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WO2019020102A1 - 一种嘧啶酮并杂芳基类衍生物的制备方法及其中间体 - Google Patents

一种嘧啶酮并杂芳基类衍生物的制备方法及其中间体 Download PDF

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Publication number
WO2019020102A1
WO2019020102A1 PCT/CN2018/097365 CN2018097365W WO2019020102A1 WO 2019020102 A1 WO2019020102 A1 WO 2019020102A1 CN 2018097365 W CN2018097365 W CN 2018097365W WO 2019020102 A1 WO2019020102 A1 WO 2019020102A1
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ion
acid
group
formula
metal cation
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PCT/CN2018/097365
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English (en)
French (fr)
Inventor
贾君磊
刘兵
高晓晖
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江苏恒瑞医药股份有限公司
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Priority to UAA202001046A priority Critical patent/UA126345C2/uk
Priority to EP18837896.2A priority patent/EP3660017A4/en
Priority to BR112020000725-0A priority patent/BR112020000725A2/pt
Priority to CN201880004383.6A priority patent/CN109983017B/zh
Priority to RU2020105728A priority patent/RU2741788C1/ru
Priority to US16/632,698 priority patent/US11306085B2/en
Priority to KR1020207003768A priority patent/KR20200035043A/ko
Priority to AU2018305633A priority patent/AU2018305633B2/en
Priority to JP2020502943A priority patent/JP2020528060A/ja
Publication of WO2019020102A1 publication Critical patent/WO2019020102A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for the preparation of a pyrimidinone-heteroaryl derivative and an intermediate thereof.
  • Endometriosis is a common estrogen-dependent gynecological disease that often occurs during the reproductive years of women, and its mechanism of action remains unclear. Difficulties in the diagnosis of endometriosis and complex symptoms such as unknown etiology have severely blocked the discovery of effective treatments.
  • endometriosis is mainly diagnosed by laparoscopic surgery and treated by surgery, or by taking birth control pills, GnRH receptor agonists or progesterone to reduce estrogen levels in the body to control.
  • Gonadoliberin (Gonadoliberin; gonadotropin releasing hormone; GnRH), also known as luteinizing hormone releasing hormone (LHRH), is a decapeptide hormone synthesized by hypothalamic neuroendocrine cells (pGlu-His-Trp-Ser-Tyr-Gly- Leu-Arg-Pro-Gly-NH2) is a central regulator of the endocrine reproductive system. It is transported to the pituitary gland through the hypothalamic pituitary portal circulatory system, which binds to the GnRH receptor cells in the anterior pituitary, gonadotropins such as Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH).
  • LH Luteinizing Hormone
  • FSH Follicle-Stimulating Hormone
  • the GnRH receptor exerts its regulation by coupling with the G protein that activates the second messenger system of phosphatidylinositol calcium, while LH regulates the production of sex steroids, which regulate male spermatogenesis and female follicular development.
  • WO2015062391A1 discloses a class of small molecule GnRH receptor antagonists for the treatment of endometriosis, uterine fibroids and prostate cancer, the chemical name is 1-(4-(7-( 2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4,6-dioxo-4,5, a compound of 6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxyurea, which has good activity and can be effectively treated Endocrine and reproductive system diseases, the structure of which is shown in formula (I-1),
  • Example 11 of WO2015062391A1 discloses a process for the preparation of the compound of the formula (I-1) in a total of five steps, the specific reaction being as follows:
  • the method has the problems of small batch size, post-treatment method using thin layer chromatography purification, low yield, etc., wherein the reaction yield of the compound 9d is 69%, and the yield of the product 11 prepared in the last step is only 24.7%, which is unfavorable to the industry.
  • the production is expanded; and hydrochloric acid is added to the post-treatment of Preparation 9e, resulting in the generation of chlorinated impurities, which are not easily removed, and it is necessary to improve the preparation method thereof.
  • the technical problem to be solved by the present invention is to provide a method for preparing a compound of the formula (I) different from the prior art, changing the starting materials and intermediates to prepare the target product, by shortening the reaction steps, starting materials and the like
  • the method is simple and easy to purchase, the reaction conditions are simple and controllable, and the post-reaction treatment method is simple, and the preparation method is optimized to improve the yield and facilitate industrial expansion.
  • the present invention provides a process for the preparation of a compound of the formula (I) or a stereoisomer thereof, which comprises a compound of the formula (III), a salt thereof or a stereoisomer thereof and a formula (II) a step of reacting the compound or a salt thereof to give a compound of the formula (I),
  • R 1 is selected from alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or -OR 5 , wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently Optionally further one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - OR 5 , -C(O)OR 5 , -OC(O)R 5 , -NHS(O) m R 5 , -C(O)R 5 , -NHC(O)R 5 , -NHC(O)OR 5, -NR 6 R 7, -OC (O) NR 6 R 7, -C (O) NR 6 R 7, -NHC (O) NHR 5 group, or a substituted -NHC (
  • R 2 is selected from the group consisting of alkyl, wherein said alkyl group is further substituted with one or more substituents selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further substituted by one or more One selected from the group consisting of halogen, alkyl, haloalkyl, cyano, nitro, -C(O)OR 5 , -C(O)NR 6 R 7 , -OC(O)NR 6 R 7 , -OR 5 ,- Substituted by a substituent of NHS(O) m R 5 , -NHC(O)R 5 or -NR 6 R 7 wherein the haloalkyl group is preferably a trifluoromethyl group;
  • R 3 is selected from an alkyl group
  • R 4 is selected from a hydrogen atom, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 5 , -NR 6 R 7 or -NR 6 S(O) m R 5 , wherein the alkyl group,
  • the cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, oxo, alkyl, haloalkyl, hydroxyalkyl, -OR 5 , -C(O)OR Substituting 5 , -OC(O)R 5 , -NR 7 S(O) m R 5 , -S(O) m R 5 , -C(O)R 5 or -NHC(O)R 5 ;
  • R 5 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently Optionally further substituted by one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters ;
  • R 6 or R 7 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group
  • the groups are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters. Substituted by a substituent;
  • R 6 or R 7 together with a nitrogen atom to which they are attached form a heterocyclic group, wherein said heterocyclic group contains one or more N, O or S(O) m heteroatoms, and said heterocyclic group Optionally further substituted by one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters Replace
  • R a is selected from an alkyl group, wherein the alkyl group is optionally further selected from one or more selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, and a carboxy group. Substituted by a substituent of an acid or a carboxylic acid ester;
  • n 0, 1 or 2;
  • n 1, 2, 3 or 4.
  • the method further includes
  • n, D, E, G, R 1 , R 2 , R 3 , R 4 are as defined in formula (I);
  • the compound represented by the formula (VI) is a monometal alkoxide or a bimetal alkoxide, and M is selected from a monovalent metal cation, a divalent metal cation, a trivalent metal cation or a tetravalent metal cation, preferably sodium ion, potassium ion, lithium ion , calcium ion, magnesium ion, barium ion, aluminum ion, copper ion, zinc ion, zirconium ion, barium ion, boron ion, titanium ion or silicon ion, more preferably sodium ion;
  • X is halogen, preferably fluorine atom, chlorine atom or Bromine atom.
  • the method further comprises reacting the compound of the formula (VII) with a metal alkoxide to obtain a compound of the formula (VI).
  • n, D, E, G, R 1 , R 3 , R 4 are as defined in formula (I);
  • R b is selected from an alkyl group
  • the compound represented by the formula (VI) is a monometal alkoxide or a bimetal alkoxide, and M is selected from a monovalent metal cation, a divalent metal cation, a trivalent metal cation or a tetravalent metal cation, preferably sodium ion, potassium ion, lithium ion , calcium ion, magnesium ion, barium ion, aluminum ion, copper ion, zinc ion, zirconium ion, barium ion, boron ion, titanium ion or silicon ion, more preferably sodium ion.
  • the structure of the compound represented by the above formula (VI) is a simplified writing method, and in fact, the structure of the compound represented by the formula (VI) can also be Wherein p is 1, 2, 3 or 4, p' is 4 or 9, o is 2, 3 or 4, M' is different from M, and M and M' are respectively selected from monovalent metal cations and divalent metal cations.
  • a trivalent metal cation or a tetravalent metal cation preferably sodium ion, potassium ion, lithium ion, calcium ion, magnesium ion, barium ion, aluminum ion, copper ion, zinc ion, zirconium ion, strontium ion, boron ion, titanium ion Or silicon ion, more preferably sodium ion.
  • the present invention provides a method for producing a compound of the formula (I-1), characterized in that the method is
  • the method further includes
  • the compound represented by the formula (VI-1) is a monometal alkoxide or a bimetal alkoxide, and M is selected from a monovalent metal cation, a divalent metal cation, a trivalent metal cation or a tetravalent metal cation, preferably sodium ion, potassium ion, Lithium ion, calcium ion, magnesium ion, barium ion, aluminum ion, copper ion, zinc ion, zirconium ion, barium ion, boron ion, titanium ion or silicon ion, more preferably sodium ion.
  • the method further comprises reacting a compound represented by the formula (VII-1) with a metal alkoxide to obtain a compound represented by the formula (VI-1).
  • the acid being selected from the group consisting of organic or inorganic acids, preferably trifluoroacetic acid or acetic acid, preferably the hydrochloric acid.
  • the present invention also provides a compound of the formula (VI), a salt thereof or a stereoisomer thereof,
  • n, D, E, G, R 1 , R 3 , R 4 are as defined in formula (I);
  • the compound represented by the formula (VI) is a monometal alkoxide or a bimetal alkoxide, and M is selected from a monovalent metal cation, a divalent metal cation, a trivalent metal cation or a tetravalent metal cation, preferably sodium ion, potassium ion, lithium ion , calcium ion, magnesium ion, barium ion, aluminum ion, copper ion, zinc ion, zirconium ion, barium ion, boron ion, titanium ion or silicon ion, more preferably sodium ion.
  • the compound is selected from the group consisting of
  • the compound is selected from the group consisting of
  • the present invention provides a process for the preparation of a compound of the formula (VI), which is characterized in that the compound of the formula (VII) is reacted with a metal alkoxide to give a compound of the formula (VI).
  • n, D, E, G, R 1 , R 3 , R 4 are as defined in formula (I);
  • R b is selected from an alkyl group
  • the compound represented by the formula (VI) is a monometal alkoxide or a bimetal alkoxide, and M is selected from a monovalent metal cation, a divalent metal cation, a trivalent metal cation or a tetravalent metal cation, preferably sodium ion, potassium ion, lithium ion , calcium ion, magnesium ion, barium ion, aluminum ion, copper ion, zinc ion, zirconium ion, barium ion, boron ion, titanium ion or silicon ion, more preferably sodium ion.
  • the present invention also provides a process for producing a compound of the formula (VI-1), which is characterized in that the compound represented by the formula (VII-1) is reacted with a metal alkoxide to give a formula (VI-1).
  • the compound represented by the formula (VI-1) is a monometal alkoxide or a bimetal alkoxide
  • M is selected from a monovalent metal cation, a divalent metal cation, a trivalent metal cation or a tetravalent metal cation, preferably sodium ion or potassium.
  • Ions lithium ions, calcium ions, magnesium ions, barium ions, aluminum ions, copper ions, zinc ions, zirconium ions, barium ions, boron ions, titanium ions or silicon ions, more preferably sodium ions.
  • the acid is not added to the post-reaction treatment step of the method, and the acid is selected from an organic acid or an inorganic acid, and the organic acid is preferably trifluoroacetic acid or acetic acid, and the inorganic acid is preferably hydrochloric acid.
  • the structure of the compound represented by the above formula (VI-1) is a simplified writing method, and the structure of the compound represented by the formula (VI) may also be Wherein p is 1, 2, 3 or 4, p' is 4 or 9, o is 2, 3 or 4, M' is different from M, and M and M' are respectively selected from monovalent metal cations and divalent metal cations.
  • a trivalent metal cation or a tetravalent metal cation preferably sodium ion, potassium ion, lithium ion, calcium ion, magnesium ion, barium ion, aluminum ion, copper ion, zinc ion, zirconium ion, strontium ion, boron ion, titanium ion Or silicon ion, more preferably sodium ion.
  • the method is
  • the present invention also provides a method for producing a compound of the formula (I-1), characterized in that the method is
  • the acid is not added to the post-reaction treatment step of the method for preparing the formula (VI-1-1) from the compound of the formula (VII-1), and the acid is selected from an organic acid or an inorganic acid, and the organic acid is preferably used.
  • Trifluoroacetic acid or acetic acid, and the inorganic acid is preferably hydrochloric acid.
  • the present invention also provides a method of producing a compound of the formula (I-2), characterized in that the method is
  • the method further includes
  • the compound represented by the formula (VI-2) is a monometal alkoxide or a bimetal alkoxide, and M is selected from a monovalent metal cation, a divalent metal cation, a trivalent metal cation or a tetravalent metal cation, preferably sodium ion, potassium ion, Lithium ion, calcium ion, magnesium ion, barium ion, aluminum ion, copper ion, zinc ion, zirconium ion, barium ion, boron ion, titanium ion or silicon ion, more preferably sodium ion.
  • the method further includes
  • the acid being selected from the group consisting of organic or inorganic acids, preferably trifluoroacetic acid or acetic acid, preferably the hydrochloric acid.
  • the structure of the compound represented by the above formula (VI-2) is a simplified writing method, and the structure of the compound represented by the formula (VI) may also be Wherein p is 1, 2, 3 or 4, p' is 4 or 9, o is 2, 3 or 4, M' is different from M, and M and M' are respectively selected from monovalent metal cations and divalent metal cations.
  • a trivalent metal cation or a tetravalent metal cation preferably sodium ion, potassium ion, lithium ion, calcium ion, magnesium ion, barium ion, aluminum ion, copper ion, zinc ion, zirconium ion, strontium ion, boron ion, titanium ion Or silicon ion, more preferably sodium ion.
  • the present invention also provides a method for producing a compound of the formula (I-2), characterized in that the method is
  • the acid is not added to the post-reaction treatment step of the method of the formula (VI-2-1) by the compound of the formula (VII-2), and the acid is selected from an organic acid or an inorganic acid, and the organic acid is preferably used.
  • Trifluoroacetic acid or acetic acid, and the inorganic acid is preferably hydrochloric acid.
  • the present invention also provides a method of producing a compound of the formula (I-3), characterized in that the method is
  • the method further includes
  • the compound represented by the formula (VI-3) is a monometal alkoxide or a bimetal alkoxide, and M is selected from a monovalent metal cation, a divalent metal cation, a trivalent metal cation or a tetravalent metal cation, preferably sodium ion, potassium ion, Lithium ion, calcium ion, magnesium ion, barium ion, aluminum ion, copper ion, zinc ion, zirconium ion, barium ion, boron ion, titanium ion or silicon ion, more preferably sodium ion.
  • the method further includes
  • the acid being selected from the group consisting of organic or inorganic acids, preferably trifluoroacetic acid or acetic acid, preferably the hydrochloric acid.
  • the structure of the compound represented by the above formula (VI-3) is a simplified writing method, and in fact, the structure of the compound represented by the formula (VI) can also be Wherein p is 1, 2, 3 or 4, p' is 4 or 9, o is 2, 3 or 4, M' is different from M, and M and M' are respectively selected from monovalent metal cations and divalent metal cations.
  • a trivalent metal cation or a tetravalent metal cation preferably sodium ion, potassium ion, lithium ion, calcium ion, magnesium ion, barium ion, aluminum ion, copper ion, zinc ion, zirconium ion, strontium ion, boron ion, titanium ion Or silicon ion, more preferably sodium ion.
  • the present invention also provides a method of producing a compound of the formula (I-3), characterized in that the method is
  • the acid is not added to the post-reaction treatment step of the method for preparing the formula (VI-3-1) from the compound of the formula (VII-3), and the acid is selected from an organic acid or an inorganic acid, and the organic acid is preferably used.
  • Trifluoroacetic acid or acetic acid, and the inorganic acid is preferably hydrochloric acid.
  • the organic acid is selected from the group consisting of acetic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, preferably acetic acid;
  • the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
  • halogen or halogen atom as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
  • alkyl group in the present invention means a linear or branched alkyl group having 1 to 20 carbon atoms, and includes, for example, "C 1-6 alkyl group", “C 1-4 alkyl group”, etc., specific examples Including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, Neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2- Ethyl butyl,
  • alkenyl group as used in the present invention means a straight or branched chain group having at least one double bond and having 2 to 20 carbon atoms, and includes, for example, "C 2-6 alkenyl group, C 2-4 alkenyl group”. Wait. Examples thereof include, but are not limited to, ethenyl, propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, and the like.
  • alkynyl group as used in the present invention means a straight or branched chain group having at least one triple bond and having 2 to 20 carbon atoms, and includes, for example, "C 2-6 alkynyl group, C 2-4 alkynyl group". Wait. Examples thereof include, but are not limited to, ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3 - hexynyl, 5-methyl-2-hexynyl and the like.
  • haloalkyl refers to a group derived by substituting one or more "halogen atoms” for one or more hydrogen atoms on an "alkyl group” as described above. Defined.
  • hydroxyalkyl or hydroxyalkyl refers to a radical derived from one or more "hydroxy” groups substituted by one or more hydrogen atoms on an "alkyl” group as previously described. definition.
  • alkylsulfonylamino or alkylsulfonyl means alkyl-O-, haloalkyl-O-, alkyl-C(O)-, alkyl-OC(O)-, C(O)-alkane -O-, alkyl-C(O)-NH-, alkyl-NH-C(O)-, alkyl-NH-, (alkyl) 2 -N-, alkyl-S(O) 2 a group to which -NH- or alkyl-S(O) 2 - is attached, wherein "alkyl, haloalkyl” is as defined above.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which includes from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably cycloalkyl.
  • the ring contains from 3 to 10 carbon atoms, and most preferably the cycloalkyl ring contains from 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • aryl group as used in the present invention means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (that is, a ring sharing a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10
  • the aryl group is more preferably a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein at least one of the ring atoms is a hetero atom such as a nitrogen atom or oxygen.
  • An atom or a sulfur atom, and the remaining ring atoms are carbon; optionally, a ring atom (for example, a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxidized.
  • it comprises 3 to 12 ring atoms or 5 to 12 ring atoms, wherein 1 to 4 are hetero atoms, more preferably the heterocyclic ring contains 3 to 8 ring atoms, and more preferably the heterocyclic ring contains 5 to 6 Ring atom.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • heteroaryl refers to a 5 to 14 membered aryl group having from 1 to 4 heteroatoms as ring atoms and the remainder of the ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur or nitrogen.
  • the "alcohol solvent” as used in the present invention means a group derived from one or more "hydroxyl groups” substituted with one or more hydrogen atoms on the "C 1-6 alkyl group", said "hydroxyl group” and "C” 1-6 alkyl” is as defined above, and specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol.
  • the "metal alkoxide” as used in the present invention refers to a compound formed by replacing a hydrogen of a hydroxyl group in an alcohol with a metal element, which is also called a metal acid ester or a metal alkoxide compound, and the metal alkoxide is classified into a single metal alkoxide and a bimetal alkoxide.
  • the metal element may be a monovalent, divalent, trivalent or tetravalent metal, and specific examples include, but are not limited to, lithium methoxide, sodium methoxide, sodium ethoxide, calcium dimethoxide, aluminum tripropoxide, silicon tetraethoxide, magnesium ethoxide Aluminum or n-butanol magnesium aluminum.
  • the “stereoisomers” described in the present invention are classified into conformational and conformational isomers, and the configurational isomerization is further classified into cis-trans isomerization and optical isomerization (or enantiomeric).
  • Conformational isomerism refers to a stereoisomerism in which organic molecules of a certain configuration cause different arrangement of atoms or groups of molecules in space due to the rotation or distortion of carbon and carbon single bonds. Common alkanes and rings are common. The structure of an alkane compound, such as the chair conformation and the ship conformation that appear in the cyclohexane structure.
  • optical isomer means that when the compound of the invention contains one or more asymmetric centers, it can be used as a racemate and a racemic mixture, a single enantiomer, or a non- Enantiomeric mixtures and single diastereomers.
  • the compounds of the invention have asymmetric centers, each of which will independently produce two optical isomers, the scope of the invention including all possible optical isomers and mixtures of diastereomers and pure or partially Pure compound. If the compound of the present invention contains an olefinic double bond, the present invention includes a cis isomer and a trans isomer unless otherwise specified.
  • the compounds of the present invention may exist in tautomeric forms which have different hydrogen attachment points by displacement of one or more double bonds.
  • a ketone and its enol form are keto-enol tautomers.
  • Each tautomer and mixtures thereof are included in the present invention.
  • the starting materials and intermediates of the present invention are different, providing a completely different synthetic method, and the starting materials and reactants are simple and easy to purchase.
  • the post-treatment of the reaction is simple, and the purification method is not required to be separated by column chromatography. After the reaction is completed, the solid is directly obtained, and the filtration can be obtained, and the acid treatment is avoided, and the post-treatment method is easy to industrially expand production.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR measurement was carried out using a Bruker AVANCE-500 nuclear magnetic apparatus, and the solvent was determined to be a deuterated reagent, and the internal standard was tetramethylsilane (TMS).
  • Example 1 1-(4-(7-(2,6-Difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl) Of -4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxyurea
  • Raw material VII-1 (90 g) was suspended in methanol (900 mL), 30% sodium methoxide methanol solution (101 g) was added, and the reaction was stirred at 30 ° C for about 15 hours in an oil bath. After the reaction was completed, isopropanol (1.8 L) was added. Stir well, cool to room temperature, freeze and crystallize for 4 h; filter, collect the filter cake, beat with acetone (320 mL) for 1.5 hours, cool in an ice bath, filter, collect the filter cake, and dry in vacuo to give the title product (65.9 g). The rate was 81.0% and the purity was 99.27%.
  • the acetone/purified water mixed solvent (5.2 kg acetone/2.2 kg purified water) and the above filter cake were added to the reaction flask, heated under reflux for 0.5 h with stirring, cooled to 0-10 ° C, stirring was continued for 2 h, filtered, and acetone/purified.
  • the mixed solvent of water (1.2 kg of acetone / 0.5 kg of purified water) was washed and dried to give a solid (1203.1 g), yield 95%, purity 93.64%.
  • Example 2 Preparation of the compound 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-) by the method of the above Example 1.
  • Example 3 Preparation of the compound 1-(4-(5-((benzyl)methyl)methyl)-1-(2,6-difluorobenzyl)-2) by the method of the above Example 1. ,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea (formula I-3))

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Abstract

本发明涉及一种嘧啶酮并杂芳基类衍生物的制备方法及其中间体。具体而言，本发明通过改变起始原料和中间体来制备嘧啶酮并杂芳基类衍生物。该方法缩短了反应步骤、提高了反应产率、简单易操控、利于工业扩大生产。

Description

一种嘧啶酮并杂芳基类衍生物的制备方法及其中间体 技术领域
本发明涉及一种嘧啶酮并杂芳基类衍生物的制备方法及其中间体。
背景技术
子宫内膜异位症是一种常见的雌激素依赖的妇科疾病，常发生于女性生育年龄期间，其作用机制尚不清楚。子宫内膜异位症的诊断困难及病因不明等复杂的症状，严重阻滞了其有效治疗方法的发现。目前，子宫内膜异位症主要通过腹腔镜手术诊断，并通过外科手术进行治疗，或者服用避孕药，GnRH受体激动剂或孕激素减少体内雌激素水平来进行控制。
促性腺激素释放激素(Gonadoliberin；gonadotropin releasing hormone；GnRH)也称黄体生成素释放激素(LHRH)，是由下丘脑神经内分泌细胞合成的十肽激素(pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2)，是内分泌生殖系统中的中枢调节因素。其通过下丘脑垂体门脉循环系统将其输送到垂体，与垂体前叶的GnRH受体细胞结合，促性腺激素如黄体生成素(Luteinizing Hormone,LH)和卵泡刺激素(Follicle-Stimulating Hormone,FSH)的分泌和释放，调节卵巢和黄体的正常发育，在下丘脑-垂体-性腺轴发挥重要作用。GnRH受体通过与能够激活磷脂酰肌醇钙第二信使体系的G蛋白偶联发挥其调节作用，而LH则调节性类固醇的产生，FSH调节男性精子发生及女性卵泡的发育。
WO2015062391A1(公开日2015.05.07)公开了一类小分子GnRH受体的拮抗剂，用于治疗子宫内膜异位症、子宫肌瘤和前列腺癌，化学名为1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二氧代-4,5,6,7-四氢-2H-吡唑[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲的化合物，该类结构的化合物具有良好的活性，能够有效治疗内分泌生殖系统疾病，其结构如式(I-1)所示，
Figure PCTCN2018097365-appb-000001
WO2015062391A1的实施例11公开了式(I-1)所示化合物的制备方法，总计五步反应，具体反应如下所示：
Figure PCTCN2018097365-appb-000002
该方法存在批量小、后处理方法使用薄层色谱法纯化、产率低等问题，其中制备化合物9d的反应产率为69％，最后一步制备产物11的产率仅为24.7％，不利于工业扩大生产；并且，在制备9e的后处理中加入盐酸，导致氯代杂质的产生、该杂质不易除去，有必要改进其制备方法。
发明内容
本发明要解决的技术问题是提供一种与现有技术不同的制备式(I)所示化合物的方法，改变起始原料和中间体制备目标产物，通过缩短反应步骤、起始原料等反应物简单易购买、反应条件简单可控、反应后处理方法简单等途径优化制备方法，提高产率、利于工业扩大生产。
本发明的技术方案如下：
本发明提供一种制备式(I)所示化合物或其立体异构体的方法，其特征在于，所述方法包括式(III)所示化合物、其盐或其立体异构体与式(II)所示化合物或其盐 反应得到式(I)所示化合物的步骤，
Figure PCTCN2018097365-appb-000003
其中，
当G为N时，D为C，E为-CH-；
当G为C时，D和E为N或D为C、E为S；
R 1选自烷基、环烷基、杂环基、芳基、杂芳基或-OR 5，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、氰基、硝基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR 5、-C(O)OR 5、-OC(O)R 5、-NHS(O) mR 5、-C(O)R 5、-NHC(O)R 5、-NHC(O)OR 5、-NR 6R 7、-OC(O)NR 6R 7、-C(O)NR 6R 7、-NHC(O)NHR 5或-NHC(O)NHOR 5的取代基所取代；
R 2选自烷基，其中所述的烷基进一步被一个或多个选自芳基或杂芳基的取代基所取代，其中所述的芳基或杂芳基任选进一步被一个或多个选自卤素、烷基、卤代烷基、氰基、硝基、-C(O)OR 5、-C(O)NR 6R 7、-OC(O)NR 6R 7、-OR 5、-NHS(O) mR 5、-NHC(O)R 5或-NR 6R 7的取代基所取代，其中所述的卤代烷基优选为三氟甲基；
R 3选自烷基；
R 4选自氢原子、环烷基、杂环基、芳基、杂芳基、-OR 5、-NR 6R 7或-NR 6S(O) mR 5，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、氧代基、烷基、卤代烷基、羟烷基、-OR 5、-C(O)OR 5、-OC(O)R 5、-NR 7S(O) mR 5、-S(O) mR 5、-C(O)R 5或-NHC(O)R 5的取代基所取代；
R 5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
R 6或R 7各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
或者，R 6或R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基内含有一个或多个N、O或S(O) m杂原子，并且所述杂环基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、羧 酸或羧酸酯的取代基所取代；
R a选自烷基，其中所述的烷基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
m为0、1或2；
n为1、2、3或4。
上述方案中，所述方法还包括
Figure PCTCN2018097365-appb-000004
其中，n、D、E、G、R 1、R 2、R 3、R 4的定义如式(I)中所述；
式(VI)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子；X为卤素，优选氟原子、氯原子或溴原子。
上述方案中，所述方法进一步包括式(VII)所示化合物与金属醇盐反应得到式(VI)所示化合物
Figure PCTCN2018097365-appb-000005
其中，n、D、E、G、R 1、R 3、R 4的定义如式(I)中所述；
R b选自烷基；
式(VI)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
上述式(VI)所示化合物结构是一种简化写法，事实上式(VI)所示化合物结构还 可以为
Figure PCTCN2018097365-appb-000006
其中，p为1、2、3或4，p′为4或9，o为2、3或4，M′与M不相同，M、M′分别选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
本发明提供一种制备式(I-1)所示化合物的方法，其特征在于，所述方法为
Figure PCTCN2018097365-appb-000007
上述方案中，所述方法还包括
Figure PCTCN2018097365-appb-000008
式(VI-1)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
上述方案中，所述方法还包括式(VII-1)所示化合物与金属醇盐反应得到式(VI-1)所示化合物
Figure PCTCN2018097365-appb-000009
优选的，所述方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机 酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
本发明还提供一种式(VI)所示化合物、其盐或其立体异构体，
Figure PCTCN2018097365-appb-000010
其中，n、D、E、G、R 1、R 3、R 4的定义如式(I)中所述；
式(VI)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
优选的，所述化合物选自
Figure PCTCN2018097365-appb-000011
更优选的，所述化合物选自
Figure PCTCN2018097365-appb-000012
本发明提供一种制备式(VI)所示化合物的方法，其特征在于，所述方法为式(VII)所示化合物与金属醇盐反应得到式(VI)所示化合物
Figure PCTCN2018097365-appb-000013
其中，n、D、E、G、R 1、R 3、R 4的定义如式(I)中所述；
R b选自烷基；
式(VI)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价 金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
本发明还提供一种制备式(VI-1)所示化合物的方法，其特征在于，所述方法为式(VII-1)所示化合物与金属醇盐反应得到式(VI-1)所示化合物
Figure PCTCN2018097365-appb-000014
其中，式(VI-1)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
上述方案中，所述方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
上述式(VI-1)所示化合物结构是一种简化写法，事实上式(VI)所示化合物结构还可以为
Figure PCTCN2018097365-appb-000015
其中，p为1、2、3或4，p′为4或9，o为2、3或4，M′与M不相同，M、M′分别选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
优选的，所述方法为
Figure PCTCN2018097365-appb-000016
本发明还提供一种制备式(I-1)所示化合物的方法，其特征在于，所述方法为
Figure PCTCN2018097365-appb-000017
上述方案中，由式(VII-1)所示化合物制备式(VI-1-1)方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
本发明还提供一种制备式(I-2)所示化合物的方法，其特征在于，所述方法为
Figure PCTCN2018097365-appb-000018
上述方案中，所述方法还包括
Figure PCTCN2018097365-appb-000019
式(VI-2)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼 离子、钛离子或硅离子，更优选钠离子。
上述方案中，所述方法还包括
Figure PCTCN2018097365-appb-000020
优选的，所述方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
上述式(VI-2)所示化合物结构是一种简化写法，事实上式(VI)所示化合物结构还可以为
Figure PCTCN2018097365-appb-000021
其中，p为1、2、3或4，p′为4或9，o为2、3或4，M′与M不相同，M、M′分别选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
本发明还提供一种制备式(I-2)所示化合物的方法，其特征在于，所述方法为，
Figure PCTCN2018097365-appb-000022
上述方案中，由式(VII-2)所示化合物制备式(VI-2-1)方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
本发明还提供一种制备式(I-3)所示化合物的方法，其特征在于，所述方法为
Figure PCTCN2018097365-appb-000023
上述方案中，所述方法还包括
Figure PCTCN2018097365-appb-000024
式(VI-3)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
上述方案中，所述方法还包括
Figure PCTCN2018097365-appb-000025
优选的，所述方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
上述式(VI-3)所示化合物结构是一种简化写法，事实上式(VI)所示化合物结构还可以为
Figure PCTCN2018097365-appb-000026
其中，p为1、2、3或4，p′为4或9，o为2、3或4，M′与M不相同，M、M′分别选自一价 金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
本发明还提供一种制备式(I-3)所示化合物的方法，其特征在于，所述方法为
Figure PCTCN2018097365-appb-000027
上述方案中，由式(VII-3)所示化合物制备式(VI-3-1)方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
一种制备式(I-1)、式(I-2)、式(I-3)所示化合物的药学上可接受的盐的方法，包括前述方案中的步骤，以及通过式(I-1)、式(I-2)、式(I-3)所示化合物与酸反应制备得到其药学上可接受的盐的步骤，所述酸选自有机酸或无机酸，优选有机酸；所述有机酸选自乙酸、马来酸、富马酸、甲磺酸、苯磺酸或对甲苯磺酸，优选乙酸；所述无机酸选自盐酸、氢溴酸、硫酸或磷酸。
发明详述
为了更容易理解本发明，以下具体定义了某些技术和科学术语。除显而易见在本文件中的它处另有明确定义，否则本文使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
本发明所述“卤素或卤素原子”是指氟原子、氯原子、溴原子、碘原子等。
本发明所述“烷基”是指直链或支链的含有1-20个碳原子的烷基，包括例如“C 1-6烷基”、“C 1-4烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异 丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本发明所述“烯基”是指含有至少一个双键且碳原子数为2-20的直链或支链的基团，包括例如“C 2-6烯基、C 2-4烯基”等。其实例包括但不限于：乙烯基、丙烯基、2-丁烯基、2-戊烯基、3-戊烯基、2-己烯基、3-己烯基等。
本发明所述“炔基”是指含有至少一个三键且碳原子数为2-20的直链或支链的基团，包括例如“C 2-6炔基、C 2-4炔基”等。其实例包括但不限于：乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基、5-甲基-2-己炔基等。
本发明所述的“卤代烷基”指一个或多个“卤素原子”取代“烷基”上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“烷基”如前文所定义。
本发明所述的“羟基烷基或羟烷基”指一个或多个“羟基”取代“烷基”上的一个或多个氢原子所衍生的基团，所述“烷基”如前文所定义。
本发明所述的“烷氧基、卤代烷氧基、烷基羰基、烷氧羰基、烷氧羰基、羰基烷氧基、烷基羰基氨基、烷基氨基羰基、烷基氨基、二烷基氨基、烷基磺酰氨基或烷基磺酰基”是指以烷基-O-、卤代烷基-O-、烷基-C(O)-、烷基-O-C(O)-、C(O)-烷基-O-、烷基-C(O)-NH-、烷基-NH-C(O)-、烷基-NH-、(烷基) 2-N-、烷基-S(O) 2-NH-或烷基-S(O) 2-方式连接的基团，其中“烷基、卤代烷基”如前文所定义。
本发明所述的“氧代基”指＝O。
本发明所述“环烷基”是指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至10个碳原子，最优选环烷基环包含3至6个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。多环环烷基包括螺环、稠环和桥环的环烷基。
本发明所述的“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元的芳基，更优选苯基和萘基，最优选苯基。
本发明所述的“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子，其余环原子为碳；任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧化。优选包括3至12个环原子或5至12个环原子，其中1-4个是杂原子，更优选杂环基环包含3至8个环原子，更优选杂环基环包含5至6个环原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、四氢呋喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。
本发明所述的“杂芳基”指具有1至4个杂原子作为环原子，其余的环原子为碳的5至14元芳基，其中杂原子包括氧、硫或氮。优选为5至10元的杂芳基，更优选为5元至6元的杂芳基，具体实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等；所述杂芳基还可以稠合于芳基、杂环基或环烷基环上。
本发明所述的“碳原子、氮原子或硫原子被氧代/氧化”是指形成C＝O、N＝O、S＝O或SO2的结构。
本发明所述的“醇类溶剂”是指一个或多个“羟基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“羟基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。
本发明所述的“金属醇盐”指由金属元素置换醇中羟基的氢所形成的化合物，又称金属酸酯或金属烷氧基化合物，金属醇盐分为单金属醇盐、双金属醇盐等，金属元素可以是一价、二价、三价或四价金属，具体实例包括但不限于：甲醇锂、甲醇钠、乙醇钠、二甲醇钙、三丙醇铝、四乙醇硅、乙醇镁铝或正丁醇镁铝等。
本发明所述的“立体异构”分为构象异构和构型异构，而构型异构还分为顺反异构和旋光异构(或对映异构)。构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象，常见的有烷烃和环烷烃类化合物的结构，如环己烷结构中出现 的椅式构象和船式构象。“旋光异构体(或对映异构体)”，指当本发明化合物含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心，这类不对称中心各自会独立地产生两个光学异构体，本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物若含有烯烃双键，除非特别说明，本发明包括顺式异构体和反式异构体。本发明所述的化合物可以以互变异构体形式存在，其通过一个或多个双键位移而具有不同的氢的连接点。例如，酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明中。对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物，均包括在本发明范围中。
发明的有益效果
与现有技术相比，本发明制备式(I)所示化合物的技术方案具有以下优点：
(1)与现有技术比较，本发明的起始原料和中间体不相同，提供了一种完全不同思路的合成方法，并且起始原料和反应物均简单、易购买。
(2)产率提高，现有技术公开的终产物产率为24.7％，本发明终产物产率为80％。
(3)反应的后处理简单，不需要通过柱色谱分离提纯方法，反应结束后直接得到固体，过滤即可得到，避免加酸处理，该后处理方法易于工业扩大生产。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-500核磁仪，测定溶剂为氘代试剂，内标为四甲基硅烷(TMS)。
5-((二甲氨基)甲基)-3-(3-(6-甲氧基哒嗪-3-基)脲基)-1-(4-硝基苯基)-1H-吡唑-4-羧酸乙酯(式(VII-1)化合物)的制备可参照专利申请WO2015062391A1(公开日2015.05.07)实施例9中的方法，
Figure PCTCN2018097365-appb-000028
实施例1、1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二氧代-4,5,6,7-四氢-2H-吡唑[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲的制备
Figure PCTCN2018097365-appb-000029
第一步、式(VI-1-1)化合物的制备
将原料VII-1(90g)悬浮于甲醇(900mL)中，加入30％甲醇钠甲醇溶液(101g)，油浴30℃下搅拌反应约15小时，反应结束后，加入异丙醇(1.8L)，搅拌均匀，冷却至室温后冷冻析晶4h；过滤，收集滤饼，用丙酮(320mL)打浆1.5小时，冰浴冷却，过滤，收集滤饼，真空干燥，得到标题产物(65.9g)，产率81.0％，纯度为99.27％。
第二步、式(IV-1)化合物的制备
将原料VI-1-1(1100g)、N,N-二甲基甲酰胺(7.0kg)加入反应瓶中，搅拌均匀，加入2,6-二氟氯苄(427.2g)和N,N-二异丙基乙胺(926.4g)，升温至80-110℃搅拌反 应1～3h，反应结束后，将反应液冷却，取纯化水(30.0kg)加入反应瓶中，冷却至0～10℃，搅拌下将上述反应液倒入预冷的纯化水中，搅拌0.5h，甩滤，滤饼用纯化水(25.0kg×2)洗涤，收集滤饼；
将丙酮/纯化水混合溶剂(5.2kg丙酮/2.2kg纯化水)和上述滤饼加入反应瓶中，搅拌下加热回流0.5h，冷却至0-10℃后继续搅拌2h，过滤，用丙酮/纯化水混合溶剂(1.2kg丙酮/0.5kg纯化水)洗涤，干燥后得固体(1203.1g)，产率95％，纯度为93.64％。
第三步、式(III-1)化合物的制备
将原料IV-1(1201.1g)、无水乙醇(4.0kg)加入反应瓶中，搅拌下冷却至0-15℃，加入盐酸(5.8kg)，搅拌均匀，加入二水合氯化亚锡(2400.6g)，于15-40℃搅拌反应1-3.5h，反应结束后，控制25℃以下，用25％(w/w)氢氧化钠溶液(4.1kg氢氧化钠溶于12.3kg纯化水中)，调节pH＝11-12，甩滤，用纯化水(10.0kg)洗涤，滤饼干燥后柱层析纯化，减压浓缩后，残余物加入正己烷(7.0kg)，室温搅拌0.5h，过滤，干燥后得固体(972.6g)，产率90％，纯度为98.01％。
第四步、式(I-1)化合物的制备
将原料III-1(970.6g)、四氢呋喃(11.5kg)、4-甲氧基氨基甲酸硝基苯酯(423.8g，采用专利申请WO2011090935A1公开的方法制备而得)、N,N-二异丙基乙胺(704.1g)加入反应瓶中，于15-40℃搅拌反应16-18h，反应结束后，冷却至0～10℃搅拌2h，过滤，滤饼加入四氢呋喃(6.0kg)中，室温搅拌1.5h，过滤，滤饼用四氢呋喃(1.0kg)洗涤，干燥后得固体(807.9g)，产率80％；
将上述所得粗品(805.9g)、丙酮/纯化水的混合溶剂(7897.8g丙酮/2014.8g纯化水)加入反应瓶中，升温至回流搅拌溶清，趁热过滤，滤液自然冷却至室温，继续搅拌20-24h，冷却至0-15℃搅拌2h，过滤，用纯化水(2.5kg×2)洗涤，干燥后得固体(606.1g)，产率90％，纯度为99.9％。
MS m/z(ESI):608.3[M+1]
1H-NMR(400MHz,DMSO-d 6)δ9.69(s,1H),9.17(s,1H),7.79-7.82(d,2H),7.73-7.75(d,1H),7.68-7.70(d,2H),7.42-7.45(d,1H),7.37-7.41(m,1H),7.06-7.12(m,2H),5.28(s,2H),4.09(s,3H),3.67(s,2H),3.66(s,3H),2.17(s,6H).
实施例2、参考上述实施例1中的方法制备化合物1-(4-(1-(2,6-二氟苄基)-5-((二甲氨基)甲基)-3-(6-甲氧基哒嗪-3-基)-2,4-二氧代-1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲(式(I-2)所示)
Figure PCTCN2018097365-appb-000030
实施例3、参考上述实施例1中的方法制备化合物1-(4-(5-((苄基(甲基)氨基)甲基)-1-(2,6-二氟苄基)-2,4-二氧代-3-苯基-1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-3-甲氧基脲(式(I-3)所示)
Figure PCTCN2018097365-appb-000031

Claims (29)

  1. 一种制备式(I)所示化合物或其立体异构体的方法，其特征在于，所述方法包括式(III)所示化合物、其盐或其立体异构体与式(II)所示化合物或其盐反应得到式(I)所示化合物的步骤，
    Figure PCTCN2018097365-appb-100001
    其中，
    当G为N时，D为C，E为-CH-；
    当G为C时，D和E为N或D为C、E为S；
    R 1选自烷基、环烷基、杂环基、芳基、杂芳基或-OR 5，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、氰基、硝基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR 5、-C(O)OR 5、-OC(O)R 5、-NHS(O) mR 5、-C(O)R 5、-NHC(O)R 5、-NHC(O)OR 5、-NR 6R 7、-OC(O)NR 6R 7、-C(O)NR 6R 7、-NHC(O)NHR 5或-NHC(O)NHOR 5的取代基所取代；
    R 2选自烷基，其中所述的烷基进一步被一个或多个选自芳基或杂芳基的取代基所取代，其中所述的芳基或杂芳基任选进一步被一个或多个选自卤素、烷基、卤代烷基、氰基、硝基、-C(O)OR 5、-C(O)NR 6R 7、-OC(O)NR 6R 7、-OR 5、-NHS(O) mR 5、-NHC(O)R 5或-NR 6R 7的取代基所取代，其中所述的卤代烷基优选为三氟甲基；
    R 3选自烷基；
    R 4选自氢原子、环烷基、杂环基、芳基、杂芳基、-OR 5、-NR 6R 7或-NR 6S(O) mR 5，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、氧代基、烷基、卤代烷基、羟烷基、-OR 5、-C(O)OR 5、-OC(O)R 5、-NR 7S(O) mR 5、-S(O) mR 5、-C(O)R 5或-NHC(O)R 5的取代基所取代；
    R 5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    R 6或R 7各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多 个选自烷基、卤素、羟基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    或者，R 6或R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基内含有一个或多个N、O或S(O) m杂原子，并且所述杂环基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    R a选自烷基，其中所述的烷基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    m为0、1或2；
    n为1、2、3或4。
  2. 如权利要求1所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018097365-appb-100002
    其中，n、D、E、G、R 1、R 2、R 3、R 4的定义如权利要求1中所述；
    式(VI)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子；X为卤素，优选氟原子、氯原子或溴原子。
  3. 如权利要求2所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018097365-appb-100003
    其中，n、D、E、G、R 1、R 3、R 4的定义如权利要求1中所述；
    M的定义如权利要求2中所述；
    R b选自烷基。
  4. 一种制备式(I-1)所示化合物的方法，其特征在于，所述方法为
    Figure PCTCN2018097365-appb-100004
  5. 如权利要求4所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018097365-appb-100005
    式(VI-1)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
  6. 如权利要求5所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018097365-appb-100006
  7. 如权利要求6所述的方法，其特征在于，所述方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
  8. 一种式(VI)所示化合物、其盐或其立体异构体，
    Figure PCTCN2018097365-appb-100007
    其中，n、D、E、G、R 1、R 3、R 4的定义如权利要求1中所述；
    式(VI)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
  9. 如权利要求8所述的化合物，所述化合物选自
    Figure PCTCN2018097365-appb-100008
  10. 如权利要求9所述的化合物，所述化合物选自
    Figure PCTCN2018097365-appb-100009
  11. 一种制备式(VI)所示化合物的方法，其特征在于，所述方法为
    Figure PCTCN2018097365-appb-100010
    其中，n、D、E、G、R 1、R 3、R 4的定义如权利要求1中所述；
    R b选自烷基；
    式(VI)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、 钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
  12. 一种制备式(VI-1)所示化合物的方法，其特征在于，所述方法为
    Figure PCTCN2018097365-appb-100011
    其中，式(VI-1)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
  13. 如权利要求12所述的方法，其特征在于，所述方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
  14. 如权利要求13所述的方法，其特征在于，所述方法为
    Figure PCTCN2018097365-appb-100012
  15. 一种制备式(I-1)所示化合物的方法，其特征在于，所述方法为
    Figure PCTCN2018097365-appb-100013
  16. 如权利要求15所述的方法，其特征在于，由式(VII-1)所示化合物制备式(VI-1)方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
  17. 一种制备式(I-2)所示化合物的方法，其特征在于，所述方法为
    Figure PCTCN2018097365-appb-100014
  18. 如权利要求17所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018097365-appb-100015
    式(VI-2)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
  19. 如权利要求18所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018097365-appb-100016
  20. 如权利要求19所述的方法，其特征在于，所述方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
  21. 一种制备式(I-2)所示化合物的方法，其特征在于，所述方法为，
    Figure PCTCN2018097365-appb-100017
  22. 如权利要求21所述的方法，其特征在于，由式(VII-2)所示化合物制备式(VI-2-1)方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
  23. 一种制备式(I-3)所示化合物的方法，其特征在于，所述方法为
    Figure PCTCN2018097365-appb-100018
  24. 如权利要求23所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018097365-appb-100019
    式(VI-3)所示化合物为单金属醇盐或双金属醇盐，M选自一价金属阳离子、二价金属阳离子、三价金属阳离子或四价金属阳离子，优选钠离子、钾离子、锂离子、钙离子、镁离子、钡离子、铝离子、铜离子、锌离子、锆离子、锗离子、硼离子、钛离子或硅离子，更优选钠离子。
  25. 如权利要求24所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018097365-appb-100020
  26. 如权利要求25所述的方法，其特征在于，所述方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
  27. 一种制备式(I-3)所示化合物的方法，其特征在于，所述方法为
    Figure PCTCN2018097365-appb-100021
  28. 如权利要求27所述的方法，其特征在于，由式(VII-3)所示化合物制备式(VI-3-1)方法的反应后处理步骤中不加入酸，所述酸选自有机酸或无机酸，所述有机酸优选三氟乙酸或乙酸，所述无机酸优选盐酸。
  29. 一种制备式(I-1)、式(I-2)、式(I-3)所示化合物的药学上可接受的盐的方法，包括权利要求1至7、15至16、17至22、23至28中任一项所述的步骤，以及通过式(I-1)、式(I-2)、式(I-3)所示化合物与酸反应制备得到其药学上可接受的盐的步骤，所述酸选自有机酸或无机酸，优选有机酸；所述有机酸选自乙酸、马来酸、富马酸、甲磺酸、苯磺酸或对甲苯磺酸，优选乙酸；所述无机酸选自盐酸、氢溴酸、硫酸或磷酸。
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WO2023030293A1 (zh) * 2021-08-30 2023-03-09 江苏恒瑞医药股份有限公司 一种GnRH受体拮抗剂的结晶工艺
CN114230576A (zh) * 2021-12-21 2022-03-25 伊诺药物研究(南京)有限公司 一种瑞卢戈利的制备方法
CN115417883A (zh) * 2022-09-16 2022-12-02 浙江科聚生物医药有限公司 一种瑞卢戈利的晶型及其制备方法
WO2024126674A1 (en) 2022-12-15 2024-06-20 Medichem, S.A. Process for the preparation of relugolix

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EP3660017A1 (en) 2020-06-03
KR20200035043A (ko) 2020-04-01
AU2018305633A1 (en) 2020-01-30
CN109983017A (zh) 2019-07-05
RU2741788C1 (ru) 2021-01-28
BR112020000725A2 (pt) 2020-07-14
US20200140434A1 (en) 2020-05-07
US11306085B2 (en) 2022-04-19
UA126345C2 (uk) 2022-09-21
JP2020528060A (ja) 2020-09-17
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