KR100441901B1 - Improved process for the preparation of cephalosporin derivatives - Google Patents

Abstract

The present invention relates to an improved process for the preparation of cephalosporin derivatives, wherein, in an organic solvent, a radical reaction of (cis) -3-acetoxypropene-cephalosporinic acid starting material with benzenethiol and azobisisobutyronitrile To a trans form, followed by reaction with (trans) -4-ethylmethylamino-2-butenamide, wherein the compound thus prepared is acylated by reaction with an acylide and a silylate under mild reaction conditions. Cefalosporin derivative, which is an excellent antibiotic {7-[(cis) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido]- 3-[(trans) -3- (trans)-(1-carbamoyl-1-propen-3-yl) -3-ethylmethylammonio] -1-propen-1-yl] -3-cepem -4-carboxylate} can be easily produced in high yield.

Description

IMPROVED PROCESS FOR THE PREPARATION OF CEPHALOSPORIN DERIVATIVES}

The present invention relates to a method for the simple production of cephalosporin derivatives from (cis) -3-acetoxypropene-cephalosporinic acid in high yield.

A cephalosporin derivative of the general formula 1 {7-[(cis) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3 -[(Trans) -3- (trans)-(1-carbamoyl-1-propen-3-yl) -3-ethylmethylammonio] -1-propen-1-yl] -3-cepem- 4-carboxylate} is known as an antibiotic with very good antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria ( J. of Antibiotics , Vol. 51, pp 378-380 (1998), Domestic Patent No. 174,117 and United States) Patent 6,063,778).

US Patent No. 6,063,778 uses a compound of formula 2 (7-benzoylamino-3-chloromethyl-2- (4-methoxybenzyl) cepem-3-carboxylic acid) as starting material, as shown in Scheme 1 below. To synthesize a compound of Formula 3, and then acylate the compound of Formula 7 (aminothiadiazole-acetic acid chloride) to prepare a cephalosporin derivative of Formula 1.

However, this method is low in yield and complex because of the synthesis of the compound of Formula 3 through 8 steps including the protecting group removal reaction from the compound of Formula 2, toxic phosphoryl pentachloride in the preparation of the compound of Formula 7 It is difficult to manufacture a large amount because of using, and has the trouble of purifying the final compound by passing the ion exchange resin.

Therefore, the inventors continued to study, using (cis) -3-acetoxypropene-cephalosporinic acid prepared from inexpensive 7-amino-cephalosporinic acid as a starting material, and a carboxylic acid or amino group as a silylate. It was found that the desired cephalosporin derivatives can be easily produced in high yield by simply performing protection and deprotection in a reactor, and performing acylation under mild reaction conditions. The invention was completed.

It is an object of the present invention to provide an improved process for the efficient and convenient preparation of cephalosporin derivatives.

In the present invention according to the above object,

(a) In an organic solvent, a compound of formula 5 is radically reacted with benzenethiol and azobisisobutyronitrile as a radical initiator to be converted into a trans form, followed by reaction with a compound of formula 10 to Producing a compound, and

(b) acylating the compound of formula 3 produced in step (a) in an organic solvent with an acylide of formula 8 and a silylide of formula 9

It includes, provides a method for producing a cephalosporin derivative of the formula (1).

Formula 1

Hereinafter, the present invention will be described in more detail.

The method for producing cephalosporin derivatives of the present invention is as follows.

In Scheme 2, the compound of formula 5 ((cis) -3-acetoxypropene-cephalosporinic acid) which is a starting material of the present invention is known from 7-amino-cephalosporinic acid of formula 4 It can be prepared easily according to the method described (see German Patent No. 382,875 and European Patent No. 503,453).

According to step (a) of the preparation method of the present invention, the compound of formula 5 having a cis type vinyl group ((cis) -3-acetoxypropene-cephalosporinic acid) as an benzenethiol and a radical initiator in an organic solvent A radical reaction with azobisisobutyronitrile was carried out to convert the trans-transformation compound ((trans) -3-acetoxypropene-cephalosporinic acid), which is thermodynamically stable, to a compound of formula 10 ((trans ) -4-ethylmethylamino-2-butenamide) to give a compound of formula 3 (7-amino-3-[(trans) -3- (trans)-(1-carbamoyl-1-propene-3 -Yl) -3-ethylmethylammonio-1-propen-1-yl] -3-cefe-4-carboxylate).

Specifically, in step (a) according to the method of the present invention, the compound of formula 5 is suspended in an organic solvent and silyl-protected to dissolve in an organic solvent, and then azobisisobutyronitrile as a radical initiator is represented by formula 5 It can be converted into a trans compound of Formula 6 by adding 0.2 to 0.3 equivalent ratios of the compound of, and adding benzenethiol in a 0.4 to 0.6 equivalent ratio of the compound of Formula 5, and heating under reflux at 100 to 120 ° C. for 20 to 40 hours. (Step (a-1)).

Subsequently, the reaction solution was concentrated under reduced pressure, and then the obtained residue was dissolved in an organic solvent. At the time of concentration, the deprotected compound was silyl-protected and the acetoxymethyl group was converted to methyl iodide. The compound of Formula 3 may be prepared by adding 1.1 to 1.3 equivalents to the compound of Formula 5 and reacting at −20 to −10 ° C. for 2 to 4 hours (step (a-2)). If necessary, in the reaction of step (a-2), an appropriate amount of a tertiary amine (eg, triethylamine, diisopropylethylamine) may be added to remove the iodide generated as a byproduct. In addition, the insoluble compound of the formula (10) is added in the form of a solution by mixing with saccharin and silylide in an organic solvent and sufficiently refluxing.

Organic solvents usable in step (a) according to the method of the present invention include benzene, toluene, xylene, nitrobenzene, methylene chloride, and the like, toluene in step (a-1), step (a-2) Methylene chloride can be preferably used.

The compound of formula 3 prepared in step (a) can simply be crystallized from isopropanol or a mixture of isopropanol and water.

Subsequently, by step (b) according to the method of the present invention, the compound of formula (3) produced in step (a) is subjected to acyl compound ((cis) -2- (5-amino-1, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid) and silylide of formula 9 (1-methanesulfonyl-6-trifluoromethyl-1H-benzotriazole, FMS) The desired cephalosporin derivative of Formula 1 can be prepared.

Specifically, in step (b) according to the method of the present invention, after dissolving the compound of formula 3 in an organic solvent, the compound of formula 8 and 9 is added in an amount of 0.8 to 1.0 equivalent ratio and 0.9 to 1.0 for the compound of formula 3, respectively. The cephalosporin derivative of Chemical Formula 1 may be prepared by adding 1.2 equivalent ratio and reacting at 0 to 30 ° C. for 2 to 5 hours. If necessary, an appropriate amount of tertiary amines (eg triethylamine, diisopropylethylamine) can be added for the purpose of activating the reaction.

Organic solvents usable in the step (b) according to the method of the present invention include dimethylformamide and dimethylacetamide, and dimethylformamide may be preferably used.

The cephalosporin derivative, the final target compound prepared in step (b), can be easily crystallized with organic solvents such as ethyl ether, ethyl ester and methylene chloride, and subjected to silica gel column chromatography using a mixture of acetonitrile and water as eluent. It can be purified to a more pure form.

As described above, according to the method for preparing cephalosporin derivatives of the present invention, the target compound can be obtained in high yield easily in a short time under mild reaction conditions by using a low-cost starting material, so that the cephalosporin derivative is an excellent antibiotic. It can lead to industrial mass production.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited by the embodiment.

Reference Example: Preparation of (Trans) -3-acetoxypropene-cephalosporinic acid (Compound 6) and comparison of trans conversion rate according to reaction conditions

1) Preparation of (trans) -3-acetoxypropene-cephalosporinic acid (compound of formula 6)

0.5 g (1.67 mmol) of (cis) -3-acetoxypropene-cephalosporinic acid (compound of formula 5) was stirred in 9 ml of toluene, while 0.3 ml of iodine trimethylsilane (catalyst amount) and hexamethyldisilazane 0.5 ml (1.67 mmol) was added and the mixture was stirred under reflux for 1 hour under a nitrogen stream. Subsequently, 105 mg (0.83 mmol) of benzenethiol and 43 mg (0.25 mmol) of azobisisobutyronitrile as a radical initiator were added to the mixed solution, and the mixture was stirred under heat and reflux at 110 ° C. for 30 hours. The reaction solution was cooled to room temperature, 9 ml of methanol was added, 1-normal hydrochloric acid was added slowly to adjust the acidity to 3.5, and the resulting solid was filtered, washed with methanol and dried in vacuo to yield 45 mg of a light yellow solid (yield). 91%, cis: trans = 2.0: 98.0).

_{^{1 H-NMR (DMSO- d 6}} , 200MHz): δ6.82 (d, J = 15.8Hz, 1H), 6.13-6.02 (dt, J = 15.8, 6.1Hz, 1H), 5.00 (d, J = 5.4 Hz, 1H), 4.78 (d, J = 4.8 Hz, 1H), 4.61 (d, J = 5.9 Hz, 2H), 3.83-3.48 (q, J = 17.1 Hz, 2H), 2.01 (s, 3H).

2) Trans Conversion Rate Comparison

In this regard, the reaction solvent, radical initiator and / or reaction time were changed as shown in Table 1 below to measure the cis: trans ratio obtained in each case, and the results are shown in Table 1 below.

division menstruum Radical initiator Reaction time Sheath: trans ratio 1 ^* Methylene chloride t-butylperbenzoate 2 28.7: 71.3 2 toluene " 12 24.5: 75.5 3 " " 24 18.7: 81.3 4 " Azobisisobutyronitrile 2 38.8: 61.2 5 " " 12 23.5: 76.5 6 " " 18 18.0: 82.0 7 " " 30 2.0: 98.0 * 1: Method disclosed in WO97 / 03990

From Table 1, it can be seen that a high trans conversion rate of 98% is achieved by the method of the present invention which is sufficiently reacted for about 30 hours using azobisisobutyronitrile as the radical initiator.

Example 1 7-amino-3-[(trans) -3- (trans)-(1-carbamoyl-1-propen-3-yl) -3-ethylmethylammonio-1-propene-1 Preparation of -yl] -3-cepem-4-carboxylate (compound of formula 3) (step (a))

While stirring 200 g (0.67 mol) of (cis) -3-acetoxypropene-cephalosporinic acid (compound of formula 5) in 2 L of toluene, it was added to 95 µl of iodine trimethylsilane (catalyst amount) and 198 ml of hexamethyldisilazane. (0.93 mol) was added thereto, and the mixture was stirred under heating at reflux for 1 hour under a nitrogen stream. Subsequently, 41 g (0.33 mol) of benzenethiol and 16.5 g (0.19 mol) of azobisisobutyronitrile as a radical initiator were added to the mixed solution, and the mixture was stirred under heat and reflux at 110 ° C. for 30 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was dissolved in 2 L of methylene chloride, and 84 ml (0.40 mol) of hexamethyldisilazane was added thereto, followed by heating under reflux for 30 minutes. Subsequently, the reaction solution was cooled to −20 ° C., and 267 ml (1.87 mol) of iodine trimethylsilane was slowly added thereto, followed by stirring at the same temperature for 15 hours. To this mixture, 114 g (0.8 mol) of (trans) -4-ethylmethylamino-2-butenamide (compound of formula 10), 6.1 g (0.03 mol) of saccharin, and 260 ml (1.23 mol) of hexamethyldisilazane were chlorinated. The solution was refluxed overnight at 100 ml of methylene and 275 ml (1.57 mol) of diisopropylethylamine were sequentially added slowly and reacted at -10 ° C for 3 hours. 1.5 L of isopropanol and 10 ml of water were added to the reaction solution, and the mixture was stirred at 5 ° C. for 1.5 hours. The resulting solid was filtered, washed with isopropanol and methylene chloride and dried in vacuo to give 228 g of a light brown solid (yield 90%).

¹ H-NMR (D ₂ O, 200 MHz): δ6.75 (d, J = 15.6 Hz, 1H), 6.63 (dt, J = 15.6, 7.6 Hz, 1H), 6.34 (d, J = 15.4 Hz, 1H ), 5.73 (dt, J = 15.4, 6.3 Hz, 1H), 4.84 (d, J = 5.1 Hz, 1H), 4.18 (d, J = 5.1 Hz, 1H), 3.90 (dd, J = 7.0, 4.0 Hz , 2H), 3.85 (dd, J = 7.5, 3.5 Hz, 2H), 3.23 (q, J = 17.3 Hz, 2H), 2.86 (s, 3H), 1.22 (t, J = 7.3 Hz, 3H); ¹³ C-NMR (D ₂ O, 50 MHz): δ 185.0, 170.2, 169.3, 139.9, 134.4, 134.2, 130.5, 116.2, 115.2, 64.3, 63.4, 61.3, 59.4, 58.0, 47.7, 23.9, 8.2; MS (CI, 70 eV) M < + > HRMS (FAB) calc'd for C ₁₇ H ₂₅ N ₄ O ₄ S: 381.1597, found: 381.1596.

Example 2 7-[(cis) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-[(trans) -3- (trans)-(1-carbamoyl-1-propen-3-yl) -3-ethylmethylammonio] -1-propen-1-yl] -3-cepem-4-carboxylate ( Preparation of Compound 1) (Step (b))

155 g (0.55 mol) of 1-methanesulfonyl-6-trifluoromethyl-1H-benzotriazole (compound of formula 9) was dissolved in 1 L of dimethylformamide, followed by (cis) -2- (5-amino 106 g (0.52 mol) of -1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (compound of formula 8) and 80 ml (0.57 mol) of triethylamine were added thereto, and 30 minutes at 0 ° C. Was stirred. To this mixture, 7-amino-3-[(trans) -3- (trans)-(1-carbamoyl-1-propen-3-yl) -3-ethylmethylammonio prepared in Example 1 above. 200 g (0.52 mol) of -1-propen-1-yl] -3-cefe-4-carboxylate (compound of formula 3) was added and reacted at room temperature for 3 hours. When the reaction was completed, 2L of ethyl acetate was added to the reaction solution, the resulting solid was filtered, washed with ethyl ether, and dried in vacuo to give 267 g of a light brown solid (yield 91%).

The obtained compound was dissolved in water, purified by silica gel column chromatography (acetonitrile: water = 4: 1), dissolved in an organic solvent, concentrated under reduced pressure at low temperature, and lyophilized to obtain 140 g of pure target compound (yield 48%).

¹ H-NMR (D ₂ O, 200 MHz): δ6.76 (d, J = 15.6 Hz, 1H), 6.63 (dt, J = 15.6, 7.5 Hz, 1H), 6.31 (d, J = 15.3 Hz, 1H ), 5.73 (dt, J = 15.3, 7.2 Hz, 1H), 5.69 (d, J = 4.9 Hz, 1H), 5.10 (d, J = 4.9 Hz, 1H), 3.92 (s, 3H), 3.91-3.78 (m, 4H), 3.52 (q, J = 17.3 Hz, 2H), 3.20 (q, J = 7.3 Hz, 2H), 2.85 (s, 3H), 1.10 (t, J = 7.3 Hz, 3H); ¹³ C-NMR (D ₂ O, 50 MHz): δ 185.0, 169.1, 164.4, 164.3, 161.8, 147.4, 139.8, 134.1, 132.2, 130.3, 116.5, 115.5, 64.3, 61.3, 59.8, 58.4, 58.1, 56.2, 47.7, 23.9, 8.2; MS (CI, 70 eV) M < + > HRMS (FAB) calcd for C ₂₂ H ₂₉ N ₈ O ₆ S ₂ : 565.1651. Found: 565.1653.

According to the method for producing cephalosporin derivatives of the present invention, the target compound can be easily obtained in high yield within a short time under mild reaction conditions using a low-cost starting material, leading to the industrial mass production of the excellent antibiotic cephalosporin derivatives. Can be.

Claims (8)

(a) In an organic solvent, a compound of formula 5 is radically reacted with benzenethiol and azobisisobutyronitrile as a radical initiator to be converted into a trans form, followed by reaction with a compound of formula 10 to Producing a compound, and (b) acylating the compound of formula 3 produced in step (a) in an organic solvent with an acylide of formula 8 and a silylide of formula 9 A method of preparing a cephalosporin derivative of Formula 1, comprising: Formula 1 Formula 3 Formula 5 Formula 8 Formula 9 Formula 10 The method of claim 1, The radical reaction in step (a) is carried out at 100 to 120 ℃ for 20 to 40 hours. The method of claim 1, The reaction with the compound of formula 10 in step (a) is carried out at -20 to -10 ℃ for 2 to 4 hours. The method of claim 1, The organic solvent of step (a) is selected from the group consisting of benzene, toluene, xylene, nitrobenzene and methylene chloride. The method of claim 1, Prior to step (b), the method further comprises crystallizing the compound of formula 3 prepared in step (a) from the reaction solution using isopropanol or a mixture of isopropanol and water. The method of claim 1, Step (b) is carried out at 0 to 30 ° C. for 2 to 5 hours. The method of claim 1, The organic solvent of step (b) is dimethylformamide or dimethylacetamide. The method of claim 1, And further crystallizing the compound of formula 1 prepared in step (b) from the reaction solution using ethyl ether, ethyl ester or methylene chloride.