CN112830892A - Synthesis method of pyridine-3-sulfonyl chloride - Google Patents
Synthesis method of pyridine-3-sulfonyl chloride Download PDFInfo
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- CN112830892A CN112830892A CN201911164062.5A CN201911164062A CN112830892A CN 112830892 A CN112830892 A CN 112830892A CN 201911164062 A CN201911164062 A CN 201911164062A CN 112830892 A CN112830892 A CN 112830892A
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- pyridine
- sulfonyl chloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
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- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a synthetic method for synthesizing pyridine-3-sulfonyl chloride. The synthesis of pyridine-3-sulfonyl chloride is carried out by taking 3-aminopyridine as initial raw material, separating out intermediate fluoboric acid diazonium salt, and 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 industrial scale-up production.
Description
The technical field is as follows:
the invention relates to the field of medicinal chemistry, in particular to a novel synthesis method of pyridine-3-sulfonyl chloride.
Background art:
pyridine-3-sulfonyl chloride has the structural formula:
pyridine-3-sulfonyl chloride is an important medical intermediate, and is widely applied to the synthesis of medicines, wherein the pyridine-3-sulfonyl chloride is mainly used for preparing TAK-438.
With respect to the synthesis of pyridine-3-sulfonyl chloride, it is currently mainly synthesized by the following route:
route one: reference may be made to the method of CN 201810991672.1:
the route uses sodium hydrosulfide or potassium hydrosulfide, and the like, although the cost is low, the odor of the sulfhydryl compound is heavier in the industrial production process, and chlorine gas needs to be introduced in the second step, so that the safety risk is higher, and the factors are not beneficial to industrial production.
And a second route: journal of the American Chemical Society,1992, vol.114, #12, p.4889-4898
In the first step, sulfuric acid or chlorosulfonic acid is used to produce pyridine-3-sulfonic acid, and in the second step, phosphorus trichloride or the like is used for chlorination. In the route, when pyridine-3-sulfonic acid is generated in the first step, a small amount of pyridine-3-sulfonic acid can be positioned to 2 or 4 positions and is not easy to separate; secondly, the pollution is very big, produces a lot of waste acid water, again, uses concentrated sulfuric acid or phosphorus oxychloride etc. and is dangerous chemicals, and the safety risk is also bigger.
And a third route: organic Process Research and Development,2009, vol.13, #5, p.875-879; CN106432067 and the like
The method is a diazotization reaction, the chloro-heavy chloride salt generated in the middle is unstable, side reactions are more, and the product pyridine-3-sulfonyl chloride is colorless liquid, but the sulfonyl chloride may deteriorate during high-temperature distillation, so the requirement on the purity of the reaction process is higher, namely, the side reaction cannot be caused during the reaction, and obviously, the route cannot meet the requirement.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, provides a preparation method of pyridine-3-sulfonyl chloride with high yield and environmental protection, and mainly improves a diazotization route, wherein the specific reaction equation is as follows:
the synthesis scheme preferably comprises the following steps:
the first step is as follows: adding 3-aminopyridine and 6-10 mol/L diluted hydrochloric acid into a reaction kettle, cooling to 0-5 ℃, dropwise adding a sodium nitrite aqueous solution, controlling the temperature to 0-5 ℃, then dropwise adding a sodium fluoborate aqueous solution, controlling the temperature to 0-5 ℃, stirring for 30-60 minutes at 0-5 ℃ after dropwise adding, performing suction filtration, leaching a filter cake for 1 time by using 6-10 mol/L diluted hydrochloric acid, and drying for later use.
The second step is that: dropwise adding thionyl chloride into water, then cooling to about 0-5 ℃, after dripping, adding cuprous chloride, adding the diazonium fluoroborate prepared in the previous step into the solution in batches, controlling the temperature to be 0-5 ℃, then reacting at the same temperature overnight, after reacting, extracting dichloromethane, washing an organic layer with saturated sodium bicarbonate aqueous solution for 1 time, then washing with water for one time, finally washing with saturated salt for 1 time, then drying with anhydrous sodium sulfate, carrying out suction filtration, and concentrating the filtrate to remove dichloromethane to obtain a pure product.
The sodium fluoroborate may be replaced by 40% aqueous solution of fluoroboric acid. Wherein the molar ratio of the 3-aminopyridine, the sodium nitrite, the sodium fluoborate or 40 percent fluoboric acid and the dilute hydrochloric acid in the first step is 1 (1.0-1.2) to 1.0-1.3 to 3-4; the molar ratio of the diazonium fluoroborate, the thionyl chloride and the cuprous chloride in the second step is 1 (2-2.2) to 0.005-0.01, wherein the reaction temperature in the first step and the reaction temperature in the second step are both controlled to be 0-5 ℃.
Compared with the prior art, the invention has the advantages that:
1. compared with the traditional diazonium salt hydrochloride or diazonium hydrogen sulfate, the 3-pyridine fluoboric acid diazonium salt has more stable property, and even can separate out a solid pure product, so that the occurrence of side reactions is reduced in the next reaction step, the second reaction step is directly extracted, and then a small amount of extracted thionyl chloride and other substances are washed off and directly concentrated to obtain a product pure product with the purity of more than 98 percent, which can not be achieved by the traditional diazotization reaction, and the used raw materials are cheap and easy to obtain, the separation is simple and convenient, the operation is simple, and the industrial production is convenient;
2. in the conventional diazotization reaction, because the water solubility of the diazonium salt is good, the diazonium salt reaction solution can only be directly put into the next reaction, so that the acid water cannot be recycled.
3. The sodium bicarbonate aqueous solution, the extraction and washing water, the saturated sodium chloride aqueous solution, the anhydrous sodium sulfate and the like used in the reaction can be repeatedly used by supplementing corresponding inorganic salts; furthermore, the dichloromethane used for extraction can be reused for many times. This reduces raw material costs and waste disposal costs.
Drawings
In the drawings of the specification: FIG. 1 shows an HPLC chromatogram and related data for compound C (i.e., pyridine-3-sulfonyl chloride).
FIG. 2 is a scheme showing the synthesis scheme of pyridine-3-sulfonyl chloride.
Detailed Description
In order to make the technical means, creation features, work flow and use method of the present invention easily understood and appreciated, the present invention will be further described with reference to the following detailed drawings.
Synthesis of Compound B:
adding 94 g (1mol) of 3-aminopyridine and 670ml of 6mol/L diluted hydrochloric acid into a reaction bottle, cooling to 0-5 ℃, dropwise adding a sodium nitrite aqueous solution (72.45g +150ml of water), controlling the temperature to 0-5 ℃, then dropwise adding a sodium fluoroborate aqueous solution (131.g +260ml of water), controlling the temperature to 0-5 ℃, stirring for 30-60 minutes at 0-5 ℃ after finishing dropping, carrying out suction filtration, leaching a filter cake for 1 time by using 100ml of 6mol/L diluted hydrochloric acid (0-5 ℃) of ice, and drying to obtain a compound B180.9g, wherein the yield is 95.3%.
Synthesis of Compound C:
adding 238 g (2mol) of thionyl chloride into 500ml of water, cooling to about 0-5 ℃, adding 1g (0.01mol) of cuprous chloride after dripping, adding 189.8g (1mol) of the diazonium fluoroborate prepared in the first step into the solution in batches, controlling the temperature to 0-5 ℃, reacting overnight at 0-5 ℃, extracting with dichloromethane (300ml for 2 times) after reacting, combining organic layers, washing the organic layers with 300ml of saturated sodium bicarbonate aqueous solution for 1 time, washing with 300ml of water for one time, and finally washing with 300m of waterl saturated common salt water was washed 1 time, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove methylene chloride, to obtain 161.0g of compound C, i.e., pyridine-3-sulfonyl chloride, in 90.7% yield. The HPLC detection spectrum is shown as figure 1 in the attached drawing of the specification. Nuclear magnetic data:1H NMR(400MHz，CDCl3),δ:7.70-7.74(dd，1H),8.43-8.45(dd,1H),9.03-9.05(dd,1H),9.31-9.32(d,1H).
the foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. The synthesis method of pyridine-3-sulfonyl chloride is characterized in that 3-aminopyridine is used as an initial raw material, and the pyridine-3-sulfonyl chloride is prepared by diazotization reaction of fluoroboric acid:
the first step is that the compound A is subjected to diazotization reaction with sodium nitrite aqueous solution and sodium fluoroborate aqueous solution in acid solution to generate the fluoborate diazonium salt with the structure of the compound B. . The second step is that the compound B and thionyl chloride generate a compound C under the condition of a catalyst.
2. The method for preparing pyridine-3-sulfonyl chloride according to claim 1, wherein the acidic solution is dilute hydrochloric acid of 6 to 10 mol/L.
3. The method for producing pyridine-3-sulfonyl chloride according to claim 1, wherein the molar ratio of the aqueous solution of sodium nitrite to the aqueous solution of sodium fluoroborate to the compound a is 1.05 to 1.1:1.1 to 1.3: 1.
4. The process for producing pyridine-3-sulfonyl chloride according to claim 1, wherein the reaction temperature of the diazotization reaction is 10 ℃ or less.
5. The process for preparing pyridine-3-sulfonyl chloride according to claim 1, wherein said compound B, which is diazonium fluoroborate, is subjected to an acylchlorination reaction to obtain said compound C, which is pyridine-3-sulfonyl chloride.
6. The process for preparing pyridine-3-sulfonyl chloride according to claim 1, wherein the diazonium fluoroborate having the structure of formula II is subjected to the acylchlorination reaction with a thionyl chloride solution containing a catalyst to produce the compound C, i.e., pyridine-3-sulfonyl chloride.
7. The process for the preparation of pyridine-3-sulfonyl chloride as claimed in claim 1 wherein the catalyst is cuprous chloride or cupric chloride.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115974772A (en) * | 2023-01-05 | 2023-04-18 | 山东铂源药业股份有限公司 | Method for preparing pyridine-3-sulfonyl chloride by using microchannel reactor |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115974772A (en) * | 2023-01-05 | 2023-04-18 | 山东铂源药业股份有限公司 | Method for preparing pyridine-3-sulfonyl chloride by using microchannel reactor |
| CN115974772B (en) * | 2023-01-05 | 2024-06-14 | 山东铂源药业股份有限公司 | Method for preparing pyridine-3-sulfonyl chloride by utilizing microchannel reactor |
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Application publication date: 20210525 |