CN110903245B - Key intermediate for synthesizing 1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole and preparation method thereof - Google Patents
Key intermediate for synthesizing 1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a key intermediate for synthesizing 1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole and a preparation method thereof, mainly solving the technical problem of lack of a synthesis process of 1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole, and comprising the following steps: taking a compound II (2-trifluoromethyl benzimidazole) as a raw material, and carrying out alkylation to generate a compound III; oxidizing to open benzene ring to obtain diacid compound IV; esterifying the compound IV to generate a compound V; then hydrolyzing to obtain a compound VI; compound VI is rearranged into compound VII through curtius; hydrolyzing an ester group of the compound VII to generate a compound VIII; finally decarboxylating and removing the tert-butyloxycarbonyl to obtain the compound I (1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole).
Description
Technical Field
The invention relates to the field of synthesis of drug intermediates, in particular to a key intermediate for synthesizing 1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole and a preparation method and application thereof.
Background
Imidazole compounds widely exist in alkaloids and amino acids in human bodies, are important structural units in the human bodies, and have important influence on the functions of the human bodies; imidazole compounds have important application in the field of medicine, for example, a second generation antihistamine mizolastine prepared by the imidazole compounds has good curative effect on allergic rhinitis and chronic idiopathic urticaria; levamisole can be used for treating chronic hepatitis B and chronic aplastic anemia; the imidazole tranquilizer has the advantages of strong drug effect, small side effect on cardiovascular vessels, and the like, and can be widely applied to safe tranquilization in various conditions, particularly operative sedation and analgesia and epilepsy treatment; albendazole is commonly used in the treatment of a variety of parasites in any animal. Therefore, the imidazole compound has wide application prospect, and the trifluoromethyl is introduced into the imidazole ring, so that the acidity, dipole moment, fat solubility, membrane permeability and chemical and metabolic stability of molecules can be effectively changed.
1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole is an imidazole compound containing a trifluoromethyl substituent with application value, and as reported in the international publication of WO2010132404A1, 1-methyl-2-trifluoromethyl-5-amino-1H-imidazole can be used for preparing halogenated alkyl heteroaryl benzoyl compounds (compound IX/compound X), and the compounds show strong activity to hepatitis viruses.
At present, no literature report exists on a synthesis method of 1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole, so that the development of a synthesis route which has the advantages of readily available raw materials, convenient operation, easily controlled reaction and proper overall yield is necessary.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a synthesis method of 1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole, which mainly solves the technical blank of the existing preparation method. Provides a synthesis route which has the advantages of easily obtained raw materials, convenient operation, easily controlled reaction and proper overall yield.
Taking a compound II (2-trifluoromethyl benzimidazole) as a raw material, and carrying out alkylation to generate a compound III; oxidizing to open benzene ring to obtain diacid compound IV; esterifying the compound IV to generate a compound V; then hydrolyzing to obtain a compound VI; compound VI is rearranged into compound VII through curtius; hydrolyzing an ester group of the compound VII to generate a compound VIII; finally decarboxylation and removal of tert-butyloxycarbonyl are carried out to obtain the compound I (1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole).
In one aspect, the present invention discloses compounds of structural formula (VII) and formula (VIII):
wherein: r is 1 Is methyl, ethyl or isopropyl; r is 2 Is methyl or ethyl.
In another aspect, the present invention provides a process for the preparation of compound VIII, comprising:
wherein: r is 1 Is methyl, ethyl or isopropyl; r 2 Is methyl or ethyl.
In another aspect, the present invention provides a process for the preparation of compound VIII, comprising:
wherein: r is 1 Is methyl, ethyl or isopropyl; r 2 Is methyl or ethyl.
Preferably, in the step of preparing compound III from compound II, the alkyl iodide is selected from methyl iodide, ethyl iodide or isopropyl iodide; the base 1 is selected from potassium carbonate, cesium carbonate, potassium tert-butoxide or sodium hydride;
preferably, in the step of preparing compound VI from compound V, the base 2 is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.
Preferably, in the step of preparing the compound VII from the compound VI, the base 1 is triethylamine or N, N-diisopropylethylamine; the reaction temperature range is 100-120 ℃; the molar ratio of the compound VI to the diphenyl phosphorazidate to the alkali is 1: 1.5-3;
preferably, in the step of preparing the compound VIII from the compound VII, the base 2 is sodium hydroxide, potassium hydroxide or lithium hydroxide; the reaction temperature is 0-30 ℃; the molar ratio of the compound VII and the alkali is 1: 1-1: 2.
In another aspect, the present invention provides a process for preparing compound (I) from compound (VIII), comprising:
preferably, in the step of preparing compound I from compound VIII, the acid is selected from p-toluenesulfonic acid, a hydrate of p-toluenesulfonic acid, methanesulfonic acid, concentrated sulfuric acid or hydrochloric acid.
Preferably, in the step of preparing the compound I by using the compound VIII, the molar ratio of the compound VIII to the acid is in a range of 1: 2; the reaction temperature range is 90-100 ℃.
Advantageous effects
The invention provides a simple, convenient and effective synthetic route for the first time, the imidazole compound containing trifluoromethyl and amino substituent groups is synthesized, the technical blank of the preparation method of 1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole is made up, the reaction condition is mild, the operation is simple and convenient, and the rapid preparation in a laboratory can be realized.
Abbreviations for the reagents referred to in the specification are as follows:
DPPA: diphenyl phosphorazidate;
TEA: triethylamine;
DIPEA: n, N-diisopropylethylamine;
PE: petroleum ether;
THF: tetrahydrofuran;
DMF is N, N-dimethylformamide;
and (3) MTBE: methyl tert-butyl ether;
DCM: dichloromethane;
MeOH: methanol;
EtOH: ethanol;
EA: and (3) ethyl acetate.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, which are carried out in the light of the technical solutions of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1
Preparation of Compound III-1
Adding compound II (60.00g, 0.322mol, 1.0eq.) and cesium carbonate (159.98g, 0.483mol, 1.5eq.) into 600mL of DMF, dropwise adding iodomethane (68.32g, 0.483mol, 1.5eq.) at 0 ℃, reacting at 25 ℃ for 1h after the addition is finished, TLC shows that the raw materials are reacted completely, pouring the system into 1L of ice water, filtering to obtain a white solid, washing with water (100mL. Multidot.2), dissolving the white solid with ethyl acetate, drying anhydrous magnesium sulfate, and concentrating to obtain compound III-1 as a white solid, wherein the yield is as follows: 94 percent. 1 H NMR(400MHz，CDCl 3 )δ(ppm)：7.40(m，2H)，7.20(m，2H)，3.40(s，3H)。
Preparation of Compound IV-1
Adding the compound III-1 (60.00g, 0.30mol and 1.0eq.) into 400mL of concentrated sulfuric acid in batches (the temperature of the system is raised to about 70 ℃), heating to 120 ℃, dropwise adding 40mL of hydrogen peroxide, releasing heat violently, stirring at 120 ℃ after the addition for reacting for 0.5h, cooling to about 10 ℃, pouring the system into ice water (1L), extracting with MTBE (300mL & lt3), drying, concentrating, pulping with n-heptane/MTBE (20/1) to obtain 62.00g of compound IV-1 as a yellow solid, wherein the yield is as follows: 85 percent.
Preparation of Compound V-1
Compound IV-1 (62.00g, 0.260mol, 1.0eq.) was added to trimethyl orthoacetate (400 mL), and the mixture was stirred under reflux for 6 hours, and the starting material was detected by TLC to be reacted completely. Concentrating, preparing sand column, performing column chromatography purification (PE/EA elution) to obtain 47.00g of a colorless liquid of the compound V-1, wherein the yield is as follows: 68 percent.
Preparation of Compound VI-1
V-1 (47.00g, 0.178mol, 1.0eq.) was added to methanol/THF (150 mL/150 mL), 75mL of an aqueous solution of lithium hydroxide (7.71g, 0.183mol, 1.03eq.) was added dropwise at 0 ℃, the reaction was stirred at 25 ℃ after the addition was complete for 3h, tlc showed the completion of the reaction of the starting material, concentrated at 30 ℃ to remove most of the solvent, adjusted pH =3 with 1N HCl, extracted with MTBE (200ml × 3), dried, and concentrated to give compound VI-1 as a yellow solid at 40.00g, yield: 90 percent of
Preparation of Compound VII-1
Compound VI-1 (40.00g, 0.159mol, 1.0eq.) and DPPA (65.52g, 0.238mol, 1.5eq.) were added to t-butanol (400 mL), heated to reflux, stirred for 24h, and assayed by TLC to show that the starting materials were reacted. Concentrating, and performing column chromatography purification (PE/EA elution) to obtain 34.00g of a yellow solid of the compound VII-1, wherein the yield is as follows: 66 percent. 1 HNMR(400MHz，CDCl 3 )δ(ppm)：3.60(s，3H)，3.47(s，3H)，1.52(s，9H)，(ESI-TOF)m/z：[M+H] + calcd for C 12 H 16 N 3 O 4 F 3 ：323；found：324。
Preparation of Compound VIII-1
Compound VII-1 (34.00g, 0.105mol, 1.0eq.) was added to methanol/THF (150mL/150 mL), 75mL of an aqueous solution of lithium hydroxide monohydrate (8.84g, 0.210mol,2.0 eq.) was added dropwise at 0 ℃ and after the addition was complete, the reaction was stirred at 25 ℃ for 169h and the completion of the reaction was monitored by TLC. Concentration at 30 ℃ to remove most of the solvent, 1N HCl pH =3, mtbe (200ml × 3) extraction, after separation, the combined organic phases were dried and concentrated to give compound VIII-1 as a yellow solid 25.00g, yield: 77 percent. 1 HNMR(400MHz，CDCl 3 )δ(ppm)：7.44(s，1H)，3.73(s，3H)，1.54(s，9H)，(ESI-TOF)m/z：[M+H] + calcd for C 11 H 14 N 3 O 4 F 3 ：309；found：310。
Example 2
Preparation of Compound III-1
Compound II (60.00g, 0.322mol, 1.0eq.) and potassium carbonate (89.01g, 0.644mol, 2.0eq.) were added to 600mL of DMF, methyl iodide (91.4g, 0.644mol, 2.0eq.) was added dropwise at 0 ℃, reaction was performed at 25 ℃ after completion of the addition for 1h, tlc showed that the raw material had reacted, the system was poured into 1L of ice water, washed with water (100ml × 2), filtered to obtain a white solid, washed with water (100ml × 2), the white solid was dissolved with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to obtain compound III-1 as a white solid, 62.00g, yield: 97.1 percent. 1 H NMR(400MHz，CDCl 3 )δ(ppm)：7.40(m，2H)，7.20(m，2H)，3.40(s，3H)。
Preparation of Compound IV-1
Adding the compound III-1 (60.00g, 0.30mol, 1.0eq.) into 400mL of concentrated sulfuric acid in batches (the temperature of the system is raised to about 70 ℃), heating to 100 ℃, dropwise adding 40mL of hydrogen peroxide, releasing heat violently, stirring at 100 ℃ after the addition for reacting for 2 hours, cooling to about 10 ℃, pouring the system into ice water (1L), extracting with MTBE (300mL of 3), drying, concentrating, and pulping with n-heptane/MTBE (20/1) to obtain 60.00g of compound IV-1 as a yellow solid, wherein the yield is as follows: 82.2 percent.
Preparation of Compound V-1
Compound IV-1 (60.00g, 0.252mol, 1.0eq.) was added to trimethyl orthoacetate (400 mL), and the mixture was heated to reflux and stirred for reaction for 18h, and the completion of the reaction of the starting materials was detected by TLC. Concentrating, performing sand column chromatography purification (PE/EA elution) to obtain 43.00g of a compound V-1 which is colorless liquid, wherein the yield is as follows: 65 percent.
Preparation of Compound VI-1
V-1 (40.00g, 0.151mol, 1.0eq.) was added to methanol (400 mL), sodium hydroxide (6.06g, 0.151mol, 1.0eq.) was added dropwise at 0 ℃ in 75mL of an aqueous solution, after the addition was completed, the reaction was stirred at 25 ℃ for 2h, tlc showed that the starting material had reacted, concentrated at 30 ℃ to remove most of the solvent, adjusted to pH =3 with 1N HCl, extracted with MTBE (200ml × 3), dried, and concentrated to give compound VI-1 as a yellow solid, 36.00g, yield: 95.3 percent
Preparation of Compound VII-1
Compound VI-1 (40.00g, 0.159mol, 1.0eq.) and DPPA (96.10g, 0.349mol, 2.2eq.) and DIPEA (44.98g, 0.349mol, 2.2eq.) were added to t-butanol (400 mL), heated to reflux, stirred for 18h and checked by TLC to show that the starting materials were reacted. Concentrating, and performing column chromatography purification (PE/EA elution) to obtain the compound VII-1 as a yellow solid 40.00g, wherein the yield is as follows: 77.8 percent. 1 HNMR(400MHz，CDCl 3 )δ(ppm)：3.60(s，3H)，3.47(s，3H)，1.52(s，9H)，(ESI-TOF)m/z：[M+H] + calcd for C 12 H 16 N 3 O 4 F 3 ：323；found：324。
Preparation of Compound VIII-1
Compound VII-1 (30.00g, 0.0928mol, 1.0eq.) was added to 300mL of methanol, 30mL of an aqueous solution of NaOH (3.71g, 0.0928mol, 1.0eq.) was added dropwise at 0 ℃ and, after completion of the addition, the reaction was stirred at 25 ℃ for 10 hours, and completion of the reaction was monitored by TLC. Concentration at 30 ℃ removed most of the solvent, 1N HCl adjusted pH =3, mtbe (200ml × 3) extraction, after separation, combined organic phases, dried, and concentrated to give compound VIII-1 as a yellow solid 22.87g, yield: 79.7 percent. 1 HNMR(400MHz，CDCl 3 )δ(ppm)：7.44(s，1H)，3.73(s，3H)，1.54(s，9H)，(ESI-TOF)m/z：[M+H] + calcd for C 11 H 14 N 3 O 4 F 3 ：309；found：310。
Example 3
Preparation of Compound III-1
Dispersing NaH (w/w 60%,12.89g,0.322mol, 1.0eq.) in 600mL of DMF, adding compound II (60.00g, 0.322mol, 1.0eq.) in portions at 0 ℃, adding completely, stirring for 5min, dropwise adding methyl iodide (45.7g, 0.322mol, 1.0eq.) at 0 ℃, reacting at 25 ℃ for 1h after adding, TLC indicating that the raw material is completely reacted, pouring the system into 1L of ice water, washing with water (100mL 2), filtering to obtain a white solid, washing with water (100mL 2), dissolving the white solid with ethyl acetate, drying anhydrous magnesium sulfate, concentrating to obtain compound III-1 as a white solid, wherein the yield is 55.00 g: 86.2 percent. 1 H NMR(400MHz，CDCl 3 )δ(ppm)：7.40(m，2H)，7.20(m，2H)，3.40(s，3H)。
Preparation of Compound IV-1
Adding the compound III-1 (55.00g, 0.275mol, 1.0eq.) into 400mL of concentrated sulfuric acid in batches (the temperature of the system is raised to about 70 ℃), heating to 110 ℃, dropwise adding 60mL of hydrogen peroxide, releasing heat violently, stirring at 110 ℃ after the addition for reacting for 2 hours, cooling to about 10 ℃, pouring the system into ice water (1L), extracting with MTBE (300mL of 3), drying, concentrating, pulping with n-heptane/MTBE (20/1) to obtain 60.3g of a compound IV-1 as a yellow solid, wherein the yield is as follows: 90 percent.
Preparation of Compound V-2
Compound IV-1 (60.3g, 0.253mol, 1.0eq.) was added to triethyl orthoformate (400 mL), the mixture was heated to reflux and stirred for reaction for 8h, and the completion of the reaction of the starting materials was checked by TLC. Concentrating, preparing sand column, performing column chromatography purification (PE/EA elution) to obtain 45.00g of a colorless liquid of the compound V-2, wherein the yield is as follows: 60.5 percent.
Preparation of Compound VI-2
V-2 (45.00g, 0.153mol, 1.0eq.) was added to ethanol (150 mL/150 mL), 60mL of an aqueous solution of potassium hydroxide (31.2g, 0.56mol, 1.05eq.) was dropped at 0 ℃, after the addition was completed, the reaction was stirred at 25 ℃ for 3h, tlc showed the completion of the reaction of the starting material, concentrated at 30 ℃ to remove most of the solvent, adjusted pH =3 with 1N HCl, extracted with MTBE (200ml × 3), dried, and concentrated to give compound VI-2 as a yellow solid, 40.00g, yield: 98.3 percent
Preparation of Compound VII-2
Compound VI-2 (40.00g, 0.15mol, 1.0eq.) and DPPA (124.1g, 0.45mol, 3.0eq.) were added to t-butanol (400 mL), heated to reflux, stirred for 20h, and checked by TLC to show that the starting materials were reacted. Concentrating, and performing column chromatography purification (PE/EA elution) to obtain 42.00g of a yellow solid of the compound VII-2, wherein the yield is as follows: 83 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C 13 H 18 N 3 O 4 F 3 ：337；found：338。
Preparation of Compound VIII-1
Compound VII-2 (30.00g, 0.089mol, 1.0eq.) was added to 300mL of ethanol, 30mL of an aqueous solution of KOH (7.49g, 0.133mol, 1.5eq.) was added dropwise at 10 ℃, the reaction was stirred at 25 ℃ for 10h after the completion of the addition, and the completion of the reaction was monitored by TLC. Concentration at 30 ℃ removed most of the solvent, 1N HCl adjusted pH =3, mtbe (200ml × 3) extraction, after separation of the liquids, combined organic phases, dried, and concentrated to give compound VIII-1 as a yellow solid 23.26g, yield: 84.5 percent. 1 HNMR(400MHz，CDCl 3 )δ(ppm)：7.44(s，1H)，3.73(s，3H)，1.54(s，9H)，(ESI-TOF)m/z：[M+H] + calcd forC 11 H 14 N 3 O 4 F 3 ：309；found：310。
Example 4
Preparation of Compound III-2
Adding compound II (60.00g, 0.322mol, 1.0eq.) and cesium carbonate (159.98g, 0.483mol, 1.5eq.) into 600mL of DMF, dropwise adding iodoethane (75.33g, 0.483mol, 1.5eq.) at 0 ℃, reacting for 1h at 25 ℃, TLC indicating that the raw materials are reacted completely, pouring the system into 1L of ice water, washing with water (100mL x 2), filtering to obtain a white solid, washing with water (100mL x 2), dissolving the white solid with ethyl acetate, drying with anhydrous magnesium sulfate, concentrating to obtain compound III-2 as a white solid 61.01g, and obtaining the yield: 88.5 percent.
Preparation of Compound IV-2
Adding the compound III-2 (60.00g, 0.28mol and 1.0eq.) into 400mL of concentrated sulfuric acid in batches (the temperature of the system is raised to about 70 ℃), heating to 120 ℃, dropwise adding 40mL of hydrogen peroxide, releasing heat violently, stirring at 120 ℃ after the addition for reacting for 0.5h, cooling to about 10 ℃, pouring the system into ice water (1L), extracting with MTBE (300mL & lt3), drying, concentrating, pulping with n-heptane/MTBE (20/1) to obtain 63.21g of a compound IV-2 as a yellow solid, wherein the yield is as follows: 89.5 percent.
Preparation of Compound V-3
Compound IV-2 (62.00g, 0.246mol, 1.0eq.) was added to trimethyl orthoacetate (400 mL), the mixture was heated to reflux and stirred for 6h, and the completion of the reaction of the starting materials was detected by TLC. Concentrating, preparing sand column, performing column chromatography purification (PE/EA elution) to obtain 50.00g of a colorless liquid of the compound V-3, wherein the yield is as follows: 72.5 percent.
Preparation of Compound VI-3
V-3 (50.00g, 0.178mol, 1.0eq.) was added to methanol/THF (150/150 mL), lithium hydroxide monohydrate (7.71g, 0.183mol, 1.03eq.) in 75mL of water was added dropwise at 0 ℃, after which the reaction was stirred at 25 ℃ for 3h, tlc showed the completion of the reaction of the starting material, concentrated at 30 ℃ to remove most of the solvent, adjusted pH =3 with 1N HCl, extracted with MTBE (200ml × 3), dried, and concentrated to give compound VI-3 as a yellow solid 43.00g, yield: 90.7 percent
Preparation of Compound VII-3
The compound VI-3 (40.00g, 0.15mol, 1.0eq.) and DPPA (61.94g, 0.225mol, 1.5eq.) and TEA (22.690g, 0.225mol, 1.5eq.) were added to t-butanol (400 mL), heated to reflux, stirred for 24h, and TLC indicated that the starting material was reacted. Concentrating, preparing a sand column, performing column chromatography purification (PE/EA elution) to obtain 40.00g of a yellow solid of the compound VII-3, wherein the yield is as follows: 79.01 percent. (ESI-TOF) m/z: [ M + H ]] + calcd for C 13 H 18 N 3 O 4 F 3 ：337；found：338。
Preparation of Compound VIII-2
Compound VII-3 (40.00g,0.119mol, 1.0eq.) was added to methanol/THF (150/150 mL), and 75mL of an aqueous solution of lithium hydroxide monohydrate (9.98g, 0.237mol, 2.0eq.) was added dropwise at 0 ℃ and after the addition was completed, the reaction was stirred at 25 ℃ for 169h, and the completion of the reaction was monitored by TLC. Concentration at 30 ℃ removed most of the solvent, 1N HCl adjusted pH =3, mtbe (200ml × 3) extraction, separation, combined organic phases, dried, and concentrated to give compound VIII-2 as a yellow solid 30.01g, yield: 78.0 percent. (ESI-TOF) m/z: [ M + H ]] + calcd for C 12 H 16 N 3 O 4 F 3 ：323；found：324。
Example 5
Preparation of Compound III-3
Compound II (60.00g, 0.322mol, 1.0eq.) and potassium tert-butoxide (72.26g, 0.644mol, 2.0eq.) were added to 600mL DMF, iodomethane (91.4g, 0.644mol, 2.0eq.) was added dropwise at 0 ℃, reaction was performed at 25 ℃ for 1h after addition, tlc showed that the starting material had reacted, the system was poured into 1L of ice water, washed with water (100ml × 2), filtered to give a white solid, washed with water (100ml × 2), the white solid was dissolved with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to give compound III-3 as a white solid 60.01g, yield: 81.6 percent.
Preparation of Compound IV-3
Adding the compound III-3 (60.00g, 0.26mol and 1.0eq.) into 400mL of concentrated sulfuric acid in batches (the temperature of the system is raised to about 70 ℃), heating to 100 ℃, dropwise adding 40mL of hydrogen peroxide, releasing heat violently, stirring at 100 ℃ after the addition is finished for reacting for 2 hours, cooling to about 10 ℃, pouring the system into ice water (1L), extracting by using MTBE (300mL of 3), drying, concentrating, pulping by using n-heptane/MTBE (20/1) to obtain 62.01g of compound IV-3 as a yellow solid, wherein the yield is as follows: 89.5 percent.
Preparation of Compound V-1
Compound IV-3 (60.00g, 0.225mol, 1.0eq.) was added to trimethyl orthoacetate (400 mL), the mixture was heated to reflux and stirred for reaction for 18h, and the completion of the reaction of the starting materials was detected by TLC. Concentrating, performing sand column chromatography purification (PE/EA elution) to obtain 45.01g of a compound V-4 as a colorless liquid, wherein the yield is as follows: 67.9 percent.
Preparation of Compound VI-4
V-4 (40.00g, 0.136mol, 1.0eq.) was added to methanol (400 mL), 75mL of an aqueous solution of sodium hydroxide (5.46g, 0.136mol, 1.0eq.) was dropped at 0 ℃, the reaction was stirred at 25 ℃ for 2h after the addition, tlc showed that the starting material had reacted, the bulk of the solvent was removed by concentration at 30 ℃, pH =3 was adjusted with 1N HCl, extraction was performed with MTBE (200ml × 3), drying and concentration were performed to obtain compound VI-4 as a yellow solid, 32.00g, yield: 84.0 percent
Preparation of Compound VII-4
Compound VI-4 (30.00g, 0.107mol, 1.0eq.) and DPPA (64.85g, 0.236mol, 2.2eq.) were added to t-butanol (400 mL), heated to reflux, stirred for 18h, and TLC detection indicated that the starting material was reacted. Concentration and column chromatography purification (PE/EA elution) to obtain the compound VII-4 as a yellow solid (26.31 g), yield: 70.0 percent. (ESI-TOF) m/z: [ M + H ]] + calcd for C 14 H 20 N 3 O 4 F 3 ：351；found：352。
Preparation of Compound VIII-3
Compound VII-4 (25.01g, 0.0712mol,1.0 eq.) was added to 300mL of methanol, 30mL of an aqueous solution of NaOH (2.85g, 0.0712mol,1.0 eq.) was added dropwise at 0 ℃, the reaction was stirred at 25 ℃ for 10h after the addition was complete, and the completion of the reaction was monitored by TLC. Concentration at 30 ℃ to remove most of the solvent, 1N HCl pH =3, mtbe (200ml × 3) extraction, after separation, the combined organic phases were dried and concentrated to give compound VIII-3 as a yellow solid 20.01g, yield: and 83.3 percent. (ESI-TOF) m/z: [ M + H ]] + calcd for C 13 H 18 N 3 O 4 F 3 ：337；found：338。
Example 6
Preparation of Compound I-1
Compound VIII-1 (18.00g, 0.0582mol)1.0 eq.), p-toluenesulfonic acid monohydrate (11.62g, 0.0611mol, 1.05eq.), sodium chloride (6.72g, 0.116mol, 2.0eq.) were added to acetonitrile/water (20/10 mL), and the reaction was stopped with stirring at 100 ℃ for 20 min. Cooled to 0 ℃, poured into ice saturated aqueous sodium bicarbonate (100 mL), added EA (100 mL) for liquid separation, dried, concentrated, slurried with n-heptane/MTBE (5/1), filtered to give compound I-1 as a white solid 4.20g, yield: 44 percent. (ESI-TOF) m/z: [ M + H ]] + calcd for C 5 H 6 N 3 F 3 :165; found:166. purity: 98 percent; 1 HNMR(400MHz，CDCl 3 )δ(ppm)：6.56(s，1H)，3.61(s，3H)，3.24(br，2H)。
example 7
Preparation of Compound I-1
Compound VIII-1 (18.00g, 0.0582mol, 1.0eq.), methanesulfonic acid (5.60g, 0.0582mol, 1.0eq.) was added to acetonitrile/water (20/10 mL), and the reaction was stopped by stirring at 100 ℃ for 10 min. Cooled to 0 ℃, poured into ice saturated aqueous sodium bicarbonate (100 mL), added EA (100 mL) for liquid separation, dried, concentrated, slurried with n-heptane/MTBE (5/1), filtered to give compound I-1 as a white solid 4.51g, yield: 47.0 percent. (ESI-TOF) m/z: [ M + H ]] + calcdfor C 5 H 6 N 3 F 3 :165; found:166. purity: 98 percent; 1 HNMR(400MHz，CDCl 3 )δ(ppm)：6.56(s，1H)，3.61(s，3H)，3.24(br，2H)。
example 8
Preparation of Compound I-2
Adding compound VIII-2 (18.00g, 0.0557mol, 1.0eq.) into 20mL of water, dropwise adding concentrated sulfuric acid (8.19g, 0.0835mol, 1.5eq.) at 0 deg.C, stirring at 90 deg.C, reacting for 10min, and stopping reactionAnd (4) reacting. Cooled to 0 ℃, poured into ice saturated aqueous sodium bicarbonate (100 mL), EA (100 mL) added, stirred, separated, dried, concentrated, slurried with PE/MTBE and filtered to give compound I-2 as a white solid 4.81g, yield: 48 percent. (ESI-TOF) m/z: [ M + H ]] + calcdfor C 6 H 8 N 3 F 3 :179; found:180. purity: 98 percent.
Example 9
Preparation of Compound I-3
Compound VIII-3 (18.00g, 0.053mol, 1.0eq.) was added to 20mL of 6N hydrochloric acid, and the reaction was stopped by stirring at 100 ℃ for 20 min. Cooled to 0 ℃, poured into ice saturated aqueous sodium bicarbonate (100 mL), added with EA (100 mL) for liquid separation, dried, concentrated, slurried with PE and filtered to give compound I-3 as a white solid 5.01g, yield: 49.0 percent. (ESI-TOF) m/z: [ M + H ]] + calcd for C 7 H 10 N 3 F 3 :193 (b); found:194. purity: 98 percent.
Claims (5)
1. A method for preparing a compound VIII, comprising:
wherein: r 1 Is methyl, ethyl or isopropyl; r is 2 Is methyl or ethyl.
2. The method of claim 1, wherein: compound II in the step of preparing compound III, the alkyl iodide is selected from methyl iodide, ethyl iodide or isopropyl iodide; the base 1 is selected from potassium carbonate, cesium carbonate, potassium tert-butoxide or sodium hydride.
3. The production method according to claim 1, characterized in that: in the step of preparing compound VI from compound V, the base 2 is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.
4. The method of claim 1, wherein: in the step of preparing the compound VII from the compound VI, the base 3 is triethylamine or N, N-diisopropylethylamine; the reaction temperature is 100-120 ℃; the molar ratio of the compound VI, the nitrine diphenyl phosphate and the alkali is 1: 1.5-3.
5. The production method according to claim 1, characterized in that: in the step of preparing the compound VIII from the compound VII, the alkali 4 is sodium hydroxide, potassium hydroxide or lithium hydroxide; the reaction temperature range is 0-30 ℃; the molar ratio of the compound VII and the alkali is 1: 1-1: 2.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1544420A (en) * | 1997-12-22 | 2004-11-10 | Inhibition of raf kinase using substituted heterocyclic ureas | |
| CN103781768A (en) * | 2011-09-06 | 2014-05-07 | 霍夫曼-拉罗奇有限公司 | PDE10 modulators |
| CN106573896A (en) * | 2014-06-26 | 2017-04-19 | 庵原化学工业株式会社 | Fluoroalkylating agent |
-
2018
- 2018-09-17 CN CN201811079462.1A patent/CN110903245B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1544420A (en) * | 1997-12-22 | 2004-11-10 | Inhibition of raf kinase using substituted heterocyclic ureas | |
| CN103781768A (en) * | 2011-09-06 | 2014-05-07 | 霍夫曼-拉罗奇有限公司 | PDE10 modulators |
| CN106573896A (en) * | 2014-06-26 | 2017-04-19 | 庵原化学工业株式会社 | Fluoroalkylating agent |
Non-Patent Citations (2)
| Title |
|---|
| RN：1368300-02-0;美国化学会;《STNEXT》;20120415;第1-3页 * |
| Synthesis of tetra-substituted pyrazoles;Anne J. Ruger, et al;《Tetrahedron》;20120807;第68卷(第42期);第8823-8829页 * |
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