JPS59134796A - Preparation of 6-aminopenicillanic acid ester using tetraalkylammonium salt of 6-aminopenicillanic acid - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as an intermediate for the preparation of an oral antibacterial agent, in high efficiency, by contacting 6- aminopenicillanic acid tetraalkylammonium salt with a specific compound in an inert solvent. CONSTITUTION:The objective compound of formula VI can be prepared by contacting the 6-aminopenicillanic acid tetraalkylammonium salt of formula I (R1- R4 are 1-4C alkyl) with the compound of formula X-Y (X is group of formula II-V; Y is easily eliminable group) preferably at a molar ratio of 1:1.5, in an inert solvent such as chloroform preferably at 60-70 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 6-amine nidylanic acid ester using a 6-amitubenicilanic acid tetraalkylammonium salt. These esters are valuable as intermediates in the production of several important oral antibacterial agents and are represented by the following formula (1). Furthermore, the present invention also relates to a method for producing an oral antibacterial agent obtained from the above intermediate. In detail, the light antibacterial agent is 6
- (D H-α-aminophenyl acetamide) An ester of hanischicic acid (generic name: ampicillin), which is a compound of formula (1), and also includes scientifically acceptable acid addition salts thereof.

The above formula (ID also includes diastereomers and racemic mixtures.

These ampicillin esters are efficiently absorbed orally and converted to ampicillin in vivo. Ampicillin itself is an important antibiotic with broad spectrum antibacterial properties, but it is not completely absorbed when administered orally.

In order to improve this poor absorption efficiency during oral administration, research has been conducted to develop various ampicillin prodrugs that are easily absorbed and hydrolyzed in vivo to release ampicillin into the bloodstream.

Special Publication No. 53-17.597 (published on June 9, 1978) is an ester of formula (11) (wherein R is ampicillin)
and its manufacturing method are disclosed.

German Patent No. 2,012,022 discloses esters of formula (It) in which R is the group -CH20CG(CH3)3 (common name: pivambicillin).

JP-A-48-5793 (published on January 24, 1972)
is an ester of formula (1) (wherein R is among these ampicillin esters, bacampicillin is particularly valuable because pacampicillin has good oral absorption and is easily hydrolyzed in vivo after administration; The blood concentration of ampicillin produced is higher than the blood concentration of ampicillin obtained when a considerable amount of ampicillin itself is administered.Moreover, bacanbicillin has almost no side effects when administered, and it does not cause gastrointestinal symptoms such as diarrhea. No disability.

One method for producing vacambicillin of formula (V) is
It is described in Japanese Patent No. 4597, and is shown by the following reaction formula (5).

(1) (47) C''30 In the above formula (2), A is an amino group or a functional group that can be converted into an amino group, and -COY is an amide bond (-CON) (-) together with an amine group. Regarding the synthesis of the compound of formula (■), according to the above-mentioned patent publication, it is possible to synthesize the compound of formula (■) by combining industrially available dinidine or other salts with α-chlorodiethyl represented by formula (Vl). A synthesis method is described that consists of two steps: a step of reacting with a carbonate, and a step of cleaving the side chain at the 6-position of the resulting nidyline ester by a method known in the literature. is a compound of formula (IV) or a similar 6-amitsinisilane ester, which is 6-amine hanisilanic acid (hereinafter referred to as 1SA).
It teaches that it can be synthesized by combining PA (also abbreviated as PA) or a salt thereof with an appropriate alkyl chloride.

However, for example, a compound of formula (fl) and 6-APA
It is quite possible that the 6-amino group of 6APA interferes with the esterification reaction with 6APA, and in that case, the yield of the product of formula (IV) ultimately decreases significantly. right. In such cases, it is common knowledge for those skilled in the art that it is advantageous to protect the amine group with a suitable protecting group prior to the esterification reaction, and then remove the protecting group after the reaction to free up the free amino groups. be.

As a result of intensive research, the present inventors found that 6-AP of general formula (1)
In the method for producing A ester, it was discovered that the esterification reaction occurs efficiently between the tetraalkylammonium salt of 6-APA and the alkylating agent despite the presence of free amine groups, and the present invention was achieved. completed.

The production method of the present invention is exemplified by the following reaction formula (B).

(Vj) (V) (1) In the above formula (■), R1, R2, R3, and R4 are the same or different, and each is an alkyl group having 1 to 4 carbon atoms. In formula (■), X is as previously defined for the ester of formula (I) and Y is a readily removable group. The ru groups which can be easily eliminated here include tohachloro, furomo, iodo, alkylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy, and the like. Preferred compounds are those in which Y is chloro or meromo.

Therefore, according to the present invention, general formula (1) (wherein X bar CHOCOC2H5, -CH20CG (OH3)
The 6-amine represented by the general formula (■) (where R1, R2, R3, R4 are the same or different and each has a carbon number 1 to 4 alkyl groups) and the general formula (1) X-Y (Vl) (wherein, X is as defined above, and Y is easily A method is provided, which comprises contacting a compound (which is a group capable of leaving) in a reaction-inert solvent.

In this manufacturing method, preferably R,, R2°R3,
Tetraalkylammonium salts are used in which all R4's are n-dutyl groups.

The reaction between a compound of formula (■) and a compound of formula (vill) is usually carried out by mixing these reagents in a reaction-inert organic solvent for about 20 minutes.
Contacting is carried out at a temperature in the range of from 60° to 70°C, preferably from 60° to 70°C. Suitable solvents that can be used for the reaction include acetonitrile, acetone,
Chloroform, dichloromethane, dimethylformamibi, dimethylsulfoxibi, dioxane, ethyl acetate, tetrahydrofuran, with acetonitrile and chloroform being preferred. Although it is appropriate to use at least 1 mole of compound (1) per mole of compound of formula (■), an excess of formula (VJII
), preferably in a 1.5 molar amount. The reaction time usually takes several hours, and after the reaction is complete,
The ester of formula (1) is isolated according to conventional methods. This ester was found to be relatively unstable if left standing, so when the ester was used in further reactions,
It is desirable to use it without isolation.

The production method of the present invention has a number of advantages when compared to the direct esterification reaction of 6-APA and an alkylating agent described in Japanese Patent Publication No. 53-17.597. For example, according to the process of the present invention, the participation of free amine groups in the esterification reaction is avoided and there is no need to protect the amino groups, so that the desired products are obtained in high yields.

The starting material, compound (■), can be prepared by contacting 6-APA or its salt with an appropriate quaternary ammonium salt in a reaction inert solvent. Typical salts of 6-APA include alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium, magnesium, and barium, and amine salts such as triethylamine. Particularly suitable The preferred metal salt is the potassium salt. Suitable quaternary ammonium salts include tetraalkylammonium hydroxide, tetraalkylammonium hydrogen sulfate and tetraalkylammonium halides. Preferably, tetraalkylammonium hydroxide and sulfuric acid are used. Tetraalkylammonium hydrogen is used.

The reaction between the quaternary ammonium salt and (5APA) is carried out in a reaction-inert organic solvent at 0° to 40 tl', preferably at 15°.
It is carried out at 25C to 25C. Suitable inert solvents include chloroform, dichloromethane, 1,2-dichloroethane,
These are dimethyl sulfoxide 8, ethyl acetate, and trichloroethylene. Quaternary ammonium salts and 6-APA are usually
Although the reagents are contacted in a substantially equimolar ratio, either one of the reagents may be used in excess. The product (■) is isolated according to the conventional method of extraction with a solvent and evaporation of the solvent, but can be used in the next step without purification.

For the production of the compound of formula (■), the above method is preferable from the viewpoint of yield, but according to another method, 6-AP
Compound (■) can also be obtained by contacting the alkali metal salt of A with a tetraalkyl halide in the presence of compound (vlI). In this method, the tetraalkylammonium salt (■) produced by compound (1) present in the reaction system is directly alkylated, so that the compound of formula (1) is obtained as a reaction product. In this way, compound (1) can be synthesized in one step from the alkali metal salt of 6-APA. The reaction conditions used in this method are the same as described above for the reaction of equation S). The ammonium quaternary salt used is preferably tetraalkylammonium bromide 8. It is not necessarily necessary to use an amount of 1 molar tetraalkyl halide per mole of 6-APA, since the tetraalkyl ammonium halide is regenerated while the reaction of equation (B) takes place, but at least 0 It is desirable to use .25 molar equivalents (preferably 0.5 molar equivalents) of the tetraalkyl-ammonium halide.

The present invention further provides a method for producing a 6-amino nidylanic acid ester represented by the general formula (I), which comprises converting 6-amitubenicilanic acid or a salt thereof into the general formula (■) (wherein itl, R2, R3 , R4 are the same or different,
each of which is an alkyl group having 1 to 4 carbon atoms), and then combined with the ammonium salt with ff formula (Vl,) X-Y (Gill)( A method is provided, characterized in that the compound of the formula (wherein X has the above definition and Y is a group that can be easily eliminated) is contacted in a reaction-inert solvent.

A preferred embodiment of this production method of the present invention is to simply add the compound (@) directly to the reaction mixture after preparing the tetraalkylammonium salt (■) and bring both reagents into contact.

Esters of formula (I) are derived from known antimicrobial agents of formula (...) by methods known in the literature. However, compound (I) (in the formula, when R is an indyl group -0H2Q) cannot be directly converted into these known light-tasting antibacterial agents;
, 623,499 (where R1
is a phenyl or 6-chenyl group, and R2 is hydrogen or a benzyl group), and is used as an intermediate in the synthesis of these compounds. Compound (X) (wherein R2 is a benzyl group) is subjected to catalytic hydrogenation (e.g. Pa/C or P d/G a
on GO3) to give compound (X), where R2 is hydrogen. This compound or its pharmacologically acceptable salts are effective as antibacterial agents, particularly against bacteria that produce β-lactamase. These antibacterial agents are hydrolyzed in vivo into R-nigilins (eg carbenicillin) and β-lactamase inhibitors (nidylanic acid 161-dioxaibi).

The present invention also provides a method for producing an antibacterial agent (2). This production method is a method for producing a compound represented by the general formula (11) and its pharmacologically acceptable acid addition salt, and includes the step (→: 6-amine is a method for producing a compound represented by the general formula (11) and a pharmacologically acceptable acid addition salt thereof. ) (In the formula, R1,' R2+ R3+ R, s are the same -
or different, each of which is an alkyl group having 1 to 4 carbon atoms) into a tetraalkylammonium salt of nidylanic acid; Step (b): The tetraalkylammonium salt obtained in step () and a compound of the general formula R-Y (XI) (wherein R has the above definition and Y is a group that can be easily eliminated) in a reaction inert solvent. (2) producing a 6-amine 4-nidylanic acid ester represented by the formula (wherein R has the above definition); and step (C): converting the ester obtained in step (b) to D□-2 - It is characterized by comprising the steps of contacting a reactively active derivative of deminor 2-phenylacetic acid in a reaction inert solvent, and optionally converting the produced compound into a pharmacologically acceptable acid addition salt. It's a method.

Pharmaceutically acceptable acid addition salts of ampicillin ester represented by formula (It) include hydrochloride, sulfate, phosphate, maleate, tartrate, citrate, fumarate, succinate. , methanesulfonate, p-)luenesulfonate, and the like. These acid addition salts can be prepared using standard methods for compounds such as formula (If).
is prepared by mixing a solution of the compound in a suitable solvent with a solution containing a stoichiometric equivalent of the appropriate acid.

The salt formed can be removed or alternatively recovered by evaporation of the solvent or, if still in aqueous solution, by lyophilization.

Steps (a) and (b) are carried out in the manner described above, while step (C) is carried out in the manner detailed below. A typical acylation reaction involves combining a compound of formula (D) and about 0.5 to about 6 molar equivalents of a reactive derivative of D-2-amino-2-phenylacetic acid in an inert solvent at about -40° or about 3
0t? make contact with it. The reaction inert solvents used in this acylation reaction include chlorinated hydrocarbons, (e.g. chloroform, dichloromethane) diethyl ether, tetrahydrol
Ethers such as lofuran, low molecular weight esters such as ethyl acetate and butyl acetate, low molecular weight aliphatic ketones such as acetone and methyl ethyl ketone, tertiary amides such as N,N dimethylformamide and N-methylpyrrolidone, acetonitrile and It is a mixture of these.

A commonly used reactive derivative of D-2-amino-2-phenylacetic acid is an acid halide. In this case, it is preferred, although not essential, that the acylation reaction be carried out in the presence of an acid binder. Suitable acid binders include trialkylamines, (eg triethylamine) N-methylmorpholine,
These include tertiary amines such as N,N-dimethylaniline and pyridine. Other reactive derivatives of acids that can be used include active esters or mixed anhydrides, which are prepared by methods well known to those skilled in the art.

Prior to the acylation reaction, the amine group of the reactive derivative of the nucleic acid is usually protected by a suitable protecting group.

Suitable protecting groups include the benzyloxycarbonyl group, the 4-nitrobenzyloxycarbonyl group, and the acetoacetic acid alkyl ester, which is well known to those skilled in the art of R-nidyline synthesis by condensation with β-dicary sonyl compounds. It is an enamine that is formed. After the acylation reaction is completed, the amine protecting group is removed according to a conventional method. When acid halides 9, such as acid chlorides, are used as reactive derivatives, a particularly convenient method for protecting the amino group is salt formation, for example hydrochloride formation. If the amine group is protected by the formation of a pharmacologically acceptable acid addition salt, it can be used directly as a therapeutic antibacterial agent without the need to remove the protecting group.

After completion of the acylation reaction, a compound of formula (ID) is
The amine protecting group is removed, and the product is isolated and purified using conventional methods.

If desired, it can also be converted into various pharmacologically acceptable acid addition salts as described above. In the method for producing the antibacterial agent of formula (1) of the present invention, each step (a), (
It is particularly preferred to carry out b) and (C) continuously.

The present invention will be explained in more detail below with reference to Examples, but the present invention is not limited to these Examples. In the example, the nuclear magnetic resonance (NM'R) spectrum was measured at 6QMHz in a deuterated chloroform solution, and the absorption peak was 1 million minutes down the magnetic field side from the internal standard tetramethylsilane. 1 unit (ppm
) (・ru. The following abbreviations are used to represent the shape of the peak.

S-singlet, d-doublet, triplet, q-quartet.

m - multiplet, br - broad line.

River 6-amine is dilanic acid tejipuni ammonium hydrogen sulfate tetrabutylammonium 26. OF! (furomimol) was dissolved in 150 ml of water, and a 2N aqueous sodium hydroxide solution was added thereto to adjust the pH to Z5. Add 208 ml of dichloroethane and 6-APA 16 to this solution.
．． Add 2 g (75 mmol) and then add 2N aqueous sodium hydroxide solution to bring the pH of the solution to 8.2. Add 48 g of anhydrous sodium sulfate and stir for 10 minutes. When the dichloromethane layer was separated and the solvent was distilled off under reduced pressure, 40
．． The target compound of OI is obtained (yield: 96%). The infrared absorption (IFI) spectrum of the compound (measured with a liquid film) shows an absorption derived from the β-lactam ring at 1760 (1771'). The NMR spectral range is 0.80 to 2.1.
0 (m, 34H), 2.50 (br s, 2H,
amino group), 6.10-3.70 (m, 8H), 4.
22 (s, IH).

4.43 (d, IH), and 5.64 (d, IH) ppm
shows absorption.

A. 40 g of tetraphthylammonium 6-amitsuinisilane obtained in the reference example (72 mm!J model) is passed through alumina and dried, and chloroform is added to make a solution of C2C25O. 8.6.9 (57 mmol) of α-chlorodiethyl carbonate is added to about half of this chloroform solution, refluxed for 1.5 hours, and then cooled. The solvent is distilled off under reduced pressure at a temperature below 40C, 5Qm/n-butyl acetate is added to the resulting oily substance, and the remaining chloroform is distilled off again at a temperature below 40C. Add 1504 butyl acetate and 100 ml of water to this concentrated solution, and stir at room temperature for 5 minutes. A 2% aqueous sodium hydroxide solution is added to this to adjust the pH of the solution to 6.5. After standing for 60 minutes at room temperature, the organic and aqueous phases are separated. The organic phase was dissolved in water (50
Wash with mX2), add anhydrous sodium sulfate, and stir for 10 minutes. After filtration and distillation of the solvent at a temperature below 40C, 10.5 g of the target compound is obtained as an oily substance.

The infrared absorption (IR) spectrum of the compound (liquid film) exhibits an absorption derived from the β-lactam ring at 1760CfrL-1.

NMR Su-4! Kutle is 0.70-2.50 (m,
12H).

2.10 (br, s, 2H), 4.26 (q
-2H, J=7Hz).

4.37 (s, IH), 4.67 (d, IH
, J=4Hz), 5.57(d + i H−J
= 4 Hz) and 6.87 (q, IH, J = 7 Hz)p
Shows absorption at pm.

B. For the remaining half of the chloroform solution of 6-amino labeled tetracybutylammonium dilanate used in a above, 8.6.5'
(57 mmol) and reflux for 1.5 hours. Repeat the separation procedure detailed in a. After drying with anhydrous sodium sulfate, 140 mL of a butyl acetate solution of the target compound is obtained.
1 is obtained.

Example 2 Benzyl 6-amine penicillate hydrochloride tetrabutylammonium hydrogen sulfate is, sg 62r
ne water, and neutralized by adding 11.4 ml of 4N aqueous sodium hydroxide solution. Add 185ml of chloroform and 10I of 6-APA to this aqueous solution! Then, while stirring, 11.4 ml of a 4N aqueous sodium hydroxide solution was added to adjust the pH of the solution to 95. Separate the organic phase and
After drying with anhydrous sodium sulfate, about 120 ml under reduced pressure
Concentrate on VC. 3. benzyl chloride to this concentrate.
Add Qrnl; and heat to reflux for about 60 minutes.

The reaction mixture is cooled to room temperature and water (100 mA') is added. The organic phase is separated and concentrated under reduced pressure to give a yellow oil. This oil is dissolved in 13 Qm/ethyl acetate and washed three times with water. Add 100 ml of water and adjust the pH to 1.5 with 6N diluted hydrochloric acid. Separate the aqueous phase and wash the organic phase with 5r:Jml of water. The combined aqueous phases are extracted with 100ml of ethyl acetate. The organic phases are combined and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure and concentration to a volume of approximately 115 times the original solution yields a white gel-like material. Addition of 10M ethyl acetate to the gel-like material induces crystallization. The crystals are filtered and dried to obtain 8.54 g of the hydrochloride of the target compound (yield: 5 filtration, 9%).

NMR spectrometer (deuterated DMSO) is 1.40 (s
+ RoH), 1.62 (s, 3H), 4.59 (s,
IH).

5.10 (d, IH), 5.28 (79, 2H), 5.
59 (d.

IH) and 7.47 (s, 5H) ppm.

A, 140d of a butyl acetate solution of 1'-ethoxycarbonyloxyethyl 6-amino R-nisilate is added to -25C
Cool to N,N-diethylaniline in the cooled solution3.
69 and D←) Phenylcrisyl chloride hydrochloride 6.2
g and the reaction mixture is allowed to react for 30 minutes at a temperature of about -22C to -20iC. Add 2.5g of sodium bicarbonate and 150mA to the reaction mixture! Add Ω saturated salt solution, 1
Stir for 0 minutes. The pH of the reaction mixture was adjusted to 1 with 6N hydrochloric acid solution.
．． 5 and let stand at room temperature for 60 minutes. Separate the organic layer and extract the aqueous layer with butyl acetate (100ml). The extract and organic phase are combined, washed with 150 ml of 15% brine, and then extracted six times with water (500 ml). 150m/! for the extracted aqueous solution! After adding butyl acetate, the mixture is saturated with IJ chloride under stirring and left to stand at room temperature. The butyl acetate phase was separated, and this was coated with celite (CeA'ite).
) Add 5 g and get 1 chance. When the solvent is distilled off under reduced pressure at a temperature below 40C and the r liquid is concentrated, the hydrochloride of the title compound is precipitated as white crystals. When this crystalline filtration is dried, it becomes 1
A 2.4N hydrochloride salt (melting point 171-176C) is obtained.

8, 10.2 g (40 mmol) of 6APA potassium and 6.5 g (20 mmol) of tetrazotylammonium hydrobromide were suspended in 5Qme acetonitrile, and 60 t
, heat to '. To this suspension, 13 ml of α-chlorodiethyl carbonate is gradually added dropwise over 10 minutes. After the dropwise addition was completed, the reaction temperature was maintained at 65C, and then the temperature was increased to 8C.
The temperature was raised to 0 tl' and kept at the same temperature for 60 minutes. After the reaction,
The solvent is distilled off under reduced pressure below 40C. Add 5 ethyl acetate to the residue
Add ON and 50ynl of water and stir for 10 minutes. A 2% aqueous sodium hydroxide solution is added to this solution to adjust the pH of the solution to 6.5. After standing still, the organic phase and the aqueous phase are separated.

Anhydrous sodium sulfate was added to the organic phase, and after stirring for 10 minutes,
I will treat you p. The ethyl acetate solution obtained in this way was
Cool to around C and add N,N-dimethylformamide6.
Add 7d and D (-)-phenylglycyl chloride hydrochloride 8.21 and stir for 30 minutes. 6.5 g of sodium hydrogen carbonate and 150 g of 10% saline were added to the reaction mixture, and the pH and H were adjusted to 1.5 with 6N aqueous hydrochloric acid. The solution is allowed to stand at room temperature for 60 minutes, and the ethyl acetate layer is separated. Extract the aqueous phase with ethyl acetate (251111), combine the extract and the separated ethyl acetate phase, and add 1QQx
/ Extract 6 times with water. Activated carbon (Dh, r
co KBB) 1y and super se/L/ (5uper
ce1. l) Add 1 g and stir at 5C for 15 minutes. After filtration, 60 g of sodium chloride is added to the aqueous solution, dissolved, and extracted twice with 100 ml of methyl acetate. The butyl acetate solution was concentrated under reduced pressure to 100 ml, and the precipitated crystals were collected and dried under vacuum overnight at a temperature below 40C to give the title compound hydrochloride 15.2. ! i' (yield, 75%)
is obtained as white crystals.

Patent applicant Taito Pfizer Co., Ltd. (4 other people) 1-48-40 Nanyo-dori, Minami-ku, Nagoya No. 2

Claims (1)

[Scope of Claims] 1. A method for producing a 6-aminobenicillanic acid ester represented by the general formula (selected from the general formula), wherein R1, R2, R3, and R4 are the same or different, and each 6-amino represented by the formula (1 to 4 alkyl group) is a tetraalkylammonium nidilanic acid salt and the general formula ) in a reaction inert solvent. 2. The manufacturing method according to claim 1, wherein R, , R2, R3, and R4 are all n-butyl and halogen. The manufacturing method according to claim 1, wherein halogen is used. 4. A method for producing a 6-amitsuinisilanic acid ester represented by the general formula (selected from the general formula), comprising: or different, each being an alkyl group having 1 to 4 carbon atoms), and then combined with the ammonium salt and the general formula A method characterized in that R1, R21, R3, R4 are all normal methyl, 1 cogen. 6. f?1. R2, R3, and R4 are all human rumalbutyl groups, X is a -CH2O group, and Y is a halogen. The manufacturing method according to claim 4. 7. A method for manufacturing a compound of the general formula and a pharmacologically acceptable acid addition salt thereof, in which step (a): 6-amine is nidylanic acid or a salt thereof. is the general formula (in the formula,
Step (b): Step (R3) The tetraalkylammonium salt obtained in step 1 is brought into contact with a compound of the general formula RY (wherein R has the above definition and Y is a group that can be easily eliminated) in a reaction inert solvent. whereby the 6-amine of the general formula (wherein R has the above definition) forms a nidylanic acid ester; and step (C): the ester obtained in step (b). (-) -2-
It is characterized by comprising the steps of contacting with a reactive derivative of amino-2-phenylacetic acid in a reaction inert solvent, and optionally converting the produced compound into a pharmacologically acceptable acid addition salt. how to. 3. The manufacturing method according to claim 7, wherein R1, R2, R3, and R4 are all n-butyl halogens.