CN115138396A - Catalyst system for Sonogashira coupling reaction and in-situ ring closing reaction - Google Patents

Catalyst system for Sonogashira coupling reaction and in-situ ring closing reaction Download PDF

Info

Publication number
CN115138396A
CN115138396A CN202110354708.7A CN202110354708A CN115138396A CN 115138396 A CN115138396 A CN 115138396A CN 202110354708 A CN202110354708 A CN 202110354708A CN 115138396 A CN115138396 A CN 115138396A
Authority
CN
China
Prior art keywords
reaction
catalyst system
catalyst
molar ratio
cui
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.)
Pending
Application number
CN202110354708.7A
Other languages
Chinese (zh)
Inventor
掌子龙
李争峰
蒋群
刘军涛
杜争鸣
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.)
Baiji Shenzhou Suzhou Biotechnology Co ltd
Original Assignee
Baiji Shenzhou Suzhou Biotechnology Co ltd
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 Baiji Shenzhou Suzhou Biotechnology Co ltd filed Critical Baiji Shenzhou Suzhou Biotechnology Co ltd
Priority to CN202110354708.7A priority Critical patent/CN115138396A/en
Publication of CN115138396A publication Critical patent/CN115138396A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • 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
    • B01J31/22—Organic complexes
    • B01J31/2282—Unsaturated compounds used as ligands
    • B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B01J2231/4266—Sonogashira-type, i.e. RY + HC-CR' triple bonds, in which R=aryl, alkenyl, alkyl and R'=H, alkyl or aryl
    • 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
    • B01J2531/0225—Complexes comprising pentahapto-cyclopentadienyl 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
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/824—Palladium

Abstract

The invention relates to a catalyst system suitable for Sonogashira coupling reaction and in-situ cyclization reaction, which is particularly suitable for a method for preparing an intermediate (R) -2- (1- (2- (tert-butyloxy) -2-oxoethyl) -2-methylpyrrolidin-2-yl) -6-fluoro-1-tosyl-1H-indole-4-carboxylic acid methyl ester of Pamiparib. The invention also relates to the use of the catalyst system for the synthesis of desired intermediates.

Description

Catalyst system for Sonogashira coupling reaction and in-situ ring closing reaction
Technical Field
The invention relates to a catalyst system suitable for Sonogashira coupling reaction and in-situ cyclization reaction, which is particularly suitable for a method for preparing an intermediate (R) -2- (1- (2- (tert-butyloxy) -2-oxoethyl) -2-methylpyrrolidin-2-yl) -6-fluoro-1-tosyl-1H-indole-4-carboxylic acid methyl ester of Pamiparib. The invention also relates to the use of the catalyst system for the synthesis of desired intermediates.
Background
The Sonogashira coupling reaction uses a palladium catalyst to form a carbon-carbon bond between the terminal alkyne and the aryl or vinyl halide. The Sonogashira coupling reaction typically uses both a palladium catalyst and a copper catalyst.
WO2017/032289A1 discloses the large-scale synthetic preparation of (R) -2-fluoro-10 a-methyl-7,8,9,10,10a, 11-hexahydro-5,6,7a, 11-tetraazacyclohepta [ def ]]Cyclopenta [ a ] s]Fluoren-4 (5H) -one(s) ((R)) pamiprarib) of a microorganism, wherein
Figure BDA0002999464620000011
Is an important intermediate in the preparation process of Pamiparib. According to step 5 of example 1 of WO2017/032289A1,
Figure BDA0002999464620000012
(BG-5) with
Figure BDA0002999464620000013
(BG-10) in Pd (Ph) 3 ) 2 Cl 2 Carrying out Sonogashira coupling reaction and in-situ ring closing reaction under the catalysis of CuI to finally generate the intermediate
Figure BDA0002999464620000014
Namely (R) -2- (1- (2- (tert-butyloxy) -2-oxoethyl) -2-methylpyrrolidin-2-yl) -6-fluoro-1-tosyl-1H-indole-4-carboxylic acid methyl ester (BG-11). Although Pd (Ph) was used for the reaction 3 ) 2 Cl 2 And CuI as a catalyst, a large amount of BG-10 still cannot complete the conversion at the end of the reaction, resulting in difficult purification and poor yield.
In order to solve the problem of low conversion of the reaction raw material, CN111184693A discloses the use of a different palladium catalyst, i.e. Pd (dppf) Cl, by catalyst screening 2 And Pd (dtbpf) Cl 2 One or two of the above and cuprous salt as catalyst, the reaction can be within 36The BG-10 is completed in time, and only about 0.3 percent of the BG-10 is remained, so that the conversion rate of the BG-10 is greatly improved. After post-treatment and crystallization purification, the product with HPLC purity more than 99.0% and chiral purity more than 99.0% can be obtained. But there is still a problem that the yield is not ideal and the yield ranges only between 65-85%. In addition, the above reaction requires the use of a high loading of Pd catalyst, resulting in a great increase in production costs.
The inventor of the invention finds a catalyst system for Sonogashira coupling reaction and in-situ loop closing reaction, and the catalyst system greatly improves the yield by the type and the dosage ratio of a catalyst, cuprous salt and phosphino ligand, achieves the chiral purity, reaches more than 90 percent, even improves the yield to more than 95 percent, ensures the enantioselectivity of the reaction and reduces the Pd carrying capacity of the catalyst. The technical improvement is particularly suitable for large-scale production of medicines, simplifies the separation means, greatly improves the production efficiency and reduces the cost.
Disclosure of Invention
Therefore, the invention provides a catalyst system for Sonogashira coupling reaction and in-situ cyclization reaction, and the catalyst system not only ensures the chiral purity of the prepared product, but also greatly improves the yield to more than 90 percent, even to more than 95 percent, ensures the enantioselectivity of the reaction and reduces the Pd load of the catalyst when preparing the (R) -2- (1- (2- (tert-butyloxy) -2-oxoethyl) -2-methylpyrrolidin-2 yl) -6-fluoro-1-tosyl-1H-indole-4-carboxylic acid methyl ester (BG-11) intermediate. Therefore, the catalyst system is particularly suitable for large-scale production of Pamiparib medicaments, simplifies the separation means, greatly improves the production efficiency and reduces the cost. Pamiprarib was first disclosed in WO2013/097225A1 as poly (ADP-ribosyl) transferase (PARPs) inhibitors, which are inhibitors of poly Adenosine Diphosphate (ADP) ribose polymerase (PARP), which are highly selective for PARP-1/2 and are effective in inhibiting proliferation of cell lines with BRCA1/2 mutations or other HR defects, significantly inducing tumor regression in BRCA1 mutant breast cancer xenograft models at doses much lower than olaparib, which compounds have excellent DMPK properties and significant brain permeability.
The present invention relates to, but is not limited to, the following aspects:
in one aspect, the invention relates to a catalyst system for Sonogashira coupling and in situ ring closure reactions comprising a palladium catalyst [ Pd]A phosphine based ligand, a cuprous salt and a base, wherein the palladium catalyst is selected from the group consisting of [ (cinnamyl) PdCl] 2 And/or [ Pd (C) 3 H 5 )Cl] 2 The phosphine group ligand is J-009 and/or XantPhos, the cuprous salt is CuI, and the alkali is tetramethylguanidine and/or DBU; the molar ratio of the palladium catalyst to the phosphine based ligand is 1.
In one embodiment, the palladium catalyst is selected from [ (cinnamyl) PdCl] 2 And [ Pd (C) 3 H 5 )Cl] 2 To (3) is provided.
In one embodiment, the phosphino ligand is one selected from the group consisting of J-009 from CAS:158923-11-6 and XantPhos.
In one embodiment, the base is one selected from tetramethylguanidine and DBU.
In one embodiment, the molar ratio of the palladium catalyst to the cuprous salt is 1.
In one embodiment, the molar ratio of the palladium catalyst [ Pd ], phosphine-based ligand, cuprous salt, and base is 1.
In one embodiment, the molar ratio of the palladium catalyst [ Pd ], phosphine-based ligand, cuprous salt, and base is 1.
In one embodiment, the molar ratio of the palladium catalyst [ Pd ], phosphine-based ligand, cuprous salt, and base is 1.
In one embodiment, the [ (cinnamyl) PdCl] 2 J-009, cuI and TMG in a molar ratio of 1 3 H 5 )Cl] 2 J-009, cuI and TMG in a molar ratio of 1] 2 Xanthphos, cuI and TMG in a molar ratio of 1] 2 Xanthphos, cuI and TMG in a molar ratio of 1.
In another aspect, the present invention relates to the use of the above catalyst system for Sonogashira coupling and in situ ring closure reaction for the preparation of (R) -methyl 2- (1- (2- (tert-butyloxy) -2-oxoethyl) -2-methylpyrrolidin-2-yl) -6-fluoro-1-toluenesulfonyl-1H-indole-4-carboxylate (BG-11), wherein said (R) -methyl 2- (1- (2- (tert-butyloxy) -2-oxoethyl) -2-methylpyrrolidin-2-yl) -6-fluoro-1-toluenesulfonyl-1H-indole-4-carboxylate (BG-11) is prepared by reacting BG-10 with BG-5 in an organic solvent in the presence of the above catalyst system,
Figure BDA0002999464620000031
in one embodiment, the phosphino ligand is selected from the group consisting of J-009, ph 2 Cy、Ph 2 DavePhos、(p-anisyl) 3 P、BrettPhos、Ph 2 P-CH 2 CH 2 - (2-Pyr), cy-BippyPhos, xantPhos and Ph 3 One or more of P; preferably, the phosphino ligand is selected from one or more of X-Phos, J-009, ruPhos and XantPhos; more preferably, the phosphino ligand is J-009.
In one embodiment, the cuprous salt is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride, cuprous acetate, and cuprous triflate; preferably, the cuprous salt is selected from one or more of cuprous iodide, cuprous bromide and cuprous chloride; more preferably, the cuprous salt is cuprous iodide.
In one embodiment, the base is selected from Diisopropylethylamine (DIPEA), triethylamine (TEA), pyridine, tetramethylguanidine (TMG), nitromethylmorpholine (NMP), potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, triethylenediamine (DABCO), and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), and any combination thereof; preferably, the base is selected from one or more of Diisopropylethylamine (DIPEA), triethylenediamine (DABCO), tetramethylguanidine (TMG) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU); more preferably, the base is selected from Tetramethylguanidine (TMG) and/or 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU); more preferably, the base is Tetramethylguanidine (TMG).
In one embodiment, the organic solvent is selected from: one or more of Dimethylsulfoxide (DMSO), N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), toluene, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), acetonitrile, and dioxane; preferably, the organic solvent is selected from: one or more of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), toluene, and 2-methyltetrahydrofuran (MeTHF); more preferably, the organic solvent is toluene.
In one embodiment, the reaction is carried out at a temperature of not less than 60 ℃; preferably, the reaction is carried out at a temperature of not less than 80 ℃; more preferably, the reaction is carried out at a temperature of not less than 90 ℃. In one embodiment, the reaction is carried out at the reflux temperature of the solvent used or at a temperature that does not decompose the reaction mass. In other embodiments, the temperature of the reaction will increase as pressure is applied.
In one embodiment, the reaction is carried out for at least 12 hours; preferably, the reaction is carried out for at least 16 h; more preferably, the reaction is carried out for at least 18h; more preferably, the reaction is carried out for 18-24h.
In one embodiment, the palladium catalyst is [ (cinnamyl) PdCl] 2 The phosphine ligand is J-009, the cuprous salt is CuI, and the alkali is tetramethylguanidine; the reaction is carried out in toluene; the reaction is carried out at a temperature of not less than 80 ℃; the reaction is carried out for 18-24h.
In one embodiment, the palladium catalyst is [ (cinnamyl) PdCl ]2, the phosphine ligand is XantPhos, the cuprous salt is CuI, and the base is tetramethylguanidine; the reaction is carried out in toluene; the reaction is carried out at a temperature of 90 ℃; the reaction is carried out for 18-24h.
In one embodiment, the palladium catalyst is [ Pd (C3H 5) Cl ]2, the phosphine based ligand is J-009, the cuprous salt is CuI, the base is tetramethylguanidine; the reaction is carried out in toluene; the reaction is carried out at a temperature of not less than 80 ℃; the reaction is carried out for 18-24h.
In one embodiment, the palladium catalyst is used in an amount greater than or equal to 0.2 mol% of the amount of BG-10, the phosphine based ligand is used in an amount greater than or equal to 0.4 mol% of the amount of BG-10, the cuprous salt is used in an amount greater than or equal to 3.0 mol% of the amount of BG-10, and the base is used in an amount greater than or equal to 2.0 equivalents of the amount of BG-10.
In one embodiment, the palladium catalyst is used in an amount greater than or equal to 0.5mol% of BG-10, the phosphino ligand is used in an amount greater than or equal to 1.0mol% of BG-10, the cuprous salt is used in an amount greater than or equal to 5.0mol% of BG-10, and the base is used in an amount greater than or equal to 3.0 equivalents of BG-10.
Detailed Description
The following is intended to be illustrative and is intended to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for within the knowledge of one skilled in the art. Unless otherwise specified, temperatures are in degrees Celsius.
The compounds BG-5 and BG-10 used hereinafter were synthesized according to the method disclosed in WO2017/032289A1, the entire content of which is incorporated herein by reference.
BG-5 and BG-10 react in the presence of a palladium catalytic precursor, cuprous ions, a phosphine ligand and alkali to generate an intermediate BG-11A, and an in-situ cyclization reaction is further carried out to produce BG-11.
Figure BDA0002999464620000051
The reaction solution was analyzed for purity and analytical yield using the following analytical methods in the examples:
Figure BDA0002999464620000052
chiral analysis of the reaction solution was performed in the examples using the following analytical methods:
Figure BDA0002999464620000053
Figure BDA0002999464620000061
experimental example 1
Starting with 1.0 equivalent of BG-10 (10.46 mg) and 1.2 equivalents of BG-5, 3.0 equivalents of TMG as base, 4.0mol% Pd (OAc) 2 As a palladium reaction precursor (precursor), 24 phosphine based ligands (CC-I and CC-II) were tested in 4 solvents (10.0 vol. DMF, toluene, t-amyl alcohol or 2-methyl tetrahydrofuran) in the presence of 10mol% CuI, and reacted at 70 ℃ for 16 hours and then at 80 ℃ for 6 hours, respectively.
TABLE 1
Figure BDA0002999464620000062
Figure BDA0002999464620000071
Figure BDA0002999464620000081
Figure BDA0002999464620000091
According to the conversion rate, the reaction yield and the like, X-Phos, J-009, ruphos and Xantphos are determined to be applied to the next round of screening as candidate ligands with better effect. Furthermore, DMF, toluene and tert-amyl alcohol were used as solvents in the subsequent screening.
Example 2
Starting with 1.0 equivalent of BG-10 (10.46 mg) and 1.2 equivalents of BG-5, 3.0 equivalents of TMG as the base, 4.0mol% Pd (OAc) 2 、[PdCl(C 3 H 5 )] 2 、Pd(TFA) 2 、Pd(MeCN) 2 Cl 2 、Pd 2 (dba) 3 And [ (cinnamyl) PdCl] 2 As palladium reaction precursor (precursor), X-Phos, J-009, ruPhos and XantPhos as ligands, the molar ratio of Pd: P was 1. The solvent was 15.0 volumes of DMF, toluene and t-amyl alcohol. The reaction is carried out for 16h at 80 ℃.
TABLE 2
Figure BDA0002999464620000092
Figure BDA0002999464620000101
Figure BDA0002999464620000111
Toluene was experimentally determined to be the more preferred solvent, [ (cinnamyl) PdCl] 2 Is a more preferred palladium reaction precursor. J-009 is a more preferred phosphino ligand. Under the condition, the conversion rate is higher,>99 percent and the intermediate BG-11A is completely converted.
Example 3
Starting with 1.0 equivalent of BG-10 (20.93 mg) and 1.2 equivalents of BG-5, 1.0mol% of [ (cinnamyl) PdCl] 2 As a palladium reaction precursor (precursor), 10% by mol% of CuI, 3.0 equivalent of TMG, and 10.0 times by volume of toluene were added, and the mixture was reacted at 60 ℃ for 16 hours and further at 80 ℃ for 6 hours, to thereby screen 72 ligands.
TABLE 3-1A 60 ℃ results
Figure BDA0002999464620000112
Figure BDA0002999464620000121
Figure BDA0002999464620000131
TABLE 3-1B 80 ℃ results
Figure BDA0002999464620000132
Figure BDA0002999464620000141
Figure BDA0002999464620000151
Figure BDA0002999464620000161
Data studies have found that the conversion is greatly increased after the reaction at 80 ℃ compared to the result at 60 ℃. This result suggests that the second conversion step (cyclization reaction) may require higher energy, and thus higher reaction temperature may bring better reaction results. Therefore, the above screening was performed again at 80 ℃. A series of phosphino ligand-binding [ (cinnamyl) PdCl] 2 Can realize>80% conversion, with a BG-11A/product ratio between 10% and 20%. Using J-009 as ligand, reaction at 80 deg.C for 16h could be achieved>The 99% conversion and the BG-11A/product ratio were 20%.
TABLE 3-2
Figure BDA0002999464620000162
Figure BDA0002999464620000171
Figure BDA0002999464620000181
Example 4
1.0mol% of BG-10 (41.86 mg) and 1.2 equivalents of BG-5 were reacted at 10mol% of CuI, 3.0 equivalents of TMG, 10.0 volumes of toluene, and 80/90 ℃ for 18 hours to screen 6 kinds of palladium reaction precursors Pd (OAc) at 1.0mol% 2 、[Pd(C 3 H 5 )Cl] 2 、Pd(TFA) 2 、Pd(MeCN) 2 Cl 2 、Pd 2 (dba) 3 、[(cinnamyl)PdCl] 2 With 9 phosphino ligands J-009, ph 2 Cy、Ph 2 DavePhos、(p-anisyl) 3 P、BrettPhos、Ph 2 P-CH 2 CH 2 -(2-Pyr)、Cy-BippyPhos、XantPhos、Ph 3 A combination of P.
TABLE 4
Figure BDA0002999464620000182
Figure BDA0002999464620000191
Figure BDA0002999464620000201
Figure BDA0002999464620000211
Figure BDA0002999464620000221
Phosphino ligands J-009 or XantPhos with [ (cinnamyl) PdCl) at 90 ℃ were found] 2 And/or [ Pd (C) 3 H 5 )Cl] 2 Can realize>98% conversion and<1.5% BG-11A/product.
Example 5
1.0 equivalent of BG-10 (41.86 mg) and 1.2 equivalents of BG-5 as starting materials, and 3.0 equivalents of TMG and/or DBU as an alkali were reacted in the presence of 10mol% of CuI, 10.0 volumes of toluene, at 90 ℃ for 18 hours, and 0.1 to 1.0mol% equivalent of a palladium reaction precursor was selected.
TABLE 5
Figure BDA0002999464620000222
Figure BDA0002999464620000231
TMG was found to be J-009/[ (cinnamyl) PdCl] 2 Or J-009/[ Pd (C) 3 H 5 )Cl] 2 Catalytic combinations are preferred bases. And DBU is XantPhos/[ (cinnamyl) PdCl] 2 Catalytic combinations are preferred bases. The preferred amount of palladium precursor is 0.8to 1.0mol%.
Example 6
Conditions such as the amount of different optimized materials and the temperature were optimized again by using 1.0 equivalent of BG-10 (41.86 mg) and 1.2 equivalents of BG-5 as starting materials and toluene as a solvent at 90 ℃.
Figure BDA0002999464620000241
Figure BDA0002999464620000251
The reaction conditions which ultimately determine the most preferred are:
(1) 1.0 equivalent of BG-10,1.2 equivalents of BG-5,0.5mol% of [ (cinnamiyl) PdCl] 2 (CAS: 12131-44-1), 1.0mol% J-009 (CAS: 158923-11-6), 5.0mol% CuI and 3.0 equivalent of TMG were reacted in 10 times of toluene at 90 ℃ for 20 hours, and the reaction could reach>98 percent conversion rate,>Yield (assay) was 99%.
(2) 1.0 equivalent of BG-10,1.2 equivalents of BG-5,0.5mol% of [ (cinnamyl) PdCl] 2 (CAS: 12131-44-1), 1.0mol% XantPhos (CAS: 161265-03-8), 20.0mol% CuI and 3.0 equivalents DBU were reacted in 10 times of toluene at 90 ℃ for 20 hours, and the reaction was allowed to reach>98 percent of conversion rate,>Yield (assay yield) was 97%.
(3) 1.0 equivalent of BG-10,1.2 equivalents of BG-5,0.5mol% of [ (cinnamyl) PdCl] 2 (CAS: 12131-44-1), 1.0mol% XantPhos (CAS: 161265-03-8), 15.0mol% CuI and 3.0 equivalents DBU were reacted in 10 times of toluene at 90 ℃ for 20 hours, and the reaction was allowed to reach>98 percent of conversion rate,>Yield (assay) was analyzed at 92%.
Example 7
1.0 equivalent of BG-10 (523.2 mg) and 1.2 equivalents of BG-5 as starting materials, 3.0 equivalents of TMG as a base, in the presence of 5mol% of CuI, 10.0 volumes of toluene, 90 ℃ for 18h, with J-009 as a phosphino ligand, and [ (cinnamyl) PdCl] 2 、[Pd(C 3 H 5 )Cl] 2 The stereoselectivity of the reaction was tested as a palladium catalyzed precursor.
TABLE 7
Figure BDA0002999464620000261
Example 8
Starting with 1.0 equivalent of BG-10 (523.2 mg) and 1.2 equivalents of BG-5, 3.0 equivalents of DBU as base, 0.5mol% of [ (cinnamyl) PdCl] 2 (CAS: 12131-44-1), 1.0mol% XantPhos, in the presence of 10mol% to 20mol% CuI, 10.0 times the volume of toluene, at 90 ℃ for 18h, and the stereoselectivity of the reaction was tested.
Figure BDA0002999464620000262

Claims (9)

1. Catalyst system for Sonogashira coupling and in situ ring closure reactions comprising a palladium catalyst [ Pd]A phosphine based ligand, a cuprous salt and a base, wherein the palladium catalyst is selected from the group consisting of [ (cinnamyl) PdCl] 2 And/or [ Pd (C) 3 H 5 )Cl] 2 The phosphine group ligand is J-009 and/or XantPhos, the cuprous salt is CuI, and the alkali is tetramethylguanidine and/or DBU; the molar ratio of the palladium catalyst to the phosphine based ligand is 1.
2. The catalyst system of claim 1, wherein the palladium catalyst is selected from the group consisting of [ (cinnamyl) PdCl] 2 And [ Pd (C) 3 H 5 )Cl] 2 One kind of (1).
3. The catalyst system of claim 1, wherein the phosphino ligand is one selected from the group consisting of J-009 and XantPhos.
4. The catalyst system of claim 1, wherein the base is one selected from the group consisting of tetramethylguanidine and DBU.
5. The catalyst system according to claim 1, wherein the molar ratio of the palladium catalyst to the cuprous salt is 1.
6. The catalyst system of claim 1, wherein the molar ratio of the palladium catalyst [ Pd ], phosphine-based ligand, cuprous salt, and base is 1.
7. The catalyst system of claim 1, wherein the molar ratio of the palladium catalyst [ Pd ], phosphine-based ligand, cuprous salt, and base is 1.
8. The catalyst system of claim 1, wherein the molar ratio of the palladium catalyst [ Pd ], phosphine-based ligand, cuprous salt, base is 1.
9. The catalyst system of claim 1, wherein said [ (cinnamyl) PdCl] 2 J-009, cuI and TMG in a molar ratio of 1 3 H 5 )Cl] 2 J-009, cuI and TMG in a molar ratio of 1] 2 The molar ratio of XantPhos, cuI and TMG is 1] 2 The molar ratio of XantPhos, cuI and TMG is 1.
CN202110354708.7A 2021-03-30 2021-03-30 Catalyst system for Sonogashira coupling reaction and in-situ ring closing reaction Pending CN115138396A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110354708.7A CN115138396A (en) 2021-03-30 2021-03-30 Catalyst system for Sonogashira coupling reaction and in-situ ring closing reaction

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110354708.7A CN115138396A (en) 2021-03-30 2021-03-30 Catalyst system for Sonogashira coupling reaction and in-situ ring closing reaction

Publications (1)

Publication Number Publication Date
CN115138396A true CN115138396A (en) 2022-10-04

Family

ID=83405259

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110354708.7A Pending CN115138396A (en) 2021-03-30 2021-03-30 Catalyst system for Sonogashira coupling reaction and in-situ ring closing reaction

Country Status (1)

Country Link
CN (1) CN115138396A (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106488902A (en) * 2014-05-29 2017-03-08 盐野义制药株式会社 The manufacture method of alkynyl ketone derivatives
CN107175134A (en) * 2017-05-31 2017-09-19 成都西岭源药业有限公司 It is a kind of to be used to prepare 3-aminophenylacetylene or the composition of its salt and application thereof
CN107226779A (en) * 2016-03-23 2017-10-03 国际香料和香精公司 For making the method that substitution diene hydrocarbon-selective palladium chtalyst is telomer
US20200016582A1 (en) * 2017-03-28 2020-01-16 Yale University Cross-Coupling Reaction Catalysts, and Methods of Making and Using Same
CN111171002A (en) * 2019-05-16 2020-05-19 百济神州(苏州)生物科技有限公司 Preparation method of PARP inhibitor intermediate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106488902A (en) * 2014-05-29 2017-03-08 盐野义制药株式会社 The manufacture method of alkynyl ketone derivatives
CN107226779A (en) * 2016-03-23 2017-10-03 国际香料和香精公司 For making the method that substitution diene hydrocarbon-selective palladium chtalyst is telomer
US20200016582A1 (en) * 2017-03-28 2020-01-16 Yale University Cross-Coupling Reaction Catalysts, and Methods of Making and Using Same
CN107175134A (en) * 2017-05-31 2017-09-19 成都西岭源药业有限公司 It is a kind of to be used to prepare 3-aminophenylacetylene or the composition of its salt and application thereof
CN111171002A (en) * 2019-05-16 2020-05-19 百济神州(苏州)生物科技有限公司 Preparation method of PARP inhibitor intermediate

Similar Documents

Publication Publication Date Title
RU2631243C2 (en) Dimethylamide 7-cyclopentyle-2-(5-piperazin-1-il-pyridine-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carbonic acid salt (salts) and method for their production
CN107880079B (en) Cyclic N-heterocyclic bis-carbene-palladium complex and preparation method and application thereof
CN107176955A (en) A kind of Ba Rui replaces the preparation method of Buddhist nun
CN105777710A (en) Synthesis method of Alectinib
CN106831737A (en) The preparation of Wei Patawei and its derivative
CN105985345A (en) Preparation method for ibrutinib and intermediate of ibrutinib
CN109970719B (en) Pyrazole ligand-based alkali-stable metal organic framework material, and preparation method and application thereof
CN108864147B (en) Octanitrogen oxygen heterocyclic spiro indolone compound and preparation method thereof
EP4045494B1 (en) Synthesis of 6-methyl-n1-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine
CN115138396A (en) Catalyst system for Sonogashira coupling reaction and in-situ ring closing reaction
CN111171002B (en) Preparation method of PARP inhibitor intermediate
CN107827705A (en) A kind of single arylation method of dichloro benzene-like compounds
CN115141178A (en) Method for preparing PARP inhibitor intermediate
CN114014805B (en) Preparation method of trifluoromethyl 2, 4-quinoline diketone compound
CN113004248B (en) Method for synthesizing carbazole compound by catalyzing hydrocarbon amination reaction with cobalt
CN109020977B (en) Preparation method of Acaraburtinib
CN110437277B (en) Synthetic method of phosphoalkenyl ester compound
CN108484499B (en) Method for preparing polysubstituted isoquinoline derivative from hydroxylamine and alkyne
CN112225729A (en) Pyrimidine derivative, preparation method and application thereof and pharmaceutical composition
CN104945434A (en) (2-disubstituted phosphino-phenyl)-1-alkyl-indol-phosphine ligand and synthetic method and application thereof
CN109153652A (en) The preparation process of 1- (aryl methyl) quinazoline -2,4 (1H, 3H)-diketone
CN112898277B (en) Preparation method of afatinib intermediate
CN105367567B (en) A kind of compound and its application in the western croak of Leo is prepared
CN111943853B (en) Preparation method of pezopanib impurity
CA3225147A1 (en) Synthesis of a bis-mesylate salt of 4-amino-n-(1 -((3-chloro-2- fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2- d]pyrimidine-7-carboxamide and intermediates thereto

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination