HUE025022T2 - Új eljárások propán-1-szulfonsav-{3-[5-(4-klór-fenil)-1H-pirrolo[2,3-B]piridin-3-karbonil]-2,4-difluorfenil}-amid elõállítására - Google Patents

Új eljárások propán-1-szulfonsav-{3-[5-(4-klór-fenil)-1H-pirrolo[2,3-B]piridin-3-karbonil]-2,4-difluorfenil}-amid elõállítására Download PDF

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HUE025022T2
HUE025022T2 HUE11735858A HUE11735858A HUE025022T2 HU E025022 T2 HUE025022 T2 HU E025022T2 HU E11735858 A HUE11735858 A HU E11735858A HU E11735858 A HUE11735858 A HU E11735858A HU E025022 T2 HUE025022 T2 HU E025022T2
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compound
reaction
reacted
phenyl
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Corey James Brumsted
Hendrik Moorlag
Roumen Nikolaev Radinov
Yi Ren
Pius Waldmeier
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Hoffmann La Roche
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
    • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
    • B01J23/44—Palladium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)

Description

• KUMAR V ET AL: "SYNTHESIS OF 7-AZAINDOLE AND 7-AZAOXINDOLE DERIVATIVES THROUGH A PALLADIUM-CATALYZED CROSS-COUPLING REACTION", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, EASTON.; US, vol. 57, no. 25, 4 December 1992 (1992-12-04), pages 6995-6998, XP000578238, ISSN: 0022-3263, DÓI: 10.1021/J000051A062
Description [0001] The present invention is related to alternative synthesis routes to obtain the compound Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (formula 1).
Formula 1
[0002] The synthesis of the compound of formula 1 has been described before in WO 2007002433 and WO 2007002325.
[0003] The present invention discloses alternative reactions to obtain compound 1. The reactions and processes disclosed herein use few reaction steps, and lead to good overall yield of compound 1, inter alia due to few separation steps and work-up procedures. Moreover, the processes disclosed herein can be carried out with relatively small amounts of starting material and may therefore be safer for use in large scale production, interesting from a cost perspective and environmentally friendly.
[0004] In addition, the present invention provides novel synthesis methods to obtain key intermediates used in the manufacture of the compound of formula 1, such as pinacol vinylboronates.
Detailed Description of the Invention [0005] Disclosed herein is a process for the manufacture of the compound of formula 1,
(1). comprising at least one Suzuki-Miyaura reaction followed by a Friedel-Crafts acylation.
[0006] In one embodiment, the present invention provides a process for the manufacture of the compound of formula 1, wherein a) the compound of formula 2
(2) is reacted in the presence of a palladium catalyst, a base and the compound of formula 3 (1st Suzuki-Miyaura reaction)
(3), to give the compound of formula 4
(4) ; b) said compound of formula 4 is further reacted in the presence of a halogénation reagent to give a compound of formula 5
(5) , wherein X is I (5a) or Br (5b); and said compound of formula 5 is further reacted in the presence of either c-1) a compound of formula (D) (2nd Miyaura reaction); or c-2) a compound of formula 7 (Sonogashira reaction)
(D) or
(7); to give the compound of formula 8
(8); and d) said compound of formula 8 is subsequently reacted in the presence of the compound of formula 9 and under the conditions of a Friedel-Crafts Acylation
(9). to give the compound of formula 1, wherein R1, R2, R3 and R4 are all methyl, or together with the carbon atoms to which they are attached form a phenyl ring; and R5 is -(C1-C6)alkyl or benzyl.
[0007] In another preferred embodiment there is provided the above described process wherein R1 to R4are all methyl; and R5 is ethyl.
[0008] In still another embodiment according to the present invention there is provided the above described process a) to d) for the manufacture of the compound of formula 1, wherein steps a) and b) are as described above; and
c-1) said compound of formula 5 according to step b) is further reacted in the presence of a palladium catalyst and a base, which can both be the same or different as under step a), and the compound of formula D
(D), followed by treatment with an acid to give the compound of formula 8
(8); and d) said compound of formula 8 is further reacted with the compound of formula 9
(9).
[0009] In the presence of (COCI)2 and AICI3, to give the compound of formula 1, and R1 to R5 are as defined above.
[0010] In still another preferred embodiment according to the present invention there is provided the process for the manufacture of the compound of formula 1 according to steps a) to d) above, wherein a) the compound of formula 2
(2) is reacted in the presence of PdCI2(dppf)CH2Cl2, Pd(OAc)2, Na2COs and the compound of formula 3
(3), to give the compound of formula 4
(4) ; b) said compound of formula 4 is further reacted in the presence of N-iodosuccinimide (NIS) and CF3COOH, or N-bromosuccinimide (NBS) to give a compound of formula 5
(5) , wherein X is -I (5a) or -Br (5b); c-1) said compound of formula 5 is further reacted in the presence of PdCI2(dppf)CH2CI2, LiOH and the compound of formula 6,
(6), and subsequently treated with HCI to give the compound of formula 8
(8); and d) said compound of formula 8 is further reacted with the compound of formula 9
(% [0011] In the presence of (COCI)2 and AICI3, to give the compound of formula 1.
[0012] In an especially preferred embodiment according to the present invention, the reaction step b) prior to the reaction step c-1) as mentioned above is carried out in the presence of NBS to give the compound of formula 5, wherein X is bromo (5b).
[0013] In yet another embodiment according to the present invention there is provided a process for the manufacture of the compound of formula 1, wherein reaction steps a) and b) are as described herein before; and c-2) the compound of formula 5 from reaction step b) is further reacted in the presence of a palladium catalyst and a base, which may both be the same or different as in step a), Cul, tetramethylguanidine (TMG) and the compound of formula 7,
(7), followed by the reaction with a strong base, to give the compound of formula 8
(8); and d) said compound of formula 8 is further reacted with the compound of formula 9
(9).
[0014] In the presence of (COCI)2 and AICI3, to give the compound of formula 1.
[0015] In a still preferred embodiment according to the present invention, there is provided the process for the manufacture of the compound of formula 1 according to steps a) to d) above, wherein a) the compound of formula 2
(2) is reacted in the presence of PdCI2(dppf)CH2Cl2, Pd(OAc)2, Na2C03 and the compound of formula 3
(3), to give the compound of formula 4
(4); b) said compound of formula 4 is further reacted in the presence of N-iodosuccinimide (NIS) and CF3COOH, or N-bromosuccinimide (NBS) to give a compound of formula 5
(5), wherein X is -I (5a) or -Br (5b); c-2) said compound of formula 5 is further reacted in the presence of PdiPPI^C^, Cul, tetramethylguanidine (TMG) and the compound of formula 7,
(7), followed by the reaction with KOtBu in NMP, to give the compound of formula 8
(8); and d) said compound of formula 8 is further reacted with the compound of formula 9
(9), [0016] In the presence of (COCI)2 and AICI3, to give the compound of formula 1.
[0017] In still another preferred embodiment there is provided the process as described above, wherein the reaction step b) prior to the reaction step c-2) is carried out in the presence of NBS to give the compound of formula 5, wherein X is bromo (5b).
General synthesis route [0018] The reaction partners and conditions of the above-mentioned Suzuki-Miyaura-, Sonogashira-and Friedel Crafts reactions are generally known to the person of skill in the art of synthetic organic chemistry and are inter alia described or referred to in common textbooks of Organic Chemistry. If not explicitly otherwise stated, the above described preferred reaction conditions to obtain the compound of formula 1 can be summarized, but not limited, according to the following general reaction scheme 1. The key reaction step according to the present invention, namely the reactions from compound 5 to 8, can be accomplished either via the reaction with a compound D, preferably the compound 6 (Suzuki-Miyaura Route) or via the reaction with compound 7 (Sonogashira Route):
scheme 1 [0019] In accordance with the present invention, the reaction partner of the first Suzuki-Miyaura reaction is 4-chlo-rophenylboronicacid (3). The reaction partner of the second Suzuki-Miyaura reaction is a vinyl ether boronate of formula (D), such as catechol vinylboronate or pinacol vinylboronate (1-ethoxyethene-2-boronic acid pinacol ester, 6), with the pinacol vinylboronate being especially preferred. If not explicitly otherwise stated the compounds (D) or (6) are present as mixtures of their E/Z isomers.
The reaction is carried out in the presence of palladium (Pd) catalysts, more preferably, PdCl2(dppf)CH2CI2, Pd(OAc)2 and the like. In addition, both Suzuki-Miyaura reactions take place under basic conditions (pH-valuesabove7) inorganic solvents or mixtures of organic solvents with water. Preferred bases according to the present invention are organic bases or alkali metal bases, more particularly N(CH2CH3)3, Na2COs, LiOH and the like. Preferred organic solvents are toluene, dimethylformamide (DMF) or mixtures of dioxane and water.
Subsequent to the second Suzuki-Miyaura reaction the compound of formula (8) is obtained by cyclization-reaction in the presence of an acid. Suitable acids are well known to the person of skill in the art and encompass organic and inorganic or mineral acids. Preferred acids according to the present invention are HCI, H2S04, HN03, CF3COOH and the like; with HCI being especially preferred.
[0020] According to the present invention, the preferred reaction partner in the Sonogashira reaction is ethynyltrimeth-ylsilane (7). The reaction is preferably carried out in the presence of Pd(PPh3)2CI2 and Cul in toluene. Strong bases in N-methyl-2-pyrrolidone (NMP) subsequently used in the reaction to obtain the compound of formula (8) are bases with a higher strength than those used in the Suzuki-Miyaura reactions together with the palladium catalysts as described before. Such strong bases are preferably alkali metal alcoholates and the like. Especially preferred according to the present invention is KOtBu used in N-methyl-2-pyrrolidone (NMP).
[0021] The Suzuki-Miyaura- and Sonogashira reactions are preferably carried out in a temperature range between 70 and 120 °C, or under reflux of the solvent or solvent mixture used.
[0022] The final Friedel-Crafts reaction, also named Friedel-Crafts acylation, preferably takes place in the presence of (COCI)2 and AICI3 in DMF and CH2CI2 at room temperature (rt). The term "room temperature" (rt) as used herein means the ambient temperature of the place where the reaction is carried out without any additional heating or cooling. According to the present invention, room temperature is preferably between 18 and 26 °C, more preferably 20 to 24 °C.
[0023] The term -(C1-C6)alkyl as used herein means a linear or branched, saturated hydrocarbon containing from one to six carbon-atoms, preferably from 2 to 4 carbon-atoms. The most preferred -(C1-C6)alkyl group according to the present invention is ethyl.
[0024] The term "halogénation reaction" as mentioned above is a reaction of the product of the first Suzuki-Miyaura reaction with a "halogenating reagent" selected from either N-iodosuccinimide (NIS) to introduce one iodo-atom or others (e.g. I2); or N-bromosuccinimide (NBS) to introduce one bromo-atom in said product of the first Suzuki-Miyaura reaction. The reaction with NIS is preferably carried out in the presence of trifluoroacetic acid (TFA) and DMF. The reaction with NBS is preferably carried out in DMF.
Intermediates h 5-substituted-7-azaindoles [0025] The compound of formula A,
(A), can for example be synthesized by a method, wherein
a) a compound of formula B
(B)
is reacted in the presence of a halogénation reagent, optionally followed by the introduction of amino-protecting groups, to give a compound of formula C
(C); b) said compound of formula C is further reacted in the presence of a palladium catalyst, a base and a compound of the formula D or 7
(D), or
(7) to give the compound of formula E or F, respectively
(E), or
(F); and c-1) the compound of formula E is further treated with an acid; or c-2) the compound of formula F is further treated with a strong base; to give a compound of formula A; wherein R is phenyl, which is unsubstituted or once or several times substituted by halogen, or -Br; R1, R2, R3 and R4 are all methyl, or together with the carbon atoms to which they are attached form a phenyl ring; R5 is -(C1-C6)alkyl or benzyl; X is -Br or -I; and Y1 and Y2 are independently selected from benzyl, trifluoroacetyl, acetyl, and hydrogen.
[0026] If not explicitly otherwise stated, the compounds of formula (D) and (E) are present as mixtures of their E/Z isomers.
[0027] The term "halogénation reagent" as used herein means N-bromosuccinimide (NBS), N-iodosuccinimide (NIS) orsodiumperiodate in combination with iodine (I2/Nal04). For the iodination of a compound of formula B, the use of NIS in the presence of trifluoroacetic acid (TFA) is especially preferred.
[0028] The term -(C1-C6)alkyl as used herein means a linear or branched, saturated hydrocarbon containing from one to six carbon-atoms, preferably from 2 to 4 carbon-atoms. The most preferred -(C1-C6)alkyl group according to the present invention is ethyl.
[0029] The term "amino-protecting groups" as used herein means any protecting group known to the person of skill in the art of organic chemistry to protect an amino group against reactions. Preferred amino protecting groups according to the present invention are benzyl, trifluoroacetyl and acetyl.
[0030] Preferred palladium catalysts and bases as used in the process to obtain the compounds of formula A are the same as described above in connection with the reactions according to scheme 1. In particular, the reaction step b) which leads to a compound of formula E as described above is preferably carried out in the presence of PdCI2(dppf)CH2CI2 as Palladium catalyst, and LiOH as base. The reaction step b) which leads to a compound of formula F as described above is preferably carried out in the presence of Pd(PPh3)2Cl2, Cul and tetramethylguanidine (TMG).
[0031] The term "strong bases" means bases with a higher strength than those used in the Suzuki-Miyaura reactions together with the palladium catalysts as described above. Preferably the term "strong bases" means alkali metal alco-holates and the like. An especially preferred strong base according to the present invention is KOtBu, which is preferably used in N-methyl-2-pyrrolidone (NMP).
[0032] The term "acid" as used herein means organic- and inorganic or mineral acids. Preferred acids according to the present invention are HCI, H2S04, HN03, CF3COOH and the like; with HCI being especially preferred.
[0033] The compound of formula A as described above,
(A), can also be obtained by a process, wherein
a) a compound of formula B
(B)
is reacted in the presence of N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) or sodiumperiodate in combination with iodine (I2/Nal04), optionally followed by the introduction of amino-protecting groups, to give a compound of formula C
(C);
b) said compound of formula C is further reacted in the presence of PdCI2(dppf)CH2CI2, LiOH and a compound of the formula D
(D) ,
to give the compound of formula E
(E) ; and c-1) the compound of formula E is further treated with HCI, to give a compound of formula A; wherein R is phenyl, which is unsubstituted or once or several times substituted by halogen, or -Br; R1, R2, R3 and R4 are all methyl, or together with the carbon atoms to which they are attached form a phenyl ring; R5 is -(C1-C6)alkyl or benzyl; X is -Br or -I; and Y1 and Y2 are independently selected from benzyl, trifluoroacetyl, acetyl, and hydrogen.
[0034] The compound of formula A may also be prepared via the compound of formula F and reaction step c-2) as described above,
(A), said process being characterized in that
a) a compound of formula B
(B)
is reacted in the presence of N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) orsodiumperiodate in combination with iodine (I2/Nal04), optionally followed by the introduction of amino-protecting groups, to give a compound of formula C
(C); b) said compound of formula C is further reacted in the presence of Pd(PPh3)2Cl2, Cul, tetramethylguanidine and the compound of the formula 7
(7),
to give a compound of formula F
(F); and c-2) said compound of formula F is further reacted in the presence of KOtBu to give a compound of formula A; wherein R is phenyl, which is unsubstituted or once or several times substituted by halogen, or -Br; X is -Br or -I; and Y1 and Y2 are independently selected from benzyl, trifluoroacetyl, acetyl, and hydrogen.
[0035] Within the above process, the reaction step a) is preferably carried out in the presence of N-iodosuccinimide (NIS) and trifluoracetic acid; the reaction step b) is carried out in the presence of Pd(PPh3)2CI2, Cul, tetramethylguanidine and the compound of formula 7 in toluene; the reaction step c-2) is carried out in the presence of KOtBu in N-methyl-2-pyrrolidon; and R is -Br; X is -I; and Y1 and Y2 are both hydrogen. II) Pinacol Vinvlboronates [0036] According to the present invention, the above described improved synthesis of the compounds of formula A, and subsequently also of the compound of formula 1, is in particular based on the use of vinylboronates in the corresponding Suzuki-Miyaura reactions which lead to the compounds of formula A, in particular the 5-Br-7-azaindole and the 5-(4-CI-phenyl)-7-azaindole. The use of vinylboronates and their preparation is generally known in the art.
[0037] Catechol vinylether boronate (the compound of formula D, wherein R1 to R4 together with the carbon-atoms to which they are attached form a phenyl ring) can be prepared according to the procedure described in Satoh, M.; Miyaura, N,; Suzuki, A.; Synthesis 1987, 373 and according to the following reaction scheme 2:
40-50% (distilled)
Scheme 2 [0038] Pinacol vinylether boronate (the compound of formula D, wherein R1 to R4 are all methyl) can be prepared according to the reaction scheme 3 below.
Scheme 3 [0039] However, both synthesis routes use highly flammable ethoxyacetylene, which leads to tremendous safety concerns when used on an industrial scale.
[0040] Vinylether boronates have also been prepared using dehydrogenative borylation of alkenes. This reaction consists of a catalytic hydroboration of an alkene with a monohydrido borane, followed by the elimination of hydrogen. Rhodium, titanium and ruthenium catalysts are often used in this type of reaction. A main issue with these catalysts is that many are also efficient hydrogenation catalysts and therefore competing hydrogenation and hydroboration can occur under the reaction conditions.
[0041] There remains a need to find catalysts able to perform the dehydrogenative borylation without competing hydroboration or hydrogenation of the vinylboronate and to overcome the above described safety issues.
[0042] It has now surprisingly been found that with certain rhodium-, ruthenium- or palladium catalysts out of a list of commonly used catalysts the desired pinacol vinylether boronate was formed almost exclusively. Only small amounts (ca. 3%) of the hydroboration product could be detected.
[0043] Consequently, in another embodiment of the present invention, there is provided a process for the manufacture of the compounds of formula D „1
(D),
wherein the compound of formula G
(G)
is reacted with a compound of formula H
(H) in the presence of a palladium, rhodium or ruthenium -catalyst to give a compound of formula D, wherein R1, R2, R3 and R4 are all methyl, or together with the carbon atoms to which they are attached form a phenyl ring; and R5 is -(C1-C6)alkyl or benzyl.
[0044] In a preferred embodiment there is provided the above described process for the manufacture of the compounds of formula D, wherein R1, R2, R3 and R4 are all methyl; and R5 is ethyl.
[0045] In another preferred embodiment the above described process for the manufacture of the compounds of formula D is carried out in the presence of Pd(OAc)2, Pd2 (dba)3, Pd(N03)2, Pd/C (5%), PdCI2, Rh(OAc)2 or RuCI3.
[0046] In another preferred embodiment the above described process for the manufacture of the compounds of formula D is carried out in the presence of 0.05 to 0.5 mol% Pd(OAc)2 at room temperature.
[0047] The term "room temperature" (rt) as used herein means the ambient temperature of the place where the reaction is carried out without any additional heating or cooling. According to the present invention, room temperature is preferably between 18 and 26 °C, more preferably 20 to 24 °C.
[0048] The invention is now illustrated by the following accompanying, not limiting working examples. Examples 6,7 and 8 are provided as reference examples.
Examples
Example 1 2-amino-5-(4-chlorophenyl)-pyridine (4, first Suzuki-Miyaura reaction) [0049]
[0050] 2-Amino-5-bromopyridine (2) was reacted with 4-chlorophenylboronic acid (3) in dioxane/water in the presence of 2.2 equivalents of Na2COs and 1 mol% Pd(OAc)2 plus 1 mol% PdCI2(dppf).CH2CI2 at 90°C for 1.5 h. After cooling to room temperature the product (4) was precipitated as the HCI salt by adding HCI (25%, 6 equiv) followed by removal of dioxane under vacuum. The salt was filtered, digested in diethylether, filtered and then converted to the free amine by treatment with aqueous NaOH. After filtration, the product was isolated in 78% yield. Alternatively, the product has been isolated by chromatography in 83% yield. MS (Turbo Spray): 207 (52%), 205 (M+H+, 100%), 170 (9%).
Example 2
Halogénation of 2-amino-5-(4-chlorophenyl)-pyridine (4) [0051]
[0052] 2-Amino-5-(4-chlorophenyl)-pyridine (4) was converted to the aminopyridine iodide (5a) and the aminopyridine bromide (5b). lodination of (4) using iodine and AgS04 gave only 75% conversion after 3 days at room temperature. Better results were obtained with NIS/TFA. The pyridine bromide could be prepared using NBS. a) lodination of (4) [0053] To a solution of (4) and trifluoroacetic acid (1.2 equiv) in DMF was added N-iodosuccinimide (NIS, 1.1 equiv) in DMF. After stirring for 2.5 h at 80°C, the reaction was complete. After aqueous workup, the product 5a was isolated in 98% yield. MS (Turbo Spray): 331 (100%), 205 (42%), 122 (19%). b) Bromination of (4) [0054] To a solution of (4) in DMF was added N-bromosuccinimide and the resulting reaction solution was stirred at room temperature for 1 h. After adding the solution to water, the product precipitated and then was filtered. Minor impurities were removed by digesting the product in hexanes. The aminopyridine bromide (5b) was isolated in a yield of 91%. MS (GC-Split): 284 (100%), 282 (77%, M), 168 (34%), 151 (14%), 140 (18%), 113 (10%).
Example 3 5-(4-CI-phenyl) azaindole (8, via second Suzuki-Miyaura reaction) I. Pinacol vinylboronate coupling [0055]
l-a) Cyclization of the Iodide (5a): [0056] To a mixture of iodide (5a) and pinacol vinylboronate (6, 1.3 equiv) in DMF was added LiOH (3 equiv) followed by PdCI2(dppf).CH2Cl2 (3 mol%) under an inert atmosphere (Ar). The reaction mixture was heated to 70°C and stirred for 18 h. HPLC analysis indicated complete conversion to the vinylether"lntermediate-A" (MS: (Turbo Spray) 277 (33%), 275 (M+H+, 100%), 231 (22%), 229 (84%), 205 (11 %)).
After cooling to 50°C, 25% HCI (15 equiv) was added. The mixture was kept at this temperature for 1 h. After workup, the azaindole 8 was isolated as a crystalline solid in 92% yield. MS (Turbo Spray): 231 (26%), 229 (M+H+, 100%). l-b) Cyclization of the bromide: [0057] To a mixture of bromide (5b) and pinacol vinylboronate (6,1.2 equiv) in DMF was added LiOH (3 equiv) followed by PdCI2(dppf).CH2CI2 (3 mol%). The reaction mixture was heated to 70°C and stirred for 18 h. HPLC analysis indicated complete conversion to the vinylether intermediate. After cooling the reaction mixture to 50°C, HCI (25%) was added and the mixture was stirred at this temperature for 1 h. The reaction was complete at this point. After workup, compound 8 was isolated as a crystalline solid in 78% yield. MS (Turbo Spray): 231 (35%), 229 (M+H+, 100%). II. Catechol vinylboronate coupling [0058]
[0059] To a mixture of iodide (5a) and catechol vinylboronate (6a, 1.1 equiv) in dioxane/water (80:20) was added LiOH (3 equiv) followed by PdCI2(dppf).CH2Cl2 (3 mol%). The reaction mixture was heated to 80°C and stirred for 24 h. HPLC analysis indicated complete conversion to the vinylether intermediate. After cooling to 50°C, 25% HCI (15 equiv) was added and the mixture was kept at this temperature for 1 h. After workup, the azaindole 8 was isolated as a crystalline solid in 68% yield. MS (Turbo Spray): 231 (26%), 229 (M+H+, 100%)
Example 4
Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (1) [0060]
[0061] A suspension of sulfonamide acid (9) (1.2 eq.) in CH2CI2 was treated at room temperature with cat. amount of DMF (0.11 eq.). Within 30 min a solution of oxalylchloride (1.30 eq.) in CH2CI2 was added and the reaction mixture was stirred for 2 h, whereby the corresponding acid chloride was formed. A suspension of aluminium chloride (AICI3, 4 eq.) in CH2CI2 was treated at 0°C with a solution of Cl-phenyl azaindole (8) in CH2CI2. To the reaction mixture was subsequently added at room temperature the freshly prepared (above described) acid chloride. Stirring at room temperature for 3 h, aqueous work-up and crystallization from THF/heptane provided the title compound (1) as off-white powder in 85% yield. MS (Turbo Spry): 509 (48%), 507 (M+NH4+, 100%), 492 (40%), 490 (M+H+, 84%).
Example 5 5-(4-CI-phenyl)azaindole (8, via Sonogashira reaction) [0062]
[0063] A solution of bromide 5b in toluene was degassed with argon and then treated with PdCyPPt^C^ (0.17 eq.) and Cul (0.17 eq.) and degassed with argon again. To the suspension was added tetramethylguanidine (1.4 eq.) and ethyltrimethylsilane (2 eq.) and stirred at 100°C for 2 h. After cooling to room temperature, extractive work-up and chromatographic purification the intermediate F was collected in 93% yield. MS (Turbo Spray): 303 (49%), 301 (M+H+, 100%) A solution of the intermediate F in 1-methyl-2-pyrrolidinone (NMP) was treated at room temperature with potassium tert. butylate (2 eq.). The mixture was heated to 120°C and stirred for 2 h. After cooling to room temperature, extractive workup and crystallization from EtOH/waterthe title compound (8) was collected in 80% yield. MS (Turbo Spray): 231 (26%), 229 (M+H+, 100%)
Intermediate X: MS (Turbo Spray): 231 (41%), 229 (M+H+, 100%)
Example 6 (Reference Example^ 2-amino-5-bromo-3-iodopyridine (11) [0064]
a) NIS procedure: [0065] To a solution of 2-amino-5-bromopyridine (2) in DMF was added trifluoroacetic acid (1.2 equiv). At room temperature, N-iodosuccinimide (1.1 equiv) was added and the reaction mixture was heated at 50°Cfor3 h. HPLC indicated complete conversion.
After cooling to room temperature the product was precipitated by adding the reaction mixture to water. After neutralization with sodiumthiosulfate and 1 N NaOH the title compound (11) was collected by filtration as a brown solid in 90% yield. b) I2/Nal04 procedure: [0066] To a solution of 2-amino-5-bromopyridine (2) in acetonitrile was added sodiumperiodate (0.4 equiv) and iodine (0.65 equiv). Trifluoroacetic acid (0.65 equiv) was added over 15 min and the reaction mixture was heated at 80°C overnight. HPLC indicated 96% conversion at this point. An aqueous solution of sodium sulfite was added, followed by more water to precipitate the product which was filtered off and washed with water. The title compound (11 ) was isolated as a brown crystalline solid in 75% yield. MS (Turbo Spray): 298 (M+H+, 100%)
Example 7 (Reference Example^ 5-bromo-7-azaindole (12, via Suzuki-Miyaura reaction) [0067]
E/Z mixture [0068] 2-Amino-3-iodo-5-bromopyridine (11) was reacted with pinacol vinylethylether boronate (6, 1.3 equiv) in the presence of LiOH (3 equiv) and PdC^dppfyCh^C^ (1 mol%). After 18 h at 70°C, complete conversion to the amino pyridine vinyl ether was observed (Intermediate-C). The vinyl ether was immediately hydrolyzed by adding 25% HCI and stirring the reaction mixture at50°Cfor 1 h. Workup and crystallization from toluene/heptane gave the title compound (12) in 87% yield. MS (Turbo Spray): 199 (M+H+, 100%). Intermediate: MS (Turbo Spray): 243 (M+H+), 199.
Example 8 (Reference Examolet 5-bromo-7-azaindole (12, via Sonogashira reaction) [0069]
[0070] A solution of 2-Amino-3-iodo-5-bromopyridine (11 ) in toluene was degassed with argon and then treated with PdCl2(PPh3)2Cl2 (0.17 eq.) and Cul (0.17 eq.) and degassed with argon again. To the suspension was added tetrame-thylguanidine (1.4 eq.) and ethyltrimethylsilane (2 eq.) and stirred at 80°C for 1 h. After cooling to room temperature, extractive work-up the intermediate was collected in 83% yield as brown solid.
[0071] Asolutionofthe intermediate in 1-methyl-2-pyrrolidinone(NMP) was treated at room temperature with potassium tért. butylate (2 eq.). The mixture was heated to 80°C and stirred for 1 h. After cooling to room temp®ratur®’ extractive work-up and chromatographic purification the title compound (12) was collected in non optimized 53 /« yie
Example 9
Pinacol vinylboronate (6) [0072]
[0073] Pinacolborane (10) and 4.1 equivalents of ethyl vinylether are stirred at room temperature in the presence of 0. 05 mol% Pd(OAc)2 until reaction completion (20 h). The mixture is then concentrated and the product distilled under vacuum to afford pinacol vinylboronate (6) as a colorless liquid in 83% yield. The product consists of a mixture of E/Z isomers (ratio ca. 2:1). MS (Turbo Spray): 199 (M+H+, 100%), 216 (M+NH4+).
Claims 1. A process for the manufacture of the compound of formula 1,
(1), wherein a) the compound of formula 2
(2) is reacted in the presence of a palladium catalyst, a base and the compound of formula 3 (1st Suzuki-Miyaura reaction)
(3), to give the compound of formula 4
(4); b) said compound of formula 4 is further reacted in the presence of a halogénation reagent to give a compound of formula 5
(5), wherein X is I (5a) or Br (5b); and said compound of formula 5 is further reacted in the presence of either c-1) a compound of formula (D) (2nd Miyaura reaction); or c-2) a compound of formula 7 (Sonogashira reaction)
(D) or
(7); to give the compound of formula 8
(8); and d) said compound of formula 8 is subsequently reacted in the presence of the compound of formula 9 and under the conditions of a Friedel-Crafts Acylation
(9), to give the compound of formula 1, wherein R1, R2, R3 and R4 are all methyl, or together with the carbon atoms to which they are attached form a phenyl ring; and R5 is -(C1-C6)alkyl or benzyl. 2. The process according to claim 1, wherein a) the compound of formula 2
(2) is reacted in the presence of PdCI2(dppf)CH2CI2, Pd(OAc)2, Na2COs and the compound of formula 3
(3), to give the compound of formula 4
(4) ; b) said compound of formula 4 is further reacted in the presence of N-iodosuccinimide (NIS) and CF3COOH, or N-bromosuccinimide (NBS) to give a compound of formula 5
(5) , wherein X is -I (5a) or -Br (5b); c-1) said com pound of formula 5 is further reacted in the presence of PdCI2(dppf)CH2Cl2, LiOH and the compound of formula 6
(6), to give the compound of formula 8
(8); and d) said compound of formula 8 is further reacted with the compound of formula 9
(9),
In the presence of (COCI)2 and AICI3, to give the compound of formula 1. 3. The process according to claim 2, wherein the reaction step b) is carried out in the presence of NBS to give the compound of formula 5, wherein X is bromo (5b). 4. The process according to claim 1, wherein a) the compound of formula 2
(2) is reacted in the presence of PdCI2(dppf)CH2CI2, Pd(OAc)2, Na2C03 and the compound of formula 3
(3), to give the compound of formula 4
(4) ; b) said compound of formula 4 is further reacted in the presence of N-iodosuccinimide (NIS) and CF3COOH, or N-bromosuccinimide (NBS) to give a compound of formula 5
(5) , wherein X is -I (5a) or -Br (5b); c-2) said compound of formula 5 is further reacted in the presence of Pd(PPh3)2CI2, Cul, tetramethylguanidine (TMG) and the compound of formula 7,
(7), followed by the reaction with KOtBu, to give the compound of formula 8
(8); and d) said compound of formula 8 is further reacted with the compound of formula 9
(9),
In the presence of (COCI)2 and AICI3, to give the compound of formula 1.
5. The process according to claim 1, wherein the compounds of formula D
(D);
are obtained by reacting a compound of formula G
(G)
with a compound of formula H
(H) , in the presence of a palladium, rhodium or ruthenium -catalyst to give a compound of formula D, wherein R1, R2, R3 and R4 are all methyl, or together with the carbon atoms to which they are attached form a phenyl ring; and R5 is -(C1-C6)alkyl or benzyl. 6. The process according to claim 5, wherein R1, R2, R3 and R4 are all methyl; and R5 is ethyl. 7. The process according to claim 5 or 6, wherein said process is carried out in the presence of a catalyst selected from the group consisting of Pd(OAc)2, Pd2 (dba)3, Pd(N03)2, Pd/C, PdCI2, Rh(OAc)2 or RuCI3.
Patentansprüche 1. Ein Verfahren zur Herstellung der Verbindung der Formel 1,
(1), wobei a) die Verbindung der Formel 2
(2) umgesetzt wird in Gegenwart eines Palladiumkatalysators, einer Base und der Verbindung der Formel 3 (1. Suzuki-Miyaura-Reaktion)
(3), um die Verbindung der Formel 4 zu erhalten
W. b) die Verbindung der Formel 4 weiter umgesetzt wird in Gegenwart eines Halogenierungsreagenz, um eine Verbindung der Formel 5 zu erhalten
(5), wobei X gleich I (5a) oder Br (5b) ist; und die Verbindung der Formel 5 weiter umgesetzt wird in Gegenwart von entweder c-1) einer Verbindung der Formel (D) (2. Miyaura-Reaktion); oder c-2) einer Verbindung der Formel 7 (Sonogashira-Reaktion)
(D)
(7), um die Verbindung der Formel 8 zu erhalten
(8). und d) die Verbindung der Formel 8 anschließend umgesetzt wird in Gegenwart der Verbindung der Formel 9 und unter den Bedingungen einer Friedel-Crafts-Acylierung
(9), um die Verbindung der Formel 1 zu erhalten, wobei R1, R2, R3 und R4 alle Methyl sind oder zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, einen
Phenylring bilden; und R5 gleich -(C1-C6)-Alkyl oder Benzyl ist. 2. Das Verfahren gemäß Anspruch 1, wobei a) die Verbindung der Formel 2
(2) umgesetzt wird in Gegenwart von PdCI2(dppf)CH2Cl2, Pd(OAc)2, Na2C03 und der Verbindung der Formel 3
(3). um die Verbindung der Formel 4 zu erhalten
H); b) die Verbindung der Formel 4 weiter umgesetzt wird in Gegenwart von N-Iodsuccinimid (NIS) und CF3COOH oder N-Bromsuccinimid (NBS), um eine Verbindung der Formel 5 zu erhalten
(5), wobei X gleich -I (5a) oder -Br (5b) ist; c-1) die Verbindung der Formel 5 weiter umgesetzt wird in Gegenwart von PdCI2(dppf)CH2Cl2, LiOH und der Verbindung der Formel 6
(6), um die Verbindung der Formel 8 zu erhalten
(8); und d) die Verbindung der Formel 8 weiter umgesetzt wird mit der Verbindung der Formel 9
(9) in Gegenwart von (COCI)2 und AICI3, um die Verbindung der Formel 1 zu erhalten. 3. Das Verfahren gemäß Anspruch 2, wobei die Reaktionsstufe b) durchgeführt wird in Gegenwart von NBS, um die Verbindung der Formel 5 zu erhalten, wobei X Brom ist (5b). 4. Das Verfahren gemäß Anspruch 1, wobei a) die Verbindung der Formel 2
(2) umgesetzt wird in Gegenwart von PdCI2(dppf)CH2Cl2, Pd(OAc)2, Na2C03 und der Verbindung der Formel 3
(3). um die Verbindung der Formel 4 zu erhalten
W. b) die Verbindung der Formel 4 weiter umgesetzt wird in Gegenwart von N-Iodsuccinimid (NIS) und CF3COOFI oder N-Bromsuccinimid (NBS), um eine Verbindung der Formel 5 zu erhalten
(5), wobei X gleich -I (5a) oder -Br (5b) ist; c-2) die Verbindung der Formel 5 weiter umgesetzt wird in Gegenwart von Pd(PPh3)2CI2, Cul, Tetramethylguanidin (TMG) und der Verbindung der Formel 7
(7), gefolgt von der Umsetzung mit KOtBu, um die Verbindung der Formel 8 zu erhalten
(8); und d) die Verbindung der Formel 8 weiter umgesetzt wird mit der Verbindung der Formel 9
(9), in Gegenwart von (COCI)2 und AICI3, um die Verbindung der Formel 1 zu erhalten.
5. Das Verfahren gemäß Anspruch 1, wobei die Verbindungen der Formel D
(D)
erhalten werden durch Umsetzen einer Verbindung der Formel G
(G) mit einer Verbindung der Formel Fl
(H) in Gegenwart eines Palladium-, Rhodium- oder Rutheniumkatalysators, um eine Verbindung der Formel D zu erhalten, wobei R1, R2, R3 und R4 alle Methyl sind oder zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, einen
Phenylring bilden; und R5 gleich -(C1-C6)-Alkyl oder Benzyl ist. 6. Das Verfahren gemäß Anspruch 5, wobei R1, R2, R3 und R4 alle Methyl sind; und R5 Ethyl ist. 7. Das Verfahren gemäß Anspruch 5 oder 6, wobei das Verfahren durchgeführt wird in Gegenwart eines Katalysators, ausgewählt aus der Gruppe, bestehend aus Pd(OAc)2, Pd2(dba)3, Pd(N03)2, Pd/C, PdCI2, Rh(OAc)2 oder RuCI3.
Revendications 1. Procédé de fabrication du composé de formule 1,
0), dans lequel a) le composé de formule 2
(2) est mis à réagir en présence d’un catalyseur de palladium, d’une base et du composé de formule 3 (1ère réaction de Suzuki-Miyaura)
(3), pour donner le composé de formule 4
(4); b) ledit composé de formule 4 est en outre mis à réagir en présence d’un réactif d’halogénation pour donner un composé de formule 5
(5), dans lequel X est I (5a) ou Br (5b) ; et ledit composé de formule 5 est en outre mis à réagir en présence soit c-1) d’un composé de formule (D) (2nde réaction de Miyaura) ; soit c-2) d’un composé de formule 7 (réaction de Sonogashira)
(D) (7); ou pour donner le composé de formule 8
{8) 9 et d) ledit composé de formule 8 est ultérieurement mis à réagir en présence du composé de formule 9 et dans les conditions d’une acylation de Friedel-Crafts
(9), pour donner le composé de formule 1, où R1, R2, R3 et R4 sont tous des méthyles, ou conjointement avec les atomes de carbone auxquels ils sont attachés, forment un cycle phényle ; et R5 est -alkyle (en Ci à C6) ou benzyle. 2. Procédé selon la revendication 1, dans lequel a) le composé de formule 2
(2) est mis à réagir en présence de PdCI2(dppf)CH2CI2, Pd(OAc)2, Na2C03 et le composé de formule 3
(3), pour donner le composé de formule 4
(4); b) ledit composé de formule 4 est en outre mis à réagir en présence de N-iodosuccinimide (NIS) et de CF3COOH, ou de N-bromosuccinimide (NBS) pour donner un composé de formule 5
(5), où X est -I (5a) ou -Br (5b) ; c-1) ledit composé de formule 5 est en outre mis à réagir en présence de PdCl2(dppf)CH2CI2, LiOH et le composé de formule 6
(6), pour donner le composé de formule 8
(8). 5 et d) ledit composé de formule 8 est en outre mis à réagir avec le composé de formule 9
(9), en présence de (COCI)2 et AICI3, pour donner le composé de formule 1. 3. Procédé selon la revendication 2, dans lequel l’étape de réaction b) est réalisée en présence de NBS pour donner le composé de formule 5, dans lequel X est bromo (5b). 4. Procédé selon la revendication 1, dans lequel a) le composé de formule 2
(2) est mis à réagir en présence de PdCI2(dppf)CH2CI2, Pd(OAc)2, Na2C03 et le composé de formule 3
(3), pour donner le composé de formule 4
(4) ; b) ledit composé de formule 4 est en outre mis à réagir en présence de N-iodosuccinimide (NIS) et de CF3COOH, ou de N-bromosuccinimide (NBS) pour donner un composé de formule 5
(5) , où X est -I (5a) ou -Br (5b) ; c-2) ledit composé de formule 5 est en outre mis à réagir en présence de Pd (PPh3)2CI2, Cul, tétraméthylgua-nidine (TMG) et le composé de formule 7,
(7), suivi par la réaction avec du KOtBu, pour donner le composé de formule 8
{8). s et d) ledit composé de formule 8 est en outre mis à réagir avec le composé de formule 9
(9), en présence de (COCI)2 et AICI3, pour donner le composé de formule 1.
5. Procédé selon la revendication 1, dans lequel les composés de formule D
(D);
sont obtenus par la mise en réaction d’un composé de formule G
(G)
avec un composé de formule H
(H), 2en présence d’un catalyseur de palladium, rhodium ou ruthénium pour donner un composé de formule D, où R1, R2, R3 et R4 sont tous des méthyles, ou conjointement avec les atomes de carbone auxquels ils sont attachés, forment un cycle phényle ; et R5 est -alkyle (en C1 à C6) ou benzyle. 6. Procédé selon la revendication 5, dans lequel R1, R2, R3 et R4 sont tous des méthyles ; et R5 est un éthyle. 7. Procédé selon la revendication 5 ou 6, dans lequel ledit procédé est réalisé en présence d’un catalyseur choisi dans le groupe consistant en Pd(OAc)2, Pd2(dba)3, Pd(N03)2, Pd/C, PdCI2, Rh(OAc)2 ou RuCI3.

Claims (2)

  1. Az. EF 2 SSI'S 958 iajsímmaxémú európai szabadalom Igénypontjainak magyar fordítása:
  2. 1. Eljárás az 1 képletö vágyóié! előállítására.
    a) a 2 képlelá^ vegy öletet
    (2) patléáínmkatafzátep bázis és a 3 képletet vagy lile!
    m jelenlétében reagáítatjuk fi, SuzukAMiysura reakció) a 4 képletö vegyűiet előállítására:
    (A)i b) az ereilet! 4 képlete vegyölelei tovább reagáltaöuk balegéneao reagens Jelenlétében S: képletö vegyűiet előállítására
    (6), aboi X Jelentése i (6a) vagy Br (5b); és az említett S képlete vegyulefet tovább reagsitaijak vagy c-1 ) (D) képlete vegyűiet jelenlétében
    m (2. Mlyaura reakció); vagy C"2) 7 képlet y vegyidet jele alátéten
    (7} (Sonogashira mûkdà) a 8 képleté vegyûlet előállítására
    <*>: és d) sz említett 8 képleté vegyületet ezt követően a 9 képleté vegyidet
    jelenlétében és a FnedekCratts adtezest reakolé körülményei között reagátfatjek 1 képleté vegyÖlet előállítására s ahol R\ Ry R3 és R4 mindegyikének a jelentése meiilcsopert vagy együtt a szénatommai amelyhez kapcsolódnák feollgyörűt alkotnak; és R5 jelentése (Ci~C:8)alkík vagy deazllcsopod- 2* Az 1. Igénypont szerinti eljárás, ahol a) a 2 képleté vegyötetet
    (2) FelCb|dppf}CH3Ck, PdtöAop, N92CQ3 és· a 3 képleté vegyűlet
    mi jelenlétében reegálteííuk 4 képleté vegyűlet előállítására:
    C4); b) az:említet 4 képtetCl vegyületet tovább reagáíiatfuk NgodeezukclnlrnkJ (NIS) és CF^COOH, vagy N-árómszukcíolmldi (NEltS) jelenlétében olyan f képleté vegyűlet előállítására:
    (5),....................... aboi X jelentése 4 (baj vagy ~Br (6b); G“1) az említett 5 képleté vegyületet tovább reagáltalak FdCb(dppf)CH2Cb:! LION és a 8 képleté vegyűlet
    (ej jelenlétében 8 képleté vegyűlet előállítására:
    (8): és d) az említett 8 képleté vegyületet tovább reagáltatok a S képleté vegyüíettel
    m (GOClp és AIC!> jelein lététen az 1 képleté vegyűlet előállítására. 3» A 2, Igénypont szerinti eljárás, ahol a b) æakoiôlépést NS'S jelenlétében végezzük olyan 6 képleté vegyuiet előállítására, ahol X Jelentése érőm (Sb). 4 Az 1, igénypont szerinti eljárás, ebei a) a 2 képleté vegyületet
    12} reagáftatljuk PdChtdppfjCkkCk, Pd(OÄc);>, Na2C€X és a 3 képletű vegyűlet
    13} jelenlétében 4 képleté vegyuiet előállítására:
    14): b) az említett 4 képletű vegyületet tovább reagáltatok Ν-jôdszukdnimld (MIS) és Cf'sCÖOH vagy N-brémszekülnimld (MBS) jelenlétében olyan 5 képleté: vegyuiet előállításáig:
    <5>, ahol X jelentése -I (őa) vagy ~Br (Sb); e~2) az említett 5 képletű vegyületet tovább reagáítaífok Pd(PPlp)2Cb, Oui tetrametltguanldtn (ÏMG) és a 7 képletű vegynlet
    m 6 jelenlétében, majd KOtSn-val reagálhatjuk 8 képletű vegyuiet előállítására:
    <8>: és d) az említett 8 képletű vegyílíetet topább reagáltatjuk a 9 képielö vegyOletfföl
    < i'A \ l ÍS } íCOCb;. és ÂlCk jelenlétében 1 képletű vegyütet előállítására 5. Az 1. igénypont szériáit eprés, aboi a 0 kápletb vagyOJeieket
    m úgy kapjuk: bogy G képleté vegyü letet
    ? ,*'W ......................................... \Uí ...................................................................................... H képletű vegyűleitel
    (H) reagáftatunk pailáé!ym-; rádium- vagy futénturekaiaifeátar jelenlétében olyan D képlete vegyüiei eiéâtlltâeâfa, aboi R\ Ry R·3 és R4 mindegyikének a jelentése metleseporl vagy együtt a szénatommal amelyhez kapcsolódnak, lénltgyurCit képeznek; és FA' jelentése (C1~C6)é!kíl~ vagy benzlesopott. Ci.. Az 5. igénypont szerinti ..eljárás, ahol R\ Ry R" és R- mindegyikének a Jelentése metilcsepori; és R* jelentése etilcsoport: ?v Az δ. vagy 6, igénypont szerinti epres, ahol az említett eljárást a Pd(0A.cA, PdAdbak PdíNü.p, Pd/C, PdCt2, Rh(0Ac)2 zagy a RoCA által alkotott csoportból választott katalizátor leienlétèèen végezzük.
HUE11735858A 2010-07-21 2011-07-18 Új eljárások propán-1-szulfonsav-{3-[5-(4-klór-fenil)-1H-pirrolo[2,3-B]piridin-3-karbonil]-2,4-difluorfenil}-amid elõállítására HUE025022T2 (hu)

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