SU747430A3 - Method of producing glucosamine or salts thereof - Google Patents

Abstract

Glucosamine derivatives of the formula <IMAGE> (X, R, R1, R2, R4, R6-R9 have the meaning stated in Claim 1) are prepared by condensation of corresponding 3-O-carboxymethylglucopyranosides with corresponding dipeptides. These glucosamine derivatives have the ability to increase the immunogenicity of an antigen on admixture therewith and, on systemic administration, to enhance the immunological reactivity of the treated organism. They can thus be used as adjuvants to increase the vaccine protection from bacterial, viral or parasitic pathogens.

Description

54) METHOD FOR OBTAINING GLUCOSAMINE OR ITS SALTS

The invention relates to a process for the preparation of new derivatives of goocosamine, which have valuable pharmacological properties. The purpose of the invention is to obtain new compounds expanding the arsenal of means of action on living organisms. A method for producing glucosamine of the general formula (iHjORg-0 / O VO-K, .RO / i- / / YH-X- K g (- "C (1-1 n--(okn-C1C; n2 g 9 -carbonyl;, d-alkyl; phenyl-hydrogen, C, -C4-alkyl or benzyl; -hydrogen;" 4 b C, -Cj, alkyl, hydroxymethyl-or phenyl, non-esterified or esterified into an ester of Ct-Cd-alkyl carboxyl groups or not substituted or substituted by C -C-alkane, carboxamidomethyl and KapCoKcaNMflogruppy and benzyl, wherein R contains more than 1 carbon atom when Rg and Rg each - carboxyl, comprising the general formula e -Rg rivedennye above about cleavable

R-, is the residue of the formula, 1 R, or an easily detachable protective group, and the available okigroups can be protected by an easily detachable protective group,

subjected to interaction with the compound of the formula

d

Rfl

z-iH-c: oNHi ::; i - (, - (ln - ((, n

where Z is a reactive esterified ester hydroxy group;

R °, Rg and Rg have the same meanings as R, Rg and Rg, provided that the carboxyl and hydroxyl groups of these residues are protected by easily cleaved protective groups, followed by cleavage of protective groups.

The desired product is isolated in the free state or in the form of a salt by known methods.

The compounds according to the invention, depending on their substituents, are acidic, neutral or basic substances. When there is an excess of acidic groups, these compounds form salts with bases, for example, ammonium salts or salts with alkali or alkaline earth metals, for example sodium, magnesium or potassium salts. With an excess of basic groups, they form acid addition salts — especially pharmaceutically-applicable; non-toxic acid addition salts, such as salts with inorganic acids, such as hydrochloric, hydrobromic, nitric, sulfuric or phosphoric, or with organic carboxylic acids, such as acetic, propionic glycolic, amber, maleic, oxymaline, methylmaleic, fumaric, block, tartaric, citric, benzoic, cinnamon, almond, salicylic, 4-amino-scicilic, 2-phenoxybenzoic, 2-ac toxobenzoic, ambonic, nicotinic or azonicotinic, or with organic sulfonic acids, in particular methanesulfonic, ethanesulfonic 2-hydroxyethanesulfonic, ethane-1,2-disulfonic, benzenesulfonic, p-toluenesulfonic or naphthalene-2-sulfonic, I can also be added; which can be used, for example, as intermediates, in particular for the purification of free compounds or in the preparation of other salts, as well as for identification, for example acid addition salts with picric, picronic, flu vainovoy, phosphors olframovoy, phosphomolybdic, chloroplatinic acid, Reinecke acid or perchloric acid.

Esterified Oxidation Reactant Ox - Group: Oh, the hydroxy group esterified with a strong inorganic or organic acid is, in the first instance, that esterified with hydrohalic acid, for example hydrochloric, hydrobromic or hydroiodic.

Easily removable protecting groups are those that are known from the chemistry of peptides and sugars. As carboxyl groups, in particular, tert-butyl, benzyl or benzhydryl should be mentioned, and as hydroxy groups, in particular, ayostatoki, for example, lower alkanoylterotatons, such as gsac acetyl, aroyl, benzoyl and, above all, residues derived from carbonic acid, for example benzyloxycarbonyl or lower alkoxycarbonyl, or alkyl, in particular tert.-butyl, optionally substituted with nitro, lower alkoxy, or benzyl halogen or tetrahydropyranyl, or in appropriate case substituted alkylidene residues, which oxygen atoms in positions 4 and 6 are bound. Such alkylidenestaton :: ami is, in h-type, lower alkylidenestato in the first O-sequence of ethylidene, isopropylidene or propylidene, or also substituted in the corresponding case preferably. .

These closed groups can be cleaved in a known manner: by hydrogenolysis, for example, with hydrogen in the presence of a noble metal catalyst, such as Pschladium or platinum, or by acid hydrolysis.

In the embodiment of the method, the starting materials of this method are known.

The synthesized compounds can be converted by known methods into their salts, for example, by reacting the resulting acidic compounds with 11-alkali metal or alkaline earth metal hydroxides or the resulting basic compounds with acids.

The proposed method is carried out without use or with the use of diluents or solvents, if necessary, with cooling or heating, under elevated pressure and / or in an atmosphere of an inert gas, such as nitrogen.

In this case, taking into account all substituents in the molecule, especially in the presence of easily hydrolized 0-acyl-residues, the method should be carried out under very mild conditions, such as a short reaction time, the use of mild acidic or fixed assets in low concentrations , stoichiometric amounts: hardened conditions, the selection of suitable catalysts, solvents, temperatures; -; th conditions and / or pressure conditions. Example 1. 4.1 g of benzyl-2-acetamido-2-deoxy-4, 6-benzylidene - (LO-glucopyranoside is dissolved in 30 MP N, AND-dimethylformamide and first mixed at 40 ° C with 0.5 g of dispersion sodium hydride-mineral oil with exclusion of moisture and then at room temperature until a homogeneous solution is obtained. Then a solution of 4.76 g of N-iodoacetyl-1-alanyl-0-isoglutamine-benzyl is added dropwise with cooling at H-C ether in 15 ml of N, N-dimethylformamide and stirred for a day at room temperature. Then filtered, neutralized with acetic acid and evaporated in The solution of 8 g of the obtained compound in 400 ml of 60% acetic acid is kept for 1 hour at 80 ° C. After cooling, the solution is evaporated to dryness to the residue two more times added to 50 ml of water and in case of evaporation to dryness. The resulting crystalline residue is stirred with a small amount of water, the crystals are filtered off with suction and dried, and benzyl-2-acetamido-3-O- (LI- (D-1-carbamoyl-3-carboxypropyl) -carbamoylethyl-carbamoylmethyl} - 2-deoxy A-0-glucopyranoside-benzyl ether, so pl. 200-202 ° С, 1 + 77 t1 ° (dimethylformamide, with 0.599 Solution of 4 g of benzyl-2-acetamido-3-0-Ll- (0-1-carbamoyl-3-carboxypropyl) -carbamoyl ethyl 5-carbamoylmethyl -2-deoxy -c-D-glucopyranoside-benzyl ether in 80 ml of methanol is hydrogenated with 0.4 g of 5% palladium on carbon as a catalyst under normal pressure and at room temperature until the reaction stops. The catalyst is filtered off and washed with a small amount of methanol. and the filtrate is evaporated to dryness in a vacuum created by a water-jet pump. The residue is dissolved in 50 ml distilled water and hydrogenate 1 g of 5% palladium on carbon as a catalyst at normal pressure, at room temperature until the reaction is stopped. The catalyst is filtered off, washed with an additional small amount of water and the filtrate is evaporated to dryness. O-L-1- (D-1-carbamoyl-3-carboxylpropyl) -carbam ilethyl-carbamoylmethyl -2-deoxy-0-glucose is dried with phosphorus chloride in high vacuum, p. -10 -t 1 (water, p. 0.930). 75% yield. In a similar way, a compound is obtained in a similar manner, with the outcome 1; 3 COOTFC-CTFyWITlliX of the original compounds; 2-atseta.m; 1DO-3 0- (O-1-karbelyuil-3-carboxypropyl) -carbamoylmethyl1-carba or lmethyl-2-deoksk-0-glucose, (water, from 0.944), you2-acetau, ids -3-0- {D-1-carbamoyl-3-carboxylpropyl) -carbamoylethyl-carbamoylmethyl-2-deoxy-O-glogIC 3 a, yield 61 °; 3-0- (O- 1-carbamoyl-3-carboxypropyl (-carbaladyl-methyl-carbamoyl-2-deox-2-propion amido-0-glucose, + 8 t 1 ° (water, with 1.146), yield 68%; 3 -0- C1-1- (D-1-carbamoyl-3-carboxypropyl-carbamoylethyl-carbamoylmethyl -2 -capricoyls o-2-deoxy-O- glucose, o.jlj 11 t 1 ° (water, with 1.052}, output 82%; 2-acetamido-3-O-ll- (D-1-carbamoyl-3-carboxypropyl) -carbamoyl-2-hydroxyethyl-carbyl or methyl-2-deoxy-0-glucose, s + 10 ± 1 ° (water , with 1.053), 71% yield; 2-acetates.; ilo-3-0-L-1- {D-1-carbamoyl-3-carboxypropyl) -carbamoyl butyl-carbobalgaclmethyl -2-deoxy-0-glucose a, + 12 t 1 ° (water, s 0.722), vyd745; 3-0- (0-1-carbamo L-3-carboxypropyl) carbamoylethyl-carbamoylmethyl -2-deoxy-2- stearoyl agigido-O-glucose, + 24 ± 1 ° (DMF, from 0.633) yield 62%; 2-acetamide-3-O-ll - (D-1-carbamoyl-3-carboxypropyl) -carbamoyl-2-methylpropyl -carbamoylmethyl -2-deoxy-0-glucose + 11 t 1 ° (water, with 1.096), 65% yield; 2-acetamido- 3-0- {1-1- (D-1-carbamoyl-3-carboxypropyl) -carbamoyl-3-methylbutyl-carbamoylmethyl -2-deoxy-O-glucose, + 16 t 1 ° (water, with 1.060), yield 66%; 2-acetamido-3-O- {L-1-carbamoyl-3-carboxypropyl) -carbamoylpropyl-carbamoylmethyl} -2-deoxy-O - glucose, .1b + 11-1 (water, from 1.019), 71% yield ; 2-acetamido-3-O-L-1- (D-1-carbamoyl-3-carboxypropyl) -carbamoylphenylmetry arb amoylmethyl -2-deoxy-O-glucose, Gy + 17 t 1 ° (water, s 0.987), yield 80%; 2-trimethylacetamido-2-deoxy-3-0-L-1- (O-A-carbamoyl-3-carboxypropyl) -1-carbamoyl ethyl carbamoylmethyl-D-glucose a, cAjt (methanol, c 0.6), yield 73% EXAMPLE 2: 4.5 g of benzyl 2-benzamido-2-deoxy-4, 6-bezilyl-cA-O-glucopyranoside is dissolved in 30 ml of N, N-dimethylformamide and stirred at 20 s with 0 , 5 g sodium hydride dispersion - mineral oil

with exclusion of moisture to obtain a homogeneous solution. Then it is added dropwise while cooling with a solution of 5.1 g of N-bromo-acetyl-1-alanyl-O-isoglutamine-y-benzyl ether in 15 ml of N, N-dimethylformacushta and stirred for 2 hours at room temperature. Then it is evaporated in vacuo to obtain a syrup, which is dissolved in 400 ml of 60% acetic acid and the solution is removed, and the virus is washed for 1 hour at. After cooling, the solution is evaporated to dryness to the residue, twice more, 50 ml of water are added and in each case evaporated to dryness. The resulting crystalline residue is stirred with a small amount of water, the crystals are sucked off and dried. The benzyl-2-benzamido-3-O- {L-1- (0-1-carbamoyl 3-carboxypropyl) -carbamoylztil-carbamoylmethyl -2 deoxycL 0-glucopyranoside-benzyl ester is obtained.

The product obtained is taken up in 80 ml of methanol and hydrogenated from 0.4 g of 5% palladium on carbon as a catalyst at normal pressure and room temperature until the reaction stops. The catalyst is filtered, additionally washed with a small amount of methanol and the filtrate is evaporated to dryness in a vacuum created by a water-jet pump. The residue is dissolved in 50 ml of distilled water and 1 g of palladium-carbon is hydrogenated as a catalyst under normal pressure and at room temperature until the reaction is stopped. The catalyst is filtered off, washed with an additional small amount of water and the filtrate is evaporated to dryness. The resulting 2-acetamido-3-O- (D-1-carbamoyl-3-carboxylpropyl) -carba .moylethyl-carbamoylmethyl 2 deoxy-D-glucose is dried with phosphorus chloride in a high vacuum, t, mp. 175-177 ° C (as a hydrate), yield 82%.

On the basis of the corresponding 11 starting materials, similarly, the following compounds are obtained:

2-Benz 4ido-3-desoxy-3 0-L-1- (D-1, 3-bis-O-methylcarbamoylpropyl) -carbamoyl ethyl-carbamoylmethyl-O-glopyranose, so pl. 125 136 ° С, + 24 (water, s 0.93), yield 67%;

2-benzamido-2-deoxy 3-0-l.l - (0-1-carbamoyl-3-carboxypropyl) -carbamoylpropylJ-carbamoylmethyl-0 glucopyranose, mp, 114-155®С, yield 74% J

2-benzamido-3 deoxy-3-0-L-1- {D-1-carbamoyl-3-carboxypropyl) -carbamoyl-2-methylpropyl -1-carbamoylmethyl-O-glucopyranose, -3 3 (zod, s 0 , 78), yield 80%;

2-benzamido-2-deoxy-3-0-1-L- (l-D-carbamoyl-3-carboxypropyl) -carbamoyl-2-hydroxyethyl-carbamoylmethyl - 0-glucopyranose, m.p. 100115 ° С, ° 4 23 ° (water, from 0.886) yield 65%;

2-Benzamido-2-deoxy-3-0- (D-1-carbamoyl-3-carboxypropyl) carbamoylmethyl-carbamoyl 4-methyl-0 glucose a, so pl. 115-155 ° C, o.20 34 ° (water,

Q with 0.81), yield 84%.

Example 3 3.9 g E-ethyl-2-benzamido-2-deoxy-4, b-benzylidane 0-glucopyranoside is dissolved in 30 ml of N, N-dimethylformamide and stirred at room temperature with 0.5 g of sodium hydride dispersion - mineral oil with the exception of moisture to obtain a homogeneous solution. The solution is then added dropwise while cooling with a solution of 4.76 g of N-iodo-cetyl-1-alanyl-0-isoglutamine-5-benzyl ether in 15-sh and N, N-dimethylformamide and stirred for 3 hours at room temperature / temperature. Next, filter, neutralize with acetic acid.

5 acid and evaporated in vacuo to a syrup. This syrup is poured into 400 ml of 60% acetic acid and kept for 1 hour at 80 ° C. After cooling, the solution is evaporated to dryness.

0 to the residue is added two more times 50 liters of water and in case of evaporation to dryness. The resulting crystalline residue is stirred with a small amount of water, the crystals are sucked off and dried. So, get-ethyl-2-benzamido 3-0- (D-1-carbamoyl-3-carboxyprspil) -carbamoyl ethyl -carbamoylmethyl j 2-deoxy-SL 0-glucopyranoside-benzyl ether,

which is hydrogenated in 80 t-l of methanol

0.4 g of palladium on carbon as a catalyst under normal pressure and at room temperature until the reaction stops. The catalyst is filtered off, additionally npoivMvat it with a small amount of M methanol and the filtrate is evaporated to dryness in a vacuum created by a water-jet pump.

Ethyl-2-benzag etdo-3 0 obtained

0 - (0 1 carbamoyl-3-carboxypropyl) -carbamoyl ethyl-carbamoylmethyl) -2-deoxy 0-glucofuranoeid is dried with phosphorus chloride in a high vacuum, so pl. 215-217 ° C, - 22

5 (methanol, with 0.97). yield 73%,

Similarly, starting from the corresponding starting materials, methn-2-acetamido-3-O- (L-1- (0-1-carbamoyl-3-carboxypropyl-0 carbamoylethyl-carbamoylmethyl-2-deoxy-A-0-glucopyranoside, from + 491-1 ° (water, from 0.939), output

Example 4. 4.5 g of benzyl 2 benzamido-2-deoxm-4, 6-benzylidene-o-glucopyranoside is dissolved in 30 ml of N, N-dimethylformamide and stirred at 0.5 g of the dispersion sodium hydride-mineral oil with the exclusion of moisture to obtain a homogeneous solution. A solution of 5.6 g of N-iodoacetyl-1-anilyl-O-glutamic acid of bis-N-methylamide in 20 ml of N, M-dimethylformamide is then added dropwise, while cooling at -5 ° C, and stirred for 2 hours at room temperature. . It is then evaporated in vacuo to obtain a syrup.

This syrup is poured into 400 ml of 60% acetic acid and kept for 1 hour at. After cooling, the solution is evaporated to dryness to the residue, twice more, 50 ml of water are added and in each case evaporated to dryness. The resulting oily residue is stirred with a small amount of water, the crystals are sucked off and dried. Benzyl-2-benzamido-3-O-L-1- (D-1,3-bis-M-methylcarbamoylpropyl) -carbamoyl ethyl -carbamoylmethyl -2-deoxy-CX-O-glucopyranoside benelyl ether is obtained, which is dissolved 80 ml of methanol and 0.4 g of 5% palladium-carbon as a catalyst is hydrogenated as a catalyst under normal pressure and at room temperature until the reaction stops. The catalyst is filtered off, washed with a small amount of methanol and the filtrate is evaporated to dryness in a vacuum created by a water-jet pump. The resulting 2-benzamido-3-O-L-1- (0-1, 3-bis-N-methylcarbamoylpropyl) -carbamoyl ethyl-carbamoylmethyl -2-deoxy-O-glucose is dried with phosphorus chloride in high vacuum so pl. 125-132 ° C, (+ 240 (water from 0.93), yield 82%.

Similarly, starting from the corresponding starting materials, the following compounds are obtained:

-ethyl-2-benzamido-2-deoxy-3-0-L-I- (D-1, 3-bis-H-methylcarbamoylpropyl) -carbamoyl-methyl-carbamoylmethyl-O-glucopyranoside, so pl. 233240 ° C - 20 (methanol, with 0.937 yield 78%;

2-benzamido-2-deoxy-3-0-L-1- (D-1,3-bismethoxycarbonylpropyl) -carbamoylethyl -carbamoylmethyl-O-glucopyranose as a hydrate, mp 80-90 C, | ° + 25 ( methanol, from 1.017), yield 77%;

ethyl 2-benzamido-2-deoxy-3-0-L-I- (0-1,3-bismethoxycarbonylpropyl) -carbamoyl ethyl -carbamoylmethyl-D-glucopyranoside, so pl. 127-135s l (f.iO 170 (methanol, s 1.024), yield 68%;

2-benzamido-2-deoxy-3-0- - (D-l-N-carbamoyl methylcarbamoyl-3-carboxypropyl) -carbamoyl tcl-canob amoylmethyl-O-glucopaca a, t.gtl. 1bЗ-170 ° С, lcx 21 (water, с 1.08), yield 72%;

2-benzamkdo-2-deoxy-3-0- 1-1- (carbamoyl-3-carboxypropyl) -carbamoylbutyl3 -carbamoylmethyl-O-glucopr. 40 3 a, Go If - 12 (methanol, with 1D2 );

2-acetamido-3-O-LL-l-CD-1,3-dicarbamoylpropyl) -carbamoyl ethyl -carbamoylmethyl} -2-deoxy-0-glucose + 7 t p (water, from 0.514), 60% yield;

dimethyl ester of 2-acetamido-3-O- (D-1, 3-dicarboxypropyl) -caramoylethyl -carbamoylmethyl} -2-Ehoxy-0-gl: okozy, + (water, with 0.814) -,

2-acetamide-2-deoxy-3-0-CH-1- (D-1,3-bismethylcarbamoylpropyl) -carbamoylethyl-carbamoylmethyl) -0-glucose, + 31 1, (water, s 0.41); .

benzyl-3-acetamido-3-0- (0-1,3-biscarbamoylpropyl) -carbamoyl et arb amoyl methyl or -2-deoxy-O-glucopyranoside, -44 11, (N, H-dimethylformamide, s 0.989), yield 69%;

benzyl-2-acetamido-3-O- H L-1- (D-1,3-biscarbokskpropil) -carbamoylethyl -carbamonylmethyl -2-deoxy-p | -0 glucopyranoside-dimethyl ether so pl. 195-197С, Л 31 tl (methanol, с 0,553), yield 78%;

2-acetamndo-3-O- 1-1- (D-1-carbamoylmethylcarbamoyl-3-carboxypropyl) -carbamoyl ethyl -carbamoylmethyl -2-deoxy-0-glucace, white powder, + 10 ± 1 ° (water, from 0.706) ;

2-ben3amide-2-deoxy-3-0-l-L- (1-D-3-dicarboxypropyl) -carbamoylethyl-carbamoylmethyl-O-glucopyranose (+ 25 (water, from 0.997), 76% yield;

2-benz G.1ido-2-, Tloxy-3-0-Ll-L- (1-O-M-p-propylcarbamoyl-3-carboxpropyl) -carbamoyl ethyl-carbamoylmethyl-O-glucopyranose, mp. 65-140 C d + 28 (water, with 1.03), yield 73%;

2-Benza 1-2-deoxy-3-0-L-1- (D-1, 3 dicarbamoylpropyl) -carbamoyl ethyl-carbamoylmethyl-O-glucopyranose, so pl. 82-143 С, W + 24 ° (water, from 0.98), 78%.

Claims (1)

Claim method, method of obtaining - glucosamine of general formula CHjORg Oh Jo vO-R, 8K-A - R 87 Rg so-k-sh-yoknn her L-E (B) where X is carbonyl; R is C -Cg-alkyl, phenyl; Ci-C4R is hydrogen, -alkyl or benzyl R, R and R are hydrogen-, R ,. - hydrogen, C-C-alkyl, hydroxymethyl or phenyl; RQ and Rg are non-esterified or esterified into ester with C, -C-alkyl carboxyl groups or unsubstituted or substituted by C-Cd-al kil, carboxam domethyl or benzyl carboxamido, and the residue R contains more than 1 carbon atom, if Rg and RQ are each carboxyl, or its salts, characterized in that the compound of the general formula CHj-O-Rj kn-x-to R have the aforementioned values. where X and cheni; R R is easily removable protecting groups; R is a residue of the formula R or an easily detachable protecting group, and the hydroxy groups can be protected by a easily cleavable protecting group, are reacted with a compound of the general formula 2-Ch; ok n-co nn - {"1a) 2-8 | where Z is the reactive esterification of the hydroxy ester into the ester, Rfl and R ° have the same meaning as Kf, Rg and Rg, provided that the carboxyl and hydroxyl groups present in these residues are protected by easily detachable protective groups and isolating the desired product in free form or as a salt. Sources of information taken into account in the examination 1. Thieme Taschen ehrbuch. der organischen Chemie B. Spezielle Gebiete, Stuttgart, 1975, p. 134.