CN110511206A - Aryl -2- thiohydantoin class compound intermediate, preparation method and application - Google Patents
Aryl -2- thiohydantoin class compound intermediate, preparation method and application Download PDFInfo
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- CN110511206A CN110511206A CN201910520551.3A CN201910520551A CN110511206A CN 110511206 A CN110511206 A CN 110511206A CN 201910520551 A CN201910520551 A CN 201910520551A CN 110511206 A CN110511206 A CN 110511206A
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
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.
Description
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.
1 prepare compound M1 of embodiment --- 1- amino ring fourth formyl chloride hydrochloride
Reaction route is as follows:
Specific step is as follows:
It is separately added into reaction vessel, 2- oxazolidone (46.15g), acetonitrile is added in phosphorus pentachloride (146.90g)
680ml is stirred under room temperature after 1- amino ring fourth formic acid SM1 (50.00g) charging is added after 2h, after 4h is stirred at room temperature, analysis
A large amount of white solids out.Reaction solution is filtered, filter cake is washed with a small amount of acetonitrile, is dried under reduced pressure to obtain 1- amino ring fourth formyl chloride hydrochloride
(M1) 65.16g, yield 88.30%.
As shown in Figure 1, HNMR:(400MHz, DMSO-d6) 8.841 (s, 3H), 2.510-2.383 (m, 4H), 2.036-
1.971 (m, 2H)
2 prepare compound M1 of embodiment --- 1- amino ring fourth formyl chloride hydrochloride
Reaction route is as follows:
Specific step is as follows:
It being separately added into reaction vessel, DMAc (9.85g), methylene chloride 80ml is added in phosphorus pentachloride (23.51g) ,-
It is to slowly warm up to room temperature after being stirring evenly and then adding into 1- amino ring fourth formic acid SM1 (8.00g) charging at 20 DEG C, room temperature is stirred
Mix 12h.Reaction solution is filtered, filter cake is dried under reduced pressure to obtain 1- amino ring fourth formyl chloride hydrochloride (M1) 6.14g, yield 52.1%.
HNMR result is coincide with 1 product of embodiment.
3 prepare compound M1 of embodiment --- 1- amino ring fourth formyl chloride hydrochloride
Reaction route is as follows:
Specific step is as follows:
It is separately added into reaction vessel, 2- oxazolidinedione (5.26g), methylene chloride is added in phosphorus pentachloride (14.92g)
80ml is to slowly warm up to room temperature, room after being stirring evenly and then adding into 1- amino ring fourth formic acid SM1 (5.00g) charging at 0 DEG C
Temperature stirring 12h.Reaction solution is filtered, filter cake is dried under reduced pressure to obtain 1- amino ring fourth formyl chloride hydrochloride (M1) 5.32g, yield
72.0%.
HNMR result is coincide with 1 product of embodiment.
Embodiment 4 utilizes compound M1 prepare compound M2
Reaction route is as follows:
Specific step is as follows:
Compound M1 (60.00g) made from embodiment 1,2- cyano -3- trifluoromethyl-are separately added into reaction vessel
5- aminopyridine SM2 (52.80g) and acetonitrile 500ml reaction system stir 5h at room temperature, and it is complete that HPLC monitors raw material conversion
Afterwards, after potassium phosphate (149.60g) adjusting reaction solution PH=7~8 are added, reaction system is poured into 3000ml ice water system, adds
During entering, there is solid to be dispersed to precipitate, after being kept stirring 1h, filters, washing, filter cake dries to obtain compound M2 71.1g yield
88.70%HPLC purity 97.36%.
The LCMS of compound M2 is as shown in Figure 2;The HNMR of compound M2 is as shown in Figure 3.
LCMS:[M+1]=285.2
HNMR:400MHz, DMSO-d6) 9.31 (s, 1H), 8.82 (s, 1H), 5.32 (s, 1H), 2.55~2.49 (m,
2H), 1.97~1.90 (m, 3H), 1.78~1.75 (m, 1H).
Embodiment 5 utilizes compound M1 prepare compound M2
Reaction route is as follows:
Specific step is as follows:
Compound M1 (3.00g) and potassium carbonate (6.65g) and acetonitrile made from embodiment 2 are added into reaction vessel
15ml, stirs 30min at room temperature, enters compound SM2 (3.27g) in batches, and 5h is stirred at room temperature after charging, and HPLC detects raw material
After conversion completely, water quenching is added to go out reaction system, filtered, after filter cake washing, ethyl alcohol recrystallization obtains compound M2 (3.09g), yield
68%, HPLC:98.8%
LCMS:[M+1]=285.2
HNMR is compareed with 4 product of embodiment, is coincide.
Embodiment 6 utilizes compound M2 prepare compound M3
Reaction route is as follows:
Specific step is as follows:
Be separately added into 100ml there-necked flask compound M2 (20.00g) made from embodiment 4 and DMAP (8.60g) and
DMAC 60ml is added 1,1- thiocarbonyl-Dl-2 (1H)-pyridine (32.00g) reaction system and reacts 4h at 120 DEG C.HPLC
Reaction process is monitored, after completion of the reaction, reaction solution is cooled to room temperature, is slowly added dropwise in 600ml ice water, has solid precipitation, adds
Enter dilute HCl solution 20ml, filtered after stirring, filter cake washing, ethyl acetate/n-hexane mixed solvent recrystallizes to obtain compound IV
15.36g, yield 67%, HPLC:95.66%
The LCMS of compound M3 is as shown in Figure 4;The HNMR of compound M3 is as shown in Figure 5.
LCMS:[M+1]=327.1
HNMR:(400MHz, DMSO-d6) 11.32 (s, 1H), 9.15 (s, 1H), 8.70 (s, 1H), 2.64~2.60 (m,
2H), 2.59~2.47 (m, 2H), 2.03~2.00 (m, 1H), 1.98~1.96 (m, 1H).
Embodiment 7 utilizes compound M2 prepare compound M3
Reaction route is as follows:
Specific step is as follows:
Be separately added into 100ml there-necked flask compound M2 (5.00g) made from embodiment 5 and DMAP (2.15g) and
DMAC 20ml.It is added dropwise to thiophosgene (2.05ml) at room temperature rear reaction system is added dropwise and reacts 2h at 50 DEG C, HPLC monitoring
After the conversion completely of reaction process raw material, reaction solution is cooled to room temperature, and reaction system is slowly added in ice water, ethyl acetate extraction,
Merge organic phase, the washing of organic phase saturated common salt, washing is concentrated to give concentrate after dry.Concentrate adds dehydrated alcohol to recrystallize
Obtain compound M3.7g, yield 64.4%, HPLC:92.7%
LCMS:[M+1]=327.1
HNMR is compareed with 6 product of embodiment, is coincide.
Embodiment 8 utilizes compound M2 prepare compound M3
Reaction route is as follows:
Specific step is as follows:
Be separately added into 100ml there-necked flask compound M2 (3.00g) made from embodiment 4 and DMAP (1.29g) and
DMAC 10ml.Reaction system is reacted at 90 DEG C after thio-carbonyldiimidazole (3.76g) charging is added portionwise at room temperature
After 2h, HPLC monitor the conversion completely of reaction process raw material, reaction solution is cooled to room temperature, and reaction system is slowly added in ice water, second
Acetoacetic ester extraction, merges organic phase, the washing of organic phase saturated common salt, and washing is concentrated to give concentrate after dry.Concentrate adds ethyl alcohol
Recrystallize to obtain compound M3 2.07g, yield 60.2%, HPLC:98.7%
LCMS:[M+1]=327.1
HNMR is compareed with 6 product of embodiment, is coincide.
Embodiment 9 prepares Apalutamine using compound M3
Reaction route is as follows:
Specific step is as follows:
6 gained intermediate M3 (3.26g, 10.0mmol) of embodiment is added into 100ml there-necked flask, N- methyl -4- is bromo-
The fluoro- benzamide of 2- (2.55g, 11.0mmol) and K2CO3(Isosorbide-5-Nitrae-dioxane (10.0ml) nitrogen is added in 4.14g, 30.0mmol
Gas shielded is stirred at room temperature lower addition Pd2 (dba) 3 (20mg) and Xanphos (20mg) and heats 125 DEG C after nitrogen displacement three times
8h is reacted, after HPLC monitors fully reacting, ice water quenching reaction system, ethyl acetate 20ml*3 extraction is spin-dried for molten after dry
Agent adds isopropanol 10ml, is beaten 2h under the conditions of 0~5 DEG C, filters to obtain light yellow solid 2.53g yield 53.6%, HPLC:
97.6%
LCMS:[M+1]=478.3
HPLC appearance time coincide with Apalutamine standard items appearance time.
Embodiment 10 prepares Apalutamine using compound M3
8 gained intermediate M3 (5.00g, 15.34mmol) of example, the bromo- 2- of N- methyl -4- are added into 100ml there-necked flask
Fluoro- benzamide (3.92g, 16.87mmol), potassium carbonate (5.30,38.35mmol) and DMF (60ml) are stirred at room temperature uniformly,
Active cuprous iodide (0.30,1.53mmol) and ligand (1S, 2S)-(+)-N, N'- diformazan is added in nitrogen displacement afterwards three times
Base -1,2- cyclohexanediamine (0.22,1.53mmol) reacts 12h under the conditions of 120 DEG C and adds water after HPLC monitors fully reacting
200ml, ethyl acetate 50ml*3 extraction, organic phase is washed again after saturated common salt is washed, after anhydrous sodium sulfate dry filter,
It is spin-dried for solvent and obtains grease, which adds isopropanol 20ml to be beaten 2h crystallization under the conditions of 0~5 DEG C, filters to obtain filter cake, filter cake
Off-white powder is recrystallized to obtain with the mixed solvent (15V, ethyl acetate: normal heptane=1:2) of ethyl acetate and normal heptane
3.51g, yield 48.3%HPLC:99.2%
LCMS:[M+1]=478.3
HPLC appearance time coincide with Apalutamine standard items appearance time.
11 prepare compound M1-1 of embodiment (the third formyl chloride of 2- methyl-2-amino hydrochloride)
Reaction route is as follows:
Specific step is as follows:
Phosphorus pentachloride (6.4g) is added into reaction vessel, acetonitrile 30ml is added, 2- methyl is added after 2h is stirred under room temperature
After alanine SM1-1 (3.2g) feeds, after 4h is stirred at room temperature, a large amount of white solids are precipitated.Reaction solution is filtered, filter cake is used
A small amount of acetonitrile is washed, and 2- methyl-2-amino the third formyl chloride hydrochloride (M1-1) 3.2g, yield 65.2% are dried under reduced pressure to obtain.
Embodiment 12 prepares M2-1 using compound M1-1
Reaction route is as follows:
Specific step is as follows:
Compound M1-1 (6.00g) prepared by embodiment 10, -5 benzene of 3- trifluoromethyl -4- cyano are added into reaction vessel
Amine SM2-1 (6.00g) and acetonitrile 20ml reaction system stir 8h at room temperature and phosphorus are added after HPLC monitors raw material conversion completely
Sour potassium (20.00g) adjusts reaction solution PH, and reaction system pours into 300ml ice water system, has solid to be dispersed to precipitate, keep stirring
It after mixing 1h, filters, washing, filter cake dries to obtain compound M2-1 7.95g yield 91.0%HPLC purity 97.88%.
LCMS:[M+1]=272.1
Embodiment 13 prepares M3-1 using compound M2-1
Reaction route is as follows:
Compound M2-1 (8.00g) and DMAP (3.6g) and DMAC 16ml are added into reaction vessel.Add in batches at room temperature
Reaction system reacts 1h at 70 DEG C after entering thio-carbonyldiimidazole (10.5g) charging, and HPLC monitors reaction process raw material
After conversion completely, reaction solution is cooled to room temperature, and reaction system is slowly added in ice water, filters, and washing, filter cake ethyl alcohol recrystallization obtains
Compound M3-1 6.74g, yield 73.0%, HPLC:99.2%
LCMS:[M+1]=314.4
Embodiment 14 prepares Enzalutamide using compound M3-1
13 gained intermediate M3-1 (9.39g, 30.00mmol) of example, N- methyl -4- are added into 100ml there-necked flask
The bromo- fluoro- benzamide of 2- (7.03g, 30.3mmol), potassium carbonate (10.36,75.0mmol) and DMF (80ml), are stirred at room temperature
Uniformly, nitrogen displacement be added afterwards three times cuprous iodide (0.57,3.0mmol) and ligand 2- acetyl cyclohexanone (0.42,
8h 3.0mmol) is reacted under the conditions of 120 DEG C, after HPLC monitors fully reacting, water 260ml, ethyl acetate 50ml*3 is added to extract,
Organic phase is washed again after saturated common salt is washed, and after anhydrous sodium sulfate dry filter, is spin-dried for solvent and is obtained grease, the grease
Add isopropanol 27ml to be beaten 2h crystallization under the conditions of 0~5 DEG C, filters to obtain filter cake, the mixing of filter cake ethyl acetate and n-hexane
Solvent (10V, ethyl acetate: normal heptane=1:5) recrystallizes to obtain off-white powder 10.58g, yield 76.1%, HPLC:
98.8%
LCMS:[M+1]=465.4
HPLC appearance time coincide with Enzalutamide standard items appearance time.
Claims (14)
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).
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