CN116925076A - Nevirapine intermediate compound and preparation method and application thereof - Google Patents

Nevirapine intermediate compound and preparation method and application thereof Download PDF

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CN116925076A
CN116925076A CN202210368282.5A CN202210368282A CN116925076A CN 116925076 A CN116925076 A CN 116925076A CN 202210368282 A CN202210368282 A CN 202210368282A CN 116925076 A CN116925076 A CN 116925076A
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compound
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nevirapine
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鲍广龙
文浩
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a nevirapine intermediate compound, a preparation method and application thereof. The invention provides a new nevirapine intermediate, which is prepared by taking 2-chloro-4-methylpyridine and 2-chloronicotinyl chloride as raw materials, preparing an intermediate compound I-2, and then reacting with cyclopropylamine and hydroxylamine hydrochloride to obtain the nevirapine intermediate; the new intermediate itself expands the ring to prepare the target compound nevirapine, the intermediate compound is used for preparing the nevirapine, and the amide bond is constructed through simple rearrangement reaction, so that the generation of ring-opening side reaction in the final cyclization preparation in the prior art can be effectively avoided, the operation is simple and convenient, the yield is higher, and the method is more suitable for industrial mass production.

Description

Nevirapine intermediate compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a nevirapine intermediate compound, a preparation method and application thereof.
Background
Nevirapine (Nevirapine), chemical name of which is 11-cyclopropyl-4-methyl-5, 11-dihydro-6H-dihydropyrido [3,2-b:2',3' -e ] [1,4] diazepin-6-one, is a high-selectivity and non-competitive HIV-1 virus reverse transfer enzyme inhibitor. The English trade name of the medicine is: viramune, chinese trade name: violet, developed by Germany Boehringer Ingelheim, was approved by the United states FDA for 24 days in 6, 1996, and was the first non-nucleoside reverse transcriptase inhibitor approved by the United states FDA. Nevirapine is one of the most widely used anti-AIDS drugs in the world at present, can permeate placenta, can be used for preventing HIV infection and maternal and infant transmission by singly using the nevirapine, and has the chemical structural formula:
the existing synthesis method of nevirapine mainly comprises the following steps:
U.S. Pat. No. 3,182 discloses a process for preparing nevirapine by reacting 2-chloro-3-amino-4-methylpyridine (CAPIC) with 2-chloronicotinyl chloride to form 2-chloro-N- (2-chloro-4-methyl-3-pyridyl) -3-pyridinecarboxamide, then refluxing with cyclopropylamine in xylene to obtain 2-cyclopropylamino-N- (2-chloro-4-methyl-3-pyridyl) -3-pyridinecarboxamide, and finally ring-closing under the action of strong base (such as sodium hydride). The route is the earliest reported nevirapine synthesis route, and the yield and purity meet the requirements, thus being suitable for industrial production. The synthetic route is as follows:
however, this process has the disadvantage that the mixed solvent of cyclohexane and 1, 4-dioxane in step 1. Hexane is toxic and flammable, and requires enhanced safety precautions for storage and handling, otherwise there is a risk of causing a combustion explosion. If the 1, 4-dioxane flows into soil, the 1, 4-dioxane is difficult to degrade biologically, and the pyridine has malodor, so that the environment is polluted; the reaction temperature of the step 2 is 130-145 ℃, cyclopropylamine is unstable at such high temperature, and 2-cyclopropylamino-N- (2-chloro-4-methyl-3-pyridyl) -3-pyridine carboxamide is also unstable after reaching 145 ℃, so that the reaction temperature needs to be carefully controlled, otherwise explosion is easily caused. However, the reaction itself is exothermic, and it is difficult to control the temperature to 145 ℃ or lower until the reaction is completed. Meanwhile, cyclopropylamine is easy to gasify at high temperature, the reaction is required to be carried out in a closed container, the operation difficulty is increased, and the requirement on equipment is high; the final cyclization process uses sodium hydride as a catalyst. Because the sodium hydride has high chemical reaction activity, spontaneous combustion can be realized in moist air, heat and hydrogen are released when the sodium hydride is reacted with water vigorously, combustion and explosion are caused, and meanwhile, the generated hydroxide has strong corrosiveness. When the reaction is completed, water is carefully added to the hydrolysis residue, and the operation conditions are severe.
Patent WO2007010352, CN101585836A and Navirapine synthesis in Chinese journal of pharmaceutical industry 2012,43 (6): 411-413 are prepared from CAPIC and 2-chloronicotinyl chloride as raw materials, and potassium carbonate as acid-binding agent by heating (75-80 ℃) in toluene to obtain 2-chloro-N- (2-chloro-4-methylpyridin-3-yl) nicotinamide with a yield of about 87.8%. Then under the catalysis of cuprous chloride, ullmann reaction is carried out on the N- (2-chloro-4-methylpyridine-3-yl) -2- (cyclopropylamino) nicotinamide and cyclopropylamine, finally, reflux is carried out on the N- (2-chloro-4-methylpyridine-3-yl) -2- (cyclopropylamino) nicotinamide in toluene solvent under the action of potassium tert-butoxide, and nevirapine is obtained through ring closure reaction, wherein the yield of the two steps of reaction is 82%. However, the yield of the synthesis method is general, and for large-scale industrial production, there is still further room for improvement, optimization and perfection. The synthetic route is as follows:
U.S. Pat. No. 3,979 and J.org.chem. 1995,60 (6) were prepared by stirring 1875-877 with 3-amino-2-methoxy-4-methylpyridine as starting material, 2-chloronicotinyl chloride, ethyl acetate and N, N-diisopropylethylamine in a reactor at 0deg.C for 10h, washing with hydrochloric acid, and drying to give 2-chloro-N- (2-methoxy-4-methylpyridin-3-yl) nicotinamide in 88% yield. Then the mixture and cyclopropylamine are placed in a closed container and heated to 110 ℃ to react to obtain 2- (cyclopropylamino) -N- (2-methoxy-4-methylpyridin-3-yl) nicotinamide with 86 percent of yield. Finally, under the protection of argon, ring-closing reaction is carried out on the product in dry pyridine by NaH or hexamethyldisilazide sodium amide to obtain the target product with the yield of 91 percent. However, the final product of the synthesis method needs to be purified by chromatography, has strict process conditions and high production cost, can only be used for laboratory preparation, and is not suitable for industrial production. The synthetic route is as follows:
chinese patent application CN102127077B and literature hetercycl.chem 1995,32 (1): 259-263 amidation of 2, 6-dichloro-3-amino-4-methylpyridine with 2-chloronicotinyl chloride or 2-chloronicotinic acid to give 2-chloro-N- (2, 6-dichloro-4-methylpyridin-3-yl) nicotinamide. Then heating the mixture with cyclopropylamine in a dimethylbenzene solvent to 120 ℃ for reaction for 48 hours, filtering, washing with water, and drying in vacuum to obtain 2- (cyclopropylamino) -N- (2, 6-dichloro-4-methylpyridin-3-yl) nicotinamide with a yield of 84%. Under the protection of nitrogen, 2-methoxyl diethyl ether is taken as a solvent, strong alkali NaH is added, the mixture is heated to 120 ℃ for reflux reaction, and then Pd/C is used for catalytic hydrogenation and dechlorination to obtain a target product, wherein the yield of the two-step reaction is 55%. However, the method has the advantages of long reaction steps, more side reactions, long preparation period and low yield. The synthetic route is as follows:
U.S. Pat. No. 3,3779,CN 1653065A, WO2004002988 in the form of 2-chloro-3-pyridinecarbonitrile with cyclopropylamine in ethanol or 1-propanol solvent and adding K 3 PO 4 Or reflux-extracting triethylamine, adjusting pH with hydrochloric acid, adding chlorinating agent such as SOCl 2 Refluxing in toluene or THF solvent, and adding anhydrous K with CAPIC in acetonitrile 3 PO 4 Amidation, addition of a strong base such as NaH or NaH-MDS, and cyclization of nevirapine in an inert solvent such as toluene or THF. However, the last step of the process adopts NaH or NaH-DMS with high price, and the raw material has cyano group which is toxic, so that the process has environmental pollution and is not beneficial to mass production. The synthetic route is as follows:
from the above, the prior process for preparing nevirapine has many disadvantages. Therefore, research and search for a process suitable for industrial production of nevirapine with mild reaction conditions, simple operation process, high product yield and high purity still needs to be solved.
Disclosure of Invention
Aiming at the problems of the existing nevirapine preparation technology, the invention provides a novel nevirapine intermediate compound and a method for preparing nevirapine by utilizing the novel intermediate, the method has mild reaction conditions and simple operation process, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
the first aspect of the invention provides a nevirapine novel intermediate compound, which has a structure shown in a formula I-3:
the second aspect of the invention provides a preparation method of a nevirapine intermediate compound I-3, which is characterized by comprising the following steps:
step 1: temperature control T A1 Adding 2, 6-tetramethyl piperidine and n-butyl lithium into dry tetrahydrofuran solution, adding tetramethyl ethylenediamine, copper catalyst, SM-1, and controlling temperature T A2 Adding compound SM-2, and controlling temperature T A3 After the reaction is finished, the compound I-1 is prepared through post-treatment;
step 2: controlling the temperature T of the mixture of the compound I-1 and the cyclopropylamine B1 After the reaction is detected, methylene dichloride is added for dilution, filtration is carried out, filtrate is concentrated to dryness under reduced pressure, then organic solvent B is used for dissolution, sodium hydride is added, and temperature T is controlled B2 Reacting, and after the detection reaction is finished, preparing a compound I-2 through post-treatment;
step 3: adding compound I-2, hydroxylamine hydrochloride and alkali into the reaction solvent C, and controlling the temperature T C After the reaction is detected, filtering is carried out, and the obtained filter cake is decompressed and dried to obtain an intermediate compound I-3;
the synthetic route is as follows:
preferably, the copper catalyst in step 1 is selected from one of cuprous chloride, cuprous bromide and cuprous iodide.
Preferably, the molar ratio of compound SM-1 to 2, 6-tetramethylpiperidine, n-butyllithium, tetramethylethylenediamine, copper catalyst, compound SM-2 in step 1 is 1:1.8 to 2.5:1.8 to 2.5:0.8 to 1.5:0.8 to 1.5:1.2 to 1.6, preferably 1:2.0:2.0:1.0:1.0:1.5.
preferably, the reaction temperature T described in step 1 A1 Is at-10 to 10 ℃, preferably 0 to 5 ℃; t (T) A2 15-30 ℃, preferably 20-25 ℃; t (T) A3 The temperature is 40 to 66℃and preferably 55 to 60 ℃.
Preferably, the feeding mole ratio of the compound I-1 to cyclopropylamine and sodium hydride in the step 2 is 1:1.5 to 2.5:1.0 to 1.5, preferably 1:2.0:1.0.
preferably, the organic solvent B in step 2 is selected from one or a combination of tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol diethyl ether, preferably N, N-dimethylformamide.
Preferably, the reaction temperature T described in step 2 B1 60 to 100 ℃, preferably 75 to 80 ℃; t (T) B2 15 to 40℃and preferably 20 to 25 ℃.
Preferably, the base in step 3 is selected from one of sodium acetate, potassium acetate, triethylamine and sodium carbonate, preferably sodium acetate.
Preferably, the reaction solvent C in the step 3 is selected from one or a combination of methanol, ethanol, tetrahydrofuran, acetonitrile, 1, 4-dioxane and water.
Preferably, the feeding mole ratio of the compound I-1 to hydroxylamine hydrochloride to alkali in the step 3 is 1:1.2 to 1.8:1.2 to 1.8, preferably 1:1.5:1.5.
preferably, the reaction temperature T described in step 3 C 60 to 90℃and preferably 75 to 80 ℃.
In a preferred embodiment, after the reaction is completed, a post-treatment operation is performed, and the post-treatment in step 1 specifically includes: cooling the reaction solution to room temperature, then adding 1M NaOH aqueous solution to quench the reaction solution, extracting with methyl tert-butyl ether, and saturating with NH 4 The organic phase was washed with aqueous Cl and dried over anhydrous Na 2 SO 4 After drying, the organic phase is concentrated to dryness under reduced pressure, namely the compound I-1; the post-treatment step of the step 2 is as follows: cooling the reaction liquid to room temperature, adding water for quenching reaction, extracting with dichloromethaneWashing an organic phase with saturated saline, and concentrating under reduced pressure until the organic phase is dried to obtain a compound SM-1; the post-treatment of the step 3 is as follows: the reaction solution is filtered, and the obtained filter cake is decompressed and dried to obtain the intermediate I-3.
In a third aspect, the invention provides the use of a new intermediate compound I-3 of nevirapine for preparing nevirapine.
Use of nevirapine novel intermediate compound I-3 for preparing nevirapine, the preparation method comprising the steps of: adding compound I-3, p-toluenesulfonic acid and Lewis acid into organic solvent D at room temperature, and controlling temperature T D After the reaction is detected, the target product I is prepared through post-treatment, and the reaction route is as follows:
preferably, the organic solvent D is selected from one or a combination of acetonitrile, propionitrile and nitromethane, preferably acetonitrile.
Preferably, the Lewis acid is selected from ZnCl 2 、SnCl 4 、FeCl 3 、InCl 2 One of them, preferably ZnCl 2 。
Preferably, the feeding mole ratio of the compound I-1 to the p-toluenesulfonic acid and the Lewis acid is 1:0.05 to 0.15:0.05 to 0.15, preferably 1:0.1:0.1.
preferably, the reaction temperature T D 60 to 90℃and preferably 75 to 80 ℃.
Preferably, the post-treatment is: after the reaction is finished, the reaction is quenched by saturated sodium bicarbonate solution, extracted by an organic solvent, dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain the compound I, wherein the extractant is one or a combination of dichloromethane, chloroform, ethyl acetate and methyl tertiary butyl ether, and dichloromethane is preferred.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a new intermediate compound I-3 of nevirapine, which is used as a starting material for preparing nevirapine, and an amide bond is constructed through a simple rearrangement reaction, so that the generation of ring-opening side reaction in the final cyclization preparation in the prior art can be effectively avoided;
(2) when the compound I-3 is prepared by the process, the reaction temperature can be effectively reduced, the operation is more suitable for industrial production, no further separation and purification are needed, and related products can be directly prepared by a one-pot method after simple post-treatment, so that the unit operation is simplified;
(3) the target product obtained by the process has higher purity and yield, and is suitable for industrial scale-up production.
In summary, the invention provides a novel method for preparing nevirapine, which has simple synthesis operation, high yield and purity and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
The invention adopts HPLC to measure the purity of nevirapine, and the chromatographic conditions are as follows:
chromatographic column: supelco LC-ABE C 18 Columns (4.6 mm. Times.150 mm,5 μm) or columns of comparable performance;
mobile phase: acetonitrile: 25mmol/L monoammonium phosphate (pH 5.0 with sodium hydroxide) (25:75);
isocratic elution;
column temperature: 35 ℃;
detection wavelength: 220nm;
flow rate: 0.8ml/min;
sample injection amount: 20 μl;
the structure of the compound I-1 obtained by the invention is confirmed as follows:
ESI-HRMS(m/z):267.0084、269.0053[M+H] + ； 1 H NMR(400MHz，DMSO-d 6 )δ：8.51(d,J＝6.8Hz,1H),8.47(dd,J＝6.4、1.2Hz,1H),8.26(dd,J＝6.4、1.2Hz,1H),7.63～7.67(m,2H),2.51(s,3H)； 13 C NMR(101MHz,DMSO-d 6 )δ：181.73,153.60,152.92,150.87,150.79,150.15,138.89,135.67,133.55,125.15,120.91,19.96。
the structure of the compound I-2 obtained by the invention is confirmed as follows:
ESI-HRMS(m/z):252.1128[M+H] + ； 1 H NMR(400MHz,DMSO-d 6 )δ：8.52(dd,J＝6.4、1.2Hz,1H),8.27(d,J＝6.5Hz,1H),8.05(dd,J＝6.8、1.3Hz,1H),6.92～6.95(m,2H),3.02～3.05(m,1H),2.44(s,3H),0.69～0.73(m,2H),0.38～0.41(m,2H)； 13 C NMR(101MHz,DMSO-d 6 )δ：181.68,156.51,155.24,151.92,149.71,144.48,132.79,116.63,115.94,114.37,112.66,33.63,19.93,10.56。
the structure of the compound I-3 obtained by the invention is confirmed as follows:
ESI-HRMS(m/z):265.1057[M-H] - ； 1 H NMR(400MHz,DMSO-d 6 )δ：8.51(dd,J＝6.8、1.4Hz,1H),8.33(d,J＝6.6Hz,1H),7.96(dd,J＝7.2、1.6Hz,1H),7.01～7.05(m,2H),2.98～3.02(m,1H),2.39(s,3H),0.72～0.76(m,2H),0.35～0.38(m,2H)； 13 C NMR(101MHz,DMSO-d 6 )δ：154.51,152.69,146.73,145.82,144.40,135.17,133.26,116.74,115.57,115.03,106.52,33.78,20.57,10.36。
the structure of the compound I obtained by the invention is confirmed as follows:
ESI-HRMS(m/z):267.1238[M+H] + ； 1 H NMR(400MHz,DMSO-d 6 )δ：9.90(s,1H),8.41(dd,J＝4.8、1.7Hz,1H),8.23(d,J＝4.8Hz,1H),8.13(dd,J＝7.9、1.7Hz,1H),7.43(d,J＝5.0Hz,1H),6.85(dd,J＝7.6、4.8Hz,1H),2.88～2.93(m,1H),2.27(s,3H),0.73～0.78(m,2H),0.35～0.38(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ：166.19,158.75,150.06,149.44,147.36,146.16,136.03,129.60,125.90,111.21,108.41,23.82,18.24,6.54.
in the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
Synthesis of Compound I-1
Example 1
2, 6-tetramethylpiperidine (14.13 g,0.1 mol) and n-butyllithium (1.6M hexane solution, 0.1 mol) are added into dry tetrahydrofuran (120 ml), tetramethyl ethylenediamine (5.81 g,0.05 mol) and CuCl (4.95 g,0.05 mol) are added, after stirring and mixing uniformly, compound SM-1 (6.38 g,0.05 mol) is added, stirring is continued for 30min, after controlling the temperature to 20-25 ℃, compound SM-2 (13.20 g,0.075 mol) is added, the temperature to 55-60 ℃ is controlled for reaction, after detection reaction is completed, the reaction solution is cooled to room temperature, then 1M NaOH aqueous solution is added to quench the reaction solution, methyl tertiary butyl ether (50 ml multiplied by 3) is extracted, and saturated NH is saturated 4 Aqueous Cl (50 ml. Times.2) was used to wash the organic phase and anhydrous Na 2 SO 4 After drying, the organic phase was concentrated to dryness under reduced pressure to give Compound I-1 in a yield of 95.9% and an HPLC purity of 99.95%.
Example 2
2, 6-tetramethylpiperidine (12.71 g,0.09 mol) and N-butyllithium (1.6M hexane solution, 0.09 mol) are added into a dry tetrahydrofuran (120 ml) solution, tetramethyl ethylenediamine (5.81 g,0.05 mol) and CuBr (7.17 g,0.05 mol) are added, the mixture is stirred and mixed uniformly, compound SM-1 (6.38 g,0.05 mol) is added, stirring is continued for 30min, compound SM-2 (10.56 g,0.06 mol) is added at a temperature of 15-20 ℃, the temperature of 40-45 ℃ is controlled for reaction, after the detection reaction is completed, the reaction solution is cooled to room temperature, then 1M NaOH aqueous solution is added to quench the reaction solution, methyl tert-butyl ether (50 ml. Times.3) is extracted, and saturated N is extractedH 4 Aqueous Cl (50 ml. Times.2) was used to wash the organic phase and anhydrous Na 2 SO 4 After drying, the organic phase was concentrated to dryness under reduced pressure to give Compound I-1 in 92.4% yield and 99.61% purity by HPLC.
Example 3
Controlling the temperature to be 5-10 ℃, adding 2, 6-tetramethylpiperidine (12.71 g,0.09 mol) and n-butyllithium (1.6M hexane solution, 0.09 mol) into a dry tetrahydrofuran (120 ml), adding tetramethyl ethylenediamine (5.81 g,0.05 mol) and CuBr (7.17 g,0.05 mol), stirring and mixing uniformly, adding a compound SM-1 (6.38 g,0.05 mol), continuously stirring for 30min, controlling the temperature to be 25-30 ℃ and adding a compound SM-2 (14.08 g,0.08 mol), controlling the temperature to be 60-66 ℃ for reaction, cooling the reaction solution to room temperature after detection reaction is finished, adding a 1M NaOH aqueous solution to quench the reaction solution, extracting methyl tertiary butyl ether (50 ml multiplied by 3), and saturating NH 4 Aqueous Cl (50 ml. Times.2) was used to wash the organic phase and anhydrous Na 2 SO 4 After drying, the organic phase was concentrated to dryness under reduced pressure to give Compound I-1 in 93.0% yield and 99.52% purity by HPLC.
Example 4
2, 6-tetramethylpiperidine (14.13 g,0.1 mol) and n-butyllithium (1.6M hexane solution, 0.1 mol) are added into dry tetrahydrofuran (120 ml), tetramethyl ethylenediamine (4.65 g,0.04 mol) and CuCl (4.95 g,0.05 mol) are added, after stirring and mixing evenly, compound SM-1 (6.38 g,0.05 mol) is added, stirring is continued for 30min, compound SM-2 (13.20 g,0.075 mol) is added at a temperature of 25-30 ℃, the temperature of 45-50 ℃ is controlled for reaction, after detection reaction is completed, the reaction solution is cooled to room temperature, 1M NaOH aqueous solution is added to quench the reaction solution, methyl tert-butyl ether (50 ml×3) is extracted, saturated NH is saturated 4 Aqueous Cl (50 ml. Times.2) was used to wash the organic phase and anhydrous Na 2 SO 4 After drying, the organic phase was concentrated to dryness under reduced pressure to give Compound I-1 in 91.2% yield and 99.70% purity by HPLC.
Example 5
2, 6-tetramethylpiperidine (14.13 g,0.1 mol) and n-butyllithium (1.6M hexane solution, 0.1 mol) were added to a dry tetrahydrofuran (120 ml) solution, tetramethyl ethylenediamine (8.72 g,0.075 mol) and CuI (9.52 g,0.05 mol) were added, and after stirring and mixing,adding compound SM-1 (6.38 g,0.05 mol), stirring for 30min, adding compound SM-2 (13.20 g,0.075 mol) at 25-30deg.C, reacting at 60-66 deg.C, cooling the reaction solution to room temperature after detecting the reaction, adding 1M NaOH aqueous solution to quench the reaction solution, extracting with methyl tert-butyl ether (50 ml×3), and saturating NH 4 Aqueous Cl (50 ml. Times.2) was used to wash the organic phase and anhydrous Na 2 SO 4 After drying, the organic phase was concentrated to dryness under reduced pressure to give Compound I-1 in 92.2% yield and 99.55% purity by HPLC.
Example 6
2, 6-tetramethylpiperidine (12.71 g,0.09 mol) and n-butyllithium (1.6M hexane solution, 0.09 mol) were added to a dry tetrahydrofuran (120 ml) solution at a temperature of-10-5 ℃, tetramethylethylenediamine (5.81 g,0.05 mol) and CuCl (3.96 g,0.04 mol) were added, stirred and mixed uniformly, then compound SM-1 (6.38 g,0.05 mol) was added, stirring was continued for 30 minutes, then compound SM-2 (13.20 g,0.075 mol) was added at a temperature of 25-30 ℃, a reaction was carried out at a temperature of 60-66 ℃, after the completion of the detection reaction, the reaction solution was cooled to room temperature, then 1M NaOH aqueous solution was added to quench the reaction solution, methyl tert-butyl ether (50 ml. Times.3) was extracted, saturated NH was obtained 4 Aqueous Cl (50 ml. Times.2) was used to wash the organic phase and anhydrous Na 2 SO 4 After drying, the organic phase was concentrated to dryness under reduced pressure to give Compound I-1 in a yield of 90.9% and an HPLC purity of 99.71%.
Example 7
Controlling the temperature to be 5-10 ℃, adding 2, 6-tetramethylpiperidine (17.66 g,0.125 mol) and n-butyllithium (1.6M hexane solution, 0.125 mol) into dry tetrahydrofuran (120 ml), adding tetramethyl ethylenediamine (8.72 g,0.075 mol) and CuCl (7.43 g,0.075 mol), stirring and mixing uniformly, adding compound SM-1 (6.38 g,0.05 mol), continuously stirring for 30min, controlling the temperature to be 25-30 ℃ and adding compound SM-2 (13.20 g,0.075 mol), controlling the temperature to be 60-66 ℃ for reaction, cooling the reaction solution to room temperature after detection reaction, adding 1M NaOH aqueous solution to quench the reaction solution, extracting methyl tertiary butyl ether (50 ml multiplied by 3), and saturating NH 4 Aqueous Cl (50 ml. Times.2) was used to wash the organic phase and anhydrous Na 2 SO 4 After drying, the organic phase was concentrated to dryness under reduced pressure to give Compound I-1 in 93.1% yield and 99.45% purity by HPLC.
Example 8
2, 6-tetramethylpiperidine (10.60 g,0.075 mol) and n-butyllithium (1.6M hexane solution, 0.075 mol) are added into dry tetrahydrofuran (120 ml), tetramethylethylenediamine (3.49 g,0.03 mol) and CuCl (2.97 g,0.03 mol) are added, stirring and mixing are carried out uniformly, compound SM-1 (6.38 g,0.05 mol) is added, stirring is continued for 30min, compound SM-2 (8.80 g,0.05 mol) is added at a temperature of 10-15 ℃, reaction is carried out at a temperature of 35-40 ℃, after detection reaction is carried out, the reaction solution is cooled to room temperature, 1M NaOH aqueous solution is added to quench the reaction solution, methyl tert-butyl ether (50 ml. Times.3) is extracted, saturated NH 4 Aqueous Cl (50 ml. Times.2) was used to wash the organic phase and anhydrous Na 2 SO 4 After drying, the organic phase was concentrated to dryness under reduced pressure to give Compound I-1 in 85.2% yield and 98.65% purity by HPLC.
Example 9
2, 6-tetramethylpiperidine (19.07 g,0.135 mol) and n-butyllithium (1.6M hexane solution, 0.135 mol) are added into dry tetrahydrofuran (120 ml), tetramethyl ethylenediamine (10.46 g,0.09 mol) and CuCl (8.91 g,0.09 mol) are added, after stirring and mixing uniformly, compound SM-1 (6.38 g,0.05 mol) is added, stirring is continued for 30min, after stirring for 30min, compound SM-2 (15.84 g,0.09 mol) is added at 30-35 ℃, temperature is controlled for 66-70 ℃ for reaction, after detection reaction is completed, the reaction solution is cooled to room temperature, 1M NaOH aqueous solution is added to quench the reaction solution, methyl tertiary butyl ether (50 ml×3) is extracted, and NH is saturated 4 Aqueous Cl (50 ml. Times.2) was used to wash the organic phase and anhydrous Na 2 SO 4 After drying, the organic phase was concentrated to dryness under reduced pressure to give Compound I-1 in 86.6% yield and 97.89% purity by HPLC.
Synthesis of Compound I-2
Example 10
In a closed device, a mixture of a compound I-1 (26.71 g,0.1 mol) and cyclopropylamine (11.42 g,0.2 mol) is reacted at a temperature of 75-80 ℃, after the detection reaction is finished, dichloromethane (500 ml multiplied by 2) is added for dilution, filtration, the filtrate is concentrated to dryness under reduced pressure, then N, N-dimethylformamide (300 ml) is used for dissolution, naH (2.40 g,0.1 mol) is added for reaction at a temperature of 20-25 ℃, after the detection reaction is finished, the reaction solution is cooled to room temperature, water quenching reaction is added, dichloromethane (200 ml multiplied by 3) is extracted, an organic phase saturated saline solution (200 ml multiplied by 2) is washed, and the organic phase is concentrated to dryness under reduced pressure, thus obtaining the compound I-2, the yield is 97.6%, and the HPLC purity is 99.89%.
Example 11
In a closed device, a mixture of a compound I-1 (26.71 g,0.1 mol) and cyclopropylamine (8.56 g,0.15 mol) is reacted at a temperature of 60-65 ℃, after the detection reaction is finished, dichloromethane (500 ml multiplied by 2) is added for dilution, filtration, the filtrate is decompressed and concentrated to dryness, then N, N-dimethylacetamide (300 ml) is used for dissolution, naH (2.40 g,0.1 mol) is added for reaction at a temperature of 15-20 ℃, after the detection reaction is finished, the reaction solution is cooled to room temperature, water quenching reaction is added, dichloromethane (200 ml multiplied by 3) is extracted, an organic phase saturated saline solution (200 ml multiplied by 2) is washed, and the organic phase is decompressed and concentrated to dryness to obtain the compound I-2, the yield is 93.2%, and the HPLC purity is 99.62%.
Example 12
In a closed device, a mixture of a compound I-1 (26.71 g,0.1 mol) and cyclopropylamine (14.27 g,0.25 mol) is reacted at a temperature of 95-100 ℃, after the detection reaction is finished, dichloromethane (500 ml multiplied by 2) is added for dilution, filtration, the filtrate is decompressed and concentrated to dryness, then 1, 4-dioxane (300 ml) is used for dissolution, naH (2.40 g,0.1 mol) is added for reaction at a temperature of 35-40 ℃, after the detection reaction is finished, the reaction solution is cooled to room temperature, water quenching reaction is added, dichloromethane (200 ml multiplied by 3) is extracted, an organic phase saturated saline solution (200 ml multiplied by 2) is washed, and the organic phase is decompressed and concentrated to dryness to obtain the compound I-2, the yield is 95.1%, and the HPLC purity is 99.41%.
Example 13
In a closed device, a mixture of a compound I-1 (26.71 g,0.1 mol) and cyclopropylamine (11.42 g,0.2 mol) is reacted at a temperature of 75-80 ℃, after detection reaction is finished, dichloromethane (500 ml multiplied by 2) is added for dilution, filtration, filtrate is decompressed and concentrated to dryness, then is dissolved by ethylene glycol dimethyl ether (300 ml), naH (3.60 g,0.15 mol) is added for reaction at a temperature of 20-25 ℃, after detection reaction is finished, the reaction solution is cooled to room temperature, water quenching reaction is added, dichloromethane (200 ml multiplied by 3) is extracted, an organic phase saturated saline (200 ml multiplied by 2) is washed, and an organic phase is decompressed and concentrated to dryness to obtain the compound I-2, the yield is 93.6%, and the HPLC purity is 99.44%.
Example 14
In a closed device, a mixture of a compound I-1 (26.71 g,0.1 mol) and cyclopropylamine (9.14 g,0.16 mol) is reacted at a temperature of 55-60 ℃, after detection reaction is finished, dichloromethane (500 ml multiplied by 2) is added for dilution, filtration, concentration of filtrate under reduced pressure is carried out to dryness, diethylene glycol dimethyl ether (300 ml) is used for dissolution, naH (3.60 g,0.15 mol) is added for reaction at a temperature of 10-15 ℃, after detection reaction is finished, the reaction solution is cooled to room temperature, water quenching reaction is added, dichloromethane (200 ml multiplied by 3) is used for extraction, organic phase saturated saline (200 ml multiplied by 2) is used for washing, and organic phase is concentrated under reduced pressure to dryness to obtain the compound I-2, the yield is 89.0%, and the HPLC purity is 98.84%.
Example 15
In a closed device, a mixture of a compound I-1 (26.71 g,0.1 mol) and cyclopropylamine (15.42 g,0.27 mol) is reacted at a temperature of 100-105 ℃, after detection reaction is finished, dichloromethane (500 ml multiplied by 2) is added for dilution, filtration, concentration of filtrate under reduced pressure is carried out to dryness, diethylene glycol diethyl ether (300 ml) is used for dissolution, naH (4.08 g,0.17 mol) is added for reaction at a temperature of 40-45 ℃, after detection reaction is finished, the reaction solution is cooled to room temperature, water quenching reaction is added, dichloromethane (200 ml multiplied by 3) is used for extraction, organic phase saturated saline (200 ml multiplied by 2) is used for washing, and organic phase is concentrated under reduced pressure to dryness to obtain the compound I-2, the yield is 86.8%, and the HPLC purity is 97.85%.
Synthesis of Compound I-3
Example 16
At room temperature, compound I-2 (25.13 g,0.10 mol), hydroxylamine hydrochloride (10.42 g,0.15 mol), sodium acetate (12.31 g,0.15 mol) were added to ethanol/water (V Ethanol :V Water and its preparation method =1:1, 300 ml), controlling the temperature to be 75-80 ℃ for reaction, filtering after the detection reaction is finished, and drying the obtained filter cake under reduced pressure to obtain an intermediate I-3, wherein the yield is 95.3%, and the HPLC purity is 99.89%.
Example 17
Compound I-2 (25.13 g,0.10 mol), hydroxylamine hydrochloride (8.34 g,0.12 mol), potassium acetate (14.72 g,0.15 mol) were added to methanol/water (V Methanol :V Water and its preparation method =1:1, 300 ml), controlling the temperature to be 60-65 ℃ for reaction, filtering after the detection reaction is finishedThe obtained filter cake is dried under reduced pressure to obtain the intermediate I-3, the yield is 92.2%, and the HPLC purity is 99.61%.
Example 18
Compound I-2 (25.13 g,0.10 mol), hydroxylamine hydrochloride (12.51 g,0.18 mol), triethylamine (15.18 g,0.15 mol) were added to tetrahydrofuran/water (V Tetrahydrofuran (THF) :V Water and its preparation method =1:1, 300 ml), controlling the temperature to be 85-90 ℃ for reaction, filtering after the detection reaction is finished, and drying the obtained filter cake under reduced pressure to obtain an intermediate I-3, wherein the yield is 93.1% and the HPLC purity is 99.51%.
Example 19
Compound I-2 (25.13 g,0.10 mol), hydroxylamine hydrochloride (10.42 g,0.15 mol), sodium carbonate (12.72 g,0.12 mol) were added to acetonitrile/water (V Acetonitrile :V Water and its preparation method =1:1, 300 ml), controlling the temperature to be 75-80 ℃ for reaction, filtering after the detection reaction is finished, and drying the obtained filter cake under reduced pressure to obtain an intermediate I-3, wherein the yield is 90.1%, and the HPLC purity is 99.42%.
Example 20
Compound I-2 (25.13 g,0.10 mol), hydroxylamine hydrochloride (10.42 g,0.15 mol) and sodium acetate (14.77 g,0.18 mol) were added to water (300 ml) at room temperature, the temperature was controlled at 85-90 ℃ for reaction, after completion of the detection reaction, filtration was carried out, and the obtained cake was dried under reduced pressure to obtain intermediate I-3, yield 92.3% and HPLC purity 99.33%.
Example 21
Compound I-2 (25.13 g,0.10 mol), hydroxylamine hydrochloride (6.95 g,0.1 mol), sodium acetate (8.20 g,0.1 mol) were added to ethanol/water (V) Ethanol :V Water and its preparation method =1:1, 300 ml), controlling the temperature to be 55-60 ℃ for reaction, filtering after the detection reaction is finished, and drying the obtained filter cake under reduced pressure to obtain an intermediate I-3, wherein the yield is 84.6%, and the HPLC purity is 98.79%.
Example 22
Compound I-2 (25.13 g,0.10 mol), hydroxylamine hydrochloride (13.90 g,0.2 mol), sodium acetate (16.40 g,0.2 mol) were added to 1, 4-dioxane/water (V) 1, 4-Dioxahexacyclic ring :V Water and its preparation method =1:1, 300 ml), controlling the temperature to be 90-95 ℃ for reaction, filtering after the detection reaction is finished, and drying the obtained filter cake under reduced pressure to obtain the intermediateThe yield of the body I-3 was 88.6%, and the HPLC purity was 97.66%.
Preparation of Compound I
Example 23
Compound I-3 (13.32 g,0.05 mol), p-toluenesulfonic acid (0.86 g,5 mmol) was added to dry acetonitrile (130 ml), znCl was added at room temperature 2 (0.68 g,0.005 mol), controlling the temperature to be 75-80 ℃, quenching the reaction by using saturated sodium bicarbonate solution after the detection reaction is finished, extracting methylene dichloride (100 ml multiplied by 3), drying anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dried, thus obtaining the compound I, the yield is 97.6%, and the HPLC purity is 99.98%.
Example 24
Compound I-3 (13.32 g,0.05 mol), p-toluenesulfonic acid (0.43 g,2.5 mmol) was added to dry propionitrile (130 ml), snCl was added at room temperature 4 (1.30 g,0.005 mol), controlling the temperature to be 60-65 ℃, quenching the reaction by using saturated sodium bicarbonate solution after the detection reaction is finished, extracting by using chloroform (100 ml multiplied by 3), drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dried, thus obtaining the compound I, the yield is 93.3%, and the HPLC purity is 99.62%.
Example 25
Compound I-3 (13.32 g,0.05 mol), p-toluenesulfonic acid (1.29 g,7.5 mmol) was added to dry nitromethane (130 ml) at room temperature, feCl was added 3 (0.81 g,0.005 mol), controlling the temperature to be 85-90 ℃, quenching the reaction by using saturated sodium bicarbonate solution after the detection reaction is finished, extracting by using ethyl acetate (100 ml multiplied by 3), drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dried, thus obtaining the compound I, wherein the yield is 94.1%, and the HPLC purity is 99.41%.
Example 26
Compound I-3 (13.32 g,0.05 mol), p-toluenesulfonic acid (0.86 g,5 mmol) was added to dry acetonitrile (130 ml), znCl was added at room temperature 2 (0.34 g,2.5 mmol), controlling the temperature to be 60-65 ℃, quenching the reaction by using saturated sodium bicarbonate solution after the detection reaction is finished, extracting methyl tertiary butyl ether (100 ml multiplied by 3), drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dried, thus obtaining the compound I, wherein the yield is 92.4%, and the HPLC purity is 99.60%.
Example 27
Compound I-3 (13.32 g,0.05 mol), p-toluenesulfonic acid (0.86 g,5 mmol) was added to dry nitromethane (130 ml) at room temperature, znCl was added 2 (1.02 g,7.5 mmol), controlling the temperature to be 85-90 ℃, quenching the reaction by using saturated sodium bicarbonate solution after the detection reaction is finished, extracting methyl tertiary butyl ether (100 ml multiplied by 3), drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dried, thus obtaining the compound I, wherein the yield is 93.1%, and the HPLC purity is 99.41%.
Example 28
Compound I-3 (13.32 g,0.05 mol), p-toluenesulfonic acid (0.26 g,1.5 mmol) was added to dry acetonitrile (130 ml), znCl was added at room temperature 2 (0.20 g,1.5 mmol), controlling the temperature to 55-60 ℃, quenching the reaction by using saturated sodium bicarbonate solution after the detection reaction is finished, extracting methylene dichloride (100 ml multiplied by 3), drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dried, thus obtaining the compound I, the yield is 85.3%, and the HPLC purity is 98.65%.
Example 29
Compound I-3 (13.32 g,0.05 mol), p-toluenesulfonic acid (1.46 g,8.5 mmol) was added to dry nitromethane (130 ml) at room temperature, inCl was added 2 (1.58 g,8.5 mmol), controlling the temperature to be 90-95 ℃, quenching the reaction by using saturated sodium bicarbonate solution after the detection reaction is finished, extracting methylene dichloride (100 ml multiplied by 3), drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dried, thus obtaining the compound I, the yield is 88.2%, and the HPLC purity is 97.55%.

Claims (10)

1. The nevirapine intermediate compound is characterized in that the structure is shown as a formula I-3:
2. a process for the preparation of nevirapine intermediate compound I-3 according to claim 1, comprising the steps of:
step 1: temperature control T A1 Adding 2, 6-tetramethyl piperidine and n-butyl lithium into dry tetrahydrofuran solution, adding tetramethyl ethylenediamine, copper catalyst, SM-1, and controlling temperature T A2 Adding compound SM-2, and controlling temperature T A3 After the reaction is finished, the compound I-1 is prepared through post-treatment;
step 2: controlling the temperature T of the mixture of the compound I-1 and the cyclopropylamine B1 After the reaction is detected, methylene dichloride is added for dilution, filtration is carried out, filtrate is concentrated to dryness under reduced pressure, then organic solvent B is used for dissolution, sodium hydride is added, and temperature T is controlled B2 Reacting, and after the detection reaction is finished, preparing a compound I-2 through post-treatment;
step 3: adding compound I-2, hydroxylamine hydrochloride and alkali into the reaction solvent C, and controlling the temperature T C After the reaction is detected, filtering is carried out, and the obtained filter cake is decompressed and dried to obtain an intermediate compound I-3;
the synthetic route is as follows:
3. the method of claim 2, wherein the copper catalyst in step 1 is one selected from the group consisting of cuprous chloride, cuprous bromide, and cuprous iodide.
4. The preparation method according to claim 2, wherein the feeding mole ratio of the compound SM-1 to the 2, 6-tetramethylpiperidine, n-butyllithium, tetramethylethylenediamine, copper catalyst and the compound SM-2 in the step 1 is 1:1.8 to 2.5:1.8 to 2.5:0.8 to 1.5:0.8 to 1.5:1.2 to 1.6; reaction temperature T described in step 1 A1 Is-10 to 10 percent; t (T) A2 15-30 ℃; t (T) A3 Is 40-66 ℃.
5. The preparation method according to claim 2, wherein the compound I-1 in step 2 is added with cyclopropylamine and sodium hydrideThe molar ratio is 1:1.5 to 2.5:1.0 to 1.5; the organic solvent B in the step 2 is selected from one or a combination of tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; reaction temperature T as described in step 2 B1 At 60-100 ℃, T B2 15-40 ℃.
6. The preparation method according to claim 2, wherein the base in the step 3 is one selected from sodium acetate, potassium acetate, triethylamine and sodium carbonate; the reaction solvent C in the step 3 is selected from one or a combination of methanol, ethanol, tetrahydrofuran, acetonitrile, 1, 4-dioxane and water; the feeding mole ratio of the compound I-1 to hydroxylamine hydrochloride to alkali in the step 3 is 1:1.2 to 1.8:1.2 to 1.8; reaction temperature T described in step 3 C 60-90 ℃.
7. Use of a nevirapine intermediate compound of claim 1 for the preparation of nevirapine.
8. Use of a nevirapine intermediate compound according to claim 7 for the preparation of nevirapine, characterized in that the preparation process comprises the steps of: adding compound I-3, p-toluenesulfonic acid and Lewis acid into organic solvent D at room temperature, and controlling temperature T D After the reaction is detected, the target product I is prepared through post-treatment, and the synthetic route is as follows:
9. the use according to claim 8, wherein the Lewis acid is selected from ZnCl 2 、SnCl 4 、FeCl 3 、InCl 2 One of them.
10. According to claim 8The application is characterized in that the organic solvent D is one of acetonitrile, propionitrile and nitromethane; the feeding mole ratio of the compound I-1 to p-toluenesulfonic acid to Lewis acid is 1:0.05 to 0.15:0.05 to 0.15; the reaction temperature T D 60-90 ℃.
CN202210368282.5A 2022-04-02 2022-04-02 Nevirapine intermediate compound and preparation method and application thereof Pending CN116925076A (en)

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