released and water (3 vol) was added to the batch. After allowing to settle, the batch was filtered through a slurry of cellulose powder (20 micron, 0.2 wt.) in water (1 vol). Water (2 vol) was added to the remaining solids/slurry in the reactor and this was filtered through a sintered glass funnel. This filtrate was then further filtered through the cellulose pad to afforded 11.2 L of product solution (13.2 vol).
• Heptane (5 vol) was added to the reactor, the contents of the reactor were transferred to a separatory funnel and the two phases were separated.
• the aqueous phase (11.2 L, 13.2 vol) was charged to the 22-L reactor, diluted to 14 vol with water and then a slurry of Darco G-60 (0.2 wt) in water (1 vol) was charged to the reactor.
• the mixture was heated to 60 0 C and stirred at 60 0 C for 2 hours. The heat was switched off and the batch was stirred over the weekend.
• the batch was filtered through a pad of Celpure P300 (0.2 wt, Sigma) and washed with water (2 x 1.2 vol).
• a 22-L, round-bottom flask equipped with a mechanical stirrer, a thermocouple attached to a temperature controller, and pH probe attached to a pH meter was charged with citric acid (127.5 g, 0.15 wt) and water (2 vol).
• the solution was heated to 40 0 C and the pH of the solution was adjusted to 4.0 with a 2 M solution of sodium hydroxide.
• a solution of citric acid (40 wt%, 2 L) was charged to an addition funnel and was attached to the reactor.
• the basic solution of 8 was then transferred via peristaltic pump through an in-line filter to the citric acid solution and the pH was maintained at pH 4.0 with the 40% citric acid solution. Once the addition was complete, the batch was heated to 60 0 C and stirred for 2 hours.
• the resulting mixture was concentrated under vacuum to -300 mL at 30 ⁇ 40°C and then flushed with toluene (500 g).
• the resulting mixture was cooled to 0 ⁇ 5°C and stirred for 60-80 minutes at 0 ⁇ 5°C, and then filtered.
• the wet cake was washed with toluene (43 g) and dried in vacuum oven at 40 ⁇ 45°C for 12 hours to afford 82.3g of the monochloride toluene solvate 8 as an off-white solid in 66% yield corrected for 80w% purity (96.3A%).
• the non-solvated product can be isolated from acetonitrile (5Og scale of boronic acid 7).
• the combined organic extraction was concentrated under vacuum to -150 mL (3.0X) at 40 0 C, followed by addition of 500 g (10X) Of CH 3 CN, and then concentrated to -250 mL (5.0X).
• the resulting slurry was stirred for 2 hours at 60 0 C, and then filtered.
• the wet cake was washed with 50 g (1.0X) of CH 3 CN twice and dried in vacuum oven at 40 0 C to afford 37.3 g of the desired product as white powder in 72% yield after correcting for w% purity (97.2 A%, 96.9 wt%, Pd: 22 ppm).
• the crude 8 as prepared from examples 5.11 or 5.12 is impure and usually contains about 6% of the diacid impurity (A) and about 4% amination product (B). This material can be used directly in the next step or it can optional purified by the following methods.
• the mixture was stirred and the catalyst bis(triphenylphosphine)palladium(II) dichloride (359 mg, 1 mol%) was added.
• the mixture was heated to 80 0 C and stirred for 2 hours.
• the reaction was cooled to room temperature and diluted with water (100 ml).
• the mixture was then concentrated under reduced pressure to remove most of ethanol and 1 N NaOH (60 ml) was added.
• the mixture was extracted twice with ethyl acetate (2x200 ml) and the aqueous layer was acidified to pH ⁇ 3 using 1 N HCl.
• an aqueous solution of the lithium salt of compound 7 in 100 ml water prepared from 5.O g of Boc-Tyr-OMe (4, 17 mmol), was mixed 2-amino-4,6- dichloropyrimidine (3.3 g, 1.2 eq), potassium bicarbonate (5.0 g, 3 eq), bis(triphenylphosphine)palladium(II) dichloride (60 mg, 0.5 mol%), and 100 ml ethanol. The resulting mixture was heated at 70 0 C for 5 hours.
• the boronic acid compound 11 (Ryscor Science, Inc., North Carolina, 1.0 g, 4.8 mmol) and potassium carbonate (1.32 g, 2 eq) were mixed in aqueous ethanol (15 ml ethanol and 8 ml water). Di-te/t-butyldicarbonate (1.25 g, 1.2 eq) was added in one portion. After 30 minutes agitation at room temperature, HPLC analysis showed complete consumption of the starting compound 11.
• the boronic acid compound 11 (10 g, 48 mmol) and potassium bicarbonate (14.4 g, 3 eq) were mixed in aqueous ethanol (250 ml ethanol and 50 ml water). Di-tert- butyldicarbonate (12.5 g, 1.2 eq) was added in one portion. HPLC analysis indicated that the reaction was not complete after overnight stirring at room temperature Potassium carbonate (6.6 g, 1.0 eq) and additional di-t ⁇ t-butyldicarbonate (3.1 g, 0.3 eq) were added. After 2.5 hours agitation at room temperature, HPLC analysis showed complete consumption of the starting compound 11.
• the 2-amino-4,6-dichloropyrimidine (11.8 g, 1.5 eq) and the catalyst bis(triphenylphosphine)-palladium(II) dichloride (0.34 g, 1 mol%) were added and the resulting mixture was heated at 75-80 0 C for 2 hours. HPLC analysis showed complete consumption of compound 12.
• the mixture was concentrated under reduced pressure and filtered. The filtrate was washed with ethyl acetate (200 ml) and diluted with 3 : 1 THF/MTBE (120 ml). This mixture was acidified to pH about 2.4 by 6 N hydrochloric acid. The organic layer was washed with brine and concentrated under reduced pressure.
• thermocontroller To a 250 ml 3 -neck round-bottom flask equipped with a mechanical stirrer, a thermocontroller was charged monochloride 8 (20.39 g, 51.9 mmol), alcohol 3 (17.58 g, 1.2 equiv), cesium carbonate (84.55, 5.0 equiv) and dioxane (205 ml). The mixture was heated to 100 0 C and stirred for 17 hours. The reaction was cooled to room temperature and diluted with water (80 ml). Two phases were split and the organic layer was collected and diluted with ethyl acetate (200 ml), washed with a mixture of brine (50 ml) and 1 N HCl (50 ml).
• the reaction mixture was transferred to a 500 ml separatory funnel.
• the round-bottom flask was washed with water (2 x 40 ml) and the washes were also transferred to the funnel.
• the mixture was washed with ethyl acetate (2 x 100 ml) and the aqueous layer was collected and concentrated at 40 0 C (bath temperature) under 80 mbar vacuum to remove any remaining organic solvents.
• the resulting aqueous solution was then transferred to a 500 ml three-necked round-bottom flask equipped with a mechanical stirrer, a pH meter, a thermocontroller and an addition funnel.
• the beaker containing 8 was rinsed with 1,4-dioxane (0.5 vol) and added to the reactor. The reaction became thick briefly after stirring for 15-30 minutes but the entire batch was stirrable. The controller was heated at 78°C overnight followed by heating at 98°C for 8 hours then 85°C overnight. HPLC analysis indicated that there were 2.1% of 8 remaining. The reaction was quenched at 78°C with water (6 vol) and then cooled further. At 42°C, the batch was transferred to a separatory funnel and the two phases separated. The organic phase was then diluted with THF (8 vol) and washed with brine (5 vol). The phases were separated and the organic phase was washed with brine (5 vol).
• the aqueous phase was then concentrated under reduced pressure at 45°C using a 20-L, rotary evaporator until the mixture turned cloudy (2-3 h).
• the volume of distillate collected was approximately 3.3 L.
• the batch was then transferred back to a 22-L reactor and held at 40 0 C overnight.
• the batch was heated to 60 0 C whereupon the batch turned from cloudy to clear.
• water (1.6 vol) and 85% phosphoric acid (0.24 vol) was adjusted to 6.5 using a 50% NaOH solution (approximately 0.3 vol).
• the acidic product solution was then transferred via peristaltic pump to the reactor containing the pH 6.5 buffered solution and the pH was maintained within 6 and 7 through the addition of 50% NaOH (approximately 3.5 vol).
• the temperature of the reactor was maintained between 55 and 65°C (2-h addition time). Once the addition was complete, the slurry was heated at 60- 65°C for 90 minutes, filtered, and washed with water (2 x 6.7 vol).
• the wet cake was dried in a vacuum oven at 55°C for 39 hours to afford 635 g of crude 10 as a yellow solid (66% yield).
• the purity of the product was 93.2% (AUC).
• the orange solution was heated at 65°C for 30 minutes IPA (10 vol) was slowly added maintaining the temperature between 60-70 0 C. Once the addition was complete, the mixture was stirred for 20 minutes and then IPAc (10 vol) was slowly added maintaining the temperature between 60-70 0 C. Once the addition was complete, the thick slurry was stirred at 65°C for 1 hours and then cooled to 27°C over 4.5 hours. The solids were filtered and washed with IPA (2 x 3 vol). The product was dried in a vacuum oven at 55°C for 15 hours to afford 630 g of 10 diHCl salt (88% yield) with a purity of 95.0% (AUC).
• a 12-L, round-bottom flask equipped with a mechanical stirrer, a thermocouple attached to a temperature controller, and a pH probe attached to a pH meter was charged with 10 diHCl salt (620 g, 1 wt) followed by an aqueous solution of 1 M NaOH (10 vol). The mixture was heated to 40 0 C, stirred until all the solids dissolved (2 h), and then transferred to a 10-L carboy.
• the 12-L, round-bottom flask was washed with water and then 85% phosphoric acid (124 ml, 0.2 vol) and water (1.3 vol) were charged to the reactor.
• the pH was adjusted to 6.5 using 50% NaOH (0.24 vol) and then heated to 65°C.
• the product solution in the carboy was transferred via peristaltic pump to the pH buffered solution and the pH was maintained between 6 and 7 through the addition of an aqueous solution of 6 M HCl (0.67 L). Once the addition was complete, the slurry was heated at 65°C for 3 hours and the solids were filtered. The cake was washed with water (3 x 5 vol) and then dried in a vacuum oven at 55°C for 41 hours to afford 473 g of 10 as a light yellow solid (87% yield) with a purity of 97.7% (AUC).
• reaction mixture was then stirred at 100 0 C for 22 hours.
• the mixture was cooled to 90 0 C, water (3.75 L, 7.5 X) was added, the mixture was allowed to cool to 30 0 C, and a solution of di-tert-buty ⁇ dicarbonate (33.1 g, 0.15 mol) in 1,4-dioxane (50 mL, 0.1 X) was added.
• toluene (2.25 L, 4.5 X) was added, stirred for 30 minutes, settled, and the aqueous layer was split off.
• the organic layer was then acidified with 2 NHCl (0.78 L, ca. 1.5 X) at 20-25 0 C to 3.1.
• H 2 SO 4 (5.0 M, 68.5 mL, 2.0 eq) was added to a solution of the Boc-acid (107.3 g, 94 A%, 92.5 w%, 155 mmol corrected for purity) in THF (321 mL). The mixture was heated to 60 0 C over 15 minutes and then aged at this temperature for 6 hours. It was neutralized with 2.0 N NaOH until pH reached 6.6 (336.5 mL NaOH).
• the aqueous layer (300 mL) contained no product and was discarded.
• Water (165 mL) was added to the organic layer and then seeded with (S)-2-amino-3-(4-(2-amino-6-((R)- 2,2,2-trifluoro- 1 -(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate (0.9 g THF solvate and 1.5 g non-solvate). It slowly became a thick slurry. The mixture was aged at 40 0 C for 2 hours and more water (377 mL) was added slowly over 3 hours at 40 0 C.

Priority Applications (11)

Applications Claiming Priority (1)

Publications (1)

Family

ID=40785295

Family Applications (1)

Country Status (11)

Cited By (3)

Citations (2)

• 2008
  • 2008-10-24 CN CN2008801316930A patent/CN102203069A/zh active Pending
  • 2008-10-24 KR KR1020117009174A patent/KR20110074875A/ko not_active Application Discontinuation
  • 2008-10-24 AU AU2008363274A patent/AU2008363274A1/en not_active Abandoned
  • 2008-10-24 JP JP2011533149A patent/JP2012506427A/ja not_active Withdrawn
  • 2008-10-24 CA CA2741563A patent/CA2741563A1/en not_active Abandoned
  • 2008-10-24 RU RU2011120822/04A patent/RU2011120822A/ru unknown
  • 2008-10-24 BR BRPI0823136-2A patent/BRPI0823136A2/pt not_active IP Right Cessation
  • 2008-10-24 WO PCT/US2008/081054 patent/WO2010047712A1/en active Application Filing
  • 2008-10-24 EP EP08876427A patent/EP2358685A1/en not_active Withdrawn
  • 2008-10-24 MX MX2011004168A patent/MX2011004168A/es not_active Application Discontinuation
• 2011
  • 2011-03-29 IL IL211996A patent/IL211996A0/en unknown

Patent Citations (2)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events