CN116102415A - 5H-dibenzo [ a, d ] cycloheptatrien-5-one intermediate compound - Google Patents

5H-dibenzo [ a, d ] cycloheptatrien-5-one intermediate compound Download PDF

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CN116102415A
CN116102415A CN202111331572.4A CN202111331572A CN116102415A CN 116102415 A CN116102415 A CN 116102415A CN 202111331572 A CN202111331572 A CN 202111331572A CN 116102415 A CN116102415 A CN 116102415A
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鲍广龙
李涛
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Shandong New Time Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
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    • C07—ORGANIC CHEMISTRY
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a 5H-dibenzo [ a, d ] cycloheptatriene-5-one intermediate compound and a method for preparing the 5H-dibenzo [ a, d ] cycloheptatriene-5-one. The method takes SM-1 as a starting material, firstly reacts with ethanethiol, then is coupled with SM-2 to prepare an intermediate compound I-2, and the compound I-2 reacts in one step under the action of a catalyst to prepare 5H-dibenzo [ a, d ] cycloheptatrien-5-ketone. The preparation method solves the problems of complex operation and high toxicity in the prior art, is simple and convenient to operate, and the obtained product has high yield and purity and short reaction period, and is suitable for industrial production.

Description

5H-dibenzo [ a, d ] cycloheptatrien-5-one intermediate compound
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a 5H-dibenzo [ a, d ] cycloheptatriene-5-ketone intermediate compound.
Background
Cyclobenzaprine hydrochloride (cyclobenzaprine hydrochloride), known as 5- (3-dimethylaminopropylene) dibenzo [ a, d ] cycloheptene hydrochloride, is a muscle relaxant developed by Merck corporation in the united states, and is now marketed in multiple countries under the trade name Flexeril, and is clinically used to relieve muscle spasms and concomitant severe pain in skeletal muscles. The product has quick response, good spasmolytic effect and small adverse reaction, and is the first choice for treating the pain. The chemical structural formula is as follows:
Figure BDA0003349083470000011
the preparation method of the preparation is disclosed in patents US3454643A, 387CHE2005, 171MUM2011, WO2012098563A2, CN102942489A, CN103242170B and literature acta.chemical Scandinavica,1963,17,2437-2443, journal of Medicinal and Pharmaceutical Chemistry,1962,5,2,373-383, the study on the synthesis of cyclobenzaprine, the university of Paeonia suffruticosa medical school, 2008,29 (2), 18-20, the synthesis of cyclobenzaprine hydrochloride, journal of Chinese medical industry, 2008,39 (8), 569-570, the simple synthesis of cyclobenzaprine, contemporary medicine, 2009,15 (3), 15-16, the improvement on the synthesis process of cyclobenzaprine hydrochloride, journal of Chinese medicinal chemistry, 2015,25 (2), 115-117.
5H-dibenzo [ a, d ] cycloheptatrien-5-one is used as a key intermediate for synthesizing cyclobenzaprine hydrochloride, directly affects the production, market supply and quality problems of the medicine, and has the following structural formula:
Figure BDA0003349083470000012
in addition, 5H-dibenzo [ a, d ] cycloheptatrien-5-one can be further used for synthesizing cyproheptadine hydrochloride, amitriptyline hydrochloride and metabolites nortriptyline thereof, and related structural formulas are as follows:
Figure BDA0003349083470000021
the preparation method reported at present for 5H-dibenzo [ a, d ] cycloheptatrien-5-one is as follows:
literature on study of the Synthesis of cyclobenzaprine, report of the university of Paeonia suffruticosa, 2008,29 (2), brief Synthesis of cyclobenzaprine, contemporary medicine, 2009,15 (3), dibenzo [ a, d ] in 15-16]Cyclohepta-5-one as starting material in CCl 4 And (3) carrying out bromine bromination reflux reaction for 18h, then adding triethylamine, and then continuously refluxing for 16h, and carrying out post-treatment to obtain the target product. However, the reaction needs carbon tetrachloride and bromine with larger toxicity, has lower operation safety and longer reaction period, and is not suitable for process magnification. The product is prepared by brominating NBS and then treating with tertiary amine in U.S. Pat. No. 3,182A。
Figure BDA0003349083470000022
Furthermore, U.S. Pat. No. 3,182A employs Friedel-Crafts acylation as AlCl 3 Preparation of the target product for the catalyst, but anhydrous AlCl 3 The application risk is high, and aluminum ions are easy to bring into the product.
Figure BDA0003349083470000023
In the literature ACS catalyst.2014, 4,11,4034-4039, trans dibromo is used as a substrate, and under the action of argon protection and alpha-selenothiophene and tetramethyl ethylenediamine, the target product is prepared by reacting in a Schlenk tube device under the action of light radiation. However, the related substrate still needs to be prepared by substituting bromine with high toxicity, meanwhile, the organic selenium catalyst is not easy to obtain, and the preparation of the target product is in milligram level, and the preparation needs column chromatography purification, so that the mass production is difficult. The document Bull. Korea chem. Soc.34 (2013) 7,1951-1952 uses NbCl 5 The In system selectively debrominates vic-dibromide to olefins, but the catalyst is costly.
Figure BDA0003349083470000024
Literature ACS catalyst.2018, 8,4,3030-3034 uses an alcohol oxidation strategy to produce the target product, a reaction that requires CO 2 The reaction is carried out for 48 hours at 90 ℃ in the environment, the process operation needs to be strictly carried out in a glove box without water, the reaction period is longer, the target product also needs column chromatography purification, and the mass production is difficult. The documents Tetrahedron Letters,55 (2014) 6895-6898 are prepared by Swern-type oxidation, but the reaction needs to be carried out at-30 ℃, has high equipment requirements, is easy to generate malodorous dimethyl sulfide toxic gas after the reaction, and is difficult to produce in mass production, and the prepared product is also in millimole grade. In the literature Nat.Commun.10,2796 (2019), the preparation is carried out by adopting a micro-channel continuous flow reactor, and the production cost is higher。
Figure BDA0003349083470000031
In summary, the existing preparation method of 5H-dibenzo [ a, d ] cycloheptatriene-5-ketone has the problems of high process risk, complex operation, lower yield, higher cost and the like. Therefore, the research and search of a reaction route which is simple and convenient in operation process, high in product yield, high in purity and low in production cost and is suitable for industrial production of 5H-dibenzo [ a, d ] cycloheptatriene-5-ketone still needs to be solved at present.
Disclosure of Invention
Aiming at the problems of the existing 5H-dibenzo [ a, d ] cycloheptatriene-5-ketone preparation technology, the invention provides a novel intermediate compound I-2 and a novel method for preparing 5H-dibenzo [ a, d ] cycloheptatriene-5-ketone by using the intermediate. The 5H-dibenzo [ a, d ] cycloheptatriene-5-ketone prepared by the method has higher purity and yield, low production cost and high operation safety.
The specific technical scheme of the invention is as follows:
in a first aspect, the present invention provides a 5H-dibenzo [ a, d ] cycloheptatrien-5-one intermediate compound having the structure shown in formula I-2:
Figure BDA0003349083470000032
in a second aspect, the present invention provides a process for the preparation of a 5H-dibenzo [ a, d ] cycloheptatrien-5-one intermediate compound comprising the steps of:
Figure BDA0003349083470000033
step 1: dissolving SM-1 and ethanethiol in anhydrous organic solvent A, adding catalyst, and controlling temperature T A Stirring for reaction to obtain a compound I-1;
step 2: under the protection of inert gas, I-1, SM-2, cuTC, catalyst and ligandAdding the mixture into a reaction solvent B, controlling the temperature T B And continuing stirring reaction to prepare the compound I-2.
Preferably, the organic solvent a in step 1 is selected from one of acetonitrile and tetrahydrofuran, preferably acetonitrile.
Preferably, the catalyst in step 1 is selected from one of trifluoroacetic acid, p-toluenesulfonic anhydride, preferably trifluoroacetic acid.
Preferably, in the step 1, the feeding mole ratio of SM-1 to ethanethiol to catalyst is 1:1.0 to 1.25:0.2 to 0.5, preferably 1:1.05:0.3.
preferably, the reaction temperature T in step 1 A The temperature is 40 to 65℃and preferably 55 to 60 ℃.
Preferably, the anhydrous organic solvent in step 1 may be prepared by a method conventional in the art, such as re-evaporation, drying, or directly purchased.
In a preferred scheme, after the reaction in the step 1 is finished, post-treatment operation is needed, and the specific steps are as follows: adding saturated sodium carbonate solution to the reaction solution until the pH value is 8-9, stirring, extracting with an organic solvent, combining organic phases, washing with saturated saline solution, and concentrating the organic phases under reduced pressure until the organic phases are dried to obtain the compound I-1. Preferably, the extractant is selected from one or a combination of dichloromethane, chloroform, ethyl acetate and methyl tertiary butyl ether, preferably ethyl acetate and dichloromethane.
Preferably, the catalyst in step 2 is selected from palladium dichloride (PdCl 2 ) Palladium acetate [ Pd (OAc) 2 ]Tris (dibenzylideneacetone) dipalladium [ Pd ] 2 (dba) 3 ]One of them, preferably PdCl 2 。
Preferably, the ligand in step 2 is selected from triphenylphosphine (PPh) 3 ) Tri-tert-butylphosphine [ P (t-Bu) ] 3 ]Tricyclohexylphosphine (PCy) 3 ) Trio-tolylphosphine [ P (o-tol) 3 ]One of tris (2-furyl) phosphine (TFP), preferably triphenylphosphine.
Preferably, the feeding mole ratio of the compound I-1 to the SM-2, the CuTC, the catalyst and the ligand in the step 2 is 1:1.0 to 1.3:1.2 to 1.8:0.5% -4.0%: 0.5% -5.0%, preferably 1:1.1:1.6:1.0%:2.0%, wherein the catalyst is calculated as Pd.
Preferably, the reaction temperature T in step 2 B The temperature is 40 to 78 ℃, preferably 50 to 55 ℃.
Preferably, the reaction solvent B in step 2 is selected from one or a combination of tetrahydrofuran, ethanol and isopropanol, preferably tetrahydrofuran.
Preferably, the inert gas in the step 2 is one of argon and nitrogen.
In a preferred scheme, after the reaction in the step 2 is finished, post-treatment operation is needed, and the specific steps are as follows: the reaction solution was poured into dilute hydrochloric acid, filtered, the filtrate was adjusted to ph=10 to 11 with alkali, extracted with an organic solvent, the organic phases were combined, washed with saturated brine, and concentrated to dryness under reduced pressure to obtain the objective compound I-2. Preferably, the concentration of the dilute hydrochloric acid is 0.5 to 2mol/L, preferably 1mol/L. Preferably, the base comprises sodium hydroxide, potassium hydroxide. Preferably, the extractant is selected from one of dichloromethane, ethyl acetate, chloroform, methyl tert-butyl ether, preferably dichloromethane.
In another aspect, the present invention provides a method for preparing 5H-dibenzo [ a, d ] from compound I-2]The method for preparing the cycloheptatrien-5-ketone comprises the following specific steps: under the protection of inert gas, adding the compound I-2, a catalyst and alkali into the reaction solvent C, and controlling the temperature T C Continuing stirring reaction to prepare a compound I, wherein the reaction formula is as follows:
Figure BDA0003349083470000051
preferably, the catalyst is selected from Pd (PPh 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd(dppf)Cl 2 One of or a combination thereof, preferably Pd (PPh) 3 ) 2 Cl 2 。
Preferably, the reaction solvent C is one or a combination of acetonitrile, 1, 4-dioxane, toluene, N, N-dimethylformamide and dimethyl sulfoxide.
Preferably, the base is Na 2 CO 3 ，K 3 PO 4 ，CH 3 COONa，CH 3 One or a combination of COOK, t-Buona, preferably CH 3 COOK。
Preferably, the feeding mole ratio of the compound I-2 to the alkali and the catalyst is 1:2 to 6:3% -7%, preferably 1:4:5%.
Preferably, the reaction temperature T C Is 82 to 110℃and preferably 90 to 95 ℃.
In a preferred embodiment, the post-treatment operation is performed after the reaction is completed, and the specific steps are as follows: the reaction solution was filtered, the filtrate was poured into purified water, extracted with an organic solvent, the organic phases were combined, washed with saturated brine, and concentrated to dryness under reduced pressure to obtain compound I. Preferably, the extractant is selected from one or a combination of dichloromethane, chloroform, ethyl acetate and methyl tert-butyl ether, preferably dichloromethane.
Preferably, the inert gas is one of argon or nitrogen, preferably argon.
The invention has the beneficial effects that:
the invention provides a novel 5H-dibenzo [ a, d ] cycloheptatrien-5-one intermediate compound I-2 and provides a novel method for preparing the 5H-dibenzo [ a, d ] cycloheptatrien-5-one by using the compound I-2. The preparation method uses SM-1 as a starting material, prepares thiomethyl ester with ethanethiol, and then prepares 5H-dibenzo [ a, d ] cycloheptatriene-5-ketone through two-step coupling reaction, thereby solving the problems of complex operation and higher toxicity in the prior art. The 5H-dibenzo [ a, d ] cycloheptatriene-5-ketone prepared by the intermediate compound I-2 has higher yield and purity, is simple and convenient to operate, has short reaction period, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
The invention adopts HPLC to measure the purity of 5H-dibenzo [ a, d ] cycloheptatrien-5-ketone, and the chromatographic conditions are as follows:
chromatographic column: hypersil BDS-C 18 Columns (4.6 mm. Times.250 mm,5 μm) or columns of comparable performance;
mobile phase: acetonitrile-0.085% phosphoric acid in water (triethylamine pH 6.5) (65:35)
Column temperature: 30 ℃;
detection wavelength: 210nm;
flow rate: 1.0ml/min;
sample injection amount: 20 μl;
wherein the retention time of 5H-dibenzo [ a, d ] cycloheptatrien-5-one is about 41.913 min.
In the examples that follow, various processes and methods not described in detail are conventional methods well known in the art, and reagents used are not labeled as either commercially pure or chemically pure in source and specification.
Synthesis of Compound I-1
Example 1
Trifluoroacetic acid (2.23 ml,0.03 mol) was added dropwise to a solution of SM-1 (16.22 g,0.1 mol) and ethanethiol (6.52 g,0.105 mol) in anhydrous acetonitrile (100 ml), the reaction was stirred at 55 to 60℃and, after the completion of the reaction, a saturated sodium carbonate solution was added to the reaction mixture to a pH of 8 to 9, stirred, extracted with ethyl acetate (30 ml. Times.3), the organic phases were combined, washed with saturated brine (30 ml. Times.2), and the organic phase was concentrated to dryness under reduced pressure to give compound I-1 in a yield of 98.6% and a purity of 99.37%. ESI-HRMS (m/z): 193.0517[ M+H ]]； 1 H-NMR(600MHz,CDCl 3 )δ:7.80(d,J＝7.6Hz,1H),7.62(td,J＝7.6、2.3Hz,1H),7.36～7.42(m,3H),5.54(dd,J＝13.4、1.6Hz,1H),5.50(dd,J＝8.0、1.7Hz,1H),2.98(q,2H),1.28(t,3H)； 13 C-NMR(151MHz,CDCl 3 )δ:188.57,138.29,135.62,133.48,132.68,131.49,129.08,127.43,118.37,22.75,12.62.
Example 2
P-toluenesulfonic acid (5.17 g,0.03 mol) was added dropwise to a solution of SM-1 (16.22 g,0.1 mol) and ethanethiol (6.21 g,0.1 mol) in anhydrous acetonitrile (100 ml), the reaction was stirred at 50 to 55℃and, after the completion of the reaction, a saturated sodium carbonate solution was added to the reaction mixture to pH=8 to 9, stirred, extracted with methyl t-butyl ether (30 ml. Times.3), the organic phases were combined, washed with saturated brine (30 ml. Times.2) and concentrated to dryness under reduced pressure to give compound I-1 in a yield of 94.5% and a purity of 99.04%.
Example 3
P-toluenesulfonic anhydride (9.79 g,0.03 mol) was added dropwise to a solution of SM-1 (16.22 g,0.1 mol) and ethanethiol (5.59 g,0.09 mol) in anhydrous tetrahydrofuran (100 ml), the reaction was stirred at 60 to 65℃and, after the completion of the reaction, a saturated sodium carbonate solution was added to the reaction mixture to pH=8 to 9, stirred, extracted with chloroform (30 ml. Times.3), the organic phases were combined, washed with saturated brine (30 ml. Times.2) and concentrated to dryness under reduced pressure to give Compound I-1 in a yield of 91.2% and a purity of 98.55%.
Example 4
Trifluoroacetic acid (2.23 ml,0.03 mol) was added dropwise to a solution of SM-1 (16.22 g,0.1 mol) and ethanethiol (7.77 g,0.125 mol) in anhydrous acetonitrile (100 ml), the reaction was stirred at 45 to 50℃and, after the completion of the reaction, a saturated sodium carbonate solution was added to the reaction mixture to a pH of 8 to 9, stirred, extracted with methylene chloride (30 ml. Times.3), the organic phases were combined, washed with saturated brine (30 ml. Times.2), and the organic phase was concentrated to dryness under reduced pressure to give compound I-1 in a yield of 97.0% and a purity of 98.83%.
Example 5
Trifluoroacetic acid (2.23 ml,0.03 mol) was added dropwise to a solution of SM-1 (16.22 g,0.1 mol) and ethanethiol (8.07 g,0.130 mol) in anhydrous acetonitrile (100 ml), the reaction was stirred at a temperature of 40 to 45 ℃, a saturated sodium carbonate solution was added to the reaction mixture to ph=8 to 9 after the completion of the reaction, the mixture was stirred, extracted with methylene chloride (30 ml×3), the organic phases were combined, washed with saturated brine (30 ml×2), and the organic phase was concentrated to dryness under reduced pressure to give compound I-1 in a yield of 92.9% and a purity of 98.31%.
Example 6
Trifluoroacetic acid (1.49 ml,0.02 mol) was added dropwise to a solution of SM-1 (16.22 g,0.1 mol) and ethanethiol (6.52 g,0.105 mol) in anhydrous acetonitrile (100 ml), the reaction was stirred at 55 to 60℃and, after the completion of the reaction, a saturated sodium carbonate solution was added to the reaction mixture to a pH of 8 to 9, stirred, extracted with ethyl acetate (30 ml. Times.3), the organic phases were combined, washed with saturated brine (30 ml. Times.2), and the organic phase was concentrated to dryness under reduced pressure to give compound I-1 in a yield of 95.3% and a purity of 99.19%.
Example 7
Trifluoroacetic acid (3.72 ml,0.05 mol) was added dropwise to a solution of SM-1 (16.22 g,0.1 mol) and ethanethiol (6.52 g,0.105 mol) in anhydrous acetonitrile (100 ml), the reaction was stirred at 55 to 60℃and, after the completion of the reaction, a saturated sodium carbonate solution was added to the reaction mixture to a pH of 8 to 9, stirred, extracted with methylene chloride (30 ml. Times.3), the organic phases were combined, washed with saturated brine (30 ml. Times.2) and concentrated to dryness under reduced pressure to give compound I-1 in a yield of 97.8% and a purity of 99.06%.
Synthesis of Compound I-2
Example 8
Under the protection of argon, I-1 (19.20 g,0.1 mol), SM-2 (22.09 g,0.11 mol), cuTC (30.51 g,0.16 mol), pdCl were introduced into the reactor 2 (0.18 g,1.0 mmol) and triphenylphosphine (0.52 g,2.0 mmol) were added to tetrahydrofuran (200 ml), the reaction was carried out at a temperature of 50 to 55℃and after completion of the detection reaction, the reaction mixture was poured into 1mol/L diluted hydrochloric acid (200 ml), filtered, the filtrate was adjusted to pH=10 to 11 with sodium hydroxide, extracted with methylene chloride (100 ml. Times.3), the organic phases were combined, washed with saturated brine (100 ml. Times.2) and concentrated to dryness under reduced pressure to give Compound I-2 in a yield of 94.6% and a purity of 99.42%. ESI-HRMS (m/z): 287.0068, 289.0032[ M+H ]]； 1 H-NMR(600MHz,CDCl 3 )δ:7.74～7.80(m,2H),7.61～7.63(m,2H),7.49～7.53(m,1H),7.44～7.46(m,2H),7.34～7.40(m,3H),5.63(dd,J＝13.5、1.6Hz,1H),5.56(dd,J＝8.0、1.7Hz,1H)； 13 C-NMR(151MHz,CDCl 3 )δ:193.26,139.17,138.42,136.83,133.58,132.95,131.77,131.09,120.02,129.33,127.46,127.38,127.06,124.46,117.03.
Example 9
Under argon, I-1 (19.20 g,0.1 mol), SM-2 (21.09 g,0.105 mol), cuTC (30.51 g,0.16 mol), pd (OAc) 2 (0.22 g,1.0 mmol) and triphenylphosphine (0.52 g,2.0 mmol) are added into tetrahydrofuran (200 ml), the temperature is controlled between 55 and 60 ℃ for reaction, after the detection reaction is finished, the reaction solution is poured into 1mol/L dilute hydrochloric acid (200 ml), filtration is carried out, the pH value of the filtrate is adjusted to be between 10 and 11 by potassium hydroxide, and dichloromethane (100 ml multiplied by 3) is used for extractionThe organic phases were combined, washed with saturated brine (100 ml. Times.2), and concentrated to dryness under reduced pressure to give Compound I-2 in a yield of 90.7% and a purity of 99.16%.
Example 10
Under the protection of argon, I-1 (19.20 g,0.1 mol), SM-2 (20.09 g,0.10 mol), cuTC (30.51 g,0.16 mol), pdCl were introduced into the reactor 2 (0.18 g,1.0 mmol), triorthophenylphosphine [ P (o-tol) 3 ，0.61g，2.0mmol]Adding into ethanol (200 ml), controlling the temperature to be 45-50 ℃ for reflux reaction, pouring the reaction liquid into 1mol/L dilute hydrochloric acid (200 ml) after the detection reaction is finished, filtering, adjusting the pH value of the filtrate to be 10-11 by sodium hydroxide, extracting with methylene dichloride (100 ml multiplied by 3), washing with saturated saline (100 ml multiplied by 2), concentrating the organic phase under reduced pressure to dryness, and obtaining the compound I-2 with the yield of 85.8% and the purity of 98.60%.
Example 11
Under nitrogen, I-1 (19.20 g,0.1 mol), SM-2 (26.11 g,0.13 mol), cuTC (30.51 g,0.16 mol), pd were reacted with a nitrogen atmosphere 2 (dba) 3 (0.92 g,1.0 mmol) and triphenylphosphine (0.52 g,2.0 mmol) were added to tetrahydrofuran (200 ml), the reaction was carried out at a controlled temperature of 40 to 45 ℃, after completion of the detection reaction, the reaction solution was poured into 2mol/L diluted hydrochloric acid (150 ml), filtered, the filtrate was adjusted to ph=10 to 11 with sodium hydroxide, dichloromethane (100 ml×3) was extracted, the organic phases were combined, washed with saturated brine (100 ml×2), and the organic phases were concentrated to dryness under reduced pressure to give compound I-2 in a yield of 93.2% and a purity of 98.91%.
Example 12
Under the protection of argon, I-1 (19.20 g,0.1 mol), SM-2 (27.11 g,0.11 mol), cuTC (30.51 g,0.16 mol), pdCl were introduced 2 (0.18 g,1.0 mmol) and tris (2-furyl) phosphine (TFP, 0.46g,2.0 mmol) were added to tetrahydrofuran (200 ml), the reaction was carried out at a temperature of 55 to 60℃and after completion of the detection, the reaction mixture was poured into 1mol/L diluted hydrochloric acid (200 ml), filtered, the filtrate was adjusted to pH=10 to 11 with sodium hydroxide, methyl t-butyl ether (100 ml. Times.3) was extracted, the organic phases were combined, saturated brine (100 ml. Times.2) was washed, and the organic phase was concentrated to dryness under reduced pressure to give Compound I-2 in a yield of 87.6% and a purity of 98.43%.
Example 13
Argon protectionNext, I-1 (19.20 g,0.1 mol), SM-2 (22.09 g,0.11 mol), cuTC (22.84 g,0.12 mol), pdCl were added 2 (0.18 g,1.0 mmol), tri-tert-butylphosphine [ P (t-Bu) ] 3 ，0.40g，2.0mmol]Adding into isopropanol (200 ml), controlling the temperature to be 75-78 ℃ for reflux reaction, pouring the reaction liquid into 0.5mol/L dilute hydrochloric acid (250 ml) after the detection reaction is finished, filtering, adjusting the pH of the filtrate to be 10-11 by sodium hydroxide, extracting with dichloromethane (100 ml multiplied by 3), washing with saturated saline (100 ml multiplied by 2), concentrating the organic phase under reduced pressure to dryness, and obtaining the compound I-2 with the yield of 91.5% and the purity of 99.26%.
Example 14
Under the protection of argon, I-1 (19.20 g,0.1 mol), SM-2 (22.09 g,0.11 mol), cuTC (34.27 g,0.18 mol), pdCl were introduced into the reactor 2 (0.18 g,1.0 mmol), tricyclohexylphosphine (PCy) 3 0.56g,2.0 mmol) of tetrahydrofuran (200 ml) was added to the reaction mixture, the temperature was controlled to 50 to 55℃and after completion of the reaction, the reaction mixture was poured into 1mol/L of diluted hydrochloric acid (200 ml), the mixture was filtered, the filtrate was adjusted to pH=10 to 11 with sodium hydroxide, dichloromethane (100 ml. Times.3) was used for extraction, saturated brine (100 ml. Times.2) was used for washing, and the organic phase was concentrated to dryness under reduced pressure to give Compound I-2 in a yield of 93.8% and a purity of 99.04%.
Example 15
Under the protection of argon, I-1 (19.20 g,0.1 mol), SM-2 (22.09 g,0.11 mol), cuTC (30.51 g,0.16 mol), pdCl were introduced into the reactor 2 (0.09 g,0.5 mmol), triphenylphosphine (0.13 g,0.5 mmol) were added to isopropanol (200 ml), the temperature was controlled at 65-70 ℃ and after completion of the reaction, the reaction mixture was poured into 1mol/L diluted hydrochloric acid (200 ml), filtered, the filtrate was adjusted to ph=10-11 with sodium hydroxide, extracted with ethyl acetate (100 ml×3), washed with saturated brine (100 ml×2), and the organic phase was concentrated to dryness under reduced pressure to give compound I-2 in a yield of 91.2% and a purity of 99.12%.
Example 16
Under the protection of argon, I-1 (19.20 g,0.1 mol), SM-2 (22.09 g,0.11 mol), cuTC (30.51 g,0.16 mol), pdCl were introduced into the reactor 2 (0.53 g,3.0 mmol) and triphenylphosphine (1.05 g,4.0 mmol) are added into isopropanol (200 ml), the temperature is controlled between 70 and 75 ℃ for reaction, after the detection reaction is finished, the reaction solution is poured into 1mol/L dilute hydrochloric acid (200 ml), and the filtrate is filteredThe pH was adjusted to 10 to 11 with sodium hydroxide, extracted with chloroform (100 ml. Times.3), washed with saturated brine (100 ml. Times.2), and the organic phase was concentrated to dryness under reduced pressure to give Compound I-2 in 93.3% yield and 99.01% purity.
Synthesis of Compound I
Example 17
Intermediate I-2 (14.36 g,0.05 mol), pd (PPh) under argon 3 ) 2 Cl 2 (1.75g，2.5mmol)、CH 3 COOK (19.63 g,0.2 mol) was added to dimethyl sulfoxide (150 ml), the temperature was controlled at 90 to 95℃and after completion of the reaction, the reaction solution was filtered, the filtrate was poured into purified water (1200 ml), methylene chloride (400 ml. Times.3) was extracted, the organic phases were combined, washed with saturated brine (400 ml. Times.2), and the organic phase was concentrated to dryness under reduced pressure to give the objective compound I in 97.7% yield and 99.19% purity. ESI-HRMS (m/z): 207.0802[ M+H ]]； 1 H-NMR(600MHz,DMSO-d 6 )δ:8.11(dd,J＝8.64、1.02Hz,2H),7.74～7.79(m,4H),7.63～7.66(m,2H),7.24(s,2H)； 13 C-NMR(151MHz,DMSO-d 6 )δ:191.92,137.78,134.42,132.35,131.37,130.96,129.52,129.03.
Example 18
Intermediate I-2 (14.36 g,0.05 mol), pd (PPh) under argon 3 ) 4 (1.73g，1.5mmol)、K 3 PO 4 (42.45 g,0.2 mol) was added to toluene (150 ml), the temperature was controlled to 105 to 110 ℃, after completion of the reaction, the reaction solution was filtered, the filtrate was washed with purified water (50 ml. Times.3), and saturated brine (50 ml. Times.2) was washed, and the organic phase was concentrated to dryness under reduced pressure to give the objective compound I in a yield of 93.2% and a purity of 98.62%.
Example 19
Intermediate I-2 (14.36 g,0.05 mol), pd (dppf) Cl under nitrogen 2 (2.56g，3.5mmol)、CH 3 COONa (16.41 g,0.2 mol) was added to acetonitrile (150 ml), the reaction was refluxed at a temperature of 82 to 87 ℃ and after completion of the detection, the reaction solution was filtered, the filtrate was poured into purified water (1200 ml), methyl tert-butyl ether (400 ml. Times.3) was extracted, the organic phases were combined, washed with saturated brine (400 ml. Times.2), and the organic phases were concentrated to dryness under reduced pressure to give the objective compound I in 96.0% yield, pureThe degree is 98.80%.
Example 20
Intermediate I-2 (14.36 g,0.05 mol), pd (PPh) under argon 3 ) 2 Cl 2 (1.75g，2.5mmol)、Na 2 CO 3 (21.20 g,0.2 mol) was added to N, N-dimethylformamide (150 ml), the temperature was controlled at 100 to 105℃and after completion of the reaction, the reaction mixture was filtered, the filtrate was poured into purified water (1200 ml), chloroform (400 ml. Times.3) was extracted, the organic phases were combined, and the saturated brine (400 ml. Times.2) was washed, and the organic phase was concentrated to dryness under reduced pressure to give the objective compound I in a yield of 94.6% and a purity of 98.91%.
Example 21
Intermediate I-2 (14.36 g,0.05 mol), pd (PPh) under argon 3 ) 2 Cl 2 (1.75 g,2.5 mmol), t-Buona (19.22 g,0.2 mol) and 1, 4-dioxane (150 ml) were added to react at a temperature of 95-100 ℃, after completion of the detection reaction, the reaction solution was filtered, the filtrate was poured into purified water (1200 ml), ethyl acetate (400 ml. Times.3) was extracted, the organic phases were combined, saturated brine (400 ml. Times.2) was washed, and the organic phases were concentrated to dryness under reduced pressure to give the objective compound I in a yield of 97.1% and a purity of 98.83%.

Claims (10)

1. A 5H-dibenzo [ a, d ] cycloheptatrien-5-one intermediate compound, which is characterized in that the structure of the compound is shown as a formula I-2:
Figure FDA0003349083460000011
2. a process for the preparation of an intermediate compound according to claim 1, characterized by the steps of:
Figure FDA0003349083460000012
step 1: dissolving SM-1 and ethanethiol in anhydrous organic solvent A, adding catalyst, and controlling temperatureT A Stirring for reaction to obtain a compound I-1;
step 2: under the protection of inert gas, adding I-1, SM-2, cuTC, catalyst and ligand into reaction solvent B, controlling temperature T B And continuing stirring reaction to prepare the compound I-2.
3. The preparation method according to claim 2, wherein the catalyst in step 1 is one selected from trifluoroacetic acid, p-toluenesulfonic acid and p-toluenesulfonic anhydride.
4. The preparation method according to claim 2, wherein the reaction temperature T A 40-65 ℃, the reaction temperature T B The temperature is 40-78 ℃.
5. The preparation method according to claim 2, wherein the catalyst in the step 2 is selected from one of palladium dichloride, palladium acetate and tris (dibenzylideneacetone) dipalladium, and the ligand is selected from one of triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri-o-tolylphosphine and tris (2-furyl) phosphine.
6. The preparation method according to claim 2, wherein the molar ratio of the compound I-1 to SM-2, cut c, catalyst and ligand in step 2 is 1:1.0 to 1.3:1.2 to 1.8:0.5% -4.0%: 0.5 to 5.0 percent.
7. Use of the intermediate compound I-2 according to claim 1 for the preparation of 5H-dibenzo [ a, d ] cycloheptatrien-5-one.
8. Use according to claim 7, characterized in that the preparation steps are as follows: under the protection of inert gas, adding the compound I-2, a catalyst and alkali into the reaction solvent C, and controlling the temperature T C Continuing the reaction to prepare a compound I, wherein the reaction formula is as follows:
Figure FDA0003349083460000013
9. use according to claim 8, characterized in that the catalyst is selected from Pd (PPh 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd(dppf)Cl 2 One or a combination of the above, wherein the alkali is selected from Na 2 CO 3 ，K 3 PO 4 ，CH 3 COONa，CH 3 COOK, t-Buona or a combination thereof.
10. The use according to claim 8, characterized in that the reaction temperature T C Is 82-110 ℃.
CN202111331572.4A 2021-11-11 2021-11-11 5H-dibenzo [ a, d ] cycloheptatrien-5-one intermediate compound Pending CN116102415A (en)

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