JP3081250B2 - Method for producing substituted azetidinone - Google Patents

Description

BACKGROUND OF THE INVENTION Elastase is one of the proteases of the enzyme.
Proteases from granulocytes and macrophages have been reported to be responsible for chronic tissue destruction mechanisms associated with inflammation, including rheumatoid arthritis and emphysema. Thus, specific and selective inhibitors of these proteases are e.g. Powerful anti-inflammatory agents useful in treating inflammatory conditions that cause connective tissue destruction such as sclerosis, sepsis, sepsis, shock symptoms, myocardial infarction, reperfusion injury, periodontitis, cystic fibrosis and acute respiratory distress syndrome Is a candidate for

The role of proteases from granulocytes, leukocytes or macrophages relates to a rapid series of events that occur during the development of inflammatory conditions: (1) There is a rapid production of prostaglandins (PG) and related compounds synthesized from arachidonic acid. This PG synthesis was shown to be inhibited by aspirin-related non-steroidal anti-inflammatory drugs, including indomethacin and phenylbutazone. There is some evidence that protease inhibitors prevent PG production; (2) there is also a change in vascular permeability, causing fluid leakage to the site of inflammation, and the resulting edema is generally a marker for measuring the degree of inflammation used. This process has been found to be triggered by the proteolytic and peptide-cleaving activities of proteases, especially those contained in granulocytes, for which a variety of synthetic protease inhibitors such as N-acylbenzisothiazolones and the respective 1,1- Can be inhibited by dioxide. Morris Zimmerman et al., J. Biol. Chem.,
255, p.9848 (1980); (3) lymphocytes, particularly macrophages and granulocytes (PM
N) occurrence and / or presence. Various proteases are known to be released from macrophages and PMNs, further indicating that proteases play important roles in inflammation.

In general, proteases are essential for a variety of normal biological activities whose components are such as digestion, formation and lysis of blood clots, generation of active forms of hormones, immune response to foreign cells and organs, and the like. Is an important homologue of the enzyme in pathological conditions, such as the degradation of structural proteins of the articular cartilage / pannus junction, such as within peptide bond cleavage enzymes, and rheumatoid arthritis.

Elastase is one of the proteases. It is an enzyme capable of hydrolyzing connective tissue, a property not included in the total amount of proteases present in mammals. Acts on the non-terminal binding of proteins adjacent to aliphatic amino acids. Neutrophil elastase is of particular interest because it has the broadest spectrum of activity on natural connective tissue substrates. In particular,
As described above, elastase of granulocytes is important because granulocytes are involved in acute inflammation and in acute relapse of a chronic form of inflammation that characterizes many clinically important inflammatory diseases.

Proteases will be inactivated with inhibitors that block by binding tightly to the active site of the enzyme. Naturally occurring protease inhibitors form part of a regulatory or defense mechanism that is important for organ safety. Without these control mechanisms, proteases will destroy any protein within range. Naturally occurring enzyme inhibitors have been shown to have the proper configuration to allow tight binding to the enzyme. This configuration is part of the reason that inhibitors bind tightly to enzymes (Stroud, "A Family of Proteins").
-Cutting Proteins "Sci., Am. July 1974, pp. 74-88). For example, one of the natural inhibitors, α1-antitrypsin, among other enzymes, is from both the pancreas and PMN.
Glycoproteins contained in human serum with elastase covering a broad inhibitory spectrum. This inhibitor is hydrolyzed with a protease to form a stable acyl enzyme in which the active site is no longer effective. Significant reduction of serum α1-antitrypsin, either genetically or by oxidants, was associated with progressive loss of lung elasticity and resulting dyspnea. This loss of lung elasticity has been reported to result from progressive and uncontrolled proteolysis or disruption of lung tissue structure by proteases such as elastase released from leukocytes. JCPowers, TIBS, 211 (1976).

Rheumatoid arthritis is a free surface that borders the joint space,
It is characterized by the progressive destruction of articular cartilage both at the erosion front created by the synovial tissue towards the cartilage. This destruction process can be attributed to the protease elastase, a natural protease present in human granulocytes. This conclusion was supported by the following observations: (1) recent histochemical studies showed accumulation of granulocytes at the cartilage / pannus junction of rheumatoid arthritis; and (2) in response to challenge with purified elastase Recent studies of the mechanical behavior of cartilage have shown the direct involvement of granulocyte enzymes, especially elastase, in rheumatoid cartilage destruction. H. Menninger et al., In Biological Functions of
Proteinase, H. Holzer and H. Tschesche, eds.Spring
er-Verlag, Berlin, Heidelberg, New York, pp. 196-20
6,1979.

The second embodiment of the present invention is a non-lymphoblastic leukemia, acute myeloid leukemia (FAB M1 and FAB M2), acute myelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4),
Acute monocytic leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia, and leukemia-related conditions, including PMN neutral protease activity,
For example, the use of novel azetidinones in the treatment of certain cancers, including disseminated intravascular blood clotting. The substituted azetidinones disclosed herein are inhibitors of proteinase 3 (PR-3), also known as myeloblastin.

C. Labbaye, et al., Proc. Natl. Acad. Sci. USA, Vol. 88, 9253.
-9256, (1991), Wegner autoantigen and myeloblastin are encoded by a single mRNA; D. Campanelli, et al., J. Exp. Me.
d., Vol. 172, 1709-1714, (1990), Cloning of cDNA for proteinase 3: serine proteases, antibiotics, and autoantigens from human neutrophils;
See, Cell Vol. 59, 959-968, (1989) Downregulation of the serine protease, myeloblastin, results in growth arrest and differentiation of myelocytic leukemia.

Recently, down regulation of PR-3 has been implicated in the growth and maintenance of certain leukemia cells. In particular, Bories, et al., Indicate that expression of this enzyme, in the future, will show proteinase 3 / myeloblastin, but can be inhibited by treatment of HL-60 human leukemia cells with antisense oligodeoxynucleotides, and that such treatments It has been shown to induce differentiation and inhibit the growth of such cells. In addition, we have now shown that, among other things, treatment of HL-60 cell human leukemia cells with compounds of the present invention also results in inhibition of proliferation and induction of differentiation of such cells.

Therefore, such non-lymphocytic leukemia, acute myeloid leukemia (FAB M1 and FAB M2), acute myeloid leukemia (FAB M1)
M3), acute myelomonocytic leukemia (FAB M4), acute monocyte leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, and leukemia-related conditions including the activity of PMN neutral protease,
It is believed that treatment of leukemia, comprising administration of a therapeutically effective amount of a compound of Formula I, such as disseminated intravascular coagulation, will result in amelioration of the disease state. Administration will be either oral or parenteral.

SUMMARY OF THE INVENTION The present invention relates to [S- (R ^* , S ^* )]-N- [1- (1,3
-Benzodioxol-5-yl) butyl] -3,3-diethyl-2- [4-[(4-methyl-1-piperazinyl) carbonyl] phenoxy] -4-oxo-1-azetidine-carboxamide (formula It relates to a process for the preparation of I). The focusing route uses a chiral β-lactam intermediate prepared using a resolution-based means and a chiral isocyanate intermediate prepared using chiral propylation of piperonal, followed by azide inversion of the alcohol.

DETAILED DESCRIPTION OF THE INVENTION The convergent approach is [S- (R ^* ,
S ^* )]-N- [1- (1,3-benzodioxole-5-
Yl) butyl] -3,3-diethyl-2- [4-[(4-
Methyl-1-piperazinyl) carbonyl] phenoxy]
-4-oxo-1-azetidinecarboxamide (formula I)
Prepared via intermediates 4 and 9 prepared optically.

The process for preparing the compound of formula I below With azetidinone of the formula With an isocyanate of the formula Coupling in the presence of a catalytic amount of a base and a solvent in a temperature range from about -10C to about 25C.

In one embodiment of this method, the base is an amine base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), or 1,5-diazabicyclo [4.3.0] non-
Inorganic bases such as 5-ene (DBN), and potassium carbonate. The base is used in a catalytic amount ranging from about 1 mole% to about 100 mole%. A preferred range is from about 5 mol% to about 25 mol%. If DBU was the base used, 10 mol% was used to cause the coupling reaction.
In another embodiment of this method, the solvent is acetonitrile,
Selected from toluene, methyl-t-butyl ether, and isopropyl acetate. If the coupling reaction is performed using DBU, the solvent used is acetonitrile.

The coupling reaction can be performed in a temperature range from about -10C to about 25C. Suitable temperatures for the coupling reaction range from about 0 ° C to about 10 ° C.

Process for the preparation of azetidinone (production method)
Is: It comprises the following steps: (a) Propionyloxyester: Benzyl paraben (benzyl 4-hydroxybenzoate)
With a base in a polar solvent to yield a benzyl ester of the formula: (B) hydrogenolysis of the benzyl ester with a metal catalyst or with a noble metal catalyst in the presence of cyclohexene to give ceramic acid: (C) In a solvent mixture, R-methylbenzylamine (R
-MBA) to react with racemic acid,
Crystalline R, R-MBA salt: And a mother liquor containing the S-acid: (D) the mother liquor S-acid is separated via filtration; (e) S-methylbenzylamine (S-
MBA) and the mother liquor S-acid to form a crystalline S, S-MBA salt: (F) separating the crystalline S, S-MBA salt via filtration; (g) recrystallizing the crystalline S, S-MBA salt using a solvent mixture; (h) inorganic in a water-organic solvent mixture. Recrystallized with strong acid S,
Decompose the S-MBA salt or the crystalline S, S-MBA salt to give the S-acid: (I) reacting the activator with the S acid to form an activated substrate in situ; (j) reacting N-methylpiperazine with the activated substrate to form azetidinone: (K) Recrystallization of azetidinone using a solvent selected from ethyl acetate, propyl acetate and isopropyl acetate.

In one embodiment of this method, is selected from the group base used in substitution step consists K ₂ CO ₃ and Cs ₂ CO _3. In another embodiment of this method, the polar solvent system used in the displacement step is aqueous acetonitrile or dimethylformamide (DM
Selected from the group consisting of F).

In another embodiment of the process for the preparation of azetidinone, polar solvent system used in the substitution reaction is aqueous acetonitrile, the base is Cs ₂ CO _3.

In another embodiment of the process for the preparation of azetidinone, the noble metal catalyst used in the hydrocracking step is selected from the group consisting of a palladium catalyst in the presence of cyclohexene or a palladium catalyst under a hydrogen atmosphere.

In another embodiment of the process for the preparation of azetidinone, the noble metal catalyst used in the hydrocracking step is palladium on carbon in the presence of cyclohexane.

In another embodiment of the process for the preparation of azetidinone, the solvent mixture used in the crystallization step to form the R, R-MBA salt is isopropanol: acetonitrile.

In another embodiment of the process for the preparation of azetidinone, the solvent mixture used in the crystallization step to form the R, R-MBA salt has a ratio of about 1: 2 to about 2: 1 of isopropanol: Acetonitrile.

In another embodiment of the process for the preparation of azetidinone, the solvent mixture used in the crystallization step to form the R, R-MBA salt is about a 1: 1 ratio of isopropanol: acetonitrile.

In another embodiment of the process for the preparation of azetidinone, the activator is dicyclohexylcarbodiimide.

In another embodiment of the process for the preparation of azetidinone, the activating substrate is reacted with N-methylpiperazine in the presence of the base 1-hydroxybenzotriazole hydrate.

In another embodiment of the process for the preparation of azetidinone, azetidinone is crystallized from isopropyl acetate.

The process for the preparation of isocyanates is (A) di-n-propyl zinc and bistrifluorosulfonamide-catalyzed complex of trans-R, R-1,2-diaminocyclohexene and titanium tetraisopropoxide to alkylate piperonal , Forming an S-alcohol; (B) reacting a solution of diphenylphosphoryl azide and a base with an S-alcohol in an organic solvent to produce R-azide; (C) reducing azide with a reducing agent (lithium aluminum hydride or triphenylphosphine) in an organic solvent,
Forming an R-amine; (D) predominant resolution of the R-amine using D-pyroglutamic acid in an organic solvent mixture to produce an R-amine-D-pyroglutamate having an enhanced enantiomeric excess; (e) Decomposing the R-amine-D-pyroglutamate with an inorganic base to form an enantiomerically enriched R-amine; (f) reacting the enantiomerically enriched R-amine with hydrochloric acid (G) reacting the phosgene in an aromatic solvent solution with R-amine hydrochloride in a dry aromatic solvent at a temperature from about 90 ° C. to about 105 ° C. to produce an isocyanate To form: In one embodiment of the process for the preparation of isocyanates, the base of the azide formation step is 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO), triethylamine, 4-dimethylaminopyridine (DMAP), quinuclidine, pentamethylpiperidine, 2-t-butyl-1,1,3,
3-tetramethylguanidine and pentamethylguanidine.

In one embodiment of the process for the preparation of the isocyanate, the solvent for the azide formation step is toluene, xylene, tetrahydrofuran, methyl-t-butyl ether, isopropyl acetate, and cyclohexane. In one embodiment of this embodiment of the process for the preparation of the isocyanate, when the base of the azide formation step is 1,8-diazabicyclo [5.4.0] undec-7-ene, the solvent is toluene.

In one embodiment of the process for the preparation of the isocyanate, the reducing agent of the azide reduction step is lithium aluminum hydride, sodium borohydride, triphenylphosphine and water or catalytic hydrocracking.

In one embodiment of the process for the preparation of the isocyanate, the solvent for the azide reduction step is 1: 1 tetrahydrofuran: toluene.

In one embodiment of the process for the preparation of the isocyanate, the split stage organic solvent mixture consists of a mixture of a first solvent and a second solvent.

In one embodiment of the process for the preparation of the isocyanate, the organic solvent mixture of the splitting step comprises a first solvent selected from the group consisting of isopropyl acetate or ethyl acetate.

In one embodiment of the process for the preparation of isocyanates, the organic solvent mixture of the splitting step is isopropanol,
It comprises a second solvent selected from the group consisting of ethanol or methanol.

In one embodiment of the process for the preparation of the isocyanate, the organic solvent mixture of the split stage consists of ethyl acetate: ethanol.

In one embodiment of the process for the preparation of the isocyanate, the ratio of the first solvent to the second solvent of the organic solvent mixture of the split stage consists of about 95: 5 ethyl acetate: ethanol.

In one embodiment of the process for the preparation of isocyanates, the inorganic base used in the decomposition step is NaOH, KOH, or Cs
Selected from the group consisting of CO ₃ .

In one embodiment of the process for the preparation of the isocyanate, the aromatic solvent used in the isocyanate production stage is selected from the group consisting of toluene, xylenes or chlorinated benzenes.

In one embodiment of the process for the preparation of isocyanate, the aromatic solvent used in the isocyanate production stage is toluene.

In one embodiment of the process for the preparation of isocyanate, the isocyanate formation step is performed at a temperature in the range of about 97 ° C to about 103 ° C.

One embodiment of a process for the preparation of compounds of the following formula: By successive resolution of a racemic mixture of the following formula using an ethanol-water solvent system: One embodiment of the present invention is a process for the preparation of a compound of the formula: The ketone of the following formula Reacting with a chiral borane reducing agent such as (R) -oxazaborolidine-borane complex.

Amide 4 is 18% according to the following sequence (see Scheme 1):
Synthesized in four steps with overall yield and 99.4% ee: Reaction of Cs ₂ CO ₃ at a is the 4-hydroxybenzoic acid benzyl mediated 3,3-dimethyl-4-propionyloxy-2-azetidinone; ester debenzylation Resolution with chiral methylbenzylamine to yield (S) -acid; and amide formation with N-methylpiperazine using DCC. Isocyanate 9 was prepared as follows (see Scheme 2) in 57% overall yield and 98.2% ee: n-Pr ₂ Z to piperonal
chiral addition of n; inversion of the resulting alcohol to azide with diphenylphosphoryl azide; reduction to amine with lithium aluminum hydride; upgrading of ee with D-pyroglutamate; and conversion to isocyanate with phosgene.

Although not described in Reaction Scheme 1, azetidinone 1
Was prepared by addition of chlorosulfonyl isocyanate (CSI) to 2,2-diethylvinyl propionate in the presence or absence of a solvent (eg, toluene) at t1 / 2 for about 8 hours. The use of the 4-propionyloxy group for the acetyl homologue series was supported by the instability of the former homologous series and the low yield resulting from its substitution. Other congeners, such as isobutyloxy, did not provide any yield advantage in the substitution reaction.

Replacement of the propionyloxy group was initially performed in the presence of potassium carbonate, a reaction requiring large amounts of β-lactam, but gave poor product yields. Switching to cesium carbonate in aqueous acetonitrile is a rapid displacement, β-
Low lactam hydrolysis and 3,3-diethyl-4-
(4'-benzyloxycarbonyl) phenoxy-2-
This led to high yields of azetidinone (benzyl ester 2). The method used to remove benzyl ester 2 was transfer hydrogenation, but additional noble metal catalyst and hydrogen could be used to produce racemic acid 3.

Experimenting with various resolving bases and solvents, (S)
The method chosen to provide the best recovery of the acid involved the initial removal of the (R) acid from isopropanol: acetonitrile. The use of insufficient (R) -methylbenzylamine (less than the stoichiometric amount of amine relative to the amount of (R-acid)) results in the initial formation and removal of the (R, R) -salt, Subsequent addition of a stoichiometric amount (based on the amount of (S) -enantiomer of acid) of methylbenzylamine results in a ratio of enantiomer of (S)-of 75:25 (S: R)- The enantiomer was provided. Recrystallization follows (S, S)
-Improved the purity of the MBA salt, giving 94-96% ee with 24% recovery. Each crystallization gives a mother liquor, which gives a 11: 1 mixture of enantiomers, which is reprocessed by resolution to give
A total (S) -acid 3- (4S) recovery of 7% (54% of available (S) -enantiomer) was provided.

DCC, H of (S) -acid 3- (4S) in isopropyl acetate
The reaction with OBT and N-methylpiperazine proceeded in 9595% yield, and the product amide 4 could be separated by recrystallization from the reaction mixture, following removal of dicyclohexylurea.
Although the recovery was low (66%), the enantiomeric excess of the product increased to> 99% during crystallization. Another solvent for crystallization is ethyl acetate or propyl acetate, but a preferred solvent is isopropyl acetate.

Another method for amide formation was studied with methanesulfonyl chloride (MsCl). With the use of tripropyl- or tributylamine, amide 4 was produced in> 90% yield (solution).

Racemic amide 4 was also prepared by replacement of β-lactam 1 with 4-hydroxybenzoic acid by N-methylpiperazinylamide. Attempts to resolve this material have yielded mixed crystalline salts with negligible differentiation.

In addition, benzyl ester 2 was found to be a racemic mixture by X-ray crystallography and thus could be resolved using a continuous resolution by suitable crystallization. Then, necessary S
The -benzyl ester was hydrogenated to give 3- (4S) acid, which reacted with DCC, HOBT and N-methylpiperazine in isopropyl acetate to give amide 4.

Successive resolution of the racemic mixture of benzyl ester 2
Dolling, UH, et al. J. Org.
m., Vol. 43, No. 9, pp. 1634 (1978). Resolution could be performed using an ethanol-water solvent mixture.

The isocyanate synthesis is described in Scheme 2 and begins with the Yoshioka method for enantioselective addition of a dialkyl zinc reagent to an aldehyde. [H.Takahashi, T.Kawaki
ta, M. Yoshioka, and M. Ohno, Tetrahedron Letters, 30, 7
095 (1989). In this method, trans- (R), (R)
A chiral complex prepared from bistrifluorosulfonamide (ditrifluamide) of 1,2-diaminocyclohexane and titanium tetraisopropoxide catalyzes the addition of di-n-propylzinc to piperonal 5. The reaction gave the product in excellent yield (98%) and optical purity (> 99% ee) without requiring any effort to modify the zinc reagent or catalyst equivalents used.

Azide 7 was prepared by treating a toluene solution of alcohol with diphenylphosphoryl azide, followed by DBU.
And prepared by co-workers. [A. Thompson, GH
umphrey, A.DeMarco, D.Mathre, E.Grabowski, J.Organic
Chemistry, 58, 5886 (1993) ..] The reaction proceeded via an intermediate phosphate ester observable by NMR. The product is about 65
After workup in% yield, it was obtained as a toluene solution. Some racemization occurred during the conversion of the piperonal-derived alcohol, resulting in an 85% azide enantiomeric excess (> 99% ee for alcohol 6).

The azide product, as an oil or in a solution of typical operating concentrations in toluene, is potentially impact sensitive and has a heat release in excess of 1200 cal / g. The first exotherm begins at about 50 ° C. As a result, agitation should be limited and operating temperatures should be carefully monitored and controlled.

Amine 8 was obtained from the azide in about 95% yield by reduction with lithium aluminum hydride in tetrahydrofuran. The aluminum salt formed in the post-reaction treatment was separated by quenching with a solution of Rochelle salt. The amine is produced by the reduction of excess (PhO) ₂ P (O) N ₃ (PhO) ₂ P
Separation from neutral by-products, including (O) NH ₂ , by extraction into dilute acid.

The azide was also reduced by triphenylphosphine to give phosphinimine, which was hydrolyzed to amine with aqueous NaOH. Although it was difficult to drive the hydrolysis completely, the product was obtained in lower purity than by LAH reduction. No other reduction methods were tested.

The optical purity of amine 8 is 20: 1 with D: EtOAc: EtOH.
Improved by crystallization of pyroglutamate. 85%
The amine 8 in ee gave 93% yield ((R)-
(Based on amines) increased to a height of 99.4%. The optical purity of the resolving amine is 98.0-99.4 depending on the conditions of the resolving.
% Ee range.

In the formation of isocyanate 9, amine 8 was first converted to the hydrochloride salt, which reacted with phosgene, but was not the desired product (isocyanate 9). In a laboratory scale reaction, three equivalents of phosgene were required to completely consume the amine. On a manufacturing scale, it is believed that the long addition time of the reagents (2 hours vs. 0.5 hours) required the use of a lot of reagents, although not much needed. The toluene solution of the product did not decompose during aqueous work-up, but a small amount of acidic carbonate catalyzed the decomposition of the oily concentrate into a mixture of amine and symmetric urea. Racemization of the chiral center did not occur at this stage.

Of Piperoniruketon (S) - oxazaborolidine - chiral reduction with borane complex _{[(S) -OAB-BH 3} ] Alternatively, (S) -alcohol 6 can be
(R) -oxazaborolidine-borane complex [(R) -OA
B-BH ₃ ] using chiral borane reduction of a ketone, α-propylpiperonyl ketone. Ketones are readily available starting materials from butyryl anhydride,
It could be prepared using a conventional Friedel Crafts acylation reaction of 3-benzodioxazole, or oxidation of racemic alcohol 6, available from conventional Grignard addition to piperanol. Chiral borane, such as that used in the above reaction scheme, was used to effect chiral reduction. Mathre, ENG GB
DJ, Thompson, AS, Douglas, AW, Hoogsteen, K., Carro
ll, JD, Corley, EG, Grabowski, EJJJOrg. Chem. 199
See 3,58,2880.

The coupling of β-lactam 4 with isocyanate 9 is described in Scheme 3. Coupling does not proceed without the addition of a base. Will powder K ₂ CO ₃ is used, generated symmetry urea 0.5～2.0A%, which the product was dissolved in a difficult impurities (but aqueous acetic acid removed during crystallization, Insoluble urea can be removed by filtration). The reaction with this base in the solvents acetonitrile (AcCN), toluene and methyl-t-butyl ether (MTBE) favors the unwanted isomers, 1.4% each,
It showed diastereoselectivity of 7.6% and 25%. The best way to avoid the formation of symmetric ureas was to use a catalytic amount of 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU) in acetonitrile. Other solvents (MTBE, i
The use of DBU in PrOAc) has not been as successful. [S- (R ^* , S ^* )]-N- [1- (1,3-benzodioxol-5-yl) butyl] -3,3-diethyl-2
-[4-[(4-Methyl-1-piperazinyl) -carbonyl] phenoxy] -4-oxo-1-azetidinecarboxamide was crystallized from MTBE for the final product.

[S- (R ^* , S ^* )]-N- [1- (1,3-benzodioxol-5-yl) butyl] -3,3-diethyl-2
-[4-[(4-Methyl-1-piperazinyl) carbonyl] phenoxy] -4-oxo-1-azetidine-carboxamide is silica gel 60, 230-400 mesh 50: 1.
Using the load, elution with EtOAc can be performed and chromatographic removal of the neutral components followed by EtOAc / MeOH / TEA88
Switch to / 10/2 to elute product and basic impurities.

The present invention can be further understood by the following examples, which do not limit the invention.

Example 1 3,3-Diethyl-4-[(4′-benzyloxycarbonyl) phenoxy] -2-azetidinone (2) Benzyl 4-hydroxybenzoate (acetonitrile: water (1: 1 v / v, 40 L)) Benzylparaben) (6.03Kg, 2
6.4 mol) and cesium carbonate (13 kg, 39.9 mol). The resulting biphasic mixture was heated to 30 ° C. 3,3-Diethyl-4-propionyloxy-2-azetidinone (7 kg, 35.2 mol) [Claus, K et al., Liebigs Ann. Chem., 19
74, p. 539] was added dropwise over 60 minutes while maintaining the temperature of the reaction mixture at 32 ± 3 ° C. The reaction mixture is 30-35
The mixture was aged by stirring at 90 ° C. for 90 minutes. 95% response at this point
Completed.

HPLC test Sample preparation: 1 ml reaction diluted to 250 mL with acetonitrile; Altex: Ultrasphere Octyl; 250 x 4.6 mm; 5 μ CH ₃ CN: H ₂ O each containing 0.1% H ₃ PO ₄ ; gradient elution 50:
254 nm, 25 ° C, 2.0 m from 50 to 90:10 over 30 minutes
L / min.

tR: product, 12.0 minutes; benzylparaben, 5.4 minutes.

After the reaction mixture was cooled to room temperature, water (19 L) and MTBE (1
9L) was added. The aqueous phase is separated and the organic phase is water (3 ×
19L). At this point, the batch was merged with a second batch (same size) and the merged batch (55 L) was concentrated to 20 L in vacuo (40 ° C., 28 inches of mercury).
It was then diluted with ethanol (10 L) and re-concentrated in vacuo. The batch was diluted to a volume of 57 L with ethanol (40 L) and tested by HPLC (see method above). 1
9 in two batches combined with 6.8 kg (295 g / L) ester
Obtained in 3% yield (based on benzylparaben). The benzyl ester could be crystallized from ethanol: water (1: 1). 78.5-80.9 ° C.

Example 2 3,3-Diethyl-4- (4'-carboxyphenoxy)
-2-azetidinone (3) Benzyl ester from Example 1 (23.7 L, 7.0 kg, 20.5
Mol) in ethanol was added cyclohexene (10 L) and 5% Pd / C (500 g). The reaction was stirred at reflux for 2 hours.

Two hours after the reaction test, 1 mL of the solution was diluted with CH ₃ CN to 100 mL,
Tested by PLC and showed less than 0.5 area% ester.

HPLC test: Altex Ultrashere Octyl; 250 × 4.6 mm; 5 μ CH ₃ CN: H ₂ O (each containing 0.1% H ₃ PO ₄ ); gradient elution from 50:50 to 90:10 over 30 minutes, 254 nm, 2
5 ° C, 2 mL / min.

tR: acid, 2.3 minutes; benzyl ester, 12.0 minutes.

The mixture was filtered through Solka-Floc (1 Kg) to remove the catalyst and the Solka-Floc cake was ethanol (2 × 1).
L). The ethanol solution was combined with a second batch (same size). The combined batch is vacuum (30 ° C, 29
(In inches of mercury) to a volume of 20 L. The concentrate was diluted with methyl-t-butyl ether (10 L) and re-concentrated in vacuo to a solid slurry. Methyl-t-butyl ether (10 L) was added and the product was filtered,
Washed with methyl-t-butyl ether (20 L) and dried with a stream of nitrogen to give 8.77 Kg of product in 82% yield. 168.5-170.7 ° C.

HPLC test: see above conditions 99.2 area%,> 99% by weight vs. the relevant standard Example 3 3,3-Diethyl-4S- (4'-carboxyphenoxy)
Azetidin-2-one-S-(-) α-methylbenzylammonium salt Step A: Crystallization of R, R diastereoisomer salt (3-R, R salt) Racemic acid from Example 2 (3.9 Kg, 14.8 mol) was dissolved in isopropanol: acetonitrile (1: 1, 70 L) at 70 ° C. R-(+)-α-methylbenzylamine (883m
L, 830 g, 6.85 mol, d = 0.940). The solution was cooled to room temperature over 4 hours and the slurry
Aged for 16 hours.

 Crystallization started spontaneously during cooling at 40-50 ° C.

R, R salt is filtered, iPrOH: CH ₃ CN: washed with (1 1,7L), and dried in a stream of nitrogen, 76: thick and requires the mother liquor as a 24 mixture (S) - enantiomer In the body, 1.88Kg (33
% Yield).

Chiral SFC HPLC test: Chiracel OD (H), 250 × 4.6 mm; 22% methanol (85
% HClO ₄ containing 0.1% by volume) moderator; 300 atm, 1.0 mL / min,
248 nm.

tR: (S) -acid, 7.6 min; (R) -acid, 9.5 min.

Step B: Crystallization of S, S Diastereoisomer Salt (3-S, S Salt) To the mother liquor from R, R salt crystallization (see above method)
(−)-Α-Methylbenzyl (850 mL) was added with stirring. The slurry was aged at room temperature for 16 hours. Crystallization begins immediately. Seeding was not required. The S, S salt was filtered, washed with 1: 1 iPrOH: CH ₃ CN (5 L) and dried with a stream of nitrogen to give the product as a wet cake.

Chiral SFC HPLC test: (see conditions cited in Example 3, Step A) Solid enantiomeric ratio: S: R = 77: 23 Step C: Recrystallization of (S, S) salt isopropanol: acetonitrile ( 1: 1, 80L)
The S, S diastereoisomer salt was added. The slurry was heated at reflux to obtain a clear solution, then cooled to room temperature over 6 hours and aged at room temperature for 16 hours. Crystallization began to occur during the cooling at 40-50 ° C. and no seeding was necessary. The (S, S) salt was filtered and 1: 1 iPrOH: CH ₃ CN (6
L), dried with a stream of nitrogen, and solid (1.2 kg,
21.5% yield from racemic acid).

Chiral SFC HPLC test (see conditions cited in Example 3, Step A) Enantiomeric ratio: S: R = 98.2: 1.8 (96.4% ee).

The resolving method is repeated using 4.8 kg of racemic acid and 1.7 kg
(24% yield) of the S, S-diastereoisomer salt.

Chiral SFC HPLC test: (see conditions quoted in Example 3, Step A) Enantiomeric ratio: S: R = 97.3: 2.7 (94.6% ee) Step D: Recrystallization of secondary crop From above method All mother liquors and cake washes were combined (enantiomeric ratio = 1: 1) and concentrated in vacuo (30 ° C., 29 inches of mercury) to a volume of 10 L. The concentrate is iPrOAc
(10 L), re-concentrated, and diluted again with iPrOAc (20 L). Water was added, pH of the aqueous phase with 85% H ₃ PO ₄ 2.0
Was adjusted to. The phases were separated and the organic phase was washed with water (5L). The organic layer was concentrated under vacuum (30 ° C., 29 inches of mercury) to a concentration of 4 L. The batch is diluted with MTBE (4L),
Concentrated in vacuo to a crystalline slurry, which is MTBE (8
L), filtered, washed with MTBE (1 L) and dried with a stream of nitrogen to give 1.7 Kg of racemic acid. The above resolution was repeated to give 502 g of purified S, S-diastereoisomer salt.

SFC chiral HPLC test: (see examples, conditions cited in step A) Enantiomeric ratio: S: R = 98.05: 1.95 (96.1% ee) This resolution method is 3.4% in 27% overall yield from racemic acid. Kg S, S
Diastereoisomeric salts were prepared.

Example 4 3,3-Diethyl-4S-[(4'-N-methylpiperazinylcarboxamide) phenoxy] -2-azetidinone (4) Resolving acid-MBA salt from Example 3, Steps C and / or D (3.30 Kg, 8.58 mol, 96% ee) was suspended in isopropyl acetate (30 L) in a 100 L reactor and equipped with a pH electrode.
Water (1 L) is added and the mixture is kept at 25 ° C. with 1N
Until aqueous H ₃ PO ₄ solution (total volume = 11.8 L) is dissolved total solids (~7L, pH = 3.4) is added dropwise, a constant pH of 2.0 was achieved. NaCl (1.0Kg) was added (Note: it was added dropwise to 1.75)
pH), the phases were separated. The iPrOAc solution was concentrated in vacuo to 1616 L (KF = 〜8 mg / mL), where the acid began to crystallize. Dry iPrOAc (10 L) was added and vacuum distillation continued. After a second loading of iPrOAc (10 L) and concentration in vacuo, the KF of the solution = 0.4 mg / mL. The mixture is warmed to 55 ° C,
N-methylpiperazine (1.05 Kg) was added.

Hydroxybenzotriazole hydrate (HOBT) (146
g, 1.08 mol) was added, followed by a solution of dicyclohexylcarbodiimide (DCC) (2.97 Kg, 14.4 mol) in iPrOAc (3 L) over 5 minutes. Reaction temperature is 48
Adjusted to -50 ° C, aged for 1.5 hours, HPL as described below
Monitored at C.

Reaction test: A 10 mL sample of the reaction mixture was CH ₃ CN (10 mL) and 0.1% H ₃
Diluted to 100 mL with PO ₄ (90 mL), tested by HPLC,
It was shown to be less than 5 area% acid.

HPLC test: Inertsil C8, 250 × 4.6 mm; 5 μ; CH ₃ CN: H ₂ O (0.1% H ₃ PO ₄
Gradient elution: from 3:97 to 80:20 over 20 minutes,
248 nm, 25 ° C, 2.0 mL / min.

tR: amide, 7.9 min; acid, 14.2 min.

The reaction mixture was cooled to 18 ° C. and filtered. The cake was washed with iPrOAc (3 L) and the filtrate (19.5 L) was concentrated in vacuo to a volume of 8-9 L (amide concentration was 25-30% by weight).

Crystallization began during the distillation (internal temperature dropped to ５5 ° C.). The mixture is aged at 18 ° C for 18 hours, then at 10 ° C
And aged for 2 hours. The mixture is filtered and
Washed with cold iPrOAc (3 L). Cake is 40 in a stream of nitrogen
After drying for hours, the product (1.98K
g, 99.5 area%, 66% separation yield). 8 mother liquor losses
The amount was 50 g (crystallization recovery = 70%, reaction yield = 94%).
Chiral SFC testing showed that crystallization concentrated the (S) -enantiomer (solid: 99.4% ee; mother liquor: 87.2% e.
e.). 117.5-120.7 ° C.

HPLC test (conditions quoted above) SFC chiral HPLC test: Chiralcel OD (H), 250 x 4.6 mm: 20% methanol (0.
1% TEA) modulator; 1.0 mL / min, 300 bar, 248 nm.

tR: (S) -enantiomer, 7.3 min; (R) -enantiomer,
10.1 minutes.

Example 5 α-Propyl piperonyl alcohol (6) Dry toluene (1.25 L) and (R, R) -diene in a 3 L three-neck flask equipped with a mechanical stirrer, N ₂ feed port, and stopper under N _2. −
Trifluamide (29.6 g, 0.078 mol) was charged. Isopropoxy titanium (IV) (226 mL, 0.74 mol, d = 0.95
5) was charged to a graduated pressure-regulating addition funnel in a nitrogen glove bag and added to the di-trifluamide slurry once at room temperature. The addition funnel was replaced with a septum and thermocouple, and the mixture was heated to 40 ° C for 20 minutes, then 20 ° C
Cooled down.

A 22 L four-necked flask equipped with a mechanical stirrer, N ₂ feed, thermocouple, and addition funnel was charged with dry hexane (5.6 L) under N ₂ and then cooled to 0 ° C. The addition funnel was replaced with a septum. n-Pr ₂ Zn (850 g, 5.60 mol, d = 1.0
8) The contents of two metal cylinders, each containing about one pound, were transferred to hexane with a cannula and nitrogen pressure. The cannula was washed with hexane (20 mL). Solution is -5
Cooled to ° C.

The titanium catalyst mixture is directly exposed to the cannula and nitrogen pressure.
Transferred to L flask (addition was exothermic).

Mechanical stirrer, N ₂ inlet, and 5L three-necked flask equipped with a septum was charged with piperonal under N ₂ (619 g) and dry toluene (1.9 L).

The septum of the 22L flask was replaced with an addition funnel. The piperonal solution was added to the addition funnel with a cannula and nitrogen pressure, and then slowly (approximately 20 minutes) to the contents of the flask, maintaining a temperature of -5 to -2 ° C. The mixture is stirred at −2 to 0 ° C. for 2-4 hours, then HPLC
Showed <1% piperonal.

HPLC Test: Zorbax Phenyl, 250 × 4.6mm, 5m, 210nm, CH 3 CN: 0.1%
H ₃ PO _4, gradient: t = 0 minutes 50: 50, t = 18 minutes 90: 10,1.0ml
Per minute.

tR: alcohol, 5.8 min; piperonal, 3.8 min; toluene, 7.7 min; ether dimer, 16.1 min.

The reaction was maintained at 0-5 ° C with cold 2N HCl (8.8
It was quenched by the slow addition of L). The addition of 2N HCl was initially very exothermic.

The mixture was transferred to a 50 L extraction vessel and the layers were separated. The acidic aqueous layer was extracted with a mixture of hexane (1L) and toluene (1L). The layers are separated, the organic layers are combined and the water (1.
Extracted with a solution of NaHCO ₃ (100 g) in 5 L) and water (1.5 L)
A solution of NaCl (150 g) in was followed. The organic layer is Na ₂ SO ₄ (70
0 g) and filtered. The filtrate was stored at 0-5 ° C. The enantiomeric purity of the product was 99.2% ee.

Optical purity was determined for aliquots of the product solution by HPLC using the following method.

HPLC test: Chiralcel-OD, 250 x 4.6 mm, 280 nm, IPA: hexane, isocratic 7.5: 92.5, 1.5 ml / min.

tR: (R) -isomer, 5.3 minutes; (S) -isomer, 7.5 minutes.

Example 6 (R) -α-propylpiperonyl azide (7) A 50 L multi-neck reaction vessel was equipped with a mechanical stirrer, nitrogen inlet, thermocouple, glycol cooling, and an addition funnel. 1.20
The volume of the solution of the alcohol product from Example 5 above, corresponding to Kg or 6.2 moles of alcohol, was concentrated to about 6 L using a Buchi rotary evaporator. The concentrate was charged to a 50 L reaction vessel. 12L dry toluene volume
And the solution was cooled to 5 ° C.

Diphenyl phosphoryl azide (1.60 L, 7.42 mol, d
= 1.277) was charged to a 2 L pressure-regulating addition funnel and then added to the alcohol. The addition funnel was washed with toluene (0.3 L). When the addition is complete, 1.11 L (7.42 mol)
1,8-diazabicyclo [5.4.0] undec-7-ene (DB
U) was charged to the addition funnel and added to the reaction mixture at a rate to maintain a temperature of ≦ 5 ° C. The funnel is toluene (0.1
L).

Upon completion of the addition, the reaction was warmed to room temperature over 2-3 hours. The traveling wave of the reaction was monitored by HPLC using the conditions quoted below. [Note: Azides and azide solutions are shock-sensitive and undergo an exothermic decomposition at about 50 ° C. HPLC conditions: Inertsil Phenyl, 250 × 4.6 mm; 5 μ; 210 mm; CH ₃ CN: 0.1%
H ₃ PO _4, gradient: t = 0 minutes 50: 50, t = 8 minutes 90: 10,1.0ml
Per minute.

tR: α-propyl-piperonyl alcohol, 5.9 minutes; toluene, 7.8 minutes; (PhO) ₂ P (O) N ₃ , 9.3 minutes; olefin by-product, 10.6 minutes; α-propyl-piperonyl azide, 1
1.4 minutes.

The reaction was stirred for 16 hours at room temperature, at which point the reaction was complete. The two liquid phases were diluted with water (7L) and separated. The lower aqueous layer was extracted with toluene (1L). The combined organic extracts were water (7L), cold 1N HCl (4L), water (4L),
And 10% NaCl (4 L). Organic layer is anhydrous
Dried Na ₂ SO ₄ 1-2 hours (700 g), and filtered. The cake was washed with toluene (2 × 0.2 L). The filtrate and washings were combined and used in the next step.

Example 7 (R) -α-Propyl-piperonylamine (8) A 50 L multi-neck reaction vessel equipped with a mechanical stirrer, N ₂ feed, thermocouple, glycol cooling, and addition funnel was dried under N ₂ in THF.
(6.3 L) and the solvent was cooled to about 10 ° C. A solution of 1 M lithium aluminum hydride in toluene (6.0 L, 6.0 mol) was transferred from the metal container to the addition funnel,
Added to F. The azide solution from Example 6 above (1.3
6Kg, 6.20 mol, about 12L) is charged into the addition funnel at once,
LA for 1-2 hours at a rate that maintains a temperature of 23 ± 2 ° C
Added to H. Upon completion of the addition, the reaction was aged until gas evolution ceased. The addition was a mild exotherm.
N ₂ evolution lasted about 6 hours.

The reaction mixture is cooled to 0 ° C. and excess LAH is ≦ 5 ° C.
Quenched by the slow addition of water (400 mL) while maintaining the temperature. A solution of potassium sodium tartrate (8.5 kg) in water (40 L) was prepared in a 200 L extraction vessel, two liters were added to the reaction mixture, and another 6 L was reserved for washing. The reaction mixture was transferred to a 200 L vessel and the vessel was washed with 6 L of the washing solution. The wash was added to the vessel and the mixture was stirred at room temperature for 16 hours.

Upon dissolution of the aluminum salt, the two liquid layers were separated. The lower aqueous layer was extracted with toluene (2L). The combined organic extracts were washed with water (7L). The product is then 7L
Extracted with cold 1N HCl. The aqueous solution is adjusted to pH 13 with the addition of a solution of NaOH (300 g) in
Adjusted to -14. The mixture was extracted with toluene (4L), and the toluene was washed with 10% NaCl (4L). The organic layer was dried with anhydrous Na ₂ SO ₄ (500 g). The mixture is filtered and
The filtrate was concentrated to an oil. Weight: 740 g (57% yield of R-isomer in two steps, 85% ee) HPLC test: Inertsil ODS-2, 250 × 4.6 mm, 5μ; 230 nm; CH ₃ CN: 10
mM pH 6.5 potassium phosphate buffer: MeOH; gradient t = 0 min at 36:
60: 6, 64: 30: 6 at t = 12 minutes, 67: 27: 6 at t = 18 minutes, t = 19
74: 20: 6 min, 74: 20: 6 at t = 25 min; 1.0 ml / min; 30 ° C. tR: amine, 5.0 min; ethyl homologue, 4.3 min; toluene, 1
4.7 minutes.

The ratio of enantiomers was determined directly by any of the two HPLC method: HPLC Conditions: Chiralcel OD-R, 250 × 4.6mm, 238nm, CH 3
CN: 0.1% HClO ₄ ; isocratic: 15:85; 1.0 ml / min; 23 ° C.

tR: (R) -isomer, 7.3 minutes; (S) -isomer, 15.0
Minutes.

SFC HPLC: Chiracel OD (H); 250 x 4.6 mm; 238 nm: 22%
MeOH modifier (containing 0.1% by volume of 70% HClO ₄ ); 1 mL / min; 35
° C, 300 bar tR: (R) -isomer, 6.1 min; (S) -isomer, 8.8 min.

Example 8 Optical Purification of (R) -α-propylpiperonylamine (8) A 50 L reaction vessel equipped with a mechanical stirrer, N ₂ feed port, and thermocouple was dried under N ₂ with EtOAc (30.5 L), EtOH (1.5L, 100
%), And α-propylpiperonylamine from Example 7 (1.523 Kg, 7.88 mol). The solution is 50-55
Heated to ° C. A charge of D-pyroglutamic acid of about 15% (150 g in 919 g, 7.12 mol) was added and the solution was seeded with amine / pyroglutamate (5 g). The balance of solid D-pyroglutamic acid was added in one portion over 30 minutes as the salt crystallized. The mixture takes 20 to 2-3 hours.
Cooled to −22 ° C. and stirred at that temperature for 16 hours.

The slurry is filtered and the cake is made up of EtOAc (5 L) and EtOH
(0.25 L) of the mixture. The cake is toluene (6
L) and a cold aqueous solution of NaOH (378 g) in water (15 L). The layers were separated and the toluene layer was 10% NaCl
(3L) extracted. The organic layer was dried with anhydrous Na ₂ SO ₄ (500 g). The mixture was filtered and the filtrate was concentrated in oil.
Weight: 1.315 kg (92% yield of available R-isomer, 98.2
% Ee).

The product will be analyzed by HPLC using the following method: HPLC test: Inertsil ODS-2; 250 × 4.6 mm; 5μ; 210 nm; CH ₃ CN: 10 mM pH
6.5 Potassium phosphate buffer: MeOH; gradient t = 0 min at 36:60:
6, 64: 30: 6 at t = 12 minutes, 67: 27: 6 at t = 18 minutes, 74: 20: 6 at t = 19 minutes, 74: 20: 6 at t = 25 minutes, 1.0 ml / min , 30 ° C.

tR: α-propylpiperonylamine, 5.1 min; ethyl homologue, 4.3 min; toluene, 14.7 min.

The enantiomeric ratio is also determined by HPLC as follows: HPLC conditions: Chiralcel OD-R, 250 × 4.6 mm, CH ₃ CN: 0.1% HClO ₄ ; isocratic 15:85; 1.0 ml / min; 23 C, 238 nm tR: (R) -isomer, 7.3 minutes; (S) -isomer, 15.0 minutes.

SFC HPLC: Chiralcel OD (H); 250 × 4.6 mm; 238 nm: 22% MeOH modifier (containing 0.1% by volume of 70% HClO ₄ ); 1 mL / min; 35 ° C., 300 bar tR: (R) -isomer , 6.1 min; (S) -isomer, 8.8 min.

Example 9 (R) -α-propylpiperonyl isocyanate (9) equipped with a mechanical stirrer, N ₂ supply port, thermocouple, Dean Stark trap, reflux condenser, CaCl ₂ drying tower, and vapor trap for phosgene 50L reaction vessel under N ₂ toluene (24L)
And α-propylpiperonylamine (1.186 kg, 6.14 mol). To the solution was added 12N HCl (582 mL, 6.75 mol) over 5-10 minutes.

The mixture was heated to reflux and water was removed azeotropically. When the new effluent becomes clear, additional toluene (2.
4L) was drained to further dry the system. The mixture was then cooled to 100 ° C. The Dean-Stark trap was replaced with an addition funnel. A solution of phosgene in toluene (9.
54L, 18.4 moles) was added over 1 hour while maintaining a temperature of 100 ° C. The solution was heated at 100.degree. C. for an additional 20 minutes and then cooled to 0.degree.

The solution is analyzed by HPLC. If there was unreacted amine, the mixture had to be reheated to 100 ° C. and additional phosgene was added. The presence of unreacted amine was also indicated by the formation of a solid upon cooling of the reaction solution.

HPLC test: Inertsil ODS-2, 250 × 4.6 mm; 5 μ, 210 nm; CH ₃ CN; 10 m
MpH 6.5 potassium phosphate buffer: MeOH; gradient 64: 30: 6, 1.0
ml / min.

tR: amine, 4.9 min; isocyanate, 10.4 min; ethyl homologue, 7.8 min; symmetric urea, 6.5 min; toluene, 7.2 min.

The cold reaction solution was extracted once with 5% NaHCO ₃ (1 × 18 L, 2 × 9 L). The toluene layer was washed with water (2 × 9 L) and then dried over anhydrous Na ₂ SO ₄ (2.4 kg). The mixture was filtered and the filtrate was concentrated to an oil. Product weight is 1.346kg
(> 98% yield). HPLC showed 0.3 area% amine and some residual toluene.

Example 10 [S- (R ^* , S ^* )]-N- [1- (1,3-benzodioxol-5-yl) butyl] -3,3-diethyl-2-
[4-[(4-Methyl-1-piperazinyl) carbonyl] phenoxy] -4-oxo-1-azetidinecarboxamide (I) Step A: [S- (R ^* , S ^* )]-N- [1- (1,3-benzodioxol-5-yl) butyl] -3,3-diethyl-2- [4-[(4-methyl-1-piperazinyl) carbonyl] phenoxy] -4-oxo-1-azeti Preparation of Zincarboxamide (S) -β in acetonitrile (23.5 L, 5.12 mol)
-Lactam piperazinylamine 4 (1.77 kg) and (R)
A slurry of -1- (3,4 methylenedioxyphenyl) butyl isocyanate 9 (1.12 kg, 5.11 mol) was cooled to 4 ° C. under nitrogen. DBU (76 g, 0.50 mol) dissolved in acetonitrile (0.5 L) was added to the mixture over 1 minute with cooling.

Addition of the intermediate of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) to the mixture exothermed at 6 ° C. within 1.5 minutes, at which point the reaction was 99% complete. After two minutes,
The batch began to cool and reached 5 ° C. after 20 minutes. This process yielded <0.2% symmetric urea by-product from the isocyanate, had <0.5% β-lactam starting material residue, and required the use of only stoichiometric proportions of the intermediate. Testing of the homogeneous reaction solution gave a 98% yield of the title product.

HPLC test: 20 μl of the mixture was diluted to 5 mL with acetonitrile.

Inertsil C8, 250 x 4.6 mm; acetonitrile: water (0.1%
HClO ₄ ), gradient: from 25:75 to 100: 0 over 20 minutes; 2.0
mL / min, 230 nm, 25 ° C. tR: β-lactampiperazinylamide, 3.6 min; title compound, 9.8 min; urea, 12.5 min; isocyanate, 13.8 min.

The mixture was aged for a total of 60 minutes, then water (100 L, 1
Wt% sodium chloride) and iPrOAc (50 L). The organic phase is water (2 × 20
L, containing 1% by weight of sodium chloride) and saturated with aqueous sodium chloride solution. Organic phase in vacuum 40
Concentrated to 1 L, diluted with iPrOAc (20 L), dried the solution and re-concentrated to remove acetonitrile. HP
LC tests showed that no material loss occurred.

HPLC test: Inertsil C8, 250 × 4.6 mm, 20 μl of the mixture diluted to 5 mL with acetonitrile; acetonitrile: water (0.1%
HClO ₄ ) Gradient: 2.0 mL from 1:99 to 100: 0 over 20 minutes
/ Min, 230 nm, 25 ° C tR: DBU, 5.4 min; iPrOAc, 9.7 min; title product, 13.3 min.

The iPrOAc solution was filtered through a 5μ line filter into a 20 L round bottom flask and concentrated in vacuo to 66 L. The concentrate was diluted with MTBE (4 L), re-concentrated and diluted with MTBE (4 L). After dilution to a total volume of 11 L, the mixture is
Aged for hours.

The batch was heated to reflux under N _2, it was dissolved completely product. Upon cooling, the product crystallized rapidly at 4747 ° C. Cooling was continued to 0 ° C. The batch was aged for 1 hour and then filtered. Cake (cake volume = 5.
(0 L) was washed with cold (−10 ° C.) MTBE (6 L) and dried at room temperature with a stream of nitrogen for 18 hours to give 2.25 Kg of the title compound. The title compound is 99.6 area% pure, and ~ 0.2% by weight MTB
Tested by NMR with E. Chiral SFC-HPLC tests indicated that only one diastereomer was present. Particle size was determined to be 95% <128μ. Melting point = 117.5-118.8
° C.

HPLC test: Inertsil ODS-2 (250 × 4.6 mm) CH ₃ CN: 10 mm pH 6.5 Potassium phosphate buffer: CH ₃ OH 64: 30: 6,
Isocratic; 1.0 mL / min, 210 nm, 25 ° C. tR: urea, 6.50 min; ethyl homologue, 7.46 min; diastereoisomer, 9.72 min; title compound, 10.49 min.

SFC chiral HPLC test: Chiralcel OD (H), 250 × 4.6 mm, methanol (0.1%
Modulator with TEA, gradient (from 8% to 32%, speed: 1%
/ Min) 30 min, 300 bar, 1.0 mL / min, 35 ° C, 230 nm.

tR: symmetric urea, 0.30 min; (R, R) -diastereoisomer, 11.65 min; (R, S) -diastereoisomer, 12.19
Min; (S, S) of the title compound, 14.76 min; (S, S) diastereoisomer, 20.37 min.

Step B: [S- (R ^* , S ^* )]-N- [1- (1,3-benzodioxol-5-yl) butyl] -3,3-diethyl-2- [4-[( 4-methyl-1-piperazinyl) carbonyl] phenoxy] -4-oxo-1-azetidinecarboxamide (I) [S- (R ^* , S ^* )]-N- [1- (1,3-benzodioxy) Sole-5-yl) butyl] -3,3-diethyl-2
-[4-[(4-Methyl-1-piperazinyl) carbonyl] phenoxy] -4-oxo-1-azetidinecarboxamide (2.2 Kg) in 2 L of cold water (QC deionized, filtered through a 5μ in-line filter). 300-400g
Waring with 1 gallon jacket while cooling with ice water to keep the internal temperature of ~ 20-25 ° C
It was mixed in a commercial mixer.

[S- (R ^* , S ^* )]-N- [1-
(1,3-benzodioxol-5-yl) butyl] -3,3
-Diethyl-2- [4-[(4-methyl-1-piperazinyl) -carbonyl] phenoxy] -4-oxo-1-
A portion of the azetidine carboxamide was transferred to a 22 L RB flask, cooled and stirred. With the addition of the last portion of the wet-milled title compound, the mixture was stirred for 分 間 30 minutes and then filtered. The wet cake was transferred to two Pyrex drying dishes and dried in vacuum (Hull Dryer, 25
Inch vacuum, nitrogen sweep at 25 ° C). Periodically, samples were removed to determine weight loss and the bottom of the Hull Dryer dish was briefly warmed to 40-45 ° C and then allowed to cool. Dried title compound (2.05 Kg) was packaged with a particle size of 95% <28μ; HPLC test: 99.3 area%; NMR: ~ 0.2 wt% MTB
E.

HPLC test: Inertsil ODS-2,250 × 4.6 mm; CH ₃ CN: water (20 mM TEA + H
OAc pH 4.5); 1.5 mL / min; 25 ° C, 230 nm tR: ethyl homologue, 8.06 min; title compound, 12.16 min.

Example 11 3,3-Diethyl-4S-[(4'-benzyloxycarbonyl) phenoxy] -2-azetidinone (2) The product of Example 1 was obtained from Dolling, UH et al., J. Org. Chem.,
Vol. 43, No. 9, pp. 1634 (1978), and can be resolved using any suitable crystallization method, such as the citation included therein.

Example 12 3,3-Diethyl-4S- (4'-carboxyphenoxy)
-2-Azetidinone (3) To a solution of the benzyl ester from Example 11 in ethanol (23.7 L of solution, 7.0 kg, 20.5 mol) is added cyclohexane (10 L) and 5% Pd / C (500 g). The reaction was stirred at reflux for 2 hours. The title product can be separated as described in Example 2.

Example 13 3,3-Diethyl-4S-[(4'-N-methylpiperazinylcarboxamide) phenoxy) -2-azetidinone (4) Using the product of Example 12 according to the method described in Example 4. To prepare the title product.

Example 14 (R) -α-propylpiperonyl alcohol (S) -OAB-BH _{3 in} methylene chloride (3 mL) (400 mg,
1.37 mmol) was cooled to -20 ° C. Α-propyl piperonyl ketone (192 in methylene chloride (5 mL)
mg, 1.00 mmol) was added dropwise over 45 minutes. The mixture was aged for 30 minutes and then the reaction was quenched by the addition of methanol (1 mL). After aging overnight, the solution should be 1
Washed with volume% acetic acid then evaporated to an oil. Chiral SFC-HPLC test (Chiralpak AD, 8% by volume methanol, 300 bar, 1.0 mL / min, 35 ° C .; tR (min): (S) -enantiomer, 8.1; (R) -enantiomer, 9.9) Is 97.5% e.
e. was achieved in favor of the (R) -enantiomer.

────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kuvetovitz, Raymond United States, New Jersey 07065, Lowway, East Linkane Avenue avenue 126 (72) Inventor Hartner, Frederiks United States, New Jersey 07065, Lowway, East Linkane Avenue, 126 (56) References JP-A-6-329625 (JP, A) JP-A-5-194501 (JP, A) JP-A-6-263723 (JP, A) United States U.S. Pat. No. 5,489,838 (US, A) U.S. Pat. Org. Chem. 43, no. 9 (1978) p. 1634-1640 Tetrahedron Asymm entry, Vol. 5, No. 2 (1994) p. 165-168 Tetrahedron Letters, Vol. 30, No. 50 (1989) p. 7095-7098 (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 405/12 CA (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. The method according to claim 1, wherein the base is 1,8-diazabicyclo [5.4.0] undec-7-ene or 1,5-diazabicyclo [4.3.0] non-5 in a temperature range from -10 ° C. to about 25 ° C. An isocyanate in the presence of a catalytic amount of a base, and a solvent, which is an ene: Azetidinone: And coupling: Manufacturing method. 2. The method according to claim 1, wherein the amount of the base ranges from about 1 mol% to about 100 mol%. 3. A catalyst comprising from about 5 mol% to about 25 mol% of a base.
The method of claim 1, wherein 4. The method according to claim 3, wherein the solvent is selected from the group consisting of acetonitrile, toluene, methyl-t-butyl ether, and isopropyl acetate. 5. The method according to claim 4, wherein the solvent is acetonitrile. 6. The method according to claim 5, wherein the catalytic amount of the base is about 10 mole% of 1,8-diazabicyclo [5.4.0] undec-7-ene and the solvent is acetonitrile. 7. A temperature range from about 0 ° C. to about 10 ° C.
The method of claim 6.