FR3121440A1 - Process for the preparation of 4',5'-dihydrocefradine - Google Patents

Abstract

The present invention relates to a process for the preparation of 4',5'-dihydrocephradine from (R)-(-)-2-(2,5-dihydrophenyl)glycine. The process includes the steps of Boc (tert-butoxycarbonyl) protection, reduction, amide formation and deprotection. This invention provides mild conditions, simple processing procedures, process reliability, good selectivity and high workability. The 4',5'-dihydrocephradine synthesized by this method is of high purity and can be used as a reference standard for quality control of cefradine, which is of great value.

Description

Process for the preparation of 4',5'-dihydrocefradine

Field of invention

The present invention relates to a process for the preparation of 4',5'-dihydrocefradine of formula V:

in the field of drug synthesis.

Background of the invention

Cefradine is a semi-synthetic cephalosporin antibiotic which was prepared by the American company Squibb in 1972 and belongs to the first generation cephalosporins. Cefradine became available in the 1970s and is still the only one that can be taken both orally and by injection. It has the advantages of convenient clinical use, good pharmacokinetics, high stability to β-lactamase, low kidney and liver toxicity and irritation, and low possibility of secondary infection. Cefradine exhibits strong resistance to β-lactamase from different bacteria and good antibacterial activity against susceptible strains, including Staphylococcus aureus (including penicillin-resistant Gram-positive bacteria), Streptococcus haemolyticus , Escherichia coli , Proteus mirabilis , Klebsiella pneumoniae and Haemophilus influenzae . Apart from high safety, its therapeutic effect towards respiratory tract infections, urinary tract infections, skin and soft tissue infections, gastrointestinal tract infections, bone and joint infections, sepsis, as well as infective endocarditis, is above average, leading to wide application in clinical use.

For safety reasons, the limit of unknown impurities in active pharmaceutical ingredients for medicinal products for human use is very low. Usually, it must be less than 0.1% by weight, as required by national and international authorities. To ensure that an active pharmaceutical ingredient is qualified for the standards and can be used for a safe and effective pharmaceutical preparation, a thorough study of significant impurities is necessary. Some of the impurities arise from the degradation of the active pharmaceutical ingredient, or the process of preparation, including unreacted starting materials, derivatives of impurities in the starting material, by-products, degradation products, etc If we can come to know the structure of the impurities and their route of synthesis, and identify the parameters that can influence the content of impurities in the final product, this can greatly help to control the associated impurities.

The impurity prepared by this invention is a reduction by-product of cefradine and is highly similar in structure to cefradine. It represents approximately 0.3% of the active pharmaceutical ingredient and therefore has a significant impact on the safety and efficacy of cefradine.

A process for the preparation of 4',5'-dihydrocefradine is reported (Journal of Pharmaceutical and Biomedical Analysis, vol 12, pages 1137-40, 1994) and it starts from (R)-(-)-2-(2 ,5-dihydrophenyl)glycine. The target compound is obtained after reductive hydrogenation, Boc (tert-butoxycarbonyl) protection, amide formation and deprotection. The synthetic route is shown below:

The reductive hydrogenation step requires special equipment to achieve the high pressure condition. Also, catalytic hydrogenation using palladium on charcoal has poor chemoselectivity and the process is unreliable. In addition, the over-reduction product D-alpha-cyclohexylglycine is often found due to poor control of the progress of the reaction. Based on these technical problems, the present invention has developed a simple and reliable process for the preparation of 4',5'-dihydrocefradine, which exhibits good selectivity. This helps in the in-depth study of this impurity.

The present invention relates to a novel process for the preparation of 4',5'-dihydrocefradine. The process is easy to follow and the yield is high, providing qualified reference standards for quality control and the study of the safety of cefradine.

To this end, the method according to the present invention is characterized in that it comprises the following steps:

(A) (R)-(-)-2-(2,5-dihydrophenyl)glycine of formula I is dissolved:

in a mixture of acetonitrile (ACN) and water, followed by the addition of a base and di-tert-butyl dicarbonate (Boc ₂ O), and reacted to obtain the compound of formula II:

;

(B) to a solution in an organic solvent of the compound of formula (II) and hydrazine hydrate, hydrogen peroxide is added and the mixture is heated to react in order to obtain the compound of formula III:

(VS)

(Ca) trimethylacetyl chloride (pivaloyl chloride) is added to a solution of the compound of formula III and of a base in an organic solvent, at a temperature of -40°C - -30°C and the mixture is stirred at a temperature of -30°C - -10°C;

(Cb) the mixture obtained in step (Ca) is added to a solution of 7-aminodeacetoxycephalosporanic acid (7-amino-3-methyl-3-cephem-4-carboxylic acid) (7-ADCA) in said solvent organic and an organic co-solvent, at a temperature of -40°C - -30°C, and the mixture is stirred at this temperature for the purpose of the reaction, in order to obtain a compound of formula IV:

(D) Trifluoroacetic acid is added to the compound of formula (IV), the mixture is stirred for the reaction to obtain the compound of formula V.

In accordance with preferred features of the present invention:

In step (A), at least one of potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide can be used as the base.

In step (A), the volume ratio of acetonitrile to water can be from 1:1 to 1:3; and the molar ratio of (R)-(-)-2-(2,5-dihydrophenyl)glycine to base may be from 1:1 to 1:5.

In step (B), the molar ratio of compound II, hydrazine hydrate and hydrogen peroxide can be from 1:1:1 to 1:3:2.

In step (Ca), the base can be at least one of triethylamine and N,N-diisopropylethylamine.

In step (Ca), the organic solvent can be dichloromethane (DCM).

In step (Ca), the molar ratio of compound III, trimethylacetyl chloride (pivaloyl chloride) and base can be from 1:1:1 to 1:1.5:3; and the reaction temperature may be -30 to 0°C.

In step (Cb), the organic co-solvent may be at least one of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine (TEA) and tetramethylguanidine ( TMG).

In step (Cb), the molar ratio of 7-ADCA and co-solvent can be 1:1 to 1:2.

In step (D), the mass (in g) to volume (in ml) ratio of compound IV to trifluoroacetic acid can be from 1:5 to 1:10; the reaction temperature may be 0 to 25°C; and the reaction time can be 10 to 30 minutes.

Example

The invention is described by way of example with reference to the reaction scheme below:

A - Preparation of the compound of formula II :

To (R)-(-)-2-(2,5-dihydrophenyl)glycine (compound of formula I) (3.14g, 20mmol, 1eq) in H ₂ O/acetonitrile (40ml/20ml), we have added NaOH (2.0 g, 50mmol, 2.5eq) and di-tert-butyl dicarbonate (Boc ₂ O) (6.6g, 30mmol, 1.5eq).

The mixture was stirred for 5 hours at room temperature, the mixture was acidified with concentrated HCl to pH=3, water (50ml) was added to the reaction mixture and the latter was extracted with ethyl acetate three times.

The organic layers were combined, washed with water and brine and dried over Na ₂ SO ₄ . The solvent was evaporated to provide crude product (4.5g).

B - Preparation of the compound of formula III :

To a stirred solution of the compound of formula II, obtained in A (2.53 g, 10 mmol, 1 eq) and hydrazine hydrate at 80% by weight in water (80% N ₂ H ₄ , H ₂ O) (1.5g, 30mmol, 3eq) in MeOH (30ml), hydrogen peroxide at 30% by weight in water (1.1g, 10mmol, 1eq) was added.

The mixture was stirred for 2 hours at 70°C; it was acidified with concentrated HCl to pH=3; Water (50ml) was added to the reaction mixture and it was extracted with ethyl acetate three times.

The organic layers were combined, washed with water and brine and dried over Na ₂ SO ₄ .

The solvent was evaporated to provide crude product.

The crude product was loaded onto a column of silica gel (PE:EA=5:1, R _f =0.4) to give the compound of formula III (2.0 g, yield: 79%).

C - Preparation of the compound of formula IV :

1. To a solution of compound III (2.5g, 10mmol, 1eq) and N,N-diisopropylethylamine (DIPEA) (20mmol) in dichloromethane (DCM), trimethylacetyl chloride (pivaloyl chloride) (1.27g, 10 .5mmol, 1.05eq) was added at -40°C, then the mixture was stirred at -25°C for 30 minutes.
2. Then the mixture was added at -40°C to a solution of 7-aminodeacetoxycephalosporanic acid (7-ADCA) (2.14g, 10mmol, 1eq) and 1,1,3,3-tetra-methylguanidine (TMG) (1.15g, 10mmol, 1eq) in 30 ml of DCM.

The mixture was stirred for 12 hours at -40°C.

A saturated aqueous solution of ammonium chloride (20ml) and acetonitrile (20ml) was added. The mixture was filtered, the filter cake was collected to give the compound of formula IV (1.8g as a white solid, yield: 39.8%).

D - Preparation of the compound of formula V :

In a round-bottomed three-necked flask, compound IV (1.8 g, 4 mmol, 1 eq) was added, then trifluoroacetic acid (TFA) (25 ml) was added to the flask. 10 minutes later, the mixture was poured into H ₂ O (50ml). The resulting mixture was purified by column chromatography to provide Compound V.

¹ H NMR (400 MHz, D ₂ O) δ 6.18(1H), 5.71(1H), 5.15(1H), 4.60(1H), 3.64(1H), 3.26 (1H), 2.15(1H), 2.04-2.09(1H), 1.95-1.98(4H), 1.60-1.74(4H).

These are the preferred embodiments of the invention. However, within the main guidelines of this invention, those skilled in the art may make certain changes and improvements. It should be emphasized that these changes and improvements are still within the scope of this patent protection.

Claims (10)

Process for the preparation of 4',5'-dihydrocephradine of formula V:

characterized in that it comprises the following steps:
(A) (R)-(-)-2-(2,5-dihydrophenyl)glycine of formula I is dissolved:

in a mixture of acetonitrile (ACN) and water, followed by the addition of a base and di-tert-butyl dicarbonate (Boc ₂ O) and reacted to obtain the compound of formula II :
;
(B) to a solution in an organic solvent of the compound of formula (II) and of hydrazine hydrate, hydrogen peroxide is added and the mixture is heated to react in order to obtain the compound of formula III:

(VS)
(Ca) trimethylacetyl chloride (pivaloyl chloride) is added to a solution of the compound of formula III and of a base in an organic solvent, at a temperature of -40°C - -30°C and the mixture is stirred at a temperature of -30°C - -10°C;
(Cb) the mixture obtained in step (Ca) is added to a solution of 7-aminodeacetoxycephalosporanic acid (7-amino-3-methyl-3-cephem-4-carboxylic acid) (7-ADCA) in said solvent organic and an organic co-solvent, at a temperature of -40°C - -30°C, and the mixture is stirred at this temperature for the purpose of the reaction, in order to obtain a compound of formula IV:

(D) trifluoroacetic acid is added to the compound of formula (IV), the mixture is stirred for reaction to obtain the compound of formula V. Process according to Claim 1, characterized in that in stage (A), at least one of potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide. Process according to one of Claims 1 and 2, characterized in that in stage (A), the volume ratio of acetonitrile to water is from 1: 1 to 1: 3; and the molar ratio of (R)-(-)-2-(2,5-dihydrophenyl)glycine to base is 1:1 to 1:5. Process according to one of Claims 1 to 3, characterized in that in stage (B), the molar ratio of compound II, of hydrazine hydrate and of hydrogen peroxide is 1: 1 :1 to 1:3:2. Process according to one of Claims 1 to 4, characterized in that in stage (Ca), the base is at least one of triethylamine and N,N-diisopropylethylamine. Process according to one of Claims 1 to 5, characterized in that in stage (Ca), the organic solvent is dichloromethane (DCM). Process according to one of Claims 1 to 6, characterized in that in stage (Ca), the molar ratio of compound III, of trimethylacetyl chloride (pivaloyl chloride) and of the base is 1: 1 : 1 to 1: 1.5: 3; and the reaction temperature is -30 to 0°C. Process according to one of Claims 1 to 7, characterized in that in stage (Cb), the organic co-solvent is at least one of 1,8-diazabicyclo[5.4.0]undec- 7-ene (DBU), triethylamine (TEA) and tetramethylguanidine (TMG). Process according to one of Claims 1 to 8, characterized in that in stage (Cb), the molar ratio of 7-ADCA and of the co-solvent is from 1: 1 to 1: 2. Process according to one of Claims 1 to 9, characterized in that in stage (D), the mass (in g) to volume (in ml) ratio of compound IV to trifluoroacetic acid is 1 : 5 to 1:10; the reaction temperature is 0 to 25°C; and the reaction time is 10 to 30 minutes.