DE1795209A1 - New process for the production of amino compounds - Google Patents

Description

P: · ι -5

β α λ κ τ ι ε ν (:; - ::: ^ ellschaf τ, β as l ,. (■; c, -ί \ χ .5 1 /.)

Today's process for the production of Ami noverbitidungen

The subject of the application is a new process for Production of 7-amino-cephalosporanic acid (7-ACA).

It is known from the main patent (note no. P 14 45 615 * 6 ^ French patent no. 1 394 820) to produce 7-ACA by using an imide halide of an N-protected cephalosporin C diester of the formula

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BATH ORIGINAL

Hal Y-GH- (CH ₂ ) -C = If

C = O

OR

N // - CH ₂ -O-COCH ₃ C = O OR

wherein Y is a protected amino group and OR is removable ester groups are, in a corresponding iminoether ,, for example Lower alkylimino ether, converted., The imino ether solvolyzed and optionally a 7-ACA ester obtained saponified to give the free acid.

It has now surprisingly been found that 7-ACA can be gained in a more beneficial way by having a Zinc complex of cephalosporin C treated with a silylating or stannylating agent, preferably in excess, the compound thus obtained is converted by the process of the main patent into an imide halide of the formula I, in which OR stands for is a silyl or stannyl ester group and Y is optionally one silylated or stannylated amino group, this compound is converted into an imino ether by means of an alcohol and the iminoether double bond by treatment with a hydroxyl group Solvent cleaves. According to the process, 7-ACA is therefore produced by adding a zinc complex of cephalosporin C with a silylating or stannylating

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BATH

Agent, preferably in excess, treated, converts the compound thus obtained into an imide halide of the formula X, in which -OR stands for a silyl or stannyl ester group and Y stands for an optionally silylated or stannylated amino group, this compound is converted into an imino ether by means of an alcohol and the iminoether double bond is cleaved by treatment with a solvent containing hydroxyl groups. The imide halide group is preferably converted into an imino ether group by treatment with a lower alkanol, in particular methanol. The double bond of the imino ether is cleaved, for example by treatment with water, for example at a pH of approx. 0 to 4, preferably approx.

These operations can be carried out in a manner known per se, ZoB. as described in French patent 1,394-820. The formation of the imino ether is absent ■■ made by water.

The new process offers extremely valuable possibilities for a simple implementation on an industrial scale. So one can proceed expediently in such a way that one out of fermentation solutions Cephalosporin G precipitates and separates as a crystalline zinc complex and this product is treated directly with a silylating or stannylating agent without further purification. This gives, optionally after filtration, an almost colorless, clear solution that can be used directly to make the imide halide. In the same

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BAD ORiOJNAL

■ * :. ': ■ (* ■: ■; ■; ■■

The reaction medium also results in the formation of the imino ether and its solvolysis to 7-ACA. The crystallizes from the solution 7-ACA directly from, preferably at a pH of 3 ~ ^ · It is of such purity (uniformly according to thin layer chromatography) that they lead directly to acylation at the 7-amino group can be used.

The silyl or stannyl ester groups are groups of the formula

E ₂ -AO-

where A stands for Si or'Sn and R ₁ , R ₂ and R ^, are identical or different and stand for alkyl, in particular lower alkyl, aryl, for example phenyl, or aralkyl, for example benzyl. Preferably R ₁ , Rp and R ^ are the same and represent methyl, ethyl or n-butyl.

The ester groups and optionally an N-silyl or N-stannyl protective group are introduced, for example with a compound of the formula

E ₂ AX

wherein A, R- ,, Rp and R, have the above meaning and X is halogen, especially chlorine.

109853/1833

BATH ORIGINAL

For example, the zinc complex is made from cephalosporin C reacted with chlorotrimethylsilane or tri-n-butyltin chloride. To introduce the silyl ester group, one can also with hexamethylsilazane or N-trimethylsilyl diethylamine or with bis-trimethylsilylacetamide or trimethylsilyl-N-methylacetamide convert, while the stannyl residue can also be introduced by means of the corresponding distanny oxide. The implementation

. of alcohol
In the absence / and in the absence of such amounts of water that cannot be consumed by the excess of silylating or stannylating agent, in an inert organic solvent, such as hydrocarbons, e.g. benzene or toluene, or preferably chlorinated hydrocarbons, such as chloroform or methylene chloride , or in ethers such as tetrahydrofuran, ethylene glycol dimethyl ether or nitriles such as acetonitrile, preferably at room temperature or at a slightly elevated temperature (up to 60 C).

The transfer of the protected connection into the Imide halide takes place according to known methods, e.g. as described in French patent 1.39 ^ 820, by reaction with imide halide-forming agents, such as acid halides, especially chlorides, which differ from phosphorus, sulfur, carbon or derive their oxygen acids, e.g. with phosphorus oxychloride, Phosphorus trichloride, thionyl chloride, phosgene, oxalyl chloride, pyrocatechyl phosphorus trichloride, especially with

109853/1833

Phosphorus pentachloride. The implementation is preferably in above mentioned inert organic solvents and in the presence of tertiary amines, e.g. triethylamine, quinoline or preferably Pyridine or dimethylaniline.

The invention is illustrated in the examples below described. The temperatures are given in degrees Celsius.

The following systems are used for thin-layer chromatography (on silica gel): ■ ■.

System 101A: n-Butanol-Pyri.din-Elsessig-Wasser (40: 24: 4: 30)

System 110: ethyl acetate-n-butanol-pyridine-glacial acetic acid-water (42: 21: 21: 6: 10).

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Example It

10 g approx. 80% cephalosporin C zinc complex slurried in 700 ml of absolute methylene chloride. The suspension is mixed with 8.38 ml of absolute pyridine with thorough stirring and 19 * 1 ml of trimethylchlorosilane are added and the mixture is warmed to 30. A clear, light yellow solution is obtained within 30 minutes. To A total of 2 hours of stirring at 30 is cooled to room temperature and adds 22.7 ml of absolute pyridine. Then cool one in the dry ice-ethanol bath to below -20 and leaves 185 ml of 8% phosphorus pentachloride solution in absolute methylene chloride run in such a way that the internal temperature falls to -15 his -10 increases. The reaction is allowed to complete for 10 minutes at about -12, the pale yellow solution gradually turning slightly red-brown colors. After cooling again to below -20 °, 230 ml of absolute methanol are allowed to flow in, with good cooling keeps the indoor temperature below -10 °. The reaction mixture, which is slightly discolored again, is 30 minutes at -10 ° stirred, then warmed to room temperature and more Allowed to react for 30 minutes. This is followed by stirring Add 25 ml of 50% aqueous formic acid and filter the reaction mixture immediately with the addition of "Hyflo" (diatomaceous earth) .. This is increased by adding triethylamine (approx. 16 ml) pH to 2.0. Microcrystalline 7-amino-cephalosporanic acid begins to form at a pH of approx. 1.5 to be deposited. The suspension becomes ^ 5

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Stirred gently for minutes at room temperature. The pH is then increased to 3 * 3 by adding 3 ^ ml of triethylamine. The suspension is left to stand in an ice bath for 2 hours and then filtered. · The precipitate is washed with methylene chloride and ether, dried in a water jet vacuum, pulverized and dried in a high vacuum. The product shows in the UV spectrum in 0.1-n.

Sodium bicarbonate ^ = 203 np (£ = 78θθ}. Ca] S ⁰ = + 110 ° + 1 °

max / YY "~"

-. '■ ·. ■■■

(c = 1% in 0.5-n. NaHCO ^). In the thin-layer chromatogram on silica gel, Rf _101A = 0.30; Hf ₁₁₀ = 0y25 (with iodine as an indicator).

Example 2;

g of anhydrous cephalosporin C zinc complex (10 mmol) are suspended in 300 ml of absolute methylene chloride and with 4.02 ml of absolute pyridine and 9 * 25 ml Trimethylchlorosilane added. The suspension is flushed with dried nitrogen and with vigorous stirring Left to react for 2 hours at 30 °.

The almost colorless reaction solution is cooled to below -20 ° after the addition of 10.1 ml of absolute pyridine and in portions with 65.6 ml of 1 oil solution of phosphorus pentachloride added in methylene chloride, the internal temperature not rising above -10. The milky solution is during 40 Stirred minutes at about -12 °. After cooling down again to - ^ 20 °

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120 ml of absolute methanol are added in portions to Hessen, the internal temperature rising to -10 °. One lets 30 minutes at this temperature and another 30 minutes at React + 25 °.

For hydrolysis, 15 ml of 50% aqueous formic acid are added and the pH of the suspension is adjusted by adding triethylamine (9 ml) of approx. 0.2 "to 2.0. The mixture is stirred for 5 minutes at room temperature, an intensive precipitate of fine, almost white material being formed. The pH is adjusted to 3.35 by adding 19/6 ml of triethylamine The reaction mixture is left to stand in an ice bath for 90 minutes, the fine precipitated material settling out. The precipitate is removed by suction and washed with methylene chloride. The crude product is washed several times on the suction filter with water, then with methanol and finally with ether and dried in a vacuum desiccator (1.98 g). The 7-ACA shows a purity of 90.5 #. (Λ ' = 263 [X = 750O]).

mapc

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example

3.5 ² l g approx. 91. Seiger Cephalosporin C zinc complex are suspended in 200 ml of absolute methylene chloride and mixed with 3.94 ml of absolute pyridine and 3.12 ml of dimethyl dichlorosilane (η = 1,4θ4). After 2 hours of agitation at ..

30, it is cooled, the clear lemon-yellow solution to below -20 °, and outputs 8.16 ml of absolute pyridine to, were then added 65.5 ml of an 8 percent solution of phosphorus pentachloride in methylene chloride abso- _t lutem zu'fech 40 minutes at - 12 ° the solution is cooled again to approx. -20 °. 90 ml of absolute methanol are then allowed to flow in, the internal temperature not being allowed to rise above -10. "The golden yellow solution is stirred for 30 minutes at -10 ° and 30 minutes at room temperature. Then 20 ml of 25 percent aqueous formic acid are added and adjusts the pH from 1.35 to 2.0 by adding 3/4 ml of triethylamine. This causes severe turbidity. The suspension is stirred for 45 minutes at room temperature and the pH is then increased to 3.35. , for which 15.7 ml of triethylamine are required. After 90 minutes of cooling in an ice bath, the fine precipitate is suction filtered and washed on the filter plate with methylene chloride, methanol and ether. After drying in a vacuum desiccator, 1.442 g of white product is obtained, which according to ÜV- Extin ^ tion at ^; 2β3 πιμ has a purity of 99 * 5 #. (UV: ^ _mav «263 πιμ (£ = 8250) j

ⁱⁿ 0.1-n. NaHCO ₃ )

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■■ * XX «··.

Example 4;

2,4θ about 73 ^g-pr> ig ^{Dozent it} cephalosporin C zinc salt are suspended in 250 ml of absolute methylene chloride. After adding 2.42 ml of absolute pyridine and 528 ml of trimethylchlorosilane, the mixture is stirred at 30 for 2 hours, a colorless, almost clear solution being obtained. 5.44 ml of absolute pyridine are added to this. After the solution has cooled to below -20, 44.4 ml of an 8 percent strength solution of phosphorus penta chloride in methylene chloride are run in and the mixture is stirred at -12 for 40 minutes. After cooling again below -20, 56 ml of absolute methanol are added dropwise. The reaction is allowed to complete for 30 minutes at -10 and a further J> 0 minutes at room temperature. The cloudy solution is filtered aqueous formic acid after the addition of 12 ml of 25 percent and pH of 1.3 ^au f increases 2.0, to which 5> 6 ml of triethylamine are needed. The suspension formed is stirred for 45 minutes at room temperature. A pH of 3.25 is then set using triethylamine (8.5 ml). After cooling for 90 minutes in an ice bath, the reaction mixture is filtered. The residue is washed well with methanol. The almost colorless precipitate is washed with methylene chloride and ether and dried in vacuo. 0.75 g of 7-ACA of 94 percent purity is obtained. In the UV spectrum (in 0.1 N NaHCO3) - λ is . = 2β4 πιμ

j max

\ t = 8 000) j A _min = 222 (^ = 4 300).

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BAD ORlGtMAt

Example 5t

2.41 g maximum 91.5% cephalosporin C zinc complex are slurried in 150 ml of chloroform and briefly Stirring brought into solution with 1.26 ml of absolute pyridine. After adding 4.42 ml of tri-n-butyltin chloride, the mixture is left the pale yellowish colored solution stand overnight at room temperature «

It is then cooled to below -20 ° and mixed with 5.43 ml of absolute pyridine, then with 44.3 ml of an 8 percent strength Solution of phosphorus pentachloride in absolute methylene chloride. The mixture is stirred for 40 minutes at -12 °. After cooling down again to below -20, 60.6 ml of absolute methanol are added within a few minutes. After 30 minutes at -10 and a further 30 minutes of reaction time at room temperature, a clear golden yellow solution is obtained.

For hydrolysis, 10 ml of 25 percent strength aqueous formic acid are added and the amount is increased by adding 1.4 ml of triethylamine the pH-V / er t from 1.6 to 2.0. After approx. 20 minutes Stirring at room temperature, a fine precipitate begins to separate out. After 2 1/2 hours the pH is increased the suspension to 3 * 3 by adding a further 9 ml Triethylamine and let stand in an ice bath for 9 ° minutes. Of the

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BAD ORfGiNAL

Precipitate is filtered off and washed with methanol, methylene chloride and ether washed and dried in a high vacuum. The colorless 7-ACA obtained, which in the UV (in 0.1 N NaHCO) has an extinction of 8,450 at 263 πιμ, is thin-layer chromatography from authentic 7-ACA not to differentiate. . "

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Claims (13)

Patent claims: 1. Process for the preparation of 7-amino-cephalosporanic acid according to main patent no. (registration P 14 45 615.6 Case 5240 / 1-8) by converting cephalosporin C into a Imide halide of the formula I. Y-CH- (CH ₀ ), -C = CH ₂ -O-COCH ₃ (I) where Y is a protected amino group and OR is removable Ester groups are, conversion of the imide halide into one corresponding imino ethers, solvolysis of the imino ether and optionally Saponification of the ester group of a 7-ACA ester obtained, characterized in that a zinc complex of Cephalosporin C treated with a silylating or stannylating agent, preferably in excess, the thus obtained Compound converted into an imide halide of the formula I, in which OR for a silyl or stannyl ester group and Y for an optionally silylated or stannylated amino group, this compound is converted into an imino ether by means of an alcohol and the iminoether double bond by treatment with a hydro- 109853/1833 Cleaves solvents containing xyl groups. 2. The method according to claim 1, characterized in that the ester group OR is a group of the formula α - si - R ₂ in which IL, R ₂ and R ^ are identical or different and are / used for alkyl, aralkyl or aryl. 3. The method according to claim 1, characterized in that that the ester group OR is a group of the formula Ο — Sn- in which R ₁ , R 2 and R are identical or different and represent alkyl, aralkyl or aryl, is used. 4. The method according to any one of claims 2 or 3> characterized in that R ₁ , Rp and R, stand for lower alkyl. 109853/1833 5. The method according to claim 2, characterized in that that R,, Rp and R ^, stand for methyl. 6. The method according to claim 3j, characterized in that that R,, Rp and R-, stand for η-butyl. 7 · method according to one or more of claims 1-6, characterized in that phosphorus pentachloride is used for the formation of the imide halide. 8. The method according to one or more of claims 1-7 * characterized in that a lower alkanol is used as the alcohol for imino ether formation. 9. The method according to claim 8, characterized in that that methanol is used as the alcohol. 10. The method according to one or more of claims 1-9j, characterized in that the imino ether is saponified at a pH of about 0 to h with water / water. 11. The method according to one or more of claims 1-9 * characterized in that the imino ether is saponified with water at a pH of about 2. 109853/1833 - j. ι 12. The method according to one or more of claims 1-11, characterized in that the 7-amino-cephalosporanic acid allowed to crystallize out of the solution at a pH of 3 to 4 13. Process for the preparation of 7-amino-cephalosporanoic acid as described in the examples. lh. The 7-amino-cephalosporanic acid obtained by the process of the preceding claims. 109853/183 3