CS262699B2 - Process for preparing heat stable crystalline cephalosporines - Google Patents

Description

A process for the preparation of stable crystalline cephalospoirins of formula I wherein X is hydrogen chloride or hydrogen iodide by reacting a compound of formula VL with a solution of a compound of formula IVa in 1,1,2-trichlorotrifluoroethane, cleavage of silf groups, lower alkanol hydrogen iodide. The compounds produced serve as intermediates for the preparation of cephalosporin antibiotics with a broad spectrum of activity.

(CH 2 SO 2)

CH 2 OOC 4

282899

The invention relates to thermostable crystalline salts of the cephalosporin derivatives of the general formula I

in which

X is hydrogen iodide or hydrogen chloride (HI or HCl).

These compounds are substantially free of the AMsomer 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 salts of formula (I) above.

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

Ph is phenyl and compounds 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 (acylation and then cleavage of the protective sapscripts 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 final products described in U.S. Pat. No. 4,406,899 require the inclusion of a chromatographic purification step to separate the resulting mixture of Δ ² - and AMsomerů.

U.S. Pat. No. 4,168,309, issued September 18, 1979 to Eerry E. Ayres, discloses compounds of the general formula:

in which

R "‘ represents a carboxyl function protecting group,

R ^1, together with the carbon atoms to which it is attached, forms an optionally substituted saturated or partially saturated four to ten membered heterocyclic ring, which may contain one or more additional heteiroatoms selected from oxygen, nitrogen and sulfur, the dashed line being either a cef- 2-em- or cef-3-emderivative a

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

In the cited patent, these compounds are not exemplified by embodiments, but are described only by structural formulas as intermediates for the alternative synthesis of certain cephalosporins (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 deprotection of the carboxyl function).

The use of protected carboxyl functions in the processes of the two aforementioned patents is disadvantageous because it requires cleavage of the protecting groups after acylation, 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.

fCA / ₃ ) ₃ S / _O C / VH

O

CO O A

202699 in which

B represents a chlorine atom, a methoxy group or a —CH2E radical in which E represents hydrogen, a group —OCCH3,

II o

—-OCNH2 or SZ,

Wherein Z is an optionally substituted 5- or 6-membered heterocyclic ring containing 2 to 4 nitrogen atoms and optionally 1 oxygen or sulfur atom, wherein the sulfur atom in the —SZ group is 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 the 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 for a partially continuing 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 William H. W, Lunn, discloses compounds of Formula I

(I) and their preparation by reacting compounds of formula II

C-CONH

II

N ⁰

() with a silylating agent, such as trimethylsilylacetamide, bistrimethylsilylacetamide and the like, to form a compound of formula III

C-CONH-

Λ

O ll

Y ^ ch ₂ occh ₃

COOS ^ CH ^

Cm) reacting a compound of formula III with trimethylsilyl iodide to form a compound of formula IV r 1 - ( ^X) O (IV) which is then reacted with a compound of formula II

To give 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 processes wherein R is, for example, an amino-substituted oxazole, oxadiazole or isoxazole ring and the substituent at the 3-position is for example an optionally substituted pyridine, quinoline or isoquinoline residue.

South African Patent Publication No. 84/3343, issued October 25, 1984, describes a process for preparing cephalosporins of Formula I

P&N H O 's

COOH

in which

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

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

O'

Γ *

r-c-cqnh

AND!

W «^ OP

COO CH _Z A (III) which is then (after deprotection of the amine function) is acylated with an acid of formula IV (I) wherein

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

R ¹ represents a hydrogen atom or a methoxy group,

R ^z is one of the numerous substituents known in the chemistry of cephalosporins and

A represents an optionally substituted quinolinium, isoquinolinium or pyridinium residue.

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

R = C-COOH

N ² > R ² (IV)

Suitable R ⁷ groups include acetoxy, propionyloxy, chloroacetoxy, acetylacetoxy and carbamoyloxy. Suitable solvents include the following solvents:

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 achieved 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 EU priority is given to the above-mentioned South African patent, mentions the same solvents 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.

Compounds of formula (I)

C 'coo (!) In which

X is hydrogen iodide or hydrogen chloride prepared by the process of the invention are crystalline, temperature stable and practically free of the corresponding ^{2 2} -isomer. Due to the absence of this tohoto ² -isomer, the above compounds can be converted by acylation to a wide variety of cephalosporins, which are also virtually free of the is ² -isomer and thus do not require chromatographic separation of the ^{2 2} - and s-isomers. Due to the temperature stability of the compounds of the invention, they can be isolated and stored, and converted to the resulting products only then. when it is desired. A further advantage of the intermediates of formula I is that they do not require protection of the carboxyl group prior to acylation and consequently there is no need to cleave the carboxyl function protecting group after acylation, thereby improving the efficiency of the process.

In accordance with the invention, the compounds of the formula I are prepared by treating a compound of formula VI ' 1 and M-Si-H fc ΐ CH ₃ (in the IE is reacted with. A solution of compound IVa pattern ce

CO 2, 1,1,2-trichlorotrifluoroethanol, removal of the lower alkanol removes the silyl groups and the product is acidified with hydrogen chloride or hydrogen iodide to give the corresponding hydrochloride or hydroiodide.

The reaction of N-methyl, 1-N-trimethylsilylpyrrolidinium iodide (VI) with a solution of compound (IV) and 1,1,2-trichlorotrifluoroethane is carried out at a temperature of about 5 ° C to 45 degrees Celsius. Conveniently the reaction is carried out at a temperature of 35 ° C. The compound of formula VI can be used in an amount of about 1.0 to 20 equivalents, preferably about 1.2 to 1.5 equivalents for each equivalent of the compound of formula IVa. If desired, a small amount of imidazole (e.g. 0.1 equivalent) can be added to the reaction mixture to reduce the reaction time.

The above reaction of the compounds of formulas IVa and VI results in an II solution of the compound of formula (CH3SiHN-y4O).

WHAT. ₇ Network (CW ₃ ) ₃

OD in 1,1,2-trichlorotrifluoroethane (Freon TF), which is then treated with lower alkanol or water to remove 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 trimethylsilyl groups. The reaction is carried out at a temperature of about -10 ° C to 25 ° C, preferably at about 0 to 10 ° C. About 2 to 5 equivalents of methanol, preferably about 3 to 4 equivalents of methanol are used for each equivalent of the starting compound.

The compound of formula VI can be prepared by reacting N-methylpyrrolidine with approximately an equimolar amount of trimethylsilyl iodide in the

1,1,2-trichlorotrifluoroethane or 1,1,1 trichlorotrifluoroethane as the solvent, at a temperature ranging from about -10 ° C to d ° C, preferably from 0 to 5 ° C. The ratio of N-methylpyrrolidine to trimethylsilyl iodide in this reaction may vary, but equimolar amounts of these compounds are excellent.

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

The compound of the above formula can also be obtained by other methods forming part of the subject-matter of the inventions of our two related Czechoslovak patents Nos. AO 262 674, AO 262 698.

The compounds of formula (I) can be readily converted to a wide variety of antibiotics by acylation with the appropriate side chain forming acid. For example, a compound of formula (I) wherein X is hydrogen chloride or hydrogen iodide is converted to 7- [ice- (2-aminothiazol-4-yl) -α- (Z-methoxyiminoacetamido) -3 - [(1-methyl-1)]. -pyrrolidinomethylmethyl-3-cephem-4-carboxylate of formula VIII by N-acylation with an activated ester of 1-benzotriazolyl (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetate according to the following reaction procedure scheme:

θ ’(I)

H, C .......

\ to ^ CH; rN | * ’V_j what about” --T-C-COO ......... N j h (j i,

W__C-CONH.

Ji lj π ^N

, .....

i i \ (»'» AJ

T J

C00 'i (V / II)

This reaction is readily accomplished 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 dropwise with sodium hydroxide 5.5 to 6, tetrahydrofuirane 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 Kokal 54-95593 (28 07 79) (Hoechst) and in German Patent Application Publication No. 275S000.3 (24 12 77J). The use of compounds of formula VIII is described in U.S. Pat. No. 4,406,899 (Aburaki et al.

The compound of formula (I) may 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 = mul tip flight w == wide signal d = doublet q = quartet dd = double doublet

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

Method A

The oven-dried flask equipped with the Friedrich condenser was cooled to room temperature in a stream of dry nitrogen and charged with 50.0 g (184 mmol) of 7-amino-13 cephalosporanic acid of 97.2% purity and 400 ml of 1,1,2-trichloirtrifluoroethane. dried over the molecular sieve. With vigorous stirring and in the absence of moisture, 46.5 ml (222 millimoles; 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 slightly cloudy reaction mixture showed greater than 95% conversion to the desired product.

NMR (perdeuterodichloromethane, 360 MHz, δ values):

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, - SCH 2 -),

3.61 (d, 1H, J = 18.3 Hz, —SCH2),

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

4.83 (d, 1H, J = 13.2Hz, —CH2OCOCH3),

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

5.11 (d, 1H, J 13 2 Hz, - CH 2 OCOCH 3). Method B

The oven-dried flask equipped with a Friedrich condenser was cooled to room temperature in a dry nitrogen stream, and 10.0 g (36.7 mmol) of 7-aminocephalosporanic acid having a purity of 97.2% and 80 ml of dry 1,1,2- of trichlorotrifluoroethane dried over molecular sieves To the resulting suspension was added 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 M hydrogen iodide solution in

1,1,2-trichlorotrifluoroethane (prepared by introducing hydrogen iodide to dry 1,1,2-trichlorotrifluoroethane and titrating the resulting saturated solution to phenolphthalein). The reaction slurry was vigorously refluxed for 22 hours with vigorous stirring to eliminate the ingress of moisture, then cooled to room temperature. ^{The 1} H-NMR spectrum measured in perdeuterodichloromethane at 360 MHz indicated greater than 95 percent conversion to the desired product.

Method C

The oven-dried flask equipped with a 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 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 slurry with vigorous stirring and exclusion of moisture. 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. ¹ H-NMR spectrum measured in perdeuterodichloromethane at rt. 360 MHz indicates greater than 93% conversion to the desired product.

Example 2

N-methyl-N-trimethylsilylpyrrolidinium iodide

The oven-dried flask was cooled to room temperature in a stream of nitrogen and charged with 25 mL of 1,1,2-trichlorotrifluoroethane dried over a molecular sieve and 1.42 (10.0 mmol; 1.0 equivalent) of trimethylsilyl iodide. The resulting solution was cooled to 0-5 ° C under an atmosphere of dry nitrogen, a total of 1.04 mL (10.0 mmol; 1.0 equivalent) of dry 97% N-methylpyrrolidine dried over a molecular sieve was added dropwise and the resulting suspension was The mixture was stirred at 0-5 ° C for 30 minutes. After this time, the suspension is filtered under a positive pressure of nitrogen and the solid material is washed twice with 25 ml each of fresh dry 1,1,2-trichlorotrifluoroethane. The filter cake is partially dried by suction under nitrogen pressure for 15 minutes. After further drying for 12 hours at room temperature under a vacuum of 6.7 Pa, 2.51 g (89%) of N-methyl-N-trimethylsilylpyrrolidinium iodide is obtained as a colorless solid which is extremely sensitive to the presence of air.

Analysis calculated for

44.49% I, found:

44.40% I (iodide ion chromatographic analysis).

In another experiment, the reaction is generally carried out as above, except that 0.40 ml of 10.0 mmol is added dropwise to a suspension of the salt in 1,1,2-trichlorotrifluoroethane at 0-5 ° C; 1.0 equivalents) of methanol. The resulting heterogeneous mixture was stirred at 0-5 ° C under nitrogen for an additional 30 minutes. The suspension is filtered in the absence of moisture, and the filter cake is washed twice with 25 ml of fresh each

Of 1,1,2-triclorotrifluoroethane and dried at room temperature under a vacuum of 6.7 Pa for 3 hours. 1.93 g (91%) of a solid, identified as N-methylpyrrolidinohydroiodide, melting at 80-82 ° C (uncorrected), was obtained. An authentic sample is prepared in a separate experiment by adding hydrogen iodide gas to a solution of N-methylpyrrolidine in 1,1,2-trichlorotrifluoroethane. The isolated solid melted at 83.5-85.3 ° C (uncorrected). ^{The 1} H-NMR spectrum of this material, measured at 360 MHz in deuterium oxide, corresponds to the spectrum measured for the salt isolated from the methanol-containing reaction mixture.

^{The 1} H-NMR spectrum of the filtrate obtained in a methanol reaction, measured at 360 MHz, contains 17: 1 methoxytrimethylsilane and methyl iodide as major constituents, and a small amount of hexamethyldisiloxane.

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

Method A

The oven-dried flask was cooled to room temperature in a stream of dry nitrogen and charged with 15.7 mL (110 mmol;

1.5 equivalents) of trimethylsilyl iodide and 140 ml of 1,1,2-trichlorotrifluoroethane dried over a molecular sieve. The resulting solution was cooled to 0-5 ° C at such a rate that the reaction temperature was kept below 10 C ^and was added dropwise 10.7 ml (103 mmol; 1.4 eq) of 97% N-methylpyrrolidine. After the addition was complete, the suspension was stirred at 0-5 ° C for 30 minutes under nitrogen and then allowed to warm to room temperature.

To a mixture of N-methylpyrrolidine and trimethylsilyl iodide, a reaction mixture containing (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-acetoxymethylcef-3-em-4-carboxy, (obtained by according to Method A of Example 1 using 20.0 g of 7-aminocephalosporanoic acid). The resulting heterogeneous mixture was stirred at room temperature for 14 days while the progress of the reaction was monitored periodically by high resolution liquid chromatography. While the area corresponding to 7-aminocephalosparanic acid is less than 2% of the total signal area, 6.0 mL (147 mmol; 2.0 equivalents) of methanol is added dropwise and stirring is continued for a further 30 minutes. The crude product is filtered off, washed once with 300 ml of fresh 1,1,2-trichlorotrifluoroethane, partially dried by suction for 15 minutes, then dried in vacuo at room temperature for 16 hours.

The crude product obtained is slurried in 80 ml of deionized water and the pH of the suspension is dropped to 0.50 with the dropwise addition of concentrated hydrochloric acid with vigorous stirring. Activated carbon was added in an amount corresponding to 20% by weight of the crude product, stirred for a further 45 minutes, then filtered in vacuo through a pad of diatomaceous earth, which was washed with deionized water. 900 ml of isopropyl alcohol are added dropwise to the aqueous phase with gentle stirring over 1 hour, the suspension is stirred at 25 ° C for 1 hour, then cooled to 0-5 ° C and stirred for an additional hour. After filtration, washing with 200 ml of cold (0 to 5CJ mixture of isopropyl alcohol and water (9: 1) and 200 ml of acetone and drying under vacuum at 25 ° C for 1 hour), 15.5 g (63%) of crystalline (6R, 7R) ) -7-amino-3- (1-methyl-1-pyrrolidinio) methylcef-3-em-4-carboxylate monohydrochloride,

NMR (deuterium oxide, 360 MHz, values):

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, -CH 2),

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 = 5.1 Hz, 'COCHCHS'),

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

Method B

To a suspension of N-methylpyrrolidine, iodotrimethylsilane and 1,1,2-trichlorotrifluoroethane (see Method A) at 0-5 ° C was added 0.50 g (7.3 mmol; 0.10 equivalents) of imidazole. This modification of the process results in a slight increase in the reaction rate, so that after 10 days the content of 7-aminocephalosporanic acid is less than 2% (based on the total area of the strip in high performance chromatographs). By working up the reaction mixture as in Method A, 14.7 g (60%) of crystalline (6R, 7R) -7-amino-3- (1-methyl-1-pyrrolidinomethylmethyl-3-em-4-carboxylate) are obtained. monohydrochloride.

Example 4

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

1.

To 125 ml (3.51 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 formula I (notes 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 45 minutes.

4.

The suspension is suction filtered 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 μΐη filter to give a sparkling clear 170 ml aqueous filtrate.

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 15 minutes, during which time seed crystals developed well.

7.

An additional 475 ml of isopropyl alcohol is added dropwise with vigorous stirring over a period of 25 minutes (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.

10.

The filter cake is partially dried by suction for 15 minutes. Further drying in a vacuum pump at 40 ° C for 15 hours afforded 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 hydrochlorides of the 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 volume of isopropyl alcohol used for crystallization is 600 ml, which is 3.5 times the volume of the clarified aqueous filtrate from step 5.

Note 4:

The washing mixture of isopropanol and water, consisting of 108 roles of isopropanol and 12 ml of water, is cooled in ice to 0 to 5 degrees Celsius.

Note 5:

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

analysis calculated found corrected for KF % C 46.77 46.02 46.71 % H 6.04 6.17 6.10 % N 12.59 12.31 12.49 % S 9.61 9.50 9.64 KF (H2O) - 1.47

residue (kraft ash) -

The high performance liquid chromatography performance is 99.5% over a standard sample of hydrochlorides of formula I. Klett number = 3 (100.0 mg sample in a volumetric flask diluted with purified water [Milli-Q] to 10 ml and filtered through a special high-resolution liquid chromatography filter [Millexj; cold light; path length 1.2 cm).

In general, it has been found that the "crude" hydrochloride of formula I, obtained by adding hydrogen chloride to the final mixture, contains some <0.1 amount of the hydroiodide of formula I, which is formed from the iodide present in the intermediate of formula II. Thus, despite its high antibacterial purity, this product must normally be recrystallized 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 5

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

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 the 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-methoxyiminoacetate) activated ester was added in 5 equal portions over 45 minutes. After addition of the first activated ester portion, the cooling bath was removed and the pH of the reaction mixture was 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 was 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. Total consumed

29.5 mL of 2N sodium hydroxide (0.059 mol; 0.97 equivalents). 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 fractions 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 is acidified with vigorous stirring by dropwise addition of 14.5 ml of 4N sulfuric acid to pH 3.7 (range 3.5-400). After this acidification, the mixture becomes cloudy and crystallizes the addition salt of compound VIII. with sulfuric acid.

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. The mixture was cooled to 0-5 ° C and an additional 63.5 mL of 4N sulfuric acid was added over 20-30 minutes to give a pH of 1.3-1.5. After the addition of sulfuric acid 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 aspirated, partially dried for 15 minutes, washed twice with 100 ml of acetone twice, partially dried again 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 each time and in vacuo with 1333 to 100 ml

Dry at constant temperature (3-6 hours) at 35-400C.

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

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.

EXAMPLE 1 a d 7 (6R, 7R) -trimethylsilyl-7- (trimethylsilyl) amino-3-acetoxymethylcef-3-em-4-carboxylate

θ ^Ac CO 2 TMS

The flask, dried in a reflux condenser, was cooled to room temperature in a stream of nitrogen and then charged with 10.0 g (36.7 mmol) of 7-aminocephalosporanic acid of 97.2% purity and 70 ml of 1.1, Of 2-trichlorotrifluarethane 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 were added to the resulting suspension with vigorous stirring and exclusion of moisture. (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 of fresh 1,1,2-trichlorotrifluoroethane. ^* H-NMR spectrum of a sample slightly turbid reaction mixture indicates greater than 95% conversion to the desired product, identical with the product of Example 1. ^X H-NMR spectrum is identical with the spectrum of the product indicated in method A of example 1.

Claims (1)

Subject The process for the preparation of the temperature-stable crystalline cephalosporins of the formula I is reacted with a solution of a compound of formula IVa (C ^) ₃ SH '/ N coo (0 in. COgSi (ch ₃ ) ₃ o (Iv a) in which: X is hydrogen chloride or hydrogen iodide virtually free of the corresponding A ² -isome, characterized in that the compound of formula VI in 1,1,2-trichlorotrifluoroethane is treated with a lower alkanol to remove silyl groups and acidified with hydrogen chloride or iodide to give the corresponding hydrochloride or hydroiodide.