JPS60248637A - Manufacture of scylloinositol - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides the production of myo-inositol from myo-inositol.
The present invention relates to a method for producing cyllo)-inositol.

A large number of methods are already known for the production of dilo-inositol, a natural product widely found in plants and animals, such as by biological oxidation and reduction of myo-inositol to myo-inosose [Th
, Po5ternak: He1v, Chim, A
cta, 24.1045 J, (1941)];
Method by hydrogenation of hexahydroxybenzene (R,
C9Anaerson and B,S,W,alli
s;, T, Am.

Chem, SOc, 7Q, p. 293 (1948)
];] Method by reduction and hydrolysis of pentaacetyl-mioinosode with NaBH4 (N, Z, 5t
anazev and M, Kates: J, Org.
, Chem, p. 26.912 (1961)]]i
D-*Method by basic condensation and reduction of silohexosose 5-10- to myo-inosose [D, F, Kie
ly and HlG, Fletscher; J, Am;
Chem. SOC, 90, 3289Q (1968);
er, HoFritz and H, Pr1nzbach.
: Angew, Chem.

85, 1110 (1973)].

] The hydroxyl group in the axial direction of myo-inosyto is Pt1
Selective catalytic oxidation of myo-inosose with 02 [K,
Heyns and H. Paulsen: Chem.

Ber, p. 85.833 (1953) and Ang.
ew, Chem.

See Figure, p. 600 (1957)] and this myo-
CD, Reymond, reducing inosose:
He1v.

Chim, Acta, 59.492 pages (1957)
The process is envisaged as starting from cheap and readily available starting materials and leading to the desired product in as few synthesis and silk-making steps as possible.

However, in this oxidation of myo-inositol, a conversion rate of only about 75 to 80% is obtained, so in order to obtain high purity diro-inositol in the subsequent reduction, it is necessary to separate the unconverted raw material. Must be. The phenylhydrazone route of myo-inosose suggested by Heyns and J. Paulsen cannot yet be carried out at an acceptable cost on an industrial scale, and furthermore, the desirability of the effluent is It also causes unnecessary pollution. Furthermore, experiments have shown that this phenylhydrazone process is extremely difficult to reproduce.

It is an object of the present invention to provide an improved method for the synthesis of dilo-inositol and an improved method for the separation of unconverted myo-inositol from myo-inosose-containing oxidation products, which have only a slight, if any, drawback as mentioned above. It was about finding out.

This objective was achieved by subjecting the mixture obtained after oxidation of myo-inositol to an esterification treatment and selectively crystallizing the myo-inosose as an easily crystallized ester.

This ester can then be converted to dilo-inositol by reduction and hydrolysis.

Therefore, the present invention relates to a method for producing giro-inositol from myo-inositol via myo-inosose,
The method of the invention involves subjecting the mixture obtained after oxidation to esterification, in which esters of myo-inosose easily crystallize? In this method, 4E is formed, which is then converted to diro-inositol by reduction and hydrolysis.

Furthermore, the present invention relates to a method for separating unconverted myo-inositol from its myo-inosose-containing oxidation products, which method is characterized in that the myo-inosose is selectively crystallized as an easily crystallized ester. This is the way to do it.

Myo-inositol can be oxidized in principle by any conventional method, for example by biological oxidation or by N-
This can be done by using selective oxidizing agents such as bromosuccinimide, silver carbonate/celite or chlorine/pyridine. The oxidation is carried out as a catalytic dehydrogenation using a bullion catalyst, preferably a platinum catalyst and oxygen.
It is preferable to carry out the reaction in an aqueous solution at 0°C, especially 45 to 60'C.

The reaction mixture can be esterified without further purification operations. Preferably, the reaction mixture is evaporated after removing the catalyst.

The residue is esterified with the acid or one of its reactive derivatives. Particularly suitable reactive derivatives are halides of acids, especially chlorides and bromides, anhydrides (including mixed anhydrides), and azides or esters, especially alkyl esters having 1 to 4 C atoms in the alkyl group. be.

Esterification can be carried out in the presence of an inert solvent. In particular, suitable solvents include dimethylformamide, dimethylacetamide, amides such as 1,3-dimethyl-2-imidazolitone or hexamethylphosphoric triamide, and sulfoxides such as dimethylsulfoxide or sulfolane. The esterification can also advantageously be carried out in the absence of a solvent, for example by simply mixing the reaction components, optionally in the presence of a strong acid. The reaction temperature is usually -n'c to so'
c, preferably o'c to 50°C. At these temperatures, the esterification reaction is generally complete after 15 minutes to 48 hours.

The specific reaction conditions for esterification will vary substantially depending on the nature of the acids or reactive derivatives thereof used. Therefore, the free carboxylic acid is generally reacted in the presence of a strong acid, such as a mineral acid such as hydrochloric acid or sulfuric acid. A preferred reaction method comprises converting the reaction mixture into an acid anhydride (preferably
Carboxylic anhydrides such as acetic anhydride, propionic anhydride or butyric anhydride) are still reacted with acid chlorides. This reaction is preferably carried out in an acidic medium; important acids include mineral acids such as hydrochloric acid or sulfuric acid, organic acids such as p-)luenesulfonic acid and Lewis acids.

However, this reaction can also be carried out in a basic medium, e.g. alkali metal carbonates or bicarbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, sodium acetate or potassium acetate. It can also be carried out in the presence of alkaline earth hydroxides such as acetate, calcium hydroxide, or organic bases such as triethylamine, pyridine, lutidine, collidine or even quinoline.

Particularly suitable acids are aliphatic carboxylic acids (e.g. acetic acid,
zoropionic acid or butyric acid), or aromatic carboxylic acids (eg benzoic acid). Substituted benzoic acids can also be used.

The reaction mixture from the esterification is worked up in a manner known per se and the ester derivative of myoinosose is obtained by crystallization from a suitable solvent. Particularly suitable solvents are ethers such as diethyl ether, diisozorobyl ether, di-n-propyl ether or di-n-butyl ether, ketones such as acetone or methyl ethyl ketone, methanol, ethanol, n-propanol or isozoronyl ether. Alcohols such as Q-nol, esters such as ethyl acetate, or mixtures of these solvents. Mainly composed of ether, containing 1 to 1 alcohol
Particularly preferred are solvent mixtures containing 0 volume fractions, especially 2 to 5 volume fractions.

The easily crystallized ester derivatives of myo-inosose are substantially free of ester derivatives of myo-inositol and can be used in the production of diro-inositol or for other intended uses. Further recrystallization generally results in a decrease in the melting point.

[ A.

Kirsch, C0Von Sonntag and Tori, 5 Chulte-Frohlins: J, Ch.
em, S'oc, Perkin ■, 1975.133
Page 4 and N, Z, S'tanazev and M,
J, Org, Chem, 26.9 by Kates
12 (1961)].

The ester derivative of myo-inosose is reduced using sodium borohydride/methanol.

In order to separate the borate, the reaction mixture is acidified, then methanol is added repeatedly and then distilled without vacuum. Pure dilo-inositol is obtained from the residue by crystallization.

The following section describes the invention, but does not limit the invention thereto.

Preparation of Platinum Catalyst 8.5 g of platinum oxide (ml 125 g) in water was stirred at room temperature and under atmospheric pressure until hydrogen absorption completely ceased or slowed down substantially (approximately U hours). , hydrogenated. In this process, perhydrogenation, which is noticeable by deposits on the metal mirror or polished metal pieces, should be avoided; otherwise the activity will be reduced. The platinum suspension obtained in this way Hydrogen is removed from the liquid by repeated application of reduced pressure. The product can be used directly in the subsequent process. The catalyst can be used in several reaction cycles.

700ml of water and 16. A stirred mixture of Or and a Pt catalyst obtained by hydrogenation of 8.5 f of platinum (n) oxide was heated at 50-55 °C with a stream of oxygen of 5
pass the time. The catalyst is then filtered off; it can be used repeatedly. The filtrate is evaporated, a mixture of acetic anhydride and concentrated sulfuric acid is added to the reaction mixture while cooling with ice, and the mixture is stirred at room temperature for U hours. The reaction mixture was mixed with 500 mg of water.
The organic phases are washed three times with 100 mg of saturated sodium bicarbonate solution and three times with sodium chloride solution, dried over magnesium sulfate, filtered and then evaporated.

10 rrtll of methanol are first added to the residue, then 300-400 ml of ether are added and the mixture is left to cool overnight. Remove the formed crystal precipitate using a suction furnace and rinse with ether. Yield: 11ri melting point.

205-209°C6 The sterile acetate thus obtained is 400 M
Although the B2 NMR spectrum still shows a slight contamination with the hexaacetate of myo-inositol, it can be used in the process for producing diro-inositol without further purification.

A solution of 0.75 F of thorium borohydride in diroy-inositol anhydrous methanol 125 rne was added at room temperature to a stirred suspension of 5.0 P of penta-acetate of myo-inosose in anhydrous methanol 125 + y6, and stirring was then continued for 30 min at room temperature.
Continue for a minute. The solution was acidified with 2N hydrochloric acid, then 20
Evaporate to mg. To separate the borate, 200 portions of methanol are added repeatedly each time and the methanol is then distilled off. The mixture was then evaporated to dryness and the residue was dissolved in 3 ml of water.
0 to 50 rae, and the solution was applied to a cation exchange column [Levatic 8C302, H1
00f] and the column is then rinsed with water until the P solution shows a neutral reaction. Evaporate the aqueous solution in about 20 ml, and methanol 200-250 ml, l! and allow the mixture to cool.

The giro-inositol which precipitated as fine colorless crystals is filtered off with suction and then rinsed with methanol. Yield: ], 6~
1. ．． 8f; melting point, 345-347°C0 By evaporating the mother liquor, a crystalline product with low purity can be obtained as a second product.

Special Remarks' (Applicant: Merck, 9 Sons, Geselschaft, Mitbe, 7, Jülenkter) 1 Futsung F Continued Supplement +1g i! 7 (Method) % formula % 1, Indication of the case 1985 Patent Application No. 26630 2, Name of the invention Zyrow-inositol Ma Method 1, Person making the amendment Relationship with the IS case Address of the person who issued Special 41 Federal Republic of Germany Republic D-6100 Darmstein, Frankfurthill Name: Merck Patent φGesellschaft Mitsut Heschlenkter /\Futsung 4, Agent address: 3 Kojimachi, Chiyogawa-ku, Tokyo 'T'! -1 2 i
Chisou Til Daiichi Building (shipment date: May 2811, 1985) 7 Self-answer to Sen 1 (1) 1 IM 11 divination, method according to 1 of 2 Q 10 line” 1 (Diech Postelner Mr. Ri
Insert the description "Helvetia stain force acta)".

(After the description of method J according to 1 on page 2, line 12, twice,
[Mr. R.C.
Insert the entry from Mr. Wallis's Journal of the American Chemical Society).

(3) After the description of ``Method according to 1 on page 2, line 16,''
(Journal of Orkanitsk Chemistry by Mr. F. Set Stanatsuev and Mr. M. Kates)
” is inserted.

(4) After the description of Song Zhu's "method by" on page 2, "
(D.F. Keely and H.G. Fletscher, J.C. of American Chemical Society)" is inserted.

(5) After the description of ``Method according to 1, page 3, line 3'' of the same, ``
(Mr. Earl Schwesinger, Mr. H. Fritz and Mr. H. Brisippatzuba's Angepante Δ, Mi)" is inserted.

(6) On page 3, line 8, after the description of “catalytic oxidation”, “(
Insert the description of ``Hemischenberichte'' by Mr. Keheins and Mr. Etsch Boersen).

(7) Ibid., 3I-J, line 9, after the statement “and”,
Insert the description "(Angepante Hemi-)".

(8) Same, page 3, line 11, after the statement “reduce”,
Insert the description "(Mr. de F. Raymond's Helvetia stain force acta)".

(9)th, 3Q, Subsha-4!5i line r Heyns and Paulsen J.
Correct it to J.

(10) Ibid., page 9, line 14, “After the description of preferred J,
"(Mr. Nygirsch, Mr. Schie Fountak and Mr. Hityschulte Florin's Journal of the Chemical Society Parkin ■, Bido, 1
Insert page 334 and the description of ``Nyarnal of Ogre Chemistry'' by Mr. F. Z. Stanatsuev and Mr. M.

I-

Claims (1)

[Scope of Claims] (I) A method for producing dilo-inositol from myo-inositol via myo-inosose, which comprises subjecting the mixture obtained after oxidation to esterification to produce easily crystallized myo-inosose. A method for producing diro-inositol, which comprises producing an ester and then converting it to 70-inositol by reduction and hydrolysis. (2) The method according to claim 1, wherein the esterification is carried out using a carboxylic acid compound or a reactive derivative thereof. (3) A method for separating unconverted myo-inositol from myo-inosose-containing oxidation products, which method comprises selectively crystallizing the myo-inosose as an easily crystallized ester. -7-, Hirufuna ancient method of amutated myo-inositol.