CN102336655B - Industrial production method for trans-beta-formyl crotonic acid - Google Patents

Abstract

The invention discloses an industrial production method for trans-beta-formyl crotonic acid, characterized by using 5-hydroxy-4-methyl-2-5[H]-furanone as raw material, using water as a solvent, and adding inorganic base for reaction. Ring-opening reaction is carried out on the raw material 5-hydroxy-4-methyl-2-5[H]-furanone and inversion of configuration occurs, so that a target compound is obtained.

Description

The method of the trans-β of a kind of preparation of industrialization-formyl radical β-crotonic acid

Technical field:

The present invention relates to the method for the trans-β of a kind of preparation of industrialization-formyl radical β-crotonic acid.

Background technology:

Trans-β-formyl radical β-crotonic acid (formula I) is intermediate important in pharmaceutical industry, and the preparation method of prior art mainly contains following several:

Document Tetrahedron letter, vol 26, No 28pp3307-3310,1985 and patent WO200489887 all to mention with trans-β-formyl radical crotonate as after raw material is hydrolyzed in alkaline solution, generate trans-β-formyl radical β-crotonic acid through acid neutralization.But raw materials used trans-β-formyl radical crotonate not commercialization, needs preparation, and preparation method reacts through comprising periodate oxidation multi-step chemical, complex process, and cost is high, pollute large, suitability for industrialized production difficulty.

Document J.Chem.Soc. (C), 1968,1984-1997 report and for raw material with 5-hydroxy-4-methyl-2-5 [H]-furanone (preparation can reference JP10298173), are solvent, add sodium methylate and react with methyl alcohol.Though this method can-step synthesis of trans-β-formyl radical β-crotonic acid, need use expensive sodium methylate, and solvent methanol can not reclaim, thus cost is higher.

Summary of the invention:

The object of this invention is to provide a kind of cheap, pollute little, unit operation is few, is easy to the method for the trans-β of suitability for industrialized production-formyl radical β-crotonic acid.Specific purposes are the trans-β of one-step synthesis-formyl radical β-crotonic acids, do not use expensive sodium methylate, also do not use methyl alcohol as solvent.

Technical scheme of the present invention is: with 5-hydroxy-4-methyl-2-5 [H]-furanone for raw material, take water as solvent, add mineral alkali and react.Also there is configuration conversion in raw material 5-hydroxy-4-methyl-2-5 [H]-furanone open loop, obtains the trans-β of target compound-formyl radical β-crotonic acid.

Concrete reaction and separation processes method is as follows:

Soluble in water for 5-hydroxy-4-methyl-2-5 [H]-furan food in one's mouth ketone (formula II), add mineral alkali, configuration conversion reaction is complete, acid neutralization, then with solvent extraction after salt adding, obtains product I after concentrating under reduced pressure solvent.

Described mineral alkali can be metal hydroxides, is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide etc., preferred sodium hydroxide.

The present inventor is through a large amount of experimental study repeatedly, compared for the reaction effect (detailed in Example) under differential responses temperature, differential responses time, the potential of hydrogen of different reaction solns, different reaction solvent conditions, obtain suitable as follows with best reaction conditions:

The amount adding mineral alkali is: make the pH value of reaction system reach 9 ~ 14, and this is the pH value needed for configuration conversion reaction; Directly can add solid alkali, add after also alkali can being made into the aqueous solution.

The mass ratio of water and raw material 5-hydroxy-4-methyl-2-5 [H]-furanone is 1 ~ 50: 1, and higher ratio can be used, but is unfavorable for the extraction of latter products.

Temperature of reaction is 0 ~ 50 DEG C, and temperature is too low, sluggish, and temperature is too high, and impurity can increase.

Reaction times is 1 ~ 10 hour.

Described acid neutralization, acid can be hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, and acid adding amount is 0 ~ 4 for making solution ph, so that all products can dissociate out.

Because product has certain solubility in water, therefore to salt adding in the aqueous solution when extracting, utilize salting out that product is separated out, described salt can be villaumite, vitriol, nitrate, phosphoric acid salt, as sodium-chlor, Repone K, sodium sulfate, magnesium sulfate, saltpetre, SODIUMNITRATE, SODIUM PHOSPHATE, MONOBASIC etc.

The solvent used in described extraction is a kind of esters solvent or ether solvent, and ester class solution comprises the ester containing 2-6 carbon, as methyl acetate, and ethyl acetate, n-propyl acetate, butylacetate, ethyl propionate etc.; Ether solvent is that the ether of 2-6 carbon is as ether, isopropyl ether and methyl tertiary butyl ether etc.

Described Extraction solvent ethyl acetate, its consumption is 1 ~ 50 times of raw materials quality, preferably 3 ~ 10 times, so both economical, and yield can be made again to be guaranteed.

The advantage of present method is:

1, cost is low: the more cheap mineral alkali of present method replaces sodium methylate, and use water as solvent replaces methyl alcohol, cost is low.

2, environmental protection: do not use methyl alcohol as solvent, pollute little, be suitable for suitability for industrialized production.

3, easy to operate: to react a step and complete, convenient product separation.

4, yield is high: yield can reach more than 82%.

5, product quality is good: trans-β-formyl radical β-crotonic acid purity prepared by present method can reach more than 95%.

Embodiment:

The preparation of the trans-β of embodiment 1-formyl radical β-crotonic acid

Under room temperature, 100g raw material 5-hydroxy-4-methyl-2-5 [H]-furanone is dissolved in 300ml water, then drips 50% sodium hydroxide solution adjust pH to 11.0, dripping and finish, in 10 DEG C of reactions 3 hours, is then 2 by the pH value that 3N hydrochloric acid is neutralized to solution, add 25g sodium-chlor, extract with ethyl acetate 3 × 200ml, saturated brine 2 × 50ml washs, and anhydrous magnesium sulfate 20g is dry, filter, concentrating under reduced pressure obtains product 94.5g, and yield is 94.5%, and purity is 97.2%.The preparation of the trans-β of embodiment 2 ~ 9-formyl radical β-crotonic acid---investigate PH change to the impact of reaction

8 embodiments below, only change configuration conversion reaction pH value, other reaction conditions is with embodiment 1, and situation is in table 1:

Reaction result in the different PH situation of table 1

Embodiment	PH value	The complete raw material of unreacted (%)	Purity (%)
				2	7.0	17.5	80.3
3	8.0	7.3	89.8
				4	9.0	2.0	96.8
5	10.0	1.5	97.3
				6	11.0	1.2	97.2
7	12.0	1.0	97.5
				8	13.0	0.6	96.1
9	14.0	0.1	95.1

The preparation of the trans-β of embodiment 10 ~ 15-formyl radical β-crotonic acid---investigate temperature and time change to the impact of reaction

Change the temperature of configuration conversion reaction, the reaction times changes with it, and other reaction conditions is with embodiment 1, and situation is as following table:

The reaction result in table 2 differential responses temperature and reaction times

Embodiment	Temperature (DEG C)	Reaction times (h)	Yield	Purity (%)
					10	0	9	83.3	95.0
11	10	3	94.5	96.8
					12	20	2	94.1	97.2
13	30	2	87.3	96.2
					14	50	1.5	85.5	95.4
15	60	1	82.9	92.5

The preparation of the trans-β of embodiment 16 ~ 22-formyl radical β-crotonic acid---investigate the reaction times that the impact of reaction times change on reaction only changes configuration conversion reaction, other reaction conditions is with embodiment 1, and situation is as following table:

The reaction result of table 3 differential responses time

Embodiment	Reaction times (h)	The complete raw material of unreacted (%)	Purity (%)
				16	1	3.3	95.2
17	2	1.5	97.4
				18	3	1.2	97.5
19	4	1.2	97.3
				20	6	1.1	96.2
21	10	1.0	95.3
				22	12	0.9	93.1

The preparation of the trans-β of embodiment 23 ~ 25-formyl radical β-crotonic acid---investigate Extraction solvent change changes Extraction solvent kind and consumption on the impact of product, other extraction conditions is with embodiment 1, and situation is as following table:

Table 4 different solvents is on the impact of product

Embodiment	Extraction solvent	Consumption is (with raw materials quality ratio (%)	Yield (%)	Purity (%)
					23	Ethyl acetate	5	94.5	97.2
24	Isopropyl ether	5	87.2	97.5
					25	Methyl tertiary butyl ether	5	83.1	97.1
26	Ethyl acetate	3	93.1	97.3
					27	Ethyl acetate	10	95.0	97.0
28	Ethyl acetate	20	95.1	96.8

The method of the trans-β of embodiment 29 preparation of industrialization-formyl radical β-crotonic acid

Under room temperature, 150kg raw material 5-hydroxy-4-methyl-2-5 [H]-furanone is dissolved in 400L water, stirring and dissolving, dripping 50% sodium hydroxide solution adjusts solution ph to 11, reacts 3 hours, then neutralizes solution ph 2 with 3N hydrochloric acid, add 37.5kg sodium-chlor, stirring and dissolving, then use ethyl acetate 3 × 250kg to extract, saturated brine 2 × 70kg washs, anhydrous magnesium sulfate 25kg is dry, and filter, concentrating under reduced pressure obtains product 139.8kg, yield is 93.2%, and purity is 96.3%.

Claims (5)

1. a preparation method for trans-β-formyl radical β-crotonic acid, with 5-hydroxy-4-methyl-2-5 [H]-furanone for raw material, feature is solvent with water, adds mineral alkali and react;

Operation steps is: 5-hydroxy-4-methyl-2-5 [H]-furanone is soluble in water, adds mineral alkali, acid neutralization after configuration conversion reaction, then with solvent extraction after salt adding, obtains product after concentrating under reduced pressure Extraction solvent;

Described mineral alkali is metal hydroxides, is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide; The amount adding mineral alkali is: make the pH value of reaction system reach 9 ~ 14;

Described acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid; The consumption of acid is 0 ~ 4 for making solution ph;

The mass ratio of water and raw material 5-hydroxy-4-methyl-2-5 [H]-furanone is 1 ~ 50: 1.

2. preparation method according to claim 1, described metal hydroxides is sodium hydroxide.

3. the preparation method described in claim 1 or 2, temperature of reaction is 0 DEG C ~ 50 DEG C, and the reaction times is 1 ~ 10 hour.

4. the preparation method described in claim 1 or 2, described salt is selected from villaumite, vitriol, nitrate, phosphoric acid salt.

5. the preparation method described in claim 1 or 2, described Extraction solvent is ester or ether.