JPS6011448A - Manufacture of hydrazinocarboxylic acid derivative by n-amination of aminocarboxylic acid derivative - 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 Field of application of the invention HyP-radinocarzenic acid and its derivatives are of interest, for example as intermediates for the synthesis of peptyl analogues and as biologically active compounds α](W, Knobl
och et al., J-prakt, Chem, 36 (1
967)29). For example, L-2-hiraj/-2-(
3.

4-Dihydroxybenzyl)zolopionic acid+i is an effective L-DOPA-decaldecyclase inhibitor that does not cross the blood-brain barrier.

Characteristics of the known technology The method for producing optically active hyr-radinocardic acid from technically available amino acids has the following advantages: 1. If optically active raw materials are used, the expensive racemate separation step can be omitted;
In terms of synthetic strategy, it is superior to total synthesis (eg, Schdrecker synthesis using hydrazine, substitution of halogencarzenic acid with hydrazino). However, these advantages in the processes hitherto described or considered are largely diminished due to the expensive operations or insufficient selectivity of the chemical reactions.

As a typical example, L-2-hirradino2-(3,4
-Dihypo:dibenzyl)zolopionic acid (1) is synthesized.

This has been very well researched ('2) (
S.

Karady et al., J, org, Chem, 36
(197], ) 1946 >, ■((Same as 21,
1949), (:4:N December 16, 1970, DD-PS 88091 and related patents).

Raw material that can be N-minated, L-α-methyl-
DOPA (2+) is an antihypertensive drug used worldwide and manufactured in tons by several companies. The process is described in detail in the above-mentioned literature.

(a) 0 with hydroxylamine-〇-sulfo/acid
, substitution of 0-dimethyl precursor (3).

(4) A mixture of raw material and hydrazino derivative is obtained, which can be separated only by very difficult methods (chromatography). According to the authors' own expression, they are abandoning ``methods that cannot be used for mass production'' [3].

(bl L-α-methyl-DOPA with chloroamine
= Substitution of the anion (5) of the precursor.

(5) 80R R=Me, Ph This process has the following drawbacks.

The production of the one-done anion (5) is expensive (acyl protecting group, use of NaH in DMSO).

- Handling of chloroamines.

- Long reaction times (up to 12 hours).

- low yield of amination product (6); in this case,
The research conducted by the present inventors confirmed the view stated in the literature ■ that amination is not completely successful and that a chromatographic separation step must be carried out in order to obtain a product that does not contain raw materials. There is.

(C) Replacement of hydantoic acid (7) with hypochlorite solution and hydrazine.

This method also presents major drawbacks.

0, respectively, according to the description in (4)). The reason for the stiffness is that the introduction of the N-carbamoyl group is not quantitatively successful.

- Separation of the final product is troublesome. This is because the colored decomposition product (4) (3,4-dimethoxyphenylacetone and condensation product) must be removed by extraction.

Other processes disclosed in Reference a] and related patents without yield statements involve expensive procedures (multiple steps, long reaction times, expensive reagents, moisture prohibition) and often dangerous procedures ( The use of gold, sodium, chloroamines, phosgene, N-nitroso compounds as intermediate steps makes them unsuitable for rational technical use.

The ability of certain oxacylidines to react with strongly basic secondary aliphatic amines to form N-N bonds was recently confirmed [5
]. (E, Schmjtz et al. J, prakt
, Chem.

319 (1977) 195). For example, morpholine is 89
% was converted to N-aminomorpholine. However, other studies, for example with aromatic amines, have shown that the range of applications of this reaction is generally unpredictable (6). (E,
Schmitz et al., Liebigs Ann, C.
bem, 725 (1969) 1). In the case of substitution with aniline, only 22% of the theoretical phenylhydrazine was precipitated by benzaldehyde.

Therefore, in α-amino acid derivatives, such as esters, which have one electron-withdrawing deactivating group adjacent to the amino group, the unprotected (and undeprotonated) amine group can be directly aminated with oxaciridine. was not expected to be suitable.

Regarding the charging of amino acid esters with free amine groups, there are no examples to date of using other N-amination reactions suitable for the production of algylhydrazines (Claim (4)). reference). However, regarding the possibility of replacing amino acids and their esters with hyproxylamine-○-sulfonic acid, this method requires charging a large excess of the starting amino acid, so optically active α-hyrradinic acid The view that it is ``totally uneconomical'' to obtain 0) is advocated in the literature.

OBJECTS OF THE INVENTION The object of the present invention is to produce hyP-radinocarzenic acid in a rational operating manner by a novel process for the N-amination of readily available N-unprotected amino acid derivatives, in which case the necessary The aim is to preserve the asymmetric centers that exist accordingly.

3. DETAILED DESCRIPTION OF THE INVENTION The basic object of the present invention is to avoid the deficiencies of known processes by a corresponding selection of reaction conditions and by preventing interfering by-products. The object of the present invention is to develop a technically simple and reliable method for producing hiradinocarzenic acid.

This objective is achieved by the following method. That is, a method for producing a hydrazinocarzenic acid derivative of the following general formula I, comprising: 2 R-C-(CRR)-R"I!NH-NH2, where ] □ to C8), branched or unbranched, optionally substituted); , those substituted with an a/ruo group, an argyl group, an alkoxyalkylidene group, a ky/ group, an algylidene dioxy group and a methylthiomethyl group, and 2-
ethoxy-2-methyl-benzo-1,3-dioxolane-5-alkylidene), n is 0 (α-hyP radinocarzenic acid derivative), or 1
1 to 6, 6 R is COOR, CN, or CONH2, R6 is H, alkali metal or alkaline earth metal, argyl (
C□ to C18, branched or unbranched, optionally substituted), aryl or aralkyl (optionally substituted).

According to the present invention, an aminocarzenic acid derivative of the following general formula II is reacted with oxaziridine of the following general formula (1) in a solvent or a soluble compound at a temperature of -20°C to +200°C.

8 R-C-(CR9R10) -R" 11N1 (2 Here, R to R10 and n11 have the above-mentioned meanings for R1 to R and R, but the treatment mode for each functional group is the same as these. It doesn't have to be.

Here, R and R are H, alkyl (C1 to C18, branched or unbranched, optionally substituted, or forming a common ring). The substitution reaction time is up to 12 hours. However, preferably 1 to 4 hours.

Solvents and 1 to 1 are preferably water-immiscible solvents, such as toluene, chlorobenzene, diethyl ether,
Methylene chloride is preferred. Compound T in its solvent
I is already present in dissolved form in the production process according to the known process [5], and the reaction product I is then converted into a salt with an aqueous inorganic acid, preferably with a hydrohalic acid.
It is easily extracted.

Due to the delicate reaction conditions, no interfering by-products are produced. A portion of compound ■ that is not incorporated into reaction product I,
In particular, the moiety having the general formula RRCO (R and R as in formula (2)) remains in the organic phase and can be treated by distillation like a solvent and used again for the production of formula (2).

Various modifications are possible in the treatment of the precipitate. In this case, the conditions of application are e.g. heating of the inorganic acid extract in the temperature range from 1 to 160 °C, optionally under a pressure in the range of side pressure and optionally under protective gas, the formula II The conversion of the functional substituents R to R of formula I to the functional substituents R to R of formula I can occur, for example, by hydrolysis occurring with side reactions and 1-. In the process according to the invention, a very wide range of molecular transformations can be carried out by means of very small technological steps.

For example, from the readily available esterified α-methyl-DOPA-precursor (8), with fewer and simpler technical operations, and already mentioned above, the hydrazinocarzenic acid (1) can be prepared in high yield and with high efficiency. For the first time, it is possible to manufacture with quality.

The total yield of (8)→(1) reaches % or more. In the process of the invention, the disadvantages encountered in the above-mentioned processes do not occur, and far fewer auxiliary substances and by-products are produced.

In a particularly preferred embodiment of the invention, L-α-methyl-DOPA in the form of lower argylester or alkali salt or alkaline earth gold salt is converted to hydrazinocarzenic acid (1). In that case, the replacement by nr is
in a two-phase solvent (e.g. toluene and water) in the presence of a boric acid derivative (e.g. sodium tetraborate or orthoborate alkyl ester) suitable for temporary complex formation with orthohydric acid or phenolic hydroxyl groups; In some cases, it is desirable to add a phase transfer catalyst (for example, a quaternary ammonium salt).

At present, the detailed mechanism and scope of application of the N-amination reaction have not yet been completely elucidated. therefore,
It is believed that still other specialized amino compounds or catalytic effects will be discovered that can be used in the process of the invention.

The following examples are for a more detailed explanation of the invention. The compounds presented were comparable with respect to their properties and spectra to products obtained by other methods, unless detailed data are given.

EXAMPLES Example I L-N-aminovaline 5.2.9 (40 mmol) of L-nonoline methyl ester in a toluene solution containing 50-55 mmol of 3.3-pentamethyleneoxacyridine In step (5), it is produced and heated. The end product of the reaction is obtained when the oxidation effect of the metallurgical product (titration with thiosulfate of the iodide isolated from potassium iodide/acetic acid) has fallen to an approximately constant afterimage. In this reaction, 11
At 0°C, about 1 to 4 hours is sufficient, depending on the concentration of the reaction mixture.

The cooled mixture is extracted with 6N HCI and the combined extracts are evaporated to dryness under reduced pressure at 90-95° C. after 2 hours. Take up the residue in 95% alcohol.

The final product is isolated in crystalline form by adjusting the pH value by adding diethylamine. Yield 2.9g (55
%), melting point 246°C (decomposition) Example 2 L-N-amitunomarine methyl ester (hydrochloride) Analogously to Example 1, the aqueous extract of the reaction mixture obtained with 2N HCI is immediately evaporated under reduced pressure. Then ha, 5. S
L-parin methyl ester (40 mmol)
．． 5 # (62%) of the desired product in syrup form (acidic or alkaline saponification yields L-N-aminovaline).

Example 3 D, L-N-aminophenylglycine Same as Example 1, 6.61I (40 mmol) glue, L-phenylglycine methyl ester + '12.411 (36%)
to produce a desired product or product.

Melting point 191-192°C (decomposed) %J4 D,L-N-amino-3-phenylalanine 7.2F (40 mmol) glue, L
-3-phenylalanine methyl ester is 3.7. F.C.
51%) of the desired product.

Melting point 1935194°C (decomposed) Example 5 L-2-hydrazino-3-(3,4-dimethoxykphenyl)propio/acid Similarly to Example 1, 9.611 (40 mmol) of L-
3-(3,4-dimethoxy/phenyl)alanine methyl ester yields 6.5.9 (67%) of the desired product.

Example 6 L-2-hydrazino-3-(3,4-dihyprogyphenyl)furopionic acid The anti-Um compound extract obtained using 45% HBr at 100 mA was heated for 2 hours at 100-C. After heating the extract obtained with , or 6NHC1 under pressure for 2 hours, 3.1 (41%) of the desired product is obtained.

Example 7 L-2-hyf'us7/-3-(3,4-dimethoxyphenyl)propionic acid methyl ester (hydrochloride) Same as Example 2, 9.6.9 (40 mlJ mol) Noshi-3-(3,4-dimethoxyphenyl)alanine methyl ester yields 7.9.9 (68%) crystalline desired product (acidic or alkaline saponification produces L-2-hirradino-3-( Heating with 45% HBr yields L-2-hydrazino-3-(3,4-dimethoxyphenyl)propionic acid.

Example 8 L-2-hi)'lada/-2-(3,4-dimethoxybenzyl)propionic acid 10.3, F (40 mmol) in the same manner as in Example 1.
L-2-(3,4-dimethoxybenzyl)alanine methyl ester of s, 4. p (77%) of the desired product as a monohydrate.

Melting point 179-181℃ (decomposed) [α) 20 10° (C=1, H2O) 46- (If heated with 45% HBr, L of 80% of the theoretical value
-2-ti)'lada/-2-(3,4-jihil't=l
-7penzyl)propionic acid) Example 9 L-2-hyPradino-2-(3,4-dihydroquinbenzyl)propionic acid Extraction of the reaction mixture obtained analogously to Example 8 with 45% HBr After heating for 2 hours or the extract obtained with 6N HCl under pressure for 2 hours,
．． 1 (62%) of the desired product is obtained as a monohydrate.

Melting point 196-198°C [α] 20--18° [C=
1, Meoa) 46- After recrystallization from methanol and water under protective gas,
The melting point reaches 203-206°C (decomposition).

Example LOL-2-Pradino 2-(3,4-dimethoxybenzyl)propionic acid methyl ester (hydrochloride) In the same manner as in Example 2, 10.3, ? (40 mmol) of L-2-(3,4-dimethoxybenzyl)alanine methyl ester yields 10.4 g (85%) of the desired product.

Melting point 206-207°C (P+ solution soaked or reprecipitated with alcohol/ether) Cα〕6 = '7° (C = 1', MeOH)
.

D, L-Melting point of compound 1895190°C (decomposition) (acidic or alkaline saponification is 85% of the theoretical value of L-2-
HyPradino-2-(3,4-dimethoxybenzyl)propionic acid is produced. When heated together with 45% HBr, L-2-HBr 2-(3,4-
dihydroxybenzyl)progionic acid).

Example 1 IL-2-Pradino 2-(3,4-dimethoxybenzyl)propionic acid methyl ester (hydrochloride) Approximately 80% of the solvent is distilled from a mixture of 54 mmol of benzyl)alanine methylnistert with 3,3-pentamethyleneoxaziridine.The residual solvent and the cyclohexanone formed as a by-product are distilled into 30 m of 2N HCl From the 6 residue which is blown off with water vapor after the addition of The desired product is obtained in a yield of 9.9FC81%.

%J12 L-z-hyler, y-no 2-<3.4-dimethoxybenzyl)propionic acid Similarly to Example 11, residual solvent was added at 12 mMCI of 251, then blown off with water vapor, and further incubated for L5 hours. , heat at 95°C. The desired product is separated from the ethanol as described in Example 1. -Yield as hydrate
L2,9 (75%).

Melting point 179-180°C (decomposition) Example 13 L-2-hydrazino-2-(3,4-dihydroxybenzyl)solopionic acid 12.4 Ji' (40 mmol) of L-2-amino-2
Methyl-(3,4-diacetoxybenzyl)propionate
c, 79 (1957) 4360, H, J-Ha
Similar to the method of Rwood et al., Kl, Te production) was carried out in the same manner as in the previous example in 13. ．． This yields 5.9 (36%) of the desired product as a monohydrate.

Melting point 198\200°C (decomposed) Example 14 L-2-hyPradino-2-(3,4-diisozolopylidenedioxy/benzyl)propionic acid 10.6,! i' (40 mmol) of I,-2-amino-2-(3,4-diisozolopylidenedioxy/benzyl)propionic acid methyl ester was prepared by alkaline saponification of the aqueous solution and careful neutralization as in Example 2. Later, 5.1
(58%) of the desired product as a white crystalline material.

Melting point 197-198°C (decomposition) 1H-NMJI (DMSO (-d6/HMDS)) M
e 1.05 (S.

(s, 6H), aromatic protons 6-5 to 6.8 (m,
3H), D20 exchangeable protoy5.5-5.6 (bs
, 4H), MS (70 eV) = M = 266, main beak, 163/164 and 103 (7 fragments of benzyl splitting), 85 (7 fragments of 4-methyl-1,2-diazetidinone).

Example 15 10.6 g (40 mmol) of L-2-amino-2-2-(3,4-dihydroxybenzyl)propionic acid
(3,4-diisozolopylidenedioxy/benzyl)propionic acid methyl ester was prepared in the same manner as in Example 1, and 6.7
9 (69%) of the desired product is produced as a monohydrate.

Melting point 198-200°C (min wl) Example 16 L-2-hyI-'7di/-2-(3,4-dihydroxybenzyl)propionic acid 10 g (44 mmol) L-2-amino-2-( 3°4-dihydroxybenzyl)propionate methyl ester is added to a suspension of 18 g of sodium tetraborate hydrate (borax) in 55 mi distilled water under gentle heat until the amino acid ester is dissolved. Stir until

This mixture was vigorously stirred with millimoles of 2,2-pentamethyleneoxaziridine in toluene under an inert atmosphere at 70°C for 1 hour, then at 85°C for 2 hours, and then cooled. Phase separation is carried out later. Izu aspect 10
Extract with 6N HCl 0 and heat the combined extracts at 95° C. for 2 hours under protective gas.

By treating the residue obtained by evaporation under reduced pressure with 95% ethanol and adjusting the pH value to 6-6.5, the desired product is separated from this solution together with diethylamine in the form of a crystalline hydrate. .

Yield 1jt-; 5-2jj (48%), or 78.2% calculated on the substituted raw materials Melting point 192 to 194"C (decomposition) from water containing small amounts of sodium bistatite Recrystallization of the crude product yields a purer fraction with a melting point of 203-205°C (min M).

Example 17 L-2-hyPradino-2-(3,4-dihydroxybenzyl)zolopionic acid 11, Fl (40 mmol) in L-2-amino-2-methyl-3-(2-ethogyne-2-methyl-benzo -1,
3-Dioxirane-5) Propionic acid methyl ester Me ([er, Dtsch, Chem, Ges, 99 (1
966), 2625 H.

Q ros s and 1. By Rnehe's method,
Compound prepared from L-2-,7+ thyl-DOPA-methyl ester and triethyl orthoacetic acid) was prepared in Example 1
4.1 (42%) of the desired product is obtained as a monohydrate. Melting point 198-200℃ Example 18L-2
-HiPradino-2-(3,4-dihydroxybenzyl)
1 fl (42 mmol) of propionic acid I,-2-amino-2-(3
,4-dihydroxybenzyl)propion acid competition 1.5H
20 was added to a suspension of 1 l of sodium tetraborate 1L in 5ON distilled water and stirred and nitrogen was introduced for about 40 minutes until a clear solution was obtained.
Heat to ℃.

10μ of 4N hydroxide) IJium solution and 2.9% of triethylpendylammonium chloride (TEBA)
After adding , the mixture was heated under an inert atmosphere to 84
with a toluene solution of mmol of 2,2-pentamethyleneoxysweet silysine at 70°C for 1 hour and at 85°C for 3 hours.
Stir vigorously for an hour.

After cooling, phase separation is carried out and the organic phase is extracted with 30 portions of 6N hydrochloric acid. The hydrochloric acid extract is added to the alkaline aqueous phase of the reaction mixture and the whole is evaporated to dryness under reduced pressure.

The residue was soaked in 80 mL of absolute ethanol under cooling, and after addition of 0.5 mL of distilled water, the desired product was extracted from the alcohol solution with diethylamine at pH
By adjusting the value to 6.5, the crystal-hydrate form is separated.

Yield 6.1!1 (59%), melting point 192-194℃
(Decomposition) Example 19 L-2-Pradino-2-(3,4-dihyroxypenzyl)propionic acid L(['(0,44 mmol) of L-2-amino-2-
(3,4-dihy)'o*dibenzyl)-propionic acid methyl ester was added to a solution of 2,9 g of orthoboric acid in 90°C distilled water and heated under mild heat until the amino e derivative was dissolved. Stir.

Then 55 mmol of 2.2-'! A toluene solution of tyrene oxaziridine was added and the mixture was allowed to stand for 4 hours.
Stir vigorously at 80-85°C.

After cooling, phase separation was carried out and 100 m6 of 6NHCI
The organic phase was extracted with water.

Combine the hydrochloric acid extract with protective gas for 2 hours.
Heat at 95° C. and evaporate to dryness under reduced pressure. By treating the residue thus obtained with 95% ethanol and adjusting the pH value to 6.4, the desired product is separated from this solution together with diethylamine in the form of a crystalline hydrate.

Yield: 6.7g (62%) Melting point: 192-194℃ (decomposition) Applicant's agent Kiyoshi Inomata Continuation of page 1 @Inventor Frank Michael Alberto German Democratic Republic 9590 Zubikau ・Johannes Sue Rubetshier Strasse 16 0 shots clearer Dieter Lohmann German Democratic Republic 9590 Zubikau ・Blue Menbake 32 A'

Claims (1)

[Scope of Claims] 1. In producing the hydrazinocarzenic acid derivative of the following general formula I, an amino acid derivative of the following general formula (1) is mixed with an oxacylidine of the following general formula (2) in one type of solvent or in a solvent mixture. React at a temperature of 1°C to +200°C,
From the resulting reaction mixture, the desired product (2) is obtained as a dissolved salt with an aqueous inorganic acid, and then as required by removing water and residual inorganic acid and/or by adjusting to a specific pH range. 1. A method for producing a hyP-radinocarzenic acid derivative, characterized in that it is separated as a largely crystalline substance in other solvents accordingly. R1-♂-(CR3R')-R51-N)I2 (wherein R1 to R4 are ■, alkyl (C□ to C8, substituted by a branched or unbranched one),
aryl or aralkyl (optionally substituted), and n is. (α-hyP radinocarzenic acid derivative), 1 to 6, and R5+'! , COOR6, CN
,ball&'! C0N) (2te, bri, RbaH, alkali or alkaline earth metal, argyl (substituted by a branched or unbranched 4-bond of co to C□8), aryl or alkali 8 R7-C-(CR9R10)-R"' I1n H2 (wherein, R7 to R10 or R11 are R1 to R11)
4 or R5, but need not necessarily be the same. ) (wherein R and R are Hl or alkyl (C□ to C□8, branched or unbranched, optionally substituted or common ring).) 2, R7 is 3,4-dimethoxybenzyl and R8 to R10 and R11 have the above definitions for R2 to R4 and R5 to prepare compound I, the reaction is carried out with orthoboric acid in a biphasic solvent. Alternatively, the method according to claim 1, which is carried out in the presence of a boric acid compound by adding an appropriate phase transfer catalyst as necessary. 3. Compound I is obtained as a dissolved salt by an extraction step;
3. The method as claimed in claim 1, wherein the extractant is a hydrohalic acid. 4. The aqueous inorganic acid extract was heated at a pressure up to an applied voltage, optionally under protective gas, at 160 mL before separation of compound I.
4. A method according to any one of claims 1 to 3, wherein the method is carried out at a temperature of up to .degree. 5-oxacylidine, 3,3-pentamethyleneoxacylidine III (R and R13 are -(CH2)5
- Claim 1 or 2 characterized in that
The method described in section. 6. Amino acid derivative II 0.8-2.
6. Process according to claim 1, 2 or 5, characterized in that 0 mol of 3,3-pentamethyleneoxasilidine is used. 7. The method according to claim 1, 2, 5 or 6, characterized in that toluene or a mixture of water and toluene is used as the solvent for heating TI and (1). 8. II and ■ are heated by partial distillation of the solvent or by refluxing for up to 12 hours, claims 1 and 2.
The method according to any one of Items 5 to 7. 9, α-aminocarzenate II (n=o. The method according to any one of claims 1 to 3 and 5 to 8, wherein L-2-amino-2-(3,4-disubstituted benzyl) is converted. Propionate methyl ester II (R”=3゜4
-dimethoxybenzyl or 3,4-dihydroxy7pendyl, R8=Me, n=o, R''=COOMe),
L-2-hyPradino-2-(3,4-disubstituted benzyl)
claims 1 to 3 and The method according to any one of Items 5 to 9. 11, α-aminocardanic acid ester II (n==Q. 9. A method according to any one of claims 1 to 8, wherein the method is characterized in that 12, L-2-amino-2-(3,4-dimethoxybenzyl)propionic acid methyl ester ■(R””3
+ 4- Simeto*'/Heyi, R8=Me, n=Q,
R-COOMe), L-2-hyPradino-2-(3,
4-dimethoxybenzyl)zolopionic acid or L-2-
Hirradino 2-(3゜4-dihydroxy7penzyl)propionic acid ICR' = 3,4-dimethoxybenzyl, 3
,4-dihydroginobenzyl, R2=l=Me%n=Q
, R”:C00H).
The method according to any one of Items 8 to 8 and 11. 13, L-2-7mi/-2-(3,4-dihi IFc+$
dibenzyl)propionate methyl ester 1f (R7”
3 , 4- ') hi)' 口,,+ kuhe7911
i, R8=Me, n=Q, R-COOMe) is L-
Converted to 2-(3,4-dihydroxypentyl)-prodionic acid 1 (R=3,4-di-hydroxybenzyl, R=Me, n=o, R-COOH) The method according to any one of claims 1 to 8 and 11, wherein: 14, T, -2-amino-2-(3,4-dihydroxybenzyl)-propionill'! ): or its sodium salt (R-3,4-dihydroxybenzyl, R8
=Me, n=OlR-C00II or COO
Na) is converted to T,-2-hyPradino-2-(3,4-dihydroxybenzyl)propionic acid I (R-3゜4-dihydroxybenzyl, R-Me, n=o. R5=: C0OH) Claim 1
The method according to any one of Items 8 to 11. 15, L-2-amino-2-(3,4-diacetoxy- or:4-isopropylidene dioxypenzyl)propionic acid methyl ester]r (R7=3.4
-diacetoxybenzyl, 3,4-impropylidenedioquipenzyl, R-Me, n=o, R-COOM
e) is L-2-hydrazino-2-(3,4-dihydroxybenzyl)zolopionic acid 1 (R”=3,4-dihydroxybenzyl, R2=Me, n=Q, R5=C0
12. A method according to any one of claims 1 to 8 and 11, wherein the method is converted to OH).