JPS59170096A - Carbapenem intermediate - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for the preparation of key intermediates used in the synthesis of chenamycin and other carbapenem antibiotics.

The antibiotic chenamycin with
It was obtained by fermentation of Streptomyces cattleya as described in No. 50°357. Chenamycin has been shown to be used in organisms that are apparently resistant to beta-lactam antibiotics, including various
It is a particularly potent broad-spectrum antibiotic with strong activity against Tomonas spp.

Because of the special biological activity of chenamycin, a large number of derivatives have been produced. Attempts have been made to synthesize derivatives having various substituents other than hydroxyethyl at the 6-position of the carbapenem ring, but the 6-substituent is considered to be the most convenient for the hydroxyethyl group in order to achieve optimal activity.

Since the fermentation method for producing chenamycin and its derivatives is unsatisfactory, a'1. The total synthesis method of σ is described in the literature (for example, U.S. Pat.
No. '1.282.1'48, No. 4,273,709, No. 4.290.947, and European Patent No. 7973). The various synthetic methods use different application materials, but all have the formula:.

One of the most preferred carboxyl protecting groups for Intermediate I via the common diazo intermediate with (R, represents a common carboxyl protecting group) is the p-nitrobenzyl group, which forms the final carbapenem product. It can be easily removed by postfix β1112 hydrogenation.

Recently, attempts have been made to synthesize intermediate 1 (and subsequently chenamycin and other carbapenem derivatives) from the readily available 6-APA. For example, J, Atn,, Chcrn
, soc, 103(22): 6765-6767
(1c + sx >, Karaday et al. has announced a method for producing a diazo intermediate with

1'etrahedron Lett, 23(22)
: 2293-2296 (1982) converts 4-acetoxy-3-(1-hydroxyethyl)-2-azetidinone into a diazo with the formula by the Lewis acid-catalyzed alkylation method using the corresponding silylenol ether with the formula: An intermediate production method has been announced.

Chern, Pharrn, Bul 1.29 (
10): Yoshida et al., Tetrahedron Lett, 2899-2909 (1981).

have reported another synthetic method for converting 6-APA to a 0-protected azetidinone with formula: which can be converted to a diazo intermediate with formula I by the method described in .

Since diazo intermediates of formula I with a p-nitrobenzyl ester anchoring group are preferred carbapenem intermediates, the general formula: It would be desirable to have a method for converting readily available azetidinone compounds with common hydroxyl-protecting groups, such as triorganosilyl, into the corresponding p-nitrobenzyl ester intermediates of formula (1).

Lewis hexa-catalyzed alkylation of ketones as their silyl enol ethers has been reported in the literature (e.g. Tetr
ahedron Lett, 23 (22):2
293 2296y1982 and Tetrahedr
on Lett, 23 (4'): 379-3
82 (1982)), so the desired p.
-Nitrobenzyl ester intermediate I or its hydroxy-protected derivatives can be substituted with suitable azetidinone compounds. It is expected that it can be produced by catalytic alkylation with Lewis acid using the enolsilyl ether of nitrobenzyldiazoacetoacetate.

Unfortunately, Applicants have discovered that known methods for preparing compounds with 2 and 3 do not work when a p-nitrobenzyl-protecting group is desired. Therefore, the conventional method for producing enol silyl ether of diazoacetoacetite is to use a strong base,
For example - using a triorganosilyl halide silylating agent in the presence of trimethylchlorosilane and a lithium base, e.g. lithium hexamethyldisilazide, the diazoacetate of the formula: (R1 is a carboxyl-protecting group); the enol of the acetite ester A silylation method is used to form a silyl ether ester or "2 (in the formula, R1, R21 and R3 independently represent ClC4 alkyl-L).The conventional silylation method uses p-nitrobenzyl ester. The strong base required to form eluite is not compatible with p-nitrobenzyl ester due to the highly reactive methylene groups.However, a weak organic base such as a trialkylamine can be used with a triorganosilyl halide silylation agent to form the desired enol silyl ether. does not generate.

2 ■ p-nitrobenzylsilyl enol ether 1 N2 ■ c In the formula, R1, R2 and R3 are each independently ct C4
It was an object of the present invention to provide a silylation process for producing alkyl (representing alkyl).

Successful preparation of intermediate III allows it to be reacted with a suitable 〇-protected azetidinone of the formula: where P and L are as defined above, removing the hydroxyl-protecting group if necessary. The important carbapenem intermediate a or its hydroxyl-protected derivatives are prepared.

The present invention provides novel carbapenem intermediates having the formula: where R1, R'' and R3 independently represent CI-C, A/L-key.

Still according to the invention, a compound of the formula 1 is obtained by reacting a silyl triflate of the formula: in which R1, R2 and R3 independently represent cl-c4aIL/L in the presence of an organic base in an inert solvent. A method for producing an intermediate is provided.

Furthermore, according to the present invention, the formula ■: ■ (wherein R4' is a conventional hydroxyl-protecting group and L is a conventional leaving group such as acetoxy, glopionyloxy, t-butyryloxy, or chloro) In the presence of a Lewis acid catalyst in an organic solvent, a compound with the formula;
In the formula, R1, R2 and R3 are independently c, -'c4
A process is provided for the preparation of intermediates with 2 lb=b (wherein R4 represents hydrogen or a common hydroxyl-retaining group) by reacting with a silyl enol ether having silyl enol ethers (representing alkyl).

The present invention describes the preparation of p-nitrobenzyldiazoacetoacetate intermediates having the formula (1): N2 (2) in the presence of an organic group in an inert organic vehicle with the formula V: (R2-8i -08O2CF3 v3 (wherein R), R2 and R3 are each independently cl-c
4A/L, Ki 7L.

The triorganosilyl triflate having the formula: This is based on the unexpected discovery that it can be converted into If a silyl triflate silylating agent is used in place of a conventional silyl chloride reagent, a thoria/L, ki/L amine [e.g. tri(C1'C
4) Since organic bases such as alkylamines can be used, the desired silyl enol ether intermediate (1) can be successfully prepared in high yield despite the presence of highly reactive methylene groups in the p-nitrobenzyl moiety.

The reaction between the intermediate ■ and the triorganosilyl triflate silylating agent involves methylene chloride, tetrahydrofuran,
in an inert organic solvent such as carbon tetrachloride, dioxane, dimethoxyethane, diethyl ether or chloroform.
It is carried out at a temperature range of 40°C to about 30°C. The reaction most conveniently occurs at temperatures of about 0-5°C. The triorganosilyl triflate can be trialkylsilyltrifluorometersulfonate, but trimethylsilyltrifluoromethylsulfonate or
Commercially available reagents such as -butyldimethylsilyl trifluoromethylsulfonate are preferred. The most preferred silylating agent is tert-butyldimethylsilyl
It is trifluoromethyl sulfonate.

Organic amine bases, such as diimpropylethylamine,
DBtj (1.8-diazabicyclo[5.40]undes-7-ene), DBN (1.5-diazabicyclo(4.3.0]non-5-ene) and Tri-(C)
l-C4) Alkylamines (eg trimethylamine, triethylamine, tributylamine, trizolobylamine) are suitable for use with triorganosilyltriflate silylating agents.

Generally, the organic base, triorganosilyl triflate, and the intermediate (2) are reacted in approximately equimolar amounts, and the base is used in excess.

Best Intermediate ■ Nitriorganosilyl triflate:base molar ratio is about 1:1.2:1.4.

The desired silyl enol ether intermediates having general formula 1.1 are obtained in high yield using the above method.

The most preferred compounds within the range of novel intermediates having formula (1) are those with trimethylsilyl or tert-butyldimethylsilyl protecting groups.

Once the intermediates with 2 and 3 have been prepared, they can be used to prepare the known diazo intermediates Ia in the process of the invention. Therefore, intermediate ① is a compound of zinc chloride, zinc iodide, zinc bromide, titanium tetrachloride, bromide in an inert solvent such as methylene chloride, chloroform, carbon tetrachloride, dioxane, diethyl ether, tetrahydrofuran or dimethoxyethane. React with the appropriate 0-protected azetidinone of formula U in the presence of a Lewis acid catalyst such as magnesium, boronic trifluoride, aluminum chloride, stannic chloride, or ferric chloride. The preferred solvent is methylene chloride and the preferred catalyst is zinc chloride.

Azetidinones of formula (1) are known compounds and can be prepared by known methods. The hydroxyalkyl groups of this compound are protected with conventional hydroxy-protecting groups. The protecting groups used are not critical and may be selected from a large number of such groups known in the art, but the triorganosilyl protecting group may be methanolic HCt or a fluoride ion (e.g. tetra-n-butynoammonium fluoride/tetrahydrofuran). Such trimethy/Lsilyl or tert-butyldimethylsilyl groups are preferably used because they can be easily removed by treatment with.

Examples of other suitable hydroxy-protecting groups include p-nitromandyloxycarbonyl, which can be removed by catalytic hydrogenation.
．． ．． pd(PO3)4-allyloxycarbopyl, which can be removed by catalytic reaction, and 2-trihaloethoxycarbonyl (-co2cH2cx3, ゛ where X is Ct or Br), which can be removed by treatment with n-acetic acid in methanol.
). The leaving group may be the usual no(eg chloro) or acyloxy (eg acetoxy, propionyloxy or t-butyryloxy), but most preferably acetoxy. It is generally preferred to add an excess of silyl enol ether to azetidinone H.

The alkylation reaction to form the hydroxyl-protected diazo intermediate is followed by removal of the protecting group by known methods to yield the desired intermediate 1a. As mentioned above, trioprecipitate; 14 is particularly preferred because it can be easily removed without decomposing the remainder of the molecule.

Diazo intermediate 1a can be converted in known manner to chenamycin and various other carreno(venem derivatives) with antibacterial activity.

The following examples illustrate the invention but do not limit the scope of the invention.

Example 1 A/C02PNB Ethylacetoacetite 1401 (in toluene 1)
1,08 mol) and p-nitrobenzyl alcohol 15
311.00 mol, washed with diethyl ether before use)
The mixture of
ml was collected. After cooling, insoluble matter was filtered through Celite, washed with toluene, and evaporated in vacuo to obtain crude oil 2802.

The oil was crystallized from 280 ml of diethyl ether at 5°C to give 181.559 (0.766 g) off-white crystals of the title compound.
mol, yield 76.6%). Melting point 40-42℃:
IR (film) syrnax: 1740 (ester),
1715 (C=(5), 1515 and 1345 (NO2
)crn; Hrnr (CDCl2)δ:L98(
s, impurity), 2.32 (3H, s, CH3), 3
．． 62 (2) 1°S, COCH2CO2R),
5.08 (s, impurity), 5.28 (2H, s, -C
O2CH2Ar ), 7.53 (2H, “d”, J:”
9H2, Ar) f's ) and 8.23 ppm (2H
, "d", J-9Hz, Arc's)
(t'f'O, a4 5 (diethyl ether).

An analytical sample was obtained by recrystallization from toluene-hexane.

Melting point 47-49°C.

Analytical value for CIl Ill NO5: Calculated value: C
,55,70; u, 4.67; N, 5.910 Measured value: C, 55,59; H, 4,62; N, 5,85
°C) (3cN 134.69 ('0.568 mol) p-nitrobenzylacetoacetite in 340 ml
And triethinoamine 79.0m/! (0,568 mol) pL toluene sulfate 7 in a nitrogen atmosphere at O-5°C.
onyl azide 130 f (0,639 mol, 97%
purity) was added over a period of 15 minutes. During this time, the title compound began to precipitate. The cooling bath was removed and the mixture was stirred at room temperature for 3 hours. The mixture was cooled in a water bath for 30 minutes, and the precipitate was filtered, washed with 75 ml of cold CH3CN and then with 200 ml of diethyl ether, and dried to give the title compound as a pale yellow powder.
．． 06F (0,514 mol, yield 90.4%) was obtained.

” Hm r (CDC7a) δ: 2.50 (3
'H,S, -CH3), 5,38 (2H,s.

C02CHzAr),? , 53 (2H, “d”,
J=9Hz, aromatic Hs) and 8.27 pl)
m (2H, "d", J=9Hz, aromatic H3)
; I R(CH2CZ2,) νmax: 213
0 (N2), 1720 (ester), 1655 (C
=0), 1520 and 1350 cm, (NO
2); R1O,65 (ethyl acetite).

Riloxiputenoate CH2C 122ml! , p-nitrobenzyl 0-
Diazoacetoacetite 236 (1 mmol) and triethylamine, 0.15 me (1.08 mmol) were added to a suspension of sulfur solution at 0-5°C under a nitrogen atmosphere to form silyl trifluoromethyl sulfonate 0,'2'2m. /! was added and the mixture was stirred for 30 minutes. 30 ml of dry hexane was added to this clear yellow liquid and the mixture was stirred for 10 minutes. The oily precipitate was removed, the hexane solution was evaporated in vacuo, and the resulting yellow solid was redissolved in 5 Qml of dry hexane. The insoluble material was filtered through Celite, and the P solution was evaporated in vacuo to obtain the title yellow crystal compound 27.
7η (0.90 mmol, yield 90%) was obtained. IR(
Film) νrnax: 2100 (N2), 17
05 (ester), 1520 and 1345z' (NO2
), ; “Phnr (CDCl2) δ:0.
27 (9H,s, -8iMe3'), 4.23 (IH
, d, J=2Hz.

vinyl proton), 4.93 (4I4.d, 5=2Hy
,, vinyl proton), 5.32 (2H,s,
COzbei! Ar), 7.48 (2H, “d”,
J==9Hz, aromatic proton) and 8.23
ppm (2i(,"d", J=9Hz, aromatic peloton) Example 2 p=nitrobenzyl a-diazoacetoacetyl 1-26.30 (0,10) in 2oomes of dry methylene chloride
and triethylamine 14.57 t (20,00ml
, 0.14 mol) of tert-butyldimethylsilyl trifluoromethylsulfonate at 2° C. for 30 minutes under a nitrogen atmosphere. (27,
50ml) was added and stirred at 2°C for 1 hour. Dilute the clear orange solution with 50ml of methylene chloride and add 3x200ml of water.
/! After washing with 1 oome of salt solution, drying with Na2SO4 and evaporating the title yellow solid compound 37.4010.0
99 mol, yield 99%).

1) hnr (CDC13, FiM-36OA, 6
0MHz) δ: 0.26 (6H,s, Si<C
H3)z), 0.96 (9H,s, Si'C(
CH3)5), 4.25 (IH, -, d, J=2
．． 5Hz, 4-H), 4.97 (IH, d,
J=2.5H;, 4-H), 5.32 (2H.

s, -C%cn, Ar ), 7.48 (2H, “d”
, J=9.0Hz, ArH's) and 8.22
pprn (2H, “d”, J=9.0 Hz
, ArH' S ); I R (film) νm
ax: 20910 (N12), 1694 (ester), 1600 (C5C) and 1344σ (NO2
) Example 3 Production In methylene chloride Zme, anhydrous lead chloride 34■, (0,2
5 mmol) α1■ To the suspension, add (1
'R, 3μ.

ethyl)-4-acetoxyazetidin-2-one'14
4 (0.5 mmol) and then 350 μ (0.93 mmol) of the isomer 4-nitrobenzyl-2-diazo-3-tert-butyldimethylsilyloxy-3-butenoate under nitrogen atmosphere. added. The mixture was stirred at room temperature under a nitrogen atmosphere for 4.5 hours. The mixture was diluted with ethyl acetate 5' (Jml) and washed with 2x25mg of saturated sodium bicarbonate solution and further washed with 30ml of saturated sodium bicarbonate solution (Na2S).
Drying over O4 and evaporation gave a crude yellow oily solid. This was purified by tube chromatography (5 iOz 30?, eluted with methylene chloride:ethyl acetate 4:1) to produce the title compound 198 as an oil, which was identified (tic, 'Hmr) as a certified sample produced by conventional methods. ■(0,405 mmol,
81%).

Example 4 Preparation of (3R,4FL)-3-[(lfi)-hydroxyethyl]-4-(3-(4-nitrobenzyloxy)carbonyl-2) (3R,4a)-1-(( ,t
3)-(t-butyldimethylsilyloxy)ethyl 7L
]-4-((4-nitrobenzyloxy)katbonyl-2-offso-3-diasobrovir)azetidine-2
-INH in a solution containing 72■ (0.15 mmol) of
C/1. 0.2-liter of water bath solution was added and the mixture was stirred at room temperature for 2 hours. At this point ttc (ethyl acetate) indicated the reaction was complete. During this time, the title compound 9 was precipitated. This was washed with cold CH30H-H20 (9:1) and then with cold diethyl ether to give the title compound as a white solid.
, ii mmol, yield 73%). Similarly, the title compound is (3R,4)-3-(-(1煕)-((2,4
, 6-tert-butylphenoxy)dimethylsili/Loxy]1tyl>-a43-(4-nitrobenzyloxy)carbonyl-2-ocune-3-diazopropyl]acetidin-2-one.

Example 5 (3R,4K)-3-((1 ship)-((2,4,6-
Preparation of tri-tert-7'' tylphenoxy) dimethylsilyloxyl l-4-(3-(4-nitropendino)oxycarbonyl-2-ocun-3-dianpropyl]azetidin-2-one dimethylsilyloxy]ethyl)-2- The title compound was prepared in 84% yield from azetidinone by the corresponding method described above for the monobutyldimethylsilyl derivative.

') hnr (CDCl2.80 MHz) δ:
0.26 (3HI S+SiMe), 0.40 (
3H,S, SiMe), 1.27 (9H.

s,,t-Bu), 1.41 (18H,s,' (
t-Bu) 2), 292 (IH, dd, J,,' =
4.7H2, Yi, -4==2,51 (Z, 3-H)
, 2.97 (1■I, dd, J-17, 6H7, 〃
b-14eIn =9.6Hz, 1"-Hb), 3.40 (I H
,dd,ug'em=17.6Hz, J,'' ,=3
．． 5Hz, 1"-Ha), 398--4.24 (I H, rn, 4-H), 4.32
．． 4.57 (I H, m.

+'-H), 5.35 (2H,S, CQ2CH
2Ar), 5.95(1i(, br, s, Nu
), 7.22 (Zf■, s, ArH' of ether
s), 7.52 (2H,"d-・J=8.7Hz, xrH's of ester) and 8.25 ppm (2
H,"d-J=8.7H2, ester ArH's)
: I n ni-t) νInaX : 3300 (b
r, NH), 2137 (N2), 1755 (β-lactam), 1720 (ester), 1651 (C-0)
, 1523 and 1345 (7) (NO2).

Claims (1)

[Claims] 1. A compound represented by the formula: c, in which R1, R2 and R3 independently represent c, -c4 alkyl. 2. The compound according to claim 1, which is represented by the formula: 31. The compound according to claim 1, which is represented by the following formula: 2 in the presence of an organic base in an inert solvent with the formula:
% (wherein R1, R2 and R3 independently represent C, -C, alkyl) Patent No. (as defined above). 5. The method of claim 4, wherein the reaction is carried out at a temperature range of about -40°C to +30°C. 6. The method according to claim 4 or 5, when the organic base is Cl-C4) realkylamine and the solvent is methylene chloride. or a process according to claim 4 for preparing a compound having the formula: (3) in which R represents a conventional leaving group and R4' represents a conventional hydroxyl-protecting group. The compound is reacted with an enol silyl ether compound of the formula: (wherein R1, R2 and R3 are independently c, -c4) under a Lewis acid catalyst in an inert organic solvent. A process for the preparation of compounds of the formula: in which R4 represents hydrogen or a common hydroxyl protecting group, characterized by reaction and, if necessary, removal of the hydroxyl-protecting group to give the corresponding hydroxyethyl intermediate. . 9. The method according to claim 8, wherein the leaving group is -0-δCH3. 10. The method according to claim 8 or 9, wherein the Lewis acid catalyst is ZNC12. 11. The method according to any one of claims 8 to 10, wherein the solvent is methylene chloride. 12, the hydroxyl-protecting group is tert-butyldimethylsilyl, trimethylsilyl or (2,4,6-tert
The method according to any one of claims 8 to 11, comprising t-butylphenoxy)dimethylsilyl.