PROCESS FOR PREPARATION OF ESTERS OF 2-DIAZO-3-TRIMETHYLSILYLOXY-3-BUTENOIC ACID
Technical Field of the Invention
The present invention relates to a process for the preparation of esters of 2-diazo-3-lrimethylsilyloxy-3-butenoic acid, which are useful intermediates for the synthesis of thienamycin, imipenem and other carbapenem antibiotic compounds.
Background of the Invention
2-diazo-3-trimethylsilyloxy-3-butenoic acid esters, which are prepared by silylation of diazoacetoacetate with trimethylsilylchloride and hexamethyldisilazane, has been disclosed. The preparation of 2-diazo-3-trisubstituted silyloxy-3-butenoate ester comprising silylating substituted diazoacetoacetate with trisubstituted silyl halide in the presence of a base and alkali metal halide also have been disclosed. In addition, the preparation of 2-diazo-3-trisubstituted silyloxy-3-butenoate ester comprising reacting substituted diazoacetoacetate with silyl inflate in an inert solvent and in the presence of an organic base has been disclosed.
It has been observed that large quantity of byproducts, such as insoluble salts of alkali metal halide are formed during the reaction, which further interfere with the subsequent reactions. Therefore, removal of such byproducts is required.
Accordingly, there remains a need for a process for preparing such esters while avoiding the formation of byproducts, such as insoluble alkali metal halide salts.
Summary of the Invention
The present invention encompasses a process for the preparation of compound of
Formula I,
(Figure Removed)
comprising reacting diazoacetoacetate of Formula II
with iodotrimethylsilane in the presence of an organic base,
wherein R is hydrogen, Ci-CV,-alkyl, CVC6-alkenyl, substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl, and
wherein iodotrimethylsilane is prepared by reacting hexamethyldisilane with iodine. Preferably R is hydrogen, methyl, ethyl, p-nitro benzyl and p-methoxy benzyl.
The organic base can be an amine, such as trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, l,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU), l,5-dia7abieyclo-[4.3.0]-non-5-ene (DBN), 4-dimethylamino pyridine or mixtures thereof.
The reaction can be performed in an inert solvent, such as an alkyl ether, a chlorinated hydrocarbon, an ester, a hydrocarbon, a nitrile, a dipolar aprotic solvents or a mixture thereof. The nitrile can be acetonitrile, benzonitrile or a mixture thereof. The chlorinated hydrocarbon can be methylene chloride, ethylene dichloride, carbon tetrachloride or a mixture thereof. The hydrocarbon can be hexane, cyclohexane, toluene, heptane, octane or a mixture thereof. The dipolar aprotic solvent can be dimethylsulfoxide, dimethylformamide or a mixture thereof. The cyclic ether can be dioxane, tetrahydrofuran and a mixture thereof.
In one embodiment, the reaction of the diazoacetoacetate of Formula II

(Figure Removed)
with iodolrimethylsilane is carried out at temperature of from about 10°C to about 30°C.
The iodotrimethyl si lane can be prepared by refluxing a mixture of iodine and hcxamethyldisilane in an organic solvent, such as methylene chloride, ethylene dichloride, toluene, tetrahydroiuran, dioxane, acetonitrile or a mixture thereof.
Conversion of a compound of Formula I to a substituted diazoazetidinone is also contemplated. Thus, the present invention encompasses a process for the preparation of a substituted diazoazetidinone of Formula III

comprising reacting a silyl enol ether of Formula I,

with an azetidinone of Formula IV, (Figure Removed)

in the presence of catalytic amount of a Lewis acid, wherein R is hydrogen, C|-C6-alkyl, C2-C6-alkenyl. substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl; R1 is hydrogen or nitrogen protecting group; R2 is trialkylsilyl group; and R3 is a leaving group. The Lewis acid can be silver letrafluoroborate, mercury trifluoroacetate, titanium tetra chloride, silver perchlorate, zinc bromide, or a mixture thereof.
Also contemplated is converting the substituted diazoazetidinone of Formula III to a bicyclo ketoester. Accordingly, the present invention encompasses the conversion of a substituted diazoazetidinone of Formula III,
(Figure Removed)

to a bicyclo ketoester of Formula V,
(Figure Removed)

by cyclization of the substituted diazoazetidinone of Formula III, in the presence of a catalyst. The catalyst can be rhodium acetate, palladium acetate, rhodium octanoate, copper acctonate, copper sulfate, copper powder, and a mixture thereof.
The present invention also encompasses a process for making carbapenem antibiotic compounds, comprising:
a. reacting a diazoacetoacetate of Formula II

(Figure Removed)
with iodotrimethylsilane in the presence of an organic base, wherein iodotrimethylsilane is
prepared by reacting hexamethyldisilane with iodine, to form a silylenol ether of Formula 1

b. reacting the silyl enol ether of Formula I with an azetidinone of Formula IVto form a substituted diazoazetidinone of Formula III
c. cyclization of the substituted diazoazetidinone of Formula III to the bicyclo
ketoester of Formula V in the presence of a catalyst,
wherein R is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl; R1 is hydrogen or nitrogen protecting group; R2 is trialkylsilyl group; and R3 is a leaving group,and
d. converting the compound of Formula V to a carbepenem antibiotic
compound.
In one embodiment, the conversion of the compound of Formula V to a carbepenem antibiotic compound comprises
a. acylation of the keto ester functionality of the compound of Formula V with
an acylating agent;
b. treating the acylated compound resulting from step with a mercaptan reagent
of formula 1ISCI bCHpNIIR8 [wherein R8 is selected from hydrogen, a protecting group
(selected from p-nitrobenzoxycarbonyl, o-nitrobenzoxycarbonyl, phenylacetyl,
phenoxyacetyl, or trimethylsilyl), or -CH=Ry, (wherein R9 is a protecting group selected
from p-nitroben/.oxycarbonyl, o-nitrobenzoxycarbonyl, phenylacetyl, phenoxyacetyl, or
triinethylsilyl)]; and
c. deblocking the compound resulting from step b by hydrolysis or
hydrogenation to form a carbepenem antibiotic compound.

In another embodiment, the conversion of the compound of Formula V to a carbepenem antibiotic compound comprises
a. phosphorylating the keto ester functionality of the compound of Formula V
with a phosphorohalidate to form an enolphosphate; and
b. reacting the enolphosphate with a thioalkylamine of formula HS(CH2)2NH2, or
an acid addition salt thereof, to form a carbepenem antibiotic compound.
Detailed Description of the Invention
The present invention relates to a process for the preparation of 2-diazo-3-trimethylsilyloxy-3-butenoates derivatives of Formula I,

(Figure Removed)

comprising reacting diazoacetoacetate of Formula 11,
(Figure Removed)

with iodotrimeihylsilane in the presence of an organic base, wherein iodotrimethylsilane is
prepared by reacting hexamethyldisilane with iodine and wherein R can be hydrogen, alkyl, alkenyl, substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl. Preferably, alkyl is C1-C6-alkyl and alkenyl is C2-C6-alkenyl. Use of iodotrimethylsilane. which is prepared from hexamethyldisilane and iodine, does not generate any alkali metal halide salts during silylation.

Alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, secondary butyl or tertiary butyl. Alkenyl groups include, but are not limited to, vinyl, allyl, isopropenyl, pentenyl or hexenyl. Substituted phenyl includes, but is not limited to, phenyl having 1-3 substituents, which independently can be hydrogen, bromine, chlorine, fluorine, C1~C4-alkyl, C1i-C4-alkoxy, or nitro. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy or butoxy. Substituted benzyl includes, but is not limited to. p-nitro ben/yl, p-methoxy benzyl, o-nitro benzyl, p-bromo benzyl or 2,4,6, trimethyl ben/yl.
Suitable organic bases that can be used in the reaction of diazoacetoacetate of Formula II with iodotrimethylsilane are amines, such as trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, DBU (1,8-diazabicyclo- |5.4.0]-undec-7-ene), DBN (l,5-diazabicyclo-[4.3.0]-non-5-ene), 4-dimethylamino pyridine, or mixtures thereof.
Suitable solvents for the reaction of compounds of Formula II with iodotrimethylsilane include inert organic solvents that do not change under the reaction conditions. Such solvents include, but are not limited to, alkyl ethers, such as diethylether, diisopropylether or dimethoxyethane; nitriles, such as acetonitrile or benzonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylene dichloride or carbon tetrachloride; esters, such as ethylacetate or isopropylacetate; hydrocarbons, such as hexane, cyclohexane, toluene, heptane or octane; dipolar aprotic solvents, such as dimethylsulfoxide or dimethyl formamide; cyclic ethers, such as dioxane or tetrahydroluran or mixtures (hereof.
The reaction can be performed at temperatures of from about 10 °C to about 45 °C. In another embodiment, the reaction may be performed at temperatures of from about 15
°C to 25 °C.
Iodotrimethylsilane may be prepared by refluxing a mixture of iodine and hexamethyl disilanc in an organic solvent. Suitable organic solvents utilized in preparing iodotrimethylsilane include, but are not limited to, methylene chloride, ethylene dichloride, toluene, tetrahydroluran, dioxane, acetonitrile or mixtures thereof.
The diazoacetoacetate of Formula II,

may he obtained by known processes, such as those processes disclosed in U.S. Patent Nos. 5,340,927; 4,683,296 and 4.525,582, each of which are incorporated herein by reference.
The compound of Formula 1 can be converted to substituted diazoazetidinone of Formula III,

(Figure Removed)
ted or unsubstituted phenyl, benzhydryl. triphenylmethyl, or substituted or unsubstituted benzyl; and R1 can be hydrogen or nitrogen protecting group) by known methods, such as those methods disclosed in U.S. Patent Nos. 5,998,612; 5,340,927; 5,071,966; 4,525,582 and 4,683,296, each of which are incorporated herein by reference.
In general, azetidinone of Formula IV(Figure Removed)

s reacted with silyl enol ether of Formula I in the presence of catalytic amount of a Lewis acid in an inert organic solvent, wherein R1 can be hydrogen or nitrogen protecting group, Rº can he trialkyl silyl group and R can be a leaving group. The Lewis acid can be, for example, silver tetrailuoroborate, mercury trifluoroacetate, titanium tetrachloride, silver perchlorate or zinc bromide. The reaction can be worked up with excess of methanol, and methane sulfonic acid or hydrochloric acid to yield the compound of Formula III.
The compounds of Formula III can also be prepared by reacting a silyl enol ether of Formula I and an a/etidinone of Formula IV in the presence of a highly reactive silylating agent, such as Inmethylsilyltriflate.
The compound of Formula III can in turn be converted to a bicyclo ketoester of Formula V
(Figure Removed)
by methods known in the art, such as, for example, in U.S. Patent No. 4,739,048, which is incorporated herein by reference.
In general, bicyclo ketoesters of Formula V is prepared by the cyclization of diazoaz.etidinone of Formula III. The reaction can be performed in the presence of a catalyst, such as rhodium acetate, palladium acetate, rhodium octanoate, copper acetonate, copper sulfate or copper powder. The reaction can be performed in a solvent, such as toluene or tetrahydrofuran at a temperature of 50 °C to 110 °C.
The compound of Formula V can be converted to thienamycin, imipenem, penepcenem and other carbapenem antibiotic compounds by methods known in art, such as, for example, in U.S. Patent Nos. 4,739,048; 4,894,450; 4,292,436 and PCT Applications WO 02/94828 and WO 02/36594, each of which references are incorporated by reference in their entiretv.

For example, I l.S. Patent Nos. 4,739,048, and 4,292,436 disclose acylating the keto ester functionality of the compound of Formula V with an acylating agent such as R°X such as p-toluenesulfonic acid anhydride, p-nitrophenylsulfonic acid anhydride, 2,4,6-triisopropylphenylsulfonic acid anhydride, methanesulfonic acid anhydride, toluenesulfonyl chloride, p-bromophenylsulfonyl chloride, or the like wherein X is the corresponding leaving group such as toluene sulfonyloxy, p-nitrophenylsulfonyloxy, methanesulfonyloxy, p-bromophenylsulfonyloxy and other leaving groups which are established by conventional procedures and are well known in the art, thereby forming a compound which is treated in a solvent with a mercaptan reagent of formula HS(CH2)2-NHRX, wherein Rs can be hydrogen, a protecting group (selected from p-nitroben/oxycarbonyl, o-nitrobenzoxycarbonyl, phenylacetyl, phenoxyacetyl, or trimethylsilyl), or -CH=R9, (wherein R9 is a protecting group selected from p-nitrobenzoxycarbonyl, o-nitrobenzoxycarbonyl, phenylacetyl, phenoxyacelyl, or trimethylsilyl), and deblocking the resulting compound by hydrolysis or hydrogenolysis to form a carbepenem antibiotic compound.
For example, U.S. Patent No. 4,894,450 discloses phosphorylation of a compound of Formula V with phosphorohalidates in a substantially inert organic solvent containing a suitable tertiary amine or a hindered base to form an enolphosphate, which is thereafter reacted with a thioalkylamine of formula HS(CH2)2-NH2 to form a carbepenem antibiotic compound.
In the following section embodiments are described by way of examples to illustrate the process of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
Examples Preparation of lodotrimethysilane (Me3Sil)
Iodine (63.7 g) was suspended in methylene chloride (200 mL) and stirred for 10 to 15 minutes. Hexamethyl disilane (39.0 g) was then added in 35 to 40 minutes at room temperature and the reaction mixture was allowed to stir for 30 minutes. The mixture was heated to reflux and refluxing was continued for 2.0 hours. The reaction mixture containing iodotirimethylsilane was cooled to 20 to 25°C before use.

Example 1; Preparation of p-nitrobenzyl-2-diazo-3-trimethylsilyloxy-3-butenoate
p-Nitrobenzyl-2-diazoacetoacetate (120 g) was suspended in a mixture of methylene chloride (50 mL) and toluene (100 mL) and was cooled to 18 to 20 °C. Triethylamine (54.3 g) was added and stirred for 5 minutes, lodotrirnethylsilane reagent was added in 30 to 35 minutes at 20 to 30°C. Stirring was continued for 2.5 to 3.0 hours at 20 to 25°C. The reaction mixture was then diluted with toluene (700 mL) and the mixture of methylene chloride and toluene was evaporated (-500 mL) under vacuum (650 mmHg lo 700 mmHg) to give a slurry containing p-nitrobenzyl-2-diazo-3-trimethylsilyloxy-3-butenoate. The slurry was filtered through cloth and the filtered material was washed with toluene.
Example 2: Preparation of (3S,4R)-3-[(lR)-hydroxyethyl1-4-[3-(4-nitrobenzvloxy)carbonyl-2-oxo-3-diazopropyl]azetidin-2-one
(3R.4R)-3-|(lR)-tert-butyldimethylsilyloxyethyl]-4-acetoxyazetidin-2-one (100 g) and anhydrouszinc chloride (16 g) was added to the filtrate obtained from Example 1 at 25 °C and the reaction mixture was stirred for 15 hours at 20 to 30 °C. After 15 hours, methanol (250 ml.) and methane sulfonic acid (14.2 g) were added to the above reaction mixture. The precipitation of solid began after about 60 minutes. The reaction mixture was allowed to stir for an addiiional 12 to 15 hours until unreacted p-nitrobenzyl-2-diazo-3-lrimethylsilyloxy-3-bulenoate was not present at more than 2.0% by HPLC analysis. The slurry was cooled to 0 °C to 5 °C and stirred for 60 minutes. The product was filtered and washed with toluene. The material was dried to obtain a free flowing solid. The solid was suspended in methanol (300 ml) and cooled to 3 °C to 5°C and the suspension was stirred for 30 minutes, filtered and washed with methanol (100 mL). The product was air dried at 45 to 50°C till moisture content was less than 1.0% weight by weight.
Yield: 108g
Example 3: Preparation of'(5R,6S)p-Nitrobenzyl-6-[(lR)-hvdroxvethyl]-l-azabicyclo[3.2.0] rieptane-3,7-dione-2-carboxylate
(3S.4R)-3-[(lR)-hydroxyethyl]-4-[3-(4-nitrobenzyloxy)carbonyl-2-oxo-3-diazopropyl] azetidin-2-one (250 g) and rhodium octanoate dimmer (1.0 g) were added to dichloromethane (2.5 1,) and heated to reflux for 4 to 5 hours. The reaction was monitored by HPLC' until unreacted azetidinone was not more than 2.0%. To the clear

dichloromethane solution, cvclohexane was added to precipitate the product at 20 °C to 30 °C. The product was filtered, washed with cyclohexane and dried.
Yield: 188g
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

WE CLAIM:
A process lor the preparation of compound of Formula 1,
comprising reacting diazoacetoacetate of Formula II with iodotrimethylsilane in the presence of an organic base,
(Figure Removed)

wherein R is hydrogen. C1-C6-alkyl, C2-C6-alkenyl, substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl, and
wherein iodotrimethylsilane is prepared by reacting hexamethyldisilane with iodine.
2. The process according to claim 1, wherein R is hydrogen, methyl, ethyl, p-
nitro benzyl and p-methoxy benzyl.
3. The process according to claim 1, wherein the organic base is an amine.
4. The process according to claim 3, wherein the amine is selected from the
group consisting of trimethylamine, triethylamine, tributylamine, triisopropylamine,
diisopropylethylamine. l,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU), 1,5-diazabicyclo-
|4.3.0|-non-5-ene (DBN), 4-dimethylamino pyridine and a mixture thereof.
5. The process according to claim 1, wherein the reaction is performed in an
inert solvent.

The process according to claim 5 wherein the inert solvent is selected from
, tic solvents and a mixture thereof.
claim 1, wherein the reaction of
6. The process according to claim 5 wherein the inert solvent is selected fromthe group consisting of an alkyl ether, a chlorinated hydrocarbon, an ester, a hydrocarbon, a
nitrile, a dipolar aprotic solvents and a mixture thereof.
7. The process according to
cliazoacetoacetate of Formula 11

(Figure Removed)
with iodotrimethylsilane is carried out at temperature of from about 10 °C to about 30 °C.
8. The process according to claim 1, wherein iodotrimethyl silane is prepared
by re flux ing a mixture of iodine and hexamethyldisilane in an organic solvent.
9. The process according to claim 8, wherein organic solvent is selected from
the group consisting ofmethylene chloride, ethylene dichloride, toluene, tetrahydrofuran,
dioxane, acetonitrile and a mixture thereof.
10. A process for the preparation of a substituted diazoazetidinone of Formula(Figure Removed)
comprising reacting a silyl enol ether of Formula I,

with an azetidinone of Formula IV,

(Figure Removed)
in the presence of catalytic amount of a Lewis acid,
wherein R is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl; R1 is hydrogen or nitrogen protecting group; R2 is trialkylsilyl group; and R3 is a leaving group.
11. The process according to claim 10, wherein the Lewis acid is selected from
the group consisting of silver tetrafluoroborate, mercury trifluoroacetate, titanium tetra
chloride, silver perchlorate, zinc bromide, and a mixture thereof.
12. The process according to claim 10, further comprising converting the
substituted diazoazetidinone of Formula III, (Figure Removed)
to a bicyclo ketoeste of Formula V,

(Figure Removed)
by cyclization of the substituted diazoazetidinone of Formula III, in the presence of a
catalyst.
13. The process according to claim 12, wherein the catalyst is selected from the
group consisting of rhodium acetate, palladium acetate, rhodium octanoate, copper
acetonate. copper sulfate, copper powder, and a mixture thereof.
14. A process for the preparation of a bicyclic ketoester of Formula V


comprising the steps of
a. reacting a diazoacetoacetate of Formula II
with iodotrimethylsilane in the presence of an organic base, wherein iodotrimethylsilane is prepared by reacting hexamethyldisilane with iodine, to form a silyl enol ether of Formula 1
(Figure Removed)
b. reacting the silyl enol ether of Formula I with an azetidinone of Formula IV
to form a substituted diazoazetidinone of Formula III

and

c. cyclization of the substituted diazoazetidinone of Formula III to the bicyclo ketoester of Formula V in the presence of a catalyst,
wherein R is hydrogen. C1-C6-alkyl, C2-C6-alkenyl, substituted or unsubstituted phenyl, ben/hydryl, tnphenylmethyl, or substituted or unsubstituted benzyl; R1 is hydrogen or nitrogen protecting group; R2 is trialkylsilyl group; and R3 is a leaving group.
1 5. A process lor making carbapenem antibiotic compounds, comprising:
(Figure Removed)

reacting a diazoacetoacetate of Formula II
with iodotrimethylsilane in the presence of an organic base, wherein iodotrimethylsilane is prepared by reacting hexamethyldisilane with iodine, to form a silyl enol ether of Formula 1

h.
Formula I reacting the silyl enol ether of Formula I with an azetidinone of Formula IV

10 form a substituted diazoa/etidinone of Formula III
(Figure Removed)
c. cyclizaiion of the substituted diazoazetidinone of Formula III to the bicyclo
ketoester of Formula V in the presence of a catalyst,
wherein R is hulrogen, C1-C6-alkyl, C2-C6-alkenyl, substituted or unsubstituted phenyl. benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl; R1 is hydrogen or nitrogen protecting group; R2 is trialkylsilyl group; and R3 is a leaving
group, and
d. converting the compound of Formula V to a carbepenem antibiotic
compound.
16. The process of claim 15, wherein conversion of the compound of Formula V
to a carbepenem antibiotic compound comprises
a. acylation of the keto ester functionality of the compound of Formula V with
an acylating agent;
b. treating the acylated compound resulting from step with a mercaptan reagent
of formula HSCH2 HR8 [wherein R8 is selected from hydrogen, a protecting group
(selected from p-nitrobenzoxycarbonyl, o-nitrobenzoxycarbonyl, phenylacetyl,
phenoxyacetyl, or trimethylsilyl), or -CH=R9, (wherein R9 is a protecting group selected
from p-nitrobenzoxycarbonyl, o-nitrobenzoxycarbonyl, phenylacetyl, phenoxyacetyl, or
trimethylsilyl)|; aru'
c. deblocking the compound resulting from step b by hydrolysis or
hydrogenation to form a carbepenem antibiotic compound.
17. The process of chCFFMlaim 16, wherein conversion of the compound of Formula V
to a carbepenem antibiotic compound comprises

a. phosphorylating the keto ester functionality of the compound of Formula V
with a phosphorohalidate to form an enolphosphate; and
b. reacting the enolphosphate with a thioalkylamine of formula HS(CH2)2NH2,
or an acid addition salt thereof to form a carbepenem antibiotic compound.