CN108383749B - Synthetic method of apaluamide and intermediate thereof - Google Patents

Synthetic method of apaluamide and intermediate thereof Download PDF

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CN108383749B
CN108383749B CN201810408838.2A CN201810408838A CN108383749B CN 108383749 B CN108383749 B CN 108383749B CN 201810408838 A CN201810408838 A CN 201810408838A CN 108383749 B CN108383749 B CN 108383749B
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compound
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intermediate compound
apaluamide
apaluramine
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CN108383749A (en
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郑旭春
张一平
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Hangzhou Cheminspire Technologies Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Abstract

The invention discloses a synthesis method of apaluramine, which comprises the steps of carrying out Ullmann reaction condensation on N-methyl-2-fluoro-4-halogeno-benzamide compound 1 and cyclobutyrate hydrochloride 2 serving as initial raw materials to obtain an intermediate compound 3, esterifying the intermediate compound to obtain an intermediate compound 4, reacting the intermediate compound with thiocyanate to cyclize to obtain a compound 5, and coupling and condensing the compound with the compound 5 to obtain the apaluramine. The synthetic method greatly shortens the route steps, improves the route efficiency, avoids using noble metal catalysts, reduces the process cost, reduces the generation of byproducts, and is beneficial to improving the purity of the final finished product. The route is as follows:

Description

Synthetic method of apaluamide and intermediate thereof
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a novel synthetic method for preparing apaluramine and an intermediate involved in the method.
Background
Apaluamide (apaluamide, code ARN-509) is a second generation androgen receptor signaling inhibitor, developed by Aragon pharmaceutical, usa, and is subsequently purchased commercially by the united states. The medicine can be used for treating castration-resistant prostate cancer, and has good effect in inhibiting survival and growth of cancer cells. At present, the three-phase clinical experiment also progresses smoothly, and if the three-phase clinical experiment is approved, the requirements of a plurality of prostate cancer patients can be met, so the three-phase clinical experiment has great market prospect.
The chemical name of apaluramine is: 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl) -2-fluoro-N-methylbenzamide having the formula:
Figure BDA0001642151530000011
PCT patent WO2007126765 reports a synthesis method of apaluramine, which uses 2, 4-difluorobenzoyl chloride as a starting material, and performs condensation with methylamine, then performs an ammonification reaction with 4-methoxybenzylamine, and then performs acid release PMP protection to obtain a key intermediate i: n-methyl-2-fluoro-4-aminobenzamide; iodinating and chlorinating 3- (trifluoromethyl) pyridine-2-alcohol to obtain 2-chloro-3-trifluoromethyl-5-iodopyridine, coupling with 4-methoxybenzylamine under the catalysis of palladium, performing cyanation reaction with zinc dicyanide, and removing PMP protecting group to obtain a key intermediate II: 2-cyano-3-trifluoromethyl-5-aminopyridine. And then carrying out Strecker reaction on N-methyl-2-fluoro-4-aminobenzamide, sodium cyanide and cyclobutanone to obtain a cyclobutanamine intermediate, and carrying out condensation cyclization on a thioisocyanate intermediate obtained by the reaction of 2-cyano-3-trifluoromethyl-5-aminopyridine and thiophosgene to obtain a final product. The linear steps of the route are too long, the highly toxic sodium cyanide is used in the route, the process operation is relatively complicated, the multi-step reaction needs to be catalyzed by noble metal palladium, and the cost of the amplified production route is high.
Figure BDA0001642151530000012
Figure BDA0001642151530000021
PCT patent WO2016100645 simplifies a new synthesis method of apaluramine, which comprises the steps of carrying out bromination and cyanation reactions on 3-trifluoromethyl-5-nitropyridine, carrying out palladium-carbon hydrogenation reduction to obtain an intermediate 2-cyano-3-trifluoromethyl-5-aminopyridine, carrying out condensation cyclization on a cyclobutylamino nitrile intermediate obtained by a Strecker reaction of 3-fluoro-4-iodoaniline, cyclobutanone and cyanide under the action of a thiocarbonyl compound with 2-cyano-3-trifluoromethyl-5-aminopyridine under the catalysis of noble metal palladium to obtain a carboxylic ester intermediate or reacting the carboxylic acid intermediate with dry ice after Grignard exchange, and carrying out amidation to obtain the final product of apaluramine. Although the route has short steps, the cost of the palladium-catalyzed carbonyl insertion reaction or Grignard exchange reaction route is high, the process production experiment conditions are harsh, and a method which is simple in process route, high in yield, low in cost and suitable for industrial production is required to be found for synthesizing the apaluramine.
Figure BDA0001642151530000022
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel synthetic method of apaluramine and a key intermediate thereof, which has the advantages of simple process route, low cost and suitability for industrial production.
One of the purposes of the invention is to provide a novel intermediate 4 of apaluridine and a synthetic method thereof.
The apalumide intermediate compound 4 has a structural formula as follows:
Figure BDA0001642151530000031
wherein the R substituent represents an alkyl group including, but not limited to, methyl or ethyl.
The synthetic method of the apaluamide intermediate compound 4 comprises the following steps:
(1) carrying out Ullmann reaction on N-methyl-2-fluoro-4-halogenated-benzamide compound 1 and cyclobutylic acid hydrochloride 2 under the catalysis of copper salt to obtain an intermediate compound 3;
Figure BDA0001642151530000032
wherein, X can be selected from iodine, bromine or chlorine;
(2) the compound 3 is subjected to esterification reaction to obtain a compound 4;
Figure BDA0001642151530000033
when R is Me and Et, correspondingly, methanol and ethanol are selected as reaction solvents in the esterification reaction; the acylating reagent is thionyl chloride; the reaction temperature is 0-100 ℃.
Preferably, the catalyst selected for the Ullmann coupling reaction is cuprous chloride, cuprous bromide or cuprous iodide and the like; the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, etc.; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and the like.
The second objective of the invention is to provide an intermediate compound 5 of apaluridine and a synthetic method thereof.
The apalumide intermediate compound has a structural formula as follows:
Figure BDA0001642151530000041
a method for synthesizing an apaluramine intermediate compound, comprising cyclizing a compound of formula 4 with thiocyanide under suitable conditions to obtain a compound of formula 5;
Figure BDA0001642151530000042
preferably, the thiocyanide in the reaction is selected from potassium thiocyanate, sodium thiocyanate and the like; the base is selected from triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO and the like; selecting no additive or water as an additive; the selected reaction solvent is N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran or 1, 4-dioxane, etc.
The invention also aims to provide a new synthetic method of the apaluramine, which comprises the following steps:
the synthetic method of the apaluamide comprises the steps of carrying out coupling reaction on a compound 5 and a compound 6 to obtain a final product 7 of the apaluamide;
Figure BDA0001642151530000051
preferably, the catalyst selected for the coupling reaction is cuprous chloride, cuprous bromide or cuprous iodide and the like; the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, etc.; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
The method comprises the steps of taking N-methyl-2-fluoro-4-halogenated-benzamide compound 1 and cyclobutane hydrochloride 2 as initial raw materials, condensing through an Ullmann reaction to obtain an intermediate compound 3, esterifying to obtain an intermediate compound 4, carrying out a cyclization reaction on the intermediate compound 4 and potassium thiocyanate to obtain an intermediate 5, and finishing a coupling reaction with 5-bromo-3-trifluoromethyl-2-cyanopyridine 6 to obtain a final product 7. The initial raw materials of the route are simple and easy to obtain, the cyclobutyrate hydrochloride with better crystallinity and stability is directly used, the use of virulent sodium cyanide in the original route is avoided, and the process operation is simple and convenient. The optimization of the subsequent steps not only simplifies the process route, improves the route efficiency, avoids the use of noble metal catalysts, reduces the process cost, but also reduces the generation of byproducts, and is beneficial to improving the purity of the final finished product. 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.
The route is as follows:
Figure BDA0001642151530000052
wherein the R substituent represents an alkyl group including, but not limited to, methyl or ethyl.
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 BDA0001642151530000061
N-methyl-2-fluoro-4-bromo-benzamide 1a (23.21g,100mmol), cyclobutylic acid hydrochloride 2 (15.16100 mmol) and N, N-dimethylacetamide (116mL) were added to a three-neck flask, cuprous iodide (1.90g,10mmol) and cesium carbonate (71.68g,220mmol) were added under nitrogen protection, and after stirring, the mixture was heated to 90-95 ℃ for reaction overnight. After the reaction, water (232mL) and isopropyl acetate (232mL) were added, followed by stirring and liquid separation, and the aqueous phase was collected and the pH was adjusted to 3 to 4 with 4N hydrochloric acid to precipitate a large amount of solid, which was filtered and dried to obtain Compound 3(17.88g, 79%). MS (ESI) M/z 227.2[ M + H ]]+。
The cuprous iodide can be replaced by cuprous chloride or cuprous bromide; the alkaline substance cesium carbonate can be replaced by potassium carbonate and sodium carbonate; the solvent N, N-dimethyl acetamide can be replaced by N, N-dimethyl formamide and N-methyl pyrrolidone.
Where Br in compound 1a can be replaced by I or Cl, it can also be used to prepare compound 3.
Example 2
Figure BDA0001642151530000062
Adding the compound 3(26.63g,100mmol) and methanol (133mL) into a three-neck flask, stirring uniformly, slowly adding thionyl chloride (17.85g,150mmol), heating to 40-45 ℃ and reacting for 6-8 hours. After the reaction is finished, part of methanol is removed by rotation, water (266mL) is slowly added for pulping, the filtration is carried out, the crude product is further pulped by the mixed solvent of the methanol and the petroleum ether, and the filtration and the drying are carried out to obtain the compound 4a (25.79g, 92%). MS (ESI) M/z 281.2[ M + H ]]+1H NMR(400MHz,DMSO-d6)δ7.67-7.45(m,2H),6.80(s,1H),6.22-6.41(m,1H),5.98-6.17(m,1H),3.62(s,3H),2.82-2.67(m,5H),2.62-2.50(m,2H),2.32-2.26(m,1H),1.82-1.67(m,1H)ppm。
Example 3
Figure BDA0001642151530000071
Adding 7(28.03g,100mmol) and 75% methanol (280mL) into a three-neck flask, stirring uniformly, adding potassium thiocyanate (23.00g,120mmol) and diisopropylethylamine (25.85g,200mmol), and refluxing for 6-8 hours after the addition is finished. After the reaction, part of water was removed by rotation, water (248mL) was added and the mixture was slurried, recrystallized from a mixed solvent of ethyl acetate and petroleum ether, filtered and dried to give Compound 5(27.56g, 85%). MS (ESI) M/z 308.0[ M + H ]]+1HNMR(400MHz,DMSO-d6)δ9.32(br,1H),δ7.70-7.55(m,2H),6.82-6.70(m,1H),6.12(br,1H),2.84-2.65(m,5H),2.63-2.50(m,2H),2.35-2.25(m,1H),1.85-1.65(m,1H)ppm。
The potassium thiocyanate can be replaced by sodium thiocyanate; the basic substance diisopropylethylamine can be replaced by triethylamine, pyridine, DMAP, DBU or DABCO; the solvent methanol can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, ethanol, isopropanol, acetonitrile, tetrahydrofuran or 1, 4-dioxane.
Example 4
Figure BDA0001642151530000072
Adding a compound 5(30.73g and 100mmol) and a compound 6(25.10g and 100mmol) into a three-neck flask, adding N, N-dimethylformamide (154mL), stirring and dissolving, adding potassium carbonate (27.64g and 200mmol), uniformly stirring, switching nitrogen for 3 times in vacuum, adding cuprous iodide (952mg and 5.0mmol) under the protection of nitrogen, and heating to 100-110 ℃ for reacting for 6-8 hours. Cooling to room temperature after reaction, adding water (307mL), ethyl acetate (307mL), stirring, separating, extracting the water phase with ethyl acetate (154mL) for 1 time, combining organic phase saturated saline solution (154mL) and washing for 2 times, drying with sodium sulfate, filtering, concentrating to remove most of solvent, adding petroleum ether (307mL), heating, cooling, pulping, filtering, and drying to obtain the final productProduct 7(36.29g, 76% yield). MS (ESI) M/z 478.1[ M + H ]]+。
The cuprous iodide can be replaced by cuprous chloride or cuprous bromide; the alkaline substance potassium carbonate can be replaced by sodium carbonate, cesium carbonate and potassium phosphate.

Claims (7)

1. The apalumide intermediate compound 5 has a structural formula as follows:
Figure FDA0002906580570000011
2. a synthesis method of an apaluamide intermediate compound 5 is characterized by comprising the following steps of cyclizing a compound shown in a formula 4 and thiocyanide under proper conditions to obtain a compound shown in a formula 5;
Figure FDA0002906580570000012
3. a process for the synthesis of apaluamide intermediate compound 5 as claimed in claim 2, wherein the thiocyanide in the reaction is selected from potassium or sodium thiocyanide; the used base is selected from triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO; selecting no additive or water as an additive; the reaction solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran or 1, 4-dioxane.
4. The method for synthesizing an apaluamide intermediate compound 5 as claimed in claim 2, wherein the method for synthesizing the apaluamide intermediate compound 4 comprises the steps of:
(1) carrying out Ullmann reaction on N-methyl-2-fluoro-4-halogenated-benzamide compound 1 and cyclobutylic acid hydrochloride 2 under the catalysis of copper salt to obtain an intermediate compound 3;
Figure FDA0002906580570000013
wherein X is selected from iodine, bromine or chlorine;
(2) carrying out esterification reaction on the compound 3 to obtain a compound 4;
Figure FDA0002906580570000021
5. a synthesis method of an apaluamide intermediate compound 5 as claimed in claim 4, wherein the catalyst used in the Ullmann coupling reaction is cuprous chloride, cuprous bromide or cuprous iodide; the used base is selected from potassium carbonate, sodium carbonate, cesium carbonate; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
6. The synthetic method of the apaluramine is characterized by comprising the steps of carrying out coupling reaction on a compound 5 and a compound 6 to obtain the apaluramine 7;
Figure FDA0002906580570000022
7. the synthesis method of apaluamide as claimed in claim 6, wherein the catalyst selected for the coupling reaction is cuprous chloride, cuprous bromide or cuprous iodide; the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
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US10513504B2 (en) 2018-03-08 2019-12-24 Apotex Inc. Processes for the preparation of apalutamide and intermediates thereof
CN113754632A (en) * 2020-06-04 2021-12-07 上海天慈国际药业有限公司 Preparation method of cancer treatment medicine
CN112194633B (en) * 2020-11-06 2022-07-05 杭州新拜思生物医药有限公司 Method for synthesizing apaluamide and intermediate thereof and intermediate
CN114621184B (en) * 2020-12-10 2024-04-26 奥锐特药业股份有限公司 Preparation method of apatamide
CN113402466B (en) * 2021-06-18 2022-08-16 南京方生和医药科技有限公司 Apaglucone intermediate and method for preparing apalone

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