WO2020132820A1

WO2020132820A1 - Synthesis method for 3-(benzyloxy)-4-oxo-4h-pyran-2-carboxylic acid

Info

Publication number: WO2020132820A1
Application number: PCT/CN2018/123144
Authority: WO
Inventors: 叶伟平; 周章涛; 费安杰; 谢阳银; 习林刚
Original assignee: 广东莱佛士制药技术有限公司
Priority date: 2018-12-24
Filing date: 2018-12-24
Publication date: 2020-07-02

Abstract

Disclosed is a synthesis method for 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. The acid takes furfuryl alcohol as a starting material and is prepared with four steps: rearrangement, addition, hydroxyl protection and oxidation.

Description

Synthesis method of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid

Technical field

The present invention relates to the field of organic chemical synthesis, and more specifically, to a method of synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

Background technique

There are a variety of preclinical, clinical, and marketed new drugs that contain 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid fragments. As shown in the figure below, several types of drug molecules, as well as the marketed drugs such as dulutevir (GSK1349572) and baloxavir (Baloxavir) contain this important structural fragment.

At present, this structure sheet has two main synthetic routes, as shown in the figure below. The main drawback of this route is that the materials are expensive, the steps are long, and it is difficult to scale up safely:

Another synthetic method is the following synthetic route. This synthetic route is relatively superior, but selenium dioxide is highly toxic and the amount used is large.

However, when these two routes were used to synthesize the target structure fragments, it was found that the yield was very low and the repeatability was poor.

In summary, the development of the pharmaceutical industry requires 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid as a pharmaceutical intermediate. However, its process route has harsh reaction conditions and material safety The problem is low, and it is difficult to produce amplification.

Summary of the invention

In view of the shortcomings of the existing technology, in order to improve the shortcomings of the reaction route of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid synthesis process, the process safety is low, the production scale is difficult to scale up The invention provides a method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

The present invention is achieved through the following technical solutions:

A method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid, characterized in that the synthetic route is:

Further, it includes the following steps,

S1, in the presence of a solvent and a weak base salt catalyst, Compound I and chlorine gas undergo rearrangement reaction to obtain Compound II;

S2. In the presence of a solvent and a strong base, compound III and aldehyde are added to give compound III;

S3. In the presence of a solvent and a base, compound III is reacted with a benzyl compound to obtain compound IV;

S4, compound IV and oxidizing agent are oxidized to obtain compound VI;

Among them, compound I is

Compound II is

Compound III is

Compound IV is

Compound VI is

Further, in steps S1-S3, the solvent is selected from methanol, isopropanol, tetrahydrofuran, 1,4-dioxane or ethanol, preferably methanol.

Further, in step S1, the weak base salt catalyst is selected from sodium acetate or potassium acetate, preferably sodium acetate.

Further, in step S1, the molar ratio of the compound I to chlorine gas is 1:1-2; wherein, when chlorine gas is introduced, the system temperature is controlled at -10°C-25°C, preferably -5°C-5°C.

The temperature of the rearrangement reaction is controlled at 50°C-80°C, preferably 60°C-70°C.

In the present invention, the rearrangement reaction is used in step S1, and the yield is high, which can reach more than 50%, which facilitates the subsequent reaction, so that the subsequent reaction only needs four steps of addition, hydroxyl protection, and oxidation to prepare the target product.

Further, in step S2, the strong base is selected from sodium hydroxide, sodium methoxide or sodium ethoxide, preferably sodium hydroxide.

Further, in step S2, the aldehyde is selected from formaldehyde or paraformaldehyde, preferably formaldehyde.

Further, in step S3, the base is selected from sodium hydroxide, sodium methoxide, 1,8-diazabicycloundec-7-ene (DBU), 1,5,7-triazabicarbonate Cyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), potassium tert-butoxide, Sodium ethoxide or potassium carbonate is preferably sodium hydroxide.

Further, in step S3, the benzyl compound is selected from benzyl bromide or benzyl chloride, preferably benzyl chloride.

Further, in step S4, the oxidizing agent is selected from the group consisting of manganese dioxide, dimethyl sulfoxide, (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodide -3(1H)-one (Dess-Martin oxidant), 2,2,6,6-tetramethylpiperidine-nitrogen-oxide (TEMPO), o-iodylbenzoic acid (IBX), pyridine chlorochromate (PCC), Jones reagent (JONE'S reagent), sodium chlorite or oxygen, preferably 2,2,6,6-tetramethylpiperidine-nitrogen oxide (TEMPO).

Compared with the prior art, the present invention has the following advantages:

1. Synthesize 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid in the method provided by the present invention. Its raw material is furfuryl alcohol, which is oxidized with chlorine gas in the presence of sodium acetate or potassium acetate Ring expansion rearrangement occurs, and the rearrangement reaction uses a common weak base salt catalyst, which is simple and easy to obtain, the catalyst cost is low, and the conditions of the rearrangement reaction are strictly controlled, such as the system temperature and the temperature of the rearrangement reaction when chlorine gas is introduced .

2. The technical scheme of the present invention has a novel synthetic route, taking furfuryl alcohol as the starting material, after four steps of rearrangement, addition, hydroxyl protection, and oxidation, the whole preparation process is simple, the steps are few, the raw materials are cheap and easily available, and the use or production is avoided. The total molar yield of toxic products and by-products is greater than 32%. It has the characteristics of relatively mild reaction conditions and significantly improves the yield of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid Rate and purity, at the same time, the conditions of the present invention are controllable, the process is stable, the repeatability is strong, and industrial mass production can be achieved.

3. The synthetic route of the technical solution of the present invention does not use expensive raw materials, which greatly reduces the production cost, and the product does not contain heavy metal elements that cause serious pollution to the environment, making it more in line with environmental protection standards.

detailed description

The invention discloses a method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. The synthetic route is:

It includes the following steps,

S4, the compound IV and the oxidant undergo an oxidation reaction to form an intermediate V, and then a compound VI is obtained;

Among them, compound I is

Compound II is

Compound III is

Compound IV is

Intermediate V is

Compound VI is

The following describes the preferred embodiments of the present invention in detail so that the advantages and features of the present invention can be more easily understood by those skilled in the art, so as to make the protection scope of the present invention more clearly defined.

Example 1

1. Synthesis of 3-hydroxy-4H-pyran-4-one (Compound II)

Methanol (60L), water (40L) and sodium acetate (20Kg) were added to the reaction kettle, and the temperature was lowered to -5°C. Furfuryl alcohol (Compound I) (40 kg) was dissolved in methanol (40 L) and water (20 L), added dropwise to the reaction kettle at a temperature control of -5°C, and chlorine gas (57.8 kg) was introduced into the reaction kettle while dropping. Incubate for 1h, the reaction is over, incubate overnight and filter. The mother liquor was heated to 50°C, stirred for 2h, and cooled to room temperature. filter. It was concentrated under reduced pressure to remove methanol and crystallized to obtain 26.7 kg of 3-hydroxy-4H-pyran-4-one (Compound II) with a purity of 95% and a yield of 59%. LC-MS: [M+H] ⁺ = 113.02.

2. Synthesis of 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (compound III)

3-Hydroxy-4H-pyran-4-one (Compound II) (26.7 kg) and methanol (134 L) were added to the reaction kettle and stirred. The temperature was lowered to 10°C, and a mixed solution of sodium hydroxide (11.1Kg) and water (38L) was added dropwise. After stirring for 1h, 37% formaldehyde (48L) was added dropwise. The temperature was raised to room temperature and stirred for 24 h. The reaction was completed, the temperature was lowered to 10° C., the pH was adjusted to 1 with concentrated hydrochloric acid, the methanol was concentrated under reduced pressure, and dichloromethane (116 L) was added and stirred. Then, the inorganic salts are filtered and separated. The aqueous phase was extracted twice more with dichloromethane (87L). The organic phases were combined and concentrated under reduced pressure. The solid was distilled out of the isopropanol jacket and filtered under reduced temperature to obtain 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (Compound III) 29.1Kg with a purity of 97%. The yield was 86%. LC-MS: [M+H] ⁺ = 143.03.

3. Synthesis of 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (Compound IV)

Add 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (Compound III) (29.1Kg), methanol (148L), water (55L) and sodium hydroxide (9.8Kg) to the reaction kettle ), start stirring, and raise the temperature to 70 ℃. Benzyl chloride (28.6Kg, 1.1eq.) was added dropwise and kept at 70℃ for 3.0h. After the reaction, the temperature was lowered to room temperature, filtered, and methanol was concentrated. The aqueous phase was extracted three times with dichloromethane (60 L), the organic phases were combined, concentrated under reduced pressure, and filtered under reduced temperature to obtain 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (compound IV) 39.8Kg, purity 98%, yield 84%. LC-MS: [M+H] ⁺ = 233.08.

4. Synthesis of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (Compound VI)

Add 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (Compound IV) 39.8Kg, dichloromethane (340L) and water (170L) to the reaction kettle to start stirring. Then add sodium bicarbonate (77Kg), sodium bromide (1.6Kg) and 2,2,6,6-tetramethylpiperidine-nitrogen-oxide (TEMPO) (2.3Kg), cool to 5℃, drop Add 10% sodium hypochlorite (340Kg). After the dropwise addition, stir at 5°C for 1 hour. The reaction is completed. Add 30% aqueous sodium thiosulfate solution (242L) and stir for 1 h. Add concentrated hydrochloric acid to adjust pH=4, separate the organic phase, extract the aqueous phase twice with dichloromethane (120L), combine the organic phases, and concentrate under reduced pressure to obtain the crude product. The crude product was recrystallized from acetonitrile to obtain 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (Compound VI) 32.4Kg, purity 99%, yield 77%. LC-MS: [M+H] ⁺ = 247.06, [M] ⁺ = 245.05; ¹ H NMR (DMSO-d ₆ ) δ8.00 (d, J = 5.6 Hz, 1H), 7.17 (s, 5H), 6.34 (d, J = 5.7 Hz, 1H), 4.91 (s, 2H), 2.30 (s, 1H).

Example 2

1. Synthesis of 3-hydroxy-4H-pyran-4-one (Compound II)

Ethanol (30L), water (20L) and sodium acetate (10Kg) were added to the reaction kettle, and the temperature was lowered to 5°C. Furfuryl alcohol (Compound I) (20 kg) was dissolved in ethanol (20 L) and water (10 L), added dropwise to the reaction kettle at a temperature control of 5°C, and chlorine gas (25.5 kg) was introduced into the reaction kettle while dropping. Incubate for 1h, the reaction is over, incubate overnight and filter. The mother liquor was heated to 70°C, stirred for 2h, and cooled to room temperature. filter. Concentrate under reduced pressure to remove ethanol and crystallize to obtain 14.2 kg of 3-hydroxy-4H-pyran-4-one (Compound II) with a purity of 94% and a yield of 62%. LC-MS: [M+H] ⁺ = 113.02.

2. Synthesis of 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (compound III)

3-Hydroxy-4H-pyran-4-one (Compound II) (14.2 kg) and methanol (70 L) were added to the reactor and stirred. The temperature was lowered to 5°C, and a mixed solution of sodium hydroxide (5.6Kg) and water (18L) was added dropwise. After stirring for 1h, 37% formaldehyde (25L) was added dropwise. The temperature was raised to room temperature and stirred for 24 h. The reaction was completed, the temperature was lowered to 5° C., the pH was adjusted to 1 with concentrated hydrochloric acid, the methanol was concentrated under reduced pressure, and dichloromethane (56 L) was added to stir. Then, the inorganic salts are filtered and separated. The aqueous phase was extracted twice more with dichloromethane (45L). The organic phases were combined and concentrated under reduced pressure. The solid was distilled out of the isopropanol jacket, and the temperature was filtered to obtain 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (Compound III) 15.5 Kg, purity 96%. The yield was 86%. LC-MS: [M+H] ⁺ = 143.03.

3. Synthesis of 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (Compound IV)

Add 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (Compound III) (15.5Kg), methanol (65L), water (28L) and sodium hydroxide (4.8Kg) to the reaction kettle ), start stirring, and raise the temperature to 70 ℃. Benzyl chloride (28.6Kg, 1.1eq.) was added dropwise and kept at 70℃ for 3.0h. After the reaction, the temperature was lowered to room temperature, filtered, and methanol was concentrated. The aqueous phase was extracted three times with dichloromethane (35L), the organic phases were combined, concentrated under reduced pressure, and filtered under reduced temperature to obtain 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (compound IV) 19.8Kg, purity 96%, yield 78%. LC-MS: [M+H] ⁺ = 233.08.

4. Synthesis of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (Compound VI)

Add 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (Compound IV) 19.8Kg, dichloromethane (176L) and water (85L) to the reaction kettle to start stirring. Then add sodium bicarbonate (46Kg), sodium bromide (0.9Kg) and 2,2,6,6-tetramethylpiperidine-nitrogen-oxide (TEMPO) (1.4Kg), drop the temperature to 5℃, drop Add 10% sodium hypochlorite (175Kg). After the dropwise addition, stir at 5°C for 1 h. The reaction is completed. Add 30% aqueous sodium thiosulfate solution (119L) and stir for 1 h. Add concentrated hydrochloric acid to adjust pH=3.5, separate the organic phase, extract the aqueous phase twice with dichloromethane (65L), combine the organic phases, and concentrate under reduced pressure to obtain the crude product. The crude product was recrystallized from acetonitrile to obtain 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (Compound VI) 17.5Kg, purity 99%, yield 83%. LC-MS: [M+H] ⁺ = 247.06, [M] ⁺ = 245.05; ¹ H NMR (DMSO-d ₆ ) δ8.00 (d, J = 5.6 Hz, 1H), 7.17 (s, 5H), 6.34 (d, J = 5.7 Hz, 1H), 4.91 (s, 2H), 2.30 (s, 1H).

Example 3

1. Synthesis of 3-hydroxy-4H-pyran-4-one (Compound II)

Tetrahydrofuran (30L), water (20L) and potassium acetate (10kg) were added to the reaction kettle and the temperature was lowered to 5°C. Furfuryl alcohol (Compound I) (20kg) was dissolved in tetrahydrofuran (20L) and water (10L), added dropwise to the reaction kettle at a temperature control of 5°C, and chlorine gas (30kg) was introduced into the reaction kettle while dropping. Incubate for 1h, the reaction is over, incubate overnight and filter. The mother liquor was heated to 60°C, stirred for 2h, and cooled to room temperature. filter. Concentrate under reduced pressure to remove tetrahydrofuran and crystallize to obtain 12.4 kg of 3-hydroxy-4H-pyran-4-one (Compound II) with a purity of 95% and a yield of 54%. LC-MS: [M+H] ⁺ = 113.02.

2. Synthesis of 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (compound III)

3-Hydroxy-4H-pyran-4-one (Compound II) (12.4 kg) and methanol (76 L) were added to the reaction kettle and stirred. The temperature was lowered to 10°C, and a mixed solution of sodium methoxide (7.2Kg) and methanol (45L) was added dropwise. After stirring for 1 h, 40% formaldehyde (22.5 L) was added dropwise. The temperature was raised to room temperature and stirred for 24h, the reaction was completed, the temperature was lowered to 10°C, the pH was adjusted to 1 with concentrated hydrochloric acid, the methanol was concentrated under reduced pressure, and dichloromethane (60L) was added to stir. Then, the inorganic salts are filtered and separated. The aqueous phase was extracted twice more with dichloromethane (45L). The organic phases were combined and concentrated under reduced pressure. The solid was distilled out of the isopropanol jacket and filtered under reduced temperature to obtain 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (Compound III) 12.7 Kg with a purity of 96%. The yield was 82%. LC-MS: [M+H] ⁺ = 143.03.

3. Synthesis of 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (Compound IV)

Add 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (Compound III) (12.7Kg), methanol (127L) and potassium carbonate (18.5Kg) to the reaction kettle, start stirring and heat up To 70°C. Benzyl bromide (16.8Kg, 1.1eq.) was added dropwise and kept at 70°C for 2.0h. After the reaction, the temperature was lowered to room temperature, filtered, and methanol was concentrated. Water (60 L) and dichloromethane (120 L) were added, washed, and the layers were separated. The aqueous phase was extracted three times with dichloromethane (30 L). The organic phases were combined, concentrated under reduced pressure, and filtered under reduced temperature to obtain 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (Compound IV) 16.8Kg, purity 98%, yield 81 %. LC-MS: [M+H] ⁺ = 233.08.

4. Synthesis of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (Compound VI)

Add 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (Compound IV) (16.8Kg), acetonitrile (135L) and o-iodoylbenzoic acid ( IBX) (24.3kg), heated to reflux for 6h. TLC monitored the disappearance of the raw materials, cooled to room temperature, and filtered. Sodium chlorite (19.5kg) and water (135L) were added to the filtrate and stirred at room temperature for 10h. Filter, add 30% sodium thiosulfate (113L) to the filtrate and stir for 1 h, add concentrated hydrochloric acid to adjust pH=4, concentrate under reduced pressure to remove acetonitrile, add ethyl acetate (120L) for extraction three times. The organic phases were combined, concentrated under reduced pressure, and filtered under reduced temperature to obtain a crude product. The crude product was recrystallized from acetonitrile to obtain 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (Compound VI) 12.7 Kg, purity 99%, yield 71.3%. LC-MS: [M+H] ⁺ = 247.06, [M] ⁺ = 245.05; ¹ H NMR (DMSO-d ₆ ) δ8.00 (d, J = 5.6 Hz, 1H), 7.17 (s, 5H), 6.34 (d, J = 5.7 Hz, 1H), 4.91 (s, 2H), 2.30 (s, 1H).

Example 4

1. Synthesis of 3-hydroxy-4H-pyran-4-one (Compound II)

Tetrahydrofuran (50L), water (20L) and potassium acetate (10kg) were added to the reaction kettle and the temperature was lowered to 5°C. Furfuryl alcohol (Compound I) (25 kg) was dissolved in tetrahydrofuran (20 L) and water (10 L), added dropwise to the reaction kettle at a temperature control of 5° C., and chlorine gas (36.5 kg) was added to the reaction kettle while dropping. Incubate for 1h, the reaction is over, incubate overnight and filter. The mother liquor was heated to 80°C, stirred for 2h, and cooled to room temperature. filter. Concentrate under reduced pressure to remove tetrahydrofuran and crystallize to obtain 16.5 kg of 3-hydroxy-4H-pyran-4-one (Compound II) with a purity of 95% and a yield of 58%. LC-MS: [M+H] ⁺ = 113.02.

2. Synthesis of 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (compound III)

3-Hydroxy-4H-pyran-4-one (Compound II) (16.5 kg) and ethanol (86 L) were added to the reaction kettle and stirred. The temperature was lowered to 10°C, and a mixed solution of sodium ethoxide (8.4Kg) and ethanol (56L) was added dropwise. After stirring for 1 h, 40% formaldehyde (25.5 L) was added dropwise. The temperature was raised to room temperature and stirred for 24h, the reaction was completed, the temperature was lowered to 10°C, the pH was adjusted to 1 with concentrated hydrochloric acid, the ethanol was concentrated under reduced pressure, and dichloromethane (75L) was added and stirred. Then, the inorganic salts are filtered and separated. The aqueous phase was extracted twice more with dichloromethane (50 L). The organic phases were combined and concentrated under reduced pressure. The solid was distilled out of the isopropanol jacket and filtered under reduced temperature to obtain 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (Compound III) 15.5Kg with a purity of 97%. The yield is 74%. LC-MS: [M+H] ⁺ = 143.03.

3. Synthesis of 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (Compound IV)

Add 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (Compound III) (15.5Kg), methanol (135L) and potassium carbonate (24Kg) to the reaction kettle, start stirring, and warm up to 70℃. Benzyl bromide (18.6Kg, 1.1eq.) was added dropwise and kept at 70°C for 2.0h. After the reaction, the temperature was lowered to room temperature, filtered, and methanol was concentrated. Water (65L) and dichloromethane (135L) were added, washed, and the layers were separated. The aqueous phase was extracted three times with dichloromethane (35L). The organic phases were combined, concentrated under reduced pressure, and filtered under reduced temperature to obtain 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (Compound IV) 19.4Kg, purity 98%, yield 76 %. LC-MS: [M+H] ⁺ = 233.08.

4. Synthesis of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (Compound VI)

Add 2-(hydroxymethyl)-3-(benzyloxy)-4H-pyran-4-one (Compound IV) (19.4Kg), acetonitrile (145L) and o-iodoylbenzoic acid ( IBX) (25.6kg), heated to reflux for 6h. TLC monitored the disappearance of the raw materials, cooled to room temperature, and filtered. Sodium chlorite (24.2kg) and water (145L) were added to the filtrate and stirred at room temperature for 10h. Filter, add 30% sodium thiosulfate (125L) to the filtrate and stir for 1 h, add concentrated hydrochloric acid to adjust pH=4, concentrate under reduced pressure to remove acetonitrile, add ethyl acetate (138L) for extraction three times. The organic phases were combined, concentrated under reduced pressure, and filtered under reduced temperature to obtain a crude product. The crude product was recrystallized from acetonitrile to obtain 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (Compound VI) 14.6 Kg, purity 99%, yield 71%. LC-MS: [M+H] ⁺ = 247.06, [M] ⁺ = 245.05; ¹ H NMR (DMSO-d ₆ ) δ8.00 (d, J = 5.6 Hz, 1H), 7.17 (s, 5H), 6.34 (d, J = 5.7 Hz, 1H), 4.91 (s, 2H), 2.30 (s, 1H).

The above are only preferred embodiments of the present invention and do not limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made by the description of the present invention, or directly or indirectly used in other related technical fields, the same is true Included in the patent protection scope of the present invention.

Claims

A method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid, characterized in that the synthetic route is:
The method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid according to claim 1, characterized in that it includes the following steps,

S1, in the presence of a solvent and a weak base salt catalyst, Compound I and chlorine gas undergo rearrangement reaction to obtain Compound II;

S2. In the presence of a solvent and a strong base, compound III and aldehyde are added to give compound III;

S3. In the presence of a solvent and a base, compound III is reacted with a benzyl compound to obtain compound IV;

S4, compound IV and oxidizing agent are oxidized to obtain compound VI;

Among them, compound I is
Compound II is
Compound III is
Compound IV is
Compound VI is
The method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid according to claim 2, wherein in steps S1-S3, the solvent is selected from Including methanol, isopropanol, tetrahydrofuran, 1,4-dioxane or ethanol.
The method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid according to claim 2, wherein in step S1, the weak base salt catalyst is selected It includes sodium acetate or potassium acetate.
The method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid according to claim 2, wherein in step S1, the compound I and chlorine The molar ratio is 1:1-2; the temperature of the rearrangement reaction is controlled at 50°C-80°C.
The method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid according to claim 2, wherein in step S2, the strong base is selected from the group consisting of Sodium hydroxide, sodium methoxide or sodium ethoxide.
The method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid according to claim 2, wherein in step S2, the aldehyde is selected from formaldehyde Or paraformaldehyde.
A method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid according to claim 2, wherein in step S3, the base is selected from hydrogen Sodium oxide, sodium methoxide, DBU, TBD, MTBD, potassium tert-butoxide, sodium ethoxide or potassium carbonate.
The method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid according to claim 2, wherein in step S3, the benzyl compound is selected from Including benzyl bromide or benzyl chloride.
The method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid according to claim 2, wherein in step S4, the oxidizing agent is selected from Manganese oxide, dimethyl sulfoxide, Dess-Martin reagent, TEMPO, IBX, PCC, JONE'S reagent, sodium chlorite or oxygen.