DE1193502B - Process for the preparation of beta, beta-penta-methylenebutyrolactone - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. CL:

Number:
File number:
Registration date:
Display day:

C07d

German class: 12 ο - 25

W28598IVb / 12o
September 21, 1960
May 26, 1965

The invention is concerned with the task, ^, jS-Pentamethylenbutyrolacton, which is known as well as the derivatives of ^, ß-pentamethylene ^ hydroxybutyric acid derived therefrom as a side reaction free Central nervous system stimulant with high therapeutic index is of value in high Yield and cheap to manufacture, so that large-scale production becomes possible.

The classical synthesis of ^, jS-pentamethylene butyrolactone, as described by Wi η d a u s, Ber.dtsch.chem. Ges., Vol. 55 B, 1922, p. 3981 in the conversion of cyclohexane-l, l-diacetic acid into its disilver salt and subsequent conversion this disilver salt with iodine in the presence of sand to the lactone. The lactone can then be converted into the desired salt of 3,3-pentamethylene-4-hydroxybutyric acid can be converted.

An improvement of this classic Windaus method can according to an earlier proposal can be achieved by not reacting the disilver salt with iodine in the presence of Sand but in an aromatic solvent. This achieves an essential one Simplification of the process engineering and an increased yield. However, just like with classic viewing Windaus method for every mol of cyclohexane-l, l-diacetic acid to be converted, 2MoI silver is required, which is costly.

The invention is now primarily aimed at a reduction and, in particular, complete avoidance of silver consumption. For this purpose, the dibasic cyclohexane-1.l-diacetic acid is not used themselves, but worked with their monoalkyl ester, so that only the Half of the required reagents is required.

The invention accordingly consists of the process for the preparation of / ?, (8-pentamethylene butyrolactone, Its special feature is that the anhydride of cyclohexane-l, l-diacetic acid is used in known way with a lower alkanol with at least 2 carbon atoms to a lower one Monoalkyl ester of cyclohexane-l, l-diacetic acid converts, the monoester obtained in a known manner Way into its silver, potassium or mercury (II) salt, the metal salt at about 60 to 90 ° C with bromine or iodine in the presence of a solvent such as carbon tetrachloride, under anhydrous Conditions in the corresponding lower monoalkyl ester of 3,3-pentamethylene-4-halobutyric acid transferred, this reacts in a known manner with sodium or potassium hydroxide and then acidify the resulting solution.

Process for the preparation of /?, /? - pentamethylene butyrolactone

Applicant:

Warner-Lambert Pharmaceutical Company,

Morris Plains, N.J. (V. St. A.)

Representative:

Dr.phil.G. Henkel

and Dr. rer. nat. W.-D. Henkel, patent attorneys,

Munich 9, Eduard-Schmid-Str. 2

Named as inventor:

John Shavel Jun "Mendham, N. J .;

Robert Israel Meltzer, Rockaway, N.J. (V. St. A.); Wolf-Dieter Vigelius, Memmingen

Claimed priority:

V. St. v. America 17 December 1959

(860 069),

dated March 1, 1960 (11,987) - -

The sodium as well as the silver salt of the monomethyl ester of cyclohexane-l, l-diacetic acid and its Preparation by partial esterification of the anhydride of this acid with methanol and conversion of the acid esters in salt form are already in a work on keto-lactol tautomerism and its influence by the cyclohexane ring (J. Chem. Soc, 1929, p. 718). The salts served here but as an intermediate for the synthesis of methylcyclohexane-1-acetone-1-acetate.

The conversion of the monoester of cyclohexane-1,1-diacetic acid in its silver, potassium or mercury (II) salt takes place according to a preferred embodiment of the invention with the help of silver nitrate, potassium hydroxide or mercury (II) oxide.

The new procedure is more extensive than the classic in terms of the number of work steps Windaus method. The detour via the anhydride and the monoalkyl ester is procedural easily controllable and economical. As mentioned above, there is the basic idea of the invention therein, one of the two acidic groups of cyclohexane-l, l-diacetic acid by esterification to block the formation of salt, so that at

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the formation of a silver salt evidently that of a suitable solvent so slowly that the The silver requirement is only half that of the known reaction mixture under reflux, and so long Procedure is. In addition, it has been found to be added until the characteristics persist at all If you have not worked with a silver compound, bromine or iodine coloration of the solution is the cause but instead a Mercury 5 indicates an excess. When moving A silver compound, but above all a potassium compound, a silver or mercury (II) salt, is formed dung can be used for salt formation. The precipitate of silver or mercury (II) halo invention thus contributes in several ways to genid, which is entdie by filtering or centrifuging Production of the / 3, / 7-pentamethylene butyrolactone is removed. In order to get rid of the excess In comparison to the known process of economical halogen, the liquid phase is then diluted with to make it lighter. Alkali solution, for example sodium hydroxide or the starting material, namely the cyclohexane sodium carbonate, treated. The organic phase 1,1-diacetic acid, can after any known one for the purpose of removal of the solution process, for example, according to T h ο r ρ e, J. Chem. by means of distillation and leaves a residue that Soc. (London), Vol. 99, 1911, pp. 445/446, and Vol. 115, 15 from the desired monoalkyl ester of 3,3-Penta-1919, Pp. 686 to 704. methylene-4-halobutyric acid.

The conversion of the starting acid into its monoalkyl ester is then converted into a derivative Monoalkyl esters via the anhydride can, for example, be converted from 3,3-pentamethylene-4-hydroxybutyric acid converts according to the already mentioned working method. First is with an aqueous solution J. Chem. Soc, 1929, p. 718. Among the 20 sodium or potassium hydroxides here, there is an aqueous one used expression »lower alkanol with min-solution of sodium or potassium-3,3-pentamethyIend at the least 2 carbon atoms «fall alkanols with up to 4-hydroxybutyrate, which are then in per se 4 carbon atoms, such as ethanol, n-propanol, acidified, heated, cooled and with Isopropanol or n-butanol. an aromatic solvent, such as benzene, ex-For the conversion of the lower monoalkyl ester 25 is traced. The extract can then contain /?, / S-pentaders Cyclohexane-1,1-diacetic acid in its metal salt methylenebutyrolactone as therapeutically useful According to the invention, only the silver, potassium substance can be obtained.

or mercury (II) salts as satisfactory products. The examples below serve for further purposes

Duct-supplying reagents into consideration, because the salts explain the process according to the invention. For

other metals in the subsequent reaction 30 the production of the starting material will protection

fail with bromine or iodine. With regard to this, within the scope of the present invention, not

that this next step is claimed under strictly anhydrous. The starting material can be produced as follows

Conditions must be carried out will already be set:

the salt formation carried out under conditions that 3.1 g (corresponding to 0.0155MoI) cyclohexane-l ^ -di

the salt is obtained in a practically anhydrous form 35 acetic acid are so in a vacuum on the steam bath

permit. long heated with 9,3 ecm acetic acid hydride until everything

The silver salt can be removed from the monoester or volatile material. The residue is in

its ammonium salt is cooled by reacting it with a reaction vessel, 2.9 g of cyclohexane

water soluble silver compound, e.g. B. silver nitrate, in diacetic anhydride, b.p. 55 ° C, can be obtained.
aqueous medium because it is insoluble in water 40

and is therefore obtained by filtering and drying Example 1
can be.

The potassium or mercury (II) salt wins ( _a ) Monoethyl ester of cyclohexane-1,1-acetic acid by reacting the monoester z. B. with the

corresponding metal oxide or hydroxide in water 45 The above product is 6 hours on the

or a suitable organic solvent, steam bath heated with 0.75 g absolute ethanol.

z. B. a lower alkanol, such as Metahnol, or Here all volatile material goes away, and it

Carbon tetrachloride. The water that remains with the remains a liquid residue of the monoethyl ester

Reaction forms or is present as a solvent of the cyclohexanediacetic acid.
is, either by evaporating the reaction 50

mixed or when using tetrachloro, ", _T ,,. ,, ,, ..,,. ^,,.

carbon removed by azeotropic distillation. ( ^b ) Potassium salt of the monoethyl ester of cyclohexane

In the latter case, the water 1,1-diacetic acid formed
free salt suspension without further purification directly

for the subsequent reaction with bromine or iodine 55 The product from step (a) will be used with a solution. of 0.868 g (0.0155 mol) of potassium hydroxide in 20 ecm. The silver, potassium or mercury (II) salt is mixed with ethanol and the mixture is then removed for the purpose of dehydration in the corresponding mono-distillation of the ethanol in vacuo on the steam bath 3,3-Pentamethylene-4-halobutyric acid heated. The residue is dissolved in 80 cc tetrachloride converted that carbon suspended in about 60 to about 9O ⁰ C and 60, the suspension again in an equivalent amount of bromine or iodine reacted vacuo on the steam bath until removal of all becomes using a suitable bromine or Heated iodine solution volatile material and this second return agent, preferably carbon tetrachloride, was used again in 80 ecm carbon tetrachloride is suspended. It is imperative that anhydrous conditions are dated. This second suspension is heated for as long as it is paused. The salt is in the reaction - 65 to 30 ecm of carbon tetrachloride have been distilled off, suspended in the medium and the mixture is heated for the purpose of removing an anhydrous suspension of all the water from the salt. Salt of the monoethyl ester of cyclohexane-1,1-di-Then a bromine or iodine solution in acetic acid remains.

(c) Monoethyl ester of 3,3-pentamethylene-4-bromobutyric acid

A solution of 0.8 ecm (0.0155 mol) of bromine in 7.2 ecm of carbon tetrachloride is added dropwise to the anhydrous suspension obtained in step (b) with constant stirring, the reaction mixture being kept under reflux. The addition of bromine is stopped as soon as it becomes excess, which is shown by the lack of further discoloration after 15 minutes of boiling. The reaction mixture is cooled and, after adding 15 ecm of water, stirred until all of the solid constituents have dissolved. Thereafter, 15 cc of a 10% ^en aqueous sodium carbonate are added, the mixture stirred again, collected the organic phase, dried over anhydrous sodium sulfate, the drying agent by filtration, and finally the carbon tetrachloride by steam heating removed under vacuum. This leaves a liquid residue which consists of the monoethyl ester of 3,3-pentamethylene-4-bromobutyric acid.

(d) | 8, β-pentamethylene butyrolactone

The product from step (c) is 6 hours with a solution of 2 g (0.05 mol) of sodium hydroxide boiled under reflux in 20 ecm of water. The mixture is then cooled to remove it Any solid components filtered, acidified with hydrochloric acid and heated to 85 ° C. The one that cooled down again Solution is extracted three times with 10 ecm benzene each time. The combined benzene extracts are with 10 ecm Treated saturated aqueous potassium bicarbonate solution, and then the benzene phase is anhydrous by means of Dried sodium sulfate. After removing the drying agent by filtration and des Benzene by vacuum distillation leaves a yield of 1.4 g of a brownish, liquid residue, that of the desired ^, jS-pentamethylene butyrolactone consists.

Example 2

(a) Silver salt of the monoethyl ester of cyclohexane

1,1-diacetic acid

The product obtained according to Example 1 (a) is treated with about 3 g of ethanol on the steam bath for 5 hours heated and then with a mixture of 200 ecm water and 4.7 ecm 24% aqueous ammonia offset. Then a solution of 10.3 g of silver nitrate in 30 ecm of water is added with effective stirring. The precipitate formed is separated off in a centrifuge, slurried in 120 ecm of water, centrifuged again and finally dried for 8 days in the dark at 60 ° C.

In this way, 18.3 g of the silver salt of the monoethyl ester of cyclohexane-l, l-diacetic acid are obtained.

(b) Sodium 3,3-pentamethylene 4-hydroxybutyrate

The silver salt obtained according to Example 1 (b) is suspended in 190 g of carbon tetrachloride and the The suspension is heated on the steam bath until 50 ecm carbon tetrachloride has distilled off. to the resulting anhydrous suspension of the silver salt in carbon tetrachloride becomes a solution of 9.1 g of bromine in 3 ecm of carbon tetrachloride added dropwise and so slowly that the reaction mixture remains in cooking. With the addition is stopped as soon as it is through the characteristic Bromine color indicates an excess of bromine in the reaction mixture. Heating will be another 30 minutes continued and then the mixture cooled, the supernatant clear liquid by decanting subtracted and the one consisting of silver bromide

ίο Precipitation separated by means of a centrifuge. That Silver bromide is slurried again in 50 ecm carbon tetrachloride and centrifuged again. the The combined liquid phase is mixed with 6 ecm each of a 10% aqueous sodium hydroxide solution extracted until the solution is clear. Then the organic phase is separated and for removal of the volatile solvent is distilled in vacuo. Thereafter, the residue is 6 hours at 95 ° C with a solution of 8.2 g of sodium hydroxide in 30 ecm

zo water heated.

This alkaline solution is heated to 85 ° C. with 12N HCl, cooled and extracted with benzene. The benzene extract is treated with a 20% potassium carbonate solution; the organic phase is separated off, the solvent is distilled off and the residue is distilled in vacuo, with 8, /? - pentamethylene butyrolactone, b.p. ₁₄ = 138 to 141 ° C., being obtained.

Example3

10.7 g (0.05MoI) of the monoethyl ester of cyclohexane-l, l-diacetic acid, as it was obtained by the method according to Example 1 (a) and (b), are dissolved in 500 ecm carbon tetrachloride, and the resulting 5.4 g (0.025 mol) of mercury (II) oxide are added to the solution.

After boiling the reaction mixture for 7 hours, a clear solution of the mercury (II) salt of the monoethyl ester of cyclohexane-ljl-diacetic acid is obtained in a volume of about 250 ecm. The resulting clear solution is mixed with 5 ecm of a solution of 1 part by volume of bromine in 1 part by volume of carbon tetrachloride (corresponding to 0.05 mol of bromine) while stirring. The precipitated mercury (II) bromide is removed by filtration and washed with 5 ecm carbon tetrachloride. The filtrate and washings are combined and added portionwise so long stirred successively with a 10 _^0/0 aqueous sodium carbonate solution until the aqueous phase remains alkaline. The organic phase is then distilled in vacuo to remove all volatile solvent.
The distillation residue is ig ^he boiled for 10 hours by 45 cc of 20% sodium hydroxide solution. The mixture is cooled, acidified with concentrated hydrochloric acid, heated to 90 ⁰ C, cooled again and then extracted twice with 10 cc of benzene. The benzene extracts are combined, extracted ⁰ /, ^ ^«1 aqueous solution of sodium carbonate for the purpose of removing the acidic ingredients with a lO, dried over anhydrous sodium sulfate and distilled in vacuo. This gives ^, / 3-pentamethylene butyrolactone. The above examples explain the preparation according to the invention of the lactone of 3,3-pentamethylene-4-hydroxybutyric acid. In Example 1 the potassium, in Example 2 the silver and in Example 3 the mercury (II) salt of monoethyl

ester of cyclohexane-1,1-acetic acid as an intermediate obtain.

Claims (2)

Patent claims: 1. A process for the preparation of ßß-penta methylenebutyrolactone, characterized in that the anhydride of cyclohexane-1,1-diacetic acid in a known manner with a lower alkanol having at least 2 carbon atoms to a lower monoalkyl ester of cyclohexane-1,1- converts diacetic acid, converts the monoester obtained in a manner known per se into its silver, potassium or mercury (II) salt, the metal salt at about 60 to 90 ° C with bromine or iodine in the presence of a solvent such as carbon tetrachloride, under anhydrous Conditions in the corresponding, lower monoalkyl ester of 3,3-pentamethylene-4-halobutyric acid transferred, this reacts in a known manner with sodium or potassium hydroxide and then the obtained Solution acidifies. 2. The method according to claim 1, characterized in that the conversion of the monoester the cyclohexane-1,1-diacetic acid into its silver, potassium or mercury salt by reacting with Silver nitrate, potassium hydroxide or mercury (II) oxide is effected. Considered publications:
J. Chem. Soc, 1929, pp. 713 to 721;
J. Indian Chem. Soc, Vol. 34, 1957, pp. 898 to 900; Ber. German chem. Ges., Vol. 55 B, 1922, pp. 3981 to 3987. 509 577/434 5.65 © Bundesdruckerei Berlin