JPH0243729B2 - KAGAMIZOISEI33AMINOO22HIDOROKISHIPUROPIONSANTOSONONNBUROTSUKUSARETAJUDOTAINOSEIZOHOHO - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel process for converting glycoses into enantiomeric 3-amino-2-hydroxypropionic acid, which
Amino-2-hydroxypropionic acid, when N-blocked and converted to an active ester, reacts with the appropriate aminoglycoside antibiotic to produce the known active semi-synthetic antimicrobial agent.

Specifically, the present invention provides D-glucose or D-glucose
- Conversion of mannose to S- or R-3-(N-blocked amino)-2-hydroxypropionic acid active ester, which
For example, it can be reacted with a 1-N-unsubstituted poly-N-blocked aminoglycoside,
The resulting compound can then be unblocked to produce a 1-N (S or R-3-amino-2-hydroxypropionyl) aminoglycoside antibiotic.

In particular, the present invention combines D-glucamine or D-mannamine with S-inserin or R-inserin, respectively.
S-3-amino- known as isoserine
The present invention relates to a method for converting into 2-hydroxypropionic acid or R-3-amino-2-hydroxypropionic acid.

There are many methods for producing S-isoserine or R-isoserine, but to name just a few examples, Ber.47 (2027) 1914, JP-A-49-135,
No. 922 and Japanese Unexamined Patent Publication No. 50-37, 723. In the Ber. literature, a resolution requiring the use of brucine salt is part of the method. Japanese Patent Application Publication 1973
In JP-A-135,992, this product is obtained as a result of fermentation, and in JP-A-50-37,723, the starting material L-asparagine is expensive and the final product is It takes time to isolate.

In terms of method, the present invention provides enantiomeric 3-amino-2
-Hydroxypropionic acid, the process involves (a) cyclic 1,2-N,O-carbonylation, (b) periodic cleavage, (c) periodine cleavage on glycamine in an aqueous lower alkanol solvent. It consists of carrying out a sequential process consisting of manganate oxidation, (d) acid hydrolysis, followed by (e) treatment with a base.

It is otherwise known as S-isoserine or R-isoserine, and is also known as S-HAPA or R-isoserine.
Enantiomeric (i.e. S or R) 3-amino-2-hydroxypropionic acid, also called HAPA, is an important aminoglycoside antibiotic, such as 1-N-S-HAPA-gentamicin B or 1-N-R-HAPA- It was found to be useful in the production of gentamicin B. The preparation of these compounds is described in US Pat. No. 4,136,254.

However, as shown in the references cited above, previous methods of making enantiomeric isoserines have limited the raw materials to (a) toxicity problems, such as brucine salts,
(b) fermentation methods; or (c) expensive and tedious reactions;
It was used in conjunction with one of the following.

According to our novel method, S- or R-
HAPA can be produced from a variety of glucoses. S- or R-HAPA can be used as a free amino acid, as an acid addition salt, or in place of N
-S- or R-N-blocked substances commonly useful in the preparation of substituted aminoglycoside antibiotics
Can be manufactured as HAPA. The best known examples of the latter are those in which the S- or R-HAPA moiety is in the 1-amino position.

The glucoses used to obtain the starting materials for the process of the invention are those known in the art, such as D-glucose, D-mannose, D
-ribose, D-albinose, etc. The glycoses are first converted into their respective glycamines. For example, D-glucose is catalytically reduced to D-glucamine through the steps described in U.S. Pat. Nos. 2,621,175 and 2,830,983; similarly, D-mannose is D-ribose can be changed to D-rivamine; D-arabinose can be changed to D-arabinamine; and so on. Preferentially, we prefer, due to its usefulness and cheapness,
D-glucose and D-mannose are utilized as starting materials.

It will be clear to those skilled in the art that the starting material glycose will determine the resulting enantiomeric form. The following reaction formula converts D-glucamine to S-HAPA, or
Moreover, its N-blocked derivatives
It explains our method of change. Similarly, D-mannamine can be used as R-HAPA or its N-
It is originally included in the description given in this figure that it can be converted into a blocked derivative.

The reaction formula is D in an aqueous lower alkanol solvent.
- glucamine with (a) 1,2-N,O-carbonyl to produce 1,2-N,O-carbonyl-D-glucamine (compound 2), (b) periodine cleavage, (c) S -permanganate oxidation to produce 2,3-N,O-carbonyl isoserine (compound 3); (d) acid hydrolysis to produce acid addition salt of S-isoserine (compound 4); and (e) a base treatment to neutralize the acid addition salt and produce S-isoserine (Compound 5).

When used as the moiety to be attached to an aminoglycoside, S-isoserine is usually suitably N-blocked. Therefore, the reaction equation further states that, alternatively, the acid addition salt is the following S-(N-
Blocked)-isoserine, in the above case, can be treated with sufficient base as a preparatory step to the conversion step to the p-methoxybenzyloxycarbonylamino derivative (compound 6).

When D-glucamine is replaced with D-mannamine, compound 2 becomes 1,2-N,O-carbonyl-
D-mannamine, and compound 3 is R-2,3-
N,O-carbonyl isoserine, compound 4
is an acid addition salt of R-isoserine, and it is within the scope of the description of the reaction scheme that compound 5 would be R-isoserine. As in the case of S-isoserine, compound 6, e.g. R-N-
The following steps can be used to obtain (p-methoxybenzyloxycarbonyl)isoserine.

Lower alkanols useful as solvents for this reaction include preferably, but not necessarily, those that will form a 50:50 mixture with water, i.e., having from 1 to about 3 carbon atoms. It is alkanol.

Cyclic 1,2-N,O-carbonylation is carried out using hydrocarbon oxycarbonyl chloride or phosgene. Hydrocarbon oxycarbonyl chloride reactants contemplated by this invention include substituted alkoxycarbonyl chlorides such as methoxycarbonyl chloride, phenoxycarbonyl chloride, alkyl-phenoxycarbonyl chloride, and p-nitrophenoxycarbonyl chloride. phenoxycarbonyl chloride. It will be clear to those skilled in the art that the reaction conditions will vary slightly depending on which of the aforementioned reactants is used.

Periodic acid cleavage is carried out using alkali metal salts of metaperiodic acid, such as the sodium, potassium, calcium and ammonium salts of metaperiodic acid. Under the conditions of using metaperiodate alkali metal salts, we use potassium permanganate as the oxidizing agent. This combination is a technology recognized as Lemieux oxidation.

Mineral acid aqueous solutions contemplated by the present invention include hydrochloric acid, sulfuric acid,
There are hydrobromic and phosphoric acids. Bases used in base treatments include hydroxides or carbonates of alkali metals such as sodium, potassium and calcium.

Amino protecting groups contemplated in the subsequent conversion step to S- or R-N- (blocked/protected) isoserine include Schiff bases, amides (e.g. phthallimide, succinimide groups) and acyl groups, especially p-methoxybenzyloxycarbonyl, benzyloxycarbonyl, 2,2,2
-trichloroethoxycarbonyl, t -butoxycarbonyl, t -amyloxycarbonyl and acetyl groups. The foregoing protecting groups and the corresponding protecting group reagents from which they are formed are well known in the art.

The invention described above is illustrated in detail in the following examples, which should not be construed as limiting the scope of the invention.

Example S or R-3-(N-blocked)amino-2-hydroxypropionic acid A S-3-p-methoxybenzyloxycarbonylamino-2-hydroxypropionic acid 9.05 g D in 140 ml 50% aqueous methanol - Dissolve glucamine (50 mmol). While stirring, add 7.5 ml of phenyl chloroformate dropwise, moderately quickly. Immediately after this addition, the pH is brought to 8±0.5 by adding Amberlite IRA-401S OH ^- ion exchange resin. Another hour
After maintaining the pH, the resin is removed by filtration and washed three times with water (3 x 100 ml). The aqueous solution is extracted once with ethyl acetate (100 ml) and the methanol is evaporated. Dilute the aqueous layer to 500 ml with water.

While stirring, add 32 g of sodium metaperiodate and adjust the pH to 6.0 by adding a saturated solution of potassium carbonate. After stirring for 15 minutes, adjust the pH to 7.7 using potassium carbonate. Add 15.8g of potassium permanganate. PH
After keeping the pH at 7.7 for 1 hour, increase the pH. After stirring for 15 hours, the solids are removed by filtration, washed with water (200 ml), and the solution (after checking on starch iodide paper) is evaporated to give a residue.
The residue is extracted by trituration three times (3 x 150 ml) with a solvent mixture consisting of chloroform, methanol and ammonium hydroxide (3:4:2). These solvents are evaporated in vacuo to obtain a residue. This residue is dissolved in 4N hydrochloric acid (100ml) and heated to reflux for 15 hours. Cool to 45°C and concentrate and dry in vacuo. This residue is dissolved in water (125 ml) and the pH is adjusted to 9 using 20% sodium hydroxide solution. Dioxane (125
ml) and stir. Dioxane (70
A solution of p-methoxybenzyl S-(4,6-dimethyl-pyrimidin-2-yl)-thiol carbonate (14.8 g) in ml) is added dropwise. Add potassium carbonate to maintain pH at 9.0. 2 hours later,
The mixture is evaporated in vacuo to remove dioxane and the aqueous solution is extracted with ethyl acetate (100ml).
While stirring the aqueous layer, adjust the pH to 2 with 4N hydrochloric acid. This coordinated solution was extracted with ethyl acetate (3 x 200 ml), and the combined organic layers were extracted with 1N
Wash with hydrochloric acid (100ml). The ethyl acetate layer is dried over anhydrous magnesium sulphate, filtered and the solid residue is evaporated in vacuo. The residue was recrystallized by dissolving in boiling chloroform (50 ml) to give the named compound; mp 137-
138° [α] ²⁶ _D +3.1° (C, 0.5 in methanol) is obtained.

B R-3-p-Methoxybenzyloxycarbonylamino-2-hydroxypropionic acid In a similar manner to Example A, substituting D-mannamine for D-glucamine gives the above-mentioned compound.

C S-3-(2,2,2-trichloroethoxycarbonylamino)-2-hydroxypropionic acid 9.05 g of D-glucamine (50 mmol) was added to 50
% aqueous methanol 140 ml. While stirring moderately quickly, add phenyl chloroformate 7.5
Add ml dropwise. Immediately after this addition, the pH is brought to 8±0.5 by adding Amberlite IRA-401S OH ^- ion exchange resin. Another hour
After maintaining the pH, the resin is removed by filtration and washed three times with water (3 x 100 ml). This aqueous solution is extracted once with ethyl acetate (100 ml) and the methanol is evaporated. Dilute the aqueous layer with water to 500ml
shall be.

While stirring, add sodium metaperiodate.
Add 32 g and adjust the pH to 6.0 by adding a saturated solution of potassium carbonate. After stirring for 15 minutes,
Adjust the pH to 7.7 with potassium carbonate. Add 15.8g of potassium permanganate. After maintaining the pH at 7.7 for 1 hour, increase the pH. After stirring for 15 hours, the solids were removed by filtration, washed with water (200 ml), and (after checking with iodized starch paper)
Evaporate the solution to obtain a residue. The residue was quenched with a solvent mixture of chloroform, methanol and ammonium hydroxide (3:4:2).
Extract by trituration twice (3 x 150 ml).
Evaporate these solvents in vacuo to obtain a residue.
This residue is dissolved in 4N hydrochloric acid (100ml) and heated under reflux for 15 hours. Cool to 45°C and concentrate to dryness in vacuo. This residue is dissolved in water (125 ml) and the pH is adjusted to 9 with 20% sodium hydroxide solution. Dioxane (125 ml) is added and stirred, followed by the dropwise addition of a solution of 2,2,2-trichloroethoxycarbonyl chloride (6.83 g) in 10 ml dioxane. Stir and maintain pH at 9.0 using potassium carbonate. After 2 hours, the mixture is evaporated in vacuo to remove dioxane and the aqueous solution is extracted with ethyl acetate (100ml). While stirring, the aqueous layer was conjugated using 4N hydrochloric acid,
Set the pH to 2. The conjugated solution is extracted with ethyl acetate (3 x 200 ml). The ethyl acetate layer is dried over anhydrous magnesium sulfate, filtered and the solid residue is evaporated in vacuo. This residue was recrystallized by dissolving in boiling chloroform (50 ml) to give the designated compound;
107° [α] ²⁶ _D +4.9° (C, 0.6 in methanol) is obtained.

D R-3-(2,2,2-trichloroethoxycarbonylamino)-2-hydroxypropionic acid The above compound was prepared in a similar manner to Example C by replacing D-glucamine with D-mannamine. obtain.

Example S or R-3-amino-2-hydroxypropionic acid A S-3-amino-2-hydroxypropionic acid 9.05 g of D-glucamine (50 mmol) are dissolved in 140 ml of 50% aqueous methanol. While stirring moderately quickly, add phenyl chloroformate 7.5
Add ml dropwise. Immediately after this addition, Amberlite IRA−401S OH ^-ion exchange resin was added to adjust the pH.
is 8±0.5. After maintaining this pH for an additional hour, the resin was removed by filtration and washed with water three times (3 times).
×100ml) Wash. The aqueous solution is extracted once with ethyl acetate (100 ml) and the methanol is removed by evaporation. Dilute the aqueous layer to 500 ml with water.

While stirring, add sodium metaperiodate.
Add 32 g and adjust the pH to 6.0 by adding a saturated solution of potassium carbonate. Stir for 15 minutes, then adjust the pH to 7.7 with potassium carbonate.
Add 15.8g of potassium permanganate. 1 hour PH
Keep the pH at 7.7, then stir for 15 hours to bring the pH to 9.0.
Raise to ~9.3. Remove solids by filtration;
After washing with water (200 ml) and checking with starch iodide paper for the presence of excess periodate ions in the reaction product, the solution is evaporated to give a residue. It is well known in the art to perform such checks, usually with iodized starch paper, to prevent workup of the reaction mixture in the presence of the oxidant. This residue was treated three times (3×
150ml) Extract by stirring. Evaporate these solvents in vacuo to obtain a residue. This residue is dissolved in 4N hydrochloric acid (100ml) and heated under reflux for 15 hours. Cool to 45°C and concentrate to dryness in vacuo. The residue was dissolved in a minimum amount of water, neutralized with dilute sodium hydroxide to a pH of 4, and applied to a column consisting of 500 gms of Amberline IRC-50 (H ⁺ ), which was fractionated with 3 liters of water. do.
The homogeneous fractions are evaporated to yield the pure product S-3-amino-2-hydroxypropionic acid as residue.

B R-3-amino-2-hydroxypropionic acid In a similar manner to Example A, by replacing D-glucamine with D-mannamine, the above-mentioned compound is obtained.

Claims (1)

[Scope of Claims] 1. Glucamine or mannamine in an aqueous lower alkanol solvent, a. enantiomers 2,3 by periodine cleavage, and c permanganate oxidation to produce
-N,O-carbonyl isoserine, d. Acid hydrolysis to form an acid addition salt of the enantiomeric isoserine, followed by e. Treatment with a base to neutralize the acid addition salt to form the enantiomeric isoserine. and, if necessary or desired, by subsequent reaction with the product of step e above of an amino protecting group reagent f. A process for the preparation of enantiomeric 3-amino-2-hydroxypropionic acid and its N-blocked derivatives, comprising carrying out a series of steps comprising: - producing hydroxypropionic acid. 2 The amino protecting group is p-methoxybenzyloxycarbonyl, benzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, t
2. The method according to claim 1, wherein the group is selected from -butoxycarbonyl, t -amyloxycarbonyl and acetyl groups. 3 glucamine or mannamine in an aqueous lower alkanol medium, a. forming the corresponding enantiomeric 1,2-N,O-carbonylglycamine by cyclic 1,2-N,O-carbonylation, b. periodine. enantiomer 1 by cleavage, and c permanganate oxidation,
producing 2-N,O-carbonyl isoserine; d producing an acid addition salt of enantiomeric isoserine by acid hydrolysis; e neutralizing the acid addition salt by treatment with a base to produce enantiomeric isoserine. and forming an N-protected enantiomeric isoserine by reaction of an amino protecting group reagent with an enantiomeric isoserine. The method described in. 4. The method according to any one of claims 1 to 3, wherein the glucamine is D-glucamine. 5. The method according to any one of claims 1 to 3, wherein the mannamine is D-mannamine. 6 D-glucamine in an aqueous lower alkanol solvent is converted to 1,2 by a 1,2-N,O-carbonylation.
S-2,3- by periodine cleavage and c permanganate oxidation to produce 2-N,O-carbonyl-D-glucamine.
producing N,O-carbonyl isoserine, d producing an acid addition salt of S-isoserine by acid hydrolysis, and then e neutralizing the acid addition salt by base treatment to produce S-isoserine. the N-protected enantiomeric 3-amino-2-hydroxy by reacting, if necessary or desired, with the product of step e above of an amino protecting group reagent. 5. A method according to claim 4, comprising carrying out a continuous step consisting of: producing propionic acid. 7 D-mannamine in an aqueous lower alkanol solvent by a 1,2-N,O-carbonylation,
R-2,3- by periodine cleavage and c permanganate oxidation, producing 1,2-N,O-carbonyl-D-mannamine.
producing N,O-carbonyl isoserine, d producing an acid addition salt of R-isoserine by acid hydrolysis, and then e neutralizing the acid addition salt by base treatment to produce R-isoserine. and, if necessary or desired,
followed by a series of steps consisting of forming an N-protected enantiomeric 3-amino-2-hydroxypropionic acid by reacting an amino protecting group reagent with the product of step e. A method according to claim 5, comprising: 8 In the above sequence of steps, a cyclic 1,2-N,O-carbonylation is carried out using hydrocarbon oxycarbonyl chloride or phosgene, and b periodine cleavage is carried out using an alkali metal salt of metaperiodate. , c the oxidation is carried out using potassium permanganate, d the acid hydrolysis is carried out using an aqueous mineral acid solution,
and e treatment with a base is carried out with an alkali metal hydroxide or carbonate, and if necessary or desired,
followed by a series of steps consisting of forming an N-protected enantiomeric 3-amino-2-hydroxypropionic acid by reacting an amino protecting group reagent with the product of step e. A method according to any one of claims 1 to 7, comprising: 9. The cyclic 1,2-N,O-carbonylation of step a is carried out by using an alkoxycarbonyl chloride or a substituted or unsubstituted phenoxycarbonyl chloride; the cleavage of step b is the acid hydrolysis of step b is carried out with an aqueous solution of a mineral acid, preferably hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. ; and the treatment with a base in step e is carried out with an alkali metal hydroxide or carbonate, preferably sodium carbonate, potassium hydroxide, potassium carbonate, calcium hydroxide or calcium carbonate; Claims The method according to any one of items 1 to 8.