CN113402502B - Material combination system for preparing PARP inhibitor intermediate - Google Patents

Material combination system for preparing PARP inhibitor intermediate Download PDF

Info

Publication number
CN113402502B
CN113402502B CN202110525007.5A CN202110525007A CN113402502B CN 113402502 B CN113402502 B CN 113402502B CN 202110525007 A CN202110525007 A CN 202110525007A CN 113402502 B CN113402502 B CN 113402502B
Authority
CN
China
Prior art keywords
material combination
combination system
reaction
dtbpf
mole ratio
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.)
Active
Application number
CN202110525007.5A
Other languages
Chinese (zh)
Other versions
CN113402502A (en
Inventor
王卫娟
刘军涛
掌子龙
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 CN202110525007.5A priority Critical patent/CN113402502B/en
Publication of CN113402502A publication Critical patent/CN113402502A/en
Application granted granted Critical
Publication of CN113402502B publication Critical patent/CN113402502B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/08—Halides
    • B01J27/122—Halides of copper
    • 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
    • B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
    • 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
    • B01J35/00—Catalysts, in general, characterised by their form or physical properties
    • B01J35/19—Catalysts containing parts with different compositions
    • 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
    • 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
    • B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
    • B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
    • 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
    • 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
    • B01J2531/84—Metals of the iron group
    • B01J2531/842—Iron
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

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

Abstract

The present invention relates to a material combination system in the preparation process of (R) -2- (1- (2- (tert-butyloxy) -2-oxoethyl) -2-methylpyrrolidin-2-yl) -6-fluoro-1-tosyl-1H-indole-4-carboxylic acid methyl ester, an intermediate of Pamiparib, in particular, in the presence of a palladium (Pd) catalyst and cuprous iodide (Cul), wherein the palladium catalyst at least comprises one or two of Pd (dppf) Cl2 and Pd (dtbpf) Cl 2. The material combination system can improve the conversion rate of raw materials and obtain products with high chiral purity, is stable in production, good in repeatability and high in yield, and saves production cost in industrial mass production.

Description

Material combination system for preparing PARP inhibitor intermediate
Technical Field
The invention discloses a material combination system for PARP inhibitor intermediate preparation, and particularly relates to a material combination system for preparation of an intermediate (R) -2- (1- (2- (tert-butyloxy) -2-oxoethyl) -2-methylpyrrolidine-2-yl) -6-fluoro-1-tosyl-1H-indole-4-carboxylic acid methyl ester of Pamiparib.
Background
WO2013/097225A1 discloses inhibitors as poly (ADP-ribosyl) transferases (PARPs) and specifically discloses compounds
Figure BDA0003065599250000011
I.e. (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, an inhibitor of poly Adenosine Diphosphate (ADP) ribose polymerase (PARP), which is highly selective for PARP-1/2 and 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 Olapanib, with excellent DMPK properties andsignificant brain permeability. WO2017/032289A1 discloses (R) -2-fluoro-10 a-methyl-7,8,9, 10, 10a, 11-hexahydro-5,6,7a, 11-tetraazacyclohepta [ def ]]Cyclopenta [ a ]]A process for the large-scale synthesis of fluoren-4 (5H) -one, wherein,
Figure BDA0003065599250000012
is an important intermediate in the preparation process of Pamiparib. In the large scale synthesis process disclosed in WO2017/032289A1,
Figure BDA0003065599250000013
(BG-5) with
Figure BDA0003065599250000014
(BG-10) in Pd (Ph) 3 ) 2 Cl 2 And Cul to form the intermediate
Figure BDA0003065599250000015
I.e. (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), however when Pd (Ph) is used 3 ) 2 Cl 2 And Cul as a catalyst, there is a large amount of BG-10 that cannot complete the conversion, resulting in difficulty in purification and poor yield.
The inventors of the present invention have found, through a large number of inventive investigations, that Pd (dppf) Cl is used 2 And cuprous salt is used as a catalyst, so that the problem of low conversion rate is solved, the reaction can be completed within 36 hours, only about 0.3 percent of BG-10 remains, and the conversion rate of BG-10 is greatly improved.
However, in the use of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl 2 ) And cuprous salt is used as a catalyst, BG-10 generates partial racemization in the reaction process, and the chiral purity of the obtained product is only about 90 percent. Additional chemical resolution operations are required in subsequent steps to achieve the desired chiral purity of the downstream drug substance (not less than 98.5%), which results in increased production costs and material loss. On the basis, the inventor further screens various catalysts and catalytic systemsIt was found that when 1,1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (Pd (dtbpf) Cl) was added 2 ) And cuprous salt is used as a catalyst, so that the high reaction conversion rate of BG-10 can be ensured, and the chiral purity of the reaction liquid is controlled to be about 99.0 percent. After post-treatment and crystallization purification, the product with HPLC purity of more than 99.0% and chiral purity of more than 99.0% can be obtained, and the yield ranges from 65% to 85%.
Disclosure of Invention
The invention relates to a PARP inhibitor intermediate, in particular to an intermediate of pamiprarib
Figure BDA0003065599250000021
Namely (R) -2- (1- (2- (tert-butyloxy) -2-oxoethyl) -2-methylpyrrolidin-2-yl) -6-fluoro-1-tosyl-1H-indole-4-carboxylic acid methyl ester (i.e., BG-11), using a method comprising the steps of:
reacting BG-10 with BG-5 in an organic solvent to obtain BG-11;
Figure BDA0003065599250000022
the reaction is carried out using a palladium (Pd) catalyst and a cuprous salt,
the palladium catalyst at least comprises Pd (dppf) Cl 2 And Pd (dtbpf) Cl 2 One or two of them.
Preferably, the palladium catalyst comprises Pd (dtbpf) Cl 2 。
Optionally, the palladium catalyst may also optionally comprise Pd (PPh) 3 ) 2 Cl 2 Pd (dibenzylideneacetone) Cl 2 P (cyclohexyl) 3 、PPh 3 、BINAP、P(n-Bu) 3 、P(t-Bu) 3 One or more ligands of dtbpf, and/or Pd (OAc) 2 、PdCl 2 And any combination of one or more palladium salts.
Preferably, the palladium catalyst is Pd (dPPf) Cl 2 。
More preferablyThe palladium catalyst is Pd (dtbpf) Cl 2 。
The cuprous salt may be selected from the group including, but not limited to, cuprous iodide, cuprous bromide, cuprous chloride, cuprous acetate, cuprous triflate, and any combination thereof.
Preferably, the organic solvent may be selected from the group including, but not limited to: dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), toluene, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), acetonitrile, dioxane, and any combination thereof.
Preferably, the mole ratio of BG-10 to BG-5 is 1: 0.8-1: 3; preferably 1: 0.9-1: 2; more preferably 1: 1 to 1: 1.5; even more preferably 1: 1.2 to 1: 1.4.
Preferably, the mole ratio of BG-10 to palladium catalyst is 1: 0.01-1: 0.1; preferably, the following components are used: 1: 0.05-1: 0.1; more preferably 1: 0.05 to 1: 0.08.
Preferably, BG-10 is reacted with Pd (dpPf) Cl 2 The molar ratio of (1: 0.01) - (1: 0.1); preferably: 1: 0.05-1: 0.1; more preferably 1: 0.05 to 1: 0.08.
Preferably, BG-10 and Pd (dtbpf) Cl are mentioned 2 The molar ratio of (1: 0.01) - (1: 0.1); preferably: 1: 0.05-1: 0.1; more preferably 1: 0.05 to 1: 0.08.
Preferably, the weight-to-volume ratio (M/V, g/ml) of BG-10 to the organic solvent is 1: 1-1: 10, preferably 1: 1-1: 6; more preferably 1: 2; 1: 3; 1: 4 and 1: 5.
Preferably, the mole ratio of BG-10 to cuprous salt is 1: 0.01-1: 0.1; more preferably: 1: 0.05-1: 0.1; most preferably 1: 0.05-1: 0.08.
Preferably, alkaline substances are also used in the material combination system. The basic material is selected from the group consisting of, but not limited to, diisopropylethylamine (DIPEA), triethylamine, pyridine, tetramethylguanidine, azomethine morpholine, potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, triethylenediamine (DABCO), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), and any combination thereof; more preferably, the composition comprises a compound selected from the group consisting of diisopropylethylamine, cesium carbonate, triethylenediamine (DABCO), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), tetramethylguanidine, and any combination thereof.
Preferably, the mole ratio of BG-10 to alkaline substance is 1: 0.5-1: 6; preferably 1: 0.8-1: 4; most preferably 1: 1 to 1: 3.
Preferably, the reaction of the material combination system is carried out in a reaction kettle. More preferably, the reaction vessel is purged with nitrogen.
Preferably, the temperature of the reaction of the material combination system is 50 to 100 ℃, preferably 60 to 85 ℃, more preferably 70 to 80 ℃, and most preferably 75 to 80 ℃.
Preferably, the reaction time of the material combination system is 1 to 48 hours, preferably 5 to 40 hours, and more preferably 12 to 30 hours.
Preferably, the temperature is reduced to 15-30 ℃ after the material combination system is reacted, and preferably the temperature is reduced to room temperature.
Preferably, BG-5 is a free base.
The use method of the material combination system also comprises the step of preparing BG-5 free base: the BG-5 salt compound is treated with a base to obtain the free base of BG-5.
The base includes but is not limited to potassium hydroxide, sodium hydroxide, ammonia, sodium carbonate, sodium bicarbonate, potassium carbonate, ammonium bicarbonate.
Preferably, this step is carried out in a mixed solution of n-heptane and water. Preferably, the preparation of BG-5 free base comprises the steps of: suspending BG-5 salt in a mixed solvent of n-heptane and water, and adding an alkaline solution to the above mixed solution to carry out a reaction, thereby obtaining the BG-5 free base.
The specific operation of the reaction is as follows: stirring, reacting, standing for layering, collecting an organic phase, washing with water, and filtering to remove insoluble substances; and concentrating the organic phase, azeotropically removing water, adding N, N-Dimethylformamide (DMF), and continuously distilling to remove residual N-heptane to obtain a DMF solution of BG-5 free base.
Preferably, the method for using the material combination system further comprises the steps of purification and recrystallization after the reaction.
The use method of the material combination system further comprises the step of recrystallizing the BG-11.
Preferably, said recrystallization is carried out in an alcoholic solvent. More preferably, the recrystallization is carried out in methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol. Even more preferably, said recrystallization is carried out in methanol.
The material combination system has stable production, good repeatability and high yield, does not need to carry out additional splitting operation in subsequent steps, saves the production cost in industrial mass production, and has good economic value.
Detailed Description
Experimental example-screening of catalysts
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.
Experimental example 1
The compound BG-10 (5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to a reaction vessel, 25mL of N, N-dimethylformamide was then added, the reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (dppf) Cl were added 2 (0.746mmol, 0.06eq.). Heating the reaction system to 75-80 ℃, and stirring for reaction for 15 hours. After the reaction is finished, cooling the reaction system to room temperature.
Wherein eq (equivalent) refers to the molar ratio of other substances based on the main raw material (set to 1 eq.), and if the raw material Cul is 0.06eq, the molar ratio of the raw material Cul to the main raw material BG-10 is 0.06: 1.
Figure BDA0003065599250000051
The intermediate impurity BG-11A is generated in the process of reaction, and the impurity is one of important indexes needing to be monitored in a central control link. The experimental conversion rate was intermediately controlled using Agilent HPLC (high performance liquid chromatography) taking into account the content percentages of the raw material BG-10, the intermediate impurity BG-11A remaining in the reaction solution and the product BG-11 (i.e. the intermediate control result). After the reaction is carried out for 12-120 hours, the temperature is reduced to below 50 ℃, about 0.2mL of reaction liquid is taken, acetonitrile/water (volume ratio is 8/2) is added for dissolution, and HPLC sample injection test is carried out. All chromatographic peaks above the limit of detection were integrated and the percentage of the corresponding compound HPLC peak area read.
The chiral purity of BG-11 in the reaction solution was tested by HPLC using a chiral liquid chromatography column: reacting for a period of time, cooling to below 50 ℃, taking about 0.2ml of reaction liquid, adding ethanol for dissolving, adopting HPLC sample injection test loaded with a chiral liquid chromatographic column, integrating the product BG-11 and the corresponding isomer thereof, and calculating the percentage of the two respectively.
The control result is as follows: BG-10/BG-11A/BG-11=0.3%/0.8%/88.2%, chiral purity by HPLC 90.1%.
In order to further improve the purity of BG-11, the following operations are still required: adding 30-50 g of methyl tert-butyl ether and 50-60 g of water, stirring, standing for layering, stirring the organic phase for a period of time, standing for layering, removing the water phase, and washing the organic phase with water. The organic phase was washed twice with 15-25g of 10% aqueous thiourea solution and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, carrying out solvent replacement by using 10-30 g of n-heptane, adding 8-10 g of ethyl acetate to obtain an n-heptane/ethyl acetate solution of the BG-11 crude product, carrying out decolorization and secondary silica gel column treatment, concentrating the filtrate, and carrying out solvent replacement by using 10-15 g of ethyl acetate. The BG-11 ethyl acetate solution (96% HPLC purity, 92.1% chiral purity, 68% yield) was obtained and used directly in the next step.
Experimental example 2
The compound BG-10 (5.0 g,12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reactor followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (PPh) were added 3 ) 2 Cl 2 (0.746mmol, 0.06eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.
Then, intermediate control and test were carried out in the same manner as in example 1 to obtain the control result of example 2 of BG-10/BG-11A/BG-11=31.6%/5.9%/50.4% and HPLC chiral purity of 97.1%.
Experimental example 3
The compound BG-10 (5.0 g,12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reactor followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (dppf) Cl were added 2 (0.746mmol, 0.06eq.) and PPh 3 (1.491mmol, 0.12eq). The temperature of the reaction system is raised to 75-80 ℃, and the reaction is stirred for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.
Then, intermediate control and test were carried out in the same manner as in example 1 to obtain the control result of example 3 of BG-10/BG-11A/BG-11=0.1%/2.6%/81.1% and HPLC chiral purity of 91.4%.
Experimental example 4
The compound BG-10 (5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to a reaction vessel, followed by addition of 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (dPPf) Cl were added 2 (0.249mmol, 0.02eq.) and Pd (PPh) 3 ) 2 Cl 2 (0.249mmol, 0.02eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.
Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 4 was obtained as follows: BG-10/BG-11A/BG-11=2.9%/2.1%/85.2%, HPLC chiral purity 93.1%.
Experimental example 5
The compound BG-10 (5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to a reaction vessel, followed by addition of 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (dibenzylideneacetone) Cl were added 2 (Pd(dibenzalacetone)Cl 2 ) (0.746mmol, 0.06eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.
Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 5 was obtained as follows: BG-10/BG-11A/BG-11=92.7%/0%/0.5%, HPLC chiral purity was not determined.
Experimental example 6
The compound BG-10 (5.0 g,12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to a reaction vessel, followed by addition of 25ml of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (PPh) were added 3 ) 4 (0.746mmol, 0.06eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.
Then, intermediate control and test were carried out in the same manner as in example 1 to obtain the control result of example 6 of BG-10/BG-11A/BG-11=46.9%/8.6%/26.6% and HPLC chiral purity of 98.8%.
Experimental example 7
The compound BG-10 (5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to a reaction vessel, followed by addition of 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (dtbpf) Cl were added 2 (0.746mmol, 0.06eq.)). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.
Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control results in experimental example 7 were: BG-10/BG-11A/BG-11=2.6%/3.1%/82.6%, HPLC chiral purity 99.0%.
Experimental example 8
The compound BG-10 (5.0 g,12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reactor followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (OAc) were added 2 (0.746mmol, 0.06eq.), P (cyclohexyl) 3 (P(cyclohexyl) 3 ) (1.491mmol, 0.12eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.
Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control results in experimental example 8 were: BG-10/BG-11A/BG-11=80.3%/2.6%/9.8%, chiral purity by HPLC 88.1%.
Experimental example 9
The compound BG-10 (5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to a reaction vessel, followed by addition of 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (OAc) were added 2 (0.746mmol, 0.06eq.), BINAP (0.746mmol, 0.06eq.). The temperature of the reaction system is raised to 75-80 ℃, and the reaction is stirred for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.
Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 9 was obtained as follows: BG-10/BG-11A/BG-11=83.8%/2.1%/9.7%, HPLC chiral purity 96.4%.
Experimental example 10
The compound BG-10 (5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to a reaction vessel, followed by addition of 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (OAc) were added 2 (0.746mmol，0.06eq.)，P(Bu) 3 (1.491mmol, 0.12eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.
Then, intermediate control and test were carried out in the same manner as in example 1 to obtain the control result of experiment 10, BG-10/BG-11A/BG-11=90.4%/0%/1.0%, and since the yield of BG-11 was too low, the chiral purity of HPLC was not measured.
Experimental example 11
The compound BG-10 (5.0 g,12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reactor followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (OAc) were added 2 (0.746mmol，0.06eq.)，PPh 3 (1.491mmol, 0.12eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.
Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 11 was obtained as follows: BG-10/BG-11A/BG-11=39.5%/4.8%/43.1%, HPLC chiral purity 96.0%.
Experimental example 12
The compound BG-10 (5.0 g,1.491mmol, 0.12eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reactor followed by 25mL of N,/N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (OAc) were added 2 (0.746 mmol, 0.06eq.), dtbpf (0.746 mmol, 0.06eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, cooling to room temperature.
Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 12 was obtained as follows: BG-10/BG-11A/BG-11=11.8%/0.8%/75.3%, HPLC chiral purity 98.9%.
Experimental example 13
The compound BG-10 (5.0 g,12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29 mmol,3 eq.) was added to the kettle followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746 mmol, 0.06eq.) and Pd (OAc) were added 2 (0.746mmol，0.06eq.)，P(t-Bu) 3 (0.746mmol, 0.06eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.
Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control results in experimental example 13 were: BG-10/BG-11A/BG-11=27.9%/3.4%/59.2%, HPLC chiral purity 99.0%.
Experimental example 14
The compound BG-10 (1.0 g,2.49mmol, 1eq.), BG-5 free base (3.49mmol, 1.4eq.), and Diisopropylethylamine (DIPEA) (7.47mmol, 3eq.) were added to the reactor followed by 4mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.149mmol, 0.06eq.) and Pd (OAc) were added 2 (0.149mmol，0.06eq.)，P(t-Bu) 3 HBF 4 (0.149mmol, 0.06eq.) and reacted at 60 ℃ for 17 hours. The reaction system is heated to 80 ℃ and stirred for reaction for 48 hours. After the reaction was completed, a sample was taken for central control testing.
Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 14 was obtained as follows: BG-10/BG-11A/BG-11=31.65%/0%/50.66%.
Experimental example 15
Compound BG-10 (1.0g, 2.49mmol, 1eq.), BG-5 free base (3.49mmol, 1.4eq.) and azabicyclo (DBU) (7.47mmol, 3eq.) were added to the reactor, followed by 4mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.149mmol, 0.06eq.) and Pd (OAc) were added 2 (0.149mmol，0.06eq.)，P(t-Bu) 3 HBF 4 (0.149mmol, 0.06eq.) and reacted at 60 ℃ for 17 hours. The reaction system is heated to 80 ℃ and stirred for reaction for 48 hours. After the reaction is finished, sampling and carrying out central control testing.
Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control results of experimental example 15 were obtained as follows: BG-10/BG-11A/BG-11=0%/1.41%/54.30%.
TABLE 1 results of catalyst screening
Figure BDA0003065599250000101
As can be seen from the screening results, when Pd (PPh) is used 3 ) 2 Cl 2 、Pd(dibenzalacetone)Cl 2 And Pd (PPh) 3 ) 4 、Pd(OAc) 2 (use Pd (OAc) 2 Used together with a phosphine ligand when used as a catalyst), etc., a large amount of BG-10 is present and cannot be converted into BG-11. Pd (PPh) was used as in Experimental example 2 3 ) 2 Cl 2 As a catalyst, 31.6% of BG-10 was not converted, and the controlled conversion of BG-10 was 50.4%. When Pd (dppf) Cl is used 2 And/or Pd (dtbpf) Cl 2 When used as a catalyst, the conversion rate of BG-10 can be greatly improved, and Pd (dppf) Cl is used in examples 1 and 3 2 The balance of BG-10 was only 0.3% and 0.1%; using Pd (dtbpf) Cl 2 The remaining amount of the catalyst BG-10 was only 2.6%.
Although Pd (dppf) Cl was used 2 When the catalyst is used as a catalyst, the conversion rate of BG-10 is high, but the chiral purity of the obtained BG-11 is only 90.1% (Experimental example 1), and the purity cannot be directly used for the next drug production, and the chiral purity needs to be improved by chemical resolution in the subsequent production steps.
And Pd (dtbpf) Cl is used 2 The experimental example 7 as the catalyst has higher BG-10 conversion rate, the chiral purity of the reaction product BG-11 in the step can reach 99.0 percent, and the step of chemical resolution can be omitted, so that the production cost is reduced.
Example 1
64.0g of BG-5 salt (105mmol, 1.4 eq.) was suspended in a mixed solvent composed of 150mL of n-heptane and 60mL of water to form a suspension, and the temperature of the suspension was lowered to 5 ℃. 23.4g of potassium hydroxide was dissolved in 75mL of water, added to the suspension, stirred for 2 hours, and then warmed to room temperature. Standing for phase separation, collecting organic phase, and comparingThe organic phase was washed with water and filtered to remove insoluble material. The organic phase was concentrated, azeotroped and water removed, then 60mL of N, N-Dimethylformamide (DMF) was added and the remaining N-heptane was distilled off to give a solution of BG-5 free base in N, N-dimethylformamide. The BG-5 solution was transferred to a reaction vessel, and then 30.0g of BG-10 (75mmol, 1.0 eq.), 25.8g of tetramethylguanidine and 60mL of N, N-dimethylformamide were added. The reaction vessel was purged with nitrogen, and then cuprous iodide (4.5mmol, 0.060eq.) and Pd (dtbpf) Cl were added 2 (4.5mmol, 0.060eq.). The reaction was warmed to 80 ℃ and the reaction mixture was stirred for 22 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butyl ether and 250-300 g of water. After stirring for a while, the mixture was allowed to stand to separate the aqueous phase and the organic phase was washed with water. The organic phase was washed with 120 to 160g of a mixed aqueous solution containing 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, adding 150-180 g of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Heating to dissolve the solid generated in the system, then cooling to 40 ℃, adding crystal seeds BG-11 to induce crystallization, slowly adding water to fully separate out the product, and then cooling to 5 ℃. The solid is collected by filtration and washed by a methanol/water mixed solvent, and the wet product is dried in vacuum at 40-45 ℃ to obtain the product BG-11 (the HPLC purity is 99.8 percent, the chiral purity is 99.3 percent, and the control result is that BG-10/BG-11A/BG-11=0%/3.6%/81.3 percent, the raw material BG-10 is completely converted, the residual intermediate BG-11A is 3.6 percent, BG-11 is 81.3 percent, and the yield is 75.1 percent).
Example 2
64.0g of BG-5 salt (105mmol, 1.4 eq.) was suspended in a mixed solvent composed of 150mL of n-heptane and 45mL of water, and the temperature was reduced to 5 ℃. 23.4g of potassium hydroxide was dissolved in 120mL of water, added to the suspension, stirred for 2 hours, and then warmed to room temperature. Standing for phase separation, collecting organic phase, washing with water, and filtering to remove insoluble substances. The resulting organic phase was concentrated to remove water azeotropically, then 90mL of N, N-Dimethylformamide (DMF) was added and the remaining N-heptane was distilled off to give a solution of BG-5 free base in N, N-dimethylformamide. Transferring BG-5 solution into a reaction kettle, and then30.0g of BG-10 (75mmol, 1.0 eq.), 25.8g of tetramethylguanidine and 90mL of N, N-dimethylformamide were added. The autoclave was purged with nitrogen, and then cuprous iodide (4.5mmol, 0.060eq.) and Pd (dtbpf) Cl were added 2 (4.5mmol, 0.060eq.). The reaction system is heated to 80 ℃ and stirred for reaction for 24 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butyl ether and 250-300 g of water. After stirring for a while, the mixture was allowed to stand to separate the aqueous phase and the organic phase was washed with water. The separated organic phase was washed with 120 to 160g of a mixed aqueous solution containing 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, adding 150-180 g of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Distilling the mixture, heating to dissolve solid generated in the system, then cooling to 40-45 ℃ for crystallization, adding crystal seed BG-11 for inducing crystallization, slowly adding water to fully separate out a product, and then cooling to 5 ℃. The solid was collected by filtration, washed with a mixed solvent of methanol/water, and dried in vacuo at 45 ℃ to give BG-11 (chiral purity 99.53%, yield 68.28%) as a product.
Example 3
64.0g of BG-5 salt (105mmol, 1.4 eq.) was suspended in a mixed solvent composed of 150mL of n-heptane and 60mL of water, and the temperature was reduced to 5 ℃. 23.4g of potassium hydroxide was dissolved in 120mL of water, added to the suspension, stirred for 2 hours, and then warmed to room temperature. Standing for phase separation, collecting organic phase, washing with water, and filtering to remove insoluble substances. The resulting organic phase was concentrated for azeotropic removal of water, then 60mL of N, N-Dimethylformamide (DMF) was added and the remaining N-heptane was distilled off to give a solution of BG-5 free base in N, N-dimethylformamide. The BG-5 solution was transferred to a reaction vessel, and then 30.0g of BG-10 (75mmol, 1.0 eq.), 25.8g of tetramethylguanidine and 60mL of a solution of N, N-dimethylformamide were added. The reaction vessel was purged with nitrogen, and then cuprous iodide (4.5mmol, 0.060eq.) and Pd (dtbpf) Cl were added 2 (6.0 mmol, 0.080eq.). The reaction system was heated to 80 ℃ and stirred for 22 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butyl ether and 250-300 g of water. Stirring for a while, standing to remove water phase, adding organic phaseAnd (4) washing with water. The separated organic phase was washed with a mixed aqueous solution containing 120 to 160g of 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, supplementing 150-180 q of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Distilling the mixture, heating to dissolve solid generated in the system, then cooling to 40-45 ℃ for crystallization, adding crystal seed BG-11 for inducing crystallization, slowly adding water to fully separate out a product, and then cooling to 5 ℃. The solid was collected by filtration, washed with a mixed solvent of methanol/water, and dried in vacuo at 45 ℃ to give BG-11 (chiral purity 99.43%, yield 76.98%) as a product.
Example 4
64.0g of BG-5 salt (105mmol, 1.4 eq.) was suspended in a mixed solvent composed of 150mL of n-heptane and 60mL of water, and the temperature was reduced to 5 ℃. 23.4g of potassium hydroxide was dissolved in 120mL of water, added to the suspension, stirred for 2 hours, and then warmed to room temperature. Standing for phase separation, collecting organic phase, washing with water, and filtering to remove insoluble substances. The resulting organic phase was concentrated for azeotropic removal of water, then 60mL of N, N-Dimethylformamide (DMF) was added and the remaining N-heptane was distilled off to give a solution of BG-5 free base in N, N-dimethylformamide. The BG-5 solution was transferred to a reaction kettle and then 30.0g of BG-10 (75mmol, 1.0 eq.), 25.8g of tetramethylguanidine and 60mL of N, N-dimethylformamide were added. The reaction vessel was purged with nitrogen, and then cuprous iodide (3.75mmol, 0.050eq.) and Pd (dtbpf) Cl were added 2 (4.5mmol, 0.060eq.). The reaction system was heated to 80 ℃ and stirred for 22 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butyl ether and 250-300 g of water. After stirring for a while, the mixture was allowed to stand to separate the aqueous phase, and the organic phase was washed with water. The separated organic phase was washed with 120 to 160g of a mixed aqueous solution containing 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, adding 150-180 g of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Distilling the mixture, heating to dissolve the solid generated in the system, then cooling to 40-45 ℃ for crystallization, adding crystal seed BG-11 for inducing crystallization, slowly adding water to fully separate out the product,then the temperature is reduced to 5 ℃. The solid was collected by filtration, washed with a mixed solvent of methanol/water, and dried in vacuo at 45 ℃ to give BG-11 (chiral purity 99.50%, yield 69.93%) as a product.
Example 5
64.0g of BG-5 salt (105mmol, 1.4 eq.) was suspended in a mixed solvent consisting of 150mL of n-heptane and 60mL of water and cooled to 5 ℃. 23.4g of potassium hydroxide was dissolved in 120mL of water, added to the suspension, stirred for 2 hours, and then warmed to room temperature. Standing for phase separation, collecting organic phase, washing with water, and filtering to remove insoluble substances. The resulting organic phase was concentrated to remove water azeotropically, then 60mL of N, N-Dimethylformamide (DMF) was added and the remaining N-heptane was distilled off to give a solution of BG-5 free base in N, N-dimethylformamide. The BG-5 solution was transferred to a reaction vessel, and then 30.0g of BG-10 (75mmol, 1.0 eq.), 25.8g of tetramethylguanidine and 60mL of a solution of N, N-dimethylformamide were added. The autoclave was purged with nitrogen, and then cuprous iodide (4.5mmol, 0.060eq.) and Pd (dtbpf) Cl were added 2 (4.5mmol, 0.060eq.). The reaction system is heated to 80 ℃ and stirred for reaction for 24 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butyl ether and 250-300 g of water. After stirring for a while, the mixture was allowed to stand to separate the aqueous phase and the organic phase was washed with water. The separated organic phase was washed with 120 to 160g of a mixed aqueous solution containing 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, adding 150-180 g of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Distilling the mixture, heating to dissolve the solid generated in the system, then cooling to 40-45 ℃ for crystallization, adding crystal seeds BG-11 for induced crystallization, slowly adding water to fully separate out the product, and then cooling to 3 ℃. The solid was collected by filtration, washed with a mixed solvent of methanol/water, and dried under vacuum at 45 ℃ to obtain BG-11 (chiral purity 99.32%, yield 75.01%).
Example 6
64.0g of BG-5 salt (105mmol, 1.4 eq.) was suspended in a mixed solvent of 150mL of n-heptane and 60mL of water, and the temperature was lowered to 5 ℃. 23.4g of potassium hydroxide was dissolved in 120mL of water, added to the above suspension, and thenStirred for 2 hours and then warmed to room temperature. Standing for phase separation, collecting organic phase, washing with water, and filtering to remove insoluble substances. The organic phase was concentrated to remove water azeotropically, 60mlN, N-Dimethylformamide (DMF) was then added and the remaining N-heptane was distilled off to give a solution of BG-5 free base in N, N-dimethylformamide. The BG-5 solution was transferred to a reaction vessel, and then 30.0g of BG-10 (75mmol, 1.0 eq.), 25.8g of tetramethylguanidine and 60mL of a solution of N, N-dimethylformamide were added. The reaction vessel was purged with nitrogen, and then cuprous iodide (4.5mmol, 0.060eq.) and Pd (dtbpf) Cl were added 2 (4.5mmol, 0.060eq.). The reaction system is heated to 80 ℃ and stirred for reaction for 24 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butyl ether and 250-300 g of water. After stirring for a while, the mixture was allowed to stand to separate the aqueous phase, and the organic phase was washed with water. The separated organic phase was washed with 120 to 160g of a mixed aqueous solution containing 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, adding 150-180 g of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Distilling the mixture, heating to dissolve solid generated in the system, then cooling to 35-45 ℃ for crystallization, adding crystal seed BG-11 for inducing crystallization, slowly adding water to fully separate out the product, and then cooling to 5 ℃. The solid was collected by filtration, washed with a mixed solvent of methanol/water, and dried in vacuo at 45 ℃ to give BG-11 (chiral purity 99.35%, yield 67.69%).
It is noted that BG-11 seeds can be prepared according to the methods described in any of the examples (without the addition of seeds). The crystal form is prepared in small batches for the first time, and the subsequent preparation and production can use the product of the previous batch as the seed crystal. The seed crystal is added mainly for better controlling the crystallization process, so that the product is stably separated out and is prevented from being separated out suddenly. Seeding is not an essential operation, and crystallization can be carried out without seeding to obtain the required crystals.
The invention has been described in detail with respect to the general description, specific embodiments and experiments, and it is intended that all modifications and improvements made without departing from the spirit of the invention are within the scope of the invention as claimed. All cited references are incorporated by reference in their entirety into this application.

Claims (31)

1. A material combination system prepared from PARP inhibitor intermediate has a structure shown in formula (I),
Figure FDA0003667192140000011
the material combination system comprises: BG-10, BG-5, palladium catalyst [ Pd]And a cuprous salt, wherein the palladium catalyst comprises at least Pd (dppf) Cl 2 And Pd (dtbpf) Cl 2 One or two of them, and
the reaction of the material combination system comprises the following steps: reacting BG-10 with BG-5 in an organic solvent to obtain an intermediate represented by formula (I);
Figure FDA0003667192140000012
2. the material combination system of claim 1, wherein said palladium catalyst comprises Pd (dppf) Cl 2 。
3. The material combination system of claim 1, wherein the palladium catalyst comprises Pd (dtbpf) Cl 2 。
4. The material combination system of any one of claims 1-3, wherein the palladium catalyst further optionally comprises Pd (PPh) 3 ) 2 Cl 2 Pd (dibenzylideneacetone) Cl 2 (ii) a Or P (cyclohexyl) 3 、PPh 3 、BINAP、P(n-Bu) 3 、P(t-Bu) 3 One or more ligands of dtbpf, and/or Pd (OAc) 2 、PdCl 2 One or more palladium salts.
5. The material combination system of any one of claims 1-3, the organic solvent being selected from the group consisting of: dimethylsulfoxide DMSO, N-dimethylformamide DMF, N-dimethylacetamide DMAC, nitrogen methyl pyrrolidone NMP, toluene, tetrahydrofuran THF, 2-methyltetrahydrofuran MeTHF, acetonitrile, dioxane, and any combination thereof; the cuprous salt is selected from cuprous iodide, cuprous bromide, cuprous chloride, cuprous acetate, cuprous trifluoromethanesulfonate and any combination thereof.
6. The material combination system according to any one of claims 1 to 3, wherein the mole ratio of BG-10 to BG-5 is 1: 0.8-1: 3; and/or the mole ratio of BG-10 to palladium catalyst is 1: 0.01-1: 0.1.
7. The material combination system according to claim 6, wherein the mole ratio of BG-10 to BG-5 is 1: 0.9-1: 2; and/or the mole ratio of BG-10 to palladium catalyst is 1: 0.05-1: 0.1.
8. The material combination system according to claim 6, wherein the mole ratio of BG-10 to BG-5 is 1: 1 to 1: 1.5; and/or the mole ratio of BG-10 to palladium catalyst is 1: 0.05-1: 0.08.
9. The material combination system according to claim 6, wherein the mole ratio of BG-10 to BG-5 is 1: 1.2 to 1: 1.4.
10. The material combination system of any one of claims 1-3, wherein the palladium catalyst is Pd (dppf) Cl 2 Or Pd (dtbpf) Cl 2 (ii) a BG-10 and Pd (dppf) Cl 2 The molar ratio of (1: 0.01) - (1: 0.1); BG-10 and Pd (dtbpf) Cl 2 The molar ratio of (1: 0.01) - (1: 0.1).
11. The material combination system of any one of claims 1-3, wherein the palladium catalyst is Pd (dppf) Cl 2 Or Pd (dtbpf) Cl 2 (ii) a What is neededBG-10 and Pd (dppf) Cl 2 The molar ratio of (1: 0.05) - (1: 0.1); BG-10 and Pd (dtbpf) Cl 2 The molar ratio of (1: 0.05) to (1: 0.1).
12. The material combination system of any one of claims 1-3, wherein the palladium catalyst is Pd (dppf) Cl 2 Or Pd (dtbpf) Cl 2 (ii) a BG-10 and Pd (dppf) Cl 2 The molar ratio of (1: 0.05) - (1: 0.08); BG-10 and Pd (dtbpf) Cl 2 The molar ratio of (A) to (B) is 1: 0.05-1: 0.08.
13. The material combination system according to any one of claims 1 to 3, wherein the weight-to-volume ratio M/V and g/mL of BG-10 to the organic solvent is 1: 1-1: 10; and/or the mole ratio of BG-10 to cuprous salt is 1: 0.01-1: 0.1.
14. The material combination system according to claim 13, wherein the weight-to-volume ratio M/V and g/mL of BG-10 to the organic solvent is 1: 1-1: 6; and/or the mole ratio of BG-10 to cuprous salt is 1: 0.05-1: 0.1.
15. The material combination system according to claim 13, wherein the weight-to-volume ratio of BG-10 to organic solvent, M/V and g/mL, is 1: 2; 1: 3; 1: 4 or 1: 5; and/or the mole ratio of BG-10 to cuprous salt is 1: 0.06-1: 0.08.
16. The material combination system of any one of claims 1-3, wherein a basic material is further used in the reaction; the basic material is selected from diisopropylethylamine DIPEA, triethylamine TEA, pyridine, tetramethylguanidine TMG, N-methylmorpholine NMP, potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, triethylenediamine DABCO, 1, 8-diazabicyclo [5.4.0] undec-7-ene DBU, and any combination thereof.
17. The material combination system of claim 16, wherein an alkaline substance is further used in the reaction; the basic substance is selected from diisopropylethylamine DIPEA, cesium carbonate, triethylenediamine DABCO, azabicyclic DBU, tetramethylguanidine TMG and any combination thereof.
18. The material combination system of claim 16, wherein the mole ratio of BG-10 to the basic substance is 1: 0.5-1: 6.
19. The material combination system of claim 16, wherein the mole ratio of BG-10 to the basic substance is 1: 0.8-1: 4.
20. The material combination system of claim 16, wherein the mole ratio of BG-10 to the basic substance is from 1: 1 to 1: 3.
21. The material combination system according to any one of claims 1 to 3, wherein the reaction is carried out in a reaction kettle; the reaction temperature is 50-100 ℃; the reaction time is 1-48 hours.
22. The material combination system of claim 21, wherein the reaction kettle is replaced by nitrogen; the reaction temperature is 60-85 ℃; the reaction time is 5 to 40 hours; after the reaction, the temperature is reduced to 15-30 ℃.
23. The material combination system of claim 21, wherein the reaction temperature is 70-80 ℃; the reaction time is 12 to 30 hours; after the reaction, the temperature is reduced to room temperature.
24. The material combination system of claim 21, wherein the reaction temperature is 75-80 ℃.
25. The material combination system of any one of claims 1-3, a method of using the material combination system further comprising the step of preparing BG-5 free base: BG-5 salt was treated with base to obtain the free base of BG-5.
26. The material combination system of claim 25, wherein the step of treating BG-5 salt with a base to obtain the free base of BG-5 is performed in a mixed solution of n-heptane and water.
27. The material combination system of claim 25, wherein the preparation of BG-5 free base comprises the steps of: the BG-5 salt is suspended in a mixed solvent of n-heptane and water, and an alkaline solution is added to the above mixed solution to perform a reaction, thereby obtaining the BG-5 free base.
28. The material combination system according to any one of claims 1-3, the method of using the material combination system further comprising the steps of purification and recrystallization.
29. The material combination system of claim 28, wherein the recrystallization is performed in an alcohol solvent.
30. The material combination system of claim 28, wherein the recrystallization is performed in methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol.
31. The material combination system of claim 28, wherein the recrystallization is performed in methanol.
CN202110525007.5A 2019-05-16 2019-05-16 Material combination system for preparing PARP inhibitor intermediate Active CN113402502B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110525007.5A CN113402502B (en) 2019-05-16 2019-05-16 Material combination system for preparing PARP inhibitor intermediate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910405969.XA CN111171002B (en) 2019-05-16 2019-05-16 Preparation method of PARP inhibitor intermediate
CN202110525007.5A CN113402502B (en) 2019-05-16 2019-05-16 Material combination system for preparing PARP inhibitor intermediate

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201910405969.XA Division CN111171002B (en) 2019-05-16 2019-05-16 Preparation method of PARP inhibitor intermediate

Publications (2)

Publication Number Publication Date
CN113402502A CN113402502A (en) 2021-09-17
CN113402502B true CN113402502B (en) 2022-10-14

Family

ID=70622376

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201910405969.XA Active CN111171002B (en) 2019-05-16 2019-05-16 Preparation method of PARP inhibitor intermediate
CN202110525007.5A Active CN113402502B (en) 2019-05-16 2019-05-16 Material combination system for preparing PARP inhibitor intermediate

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201910405969.XA Active CN111171002B (en) 2019-05-16 2019-05-16 Preparation method of PARP inhibitor intermediate

Country Status (1)

Country Link
CN (2) CN111171002B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115138396B (en) * 2021-03-30 2024-06-14 百济神州(苏州)生物科技有限公司 Catalyst system for Sonogashira coupling reaction and in-situ cyclization reaction

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104974140A (en) * 2014-04-14 2015-10-14 上海海雁医药科技有限公司 2,3,4,6-tetrasubstituted benzene-1,5-diamine derivatives, preparation method thereof and medicinal application thereof
WO2017032289A1 (en) * 2015-08-25 2017-03-02 Beigene, Ltd. Process for preparing parp inhibitor, crystalline forms, and uses thereof
CN107108605A (en) * 2014-08-27 2017-08-29 盐野义制药株式会社 7-azaindole derivatives with AMPK activations

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK2797921T3 (en) * 2011-12-31 2017-10-02 Beigene Ltd FUSED TETRA- OR PENTA-CYCLIC DIHYDRODIAZEPINOCARBAZOLONES AS PARB INHIBITORS
US10899763B2 (en) * 2017-02-28 2021-01-26 Beigene, Ltd. Crystalline forms of salts of fused penta-cyclic dihydrodiazepinocarbazolones, and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104974140A (en) * 2014-04-14 2015-10-14 上海海雁医药科技有限公司 2,3,4,6-tetrasubstituted benzene-1,5-diamine derivatives, preparation method thereof and medicinal application thereof
CN107108605A (en) * 2014-08-27 2017-08-29 盐野义制药株式会社 7-azaindole derivatives with AMPK activations
WO2017032289A1 (en) * 2015-08-25 2017-03-02 Beigene, Ltd. Process for preparing parp inhibitor, crystalline forms, and uses thereof

Also Published As

Publication number Publication date
CN111171002B (en) 2021-04-06
CN111171002A (en) 2020-05-19
CN113402502A (en) 2021-09-17

Similar Documents

Publication Publication Date Title
AU2018244451A1 (en) Crystal form of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3) pyridazine-3-carboxamide
CN101959856A (en) Preparation of lenalidomide
CN108440330B (en) Preparation method of doxycycline hydrochloride
CN110372562B (en) Crystal form of key intermediate of BTK kinase inhibitor and preparation method thereof
CN107118207A (en) The preparation method of one class CDK inhibitor
CN113402502B (en) Material combination system for preparing PARP inhibitor intermediate
CN114573506B (en) Drug intermediate and synthetic method thereof, isoquinoline derivative and synthetic method thereof
CN108495632A (en) It is used to prepare difficult to understand this and replaces Buddhist nun（AZD9291）Or the improved method of its salt and " AZD9291 aniline " or its salt
CN101973981A (en) Refining method of 1-(5-isoquinoline sulfonyl) homopiperazine hydrochloride
CN108276414B (en) A kind of preparation method of citric acid tropsch imatinib
CN108640923A (en) A kind of support method replaces the preparation method of cloth key intermediate
EP4046687A1 (en) Method for producing centanafadine
CN112225729B (en) Pyrimidine derivative, preparation method and application thereof and pharmaceutical composition
JP2024508329A (en) Synthetic methods and intermediates for producing compounds for treating KIT- and PDGFRA-mediated diseases
CA3073613A1 (en) Crystal form of parp-1 inhibitor and preparation method therefor
CN102964336A (en) Refining method of proton pump inhibitor and reducing method of N-oxide of proton pump inhibitor
CN105073739B (en) Intermediate for preparing indazole derivative and preparation method thereof
CN105801559B (en) The preparation method of 4- methyl -3- [[4- (3- pyridyl group) -2- pyrimidine radicals] amino] ethyl benzoate
CN115138396B (en) Catalyst system for Sonogashira coupling reaction and in-situ cyclization reaction
CN112898277B (en) Preparation method of afatinib intermediate
CN115141178A (en) Method for preparing PARP inhibitor intermediate
CN110903338B (en) Sulfur-containing urea arsenic sugar with antitumor activity and preparation method and application thereof
CN105777616B (en) Synthetic intermediate of Ceritinib and preparation method thereof
CN114920689B (en) Preparation method of regorafenib intermediate
CN108069900A (en) The preparation method and purposes of Aripiprazole hydrochloride

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
GR01 Patent grant
GR01 Patent grant