DE3408196C2 - - Google Patents

Description

The invention relates to p-nitrobenzylsilylenol ether, a Processes for their manufacture and their further processing to an important interconnection, the in the synthesis of thienamycin and other carbapenem Antibiotics are used.

The antibiotic thienamycin of the formula

was originally fermented by Streptomyces obtained cattleya (see US Pat. No. 3,950,357). Thienamycin is an exceptionally effective broad spectrum antibiotic, the remarkable activity against various Pseudomonas Owns species. These organisms are opposite β-lactam antibiotics extremely resistant.

Because of the extraordinary biological activity Thienamycin has been used in a large number of derivatives produced. Although attempts have been made to derivate to synthesize where the hydroxyethyl group in the 6-position of the carbapenem ring system is replaced by various other substituents, the hydroxylethyl group is still considered to be optimal Activity of preferred substituent in the 6-position viewed.

As the fermentation process for the production of thienamycin and its derivatives are unsatisfactory various methods for total synthesis in the literature  described (see, for example, US-PS 42 87 123, 42 69 772, 42 82 148, 42 73 709, 42 90 947 and the European Patent application 7,973). Although the different Manufacturing process different starting materials use, they run over a common one Diazo intermediate of formula I.

wherein R₁ represents a common carboxyl protecting group. One of the most preferred carboxyl protecting groups for the intermediate compound I is the p-nitrobenzyl group, which after the formation of the final carbapenem product easy to remove by catalytic hydrogenation can.

Attempts have been made recently to: Interconnect 6-APA (and then thienamycin and other carbapenem derivatives). Karady et al. report for example in J. Am. Soc. 103 (22): 6765-6767 (1981), such a method that leads to the diazo Intermediate compound of the formula

leads, where P is t-butyldimethylsilyl. With this The process is the O-protected azetidinone of the formula

with an enol silyl ether of benzyl 2-diazoacetoacetate of the formula

implemented.

In Tetrahedron Lett., 23 (22): 2293-2296 (1982), the Preparation of the intermediate diazo compound of the formula

described. 4-Acetoxy-3- (1-hydroxyethyl) - 2-azetidion using a Lewis acid catalyst with the corresponding silylenol ether of the formula

alkylated.

Yoshida et al. describe in Chem. Pharm. Bull 29 (10): 2899-2909 (1981), another manufacturing process for Conversion of the 6-APA connection into the O-protected Azetidinone of the formula

The latter connection can be made according to the procedure that in the above-mentioned Tetrahedron Lett. reference is described in a diazo interconnect Convince Formula I.

Since the diazo intermediate of formula I with a p-nitrobenzyl ester protecting group a preferred carbapenem Interconnect is it would be desirable to have a process available where the easy accessible azetidinone compounds of the general Formula II

where L is a common leaving group such as a halogen  or acetoxy group, and P is a common hydroxy Protecting group, such as a triorganosilyl group, into the corresponding p-nitrobenzyl intermediate of the formula I are transferred.

Since the alkylation of Ketones with silylenol ethers described in the literature is [cf. e.g. B. Tetrahedron Lett. 23 (22): 2293-2296 (1982) and also Tetrahedron Lett. 23 (4): 379-382 (1982)], one could have expected that the desired one p-nitrobenzyl ester intermediate I or a hydroxy-protected derivative thereof by using Lewis acids catalyzed alkylation of a suitable Azetidinone compound II with an enolsilyl ether of p-Nitrobenzyl diazoacetoacetate of the formula III

wherein R¹, R² and R³ each independently represent a C _1-4 alkyl group. Unfortunately, however, one cannot proceed according to this known process for the preparation of the compounds of the formula III if a p-nitrobenzyl protective group is used. Therefore, in the known process for the preparation of enol silyl ethers of diazoacetoacetates, a diazoacetoacetate ester of the formula

wherein R₁ is a carboxyl protecting group, to one Enol silyl ether ester

wherein R¹, R² and R³ each independently represent a C _1-4 alkyl group, silylated using a triorganosilyl halide silylating agent and working in the presence of a strong base; ie one works, for example, with trimethylchlorosilane using a lithium base, such as lithium hexamethyldisilazide. If the p-nitrobenzyl ester is used in this known silylation process, then the strong base required for the enolate formation is due to the highly reactive methylene group with the p-nitrobenzyl ester

incompatible. When using weaker organic Bases, such as trialkylamines, with the triorganosilyl halide However, silylating agents are not available desired enol silyl ether.

The object of the present invention is therefore the provision a silylation process for manufacturing of p-nitrobenzylsilylenol ether of the general formula III

wherein R¹, R² and R³ each independently represent a C _1-4 alkyl group, from the intermediate compound of the general formula IV

The Successful Preparation of Interconnect III would then manufacture the important carbapenem Intermediate compound of formula Ia

or a hydroxy-protected derivative thereof, by using an intermediate compound of formula III with a suitable, O-protected azetidinone general formula II

where P and L have the meanings given above, implemented and, if desired, the hydroxy Protection group removed.

The invention relates to p-nitrobenzylsilylenol ethers of the general formula III

wherein R¹, R² and R³ each independently represent a C _1-4 alkyl group.

The invention further relates to a method for Preparation of the interconnections of the general Formula III, which is characterized in that a compound of formula IV

with a silyl triflate of the general formula V

wherein R¹, R² and R³ each independently represent a C _1-4 alkyl radical, in an inert organic solvent and in the presence of an organic base.

The invention further relates to further processing Interconnections of the general Formula Ib

wherein R⁴ is a hydrogen atom or a conventional hydroxy Protective group means that is characterized by that a compound of general formula II

wherein R ^{4 'is} a common hydroxy protecting group and L is a common leaving group, such as an acetoxy, propionyloxy, t-butyryloxy or chlorine group, in an inert organic solvent and in the presence of a Lewis acid catalyst with a Silylenol ether of the general formula III

wherein R¹, R² and R³ each independently represent a C _1-4 alkyl group.

It has surprisingly been found that the p-nitrobenzyl diazoacetoacetate intermediate compound of formula IV

successfully into the corresponding enol silyl ether intermediate of the general formula III

wherein R¹, R² and R³ each independently represent a C _1-4 alkyl group, by converting a compound of general formula IV with a triorganosilyl triflate silylating agent of general formula V

wherein R¹, R² and R³ have the meanings given above, in an inert organic solvent and in the presence of an organic base. The replacement of the known silyl chloride with the silyl triflate silylating agent enables an organic base, such as a trialkylamine, e.g. B. tri- (C _1-4 ) alkylamine. This enables the desired silylenol ether intermediate III to be prepared in high yield, although the highly reactive methylene group is present in the p-nitrobenzyl unit.

The reaction of the intermediate compound IV with the triorganosilyl triflate Silylating agents are used in  an inert organic solvent, e.g. B. in methylene chloride, tetrahydrofuran, carbon tetrachloride, Dioxane, dimethoxyethane, diethyl ether or Chloroform; one works at a temperature of about -40 ° to about + 30 ° C. Conveniently one leads the Reaction at a temperature of about 0 to 5 ° C.

The triorganosilyl triflate compound can be any trialkylsilyl trifluoromethyl sulfonate be. Preferably used but you have a commercially available compound, e.g. B. trimethylsilyl trifluoromethyl sulfonate or tert-butyldimethylsilyl trifluoromethyl sulfonate. The particularly preferred silylating agent is tert. Butyldimethylsilyl trifluoromethyl sulfonate.

Suitable organic amine bases which can be used together with the triorganosilyl triflate silylating agent are: diisopropylethylamine, DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), DBN (1,5-diazabicyclo [4.3 .0] non-5-enes and especially tri- (C _1-4 ) alkylamines (e.g. trimethylamine, triethylamine, tributylamine, tripropylamine).

In general, the organic base, the triorganosilyl triflate, is used and the intermediate IV in about equimolar amounts, with the base in a small amount There is excess. The most preferred molar Ratio of compound IV: triorganosilyl triflate: Base is about 1: 1.2: 1.4.

According to the procedure described above, the desired silylenol ether intermediates of general formula III in high yields.  

Particularly preferred new interconnections of the general formula III are those which trimethylsilyl or have tert-butyldimethylsilyl protective groups.

The invention also relates to further processing the intermediate compounds produced according to the invention the general formula III to the known Diazo interconnection Ia. To do this, an intermediate connection is made III with a suitable, O-protected Azetidinone of formula II in an inert, organic Solvents such as methylene chloride, chloroform, carbon tetrachloride, Dioxane, diethyl ether, tetrahydrofuran or dimethoxyethane, in the presence of a Lewis acid Catalyst, such as zinc chloride, zinc iodide, zinc bromide, Titanium tetrachloride, magnesium bromide, boron trifluoride, Aluminum chloride, tin (IV) chloride or iron (III) chloride, around. The preferred solvent is methylene chloride and the preferred catalyst is zinc chloride.

The azetidinone compounds of formula II are known Compounds or can be prepared by known methods will. The hydroxyalkyl group of these compounds is protected by common hydroxy protecting groups. Although the specially used protecting group is not critical is and from a large number of such known Compounds can be selected, is preferably used a triorganosilyl protecting group, such as one Trimethylsilyl or tert-butyldimethylsilyl group, since these groups are easily treated with methanolic HCl or with fluoride ions (e.g. tetra-n- butylammonium fluoride / tetrahydrofuran) can remove. Suitable hydroxyl protective groups can also be used name: p-nitrobenzyloxycarbonyl, which can be obtained by catalytic  Hydrogenation can remove allyloxycarbonyl, which to remove by Pd (PΦ₃) ₄-catalyzed reaction can, and 2-Trihaloethoxycarbonyl (-CO₂CH₂CX₃, wherein X = Cl or Br), which can be obtained by treatment with Zn-acetic acid can remove in methanol. The exiting Group L can be any usual leaving group, e.g. B. a halogen atom (e.g. chlorine atom) or an acyloxy group (e.g. an acetoxy, propionyloxy or t-butyryloxy group). However, an acetoxy group is preferably used a. In general, it is preferred to use one Excess of silylenol ether III to the azetidinone II to admit.

After alkylation to form the hydroxy protected The protective group can then be diazo interconnected remove by known methods, whereby the desired intermediate compound Ia is obtained. In particular the above-mentioned triorganosilyl- Protecting groups, since they can be destroyed without remaining part of the molecule can be easily removed.

The diazo intermediate of formula Ia can be known methods in the thienamycin or in various other carbapenem derivatives with more useful convince antibacterial effectiveness.

The following examples serve to illustrate the invention.  

Example 1 Preparation of p-nitrobenzyl-2-diazo-3-trimethylsilyloxy 3-butenoate A. p-nitrobenzyl acetoacetate

A mixture of 140 g (1.08 mol) of ethyl acetoacetate and 153 g (1.00 mol) of p-nitrobenzyl alcohol (washed with diethyl ether before use) in 1 liter of toluene is slowly distilled and 900 ml of the solvent are collected over a period of 15 H. After cooling, insoluble material is removed by filtration through Celite, washed with toluene and evaporated in vacuo to give 280 g of a crude oil. This oil is crystallized at 5 ° C. in 280 ml of diethyl ether, 181.55 g (0.766 mol; 76.6% yield) of the title compound being obtained as white crystals; Mp 40-42 ° C.
IR (film) ν _max : 1740 (ester), 1715 (C = O), 1515 and 1345 (NO₂) cm⁻¹;
1 H-NMR (CDCl₃) δ: 1.98 (s, impurity), 2.32 (3H, s, CH₃), 3.62 (2H, s, -CO CH ₂R), 5.08 (s, impurity) , 5.28 (2H, s, -CO₂ CH ₂Ar), 7.53 (2H, d, J = 9 Hz, ArH groups) and 8.23 ppm (2H, d, J = 9 Hz, ArH groups );
Rf = 0.45 (diethyl ether).
An analytical sample was obtained by recrystallization from toluene-hexanes: mp 47 to 49 ° C.

Analysis for C₁₁H₁₁NO₅:
calculated:
C 55.70%, H 4.67%, N 5.91%;
found:
C 55.59%, H 4.62%, N 5.85%.

B. p-Nitrobenzyl-2-diazo-3-ketobutenoate

130 g (0.639 mol) of p- are added to a solution of 134.6 g (0.568 mol) of p-nitrobenzylacetoacetate and 79.0 ml (0.568 mol) of triethylamine in 340 ml of CH₃CN under a nitrogen atmosphere at 0 to 5 ° C for 15 min. Toluene sulfonyl azide (97% pure), during which time the title compound precipitates. The cooling bath is removed and the mixture is stirred for 3 hours at room temperature. The mixture is then cooled in an ice bath for 30 min and the precipitate is filtered off, which is washed with 75 ml of cold CH₃CN and then with 200 ml of cold diethyl ether. Then it is dried and 135.06 g (0.514 mol) of the title compound (90.4% yield) are obtained as a pale yellow powder.
1 H-NMR (CDCl₃) δ: 2.50 (3H, s, -CH₃), 5.38 (2H, s, -CO₂ CH ₂Ar), 7.53 (2H, d, J = 9 Hz, aromatic H) and 8.27 ppm (2H, d, J = 9 Hz, aromatic H);
IR (CH₂Cl₂) ν _max : 2130 (N₂), 1720 (ester), 1655 (C = O), 1520 and 1350 cm⁻¹ (NO₂);
Rf = 0.65 (ethyl acetate).

C. p-Nitrobenzyl-2-diazo-3-trimethylsilyloxy-3-butenoate

To a suspension of 236 mg (1 mmol) of p-nitrobenzyl-α-diazoacetoacetate and 0.15 ml (1.08 mmol) of triethylamine in 2 ml of CH₂Cl₂, 0.22 ml of trimethylsilyl-trifluoromethylsulfonate is added under a nitrogen atmosphere at 0 to 5 ° C and stir the mixture for 30 min. 30 ml of dry hexane are added to this clear, yellow solution and the reaction mixture is stirred for 10 min. After removal of the oily deposit, the hexane solution is concentrated in vacuo to give a yellow solid which is redissolved in 50 ml of dry hexane. The insoluble material is filtered through Celite and the filtrate is concentrated in vacuo to give 277 mg (0.90 mmol; yield 90%) of the title compound as yellow crystals.
IR (film) ν _max : 2100 (N₂), 1705 (ester), 1520 and 1345 cm⁻¹ (NO₂);
1 H-NMR (CDCl₃) δ: 0.27 (9H, s, -SiMe₃), 4.23 (1H, d, J = 2 Hz, vinyl proton), 4.93 (1H, s, J = 2 Hz, vinyl proton) ), 5.32 (2H, s, -CO₂ CH ₂Ar), 7.48 (2H, d, J = 9 Hz, aromatic protons) and 8.23 ppm (2H, d, J = 9 Hz, aromatic protons) .

Example 2 Preparation of p-nitrobenzyl-2-diazo-3-tert-butyldimethylsilyloxy 3-butenoate

A suspension of 26.30 g (0.10 mol) of p-nitrobenzyl-α-diazoacetoacetate and 14.57 g (20.00 ml; 0.14 mol) of triethylamine in 200 ml of dry methylene chloride is added at 2 ° C. during over a period of 30 min under a nitrogen atmosphere, 31.72 g (27.50 ml; 0.12 mol) of tert-butyldimethylsilyl trifluoromethylsulfonate, the mixture is then stirred for 1 h at 2 ° C., the clear, orange solution is diluted with 50 ml of methylene chloride , washed with 3 × 200 ml of water and then with 100 ml of brine, dried (Na₂SO₄) and concentrated to give 37.40 g (0.099 mol; yield 99%) of the title compound as a yellow solid.
1 H-NMR (CDCl₃, EM-360A, 60 MHz) δ: 0.26 (6H, s, Si (CH₃) ₂), 0.96 (9H, s, SiC (CH₃) ₃), 4.25 (1H , d, J = 2.5 Hz, 4-H), 4.97 (1H, d, J = 2.5 Hz, 4-H), 5.32 (2H, s, -CO₂ CH ₂Ar), 7 , 48 (2H, d, J = 9.0 Hz, ArH groups) and 8.22 ppm (2H, d, J = 9.0 Hz, ArH groups);
IR (film ν _max : 2090 (N₂, 1694 (ester), 1600 (C = C) and 1344 cm⁻¹ (NO₂).

Example 3 Preparation of (3S, 4R) -3 - [(1R) -hydroxyethyl] -4- [3- (4- nitrobenzyloxy) carbonyl-2-oxo-3-diazopropyl] -azetidine- 2-on

To a suspension of 34 mg (0.25 mmol) anhydrous Zinc chloride in 2 ml of methylene chloride is added Nitrogen a solution of 144 mg (0.5 mol) (1′R, 3R, 4R) - 3- (1'-tert-butyldimethylsilyloxyethyl) -4-acetoxy- azetidin-2-one) in 4 ml of methylene chloride and then 350 mg (0.93 mmol) solid 4-nitrobenzyl-2-diazo-3-tert.- butyldimethylsilyloxy-3-butenoate, the mixture is stirred 4.5 h under nitrogen at room temperature, the diluted Mixture with 50 ml of ethyl acetate, washed with 2 × 25 ml saturated sodium bicarbonate solution and then with 30 ml Saline, dries (Na₂SO₄) and concentrated, whereby a crude, oily, yellow solid is obtained which it is purified by column chromatography [30 g SiO₂, eluted  with methylene chloride / ethyl acetate (4: 1)], whereby 198 mg (0.405 mmol; 81% yield) of the title compound as an oil receives that with a manufactured by a known method Sample is identical (TLC, 1 H NMR).

Example 4 Preparation of (3S, 4R) -3 - [(1R) -hydroxyethyl] -4- [3- (4- nitrobenzyloxy) carbonyl-2-oxo-3-diazopropyl] -azetidine- 2-on

To a solution of 72 mg (0.15 mmol) (3S, 4R) -3 - [(1R) - (tert-Butyldimethylsilyloxy) ethyl] -4- [3- (4-nitrobenzyloxy) - carbonyl-2-oxo-3-diazopropyl] azetidin-2-one in 1.0 ml of methanol are added 0.2 ml of 1N aqueous HCl and stirred the mixture for 2 hours at room temperature. After this time shows thin layer chromatography (TLC) (ethyl acetate), that the implementation is complete. During this time the title link fails. This is filtered off and rinsed with cold CH₃OH / H₂O (9: 1) and then with cold diethyl ether, giving 43 mg (0.11 mmol; yield 73%) of the title compound is obtained as a white solid. The title compound is obtained in a similar manner  from (3S, 4R) -3 - [(1R) - [2,4-tri-tert-butylphenoxy) dimethylsilyloxy) - ethyl] -4- [3- (4-nitrobenzyloxy) carbonyl- 2-oxo-3-diazopropyl] -azetidin-2-one.

Example 5 Preparation of (3S, 4R) -3 - [(1R) - [2,4,6-tri-tert-butylphenoxy) - dimethylsilyloxy) ethyl] -4- [3- (4-nitrobenzyl) - oxycarbonyl-2-oxo-3-diazopropyl] azetidin-2-one

The title compound is prepared in 84% yield from (3R, 4R and 4S) -4-acetoxy-2 - [(1R) - [(2,4,6-tri-tert-butylphenoxy) dimethylsilyloxy] ethyl] -2-azetidinone according to the method described above for the corresponding t-butyldimethylsilyl derivative.
1 H-NMR (CDCl₃, 80 MHz) δ: 0.26 (3H, s, SiMe), 0.40 (3H, s, SiMe), 1.27 (9H, s, t-Bu), 1.41 ( 18H, s, (t-Bu) ₂), 2.92 (1H, dd, J _3-1 = 4.7 Hz, J _3-4 = 2.5 Hz, 3-H), 2.97 (1H , dd, J _gem = 17.6 Hz, = 9.6 Hz, 1 ′ ′ - H _b ), 3.40 (1H, dd, J _gem = 17.6 Hz, = 3.5 Hz, 1 ′ ′ -H _a ), 3.98-4.24 (1H, m, 4-H), 4.32-4.57 (1H, br.s, NH), 7.22 (2H, s, ArH of the ether ), 7.52 (2H, d, J = 8.7 Hz, ArH of the ester) and 8.25 ppm (2H, d, J = 8.7 Hz, ArH of the ester);
IR (neat) ν _max : 3300 (br., NH), 2137 (-N₂), 1755 (β-lactam), 1720 (ester), 1651 (C = O), 1523 and 1345 cm⁻¹ (NO₂).

Claims (11)

1. p-nitrobenzylsilylenol ether of the general formula III wherein R¹, R² and R³ each independently represent a C _1-4 alkyl group. 2. A compound according to claim 1 having the formula 3. A compound according to claim 1 having the formula 4. A process for the preparation of the compounds according to any one of claims 1 to 3, characterized in that a compound of general formula IV with a silyl triflate of the general formula V wherein R¹, R² and R³ have the meanings given above, in an inert organic solvent and in the presence of an organic base. 5. The method according to claim 4, characterized in that the reaction at a temperature of about -40 ° to about + 30 ° C. 6. The method according to claim 4 or 5, characterized in that a C _1-4 - trialkylamine is used as the organic base and methylene chloride is used as the solvent. 7. A method for further processing the compounds according to claim 1 for the preparation of the compounds of general formula Ib wherein R⁴ represents a hydrogen atom or a customary hydroxyl protective group, characterized in that a compound of the general formula II wherein
L a usual leaving group and
R ^{4 ′ represent} a customary hydroxyl protective group,
in an inert, organic solvent and in the presence of a Lewis acid catalyst with an enolsilyl ether of the general formula III wherein R¹, R² and R³ each independently represent a C _1-4 alkyl group, reacted and, if desired, the hydroxy protecting group removed to obtain the corresponding hydroxyethyl intermediate. 8. The method according to claim 7, characterized in that the leaving group L for stands. 9. The method according to claim 7 or 8, characterized in that as a Lewis acid catalyst ZnCl₂ starts. 10. The method according to any one of claims 7 to 9, characterized characterized in that the solvent is methylene chloride starts. 11. The method according to any one of claims 7 to 10, characterized in that as a hydroxy protecting group a tert-butyldimethylsilyl, trimethylsilyl or (2,4,6-tri-tert-butylphenoxy) dimethylsilyl group.