FI69080B - MELLANPRODUKT ANVAEND VID FRAMSTAELLNING AV ANTIBAKTERISK 2BETA-KLORMETYL-2ALFA-METYLPENAM-3ALFA-CARBOXYLSYRASULFON - Google Patents

Description

69080

Intermediate for the preparation of the antibacterial 2? -Chloromethyl-2X-methylpenen-3 ού-carboxylic acid sulfone 5 Separated from application 810121 - patent 67,553

The invention relates to intermediates for the preparation of the antibacterial 2β-chloromethyl-2- [methyl-penam-3? -Carboxylic acid sulfone.

10 Formula S »

_C, I2CL

! I | CH3 u, 15 N ---

O 'COOH

The 2β-chloromethyl-2β-methylpenam-3β, carboxylic acid sulfone, pharmaceutically acceptable salts and easily hydrolyzable esters of the present invention are particularly effective against β-lactamase-producing bacteria.

The invention relates to an intermediate 6 ', X-bromo-2 2 -chloromethyl-2 * O-methylpenar-3,6-carboxylate, which is used as an intermediate in the preparation of the final product of formula I.

Bt *

'.t / ^ »S \ ^ CH2C; L

'CH3 30____ (11)

O ^ 'v C-OR

II

O

wherein R is benzyl or p-nitrobenzyl.

2 69080

The invention also relates to the 6? -Bromo-2- (2-chloromethyl-2 * -methylpenam-3C-C-carboxylate sulfoxide of the formula I) used in the preparation of the final product of formula I.

5 O

Br ^ CH Cl

Br, _2 1 i 1 '✓ / // o c-or

10 II

o wherein R is benzyl or p-nitrobenzyl.

The final product of formula I can be prepared by a) catalytic hydrogenation, for example using a noble metal catalyst such as palladium, an ester of formula

O

f .CH2C1 20 Br '..___ I) CH3 Λ N \

o CO2R

Wherein R is benzyl or p-nitrobenzyl or then b) oxidizing the hydrogenated product to give the desired acid or salt thereof, and optionally c) esterifying the acid or salt thereof to a readily hydrolyzable ester.

Example 1

Preparation of potassium 2/3-chloromethyl-2-O-methylpenam-3'-carboxylate sulfone (potassium salt of the compound of formula I) (BL-P2013) 3 69080 5 Br ft ^ ^ Br% '"[- T ^ s Ύ 0 N N ° -102 (CO2-CH2XO) -NO2 - 2O2t

15 ΪBr .s / CH, CX

1 pcH3 „_" r - ^^ cnl N / - \ JN-, co2-ch2 ^> - No2 cf- tSo2-CH2 ^, o2 20 <Π2 V 2 11% /? 25 ^ äv.> CII, C1 trii - S /> CH, C1 rj I ™; .1 ^ ^ rf v, c „3 <y N \ o H / ~ N - '%

2 ° C02K

30 5 4 ΙΓΓ 69080 6ο (-bromopenicillanic acid S-sulfoxide (1) 30 g (37/5 mmol) of 6c <-bromopenicillanic acid-N, N * -dibenzylethylene diamine salt / G.Cignarella et al., J.Org.Chem 27, 2668 (1962) and E. Evrard, Nature 5 201, 1124 (1964) (dissolved in 330 ml of methylene chloride dia.) The solution is cooled to 0 [deg.] C. and 13 ml (156 mmol) of concentrated hydrochloric acid are slowly added. The dibenzylethylenediamine HCl salt (DBED.HCl) precipitates after stirring for 10 minutes at 0-5 [deg.] C. The DBED.HCl precipitate is filtered through a pad of diatomaceous earth and washed with 150 ml of methylene chloride. the washings are washed with 60 ml of cold water and concentrated in vacuo to 65-80 ml, stirred and cooled to 5 [deg.] C. 13 ml (86.9 mmol) are added over 30 minutes with gentle stirring. 50% peracetic acid The reaction is exothermic and the temperature of the mixture is kept in an ice bath with cooling between 15-18 ° C. after maturation, the sulfoxide begins to crystallize. The mixture is cooled and stirred at 0-5 ° C for two hours, then filtered and washed in the following order: 10 ml of water at 5 ° C, 10 ml of methylene chloride at 0-5 ° C, and finally with 15 ml of heptane. The precipitate is dried at 45 ° C. 16.26 g of the title compound are obtained, yield 73.24%.

25 p-Nitrobenzyl 6 ° -bromopenicillanate S-sulfoxide (2)

To a solution of 12 g (0.04 mol) of 6® <bromo-penicillanic acid S-sulfoxide in 100 ml of acetone is added 7.5 g (0.041 mol) of potassium 2-ethylhexanoate.

The salt is filtered, washed with cold acetone and air dried. The obtained potassium salt (10 g) is dissolved in 75 ml of dimethylacetamide, and 7.8 g (0.04 mol) of p-nitrobenzyl bromide are added to the solution. The solution is stirred at 23 ° C for 24 hours, diluted with 500 ml of water and extracted with ethyl acetate. The extract is washed four times with water, dried over anhydrous magnesium sulfate and evaporated at 69080 5 at 35 ° C (15 mm Hg) to an oil which crystallizes on standing. The light brown crystals are slurried in ether and filtered to give the title compound 9 g (70%), m.p. 124-125 ° C (decomposes).

5 Analysis:

Calcd for C 18 H 15 BrN 2 O 8 S: C, 41.98; H, 3.05; N, 6.52

Found: C, 42.00; H, 3.48; N, 6.98.

IR (KBr): 1800 (s), 1740 (s), 1610 (w), 1520 (s), 1450 (m), 10 -1 * 1350 (s), 1060 (m), 740 (n) cm-1. 1 H-NMR (60 MHz, DMSO): δ 1.22 (s, 3H), 1.6 (s, 3H), 4.67 (s, 1H), 5.2 (d, 1-5 Hz, 1H ), 5.45 (s, 2H), 5.68 (d, 1-5 Hz, 1H), 7.5-8.5 (m, 4H).

p-Nitrobenzyl 2H-chloromethyl-2-methyl-6-bromopenam-3-carboxylate (3)

A solution of 5 g (0.012 mol) of p-nitrobenzyl-6 <X-bromopenicillanate S-sulfoxide (2) in 1.5 g (0.012 mol) of quinoline and 1.6 g (0.012 mol) of benzoyl chloride 120 in 1 ml of dry dioxane, reflux under nitrogen for 4 hours. The solution is diluted with 600 ml of water and extracted with ethyl acetate. The ethyl acetate extract is washed with 5% sodium hydrogen carbonate solution, 5% phosphoric acid solution and finally with water. The organic layer is dried over anhydrous magnesium sulfate and evaporated at 35 ° C (15 mm Hg) to give an oil which crystallizes. The crystals are washed with ether and finally with cold toluene to give the title compound 3.5 q (65%), m.p. 130-135 ° C (decomposes).

Analysis:

Calcd for C 18 H 18 ClBrN 2 O 2 S: C, 40.06; H, 3.14; N, 6.23

Found: C, 40.19; H, 3.12; N, 6.75.

IR (KBr): 1792 (s), 1740 (s), 1610 (w), 1520 (s), 1353 (s), 1280 (m), 1025 (w), 990 (w), 750 (w) cm "1.

NMR (60 MHz, DMSO): δ 1.45 (s, 3H), 3.5-4.3 (n, 2H), 5.05 δ (s, 1H), 5.42 (s, 2H) Δ 5.5 (d, J 1 δ 1.5 Ηζ, ΐΗ), 5.62 (d, J / N / 1.5 Hz, 1H), 7.5-8.5 (m, 4H).

6 69080 p-Nitrobenzyl-6 ¢ 6-bromo-2 β-chloromethyl-2 <*> -methylpenam-3o-carboxylate sulfoxide (4) To a solution of 1 g (0.0022 mol) of p-nitrobenzyl-3 / 8-chloromethyl-2 oi. -methyl-6 <= <-bromopenam-5 3 ° (carboxylate (3) dissolved in 50 ml of methylene chloride, 473 mg (0.0022 mol) of m-chloroperoxybenzoic acid are added. The solution is stirred at 23 ° C 3 hours, then the solution is evaporated to 20 ml of 15 mm Hg in vacuo at 33 ° C and the concentrated solution is diluted with 50 ml of heptane-10 ("Skellysolve B"), the solvent is decanted off and the residue is slurried in ether to give a crystalline title compound. compound, 250 mg, 24%, mp 136-137 ° C (dec).

Analysis:

Calculated for 1 H-H 2 ClCl 3 O 5 S: 15 C, 38.68; H, 3.02; N, 6.02

Found: C, 39.14; H, 3.13; N, 5.96.

IR (KBr): 1800 (s), 1760 (s), 1520 (s), 1350 (s), 1200 (s), 1050 (m), 230 (w) cm -1. 1 H-NMR (60 mHz, DNSO): δ 1.32 (s, 3H), 3.8-4.5 (m, 2H), 4.97 (s, 1H), 5.25 (D, J- 1.5 1.5 Hz, 1H), (s, 3H), 3.8-4.5 (m, 2H), 4.97 (s, 1H), 5.25 (d, J 1.5 Hz, 1H), 5.45 ( s, 2H), 5.6 (d, J, 1.5 Ηζ, ΙΗ), 7.8-8.5 (m, 4H).

Potassium 2H-chloromethyl-20 (methylmetenam-3c) -carboxylate sulfone (5) (BL-P2013) To a solution of 7 g (0.015 moles) of p-nitrobenzyl-2/8-chloromethyl-2 «K-methyl-6 ° (-bromopentam-3 ° <-carboxylate sulfoxide (4) in 150 ml of ethyl acetate, add a suspension of 4 g of 30% palladium-diatomaceous earth (" Celite ") and 2.8 g of sodium hydrogen carbonate in 150 ml of water at 3 [deg.] C. The mixture is hydrogenated for 3 hours at 345 kPa, the catalyst is filtered off and the aqueous layer is separated and treated with 1.5 g of potassium permanganate in 50 ml of water. 250 mg of sodium hydrogen sulphite are added, the mixture is filtered and the filtrate is adjusted to pH 35 with concentrated hydrochloric acid. Freeze-drying to give a white amorphous powder is extracted with ethyl acetate, the extract is evaporated to 20 ml and then diluted with 100 ml of Sane. ve B "). White, hygroscopic, solid 2β> -chloromethyl-5 2 <X.-methylpenen-3 <7 ^ -carbamate the oxylic acid sulfone was collected. The acid is dissolved in acetone and solid potassium 2-ethylhexanoate is added to the solution to give 170 mg of a crystalline white salt, m.p. > 140 ° C (decomposes). Analysis: Calculated for C 9 H 11 ClNO 3 S 2 O 2: C, 28.27; H, 3.24; N, 41.2 Found; C, 28.27; H, 3.69; N, 3.84.

IR (KBr): 1790 (s), 1770 (m), 1620 (s), 1460 (m), 1370 (s), 1310 (s), 1200 (s), 1140 (s), 955 (m), 740 (n) cm ”1. 1 H-NMR δ (100 mHz), D 2 O): δ 1.68 (s, 3H), 3.2-3.9 (m, J

Hz, J ^ 6 Hz, 2H), 4.0-4.4 (m, 2H), 4.3 (s, 1H), 5.02 (dd, J- ^ MHz), J ^ 2Hz, 1H) .

Example 2 p-Nitrobenzyl 6 <* - bromo-2A-chloromethyl-2 <* 3 -20 methylpenam-3 g6-carboxylate 0 f B \ -A Sxu ΒΓ, y.s 25 ['-> Π | f®3 o7 coch2— <f ^) - N0 „0 7 // // Γ ~ \ 2 2 \ _ / 2 O 002CH2 _ // \\ _ NO2

Mp. 446.71 30

To a liter of p-dioxane was added 70 g (0.16 moles) of p-nitrobenzyl 6-o-bromopenicillanate sulfoxide, followed by 21.2 ml (0.10 moles) of benzoyl chloride and 21.8 ml (0.19 moles) of quinoline. The reaction mixture was boiled for 4 hours and then cooled to 22 ° C, poured into 2500 ml of H 2 O and extracted with 3 x 800 ml of ethyl τττ: 8 69080 acetate. The combined ethyl acetate extracts were washed with 300 mL of 5% aqueous sodium bicarbonate, 300 mL of 5% aqueous phosphoric acid and 300 mL of H 2 O. The ethyl acetate solution was dried over sodium sulfate for 1/2 hour and the sodium sulfate was removed by filtration. The filtrate was evaporated in vacuo to a residue which was redissolved in a liter of ethyl acetate and evaporated again in vacuo to a residue. 1 liter of diethyl ether was then added and the product was collected by filtration to give 41 g (57%) of 10β-nitrobenzyl 6β-bromo-2- [3-chloromethyl-2 ', -methyl-penam-3β-carboxylate, m.p. . 132 °. The IR and NMR spectra were of the desired structure.

Analysis:

Calcd for C 18 H 18 BrCl 3 O 3 S: 15 C, 40.06; H, 3.14; N, 6.23;

Found: C, 40.62; H, 3.11; N, 6.13.

Example 3 p-Nitrobenzyl 6- [30'-bromo-2/3-chloromethyl-2% methylpenen-3'-carboxylate sulfoxide 20

O

1 “B% _ ^ 201 Br,. ^ _ / S + m2Cl -> lj _T013

Mp. To 1200 ml of methylene chloride was added 51 g (0.11 moles) of p-nitrobenzyl 6 -? - bromo-2/3-chloromethyl-2-methylpenam-3,4-carboxylate, followed by 23 g (0 , 12 moles) of m-chloroperoxybenzoic acid. The solution was stirred at 22 ° C for 2 hours and evaporated in vacuo to a wet residue. The residue was stirred with 4 liters of diethyl ether for 1 hour and then allowed to stand at 9 ° C for 20 hours. The product crystallized out and was collected by filtration, washed with 2 x 200 ml of diethyl ether and dried to give 39 g of p-nitrobenzyl-6β-bromo-2/3-chloromethyl-2 '; -5-methylpenam-306-carboxylate sulfoxide (75%), m.p. 132 ° C. The IR and NMR spectra were of the desired structure.

Analysis:

Calculated for C 18 H 18 BrCl 3 O 5 S: 10 C, 38.69; H, 3.03; N, 6.07;

Found: C, 38.98; H, 3.04; N, 5.84; H 2 O, 0.35.

Example 4

Potassium 2β-chloromethyl-2 <X-methylpenam-3 <* - carboxylate sulfone (BL-P2013) 15 ° Fc ° F

2 ° '[\ f> □ _H

J COJ3L · N02 ° Ό ί \ - ^ BL-P2013

Mp. 305.77 To 600 ml of H 2 O was added 8 g of 30%

Pd / Celite catalyst and 16 g (0.19 moles) of sodium bicarbonate. 32 g (0.69 moles) of p-nitrobenzyl-6β-bromo-2,3-chloromethyl-2α-methylpenam-3α-carboxylate thisulfoxide were then dissolved in 400 ml of ethyl acetate and added. an aqueous slurry. The mixture was hydrogenated on a Parr apparatus at 345 kPa at 22 ° C for 4 hours. The slurry was filtered through a thin pad of Celite in a sintered glass funnel, the pad was washed with 2 x 50 mL H 2 O 35 and the aqueous layer of the combined filtrate and washings was separated. The aqueous layer was washed with 200 mL of diethyl ether. then cooled to 5 ° C and, with stirring, a solution of 12 g (0.076 mol) of KMnO 2 in 200 ml of IVO was added dropwise over 1/2 hour, maintaining the pH between 7.5 and 8.0 by adding 40 After 5 minutes of pink color persisted, no more KMnO 2 solution was added, the reaction mixture was stirred with a small amount (about 50 mg) of sodium bisulfite for 1/2 hour, and then the slurry was filtered to “Celite”. The mattress was washed with 2 x 50 mL H 2 O. A combined 500 mL filtrate and washings were poured into a 500 mL ethyl acetate layer and the pH was adjusted, with stirring, to 1.5 by the addition of 2N HCl. The layer was saturated with sodium sulfate and re-extracted 2 x 400 ml of ethyl acetate and the combined ethyl acetate extracts were dried over sodium sulfate for 1/2 hour at 5 °. The sodium sulfate was removed by filtration and the filtrate was evaporated in vacuo to a residue.

That residue was dissolved in 160 ml of acetone, and 160 ml of diethyl ether and a 50% by weight solution of potassium 2-20 ethyl hexanoate in n-butanol were added until the solution was neutral on moist pH paper. The separated crystalline potassium salt of BL-P2013 was collected by filtration, washed with diethyl ether and dried. Yield 16 g of potassium 2/2-chloromethyl-2 ° C-methylpenam-3β-carboxylate sulfone 25 (BL-P 2 O 3) (76%), m.p. 202 ° C. The IR and NMR spectra were of the desired structure.

Analysis:

Calcd for C 9 H 11 ClNO 3 S: C, 31.42; H, 2.97; N, 4.58; Found: C, 31.18; H, 2.98; N, 4.51; H 2 O, 0.93.

Example 5

Improved Synthesis of BL-P2013 This method simplifies the preparation of BL-P2013 by eliminating the previously used catalytic reduction.

li

Step 1 11 69080

O

f

Br '' s / 7 j + CH-CCl.> + Dicyclohexyl-5 II carbodiimide

i — N-- 'OH

g / COOH

Pyridine 10 CH2Cl2

O

t * \ / 8v7 I r 2 15 // - N-V, o C-OCH-CCl-,

Il 2 3

O

(See page 20,633 of Cephalosporins and Penicillins, edited by Edwin H. Flynn, Academic Press, New

York, 1972).

6β-Bromopenicillanic acid sulfoxide (1) (30 g, 0.1 mol) was dissolved in one liter of dry CH 2 Cl 2 and then 16.2 ml (0.2 mol) of pyridine and 29.8 g (0.2 mol) of pyridine were added. ) trichloroethanol. 20 g (0.1 mol) of dicyclohexylcarbodiimide were then added and the mixture was stirred at 22 ° C for 16 hours. Began to crystallize dicyclohexylurea; upon completion of crystallization, it was removed by filtration. The filtrate was washed with 200 ml of 5% aqueous sodium bicarbonate solution, 200 ml of 10% phosphoric acid and 100 ml of saturated aqueous sodium sulfate solution. The organic phase was dried over sodium sulfate at 5 ° C for 30 minutes, filtered and evaporated to an oil. Diethyl ether was added and product 2-35 precipitated on scraping (27 g, 63% yield).

12 69080

Step 2 - * Cj * - Jcl 5

quinoline

V

O

Br 2 CHOCl

10 - ^ S

! | Γ7! CH ~ J— N-3 O C-OCHoCClo Ä 2 3 15

Compound 2 (26.5 g, 0.062 mol) was dissolved in 500 p-dioxane and 8.5 ml (0.078 mol) of benzoyl chloride and 8.75 ml (0.078 mol) of quinoline were added. The solution was boiled for four hours and then poured into 20,100 of any water and the product 3 was extracted with 2 x 400 ml of ethyl acetate. The ethyl acetate extracts were combined, washed successively with 200 ml of 5% aqueous sodium hydrogen carbonate solution, 200 ml of 5% phosphoric acid and 200 ml of saturated aqueous sodium sulphate solution, dried for forty minutes over sodium sulphate at 5 ° C and evaporated to dryness. , which was used "as such" in the next reaction.

It 69080 13 3 + ΚΜη04 + Η202 5 In glacial acetic acid \ / 0. p 10 Br ^ CH ~ C1% I 1 "l" CH3 l "c-OCH-CCl. ~ ° Ä 2 3 15

The product 3 obtained in the previous step was dissolved in a liter of glacial acetic acid and, with stirring at 22 ° C, a saturated aqueous solution of KMnO 2 was added dropwise until a reddish color of the rose-20 persisted (i.e., a drop instilled on a piece of filter paper gave a pinkish red spot). 30% H 2 O 2 was then added dropwise with cooling until the solution was clear; there was a little white precipitate in it. The solution was poured into 2.5 liters of water and the product was extracted into 3 x 500 mL of ethyl acetate. The ethyl acetate extracts were washed with 5% aqueous sodium bicarbonate until neutral (i.e., no more bubbling occurred upon addition), dried over sodium sulfate and evaporated to dryness to leave compound 4 as a residue. It was allowed to stand at 10 ° C for one day and then triturated with "Skellysolve B" to give 9.1 g of solid compound 4. For steps 2 and 3, the total yield was 28% of theory.

Step 4 69080 14

4 + (1) Zn in acetic acid 5 + (2) KEH

10

O \ y.O

_ ^ S ^ CU2Cl

I-1 ^ CH

I I LH3 5 (BL-P2013) / “N” · <

15 U COOK

(See U.S. Patent 4,164,497)

Zinc dust (3.75 g) was slurried in 5 ml of glacial acetic acid and cooled to 5 ° C. To this mixture was added a solution of compound 4 (3 g, 0.0057 mol) in 15 ml of dimethylformamide and the resulting slurry was stirred at 5 ° C for 2.5 hours.

The zinc was then filtered off and the pale yellow solution was poured into 80 ml of 5% aqueous hydrochloric acid. That mixture was extracted with 3 x 25 mL of ethyl acetate. The combined ethyl acetate extracts were extracted with 3 x 20 mL of 5% aqueous sodium bicarbonate, adjusting the ethyl acetate phase after separation.

The bicarbonate extracts were combined, poured under 30 layers of ethyl acetate, adjusted to pH 1.5 with 2-norm HCl and saturated with sodium sulfate. The ethyl acetate portion was separated and the aqueous phase was extracted with 2 x 30 mL of ethyl acetate.

All of the above ethyl acetate phases were combined, dried over sodium sulfate and evaporated to an oil (free of BL-P2013 acid), 11,69080 which was dissolved in about 20 ml of acetone, to which was then added 20 ml of diethyl ether. 50% Potassium 2-ethylhexanoate (KEH) in dry n-butanol was then added until the mixture was neutral. Product 5 5 (BL-P2013) crystallized apart. After stirring for 0.5 h at 22 ° C, the product was collected by filtration to give 650 mg of compound 5 (yield 37%).

A 50 mg portion of compound 5 was dissolved in 0.5 ml of water and 20 mg of N, N'-dibenzylethylenediamine 10 (DBED) diacetate was added. The DBED salt of compound 5 crystallized apart, was collected by filtration, washed with water and dried over P 2 O 4 in vacuo to give Ν, Ν'-di-benzylethylenediamine-2β-chloromethyl-20-methyl-penam-30 ° C-carboxylate sulfone ( 5 DBED-15 salts of free acid).

Another batch of compound 5 (450 mg) was dissolved in 3 ml of water, to which was added a solution of 270 mg of DBED diacetate in 2 ml of IVO. Upon scraping, the DBED salt of compound 5 crystallized apart (430 mg). Recrystallization from about 5 ml of boiling acetone gave 270 mg.

Claims (4)

1. In the preparation of the antibacterial 2β-chloro-methyl-2,6-ethylethylpenam-3 (τύ-carboxylic acid sulfone (I) as an intermediate useful 6β-bromo-2β-chloromethyl-2 <* C-methylpenamyl) 3 oC carboxylate of the formula Br + __S ® \> * · i-Γ 'ff CH 10. C-OR 0 wherein R is a benzyl or p-nitrobenzyl group. 2. An intermediate useful in the preparation of compound (I) as 6 oC-bromo-2β-chloromethyl-2 <x-methylpenam-3i * r - carboxylate sulfoxide of the formula O f Br. \> CH0C1 "~ Λ T« » 20. N '' where R is a benzyl or p-nitrobenzyl group. A process for preparing the compound of formula (II), characterized in that the compound of formula 25 wherein R has the above-mentioned meaning is heated in an inert anhydrous organic solvent in the presence of a weak tertiary amine and an acid chloride. Process for preparing the compound of formula (III), characterized in that the compound of formula (II) is oxidized in an inert solvent at about room temperature with a peracid. *