FI59410C - MELLAN PRODUCTS FOR FRAMSTAELLNING AV EN PTHALIDESTER AV 6- (D (-) - ALPHA-AMINOPHENYLACETAMIDO) PENICILLANSYRA - Google Patents

Description

ι, τ ^ ·;, | r, advertisement publication COil, A

w (11> utlAggningsskrift 5 9410 (51) Kv.ik.Wct3 σ 07 D * 99 / * 2. * 99/32 FINLAND — FINLAND (21) 773i99 (22) HtkmrttfUH - Ai · ** · ***** 26.10.77 '(23) Alkuptfvt — GtoglMtadac 06.06.72 (41) ThHm («IklMiial — Mivk eHwtNf 2g q jj PMmttl · and rakistarihHtut (44) NihtivtktlpMon i · iuwt | vHuinM pvm.— · h * r * tyr «lMn 'AiwMtan uthfd octi utUkrUMn pvMc * rad 30,01.81 (32) (33) (31) * rr *« * y · ο · * λ «· -» «*» η prtork * 09.06.71 United Kingdom-United Kingdom (GB) I960I / 71 (71) Beecham Group Limited, Beecham House, Great West Road, Brentford, Middlesex, United Kingdom-United Kingdom (GB) (72) John Peter Clayton, Horsham, Sussex, Harry Ferres , Horsham, Sussex, United Kingdom-Storbritannien (GB) (7b) Berggren Oy Ab (5l) Intermediate 6 - / D (-) -0 <: - which does not give a phthalide ester of silyanic acid - Mellanprodukt för framställning av en ptalidester av 6- / 1) (-) - ftr-aminophenylacetamido / penicillansyra (62) Divided by application 1597/72 (patent 58612) -Avdelad fr & n ansokan 1597 / 72 (Patent 58612) This invention relates to a novel intermediate for the use of a phthalide ester of 6- [D (-) - α-aminophenylacetamido] penicillanic acid of formula 1 / r (D) / oh3.

<y— CH - CO - NH - CH - CH C

III CIi3

NH "CO - N -CH- CO - O - CH

to prepare ti (I) 0 and pharmaceutically acceptable acid addition salts thereof.

The new intermediate 6-aminopenicillanic acid phthalic diester has the formula 59410 2 / Ch3 NH2 - CH - CHCl2 I oh3 / h

CO - N -CH - CO - 0 - C

c/o

II

o 6- / D (-) - α-Aminophenylacetamido7penicillanic acid is a widely used broad-spectrum antibiotic. However, when taken orally, it is not completely absorbed into the blood. Some medical practitioners believe that this is detrimental, and therefore few attempts have been made to find 6- / D (-) - α-aminophenylacetamido-7-penicillanic acid derivatives that would give higher blood concentrations of cantapenicillin after oral administration than those available in their own capsules.

It is an object of the present invention to provide an intermediate for the preparation of a novel 6- / D (-) - α-aminophenylacetamido] penicillanic acid ester which is hydrolyzed only in the blood and gives higher oral whey concentrations of cantapenicillin than the above-mentioned known compounds.

The preferred acid addition salt of the compound of formula I is the hydrochloride, but salts of other inorganic or organic acids may also be used, especially those used to form salts with 6- / D (-) - α-aminophenylacetamido] penicillanic acid itself. The compound of formula I further forms salts with other penicillanic acids, e.g. 3- (2'-chloro-61-fluorophenyl) -5-methyl-N-isoxazolylpenicillin.

The ester of formula I can be prepared from the intermediate 6-aminopenicillanic acid phthalide ester of the invention by reacting this or a silyl derivative thereof with a reactive N-acylating derivative of the (D) -isomer of a compound of formula (II) CH - COOH (II) X · 359410 wherein X is an amino group, a protected amino group or an azide group in a known manner, wherein the silyl group, if present, is removed by hydrolysis or alcoholysis, and if X is not an amino group, it is reacted into such a group under neutral or acidic conditions.

By the silyl derivative of the phthalide ester of 6-aminopenicillanic acid is meant the reaction of a β-aminopenicillanephthalide ester with a silylating agent such as a halotrialkylsilane, a dihalodialkylsilane-arylisilane and an arylisilane arylisilane Halogenotrialkylsilanes are generally preferred, especially trimethylchlorosilane. Silylated derivatives of 6-aminopenicillanic acid phthalide ester are highly sensitive to moisture and hydroxyl compounds, and after reaction with a reactive derivative of compound (II), the silyl group of the acylated intermediate compound can be removed by hydrolysis or alcoholysis.

Compound (11) has a group X amino group, an amino group protected in a known manner or an azide group.

Examples of the protected amino group include a protonated amino group (X = NH *) which, after the acylation reaction, can be reacted to a free amino group by simple neutralization, and various groups which regenerate the amino group in the mild acid hydrolysis after the acylation reaction. Examples of such groups are enamine groups of general formula (III) or tautomeric modifications thereof and α-hydroxyarylidene groups of general formula (IV) or tautomeric modifications thereof: R 1 sCH v - C N - / ^ C N -, 11 U:

R - C H H

0 '0 (III) (IV)

In formula (III) and (IV), the dashed lines denote hydrogen bonds. In formula (III), R is a lower alkyl group, R is either a hydrogen atom or together with the group forms a carbocyclic ring, and R 1 is a "lower alkyl, aryl or lower alkoxy group. In formula (IV), Z represents a substituted or unsubstituted a residue of a benzene or naphthalene ring.Basic hydrolysis is generally not used because the hydrolysis of the phthalide group takes place under basic conditions.

The azide group is converted to a Ni 2 group by either catalytic hydrogenation or electrolytic reduction.

The above process uses a reactive N-acylating derivative of acid (II), the chemical nature of the α-substituent X will, of course, influence the choice of the reactive derivative. Thus, when X is an acid stable group such as a protonated amino group NH * or an azido group, it is often convenient to react the acid (II) to an acid halide, e.g. by treating it with thionyl chloride or phosphorus pentachloride to give the acid chloride.

However, such reagents should be avoided when X is an acid labile group of type (III) or (IV). In such cases, it is often appropriate to use mixed anhydride. Particularly suitable mixed anhydrides for this purpose are alkoxy formic anhydrides, which are preferably prepared by treating the alkali metal or tertiary amine salt of acid (II) with a suitable alkyl chloroformate in an anhydrous medium at or below room temperature.

Other reactive N-acylating derivatives of acid (II) are the reactive intermediate formed in the in situ reaction of carbodiimide or carbonyldiimidazole.

The intermediate 6-aminopenicillanic acid phthalide ester of the invention can be prepared, albeit in poor yield, by coupling β-aminopenicillanic acid directly to 3-bromophthalide in the presence of a base. In this process, some epimerization occurs at the Cg position and therefore this process is not completely satisfactory.

Much better yields of 6-aminopenicillanic acid phthalide diester can be obtained by coupling an N-protected derivative of 6-aminopenicillanic acid (e.g. triphenylmethyl derivative) with 3-bromophthalide and then removing the protected group (e.g. by slight acid hydrolysis in the case of a triphenylmethyl derivative).

Alternative types of N-protected 6-aminopenicillanic acids are 6-acylaminopenicillanic acids. Techniques for removing the 6-acyl side chain from, e.g., benzylpenicillins and phenoxymethylpenicillin are well known (see British Patent No. 1,189,022) and generally involve treating the 6-acylaminopenicillanic acid ester with 6-acyl amidoside to form the phosphorus pentachloride. the iminochloride is treated with an alcohol to form an iminoether and then the imino bond is hydrolyzed to form a 6-aminopenicillanic acid ester. In the present case, it is possible to start from a phthalic diester of penicillin G or penicillin V prepared, for example, by reacting the sodium or potassium salt of penicillin with 3-bromophthalide and cleaving the acyl side chain to prepare a phthalide ester of 6-aminopenicillanic acid.

The 6- [D (-) - o-aminophenylacetamido] penicillanic acid phthalide ester prepared from the intermediate of the invention is well absorbed when administered orally to humans and animals. High concentrations of strain-6- / D (-) - α-aminophenylacetamido7penicillanic acid are obtained in the blood whey.

The invention is described in more detail below by means of examples:

Example 1 (a) 3-Bromophthalide- [3-bromo-1- (3H) -isobenzofuranone.7

Phthalide (10.0 g, 0.075 mol) and N-bromosuccinimide were refluxed in dry carbon tetrachloride (200 mL) in the presence of a catalytic amount of α-azoisobutyronitrile for 3-4 hours. Completion of the reaction was manifested by the disappearance of N-bromosuccinimide from the bottom of the reaction vessel and the accumulation of succinimide at the top. The succinimide was removed by filtration and the filtrate was concentrated in vacuo to 15-20 mL. By cooling this concentrate and filter. after that, 13.0 g (8l of Y5 yield) of crude 3-bromophthalide are obtained, m.p. 75-80 ° C as a white crystalline solid. The product was recrystallized from cyclohexane as colorless plates, m.p. 78-80 ° C 95 5! »In the same yield.

N.m.r. (CCljj) B- δ = 7.67 (4H.m. aromatic), δ = 7.38 (1H.s. CH-)

> A

6 and 5941 0

Example 2

Phthalide 6-aminopenicillanate

Method 1

A mixture of 6-aminopenicillanic acid (10.8 g, 0.05 M) and triethylamine (6.9 mL, 0.05 M) was stirred in dry acetone (20 mL) for 1/2 hour at ambient temperature. The mixture was cooled to 0 ° C and a solution of 3-bromophthalide (10.65 g, 0.05 M) in dry acetone (20 ml) was added in one portion and the resulting yellow mixture was stirred at ambient temperature for 5 hours. The reaction mixture was diluted with dry diethyl ether (150 mL) and filtered. The clear yellow filtrate was washed with 1N sodium bicarbonate (100 mL) and brine (100 mL). A solution of p-toluenesulfonic acid monohydrate (9.5 g, 1 equivalent) in dry acetone (150 mL) was added to a clear dry yellow filtrate and phthalide epi-6-aminopenicillanate immediately crystallized from solution as the p-toluenesulfonate salt.

6-a (trans) isomer: n.m.r. / (CD3) 2SO7: L δ = 7.84 (4H.s. phthalide aromatics) δ = 7.58 (1H.s. CO.O.CH), δ = 7.30 (4H.q. sulfonate aromatics), δ = 5.35 (1H, C-5 proton, J = 2 Hz), δ = 4.89 (1H, C-3 proton) δ = 4.70 (1H, C-6 proton). proton, J = 2Hz), δ = 2.30 (3H.s. CH3), δ = 1.48 (6H.d. gemdimethyl).

The infrared spectrum (KBr plate) had strong lines ranging from 1780 cm-1 1210 cm-1170 cm-111010 cm -1,970 cm -1,682 cm 1,574 cm The residual oil was obtained from the mother liquor to give a small amount (about 5%) of phthalide. A reasonably pure sample of the natural cis isomer of -6-aminopenicillanate as its p-toluenesulfonate salt, 7,59410 by repeated crystallization of the 6-α (trans) isomer from an acetone: ether solvent mixture (3: 1).

6 - $ (cis) isomer: n.m.r. Δ = 7.84 (4H.s. phthalide aromatics), δ = 7.58 (1H.s. CO 0 CH), δ = 7.30 (4H.q. sulfate aromatics), δ = 5.50 (1H.d. C-5 proton, J = 4Hz), δ = 5.14 (1H.d. C-6 proton, J = 4Hz), δ = 4.68 (1H.s. C-3 proton), δ = 2.27d (3H.s. CH 2), δ = 1.53 (6H.d. gem dimethyls).

‘_ Ί

In the infrared spectrum (KBr plate) strong lines in the values 1780 cm 1210 cm-1 1170 cm "1 1010 cm'1 970 cm'1 682 cm" 1 574 cm "1.

Method 2

A solution of 6-tritylaminopenicillanic acid (9.8 g, 0.02 M) in dry acetone (100 mL) was cooled to 0 ° C, triethylamine (2.9 mg, 0.02 M) was added followed by 3 “Bromophthalide (4.1 g, 0.02M) in dry acetone (20 mL) and the reaction mixture was kept at 0 ° C with stirring for 2 hours and finally at ambient temperature for 1 hour. The precipitated triethylammonium bromide was removed by filtration, the evaporated filtrate was dissolved in ethyl acetate (150 ml) and after two washes with cold aqueous sodium bicarbonate 255 (2 x 150 ml) and ice water (2 x 100 ml) and the ethyl acetate layer was dried over anhydrous magnesium sulphate to give solvent silicon removed in vacuo, phthalide-6-tritylaminophenicillanate as a white amorphous solid.

n.m.r. / TCD 2) 2 SO 7: δ = 7.4 (20H. Broad single line with small shoulder at δ = 7.80, aromatic protons and CO 0 CH-), S f 4.41 (2H.m. (3-lactam protons)) , δ = 4.15 (1H. broad single line C-3 proton), δ = 1.38 (6H.d. gem-dimethyls).

In the infrared spectrum (KBr plate) strong lines in the values 1745 cm "1 980 cm 1 750 cm 1 708 cm 1.

Phthalide-6-tritylaminophenicillanate (5.9 g, 0.01 M) in acetone (200 mL with 0.2¾ water) was treated with p-toluenesulfonic acid monohydrate (1.9 g, 0.01 M). After standing at room temperature for 2 hours, water (0.25 ml) was added and a precipitate of phthalide-6-aminopenicillate p-toluenesulfonate was obtained by slow addition of petroleum ether, b.p. 40-60 ° C (250 mL). Filtration and repeated washing with petroleum ether give the crude p-toluenesulfonate salt. The sample was recrystallized from acetone-diethyl ether in $ 85 yield.

e 59410 n.m.r. / JCD ^) SO7: δ = 7.8 * 1 (*! Hs phthalide aromatics), δ = 7.58 (1H.s. -C0.0 CH-), δ = 7.30 (* 1 * 1.9 q · sulfonate aromatics), δ = 5.50 (1H.d. β-lactams, J = * 1Ηζ), δ = 5.1 * 1 (1H.d. β-lactam, J = * 1Hz), 6 = * 1.68 (1H.s. C-3 proton), δ = 2.27 (3H.s. CH-j), δ = 1.53 (6H.d. gem dimethyls).

C23H2 * 1N2S2O8 requires: C 53.08, H * 1.61, N 5.39, S 12.31.

found: C 52, 32, H 4.60, N * 1.9 * 1, S 12.27.

Method 3

Bentsyylipenisiiliftalidiesteri

The potassium salt of benzylpenicillin (20.0 g, 10.05 x 1 mol) was dissolved in dry dimethylformamide (50 ml) and cooled to 0 ° C. To this stirred solution was added 3-bromophthalide (11.5 g, 0.05 x 1 mol) in dry dimethylformamide (20 mL) in a single portion. The reaction mixture was allowed to warm to room temperature and then stirred for an additional 2 hours. The mixture was then poured into ice-cold water (600 ml) and stirred vigorously. The distinctive white solid precipitate was collected and washed well with water. After drying, the material was recrystallized from hot isopropyl alcohol to give a white crystalline product (10.5 g, * 11.9Ϊ), m.p. 167-169 ° C.

The infrared spectrum (Nujol) contained m.m. strong lines: 1770 cm-1 1678 cm "1 152 * 1 cm 1 970 cm" 1.

n.m.r. / TCD 2) 2 SO / D 2 O 7 contains peaks in the values: δ = 7.88 (* 1HH. Phthalide aromatics), δ = 7.61 (1H.s. CO.O CH-), δ = 7.28 (5H. s. aromatics), δ = 5.55 (2H.m. β-lactams), δ = * 1.55 (1H.s.-proton), δ = 3.56 (2H.s. PhCH2CO), δ = 1.53 (6H.d. gem dimethyls).

The purity was arranged by hydroxylamino test and was 109.2%. Found C 61.55, H * 1.90, N 5.87, S 6.72, C 21 H 22 N 2 SO 6 found: C 61.80, H * 1.72, N 6.02, S 6.86.

Benzylpenicillin phthalide ester (11.6 g, 0.025 M) was dissolved in dry methylene dichloride (250 mL) and cooled to -25 ° C. N-methylmorpholine (5.60 mL, 0.025 M) was added followed by a solution of phosphorus pentachloride (6.0 g) in methylene dichloride (150 mL) over 5 minutes. A pale yellow color appeared and after stirring for 1/2 hour the temperature rose to 0 ° C. The reaction mixture was re-cooled to -25 ° C and N-methylmorpholine (5.60 mL) and dry methanol were added to give a slow temperature rise to about -10 ° C.

After stirring at -5 to 0 ° C for 2 hours, water (400 ml) was added with vigorous stirring until the pH of the mixture was adjusted to 1.2-6.0 with dilute sodium hydroxide solution.

The organic phase was separated, washed with water and brine, and filtered through silicone paper.

A solution of p-toluene, sulfonic hup monolithium hydrate (4.75 G, 0.025 M) in acetone (100 mL) was added with stirring to the organic layer and ether was added until the solution became cloudy. After standing overnight at 0 ° C, 7.0 g of white crystalline 6-aminopenicillanic acid phthal ester di-p-toluene sulfonate were obtained and a further 2.5 g were obtained by concentrating the supdate. Total yield = 9.5 g, 75.4¾.

n.m.r. (JCD ^ pSO '): δ - 7.84 (411.s. phthalide aromatics), δ = 7.58 (1H.s. -C0.0 CU) δ =. 7.30 (4H.s. sulfonate aromatates), δ = 5.50 (1H.d. β-lactam, J = 4Hz), δ = 5.14 (III.d. 6-lactam, J = 4Hz), δ = 4.68 (li. S. C 1 proton), δ = 2.27 (3H.s. CH 2 -), δ = 1.53 (6H, d. Gem-dimethyl).

° 23Η24Ν2Γ'2ύ8 requires: C 53.08, N 4.61, N 5.39, S 12.31

Found: C 52.50, H 4.62, N 4.98, S 12.34.

Example 3

Ampicillin phthalide ester (I) by coupling phthalide-6-aminopenis11a-enate with enamine-protected α-aminophenylacetic acid-Selca anhydride over f ~ \ (D) (D) ζ J "over - CO 2 Na Vy f 1" CO ", ° COOC 2 n 5 / N \ / N \

CIU-C H CH, -C II

3 !! ! 3 II

CI | J>, CH 0

Y

OOH3 OCHj \ \ 6-APA- phthalide __ S *

^ V-CHCONH - T-f V

(I) <-SLiύ / "N J — N-Lc0.

“* 1 ϊ <Vi cv °. y ° OCH7j 10 5941 0

Phthalide-6-aminopenicillanate p-toluenesulfonate (10.4 g) was suspended in ethyl acetate (60 ml) and stirred vigorously with 1N sodium bicarbonate (135 ml) for 20 min. at ambient temperature. The organic layer was separated, washed with water (100 ml) containing 2% sodium bicarbonate (5 ml) and dried over anhydrous magnesium sulfate, filtered and kept at -15 ° C.

Sodium D (-) - N- (1-methoxycarbonylpropen-2-yl) -α-aminophenylacetate mixed anhydride (5.4 g) in ethyl acetate (30 ml) was prepared by adding ethyl chloroformate (2 ml) and pyridine ( 2 drops) at -15 ° C and stirring the reaction mixture for 10 min. at a temperature between -15 and -20 ° C. To this mixed anhydride solution was added an ethyl acetate solution of phthalide-6-aminopenicillanate, and the mixture was stirred at -15 ° C for 15 min. and then another 45 min. without additional cooling.

Water (75 ml) was added, then 2N hydrochloric acid (10 ml) and the reaction mixture was stirred vigorously for 25 min. Petroleum ether, b.p. 60-80 ° C (250 ml) was added slowly with stirring. The aqueous layer was separated and saturated with sodium chloride, and the separating oil was extracted with ethyl acetate (2 x 100 mL) and dried over anhydrous magnesium sulfate.

After filtration, the solution was concentrated in vacuo to about a quarter of its volume, dry ether (about 250 mL) was added slowly, and the ampicillin phthalide (4.0 g, 40%) precipitated as a white amorphous hydrochloride salt was collected and washed well with ether. Hydroxylamine test = 76.1 #, iodometric test = 77.5%, chlorine content = 7.07% (theoretical = 6.85%).