WO2022041608A1 - Lasmiditan的合成工艺 - Google Patents

Lasmiditan的合成工艺 Download PDF

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WO2022041608A1
WO2022041608A1 PCT/CN2020/140026 CN2020140026W WO2022041608A1 WO 2022041608 A1 WO2022041608 A1 WO 2022041608A1 CN 2020140026 W CN2020140026 W CN 2020140026W WO 2022041608 A1 WO2022041608 A1 WO 2022041608A1
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lasmiditan
ethylenediamine
reaction
washed
ligand
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PCT/CN2020/140026
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English (en)
French (fr)
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赵学清
徐伟
马驰
俞墨涵
成佳威
郑治尧
李梦娜
林燕琴
范琳
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南京三元阳普医药科技有限公司
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Publication of WO2022041608A1 publication Critical patent/WO2022041608A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
    • B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0213—Complexes without C-metal linkages
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
    • B01J2531/16—Copper

Definitions

  • the invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis process of 5-HT If receptor agonist- Lasmiditan .
  • Migraine is characterized by repeated episodes of mild to severe headaches, usually unbearable headaches during attacks, seriously affecting sleep quality, accompanied by nausea, anxiety, depression, etc. It will affect the social skills and academic performance of adolescents, and it will directly lead to adults. Decreased labor capacity, affecting approximately 10% of the global population, is three times more common in women than in men. There is still no cure for migraine headaches. In 2017, there were more than 36 million migraine patients in the United States, 8 million in Japan, and approximately 13 million in China. Migraine costs tens of billions of dollars in healthcare spending and economic losses each year in the United States.
  • Lasmiditan (Formula 1) is the first innovative drug for emergency treatment of migraine in nearly 20 years, the first with a new mechanism of action, which acts on the 5-HT 1f receptor in the trigeminal nerve pathway and penetrates the central nervous system Works to block the sensation of pain and relieve migraine symptoms.
  • lasmiditan is expected to meet the clinical treatment needs of 40% of these patients. Compared with traditional triptans, it does not constrict blood vessels and thus does not increase the risk of cardiovascular disease. For this part of patients who have or may suffer from cardiovascular disease, this product provides a better solution [Proc. Natl. Acad. Sci.
  • the synthetic routes of Lasmiditan APIs reported in the literature include route A and improved routes B, C, and D respectively.
  • the 2-chloropyridine derivative (2) reacts with benzophenone under the catalysis of noble metal complex (Pd 2 dba 3 ) and expensive organophosphorus (BINAP).
  • the imine forms 2-iminopyridine compounds (3), which are then hydrolyzed under acidic conditions to obtain 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (4), which is finally combined with 2,4 , 6-Trifluorobenzoyl chloride (5) is condensed to obtain Lasmiditan (WO2003/084949, or CN100352817C).
  • trifluorobenzoyl chloride (5) is acylated by trifluorobenzoic acid with an acylating agent (thionyl chloride or oxalyl chloride), after the solvent is removed, there are more hydrochloric acid and acylating agent left in it, which needs to be treated with an acylating agent (thionyl chloride or oxalyl chloride).
  • Trifluorobenzoyl chloride was purified by distillation under reduced pressure before acylation with the amino group of intermediate 4 to yield Lasmiditan.
  • this diacylated by-product needs to be hydrolyzed by 20% NaOH, which can be regenerated into Lasmiditan; in addition, intermediate 4 can be salified with the hydrochloric acid produced by the reaction and is insoluble in the solvent used in the reaction, so that intermediate 4 cannot completely participate in amidation. reaction. Even if a large amount of triethylamine is used to exchange the free intermediate 4, the raw material intermediate 4 is difficult to be completely consumed, and the large amount of triethylamine used cannot be recovered and reused. So there are too many process problems in this step.
  • route B has made many improvements.
  • trifluorobenzamide is easy to prepare: by acylating trifluorobenzoic acid with an acylating agent (thionyl chloride or oxalyl chloride), after removing the solvent, even if the residual trifluorobenzoyl chloride is relatively small
  • an acylating agent thionyl chloride or oxalyl chloride
  • the crude acid chloride can be directly prepared by reacting with excess concentrated ammonia water, and the reaction yield is high, the operation is simple, and the equipment corrosion and air pollution are reduced. If the coupling problem of trifluorobenzamide (10) and 9 can be solved, this route has great industrial application value.
  • Goldberg aramidation is a classical coupling reaction between aryl halides and amides catalyzed by copper catalysts (a. Goldberg, I. Chem. Ber. 1906, 39, 1691; b. Goldberg, I. Chem. Ber. . 1907, 40, 4541; c. Review: Org. React. 1965, 14, 19).
  • This is a facile and inexpensive organic synthesis method, and the reaction has been widely used in laboratory and industrialization since its discovery in the early last century.
  • the reaction conditions are usually harsh, such as (1) the reaction temperature is generally 140 ° C, or even higher; (2) part of the reaction requires one mole or more of copper to participate in the reaction; (3) generally requires high polarity and toxicity in larger solvents.
  • Cs 2 CO 3 has its unique advantages as a base, such as it can tolerate some common groups such as nitrile, nitro, ester and aldehyde (Joseph M.Fox.Xiaohua Huang.André Chieffi et al.J.Am). Chem. Soc. 2000, 122, 1360-1370).
  • Pd catalysis has the advantages of mild conditions and simple reaction. But palladium catalysts and their ligands are too expensive (Route C is the way to go).
  • the above-mentioned inorganic solid weak base is potassium carbonate, and the molar amount of the inorganic solid weak base is 1 to 6 moles of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone times.
  • the molar amount of the above-mentioned inorganic solid weak base is 2.5 times the molar amount of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone.
  • the molar amount of the above-mentioned 2,4,6-trifluorobenzamide is 0.8-2.0 times the molar amount of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone .
  • the above-mentioned cuprous salt is CuI, CuBr or CuCl, and the molar amount of the cuprous salt is 1% of the mole number of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone ⁇ 100%.
  • the above-mentioned organic solvent is a small molecular weight monoester, monooxyether, monoketone or alcohol with carbon number less than or equal to 6.
  • the aromatic ring in the above-mentioned ligand is a benzene ring, a pyridine ring, an imidazole ring or a benzoheterocyclic ring.
  • the substituent on the aromatic ring in the above-mentioned ligand is a hydrocarbon group, F, Cl, Br, an electron-withdrawing ester group, a nitrile group, a carboxyl group, a carbonyl group or a nitro group.
  • the above reaction temperature is 20-30°C.
  • DMF and DMSO can be used for raw materials such as amides, acetamides and lactamides with high polarity.
  • the effect is better than that of toluene as a solvent, and these aprotic polar solvents often give the best results. , but still almost no reaction occurs in these solvents in this case.
  • the base used in the reaction is: K 2 CO 3 or Cs 2 CO 3 , preferably K 2 CO 3 , and the amount (mole) of the base is 1 to 6 times that of the reaction substrate 9 (mole), preferably 2.5 times.
  • K 3 PO 4 Commonly used bases in the literature are K 3 PO 4 , Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , and K 3 PO 4 usually has the best effect, but in this case, its effect is very poor. If K 2 CO 3 is used as the base, if toluene, Dioxane, DMF, ethylene glycol diethyl ether are used as the solvent, and N,N'-dimethyl-1,2-ethylenediamine is used as the ligand of CuI, And change each ratio, but the reaction conversion rate does not exceed 20% (even if the temperature is raised to 50 ° C). K 2 CO 3 is also only effective in our selected solvent; Cs 2 CO 3 is not as effective as K 2 CO 3 , and the use of Cs 2 CO 3 will greatly increase the amount of 1,2-ethylenediamine ligands.
  • the molar amount of the ligand is 10% to 100% of the molar amount of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (9), preferably 20%.
  • N,N'-bis(hydrocarbylmethyl)-1,2-ethylenediamine ligands are listed in the literature, such as 11a-e, among which 11a-c shows good catalytic effect, 11c is the most Well, the catalytic effect of 11d and 11e is greatly decreased, and it is explained that the catalytic activity decreases due to the increase of steric hindrance, and it is described that different 1,2-ethylenediamine ligands can be applied to different reaction substrates:
  • N,N'-bis(arylmethyl) substituted 4b analogs can only be weak electron donating hydrocarbon groups or halogens (F, Cl, Br), or electron withdrawing groups Such as nitrile group, nitro group, acyl group, carboxyl group, ester group, etc., or relative to the benzene ring system, the entire aromatic ring system after substitution is electron-deficient.
  • Substituents with strong electron-donating groups greatly reduce the catalytic activity of ligands, such as 4j substituted with 4-methoxyl group, the conversion rate of bromopyridone (9) is only 10% at room temperature; and when the aromatic ring is replaced by electron-withdrawing substituents Or in the case of electron-deficient heterocycles (such as pyridine rings), such as 4c-i, the catalytic efficiency of the ligands is enhanced, and the reason remains to be further studied.
  • the molar ratio of trifluorobenzamide (10) to (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (9) is between 1:1 and 1:2, 1.1:1 is preferred because excess trifluorobenzamide is easily removed.
  • the reaction material is filtered, and the filter cake is washed with the solvent used in the reaction. If the solvent used in the reaction is miscible with water, or the solubility in water is too large, it is necessary to concentrate the filtrate and dissolve the residue in ethyl acetate. Continue with subsequent processing.
  • the filtrate was washed with dilute sodium sulfide solution to remove copper salt, and then washed with water; therefore, 1,2-diethylamine ligands are more preferentially hydrochloride than lasmiditan, and have great water solubility, so they can be added to
  • An appropriate amount of dilute hydrochloric acid was used to wash off the 1.2-ethylenediamine ligands, and then lasmiditan was salted with excess hydrochloric acid and dissolved in water.
  • the aqueous solution containing the product hydrochloride was decolorized with activated carbon, and the aqueous solution was alkalized to precipitate lasmiditan.
  • the reaction conditions are mild and easy to control, the technological process is simple, a large number of "three wastes" are reduced, and the industrial manufacturing cost is greatly reduced.
  • reaction mass was filtered, the solid was washed with tetrahydrofuran (the solid was discarded), and the filtrate was washed with 50 mL (5.0 mmol) of 0.10M sodium sulfide solution and 50 mL of water, and then 50 mL (10.0 mmol) of 0.20M hydrochloric acid was washed to remove ethylene glycol.
  • Example 2 was the same as Example 1, except that the amount of cuprous iodide was halved to 444 mg (2.33 mmol)
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was alkalized by 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and the residual oily 5-10 mL of n-hexane was added to the mixture, and lasmiditan was milled and precipitated.
  • the light yellow solid was 13.9 g, the yield was 79%, and the purity was 97.2%.
  • Example 3 was the same as Example 1, except that the amount of cuprous iodide was doubled to 1.74g (9.32mmol)
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was alkalized by 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and the residual oily 5-10 mL of n-hexane was added to the mixture, and lasmiditan was milled and precipitated.
  • the light yellow solid was 13.9 g, the yield was 79%, and the purity was 97.0%.
  • reaction mass was filtered, the solid was washed with tetrahydrofuran, and then the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, and then 50 mL of 0.20M hydrochloric acid was washed to remove the ethylenediamine ligands, and then the lasmiditan was washed with 100 mL of 0.15M hydrochloric acid.
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was alkalized by 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and the residual oily 5-10 mL of n-hexane was added to the mixture, and lasmiditan was milled and precipitated.
  • the light yellow solid was 13.5 g, the yield was 77%, and the purity was 98.1%.
  • Example 5 was the same as Example 1, except that the same moles of cuprous chloride (4.66 mmol) were used instead of cuprous iodide
  • reaction mass was filtered, the solid was washed with tetrahydrofuran, and then the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, and then 50 mL of 0.20M hydrochloric acid was washed to remove the ethylenediamine ligands, and then the lasmiditan was washed with 100 mL of 0.15M hydrochloric acid.
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was alkalized by 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and the residual oily 5-10 mL of n-hexane was added to the mixture to grind and precipitate lasmiditan, 13.3 g of pale yellow solid, yield 76%; purity 97.8%.
  • reaction mass was filtered, the solid was washed with tetrahydrofuran, and then the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, and then 50 mL of 0.20M hydrochloric acid was washed to remove the ethylenediamine ligands, and then the lasmiditan was washed with 100 mL of 0.15M hydrochloric acid.
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was alkalized by 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and the residual oily 5-10 mL of n-hexane was added to the mixture, and lasmiditan was milled and precipitated, 13.5 g of pale yellow solid, yield 77%, and purity 96.8%.
  • Embodiment 7 is the same as embodiment 1, but the consumption of ligand-N,N'-dimethyl-1,2-ethylenediamine is halved, and the reaction process control is the same as that of case 1
  • reaction mass was filtered, the solid was washed with methyltetrahydrofuran, the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, and then 50 mL of 0.20M hydrochloric acid was washed to remove ethylenediamine ligands, and then 100 mL of 0.15M hydrochloric acid was used.
  • the lasmiditan was salified and dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was basified with 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, To the residual oil, 5-10 mL of n-hexane was added to grind and precipitate lasmiditan, 14.1 g of pale yellow solid, yield 80%; purity 98.1%.
  • Example 9 is the same as Example 1, except that the solvent replaces tetrahydrofuran with an equal volume of cyclopentyl methyl ether
  • reaction mass was filtered, the solid was washed with cyclopentyl methyl ether, and the filtrate was washed with 50 mL of 0.10M sodium sulfide solution, 50 mL of water, and 50 mL of 0.20M hydrochloric acid to remove the ethylenediamine ligands, and then washed with 0.15 mL of 0.15 mL of water.
  • 100 mL of M hydrochloric acid was used to dissolve lasmiditan into water, and the aqueous solution containing the product hydrochloride was decolorized with activated carbon.
  • the aqueous solution was basified with 3.4 mL of 5M NaOH solution to precipitate lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), and dried over anhydrous sodium sulfate. , concentrated, and 5-10 mL of n-hexane was added to the residual oil to grind and precipitate lasmiditan, 14.2 g of pale yellow solid, yield 81%; purity 97.6%.
  • Example 10 is the same as Example 1, and the solvent is replaced by an equal volume of acetonitrile for tetrahydrofuran
  • the ethyl acetate solution was washed with 50 mL of 0.10M sodium sulfide solution, 50 mL of water, and 50 mL of 0.20M hydrochloric acid.
  • the ethylenediamine ligands were washed away, then lasmiditan was dissolved in water with 100 mL of 0.15M hydrochloric acid, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, and the aqueous solution was alkalized with 3.4 mL of 5M NaOH solution to separate out lasmiditan, and ethyl acetate was used to separate out lasmiditan.
  • Example 11 is the same as Example 1, and the solvent is replaced by ethyl acetate with an equal volume of tetrahydrofuran
  • reaction mass was filtered, the solid was washed with ethyl acetate, and then the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, and then 50 mL of 0.20M hydrochloric acid was washed to remove the ethylenediamine ligand, and then 100 mL of 0.15M hydrochloric acid was used.
  • the lasmiditan was salified and dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was basified with 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, 5-10 mL of n-hexane was added to the residual oil, and lasmiditan was milled and precipitated.
  • the light yellow solid was 12.3 g, the yield was 70%, and the purity was 96.2%.
  • Example 12 is the same as Example 1, except that the solvent replaces tetrahydrofuran with an equal volume of propyl acetate
  • reaction mass was filtered, the solid was washed with propyl acetate, and the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, respectively, and then 50 mL of 0.20M hydrochloric acid was washed to remove the ethylenediamine ligands, and then 100 mL of 0.15M hydrochloric acid was used.
  • the lasmiditan was salified and dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was basified with 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, 5-10 mL of n-hexane was added to the residual oil, and lasmiditan was milled and precipitated.
  • the light yellow solid was 12.6 g, the yield was 72%, and the purity was 97.1%.
  • Example 13 is the same as Example 1, except that the solvent replaces tetrahydrofuran with an equal volume of isopropyl acetate
  • Example 14 is the same as Example 1, except that the solvent replaces tetrahydrofuran with an equal volume of butanone
  • Embodiment 15 replaces potassium carbonate with cesium carbonate, and the amount of ligand is 40% eq of bromopyridone
  • the treatment method was the same as that of Example 1, and 5.71 g of light yellow solid was obtained, the yield was 65%, and the purity was 96.2%.
  • Example 16 is the same as Example 1, except that the reaction temperature is 10-15°C and the reaction time is 36 hours
  • reaction mass was filtered, the solid was washed with tetrahydrofuran, and then the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, and then 50 mL of 0.20M hydrochloric acid was washed to remove the ethylenediamine ligands, and then the lasmiditan was washed with 100 mL of 0.15M hydrochloric acid.
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was alkalized by 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and the residual oily 5-10 mL of n-hexane was added to the mixture, and lasmiditan was milled and precipitated, 13.2 g of pale yellow solid, yield 75%, and purity 97.0%.
  • Example 17 is the same as Example 1, except that the reaction temperature is 50-55°C and the reaction time is 15 hours
  • reaction mass was filtered, the solid was washed with tetrahydrofuran, and the filtrate was washed with 50 mL of 0.10M sodium sulfide solution, 50 mL of water, and 50 mL of 0.20M hydrochloric acid to remove the ethylenediamine ligands, and then the lasmiditan was washed with 100 mL of 0.15M hydrochloric acid.
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was alkalized by 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and the residual oily 5-10 mL of n-hexane was added to the mixture, and lasmiditan was milled and precipitated, 10.7 g of pale yellow solid, yield 61%, and purity 95.2%.
  • Example 18 is the same as Example 1, except that N,N'-dimethyl-1,2-ethylenediamine is replaced by the same moles of N,N'-dibenzyl-1,2-ethylenediamine
  • reaction mass was filtered, the solid was washed with tetrahydrofuran, and then the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, and then 50 mL of 0.20M hydrochloric acid was washed to remove the ethylenediamine ligands, and then the lasmiditan was washed with 100 mL of 0.15M hydrochloric acid.
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was alkalized by 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and the residual oily 5-10 mL of n-hexane was added to the mixture, and lasmiditan was milled and precipitated, 14.1 g of pale yellow solid, yield 80%, and purity 97.8%.
  • Example 19 is the same as Example 1, except that N,N'-dibenzyl-1,2-ethylenediamine is replaced by half the amount (moles) of N,N'-dimethyl-1,2-ethyl Diamine
  • Example 20 is the same as Example 1, except that N,N'-dimethyl-1 is replaced with the same moles of N,N'-bis(4-cyanophenyl)methyl-1,2-ethylenediamine ,2-Ethylenediamine
  • reaction mass was filtered, the solid was washed with tetrahydrofuran, and the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, respectively, and then 50 mL of 0.20M hydrochloric acid was used to wash off the ethylenediamine ligands, and then 100 mL of 0.15M hydrochloric acid was used to form lasmiditan.
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was basified with 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and residual oil was obtained. 5-10 mL of n-hexane was added to the mixture, and lasmiditan was milled and precipitated, and 14.2 g of light yellow solid was obtained, the yield was 81%, and the purity was 98.3%.
  • Example 21 is the same as Example 1, except that N,N'-dimethyl-1 is replaced with the same moles of N,N'-bis(2-cyanophenyl)methyl-1,2-ethylenediamine ,2-Ethylenediamine
  • reaction mass was filtered, the solid was washed with tetrahydrofuran, and the filtrate was washed with 50 mL of 0.10M sodium sulfide solution, 50 mL of water, and 50 mL of 0.20M hydrochloric acid to remove the ethylenediamine ligands, and then the lasmiditan was washed with 100 mL of 0.15M hydrochloric acid.
  • the salt is dissolved in water, the aqueous solution containing the product hydrochloride is decolorized with activated carbon, the aqueous solution is alkalized by 3.4 mL of 5M NaOH solution to precipitate lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and residual oily 5-10 mL of n-hexane was added to the mixture, and lasmiditan was milled and precipitated.
  • the light yellow solid was 13.5 g, the yield was 83%, and the purity was 98.0%.
  • Example 22 was the same as Example 1, except that N,N'-dimethyl-1,N'-dimethyl-1,N'-dimethyl-1, was replaced by the same moles of N,N'-bis(pyridin-4-yl)methyl-1,2-ethylenediamine.
  • reaction mass was filtered, the solid was washed with tetrahydrofuran, and then the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, and then 50 mL of 0.20M hydrochloric acid was washed to remove the ethylenediamine ligands, and then the lasmiditan was washed with 100 mL of 0.15M hydrochloric acid.
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was alkalized by 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and the residual oily 5-10 mL of n-hexane was added to the mixture to grind and precipitate lasmiditan, 13.7 g of pale yellow solid, yield 78%; purity 97.2%.
  • Example 23 was the same as Example 1, except that N,N'-dimethyl-1,N'-dimethyl-1,N'-dimethyl-1,N'-dimethyl-1,N'-dimethyl-1, was replaced by the same moles of N,N'-bis(pyridin-2-yl)methyl-1,2-ethylenediamine. 2-Ethylenediamine
  • reaction mass was filtered, the solid was washed with tetrahydrofuran, and then the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, and then 50 mL of 0.20M hydrochloric acid was washed to remove the ethylenediamine ligands, and then the lasmiditan was washed with 100 mL of 0.15M hydrochloric acid.
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was alkalized by 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and the residual oily 5-10 mL of n-hexane was added to the mixture, and lasmiditan was milled and precipitated, 13.2 g of pale yellow solid, yield 75%, and purity 96.5%.
  • Example 24 was the same as Example 1, except that N,N'-dimethyl-1,N'-dimethyl-1,N'-dimethyl-1, was replaced by the same moles of N,N'-bis(4-chlorophenylmethyl)-1,2-ethylenediamine.
  • reaction mass was filtered, the solid was washed with tetrahydrofuran, and then the filtrate was washed with 50 mL of 0.10M sodium sulfide solution and 50 mL of water, and then 50 mL of 0.20M hydrochloric acid was washed to remove the ethylenediamine ligands, and then the lasmiditan was washed with 100 mL of 0.15M hydrochloric acid.
  • the salt was dissolved in water, the aqueous solution containing the product hydrochloride was decolorized with activated carbon, the aqueous solution was alkalized by 3.4 mL of 5M NaOH solution to separate out lasmiditan, extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated, and the residual oily 5-10 mL of n-hexane was added to the mixture to grind and precipitate lasmiditan, 12.6 g of pale yellow solid, yield 72%, and purity 96.1%.

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Abstract

Lasmiditan的合成工艺，采用2,4,6-三氟苯甲酰胺与(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮,在碳酸钾或碳酸铯存在下，经亚铜盐(CuX,X＝I、Br、Cl)与其配体N,N'-二甲基-1,2-乙二胺或N,N'-二(芳基甲基)-1,2-乙二胺(RCH 2NHCH 2CH 2NHCH 2R,R＝H或Ar)的催化，在有机溶剂中，于0-60℃反应，物料经分离得到Lasmiditan，收率与质量良好。该反应条件温和，副产物少，工艺操作简洁，无需使用贵金属，工业成本大幅下降。

Description

Lasmiditan的合成工艺 技术领域
本发明属有机合成技术领域，具体涉及到5-HT 1f受体激动剂—Lasmiditan的合成工艺。
背景技术
偏头痛表现为反复发作的轻至重度头痛，发作时通常会头痛难忍，严重影响睡眠质量，伴有恶心、焦虑、抑郁等，会影响青少年的社交能力和学习成绩，对成人则会直接导致劳动能力下降，影响全球大约10％的人口，女性的发病率是男性的3倍。目前仍无能够彻底治愈偏头痛的药物。在2017年，美国大有超过3600万例偏头痛患者，日本有800万例患者，中国大约1300万例患者。美国每年因偏头痛造成的医疗卫生支出和经济损失达到数百亿美元。
Figure PCTCN2020140026-appb-000001
Lasmiditan(式1)是近20年来首个用于紧急治疗偏头痛的创新性药物，首个具有新的作用机制，其作用于三叉神经通路中的5-HT 1f受体，穿透中枢神经系统发挥作用，阻断疼痛的感觉，缓解偏头痛症状。针对曲坦类药物或其他现有疗法无缓解的偏头痛患者群体，lasmiditan有望满足其中40％患者的临床治疗需求。相比传统曲坦类药物，不收缩血管，从而不增加心血管疾病的风险，对于此部分患有或者可能会患上心血管疾病的患者，本品提供了一个更好的解决方案[Proc.Natl.Acad.Sci.USA,1993,90:408-412；Reuter et al,Drugs of the Future,2012,37(10):709-716]。2019年10月5-HT 1f受体激动剂—Lasmiditan半琥珀酸盐在美国上市。
文献报道Lasmiditan原料药的合成路线，分别有路线A，及改良的路线B、C、D。
路线A：
Figure PCTCN2020140026-appb-000002
此路线为早期药物发现研究时所采用的技术路线，2-氯吡啶衍生物(2)在贵金属复合物(Pd 2dba 3)及昂贵的有机磷(BINAP)催化下，与二苯甲酮的亚胺形成2-亚胺吡啶类化合物(3)，再于酸性条件下水解得到2-氨基-6-(1-甲基哌啶-4-基羰基)吡啶(4)，最后与2,4,6-三氟苯甲酰氯(5)缩合得到Lasmiditan(WO2003/084949,或CN100352817C)。
从2-氯吡啶至2-氯吡啶衍生物(2)，收率极低(约10％)，且后期采用贵重金属及昂 贵的试剂(BINAP)，很显然，从中间体2至4的路线不适合工业化。
此外，因三氟苯甲酰氯(5)是由三氟苯甲酸经酰化剂(氯化亚砜或草酰氯)酰化，除去溶剂后，其中残留较多的盐酸及酰化剂，需经减压蒸馏纯化三氟苯甲酰氯，然后才可与中间体4的氨基进行酰化反应，生成Lasmiditan。减压蒸馏时会大量产生挥发性的酸性腐蚀物质(如盐酸、酰化剂、三氟苯甲酰氯等)，对设备腐蚀性极大，也污染空气若不蒸馏纯化酰氯，则导致下一步的大量杂质；此外产物Lasmiditan还可以进一步被酰化，可形成二酰化副产物(6)，从而增加了三氟苯甲酰氯的单耗(大约需1.5当量)：
Figure PCTCN2020140026-appb-000003
最后此二酰基化副产物还需经20％NaOH水解，可再生成Lasmiditan；此外中间体4可与反应产生的盐酸成盐而不溶于反应所用的溶剂，从而使得中间体4不能完全参加酰胺化反应。即使使用了大量的三乙胺以交换出游离的中间体4，原料中间体4也难以被消耗完全，所用大量的三乙胺也无法回收再利用。因此此步骤中存在太多的工艺问题。
路线B：
Figure PCTCN2020140026-appb-000004
针对路线A中2-氨基吡啶类中间体4的技术缺点，路线B进行了许多改良。
以2,6-二溴吡啶(7)，经丁基锂或异丙基溴化镁氯化锂络合物转变成相应的吡啶有机金属，再继续与N,N,1-三甲基哌啶-4-甲酰胺(8)加成，得到(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮(9)，此溴化物以乙二醇作溶剂，可经廉价的Cu 2O催化加压氨化，得到中间体4，收率并不高，只有50-75％，且其纯化过程复杂，且因水中的乙二醇及氨无法回收而产生大量含乙二醇的废氨水(全球PCT WO2003/084949,或专利CN100352817C，或专利US 8697876，2014]：
路线C：
Figure PCTCN2020140026-appb-000005
2006年原研化合物专利US 8748459中描述了一种方法(Goldberg芳酰胺化反应)：由2,4,6-三氟苯甲酰胺(10)与化合物9在叔丁醇钠存在下，经三(二亚苄基丙酮)二钯(Pd 2dba 3)、1,1'-联萘-2,2'-双二苯膦(BINAP)催化反应，直接得到目标产物—Lasmiditan(1)，但收率仅37％。该工艺的条件苛刻(叔丁醇钠)，需要用贵金属催化剂及价格高的BINAP，而收率太低。
但此路线的原材料—三氟苯甲酰胺，很容易制备：由三氟苯甲酸经酰化剂(氯化亚砜或草酰氯)酰化，除去溶剂后，即使三氟苯甲酰氯中残留较多的盐酸及酰化剂，也无需减压蒸馏，粗品酰氯可就直接与过量的浓氨水反应制得，反应收率高，操作简易，减少了设备 腐蚀及空气污染。若能解决三氟苯甲酰胺(10)与9的偶联问题，则此路线极具有工业应用价值。
路线D
为本申请人已申请的关于中间体4的合成路线发明【CN201911031768.4】：
Figure PCTCN2020140026-appb-000006
尽管此路线每步的收率都较好，解决了路线B中从二溴吡啶(6)制备中间体9及4的系列问题，但此工艺采用了价格较高的特戊酰胺及Weinreb’s酰胺，增加了成本，且仍没有解决后续的中间体4与三氟苯甲酰氯的酰胺化过程中存在的诸多问题。
Goldberg芳酰胺化反应
Goldberg芳酰胺化反应是用铜催化剂催化的芳基卤代物与酰胺之间的经典偶联反应(a.Goldberg,I.Chem.Ber.1906,39,1691；b.Goldberg,I.Chem.Ber.1907,40,4541；c.Review:Org.React.1965,14,19)。这是一种简捷而且廉价的有机合成方法，该反应自从上世纪初发现以来，在实验室和工业化中得到了广泛的应用。但是反应条件通常比较苛刻，如(1)反应温度一般是140℃，甚至更高；(2)部分的反应需要一个摩尔或更多的铜参与反应；(3)一般需要在高极性而且毒性较大的溶剂中进行。
上个世纪九十年代Buchwald就发现钯可催化Goldberg酰胺化反应。进一步改良，如用Pd(OAc) 2或Pd 2(dba) 3做催化剂，Xantphos为配体，Cs 2CO 3为碱，在四氢呋喃，1，4-二氯六环或甲苯里回流可以使大部分酰胺与芳基溴或氯顺利进行芳基化【a).Yin J.and Buchwald Stephen L.Org.Lett.2000,2,1101-1104；b).Jingjun Yin and Stephen L.Buchwald.J.Am.Chem.Soc.2002,124,6043-6048】。其中Cs 2CO 3做碱有其独特的优势，如它可以耐受腈基、硝基、酯和醛等一些常见的基团(Joseph M.Fox.Xiaohua Huang.André Chieffi et al.J.Am.Chem.Soc.2000,122,1360-1370)。Pd催化较传统的Goldberg反应具有条件温和、反应简单等优点。但是钯催化剂及其配体太贵(路线C就是采用此方法)。
1998年Buchwald等人【a).Ma,D.；Zhang,Y.；Yao,J.；Wa,S.；Tao,F.J.Am.Chem.Soc.1998,120,12459；b).Klaper,A.；Huang,X.and Buchwald Stephen L.J.Am.Chem.Soc.2002,124,7421-7428】报道了，用10％～20％eq的1,2-乙二胺类化合物做铜盐的配体，以1％～10％eq的铜盐代替金属钯催化Goldberg反应，选择合适的铜盐、溶剂、弱碱能够使得交叉偶联反应可在较温和的条件下进行。常用的配体有：N,N’-二甲基乙二胺和反式-N,N’-二甲基环己二胺，但是后者太贵:
Figure PCTCN2020140026-appb-000007
在此之后，报道了该类配体的应用及新的类似于1,2-乙二胺的衍生配体：α-氨基酸、三羟基乙烷、1,10-啡啰啉等【a)Kang,S.K.et al.Synlett,2002,427；b)Crawford,K.R et al.Tetrahedron Lett.2002,43,7365；c)Deng,W.et al.Tetrahedron Lett.2004,45,2311；d)Moriwaki,K.et al.Tetrahedron Lett.2005,46,7559；e)Jiang,L.et al.Org.Lett.2003,5,3667；f)Chen,Y.J.et al.Org.Lett.2006,8,5609；Cortes-Salva,M.et al.Org.Lett.2010,12,1316-1319；Xing,H.J.Org.Chem.2012,77,5449-5453】。
发明内容
解决的技术问题：针对现有技术已开发路线A-D中存在的诸多问题，本发明提供了一种5-HT 1f激动剂Lasmiditan的合成工艺。
技术方案：Lasmiditan(式1)的合成工艺，制备步骤如下：2,4,6-三氟苯甲酰胺(式2)与(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮(式3)，在无机固体弱碱的存在下，经亚铜盐与配体N,N’-二甲基-1,2-乙二胺或N,N’-二(芳基甲基)-1,2-乙二胺(式4)的催化，在有机溶剂中，于0-60℃反应，生成Lasmiditan，反应式如下：
Figure PCTCN2020140026-appb-000008
优选的，上述无机固体弱碱为碳酸钾，无机固体弱碱的摩尔用量为(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮摩尔数的1～6倍。
优选的，上述无机固体弱碱的摩尔用量为(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮摩尔数的2.5倍。
优选的，上述2,4,6-三氟苯甲酰胺的摩尔用量是(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮摩尔数的0.8～2.0倍。
优选的，上述亚铜盐为CuI、CuBr或CuCl，亚铜盐的摩尔用量为(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮摩尔数的1％～100％。
优选的，上述有机溶剂为碳数小于等于6的小分子量单酯、单氧醚、单酮或醇。
优选的，上述酯可为乙酸乙酯、甲酸乙酯或甲酸丙酯；单氧醚可为环戊基甲基醚、四氢呋喃、甲基四氢呋喃或乙醚；酮可为丙酮或丁酮；腈为乙腈、丙腈或丁腈；醇为乙醇、异丙醇或正丙醇。
上述亚铜盐配体N,N’-二甲基-1,2-乙二胺或N,N’-二(芳基甲基)-1,2-乙二胺，其结构式为：RCH 2NHCH 2CH 2NHCH 2R，其中R＝H或Ar；Ar为芳环，配体的摩尔用量为(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮摩尔用量的10％～100％。
优选的，上述配体中芳环为苯环、吡啶环、咪唑环或苯并杂环。
优选的，上述配体中芳环上的取代基是烃基、F、Cl、Br、吸电子的酯基、腈基、羧基、羰基或硝基。
优选的，上述反应温度为20-30℃。
以下对本发明中所涉及的技术要点做进一步说明：
1、反应温度研究
首先发现中间物料9在60℃以上分解严重，会形成褐色胶状物，因此反应温度不宜 超过60℃，低于0℃反应速度太慢，最适合在20～30℃，针对不同的1,2-乙二胺类配体与溶剂，最佳反应温度会有微小差别。
文献中此类反应通常是在高于80℃上进行，也许由于本案中不能升高反应温度，从而导致一系列问题：通常可用的溶剂(如甲苯、二氧六环、乙二醇缩二乙醚、DMF、DMSO等)、碱(K 3PO 4、Cs 2CO 3、K 2CO 3)、一价和二价的铜盐及其1,2-乙二胺类配体，而在本案中则不可用、或相互之间不匹配。
2、溶剂的选择
适用于本反应的有机溶剂为碳数小于等于6的小分子量单酯、单氧醚、单酮、单腈。小分子量的酯，如乙酸乙酯、甲酸乙酯、乙酸甲酯等；小分子量的单氧醚，如环戊基甲基醚、四氢呋喃、2-甲基四氢呋喃、乙醚等；小分子量的酮，如丙酮、丁酮、环戊酮等；低分子量的腈，如乙腈、丙腈、丁腈等。而这些溶剂在此类偶联文献中鲜有提到或用到。文献中此类反应的温度几乎都需在80℃以上，如此高的温度有助于大幅增加酰胺的溶解度。而室温下三氟苯甲酰胺在极性小的溶剂中，甚至在二氯甲烷溶剂中溶解度都很小。我们最初的研究发现：1)以很适合对于绝大多数偶联反应的甲苯作溶剂，而本案中也许由于三氟苯甲酰胺在甲苯中的溶解度极差，在不同碱—K 3PO 4、Cs 2CO 3、K 2CO 3存在下，室温下转化率都很低，K 3PO 4作碱效果最好，在50℃时转化率也只有约20％；但当温度超过60℃时，反应速度加快，但物料分解严重；2)文献中还常使用极性较大的溶剂来增加酰胺的溶解度，如二氧六环、乙二醇二乙基醚、乙二醇二甲基醚、缩乙二醇二甲醚、缩乙二醇二乙醚等，但对于本案例，在这些溶剂中室温下或温热下几乎无偶联反应发生；3)文献中认为极性溶剂对铜催化的偶联反应至关重要，对于极性大的酰胺、乙酰胺和乳酰胺等原料，可采用DMF、DMSO，其效果要好于甲苯做溶剂，且这些非质子性极性溶剂往往给出最佳效果，但是在本案例中在这些溶剂中仍然几乎无反应发生。
然而，我们惊讶地发现，文献中鲜有提到或用到的溶剂：如在乙酸乙酯、丙酮、THF、环戊基甲醚、乙腈、异丙醇等中，仅在以K 2CO 3作碱、以N,N’-二甲基-1,2-乙二胺作亚铜盐(CuX，X＝I、Br、Cl)配体时，反应效果才会很好。这些溶剂中，醇类溶剂的反应效果相当较差一点，但对于小分子醚溶剂，也不是在所有小分子醚中的反应效果都好，当以叔丁基甲醚或二异丙基醚作溶剂，则反应效果则很差。
3、碱的选择
也很非常关键，反应所用碱为：K 2CO 3或Cs 2CO 3，优选K 2CO 3，碱的用量(摩尔数)为反应底物9(摩尔数)的1～6倍，优选2.5倍。
文献中常用碱为K 3PO 4、Cs 2CO 3、K 2CO 3、Na 2CO 3，通常效果最好的为K 3PO 4，但在本案中其效果却很差。如果采用K 2CO 3作碱，若以甲苯、Dioxane、DMF、缩乙二醇二乙醚等做溶剂，以N,N’-二甲基-1,2-乙二胺作CuI的配体，并改变各配比，但是反应转化率不超过20％(即使升温至50℃)。K 2CO 3也只有在我们选定的溶剂中效果才好；Cs 2CO 3效果不如K 2CO 3，而使用Cs 2CO 3会大幅增加1,2-乙二胺类配体的用量。
4、亚铜盐的选择
仅亚铜盐CuX(X＝Cl、Br、I)有足够的催化效力，其用量(摩尔数)为反应底物9(摩尔数)的1％～100％，优选最经济的CuCl(5-10％mol)。
尽管文献中描述，一价铜和二价铜的许多铜盐对反应都很有效，但二价铜盐，如 CuX 2(X＝I、Br、Cl)、CuSO 4·5H 2O、Cu(OAc) 2、Cu(acac) 2等对本案例的催化无效或效果很差；一价铜化合物，如CuCN、CuCN·LiCl、Cu 2O、CuSCN等对本案例的催化效果也很差(不反应或转化率难以超过10％)，仅CuX(X＝I、Br、Cl)三者的催化效果好。
5、亚铜盐配体
亚铜盐的配体为N,N’-二甲基-1,2-乙二胺或二(芳基甲基)-1,2-乙二胺，分子式为RCH 2NHCH 2CH 2NHCH 2R(式4),其中R为–H(4a)或-Ar(4b-i)等；Ar可为苯环、吡啶环及咪唑环、或苯并杂环；这些芳环上的取代基可以是烃基或卤素(F、Cl、Br)、或吸电子的酯基、腈基、羧基、羰基、硝基等，如4b-i：
Figure PCTCN2020140026-appb-000009
该配体的摩尔用量为(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮(9)摩尔用量的10％～100％，优选20％。
文献中列举了一些类似结构的N,N’-二(烃甲基)-1,2-乙二胺类的配体，如11a-e，其中11a-c显示有良好的催化效果，11c最好，11d与11e的催化效果大幅下降，并解释为是由于立体位阻的增加导致催化活性下降，且描述了不同的1,2-乙二胺类配体可适用于不同的反应底物：
Figure PCTCN2020140026-appb-000010
而在本案中从文献中提及的配体4a及11a-e中，经筛选在适合的碱与溶剂中，在室温下仅4a的催化效果良好，而11c的效果却远不如4a，且其价格昂贵。此外，大约10～20％的4a仍参与了反应，形成了下列副产物：
Figure PCTCN2020140026-appb-000011
为减少或避免类似于12的副产物，于是我们选用立体位阻大的11f，结果显示，室温下11f几乎无催化活性，再改用立体位阻较4a稍大的11g，仍然仅有微弱的催化作用。但尝试了与11g立体位阻相近的4b，惊讶地发现，在室温下4b的活性比11a及11g强许多，几乎与4a的相当，且与类似12的副产物较少。
Figure PCTCN2020140026-appb-000012
经检索，文献(Ghaffarinia,A.et al.J.Chin.Chem.Soc.2005,52,531)中已报道了配体4b及其类似物，在强烈的条件下(甲苯、110℃、2.0eq碘苯、5.0eq KF/Al 2O 3)，可对活性大的碘代芳烃具有很好的催化作用。而我们的案例是在温和条件下，以溴代物做底物，反应却可很好地完成。
为验证是否是脂溶性因素影响了催化效果，我们又尝试了11h和11i，结果显示11h-i室温下或温热下几乎无催化效果。
Figure PCTCN2020140026-appb-000013
进一步研究发现，N,N’-二(芳基甲基)取代的4b类似物中芳烃上的取代基仅可以是供电子弱的烃基或卤素(F、Cl、Br)，或吸电子基团如腈基、硝基、酰基、羧基、酯基等，或者相对于苯环体系来说，取代后的整个芳环体系是缺电子的。供电子强的取代基使得配体的催化活性大幅下降，如4-甲氧基取代的4j，室温下溴吡啶酮(9)仅有10％的转化率；而当芳环被吸电子取代基或是缺电子的杂环(如吡啶环)时，如4c-i，则配体催化效力增强，其原因有待深入研究。
Figure PCTCN2020140026-appb-000014
4b作为青霉素G类药物原料，已是大规模工业化的产品，其价格低廉。此类似配体N,N’-二(芳基甲基)的制备方法也较简易：1)ArCHO与乙二胺的还原法；2)ArCH 2Cl与乙二胺烃化法；3)ArCH 2NH 2与乙二醛的还原法等【a)Shanshan,W.et a1J.Inorg.Biochem.2008,102(11):2026-2034；b)Vibha,S.et al.Eur.J.Med.Chem.2001,36:651-658；c)Naokik,et a1.J.Org.Chem.1995,60:3980-3992；d)Robert A.M.et al.Tetrahedron Letters,1984,25(10):1023-1026；e)Hya,L.et a1.Tetrahedron.Asymmetry,2005,16:2901-2907】。
6、主要反应物料的配料比
三氟苯甲酰胺(10)与(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮(9)的摩尔比在1:1～1:2之间，优选1.1:1，因为过量的三氟苯甲酰胺易被除去。
7、反应的后处理
反应物料经过滤，滤饼以反应所用溶剂洗涤，如果反应所用的溶剂与水混溶，或在水中的溶解度过大，则需要浓缩滤液后，将残留物加乙酸乙酯溶解后，才可以再继续后续的处理。此滤液分别以稀硫化钠溶液洗涤，以除去铜盐，再水洗涤；因此1,2-二乙胺类配体较lasmiditan更优先成盐酸盐，且有极大的水溶性，故可以加以适量的稀盐酸先洗去1.2-乙二胺类配体，再以过量的盐酸将lasmiditan成盐而溶于水中，含产品盐酸盐的水溶液以活 性炭脱色，水溶液经碱化析出lasmiditan，以少量乙酸乙酯提取，无水硫酸钠干燥，浓缩，残留油状物中加入少量极性很小的溶剂，如正己烷，可析出lasmiditan(式1)。
有益效果：本发明首次使用易制备的2,4,6-三氟苯甲酰胺，与(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮，在室温或温热条件下，选择了恰当的溶剂，在亚铜盐(CuX，X＝I、Br、Cl)与N,N’-二甲基-1,2-乙二胺或N,N’-二芳甲基-1,2-乙二胺类配体的催化下，直接偶联，收率与质量均优良。反应条件温和且易于控制，工艺过程简洁，减少了大量“三废”，工业制造成本大幅下降。
具体实施方式
下面的实施例是以Lasmiditan的合成工艺为例，说明5-HT 1f激动剂Lasmiditan的新合成工艺，此可使本专业技术人员更全面地理解本发明，但不以任何方式限制本发明。
实施例1
2,4,6-三氟苯甲酰胺的制备
2,4,6-三氟苯甲酸175g(1.00mol)与氯化亚砜429g(261mL，3.60mol)，回流3小时后，蒸馏出绝大部分过量的氯化亚砜。将反应物料加入至28％氨水200mL中，控制氨化反应温度小于5℃，加毕，再搅拌反应2h，抽滤，冷水洗涤、烘干得2,4,6-三氟苯甲酰胺(以下简称：三氟苯甲酰胺)淡黄色固体160g，收率91.0％； 1H NMR(600M Hz，DMSO-d 6):δ8.14(s,1H),7.88(s,1H),7.26(dd,J＝9.1/8.0Hz,2H).
纯度:99.51％(HPLC条件：色谱柱Gemini 5μC18 110A,250mm×4.6mm,乙腈：水＝12:88,pH 5,λ230nm,流速1.0ml/mL,R t 11.89min)。
Lasmiditan的制备
在反应瓶中加入无水碳酸钾19.4g(141mmol)、三氟苯甲酰胺9.0g(51mmol)、碘化亚铜887mg(4.66mmol)，除去空气(真空减压抽除空气后通入氮气，反复三次)，加入四氢呋喃300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL(825mg，9.38mmol)、(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮(以下简称：溴吡啶酮)13.2g(46.6mmol)，再将混合物料于室温下搅拌反应，TLC跟踪反应，约24小时溴吡啶酮消失，得到绿色反应物料。
反应物料经过滤，以四氢呋喃洗涤固体(固体弃去)，再将此滤液分别以0.10M硫化钠溶液50mL(5.0mmol)、水洗涤50mL，再0.20M盐酸50mL(10.0mmol)先洗去乙二胺类配体，再以0.15M盐酸100mL(15mmol)将lasmiditan成盐溶于水中(以TLC检测有机相中是否还有lasmiditan？)，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL(17mmol)碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体13.7g，收率78％；纯度：97.5％(HPLC条件：色谱柱Gemini 5μC18 110A,250mm×4.6mm,乙腈：水＝35:65,pH 5,λ230nm,流速1.0ml/mL,R t 5.79min)； 1H NMR(CDCl 3,600MHz):δ8.51(d,J＝8.0Hz,1H),8.41(s,1H),7.92(t,J＝7.9Hz,1H),7.82(dd,7.6/0.8Hz,1H),6.84-6.79(m,2H),3.61(dt,J＝14.9/5.3Hz,1H),2.91(d,J＝11.6Hz,2H),2.29(s,3H),2.08(td,J＝11.3/3.0Hz,2H),1.90-1.81(m,4H)。
实施例2与实施例1相同，除了碘化亚铜的用量减半至444mg(2.33mmol)
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜444mg (2.33mmol)，除去空气，加入四氢呋喃300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体13.9g，收率79％；纯度97.2％。
实施例3与实施例1相同，除了碘化亚铜的用量加倍至1.74g(9.32mmol)
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜1.74g(9.32mmol)，除去空气，加入四氢呋喃300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体13.9g，收率79％；纯度97.0％。
实施例4与实施例1相同，除了以相同摩尔数的溴化亚铜(4.66mmol)代替碘化亚铜
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、溴化亚铜668mg(4.66mmol)，除去空气，加入四氢呋喃300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体13.5g，收率77％；纯度98.1％。
实施例5与实施例1相同，除了相同摩尔数的氯化亚铜(4.66mmol)代替碘化亚铜
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、氯化亚铜461mg(4.66mmol)，除去空气，加入四氢呋喃300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体13.3g，收率76％；纯度97.8％。
实施例6与实施例5相同，除了氯化亚铜的用量减少至(231mg，2.33mmol)
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、氯化亚铜231mg(2.33mmol)，除去空气，加入四氢呋喃300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二 胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体13.5g，收率77％；纯度96.8％。
实施例7与实施例1相同，但配体—N,N’-二甲基-1,2-乙二胺的用量减半，反应过程控制与案例1相同
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg(4.66mmol)，除去空气，加入四氢呋喃300mL、配体—N,N’-二甲基-1,2-乙二胺0.45mL(413mg，4.69mmol)、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时，溴吡啶酮大约剩余50％未消耗。反应物料经过滤，滤液经浓缩，残留物经柱层析得lasmiditan，淡黄色固体5.97g，收率34％。
实施例8与实施例1相同，溶剂以等体积的甲基四氢呋喃代替四氢呋喃
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入甲基四氢呋喃300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以甲基四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体14.1g，收率80％；纯度98.1％。
实施例9与实施例1相同，溶剂以等体积的环戊基甲基醚代替四氢呋喃
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入环戊基甲基醚300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以环戊基甲基醚洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体14.2g，收率81％；纯度97.6％。
实施例10与实施例1相同，溶剂以等体积的乙腈代替四氢呋喃
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入乙腈300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以乙腈洗涤固体，乙腈滤液经浓缩后，再加入乙酸乙酯200mL溶解残留物，此乙酸乙酯溶液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体12.8g，收率73％；纯度96.5％。
实施例11与实施例1相同，溶剂以等体积的乙酸乙酯代替四氢呋喃
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入乙酸乙酯300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以乙酸乙酯洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体12.3g，收率70％；纯度96.2％。
实施例12与实施例1相同，溶剂以等体积的乙酸丙酯代替四氢呋喃
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入乙酸丙酯300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以乙酸丙酯洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体12.6g，收率72％；纯度97.1％。
实施例13与实施例1相同，溶剂以等体积的乙酸异丙酯代替四氢呋喃
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入乙酸异丙酯300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以乙酸异丙酯洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体13.5g，收率77％；纯度96.5％。
实施例14与实施例1相同，溶剂以等体积的丁酮代替四氢呋喃
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入丁酮300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以丁酮洗涤固体，丁酮溶液经浓缩后，残留物加入乙酸乙酯200mL溶解，此溶液再分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体11.9g，收率68％；纯度96.1％。
实施例15以碳酸铯代替碳酸钾，配体用量为溴吡啶酮的40％eq
在反应瓶中加入无水碳酸铯23.3g(71.5mmol)、三氟苯甲酰胺4.50g(25.5mmol)、碘化亚铜443mg(2.33mmol)，除去空气，加入四氢呋喃(150mL)、配体—N,N’-二甲基-1,2-乙二胺1.00mL(828mg，9.40mmol)、溴吡啶酮6.60g(2.33mmol)，再将混合物料于室温下搅拌反 应，约24小时后，得到绿色反应物料。
处理方法同实施例1，得淡黄色固体5.71g，收率65％；纯度96.2％。
实施例16与实施例1相同，除了反应温度在10-15℃和反应时间36小时
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入四氢呋喃300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于10-15℃下搅拌反应，约36小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体13.2g，收率75％；纯度97.0％。
实施例17与实施例1相同，除了反应温度在50-55℃和反应时间15小时
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入四氢呋喃300mL、配体—N,N’-二甲基-1,2-乙二胺0.99mL、溴吡啶酮13.2g，再将混合物料于50-55℃下搅拌反应，约15小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体10.7g，收率61％；纯度95.2％。
实施例18与实施例1相同，除了以相同摩尔数的N,N’-二苄基-1,2-乙二胺代替N,N’-二甲基-1,2-乙二胺
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入四氢呋喃300mL、配体—N,N’-二苄基-1,2-乙二胺2.25g(9.38mmol)、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体14.1g，收率80％；纯度97.8％。
实施例19与实施例1相同，除了以减半量(摩尔数)的N,N’-二苄基-1,2-乙二胺代替N,N’-二甲基-1,2-乙二胺
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg(4.66mmol)，除去空气，加入四氢呋喃300mL、配体—N,N’-二苄甲基-1,2-乙二胺1.13g(4.70mmol)溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时，溴吡啶酮大约剩余50％未消耗。反应物料经过滤，以四氢呋喃洗涤固体，物料浓缩，经柱层析得lasmiditan，淡黄色固体6.67g，收率38％。
实施例20与实施例1相同，除了以相同摩尔数的N,N’-二(4-氰基苯基)甲基-1,2-乙二胺代替N,N’-二甲基-1,2-乙二胺
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入四氢呋喃300mL、配体—N,N’-二(4-氰基苯基)甲基-1,2-乙二胺2.72g(9.38mmol)、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约20小时。反应物料经过滤，以四氢呋喃洗涤固体，再将滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体14.2g，收率81％；纯度98.3％。
实施例21与实施例1相同，除了以相同摩尔数的N,N’-二(2-氰基苯基)甲基-1,2-乙二胺代替N,N’-二甲基-1,2-乙二胺
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入四氢呋喃300mL、配体—N,N’-二(2-氰基苯基)甲基-1,2-乙二胺2.72g(9.38mmol)、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体13.5g，收率83％；纯度98.0％。
实施例22与实施例1相同，除了以相同摩尔数的N,N’-二(吡啶-4-基)甲基-1,2-乙二胺代替N,N’-二甲基-1,2-乙二胺
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入四氢呋喃300mL、配体—N,N’-二(吡啶-4-基)甲基-1,2-乙二胺2.50g(9.38mmol)、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体13.7g，收率78％；纯度97.2％。
实施例23与实施例1相同，除了以相同摩尔数的N,N’-二(吡啶-2-基)甲基-1,2-乙二胺代替N,N’-二甲基-1,2-乙二胺
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入四氢呋喃300mL、配体—N,N’-二(吡啶-2-基)甲基-1,2-乙二胺2.50g(9.38mmol)、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体13.2g，收率75％；纯度96.5％。
实施例24与实施例1相同，除了以相同摩尔数的N,N’-二(4-氯苯基甲基)-1,2-乙 二胺代替N,N’-二甲基-1,2-乙二胺
在反应瓶中加入无水碳酸钾19.4g、三氟苯甲酰胺9.0g、碘化亚铜887mg，除去空气，加入四氢呋喃300mL、配体—N,N’-二(4-氯苯基甲基)-1,2-乙二胺2.99g(9.38mmol)、溴吡啶酮13.2g，再将混合物料于室温下搅拌反应，约24小时。反应物料经过滤，以四氢呋喃洗涤固体，再将此滤液分别以0.10M硫化钠溶液50mL、水洗涤50mL，再0.20M盐酸50mL先洗去乙二胺类配体，再以0.15M盐酸100mL将lasmiditan成盐溶于水中，含产品盐酸盐的水溶液以活性炭脱色，水溶液经5M NaOH溶液3.4mL碱化析出lasmiditan，以乙酸乙酯(50mL×2)提取，无水硫酸钠干燥，浓缩，残留油状物中加入正己烷5～10mL碾磨析出lasmiditan，淡黄色固体12.6g，收率72％，纯度96.1％。

Claims (10)

  1. Lasmiditan的合成工艺，其特征在于制备步骤如下：
    2,4,6-三氟苯甲酰胺与(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮，在无机固体弱碱的存在下，经亚铜盐与配体N,N’-二甲基-1,2-乙二胺或N,N’-二(芳基甲基)-1,2-乙二胺的催化，在有机溶剂中，于0-60℃反应，生成Lasmiditan。
  2. 根据权利要求1所述Lasmiditan的合成工艺，其特征在于所述无机固体弱碱为碳酸钾或碳酸铯，无机固体弱碱的摩尔用量为(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮摩尔数的1～6倍。
  3. 根据权利要求1所述Lasmiditan的合成工艺，其特征在于所述2,4,6-三氟苯甲酰胺的摩尔用量是(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮摩尔数的0.8～2.0倍。
  4. 根据权利要求1所述Lasmiditan的合成工艺，其特征在于所述亚铜盐为CuI、CuBr或CuCl，亚铜盐的摩尔用量为(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮摩尔数的1％～100％。
  5. 根据权利要求1所述Lasmiditan的合成工艺，其特征在于所述有机溶剂为碳数小于等于6的小分子量单酯、单氧醚、单酮或醇。
  6. 根据权利要求5所述Lasmiditan的合成工艺，其特征在于所述酯为乙酸乙酯、甲酸乙酯或甲酸丙酯；单氧醚为环戊基甲基醚、四氢呋喃、甲基四氢呋喃或乙醚；酮为丙酮或丁酮；腈为乙腈、丙腈或丁腈；醇为乙醇、异丙醇或正丙醇。
  7. 根据权利要求1所述Lasmiditan的合成工艺，其特征在于所述亚铜盐的配体N,N’-二甲基-1,2-乙二胺或N,N’-二(芳基甲基)-1,2-乙二胺，其结构式为：RCH 2NHCH 2CH 2NHCH 2R，其中R＝H或Ar；Ar为芳环，配体的摩尔用量为(6-溴吡啶-2-基)(1-甲基哌啶-4-基)甲酮摩尔用量的10％～100％。
  8. 根据权利要求7所述Lasmiditan的合成工艺，其特征在于所述配体结构中芳环为苯环、萘环、吡啶环、咪唑环或苯并杂环。
  9. 根据权利要求所述Lasmiditan的合成工艺，其特征在于所述配体结构中芳环上的取代基是烃基、F、Cl、Br，或吸电子的酯基、腈基、羧基、羰基或硝基。
  10. 根据权利要求1所述Lasmiditan的合成工艺，其特征在于反应温度为20-30℃。
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