CN110903245A - 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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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
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 cardiovascular side effect and the like, and is widely applied to safe tranquilization of various conditions, especially 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 which has 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 synthetic route which has the advantages of easily obtained raw materials, convenient operation, easy control of 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 decarboxylating and removing the tert-butyloxycarbonyl 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: r1Is methyl, ethyl or isopropyl; r2Is methyl or ethyl.
In another aspect, the present invention provides a process for the preparation of compound VIII, comprising:
wherein: r1Is methyl, ethyl or isopropyl; r2Is methyl or ethyl.
In another aspect, the present invention provides a process for the preparation of compound VIII, comprising:
wherein: r1Is methyl, ethyl or isopropyl; r2Is 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 range is 0-30 ℃; the molar ratio of the compound VII to 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 from 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;
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 by the following specific examples, which are carried out on the premise of the technical scheme 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 methyl iodide (68.32g, 0.483mol, 1.5eq.) at 0 ℃, reacting for 1h at 25 ℃ 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 × 2), dissolving the white solid with ethyl acetate, drying with anhydrous magnesium sulfate, and concentrating to obtain compound III-1 as a white solid 60.00g, yield: 94 percent.1H NMR(400MHz，CDCl3)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 concentrated sulfuric acid in batches (the system is heated to about 70 ℃), heating to 120 ℃, dropwise adding 40mL hydrogen peroxide, releasing heat violently, stirring and reacting at 120 ℃ for 0.5h after the addition is finished, cooling to about 10 ℃, pouring the system into ice water (1L), extracting with MTBE (300mL 3), 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 (400mL), heated to reflux and stirred for 6h, and the starting material was detected by TLC to be reacted. Concentrating, performing sand column chromatography purification (PE/EA elution) to obtain 47.00g of a compound V-1 which is colorless liquid, 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 (150mL/150mL), 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 ℃ for 3h after the addition, TLC showed the completion of the reaction of the starting material, 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 40.00g, yield: 90 percent of
Preparation of Compound VII-1
Compound VI-1(40.00g,0.159mol, 1.0eq.), DPPA (65.52g, 0.238mol, 1.5eq.) and TEA (24.00g, 0.238mol, 1.5eq.) were added to t-butanol (400mL), heated to reflux, and the reaction was stirred for 24h, with TLC detection indicating complete reaction of the starting materials. 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.1HNMR(400MHz，CDCl3)δ(ppm)：3.60(s，3H)，3.47(s，3H)，1.52(s，9H)，(ESI-TOF)m/z：[M+H]+calcd for C12H16N3O4F3：323；found：324。
Preparation of Compound VIII-1
Compound VII-1(34.00g, 0.105mol, 1.0eq.) was added to methanol/THF (150mL/150mL), and 75mL of aqueous solution of lithium hydroxide monohydrate (8.84g, 0.210mol, 2.0eq.) was added dropwise at 0 deg.C, after addition was complete, the reaction was stirred at 25 deg.C for 16h, and the completion of the reaction was monitored by TLC. Concentration at 30 ℃ removed most of the solvent, pH adjusted to 3 with 1N HCl, MTBE (200mL × 3) extraction, separation, combined organic phases, dried, and concentrated to give compound VIII-1 as a yellow solid 25.00g, yield: 77 percent.1HNMR(400MHz，CDCl3)δ(ppm)：7.44(s，1H)，3.73(s，3H)，1.54(s，9H)，(ESI-TOF)m/z：[M+H]+calcdfor C11H14N3O4F3：309；found：310。
Example 2
Preparation of Compound III-1
Adding compound II (60.00g, 0.322mol, 1.0eq.) and potassium carbonate (89.01g, 0.644mol, 2.0eq.) into 600mL of DMF, dropwise adding methyl iodide (91.4g, 0.644mol, 2.0eq.) at 0 ℃, reacting for 1h at 25 ℃ after adding, TLC shows that the raw materials are reacted completely, 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 with anhydrous magnesium sulfate, and concentrating to obtain compound III-1 as a white solid, with the yield of 62.00 g: 97.1 percent.1H NMR(400MHz，CDCl3)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 concentrated sulfuric acid in batches (the system is heated to about 70 ℃), heating to 100 ℃, dropwise adding 40mL hydrogen peroxide, releasing heat violently, stirring and reacting at 100 ℃ for 2h after the addition is finished, cooling to about 10 ℃, pouring the system into ice water (1L), extracting with MTBE (300mL 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 (400mL), heated to reflux and stirred for 18h, and the starting material was detected by TLC to be reacted. 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 (400mL), sodium hydroxide (6.06g, 0.151mol, 1.0eq.) was added dropwise at 0 ℃ in 75mL of an aqueous solution, and after addition, the reaction was stirred at 25 ℃ for 2h, TLC showed 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 (400mL), heated to reflux and stirred for 18h, and TLC showed the starting material was 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.1HNMR(400MHz，CDCl3)δ(ppm)：3.60(s，3H)，3.47(s，3H)，1.52(s，9H)，(ESI-TOF)m/z：[M+H]+calcd for C12H16N3O4F3：323；found：324。
Preparation of Compound VIII-1
Compound VII-1(30.00g, 0.0928mol, 1.0eq.) was added to 300mL of methanol, 30mL of aqueous NaOH (3.71g, 0.0928mol, 1.0eq.) was added dropwise at 0 deg.C, and after completion of the addition, the reaction was stirred at 25 deg.C for 10h, and the completion of the reaction was monitored by TLC. Concentration at 30 ℃ removed most of the solvent, pH adjusted to 3 with 1N HCl, MTBE (200mL × 3) extraction, separation, combined organic phases, dried, and concentrated to give compound VIII-1 as a yellow solid 22.87g, yield: 79.7 percent.1HNMR(400MHz，CDCl3)δ(ppm)：7.44(s，1H)，3.73(s，3H)，1.54(s，9H)，(ESI-TOF)m/z：[M+H]+calcd for C11H14N3O4F3：309；found：310。
Example 3
Preparation of Compound III-1
Dispersing NaH (w/w 60%, 12.89g, 0.322mol, 1.0eq.) in 600mL DMF, adding Compound II (60.00g, 0.322mol, 1.0eq.) in portions at 0 ℃, stirring for 5min, adding iodomethane (45.7g, 0.322mol, 1.0eq.) dropwise at 0 ℃, reacting for 1h at 25 ℃, TLC showing that the raw materials have 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 over anhydrous magnesium sulfate, concentrating to obtain Compound III-1 as a white solid, 55.00g, yield: 86.2 percent.1H NMR(400MHz，CDCl3)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 concentrated sulfuric acid in batches (the system is heated to about 70 ℃), heating to 110 ℃, dropwise adding 60mL hydrogen peroxide, releasing heat violently, stirring and reacting at 110 ℃ for 2h after the addition is finished, cooling to about 10 ℃, pouring the system into ice water (1L), extracting with MTBE (300mL 3), drying, concentrating, and pulping with n-heptane/MTBE (20/1) to obtain 60.3g of 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 (400mL), heated to reflux and stirred for 8h, and the starting material was detected by TLC to be reacted. Concentrating, performing sand column chromatography purification (PE/EA elution) to obtain 45.00g of a compound V-2 which is colorless liquid, 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 (150mL/150mL), 60mL of an aqueous solution of potassium hydroxide (31.2g, 0.56mol, 1.05eq.) was added dropwise at 0 ℃, the reaction was stirred at 25 ℃ for 3h after addition, TLC showed the starting material had reacted, most of the solvent was removed by concentration at 30 ℃, pH 3 was adjusted with 1N HCl, MTBE (200mL × 3) was extracted, 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.), DPPA (124.1g, 0.45mol, 3.0eq.), and TEA (45.50g, 0.45mol, 3.0eq.) were added to t-butanol (400mL), heated to reflux, and the reaction stirred for 20h, with TLC detection indicating complete reaction of the starting materials. 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 C13H18N3O4F3：337；found：338。
Preparation of Compound VIII-1
Compound VII-2(30.00g, 0.089mol, 1.0eq.) was added to 300mL of ethanol, 30mL of aqueous KOH (7.49g, 0.133mol, 1.5eq.) was added dropwise at 10 deg.C, and after completion of the addition, the reaction was stirred at 25 deg.C for 10h, and the completion of the reaction was monitored by TLC. Concentration at 30 ℃ removed most of the solvent, pH adjusted to 3 with 1N HCl, MTBE (200mL × 3) extraction, separation, combined organic phases, dried, and concentrated to give compound VIII-1 as a yellow solid 23.26g, yield: 84.5 percent.1HNMR(400MHz，CDCl3)δ(ppm)：7.44(s，1H)，3.73(s，3H)，1.54(s，9H)，(ESI-TOF)m/z：[M+H]+calcd forC11H14N3O4F3：309；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 ℃ after the addition is finished, TLC shows that the raw materials are 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 with anhydrous magnesium sulfate, and concentrating to obtain compound III-2 as a white solid 61.01g, yield: 88.5 percent.
Preparation of Compound IV-2
Adding the compound III-2(60.00g, 0.28mol, 1.0eq.) into 400mL concentrated sulfuric acid in batches (the system is heated to about 70 ℃), heating to 120 ℃, dropwise adding 40mL hydrogen peroxide, releasing heat violently, stirring and reacting at 120 ℃ for 0.5h after the addition is finished, cooling to about 10 ℃, pouring the system into ice water (1L), extracting with MTBE (300mL 3), drying, concentrating, and pulping with n-heptane/MTBE (20/1) to obtain 63.21g of 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 (400mL), heated to reflux and stirred for 6h, and the starting material was detected by TLC to be reacted. Concentrating, performing sand column chromatography purification (PE/EA elution) to obtain 50.00g of a compound V-3 which is colorless liquid, wherein the yield is as follows: 72.5 percent.
Preparation of Compound VI-3
V-3(50.00g, 0.178mol, 1.0eq.) was added dropwise to methanol/THF (150/150mL), 75mL of an aqueous solution of lithium hydroxide monohydrate (7.71g, 0.183mol, 1.03eq.) was added dropwise at 0 ℃, the reaction was stirred at 25 ℃ for 3h after the addition, TLC showed the completion of the reaction of the starting material, 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-3 as a yellow solid 43.00g, yield: 90.7 percent
Preparation of Compound VII-3
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 (400mL) and heated to reflux and the reaction stirred for 24h, with TLC detection indicating complete reaction of the starting materials. Concentrating, and performing column chromatography purification (PE/EA elution) to obtain a compound VII-3 which is 40.00g of yellow solid and has the yield: 79.01 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C13H18N3O4F3：337；found：338。
Preparation of Compound VIII-2
Compound VII-3(40.00g, 0.119mol, 1.0eq.) was added to methanol/THF (150/150mL), and 75mL of aqueous solution of lithium hydroxide monohydrate (9.98g, 0.237mol, 2.0eq.) was added dropwise at 0 deg.C, after addition was complete, the reaction was stirred at 25 deg.C for 16h, and TLC monitored for completion. Concentration at 30 ℃ removed most of the solvent, pH adjusted to 3 with 1N HCl, 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 C12H16N3O4F3：323；found：324。
Example 5
Preparation of Compound III-3
Adding compound II (60.00g, 0.322mol, 1.0eq.) and potassium tert-butoxide (72.26g, 0.644mol, 2.0eq.) into 600mL of DMF, dropwise adding methyl iodide (91.4g, 0.644mol, 2.0eq.) at 0 ℃, reacting for 1h at 25 ℃ after the addition is finished, TLC shows that the raw materials are reacted completely, 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 with anhydrous magnesium sulfate, and concentrating to obtain compound III-3 as a white solid 60.01g, with the yield: 81.6 percent.
Preparation of Compound IV-3
Adding the compound III-3(60.00g, 0.26mol, 1.0eq.) into 400mL concentrated sulfuric acid in batches (the system is heated to about 70 ℃), heating to 100 ℃, dropwise adding 40mL hydrogen peroxide, releasing heat violently, stirring and reacting at 100 ℃ for 2h after the addition is finished, cooling to about 10 ℃, pouring the system into ice water (1L), extracting with MTBE (300mL 3), drying, concentrating, and pulping with 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 (400mL), heated to reflux and stirred for 18h, and the starting material was detected by TLC to be reacted. Concentrating, and performing column chromatography purification (PE/EA elution) to obtain 45.01g of a compound V-4 which is 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 (400mL), sodium hydroxide (5.46g, 0.136mol, 1.0eq.) was added dropwise at 0 ℃ in 75mL of an aqueous solution, and after addition, the reaction was stirred at 25 ℃ for 2h, TLC showed the completion of the reaction of the starting material, 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-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.), DPPA (64.85g, 0.236mol, 2.2eq.), and DIPEA (30.42g, 0.236mol, 2.2eq.) were added to t-butanol (400mL), heated to reflux, stirred for 18h, and TLC indicated complete reaction of the starting materials. Concentrating, and performing column chromatography purification (PE/EA elution) to obtain 26.31g of a yellow solid of the compound VII-4, wherein the yield is as follows: 70.0 percent. (ESI-TOF) m/z: [ M + H ]]+calcd for C14H20N3O4F3：351；found：352。
Preparation of Compound VIII-3
Compound VII-4(25.01g, 0.0712mol, 1.0eq.) was added to 300mL of methanol, 30mL of an aqueous solution of NaOH (2.85g, 0.0712mol, 1.0eq.) was added dropwise at 0 deg.C, and after the addition was complete, the reaction was stirred at 25 deg.C for 10h, and the completion of the reaction was monitored by TLC. Concentrating at 30 deg.C to remove most solvent, adjusting pH to 3 with 1N HCl, extracting with MTBE (200 mL. times.3), separating, and mixingAnd the organic phase is dried and concentrated to obtain the compound VIII-3 as a yellow solid 20.01g, and the yield is as follows: 83.3 percent. (ESI-TOF) m/z: [ M + H ]]+calcdfor C13H18N3O4F3：337；found：338。
Example 6
Preparation of Compound I-1
Compound VIII-1(18.00g, 0.0582mol, 1.0eq.), p-toluenesulfonic acid monohydrate (11.62g, 0.0611mol, 1.05eq.), sodium chloride (6.72g, 0.116mol, 2.0eq.) were added to acetonitrile/water (20/10mL), and the reaction was stopped with stirring at 100 ℃ for 20 min. Cooled to 0 ℃, poured into ice saturated aqueous sodium bicarbonate (100mL), added EA (100mL) 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 C5H6N3F3: 165; found: 166. purity: 98 percent;1HNMR(400MHz，CDCl3)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.) and methanesulfonic acid (5.60g, 0.0582mol, 1.0eq.) were added to acetonitrile/water (20/10mL), and the reaction was stopped with stirring at 100 ℃ for 10 min. Cooled to 0 ℃, poured into ice saturated aqueous sodium bicarbonate (100mL), added EA (100mL) 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 C5H6N3F3: 165; found: 166. purity: 98 percent;1HNMR(400MHz，CDCl3)δ(ppm)：6.56(s，1H)，3.61(s，3H)，3.24(br，2H)。
example 8
Preparation of Compound I-2
Compound VIII-2(18.00g, 0.0557mol, 1.0eq.) was added to 20mL of water, concentrated sulfuric acid (8.19g, 0.0835mol, 1.5eq.) was added dropwise at 0 ℃, and the reaction was stopped with stirring at 90 ℃ for 10 min. Cooled to 0 ℃, poured into ice saturated aqueous sodium bicarbonate (100mL), EA (100mL) 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 ]]+calcdforC6H8N3F3: 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 (100mL), added EA (100mL) 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 C7H10N3F3: 193 (b); found: 194. purity: 98 percent.
Claims (10)
1. A compound of the structural formulae (VII) and (VIII):
wherein: r1Is methyl, ethyl or isopropyl; r2Is methyl or ethyl.
2. A process for the preparation of compound VIII according to claim 1, which comprises:
wherein: r1Is methyl, ethyl or isopropyl; r2Is methyl or ethyl.
3. A process for the preparation of compound VIII according to claim 1, which comprises:
wherein: r1Is methyl, ethyl or isopropyl; r2Is methyl or ethyl.
4. The production method according to claim 3, characterized in that: compound II 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.
5. The production method according to claim 3, 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.
6. The production method according to claim 2 or claim 3, characterized in that: in the step of preparing the compound VII from the compound VI, the base 3 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.
7. The production method according to claim 2 or claim 3, 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 to the alkali is 1: 1-1: 2.
8. A process for preparing compound (I) from compound (VIII) according to claim 1, which comprises:
wherein: r1Is methyl, ethyl or isopropyl.
9. The method of claim 8, wherein: in the step of preparing the compound I from the compound VIII, the acid is selected from p-toluenesulfonic acid, hydrate of p-toluenesulfonic acid, methanesulfonic acid, concentrated sulfuric acid or hydrochloric acid.
10. The production method according to claim 8 or claim 9, characterized in that: in the step of preparing the compound I from the compound VIII, the molar ratio of the compound VIII to acid is 1: 1-1: 2; the reaction temperature range is 90-100 ℃.
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Citations (3)
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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 |
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| 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 |
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| ANNE J. RUGER, ET AL: "Synthesis of tetra-substituted pyrazoles", 《TETRAHEDRON》 * |
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