AU696543B2 - Improved process for synthesizing carbapenem intermediates - Google Patents

Improved process for synthesizing carbapenem intermediates Download PDF

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AU696543B2
AU696543B2 AU63921/96A AU6392196A AU696543B2 AU 696543 B2 AU696543 B2 AU 696543B2 AU 63921/96 A AU63921/96 A AU 63921/96A AU 6392196 A AU6392196 A AU 6392196A AU 696543 B2 AU696543 B2 AU 696543B2
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pnb
document
compound
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pct
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Chunhua Yang
Nobuyoshi Yasuda
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

I I WO 97/01564 PCT/US96/10783 -1- IMPROVED PROCESS FOR SYNTHESIZING CARBAPENEM
INTERMEDIATES
BACKGROUND OF THE INVENTION The present invention is related to an improved synthesis of carbapenem intermediates, and in particular, the following compounds:
PO
PO R N H R N H H HH N HC HOPNB H3C 0 0 0 N\ HzC O S H 1 and 2 CO 2
PNB
wherein R represents hydrogen or methyl and P represents triethylsilyl or trimethylsilyl. Similar such intermediates have been used in the past to synthesize carbapenem antibiotics. However, to date, the synthesis pathway for these antibiotics has required the use of extremely unstable intermediates. Additionally, the syntheses disclosed in the past result in low yields and require numerous separation and purification steps.
The intermediates for carbapenem antibiotics described herein are addressed in, U. S. Pat. No. 4,350,631 issued to Christensen, et al. on September 21, 1982 and U. S. Pat. No. 4,994,568 issued to Christensen on February 19, 1991. In the process described in each of these patents, a diazo compound of the formula: 4 R 1
R
2
R
3
N
0 H N 2 C0 2
R
7 I WO 97/01564 PCT/US96/10783 -2is cyclized using a catalyst or irradiation. This generates a mixture of 1-o and 1-3 methyl isomers, which in turn requires separation prior to further chemical modification.
Lastly, many of the prior processes of synthesizing carbapenem antibiotics utilize an intermediate of the formula:
OH
H H CH 3 H3C N OTf 0 CO2PNB which has an active leaving group at position 2, namely the triflate. This compound is extremely unstable, and cannot be utilized in large scale synthesis with an acceptable level of efficiency. As such, one of the objectives of the present invention is to avoid this intermediate.
The present invention overcomes these disadvantages, providing a scheme which avoids unstable intermediates, and in many instances, producing intermediates which are in crystalline form, requiring little or no purification before futher use.
SUMMARY OF THE INVENTION A process of synthesizing a compound of the formula:
PO
H RR P H N, P R J I 1 OPNB H 3 C 1 or 2 C02PNB LI1 r_ WO 97/01564 PCT/US96/10783 -3is disclosed wherein R represents H or methyl and P represents triethylsilyl or trimethylsilyl. The process comprises treating a compound of the formula:
HO
H O /PN 3 H3C 0 H 3 or 4 CO2PNB with P-Cl wherein P is as defined above, in the presence of base and a substantially non-reactive solvent to produce:
PO
PO R N2 H i H PNB H3C HH O H3CN 0 0 N,
N
H or 2 C 0 2
PNB
DETAILED DESCRIPTION OF THE INVENTION The 1-P methyl isomer of the diazo compound I and the bicyclic ketoester 2 (R methyl) which are shown above are highly desired and useful as carbapenem intermediates, because 1-P methyl carbapenem antibiotics have a reduced tendency toward biological inactivation by the enzyme dehydropeptidase when administered to a mammalian patient to treat a bacterial infection. Generally, the 1-3 methyl isomer of the final product is more resistant to deactivation than the 1H or the 1-o methyl isomer.
The bicyclic ketoester 2 can be further reacted at the 2position to establish a leaving group, L, which represents diphenyl phosphate, triflate, tosylate, mesylate, fluorosulfonate, chloride and the like, to form the appropriate activated carbapenem intermediate. The WO 97/01564 PCT/US96/10783 -4activated carbapenem intermediate is suitable for coupling to a substituent at position 2, for example, through the use of a palladium catalyst, Pd2(dba)3-CHC3, and tris(2, 4, 6trimethoxyphenyl)phosphine in a suitable solvent. Further details regarding coupling reactions can be obtained from U.S. Patent No.
5,034,384.
In one preferred embodiment of the invention, a compound of formula 3 wherein R represents H or methyl is reacted with P-Cl in the presence of base and a substantially non-reactive solvent to produce a compound of formula 1:
HC'
In a more preferred embodiment of the invention, a compound of formula 3 is reacted with P-CI wherein P represents triethylsilyl to produce a compound of formula la:
H
3
C
In another more preferred embodiment of the invention, a compound of formula 3 is reacted with P-CI wherein P represents trimethylsilyl to produce a compound of formula 1b: WO 97/01564 PCT/US96/10783 TMSO
R
H H
OPNB
H3C N\ 0 0 O0 H Ib wherein R base and a formula 2: In another preferred embodiment, a compound of formula 4 represents H or methyl, is reacted with P-CI in the presence of substantially non-reactive solvent to produce a compound of
H
3
C
In another more preferred embodiment of the invention, a compound of formula 4 is reacted with P-Cl wherein P represents triethylsilyl to produce a compound of formula 2a:
CO
2
PNB
In another more preferred embodiment of the invention, a compound of formula 4 is reacted with P-Cl wherein P represents trimethylsilyl to produce a compound of formula 2b: WO 97/01564 PCT/US96/10783 -6-
TMSO
H U
H
3
C
0
N
O
2b
CO
2
PNB
In another preferred embodiment, the substituted azetidinone is cyclized before protection of the hydroxyethyl side chain. After cyclization, the side chain is protected with P.
HO
HO R N R H HH *OPNB H3 c H3C Y
O
O O N NN O 0 H
CO
2
PNB
3 PO R
R
H H
H
3
C
N
2
CO
2
PNB
As used herein, PNB refers to the protecting group paranitrobenzyl.
The abbreviation THF refers to tetrahydrofuran.
The abbreviation OAc refers to acetate, CH3C(O)O-.
Hence, the solvent ethyl acetate is abbreviated as EtOAc and isopropyl acetate is abbreviated iPrOAc.
TES refers to the group triethylsilyl.
TMS refers to the group trimethylsilyl.
Et3N refers to triethylamine.
dba refers to dibenzylideneacetone.
1- WO 97/01564 PCT/US96/10783 -7- Generally, the objects of the present invention are to utilize crystalline intermediates and to avoid unstable intermediates.
Additionally, stereospecificity and regiospecific reactions are favored.
The following schemes are representative.
SCHEME 1 HO H HR
N
2
H
3 C CO 2
PNB
N 0 0 O H (Crystalline) (Crystalline)
P-CI
Solvent Cyclize
PNB
H
3
C
(Crystalline)
H
3
C
L-X or L 2 0 X leaving group PO
R
SLPN
0N 5 C02PNB 2 (Stable)
CO
2
PNB
Coupling Reaction 2-Substituted Carbapenems WO 97/01564 PCT/US96/10783 SCHEME 2 HO H HR
N
2
H
3 C
CO
2
PNB
NO 0 O
H
(Crystalline) Cyclize
P-CI
Solvent (Stable)
CO
2
PNB
L
2 0 or L-CI =0 base solvent
,PNB
H
3
C'
2 PO
R
H H3C N L 5 O s T^i Coupling Reaction 2-Substituted Carbapenems CO0PNB The starting materials for schemes 1 and 2 can be obtained in accordance with U.S. Patent Nos. 4,454,332 (issued on June 12, 1984) and 4,312,871 (issued on January 26, 1982). For each of the schemes noted above, by reacting compound 3 or 4 with P-Cl in the presence of base, stable and even crystalline intermediates are realized. This is an unexpected and surprising advantage over other processes of synthesizing carbapenems.
WO 97/01564 PCITUS96/10783 -9- There are numerous methods of cyclizin- 'te diazo intermediates noted above to produce the bicyclic ketoester 2 or 4. The preferred method of cyclization involves a reaction in the presence of a rhodium catalyst, such as rhodium acetate or rhodium octanoate.
Likewise, when activating the bicyclic ketoester 2 at position two, the anhydride L 2 0 or the halide L-CI can be combined with the bicyclic ketoester in the presence of a nitrogen containing base and in a substantially non-reactive solvent to produce the activated carbapenem The activated carbapenem 5, with the appropriate group L at position 2, can then be coupled to an appropriate substituent according to the procedures set forth in U. S. Pat. No. 5,034,384. Carbapenems which can be synthesized in accordance with the process described herein are disclosed, and the groups which are appropriate for such attachment, can be found, in U.S. Pat. No. 5,034,384.
The preferred substantially non-reactive solvents used herein are dimethylformamide, tetrahydrofuran (THF), isopropyl acetate, ethyl acetate and methylene chloride. Most preferably, mixtures thereof are used.
The preferred base used in the processes described herein is imidazole.
The nitrogen containing bases for use in the activating reaction with L20 or L-CI include triethylamine, diisopropylethylamine and diisopropylamine.
Preferred values for L include the sulfonate leaving groups, such as trifluoromethanesulfonate (triflate), methanesulfonate (mesylate), toluenesulfonate (tosylate) and fluorosulfonate, the phosphonic acid residues, such as diphenylphosphonate and the halide leaving groups, such as chloride, bromide or iodide. Most preferred are triflate (OTf), flurorosulfonate (OSO2F), mesylate (OMs), diphenyl phosphate and tosylate (OTs).
WO 97/01564 PCT/US96/10783 EXAMPLE ONE HO HMSO CH3 CH 2 H g N2 H H NPNB I OPNB H3
C
H3C 7 HC TMS-CI O O N imidazole O H 0 H 3a CH 2 CI2 Ic Compound 3a (7.8 and imidazole (3.4 are dissolved in ethyl acetate (70 mL, sieve dried) and the solution is stirred for 10 min. at room temperature. The solution is cooled and trimethylsilyl chloride (3.57 mL) is added while maintaining the temperature at -10 to -1 oC. A white-yellow suspension formed.
The suspension is allowed to warm to room temperature and stirred at room temperature for 1.5 hrs. Pour into phosphate buffer (0.01 M, 80 mL, pH Separate phases and wash the organic phase with aq. NaHCO3 solution (saturated, 40 mL). Dry over Na2SO4. Filter and evaporate the filtrate to dryness. Load the filtrate onto a flash silica column (40 cm diam x 180 cm high). packed in 30% EtOAc and hexane 0.025% Et3N). Fractions 18 55 contained compound Ic EXAMPLE TWO HO CH TESO CH3 N2 OPNB OPNB H3C
HC
O T E S C I 0 0 N imidazole N O H 3a CH2CI2 H Id A 250 mL 3-neck flask equipped with a N2 inlet, a thermocouple probe, and a dropping funnel was charged with THF mL; KF 5 80 gg/mL), isopropylacetate (IPAC; 90 mL; KF 80 gg/mL), compound 3a (15 g; 38.4 mmol) and imidazole (4.7 g; 69.0 mmol). The slurry was stirred at room temperature for 10 minutes until dissolution WO 97/01564 PC1YUS96/10783 -11was complete (KF 140 p.g/mL). The solution was maintained at 18-22 °C as TESCI (9.0 mL; 53.6 mmol) was added slowly over 100 minutes.
After the addition was completed, the batch was aged at 20 "C for 2 hr.
The reaction mixture was assayed by HPLC. The starting material should be less than 0.15 area at 245 nm.
Reaction mixture was quenched into a mixture of heptanes mL) and 0.01 M phosphate buffer (100 mL; pH 6.8) at room temperature. After 30 minutes of stirring at room temperature, the organic layer was separated. The organic layer was washed twice with 0.01 M phosphate buffer (pH 6.8; 100 mL each).
The organic layer was concentrated to about 35 mL at 18 20°C/110 80 mm Hg (GC showed 6.3 v/v heptanes). Heptanes mL) was slowly added during further concentration at 18 20"C/1 10 mm Hg keeping the volume at about 40 mL.
After crystallization took place, additional heptane (90 mL) was added slowly at room temperature and the suspension wa,, 1 at for 1 hr then 0°C for I hr.
The crystals were filtered and washed (slurry then displacement) with a mixture of IPAC and heptane (3 97 v/v; 100mL), and then dried under a nitrogen stream. The product (18 g; 93 yield; 99.6 area was obtained as a white crystalline solid.
EXAMPLE THREE HO TMSO HO H N2 PNB TMSO H N2 "PN OPNB H3C TMS-C
H
3
C
N 0 imidazole 0 0 3b H CH 2 C2 0 'H le Starting from compound 3b, using the procedure set forth in Example One, compound le is obtained.
WO 97/01564 PCT/US96/10783 -12- EXAMPLE FOUR
PNB
TI f" TES-CI H3C' -N O O imidazole 3b H EtOAc 3b To a solution of 3b (245 mg) in a mixture of THF (1 mL) and EtOAc (2 mL) was added imidazole (80 mg) and TESCI (0.15 mL) at room temperature. After stirring for 2 hrs, the reaction mixture was diluted with hexanes (3 mL) and washed with phosphate buffer (pH 6 mL) twice. The organic layer was dried over MgSO4 and concentrated to give crude If, which was further purified by silica gel column chromatography using a mixture of hexanes and EtOAc (3 2 to 1 1) to give pure If (310 mg).
EXAMPLE FIVE
TESO
TESO
H
a
C
0' H id 2d CO 2
PNB
Compound Id (16.0 kg), rhodium octanoate (0.123 kg), anhydrous zinc bromide (71 and dry dichloromethane (63.42 L; KF 100g/mL) are charged to a dry reactor. The solution is deoxygenated with three vacuum/nitrogen-fill cycles, then heated to reflux under nitrogen for 90 min to give a solution of Compound 2d.
WO 97/01564 0CTIJUS9/1 0783 -13- EXAMPLE SIX
TMSO
H
3
C
0
H
ic c CO 2
PNB
Starting from compound Ic, using the procedure Example Five, compound 2c is obtained.
set forth in EXAMPLE SEVEN OH CH 3
N
2 H H
H
3 C C OPNB -N O O H H H
H
3 C 0
N
Rh 2 (octa) 4 0 ZnBr 2 4a C OPNB CH2C12
TESCI
Imidazole OTES
CH
3 H H
H
3
C
N
2d CO 2
PNB
A solution of Compound 3a (1.1 g) in methylene chloride (4 mL) was heated under reflux with zinc bromide (10 mg) and rhodium octanate (10 mg) for 4 hours. The solution containing Compound 4a was cooled down to -78 To this solution was added a mixture of triethylsilyi chloride (0.65 mL) and imidazole (285 mg) at -78 After aged for 1 hr at -78 The reaction mixture was slowly warmed up to 0 WO 97/01564 PCT/US96/10783 -14- From NMR and HPLC analysis, the solution contained mainly Compound 2d.
EXAMPLE EIGHT
TESO
)PNB
HaC HaC' 0' H if 2f CO 2
PNB
A solution of If (291 mg) in methylene chloride (5 mL) is heated with 10 mg of rhodium octanoate dimer at 30°C for 3 hrs. The reaction mixture was concentrated under reduced pressure to give crude 2f (260mg).
EXAMPLE NINE
TMSO
TMSO H H H H OPNB H3C HaC
O
H3C
N
N
0 H l 2e CO 2
PNB
Starting from compound Ie, using the procedure set forth in Example Eight, the TMS protected intermediate 2e is obtained.
WO 97/01 5 64 IPCT/US96/10783 EXAMPLE TEN OH
OTES
HH
HH
Me M e
O
4a CO 2 PNB
CO
2
PNB
2f To a solution of 4a (0.97 g) and imidazole (343 mg) in a mixture of THF (5 mL) and EtOAc (5 mL) was slowly added TESCI (0.66 mL) at room temperature. After stirring for 2 hrs, the reaction mixture was diluted with 10 mL of EtOAc and washed with phosphate buffer (pH 7.0; 15 mL) twice. The organic layer was dried over MgSO4, concentrated under reduced pressure to give crude 2f (1.235 g).

Claims (15)

1. A process of synthesizing a compound of the formula: )PNB C0 2 PNB wherein R represents H or methyl and P represents triethylsilyl or trimethylsilyl comprising treating a compound of the formula: PNB H 3 C' H 3 3 4 CO 2 PNB with P-CI wherein P is as defined above, in the presence of base and a substan.ially non-reactive solvent to produce: PNB H a C H 3 C' CO 2 PNB
2. A process of synthesizing a compound of the formula: WO 97/01564 PCT/US96/10783 -17- TESO 0 H wherein R represents H or methyl, comprising treating a compound of the formula: IPNB H 3 C with triethylsilyl chloride in the presence of base and a substantially non- reactive solvent to produce TESO H 3 C iPNB
3. A process in accordance with claim I wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.
4. A process in accordance with claim 3 wherein the base is imidazole. A process of synthesizing a compound of the formula: WO 97/01564 PCT/US96/10783 -18- TESO CH 3 CO 2 PNB wherein R represents H or methyl, comprising treating a compound of the formula: CH 3 CO 2 PNB with triethylsilyl chloride in the presence of a nitrogen containing base and a substantially non-reactive solvent to produce: TESO CH 3 CO 2 PNB
6. A process in accordance with claim 5 wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.
7. A process in accordance with claim 6 wherein the base is imidazole.
8. A process ol synthesizing a compound of the formula: WO 97/01564 PCT/US96/10783 -19- TMSO R H HO PNB H3C S I O O 0 H wherein R represents H or methyl, comprising treating a compound of the formula: OH R with trimethylsilyl chloridete in the presence of base and a substantially non-reactive solvent to produce N2 TMSO R S NN 0 H
9. A process in accordance with claim 8 wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride. A process in accordance with claim 9 wherein the base is imidazole.
11. A process of synthesizing a compound of the formula: WO 97/01064 PCT/(JS96/10783 TMSO H H CH 3 0 N 0 CO 2 PNB wherein R represeints H or methyl, comprising treating a compound of the formula: GH R H H CH 3 R 0 N" 0 CO 2 PNB with trimethylsilyl chloride in the presence of base and a substantially non-reactive solvent to produce: TMSO HH CH 3 -o N CO 2 PNB
12. A process in accordance with claim 11 wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.
13. A process in accordance with claim 12 wherein the base is imidazole.
14. A process of synthesising a 4-j.3-(l-silyloxyethiyl)A4-oxoazetidiin-2-yl]-3- oxobtityric acid 4-nitrobenzyl ester derivative, substantially as hercinbefore described with reference to any one of the Examples. process of synthesising a 6-(silyloxyethyl)-3,7-dioxo-1I- azabicyc 1 A]heptane-2-carboxylic acid 4-nitrobenzyl ester derivative, substantially as hereinbefcre described with reference to any one of the Examples.
16. A -silyloxyethiyl)-4-oxoazetidin-2-yl]-3 -oxobutyric acid 4-nitrobenzyl ester derivative or 6-(silyloxyethyl)-3,7-dioxo-1-azabicycloj3 .2.0]heptane-2-carboxylic acid 4-nitrobenzyl ester derivative synthesised by the process of any one of claims 1 to Dated 29 January, 1998 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON *ftftftftft ft. ft ft ft... o ft ft ft ft ft. ft. ft. ft ft ft ft ft ft *0 ft ft... ft. ft ft ft ft ft. ft... a ft ft. ft ft ft ft ft. ft ft ft ft... ft. ft. o ft ft ft ft ft ft ,a:\ibc]03 133:MEF IENA710NL EA~W.1 RUPOR3' 11 prlw N PCT/US 98/10783 0** I I II I 1111~-L A' CLASSIIIC' OFN OP SUWYGI' MATVI'R IPC6 C07F7/18 According to IlemrnAional Patent Clssfication (IPC) or to both national classification and IPC B, FIELDS SEARCHED Minimum documentation searched (classification system followed by classfication symbols) IPC 6 CO7F CO7D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the itematonal search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category" Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X GB,A,2 165 247 (BRISTOL-MYERS COMPANY) 9 1-13 April 1986 see page 23, line 45 line 63; claims Y EP,A,0 414 904 (KANEGAFUCHI 6 1-13 March 1991 see the whole document Y EP,A,O 409 331 (MERCK CO. INC.) 23 1-13 January 1991 see the whole document A EP,A,O 422 472 (BAYER AG.) 17 April 1991 1-13 see the whole document E Further documents are listed in the continuation of box C. Patent family members are listed in annex. SSpecial categories of cited documents: later document published after the international filing date or prnonty date and not in conflict with the application but document defining the general state of the art which is not ated to understand the pnnciple or theory underlying the considered to be of particular relevance mvention earlier document but published on or after the nternational document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on pnonty claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other specal reason (as specified) cannot be considered to involve an inventve step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu. other means ments, such combination being obvious to a person skilled document published pnor to the international filing date but the art. later than the pnonty date claimed document member of the same patent family Date of the actual completion of the Internatonal search Date of mailing of the International search report October 1996
17.10.96 Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rilswijk Tel. (+31-70) 340-2040, Tx. 31 651 eponl, Chouly, J Fax: (+31-70) 340-3016 Forin PCT/1SA210 (second iealt) (July 1992) INERNAVfONAL SK AROY ftlrn i pplieAllon No F PCQTUS 96/10783 Patent document Pubficaticon P Iatent famnily I Publication cited In search report date I member(s) Idate GB -A-2 165247 09-04-86 US-A- AT-B- AT-B- AU-B- AU-A- BE-A- CA-A- CH-A- DE-A- FR-A- JP-A- LU-A- NL-A- OA-A- SE-B- SE-A- DE-D- DE-T- CA-A ES-T- WO-A- US-A- JP-A- 4683301 395151 396473 575432 4810285 903353 1260945 665640 3535196 2571054 61087682 86105 8502681 8113 466202 8504538
69018163- 69018163 2025108 2073017 9008149 5071966 2275888 28-07 -87 12-10-92 27-09-93 28-07-88 10-04-86 01-04-86 26-09-89 31-05-88 10-04-86 04-04-86 06-05-86 11-06-86 01-05-86 3 1-03-87 13 -01-92 03-04-86 04-05-95 08-95 13-07-90 01-08 26 -07-90 10-12-9 1 09- 11-90 EP-A-414904 06-03 -91 EP-A-409331 23-01-91 AU-B- 625924 16-07-92 AU-A- 5913090 24-01-91 CA-A- 2021253 19-01-91 Fl-B- 93363 15-12-94 IL-A- 95024 24-01-95 JP-A- 3095193 19-04-91 NO-B- 177307 15-05-95 US-A- 5340927 23-08-94 EP-A-422472 17-04-91 DE-A- 3934100 18-04-91 AT-T- 132155 15-01-96 CA-A- 2026031 13-04-91 DE-D- 59010006 08-02-96 ES-T- 2083410 16-04-96 JP-A- 3135986 10-06-91 Formn PCT/ISA,'210 (patent family annex) (July 1992) page 1 of 2 I I# SERC REOR iinjon m) p~wit ~i1)l' moomri 1wo ~I i l Aj1f4io1)orl No PCT/US 96/10783 PIalCoif (Jocump1)L I publicauOn Ph oi rimily I pubikt.Uwi diod~ In ot~c Ieo t. d Ko mber(p) Id t EP-A-422d172 US-A- 5142081 25-08-92 Foffn PCT/ISA/2LI (Patent~ fliilY anne) (July 199n) page 2 of 2
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2165247A (en) * 1984-10-02 1986-04-09 Bristol Myers Co Azabicycloheptene derivatives
EP0409331A2 (en) * 1989-07-18 1991-01-23 Merck & Co. Inc. A novel process for the preparation of 2-diazo-3-trisubstituted silyloxy-3-butenoates
EP0414904A1 (en) * 1989-01-12 1991-03-06 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Preparation of enol silyl ether compounds

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* Cited by examiner, † Cited by third party
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DE3934100A1 (en) * 1989-10-12 1991-04-18 Bayer Ag METHOD FOR PRODUCING 0-SILYLATED HYDROXYL COMPOUNDS AND THE USE THEREOF FOR PRODUCING ISOCYANATES HAVING ESTER GROUPS

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2165247A (en) * 1984-10-02 1986-04-09 Bristol Myers Co Azabicycloheptene derivatives
EP0414904A1 (en) * 1989-01-12 1991-03-06 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Preparation of enol silyl ether compounds
EP0409331A2 (en) * 1989-07-18 1991-01-23 Merck & Co. Inc. A novel process for the preparation of 2-diazo-3-trisubstituted silyloxy-3-butenoates

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