CS262698B2 - Process for preparing heat stable crystalline cephalosporines - Google Patents

Abstract

A process for the preparation of stable crystalline cephalosporins of the general formula (yilb) wherein X is hydrogen iodide or hydrogen chloride and -Nu is a pyridinium, N-methylmorpholinium, N- methylpyrrolidinium or 2,3-cyclopentenopyridinium radical characterized in in 1,1,2-trichlorotrifluoroethane, it acts in any order with iodotrimethylsilane and pyridine, N-methylmorpholine, N-methylpyrrolidine or 2,3-cyclopentenopyridine; .odod. The compounds produced serve as intermediates for the preparation of broad-spectrum cephalosporin antibiotics.

Description

A process for the preparation of stable crystalline cephalosporins of the formula yilb wherein X is hydrogen iodide or hydrogen chloride and -Nu represents a pyridinium, N-methylmorpholinium, N-methylpyrrolidinium or 2,3-cyclopentenopyridinium radical, characterized in that 1,2-trichlorotrifluoroethane is treated in any order with iodotrimethylsilane and pyridine, N-methylmorpholine, linen, N-methylpyrrolidine or 2,3-cyclopentenopyridine, the silyl groups are removed from the product by treatment with lower alkanol and the product is acidified with hydrogen chloride or iodine hydrogen chloride. The compounds produced serve as intermediates for the preparation of cephalosporin antibiotics with a broad spectrum of activity.

The present invention relates to thermostable crystalline salts of the cephalosporin derivatives of formula VIIb

Ni.Η, Ν · ^ _X With ni

CR, -N: and coo (V and ib) where

X is hydrogen chloride or hydrogen iodide and + -Nu is the radical of formula

in which

B ¹ is hydrogen or a conventional carboxyl protecting group and the N-silyl derivatives.

In the above-cited patent, these compounds are not exemplified but are only described by structural formulas as intermediates for an alternative sequence of reactions for the preparation of certain cephalosporins (by acylation and then cleavage of the protecting group from the carboxyl function). The examples illustrating this sequence of reactions do not use the compounds listed above (and also need to be carried out as the final reaction step for the deprotection of the carboxyl function). All of the final products described in U.S. Pat. No. 4,406,899 require the inclusion of chromatographic purification to separate the resulting mixture of the A ² - and A ³ -isomers.

U.S. Pat. No. 4,168,309, issued September 18, 1979 to Earry E. Ayres.

These compounds are in the ^{2 2} -isomer and can be converted to cephalosporin antibiotics without the need for cleavage of the carboxyl function protecting group.

It is an object of the present invention to provide a process for the preparation of the salts of formula (IIIb) above.

U.S. Patent No. 4,406,899, issued Aug. 27, 1983 to Aburaki et al.

where

Ph is phenyl and compounds of formula

in which

R "‘ represents a carboxyl function protecting group,

R ¹ together with the carbon atoms to which it is attached form an optionally substituted saturated or partially saturated four to ten membered heterocyclic ring, which may contain one or more additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; 2-em- or cef-3-emderivative a

X ^- represents an anion, and their acid addition salts and N-silylated derivatives.

These compounds are not exemplified in the cited patent, but are described only by structural formulas as intermediates for alternative synthesis of certain cephalosporins (by acylation and then cleavage of the carboxyl group). The examples illustrating this synthesis do not use these compounds (and also need to be carried out as the final reaction step for the removal of the carboxyl function protecting group).

The use of protected carboxyl functions in the processes of the two aforementioned patents is disadvantageous because it requires, after acylation, the cleavage of the protecting groups, which also partially cleaves the acyl residue, so that the yield obtained is less than 100%.

U.S. Patent 4,223,135, issued September 16, 1980 to Derek Walker et al.

in which

B represents a chlorine atom, a methoxy group or a radical —CH2E, wherein E represents hydrogen, a group —OCCH3, —CNH2 or —SZ,

Wherein Z represents an optionally substituted 5- or 6-membered heterocyclic ring containing 2 to 4 nitrogen atoms and optionally 1 oxygen or sulfur atom, the sulfur atom in the —SZ group being attached to the carbon atom of the heterocyclic ring as Z and

A represents a trimethylsilyl group or an easily cleavable ester protecting group.

These compounds are prepared by adding dry carbon dioxide to a solution of a compound of formula

in which

A and B are as defined above, in an inert organic solvent, which is preferably methylene chloride.

U.S. Pat. No. 4,316,017, which has been granted on the continuation application of U.S. Pat. No. 4,223,135, has essentially the same description.

U.S. Patent 4,336,253, issued June 22, 1982 to Willlam H.W. Lunn, discloses compounds of Formula I

dl

......

and preparing them by reacting a compound of formula II

N .....— ~ r

C-CONH

II

N.

O

STEED

OCCH ₃ cooh til} with a silylating agent such as trimethylsilylacetamide, bistrimethylsilylacetamide and the like to give a compound of formula III

SiHN

by reacting a compound of formula III with trimethylsilyl iodide to form a compound of formula IV

N

C ~ CONH- j- / '

J-WV 'CH 1 ^0R COQSiJCHJ.

itV) which is then reacted with a compound of formula I to form a compound of formula I.

Solvents suitable for the reactions leading to compounds of formulas III and IV include chlorinated hydrocarbons and lower alkylnitriles.

U.S. Patent Nos. 4,379,787, 4,382,931 and 4,382,932 (William HW Lunn et al.) Relate to analogous compounds and procedures wherein R is, for example, an amino-substituted oxazole, oxadiazole or isoxazole ring and a substituent at the 3-position. is, for example, an optionally substituted pyridine, quinoline or isoquinoline residue.

South Africa Patent No. 84/3343, issued October 25, 1984, discloses a process for the preparation of cephalosporins of Formula I

in which

R is a thiazolyl or 1,2,4-thiadiazolyl radical,

R ¹ represents a hydrogen atom or a methoxy group,

R ² represents one of a number of substituents known in the cephalosporin and

A represents an optionally substituted quinolinium or pyridinium radical.

The compounds of formula (I) above are prepared by reacting a compound of formula (II)

in which

R ⁸ represents a hydrogen atom or an amino function protecting group and

R ⁷ represents a group which can be replaced by treatment with a base corresponding to residue A, reacted with a base corresponding to residue A in the presence of a trialkyl iodosilane to give a compound of formula III

R <

r ⁸ nh - 4 o | yy coo ', flax which is then (after removal of the amino function protecting group) acylated with an acid of formula IV

R = C-COOH

OR ²

Suitable R ⁷ groups include acetoxy, propionyloxy, chloroacetoxy, acetylacetoxy and carbamoyloxy. Suitable solvents include methylene chloride, chloroform, dichloroethane, trichloroethane, carbon tetrachloride, acetonitrile, propionitrile and frigands. The most preferred solvent is methylene chloride.

It is recognized in the above-cited patent that the above general procedure is known, but the inventors have found that surprisingly high yields can be obtained when the nucleophilic substitution reaction of a compound of formula II (leading to a compound of formula III) is by adding an excess (up to 20-fold excess) of the base corresponding to residue A and then adding a trialkyl iodosilane in an amount up to 10-fold excess.

German Patent Application Publication No. P 3316798.2, filed May 7, 1983, from which the above-mentioned South African Patent No. 662698 applies, the same solvents are used as above, except that the term "frigand" is used instead of "frigand" "frigen". In the 10th edition of the Merck Index, Frigen 11, Frigen 12 and Frigen 114 are mentioned as other designations of Freon 11, Freon 12 and Freon 114, which are trichlorofluoromethane, dichlorodifluoromethane, respectively. 1,2-dichloro-1,1,2,2-tetrafluoroethane.

The compounds of the above general formula (IIIb) which are prepared by the process according to the invention are crystalline, thermally stable and practically free of the corresponding A ² -isomer. In the absence of this důsleduk A ² isomer can be converted into the above mentioned compounds on a wide variety of acylation cefalosportnů which are also substantially free of an A ² isomer which is not necessary to perform a chromatographic separation A- ² aA ³ -isomers. Due to the temperature stability of the compounds of the invention, these compounds can be isolated and stored, and converted to the resulting products only when desired. A further advantage of the compounds of formula (IIIb) is that they do not require protection of the carboxyl group prior to acylation and consequently there is no need to cleave the carboxyl functionality after the acylation, thereby improving the efficiency of the process.

In accordance with the invention, the compounds of formula VIIb are prepared by preparing a solution of the compound of formula IVa

(IV&A in 1,1,2-trichlorotrifluoroethane acts in any order with at least one equivalent of iodotrimethylsilane and at least one equivalent of a compound of the general formula

silyl groups are removed from the resulting product by treatment with a lower alkanol and the product is acidified with hydrogen chloride or hydrogen iodide.

Thus, according to one embodiment of the method of the invention, a solution of the compound of formula IVa τΎ se is added

AND

O i;

CH-GC CH (IVaJ in 1,1,2-trichlorotrifluoroethane is treated with trimethylsilyl iodide (iodotrimethylsilane). This solvent surprisingly results in the compound of formula Iita below, which is practically free of the A ² -isomer, while using similar conventional solvents, e.g. 2-dichloroethane yields a compound of formula IIIa containing a considerable amount (e.g. 25%) of the undesired A ² -isomer The use of other conventional solvents such as chlorobenzene, dioxane, carbon tetrachloride and the like also results in significant amounts of the undesired A ² -isomer.

The above reaction is carried out at a temperature of about 5 ^° C to 45 ° C, conveniently at room temperature. At least one equivalent of trimethylsilyl iodide is required to convert the entire amount of the compound of formula IVa to the compound of formula IIIa. In practice, about 0.9 to 1.5, most preferably about 1.0 to 1.2 equivalents of trimethylsilyl iodide are used for each equivalent of the compound of formula IVa.

The resulting compound corresponding to Formula IIIa

(CHJ., Si.hN ~~ o

Then, 1,1,1-trichlorotrifluoroethane is reacted with the above nucleophiles to form the compound of formula IIa below. Surprisingly, 1,1,2-trichlorotrifluoroethane is used as solvent to form the compound practically free of the A ² -isomer, while the use of conventional solvents such as methylene chloride, tetrahydrofuran, chloroform or dioxane yields a compound of Formula II containing a large amount of the undesired A ² -isomer (e.g., 50% A ² -isomer).

The reaction is carried out at a temperature of about -10 ° C to 25 ° C, preferably about 0 ° C to 10 ° C. Although greater or lesser nucleophile may be used, the purest product is obtained when about 1 equivalent of nucleophile is used for each equivalent of the compound of formula IIIa.

To the solution of formula IIIa compounds common (CHJ, SLHN-r— w * »> ς τη - £ - 'M' * 0 í ‘’> ?. what, mesh:

in 1,1,2-trichlorotrifluoroethane (Freon TF] is then treated with a lower alkanol or water to remove the trimethylsilyl groups and then with hydrogen chloride or iodide to form the hydrochloride or hydroiodide, preferably lower alkanol, most preferably methanol, is used to cleave the trimethylsilyl groups. The reaction is carried out at a temperature of from about -10 ° C to about 25 ° C, preferably at about 0 to about 10 ° C. About 2 to 5 equivalents of methanol, preferably about 3 to 4 equivalents, are used for each equivalent of the compound of Formula IIIa. of methanol.

According to an alternative process for preparing the compound of formula IIIa, a nucleophile and then at least 1 equivalent of trimethylsilyl iodide are added to a solution of the compound of formula IVa in 1,1,2-trichlorotrifluoroethane. This reaction can be carried out at a temperature of about 5 to 45 ° C, conveniently at a temperature of about 35 ° C. The nucleophile may be used in an amount of about 1.0 to 2.0 equivalents for each equivalent of the compound of formula IVa, preferably in an amount of about 1.2 to 1.5 equivalents. The trimethylsilyl iodide is from about 1.5 to 2.0 equivalents for each equivalent of the compound of formula IVa.

The compound of formula IVa can be prepared by reacting 7-aminocephalosporanic acid (7-ACA), i.e. a compound of formula V

H ₂ Nr — S ₀

COgH (V!

with hexamethyldisllazane in the presence of about 0.01 to 0.1 equivalents of trimethylsilyl iodide for each equivalent of 7-aminocephalosporanic acid, v, 1,1,2-trichlorotrifluoroethane or methylene chloride, at a temperature from room temperature to the boiling point of the solvent. Preferably, the reaction is carried out at reflux. Hexamethyldisilazane may be used in an amount of about 0.95 to 1.4 equivalents for each equivalent of 7-aminocephalosporanic acid, preferably about 1.0 to 1.3 equivalents, and most preferably 1.2 equivalents for each equivalent Of 7-aminocephalosporanic acid.

The process according to the invention is preferably carried out in a single reaction vessel, i.e. without isolation of the intermediates.

In carrying out the reaction sequence described above, it has been found that rather than the corresponding 3-chloromethyl derivative or 3-bromomethyl derivative, it is necessary to proceed through the 3-iodomethyl derivative of formula IIIa. Surprisingly, it has been found that the reaction of a compound of formula IVa with trimethylsilyl chloride or trimethylsilyl bromide produces a smaller amount of the expected 3-chloromethyl or 3-bromomethylanalog of the compound of formula IIIa, for example even after heating for 10 days at reflux maximum 5-15%.

Compounds of formula VIIIb can be readily converted to a wide variety of antibiotics by acylation with the appropriate side chain forming acid. For example, a preferred compound corresponding to Formula IIIb, +

wherein —Nu represents an N-methylpyrrolidinium radical and X is as defined above (compound of formula I) is converted to 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3- [(1-methyl-11-pyrrolidinio) methyl] -3-cephem-4-carboxylate of formula VIII by N-acylation-activated ester of 1-benzotriazoles 1- (Z) -2- (2-aminothiazol-4-yl) - 2-methoxyiminoacetate according to the following reaction scheme:

OCONH li

N.

.WITH.

\

OC i — i

..\to

COO (Vlil)

This reaction is readily carried out in the presence of Ν, Ν-dimethylaniline in dimethylformamide at room temperature and at a reaction time ranging from 10 to 20 hours, or by dissolving the compound of formula I in water and dimethylformamide, added to the solution under ice cooling. sodium bicarbonate; and

The mixture is allowed to react at room temperature for about 30 minutes to 5 hours, or by dissolving the compound of formula I in water, cooling the solution to 5-15 ° C, adjusting the pH to 5 by dropping sodium hydroxide, 5 to 6, tetrahydrofuran is added, pH is adjusted to 6.7 to 6.9 with sodium hydroxide, activated ester is added and the reaction is allowed to proceed for 1 to 5 hours at room temperature. The activated ester used is known and is described, for example, in Japan Kokai 54-95593 (28 07 79) (Hoechst), and German published patent application no.

2758000.3 (241277). The use of compounds of formula VIII is described in U.S. Patent No. 4,406,899 to Aburaki et al.

Other compounds of formula (IIIb) can also be acylated in an analogous manner to form a large amount of broad-spectrum cephalosporins.

The invention is illustrated by the following non-limiting examples. Signal shapes in NMR spectra are designated by the following common abbreviations:

s = singlet t = triplet m - multiplet w = broad signal d = doublet q - quartet dd = double doublet

Example 1 (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-acetoxymethylcef-3-em-4-carboxylate

Method A

An oven-dried flask equipped with a Friedrich condenser was cooled to room temperature in a stream of dry nitrogen, and 50.0 g (184 mmol) of 7-aminocephalosporanic acid having a purity of 97.2% and 400 ml of dried 1,2,2-trichlartrifluoroethane dried were added. over the molecular sieve. With vigorous stirring and in the absence of moisture, 46.5 ml (222 mmol; 1.2 equivalents) of 98% 1,1,1,3,3,3-hexamethyldisilazane and 0.80 ml (5.6 mmol) were added to the resulting suspension. 0.03 equivalents) of iodotrimethylsilane. The suspension was refluxed vigorously for 16 to 18 hours, then cooled to room temperature. ^{The 1} H-NMR spectrum of a sample of a slightly turbid reaction mixture indicated greater than 95% conversion to the desired product.

NMR (CDCl 3, 360 MHz, δ):

0.23 [s, 9H, N-Si (CH 3) 3],

0.38 [s, 9H, -COOSi (CH3) 3],

1.51 (d, 1H, J = 13.6Hz, NH--),

2.09 (s, 3H, —COCH3),

3.41 (d, 1H, J = 18.3 Hz, —SCH3 -),

3.61 (d, 1H, J = 18 Hz, - SCHa),

4.80 [dd, 1H, J = 4.5, 13.6 Hz, —COCH / NHSi (CH3) 3]],

4.83 (d, 1H, J = 13.2 Hz, —CH2OCOCH3),

4.91 [d, 1H, 1 = 4.5 ¹ Hz, -COCH / NHSi (CH3) 3CH- /]

5.11 (d, 1H, J = 13.2 Hz, -CH 2 OCOCH 3). Method B

The oven-dried flask equipped with the Friedrich condenser was cooled to room temperature in a stream of dry nitrogen and charged with 10.0 g (36.7 mmol) of 7-aminocephalosporanic acid of 97.2% purity and 80 ml of dry 1,1.2 -trichlorotrifluoroethane dried over a molecular sieve. 9.3 ml (44.1 millimoles; 1.2 equivalents) of 98% 1,1,1,3,3,3-hexamethyldisilazane and 44 ml (1.1 mmol; 0.03 equivalents) of 0.025 were added to the resulting suspension. M solution of hydrogen iodide in

1,1,2-trichlorotrifluoroethane (prepared by bringing the hydrogen iodide into dry 1,1,2-trichlorotrifluoroethane and titrating the resulting saturated solution to phenolphthalein. The reaction suspension is vigorously refluxed for 22 hours with vigorous stirring and exclusion of moisture. cooled to room temperature. ^* H-NMR spectrum measured at 360 MHz in perdeuterodichlormethanu indicates greater than 95% conversion to the desired product.

Method C

The oven-dried flask equipped with the Friedrich condenser was cooled to room temperature in a stream of dry nitrogen and charged with 10.0 g (36.7 mmol) of 97.2% pure 7-aminocephalosporanic acid and 80 ml of dichloromethane dried over a molecular sieve. 9.3 ml (44.1 mmol; 1.2 equivalents) of 98% 1,1,1,3,3,3-hexamethyldisilazane and 0.16 ml (1 ml) were added to the resulting suspension under vigorous stirring and to avoid moisture ingress. 1 mmol (0.03 equivalents) trimethylsilyl iodide. The reaction suspension was vigorously refluxed for 5 hours, after which the slightly cloudy reaction mixture was cooled to room temperature. ^{The 1} H-NMR spectrum measured in perdeuterodichloromethane at 360 MHz indicated greater than 95% conversion to the desired product. Example 2 (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-iodomethylceph-3-em-4-carboxylate

Method A

To a reaction mixture containing (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-acetoxymethylcef-3-em-4-carboxylate in 1,1,2-trichloro262698 trifluoroethane (prepared according to Method A of Example 1 of 50, A total of 30 ml (210 mmol; 1.15 equivalents) of trimethylsilyl iodide was slowly added at room temperature under a dry nitrogen atmosphere (0 g) of 7-aminocephalosporanic acid. The progress of the reaction was monitored by ¹ H-NMR spectroscopy (in the acetate region). After one hour, the reaction suspension is filtered under a positive pressure of nitrogen and the solid material is washed once with 100 ml of fresh 1,1,2-triclorotrifluoroethane. A sample of the filtrate had the following ¹ H-NMR spectrum, indicating that (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-iodomethylceph-3-em-4-carboxylate was formed in situ.

NMR (CDCl 3, 360 MHz, δ values):

0.16 [s, 9H, NHSi (CH3) 3],

0.40 [s, 9H, —COOSi (CH3) 3],

1.51 (d, 1H, J = 13.4Hz, NH),

3.54 (d, 1H, J = 17.9 Hz, —SCH 2 -),

3.80 (d, 1H, J = 17.9 Hz, - SCH 2 -),

4.37 (d, 1H, J = 9.2Hz, —CH2),

4.49 (d, 1H, J = 9.2 Hz, -CH 2),

4.75 [dd, 1H, J = 4.6, 13.4 Hz, —COCH / NHSi [CH3] 3],

4.89 [d, 1H, J = 4.6 Hz, -COCH / NHSi; (iCH 3) 3 / CH-].

Method B

To a stirred solution of (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-acetoxymethylcef-3-em-4-carboxylate in dichloromethane [prepared according to Method C of Example 1, 20 ml of the reaction mixture (for this reaction was used 11.7 mmol of starting material)] and 1.66 mL (11.7 mmol; 1.0 equivalents) of iodotrimethylsilane was slowly added at room temperature under a nitrogen atmosphere. After further stirring for ¹ hour, the ¹ H-NMR spectrum (acetate region) of the reaction mixture sample showed greater than 95% conversion to the desired (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-iodomethylcef-3-em-4- carboxylate.

Example 3 (6R, 7R) -7-Amino-3- (1-methyl-1-pyrrolidinio) methylcef-3-em-4-carboxylate monohydrochloride

Method A

To a solution of (6R, 7R) -trimethylsilyl-7-i [trimethylsilyl) amino-3-iodomethylcef-3-em-4-carboxylate in 1,1,2-trichlorotrifluoroethane (prepared according to Method A of Example 2 of 50.0 g of 7-aminocephalosporanic acid) was added dropwise at 0-5 ° C in a dry nitrogen atmosphere at a rate such that the temperature of the reaction mixture was kept below 10 ° C, 19.0 mL (183 mmol; 1.0 equivalents) of 97% N -methylpyrrolidime dried over a molecular sieve. After the addition was complete, the resulting suspension was stirred vigorously at 0-5 ° C for 15 minutes, then an additional 100 mL of dry 1,1,2-trichlorotrifluoroethane was added to facilitate stirring, followed by stirring at a rate such that the temperature of the reaction mixture was maintained. below 10 ° C, dropwise addition of 25 mL (615 mmol; 3.35 equivalents) of methanol. The suspension was then stirred vigorously at 0-5 ° C for a further 15 minutes. The reaction mixture was filtered and the collected solid material was washed once with 100 ml of fresh 1,1,2-trichlorotrifluoroethane. The product was first partially dried with 15 ml suction and then dried under vacuum at room temperature for 16 hours. It is obtained

71.3 g (&gt; 100%) of the crude product.

200 ml of water are added to the above material, the pH of the suspension (2.40) is lowered to 0.50 by dropwise addition of concentrated hydrochloric acid, 10.0 g of activated carbon are added, and the resulting suspension is stirred at room temperature for 15 minutes. The activated carbon was filtered through a pad of 10.0 g of diatomaceous earth, which was then washed once with 25 ml of freshly deionized water. The product is precipitated from the aqueous solution by dropwise addition of 5 volumes of acetone. The resulting suspension was cooled to 0-5 ° C and held at this temperature for 30 minutes, then filtered in vacuo. The filter cake is washed successively with 50 ml of cold (0 to 5 ° C) acetone / water (5: 1) and twice with 50 ml of acetone each, partially dried by suction for 15 minutes and then dried in vacuo. 23.3 g (39 percent) of snow-white crystalline (6R, 7R) -7-amino-3- (1-methyl-1-pyrrolidinio) methylcef-3-em-4-carboxylate monohydrochloride are obtained.

According to high performance liquid chromatography, the purity of the product was 96.3%.

NMR (deuterium oxide, 360 MHz, delta):

2,14-2,32 [unclear signal form, 4H, —N (CH3) CH2CH2—],

3.00 (s, 3H, NCH 3),

3.46-3.67 [m, 5H, -N (CH3), CH2CH2,

SCH2],

3.96 (d, 1H, J = 16.9 Hz, —SCH2),

4.09 (d, 1H, J = 13.9 Hz, CCH 2 N -),

4.73 (d, 1H, J = 13.9 Hz, = CCH 2 N -),

5.21 (d, 1H, J = 51 Hz, 1 Hz, - COCHCH 3 -),

5.41 (d, 1H, J = 5.1 Hz, --COCHCH3 -).

Method B

To a suspension of (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3- (1-methyl-1-pyrrolidino) methylcef-3-em-4-carboxylate iodide in 1,1,2-trichlorotrifluoroethane (prepared according to Method A, from 20.0 g of 7-aminocephalosporanic acid) cooled to 0-5 ° C, dropwise in 5 minutes under a dry nitrogen atmosphere, maintaining the temperature below 9 ° C (246 mmol; 3.35 equivalents) of methanol. After the addition was complete, the suspension was stirred at room temperature for 15 minutes, then 50 ml of 3N hydrochloric acid (prepared by adding 250 ml of concentrated hydrochloric acid to 756 ml of deionized water) was added dropwise over 10 minutes. After the addition was complete, the cooling bath was removed, the reaction mixture was stirred for 15 minutes, then the phases were separated, the volume of the aqueous phase was adjusted to 100 ml, and the aqueous layer was stirred at room temperature for 30 minutes with 4.0 g. aminosporanic acid) activated carbon. The resulting suspension is filtered through a pad of 4.0 g of diatomaceous earth, which is then washed once with 10 ml of deionized water. Adjust the volume of the aqueous filtrate to 1-10 milliliters.

Crystallization Method 1:

250 ml (5 volumes) of acetone are added dropwise to 50 ml of the above-concentrated layer. The resulting suspension was stirred under ice-water cooling for 1 hour, then filtered off with suction, the filter residue was washed successively twice with 40 ml of 5: 1 acetone / water each time and once with 40 ml of acetone (0-5 ° C washes). ), partially dried by suction for 15 minutes and then dried in vacuo at room temperature (15 hours). 4.48 g (37%, based on 50% of the theoretical yield of 20.0 g of the starting 7-aminocephalosporanic acid) of colorless crystalline (6R, 7R) -7-amino-3- (1-methyl-1-pyrrolidinlo) are obtained. methyl methyl-3-em-4-carboxylate monohydrochloride. Crystallization Method 2:

150 ml (3 volumes) of isopropyl alcohol are added dropwise to the 50 ml of the concentrated aqueous layer prepared above. The resulting suspension is stirred for 1 hour under ice-water cooling, then filtered off with suction, and the filter residue is washed successively with 2 times 40 ml of isopropanol / water (9: 1) and once with 40 ml of acetone (0-5C washes). it is partially dried by suction for 10 minutes and then dried under vacuum at room temperature (15 hours). 5.46 g (45%, based on 50% of the theoretical yield of 20.0 g of the starting 7-amino-naphthalosporanic acid) of off-white crystalline (6R, 7R) -7-amino-3- (1-methyl-1-pyrrolidinio) are obtained. ) methylcef-3-em-4-carboxylate monohydrochloride.

Method C

To a solution of (6R, 7R) -trimethylsilyl-7-trimethylsilyl) amino-3-iodomethylcef-3-em-4-carboxylate in dichloromethane (prepared according to Method B of Example 2) at 0-5 ° C in to a dry nitrogen atmosphere at a rate such that the temperature was maintained below 10 ° C was added dropwise 1121 mL (11.7 mmol; 1.0 equivalents) of 97% N-methylpyrrole, the lidine dried over the molecular sieve. After the addition was complete, the suspension was stirred at 0-5 ° C for 15 minutes, then 0.95 ml (23.5 mmol; 2.0 equivalents) of methanol was added dropwise at below 10 ° C and stirred at 0 to 5 ° C. 5 ° C was continued for 15 minutes. The solid material is filtered off with suction, washed once with 50 ml of methanol and once with 50 ml of dichloromethane and dried under vacuum at room temperature. 2.65 g (76% of crude, (6R, 7R) -7-amino-3- (1-methyl-11-pyrrolidinio) methylceph-3-em-4-carboxylate (as hydroiodide) are obtained as a slightly red solid. yellow solid. ^{The 1} H-NMR spectrum of this material (360 MHz) indicated that the product was a 65:35 mixture of the Δ ² - and ^{3 3} -isomers.

Example 4

(6R, 7R) -7-Amino-3- (pyridinio) methylcef-3-em-4-carboxylic acid dihydrochloride

To a stirred solution of (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-iodomethylceph-3-em-4-carboxylate in 1,1,2-trichlorotrifluoroethane (prepared according to Method A of Example 2 of 2), 50 g of 7-amirtocephalosporanic acid) was added dropwise at 0-5 ° C under a dry nitrogen atmosphere over 10 minutes, a solution of 1.6 ml (20.0 mmol; 2.2 equivalents) of pyridine dried over potassium hydroxide in 5 ml 1.1 Of 2-trichlorotrifluoroethane dried over a molecular sieve. After the addition was complete, the reaction mixture was stirred for a further 15 minutes, then 1.5 ml (37.0 mmol; 4.0 equivalents) of methanol was added dropwise, and the resulting suspension was stirred at 0-5 ° C for 15 minutes. The solid material is filtered off with suction, washed with fresh 1,1,2-trichlorotrifluoromethane and dried under vacuum to constant weight. 3.0 g of crude product are obtained.

The presence of the desired (6R, 7R) -7-amino-3- (pyrrolidinio) methylcef-3-em-4-carboxylate (as hydroiodide) in this crude material was confirmed by comparison of the ¹ H-NMR spectrum (360 MHz) and the chromatogram obtained by high resolution liquid chromatography (purity 34%) with spectrum and chromatogram of an authentic sample of this material prepared in an independent manner (see also GCD Smith, European Patent Publication No. 70706, 26 01 83, p. 21).

Example 5

Attempt to prepare (6R, 7R) -7-amino-3- (1-methyl-1-pyrrolidinio) methylcef-3-em-4-carboxylate monohydrochloride by sequential reaction of (6R, 7R) -trimethylsilyl-7- (trimethylsllyl) amino-3-aceto262698 xylmethylcef-3-em-4-carboxylate v

1,1,2-trichlorotrifluoroethane with trimethylsilane, N-methylpyrrolidine and aqueous hydrochloric acid

To a slightly turbid reaction mixture containing (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) aimino-3-acetoxymethylcef-3-em-4-carboxylate in 1,1,2-trichlorotrifluoroethane (prepared according to Method A of Example 1 of 10) 1.0 g of 7-aminocephalosporanic acid) is slowly added over 1 minute with stirring at room temperature under a dry nitrogen atmosphere.

4.3 mL (42.2 mmol; 1.15 equivalents) of 98% bromotrimethylsilane. The progress of the reaction was monitored by ¹ H-NMR spectroscopy. After stirring at room temperature for 90 minutes, only traces of reaction products (3-bromomethylcephalosporin and trimethylsilyl acetate) can be detected in the reaction mixture. The reaction mixture was gently heated under nitrogen to reflux and the reaction was further pursued ^X H-NMR spectroscopy. After 10 days, the starting materials predominate in the reaction mixture. In the analysis of the reaction mixture ^X H-NMR spectroscopy (360 MHz) was found at best only 15% (by area signal) conversion to the desired (6R, 7R) -trimethylsilyl 7- (trimethylsilyl) amino-3-Br-3 ommethylcef -em-4-carboxylate.

Example 1 a d 6

Attempt to prepare. (6R, 7R) -7-amino-3- (1-methyl-1-pyrrolidinio) methylcef-3-em-4-carboxylate monohydrochloride by sequential reaction of (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino- 3-acetoxymethylcef-3-em-4-carboxylate v

1,1,2-trichlorotrifluoroethane with chlorotrimethylsilane, N-methylpyrrolidine and aqueous hydrochloric acid

This experiment was carried out as described in Example 5 except that 5.4 ml (42.2 mmol; 1.15 equivalents) of chlorotrimethylsitane was used instead of bromotrimethylsilane. LOdenním After heating the reaction mixture under nitrogen at reflux ^X indicates H-NMR spectroscopy (360 MHz) on the presence of predominantly chloro trimethylsilane and (6R, 7R) trimethylsilyl 7- (trimethylsilyl) amino-3-acetoxymethylcef-3-em-4 -carboxylate.

A maximum of 5% (by signal area) conversion to the desired (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-chloromethylceph-3-em-4-carboxylate was found.

Example 7

Reaction scheme for the preparation of (6R, 7R) -7-amino-3- (1-methyl-1-pyrrolidinio) methylcef-3-em-4-carboxylate hydrochloride or hydroiodide in one reaction vessel, ie without isolation of intermediates

The following section provides an overview of the experience and observations obtained by repeated reactions using the same amounts of reagents, reaction temperatures, and the like.

Method

1.

To 50 ml of 1,1,2-trichlorotrifluoroethane was added 50.0 g (0.184 mol) of 7-aminocephalosporanic acid under a nitrogen atmosphere (Note 1).

2.

To the suspension prepared above was added 1,1,1,3,3,3-hexamethyldisilazane (46.5 mL, 0.22 mol; 1.2 equivalents) in a single portion with stirring.

3.

Trimethylsilyl iodide (0.78 ml, 6.0 mmol; 0.03 equivalents) was added to the mixture in a single dose using a single syringe (Note 2).

4.

The reaction mixture is refluxed for 7 to 10 hours (notes 3 and 4), monitoring the progress of the reaction by NMR spectroscopy (note 5).

The silylation mixture was cooled to room temperature, diluted with 150 mL of 1,1,2-trichlorotrifluoroethane and cooled to 5 ° C under nitrogen.

6.

26.83 ml (0.26 mol; 1.4 equivalents) of N-methylpyrrolidine are added with vigorous stirring over 10 minutes, maintaining the reaction temperature below 10 ° C (Note 6).

7.

Trimethylsilyl iodide (47.1 ml, 0.33 mol; 1.8 equivalents) was slowly added to the mixture from Step 6 at 5 ° C with vigorous stirring over a period of 10-15 minutes.

A slight exothermic reaction occurs during the addition of trimethylsilyl iodide. The reaction suspension was stirred at 5 ° C for 30 minutes under a dry nitrogen atmosphere.

8.

The resulting suspension was carefully warmed to 35-36 ° C and stirred at this temperature for 45-55 hours. The progress of the substitution reaction is monitored by high resolution liquid chromatography (Note 7).

9.

Both the volume of the reaction mixture and the stirring rate are checked regularly. An additional 100 ml of 1,1,2-trichlorotrifluoroethane is added as required (Note 8).

10.

After completion of the reaction (in the high resolution liquid chromatography chiromatogram, the area corresponding to 7-aminocephalosporanic acid is less than 2% of the total area), the resulting suspension is cooled to 5 ° C under nitrogen and stirred at 5 ° C for 8 minutes. 25 ml (0.615 mol) of methonal is added dropwise (Note 9).

11.

After the addition of methanol, after which the suspension becomes considerably thin, the mixture is stirred at 5-10 ° C for a further 15 minutes.

12.

Remove the cooling bath and add 125 ml of 3N hydrochloric acid prepared by adding 250 ml of concentrated hydrochloric acid to 756 ml of water over 2 minutes with vigorous stirring. During this addition, the temperature of the reaction mixture rises to 12-15 ° C.

13.

The hydrolysis mixture is heated to 20-25 ° C (but not above 25 ° C) as quickly as possible and stirred at 20-25 ° C for 15 minutes.

14.

The phases are separated and the organic phase (from the bottom of the phase) is extracted once with 50 ml of water. This aqueous phase is used to wash while filtering the separated aqueous solution.

15 Dec

2.5 g of diatomaceous earth were added to the separated aqueous solution from step 14 and the mixture was filtered through a pad of 7.5 g of diatomaceous earth. The diatomaceous earth layer is washed with the aqueous phase obtained in the extraction of the organic phase in step 14 and then with 25 ml of deionized water.

16.

The aqueous phase was combined with the wash liquids and the resulting solution, approximately 270 ml, which was reddish brown, was stirred at 10 to 23 ° C for 30 minutes with 10 g of activated carbon. After the addition of 2.5 g of diatomaceous earth, the mixture was stirred for a further 5 minutes.

17.

The charcoal is filtered through a pad of 7.5 g of diatomaceous earth, the filter cake is washed once with 75 ml of water and sucked dry for 5 minutes.

18.

If necessary, any residues are separated

1,1,2-trichlorotrifluoroethane under aqueous solution.

19 Dec

Isopropanol is added dropwise to the clear, orange-colored aqueous solution having a volume of about 350 ml and a pH of 0.9 to 1.15 until the onset of turbidity (Note 10).

20 May

The addition of isopropyl alcohol is stopped and the mixture is left to crystallize at 21 to 23 ° C for 15 minutes.

21.

After this time, additional isopropanol was added to the suspension over 45-60 minutes (a total of 1.2 liters of isopropanol was added) and the resulting suspension was stirred for 60 minutes while cooling to 0-5 ° C.

22nd

The product was filtered off and the filter cake was washed with a cold (0-5 ° C) mixture of isopropanol and water 9: 1 (twice 100 mL; Note 11) and once with 100 mL acetone. The product (Note 12) was vacuum dried for 15 minutes and then dried to constant weight in vacuo. 46 to 51 g (75 to 83%) of a crude mixture of hydrochloride and hydroiodide of the title compound (compound of formula I) are obtained in the form of an off-white to white crystalline substance. percent.

23.

According to NMR spectroscopy, the product has a purity of greater than 95%. The high-resolution liquid chromatography ratio compared to the analytical formula 4 of the ^3-form hydrochloride of the compound of formula (I) is 750 to 800 µg / mg. The purity calculated from the signal area is greater than 95 percent.

Note 1:

7-Aminocephalosporanic acid is an extremely dusty solid to be weighed in a fume cupboard or other place with adequate ventilation. Respirators and, where appropriate, appropriate protective clothing or equipment should be worn to protect against 7-aminocephalosporanic acid dust particles.

Note 2:

All operations with trimethylsilyl iodide should be carried out with the greatest possible exclusion of moisture.

Note 3:

It has been found that the reaction time varies and is likely to depend on the presence of trimethylsilyl iodide or its reactive equivalent as a catalyst. If the reaction is slow, it is accelerated and completed by the addition of additional trimethylsilyl iodide.

Note 4:

It is important to maintain vigorous reflux under reflux since the main driving force of the reaction is the removal of the ammonia produced.

Note 5:

When sampling the reaction mixture, it is important to operate under anhydrous conditions, which applies to all reactions of this procedure. Note 6:

A temperature rise above 10 ° C during the addition of N-methylpyrrolidine results in a higher amount of undesired A ² -isomer (1: 26).

Note 7:

Samples should be analyzed by high resolution liquid chromatography every 4 to 6 hours. The reaction temperature, the reaction time, the concentration and the number of equivalents of trimethylsilyl iodide as well as the alkalinity of the reaction medium play a decisive role in this reaction.

Note 8:

The suspension becomes very thick and the mixture should be diluted with some 1,1,2-trichlorotrifluoroethane to facilitate stirring.

Note 9:

Prior to the addition of methanol, the slurry is so thick that clumps of material adhere to the walls of the reaction vessel, making it difficult to mix thoroughly with methanol. It is necessary to observe and check that there is good and complete mixing at all points in the reaction vessel.

Note 10:

Typically, 0.5 to 1.0 volumes of isopropanol are required.

Note 11.

The washing liquid is prepared by mixing 90 ml of isopropanol and 10 ml of water and cooling the mixture in ice-water to 0-5 ^° C.

Note 12:

In a separate experiment, the product is isolated as pure hydroiodide by treating the slurry from reaction step 11 with 125 ml of 3N hydrogen iodide instead of 125 ml of 3N hydrogen chloride (as in step 12). Working up (see steps 13 to 21) of the aqueous phase as described above gave 44.3 g of white crystalline hydroiodide. The corrected high performance liquid chromatography performance of the hydrochloride analytical standard is 105%. The yield based on 7-aminocephalosporanoic acid (calculated on efficiency) is 56.7%.

Example 8

Recrystallization of (6R, 7R) -7-amino-3- (1-methyl-1-pyrrolidinio) methylcef-3-em-4-carboxylate monohydrochloride (hydrochloride of formula I)

METHOD

1.

To 125 ml (3.5 mol; 3.50 equivalents) of 1N hydrochloric acid is added, under vigorous stirring, in one portion, 15.0 g (0.045 mol) of the crude hydrochloride of the formula I (Note 1, 2).

2.

The resulting mixture was stirred at room temperature for 5 minutes.

3.

8.0 g of activated carbon are added in a single portion with vigorous stirring, and the suspension is stirred for a further 45 minutes,

8 2 N 9 δ

4.

The suspension is filtered off with suction through a pad of 8.0 g of diatomaceous earth, the filter cake is washed once with 35 ml of water and sucked dry for 5 minutes.

5.

The slightly cloudy filtrate is clarified through a 5 μηι pore filter to give a sparkling clear aqueous filtrate of 170 ml.

6.

With vigorous stirring, isopropyl alcohol (125 mL) was added dropwise over 25 minutes to the beginning of the turbidity, whereupon the addition of isopropanol was stopped.

The resulting suspension was stirred at room temperature for 1.5 minutes, during which time crystals developed well.

7.

Within 25 minutes, more is added dropwise with vigorous stirring. 475 ml of isopropyl alcohol (Note 3).

8.

The resulting suspension was stirred under ice-water cooling for 1 hour.

9.

The suspension is filtered and washed successively at 0 to 5 ° C twice with 120 ml of a 9: 1 mixture of isopropanol and water (note 4) and once with 120 ml of acetone, analysis calculated

10.

The filter cake is partially dried by suction for 15 minutes. Further drying in a vacuum pump at 40 ° C for 15 hours gave 7.87 g (52%) of the snow-white electrostatic crystalline hydrochloride of formula I (Note 5).

Note 1:

The number of moles of the starting hydrochloride of formula I is based on 100% purity.

Note 2:

A 1N hydrochloric acid solution is prepared by adding 83 ml of concentrated hydrochloric acid to 920 ml of distilled water.

Note 3:

The total isopropyl alcohol used for crystallization is činí00 ml, which is 3.5 times the volume of the clarified aqueous filtrate from step 5.

Note 4:

The isopropanol / water wash mixture consisting of 108 ml of isopropyl alcohol and 12 ml of water is cooled to 0-5 ° C in ice. Note 5:

The analytical data of the recrystallized hydrochloride of formula I is given in the following section:

found corrected for KF% C% H% N% S KF (H2) residue (kraft ash)

The high performance liquid chromatography performance is 99.5% over a standard hydrochloride sample of formula (I). Klett's number - 3 (100.0 mg sample in a volumetric flask is diluted with purified water [Milli-Q] n, and the volume is 10 ml and the solution is filtered through a special high-performance liquid chromatography filter [Millex]; path length 1.2 cmj.

It has generally been found that the "crude" hydrochloride of formula I, obtained by adding hydrogen chloride to the final mixture, contains some of the hydroiodide of formula I formed from the iodide present in the intermediate of formula II. Despite its high antibacterial purity, this product

46.77 46.02 46.71 6.04 6.17 6.10 12.59 12.31 12.49 9.61 9.50 9.64 - 1.47

<0.1 m. Recrystallize as described above to remove the hydroiodide of formula I.

In contrast, the hydroiodide of formula I, prepared by adding hydrogen iodide to the final reaction mixture, does not contain the hydrochloride of formula I after basic crystallization. Accordingly, the hydroiodide of formula I is normally highly pure and does not require recrystallization.

Example 9

Conversion of a compound of formula I (X = HCl) to a compound of formula VIII

6 2 6 9 N

21.72 g (0.0612 mol) of the compound of formula I in which X is hydrogen chloride are dissolved in 190 ml of water at 25 ° C with stirring. The mixture is cooled to 8-10 ° C and its pH. is adjusted from 2.5 to 5.8 (range 5.7-5.9) by dropwise addition of 30.5 ml (0.061 mol; 1.0 equivalent) of 2N sodium hydroxide solution. The total volume of the mixture was 214 ml.

555 ml of tetrahydrofuran are added in three portions. After each addition, the temperature of the mixture rises to 12-13 ° C and is lowered again to 8-10 ° C before the addition. The addition lasts a total of 10 minutes, the pH of the reaction mixture being 5.8 to 6.1.

The pH of the mixture was adjusted to 6.8 (range 6.7 to 6.9) by dropwise addition of 2.0 mL (0.004 mol) of 2N sodium hydroxide solution.

A total of 29.5 g (0.0927 mol) of activated [1-benzotriazole- (Z) -2- (2-aminothiazol-4-yl) -2-methyloxyiminoacetate, activated ester, was added to the mixture in 45 equal portions over 45 minutes. adding the first activated ester portion, the cooling bath is removed and the pH of the reaction mixture is again adjusted to 6.5 (range 6.5-6.7) by dropwise addition of 2N sodium hydroxide solution before each additional portion of activated ester is added.

The clear pale orange reaction mixture was stirred at 25 ° C for 2 to 3 hours, adjusting the pH to 6.5 (range 6.5 to 6) every 5 to 10 minutes by adding 2N sodium hydroxide solution every 5 to 10 minutes. 7). For the remaining reaction time, the pH was adjusted to 6.5 every 15 minutes. A total of 29.5 mL of 2N sodium hydroxide (0.059 mol; 0.97 equivalents) was consumed. The completion of the reaction was confirmed by high resolution liquid chromatography.

The solids were filtered from the reaction mixture and washed twice with 5 ml of water each time. The filtrate was extracted with 790 ml of methyl isobutyl ketone and the aqueous layer was separated. The organic phase is washed with 64 ml of water, the aqueous phases are combined and stirred for 10 minutes with 5.1 g of Dicalite. The solids were filtered off with suction and washed twice with 5 ml of water each time.

The resulting 314 ml clear orange solution was acidified with vigorous stirring by dropwise addition of 14.5 ml of 4N sulfuric acid to a pH of 3.7 (range 3.5-4.0). After acidification, the mixture becomes cloudy and sulfuric acid addition salt of the compound of formula VIII begins to crystallize therefrom.

The crystallization is allowed to proceed for 10 to 15 minutes and then the pH is adjusted to 3.0 (range 2.9 to 3.1) by dropwise addition of 7.5 ml of 4N sulfuric acid. An additional 63.5 mL of 4N sulfuric acid was added thereto for 30 minutes, so that the resulting mixture had a pH of 1.3-1.5, and after the addition was complete, the suspension was stirred at 0-5 ° C for 1 hour.

The white crystalline product is filtered off with suction and washed with 63.5 ml of 0.5N sulfuric acid. The solids were filtered off with suction, dried for 15 minutes with suction, washed twice with 100 ml of acetone each time, partially dried for 10 minutes with suction, and then vigorously stirred in 400 ml of acetone for 1 hour. The solid material is filtered off with suction, washed twice with 100 ml of acetone and dried at a constant weight (3 to 6 hours) at a temperature of 35 to 40 [deg.] C. under a vacuum of 50 mmHg.

The product, which is the sulfuric acid addition salt of the compound of formula VIII, is isolated as a slightly electrostatic white crystalline solid.

The yield was 28.79 g (81.4%).

Example 10

Conversion of a compound of formula I (X · HI) to a compound of formula VIII

The general procedure described in the previous example was repeated except that an equimolar amount of the hydroiodide of formula I was used instead of the hydrochloride of formula I to give the title compound.

Further details of the process according to the invention are illustrated by the following examples. In the examples given in these examples, the abbreviation Ac represents an acetyl group and the abbreviation IMS represents a trimethylsilyl group.

Example 11 (6R, 7R) -Rimethylsilyl-7- (trimethylsilyl) amino-3-acetoxymethylcef-3-em-4-carboxylate (f)

H

TNS N.

and

CQ-H

2.

c> .....

CO, TMS

The flask, dried in a reflux condenser, was cooled to room temperature under a stream of nitrogen, and 10.0 g (36.7 mmol of 7.2-amino-naphthalosporanic acid of 97.2% purity and 70 ml of 1.1.2) were charged. 9.3 ml (44.1 mmol; 1.2 equivalents) of 98% 1,1,1,3,3,3 are added by syringe with vigorous stirring and exclusion of moisture. hexamethyldisilazane and 0.16 ml (1.1 millimoles; 0.03 equivalents) of iodotrimethylsilane The suspension is vigorously refluxed for 7-10 hours under gentle nitrogen, then cooled to room temperature under a dry nitrogen atmosphere and diluted with 30 ml. The ¹ H-NMR spectrum of a sample of a slightly cloudy reaction mixture showed greater than 95% conversion to the desired product, which was identical to the product of Example 1. The ¹ H-NMR spectrum of the product was identical to spectrum of product shown in Method A of Example 1.

EXAMPLE 12 (6R, 7R) -7-Amino-3- (1,1'-methyl-1-pyrrolidinomethyl-methyl-3-em-4-carboxylate-monohydroiodide)

To a slightly turbid solution of (6R, 7R) -trimethylsilyl-7 (trimethylsilyl) amino-3-acetoxymethylcef-3-em-4-carboxylate in 1,1,2-trichlorotrifluoroethane (prepared according to the procedure of Example 11i) was added within 1 to 2 minutes with vigorous stirring at 0-5 ° C in a dry nitrogen atmosphere, 5.35 ml (51.4 mmol; 1.4 equivalents) of 97% N-methylpyrrolidine dried over a molecular sieve was added dropwise, followed by vigorous stirring over 5 minutes 9.40 ml (66.1 mmol; 1.8 equivalents) of trimethylsilyl iodide was added via syringe and the reaction temperature was kept below 10 DEG C. The resulting suspension was stirred at 0-5 DEG C. for a further 30 min. The reaction is monitored by high-resolution liquid chromatography, and after 45 to 48 hours the reaction is complete (7-aminocephalosporanic acid content is lower than 100 ml). The reaction mixture was cooled to 0-5 ° C under a dry nitrogen atmosphere and a total of 5.0 mL (123 mmol; 3.35 equivalents) of methanol while maintaining the temperature below 10 ° C. The suspension was stirred for 15 minutes at 0-5 ° C, then 25 mL of 3N aqueous hydrogen iodide solution (75 mmol; 2.0 equivalents) was added in one portion, after which the cooling bath was removed and the biphasic mixture was removed. The reaction mixture was rapidly heated to 20-25 ° C, at which temperature it was stirred vigorously for 15 minutes, the phases were separated and the organic phase was extracted once more with 10 milliliters of water.

The main aqueous phase was stirred with 0.5 g of diatomaceous earth at 20-25 degrees Celsius for 10 minutes. The suspension is filtered through a pad of 1.5 g of diatomaceous earth previously washed with 50 ml of water. After filtration, the diatomaceous earth layer is washed first with the aqueous extract obtained above and then once with 5 ml of water. The filter cake is partially vacuum dried for 5 minutes. After adding 2.0 g of activated carbon to the filtrate, the suspension was stirred at 20-25 ° C for 30 minutes, 0.5 g of diatomaceous earth was added thereto, and stirring was continued for 5 minutes. The resulting suspension is filtered through 1.5 g of diatomaceous earth, prewashed with 50 ml of water, and after filtration, this layer is washed once with 5 ml of water and then partially dried by suctioning for one minute. The filtrate is clarified by filtration through a 5 μτη pore size filter.

3.5 volumes of isopropanol were added dropwise to the clear, amber-colored aqueous phase at 20-25 ° C to precipitate the product. The resulting suspension was cooled to 0-5 ° C, allowed to stand for 1 hour, filtered and the residue washed at 0-5 ° C first twice with 20 ml of isopropanol / water (4: 1 v / v) first and then twice with 20 ml of acetone. The filter cake is first partially dried by suction for 5 minutes and then dried under vacuum at 20-25 degrees Celsius to constant weight. 8.94 g (57%) of white crystalline (6R, 7R) -7-amino-3- (1-methyl-1-pyrrolidinio) methylcef-3-em-4-carboxylate monohydiodide are obtained. According to liquid chromatography with high resolution the purity of the salt 97% (calculated from the area and ^X H-NMR (360 MHz) monohydroiodide title compound is identical to the ^X-H NMR spectrum of the hydrochloride of the corresponding product prepared by the method of Example A third

Example 13 (6R, 7R) -7-Amino-3- (4-methyl-4-morpholino) methylcef-3-em-4-carboxylate monohydroiodide

H

Ti / iSir (ý __ /, 5 ,.

..... ^CA ^ ______ '· cor Ci

262S98

The title compound was prepared from a solution of (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-cetoxymethylcef-3-em-4-carboxylate in 1,1,2-trichlorotrifluoroethane (from 50.0 g). starting from 7-aminocephalospoanoic acid) as described in Example 12 except that 28.3 ml (257 mmol; 1.4 equivalents) of N-methylmorpholine dried over the molecular sieve was used in place of N-methylpyrrolidine. The reaction is complete in 7-8 hours at 35-36 [deg.] C. The reaction mixture is worked up as described in Example 12 (due to the increased amount of starting material, the amount of all materials used is multiplied 5-fold), 36.0 g (41%) of slightly off-white crystalline (6R, 7R) -7-amino-3- (4-methylmorpholinio) methylcef-3-em-4-carboxylate monohydiodide is obtained. Product purity (calculated from an area greater than 95 ° / o.

¹ H-NMR (deuterium oxide, 360 MHz, δ values):

calculated:

% C, 40.40;% H, 4.34;% N, 9.53.

C, 34.99; H, 4.38; N, 9.35. Example 14 (6R, 7R) -7-Amino-3- (1-pyridinio) methylcef-3-em-4-carboxylate monohydiodide

H

TMS M

0 '

Ϊ what, p.

\

OAc cojhs

3.30 (s, 3H, N - CH3),

3.60 [m, 4H, -N (CH 3) CH 2 CH 2 OCH 2 CH 2],

3.68 (d, 1H, J · 10 Hz, -SCIH1).

4.04 (d, 1H, J = 10 Hz, - SC1 · -),

4.2 [m, 4H, -N (CH 3) 1 CH 2 CH 2 OCH 2 CH 2],

4.25 (d, 1H,) - 14Hz,

V>

- • ^C + V / ^ch

4.93 (d, 1Η, J = 14Hz,

5.30 (d, 1H, J = 5Hz)

C-6/3-lactam),

5.53 (d, 1H, J = 5 Hz, C-7 (S-lactam). IR (KBr):

460, 1,795 and 1,600 cnv ¹ .

Analysis for: C 13 H 19 N 3 O 4 S. H1

The title compound was prepared from a solution of (6R, 7R) -trimethylsiilyl-7- (trimethylsilyl) amino-3-acetoxymethylcef-3-em-4-carboxylate in 1,1,2-trichlorotrifluoroethane (from 10.0 g of the starting material). (aminoccephalosporanic acid) according to the procedure described in Example 12 except that 4.2 ml (51.4 mol; 1.4 equivalents) of pyridine dried over potassium hydroxide was used instead of N-methylpyrrolidine. The progress of the reaction is monitored by high resolution liquid chromatography. At 35-36 ° C the reaction is complete in 51 hours. The resulting suspension was filtered under nitrogen pressure and the filter residue was washed twice with 100 ml of fresh 1,1,2-trichlorotrifiluoroethane twice. The filter cake was quickly added to 50 mL of dry dichloromethane pre-cooled in ice-water to 0-5 ° C and 5.0 mL (123 mmol; 3.35 equivalents) was added dropwise with vigorous stirring at a temperature below 10 ° C. of methanol. The resulting suspension was stirred at 0-5 ° C for 15 minutes, then the solid was filtered off and washed with fresh dichloromethane (2 x 50 ml). The filter cake is suspended in 150 ml of dichloromethane, stirred for 1 hour, then the solid product is filtered off and, after washing twice with 50 ml of dichloromethane each time, dried under vacuum at 20-25 ° C to constant weight. 14.7 g (95%) of crude (6R, 7R) -7-amino-3- (1-pyridinio) methylcef-3-em-4-carboxylate monohydiodide are obtained.

1 H-NMR spectrum, measured at 360 MHz and chromatogram obtained by liquid chromatography of the above-obtained material with a high resolution (purity 65% - calculated from the area; the main impurity is pyridine hydroiodide, 13%) corresponding to the spectrum and chromatogram an authentic sample prepared in an independent manner (see also GCD Smith, European Patent Publication No. 70706, January 26, 1983, p. 21).

Example 15 (6R, 7R) -7-Amino (1- (2,3-cyclopenteno) pyridinio) methylcef-3-em-4-carboxylate monohydiodide

H

T / S; M

O'

-...... / c

.....

cr

O

The title compound was prepared from a solution of (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-acetoxymethylcef-3-em-4-carboxylate in 1,1,2-trichlorotrifluoroethane (from 10.0 g). starting 7-aminocephalosporanic acid) according to the procedure of Example 12 except that 6.02 ml (51.4 mmol; 1.4 equivalents) of 2,3-cyclopentenopyridine dried over a molecular sieve was used instead of N-methylpyrrolidine. The progress of the reaction is monitored by high-resolution liquid chromatography. At 35-36 ° C, the reaction is complete in 52 hours. Work-up of the reaction mixture using the procedure described in Example 14 gave 13.2 g (78%) of crude (6R, 7R) -7-amino-3- (1- (2,3-cyclopenteno) pyridinio] methylcef-3. -em-4-carboxylate-monohydroiodide.

The @ 1 H-NMR spectrum of this material, measured at 360 MHz, and the high resolution liquid chromatography chromatogram (92% purity calculated from area) correspond to the spectrum and chromatogram of an authentic sample of this product prepared independently.

EXAMPLE 16 (6R, 7R) -7-Amino-3-11- (2-acetoxy) ethyl-1-pyrrolidinomethylmethyl-3-em-4-carboxylate-monohydroiodide

The title compound was prepared from a solution of (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-acetoxymethylcef-3-em-4-carboxylate in 1,1,2-trichlorotrifluoroethane (from 10.0 g starting 7). -aminocephalospoic acid) as described in Example 12, except that 8.08 g (51.4 mmol) of N (2-acetoxy) ethylpyrrolidine was used in place of N-methylpyrazolidine. High-resolution liquid chromatography The oil is separated from the reaction mixture during the first 22 hours at 35 to 36 ° C and no further consumption of the starting material occurs after a total of 48 hours (at 35 to 36 ° C). The reaction mixture was cooled to 0-5 ° C under an atmosphere of dry nitrogen, and a solution of 7.45 mL (184 mmol; 5.0 equivalents) of methanol in 50 mL of 1,1,2- mL was added dropwise while maintaining the temperature below 10 ° C. After the addition was complete, the resulting suspension was not allowed to cool It is first stirred for 3.5 hours at 0-5 ° C, then filtered off with suction, the filter cake is washed twice with 50 ml of 1,1,2-trichlorotrifluoroethane in each case and dried under vacuum at 20-25 ° C to constant weight. 27.9 g (&gt; 100%) of the crude product are obtained.

The presence of the desired (6R, 7R) -7-amino-3- [1- (2-acetoxy) ethyl-1-pyrrolidinio] methylcef-3-em-4-carboxylate monohydiodide in this crude material was verified by comparison of the ⁴ H-NMR spectrum (360 MHz) of this material and its chromatogram obtained by high resolution liquid chromatography with spectrum and chromatogram of authentic material prepared by an independent procedure. According ^X H-NMR spectrum (360 MHz is a product comprising A ³ A ² isomer and isomer ratio 1: 1.7 and a substantial amount of starting amine. The chromatogram engage and ^3-isomer and 24% of unwanted isomer A ² is present in an amount corresponding to 34% of the area.

Example 17 (6R, 7R) -7-Amino-3- [1- (2-trimethylsilyloxy) -ethyl-1-pyrrolidinio] -methylcef-3-em-4-carboxylate-monohydiodide

The title compound was prepared from a solution of (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-acetoxymethyl-Ice-3-em-4-carboxylate in 1,1,2-trichlorotriuoroethane (from 10.0 g starting material). Of 7-aminocephalospnanoic acid] as described in Example 12, except that 9.63 g (51.4 mmol; 1.4 equivalents) of N- (2-trimethylsilyloxy) ethylpyrrolidine was used in place of N-methylpyrrolidine. The resulting mixture of the A ³ - and A ² -isomers of the title compound is detected as a mixture of the corresponding free hydroxy compounds, due to the hydrolysis of the trimethylsilyl residue during chromatography, during the first 23 hours at 35-36 ° C. After starting the reaction for a total of 30 hours at 35 to 36 ° C, no starting material is consumed. of the mixture as in Example 16, 29.77 g (&gt; 100%) of the crude product were obtained.

The presence of the desired (6R, 7R) -7-amino-3- (1- (2-trimethylsilyloxy) ethyl-1-pyrrolidinio] methylcef-3-em-4-carboxylate monohydiodide in this crude material was verified by ¹ H-NMR comparison. spectra (360 MHz) of this material and its chromatogram obtained in the liquid chromatography of high-resolution spectra and chromatogram with authentic material prepared independently. By ^X H-NMR spectra (360 MHz) contains the product a ³ and a ² isomer in -lsomer ratio of 1: 3.3 and a substantial amount of starting amine. the chromatogram assigned and occupies 16% of ^3-isomer and the a ² surface -isomeT is present in an amount corresponding to 60% of the area.

Example 18

7- [α- (2-aminothiazole-4-yl) -α- (Z) -methoxy iminoacetamido) -3 - ((1-methyl-1-pyrrolidinio) methyl) -3-cephem 4-carboxylate

Ο ^! 3 ........... x, i

CO £ CH ₃

In 87 ml of water, 12.76 g (30 mmol) of (6R, 7R) -7-amino-3- (1-methyl-1-pyrrolidinomethylmethyl) -f-3-em- (1-methyl-1-pyrrolidinoyl) -carbonyl are suspended at 20-25 ^° C with vigorous stirring. 4-carboxylate monohydroiodide (prepared in Example 12), the suspension is cooled to 8-10 ° C and its pH is dropped at 7 ° C by dropwise addition of 13.0 ml of 2N sodium hydroxide solution (26 mmol; 0.87 equivalents) over a period of 7 hours. After the addition of 555 ml of tetrahydrofuran, the pH of the resulting solution at 10 ° C is increased by dropwise addition of 1.9 ml of 2N sodium hydroxide solution (3.8 mmol; 0.13 equivalents) to 6.8. The bath was removed and 29.5 g (92.7 mmol; 1.5 equivalents) of activated syn-2-i (2-aminothiazol-4) activated hydroxybenzotriazolylesterate were added in two equal portions of 14.75 g each 30 min. After each addition, the pH is adjusted every 5 to 10 minutes by dropwise addition of 2N sodium hydroxide solution to the pH. For the remaining reaction time, the pH is again adjusted to 6.5 by dropwise addition of 2N sodium hydroxide solution every 15 minutes. A total of 28.6 mL of 2N sodium hydroxide (57.2 mmol; 1.91 equivalents) was consumed. The completion of the reaction was determined by high resolution liquid chromatography.

After 1.75 hours, the resulting dark solution is poured into 365 ml of methyl isobutyl ketone, the lower aqueous phase is separated and the organic phase is extracted once more with 30 ml of water. The combined aqueous phases are stirred for 10 minutes at 20-25 ° C and 2.35 g of diatomaceous earth, the insoluble material is filtered off with suction and the filter cake is washed once with 5 ml of water. The amber-colored aqueous phase is clarified by filtration through a 5 µm filter. At 17 ° C the solution has a pH of 6.40.

To this solution was added, with vigorous stirring, 6.7 ml of 4N sulfuric acid, resulting in a cloudy solution having a pH of 3.82 at 18 ° C. The product was allowed to crystallize from this solution with vigorous stirring for 5 minutes, and an additional 3.5 ml of 4N sulfuric acid was added. The resulting suspension, which has a pH of 3.09 at 20 ° C, was cooled to 0-5 ° C and 30 ml of 4N sulfuric acid was added dropwise over 20 minutes. The mixture is stirred at 0-5 ° C for 1 hour, then the precipitate is filtered off and washed once with 30 ml of 0.5N sulfuric acid. The filter cake is partially dried by suction for 15 minutes, then washed twice with 50 ml of acetone each time, again partially dried by suction for 15 minutes and then stirred in 200 ml of acetone at 20-25 ° C for 1 hour. The salt was filtered off, washed twice with 50 ml of acetone each, partially dried by suction for 1 minute and then dried under vacuum at 40 ° C to constant weight. 12.41 g (72%) of the crystalline, slightly off-white title compound are obtained as the sulfuric acid salt.

¹ H NMR (deuterium oxide, 360 MHz, delta):

2.16 - 2.33 [obscured signal, 4H, —N (CH3) CH2CH2CH2],

3.01 (s, 3H, N - CH 3),

3.45-3.65 [m, 5H, -N (CH 3) CH 2 CH 2 CH 2, -SCH 2 -),

3.95 (d, 1H, J = 17Hz, - SCH2 -), 4.04 (d, 1H, J = 14Hz,

I r ¹ o

4.08 [s, 3H, -OCH 3], 4.75 (d, 1H, I = 14 Hz,

5.37 (d, 1H, J = 5Hz, C-6/3-lactam), 5.86 (d, 1H, J = 5Hz, C-7, 3-lactam),

7.16 (s, 1H, C-5 thtazole).

Analysis for: C 19 H 24 N 6 O 5 S 2. H2SO4 calculated:

% C, 39.43;% H, 4.53;% N, 14.53;% S, 16.63;

% C, 40.40;% H, 4.47;% N, 14.39.

Example 19

7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3 - ((4-methyl-4-morpholinio) methyl-3-cephem-4-carboxylate) 0 _X OCR NH 'aV ·

N-I ^£ lj '. Ó ^u o

OI i, co ^Ch sz <- ^{, H} and ^sat 4

I% j what _s

CH

40

The title compound was prepared according to the procedure in Example 18, starting with 54.0 g (122 mmol) of (6R, 7R) -7-amino-3- (4-methyl-4-morpholinio) methylcef-3-em-4-carboxylate. monohydroiodide (prepared in Example 13) and 59.0 g (184 mmol; 1.5 equivalents) of activated syn-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetic acid hydroxybenzotriazolylester.

A total of 60.1 g (84%) of the white crystalline title compound was obtained as a sulfuric acid salt.

@ ¹ H-NMR (360 MHz, deuterium oxide / deuterated sodium bicarbonate) .delta.

4.95 (d, 1H, J = 14Hz, +/– CH, N0)

5.47 (d, 1H, J = 5Hz, C-6/3-lactam),

5.96 (d, 1H, J = 5 Hz, C-70-lactam), 7.10 (s, 1H, C-5 thiazole).

Analysis for: C 19 H 24 N 6 O 6 S 3. H2SQ4

3.30 (s, 3H, NCH 3),

3.55 [m, 5H, - N (CH 3) CH 2 CH 2 OCH 2 CH 2, —SCH 2 - 1,

4.05 (d, 1H, J = 16Hz, -SCH 2 -), 4.10 (s, 3H, -OCH 3),

4.1 [m, 4H, -N (CH 3) CH 2 CH 2 OCH 2 CH 2],

4.21 (d, 1H, J = 14Hz)

-CH 2), ch ₅ .

Table compound yield (example.) (%)

12 57 13 41 14 95 15 Dec 78 16 > 100 ^d > 17 > 100 ^d)

Legend:

calculated:

% C, 38.37;% H, 4.41;% N, 14.13;% S, 16.18%.

% C, 38.16;% H, 4.32;% N, 14.08.

Example 20

The following table summarizes the results obtained when analyzing products from some examples. With the exception of the compounds of Examples 12 and 13, the reported data relate to sulphide hydroiodides isolated by filtration of the sus pension after addition of methanol. The compounds of Examples 12 and 13 were isolated from this suspension after addition of 3N aqueous iodoic acid.

purity of A ³ -isomer (area% HPLC) HPLC ratio A ³ : A ² -isomer a ⁾ NMR ^b) 97 97: 0 - > 95 > 95: 0 - 65 ^c > 65: 6 - 92 92: 0 - 24 24: 34 1: 1.7  16 16: 80 1: 3.3

^and, reported data is the area percent for each isomer in the chromatogram obtained with high resolution liquid chromatography of the isolated hydroiodic acid salt;

^{b, said} data being the ratio of isomers obtained by comparative signal integration for the individual isomers;

^{(c) the} major impurity is pyridine hydroiodide (24% area);

^{d) The} NMR spectrum of the sodium iodide, measured at 360 MHz, indicates that the main impurity is the unreacted starting amine.

Claims (3)

SUBJECT VYNALEZU A process for the production of temperature-stable crystalline cephalosporins of the formula VIIIb IVU b) in 1,1,2-trichlorotrifluoroethane operate in any order at least one equivalent of iodotrimethylsilane and at least one equivalent of a compound of formula b is running / \ "...... / _CH3 in... where X is hydrogen chloride or hydrogen iodide and, 4-Nu is a radical of formula CH ₃ from the resulting product by treatment with a lower alkanol and removing the silyl group product is acidified with hydrogen chloride or hydrogen iodide. 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula VIIIb wherein X is as defined above + and —Nu represents a radical of formula virtually free of the A ² -isomer, characterized in that a solution of the compound of formula IVa UV &.} 3. A process according to claim 1 or 2, wherein the corresponding starting materials are used to form a compound of formula VIIb wherein -Nu is a 1-methyl-1-pyrrolidinium radical and X is as defined above.