DK153153B - PROCEDURE FOR PREPARING 7-AMINO-7-ALCOX YCEPHALOSPORINES - Google Patents

Description

DK 153153 B

i. i ''

The present invention relates to a particular process for the preparation of 7-amino-7-alkoxycephalosporins, thereby reacting a 7- (5-amino-5-carboxyvaleramido) -7-methoxycephalo-sporin, wherein the amino and acid groups are protected by reaction with phosphorus pentachloride or another agent capable of forming an imino halide, under substantially non-aqueous conditions, with a primary alkanol having 1-4 carbon atoms or with methane-d3-ol to give a nucleus having a 7-alkoxy group derived of the primary alkanol or methane-d 2 -ol.

DK 1531S3 B

In J. Am. Chem. Soc. 93: 9 (May 5, 1971) describes new antibiotics having the following structural formula: OCH's HOOC-CH (CHa) aCONH-r- 'km 76 "· o j5 Λ s -CHaOCCH 3" /

and 0 I

COOH AND S.

HOOC-CH (CH?) SCOHH .--- S

NHa 'O

, L, ii -CHeOCNHe o / \

COOH

These antibiotics are called 7- (5-amino-5-carboxyvaleramido) -7-methoxycephalosporic acid and 7- (5-amino-5-carboxyvaleramido) -7-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, respectively. Alternatively, these antibiotics are referred to as A16884 and A16886I, respectively; See Belgian Patent Nos. 754,424 and 754,693. The latter of these antibiotics is also described as antibiotic "842A" in Belgian Patent Specification No. 764,160.

In addition, Belgian patent specification 764,160 discloses an antibiotic "810A" having the formula:

AND 3 S

HOOC-CH (CHe) sCONH_ -X \ NHa yy

- CHaOC-C = CH --- / ()> - OH

/ T 0CHS

O COOH v '

This antibiotic is called 7- (5-amino-5-carboxyvaleramido) -7-methoxy-3- (a-methoxy-p-hydroxycinnamoyloxymethyl) -3-cephem-4-carboxylic acid.

3

DK 153153 B

Like other cephalosporins, these antibiotics can be treated by the phosphorus pentachloride method to remove the 7-acyl group and give a core. If desired, this core can be reacylated, thereby introducing another 7-acyl group. However, an improved method has now been found for cleavage of the above antibiotics and other 3-position modifications thereof. In addition, the process can be used as a method for introducing another 7-alkoxy moiety or a 7-methoxy-d 2 moiety instead of the original 7-methoxy moiety.

Thus, the present invention relates to a process for the preparation of compounds having the general formula set out in the preamble of claim 1. The process according to the invention is characterized by the characterizing part of claim 1.

The imino halide used as starting material is preferably prepared in situ by reacting a compound of the formula: OCHs S.

Rs0OOC-CH (CH2) sCONH --- 1], U 2 -R1 o LoqrAl> with phosphorus pentachloride or another acid haloginide.

2A

When the resulting compounds in which R represents hydrogen is reacylated, they have antibacterial activity. When it comes to reactivity

2A

For example, in the case of compound compounds wherein R represents any of the ester groups indicated or where other protecting groups are present, the reacylated compounds can be deesterified, after which such other protecting groups can be removed to obtain products having antibacterial activity.

The starting materials for use in the process of the invention are prepared by known methods. More specifically, antibiotics A16884, A16886I or 810 (1) are reacted to protect the amino group, (2) to protect acid groups and, in the case of antibiotic 810A, (3) to protect the hydroxy group.

4 DK 153153 B

Protection of the amino group can be achieved in known manner by reacting antibiotic A16884, A16886I or 810A with a suitable acyl halide or anhydride or with a suitable chain to form an acylamide group. Which acylamido group formed is not critical. Suitable acylamido groups are those wherein the acyl group is alkanoyl of 1-4 carbon atoms, benzoyl, naphthoyl, alkoxycarbonyl of 2-5 carbon atoms, cycloalkoxycarbonyl of 6-7 carbon atoms, benzyloxycarbonyl, naphthyloxycarbonyl, each of the above groups being substituted with 1-3 groups each selected from halogen, nitro, alkoxy of 1-4 carbon atoms, cyano and, in the case of benzoyl, naphthoyl, benzyloxy and naphthyloxy, with alkyl of 1-4 carbon atoms, or phthaloyl.

Halogen refers to bromine, chlorine, iodine and fluorine. Representative groups include the following; formyl, acetyl, propionyl, chloroacetyl, dichloroacetyl, benzoyl, p-nitrobenzoyl, phthaloyl, p-methoxybenzoyl, cyclohexyloxycarbonyl, tert-butoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl. For convenience, a salt of the protected amino compound is prepared upon separation. .

In one embodiment, the carboxylic acid groups are protected by esterification. The identity of the ester group is not critical; suitable groups are those that can be easily detached when protection is no longer required. Representative and suitable groups include alkyl of 1-6 carbon atoms, 2,2,2-trichloroethyl, 2-iodoethyl, tert.-alkenyl of 5-7 carbon atoms, tert.-alkynyl of 5-7 carbon atoms, benzyl, nitrobenzyl, tetrahydropyranyl, succinimidomethyl, phthalimido methyl, methoxybenzyl, dimethoxybenzyl, cyanomethyl, nitrophenyl, dinitrophenyl, 2,4,6, -trinitrophenyl, bis- (p-methoxyphenyl) methyl, triphenylmethyl, diphenylmethyl, benzyloxymethyl, alkanoyloxymethyl and alkanoyloxymethyl

In a second and often fc retracted embodiment, the protection of the carboxylic acid group is carried out as a first part of the cleavage reactions.

DK 153153 B

using either a mixed anhydride reactant or a silane compound. The mixed anhydride is separated in the usual manner, e.g. by reacting the antibiotic with an acyl halide. The identity of the latter reactant and its corresponding part in the mixed anhydride is not critical. Suitable groups include lower alkanoyl moieties and substituents herein. However, the simpler lower alkanoyl groups, such as those containing 2-4 carbon atoms, are preferred.

Silane compounds which can be used to protect the carboxylic acid groups are compounds of the formula: R 3 R 2 Si-R 3 V "R 3 'wherein each of the substituents R represents alkyl of 1-4 carbon atoms or halogen selected from bromine, chlorine, fluorine and iodine, however, with the restriction that at least one of the substituents R represents halogen 3 and at least one of the substituents R represents alkyl as defined above A preferred silane compound is trimethylchlorosilane, other suitable compounds include dimethyldichlorosilane, methyltrichlorosilane, diethyldifluorosilane and bromomethylsilane.

The protective group & can also be introduced by reacting the antibiotic with a silyl amide, with urea or with urethane as described in Belgian Patent No. 737,761. In the cases where both cilyl ester and mixed anhydride are present as protecting groups, the reaction between the amino halide and the alcohol of the present invention removes such groups and gives the nucleus as free acid. Alternatively, the carboxylic acid group and amino groups of the α-amino-adipoyl side chain may be blocked by cyclization, e.g. by forming an imidazolidine ring.

6 DK 153153 B

In the case of antibiotic 810A, the OH group can be protected by known methods, e.g. by reaction with chloro-methyl-methyl ether or with p-bromo-phenacyl bromide {see Fieser & Fieser, Reagents for Organic Synthesis, John Wiley & Sons, New York 1968, Vol. I, page 133 and Vol. Ill, page 34).

The compounds to be used as starting materials wherein propionyloxy, benzoyloxy, methoxy, methylthio, 1-methyl-1,2,3,4-tetrazol-5-ylthio or 5-methyl-1,3,4-thiadiazole-2 -ylthio, is prepared as described in Belgian Patent No. 768,528. The compounds can then be treated as described above to protect the amino and acid groups.

Whichever method is used, the resulting protected compound OCR 3 is reacted

RsB00C-CH (CHs) s-COMH_

R4 I

/ - CH-R 1

O I oB

COOfT

then with an agent capable of forming an imino halide. Although phosphorus pentachloride is a preferred agent, other acid halides can be used. Thus, other suitable agents include phosphorus oxychloride, phosphorus trichloride, thionyl chloride, phosgene, oxalyl chloride and complexes formed from o-dihydroxybenzene and phosphorus trichloride.

The starting compound and the imino halide forming agent are reacted with each other in any convenient manner. In general, good results are obtained when the reactants are used in amounts on a molar equivalent starting compound and 2-5 molar equivalents of iminohalide forming agent. The reaction takes place at temperatures between -50 and + 50 ° C, but it is preferable to carry out the reaction at room temperature. The reaction is carried out in the presence of a tertiary amine, e.g. triethylamine, pyridine or dimethylaniline.

7 DK 153153 B

In this reaction, an imino halide of the formula: X X OCHa ς

Rsb00C-CH (CH s) 3-C = N_L_ * LJ L_ · J-CHsR * COOR20 which is then treated without separation in the critical step of the present invention. It has been found that when the imino halide is treated with an alcohol as defined in the present invention, the desired compound is obtained directly.

0R °

__ ^ X

HsN Γ 1 β-CHsR *

° 'I aA

COORsft

Using an alcohol of the present invention avoids the need for water as described in the prior art, thereby also avoiding the risk of degradation of the compound which is less stable in aqueous media.

In addition to the aforementioned advantages, one can provide a method of introducing another 7-alkoxy group or introducing the methoxy-d3 group by using the alcohol in question.

The precise mechanism is not understood, but the treatment with an alcohol of the present invention results in a compound containing a 7-alkoxy group derived from the alkanol used. When it is desired to maintain a 7-methoxy group, methanol is used,

Introduction of the 7-alkoxy group from the alcohol is accompanied by some epimerization at the 7-position. Antibiotics A16884, A16886I and 810A (as well as the other 3-position derivatives thereof) are believed to exist in 7-α-methoxy configuration, and 7- (5-amino-5-carboxyvaleramido)

8 DK 153153 B

pen is in β configuration. Reacylated compounds prepared by the present process exist as a mixture of α- and β-alkoxy compounds, and the precise ratio varies with the acyl moiety used in each case.

Alcohols that can be used in this step of the present invention can be any primary alkanol having 1-4 carbon atoms, i. methanol, ethanol, n-propanol, n-butanol or isobutanol, or the alcohol may be methane-d In carrying out the reaction, the alcohol is added to the solution containing the imino halide intermediate. It is essential to obtain good results that the solution is substantially non-aqueous and remains substantially non-aqueous until the compound is reacylated. The reaction takes place between -70 and + 50 ° C. Preferably, the reaction is initially carried out at 0 ° C followed by warming to room temperature for a few minutes and then cooled to 0 ° C.

The amounts of imino halide and alcohol are not critical and vary depending on the reaction and the reactants. It is believed that the reaction between imino halide and alcohol per se consumes two molar equivalents of alcohol per molar equivalent of imino halide. However, additional alcohol is consumed by the excess phosphorus pentachloride or by another acid halide. Likewise, the alkanol is consumed where the acid groups are protected with a mixed anhydride 2 or a silyl group (R = lower alkanoyl or by reaction with these groups. In practice, it has been found that good results are obtained by using alcohol in large excess , such as 5-10 molar equivalents of alcohol per molar equivalent of imino halide.

9 DK 153153 B

Product: 0R ©

HaN - S '/ —y-— ch2r- o

o A

COOR2 can be separated from the reaction mixture if desired; however, such separation must be charged under weakly basic conditions. The acylation reaction can be carried out in known manner, either with the reaction mixture or with the separated product. The compound obtained: OR® p

RS “NH 1 I

J-IkJ- "char1

coorøA

2A

is useful since those of the compounds wherein R is an ester-p n group can be hydrolyzed to the free acid compound (R = H).

The free acids with the OR ° group in α configuration are useful as anti-bacterial agents, see Belgian Patent No. 768,528.

In the β-OR ° epimeric form, the esters can be treated according to the present process to obtain a mixture of α- and β-alkoxy esters, the α-alkoxy epimer being useful as described above.

The following examples further illustrate the method of the invention. In several of the syntheses reported in these examples, deuterized compounds were used as solvents and reagents to make it easy to identify the product by NMR spectroscopy. The use of such deuterized compounds is therefore not critical in carrying out the present process.

DK 153153 B

EXAMPLE 1; PREPARATION OF 7-AMINO-7-METHOXYCEPHALOSPORAN

ACID acid methyl ester

60.4 mg (0.1 millimole) of 7- (5-phthalimido-5-carboxyvaleramido) -7-methoxycephalosporanoic acid dimethyl ester were mixed at room temperature with 0.5 milliliters of methylene chloride-d2, 21 mg (0.25 millimole) of pyridine dj . and 42 mg (0.2 millimoles) of phosphorus pentachloride. The reaction mixture was kept stirred for one hour, cooled to 0 ° C and kept at this temperature for an additional hour. 50 mg (1.44 millimoles) of methanol-d was added and the reaction mixture was stirred for half an hour to give the desired 7-amino-7-methoxycephalosporanoic acid methyl ester in situ.

During preparation, the reaction mixture was analyzed by NMR spectroscopy. The addition of phosphorus pentachloride resulted in a shift in the signal of the α-methylene group in the valeramido side chain. Prior to the addition of the phosphorus pentachloride, there was a broad 4-proton resonance centered around 2.35 ppm; after the addition (but before the addition of methanol), there was a 2-proton triplet at 2.74 ppm (J = 7 cps), indicating formation of the iminochloride. After the addition of methanol, the triplet disappeared and a 4-proton resonance centered at 2.35 ppm was restored.

EXAMPLE 2: PREPARATION OF 7-AMINO-7-METHOXYCEPHALOSPORANIC ACID

57.6 mg (0.1 millimole) of 7- (5-phthalimido-5-carboxyvaleramido) -7-methoxycephalosporanoic acid were mixed with 0.5 ml of methylene chloride-d2 and the mixture was cooled to 0 ° C. 80.5 mg of dimethyl-aniline (0.72 millimole) and 28.5 mg (0.35 millimole) of acetyl chloride-d3 were added and the reaction mixture was kept at 0 ° C with shaking. Within 15 minutes all the solids had dissolved. One hour later, 73 mg (0.35 millimole) of phosphorus pentachloride was added and the reaction mixture was shaken as above. Within 25 minutes, the phosphorus pentachloride had dissolved and the reaction mixture was allowed to stand for several hours. The mixture was placed in dry ice for two hours and then warmed up to 0 ° C. 96 mg (3.0 millimoles) of methanol-d was added and the reaction mixture was shaken and warmed to room temperature 5 minutes later to give the desired 7-amino-7-methoxycephalosporanoic acid in situ.

11 DK 153153B

EXAMPLE 3: PREPARATION OF 7-AM1NO-7-METHOXY-CEPHALOSPORANE

ACID

7-Amino-7-methoxycephalosporanoic acid was prepared in the same manner as described in Example 2. However, 7- (5-chloroacetamido-5-carboxylvaleramido) -7-methoxycephalosporanoic acid (52.2 mg, 0.1 milmolol) was used as starting material. The other reactants were methylene chloride-d 2 (0.5 mL), 80 µg mg (0.72 millimole) Ν, Ν-dimethylaniline and 28.5 mg (0.35 millimole) acetyl chloride-d 2. Next, 73 mg (0.35 millimoles) of phosphorus pentachloride was added, after which amounts and reagents were the same as in Example 2.

EXAMPLE 4; PREPARATION OF 7-AMINO-7-METHOXY-d, -CEPHALOSPO- RANIC ACID - METHYL ESTER ^ 60.4 mg (0.1 millimole) 7- {5 ** phthalimido-5-carboxyvaleramido) -7-methoxycephalosporanoic acid dimethyl ester, 5 ml of methylene chloride-d 2 and 21 mg, (0.31 millimole) of pyridine-d 2 were mixed at room temperature and 42 mg (0T 2 millimole) of phosphorus pentachloride was added. After standing for 5 hours, cooled to 0 ° C and methane-d3-ol-d (52 mg, 1.44 millimoles) was added. As a result of these operations, the desired 7-amino-7-methoxy-d3-cephalosporanoic acid methyl ester was obtained in situ.

EXAMPLE 5: PREPARATION OF 7-AMINO- 7-METHOXYCEPHALOSPORANSYL

RE - BENZYDRYLYESTER

910 mg (1 millimole) of 7- (5-phthalimido-5-carboxyvaleramido) -7-methoxycephalosporanoic acid dibenzhydryl ester was dissolved in 5 ml of methylene chloride and the solution was stirred at 0 ° C. 0.198 g (0.20 ml, 2.5 millimoles) of oyridine was added followed by 0.42 g (2.0 µm-limol) of phosphorus pentachloride. The reaction mixture was stirred at room temperature for 1.5 hours. 0.46 g (0.59 ml, 14.4 millimoles) of anhydrous methanol was added followed by stirring for 10 minutes at 0 ° C and 5 minutes stirring at room temperature. The resulting reaction mixture containing the desired benzhydrylesi was cooled to 0 ° C and divided into two parts.

12 DK 153153 B

EXAMPLE 6; EPIMERIZATION AP 7-AMINO-7-METHOXYCEPHALOSPORAN

ACID acid benzhydryl ester

To one of the above portions of the reaction mixture containing 7-amino-7-methoxy-cephalosporanoic acid benzhydryl ester was added 2.5 ml of chloroform containing 0.60 ml (7.6 millimoles) of pyridine. The reaction mixture was stirred for 5 minutes and then 0.68 g (3.85 millimoles) of phenoxyacetyl chloride was added. The reaction mixture was stirred at 0 ° C for 15 minutes and then at room temperature for 10 minutes.

Dry methanol (0.3 ml) was added and the reaction mixture was stirred at room temperature for an additional 5 minutes. The reaction mixture was then poured into ice water and the chloroform phase was washed with dilute HCl and then with several volumes of water. The chloroform phase was then dried over sodium chloride and magnesium sulfate. The chloroform was removed on a rotary evaporator to give an oil (1.14 g total).

This oil was chromatographed and the fraction containing the desired benzhydryl ester was separated and subjected to NMR spectroscopy (CDCl3): δ 1.97, 1.98 (2 s, 3H, 3-CH 2 COCH 3); 3.4 (2 q, 2H, 2-CH 2); 3.54 (broad, 3H, 7-0CH3); 4.56 (2 s, 2H, OOCHg-CONH); 4.9 (2 q, 2H, 3-CH 2 CO 2 CH 3); 5.11 (s, 0.4H, 6-H of 7-α-OCH 3 epimer); and 5.24 ppn (s, 0.6H, 6-H of 7-β-00Η3 epimer).

This same fraction was chromatographed in two parts, one containing the 7-3-methoxy stereoisomer (32 mg) and the other containing both the 7-α-methoxy and 7-3-methoxy epimers (57 mg).

The fraction containing both the 7-α-methoxy and 7-β-methoxy epimers was then treated to remove the benzhydryl ester. The fraction was dissolved in a 1: 1 mixture of trifluoroacetic acid and formic acid (0.2 ml) and after 5 minutes at room temperature 4 ml of methylene chloride was added. Evaporated on a rotary evaporator to dryness at room temperature. Ethyl acetate was then added and the mixture extracted with dilute sodium bicarbonate. The sodium bicarbonate extract was washed with ethyl acetate and acidified to pH

1.5 with ethyl acetate. The phases were separated and the ethyl acetate dried over magnesium sulfate, filtered and evaporated to dryness. The preceding procedure gave the α-epimer: NMR (CDCl 3), δ * 2.06 (s, 3H, 3-CH 2 OCOCH 3); 3.36 (q, 2H, 2-CH 2; 3.54 (s, 3H, 7-OCH 3); 4.61 (broad, 2H, 00CH 2 CONH); 5.04 (q, 2H, 3-CH 2 OCOCH 3); and 5.12 ppm (s, 1H, 6-H).

Claims (3)

13 DK 153153B Patent Claims i A process for the preparation of 7-amino-7-alkoxycephalosporins of the general formula: OR0 s HsN - i- ^ N y - - ch s 1 r coor2A wherein R ° represents a primary alkyl group of 1-4 carbon atoms or methyl-d 2; R ^ represents aceboxy, carbamoyloxy, α-mebhoxy-β-hydroxy-cinnamoyloxy, propionyloxy, benzoyloxy, methoxy, methylthio, 1- mebhyl-1,2,3,4-tetrazol-5-ylbhio or 5-methyl-1,3 , 4-Thiadiazole-2A 2 2 2-ylbhio, and R represents hydrogen or R, wherein R represents alkyl of 1-6 carbon atoms, 2 "2,2-trichloroethyl, 2-iodoethyl, berthi-alkenyl of 5-7 carbon atoms, tertiary alkynyl having 5-7 carbon atoms, benzyl, nitrobenzyl, tetrahydropyranyl, succinimidomethyl, phthalimidomethyl, methoxybenzyl, dimethoxybenzyl, cyanomethyl, nitrophenyl, dinitrophenyl, 2,4,6-trinitrophenyl, bis (p-methoxy) triphenylmethyl, diphenylmethyl, benzyloxymethyl, alkanoyloxymethyl having 3-6 carbon atoms or phenacyl; characterized in that an imino halide compound of the general formula is reacted: OCHs s R2B00C ”CH (CH3) .3 - $ - N ^ y - CHa-R * 0 In ØB COOR wherein X represents bromine or chlorine; has the same meaning as p * p p above, R represents R as defined above, alkanoyl of 2-4 carbon atoms or a group of the formula: Wherein each of the groups R independently represents alkyl of 1-4 carbon atoms or halogen selected from bromine, chlorine, fluorine and iodine, 3 but at least one of the groups R represents alkyl as defined above 4 ; and R represents an acylamido group wherein acyl is alkanoyl of 1-4 carbon atoms, benzoyl, naphthoyl, alkoxycarbonyl of 2-5 carbon atoms, cycloalkoxycarbonyl of 6-7 carbon atoms, benzyloxycarbonyl, naphthyloxycarbonyl, wherein each of the above acyl groups may be substituted with 1-3 groups each selected from halogen, nitro, lower alkoxy of 1-4 carbon atoms, cyano and, in the case of benzoyl, naphthoyl, benzyloxy and naphthyloxy, of lower alkyl of 1-4 carbon atoms, or phthaloyl; with an alcohol of the formula R ° -OH, wherein R ° has the above meaning, under substantially non-aqueous conditions. Process according to claim 1, characterized in that R 1 is acetoxy. Process according to claim 1, characterized in that R 1 is carbamoyloxy.