CN111943930B - Synthesis process of Lasmidinan - Google Patents

Synthesis process of Lasmidinan Download PDF

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CN111943930B
CN111943930B CN202010861621.4A CN202010861621A CN111943930B CN 111943930 B CN111943930 B CN 111943930B CN 202010861621 A CN202010861621 A CN 202010861621A CN 111943930 B CN111943930 B CN 111943930B
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ethylenediamine
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tetrahydrofuran
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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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Nanjing Sanyuanyangpu Pharmaceutical Technology Co ltd
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Abstract

The synthesis process of Lasmidinan adopts 2,4, 6-trifluorobenzamide and (6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone to react with a cuprous salt (CuX, X = I, br, cl) and a ligand N, N '-dimethyl-1, 2-ethylenediamine or N, N' -di (arylmethyl) -1, 2-ethylenediamine (RCH) in the presence of potassium carbonate or cesium carbonate2NHCH2CH2NHCH2R, R = H or Ar) in an organic solvent at 0-60 ℃, and separating the materials to obtain the Lasmidinan with good yield and quality. The reaction condition is mild, the byproducts are few, the process operation is simple, noble metals are not needed, and the industrial cost is greatly reduced.

Description

Synthesis process of Lasmidinan
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to 5-HT1fA synthesis process of a receptor agonist, namely Lasmidinan.
Background
Migraine is manifested by recurrent mild to severe headache, which usually causes headache during the attack, seriously affects sleep quality, accompanied by nausea, anxiety, depression, etc., and affects social ability and learning performance of teenagers, and directly causes labor capacity reduction for adults, and affects about 10% of the population worldwide, and the incidence rate of women is 3 times that of men. At present, no medicine for completely curing migraine exists. In 2017, there are over 3600 million migraine sufferers in the united states, 800 million patients in japan and about 1300 million patients in china. The medical health costs and economic losses due to migraine headaches in the united states reach hundreds of billions of dollars each year.
Figure BDA0002648332780000011
Lasiditan (formula 1) was the first innovative drug for the emergency treatment of migraine for nearly 20 years, the first with a new mechanism of action, acting on 5-HT in the trigeminal pathway1fReceptors, which penetrate the central nervous system to act, block the sensation of pain, and relieve migraine symptoms. For the migraine patient population, who is not alleviated by triptans or other existing therapies, lasmiditan is expected to meet the clinical therapeutic needs of 40% of patients. Compared with the traditional triptans, the triptans do not shrink blood vessels, so that the risk of cardiovascular diseases is not increased, and the triptans provide a better solution for patients suffering from or possibly suffering from cardiovascular diseases [ proc.natl.acad.sci.usa,1993, 408-412; reuter et al, drugs of the Future,2012,37 (10): 709-716]. 5-HT of 10 months in 20191fThe receptor agonist, lasiditan hemisuccinate, is marketed in the united states.
The literature reports the synthetic routes of the Lasmidin bulk drug, namely a route A and improved routes B, C and D.
Route a:
Figure BDA0002648332780000012
Figure BDA0002648332780000021
the route is a technical route adopted in early drug discovery research, and the 2-chloropyridine derivative (2) is used in a noble metal compound (Pd)2dba3) And expensive organophosphorus (BINAP) to form 2-imine pyridine compound (3) with benzophenone imine, hydrolyzing under acidic condition to obtain 2-amino-6- (1-methylpiperidine-4-ylcarbonyl) pyridine (4), and mixing with 2,4, 6-trifluorobenzeneThe formyl chloride (5) is condensed to obtain Lasmidinan (WO 2003/084949 or CN 100352817C).
From 2-chloropyridine to 2-chloropyridine derivative (2), the yield was extremely low (about 10%), and the late use of noble metals and expensive reagents (BINAP) made it clear that the route from intermediate 2 to 4 was not suitable for industrialization.
In addition, because the trifluorobenzoyl chloride (5) is prepared by acylating trifluorobenzoic acid with an acylating agent (thionyl chloride or oxalyl chloride), removing the solvent, and then carrying out reduced pressure distillation to purify the trifluorobenzoyl chloride after more hydrochloric acid and the acylating agent are remained, and then carrying out acylation reaction with the amino group of the intermediate 4 to generate the lasiditan. Volatile acidic corrosive substances (such as hydrochloric acid, an acylating agent, trifluorobenzoyl chloride and the like) are generated in a large amount during reduced pressure distillation, the corrosive substances are extremely corrosive to equipment, and if polluted air is not distilled to purify acyl chloride, a large amount of impurities in the next step are caused; in addition, the product Lasmidin can be further acylated to form a diacylated byproduct (6), thereby increasing the unit consumption of trifluorobenzoyl chloride (about 1.5 equivalent):
Figure BDA0002648332780000022
finally the diacylated by-products are hydrolyzed by 20% NaOH and can be regenerated to Lasmidinan; furthermore, intermediate 4 can form a salt with the hydrochloric acid produced by the reaction and is insoluble in the solvent used for the reaction, so that intermediate 4 cannot completely participate in the amidation reaction. Even if a large amount of triethylamine is used to exchange the free intermediate 4, the starting intermediate 4 is difficult to consume completely, and the large amount of triethylamine used cannot be recovered and reused. There are too many process problems in this step.
Route B:
Figure BDA0002648332780000023
route B has made many improvements to the technical shortcomings of 2-aminopyridine intermediate 4 in route a.
With 2, 6-dibromopyridine (b)7) Butyl lithium or isopropyl magnesium bromide lithium chloride complex is converted into corresponding pyridine organic metal, and then is continuously added with N, N, 1-trimethyl piperidine-4-formamide (8) to obtain (6-bromopyridine-2-yl) (1-methyl piperidine-4-yl) methanone (9), and the bromide takes ethylene glycol as solvent and can be added with cheap Cu2The intermediate 4 is obtained by O catalytic pressure ammoniation, the yield is not high and is only 50-75%, the purification process is complex, and a large amount of waste ammonia water containing glycol is generated because glycol and ammonia in water cannot be recovered (PCT WO2003/084949, or CN100352817C, or US 8697876, 2014 all over the world)]：
Route C:
Figure BDA0002648332780000031
one method (Goldberg arylamidation reaction) is described in the 2006 original compound patent US 8748459: 2,4, 6-trifluorobenzamide (10) and a compound 9 are reacted with tris (dibenzylideneacetone) dipalladium (Pd) in the presence of sodium tert-butoxide2dba3) 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine (BINAP) to directly obtain the target product, namely the Lasmiditan (1), but the yield is only 37 percent. The process is very demanding (sodium tert-butoxide), requires noble metal catalysts and expensive BINAP, and yields are too low.
However, the starting material of this route, trifluorobenzamide, is readily prepared: the trifluorobenzoic acid is acylated by an acylating agent (thionyl chloride or oxalyl chloride), and after a solvent is removed, even if more hydrochloric acid and the acylating agent are remained in the trifluorobenzoyl chloride, reduced pressure distillation is not needed, the crude acyl chloride can be directly reacted with excessive concentrated ammonia water to prepare the trifluorobenzoic acid chloride. If the problem of coupling the trifluorobenzamide (10) and the trifluorobenzamide (9) can be solved, the route has great industrial application value.
Route D
The invention is a synthetic route which is applied by the applicant and relates to an intermediate 4 [ CN201911031768.4 ]:
Figure BDA0002648332780000032
although the yield of each step of the route is better, the series of problems of preparing the intermediates 9 and 4 from the dibromopyridine (6) in the route B are solved, the process adopts pivalamide and Weinreb's amide with higher price, the cost is increased, and a plurality of problems existing in the subsequent amidation process of the intermediate 4 and the trifluorobenzoyl chloride are still not solved.
Goldberg arylamidation reaction
Goldberg arylamidation reaction is a classical coupling reaction between an aryl halide and an amide catalyzed with a copper catalyst (a. Goldberg, i.chem. Ber.1906,39,1691 b. Goldberg, i.chem. Ber.1907,40,4541 c.review. This is a simple and inexpensive organic synthesis method, and since the first discovery of the last century, this reaction has been widely used in laboratories and in industrialization. However, the reaction conditions are usually harsh, such as (1) the reaction temperature is usually 140 ℃ or higher; (2) Partial reaction requires one mole or more of copper to participate in the reaction; (3) Generally, it is necessary to work in a highly polar and toxic solvent.
Buchwald discovered that palladium can catalyze the Goldberg amidation reaction in the nineties of the last century. Further improvements, e.g. by Pd (OAc)2Or Pd2(dba)3As catalyst, xantphos as ligand, cs2CO3The base, refluxing in tetrahydrofuran, 1, 4-dichloro-hexacyclic or toluene, allows the facile arylation of most amides with aryl bromide or chloride [ 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. Wherein Cs2CO3The base has unique advantages such as it can tolerate some common groups such as nitrile groups, nitro groups, esters and aldehydes (Joseph M. Fox. Xiaoohua Huang. Andre Chieffi et al J. Am. Chem. Soc.2000,122, 1360-1370). Compared with the traditional Goldberg reaction, pd catalysis has the advantages of mild conditions, simple reaction and the like. However, palladium catalysts and their ligands are too expensive (route C is the method used).
1998 Buchwald et al [ 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 reports that the Goldberg reaction is catalyzed by using 10-20% eq of 1, 2-ethanediamine compound as a ligand for the copper salt, and replacing the palladium metal with 1-10% eq of copper salt, and selecting appropriate copper salt, solvent and weak base can enable the cross-coupling reaction to be carried out under milder conditions. Commonly used ligands are: n, N '-dimethylethylenediamine and trans-N, N' -dimethylcyclohexanediamine, but the latter is too expensive:
Figure BDA0002648332780000041
after this, the use of such ligands and novel derivatized ligands similar to 1, 2-ethylenediamine were reported: alpha-amino acid, trihydroxyethane, 1, 10-phenanthroline and the like [ 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; cortex-Salva, M.et al.org.Lett.2010,12,1316-1319; xing, h.j.org.chem.2012,77,5449-5453 ].
Disclosure of Invention
The technical problem to be solved is as follows: in response to the problems of routes A-D developed in the prior art, the present invention provides a 5-HT system1fA synthesis process of an agonist Lasmidin.
The technical scheme is as follows: the synthesis process of the Lasmidan (formula 1) comprises the following preparation steps: 2,4, 6-trifluorobenzamide (formula 2) and (6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (formula 3) are reacted in an organic solvent at 0-60 ℃ in the presence of a weak inorganic solid base, catalyzed by a cuprous salt and the ligand N, N '-dimethyl-1, 2-ethylenediamine or N, N' -bis (arylmethyl) -1, 2-ethylenediamine (formula 4), to form lasiditan, according to the following reaction scheme:
Figure BDA0002648332780000051
preferably, the inorganic solid weak base is potassium carbonate, and the molar amount of the inorganic solid weak base is 1 to 6 times of the molar number of (6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone.
Preferably, the molar amount of the inorganic solid weak base is 2.5 times of the molar number of (6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone.
Preferably, the above-mentioned 2,4, 6-trifluorobenzamide is used in an amount of 0.8 to 2.0 times by mole the amount of (6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone.
Preferably, the cuprous salt is CuI, cuBr or CuCl, and the molar amount of the cuprous salt is 1-100% of the molar number of (6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone.
Preferably, the organic solvent is a small molecular weight monoester, monoether, monoketone or alcohol having 6 or less carbon atoms.
Preferably, the ester can be ethyl acetate, ethyl formate or propyl formate; the monoether can be cyclopentyl methyl ether, tetrahydrofuran, methyl tetrahydrofuran or diethyl ether; the ketone can be acetone or butanone; the nitrile is acetonitrile, propionitrile or butyronitrile; the alcohol is ethanol, isopropanol or n-propanol.
The cuprous salt ligand N, N '-dimethyl-1, 2-ethylenediamine or N, N' -di (arylmethyl) -1, 2-ethylenediamine has a structural formula: RCH2NHCH2CH2NHCH2R, wherein R = H or Ar; ar is aromatic ring, the molar dosage of the ligand is 10-100% of the molar dosage of (6-bromopyridine-2-yl) (1-methylpiperidine-4-yl) ketone.
Preferably, the aromatic ring in the ligand is a benzene ring, a pyridine ring, an imidazole ring or a benzo heterocycle.
Preferably, the substituent on the aromatic ring in the ligand is alkyl, F, cl, br, electron-withdrawing ester group, nitrile group, carboxyl group, carbonyl group or nitro group.
Preferably, the reaction temperature is 20 to 30 ℃.
The technical points involved in the invention are further explained as follows:
1. study of reaction temperature
Firstly, the intermediate material 9 is seriously decomposed at the temperature of more than 60 ℃ and can form brown jelly, so the reaction temperature is not suitable to exceed 60 ℃, the reaction speed is too slow at the temperature of less than 0 ℃, the optimal reaction temperature is slightly different for different 1, 2-ethanediamine ligands and solvents, and the optimal reaction temperature is most suitable to be between 20 and 30 ℃.
In the literature, such reactions are generally carried out at temperatures above 80 ℃ and, perhaps because the reaction temperature cannot be raised in this case, this leads to a series of problems: commonly available solvents (e.g., toluene, dioxane, diethyl glycol, DMF, DMSO, etc.), bases (K)3PO4、Cs2CO3、K2CO3) Monovalent and divalent copper salts and 1, 2-ethanediamine ligands thereof, which are not usable in this case or are not compatible with one another.
2. Selection of solvents
The organic solvent suitable for the reaction is monoester, monoether, monoketone and mononitrile with small molecular weight and carbon number less than or equal to 6. Small molecular weight esters such as ethyl acetate, ethyl formate, methyl acetate, and the like; low molecular weight monoethers such as cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, etc.; small molecular weight ketones such as acetone, butanone, cyclopentanone, and the like; low molecular weight nitriles such as acetonitrile, propionitrile, butyronitrile, and the like. These solvents are rarely mentioned or used in such coupling literature. The temperatures of such reactions in the literature are almost always above 80 ℃, and such high temperatures help to greatly increase the solubility of the amide. At room temperature, however, trifluorobenzamide has little solubility in solvents with low polarity, even in methylene chloride solvents. Our initial study found that: 1) Toluene, which is very suitable for most coupling reactions, is used as a solvent, and in this case, perhaps due to the very poor solubility of trifluorobenzamide in toluene, it is present in different bases-K3PO4、Cs2CO3、K2CO3In the presence of K, the conversion rate at room temperature is very low3PO4The best effect is achieved as alkali, and the conversion rate is only about 20% at 50 ℃; however, when the temperature exceeds 60 ℃, the reaction rate is accelerated, but the decomposition of the material is severe(ii) a 2) More polar solvents are also commonly used in the literature to increase the solubility of amides, such as dioxane, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, etc., but for this case, little coupling reaction occurs in these solvents at room temperature or with warming; 3) In the literature, polar solvents are considered to be important for copper-catalyzed coupling reactions, DMF and DMSO can be used as raw materials of amide, acetamide, lactamide and the like with high polarity, the effect is better than that of toluene, and aprotic polar solvents are usually used for giving the best effect, but almost no reaction occurs in the solvents in the case.
However, we have surprisingly found that there are few solvents mentioned or used in the literature: e.g. in ethyl acetate, acetone, THF, cyclopentyl methyl ether, acetonitrile, isopropanol, etc., only in K2CO3When N, N' -dimethyl-1, 2-ethylenediamine is used as a cuprous salt (CuX, X = I, br, cl) ligand, the reaction effect is good. Among these solvents, the reaction effect of the alcohol solvent is rather poor, but the reaction effect is not good in all the small molecular ethers, and the reaction effect is poor when tert-butyl methyl ether or diisopropyl ether is used as the solvent.
3. Selection of the base
It is also very critical that the base used in the reaction is: k is2CO3Or Cs2CO3Preferably K2CO3The amount (moles) of the base used is 1 to 6 times, preferably 2.5 times, the amount (moles) of the reaction substrate 9.
The common base in the literature is K3PO4、Cs2CO3、K2CO3、Na2CO3Usually, the best effect is K3PO4But the effect is poor in the present case. If K is adopted2CO3As the alkali, toluene, dioxane, DMF, ethylene glycol diethyl ether and the like are used as solvents, N' -dimethyl-1, 2-ethylenediamine is used as a ligand of CuI, and the mixture ratio is changed, but the reaction conversion rate is not more than 20% (even if the temperature is raised to 50 ℃). K2CO3Also only in our choosingThe effect is good in the solvent; cs2CO3Is not as effective as K2CO3And using Cs2CO3The dosage of the 1, 2-ethanediamine ligand is greatly increased.
4. Selection of cuprous salts
Only cuprous salt CuX (X = Cl, br, I) has sufficient catalytic efficacy, and its amount (moles) is 1% to 100% of the reaction substrate 9 (moles), preferably the most economical CuCl (5-10% by mol).
Although many copper salts of monovalent and divalent copper are described in the literature as being effective for the reaction, divalent copper salts, such as CuX2(X＝I、Br、Cl)、CuSO4·5H2O、Cu(OAc)2、Cu(acac)2The catalysis of the present case is ineffective or poor; monovalent copper compounds, e.g. CuCN, cuCN. LiCl, cu2O, cuSCN, and the like also have a poor catalytic effect on this case (no reaction or a conversion rate hardly exceeding 10%), and only CuX (X = I, br, cl) has a good catalytic effect.
5. Cuprous salt ligands
The ligand of cuprous salt is N, N' -dimethyl-1, 2-ethylenediamine or di (arylmethyl) -1, 2-ethylenediamine, and its molecular formula is RCH2NHCH2CH2NHCH2R (formula 4) wherein R is-H (4 a) or-Ar (4 b-i), etc.; ar can be benzene ring, pyridine ring, imidazole ring or benzo heterocycle; the substituents on these aromatic rings may be hydrocarbyl or halogen (F, cl, br), or electron withdrawing ester, nitrile, carboxyl, carbonyl, nitro groups, etc., such as 4b-i:
Figure BDA0002648332780000071
the molar amount of the ligand is 10-100 percent of the molar amount of (6-bromopyridine-2-yl) (1-methylpiperidine-4-yl) methanone (9), and the preferred molar amount is 20 percent.
Some ligands of the N, N' -di (hydronomethyl) -1, 2-ethanediamine class of similar structure are cited in the literature, such as 11a-e, where 11a-c shows good catalytic effect, 11c is the best, the catalytic effect of 11d and 11e is greatly reduced, and is explained as a reduction in catalytic activity due to an increase in steric hindrance, and it is described that different ligands of the 1, 2-ethanediamine class can be adapted to different reaction substrates:
Figure BDA0002648332780000081
in the present case, ligands 4a and 11a-e, which are mentioned in the literature, are selected in suitable bases and solvents, and only 4a is good at room temperature, while 11c is far less effective than 4a and is expensive. In addition, about 10-20% of 4a still participates in the reaction, forming the following by-products:
Figure BDA0002648332780000082
in order to reduce or avoid by-products like 12 we then chose 11f with a large steric hindrance, which shows that 11f has almost no catalytic activity at room temperature, and then change to 11g with a slightly larger steric hindrance than 4a, still only weakly catalytic. But 4b, which is close to 11g steric hindrance, was tried and it was surprisingly found that 4b is much more active than 11a and 11g at room temperature, almost comparable to 4a, and less by-product like 12.
Figure BDA0002648332780000083
By search, ligand 4b and its analogues have been reported in the literature (Ghaffarinia, a.et al.j.chi.chem.soc.2005, 52,531) under vigorous conditions (toluene, 110 ℃, 2.0eq iodobenzene, 5.0eq KF/Al)2O3) It has good catalytic action on iodo-aromatic hydrocarbon with large activity. In our case, the reaction is well completed under mild conditions by using bromide as a substrate.
To verify whether fat soluble factors affect the catalytic effect, we tried 11h and 11i again, and the results show that 11h-i has little catalytic effect at room temperature or warm.
Figure BDA0002648332780000084
Further research shows that the substituent on the aromatic hydrocarbon in the N, N' -di (arylmethyl) substituted 4b analogue can only be hydrocarbon group with weak electron donor or halogen (F, cl, br), or electron-withdrawing group such as nitrile group, nitro group, acyl group, carboxyl group, ester group and the like, or relative to the benzene ring system, the whole substituted aromatic ring system is electron-deficient. The substituent group with strong electron donor greatly reduces the catalytic activity of the ligand, such as 4-methoxy substituted 4j, and the bromopyridone (9) has only 10% of conversion rate at room temperature; the reason why the catalytic effect of the ligand is enhanced when the aromatic ring is substituted with an electron-withdrawing group or an electron-deficient heterocyclic ring (e.g., pyridine ring) such as 4c-i is studied intensively.
Figure BDA0002648332780000091
4b is used as a raw material of penicillin G medicaments, is a large-scale industrialized product and has low price. The preparation method of the similar ligand N, N' -di (arylmethyl) is also simpler: 1) Reduction of ArCHO and ethylenediamine; 2) ArCH2A Cl and ethylenediamine alkylation method; 3) ArCH2NH2Reduction with glyoxal [ a) Shanshan, W.et a1 J.Inorg.biochem.2008,102 (11): 2026-2034; b) Vibha, s.et al.eur.j.med.chem.2001, 36; c) Naokik, et a1.j.org.chem.1995, 60; 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. Proportioning ratio of main reaction materials
The molar ratio of trifluorobenzamide (10) to (6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (9) is between 1 and 1, preferably 1.1.
7. Work-up of the reaction
Filtering the reaction material, washing a filter cake by using a solvent used for the reaction, and if the solvent used for the reaction is miscible with water or has high solubility in water, concentrating the filtrate, adding ethyl acetate into the residue to dissolve the residue, and then continuing subsequent treatment. Washing the filtrate with dilute sodium sulfide solution to eliminate copper salt and water; therefore, 1, 2-diethylamine ligand is more preferentially formed into hydrochloride than lasidan and has extremely high water solubility, so that a proper amount of diluted hydrochloric acid can be added to wash out the 1, 2-diethylamine ligand, then the excess hydrochloric acid is used for salifying the lasidan and dissolving the salt into water, the aqueous solution containing the product hydrochloride is decolored by active carbon, the aqueous solution is alkalized to separate out the lasidan, a small amount of ethyl acetate is used for extraction, anhydrous sodium sulfate is used for drying and concentration, and a small amount of solvent with small polarity, such as n-hexane, is added into residual oily matter to separate out the lasidan (formula 1).
Has the beneficial effects that: the invention uses easily prepared 2,4, 6-trifluorobenzamide and (6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone for the first time, selects proper solvents under the room temperature or warm condition, and directly couples cuprous salt (CuX, X = I, br, cl) with N, N '-dimethyl-1, 2-ethylenediamine or N, N' -diarylmethyl-1, 2-ethylenediamine ligand under the catalysis of the cuprous salt, and has excellent yield and quality. The reaction condition is mild and easy to control, the process is simple, a large amount of three wastes are reduced, and the industrial manufacturing cost is greatly reduced.
Detailed Description
The following examples illustrate the synthesis of Lasmidin1fThe novel synthesis of the agonist lasiditan, which allows the skilled person to more fully understand the present invention, is not intended to limit the invention in any way.
Example 1
Preparation of 2,4, 6-trifluorobenzamide
175g (1.00 mol) of 2,4, 6-trifluorobenzoic acid and 429g (261mL, 3.60mol) of thionyl chloride were refluxed for 3 hours, and most of the excess thionyl chloride was distilled off. Adding the reaction materials into 200mL of 28% ammonia water, controlling the temperature of the ammoniation reaction to be less than 5 ℃, after the addition is finished, stirring the mixture for reaction for 2 hours, performing suction filtration, washing the mixture with cold water and drying the mixture to obtain 160g of 2,4, 6-trifluoro-benzamide (hereinafter referred to as trifluoro-benzamide) light yellow solid, wherein the yield is 91.0%;1H NMR(600M Hz，DMSO-d6):δ8.14(s,1H),7.88(s,1H),7.26(dd,J＝9.1/8.0Hz,2H).
purity 99.51% (HPLC conditions: column Gemini 5 μ C18 110a,250mm × 4.6mm, acetonitrile: water =12, ph 5,. Lambda.230 nm, flow rate 1.0mL/mL, Rt 11.89min)。
Preparation of Lasmidian
The reaction flask was charged with anhydrous potassium carbonate 19.4g (141 mmol), trifluorobenzamide 9.0g (51 mmol), cuprous iodide 887mg (4.66 mmol), air was removed (vacuum reduced pressure was evacuated and then nitrogen gas was introduced, and the process was repeated three times), and then tetrahydrofuran 300mL, ligand-N, N' -dimethyl-1, 2-ethylenediamine 0.99mL (825mg, 9.38mmol) and 6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (hereinafter referred to as bromopyridone) 13.2g (46.6 mmol) were added, and the mixture was stirred at room temperature for reaction, followed by TLC, and bromopyridone disappeared for about 24 hours to obtain a green reaction material.
Filtering the reaction material, washing the solid with tetrahydrofuran (solid is discarded), washing the filtrate with 50mL (5.0 mmol) of 0.10M sodium sulfide solution and 50mL of water, washing with 50mL (10.0 mmol) of 0.20M hydrochloric acid, washing with ethylenediamine ligand, dissolving lasidinan salt in water with 100mL (15 mmol) of 0.15M hydrochloric acid (TLC is used to detect whether lasidinan exists in the organic phase), decolorizing the aqueous solution containing the product hydrochloride with activated carbon, alkalifying the aqueous solution with 3.4mL (17 mmol) of 5M NaOH solution to separate out lasidinan, extracting with ethyl acetate (50 mL multiplied by 2), drying with anhydrous sodium sulfate, concentrating, adding n-hexane into the residual oily substance to 5-10 mL of milling to separate out lasidinan yellowish solid 13.7g, and obtaining a yield of 78%; purity: 97.5% (HPLC conditions: chromatographic column Gemini 5. Mu.C 18 110A, 250mm. Times.4.6 mm, acetonitrile: water = 65, pH 5,. Lambda.230 nm, flow rate 1.0mL/mL, Rt 5.79min)；1H NMR(CDCl3,600M Hz):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)。
Example 2 same as example 1 except that the amount of cuprous iodide halved to 444mg (2.33 mmol)
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, and 444mg (2.33 mmol) of cuprous iodide, and then air was removed, 300mL of tetrahydrofuran, 0.99mL of ligand-N, N' -dimethyl-1, 2-ethylenediamine, and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 24 hours. Filtering the reaction material, washing the solid with tetrahydrofuran, washing the filtrate with 50mL of 0.10M sodium sulfide solution and 50mL of water respectively, washing with 50mL of 0.20M hydrochloric acid to remove ethylenediamine ligand, dissolving lasidamin salt in water with 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride with active carbon, alkalizing the aqueous solution with 3.4mL of 5M NaOH solution to separate out lasidamin, extracting with ethyl acetate (50 mL multiplied by 2), drying with anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily substance, grinding to separate out lasidamin, wherein 13.9g of light yellow solid is obtained, and the yield is 79%; the purity is 97.2%.
Example 3 same as example 1 except that the amount of cuprous iodide doubled to 1.74g (9.32 mmol)
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, and 1.74g (9.32 mmol) of cuprous iodide, air was removed, 300mL of tetrahydrofuran, 0.99mL of ligand-N, N' -dimethyl-1, 2-ethylenediamine, and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 24 hours. Filtering the reaction material, washing the solid by tetrahydrofuran, washing the filtrate by 50mL of 0.10M sodium sulfide solution and 50mL of water respectively, washing by 50mL of 0.20M hydrochloric acid firstly to remove ethylenediamine ligand, dissolving lasidan salt into water by 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride by active carbon, alkalifying the aqueous solution by 3.4mL of 5M NaOH solution to separate out lasidan, extracting by ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily matter, grinding to separate out lasidan, wherein 13.9g of light yellow solid is obtained, and the yield is 79%; the purity is 97.0%.
Example 4 is the same as example 1 except that cuprous iodide is replaced with the same number of moles of cuprous bromide (4.66 mmol)
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, 668mg (4.66 mmol) of cuprous bromide, air removed, 300mL of tetrahydrofuran, 0.99mL of ligand-N, N' -dimethyl-1, 2-ethylenediamine, and 13.2g of bromopyridone, and the mixture was stirred at room temperature for about 24 hours. Filtering the reaction material, washing the solid with tetrahydrofuran, washing the filtrate with 50mL of 0.10M sodium sulfide solution and 50mL of water respectively, washing with 50mL of 0.20M hydrochloric acid to remove ethylenediamine ligand, dissolving lasidamin salt in water with 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride with active carbon, alkalizing the aqueous solution with 3.4mL of 5M NaOH solution to separate out lasidamin, extracting with ethyl acetate (50 mL multiplied by 2), drying with anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily substance, grinding to separate out lasidamin, wherein the yield is 77 percent, 13.5g of light yellow solid; the purity is 98.1%.
Example 5 is the same as example 1 except that the same number of moles of cuprous chloride (4.66 mmol) are used instead of cuprous iodide
A reaction flask was charged with anhydrous potassium carbonate 19.4g, trifluorobenzamide 9.0g, cuprous chloride 461mg (4.66 mmol), air removed, tetrahydrofuran 300mL, ligand-N, N' -dimethyl-1, 2-ethylenediamine 0.99mL, and bromopyridone 13.2g, and the mixture was stirred at room temperature for about 24 hours. Filtering the reaction material, washing the solid by tetrahydrofuran, washing the filtrate by 50mL of 0.10M sodium sulfide solution and 50mL of water respectively, washing by 50mL of 0.20M hydrochloric acid firstly to remove ethylenediamine ligand, dissolving lasidan salt into water by 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride by active carbon, alkalifying the aqueous solution by 3.4mL of 5M NaOH solution to separate out lasidan, extracting by ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily matter, grinding to separate out lasidan, wherein 13.3g of light yellow solid is obtained, and the yield is 76%; the purity is 97.8%.
Example 6 same as example 5 except that the amount of cuprous chloride was reduced to (231mg, 2.33mmol)
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, 231mg (2.33 mmol) of cuprous chloride, air removed, 300mL of tetrahydrofuran, 0.99mL of ligand-N, N' -dimethyl-1, 2-ethylenediamine, and 13.2g of bromopyridone, and the mixture was stirred at room temperature for about 24 hours. Filtering the reaction material, washing the solid with tetrahydrofuran, washing the filtrate with 50mL of 0.10M sodium sulfide solution and 50mL of water respectively, washing with 50mL of 0.20M hydrochloric acid to remove ethylenediamine ligand, dissolving lasidamin salt in water with 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride with active carbon, alkalizing the aqueous solution with 3.4mL of 5M NaOH solution to separate out lasidamin, extracting with ethyl acetate (50 mL multiplied by 2), drying with anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily substance, grinding to separate out lasidamin, wherein the yield is 77 percent, 13.5g of light yellow solid; the purity is 96.8%.
Example 7 is the same as example 1, but the amount of the ligand, N' -dimethyl-1, 2-ethylenediamine, is halved and the reaction is controlled in the same manner as in case 1
A reaction flask was charged with anhydrous potassium carbonate 19.4g, trifluorobenzamide 9.0g, cuprous iodide 887mg (4.66 mmol), air removed, tetrahydrofuran 300mL, ligand-N, N' -dimethyl-1, 2-ethylenediamine 0.45mL (413mg, 4.69mmol), and bromopyridone 13.2g, and the mixture was stirred at room temperature for about 24 hours with approximately 50% of bromopyridone remaining unconsumed. The reaction mass was filtered, the filtrate was concentrated, and the residue was subjected to column chromatography to give lasmidatan as a pale yellow solid 5.97g, yield 34%.
Example 8 same as example 1, solvent equal volume of methyltetrahydrofuran instead of tetrahydrofuran
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, and 887mg of cuprous iodide, air was removed, 300mL of methyltetrahydrofuran, 0.99mL of ligand-N, N' -dimethyl-1, 2-ethylenediamine, and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 24 hours. Filtering the reaction material, washing the solid with methyltetrahydrofuran, washing the filtrate with 50mL of 0.10M sodium sulfide solution and 50mL of water respectively, washing with 50mL of 0.20M hydrochloric acid to remove ethylenediamine ligand, dissolving the salt of lasidamidan in 100mL of 0.15M hydrochloric acid in water, decoloring the aqueous solution containing the product hydrochloride with activated carbon, alkalizing the aqueous solution with 3.4mL of 5M NaOH solution to separate out lasidamidan, extracting with ethyl acetate (50 mL multiplied by 2), drying with anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily substance, grinding to separate out lasidamidan, wherein the yield is 80%; the purity is 98.1%.
Example 9 same as example 1, solvent equal volume of cyclopentyl methyl ether instead of tetrahydrofuran
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, and 887mg of cuprous iodide, air was removed, 300mL of cyclopentyl methyl ether, 0.99mL of ligand-N, N' -dimethyl-1, 2-ethylenediamine, and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 24 hours. Filtering the reaction material, washing the solid by cyclopentyl methyl ether, washing the filtrate by 50mL of 0.10M sodium sulfide solution and 50mL of water respectively, washing by 50mL of 0.20M hydrochloric acid firstly to remove ethylenediamine ligand, dissolving lasidan salt into water by 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride by active carbon, alkalifying the aqueous solution by 3.4mL of 5M NaOH solution to separate out lasidan, extracting by ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily matter, grinding to separate out lasidan, wherein the yield is 81%; the purity was 97.6%.
Example 10 same as example 1, solvent equal volume of acetonitrile instead of tetrahydrofuran
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, and 887mg of cuprous iodide, and then air was removed, 300mL of acetonitrile, 0.99mL of ligand-N, N' -dimethyl-1, 2-ethylenediamine, and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 24 hours. Filtering a reaction material, washing a solid with acetonitrile, concentrating an acetonitrile filtrate, adding 200mL of ethyl acetate to dissolve a residue, washing 50mL of the ethyl acetate solution with 0.10M sodium sulfide solution and 50mL of water respectively, washing 50mL of the ethyl acetate solution with 0.20M hydrochloric acid, washing with 50mL of the hydrochloric acid, removing ethylenediamine ligand, dissolving a lasidamin salt in water with 100mL of 0.15M hydrochloric acid, decoloring an aqueous solution containing a product hydrochloride with activated carbon, alkalifying the aqueous solution with 3.4mL of 5M NaOH solution to separate out lasidan, extracting with ethyl acetate (50 mL multiplied by 2), drying with anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane to the residual oily matter, grinding to separate out the lasidan, wherein 12.8g of a light yellow solid is obtained, and the yield is 73%; the purity is 96.5%.
Example 11 same as example 1, solvent equal volume of ethyl acetate instead of tetrahydrofuran
A reaction flask was charged with anhydrous potassium carbonate 19.4g, trifluorobenzamide 9.0g, cuprous iodide 887mg, and then, after removing air, ethyl acetate 300mL, ligand-N, N' -dimethyl-1, 2-ethylenediamine 0.99mL, and bromopyridone 13.2g were added thereto, and the mixture was stirred at room temperature for about 24 hours. Filtering a reaction material, washing a solid by ethyl acetate, washing 50mL of the filtrate by 0.10M sodium sulfide solution and 50mL of water respectively, washing 50mL of 0.20M hydrochloric acid firstly to remove ethylenediamine ligand, dissolving lasidan salt in 100mL of 0.15M hydrochloric acid in water, decoloring aqueous solution containing product hydrochloride by active carbon, alkalizing the aqueous solution by 3.4mL of 5M NaOH solution to separate out lasidan, extracting by ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into residual oily matter, grinding to separate out lasidan, wherein 12.3g of light yellow solid is obtained, and the yield is 70%; the purity is 96.2%.
Example 12 same as example 1, solvent equal volume of propyl acetate instead of tetrahydrofuran
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, and 887mg of cuprous iodide, air was removed, 300mL of propyl acetate, 0.99mL of ligand-N, N' -dimethyl-1, 2-ethylenediamine, and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 24 hours. Filtering a reaction material, washing a solid by propyl acetate, washing 50mL of the filtrate by 0.10M sodium sulfide solution and 50mL of water respectively, washing 50mL of 0.20M hydrochloric acid firstly to remove ethylenediamine ligand, dissolving lasidan salt in 100mL of 0.15M hydrochloric acid in water, decoloring aqueous solution containing product hydrochloride by using activated carbon, alkalizing the aqueous solution by 3.4mL of 5M NaOH solution to separate out lasidan, extracting by using ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into residual oily matter, grinding to separate out lasidan, wherein the yield is 72 percent, and the yield is 12.6g of a light yellow solid; the purity is 97.1%.
Example 13 same as example 1, solvent equal volume of isopropyl acetate instead of tetrahydrofuran
A reaction flask was charged with anhydrous potassium carbonate 19.4g, trifluorobenzamide 9.0g, cuprous iodide 887mg, air removed, isopropyl acetate 300mL, ligand-N, N' -dimethyl-1, 2-ethylenediamine 0.99mL, bromopyridone 13.2g, and the mixture was stirred at room temperature for about 24 hours. Filtering a reaction material, washing a solid by isopropyl acetate, washing 50mL of the filtrate by 0.10M sodium sulfide solution and 50mL of water respectively, washing 50mL of 0.20M hydrochloric acid firstly to remove ethylenediamine ligand, dissolving lasidan salt in 100mL of 0.15M hydrochloric acid in water, decoloring aqueous solution containing product hydrochloride by active carbon, alkalizing the aqueous solution by 3.4mL of 5M NaOH solution to separate out lasidan, extracting by ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into residual oily matter, grinding to separate out lasidan, wherein 13.5g of light yellow solid is obtained, and the yield is 77%; the purity is 96.5%.
Example 14 same as example 1, solvent equal volume of butanone instead of tetrahydrofuran
In a reaction flask were added 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide and 887mg of cuprous iodide, air was removed, 300mL of butanone, 0.99mL of ligand-N, N' -dimethyl-1, 2-ethylenediamine and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for reaction for about 24 hours. Filtering a reaction material, washing a solid with butanone, concentrating a butanone solution, adding 200mL of ethyl acetate into a residue to dissolve the residue, then respectively washing the solution with 50mL of 0.10M sodium sulfide solution and 50mL of water, then washing with 50mL of 0.20M hydrochloric acid to remove ethylenediamine ligand, dissolving a lasiditan salt in water with 100mL of 0.15M hydrochloric acid, decoloring an aqueous solution containing a product hydrochloride with activated carbon, alkalifying the aqueous solution with 3.4mL of 5M NaOH solution to separate out lasiditan, extracting with ethyl acetate (50 mL multiplied by 2), drying with anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into a residual oily substance to mill and separate out lasiditan, wherein 11.9g of a light yellow solid is obtained, and the yield is 68%; the purity is 96.1%.
Example 15 replacement of Potassium carbonate with Cesium carbonate, 40% of the amount of ligand bromopyridone
A reaction flask was charged with 23.3g (71.5 mmol) of anhydrous cesium carbonate, 4.50g (25.5 mmol) of trifluorobenzamide, and 443mg (2.33 mmol) of cuprous iodide, and air was removed, and tetrahydrofuran (150 mL), 1.00mL (828mg, 9.40mmol) of ligand-N, N' -dimethyl-1, 2-ethylenediamine, and 6.60g (2.33 mmol) of bromopyridone were added to stir the mixture at room temperature for about 24 hours to obtain a green reaction material.
The treatment method is the same as example 1, and light yellow solid 5.71g is obtained, and the yield is 65%; the purity is 96.2%.
Example 16 the same as example 1 except that the reaction temperature was 10-15 ℃ and the reaction time was 36 hours
19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide and 887mg of cuprous iodide are added into a reaction flask, air is removed, 300mL of tetrahydrofuran, 0.99mL of ligand-N, N' -dimethyl-1, 2-ethylenediamine and 13.2g of bromopyridone are added, and the mixture is stirred at 10-15 ℃ for about 36 hours. Filtering a reaction material, washing a solid by tetrahydrofuran, washing 50mL of the filtrate by a 0.10M sodium sulfide solution and 50mL of water respectively, washing 50mL of 0.20M hydrochloric acid firstly to remove an ethylenediamine ligand, dissolving a lasidamin salt in water by 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride by active carbon, alkalizing the aqueous solution by 3.4mL of a 5M NaOH solution to separate out lasidan, extracting by ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily substance, grinding to separate out the lasidamin, wherein 13.2g of a light yellow solid is obtained, and the yield is 75%; the purity is 97.0%.
Example 17 the same as example 1, except that the reaction temperature in 50-55 ℃ and reaction time 15 hours
19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide and 887mg of cuprous iodide are added into a reaction flask, air is removed, 300mL of tetrahydrofuran, 0.99mL of ligand-N, N' -dimethyl-1, 2-ethylenediamine and 13.2g of bromopyridone are added, and the mixture is stirred at 50-55 ℃ for reaction for about 15 hours. Filtering a reaction material, washing a solid by tetrahydrofuran, washing 50mL of the filtrate by a 0.10M sodium sulfide solution and 50mL of water respectively, washing 50mL of 0.20M hydrochloric acid firstly to remove an ethylenediamine ligand, dissolving a lasidamin salt in water by 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride by active carbon, alkalizing the aqueous solution by 3.4mL of a 5M NaOH solution to separate out lasidan, extracting by ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily substance, grinding to separate out lasidamin, wherein the yield is 61 percent, and the light yellow solid is 10.7 g; the purity is 95.2%.
Example 18 the same as example 1 except that N, N '-dimethyl-1, 2-ethylenediamine was replaced with the same molar amount of N, N' -dibenzyl-1, 2-ethylenediamine
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, and 887mg of cuprous iodide, air was removed, 300mL of tetrahydrofuran, 2.25g (9.38 mmol) of ligand-N, N' -dibenzyl-1, 2-ethylenediamine, and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 24 hours. Filtering a reaction material, washing a solid by tetrahydrofuran, washing 50mL of the filtrate by a 0.10M sodium sulfide solution and 50mL of water respectively, washing 50mL of 0.20M hydrochloric acid firstly to remove an ethylenediamine ligand, dissolving a lasidamin salt in water by 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride by active carbon, alkalizing the aqueous solution by 3.4mL of a 5M NaOH solution to separate out lasidan, extracting by ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily substance, grinding to separate out the lasidamin, wherein the yield is 80 percent, and the weight of a light yellow solid is 14.1 g; the purity is 97.8%.
Example 19 the same as example 1 except that N, N '-dimethyl-1, 2-ethylenediamine was replaced by a halved amount (in moles) of N, N' -dibenzyl-1, 2-ethylenediamine
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, 887mg (4.66 mmol) of cuprous iodide, air was removed, 300mL of tetrahydrofuran, 1.13g (4.70 mmol) of ligand-N, N' -dibenzylmethyl-1, 2-ethylenediamine and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 24 hours until about 50% of bromopyridone remained unconsumed. The reaction mass was filtered, the solid was washed with tetrahydrofuran, the mass was concentrated and column chromatographed to give lasmidatan as a pale yellow solid 6.67g with a yield of 38%.
Example 20 the same as example 1 except that N, N '-dimethyl-1, 2-ethylenediamine was replaced with the same molar amount of N, N' -bis (4-cyanophenyl) methyl-1, 2-ethylenediamine
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, and 887mg of cuprous iodide, air was removed, 300mL of tetrahydrofuran, 2.72g (9.38 mmol) of ligand-N, N' -bis (4-cyanophenyl) methyl-1, 2-ethylenediamine, and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 20 hours. Filtering a reaction material, washing a solid by tetrahydrofuran, washing a filtrate by 50mL of 0.10M sodium sulfide solution and 50mL of water respectively, washing 50mL of 0.20M hydrochloric acid by 50mL, washing out an ethylenediamine ligand, dissolving lasidamin salt in water by 100mL of 0.15M hydrochloric acid, decoloring aqueous solution containing a product hydrochloride by using activated carbon, alkalizing the aqueous solution by 3.4mL of 5M NaOH solution to separate out lasidamin, extracting by using ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into a residual oily substance, grinding to separate out lasidamin, wherein the yield of a light yellow solid is 14.2g, and the light yellow solid is 81%; the purity is 98.3%.
Example 21 the same as example 1 except that N, N '-dimethyl-1, 2-ethylenediamine was replaced with the same molar amount of N, N' -bis (2-cyanophenyl) methyl-1, 2-ethylenediamine
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, and 887mg of cuprous iodide, air was removed, 300mL of tetrahydrofuran, 2.72g (9.38 mmol) of ligand-N, N' -bis (2-cyanophenyl) methyl-1, 2-ethylenediamine, and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 24 hours. Filtering a reaction material, washing a solid by tetrahydrofuran, washing 50mL of the filtrate by a 0.10M sodium sulfide solution and 50mL of water respectively, washing 50mL of 0.20M hydrochloric acid firstly to remove an ethylenediamine ligand, dissolving a lasidamin salt in water by 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride by active carbon, alkalizing the aqueous solution by 3.4mL of a 5M NaOH solution to separate out lasidan, extracting by ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily substance, grinding to separate out the lasidamin, wherein 13.5g of a light yellow solid is obtained, and the yield is 83%; the purity is 98.0%.
Example 22 the same as example 1 except that N, N '-dimethyl-1, 2-ethylenediamine was replaced with the same number of moles of N, N' -di (pyridin-4-yl) methyl-1, 2-ethylenediamine
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, and 887mg of cuprous iodide, air was removed, 300mL of tetrahydrofuran, 2.50g (9.38 mmol) of ligand-N, N' -bis (pyridin-4-yl) methyl-1, 2-ethylenediamine, and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 24 hours. Filtering a reaction material, washing a solid by tetrahydrofuran, washing 50mL of the filtrate by a 0.10M sodium sulfide solution and 50mL of water respectively, washing 50mL of 0.20M hydrochloric acid firstly to remove an ethylenediamine ligand, dissolving a lasidamin salt in water by 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride by active carbon, alkalizing the aqueous solution by 3.4mL of a 5M NaOH solution to separate out lasidan, extracting by ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily substance, grinding to separate out the lasidamin, wherein 13.7g of a light yellow solid is obtained, and the yield is 78%; the purity was 97.2%.
Example 23 the same as example 1 except that N, N '-dimethyl-1, 2-ethylenediamine was replaced with the same number of moles of N, N' -di (pyridin-2-yl) methyl-1, 2-ethylenediamine
A reaction flask was charged with anhydrous potassium carbonate 19.4g, trifluorobenzamide 9.0g, cuprous iodide 887mg, air removed, tetrahydrofuran 300mL, ligand-N, N' -bis (pyridin-2-yl) methyl-1, 2-ethylenediamine 2.50g (9.38 mmol), and bromopyridone 13.2g, and the mixture was stirred at room temperature for about 24 hours. Filtering the reaction material, washing the solid by tetrahydrofuran, washing the filtrate by 50mL of 0.10M sodium sulfide solution and 50mL of water respectively, washing by 50mL of 0.20M hydrochloric acid firstly to remove ethylenediamine ligand, dissolving lasidan salt into water by 100mL of 0.15M hydrochloric acid, decoloring the aqueous solution containing the product hydrochloride by active carbon, alkalifying the aqueous solution by 3.4mL of 5M NaOH solution to separate out lasidan, extracting by ethyl acetate (50 mL multiplied by 2), drying by anhydrous sodium sulfate, concentrating, adding 5-10 mL of n-hexane into the residual oily matter, grinding to separate out lasidan, wherein 13.2g of light yellow solid is obtained, and the yield is 75%; the purity is 96.5%.
Example 24 the same as example 1 except that N, N '-dimethyl-1, 2-ethylenediamine was replaced with the same molar amount of N, N' -bis (4-chlorophenylmethyl) -1, 2-ethylenediamine
In a reaction flask were charged 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, and 887mg of cuprous iodide, air was removed, 300mL of tetrahydrofuran, 2.99g (9.38 mmol) of ligand-N, N' -bis (4-chlorophenylmethyl) -1, 2-ethylenediamine, and 13.2g of bromopyridone were added, and the mixture was stirred at room temperature for about 24 hours. The reaction material is filtered, the solid is washed by tetrahydrofuran, the filtrate is respectively washed by 50mL of 0.10M sodium sulfide solution and 50mL of water, then 50mL of 0.20M hydrochloric acid is firstly washed to remove ethylenediamine ligand, 100mL of 0.15M hydrochloric acid is used to dissolve lasidamin salt into water, the aqueous solution containing the product hydrochloride is decolored by active carbon, 3.4mL of 5M NaOH solution is used to alkalify the aqueous solution to separate out lasidamin, ethyl acetate (50 mL multiplied by 2) is used for extraction, anhydrous sodium sulfate is used for drying and concentration, 5-10 mL of n-hexane is added into the residual oily substance to mill and separate out lasidamin, 12.6g of light yellow solid, the yield is 72%, and the purity is 96.1%.

Claims (1)

  1. The synthesis process of the Lasmidinan is characterized by comprising the following preparation steps: reacting 2,4, 6-trifluorobenzamide and (6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone in an organic solvent at 0-60 ℃ in the presence of inorganic solid weak base under catalysis of cuprous salt and ligand to generate Lasmidinian; the inorganic solid weak base is potassium carbonate or cesium carbonate, and the molar amount of the inorganic solid weak base is 1-6 times of the molar number of (6-bromopyridine-2-yl) (1-methylpiperidine-4-yl) ketone; the molar amount of the 2,4, 6-trifluorobenzamide is 0.8-2.0 times of the molar number of (6-bromopyridine-2-yl) (1-methylpiperidin-4-yl) methanone; the cuprous salt is CuI, cuBr or CuCl, and the molar amount of the cuprous salt is 1-100% of the molar number of (6-bromopyridine-2-yl) (1-methylpiperidine-4-yl) ketone; the organic solvent is ethyl acetate, ethyl formate, propyl formate, cyclopentyl methyl ether, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether, acetone, butanone, acetonitrile, propionitrile, butyronitrile, ethanol, isopropanol or n-propanol; the ligand is one of the following structures:
    Figure FDA0003838361090000011
    ，
    the molar dosage of the ligand is 20 to 100 percent of the molar dosage of (6-bromopyridine-2-yl) (1-methylpiperidine-4-yl) ketone.
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