CN104447499A - Method of synthesizing pyrroloseven-membered-ring derivative by Au-catalyzed alkyl pyrrole - Google Patents

Method of synthesizing pyrroloseven-membered-ring derivative by Au-catalyzed alkyl pyrrole Download PDF

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CN104447499A
CN104447499A CN201310443028.8A CN201310443028A CN104447499A CN 104447499 A CN104447499 A CN 104447499A CN 201310443028 A CN201310443028 A CN 201310443028A CN 104447499 A CN104447499 A CN 104447499A
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pyrrolo
ring derivative
membered ring
phenyl
compound
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CN104447499B (en
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万伯顺
潘斌
吴凡
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Zhongke Yulin Energy Technology Operation Co ltd
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Dalian Institute of Chemical Physics of CAS
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    • 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
    • C07D209/52—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 condensed with a ring other than six-membered
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • B01J2231/324—Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • B01J2231/324—Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions
    • B01J2231/326—Diels-Alder or other [4+2] cycloadditions, e.g. hetero-analogues
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
    • B01J2531/0266—Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL"
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
    • B01J2531/18—Gold

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention relates to a method of synthesizing pyrroloseven-membered-ring derivative by Au-catalyzed alkyl pyrrole. The method comprises the following steps: preparing the pyrroloseven-membered-ring derivative by a 3-alkynyl-substitued pyrrole compound in the presence of an Au catalyst. According to the method disclosed by the invention, cheap and easily available starting materials are adopted, and the method has convenience in operation, and mild conditions.

Description

The alkynyl pyrroles of Au catalysis synthesizes the method for pyrrolo-seven-membered ring derivative
Technical field
The present invention relates to a kind of method preparing pyrrolo-seven-membered ring derivative.Concrete grammar is the azole compounds being had alkynyl substituted by 3-position, with for catalyzer, there is cyclization and prepare pyrrolo-seven-membered ring derivative.
Background technology
Pyrrolo-seven-membered ring derivative is one of important heterogeneous ring compound, is the component units of many natural products and artificial-synthetic compound.The compound with pyrrolo-seven-members ring structure has physiology and pharmacological activity widely usually, and such as compd A has improvement result (WO2005/94833A1) for female hormone relative disease and female hormone disorder; Compd B has good antagonistic action for prostate gland acceptor Crth2, is the active compound (WO2010/039982A1) (formula 1) of potential treatment asthma, allergic rhinitis and obstructive type pulmonary disorder; Compound C has the effect (WO2012/101032A1) of Function protein kinase activity; And Compound D is Cannabinoid receptor agonistic effect, potential analgesic effect (WO2011/100359A1) may be had.In addition, human low density lipoprotein (LDL) the peroxidation process also having report research compound 3c to mediate for copper has very strong restraining effect, can prevention of arterial atherosis and there is certain anti-inflammatory action (Kuehm, C.C.et al.J.Med.Chem.1997,40,1201.).
Just because of pyrrolo-seven-membered ring derivative biological activity and be widely used, the synthetic method studying this compounds is very important.The cyclization of Au catalysis, because catalytic activity is high, mild condition, is therefore applied (document 2:Ferrer, C.Echavarren, A.M.Angew.Chem.2006,118,1123.) in the synthesis of this compounds.But report is also less at present.
Summary of the invention
The present invention relates to a kind of azole compounds by 3-position alkynyl substituted is raw material, synthesizes the method for pyrrolo-seven-membered ring derivative under Au catalytic condition.
The alkynyl pyrroles of Au catalysis synthesizes the method for pyrrolo-seven-membered ring derivative: with the pyrrole of the 3-position alkynyl substituted shown in following formula
Cough up as Material synthesis pyrrolo-seven-membered ring compounds, reaction formula is as follows:
Wherein R is the one in the benzyl of C1-C8 alkyl, C3-C8 cycloalkyl, phenyl, the phenyl of replacement, naphthyl, benzyl, replacement, and the substituting group on phenyl or benzyl is C1-C8 alkyl, C1-C8 alkoxyl group ,-F ,-Cl ,-Br ,-I ,-NO 2in one, two kinds or three kinds, substituent number is 1-6;
R 1, R 2be respectively methyl, phenyl, C2-C8 alkyl, trimethyl silicon based in one; X is-O-,-T sn-,-CH 2-,-C (CO 2cH 3) 2-,-C (CO 2c 2h 5) 2-or-C (CO 2bn) 2-; [Au] is
Concrete operation step is as follows:
React in reactor, reactor vacuumizes rear logical nitrogen or inert gas replacement, add catalyzer [Au] and with dissolution with solvents, by compound 1 with being added dropwise in catalyzer after dissolution with solvents, at 20 DEG C-40 DEG C react 1 day-7 days; After reaction terminates, take out solvent, after Purify, obtain pyrrolo-seven-membered ring derivative 2.
Solvent is one or two or more kinds in methylene dichloride, ethylene dichloride, methyl alcohol, tetrahydrofuran (THF), DMF, benzene, toluene, ether, tetracol phenixin, Isosorbide-5-Nitrae-dioxane, acetonitrile.
Catalyzer is 3mol%-20mol% relative to the consumption of compound 1.
Solvent phase is 5ml/mmol-30ml/mmol for the consumption of compound 1.
Rare gas element is argon gas; After reaction terminates, take out solvent with Rotary Evaporators, solid is dissolved in methylene dichloride loading and carries out silica gel column chromatography, obtains pyrrolo-seven-membered ring derivative 2.
Does tool of the present invention have the following advantages: (advantage is too simple, please again supplements also refinement, specializes?)
The azole compounds of the method starting raw material 3-position alkynyl substituted can be obtained by single step reaction by N-substituted methylene ethylenimine and diine.Starting raw material under Au catalyst action, by simple operations, under mild conditions can efficiently and the preparation pyrroles pyrrolo-seven-membered ring derivative of high yield.
Accompanying drawing explanation
Fig. 1 is embodiment 1 product 1h NMR spectrogram;
Fig. 2 is embodiment 1 product 13c NMR spectrogram;
Fig. 3 is the high resolution mass spectrum spectrogram of embodiment 1 product;
Fig. 4 is embodiment 2 product 1h NMR spectrogram;
Fig. 5 is embodiment 2 product 13c NMR spectrogram;
Fig. 6 is the high resolution mass spectrum spectrogram of embodiment 2 product;
Fig. 7 is embodiment 3 product 1h NMR spectrogram;
Fig. 8 is embodiment 3 product 13c NMR spectrogram;
Fig. 9 is the high resolution mass spectrum spectrogram of embodiment 3 product.
Embodiment
(1) reference literature, through two step synthesis N-substituted methylene ethylenimine: the first step, amine and 2,3-dibromo second propylene generate compound 4(document 5:Mori, M. in DMF; Chiba, K.; Okita, M.; Kayo, I.; Ban, Y.Tetrahedron1985,41,375.) (formula 1, reaction equation 1).Second step, prepares the liquefied ammonia suspension liquid of sodium amide, slowly drips the diethyl ether solution of compound 4, is obtained by reacting N-substituted methylene ethylenimine 5(document 7:Jason J.S.; Michael S.; Jerome F.H.; Alexandra M.Z.J.Am.Chem.Soc.2004,126,6868.) (formula 1, reaction equation 2).
The synthesis step of formula 1.N-substituted methylene ethylenimine
(2) reference literature, synthesis 3-position alkynyl substituted azole compounds: react in reactor, after reactor vacuumizes rear logical argon replaces three times, add the catalyzer of 5-20mol%, then the diine 6 of N-substituted methylene ethylenimine 5 and 0.2mmol is added, add 1ml solvent, react 1 day at 20 DEG C-40 DEG C.Revolve after reaction terminates after evaporating solvent, solid carries out silica gel column chromatography, obtains halo 3-alkynyl substituted pyrrole derivative 1(document: Pan B.; Wang C.X.; Wang D.P.; WuF.; Wan B.S.Chem.Commun.2013,49,5073.) (formula 2).
The synthesis step of formula 2.1,2,3-tri-substituted azole derivatives
(3) pyrrolo-seven-membered ring derivative is synthesized by 3-alkynyl substituted pyrroles
The synthesis step of formula 3. pyrrolo-seven-membered ring derivative
React in reactor, reactor vacuumizes rear logical nitrogen or inert gas replacement, add catalyzer and with dissolution with solvents, by 1 with being added dropwise in catalyzer after dissolution with solvents, at 20 DEG C-40 DEG C reaction 1 day-7 days; Revolve after reaction terminates after evaporating solvent, solid carries out silica gel column chromatography, obtains pyrrolo-seven-membered ring derivative 2.
Embodiment 1
React in 10ml Schlenk reaction tubes, reactor adds the catalyzer of 10mg (5mol%) after vacuumizing rear logical argon replaces three times then adding after 1a (100mg) being dissolved in 5ml methylene dichloride is equipped with in the reactor of catalyzer, reacts 1 day at 25 DEG C.Reaction terminates rear solvent evaporated, and solid carries out silica gel column chromatography, with sherwood oil: the eluent of ethyl acetate=20:1 rinses pillar, and obtain the 2a of 85mg, separation yield is 85%.
The sign number of 2a is as follows: ( 1h NMR; 13c NMR; High resolution mass spectrum.Spectrogram is shown in Figure of description 1, Fig. 2, Fig. 3)
Embodiment 2
React in 10ml Schlenk reaction tubes, reactor adds the catalyzer of 2.9mg (5mol%) after vacuumizing rear logical argon replaces three times then adding after 1b (31mg) being dissolved in 2ml methylene dichloride is equipped with in the reactor of catalyzer, reacts 1 day at 25 DEG C.Reaction terminates rear solvent evaporated, and solid carries out silica gel column chromatography, with sherwood oil: the eluent of ethyl acetate=20:1 rinses pillar, and obtain the 2b of 30mg, separation yield is 97%.
The sign number of 2b is as follows: ( 1h NMR; 13c NMR; High resolution mass spectrum.Spectrogram is shown in Figure of description 4, Fig. 5, Fig. 6)
Embodiment 3
React in 10ml Schlenk reaction tubes, reactor adds the catalyzer of 4.3mg (5mol%) after vacuumizing rear logical argon replaces three times then adding after 1c (44mg) being dissolved in 3ml methylene dichloride is equipped with in the reactor of catalyzer, reacts 1 day at 25 DEG C.Reaction terminates rear solvent evaporated, and solid carries out silica gel column chromatography, with sherwood oil: the eluent of ethyl acetate=20:1 rinses pillar, and obtain the 2c of 37mg, separation yield is 83%.
The sign number of 2c is as follows: ( 1h NMR; 13c NMR; High resolution mass spectrum.Spectrogram is shown in Figure of description 7, Fig. 8, Fig. 9)

Claims (6)

  1. The alkynyl pyrroles of 1.Au catalysis synthesizes the method for pyrrolo-seven-membered ring derivative
    With the pyrroles of the 3-position alkynyl substituted shown in following formula for Material synthesis pyrrolo-seven-membered ring compounds, reaction formula is as follows:
    Wherein R is the one in the benzyl of C1-C8 alkyl, C3-C8 cycloalkyl, phenyl, the phenyl of replacement, naphthyl, benzyl, replacement, and the substituting group on phenyl or benzyl is C1-C8 alkyl, C1-C8 alkoxyl group ,-F ,-Cl ,-Br ,-I ,-NO 2in one, two kinds or three kinds, substituent number is 1-6;
    R 1, R 2be respectively methyl, phenyl, C2-C8 alkyl, trimethyl silicon based in one; X is-O-,-T sn-,-CH 2-,-C (CO 2cH 3) 2-,-C (CO 2c 2h 5) 2-or-C (CO 2bn) 2-; [Au] is
  2. 2. in accordance with the method for claim 1, it is characterized in that:
    Concrete operation step is as follows:
    React in reactor, reactor vacuumizes rear logical nitrogen or inert gas replacement, add catalyzer [Au] and with dissolution with solvents, by compound 1 with being added dropwise in catalyzer after dissolution with solvents, at 20 DEG C-40 DEG C react 1 day-7 days; After reaction terminates, take out solvent, after Purify, obtain pyrrolo-seven-membered ring derivative 2.
  3. 3. according to the method described in claim 1 or 2, it is characterized in that: solvent is methylene dichloride, ethylene dichloride, methyl alcohol, tetrahydrofuran (THF), N, one or two or more kinds in dinethylformamide, benzene, toluene, ether, tetracol phenixin, Isosorbide-5-Nitrae-dioxane, acetonitrile.
  4. 4. according to the method described in claim 1 or 2, it is characterized in that: catalyzer is 3mol%-20mol% relative to the consumption of compound 1.
  5. 5. according to the method described in claim 1 or 2, it is characterized in that: solvent phase is 5ml/mmol-30ml/mmol for the consumption of compound 1.
  6. 6. in accordance with the method for claim 2, it is characterized in that:
    Rare gas element is argon gas; After reaction terminates, take out solvent with Rotary Evaporators, solid is dissolved in methylene dichloride loading and carries out silica gel column chromatography, obtains pyrrolo-seven-membered ring derivative 2.
CN201310443028.8A 2013-09-25 2013-09-25 The method that the alkynyl pyrroles of Au catalysis synthesizes pyrrolo-heptatomic ring derivant Active CN104447499B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108017634A (en) * 2017-12-15 2018-05-11 清华大学 A kind of method for preparing pyrrolo- Polycyclic derivative

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008053341A2 (en) * 2006-11-03 2008-05-08 Glenmark Pharmaceuticals S.A. Bridged bicyclic indazoles as cannabinoid receptor ligands

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008053341A2 (en) * 2006-11-03 2008-05-08 Glenmark Pharmaceuticals S.A. Bridged bicyclic indazoles as cannabinoid receptor ligands

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108017634A (en) * 2017-12-15 2018-05-11 清华大学 A kind of method for preparing pyrrolo- Polycyclic derivative

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