WO2019196945A1 - 一种合成氘代酰胺及氘代磺酰胺的新方法 - Google Patents
一种合成氘代酰胺及氘代磺酰胺的新方法 Download PDFInfo
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- This invention relates to a novel process for the synthesis of halogenated amides and deuterated sulfonamides.
- Deuterated drugs are a hot research field in the development of new drugs.
- Deuterated drugs refer to the replacement of some of the hydrogen atoms in a drug molecule with hydrazine. Since strontium is close in shape and volume to hydrogen in the drug molecule, deuterated drugs generally retain the biological activity and selectivity of the original drug. Since the C-D bond is more stable than the C-H bond, the C-D bond is less likely to break during the metabolic reaction, the half-life may be prolonged, and the metabolites may be reduced to achieve better pharmacokinetics.
- AUSTEDO deutetrabenazine
- AUSTEDO deutetrabenazine
- Enzalutamide is an androgen receptor androgen-receptor (AR) antagonist for prostate cancer patients treated with the anticancer drug docetaxel. Enzalutamide is the latest method to treat this disease that has been shown to prolong patient life.
- Apalutamide (ARN-509) is a selective, competitive androgen receptor inhibitor that is effective in the treatment of prostate cancer.
- Sorafenib is a novel multi-targeted oral drug for the treatment of tumors. Its primary development goal is to treat gastrointestinal stromal tumors and metastatic renal cells that are not responsive or intolerant to standard therapies. Receptors that target certain proteins, which are thought to play a molecular switch-like role in tumor growth.
- Regorafenib is a multi-target inhibitor that targets VEGFR1/2/3, PDGFR ⁇ , Kit, RET and Raf-1.
- Rebastinib is a Bcr-Abl inhibitor.
- Axitinib can be used in other systemic treatments for advanced kidney cancer.
- Sumatriptan is a 5-HT1 receptor agonist.
- the above drugs are all amide or sulfonamide drugs, and their deuterated compounds have many important uses in drug research. For example, compounds 1, 2, 3 have entered the clinical or preclinical development stage. How to use the above drugs to prepare their deuterated drugs gently and efficiently is of great significance. They can be used not only as an alternative to non-deuterated drugs, but also as an isotope standard for drug metabolism research.
- the present invention provides a novel method for synthesizing a halogenated amide and a halogenated sulfonamide.
- the invention provides a method for synthesizing a halogenated amine, the steps are as follows:
- L is selected from a carbonyl group and a sulfo group
- R 1 is selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group;
- R 3 is selected from -CO-R 6 , -SO 2 R 7 ;
- X is a leaving group;
- R 6 and R 7 are each independently selected from the group consisting of an alkoxy group, an alkyl group, a substituted alkyl group, and an aryl group;
- R 4 and R 5 are each independently selected from H, deuterated substituted or unsubstituted alkyl, deuterated cycloalkyl, deuterated heterocyclic, deuterated aryl, deuterated heteroaryl, And R 4 and R 5 are not hydrogen at the same time;
- R 3 is selected from -CO-R 6 , -SO 2 R 7 ;
- X is selected from -OR 3 , Cl, Br;
- R 6 and R 7 are each independently selected from the group consisting of t-butoxy, isopropoxy, benzyloxy, methyl, trifluoromethyl, phenyl, tolyl.
- R 3 is selected from the group consisting of -CO-R 6 and -SO 2 R 7 ;
- R 6 is selected from the group consisting of t-butoxy, isopropoxy and benzyloxy; and R 7 is selected from the group consisting of methyl, trifluoromethyl, phenyl and tolyl.
- R 3 is selected from -CO-R 6 ;
- X is -OR 3 ;
- R 6 is selected from the group consisting of t-butoxy groups.
- R 4 and R 5 are each independently selected from H, deuterated alkyl groups, and R 4 and R 5 are not hydrogen at the same time.
- R 4 and R 5 are each independently selected from H, deuterated methyl, and R 4 and R 5 are not hydrogen at the same time.
- R 2 is selected from a substituted or unsubstituted C 1 -C 6 alkyl group.
- R 2 is selected from the group consisting of C 1 -C 4 alkyl groups.
- R 2 is selected from a methyl group.
- R 1 is selected from one of the following structures:
- compound I is selected from one of the following structures:
- the solvent is a polar solvent or a non-polar solvent.
- the polar solvent is selected from the group consisting of dichloromethane, dichloroethane, formamide, trifluoroacetic acid, DMSO, acetonitrile, DMF, hexamethylphosphoramide, methanol, ethanol, acetic acid, isopropanol, pyridine, Tetramethylethylenediamine, acetone, triethylamine, n-butanol, dioxane, tetrahydrofuran, methyl formate, tributylamine, methyl ethyl ketone, ethyl acetate, chloroform, trioctylamine, dimethyl carbonate, diethyl ether , isopropyl ether, n-butyl ether, trichloroethylene, diphenyl ether.
- the polar solvent is selected from the group consisting of dichloromethane.
- non-polar solvent is selected from the group consisting of benzene, toluene, carbon tetrachloride, carbon disulfide, cyclohexane, and hexane.
- the molar ratio of the compound M, DMAP, and R 3 -X is 1:1 to 3:1 to 10, preferably 1:2 to 3:1.5 to 2.
- the ratio of the compound M to the solvent is from 1:2 to 20 mmol/mL; preferably from 1:2 to 15 mmol/mL, more preferably from 1:5.5 to 10 mmol/mL.
- the reaction temperature is 10 to 60 °C.
- reaction temperature is 20 to 30 ° C, preferably 25 ° C.
- the reaction time is 10 to 120 h, preferably 10 to 16 h, more preferably 10 to 14 h, still more preferably 12 h.
- the solvent is a polar solvent or a non-polar solvent.
- the polar solvent is selected from the group consisting of dichloromethane, dichloroethane, formamide, trifluoroacetic acid, DMSO, acetonitrile, DMF, hexamethylphosphoramide, methanol, ethanol, acetic acid, isopropanol, pyridine, Tetramethylethylenediamine, acetone, triethylamine, n-butanol, dioxane, tetrahydrofuran, methyl formate, tributylamine, methyl ethyl ketone, ethyl acetate, chloroform, trioctylamine, dimethyl carbonate, diethyl ether , isopropyl ether, n-butyl ether, trichloroethylene, diphenyl ether.
- the polar solvent is selected from the group consisting of acetonitrile.
- non-polar solvent is selected from the group consisting of benzene, toluene, carbon tetrachloride, carbon disulfide, cyclohexane, and hexane.
- the feed ratio of the compound N to the solvent is 1:1 to 25 mmol/mL, preferably 1:1 to 20 mmol/mL, and more preferably 1:2.5 to 15 mmol/mL.
- the base is an organic base or an inorganic base.
- the organic base is selected from the group consisting of DBU, sodium methoxide, potassium ethoxide, potassium t-butoxide, sodium t-butoxide, triethylamine, triethylenediamine, DBN, DMAP, pyridine, N-methylmorpholine, tetra Methylethylenediamine, TMG, n-butyllithium, LDA.
- organic base is selected from the group consisting of DBU.
- the inorganic base is selected from the group consisting of potassium hydroxide, barium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, copper hydroxide, iron hydroxide, lead hydroxide, hydrogen.
- the molar ratio of the compound N, R 4 -NH-R 5 or a salt thereof to the base is 1:1 to 4:1 to 5, preferably 1:1 to 4:1. 4.5.
- the molar ratio of the compound N, R 4 -NH-R 5 or a salt thereof to a base is 1:3:4.
- the reaction temperature is 10 to 100 ° C, preferably 20 to 30 ° C, and more preferably 25 ° C.
- the reaction time is 10 to 120 h, preferably 10 to 14 h, and more preferably 12 h.
- the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
- the structures of the compounds described in the present invention all refer to structures which are stably present.
- substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
- ⁇ refers to the isotope of hydrogen (H), also known as heavy hydrogen, and the elemental symbol is generally D or 2H.
- alkyl group is a hydrocarbon group in which one hydrogen atom is lost in an alkane molecule, for example, methyl-CH 3 , ethyl-CH 3 CH 2 or the like.
- substituted or unsubstituted C 1-4 alkyl group means that the C 1-4 alkyl group may be substituted or unsubstituted.
- Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a conjugated ⁇ -electron system, such as phenyl and naphthyl.
- the aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but may not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be in a conjugated pi-electron system.
- the aryl group can be substituted or unsubstituted.
- Heteroaryl refers to a heteroaromatic group containing one to more heteroatoms. Containing at least one ring heteroatom selected from N, O or S, the remaining ring atoms are C, and additionally have a fully conjugated pi-electron system.
- furyl pyrrolyl, quinolyl, thienyl, pyridyl, pyrazolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, thienopyridinyl and the like.
- the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring.
- the heteroaryl group can be optionally substituted or unsubstituted.
- Cycloalkyl means a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic.
- C 3-8 cycloalkyl means a cycloalkyl group having 3 to 8 carbon atoms.
- Heterocyclyl means a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and carries at least one cycloalkyl selected from O, S or substituted nitrogen atoms, the remainder The ring atom is carbon.
- C 3-8 heterocyclic group means a heterocyclic group having 3 to 8 carbon atoms and a hetero atom number. The heterocyclic group may be unsubstituted or substituted with one or more substituents.
- Compound 1 is a deuterated anti-prostate cancer drug Enzalutamide
- compound 2 is a deuterated anti-prostate cancer drug Apalutamide
- compound 3 is a deuterated anticancer drug Sorafenib
- compound 4 is a deuterated anticancer drug Regorafenib
- compound 5 is Rebastinib.
- Compound 6 is deuterated Axitinib.
- Compound 7 is a deuterated drug for the treatment of migraine, Sumatriptan.
- the "room temperature” described in the present invention is "25 ⁇ 5 ° C”.
- the “overnight” in the present invention is “12 ⁇ 1 h”.
- the invention provides a novel method for synthesizing deuterated amide and deuterated sulfonamide.
- the method has mild reaction conditions and short route, and can be obtained in only two steps, and can be applied to raw materials which are not applicable to existing methods, and improves synthesis efficiency. It can be applied to many amide compounds and has strong universality. It provides a new choice for the preparation of amide and sulfonamide compounds of halogenated amines.
- the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
- Axitinib (3-1, 193 mg, 0.5 mmol, 1.0 eq) was dissolved in dichloromethane (10 ml), DMAP (183 mg, 1.5 mmol) was added with stirring, and Boc anhydride (327 mg, 1.5 mmol) was added.
- the reaction was carried out at room temperature for 16 hours, and the reaction was completed by TLC until the reaction was completed.
- the reaction mixture was washed with 0.1N aqueous hydrochloric acid until the DMAP was washed.
- the organic layer was washed with saturated aqueous NaHCO 3 and aqueous NaCI, dried over Na 2 SO 4 and dried.
- N-methylhexanoamide (8-1, 129 mg, 1 mmol) was dissolved in dichloromethane (5 ml), DMAP (244 mg, 2 mmol) was added with stirring, and Boc anhydride (436 mg, 2 mmol) was added and reacted at room temperature 16
- the reaction was carried out with 0.1N aqueous hydrochloric acid until the DMAP was washed.
- the organic layer was washed with saturated aqueous NaHCO 3 and aqueous NaCI, dried over anhydrous Na 2 SO 4
- the present invention provides a novel method for synthesizing deuterated amides and deuterated sulfonamides.
- the method has mild reaction conditions and a short route, and can be obtained in only two steps, and can be applied to raw materials which are not applicable to existing methods. Improve the synthesis efficiency, can be applied to many amide compounds, has a strong universality, and provides a new choice for the preparation of amide and sulfonamide compounds of halogenated amines.
Abstract
Description
Claims (33)
- 一种合成氘代胺的方法,其特征在于:步骤如下:式中,L选自羰基、磺基;R 1选自取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环基;R 2选自取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;R 3选自-CO-R 6、-SO 2R 7;X为一个离去基团;其中,R 6、R 7各自独立地选自烷氧基、烷基、取代的烷基、芳基;R 4、R 5各自独立地选自H、氘代的取代或未取代的烷基、氘代的环烷基、氘代的杂环基、氘代的芳基、氘代的杂芳基,且R 4、R 5不同时为氢;(1)将化合物M、DMAP、R 3-X加入到溶剂中,反应完全后得化合物N;(2)将化合物N、R 4-NH-R 5或其盐、碱加入到溶剂中,反应完全后,纯化得化合物Ⅰ。
- 根据权利要求1所述的合成方法,其特征在于:R 3选自-CO-R 6、-SO 2R 7;X选自-OR 3、Cl、Br;其中,R 6、R 7各自独立地选自叔丁氧基、异丙氧基、苄氧基、甲基、三氟甲基、苯基、甲苯基。
- 根据权利要求2所述的合成方法,其特征在于:R 3选自-CO-R 6、-SO 2R 7;其中,R 6选自叔丁氧基、异丙氧基、苄氧基;R 7选自甲基、三氟甲基、苯基、甲苯基。
- 根据权利要求3所述的合成方法,其特征在于:R 3选自-CO-R 6;X为-OR 3;其中,R 6选自叔丁氧基。
- 根据权利要求1所述的合成方法,其特征在于:R 4、R 5各自独立地选自H、氘代的烷基,且R 4、R 5不同时为氢。
- 根据权利要求5所述的合成方法,其特征在于:R 4、R 5各自独立地选自H、氘代的甲基,且R 4、R 5不同时为氢。
- 根据权利要求1所述的合成方法,其特征在于:R 2选自取代或未取代的C 1~C 6烷基。
- 根据权利要求7所述的合成方法,其特征在于:R 2选自C 1~C 4烷基。
- 根据权利要求8所述的合成方法,其特征在于:R 2选自甲基。
- 根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(1)中,所述溶剂为极性溶剂或非极性溶剂。
- 根据权利要求12所述的合成方法,其特征在于:所述极性溶剂选自二氯甲烷、二氯乙烷、甲酰胺、三氟乙酸、DMSO、乙腈、DMF、六甲基磷酰胺、甲醇、乙醇、乙酸、异丙醇、吡啶、四甲基乙二胺、丙酮、三乙胺、正丁醇、二氧六环、四氢呋喃、甲酸甲酯、三丁胺、甲乙酮、乙酸乙酯、氯仿、三辛胺、碳酸二甲酯、***、异丙醚、正丁醚、三氯乙烯、二苯 醚。
- 根据权利要求13所述的合成方法,其特征在于:所述极性溶剂选自二氯甲烷。
- 根据权利要求12所述的合成方法,其特征在于:所述非极性溶剂选自苯、甲苯、四氯化碳、二硫化碳、环己烷、己烷。
- 根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(1)中,所述化合物M、DMAP、R 3-X的摩尔比为1:1~3:1~10,优选为1:2~3:1.5~2。
- 根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(1)中,所述化合物M与溶剂的投料比为1:2~20mmol/mL;优选为1:2~15mmol/mL,更优选为1:5.5~10mmol/mL。
- 根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(1)中,所述反应温度为10~60℃。
- 根据权利要求18所述的合成方法,其特征在于:所述反应温度为20~30℃,优选为25℃。
- 根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(1)中,所述反应时间为10~120h,优选为10~16h,更优选为10~14h,进一步优选为12h。
- 根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述溶剂为极性溶剂或非极性溶剂。
- 根据权利要求21所述的合成方法,其特征在于:所述极性溶剂选自二氯甲烷、二氯乙烷、甲酰胺、三氟乙酸、DMSO、乙腈、DMF、六甲基磷酰胺、甲醇、乙醇、乙酸、异丙醇、吡啶、四甲基乙二胺、丙酮、三乙胺、正丁醇、二氧六环、四氢呋喃、甲酸甲酯、三丁胺、甲乙酮、乙酸乙酯、氯仿、三辛胺、碳酸二甲酯、***、异丙醚、正丁醚、三氯乙烯、二苯醚。
- 根据权利要求22所述的合成方法,其特征在于:所述极性溶剂选自乙腈。
- 根据权利要求21所述的合成方法,其特征在于:所述非极性溶剂选自苯、甲苯、四氯化碳、二硫化碳、环己烷、己烷。
- 根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述化合物N与溶剂的投料比为1:1~25mmol/mL,优选为1:1~20mmol/mL,更优选为1:2.5~15mmol/mL。
- 根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述碱为有机碱或无机碱。
- 根据权利要求26所述的合成方法,其特征在于:所述有机碱选自DBU、甲醇钠、乙 醇钾、叔丁醇钾、叔丁醇钠、三乙胺、三乙烯二胺、DBN、DMAP、吡啶、N-甲基吗啉、四甲基乙二胺、TMG、正丁基锂、LDA。
- 根据权利要求27所述的合成方法,其特征在于:所述有机碱选自DBU。
- 根据权利要求26所述的合成方法,其特征在于:所述无机碱选自氢氧化钾、氢氧化钡、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁、氢氧化锌、氢氧化铜、氢氧化铁、氢氧化铅、氢氧化钴、氢氧化铬、氢氧化锆、氢氧化镍、氢氧化铵、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾。
- 根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述化合物N、R 4-NH-R 5或其盐、碱的摩尔比为1:1~4:1~5,优选为1:1~4:1~4.5。
- 根据权利要求30所述的合成方法,其特征在于:所述化合物N、R 4-NH-R 5或其盐、碱的摩尔比为1:3:4。
- 根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述反应温度为10~100℃,优选为20~30℃,更优选为25℃。
- 根据权利要求1~11任意一项所述的合成方法,其特征在于:步骤(2)中,所述反应时间为10~120h,优选为10~14h,更优选为12h。
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CN112679348A (zh) * | 2020-12-27 | 2021-04-20 | 河南师范大学 | 一种3-芳甲酰基茚酮-2-甲酸酯类化合物的合成方法 |
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