CN113195454A - Preparation method of amide-like derivative and intermediate thereof - Google Patents
Preparation method of amide-like derivative and intermediate thereof Download PDFInfo
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- CN113195454A CN113195454A CN201980083057.3A CN201980083057A CN113195454A CN 113195454 A CN113195454 A CN 113195454A CN 201980083057 A CN201980083057 A CN 201980083057A CN 113195454 A CN113195454 A CN 113195454A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The method can be used for efficiently, conveniently and safely preparing the compound shown in the formula VI, and obviously improving the purity of the final product, namely the compound shown in the formula VI.
Description
The invention relates to a preparation method of amide-like derivatives and intermediates thereof.
Schizophrenia is the most serious and most harmful one of all mental diseases, and the global incidence rate is about 1-2%. The life-span morbidity of patients with schizophrenia is 0.7-0.8%, and the patients have no obvious correlation with sex, race or social boundary, and the mortality is 2-3 times higher than that of general people. Recent studies show that the social burden of mental diseases is ranked first among Chinese diseases, and exceeds the diseases of cardiovascular and cerebrovascular diseases, respiratory systems, malignant tumors and the like.
Patent WO2017084627A discloses a dopamine D-acting agent2、5-HT 1AAnd 5-HT2AThe compound of the receptor and the preparation method thereof have good effect of resisting the activity of neurological diseases, and the structure of the compound is shown as follows:
however, the preparation method disclosed by the patent has the defects of high toxicity of reaction materials, overlong reaction time, high impurity content, low purity, high difficulty in industrial scale production, serious environmental pollution and the like, so that the invention provides a new synthesis thought and route, the reaction time is greatly shortened in the whole process, harsh reaction conditions are avoided, the process has strong operability, the industrial production requirement is facilitated, and the environmental protection pressure is reduced; in addition, due to the change of reaction conditions, the generation of impurities can be reduced, and the purification difficulty and cost of the final product are reduced.
Disclosure of Invention
The invention provides a preparation method for a compound shown in a formula VI and key intermediates (compounds shown in formulas III, IV and V) thereof,
wherein X1Is selected from fluorine or chlorine, and n is selected from any integer between 1 and 3.
The invention provides a preparation method of a compound shown as a formula V, which comprises the following steps: reacting a compound shown as a formula IV with a compound shown as a formula (1) in the presence of a catalyst, an alkaline substance and an organic solvent to obtain a compound shown as a formula V,
wherein n is selected from any integer between 1 and 3; the catalyst is selected from onium salt type phase transfer catalysts; the alkaline substance is selected from carbonates.
In an embodiment of the invention n is 1 or 2.
In an embodiment of the invention, the onium salt type phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (TEBA), trioctylammonium chloride (TCMAC) or cetyltrimethylammonium bromide (CTMAB), preferably TEBA.
In an embodiment of the invention, the carbonate is selected from sodium or potassium carbonate, preferably potassium carbonate.
In one embodiment of the invention, the organic solvent is selected from nitriles or ketones. In one embodiment of the invention, the nitrile is preferably acetonitrile and the ketone is selected from acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one or hexan-3-one, preferably acetone.
In an embodiment of the present invention, in order to achieve sufficient reaction and achieve better yield, the molar ratio of the compound represented by formula iv to the compound represented by formula (2) may be 1:1 to 1:4, preferably 1:2 or 1: 3; the molar ratio of the compound shown in the formula IV to potassium carbonate is 1: 1-1: 5, preferably 1:2 or 1: 3; the molar ratio of the compound shown in the formula IV to the catalyst is selected from 50: 1-20: 1, preferably 35: 1-25: 1, and further the catalyst is selected from TEBA.
In an embodiment of the present invention, in order to completely perform the reaction, the reaction time for preparing the compound represented by the formula v from the compound represented by the formula iv and the compound represented by the formula (1) is selected from 4 to 7 hours, preferably 6 hours; the reaction temperature is 50-80 ℃, preferably 50-70 ℃.
In one embodiment of the present invention, the compound represented by the formula (1) is preferably:
when the compound represented by formula (1) of the present invention is 1-bromo-3-chloropropane, it has been surprisingly found that the content of impurities in the final product can be significantly reduced, and the purity of the final product can be significantly improved.
The invention further provides a preparation method of the compound shown in the formula VI, which comprises the following steps: reacting a compound of formula V with a compound of formula (2) in the presence of a catalyst, a carbonate and an organic solvent to obtain a compound of formula VI;
wherein X1Selected from fluorine or chlorine, preferably fluorine; n is 1 or 2, preferably 1; the compound of formula (2) may also be selected from salts with acids, such as hydrochloride.
In one embodiment of the invention, the catalyst is selected from elemental iodine, potassium iodide or sodium iodide, preferably sodium iodide; the carbonate is selected from sodium carbonate or potassium carbonate.
In one embodiment of the invention, the organic solvent is selected from nitriles or ketones. In one embodiment of the invention, the nitrile is preferably acetonitrile and the ketone is selected from acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one or hexan-3-one, preferably acetone.
In an embodiment of the present invention, in order to achieve sufficient reaction and achieve better yield, the molar ratio of the compound represented by formula v to the compound represented by formula (2) may be 1:1 to 1:2, preferably 1: 1; the molar ratio of the compound shown in the formula V to potassium carbonate is selected from 1: 1-1: 5, preferably 1:2 or 1: 3; the mol ratio of the compound shown in the formula IV to the catalyst is 60: 1-30: 1, preferably 50: 1-30: 1, and further the catalyst is NaI or KI.
In one embodiment of the present invention, the compound of formula vi is preferably the following compound:
the invention further provides a preparation method of the compound shown as the formula IV, which comprises the following steps: and (3) preparing the compound shown in the formula III in the presence of Lewis acid and an organic solvent to obtain the compound shown in the formula III.
In an embodiment of the invention, the Lewis acid (Lewis acid) is selected from a molecular Lewis acid; the molecular Lewis acid is selected from boron trifluoride, ferric trichloride, aluminum trichloride, sulfur trioxide, dichlorocarbene or niobium pentachloride, and preferably the aluminum trichloride or the ferric trichloride.
In one embodiment of the invention, the organic solvent is selected from Tetrahydrofuran (THF), hexanol, methanol, toluene, N-Dimethylformamide (DMF), preferably toluene.
In one embodiment of the present invention, the molar ratio of the compound represented by formula iii to the lewis acid may be 1:1 to 1:4, preferably 1:2 or 1:3, in order to achieve sufficient reaction and achieve better yield.
In an embodiment of the present invention, in order to completely perform the reaction, the reaction time for preparing the compound of formula iv from the compound of formula iii and lewis acid may be 3 to 6 hours, preferably 4 hours; the reaction temperature is selected from 100-130 ℃, preferably 110-120 ℃.
The invention further provides a preparation method of the compound shown as the formula III, which comprises the following steps:
step 1: reacting in the presence of an acid-binding agent and an organic solvent to prepare a compound shown in a formula I;
step 2: at P2O 5Reacting with methanesulfonic acid in the presence of methanesulfonic acid to prepare a compound shown as a formula II;
and step 3: reacting with methyl iodide in the presence of strong base and an organic solvent to prepare a compound shown in a formula III;
wherein the acid-binding agent is selected from pyridine or triethylamine, preferably triethylamine; the strong base is selected from NaH or KH, preferably NaH; the organic solvent in the step 1 is selected from dichloromethane; the organic solvent in the step 3 is selected from 4-Dimethylaminopyridine (DMAP) or N, N-Dimethylformamide (DMF).
In an embodiment of the invention, in step 1, for the purpose of achieving a sufficient reaction and achieving a better yield, the molar ratio of the 4-methoxyphenethylamine to the acid-binding agent may be 1: 1-1: 2, preferably 1: 1.5; the molar ratio of the 4-methoxyphenethylamine to the ethyl chloroformate is selected from 1:1 to 1:3, preferably 1:1 to 1: 1.5.
In one aspect of the inventionIn the examples, step 2 is carried out in order to achieve a good reaction and to achieve a good yield, the compound of formula I is reacted with P2O 5The molar ratio of (a) to (b) may be 1:1 to 2:1, preferably 1:1 to 1.5: 1.
In an embodiment of the invention, in order to achieve sufficient reaction and achieve better yield in step 3, the molar ratio of the compound represented by formula ii to the strong base may be 1:1 to 1:2, preferably 1:1 to 1: 1.5; the molar ratio of the compound represented by the formula II to methyl iodide may be 1:1 to 1:2, preferably 1:1 to 1: 1.5.
The invention further provides a method for synthesizing a compound shown in a formula VI, which is shown as follows:
wherein X1Is fluorine; n is 1 or 2, preferably 1.
The invention further discloses the application of the compound shown in the formula III, the formula IV or the formula V in preparing the compound shown in the formula VI,
wherein n is 1 or 2, preferably 1; x1Is fluorine or chlorine, preferably fluorine.
The invention further provides the application of the compound shown in the formula V in preparing the compound shown in the formula VI, the purity of the prepared compound shown in the formula VI is more than 99 percent,
wherein n is 1 or 2, preferably 1; x1Is fluorine or chlorine, preferably fluorine.
The invention further provides a method for purifying and refining the compound shown in the formula VI, which comprises the following steps:
dissolving a crude compound shown as a formula VI in an organic solution;
adding active carbon, stirring and filtering;
thirdly, cooling and stirring at room temperature, and performing suction filtration to obtain a solid;
and fourthly, washing the solid by using an organic solvent, and drying for 5-10 hours to obtain a white powdery solid refined compound shown in the formula V.
In one embodiment of the invention, the organic solvent is selected from ketones, C1-3One or more of the alcohols of (a). In one embodiment of the invention, the ketones are selected from acetone or butanone; said C is1-3The alcohol is selected from methanol, ethanol, n-propanol or isopropanol.
In an embodiment of the present invention, the organic solvent is selected from a mixed solvent of acetone and methanol, and a volume ratio of acetone to methanol may be 5:1 to 10:1, preferably 10: 1.
In one embodiment of the invention, the step (i) further comprises a heating process, and the heating temperature can be 60-70 ℃.
In an embodiment of the invention, the stirring time in the third step may be 5 to 10 hours, preferably 5 to 7 hours.
In one embodiment of the present invention, the drying temperature in the step (iv) may be 50 to 70 ℃, preferably 50 to 60 ℃.
Advantageous effects of the invention
Compared with the preparation method disclosed in the prior art, the preparation method of the novel compound shown in the formula VI and the key intermediates (the compounds shown in the formulas III, IV and V) thereof can obviously improve the purity of the final product, and compared with the prior art, the purity reaches more than 99.8 percent and meets the standards of pharmaceutical grade raw material medicines for human; in addition, AlCl is adopted in the new preparation method3The compound shown in the intermediate formula IV is prepared by demethylation, the labor protection requirement is low, the operability is strong, and the method is more suitable for industrial production.
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test conditions of the apparatus used for the experiment:
1. high Performance Liquid Chromatography (HPLC)
The instrument model is as follows: agilent 1260(DAD) binary pump liquid chromatography
A chromatographic column: SHIMADZU VP-ODS C18 column (4.6X 250mm, 5 μm)
Mobile phase:
a: 0.01mol/L potassium dihydrogen phosphate, 0.1% triethylamine (pH adjusted to 2.5 with phosphoric acid) -methanol (90:10)
B: 0.01mol/L potassium dihydrogen phosphate, 0.1% triethylamine (pH adjusted to 2.5 with phosphoric acid) -methanol (20:80)
Flow rate: 1.0ml/min column temperature: 35 deg.C
Wavelength: sample volume at 210 nm: 15 μ L
Gradient conditions (volume ratio):
example 1: preparation of ethyl (4-methoxyphenylethyl) carbamate (intermediate I)
Adding 275.0g (2.55mol) ethyl chloroformate (industrial pure, purchased from Shanghai shellfish chemical Co., Ltd.) and 2500mL of dichloromethane into a 5L reaction bottle, stirring, cooling to 0 ℃ in an ice salt bath, slowly adding 350g (2.32mol) of 4-methoxyphenethylamine (industrial pure, purchased from Shanghai Michelle chemical technology Co., Ltd.) dissolved in 1000mL of dichloromethane dropwise, and controlling the system temperature to be 0-5 ℃; after finishing the dropwise addition, slowly dropwise adding 351g (3.48mol) of triethylamine, and controlling the temperature of the system to be 5-10 ℃; after completion of the dropwise addition, the mixture was stirred at room temperature (25. + -. 5 ℃ C.) for 1 hour.
After the reaction is finished, adding 1000mL of water into the reaction solution to quench the reaction, and stirring for 5 minutes; standing and separating to obtain an organic layer, and washing the organic phase with 600mL of 1mol/L hydrochloric acid solution; the organic phase is washed with 600mL of saturated sodium chloride solution, dried over 150g of anhydrous sodium sulfate for 1 hour and filtered; the filtrate was concentrated to dryness to give a pale yellow oil, which was cooled at room temperature for 1 hour to give 508g of a pale yellow solid in 98.3% yield, MS (ESI) M/z 223.3([ M + H ]] +)。
Example 2: preparation of 7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (intermediate II)
Adding 510.0g (1.80mol) of phosphorus pentoxide and 2000mL of methanesulfonic acid into a 5L reaction bottle, stirring, heating in an oil bath at 125-130 ℃ until the phosphorus pentoxide is completely dissolved; and (3) stirring and cooling the mixture at room temperature until the temperature of the system is reduced to 70 ℃, and adding 1000g (2.24mol) of the intermediate I. The mixture is heated in an oil bath for 2 hours at 125 ℃.
After the reaction is finished, cooling, adding 500g of ice to quench the reaction, adding 5000mL of water into the system, extracting 6 times (1200 mL/time) with dichloromethane, combining organic phases, adding 500g of anhydrous potassium carbonate, stirring for 0.5 hour, performing suction filtration, drying the solution for 1 hour with 500g of anhydrous sodium sulfate, performing suction filtration, concentrating the filtrate to obtain a brown oily substance, cooling for 5 hours at 0 ℃, performing suction filtration, washing a filter cake with 300mL of ethyl acetate, and drying the filter cake for 8 hours at 50 +/-5 ℃ to obtain 436.5g of white-like solid with the yield of 55.1%, and MS (ESI) M/z 177.1([ M + H ] (ESI)] +)。
Example 3: preparation of 7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (intermediate III)
Adding 54.2g (1.36mol) of 60% sodium hydride and 1000mL of N, N-dimethylformamide into a 3L reaction bottle, stirring, cooling to 0-5 ℃ in an ice salt bath, slowly dropwise adding 200g (1.13mol) of intermediate II dissolved in 500mL of N, N-dimethylformamide, and controlling the system temperature to 5-10 ℃; after the dropwise addition is finished, slowly dropwise adding 176.5g (1.24mol) of methyl iodide, and controlling the system temperature to be 10-15 ℃; after completion of the dropwise addition, the mixture was stirred at room temperature (25. + -. 5 ℃ C.) for 1 hour.
Adding 500mL of water drop into the reaction solution to quench the reaction; then adding 4L of water to mix with the reaction solution, adding 1630g of sodium chloride to saturation, extracting with ethyl acetate for 6 times (800 mL/time), combining the organic phases, washing with saturated sodium chloride solution for 3 times (500 mL/time), and drying with 300g of anhydrous sodium sulfate for 1 hour; filtering, concentrating the filtrate to dryness to obtain 258g of brown yellow oily substance with yield over 100%, and MS (ESI) M/z 191.1([ M + H ]] +)。
Example 4: preparation of 7-hydroxy-2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (intermediate IV)
257.6g (1.94mol) of anhydrous aluminum chloride and 1500mL of toluene are put into a 3L reaction flask, stirred at normal temperature (25. + -. 5 ℃), and 185.0g (0.97mol) of intermediate III dissolved in 300mL of toluene are slowly added dropwise; after the dropwise addition, the mixture is heated in an oil bath to reflux (about 114-115 ℃) and reacted for 4 hours under the protection of nitrogen.
After the reaction is finished, cooling the room temperature to 70 ℃, pouring out the toluene solution, pouring 2000mL of 4mol/L hydrochloric acid solution into a bottle, adding ice blocks to cool, stirring the mixture at the room temperature for 1 hour, filtering the mixture, and washing a filter cake to be neutral by using 500mL of water; dissolving the filter cake with 1000mL of 2mol/L sodium hydroxide solution, and washing with 500mL of toluene and 500mL of dichloromethane in sequence; adjusting the pH value of a water layer to 3-4 by using 36% hydrochloric acid solution, cooling in an ice bath, stirring for 0.5 hour, filtering, washing a filter cake to be neutral by using 500mL of water, drying the filter cake at 50 +/-5 ℃ for 12 hours to obtain 162.1g of white-like solid with the yield of 94.7%, and obtaining MS (ESI) M/z 177.2([ M + H ] M] +)。
Example 5: 7- (3-Chloropropoxy) -2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (intermediate V)
156.0g (0.88mol) of intermediate IV, 277.6g (1.76mol) of the compound represented by the formula (1), 364.9g (2.64mol) of anhydrous potassium carbonate, 6.0g (0.03mol) of benzyltriethylammonium chloride and 1600mL of acetone were put into a 3L reaction flask, heated in an oil bath to reflux (about 60 to 65 ℃ C.), and stirred for 6 hours.
After the reaction is finished, filtering, and concentrating the filtrate under reduced pressure to obtain a dry solvent to obtain a yellow oily substance; dissolving in 500mL acetone, stirring at room temperature, adding 3000mL n-hexane, stirring for 1 hr under ice-bath cooling, filtering, and drying the filter cake at 50 + -5 deg.C for 6 hr to obtain off-white solid 213.2g with yield 95.8%, MS (ESI) M/z 254.1([ M + H ]] +)。
Example 6: 7- (3- (4- (6-fluorobenzo [ d ] isoxazolin-3-yl) piperidyl-1-yl) propoxy) -2-methyl-3, 4-dihydroisoquinoline-1 (2H) -one (compound shown in formula VI, crude product)
210.0g (0.83mol) of intermediate V, 223.6g (0.87mol) of the hydrochloride of the compound represented by the formula (2), 344.3g (2.64mol) of anhydrous potassium carbonate, 3.7g (0.02mol) of sodium iodide and 2100mL of acetonitrile were put into a 5L reaction flask, heated in an oil bath to reflux (about 80 to 85 ℃ C.), and stirred for 24 hours.
After the reaction, the mixture is filtered, the filtrate is placed in an ice bath to be stirred for 3 hours, the filtration is carried out, and a filter cake is dried for 3 hours at the temperature of 50 +/-5 ℃ to obtain 264.6g of yellow solid, namely a crude product of the compound shown in the formula VI, wherein the yield is 82.6%.
Example 7: 7- (3- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidyl-1-yl) propoxy) -2-methyl-3, 4-dihydroisoquinoline-1 (2H) -one (compound shown in formula VI, purified and refined)
Adding 260.0g of a crude compound shown in the formula VI, 800mL of acetone and 80mL of methanol into a 2000mL reaction bottle, heating in a water bath until the mixture flows back (about 60-65 ℃), stirring until the mixture is completely dissolved, adding 8.0g of activated carbon, stirring for 10 minutes, filtering while the mixture is hot, transferring the filtrate into the 2000mL reaction bottle, cooling at room temperature (25 +/-5 ℃), and stirring for 4 hours; suction filtration, washing with 200mL acetone, and drying the filter cake at 50 + -5 deg.C for 6 hours to obtain 180.3g of white-like powder, i.e. CY150112 product, with 79.3% yield.
1H-NMR(600MHz，CDCl3)δ2.02-2.19(m，8H)，2.60(t，2H，J＝12Hz)，2.96(t，2H，J＝12Hz),3.09-3.11(m,3H),3.18(s,3H),3.56(t,2H,J＝12Hz),4.11(t,2H,J＝6Hz),6.98-7.00(m,1H),7.06-7.10(m,2H),7.24-7.26(m,1H),7.64(d,1H,J＝6Hz)，7.74-7.76(m,1H)·MS(ESI)m/z 438.2([M+H] +)。
Example 8: comparison of the purity of the Compound of formula VI obtained by different preparation methods (end product)
Comparative sample
The synthetic route is as follows:
the preparation method comprises the following steps: reference is made to WO2017084627A, example 1 and example 5.
The purification method comprises the following steps: the purification and purification are carried out according to the method described in example 7 of the present invention.
Test sample
The synthetic route is as follows: the preparation method is carried out according to the route of examples 1-6.
The preparation method comprises the following steps: prepared as described in examples 1-6.
The purification method comprises the following steps: the product is purified and purified by the method described in reference example 7.
And (3) measuring the comparison sample and the test sample by HPLC, calculating the mass percentage of the compound shown in the formula VI in the comparison sample and the test sample according to an area normalization method, and specifically detecting results are shown in Table 1.
TABLE 1 HPLC purities of comparative and test samples
| Sample name | Retention time (min) | Height | Area of | HPLC content (%) |
| Comparative sample | 31.820 | 90921937 | 2717110 | 92.38 |
| Test sample | 31.219 | 98195298 | 2934467 | 99.77 |
And (3) test results: in the novel preparation process of the invention, especially when AlCl is adopted in the step 43HBr is replaced, 1-bromo-3-chloropropane is used for replacing 1, 3-dibromopropane in the step 5, the purity of the compound (final product) shown in the formula VI can be remarkably improved to over 99 percent, the quality of the raw material medicine is qualified, the raw material medicine is in accordance with the grade of the raw material medicine for human use, and meanwhile, the impurities are less, so that the subsequent impurity identification work is greatly reduced. Whereas the LC purity of the comparative sample preparation process was only 92.38%,contains more unknown impurities, and the quality of the raw material medicine is unqualified and can not reach the grade of the raw material medicine for human use.
Claims (10)
- A preparation method of a compound shown as a formula V comprises the following steps: reacting a compound represented by formula IV with a compound represented by formula (1) in the presence of a catalyst, a basic substance and an organic solvent to obtain a compound represented by formula V;
wherein n is selected from any integer between 1 and 3; the catalyst is selected from onium salt type phase transfer catalysts; the alkaline substance is selected from carbonates. - The method according to claim 1, wherein n is 1 or 2; the onium salt phase transfer catalyst is selected from tetrabutylammonium bromide, benzyltriethylammonium chloride, trioctylammonium chloride or hexadecyltrimethylammonium bromide; the carbonate is selected from sodium carbonate or potassium carbonate.
- The process of claim 1 wherein the compound of formula VI is prepared by: reacting the compound shown in the formula V with the compound shown in the formula (2) in the presence of a catalyst, carbonate and an organic solvent;
wherein X1Selected from fluorine or chlorine; n is 1 or 2; the catalyst is selected from elementary iodine, potassium iodide or sodium iodide; the carbonate is selected from sodium carbonate or potassium carbonate. - The process of claim 3 wherein the compound of formula VI is:
- the production process according to any one of claims 1 to 4, wherein the organic solvent is selected from the group consisting of nitriles and ketones; the nitriles are selected from acetonitrile and the ketones are selected from acetone, 2-butanone, pentan-2-one, pentan-3-one, hex-2-one or hex-3-one.
- The preparation method according to claim 1, wherein the compound of formula iv is prepared from a compound of formula iii in the presence of a lewis acid and an organic solvent:
wherein the Lewis acid is selected from boron trifluoride, ferric trichloride, aluminum trichloride, sulfur trioxide, dichlorocarbene or niobium pentachloride, and preferably aluminum trichloride. - The process according to claim 6, wherein the organic solvent is selected from the group consisting of tetrahydrofuran, hexanol, methanol, toluene, N-dimethylformamide, preferably toluene.
- The production method according to any one of claims 6 to 7, wherein the compound represented by the formula III is produced by:
step 1: reacting in the presence of an acid-binding agent and an organic solvent to prepare a compound shown in a formula I;step 2: at P2O 5He JiaReacting in the presence of sulfonic acid to prepare a compound shown as a formula II;and step 3: reacting with methyl iodide in the presence of strong base and an organic solvent to prepare a compound shown in a formula III;wherein the acid scavenger is selected from pyridine or triethylamine; the strong base is selected from NaH or KH; the organic solvent in the step 1 is selected from dichloromethane; the organic solvent in the step 3 is selected from 4-dimethylaminopyridine or N, N-dimethylformamide. - The production process as claimed in any one of claims 3 to 4, wherein the compound represented by the formula VI is purified by a method comprising the steps of:dissolving a crude compound shown as a formula VI in an organic solution;secondly, adding active carbon, stirring and filtering;thirdly, cooling and stirring at room temperature, and performing suction filtration to obtain a solid;washing the solid with an organic solvent, and drying for 5-10 hours to obtain a refined compound shown in the formula VI;wherein the organic solvent is selected from ketones, C1-3One or more of the alcohols of (a); the ketones are selected from acetone or butanone; said C is1-3The alcohol is selected from methanol, ethanol, n-propanol or isopropanol.
- The application of the compound shown as the formula V in preparing the compound shown as the formula VI, wherein the purity of the prepared compound shown as the formula VI is more than 99 percent,
wherein n is 1 or 2, preferably 1; x1Is fluorine or chlorine, preferably fluorine.
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| CN201811545897.0A CN111320582A (en) | 2018-12-17 | 2018-12-17 | Preparation method of amide-like derivative and intermediate thereof |
| PCT/CN2019/125644 WO2020125581A1 (en) | 2018-12-17 | 2019-12-16 | Amide derivatives and preparation method for intermediates thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101155804A (en) * | 2005-04-14 | 2008-04-02 | 大塚制药株式会社 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
| CN106749219A (en) * | 2015-11-20 | 2017-05-31 | 江苏恩华药业股份有限公司 | A kind of lactam derivative and its application |
| CN106995410A (en) * | 2016-01-26 | 2017-08-01 | 江苏恩华药业股份有限公司 | A kind of lactam derivative and its application |
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| CN111320582A (en) | 2020-06-23 |
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