DK164938B - 2BETA-CHLORMETHYL-2ALFA-METHYL-6ALFA-BROMPENAM-3ALFA-CARBOXYLIC ACID ESTES AND PROCEDURES FOR PREPARING THEREOF - Google Patents

Description

in

DK 164938 B

The present invention relates to novel 2/1-chloromethyl-2a-methyl-6a-brompenam-3a-carboxylic acid esters of formula (III) below, and to a process for their preparation. The esters of the invention are valuable starting compounds in the preparation of 5β-chloromethyl-2ar-methylpenam-3α-carboxylic acid sulfone disclosed in Danish Patent Application No. 218/81.

By the process of Danish Patent Application No. 218/81 Example 1, 2 / J-chloromethyl-2a-methylpenam-3a-carboxylic acid sulfone of the formula 10o CH_C1 r- / 2 (I) // CH3 ΪΟΟΗ pharmaceutically acceptable salt of the acid or a readily hydrolyzable ester of the acid by oxidizing, in order a) in an inert solvent, preferably methylene chloride, a 2/3-chloromethyl-2a-methyl-6a-brompenam-3Q-carboxyl acid residues of the formula

BrV_ ^ s \ / H2C1 I Cii3 (III)

J_N-L

25 <y * j | -0R

wherein R represents benzyl or p-nitrobenzyl, at about room temperature 30 using a peracid, preferably m-chloro-peroxybenzoic acid; b) catalytic hydrogenates, e.g. with a precious metal catalyst such as palladium, an ester of the formula £ ch2c1, BIS_ 35 Γ "ch3 (ii) λ-N - \ χ

CO-R

O 2 2

DK 164938 B

wherein R * represents benzyl or p-nitrobenzyl, and then c) the hydrogenated product undergoes oxidation to produce the desired acid or salt thereof, and then, if desired, d) esterifies the acid or a salt thereof to form a light. 5 hydrolyzable ester of the acid.

Particularly valuable protecting groups for R * are the benzyl group and p-nitrobenzyl. The benzyl or p-nitrobenzyl group can be conveniently removed by catalytic hydrogenation. In this case, a solution in an inert solvent is stirred or shaken by the compound of formula (II) wherein R * represents benzyl or p-nitrobenzyl, under an atmosphere of hydrogen or hydrogen mixed with an inert diluent such as nitrogen or argon. the presence of a catalytic amount of a hydrogenation catalyst. Suitable solvents for this hydrogenation are lower all channels such as methanol, ethers such as tetrahydrofuran and dioxane, low molecular weight esters such as ethyl acetate and butyl acetate, water, and mixtures of these solvents. However, it is normal to choose conditions under which the starting material is soluble. The hydrogenation is usually carried out at a temperature in the range of about 0 to approx. 60 ° C and at a pressure in the range of approx. 1 to approx. 100 kg / cm 2.

The catalysts used for this hydrogenation reaction are of the type known in the art of transformation, and typical examples are precious metals such as nickel, palladium, platinum and rhodium. The catalyst is usually present in an amount of approx. 0.01 to approx.

2.5% by weight, and preferably from ca. 0.1 to approx. 1.0% by weight based on the compound of formula A. It is often convenient to suspend the catalyst on an inert carrier; a particularly suitable catalyst is palladium suspended on an inert carrier such as carbon.

Furthermore, it is customary to buffer the reaction mixture to operate at a pH in the range of from ca. 4 to 9, and preferably from 6 to 8. Borate and phosphate buffers are normally used. The reaction typically takes approx. 1 hour.

The novel starting compound of the invention is in the form of an "CH" Cl

Br / 2 35 ** - p f / CH3 (111) __N- a * r 3

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wherein R is benzyl or p-nitrobenzyl and is prepared by a process which is characterized by heating, preferably under reflux, a compound of the formula 5 Br · $ 7 '4a' (IV)

our

U II

Wherein R represents benzyl or p-nitrobenzyl, in an inert anhydrous organic solvent, preferably dioxane, in the presence of large and preferably equimolar amounts of a weak tertiary amine, preferably quinoline, and an acid chloride, preferably benzoyl chloride, until essentially the race has come to an end.

"Skellysolve B" is a petroleum ether fraction having a boiling point of 60-68 ° C consisting essentially of n-hexane ("Skellysolve" is a trade name of Skelly Oil Co.).

The methods of the invention are elucidated in the following Examples.

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Example 1

Primarily in 11 µg of p-ni trobenzyl-21-chloro oryl-20; -methyl-6tt-brompenam-3α-carboxylate) 0 0 ar - t: _ o N ^ CO H J- N: ^ / - \ io 2 co2-ch2- ^ o) -no2 - 2 Ψ 15

Br% _ ^ s ^ Acl Z * Vch2 <0> ™ 2 20 3_ 25 6a; -brompenic in 11 anic acid-S-sulphoxide (1) 1. 30 g (37.5 mmol) of 6a-brompenicillanic acid, N, N -di benzyl ethylene diamine salt [6. Cignarella et al., J. Org. Chem. 27, 2668 (1962) and E. Evrard, Nature 201, 1124 (1964)] are dissolved in 330 ml of methylene chloride.

Stir and cool to 0 ° C.

2. 13 ml (156 mmol) of concentrated hydrochloric acid are slowly added to the methylene chloride solution. Precipitation of the dibenzyl ethylenediamine, HCl salt (DBED, HCl) occurs within one minute. The slurry is stirred at 0-5 ° C for 10 minutes.

3. The precipitate of DBED, HC1 is filtered through a pre-coated diatomaceous earth filter ("Dicalite"). The cake is washed with 150 ml of methylene chloride. Filtering should be completed as soon as possible. The acidic methylene chloride solution should be stored for a prolonged period of time. There may be some filtering problems due to the fine nature of the precipitate. Addition of 5

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slurry filter aid may be helpful.

4. Wash the mixture of methylene chloride filtrate and washing liquid with 60 ml of cold water. Stir for 5 minutes and discard the aqueous phase. The pH of the wash liquid is 2.0-2.3.

5 5. Methyl enchl ori dopi ssion containing 6a-brompenic maleic acid is concentrated under reduced pressure to a volume of 65-80 ml. The solution is cooled and stirred to 5 ° C.

6. With vigorous stirring, carefully add 13 ml (86.9 mmol) of 40% peracetic acid over a period of 30 minutes. The reaction is exothermic.

10 The temperature is kept between 15 and 18 ° C with ice bath cooling. The sulfur oxide begins to crystallize after adding 10 ml of peracid. The slurry is cooled and stirred at 0-5 ° C for 2 hours.

7. The snow white cake is filtered and washed with 10 ml of 5 ° C water, then with 10 ml of 0-5 ° C methylene chloride and finally washed with 15 ml of heptane.

8. The cake is dried in an oven at 45 ° C to constant weight, whereby approx.

6-10 hours should be sufficient. Excessive warming can develop traces of a pinkish color. The weight of 1 is approx. 16.26 g, yield 73.24%.

9. The reaction mixture and final product can be analyzed by thin layer chromatography using solvent systems consisting of 20 parts of 15 parts of toluene / 4 parts of acetone / 1 part of acetic acid (HAC) or 8 parts of acetone / 8 parts of methanol / 3 parts of toluene / 1 part of HAC. The final product is analyzed by NMR and IR.

p-Nitrobenzyl-6a-brompenicinanate S-sulfoxide (2) To a solution of 12 g (0.04 mole) 620; -brompenicillanic acid S-sulfoxide in 100 ml of acetone was added 7.5 g (0.041 mole) potassium 2-ethylhexanoate.

The salt was collected by filtration, washed with cold acetone and air-dried to yield a total of 10 g. The crystalline potassium salt was dissolved in 75 ml of dimethylacetamide and 7.8 g (0.04 mole) of p-nitrobenzyl bromide was added. The solution was stirred at 23 ° C for 24 hours. The mixture was diluted with 500 ml of water and extracted with ethyl acetate. The ethyl acetate layer was washed four times with water and dried over anhydrous magnesium sulfate. The solvent was evaporated at 35 ° C (15 mm) to an oil which crystallized. The light tan crystals of 2 were slurried with ether and collected by filtration to yield 9 g (70%), m.p. 124-125 ° C dec.

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Analysis for C 15 H 15 BrN 2 ° 6S:

Calculated: 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), 1350 (s), 1060 (m), 740 (m) cm

H-NMR (60 mHz, DHSO) δ: 1.22 (s, 3H), 1.6 (s, 3H), 4.67 (s, 1H), 5.2 (d, J-1-5 Hz) , 1H), 5.45 (s, 2H), 5.68 (d, Jl-5 Hz, 1H), 7.5-8.5 (m, 4H).

10-p-nitrobenzyl-2β-chloromethyl-2-methyl-6-broropenam-3β-carboxyl (3)

A solution of 5 g (0.012 mole) of p-nitrobenzyl-6a-brompenicillanate S-sulfoxide (2) in 120 ml of anhydrous dioxane was heated at reflux under nitrogen for 4 hours with 1.5 g (0.012 mole) of quinoline and 1 6 g (0.012 mol) of benzoyl chloride. The solution was diluted with 600 ml of water and extracted with ethyl acetate. The ethyl acetate extract was washed with 5% sodium bicarbonate solution, 5% phosphoric acid solution and finally with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated to an oil at 35 ° C (15 mm). The oil crystallized and collected, washed with ether and finally with cold toluene to give a yield of 3.5, 3.5 g (65%), m.p. 130-135 ° C dec.

Analysis for CjgHjgCIBrNgOOS:

Calculated: 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), 10,1025 (w), 990 (w), 750 (w) cm "1.

NMR (60mHz, DMSO) i: 1.45 (s, 3H), 3.5-4.3 (m, 2H), 5.05 (s, 1H), 5.42 (s, 2H), δ 5 (d, J-1.5 Hz, 1H), 5.62 (d, J-1.5 Hz, 1H), 7.5-8.5 (m, 4H).

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Example 2

Preparation of the starting material p-nitrobenzyl-6oc-brompenic acid in sodium sulfide oxide

5 O

Br Τ '*

Ir! + · TEA + BrCH2 - </) ^ NOO> _ (101) O% 0 H (2l6) 10 (296) v /

Br · *. You 15 \ -V ^^ / = \ ° C02CV ^ Jv- N02 20 '(431.28)

Course of action:

To 200 ml of N, N-dimethylacetamide was added 44 g (0.148 mole) of 6a-bromo-penicillanic acid sulfoxide followed by 20.5 ml (0.148 mole) of triethylamine and 38.2 g (0.177 mole) of p-nitrobenzyl bromide. Stir at 22 ° for 20 hours.

The reaction mixture was poured into 1 liter of HgO and extracted into 3 x 300 ml of methylene chloride. The combined methyl chloride extracts were washed with 200 ml of 5% aqueous sodium bicarbonate solution and dried over sodium sulfate at 5 ° for half an hour. The solution was filtered and evaporated under vacuum to a residue. The residue was diluted with ether and the solid collected by filtration to yield 54 g of p-nitrobenzyl-6a-brompenicillinate sulfoxide after drying. Yield 85%. NMR was consistent for structure.

The yield in this step was the same as for the K-salt esterification. The advantage was that it was not necessary to prepare the K salt.

(A step that proceeds with a yield of 85-90%).

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Example 3

Preparation of the starting material p-nitrobenzyl-60; brompenic acid 11 anate sulfoxide

To 4,375 liters of Ν, Ν-dimethylacetamide was added 873.0 g (2.95 mole) of 6α-brompenicilic acid (S) sulfoxide and then, with stirring and while keeping the internal temperature below 35 ° C, 293 g (2). 95 moles of triethylamine followed by 764 g (3.54 moles) of p-nitrobenzyl bromide. The mixture was then stirred at room temperature for 5 hours and left overnight.

The reaction mixture was poured into 20 liters of water and extracted with 10 3 x 7 liters of methylene chloride. The combined organic extracts were washed with 5x7 liters of water and then with 7 liters of 5% aqueous sodium bicarbonate solution and dried over magnesium sulfate.

The magnesium sulfate was filtered off and the solution evaporated to a crystalline residue; 4 liters of diethyl ether were added and the crystals were collected to yield, after drying at room temperature, 1171 g (92%) of p-nitrobenzyl-6a-brompenicillanate sulfoxide.

Br 18.48% (calculated 18.53%), <* D (0.25% MeOH) + 162 °.

Example 4 Preparation of the starting material 60; -brompenicinanoic acid sulfoxide in - - +

Br, _Br ΓΧ / -> DJ * '6 ^ o2e: o ^ co2h MW 800.64 MW 296.14 30

To 3 liters of methylene chloride was added 300 g (0.75 mol) of 6α-brompenicilanoic acid N, N'-dibenzylethylenediamine salt and this suspension was cooled to 5 °. Then, under good stirring, 130 ml of concentrated HCl was added dropwise over 15 minutes. The slurry was stirred at 5 ° for 2 hours. It was then filtered through a ("Celite") pad of diatomaceous earth and the cake washed with 3 x 250 ml of methylene chloride.

The combined methylene chloride solutions were washed with 2 x 500 ml HgO and dried over sodium sulfate for 15 minutes. The sodium sulfate was removed

DK 164938B

9 by filtration and the filtrate was evaporated under reduced pressure to ca.

750 ml.

This solution was cooled to 5 ° and, with vigorous stirring, 130 ml of 40% peracetic acid was added dropwise, keeping the temperature 5 at 5-12 °. The addition was completely exothermic. At the end of the addition, the slurry was stirred at 5 ° for 2 hours, and the product was collected by filtration and washed with 100 ml of cold H2 O (5 °) and 100 ml of cold methylene chloride (5 °). 126 g (57%) of the 6ar bromine were obtained in c1 11 anic acid sulfoxide, m.p. 129 °. The IR and NMR spectra were consistent for the desired product.

Analysis for Cg H10BrNO4S:

Calculated: C: 32.44, H: 3.40, N: 4.73.

Found: C: 32.30, H: 3.35, N: 4.71, H 2 O: 2.18.

Preparation of the starting material potassium 6a-brompenicillanate sulfoxide

ISLAND

0 "♦

t B? .S

. 'Tfx - TO-

O% CO 2 H

..MW

To 3 liters of acetone was added 126 g (0.43 mole) of 6α-brompenicillanic acid sulfoxide and 162 ml of 50% by weight potassium 2-ethylhexanoic acid in n-butanol.

After stirring for 1 hour at 22 °, the product was collected by filtration, washed with 2 x 250 ml of acetone and dried. 127 g (90%) of potassium 6a-brompenicillanate sulfoxide, m.p. 185 °. The IR and NMR spectra were consistent for the desired structure.

Analysis for CgHgBrKNO4S:

Calculated: C: 28.75, H: 2.71, N: 4.19.

Found: C: 29.03, H: 2.78, N: 4.04.

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Preparation of the starting material p-nitrobenzyl-60; brompenicillanate sulfoxide

ISLAND ISLAND

ώ + Br Λ 5

Jr- - '' sCOzK J— * C02 MW 431-28 10

To 1 liter of Ν, Ν-dimethylacetamide was added 145 g (0.43 mole) of potassium 6a-brompenicillanate sulfoxide and, with stirring, 115 g (0.53 mole) of p-nitrobenzyl bromide was added at 22 °. The mixture was stirred at 22 ° for 20 hours.

The reaction mixture was poured into 3 liters of HgO and extracted with 3 x 1500 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 2 x 500 ml 5% aqueous sodium bicarbonate solution and dried over sodium sulfate for ½ hour. The sodium sulfate was filtered off and the filtrate was evaporated under reduced pressure to a residue to which was added 1 20 liters of diethyl ether which caused crystallization of the product. The crystals were collected by filtration, washed with 2 x 100 ml diethyl ether and dried to yield 162 g (87¾) of p-nitrobenzyl-6a-bromo-penicillanate sulfoxide, m.p. 111 °. The IR and NMR spectra were consistent for the desired structure.

Analysis for CjgHjgBrNgOgS:

Calculated: C: 41.78, H: 3.51, N: 6.50.

Found: C: 41.66, H: 3.45, N: 6.85, HgO: 0.69.

Preparation of the product p-nitrobenzyl-6ft-bromo-2g-chloromethyl-2-30 methylpenam-3-carboxyl at σ * A Br _> S iCH 2 Cl 1 "i- {" Ί-. _ ^ r ~ f p "CH, 35 J—"% CEfi \ Nn <t ~ h _ O C02CH2Aci / N02 C02C ^ - \ y — K02 MW 449.71

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π

To 1 liter of p-dioxane was added 70 g (0.16 mole) of p-nitrobenzyl-6a-bromo-penicillanate sulfoxide, followed by 21.2 ml (0.10 mole) of benzoyl chloride and 21.8 ml (0.19 mole). quinoline. The reaction mixture was refluxed for 4 hours and then cooled to 22 °, poured into 2500 ml of HgO and extracted 5 in 3 x 800 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 300 ml of 5% aqueous sodium bicarbonate solution, 300 ml of 5% aqueous phosphoric acid and 300 ml of HgO. The ethyl acetate solution was dried over sodium sulfate for ½ hour and the sodium sulfate removed by filtration. The filtrate was evaporated under reduced pressure to a residue which was redissolved in 1 liter of ethyl acetate and again evaporated under reduced pressure to a residue.

Then 1 liter of diethyl ether was added and the product was collected by filtration to yield 41 g (57%) of p-nitrobenzyl-6α-bromo-2β-chloro-methyl-2-methylpenam-3-carboxylate, m.p. 132 °. The IR and NMR spectra were consistent for the desired structure.

Analysis for CjgH₂ ^BrClNOO₂S:

Calculated: C: 40.06, H: 3.14, N: 6.23.

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

Example 5 Preparation of the potassium salt of 2fl-chloromethyl-2tt-methylpenam-3tt-carboxyl sulfone I (the BL-P2013 disclosed in Danish Patent Application No. 218/81)

Br,. ^ PH, C1 Br __ ^ 'S \ /' ™ 2C1 25 ppp2 _ pi 3 OJ (n ^ co2-CH2p) -No2

30 in I

Ψ - O - o -v / 0 • f CH-C1 A.CHLC1 n ^ Å

35 rppcH2 ^^ pi '^ h3 / -N — ΐθ2Η r- "^ CO2K

p

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12 p-Nitrobenzyl-2fl-chloromethyl-2a-methylpenam-6ct carboxylate sulfoxide (4)

A solution of 1 g (0.0022 mol) of p-nitrobenzyl-30-chloromethyl-dimethyl-6a-brompenam-3a-carboxyl (3) dissolved in 50 ml of methylene chloride was stirred with 473 mg (0.0022 mol) of m-chloroperoxide benzoic acid. . The solution 5 was stirred at 23 ° C for 3 hours. It was evaporated to 20 ml at 15 mm and 33 ° C, and the concentrated solution was diluted with 50 ml of heptane (Skellysolve B). The solvent was decanted and the residue slurried with ether, and (4) soon crystallized in a yield of 250 mg, 24%, m.p. 136-137 ° C dec.

Analysis for CjgH₂ ^ BrClNNO₂S:

Calculated: 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), 830 (w), 740 (w) cm

1 H-NMR (60 mHz, DMSO) δ: 1.32 (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 Hz, 1H), 7.8- 8.5 (m, 4H).

Potassium 28-chloromethyl-2o; -methylpenam-3tt-carboxylate sulfone (5) (BL-P2013) To a solution of 7 g (0.015 mole) of p-nitrobenzyl-2 6a-brompenam-3tt-carboxylate sulfoxide (4) in 150 ml of ethyl acetate was added a suspension of 4 g of 30% palladium-on-diatomaceous earth ("Celite") and 2.8 g of sodium bicarbonate in 150 ml of water. The mixture was hydrogenated for 3 hours at 50 psi. The catalyst was separated by filtration and the aqueous layer was separated and treated with 1.5 g of potassium permanganate in 50 ml of water. The mixture was stirred for 1 hour and 250 ml of sodium bisulfite was added. The mixture was filtered and the filtrate was adjusted to pH 2 with concentrated hydrochloric acid. The solution was lyophilized to form a white amorphous powder. The solid was extracted with ethyl acetate, evaporated to a volume of 20 ml and diluted with 100 ml of heptane (Skellysolve B). White, hygroscopic solid 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid sulfone was collected. The acid was dissolved in acetone and treated with solid potassium 2-ethyl hexanoate. A crystalline white salt precipitated to form, after filtration, 170 mg of 5, m.p. > 140 ° C dec.

Analysis for CgHyClKNOgS3 HgO:

Calculated: C: 28.27, H: 3.24, N: 4.12.

Found: C: 28.27, H: 3.69, N: 3.84.

IR (KBr): 1790 (s), 1770 (m), 1620 (s), 1460 (m), 1370 (s), 1310 (s), 13

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1200 (s), 1140 (s), 955 (m), 740 (m) cm -1.

H NMR (100 mHz, D 2 O) δ: 1.68 (s, 3H), 3.2-3.9 (m, H ~ 2 Hz, J ~ 4 Hz, J-6 Hz, 2H) 0-4.4 (m, 2H), 4.3 (s, 1H), 5.02 (dd, J ~ 4 Hz, J ~ 2 Hz, 1H).

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Claims (3)

Br'-w-sVH2C1 'CII3 (III) <y ^ ~ ° R 10 wherein R represents benzyl or p-nitrobenzyl. A process for the preparation of a compound according to claim 1, characterized in that a compound of the formula is heated. Wherein R represents benzyl or p-nitrobenzyl in an inert, anhydrous organic solvent in the presence of large, preferably equimolar, amounts of a weak tertiary amine, and an acid chloride until the reaction is substantially complete. 25 30 35