JPH0730082B2 - New production method of bacampicillin - Google Patents

Description

Detailed Description of the Invention

[0001]

This invention is of formula I

[Chemical 5] Of 6- (D-(-)-α-amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester.

[0002]

PRIOR ART The substance I is an ampicillin ester, which is extremely important from the viewpoint of therapy. The reason is that it is well absorbed when given orally and gives much higher blood ampicillin levels than ampicillin itself.

This ester has been isolated in the form of the hydrochloride salt and is known as bacampyricin hydrochloride.

Based on the methods known to date (Belgian Patent No. 7772723), bacampyricin hydrochloride can be synthesized by the following two methods. A) Reaction of potassium benzylpenicillin with α-chlorodiethyl carbonate in 70% dioxane aqueous solution in organic solvent or in the presence of sodium bicarbonate.

The resulting 1-ethoxycarbonyloxyethyl ester of benzylpenicillin was subjected to a phenylacetic acid chain removal reaction with iminochloride-iminoether to give 6-aminopenicillanic acid 1-ethoxycarbonyloxyethyl ester and the 6- The aminopenicillanic acid ester is isolated as the hydrochloride salt.

The latter intermediate is then condensed with D-(-)-α-phenylglycine to give a compound of formula I.

B) 6- (D-(-)-α-azido-α-with α-chlorodiethyl carbonate in polar solvents
Phenylacetamide) Penicillanic acid esterification reaction.

Then, 6- (D-(-)-α-azide-α-
Catalytic hydrogenation of (phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester gives compounds of formula I.

[0009]

As will be appreciated, these methods are rather complicated. The reason is that they involve the use of numerous raw materials and long processing times.

The primary object of the present invention is to provide a process for the production of related active substances which is easier to carry out and is industrially more advantageous. A more specific object of the present invention is to provide a method which considerably simplifies said method for producing bacampicillin using ampicillin as a starting material and produces a highly pure desired product. That is.

[0011]

Means for Solving the Problems As a result of earnest studies by the present inventors, the general formula

[Chemical 6] In producing 6- (D-(-)-α-amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester having: (a) ampicillin in an aprotic polar solvent
The is down good Mashiku ampicillin alkaline salt form wherein R ¹
COCHR ² COR ³ (In the formula, R ¹ represents an alkyl group having ¹ to 4 carbon atoms, a substituted or unsubstituted aryl group or an aralkyl group, R ² represents hydrogen, 1 to 4 carbon atoms. Represents an alkyl group, a substituted or unsubstituted aryl group or an aralkyl group, and R ³ represents an alkyl group, a substituted or unsubstituted aryl group or an aralkyl group containing 1 to 4 carbon atoms, 1 to 4 (Representing an alkoxy group, an aryloxy group or an amine group containing a carbon atom of

[Chemical 7] Forming the corresponding enamine of the formula: wherein R ¹ , R ² and R ³ have the meanings given above and X represents an alkali metal, alkaline earth metal or organic base, and (b) the reaction mixture Expression

[Chemical 8] Obtained by adding a compound of the formula (Z is C 1 ).
It was reacted in the presence of an intermediate catalytic by formula

[Chemical 9] Forming the corresponding ester having R ¹ , R ² and R ³ having the meanings given above, and (c) mildly hydrolyzing in an acidic medium to form a compound of formula (I). I have found a method characterized by that.

Α-Halodiethyl carbonate is used with great advantage as a reaction component in these esterification processes. The use of α-halodiethyl carbonate leads to a particularly high yield and high purity of the final product such as bacampicillin.

The esterification reaction between compounds II and V is carried out in the presence of an esterification catalyst.

The addition of catalyst at this stage considerably shortens the reaction time and gives a higher yield of product with greater purity.

Quaternary ammonium salts such as tetrabutylammonium bromide, alkali metal bromides or iodides and cyclic ethers can be used as catalysts for this purpose.

This catalyst is suitably used in an amount of 0.005 to 0.10 mol per mol of compound V.

In the present invention, examples of the groups R ¹ , R ² and R ³ are as follows.

Alkyl: CH₃, C₂H_Five, N-C₃H₇,
i-C₃H₇, N-C_FourH₉  Alkoxy (R³Only): OCH₃, OC₂H_Five, OCH
₂CH₂CH₃, OCH (CH₃)₂, O (CH₂)₃CH₃

[Chemical 10]

The group X is a group well known in the art, such as alkali metal (Na, K), alkaline earth metal (Ca, M).
g), an organic base (organic bases known in penicillin synthesis such as tertiary ammonium groups, triethylamine, ethylpiperidine and methylmorpholine).

In a preferred embodiment of the invention, the group protecting the amino group of ampicillin is a 1-methoxy-carbonyl-propen-2-yl group or a 1-ethoxycarbonyl-propen-2-yl group, for which Preferred intermediates are N- (1-methoxy-carbonyl-propen-2-yl) penicillanic acid of formula II (R ¹ = methyl, R ² = methyl, R ³ = methoxy or ethoxy, and X = Na or K), respectively. And N- (1-ethoxy-
Carbonyl-propen-2-yl) penicillanic acid sodium or potassium salt.

Intermediate IV is stable in neutral or alkaline media, while amino acid protecting groups can be removed easily, rapidly and selectively in acid media.

The group protecting the amino group of ampicillin can be selected, for example, from the groups described in British Patent 991,586 and other groups known in the art.

More specifically, the method according to the preferred embodiment of the present invention comprises the following steps. Of the corresponding enamine (II) by conversion of ampicillin trihydrate to its salt, eg the potassium salt, in a polar solvent, eg N, N-dimethylformamide, and subsequent reaction with a β-diketone, eg methylacetoacetate. Formation of an esterification catalyst, preferably tetrabutylammonium bromide, formation of 1-ethoxycarbonyloxyethyl ester (IV) of ampicillin in the enamine form by addition of α-halodiethyl carbonate to the reaction mixture, an organic solvent such as n-butyl. Hydrolysis of the protecting groups with dilute HCl in acetate / water, saturation in the aqueous phase with, for example, sodium chloride and recovery of bacampicillin hydrochloride by extraction with a suitable solvent such as n-butylacetate, product in high purity. In n-butyl acetate for crystallization Isolation by concentration of the solution at low pressure and subsequent filtration of the product.

The main advantages of the method of the present invention are:
According to this method, it is practically possible to produce bacampicillin hydrochloride in one operation and with high purity.

In fact, the impurities present in the products obtained by the process according to the invention are negligible when compared with the processes known in the art.

Another important advantage is that ampicillin trihydrate, which is readily available in pure form and at low cost, is used as the starting material.

Intermediate (II) can be obtained, for example, from British Patent No. 991,5.
By reacting ampicillin trihydrate with methyl or ethyl acetoacetate 10 to 50% above stoichiometric ratio in the presence of an organic base or an alkali metal carbonate such as potassium carbonate as described in U.S. Pat. It can be produced in a yield of 95% or more.

Intermediate (II) can be isolated and added to the esterification reaction in solid form. Or an intermediate
Without isolating (II), the esterification reaction can be carried out in the same solvent in which the enamine (II) forming reaction was carried out.

The formation reaction of ampicillin enamine (II) is carried out in a neutral polar solvent such as N, N-dimethylacetamide, N, N.
Carried out in dimethylformamide, dimethoxyethane, dimethylsulfoxide, tetrahydrofuran or dioxane.

To complete the reaction, it is sufficient to leave the components of the mixture in contact at temperatures between 0 ° C. and 60 ° C., preferably between 20 ° C. and 30 ° C. for 2-8 hours, preferably 3 hours. Is.

Compound II can be prepared by acylation of 6-aminopenicillanic acid with the corresponding enamine derivative of phenylglycine to form Compound II, which is then directly esterified without isolation to bacampicillin. Can be converted to.

The esterification reaction after adding α-halodiethyl carbonate to the above mixture is carried out at a temperature of 15 ° C. to 80 ° C., preferably 45 ° C. to 55 ° C. for 1 hour to 24 hours, preferably 5 hours to 10 hours. To be done.

The esterification reaction is suitably carried out in an organic solvent such as methylene chloride or acetone, dimethylacetamide, dimethylformamide, and dimethylsulfoxide or a mixture of organic solvents. It is also possible to use a water-containing organic solvent. The use of esterification catalysts is desirable when acetone is used as the solvent for the esterification reaction.

The easiest and most suitable conditions for industrial purposes are to dilute the esterified enamine (IV) of the reaction mixture with water and then to prepare a suitable water-immiscible solvent such as n-.
Isolate by extraction with butyl acetate.

The acetate phase is stirred with dilute HCl (0.2-0.3N) solution until the protecting groups are completely hydrolyzed. This is 2 to 8 hours at normal temperature, preferably 4
Needs ~ 5 hours.

Compound (I) is separated from the aqueous phase in the form of the hydrochloride salt by the addition of sodium chloride. This is extracted with a suitable solvent such as n-butyl acetate.

Crystallization of the product of formula (I) is carried out by concentrating this organic phase at low pressure at a temperature of 40 ° C. until a small amount remains.

The crystalline product is isolated by filtration, washing and vacuum drying.

Example 1 36.4 g (0.075 M) of potassium N- (1-methoxycarbonyl-propen-2-yl) -6- (D (-)
1-7.8 g of -amino-α-phenylacetamido) penicylate in 150 ml of N, N-dimethylformamide.
Add to the solution of (0.116M) α-chlorodiethyl carbonate and 3g (0.01M) tetrabutylammonium bromide. The temperature is raised to 45 ° C under stirring and kept at 45 ° C to 50 ° C for 5 hours.

Upon completion of heating, the reaction mixture is poured into a mixture containing 300 ml of 14% aqueous sodium chloride solution and 600 ml of n-butyl acetate. The mixture is stirred for 10 minutes, then the organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. The recombined organic phases are washed twice with 75 ml of 14% aqueous sodium chloride solution and then concentrated at low pressure until an oil is obtained.

This oil is mixed with 200 ml of tetrahydrofuran and 100 ml of water. The resulting solution (pH 4.8) is brought to pH 1.5 by adding a total of 12 ml of 6N HCl in 1 hour with stirring.

After leaving this solution at room temperature for another hour,
Tetrahydrofuran was removed at low pressure at 40 ° C, 1
50 ml of n-butyl acetate was added to this residual aqueous phase (15
0 ml) and then 15 g of sodium chloride.

The organic phase is separated off and 100 ml of the aqueous phase
Of n-butyl acetate.

The recombined organic phases are concentrated under vacuum at 40 ° C. to a volume of 120 ml.

The product is crystallized at 5 ° C. for 15 hours.

It is then filtered and washed with n-butyl acetate (50 ml) and ethyl acetate (50 ml).

It is vacuum dried at 40 ° C.

25.2 g (66.9%) of 6- (D-
(−)-Α-Amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester hydrochloride (mp. 160-2 ° C.) is obtained. The analytical measurement results are as follows.

Titer 97.82% Optical rotation + 166.3 ° (c = 1, EtOH 95 °) pH 4.05 (2% aqueous solution) Water content 0.82% Remaining solvent ethyl acetate 0.45%, n -Butylacetate 0.98% IR and NMR spectra conforming to standard 0.06% residual penicillin.

Example 2 16.2 ml (0.15 m) of methyl acetoacetate and 30.2 g (0.075M) of ampicillin trihydrate were finely powdered anhydrous in 100 ml of N, N-dimethylformamide. 12.54 g of potassium carbonate (0.0907
M) to the suspension.

This is held for 3 hours at 22 ° C. to 23 ° C. with stirring. After that, a considerable fluidization of the whole can be observed.

17.8 g (0.117 M) of α-chlorodiethyl carbonate, 3 g (0.01 M) of tetrabutylammonium bromide and 50 ml of N, N-dimethylformamide are added here in this order.

The mixture is heated at 45 ° C. to 50 ° C. for 5 hours with stirring and then left at + 5 ° C. for 15 hours.

The reaction product was treated with 600 ml of water and 200 ml.
Of n-butyl acetate and stirred until a complete solution is obtained, the aqueous phase is collected and extracted with another 50 ml of n-butyl acetate.

The recombined organic phases are washed twice with 50 ml of water each time. 75 ml 1N HCl and 185 ml water are added to this organic phase and stirred. It is left stirring at 22 ° C-23 ° C for 4 hours.

The aqueous phase is collected and the organic phase is extracted with 50 ml of water. The recombined aqueous phases are brought to pH 4 with a 10% aqueous solution of Na ₂ CO ₃ , then bleaching charcoal is added to it and it is filtered.

150 ml of n-butyl acetate and 4
0 g sodium chloride is added to this aqueous filtrate.

The organic phase is separated off and 100 ml of the aqueous phase
Of n-butyl acetate.

The phases in the recombined butyl acetate are brought to low pressure under pressure.
Concentrate to about 150 ml volume at 0 ° C.

The product is left to crystallize for 15 hours at + 5 ° C.

This was filtered and n-butyl acetate (5
Wash with 0 ml) and ethyl acetate (50 ml).

This was allowed to stand at 25 ° C. for 24 hours in the presence of water for 1 hour.
Dry under vacuum of 0 mm Hg.

Yield of 6- (D-(-)-α-amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester hydrochloride 20.8 g (55
%), Mp. 159-161. It has characteristics that match the standard sample.

Example 3 The esterification of ampicillin Dane salt (ampicillin protected at the amino group with a 1-methoxycarbonyl-propen-2-yl group) with ethyl acetoacetate was carried out by the method of Example 2. The results are as follows. Yield of white crystalline product 16.1 g, mp. 14
4-148 ° C. IR / TLC conforms to standard sample. KF
0.35%, pH 3.55 (2% aqueous solution). Purity 95.2
%. Total residual solvent 3.5%.

Alternatively, chlorodiethyl carbonate was added in two stages. Immediately add 9g in the first stage,
After 2 hours in the second stage another 9 g was added. Heated at 45 ° C. for 3 hours. The results were as follows. Yield 13.7 g of a brown crystalline product. mp. 143-146 ° C. IR
/ TLC conforms to standard sample. KF. 0.2%, pH 3.4
3 (2% aqueous solution). Purity 94.8%. Residual solvent 2.6%.

Reference Example A) Preparation of α-iododiethyl carbonate A solution of α-chlorodiethyl carbonate (26.6 g, 0.175 mol) in acetone (200 ml) was added with sodium iodide (30.0 g, 0.200 mol). ) And refluxed for 35 minutes. Evaporate the acetone under vacuum,
Then, diethyl ether (300 ml) and water (300 ml) were added to the residue. The mixture was shaken and the organic phase was washed successively with water, sodium metabisulfite (saturated solution), water (3 times) and saturated sodium chloride solution (200 ml each). The solution was dried over magnesium sulfate and the solvent was evaporated under vacuum.

B) Preparation of Ampicillin Dane Salt Methyl acetoacetate (8.1 g, 0.075 mol) and ampicillin trihydrate (15.1 g, 0.0375 mol) in N, N-dimethylformamide (50 ml). Was added to a suspension of finely ground anhydrous potassium carbonate in (6.25 g, 0.045 mol). The mixture was stirred at room temperature for 4 hours and then at + 4 ° C. overnight.

C) Preparation of Bacampicillin Tetrabutylammonium bromide (0.59 g, 0.00175 mol) was added to the mixture obtained in B), then the freshly prepared solution in A) was added to N, N-dimethylformamide ( What was dissolved in 40 ml) was added dropwise.

After reacting for 2.5 hours, the reaction mixture was mixed with water (300 ml) and n-butyl acetate (100 ml).
Was poured into the mixture and shaken until a complete solution was obtained. The aqueous phase was extracted with a further 25 ml of n-butyl acetate. The combined organic phases were washed twice with water (25 ml each time). The iodide liberated during the reaction is HN
Detection was performed by adding AgNO _{3 in} O _{3 and} then NH ₃ .

The organic phase was brought to pH 1.3 by adding water (95 ml) and 1N HCl (15 ml) with stirring. The mixture was stirred at room temperature for 1.5 hours. The aqueous phase was collected and the organic phase was washed with water (25ml). The combined aqueous phases were brought to pH 4 with 10% aqueous Na ₂ CO ₃ solution, then activated carbon was added and they were filtered.

N-Butyl acetate (75 m
l) and sodium chloride (until saturated) were added.
The organic phase was separated and the aqueous phase was extracted with another n-butyl acetate (50 ml). The combined organic phases were concentrated under reduced pressure at 40 ° C. to a volume of about 75 ml. + Product
Crystallized overnight at 5 ° C. It is filtered and n-butyl acetate (25 ml) and ethyl acetate (25 ml) are added.
And dried in vacuo overnight at room temperature.

0.3 g of 6- (D-(-)-α-amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester (mp 160-16)
2 ° C.) is obtained. The analytical measurement results agreed with the standard sample of the hydrochloride salt (for example, NMR, IR: ν = 1790 cm ^−1).
(Β-lactam carbonyl)).

[0073]

INDUSTRIAL APPLICABILITY According to the present invention, ampicillin is used as a starting material to react with alkyl acetoacetate to form an enamine intermediate, which is then esterified with α-halodiethyl carbonate in the presence of a catalyst, and the resulting product is obtained. Bacampicillin can be produced by gently hydrolyzing the above compound in an acidic medium.

In the method of the present invention, at the esterification stage α
-Using halodiethyl carbonate results in high yield and high purity of the final product bacampicillin.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 499/04 499/08 (31) Priority claim number 8300331 (32) Priority date January 1983 7 Japan (33) Priority claim United Kingdom (GB) (72) Inventor Robert Graham Tyson United Kingdom Prestate Inn Clyde. Aber Conway Drive 15 (56) References JP-A-52-73894 (JP, A) JP-A-54-44694 (JP, A)

Claims (11)

[Claims] 1. The formula: In producing 6- (D-(-)-α-amino-α-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester having: (a) ampicillin in an aprotic polar solvent
The is down good Mashiku ampicillin alkaline salt form wherein R ¹
COCHR ² COR ³ (In the formula, R ¹ represents an alkyl group having ¹ to 4 carbon atoms, a substituted or unsubstituted aryl group or an aralkyl group, R ² represents hydrogen, 1 to 4 carbon atoms. Represents an alkyl group, a substituted or unsubstituted aryl group or an aralkyl group, and R ³ represents an alkyl group, a substituted or unsubstituted aryl group or an aralkyl group containing 1 to 4 carbon atoms, 1 to 4 (Representing an alkoxy group, an aryloxy group or an amine group containing a carbon atom) of Forming the corresponding enamine of the formula: wherein R ¹ , R ² and R ³ have the meanings given above and X represents an alkali metal, alkaline earth metal or organic base, and (b) the reaction mixture To the formula Obtained by adding a compound of the formula (Z is C 1 ).
Formula ## STR4 ## are reacted in the presence of a resulting intermediate catalytic Forming the corresponding ester having R ¹ , R ² and R ³ having the meanings given above, and (c) mildly hydrolyzing in an acidic medium to form a compound of formula (I). A method characterized by the following. 2. The alkaline salt of ampicillin is obtained in a manner known per se by converting ampicillin trihydrate in a polar solvent, preferably N, N-diethylformamide. The method described. Wherein said alkali salt formation of ampicillin enamine (II) by non-protons of polar solvent 0 ° C. to 6
The process according to claim 1, which is carried out by reacting with β-diketone at a temperature of 0 ° C. for 2-8 hours. 4. A process according to claim 3, characterized in that the reaction of enamine (II) formation is carried out in the presence of an organic base or an alkali carbonate. 5. The β-diketone has a stoichiometric ratio of 10
4. The method of claim 3, wherein the amount is -50% greater methyl or ethyl acetoacetate. 6. Before SL aprotic polar solvent is N, N-dimethylacetamide, N, N- dimethylformamide,
A method according to claim 3, characterized in that it is selected from dimethoxyethane, dimethylsulfoxide, tetrahydrofuran and dioxane. 7. The method of claim 3, wherein the enamine forming reaction is carried out at a temperature between 20 ° C and 30 ° C. 8. The method of claim 3, wherein the reaction is conducted for 3 hours. 9. The method of claim 1, wherein the catalyst is selected from quaternary ammonium salts, alkali metal bromides and iodides and cyclic ethers. 10. The method of claim 9 wherein the catalyst is tetrabutylammonium bromide. 11. The catalyst is used in an amount of 0.005 to 0.10 mol, preferably 0.01 per mol of the compound (V).
Method according to any one of claims 1 to 10, characterized in that it is present in an amount of 0.10 mol.