阅读说明：本技术 芳基-2-硫代海因类化合物中间体、其制备方法及应用 (Aryl -2- thiohydantoin class compound intermediate, preparation method and application ) 是由 陈晓东 马振千 牛明玉 史登健 缪金鹏 邓洪癸 马立金 黄亚萍 于 2019-06-17 设计创作，主要内容包括：本发明涉及一种式Ⅳ-a所示的芳基-2-硫代海因类化合物,及其制备方法,以及式Ⅳ-a化合物作为关键中间体制备式Ⅴ-a化合物的方法。首先,以氨基酸为起始原料,经酰氯化,取代反应,经硫代源关环试剂关环后,即得式Ⅳ-a化合物。所述的式Ⅳ-a化合物进一步与式Ⅳ-A化合物进行偶联反应可制备第二代雄激素受体信号抑制剂。该工艺路线反应温和、操作简单,同时还避免了传统工艺中氰化物或氰基类化合物的使用,因此适合工艺化生产。(The present invention relates to aryl -2- thiohydantoin class compound shown in a kind of IV-a of formula, and preparation method thereof and method of the IV-a compound of formula as V-a compound of key intermediate preparation formula.Firstly, using amino acid as starting material, through chloride, substitution reaction, to get IV-a compound of formula after thio source cyclization reagent cyclization.IV-a the compound of formula, which further carries out coupling reaction with IV-A compound of formula, can prepare second generation androgen receptor signal inhibitor.Process route reaction is mild, easy to operate, while also avoiding the use of cyanide or cyano class compound in traditional handicraft, therefore is suitble to technology production.)

1. aryl -2- thiohydantoin the compound as shown in formula IV-a:

Wherein, R is selected from C or N；R1 is hydrogen or methyl；R2 is selected from hydrogen, methyl or naphthenic base,

When R is C, R1, R2 take methyl；When R is N, R1, R2 are altogether at loop coil；The loop coil is naphthenic base, the ring Alkyl is selected from cyclopropyl alkyl, cyclobutane base, pentamethylene base or cyclohexyl.

2. the synthetic method of IV-a compound of formula as described in claim 1, which comprises the steps of:

1) halogenating reaction: for compound of formula I under the action of chlorinating agent and acid binding agent, reaction generates chloride compounds II；Reaction Route is as follows:

2) condensation reaction: II compound of formula is mixed with Formula II-B compound in aprotic polar solvent, III-aization of production Close object；Reaction route is as follows:

3) ring closure reaction: under the action of activator, III-a compound of formula reacts generation with thio source reagent in organic solvent Thiocarbamide cyclization compound shown in IV-a of formula, i.e. aryl -2- thiohydantoin class compound；Reaction route is as follows:

In the step 1), each substituent group is defined as follows:

R is selected from C or N；R1 is hydrogen or methyl；R2 is selected from hydrogen, methyl or naphthenic base,

When R is C, R1, R2 take methyl；When R is N, R1, R2 are altogether at loop coil；The loop coil is naphthenic base, the ring Alkyl is selected from cyclopropyl alkyl, cyclobutane base, pentamethylene base or cyclohexyl；

The selection of step 2) and substituent group 3) is identical as step 1).

3. according to the method described in claim 2, it is characterized in that, chlorinating agent is phosphorus pentachloride in selected step 1).

4. according to the method described in claim 2, it is characterized in that, acid binding agent is selected from 2- oxazolidone, 2- in selected step 1) One of oxazolidinedione, DMAC N,N' dimethyl acetamide.

5. according to the method described in claim 2, it is characterized in that, reacting the work in non-protonic solvent in selected step 1) It is carried out under, the aprotic solvent is selected from one or both of acetonitrile, acetone, methylene chloride, ether, DMF, DMAC Combination.

6. according to the method described in claim 2, it is characterized in that, reaction temperature is -20 DEG C and arrives room temperature in selected step 1).

7. according to the method described in claim 2, it is characterized in that, also needing to add in the reaction process in selected step 2) Alkali.

8. the method according to the description of claim 7 is characterized in that the alkali be selected from potassium carbonate, potassium phosphate, sodium bicarbonate, Disodium hydrogen phosphate or sodium phosphate, TEA or DIPEA.

9. according to the method described in claim 2, it is characterized in that, in selected step 3), the activator be selected from DMAP, One of NaH, NaOH.

10. according to the method described in claim 2, it is characterized in that, the reaction carries out in the presence of a base in selected step 3).

11. according to the method described in claim 10, it is characterized in that, the alkali in DMAP, TEA, DIPEA one Kind.

12. according to the method described in claim 2, the thio source reagent is selected from 1 it is characterized in that, in selected step 3), 1- thiocarbonyl group-Dl-2 (1H) pyridine, thiophosgene, two pyridine sulphur carbonic esters, N, N'- thiocarbonyldiimidazole, two (1- benzotriazole Base) first thioketones, one of thio chloro-carbonic acid aromatic ester.

13. according to the method described in claim 2, it is characterized in that, the organic solvent is selected from selected step 3) One of DMAC, DMF, DMSO, toluene, acetonitrile, THF, 2- oxazolidine.

14. according to the method described in claim 2, it is characterized in that, reaction temperature is -30~100 DEG C in selected step 3).

Technical field

The present invention relates to field of medicine and chemical technology, aryl -2- thiohydantoin class compound shown in IV-a of formula is a kind of key Medicine intermediate, can be used for preparing the second generation androgen receptor signal inhibitor Apalutamine, Enzalutamide.

Background technique

Prostate cancer is the most commonly seen malignant tumour of male reproductive system, is to occur to obtain pernicious swell in prostatic epithelium Tumor mainly includes gland cancer (acinar adenocarcinoma), duct adenocarcinoma, bladder transitional cell carcinoma, squamous cell carcinoma.Adenosquamous carcinoma etc., wherein forefront Glandular scale accounts for 95%, and usually said that prostate cancer just refers to adenocarcinoma of the prostate, which is only second to lung cancer, though the age must increase and Increase incidence probability.The Method means of traditional treatment prostate cancer are by operation or male sex hormone antagonist, the hero of early stage Sex hormone antagonist mainly has Bicalutamide (Bicalutamine), abiraterone or Enzalutamide etc., but patient exists Serious drug resistance can be generated after medication a period of time, the discovery of Apalutamine compensates for early stage male to a certain extent The deficiency of hormone antagonist.

About the existing synthesis technology of Apalutamine and Enzalutamide, following classified finishing can be done:

One, the prior art of Apalutamide is synthesized

1. patent WO2008119015A2, US20110003839A1, US20100190991A1, Synthetic route disclosed in the documents such as US20130116258A1, WO2014190895A1 is as described below:

This method has the following deficiencies: under acidic environment, a large amount of Cymags, the use of potassium cyanide or TMSCN etc., In There are serious security risk in production process, there are a large amount of three wastes in production process, and difficult, environmental pollution is serious.Separately The initial feed cyclobutanone that the outer route uses is restricted by process safety, is commercially produced and is had difficulties, causes downstream product valence Lattice are high.

2. following process route disclosed in patent CN101454002A:

The route needs to be not suitable for industrial amplification production, and in the mistake of preparation intermediate A R-5 using microwave condition Cheng Zhong needs to be unfavorable for industrial operation using toxic articles such as Cymags.

3. patent WO2016100652A2, CN107501237A discloses following reaction route:

In the preparation process of two methods, it is required to using a large amount of malodorant thiophosgene, overall yield of reaction is low, route It is long, it is at high cost, be not suitable for technology and generate.

4. patent WO2007126765A2 also reports a kind of new technology route:

But this route linear step is too long, and hypertoxic Cymag has been used in route, technological operation is comparatively laborious, and Multistep reaction needs to be catalyzed using precious metal palladium, amplifies production line higher cost.

5. in addition, patent WO2016100645A1 provides a kind of novel synthesis of simplification:

Although the route steps are short, there are severe compromise in industrialized production, palladium is urged for the use of Cymag The carbonyl intercalation reaction or grignard exchange reaction route higher cost of change, reaction require harsh, unsuitable industrial production.

Two, the prior art of Enzalutamide is synthesized

1. patent WO2011029392A1 and document BioorganicMedicinalChemistry, 8150,18 (23), 2010 report following process route:

The second step reaction yield of this route only has 7%-8%, and needs to react under 110 degree of microwave conditions, is unsuitable for Industrialized production.

2. document Jung, M.E.；Ouk, S.；Yoo, D.；Sawyers, C.L.；Chen, C.；Tran, C.；Wongvipat, J.JournalofMedicinalChemistry2010,53,2779 and patent CN101222922B disclose following technique Route:

This method reaction yield is 25%, also needs the raw material for reacting under 110 degree of microwave conditions, and using in route Acetone cyanohydrin is toxic articles, and environmental pollution is bigger.In addition, column chromatography is also used in the post-processing of reaction, be not suitable for industrialization Production.

3. document JournalofmedicinalChemistry, 2779-2796,53 (7), 2010 report following technique:

Wherein, the yield of second step reaction is only 26%, and reaction needs the high temperature with highly basic and 130 DEG C or more.It is overall For, the reaction condition of the route is more harsh and yield is relatively low, and there are security risks.

4. patent CN103108549A, WO2011106570A1 discloses two kinds of routes:

Route one: the second step reaction yield of the reaction is 36%, and third step reaction yield only has 4%.In addition, third step Toxic articles thiophosgene has also been used in reaction, has larger harm to environment and human body.

Route two: although compared to route one, the third step reaction yield of the reaction, which has a distinct increment, (to be increased to 78%) it, but in second step uses hypertoxic iodomethane and does methylating reagent, be equally unsuitable for industrialized production.

5. patent WO2006124118A1, WO2013087004A1, WO2011103202A2, WO2011029392A1, US20070254933A1 and document Journal of Medicinal Chemistry, 53 (7), 2779-2796,2010； Report following synthetic route:

The route uses periodic acid, and danger coefficient is higher；Secondly, also using acetone cyanohydrin in reaction, this is severe toxicity Product；Meanwhile prepare compound A also needs the thiophosgene using severe toxicity, stench.Therefore, the route environment is unfriendly, and is not suitable for Industrialized production.

In conclusion the prior art method of the Apalutamide and Enzalutamide reported at present is more or less equal Be difficult to overcome following technological deficiency: 1, using toxic or violent in toxicity, environment is unfriendly；2, single stage or multi-step reaction yield It is low, be not suitable for large-scale production；3, severe reaction conditions are not able to satisfy the requirement of current industrialized production.

Summary of the invention

To solve above-mentioned prior art defect, the object of the present invention is to provide aryl shown in a kind of new IV-a of formula -- 2- thiohydantoin class compound and preparation method thereof and the compound further prepare Apalutamine, The novel synthesis of Enzalutamide.This method route is short, operation is controllable, process conditions are mild, is suitable for industrialized production； Moreover, also avoiding the use of severe poisonous chemicals Cymag, potassium cyanide, thiophosgene etc. using this method, three-protection design pressure is reduced Power, reaction process are environmentally protective.

Technical scheme is as follows:

The present invention provides the aryl as shown in formula IV-a -- 2- thiohydantoin class compound,

R is selected from C or N；R1 is hydrogen or methyl；R2 is selected from hydrogen, methyl or naphthenic base；

When R is C, R1, R2 take methyl；When R is N, R1, R2 are altogether at loop coil；The loop coil is naphthenic base, described Naphthenic base be selected from cyclopropyl alkyl, cyclobutane base, pentamethylene base or cyclohexyl.

Preferably,

The R is N, R1 and R2 cyclic butane group altogether, and the compound structure is as shown in formula M3:

Preferably,

The R is C, and R1 is methyl, and R2 is methyl, and the compound structure is as shown in formula M3-1:

The present invention provides the synthetic methods of the IV-a compound of formula, include the following steps:

1) halogenating reaction: for compound of formula I under the action of chlorinating agent and acid binding agent, reaction generates chloride compounds II； Reaction route is as follows:

2) condensation reaction: II compound of formula is mixed with Formula II-B compound in aprotic polar solvent, production III- A compound；Reaction route is as follows:

3) ring closure reaction: under the action of activator, III-a compound of formula reacts in organic solvent with thio source reagent Thiocarbamide cyclization compound shown in IV-a of production, i.e. aryl -2- thiohydantoin class compound；Reaction route is as follows:

In the step 1), each substituent group is defined as follows:

R is selected from C or N；R1 is hydrogen or methyl；R2 is selected from hydrogen, methyl or naphthenic base；

When R is C, R1, R2 take methyl；When R is N, R1, R2 are altogether at loop coil；The loop coil is naphthenic base, described Naphthenic base be selected from cyclopropyl alkyl, cyclobutane base, pentamethylene base or cyclohexyl.

The selection of step 2) and substituent group 3) is identical as step 1).

The present invention provides the synthetic methods of compound M3, include the following steps:

1) halogenating reaction: for compound SM1 under the action of chlorinating agent and acid binding agent, reaction generates chloride compounds M1； Reaction route is as follows:

2) condensation reaction: mixing compound M1 with compound SM2 in aprotic polar solvent, generates compound M2； Reaction route is as follows:

3) ring closure reaction: under the action of activator, compound M2 reacts generation with thio source reagent in organic solvent Thiocarbamide cyclization compound M3；Reaction route is as follows:

The present invention provides the synthetic methods of compound M3-1, include the following steps:

1) halogenating reaction: for compound SM1-1 under the action of chlorinating agent and acid binding agent, reaction generates chloride compounds M1-1；Reaction route is as follows:

2) condensation reaction: mixing compound M1-1 with compound SM2-1 in aprotic polar solvent, generates compound M2-1；Reaction route is as follows:

3) ring closure reaction: under the action of activator, compound M2-1 compound and thio source reagent are in organic solvent Reaction generates thiocarbamide cyclization compound M3-1；Reaction route is as follows:

Preferably,

In selected step 1), chlorinating agent is phosphorus pentachloride.

In selected step 1), acid binding agent in 2- oxazolidone, 2- oxazolidinedione, n,N-dimethylacetamide one Kind.

In selected step 1), reaction carried out under the action of non-protonic solvent, the aprotic solvent be selected from acetonitrile, The combination of one or both of acetone, methylene chloride, ether, DMF, DMAC.

In selected step 1), reaction temperature is -20 DEG C and arrives room temperature.

In selected step 2), also need to add alkali in the reaction process.The alkali is selected from potassium carbonate, potassium phosphate, carbonic acid Hydrogen sodium, disodium hydrogen phosphate, sodium phosphate, TEA or DIPEA.

In selected step 3), the activator is selected from one of DMAP, NaH, NaOH.

In selected step 3), which carries out in the presence of a base.The alkali in DMAP, TEA, DIPEA one Kind.

In selected step 3), the thio source reagent is selected from 1,1- thiocarbonyl group-Dl-2 (1H) pyridine, thiophosgene, two pyrroles Pyridine sulphur carbonic ester, N, one of N'- thiocarbonyldiimidazole, two (1- benzotriazole base) first thioketones, thio chloro-carbonic acid aromatic ester.

In selected step 3), the organic solvent is selected from DMAC, DMF, DMSO, toluene, acetonitrile, THF, 2- oxazolidine One of.

In selected step 3), reaction temperature is -30~100 DEG C.

Preferably,

The present invention provides the synthetic methods of IV-a compound of formula, comprise the following steps:

1) halogenating reaction: under the action of chlorinating agent and acid binding agent, raw material amino-acid compound I is in non-protonic solvent Under the action of, chloride compounds II is generated to reaction under room temperature at 0 DEG C.Selected chlorinating agent used is phosphorus pentachloride； The carboxylic moiety of amino acid can be converted to acyl chlorides under the action of adding acid binding agent, acid binding agent used has 2- oxazolidone, 2- oxazolidinedione or DMAC N,N' dimethyl acetamide etc..

2) condensation reaction: compound II be benzoylchloride hydrochloride salt compound, itself have very strong reactivity, with raw material Compound II-B mixing generates compound III-a with substitution reaction occurs in aprotic polar solvent, and post-processing is through alkaline matter After adjusting pH, after crystallization is quenched in ice water, filters, wash, dry, the processes such as recrystallization.In the synthetic reaction process, pass through addition Different alkali: the equal energy such as such as potassium carbonate, potassium phosphate, sodium bicarbonate, disodium hydrogen phosphate, sodium phosphate weak base or TEA, DIPEA Easily cause substitution reaction.Meanwhile under the acid system environment existing for itself of reaction substrate, it is anti-also easily to cause substitution Compound III-a should be synthesized.The step operation is simple, high income, purity is high.

3) ring closure reaction: under conditions of activator, compound III-a and thiocarbonyl source compound are in organic solvent In, under -30 DEG C to 100 DEG C of reaction temperature, synthesizing thiourea cyclization compound IV-a.Wherein, the activator is selected from DMAP, NaH, NaOH etc.；The organic solvent is selected from DMAC, DMF, DMSO, toluene, acetonitrile, THF, 2- oxazolidine etc..This Outside, which also needs to carry out under alkaline conditions, and compound III-a reacts with thio source reagent, closes into pentatomic sulphur urea ring.Institute The alkali stated refers to the reagents such as DMAP, TEA, DIPEA；It is 1,1- thiocarbonyl group-Dl-2 (1H) pyrrole that the thio source reagent, which is selected from, Pyridine, thiophosgene, two pyridine sulphur carbonic esters, N, N'- thiocarbonyldiimidazole, two (1- benzotriazole base) first thioketones, thio chloro-carbonic acid The reagents such as aromatic ester.

The present invention provides the aryl as shown in formula IV-a -- and 2- thiohydantoin class compound passes through a step as intermediate The method of coupling reaction preparation second generation androgen receptor signal inhibitor as shown in Formula V-a；

Reaction route is as follows:

Wherein,

X is selected from Cl, Br or I；

R is selected from C or N；R1 is hydrogen or methyl；R2 is selected from hydrogen, methyl or naphthenic base；

When R is C, R1, R2 take methyl；When R is N, R1, R2 are altogether at loop coil；The loop coil is naphthenic base, described Naphthenic base be selected from cyclopropyl alkyl, cyclobutane base, pentamethylene base or cyclohexyl.

Specific step is as follows:

There are catalyst and active ligand, IV-a compound of formula and the halogenated acyl of fragrance shown in formula IV-A V-a compound of Buchwald-Hartwig C-N coupling reaction production occurs for amine compounds.

Preferably,

The R is N, and R1, R2 are total to cyclic butane group, and X Br, the compounds Ⅳ-a are compound M3, described Compounds Ⅳ-A be compound SM3, the compound V-a be compound Apalutamine:

The synthetic route of the compound Apalutamine is as follows:

Specific step is as follows: there are catalyst and active ligand, compound shown in formula M3 and formula SM3 institute The fragrant halogen acid amide compound shown occurs Buchwald-Hartwig C-N coupling reaction and generates compound Apalutamine.

Preferably,

The R is C, and R1 is methyl, and R2 is methyl, and X Br, the compounds Ⅳ-a are compound M3-1, institute Compounds Ⅳ-the A stated is compound SM3, and the compound V-a is compound Enzalutamide；

The synthetic route of the compound Enzalutamide is as follows:

Specific step is as follows: there are catalyst and active ligand, compound shown in formula M3-1 and formula SM3 Shown in fragrance halogen acid amide compound occur Buchwald-Hartwig C-N coupling reaction generate compound Enzalutamide。

Preferably,

The catalyst is selected from divalent palladium catalyst or cuprous salt catalyst.

The divalent palladium catalyst is selected from Pd₂(dba)₃、Pd₂[(PPh)₃]₄、Pd₂(PPh)₂Cl₂、Pd(OAc)₂, allyl Any one in base palladium chloride dimer, dicyanogen methyl isophorone palladium chloride.

Any one of the cuprous salt catalyst in cuprous iodide, cuprous bromide, stannous chloride.

The active ligand be selected from Xanphos, Sphos, Ruphos, DPPF, carbenes, 2- acetyl cyclohexanone, N, N, N, N- tetramethylethylenediamine, N, N- dimethyl cyclohexane -1,2- diamines, N, any one in N- dimethyl-ethylenediamine.

The reaction carries out under alkaline conditions.

The alkali appointing in cesium carbonate, potassium carbonate, potassium phosphate, sodium acetate, sodium hydrogen, potassium tert-butoxide, sodium tert-butoxide It anticipates one kind.

The reaction process need to be passed through inert gas.

The inert gas is selected from one of nitrogen, argon gas.

The reaction temperature is 80~140 DEG C.It is preferred that 120 DEG C.

The present invention has the following technical effect that；The present invention provides new aryl -2- thiohydantoin class compound and its systems Preparation Method, and prepare second generation androgen receptor signal as intermediate using the aryl -2- thiohydantoin compound and inhibit The method of agent such as Apalutamine, Enzalutamide, preparation route is simple, operation is controllable, is suitable for industrialized production, and And also avoid the use of toxic articles Cymag, reaction process environmentally protective.

Detailed description of the invention

The HNMR of Fig. 1 compound M1；

The LCMS of Fig. 2 compound M2；

The HNMR of Fig. 3 compound M2；

The LCMS of Fig. 4 compound M3；

The HNMR of Fig. 5 compound M3.

Specific embodiment

The present invention is described in further detail combined with specific embodiments below.