DE2039751A1 - Process for the production of lysine alkyl esters - Google Patents

Description

Dr. Hans-Heinrich Willrath Dr. Dieter Weber

PATENT LAWYERS

Telegram address i WILLPATENT

Postal check: Frankfurt / Main 67S3

Bank: Dresdner Bank AG. Wiesbaden

Account No. 876 80 /

7OOO-548/651

D - 62 WIESBADEN, 10- Postfadi 1327

Gustav-Freytag-StreSe 25 • S (06121) 37 27 20

II / Wh

Allied Chemical Corporation, 40 Rector Street, New York, N.Y. 10006, USA

Method of making lysinal

kylesters

Priority; " Serial No. 852 881 and 852 94? Dated August 25, 1969 in the USA

Lysine

If

is one of the essential Ämiinosä-

H ₂ N (CH ₂ ) J ₁ -CH-COH

NH

ren known. Its use in dietary supplements is unfortunately limited by its high price. This high price arises from the fact that currently known synthetic processes for the production of lysine require expensive starting materials and reagents and / or complex process steps. ■ '

BATH ORIGINAL

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The object of the present invention was therefore to obtain an inexpensive, easy way of producing lysine.

According to the invention it has been found that lysine can be easily obtained from cyclohexanone can be obtained by the following synthesis process:

1. Nitration of cyclohexanone with formation of 2-nitrocyclohexanone (Jour, of Organic Chemistry, Volume 31, 1966, page 357, Griswold et al),

2. Nitrosation of 2-nitrocyclohexanone with formation of 2-nitro-6-oximinocyclohexanone,

3. Ring opening of 2-nitro-6-oximinocyclohexanone in an alcoholic Base with formation of 2-oximino-6-nitrocaproic acid alkyl ester,

4. Hydrogenation of the 2-oximino ~ 6 ~ nitrocaproic acid alkyl ester under Formation of an alkyl ester of lysine and

5. Saponification of the lysine alkyl ester with the formation of lysine or lysine hydrochloride.

This synthesis can be shown schematically as follows:

O O

"" NO ₂

1) Ac ₂ O or H ₂ C = C ^ tf J NOCl *

2) Acetyl Nitrate "^^^

Cyclohexanone 2-nitrocyclohexanone

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BATH ORIGINAL

ft

\ rtrj t f-Vt \ ~ Γ * -. ΠΓίΤ}

ROH / NaOH> GH ₂ (CH ₂ ) ₃ ~ C-COR _5H / catalyst

MA MfMJ ^

₂ NOH

2-Nitro-6-oximino-2-oximino-6-nitrocaproic acid alkyl ester cyclohexanone

O reflux 3H ₅ O + CH, (CH ₀ ), - CH-COR U ¹ ^ ^M01 ROH + _n

^ 2 ^NH 2 CH ₅ (CH ₉ ), - CH-COR

Alkyl esters of lysine ^NH 2 * ^HC1

f2 « ^CH 2> 3-? ^H -

NH ₂ -HCl

The nitrosation of 2-nitrocyclonexanone with the formation of

at the
2-Nitro-6-oximinocyclohexanone is most expediently carried out in an inert solvent for the nitrocyclohexanone in order to obtain good contact between the nitrocyclohexanone and the nitrosating agent and to facilitate temperature control. Although the nitrosation can be carried out at almost any temperature between the freezing point and the boiling point of the selected solvent, it has been found that the preferred reaction temperature is between -30 ° C and §5 ° C. The reaction rate is very slow below -30 ° C.

Above about 10 ° C., side reactions may occur which reduce the yield of S-mitro-S-oximinocyclohexanone and cause the formation of impurities that are difficult to remove. The preferred reaction temperature is in the range of around -20 ° C to 5 ° C.

^109811/2226 BADORialNAU

If

A suitable solvent should not only be liquid in the preferred reaction temperature range, but it must also be inert towards the nitrosating agent used. Easily available, useful solvents are, for example, halogenated C ₁ - to C ^ -alkanes and alkane mono- and diethers with M to 8 carbon atoms. The term "halogenated alkane" also means n- or isoalkanes in which at least 1/3 of the hydrogen atoms have been replaced by fluorine atoms, chlorine atoms or bromine atoms, preferably fluorine atoms or chlorine atoms. The solvent is preferably essentially or completely anhydrous. Sulfur dioxide has a number of advantages over other solvents. It is non-flammable, cheap and a very good solvent for both the reactants and the products. In addition, because of its low boiling point, SOg can be easily removed at low temperature without the need for vacuum stripping.

Suitable nitrosating agents are, for example, the C 1-6 alkyl nitrites, nitrosyl formate, nitrosyl chloride, nitrosyl bromide and N ₂ O ,. The preferred nitrosating agents are methyl nitrite or nitrosyl chloride. The nitrosation is usually carried out in such a way that the 2-nitrocyclohexanone is dissolved in the solvent, the solution is cooled to about -15 ° C. and then 1.0 to 1.5 moles of the nitrosating agent are added per mole of nitrocyclohexanone. The nitrosation is usually complete within 1 to 12 hours after at least one molar equivalent of the nitrosating agent has been added. The termination

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BATH ORIGINAL

The most convenient way of establishing the nitrosation reaction is by analysis of vapor phase chromatography part of the reaction mixture solid. Although the reaction is not highly endothermic or exothermic is, it is desirable to use the reaction mixture in the desired Maintain temperature range during the course of the nitrosation reaction. The reaction is not sensitive to pressure and can be carried out at normal pressure or above atmospheric pressure .

It has been found that the nitrosation proceeds much more easily in the presence of a strong acid as a catalyst. Any non-oxidizing acid with a pKa less than I is suitable, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid or methanesulfonic acid. The amount of acid present in the reaction mixture is not critical, but preferably it should be sufficient to render the solution 0.5 to 20 molar in terms of acid. Because of its high volatility, hydrochloric acid is easy to remove from the reaction mixture after the reaction is finished, and for this reason this acid is preferred. In the case of HCl, the preferred concentration is 5 to 20 molar. The acid can be added before or at the same time as the nitrosating agent and is preferably added before the nitrosating agent. The work-up of the nitrosation mixture after the end of the reaction is most advantageously carried out by maturing the reaction solvent, excess nitrosating agent and the HCl catalyst under reduced pressure, preferably at a temperature below about 0 ° C. If a non-volatile acid catalyst is used, it must be removed from the reaction

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mixture can be removed or neutralized before the solvent removed by stripping.

HCl has a comparatively low solubility in SOp at atmospheric pressure and a high solubility at pressures above of about 5 at. Hence the removal of both SOp as well as of HCl from the product after completion of the reaction easily by keeping the reaction mixture at a temperature lets come below about -10 ° C to atmospheric pressure, while allowing the HCl to evaporate and then the temperature to about -10 ° C can rise and so causes evaporation of the SOg, wherein the desired product remains as a residue. The residue can be reacted further without additional purification, or if desired, it can be recrystallized from a solvent such as a C 1 -C 6 alkanol.

The residue which remains after removal of the solvent, excess nitrosating agent and acid catalyst consists essentially of 2-nitro-6-oximinocyclohexanone, which can be used in the next stage without further purification. This step causes an opening, ie a splitting of the cyclohexanone ring with the formation of an alkyl ester of 2-oxiraino-6-nitrocaproic acid. The residue is preferably purified before the ring opening by triturating it with methanol or ethanol at a low temperature.

This ring opening is most conveniently effected by heating the 2-nitro-6-oximinocyclohexanone at a temperature of about 50 to 90 ° C. with an alcoholic solution of a strong base .

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Suitable alcohols are all C ₁ - to C ^ normal alkanols, ie methanol, ethanol, n-propanol and n-butanol, preferably methanol. Suitable bases are, for example, the alkali metal hydroxides or alkali metal alkoxides of the alcohol used as the solvent. The concentration of the base is not critical and it has been found that no significant differences can be observed in the range from 0.025 to 1.0 mol of base per mol of 2-nitro-6-oximinocyclohexanone. Preferably, 0.05 to 0.10 moles of base are used per mole of 2-nitro-6-oximinocyclohexanone. ί

The ring opening is rapid and heating for about 1 hour is usually sufficient to achieve complete ring opening. However, prolonged heating is not harmful. The concentration of 2-nitro-6-oximinocyelohexanone in the alcoholic base solution is not critical, but at least it should 1 mole of alcohol is present per mole of 2-nitro-6-oximinocyclohexanone be to encourage a full response. For reasons of ease of use, the concentration is on 2-Nitro-6-oximinocyelohexanone in the alcoholic solution preferably at about 1 to about 25 Sf by weight.

Heating with alcoholic base leads to ring opening with essentially simultaneous formation of the ester of 2-0ximino-6-nitroGaproic acid corresponding to the solvent used alcohol. Purification of this ester before the next stage, i.e. the reduction, is not necessary.

The reduction of the nitro and oximino groups of the ester to form of the lysine ester is best done by catalytic hy-

10 9811/2226 BAD ORIGINAL

dration. For reasons of easy handling, about 1/2 to 10% by weight solution of the 2-oximino-6-nitrocaproic acid ester in a suitable inert solvent, such as a C _{- to Cjj alcohol or a C 1} , - to Cg mono- or -Diether, such as ethylene glycol dimethyl ether (or 1,2-dimethoxyethane), diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethyl ether and the like. Dissolved, whereupon 1 to 20 weight /?, based on the weight of the ester, added to the hydrogenation catalyst and ^ the mixture of ester, solvent and catalyst, preferably with stirring, is then heated in a suitable pressure vessel under a hydrogen atmosphere at 20 to 200 ° C. A hydrogen pressure of about 0.68 to 3 ¹ 10 atmospheres (10 to 5,000 psig) is suitable. Usually a pressure of 3.4 to 34 atmospheres (50 to 500 psig) is preferred. The hydrogenation is rapid and is usually complete in about 1 to 24 hours, depending on the hydrogen pressure, the catalyst, the degree of agitation and the hydrogenation temperature.

_ Suitable catalysts are, for example, palladium on a support material such as carbon, alumina, calcium carbonate or barium sulfate. The palladium concentration on the support material is expediently about 1 to 10 μs by weight.

The lysine ester is obtained from the hydrogenation mixture by filtering off the catalyst and evaporating the solvent, the lysine ester remaining as a residue. When the ester is the ethyl ester it can be fractionated to yield the nutritionally active L-enantiomer or it can be used directly as a dietary food additive with or without further purification such as by recrystallization

^{10981 1/2226} BAD OW) INAL

Find. A suitable solvent for the recrystallization is a C ₁ - to C ^ -alkanol. If other than the ethyl ester is present, hydrolysis to lysine by refluxing the ester in aqueous hydrochloric acid followed by neutralization with one equivalent of base and cooling results in precipitation of the lysine monohydrochloride which can then be recovered by filtration. The hydrochloride is now ready for use as a food additive or for separation into the nutritionally active L-isomer according to known methods.

When basic saponification to obtain the basic lysine salt and subsequent neutralization is carried out, neutral lysine is obtained. This material is generally not used as a food additive because it has an unpleasant odor, which is why the odorless monohydric chloride is preferred. Suitable bases for the saponification or neutralization are the alkali metal hydroxides or carbonates and the Alkaline earth oxides or hydroxides.

The invention is further illustrated by the following examples. Unless expressly stated otherwise, all parts are parts by weight.

example 1

Nitrosation of 2-nitrocyclohexanone with n- butyl nitrite A solution of 31 »2 g (0.218 mol) of 2-nitrocyclohexanone in 600 ml of anhydrous ether was saturated with anhydrous HCl at 0 ° C. To this solution , 23 g (0.223 mol) of n-butyl nitrite was added dropwise over 10 minutes under a nitrogen atmosphere

'■ "...- λ ■■' ■ 10011171 ^ 20 BADOBlGtNAL

• \ '. added while maintaining the temperature at 0-5 ° C. After standing for a further 10 minutes at 0 to 5 ° C the reaction mixture under reduced pressure was stripped in a rotary evaporator _v. The light yellow crystals of 2-nitro-6-oxydminocyclohexanone ("NOC") that formed in the concentrated solution were collected by filtration, then washed with ether. Weight after drying: 13 »0 g (yield 35 %)

Example 2 Nitrosation of 2-nitrocyclohexanone with methyl nitrite in ether

10 g (0.070 mol) of 2-nitrocyclohexanone were dissolved in about 300 ml of diethyl ether dissolved at 0 ° C and atmospheric pressure with dry HCl gas had become saturated. The solution was then 6.0 ml

Treated methyl nitrite (, 6.0 g, 0.098 mol), which was added all at once at -20 ° C. The solution was allowed to warm to -10 ° C and kept at this temperature for 1.5 hours. The solution was then evaporated to dryness on a rotary evaporator while maintaining the temperature below 10 ° C. The remaining yellow oil was scraped off to induce crystallization and the resulting yellow crystals of "NOC" were triturated with cold ether (100 ml) and collected by pitration. Yield: 3 _f 8 g (32 %), P. 160 ° C (with decomposition).

Example 3

Nitrosation of 2-nitrocyclohexanone with nitrosyl chloride in ethylene glycol dimethyl ether

A sample of 10.0 g (0.070 mol) of 2-nitrocyclohexanone was dissolved in 350 ml of a solution of 10N HCl in ethylene glycol dimethyl ether, and the solution was then mixed with 3.1 ml (about 4.5 g, 0.07 mol) of nitrosyl chloride treated at -20 ° C. The temperature of the mixture was kept at -20 ° C for 2.5 hours and then at -15 ° C for 3 hours. At this point the nitrocyclo- λ hexanone conversion was 80 % and the reaction mixture was evaporated to dryness on a rotary evaporator at about -10 ° C. The residue from the evaporation was triturated with about 20 ml of cold methanol, filtered and washed with a few additional ml of cold methanol. The resulting light yellow crystal powder weighed 5.21 g. The mother liquor contained a further 0.93 g, so that the total yield was 6.14 g, corresponding to 64 % based on the converted nitrocyclohexanone.

Example 4 |

A solution of 1.5 g (10.5 millimoles) of nitrocyclohexanone was dissolved in 33 ecm of liquid SO ₂ , and this solution was then saturated with gaseous HCl at -15 ° C and about 4 atm, a solution of about 5m in HCl received. At this point the solution was cooled to -80 ° C and 1.5 g (25 millimoles) of methyl nitrite was added. The reaction mixture was brought to a reaction temperature of -15 +. Brought 2 ° .C, and this temperature was maintained for 4 hours. The existing SO ₂ and HCl were removed while maintaining the temperature below 0 ° C.

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removed and the residue was recrystallized from a small amount of methanol. 0.713 g of pure crystalline 2-nitro-6-oximinocyclohexanone were obtained, while 0.482 g of the same product remained in the filtrate. The amount of the desired product was 1.20 or 68 %, based on the 2-nitrocyclohexanone consumed. Vapor phase chromatography analysis showed that at least 99 MoI-J? of the starting material nitrocyclohexanone were consumed.

fc example 5

Ring opening of 2-nitro-6-oximinocyclohexanone ("NOC") To a solution of 10.0 g (0.058 mol) of "NOC" in 400 ml of absolute methanol, a solution of 2.40 g (0.058 mol) was added at 50.degree. Sodium hydroxide in 400 ml of absolute methanol was added. A voluminous yellow precipitate appeared which dissolved after a few minutes. On standing for 5 1/2 hours at 50 ° C., the reaction mixture was cooled to room temperature and then treated with a solution which contained 5 ml of 12m HCl and 7 g of urea ^ in 500 ml of water. The resulting solution was concentrated to 450 ml by vacuum stripping and exhaustively extracted with ether.

After drying the ether extracts and evaporating the ether , 11.6 g of crude methyl 2-oximino-6-nitrocaproate were obtained. The material was of sufficient purity to be hydrogenated without additional purification.

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Example 6 / ^

To a solution of 86 mg (0.5 millimoles) of "NOC" in 7.5 ml of methanol was added under reflux 0.5 ml of a 0.5 M solution of NaOH in methanol also at reflux temperature. The mixture remained clear. After refluxing for 140 minutes, analysis by visible spectroscopy (350-370 m, u band in 10 m aqueous NaOH) showed that the "NOC" was consumed up to at least 97%. Analysis by thin layer chromatography showed that the reaction mixture contained essentially only methyl 2-oximino-6-nitrocaproate and no starting material.

Example 7

The procedure of Example 6 was followed with varying amounts NaOH and "NOC" in methanol at reflux temperature repeated. It has been found that the ring opening of "NOC" is satisfactory took place even with NaOH / "NOC" ratios so low like 0.025. A low NaOH / "NOC" ratio has the advantage a reduced formation of salt by-products in the subsequent neutralization stage before the hydrogenation.

The conversion of "NOC" after 140 minutes of reflux boil is shown in the table below. In all cases the only detectable product was methyl S-oximino-ö-nitrocaproate.

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"NOC" implementation NaOH
(mmol) 8th in methanol under reflux Volume "NOC
ml "-Conversion
(Mol- *) Response time = 0.250 ΙΊΟ minutes 8.0 97 "NOC"
(mmol) 0.050 NaOH /
"NOC" 8.0 99 0.50 0.025 0.500 8.0 99 0.50 0.025 0.100 2.0 99 0.50 0.250 0.050 2.0 9 * 0.50 0.050 1.00 0.250 example

3.0 ml of 0.1 molar ethanolic NaOH were added under reflux to a solution of 0.258 g (1.5 millimoles) of “NOC” in 21 ml of Etnol. After refluxing for 6 hours, ultraviolet analysis of the reaction mixture indicated that 87 % of the "NOC" had been consumed. The reaction mixture was evaporated to dryness and the residue was dissolved in 3 ml of chloroform and purified by passing it through a column containing 15 g of silica gel. Chloroform was used as the eluent. A fraction was obtained which consisted of a chromatographically pure oily material. It weighed 0.166 g. The infrared spectrum of this material was in agreement with that of ethyl 2-oximino-6-nitrocaproate.

Example 9

3.0 ml of 0.1N NaOH in n-butanol were added at 85 ° C. to a solution of 0.258 g (1.5 millimoles) of “NOC” in 5.0 ml of n-butanol. After standing at 85 ° C for 6 hours, about 99 % was dee

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/ S

"NOC" consumed. The reaction mixture was then evaporated to dryness and passed through a column of Purified 15 g of silica gel using chloroform as the eluent. 0.185 g of a chromatograph was obtained pure oil. The infrared spectrum of this material was in agreement with that of 2-oximino-6-nitrocaproic acid n-butyl ester.

Example 10

Hydrogenation of methyl 2-oximino-6-nitrocaproate {

A sample of 515 mg (2.5 millimoles) of methyl 2-oximino-6-nitrocaproate was dissolved in 20 ml of methanol containing 1 ml of concentrated HCl and 500 mg of 5 % palladium on carbon. The mixture was hydrogenated in a Parr bomb at 60 ° C and 3.4 to 4.8 atmospheres of hydrogen pressure. The hydrogen uptake was 97 % of the theoretical within 69 hours. The mixture was filtered, evaporated to dryness on a rotary evaporator and the residue refluxed with 50 ml of 6N HCl for 3 hours. The resulting solution was concentrated in a rotary evaporator to a thick syrup, which was dissolved in 10 ml of 95 μg ethanol under reflux. The solution was treated with 0.5 ml of pyridine in 1 ml of 95 / S ethanol, cooled slowly and allowed to stand at room temperature for 25 hours and then in a refrigerator for 16 hours. The precipitated lysine hydrochloride was collected by suction filtration, washed with ethanol and dried in air at 120 ° C. '

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A total of 275 mg was obtained. Analysis of the mother liquors showed the presence of a further 35 mg of lysine hydrochloride, giving a total yield of 310 mg (68 %) . A small amount (30 mg) pipecolic acid was also contained in the mother liquor.

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Claims (6)

Breakfast Claims IJ. Process for the production of a Lysinalky! Ester, characterized in that one a) 2-nitrocyclohexanone by treatment with a nitrosating agent in solution for the use of a solvent which is inert towards the nitrosating agent at the reaction temperature in its nitrosation product 2-nitro-6-oximinocyclohexanone converts, b.) the 2-nitro-6-oximinocyclohexanone by treatment with a alcoholic solution of a strong base into the open-chain compound, the alkyl 2-oximino-6-nitrocaproate and c) this 2-oximino-6-nitrocaproic acid alkyl ester by treatment converted into a lysine alkyl ester with elemental hydrogen and a hydrogenation catalyst. 2. The method according to claim 1, characterized in that there is liquid as the solvent in the nitrosation stage (stage 1) Sulfur dioxide used. 3. The method according to claim 2, characterized in that the nitrosation is carried out in a temperature range of -30 to 25 C, a C ₁ - to Cjj-alkyl nitrite, nitrous oxide, a nitrosyl formate, a hitrosyl chloride. Or ■ a nitrosyl bromide is used as the nitrosating agent and adds a strong, non-oxidizing acid to the reaction mixture " ÜS811 / 222S - > * - 20397S1 4. The method according to claim 3, characterized in that the The reaction mixture is added as a strong, non-oxidizing acid, anhydrous hydrochloric acid and the reaction temperature keeps in the range of -20 to 5 ° C. 5. The method according to claim 1 to 4, characterized in that one in the ring opening stage (stage 2), the reaction mixture is heated to a temperature in the range from 50 to 90 ° C and a Solution of alkali hydroxide or alkali alkoxide in C ^ - to Cj, - * Alkanol used. 6. The method according to claim 1 to 5, characterized in that one palladium on a support material is used as the hydrogenation catalyst in the hydrogenation stage (stage 3).