CN118255718A - Synthesis method of 1-isopropyl-1H-pyrazole-3-sulfonyl chloride - Google Patents
Synthesis method of 1-isopropyl-1H-pyrazole-3-sulfonyl chloride Download PDFInfo
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- CN118255718A CN118255718A CN202211693992.1A CN202211693992A CN118255718A CN 118255718 A CN118255718 A CN 118255718A CN 202211693992 A CN202211693992 A CN 202211693992A CN 118255718 A CN118255718 A CN 118255718A
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- pyrazole
- isopropyl
- sulfonyl chloride
- compound
- chloride
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- UQKMYXQXNOLLRT-UHFFFAOYSA-N 1-propan-2-ylpyrazole-3-sulfonyl chloride Chemical compound CC(C)N1C=CC(S(Cl)(=O)=O)=N1 UQKMYXQXNOLLRT-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000001308 synthesis method Methods 0.000 title claims abstract description 5
- 239000012954 diazonium Substances 0.000 claims abstract description 33
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims abstract description 26
- -1 ferric chloride diazonium salt Chemical class 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 6
- MECWXEINLHIGIW-UHFFFAOYSA-N 1-propan-2-ylpyrazol-3-amine Chemical compound CC(C)N1C=CC(N)=N1 MECWXEINLHIGIW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract 3
- 239000007858 starting material Substances 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 9
- 238000006193 diazotization reaction Methods 0.000 claims description 8
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 7
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 7
- 235000010288 sodium nitrite Nutrition 0.000 claims description 5
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical group O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims 3
- 239000003929 acidic solution Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 150000001989 diazonium salts Chemical class 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- MZRUFMBFIKGOAL-UHFFFAOYSA-N 5-nitro-1h-pyrazole Chemical compound [O-][N+](=O)C1=CC=NN1 MZRUFMBFIKGOAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Inorganic materials [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Abstract
The invention provides a synthesis method for synthesizing 1-isopropyl-1H-pyrazole-3-sulfonyl chloride. The synthesis of the 1-isopropyl-1H-pyrazole-3-sulfonyl chloride takes 3-amino-1-isopropyl pyrazole as a starting material, and the separated intermediate ferric chloride diazonium salt is used for carrying out sulfonyl chlorination reaction. The method has the advantages of low cost, high product content, convenient operation and less three wastes, and is suitable for industrialized amplified production.
Description
Technical field:
The invention relates to the field of pharmaceutical chemistry, in particular to a novel synthesis method of 1-isopropyl-1H-pyrazole-3-sulfonyl chloride.
The background technology is as follows:
The structural formula of the 1-isopropyl-1H-pyrazole-3-sulfonyl chloride is as follows:
1-isopropyl-1H-pyrazole-3-sulfonyl chloride is an important medical intermediate, and is mainly used for preparing NLRP 3 regulation related medicines and other medicines.
Regarding the synthesis of 1-isopropyl-1H-pyrazole-3-sulfonyl chloride, it is currently mainly synthesized by the following route:
the synthesis of the compound 1-isopropyl-1H-pyrazole-3-sulfonyl chloride, namely, the compound B is prepared by taking 3-nitro-1H-pyrazole as an initial raw material through substitution reaction, the compound C is prepared by reducing nitro, and finally, the compound D, namely, the 1-isopropyl-1H-pyrazole-3-sulfonyl chloride is prepared through diazotization reaction, is finished by referring to patents such as WO2019/166627A1, WO2019/23145A1, WO 2017/140778A 1, WO2019/68772A1 and WO2020/104657A 1. Regarding the 3 rd step, the prepared diazonium hydrochloride is added into the acetic acid solution of SO 2 for reaction, and the method has the following problems:
1. The acetic acid solution of SO 2 needs to be prepared and is not easily metered, usually in large excess, which results in waste of the use of the acetic acid solution of SO 2.
2. The prepared diazonium hydrochloride aqueous solution is added into the acetic acid solution of SO 2 for reaction, SO that the acetic acid cannot be recycled, and the batch production is not facilitated, and the cost is high.
3. This step has a lower yield, only 59.8% of crude product, as described in patent WO2019/23145 A1.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and provides a preparation method of 1-isopropyl-1H-pyrazole-3-sulfonyl chloride, which is high in yield and environment-friendly, and mainly aims to improve a diazotization route, wherein a specific reaction equation is as follows:
the synthesis scheme comprises the following preferable steps:
The first step (preparation of ferric chloride diazonium salt):
Adding a compound C (3-amino-1-isopropyl pyrazole) into dilute hydrochloric acid, cooling to 10-20 ℃, dropwise adding a sodium nitrite aqueous solution, controlling the temperature below 20 ℃, dropwise adding a 30% ferric chloride aqueous solution after the completion of dropwise adding, controlling the temperature to 10-20 ℃, reacting for 0.5-1H, filtering, washing a filter cake once with ice dilute acid, washing once again with a small amount of methanol, and drying. Thus obtaining ferric chloride diazonium salt.
And a second step of:
Adding thionyl chloride into water with the temperature of 0-10 ℃ in a dropwise manner, controlling the temperature to be below 10 ℃, adding copper acetate monohydrate after the completion of the dropwise operation, adding ferric chloride diazonium salt prepared in the first step into the solution in batches, controlling the temperature to be 10-20 ℃, then carrying out overnight reaction at the same temperature, extracting ethyl acetate for 2 times after the reaction is completed, combining ethyl acetate layers, and washing with saturated sodium bicarbonate aqueous solution, water and saturated salt water for 1 time sequentially. Concentrating the ethyl acetate, stirring, cooling to-5 ℃, crystallizing, filtering, and drying. Obtaining the pure compound D (1-isopropyl-1H-pyrazole-3-sulfonyl chloride).
Wherein the mol ratio of the compound C (3-amino-1-isopropyl pyrazole), sodium nitrite, ferric chloride aqueous solution and dilute hydrochloric acid in the first step is 1 (1.0-1.05): 1.1-1.2): 3-4; the molar ratio of ferric chloride diazonium salt, thionyl chloride and copper acetate monohydrate in the second step is 1 (2-2.2) (0.005-0.01), wherein the reaction temperature in the first step and the second step is controlled at 10-20 ℃.
Compared with the prior art, the invention has the advantages that:
1. The traditional diazonium salt is unstable, and can be slowly decomposed even at the temperature of minus 5 ℃ to generate impurities, so that the post-treatment difficulty is increased; the ferric chloride diazonium salt is quite stable, does not have any danger, and can be prepared to separate out the ferric chloride diazonium salt of a pure product, and the ferric chloride diazonium salt cannot be decomposed even under the room temperature condition.
2. Because the ferric chloride diazonium salt has higher stability, the pure product can be separated, and then the side reaction is reduced greatly compared with the traditional diazonium salt when the ferric chloride diazonium salt is put into the next reaction, and the yield is improved correspondingly. The total yield of the traditional hydrochloric acid diazotization or dilute sulfuric acid diazotization reaction is generally 40-60%, the yield of the ferric chloride diazotization reaction can reach more than 80%, and the yield of some substrates can even reach more than 90%.
3. The reaction liquid for preparing ferric chloride diazonium salt can be repeatedly put into the next batch of reaction after the diazonium salt is separated, so that the acid wastewater is reduced. Because the stability is very high, even if a small amount of ferric chloride diazonium salt still exists in the reaction liquid, the next batch of reaction is not influenced because of the high stability; the diazonium salt prepared by the prior art is usually dissolved in water, and can only be put into the next reaction by diazonium salt aqueous solution, so that the diazonium salt cannot be reused after being put into the second reaction.
4. Because the diazotization reaction is an exothermic reaction, the heat exchange efficiency and the temperature control of the traditional diazonium salt on the reaction kettle are very high, namely the reaction time and the temperature are required at the same time, the reaction time for preparing the diazonium salt is not suitable for more than 4 hours, the temperature is different according to different reaction substrates, and the temperature for preparing the diazonium salt is usually controlled below-5 ℃, namely the temperature is required to be ensured to be not more than-5 ℃ and the time is required to be ensured to be not more than 4 hours, so that the heat exchange efficiency of the reaction kettle is very high. The preparation condition of ferric chloride diazonium salt is mild, and the compound C is taken as an example, so that the reaction temperature can be controlled below 20 ℃ generally, side reactions can not occur, the requirements on a refrigerator are not high, the temperature controllable range is much larger, and the reaction time can be prolonged to 6-8 hours and decomposition can not occur.
5. Among the ferric chloride diazonium salts, only fluoroboric acid diazonium salts, zinc chloride diazonium salts, ferric chloride diazonium salts, etc. are currently available in consideration of operability, yield, by-products, three wastes, etc., and the ferric chloride diazonium salt has the lowest cost.
Drawings
In the drawings of the specification: FIG. 1 is a HPLC chart of compound C (i.e., 1-isopropyl-1H-pyrazole-3-sulfonyl chloride) and related data.
FIG. 2 is a synthetic route diagram of 1-isopropyl-1H-pyrazole-3-sulfonyl chloride.
Detailed Description
The invention is further described with reference to the following detailed drawings, in order to make the technical means, authoring features, workflow, and usage method of the invention achieve the purpose and efficacy easily understood.
Synthesis of Compound M:
125 g (1 mol) of compound C (3-amino-1-isopropyl pyrazole) is added into a reaction bottle, 670ml of 6mol/L dilute hydrochloric acid is cooled to 10-20 ℃, aqueous solution of sodium nitrite (72.5 g+200ml of water) is added dropwise, the temperature is controlled to 10-20 ℃, aqueous solution of ferric chloride (162.4 g, 400 ml) is added dropwise, the temperature is controlled to 10-20 ℃, the reaction is carried out for 0.5-1H after the dropwise, suction filtration is carried out, 100ml of 6mol/L dilute hydrochloric acid (0-5 ℃) of ice is used for leaching a filter cake for 1 time, and the filter cake is dried, thus 304.2g of compound M is obtained, the yield is 90.8%, and the filtrate is reserved as a reaction liquid for preparing diazonium salt in the next batch.
Synthesis of Compound D:
250 g (2.1 mol) of thionyl chloride is added dropwise into 500ml of ice water (0-10 ℃), 1g (0.01 mol) of cupric acetate monohydrate is added after the dropwise addition, ferric chloride diazonium salt prepared in the first step is added into the solution in batches, the temperature is controlled between 10 and 20 ℃, then the reaction is kept overnight, ethyl acetate (300 ml x2 times) is used for extraction after the reaction is finished, organic layers are combined, the organic layers are sequentially washed for 1 time by 300ml of saturated sodium bicarbonate aqueous solution, 300ml of water and 300ml of saturated salt water, then the solution is dried by anhydrous sodium sulfate, suction filtration is carried out, the filtrate is concentrated to remove ethyl acetate, and 192.8g of compound D, namely 1-isopropyl-1H-pyrazole-3-sulfonyl chloride is obtained, and the yield is 92.5%. The HPLC detection spectrogram is shown in figure 1 in the drawings of the specification. Nuclear magnetic data: 1H NMR(400MHz,CDCl3 ) Delta 7.55 (d, 1H), 6.85 (d, 1H), 4.66-4.59 (m, 1H), 1.54 (d, 6H).
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (6)
1. The synthesis method of the 1-isopropyl-1H-pyrazole-3-sulfonyl chloride is characterized in that the 1-isopropyl-1H-pyrazole-3-sulfonyl chloride is prepared by taking 3-amino-1-isopropyl pyrazole as a starting material through ferric chloride diazotization reaction:
The first step is that the compound C reacts with sodium nitrite aqueous solution and ferric chloride aqueous solution in acid solution to generate ferric chloride diazonium salt with a compound M structure. . The second step is that the compound M and thionyl chloride are reacted under the condition of catalyst to generate the compound D.
2. The process for the preparation of 1-isopropyl-1H-pyrazole-3-sulfonyl chloride according to claim 1, wherein the acidic solution is diluted hydrochloric acid of 6 to 10 mol/L.
3. The method for producing 1-isopropyl-1H-pyrazole-3-sulfonyl chloride according to claim 1, wherein the molar ratio of the aqueous sodium nitrite solution to the aqueous ferric chloride solution to the compound a is 1.0 to 1.05:1.1 to 1.2:1.
4. The process for producing 1-isopropyl-1H-pyrazole-3-sulfonyl chloride according to claim 1, wherein the diazotization reaction is carried out at a reaction temperature of 10 to 20 ℃.
5. The method for preparing 1-isopropyl-1H-pyrazole-3-sulfonyl chloride according to claim 1, wherein the ferric chloride diazonium salt of the structure of formula M reacts with a sulfoxide chloride solution containing a catalyst to form the compound D, i.e., 1-isopropyl-1H-pyrazole-3-sulfonyl chloride.
6. The method for producing 1-isopropyl-1H-pyrazole-3-sulfonyl chloride according to claim 1, wherein the catalyst is copper acetate monohydrate.
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118255718A true CN118255718A (en) | 2024-06-28 |
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