CN115536663A - Triracil intermediate and preparation and application thereof - Google Patents

Triracil intermediate and preparation and application thereof Download PDF

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CN115536663A
CN115536663A CN202211242477.1A CN202211242477A CN115536663A CN 115536663 A CN115536663 A CN 115536663A CN 202211242477 A CN202211242477 A CN 202211242477A CN 115536663 A CN115536663 A CN 115536663A
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intermediate compound
compound
palladium
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张一平
付晨晨
刘巧灵
郑旭春
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Hangzhou Cheminspire Technologies Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a synthetic method of a key intermediate compound 5 of Trasipride, which takes N- (1- ((tertiary compound 1 as an initial raw material, performs Sonogashira coupling with propiolic alcohol under the catalysis of palladium and copper to obtain a compound 2, then performs cyclization reaction to obtain a new compound 3, oxidizes primary alcohol into carboxylic acid to obtain a compound 4, and finally performs one-pot removal of Boc and cyclization to obtain the compound 5.

Description

Triracil intermediate and preparation and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a novel intermediate of traasiril, a preparation method thereof and a key intermediate of traasiril prepared from the novel intermediate.
Background
Trilaciclib (trade name: cosala) is a cyclin dependent kinase 4/6 (CDK 4/6) inhibitor developed by Protoyor medicine in cooperation with the United states biopharmaceuticals company (G1 Therapeutics) that helps protect Hematopoietic Stem and Progenitor Cells (HSPC) in the bone marrow from chemotherapy-induced myelosuppression. In 8 months 2020, the pioneer pharmaceutical industry bought the right to develop and commercialize all indications of treaxeli in china from G1. Trirasili was approved for sale in the United states at 2 months 2021 for prophylactic administration prior to treatment with a platinum-containing drug in combination with etoposide to reduce the incidence of chemotherapy-induced myelosuppression in a wide-term small cell lung cancer patient who had not previously received systemic chemotherapy. The traasiril comes into the market, becomes the first and only medicine with comprehensive bone marrow protection effect all over the world, solves the long-standing trouble of bone marrow inhibitors caused by chemotherapy, brings treatment hope for more patients, and other indications are also in clinical research.
The chemical name of traasiril is: 2'- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -7',8 '-dihydro-6' h-spiro [ cyclohexane-1, 9 '-pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidin-6' -one, the key intermediate formula of which is: 2 '-chloro-7', 8 '-dihydro-6' H-spiro [ cyclohexane-1, 9 '-pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidin-6' -one, wherein their structural formula is as follows:
Figure BDA0003885227300000011
WO2012061156A reports a synthesis method of key intermediate of traasillide, which uses 5-bromo-2, 4-dichloropyrimidine as a starting material, firstly condenses with 1- ((tert-butoxycarbonyl) aminomethyl) cyclohex-1-amine, then undergoes Sonogashira coupling reaction with 3, 3-diethoxyprop-1-yne, then cyclizes under the action of tetrabutylammonium fluoride (TBAF), removes an acetal protecting group by acetic acid, then oxidizes an aldehyde group by Oxone to obtain 7- (1- ((tert-butoxycarbonyl) aminomethyl) cyclohexyl) -2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid, and finally removes Boc and cyclizes to form lactam in a DCC/DMAP/trifluoroacetic acid system in a one-pot manner to obtain a target product of 2' -chloro-7 ',8' -dihydro-6H-spiro [ cyclohexane-1, 9' -pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidine ] -6' -ketone, wherein the synthesis route is as follows:
Figure BDA0003885227300000021
the unit price of the 3, 3-diethoxyprop-1-alkyne serving as the raw material in the route is higher, two steps of reactions of acidolysis and oxidation are needed for converting the acetal into the carboxylic acid, the route cost is further increased, and in addition, the Oxone oxidation reaction has certain potential safety hazard when the process is amplified. In a word, the route is overlong, the steps are complicated, the total yield is low, and the method is not suitable for large-scale production.
The patent publication No. CN111867592A improves the synthesis method, 5-iodine-2, 4-dichloropyrimidine is used as a starting material, and is firstly condensed with 1- ((tert-butoxycarbonyl) aminomethyl) cyclohex-1-amine, then methyl propiolate with higher activity is used for replacing 3, 3-diethoxyprop-1-yne to participate in Sonogashira coupling reaction, then cyclization is carried out under the action of TBAF, and finally Boc is removed and cyclization is carried out under the action of trifluoroacetic acid in a one-pot method to obtain a target product, wherein the synthesis route is as follows:
Figure BDA0003885227300000022
although the reaction steps are shortened in the route, the starting materials of 5-iodo-2, 4-dichloropyrimidine and methyl propiolate are high in material price, and the methyl propiolate is high in activity, self-polymerization is easy to occur under the action of alkali, the conversion rate of the starting materials participating in the Sonogashira coupling reaction is low, so that the total yield of the route is low, and the cost is high. In conclusion, the method for synthesizing the key intermediate 2 '-chloro-7', 8 '-dihydro-6' H-spiro [ cyclohexane-1, 9 '-pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidine ] -6' -ketone of traasiril has the advantages of simple process route, high yield, low cost and suitability for industrial production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel intermediate of the traasimide and a key intermediate compound 5 prepared from the intermediate, and the intermediate has the advantages of simple process route, low cost, suitability for industrial production and the like.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a traasiril intermediate compound 3 has a structural formula as follows:
Figure BDA0003885227300000031
the invention also relates to a synthesis method of the Trasipride intermediate compound 3, which adopts the following technical scheme:
a synthetic method of a traasiril intermediate compound 3 comprises the following steps:
(1) The starting material compound 1 is coupled with propiolic alcohol under the action of palladium and copper catalysts and alkali to obtain an intermediate compound 2:
Figure BDA0003885227300000032
(2) Cyclizing the intermediate compound 2 under the action of copper salt and alkali or TBAF to obtain an intermediate compound 3;
Figure BDA0003885227300000041
preferably, the palladium catalyst used in the coupling reaction in step (1) is selected from palladium-carbon, palladium acetate, palladium dichloride, dichlorobis (triphenylphosphine) palladium, pd (dppf) Cl 2 Or tetrakis (triphenylphosphine) palladium; the copper catalyst is selected from cuprous iodide, cuprous chloride or cuprous bromide; no ligand or ligand selected from triphenylphosphine, tricyclohexylphosphine, and tri-tert-butylphosphine; the base is selected from triethylamine, diisopropylethylamine, triethylenediamine, and 1, 8-diazabicyclo [5.4.0]]Undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the reaction solvent used is selected from methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene; the reaction temperature is 0-130 ℃.
Preferably, TBAF is selected as a cyclization reagent in the cyclization reaction of the step (2); the solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dichloromethane, tetrahydrofuran, 1, 4-dioxane or acetonitrile; the reaction temperature is 25-90 ℃.
Preferably, the cyclization reaction in the step (2) adopts a copper catalyst and closes a ring under the action of alkali, wherein the copper catalyst is selected from cuprous iodide, cuprous chloride or cuprous bromide; the base is selected from triethylamine, diisopropylethylamine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone or DMPU; the reaction temperature is 50-130 ℃.
The invention also relates to a synthesis method for preparing a key intermediate compound 5 from the intermediate compound 3, which adopts the following technical means:
the synthetic method of the traasiril intermediate compound 5 comprises the following steps
(1) Oxidizing the intermediate compound 3 under the action of an oxidant to obtain an intermediate compound 4;
Figure BDA0003885227300000042
(2) Removing Boc from the intermediate compound 4 under the action of acid and cyclizing by a one-pot method to obtain an intermediate compound 5;
Figure BDA0003885227300000051
preferably, the oxidation reaction in the step (1) is carried out by a TEMPO catalytic oxidation method, wherein the oxidant is selected from NBS, NCS, dibromohydantoin, iodobenzene acetate, sodium hypochlorite, sodium chlorite or TCCA; no auxiliary agent is added or an auxiliary agent selected from sodium bicarbonate, sulfamic acid, sodium bromide or isobutene is added to improve the conversion rate; the reaction solvent is selected from tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, toluene, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether; the reaction temperature is-20-90 ℃.
Preferably, the Boc removal and one-pot cyclization reaction acid in the step (2) is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid; the reaction solvent is selected from methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, toluene, xylene, chlorobenzene or trifluorotoluene; the reaction temperature is 0-150 ℃.
The invention also relates to a synthesis method of the Trasipride intermediate compound 5, which adopts the following technical scheme:
a synthetic method of a traasiril intermediate compound 5 is characterized in that N- (1- ((tert-butoxycarbonyl) aminomethyl) cyclohexyl) -5-bromo-2-chloropyrimidine-4-amine compound 1 is used as a starting material, the compound and propiolic alcohol are subjected to Sonogashira coupling under the catalysis of palladium and copper to obtain a compound 2, then a cyclization reaction is completed under the action of copper salt and alkali or TBAF to obtain a compound 3, primary alcohol is oxidized into carboxylic acid to obtain a compound 4, and finally Boc is removed in a one-pot method and cyclization is carried out to obtain a target product 2 '-chloro-7', 8 '-dihydro-6' H-spiro [ cyclohexane-1, 9 '-pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidine ] -6' -ketone compound 5. The route is as follows:
Figure BDA0003885227300000052
compared with the prior art, the synthesis method of the intermediate compound 5 of the traasiril optimizes the process, shortens the route steps, improves the route efficiency, has cheap and easily obtained propiolic alcohol raw materials, has simple step of converting the propiolic alcohol raw materials into carboxylic acid, and obviously reduces the process cost. The route is simple to operate, the total yield is high, the purity of the obtained product is high, and the route is suitable for large-scale production.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
Figure BDA0003885227300000061
Adding N- (1- ((tert-butoxycarbonyl) aminomethyl) cyclohexyl) -5-bromo-2-chloropyrimidine-4-amine compound 1 (41.97g, 100mmol), propiolic alcohol (11.21g, 200mmol), diisopropylethylamine DIPEA (25.85g, 200mmol) and isopropanol (420 mL) into a three-neck flask, uniformly stirring, switching nitrogen gas for 3 times in vacuum, adding cuprous iodide (190mg, 1mmol) and dichlorobis (triphenylphosphine) palladium (702mg, 1mmol) under the protection of nitrogen gas, heating to 55-60 ℃ after the addition, reacting for 6-8 hours, filtering after the reaction is finished, adding most isopropanol, adding 420mL of water, pulping, filtering, collecting a filter cake, and drying to obtain compound 2 (32.66g, 82.7%).
1 HNMR(500MHz,DMSO-d6)δ8.04(s,1H),6.85-7.04(m,1H),5.65-5.77(m,1H),5.32-5.41(m,1H),4.31-4.47(m,2H),3.25-3.44(m,2H),2.04-2.17(m,2H),1.15-1.62(m,17H)。
MS(ESI)m/z＝395.1[M+H] + 。
In example 1; the alkali diisopropylethylamine can be triethylamine, triethylene diamine, or 1, 8-diazabicyclo [5.4.0]Undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the solvent isopropanol can be replaced by methanol, ethanol, tert-butanol, tert-amyl alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene; the copper catalyst cuprous iodide can be replaced by cuprous chloride or cuprous bromide; the palladium catalyst dichlorobis (triphenylphosphine) palladium can be palladium carbon, palladium acetate, palladium dichloride, pd (dppf) Cl 2 Or tetrakis (triphenylphosphine) palladium; triphenylphosphine, tricyclohexylphosphine, or tri-tert-butylphosphine ligand may be added during the reaction.
Example 2
Figure BDA0003885227300000071
Adding N- (1- ((tert-butoxycarbonyl) aminomethyl) cyclohexyl) -5-bromo-2-chloropyrimidine-4-amine compound 1 (41.97g, 100mmol), propiolic alcohol (11.21g, 200mmol), diisopropylethylamine DIPEA (25.85g, 200mmol) and ethanol (420 mL) into a three-neck flask, uniformly stirring, switching nitrogen for 3 times in vacuum, adding cuprous iodide (190mg, 1mmol) and 10% palladium carbon (1064mg, 1mmol) under the protection of nitrogen, heating to 55-60 ℃ after finishing the addition, reacting for 6-8 hours, filtering to recover palladium carbon after the reaction is finished, removing most ethanol, adding 420mL of water, pulping, filtering, collecting a filter cake, and drying to obtain intermediate formula 2 (30.21g, 76.5%).
In example 1; the alkali diisopropylethylamine can be triethylamine, triethylene diamine, or 1, 8-diazabicyclo [5.4.0]Undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the solvent ethanol can be replaced by isopropanol methanol, tert-butanol, tert-amyl alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene; the copper catalyst cuprous iodide can be replaced by cuprous chloride or cuprous bromide; the palladium-carbon catalyst can be dichlorobis (triphenylphosphine) palladium, palladium acetate, palladium dichloride, pd (dppf) Cl 2 Or tetrakis (triphenylphosphine) palladium; triphenylphosphine, tricyclohexylphosphine, or tri-tert-butylphosphine ligand may be added during the reaction.
Example 3
Figure BDA0003885227300000072
Compound 2 (39.49g, 100mmol) and N-methylpyrrolidone NMP (197 mL) were added to a three-necked flask, and after stirring, nitrogen was switched in under vacuum for 3 times, cuprous chloride (990mg, 10mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene DBU (3.04g, 20mmol) were added under nitrogen protection, and after completion of the addition, the temperature was raised to 110 to 120 ℃ for reaction overnight. After the reaction is finished, 395mL of water is added to quench the reaction, the aqueous phase is extracted by ethyl acetate (395 mL), the combined organic phases are washed by water for 2 times (99 mL), dried by sodium sulfate, filtered, concentrated to a small volume, slowly added with petroleum ether, cooled to 0-5 ℃, pulped, filtered, collected filter cake and dried to obtain an intermediate formula 3 (34.67g, 87.8%).
1 HNMR(500MHz,DMSO-d6)δ8.83(s,1H),7.42-7.54(m,1H),6.53(s,1H)5.48-5.57(m,1H),4.62-4.72(m,2H),3.75-3.85(m,2H),2.67-2.85(m,2H),1.58-1.80(m,4H),1.37-1.54(m,13H)ppm.
MS(ESI)m/z＝395.1[M+H] + 。
In example 3, cuprous chloride, a copper catalyst, can be replaced with cuprous iodide or cuprous bromide; the base 1, 8-diazabicyclo [5.4.0] undec-7-ene may be replaced by triethylamine, diisopropylethylamine, triethylenediamine, potassium carbonate, sodium carbonate or potassium phosphate; the solvent N-methylpyrrolidone can be replaced by dimethylformamide, dimethylacetamide, dimethyl sulfoxide or DMPU.
Example 4
Figure BDA0003885227300000081
Compound 2 (39.49g, 100mmol) and THF (395 mL) were added to a three-necked flask, TBAF trihydrate (94.65g, 300mmol) was added, and after the addition, the temperature was raised to 55 to 60 ℃ for reaction overnight. After the reaction is finished, 395mL of water is added to quench the reaction, the aqueous phase is extracted by ethyl acetate (395 mL), the combined organic phases are washed by water for 2 times (98 mL), dried by sodium sulfate, filtered, concentrated to a small volume, slowly added with petroleum ether (316 mL), cooled to 0-5 ℃, pulped, filtered, collected filter cake and dried to obtain an intermediate formula 3 (33.37g, 84.5%).
In example 4, the solvent tetrahydrofuran may be replaced with dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, 1, 4-dioxane or acetonitrile.
Example 5
Figure BDA0003885227300000091
3 (39.49g, 100mmol) and dichloromethane (395 mL) are added to a three-neck flask, TEMPO (312mg, 2mmol) and iodobenzene acetate (96.63g, 300mmol) are added, and after the addition, the mixture is stirred at room temperature for 6 to 8 hours, and then heated to 38 to 40 ℃ for reaction overnight. After the reaction, part of dichloromethane was removed by concentration, petroleum ether (316 mL) was slowly added, the mixture was cooled to room temperature and slurried, filtered, and the filter cake was collected and dried to obtain Compound 4 (36.88g, 90.2%).
In example 5, the oxidizing agent iodobenzene acetate can be replaced by NBS, NCS, dibromohydantoin, sodium hypochlorite, sodium chlorite, or TCCA; the reaction solvent dichloromethane can be replaced by tetrahydrofuran, 1, 2-dichloroethane, toluene, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether; an auxiliary agent selected from sodium bicarbonate, sulfamic acid, sodium bromide or isobutene can also be added in the reaction process to improve the conversion rate.
Example 6
Figure BDA0003885227300000092
3 (39.49g, 100mmol) and dichloromethane (197 mL) were added to a three-necked flask, and after stirring and dissolution, the mixture was cooled in an ice bath, sodium bicarbonate (16.8g, 200mmol) was added, TEMPO (312mg, 2mmol) was added, dibromohydantoin (60.04g, 210mmol) was added in portions, and the mixture was allowed to warm to room temperature for 6 to 8 hours. After the reaction, 10% citric acid solution is added to adjust the pH value to 3-4, partial solid is removed by filtration, liquid separation is carried out, the water phase is extracted by dichloromethane (98 mL) for 1 time, organic phase water (98 mL) is combined for 2 times, anhydrous sodium sulfate is dried, filtered, concentrated, petroleum ether is added after concentration for pulping, solid is separated by filtration, and the compound of formula 4 (35.12g, 85.9%) is obtained by drying.
In example 6, the oxidant dibromohydantoin can be replaced with iodobenzene acetate, NBS, NCS, sodium hypochlorite, sodium chlorite, or TCCA; the reaction solvent dichloromethane can be replaced by tetrahydrofuran, 1, 2-dichloroethane, toluene, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether; sodium bicarbonate may be omitted or sulfamic acid, sodium bromide or isobutylene may be substituted to increase conversion during the reaction.
Example 7
Figure BDA0003885227300000101
Adding 2 (40.89g, 100mmol) and toluene (409 mL) into a three-neck flask, adding p-toluenesulfonic acid monohydrate (41.85g, 220mmol), heating to reflux, carrying out water-carrying reaction for 8-10 hours, cooling to room temperature after the reaction is finished, adding 5% sodium bicarbonate aqueous solution (205 mL), stirring, separating, washing an organic phase for 1 time, collecting the organic phase, evaporating most of toluene, slowly adding petroleum ether (245 mL), slowly cooling to 0-5 ℃, pulping, filtering, collecting a filter cake, and drying to obtain a target product of the formula 5 (33.37g, 88.1%).
In example 7, the methanesulfonic acid can be replaced by hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid; the reaction solvent toluene can be replaced by methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, xylene, chlorobenzene or trifluorotoluene.

Claims (9)

1. A traasiril intermediate compound 3 is characterized by having a structural formula as shown in the specification:
Figure FDA0003885227290000011
2. a synthetic method of a traasiril intermediate compound 3 is characterized by comprising the following steps:
(1) The starting material compound 1 is coupled with propiolic alcohol under the action of palladium and copper catalysts and alkali to obtain an intermediate compound 2:
Figure FDA0003885227290000012
(2) Cyclizing the intermediate compound 2 under the action of copper salt and alkali or TBAF to obtain an intermediate compound 3;
Figure FDA0003885227290000013
3. the method for synthesizing a traasiride intermediate compound 3 according to claim 2, wherein a palladium catalyst used in the coupling reaction in the step (1) is selected from palladium-carbon, palladium acetate, palladium dichloride, dichlorobis (triphenylphosphine) palladium, and Pd (dppf) Cl 2 Or tetrakis (triphenylphosphine) palladium; the copper catalyst is selected from cuprous iodide, cuprous chloride or cuprous bromide; without addition of ligand or with ligandFrom triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine; the base is selected from triethylamine, diisopropylethylamine, triethylenediamine, and 1, 8-diazabicyclo [5.4.0]]Undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the reaction solvent used is selected from methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene.
4. The synthesis method of the Trasipride intermediate compound 3 according to claim 2, wherein the cyclization reaction in the step (2) adopts TBAF as a cyclization reagent; the solvent is selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, tetrahydrofuran, 1, 4-dioxane or acetonitrile.
5. The synthesis method of the Trasipride intermediate compound 3 according to claim 2, wherein the cyclization reaction in the step (2) is performed by using a copper catalyst and closing a ring under the action of alkali, wherein the copper catalyst is selected from cuprous iodide, cuprous chloride or cuprous bromide; the base is selected from triethylamine, diisopropylethylamine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone or DMPU.
6. A synthetic method of a traasiril intermediate compound 5 comprises the following steps
(1) Oxidizing the intermediate compound 3 under the action of an oxidant to obtain an intermediate compound 4;
Figure FDA0003885227290000021
(2) Removing Boc from the intermediate compound 4 under the action of acid and cyclizing by a one-pot method to obtain an intermediate compound 5;
Figure FDA0003885227290000022
7. the method for synthesizing the traasiril intermediate compound 5 according to claim 6, wherein the oxidation reaction in the step (1) is carried out by a TEMPO catalytic oxidation method, wherein the oxidant is selected from NBS, NCS, dibromohydantoin, iodobenzene acetate, sodium hypochlorite, sodium chlorite or TCCA; no auxiliary agent is added or an auxiliary agent selected from sodium bicarbonate, sulfamic acid, sodium bromide or isobutene is added to improve the conversion rate; the reaction solvent is selected from tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, toluene, ethyl acetate, isopropyl acetate or methyl tert-butyl ether.
8. The synthesis method of the traasiril intermediate compound 5 according to claim 6, wherein hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid is selected as the de-Boc and one-pot cyclization reaction acid in the step (2); the reaction solvent is selected from methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, toluene, xylene, chlorobenzene or trifluorotoluene.
9. A synthetic method of a traasiril intermediate compound 5 is characterized in that N- (1- ((tert-butoxycarbonyl) aminomethyl) cyclohexyl) -5-bromo-2-chloropyrimidine-4-amine compound 1 is used as a starting material, the compound and propiolic alcohol are subjected to Sonogashira coupling under the catalysis of palladium and copper to obtain a compound 2, then a cyclization reaction is completed under the action of copper salt and alkali or TBAF to obtain a compound 3, primary alcohol is oxidized into carboxylic acid to obtain a compound 4, and finally Boc is removed in a one-pot method and cyclization is carried out to obtain a target product 2 '-chloro-7', 8 '-dihydro-6' H-spiro [ cyclohexane-1, 9 '-pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidine ] -6' -ketone compound 5, wherein the route is as follows:
Figure FDA0003885227290000031
CN202211242477.1A 2022-10-11 2022-10-11 Triracil intermediate and preparation and application thereof Pending CN115536663A (en)

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