US20190040028A1 - Arylation of aliphatic amines - Google Patents

Arylation of aliphatic amines Download PDF

Info

Publication number
US20190040028A1
US20190040028A1 US16/076,380 US201716076380A US2019040028A1 US 20190040028 A1 US20190040028 A1 US 20190040028A1 US 201716076380 A US201716076380 A US 201716076380A US 2019040028 A1 US2019040028 A1 US 2019040028A1
Authority
US
United States
Prior art keywords
substituted
alkyl
group
aryl
substituent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US16/076,380
Other languages
English (en)
Inventor
Frederik Diness
Morten Meldal
Christian Borch Jacobsen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AAA Chemistry Aps
Original Assignee
AAA Chemistry Aps
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AAA Chemistry Aps filed Critical AAA Chemistry Aps
Assigned to AAA CHEMISTRY APS reassignment AAA CHEMISTRY APS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JACOBSEN, Christian Borch, MELDAL, MORTEN, DINESS, FREDERIK
Publication of US20190040028A1 publication Critical patent/US20190040028A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C07B43/04—Formation or introduction of functional groups containing nitrogen of amino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
    • C07C209/10—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups

Definitions

  • the invention relates to a method for arylation of amines, such as aliphatic amines by reaction of aryl-halogens, e.g. chloro- or fluorobenzene derivatives without strongly electron withdrawing substituents in the presence of a strong base.
  • aryl-halogens e.g. chloro- or fluorobenzene derivatives without strongly electron withdrawing substituents in the presence of a strong base.
  • N-arylations of aliphatic amines are important chemical transformations as the resulting aniline derivatives have found broad applications as pharmaceuticals, materials for organic electronics and dyes for industrial and research applications.
  • Pyrazine and morpholine derivatives are of special interest, as these are found in a range of top selling pharmaceuticals.
  • transition metal-catalyzed reactions A range of transition metal-catalyzed reactions has been developed for the formal halide to nitrogen substitution on aryl halides. Most renowned are the Ullmann and Buchwald-Hartwig couplings employing copper and palladium catalysis respectively. These results notwithstanding, the employment of transition metals as catalysts has several drawbacks in industrial applications, especially due to high costs, oxygen sensitivity, challenging purifications and toxic metal contaminants being present in the final products.
  • WO 2014/191548 discloses a synthetic process for the production of 1-(2-((2,4-dimethyl-phenyl)sulfonyl)phenyl)piperazine by arylation in the presence of Cs 2 CO 3 . The process however requires incubation at elevated temperature for more than 14 days.
  • the present invention provides catalyst free N-arylation of amines.
  • the methods are very effective, and can typically results in high yields.
  • the invention provides methods for preparing an arylated amine, said method comprising the steps of
  • FIG. 1 Examples of pharmaceuticals containing an N-arylated secondary amine.
  • FIG. 2 shows the yield of catalyst-free N-arylation of morpholine using various different polyfluorinated benzene derivatives.
  • FIG. 3 shows the yield of catalyst-free N-arylation of various amines.
  • General reaction conditions used in is: Amine (1.0 eq.), LiHMDS (1.0M in THF, 1.5 eq.) and benzene derivative (1.5 eq.) were mixed and heated.
  • Compounds 3r, 3s, 3t, 3ad, 3ae, 3af, and 3ag were synthesized by slightly modified procedures.
  • alkane refers to saturated linear or branched carbohydrides of the general formula C n H 2n+2 .
  • alkenyl refers to a substituent derived from an alkene by removal of one —H.
  • An alkene may be any acyclic carbonhydride comprising at least one double bond. Frequently, alkenyl will have the general formula —C n H 2n ⁇ 1 .
  • alkyl refers to a substituent derived from an alkane by removal of one —H.
  • alkynyl refers to a substituent derived from an alkyne by removal of one —H.
  • An alkyne may be any acyclic carbonhydride comprising at least one triple bond. Frequently, alkynyl will have the general formula —C n H 2n ⁇ 3 .
  • amino refers to a substituent of the general formula
  • the waved line indicates the point of attachment of the substituent.
  • Amino may thus for example be —NH 2 or —NH—.
  • arene refers to aromatic mono- or polycyclic carbonhydrides.
  • aromatic refers to a chemical substituent characterised by the following:
  • aryl refers to a substituent derived from an arene by removal of one —H from a C in the ring.
  • Examples of useful aryls to be used with the present invention comprise phenyl, napthyl, anthracenyl, phenanthrenyl, and pyrenyl.
  • halogen refers to a substituent selected from the group consisting of —F, —Cl, —Br and —I.
  • heteroalkenyl refers to an alkenyl group, of which one or more carbon has been replaced by a heteroatom selected from S, O and N.
  • heteroalkyl refers to a straight- or branched-chain alkyl group, of which one or more carbon has been replaced by a heteroatom selected from S, O and N.
  • exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, and alkyl sulfides.
  • heteroaryl refers to a substituent derived from an heteroarene by removal of one —H from an atom in the ring structure of said heteroarene.
  • Heteroarenes are mono- or polycyclic aromatic compounds comprising one or more heteroatoms in the ring structure. Said heteroatoms are preferably selected from the group consisting of S, N and O.
  • Non limiting examples of useful heteroaryls to be used with the present invention comprise azolyl, pyridinyl, pyrimidinyl, furanyl, and thiophenyl.
  • non-aromatic heterocycle refers to a mono- or polycyclic compound, which is not aromatic, and which comprises one or more heteroatom in the ring structure. Said heteroatoms are preferably selected from the group consisting of S, N and O. Examples of non-aromatic heterocycle includes but are not limited to pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine.
  • phosphinyl refers to a substituent of the general structure
  • phosphinyl may be —PH 3 .
  • K a also called the acidity constant, is defined as:
  • substituted refers to hydrogen group(s) being substituted with another moiety.
  • substituted with X refers to hydrogen group(s) being substituted with X.
  • substituted X refers to X, wherein one hydrogen group has been substituted with another moiety.
  • substituted alkyl refers to alkyl-R, wherein R is any moiety but —H.
  • substituted refers to an atom or group of atoms substituted in place of a hydrogen atom.
  • strongly electron withdrawing substituents refers to substituents with a Hammet meta substituent constant above 0.5, as described in Hanhsch 1991, and/or substituents having a double bond to oxygen of the linking atom.
  • thioalkyl refers to a substituent of the general formula —S-alkyl.
  • thioaryl refers to a substituent of the general formula —S-aryl.
  • transition metal catalyst refers to a compound capable of catalysing a chemical reaction, wherein said compound comprises a transition element or an ion of a transition element.
  • a transition element is an element whose atom has an incomplete d sub-shell, or which can give rise to cations with an incomplete d sub-shell.
  • the present invention provides methods for preparing arylated amines.
  • the methods of the present invention can be performed even in the absence of a transition metal catalyst.
  • the methods of the invention may comprise the steps of
  • step e) comprises the sub-steps of
  • nucleophile provided in a) comprises more than one —NH— and/or —NH 2 group
  • amino group mentioned in a) is the amine acting as nucleophile in reaction to obtain the arylated amine.
  • one advantage of the methods according to the present invention is that the methods can be performed in the absence of a transition metal catalyst.
  • step e. is performed in the absence of a transition metal catalyst.
  • the methods are performed in the absence of any transition metals, and in particular that step e. is performed in the absence of any transition metals.
  • the methods are performed in the absence of cupper, palladium and nickel, and in particular that step e. is performed in the absence of any cupper, palladium and nickel.
  • the reaction, and in particular step e. is preferably performed in the absence of cupper, palladium and nickel in any oxidation state and any form.
  • Reacting said nucleophile with said electrophile may be done at any useful temperature.
  • step e. may be performed at any useful temperature.
  • One advantage of the methods of the invention is that the methods generally can be performed at temperatures, which are easy to handle, even in large scare.
  • reacting said nucleophile with said electrophile may be performed at a temperature of at the most 120° C., such as at the most 110° C. Frequently even lower temperatures can be applied.
  • Reacting said nucleophile with said electrophile may be done for a time sufficient to allow the reaction.
  • step e. may be performed for sufficient time to allow the reaction.
  • One advantage of the methods of the invention is that generally a relative short time is required for the reactions.
  • said nucleophile may typically be allowed to react with said electrophile for at the most one week. Frequently, the reaction may be even faster, thus in some embodiments of the invention, said nucleophile may be allowed to react with said electrophile for at the most 900 min, such as for at the most 720 min, such as for the most 180 min, for example for in the range of 5 to 900 min or in the range of 5 to 720 min.
  • the methods of the invention involve reacting a nucleophile and an electrophile.
  • the nucleophile useful with the present invention must comprise an —NH— or and —NH 2 group.
  • said nucleophile comprises an —NH— or an —NH 2 group directly linked to only non-aromatic carbon atoms.
  • the nucleophile contains an —NH— group, which is covalently linked to two non-aromatic carbon atoms.
  • Said non-aromatic carbon atoms may for example be a carbon atom of an alkyl or of an alkyl substituted with one or more substituents. It follows that the nucleophile thus may be a secondary amine.
  • said nucleophile comprises an —NH 2 group, which is covalently linked to a non-aromatic carbon atom.
  • said nucleophile may be alkyl-NH 2 or alkyl-NH 2 , wherein said alkyl is substituted with one or more substituents. It follows that the nucleophile may be a primary amine.
  • the nucleophile may be a compound of the formula I:
  • R a and R b individually are selected from the group consisting of —H and alkyl, wherein said alkyl optionally may be substituted with aryl or substituted aryl with the proviso that only one of R a and R b may be —H; or R a and R b together forms a non-aromatic heterocycle, which optionally may comprise one or more heteroatoms, wherein said heterocycle optionally may be substituted.
  • R a may be selected from the group consisting of —H, C 1-50 -alkyl, C 1-10 -alkyl-aryl.
  • R a may be selected from the group consisting of —H, C 1-10 -alkyl and C 1-10 -alkyl-phenyl.
  • R a may be selected from the group consisting of —H, C 1-5 -alkyl and —CH 2 -phenyl.
  • R b may be selected from the group consisting of C 1-50 -alkyl, C 1-10 -alkyl-aryl.
  • R b may be selected from the group consisting of C 1-10 -alkyl and C 1-10 -alkyl-phenyl.
  • R b may be selected from the group consisting of C 1-5 -alkyl and —CH 2 -phenyl.
  • the nucleophile may also be a compound of formula I, wherein R a and R b together forms a non-aromatic heterocycle, which optionally may comprise one or more heteroatoms, and which may be substituted.
  • the nucleophile may be 4 to 10 membered non-aromatic heterocycle comprising at least one N atom.
  • the nucleophile may be a 4 to 10 membered non-aromatic heterocycle comprising 1 or 2 heteroatoms, wherein at least one is an N atom.
  • Said 4 to 10 membered non-aromatic heterocycle may for example be a monocyclic or a bicyclic non-aromatic heterocycle.
  • Said 4 to 10 membered non-aromatic heterocycle comprising at least one N atom may optionally be substituted with one or more substituents, e.g. with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl.
  • said 4 to 10 membered non-aromatic heterocycle may be substituted with one or more substituents selected from the group consisting of C 1-6 -alkyl and aryl.
  • said 4 to 10 membered non-aromatic heterocycle may be substituted with one substituent selected from the group consisting of phenyl and C 1-3 -alkyl, e.g. methyl.
  • the nucleophile may be a 4 to 8 membered non-aromatic heterocycle comprising at least one N atom.
  • the nucleophile may be a 4 to 8 membered non-aromatic heterocycle comprising only 1 heteroatom, wherein said heteroatom is an N atom.
  • the term “comprising only 1 heteroatom” as used herein refers to that the ring of said heterocycle consists of carbon atoms and said one heteroatom. Said carbon atoms may optionally be substituted.
  • said 4 to 8 membered non-aromatic heterocycle comprising at least one N atom may optionally be substituted with one or more substituents, e.g.
  • said 4 to 8 membered non-aromatic heterocycle may be substituted with one or more substituents selected from the group consisting of C 1-6 -alkyl and aryl.
  • said 4 to 8 membered non-aromatic heterocycle may be substituted with one substituent selected from the group consisting of phenyl and C 1-3 -alkyl, e.g. methyl.
  • Said non-aromatic heterocycle may for example be selected from the group consisting of piperazine, morpholine, tetrahydroisoquinoline, dioxa-azaspiro-decane, piperidine, and thiomorpholine.
  • X is NR c , NH, O or S.
  • R c may for example be aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, 3 to 8 membered cycloalkyl or 3-8 membered nonaromatic heterocycle.
  • R c may be selected from the group consisting of aryl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl and 3-8 membered nonaromatic heterocycle.
  • R c may be selected from the group consisting of phenyl, and C 1-10 -alkyl.
  • the nucleophile is selected from the group consisting of: pyrrolidine, N-methylpiperazine, 1-methylpiperazine, 1,4-dioxa-8-azaspiro[4.5]decane, piperidine, piperazine, morpholine, thiomorpholine, 1-phenylpiperazine, N-ethylbutan-1-amine, 1,2,3,4-tetrahydroisoquinoline, dibenzylamine, N-methyl-benzylamine and benzylamine.
  • nucleophile is selected from the group consisting of N-methylpiperazine, piperazine, morpholine and 1,2,3,4-tetrahydroisoquinoline. In one preferred embodiment the nucleophile is selected from the group consisting of N-methylpiperazine, piperazine and morpholine.
  • the nucleophile may also be salts of any of the aforementioned nucleophiles.
  • the nucleophile may be a salt of any of the aforementioned nucleophiles with various inorganic or organic acids.
  • said salt may be a pharmaceutically acceptable salt.
  • the methods of the invention involve reacting a nucleophile and an electrophile.
  • the electrophile useful with the present invention comprises or consists of an aryl substituted with at least one halogen and optionally further substituents.
  • the electrophile is aryl substituted with at least two substituents, wherein the first substituent is halogen and the second substituent is selected from the group of substituents consisting of halogen, aryl, substituted aryl, alkenyl, substituted alkenyl, heteroalkenyl, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, amino, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, heteroaryl, and phosphinyl, with the proviso that said aryl is substituted with at the most 4 halogens.
  • said aryl may be substituted with one or more additional substituents
  • the second substituent may also be selected from the group of substituents consisting of halogen, aryl, substituted aryl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, heteroaryl, and phosphinyl, with the proviso that said aryl is substituted with at the most 4 halogens.
  • the aryl may be any aryl, for example the aryl may be selected from the group consisting phenyl and naphtalenyl. In preferred embodiments of the invention the aryl is phenyl.
  • the electrophile may be aryl (e.g. phenyl) substituted with halogen (e.g. —F) and a 2 nd substituent.
  • the electrophile may be aryl (e.g. phenyl) substituted with halogen (e.g. —F) and a 2 nd and a 3 rd substituent.
  • the electrophile may be aryl (e.g. phenyl) substituted with halogen (e.g.
  • the electrophile may be aryl (e.g. phenyl) substituted with halogen (e.g. —F) and a 2 nd , a 3 rd , a 4 th and a 5 th substituent.
  • the electrophile may be aryl (e.g. phenyl) substituted with halogen (e.g. —F) and a 2 nd , a 3 rd , a 4 th , a 5 th , and a 6 th substituent.
  • Said 2 nd , 3 rd , 4 th , 5 th and 6 th substituent may for example be any of the substituents described herein below in this section.
  • the electrophile may be a chloro- or fluorobenzene derivative without strongly electron withdrawing substituents.
  • the electrophile may also be a weakly or non-electron deficient chloro- or fluorobenzene derivative.
  • the electrophile may also be phenyl substituted with only 2 halogens and optionally a 3 rd , 4 th , 5 th and/or 6 th substituent.
  • the phenyl is covalently linked to exactly two halogens.
  • Said halogen may in particular be —F.
  • said phenyl may be substituted with a 3 rd , 4 th , 5 th and/or 6 th substituent, which is not halogen.
  • the 3 rd , 4 th , 5 th and/or 6 th substituent may be any of the substituents described herein below in this section.
  • the electrophile may also be phenyl substituted with only 1 —F and optionally a 2 nd , 3 rd , 4 th , 5 th and/or 6 th substituent.
  • the phenyl is covalently linked to exactly one —F.
  • said phenyl may be substituted with a 2 nd , 3 rd , 4 th , 5 th and/or 6 th substituent, which is not —F, and preferably not halogen.
  • the 2 nd , 3 rd , 4 th , 5 th and/or 6 th substituent may be any of the substituents described herein below in this section.
  • Said 2 nd , 3 rd , 4 th , 5 th and 6 th substituent may be individually selected from the group of consisting of aryl,
  • R d , R e , R f , R g , R h , R i , R j , R k and R l individually are selected from the group consisting of —H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl.
  • the waved line indicates the point of attachment of the substituent.
  • Said 2 nd , 3 rd , 4 th , 5 th and 6 th substituent may be individually selected from the group consisting of
  • R d , R e , R f , R g , R h , R i and R j individually are selected from the group consisting of —H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl.
  • the waved line indicates the point of attachment of the substituent.
  • Said 2 nd , 3 rd , 4 th , 5 th and 6 th substituent may be individually selected from the group consisting of R g O—,
  • R g , R h , R i and R j individually are selected from the group consisting of —H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl.
  • the waved line indicates the point of attachment of the substituent.
  • Said 2 nd , 3 rd , 4 th , 5 th and 6 th substituent may be individually selected from the group consisting of Cl—, F—, and R j S—,
  • R j is selected from the group consisting of —H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl.
  • electrophile is aryl (e.g. phenyl) substituted with 2 to 4 substituents, wherein all of said substituents are halogen.
  • the first substituent may be halogen.
  • said halogen is selected from the group consisting of —F, —Cl and —Br, more said first substituent is selected from the group consisting of —F and —Cl, for example the first substituent is —F.
  • said halogen may be any halogen, preferably said halogen is selected from the group consisting of —F, —Cl and —Br, more preferably said halogen is selected from the group consisting of —F and —Cl.
  • the electrophile is aryl (e.g. phenyl) substituted with one or more substituents, where all of said substituents are selected from the group consisting of —F and —Cl.
  • said aryl may be selected from the group consisting of phenyl, napthyl, indenyl, and fluorenyl, in particular said aryl may be phenyl.
  • said substituted aryl may be selected from the group consisting of phenyl, napthyl, indenyl, and fluorenyl substituted with one or more selected from the group consisting of —OH, aryl, C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl, in particular said substituted aryl may be phenyl substituted with one or more selected from the group consisting of phenyl, —OH, C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl.
  • said heteroaryl may individually for example be selected from the group consisting of tetrazolyl, imidazolyl, anthracenyl, phenanthrenyl, fluorenyl, pentalenyl, azulenyl, biphenylenyl, furanyl, triazolyl, pyranyl, thiadiazinyl, benzothiophenyl, dihydro-benzo[b]thiophenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, benzisoxazolyl, quinolinyl, isoquinolinyl, phteridinyl, azepinyl, diazepinyl, imidazolyl,
  • said substituted heteroaryl may individually for example be any of the aforementioned heteroaryl substituted with one or more selected from the group consisting of —OH, aryl, C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl, in particular substituted with one or more selected from the group consisting of phenyl, —OH, C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl.
  • alkyl may individually for example be C 1-10 -alkyl, such as C 1-6 -alkyl, for example C 1-3 -alkyl.
  • alkyl may individually for example be C 1-10 -alkyl, C 1-6 -alkyl or C 1-3 -alkyl.
  • alkyl may for example be C 1-10 -alkyl, such as C 1-6 -alkyl, for example C 1-3 -alkyl, substituted with one or more selected from the group consisting of —OH and aryl, in particular substituted with one or more selected from the group consisting of phenyl and —OH.
  • alkenyl may individually for example be C 2-10 -alkenyl, C 2-6 -alkenyl or C 2-3 -alkenyl.
  • alkenyl may for example be C 2-10 -alkenyl, such as C 2-6 -alkenyl, for example C 2-3 -alkenyl, substituted with one or more selected from the group consisting of —OH and aryl, in particular substituted with one or more selected from the group consisting of phenyl and —OH.
  • alkynyl may individually for example be C 2-10 -alkynyl, C 2-6 -alkynyl or C 2-3 -alkynyl.
  • alkynyl may for example be C 2-10 -alkynyl, such as C 2-6 -alkynyl, for example C 2-3 -alkynyl, substituted with one or more selected from the group consisting of —OH and aryl, in particular substituted with one or more selected from the group consisting of phenyl and —OH.
  • said 2 nd , 3 rd , 4 th , 5 th and 6 th substituent may be individually selected from the group of consisting of —NH-alkenyl, —S-alkenyl, —O-alkenyl, —NH—(CH) n —NH, —O—(CH) n —NH, —S—(CH) n —NH, —NH—N—(CH) n —CH 2 , —NH—N ⁇ NH, —NH—(CH 2 ) n —CH 3 , —(CH 2 ) n —NH—(CH 2 ) m —CH 3 , wherein n and m are individually 0 or an integer.
  • one substituent may be fused directly with the arene. In other embodiments, the substituent is not fused with the arene.
  • Two of said 2 nd , 3 rd , 4 th , 5 th and 6 th substituents may be fused and thereby forming a ring.
  • such fused substituents form a ring selected from the group consisting of pyrrole, furan, thiophene, pyrazole, oxazole, thiazole, imidazole, 1,2,3-triazole, 3,4-dihydro-pyrrole, and 2,3-dihydro-pyrrole rings.
  • the electrophile is an indole substituted with at least one halogen on the arene.
  • the electrophile is a benzofuran substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is a benzothiophene substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is an indazole substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is a benzoxazole substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is a benzothiazole substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is a benzimidazole substituted with at least one halogen on the arene.
  • the electrophile is a benzotriazole substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is an isoindoline substituted with at least one halogen on the arene. In yet another embodiment, the electrophile is an indoline substituted with at least one halogen on the arene.
  • the electrophile is selected from the group consisting of indole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, indazole, benzotriazole, isoindoline and indoline (shown below), substituted with at least one halogen on the benzene moiety and optionally further substituents.
  • a secondary amine is present in the ring fused with the aryl, said secondary amine is preferably first transformed into a tertiary amine, such as being alkylated, alkenylated or arylated.
  • the electrophile may for example be selected from the group consisting of the following compounds, wherein said compounds are substituted with at least one halogen on the benzene moiety and optionally further substituents:
  • R p is selected from the group consisting of hydrogen, alkyl, alkenyl, carbamate, sulfone, benzyl, acetyl, benzoyl, carbobenzyloxy, p-methoxybenzyl carbonyl, tert-butyloxycarbonyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, tosyl, and trichloroethyl chloroformate.
  • R p is not hydrogen.
  • none of the said 2 nd , 3 rd , 4 th , 5 th and 6 th substituents are fused with each other.
  • the electrophile is phenyl substituted with first substituent selected from the group consisting of —F and —Cl, and with a 2 nd substituent selected from the group consisting of —F, —Cl, C 1-3 -alkoxy, C 1-3 -alkyl, thioaryl and phenyl, wherein said thioaryl may be substituted with up to 3 C 1-3 -alkyl.
  • the electrophile is phenyl substituted with first substituent selected from the group consisting of —F, —Cl, C 1-3 -alkoxy, C 1-3 -alkyl, thioaryl and phenyl, wherein said thioaryl may be substituted with up to 3 C 1-3 -alkyl.
  • the electrophile is selected from the group consisting of tetra-fluorobenzene, trifluorobenzene, difluorobenzene, fluoro-chlorobenzene, dichloro-fluorobenzene, trichlorobenzene, dichlorobenzene, chloro-difluorobenzene, methyl-difluorobenzene, methyl-chloro-fluorobenzene, methoxy-fluorobenzene, di-methyl-thiophenol-fluorobenzene, fluoro-1,1′-biphenyl, N-benzyl-3,5-difluoro-N-methylaniline and bi-phenyl.
  • the electrophile is selected from 2,3-dichloro-fluorobenzene, 1,2,3-trichlorobenzene, 2-(4,2-di-methyl-thiophenol-yl)-fluorobenzene, and 2-(4,2-di-methyl-thiophenol-yl)-chlorobenzene.
  • the electrophile may be a product of an organic synthesis and may thus be considered an intermediate.
  • the electrophile may be a product of a cross coupling reaction.
  • the methods of the present invention involve reacting a nucleophile and an electrophile in the presence of a base.
  • a base is a base, wherein the corresponding acid has a pKa above 29, such as at least 30 in DMSO. It may also be preferred that said base has a pKa above 25, preferably at least 26 in THF.
  • the base is not a weak base, for example the base is preferably not Cs 2 CO 3 .
  • the base may be a base, wherein the corresponding acid has a pKa above 32 in DMSO. In some embodiments the base may be a base, wherein the corresponding acid has a pKa above 26 in THF.
  • the base is not too strong.
  • the base is a base, wherein the corresponding acid has a pKa in the range of 29 to 49, such as in the range of 29 to 45.
  • the base is a base, wherein the corresponding acid has a pKa in the range of 32 to 49, such as in the range of 32 to 45.
  • Aforementioned pKa is preferably determined in DMSO.
  • pKa may be determined by any conventional method. pKa values in DMSO is preferably measured up to the value of 35, and values above 35 may be extrapolated as described in Bordwell, Acc. Chem. Res. 1988, 21, 456-463.
  • the corresponding acid to butyllithium (BuLi) has a pKa 50, and may thus in some embodiments be less preferable.
  • the base is a base, wherein the corresponding acid has a pKa above 29, for example above 32, with the proviso that the base is not BuLi.
  • the base is a metal hydride, such as an alkali metal hydride.
  • the base is selected from the group consisting of lithium hydride, sodium hydride, potassium hydride, cesium hydride, magnesium hydride, calcium hydride, lithium aluminium hydride, sodium aluminium hydride, potassium aluminium hydride, lithium borohydride, sodium borohydride and potassium borohydride.
  • the base is selected from the group consisting of lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium 2,2,6,6,-tertmethylpiperidide (LiTMP), and BuLi.
  • LiHMDS lithium bis(trimethylsilyl)amide
  • NaHMDS sodium bis(trimethylsilyl)amide
  • KHMDS potassium bis(trimethylsilyl)amide
  • LiTMP lithium 2,2,6,6,-tertmethylpiperidide
  • BuLi BuLi.
  • the base is a non-nucleophilic base, i.e. a base only acting as a nucleophile in the removal of protons.
  • Typical non-nucleophilic bases are sterically hindered and bulky, preventing them from attacking as nucleophiles. Hence, protons can attach to the basic center of the base but alkylation and complexation is inhibited.
  • non-nucleophilic bases are lithium diisopropylamide (LDA), LiTMP and silicon-based amides such as LiHMDS, NaHMDS and KHMDS.
  • non-nucleophilic bases are sterically hindered and bulky, and thus the base may be a base having a M w of at least 120 g/mol, preferably of at least 130 g/mol, such as of at least 140 g/mol. More preferably the base has aforementioned Mw and aforementioned pKa. Thus, it may be preferred that the base has:
  • the base is selected from the group consisting of LiHMDS, NaHMDS, KHMDS and LiTMP.
  • the methods of the present invention involve reacting a nucleophile and an electrophile in a solvent and in the presence of a base.
  • the solvent may be any organic solvent.
  • the solvent may be chosen according to the base used in the particular reaction.
  • the solvent may be an organic solvent, which is stable in the presence the base employed under the reaction conditions employed.
  • the solvent is a liquid at the reaction temperature.
  • the solvent is a solvent that only contain protons with a pKa above 35.1 in DMSO.
  • the solvent is a solvent that only contains protons with a pKa above 32 in DMSO.
  • the solvent is not DMSO.
  • the solvent may be a solvent that only contains protons with a pKa above 32 in DMSO, with the proviso that the solvent is not DMSO.
  • the solvent is a solvent that does not contain any carbonyl groups. In one embodiment the solvent is a solvent that does not contain any sulfoxide groups.
  • the solvent may for example be selected from the group consisting of ethers, alkanes, benzene and substituted benzene.
  • Ethers useful as solvent include any ether.
  • the ether may be an ether, which only contain protons with a pKa above 32, for example above 35.1 in DMSO. It may further be preferred that the ether is a liquid at the reaction temperature. It may further be preferred that the ether does not contain any carbonyl groups.
  • the ether may for example be selected from the group consisting of tetrahydrofuran (THF), dioxane, dimethoxyethane (DME), 2-methyl-tetrahydrofuran (2-Me-THF), and diethoxyethane.
  • Alkanes useful as solvent include any alkane.
  • the alkane may be an alkane, which only contain protons with a pKa above 32, for example above 35.1 in DMSO. It may further be preferred that the alkane is a liquid at the reaction temperature. It may further be preferred that the alkane does not contain any carbonyl groups.
  • the alkane may be a linear, branched or cyclic alkane, e.g. a C 4-20 linear, branched or cyclic alkane.
  • the alkane may be methylcyclohexane.
  • Substituted benzenes useful as solvent include any substituted benzene.
  • the substituted benzene may be a substituted benzene, which only contain protons with a pKa above 32, for example above 35.1 in DMSO. It may further be preferred that the substituted benzene is a liquid at the reaction temperature. It may further be preferred that the substituted benzene does not contain any carbonyl group.
  • the substituted benzene is in general different from the electrophile used in the reaction. However in some embodiments, the electrophile may also be used as solvent.
  • the substituted benzene may be substituted with one or more substituents selected from the group consisting of C 1-3 -alkyl.
  • the benzene may be substituted with up to 1 —Cl.
  • the substituted benzene may for example be selected from the group consisting of toluene, xylene and chlorobenzene.
  • the arylated amine to be prepared by the methods according to the invention may be any of the electrophiles described herein above, wherein in place of the first substituent, the aryl of the electrophile is covalently N-linked to one of the nucleophiles described herein above.
  • the arylated amine is selected from the group of compounds shown in FIG. 2 as compounds 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3l and 3m.
  • the arylated amine is selected from the group of compounds shown in FIG. 3 as compounds 3n, 3o, 3p, 3q, 3r, 3s, 3t, 3u, 3v, 3w, 3x, 3y, 3z, 3aa, 3ab, 3ac, 3ad, 3ae, 3af and 3ag.
  • the arylated amine is selected from the group of compounds shown in FIG. 1 .
  • the arylated amine may be used in further organic synthesis, and thus in some embodiments the arylated amine may be an intermediate. Thus, the arylated amine may be a substrate for further functionalization e.g. through cross coupling reactions. In other embodiments the arylated amine may be a final product.
  • the arylated amine may be purified by any conventional method including for example extraction, precipitation, crystallisation, distillation and/or chromatography.
  • N-arylation of compound 1a N-methylpiperazine
  • compound 2 (1,3,5-trifluorobenzene
  • 1a 0.2 mmol
  • base 0.5 mmol
  • solvent 0.5 mL
  • the reaction was successfully performed using LiOtBu as base, but it was significantly less efficient than using some of the other bases.
  • Morpholine 1 b (1.0 mmol), LiHMDS (1.0M in THF, 1.5 mL) and fluorobenzene derivative (1.5 mmol) was mixed and heated. Details regarding the individual reactions are given below.
  • the structure of the compounds is provided in FIG. 2 .
  • the methods are useful for arylation of a range of secondary amines as seen in FIG. 3 .
  • Both cyclic and acyclic secondary amines can be functionalized as illustrated by formation of products 3n-3ag in high yields. Thus, most of these compounds were obtained with a 75-80% yield.
  • pyrazine and 1-methylpyrazine can be employed as nucleophiles and the resultant products 3q and 3r isolated in 62 and 72% yield, respectively.
  • both mono- and diarylated pyrazines are common substructures in pharmaceutical substances. Interestingly, by simply increasing the amount of base and electrophile, the reaction switched from mono- to bis-substitution on pyrazine to afford 3r or 3s respectively.
  • the structure or the compounds is provided in FIG. 3 .
  • N-benzyl-3,5-difluoro-N-methylaniline (3o) (0.5 mmol), morpholine (1.0 mmol) and LiHMDS (1.0M in THF, 1.0 mmol) were mixed and heated. After 24 hours at 100° C. the compound 4 was isolated in 62% yield as a bright yellow oil.
  • a two steps reaction applying first a weaker nucleophile followed by an amine nucleophile also proved viable (scheme 2).
  • Applying imidazole as the weak azole nucleophile followed by addition of morpholine provided derivative 7, which is a substructure in metabotropic glutamate 5 receptor antagonists with nanomolar activity.
  • Thiophenol also proved highly applicable in this approach, illustrated by the synthesis of recently marketed pharmaceutical antidepressant Vortioxetine 9 from 1,2-difluorobenzene. This should be compared to the present industrial production process, which utilizes two subsequent cross-coupling reactions on 2-bromo-iodobenzene.
  • Morpholine 0.5 mmol
  • 1-(3,5-difluorophenyl)-1H-imidazole (6) 0.6 mmol
  • LiHMDS 1.0M in THF, 1.2 mmol
  • the invention provides a novel method for the amination of unactivated fluorobenzene derivatives.
  • a key factor for reactivity is the applied base's ability to sufficiently deprotonate the amine nucleophile under the applied reaction conditions without simultaneously degrading the fluorobenzene electrophile.
  • the reactions proceed readily by addition of a simple base such as LiHMDS, and thus circumvent the need for transition metals.
  • the reactions proceed with great regio- and chemoselectivity and are compatible with a broad range of additional substituents including alkyl, aryl, alkoxy, amine, azolyl, thioethers, fluorine and chlorine.
  • the versatility of these new reactions was illustrated by the synthesis of a variety of anilines including the antidepressant Vortioxetine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US16/076,380 2016-02-08 2017-02-06 Arylation of aliphatic amines Abandoned US20190040028A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DKPA201670066 2016-02-08
DKPA201670066 2016-02-08
PCT/DK2017/050025 WO2017137047A1 (en) 2016-02-08 2017-02-06 Arylation of aliphatic amines

Publications (1)

Publication Number Publication Date
US20190040028A1 true US20190040028A1 (en) 2019-02-07

Family

ID=58108382

Family Applications (2)

Application Number Title Priority Date Filing Date
US16/076,380 Abandoned US20190040028A1 (en) 2016-02-08 2017-02-06 Arylation of aliphatic amines
US16/072,596 Active US10562872B2 (en) 2016-02-08 2017-02-06 Synthesis of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine

Family Applications After (1)

Application Number Title Priority Date Filing Date
US16/072,596 Active US10562872B2 (en) 2016-02-08 2017-02-06 Synthesis of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine

Country Status (8)

Country Link
US (2) US20190040028A1 (es)
EP (2) EP3414231B1 (es)
JP (1) JP6987064B2 (es)
CN (2) CN109071374A (es)
BR (1) BR112017021277A2 (es)
DK (1) DK3414216T3 (es)
ES (1) ES2819831T3 (es)
WO (2) WO2017137047A1 (es)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10519121B2 (en) 2016-12-30 2019-12-31 Apicore Us Llc Process and novel polymorphic form of vortioxetine and its pharmaceutically acceptable salts
CN109608394A (zh) * 2018-12-03 2019-04-12 湖南大学 氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物
CN113943265A (zh) * 2020-07-15 2022-01-18 北京万全阳光医学技术有限公司 一种制备沃替西汀的方法
CN117164478B (zh) * 2023-08-04 2025-07-01 苏州大学 一种制备蒽环衍生物的方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4780667A (en) 1985-06-25 1988-10-25 Hewlett-Packard Company Magnetostatic wave delay line discriminator with automatic quadrature setting and automatic calibration
FR2694194B1 (fr) 1992-07-31 1994-11-04 Health Business Dev Gel hydratant, médicament et composition cosmétique le contenant, procédé de préparation dudit gel.
WO2010121621A1 (en) 2009-04-24 2010-10-28 H. Lundbeck A/S Liquid formulations of salts of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine
SMT201700238T1 (it) * 2013-02-22 2017-07-18 H Lundbeck As Procedimento per la produzione di vortioxetina
EP2970145B1 (en) * 2013-03-11 2020-05-06 The Broad Institute, Inc. Compounds and compositions for the treatment of cancer
CN105339361A (zh) 2013-05-31 2016-02-17 斯洛文尼亚莱柯制药股份有限公司 用于合成1-(2-((2，4-二甲基苯基)硫代)苯基)哌嗪的新方法
EP2930171A1 (en) 2014-04-07 2015-10-14 LEK Pharmaceuticals d.d. Synthesis of vortioxetine via (2,4-dimethylphenyl)(2-iodophenyl)sulfane intermediate

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors
US11034705B2 (en) 2018-09-18 2021-06-15 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US11459340B2 (en) 2018-09-18 2022-10-04 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as Src homology-2 phosphatase inhibitors
US11518772B2 (en) 2018-09-18 2022-12-06 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US12264167B2 (en) 2018-09-18 2025-04-01 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphate inhibitors

Also Published As

Publication number Publication date
WO2017137047A1 (en) 2017-08-17
BR112017021277A2 (pt) 2018-06-26
US10562872B2 (en) 2020-02-18
ES2819831T3 (es) 2021-04-19
EP3414231A1 (en) 2018-12-19
EP3414231B1 (en) 2020-08-19
JP6987064B2 (ja) 2021-12-22
EP3414216A1 (en) 2018-12-19
CN108473451B (zh) 2022-07-15
EP3414216B1 (en) 2020-10-21
CN109071374A (zh) 2018-12-21
JP2019506411A (ja) 2019-03-07
WO2017137048A1 (en) 2017-08-17
CN108473451A (zh) 2018-08-31
DK3414216T3 (da) 2021-01-25
US20190040027A1 (en) 2019-02-07

Similar Documents

Publication Publication Date Title
US20190040028A1 (en) Arylation of aliphatic amines
Timsina et al. Palladium-catalyzed C–H amination of C (sp2) and C (sp3)–H bonds: mechanism and scope for N-based molecule synthesis
Blastik et al. Azidoperfluoroalkanes: synthesis and application in copper (I)‐catalyzed azide–alkyne cycloaddition
Morrill et al. Catalytic asymmetric α-amination of carboxylic acids using isothioureas
Guerra et al. “Transition-metal-free” synthesis of carbazoles by photostimulated reactions of 2′-halo [1, 1′-biphenyl]-2-amines
Yin et al. Solvent-free copper-catalyzed N-arylation of amino alcohols and diamines with aryl halides
KR20200136493A (ko) 7-시클로펜틸-2-(5-피페라진-1-일-피리딘-2-일아미노)-7ｈ-피롤로[2,3-ｄ]피리미딘-6-카르복실산 디메틸아미드의 염(들) 및 그의 제조 방법
Kafle et al. A one-pot, copper-catalyzed azidation/click reaction of aryl and heteroaryl bromides in an environmentally friendly deep eutectic solvent
Patel et al. Design, synthesis and antitubercular evaluation of novel series of N-[4-(piperazin-1-yl) phenyl] cinnamamide derivatives
KR20150118146A (ko) 보르티옥세틴 제조 방법
FI85267C (fi) Foerfarande foer framstaellning av nya terapeutiskt anvaendbara 1,4-disubstituerade piperazinderivat.
RU2193554C2 (ru) Производные ароматических аминов, обладающих подавляющим оас действием, способ их получения и ингибитор ноас
JPS5850984B2 (ja) チカンジフエニルエ−テルルイ
Kwak et al. N-Aminopyridinium Ylide-Directed, Copper-Promoted Amination of sp2 C–H Bonds
WO2015079018A1 (en) Synthesis of vortioxetine via (2-(piperazine-1 -yl)phenvl)lithium intermediates
Zhou et al. The construction of C–N, C–O, and C (sp2)–C (sp3) bonds from fluorine-substituted 2-aryl benzazoles for direct synthesis of N-, O-, C-functionalized 2-aryl benzazole derivatives
Weiss et al. Cyclopropeniumyldiazonium systems: first generation of a C-sp-attached diazonium function
IE44316B1 (en) Indazole derivatives
Sakata et al. Synthesis of Azidoanilines by the Buchwald–Hartwig Amination
CN109824548A (zh) 一种n-酰基化合物的简易制备方法
CN107879965A (zh) 一种铑/碳作为催化剂制备吲哚类化合物的方法
HK40000670A (en) Synthesis of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine
HK40000670B (en) Synthesis of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine
WO2018213572A9 (en) Preparation of secondary amines with electrophilic n-linchpin reagents
CN115710210A (zh) 铁催化的c-h键胺化的方法

Legal Events

Date Code Title Description
AS Assignment

Owner name: AAA CHEMISTRY APS, DENMARK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DINESS, FREDERIK;MELDAL, MORTEN;JACOBSEN, CHRISTIAN BORCH;SIGNING DATES FROM 20180813 TO 20180828;REEL/FRAME:046895/0129

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION