JPS6069091A - Production of glucuronolactone ketal - Google Patents

Abstract

PURPOSE:To obtain the titled compound as a synthetic intermediate for vitamin C in high yield, by reacting glucuronic acid or glucurono-6,3-lactone with a ketone in the presence of hydrogen iodide, antimony pentachloride or pentafluoride. CONSTITUTION:Glucuronic acid or glucurono-6,3-lactone is reacted with a ketone, e.g. acetone, in a molar amount of 2-10 times of that of the glucuronic acid or glucurono-6,3-lactone in the presence of 0.01wt% or more preferably 0.05-5wt% based on the glucuronic acid, etc., hydrogen iodide, antimony pentachloride or pentafluoride in an amount almost equal to that of the hydrogen iodide at 0- 150 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to glucuronolactone ketal 911/f! Regarding the law. Glucuronolactone ket-μ is a compound useful, for example, as a synthetic intermediate for vitamin C (Japanese Patent Publication No. 53-36462).

Conventionally, glucuronolactone ketal is glucuronolactone i*t
Alternatively, glucurono-6,3-tuctone and ketone have been synthesized by a keter-μ-forming reaction using concentrated sulfuric acid or a strongly acidic ion exchange resin as a catalyst.

By these methods, the desired glucrinolactone ket-ρ can be obtained with a yield of about 60 to 90%. However, in the case of concentrated sulfuric acid, it is common to use a large amount as it also serves as a dehydrating agent, so it is necessary to neutralize a large amount of filc acid in the process of isolating the target product, and this requires post-treatment. It is complicated and a large amount of used salt becomes waste from Shiba production, which poses problems from the viewpoint of resource conservation. On the other hand, the method using a strong acidic resin has the disadvantages that a large amount is used, the activity tends to decrease because it is used in an organic solvent system, and the service life is short. Another major drawback of the conventional method was that the catalyst used in each case was large in amount and was a strong acid, so that side reactions such as self-condensation of ketones were likely to occur.

As a result of various studies conducted by the present inventors in order to overcome the drawbacks of these conventional methods, we found that glucuronolactone ketal can be increased by reacting in the presence of hydrogen iodide, antimony pentachloride, or expanded antimony pentafluoride as a catalyst. They found a completely new finding that the product can be obtained in high yield, conducted further research based on this finding, and completed the present invention.

That is, the present invention provides glucuronic acid or glucuronic acid
．． This is an fR production method for glucuronolactone ketal, which is characterized by reacting 3-fuctone and ketone in the presence of hydrogen iodide, antimony pentachloride, or antimony pentafluoride.

In the present invention, glucuronic acid or glucurono-6,
The 3-lactone used is one obtained by a conventional method.

The ketone used in the present invention is not particularly limited, but preferable specific examples include acetone, methyl ethyl ketone, diethyl ketone, di-n-10 pyruketone,
Examples include dialkyl ketones such as di-1-propyl ketone, and cyclic ketones such as cyclopentanone, cyclohexanone, and cyclohexanone. The amount of these ketones used is usually about 2 to 10 times the theoretical amount by mole, but more generally it is convenient to use them in large excess as both reaction reagent and solvent.

Hydrogen iodide used as a catalyst in the present invention includes:
Hydrogen iodide itself, hydrogen iodide as hydrogen iodide obtained by dissolving it in water, or existing as hydrogen iodide in the reaction system, or hydrogen iodide present in the reaction system. It may be something that generates.

Examples of things that exist as hydrogen iodide in the reaction system or generate hydrogen iodide in the reaction system include (1) metal iodide and acid, (2) iodizing agent, ( 3) an iodinating agent and a reducing agent, (4) an iodine-containing Lewis acid, and the like. Specific examples of iodides of these metals include sodium iodide, potassium iodide, magnesium iodide, μsium iodide, ammonium iodide, lead iodide, and examples of acids include phosphoric acid, nitric acid, etc. , sulfuric acid.

Examples of the iodinating agent include hydrochloric acid, hydrobromic acid, trifluoro-18ip acid, perchloric acid, etc., and examples of the iodinating agent include iodine, -agglomerated iodine, -iodine bromide, iodine trichloride, phosphorus iodide, and N-iodosuccinic acid. Examples of the reducing agent include hydrogen sulfide, pentahypophosphorous acid, sulfurous acid,
Examples include hydriodine, L-ascorbic acid, and D-erythorbic acid.

In addition, the iodine-containing Lewis acid includes aluminum diuride,
Examples include boron iodide and titanium iodide. The amount of hydrogen iodide used or the amount of hydrogen iodide in the reaction system is about 0% by weight or more, preferably about 0.03% by weight based on glucuronic acid or glucurono-6,3-lactone.
Glucuronic acid or glucurono-6,3 is more preferably used.
- About 0.05% to about 5% to 7% based on lactone
(in the range of ).

Next, antimony pentachloride or antimony pentafluoride used as a catalyst in the present invention may be either an anhydride or a monohydrate, and may be used after being diluted with a solvent such as dichloromethane or chloroform.

The amount of antimony pentachloride or antimony pentafluoride used is within the same range as that of hydrogen iodide described above. Hydrogen iodide, antimony pentachloride, and antimony pentafluoride may be used in any combination.

Reaction 1 as a reaction solvent used in the production method of the present invention
Any solvent can be used as long as it does not cause problems. Examples include, for example, acetonitrile, propionitrile, nitromethane.

Dichloroethane, chloroform, four groups (IJ element, 1°1
-dichloroethane, 1,2-dichloroethane.

Examples include pentane, cyclobencune, hexane, V-chlorohexane, heptane, benzene, toluene, xylene, etc. Furthermore, the above-mentioned ketones can also be used as a solvent, and the reaction can be carried out in a mixed solvent consisting of two or more of these solvents. You can also do this. Furthermore, a small amount of water may be added at the start of the reaction in order to increase the solubility of glucuronic acid or glucurono-6.3-lactone or the catalyst in the solvent.

This reaction is a horizontal reaction, and since the yield is generally better if the water produced in the reaction is removed, the reaction may be carried out while removing water from the reaction system by a known method. In this case, known methods include distilling off the water and using an L desiccant. When water is distilled off, a common method is to utilize azeotropy between the solvent and water, and the azeotropic vapor is removed by /? Molecule I of water from the liquid obtained by 1! The remaining solvent may be returned to the reactor, or the azeotropic vapor may be removed from the reaction system and the same amount of dry solvent may be newly added to the reaction system.

In addition, as a method of using a desiccant, the liquid obtained by directly or once cooling the co-produced steam is dried with a desiccant such as anhydrous sulfuric acid, Moregular Sheets, Amiumina, etc. After that, it may be returned to the reactor.

The reaction temperature is usually in the range of about 0°C to 150°C (
), preferably in the range of about 20°C to 100°C. Also, a combination of a solvent or a ketone and water011
The reaction may be performed in reduced order to adjust the point.

The reaction time varies depending on the type of ketone, Km and reaction conditions, but is usually about 30 minutes to about 10:11, preferably about 1 hour to 8 hours.

To isolate the glucuronoctone ketal thus obtained from the reaction system, the reaction solvent may be distilled off, or a small amount of alkali (eg, sodium bicarbonate, potassium bicarbonate, sodium carbonate) may be used.

Potassium carbonate, sodium hydroxide, water lent potassium,
Ammonia) or a water solution of the alkali is added to make the pH of the reactant weakly alkaline (about pH T~9).・The reaction solvent may be distilled off after +8 steps. The obtained residue is extracted, column chromatographed, or recrystallized by known means to obtain the desired glucuronolactone keter/L.
/ can be easily obtained.

The present invention provides an industrially advantageous method for producing glucuronolactone ket-μ.

The method of the present invention is characterized by the use of trace amounts of hydrogen iodide, antimony pentachloride, or antimony pentafluoride as a catalyst, which allows the desired ketalization reaction to proceed sufficiently. Post-treatment is extremely easy, glucuronolactone ket-μ can be obtained in good yield, and industrial waste (e.g. ammonium sulfate) unlike conventional methods is not produced, and only a small amount of catalyst is required. Therefore, by-products (for example, ketone dimers) are significantly reduced, and the reaction time is shortened.

In the following, the present invention will be explained in more detail by refraining from examples.

Example 1 300*/20. Of's D-glucurono-
6,3-lactone and 89.8 q of 51% hydroiodic acid were added, and reflux and stirring were continued for 9.5 hours in a 60°C water bath. During this time, Molecu2 Thieves 3A (manufactured by Wako Pure Chemical Industries, Ltd.) was installed at 35F between the reactor and the cooling tube to dry the refluxing solvent. After the reaction was completed, a small amount of pyridine was added, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 volume of aqueous sodium bicarbonate and water, and then dried over anhydrous sodium sulfate. When the solvent was distilled off under reduced pressure, 24.6f of 1t2-o-impropylidene-α-D-gluco7funurono6°3-lactone (
A purity of 99.5% or higher was obtained.

Yield 99.4%.

Melting point 119-12Q, 5°C (recrystallized from benzene) IR(KBr)tyg 3425.1788.17
75N M R (CDCl5) δ1.36 (3H, s)
, 1.53 (3H.

G) 13.63 (11Lbr> +4.60 (lH, b
r) 14.75-5.05 (3H*m), 6.02 (I
H, d) Elemental analysis 1im (%) c9 ■ Calculated value as 1206 C50,00; H5,60 ri L361 (i(! C49,92; Glucurono-6,3°
-Lactone IO,Of and 25.4'l of iodine were added, and reflux and stirring were continued for 8 hours in a water bath at 60°C.

This ilJ was used to dry the refluxing solvent incorporated in Molecu2 Thieves 3At-20f between the reactor and the cooling tube. After the reaction was completed, the total amount was 1 to 200 tons, and a gas chromatograph (column: 3%≦1licon ov-11°
n Uniport HPS 3m, column temperature 20
When quantified at 0℃), it was 12.05f (yield 98.1
%) of 1.2-0-inglobylidene-a-,p-glucofonulono-6,3-lactone was obtained.

Example 3 According to the same method as in Example 2, D-glucurono-6,3-lactone and acetone were reacted in the presence of each catalyst shown in Table 1 to produce 1,2-0-isopropylidene-α- D
-Glucofuranurono-6°3-lactone was obtained. Table 1 shows the reactants used, the amount used, the reaction time, and the yield of the target product.

* Gas chromatograph quantitative value Example 4 D-glucuronic acid 1. Of and 5
17.51 Da of 7% hydroiodic acid was added, and the mixture was refluxed for 6 hours in a water bath at 60"C, and stirring was continued for 41"I:i. During this time, molecular sieves 3A was used between the reaction sugar and the cooling pipe.
20f1, and the refluxing solvent was dried. After the reaction was completed, the total amount was reduced to 100 tttl, and the amount was determined by gas chromatography, and the amount was 1.05F (yield 94.6%).
6.3 octs of 2-0-isopropylidene-a-])-]gμcofunulonol were obtained.

=NO15NOjCi Example 5 D-glucurono-6,3-lactone 20.0% was added to a mixture of 150A/l of cyclohexanone and 150#Fl of chloroform. Of and 179.614 ml of 5T% hydroiodic acid were added, and reflux and stirring were continued for 8 hours in a water bath at 80°C. During this time, 1c Molecufu Thieves 3A 35F was installed between the reactor and the cooling tube to dry the refluxing solvent. After the reaction was completed, the reaction solution was diluted with chloroform, washed with an aqueous solution and water, and dried over anhydrous sodium sulfate.

After distilling off the solvent and cyclohexanone under hostile pressure, the residue was washed with a small amount of hexane, and 1.2 of 28.6 f.
-0-Cyclohexylidene-tl-11-gluco7funurono6.3-tucton (tlluff 199.5% or more) was obtained. Yield 97.8%.

- Touch point 150-151°C (benzene crystal)
Engineering R (KBr) rIN 3400,1788. lT73
NMR (CDCl2) II 1.20-1.85 (10
u + b r ) +3.50 (111, br) +4
．． 55 (Hl, br) + 4.75 to 5.05 (3H, m
), 6.02 (IH, d) Elemental analysis value (%) C engineering, ■
Yo. +6 as HII value c 56.24; H6,
29 Actual value c 56.30; H6゛, 25 Example 6 D-glucuronic acid 1. Of, 5T% hydrogen iodide, and 22.5 tons of acid were added, and the mixture was refluxed and stirred in a 68°C water bath for 8 hours. continued. During this time, install Molecu2 Thieves 3A 20f between the reactor and the cooling pipe, and
Drying of the π-flow solvent was performed. After the reaction is complete, a total of 1 jit''
f: 100m/bound gas chromatograph (column: 3%
5ilicon 0V-1+ onChromoeor
b W+ 2m; column temperature 200°C), 1.20f of 1.2-0-cyclohexylidene-
α-D-glucofuranurono-6°3-tuctone was obtained. Yield 90.0%.

Example 7 100 Mj of cyclohexanone and 10 Mj of cyclohexanone a)V
D-glucurono-6,3-tuctone 10 in a mixture with methane, Of, iodine 50.8q and hypophosphorous acid 100
The mixture was refluxed and stirred for 8 hours in a 68°C water bath.During this time, 20ft of Molecu2 Sieves 3A was added between the reactor and the cooling tube to dry the refluxing solvent. After the reaction was completed, quantitative analysis using a gas chromatograph (conditions were the same as in Example 6) revealed that 1.2-
0-Cyclohexylidene-a-I)-gluco7funurono6°3-tuctone was obtained. Yield 98.1%.

Example 8 300 resistant acetone with 20. Of D-glucurono-6
, 3-lactone and pentachloride angoumole 119.6#iN
were added, and reflux and stirring were continued for 8 hours in a 60°C water bath. Reaction to this song! 35 f of 1c Molecuo Thieves 3A (manufactured by Wako Reyaku Kogyo Co., Ltd.) was installed between the vessel and the cooling tube, and the refluxing solvent was dried. After the reaction is complete, add a small amount of pyridine and remove the solvent under reduced pressure to leave a residue.
It was dissolved in ethyl acetate, washed with Jll aqueous solution and water, and then dried over anhydrous sodium sulfate. When the solvent was distilled off under reduced pressure, 24.4F of 1,2-0-isopropylidene-α-D-glucofuranurono-6,3-lactone (
A purity of 99.5% or higher was obtained.

Yield 99.0%.

Melting point: 119-120.5°C (recrystallized from benzene)
Engineering R (KBr) or13425.17[18,1775
N 11 R (CDC13) δ 1.36 (3H, s)
, 1.53 (3H.

e), 3.63 (IH, br), 4.60 (IH, br
).

4.75-5.05 (3H, m), 6.02 (IH, d
) Example 9 D-glucurono-6,3-lactone IO,Of and antimony pentafluoride 21.7W9 were added to 200 wl of acetone, and the mixture was refluxed and stirred in a 60°C water bath for 8 hours. During this time, Molecutu-V-
The refluxing solvent was dried using Bus 3A at 20f.

After the reaction was completed, the total volume was adjusted to 200 ml, and a gas chromatograph (column: 3%, 5ilicon 0V-17+ on
Uniport IIP8 3m + column temperature 20
12.21 g (yield: 99.9 g).
5%) of 1,2-o-isopropylidene-α-D-gluco-7onulon-6,3-lactone was obtained.

Example 10 1. D-glucuronic acid in 100*t acetone. Of and antimony pentachloride 9.09 were added, and 8
Reflux and stirring were continued for an hour. During this time, Molecular Sieves 3A 20f was installed between the reactor and the cooling tube to dry the refluxing solvent. After the reaction is complete, the total amount is 100r/
When quantified using a gas chromatograph, it was found to be 1.132
1,2-0-isopropylidene-α-D-gμcofuranurono-6,3-lactone of F (yield 91.5%) was obtained.

Example 11 D-glucurono-6°3-lactone 20. Of and 7'l of antimony pentafluoride were added, and the mixture was refluxed and stirred for 1 m in a 68°C water bath for 8 hours.

During this time, -11 was poured into Molecu2 Thieves 3A 35f1 between the reactor and the cooling tube, and the refluxing solvent was dried. After the reaction was completed, the reaction solution was diluted with dichloromethane and diluted with deuterium aqueous solution.

Washed with water and subsequently dried with anhydrous sulfuric acid.

After distilling off the solvent and cyclohexanone under reduced pressure, the residue was washed with a small amount of hexane to give 28.10 f l*
2-O-y9a hexylidene-α-D-glucofonuronol-6.3-lactone (purity of 99.5% or more) was obtained. Yield 96.1%.

Engineering R (KBr) jfl 3400.178B, 177
3N MR (CDC13) δ 1.20-1.85 (
10H, br).

3.50 (1■, br), 4.55 (IH, br),
4.75-5.05 (31i, m), 6.02 (IH,
d) Example 12 D-glucuronic acid 1. Of and 15,0q of antimony pentafluoride were added and heated in a water bath at 68°C.
Reflux and stirring were continued for an hour. During this time, Molecu2 Thieves 3A 20F was installed between the reactor and the cooling pipe.
The refluxing solvent was dried. After the reaction is complete, the total amount is t100
ml gas chromatograph (column: 3% 5ilic)
on 0v-L onChromoeorb VL 2
m; Column Ax degree 200°C), 1.
22F 1+2-o-V chlorohexylidene-a-D-glucofuranurono-6°3-lactone was obtained. Yield 9
2.5%.

Example 13 100 * / cyclohexanone and 120 * chloractone 10. Add 44.9 liters of of and antimony pentachloride,
Reflux and stirring were continued for 7 hours in a 78°C water bath. Molecular Thieves 3A is used for this same reactor and cooling pipe song.
'20f was incorporated and the refluxing solvent was dried. After completion of the reaction, unreacted D-glucurono-6,3-lactone 4.
I took the 70f. When the total amount of f5 liquid was adjusted to 200 r/ml and subjected to a gas chromatograph (the conditions were the same as in Example 12), 7.36F 1,2-0-cyclohexylVylidene-a7D-gμcofuranurono-6,3-lactone was obtained. . Yield based on consumed raw materials: 95.5%.

Example 14 20.Of D-glucurono-6,3-lactone and 254 m/m of iodine were added to a mixture of 250 m/m of V clopentanone and 15(Lyl) of dichloromethane, and the mixture was refluxed in a water bath at 70°C for 8 hours. , continued stirring.

This reactor and a cooling tube were assembled into a 1'% I: Molecufu Thieves 3A 3511, and the refluxing solvent was dried. After the reaction was completed, a small amount of pyridine was added and evaporated under reduced pressure, and the residue was subjected to yliage column chromatography (solvent: chloroform) to give 23.49F (yield: 85.4).
%) of 1.2-. 0-cyclopentylidene-n-7)-
Gumuco7 funurono6.3-lactone was obtained.

Melting point 11B-119°C (h+: acid ethyl ester/l/
-H-hexane recrystallization) Engineering R (nea, t) CM3440, 180ON
MR (CDC13) 31.4-2.1 (br, 8H),
3.95 (br, 1ll), 5.93 (d, J=3.
5Hz+IH).

4.5-5 (m, 4H) Elemental analysis value (%) C engineering, H engineering. Calculated value as 06
C54,54; H5-83

Claims (1)

[Claims] A method for producing glucrinolactone ket-μ, which comprises reacting glucuronic acid or glucurono-6,3-tuctone with a ketone in the presence of hydrogen iodide, antimony pentachloride or antimony pentafluoride.