CN107759574B - A kind of 5-fluoro-1H-pyrazole-3-carboxylate intermediate and its synthesis method - Google Patents

Abstract

The invention discloses a compound of structural formula IV and a synthesis method thereof, as well as the application of compound IV in the synthesis of 5-fluoro-1H-pyrazole-3-formate (compound I), belonging to the field of organic chemical synthesis. The method Using N-substituted 5-fluoro-pyrazole (compound II) as raw material, rearrangement under catalyst action obtains compound III, and then substituted 1H-pyrazole-3 can be smoothly synthesized through carboxylation and esterification reactions ‑ Formate. The method has the advantages of simple operation, short route and high product yield, which is suitable for large-scale production.

Description

A kind of 5-fluoro-1H-pyrazole-3-carboxylate intermediate and its synthesis method

technical field

The invention relates to the field of organic chemical synthesis, in particular to the synthesis of a 5-fluoro-1H-pyrazole-3-carboxylate intermediate and a synthesis method thereof.

Background technique

Halogen-substituted 1H-pyrazole-3-carboxylate has a wide range of applications in the field of medicine, such as the preparation of heterocyclic regulator compounds for lipid synthesis and pharmaceutically acceptable salts thereof, and the synthesis of 11-β hydroxy steroids. Hydrogenase type 1 inhibitors and V1b receptor antagonists, etc.

The route reported in CN 106061963 A is as follows:

Reagents and yields: (a) MeOH, _H2SO4 , 70% yield; (b) Pd/C, _H2 , MeOH, 73% yield _; (c _{) NaNO2} , KI, _H2SO4 , H ₂ O, yield 30%.

The reported method has the following shortcomings: the total yield of the synthetic route is 15.3%, and the yield is relatively low; the hydrogenation reaction in step b has certain danger; the diazotization reaction in step c has fire hazard, and the diazotization reaction is dangerous. The diazonium salt produced by the reaction is easy to decompose under the action of slightly higher temperature or light, and some can even decompose at room temperature. , impact, can decompose and explode.

Venkat Gaddamidi et al. reported in J.Agric.Food Chem., 2011, 59, 9424–9432 that 3-bromopyrazole was used as a raw material, first reacted with dimethylsulfuryl chloride to form N-dimethylsulfanyl derivatives, Protected nitrogen, then reacted with lithium diisopropylamide at -70°C, quenched with carbon dioxide, and finally esterified with methanol to give methyl 3-bromo-1H-pyrazole-5-carboxylate.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a new intermediate (compound IV) of 5-fluoro-1H-pyrazole-3-carboxylate, and obtain 5-fluoro-1H-pyrazole-3-carboxylate from compound IV by one-step reaction acid ester. Meanwhile, in the present invention, compound II is used as a raw material, and compound III is obtained by rearrangement under the action of a catalyst, and then compound IV is synthesized through carboxylation.

A compound of formula IV:

The preparation method of compound IV: using compound II as raw material,

(1) First rearrangement under the action of a catalyst to obtain compound III

(2) then carboxylate with carbon dioxide or dry ice under the action of strong base to obtain compound IV

In step (1), the catalyst can be selected from: trifluoroacetic acid, p-toluenesulfonic acid monohydrate, trifluoromethanesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; the solvent can be selected from: xylene, toluene, chlorine benzene. The reaction temperature ranges from 110 to 140°C; the reaction time ranges from 6 to 60 hours.

The strong base described in step (2) can be selected from n-butyllithium, tert-butyllithium, lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS), bis(trimethyl) Silyl) sodium amide (NaHMDS), magnesium dichloride (2,2,6,6-tetramethylpiperidine) lithium salt, phenyllithium. The molar ratio of compound III to strong base is 1.0:1.0～1.0:3.0. The reaction temperature is -78 to -30°C. The reaction solvent is selected from tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, and cyclopentyl methyl ether.

Process for preparing compound I from compound IV, compound IV

Under the action of thionyl chloride, compound I is obtained by esterification with ROH

wherein R is methyl or ethyl. The molar ratio of compound IV to thionyl chloride is 1.0:1.5-1.0:3.5.

The method for preparing compound I from compound II: using compound II as starting material,

(1) First rearrangement under the action of a catalyst to obtain compound III

(2) then carboxylate with carbon dioxide or dry ice under the action of strong base to obtain compound IV

(3) under the action of thionyl chloride, esterification with ROH to obtain compound I

wherein R is methyl or ethyl. The molar ratio of compound IV to thionyl chloride is 1.0:1.5-1.0:3.5.

Beneficial effects:

Although halogen-substituted 1H-pyrazole-3-carboxylates have been studied to some extent in the prior art, fluorinated 1H-pyrazole-3-carboxylates have not been reported in the art. In medicine, a class of medicines with fluorine-containing aromatic compounds as active groups plays a pivotal role. When a fluorine atom or a fluorine-containing group is introduced into a compound, its electrical effect and analog effect change the distribution of electron density inside the molecule, affect the acidity and alkalinity of the internal structure of the compound, and then change its activity, and can also improve the lipid of the compound. soluble. The fluorine atom replaces the hydrogen atom in the compound, and the solubility of the ester compound in the biofilm is enhanced, which promotes the transfer speed of its absorption in the living body, and changes the physiological effect. Therefore, many fluorine-containing compounds have the advantages of less dosage, lower toxicity, higher efficacy and stronger metabolism than non-fluorine-containing compounds in terms of pharmaceutical properties such as medicines and pesticides.

The present invention provides a novel intermediate of 5-fluoro-1H-pyrazole-3-carboxylate (compound IV), and 5-fluoro-1H-pyrazole-3-carboxylate can be obtained by one-step reaction of compound IV. Meanwhile, in the present invention, compound II is used as a raw material, and compound III is obtained by rearrangement under the action of a catalyst, and then compound IV is synthesized through carboxylation. The steps involved in this route are short, the operation is simple, the process repeatability is good, the purification is easy, the total yield is as high as 61.1%, and the batch production is easy.

The abbreviations of the reagents involved in the specification are as follows:

LiHMDS lithium bis(trimethylsilyl)amide;

LDA lithium diisopropylamide;

NaHMDS sodium bis(trimethylsilyl)amide;

LTMPMgCl ₂ magnesium dichloride (2,2,6,6-tetramethylpiperidine) lithium salt;

THF tetrahydrofuran;

TsOH·H ₂ O p-toluenesulfonic acid monohydrate.

Detailed ways

The present invention uses the following examples to further illustrate the present invention, but the protection scope of the present invention is not limited to the examples. Those skilled in the art can make many other changes and modifications without departing from the spirit and protection scope of the present invention, and these changes and modifications are still included in the protection scope of the claims.

Example 1

Compound II prepares compound III:

Compound II (120.0g, 0.705mol, 1.0e.q.) was added to xylene (1200mL), and then trifluoroacetic acid (4.02g, 0.0353mol, 0.05e.q.) was added, and the temperature was raised to 140°C after the addition, reacted for 6 hours, and detected by GC The raw materials were reacted, washed with saturated aqueous sodium carbonate solution, extracted with ethyl acetate (3×900 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness to obtain compound III yellow liquid 108.0 g, yield 90.0%.

Compound III prepares compound IV:

Compound III (70.0g, 0.411mol, 1.0e.q.) was dissolved in THF (700mL), under nitrogen protection, 2.5M n-butyllithium/n-hexane (197mL, 0.494mol, 1.2e.q.) was added dropwise at -78°C, After dripping at -78°C for 20 minutes, slowly introducing dry carbon dioxide gas for about 15 minutes, stopping the introduction of carbon dioxide, starting to drip 1N aqueous hydrochloric acid solution, adjusting pH=2, adding 1L ethyl acetate for extraction, drying and concentrating to obtain The yellow oil was added with 500 mL of petroleum ether to make a slurry, and the solid was precipitated and filtered to obtain 70.5 g of compound IV as a white solid with a yield of 80.0%.

Compound IV prepares compound I-1:

Compound IV (70.0 g, 0.327 mol, 1.0 e.q.) was dissolved in methanol (500 mL), and thionyl chloride (77.8 g, 0.654 mol, 2.0 e.q.) was added dropwise under ice-water bath conditions, refluxed for 10 h after dripping, and the reaction was concentrated. The solution was adjusted to pH=8 with saturated sodium bicarbonate, extracted with ethyl acetate (500 mL×2), dried and concentrated, and the concentrate was slurried with ethyl acetate and petroleum ether (v:v=1:50) to obtain compound I -1 White solid 36.9 g, yield 78.2%.

Example 2

Compound II prepares compound III:

Compound II (125.4g, 0.737mol, 1.0e.q.) was added to toluene (1200mL), and then p-toluenesulfonic acid monohydrate (7.00g, 0.0369mol, 0.05e.q.) was added, and the temperature was raised to 110°C after the addition was completed. After 60 hours, the reaction of the raw materials was detected by GC, washed with saturated aqueous sodium carbonate solution, extracted with ethyl acetate (3×900 mL), dried with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give compound III yellow liquid 117.0 g, yield 93.3 %.

Compound III prepares compound IV:

Compound III (75.1g, 0.441mol, 1.0e.q.) was dissolved in ether (650mL), under nitrogen protection, 1.3M tert-butyllithium/heptane (407mL, 0.529mol, 1.2e.q.) was added dropwise at -78°C, dropwise After finishing the temperature at -78°C for 35 minutes, slowly introducing dry carbon dioxide gas for about 20 minutes, stopping the introduction of carbon dioxide, starting to drip 1N aqueous hydrogen chloride solution, adjusting pH=2, adding 1L ethyl acetate for extraction, drying and concentrating to obtain yellow The oily substance was added with 500 mL of petroleum ether to make a slurry, and the solid was precipitated and filtered to obtain 77.4 g of compound IV as a white solid with a yield of 81.9%.

Compound IV prepares compound I-1:

Compound IV (70.0g, 0.327mol, 1.0e.q.) was dissolved in methanol (500mL), under ice-water bath conditions, thionyl chloride (58.4g, 0.491mol, 1.5e.q.) was added dropwise, refluxed for 10h after dripping, and the reaction was concentrated The solution was adjusted to pH=8 with saturated sodium bicarbonate, extracted with ethyl acetate (500 mL×2), dried and concentrated, and the concentrate was slurried with ethyl acetate and petroleum ether (v:v=1:50) to obtain compound I -1 White solid 37.7 g, yield 80.1%.

Example 3

Compound II prepares compound III:

Compound II (122.6g, 0.720mol, 1.0e.q.) was added to chlorobenzene (1200mL), then benzenesulfonic acid (5.69g, 0.0360mol, 0.05e.q.) was added, the temperature was raised to 130°C after the addition, and the reaction was performed for 20 hours. After the raw materials were reacted, a saturated aqueous sodium carbonate solution was added to wash, extracted with ethyl acetate (3×900 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 112.5 g of compound III as a yellow liquid with a yield of 91.8%.

Compound III prepares compound IV:

Compound III (80.3g, 0.472mol, 1.0e.q.) was dissolved in 2-methyltetrahydrofuran (800mL), under nitrogen protection, 2.0M LDA/n-hexane (283mL, 0.566mol, 1.2e.q.) was added dropwise at -60°C , keep the temperature at -60°C for 60 minutes after dripping, slowly introduce dry carbon dioxide gas for about 30 minutes, stop the introduction of carbon dioxide, start to drip 1N aqueous hydrogen chloride solution, adjust pH=2, add 1L of ethyl acetate for extraction, dry and concentrate A yellow oil was obtained, and 500 mL of petroleum ether was added to make a slurry, and a solid was precipitated, which was filtered to obtain 81.2 g of compound IV as a white solid with a yield of 80.3%.

Compound IV prepares compound I-1:

Compound IV (70.0 g, 0.327 mol, 1.0 e.q.) was dissolved in methanol (500 mL), thionyl chloride (97.3 g, 0.818 mol, 2.5 e.q.) was added dropwise under ice-water bath conditions, refluxed for 10 h after dripping, and the reaction was concentrated. The solution was adjusted to pH=8 with saturated sodium bicarbonate, extracted with ethyl acetate (500 mL×2), dried and concentrated, and the concentrate was slurried with ethyl acetate and petroleum ether (v:v=1:50) to obtain compound I -1 White solid 37.5g, yield 79.5%.

Example 4

Compound II prepares compound III:

Compound II (123.3g, 0.724mol, 1.0e.q.) was added to chlorobenzene (1200mL), then methanesulfonic acid (3.48g, 0.0362mol, 0.05e.q.) was added, and the temperature was raised to 120°C after the addition, reacted for 40 hours, and detected by GC After the reaction of the raw materials was completed, a saturated aqueous sodium carbonate solution was added to wash, extracted with ethyl acetate (3×900 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 111.9 g of compound III as a yellow liquid with a yield of 90.8%.

Compound III prepares compound IV:

Compound III (81.6g, 0.479mol, 1.0e.q.) was dissolved in cyclopentyl methyl ether (550mL), and 1.5M phenyllithium/tetrahydrofuran (383mL, 0.575mol, 1.2e.q.) was added dropwise at -60°C under nitrogen protection. After dripping, the temperature was kept at -60 °C for 45 minutes, and after about 25 minutes of dry carbon dioxide gas was slowly introduced, the introduction of carbon dioxide was stopped, and 1N aqueous hydrogen chloride solution was added dropwise. A yellow oil was obtained, and 500 mL of petroleum ether was added to make a slurry, and a solid was precipitated, which was filtered to obtain 82.2 g of compound IV as a white solid with a yield of 80.1%.

Compound IV prepares compound I-1:

Compound IV (70.0 g, 0.327 mol, 1.0 e.q.) was dissolved in methanol (500 mL), thionyl chloride (136.2 g, 1.15 mol, 3.5 e.q.) was added dropwise under ice-water bath conditions, refluxed for 10 h after dripping, and the reaction was concentrated. The solution was adjusted to pH=8 with saturated sodium bicarbonate, extracted with ethyl acetate (500 mL×2), dried and concentrated, and the concentrate was slurried with ethyl acetate and petroleum ether (v:v=1:50) to obtain compound I -1 White solid 37.2 g, yield 79.0%.

Example 5

Compound II prepares compound III:

Compound II (122.1g, 0.717mol, 1.0e.q.) was added to toluene (1200mL), then trifluoromethanesulfonic acid (5.38g, 0.0359mol, 0.05e.q.) was added, and the temperature was raised to 110°C after the addition, and the reaction was performed for 60 hours, GC After the reaction of the raw materials was detected, saturated aqueous sodium carbonate solution was added for washing, extracted with ethyl acetate (3×900 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 111.5 g of compound III as a yellow liquid with a yield of 91.3%.

Compound III prepares compound IV:

Compound III (76.9g, 0.452mol, 1.0e.q.) was dissolved in tetrahydrofuran (600mL), and under nitrogen protection, 2.0M LDA/n-hexane (271mL, 0.542mol, 1.2e.q.) was added dropwise at -65°C, and the dropwise completed- Incubate at 65°C for 45 minutes, add dry ice in batches within 30 minutes, then start to drip 1N aqueous hydrogen chloride solution, adjust pH=2, add 1L of ethyl acetate for extraction, dry and concentrate to obtain a yellow oil, add 500mL of petroleum ether to beat, The solid was precipitated and filtered to obtain 78.8 g of compound IV as a white solid with a yield of 81.4%.

Compound IV prepares compound I-1:

Compound IV (70.0g, 0.327mol, 1.0e.q.) was dissolved in methanol (500mL), under ice-water bath conditions, thionyl chloride (58.4g, 0.491mol, 1.5e.q.) was added dropwise, refluxed for 10h after dripping, and the reaction was concentrated The solution was adjusted to pH=8 with saturated sodium bicarbonate, extracted with ethyl acetate (500 mL×2), dried and concentrated, and the concentrate was slurried with ethyl acetate and petroleum ether (v:v=1:50) to obtain compound I -1 White solid 38.4g, yield 81.5%.

Example 6

Compound II prepares compound III:

It was prepared by the same method as in Example 1, and finally 112.2 g of compound III was obtained as a yellow liquid with a yield of 92.1%.

Compound III prepares compound IV:

III (82.0g, 0.482mol, 1.0e.q.) was dissolved in THF (550mL), under nitrogen protection, 1.0M LiHMDS/tetrahydrofuran (578mL, 0.578mol, 1.2e.q.) was added dropwise at -65°C, and the temperature was kept at -65°C. After 20 minutes, dry carbon dioxide gas was slowly introduced for about 25 minutes, the introduction of carbon dioxide was stopped, 1N aqueous hydrochloric acid solution was added dropwise, pH=2, 1L of ethyl acetate was added for extraction, dried and concentrated to obtain a yellow oil, and 500mL was added. 83.9 g of compound IV white solid was obtained by slurring the obtained petroleum ether, the solid was precipitated, and the yield was 81.3%.

Compound IV prepares compound 1-2:

It was prepared by the same method as in Example 1, except that 500 mL of ethanol was used instead of methanol as a solvent to participate in the reaction to obtain 42.2 g of compound I-2 as a white solid with a yield of 81.6%.

Example 7

Compound II prepares compound III:

It was prepared by the same method as in Example 2, and finally 117.0 g of compound III was obtained as a yellow liquid with a yield of 92.5%.

Compound III prepares compound IV:

III (77.3g, 0.454mol, 1.0e.q.) was dissolved in ether (600mL), under nitrogen protection, 1.0M magnesium dichloride (2,2,6,6-tetramethylpiperidine) lithium salt was added dropwise at -30°C /THF (545mL, 0.545mol, 1.0e.q.), after dripping, keep at -60°C for 20 minutes, slowly introduce dry carbon dioxide gas for about 30 minutes, stop the introduction of carbon dioxide, start to drip 1N aqueous hydrogen chloride solution, adjust pH= 2. Add 1 L of ethyl acetate for extraction, dry and concentrate to obtain a yellow oil, add 500 mL of petroleum ether to make a slurry, precipitate a solid, and filter to obtain 76.4 g of compound IV as a white solid with a yield of 80.8%.

Compound IV prepares compound I-1:

It was prepared by the same method as in Example 2, except that 500 mL of ethanol was used instead of methanol as a solvent to participate in the reaction to obtain 41.8 g of compound I-2 as a white solid with a yield of 80.9%.

Example 8

Compound II prepares compound III:

It was prepared by the same method as in Example 3, except that xylene was used instead of toluene as the solvent, and finally 115.3 g of compound III was obtained as a yellow liquid with a yield of 90.9%.

Compound III prepares compound IV:

III (82.1g, 0.482mol, 1.0e.q.) was dissolved in 2-methyltetrahydrofuran (550mL), under nitrogen protection, 1.2M LDA/THF (482mL, 0.578mol, 1.2e.q.) was added dropwise at -60°C, and the drop was completed. -60°C for 35 minutes, slowly feed dry carbon dioxide gas for about 35 minutes, stop feeding carbon dioxide, start dropwise addition of 1N aqueous hydrogen chloride solution, adjust pH=2, add 1L of ethyl acetate for extraction, dry and concentrate to obtain a yellow oil 500 mL of petroleum ether was added to make slurry, and the solid was precipitated and filtered to obtain 83.9 g of compound IV as a white solid with a yield of 81.3%.

Compound IV prepares compound I-1:

It was prepared by the same method as in Example 3, except that 500 mL of ethanol was used instead of methanol as a solvent to participate in the reaction to obtain 42.4 g of compound I-2 as a white solid with a yield of 82.0%.

Example 9

Compound II prepares compound III:

It was prepared by the same method as in Example 1, and finally 114.1 g of compound III was obtained as a yellow liquid with a yield of 91.3%.

Compound III prepares compound IV:

III (83.1g, 0.488mol, 1.0e.q.) was dissolved in cyclopentyl methyl ether (800mL), under nitrogen protection, 2.5M n-butyllithium/n-hexane (234mL, 0.586mol, 1.2e.q.) was added dropwise at -78°C. ), keep the temperature at -60°C for 30 minutes after dripping, add dry ice in batches within 20 minutes, then start to drip 1N aqueous hydrogen chloride solution, adjust pH=2, add 1L ethyl acetate for extraction, dry and concentrate to obtain a yellow oil, add 500mL 81.2 g of compound IV white solid was obtained by slurring the obtained petroleum ether, the solid was precipitated, and the yield was 81.1%.

Compound IV prepares compound 1-2:

It was prepared by the same method as in Example 4, except that 500 mL of ethanol was used instead of methanol as the solvent to participate in the reaction to obtain 41.2 g of compound I-2 as a white solid with a yield of 79.8%.

Example 10

Compound II prepares compound III:

It was prepared by the same method as in Example 1, except that trifluoromethanesulfonic acid was used instead of trifluoroacetic acid, and finally 113.6 g of compound III was obtained as a yellow liquid with a yield of 90.8%.

Compound III prepares compound IV:

Compound III (75.3g, 0.442mol, 1.0e.q.) was dissolved in 2-methyltetrahydrofuran (600mL), under nitrogen protection, -65°C 1.0M LiHMDS/tetrahydrofuran (530mL, 0.530mol, 1.2e.q.), dropwise - Incubate at 65°C for 45 minutes, slowly feed dry carbon dioxide gas for about 35 minutes, stop feeding carbon dioxide, start dropwise addition of 1N aqueous hydrogen chloride solution, adjust pH=2, add 1L of ethyl acetate for extraction, dry and concentrate to obtain a yellow oil , 500 mL of petroleum ether was added to make slurry, the solid was precipitated, and filtered to obtain 76.1 g of compound IV as a white solid with a yield of 80.4%.

Compound IV prepares compound 1-2:

It was prepared by the same method as in Example 6 to obtain 42.4 g of compound I-2 as a white solid with a yield of 82.1%.

Table 1. Compound structure analysis

Claims (9)

1. A process for the preparation of compound IV, which comprises:

starting from compounds II

(1) Firstly, rearrangement is carried out under the action of a catalyst to obtain a compound III

(2) Then carboxylating with carbon dioxide or dry ice under the action of strong alkali to obtain a compound IV

In the preparation of compound II compound III step (1) the catalyst is selected from: trifluoroacetic acid, p-toluenesulfonic acid monohydrate, trifluoromethanesulfonic acid, benzenesulfonic acid, methanesulfonic acid.

2. The process for the preparation of compound IV according to claim 1, compound III in step (1) of compound II

The medium solvent is selected from: xylene, toluene, chlorobenzene.

3. The method for preparing the compound IV according to claim 1, wherein the reaction temperature in the step (1) of preparing the compound III from the compound II is in the range of 110-140 ℃; the reaction time is 6-60 hours.

4. The process for the preparation of compound IV according to claim 1, wherein in the step (2) of the preparation of compound IV from compound III, the strong base is selected from the group consisting of n-butyllithium, t-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium magnesium dichloride (2,2,6, 6-tetramethylpiperidine), and phenyllithium.

5. The process for producing compound IV according to claim 1 or claim 4, wherein the molar ratio of compound III to the strong base in the step (2) of producing compound IV from compound III is 1.0: 1.0 to 1.0: 3.0.

6. The process for the preparation of compound IV according to claim 1 or claim 4, wherein the reaction temperature in the step (2) of preparing compound IV from compound III is-78 to-30 ℃.

7. The process for the preparation of compound IV according to claim 1 or claim 4, wherein the reaction solvent in step (2) of the preparation of compound IV from compound III is selected from the group consisting of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, and cyclopentylmethyl ether.

8. A process for the preparation of a compound of formula I, characterized in that a compound IV

Under the action of thionyl chloride, the compound and ROH are subjected to esterification reaction to obtain a compound I

Wherein R is methyl or ethyl;

further comprising the step of preparing compound IV according to claim 1.

9. The method for preparing the compound of formula I according to claim 8, wherein the molar ratio of the compound IV to the thionyl chloride is 1.0: 1.5-1.0: 3.5.