A method for the synthesis of vitamin b6

Abstract

The application provides a synthesis method of vitamin B6. Specifically provided is a synthesis method of a compound VI or a salt thereof, which comprises the following steps: step (1): performing a hydrolysis reaction on a compound II in a solvent to obtain a compound IV; step (2): performing a decarboxylation reaction on the compound IV in a solvent to obtain a compound V; and step (3): performing a hydrolysis reaction on the compound V in the presence of an acid to obtain the compound VI or the salt thereof. The synthesis method provided by the application has high yield, simple operation and good industrialization prospect.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically to a method for synthesizing vitamin B6. Background Technology

[0002] Vitamin B6 has a wide range of physiological functions and is one of the essential vitamins for the human body. Industrially, there are two main methods for synthesizing vitamin B6: the pyridone process and the oxazole process. The pyridone process was used in early industrial production, but due to its long process, low yield, and severe equipment corrosion, it was gradually replaced by the later-developed oxazole process.

[0003] The oxazole process uses 2-n-propyl-1,3-dioxane and 4-methyl-5-ethoxyoxazole in a three-step reaction involving addition, aromatization, and hydrolysis to obtain vitamin B6.

[0004] Journal of Medicinal Chemistry, 2006, 49 , 21 reported an example of a pyridine compound undergoing a hydrolysis reaction in a sodium hydroxide solution at 100 °C, followed by a high-temperature decarboxylation reaction in diphenyl ether, which successfully yielded the desired target compound (the product after decarboxylation of the pyridine ring).

[0005] Currently, in the industrial production of 4-methyl-5-ethoxyoxazole, oxazole carboxylate is used as a reaction intermediate. Oxazole carboxylate is saponified to obtain sodium oxazole carboxylate, which is then decarboxylated with hydrochloric acid to a strongly acidic environment and heated to yield 4-methyl-5-ethoxyoxazole. This method for preparing 4-methyl-5-ethoxyoxazole has a relatively low yield, and the further addition reaction with the heptacyclic ring is time-consuming and inefficient. There are currently no reported cases of directly synthesizing vitamin B6 using oxazole carboxylate and the heptacyclic ring. Therefore, it is essential to develop a high-yield, simple method for synthesizing vitamin B6 using oxazole carboxylate and the heptacyclic ring as raw materials. Summary of the Invention

[0006] The technical problem to be solved by this invention is to overcome the shortcomings of existing vitamin B6 synthesis methods, such as low yield and complex operation. Therefore, this invention provides a vitamin B6 synthesis method. The vitamin synthesis method provided by this invention is simple to operate, has a high yield, and has good prospects for industrialization.

[0007] This invention provides a method for synthesizing compound VI or a salt thereof, comprising the following steps: Step (1): In a solvent, compound II is hydrolyzed to obtain compound IV;

[0008] R1 is C 1-6 alkyl; R2 is C1-6 alkyl; Step (2): Compound IV is decarboxylated in a solvent to obtain compound V;

[0009] Step (3): In the presence of acid, compound V is hydrolyzed to obtain compound VI or its salt; .

[0010] In one embodiment, the synthesis method described in any embodiment of the present invention has the following technical features, and the technical features not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment").

[0011] In one embodiment, step (1) of the hydrolysis reaction includes the following steps: in a solvent, compound II is saponified in the presence of an alkali to obtain a salt of compound II (e.g., a sodium salt); in the presence of an acid, the salt of compound II reacts with the acid to obtain compound IV;

[0012] R1 and R2 are groups defined in any embodiment of the present invention.

[0013] In one scheme, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0014] In one scheme, R1 is n-propyl.

[0015] In one particular scheme, R2 is an ethyl group.

[0016] In one embodiment, in step (1), the solvent in the saponification reaction is an inorganic solvent, such as water.

[0017] In one embodiment, in step (1), the alkali in the saponification reaction is an inorganic alkali, such as an alkali metal hydroxide (the alkali metal is, for example, sodium, potassium, or lithium), such as sodium hydroxide. In the saponification reaction, the inorganic alkali may be used in the form of its aqueous solution.

[0018] In one embodiment, in step (1), the mass ratio of the solvent to compound II in the saponification reaction is (2~15):1, preferably (8~10):1, for example 5:1, 7:1, 8:1, 8.3:1, 9:1 or 10:1.

[0019] In one embodiment, in step (1), the molar ratio of the alkali to the compound II in the saponification reaction is (1~5):1, preferably (1.5~2):1, for example 1.5:1, 2:1, 1.8:1, 1:1 or 3:1.

[0020] In one scheme, in step (1), the saponification reaction is carried out at 50~110°C, preferably 80~90°C, for example 80°C, 90°C, 85°C, 60°C or 100°C.

[0021] In step (1), the saponification reaction process can be monitored using conventional methods in the art, such as HPLC or TLC. Preferably, the reaction time is 2-4 hours, preferably 2.5-3.5 hours, until compound II no longer converts to the reaction endpoint.

[0022] In one embodiment, step (1) of the saponification reaction includes the following post-processing step: recovering the alcohol reagent (HO-R2), such as ethanol, for example, by vacuum distillation.

[0023] In one embodiment, in step (1), the acid is an inorganic acid, such as hydrochloric acid. The hydrochloric acid can be used as an aqueous solution with a hydrochloric acid mass content of 5% to 32%, more preferably as an aqueous solution with a hydrochloric acid mass content of 10% to 15% (e.g., 10%, 15%, 12%, 5% or 25%).

[0024] In one embodiment, in step (1), the amount of acid used is to adjust the pH range to 2.0~3.5; preferably 2.0~2.5, for example, pH 2, 2.5 or 3.

[0025] In one embodiment, step (1) after the salt and acid reaction of compound II is completed includes the following post-treatment: filtration, preferably at 0-20°C, more preferably at 5-10°C, for example at 0°C, 5°C, 8°C, 10°C or 20°C.

[0026] In one embodiment, the reaction raw materials in step (1) are the solvent, compound II, the base, and the acid.

[0027] In step (1), the salt and acid reaction process of compound II can be monitored using conventional methods in the art, such as HPLC or TLC, preferably with the reaction endpoint being the point at which compound IV is no longer generated.

[0028] In one embodiment, in step (2), the solvent is an organic solvent, preferably selected from one or more of aromatic hydrocarbon solvents, ether solvents, amide solvents, alcohol solvents and sulfone solvents, for example, selected from aromatic hydrocarbon solvents or ether solvents; the aromatic hydrocarbon solvent may be m-xylene, the ether solvent may be n-butyl ether, and the amide solvent may be N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMAC) (preferably an aromatic hydrocarbon solvent).

[0029] In one embodiment, in step (2), the solvent is an alcohol solvent and / or water.

[0030] In one embodiment, in step (2), the mass ratio of the solvent to compound IV is (2~15):1, preferably (4~12):1, for example 5:1, 4.5:1, 4:1, 3:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1 or 13:1.

[0031] In one scheme, in step (2), the decarboxylation reaction temperature is 150~220℃, preferably 185~195℃, for example 185℃, 195℃, 190℃, 180℃ or 200℃.

[0032] In one embodiment, step (2) of the decarboxylation reaction includes the following post-processing steps: after the reaction is completed, the solvent is recovered (e.g., by vacuum distillation, for example, to recover 80%-90% of the solvent), water is added for azeotropic distillation (e.g., water is added at a mass equal to that of m-xylene, and the mixture is azeotropically distilled under reduced pressure) to obtain compound V, and / or the post-processing further includes washing with water and filtering to obtain compound V.

[0033] In one embodiment, the reaction raw materials for step (2) are the solvent and compound IV.

[0034] In step (2), the decarboxylation reaction process can be monitored using conventional methods in the art, such as HPLC or TLC, preferably until compound IV no longer converts to the reaction endpoint. The decarboxylation reaction time can be 0.5 to 3 hours, more preferably 1 to 2 hours.

[0035] In one embodiment, in step (3), the hydrolysis reaction is carried out in an inorganic solvent, such as water.

[0036] In one embodiment, in step (3), the acid in the hydrolysis reaction is an inorganic acid, such as hydrochloric acid. The hydrochloric acid can be an aqueous solution (e.g., a 10 mol / L aqueous solution of hydrochloric acid).

[0037] In one scheme, in step (3), the amount of acid used in the hydrolysis reaction is to adjust the pH range to 0.5-2, for example 0.5-1 (for example 0.5).

[0038] In one embodiment, in step (3), the mass-volume ratio of compound V to solvent in the hydrolysis reaction can be (0.1-5):1 g / mL, preferably (1-2):1 g / mL, for example 1.5:1 g / mL.

[0039] In one embodiment, in step (3), the hydrolysis reaction is carried out at 40-80°C, for example, 60°C or 65°C. In another embodiment, after the hydrolysis reaction is completed, step (3) includes the following post-treatment: recovering (e.g., vacuum distillation) the aldehyde reagent (R1-CHO), adding an alcohol solvent (e.g., ethanol), and filtering at 10-30°C to obtain the compound VI or its salt; wherein the mass ratio of the alcohol solvent to compound V can be (0.5-1.5):1, for example, 0.5:1 or 1:1, preferably filtered at 15-20°C, for example, at 15°C, 20°C, 17°C, 10°C or 30°C.

[0040] In step (3), the hydrolysis reaction process can be monitored using conventional methods in the art, such as HPLC or TLC, preferably with the reaction endpoint being when compound IV is no longer generated.

[0041] In one embodiment, the synthesis method includes the following steps: Step (1): In an aqueous solvent, compound II is saponified in the presence of an alkali metal hydroxide to obtain compound III. The alcohol (HO-R2, such as ethanol) reagent is recovered. In the presence of an inorganic acid, at a pH range of 2.0 to 3.5, compound III is reacted to obtain compound IV. The mixture is then filtered at 0 to 20°C.

[0042] R1 and R2 are groups defined in any embodiment of the present invention; M is an alkali metal ion; Step (2): Add aromatic hydrocarbon solvent or ether solvent, and decarboxylate compound IV at 150~220℃ to obtain compound V, and recover the solvent; Step (3): Add water and inorganic acid, with a pH range of 0.5-1, and hydrolyze compound V to obtain compound VI or its salt (preferably compound VI hydrochloride).

[0043] In one embodiment, the salt of compound VI is a hydrochloride salt, such as a hydrochloride salt.

[0044] In one scheme, compound II is .

[0045] In one scheme, compound III is .

[0046] In one scheme, compound IV is .

[0047] In one scheme, compound V is .

[0048] In one scheme, compound VI is .

[0049] In one scheme, the salt of compound VI is .

[0050] In one embodiment, the method for synthesizing compound VI or its salt may further include the following steps: in a solvent and in the presence of an acid, compound I undergoes an aromatization reaction to obtain compound II;

[0051] R1 and R2 are groups defined in any embodiment of the present invention; R3 is C 1-6 alkyl.

[0052] In one particular scheme, R3 is an ethyl group.

[0053] In one embodiment, during the aromatization reaction, the solvent is an organic solvent and / or an inorganic solvent, such as an alcohol solvent, for example ethanol, and the inorganic solvent may be water, wherein the ethanol may be used in the form of an aqueous solution with a mass content of 95%.

[0054] In one embodiment, the aromatization reaction is carried out in a protective atmosphere, such as nitrogen.

[0055] In one embodiment, the acid in the aromatization reaction is an inorganic acid, such as hydrochloric acid. The hydrochloric acid can be an aqueous solution (e.g., a 0.4 mol / L aqueous solution).

[0056] In one embodiment, the aromatization reaction is carried out at a pH of 2.5-4.5, preferably at a pH of 3.5-4 (e.g., 3.6).

[0057] In one embodiment, during the aromatization reaction, the solvent, compound I, and acid are mixed at room temperature.

[0058] In one embodiment, during the aromatization reaction, the solvent is an alcohol solvent and water. The mass ratio of the alcohol solvent to compound I can be (0.2-4):1, preferably (0.2-1):1, for example, 0.4:1, 0.6:1, 0.7:1, or 1:1. The mass ratio of water to the alcohol solvent can be 1:(0.2-2), preferably 1:(1-1.5). Preferably, the water is water in an aqueous solution of hydrochloric acid.

[0059] In one embodiment, the reaction temperature of the aromatization reaction is 10-60°C, preferably 20-50°C, for example, 20°C, 30°C, 38°C, 45°C, or 50°C. The reaction time can be 14-24 hours.

[0060] In one embodiment, the reaction temperature of the aromatization reaction is 140-170°C, preferably 145-160°C, for example 150°C, 155°C, 153°C, 145°C, or 160°C. The reaction time can be 2-5 hours.

[0061] In one embodiment, the aromatization reaction includes the following post-processing steps: neutralization to neutrality, recovery (e.g., vacuum distillation) of the alcohol reagent (e.g., ethanol).

[0062] In one embodiment, after the aromatization reaction is completed, the mixture is neutralized to neutral, the alcohol reagent (e.g., ethanol) is recovered (e.g., by vacuum distillation), and then the inorganic solvent is added to carry out the saponification reaction.

[0063] In one embodiment, the aromatization reaction comprises the following steps: mixing compound I, an alcohol solvent, and an aqueous hydrochloric acid solvent, and carrying out the aromatization reaction at a pH of 3.5-4 and at 20-50°C or 145-160°C.

[0064] The aromatization reaction process can be monitored using conventional methods in the art, such as HPLC or TLC, preferably until compound I no longer transforms into the reaction endpoint. The aromatization reaction time can be 14-24 h or 2-5 h.

[0065] In one embodiment, compound I is .

[0066] In one embodiment, the method for synthesizing compound VI or its salt further comprises the following step: performing an addition reaction between compound A and compound B to obtain compound I; ; R1, R2, and R3 are groups defined in any embodiment of the present invention.

[0067] In one embodiment, the mass ratio of compound A to compound B can be 1:(4-15), preferably 1:(5-10), for example 1:8, 1:10, 1:9, 1:5 or 1:7.

[0068] In one embodiment, the addition reaction temperature is 130℃-170℃, preferably 140℃-160℃, for example 145℃, 155℃, 150℃, 140℃ or 160℃.

[0069] In one embodiment, the addition reaction is carried out in a protective atmosphere, such as nitrogen or argon.

[0070] In one embodiment, the addition reaction includes the following post-processing step: after the reaction is complete, compound B is recovered (e.g., by vacuum distillation).

[0071] In one embodiment, after the addition reaction is completed, compound B is recovered (e.g., by vacuum distillation), and the alcohol solvent and an aqueous solution of an inorganic acid are added to carry out the aromatization reaction.

[0072] The addition reaction process can be monitored using conventional methods in the art, such as HPLC or TLC. Preferably, the reaction endpoint is defined as the point at which compounds A and B no longer convert (or compound I no longer forms). The reaction time can be 8-20 hours.

[0073] In one embodiment, the method for synthesizing compound VI or a salt thereof comprises the following steps: Step (s1): Compound A and compound B undergo an addition reaction to obtain compound I; ; R1 is C 1-6 alkyl; R2 is C 1-6 alkyl; R3 is C 1-6 alkyl; Step (s2): In a solvent and in the presence of an acid, compound I undergoes an aromatization reaction to give compound II;

[0074] Step (1): In a solvent, compound II is hydrolyzed to obtain compound IV;

[0075] Step (2): Compound IV is decarboxylated in a solvent to obtain compound V;

[0076] Step (3): In the presence of acid, compound V is hydrolyzed to obtain compound VI or its salt (e.g., a hydrochloride salt of compound VI). ; The conditions and operations of the addition reaction, the aromatization reaction, and steps (1), (2), and (3) are as described in any embodiment of the present invention.

[0077] The present invention provides a method for synthesizing compound VI or a salt thereof, comprising the following steps: hydrolyzing compound V in the presence of an acid to obtain compound VI or a salt thereof;

[0078] R1 is defined as in any embodiment of the present invention; The conditions and operation of the hydrolysis reaction are as described in any embodiment of the present invention; preferably, the synthesis method further includes steps (1) and (2) as described in any embodiment of the present invention.

[0079] The present invention provides a method for synthesizing compound V, which includes the following steps: in a solvent, compound IV is subjected to a decarboxylation reaction to obtain compound V;

[0080] R1 is defined as in any embodiment of the present invention; The conditions and operation of the decarboxylation reaction are as described in any embodiment of the present invention; preferably, the synthesis method further includes step (1) as described in any embodiment of the present invention.

[0081] The present invention provides a method for synthesizing compound IV, comprising the following steps: hydrolyzing compound II in a solvent to obtain compound IV;

[0082] R1 and R2 are defined as in any embodiment of the present invention; The conditions and operation of the hydrolysis reaction are as described in any embodiment of the present invention; preferably, the synthesis method further includes the aromatization reaction and addition reaction described in any embodiment of the present invention.

[0083] The present invention provides a method for synthesizing compound II, comprising the following steps: in a solvent and in the presence of an acid, compound I undergoes an aromatization reaction to obtain compound II;

[0084] R1 and R2 are groups defined in any embodiment of the present invention; The conditions and procedures for the aromatization reaction are as described in any embodiment of the present invention; preferably, the synthesis method further includes the addition reaction described in any embodiment of the present invention.

[0085] The present invention provides a method for synthesizing compound I, which includes the following steps: performing an addition reaction between compound A and compound B to obtain compound I; ; R1, R2 and R3 are groups defined in any embodiment of the present invention; The conditions and procedures for the addition reaction are as described in any embodiment of the present invention.

[0086] This invention provides a compound I; , R1, R2, and R3 are functional groups defined in any embodiment of the present invention, preferably... .

[0087] This invention provides a compound II;

[0088] R1 and R2 are functional groups defined in any embodiment of the present invention, preferably... .

[0089] This invention provides a compound III;

[0090] R1 and M are as defined in any embodiment of the present invention, preferably... .

[0091] This invention provides a compound IV;

[0092] R1 is a group defined in any embodiment of the present invention, preferably... .

[0093] Terminology Explanation: The term "salt" refers to the salt formed during the preparation and separation of compound VI, including pharmaceutically acceptable salts, such as the monohydrochloride salt of compound VI.

[0094] The term "pharmaceutically acceptable" refers to salts prepared from relatively non-toxic, pharmaceutically acceptable acids or bases that conform to the guidelines for drug use.

[0095] Term "C" 1-6 "Alkyl" refers to a saturated hydrocarbon group containing 1-6 carbon atoms, including C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.

[0096] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0097] The reagents and raw materials used in this invention are all commercially available.

[0098] The positive and progressive effects of this invention are as follows: the preparation method provided by this invention has one or more advantages as follows: (1) The synthesis method provided by this method is simple to operate, has a high yield, and has good prospects for industrialization; (2) The intermediate provided in this application has high reaction efficiency, which can shorten the reaction time and improve production efficiency. Attached Figure Description

[0099] Figure 1 The infrared spectrum of the vitamin B6 product obtained in the example is shown. Detailed Implementation

[0100] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0101] The raw materials, acids, solvents, etc. used in the following examples and comparative examples were all commercially available. Purity was determined by gas / liquid chromatography, and yield was calculated as actual yield / theoretical yield. Calculated with 100% accuracy.

[0102] In the following examples, liquid alkali and 40% liquid alkali are 40 wt% NaOH aqueous solutions.

[0103] In the following examples, Y% hydrochloric acid refers to an aqueous solution with a mass content of Y% HCl, and 10% hydrochloric acid in the following examples refers to a 10wt% hydrochloric acid aqueous solution.

[0104] In the following examples, 95% ethanol refers to a 95 wt% aqueous solution of ethanol. Unless otherwise specified, all raw material ethanol is a 95 wt% aqueous solution of ethanol.

[0105] Example 1

[0106] (1) Addition reaction: 70.5 g of oxazolyl carboxylate and 564 g of heptacyclic ring were heated to 145 °C and kept at the temperature for 15 h in an inert gas (nitrogen) atmosphere. After the reaction was completed, the excess heptacyclic ring was recovered (dilution distillation controlled within 130 °C) to obtain intermediate I. (2) Aromatic reaction: In a nitrogen atmosphere, after intermediate I is cooled to room temperature, 48g of ethanol (95% ethanol aqueous solution, about 0.4 times the mass of intermediate I) and 110g of hydrochloric acid solution (0.4mol / L) are added. The pH value is controlled at 3.6 and the reaction temperature is kept at 30℃ for 16h. After the aromatic reaction is completed, the mixture is neutralized to neutral and the ethanol is recovered (controlled vacuum distillation at -0.08MPa) into the reaction flask as a thin paste. (3) Saponification reaction: Add 800g of water (approximately 8 times the mass of intermediate II) and 53g of 40% alkali solution (approximately 1.5 times the equivalent of intermediate II as NaOH), heat to 80℃ and hold for 2.5h. After holding, recover (controlled vacuum distillation at -0.08MPa) ethanol. Adjust the pH to 2 with 10% hydrochloric acid, cool to 5℃ and filter to obtain intermediate IV; (4) Decarboxylation reaction: Add 1070g of m-xylene, heat to 185℃ for 1h to decarboxylate, and recover (control the internal temperature to within 65℃ by vacuum distillation) the solvent (about 90%), and use water azeotropically with the solvent (add water with a mass equal to that of m-xylene, control the vacuum to -0.06MPa and use water azeotropically with m-xylene) to obtain intermediate V; (5) Hydrolysis reaction: Add 47 ml of concentrated hydrochloric acid (concentration 10 mol / L), control the pH of the reaction solution to 0.5, and intermediate V undergoes hydrolysis (at a temperature of about 65℃). Recover the butyraldehyde generated by the reaction (controlled distillation at an internal temperature of 65~70℃), add 80 g of ethanol (95% ethanol aqueous solution), cool to 15℃, and filter to obtain 61.85 g of crude vitamin B6 (see infrared spectrum). Figure 1 (The infrared spectrum of the standard VB6 hydrochloride was consistent with that of the standard), the external standard content in the liquid phase was 98.00%, and the molar yield relative to oxazolyl ester was 83.2%.

[0107] Example 2

[0108] According to Example 1, the process parameters for each reaction step were adjusted as follows: Adjustments to the addition reaction process parameters: The amount of heptacyclic feed was increased to 10 times the mass of oxazole carboxylic acid ester, the addition holding temperature was changed to 155℃, and the addition holding time was changed to 20h.

[0109] The process parameters for the aromatization reaction were adjusted as follows: the mass ratio of ethanol to intermediate I was changed to 0.7:1, the aromatization holding temperature was changed to 45℃, and the aromatization holding time was changed to 24h.

[0110] Adjustments to saponification reaction process parameters: The mass ratio of water to intermediate II is increased to 10 times, the molar ratio of liquid alkali (calculated as NaOH) to intermediate II is increased to 2 times, the saponification reaction temperature is adjusted to 90℃, the saponification time is changed to 3.5h, after ethanol recovery at the end of saponification, the concentration of hydrochloric acid used for acid adjustment is changed to 15%, the pH after acidification is adjusted to 2.5, and the cooling and filtration temperature after acidification is adjusted to 10℃.

[0111] Adjustments to decarboxylation reaction process parameters: The decarboxylation solvent ratio was adjusted to 5 times the mass of intermediate IV, the decarboxylation temperature was adjusted to 195℃, and the decarboxylation time was adjusted to 2h.

[0112] Hydrolysis reaction process parameters adjustment: The hydrolysis cooling crystallization temperature was adjusted to 20℃.

[0113] 62.47 g of crude vitamin B6 was obtained, with an external standard content of 97.50% in liquid chromatography and a molar yield of 83.6% relative to oxazolyl ester.

[0114] Example 3

[0115] According to Example 1, the process parameters for each reaction step were adjusted as follows: Adjustments to the addition reaction process parameters: The amount of heptacyclic feed was increased to 9 times the mass of oxazole carboxylic acid ester, the addition holding temperature was changed to 150℃, and the addition holding time was changed to 18h.

[0116] Adjustments to the aromatic reaction process parameters: The mass ratio of ethanol to intermediate I was changed to 0.6:1, the aromatic holding temperature was changed to 38℃, and the aromatic holding time was changed to 20h.

[0117] Adjustments to saponification reaction process parameters: The mass ratio of water to intermediate II is increased to 9 times, the molar ratio of liquid alkali (calculated as NaOH) to intermediate II is increased to 1.8 times, the saponification reaction temperature is adjusted to 85℃, the saponification time is changed to 3.0h, after ethanol recovery at the end of saponification, the concentration of hydrochloric acid used for acid adjustment is changed to 12%, the pH after acidification is adjusted to 2.3, and the cooling and filtration temperature after acidification is adjusted to 8℃.

[0118] Adjustments to decarboxylation reaction process parameters: The decarboxylation solvent was changed to n-butyl ether, the decarboxylation solvent ratio was adjusted to 4.5 times the mass of intermediate IV, the decarboxylation temperature was adjusted to 190℃, and the decarboxylation time was adjusted to 1.5h.

[0119] Hydrolysis reaction process parameters adjustment: The hydrolysis cooling crystallization temperature was adjusted to 17℃.

[0120] 62.13 g of crude vitamin B6 was obtained, with an external standard content of 98.50% in liquid chromatography and a molar yield of 84.0% relative to oxazolyl ester.

[0121] Example 4

[0122] According to Example 1, the process parameters for each reaction step were adjusted as follows: Adjustments to the addition reaction process parameters: The amount of heptacyclic feed was changed to 5 times the mass of oxazole carboxylic acid ester, the addition holding temperature was changed to 140℃, and the addition holding time was changed to 8h.

[0123] Adjustments to the aromatic reaction process parameters: The mass ratio of ethanol to intermediate I was changed to 1:1, the aromatic holding temperature was changed to 20℃, and the aromatic holding time was changed to 14h.

[0124] Adjustments to saponification reaction process parameters: The mass ratio of water to intermediate II is adjusted to 5 times, the molar ratio of liquid alkali (calculated as NaOH) to intermediate II is adjusted to 1 time, the saponification reaction temperature is adjusted to 60℃, the saponification time is changed to 2.0h, after ethanol recovery at the end of saponification, the concentration of hydrochloric acid used for acid adjustment is changed to 5%, the pH after acidification is adjusted to 3.0, and the cooling and filtration temperature after acidification is adjusted to 0℃.

[0125] Adjustments to decarboxylation reaction process parameters: The decarboxylation solvent was changed to DMF, the decarboxylation solvent ratio was adjusted to 3 times the mass of intermediate IV, the decarboxylation temperature was adjusted to 180℃, and the decarboxylation time was adjusted to 0.5 h. After decarboxylation, water was added, filtered, and washed with water to obtain intermediate V.

[0126] Hydrolysis reaction process parameters adjustment: The hydrolysis cooling crystallization temperature was adjusted to 10℃.

[0127] 60.86 g of crude vitamin B6 was obtained, with an external standard content of 96.00% in liquid chromatography and a molar yield of 80.2% relative to oxazolyl ester.

[0128] Example 5

[0129] According to Example 1, the process parameters for each reaction step were adjusted as follows: Adjustments to the addition reaction process parameters: The amount of heptacyclic feed was changed to 7 times the mass of oxazole carboxylic acid ester, the addition holding temperature was changed to 160℃, and the addition holding time was changed to 20h.

[0130] Adjustments to the aromatic reaction process parameters: The mass ratio of ethanol to intermediate I was changed to 1:1, the aromatic holding temperature was changed to 50℃, and the aromatic holding time was changed to 14h.

[0131] Adjustments to saponification reaction process parameters: The mass ratio of water to intermediate II is adjusted to 7 times, the molar ratio of liquid alkali (calculated as NaOH) to intermediate II is adjusted to 3 times, the saponification reaction temperature is adjusted to 100℃, the saponification time is changed to 4.0h, after ethanol recovery at the end of saponification, the concentration of hydrochloric acid used for acid adjustment is changed to 25%, the pH after acidification is adjusted to 3.0, and the cooling and filtration temperature after acidification is adjusted to 20℃.

[0132] Adjustments to the decarboxylation reaction process parameters: The decarboxylation solvent was changed to sulfolane, the decarboxylation solvent ratio was adjusted to 6 times the mass of intermediate IV, the decarboxylation temperature was adjusted to 200℃, and the decarboxylation time was adjusted to 3.0 h. After decarboxylation, water was added, filtered, and washed with water to obtain intermediate V.

[0133] Hydrolysis reaction process parameters adjustment: The hydrolysis cooling crystallization temperature is adjusted to 30℃.

[0134] 61.41 g of crude vitamin B6 was obtained, with an external standard content of 95.50% in liquid chromatography and a molar yield of 80.5% relative to oxazolyl ester.

[0135] Example 6

[0136] Referring to Example 1, the aromatization process parameters were adjusted as follows: The high-temperature aromatization temperature was 150℃, and the aromatization time was 3 hours.

[0137] 61.75 g of crude vitamin B6 was obtained, with an external standard content of 97.80% in liquid chromatography and a molar yield of 82.9% relative to oxazolyl ester.

[0138] Example 7

[0139] Referring to Example 2, the aromatization process parameters were adjusted as follows: The high-temperature aromatization temperature was 155℃, and the aromatization time was 4 hours.

[0140] 62.41 g of crude vitamin B6 was obtained, with an external standard content of 97.00% in liquid chromatography and a molar yield of 83.1% relative to oxazolyl ester.

[0141] Example 8

[0142] Referring to Example 3, the aromatization process parameters were adjusted as follows: The high-temperature aromatization temperature was 153℃, and the aromatization time was 3.5h.

[0143] 62.07 g of crude vitamin B6 was obtained, with an external standard content of 98.00% in liquid chromatography and a molar yield of 83.5% relative to oxazolyl ester.

[0144] Example 9

[0145] Referring to Example 4, the aromatization process parameters were adjusted as follows: The high-temperature aromatization temperature was 145℃, and the aromatization time was 2 hours.

[0146] 60.91 g of crude vitamin B6 was obtained, with an external standard content of 95.80% in liquid chromatography and a molar yield of 80.1% relative to oxazolyl ester.

[0147] Example 10

[0148] Referring to Example 5, the aromatization process parameters were adjusted as follows: The high-temperature aromatization temperature was 160℃, and the aromatization time was 5 hours.

[0149] 61.91 g of crude vitamin B6 was obtained, with an external standard content of 94.50% in liquid chromatography and a molar yield of 80.3% relative to oxazolyl ester.

[0150] Comparative example (using oxazolyl ester as raw material, saponification and decarboxylation to obtain oxazol, and then using oxazol and heptacyclic to obtain vitamin B6 through addition, aromatization and hydrolysis)

[0151] 70.5 g of oxazole carboxylic acid ester was added to a 500 mL three-necked flask, and 86 mL of a 5 mol / L NaOH aqueous solution was added dropwise while stirring. After the addition was complete, the internal temperature was maintained at 70 °C for 30 min, and the ethanol produced in the reaction was distilled off. The mixture was cooled to room temperature, and the pH was adjusted to 2 with hydrochloric acid. The temperature was then raised to about 60 °C to remove acid until no more carbon dioxide was released. The pH of the reaction solution was adjusted to 8 with an aqueous sodium hydroxide solution, and the mixture was steam distilled. The distillate collected at 95-100 °C yielded 40 g of 4-methyl-5-ethoxyoxazole, with a purity of 99% and a yield of 88.9%.

[0152] In an inert gas (nitrogen) atmosphere, 40g of oxazole obtained from the above reaction was added to 400g of heptacyclic compound, heated to 150℃ and held for 20h, then recovered (dilution distillation controlled below 130℃). Excess heptacyclic compound was obtained as the adduct. After cooling to room temperature, 43g of ethanol and 100g of hydrochloric acid (0.4mol / L) were added, controlling the pH value to 3.5-4. The reaction was held at 30℃ for 16h in a nitrogen atmosphere. After the aromatization was completed, ethanol was recovered (vacuum controlled at -0.08). Distilled under reduced pressure (MPa) until a thin paste forms in the reaction flask; add 42 ml of concentrated hydrochloric acid (10 mol / L), control the pH of the reaction solution to 0.5-1, and allow the hydrolysis reaction to occur at approximately 65°C. Recover the butyraldehyde generated by the reaction (controlled under reduced pressure at 65-70°C), add 71 g of ethanol (95%), cool to 15°C, and filter to obtain 57.21 g of crude vitamin B6. The external standard content in the liquid phase is 98.30%, and the molar yield relative to oxazolyl ester is 77.2%.

[0153] As can be seen from the data above, the method of Embodiments 1-10 of the present invention can achieve a higher vitamin B6 yield than the current route.

[0154] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple combinations of the technical solutions of the present invention can be made, including combining the various technical features in any other suitable manner. These simple combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for synthesizing compound VI or a salt thereof, characterized in that, It includes the following steps: Step (1): In a solvent, compound II is hydrolyzed to obtain compound IV; R1 is C 1-6 alkyl; R2 is C 1-6 alkyl; Step (2): Compound IV is decarboxylated in a solvent to obtain compound V; Step (3): In the presence of acid, compound V is hydrolyzed to obtain compound VI or its salt; 。 2. The method for synthesizing compound VI or its salt as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In step (1), the hydrolysis reaction includes the following steps: in a solvent, compound II is saponified in the presence of an alkali to obtain a salt of compound II, such as a sodium salt; in the presence of an acid, the salt of compound II reacts with the acid to obtain compound IV; R1 and R2 are as defined in claim 1; (2) The C 1-6 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; R1 can be n-propyl, and R2 can be ethyl; (3) In step (2), the decarboxylation reaction includes the following post-processing steps: after the reaction is completed, the solvent is recovered, water is added for azeotroping to obtain compound V, and / or the post-processing further includes washing with water and filtering to obtain compound V; (4) In step (3), after the hydrolysis reaction is completed, the following post-treatment is included: recovering the aldehyde reagent, adding an alcohol solvent, such as ethanol, and filtering at 10-30°C to obtain the compound VI or its salt; wherein the mass ratio of the alcohol solvent to compound V can be (0.5-1.5):1, for example 0.5:1 or 1:1, preferably filtered at 15-20°C, for example 15°C, 20°C, 17°C, 10°C or 30°C.

3. The method for synthesizing compound VI or its salt as described in claim 1 or 2, characterized in that, It satisfies one or more of the following conditions: (1) In step (1), the solvent in the saponification reaction is an inorganic solvent, such as water; (2) In step (1), the base in the saponification reaction is an inorganic base, such as an alkali metal hydroxide, such as sodium hydroxide; the inorganic base can be used in the form of its aqueous solution in the saponification reaction; (3) In step (1), in the saponification reaction, the mass ratio of the solvent to compound II is (2~15):1, preferably (8~10):1, for example 5:1, 7:1, 8:1, 8.3:1, 9:1 or 10:1; (4) In step (1), the molar ratio of the alkali to the compound II in the saponification reaction is (1~5):1, preferably (1.5~2):1, for example 1.5:1, 2:1, 1.8:1, 1:1 or 3:1; (5) In step (1), the saponification reaction is carried out at 50~110°C, preferably 80~90°C, for example 80°C, 90°C, 85°C, 60°C or 100°C; (6) In step (1), the saponification reaction includes the following post-processing step: recovering alcohol reagents, such as ethanol, the recovery operation being, for example, vacuum distillation; (7) In step (1), the acid is an inorganic acid, such as hydrochloric acid; the hydrochloric acid can be used in the form of an aqueous solution with a hydrochloric acid mass content of 5% to 32%, more preferably an aqueous solution with a hydrochloric acid mass content of 10% to 15%; (8) In step (1), the amount of acid used is to adjust the pH range to 2.0~3.5; preferably 2.0~2.5, for example, pH is 2, 2.5 or 3; (9) After the salt and acid reaction of compound II is completed, the following post-treatment is included: filtration, preferably filtration at 0~20°C, more preferably filtration at 5-10°C, for example filtration at 0°C, 5°C, 8°C, 10°C or 20°C; (10) The reaction raw materials in step (1) are the solvent, compound II, the base and the acid; (11) In step (2), the solvent is an organic solvent, preferably selected from one or more of aromatic hydrocarbon solvents, ether solvents, amide solvents, alcohol solvents and sulfone solvents, for example selected from aromatic hydrocarbon solvents or ether solvents; the aromatic hydrocarbon solvent may be m-xylene, the ether solvent may be n-butyl ether, and the amide solvent may be N,N-dimethylformamide or N,N-dimethylacetamide; Alternatively, in step (2), the solvent is an alcohol solvent and / or water; (12) In step (2), the mass ratio of the solvent to the compound IV is (2~15):1, preferably (4~12):1, for example 5:1, 4.5:1, 4:1, 3:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1 or 13:1; (13) In step (2), the decarboxylation reaction temperature is 150~220℃, preferably 185~195℃, for example 185℃, 195℃, 190℃, 180℃ or 200℃; (14) The reaction raw materials for step (2) are the solvent and compound IV; (15) In step (3), the hydrolysis reaction is carried out in an inorganic solvent, such as water; (16) In step (3), the acid in the hydrolysis reaction is an inorganic acid, such as hydrochloric acid; the hydrochloric acid can be used in the form of an aqueous solution of hydrochloric acid; (17) In step (3), the amount of acid used in the hydrolysis reaction is to adjust the pH range to 0.5-2, for example 0.5-1; (18) In step (3), in the hydrolysis reaction, the mass-volume ratio of compound V to solvent is (0.1-5):1 g / mL, preferably (1-2):1 g / mL, for example 1.5:1 g / mL; (19) In step (3), the hydrolysis reaction is carried out at 40-80°C, for example 60°C or 65°C; (20) The compound II is ; (21) Compound IV is ; (22) The compound V is ; (23) The compound VI is ; (24) The salt of compound VI is .

4. The method for synthesizing compound VI or its salt as described in claim 1 or 2, characterized in that, The synthesis method includes the following steps: Step (1): In an aqueous solvent, compound II is saponified in the presence of an alkali metal hydroxide to obtain compound III. The alcohol reagent is recovered. In the presence of an inorganic acid, at a pH range of 2.0 to 3.5, compound III is reacted to obtain compound IV. The mixture is then filtered at 0 to 20°C. R1 and R2 are groups as defined in claim 1 or 2; M is an alkali metal ion; Step (2): Add aromatic hydrocarbon solvent or ether solvent, and decarboxylate compound IV at 150~220℃ to obtain compound V, and recover the solvent; Step (3): Add water and an inorganic acid, with a pH range of 0.5-1, to hydrolyze compound V to obtain compound VI or its salt, preferably compound VI hydrochloride; the compound III may be... .

5. The method for synthesizing compound VI or its salt as described in claim 1, characterized in that, It further includes the following steps: in a solvent, in the presence of an acid, compound I undergoes an aromatization reaction to give compound II; R1 and R2 are the groups defined in claim 1; R3 is a C 1-6 alkyl.

6. The method for synthesizing compound VI or its salt as described in claim 5, characterized in that, It satisfies one or more of the following conditions: (1) R3 is an ethyl group; (2) In the aromatization reaction, the solvent is an organic solvent and / or an inorganic solvent, the organic solvent being an alcohol solvent, such as ethanol, and the inorganic solvent being water, wherein the ethanol may be used in the form of an aqueous solution with a mass content of 95% ethanol; (3) The aromatization reaction is carried out in a protective atmosphere, such as nitrogen: (4) In the aromatization reaction, the acid is an inorganic acid, such as hydrochloric acid; the hydrochloric acid can be used in the form of an aqueous solution of hydrochloric acid; (5) In the aromatization reaction, the aromatization reaction is carried out at a pH of 2.5-4.5, preferably at a pH of 3.5-4: (6) In the aromatization reaction, the solvent, compound I, and acid are mixed at room temperature; (7) In the aromatization reaction, the solvent is an alcohol solvent and water, and the mass ratio of the alcohol solvent to compound I can be (0.2-4):1, preferably (0.2-1):1, for example 0.4:1, 0.6:1, 0.7:1 or 1:1; the mass ratio of water to the alcohol solvent can be 1:(0.2-2), preferably 1:(1-1.5); (8) The reaction temperature of the aromatization reaction is 10-60℃, preferably 20-50℃, for example 20℃, 30℃, 38℃, 45℃ or 50℃, or the reaction temperature of the aromatization reaction is 140-170℃, preferably 145-160℃, for example 150℃, 155℃, 153℃, 145℃ or 160℃; (9) The aromatization reaction includes the following post-processing steps: neutralization to neutral and recovery of alcohol reagents; (10) After the aromatization reaction is completed, the mixture is neutralized to neutral, the alcohol reagent is recovered, and the inorganic solvent is added to carry out the saponification reaction. (11) The aromatization reaction comprises the following steps: mixing compound I, an alcohol solvent and hydrochloric acid aqueous solvent, and carrying out the aromatization reaction at pH 3.5-4 and at 20-50°C or 145-160°C; (12) The compound I is .

7. The method for synthesizing compound VI or its salt as described in claim 5 or 6, characterized in that, It further includes the following steps: performing an addition reaction between compound A and compound B to obtain compound I; ； R1, R2 and R3 are groups as defined in claim 5 or 6; Preferably, the addition reaction satisfies one or more of the following conditions: (1) The mass ratio of compound A to compound B is 1:(4-15), preferably 1:(5-10), for example 1:8, 1:10, 1:9, 1:5 or 1:7; (2) The addition reaction temperature is 130℃-170℃, preferably 140℃-160℃, for example 145℃, 155℃, 150℃, 140℃ or 160℃; (3) The addition reaction is carried out in a protective atmosphere, such as nitrogen or argon; (4) The addition reaction includes the following post-processing steps: after the reaction is completed, compound B is recovered; (5) After the addition reaction is completed, compound B is recovered and the alcohol solvent and inorganic acid aqueous solution are added to carry out the aromatization reaction.

8. A method for synthesizing compound VI or its salt, compound V, compound IV, compound II or compound I, characterized in that, It is any of the following schemes: Scheme 1 includes the following steps: in the presence of an acid, compound V is hydrolyzed to obtain compound VI or its salt; ； R1 is as defined in claim 1 or 2; The conditions and operation of the hydrolysis reaction are as described in claim 1 or 2; Scheme 2 includes the following steps: in a solvent, compound IV is decarboxylated to obtain compound V; R1 is as defined in any one of claims 1-4; The conditions and operation of the decarboxylation reaction are as described in any one of claims 1-4; Scheme 3 includes the following steps: In a solvent, compound II is hydrolyzed to obtain compound IV; R1 and R2 are as defined in any one of claims 1-4; The conditions and operation of the hydrolysis reaction are as described in any one of claims 1-4; Scheme 4 includes the following steps: in a solvent and in the presence of an acid, compound I undergoes an aromatization reaction to obtain compound II; R1 and R2 are as defined in claim 5 or 6; The conditions and procedures for the aromatization reaction are as described in claim 5 or 6; Scheme 5 includes the following steps: performing an addition reaction between compound A and compound B to obtain compound I; ； R1, R2 and R3 are as defined in claim 7; The conditions and operation of the addition reaction are as described in claim 7.

9. A fused-ring compound, characterized in that, It is compound I, compound II, compound III, or compound IV. ， ， ， R1, R2 and R3 are as defined in any one of claims 1-7.

10. The cyclic compound of claim 9, characterized in that, The compound I is ; Alternatively, compound II is ; Alternatively, compound III is ; Alternatively, compound IV is .

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