WO2022206742A1

WO2022206742A1 - Method for synthesizing thiohydantoin derivative by means of one-step method

Info

Publication number: WO2022206742A1
Application number: PCT/CN2022/083607
Authority: WO
Inventors: 童友之; 许若; 吴晓君; 申剑冰
Original assignee: 苏州开拓药业股份有限公司
Priority date: 2021-03-30
Filing date: 2022-03-29
Publication date: 2022-10-06
Also published as: CN117120436A

Abstract

The present invention belongs to the technical field of medicine synthesis, and in particular relates to a method for synthesizing a thiohydantoin derivative by means of a one-step method. By means of taking three components, i.e., an amino acid derivative, an amino compound (especially an arylamine compound) and a thio-source reagent, as raw materials, a thiohydantoin derivative can be directly prepared by means of a one-pot method. Thus, first preparing isothiocyanate (a compound containing a -NCS group), and separating and purifying the isothiocyanate are not necessary, so that the reaction period is greatly shortened, and the production cost is reduced; moreover, the use of an acid and an alkali in the reaction process are avoided, thereby achieving environmental protection.

Description

A kind of method for one-step synthesis of thiohydantoin derivatives

Citations to Related Applications

The present invention claims the priority of the invention patent application with the application number of 202110337832.2, entitled "A method for one-step synthesis of thiohydantoin derivatives", which was submitted in China on March 30, 2021. The entire contents of this patent application are incorporated herein.

technical field

The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a method for synthesizing thiohydantoin derivatives by one-step method.

Background technique

Thiohydantoin derivatives are important structural fragments of androgen receptor antagonists, such as enzalutamide, apalutamide (ARN-509), proclutamide, HC-1119 deuterated enzalutamide, etc. drug. At present, in the construction of thiohydantoin, most of these compounds are prepared by the reaction between compounds containing -NCS groups and ester closure, wherein the compounds containing -NCS groups are prepared by the corresponding amine compounds and sulfur light. Prepared by gas reaction, such as prior art CN 107635969 A, European Journal of Medicinal Chemistry, 118(2016): 230-243, US 10626091 B2, WO 2010/118354 A1, WO 2020/112088 A1. However, thiophosgene is a highly toxic volatile substance, and its production, storage, transportation and use are unsafe, inconvenient, and harmful to the environment.

In CN 1500081 A, in order to remove the defect of thiophosgene, thiocarbonyldiimidazole is used to replace thiophosgene (for example, preparation example IV) and react with aromatic amine to prepare the corresponding -NCS group-containing compound (the isothiocyanate compound is not It is stable and has defects during transportation and storage), but its preparation process is cumbersome. After the organic phase reaction is completed, it is poured into water for extraction, and purified by silica gel chromatography to obtain a compound containing -NCS group. The -NCS group-containing compound is reacted with an amino acid under alkaline conditions, or with an amino acid ester under a weakly acidic condition, or with an amino acid ester under a weak acid and microwave irradiation condition to obtain a thiohydantoin derivative. Although this method does not use thiophosgene, the reaction system is relatively complicated, and the reaction process for preparing the -NCS group-containing compound and the thiohydantoin derivative requires the addition of acid and alkali, or a large amount of extraction is required in the post-treatment process. purification steps.

Therefore, when preparing thiohydantoin derivatives in the prior art, at least there are inconvenient production, storage and use of thiophosgene; the intermediate isothiocyanate is unstable and unfavorable for storage and transportation; the reaction process is cumbersome, It is necessary to add acid and alkali into the reaction system, which leads to the defects of difficult sewage treatment, high environmental protection pressure, and complicated post-treatment process.

SUMMARY OF THE INVENTION

In order to solve the defects in the prior art, the present invention finds that hydantoin sulfide can be directly prepared by a one-pot method using three components of amino acid derivatives, amine compounds (especially aromatic amine compounds) and thio source reagents as raw materials Urea derivatives do not need to first prepare isothiocyanates (compounds containing -NCS groups) and separate and purify them, which greatly shortens the reaction period and conditions; at the same time, the use of acids and bases in the reaction process is avoided, and it is environmentally friendly.

The present invention achieves the above object through the following technical solutions, a three-component one-pot method for synthesizing the thiohydantoin compound shown in formula 1 or its deuterated product, using compound A, compound B and a thio source reagent as The raw material, in an organic solvent, generates the thiohydantoin derivative or its deuterated product shown in formula 1 through a one-pot reaction;

in:

R ₁ and R ₂ are separated by one or more of C ₁ -C ₆ alkyl, C(O)NHR, SO ₂ NHR, cyano, hydroxyl, alkyloxy, C(S)NHR, C(O)OR , CH ₂ (CH ₂ ) _m Q, halogen or aryl substituted with 5-6 membered heteroaryl; or R ₁ and R ₂ are one or more C ₁ -C ₆ alkyl, C(O)NHR , SO ₂ NHR, cyano, hydroxyl, alkyloxy, C(S)NHR, C(O)OR, CH ₂ (CH ₂ ) _m Q, halogen or heteroaryl substituted with 5-6 membered heteroaryl wherein R is selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkenyl; m is an integer selected from 0-6, and Q is selected from C(O) NHR, _SO2R , _SO2NHR , cyano, hydroxy, alkyloxy, C(S)NHR and C(O)OR _; or R1 and R2 are alkyl or heterocyclyl _;

wherein the alkyl group contains 1-20 aliphatic carbon atoms; the aryl group is a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings; the heteroaryl group has 5-10 rings A cyclic aromatic group of atoms, wherein one ring atom is selected from S, O and N; the heterocyclic group is selected from 3-piperidine, 4-piperidine, tetrahydrofuran, 3-pyrrolidine or tetrahydropyran;

R ₅ is independently selected from linear or branched C ₁ -C ₆ alkyl, monocyclic or bicyclic aryl or heteroaryl having 5-10 ring atoms;

_R3 and R4 are independently selected from hydrogen, _C1 _- _C6 alkyl, _C1 _- _C6 alkyl optionally substituted with one or more halo or hydroxy, or _R3 and R4 and the The carbons together form a 3-6 membered cycloalkyl ring in which one or more carbons are optionally substituted with one or more halogens or hydroxy;

The thio source reagent is selected from 1,1-thiocarbonyl-Dl-2(1H)pyridine

Thiophosgene

Dipyridine thiocarbonate

N,N'-thiocarbonyldiimidazole

Bis(1-benzotriazolyl)methione

One of the aromatic thiochloroformate esters. The aromatic thiochloroformate can be, for example, phenyl thiochloroformate.

Preferably, the R ₂ is selected from

in

represents the attachment site of R ₂ and -NH ₂ ; Y is independently selected from N, CH, CR _1a ; R _1a is independently selected from cyano, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy radical, C ₁ -C ₆ alkyl optionally substituted with one or more halogen or hydroxy; t=0, 1, 2, 3 or 4;

Preferably, the R ₂ is selected from

Y is independently selected from N or CH; R _1a is independently selected from cyano, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, optionally substituted with one or more halogen or hydroxy C ₁ -C ₆ alkyl; t=0, 1, 2, 3 or 4; R _1a is further preferably cyano, trifluoromethyl, fluorine, methoxy.

Further preferably, in said compound A, R ₁ is C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, and said aryl and heteroaryl are independently optionally selected from C ₁ -C ₆ Substituted with one or more primary substituents of alkyl, C(O)NH( _C1 - _C6 alkyl), halogen and _C6 - _C10 aryl, said one or more primary substituents independently optionally substituted with one or more secondary substituents selected from deuterium, 5-10 membered heteroaryl, and -O(C ₁ -C ₆ alkyl)-O(C ₁ -C ₆ alkyl)-Boc; Preferably, R ₁ is phenyl or pyridyl independently optionally selected from -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -C(O)NHCH ₃ , _-C (O)NHCH2CH3, F, _Cl , Br, phenyl, and naphthyl substituted with one or more primary substituents independently optionally selected Substituted with one or more secondary substituents from deuterium, imidazolyl, oxazolyl, thiazolyl and -O( _C1 _- C4alkyl) _-OCH2 -Boc;

R ₅ is C ₁ -C ₆ alkyl; preferably, R ₅ is methyl, ethyl, isopropyl or tert-butyl;

_R3 and R4 are independently _C1 _- _C6 alkyl, or _R3 and R4 together with the carbon to which they are attached form a 3-6 _membered cycloalkyl ring _; preferably, _R3 and R4 are independently _The methyl group, or _R3 and R4 together with the carbon to which they are attached form a cyclobutane ring.

Further preferably, in the compound B, R ₂ is

in

represents the site of attachment of R ₂ to -NH ₂ ; Y is selected from N, CH, and CR _1a ; each R _1a is independently cyano, halogen, C ₁ -C ₆ alkoxy or by one or more halogen or hydroxy-substituted _C1 - _C6 alkyl; t is 0, 1, 2, 3 or 4; preferably, Y is selected from N or CH; each R _1a is independently cyano, trifluoromethyl, fluoro or Methoxy; t is 0, 1, 2, or 3.

Further preferably, the thio source reagent is selected from

Further preferably, the compound A is selected from:

Further preferably, the compound B is selected from:

Further preferably, the thio source reagent is selected from:

Preferably, the thiohydantoin derivative represented by the formula 1 or its deuterated product is selected from the following specific compounds:

Preferably, in the method, the organic solvent is an alkyl ester, linear or branched alkyl ether or cyclic ether, aryl ether, chlorinated hydrocarbon, aromatic hydrocarbon, halogenated aromatic hydrocarbon, alkyl ketone, Straight or branched C ₂ -C ₆ n-propyl acetate; the straight or branched alkyl ether is diethyl ether or methyl tert-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 chlorine The aromatic hydrocarbon is chlorobenzene; the alkyl ketone is acetone, methyl ethyl ketone or methyl isobutyl ketone; the C ₂ -C ₆ nitrile is acetonitrile, propionitrile, n-butyronitrile or isobutyronitrile; The 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 ester, a chlorinated hydrocarbon or an alkyl ketone.

More preferably, the organic solvent is ethyl acetate, dichloromethane, chloroform, toluene, or acetone.

Preferably, in the method, calculated according to the molar ratio, compound A: compound B: thio source reagent=1:0.5-5:1-5; more preferably 1:0.5-2:1-5, more preferably is 1:1.5-2:2-5, for example 1:2:3.

Preferably, in the method, compound A, compound B and thio source reagent are simultaneously added to the organic solvent for stirring reaction; or firstly, compound A and B are added to the organic solvent for stirring, and then the thio source is added in batches or react by adding compound A and a thio-source reagent into an organic solvent firstly, and then adding compound B in batches for reaction.

Preferably, in the method, the reaction temperature is 0°C to below the boiling point, preferably 20°C to below the boiling point, such as 20-100°C, 30-90°C, 40-80°C or 50-70°C; ordinary skills in the art Personnel can determine the appropriate reaction temperature in combination with the reaction rate and the specific reaction solvent.

Preferably, in the method, the thiohydantoin compound of formula 1 is

Compound A is

Compound B is

The thio source reagent is

Preferably, in the method, the thiohydantoin compound of formula 1 is

Compound A is

Compound B is

The thio source reagent is

further preferred

Preferably, in the method, the thiohydantoin compound represented by formula 1 is

Compound A is

Compound B is

The thio source reagent is

further preferred

Compound A is

Compound B is

The thio source reagent is

Compound A is

Compound B is

The thio source reagent is

Compound A is

Compound B is

The thio source reagent is

Further preferably, in the method, the organic solvent is an alkyl ester, a chlorinated hydrocarbon or an alkyl ketone.

Compared with the prior art, the technical conception of the present invention for preparing the thiohydantoin compound is completely different, and has the following beneficial effects:

1) The present invention adopts the one-pot method to prepare the thiohydantoin compound for the first time, overcomes the trivial steps of first preparing the isothiocyanate intermediate in the traditional preparation process, and then carrying out the ring-closing reaction, greatly shortening the production period, reducing production cost.

2) The method of the present invention does not need to prepare an isothiocyanate intermediate, and overcomes the defects of poor stability of isothiocyanate and unfavorable storage and transportation.

3) The one-pot reaction process of the method of the present invention does not need to add acid or alkali, and the sewage treatment is simple and environmentally friendly.

4) The method of the present invention has strong versatility for different substrates, and different material ratios and solvents can basically achieve excellent technical effects, can realize process amplification, and have industrial production and application prospects.

5) For some specific thiohydantoin compounds, the applicant has surprisingly found that different thio-derived reagents have a significant impact on the reaction, and the one-pot reaction is carried out using the thio-derived reagents shown in C2 or C3 in the embodiment. The experimental results are excellent; especially the selected thio-derived reagents shown by C2 can achieve high yields for multiple substrates.

Detailed ways

The invention can be further understood by the examples, however, it is to be understood that these examples do not limit the invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention 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 the reaction flask, the solvent ethyl acetate (30 mL) was added, and the temperature was raised to 50° C.; Compound C1 (5.0 g, 30.0 mmol) was added in 6 batches mmol), the addition was completed, and the reaction was incubated for 20 hours.

Post-processing: add ethyl acetate (20 mL), water (50 mL), extract and separate layers, extract the aqueous layer with ethyl acetate (30 mL*2), combine the ethyl acetate layers, wash with water (30 mL*2), saturated sodium chloride Washed with aqueous solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and spin-dried to obtain 11.0 g of crude product.

Add dichloromethane (40mL) to dissolve the crude product and stir for 1 hour, filter with suction, spin dry to obtain 7.6g of crude oily product, add isopropanol (20mL) and stir until completely dissolved, spin to dryness, add isopropanol (40.0g) , heated to 80°C and refluxed for 1 hour, slowly lowered the temperature for 4-5 hours, suction filtered, washed the filter cake with isopropanol (10 mL) and petroleum ether (10 mL), and dried to obtain 2.21 g of the product, yield: 38.4%.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ 8.49 (d, J=2.5Hz, 1H), 7.84 (dd, J=8.4, 1.7Hz, 1H), 7.79 (dd, J=8.2, 2.6 Hz, 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50 °C, and compound B2 (135 mg, 0.66 mmol) was added in 4 batches, After the addition was completed, the reaction was incubated for 20 hours.

Post-processing: directly on a thick preparative plate (DCM:MeOH=20:1) for purification to obtain 3 mg of the target product, 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours. .

Post-processing: Purify directly on thick preparative plate (DCM:MeOH=20:1) to obtain 103 mg of product, yield: 53.1%.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ 8.45 (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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours. .

Post-processing: Purify directly on thick preparative plate (DCM:MeOH=20:1) to obtain 16 mg of product, yield: 9.0%.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ 8.49 (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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours. .

Post-processing: directly on a thick preparative plate (DCM:MeOH=20:1) for purification to obtain 20 mg 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours. .

Post-processing: Purify directly on thick preparative plate (DCM:MeOH=20:1) to obtain 93 mg 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours. .

Post-processing: Purify directly on thick preparative plate (DCM:MeOH=20:1) to obtain 55 mg of product, yield: 32.4%.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ 8.49 (d, J=2.5Hz, 1H), 8.17 (dd, J=9.7, 1.7Hz, 1H), 7.94 (dd, J=8.3, 1.7 Hz, 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours. .

Post-processing: Purify directly on thick preparative plate (DCM:MeOH=20:1) to obtain 52 mg 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours. .

Post-processing: directly on a thick preparative plate (DCM:MeOH=20:1) for purification to obtain 29 mg of product, yield: 18.8%.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ 8.54 (d, J=2.5Hz, 1H), 8.02 (ddd, J=8.4, 6.3, 1.9Hz, 1H), 7.99 (d, J=0.8 Hz, 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours.

Post-processing: directly on a thick preparative plate (DCM:MeOH=20:1) for purification to obtain 18 mg 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours.

Post-processing: directly on a thick preparative plate (DCM:MeOH=20:1) for purification to obtain 42 mg of product, yield: 25.5%.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ 9.25 (d, J=2.1 Hz, 1H), 8.83 (d, J=2.1 Hz, 1H), 8.49 (d, J=2.5 Hz, 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 the reaction flask, and the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours.

Post-processing: Purify directly on thick preparative plate (DCM:MeOH=20:1) to obtain 27 mg of product, yield: 18.2%.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ 8.53 (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 (199 mg, 1.12 mmol), and compound B3 (139 mg, 0.74 mmol) were added to the reaction flask, the solvent acetone (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours.

Post-processing: Purify directly on thick preparative plate (DCM:MeOH=20:1) to obtain 3 mg 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 the reaction flask, the solvent acetone (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours.

Post-processing: Purify directly on thick preparative plate (DCM:MeOH=20:1) to obtain 29 mg of product, yield: 16.8%. The nuclear magnetic data are 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours.

Post-processing: Purify directly on thick preparative plate (DCM:MeOH=20:1) to obtain 120 mg of product, 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours.

Post-processing: Purify directly on thick preparative plate (DCM:MeOH=20:1) to obtain 81 mg 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours.

Post-processing: Purify directly on thick preparative plate (DCM:MeOH=20:1) to obtain 88 mg of product, 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 the reaction flask, the solvent ethyl acetate (1 mL) was added, the temperature was raised to 50° C., and the reaction was incubated for 20 hours.

Post-processing: Purify directly on a thick preparative plate (DCM:MeOH=20:1) to obtain 70 mg of product, yield: 37.9%. The nuclear magnetic data are the same as in Example 1.

实施例Example	化合物ACompound A	化合物BCompound B	硫代源试剂Thio source reagent	当量比Equivalent ratio	收率/％Yield/%
11	A1A1	B1B1	C1C1	1:3:21:3:2	38.438.4
22	A2A2	B2B2	C1C1	1:2:31:2:3	1.81.8
33	A1A1	B3B3	C1C1	1:2:31:2:3	53.153.1
44	A1A1	B4B4	C1C1	1:2:31:2:3	9.09.0
55	A1A1	B5B5	C1C1	1:2:31:2:3	10.510.5
66	A1A1	B6B6	C1C1	1:2:31:2:3	47.747.7
77	A1A1	B7B7	C1C1	1:2:31:2:3	32.432.4
88	A2A2	B3B3	C1C1	1:2:31:2:3	31.631.6
99	A2A2	B4B4	C1C1	1:2:31:2:3	18.818.8
1010	A2A2	B5B5	C1C1	1:2:31:2:3	11.111.1
1111	A2A2	B6B6	C1C1	1:2:31:2:3	25.525.5
1212	A2A2	B7B7	C1C1	1:2:31:2:3	18.218.2
1313	A3A3	B3B3	C1C1	1:2:31:2:3	1.71.7
1414	A3A3	B3B3	C2C2	1:2:31:2:3	16.816.8
1515	A2A2	B2B2	C2C2	1:2:31:2:3	70.370.3
1616	A2A2	B1B1	C2C2	1:2:31:2:3	51.251.2
1717	A2A2	B2B2	C3C3	1:2:31:2:3	51.851.8
1818	A1A1	B1B1	C2C2	1:2:31:2:3	37.937.9

Comparative example:

The preliminary research of the present invention has adopted the following synthesis procedure with reference to the method in Preparation Example IV of CN 1500081 A: firstly, compound B2 and compound C1 are reacted (the expected reaction scheme is shown below), and then compound A is added to generate the target product.

However, the actual result proves, adopt compound B2 and compound C1 to carry out the reaction, cannot generate the desired target product or its thiourea type or isothiocyanate type intermediate, and the main product obtained is benzothiazole compound 3 ( The reaction scheme is shown below).

The specific process of the corresponding experiments 1-6 is as follows:

Experiment 1: Add compound B2, compound C1 and alkali into a stuffy tank, add DCM, seal the tank mouth, place it in a 40°C oil bath and stir, and keep the reaction for a certain period of time. By TLC monitoring, there is basically no response.

Experiment 2: Add compound B2, compound C1 and alkali into a stuffy jar, add Tol, seal the jar mouth, place it in an oil bath at 80°C and stir, and keep reacting for a certain period of time. The product was obtained after purification on thick preparative plates (PE:EA=100:1:1).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.73(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: The compound B2, the compound C1 and the base were added to the reaction flask, and Tol was added, placed in an oil bath at 80°C and stirred, and the reaction was kept for a certain period of time. After purification by column chromatography, the product was obtained.

Experiment 4: The compound B2, the compound C1 and the base were added to the reaction flask, ACN was added, and the mixture was stirred in an oil bath at 79° C., and the reaction was maintained for a certain period of time. After monitoring by TLC, the reaction was basically complete without further separation and purification.

Experiment 5: The compound B2, the compound C1 and the base were added to the reaction flask, and Tol was added, and the mixture was placed in an oil bath at 80°C and stirred, and the reaction was maintained for a certain period of time. After monitoring by TLC, the reaction was basically complete without further separation and purification.

Experiment 6: Add compound B2, compound C1 and alkali into a stuffy tank, add Tol, seal the tank mouth, place it in an oil bath at 80°C and stir, and keep reacting for a certain period of time. After monitoring by TLC, the reaction was basically complete, and no further separation and purification was performed.

The reaction parameters for experiments 1-6 are shown in the table below.

Note: "/" represents the situation that the yield is not counted due to no separation and purification.

It can be seen from experiments 1-6 that although the method in CN 1500081 A provides that thiocarbonyldiimidazole can be used to replace thiophosgene to prepare compounds containing -NCS groups, its versatility is poor. For the above compounds B2 and C1 are different from the above. Under the reaction conditions, the target product could not be generated, and the thiohydantoin derivative could not be generated by further ring-closing reaction with the corresponding amino acid ester.

Example 20:

In order to further illustrate that the method of the present invention not only has excellent versatility for different substrates, but also can basically realize the technical effect of the present invention by adopting different material ratios, experiments 1-4 corresponding thereto are designed, and the specific process is as follows:

Experiment 1-4: Put compound A2, compound B2, and compound C2 into a stuffy tank, add DCM, seal the tank mouth, place it in a 40°C oil bath and stir, and keep the reaction for a certain period of time. Purification by thick prep plates (DCM:MeOH=30:1) gave the product.

The reaction parameters for experiments 1-4 are shown in the table below.

The summary of the present invention only illustrates some specific embodiments of the claimed protection, wherein the technical features recorded in one or more technical solutions can be combined with any one or more technical solutions, and the technical solutions obtained by combining these technical solutions It is also within the protection scope of the present application, just as the technical solutions obtained by combining these have been specifically described in the disclosure of the present invention.

Claims

A three-component one-pot method for synthesizing a thiohydantoin compound or a deuterated compound thereof, characterized in that: using compound A, compound B and a thiol source reagent as raw materials, in an organic solvent, reacting by a one-pot method Generate the thiohydantoin derivative or its deuterated product shown in formula 1;

in:

R 1 and R 2 are separated by one or more of C 1 -C 6 alkyl, C(O)NHR, SO 2 NHR, cyano, hydroxyl, alkyloxy, C(S)NHR, C(O)OR , CH 2 (CH 2 ) m Q, halogen or aryl substituted with 5-6 membered heteroaryl; or R 1 and R 2 are one or more C 1 -C 6 alkyl, C(O)NHR , SO 2 NHR, cyano, hydroxyl, alkyloxy, C(S)NHR, C(O)OR, CH 2 (CH 2 ) m Q, halogen or heteroaryl substituted with 5-6 membered heteroaryl wherein R is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkenyl; m is an integer selected from 0-6, and Q is selected from C(O) NHR, SO2R , SO2NHR , cyano, hydroxy, alkyloxy, C(S)NHR and C(O)OR ; or R1 and R2 are alkyl or heterocyclyl ;

wherein the alkyl group contains 1-20 aliphatic carbon atoms; the aryl group is a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings; the heteroaryl group has 5-10 rings A cyclic aromatic group of atoms, wherein one ring atom is selected from S, O and N; the heterocyclic group is selected from 3-piperidine, 4-piperidine, tetrahydrofuran, 3-pyrrolidine or tetrahydropyran;

R 5 is independently selected from straight-chain or branched C1-C6 alkyl groups, aryl or heteroaryl groups having 5-10 ring atoms with one or two aromatic rings;

R3 and R4 are independently selected from hydrogen, C1 - C6 alkyl, C1 - C6 alkyl optionally substituted with one or more halo or hydroxy, or R3 and R4 and the The carbons together form a 3-6 membered cycloalkyl ring in which one or more carbons are optionally substituted with one or more halogens or hydroxy;

or, where:

R 1 is C 6 -C 10 aryl or 5-10 membered heteroaryl, said aryl and heteroaryl independently being optionally selected from C 1 -C 6 alkyl, C(O)NH(C 1 -C 6 alkyl), halogen and C 6 -C 10 aryl with one or more primary substituents independently optionally selected from deuterium, 5-10 membered Heteroaryl is substituted with one or more secondary substituents of -O(C 1 -C 6 alkyl)-O(C 1 -C 6 alkyl)-Boc; preferably, R 1 is phenyl or pyridyl , the phenyl and pyridyl groups are independently optionally selected from -CH3 , -CH2CH3 , -CH2CH2CH3 , -C (O ) NHCH3 , -C (O ) NHCH2CH3 , F, Cl, Br, phenyl and naphthyl substituted with one or more primary substituents independently optionally selected from deuterium, imidazolyl, oxazolyl, thiazole substituted with one or more secondary substituents of -O(C 1 -C 4 alkyl)-OCH 2 -Boc;

R 5 is C 1 -C 6 alkyl; preferably, R 5 is methyl;

R3 and R4 are independently C1 - C6 alkyl, or R3 and R4 together with the carbon to which they are attached form a 3-6 membered cycloalkyl ring ; preferably, R3 and R4 are independently The methyl group, or R3 and R4 together with the carbon to which they are attached form a cyclobutane ring.
The method according to claim 1, wherein the thio-derived reagent is selected from the group consisting of
A kind of aromatic thiochloroformate;

Further preferably,

The thio source reagent is selected from
The method according to claim 1 or 2, wherein the R 2 is selected from

in
represents the attachment site of R 2 and -NH 2 ; Y is independently selected from N, CH, CR 1a ; R 1a is independently selected from cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy radical, C 1 -C 6 alkyl optionally substituted with one or more halogen or hydroxy; t=0, 1, 2, 3 or 4;

Further preferably,

Y is selected from N, CH and CR 1a ; each R 1a is independently cyano, halogen, C 1 -C 6 alkoxy, or C 1 -C 6 alkyl substituted with one or more halogen or hydroxy; t is 0, 1, 2, 3 or 4.
The method according to claim 3, characterized in that: the R 2 is selected from

Y is independently selected from N or CH; R 1a is independently selected from cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, optionally substituted with one or more halogen or hydroxy C 1 -C 6 alkyl; t=0, 1, 2, 3 or 4;

Further preferably,

Each R 1a is independently cyano, trifluoromethyl, fluoro or methoxy; t is 0, 1, 2 or 3.
The method of claim 1, wherein the compound A is selected from the group consisting of:
The method according to claim 1 or 5, characterized in that:

The compound B is selected from:
The method according to claim 1, wherein the thiohydantoin derivative represented by the formula 1 is selected from the following compounds or their deuterated products:
The method according to claim 1, wherein the solvent is an alkyl ester, a linear or branched alkyl ether or a cyclic ether, an aryl ether, chlorinated hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, alkanes Ketones, linear or branched C2-C6 nitriles, dimethyl sulfoxide, or chain or cyclic amides.
The method according to claim 1, wherein: according to the molar ratio calculation, in the method, compound A: compound B: thio source reagent=1:0.5-5:1-5, preferably 1:0.5-2 : 1-5, more preferably 1: 1.5-2: 2-5.
The method according to claim 1, characterized in that: in the method, compound A, compound B and thio source reagent are simultaneously added to an organic solvent for stirring reaction; or firstly, compounds A and B are added to the organic solvent Stirring is performed, and then the thio-derived reagent is added in batches to carry out the reaction; or the compound A and the thio-derived reagent are firstly added to the organic solvent for stirring, and then the compound B is added in batches to carry out the reaction.
The method according to any one of claims 1-10, wherein:

In the method, the thiohydantoin compound shown in formula 1 is
Compound A is
Compound B is
The thio source reagent is

Or in the method, the thiohydantoin compound shown in formula 1 is
Compound A is
Compound B is
The thio source reagent is
further preferred

Or in the method, the thiohydantoin compound shown in formula 1 is
Compound A is
Compound B is
The thio source reagent is

further preferred

Or in the method, the thiohydantoin compound shown in formula 1 is
Compound A is
Compound B is
The thio source reagent is

Or in the method, the thiohydantoin compound shown in formula 1 is
Compound A is
Compound B is
The thio source reagent is

Or in the method, the thiohydantoin compound shown in formula 1 is
Compound A is
Compound B is
The thio source reagent is

Preferably, the organic solvent is an alkyl ester, a chlorinated hydrocarbon or an alkyl ketone.