WO2022170737A1 - 高纯度的噻吩并嘧啶化合物及其制备方法 - Google Patents

高纯度的噻吩并嘧啶化合物及其制备方法 Download PDF

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WO2022170737A1
WO2022170737A1 PCT/CN2021/107295 CN2021107295W WO2022170737A1 WO 2022170737 A1 WO2022170737 A1 WO 2022170737A1 CN 2021107295 W CN2021107295 W CN 2021107295W WO 2022170737 A1 WO2022170737 A1 WO 2022170737A1
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compound
formula
impurity
chloride
reaction
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PCT/CN2021/107295
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French (fr)
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郭万成
张富昌
段永立
段雄朋
王国平
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奥锐特药业(天津)有限公司
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Priority to US18/546,049 priority Critical patent/US20240317773A1/en
Priority to EP21925390.3A priority patent/EP4293026A1/en
Publication of WO2022170737A1 publication Critical patent/WO2022170737A1/zh

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    • 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
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N2030/042—Standards

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and in particular relates to a high-purity relugolix and a preparation method thereof. .
  • Relugolix alias RVT-601, TAK-385, is a once-daily, oral, gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits testosterone production, a hormone that stimulates prostate cancer growth.
  • GnRH gonadotropin-releasing hormone
  • relugolix also reduces ovarian production in women by blocking GnRH receptors in the pituitary gland, reducing ovarian estradiol production, and reducing the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). estrogen levels and testosterone production in men. Its structural formula is as follows:
  • Ruilugoli was approved by the Japan Pharmaceuticals and Medical Devices Agency (PMDA) for marketing, and was marketed by Takeda and Aska pharmaceutical under the trade name of 40 mg/tablet, approved for the treatment and symptomatic relief of uterine fibroids; approved by the U.S. Food and Drug Administration (FDA) on December 18, 2020, under the trade name ORGOVYX, 120 mg/tablet.
  • PMDA Japan Pharmaceuticals and Medical Devices Agency
  • FDA U.S. Food and Drug Administration
  • the condensing agent diethyl cyanophosphate (DEPC) was used in the condensation reaction of the intermediate obtained in step 3 in route 1 with 3-amino-6-methoxypyridazine, and route 2 and route 3 correspond to 3-
  • the condensation reaction of amino-6-methoxypyridazine uses the condensing agent propylphosphoric anhydride (T3P). Both DEPC and T3P are highly toxic and expensive.
  • the alkali used in the ring-closing reaction after the condensation reaction of the above-mentioned 3 routes is a strong base sodium alkoxide, so that the ring-closing product has a dark color and many by-products of the reaction.
  • the reaction conditions of patent CN111333633A the ratio of the raw material conversion to impurities is very high. , resulting in a decrease in yield, an increase in the difficulty of product purification, and the content of impurities in the product is likely to exceed the standard.
  • the purpose of the present invention is to provide a high-purity thienopyrimidine compound (such as relugolix), a preparation method thereof, and a related impurity reference substance for quality control.
  • a method for preparing a compound of formula N comprising the steps of:
  • R is a C 1-6 alkyl group
  • R 1 is -NO 2 or -NHCONHOCH 3 .
  • the organic base is an organic compound containing 1-3 nitrogens and 3-20 carbons.
  • the organic base is selected from the compounds of the following group: R 2 NH 2 , (R 2 ) 2 NH, (R 2 ) 3 N, 4 containing N heteroatoms to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl containing N heteroatoms, or a combination thereof; wherein, R 2 is C 1-6 alkyl;
  • the organic base is selected from the group consisting of triethylamine, pyridine, or a combination thereof.
  • the acid chloride is selected from: phosphorus oxychloride, thionyl chloride, C 1-8 alkylsulfonyl chloride, C 4-20 arylsulfonyl chloride, C 1 -8 Alkyl chloride, C 4-20 aryl chloride.
  • the C 4-20 aryl group refers to an aromatic group containing 4-20 carbon atoms and 0-3 heteroatoms (preferably, the heteroatoms are selected from O, N, S) radical or heteroaryl.
  • the C 4-20 aryl group is a C 6-10 aryl group or a 5-10-membered heteroaryl group; 4 alkyl or halogenated C 1-4 alkyl substituted.
  • the acid chloride is selected from: benzenesulfonyl chloride, methylsulfonyl chloride, thionyl chloride, or a combination thereof.
  • the inert solvent A is selected from the following group: N,N-dimethylformamide (DMF), N-methylpyrrolidone, N,N-dimethylformamide Acetamide, tetrahydrofuran, dichloromethane (DCM), acetone, or a combination thereof.
  • DMF N,N-dimethylformamide
  • DCM dichloromethane
  • the base is an inorganic base.
  • the inorganic base is selected from the following group: carbonate, phosphate, bicarbonate, hydrogen phosphate, or a combination thereof; preferably, is selected from the following group: Potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, or a combination thereof.
  • the alkali is selected from the following group: carbonate, phosphate, bicarbonate, hydrogen phosphate, or a combination thereof; more preferably, is selected from the following group: Potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, or a combination thereof.
  • the inert solvent B is selected from the following group: N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide acetamide, or a combination thereof.
  • the inert solvent A and the inert solvent B may be the same or different.
  • step (a) the molar ratio of the compound of formula N-2 to 3-amino-6-methoxypyridazine is 1:1-3; preferably, 1:1.1-2.0; More preferably, 1:1.4 ⁇ 1.6.
  • step (a) the molar ratio of the compound of formula N-2 to the organic base is 1:1.5-5; preferably, 1:1.1-2.5; more preferably, 1:1.4-2.1 .
  • step (a) the molar ratio of the compound of formula N-2 to the acid chloride is 1:1-3; preferably, 1:1.1-2.0; more preferably, 1:1.4-1.6.
  • step (a) the molar ratio of the acid chloride to the organic base is 1:0.5-2; preferably, 1:0.5-1.4.
  • step (a) the weight-to-volume (g:mL) ratio of the compound of formula N-2 to the inert solvent A is 1:3-20; preferably, it is 1:3-10.
  • the reaction temperature of the reaction is -10-20°C, preferably -10-0°C or 0-10°C.
  • step (a) further includes a post-processing step for separating and/or purifying the compound of formula N-1.
  • the post-processing step for separating and/or purifying the compound of formula N-1 does not include chromatographic separation.
  • step (b) the molar ratio of the compound of formula N-1 to the inorganic base is 1:0.5-3; preferably, 1:0.5-2.0; more preferably, 1:0.7-1.1.
  • step (b) the weight-to-volume (g:mL) ratio of the compound of formula N-1 to the inert solvent B is 1:1-20, preferably 1:2.5-10.
  • the reaction temperature of the reaction is 0-80°C; preferably, 20-60°C; more preferably, 40-50°C.
  • step (b) further comprises a post-processing step for separating and/or purifying the compound of formula N.
  • the post-processing step for separating and/or purifying the compound of formula N does not include chromatographic separation.
  • the post-processing steps for separating and/or purifying the compound of formula N include: optionally cooling to 0-10° C., adding water, filtering the solid, and optionally recrystallization.
  • the recrystallization includes the steps of: dissolving the solid in the organic solvent 1, adding the organic solvent 2, optionally stirring (such as stirring for 1 to 3 hours) and cooling down for crystallization (preferably cooling down the temperature). to 0 ⁇ 5°C).
  • the organic solvent 1 is DMSO
  • the organic solvent 2 is an alcohol solvent (preferably, ethanol).
  • the volume ratio of the organic solvent 1 to the organic solvent 2 is 1:0.5-5 (preferably, 1:0.5-3).
  • the compound of formula N is a compound of formula N-a
  • the compound of formula N is a compound of formula N-b
  • the purity of the compound of formula N is ⁇ 99.5%.
  • the content of any single impurity in the compound of formula N is ⁇ 0.15% (preferably, ⁇ 0.10%).
  • the single impurity refers to impurity N-b1, impurity i (including impurity i-a or impurity i-b), impurity N-b3, impurity N-b4, impurity e (including impurity e-a or impurity e-b), Any one of RS-1, RS-2, RS-3, impurity e-a, impurity f, impurity g, impurity h, impurity i-a, impurity j, and impurity k.
  • the content of impurity i and/or impurity f in the compound of formula N is ⁇ 0.15 (preferably, ⁇ 0.10%).
  • the compound of formula N is a compound of formula N-a; and wherein, the content of impurity k (compound of formula k) is less than or equal to 0.15%; preferably, less than or equal to 0.10%.
  • the compound of formula N is a compound of formula N-a; and wherein, the content of impurity g (compound of formula g) is ⁇ 0.15%; preferably, ⁇ 0.10%.
  • the compound of formula N is a compound of formula N-a; and wherein the average content of impurity k and impurity g is ⁇ 0.15%; preferably, ⁇ 0.10%.
  • R 1 is -NO 2 or -NHCONHOCH 3 .
  • the purity of the compound is above 90%; preferably, above 95%; more preferably, above 99%.
  • the compound is a compound that can be used as a reference substance for quality control of the compound of formula N, and the compound of formula N is as defined in the first aspect.
  • a compound of formula f is provided, as follows:
  • R is NH 2 or C 1-6 alkoxy.
  • the purity of the compound is above 90%; preferably, above 95%; more preferably, above 99%.
  • the compound is a compound that can be used as a reference substance for quality control of the compound of formula N, and the compound of formula N is as defined in the first aspect.
  • a compound of formula h is provided, as follows:
  • the purity of the compound is above 90%; preferably, above 95%; more preferably, above 99%.
  • the compound is a compound that can be used as a reference substance for quality control of the compound of formula N, and the compound of formula N is as defined in the first aspect.
  • R 1 is -NO 2 or -NHCONHOCH 3 .
  • the purity of the compound is above 90%; preferably, above 95%; more preferably, above 99%.
  • the compound is a compound that can be used as a reference substance for quality control of the compound of formula N, and the compound of formula N is as defined in the first aspect.
  • the eighth aspect of the present invention there is provided a use of the compound according to any one of the third to seventh aspects and the thirteenth to fifteenth aspects, which is used as an impurity control in the detection of the compound of formula N product, wherein the compound of formula N is as defined in the first aspect.
  • the impurity reference substance is used as an impurity reference substance in the impurity detection of the compound of formula N bulk drug or pharmaceutical composition or pharmaceutical preparation.
  • the compound of formula N is reslugoli (ie, the compound of formula N-a).
  • an impurity of the compound according to any one of the third to seventh aspects and the thirteenth to fifteenth aspects in relugolix (formula N-a) raw drug or preparation Use as an impurity reference in detection.
  • R 1 is C 1-6 alkyl
  • the method comprises the steps of: ring-closing the compound of formula g-1 under the action of a base to obtain the compound of formula g;
  • the method comprises the steps of: subjecting two compounds of formula N-a to intermolecular substitution reaction under alkaline conditions to obtain a compound of formula g.
  • the base is an inorganic base, preferably, the inorganic base is as defined in the first aspect.
  • a compound used as a reference substance for detecting impurities wherein the compound is such as formula N-b1, formula i-b, formula N-b3, formula N-b4, formula e-b, Any of formula e-a, formula f, formula g, formula h, formula i-a, formula j, formula k, formula 1 is shown;
  • the compound is a compound that can be used as a reference substance for quality control of the compound of formula N, and the compound of formula N is as defined in the first aspect.
  • the compound is a compound that can be used as a reference substance for quality control of the compound of formula N, and the compound of formula N is as defined in the first aspect.
  • the compound is a compound that can be used as a reference substance for quality control of the compound of formula N, and the compound of formula N is as defined in the first aspect.
  • Fig. 1 shows the HPLC detection and analysis chromatogram after 10 hours of reaction in step a of Example 9;
  • Fig. 2 shows the HPLC detection and analysis spectrum after the purification of the product in step a of Example 9;
  • Figure 3 shows the HPLC detection and analysis chromatogram of the comparative example 1.1 after the temperature was raised to 60°C and reacted for 0.5 hours;
  • Figure 4 shows the HPLC detection and analysis chromatogram of the comparative example 1.2 after the temperature was raised to 60 °C and reacted for 1 hour;
  • Figure 5 shows the HPLC detection and analysis chromatogram of the comparative example 1.3 after the temperature was raised to 60°C and reacted for 2 hours;
  • Fig. 6 has shown the HPLC detection and analysis spectrum of the crude product of step b of embodiment 9;
  • Fig. 7 has shown the HPLC detection and analysis spectrum of the refined product of step b of embodiment 9;
  • Figure 8 shows the HPLC detection and analysis chromatogram of Comparative Example 2.1 after the temperature was raised to 60°C for 0.5 hours;
  • Figure 9 shows the HPLC detection and analysis chromatogram of Comparative Example 2.2 after the temperature was raised to 60°C for 0.5 hours;
  • Figure 10 shows the HPLC detection and analysis chromatogram of Comparative Example 2.2 after the temperature was raised to 60°C and reacted for 1 hour;
  • Figure 11 shows the HPLC detection and analysis chromatogram of Comparative Example 2.2 after the temperature was raised to 60°C for 1.5 hours;
  • Figure 12 shows the HPLC detection and analysis chromatogram of Comparative Example 2.2 after the temperature was raised to 60°C for 2 hours;
  • Figure 13 shows the mass spectrometry results of formula N-a.
  • Figure 14 shows the mass spectrum results of impurity 1, the [M+H] + of impurity 1 is 642.32.
  • the inventors have also identified multiple impurities and their structures that affect the purity of the desired product thienopyrimidine compound (shown as formula N) for the first time, and further analyzed the causes of the impurities. , thereby further providing a preferred method for preparing thienopyrimidine compounds with higher purity and less single impurity content.
  • the method of the present invention analyzes the cause of impurity generation to avoid easy generation.
  • the impurity reaction reagents and conditions can effectively control the content of each impurity in the product, so that high-purity thienopyrimidine compounds can be obtained without using chromatographic separation. Based on this, the inventors have completed the present invention.
  • alkyl refers to a straight or branched chain saturated hydrocarbon group containing the specified number of carbon atoms
  • C1-6 alkyl refers to a straight or branched chain saturated hydrocarbon group containing 1-6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl or isopropyl), butyl (including n-butyl, isobutyl, tert-butyl), and the like.
  • alkoxy refers to an alkyl group (wherein, alkyl is as previously defined) attached to the rest of the molecule through an oxygen atom, eg, C1-6alkoxy ie C1-6alkyl- O-.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, and the like.
  • an aryl group refers to an aromatic group including the specified number of carbon atoms, eg, C 4-20 refers to an aromatic group containing 4-20 carbon atoms. Specific examples of aromatic groups include substituted or unsubstituted aryl groups and heteroaryl groups.
  • aryl refers to a polyunsaturated (usually aromatic) hydrocarbon group, which may be a single ring or multiple rings fused together or covalently linked.
  • heteroaryl refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl groups include phenyl, and naphthyl, while non-limiting examples of heteroaryl groups include pyridyl and the like.
  • the above aryl and heteroaryl groups can also be substituted with one or more (eg 1, 2 or 3) halogen, C 1-4 alkyl or haloC 1-4 alkyl.
  • compound of formula g and “impurity g” are used interchangeably and refer to a compound as represented by formula g herein.
  • compound of formula i and “impurity i”, or “compound of formula h” and “impurity h”, etc. can be used interchangeably, and refer to the compound represented by the corresponding structural formula.
  • the object of the present invention is to provide a novel method for preparing a compound of formula N such as relugolix that does not require toxic and expensive reagents, has mild reaction conditions, and has high product purity and is suitable for industrial production.
  • One of the objects of the present invention is to provide a kind of method for preparing the compound of formula N, comprising the following steps:
  • R is a C 1-6 alkyl group (such as methyl, ethyl, propyl, etc.), and R 1 is NO 2 , NH 2 or NHCONHOCH 3 .
  • the organic base is selected from organic compounds containing 1-3 nitrogens and 3-20 carbons, preferably triethylamine and pyridine.
  • the acid chloride is selected from: phosphorus oxychloride, thionyl chloride, C 1-8 linear or branched alkyl sulfonyl chloride, C 4-20 arylsulfonyl chloride, C 1-8 linear or branched chain Alkyl acid chloride, C 4-20 aryl acid chloride, preferably benzenesulfonyl chloride, methylsulfonyl chloride, thionyl chloride.
  • the inert solvent A is selected from one or more combinations of N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, dichloromethane and acetone .
  • the inorganic base is selected from one or a combination of carbonate or phosphate, bicarbonate, and hydrogen phosphate, preferably potassium carbonate, sodium carbonate, cesium carbonate, and potassium phosphate.
  • the solvent B is selected from one or more of N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, and N,N-dimethylacetamide.
  • the inert solvent A and the inert solvent B may be the same or different.
  • R 1 is NHCONHOCH 3 , it is a compound of formula Na, that is, Relugoly.
  • step a the molar ratio of the compound of formula N-2 to 3-amino-6-methoxypyridazine is 1:1-3, preferably 1:1.1-1.5; and/or the molar ratio of the compound of formula N-2 to the organic base is 1:1.5-5, preferably 1:2-3; the molar ratio of the compound of formula N-2 to the acid chloride is 1:1.5-5, preferably 1:2-3; and/or the ratio of the compound of formula N-2 to solvent A
  • the weight-to-volume ratio is 1:3-20, preferably 1:3-10; and/or the reaction temperature is -10-20°C, preferably 0-10°C.
  • step b the molar ratio of the compound of formula N-1 to the inorganic base is 1:3-20, preferably 1:3-5; and/or the weight to volume ratio of the compound of formula N-1 to solvent B is 1:3-20, preferably 1 : 3-10.
  • Another object of the present invention is to provide a compound of formula N-a or a salt thereof,
  • the compound of formula N-a contains no more than 0.15% of the compound of formula g.
  • Another object of the present invention is to provide a compound represented by the formula N-a or a salt thereof,
  • the compound contains no more than 0.15% of the compound of formula k.
  • Another object of the present invention is to provide a compound represented by the formula N-a or a salt thereof,
  • the compound contains no more than 0.15% of the compound of formula g and the compound of formula k.
  • the inventor also found that the use of a strong base sodium alkoxide for ring-closing reaction would easily cause the content of impurity i to exceed the standard, and because the content of impurities i and l was too high, resulting in a decrease in yield.
  • the present invention also provides a plurality of impurity structures of thienopyrimidine compounds (such as relugolix) and their impurity structures.
  • the present invention provides a novel thienopyrimidine compound (eg, relugolix) drug substance impurity e.
  • the source of impurity e has the following two ways. Most of it comes from the residue of the intermediate in the previous step. For example, the first step bromination reaction in WO2014051164 or CN111333633A is incomplete, or the subsequent catalytic hydrogenation and reduction of the nitro step removes the dimethylamino by-product derivative product.
  • R is a C 1-6 linear or branched alkyl group, and R 1 is NO 2 or NHCONHOCH 3 .
  • the present invention provides a novel thienopyrimidine compound (eg, relugolix) drug substance impurity f.
  • R is NH 2 or C 1-6 linear or branched alkoxy.
  • the impurity f is derived from the aminolysis or alcoholysis of the urea side chain group.
  • the source of ammonia or alcohol can be the residual ammonium salt after the reaction, such as ammonium chloride, ammonium acetate, or the reaction solvent, the residual solvent, etc. It is generated under cyclic conditions, and also comes from ammonia that is unstable and decomposed during the reaction process. This impurity is difficult to purify, and it is necessary to strictly control the ammonium salt from the raw material and the residual ammonium salt after the reaction. Under the conditions of optimizing the ring closure reaction, the reaction system can control the amount of this impurity generated in the reaction process to be less than 0.1% or even 0.05%.
  • the present invention provides a method for the preparation of impurity f.
  • impurity f can be obtained by the following two reaction routes.
  • Route 1 The compound of formula f-1 is ring-closed under basic conditions to obtain the compound of formula f.
  • R 1 is a C 1-6 linear or branched alkyl group.
  • impurity f can be obtained by the following two ways:
  • Route 1 The compound of formula f-2 is condensed with CDI and amine water/ammonia to obtain the compound of formula f.
  • Route 2 The compound of formula N-a attacks the carbonyl carbon of the side chain urea under the action of amine water or ammonia gas, and a substitution reaction occurs to obtain the compound of formula f.
  • the present invention provides a novel thienopyrimidine compound (such as relugolix) API impurity g.
  • the impurity g is produced when the ring is closed under alkaline conditions, and the amount produced is positively correlated with the strength of the basicity.
  • the source of impurity g is the substitution derivatization reaction of two molecules of urea groups. This impurity is not easy to purify and needs to be precisely controlled in the reaction process, and the amount of this impurity generated varies greatly with different reaction conditions.
  • the source is as follows:
  • the present invention provides a novel thienopyrimidine compound (eg, relugolix) API impurity h.
  • the source of the impurity h is the derivative of the condensation reaction between the methoxyamine and the intermediate h-2 produced by the residue or degradation in the previous step. This impurity needs to control the residual methoxyamine before two steps, and control the reaction conditions to prevent the degradation of the side chain urea to generate methoxyamine. As follows:
  • the fifth aspect of the impurity research section of the present invention provides a novel thienopyrimidine compound (eg, relugolix) drug substance impurity i.
  • the impurity i is derived from the degradation of the uracil six-membered ring structure under the alkaline condition. In two ways as shown below:
  • R 1 is NO 2 or NHCONHOCH 3 .
  • the present invention provides a novel thienopyrimidine compound (eg, relugolix) API impurity j.
  • Impurity j is an oxidative degradation impurity of a thienopyrimidine compound such as relugolix. Impurity j is easily formed in the presence of oxidant, as follows:
  • the present invention provides a novel thienopyrimidine compound (eg, relugolix) drug substance impurity k.
  • Impurity k is the degradation impurity of thienopyrimidine compounds (such as relugolix), which is partly derived from the urea side chain substitution reaction of two-molecule thienopyrimidine compounds (such as relugolix) or the material control is not allowed when the side chain is generated earlier lead to.
  • thienopyrimidine compounds such as relugolix
  • the method of the present invention has few reaction by-products, thereby avoiding various impurities that are difficult to separate.
  • one purification (such as recrystallization) can make the chemical purity of the product formula N compound (such as the formula N-a compound) as high as 99.7% without using purification methods such as chromatography, and many impurities are easily Controlled below 0.1%.
  • the compound of formula N-2a (10.5 g, 18.2 mmol HPLC purity 97.77%) was added to 50 ml of DMF, and the temperature was lowered to -10 to 0 °C. Triethylamine (3.8 g, 37.5 mmol) was added, and thionyl chloride (3.40 g, 28.6 mmol) was added dropwise. After the dropwise addition, 6-methoxy-3-aminopyridazine (3.58g, 28.6mmol) was added in batches, and the reaction was incubated for 10 hours. rate 93.5%).
  • step a The compound of formula N-1a obtained in step a (5.0 g, 7.3 mmol) and potassium carbonate (0.8 g, 5.8 mmol) were added to 50 ml of DMF, the temperature was raised to 40-50 ° C, and stirring was continued for 6 hours. Cool to 0 ⁇ 10°C, add 100ml of water dropwise. It was filtered and dried to obtain 4.4 g of white solid with a yield of 96.5% and a purity of 97.58%.
  • the HPLC detection and analysis pattern is shown in Figure 6 .
  • N-2a (2.50g, 4.34mmol, purity 97.77%), N,N-dimethylacetamide (25ml), 3-amino-6-methoxypyridazine (0.79g) , 6.34mmol), N,N-diisopropylethylamine (0.77g, 5.95mmol), 50% ethyl acetate solution of propylphosphoric acid anhydride (7.84g, 12.33mmol) system was heated to 60°C and then incubated for 0.5 After 1 hour, the system was taken and sent to liquid phase detection, and the liquid phase purity was 89.99% (HPLC detection and analysis spectrum is shown in Figure 3).
  • reaction mixture contained 87.95% of the product after 1 hour (the HPLC detection and analysis pattern is shown in Figure 4), and the yield was 87.5%.
  • the propylphosphoric anhydride (T3P) used in the comparative example is expensive, and its molar price is much higher than that of the reagent acid chloride used in the present application, even about 50 times that of the reagent thionyl chloride used.
  • T3P has a large molecular weight and low atomic utilization rate, so it can only be transported and stored in solution. After treatment of 1 molecule of propylphosphoric anhydride, 3 molecules of phosphorus-containing wastewater are produced, which is harmful to the environment.
  • N-2a (2.50 g, 4.34 mmol, purity 97.77%), N,N-dimethylacetamide (25 mL), 3-amino-6-methoxypyridazine (0.79 g , 6.34mmol), N,N-diisopropylethylamine (0.77g, 5.95mmol), 1-(3-dimethoxypropyl)-ethylcarbodiimide hydrochloride (1.66g, 8.68 mmol), 4-dimethylaminopyridine (0.05 g, 0.41 mmol), the system was heated to 60° C. and then kept for 5 hours, and the system was taken and sent to the liquid phase to detect the product purity of 50.88%.
  • Comparative Example 2.1 After calculation, the yield of Comparative Example 2.1 is about 5%, and the maximum yield of Comparative Example 2.2 is about 82%.
  • RS-3 is a urea by-product.
  • the high content of alkali degradation impurities i and l is due to the use of a strong base sodium alkoxide in the ring closure reaction.
  • the compound of formula N-2b (20 g, 38.5 mmol) was added to 100 ml of DCM, and the temperature was lowered to 0-10 °C. Triethylamine (5.84 g, 57.7 mmol) was added, and benzenesulfonyl chloride (11.1 g, 57.7 mmol) was added dropwise. After the dropwise addition, 6-methoxy-3-aminopyridazine (7.2 g, 57.7 mmol) was added, and the reaction was incubated for 10 hours.
  • Example 11 The compound of formula N-1b (2.0 g, 3.19 mmol) and cesium carbonate (0.52 g, 1.59 mmol) obtained in step a of Example 10 were added to 5 ml of DMSO, the temperature was raised to 40-50 ° C, and stirring was continued for 6 hours . Cool to 0 ⁇ 10°C, add 10ml of water dropwise. It was filtered and dried to obtain 1.70 g of a white solid with a yield of 91.9% and a purity of 98.5%.

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Abstract

一种噻吩并嘧啶化合物（式N化合物）及其制备方法。具体地，提供的制备方法包括步骤：(a)溶剂A中，在有机碱和酰氯的存在下，使式N-2化合物和3-氨基-6-甲氧基哒嗪进行反应，得到式N-1化合物；和(b)溶剂B中，在碱存在下，式N-1化合物转化为式N化合物。该制备方法无需有毒且昂贵的试剂，反应条件温和，产品纯度高，适合工业化生产。

Description

高纯度的噻吩并嘧啶化合物及其制备方法
本申请要求申请日为2021年2月10日的中国专利申请CN202110185444.7的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物化学技术领域，具体涉及一种高纯度的瑞卢戈利及其制备方法。。
背景技术
瑞卢戈利，别名RVT-601，TAK-385，是一种每日一次、口服、促性腺激素释放激素(GnRH)受体拮抗剂，能抑制睾丸睾酮的生成，这种激素可刺激前列腺癌的生长。此外，瑞卢戈利也可通过阻断垂体腺中的GnRH受体，减少卵巢雌二醇的生成，减少促黄体生成激素(LH)和卵泡刺激素(FSH)的释放，从而降低女性卵巢生成的雌激素水平和男性睾丸激素的产生。其结构式如下：
Figure PCTCN2021107295-appb-000001
瑞卢戈利于2019年1月8日获日本医药品医疗器械综合机构(PMDA)批准上市，由武田和Aska pharmaceutical上市销售，商品名为
Figure PCTCN2021107295-appb-000002
40毫克/片，被批准用于子宫肌瘤的治疗和症状缓解；于2020年12月18日获美国食品药品监督管理局(FDA)批准上市，商品名为ORGOVYX，120毫克/片。
目前有多个文献报道了制备瑞卢戈利的方法，其中WO2004067535公开的制备方法如路线1所示：
Figure PCTCN2021107295-appb-000003
路线1
WO2014051164公开的制备方法如路线2所示：
Figure PCTCN2021107295-appb-000004
CN111333633A公开的制备方法如路线3所示：
Figure PCTCN2021107295-appb-000005
路线1中第3步得到的中间体与3-氨基-6-甲氧基哒嗪的缩合反应中使用了缩合剂氰基磷酸二乙酯(DEPC)，路线2和路线3相应的与3-氨基-6-甲氧基哒嗪的缩合反应均使用了缩合剂丙基磷酸酐(T3P)，DEPC和T3P均属于剧毒品，且价格昂贵。
此外，上述3条路线的缩合反应之后的关环反应使用的碱均为强碱醇钠，使得关环产品颜色深，反应副产物多，按照专利CN111333633A反应条件，原料转化为杂质的比例很高，导致收率的下降，产品纯化难度的增大，产物中杂质的含量容易超标。
因此，本领域迫切需要开发一种环境友好，成本更低的，质量控制更好的制备噻吩并嘧啶化合物如瑞卢戈利的新方法。
发明内容
本发明的目的就是提供一种高纯度的噻吩并嘧啶化合物(如瑞卢戈利)及其制备方法及用于质控的相关的杂质对照品。
在本发明的第一方面中，提供了一种制备式N化合物的方法，所述的方法包括步骤：
Figure PCTCN2021107295-appb-000006
(a)在惰性溶剂A中，在有机碱和酰氯的存在下，使式N-2化合物和3-氨基-6-甲氧基 哒嗪进行缩合反应，从而得到式N-1化合物；和
(b)在惰性溶剂B中，在碱存在下，使式N-1化合物发生关环反应，从而得到式N化合物；
各式中，R为C 1-6烷基，R 1为-NO 2或-NHCONHOCH 3。
在另一优选例中，步骤(a)中，所述有机碱为含1-3个氮且含3-20碳的有机化合物。
在另一优选例中，步骤(a)中，所述的有机碱选自下组的化合物：R 2NH 2、(R 2) 2NH、(R 2) 3N、含N杂原子的4至7元杂环烷基、含N杂原子的5至6元杂芳基，或其组合；其中，R 2为C 1-6烷基；。
在另一优选例中，步骤(a)中，所述有机碱选自下组：三乙胺、吡啶，或其组合。
在另一优选例中，步骤(a)中，所述的酰氯选自：三氯氧磷，二氯亚砜，C 1-8烷基磺酰氯，C 4-20芳香基磺酰氯，C 1-8烷基酰氯，C 4-20芳香基酰氯。
在另一优选例中，所述C 4-20芳香基是指含4-20个碳原子和0-3个杂原子(较佳地，所述杂原子选自O、N、S)的芳基或杂芳基。
在另一优选例中，所述C 4-20芳香基为C 6-10芳基或5-10元杂芳基；并且上述芳基或杂芳基还能任选地被卤素、C 1-4烷基或卤代C 1-4烷基所取代。
在另一优选例中，步骤(a)中，所述酰氯选自：苯磺酰氯、甲基磺酰氯、二氯亚砜，或其组合。
在另一优选例中，步骤(a)中，所述的惰性溶剂A选自下组：N,N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮、N,N-二甲基乙酰胺、四氢呋喃、二氯甲烷(DCM)、丙酮，或其组合。
在另一优选例中，步骤(b)中，所述的碱为无机碱。
在另一优选例中，步骤(b)中，所述无机碱选自下组：碳酸盐、磷酸盐、碳酸氢盐、磷酸氢盐，或其组合；较佳地，选自下组：碳酸钾、碳酸钠、碳酸铯、磷酸钾，或其组合。
在另一优选例中，步骤(b)中，所述的碱选自下组：碳酸盐、磷酸盐、碳酸氢盐、磷酸氢盐，或其组合；更佳地，选自下组：碳酸钾、碳酸钠、碳酸铯、磷酸钾，或其组合。
在另一优选例中，步骤(b)中，所述惰性溶剂B选自下组：N,N-二甲基甲酰胺、二甲亚砜、N-甲基吡咯烷酮、N,N-二甲基乙酰胺，或其组合。
在另一优选例中，所述惰性溶剂A与惰性溶剂B可以相同或不相同。
在另一优选例中，步骤(a)中，式N-2化合物与3-氨基-6-甲氧基哒嗪的摩尔比为1：1～3；较佳地，1：1.1～2.0；更佳地，1：1.4～1.6。
在另一优选例中，步骤(a)中，式N-2化合物与有机碱的摩尔比为1：1.5-5；较佳地，1:1.1～2.5；更佳地，1：1.4～2.1。
在另一优选例中，步骤(a)中，式N-2化合物与酰氯的摩尔比为1：1～3；较佳地，1：1.1～2.0；更佳地，1：1.4～1.6。
在另一优选例中，步骤(a)中，酰氯与有机碱的摩尔比为1：0.5～2；较佳地，1：0.5～1.4。
在另一优选例中，步骤(a)中，式N-2化合物与惰性溶剂A的重量体积(g：mL)比为1：3-20；较佳地，为1：3～10。
在另一优选例中，步骤(a)中，所述反应的反应温度为-10～20℃，优选-10～0℃或0～10℃。
在另一优选例中，步骤(a)还包括用于分离和/或纯化式N-1化合物的后处理步骤。在另一优选例中，所述用于分离和/或纯化式N-1化合物的后处理步骤不包括色谱分离。
在另一优选例中，步骤(b)中，式N-1化合物与无机碱的摩尔比1：0.5～3；较佳地，1：0.5～2.0；更佳地，1：0.7～1.1。
在另一优选例中，步骤(b)中，式N-1化合物与惰性溶剂B的重量体积(g：mL)比为1：1-20，优选1：2.5-10。
在另一优选例中，步骤(b)中，所述反应的反应温度为0～80℃；较佳地，20～60℃；更佳地，40～50℃。
在另一优选例中，步骤(b)还包括用于分离和/或纯化式N化合物的后处理步骤。
在另一优选例中，所述用于分离和/或纯化式N化合物的后处理步骤不包括色谱分离。
在另一优选例中，所述用于分离和/或纯化式N化合物的后处理步骤包括：任选地降温至0～10℃，加水，过滤的固体，和任选的重结晶。
在另一优选例中，所述的重结晶包括步骤：将固体溶解在有机溶剂1中，加入有机溶剂2，任选地搅拌(如搅拌1～3小时)和降温析晶(较佳地降温至0～5℃)。
在另一优选例中，所述有机溶剂1为DMSO，有机溶剂2为醇类溶剂(较佳地，乙醇)。
在另一优选例中，所述有机溶剂1与有机溶剂2的体积比为1:0.5～5(较佳地，1:0.5～3)。
在另一优选例中，所述的式N化合物为式N-a化合物，
Figure PCTCN2021107295-appb-000007
在另一优选例中，所述的式N化合物为式N-b化合物，
Figure PCTCN2021107295-appb-000008
在本发明的第二方面中，提供了一种如第一方面所述方法制备得到的式N化合物或其盐，
Figure PCTCN2021107295-appb-000009
其中，所述式N化合物的纯度≥99.5％。
在另一优选例中，所述式N化合物中任意单一杂质含量≤0.15％(较佳地，≤0.10％)。
在另一优选例中，所述单一杂质是指杂质N-b1、杂质i(包括杂质i-a或杂质i-b)、杂质N-b3、杂质N-b4、杂质e(包括杂质e-a或杂质e-b)、RS-1、RS-2、RS-3、杂质e-a、杂质f、杂质g、杂质h、杂质i-a、杂质j、杂质k中的任意一种。
在另一优选例中，所述式N化合物中杂质i和/或杂质f的含量≤0.15(较佳地，≤0.10％)。
在另一优选例中，所述式N化合物为式N-a化合物；并且其中，杂质k(式k化合物)的含量≤0.15％；较佳地，≤0.10％。
在另一优选例中，所述式N化合物为式N-a化合物；并且其中，杂质g(式g化合物)的含量≤0.15％；较佳地，≤0.10％。
在另一优选例中，所述式N化合物为式N-a化合物；并且其中，杂质k和杂质g的含量均量≤0.15％；较佳地，≤0.10％。
在本发明的第三方面提供了，一种式e化合物，如下所示
Figure PCTCN2021107295-appb-000010
式中，R 1为-NO 2或-NHCONHOCH 3。
在另一优选例中，所述化合物的纯度为90％以上；较佳地，为95％以上；更佳地，为99％以上。
在另一优选例中，所述化合物为可用作式N化合物的质控用对照品的化合物，所述式N化合物如第一方面中定义。
在本发明的第四方面中，提供了一种式f化合物，如下所示：
Figure PCTCN2021107295-appb-000011
式中R为NH 2或C 1-6烷氧基。
在另一优选例中，所述化合物的纯度为90％以上；较佳地，为95％以上；更佳地，为99％以上。
在另一优选例中，所述化合物为可用作式N化合物的质控用对照品的化合物，所述式N化合物如第一方面中定义。
在本发明的第五方面中，提供了一种式h化合物，如下所示：
Figure PCTCN2021107295-appb-000012
在另一优选例中，所述化合物的纯度为90％以上；较佳地，为95％以上；更佳地，为99％以上。
在另一优选例中，所述化合物为可用作式N化合物的质控用对照品的化合物，所述式N化合物如第一方面中定义。
在本发明的第六方面中，提供了一种式i化合物，如下所示：
Figure PCTCN2021107295-appb-000013
式中R 1为-NO 2或-NHCONHOCH 3。
在另一优选例中，所述化合物的纯度为90％以上；较佳地，为95％以上；更佳地，为99％以上。
在另一优选例中，所述化合物为可用作式N化合物的质控用对照品的化合物，所述式N化合物如第一方面中定义。
在本发明的第七方面中，提供了一式j化合物，如下所示：
Figure PCTCN2021107295-appb-000014
在本发明的第八方面中，提供了一种如第三至第七方面、第十三至第十五方面任一所述的化合物的用途，其在式N化合物的检测中用作杂质对照品，其中式N化合物如第一方面中所定义。
在另一优选例中，所述杂质对照品用于式N化合物原料药或药物组合物或药物制剂的杂质检测中的杂质对照品。
在另一优选例中，所述式N化合物是瑞卢戈利(即式N-a化合物)。
在本发明的第九方面中，提供了一种如第三至第七方面、第十三至第十五方面任一所述的化合物在瑞卢戈利(式N-a)原料药或制剂的杂质检测中作为杂质对照品的用途。
在本发明的第十方面中，提供了一种式g化合物的制备方法，
Figure PCTCN2021107295-appb-000015
各式中，R 1为C 1-6烷基；
所述的方法包括步骤：使式g-1化合物在碱作用下关环得到式g化合物；
或者，
所述的方法包括步骤：使两分子式N-a化合物在碱性条件下发生分子间的取代反应得到式g化合物。
在另一优选例中，所述的碱为无机碱，较佳地，所述的无机碱如第一方面中定义。
在本发明的第十一方面，提供了一种式k化合物的制备方法，
Figure PCTCN2021107295-appb-000016
包括步骤：使式k-1化合物在碱性条件下发生合环反应得到式k化合物；或者
包括步骤：使两分子式f-2化合物在CDI固体光气的作用下缩合得到式k化合物。
在本发明的第十二方面中，提供了一种作为检测杂质用对照品的化合物，其中，所述化合物如式N-b1、式i-b、式N-b3、式N-b4、式e-b、式e-a、式f、式g、式h、式i-a、式j、式k、式1中的任一所示；
Figure PCTCN2021107295-appb-000017
在本发明的第十三方面中，提供了一种式g化合物
Figure PCTCN2021107295-appb-000018
在另一优选例中，所述化合物为可用作式N化合物的质控用对照品的化合物，所述式N化合物如第一方面中定义。
在本发明的第十四方面中，提供了一种式k化合物
Figure PCTCN2021107295-appb-000019
在另一优选例中，所述化合物为可用作式N化合物的质控用对照品的化合物，所述式N化合物如第一方面中定义。
在本发明的第十五方面中，提供了一种式l化合物
Figure PCTCN2021107295-appb-000020
在另一优选例中，所述化合物为可用作式N化合物的质控用对照品的化合物，所述式N化合物如第一方面中定义。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了实施例9步骤a反应10小时后的HPLC检测分析图谱；
图2显示了实施例9步骤a产物纯化后的HPLC检测分析图谱；
图3显示了对比例1.1中升温至60℃后反应0.5小时后的HPLC检测分析图谱；
图4显示了对比例1.2中升温至60℃后反应1小时后的HPLC检测分析图谱；
图5显示了对比例1.3中升温至60℃后反应2小时后的HPLC检测分析图谱；
图6显示了实施例9步骤b粗品的HPLC检测分析图谱；
图7显示了实施例9步骤b精制品的HPLC检测分析图谱；
图8显示了对比例2.1升温至60℃后反应0.5小时后的HPLC检测分析图谱；
图9显示了对比例2.2升温至60℃后反应0.5小时后的HPLC检测分析图谱；
图10显示了对比例2.2升温至60℃后反应1小时后的HPLC检测分析图谱；
图11显示了对比例2.2升温至60℃后反应1.5小时后的HPLC检测分析图谱；
图12显示了对比例2.2升温至60℃后反应2小时后的HPLC检测分析图谱；
图13显示了式N-a的质谱结果。
图14显示了杂质l的质谱结果，杂质l的[M+H] +为642.32。
具体实施方式
发明人经过广泛而深入地研究，意外地发现在酰氯的存在下进行缩合反应能够获得与现有技术中采用昂贵且毒性高的缩合剂氰基磷酸二乙酯(DEPC)或丙基磷酸酐(T3P)进行缩合反应类似甚至更好的收率和产物纯度等技术效果，从而提供了一种新的、成本更低的、环境友好的噻吩并嘧啶化合物(如式N所示)的制备方法。基于此，发明人完成了本发明。
此外，发明人在长期而深入地研究后还首次确定了影响所需产物噻吩并嘧啶化合物(如式N所示)纯度的多个杂质及其结构，并对杂质产生的原因进行了进一步的分析，从而进一步提供了一种纯度更高且各单杂含量更少的优选的制备噻吩并嘧啶化合物方法，本发明的方法，在杂质研究的基础上，对杂质产生的原因进行分析避免了易产生杂质的反应试剂和条件等从而有效地控制了产物中各杂质的含量，从而在不使用色谱分离的情况下，能够获得高纯度的噻吩并嘧啶化合物。基于此，发明人完成了本发明。
术语
如本文所用，术语“烷基”是指含指定碳原子数的直链或支链饱和烃基，例如C 1-6烷基是指含1-6个碳原子的直链或支链饱和烃基。烷基的例子包括但不限于：甲基、乙基、丙基(包括：正丙基或异丙基)、丁基(包括正丁基、异丁基、叔丁基)等。
如本文所用，术语“烷氧基”是指通过氧原子与分子的其他部分连接的烷基(其中，烷基如前定义)，例如C 1-6烷氧基即C 1-6烷基-O-。烷氧基的例子包括但不限于：甲氧基、乙氧基等。
除非另有定义，在本文中，芳香基是指包括指定碳原子数的芳香性基团，例如，C 4-20是指含4-20个碳原子的芳香性基团。芳香性基团的具体例子包括取或未取代的芳基和杂芳基。术语“芳基”表示多不饱和的(通常芳香性)的烃基，其可以是单环或稠合在一起或共价连接的多环。术语"杂芳基"是指含有1至5个选自N、O、和S的杂原子的芳基(或环)。杂芳基可通过杂原子连接于分子的其余部分。芳基的非限制性例子包括苯基、和萘基，而杂芳基的非限制性例子包括吡啶基等。以上芳基和杂芳基还能被一个或多个(如1、2或3个)卤素、C 1-4烷基或卤代C 1-4烷基所取代。
在本文中，“式g化合物”和“杂质g”可以互换使用，是指如本文中式g所示的化合物。类似地，“式i化合物”和“杂质i”、或“式h化合物”和“杂质h”等可以互换使用，是指相应结构式所示的化合物。
高纯度的噻吩并嘧啶化合物及其制备方法
针对现有技术存在的上述问题，本发明的目的就是提供一种无需有毒且昂贵的试剂，反应条件温和，产品纯度高，适合工业化生产的制备式N化合物如瑞卢戈利的新方法。
本发明的目的之一是提供一种制备式N化合物的方法，包括以下步骤：
a)溶剂A中，在有机碱和缩合剂酰氯的存在下，使式N-2化合物和3-氨基-6-甲氧基哒嗪进行反应，得到式N-1化合物；
b)溶剂B中，在碱(如无机碱)存在下，使式N-1化合物关环得到式N化合物。
反应式如下：
Figure PCTCN2021107295-appb-000021
其中，R为C 1-6烷基(如甲基、乙基、丙基等)，R 1为NO 2，NH 2或NHCONHOCH 3。
优选地，所述有机碱选自含1-3个氮，含3-20碳的有机化合物，优选为三乙胺，吡啶。
优选地，所述酰氯选自：三氯氧磷，二氯亚砜，C 1-8直链或支链烷基磺酰氯，C 4-20芳香基磺酰氯，C 1-8直链或支链烷基酰氯，C 4-20芳香基酰氯，优选苯磺酰氯，甲基磺酰氯，二氯亚砜。
优选地，所述惰性溶剂A选自N,N-二甲基甲酰胺，N-甲基吡咯烷酮，N,N-二甲基乙酰胺，四氢呋喃，二氯甲烷，丙酮的一种或多种组合。
优选地，所述无机碱选自碳酸盐或磷酸盐，碳酸氢盐，磷酸氢盐中的一种或几种组合，优选碳酸钾，碳酸钠，碳酸铯，磷酸钾。
优选地，所述溶剂B选自N,N-二甲基甲酰胺，二甲亚砜，N-甲基吡咯烷酮，N,N-二甲基乙酰胺的一种或几种。
优选地，所述惰性溶剂A与惰性溶剂B可以相同或不相同。
当R 1为NHCONHOCH 3时为式N-a化合物，即瑞卢戈利。
步骤a中式N-2化合物与3-氨基-6-甲氧基哒嗪的摩尔比为1：1-3，优选1：1.1-1.5；和/或式N-2化合物与有机碱的摩尔比为1：1.5-5，优选1：2-3；式N-2化合物与酰氯的摩尔比为1：1.5-5，优选1：2-3；和/或式N-2化合物与溶剂A的重量体积比为1：3-20，优选1：3-10；和/或反应温度为-10-20℃，优选0-10℃。
步骤b中式N-1化合物与无机碱的摩尔比1：3-20，优选1：3-5；和/或式N-1化合物与溶剂B的重量体积比为1：3-20，优选1：3-10。
本发明的另一个目的是提供一种式N-a的化合物或其盐，
Figure PCTCN2021107295-appb-000022
所述式N-a化合物包含不高于0.15％的式g化合物。
Figure PCTCN2021107295-appb-000023
本发明的另一个目的是提供一种由式N-a表示的化合物或其盐，
Figure PCTCN2021107295-appb-000024
所述化合物包含不高于0.15％的式k化合物。
Figure PCTCN2021107295-appb-000025
本发明的另一个目的是提供一种由式N-a表示的化合物或其盐，
Figure PCTCN2021107295-appb-000026
所述化合物包含不高于0.15％的式g化合物和式k化合物。
Figure PCTCN2021107295-appb-000027
噻吩并嘧啶化合物的杂质及其制备方法及其作为检测对照品的用途
药物研究中杂质的研究是极其重要的部分。目前只有WO2014051164报道了瑞卢戈利的三个杂质RS-1，RS-2，RS-3(如下式所示)，而实际上要达到对原料药及制剂产品质量的控制，只分析检测三个杂质是远远不够的。需要对工艺中间体和原料药中的杂质做系统的研究，包括反应产生的杂质，产品氧化杂质和降解杂质。
Figure PCTCN2021107295-appb-000028
发明人在重复CN111333633A的方法时，发现其缩合反应产物和关环产物的化学纯 度并没有报道的那么高。用同样纯度(97.77％)的原料投料缩合反应，缩合产物体系只有不到90％的纯度，且后处理要柱层析操作。不适合工业放大。
此外，发明人还发现使用强碱醇钠进行关环反应会使得杂质i的含量容易超标，而且由于转化为杂质i和l的含量过高，导致收率的降低。
此外，当在侧链甲氧基脲基团的存在下进行缩合和关环，造成副反应更多。用同样纯度(99.11％)的原料投料关环反应，只有少量产物，大部分转化为两个降解杂质i和l。优化条件下也只有82％左右转化为目标产品(杂质l为根据质谱信息推测结构，质谱结果如图14所示，[M+H] +为642.32)。
为了克服现有技术对噻吩并嘧啶化合物(如瑞卢戈利)工艺及工艺中杂质研究的普遍不足，本发明的还提供了噻吩并嘧啶化合物(如瑞卢戈利)多个杂质结构及其制备方法，可以对噻吩并嘧啶化合
物(如瑞卢戈利)原料药和制剂产品进行更好的质量控制，为原料药和的制剂的生产提供了更全面更直观的质量控制标准。
在一个具体实施方案中，本发明提供了一种新的噻吩并嘧啶化合物(如瑞卢戈利)原料药杂质e。
Figure PCTCN2021107295-appb-000029
杂质e的来源有以下两种途径大部分来自前面步骤中间体残留，比如WO2014051164或CN111333633A中第一步溴化反应不完，或者后面催化氢化还原硝基步骤脱二甲胺基副产物衍生产物。
Figure PCTCN2021107295-appb-000030
其中R为C 1-6直链或支链的烷基，R 1为NO 2或NHCONHOCH 3。
在一个具体实施方案中，本发明提供了一种新的噻吩并嘧啶化合物(如瑞卢戈利)原料药杂质f。
Figure PCTCN2021107295-appb-000031
式中R为NH 2或C 1-6直链或支链的烷氧基。
杂质f来源于脲侧链基团的氨解或醇解，氨或醇的来源可以是反应后处理残留的铵盐，比如氯化铵，乙酸铵，或反应溶剂，残留溶剂等在碱性关环条件下生成，也有来源于反应过程中产品不稳定分解出的氨。此杂质很难纯化，需要严格控制原料来源的铵盐及反应后处理残留的铵盐，优化关环反应的条件下，反应体系可以控制反应过程中该杂质产生量在0.1％甚至0.05％以下。
在另一个具体实施方案中，本发明提供了杂质f的制备方法。
典型地，当杂质f中R为C 1-6直链或支链烷氧基时，杂质f可通过以下两种反应途径得到。
途径1：式f-1化合物在碱性条件下合环得到式f化合物。
途径2：式N-a化合物在醇钠的作用下进攻侧链脲羰基碳，发生取代反应得到式f化合物。
Figure PCTCN2021107295-appb-000032
式中R 1为C 1-6直链或支链的烷基。
典型地，当杂质f中R为NH 2时，杂质f可通过以下两种途径反应得到：
途径1：式f-2化合物与CDI和胺水/氨气缩合得到式f化合物。
途径2：式N-a化合物在胺水或氨气的作用下进攻侧链脲羰基碳，发生取代反应得到式f化合物。
Figure PCTCN2021107295-appb-000033
在一个具体实施方案中，本发明提供了一种新的噻吩并嘧啶化合物(如瑞卢戈利)原料药杂质g。
Figure PCTCN2021107295-appb-000034
杂质g于碱性条件下关环时产生，产生量与碱性强度正相关。杂质g来源是两分子脲基团的取代衍生反应。此杂质不易纯化，需要在反应过程精确控制，反应条件的不同此杂质生成量差别很大，通过本发明的方法得到的产品可以控制杂质g在0.1％甚至0.05％以下。来源如下所示：
Figure PCTCN2021107295-appb-000035
在一个具体实施方案中，本发明提供了一种新的噻吩并嘧啶化合物(如瑞卢戈利)原料药杂质h。
Figure PCTCN2021107295-appb-000036
杂质h来源是上步残留或降解产生的甲氧基胺与中间体h-2缩合反应的衍生物。此杂质需要在两步之前控制甲氧基胺的残留，以及控制好反应条件防止侧链脲的降解产生甲氧基胺。如下所示：
Figure PCTCN2021107295-appb-000037
在一个具体实施方案中，本发明的杂质研究部分第五方面提供了一种新的噻吩并嘧啶化合物(如瑞卢戈利)原料药杂质i。
Figure PCTCN2021107295-appb-000038
杂质i来源自尿嘧啶六元环结构的碱性条件下的降解，反应所用碱的碱性越强，杂质i的产生量越大。在如下所示两种途径：
Figure PCTCN2021107295-appb-000039
其中R 1为NO 2或NHCONHOCH 3。
在一个具体实施方案中，本发明提供了一种新的噻吩并嘧啶化合物(如瑞卢戈利)原料药杂质j。
Figure PCTCN2021107295-appb-000040
杂质j是噻吩并嘧啶化合物(如瑞卢戈利)的氧化降解杂质。在氧化剂存在条件下杂质j极易生成，如下所示：
Figure PCTCN2021107295-appb-000041
在一个具体实施方案中，本发明提供了一种新的噻吩并嘧啶化合物(如瑞卢戈利)原料药杂质k。
Figure PCTCN2021107295-appb-000042
杂质k是噻吩并嘧啶化合物(如瑞卢戈利)的降解杂质，部分来源自两分子噻吩并嘧啶化合物(如瑞卢戈利)的脲侧链取代反应或者前面生成侧链时候物料控制不准导致。如下所示：
Figure PCTCN2021107295-appb-000043
本发明的主要优点包括：
(1)无需有毒且昂贵的试剂(如T3P等)，所用试剂价廉易得，大大降低了生产成本，适合工业化大生产。
(2)本发明方法的反应副产物少，从而避免了难以分离的多种杂质。
(3)采用本发明方法，可无需使用诸如色谱等纯化方法，一次精制(如重结晶)便可使得产品式N化合物(如式N-a化合物)的化学纯度高达99.7％，且多个杂质很容易控制在 0.1％以下。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
原料和通用方法：
1、实施例中所用原料参考WO2004067535、WO2014051164和CN111333633A制备得到。
2、核磁 1H-NMR测定方法
300MHz，Bruker AV III 300 spectrometer。
实施例1：制备杂质e-a对照品
Figure PCTCN2021107295-appb-000044
取0.52g N,N'-羰基二咪唑溶于3ml乙腈中，加入0.2g三乙胺和0.3g甲氧基胺盐酸盐，搅拌10分钟。加入式e-2化合物1.0g，升温至45～55℃。TLC跟踪至原料转化完全，降温至15-25℃。向溶液中滴加水4ml，滴毕，继续搅拌2小时。过滤，干燥得到杂质e 1.05g，HPLC纯度为98.8％。 1H-NMR(300MHz,CDCl 3)δ:2.46(3H,s),3.82(3H,s),4.19(3H,s),5.33(2H,s),6.92(2H,t,J＝8.1Hz),7.14(1H,d,J＝9.1Hz),7.33(2H,d,J＝8.5Hz),7.40(1H,d,J＝9.1Hz),7.55(2H,d,J＝8.5Hz),7.67(1H,s).
实施例2：制备杂质f(R＝OMe)对照品
Figure PCTCN2021107295-appb-000045
取瑞卢戈利中间体f-2 5.0g溶于50ml二氯甲烷中，加入1.3g三光气，降温至0～10℃，滴加2.2g吡啶，反应1小时后加入5ml甲醇，升温15～25℃反应至原料转化完全，减压浓缩，柱层析纯化得到化合物f 3.90g，HPLC纯度为98.5％。1H-NMR(300MHz,DMSO-d6)δ:2.58(6H,s),3.69(3H,s),4.09(3H,s),4.38(2H,s),5.35(2H,d,J＝55.1Hz),7.16(2H,t,J＝8.2Hz),7.42-7.51(4H,m),7.64(2H,d,J＝8.6Hz),7.82(1H,d,J＝9.2Hz),9.10(1H,s),10.01(1H,s).
实施例3：制备杂质f(R＝NH 2)对照品
Figure PCTCN2021107295-appb-000046
取瑞卢戈利中间体f-1 5.0g溶于50ml二氯甲烷中，加入1.3g三光气，降温至0～10℃，滴加2.2g吡啶，反应1小时后加入5ml氨水，升温15～25℃反应至原料转化完全，减压浓缩，柱层析纯化得到化合物f 2.60g，HPLC纯度为97.5％。1H-NMR(300MHz,DMSO-d6)δ:2.03(6H,s),3.57(2H,d,J＝35.2Hz),4.09(3H,s),5.30(2H,d,J＝45.3Hz),5.95(2H,s),7.15(2H,t,J＝8.2Hz),7.41-7.53(6H,m),7.75(1H,d,J＝9.2Hz),8.75(1H,s).
实施例4：制备杂质g对照品
Figure PCTCN2021107295-appb-000047
取瑞卢戈利10.0g溶于500ml二甲基亚砜中，加入2.2g无水碳酸钾，升温30～40℃反应至大部分原料转化完全，将反应液滴加入500ml水中，滴毕，搅拌2小时，过滤得9g粗品，粗品经柱层析纯化得到化合物g 0.60g，HPLC纯度为95.8％。 1H-NMR(300MHz,DMSO-d6)δ:2.03(12H,s),3.58(4H,d,J＝33.1Hz),3.85(3H,s),4.06(6H,s),5.27(4H,d,J＝43.1Hz),7.12(4H,t,J＝8.1Hz),7.43(4H,d,J＝9.0Hz),7.58-7.75(10H,m),10.33(2H,s).
实施例5：制备杂质h(R 1＝iPr)对照品
Figure PCTCN2021107295-appb-000048
取瑞卢戈利中间体h-1 10.0g溶于50ml二甲基亚砜中，加入2.4g无水碳酸钾，升温40～50℃反应至大部分原料转化完全，降温至15-25℃向溶液滴加入100ml水中，有油状物析出，分液，粗品油状物经柱层析纯化得到化合物h 5.20g，HPLC纯度为97.5％。 1H-NMR(300MHz,DMSO-d6)δ:2.08(6H,s),3.63(5H,s),3.87(3H,s),5.30(2H,s,),7.14(2H,t,J＝8.3Hz),7.41-7.53(3H,m),7.69(2H,d,J＝8.6Hz),9.06(1H,s),9.62(1H,s).
实施例6：制备杂质i(式i-a，R 1＝NHCONHOCH 3)对照品
Figure PCTCN2021107295-appb-000049
取瑞卢戈利中间体i-1 1.0g溶于20ml甲醇中，加入0.82g无水碳酸钾，升温30～40℃反应至大部分原料转化完全，减压浓缩，粗品油状物经柱层析纯化得到化合物i 0.50g，HPLC纯度为96.7％。 1H-NMR(300MHz,CDCl 3)δ:2.30(6H,s),3.47(2H,s),3.83(3H,s),4.08(3H,s),4.50(2H,d,J＝5.9Hz),6.86-6.99(3H,m),7.21-7.31(3H,m),7.53(2H,d,J＝8.6Hz),7.63(1H,s),7.40(1H,d,J＝9.5Hz),8.90(1H,t,J＝6.0Hz),14.45(1H,s).
实施例7：制备杂质j对照品
Figure PCTCN2021107295-appb-000050
取瑞卢戈利4.0g溶于80ml乙腈中，加入4.0g 30％双氧水，室温15～25℃反应至大部分原料转化完全，减压浓缩，经柱层析纯化得到化合物j 2.20g，HPLC纯度为98.5％。 1H-NMR(300MHz,DMSO-d6)δ:2.82(6H,s),3.62(3H,s),4.09(3H,s),4.72(2H,s),5.32 (2H,d,J＝36.6Hz),7.15(2H,t,J＝8.2Hz),7.42-7.51(2H,m),7.70(2H,d,J＝8.7Hz),7.73-7.82(3H,m),9.25(1H,s),9.89(1H,s).
实施例8：制备杂质k对照品
Figure PCTCN2021107295-appb-000051
取瑞卢戈利中间体f-2 5.0g溶于50ml二氯甲烷中，加入0.5g三光气，降温至0～10℃，滴加1.1g吡啶，滴毕，回温至室温反应至大部分原料转化完全，过滤，滤饼经柱层析纯化得到化合物k 1.60g，HPLC纯度为97.8％。 1H-NMR(300MHz,DMSO-d6)δ:2.62(12H,s),4.10(6H,s),4.42(4H,s),5.35(4H,d,J＝53.9Hz),7.18(4H,t,J＝8.2Hz),7.44-7.56(8H,m),7.67(4H,d,J＝8.6Hz),7.21(2H,m),10.18(2H,s).
实施例9：制备式N-a化合物
步骤a：制备式N-1a化合物
Figure PCTCN2021107295-appb-000052
将式N-2a化合物(10.5g，18.2mmol HPLC纯度97.77％)加入50ml DMF中，降温至-10～0℃。加入三乙胺(3.8g，37.5mmol)，滴加二氯亚砜(3.40g，28.6mmol)。滴加毕，分批加入6-甲氧基-3-氨基哒嗪(3.58g，28.6mmol)，保温反应10小时，HPLC检测分析图谱如图1所示(反应液中产物纯度93.56％，收率93.5％)。
滴加入0～10℃的饱和碳酸氢钠溶液50ml，析出固体。过滤，水洗，浓缩，50ml乙酸乙酯重结晶得到黄色固体11.25g，摩尔收率90.0％，HPLC纯度99.11％，HPLC检测分析图谱如图2所示。 1H-NMR(300MHz,DMSO-d6)δ:0.9～1.44(6H,br.),2.1(6H,s),3.56(2H,s),3.64(3H,s),4.00(3H,s),4.70～5.10(3H,br.),6.90～7.10(2H,t,J＝8.5Hz),7.10-7.40(4H,m),7.60～7.80(2H,d,J＝8.5Hz),8.30～8.50(2H,d,J＝9.5Hz),9.11(1H,s),9.65(1H,s).
步骤b：制备式N-a化合物
Figure PCTCN2021107295-appb-000053
将步骤a得到的式N-1a化合物(5.0g，7.3mmol)和碳酸钾(0.8g，5.8mmol)加入到50ml DMF中，升温至40～50℃，继续搅拌6小时。降温至0～10℃，滴加100ml水。过滤，干燥得到白色固体4.4g，收率96.5％，纯度97.58％，HPLC检测分析图谱如图6所示。
粗品加入8.8ml DMSO，升温至40℃使溶解。控温35～45℃，加入22ml乙醇，35～45℃保温2小时。降温至0～5℃，搅拌2小时。过滤，干燥得式N-a化合物4.1g，收率93.2％，HPLC检测分析图谱如图7所示(纯度99.75)。[M+H] +：624.31； 1H-NMR(300MHz,DMSO-d6)δ:2.04(6H,s),3.40～3.70(2H,br.),3.64(3H,s),4.09(3H,s),5.10～5.50(2H,br.),7.10～7.20(2H,t,J＝8.2Hz),7.40-7.60(4H,m),7.80～7.92(3H,m),9.10(1H,s),9.63(1H,s).
HPLC检测纯度和杂质情况如下(％)：
式N-a RS-1 RS-2 RS-3 杂质e-a 杂质f 杂质g 杂质h 杂质i-a 杂质j 杂质k 杂质l
97.58 N.D. 0.57 N.D. 0.52 0.15 0.08 0.10 0.30 N.D. 0.05 0.02
99.75 N.D. 0.09 N.D. N.D. 0.03 0.03 N.D. N.D. N.D. 0.02 N.D.
N.D.:未检出(＜0.01％)
对比例1：缩合步骤
对比例1.1
100mL反应瓶中依次加入：N-2a(2.50g，4.34mmol，纯度97.77％)，N,N-二甲基乙酰胺(25毫升)，3-氨基-6-甲氧基哒嗪(0.79g，6.34mmol)，N,N-二异丙基乙基胺(0.77g，5.95mmol)，50％的丙基磷酸酐乙酸乙酯溶液(7.84g，12.33mmol)体系升温60℃后保温反应0.5小时，取体系送液相检测，液相纯度89.99％(HPLC检测分析图谱如图3所示)。
对比例1.2
步骤与实施例1.1相同，区别在于反应时间为1小时。
经取样检测，1小时后反应混合物含产品87.95％(HPLC检测分析图谱如图4所示)， 收率87.5％。
对比例1.3
步骤与实施例1.1相同，区别在于反应时间为2小时。
经取样检测，2小时后含产品纯度89.64％(HPLC检测分析图谱如图5所示)，收率89.5％。
三次跟踪产品含量均没有超过90％，因此反应结束后经常规的后处理得到的粗品固体不能通过结晶纯化，需要柱层析纯化。尝试硅胶柱层析时发现此产品在柱层析过程稳定性差，柱层析纯化后纯度不能提高。
此外，对比例中所使用的丙基磷酸酐(T3P)价格昂贵，其摩尔价格远远高于本申请所用试剂酰氯，甚至是使用的试剂二氯亚砜的50倍左右。而且T3P分子量大，原子利用率低，只能溶液运输存放，1分子丙基磷酸酐后处理产生3分子含磷废水，对环境危害较大。
对比例1.4
100mL反应瓶中依次加入：N-2a(2.50g，4.34mmol，纯度97.77％)，N,N-二甲基乙酰胺(25毫升)，3-氨基-6-甲氧基哒嗪(0.79g，6.34mmol)，N,N-二异丙基乙基胺(0.77g，5.95mmol)，1-(3-二甲氧基丙基)-乙基碳二亚胺盐酸盐(1.66g，8.68mmol)，4-二甲氨基吡啶(0.05g，0.41mmol)体系升温60℃后保温5小时，取体系送液相检测产品纯度50.88％。
对比例2：关环步骤
对比例2.1
(1)100mL反应瓶中依次加入：N-1a(1.50g，2.19mmol，纯度99.11％)，异丙醇(35毫升)，乙醇钠固体(0.48g，7.05mmol)，将得到的体系升温到70℃保温反应0.5小时后取样分析。经测试反应混合物中式N-a的(保留时间为15.833min)含量只有5.08％，HPLC检测分析图谱如图8和表1所示。
(2)100mL反应瓶中依次加入：N-1a(1.50g，2.19mmol，纯度99.11％)，甲醇(35毫升)，甲醇钠固体(0.48g，7.05mmol)，将得到的体系升温到60℃保温反应0.5小时取样分析。经测试，反应混合物中式N-a的含量4.58％。
(3)100mL反应瓶中依次加入：N-1a(1.50g，2.19mmol，纯度99.11％)，乙醇(35毫升)， 乙醇钠固体(0.48g，7.05mmol)，将得到的体系升温到60℃保温反应1.0小时取样分析。经测试，反应混合物中式N-a的含量6.26％。
对比例2.2(1)100mL反应瓶中依次加入：N-1a(1.50g，2.19mmol，纯度99.11％)，乙醇(35毫升)，乙醇钠固体(0.15g，2.19mmol)，体系升温到60℃保温0.5小时取样，反应混合物中式N-a的含量63.08％(HPLC分析结果如图9和表1所示)。
(2)0.5小时取样后其余反应混合物在60℃下继续保温反应，在保温反应1小时(即继续反应0.5小时)取样(HPLC分析结果如图10和表1所示)。
(3)1小时取样后其余反应混合物在60℃下继续保温反应，在保温反应1.5小时(即继续反应0.5小时)取样(HPLC分析结果如图11和表1所示)。
(4)1.5小时取样后其余反应混合物在60℃下继续保温反应，在保温反应2小时(即继续反应0.5小时)取样(HPLC分析结果如图12和表1所示)。
表1 HPLC分析结果(％)
Figure PCTCN2021107295-appb-000054
经计算，对比例2.1收率约为5％，对比例2.2的最大收率约为82％。
注：RS-3为一种缩脲副产物。碱降解杂质i和l含量高是因为关环反应使用了强碱醇钠。
HPLC检测条件：
仪器：Agilent 1260 series HPLC.
色谱柱：Waters XSelect CSH C18,4.6mm×250mm,5μm
柱温:10℃
样品室温度:5℃
流动相A:PH＝2的磷酸盐缓冲液
流动相B:色谱纯乙腈
Figure PCTCN2021107295-appb-000055
流速：1.0毫升/分钟
测定时间：68分钟
检测波长：230纳米
实施例10：制备式N-b化合物
步骤a：制备式N-1b化合物
Figure PCTCN2021107295-appb-000056
将式N-2b化合物(20g，38.5mmol)加入100ml DCM中，降温至0～10℃。加入三乙胺(5.84g，57.7mmol)，滴加苯磺酰氯(11.1g，57.7mmol)。滴加毕，加入6-甲氧基-3-氨基哒嗪(7.2g，57.7mmol)，保温反应10小时。
滴加入0～10℃的饱和碳酸氢钠溶液150ml，分液，50ml水洗，浓缩溶剂置换为100ml乙酸乙酯，产品析出，过滤干燥得到黄色固体N-1b 23.2g，摩尔收率96.0％。 1H-NMR(CDCl 3)δ:1.10～1.40(3H,m),2.20(6H,s),3.51(2H,s),4.10(3H,s),4.20～4.35(2H,m),5.06(2H,s),6.70～6.80(2H,m),6.99(1H,d,J＝9.5Hz),7.10～7.20(1H,m),7.45～7.55(2H,m),8.25～8.35(2H,m),8.54(1H,d,J＝9.5Hz).
步骤b：制备式N-b化合物
Figure PCTCN2021107295-appb-000057
将式N-1b化合物(20g，31.9mmol)和碳酸钾(4.4g，31.9mmol)加入到50ml DMF中，升温至40～50℃，继续搅拌6小时。降温至0～10℃，滴加100ml水。过滤，干燥得到白色固体17.9g，收率97.0％，纯度98.6％。
粗品加入38ml DMSO，升温至40℃使溶解。控温35～45℃，加入100ml乙醇，35～45℃保温2小时。降温至0～5℃，搅拌2小时。过滤，干燥得式N-b化合物17.0g，纯度99.60％，收率97.0％。 1H-NMR(CDCl 3)δ:2.20(6H,s),3.72(2H,s),4.19(3H,s),5.38(2H,brs),6.95(2H,t,J＝8.2Hz),7.14(1H,d,J＝9.0Hz),7.20～7.35(1H,m),7.42(1H,d,J＝9.0Hz),7.89(2H,d,J＝8.8Hz),8.28(2H,d,J＝8.8Hz).
实施例11将实施例10步骤a得到的式N-1b化合物(2.0g，3.19mmol)和碳酸铯(0.52g，1.59mmol)加入到5ml DMSO中，升温至40～50℃，继续搅拌6小时。降温至0～10℃，滴加10ml水。过滤，干燥得到白色固体1.70g，收率91.9％，纯度98.5％。
干燥后粗品加入3.5ml DMSO，升温至40℃使溶解。控温35～45℃，加入12ml乙醇，35～45℃保温2小时。降温至0～5℃，搅拌2小时。过滤，干燥得式N-b化合物1.65g，纯度99.68％，收率97.0％。
HPLC检测纯度和杂质情况如下：
Figure PCTCN2021107295-appb-000058
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限。

Claims (10)

  1. 一种制备式N化合物的方法，其特征在于，所述的方法包括步骤：
    Figure PCTCN2021107295-appb-100001
    (a)在惰性溶剂A中，在有机碱和酰氯的存在下，使式N-2化合物和3-氨基-6-甲氧基哒嗪进行缩合反应，从而得到式N-1化合物；和
    (b)在惰性溶剂B中，在碱存在下，使式N-1化合物发生关环反应，从而得到式N化合物；
    各式中，R为C 1-6烷基，R 1为-NO 2或-NHCONHOCH 3。
  2. 如权利要求1所述的方法，其特征在于，步骤b)中所述的碱为无机碱；较佳地，所述的碱选自下组：碳酸盐、磷酸盐、碳酸氢盐、磷酸氢盐，或其组合；更佳地，选自下组：碳酸钾、碳酸钠、碳酸铯、磷酸钾，或其组合。
  3. 如权利要求1所述的方法，其特征在于，所述的方法具有下述一个或多个特征：
    a.所述有机碱为含1-3个氮且含3-20碳的有机化合物；较佳地，所述的有机碱选自下组的化合物：R 2NH 2、(R 2) 2NH、(R 2) 3N、含N杂原子的4至7元杂环烷基、含N杂原子的5至6元杂芳基，或其组合；更佳地，所述有机碱选自下组：三乙胺、吡啶，或其组合；其中，R 2为C 1-6烷基；
    b.所述的酰氯选自：三氯氧磷、二氯亚砜、C 1-8烷基磺酰氯、C 4-20芳香基磺酰氯、C 1-8烷基酰氯、C 4-20芳香基酰氯；较佳地，所述酰氯选自：苯磺酰氯、甲基磺酰氯、二氯亚砜，或其组合。
  4. 如权利要求1所述的方法，其特征在于，步骤(a)具有下述一个或多个特征：
    a.式N-2化合物与3-氨基-6-甲氧基哒嗪的摩尔比为1：1～3；较佳地，1：1.1～2.0；更佳地，1：1.4～1.6；
    b.式N-2化合物与有机碱的摩尔比为1：1.5-5；较佳地，1:1.1～2.5；更佳地，1：1.4～2.1；
    c.式N-2化合物与酰氯的摩尔比为1：1～3；较佳地，1：1.1～2.0；更佳地， 1：1.4～1.6。
  5. 如权利要求1所述的方法，其特征在于，步骤(b)中，式N-1化合物与碱的摩尔比1：0.5～3；较佳地，1：0.5～2.0；更佳地，1：0.7～1.1。
  6. 如权利要求1所述的方法，其特征在于，所述的式N化合物为式N-a化合物，
    Figure PCTCN2021107295-appb-100002
  7. 一种可用作式N化合物的质控用对照品的化合物，所述式N化合物如权利要求1中定义；其特征在于，
    所述化合物为式e化合物，其如下所示
    Figure PCTCN2021107295-appb-100003
    式中，R 1为-NO 2或-NHCONHOCH 3；
    和/或，所述化合物为式f化合物，其如下所示：
    Figure PCTCN2021107295-appb-100004
    式中R为NH 2或C 1-6烷氧基；
    和/或，所述化合物为式h化合物，其如下所示：
    Figure PCTCN2021107295-appb-100005
    和/或，所述化合物为式i化合物，其如下所示：
    Figure PCTCN2021107295-appb-100006
    式中R 1为-NO 2或-NHCONHOCH 3；
    和/或，所述化合物为式j化合物，其如下所示：
    Figure PCTCN2021107295-appb-100007
    和/或，所述化合物为式g化合物，其如下所示：
    Figure PCTCN2021107295-appb-100008
    和/或，所述化合物为式k化合物，其如下所示：
    Figure PCTCN2021107295-appb-100009
    和/或，所述化合物为式l化合物，其如下所示：
    Figure PCTCN2021107295-appb-100010
  8. 一种如权利要求7所述的化合物的用途，其特征在于，在式N化合物的检测中用作杂质对照品，其中式N化合物如权利要求1中所定义。
  9. 如权利要求7所述的用途，其特征在于，所述杂质对照品用于式N化合物(较佳地，式N-a化合物)原料药或药物组合物或药物制剂的杂质检测中的杂质对照品。
  10. 一种如权利要求1所述方法制备得到的式N化合物或其盐，
    Figure PCTCN2021107295-appb-100011
    其中，所述式N化合物的纯度≥99.5％；较佳地，≥99.6％；并且
    所述式N化合物中杂质i和/或杂质f的含量≤0.15(较佳地，≤0.10％)；其中，杂质i为如权利要求7中定义的式i化合物，杂质f为如权利要求7中定义的式f化合物。
PCT/CN2021/107295 2021-02-10 2021-09-06 高纯度的噻吩并嘧啶化合物及其制备方法 WO2022170737A1 (zh)

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