WO1988000941A1

WO1988000941A1 - ASYMETRIC SYNTHESIS OF ENANTIOMERICALLY PURE MONOCLYCLIC beta-LACTAM INTERMEDIATES

Info

Publication number: WO1988000941A1
Application number: PCT/US1987/001684
Authority: WO
Inventors: Richard C. Thomas
Original assignee: The Upjohn Company
Priority date: 1986-08-08
Filing date: 1987-07-22
Publication date: 1988-02-11
Also published as: EP0316360A1; AU7855787A; JPH01503625A

Abstract

Monocyclic beta-lactam intermediates and process for their preparation. The compounds of the present invention are of formula (I), and are useful as intermediate for preparing highly active C-4 substituted monobactams.

Description

ASYMMETRIC SYNTHESIS OF ENANTIOMERICALLY PURE MONOCYCLIC β-LACTAM INTERMEDIATES FIELD OF INVENTION

This invention concerns enantiomerically pure monocyclic β-lactam intermediates and a process for preparing them. INFORMATION DISCLOSURE

C-4-hydroxymethyl-azetidinones and their use to synthesize antibacterial monobactams are known in the art. The compound (3S,4S)-3-tert-butoxycarbonylamino-4-hydroxymethyl-azetidin-2-one and its use as an intermediate for the synthesis of antibacterial monobactams is disclosed in E.P. 76,758. See also Chem. Abst. 99(13):105052r. The compound (3S,4S)-3-benzyloxycarbonylamino-4- hydroxymethyl-azetidin-2-one is disclosed in E.P. 93,376 and E.P. 144,840. Also, see J. Antibiotics, 38:346-371 (1985) and Evans et al., Tetrahedron Lett., 26:3783-3786 (1985).

Annelation at -20ºC of a triphenylsilyl ether derivative with a Dane salt from glycine, triethylamine and ethyl chloroformate led in 50-60% yield to an optically active cis-β-lactam. A.K. Bose et al., Tetrahedron Lett., 26:33-36 (1985). G. Teutsch and A. Bonnett, Tetrahedron Lett., 25:1561-1562 (1984), describes the enantioselective synthesis of a 4-flύoromethyl- azetidinone based on the cycloaddition reaction of phthalimidoacetyl- chloride with a chiral imine of fluoroacetaldehyde.

The tert-butyl-dimethylsilyl derivative of L-serine methyl ester hydrochloride was transformed to its cinnamyl Schiff base, which upon reaction with azidoacetyl chloride and triethylamine in methylene chloride at -10°C gave the desired β-lactam in 50% yield. G. Just and T. Liak, Can. J. Chem., 56:211-217 (1978).

Starting from D-threonine, S.M. Tenneson and B. Belleau, Can. J. Chem., 58:1605-1607 (1980), accomplished an asymmetric synthesis of the dextrorotatory bioactive enantiomer of 3-methyl-7-phenylaceta- mido-0-2-isocephem. The key step, where asymmetric cycloaddition of azidoacetyl chloride to the cinnamylidene Schiff base of protected Dthreonine is induced, generates the desired cis-β-lactam in 90% optical yield.

The application of 4-phenyloxazolidylacetyl chloride in the Stauditiger reaction provided a synthetic route to homochiral cisfused azetidinones. D.A. Evans and E.B. Sjogren, Tetrahedron Lett., 26:3783-3786 (1985).

C. Hubschwerlen and G. Schmid, Helv. Chim. Acta., 66:2206-2209 (1983), observed complete diastereoselectivity during the cyclocon¬densation of activated glycine derivatives with aldimines derived from L-(S)-glyceraldehyde acetonide to yield 3 ,4-cis-β-lactams.

E.P. 96,296 (Hoffman LaRoche) discloses 3-imino-acetamido- azetidinone-1-sulphonic acid derivatives with broad spectrum antibacterial activity and the synthesis thereof.

In E.P. 144,840 (Takeda) discloses new optically active 3-amino1,4-disubstituted-2-azetidinones which preferably have a phthalimido or benzyloxycarbonylamino group at the 3-position, a styryl group at the 4-positIoh and an ester or amide group, derived from an optically active α-amino acid, at the 1-position. These compounds are useful as intermediates in the synthesis of β-lactam antibiotics. E.P. 144,840 also discloses a method of producing these compounds, which uses chiral amino acids as the source of asymmetry.

Derwent Basic Abstract, Accession Number 84-057614, discloses β- lactam derivatives as intermediates for antimicrobials which may have a lower 2-alkenyl, -CH₂-CHO or -CH=CH-amino at the 1-position, a phthalimido group at the 3-position and a styryl group at the 4- position.

Derwent Basic Abstract, Accession Number 43419Y, discloses intermediates for antimicrobial (acyl)amino azetidinones which may have a carboxyl function or ester thereof at the 1-position and a styryl group at the 4-position.

Derwent Basic Abstract, Accession Number 25257Y, discloses antibacterial azetidinones with a carboxyalk(en)yl side chain at the 1-position and an aryl, aralkenyl or nucleophile group at the 4- position. Derwent Basic Abstract, Accession Number 85-128883, discloses azetidin-2-one derivatives which are useful as intermediates and which may have a carboxyl function, or ester thereof at the 1-position and an acyloxy group at the 4-position.

SUMMARY OF THE INVENTION The present invention particularly provides: A compound having the formula I wherein R₃ is tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Cbz) and R₂ is hydrogen; or wherein -N(R₂) (R₃) is phthalimido ; wherein R₄ is

(a) -CH=CH-C₆H₅ , or

(b) -CH₂OH; wherein Ph is phenyl.

A process for preparing a compound of formula II wherein R₅ is tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Cbz) and R₆ is hydrogen; or wherein -N(R₅)(R₆) is phthalimido; wherein Ph is phenyl; which comprises:

(a) reacting a Dane salt of formula VI with a (C₁-C₄) alkyl chloroformate and a base;

(b) reacting R- (+) -α-methylbenzylaine and cinnamaldehyde and removing the liberated water from the mixture;

(c) reacting the mixture of step (a) with the mixture of step (b) in the presence of a base;

(d) treating the resulting mixture of step (c) with an acid and then introduction of a benzyloxycarbonyl, tert-butoxycarbonyl or phthalimido group.

A process for preparing a compound of formula IV wherein R₅ is tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Cbz) and R₆ is hydrogen; or wherein -N(R₅)(R₆) is phthalimido; which comprises cleaving the α-methylbenzyl group from the β -lactam nitrogen of a compound of formula III wherein Ph is phenyl.

The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (C_i-C_j) indicates a moiety of the integer "i" to the integer "j " carbon atoms, inclusive. Thus, for example, (C₁-C₃) alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl, and isopropyl. Examples of alkyl of one to nine carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and nonyl, and isomeric forms thereof.

The process of the present invention relies on asymmetric indue tion in the 2 + 2 cycloaddition method for β-lactam formation. An important feature of the process is the proper selection of all components to produce the highly crystalline compound of formula II. This allows for extremely facile separation of the diastereomers produced in the condensation reaction, thus obviating the need for more complicated classical resolution methods or for additional separation procedures. Another important feature of the process is the commercial availability and low cost of the aldehyde and chiral amine employed. Thus, the process of the present invention Is less expensive, has fewer steps and provides higher yields than known processes for synthesizing chiral monobactam intermediates.

Chart A The process of Chart A is used to obtain the desired compound of formula A-7 in pure form. The nitrogen atom of glycine is temporarily protected as the Dane salt of formula A-1. A.K. Bose et al., Tetrahedron Lett., 26:33-36 (1985). Activation with ethyl chloroformate and base treatment generates the requisite active ester of formula A-2 in situ. The activation can be done using other chloroformate or related reagents such as isobutylchloroformate, n-butylchloroformate, and methylchloroformate, and the base employed can be varied from among triethylamine, diisopropylethylamine, and tributylamine.

The imine component of formula A-5 is prepared from cinnamaldehyde of formula A-3 and R-(+) -α-methylbenzylamine of formula A-4, removing the liberated water by azeotropic distillation or with a drying agent such as magnesium sulfate, calcium sulfate, sodium sulfate or molecular sieves. The amine component should, for practical reasons, be a commercially available, optically active amine. Both enantiomers of α-methylbenzylamine are readily available at low cost.

The imine of formula A-5 and active ester of formula A-2 are reacted in the presence of a base such as triethylamine to form the condensation product of formula A-6. This reaction is conducted at a temperature of about 0 to 25°C for a period of about 1 to 24 hours. The molar ratio of active ester to imine used is about 2 to 1. It is possible to isolate the compound of formula A-6, but it is convenient not to do so.

The condensation product of formula A-6 is treated with acid, such as hydrochloric acid, to produce the deprotected amine of formula A-6a, which is then protected on the C-3 amine nitrogen, e.g., with a benzyloxycarbonyl or t-butoxycarbonyl group or as the phthalimide, to yield the compounds of formula A-7 and A- 8, wherein R₅ is benzyloxycarbonyl or tert-butoxycarbonyl and Rg is hydrogen, or wherein -N(R₅)(R₆) is phthalimido. The formulas A-6 and A-6a represent a mixture of the two cis diastereomers. The use of the benzyloxycarbonyl group is preferred. Proton and carbon-13 NMR analysis of the crude mixture of the compounds of formulas A-7 and A- 8 showed that the desired compound of formula A- 7 predominates over the compound of formula A-8.

As a consequence of the proper choice of starting materials and nitrogen-protecting groups, when R₅ is benzyloxycarbonyl and R₆ is hydrogen, the desired compound of formula A-7 is isolated easily from the reaction mixture in pure form. A single recrystallization of. the reaction product from acetone/hexane gives the optically and chemically pure compound of formula A-7, wherein R₅ is benzyloxycarbonyl and R₆ is hydrogen. Thus in a single step, the optically pure compound of formula A-7 is synthesized in good yield from readily available and inexpensive precursors.

Chart B

The formula A-7 compound of Chart A is used as the formula B-1 starting material. Treatment of the compound of formula B-1 with ozone at 0°C in chloroform, followed by a reductive workup with aqueous ethanolic sodium borohydride, gives the 4-hydroxymethyl substituent of the formula B-2 compound.

The α-methylbenzyl group is removed from the β-lactam nitrogen of the formula B-2 compound by oxidative cleavage or reductive cleavage. In oxidative cleavage, oxidation of the compound of formula B-2 with excess ammonium persulfate in aqueous acetonitrile gives the compound, of formula B-3. This method for cleavage of carbon-nitrogen bonds has been studied extensively and numerous modifications of reaction conditions are known in the art. Other oxidative methods of lactam cleavage are known, for example, M. Mori and Y. Ban, Heterocycles, 23:317-323 (1985).

Chart C Chart C illustrates the reductive cleavage of the α-methylbenzyl group using dissolving metal reduction and subsequent protecting group manipulation. The BOC protecting group is used because it is Inert to the reaction conditions. The ring nitrogen of the compound of formula C-1 is very cleanly deprotected by reaction with sodium in liquid ammonia to afford the compound of formula C-2, which is isolated by known means, e.g., by extraction, crystallization, etc. The formula C-2 compound is optionally converted to the formula C-3 compound by removal of the BOC group and introduction of the CBz group .

The preferred sequence of process steps of this invention is: (1) the use of the Cbz group for the process of Chart A; (2) the conversion of B-l to B-2 (R5 is Cbz) of Chart B; (3) replacement of the Cbz group with the BOC group; (4) conversion of C-1 to C-2 of Chart C; and (5) if the Cbz group Is desired for further synthetic reactions, conversion of C-2 to C-3. Introduction and removal of nitrogen protecting groups are well known in the art of organic chemistry. See, for example, J.F.W. McOmie, Advances in Organic Chemistry, Vol. 3, pages 191-281 (1963); R.A. Boissonas, Advances in Organic Chemistry, Vol. 3, pages 159-190 (1963); "Protective Groups in Organic Chemistry," J.F.W. McOmie, Ed., Plenum Press, New York, 1973, page 74; Protective Groups in Organic Synthesis, Theodora W. Greene, John Wiley and Sons", New York, 1981; M. Gall et al., U.S. 3,957,761; and S. Wolfe et al., Can. J. Chem., 48:3572-3579 (1970). For example, the benzyloxycarbonyl group is introduced by reaction of an amine with benzylchloroformate (also known as benzyloxycarbonyl chloride), and it is removed by hydrogenolysis over a palladium black catalyst. For example, the t-butoxycarbonyl group is introduced by reaction of an amine with di-t-butyl dicarbonate, and it is removed by reaction with trifluoroacetic acid. For example, an amine is protected as the phthalimide by reacting the amine with N-carboethoxyphthalimide or with phthalic anhydride, and the phthalimido group is converted to the primary amine by reaction with hydrazine hydrate or methylamine.

The compounds of formula C-2 and C-3, which can be prepared utilizing the intermediates and processes of this invention, and their use as intermediates for the synthesis of antibacterial monobactams are known in the art as is shown in E.P. 76,758; E.P. 93,376; E.P. 144,840 and other publications cited above. DESCRIPTION OF THE PREFERRED EMBODIMENTS Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the intermediates and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

Example 1 (3S , 4R) -1- (R-1-ρhenylethyl)-3-benzyloxycarbonylami- no-4-(2-phenylethenyl)azetidin-2-one (Formula A-7: R₅ is benzyloxycarbonyl and R₆ is hydrogen) Refer to Chart A. R- (+) -α-methylbenzylamine (25.0 g) and 25.9 g of cinnamaldehyde are dissolved in 500 ml of methylene chloride. The mixture is heated, distilling off methylene chloride for one hour, adding additional solvent as needed. The mixture is cooled to room temperature treated with 20 g of anhydrous magnesium sulfate for one hour , filtered and concentrated to give the crude imine.

The Dane salt (87.0 g) is slurried in 500 ml of tetrahydrofuran at -78°C under a nitrogen atmosphere and treated with 62.9 ml of triethylamine. A solution of 43.3 ml of ethyl chloroformate in 320 ml of tetrahydrofuran is added over 15 minutes and the mixture is stirred one hour at -78°C. A solution of the crude imine and 28.6 ml of triethylamine in 300 ml of tetrahydrofuran is added to the reaction mixture over 60 minutes. The mixture is allowed to gradually come to room temperature and stirred 18 hours. The tetrahydrofuran is removed in vacuo and the residue is partitioned between 1 L of methylene chloride and 300 ml of water. The organic layer is washed with 100 ml of water and then concentrated. The residue is dissolved in 600 ml of acetone and treated with 200 ml of 2.0 N hydrochloric acid for one hour at room temperature. Benzylchloroformate (60.0 ml) is added followed by 65 g of potassium carbonate in 300 ml of water and then solid potassium carbonate to bring the pH to 8.5. The mixture is stirred two hours at room temperature, during which time some of the major isomer crystallizes out. The acetone is removed in vacuo and the residue is extrccted with 1 L and then 200 ml of methylene chloride. The organic phase is washed with brine and dried with magnesium sulfate, adding Darco carbon for decolorlzation. Removal of solvent gives a light orange oil. The oil is dissolved in 400 ml of acetone and 1.2 L of n-hexane is added. The product is collected by filtration to afford the pure title product as an off-white crystalline solid. The mother liquors contain more of the title compound and its diastereomer. A portion of the product is recrystallized from ethyl acetate to provide an analytical sample as a white crystalline solid. Physical characteristics are as follows: M.p.: 150.0-150.9; [α]_D: -64 (c 0.78, chloroform).

IR (cm^-1, chloroform): 3435, 3001, 1745, 1510, 1470, 1390, 1325, 1220. 1H NMR (δ, CDC1₃) : 7.3, 6.5, 6.07, 5.88, 5.0, 4.26, 1.60.

¹³C NMR (δ, CDC1₃): 166, 156, 140, 135.9, 128.8, 128.6, 128.4, 128.2, 127.9, 127.2, 126.7, 67.0, 61.0, 60.5, 52.3, 19.4.

Mass spectrum (m/z) : 426 , 291 , 275 , 231, 187 , 171 , 105 , 91. Anal , found for C₂₇H₂₆N2O₃ : C , 75.65 ; H, 6.20 ; N, 6.58 . Example 2 ( 3 S , 4S ) - 1- (R- 1 -phenylethyl ) - 3 -benzyloxycarbonyla- mino-4-hydroxymethylazetidin- 2-one (Formula B-2 : R₅ is benzyloxycarbonyl and R₆ is hydrogen) Refer to

Chart B .

A solution of 10.0 g of the title product of Example 1 in 300 ml of chloroform is cooled to 0°C and a stream of ozone is bubbled through until TLC (silica gel, 50% ethyl acetate/hexane) shows no more starting material (seven hours). A solution of 2.64 g of sodium borohydride in 500 ml of cold 25% aqueous ethanol is added. The reaction is allowed to warm to room temperature and stirred for five hours. The solvent is removed In vacuo and the residue is taken up in 300 ml of ethyl acetate and 100 ml of water. The pH is adjusted to 2 with 10% hydrochloric acid and the layers are separated. The aqueous phase is extracted with 50 ml more of ethyl acetate. The combined organic layers are washed with 40 ml of water, 50 ml of brine and dried over magnesium sulfate. Removal of solvent in vacuo gives 10.8 g of colorless oil. The material is rapidly chromatographed on an 800 ml bed of silica gel, eluting with 1 L each of 10,

20, 30, 40 and 50% ethyl acetate/methylene chloride. The product is pooled on the basis of TLC (Rf=0.23, silica gel, 50% ethyl acetate/- hexane) to afford the title product as a crystalline solid. Recrystallization of a portion from ethyl acetate/hexane gives an analytical sample of the title compound as hard white crystals. Physical characteristics are as follows: M.p.: 84.5°-85.9°C. [α]_D: -41° (c 0.8165, chloroform).

IR (cm^-1, chloroform): 3420, 3300, 1745, 1720, 1512, 1450, 1390, 1370, 1310, 1230, 1060, 910, 700. 1H NMR (δ,CDC1₃): 7.35, 5.93, 5.10, 4.74, 3.65, 2.2, 1.73.

¹³C NMR (δ, CDC1₃): 167, 156, 140, 136, 130, 129.0, 128.5, 128.1, 126.8, 67.3, 59.2, 58.5, 52.9, 19.3.

Mass spectrum (m/z , CI-NH₃): 372 (M+NH₄ ⁺) . Anal, found for C₂₀H22N₂O₄: c, 67.55; H, 6.43; N, 7.83. Example 3 (3S ,4S) -3-benzyloxycarbonylamino-4-hydroxymethylazeti- din-2-one (Formula B-3: R₅ is benzyloxycarbonyl and R₆ is hydrogen) Refer to Chart B. A solution of 512 mg of ammonium persulfate and 374 mg of potassium hydrogen phosphate in 10 ml of water is heated to 90°C. A solution of 70 mg of cupric sulfate pentahydrate in 2 ml of water is added followed by a solution of 500 mg of the title product of Example 2 in 10 ml of acetonitrile. The mixture is refluxed for 30 minutes, cooled and concentrated to remove acetonitrile. Extraction with 75 ml of chloroform and concentration gives a brown solid. Chromatography of the product on silica gel (methanol/chloroform gradient) gives recovered starting material and the title product.

Repetition of this sequence with the enantiomer of the indicated starting material gives (3R,4R)3-benzylαxycarbonylamino-4-hydroxy- methylazetidin-2-one. Some starting material is recovered. Physical characteristics are as follows:

¹H NMR (δ, CDC1₃): 7.3, 6.9, 6.3, 5.0, 3.65.

¹³C NMR (δ, CDC1₃): 170.8, 156.9, 136.6, 129.3, 128.9, 67.8, 60.2, 59.5, 55.

[α]_D: -11.4º (c, 1.50, chloroform). Example 4 (3S , 4S) -1- (R-1-phenylethyl)-3-tert-butoxycarbonyla- mino-4-hydroxymethylazetidin-2-one (Formula C-1) Refer to Chart C. To a solution of 1.7 g of the title product of Example 2 in 30 ml of tetrahydrofuran is added 500 mg of palladium black. The mixture is stirred one hour at room temperature under a hydrogen atmosphere. A white precipitate forms. Methanol (5 ml) is added and the reaction is continued for 30 minutes, filtered and concentrated in vacuo. The residue is dissolved in 15 ml of tetrahydrofuran and 1.09 g of di-t-butyldicarbonate is added. The mixture is stirred 2.25 hours at room temperature, filtered to remove haze and concentrated to give a white solid. Recrystallization from chloroform (2 ml)/hexane (35 ml) gives a first crop of the title compound as a white solid.

Physical characteristics are as follows: M.p.: 134.1-135.5°C. [α]_D: -16° (c 0.86, chloroform).

IR (cm^-1, chloroform): 3440, 2980, 1745, 1710, 1500, 1370, 1230, 1160.

¹H NMR (5, CDC1₃): 7.37, 5.60, 4.96, 4.77, 3.7, 2.1, 1.70, 1.44.

Mass spectrum (m/z, FAB): 321 [M.+H]⁺; Exact mass found for C₁₇H₂₅N₂O₄: 321.1828. Anal, found for C₁₇H₂₄N₂O4: C, 63.58; H, 7.62; N, 8.72.

Example 5 (3S, 4S)-3-tert-butoxycarbonylamino-4-hydrOxymethyl- azetidin-2-one (Formula C-2) Refer to Chart C.

Ammonia (30 ml) is condensed using a dry ice condenser and 360 mg of sodium metal is added, stirring for 10 minutes to dissolve. To the reaction is added a solution of 1.00 g of the title product of

Example 4 in 10 ml of tetrahydrofuran, rinsing in with 2 ml more of tetrahydrofuran. The mixture is stirred 10 minutes and 1.00 g of ammonium chloride is added. When the blue color has discharged, the ammonia and tetrahydrofuran are removed with a stream of nitrogen. The residue is taken up on 40 ml of water and 200 ml of methylene chloride and continuously extracted overnight. Concentration of the extract, in vacuo gives 650 mg of the title product as white solid which is pure by TLC. Recrystallization from acetone/chloreform/- hexane gives a first crop of the title product as a white crystalline solid.

Physical characteristics are as follows:

M.p.: 167.0-167.5ºC.

[α]^D: +21 (c, 0.5185, acetone). IR (cm^-1, ATR): 3320, 2990, 2970, 1740, 1690, 1525, 1365, 1330, 1245, 1160, 1050.

¹H NMR (δ, acetone d₆): 6.30, 5.04, 3.7-4.2, 2.80, 1.44. 1³C NMR (δ, DMSO d₆): 168.1, 155.0, 78.5, 61.0, 58.9, 54.1, 28.1.

Mass spectrum (m/z, Cl-isob): 217 [M+H]⁺, 161. Anal, found for C₉H₁₆N2O₄: C, 49.62; H, 7.27; N, 12.67. Example 6 (3S ,4S) -3-benzyloxycarbonylamino-4-hydroxymethylazeti- din-2-one (Formula C-3) Refer to Chart C. To a solution of 115 mg of the title product of Example 5 in 3 ml of methylene chloride, stirred at 0°C under a nitrogen atmosphere, is added 0.7 ml of trifluoroacetic acid. The mixture is stirred 2 hrs at 0ºC, concentrated in vacuo and reconcentrated from 10 ml of methylene chloride. The residue is dissolved in 5 ml of acetone and 2 ml of water is added, followed by 210 mg of sodium bicarbonate and 0.08 ml of benzyloxycarbonyl chloride. The mixture is stirred for 2 hrs at ambient temperature, concentrated in vacuo to remove the acetone and taken up in 25 ml of ethyl acetate and 2 ml of water. The ethyl acetate layer is dried over sodium sulfate and concentrated to afford 154 mg of crude product. The material is chromatographed on 10 g of silica gel with ethyl acetate, pooling fractions on the basis of TLC (R_f = 0.35, 10% methanol/chloroform, silica gel), to afford the title product as a white crystalline solid. Recrystallization from ethyl acetate/hexane affords a white crystalline solid. Physical characteristics are as follows: M.p.: 127.0-128. OºC. [α]_D: +9º (c, 0.9305, chloroform).

IR (cm^-1, chloroform): 3420, 1764, 1715, 1510, 1318, 1220, 1060. 1E NMR (δ, CD₃COCD₃): 7.35, 6.8, 5.1, 4.2, 3.7. Mass spectrum (m/z, Cl-isob): 251 [M+H]⁺.

Claims

1. A compound having the formula I

wherein R₃ is tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Cbz) and R₂ is hydrogen; or wherein -N(R₂)(R₃) is phthalimido; wherein R₄ is

(a) -CH=CH-C₆H₅, or (b) -CH₂OH; wherein Ph is phenyl.

2. A compound of claim 1, (3S,4R)-1-(R-1-phenylethyl)-3-benzyl- oxycarbonylamino-4-(2-phenyletheny1)azetidin-2-one.

3. A compound of claim 1, (3S.4R)-1-(R-1-phenylethyl)-3-tert- butoxycarbonylamino-4-(2-phenylethenyl)azetidin-2-one.

4. A compound of claim 1, (3S,4S)-1-(R-1-phenylethyl)-3-benzyl- oxycarbonylamino-4-hydroxymethylazetidin-2-one.

5. A compound of claim 1, (3S.4S)-1-(R-1-phenylethyl)-3-tert- butoxycarbonylamino-4-hydroxymethylazetidin-2-one.

6. A process for preparing a compound of formula II

II

wherein R₅ is tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Cbz) and R₆ is hydrogen; or wherein -N(R₅)(R₆) is phthalimido; wherein Ph is phenyl; which comprises: (a) reacting a Dane salt of formula VI

VI

with a (C1-C4) alkyl chloroformate and a base;

(b) reacting- R-(+)-α-methylbenzylaine and cinnamaldehyde and removing the liberated water from the mixture; (c) reacting the mixture of step (a) with the mixture of step (b) in the presence of a base;

7. A process of claim 6 wherein the (C₁-C₄) alkyl chlorofprmate and the base of step (a) are ethyl chloroformate and triethylamine, the base of step (c) is triethylamine, and the acid of step (d) Is hydrochloric acid.

8. A process of claim 6 which further comprises: (e) isolating the compound of formula II from the reaction mixture.

9. A process of claim 6 wherein the compound of formula II is (3S ,4R) -1-(R-1-phenylethyl)-3-benzyloxycarbonylamino-4-(2-phenylethenyl)azetidin-2-one.

10. A process of claim 6 wherein the compound of formula II is (3S,4R)-1-(R-1-phenylethyl)-3-tert-butoxycarbonylamino-4-(2-phenyl- ethenyl)azetidin-2-one.

11. A process for preparing a compound of formula IV IV

wherein R₅ is tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Cbz) and R₆ is hydrogen; or wherein -N(R₅)(R₆) is phthalimido; which comprises cleaving the α-methylbenzyl group from the β-lactam nitrogen of a compound of formula III

III

12. A process of claim 11 wherein the compound of formula III is prepared from a compound of formula II

II

by ozonolysis followed by a reductive workup; wherein R₅ is tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Cbz) and R₆ is hydrogen; or wherein -N(R₅)(R₆) is phthalimido; wherein Ph is phenyl.

13. A process of claim 11 wherein R₅ is benzyloxycarbonyl and R_g is hydrogen in the compounds of formulas III and IV and wherein the α- methylbenzyl group is cleaved by oxidative cleavage.

14. A process of claim 11 wherein R₅ is tert-butoxycarbonyl and R₆ is hydrogen in the compounds of formulas III and IV and wherein the α-methylbenzyl group is cleaved by reductive cleavage.

15. A process of claim 14 which further comprises treating the compound of formula IV with acid and then introduction of a benzyloxycarbonyl group to obtain a compound of formula V