FI66187C - MELLAN PRODUCTS FOR FRAMSTAELLNING AV EN PTHALIDESTER AV 6 (D (-) - ALPHA-AMINOPHENYLACETAMIDO) PENICILLANSYRA - Google Patents

Description

___. 1 .1 r-, ANNOUNCEMENT

l J 0υ uTLAeeNiNcssKiiiPT 66187 ^ Patent aeddolat ^ ^ (S1) Kv. »? / iat.a3 C 07 D 499/68

FINLAND-FINLAND 79l6i.O

(22) HvIrvinl ^ lM - AmBtailmrig 23.05.79 (23) Alkvpilvt — GMöfh «it * d« f 06.06.72 (41) TiHfcKh »HUwtal - Mtvkallm * Mg 23.05.79 PManctl · ja rnkicfearlhallMm / 44) rTin- ifu ^ mm) · kMijuiiaiaM, date. -

Patent · och ragfitnMtyral— * AmCk— miagä od> mljfcrtto pwblicfd 31.05.84 (32X33X31) Py »4wy« cndtow-a ^ ird »rtertt * 09.06.71 United Kingdom-Storbritannien (GB) 19604/71 (71) Beeeham Group Limited, Beecham House, Great West Road, Brentford, MiddIesex, Iso-B ri Tann i a-Storbr i Tann ien (GB) (72) Harry Ferres, Horsham, Sussex, John Peter Clayton, Horsham, Sussex, 1so-Br i Tann ia-Storbr i tannien (GB) (74) Berggren Oy Ab (54) Intermediate for the preparation of phthalide ester 6- / 0 (-) - ° fc-aminophenylacetamido7penisulanic acid - Mellanproduct för framstälIning av en phthalidester av 6- / 0 (-) -t * -aminophenylacetamido7penicillan (62) Separated from application 773199 (patent 59410) -Avdelad frän ansÖkan 773199 (patent 59410) The present invention relates to a novel intermediate used in formula (I) fVr-CO - * - CH-c / SXC / CH3 IIII ^ ch3

NH „CO - N - CH - CO - O - CH

OQ

II

(i) o and pharmaceutically acceptable acid addition salts thereof.

The new intermediate has the formula 2 661 87 / τ \ ^ 8 ^ I | | ^ CH3

CO - N - CH - CO - O - C

II

o wherein X is an azido group or an enamine group of the formula R 1 2 -C -CR f (III) r 3 -C h V "1 2 3 wherein R is a lower alkyl group, R is a hydrogen atom and R is a lower alkoxy group.

6- / D (-) - α-aminophenylacetamido / penicillanic 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] enicillanic acid derivatives that would give higher blood concentrations of cantapenicillin after oral administration than can be obtained with cantilenic acid itself.

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.

3 66187

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- [5 (-) -. Alpha.-aminophenylacetamido] penicillanic acid. The compound of formula I further forms salts with other penicillanic acids, e.g. 3- (2'-chloro-6'-fluorophenyl) -5-methyl-4-isoxazolylpenicillin.

The compound of formula (I) in the form of an acid addition salt can be converted into the corresponding free amino compound by simple neutralization.

The intermediate of the invention can be converted to the ester of formula (I), depending on the nature of the group X, in the following ways.

The azido group is reacted to form an NH2 group by either catalytic hydrogenation or electrolytic reduction.

The enamine group of formula (III) or a tautomeric modification thereof is reacted to form an N 2 group by mild acid hydrolysis.

The intermediate of the invention can be prepared by reacting a 6-aminopenicillanic acid phthalic diester or a sylvyl derivative thereof with a reactive N-acylating derivative of the (D) -isomer of a compound of formula (II) CH-COOH (II)

X

wherein X is as defined above, wherein the silyl group is removed in the presence of it by hydrolysis or alcoholysis, or by reacting a compound of formula (V) 4 66187 / T 1 -C 1-3 ('x> - CH - CO - NH - CH - CH C (V) w I III ch3

CO - N - CH-COOA

wherein A represents hydrogen, a salt-forming ion or an organic acyl group and X represents the same as above, to react with a compound of formula (VI)

B H

"'c ^ <cj0

II

o wherein B represents a hydroxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group or a halogen atom.

By silyl derivative of a phthalide ester of 6-aminopenicillanic acid is meant the reaction of a 6-aminopenicillanephthalide ester with a silylating agent such as a halotrialkylsilane, dihalodialkylsilane, azalylethylsilane and haloalicylsilane In general, halogenotrialkylsilanes are 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.

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

However, such reagents should be avoided when X is an acid-labile group of type (III). In such cases, it is often appropriate to use mixed anhydride. Particularly suitable mixed anhydrides for this purpose are alkox 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 compound of formula (V) is preferably reacted in the form of the sodium or potassium salt with the compound (VI) in which B is a halogen atom, in particular bromine or chlorine.

In case the group A in the reagent (V) is hydrogen or a salt-forming ion and the group B in the reagent (VI) is a hydroxy group, it should be noted that the hydroxy compound (VI) is in fact in equilibrium as follows:

HO. / H

<2> H 2 O 2 (VI) (VIII) and in fact may be such that the isomer (VIII) reacts. In this case, however, an alkylsulfonyl ester or an arylsulfonyl ester is preferably used instead of the hydroxy compound (VI), since this gives The presence of a base is usually necessary in this reaction to obtain high yields.

6 66187

In case the group A in the reagent (V) is an organic acyl group, the compound (V) is simply a mixed anhydride with the acyl group being one of several aliphatic or aromatic acyl groups, but in general the alkoxycarbonyl groups (e.g. C 2 H 2 CO group) are satisfactory. .

The 6- / D (-) - α-aminophenylacetamido / penicillanic acid phthalide ester prepared with the intermediate of the invention is well absorbed when administered orally to humans and animals. High concentrations of strain-6- / D (-) - α-aminophenylacetamido / penicillanic acid are obtained in the blood whey. The advantageous hydrolysis properties of the ester of formula (I) are apparent from strain application 1597/72 (Patent No. 58642).

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

Example 1

Phthalide-6-D (-) - α-aminophenylacetamido-7-penicillanate hydrochloride CV | H 'CO - NHtYS Y ch3 + Br> Y ^

CH - C / 1KH N

3 il; / c \ c ^ ° (I) 0-Me //% —CH - CO - NH-Y 'ΎΥ 3 \ = - l II ch3 P »2'5.,> / N \ iN -1 CH, - CH „'Rn n ch li i * o H - cxc ^ o (II) I 0 0-Me ψ 7 66187 0-cx -» - «» -C Ych3 NH ^ .HCl JN _l

^ 0 'N

CO.O.CH

N- (1-methoxycarbonylpropen-2-yl) -α-aminophenylacetamido-penicillanic acid potassium salt I (25.18 g, 0.05 M) and 3-bromophthalide (10.65 g, 0.05 M) fine the suspension was reacted in 1: 2 acetone / ethyl acetate (1500 ml) for 24 hours. After filtration, the organic layer was washed twice with 250 mL portions of 1 N sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Addition of ether crystallized phthalidienamine-protected α-aminophenylacetamido-penicillanate (II) in 85% yield.

n.m.r. / "(CD 2) 2 SO 7: δ = 7.86 (4H.m. phthalide aromatics), δ = 7.60 (1H.s. CO.O.CH), δ = 7.35 (5H.s. aromatics) , Δ = 5.30 - 5.65 (3H.m. g-lactams and α-proton), δ = 4.53, (1H.s. C-3 proton), δ = 4.50 (1H. s. - H), δ = 3.56 (3H.s.

O CH 3), δ = 1.78 (3H.s. CH 3 ~ s), δ = 1.50 (6H.m. gemdimethyl).

C 28 H 29 N 3 O 8 S requires: c 59.26, H 5.11, N 7.40, S 5.68.

Found: C 58.83, H 5.00; IN, 6.89, S 5.34

In the biochromatogram, one spot with an Rf value of 0.95.

The enamine-protected group was removed from product (II) by dissolving 10 g in aqueous acetone (250 ml water / 250 ml acetone) and stirring this solution vigorously at pH for 2.5 hours. The acetone was removed in vacuo and the ester (III), which was salted from the aqueous phase as a random yellow resin, was dissolved in ethyl acetate (200 ml) and washed twice with 200 ml portions of 1N sodium bicarbonate and brine and dried over anhydrous magnesium sulphate. Careful addition of the dry ester (ca. 50 mL) to the dry ethyl acetate layer gave the ampicillin phthalide ester as the hydrochloride salt as a fine white amorphous solid in 80% yield.

n.m.r. (7cd) 2S ° / D 2 O 2: δ = 7.88 (4H.m. phthalide aromatics), δ = 7.60 (1H.s. CO.O CH-), δ = 7.48 (5 / 6H. m. aromatic), 6m = 5.50 (2H.m. β-lactams), δ = 5.16 (1H.s. α-proton), δ = 4.54 (1H.s. Cβ-proton) , δ = 1.45 (6H.d. gem dimethyls).

Purity was confirmed by hydroxylamine experiment = 110.3%. In the biochromatogram, one spot with an Rf value of 0.85.

C24H24N3O6SC1 Stretch: C 55.65, 1H, 4.67, N 8.11, S 6.19 Found: C 54.60, H 4.70, N 7.92, S 6.40

Example 2

Ampicillin phthalide ester (I) by coupling phthalide-6-aminopenicillanate with enamine-protected α-aminophenylacetic acid mixed anhydride (D) / ΓΛ <D> y — CH - CO 2 Na 2 __ y-CH - CO.O.COOC2H5 / N \ - * / OF\

CH0-C H CH-H

3 li: 3 il i CH 0 CH 0 \ c ^ \ c ^ I i OCH-OCH3 \ \ 6-APA-phthalide

^ V-CHCONH —j-S "Y

^ PH 2.5 W {, J__J_ [(I) <- / \ vco o “'f T ί'Υ'ϋ \ c / 7 0 OCH3 9 661 87

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-amino-phenylacetate 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 at -15 to -20 ° C for 10 min.

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 for another 45 min without further cooling.

n.m.r. / (CD 2 O 2 SO 2: δ = 7.86 (4H.m. phthalide aromatics), δ = 7.60 (1H.s. CO.O.CH), δ = 7.35 (5H.s. aromatics) ), δ = 5.30-5.65 (3H.m. β-lactams and α-proton), δ = 4.53 (1H.s. C-3 proton), δ = 4.50 (1H. m.p. (H), δ = 3.56 (3H.s.

O CH 3), δ = 1.78 (3H.s. CH 3 -), δ = 1.50 (6H.m. gem-dimethyl CH 2) C 28 H 29 N 3 O 8 S requires: c 59.26, H 5.11, N 7.40, S 5.68 Found: C 58.83, H 5.00; IN N 6.89, S 5.34.

Single spot in the biochromatogram Rf 0.95.

Water (75 ml) was added, then 2N hydrochloric acid (10 ml) and the reaction mixture was stirred vigorously for 25 min. Kerosene blades, 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 into 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 precipitated ampicillin phthalide (4.0 g, 40%) 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%).

Example 3

Phthalide ester of azidosillin

To a suspension of the potassium salt of azidosillin (6.64 g) in 30 ml of dimethylformamide was added 3.10 g of 3-bromophthalide as a solution in 10 ml of dimethylformamide at room temperature. The suspension was stirred overnight at room temperature to give a clear solution. This was poured into ice water, acidified and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate, brine, dried over magnesium sulfate and distilled to give a yellow gum, 7.3 g, 96% yield. An analytically pure sample was obtained as a white random resin by chromatography on silica gel and identified by the following properties as the p-di-azidobenzylpenicillin phthalide ester. Hydroxylamine test 105.1%.

Infrared (undiluted v max = 3280 (NH) cm -1 = 2120 (N 3) = 1775 (3-CO) = 1725 (ester) "= 1680 (amide) = 1595 (aromatic)" nmr (CDCl 3) δ = 1, 61 (6H, gem-dimethyl) δ = 4.52 (2 single lines, C 1 H -H) δ = 5.11 (single line, C 2 H) δ = 5.56 (scattered quartet, C 1 -C 4 protons ) J = 4 cps.

δ = 2.1-2.6 (9 aromatic protons, phthalide C3-H)

Claims (2)

Intermediate for the preparation of phthalide ester of 6- [D - (-) - α-aminophenylacetamide] penicillanic acid and its pharmaceutically acceptable acid addition salts, characterized in that it has the formula <^ ch-coN „-ch-ch ^ c-CH3 1 III ^ ch3 CO - N - CH - CO - O - C ^ co II o wherein X is an azido group or an enamine group of formula R1 2 R-C N I (III) R-C H 2 O 1 2 3 wherein R is a lower alkyl group, R is a hydrogen atom and R is a lower alkoxy group. Mellan products for the production of phthalides from 6- / D - (-) -? -Amino-phenylacetamido7penicillansyran and pharmaceuticals are acceptable, in addition to the formulation of the formula, CH-CONH-CH-CH I ^ CH3 ^ H CO - N - CH - CO - 0 - C _ CO II o color X is an azido group or an envelope group with a form