WO2005028449A1

WO2005028449A1 - Improved process for the manufacture of 1,2-disubstituted hexahydropyridazine-3-carboxylic acids and esters thereof

Info

Publication number: WO2005028449A1
Application number: PCT/EP2004/005284
Authority: WO
Inventors: Frank Nerenz; Günter Bartels; Andreas Kanschik-Conradsen
Original assignee: Honeywell Specialty Chemicals Seelze Gmbh
Priority date: 2003-06-26
Filing date: 2004-05-17
Publication date: 2005-03-31

Abstract

The invention relates to an improved process for the manufacture of 1,2-disubstituted hexahydro-pyridazine-3-carboxylic acids and esters thereof by reacting N,N’-disubstituted hydrazine with 2,5-dihalogenated valeric acids and thereof by means of phase transfer catalysis. Said pyridazine carboxylic acids and esters thereof can be used as intermediates for the production of pharmaceutical products

Description

Improved Process for the Manufacture of 1,2-Disubstituted Hexahydropyridazine-3- Carboxylic Acids and Esters thereof

The invention relates to an improved process for the manufacture of 1,2-disubstituted hexahydro-pydridazine-3-carboxylic acids and esters thereof by reaction of N,N'- disubstituted hydrazine with 2,5-dihalogenated valeric acids and esters thereof by means of phase transfer catalysis. These pyridazine carboxylic acids and esters thereof may be used as intermediates for the manufacture of pharmaceutical products.

Derivatives of 1,2-disubstituted hexahydro-pyridazine-3-carboxylic acids are important intermediates for the manufacture of pharmaceutical active substances. For example, 1- benzyloxycarbonyl-hexahydro-pyridazine-3-carboxylic acid can be produced from esters of l,2-dibenzyloxycarbonyl-hexahydro-pyridazine-3-carboxylic acid by saponification and hydrolysis. Said acid is a starting material for the manufacture of active agents which can inhibit special enzymes. Examples for such active agents are cilazapril (Synthetic Communications, 1988, 18, p. 2225 to 2231) or pranalcasan (WO 99/55724).

It is already known to synthesize derivatives of 1,2-disubstituted hexahydro-pyridazine-3- carboxylic acids by reacting N,N'-disubstituted hydrazine with 2,5-dihalogenated esters of valeric acid, wherein hydrogen halide is eliminated. For example, N,N'- dibenzyloxycarbonyl-hydrazine can be reacted in an alkylation reaction with an ester of 2,3-dibromovaleric acid to an ester of l,2-dibenzyloxycarbonyl-hexahydro-pyridazine-3- carboxylic acid (WO 99/55724 and WO 01/56997).

According to WO 99/55724 the alkylation reaction is carried out in diethylene glycol dimethyl ether as the solvent. In order to isolate the product the formed mixture has to be diluted with water. The ester is gained by extraction from the diluted mixture. The risk potential of diethylene glycol dimethyl ether for water is high, because said compound is toxic and soluble in water. Therefore, for the working up of the waste water, which is produced in the afore-described synthesis and which contains the diethylene glycol dimethyl ether, costly methods and safety measures have to be applied. Furthermore, in said reaction the degree of conversion is relatively low. For the isolation of the product from the formed mixture relatively awkward and involved methods are necessary, for example, chromatographic methods. Then the product can be obtained in a yield of not more than 74 % by weight. Said limitations are disadvantageous for a technical process.

For the process described in WO 01/56997, expensive DMSO is used as a solvent andNaH as a reagent, which is costly and difficult to handle in the industry. Additionally, this requires the initial separation of protecting groups and their subsequent repeated adding.

Therefore, it is the object of the present invention to provide an improved process for the manufacture of 1,2-disubstituted hexahydro-pyridazine-3-carboxylic acids and esters thereof, which provides higher yields than the process of the prior art, and which can be carried out without the release of toxic and water-risky solvents and reagents.

This object could be achieved by reacting N,N'-disubstituted hydrazine compounds with valeric acids or esters thereof, wherein the C-2 and C-3 atoms of said valeric acids or esters thereof are substituted with leaving groups, and wherein the reaction is carried out in the presence of a phase transfer catalyst and in a mixture of an organic solvent and water.

Therefore, the object of the invention is a process for the manufacture of 1,2-disubstituted hexahydro-pyridazine-3-carboxylic acids and esters thereof of the general formula (I)

comprising the reaction of compounds of the general formula (II)

with compounds of the general formula (III)

characterized in that the reaction is carried out in the presence of a phase transfer catalyst in a mixture comprising an organic solvent and water, wherein:

Z represents identical or different amino protecting groups,

R represents independently from each other hydrogen, a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl, aryl or aralkyl radical of from 1 to 30 carbon atoms, X represents identical or different leaving groups, and R¹ represents a carboxylic or ester group.

The new process provides a higher yield than the process of the prior art. Since water- insoluble solvents can be applied the costly working up of the waste water can be avoided. This is extraordinarily advantageous for the industrial application.

The hydrazine derivatives of the general formula (II) are known compounds or can be produced according to known processes. As protecting group Z all protecting groups can be used, which are suitable for a ino groups. Preferably, acyl and sulfonyl protecting groups are used. Said groups can be introduced into hydrazine by reacting hydrazine with acyl or sulfonyl chloride.

In particular, the protecting group Z is a fluorenylmethoxycarbonyl, benzyloxycarbonyl or t-butyloxycarbonyl group.

For the manufacture of the compounds of the general formula (II) which possess as protecting groups the above-defined protecting groups, hydrazine can be reacted with the relevant chlorocarbonic esters. For example, the reaction of hydrazine with chloroformic benzyl ester is described in Chem. Ber., 92, 1959, p. 1478 ff.

In said 2,5-dihalogenated valeric acids and esters thereof of the general formula (III) as leaving groups X those ones can be used, which can be substituted with nitrogen compounds in a good manner.

Preferably, in said 2,5-dihalogenated valeric acids the leaving groups X mean independently from each other a halogen, pseudohalogen or sulfonyl group. In particular, X and Y mean independently from each other a chlorine, bromine, iodine, tosyl or mesyl group.

In particular, preferred compounds of the general formula (III) are those ones, in which the groups X have the meaning of chlorine or bromine. Therein, such compounds can be used which are substituted with different halogen groups, for example only with bromine or with bromine and chlorine. Said compounds are known or can be produced according to known processes. For example, methyl 2,5-dibromovalerate can be produced directly from δ-valerolactone (Tetrahedron 54, 19, p. 4991 - 5004 (1998)) or by Hell-Volhard-Zelinskii reaction and subsequent esterification of 5 -bromo valeric acid. Alternatively, methyl 2- bromo-5-chloro-valerate can be produced by bromination and subsequent esterification of 5-chloro-valeric acid chloride. Preferably, as esterification component alcohols with an alkyl radical of from 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, or a benzyl alcohol are applied.

For phase transfer catalysts those ones can be used from the group comprising quaternary ammonium salts, phosphonium, arsonium, antimonium, bismutonium and tertiary sulfonium salts as well as crown ethers and cryptands. Said compounds are also known or can be produced according to known methods, as for instance described in E.V. Dehmlow, S.S.Dehmlow, "Phase Transfer Catalysis", 3^rd Edition, Weinheim 1993, p. 65 to 71.

Preferably, as phase transfer catalysts quaternary ammonium and phosphonium salts are applied.

Examples for such quaternary ammonium salts are trioctylmethylammonium chloride (Aliquat® 336 of company Cognis; Adogen® 464 of company Aldrich Chemical Co.), benzyltriethylammonium chloride or bromide, benzyltrimethylammonium chloride, bromide or hydroxide (Triton B), tetra-n-butylammonium chloride (Aliquat® 100 of company Cognis), bromide, iodide, hydrogen sulfate or hydroxide, methyl-tri-n-butyl- ammonium chloride (Aliquat® 175 of company Cognis) and cetyltrimethylarnmonium bromide or chloride. The chlorides and bromides of benzyltributylarnmonium, tetra-n- pentylammonium, tetra-n-hexylammonium and trioctylpropylammonium or methyltricaprylarnmonium chloride (Aliquat® 128 of company Cognis) can be applied, too.

Quaternary phosphonium salts are for example tributylhexadecylphosphonium bromide, ethyltriphenylphosphonium bromide, tetraphenylphosphonium chloride, benzyltriphenyl- phosphonium iodide, and tetrabutylphosphonium chloride.

Said phase transfer catalysts can be applied to the reaction as solids as well as aqueous solutions. Preferably, said catalysts are applied as aqueous solutions. It is possible, to use one catalyst as well as mixtures of several catalysts.

In particular, quaternary ammonium salts are applied. Most preferred is Aliquat® 175. As organic solvents preferably alcohols can be applied, for instance methanol, ethanol, propanols, butanols, pentanols, diols or polyols; ethers, for instance diethyl ether, tetrahydrofuran, dioxane, 1,2-diethoxyethane, 2-methoxyethanol; esters, as for instance methylacetate or butyrolactone; amides, as for instance N,N-dimethylformamide, N,N- dimethyl acetamide, methyl-2-pyrrolidone; ketones, as for instance acetone; nitriles, as for instance acetonitrile; sulfoxides as for instance dimethyl sulfoxide; aliphatic, cyclic, cycloaliphatic and aromatic hydrocarbons, as well as chlorinated aliphatic, cyclic, cycloaliphatic and aromatic hydrocarbons, as for instance hexane or heptane, benzene or toluene, dichloromethane, 1,2-dichloroethane and chloroform, chlorobenzene and 1,2- dichlorobenzene. It is possible, to apply mixtures of two or more of the afore-mentioned solvents.

It is known, too, to use in the application of phase transfer catalysts solvents which are immiscible with water, because otherwise the catalytic effect can be inhibited (E.V. Dehmlow, S.S. Dehmlow, "Phase Transfer Catalysis", 3^rd Edition, Weinheim, 1993, p. 72).

Therefore, it is preferred to use in the reaction of 1,2-dibenzyloxycarbonyl-hydrazine with methyl 2,5-dibromovalerate as organic solvents those ones which are immiscible with water. In particular aliphatic, cyclic, cycloaliphatic and aromatic hydrocarbons, as well as chlorinated aliphatic, cyclic, cycloaliphatic and aromatic hydrocarbons, preferably aromatic hydrocarbons can be applied for said reaction. It is preferred to apply aromatic solvents.

In particular it is preferred to apply as water-insoluble solvent toluene.

Surprisingly, a defined amount of water has to be admixed to the organic solvent in order to achieve an optimum in the reactivity of the catalyst. It is preferred to apply for the improved process said organic solvent and water in a weight ratio of from 99.9 : 0.1 to 95 ; 5. Preferably, the weight ratio is of from 99 : 1 to 96 : 4. Without addition of water and with an amount of water of approximately more than 5 % by weight the reaction results in a reduced degree of conversion with low yield, which is less than 40 %. It was not foreseeable and is therefore extraordinarily surprising that the amount of water has such an influence on the yield of the product.

It is preferred to carry out the reaction in the presence of a base, which can neutralize the hydrogen halide which is formed during the reaction. It is preferred to neutralize the hydrogen halide with an inorganic base. For example, it is possible to use sodium hydroxide and potassium hydroxide as well as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and calcium carbonate. It is also possible to use organic bases such as l,8-diazabicyclo[5.4.0]-undec-7-en.

The reaction is not limited to particular requirements concerning the temperature. However, it has proved that the reaction can be carried out in a temperature range of preferably from 20 to 200 °C in order to achieve a favorable yield and reaction velocity.

The process can be carried out in an extraordinarily simple manner. The reactants, solvent and water, phase transfer catalyst, as well as optionally the base are mixed and reacted in the desired temperature range. After completed reaction the mixture is worked up.

For the working up the organic phase can be washed with water, provided said phase is not miscible with water. Subsequently, the aqueous phase is separated off. The product of the general formula (I) can be isolated from the organic phase by distilling off the organic solvent. Mostly, the solvent can be reused without further purification steps for the process of the invention. The sewage disposal plant can be supplied with the waste water without special working up. The purity of the isolated product can be increased by the common purification steps, for instance by means of fractional crystallization, distillation or chromatography.

However, as the product mostly is obtained in a very good yield of more than 85 % and good purity, it is also possible to process said product without said steps of isolation and purification. For instance, it is possible to apply said product still dissolved in the organic phase for the manufacture of the above-mentioned hexahydro-pyridazine-3-carboxylic acid which is substituted in position 1. For instance, by hydrolysis of the organic phase with aqueous base said hexahydro-pyridazine-3-carboxylic acid which is substituted in position 1 with a protecting group can be extracted from the organic phase. For the further working up of said acid the aqueous phase is separated off and advisable mixed with n-butanol and acid, the butanol phase is separated off, cooled down and the precipitated product is isolated, for instance by filtration. Said n-butanol can be reused, as well as the solvent can be distilled and can be reused for the process of the invention.

Said process can be carried out considerably easier than the process for the manufacture of l-benzyloxycarbonyl-hexahydro-3 -pyridazine carboxylic acid as described in WO 99/55724, what is extraordinarily advantageous for the technical application. In said process of the prior art the corresponding compound of the general formula (I) is isolated in pure form, saponified with alcoholic sodium hydroxide, acidified, the liquid phase is partially distilled off and the liquid phase being left is extracted several times with dichloromethane. From the concentrated dichloromethane solution the product is precipitated with isopropyl ether.

However, in case of the mixed haloester methyl 2-bromo-5-chlorovalerate surprisingly those solvents have to be applied which are partially or completely miscible with water. For instance, acetonitrile is such a solvent. Such solvents can be risky for the waste water, wherein one of the above-described advantages of the improved process is lost. However, the combination of said solvents with the phase transfer catalysis still results in higher yields than the process of the prior art with diethylene glycol dimethyl ether as solvent. With it, at least the advantage of the higher yield is retained.

In using water soluble solvents, after completed reaction of the compound of the general formula (II) with the compound of the general formula (III) preferably the reaction mixture is filtered. Subsequently, the solvent is distilled off. With it, the product is obtained in crude form and can be purified as described afore-mentioned. Afterwards, said crude product can be transferred into said substituted hexahydro-pyridazine-3-carboxylic acid, which is substituted in position 1, by treatment with aqueous base and subsequent acidification. However, said reaction sequence can be carried out with the crude material, too.

However, it is preferred to dissolve the crude material for the processing without further purification into a solvent, which is immiscible with water, as for instance toluene. Afterwards, it is processed with aqueous base, acid and n-butanol according to the sequence as described above.

In particular, the reaction of the invention is suitable to react as compound of the general formula (IT) N,N'-dibenzyloxycarbonyl-hydrazine with an ester of 2-bromo-5-chloro- valeric acid or 2,5-dibromo-valeric acid as compounds of the general formula (III), wherein as products esters of l,2-dibenzyloxycarbonyl-hexahydro-pyridazine-3 -carboxylic acid of the general formula (I) are obtained. Preferably, as phase transfer catalysts quaternary ammonium salts and as solvents aromatic hydrocarbons or nitriles are applied.

From esters of l,2-dibenzyloxycarbonyl-hexahydro-pyridazine-3-carboxylic acids 1- benzyloxycarbonyl-hexahydro-3-pyridazine-carboxylic acid can be obtained by saponification. In general, the latter compound is obtained as a racemic mixture.

Analogous, starting with N,N'-di-t-butyloxycarbonyl-hydrazine and esters of 2-bromo-5- chloro-valeric acid or esters of 2,5-dibromo-valeric acid, esters of 1,2-di-t- butyloxycarbonyl-hexahydro-pyridazine-3-carboxylic acid can be produced. Starting with N,N'-difluorenylmethoxycarbonyl-hydrazine and esters of 2-bromo-5-chloro-valeric acid or esters of 2,5-dibromo-valeric acid, esters of 1,2-difluorenylmethoxycarbonyl- hexahydropyridazine-3-carboxylic acid can be produced. From said compounds 1-t- butyloxycarbonyl-hexahydro-pyridazine-3 -carboxylic acid or 1-fluorenylmethoxy- carbonyl-hexahydro-pyridazine-3 -carboxylic acid can be obtained by hydrolysis, whereby the reaction conditions need to be such that the protecting group remains stable.

However, it is preferred to obtain 1-benzyloxycarbonyl-, 1-t-butyloxycarbonyl- or 1- fluorenylmethoxycarbonyl-hexahydro-pyridazine-3-carboxylic acid from 1,2- dibenzyloxycarbonyl-, 1,2-di-t-butyloxycarbonyl- or 1,2-difluorenylmethoxycarbonyl- hexahydro-pyridazine-3-carboxylic esters according to the above-described reaction and working up with aqueous base, acid and n-butanol. Because of the higher sensitivity for acids and bases of said protecting groups the reaction conditions have to be selected in such a way to assure the stability of the protecting group in position 1.

Consequently, another object of the invention is the use of esters of 1,2- dibenzyloxycarbonyl-, 1,2-di-t-butyloxycarbonyl- or 1,2-difluorenylmethoxycarbonyl- hexahydropyridazine-3-carboxylic acid for the manufacture of 1-benzyloxycarbonyl-, 1-t- butyloxycarbonyl- or 1 -fluorenylmethoxycarbonyl-hexahydro-pyridazine-3 -carboxylic acid, characterized in that the process for the manufacture comprises the stages (i) to (v):

(i) saponification, (ii) addition of acid and alcohol to the saponified product obtained in stage (i), (iii) separating off the alcoholic phase, (iv) cooling down of the alcoholic phase, (v) separating off the precipitated product.

Another object of the invention is also a process for the manufacture of 1- benzyloxycarbonyl-, 1-t-butyloxycarbonyl- or 1-fluorenylmethoxycarbonyl-hexahydro- pyridazine-3-carboxylic acid from esters of 1,2-dibenzyloxycarbonyl-, 1,2-di-t- butyloxycarbonyl- or 1 ,2-difluorenyrmethoxycarbonyl-hexahydro-pyridazine-3-carboxylic acid, characterized in that said process comprises the stages (i) to (v):

Preferably, the alcohol is n-butanol.

Now, the invention is explained by examples. Examples

Reference Example 1 : Manufacture of methyl 2,5-dibromovalerate

518 g δ-valerolactone and 5 ml phosphorous tribromide were fed into a 11 three-necked flask. The mixture was heated up to a temperature of 95 °C to 105 °C under stirring and 550 g bromine were added, while the temperature was kept constant between 100 and 120 °C. Subsequently, 5 ml phosphorus tribromide and 236 g bromine were added at a temperature of 110 °C. After the reaction mixture had been allowed to stand for 30 minutes, it was cooled down to a temperature of 0 to 10 °C. Then, 11 methanol and lg p-toluenesulfonic acid were added, while the temperature was kept constant at 25 °C. After 5 hours of refluxing, the excess material was distilled off and the lower organic layer was separated. The organic layer was then washed with 500 ml of 10% sodium hydroxide and 500 ml water. After separation of the organic layer, the product was isolated by fractional distillation (139 to 142 °C /28 hPa) and 612.7 g of the title compound were obtained (yield 45%, purity > 96% by GC).

Reference Example 2: Manufacture of methyl 2-bromine-5-chIorovalerate

478 g (3.08 mole) 5-chlorovalerylchloride were fed into a 21 three-necked flask and subsequently heated up to a temperature of 95 to 105 °C. Within 5 hours 502 g (3.14 mole) bromine were added, while the temperature was kept constant between 95 and 105 °C. The reaction mixture was allowed to stand for 1 hour at a temperature of 95 to 105 °C and degased for 3 hours at a temperature of 100 to 120 °C by introducing nitrogen via a gas- dispersion tube. The reaction mixture was then cooled down to a temperature of 0 to 10 °C under stirring, followed by adding 500 ml methanol to the mixture, while the temperature was kept constant below 25 °C. The mixture was then allowed to stand for 30 minutes at a temperature of 20 to 30 °C and 500 ml of 5% aqueous sodium thiosulfate pentahydrate were added. After stirring for 15 minutes, the organic phase was separated and washed with 500 ml of 5% aqueous potassium carbonate solution. The lower organic phase contained the product and was used in the alkylation reaction described below without further purification (yield: 760 g, 90%; purity: 95%).

Example 1: Manufacture of methyl 1,2-dibenzyloxycarbonyl-hexahydro-pyridazine- 3-carboxylate from N,N'-dibenzyloxycarbonyl-hydrazine and methyl 2,5-dibromovalerate in toluene

168 g hydrazine hydrate (containing 24 % by weight of hydrazine) and 300 g deionized water were charged to a 2 1 flask. 100 g aqueous sodium hydroxide (containing 32 % by weight of sodium hydroxide) and 300 g benzyl chloroformate were added with vigorous stirring. The precipitate was filtered off and dried.

Subsequently, the obtained solid was suspended in 650 g toluene. 267 g potassium carbonate and a catalytic amount of methyl-tri-n-butylarnmonium chloride were added. Afterwards, 12 g water were added. The mixture was warmed up to 80 °C and subsequently 254 g methyl 2,5-dibromovalerate were added according to Reference Example 1, followed by determining the yield of the product by HPLC. It resulted in ~ 85 %.

The solution in toluene was used for the manufacture of 1-benzyloxycarbonyl-hexahydro- pyridazine-3 -carboxylic acid as described in Example 3.

Example 2: Manufacture of methyl 1,2-dibenzyloxycarbonyl-hexahydro-pyridazine- 3-carboxylate from N,N'-dibenzyloxycarbonyl-hydrazine and methyl 2-bromo-5- chloro-valerate in acetonitrile

The reaction was carried out analogous to Example 1 with the difference that instead of 254 g methyl 2,5-dibromo-valerate 243 g methyl 2-bromo-5-chloro-valerate according to Reference Example 2 and instead of 650 g toluene 650 g acetonitrile were applied. After completed reaction, the mixture was filtered. The yield of the product was determined by means of high-pressure liquid chromatography. A yield of 87 % by area was determined. The solution was used for the manufacture of 1-benzyloxycarbonyl-hexahydro-pyridazine- 3 -carboxylic acid as described in Example 4.

Comparison Example 1:

The reaction was carried out according to Example 1 with the difference that the solvent was water-free. The yield of product was determined by means of high-pressure liquid chromatography. A yield of merely 30 % by area was determined.

Comparison Example 2:

The reaction was carried out according to Example 1 with the difference that 35 g water were added corresponding to a concentration of approximately 5 % concerning the mixture of solvent and water. A yield of merely 35 % by area was determined by means of HPLC.

Example 3: Manufacture of methyl 1,2-dibenzyloxycarbonyl-hexahydro-pyridazine- 3-carboxylate from N,N'-dibenzyloxycarbonyI-hydrazine and methyl 2,5-dibromovalerate in toluene followed by saponification

Subsequently, the obtained solid was suspended in 650 g toluene. 267 g potassium carbonate and a catalytic amount of methyl-tri-n-butylammonium chloride were added. Afterwards, 12 g water were added. The mixture was warmed up to 80 °C and subsequently 254 g methyl 2,5-dibromovalerate were added according to Reference Example 1. After completion of the reaction the organic phase was washed with water, followed by adding 256 g of aqueous sodium hydroxide (containing 32 % by weight of sodium hydroxide) at a temperature of 0 °C. The mixture was allowed to warm up to room temperature. Afterwards, 500 g n-butanol were added and the mixture was acidified with hydrochloric acid up to a pH-value of from 1 to 2. Afterwards, the organic phase was separated and cooled down to 0 °C. The precipitate was filtered off as the desired product.

Example 4: Manufacture of methyl 1,2-dibenzyloxycarbonyl-hexahydro-pyridazine- 3-carboxylate from N,N'-dibenzyloxycarbonyl-hydrazine and methyl 2-bromo-5- chloro-valerate in acetonitrile followed by saponification

The reaction was carried out analogous to Example 1 with the difference that instead of 254 g methyl 2,5-dibromo-valerate 243 g methyl 2-bromo-5-chloro-valerate according to Reference Example 2 and instead of 650 g toluene 650 g acetonitrile were applied. After completed reaction, the solvent was largely distilled off. The raw product was dissolved in 500 g toluene and processed analogously to Example 3.

Claims

1. Process for the manufacture of 1,2-disubstituted hexahydro-pyridazine-3-carobxylic acids and esters thereof of the general formula (I)

comprising the reaction of compounds of the general formula (II)

^J\ NH (II) NH with compounds of the general formula (III)

Z represents identical or different amino protecting groups, R represents independently from each other hydrogen, a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl, aryl or aralkyl radical of from 1 to 30 carbon atoms, X represents identical or different leaving groups, and R¹ represents a carboxylic or ester group/s.

2. The process as claimed in claim 1, characterized in that said protecting groups Z represent independently from each other a fluorenylmethoxycarbonyl, benzyloxy- carbonyl- or t-butyloxycarbonyl and the leaving groups X are independently from each other a chlorine, bromine, iodine, tosyl or mesyl.

3. The process as claimed in claim 1 or 2, characterized in that said ester group R^l is an alkyl ester of from 1 to 10 carbon atoms or a benzyl ester.

4. The process as claimed in any of claims 1 to 3, characterized in that said phase transfer catalyst is a quaternary ammonium salt, phosphonium, arsonium, antimonium, bismuthonium and tertiary sulfonium salt as well as a crown ether or cryptand.

5. The process as claimed in any of claims 1 to 4, characterized in that said organic solvent is an alcohol, ether, ester, amide, ketone, nitrile, sulfoxide, an aliphatic, cyclic, cycloaliphatic or aromatic hydrocarbon, or a chlorinated aliphatic, cyclic, cycloaliphatic or aromatic hydrocarbon.

6. The process as claimed in claim 5, characterized in that said organic solvent and water are present in a weight ratio of from 99.9 : 0.1 to 95 : 5.

7. The process as claimed in claim 6, characterized in that said reaction is carried out in the presence of a base.

8. The process as claimed in claim 7, characterized in that said reaction is carried out in a temperature range of from 20 to 200 °C.

9. The process as claimed in any of claims 1 to 8, characterized in that as compound of the general formula (II) N,N'-dibenzyloxycarbonyl-hydrazine is reacted with an ester of 2-bromo-5-chloro-valeric acid or an ester of 2,5-dibromo-valeric acid as compound of the general formula (III), wherein as phase transfer catalyst a quaternary ammonium salt and as solvent an aromatic hydrocarbon or a nitrile are used.

10. The use of esters of l,2-dibenzyloxycarbonyl-hexahydropyridazine-3-carboxylic acid prepared according to claim 9 or 1,2-di-t-butyloxycarbonyl- or 1,2-difluorenyl- methoxycarbonyl-hexahydropyridazine-3-carboxylic acid prepared according to one of the claims 1 to 8 for the production of 1-benzyloxycarbonyl-, 1-t-butyloxycarbonyl- or l-fluorenylmethoxy-carbonyl-hexahydro-pyridzaine-3 -carboxylic acid, characterized in that the process for the manufacture comprises the stages (i) to (v):

11. Use according to claim 10, characterized in that the alcohol is n-butanol.

12. Process for the manufacture of 1-benzyloxycarbonyl-, 1-t-butyloxycarbonyl- or 1- fluorenylmethoxycarbonyl-hexahydro-pyridazine-3-carboxylic acid from esters of 1,2- dibenzyloxycarbonyl-, 1,2-di-t-butyloxycarbonyl- or 1,2-difluorenylmethoxycarbonyl- hexahydro-pyridazine-3-carboxylic acid, characterized in that said process comprises the stages (i) to (v):

13. Process according to claim 12, characterized in that the alcohol is n-butanol.