CN117120436A - Method for synthesizing thiohydantoin derivative by one-step method - Google Patents

Method for synthesizing thiohydantoin derivative by one-step method Download PDF

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Publication number
CN117120436A
CN117120436A CN202280025047.6A CN202280025047A CN117120436A CN 117120436 A CN117120436 A CN 117120436A CN 202280025047 A CN202280025047 A CN 202280025047A CN 117120436 A CN117120436 A CN 117120436A
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China
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compound
alkyl
thio
thiohydantoin
halogen
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童友之
许若
吴晓君
申剑冰
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Suzhou Kintor Pharmaceuticals Inc
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Suzhou Kintor Pharmaceuticals Inc
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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
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for synthesizing thiohydantoin derivatives by a one-step method. The thiohydantoin derivative can be directly prepared by a one-pot method by taking amino acid derivatives, amino compounds (especially aromatic amine compounds) and thio source reagents as raw materials, and isothiocyanate (compound containing-NCS group) is not required to be prepared and separated and purified, so that the reaction period is greatly shortened, and the production cost is reduced; meanwhile, the use of acid and alkali in the reaction process is avoided, and the method is environment-friendly.

Description

Method for synthesizing thiohydantoin derivative by one-step method
Citation of related application
The present application claims priority from an inventive patent application filed in china at 3 and 30 of 2021, entitled "one-step method for synthesizing thiohydantoin derivatives", application number 202110337832.2, the entire contents of which are incorporated herein by reference.
Technical Field
The application belongs to the technical field of medicine synthesis, and particularly relates to a method for synthesizing thiohydantoin derivatives by a one-step method.
Background
Thiohydantoin derivatives are important structural fragments of androgen receptor antagonists, such as medicines of enzalutamide, apatamide (ARN-509), praecox-lutamide, HC-1119 deuterated enzalutamide and the like. At present, most of the compounds are prepared by ring-closing reaction of compounds containing-NCS groups with esters when constructing thiohydantoin, wherein the compounds containing-NCS groups are prepared by reacting corresponding amine compounds with thiophosgene, such as in the prior art CN 107635969A, european Journal of Medicinal Chemistry,118 (2016): 230-243, US 10626091 B2, WO 2010/118354 A1 and WO 2020/112088 A1. However, thiophosgene is a highly toxic volatile substance, and is unsafe and inconvenient to produce, store and use and has great harm to the environment.
In order to overcome the defect of thiophosgene in CN 1500081A, thiocarbonyldiimidazole is used for replacing thiophosgene (for example, preparation example IV) to react with aromatic amine to prepare a corresponding compound containing an-NCS group (an isothiocyanate compound is unstable and has defects in transportation and storage processes), but the preparation process is complicated, and the compound containing the-NCS group is obtained after pouring the compound into water for extraction and silica gel chromatography purification after the organic phase reaction is finished. Reacting a compound containing an-NCS group with amino acid under alkaline conditions, or with amino acid ester under weak acid and microwave radiation conditions to obtain the thiohydantoin derivative. Although the method does not use thiophosgene, the reaction system is complex, acid and alkali are required to be added in the reaction process of preparing the compound containing the-NCS group and the thiohydantoin derivative, or a large number of extraction and purification steps are required in the post-treatment process.
Therefore, at least thiophosgene is inconvenient to produce, store and use when preparing thiohydantoin derivatives in the prior art; the intermediate isothiocyanate is unstable and is unfavorable for storage and transportation; the reaction process is complicated, acid and alkali are required to be added into the reaction system, so that the defects of difficult sewage treatment, high environmental protection pressure, complex post-treatment process and the like are caused.
Disclosure of Invention
In order to solve the defects in the prior art, the application discovers that three components of amino acid derivatives, amino compounds (especially aromatic amine compounds) and thio source reagents are used as raw materials, and the thiohydantoin derivatives can be directly prepared by a one-pot method without preparing isothiocyanate (compound containing-NCS group) and separating and purifying the isothiocyanate, thereby greatly shortening the reaction period and conditions; meanwhile, the use of acid and alkali in the reaction process is avoided, and the method is environment-friendly.
The application realizes the aim through the following technical scheme, namely a three-component one-pot method for synthesizing a thiohydantoin compound shown in a formula 1 or deuterated compound thereof, wherein a compound A, a compound B and a thio source reagent are used as raw materials, and the thiohydantoin derivative shown in the formula 1 or deuterated compound thereof is generated through one-pot reaction in an organic solvent;
wherein:
R 1 and R is 2 Is covered by one or more C' s 1 -C 6 Alkyl, C (O) NHR, SO 2 NHR, cyano, hydroxy, alkyloxy, C (S) NHR, C (O) OR, CH 2 (CH 2 ) m Q, halogen or aryl containing 5-6 membered heteroaryl substitution; or R is 1 And R is 2 Is covered by one or more C' s 1 -C 6 Alkyl, C (O) NHR, SO 2 NHR, cyano, hydroxy, alkyloxy, C (S) NHR, C (O) OR, CH 2 (CH 2 ) m Q, halogen or heteroaryl containing 5-6 membered heteroaryl substitution; wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and C 1 -C 6 Alkenyl groups; m is an integer selected from 0-6, Q is selected from C (O) NHR, SO 2 R、SO 2 NHR, cyano, hydroxy, alkyloxy, C (S) NHR, and C (O) OR; or R is 1 And R is 2 Is alkyl or heterocyclyl;
wherein the alkyl group comprises 1 to 20 aliphatic carbon atoms; the aryl is a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings; the heteroaryl has a cyclic aromatic group of 5 to 10 ring atoms, one of which is selected from S, O and N; the heterocyclic group is selected from 3-piperidine, 4-piperidine, tetrahydrofuran, 3-pyrrolidine or tetrahydropyran;
R 5 independently selected from linear or branched C 1 -C 6 Alkyl, a monocyclic or bicyclic aryl or heteroaryl group having 5 to 10 ring atoms;
R 3 and R is 4 Independently selected from hydrogen, C 1 -C 6 Alkyl, C optionally substituted by one or more halogen or hydroxy groups 1 -C 6 Alkyl, or R 3 And R is 4 Together with the carbon to which they are attached, form a 3-6 membered cycloalkyl ring in which one or more carbons are optionally substituted with one or moreA plurality of halogen or hydroxy substitutions;
the thio source reagent is selected from 1, 1-thiocarbonyl-Dl-2 (1H) pyridineThiophosgeneDipyridylthiocarbonateN, N' -thiocarbonyldiimidazoleBis (1-benzotriazole) methylthioketoneOne of the aromatic thiochloroformates. The aromatic thiochloroformate may be, for example, phenyl thiochloroformate.
Preferably, said R 2 Selected from the group consisting of
Wherein the method comprises the steps ofRepresents R 2 with-NH 2 Is a ligation site of (2); y is independently selected from N, CH, CR 1a ；R 1a Independently selected from cyano, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C optionally substituted by one or more halogen or hydroxy groups 1 -C 6 An alkyl group; t=0, 1,2,3 or 4;
preferably, said R 2 Selected from the group consisting of
Y is independently selected from N or CH; r is R 1a Independently selected from cyano, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C optionally substituted by one or more halogen or hydroxy groups 1 -C 6 An alkyl group; t=0, 1,2,3 or 4; r is R 1a Further preferred are cyano, trifluoromethyl, fluoro, methoxy.
Further preferably, in the compound a, R 1 Is C 6 -C 10 Aryl or 5-10 membered heteroaryl, said aryl and heteroaryl being independently optionally selected from C 1 -C 6 Alkyl, C (O) NH (C) 1 -C 6 Alkyl), halogen and C 6 -C 10 One or more primary substituents of the aryl group independently optionally substituted with one or more substituents selected from deuterium, 5-10 membered heteroaryl and-O (C 1 -C 6 Alkyl) -O (C) 1 -C 6 Alkyl) -Boc substituted with one or more secondary substituents; preferably, R 1 Is phenyl or pyridinyl, which are independently optionally selected from-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-C(O)NHCH 3 、-C(O)NHCH 2 CH 3 One or more primary substituents selected from the group consisting of deuterium, imidazolyl, oxazolyl, thiazolyl and-O (C 1 -C 4 Alkyl) -OCH 2 -one or more secondary substituents of Boc;
R 5 is C 1 -C 6 An alkyl group; preferably, R 5 Methyl, ethyl, isopropyl or tert-butyl;
R 3 and R is 4 Independently C 1 -C 6 Alkyl, or R 3 And R is 4 Together with the carbon to which they are attached, form a 3-6 membered cycloalkyl ring; preferably, R 3 And R is 4 Independently methyl, or R 3 And R is 4 Together with the carbon to which they are attached, form a cyclobutane ring.
Further preferably, in said compound B, R 2 Is thatWherein the method comprises the steps ofRepresents R 2 with-NH 2 Is a ligation site of (2); y is selected from N, CH and CR 1a The method comprises the steps of carrying out a first treatment on the surface of the Each R is 1a Independently cyano, halogen, C 1 -C 6 Alkoxy or C substituted by one or more halogen or hydroxy groups 1 -C 6 An alkyl group; t is 0,1,2,3 or 4; preferably, Y is selected from N or CH; each R is 1a Independently cyano, trifluoromethyl, fluoro or methoxy; t is 0,1,2 or 3.
Further preferably, the thio source reagent is selected from the group consisting of
Still more preferably, the compound a is selected from:
still more preferably, the compound B is selected from:
still more preferably, the thio source reagent is selected from the group consisting of:
preferably, the thiohydantoin derivative shown in formula 1 or its deuterated compound is selected from the following specific compounds:
preferably, in the method, the organic solvent is an alkyl acid ester, a linear or branched alkyl or cyclic ether, an aryl ether, a chlorinated hydrocarbon, an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, an alkyl ketone, a linear or branched C 2 -C 6 N-propyl acetate; the linear or branched alkyl ether is diethyl ether or methyl tertiary butyl ether, and the cyclic ether is 1, 4-dioxane or 2-methyltetrahydrofuran; the aryl ether is anisole; the chlorinated hydrocarbon is dichloromethane, chloroform or 1, 2-dichloroethane; the aromatic hydrocarbon is toluene or xylene; the chlorinated aromatic hydrocarbon is chlorobenzene; the alkyl ketone is acetone, butanone or methyl isobutyl ketoneThe method comprises the steps of carrying out a first treatment on the surface of the The C is 2 -C 6 The nitrile is acetonitrile, propionitrile, n-butyronitrile or isobutyronitrile; the chain amide is N, N-dimethylformamide or N, N-dimethylacetamide, and the cyclic amide is N-methyl-2-pyrrolidone.
Further preferably, the organic solvent is an alkyl acid ester, a chlorinated hydrocarbon or an alkyl ketone.
Still more preferably, the organic solvent is ethyl acetate, dichloromethane, chloroform, toluene, or acetone.
Preferably, in the process, compound a, calculated as molar ratio: compound B: thiogenic agent = 1:0.5-5:1-5; further preferably 1:0.5-2:1-5, more preferably 1:1.5-2:2-5, e.g. 1:2:3.
Preferably, in the method, the compound a, the compound B and the thio source reagent are simultaneously added into the organic solvent to perform a stirring reaction; or firstly adding the compounds A and B into an organic solvent, stirring, and then adding a thio source reagent in batches for reaction; or adding the compound A and the thio source reagent into the organic solvent firstly, stirring, and then adding the compound B in batches for reaction.
Preferably, in the process, the reaction temperature is from 0 ℃ to below boiling point, preferably from 20 ℃ to below boiling point, for example from 20 to 100 ℃, from 30 to 90 ℃, from 40 to 80 ℃ or from 50 to 70 ℃; one of ordinary skill in the art can determine the appropriate reaction temperature in combination with the rate of reaction and the particular reaction solvent.
Preferably, in the method, the thiohydantoin compound of formula 1 isCompound A isCompound B isThe thio source reagent is
Preferably, in the method, the thiohydantoin compound of formula 1 isCompound A isCompound B isThe thio source reagent is Further preferred is
Preferably, in the method, the thiohydantoin compound represented by formula 1 isCompound A isCompound B isThe thio source reagent is Further preferred is
Preferably, in the method, the thiohydantoin compound represented by formula 1 isCompound A isCompound B isThe thio source reagent is
Preferably, in the method, the thiohydantoin compound represented by formula 1 isCompound A isCompound B isThe thio source reagent is
Preferably, in the method, the thiohydantoin compound represented by formula 1 isCompound A isCompound B isThe thio source reagent is
Further preferably, in the method, the organic solvent is an alkyl acid ester, a chlorinated hydrocarbon or an alkyl ketone.
Compared with the prior art, the technical conception of the thiohydantoin compound preparation method is completely different, and the method has the following beneficial effects:
1) According to the application, the thiohydantoin compound is prepared by a one-pot method for the first time, so that the complex steps of preparing the isothiocyanate intermediate and then performing the ring closing reaction in the traditional preparation process are overcome, the production period is greatly shortened, and the production cost is reduced.
2) The method does not need to prepare an isothiocyanate intermediate, and overcomes the defects of poor stability and unfavorable preservation and transportation of isothiocyanate.
3) The one-pot reaction process of the method does not need acid or alkali, and the sewage treatment is simple and convenient, and is environment-friendly.
4) The method has strong universality for different substrates, can basically realize excellent technical effects for different material proportions and solvents, can realize process amplification, and has industrial production application prospects.
5) For certain specific thiohydantoin compounds, the applicant surprisingly found that different thiosource reagents have a significant effect on the reaction, and that the one-pot reaction using the thiosource reagent shown by C2 or C3 in the examples has excellent experimental results; in particular, the thio source reagent shown by C2 is selected, and high yield can be realized for a plurality of substrates.
Detailed Description
The application may be further understood by reference to examples, which are, however, not intended to limit the application. Variations of the application now known or further developed are considered to fall within the scope of the application described herein and claimed below.
Example 1
Compound A1 (3.12 g,15.0 mmol) and compound B1 (8.04 g,45.0 mmol) were added to a reaction flask, ethyl acetate (30 mL) was added as a solvent, and the temperature was raised to 50 ℃; compound C1 (5.0 g,30.0 mmol) was added in 6 portions and the reaction was incubated for 20 hours after the addition.
Post-treatment: ethyl acetate (20 mL), water (50 mL) were added, the layers were extracted, the aqueous layer was extracted with ethyl acetate (30 mL x 2), the ethyl acetate layers were combined, washed with water (30 mL x 2), with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, suction filtered, and spun dry to give 11.0g of crude product.
Dichloromethane (40 mL) is added to dissolve the crude product, stirring is carried out for 1 hour, suction filtration is carried out, isopropanol (20 mL) is added, stirring is carried out until the crude product is fully dissolved, spin evaporation is carried out until the crude product is dried, isopropanol (40.0 g) is added, reflux is carried out for 1 hour at 80 ℃, slow cooling is carried out for 4-5 hours, suction filtration is carried out, isopropanol (10 mL) and petroleum ether (10 mL) are respectively adopted for leaching filter cakes, 2.21g of product is obtained after drying, and the yield is obtained: 38.4%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.49(d,J＝2.5Hz,1H),7.84(dd,J＝8.4,1.7Hz,1H),7.79(dd,J＝8.2,2.6Hz,1H),7.51(dd,J＝8.4,6.3Hz,1H),7.47(d,J＝8.2Hz,1H),4.12(d,J＝2.5Hz,3H),2.56(s,3H),1.51(s,6H).
Example 2
Compound A2 (100 mg,0.33 mmol) and compound C1 (176 mg,0.99 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, the temperature was raised to 50℃and compound B2 (135 mg,0.66 mmol) was added in 4 portions and reacted at a constant temperature for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded the target product 3mg, yield: 1.8%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.57-8.58(d,J＝2.45Hz,1H),8.27-8.34(m,2H),7.99(s,1H),7.84-7.87(dd,J 1＝2.55Hz,J2＝8.25Hz,1H),7.50-7.53(d,J＝8.25Hz,1H),7.12(s,1H),2.91-2.95(t,J＝7.5Hz,2H),2.84-2.88(t,J＝7.45Hz,2H),2.17-2.21(m,2H),1.57(s,6H).
Example 3
Compound A1 (100 mg,0.48 mmol), compound C1 (257 mg,1.44 mmol) and compound B3 (184 mg,0.96 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 103mg of product in yield: 53.1%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.45(d,J＝2.5Hz,1H),8.40(d,J＝8.2Hz,1H),8.31(d,J＝1.9Hz,1H),8.09(dd,J＝8.1,2.0Hz,1H),7.73(dd,J＝8.2,2.6Hz,1H),7.48(d,J＝8.2Hz,1H),2.56(s,3H),1.52(s,6H).
Example 4
Compound A1 (100 mg,0.48 mmol), compound C1 (257 mg,1.44 mmol) and compound B4 (148 mg,0.96 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 16mg of product, yield: 9.0%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.49(d,J＝2.5Hz,1H),8.02(ddd,J＝8.4,6.3,1.9Hz,1H),7.80(dd,J＝8.2,2.6Hz,1H),7.75(ddd,J＝8.3,6.2,1.8Hz,1H),7.47(d,J＝8.3Hz,1H),2.56(s,3H),1.52(s,6H).
Example 5
Compound A1 (100 mg,0.48 mmol), compound C1 (257 mg,1.44 mmol) and compound B5 (171 mg,0.96 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 20mg of product, yield: 10.5%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.48(d,J＝2.5Hz,1H),7.78(dd,J＝8.2,2.6Hz,1H),7.70(d,J＝8.3Hz,1H),7.46(d,J＝8.3Hz,1H),7.40(d,J＝8.4Hz,1H),4.01(s,3H),3.84(s,3H),2.55(s,3H),1.50(d,J＝4.4Hz,6H).
Example 6
Compound A1 (100 mg,0.48 mmol), compound C1 (257 mg,1.44 mmol) and compound B6 (180 mg,0.96 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 93mg of product, yield: 47.7%.
1 H-NMR(400MHz,DMSO-d 6 ):δ9.25(d,J＝2.0Hz,1H),8.83(d,J＝2.1Hz,1H),8.45(d,J＝2.5Hz,1H),7.73(dd,J＝8.3,2.5Hz,1H),7.49(d,J＝8.2Hz,1H),2.56(s,3H),1.54(s,6H).
Example 7
Compound A1 (100 mg,0.48 mmol), compound C1 (257 mg,1.44 mmol) and compound B7 (131 mg,0.96 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 55mg of product, yield: 32.4%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.49(d,J＝2.5Hz,1H),8.17(dd,J＝9.7,1.7Hz,1H),7.94(dd,J＝8.3,1.7Hz,1H),7.88(t,J＝7.6Hz,1H),7.79(dd,J＝8.2,2.6Hz,1H),7.47(d,J＝8.3Hz,1H),2.56(s,3H),1.51(s,6H).
Example 8
Compound A2 (100 mg,0.33 mmol), compound C1 (176 mg,0.99 mmol) and compound B3 (127 mg,0.66 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 52mg of product, yield: 31.6%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.50(d,J＝2.5Hz,1H),8.40(d,J＝8.2Hz,1H),8.31(d,J＝1.9Hz,1H),8.10(dd,J＝8.3,1.9Hz,1H),7.98(s,1H),7.76(dd,J＝8.2,2.5Hz,1H),7.49(d,J＝8.3Hz,1H),7.10(s,1H),2.89(t,J＝7.6Hz,2H),2.83(t,J＝7.4Hz,2H),2.15(p,J＝7.5Hz,2H),1.53(s,6H).
Example 9
Compound A2 (100 mg,0.33 mmol), compound C1 (176 mg,0.99 mmol) and compound B4 (102 mg,0.66 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 29mg of product, yield: 18.8%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.54(d,J＝2.5Hz,1H),8.02(ddd,J＝8.4,6.3,1.9Hz,1H),7.99(d,J＝0.8Hz,1H),7.83(dd,J＝8.3,2.6Hz,1H),7.76(ddd,J＝8.4,6.3,1.8Hz,1H),7.48(d,J＝8.3Hz,1H),7.13–7.08(m,1H),2.89(t,J＝7.7Hz,2H),2.83(t,J＝7.4Hz,2H),2.15(p,J＝7.5Hz,2H),1.53(s,6H).
Example 10
Compound A2 (100 mg,0.33 mmol), C1 (176 mg,0.99 mmol) and compound B5 (118 mg,0.66 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 18mg of product, yield: 11.1%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.52(d,J＝2.5Hz,1H),7.99(d,J＝0.8Hz,1H),7.81(dd,J＝8.3,2.6Hz,1H),7.70(d,J＝8.3Hz,1H),7.48(d,J＝8.3Hz,1H),7.40(d,J＝8.3Hz,1H),7.10(s,1H),4.01(s,3H),3.85(s,3H),2.89(dd,J＝8.7,6.6Hz,2H),2.83(t,J＝7.4Hz,2H),2.15(p,J＝7.5Hz,2H),1.50(d,J＝4.8Hz,6H).
Example 11
Compound A2 (100 mg,0.33 mmol), C1 (176 mg,0.99 mmol) and compound B6 (123 mg,0.66 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 42mg of product, yield: 25.5%.
1 H-NMR(400MHz,DMSO-d 6 ):δ9.25(d,J＝2.1Hz,1H),8.83(d,J＝2.1Hz,1H),8.49(d,J＝2.5Hz,1H),7.99(d,J＝0.9Hz,1H),7.76(dd,J＝8.2,2.5Hz,1H),7.50(d, J＝8.3Hz,1H),7.11(s,1H),2.90(t,J＝7.6Hz,2H),2.83(t,J＝7.4Hz,2H),2.16(p,J＝7.5Hz,2H),1.54(s,6H).
Example 12
Compound A2 (100 mg,0.33 mmol), C1 (176 mg,0.99 mmol) and compound B7 (90 mg,0.66 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 27mg of product, yield: 18.2%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.53(d,J＝2.5Hz,1H),8.17(dd,J＝9.7,1.7Hz,1H),7.99(s,1H),7.94(dd,J＝8.4,1.7Hz,1H),7.91–7.85(m,1H),7.82(dd,J＝8.2,2.6Hz,1H),7.48(d,J＝8.3Hz,1H),7.10(s,1H),2.89(t,J＝7.6Hz,2H),2.83(t,J＝7.4Hz,2H),2.15(p,J＝7.5Hz,2H),1.52(s,6H).
Example 13
Compound A3 (100 mg,0.37 mmol), C1 (199mg, 1.12 mmol), and compound B3 (139 mg,0.74 mmol) were added to a reaction flask, acetone (1 mL) was added, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 3mg of product, yield: 1.7%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.46(s,1H),8.41(d,J＝8.2Hz,1H),8.29(s,1H),8.08(d,J＝8.0Hz,1H),7.78(t,J＝8.0Hz,1H),7.43(d,J＝11.0Hz,1H),7.33(d,J＝8.5Hz,1H),2.80(d,J＝4.5Hz,3H),1.54(s,6H).
Example 14
Compound A3 (100 mg,0.37 mmol), C2 (260 mg,1.12 mmol) and compound B3 (138 mg,0.74 mmol) were added to a reaction flask, acetone (1 mL) was added, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 29mg of product, yield: 16.8%. Nuclear magnetic resonance data were the same as in example 13.
Example 15
Compound A2 (100 mg,0.33 mmol), C2 (230 mg,0.99 mmol) and compound B2 (135 mg,0.66 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 120mg of product in yield: 70.3%. The nuclear magnetic data are the same as in example 2.
Example 16
Compound A2 (100 mg,0.33 mmol), C2 (230 mg,0.99 mmol) and compound B1 (108 mg,0.66 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 81mg of product, yield: 51.2%
1 H-NMR(400MHz,DMSO):δ8.52(d,J＝2.4Hz,1H),7.99(s,1H),7.84-7.79(m,2H),7.56(d,J＝8.2Hz,1H),7.48(d,J＝8.3Hz,1H),7.11(s,1H),3.96(d,J＝1.8Hz,3H),2.89(t,J＝7.6Hz,2H),2.83(t,J＝7.4Hz,2H),2.21–2.09(m,2H),1.51(d,J＝1.6Hz,6H).
Example 17
Compound A2 (100 mg,0.33 mmol), C3 (230 mg,0.99 mmol) and compound B2 (135 mg,0.66 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 88mg of product in yield: 51.8%. The nuclear magnetic data are the same as in example 2.
Example 18
Compound A1 (100 mg,0.48 mmol), C2 (335 mg,1.44 mmol) and compound B1 (160 mg,0.96 mmol) were added to a reaction flask, ethyl acetate (1 mL) was added as a solvent, and the temperature was raised to 50℃and the reaction was continued for 20 hours.
Post-treatment: purification by direct addition of thick prep plate (DCM: meoh=20:1) afforded 70mg of product, yield: 37.9%. The nuclear magnetic data are the same as in example 1.
Examples Compound A Compound B Sulfur source reagent Equivalence ratio Yield/%
1 A1 B1 C1 1:3:2 38.4
2 A2 B2 C1 1:2:3 1.8
3 A1 B3 C1 1:2:3 53.1
4 A1 B4 C1 1:2:3 9.0
5 A1 B5 C1 1:2:3 10.5
6 A1 B6 C1 1:2:3 47.7
7 A1 B7 C1 1:2:3 32.4
8 A2 B3 C1 1:2:3 31.6
9 A2 B4 C1 1:2:3 18.8
10 A2 B5 C1 1:2:3 11.1
11 A2 B6 C1 1:2:3 25.5
12 A2 B7 C1 1:2:3 18.2
13 A3 B3 C1 1:2:3 1.7
14 A3 B3 C2 1:2:3 16.8
15 A2 B2 C2 1:2:3 70.3
16 A2 B1 C2 1:2:3 51.2
17 A2 B2 C3 1:2:3 51.8
18 A1 B1 C2 1:2:3 37.9
Comparative example:
previous studies of the present application have referred to the method in preparation example IV of CN 1500081A by the following synthetic procedure: first, compound B2 and compound C1 are reacted (the expected reaction scheme is shown below), and then compound a is added to produce the desired product.
However, the actual results prove that the desired target product or the sulfonylurea or isothiocyanate intermediate thereof cannot be produced by the reaction of the compound B2 and the compound C1, but the main product is the benzothiazole compound 3 (the reaction scheme is shown below).
The specific procedure for experiments 1-6 corresponding thereto is as follows:
experiment 1: adding the compound B2, the compound C1 and the alkali into a closed tank, adding DCM, closing the opening of the tank, placing the tank into an oil bath at 40 ℃ for stirring, and carrying out heat preservation reaction for a certain time. The reaction was monitored by TLC and was essentially absent.
Experiment 2: adding the compound B2, the compound C1 and the alkali into a closed tank, adding the Tol, closing the opening of the tank, placing the tank into an oil bath at 80 ℃ for stirring, and carrying out heat preservation reaction for a certain time. Purification through thick prep plates (PE: ea=100:1:1) gave the product.
1 H NMR(400MHz,DMSO-d 6 )δ8.73(s,1H),8.41(d,J＝8.4Hz,1H),8.30(d,J＝8.4Hz,1H),8.12(s,1H),7.28(s,1H).
Experiment 3: adding the compound B2, the compound C1 and the alkali into a reaction bottle, adding Tol, placing in an oil bath at 80 ℃ for stirring, and carrying out heat preservation reaction for a certain time. Purifying by column chromatography to obtain the product.
Experiment 4: adding the compound B2, the compound C1 and the alkali into a reaction bottle, adding ACN, placing in an oil bath at 79 ℃ for stirring, and carrying out heat preservation reaction for a certain time. The reaction was essentially complete as monitored by TLC and was not purified further.
Experiment 5: adding the compound B2, the compound C1 and the alkali into a reaction bottle, adding Tol, placing in an oil bath at 80 ℃ for stirring, and carrying out heat preservation reaction for a certain time. The reaction was essentially complete as monitored by TLC and was not purified further.
Experiment 6: adding the compound B2, the compound C1 and the alkali into a closed tank, adding the Tol, closing the opening of the tank, placing the tank into an oil bath at 80 ℃ for stirring, and carrying out heat preservation reaction for a certain time. The reaction was essentially complete as monitored by TLC, without further isolation and purification.
The reaction parameters for experiments 1-6 are shown in the following table.
Note that: "/" represents that the yield was not counted because the isolation and purification were not performed.
From experiments 1-6, although the method in CN 1500081A shows that thiocarbonyldiimidazole can be used for preparing a compound containing a-NCS group instead of thiophosgene, the compound has poor universality, and the compound B2 and the compound C1 cannot generate target products under the above different reaction conditions, and cannot further perform ring closure reaction with corresponding amino acid esters to generate the thiohydantoin derivative.
Example 20:
in order to further explain that the method of the application not only has excellent universality for different substrates, but also can basically realize the technical effect of the application by adopting different material proportions, experiments 1-4 corresponding to the method are designed, and the specific process is as follows:
experiments 1-4: adding the compound A2, the compound B2 and the compound C2 into a closed tank, adding DCM, closing the opening of the tank, placing the tank into an oil bath at 40 ℃ for stirring, and carrying out heat preservation reaction for a certain time. Purification by thick prep plate (DCM: meoh=30:1) afforded the product.
The reaction parameters for experiments 1-4 are shown in the following table.
This disclosure merely illustrates some embodiments of the claimed subject matter, wherein one or more of the features recited in the claims may be combined with any one or more of the features, and such combined features are also within the scope of the present disclosure, as if such combined features were specifically recited in the present disclosure.

Claims (11)

  1. A method for synthesizing thiohydantoin compounds or deuterated compounds thereof by a three-component one-pot method is characterized in that: using a compound A, a compound B and a thio source reagent as raw materials, and reacting in an organic solvent by a one-pot method to generate a thiohydantoin derivative shown in a formula 1 or deuterated substances thereof;
    wherein:
    R 1 and R is 2 Is covered by one or more C' s 1 -C 6 Alkyl, C (O) NHR, SO 2 NHR, cyano, hydroxy, alkyloxy, C (S) NHR, C (O) OR, CH 2 (CH 2 ) m Q, halogen or aryl containing 5-6 membered heteroaryl substitution; or R is 1 And R is 2 Is covered by one or more C' s 1 -C 6 Alkyl, C (O) NHR, SO 2 NHR, cyano, hydroxy, alkyloxy, C (S) NHR, C (O) OR, CH 2 (CH 2 ) m Q, halogen or heteroaryl containing 5-6 membered heteroaryl substitution; wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and C 1 -C 6 Alkenyl groups; m is an integer selected from 0-6, Q is selected from C (O) NHR, SO 2 R、SO 2 NHR, cyano, hydroxy, alkyloxy, C (S) NHR, and C (O) OR; or R is 1 And R is 2 Is alkyl or heterocyclyl;
    wherein the alkyl group comprises 1 to 20 aliphatic carbon atoms; the aryl is a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings; the heteroaryl has a cyclic aromatic group of 5 to 10 ring atoms, one of which is selected from S, O and N; the heterocyclic group is selected from 3-piperidine, 4-piperidine, tetrahydrofuran, 3-pyrrolidine or tetrahydropyran;
    R 5 independently selected from linear or branched C1-C6 alkyl, aryl or heteroaryl having 5-10 ring atoms with one or two aromatic rings;
    R 3 and R is 4 Independently selected from hydrogen, C 1 -C 6 Alkyl, C optionally substituted by one or more halogen or hydroxy groups 1 -C 6 Alkyl, or R 3 And R is 4 Together with the carbons to which they are attached form a 3-6 membered cycloalkyl ring, wherein one or more carbons are optionally substituted with one or more halogens or hydroxy groups;
    alternatively, wherein:
    R 1 is C 6 -C 10 Aryl or 5-10 membered heteroaryl, said aryl and heteroaryl being independently optionally selected from C 1 -C 6 Alkyl, C (O) NH (C) 1 -C 6 Alkyl), halogen and C 6 -C 10 One or more primary substituents of the aryl group independently optionally substituted with one or more substituents selected from deuterium, 5-10 membered heteroaryl and-O (C 1 -C 6 Alkyl) -O (C) 1 -C 6 Alkyl) -Boc substituted with one or more secondary substituents; preferably, R 1 Is phenyl or pyridinyl, which are independently optionally selected from-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-C(O)NHCH 3 、-C(O)NHCH 2 CH 3 One or more primary substituents selected from the group consisting of deuterium, imidazolyl, oxazolyl, thiazolyl and-O (C 1 -C 4 Alkyl) -OCH 2 -one or more secondary substituents of Boc;
    R 5 is C 1 -C 6 An alkyl group; preferably, R 5 Is methyl;
    R 3 and R is 4 Independently C 1 -C 6 Alkyl, or R 3 And R is 4 Together with the carbon to which they are attached, form a 3-6 membered cycloalkyl ring; preferably, R 3 And R is 4 Independently methyl, or R 3 And R is 4 Together with the carbon to which they are attached, form a cyclobutane ring.
  2. The method according to claim 1, characterized in that: the thio source reagent is selected fromOne of the aromatic thiochloroformates;
    it is further preferred that the composition comprises,
    the thio source reagent is selected from
  3. The method according to claim 1 or 2, characterized in that: the R is 2 Selected from the group consisting of
    Wherein the method comprises the steps ofRepresents R 2 with-NH 2 Is a ligation site of (2); y is independently selected from N, CH, CR 1a ；R 1a Independently selected from cyano, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C optionally substituted by one or more halogen or hydroxy groups 1 -C 6 An alkyl group; t=0, 1,2,3 or 4;
    it is further preferred that the composition comprises,
    y is selected from N, CH and CR 1a The method comprises the steps of carrying out a first treatment on the surface of the Each R is 1a Independently cyano, halogen, C 1 -C 6 Alkoxy or C substituted by one or more halogen or hydroxy groups 1 -C 6 An alkyl group; t is 0,1,2,3 or 4.
  4. A method according to claim 3, characterized in that: the R is 2 Selected from the group consisting of
    Y is independently selected from N or CH; r is R 1a Independently selected from cyano, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C optionally substituted by one or more halogen or hydroxy groups 1 -C 6 An alkyl group; t=0, 1,2,3 or 4;
    it is further preferred that the composition comprises,
    each R is 1a Independently cyano, trifluoromethyl, fluoro or methoxy; t is 0,1,2 or 3.
  5. The method according to claim 1, characterized in that: the compound A is selected from the group consisting of:
  6. the method according to claim 1 or 5, characterized in that:
    the compound B is selected from:
  7. the method according to claim 1, characterized in that: the thiohydantoin derivative shown in the formula 1 is selected from the following compounds or deuterated compounds thereof:
  8. the method according to claim 1, characterized in that: the solvent is alkyl acid ester, straight-chain or branched-chain alkyl ether or cyclic ether, aryl ether, chlorinated hydrocarbon, aromatic hydrocarbon, halogenated aromatic hydrocarbon, alkyl ketone, straight-chain or branched-chain C2-C6 nitrile, dimethyl sulfoxide or chain or cyclic amide.
  9. The method according to claim 1, characterized in that: compound a in the process, calculated as molar ratio: compound B: thiogenic agent=1:0.5-5:1-5, preferably 1:0.5-2:1-5, further preferably 1:1.5-2:2-5.
  10. The method according to claim 1, characterized in that: in the method, a compound A, a compound B and a thio source reagent are simultaneously added into an organic solvent for stirring reaction; or firstly adding the compounds A and B into an organic solvent, stirring, and then adding a thio source reagent in batches for reaction; or adding the compound A and the thio source reagent into the organic solvent firstly, stirring, and then adding the compound B in batches for reaction.
  11. The method according to any one of claims 1-10, wherein:
    in the method, the thiohydantoin compound shown in the formula 1 isCompound A isCompound B isThe thio source reagent is
    Or in the method, the thiohydantoin compound shown in the formula 1 isCompound A isCompound B isThe thio source reagent isFurther preferred is
    Or in the method, the thiohydantoin compound shown in the formula 1 isCompound A isCompound B isThe thio source reagent is Further preferred is
    Or in the method, the thiohydantoin compound shown in the formula 1 isCompound A isCompound B isThe thio source reagent is
    Or in the method, the thiohydantoin compound shown in the formula 1 isCompound A isCompound B isThe thio source reagent is
    Or in the method, the thiohydantoin compound shown in the formula 1 isCompound A isCompound B isThe thio source reagent is
    Preferably, the organic solvent is an alkyl acid ester, a chlorinated hydrocarbon or an alkyl ketone.
CN202280025047.6A 2021-03-30 2022-03-29 Method for synthesizing thiohydantoin derivative by one-step method Pending CN117120436A (en)

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FR2796945B1 (en) * 1999-07-30 2002-06-28 Sod Conseils Rech Applic NOVEL DERIVATIVES OF HYDANTOINS, THIOHYDANTOINS, PYRIMIDINEDIONES AND THIOXOPYRIMIDINONES, PROCESSES FOR THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS
FR2823209B1 (en) * 2001-04-04 2003-12-12 Fournier Lab Sa NOVEL THIOHYDANTOINS AND THEIR USE IN THERAPEUTICS
RU2449993C2 (en) * 2006-03-29 2012-05-10 Те Риджентс Оф Те Юниверсити Оф Калифорния Diarylthiohydatoic compounds
TW201111378A (en) * 2009-09-11 2011-04-01 Bayer Schering Pharma Ag Substituted (heteroarylmethyl) thiohydantoins
SI2538785T1 (en) * 2010-02-24 2018-05-31 Medivation Prostate Therapeutics Llc Processes for the synthesis of diarylthiohydantoin and diarylhydantoin compounds
WO2015063720A1 (en) * 2013-10-31 2015-05-07 Ranbaxy Laboratories Limited Process for the preparation of enzalutamide
US20160318875A1 (en) * 2013-12-16 2016-11-03 Sun Pharmaceutical Industries Limited Processes and intermediates for the preparation of enzalutamide
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