JPS5835152A - Manufacture of enantiomeric 3-amino-2- hydroxypropionic acid and n-blocked derivative thereof - 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 relates to a novel process for converting glycoses into **A-type 8-amino-2-hydroxypropionic acid, in which the enantiomeric 8-amino-2-hydroxypropionic acid When @'l, N-blocked and converted to an active ester, it reacts with an appropriate aminoglycoside antibiotic to produce the known active semi-synthetic antimicrobial agent.

Specifically, the present invention relates to the conversion of D-glucose or D-mannose to S- or R-1-(#-blocked amine)-2-hydroxypropionic acid active esters, which is, for example, 14-unsubstituted poly-N
- can be reacted with a blocked aminoglycoside and the resulting compound is unblocked to produce a 1-N (S or R-8-amino-2-hydroxypropionic acid) aminoglycoside antibiotic. be able to.

In particular, the present invention provides a method for converting D-glucamine or D-mannamine into 5-B-amino-2-hydroxypropion al or R-73-amino-2-hydroxypropion, known as FjlJKS-inserin or R-inserin, respectively. Concerning how to convert it into acid.

There are many methods for producing S-inoserine or R-isoserine, for example, Ba
r, 47 (2027J 1914, Japanese Unexamined Patent Publication No. 49-18
No. 5,922 and JP-A-50-8'1. 'l
This is Publication No. 28. BaF, in the literature, a resolution that requires the use of purusin salts is part of this method. In JP-A-849-186,992, this product is obtained as a result of fermentation, and in JP-A-50-87,
In Publication No. 7284, the starting material L-asparagine is expensive and isolation of the final product is time consuming.

Process-wise, the present invention belongs to the concept of preparing enantiomeric 8-amino-2-hydroxypropionic acids, which method consists of glycamine K (,) II! in an aqueous lower alkanol solvent. Formula 1, 2-N, 0-tylpho=s, , (6) periodine cleavage, (c> permanganate oxidation, (d) acid hydrolysis followed by (-) treatment with base, from It consists of carrying out a continuous process consisting of:

It is also known as S-isoserine or R-isoserine, and is also called 5-HAPA or R-HAPA.
enantiomerism (i.e. S or R) 8-7mi/-
2-Hydroxypropionic acid has been found to be useful in the production of important aminoglycoside antibiotics, such as tjl-#-5-HAPA-gentamicin B or 1-NR-HAPA-gentamicin B1. The preparation of these compounds is described in US Pat. No. 4,186.264.

However, as shown in the references cited above, the previous method for preparing enantiomeric isoserifices is described in 1.
(a) Toxicity issues, such as purusin salts, (&) fermentation methods,
or (1) used with costly and redundant reactions.

According to our new method, S- or R-HAPA can be produced from stock glycose. S- or R-HAPA is a free amino acid, as an acid addition salt,
Or alternatively, it can be prepared as S- or RN-blocked HAPA, which is more commonly useful in the preparation of N-substituted aminoglycoside antibiotics.

The best known examples of the latter are those in which the S- or R-HAPA moiety is in the 1-amino position.

The glycoses used to obtain the starting materials for the process of the invention are those known in the art, for example 1d
D-glucose, D-mannose, D-lipose, D-
Arabinose etc. The glycoses are first converted into their respective glycamines. For example, the US wA%
, 621,175 and 2,880.988, D-glucose is catalytically reduced to D-glucamine and similarly % D-man/-
, 'klD-mannamine; D-ribose is converted to D
- can be changed to ribamine; D-arabinose can be changed to D-7-rabinamine; and so on. Preferentially, we utilize D-glucose and (JD-mannose) as starting materials due to their availability and cheapness.

It will be clear to those skilled in the art that the starting material glycose will determine the resulting mirror isomer. The following Scheme I describes our method of converting D-glucamine to 5-HAPAK% or higher 70N-blocked derivatives. It is originally included in the description given in this figure that D-mannamine can likewise be obtained as R-HAPA or the 70N-blocked derivative Kt.

Reaction formula 1 shows the reaction of D-glucamine in an aqueous lower alkanol solvent with 1(a) 1 ,2-N , 0--)ylyy
1 to produce nyl-D-glucamine (compound 2)
, 2-N, 0-carbonylation, (&)periodine 8m, (
J S-2e 8- N e O-:/F rykl
permanganate oxidation to produce niluiacerin (compound 8), acid hydrolysis to produce the (ti) acid addition salt of S-inserin (compound 4), and (-) neutralization of the acid addition salt. 2 is a description of a continuous process consisting of a base treatment to produce S-inserin (compound 6).

When used as the moiety to be attached to an aminoglycoside, S-isoserine is usually suitably KN-blocked. Therefore, Scheme I can be further modified to form an acid addition salt of 5-(N-blocked)-isoserine in the above case. - with enough base as a preparatory step for the conversion step to the methoxybenzyloxycarbonylamino derivative (compound 6) #! & explains that it can be returned.

When D-glucamine is replaced with D-mannamine, compound 2 is 1.2-s, o-carbonyl-D-mannamine, compound 8 is R-2,8-N, 0-carbonyl isoserine, Compound 4 is an acid addition salt of R-isoserine, and compound 5 t'! It is within the scope of the description of Scheme 1 that it would be R-isoserine. ↓Uni 1 compound 6 in case of S-inoserine, e.g. R
The following steps can be used to obtain -N-(p-methoxybenzyloxycarbonylisoserine).

Lower alkanols useful as solvents for this reaction include preferably, but not necessarily, those which will form a mixture with water, i.e., containing from 1 to about 8 carbon atoms. It is an alkanol with

Cyclic l,2-N,0-carbonylation is carried out using hydrocarbon oxycarbonyl chloride or phosgene. Swollen hydrogen oxycarbonyl chloride reactants contemplated by this invention include methoxycarbonyl chloride, alkoxycarbonyl chloride such as phenoxycarbonyl chloride, alkyl-phenoxycarbonyl chloride and substituted phenoxycarbonyl chloride such as p-nitrophenoxycarbonyl chloride. Carbonyl 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, including 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 technique recognized as LagLiasm oxidation.

Aqueous mineral acids contemplated by this invention include hydrochloric acid, sulfuric acid, hydrobromic acid and phosphoric acid. 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/secured) isoseli/ include ship bases, amides (e.g. phthalimide, succinimide groups) $1- and acyl group, 41IKj1-methoxybenzyloxycarbonyl, benzyloxycarbonyl, 2.2.2-)lichloroethoxycarbonyl,
Included are 1-butoxycarbonyl, -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.

50 - D of 9.06 f in aqueous methanol 14Q+wj
- Dissolve glucamine (50 mmol). While stirring, add 7.51 phenyl chloroformate dropwise at moderate speed. Immediately after this addition 1 Amberlite IRA
-4QIS OH-H by adding ion exchange resin to 8±0.6.

After holding the H for an additional hour, the resin is removed by filtration and washed 8 times (8×10 1 +j) with water.

The aqueous solution is extracted with ethyl acetate (100d) and the methanol is evaporated. Dilute the aqueous layer with water to 600-.

While stirring, add 82 t of sodium metaperiodate and adjust the Mt to 6.0 fIC by adding a saturated solution of potassium carbonate. After stirring for 16 minutes, the pH is adjusted to 7.7 using potassium carbonate. Add 15.8 f of potassium permanganate. , H to 7.7
K After keeping for 1 hour 1. Increase H. After stirring for 16 hours, the product was removed by filtration, and water (2001
11) and after checking with a starch paper (J) this solution is evaporated to obtain a residue, which is
8 times (8X 15
0d) Extract by grinding. These solvents are evaporated in vacuo to obtain a residue. This residue is dissolved in 4N hydrochloric acid (1001143K) and heated to reflux for 15 hours. Cooled to 45°C and concentrated to dryness in vacuo. The residue is dissolved in water (12681)K and treated with sodium chloride solution for 20 s. and adjust H to 9KN. Add dioxane (125d) and stir. p-methoxybenzyl 5- (4,6-
A solution of dimethyl-pyrimidin-2-yl)-thiol carbonate) (14,8f) is added dropwise. Potassium carbonate was added to bring the pH to 9. Hold OK. After 2 hours, the mixture is evaporated in vacuo to remove dioxane and the aqueous solution is extracted with ethyl acetate (10Qsd).

While stirring the aqueous layer, acidify with 4N hydrochloric acid to pH
Let be 2. This acidified solution was dissolved in ethyl acetate (8X
20 Gm) and the combined organic layers were extracted with 1jV hydrochloric acid (
10081). The ethyl acetate layer is dried over anhydrous magnesium sulphate, filtered and the solid residue is evaporated in vacuo. The residue was dissolved in boiling chloroform (5
0-→ recrystallized by K to give the named compound; melting point 1 g? −188°[aJ” +8.
t'(c, 0.5 in methanol) is obtained.

Replacement of D-glucamine with D-mannamine in a manner uniform as in Example IA gives the above-mentioned compound.

9.06 t of D-glucamine 150 mmol, 5
Dissolve in 0% aqueous methanol 140-. While shaking, add 7.5 il of 7-enyl chloroformate at a moderate pace.
Add l dropwise. Immediately after this addition 1 amber rye) I
By adding RA-401,50H-ion exchange resin, H is set to 8±0.6. For an hour this, H
After retaining this resin, remove the resin by filtration and dilute with water for 8 hours.
Wash twice (8×10011 times). The aqueous solution is extracted once with ethyl acetate (10 Qia/) and the methanol is evaporated. The aqueous layer is diluted with water to 60G-.

While stirring, add 82 f of sodium metaperiodate and add saturated solution of potassium carbonate to reduce H to 6. OK Adjust. After stirring for 16 minutes, adjust tB to 7.7 with potassium carbonate.

Add 15.8 f of potassium permanganate. , H to 1
After holding at 7.7 for a period of time, the pH is increased. After stirring for 15 hours, the solids were removed by filtration and water (20Q
aff) and evaporate the solution (after checking with iodized starch paper) to obtain a residue. This residue was treated with a solvent mixture consisting of chloroform, methanol and ammonium hydroxide <8:4:2 8 times (8
m) extract by grinding; Evaporate these solvents in vacuo to obtain a residue. This residue was dissolved in 4N hydrochloric acid (
1004) and heated under reflux for 15 hours. 4
Cool to 5°C and concentrate to dryness in vacuo. The residue is diluted with water (1
25114) Dissolve K and adjust pH to 9 with 20-sodium hydroxide solution. Dioxane (1251173
2 in Dioxa 7101J and stirred.
．． 2.2-) Lichloroethoxycarbonyl chloride (6
, 881Ll) is added dropwise. Stir and use potassium carbonate to reduce H to 9. Keep OH. After 2 hours, the mixture is evaporated in vacuo to remove dioxane and the aqueous solution is extracted with ethyl acetate (109d). While stirring, acidify the aqueous layer using 4N tri-acid to give Si2. This acidified solution was dissolved in ethyl acetate (8X
Extract at 2G01m/J. The ethyl acetate layer is dried over anhydrous magnesium sulphate, filtered and the solid residue is evaporated in vacuo. This residue was recrystallized by decomposition in boiling chloroform (60d) to give the designated compound; melting point 100-107°C, [α] +4
．． 9° (C, 0.6 in methanol) is obtained.

D, R-8-(2,2,2-)lichloroethoxycarbonylamino 1-2-hydroxyglobisue 1 In a method similar to Example IC, D-glucamine was added to D-glucamine.
- By substitution with mannamine, the abovementioned compounds are obtained.

onic acid A, 5-8-mino-hi-10 cyprobin 60% I
) Aqueous Meal 140suK9.05 ft) D-
Dissolve glucamine (50 mmol).

While stirring, remove the phenyl chloroformate.
．． 5- is added dropwise. Immediately after this addition, Amberlite IRA-4QIS OH-ion exchange resin is added to bring the H to 8±0.5. After holding this pH for an additional hour, the resin was removed by filtration and washed with water 8 times (8X1
00m) Wash. This aqueous solution was mixed with ethyl acetate (100 d
) and evaporate off the methanol. Dilute the aqueous layer with water to 600-.

While stirring, add 82f of sodium metaperiodate and add a saturated solution of potassium carbonate.
6. OK Adjust. Stir for 16 minutes and then adjust the pH to 7.7 with potassium carbonate. Add 16.8 t of potassium permanganate.

Hold H at 7.7 for 1 hour and then increase k jlH. After stirring for 15 hours, the solids are removed by filtration, washed with water (200114) and the solution is evaporated (after checking with iodized starch paper) to give a residue.

The residue is extracted by trituration 8 times (8×150 ml) with a solvent mixture consisting of chloroform, methanol and ammonium hydroxide (8:4:2). Evaporate these solvents in vacuo to obtain a residue. This residue was dissolved in 4N salt 12 (10011) K and heated under reflux for 16 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 pH 4, and txC-
In addition to the column consisting of so(H+)500-, this column is fractionated with 8 liters of water.

The homogeneous fractions are evaporated to yield the pure product 5-8-amino-2-hydroxypropionic acid as residue.

B, R-8-amino-2-hydroxypropion! In the same method as Example A, D-glucamine was
- replacing C with mannamine gives the abovementioned compounds.

% allowancettllF1 person Formed into Schering Corporation Personnel Patent attorney Yasushi Yuasa Lord -;1,000- (2 others)

Claims (1)

[Claims] υ Glycamine in an aqueous lower alkanol solvent contains 61
Formula 11 1.2-N,0·-carbonylation, h) Kayo!
/elementary cleavage C) permanganate oxidation d) @hydrolysis followed by -) enantiomeric a8- by carrying out successive steps consisting of treatment with a base.
A method for producing amino-2-hydroxypropionic acid. 2) For glycamine in an aqueous lower alkanol solvent, 1λ
81 Formula 1. 2-N,0-carbonylation produces the enantiomeric l,2-N,0-carponylglycamine, a) periodine cleavage, and C) permanganate oxidation to form the enantiomeric l,2-N,0-carponylglycamine. Opposite sex 2. d) generating an acid addition salt of the enantiomeric isoserine by acid hydrolysis, followed by a) treatment with a base to neutralize the acid addition salt to form the mirror image; 2. A method according to claim 1, comprising carrying out a continuous step consisting of: producing isomeric isoserine. 8) Kl according to claim 1 or 2, wherein the glycamine is D-glucamine or D-mannamine.
e-soft method. 4) to D-glucamine in an aqueous lower alkanol solvent by a) l,2-N,0-carbonylation to 1.2
-N,0-carbonyl-D-glucamine, &n periodine cleavage and C) permanganate oxidation Kj
d) producing an acid addition salt of S-inoserine by IP hydrolysis, followed by neutralization of the acid addition salt by -J base treatment; 9. A method according to claim 8, comprising carrying out the successive steps of producing S-inserin. 5) D-mannamine in an aqueous lower alkanol solvent, 6) 1.2-N,0-carbonylation, l,
'l-N,0-carbonyl-D-mannamine is produced; &) periodic cleavage and C) permanganate oxidation produces R-2,B-v,0-carbonylinserine; d) forming an acid addition salt of R-isoserine by acid hydrolysis, followed by neutralizing the acid addition salt by -1 base treatment to form R-isoserine. The method described in Scope Item 8. 6) In the above sequential steps, aJ II formula l,2-N,O-carbonylation is carried out using hydrocarbon oxycarbonyl chloride or phosgene, and h) periodine cleavage is carried out using an alkali metal salt of metaperiodate. 6) W1 formation is carried out using potassium permanganate, d) acid hydrolysis is carried out using an aqueous mineral acid solution, and treatment with a base is carried out using an alkali metal hydroxide or 6. The method according to any one of claims 1 to 5, which is carried out using a carbonate. 73 N-protected enantiomeric 8-amino-2-hydroxypropionic acid comprising a subsequent step consisting of reaction of an amino protecting group reagent with enantiomeric 8-amino-2-hydroxypropionic acid The method described in any one of Items 1 to 6 of the scope. 8) The amino group is cymethoxybenzyloxycarbonyl, benzyloxycarbonyl, 2.2.2-
, )'J dichlorotoxycarbonyl, t-butoxycarbonyl, l-amyloxycarbonyl and a7-ethyl group. 9) In glycamine in an aqueous lower alkanol medium, S
) cyclic 1.2-s, o-carbonylation to produce the corresponding enantiomeric 1.2-, s, o-carbonyl glycamine, b) periodine cleavage, and C) permanganate oxidation.
d) Generate the enantiomeric 1.2-N,0-carbonyl isoserine by II hydrolysis; d) Generate the enantiomeric acid addition salt of isoserine by II hydrolysis; and f) reacting an enantiomeric isoserine with an amino protecting group reagent to produce an N-protected enantiomeric inserine; or c) I171. Consisting of a continuous process of
A method according to claim 7 or 8. 10) i) cyclic 1,2-N, 0-
The carbonylation is carried out using an alkoxycarbonyl chloride or a -substituted or unsubstituted phenoxycarbonyl chloride: U) The cleavage of said step (&) is carried out using sodium, potassium, calcium or ammonium metaperiodate. 111) the acid hydrolysis of said step (d) is carried out using an aqueous solution of a mineral acid, preferably hydrochloric acid, hydrobromic acid, Il sulfuric acid or phosphoric acid: and iv) said step (-) The treatment with a base is carried out using an alkali metal hydroxide or carbonate, preferably sodium carbonate, potassium hydroxide, carbonate castum, calcium hydroxide or calcium carbonate; 9. The method according to any one of Claims@Eng.