CN114605331A - Preparation method of nilutamide and intermediate thereof - Google Patents

Preparation method of nilutamide and intermediate thereof Download PDF

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Publication number
CN114605331A
CN114605331A CN202210265578.4A CN202210265578A CN114605331A CN 114605331 A CN114605331 A CN 114605331A CN 202210265578 A CN202210265578 A CN 202210265578A CN 114605331 A CN114605331 A CN 114605331A
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formula
nilutamide
compound
reaction
added
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孟祥国
胡霞敏
邵雷
吴锴
李晨烨
王露依
郁思杰
王怡菁
常仁俊
史雨豪
曾婉婧
尹子欣
宋英玮
李临雾
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Shanghai University of Medicine and Health Sciences
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Shanghai University of Medicine and Health Sciences
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Priority to PCT/CN2023/079243 priority patent/WO2023174062A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a preparation method of nilutamide and an intermediate thereof, which comprises the following steps: at the temperature of 25-160 ℃, 4-nitro-3-trifluoromethyl aniline of formula (I) and a compound of formula (II) with an amino protecting group PG are used as raw materials to carry out condensation and ring closure reaction to respectively generate a compound of formula (III), and the compound of formula (III) is directly subjected to ring closure without purification to generate nilutamide (formula IV); or preparing nilutamide by using the compound of the formula (III) to close the ring. The method has the advantages of short reaction steps, simple operation, higher yield, mild reaction conditions and cheap and easily-obtained used reagents, and is suitable for small-scale preparation in a laboratory and industrial large-scale production. By adopting the route, a new method for constructing hydantoin ring is provided for the preparation of nilutamide, and the method has important significance for developing medicaments containing the structure.

Description

Preparation method of nilutamide and intermediate thereof
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and particularly relates to an androgen receptor antagonist, in particular to a preparation method of nilutamide shown as a formula (IV).
Background
Nilutamide is the first generation of nonsteroidal androgen receptor antagonists developed and proposed by Roussel-Uclaf, France, and binds to the androgen receptor without androgenic effects, thereby blocking the binding of androgens to these receptors and exerting an antiandrogenic effect, the anti-AR activity IC of which is in vitro50The value was 412 nM. Has substantially no effect on estrogen, progestin, salt or glucocorticoid receptor, thereby reducing side effects against other hormones. Has stable structure in vivo, long-lasting binding with receptor, long action time, and no side effect of androgen. Approved by the U.S. Food and Drug Administration (FDA) for prostate cancer at 30 D.4.1999 under the NILANDRON name, and having the formula 5, 5-dimethyl-3- [ 4-nitro-3- (trifluoromethyl) phenyl]-2, 4-imidazolidinedione, which is an oral formulation. Nilutamide (nilutamide, RU 23908), structural formula is as follows:
Figure BDA0003551668680000011
formula IV (Nilutamide, RU 23908)
The reported synthetic routes for nilutamide are two of the following:
1) the method of the patent (FR7533084A) reported by the French Roussel-Uclaf company uses 4-nitro-3-trifluoromethylaniline 1 as raw material to react with phosgene to generate an isocyanate intermediate 2, then the isocyanate intermediate 2 reacts with 2-amino-2-cyanopropane to obtain an intermediate 3, and finally the intermediate 3 is hydrolyzed to obtain the compound nilutamide with the formula IV. See scheme 1:
route 1.
Figure BDA0003551668680000012
In the method, hypertoxic gas phosgene is needed to prepare 3-trifluoromethyl-4-cyanophenyl isocyanate (an intermediate 2); the raw material 2-amino-2-cyanopropane is not easy to obtain in the market, and a hypertoxic cyanide is required for preparation; hydrochloric acid is needed to heat in the hydrolysis process, and the defects of large corrosion to equipment and the like are overcome.
2) Prun et al (journal of chinese medical industry, 2001,35 (8): 455-456) using compound 1 as raw material, carrying out diazotization iodination reaction in sulfuric acid to obtain corresponding iodobenzene compound 4, and reacting with 5, 5-dimethylhydantoin in DMF under the catalysis of cuprous oxide to obtain nilutamide, see scheme 2:
route 2.
Figure BDA0003551668680000021
The method relates to the use of strong acid, which is easy to corrode production equipment; the introduced iodine atoms need to be removed in the coupling reaction, and the molecular utilization rate is low; the heavy metal catalyst used in the Ullmann coupling reaction is easy to remain in the bulk drugs in the last step, and the quality of the bulk drugs is difficult to control.
3) Dawn red et al reports (chemical production and technology, 2014,21 (05): 9-11+7) using m-trifluoromethylaniline 5 as the starting material, under the acidic condition, carrying out diazotization iodination reaction with sodium nitrite and sodium iodide to obtain a corresponding iodo compound 6, carrying out nitration reaction on the compound 6 to obtain an intermediate 4, carrying out coupling reaction with 5, 5-dimethylhydantoin in DMF under the catalysis of cuprous oxide to obtain nilutamide, wherein the reaction yield in three steps is 35%. See scheme 3:
route 3.
Figure BDA0003551668680000022
The method relates to the use of two strong acids, namely sulfuric acid and nitric acid, and is easy to corrode production equipment; iodine atoms introduced in the first step of reaction need to be removed in the coupling reaction, so that the molecular utilization rate is low; isomers are generated by nitration reaction, impurities are easy to introduce, and purification is difficult; the Ullmann coupling reaction is used in the last step, the heavy metal catalyst used in the reaction is easy to remain in the raw material medicine, the quality of the raw material medicine is difficult to control, and the serious environmental pollution problem is caused.
In view of the above, there is still a need for further improvements in obtaining new processes suitable for the industrial production of nilutamide.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a preparation method of nilutamide shown in formula (IV) and an intermediate thereof, which is used for overcoming the defects of high cost, large environmental pollution, unstable intermediate, complex operation, serious equipment corrosion and the like of the preparation method of nilutamide in the prior art.
The first aspect of the invention discloses the technical scheme that:
a process for the preparation of nilutamide of formula (iv), characterized in that:
(1) taking a compound of a formula (II) as a raw material, adding an alkali reagent and an amide condensation reagent into an organic solvent, stirring and heating for reaction;
(2) continuing to add the compound of formula (I) and the organic solvent and reacting;
(3) adding an alkali reagent, and continuously heating for reaction to obtain a compound shown in the formula (IV);
the obtained crude product can be further purified by recrystallization or column chromatography to obtain a compound shown in formula (III) or formula (IV);
the reaction temperature of the steps (1) to (3) is 25-160 ℃, and the reaction route is as follows:
Figure BDA0003551668680000031
preferably, the PG group may be t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or fluorenylmethyloxycarbonyl (Fmoc); more preferably, the PG groups are Boc and Cbz;
for compound II, compound II-a when the PG group is t-butyloxycarbonyl (Boc); compound II-b when the PG group is benzyloxycarbonyl (Cbz); and when the PG group is fluorenylmethyloxycarbonyl (Fmoc), the compound is the compound II-c.
For compound III, compound III-a when the PG group is tert-butyloxycarbonyl (Boc); compound III-b when the PG group is benzyloxycarbonyl (Cbz); and when the PG group is fluorenylmethyloxycarbonyl (Fmoc), the compound is the compound III-c.
Preferably, the amide condensation reagent used to prepare intermediate III is 1, 1-Carbonyldiimidazole (CDI);
the alkali reagent in the reaction step is 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (DBU), triethylamine (Et)3N), N-Diisopropylethylamine (DIPEA), triethylene Diamine (DABCO), sodium methoxide (MeONa), sodium ethoxide (EtONa), sodium tert-butoxide (t-BuONa), potassium carbonate (K)2CO3) Sodium carbonate (Na)2CO3) And cesium carbonate (Cs)2CO3) One or a mixture of the above;
preferred alkali agents are: step 1 is DIPEA, and step 3 is DBU; or DIPEA in step 1 and Cs in step 32CO3；
The organic solvent is one or a mixture of toluene (Tol), Tetrahydrofuran (THF), Ethyl Acetate (EA), isopropyl acetate (IPAc), Methyl Ethyl Ketone (MEK), dioxane (1,4-dioxane), Pyridine (Pyridine), Acetone (Acetone), Acetonitrile (ACN), N-Dimethylformamide (DMF), N-dimethylacetamide (DMAc) and N-methylpyrrolidone (NMP), preferably EA, ACN, THF or DMF;
the reaction temperature can be 55-120 ℃ according to the boiling point of the selected reaction solvent; the progress of the reaction is monitored by thin-layer chromatography and the reaction is stopped at the end of the complete conversion of the compound of the formula (III) into the compound of the formula (IV). The compound of formula (III) may be isolated when the reaction is not fully converted to the compound of formula (iv).
According to the conditions, the compound of the formula (III) is prepared by taking the formula (I) and the formula (II) as initial raw materials through a condensation reaction, the formula (III) directly generates a ring closing reaction without purification, and the target compound of the formula (IV) is prepared by a one-pot method.
The second aspect of the invention discloses the technical scheme that:
the compound of formula (IV) can also be prepared by taking the compound of formula (III) as a raw material, carrying out a ring closing reaction in an organic solvent at the temperature of 25-160 ℃ under the action of an alkali reagent and a nitrogen-containing heterocycle to generate the compound of formula (IV), and carrying out recrystallization or column chromatography purification on the obtained crude product to prepare the compound of formula (IV).
Figure BDA0003551668680000041
The alkali agent according to the second aspect is DBU, Et3N、DIPEA、DABCO、MeONa、EtONa、t-BuONa、K2CO3、Na2CO3、Cs2CO3Preferably DBU or Cs2CO3；
The nitrogen-containing heterocycle is imidazole, pyrazole, 1,2, 3-triazole or 1,2, 4-triazole;
the organic solvent in the second aspect is one or a mixture of Tol, THF, EA, IPAc, MEK, 1,4-dioxane, Pyridine, Acetone, ACN, DMF, DMAc and NMP, preferably EA, ACN, THF or DMF.
The reaction temperature is controlled between 25 ℃ and 160 ℃, and is determined according to the boiling point of the reaction solvent.
In a preferred embodiment of the compound of formula (III), PG is an amino protecting group, preferably t-butoxycarbonyl.
The third aspect of the invention discloses an intermediate for synthesizing nilutamide, which is characterized in that the chemical formula is shown as formula (III), PG is tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or fluorenylmethyloxycarbonyl (Fmoc); preferably a Boc, which is a non-Boc,
Figure BDA0003551668680000051
compared with the prior art, the invention has the beneficial effects that:
short reaction steps, simple operation, higher yield, mild reaction conditions, cheap and easily obtained reagents, and is suitable for small-scale preparation in a laboratory and industrial large-scale production. By adopting the route, a new method is provided for preparing the nilutamide, and the method has important significance for developing the medicines containing the structure.
Detailed Description
The invention is further illustrated by the following examples; it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the spirit of the invention, and these modifications and decorations should also be regarded as the protection scope of the invention. The raw materials, instruments and reagents used by the invention are all commercially available products and can be purchased from the market.
The TLC described in the examples is thin layer chromatography.
The HPLC is high performance liquid chromatography.
Example 1
Under nitrogen, compound II-a (10.0g, 0.049mol) was added to a 250ml three-necked flask, the solvent anhydrous THF (3V,30ml) was added, 1-carbonyldiimidazole CDI (8.8g, 0.054mol) was added, DIPEA (7.6g, 0.059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After the reaction for 0.5 hour, 1.5ml of a THF solution of Compound I (10.6g, 0.052mol) was added, and reacted for 0.5 hour, DBU (9.0g, 0.059mol) was added. Heating and stirring are continued for 65h, TLC is carried out, and the reaction is stopped. Adding citric acid aqueous solution (citric acid)34g of the crude product is dissolved in 52ml of water), kept stand for liquid separation, the organic phase is concentrated to obtain the crude product weight, and the crude product weight is recrystallized to obtain a compound IV which is dried to obtain 8.01 g of a reddish brown solid with the yield of 51.5 percent and the m.p.148.3-149.2 ℃.1H-NMR(400M，DMSO-d6)：δ(ppm)8.793(s，1H)，8.293-8.272(d，1H，J＝8.4Hz)，8.168-8.163(d，1H，J＝2.0Hz)，8.045-8.018(dd，1H，J＝8.8，2.4Hz)，1.390(s，6H)；13C-NMR(400M，DMSO-d6)：δ(ppm)176.311，153.565，137.071，131.682，126.963，125.820，123.721，122.523-122.186，121.003，58.561，25.121；[M-H]＝316.0
Example 2
Under nitrogen, compound II-a (10.0g, 0.049mol) was added to a 250ml three-necked flask, solvent anhydrous EA (3.0V, 30ml) was added, 1-carbonyldiimidazole CDI (8.8g, 0.054mol) was added, DIPEA (7.6g, 0.059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After the reaction for 0.5 hour, 1.5ml of an EA solution of Compound I (10.6g, 0.052mol) was added, and reacted for 0.5 hour, followed by addition of DBU (9.0g, 0.059 mol). Heating and stirring are continued for 65h, TLC is carried out, and the reaction is stopped. Adding citric acid aqueous solution (34 g of citric acid dissolved in 52ml of water), standing, separating, concentrating the organic phase to obtain a crude product, recrystallizing to obtain a compound IV, and drying to obtain 9.02 g of off-white solid with the yield of 58.0 percent and the m.p.154.7-155.1 ℃.
Example 3
Under nitrogen, compound II-a (10.0g, 0.049mol) was added to a 250ml three-necked flask, solvent anhydrous acetonitrile (3.0V, 30ml) was added, 1-carbonyldiimidazole CDI (8.8g, 0.054mol) was added, DIPEA (7.6g, 0.059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After the reaction for 0.5 hour, 1.5ml of an ACN solution of Compound I (10.6g, 0.052mol) was added, and after the reaction for 0.5 hour, DBU (9.0g, 0.059mol) was added. Heating and stirring are continued for 65h, TLC is carried out, and the reaction is stopped. Adding citric acid aqueous solution (34 g of citric acid dissolved in 52ml of water), standing, separating, concentrating the organic phase to obtain crude product, recrystallizing to obtain compound IV, and drying to obtain reddish brown solid 12.10 g, yield 77.9%, m.p.154.6-155.0 deg.C.
Example 4
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, EA (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, base DBU (0.90g, 0.0059mol) was added to a parallel reaction tube. The reaction was stopped by continuing heating and stirring for 65 h. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the light yellow solid is 0.65g, and the yield is 41.9%.
Example 5
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, EA (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, the base TEA (0.60g, 0.0059mol) was added to a parallel reaction tube. The reaction was stopped by continuing heating and stirring for 65 h. Samples were taken and HPLC, conversion was less than 1.0%.
Example 6
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, EA (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, the base DIPEA (0.76g, 0.0059mol) was added to a parallel reaction tube. The reaction was stopped by continuing heating and stirring for 65 h. Samples were taken and HPLC, conversion was 1.3%.
Example 7
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, EA (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, the base DaBCO (0.66g, 0.0059mol) was added to a parallel reaction tube. The reaction was stopped by continuing heating and stirring for 65 h. Samples were taken and HPLC, conversion was less than 1.0%.
Example 8
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, EA (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, the base MeONa (0.0.32g, 0.0059mol) was added to a parallel reaction tube. The reaction was stopped by continuing heating and stirring for 65 h. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.14g, and the yield is 9.0%.
Example 9
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, EA (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, the base EtONa (0.40g, 0.0059mol) was added to a parallel reaction tube. The reaction was stopped by continuing heating and stirring for 65 h. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.12g, and the yield is 7.4%.
Example 10
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, EA (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, base (CH) was added in a parallel reaction tube3)3CONa (0.57g, 0.0059 mol). The reaction was stopped by continuing heating and stirring for 65 h. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.40g, and the yield is 25.8%.
Example 11
Under nitrogen protection, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were added to a 20ml parallel reactor tube,EA (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After reacting for 1h, adding alkali Cs into a parallel reaction tube2CO3(1.92g, 0.0059 mol). The reaction was stopped by continuing heating and stirring for 65 h. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.92g, and the yield is 58.4%.
Example 12
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, EA (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, the base NaOH (0.24g, 0.0059mol) was added to a parallel reaction tube. The reaction was stopped by continuing heating and stirring for 65 h. Sampling, HPLC, conversion rate less than 1.0%.
Example 13
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were added to a 20ml parallel reactor tube, Toluene (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃, and stirred until the solid was completely dissolved. After 1h of reaction, base DBU (0.90g, 0.0059mol) was added to a parallel reaction tube. The heating and stirring were continued for 75h to stop the reaction. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.29g, and the yield is 18.7%.
Example 14
To a 20ml parallel reaction tube, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were added under nitrogen, THF (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, base DBU (0.90g, 0.0059mol) was added to a parallel reaction tube. The heating and stirring were continued for 75h to stop the reaction. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.34g, and the yield is 21.9%.
Example 15
To a 20ml parallel reactor tube, under nitrogen, were added compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol), EA (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, base DBU (0.90g, 0.0059mol) was added to a parallel reaction tube. The heating and stirring were continued for 75h to stop the reaction. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.20g, and the yield is 12.9%.
Example 16
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, MEK (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, base DBU (0.90g, 0.0059mol) was added to a parallel reaction tube. The heating and stirring were continued for 75h to stop the reaction. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.38g, and the yield is 24.5%.
Example 17
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, Dioxane (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, base DBU (0.90g, 0.0059mol) was added to a parallel reaction tube. The heating and stirring were continued for 75h to stop the reaction. Sample was taken and HPLC, conversion was 62.2%.
Example 18
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, Pyridine (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, a base DBU (0.90g, 0.0059mol) was added to a parallel reaction tube. The heating and stirring were continued for 75h to stop the reaction. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.20g, and the yield is 12.9%.
Example 19
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, Acetone (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, base DBU (0.90g, 0.0059mol) was added to a parallel reaction tube. The heating and stirring were continued for 75h to stop the reaction. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.10g, and the yield is 6.5%.
Example 20
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, ACN (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, base DBU (0.90g, 0.0059mol) was added to a parallel reaction tube. The heating and stirring were continued for 75h to stop the reaction. The solution in the tube was concentrated to dryness to give the crude weight. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.14g, and the yield is 9.0%.
Example 21
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, DMF (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃, and stirred until the solid was completely dissolved. After 1h of reaction, base DBU (0.90g, 0.0059mol) was added to a parallel reaction tube. The heating and stirring were continued for 75h to stop the reaction. Adding citric acid aqueous solution (3.4 g of citric acid dissolved in 5.2ml of water), standing for liquid separation, and concentrating the organic phase to obtain the crude product. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.28g, and the yield is 18.1%.
Example 22
Under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were charged into a 20ml parallel reactor tube, NMP (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, a base DBU (0.90g, 0.0059mol) was added to a parallel reaction tube. The heating and stirring were continued for 75h to stop the reaction. Adding citric acid aqueous solution (3.4 g of citric acid dissolved in 5.2ml of water), standing for liquid separation, and concentrating the organic phase to obtain the crude product. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.12g, and the yield is 7.7%.
Example 23
To a 10ml Schlenk tube, under nitrogen, was added compound III-a (1.0g, 0.0026mol), EA (4.0ml) and DBU (0.9g, 0.0059 mol). Stirring and heating to 60 ℃, reacting for 45h, and stopping the reaction. And (3) concentrating and drying the solution in the Schlenk tube to obtain a crude product, adding EA (ethylene-vinyl acetate) into the crude product, and performing column chromatography to obtain a compound IV (0.07 g of a light yellow solid with the yield of 7.6 percent) after the crude product is completely dissolved.
Example 24
To a 10ml Schlenk tube were added compound III-a (1.0g, 0.0026mol) and imidazole (0.5g, 0.0078mol) under nitrogen, EA (4.0ml) and DBU (0.9g, 0.0059 mol). Stirring and heating to 60 ℃, reacting for 45h, and stopping the reaction. And (3) concentrating and drying the solution in the Schlenk tube to obtain a crude product, adding EA (ethylene-vinyl acetate) into the crude product, and performing column chromatography to obtain a compound IV (0.19 g) of light yellow solid with the yield of 20.7 percent after the compound IV is completely dissolved.
Example 25
To a 10ml Schlenk tube, under nitrogen protection, compound III-a (1.0g, 0.0026mol) and pyrazole (0.5g, 0.0073mol) were added, EA (4.0ml) was added, and DBU (0.9g, 0.0059mol) was added. Stirring and heating to 60 ℃, reacting for 48h, and stopping the reaction. Adding citric acid aqueous solution (3.4 g of citric acid dissolved in 5.2ml of water), standing for liquid separation, and concentrating the organic phase to obtain the crude product. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the compound IV is 0.51g of light yellow solid, and the yield is 32.9%.
Example 26
Under nitrogen protection, compound III-a (1.0g, 0.0026mol) and 1,2, 3-triazole (0.5g, 0.0072mol) were added to a 10ml Schlenk tube, EA (4.0ml) was added, and DBU (0.9g, 0.0059mol) was added. Stirring and heating to 60 ℃, reacting for 48 hours, and stopping the reaction. Adding citric acid aqueous solution (3.4 g of citric acid dissolved in 5.2ml of water), standing for liquid separation, and concentrating the organic phase to obtain the crude product. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of the light yellow solid is 0.56g, and the yield is 36.1%.
Example 27
Under nitrogen, compound III-a (1.0g, 0.0026mol) and 1,2,4 triazole (0.5g, 0.0072mol) were added to a 10ml Schlenk tube, EA (4.0ml) was added, and DBU (0.9g, 0.0059mol) was added. Stirring and heating to 60 ℃, reacting for 48h, and stopping the reaction. Adding citric acid aqueous solution (3.4 g of citric acid dissolved in 5.2ml of water), standing for liquid separation, and concentrating the organic phase to obtain the crude product. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the compound IV is 0.54g of light yellow solid, and the yield is 34.8%.
Example 28
To a 25ml Schlenk tube, under nitrogen, compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) were added, DMF (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 115 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, alkali DBU (0.90g, 0.0059mol) was added to a Schlenk tube. The reaction was stopped by continuing heating and stirring for 10 h. Adding citric acid aqueous solution (3.4 g of citric acid dissolved in 5.2ml of water), standing for liquid separation, and concentrating the organic phase to obtain the crude product. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the light yellow solid is 0.93g, and the yield is 60.0%.
Example 29
To a 25ml schlenk tube were added compound I (0.91g, 0.0044mol) and compound II-b (1.00g, 0.0042mol) under nitrogen, EA (4.5ml) was added, CDI (0.75g, 0.0046mol) was added, DIPEA (0.65g, 0.0050mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, base DBU (0.76g, 0.0050mol) was added to a parallel reaction tube. The reaction was stopped by continuing heating and stirring for 47 h. Adding citric acid aqueous solution (3.4 g of citric acid dissolved in 5.2ml of water), standing for liquid separation, and concentrating the organic phase to obtain the crude product. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.60g, and the yield is 38.7%.
Example 30
To a 25ml Schlenk tube were added compound I (0.68g, 0.0033mol) and compounds II-c (1.00g, 0.0031mol) under nitrogen, EA (4.5ml) was added, CDI (0.55g, 0.0034mol) was added, DIPEA (0.48g, 0.0037mol) was added and the temperature was controlled at 60 ℃ and stirred until the solids were completely dissolved. After 1h of reaction, the base DBU (0.56g, 0.0037mol) was added to a parallel reaction tube. The reaction was stopped by continuing heating and stirring for 47 h. Adding citric acid aqueous solution (3.4 g of citric acid dissolved in 5.2ml of water), standing for liquid separation, and concentrating the organic phase to obtain the crude product. And adding EA into the crude product, and performing column chromatography to obtain a compound IV, wherein the content of a light yellow solid is 0.38g, and the yield is 24.5%.
Example 31
To a 25ml Schlenk tube, under nitrogen, were added compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol), EA (4.5ml) was added, CDI (0.88g, 0.0054mol) was added, DIPEA (0.76g, 0.0059mol) was added and the temperature was controlled at 115 ℃ and stirred until the solids were completely dissolved. After 1h of reaction, base DBU (2.24g, 0.0147mol) was added to Schlenk's tube. The reaction was stopped by continuing heating and stirring for 48 h. And (3) concentrating and drying the solution in the Schlenk tube to obtain a crude product, adding EA (ethylene-vinyl acetate) into the crude product, and performing column chromatography to obtain a compound IV (0.12 g of light yellow solid) with the yield of 7.4 percent after the compound IV is completely dissolved.
Example 32
Under nitrogen protection, a 250ml three-necked flask was charged with Compound I (10.6g, 0.052mol) and Compound II-a (10.0g, 0.049mol), EA (45ml) and CDI (8.8g, 0.054mol), DIPEA (7.6g, 0.059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After reacting for 1h, adding the alkali Cs into a three-necked flask2CO3(19.2g, 0.059 mol). The heating and stirring were continued for 92h, TLC, and the reaction was stopped. Filtering by suction to remove Cs2CO3Adding citric acid aqueous solution (10 g of citric acid is dissolved in 16ml of water), standing, separating liquid, concentrating an organic phase to obtain a crude product, recrystallizing to obtain a compound IV, and drying to obtain 7.01 g of solid with the yield of 45.2%.
Example 33
Under nitrogen, compound I (10.6g, 0.052mol) and compound II-a (10.0g, 0.049mol) were charged to a 250ml three-necked flask, DMF (45ml) was added, CDI (8.8g, 0.054mol) was added, DIPEA (7.6g, 0.059mol) was added and the temperature was controlled at 60 ℃ and stirred until the solid was completely dissolved. After 1h of reaction, base DBU (9.0g, 0.059mol) was added in a three-necked flask. Heating and stirring are continued for 3h, TLC is carried out, and the reaction is stopped. Adding citric acid aqueous solution (34 g of citric acid dissolved in 52ml of water), separating out a large amount of solid, filtering to obtain a crude product, recrystallizing to obtain a compound III, and drying to obtain 14.2 g of solid, wherein the yield is 74.1%, and m.p.186.2-189.5 ℃.1H-NMR(400M，DMSO-d6)：δ(ppm)10.304(s，1H)，8.329(s，1H)，8.147(s，2H)，7.193(s，1H)，1.311(m，15H)；13C-NMR(400M，DMSO-d6)：δ(ppm)161.850，144.995，141.529，128.094，124.039，123.409，123.079，121.326，118.393-118.274，78.956，57.065，28.584，25.148；[M-H]-＝390.1
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.

Claims (16)

1. A process for the preparation of nilutamide of formula (iv), characterized in that:
(1) taking a compound of a formula (II) as a raw material, adding an alkali reagent and an amide condensation reagent into an organic solvent, stirring and heating for reaction;
(2) continuing to add the compound of formula (I) and the organic solvent and reacting;
(3) adding an alkali reagent, and continuously heating for reaction to obtain a compound shown in the formula (IV);
the reaction temperature of the steps (1) to (3) is 25-160 ℃, and the reaction route is as follows:
Figure FDA0003551668670000011
2. the method of claim 1 for the preparation of nilutamide of formula (iv), wherein: the amide condensation reagent in the reaction step is 1, 1-carbonyl diimidazole.
3. A process for the preparation of nilutamide of formula (iv) as claimed in claim 1, wherein: the alkali reagent is one or more of 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylamine, N-diisopropylethylamine, triethylene diamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide and cesium carbonate.
4. The method of claim 1 for the preparation of nilutamide of formula (iv), wherein: the alkali reagent in the step (1) is N, N-diisopropylethylamine, and the alkali reagent in the step (3) is a mixture of 1, 8-diazabicyclo [5.4.0] undec-7-ene; or N, N-diisopropylethylamine is used in the step (1), and cesium carbonate is used in the step (3).
5. A process for the preparation of nilutamide of formula (iv) as claimed in claim 1, wherein: the organic solvent is one or more of toluene, tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl ethyl ketone, dioxane, pyridine, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
6. A process for the preparation of nilutamide of formula (iv) as claimed in claim 1, wherein: the organic solvent is ethyl acetate, acetonitrile, tetrahydrofuran or N, N-dimethylformamide.
7. A process for the preparation of nilutamide of formula (iv) as claimed in claim 1 wherein the PG group is t-butyloxycarbonyl, benzyloxycarbonyl or fluorenylmethyloxycarbonyl.
8. A process for the preparation of nilutamide of formula (iv) as claimed in claim 1 wherein the PG group is t-butoxycarbonyl or benzyloxycarbonyl.
9. The process for preparing nilutamide of formula (iv) as claimed in claim 1, wherein PG is t-butyloxycarbonyl.
10. A process for the preparation of nilutamide of formula (iv), characterized in that: taking a compound shown in a formula (III) as a raw material, carrying out a ring closing reaction in an organic solvent at 25-160 ℃ under the action of an alkali reagent and a nitrogen-containing heterocycle to generate a compound shown in a formula (IV),
Figure FDA0003551668670000021
11. the process of claim 10 for the preparation of nilutamide of formula (iv), wherein: the alkali reagent is DBU and Et3N, DIPEA, DABCO, MeONa, EtONa, t-BuONa and Cs2CO3One or more of (a).
12. The process of claim 10 for the preparation of nilutamide of formula (iv), wherein: the alkali reagent is DBU or Cs2CO3。
13. The process of claim 10 for the preparation of nilutamide of formula (iv), wherein: the nitrogen-containing heterocycle is imidazole, pyrazole, 1,2, 3-triazole or 1,2, 4-triazole.
14. The process of claim 10 for the preparation of nilutamide of formula (iv), wherein: the organic solvent in the reaction step is one or more of Tol, THF, EA, IPAc, MEK, 1,4-dioxane, Pyridine, Acetone, ACN, DMF, DMAc and NMP.
15. The process of claim 10 for the preparation of nilutamide of formula (iv), wherein: the organic solvent in the reaction step is EA, ACN or THF.
16. An intermediate for synthesizing nilutamide, which is characterized in that: the chemical formula is a formula (III), PG is tert-butyloxycarbonyl, benzyloxycarbonyl or fluorenylmethyloxycarbonyl,
Figure FDA0003551668670000022
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