WO2022161469A1 - Intermediate for thiohydantoin drug, and preparation method therefor and use thereof - Google Patents
Intermediate for thiohydantoin drug, and preparation method therefor and use thereof Download PDFInfo
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- WO2022161469A1 WO2022161469A1 PCT/CN2022/074672 CN2022074672W WO2022161469A1 WO 2022161469 A1 WO2022161469 A1 WO 2022161469A1 CN 2022074672 W CN2022074672 W CN 2022074672W WO 2022161469 A1 WO2022161469 A1 WO 2022161469A1
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- WIPO (PCT)
- Prior art keywords
- compound
- formula
- preparation
- reaction
- pharmaceutically acceptable
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- 238000002360 preparation method Methods 0.000 title claims abstract description 59
- UGWULZWUXSCWPX-UHFFFAOYSA-N 2-sulfanylideneimidazolidin-4-one Chemical compound O=C1CNC(=S)N1 UGWULZWUXSCWPX-UHFFFAOYSA-N 0.000 title abstract description 21
- 239000003814 drug Substances 0.000 title abstract description 13
- 229940079593 drug Drugs 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 200
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims description 49
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 43
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical group 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 229960004926 chlorobutanol Drugs 0.000 claims description 26
- -1 C1 - C3alkoxy Chemical group 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
- 238000006467 substitution reaction Methods 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 238000005886 esterification reaction Methods 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 150000002431 hydrogen Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 239000012535 impurity Substances 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 238000004458 analytical method Methods 0.000 claims description 5
- 230000032050 esterification Effects 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000013558 reference substance Substances 0.000 claims description 2
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- 238000000034 method Methods 0.000 description 67
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
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- 239000000243 solution Substances 0.000 description 10
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- 238000001514 detection method Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
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- 239000000010 aprotic solvent Substances 0.000 description 6
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- 239000000543 intermediate Substances 0.000 description 6
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- 239000002994 raw material Substances 0.000 description 6
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- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
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- 150000001340 alkali metals Chemical class 0.000 description 4
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 4
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
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- 229940123407 Androgen receptor antagonist Drugs 0.000 description 3
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- HJBWBFZLDZWPHF-UHFFFAOYSA-N apalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C2(CCC2)C(=O)N(C=2C=C(C(C#N)=NC=2)C(F)(F)F)C1=S HJBWBFZLDZWPHF-UHFFFAOYSA-N 0.000 description 3
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- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
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- 238000001308 synthesis method Methods 0.000 description 3
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the invention belongs to the technical field of pharmaceutical synthesis, and relates to a thiohydantoin pharmaceutical intermediate and a preparation method and application thereof.
- Thiohydantoin compounds can be used to prepare androgen receptor antagonists, and a variety of androgen receptor antagonist drugs have been reported, such as Enzalutamide, Apalutamide and Proxalutamide.
- WO2006124118A1, WO2011106570A1 and CN103910679A disclose the synthesis method of enzalutamide;
- WO2007126765A2, US20110003839A1 disclose the synthesis method of apalutamide;
- US9216957B2 discloses the synthesis method of prokalutamide.
- enzalutamide, apalutamide, and proclutamide all contain thiohydantoin structural fragments, due to the large differences in other structural fragments, there are significant differences between the above methods, and none of them are versatile. Very ideal.
- TMSCN trimethylsilane cyanide
- the purpose of this invention is to provide a kind of intermediate for thiohydantoin medicine, and be used for preparing thiohydantoin medicine (especially for preparing proclutamide), solve the problem of thiohydantoin in the prior art
- the raw materials are toxic, the reaction yield is low, and the defects are not suitable for production scale-up.
- the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;
- R is selected from C 1 -C 6 alkyl.
- R is selected from C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, preferably methyl .
- the present invention provides a preparation method (method A) of a compound of formula (I), which comprises: esterification of a compound of formula (II) or a pharmaceutically acceptable salt thereof with ROH , to obtain the compound of formula (I);
- R is as defined in formula (I).
- the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, preferably methanol.
- the esterification reaction is carried out in the presence of an acid; further, the acid is sulfuric acid, hydrochloric acid, phosphoric acid or thionyl chloride, preferably thionyl chloride.
- the compound of formula (II) or a pharmaceutically acceptable salt thereof is esterified with methanol in the presence of thionyl chloride; further, calculated on the basis of the prototype compound, the chlorine
- the molar ratio of sulfoxide to the compound of formula (II) is 1.5-5.0:1, eg 2.0:1, 2.2:1, 2.5:1 or 3.0:1, preferably 3.0:1.
- the method A further comprises: reacting the compound of formula (III) or a pharmaceutically acceptable salt thereof with chlorobutanol or a hydrate thereof to obtain the compound of formula (II).
- hydrate of trichlorobutanol is trichlorobutanol hemihydrate.
- the molar ratio of the compound of formula (III) to the trichlorobutanol is 1:1.1-2.0, such as 1:1.4, 1:1.5 or 1:1.6, preferably 1:1.5 .
- the reaction is carried out in the presence of a solvent and a base, and after the reaction is completed, an acid is used for post-treatment.
- the solvent is an aprotic solvent or a mixture of any one or more of the protic solvents, wherein: the aprotic solvent includes a chain or cyclic C 1- C 6 aliphatic ketone (for example, acetone, butanone), chain or cyclic C 1 -C 6 aliphatic ethers (such as tetrahydrofuran, dimethyl ether), etc., the protic solvent includes chain or cyclic C 1 -C 6 aliphatic family of alcohols (eg methanol, ethanol, isopropanol, tert-butanol), preferably the solvent is one or a combination of acetone, tetrahydrofuran, tert-butanol.
- the aprotic solvent includes a chain or cyclic C 1- C 6 aliphatic ketone ( For example, acetone, butanone), chain or cyclic C 1 -C 6 aliphatic ethers (such as tetrahydrofuran
- the alkali is an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide; preferably, calculated with the prototype compound, the mol ratio of the alkali to the compound of the formula (III) is 2-10: 1, eg 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1, preferably 5:1.
- the acid is an inorganic acid or an organic acid, preferably an inorganic acid, such as hydrochloric acid, phosphoric acid or sulfuric acid.
- the compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with trichloro-tert-butanol hemihydrate, and the reaction is carried out in a mixture of acetone/tetrahydrofuran mixed solvent and sodium hydroxide.
- the present invention also provides a method for preparing a compound of formula (II), which comprises: reacting a compound of formula (III) or a pharmaceutically acceptable salt thereof with chlorobutanol or a hydrate thereof to obtain formula (II) Compounds.
- hydrate of trichlorobutanol is trichlorobutanol hemihydrate.
- the molar ratio of the compound of formula (III) to the trichlorobutanol is 1:1.1-2.0, such as 1:1.4, 1:1.5 or 1:1.6, preferably 1:1.5 .
- the reaction is carried out in the presence of a solvent and a base, and after the reaction is completed, an acid is used for post-treatment.
- the solvent is an aprotic solvent or a mixture of any one or more of the protic solvents, wherein: the aprotic solvent includes a chain or cyclic C 1- C 6 aliphatic ketone (for example, acetone, butanone), chain or cyclic C 1 -C 6 aliphatic ethers (such as tetrahydrofuran, dimethyl ether), etc., the protic solvent includes chain or cyclic C 1 -C 6 aliphatic family of alcohols (eg methanol, ethanol, isopropanol, tert-butanol), preferably the solvent is one or a combination of acetone, tetrahydrofuran, tert-butanol.
- the aprotic solvent includes a chain or cyclic C 1- C 6 aliphatic ketone ( For example, acetone, butanone), chain or cyclic C 1 -C 6 aliphatic ethers (such as tetrahydrofuran
- the alkali is an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide; preferably, calculated with the prototype compound, the mol ratio of the alkali to the compound of the formula (III) is 2-10: 1, eg 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1, preferably 5:1.
- the acid is an inorganic acid or an organic acid, preferably an inorganic acid, such as hydrochloric acid, phosphoric acid or sulfuric acid.
- the compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with trichlorobutanol hemihydrate in the presence of acetone/tetrahydrofuran mixed solvent and sodium hydroxide After the reaction is completed, hydrochloric acid is used for post-treatment; further, based on the prototype compound, the molar ratio of the compound of formula (III) to the trichlorobutanol hemihydrate is 1:1.1-2.0, for example 1:1.4, 1:1.5 or 1:1.6; the molar ratio of the sodium hydroxide to the compound of formula (III) is 2-10:1, such as 3:1, 4:1, 5:1, 6: 1, 7:1 or 8:1.
- the present invention provides a preparation method (method B) of a compound of formula (I), which comprises: a compound of formula (III) or a pharmaceutically acceptable salt thereof and a compound of formula (IV) Carry out the substitution reaction to obtain the compound of formula (I);
- X is Cl or Br, preferably Br; R is methyl or isopropyl, preferably methyl.
- the substitution reaction is carried out in the presence of a base; further, the base is an alkali metal alcoholate or a nitrogen-containing organic base, wherein: the alkali metal alcoholate includes sodium methoxide, Sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; the nitrogen-containing organic bases include N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), etc.; preferably nitrogen-containing organic bases Bases such as N,N-diisopropylethylamine.
- DIPEA N,N-diisopropylethylamine
- DMAP 4-dimethylaminopyridine
- the compound of formula (III) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with the compound of formula (IV), X is Br, R is methyl, and the substitution reaction is in N, carried out in the presence of N-diisopropylethylamine.
- the present invention provides a preparation method (method C) of a compound of formula (I), comprising: a compound of formula (III) or a pharmaceutically acceptable salt thereof and a compound of formula (IV-OH) ) compound is subjected to substitution reaction to obtain the compound of formula (II) or a pharmaceutically acceptable salt thereof, and then esterification is carried out with ROH to obtain the compound of formula (I);
- X is Cl or Br, preferably Br; R is methyl or isopropyl, preferably methyl.
- the substitution reaction is carried out in the presence of a base; further, the base is an alkali metal alcoholate or a nitrogen-containing organic base, wherein: the alkali metal alcoholate includes sodium methoxide, Sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; the nitrogen-containing organic bases include triethylamine, N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), etc.; Nitrogen-containing organic bases such as diisopropylethylamine or triethylamine are preferred.
- the esterification reaction is carried out in the presence of an acid; further, the acid is sulfuric acid, hydrochloric acid, phosphoric acid or thionyl chloride, preferably thionyl chloride.
- a compound of formula (III) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with a compound of formula (IV-OH), X is Br, and R is methyl, and the substitution reaction is In the presence of N,N-diisopropylethylamine and/or triethylamine, the compound of formula (II) or a pharmaceutically acceptable salt thereof is obtained, which is then subjected to an esterification reaction with ROH, and the esterification reaction is performed in In the presence of thionyl chloride, the compound of formula (I) is obtained.
- the present invention provides a preparation method of a compound of formula (VI), which comprises: subjecting a compound of formula (I) or a pharmaceutically acceptable salt thereof to a ring closure reaction with a compound of formula (V) , to obtain the compound of formula (VI);
- Y is selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano
- Z is selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy radical, C1 - C4 alkyl optionally substituted with one or more halogens and C1 - C4 alkoxy optionally substituted with one or more halogens
- R is as defined in formula (I) .
- Y is H or F; Z is CF 3 or CH 3 O; R is as defined in formula (I).
- Y is H or F, preferably F;
- Z is CF 3 or CH 3 O, preferably CF 3 ;
- R is methyl or isopropyl, preferably methyl.
- the molar ratio of the compound of formula (I) to the compound of formula (V) is 1.0:1.0-5.0, such as 1.0:2.0, 1.0:2.2, 1.0:2.5 or 1.0: 3.0, preferably 1.0:2.2.
- the ring-closing reaction is carried out in the presence of a polar organic solvent; further, the polar organic solvent is selected from acetonitrile (ACN), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), tetrahydrofuran (THF) and 2-methyltetrahydrofuran (2-MTHF), preferably N,N-dimethylformamide.
- ACN acetonitrile
- DMF N,N-dimethylformamide
- NMP N-methylpyrrolidone
- DMSO dimethylsulfoxide
- THF tetrahydrofuran
- 2-MTHF 2-methyltetrahydrofuran
- the compound of formula (VI) is purified by using an acid to form a salt; further, the acid forming the acid addition salt is an inorganic acid or an organic acid , wherein: the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; the organic acid is formic acid, acetic acid, oxalic acid, propionic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, succinic acid acid, tartaric acid, 1,5-naphthalenedisulfonic acid, citric acid or nicotinic acid, preferably hydrochloric acid and/or 1,5-naphthalenedisulfonic acid.
- the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid
- the organic acid is formic acid, acetic acid, oxalic acid, propionic acid, citric acid, methanesulfonic acid, p-
- the compound of formula (I) is prepared by the method A.
- the present invention provides the use of a compound of formula (I) in the preparation of a compound of formula (VI);
- Y is selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano
- Z is selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy radicals, C1 - C4 alkyl optionally substituted with one or more halogens, and C1 - C4 alkoxy optionally substituted with one or more halogens.
- Y is H or F and Z is CF3 or CH3O .
- Y is F and Z is CF3 .
- the present invention provides the use of the compound of formula (I) as an impurity reference and/or standard for analysis of the compound of formula (VI);
- Y is selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano
- Z is selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy radicals, C1 - C4 alkyl optionally substituted with one or more halogens, and C1 - C4 alkoxy optionally substituted with one or more halogens.
- Y is H or F and Z is CF3 or CH3O .
- Y is F and Z is CF3 .
- the present invention has the following beneficial effects:
- the present invention provides a thiohydantoin pharmaceutical intermediate, namely the compound of formula (I), which can be used to prepare the thiohydantoin medicine shown in formula (VI), which solves the problem of existing production.
- a thiohydantoin pharmaceutical intermediate namely the compound of formula (I)
- the present invention not only avoids dangerous reagents (such as TMSCN, metal Salt, etc.) use, and the ring-closing reaction yield is as high as more than 80%, which has been significantly improved;
- the present invention adopts the compound of formula (III) or its pharmaceutically acceptable salt and chlorobutanol or its hydrate for the first time to prepare the compound of formula (II), the yield of this method is high, and it is the compound of formula (I).
- the present invention adopts the compound of formula (I) and 4-cyano-2-fluoro-3-(trifluoromethyl) phenyl isothiocyanate for the first time to directly close the ring to generate Pro Vietnamese, which belongs to Pro Vietnamese
- the key impurity quality control point of the present invention when the method of the present invention is used to prepare pluclamide, the compound of formula (I) can also be used as a key organic impurity for quality control analysis.
- Fig. 1 is a reaction formula of a compound represented by formula (V) and a compound represented by formula (I) through ring closure reaction to generate a thiohydantoin drug represented by formula (VI).
- the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;
- R may be selected from C 1 -C 6 alkyl.
- R in the compound of formula (I) may be selected from C1 - C4 alkyl, preferably methyl.
- the present invention provides a preparation method (method A) of the compound of formula (I).
- Method A comprises: the compound of formula (II) or a pharmaceutically acceptable salt thereof can be esterified with ROH to obtain the compound of formula (I);
- R can be selected from C 1 -C 6 alkyl, preferably methyl.
- the ROH in method A may be methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, preferably methanol.
- the esterification reaction in method A can be carried out in the presence of an acid; further, the acid can be sulfuric acid, hydrochloric acid, phosphoric acid or thionyl chloride, preferably thionyl chloride.
- the compound of formula (II) in Method A or a pharmaceutically acceptable salt thereof can be esterified with methanol in the presence of thionyl chloride; further, calculated on the basis of the prototype compound , the molar ratio of thionyl chloride to the compound of formula (II) can be 1.5-5.0:1, preferably 3.0:1.
- method A further comprises: the compound of formula (III) or a pharmaceutically acceptable salt thereof can be reacted with chlorobutanol or its hydrate (Jocic reaction) to obtain formula ( II) Compounds.
- the hydrate of chlorobutanol in Method A may be chlorobutanol hemihydrate.
- the molar ratio of the compound of formula (III) to chlorobutanol in Method A may be 1:1.1-2.0, preferably 1:1.5, based on the prototype compound.
- the reaction (Jocic reaction) in method A can be carried out in the presence of a solvent and a base, and after the reaction is completed, an acid can be used for post-treatment;
- the solvent can be an aprotic solvent Or a mixture of any one or more of protic solvents, wherein: aprotic solvents can include chain or cyclic C 1 -C 6 aliphatic ketones (such as acetone, butanone), chain or cyclic C 1 -C 6 aliphatic ethers (such as tetrahydrofuran, dimethyl ether), etc.
- protic solvents can include chain or cyclic C 1 -C 6 aliphatic alcohols (such as methanol, ethanol, isopropanol, tertiary Butanol), preferably one of acetone, tetrahydrofuran, tert-butanol or a combination thereof;
- the alkali can be an alkali metal hydroxide,
- reaction (Jocic reaction) of the compound of formula (III) or a pharmaceutically acceptable salt thereof in method A with chlorobutanol hemihydrate (Jocic reaction) can be carried out in an acetone/tetrahydrofuran mixed solvent and in the presence of sodium hydroxide, after the reaction, hydrochloric acid can be used for post-treatment; further, calculated with the prototype compound, the mol ratio of the compound of formula (III) to trichlorobutanol hemihydrate is 1:1.1- 2.0; the molar ratio of base to compound of formula (III) is 2-10:1.
- the present invention provides a preparation method (method B) of the compound of formula (I).
- Method B comprises: the compound of formula (III) or a pharmaceutically acceptable salt thereof can undergo a substitution reaction with the compound of formula (IV) to obtain the compound of formula (I);
- X in method B can be Cl or Br, preferably Br; R can be methyl or isopropyl, preferably methyl.
- the substitution reaction in method B can be carried out in the presence of a base; further, the base can be an alkali metal alkoxide or a nitrogen-containing organic base, wherein: the alkali metal alkoxide can include sodium methoxide , sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; nitrogen-containing organic bases can include triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, etc.; preferably nitrogen-containing organic bases ( For example N,N-diisopropylethylamine or triethylamine).
- the alkali metal alkoxide can include sodium methoxide , sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.
- nitrogen-containing organic bases can include triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyr
- the compound of formula (III) or a pharmaceutically acceptable salt thereof in method B can be subjected to a substitution reaction with a compound of formula (IV), X can be Br, R can be methyl,
- the substitution reaction can be carried out in the presence of N,N-diisopropylethylamine.
- the present invention provides a method for preparing the compound of formula (I) (method C).
- Method C comprises: the compound of formula (III) or a pharmaceutically acceptable salt thereof can be subjected to a substitution reaction with a compound of formula (IV-OH) to obtain the compound of formula (II) or a pharmaceutically acceptable salt thereof, and then esterified with ROH. chemical reaction to obtain the compound of formula (I);
- X in method C can be Cl or Br, preferably Br; R can be methyl or isopropyl, preferably methyl.
- the substitution reaction in method C can be carried out in the presence of a base; further, the base can be an alkali metal alkoxide or a nitrogen-containing organic base, wherein: the alkali metal alkoxide can include sodium methoxide , sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; nitrogen-containing organic bases can include triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, etc.; preferably nitrogen-containing organic bases ( For example, triethylamine or diisopropylethylamine); the esterification reaction in method C can be carried out in the presence of an acid; further, the acid is sulfuric acid, hydrochloric acid, phosphoric acid or thionyl chloride, preferably thionyl chloride.
- the compound of formula (III) or a pharmaceutically acceptable salt thereof in method C can be subjected to a substitution reaction with a compound of formula (IV-OH), X can be Br, and R can be methyl base, the substitution reaction can be carried out in the presence of N,N-diisopropylethylamine to obtain the compound of formula (II) or a pharmaceutically acceptable salt thereof, which is then esterified with ROH, and the esterification reaction can be carried out in the presence of chlorine In the presence of sulfoxides, compounds of formula (I) are obtained.
- the present invention provides a preparation method of a compound of formula (VI) (thiohydantoin drug).
- the preparation method comprises: the compound of formula (I) or a pharmaceutically acceptable salt thereof can be subjected to a ring closure reaction with the compound of formula (V) to obtain the compound of formula (VI);
- Y can be selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano
- Z can be selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C1 - C4 alkyl optionally substituted with one or more halogens and C1 - C4 alkoxy optionally substituted with one or more halogens
- R may be selected from C1- C6 alkyl, preferably methyl.
- Y in the preparation method can be H or F; Z can be CF 3 or CH 3 O; R can be selected from C 1 -C 6 alkyl, preferably methyl.
- Y in the preparation method can be H or F, preferably F;
- Z can be CF 3 or CH 3 O, preferably CF 3 ;
- R can be methyl or isopropyl, preferably methyl.
- the molar ratio of the compound of formula (I) to the compound of formula (V) in the preparation method may be 1.0:1.0-5.0, preferably 1.0:2.2.
- the ring-closure reaction in the preparation method can be carried out in the presence of a polar organic solvent; further, the polar organic solvent can be selected from acetonitrile, N,N-dimethylformamide , N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran and 2-methyltetrahydrofuran, preferably N,N-dimethylformamide.
- a polar organic solvent can be selected from acetonitrile, N,N-dimethylformamide , N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran and 2-methyltetrahydrofuran, preferably N,N-dimethylformamide.
- the preparation method can purify the compound of formula (VI) by forming an acid into a salt; further, the acid forming an acid addition salt can be an inorganic acid or an organic acid, wherein: inorganic acid
- the acid can be hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid;
- the organic acid can be formic acid, acetic acid, oxalic acid, propionic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, succinic acid, tartaric acid, 1, 5-Naphthalenedisulfonic acid, citric acid or nicotinic acid, preferably hydrochloric acid and/or 1,5-naphthalenedisulfonic acid.
- the compound of formula (I) in the preparation method can be prepared by method A, that is, the preparation method of the compound of formula (VI) can include the following steps:
- the preparation method may further comprise the following steps: the compound of formula (II) or a pharmaceutically acceptable salt thereof can be esterified with ROH to obtain the compound of formula (I);
- the preparation method may further comprise the following steps: the compound of formula (I) or a pharmaceutically acceptable salt thereof can be subjected to a ring closure reaction with the compound of formula (V) to obtain the compound of formula (VI);
- Y may be selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano, preferably H or F, more preferably F;
- Z may be selected from halogen, cyano, C1 - C4 alkyl, C1 - C4 alkoxy, C1 - C4 alkyl optionally substituted with one or more halogens, and optionally substituted with a or multiple halogen-substituted C 1 -C 4 alkoxy groups, preferably CF 3 or CH 3 O, more preferably CF 3 ;
- R may be selected from C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl, more preferably methyl.
- the present invention provides the use of a compound of formula (I) in the preparation of a compound of formula (VI);
- Y can be selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano
- Z can be selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C1 - C4 alkyl optionally substituted with one or more halogens, and C1 - C4 alkoxy optionally substituted with one or more halogens.
- Y in this use can be H or F and Z can be CF3 or CH3O .
- Y in this use may be F and Z may be CF3 .
- the present invention provides the use of the compound of formula (I) as an impurity reference substance and/or standard substance for analysis of the compound of formula (VI);
- Y can be selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano
- Z can be selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C1 - C4 alkyl optionally substituted with one or more halogens, and C1 - C4 alkoxy optionally substituted with one or more halogens.
- Y in this use can be H or F and Z can be CF3 or CH3O .
- Y in this use may be F and Z may be CF3 .
- HPLC conditions used for content detection or purity analysis in the examples are as follows:
- Mobile phase binary mobile phase system
- mobile phase A is 0.02vol% trifluoroacetic acid aqueous solution
- mobile phase B is acetonitrile
- a pharmaceutically acceptable salt of a compound of formula (III) such as 1,5-naphthalene disulfonate can be used as starting material, pH is adjusted by adding a basic substance such as sodium carbonate, and two phases can be utilized
- the compound of formula (II) is prepared by extracting the system (eg water/dichloromethane) to obtain the compound of formula (III) in free form.
- R is methyl
- the compound of formula (II) (200 mg, 0.691 mmol) was mixed with 2 ml of isopropanol, and thionyl chloride (about 3.0 eq) was added dropwise at 5-10 °C. After dropping, the temperature was raised to 35 °C and the reaction was performed overnight; -MC detection, according to the peak area percentage calculation, the content of the target product is only 10.8%; add thionyl chloride (about 6eq), heat up to 70-80 ° C and react overnight; LC-MC detection, according to the peak area percentage calculation , the content of the target product is 74.7%.
- the compound of formula (III) (100 mg, 0.492 mmol), 2 ml of methanol and trichlorobutanol hemihydrate (138 mg, about 1.5 eq) were mixed, sodium hydroxide (102 mg, about 5.2 eq) was added at room temperature and reacted for 4 h, then the temperature was increased. Incubate the reaction at 50-60° C. (eg, 55° C.) for more than 12 h (eg, overnight). According to HPLC detection, calculated according to the peak area percentage, the target product is 25%, the compound of formula (III) is 66%, the intermediate transition state is the compound of formula (II) 7%, and the balance is unknown impurities.
- the compound of formula (I)-1 (100 mg, 0.302 mmol) and the compound of formula (V)-1 (163 mg, 2.2 eq) were taken and added to 0.5 ml of N,N-dimethylformamide, stirred at room temperature, and reacted overnight; After the reaction, 10 ml of methyl tert-butyl ether and 5 ml of water were added to extract the layers, the aqueous layer was extracted with methyl tert-butyl ether (10 ml*2), the organic layers were combined, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. , suction filtration, the filtrate was concentrated and then separated by preparative thin layer chromatography to obtain 130 mg of the target product, the yield was 83.2%, and the HPLC purity was 90.3%.
- the compound of formula (I)-2 (3.63 g, 12 mmol) and the compound of formula (V)-1 (6.5 g, 26.4 mmol) were added to 100 ml of N,N-dimethylformamide, stirred at room temperature, and reacted overnight; After the reaction, 80 ml of methyl tert-butyl ether and 100 ml of deionized water were added, and the mixture was stirred at room temperature for extraction. The aqueous layer was extracted with methyl tert-butyl ether (60 ml*2), the organic layers were combined and washed with saturated aqueous sodium chloride solution.
- the target product of the above-mentioned production method and an acid may be formed into an acid addition salt in a solvent (for example, ethanol).
- a solvent for example, ethanol
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Abstract
The present invention relates to an intermediate for a thiohydantoin drug, and a preparation method therefor and the use thereof. Specifically disclosed are a compound as represented by a formula (I) and multiple preparation methods therefor, and the thiohydantoin drug as represented by a formula (VI) and prepared by means of performing a ring closure reaction on the compound as represented by the formula (I) and a compound as represented by a formula (V) for the first time.
Description
相关申请的引用Citations to Related Applications
本发明要求2021年1月29日在中国提交的，名称为“一种硫代乙内酰脲药物用中间体及其制备方法与用途”、申请号为202110128887.2的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。The present invention claims the priority of the invention patent application with the application number of 202110128887.2, entitled "A thiohydantoin pharmaceutical intermediate and its preparation method and use", which was submitted in China on January 29, 2021. The entire contents of this patent application are incorporated herein by reference.
本发明属于药物合成技术领域，涉及一种硫代乙内酰脲药物用中间体及其制备方法与用途。The invention belongs to the technical field of pharmaceutical synthesis, and relates to a thiohydantoin pharmaceutical intermediate and a preparation method and application thereof.
硫代乙内酰脲化合物可用于制备雄激素受体拮抗剂，目前已经报道了多种雄激素受体拮抗剂类药物，如恩杂鲁胺(Enzalutamide)、阿帕他胺(Apalutamide)和普克鲁胺(Proxalutamide)。WO2006124118A1、WO2011106570A1和CN103910679A中公开了恩杂鲁胺的合成方法；WO2007126765A2、US20110003839A1中公开了阿帕他胺的合成方法；US9216957B2中公开了普克鲁胺的合成方法。虽然恩杂鲁胺、阿帕他胺和普克鲁胺中均含有硫代乙内酰脲结构片段，但是由于其它结构片段差异较大，导致上述各方法之间存在显著差异，通用性均不甚理想。Thiohydantoin compounds can be used to prepare androgen receptor antagonists, and a variety of androgen receptor antagonist drugs have been reported, such as Enzalutamide, Apalutamide and Proxalutamide. WO2006124118A1, WO2011106570A1 and CN103910679A disclose the synthesis method of enzalutamide; WO2007126765A2, US20110003839A1 disclose the synthesis method of apalutamide; US9216957B2 discloses the synthesis method of prokalutamide. Although enzalutamide, apalutamide, and proclutamide all contain thiohydantoin structural fragments, due to the large differences in other structural fragments, there are significant differences between the above methods, and none of them are versatile. Very ideal.
US9216957B2中公开的普克鲁胺的制备工艺如下所示：The preparation process of the prokluamide disclosed in US9216957B2 is as follows:
上述路线中的反应步骤较多，而且包括许多在生产规模上进行可能是危险的和/或在最终原料药中产生不可接受的副产物水平的反应步骤，例如TMSCN(三甲基氰硅烷)是一种极毒、高度易燃的化学物质，给生产和安全带来了极大挑战和隐 患；另外，在构建硫代乙内酰脲片段的关环反应步骤中，15.7％的收率显然无法满足商业化生产的需求。虽然，M.E.Jung等人(参见M.E.Jung,S.Ouk,D.Yoo,et al.,Structure-Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer(CRPC)[J],J.Med.Chem.,2010,53(7):2779-2796)公开了在制备恩杂鲁胺(即文章中的化合物92)时，同样可以采用上述方法进行关环反应，并且收率显著高于US9216957B2，但需要采用微波辅助反应，也反映出虽具有相同官能团(或结构片段)但具体结构不同的化合物在制备时针对同一方法的通用性较差，需要针对某一类特定化合物结构开发针对性的制备方法。There are many reaction steps in the above route, and includes many reaction steps that may be dangerous and/or produce unacceptable levels of by-products in the final drug substance, for example TMSCN (trimethylsilane cyanide) is An extremely toxic and highly flammable chemical substance, which brings great challenges and hidden dangers to production and safety; in addition, in the ring-closing reaction step of constructing the thiohydantoin fragment, the yield of 15.7% obviously cannot be obtained. meet the needs of commercial production. Although, M.E.Jung et al. (see M.E.Jung, S.Ouk, D.Yoo, et al., Structure-Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC) [J], J.Med.Chem ., 2010,53(7):2779-2796) discloses when preparing enzalutamide (that is, compound 92 in the article), the above-mentioned method can also be used to carry out ring-closure reaction, and the yield is significantly higher than US9216957B2, but It is necessary to use microwave-assisted reaction, which also reflects that although compounds with the same functional group (or structural fragment) but different specific structures have poor generality for the same method in preparation, it is necessary to develop a targeted preparation method for a specific type of compound structure. .
发明内容SUMMARY OF THE INVENTION
发明要解决的问题Invention to solve problem
本发明的目的是提供了一种硫代乙内酰脲药物用中间体，并用来制备硫代乙内酰脲药物(尤其是用来制备普克鲁胺)，解决现有技术中硫代乙内酰脲药物制备过程中原料毒性大、反应收率低、不适合生产放大的缺陷。The purpose of this invention is to provide a kind of intermediate for thiohydantoin medicine, and be used for preparing thiohydantoin medicine (especially for preparing proclutamide), solve the problem of thiohydantoin in the prior art In the preparation process of lactin drugs, the raw materials are toxic, the reaction yield is low, and the defects are not suitable for production scale-up.
用于解决问题的方案solution to the problem
根据本发明的第一个方面，本发明提供了一种式(I)化合物或其药学上可接受的盐；According to a first aspect of the present invention, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;
其中：R选自C
1-C
6烷基。
wherein: R is selected from C 1 -C 6 alkyl.
优选地，在所述式(I)化合物中，R选自C
1-C
4烷基，例如甲基、乙基、正丙基、异丙基、正丁基或异丁基，优选甲基。
Preferably, in said compound of formula (I), R is selected from C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, preferably methyl .
根据本发明的第二个方面，本发明提供了一种式(I)化合物的制备方法(方法A)，其包括：式(II)化合物或其药学上可接受的盐与ROH进行酯化反应，得到式(I)化合物；According to the second aspect of the present invention, the present invention provides a preparation method (method A) of a compound of formula (I), which comprises: esterification of a compound of formula (II) or a pharmaceutically acceptable salt thereof with ROH , to obtain the compound of formula (I);
其中：R如式(I)中所定义。wherein: R is as defined in formula (I).
优选地，在所述方法A中，所述ROH为甲醇、乙醇、正丙醇、异丙醇、正丁醇或异丁醇，优选甲醇。Preferably, in the method A, the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, preferably methanol.
优选地，在所述方法A中，所述酯化反应在酸的存在下进行；进一步地，所述酸为硫酸、盐酸、磷酸或氯化亚砜，优选氯化亚砜。Preferably, in the method A, the esterification reaction is carried out in the presence of an acid; further, the acid is sulfuric acid, hydrochloric acid, phosphoric acid or thionyl chloride, preferably thionyl chloride.
更优选地，在所述方法A中，式(II)化合物或其药学上可接受的盐与甲醇在氯化亚砜的存在下进行酯化反应；进一步地，以原型化合物计算，所述氯化亚砜与所述式(II)化合物的摩尔比为1.5-5.0:1，例如2.0:1、2.2:1、2.5:1或3.0:1，优选3.0:1。More preferably, in the method A, the compound of formula (II) or a pharmaceutically acceptable salt thereof is esterified with methanol in the presence of thionyl chloride; further, calculated on the basis of the prototype compound, the chlorine The molar ratio of sulfoxide to the compound of formula (II) is 1.5-5.0:1, eg 2.0:1, 2.2:1, 2.5:1 or 3.0:1, preferably 3.0:1.
优选地，所述方法A还包括：式(III)化合物或其药学上可接受的盐与三氯叔丁醇或其水合物进行反应，得到式(II)化合物。Preferably, the method A further comprises: reacting the compound of formula (III) or a pharmaceutically acceptable salt thereof with chlorobutanol or a hydrate thereof to obtain the compound of formula (II).
进一步地，所述三氯叔丁醇的水合物为三氯叔丁醇半水合物。Further, the hydrate of trichlorobutanol is trichlorobutanol hemihydrate.
优选地，以原型化合物计算，所述式(III)化合物与所述三氯叔丁醇的摩尔比为1:1.1-2.0，例如1:1.4、1:1.5或1:1.6，优选1:1.5。Preferably, based on the prototype compound, the molar ratio of the compound of formula (III) to the trichlorobutanol is 1:1.1-2.0, such as 1:1.4, 1:1.5 or 1:1.6, preferably 1:1.5 .
优选地，所述反应在溶剂和碱的存在下进行，反应结束后，采用酸进行后处理。Preferably, the reaction is carried out in the presence of a solvent and a base, and after the reaction is completed, an acid is used for post-treatment.
进一步地，所述溶剂为非质子性溶剂或质子性溶剂中的任意一种或多种的混合，其中：所述非质子性溶剂包括链状或环状的C
1-C
6脂肪族酮(例如丙酮、丁酮)、链状或环状的C
1-C
6脂肪族醚(例如四氢呋喃、二甲基醚)等，所述质子性溶剂包括链状或环状的C
1-C
6脂肪族醇(例如甲醇、乙醇、异丙醇、叔丁醇)，优选所述溶剂为丙酮、四氢呋喃、叔丁醇中的一种或其组合。
Further, the solvent is an aprotic solvent or a mixture of any one or more of the protic solvents, wherein: the aprotic solvent includes a chain or cyclic C 1- C 6 aliphatic ketone ( For example, acetone, butanone), chain or cyclic C 1 -C 6 aliphatic ethers (such as tetrahydrofuran, dimethyl ether), etc., the protic solvent includes chain or cyclic C 1 -C 6 aliphatic family of alcohols (eg methanol, ethanol, isopropanol, tert-butanol), preferably the solvent is one or a combination of acetone, tetrahydrofuran, tert-butanol.
进一步地，所述碱为碱金属的氢氧化物，优选氢氧化钠或氢氧化钾；优选地，以原型化合物计算，所述碱与所述式(III)化合物的摩尔比为2-10:1，例如3:1、4:1、5:1、6:1、7:1或8:1，优选5:1。Further, the alkali is an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide; preferably, calculated with the prototype compound, the mol ratio of the alkali to the compound of the formula (III) is 2-10: 1, eg 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1, preferably 5:1.
进一步地，所述酸为无机酸或有机酸，优选无机酸，例如盐酸、磷酸或硫酸。Further, the acid is an inorganic acid or an organic acid, preferably an inorganic acid, such as hydrochloric acid, phosphoric acid or sulfuric acid.
更优选地，在所述方法A中，式(III)化合物或其药学上可接受的盐与三氯叔丁醇半水合物进行反应，所述反应在丙酮/四氢呋喃混合溶剂和氢氧化钠的存在下进行，反应结束后，采用盐酸进行后处理；进一步地，以原型化合物计算，所述式(III)化合物与所述三氯叔丁醇半水合物的摩尔比为1:1.1-2.0，例如1:1.4、1:1.5或1:1.6；所述氢氧化钠与所述式(III)化合物的摩尔比为2-10:1，例如3:1、4:1、5:1、6:1、7:1或8:1。More preferably, in the method A, the compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with trichloro-tert-butanol hemihydrate, and the reaction is carried out in a mixture of acetone/tetrahydrofuran mixed solvent and sodium hydroxide. Carry out in the presence of, after the reaction is finished, adopt hydrochloric acid for post-treatment; For example, 1:1.4, 1:1.5 or 1:1.6; the molar ratio of the sodium hydroxide to the compound of formula (III) is 2-10:1, such as 3:1, 4:1, 5:1, 6 :1, 7:1 or 8:1.
相应地，本发明还提供了一种式(II)化合物的制备方法，其包括：式(III)化合物或其药学上可接受的盐与三氯叔丁醇或其水合物进行反应，得到式(II)化合物。Correspondingly, the present invention also provides a method for preparing a compound of formula (II), which comprises: reacting a compound of formula (III) or a pharmaceutically acceptable salt thereof with chlorobutanol or a hydrate thereof to obtain formula (II) Compounds.
进一步地，所述三氯叔丁醇的水合物为三氯叔丁醇半水合物。Further, the hydrate of trichlorobutanol is trichlorobutanol hemihydrate.
优选地，以原型化合物计算，所述式(III)化合物与所述三氯叔丁醇的摩尔比为1:1.1-2.0，例如1:1.4、1:1.5或1:1.6，优选1:1.5。Preferably, based on the prototype compound, the molar ratio of the compound of formula (III) to the trichlorobutanol is 1:1.1-2.0, such as 1:1.4, 1:1.5 or 1:1.6, preferably 1:1.5 .
优选地，所述反应在溶剂和碱的存在下进行，反应结束后，采用酸进行后处理。Preferably, the reaction is carried out in the presence of a solvent and a base, and after the reaction is completed, an acid is used for post-treatment.
进一步地，所述溶剂为非质子性溶剂或质子性溶剂中的任意一种或多种的混合，其中：所述非质子性溶剂包括链状或环状的C
1-C
6脂肪族酮(例如丙酮、丁酮)、链状或环状的C
1-C
6脂肪族醚(例如四氢呋喃、二甲基醚)等，所述质子性溶剂包括链状或环状的C
1-C
6脂肪族醇(例如甲醇、乙醇、异丙醇、叔丁醇)，优选所述溶剂为丙酮、四氢呋喃、叔丁醇中的一种或其组合。
Further, the solvent is an aprotic solvent or a mixture of any one or more of the protic solvents, wherein: the aprotic solvent includes a chain or cyclic C 1- C 6 aliphatic ketone ( For example, acetone, butanone), chain or cyclic C 1 -C 6 aliphatic ethers (such as tetrahydrofuran, dimethyl ether), etc., the protic solvent includes chain or cyclic C 1 -C 6 aliphatic family of alcohols (eg methanol, ethanol, isopropanol, tert-butanol), preferably the solvent is one or a combination of acetone, tetrahydrofuran, tert-butanol.
进一步地，所述碱为碱金属的氢氧化物，优选氢氧化钠或氢氧化钾；优选地，以原型化合物计算，所述碱与所述式(III)化合物的摩尔比为2-10:1，例如3:1、4:1、5:1、6:1、7:1或8:1，优选5:1。Further, the alkali is an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide; preferably, calculated with the prototype compound, the mol ratio of the alkali to the compound of the formula (III) is 2-10: 1, eg 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1, preferably 5:1.
进一步地，所述酸为无机酸或有机酸，优选无机酸，例如盐酸、磷酸或硫酸。Further, the acid is an inorganic acid or an organic acid, preferably an inorganic acid, such as hydrochloric acid, phosphoric acid or sulfuric acid.
更优选地，在所述方法中，式(III)化合物或其药学上可接受的盐与三氯叔丁醇半水合物进行反应，所述反应在丙酮/四氢呋喃混合溶剂和氢氧化钠的存在下进行，反应结束后，采用盐酸进行后处理；进一步地，以原型化合物计算，所述式(III)化合物与所述三氯叔丁醇半水合物的摩尔比为1:1.1-2.0，例如1:1.4、1:1.5或1:1.6；所述氢氧化钠与所述式(III)化合物的摩尔比为2-10:1，例如3:1、4:1、5:1、6:1、7:1或8:1。More preferably, in the method, the compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with trichlorobutanol hemihydrate in the presence of acetone/tetrahydrofuran mixed solvent and sodium hydroxide After the reaction is completed, hydrochloric acid is used for post-treatment; further, based on the prototype compound, the molar ratio of the compound of formula (III) to the trichlorobutanol hemihydrate is 1:1.1-2.0, for example 1:1.4, 1:1.5 or 1:1.6; the molar ratio of the sodium hydroxide to the compound of formula (III) is 2-10:1, such as 3:1, 4:1, 5:1, 6: 1, 7:1 or 8:1.
根据本发明的第三个方面，本发明提供了一种式(I)化合物的制备方法(方法B)，其包括：式(III)化合物或其药学上可接受的盐与式(IV)化合物进行取代反应，得到式(I)化合物；According to the third aspect of the present invention, the present invention provides a preparation method (method B) of a compound of formula (I), which comprises: a compound of formula (III) or a pharmaceutically acceptable salt thereof and a compound of formula (IV) Carry out the substitution reaction to obtain the compound of formula (I);
其中：X为Cl、Br或I；R如式(I)中所定义。wherein: X is Cl, Br or I; R is as defined in formula (I).
优选地，在所述方法B中，X为Cl或Br，优选Br；R为甲基或异丙基，优选甲基。Preferably, in the method B, X is Cl or Br, preferably Br; R is methyl or isopropyl, preferably methyl.
优选地，在所述方法B中，所述取代反应在碱的存在下进行；进一步地，所述碱为碱金属醇化物或含氮有机碱，其中：所述碱金属醇化物包括甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾等；所述含氮有机碱包括N,N-二异丙基乙胺(DIPEA)、4-二甲氨基吡啶(DMAP)等；优选含氮有机碱，例如N,N-二异丙基乙胺。Preferably, in the method B, the substitution reaction is carried out in the presence of a base; further, the base is an alkali metal alcoholate or a nitrogen-containing organic base, wherein: the alkali metal alcoholate includes sodium methoxide, Sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; the nitrogen-containing organic bases include N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), etc.; preferably nitrogen-containing organic bases Bases such as N,N-diisopropylethylamine.
更优选地，在所述方法B中，式(III)化合物或其药学上可接受的盐与式(IV)化合物进行取代反应，X为Br，R为甲基，所述取代反应在N,N-二异丙基乙胺的 存在下进行。More preferably, in the method B, the compound of formula (III) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with the compound of formula (IV), X is Br, R is methyl, and the substitution reaction is in N, carried out in the presence of N-diisopropylethylamine.
根据本发明的第四个方面，本发明提供了一种式(I)化合物的制备方法(方法C)，其包括：式(III)化合物或其药学上可接受的盐与式(IV-OH)化合物进行取代反应，得到式(II)化合物或其药学上可接受的盐，再与ROH进行酯化反应，得到式(I)化合物；According to the fourth aspect of the present invention, the present invention provides a preparation method (method C) of a compound of formula (I), comprising: a compound of formula (III) or a pharmaceutically acceptable salt thereof and a compound of formula (IV-OH) ) compound is subjected to substitution reaction to obtain the compound of formula (II) or a pharmaceutically acceptable salt thereof, and then esterification is carried out with ROH to obtain the compound of formula (I);
其中：X为Cl、Br或I；R如式(I)中所定义。wherein: X is Cl, Br or I; R is as defined in formula (I).
优选地，在所述方法C中，X为Cl或Br，优选Br；R为甲基或异丙基，优选甲基。Preferably, in the method C, X is Cl or Br, preferably Br; R is methyl or isopropyl, preferably methyl.
优选地，在所述方法C中，所述取代反应在碱的存在下进行；进一步地，所述碱为碱金属醇化物或含氮有机碱，其中：所述碱金属醇化物包括甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾等；所述含氮有机碱包括三乙胺、N,N-二异丙基乙胺(DIPEA)、4-二甲氨基吡啶(DMAP)等；优选含氮有机碱，例如二异丙基乙胺或三乙胺。优选地，在所述方法C中，所述酯化反应在酸的存在下进行；进一步地，所述酸为硫酸、盐酸、磷酸或氯化亚砜，优选氯化亚砜。Preferably, in the method C, the substitution reaction is carried out in the presence of a base; further, the base is an alkali metal alcoholate or a nitrogen-containing organic base, wherein: the alkali metal alcoholate includes sodium methoxide, Sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; the nitrogen-containing organic bases include triethylamine, N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), etc.; Nitrogen-containing organic bases such as diisopropylethylamine or triethylamine are preferred. Preferably, in the method C, the esterification reaction is carried out in the presence of an acid; further, the acid is sulfuric acid, hydrochloric acid, phosphoric acid or thionyl chloride, preferably thionyl chloride.
更优选地，在所述方法C中，式(III)化合物或其药学上可接受的盐与式(IV-OH)化合物进行取代反应，X为Br，R为甲基，所述取代反应在N,N-二异丙基乙胺和/或三乙胺的存在下进行，得到式(II)化合物或其药学上可接受的盐，再与ROH进行酯化反应，所述酯化反应在氯化亚砜的存在下进行，得到式(I)化合物。More preferably, in the method C, a compound of formula (III) or a pharmaceutically acceptable salt thereof is subjected to a substitution reaction with a compound of formula (IV-OH), X is Br, and R is methyl, and the substitution reaction is In the presence of N,N-diisopropylethylamine and/or triethylamine, the compound of formula (II) or a pharmaceutically acceptable salt thereof is obtained, which is then subjected to an esterification reaction with ROH, and the esterification reaction is performed in In the presence of thionyl chloride, the compound of formula (I) is obtained.
根据本发明的第五个方面，本发明提供了一种式(VI)化合物的制备方法，其包括：式(I)化合物或其药学上可接受的盐与式(V)化合物进行关环反应，得到式(VI)化合物；According to the fifth aspect of the present invention, the present invention provides a preparation method of a compound of formula (VI), which comprises: subjecting a compound of formula (I) or a pharmaceutically acceptable salt thereof to a ring closure reaction with a compound of formula (V) , to obtain the compound of formula (VI);
其中：Y选自氢、卤素、C
1-C
3烷氧基、羟基、CF
3O和氰基；Z选自卤素、氰基、C
1-C
4烷基、C
1-C
4烷氧基、任选地被一个或多个卤素取代的C
1-C
4烷基和任选地被一个或多个卤素取代的C
1-C
4烷氧基；R如式(I)中所定义。
Wherein: Y is selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano; Z is selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy radical, C1 - C4 alkyl optionally substituted with one or more halogens and C1 - C4 alkoxy optionally substituted with one or more halogens; R is as defined in formula (I) .
优选地，在所述制备方法中，Y为H或F；Z为CF
3或CH
3O；R如式(I)中所定义。
Preferably, in the preparation method, Y is H or F; Z is CF 3 or CH 3 O; R is as defined in formula (I).
更优选地，在所述制备方法中，Y为H或F，优选F；Z为CF
3或CH
3O，优 选CF
3；R为甲基或异丙基，优选甲基。
More preferably, in the preparation method, Y is H or F, preferably F; Z is CF 3 or CH 3 O, preferably CF 3 ; R is methyl or isopropyl, preferably methyl.
优选地，在所述制备方法中，所述式(I)化合物与所述式(V)化合物的摩尔比为1.0:1.0-5.0，例如1.0:2.0、1.0:2.2、1.0:2.5或1.0:3.0，优选1.0:2.2。Preferably, in the preparation method, the molar ratio of the compound of formula (I) to the compound of formula (V) is 1.0:1.0-5.0, such as 1.0:2.0, 1.0:2.2, 1.0:2.5 or 1.0: 3.0, preferably 1.0:2.2.
优选地，在所述制备方法中，所述关环反应在极性有机溶剂的存在下进行；进一步地，所述极性有机溶剂选自乙腈(ACN)、N,N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮(NMP)、二甲基亚砜(DMSO)、四氢呋喃(THF)和2-甲基四氢呋喃(2-MTHF)，优选N,N-二甲基甲酰胺。Preferably, in the preparation method, the ring-closing reaction is carried out in the presence of a polar organic solvent; further, the polar organic solvent is selected from acetonitrile (ACN), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), tetrahydrofuran (THF) and 2-methyltetrahydrofuran (2-MTHF), preferably N,N-dimethylformamide.
更优选地，在所述制备方法中，反应结束后，采用酸成盐的方式对所述式(VI)化合物进行纯化；进一步地，形成所述酸加成盐的酸为无机酸或有机酸，其中：所述无机酸为盐酸、氢溴酸、硫酸或磷酸；所述有机酸为甲酸、醋酸、草酸、丙酸、枸橼酸、甲磺酸、对甲苯磺酸、马来酸、琥珀酸、酒石酸、1,5-萘二磺酸、柠檬酸或烟酸，优选盐酸和/或1,5-萘二磺酸。More preferably, in the preparation method, after the reaction is completed, the compound of formula (VI) is purified by using an acid to form a salt; further, the acid forming the acid addition salt is an inorganic acid or an organic acid , wherein: the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; the organic acid is formic acid, acetic acid, oxalic acid, propionic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, succinic acid acid, tartaric acid, 1,5-naphthalenedisulfonic acid, citric acid or nicotinic acid, preferably hydrochloric acid and/or 1,5-naphthalenedisulfonic acid.
优选地，在上述制备方法中，所述式(I)化合物由所述方法A制备而成。Preferably, in the above preparation method, the compound of formula (I) is prepared by the method A.
根据本发明的第六个方面，本发明提供了式(I)化合物在制备式(VI)化合物中的用途；According to a sixth aspect of the present invention, the present invention provides the use of a compound of formula (I) in the preparation of a compound of formula (VI);
其中：Y选自氢、卤素、C
1-C
3烷氧基、羟基、CF
3O和氰基；Z选自卤素、氰基、C
1-C
4烷基、C
1-C
4烷氧基、任选地被一个或多个卤素取代的C
1-C
4烷基和任选地被一个或多个卤素取代的C
1-C
4烷氧基。
Wherein: Y is selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano; Z is selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy radicals, C1 - C4 alkyl optionally substituted with one or more halogens, and C1 - C4 alkoxy optionally substituted with one or more halogens.
优选地，在所述用途中，Y为H或F，Z为CF
3或CH
3O。
Preferably, in said use, Y is H or F and Z is CF3 or CH3O .
更优选地，在所述用途中，Y为F，Z为CF
3。
More preferably, in said use, Y is F and Z is CF3 .
根据本发明的第七个方面，本发明提供了式(I)化合物用作式(VI)化合物分析用杂质对照品和/或标准品的用途；According to the seventh aspect of the present invention, the present invention provides the use of the compound of formula (I) as an impurity reference and/or standard for analysis of the compound of formula (VI);
其中：Y选自氢、卤素、C
1-C
3烷氧基、羟基、CF
3O和氰基；Z选自卤素、氰基、C
1-C
4烷基、C
1-C
4烷氧基、任选地被一个或多个卤素取代的C
1-C
4烷基和任选地被一个或多个卤素取代的C
1-C
4烷氧基。
Wherein: Y is selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano; Z is selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy radicals, C1 - C4 alkyl optionally substituted with one or more halogens, and C1 - C4 alkoxy optionally substituted with one or more halogens.
优选地，在所述用途中，Y为H或F，Z为CF
3或CH
3O。
Preferably, in said use, Y is H or F and Z is CF3 or CH3O .
更优选地，在所述用途中，Y为F，Z为CF
3。
More preferably, in said use, Y is F and Z is CF3 .
发明的效果effect of invention
与现有技术相比，本发明具有如下有益效果：Compared with the prior art, the present invention has the following beneficial effects:
1)本发明提供了一种硫代乙内酰脲药物用中间体，即式(I)化合物，可用于制备如式(VI)所示的硫代乙内酰脲药物，解决了现有生产工艺的关环反应中反应条件苛刻、产品收率低的缺陷；相较于US9216957B2中的制备方法(尤其是普克鲁胺的制备方法)，本发明不仅避免了危险性试剂(如TMSCN、金属盐等)的使用，而且关环反应收率高达80％以上，得到了显著提高；1) The present invention provides a thiohydantoin pharmaceutical intermediate, namely the compound of formula (I), which can be used to prepare the thiohydantoin medicine shown in formula (VI), which solves the problem of existing production. The defect of harsh reaction conditions and low product yield in the ring-closing reaction of the technique; compared with the preparation method (especially the preparation method of Prokluamide) in US9216957B2, the present invention not only avoids dangerous reagents (such as TMSCN, metal Salt, etc.) use, and the ring-closing reaction yield is as high as more than 80%, which has been significantly improved;
2)本发明首次采用式(III)化合物或其药学上可接受的盐与三氯叔丁醇或其水合物制备式(II)化合物，该方法的收率高，为式(I)化合物的生产放大及其后续应用(例如制备式(VI)化合物，尤其是普克鲁胺)提供了基础。2) The present invention adopts the compound of formula (III) or its pharmaceutically acceptable salt and chlorobutanol or its hydrate for the first time to prepare the compound of formula (II), the yield of this method is high, and it is the compound of formula (I). Production scale-up and its subsequent applications, such as the preparation of compounds of formula (VI), especially prokalutamide, provide the basis.
3)本发明首次采用式(I)化合物与4-氰基-2-氟-3-(三氟甲基)苯基异硫氰酸酯直接关环生成普克鲁胺，属于普克鲁胺的关键杂质质控点，当采用本发明的方法制备普克鲁胺时，式(I)化合物还可以作为关键有机杂质，用于质量控制分析。3) the present invention adopts the compound of formula (I) and 4-cyano-2-fluoro-3-(trifluoromethyl) phenyl isothiocyanate for the first time to directly close the ring to generate Prokluamide, which belongs to Prokluamide The key impurity quality control point of the present invention, when the method of the present invention is used to prepare pluclamide, the compound of formula (I) can also be used as a key organic impurity for quality control analysis.
图1为如式(V)所示的化合物与如式(I)所示的化合物经关环反应生成如式(VI)所示的硫代乙内酰脲类药物的反应式。Fig. 1 is a reaction formula of a compound represented by formula (V) and a compound represented by formula (I) through ring closure reaction to generate a thiohydantoin drug represented by formula (VI).
<硫代乙内酰脲药物用中间体><Intermediate for thiohydantoin pharmaceuticals>
本发明提供了一种式(I)化合物或其药学上可接受的盐；The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;
其中：R可以选自C
1-C
6烷基。
wherein: R may be selected from C 1 -C 6 alkyl.
在本发明的一项实施方案中，式(I)化合物中的R可以选自C
1-C
4烷基，优选甲基。
In one embodiment of the present invention, R in the compound of formula (I) may be selected from C1 - C4 alkyl, preferably methyl.
<硫代乙内酰脲药物用中间体的制备方法><Preparation method of thiohydantoin pharmaceutical intermediate>
首先，本发明提供了一种式(I)化合物的制备方法(方法A)。First, the present invention provides a preparation method (method A) of the compound of formula (I).
方法A包括：式(II)化合物或其药学上可接受的盐可以与ROH进行酯化反应，得到式(I)化合物；Method A comprises: the compound of formula (II) or a pharmaceutically acceptable salt thereof can be esterified with ROH to obtain the compound of formula (I);
其中：R可以选自C
1-C
6烷基，优选甲基。
wherein: R can be selected from C 1 -C 6 alkyl, preferably methyl.
在本发明的一项实施方案中，方法A中的ROH可以为甲醇、乙醇、正丙醇、异丙醇、正丁醇或异丁醇，优选甲醇。In one embodiment of the present invention, the ROH in method A may be methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, preferably methanol.
在本发明的一项实施方案中，方法A中的酯化反应可以在酸的存在下进行；进一步地，酸可以为硫酸、盐酸、磷酸或氯化亚砜，优选氯化亚砜。In one embodiment of the present invention, the esterification reaction in method A can be carried out in the presence of an acid; further, the acid can be sulfuric acid, hydrochloric acid, phosphoric acid or thionyl chloride, preferably thionyl chloride.
在本发明的一项实施方案中，方法A中的式(II)化合物或其药学上可接受的盐可以与甲醇在氯化亚砜的存在下进行酯化反应；进一步地，以原型化合物计算，氯化亚砜与式(II)化合物的摩尔比可以为1.5-5.0:1，优选3.0:1。In one embodiment of the present invention, the compound of formula (II) in Method A or a pharmaceutically acceptable salt thereof can be esterified with methanol in the presence of thionyl chloride; further, calculated on the basis of the prototype compound , the molar ratio of thionyl chloride to the compound of formula (II) can be 1.5-5.0:1, preferably 3.0:1.
在本发明的一项优选实施方案中，方法A还包括：式(III)化合物或其药学上可接受的盐可以与三氯叔丁醇或其水合物进行反应(Jocic反应)，得到式(II)化合物。In a preferred embodiment of the present invention, method A further comprises: the compound of formula (III) or a pharmaceutically acceptable salt thereof can be reacted with chlorobutanol or its hydrate (Jocic reaction) to obtain formula ( II) Compounds.
在本发明的一项实施方案中，方法A中的三氯叔丁醇的水合物可以为三氯叔丁醇半水合物。In one embodiment of the present invention, the hydrate of chlorobutanol in Method A may be chlorobutanol hemihydrate.
在本发明的一项实施方案中，以原型化合物计算，方法A中的式(III)化合物与三氯叔丁醇的摩尔比可以为1:1.1-2.0，优选1:1.5。In one embodiment of the present invention, the molar ratio of the compound of formula (III) to chlorobutanol in Method A may be 1:1.1-2.0, preferably 1:1.5, based on the prototype compound.
在本发明的一项实施方案中，方法A中的反应(Jocic反应)可以在溶剂和碱的存在下进行，反应结束后，可以采用酸进行后处理；进一步地，溶剂可以为非质子性溶剂或质子性溶剂中的任意一种或多种的混合，其中：非质子性溶剂可以包括链状或环状的C
1-C
6脂肪族酮(例如丙酮、丁酮)、链状或环状的C
1-C
6脂肪族醚(例如四氢呋喃、二甲基醚)等，质子性溶剂可以包括链状或环状的C
1-C
6脂肪族醇(例如甲醇、乙醇、异丙醇、叔丁醇)，优选丙酮、四氢呋喃、叔丁醇中的一种或其组合；进一步地，碱可以为碱金属的氢氧化物，优选氢氧化钠或氢氧化钾；优选地，以原型化合物计算，碱与式(III)化合物的摩尔比可以为2-10:1，优选5:1；进一步地，酸可以为无机酸或有机酸，优选无机酸(例如盐酸、磷酸或硫酸)。
In an embodiment of the present invention, the reaction (Jocic reaction) in method A can be carried out in the presence of a solvent and a base, and after the reaction is completed, an acid can be used for post-treatment; further, the solvent can be an aprotic solvent Or a mixture of any one or more of protic solvents, wherein: aprotic solvents can include chain or cyclic C 1 -C 6 aliphatic ketones (such as acetone, butanone), chain or cyclic C 1 -C 6 aliphatic ethers (such as tetrahydrofuran, dimethyl ether), etc., protic solvents can include chain or cyclic C 1 -C 6 aliphatic alcohols (such as methanol, ethanol, isopropanol, tertiary Butanol), preferably one of acetone, tetrahydrofuran, tert-butanol or a combination thereof; further, the alkali can be an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide; preferably, calculated on the basis of the prototype compound, The molar ratio of the base to the compound of formula (III) may be 2-10:1, preferably 5:1; further, the acid may be an inorganic acid or an organic acid, preferably an inorganic acid (eg hydrochloric acid, phosphoric acid or sulfuric acid).
在本发明的一项优选实施方案中，方法A中的式(III)化合物或其药学上可接受的盐与三氯叔丁醇半水合物的反应(Jocic反应)可以在丙酮/四氢呋喃混合溶剂和氢氧化钠的存在下进行，反应结束后，可以采用盐酸进行后处理；进一步地， 以原型化合物计算，式(III)化合物与三氯叔丁醇半水合物的摩尔比为1:1.1-2.0；碱与式(III)化合物的摩尔比为2-10:1。In a preferred embodiment of the present invention, the reaction (Jocic reaction) of the compound of formula (III) or a pharmaceutically acceptable salt thereof in method A with chlorobutanol hemihydrate (Jocic reaction) can be carried out in an acetone/tetrahydrofuran mixed solvent and in the presence of sodium hydroxide, after the reaction, hydrochloric acid can be used for post-treatment; further, calculated with the prototype compound, the mol ratio of the compound of formula (III) to trichlorobutanol hemihydrate is 1:1.1- 2.0; the molar ratio of base to compound of formula (III) is 2-10:1.
另外，上述由式(III)化合物或其药学上可接受的盐与三氯叔丁醇或其水合物进行反应(Jocic反应)而得到式(II)化合物的方法也是本发明的范围之内。In addition, the above-mentioned method for obtaining the compound of formula (II) by reacting the compound of formula (III) or a pharmaceutically acceptable salt thereof with chlorobutanol or its hydrate (Jocic reaction) is also within the scope of the present invention.
其次，本发明提供了一种式(I)化合物的制备方法(方法B)。Secondly, the present invention provides a preparation method (method B) of the compound of formula (I).
方法B包括：式(III)化合物或其药学上可接受的盐可以与式(IV)化合物进行取代反应，得到式(I)化合物；Method B comprises: the compound of formula (III) or a pharmaceutically acceptable salt thereof can undergo a substitution reaction with the compound of formula (IV) to obtain the compound of formula (I);
其中：X可以为Cl、Br或I；R可以选自C
1-C
6烷基，优选甲基。
Wherein: X can be Cl, Br or I; R can be selected from C 1 -C 6 alkyl, preferably methyl.
在本发明的一项实施方案中，方法B中的X可以为Cl或Br，优选Br；R可以为甲基或异丙基，优选甲基。In one embodiment of the present invention, X in method B can be Cl or Br, preferably Br; R can be methyl or isopropyl, preferably methyl.
在本发明的一项实施方案中，方法B中的取代反应可以在碱的存在下进行；进一步地，碱可以为碱金属醇化物或含氮有机碱，其中：碱金属醇化物可以包括甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾等；含氮有机碱可以包括三乙胺、N,N-二异丙基乙胺、4-二甲氨基吡啶等；优选含氮有机碱(例如N,N-二异丙基乙胺或三乙胺)。In one embodiment of the present invention, the substitution reaction in method B can be carried out in the presence of a base; further, the base can be an alkali metal alkoxide or a nitrogen-containing organic base, wherein: the alkali metal alkoxide can include sodium methoxide , sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; nitrogen-containing organic bases can include triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, etc.; preferably nitrogen-containing organic bases ( For example N,N-diisopropylethylamine or triethylamine).
在本发明的一项优选实施方案中，方法B中的式(III)化合物或其药学上可接受的盐可以与式(IV)化合物进行取代反应，X可以为Br，R可以为甲基，取代反应可以在N,N-二异丙基乙胺的存在下进行。In a preferred embodiment of the present invention, the compound of formula (III) or a pharmaceutically acceptable salt thereof in method B can be subjected to a substitution reaction with a compound of formula (IV), X can be Br, R can be methyl, The substitution reaction can be carried out in the presence of N,N-diisopropylethylamine.
最后，本发明提供了一种式(I)化合物的制备方法(方法C)。Finally, the present invention provides a method for preparing the compound of formula (I) (method C).
方法C包括：式(III)化合物或其药学上可接受的盐可以与式(IV-OH)化合物进行取代反应，得到式(II)化合物或其药学上可接受的盐，再与ROH进行酯化反应，得到式(I)化合物；Method C comprises: the compound of formula (III) or a pharmaceutically acceptable salt thereof can be subjected to a substitution reaction with a compound of formula (IV-OH) to obtain the compound of formula (II) or a pharmaceutically acceptable salt thereof, and then esterified with ROH. chemical reaction to obtain the compound of formula (I);
其中：X可以为Cl、Br或I；R可以选自C
1-C
6烷基，优选甲基。
Wherein: X can be Cl, Br or I; R can be selected from C 1 -C 6 alkyl, preferably methyl.
在本发明的一项实施方案中，方法C中的X可以为Cl或Br，优选Br；R可以为甲基或异丙基，优选甲基。In one embodiment of the present invention, X in method C can be Cl or Br, preferably Br; R can be methyl or isopropyl, preferably methyl.
在本发明的一项实施方案中，方法C中的取代反应可以在碱的存在下进行；进一步地，碱可以为碱金属醇化物或含氮有机碱，其中：碱金属醇化物可以包括甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾等；含氮有机碱可以包括三乙胺、N,N-二异丙 基乙胺、4-二甲氨基吡啶等；优选含氮有机碱(例如三乙胺或二异丙基乙胺)；方法C中的酯化反应可以在酸的存在下进行；进一步地，酸为硫酸、盐酸、磷酸或氯化亚砜，优选氯化亚砜。In one embodiment of the present invention, the substitution reaction in method C can be carried out in the presence of a base; further, the base can be an alkali metal alkoxide or a nitrogen-containing organic base, wherein: the alkali metal alkoxide can include sodium methoxide , sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; nitrogen-containing organic bases can include triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, etc.; preferably nitrogen-containing organic bases ( For example, triethylamine or diisopropylethylamine); the esterification reaction in method C can be carried out in the presence of an acid; further, the acid is sulfuric acid, hydrochloric acid, phosphoric acid or thionyl chloride, preferably thionyl chloride.
在本发明的一项优选实施方案中，方法C中的式(III)化合物或其药学上可接受的盐可以与式(IV-OH)化合物进行取代反应，X可以为Br，R可以为甲基，取代反应可以在N,N-二异丙基乙胺的存在下进行，得到式(II)化合物或其药学上可接受的盐，再与ROH进行酯化反应，酯化反应可以在氯化亚砜的存在下进行，得到式(I)化合物。In a preferred embodiment of the present invention, the compound of formula (III) or a pharmaceutically acceptable salt thereof in method C can be subjected to a substitution reaction with a compound of formula (IV-OH), X can be Br, and R can be methyl base, the substitution reaction can be carried out in the presence of N,N-diisopropylethylamine to obtain the compound of formula (II) or a pharmaceutically acceptable salt thereof, which is then esterified with ROH, and the esterification reaction can be carried out in the presence of chlorine In the presence of sulfoxides, compounds of formula (I) are obtained.
<硫代乙内酰脲药物><Thiohydantoin drugs>
本发明提供了一种式(VI)化合物(硫代乙内酰脲药物)的制备方法。The present invention provides a preparation method of a compound of formula (VI) (thiohydantoin drug).
该制备方法包括：式(I)化合物或其药学上可接受的盐可以与式(V)化合物进行关环反应，得到式(VI)化合物；The preparation method comprises: the compound of formula (I) or a pharmaceutically acceptable salt thereof can be subjected to a ring closure reaction with the compound of formula (V) to obtain the compound of formula (VI);
其中：Y可以选自氢、卤素、C
1-C
3烷氧基、羟基、CF
3O和氰基；Z可以选自卤素、氰基、C
1-C
4烷基、C
1-C
4烷氧基、任选地被一个或多个卤素取代的C
1-C
4烷基和任选地被一个或多个卤素取代的C
1-C
4烷氧基；R可以选自C
1-C
6烷基，优选甲基。
Wherein: Y can be selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano; Z can be selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C1 - C4 alkyl optionally substituted with one or more halogens and C1 - C4 alkoxy optionally substituted with one or more halogens; R may be selected from C1- C6 alkyl, preferably methyl.
在本发明的一项实施方案中，该制备方法中的Y可以为H或F；Z可以为CF
3或CH
3O；R可以选自C
1-C
6烷基，优选甲基。
In an embodiment of the present invention, Y in the preparation method can be H or F; Z can be CF 3 or CH 3 O; R can be selected from C 1 -C 6 alkyl, preferably methyl.
在本发明的一项实施方案中，该制备方法中的Y可以为H或F，优选F；Z可以为CF
3或CH
3O，优选CF
3；R可以为甲基或异丙基，优选甲基。
In one embodiment of the present invention, Y in the preparation method can be H or F, preferably F; Z can be CF 3 or CH 3 O, preferably CF 3 ; R can be methyl or isopropyl, preferably methyl.
在本发明的一项实施方案中，该制备方法中的式(I)化合物与式(V)化合物的摩尔比可以为1.0:1.0-5.0，优选1.0:2.2。In one embodiment of the present invention, the molar ratio of the compound of formula (I) to the compound of formula (V) in the preparation method may be 1.0:1.0-5.0, preferably 1.0:2.2.
在本发明的一项实施方案中，该制备方法中的关环反应可以在极性有机溶剂的存在下进行；进一步地，极性有机溶剂可以选自乙腈、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜、四氢呋喃和2-甲基四氢呋喃，优选N,N-二甲基甲酰胺。In one embodiment of the present invention, the ring-closure reaction in the preparation method can be carried out in the presence of a polar organic solvent; further, the polar organic solvent can be selected from acetonitrile, N,N-dimethylformamide , N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran and 2-methyltetrahydrofuran, preferably N,N-dimethylformamide.
在本发明的一项实施方案中，该制备方法可以采用酸成盐的方式对式(VI)化合物进行纯化；进一步地，形成酸加成盐的酸可以为无机酸或有机酸，其中：无机酸可以为盐酸、氢溴酸、硫酸或磷酸；有机酸可以为甲酸、醋酸、草酸、丙酸、枸橼酸、甲磺酸、对甲苯磺酸、马来酸、琥珀酸、酒石酸、1,5-萘二磺酸、柠檬酸或烟酸，优选盐酸和/或1,5-萘二磺酸。In one embodiment of the present invention, the preparation method can purify the compound of formula (VI) by forming an acid into a salt; further, the acid forming an acid addition salt can be an inorganic acid or an organic acid, wherein: inorganic acid The acid can be hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; the organic acid can be formic acid, acetic acid, oxalic acid, propionic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, succinic acid, tartaric acid, 1, 5-Naphthalenedisulfonic acid, citric acid or nicotinic acid, preferably hydrochloric acid and/or 1,5-naphthalenedisulfonic acid.
在本发明的一项实施方案中，该制备方法中的式(I)化合物可以由方法A制备而成，即式(VI)化合物的制备方法可以包括下列步骤：In one embodiment of the present invention, the compound of formula (I) in the preparation method can be prepared by method A, that is, the preparation method of the compound of formula (VI) can include the following steps:
式(III)化合物或其药学上可接受的盐可以与三氯叔丁醇或其水合物进行反应，得到式(II)化合物；The compound of formula (III) or a pharmaceutically acceptable salt thereof can be reacted with chlorobutanol or its hydrate to obtain the compound of formula (II);
优选地，该制备方法可以进一步包括下列步骤：式(II)化合物或其药学上可接受的盐可以与ROH进行酯化反应，得到式(I)化合物；Preferably, the preparation method may further comprise the following steps: the compound of formula (II) or a pharmaceutically acceptable salt thereof can be esterified with ROH to obtain the compound of formula (I);
优选地，该制备方法可以进一步包括下列步骤：式(I)化合物或其药学上可接受的盐可以与式(V)化合物进行关环反应，得到式(VI)化合物；Preferably, the preparation method may further comprise the following steps: the compound of formula (I) or a pharmaceutically acceptable salt thereof can be subjected to a ring closure reaction with the compound of formula (V) to obtain the compound of formula (VI);
其中：in:
Y可以选自氢、卤素、C
1-C
3烷氧基、羟基、CF
3O和氰基，优选H或F，更优选F；
Y may be selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano, preferably H or F, more preferably F;
Z可以选自卤素、氰基、C
1-C
4烷基、C
1-C
4烷氧基、任选地被一个或多个卤素取代的C
1-C
4烷基和任选地被一个或多个卤素取代的C
1-C
4烷氧基，优选CF
3或CH
3O，更优选CF
3；
Z may be selected from halogen, cyano, C1 - C4 alkyl, C1 - C4 alkoxy, C1 - C4 alkyl optionally substituted with one or more halogens, and optionally substituted with a or multiple halogen-substituted C 1 -C 4 alkoxy groups, preferably CF 3 or CH 3 O, more preferably CF 3 ;
R可以选自C
1-C
6烷基，优选C
1-C
4烷基，更优选甲基。
R may be selected from C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl, more preferably methyl.
<硫代乙内酰脲药物用中间体的制备用途><Preparation of thiohydantoin pharmaceutical intermediates>
本发明提供了式(I)化合物在制备式(VI)化合物中的用途；The present invention provides the use of a compound of formula (I) in the preparation of a compound of formula (VI);
其中：Y可以选自氢、卤素、C
1-C
3烷氧基、羟基、CF
3O和氰基；Z可以选自卤素、氰基、C
1-C
4烷基、C
1-C
4烷氧基、任选地被一个或多个卤素取代的C
1-C
4烷基和任选地被一个或多个卤素取代的C
1-C
4烷氧基。
Wherein: Y can be selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano; Z can be selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C1 - C4 alkyl optionally substituted with one or more halogens, and C1 - C4 alkoxy optionally substituted with one or more halogens.
在本发明的一项实施方案中，该用途中的Y可以为H或F，Z可以为CF
3或CH
3O。
In one embodiment of the invention, Y in this use can be H or F and Z can be CF3 or CH3O .
在本发明的一项优选实施方案中，该用途中的Y可以为F，Z可以为CF
3。
In a preferred embodiment of the present invention, Y in this use may be F and Z may be CF3 .
<硫代乙内酰脲药物用中间体的使用用途><Use of intermediates for thiohydantoin pharmaceuticals>
本发明提供了式(I)化合物用作式(VI)化合物分析用杂质对照品和/或标准品的用途；The present invention provides the use of the compound of formula (I) as an impurity reference substance and/or standard substance for analysis of the compound of formula (VI);
其中：Y可以选自氢、卤素、C
1-C
3烷氧基、羟基、CF
3O和氰基；Z可以选自卤素、氰基、C
1-C
4烷基、C
1-C
4烷氧基、任选地被一个或多个卤素取代的C
1-C
4烷基和任选地被一个或多个卤素取代的C
1-C
4烷氧基。
Wherein: Y can be selected from hydrogen, halogen, C 1 -C 3 alkoxy, hydroxyl, CF 3 O and cyano; Z can be selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C1 - C4 alkyl optionally substituted with one or more halogens, and C1 - C4 alkoxy optionally substituted with one or more halogens.
在本发明的一项实施方案中，该用途中的Y可以为H或F，Z可以为CF
3或CH
3O。
In one embodiment of the invention, Y in this use can be H or F and Z can be CF3 or CH3O .
在本发明的一项优选实施方案中，该用途中的Y可以为F，Z可以为CF
3。
In a preferred embodiment of the present invention, Y in this use may be F and Z may be CF3 .
以下将结合附图和具体实施例来进一步阐述本发明的技术方案。除非另有说明，下列实施例中所使用的仪器、耗材和试剂等均可通过常规商业手段获得。The technical solutions of the present invention will be further described below with reference to the accompanying drawings and specific embodiments. Unless otherwise specified, the instruments, consumables and reagents used in the following examples can be obtained by conventional commercial means.
实施例中用于含量检测或纯度分析的HPLC条件如下：The HPLC conditions used for content detection or purity analysis in the examples are as follows:
色谱柱：Agilent ZORBAX SB-C18(4.6×150mm,3.5μm)；Chromatographic column: Agilent ZORBAX SB-C18 (4.6×150mm, 3.5μm);
流动相：二元流动相体系，流动相A为0.02vol％的三氟乙酸水溶液，流动相B为乙腈；Mobile phase: binary mobile phase system, mobile phase A is 0.02vol% trifluoroacetic acid aqueous solution, mobile phase B is acetonitrile;
洗脱时间：18min；Elution time: 18min;
洗脱方式：梯度洗脱，具体程序如表1所示；Elution mode: gradient elution, the specific procedure is shown in Table 1;
表1.梯度洗脱表Table 1. Gradient elution table
| 时间(min)time (min) | 流动相A(vol％)Mobile phase A (vol%) | 流动相B(vol％)Mobile phase B (vol%) |
| 0.000.00 | 9090 | 1010 |
| 1.0001.000 | 9090 | 1010 |
| 4.0004.000 | 7070 | 3030 |
| 6.0006.000 | 3030 | 7070 |
| 8.0008.000 | 00 | 100100 |
| 13.00013.000 | 00 | 100100 |
| 13.01013.010 | 9090 | 1010 |
| 18.00018.000 | 9090 | 1010 |
检测波长：220nm。Detection wavelength: 220nm.
实施例一：式(II)化合物的制备。Example 1: Preparation of the compound of formula (II).
方法1：以三氯叔丁醇或其水合物为原料Method 1: Using chlorobutanol or its hydrate as raw material
向反应瓶中加入式(III)化合物(4.50g，约22.2mmol)和半水合三氯叔丁醇(6.2g，约1.5eq)溶于丙酮和四氢呋喃的混合液(50ml，丙酮和四氢呋喃等体积)，搅拌溶解，然后分批加入氢氧化钠(4.4g，约5.2eq)，在10-30℃下进行反应，反应12-18h。The compound of formula (III) (4.50g, about 22.2mmol) and trichlorobutanol hemihydrate (6.2g, about 1.5eq) dissolved in acetone and tetrahydrofuran (50ml, equal volumes of acetone and tetrahydrofuran) were added to the reaction flask ), stir to dissolve, then add sodium hydroxide (4.4 g, about 5.2 eq) in batches, and carry out the reaction at 10-30° C. for 12-18 h.
反应结束后过滤，滤饼用10ml丙酮洗涤，收集洗涤液和滤液，合并浓缩，得油状物，油状物采用适量的丙酮/二氯甲烷的混合液洗涤(油状物不溶于丙酮/二氯甲烷，此处进行洗涤的主要目的是去除未反应的式(III)化合物)，洗涤后分离出油状物，加入甲醇搅拌，室温下滴加盐酸甲醇溶液，调节体系pH至4～6，过滤，浓缩滤液得5.85g式(II)化合物，收率为91.3％。After the reaction finishes, filter, filter cake is washed with 10ml acetone, collect washings and filtrate, combine and concentrate, obtain oily matter, oily matter adopts the mixed solution washing of appropriate acetone/dichloromethane (oily matter is insoluble in acetone/dichloromethane, The main purpose of washing here is to remove the unreacted compound of formula (III), the oil is separated after washing, and methanol is added to stir, and the methanol solution of hydrochloric acid is added dropwise at room temperature to adjust the pH of the system to 4-6, filter, and concentrate the filtrate. 5.85 g of the compound of formula (II) were obtained with a yield of 91.3%.
1H-NMR(400MHz,DMSO-d
6):δ7.97(s,1H),7.73(d,J＝2.8Hz,1H),7.43(d,J＝8.7Hz,1H),7.28(d,J＝8.8Hz,1H),7.08(s,1H),3.17(s,1H),2.80(dt,J＝15.3,7.5Hz,4H),2.05(p,J＝7.5Hz,2H),1.47(s,6H)。
1 H-NMR (400MHz, DMSO-d 6 ): δ 7.97(s, 1H), 7.73(d, J=2.8Hz, 1H), 7.43(d, J=8.7Hz, 1H), 7.28(d, J=8.8Hz, 1H), 7.08(s, 1H), 3.17(s, 1H), 2.80(dt, J=15.3, 7.5Hz, 4H), 2.05(p, J=7.5Hz, 2H), 1.47( s, 6H).
针对方法1，将用作碱的氢氧化钠替换为三乙胺、甲醇钠、碳酸钾和碳酸铯，以考察不同种类的碱对于反应进程的影响，结果如表2所示。For method 1, the sodium hydroxide used as a base was replaced with triethylamine, sodium methoxide, potassium carbonate and cesium carbonate to investigate the effects of different kinds of bases on the reaction progress, the results are shown in Table 2.
表2.不同的碱对于反应进程的影响Table 2. Effects of different bases on reaction progress
由表2可知，在方法1中，以碱金属的氢氧化物作为碱时，反应的收率较为理想。As can be seen from Table 2, in Method 1, when an alkali metal hydroxide is used as the base, the reaction yield is favorable.
针对方法1，将用作溶剂的丙酮/四氢呋喃替换为N-甲基吡咯烷酮、N,N-二甲基甲酰胺、1,4-二氧六环、二甲基醚/水、异丙醇和叔丁醇，以考察不同种类的溶剂对于反应进程的影响，结果如表3所示。For method 1, replace acetone/tetrahydrofuran as solvent with N-methylpyrrolidone, N,N-dimethylformamide, 1,4-dioxane, dimethyl ether/water, isopropanol and tert. Butanol was used to investigate the effect of different kinds of solvents on the reaction process. The results are shown in Table 3.
表3.不同的溶剂对于反应进程的影响Table 3. Effects of different solvents on reaction progress
由表3可知，在方法1中，以脂肪族的酮、醚和/或醇等作为溶剂时，反应的收率较为理想。As can be seen from Table 3, in Method 1, when an aliphatic ketone, ether, and/or alcohol or the like is used as a solvent, the reaction yield is more favorable.
方法2：以式(IV-OH)化合物(X为Br)为原料Method 2: Using the compound of formula (IV-OH) (X is Br) as raw material
向反应瓶中加入式(III)化合物(200mg，0.984mmol)、2-溴异丁酸(246mg，1.476mmol)、三乙胺(300mg，2.95mmol)和异丙醇(2.5ml)，搅拌溶解，在85℃下反应5h。经HPLC检测，按照峰面积百分比计算，式(II)化合物为70％，式(III)化合物为30％，未进行进一步分离纯化。The compound of formula (III) (200 mg, 0.984 mmol), 2-bromoisobutyric acid (246 mg, 1.476 mmol), triethylamine (300 mg, 2.95 mmol) and isopropanol (2.5 ml) were added to the reaction flask, and stirred to dissolve , and reacted at 85°C for 5h. According to HPLC detection, according to the peak area percentage, the compound of formula (II) is 70%, and the compound of formula (III) is 30%, and further separation and purification are not carried out.
另外，也可以使用式(III)化合物的药学上可接受的盐(例如1,5-萘二磺酸盐)作为起始原料，通过加入碱性物质(例如碳酸钠)调节pH并利用两相萃取体系(例如水/二氯甲烷)来获得游离型式(III)化合物，进而制备式(II)化合物。Alternatively, a pharmaceutically acceptable salt of a compound of formula (III) such as 1,5-naphthalene disulfonate can be used as starting material, pH is adjusted by adding a basic substance such as sodium carbonate, and two phases can be utilized The compound of formula (II) is prepared by extracting the system (eg water/dichloromethane) to obtain the compound of formula (III) in free form.
实施例二：式(I)化合物的制备。Example 2: Preparation of the compound of formula (I).
方法1：以式(II)化合物和醇为原料Method 1: Using the compound of formula (II) and alcohol as raw materials
1-1：R为甲基1-1: R is methyl
取式(II)化合物(5.08g，17.57mmol)，溶于50ml甲醇中，室温搅拌，然后降温至0-10℃，滴加氯化亚砜(52.7mmol，约3.0eq)，保温搅拌过夜。The compound of formula (II) (5.08 g, 17.57 mmol) was dissolved in 50 ml of methanol, stirred at room temperature, then cooled to 0-10° C., thionyl chloride (52.7 mmol, about 3.0 eq) was added dropwise, and the mixture was kept stirring overnight.
停止搅拌，将反应液于50℃旋干，加入50ml甲基叔丁基醚和50ml水，室温下搅拌至全部溶解，加入碳酸钠，调节pH至8-9，分层，水层用甲基叔丁基醚萃取(30ml*2)，合并有机层后，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液旋干，得到目标产物4.1g，收率为77.0％。Stop stirring, spin the reaction solution at 50°C, add 50 ml of methyl tert-butyl ether and 50 ml of water, stir at room temperature until all dissolved, add sodium carbonate, adjust pH to 8-9, separate layers, and use methyl Extracted with tert-butyl ether (30ml*2), combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 4.1 g of the target product with a yield of 77.0%.
1H-NMR(400MHz,DMSO-d
6):δ7.96(d,J＝0.9Hz,1H),7.78(dd,J＝3.0,0.7Hz,1H),7.08(d,J＝0.8Hz,1H),6.93(d,J＝8.3Hz,1H),6.67(dd,J＝8.4,2.9Hz,1H),6.03(s,1H),3.61(s,3H),2.73(t,J＝7.5Hz,2H),2.63–2.56(m,2H),1.99(p,J＝7.5Hz,2H),1.44(s,6H)。
1 H-NMR (400MHz, DMSO-d 6 ): δ 7.96 (d, J=0.9Hz, 1H), 7.78 (dd, J=3.0, 0.7Hz, 1H), 7.08 (d, J=0.8Hz, 1H), 6.93(d, J=8.3Hz, 1H), 6.67(dd, J=8.4, 2.9Hz, 1H), 6.03(s, 1H), 3.61(s, 3H), 2.73(t, J=7.5 Hz, 2H), 2.63–2.56 (m, 2H), 1.99 (p, J=7.5Hz, 2H), 1.44 (s, 6H).
1-2：R为异丙基1-2: R is isopropyl
取式(II)化合物(200mg，0.691mmol)与2ml异丙醇混合，在5-10℃下滴加二氯亚砜(约3.0eq)，滴毕，升温至35℃，反应过夜；经LC-MC检测，按照峰面积百分比计算，目标产物的含量仅为10.8％；补加二氯亚砜(约6eq)，升温至70-80℃反应过夜；经LC-MC检测，按照峰面积百分比计算，目标产物的含量为74.7％。The compound of formula (II) (200 mg, 0.691 mmol) was mixed with 2 ml of isopropanol, and thionyl chloride (about 3.0 eq) was added dropwise at 5-10 °C. After dropping, the temperature was raised to 35 °C and the reaction was performed overnight; -MC detection, according to the peak area percentage calculation, the content of the target product is only 10.8%; add thionyl chloride (about 6eq), heat up to 70-80 ° C and react overnight; LC-MC detection, according to the peak area percentage calculation , the content of the target product is 74.7%.
反应结束后，浓缩至干，加水5ml和甲基叔丁基醚10ml，然后用碳酸钠调节pH至9，分层，水层用甲基叔丁基醚萃取(10ml*2)，合并有机层后，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，浓缩，采用制备薄层色谱分离法分离，得到目标产物，收率为43.7％，HPLC纯度为93.3％。After the reaction, concentrate to dryness, add 5 ml of water and 10 ml of methyl tert-butyl ether, then adjust the pH to 9 with sodium carbonate, separate the layers, extract the aqueous layer with methyl tert-butyl ether (10 ml*2), and combine the organic layers Then, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, suction filtered, concentrated, and separated by preparative thin layer chromatography to obtain the target product with a yield of 43.7% and HPLC purity of 93.3%.
1H-NMR(400MHz,DMSO-d
6)δ7.96(d,J＝0.9Hz,1H),7.79(d,J＝2.8Hz,1H),7.08(d,J＝0.9Hz,1H),6.93(d,J＝8.4Hz,1H),6.70(dd,J＝8.4,2.9Hz,1H),5.96(s,1H),4.87(hept,J＝6.2Hz,1H),2.71(t,J＝7.5Hz,2H),2.59(t,J＝7.5Hz,2H),1.98(p,J＝7.6Hz,2H),1.43(s,6H),1.08(d,J＝6.2Hz,6H)。
1 H-NMR (400MHz, DMSO-d 6 )δ7.96(d,J=0.9Hz,1H),7.79(d,J=2.8Hz,1H),7.08(d,J=0.9Hz,1H), 6.93(d,J＝8.4Hz,1H),6.70(dd,J＝8.4,2.9Hz,1H),5.96(s,1H),4.87(hept,J＝6.2Hz,1H),2.71(t,J = 7.5Hz, 2H), 2.59 (t, J=7.5Hz, 2H), 1.98 (p, J=7.6Hz, 2H), 1.43 (s, 6H), 1.08 (d, J=6.2Hz, 6H).
方法2：以式(III)化合物和式(IV)化合物(X为Br，R为甲基)为原料Method 2: Using the compound of formula (III) and the compound of formula (IV) (X is Br, R is methyl) as raw materials
取式(III)化合物(100mg，0.492mmol)、2-溴异丁酸甲酯(178mg，2eq)、N.N-二异丙基乙胺(95mg，1.5eq)置于焖罐中，在110℃下反应2h。经HPLC检测，按照峰面积百分比计算，目标产物为51.2％。Take the compound of formula (III) (100mg, 0.492mmol), methyl 2-bromoisobutyrate (178mg, 2eq), N.N-diisopropylethylamine (95mg, 1.5eq) and put them in a steaming pot at 110°C The next reaction was 2h. Detected by HPLC, the target product was 51.2% calculated according to the percentage of peak area.
针对方法2，将用作碱的N,N-二异丙基乙胺替换为4-二甲氨基吡啶，相应的收率结果相当。For method 2, N,N-diisopropylethylamine used as the base was replaced with 4-dimethylaminopyridine and the corresponding yield results were comparable.
方法3：式(III)化合物与三氯叔丁醇或其水合物在碱性条件下一锅法制备式(I)化合物Method 3: One-pot preparation of compound of formula (I) by compound of formula (III) and chlorobutanol or its hydrate under basic conditions
3-1：以甲醇作为溶剂3-1: Use methanol as solvent
取式(III)化合物(100mg，0.492mmol)、甲醇2ml和半水合三氯叔丁醇(138mg，约1.5eq)混合，室温下加入氢氧化钠(102mg，约5.2eq)反应4h后，升温至50-60℃(例如55℃)保温反应12h以上(例如过夜)。经HPLC检测，按照峰面积百分比计算，目标产物为25％，式(III)化合物为66％，中间过渡态即式(II)化合物7％，余量为未知杂质。The compound of formula (III) (100 mg, 0.492 mmol), 2 ml of methanol and trichlorobutanol hemihydrate (138 mg, about 1.5 eq) were mixed, sodium hydroxide (102 mg, about 5.2 eq) was added at room temperature and reacted for 4 h, then the temperature was increased. Incubate the reaction at 50-60° C. (eg, 55° C.) for more than 12 h (eg, overnight). According to HPLC detection, calculated according to the peak area percentage, the target product is 25%, the compound of formula (III) is 66%, the intermediate transition state is the compound of formula (II) 7%, and the balance is unknown impurities.
3-2：以丙酮作为溶剂3-2: Using acetone as solvent
取式(III)化合物100mg、丙酮2ml和半水合三氯叔丁醇138mg混合，室温下加入氢氧化钠102mg中的一部分(约2eq)，反应30min后加入甲醇2ml，反应20min后，加入剩余的氢氧化钠，室温反应12h以上。经HPLC检测，按照峰面积百分比计算，目标产物为13.8％，式(III)化合物为19.7％，中间过渡态即式(II)化合物47.4％，余量为未知杂质。Mix 100 mg of the compound of formula (III), 2 ml of acetone and 138 mg of trichlorobutanol hemihydrate, add a part (about 2 eq) of 102 mg of sodium hydroxide at room temperature, and add 2 ml of methanol after the reaction for 30 min. After the reaction for 20 min, add the remaining Sodium hydroxide, react at room temperature for more than 12h. HPLC detection, calculated according to the peak area percentage, the target product is 13.8%, the compound of formula (III) is 19.7%, the intermediate transition state is the compound of formula (II) 47.4%, and the balance is unknown impurities.
3-3：以二氯甲烷作为溶剂3-3: Using dichloromethane as solvent
取二氯甲烷3ml和半水合三氯叔丁醇(275mg，3eq)混合，室温下加入氢氧化钠(197mg，10eq)，混合搅拌30min，然后加入式(III)化合物100mg，搅拌20min后加入甲醇(157mg，10eq)，升温至回流，反应12h以上。经HPLC检测，按照峰面积百分比计算，目标产物为4.3％，中间过渡态即式(II)化合物90.5％，余量为未知杂质。Take 3ml of dichloromethane and mix with trichlorobutanol hemihydrate (275mg, 3eq), add sodium hydroxide (197mg, 10eq) at room temperature, mix and stir for 30min, then add 100mg of the compound of formula (III), stir for 20min and then add methanol (157mg, 10eq), heated to reflux, and reacted for more than 12h. According to HPLC detection, calculated according to the peak area percentage, the target product is 4.3%, the intermediate transition state is 90.5% of the compound of formula (II), and the balance is unknown impurities.
综上可知，以三氯叔丁醇和式(III)化合物为原料，在碱性条件下通过一锅法制备式(I)化合物的方法收率偏低；与此相比，本发明采用两步法制备式(I)化 合物的方法收率得到显著提高。To sum up, it can be seen from the above that the yield of the method for preparing the compound of formula (I) by one-pot method under alkaline conditions using trichloro-tert-butanol and the compound of formula (III) as raw materials is low; compared with this, the present invention adopts two steps The yield of the method for preparing the compound of formula (I) is significantly improved.
实施例三：式(VI)化合物的制备。Example 3: Preparation of the compound of formula (VI).
示例化合物1的制法1：Preparation 1 of Example Compound 1:
取式(I)-1化合物(100mg，0.302mmol)、式(V)-1化合物(163mg，2.2eq)，加入到N,N-二甲基甲酰胺0.5ml中，室温搅拌，反应过夜；反应结束后，加入甲基叔丁基醚10ml和水5ml萃取分层，水层用甲基叔丁醚萃取(10ml*2)，合并有机层，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩后进行制备薄层色谱分离，得到目标产物130mg，收率为83.2％，HPLC纯度为90.3％。The compound of formula (I)-1 (100 mg, 0.302 mmol) and the compound of formula (V)-1 (163 mg, 2.2 eq) were taken and added to 0.5 ml of N,N-dimethylformamide, stirred at room temperature, and reacted overnight; After the reaction, 10 ml of methyl tert-butyl ether and 5 ml of water were added to extract the layers, the aqueous layer was extracted with methyl tert-butyl ether (10 ml*2), the organic layers were combined, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. , suction filtration, the filtrate was concentrated and then separated by preparative thin layer chromatography to obtain 130 mg of the target product, the yield was 83.2%, and the HPLC purity was 90.3%.
示例化合物1的制法2：Preparation 2 of Example Compound 1:
取式(I)-2化合物(3.63g，12mmol)、式(V)-1化合物(6.5g，26.4mmol)，加入到N,N-二甲基甲酰胺100ml中，室温搅拌，反应过夜；反应结束后，加入甲基叔丁基醚80ml和去离子水100ml，室温搅拌萃取，水层用甲基叔丁基醚萃取(60ml*2)，合并有机层，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩后加入二氯甲烷80ml溶解，然后加入6M盐酸60ml萃取，收集水层，水层用碳酸钠水溶液调节pH至8-9，滴加甲基叔丁基醚萃取，分液，收集有机层，浓缩，干燥，得到目标产物5.0g，收率为80.6％。The compound of formula (I)-2 (3.63 g, 12 mmol) and the compound of formula (V)-1 (6.5 g, 26.4 mmol) were added to 100 ml of N,N-dimethylformamide, stirred at room temperature, and reacted overnight; After the reaction, 80 ml of methyl tert-butyl ether and 100 ml of deionized water were added, and the mixture was stirred at room temperature for extraction. The aqueous layer was extracted with methyl tert-butyl ether (60 ml*2), the organic layers were combined and washed with saturated aqueous sodium chloride solution. Dry with sodium sulfate, suction filtration, add 80 ml of dichloromethane to dissolve the filtrate, then add 60 ml of 6M hydrochloric acid for extraction, collect the aqueous layer, adjust the pH of the aqueous layer to 8-9 with aqueous sodium carbonate solution, and add methyl tert-butyl ether dropwise Extraction, separation, collection of the organic layer, concentration and drying to obtain 5.0 g of the target product with a yield of 80.6%.
LC-MS：m/z＝518[M+H]
+。
LC-MS: m/z=518 [M+H] + .
1H-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,J
2＝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)。
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, J 2 =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).
针对制法2，将用作溶剂的N,N-二甲基甲酰胺替换为醋酸异丙酯、甲苯、乙腈和乙酸乙酯，以考察不同种类的溶剂对于反应进程的影响，结果如表4所示。For preparation method 2, the N,N-dimethylformamide used as solvent was replaced by isopropyl acetate, toluene, acetonitrile and ethyl acetate, to investigate the influence of different kinds of solvents on the reaction process, the results are as shown in Table 4 shown.
表4.不同的溶剂对于反应进程的影响Table 4. Effects of different solvents on reaction progress
由表4可知，以乙腈作为溶剂时，反应的收率与N,N-二甲基甲酰胺比较接近，适合大生产。It can be seen from Table 4 that when acetonitrile is used as a solvent, the yield of the reaction is relatively close to that of N,N-dimethylformamide, which is suitable for large-scale production.
另外，也可以使上述制法的目标产物与酸(例如1,5-萘二磺酸)在溶剂(例如乙醇)中形成酸加成盐。In addition, the target product of the above-mentioned production method and an acid (for example, 1,5-naphthalene disulfonic acid) may be formed into an acid addition salt in a solvent (for example, ethanol).
示例化合物2的制法：Preparation of Example Compound 2:
取式(I)-2化合物(100mg，0.330mmol)、式(V)-2化合物(165mg，约2.2eq)，加入到N,N-二甲基甲酰胺1ml中，室温搅拌，反应过夜；反应结束后，加入甲基叔丁基醚20ml和水10ml萃取分层，水层用甲基叔丁醚萃取(10ml)，合并有机层，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩后进行制备薄层色谱分离，得到目标产物97mg，收率为58.8％。Take the compound of formula (I)-2 (100 mg, 0.330 mmol) and the compound of formula (V)-2 (165 mg, about 2.2 eq), add them to 1 ml of N,N-dimethylformamide, stir at room temperature, and react overnight; After the reaction, 20 ml of methyl tert-butyl ether and 10 ml of water were added to extract the layers, the aqueous layer was extracted with methyl tert-butyl ether (10 ml), the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and extracted. After filtration, the filtrate was concentrated and separated by preparative thin layer chromatography to obtain 97 mg of the target product with a yield of 58.8%.
1H-NMR(400MHz,DMSO-d
6)δ8.49(d,J＝2.5Hz,1H),8.40(d,J＝8.2Hz,1H),8.31(d,J＝1.9Hz,1H),8.09(dd,J＝8.4,1.9Hz,1H),7.99(d,J＝0.9Hz,1H),7.76(dd,J＝8.2,2.5Hz,1H),7.49(d,J＝8.3Hz,1H),7.10(d,J＝1.0Hz,1H),2.86(dt,J＝25.0,7.5Hz,4H),2.20–2.11(m,2H),1.53(s,6H)。
1 H-NMR (400MHz, DMSO-d 6 )δ8.49(d,J=2.5Hz,1H),8.40(d,J=8.2Hz,1H),8.31(d,J=1.9Hz,1H), 8.09(dd,J＝8.4,1.9Hz,1H),7.99(d,J＝0.9Hz,1H),7.76(dd,J＝8.2,2.5Hz,1H),7.49(d,J＝8.3Hz,1H) ), 7.10 (d, J=1.0Hz, 1H), 2.86 (dt, J=25.0, 7.5Hz, 4H), 2.20–2.11 (m, 2H), 1.53 (s, 6H).
示例化合物3的制法：Preparation of Example Compound 3:
取式(I)-2化合物(100mg，0.330mmol)、式(V)-3化合物(151mg，约2.2eq)，加入到N,N-二甲基甲酰胺1ml中，室温搅拌，反应过夜；反应结束后，加入甲基叔丁基醚20ml和水10ml萃取分层，水层用甲基叔丁醚萃取(10ml)，合并有机层，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩后进行制备薄层色谱分离，得到目标产物90mg，收率为57.0％。Take the compound of formula (I)-2 (100 mg, 0.330 mmol) and the compound of formula (V)-3 (151 mg, about 2.2 eq), add them to 1 ml of N,N-dimethylformamide, stir at room temperature, and react overnight; After the reaction, 20 ml of methyl tert-butyl ether and 10 ml of water were added to extract the layers, the aqueous layer was extracted with methyl tert-butyl ether (10 ml), the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and extracted. After filtration, the filtrate was concentrated and subjected to preparative thin-layer chromatography to obtain 90 mg of the target product with a yield of 57.0%.
1H-NMR(400MHz,DMSO-d6)δ8.53(dd,J＝2.5,0.8Hz,1H),7.99(d,J＝0.9Hz,1H),7.83(ddd,J＝8.3,5.3,2.1Hz,2H),7.54–7.46(m,2H),7.10(d,J＝0.9Hz,1H),4.12(d,J＝2.6Hz,3H),4.06(d,J＝2.2Hz,2H),2.83(t,J＝7.4Hz,2H),2.15(p,J＝7.5Hz,2H),1.52(s,6H)。
1 H-NMR (400MHz, DMSO-d6) δ8.53 (dd, J=2.5, 0.8Hz, 1H), 7.99 (d, J=0.9Hz, 1H), 7.83 (ddd, J=8.3, 5.3, 2.1 Hz, 2H), 7.54–7.46 (m, 2H), 7.10 (d, J=0.9Hz, 1H), 4.12 (d, J=2.6Hz, 3H), 4.06 (d, J=2.2Hz, 2H), 2.83 (t, J=7.4 Hz, 2H), 2.15 (p, J=7.5 Hz, 2H), 1.52 (s, 6H).
本发明中基于实施例一的方法1、实施例二的方法1的1-1项以及实施例三的示例化合物1的制法2，得出式(VI)化合物(Y为F，Z为CF
3，即普克鲁胺)的生产工艺。各步反应收率依次为91.3％、77.0％和80.6％，涉及Jocic反应、酯化和关环三步反应的方法总收率可达56.7％，远高于US9216957B2中仅涉及取代和关环两步反应的方法总收率11.8％。
In the present invention, based on Method 1 of Example 1, item 1-1 of Method 1 of Example 2, and Preparation Method 2 of Example Compound 1 of Example 3, the compound of formula (VI) (Y is F, Z is CF) is obtained 3 , the production process of Prokluamide). The reaction yields of each step are 91.3%, 77.0% and 80.6% in turn. The total yield of the method involving the three-step Jocic reaction, esterification and ring closure can reach 56.7%, which is much higher than that in US9216957B2, which only involves substitution and ring closure. The total yield of the method for the first step was 11.8%.
Claims (13)
- 一种式(I)化合物或其药学上可接受的盐；A compound of formula (I) or a pharmaceutically acceptable salt thereof;
其中：in:R选自C 1-C 6烷基，优选C 1-C 4烷基，更优选甲基。 R is selected from C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl, more preferably methyl. - 一种根据权利要求1所述的式(I)化合物的制备方法，其包括：式(II)化合物或其药学上可接受的盐与ROH进行酯化反应，得到式(I)化合物；A preparation method of a compound of formula (I) according to claim 1, comprising: esterification of a compound of formula (II) or a pharmaceutically acceptable salt thereof with ROH to obtain a compound of formula (I);
其中：in:R如权利要求1中所定义。R is as defined in claim 1 . - 根据权利要求2所述的制备方法，其特征在于：preparation method according to claim 2, is characterized in that:所述制备方法还包括：式(III)化合物或其药学上可接受的盐与三氯叔丁醇或其水合物进行反应，得到式(II)化合物；The preparation method further comprises: reacting the compound of formula (III) or a pharmaceutically acceptable salt thereof with chlorobutanol or its hydrate to obtain the compound of formula (II);
- 一种根据权利要求1所述的式(I)化合物的制备方法，其包括：式(III)化合物或其药学上可接受的盐与式(IV)化合物进行取代反应，得到式(I)化合物；A preparation method of a compound of formula (I) according to claim 1, comprising: a compound of formula (III) or a pharmaceutically acceptable salt thereof and a compound of formula (IV) are subjected to substitution reaction to obtain compound of formula (I) ;
其中：in:X为Cl、Br或I，优选Cl或Br，更优选Br；X is Cl, Br or I, preferably Cl or Br, more preferably Br;R如权利要求1中所定义。R is as defined in claim 1 . - 一种根据权利要求1所述的式(I)化合物的制备方法，其包括：式(III)化合物或其药学上可接受的盐与式(IV-OH)化合物进行取代反应，得到式(II) 化合物或其药学上可接受的盐，再与ROH进行酯化反应，得到式(I)化合物；A preparation method of a compound of formula (I) according to claim 1, comprising: a compound of formula (III) or a pharmaceutically acceptable salt thereof and a compound of formula (IV-OH) are subjected to substitution reaction to obtain a compound of formula (II) ) compound or its pharmaceutically acceptable salt, and then carry out esterification reaction with ROH to obtain the compound of formula (I);
其中：in:X为Cl、Br或I，优选Cl或Br，更优选Br；X is Cl, Br or I, preferably Cl or Br, more preferably Br;R如权利要求1中所定义。R is as defined in claim 1 . - 一种式(II)化合物的制备方法，其包括：式(III)化合物或其药学上可接受的盐与三氯叔丁醇或其水合物进行反应，得到式(II)化合物；A preparation method of a compound of formula (II), comprising: reacting a compound of formula (III) or a pharmaceutically acceptable salt thereof with chlorobutanol or a hydrate thereof to obtain a compound of formula (II);
- 一种式(VI)化合物的制备方法，其包括：根据权利要求1所述的式(I)化合物或其药学上可接受的盐与式(V)化合物进行关环反应，得到式(VI)化合物；A preparation method of a compound of formula (VI), comprising: a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a compound of formula (V) for ring-closing reaction to obtain formula (VI) compound;
其中：in:Y选自氢、卤素、C 1-C 3烷氧基、羟基、CF 3O和氰基，优选H或F，更优选F； Y is selected from hydrogen, halogen, C1 - C3alkoxy, hydroxyl, CF3O and cyano, preferably H or F, more preferably F;Z选自卤素、氰基、C 1-C 4烷基、C 1-C 4烷氧基、任选地被一个或多个卤素取代的C 1-C 4烷基和任选地被一个或多个卤素取代的C 1-C 4烷氧基，优选CF 3或CH 3O，更优选CF 3； Z is selected from halogen, cyano, C1 - C4alkyl, C1 - C4alkoxy , C1 - C4alkyl optionally substituted with one or more halogens, and optionally substituted with one or Multiple halogen-substituted C 1 -C 4 alkoxy groups, preferably CF 3 or CH 3 O, more preferably CF 3 ;R如权利要求1中所定义。R is as defined in claim 1 . - 一种式(VI)化合物的制备方法，其包括：A preparation method of a compound of formula (VI), comprising:式(III)化合物或其药学上可接受的盐与三氯叔丁醇或其水合物进行反应，得到式(II)化合物；The compound of formula (III) or a pharmaceutically acceptable salt thereof is reacted with chlorobutanol or its hydrate to obtain the compound of formula (II);
优选地，其进一步包括下列步骤：式(II)化合物或其药学上可接受的盐与ROH进行酯化反应，得到式(I)化合物；Preferably, it further comprises the following steps: the compound of formula (II) or a pharmaceutically acceptable salt thereof is esterified with ROH to obtain the compound of formula (I);
优选地，其进一步包括下列步骤：式(I)化合物或其药学上可接受的盐与式(V)化合物进行关环反应，得到式(VI)化合物；Preferably, it further comprises the following steps: the compound of formula (I) or a pharmaceutically acceptable salt thereof is subjected to ring closure reaction with the compound of formula (V) to obtain the compound of formula (VI);
其中：in:Y选自氢、卤素、C 1-C 3烷氧基、羟基、CF 3O和氰基； Y is selected from hydrogen, halogen, C1 - C3alkoxy, hydroxyl, CF3O and cyano;Z选自卤素、氰基、C 1-C 4烷基、C 1-C 4烷氧基、任选地被一个或多个卤素取代的C 1-C 4烷基和任选地被一个或多个卤素取代的C 1-C 4烷氧基； Z is selected from halogen, cyano, C1 - C4alkyl, C1 - C4alkoxy , C1 - C4alkyl optionally substituted with one or more halogens, and optionally substituted with one or Multiple halogen-substituted C 1 -C 4 alkoxy groups;R选自C 1-C 6烷基。 R is selected from C 1 -C 6 alkyl. - 根据权利要求8所述的制备方法，其特征在于：preparation method according to claim 8, is characterized in that:Y为H或F；Z为CF 3或CH 3O；R选自C 1-C 4烷基； Y is H or F; Z is CF 3 or CH 3 O; R is selected from C 1 -C 4 alkyl;优选地，Y为F；Z为CF 3；R为甲基。 Preferably, Y is F; Z is CF3 ; R is methyl.
- 根据权利要求1所述的式(I)化合物的用途，其用于制备式(VI)化合物；Use of a compound of formula (I) according to claim 1 for the preparation of a compound of formula (VI);
其中：in:Y选自氢、卤素、C 1-C 3烷氧基、羟基、CF 3O和氰基； Y is selected from hydrogen, halogen, C1 - C3alkoxy, hydroxyl, CF3O and cyano;Z选自卤素、氰基、C 1-C 4烷基、C 1-C 4烷氧基、任选地被一个或多个卤素取代的C 1-C 4烷基和任选地被一个或多个卤素取代的C 1-C 4烷氧基。 Z is selected from halogen, cyano, C1 - C4alkyl, C1 - C4alkoxy , C1 - C4alkyl optionally substituted with one or more halogens, and optionally substituted with one or Multiple halogen substituted C 1 -C 4 alkoxy groups. - 根据权利要求10所述的用途，其特征在于：Use according to claim 10, characterized in that:Y为H或F；Z为CF 3或CH 3O； Y is H or F; Z is CF 3 or CH 3 O;优选地，Y为F；Z为CF 3。 Preferably, Y is F; Z is CF3 .
- 根据权利要求1所述的式(I)化合物的用途，其用作式(VI)化合物分析用杂质对照品和/或标准品；The use of the compound of formula (I) according to claim 1, which is used as an impurity reference substance and/or standard substance for analysis of the compound of formula (VI);
其中：in:Y选自氢、卤素、C 1-C 3烷氧基、羟基、CF 3O和氰基； Y is selected from hydrogen, halogen, C1 - C3alkoxy, hydroxyl, CF3O and cyano;Z选自卤素、氰基、C 1-C 4烷基、C 1-C 4烷氧基、任选地被一个或多个卤素取代的C 1-C 4烷基和任选地被一个或多个卤素取代的C 1-C 4烷氧基。 Z is selected from halogen, cyano, C1 - C4alkyl, C1 - C4alkoxy , C1 - C4alkyl optionally substituted with one or more halogens, and optionally substituted with one or Multiple halogen substituted C 1 -C 4 alkoxy groups. - 根据权利要求12所述的用途，其特征在于：Use according to claim 12, characterized in that:Y为H或F；Z为CF 3或CH 3O； Y is H or F; Z is CF 3 or CH 3 O;优选地，Y为F；Z为CF 3。 Preferably, Y is F; Z is CF3 .
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