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WO2013055747A1 - Procédés de fabrication de composés guanidines polycycliques alkylées - Google Patents

Procédés de fabrication de composés guanidines polycycliques alkylées Download PDF

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WO2013055747A1
WO2013055747A1 PCT/US2012/059480 US2012059480W WO2013055747A1 WO 2013055747 A1 WO2013055747 A1 WO 2013055747A1 US 2012059480 W US2012059480 W US 2012059480W WO 2013055747 A1 WO2013055747 A1 WO 2013055747A1
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certain embodiments
mixture
dialkylcarbonate
membered
polycyclic
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Thomas R. Welter
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Novomer Inc
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Novomer Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention pertains to the field of chemical synthesis. More particularly, the invention pertains to methods for the N-alkylation of polycyclic guanidine compounds using dialkylcarbonates.
  • N-methyl Triazabicyclo[4.4.0] dec-9-ene is of interest as a catalyst to replace potentially toxic tin compounds in polyurethane systems.
  • MTBD Triazabicyclo[4.4.0] dec-9-ene
  • a patent application also owned by Novomer discloses a novel and highly efficient route to make TBD (Triazabicyclo [4.4.0] ' dec-9-ene) at large scale which is the typical precursor to MTBD. Alkylation of this material to provide MTBD and related analogs remains challenging at large scale.
  • the few examples reported in the literature generally rely on deprotonation with a strong base such as sodium hydride followed by treatment with alkyl iodide. Such methods are unsuitable for large scale production of MTBD since NaH is reactive and difficult to handle and methyl iodide is highly toxic.
  • the present invention provides such methods.
  • TBD is an effective catalyst for the synthesis of alkyl carbonates by transcarbonation in the presence of alcohols:
  • the present invention encompasses among other things, the recognition that dialkylcarbonates are preferred reagents for the mono-N-alkylation of polycyclic guanidines.
  • Certain compounds of the present invention can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • inventive compounds and compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
  • the compounds of the invention are enantiopure compounds.
  • certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated.
  • the invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of enantiomers.
  • isomers includes any and all geometric isomers and stereoisomers.
  • “isomers” include cis- and trans-isomers, E- and Z- isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • a stereoisomer may, in some embodiments, be provided substantially free of one or more corresponding stereoisomers, and may also be referred to as
  • stereochemically enriched where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the opposite enantiomer, and may also be referred to as “optically enriched.”
  • Optically enriched means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • Jacques, et al Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al, Tetrahedron 33 :2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds
  • halo and halogen refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), and iodine (iodo, -I).
  • aliphatic or "aliphatic group”, as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro-fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-30 carbon atoms.
  • aliphatic groups contain 1-12 carbon atoms. In certain embodiments, aliphatic groups contain 1-8 carbon atoms. In certain embodiments, aliphatic groups contain 1-6 carbon atoms. In some embodiments, aliphatic groups contain 1-5 carbon atoms. In some embodiments, aliphatic groups contain 1 ⁇ 1 carbon atoms. In some embodiments, aliphatic groups contain 1-3 carbon atoms. In some embodiments, aliphatic groups contain 1-2 carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • cycloaliphatic used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring systems, as described herein, having from 3 to 12 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein.
  • Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl.
  • the cycloalkyl has 3-6 carbons.
  • cycloaliphatic also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.
  • aromatic or nonaromatic rings such as decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.
  • 3- to 8-membered carbocycle refers to a 3 - to 8- membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • the terms "3- to 14-membered carbocycle” and “C 3-14 carbocycle” refer to a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 7- to 14-membered saturated or partially unsaturated polycyclic carbocyclic ring.
  • the term “C 3 _2o carbocycle” refers to a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 7- to 20-membered saturated or partially unsaturated polycyclic carbocyclic ring.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals derived from an aliphatic moiety containing between one and six carbon atoms by removal of a single hydrogen atom. Unless otherwise specified, alkyl groups contain 1-12 carbon atoms. In certain embodiments, alkyl groups contain 1-8 carbon atoms. In certain embodiments, alkyl groups contain 1-6 carbon atoms. In some embodiments, alkyl groups contain 1-5 carbon atoms. In some embodiments, alkyl groups contain 1 ⁇ 1 carbon atoms. In certain embodiments, alkyl groups contain 1-3 carbon atoms. In some embodiments, alkyl groups contain 1-2 carbon atoms.
  • alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n- hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like.
  • alkenyl denotes a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Unless otherwise specified, alkenyl groups contain 2-12 carbon atoms. In certain embodiments, alkenyl groups contain 2-8 carbon atoms. In certain embodiments, alkenyl groups contain 2-6 carbon atoms. In some embodiments, alkenyl groups contain 2-5 carbon atoms. In some embodiments, alkenyl groups contain 2-4 carbon atoms. In some embodiments, alkenyl groups contain 2-3 carbon atoms. In some embodiments, alkenyl groups contain 2 carbon atoms.
  • Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.
  • alkynyl refers to a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. Unless otherwise specified, alkynyl groups contain 2-12 carbon atoms. In certain embodiments, alkynyl groups contain 2-8 carbon atoms. In certain embodiments, alkynyl groups contain 2-6 carbon atoms. In some embodiments, alkynyl groups contain 2-5 carbon atoms. In some embodiments, alkynyl groups contain 2- ⁇ carbon atoms. In some embodiments, alkynyl groups contain 2-3 carbon atoms. In some embodiments, alkynyl groups contain 2 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic and polycyclic ring systems having a total of five to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to twelve ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • aryl refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more additional rings, such as benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, and the like.
  • the terms "6- to 10-membered aryl” and ' ⁇ - ⁇ aryl” refer to a phenyl or an 8- to 10-membered polycyclic aryl ring.
  • the term "6- to 12-membered aryl” refers to a phenyl or an 8- to 12-membered polycyclic aryl ring. In certain embodiments, the term “C 6 -i 4 aryl” refers to a phenyl or an 8- to 14- membered polycyclic aryl ring.
  • heteroaryl and “heteroar-”, used alone or as part of a larger moiety e.g., “heteroaralkyl”, or “heteroaralkoxy” refer to groups having 5 to 14 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one.
  • a heteroaryl group may be mono- or bicyclic.
  • the term “heteroaryl” may be used interchangeably with the terms "heteroaryl ring"
  • heteroaryl group or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • the term “5- to 10-membered heteroaryl” refers to a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term "5- to 12-membered heteroaryl” refers to a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 12-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).
  • the term "3- to 7-membered heterocyclic” refers to a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term "3- to 8- membered heterocycle” refers to a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term "3- to 12-membered heterocyclic” refers to a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated or partially unsaturated polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term "3- to 14-membered heterocycle” refers to a 3- to 8- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 14- membered saturated or partially unsaturated polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,
  • pyrrolidonyl piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • protecting group it is meant that a particular functional moiety, e.g., O, S, or N, is masked or blocked, permitting, if desired, a reaction to be carried out selectively at another reactive site in a multifunctional compound.
  • a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group is preferably selectively removable by readily available, preferably non-toxic reagents that do not attack the other functional groups; the protecting group forms a separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group will preferably have a minimum of additional functionality to avoid further sites of reaction.
  • hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), ?-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), -methoxybenzyloxymethyl (PMBM), (4- methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), ?-butoxymethyl, 4- pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2- trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-
  • DPMS diphenylmethylsilyl
  • TMPS ?-butylmethoxyphenylsilyl
  • dimethylphosphinothioyl alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
  • Exemplary protecting groups are detailed herein, however, it will be appreciated that the present disclosure is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the method of the present disclosure. Additionally, a variety of protecting groups are described by Greene and Wuts (infra).
  • compounds of the invention may contain "optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • R° may be substituted as defined below and is independently hydrogen, Ci-8 aliphatic, -CH 2 Ph, -0(CH 2 )o_iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0 ⁇ 1 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or polycyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 y 2 R e , -(haloR*), -(CH 2 y 2 OH, -(CH 2 y 2 OR e , -(CH 2 y 2 CH(OR') 2 ; -
  • alkylene)C(0)OR or -SSR
  • each R* is unsubstituted or where preceded by "halo” is substituted only with one or more halogens, and is independently selected from Ci ⁇ aliphatic, -CH 2 Ph, -0(CH 2 )o_iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 ⁇ 1 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR 2 ) 2 -3 ⁇ -, wherein each independent occurrence of R * is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 ⁇ 1 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, -R", -(haloR"), -OH, -OR", -O(haloR'), -CN, -C(0)OH, -C(0)OR e , -NH 2 , -NHR", -NR' 2 , or -N0 2 , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci ⁇ aliphatic, -CH 2 Ph, -O(CH 2 ) 0 -iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 ⁇ 1 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ , - S(0) 2 R ⁇ , -S(0) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , -C( H)NR ⁇ 2 , or -N(R ⁇ )S(0) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, Ci_6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, -R", -(haloR*), -OH, -OR", -O(haloR'), -CN, -C(0)OH, -C(0)OR e , -NH 2 , -NHR", -NR' 2 , or -N0 2 , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 -iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 ⁇ 1 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • substituents are shown attached to a bond which crosses another bond of a depicted molecule. This means that one or more of the substituents may be attached to the molecule at any available position (usually in place of a hydrogen atom of the parent structure). In cases where an atom of a molecule so substituted has two substitutable positions, two groups may be present on the same atom. When more than one substituent is present, each is defined independently of the others, and each may have a different structure. In cases where the substituent shown crossing a bond of the molecule is -R, this has the same meaning as if the molecule were said to be "optionally substituted" as described in the preceding paragraph.
  • dialkylcarbonate as used herein means a carbonate group bearing two optionally substituted aliphatic moieties. The two moieties may be the same or different.
  • the substituents on the dialkylcarbonate are not limited to alkyl groups per se but also include unsaturated moieties such as allyl and benzyl as well as substituted moieties such as halogenated groups and the like.
  • the present invention provides methods for the N-alkylation of polycyclic guanidine compounds.
  • inventive methods comprise the step of contacting a polycyclic guanidine compound with a dialkylcarbonate.
  • the method comprises contacting the guanidine compound and the dialkylcarbonate in the absence of an added solvent.
  • the method comprises contacting the guanidine compound and the dialkylcarbonate in the presence of an added solvent.
  • the added solvent is selected from the group consisting of hydrocarbons, ethers, esters, nitriles, sulfoxides, amides, chlorinated hydrocarbons and mixtures of two or more of these.
  • the solvent comprises an aliphatic hydrocarbon.
  • the solvent comprises an aromatic hydrocarbon.
  • the solvent is provided in a quantity such that the solvent comprises about 10 to about 90 weight percent of the mixture. In certain embodiments, the solvent comprises from about 20 to about 50 weight percent of the mixture.
  • methods of the present invention further comprise the step of heating the mixture of the polycyclic guanidine compound and the dialkylcarbonate.
  • the reaction mixture is heated to between about 40 °C and 200 °C.
  • the reaction mixture is heated to between about 50 °C and about 150 °C.
  • the reaction mixture is heated to between about 80 °C and about 120 °C.
  • methods of the present invention comprise the step of removing volatiles from the mixture of the polycyclic guanidine compound and the dialkylcarbonate as it is heated.
  • the step of removing volatiles further comprises sweeping the reaction mixture with gas.
  • the reaction mixture is swept with an inert gas.
  • the inert gas comprises nitrogen, argon, helium, deoxygenated air, or carbon dioxide.
  • the step of removing volatiles comprises subjecting the reaction mixture to reduced pressure.
  • the volatiles removed comprise carbon dioxide. In certain embodiments the volatiles removed comprise an alcohol. In certain embodiments, the volatiles removed comprise a mixture of carbon dioxide and an alcohol. In certain embodiments, the alcohol removed is derived from the alkyl group present on the dialkylcarbonate (e.g. ethanol is volatilized if diethyl carbonate is used, methanol if dimethyl carbonate is used and so forth). In certain embodiments, the method comprises the further step of condensing the alcohol and recovering it as a liquid.
  • dialkylcarbonate are provided in approximately equimolar quantities.
  • the polycyclic guanidine compound is contacted with a molar excess of the dialkylcarbonate.
  • the polycyclic guanidine compound is contacted with between about 1.1 and about 20 molar equivalents of dialkylcarbonate.
  • the polycyclic guanidine compound is contacted with between 1.5 and about 15 molar equivalents of dialkylcarbonate.
  • the polycyclic guanidine compound is contacted with between 2 and about 10 molar equivalents of dialkylcarbonate.
  • the polycyclic guanidine compound is contacted with between 3 and about 8 molar equivalents of dialkylcarbonate.
  • the polycyclic guanidine compound is contacted with between 2 and about 5 molar equivalents of dialkylcarbonate. In certain embodiments, the polycyclic guanidine compound is contacted with between 5 and about 10 molar equivalents of
  • the reaction mixture is monitored and the process is allowed to continue until the amount of unalkylated polycyclic guanidine present in the mixture is less than about 5%. In certain embodiments, the process is allowed to continue until the amount of unalkylated polycyclic guanidine present in the mixture is less than about 2%, less than about 1% or less than about 0.5%.
  • the methods of the present invention further comprise isolating the alkylated polycyclic guanidine from the reaction mixture.
  • the isolation may comprise one or more steps. In certain embodiments, one or more of the following steps are performed:
  • an inorganic material e.g. silica gel, alumina, - diatomaceous earth, activated carbon and the like
  • an inorganic material e.g. silica gel, alumina, - diatomaceous earth, activated carbon and the like
  • the process of isolating the alkylated polycyclic guanidine comprises distillation. In certain embodiments, excess solvents or dialkylcarbonate are distilled from the product. In other embodiments, the alkylated polycyclic guanidine is distilled from other reaction components or byproducts. In certain embodiments the reaction mixture is washed with a hydrocarbon solvent to dissolve the alkylated polycyclic guanidine. In certain embodiments, where the reaction mixture is washed with a hydrocarbon solvent, the desired alkylated polycyclic guanidine is substantially separated from dialkylated byproducts which do not dissolve in the hydrocarbon. In certain embodiments, the reaction mixture is washed with heptane.
  • the methods comprise a further step of volatilizing the heptanes from the solution to isolate the desired alkylated polycyclic guanidine.
  • the transformations effected by the methods of the invention conform to the reaction shown in Scheme 1 :
  • Ri groups are optionally present and, if present, are at each occurrence independently selected from the group consisting of halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, and optionally substituted heteroaryl, and functional groups comprising one or more oxygen, nitrogen, sulfur, phosphorous, or silicon atoms, where two or more Ri groups can optionally be taken together with intervening atoms to form one or more optionally substituted rings optionally containing one or more heteroatoms;
  • n is an integer from 1 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • R2 groups are independently selected from optionally substituted Ci-20 aliphatic and heteroaliphatic moieties.
  • Ri groups are, at each occurrence, independently selected from the group consisting of halogen, -N0 2 , -CN, -Si(R y )3, -SR y , -S(0)R y , -S(0) 2 R y , -NR y C(0)R y , -OC(0)R y , -C0 2 R y , -NCO, -N 3 , -OR y , -OC(0)N(R y ) 2, -N(R y ) 2, -NR y C(0)R y , -NR y C(0)OR y ; or an optionally substituted radical selected from the group consisting of C 1-20 aliphatic; C 1-20 heteroaliphatic; phenyl; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7-14 carbon saturated, partially unsaturated or aromatic polycyclic carbocycle; a 5- to
  • one or more Ri groups are present and comprise alkyl groups.
  • R2 groups comprise Ci-2 0 aliphatic groups. In certain embodiments, R2 groups comprise Ci_io aliphatic groups. In certain embodiments, R2 groups comprise Ci_6 aliphatic groups. In certain embodiments, R2 groups comprise C1-4 aliphatic groups. In certain embodiments, each R2 group is
  • each R2 group is -CH2CH 3 . In certain embodiments, each R2 group is -CH2CH 3 . In certain embodiments, each R2 group is -CH2CH 3 . In certain
  • each R 2 group is -CH 3 . In certain embodiments, each R 2 group is allyl. certain embodiments, each R2 group is benzyl.
  • m and n are each independently 1 or 2. In certain embodiments, m and n are each 2. In certain embodiments, m and n are each 1. In certain embodiments, m is 1 and n is 2. In certain embodiments, m is 2 and n is 1.
  • the polycyclic guanidine is present as a salt.
  • the salt comprises carbonate, bicarbonate, a halide, or a sulfonate.
  • the method comprises contacting the polycyclic guanidine with the dialkylcarbonate in the presence of a base.
  • the present invention encompasses a method of manufacturing MTBD, comprising the step of contacting TBD with dimethyl carbonate. In certain embodiments, the method comprises heating a mixture of TBD with a molar excess of dimethyl carbonate.
  • the method comprises heating a mixture of TBD and between 3 molar equivalents and 10 molar equivalents of dimethyl carbonate. In certain embodiments, the mixture is heated to a temperature above 50 °C. . In certain embodiments, the mixture is heated to a temperature above about 75 °C. In certain embodiments, the mixture is heated to a temperature of about 90-100 °C. In certain embodiments, the method comprises heating a mixture of TBD with a molar excess of dimethyl carbonate to a temperature of about 90-100 °C, while simultaneously removing volatiles liberated from the mixture. In certain embodiments the method is performed without added solvent. In certain embodiments, the heating and removal of volatiles are continued until substantially all of the TBD has been alkylated. In certain embodiments, the method comprises the further steps of cooling the reaction mixture, and dissolving the product in a hydrocarbon solvent.
  • the present invention encompasses a method of manufacturing ethyl TBD (l-Ethyl-l,4,9-Triazabicyclo[4.4.0]dec-9-ene), comprising the step of contacting TBD with diethyl carbonate.
  • the method comprises heating a mixture of TBD with a molar excess of diethyl carbonate.
  • the method comprises heating a mixture of TBD and between 3 molar equivalents and 10 molar equivalents of diethyl carbonate.
  • the mixture is heated to a temperature above 50 °C. In certain embodiments, the mixture is heated to a temperature above about 75 °C.
  • the mixture is heated to a temperature of about 90-100 °C.
  • the method comprises heating a mixture of TBD with a molar excess of diethyl carbonate to a temperature of about 90-100 °C, while simultaneously removing volatiles liberated from the mixture.
  • the method is performed without added solvent.
  • the heating and removal of volatiles are continued until substantially all of the TBD has been alkylated.
  • the method comprises the further steps of cooling the reaction mixture, and dissolving the product in a hydrocarbon solvent.
  • the present invention encompasses a method of manufacturing methyl TBO (l-methyl-l,4, 6-triazabicyclo[3.3.0]oct-4-ene), comprising the step of contacting TBO (1 ,4, 6-triazabicyclo[3.3.0] oct-4-ene) with dimethyl carbonate.
  • the method comprises heating a mixture of TBO with a molar excess of dimethyl carbonate.
  • the method comprises heating a mixture of TBO and between 3 molar equivalents and 10 molar equivalents of dimethyl carbonate.
  • the mixture is heated to a temperature above 50 °C.
  • the mixture is heated to a temperature above about 75 °C.
  • the mixture is heated to a temperature of about 90-100 °C.
  • the method comprises heating a mixture of TBO with a molar excess of dimethyl carbonate to a temperature of about 90-100 °C, while simultaneously removing volatiles liberated from the mixture.
  • the method is performed without added solvent.
  • the heating and removal of volatiles are continued until substantially all of the TBO has been alkylated.
  • the method comprises the further steps of cooling the reaction mixture, and dissolving the product in a hydrocarbon solvent.
  • a mixture of l,4,9-triazabicyclo[4.4.0]dec-9-ene (TBD; lOO.Og, 0.719 mol) and dimethyl carbonate (DMC; 500 mL, 5.9 mol) were charged into a 1L three-necked reaction vessel.
  • the vessel was equipped with a mechanical paddle stirrer, a thermometer, and a six inch long vacuum-jacketed Vigreux column surmounted with a water-cooled distillation apparatus.
  • the otherwise sealed reaction vessel was connected, via the distillation apparatus, to a bubbler to monitor gas evolution.
  • Using a thermostated oil- bath the charged vessel was carefully warmed to an internal temperature of 97-98°C over about 30 min. During the warming, gas evolution started and eventually solution boiling began.
  • Example 3 Preparation of 1-allyl-l ,4,9-Triazabicycio[4.4.0] 'dec-9-ene
  • TBD l,4,9-triazabicyclo[4.4.0]dec-9-ene
  • Example 4 Preparation of l-methyl-l,4,6-triazabicyclo[3.3.0]oct-4-ene (Methyl TBOyrhe reaction is performed under the conditions of Example 1, substituting 1,4,6- triazabicyclo3.3.0oct-4-ene (TBO) for TBD.

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

Abstract

La présente invention concerne des procédés de synthèse de dérivés N-alkylés de guanidines polycycliques ayant un groupe NH échangeable par réaction avec des carbonates de dialkyle. Selon un aspect, l'invention concerne un procédé de fabrication du méthyle TBD (1-méthyl-1, 4, 9-triazabicyclo [4.4.0] déc-9-ène) par chauffage d'un mélange de TBD et de carbonate de diméthyle.
PCT/US2012/059480 2011-10-10 2012-10-10 Procédés de fabrication de composés guanidines polycycliques alkylées Ceased WO2013055747A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9593203B2 (en) 2011-07-18 2017-03-14 Novomer, Inc. Metal complexes
US9771388B2 (en) 2012-08-24 2017-09-26 Saudi Aramco Technologies Company Metal complexes
US9834710B2 (en) 2012-04-16 2017-12-05 Saudi Aramco Technologies Company Adhesive compositions and methods
US11185853B2 (en) 2017-12-22 2021-11-30 Saudi Aramco Technologies Company Catalysts for polycarbonate production

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WO2011079041A1 (fr) * 2009-12-24 2011-06-30 Novomer, Inc. Procédés pour la synthèse de composés de guanidine polycycliques

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9593203B2 (en) 2011-07-18 2017-03-14 Novomer, Inc. Metal complexes
US9834710B2 (en) 2012-04-16 2017-12-05 Saudi Aramco Technologies Company Adhesive compositions and methods
US9771388B2 (en) 2012-08-24 2017-09-26 Saudi Aramco Technologies Company Metal complexes
US11185853B2 (en) 2017-12-22 2021-11-30 Saudi Aramco Technologies Company Catalysts for polycarbonate production

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