JPS5867694A - Manufacture of 6-(d-(-)-alpha-(4-ethyl-2,3- dioxo-1-piperadinocarbonylamino)-penyl( or hydroxypenyl)acetamide)penicillanic acid and salt of same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new method for producing a benylin derivative represented by the following structural formula (D).

In the formula, R is hydrogen or a hydroxyl group, and M is hydrogen, an inorganic salt such as sodium, potassium, calcium, lower a/L of carbon water 1-4, or kylamine.

The first products of the present invention were the White Ear Patent No. 828.692, the French Patent No. 7.514,159, the German Patent No. 2,
No. 519,400, Japanese Patent Publication No. 5'2-106
, No. 883, etc., and the production methods of these prior art are as follows.

4-Ethyl-2,3-diolane-1-piperatinocarbonyl chloride obtained by reacting 1-ethyl-2,3-diocunepiperatine with phosgene or trichloromethylchlorocarbonate is reacted with amvicillin or amoxilino. to produce the desired product or 4-ethylzy-2,
6-T)(
-)-α-(4-ethyl-2,3-diokune, 1-
Piperatinonyl)-benylchrysine was produced, completely separated, and reacted with ethyl chlorocarbonate to produce an acid anhydride, which was then subjected to an acylation reaction with 6-acynope ξyllanthane to produce the desired product.

The manufacturing method of the present invention will be specifically explained as follows.

The present invention utilizes the following structural formula (II) according to known methods.
(-)-α-(4-ethyl-2,3-diokune-1
-piperatinocarbonyl)-benyl (also 1d) 1 idroxypenyl) chrysine, which has the following structural formula (1), N-
The acid anhydride of the following structural formula (IV) is produced by reacting with hydroxylamide.

In this case, as a catalyst, all dicyclohexylbodiamide of the following structural formula (V) is used, and the reaction is easily carried out with 6-amine benicyllanic acid of the following structural formula (vI), which gives a good yield. 0 to produce the target product of the above structural formula (■) at a rate of 0. Here, N-no-idroxylic acid amide is N-no-idroxycinnamide, N-no-idroxiptalamide, or N-hydrocyclutamide. It is.

no -z (seal)
0N=C=NOCv) In the formula, R and M are as described above, and acid anhydrides or acid chlorides are generally produced in order to carry out the acyl reaction in the process of producing penicillin or separosboa heptacid derivatives. Although it is well known that this is a conventional method, the use of acid chlorides complicates the entire process for producing acid anhydrides, which is a factor in reducing the yield of the desired product.

In order to compensate for these drawbacks, the present invention uses a catalyst that easily absorbs the product produced during the production of acid anhydride and converts it into dicyclohexylcrea of the following structural formula (to). By first producing the acid anhydride and reacting it with 6-aminopenicilane, the desired product could be produced in high yield.

As the solvent used in the process of producing acid anhydride in the present invention, tetrahydrofuran, methylene chloride, acetone, acetonitrile, etc. are effective, and among them, the use of tetrahydrofuran is the most effective, and the reaction The highest yield was obtained at a temperature of 2o-25°C.

The solvent used in the acyl('C reaction is an aqueous solution of detrohydrofuran, or an aqueous solution of acetic acid or ethyl, which gives the best results. Usually, the reaction is carried out at 20-25°C, and after removing the solvent under reduced pressure, the reaction is performed. Add ethyl acetate and adjust the pF of the solution (
21.5, the ethyl acetate layer was separated, washed with water, dried with sodium sulfate, concentrated under reduced pressure, crystals were extracted, and the crystals were recrystallized with ether to obtain a high yield of 87. Pf by getting the objective of the rate? L.

Example 1 Preparation of 6-CD(-)-α-(4-ethyl-2,3-diocun-l-biberatinocarbonylamino)-benylacetamide]penicillanic acid D -(-)-α-(4-
Ethyl-2,3-diocne-1-biperatinolpenylchloride 1.91! - After adding 20ml of tetrahydrofuran to N-hydroccincinamide, 67? Adding 1.2 t of dicyclohexyl body imite to the solution gives a clear solution. After stirring for 2 hours at room temperature, a large amount of precipitate is formed. Precipitate/filter 1" and maintain the furnace solution at 5°C.Meanwhile, 1.161P'ii of aminopenicillanic acid and 15ml of water 1K
After making the mixture cloudy, the temperature was adjusted to 3'o, and triethylamine 1++tl'i was added to it to dissolve it clearly. When the acid pyrohydride solution prepared by the above-mentioned method is added to this solution all at once, the temperature rises to 10° C., and the reaction solution turns red, and after an hour, turns pale yellow.

After reacting at room temperature for 2.5 hours, the solvent tetrahydrofuran was removed under reduced pressure. 20 ml of ethyl acetate was added to the residue, and the pM was adjusted to 2t, s with diluted hydrochloric acid at 5°C, and the ethyl acetate layer was separated. After separating and washing twice with water, the entire chin of Glauber's salt was dried and filtered, and the solvent was removed under reduced pressure.

30m1 of ether in the leftovers! ``If f is added and crystallized, the target product 2246? can be obtained.''The analysis results show that the specific rotation is +165.5° and the microbiological titer is 889.4.
It was μv thick.

Example 2 Preparation of sodium solution of 6-[D←)-α-(4-ethyl-2,3-diocn-l-piveratinocarponylamino)nirabenylacetamino]benin-tinic acid: 6-CD( -)-α-(4-ethyl-2,3-diocune-1-piperatinocarponylamino)-benylacetamide]henicyllanic acid 4.0. ! ii"! R Add 20mj of suspended water and stir in baking soda (0,627 to 5 N of water/
When completely dissolved, sterile filtered, and freeze-dried, the desired product of 3.81 was obtained.As a result of analysis, the specific optical rotation was +178.4°, and the microbiological titer was is 902.3μl-7m9, 88.7 by legal titration
It was '16.

Claims (1)

[Claims] 1. D-(-)-α-(4-ethyl-,2+3-tiocun-l-biperatinol)-benyl (also hydroxybenyl) chrysine of the following structural formula (II) and The acid anhydride of the following structural formula (IV) is produced by reacting the N-hydroxyamide of the following structural formula (1) with the dicyclohexyl carbody of the following structural formula (V) under an imide catalyst. After that, the following structure 2) was reacted with 6-amine penicyl lacissant to form 6- (■)-(-)-α of the following structure (4).
A method for producing -(4-ethyl-2,3-diocune-1-piperatinoluponylamino)-benyl (or)'loxypenyl)ace1doamide] henicilanic acid and its salts. H□-z' (1) In the formula, R is hydrogen or a hydroxyl group, and -M is hydrogen, sodium,
Inorganic salts such as potassium or calcium or carbonated water 1-4
Alkylamine method