JPH02237983A - Production of l-ascorbic acid derivative - Google Patents

Abstract

PURPOSE:To obtain the title compound through a shortened process in high yield with reduced reaction steps and the purification process omitted, by reaction, in the presence of an aprotic polar solvent and an alkali metal carbonate, between L-ascorbic acid and a halide under specified conditions. CONSTITUTION:When L-ascorbic acid and a halide {pref. a compound of the formula Y-CH2-R [Y is Cl, Br or I; R is CnH2n+1 (n is 1-18), -C(O)-OCnH2n+1, -C(O)-CnH2n+1, etc.]} are to be reacted in the presence of an aprotic polar solvent and an alkali metal carbonate to obtain the objective ether-type derivative of L-ascorbic acid with its 3-site hydroxyl group etherified, the amount of the L-ascorbic acid to be added is made excess based on the halide in terms of molar ratio and/or a quaternary ammonium salt is added and the above reaction is carried out.

Description

DETAILED DESCRIPTION OF THE INVENTION "Field of Industrial Application" The present invention relates to a new method for producing L-ascorbic acid derivatives that are expected to be useful in applications such as pharmaceuticals and cosmetics.

"Prior art" The etherification reaction of the 3-hydroxyl group of ascorbic acid that has been published so far is generally
．． 5,6- with the hydroxyl group at position 61 protected with acetone etc.
There are many examples of production using di-0-imbropylidene derivatives. Examples of these include Japanese Patent Application Laid-open No. 58-57373.
JP-A No. 59-55833, and the like.

Regarding this conventionally known method of protecting the 5.6-position hydroxyl group as an inglopylidene compound, the present inventors' research revealed that depending on the compound bonded to the 3-position of L-ascorbic acid, de-ingropylidene reaction may occur. This method was difficult to obtain desired results because it was difficult to obtain the desired results, and the decomposition of the reactants occurred at the same time.

Examples of direct reaction with L-ascorbic acid include JP-A-58-131978 and JP-A-61-26.
No. 3939, Canadian Journal, Op., Chemistry, Vol. 43, p. 450 (1965) is known.

When we investigated examples of directly reacting these with L-ascorbic acid, we found that JP-A-61-263969 did not disclose a specific production method. moreover,
Canadian Journalist, of. Chemistry Vol. 43, p. 450 (1965) and JP-A-58-13197
Although the production method is described in Publication No. 8, the yield is completely unknown.

"Problems to be Solved by the Invention" Therefore, the present inventors first attempted to solve the problem by using the prior art.
Ascorbic acid derivatives were produced.

From method number 3 of Japanese Patent Application Laid-Open No. 58-131978, 3
When -0-(n-butyl)-L-ascorbic acid was produced, the yield was 4.1%, and in the case of 3-0-(n-stearyloxylponylmethyl)-L-asconolebic acid, the yield was 4.1%. It was 8.9%. Furthermore, using 5,6-di-0-isopropylidene-di-asconolebic acid,
When 3-0-(n-stearinoleoxycanolebonylmethyl)-L-ascorbic acid was produced, the yield from 5,6-di-0-isopropylidene-dis-ascorbic acid was 7.8%. The yield is low.

Thus, with the conventional technology, the yield is less than 10%,
Moreover, the yield was lower when 5,6-di-O-impropylidene-L-ascorbic acid was used.

In producing the ether type derivative of the hydroxyl group at the 3-position of L-ascorbic acid, the present inventors focused on the fact that there is still no technology for obtaining the desired product in high yield. An object of the present invention is to develop a method for producing a compound in high yield.

"Means for Solving the Problems" The present invention has been made to solve the problems mentioned above.
Reacting L-asfulvic acid and a halokenide in the presence of a polar aprotic solvent and an alkali metal carbonate,
A method for obtaining an ether type derivative of the 3-hydroxyl group of L-ascorbic acid, which comprises adding an amount of L-ascorbic acid in excess of the halide in terms of molar ratio, or/and adding a quaternary ammonium salt. It is characterized by causing a reaction.

In the present invention, the L-ascorbic acid derivative mainly has the following general formula (I[)\CB,R (in formula (II), R represents one of the following functional groups.

-C, ■2g+1+ -C-OCsL*+++ -
C-C, II2*+1+ where n is a natural number from 1 to 18, m is 1 or 2, and X is a halogen or an alkyl group having 18 or less carbon atoms.

The main points of the present invention are that the reaction proceeds smoothly by using a quaternary ammonium salt and a high yield is obtained, and that a halide (compound of general formula (1)) Y-C [I. −
R...(I) (In formula (1), Y represents a chlorine, bromine or iodine atom, and R represents one of the following functional groups.

-C, 11, S,, -C-OC, ■2~,, -C-C
, [Izs+++ Here, m is a natural number from 1 to 18.
represents 1 or 2, and X represents a halogen or an alkyl group having 18 or less carbon atoms.
- By using an excess of ascorbic acid, various side reactions can be suppressed, and the target hydroxyl group at the 3-position can be obtained in high yield (general formula (■)) (the molar ratio of L-ascorbic acid can be adjusted to If the amount is reduced, the generation of impurities becomes significant and their separation becomes difficult.) The present invention requires the use of at least one of these two points.

The structure of the quaternary ammonium salt used in the present invention does not make any difference in reactivity, and most commonly used quaternary ammonium salts can be used. For example, common quaternary ammonium salts such as benzyltrimethylammonium bromide, phenyltrimethylammonium iodide, stearyltrimethylammonium bromide, octyltrimethylammonium bromide, n-butyltrimethylammonium bromide can be used.

Examples of the halide Y-CH,g represented by the general formula (I) in the present invention include the following compounds.

n-Butyl bromide n-pentyl bromide n-hexyl bromide n-octyl bromide n-nonyl bromide n-decyl bromide n-dodecyl bromide n-stearyl bromide ethynoleoxycanoleboninole chloride n-butyloxyluponyl chloride n-octyloxy n-decyloxylponylchloride n-decyloxylponylchloride n
- stearinoleoxycanoleponyl chloride benzinolechloride p-promobenzyl chloride p-stearinolebenzinolechloride p-octylphenyl luponylmethyl chloride p-pentylphenyl luponyl methyl Chloride p-Promobenzoyl chloride Penzoyl chloride n-cutyl force Luponylmethyl chloride n-Decyl force Luponylmethyl chloride n-Dodecyl force Luponylmethyl chloride n-Stearyl force Luponylmethyl chloride Ethyl force Luponylethyl chloride n-Pentylcarbonyl-n-propyl chloride n-decyl carbonyl ethyl chloride n-decylcarbonyl chloride 2-pyridylmethyl chloride 3-pyridylmethyl chloride 4-Biridylmethyl chloride Furthermore, compounds obtained by replacing the halogen atom with another halogen atom (bromine, iodine, chlorine, etc.)
Of course you can use it.

The general steps of this reaction are as follows. This is done as shown below.

After mixing and stirring the polar aprotic solvent and the alkali metal carbonate in an inert gas, L-ascorbic acid was added, stirring was continued for an additional 0.5 to 5 hours, and the mixture was heated to room temperature to about 100°C. The halide is added in an amount of 0.1 to less than 1 molar equivalent, preferably 0.1 to 0.5 molar equivalent, to L-ascorbic acid at a reaction temperature of . The amount of alkali metal carbonate added to the halide is 0.9
~l. 2 equivalents, preferably 1 equivalent (step 1).

Additionally, quaternary ammonium salts are added to
．． 0111i amount% to 25% by weight, preferably 0.03
After adding IO wt% from wt%, from room temperature to 100°C,
Preferably, the temperature is raised to 60°C for 0.5 to 20 hours,
Preferably, the reaction is carried out for 2 to 20 hours (Step 2).

In the step 1, the amount of L-ascorbic acid added may or may not be excessive in molar ratio to the halide, as described above. Furthermore, in step 2, a quaternary ammonium salt may or may not be added as described above.

However, the important thing is that if the amount of L-ascorbic acid added in Step 1 is not excessive in terms of molar ratio, it is necessary to add quaternary ammonium salt in Step 2; If no salt is added, step 1
In this case, it is necessary to make sure that the amount of L-ascorbic acid added is in excess in terms of molar ratio. Of course, as mentioned above, it is also possible to make the amount of L-ascorbin added in excess in terms of molar ratio in step 1, and also add the quaternary ammonium salt in step 2, thereby obtaining an even higher yield. be able to. Furthermore, whether or not the amount of L-ascorbic acid added in step 1 is excessive in terms of molar ratio, the reaction conditions such as reaction temperature and reaction time may be the same. This also applies to the reaction conditions in step 2 depending on the presence or absence of the quaternary ammonium salt.

Following step 2, the reaction solution after completion of the reaction is poured into a large amount of water, and extraction is repeated several times with ethyl acetate, chloroform, etc. The organic layer was treated with 0.1-0.01% diluted hydrochloric acid.
After washing twice, wash with water several times.

After drying the solution with a dehydrating agent such as Glauber's salt, the solution is concentrated to obtain a crystalline compound or oil (Step 3). Among these, the crystalline compound is prepared by using n-hexane in an inert gas such as nitrogen gas;
Thoroughly wash and dry using a solvent such as pentane, petroleum ether, ligroin, benzene, etc. If necessary, it is also possible to perform reprecipitation purification from methanol-water or the like. In addition, oily substances can be purified by thoroughly washing with the above-mentioned various solvents and removing the solvent with a decantation machine. The yield from these reactions is approximately 4
The target product can be obtained with an unprecedentedly high yield of 0 to 80%.

The polar aprotic solvent used in this reaction is preferably a solvent such as dimethyl sulfoxide, dimethylacetamide, or dimethylformamide, but other ketone solvents may also be used.

Furthermore, as the alkali metal carbonate, potassium carbonate,
Mention may be made of sodium carbonate, etc., and bicarbonates can also be used, but the use of the carbonates gives good results.

Another advantage of this method is that a highly purified target compound can be obtained without using column chromatography, which also shows the usefulness of this production method.

The method for producing the present compound group will be explained in more detail by way of Examples below, but the present invention is not limited in any way by the Examples below.

"Examples 1 to 4" Production according to the present invention was carried out with (Examples 1 to 3), without (comparative example) a quaternary ammonium salt, and with an excess of L-ascorbic acid (excess; Examples 1, 2, 4. The same amount; Comparative Example), etc., the results shown in Table 1 were obtained.

In Table 1, benzyltrimethylammonium bromide was used as the quaternary ammonium salt. ASA stands for L-ascorbic acid, NU stands for n-decyloxylponylmethyl chloride, and this column shows the molar ratio. The yield indicates the yield after isolation of the target product. In addition,
Dimethyl sulfoxide was used as the solvent, anhydrous potassium carbonate was used as the alkali metal carbonate salt, and N was used as the quaternary ammonium salt.
The target product was isolated by performing the same post-reaction treatment except that 1.6 g of U was added.

From this Table 1, the effect of using quaternary ammonium salt and L
- It was found that the excess ratio of ascorbic acid had a large effect on the yield.

"Example 5" Production of 3-01-stearyl-ascorbic acid 12
26.5 g of anhydrous sodium carbonate was added to 00 all dimethyl sulfoxide under a nitrogen stream, and the mixture was stirred at 60° C. for 3 hours, then cooled to room temperature, 400 g of ascorbic acid was added, and stirring was continued. After stirring for 15 minutes, 15 J of n
-Add stearyl bromide and add 3.6! After adding phenyltrimethylammonium iodide of 6
The mixture was heated to 0° C. and stirring continued for 6 hours. Thereafter, the reaction solution was returned to room temperature, poured into 2 portions of water, and extracted several times with ethyl acetate. The extract was washed once with 0.5% hydrochloric acid,
Furthermore, it was washed with water and dehydrated with sodium sulfate.

Ethyl acetate was concentrated to remove white crystals. The crystals were pulverized under a nitrogen stream, and 1M n-hexane was added.
was added and stirred for 30 minutes, and then filtered. Subsequently, 500 tons of methanol was added to dissolve the mixture, water was added, and the resulting precipitate was filtered and dried to obtain 148 g of the desired product.

・Yield: 76%, ・Melting point: 95.5-97.0°C, ・Elemental analysis value C: 67. '25% (67.29%)-H
: 10.26% (10.28%) (calculated value in parentheses), ・Infrared absorption spectrum (main absorption value) (one c+a: 2930, 2850, 1755, 1700, 1470
．． 1350 [Example 6J In 600 am of dimethyl sulfoxide under nitrogen stream,
After adding 26.5 g of anhydrous soda carbonate and stirring at 60°0 for 3 hours, the mixture was cooled to room temperature, 220 g of L-ascorbic acid was added, and stirring was continued for 30 minutes. Here is the n of the 117th ward.
-Add decyloxy-olebonylmethyl chloride,
Furthermore, benzyltrimethylammonium bromide3.
0 g was added thereto, and the mixture was stirred at 50°C under a nitrogen stream for 8 hours.

This dimethyl sulfoxide solution was poured into 1.511 water with stirring under a nitrogen stream, and extracted several times with ethyl acetate. The extract was washed once with 0.5% hydrochloric acid, then water, and dehydrated with Glauber's salt. After ethyl acetate was concentrated and distilled off, the ethyl acetate was thoroughly removed using a vacuum pump to obtain white crystals. After finely pulverizing the crystals, lll of n-hexane was added, stirred for 30 minutes under a nitrogen stream, and filtered. After repeating the same n-hexane washing, the filtered crystals were washed with 200ml methanol.
After dissolving the product in 100 g of water, water was added to recrystallize it to obtain 145 g of the desired product.

・Yield: 78%, ・Melting point: 75. O~75.8℃, Elemental analysis value C: 57.72% (57.75%), H:
8. OO% (8.02%), (calculated value in parentheses) ・Infrared absorption spectrum (main absorption value) (c+I1-
'): 2950, 2880, 1755, 1700, 14
45.1360) "Example 7" Under a nitrogen stream (
All of the following operations were performed under a nitrogen stream. ) at 69.0
g of anhydrous potassium carbonate was added, and after stirring at 60°C for 2 hours, the mixture was cooled to room temperature. To this, 200 t of L-ascorbic acid was added, and after stirring for 45 minutes, 41 g of hydrochloric acid 3-picolyl chloride was added, and 0.8 g of phenyltrimethylammonium iodide was added, followed by stirring for 8 hours. This dimethyl sulfoxide solution was poured into 1.51 g of water and extracted several times with ethyl acetate. After washing the extract twice with water,
Dehydrated with mirabilite. Thereafter, the same post-treatment as in Example 6 was performed to obtain 48.7 g of the target product.

・Yield: 73%, ・Melting point: 154.5-156.0°C, ・Elemental analysis value C: 53. ．． 97% (53.93%), H
: 4.84% (4.87%), N: 5.22% (5.24%) (calculated value in parentheses) - Infrared absorption spectrum (main absorption value Xca+-')
:1780, 1705, 1605, 134
0, "Example 8" Production of 3-0-benzy-ascorbic acid 400a
+11 in N,N-dimethylformamide under nitrogen flow (all the following operations were performed under nitrogen flow) 34.5
g of anhydrous potassium carbonate was added, and after stirring at 60'0 for 1 hour, the mixture was cooled to room temperature, and 330 g of L-ascorbic acid was added, followed by stirring for 30 minutes. 63.0 g of penzyl chloride and 2.0 k of penzyl trimethylammonium chloride were added thereto, and the mixture was stirred at 40°C for 7 hours. The reaction solution was poured into 1.511 g of water and extracted several times with ethyl acetate. The ethyl acetate solution was washed once with 0.5% hydrochloric acid, then with water, and then dehydrated with sodium sulfate. After dehydration and concentration, ethyl acetate was distilled off to obtain an oily residue. 500＠ for this residue
l! of n-hexane was added thereto, and the mixture was stirred for 10 minutes using a homogenizer. Since an oily substance would precipitate if left to stand, the n-hexane layer was removed by decantation. After repeating this operation one more time, 100 ml of ethanol was added.
After dissolving the oil, water was poured to obtain a precipitate of oil. Remove the water-ethanol layer with a decant and add 300ml of water/ethanol-100/5 (V/V) solution.
1 was added and the oily substance was washed with stirring. The upper layer was discarded by decantation, and the residue was thoroughly dried using a vacuum pump to obtain 86 g of a colorless oil.

・Yield: 65%, ・Elemental analysis value C: 58.61% (58.65%). H:
5.23% (5.26%) (calculated value in parentheses) ・Infrared absorption spectrum (main absorption value Xcm-'):
1760, 1690, 1330, "Example 9" Production of 3-0-n-decyl-L-ascorbic acid 100
34.0% in dimethyl sulfoxide at a temperature of 0.34% under a nitrogen stream (the following reactions and treatments were all carried out under a nitrogen stream).
5 g of anhydrous carbon potassium was added and stirred at 60°C for 2 hours. After cooling to room temperature, add 390 g of ascorbic acid and continue stirring for 15 minutes. Add llog of n-decyl bromide to &, add t. Phenyltrimethylammonium iodide of S (S) was added and reacted at 60°C for 6 hours. After the reaction was completed, the mixture was poured into 2I water at room temperature and extracted several times with ethyl acetate. It was washed once with .5% hydrochloric acid, further washed with water, and dehydrated with Glauber's salt.

Thereafter, the same process as in Example 5 is performed, and the target object 117
I got g.

・Yield: 74%, ・Melting point 267-68℃, ・Elemental analysis value C: 60.78% (60.76%), H:
8.82% (8.86%) (calculated value in parentheses), ・Infrared absorption spectrum (main absorption value) (C [ri: 29
30.2850, 1750, 1700, 1470.13
50 "Example 10J ・Infrared absorption spectrum (main absorption value) (C" Ri: 29
20, 2850, 1750, 1700,1
440. 1350 1200ml! dimethyl sulfoxide under a nitrogen stream (the following reaction treatments were performed under a nitrogen stream).

34.51 of anhydrous potassium carbonate was added thereto, and the mixture was stirred at 60°C for 1 hour. After cooling to room temperature, 30 J of L-ascorbic acid was added and stirring was continued, and after 15 minutes 173 g of n-stearyloxylponylmethyl chloride and 1.9
g of n-stearyltrimethylammonium bromide was added, and the mixture was reacted at 60°C for 6 hours. Thereafter, post-treatment was performed in the same manner as in Example 6 to obtain the target product 19sJ.

・Yield: 79%, ・Melting point: 292.5-93°C, ・Elemental analysis value C: 64.22% (64.20%), H:
9.43% (9.47%) Example Ill The desired product was obtained in a yield of 71% from n-butyloxytriponylmethyl chloride and ascorbic acid by the same reaction as in Example 6.10.

- Melting point: 81.5-82.5°C, - Elemental analysis value C: 49.61% (49.66%). H:
6.26% (6.21%) (calculated value in parentheses), ・Infrared spectrum (main absorption value) (cm-'): 2
920.2B50,1750, 1700,1440.1350 (calculated values in parentheses) As described above, the following compounds can be produced by the production method of the present invention.

No. l; 3-0-n-butyl-ascorbic acid 2; 3-0-n-hexyl-ascorbic acid 3; 3-0-n-nonyl-L-ascorbic acid 4; 3-0-++ monodecyl-L- ascorbic acid 5
; 3-0-n-stearyl-L-ascorbic acid 6
．． 3-0-(ethyloxycarponylmethyl)1L
-Asfulvic acid 7; 3-0-(++-butyloxylponylmethyl)-L-ascorbic acid 8; l-0-(m-octyloxylponylmethyl)-L-ascorbic acid 9; 3-0-(o-decyloxyl) 3-0-(a-stearyloxylponylmethyl)-L-ascorbic acid +1. 3-0-Pendyl-ascorbic acid 12
; 3-0-(p-promobenzyl)-L-ascorbic acid 13; 3-0-(p-promobenzyl)-L~ascorbic acid +4; 3-0-(p-promobenzyl)-L-ascorbic acid +s; 3-0-(p-bentylphenylmethyl)-L-ascorbic acid+6; 3-0-(p-bentylphenylmethyl)-L~ascorbic acid 17; 3-0 -(a-octyl grouponylmethyl)
-L-ascorbic acid 11; 3-0-(n-petinolecanolevonylmethyl)-1L~ascorbic acid 19; 3-0-(++-pentylcarponylethyl)-L~ascorbic acid 20; 3- 0-(ethyl grouponylethyl)-L-
Ascorbic acid H; 3-0-(++-pentylcarbonyl-n-probyl)-L-ascorbic acid H; 3-0-(a-decynolecanolevonylethinole)-1L-ascorbic acid 23; 3-0 -(++ monodecylcarbonyl-n-probyl)-ascorbic acid 24. 3-0-(3-pyridylmethyl)-L-ascorbic acid 25; 3-0-(2-pyridylmethyl)-L-ascorbic acid ``Effects of the invention'' As explained above, the features of the present invention are that L- In producing ascorbic acid derivatives, it is possible to provide a production method for obtaining an ether type derivative of the hydroxyl group at the 3-position in high yield without performing any protection on the hydroxyl groups at the 5- and 6-positions of L-ascorbic acid. This is due to a decrease in the number of reaction steps,
This is a short-step, high-yield production method that includes the omission of purification steps such as column chromatography 7E.

Applicant Dainippon Ink & Chemicals Co., Ltd. Foundation
Kawamura Physical and Chemical Research Institute

Claims (3)

[Claims] (1) A method for obtaining an ether type derivative of the 3-hydroxyl group of L-ascorbic acid by reacting L-ascorbic acid with a halide in the presence of a polar aprotic solvent and an alkali metal carbonate, the method comprising: Production of an L-ascorbic acid derivative, characterized in that the amount of L-ascorbic acid added is in excess of the halide in molar ratio, and/or a quaternary ammonium salt is added and reacted. Method. (2) The halide has the general formula (I) Y-CH_2-R...(I) (In formula (I), Y represents a chlorine, bromine or iodine atom, and R represents one of the following functional groups. -C_mH_2_m_+_1, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ Mathematical formulas There are , chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ where n is a natural number from 1 to 18, m is 1 or 2, and X is a halogen or an alkyl group with 18 or less carbon atoms) 2. The method for producing an L-ascorbic acid derivative according to claim 1, wherein the compound is a compound represented by: (3) The L-ascorbic acid derivative has the general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In formula (II), R represents one of the following functional groups. -C_mH_2_m_+_1 , ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ Mathematical formulas, chemical formulas, tables, etc. There are ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, n is a natural number from 1 to 18, m is 1 or 2, and X is a halogen or an alkyl group having 18 or less carbon atoms. ) The method for producing an L-ascorbic acid derivative according to claim 1, wherein the L-ascorbic acid derivative is a compound represented by: