CN112457272B - Preparation method of (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate - Google Patents
Preparation method of (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate Download PDFInfo
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- CN112457272B CN112457272B CN202011389940.6A CN202011389940A CN112457272B CN 112457272 B CN112457272 B CN 112457272B CN 202011389940 A CN202011389940 A CN 202011389940A CN 112457272 B CN112457272 B CN 112457272B
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- C07—ORGANIC CHEMISTRY
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- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
Abstract
The invention discloses a preparation method of (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate, belonging to the field of synthesis of medical intermediates. Starting from O-methylisourea hydrochloride (1), carrying out chlorination reaction to obtain an intermediate (2); and then the intermediate (2) and thiocyanate are subjected to ring closure under the presence of ytterbium catalyst to obtain an intermediate (3), and finally the intermediate (3) and phenolate react in the presence of CDI to obtain (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate. The method has the advantages of simple and stable operation, easy separation of products in each step, high yield and environmental protection, and provides a new synthetic approach for the compounds.
Description
Technical Field
The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate.
Background
1,2, 4-thiadiazole is an important heterocyclic compound, and has very wide application in the field of medicinal chemistry due to unique biological and physiological activities. The compound (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate is the compound.
At present, few published documents for synthesizing (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate exist, and the following two methods are mainly adopted:
the synthesis method reported in the first method, WO2014194741 and WO2013091539a1 comprises the following synthesis route:
method II and the synthetic method reported in WO2018095320 have the following synthetic routes:
in the two methods, the yield of the first method is only 20.8%, and a large amount of carbon disulfide is needed in the second method, wherein the carbon disulfide is highly toxic, flammable and explosive, and has great harm to the environment and the health of human bodies.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the preparation method of the (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate, which is simple, convenient and stable to operate, easy to separate products in each step, high in yield, environment-friendly and suitable for industrial large-scale production.
The invention provides a preparation method of (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate, which comprises the following synthetic route:
the method comprises the following steps: starting from O-methylisourea hydrochloride (1), carrying out chlorination reaction to obtain an intermediate (2); and then the intermediate (2) and thiocyanate are subjected to ring closure under the presence of ytterbium catalyst to obtain an intermediate (3), and finally the intermediate (3) and phenolate react in the presence of CDI to obtain (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate.
Further, the technical method provided by the invention comprises the following specific steps:
the first step is as follows: synthesis of N-chloro-O-methylisourea hydrochloride (2)
Reacting O-methylisourea hydrochloride (1) with a chlorinated reagent in an organic solvent to obtain N-chloro-O-methylisourea hydrochloride (2).
Further, the chlorinating agent is selected from sodium hypochlorite, tert-butyl hypochlorite, calcium hypochlorite, chlorine gas and the like.
Furthermore, the solvent is selected from water, methanol, ethanol and the like, mainly plays a role in dissolution, and has no obvious influence on reaction yield; preferably, the solvent is water.
Further, the molar ratio of the O-methylisourea hydrochloride (1) to the chlorinating agent is 1: 0.85-1.1.
The second step is that: synthesis of 5-amino-3-methoxy-1, 2, 4-thiazole (3)
Reacting N-chloro-O-methyl isourea hydrochloride (2), Lewis acid and thiocyanate in an organic solvent to obtain 5-amino-3-methoxy-1, 2, 4-thiazole (3).
Further, the organic solvent is selected from tetrahydrofuran, methanol, acetonitrile, isopropanol or any combination of the above solvents, preferably the solvent is methanol.
Further, the thiocyanate is selected from potassium thiocyanate, sodium thiocyanate, ammonium thiocyanate, tetramethylammonium thiocyanate, tetra-n-butylammonium thiocyanate, and the like.
Further, the lewis acid is selected from ytterbium trifluoromethanesulfonate.
Further, the molar ratio of the lewis acid to the thiocyanate of the N-chloro-O-methylisourea hydrochloride (2) is 1: 0.1-0.3: 1-3.
The third step: synthesis of phenyl (3-methoxy-1, 2, 4-thiadiazole-5-amino) formate (4)
5-amino-3-methoxy-1, 2, 4-thiazole (3), phenolate and N, N' -carbonyldiimidazole are reacted in an organic solvent to obtain (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate (4).
Further, the organic solvent is selected from tetrahydrofuran, dioxane or any combination of the above solvents, preferably the solvent is tetrahydrofuran.
Further, the phenolate is sodium phenolate, potassium phenolate or lithium phenolate, and is obtained by reacting phenol with a corresponding base (e.g., sodium hydroxide, sodium hydride, potassium hydroxide, etc.).
Further, the 5-amino-3-methoxy-1, 2, 4-thiazole (3) has a molar ratio of phenol to N, N' -carbonyldiimidazole of 1: 1-2: 1-1.5.
The invention has the beneficial effects
1) Compared with the yield (20.8%) of the existing route, the yield of the method is remarkably improved, the yield of three steps is over 75.2%, the production cost is greatly reduced, and the market competitiveness of the product is improved.
2) The invention does not use highly toxic reagents and is environment-friendly.
3) The preparation process is optimized, the byproducts in the reaction process are removed by selecting proper solvent for pulping in the final step, the operation of the post-treatment process is simple, the process reproducibility is good, and the method can be smoothly amplified to the kilogram-level reaction scale.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Drawings
FIG. 1 is the HNMR spectrum of the product of phenyl (3-methoxy-1, 2, 4-thiadiazole-5-amino) formate in example 1.
Example 1
The first step is as follows: synthesis of N-chloro-O-methylisourea hydrochloride
A5% aqueous solution of sodium hypochlorite (1.3L, 0.88mol) was slowly added dropwise to a solution of O-methylisourea hydrochloride (110.5g, 1 mol)/water (650mL) at 0 deg.C, stirred until the reaction was complete, methyl tert-butyl ether (700mL) extracted 3 times, the organic layer dried over anhydrous sodium sulfate, filtered, and spun dried to give N-chloro-O-methylisourea hydrochloride (105.2g, 83%).
The second step is that: synthesis of 5-amino-3-methoxy-1, 2, 4-thiazole
Ammonium thiocyanate (76g, 1mol) was added to a solution of ytterbium trifluoromethanesulfonate (62g, 0.1mol) and N-chloro-O-methylisourea hydrochloride (144g, 1 mol)/methanol (3L), and the reaction was stirred until completion. After filtration, the filtrate was spin-dried and passed through a column to give 5-amino-3-methoxy-1, 2, 4-thiazole (119.2g, yield: 91%).
The third step: synthesis of (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate
To a solution of 5-amino-3-methoxy-1, 2, 4-thiazole (131g, 1mol) in tetrahydrofuran (1.3L) was added N, N' -carbonyldiimidazole (210.6g, 1.3mol) and the reaction mixture was stirred at 50 ℃ for 8 hours, then sodium phenolate (151g, 1.3mol) was added and the reaction mixture was heated to 75 ℃ until the reaction was complete. Cooling the reaction solution to room temperature, adding water, extracting with dichloromethane, drying, spin-drying, pulping with methanol, filtering to obtain white product (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate (233.4g, 93%), purity of HPLC 99.6%,1H-NMR(400MHz,CDCl3) 12.17(s,1H),7.44-7.42(m,2H),7.29-7.26(m,3H),4.01(s,3H). The detailed spectrogram is shown in figure 1.
Example 2
The first step is as follows: synthesis of N-chloro-O-methylisourea hydrochloride
At 0 ℃, slowly dripping the aqueous solution of tert-butyl hypochlorite (108.6g, 1mol) into the solution of O-methyl isourea hydrochloride (110.5g, 1 mol)/methanol (650mL), stirring until the reaction is completed, extracting with petroleum ether (700mL) for 3 times, drying the organic layer with anhydrous sodium sulfate, filtering, and spin-drying to obtain N-chloro-O-methyl isourea hydrochloride (122.4g, 85%).
The second step is that: synthesis of 5-amino-3-methoxy-1, 2, 4-thiazole
Tetramethylammonium thiocyanate (264g, 2mol) was added to a solution of zinc dichloride (27.2g, 0.2mol) and N-chloro-O-methylisourea hydrochloride (144g, 1 mol)/acetonitrile and tetrahydrofuran (1:1, 3L) and the reaction was stirred until completion. After filtration, the filtrate was spin-dried and passed through a column to give 5-amino-3-methoxy-1, 2, 4-thiazole (27.5g, yield: 21%).
The third step: synthesis of (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate
To a solution of 5-amino-3-methoxy-1, 2, 4-thiazole (131g, 1mol) in dioxane (1.3L) was added N, N' -carbonyldiimidazole (162g, 1mol) and the reaction mixture was stirred at 55 ℃ for 8 hours, then potassium phenoxide (264g, 2mol) was added and the reaction mixture was heated to 75 ℃ until the reaction was complete. The reaction solution was cooled to room temperature, water was added, dichloromethane was used for extraction, drying, spin-drying, methanol pulping, and filtration were carried out to obtain a white product (phenyl 3-methoxy-1, 2, 4-thiadiazole-5-amino) formate (223.4g, 89%), purity by HPLC 99.5%.
Example 3
The first step is as follows: synthesis of N-chloro-O-methylisourea hydrochloride
Chlorine (78g, 1.1mol) was slowly bubbled through a solution of O-methylisourea hydrochloride (110.5g, 1 mol)/water (650mL) at 0 deg.C, stirred until the reaction was complete, methyl tert-butyl ether (700mL) extracted 3 times, the organic layer dried over anhydrous sodium sulfate, filtered, and spun dry to give N-chloro-O-methylisourea hydrochloride (118.1g, 82%).
The second step is that: synthesis of 5-amino-3-methoxy-1, 2, 4-thiazole
tetra-N-butylammonium thiocyanate (900g, 3mol) was added to a solution of iron (III) trifluoromethanesulfonate (150.9g, 0.3mol) and N-chloro-O-methylisourea hydrochloride (144g, 1 mol)/tetrahydrofuran (3L), and the reaction was stirred until the reaction was completed. After filtration, the filtrate was spin-dried and passed through a column to give 5-amino-3-methoxy-1, 2, 4-thiazole (58.9g, yield: 45%).
The third step: synthesis of (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate
To a solution of 5-amino-3-methoxy-1, 2, 4-thiazole (131g, 1mol) in tetrahydrofuran (1.3L) was added N, N' -carbonyldiimidazole (243g, 1.5mol) and the reaction mixture was stirred at 50 ℃ for 8 hours, then lithium phenoxide (100g, 1mol) was added and the reaction mixture was heated to 75 ℃ until the reaction was complete. Cooling the reaction solution to room temperature, adding water, extracting with dichloromethane, drying, spin-drying, pulping with methanol, filtering to obtain white product (228.4g, 91%) phenyl (3-methoxy-1, 2, 4-thiadiazole-5-amino) formate with HPLC purity of 99.6%,1H-NMR(400MHz,CDCl3):11.80(s,1H),7.44-7.42(m,2H),7.28-7.25(m,3H),4.01(s,3H)。
example 4
The first step was carried out as in example 3.
The second step is that: synthesis of 5-amino-3-methoxy-1, 2, 4-thiazole
Ammonium thiocyanate (76g, 1mol) was added to ytterbium trifluoromethanesulfonate (62g, 0.1mol) and a solution of N-chloro-O-methylisourea hydrochloride (144g, 1 mol)/acetonitrile and tetrahydrofuran (1:1, 3L), and the reaction was stirred until completion. After filtration, the filtrate was spin-dried and passed through a column to give 5-amino-3-methoxy-1, 2, 4-thiazole (112.7g, yield: 86%).
The third step was carried out as in example 3.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (7)
1. A preparation method of (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate comprises the following synthetic route:
the method is characterized by comprising the following steps: starting from O-methylisourea hydrochloride (1), carrying out chlorination reaction to obtain an intermediate (2); and (3) performing ring closure on the intermediate (2) and thiocyanate under ytterbium trifluoromethanesulfonate to obtain an intermediate (3), and finally reacting the intermediate (3) and phenolate in the presence of CDI to obtain (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate.
2. The process for producing phenyl (3-methoxy-1, 2, 4-thiadiazole-5-amino) carboxylate according to claim 1, which comprises: in the first step, O-methylisourea hydrochloride (1) and a chlorinated reagent react in solvent water, methanol and ethanol to obtain N-chloro-O-methylisourea hydrochloride (2).
3. The process for producing phenyl (3-methoxy-1, 2, 4-thiadiazole-5-amino) carboxylate according to claim 2, which comprises: the chlorinating agent is selected from sodium hypochlorite, tert-butyl hypochlorite, calcium hypochlorite or chlorine; the molar ratio of the O-methylisourea hydrochloride (1) to the chlorinated reagent is 1: 0.85-1.1.
4. The process for producing phenyl (3-methoxy-1, 2, 4-thiadiazole-5-amino) carboxylate according to claim 1, which comprises: and the second step is to react the N-chlorine-O-methyl isourea hydrochloride (2), ytterbium trifluoromethanesulfonate and thiocyanate in an organic solvent to obtain the 5-amino-3-methoxy-1, 2, 4-thiazole (3).
5. The process for producing phenyl (3-methoxy-1, 2, 4-thiadiazole-5-amino) carboxylate according to claim 4, which comprises: the organic solvent is selected from one or more of tetrahydrofuran, methanol, acetonitrile or isopropanol; the thiocyanate is selected from potassium thiocyanate, sodium thiocyanate, ammonium thiocyanate, tetramethylammonium thiocyanate or tetra-n-butylammonium thiocyanate; the molar ratio of ytterbium trifluoromethanesulfonate to thiocyanate of the N-chloro-O-methylisourea hydrochloride (2) is 1: 0.1-0.3: 1-3.
6. The process for producing phenyl (3-methoxy-1, 2, 4-thiadiazole-5-amino) carboxylate according to claim 1, which comprises: in the third step, 5-amino-3-methoxy-1, 2, 4-thiazole (3), phenolate and N, N' -carbonyldiimidazole are reacted in an organic solvent to obtain (3-methoxy-1, 2, 4-thiadiazole-5-amino) phenyl formate (4).
7. The process for producing phenyl (3-methoxy-1, 2, 4-thiadiazole-5-amino) carboxylate according to claim 6, which comprises: the organic solvent is selected from tetrahydrofuran and/or dioxane; the phenolate is sodium phenolate, potassium phenolate or lithium phenolate; the molar ratio of the 5-amino-3-methoxy-1, 2, 4-thiazole (3) to the phenate to the N, N' -carbonyldiimidazole is 1: 1-2: 1-1.5.
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| CN1216527A (en) * | 1996-02-26 | 1999-05-12 | 阿普泰克斯公司 | Process for scavenging thiols |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1216527A (en) * | 1996-02-26 | 1999-05-12 | 阿普泰克斯公司 | Process for scavenging thiols |
| US6114537A (en) * | 1996-02-26 | 2000-09-05 | Apotex Inc. | Process for scavenging thiols |
Non-Patent Citations (1)
| Title |
|---|
| Unprecedented ‘In Water’ Imidazole Carbonylation: Paradigm Shift for Preparation of Urea and Carbamate;Kamlesh J. Padiya et al;《Organic Letters》;20120518;第2815页右栏Table3 * |
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