CN116410205B - Preparation method of 3-substituted-9-methyl-thienotriazolooxazine compound - Google Patents

Preparation method of 3-substituted-9-methyl-thienotriazolooxazine compound Download PDF

Info

Publication number
CN116410205B
CN116410205B CN202111637717.3A CN202111637717A CN116410205B CN 116410205 B CN116410205 B CN 116410205B CN 202111637717 A CN202111637717 A CN 202111637717A CN 116410205 B CN116410205 B CN 116410205B
Authority
CN
China
Prior art keywords
compound
preparation
reaction
steps
organic solvent
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
CN202111637717.3A
Other languages
Chinese (zh)
Other versions
CN116410205A (en
Inventor
孙肖
张宏伟
周治国
高强
郑保富
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.)
Medchemexpress China Co ltd
Original Assignee
Medchemexpress China Co ltd
Filing date
Publication date
Application filed by Medchemexpress China Co ltd filed Critical Medchemexpress China Co ltd
Priority to CN202111637717.3A priority Critical patent/CN116410205B/en
Priority to PCT/CN2022/079070 priority patent/WO2023123655A1/en
Publication of CN116410205A publication Critical patent/CN116410205A/en
Application granted granted Critical
Publication of CN116410205B publication Critical patent/CN116410205B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The invention relates to a preparation method of 3-substituted-9-methyl-thienotriazolooxazine compounds, which overcomes the defects of long route (14 steps), low yield and poor atom economy in the prior art, and the invention uses easily available and cheap starting materials, has simple route, can be continuously made in multiple steps without post-treatment and purification, has high reaction yield, and improves the overall yield and atom economy of the route; especially for step 9, the deprotection and cyclization reaction are carried out by a one-step method, so that the problem of side reaction that benzyl chloride in a substrate structure is replaced by fluorine when TBAF is adopted to remove TBDPS protecting groups in the prior art is solved, and the problems that the byproducts are difficult to purify and the yield is reduced are effectively avoided. In addition, the synthesis method provided by the invention has the advantages of mild reaction conditions, simple and convenient operation method and good reproducibility, and is suitable for not only small-scale preparation in a laboratory, but also industrialized mass production.

Description

Preparation method of 3-substituted-9-methyl-thienotriazolooxazine compound
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of a 3-substituted-9-methyl-thienotriazolooxazine compound.
Background
3-Substituted-9-methyl-thienotriazolooxazines (structural formula A shown below) are very important pharmaceutical molecular building blocks, such as but not limited to the preparation of protein-targeted degradation chimera (PROTAC) molecules, for example, when R is a benzene ring, i.e., corresponding, to the compound 9-methyl-3- (benzyl) -4H, 6H-thieno [2,3-e ] [1,2,4] triazolo [3,4-c ] [1,4] oxazine, it is a key intermediate for the preparation of 3- (4- (5- (4- ((3-benzyl-9-methyl-4H, 6H-thieno [2,3-e ] [1,2,4] triazolo [3,4-c ] [1,4] oxazin-2-yl) ethynyl) -1H-pyrazol-1-yl) pent-1-yn-1-yl) -1-oxoisoindolin-2-dione (CAS# 2207569-08-0, structural formula shown below), which is PROTAC molecules linked by Cereblon ligands and BET ligands, with an IC 50 value of 10nM for the BRD4 BD1 protein).
The preparation method of 9-methyl-3- (benzyl) -4H, 6H-thieno [2,3-e ] [1,2,4] triazolo [3,4-c ] [1,4] oxazine (CAS No. 2126818-90-2, namely the following formula compound 16) is disclosed in the Journal of MEDICINAL CHEMISTRY (2018), 61 (15), 6685-6704 by Chong Qin et al, the synthetic route is shown in the following diagram, 14 steps of reaction are needed to prepare the molecular building block compound according to the technical scheme disclosed by the scheme, the reaction route is long, the atomic economy is very poor, and the preparation period and the cost are high. The yield of the two-step reaction from the intermediate 4 to the intermediate 6 is only 52%; and finally, benzyl needs to be introduced with benzyl potassium trifluoroborate (compound 15) through noble metal catalytic coupling reaction, the raw materials are high in price, the reaction conditions are harsh, and the cost is high.
Furthermore, the inventors found that the reaction for preparing compound 4 in the second step is very complicated, with a yield of only 10% when repeating this existing route; when tetrabutylammonium fluoride is used for removing the tertiary butyl dimethylsilyl protecting group, a great amount of byproducts are generated by substituting 3-chlorine of thiophene with fluorine, and the inventors try various purification modes to effectively remove the byproducts; and the byproduct is carried to the next ring closure reaction to prepare compound 14, which is more difficult to purify, resulting in the total yield of ring closure of only 15%. Therefore, designing and implementing a synthetic method which is suitable for industrial production, has excellent reproducibility, is easy to operate and has high yield becomes an important point for research and development of those skilled in the art.
Disclosure of Invention
The invention aims to provide a preparation method of 3-substituted-9-methyl-thienotriazolooxazine compounds, which aims to solve the problems mentioned in the background art.
In order to solve the above technical problem, a first aspect of the present invention provides a method for preparing compound XII, comprising the steps of:
Step 4: reacting the compound V with the compound VI to obtain a compound VII;
Step 5: carrying out a thio reaction on the compound VII to obtain a compound VIII;
step 6: closing the ring of the compound VIII to obtain a compound IX;
step 7: reducing the compound IX to obtain a compound X;
step 8: the compound X undergoes chlorination reaction to obtain a compound XI;
Step 9: the compound XI is subjected to deprotection cyclization reaction to obtain a compound XII;
The R 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted alkyl of C 1-C6;
The R 2 is selected from methyl or ethyl.
As a preferable technical scheme of the invention, the preparation method of the compound VIII in the step 5 comprises the following steps: dispersing the compound VII into an organic solvent, adding a thio reagent, optionally adding inorganic alkali, heating to 70-85 ℃, and reacting for 2-4 hours to obtain the compound VII; and/or the feeding mole ratio of the compound VII to the thio reagent is 1 (0.5-1.7).
As a preferable technical scheme of the invention, the preparation method of the step 8 comprises the following steps: adding the compound X into an organic solvent, cooling to 0 ℃, adding a chlorinating agent, heating to 15-30 ℃, reacting for 2-4 hours, and washing, extracting and drying after the reaction is finished to obtain the compound X; and/or the organic solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile and tetrahydrofuran; and/or the chlorinating agent is selected from thionyl chloride, sulfonyl chloride, phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride.
As a preferable technical scheme of the invention, the preparation method of the step 9 comprises the following steps: mixing a compound XI with an organic solvent, adding a deprotection cyclization reagent, and stirring for 60-80 h at normal temperature; after the reaction is finished, extracting, drying and purifying to obtain the product.
As a preferred technical scheme of the invention, the deprotection cyclization reagent is an inorganic alkaline aqueous solution; the inorganic base may be selected from one or more of lithium hydroxide, lithium hydroxide monohydrate, sodium hydroxide.
As a preferred embodiment of the invention, the molar ratio of the compound XI to the deprotected cyclizing reagent is 1 (20-30).
In a second aspect, the present invention provides a process for the preparation of compound V comprising the steps of:
step 1: vulcanizing and closing the ring by using the compound I and the compound II to prepare a thiophene product compound III;
Step 2: selectively reducing the compound III to obtain a compound IV;
step 3: dehydroxylation of the compound IV to obtain a compound V;
As a preferable technical scheme of the invention, the preparation method of the step 2 comprises the following steps: mixing the compound III with an organic solvent, cooling to-5-3 ℃, adding a reducing agent, heating to room temperature after adding, and stirring for 1-4 h; after the reaction is finished, extracting, drying and concentrating to obtain the product.
As a preferable technical scheme of the invention, the molar ratio of the compound III to the reducing agent is 1 (1-3).
As a preferable technical scheme of the invention, the preparation method of the step 3 comprises the following steps: dissolving a compound IV in an organic solvent, adding an acid after adding a silane compound, stirring for 2-4 h, and performing post-treatment after the reaction is finished to obtain the compound IV; and/or the acid is selected from acetic acid, trifluoromethanesulfonic acid, trifluoroacetic acid; and/or the feeding mole ratio of the compound IV to the silane compound is 1 (4-6).
Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
1. The invention provides a preparation method of 3-substituted-9-methyl-thienotriazolooxazine compounds, which overcomes the defects of long route (14 steps), harsh reaction conditions, low yield and poor atom economy in the prior art.
2. The invention effectively shortens the reaction steps through the special selection of the raw materials and the reaction conditions; especially for step 9, the deprotection and cyclization reaction are carried out by a one-step method, so that the problem of side reaction that benzyl chloride in a substrate structure is replaced by fluorine when TBAF is adopted to remove TBDPS protecting groups in the prior art is solved, and the problems that the byproducts are difficult to purify and the yield is reduced are effectively avoided.
3. The synthesis method provided by the invention has the advantages of mild reaction conditions, simple and convenient operation method and good reproducibility, and is suitable for not only small-scale preparation in a laboratory, but also industrialized mass production.
Detailed Description
The contents of the present invention can be more easily understood by referring to the following detailed description of preferred embodiments of the present invention and examples included. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, definitions, will control.
The term "prepared from …" as used herein is synonymous with "comprising". The terms "comprising," "including," "having," "containing," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.
When an equivalent, concentration, or other value or parameter is expressed as a range, preferred range, or a range bounded by a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. When a numerical range is described herein, unless otherwise indicated, the range is intended to include its endpoints and all integers and fractions within the range.
The singular forms include plural referents unless the context clearly dictates otherwise. "optional" or "any" means that the subsequently described event or event may or may not occur, and that the description includes both cases where the event occurs and cases where the event does not.
Approximating language, in the specification and claims, may be applied to modify an amount that would not limit the application to the specific amount, but would include an acceptable portion that would be close to the amount without resulting in a change in the basic function involved. Accordingly, the modification of a numerical value with "about", "about" or the like means that the present application is not limited to the precise numerical value. In some examples, the approximating language may correspond to the precision of an instrument for measuring the value. In the description and claims of the application, the range limitations may be combined and/or interchanged, if not otherwise specified, including all the sub-ranges subsumed therein.
Furthermore, the indefinite articles "a" and "an" preceding an element or component of the invention are not limited to the requirements of the number of elements or components (i.e. the number of occurrences). Thus, the use of "a" or "an" should be interpreted as including one or at least one, and the singular reference of an element or component also includes the plural reference unless the amount is obvious to the singular reference.
In order to solve the above technical problems, a first aspect of the present invention provides a method for preparing compound XII, comprising the steps of:
Step 4: reacting the compound V with the compound VI to obtain a compound VII;
Step 5: carrying out a thio reaction on the compound VII to obtain a compound VIII;
step 6: closing the ring of the compound VIII to obtain a compound IX;
step 7: reducing the compound IX to obtain a compound X;
step 8: the compound X undergoes chlorination reaction to obtain a compound XI;
Step 9: the compound XI is subjected to deprotection cyclization reaction to obtain a compound XII;
The R 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted alkyl of C 1-C6;
The R 2 is selected from methyl or ethyl.
In a preferred embodiment, the process for the preparation of compound VII of step 4 comprises the steps of: mixing the compound V with an organic solvent, protecting with inert gas, cooling to 0 ℃, dropwise adding oxalyl chloride or thionyl chloride, stirring for 0.5-2 h after the addition is completed to 10-15 ℃, and concentrating after the reaction is completed; dispersing the obtained oily matter into methylene dichloride, mixing, protecting with nitrogen, cooling and maintaining the reaction temperature at 0 ℃, adding organic base, adding compound VI in batches, heating to room temperature after adding, and stirring for 0.5-2 h; post-processing to obtain the final product; the organic base is selected from triethylamine, N, N-diisopropylethylamine and pyridine.
In a preferred embodiment, the process for the preparation of compound VIII of step 5 comprises the steps of: dispersing the compound VII into an organic solvent, adding a thio reagent, optionally adding inorganic alkali, heating to 70-85 ℃, and reacting for 2-4 h to obtain the compound VII.
In a preferred embodiment, the molar ratio of compound VII to the thio agent is 1 (0.5 to 1.7).
Preferably, the molar ratio of the compound VII to the sulfur-containing compound is 1:1.
In a preferred embodiment, the thio reagent is selected from the group consisting of phosphorus pentasulfide and Lawson reagent;
Optionally, an inorganic base is added in the thio reaction, wherein the inorganic base is selected from one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.
In a preferred embodiment, the process for the preparation of compound IX of step 6 comprises the steps of: adding the compound VIII into THF, adding hydrazine hydrate, stirring for 2-4 hours at normal temperature, extracting and drying after the reaction is finished, and directly using the crude product in the next step; adding the crude product into an organic solvent, adding triethyl orthoacetate, heating to 80 ℃, reacting for 0.5-1.5 h, extracting, drying and purifying after the reaction is finished, thus obtaining the product.
In a preferred embodiment, the process for preparing compound X of step 7 comprises the steps of: adding the compound IX into an organic solvent, cooling to-5 ℃, adding a reducing agent, heating to 15-25 ℃, and reacting for 10-40 h to obtain the compound.
In a preferred embodiment, the organic solvent is selected from one or more of methanol, ethanol, dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile, tetrahydrofuran.
Preferably, the organic solvent is a mixture of tetrahydrofuran and methanol, wherein the volume ratio of tetrahydrofuran to methanol is (8-12): 1.
In a preferred embodiment, the reducing agent is lithium borohydride and/or lithium aluminum hydride; preferably, the reducing agent is lithium borohydride.
In a preferred embodiment, the reducing agent is added in the form of a solution, the concentration of the lithium borohydride solution being 1.3-2.6 mol/L; the solvent is tetrahydrofuran.
In a preferred embodiment, the preparation method of step 8 comprises the following steps: adding the compound X into an organic solvent, cooling to 0 ℃, adding a chlorinating agent, heating to 15-30 ℃, reacting for 2-4 hours, and washing, extracting and drying after the reaction is finished to obtain the compound X.
In a preferred embodiment, the organic solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile, tetrahydrofuran; preferably, the organic solvent is dichloromethane.
In a preferred embodiment, the chlorinating agent is selected from thionyl chloride, sulphuryl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride; preferably, the chlorinating agent is thionyl chloride.
In a preferred embodiment, the preparation method of step 9 comprises the following steps: mixing compound XI with an organic solvent, adding a deprotection cyclization reagent, and stirring at normal temperature for 60-80h; after the reaction is finished, extracting, drying and purifying to obtain the product.
In a preferred embodiment, the organic solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile, tetrahydrofuran.
Preferably, the organic solvent is tetrahydrofuran.
In a preferred embodiment, the deprotecting reagent cyclizing reagent is an aqueous inorganic base; the inorganic base may be selected from one or more of lithium hydroxide, lithium hydroxide monohydrate, sodium hydroxide.
Preferably, the concentration of the inorganic alkaline aqueous solution is 4 to 6.3mol/L.
Preferably, the concentration of the inorganic alkaline aqueous solution is 5mol/L.
In a preferred embodiment, the molar ratio of compound XI to deprotected cyclizing reagent is 1 (20-30).
Preferably, the molar ratio of compound XI to deprotected cyclizing reagent is 1:27.6.
In a second aspect, the present invention provides a process for the preparation of compound V comprising the steps of:
step 1: vulcanizing and closing the ring by using the compound I and the compound II to prepare a thiophene product compound III;
Step 2: selectively reducing the compound III to obtain a compound IV;
step 3: dehydroxylation of the compound IV to obtain a compound V;
In a preferred embodiment, the preparation method of step 1 comprises the following steps: dispersing the compound I and the compound II into an organic solvent, adding organic alkali, stirring, adding elemental sulfur, stirring at room temperature until TLC monitoring reaction is finished, diluting the reaction solution into saturated saline, extracting, combining organic phases, drying, concentrating, and performing column chromatography to obtain the compound.
In a preferred embodiment, the organic solvent is selected from one or more of N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, methylene chloride, 1, 2-dichloroethane, 1, 4-dioxane.
In a preferred embodiment, the reaction time is from 8 to 16 hours.
In a preferred embodiment, the organic base is selected from one or more of triethylamine, N-diisopropylethylamine, pyridine.
In a preferred embodiment, the preparation method of step 2 comprises the following steps: mixing the compound III with an organic solvent, cooling to-5-3 ℃, adding a reducing agent, heating to room temperature after adding, and stirring for 1-4 h; after the reaction is finished, extracting, drying and concentrating to obtain the product.
In a preferred embodiment, the organic solvent is a small molecule alcohol; preferably, the small molecule alcohol is methanol and/or ethanol.
In a preferred embodiment, the reducing agent is selected from one of sodium borohydride, lithium borohydride, palladium on carbon, sodium dithionite; preferably, the reducing agent is sodium borohydride.
In a preferred embodiment, the molar ratio of compound III to reducing agent is 1 (1-3).
Preferably, the molar ratio of the compound III to the reducing agent is 1:2.
In a preferred embodiment, the preparation method of step 3 comprises the following steps: dissolving the compound IV in an organic solvent, adding an acid after adding a silane compound, stirring for 2-4 h, and performing post-treatment after the reaction is finished to obtain the compound IV.
In a preferred embodiment, the acid is selected from acetic acid, trifluoromethanesulfonic acid, trifluoroacetic acid; preferably, the acid is trifluoroacetic acid.
In a preferred embodiment, the silane compound is triethylsilane.
In a preferred embodiment, the molar ratio of compound IV to silane compound is 1 (4-6).
Preferably, the molar ratio of the compound IV to the silane compound is 1:5.4.
Examples
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, in which no specific conditions are noted in the examples below, is generally carried out according to conventional conditions.
The raw materials or reagents used in the examples were commercially available unless otherwise specified.
The room temperature described in the examples is 10 to 20 ℃. Unless otherwise indicated, the reagents described were used without purification. All solvents were purchased from commercial suppliers such as Aldrich (Aldrich) and used without treatment.
The reaction was judged to be terminated by TLC analysis and/or by LCMS analysis by consumption of starting material. Thin Layer Chromatography (TLC) for analysis was performed on glass plates (EMD chemicals company (EMD CHEMICALS)) pre-coated with silica gel 60 f254 0.25 mm plates, visualized with UV light (254 nm) and/or iodine on silica gel, and/or heated with TLC staining such as alcohol phosphomolybdic acid, ninhydrin solution, potassium permanganate solution or ceric sulfate solution.
Abbreviations used in the present invention have the usual meaning in the art, such as: DCM represents dichloromethane, DMF represents N, N-dimethylformamide, DIEA represents N, N-diisopropylethylamine; DCE represents 1, 2-dichloroethane; p 2S5 represents phosphorus pentasulfide; THF represents tetrahydrofuran; SOCl 2 represents thionyl chloride; CAS number 76271-74-4 for 2- ((tert-butyldiphenylsilyl) oxy) acetic acid; tosCl represents p-toluenesulfonyl chloride; TBAF represents tetrabutylammonium fluoride; TBDPS t-butyldiphenylsilane; EA represents ethyl acetate; TEA represents triethylamine; PE represents petroleum ether; naBH 4 represents sodium borohydride; etOH represents ethanol; CF 3 COOH represents trifluoroacetic acid; siHEt 3 denotes triethylsilane; liBH 4 represents lithium borohydride; liOH represents lithium hydroxide.
Example 1 preparation of Compound III-1
Compound I-1 (378 g,2.55 mol) and compound II-1 (289 g,2.55 mol) were dispersed in DMF (3L), and after addition of TEA (515 g,5.1 mol), they were gradually brown, and after addition of sulfur powder (98 g,30.6 mol), they were black; stirring and reacting for 16h at 20 ℃; after TLC monitoring reaction, pouring the reaction solution into saturated saline, adding EA (5L multiplied by 2) for extraction, combining organic phases, drying by using anhydrous sodium sulfate, spin-drying, adding EA (1L) into residues, pulping for 24 hours at 20 ℃, and filtering to obtain a compound III-1 (300 g); the filtrate was dried by spin-drying and then separated by column chromatography (PE: ea=5:1) to give compound III-1 (170 g); the combination yielded compound III-1 (470 g, 67%).
Example 2 preparation of Compound V-1
Compound III-1 (470 g,1.71 mol) was mixed with EtOH (4.7L), cooled to 0deg.C, naBH 4 (130 g,3.42 mol) was added in portions, and stirred for 2h at room temperature after addition; after completion of the reaction, the reaction mixture was poured into water (10L), extracted with DCM (5 L×2), and the combined organic phases were dried and concentrated under reduced pressure to give compound IV-1 (470 g).
Compound IV-1 (470 g) was added to DCM (2L), siHEt 3 (986 g,8.5 mol) followed by CF 3 COOH (2L), bi Jiaoban h; after the completion of the reaction, the reaction mixture was concentrated under reduced pressure, then DCM (2L) was added, the pH was adjusted to about 9 with a saturated potassium carbonate solution, the layers were left standing, an organic phase was separated, extracted with DCM (2 l×2), the organic phases were combined, the solvent was removed by spin-drying, and column chromatography (PE/ea=25/1) was performed to obtain compound V-1 (357.5 g, 80%).
Example 3 preparation of Compound V-1
Compound III-1 (0.47 g,1.71 mmol) was mixed with EtOH (4.7 mL), cooled to 0deg.C, naBH 4 (0.064 g,1.71 mmol) was added in portions, and the addition was warmed to room temperature and stirred for 2h; after completion of the reaction, the reaction mixture was poured into water (20 mL), extracted with DCM (10 mL. Times.2), and the combined organic phases were dried and concentrated under reduced pressure to give Compound IV-1 (0.47 g).
Compound IV-1 (0.47 g) was added to DCM (5 mL), siHEt 3 (0.586 g,4.6 mmol) followed by CF 3 COOH (5 mL), bi Jiaoban h; after the completion of the reaction, the reaction mixture was concentrated under reduced pressure, then DCM (20 mL) was added, the pH was adjusted to about 9 with saturated potassium carbonate solution, the mixture was allowed to stand still for separation, the organic phase was separated, extracted with DCM (20 m L X2), the organic phases were combined, the solvent was removed by rotation, and column chromatography (PE/EA=25/1) was performed to give Compound V-1 (0.34 g, 77%).
Example 4 preparation of Compound V-1
Compound III-1 (0.47 g,1.71 mmol) was mixed with EtOH (4.7 mL), cooled to 0deg.C, naBH 4 (0.194 g,5.13 mmol) was added in portions, and the addition was warmed to room temperature and stirred for 2h; after completion of the reaction, the reaction mixture was poured into water (20 mL), extracted with DCM (10 mL. Times.2), and the combined organic phases were dried and concentrated under reduced pressure to give Compound IV-1 (0.47 g).
Compound IV-1 (0.422 g,1.52 mmol) was added to DCM (5 mL), siHEt 3 (1.14 g,9.8 mmol) was added, followed by CF 3 COOH (5 mL) for Bi Jiaoban h; after the completion of the reaction, the reaction mixture was concentrated under reduced pressure, then DCM (20 mL) was added, the pH was adjusted to about 9 with saturated potassium carbonate solution, the mixture was allowed to stand still for separation, the organic phase was separated, extracted with DCM (20 m L X2), the organic phases were combined, the solvent was removed by rotation, and column chromatography (PE/EA=25/1) was performed to give Compound V-1 (0.33 g, 75%).
Example 5 preparation of Compound XI-1
Compound V-1 (457.16 g,1455.932 mmol) was dispersed in DCM (2L) and DMF (0.5 mL), cooled to 0deg.C under nitrogen protection, oxalyl chloride (243.16 g,1915.7 mmol) was added dropwise, the temperature was raised to 15deg.C after the addition was stirred for 1h, and after the reaction was completed, the mixture was concentrated to give an oil; DCM (2L) was added, cooled to 0deg.C under nitrogen protection, DIEA (296.55 g,2298.84 mmol) was added dropwise while maintaining the internal temperature at 0deg.C, 2- ((tert-butyldiphenylsilyl) oxy) acetic acid (200 g,766.28 mmol) was added in portions after the addition, and the mixture was stirred for 1h at room temperature after the addition; after the completion of the reaction, hydrochloric acid solution (2L, 1 mol/L) was added to the reaction solution, the layers were separated, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the solvent was removed by rotation, and column chromatography (PE/ea=80/1) to give compound VII-1 (314.3 g, 71%)
Compound VII-1 (300 g,0.54 mol) was mixed with DCE (6L), and after adding P 2S5 (120 g,0.54 mol) and sodium carbonate (114.5 g,1.08 mol), heated to 83 ℃ and reacted for 3 hours; after the reaction was completed, the reaction mixture was cooled to room temperature, and the silica gel powder was stirred, and the mixture was quickly eluted with DCM (10L), and the eluted fraction was concentrated and separated by column chromatography (PE: ea=50:1) to give compound VIII-1 (223.1 g, 72%).
Compound VIII-1 (217 g,378.7 mmol) was added to THF (1.5L), hydrazine hydrate (71 g,1136mmol,80% content) was added thereto, stirred at room temperature for 3h, the reaction was completed, concentrated, extracted with water (2L), DCM (2L), separated, the organic phase was washed with brine (2L), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated; the resulting concentrate was mixed with EtOH (1.5L) and THF (300 mL), triethylorthoacetate (184 g,1136 mmol) was added, then heated to 80℃and reacted for 1h, after the end of the reaction, concentrated, acetic acid (1.5L) was added to the concentrate, heated to 120℃and refluxed for 4h, after the acetic acid was again concentrated under reduced pressure, water (1L) was added to the residue, and after pH >8 was adjusted with sodium carbonate, extracted with EA (1L. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by column chromatography (EA) to give compound IX-1 (156.4 g, 70%).
Compound IX-1 (114 g,191.6 mmol) was mixed with THF (1.2L), methanol (0.12L) was further added, the temperature was lowered to 0℃and LiBH 4 (192 mL,2M in THF) was added, the temperature was raised to 20℃for 48 hours, the reaction was completed, the reaction solution was poured into 2L of saturated ammonium chloride solution, EA (2L. Times.2) was added for extraction, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by column chromatography (EA) to give Compound X-1 (81.7 g, 78%).
Compound X-1 (65 g,117.5 mmol) was mixed with DCM (1.3L), cooled to 0deg.C, SOCl 2 (42 g,352.6 mmol) was added, then heated to 20deg.C, the reaction was completed, washed with saturated Na 2CO3 (1.5L) solution, the aqueous phase was extracted with DCM (1 L×1), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate concentrated, and column chromatographed (EA) to give compound XI-1 (63.6 g, 95%).
Example 6 preparation of Compound XII-1
Compound XI-1 (10 g,17.4 mmol) was mixed with THF (100 mL), then LiOH aqueous solution (100 mL, 5M) was added, stirring was continued at 20℃for 72h, after the reaction was completed, the reaction solution was poured into saturated NH 4 Cl (1L), EA (1 L×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, followed by column chromatography (EA) to give compound XII-1 (4.75 g, 92%).
1H NMR(400MHz,CDCl3)δ7.40-7.30(m,3H),7.20(d,J＝7.2Hz,2H),6.82(s,1H),4.79(s,2H),4.73(s,2H),3.88(s,2H),2.75(s,3H).
EXAMPLE 7 preparation of Compound XII-1
Compound XI-1 (10 g,17.4 mmol) was mixed with THF (100 mL), liOH aqueous solution (69.6 mL, 5M) was added and stirring was continued at 20deg.C for 72h, after the reaction was completed, the reaction solution was poured into saturated NH 4 Cl (1L), EA (1 L×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound XII-1 (4.64 g, 90%).
Example 8 preparation of Compound XII-1
Compound XI-1 (10 g,17.4 mmol) was mixed with THF (100 mL), then LiOH aqueous solution (104 mL, 5M) was added, stirring was continued at 20℃for 72h, after the reaction was completed, the reaction solution was poured into saturated NH 4 Cl (1L), EA (1 L×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, followed by column chromatography (EA) to give compound XII-1 (4.54 g, 88%).
Example 9 preparation of Compound XII-1
Compound XI-1 (10 g,17.4 mmol) was mixed with THF (100 mL), TBAF (18.1 g,69.6 mmol) was added thereto, stirred at room temperature for 1h, EA (1L X3) was extracted after completion of the reaction, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, followed by column chromatography (EA) to give compound XII-1 (0.77 g, 15%).
Example 10 preparation of Compound XII-1
Compound X-1 (20 g,34.8 mmol) was dispersed in THF (200 mL), TBAF (13.07 g,50 mmol) was added thereto, stirred at room temperature for 1h, EA (1L X3) was extracted after completion of the reaction, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, followed by column chromatography (EA) to give compound XIII-1 (7.6 g, 70%).
Compound XIII-1 (1 g,1.74 mmol) was dispersed in THF (5 mL), DMF (5 mL), sodium hydrogen (0.1 g,4.35 mmol) was added, tosCl (0.33 g,1.74 mmol) was slowly added, stirring was performed at room temperature for 10h, after the reaction was completed, water was added to quench, EA (100 mL. Times.3) was extracted, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (EA) was used to give compound XII-1 (0.12 g, 24%).
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (8)

1. A process for the preparation of compound XII comprising the steps of:
Step 4: reacting the compound V with the compound VI to obtain a compound VII;
Step 5: carrying out a thio reaction on the compound VII to obtain a compound VIII;
step 6: closing the ring of the compound VIII to obtain a compound IX;
step 7: reducing the compound IX to obtain a compound X;
step 8: the compound X undergoes chlorination reaction to obtain a compound XI;
Step 9: the compound XI is subjected to deprotection cyclization reaction to obtain a compound XII;
The R 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted alkyl of C 1-C6;
Said R 2 is selected from methyl or ethyl;
the deprotection cyclization reagent is inorganic alkaline aqueous solution; the inorganic base is lithium hydroxide; the concentration of the inorganic alkaline water solution is 4-6.3 mol/L;
The molar ratio of the compound XI to the deprotection cyclization reagent is 1 (20-30).
2. The preparation method according to claim 1, wherein the preparation method of the compound VIII in the step 5 comprises the following steps: dispersing the compound VII into an organic solvent, adding a thio reagent, optionally adding inorganic alkali, heating to 70-85 ℃, and reacting for 2-4 hours to obtain the compound VII; the feeding mole ratio of the compound VII to the thio reagent is 1 (0.5-1.7).
3. The preparation method according to claim 1, wherein the preparation method of step 8 comprises the steps of: adding the compound X into an organic solvent, cooling to 0 ℃, adding a chlorinating agent, heating to 15-30 ℃, reacting for 2-4 hours, and washing, extracting and drying after the reaction is finished to obtain the compound X; the organic solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile and tetrahydrofuran; the chlorinating agent is selected from thionyl chloride, sulfonyl chloride, phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride.
4. The preparation method according to claim 1, wherein the preparation method of step 9 comprises the steps of: mixing a compound XI with an organic solvent, adding a deprotection cyclization reagent, and stirring for 60-80 h at normal temperature; after the reaction is finished, extracting, drying and purifying to obtain the product.
5. The preparation method according to claim 1, wherein the preparation method of the compound V comprises the steps of:
step 1: vulcanizing and closing the ring by using the compound I and the compound II to prepare a thiophene product compound III;
Step 2: selectively reducing the compound III to obtain a compound IV;
step 3: dehydroxylation of the compound IV to obtain a compound V;
6. The preparation method according to claim 5, wherein the preparation method of step 2 comprises the steps of: mixing the compound III with an organic solvent, cooling to-5-3 ℃, adding a reducing agent, heating to room temperature after adding, and stirring for 1-4 h; after the reaction is finished, extracting, drying and concentrating to obtain the product.
7. The process according to claim 6, wherein the molar ratio of the compound III to the reducing agent is 1 (1-3).
8. The preparation method according to claim 5, wherein the preparation method of step 3 comprises the steps of: dissolving a compound IV in an organic solvent, adding an acid after adding a silane compound, stirring for 2-4 h, and performing post-treatment after the reaction is finished to obtain the compound IV; the acid is selected from acetic acid, trifluoromethanesulfonic acid and trifluoroacetic acid; the feeding mole ratio of the compound IV to the silane compound is 1 (4-6).
CN202111637717.3A 2021-12-29 2021-12-29 Preparation method of 3-substituted-9-methyl-thienotriazolooxazine compound Active CN116410205B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202111637717.3A CN116410205B (en) 2021-12-29 Preparation method of 3-substituted-9-methyl-thienotriazolooxazine compound
PCT/CN2022/079070 WO2023123655A1 (en) 2021-12-29 2022-03-03 Preparation method for 3-substituted-9-methyl-thieno-triazolooxazine compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111637717.3A CN116410205B (en) 2021-12-29 Preparation method of 3-substituted-9-methyl-thienotriazolooxazine compound

Publications (2)

Publication Number Publication Date
CN116410205A CN116410205A (en) 2023-07-11
CN116410205B true CN116410205B (en) 2024-07-05

Family

ID=

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109071562A (en) * 2016-02-15 2018-12-21 密执安大学评议会 Condensed 1,4- oxygen azepine * and related analogs as BET bromine structural domain inhibitor
WO2019055444A1 (en) * 2017-09-13 2019-03-21 The Regents Of The University Of Michigan Bet bromodomain protein degraders with cleavable linkers
CN110062759A (en) * 2016-09-13 2019-07-26 密执安大学评议会 Condensed 1,4- oxygen azepine * as BET protein degradation agent

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109071562A (en) * 2016-02-15 2018-12-21 密执安大学评议会 Condensed 1,4- oxygen azepine * and related analogs as BET bromine structural domain inhibitor
CN110062759A (en) * 2016-09-13 2019-07-26 密执安大学评议会 Condensed 1,4- oxygen azepine * as BET protein degradation agent
WO2019055444A1 (en) * 2017-09-13 2019-03-21 The Regents Of The University Of Michigan Bet bromodomain protein degraders with cleavable linkers

Similar Documents

Publication Publication Date Title
WO2020147861A1 (en) Electrochemical preparation method for β-trifluoromethylamide compound
JPH04224556A (en) Chiral catalyst for producing ketone and process for preparing same
CN106316898B (en) The synthetic method of Florfenicol
CN103992212A (en) Synthesis method for cis-benvitimod, and applications of cis-benvitimod
CN101146812B (en) Optically active ammonium salt compound, production intermediate thereof and method for producing same
CN109956901B (en) Preparation method of isoquinolone compound
CN116410205B (en) Preparation method of 3-substituted-9-methyl-thienotriazolooxazine compound
CN102532109B (en) Synthetic method of lapatinib and salt of lapatinib
CN116410205A (en) Preparation method of 3-substituted-9-methyl-thienotriazolooxazine compound
CN107540655B (en) Novel method for preparing S- (perfluoroalkyl) -dibenzothiophene trifluoromethanesulfonate
CN109879792A (en) A kind of polysubstituted isoindoles compound and preparation method thereof
Dixon et al. Efficient desymmetrisation of a meso-imide using a chiral oxazaborolidine catalyst
KR102674919B1 (en) Synthesis of 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile
CN113348164B (en) Preparation method and intermediate of fused tricyclic derivative
CN115141134A (en) Compound and preparation method and application thereof
CN107513056A (en) A kind of synthetic method of the quinolines of the group containing tetrahydrofuran
Takahashi et al. Efficient and convenient method for synthesis of solenopsine A and its analogs using 1-benzyl-2, 6-dicyanopiperidine
CN111646972B (en) Preparation method of selective estrogen receptor degradation agent and intermediate thereof
CN114213354B (en) Preparation method of trans-2- (substituted phenyl) -3-oxymorphone
CN109053455A (en) A kind of α-nitro-alpha-aryl ketones compounds synthetic method
CN113248420B (en) Preparation method of 2-acyl-3-ester group indole derivatives
JPH04243875A (en) Process for producing 2-phenyl-6-(pyrimidin-2- yl)pyridine compound, intermediate compound and process for producing intermediate compound
CN113754569B (en) Intermediate compound and preparation method and application thereof
CN114349699B (en) Synthesis method of (R) -2- (4-methoxybenzyl) -4-methylene-1-p-toluenesulfonyl pyrrolidine
EP1841774A1 (en) PROCESS FOR PREPARING 5,6-DIHYDRO-4-(S)-(ETHYLAMINO)-6-(S) METHYL-4H-THIENOÝ2,3b¨THIOPYRAN-2-SULPHONAMIDE-7,7-DIOXIDE HCI

Legal Events

Date Code Title Description
PB01 Publication
SE01 Entry into force of request for substantive examination
GR01 Patent grant