WO2012147900A1 - Procédé en microréacteurs pour synthèse d'analogue d'halichondrine b - Google Patents
Procédé en microréacteurs pour synthèse d'analogue d'halichondrine b Download PDFInfo
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- WO2012147900A1 WO2012147900A1 PCT/JP2012/061307 JP2012061307W WO2012147900A1 WO 2012147900 A1 WO2012147900 A1 WO 2012147900A1 JP 2012061307 W JP2012061307 W JP 2012061307W WO 2012147900 A1 WO2012147900 A1 WO 2012147900A1
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- eribulin
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- 0 CC(CC(CCC1OC(CCC*)CC1=C)OC1CC(C2C*)OC(CC(*)C*)C2OC)C1=C Chemical compound CC(CC(CCC1OC(CCC*)CC1=C)OC1CC(C2C*)OC(CC(*)C*)C2OC)C1=C 0.000 description 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Definitions
- the present invention relates to methods for the preparation of compounds useful as intermediates in the synthesis of pharmaceutically active macrolide compounds.
- Halichondrin B is a potent anticancer agent originally isolated from the marine sponge Halichondria okadai, and subsequently found in Axinella sp., Phakellia carteri, and
- the present invention provides methods for producing eribulin, intermediates useful for synthesis of eribulin, or pharmaceutically acceptable salts thereof, e.g., eribulin mesylate:
- the invention features a method of producing a compound of Formula (II) from a compound of Formula (I) by contacting the compound of Formula (I):
- each of PG 3 , PG 4 , and PG 5 is independently a hydroxyl protecting group; Ri is CI - C6 alkyl; and is a leaving group.
- Ri is CI - C6 alkyl; and is a leaving group.
- Formula (II), taken with the oxygen atom(s) to which they are bound, are silyl ethers or arylalkyl ethers.
- one, two, or three of PG 3 , PG 4 , and PG 5 of Formula (I) or Formula (II) are t-butyldimethylsilyl (TBS) or benzyl, or all of PG 3 , PG 4 , and PG 5 of Formula (I) or Formula (II) are t-butyldimethylsilyl (TBS).
- LGi is a halogen, (Cl-C6)alkylsulfonate,
- LGi include iodide, mesylate, toluenesulfonate, isopropylsulfonate, phenylsulfonate, and benzylsulfonate.
- Exemplary reducing agents include an aluminum hydride reagent or a borohydride reagent, e.g., lithium aluminum hydride, sodium aluminum hydride, diisobutylaluminum hydride (DIBAL-H), sodium bis(2-methoxyethoxy)aluminum hydride (Red Al), sodium borohydride, potassium borohydride, rubidium borohydride, cesium borohydride, or sodium
- the temperature of the microreactor is between -80 and -20 °C.
- the residence time of the compound of Formula I in the microreactor is, e.g., 0.01 sec to 1 sec.
- the invention features a method of producing a compound of Formula (IV) from a compound of Formula (II) and a compound of Formula (III), by contacting the compound of Formula (I
- each of PG 3 , PG 4 , and PG 5 is independently a hydroxyl protecting group; and LG] is a leaving group.
- one or both of PGi and PG 2 of Formula (III), taken with the oxygen atom(s) to which they are bound, are silyl ethers or arylalkyl ethers.
- one or both of PG, and PG 2 are TBS or benzyl, or both PGi and PG 2 are TBS.
- the compound of Formula (III) has the absolute stereochemistry:
- a specific compound of Formula III) for use in the methods is ER-804028:
- the compound of Formula(II) has the absolute stereochemistry of Formula (II)-A, or the compound is ER-803896.
- the method of producing the compound of Formula (IV) may further include synthesizing the compound of Formula (II) using the methods described herein.
- the compound of Formula (IV) has the stereochemistry:
- a specific compound of Formula IV that can be produced by the methods is ER-804029:
- the base can be an organometallic reagent, such as a Grignard's reagent, potassium bis(trimethylsilyl) amide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, «-butyl lithium, sec-butyl lithium, or ter/-butyl lithium.
- organometallic reagent such as a Grignard's reagent, potassium bis(trimethylsilyl) amide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, «-butyl lithium, sec-butyl lithium, or ter/-butyl lithium.
- the temperature of the microreactor in the deprotonation and/or coupling step is between -80 to 20 °C.
- the residence time of the compound of Formula (III) in the deprotonation step is, e.g., 0.1 sec to 20 sec.
- the residence time of the compound of Formula (II) and the compound of Formula (III) in the coupling step is, e.g., 0.1 sec to 20 sec.
- the invention further features a method of producing eribulin, or a pharmaceutically acceptable salt thereof, by producing a compound of Formula (II), e.g., ER-803896, as described herein and reacting the compound of Formula (II) under suitable conditions to produce eribulin, or a pharmaceutically acceptable salt thereof, e.g., eribulin mesylate.
- the compound of Formula (II) can be coupled to a compound of Formula (III), e.g., ER-804028, to produce a compound of Formula (IV), e.g., ER-804029, and the compound of Formula (IV) can be reacted to produce eribulin, or the pharmaceutically acceptable salt thereof.
- the invention features a method of producing eribulin, or a
- a compound of Formula (IV) e.g., ER- 804029, as described herein; and reacting the compound of Formula (IV) under suitable conditions to produce eribulin, or a pharmaceutically acceptable salt thereof, e.g., eribulin mesylate.
- the present invention includes the various stereoisomers of the compounds and mixtures thereof, unless otherwise specified.
- Individual stereoisomers of the compounds of the present invention are prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers or by preparation of mixtures of compounds followed by resolution, as is well known in the art. These methods of resolution are exemplified by direct separation of the mixture of diastereomers on chiral chromatographic columns or by chiral HPLC methods.
- chiral compounds can be prepared by an asymmetric synthesis that favors the preparation of one diastereomer over another.
- Geometric isomers may also exist in the compounds of the present invention.
- the present invention includes the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond, such as isomers of the Z or E configuration. It is also recognized that for structures in which tautomeric forms are possible, the description of one tautomeric form is equivalent to the description of both, unless otherwise specified.
- a diastereomer of a compound of the invention is present in a mixture at a ratio of 10:1 , 20:1, 30:1, 50:1, or greater as compared to other diastereomers.
- Compounds useful in the invention may be isotopically labeled compounds.
- Useful isotopes include hydrogen, carbon, nitrogen, and oxygen (e.g., 2 H, 3 H, ,3 C, 14 C, I5 N, I 8 0, and 17 0).
- Isotopically-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically-labeled reagent in place of a non-isotopically-labeled reagent.
- a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety.
- other atoms such as hydrogen atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms.
- an unsubstituted C2 alkyl group has the formula -CH 2 CH 3 .
- a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups.
- a reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.
- acetal is meant -OCH O-, wherein R is H, alkyl, alkenyl, aryl, or arylalkyl.
- acyl is meant -C(0)R, wherein R is H, alkyl, alkenyl, aryl, or arylalkyl.
- R is H, C1-C12 alkyl (e.g., C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and 307
- C3-C6 alkyl C2-C12 alkenyl (e.g., C2-C8, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl), C6- C20 aryl (e.g., C6-C15, C6-C10, C8-C20, and C8-C15 aryl), monocyclic C1 -C6 heteroaryl (e.g., monocyclic C1-C4 and C2-C6 heteroaryl), C4-C19 heteroaryl (e.g., C4-C10 heteroaryl), (C6- C15)aryl(Cl -C6)alkyl, (Cl -C6)heteroaryl(Cl-C6)alkyl, or (C4-C19)heteroaryl(Cl-C6)alkyl.
- any heteroaryl group present in an acyl group has from 1 to 4 heteroatoms selected independently from O, N, and S.
- alkyl is meant a straight or branched chain saturated cyclic (i.e., cycloalkyl) or acyclic hydrocarbon group of from 1 to 12 carbons, unless otherwise specified.
- exemplary alkyl groups include C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl. Specific examples include methyl, ethyl, 1 -propyl, 2-propyl, 2 -methyl- 1 -propyl, 1 -butyl, 2-butyl, and the like.
- alkyl groups used in any context herein, are optionally substituted with halogen, alkoxy, aryloxy, arylalkyloxy, oxo, alkylthio, alkylenedithio, alkylamino,
- alkylamino is meant -NHR, wherein R is alkyl.
- [alkenyl]alkylamino is meant
- -NRR' wherein R is alkyl, and R' is alkenyl.
- [aryl] alkylamino is meant -NRR', wherein R is alkyl, and R' is aryl.
- [arylalkyl]alkylamino is meant -NRR', wherein R is alkyl, and R' is arylalkyl.
- dialkylamino is meant -NR 2 , wherein each R is alkyl, selected
- alkylene is meant a divalent alkyl group.
- Alkylene groups used in any context herein, are optionally substituted in the same manner as alkyl groups.
- a CI alkylene group is -CH 2 -.
- alkylenedithio is meant -S-alkylene-S-.
- alkylthio is meant -SR, wherein R is alkyl.
- alkenyl is meant a straight or branched chain cyclic or acyclic hydrocarbon group of, unless otherwise specified, from 2 to 12 carbons and containing one or more carbon-carbon double bonds.
- alkenyl groups include C2-C8, C2-C7, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl. Specific examples include ethenyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), and the like.
- Alkenyl groups, used in any context herein, are optionally substituted in the same manner as alkyl groups.
- Alkenyl groups used in any context herein, may also be substituted with an aryl group.
- alkoxy is meant -OR, wherein R is alkyl.
- aryl is meant a monocyclic or multicyclic ring system having one or more aromatic rings, wherein the ring system is carbocyclic or heterocyclic. Heterocyclic aryl groups are also referred to as heteroaryl groups. A heteroaryl group includes 1 to 4 atoms selected
- carbocyclic aryl groups include C6-C20, C6-C15, C6-C10, C8-C20, and C8-C15 aryl.
- a preferred aryl group is a C6-10 aryl group.
- Specific examples of carbocyclic aryl groups include phenyl, indanyl, indenyl, naphthyl, phenanthryl, anthracyl, and fluorenyl.
- heteroaryl groups include monocylic rings having from 1 to 4 heteroatoms selected independently from O, N, and S and from 1 to 6 carbons (e.g., C1-C6, C1-C4, and C2-C6).
- Monocyclic heteroaryl groups preferably include from 5 to 9 ring members.
- Other heteroaryl groups preferably include from 4 to 19 carbon atoms (e.g., C4-C10).
- Specific examples of heteroaryl groups include pyridinyl, quinolinyl, dihydroquinolinyl, isoquinolinyl, quinazolinyl, dihydroquinazolyl, and tetrahydroquinazolyl.
- aryl groups used in any context herein, are optionally substituted with alkyl, alkenyl, aryl, arylalkyl, halogen, alkoxy, aryloxy, arylalkyloxy, oxo, alkylthio, alkylenedithio, alkylamino,
- arylalkyl is meant -R'R", wherein R' is alkylene, and R" is aryl.
- arylalkyloxy is meant -OR, wherein R is arylalkyl.
- aryloxy is meant -OR, wherein R is aryl.
- carbamate is meant -OC(0)NR 2 , wherein each R is independently H, alkyl, alkenyl, aryl, or arylalkyl.
- carbonate is meant -OC(0)OR, wherein R is alkyl, alkenyl, aryl, or arylalkyl.
- carboxyl is meant -C(0)OH, in free acid, ionized, or salt form.
- cyclic boronate is meant -OBRO-, wherein R is alkyl, alkenyl, aryl, arylalkyl, alkoxy, or 2,6-diacetamidophenyl.
- cyclic carbonate is meant -OC(0)0-.
- cyclic silylene is meant -OSiR 2 0-, wherein each R is independently alkyl, alkenyl, aryl, arylalkyl, or alkoxy.
- dialkylsilylene is meant a cyclic silylene, wherein each R is alkyl.
- esters is meant -OC(0)R, where -C(0)R is an acyl group, as defined herein, that is bound to the oxygen atom of a protected hydroxyl, as defined below.
- ether is meant -OR, wherein R is alkyl, alkenyl, arylalkyl, silyl, or 2- tetrahydropyranyl .
- halogen is meant fluoro, chloro, bromo, or iodo.
- ketal is meant -OCR 2 0-, wherein each R is independently alkyl, alkenyl, aryl, or arylalkyl, or both R groups are together alkylene.
- silyl is meant -SiR 3 , wherein each R is independently alkyl, alkenyl, aryl, or arylalkyl.
- silyl groups include tri(Cl-C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 heteroaryl)silyl, di(C6-C10 aryl or C1-C6 heteroaryl)(Cl-C6 alkyl)silyl, and (C6-C10 aryl or Cl- C6 heteroaryl)di(C 1 -C6 alkyl)silyl.
- silyl group when a silyl group includes two or more alkyl, alkenyl, aryl, heteroaryl, or arylalkyl groups, these groups are independently selected. As defined herein, any heteroaryl group present in a silyl group has from 1 to 4 heteroatoms selected independently from O, N, and S.
- sulfonate is meant -OS(0) 2 R, wherein R is alkyl, alkenyl, aryl, or arylalkyl.
- R is C1-C12 alkyl (e.g., C1 -C8, C1 -C6, C1-C4, C2-C7, C3-C12, and C3- C6 alkyl), C2-C12 alkenyl (e.g., C2-C8, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl), carbocyclic C6-C20 aryl (e.g., C6-C15, C6-C10, C8-C20, and C8-C15 aryl), monocyclic C1-C6 heteroaryl (e.g., C1-C4 and C2-C6 heteroaryl), C4-C19 heteroaryl (e.g., C4-C10 heteroaryl), (C6-C 15
- sulfonyl is meant -S(0) 2 R, wherein R is alkyl, alkenyl, aryl, arylalkyl, or silyl.
- R is alkyl, alkenyl, aryl, arylalkyl, or silyl.
- Preferred R groups for sulfonyl are the same as those described above for sulfonates.
- hydro xyl protecting group is meant any group capable of protecting the oxygen atom to which it is attached from reacting or bonding. Hydroxyl protecting groups are known in the art, e.g., as described in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley- Interscience, 4 th Edition, 2006. Exemplary protecting groups (with the oxygen atom to which they are attached) are independently selected from esters, carbonates, carbamates, sulfonates, and ethers.
- R of the acyl group is C1-C12 alkyl (e.g., C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl), C2-C12 alkenyl (e.g., C2-C8, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl), carbocyclic C6-C20 aryl (e.g., C6-C15, C6-C10, C8-C20, and C8-C15 aryl), monocyclic C1-C6 heteroaryl (e.g., C1-C4 and C2-C6 heteroaryl), C4-C19 heteroaryl (e.g., C4-C10 heteroaryl), (C6-C15)aryl(Cl-C6)alkyl, (C4-C19)heteroaryl(Cl- C6)alkyl, or (
- acyl groups for use in esters include formyl, benzoylformyl, acetyl (e.g., unsubstituted or chloroacetyl, trifluoroacetyl, methoxyacetyl, triphenylmethoxyacetyl, and p-chlorophenoxyacetyl), 3-phenylpropionyl, 4- oxopentanoyl, 4,4-(ethylenedithio)pentanoyl, pivaloyl (Piv), vinylpivaloyl, crotonoyl, 4- methoxy-crotonoyl, naphthoyl (e.g., 1- or 2-naphthoyl), and benzoyl (e.g., unsubstituted or substituted, e.g., p-methoxybenzoyl, phthaloyl (including salts, such a triethylamine and potassium), p-
- R is C1-C12 alkyl (e.g., C1-C8, Cl- C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl), C2-C12 alkenyl (e.g., C2-C8, C2-C6, C2-C4, C3- C12, and C3-C6 alkenyl), carbocyclic C6-C20 aryl (e.g., C6-C15, C6-C10, C8-C20, and C8-C15 aryl), monocyclic C1-C6 heteroaryl (e.g., C1-C4 and C2-C6 heteroaryl), C4-C19 heteroaryl (e.g., C4-C10 heteroaryl), (C6-C15)aryl(Cl-C6)alkyl, (C4-C19)heteroaryl(Cl -C6)alkyl, or (Cl-C12 alkyl (e.g., C1
- C6)heteroaryl(Cl-C6)alkyl examples include methyl, 9-fluorenylmethyl, ethyl, 2,2,2- trichloroethyl, 2-(trimethylsilyl)ethyl, 2-( henylsulfonyl)ethyl, vinyl, allyl, t-butyl, p-nitrobenzyl, and benzyl carbonates.
- any heteroaryl group present in a carbonate group has from 1 to 4 heteroatoms selected independently from O, N, and S.
- each R is independently H, CI -CI 2 alkyl (e.g., C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl), C2-C12 alkenyl (e.g., C2- C8, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl), carbocyclic C6-C20 aryl (e.g., C6-C15, C6- C10, C8-C20, and C8-C15 aryl), monocyclic C1-C6 heteroaryl (e.g., C1 -C4 and C2-C6 heteroaryl), C4-C19 heteroaryl (e.g., C4-C10 heteroaryl), (C6-C15)aryl(Cl-C6)alkyl, (C4- C19)heteroaryl(Cl-C6)alkyl, or
- any heteroaryl group present in a carbamate group has from 1 to 4 heteroatoms selected independently from O, N, and S.
- ether hydroxyl protecting groups include C1-C12 alkylethers (e.g., C1 -C8)
- C1 -C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl C2-C12 alkenylethers (e.g., C2-C8, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl), (C6-C15)aryl(Cl-C6)alkylethers, (C4-C19)heteroaryl(Cl- C6)alkylethers, (Cl-C6)heteroaiyl(Cl-C6)alkylethers, (Cl-C6)alkoxy(Cl-C6)alkylethers, (Cl - C6)alkylthio(Cl -C6)alkylethers, (C6-C10)aryl(Cl-C6)alkoxy(Cl-C6)alkylethers, and silylethers (e.g., tri(Cl-C6 alkyl)silyl, tri(C6-C
- alkylethers include methyl and t-butyl, and an example of an alkenyl ether is allyl.
- alkoxyalkylethers and alkylthioalkylethers include methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, and P-(trimethylsilyl)ethoxyrnethyl.
- arylalkyl ethers examples include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, triphenylmethyl (trityl), o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, naphthylmethyl, and 2- and 4-picolyl ethers.
- silylethers include trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), and triphenylsilyl (TPS) ethers.
- TMS trimethylsilyl
- TES triethylsilyl
- TBS t-butyldimethylsilyl
- TIPS triisopropylsilyl
- TPS triphenylsilyl
- TPS triphenylsilyl
- An example of an arylalkyloxyalkylether is benzyloxymethyl ether.
- any heteroaryl group present in an ether group has from 1 to 4 heteroatoms selected independently from O, N, and S.
- Adjacent hydroxyl groups may be protected with a diol protecting group, such as acetal (e.g., C1-C6 alkyl), ketal (e.g., C3-C6 alkyl or C3-C6 cycloalkyl), cyclic silylene, cyclic carbonate, and cyclic boronate.
- acetal and ketal groups include methylene, ethylidene, benzylidene, isopropylidene, cyclohexylidene, and cyclopentylidene.
- An example of a cyclic silylene is di-t-butylsilylene.
- Another diol protecting group is 1 ,1,3,3- tetraisopropylsiloxanediyl.
- cyclic boronates include methyl, ethyl, phenyl, and 2,6- diacetamidophenyl boronates.
- Protecting groups may be substituted as is known in the art; for example, aryl and arylalkyl groups, such as phenyl, benzyl, naphthyl, orpyridinyl, can be substituted with C1 -C6 alkyl, C1-C6 alkoxy, nitro, cyano, carboxyl, or halogen.
- Alkyl groups such as methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, and sec -butyl, and alkenyl groups, such as vinyl and allyl, can also be substituted with oxo, arylsulfonyl, halogen, and trialkylsilyl groups.
- protecting groups are TBS and Piv. Protecting groups that are orthogonal are removed under different conditions, as in known in the art.
- leaving group is meant a group that is displaced during a chemical reaction.
- Suitable leaving groups are well known in the art, e.g., see, Advanced Organic Chemistry, March, 4th Ed., pp. 351-357, John Wiley and Sons, N.Y. (1992).
- Such leaving groups include halogen, C1-C12 alkoxy (e.g., C1-C8, C1-C6, C1-C4, C2-C7, and C3-C6 alkoxy), C1-C12 alkylsulfonate (e.g., C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkylsulfonate), C2-C12
- alkenylsulfonate e.g., C2-C8, C2-C6, C2-C4, C3-C12, and C3-C6 alkenylsulfonate
- carbocyclic C6-C20 arylsulfonate e.g., C6-C15, C6-C10, C8-C20, and C8-C15 arylsulfonate
- C4-C19 heteroarylsulfonate e.g., C4-C10 hetero arylsulfonate
- monocyclic C1 -C6 heteroarylsulfonate e.g., C 1-C4 and C2-C6 heteroarylsulfonate
- C6-C 15)aryl(Cl -C6)alkylsulfonate (C4-
- Alkylsulfonates, alkenylsulfonates, arylsulfonates, heteroarylsulfonates, arylalkylsulfonates, and heteroarylalkylsulfonates can be optionally substituted with halogen (e.g., chloro, iodo, bromo, or fluoro), alkoxy (e.g., C1-C6 alkoxy), aryloxy (e.g., C6-C15 aryloxy, C4-C19 heteroaryloxy, and C1-C6 heteroaryloxy), oxo, alkylthio (e.g., C1-C6 alkylthio) , alkylenedithio (e.g., C
- [arylalkyl]alkylamino e.g., [(C6-C10)aryl(Cl -C6)alkyl](Cl-C6)alkylamino, [(Cl-
- dialkylamino e.g., di(Cl-C6 alkyl)amino
- Alkenylsulfonates can be optionally substituted with carbocyclic aryl (e.g., C6-C15 aryl), monocyclic C1-C6 heteroaryl, or C4-C19 heteroaryl (e.g., C4-C10 heteroaryl).
- Arylsulfonates can be optionally substituted with alkyl (e.g., C1 -C6 alkyl) or alkenyl (e.g. C2-C6 alkenyl).
- any heteroaryl group present in a leaving group has from 1 to 4 heteroatoms selected independently from O, N, and S.
- Suitable leaving groups include chloro, iodo, bromo, fiuoro, methanesulfonate (mesylate), 4-toluenesulfonate (tosylate), trifluoromethanesulfonate (triflate, OTf), nitro-phenylsulfonate (nosylate), and bromo-phenylsulfonate (brosylate). Leaving groups may also be further substituted as is known in the art.
- microreactor used in the present specification refers to a reaction vessel in which at least two fluids are combined and allowed to react, wherein the vessel has at least one interior dimension of 1 mm or less, e.g., the diameter of tubing or a transverse dimension of a fluidic chip.
- salt a salt within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example,
- Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfon
- reaction time is meant the time during which a mixture of reactants passes through the volume of a micro reactor lying between the points at which two or more reactants first mix completely and the addition of a further reactant or quenching agent.
- Figure 1 is a schematic depiction of a microreactor system for converting ER-803895 to ER-803896.
- FIG. 2 is a schematic depiction of a microreactor system for converting ER-803895 to ER-803896.
- the lines from Pumps A, B and C are SUS ( ⁇ 0.8 mm x 2 m); the line from Pump D is Teflon ( ⁇ 0.8 mm); Pump A is Shimadzu HPLC LCIOAD; Pumps B and C are Shimadzu HPLC LC8A; and Pump D is EYELA VSP2200.
- Figure 3 is a schematic depiction of a microreactor system for producing ER-804029 from ER-804028 and ER-803896.
- Halichondrin B analogs e.g., eribulin or pharmaceutically acceptable salts thereof, can be synthesized by coupling the C1 -C13 and C14-C35 fragments as described in U.S. Patent No. 6,214,865 and International Publication No. WO 2005/118565.
- a key step in this synthesis is the coupling of an anion or dianion of a C 14-35 fragment with an aldehyde of a Cl-13 fragment.
- the C14-C35 portion, e.g., ER-804028, of the molecule is coupled to the C1 -C13 portion, e.g., ER-803896, to produce ER-804029, and additional reactions are carried out to produce eribulin (Scheme 1):
- Lithiation of the C14-C35 sulfone fragment followed by coupling to the C1-C13 aldehyde fragment furnishes a mixture of diastereomeric alcohols (ER-804029). Typically, these steps occur at low temperature, e.g., -75 °C. Additional protecting group manipulation and oxidation followed by removal of the sulfonyl group and an intramolecular Nozaki-Hiyama- Kishi (NHK) reaction affords an intermediate, which, when oxidized and treated with tetrabutylammonium fluoride, undergoes intramolecular oxy-Michael ring closure. Pyridinium />-toluenesulfonate mediated ketal formation and conversion of the terminal alcohol to an amine furnishes eribulin.
- NHK Nozaki-Hiyama- Kishi
- ER-804029 is reacted to produce ER-804030; ER-804030 is reacted to produce ER-118049; ER-118049 is reacted to produce mixture ER-118047/118048; the mixture ER-1 18047/118048 is reacted to produce ER- 118046; ER-118046 is reacted to produce ER-811475; ER-811475 is reacted to produce ER- 076349; and ER-076349 is reacted to produce eribulin.
- eribulin e.g., eribulin mesylate
- eribulin mesylate can be formed by methods known in the art, e.g., in situ during the final isolation and purification of the compound or separately by reacting the free base group with a suitable organic acid.
- eribulin is treated with a solution of MsOH and NH 4 OH in water and acetonitrile. The mixture is concentrated. The residue is dissolved in DCM-pentane, and the solution is added to anhydrous pentane. The resulting precipitate is filtered and dried under high vacuum to provide eribulin mesylate, as shown in Scheme 2.
- the present invention provides new methods for the production of a CI- 13 fragment, e.g., ER-803896, and for a CI -35 fragment, e.g., ER-804029, using microreactors.
- Microreactors allow for accurate control of reaction temperature and/or reaction time with the benefit of using higher temperatures compared to batch processing and providing greater safety for
- microreactor reactions occur as continuous flow processes, they offer the ability to sample the process stream for monitoring the progress of the reaction and, for example, the level of byproducts generated.
- CI -13 fragments have been made by reducing a carboalkoxyester, e.g., ER-803895, to provide an aldehyde, e.g., ER-803896, as described in U.S. Patent No. 6,214,865.
- the invention provides a method of reducing a compound of Formula I to an aldehyde of Formula II in a microreactor:
- each of PG 3 , PG 4 , and PG 5 is an independently selected hydroxyl protecting group; R] CI - C6 alkyl; and LGi is a leaving group.
- one, two, or three of PG 3 , PG 4 , and PG 5 of Formula (I) or Formula (II), taken with the oxygen atom(s) to which they are bound, are silyl ethers or arylalkyl ethers.
- one, two, or three of PG 3 , PG 4 , and PG 5 of Formula (I) or Formula (II) are t-butyldimethylsilyl (TBS) or benzyl.
- all of PG 3 , PG 4 , and PG 5 of Formula (I) or Formula (II) are t- butyldimethylsilyl (TBS).
- PG and PG 4 can also combine to form a diol protecting group.
- LG] is a halogen, such as iodide.
- LG] is (Cl- C6)alkylsulfonate, (C6-C10 aryl or C1-C6 heteroaryl)sulfonate, (C6-C15)aryl(Cl- C6)alkylsulfonate, or (CI -C6)heteroaryl(C 1 -C6)alkylsulfonate.
- Specific leaving groups include mesylate, toluenesulfonate, isopropylsulfonate, phenylsulfonate, or benzylsulfonate
- the compounds of Formula (I) and Formula (II) have the absolute stereochemistries depicted below:
- the compound of Formula (I) is ER-803895. In some embodiments, the compound of Formula (I) is ER-803895. In some
- the compound of Formula (II) is ER-803896.
- the present invention provides methods for producing aldehydes of Formula II by the reduction of carboalkoxyesters of Formula I in a microreactor, which allows the reaction to proceed at temperatures higher than those previously disclosed for this transformation.
- Reducing agents useful in this transformation include an aluminum hydride reagent, a borohydride reagent, or the like.
- Examples of reducing agents include lithium aluminum hydride, sodium aluminum hydride, diisobutylaluminum hydride (DIBAL-H), sodium bis(2-methoxyethoxy)aluminum hydride (Red Al), sodium borohydride, potassium borohydride, rubidium borohydride, cesium borohydride, sodium cyanoborohydride, or the like.
- DIBAL-H diisobutylaluminum hydride
- Red Al sodium bis(2-methoxyethoxy)aluminum hydride
- a preferred reducing agent is DIBAL-H.
- the reaction can be carried out in solvents purged with nitrogen, argon, or another such inert gas.
- solvents used in this synthesis include halogen solvents such as dichloromethane, chloroform, or 1,2 dichloroethane; ether solvents such as tetrahydrofuran, 1 ,2-dimethoxyethane, methyl-ter -butyl ether, cyclopentyl methyl ether, diethyl ether,
- diisopropyl ether, dibutyl ether, or dicyclopentyl ether aromatic hydrocarbon solvents such as benzene or toluene; and aliphatic hydrocarbon solvents such as heptane or hexane; or mixtures thereof.
- aromatic hydrocarbon solvents such as benzene or toluene
- aliphatic hydrocarbon solvents such as heptane or hexane; or mixtures thereof.
- a preferred solvent is toluene.
- the reaction temperature is preferably between -80 and -20 °C, e.g., between -60 and -20 °C, such as approximately -50 °C.
- the concentration of the solution containing a compound of Formula I is preferably 0.10 g/mL to 0.30 g/mL, e.g., 0.15 g/mL to 0.25 g/mL, such as approximately 0.185 g/mL.
- a residence time of the compound of Formula (I) is the time sufficient to produce the compound of Formula (II), preferably 0.01 sec to 1 sec, e.g., 0.1 sec to 0.5 sec.
- the ratio of equivalents of reducing agent, e.g., DIBAL-H, to ester is 1.0 eq to 1.5 eq, e.g., 1.215 eq to 1.485 eq, such as approximately 1.35 eq.
- Compounds of Formula (I) and ER-803895 can be produced by methods known in the art, e.g., as described in U.S. Patent No. 6,214,865 and International Publication No.
- Cl -35 fragments have been made by coupling a Cl-13 fragment, e.g., ER-803896, to a C14-34 fragment, e.g., ER-804028, as described in U.S. Patent No. 6,214,865 and International Publication No. WO 2005/118565.
- the invention provides a method of coupling an anion or 07
- PG 3 , PG 4 , PG 5 , and LGi are as defined above; each of PGi and PG 2 is independently hydrogen or a hydroxyl protecting group; and PG 6 is hydrogen or a hydroxyl protecting group.
- one or both of PGi and PG 2 of Formula (III), taken with the oxygen atom(s) to which they are bound, are silyl ethers or arylalkyl ethers.
- one or both of PGi and PG 2 are TBS or benzyl.
- both PGi and PG 2 are TBS.
- PGi and PG 2 are combined to form a diol protecting group.
- PG 6 is hydrogen.
- the compound of Formula (III) has the absolute stereochemistry depicted below:
- the compound of Formula (III) is ER-804028
- the compound of Formula (IV) has the stereochemistry depicted below:
- the compound of Formula IV is ER-804029: 07
- a compound of Formula (III) is deprotonated with a base, e.g., an organometallic reagent, to produce an anion or dianion, which is reacted with a compound of Formula (II) to obtain a compound of Formula (IV).
- a base e.g., an organometallic reagent
- organometallic reagents include a Grignard's reagent, potassium bis(trimethylsilyl) amide, sodium bis(trimethylsilyl)amide, lithium
- reaction can be carried out in solvents purged with nitrogen, argon, or another such inert gas.
- solvent used in this synthesis examples include halogen solvents such as dichloromethane, chloroform, or 1,2 dichloroethane; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, methyl- rt-butyl ether, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, dibutyl ether, or dicyclopentyl ether; aromatic hydrocarbon solvents such as benzene or toluene; and aliphatic hydrocarbon solvents such as heptane or hexane; or a mixture thereof.
- a preferred solvent is tetrahydrofuran or heptane.
- the temperature is preferably between -80 and 20 °C, e.g., between -50 to 10 °C , more preferably between -10 to 10 °C.
- the concentration of the solution containing the compound of Formula (II) or (III) is preferably 0.05 g/mL to 0.30 g/mL, e.g., 0.05 g/mL to 0.15 g/n L.
- a residence time for deprotonation of the compound of Formula (III) is the time sufficient to deprotonate the compound of formula (III), preferably 0.1 sec to 20 sec, e.g., 1 sec to 5 sec.
- a residence time for the coupling reaction between the compound of Formula (II) and the compound of Formula (HI) is the time sufficient to produce the compound of formula (IV), preferably 0.1 sec to 20 sec, e.g., 1 sec to 5 sec.
- the ratio of equivalents of base, e.g., n-butyllithium, to compound of Formula (III) is preferably 2.0 eq to 2.5 eq, e.g., 2.05 eq to 2.25 eq, such as approximately 2.15 eq.
- the coupling of a compound of Formula III with a compound of Formula II, to produce a compound of Formula IV, in a microreactor may proceed at temperatures higher than those previously disclosed for this transformation.
- Compounds of Formula (III) and ER-804028 can be prepared using methods known in the art, e.g., as described in International Publication Nos. WO 2005/118565 and WO
- Any suitable microreactor can be used in the present invention. Examples of any suitable microreactor can be used in the present invention.
- microreactors include a small fluidized bed reactor and a static microreactor.
- a microreactor can be fabricated as a single component or be made up of separate components that are connected, e.g., by tubing.
- Components of a microreactor can include mixers, fluidic chips, and other devices for the combination of two or more fluids.
- Microreactors can be designed to mix two or more fluids and combine the resulting mixture with additional fluids.
- Commercially available chips can be employed. Examples of commercially available chips include COMET X- 01 (Techno Applications Co., Ltd.), CYTOS Series (YMC Co., Ltd), micro high Mixer (Toray engineering Co., Ltd.), LLMR(ITEC Co., Ltd.), and Micro Process Server (Hitachi Plant
- a microreactor used in the present invention can be used with any desired peripheral devices, such as heaters or coolers, temperature sensors, pressure sensors, fluid pumps, mixers, or the like.
- Microreactors can also be connected to analytical instrumentation, e.g., mass spectrometers or HPLC, for in-line measurement of reactants and products.
- Microreactors can be connected to fluid pumps or collection vessels by appropriately sized tubing. Multiple microreactors can be employed in parallel to increase rate of production of products, e.g., for use in a commercial manufacturing process.
- the flow rate of the reactants is varied according to the microreactor used in the flow reaction, and the residence time is adjusted by changing the flow rate of reactants provided to the microreactor or changing a length or internal dimension of components of the microreactor.
- the flow rate of the fluids provided separately to a microreactor may be the same or different.
- the present invention is advantageous in that higher temperatures of reaction can be employed, compared to previous batch processing.
- typical batch processing temperatures for the production of ER-803896 are between -60 and -80 °C, compared to -50 °C or higher, for example from -50°C to -30°C, in the present invention.
- the deprotonation and coupling of ER-804028 typically occurs at between -20 and - 70 °C in batch processing, compared to -10 °C or higher, for example from -10°C to 10°C, in the present invention.
- microreactors can also provide products that can be employed in further reactions without chromatographic purification. Furthermore, higher concentrations of the reactants can be employed in microreactors to decrease the volume of solvents used in the reaction.
- Example 1
- a micro flow reaction was carried out in the system of Figure 1.
- the reduction of ER- 803895 using diisobutylaluminum hydride (DIBAL-H) was initiated in a CMPS-aOl (Hitachi Plant Technologies, Ltd., Japan) or CMPS-a02 (Hitachi Plant Technologies, Ltd.) chip.
- the reaction was quenched by addition of acetone to the reduction product in a CMPS- ⁇ (P N:767808-02) chip (Hitachi Plant Technologies, Ltd).
- Inlets of the CMPS chips were connected by PTFE tubing (internal diameter: 1.5 mm, length: 2.0 m) to a Micro Process Server MPS- 200 (Hitachi Plant Technologies, Ltd.) having injection syringes.
- CMPS-aOl or -a02 chip The outlet of the CMPS-aOl or -a02 chip was connected to an inlet of the CMPS- ⁇ chip by SUS316 (stainless steel) tubing (internal diameter: 0.8 mm, length: 0.1 m), and the outlet of the CMPS- ⁇ chip was connected by PTFE (polytetrafluoroethylene) tubing (internal diameter: 1.0 mm, length: 0.6 m) to a collection vessel.
- SUS316 stainless steel tubing
- PTFE polytetrafluoroethylene
- 1780 mL of toluene was prepared in a 5 L bottle, which was placed in the line of plunger pump B. 571 mL of 1.0 M solution of DIBAL-H in toluene in a 1 L bottle was placed in the line of plunger pump A. Acetone (464 mL) in toluene (1856 mL) was prepared in a 5 L bottle and placed in the line of plunger pump C. 3300 mL of 1 N HCl in a 5 L bottle was placed in the line of plunger pump D.
- ER-803895 (1.00 g, 1.30 mmol) and BHT (7.1 mg, 0.032 mmol) were dissolved in toluene (16.2 mL) and cooled to ⁇ -80°C under a nitrogen atmosphere.
- DIBAL-H 1.0 M in toluene, 1.54 ml, 1.55 mmol, 1.2 eq was added at a rate to maintain the internal reaction temperature at ⁇ -80 °C.
- ER-803895 (1.00 g, 1.30 mmol) and BHT (7.2 mg, 0.032 mmol) were dissolved in toluene (16.2 mL) and cooled to ⁇ -70 °C under a nitrogen atmosphere.
- DIBAL-H 1.0 M in toluene, 1.54 ml, 1.55 mmol, 1.2 eq was added at a rate to maintain the internal reaction temperature at ⁇ -70 °C.
- the resulting mixture was stirred for 1 hour and then quenched sequentially with anhydrous acetone (0.31 mL) in toluene (0.70 mL) and anhydrous methanol (0.17 mL) in toluene (0.70 mL), maintaining the internal reaction temperature at ⁇ -65 °C.
- the reaction mixture was allowed to warm to -30 °C, and then MTBE (5.0 mL) and 1 N HC1 (10.0 mL) were added to the reaction mixture. The mixture was stirred for 30 minutes, and the aqueous layer was drained.
- ER-803895 (1.00 g, 1.30 mmol) and BHT (7.2 mg, 0.032 mmol) were dissolved in toluene (16.2 mL) and cooled to ⁇ -60 °C under nitrogen atmosphere.
- DIBAL-H 1.0 M in toluene, 1.54 ml, 1.55 mmol, 1.2 eq was added at a rate to maintain the internal reaction temperature at ⁇ -60 °C.
- the resulting mixture was stirred for 1 hour and then quenched sequentially with anhydrous acetone (0.31 mL) in toluene (0.70 mL) and anhydrous methanol (0.17 mL) in toluene (0.70 mL), maintaining the internal reaction temperature at ⁇ -65 °C.
- the reaction mixture was allowed to warm to -30 °C, and then MTBE (5.0 mL) and 1 N HCl (10.0 mL) were added to the reaction mixture. The mixture was stirred for 30 minutes, and the aqueous layer was drained.
- a micro flow reaction was carried out in the system of Figure 3.
- the coupling reaction of ER-804028 and ER-803896 using n-butyl lithium (n-BuLi) was initiated in a series of CMPS- a02 chips.
- Inlets of the CMPS chips were connected by PTFE tubing (internal diameter: 1.5 mm, length: 2.0 m) to a Micro Process Server MPS-a200 having injection syringes.
- the outlet of the first chip (A) was connected to an inlet of the second chip (B) via SUS316 tubing (internal diameter: 0.8 mm, length: 50 cm) or PTFE tubing (internal diameter: 1.0 mm, length: 32 cm or 64 cm or 96 cm).
- the outlet of the second chip was connected by PTFE tubing (internal diameter: 1.0 mm, length: 2.0 m or 4.0 m or 6.0 m) to a collection vessel.
- a 25 mL injection syringe was filled with a solution of 8.00 g (9.397 mmol) of ER- L 804028 and 80 mL of anhydrous THF; a 10 mL injection syringe was filled with a 1.63 M solution of n-BuLi in hexane; and an additional 25 mL injection syringe was filled with a solution of 7.659 g (10.337 mmol) of ER-803896 and 76.6 mL of n-heptane.
- ER-804028, ER-803896, and n-BuLi were set in various ranges, and the reactions were carried out at -10 °C to 10 °C for various residence times.
- the resultant reaction mixture was quenched with 14% aqueous ammonium chloride and extracted with MTBE.
- the purity of the organic layer was analyzed by HPLC.
- ER-804029 was obtained with high conversion under Run 12 compared with batch reaction condition (Table 2). For Table 2, residence times were determined based on the time required for reactants to pass through the tubing connecting the outlet of the first CMPS-a02 chip and the point in the second CMPS- 02 chip where ER-803896 is added.
Abstract
La présente invention concerne des procédés d'obtention d'éribuline, d'intermédiaires utiles pour la synthèse d'éribuline, ou de sels de qualité pharmaceutique de celle-ci, par exemple du mésylate d'éribuline, à l'aide de microréacteurs.
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