CN114573557B - Preparation method of octreonazole - Google Patents
Preparation method of octreonazole Download PDFInfo
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- CN114573557B CN114573557B CN202210316682.1A CN202210316682A CN114573557B CN 114573557 B CN114573557 B CN 114573557B CN 202210316682 A CN202210316682 A CN 202210316682A CN 114573557 B CN114573557 B CN 114573557B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 150000001540 azides Chemical class 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000000746 purification Methods 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical group [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 26
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical group C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- 229960000583 acetic acid Drugs 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 239000012362 glacial acetic acid Substances 0.000 claims description 9
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 21
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 abstract description 18
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract description 16
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 229910000077 silane Inorganic materials 0.000 abstract description 2
- IDUYJRXRDSPPRC-NRFANRHFSA-N oteseconazole Chemical compound C([C@](O)(C=1C(=CC(F)=CC=1)F)C(F)(F)C=1N=CC(=CC=1)C=1C=CC(OCC(F)(F)F)=CC=1)N1C=NN=N1 IDUYJRXRDSPPRC-NRFANRHFSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- -1 1H-tetrazol-1-yl Chemical group 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 208000007288 14-alpha Demethylase Inhibitors Diseases 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000037026 Invasive Fungal Infections Diseases 0.000 description 1
- 102100021695 Lanosterol 14-alpha demethylase Human genes 0.000 description 1
- 101710146773 Lanosterol 14-alpha demethylase Proteins 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 201000007096 Vulvovaginal Candidiasis Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 229950011629 oteseconazole Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 201000005882 tinea unguium Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention provides a preparation method of octreonazole, which takes an intermediate 1 as a starting material and uses inorganic azide and trialkylchlorosilane Si (R) 3 -Cl, thereby producing the octreonazole represented by formula (i). The preparation method provided by the invention uses inorganic azide/trialkylchlorosilane to replace azido trialkyl silane reagent to carry out one-pot reaction, thereby being capable of effectively controlling the generation of formamide impurities and acetamide impurities in the reaction process, being beneficial to controlling the quality of target products, improving the utilization rate of raw materials and relieving the pressure of the subsequent purification process, in addition, the preparation method provided by the invention has simple operation, improves the process safety and reduces the generation cost, therefore, the preparation method provided by the invention is very suitable for large-scale industrial production, has important economic and social values,
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of octreonazole.
Background
Octreonazole (VT-1161, english name: oteseconazole, CAS number: 1340593-59-0), its chemical name is (R) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) propan-2-ol, its chemical structural formula is shown in formula (I):
octreonazole is a novel oral small molecule selective fungal CYP51 inhibitor developed by the company Mycovia, U.S. and has significantly better selectivity for fungal CYP51 than other commonly used azole antifungals. From the current clinical studies, octreonazole also exhibits excellent pharmacokinetic characteristics, therapeutic effects, and safety. Clinically, the composition is used for treating recurrent vulvovaginal candidiasis, invasive fungal infection, onychomycosis and other diseases.
Chinese patent CN 106458900B discloses a preparation method of octreonazole, which is prepared by reacting an intermediate 1 with an organic azide reagent TMSN3 (azido trimethylsilane) in the presence of trimethyl orthoformate and sodium acetate in an acetic acid solvent, wherein the reaction process is shown in a process route 1.
However, when TMS is adopted to synthesize VT-1161, formamide impurities (the chemical structural formula is shown as formula (II)) and acetamide impurities (the chemical structural formula is shown as formula (III)) are easy to generate in the reaction process, the content is high, the residue of raw materials is more, and therefore the quality of raw materials is not easy to control, and the pressure in the purification process is high. In addition, TMS is expensive, commercial supply is insufficient, the flash point of the substance is very low, only 75 ℃ F. Is easy to explode during industrial production, and the process safety risk is high, so that the method is not beneficial to large-scale industrial production.
Therefore, development of a new preparation method of the octreonazole is urgently needed to reduce the generation of impurities, improve the quality of target products, reduce the cost and the safety risk of the process, and make the obtained preparation process more suitable for industrial scale production.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a preparation method of the octreotide (VT-1161), which can effectively reduce the generation of formamide impurities and acetamide impurities in the preparation process, is safe in process operation and easy for industrial application, and the prepared VT-1161 has few impurities and good quality.
The preparation method of the octreonazole provided by the invention comprises the following steps: starting from intermediate 1, in the presence of an inorganic azide and a trialkylchlorosilane Si (R) 3 In the presence of Cl, thereby producing VT-1161 of formula (I),
wherein the inorganic azide is sodium azide or potassium azide, and the trialkylchlorosilane Si (R) 3 In Cl, R represents a C1-C6 alkyl group.
In preparing VT-1161 from intermediate 1, the inventors of the present invention found that neither organic azide reagent (e.g., TMS used in chinese patent CN 106458900B) nor inorganic azide (e.g., sodium azide, etc.) were used directly to achieve the desired results. The inventors of the present invention have also found that the use of inorganic azides and trialkylchlorosilanes Si (R) 3 The method can effectively reduce the generation of formamide impurities and acetamide impurities in the reaction process, and obviously reduce the residue of the raw material intermediate 1, thereby being beneficial to controlling the quality of target products and improving the utilization rate of raw materials. The subsequent purification pressure can be greatly reduced due to the reduction of impurities such as byproducts, residual raw materials and the like, so that a target product with high purity can be prepared. In addition, the use of inorganic azide and trialkylchlorosilane can also avoid directly using low-flash azido trialkyl silane reagent, so that the safety of the preparation process is improved, the production cost is further reduced, and the obtained preparation process is more suitable for industrial scale production.
In the preparation method provided by the invention, the used starting material intermediate 1 can be a commercially available product and can also be prepared by referring to Chinese patent CN 106458900B.
In some embodiments of the preparation methods according to the present invention, the inorganic azide may be sodium azide.
In some embodiments of the preparation method according to the invention, the trialkylchlorosilane Si (R) 3 R in Cl may further represent a C1-C4 alkyl group, for example, methyl, ethyl, etc.; in some preferred embodiments, the trialkylchlorosilane is trimethylchlorosilane.
In some embodiments of the preparation process according to the invention, the molar ratio of sodium azide to intermediate 1 may be from 2 to 5:1, including but not limited to 2: 1. 2.5: 1. 3:1. 3.5: 1. 4:1. 4.5: 1.5:1 equimolar ratio or any molar ratio interval; in some preferred embodiments, the molar ratio of sodium azide to intermediate 1 may be 2.5 to 4.5:1.
in some embodiments of the preparation method according to the present invention, the molar ratio of the sodium azide to the trimethylchlorosilane may be 1: 1-5, including but not limited to 1:1. 1:1.5, 1:2. 1:2.5, 1:3. 1:3.5, 1:4. 1:4.5, 1:5 equimolar ratio or any molar ratio interval; in some preferred embodiments, the molar ratio of the sodium azide to the trimethylchlorosilane may be 1:1 to 3.
In some embodiments of the production process according to the present invention, sodium acetate, trimethyl orthoformate, and a solvent system comprising glacial acetic acid are also included in the reaction system of the production process.
In some embodiments of the preparation methods according to the present invention, the solvent system may be selected from glacial acetic acid, or may be selected from a mixed solvent consisting of glacial acetic acid and one or more of ethyl acetate, 2-butanol; in some preferred embodiments, the solvent system is selected from glacial acetic acid, or from glacial acetic acid and ethyl acetate at 1:0.5 to 2 mass ratio.
In some embodiments of the preparation process according to the present invention, the solvent system may be 1.5 to 5 times the intermediate 1 by mass, including but not limited to 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, etc. or any interval of multiples.
In some embodiments of the preparation process according to the present invention, the molar ratio of sodium acetate to intermediate 1 may be 1 to 3:1, including but not limited to 1:1. 1:1.5, 1:2. 1:2.5, 1:3 equimolar ratio or arbitrary molar ratio interval; in some preferred embodiments, the molar ratio of sodium acetate to intermediate 1 may be from 1 to 1.5:1.
in some embodiments of the preparation process according to the invention, the molar ratio of trimethyl orthoformate to intermediate 1 may be between 1 and 4:1, including but not limited to 1:1. 1:1.5, 1:2. 1:2.5, 1:3. 1:3.5, 1:4 equimolar ratio or any molar ratio interval; in some preferred embodiments, the molar ratio of trimethyl orthoformate to intermediate 1 may be from 1.5 to 3:1.
in some embodiments of the preparation method according to the present invention, the temperature at which trimethyl orthoformate is added to the reaction system may be 35 to 65 ℃, and the reaction activation energy may be reached by appropriately increasing the temperature at which trimethyl orthoformate is added, so that the reaction is promoted to occur rapidly; in some preferred embodiments, the temperature at which the trimethyl orthoformate is added to the reaction system may be 45 to 55 ℃.
In some embodiments of the preparation process according to the present invention, the reaction temperature of the reaction may be 65 to 85 ℃; in some preferred embodiments, the reaction temperature of the reaction may be 75 to 85 ℃.
In some embodiments of the preparation process according to the invention, the preparation process may further comprise the following purification process: after the reaction is finished, extracting by using an organic solvent to obtain an extract, and removing the organic solvent after alkali washing and water washing to obtain a crude product, wherein the crude product is recrystallized by using isopropanol as a good solvent and n-heptane as a poor solvent.
In some preferred embodiments, the extraction solvent may be an organic solvent such as methyl t-butyl ether, ethyl acetate, or the like.
In the preparation method provided by the invention, a washing method, a filtering method (such as suction filtration, centrifugation and the like), a drying method, a crystallization method and the like which are conventional in the art can be used in the purification process.
According to the preparation method provided by the invention, the inorganic azide/trialkylchlorosilane is used for replacing an azido trialkylsilane reagent to synthesize VT-1161 by a one-pot method, and the generation of formamide impurities and acetamide impurities in the reaction process can be effectively controlled, so that the quality of a target product is favorably controlled, the utilization rate of raw materials is improved, and the pressure of the subsequent purification process is reduced. In addition, the preparation method provided by the invention is simple to operate, improves the process safety and reduces the production cost. Therefore, the preparation method provided by the invention is very suitable for large-scale industrial production, and has important economic and social values.
Detailed Description
The technical scheme of the invention is further described in detail below with reference to specific embodiments.
Intermediate 1 used in the examples and comparative examples of the present invention was prepared by referring to chinese patent CN 106458900B, and other reagents were commercially available unless otherwise specified.
The detection method of the relevant substances used in the examples and comparative examples of the present invention is high performance liquid chromatography, and other operation methods are conventional in the art unless otherwise specified.
The equipment and detection conditions used for high performance liquid chromatography are as follows:
chromatograph: agilent 1260.
Preparing a solution:
mobile phase a:0.05% trifluoroacetic acid in water.
Mobile phase B: acetonitrile solution of 0.05% trifluoroacetic acid.
Dilution liquid: acetonitrile/water (1:1, v/v).
Detection conditions:
the percentages used in the present invention are mass percentages unless otherwise indicated.
Example 1
To the reaction vessel were added 5g (0.06 mol,1.06 eq) of anhydrous sodium acetate and 70ml of glacial acetic acid, followed by 35g (0.056 mol) of intermediate 1, 10g (0.154 mol,2.74 eq) of sodium azide and 16g (0.147 mol,2.62 eq) of trimethylchlorosilane, and the temperature was raised to 45℃and 16g (0.22 mol,3.93 eq) of trimethyl orthoformate.
Then, the temperature was raised to 75-85℃and kept for 5 hours, and after the reaction was completed, the reaction mixture was sampled and examined (the results are shown in Table 1). To the reaction mixture, 100g of water and 50g of methyl t-butyl ether were added, the layers were separated, 100g of 15% sodium hydroxide solution was added to the organic layer, and the layers were washed. Then washing with 100g of water, layering, decompressing and drying the organic layer, adding 70g of isopropanol into the obtained crude product, heating to dissolve, dripping 280g of n-heptane, and cooling to 20 ℃ for crystallization. Filtering and drying to obtain 24.8g VT-1161 with purity: 99.98% (HPLC), yield 83.9%, no formamide impurity and no acetamide impurity were detected.
Example 2
To the reaction vessel was added a mixed solvent of 7g (0.08 mol,1.43 eq) of anhydrous sodium acetate, 50ml of glacial acetic acid, 50ml of ethyl acetate, and then 35g (0.056 mol) of intermediate 1, 12g (0.18 mol,3.21 eq) of sodium azide and 27g (0.25 mol,4.46 eq) of trimethylchlorosilane, and the temperature was raised to 55℃and 7g (0.07 mol,1.25 eq) of trimethyl orthoformate in 7ml of ethyl acetate was added.
Then, the temperature was raised to 65-75℃and kept for 24 hours, and after the completion of the reaction, the reaction mixture was sampled and examined (the results are shown in Table 1). To the reaction solution, 100g of water and 200g of ethyl acetate were added, the layers were separated, 100g of a 20% potassium hydroxide solution was added to the organic layer, and the layers were washed. Then washing with 100g of water, layering, decompressing and drying the organic layer, adding 100g of isopropanol into the obtained crude product, heating to dissolve, dripping 350g of n-heptane, and cooling to 0 ℃ for crystallization. Filtering and drying to obtain 25.2g VT-1161 with purity: 99.99% (HPLC), yield 85.1%, no formamide impurity and no acetamide impurity were detected.
Comparative example
Referring to 0487 of Chinese patent CN 106458900B, a VT-1161 synthetic reaction liquid is prepared, sampling and detection are carried out, and the detection result is shown in table 1.
TABLE 1 detection results of reaction solutions
| Purity of the reaction solution | Carboxamide impurities | Acetamide impurity | Intermediate 1 | |
| Example 1 | 97.33％ | 0.10％ | 0.22％ | 0.06％ |
| Example 2 | 97.48％ | 0.27％ | 0.07％ | 0.14％ |
| Comparative example | 94.61％ | 2.01％ | 0.35％ | 0.73％ |
As can be seen from the results in Table 1, the preparation method provided by the invention can effectively reduce the generation of formamide impurity and acetamide impurity in the reaction process, and the residue of the raw material intermediate 1 is also obviously reduced.
Unless otherwise defined, all terms used herein are intended to have the meanings commonly understood by those skilled in the art.
The described embodiments of the present invention are intended to be illustrative only and not to limit the scope of the invention, and various other alternatives, modifications, and improvements may be made by those skilled in the art within the scope of the invention, and therefore the invention is not limited to the above embodiments but only by the claims.
Claims (8)
1. A preparation method of the octreonazole is characterized in that an intermediate 1 is used as a starting material, and inorganic azide and trialkylchlorosilane Si (R) are used as starting materials 3 -Cl, sodium acetate, trimethyl orthoformate and a solvent system, thereby obtaining the octreonazole shown in the formula (I),
wherein the inorganic azide is sodium azide or potassium azide, and the trialkylchlorosilane Si (R) 3 -Cl, R represents a C1-C6 alkyl group, said solvent system being selected from glacial acetic acid, or from glacial acetic acid and ethyl acetate, at 1: and the mass ratio of the mixed solvent is 0.5-2, and the reaction temperature of the reaction is 65-85 ℃.
2. The method of claim 1, wherein the inorganic azide is sodium azide; the trialkylchlorosilane is trimethylchlorosilane.
3. The preparation method according to claim 2, wherein the molar ratio of the sodium azide to the intermediate 1 is 2 to 5:1, a step of; the molar ratio of the sodium azide to the trimethylchlorosilane is 1:1 to 5.
4. The preparation method according to claim 1, wherein the solvent system is 1.5 to 5 times by mass of the intermediate 1.
5. The preparation method according to claim 1, wherein the molar ratio of the sodium acetate to the intermediate 1 is 1 to 3:1.
6. the preparation method according to claim 1, wherein the molar ratio of trimethyl orthoformate to intermediate 1 is 1-4: 1.
7. the process according to claim 1, wherein the trimethyl orthoformate is added to the reaction system at a temperature of 35 to 65 ℃.
8. The method of any one of claims 1-7, further comprising the purification process of: after the reaction is finished, extracting by using an organic solvent to obtain an extract, and removing the organic solvent after alkali washing and water washing to obtain a crude product, wherein the crude product is recrystallized by using isopropanol as a good solvent and n-heptane as a poor solvent.
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102216249A (en) * | 2008-11-17 | 2011-10-12 | 霍夫曼-拉罗奇有限公司 | Naphthylacetic acids |
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