WO1988001619A1 - 1'-methyl-beta-lactam compounds and their production - Google Patents

Abstract

A 1'-methyl-beta-lactam compound of formula (I), wherein R1 is an optionally substituted diarylmethyl group or an optionally substituted aryl group and R2 is a protective group for hydroxyl, which is useful as an intermediate in the synthesis of antimicrobial agents.

Description

D E S C R I P T I O N

Title of the Invention

1 '- ETHYL-beta-LACTAM COMPOUNDS AND THEIR PRODUCTION

Technical Field

This invention relates to novel 1'-methyl-beta- lacta compounds and their production. More particularly, it relates to 1'-methyl-beta-lactam compounds useful as intermediates in the synthesis of beta-lactam compounds having a methyl group at the 1'3-position and their production.

The 1'-methyl-beta-lactam compounds of this invention are novel and can be represented by the formula:

wherein R is an optionally substituted diarylmethyl group

2 or a substituted aryl group and R is a protective group for hydroxyl.

The term "aryl" as he einabove and hereinbefore used alone or in combination with .any other group is intended to mean a σarbocyclic aromatic ring, preferably having not more than 20 carbon atoms, and its typical examples are phenyl, naphthyl, phenanthryl, etc., among which preferred is phenyl. 161 - 2 -, -

Background Art

beta-Lactam compounds of the formula:

3 wherein R is a protective group for hydroxyl are known to be useful as intermediates for the synthesis of 1' -methyl- carbapenem compounds having a potential anti-microbial activity [D.H. Shin et al.: Heterocycles, 21 , 29 (1984)] and have heretofore been produced from the corresponding desmethyl compounds by drawing out the hydrogen atom at the l¹-position in the acetic acid residue at the 4-position by the aid of a strong base and introducing a methyl group therein. In this method, however, it is essential to use lithium diisopropylamide which can be handled with great difficulty in industry. Further, it is indispensable to perform the reaction at such a low temperature as -78°C. In addition, unnecessary epimers such as beta-lactam deriva¬ tives having 1' α-methyl group are by-produced with a rela¬ tively large proportion (1'3/1'α = 1/4). It is thus clear that the conventional synthetic method has various drawbacks from the industrial viewpoint.

Disclosure of Invention

1'-Methyl-beta-lactam compounds (I) of the inven- tion have been found to be readily and advantageously converted into the beta-lactam compounds (II) without any drawback as seen in said conventional method for production of the beta-lactam compounds (II) . Thus, conversion can be accomplished substantially by elimination of the amino- protective group at the 1-position, reduction of the car- bonyl group in the side chain at the 3-position to a hydroxymethylene group and oxidation of the hydro.xymethyl group in the side chain at the 4-position into a carboxyl group in an appropriate order.

In the 1'-methyl-beta-lactam compounds (I), R may be, for instance, an optionally substituted diarylmethyl group (e.g. diphenylmethyl, di-p-anisylmethyl) , a substi¬ tuted aryl group (e.g. p-methoxyphenyl, 2,4-dimethoxyphenyl, o-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 3,4,5-tri- methoxyphenyl group), or the like. Among them, preferred are di-p-anisylmethyl, p-metoxyphenyl, etc.

Various protective groups for hydroxyl are dis¬ closed in "Protective Groups in Organic Synthesis" (1981) published by John Wiley & Sons, New York, U.S.A., "New Experimental Chemistry" ("Shin-Jikken Kagaku Koza" in Japanese) , Vol. 14 (1978) published by Maruzen, Tokyo,

Japan, etc. These conventional protective groups are

2 ordinarily usable as R in the 1'-methyl-beta-lactam com¬ pounds (I) of this invention. Specific examples of the

2 hydroxy-protective group (R ) are a straight or branched ,-C₅ alkyl group (e.g. t-butyl) , a C^-C_fi alkenyl group

(e.g. allyl), a C,-C₅ alkoxy(C,-C-.) alkyl group (e.g. methoxy methyl- 1-ethoxyethyl, isopropoxymethyl, 1-methy1-1-methoxy- ethyl, t-butoxymethyl, 1-isopropoxyethyl) , a group of the

4 4 formula: R 0(CH CH₂0)-.CH-,- wherein R is C₁-C₅ alkyl and n is an integer of 1 to 4 (e.g. 2-methoxyethoxymethyl, methoxy(triethyleneoxy)methyl) , a C,-C-. alkylthio- (C₁-C_[.)alkyl group (e.g. methylthiomethyl) , an optionally substituted arylthiomethyl group (e.g. phenylthiomethyl) , a tetrahydropyranyl, group, an optionlly substituted aryl- methyl group (e.g. benzyl, p-methoxybenzyl, 2,4-dimethoxy- benzyl, o-nitrobenzyl, p-nitrobenzyl) , an acyl group such as lower alkanoyl (e.g. acetyl) or benzoyl, etc. Among them, preferred are methoxymethyl, methylthiomethyl, phenylthio¬ methyl, 2-methoxyethoxymethyl, methoxy(triethyleneoxy) - methyl, isopropoxymethyl, 1-ethoxyethyl, 1-methy1-1-methoxy- ethyl, 1-isopropoxyethyl, allyl, t-butyl, benzyl, etc.

The 1'-methyl-beta-lactam compound (I) can be produced, for instance, according to the following scheme:

(III)

1st step R NH. (IV)

wherein R 1 and R2 are each as defined above.

The 1st step is concerned with the reaction between the aldehyde compound (III) and an a ine (IV) to give the i ine compound (V) . The reaction may be carried out in the presence or absence of an inert solvent, if necessary, in the existence of a dehydrating agent (e.g. molecular sieve, anhydrous magnesium sulf te, anhydrous sodium sulfate, calcium chloride) . Examples of the inert solvent are aromatic hydrocarbons (e.g. benzene, toluene, xylene) , ethers (e.g. ether, tetrahydrofuran, dioxane, diglyme) , etc. The reaction proceeds smoothly at a temper¬ ature of about 0 to 100°C.

The 2nd step relates to the reaction between the imine compound (V) and diketene in the presence of an imidazole compound, preferably in an inert solvent, to give the 1 '-methyl-beta-lactam compound (I) . As the imidazole compound, there may be -exemplified imidazole, 2-methyi- imidazole, 4-methylimidazole, 2 ,4-dimethylimidazole, benz- imidazole, etc. Among them, preferred are imidazole and 4-methylimidazole. The amount of the imidazole compound is usually from 0.1 to 2.0 equivalents to the imine compound (V) . Example of the inert solvent are aromatic hydrocarbons (e.g. benzene, toluene, xylene) , ethers (e.g. ether, tetra¬ hydrofuran, dioxane) , halogenated hydrocarbons (e.g. di¬ chloromethane, chloroform, carbon tetrachloride) , aliphatic hydrocarbons (e.g. hexaήe, heptane, pen ane, cyclohexane) , polar solvents (e.g. acetonitrile, dimethylformamide, dimethylsulfoxide) , their mixtures, etc. The reaction proceeds smoothly at a temperature of about -50 to 50°C.

After completion of the reaction, the product may be recovered from the reaction mixture by a per se conven¬ tional procedure for post-treatment.

The starting aldehyde compound (III) in the 1st step is obtainable, for instance, from methyl 3-hydroxy-2- methylpropionate by a known method. The use of the starting material in an optically active form can afford ultimately the product, i.e. the 1'-methyl-beta-lactam compound (I) in an optically active form.

The conversion of the 1'-methyl-beta-lactam compound (I) into the beta-lactam compound (II) can be accomplished substantially by elimination of the amino- protective group at the 1-position, reduction of the carbonyl group in the side chain at the 3-position to a hydroxymethylene group and oxidation of a hydroxymeth l group in the side chain at the 4-position to a carboxyl group. Said elimination, reduction and oxidation may be carried out in an appropriate order. During any of those reactions, any group which should not receive any influence from the reaction is protected by a per se conventional procedure. Among various procedures for the conversion, typical examples are as follows:

(VI)

(VII) (VIII)

(IX)

(X)

B D

-> (VIII) (IX) - (ID

1 2 3 wherein R , R and R are each as defined above. The step A is the conversion of a carbonyl group into a hydroxymethylene group, which may be carried out, for instance, by reduction with a metal hydride complex (e.g. sodium borohydride, potassium serectride, diborane-amine complex) . For selective production of the product having an R-configuration, there is preferably adopted reduction with potassium serectride or reduction with diborane-amine complex (Japanese Patent Publication (unexamined). No. 215667/85) .

The step B is the protection of a hydroxyl group. It s particularly preferred that the protective group R 3 to be used at this stage is the one which can be eliminated by a method different from the method to be employed for

2 elimination of the protective group R . In other words, it is favorable that the protective group R would not receive any substantial influence on elimination of R 2.

The step C is the removal of the protective group

R , which may be carried out, for instance, by oxidative treatment with cerium (IV) ammonium nitrate or treatment with trifluoroacetic acid.

The step D is the elimination of the protective

2 group R"-. For this purpose, there may be adopted, for instance, catalytic reduction using a catalyst (e.g. platinum, palladium) , reduction using a Lewis acid such as trifluoroacetic acid or boron trifluoride-ether complex or the like.

The step E is the conversion of a hydroxymethyl group into a carboxyl group, which may be achieved, for instance, by treatment with chromium trioxide-sulfuric acid (Jones' reagent) or treatment with pyridinium dichromate.

Best Mode for Carrying out the Invention

The present invention will now be illustrated in greater detail with reference to the following Examples and Reference Examples, but it should be understood that these examples are given only for illustrative purposes and are not limiting the present invention.

In Examples and Reference Examples, the following abbreviations are used:

TBDMS: t-butyldimethylsilyl group

Bn: benzyl group

Ph: phenyl group

Me: methyl group t-Bu: t-butyl group

DAM: di-p-anisylmethyl group

PMP: p-methoxyphenyl group

MOM: methoxymethyl group

MEM: methoxyethoxymethyl group

MTM: methylthiomethyl group

EE: 1-ethoxyethyl group

Im: imidazole

THF: tetrahydrofuran Example 1-(1)

(1"R,3S,4R) (1"R,3R,4S)

A suspension of (S)-3-benzyloxy-2-methylpropanal (0.80 g; 4.5 mM) and anhydrous magnesium sulfate (0.66 g? 5.5 mM) in toluene (10 ml) was ice-cooled, a solution of di-p-anisylmethylamine (1.04 g; 4.3 mM) in toluene (10 ml) was dropwise added thereto, and the resultant mixture was stirred under ice-cooling for 1.5 hours. Insoluble materials were collected by filtration and washed with benzene. The filtrate and the washings were combined together and distilled under reduced pressure. By NMR measurement of the residue, production of an imine compound was confirmed.

NMR (CDC1₃) : ό = 1.14 (d, J = 6.8 Hz_Λ 3H) , 2.7 - 3.0 (m, 1H) , 3.6 - 3.8 (m, 2H) , 3.77 (s, 6H) , 4.49 (s, 2H) , 5.28 (s, 1H) , 6.78 (d, J = 8.8 Hz, 2H) , 6.80 (d, J = 8.8 Hz, 2H) , 7.17 (d, J = 8.8 Hz, 2H) , 7.23 (d, J = 8.8 Hz, 2H) , 7.27 (s, 5H), 7.74 (d, J = 4.8 Hz, 1H) .

The above obtained imine compound (4.5 mM) was dissolved in toluene (25 ml) and cooled to -30°C, followed by addition of imidazole (0.37 g; 5.4 mM) thereto. A solution of diketene (1.88 g; 22.4 mM) in toluene (15 ml) was dropwise added thereto in more than 80 minutes, and the resultant mixture was stirred at the same temperature for 3 hours. A solution of diketene (1.12 g; 13.3 mM) in toluene (10 ml) was further added thereto, followed by stirring for 22 hours. The reaction mixture was diluted with ethyl acetate, washed with 0.IN hydrochloric acid, a saturated sodium bicarbonate solution and a saturated sodium chloride solution in order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (acetone : methylene chloride = 2 : 98) to give a mixture of (1"R,3S,4R)- and (1"R,3R,4S) -1- (di-p-anisylmethyl) -3-acetyl-4- [1"- (benzyloxymethyl) ethyl] - azetidin-2-one (0.97 g, 44 % yield) as colorless oil. The production ratio of the (1"R,3S,4R) form and the (1"R,3R,4S) form was ascertained to be 6.1 : 1 by NMR spectrum.

A portion of the above mixture (125 mg) was further purified by TLC (thin layer chromatography) (ether : hexane = 2 : 1, twice) to give each stereoisomer in a pure state.

(1"R,3S,4R) form: 107 mg

(1"R,3R,4S) form: 14 mg

The optical purity of the (1"R,3S,4R) form was determined to be more than 91 % ee by the use of a chiral type shifting agent, i.e. tris [3- (heptafluoropropylhydroxy- methylene) -d-camphorite] europium (III) . The stereoisomer was further recrystallized from isopropyl ether to give colorless crystals, of which the optical purity was more than 95 % ee when determined in the same manner as above.

Alternatively, the above obtained mixture of stereoisomers (6.1 : 1) was recrystallized directly from isopropyl ether to give a (l'^rR,3S,4R) form in a pure state, of which the optical purity was likewise determined to be more than 95 % ee.

(1"R,3S,4R) form:-

Colorless crystals (recrystallized from isopropyl ether) m.p. : 90 - 91°C; [α]²⁰ -58.1° (c = 0.53, CHC1.-) ; IR ( Br) v: 2870, 1745, 1715, 1610, 1510, 1255,

NMR (CDC1₃) : δ = 0.87 (d, J = 7.0 Hz, 3H) , 1.7 -

2.1 (m, 1H) , 2.19 (s, 3H) , 3.1 - 3.5 ( , 2H) , 3.77 (s, 3H) , 3.78 (s, 3H) , 4.0 - 4.3 (m, 2H) , 4.37 (s, 2H) , 5.56 (s, 1H) , 6.80 (d, J = 8.8 Hz, 2H) , 6.83 (d, J = 8.8 Hz, 2H) , 7.09 (d, J = 8.8 Hz, 2H) , 7.16 (d, J = 8.8 Hz, 2H) , 7.3^~0 (s, 5H) ;

Mass m/e: 487 (M)⁺, 444 (M-43)^÷, 396 (M-91)⁺;

Elementary analysis for C__nH-_NO_[-:

Calcd.: C, 73.90 %; H, 6.82 %; N, 2.87 %.

Found: C, 73.73 %; H, 6.63 %; N, 2.84 %. (1"R,3R,4S) form:-

Colorless oily substance;

^*[α]²° +26.3° (c = 0.67, CHC1₃) ;

IR (neat) v_: 2940, 1745, 1710, 1610, 1510, 1245,

NMR (CDC1-) : <5 = 0.82 (d, J = 6.8 Hz, 3H) , 1.6 -

1.9 (m, 1H) , 2.12 (s, 3H) , 3.26 (d, J = 4.8 Hz, 2H) , 3.78 (s, 6H) , 4.00 (d, J = 2.4 Hz, 1H) , 4.2 - 4.4 (m, 1H) , 4.34 (s, 2H) , 5.61 (s, 1H) , 6.81 (d, J = 8.8 Hz, 2H) , 6.83 (d, J = 8.8 Hz, 2H) , 7.10 (d, J = 8.8 Hz, 2H) , 7.16 (d, J = 8.8 Hz, 2H) . 7.30 (s, 5H) ;

Mass m/e: 487 (M)⁺, 444 (M-43)⁺, 396 (M-91)⁺; High resolution mass for C,_πH-.,NO,-: Calcd. m/e: 487.2357. Found m/e: 487.2379.

Still, the starting (S) -3-benzyloxy-2-methyl- propanal was synthesized from methyl (R) - (-) -3-hydroxy-2- methylpropionate according to the method as described in^* J.Am.Chem.Soc. , 1 5, 5015 - 5024 (1983). Example l-(2)

(1"R,3S,4R) (1^**R-3R-4S)

(S) -3-Benzyloxy-2-methylpropanal (0.99 g; 5.6 mM) and di-p-anisylmethylamine (1.30 g; 5.4 mM) were reacted in the same manner as in Example 1-(1) to give an imine compound, which was dissolved in toluene (50 ml) , followed by cooling to -30°C. To the resultant mixture, a solution of diketene (1.41 g; 16.8 mM) in toluene (5 ml) and a solution of 4-methylimidazole (0.50 g; 6.1 mM) in toluene (5 ml) were simultaneously and dropwise added in more than 2 hours, and the resulting mixture was stirred at the same temperature for 48 hours. A solution of diketene (0.93 g; 11.1 M) in toluene (5 ml) was further added thereto, followed by stirring for 12 hours. The reaction mixture was subjected to post treatment in the same manner as in Example 1-(1) to give a mixture of (1"R,3S,4R)- and (1"R,3R,4S)- 1-(di-p-anisylmethyl)-3-acetyl-4-[1"-(benzyloxymethyl)- ethyl]azetidin-2-one (1.40 g, 52 % yield) as a colorless solid. The production ratio of the (1"R,3S_Λ4R) form and the (1"R,3R,4S) form was ascertained to be 11 : 1 by NMR spectrum.

Recrystallization of the above obtained mixture from isopropyl ether gave the (l"R_r3S,4R) form in a pure state.

Examples 2 to 6

In the same manner as in Example 1-(1) , the 3- acetyl-azetidin-2-one compounds, i.e. mixtures of the (1"R,3S,4R) form (A) and the (1"R,3R,4S)-form (B) , as shown in Table 1 were obtained from the corresponding (S)-2- methylpropanal compounds. Their spectral data are given below. Table 1

Note: *1) Time for reaction between imine compou and diketene in the presencce of imidazole; reaction temperature, -30°C *2) (R)-Propanal compound was used as ' the starting material. Thus, the product was a mixture of the enan¬ tiomers (A) and (B) .

Product obtained in Example 2.:-

Colorless oil;

IR (neat) v 2940, 1750, 1715, 1610, 1515, 1250

1180, 1040 cm-1 NMR (CDC1₃) : - = 0.82 (d, J = 7.0 Hz, 1.1H ) , 0.90 (d, J = 7.0 Hz, 1.9H*) , 1.7 - 2.0 (m, 1H) , 2.23 (s, 3H) , 3.27 (s, 1.1H**) , 3.30 (s, 1.9H*) , 3.2 - 3.5 (m, 2H) , 3.79 (s, 6H) , 4.0 - 4.4 (m, 2H) , 4.48 (s, 0.7H*^*) , 4.51 (s, 1.3H^") , 5.62 (s, 0.6H") , 5.65 (s, 0.4H^**), 6.85 (d, J = 8.8 Hz, 2H) , 6.87 (d, J = 8.8 Hz, 2H) , 7.15 (d, J = 8.8 Hz, 2H) , 7.22 (d, J = 8.8 Hz, 2H) ;

*: signal of (1"R,3S,4R); **: signal of (1"R,3R,4S) ;^' Mass m/e: 396 (M-45)⁺. Product obtained in Example 3:- Colorless oil;

IR (CHC1₃) V: 2955, 1750, 1715, 1610, 1510, 1460, - 1250, 1175, 1040 cm^"1; k it

NMR (CDC1-) : δ = 0.79 (d, J = 7.4 Hz, 1.3H ) , 0.87 (d, J = 7.4 Hz, 1.7H ) , 1.7 - 2.0 (m, 1H) , 2.27 (s, 3H) , 3.3 - 3.7 (m, 6H) , 3.35 (s, 1.7H*) , 3.37 (s, 1.3H*) , 3.78 (s, 6H) , 3.9 - 4.3 (m, 2H) , 4.57 (s, 1.1H*) , 4.61 (s, 0.9H ) , 5.59 (s, 0.6H ), 5.61 (s, 0.4H *) , 6.8 - 7.3 (m, 8H);

*: signal of (1"R,3S,4R); **: signal of (1"R,3R,4S) ; Mass m/e: 485 (M)⁺, 442 (M-43)⁺, 396 (M-89)⁺. Product obtained in Example 4:- Colorless oil;

IR (neat) ^ : 2980, 1755, 1715, 1610, 1515, 1250, 1180, 1035 cm^-1;

NMR (CDC1₃) : δ = Q.81 (d, J = 6.8 Hz, 0.6H* ) , 0.88 (d, J = 6.8 Hz, 2.4H ) , 1.0 - 1.3 (m, 6H) , 1.67 - 1.9 ( , IH) , 2.27 (s, 3H) , 3.1 - 3.7 (m, 4H) , 3.79 (s, 6H) , 4.0 - 4.3 (m, 2H) , 4.4 - 4.7 (m, IH) , 5.60 (s, 0.8H*) , 5.64 (s, 0.2H**) , 6.83 (d, J = 8.8 Hz, 2H) , 6.85 (d, J = 8.8 Hz, 2H) , 7.15 (d, J = 8.8 Hz, 2H) , 7.21 (d, J = 8.8 Hz, 2H) ;

*: signal of (1"S,3S,4R) ; **: signal of (1"S,3R,4S) ; Mass m/e: 396 (M-73)⁺, 242 (M-227)^*1". . Product obtained in Example 5:- (A) Colorless oil;

[ ]²⁰ -45.6° (c = 0.51, CHC1₃) ;

IR (neat) v: 2980, 1755, 1715, 1610, 1515, 1250, 1175, 1030 cm^"1;

NMR (-CDC1 ) : δ = 0.86 (d, J = 6.8 Hz, 3H) , 1.11 (s, 9H) , 1.6 - 1.9 ( , IH) , 2.26 (s, 3H) , 3.1 - 3.2 (m, 2H) , 3.79 (s, 6H) , 4.07 (dd, J = 5.5 and 2.4 Hz, IH) , 4.30 (d, J = 2.4 Hz, IH) , 5.62 (s, IH) , 6.83 (d, J = 8.8 Hz, 2H) , 6.85 (d, J = 8.8 Hz, 2H) , 7.15 (d, J = 8.8 Hz, 2H) , 7.22 (d, J = 8.8 Hz, 2H) ;

Mass m/e: 453 (M)⁺, 396 (M-57)⁺; High resolution mass for C-_H- NO_: Calcd. m/e: 453.2512. Found m/e: 453.2497. (B) Colorless oil;

[αlp⁰ +17.9° (c = 0.86, CHC1.-) ;

IR (neat) 2975, 1750, 1715, 1610, 1510, 1250, 1175, 1030 cm^"1;

NMR (CDC1₃) : δ = 0.79 (d, J = 6.8 Hz, 3H) , 1.06 - lδ -

ts, 9H) , 1.6 - 1.8 (m, IH) , 2.25 (s, 3H) , 3.14 (d, J = 5.4 Hz, 2H) , 3.79 (s, 6H) , 4.04 (d, J = 2.4 Hz, IH) , 4.24 (dd, J = 4.0 and 2.4 Hz, IH) , 5.63 (s, IH) , 6.83 (d, J = 8.8 Hz, 2H) , 6.86 (d, J = 8.8 Hz, 2H) , 7.17 (d, J = 8.8 Hz, 2H) , 7.23 (d, J = 8.8 Hz, 2H) ;

Mass m/e: 453 (M)⁺, 396 (M-57)⁺;

High resolution mass for C₂₇H_3g O_g:

Calcd. m/e: 453.2512.

Found m/e: 453.2485. Product obtained in Example 6:~

(A) Colorless oil;

IR (neat) v: 2970, 1755, 1715, 1610, 1515, 1250, 1175 cm^"1;

NMR (CDC1₃) : δ = 0.88 (d, J = 7.0 Hz, 3H) , 1.7 - 2.0 (m, IH) , 2.09 (s, 3H) , 2.27 (s, 3H) , 3.36 (t, J = 6.0 Hz, 2H) , 3.79 (s, 6H) , 4.1 - 4.3 (m, 2H) , 4.52 (s, 2H) , 5.62 (s, IH) , 6.85 (d, J = 9.0 Hz, 2H) , 6.87 (d, J = 9.0 Hz, 2H) , 7.15 (d, J = 9.0 Hz, 2H) , 7.22 (d, J = 9.0 Hz, 2H) ;

Mass m/e: 457 (M) ⁺, 396 (M-61)⁺.

High resolution mass for C-,-H._>..N0₁-S:

Calcd. m/e: 457.1920.

Found m/e: 457.1927.

(B) Colorless oil;

IR (neat) v_: 2960, 1750, 1715, 1610, 1510, 1250,

1175 cm :

NMR (CDC1₃) : ^' = 0.80 (d, J = 7.0 Hz, 3H) , 1.7 -

1.9 (m, IH) , 2.06 (s, 3H) , 2.28 (s, 3H) , 3.30 (d, J = 5.0 Hz, 2H) , 3.79 (s, 6H) , 4.01 (d, J = 2.5 Hz, IH) , 4.30 (dd, J = 4.5 and 2.5 Hz, IH) , 4.49 (s, 2H), 5.66 (s, IH) , 6.82 (d, J = 8.5 Hz, 2H) , 6.84 (d, J = 8.5 Hz, 2H) , 7.17 (d, J = 8.5

Hz, 2H) , 7.23 (d, J = 8.5 Hz, 2H) ;

+ +

Mass m/e: 457 (M) , 396 (M-61) .

High resolution mass for C₂₅H₃₁N0₅S:

Calcd. m/e: 457.1920.

Found m/e: 457.1891.

Example 7

(1"R,3S,4R) (1"R,3R,4S)

A mixture of (S) -3-methylthiomethyloxy-2-methyl- propanal (154 mg; 1.0 mM) , p-anisidine (128 mg; 1.0 ml), anhydrous magnesium sulfate (150 mg; 1.2 mM) and benzene (5 ml) was stirred at room temperature for 1.5 hours. In¬ soluble materials were collected by filtration and washed with benzene. The filtrate and the washings were combined together and distilled under reduced pressure. The residue was subjected to NMR measurement, whereby production of an imine compound was confirmed.

NMR (CDC1₃) : δ = 1.22 (d, J = 7.0 Hz, 3H) , 2.13 (s, 3H) , 2.7 - 3.0 ( , IH) , 3.6 - 3.9 (m, 2H) , 3.80 (s, 3H) , 4. 66 ( s , 2H) , 6 .94 (AB , J^ = 8 . 8 Hz , Δ _AB = 14. 5 Hz , 4H) , 7 . 83 (d, J = 5 . 1 Hz , IH) .

The above obtained imine compound (1.0 mM) was dissolved in tetrahydrofuran (3 ml) and, after addition of imidazole (85 mg; 1.2 mM) , cooled to -30°C. A solution of diketene (260 mg; 3.0 mM) in tetrahydrofuan (2 ml) was dropwise added thereto in more than 10 minutes, and the resultant mixture was stirred at the same temperature for 14 hours. A solution of diketene (260 mg; 3.'0 mM) in tetra¬ hydrofuran (1 ml) was further added thereto, followed by stirring for 10 hours. The reaction mixture was diluted with ethyl acetate, washed successively with IN hydrochloric acid, a saturated sodium bicarbonate solution and a satu¬ rated sodium chloride .solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (acetone : dichloromethane = 2 : 98) to give a mixture of (1"R,3S,4R)- and (1"R,3R,4S)- 1-(p-methoxyphenyl) -3-acet l-4-[1"-(methylthiomethyloxy- methyl)ethyl]azetidin-2-one (134 mg, 38 % yield) as color¬ less oil. The production ratio of the (1"R,3S,4R) form and the (1"R,3R,4S) form was ascertained to be 1.5 : 1 by NMR spectrum.

IR (neat) : 2930, 1750, 1715, 1510, 1245 cm^"1.

NMR (CDC1₃) : δ -_- 0.92 (d, J = 7.0 Hz, 1.2H**), 1.05 (d, J = 7.0 Hz, 1.8H*), 2.12 (s, 1.8H*), 2.14 (s, 1.2H ), 2.36 (s, 3H) , 3.4 - 3.6 (m, 2H) , 3.79 (s, 3H) , 4.12 (d, J - 1.8 Hz, 0.4H ), 4.34 (d, J = 2.2 Hz, 0.6H*), 4.55 (s, 1.2H ), 4.59 (s, 0.8H ), 4.6 - 4.8 (m, IH) , 7.08 (AB , J-₃ = 9.2 Hz, Δ _AB = 38.9 Hz, 4H) ;

*: signal of (1"R,3S,4R) form;

**: signal of (1"R,3R,4S) form;

Mass m/e: 337 (M)⁺, 290 (M-47)^÷;

High resolution mass for C,₇H„_N0₄S:

Calcd. m/e: 337.1346.

Found m/e: 337.1334.

Examples 8 to 10

In the same manner as in Example 7, the 3- acetyl-azetidin-2-one compounds , i.e. mixtures of the (1"R,3S,4R) form (A) and the (1"R,3R,4S) form (B) , as shown in Table 2 were obtained from the corresponding (S) -2-methyl propanal compounds. Their spectra data are given below.

Table 2

Note: *1) Time for reaction between imine compound and diketene in the presence of imidazole; reaction was carried out in tetrahydrofuran at a temper¬ ature of -30°C.

Product obtained in Example 8:-

Colorless oil;

IR (CHC1₃) V: 1745, 1715, 1510, 1245 cm .-^"1

**

NMR (CDC1₃) : δ = 0.90 (d, J = 7.03 Hz, 1.35H ) ,

1.02 (d, J = 6.8 Hz, 1.65H^X) , 2.28 (s, 3H) , 2.3 - 2.6 (m,

IH) , 3.55 (t, J = 4.6 Hz, 2H) , 3.78 (s, 3H) , 4.11 (d, J =

2.5 Hz, 0.45H**) , 4.29 (d, J = 2.5 Hz, 0.55H*) , 4.5 - 4.75

(m, IH) , 4.93 (s, 1.1H*) , 4.96 (s, 0.9H**) , 6.84 (d, J = 9.0

Hz, 2H) , 7.2 - 7.6 (m, 7H) ;

*: signal of (1"R,3S,4R);

**: signal of (1"R,3R,4S) ;

Mass m/e: 399 (M)⁺, 290 (M-109)⁺;

High resolution mass for C_ H__N0.S:

22 25 4

Calcd. m/e: 399.1502. Found m/e: 399.1507. Product obtained in Example 9:- Colorless oil; IR (neat) V: 2970, 1750, 1715, 1510, 1245 cm^"1; NMR (CDC1₃) : = 0.93 (d, J = 6.8 Hz, 1.15H ) , 1.04 (d, J = 7.0 Hz, 1.85H ) , 2.25 (s, 1.25H**) , 2,28 (s, 1.85H*) , 2.3 - 2.6 (m, IH) , 3.3 - 3.6 ( , 2H) , 3.78 (s, 3H) 4.41 (s, 1.25H*), 4.43 (s, 0.75H**), 6.83 (d, J = 9.0 Hz, 2H) , 7.15 - 7.5 (m, 7H) ;

*: signal of (1"R,3S,4R); **: signal of (1"R,3R,4S) ; Mass m/e: 367 (M)⁺, 276 (M-91)⁺; High resolution mass for C-^H^-NO-. : Calcd. m/e: 367.1781. Found m/e: 367.1768. Product obtained in Example 10:- Colorless oil; IR (neat)^'v: 1745 cm^"1;

NMR (CDC1₃) : ^δ = ₀.90 (d, J = 6 Hz, 1.2H ) , 1.03 (d, J = 6 Hz, 1.8H*) , 2.1 - 2.7 (m, IH) , 2.33 (s, 3H) , 3.36 (s, 3H) , 3.40 - 3.75 (m, 12H) , 3.78 (s, 3H) , 4.12 (d, J = 2 Hz, 0.4H**) , 4.35 (d, J = 2 Hz, 0.6H ) , 4.5 - 4.8 (m, 3H) , 6.75 - 7.42 (m, 4H) .

*: signal of (1"R,3S,4R) ; **: signal of (1"R,3R,4S) . Reference Example 1-(1)

To a solution of methyl (S) - (+) -2-methy1-3- hydroxypropionate (11.8 g; 0.10 mol) and diisopropyl- ethylamine (19.4 g; 0.15 mol) in dichloromethane (80 ml) . there was dropwise added a solution of methoxyethoxymethyl chloride (MEMC1) (18.7 g; 0.15 ml) in dichloromethane (20 ml) , and the resultant mixture was stirred for 2.5 hours. The reaction mixture was combined with water (50 ml) and hexane (100 ml) for extraction, and the aqueous layer was further extracted with hexane (100 ml) twice. The extracts were combined together, washed with water (100 ml x 3) and dried over anhydrous magnesium sulfate. Removal .of the solvent by distillation gave a pale yellow oily substance (18.33 g; 89 % yield), of which a portion (3 g) was distilled to give colorless oil (2.90 g) .

B.P.: 125°C/1 Torr (bath temp.);

[ ]²⁰ +12.1° (c = 1.34, CHC1₃) ;

IR (neat) V: 1740 cm ;

NMR (CDC1₃) : δ = 1.20 (d, J = 6 Hz, 3H) , 2.60 - 2.95 (m, IH) , 3.40 (s, 3H) , 3.48 - 3.90 ( , 6H) , 3.71 (s, 3H) , 4.72 (s, 2H) .

Reference Example l-(2)

Methyl (S)-(+)-2-methyl-3-methoxyethoxymethyloxy- propionate (2.06 g; 10 mM) was dissolved in dry ether (60 ml) , followed by cooling to -70°C under argon stream. A IM hexane solution of diisobutylaluminium hydride (DIBAL) (12.5 ml; 12.5 mM) was dropwise added thereto in 15 minutes, and the resultant mixture was stirred at the same temperature for 45 minutes. Methanol (10 ml) was added to the reaction mixture, which was then heated to room temperature. Water (10 ml) was added thereto, followed by stirring to produce turbidity. The resulting mixture was dried over anhydrous magnesium sulfate, filtered through celite and washed thoroughly with ethyl acetate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate : benzene = 1 : 4) to give (S)-(+) -2-methyl-3-methoxyethoxy- methyloxypropanal as colorless oil (0.90 g'; 51 % yield). [α]²⁰ +23.8° (c = 1.25, CHC1₃) ; IR (neat) V: 2725, 1725 cm^"1;

NMR (CDC1₃) : <S = 1.10 (d, J = 6 Hz, 3H) , 2.40 - 2.80 (m, IH) , 3.38 (s, 3H) , 3.43 - 3.82 (m, 6H) , 4.70 (s, 2H) , 9.71 (d, J = 2 Hz, IH) ;

Mass m/e: 175 (M-l)⁺, 147 (M-29)⁺, 145 (M-31)⁺. Reference Examples 2 to 4

In the same manner as in Reference Example 1-(1) or l-(2), the 2-methylpropanal compounds as shown in Table 3 were produced from methyl (S)-(+) -2-methyl-3-hydroxy- propionate.

Table 3

(1) (2)

(Continued)

Reference R Physical data

Example

No.

4 CH₂(OCH₂CH₂)₃OMe (1) NMR (CDC1₃) : δ = 1.15 (d, J = 6Hz, 3H) , 2.50-

2.90 (m, IH) , 3.36 (s, 3H) ,

3.48-3.85 (m, 17H) , 4.70 (s,

2H) .

(2) NMR (CDC1₃) : δ = 1.10 (d, J = 6Hz, 3H) , 2.50-

2.80 (m, IH) , 3.38 (s, 3H) ,

3.5-3.85 (m, 14H) , 4.71 (s.

2H) , 9.73 (d, J = 2Hz, IH) .

Reference Example 5

MeOOC

(1) Methyl (S)-(+)-3-hydroxy-2-methylpropionate (1.00 g; 8.47 mM) and imidazole (1.15 g; 16.9 mM). were dissolved in dry dimethylformamide (10 ml)', and t-butyldi- methylchlorosilane (1.30 g; 8.62 mM) was added thereto at room temperature. The resultant mixture was stirred at the same temperature for 1.5 hours, and water (10 ml) and hexane (20 ml) were added thereto. The organic layer was separated, and the aqueous layer was extracted with hexane (10 ml) twice. The organic layer and the extracts were combined together, washed with water (5 ml) three times and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give methyl (S) -(+) -3- (t-butyldimethylsilyloxy)-2-methyl- propionate (1.91 g; 97 % yield) as colorless oil, of which a portion (179 mg) was distilled to give a pure product (176 mg) .

B.P.: 120°C/14 mmHg (bath temp.);

[ ]²⁰ +18.9° (c =^** 1.00, CHC1₃) ;

IR (neat) : 1740 cm ;

NMR (CDC1₃) : δ = 0.03 (s, 6H) , 0.87 (s, 9H) , 1.13

(d, J = 7 Ηz, 3H) , 2.64 (q, J = 7 Hz, IH) , 3.66 (s, 3H) ;

Mass m/e: 175 (M-57) + (2) The above obtained methyl (S)-(+) -3-(t-butyl dimethylsilyloxy)-2-methylpropionate (1.31 g; 5.6 mM) was dissolved in dry ether (18.5 ml), and a IM hexane solution of IM diisobutylaluminium hydride (8.4 ml; 8.4 mM) was dropwise added thereto at -78°C under argon stream. The reaction mixture was subjected to post-treatment in the same manner as in Reference Example l-(2) to give give (S)-(+)- 3-(t-butyldimethylsilyloxy)-2-methylpropanal (0.8.9 g; 78 % yield) as colorless oul, of whcih a portion (57 mg) was distilled to give a pure product (53 mg) .

B.P.: 110°C/14 mmHg (bath temp.);

[α]²⁰ +37.8° (c = 1.20, CHC1₃) ;

IR (neat) v: 1735 cm ;

NMR (CDC1₃) : δ •= 0.06 (s, 6H)', 0.0'8 (s, 9H) , 1.09 (d, J = 7 Hz, 3H) , 2.57 (tq, J = 7 and 6 Hz, IH) , 3.84 (d, J = 6 Hz, 2H) , 9.74 (d, J = 1.5 Hz, IH) ;

Mass m/e: 145 (M-57)⁺.

Reference Example 6

From methyl (S) -(+)-3-hydroxy-2-methylpropionate (3.10 g; 26 mM) , the corresponding methylthiomethyl ether derivative was produced according to the method as described in Aust.J.Chem. , 3_1_, 1031 (1978). A portion (1.19 g; 6.7 mM) of the methylthiomethyl ether derivative was dissolved in -dry ether (35 ml), and a 1 M hexane solution of diiso¬ butylaluminium hydride (DIBAL) (7.30 ml; 7.3 mM) was drop¬ wise added thereto at -78^σC under argon stream in more than 10 minutes, followed by stirring at the same temperature for 2 hours. The reaction mixture was subjected to post- treatment in the same manner as in Reference Example l-(2) to give (S)-3-methylthiomethyloxy-2-methylpropanal (0.59 g; 60 % yield) as colorless oil.

[ ]²⁰ +15.8° (σ = 1.01, CHC1₃) ; '

IR (neat) V: 2930, 1730, 1430, 1075 cm^"1;

NMR (CDC1₃) : ^' = 1.15 (d, J = 7.3 Hz, 3H) , 2.13 (s, 3H) , 2.5 - 2.8 (m, IH) , 3.75 (d, J = 5.9 Hz, 2H) , 4.63 (s, 3H) , 9.72 (d, J = 1.5 Hz, IH) ;

Mass m/e: 148 (M)⁺, 101 (M-47)⁺;

Elementary analysis for C^H.-O-S:

Calcd.: C, 48.61 %; H, 8.16 %; S, 21.63 %.

Found: C, 48.42 %; H, 8.07 %; S, 21.36 %.

Reference Example 7

(1) From methyl (S)-(+)-3-hydroxy-2-m thyl- propionate (137 mg; 1.2 mM) and chloromethylphenylsulfide (276 mg; 1.7 mM) , the phenylthiomethyl ether derivative (64 mg; 23 % yield) was produced according to the method as described in Chem.Lett. , 1277 (1979) (purified by silica ge column chromatography (dichloromethane : hexane = 3 : 1) ) . Colorless oil;

NMR (CDC1₃): ^δ = 1.18 (d, J = 7.0 Hz, 3H) , 2.80 (q, J = 6.0 Hz, IH) , 3.64 (s, 3H) , 4.99 (s, 3H) , 7.2 - 7.6 (m, 5H) .

(2) The above obtained phenylthiomethyl ether derivative was treated in the same manner as in Reference Example l-(2) to give (S)-3-phenylthiomethyloxy-2-methyl- propanal (36 mg; 65 % yield) as colorless oil.

IR (neat) v_: 2880, 1730, 1590, 1490, 1440, 1080

NMR (CDC1₃) : δ = 1.13 (d, J = 7.0 Hz, 3H) , 2.5 - 2.9 (m, IH) , 3.82 (d, J = 5.9 Hz, 2H) , 5.00 (s, 2H) , 7.2 - 7.6 (m, 5H) , 9.68 (d, J = 1.5 Hz, IH) ;

Mass m/e: 210 (M)⁺, 101 (M-109)⁺;

High resolution mass for C₁₁H₁₄0₂S:

Calcd. m/e: 210.0714.

Found m/e: 210.0714.

Reference Example 8

(2S)-3-(1'-Ethoxy)ethyloxy-2-methylpropanal (0.41 g; 2.5 mM) , which was obtained in the course of the synthesis of the starting material in Example 1, i.e. (S)-3- benzyloxy-2-methylpropanal, was subjected to oxidation according to the method as described in J.Am.Chem.Soc. , 105, 5021 (1983) to give (2R)-3-(l^r-ethoxy)ethyloxy-2-methyl- propanal (0.32 g; 78 ) as colorless oil.

NMR (CDC1₃) : ^δ = 1.13 (a, j _= 7.0 Hz, 3H) , 1. .20 (t, J = 7.0 Hz, 3H) , 1.30 (d, J » 5.5 Hz, 3H) , 2.5 - 2.8 ( , IH) , 3.3 - 3.9 (m, 4H) , 4.70 (q, J = 5.5 Hz, IH) , 9.73 (d, = 1.5 Hz, IH) .

Reference Example 9

(1) A solution of methyl (S)-3-hydroxy-2-methyl- propionate (2.00 g; 17 mM) in dichloromethane (30 ml) was added to isobutene (34.0 ml; 360 mM) cooled at -78°C, and five drops of cone, sulfuric acid were added thereto. The resultant mixture was gradually heated to room temperature, followed by stirring at the same temperature for 30 hours. The reaction mixture was diluted with n-hexane, washed successively with a saturated aqueous sodium bicarbonate solution and an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent by distillation under reduced pressure, the residue was purified by silica gel column chromatography (ether : hexane - 12 : 88) to give the t-butyl ether compound (2.64 g; 90 % yield) .

Colorless oil; NMR (CDC1₃) : = 1.15 (d, J = 7.0 Hz, 3H) , 1.16 (s, 9H) , 2.5 - 2.8 (m, IH) , 3.2 - 3.6 ( , 2H) , 3.69 (s, 3H)

(2) A solution of the t-butyl ether compound (1.28 g; 7.4 mM) as above obtained in tetrahydrofuran (10 ml) was dropwise added to an ice-cooled suspension of lithium aluminium hydride (0.25 g; 6.3 mM) in tetrahydro¬ furan (20 ml) , followed by stirring at the same temperature for 30 minutes. After elevating the temperature up to room temperature, stirring was further continued for additional one hour. The reaction mixture was ice-cooled, and water (0.25 ml) , 15 % aqueous sodium hydroxide solution (0.25 ml) and water (0.75 ml) were successively thereto, followed by stirring for 10 minutes. Insoluble materials were collecte by filtration and washed with ethyl acetate. The filtrate and the washings were combined together and dried over anhydrous magnesium sulfate. After removal of the solvent by distillation under reduced pressure, the residue was purified by silica gel column chromatography (ether : hexane = 45 : 55) to give the alcohol compound (0.77 g; 70 % yield) .

Colorless oil;

NMR (CDC1-) : ^δ = 0.84 (d, J = 7.0 Hz, 3H) , 1.20 (s, 9H) , 1.7 - 2.1 (m, IH) , 3.1 - 3.7 (m, 5H) .

(3) The alcohol compound (0.72 g; 4.9 mM) as above obtained was subjected to Swern's oxidation in the same manner as in Reference Example 10 to give (S)-3-t- butoxy-2-methylpropanol (0.65 g; 92 % yield) in a pure state. Colorless oil;

[α] 2²⁰ +31.5° (c = 0.11, CHC1₃) D

IR (CHC1₃) v: 2975, 1725, 1460, 1070 cm -1;

NMR (CDC1₃): δ = 1.09 (d, J = 7.0 Hz, 3H) , 1.18 (s, 9H) , 2.4 - 2.7 (m, IH) , 3.55 (d, J •= 6.0 Hz, 2H) , 9.71 (d, J = 1.5 Hz, IH) ;

Mass m/e: 129 (M-15)⁺, 87 (M-57)⁺.

Reference Example 10

(l'S,l"R,3S,4R) A suspension of (1"R,3S,4R)-1-(di-p-anisyl¬ methyl)-3-acetyl-4-[1"-(benzyloxymethyl) ethyl] zetidin-2-one (227 mg; 0.47 mM) and potassium iodide (93 mg; 0.56 mM) in tetrahydrofuran (10 ml) was stirred at room temperature for 30 minutes, followed by ice-cooling. To the suspension, a IM tetrahydrofuran solution of K-Serectride (1.12 ml; 1.12 mM) was added, and the resultant mixture was stirred under ice-cooling for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with 0.1N hydrochloric acid, a saturated sodium thiosulfate solution, a saturated sodium bicarbonate solution and a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent by distillation unde reduced pressure, the residue was purified by silica gel column chromatography (ether) to give a mixture of (l'R,l"R,3S,4R)- and (1'S,1"R,3S,4R) -1- (di-p-anisylmethyl) - 3-(1'-hydroxyethyl)-4-[1"-(benzyloxymethyl)ethyl]azetidin- 2-one (226 mg; 99 % yield). A portion of 'this mixture (125 mg) was further purified by thin layer chromatography (acetone : dichloromethane = 1 : 9, twice) to give each of the stereoisome s in a pure state.

(l'R,l"R,3S,4R) form: 115 mg; (l'S,l"R,3S,4R) form: 7 mg.

The product ratio of the (1'R,1"R,3S,4R) form and the (l'S,l"R,3S,4R) form was ascertained to be 16 : 1 on the basis of the above isolation amount. (l'R,l"R,3S,4R) form:- Colorless oil;

[α]²⁰ -55.1° (c = 0.85, CHC1₃) ;

IR (neat) v: 3460, 2980, 1735, 1610, 1510, 1250, 1180 cm^"1;

NMR (CDC1₃) : δ = 0.94 (d, J = 6.8 Hz, 3H) , 1.24 (d, J = 6.4 Hz, 3H) , 1.8 - 2.1 (m, IH) , 2.20 (brs, IH) , 3.00 (dd, J = 6.4 and 2.4 Hz, IH) , 3.35 (d, J = 5.3 Hz, 2H) , 3.70 (dd, J = 5.7 and 2.4 Hz, IH) , 3.77 (s, 3H) , 3.79 (s, 3H) , 4.0 - 4.2 (m, IH) , 4.42 (s, 2H) , 5.55 (s, IH) , 6.81 (d, J = 8.8 Hz, 2H) , 6.83 (d, J = 8.8 Hz, 2H) , 7.17 (d, J = 8.8 Hz, 2H) , 7.21 (d, J = 8.8 Hz, 2H) , 7.31 (s, 5H) ;

Mass m/e: 489 (M)⁺, 444 (M-45)^÷, 3.98 (M-91)⁺;

High resolution mass for C_3QH₃_ 0₅:

Calcd. m/e: 489.2513.

Found m/e: 489.2511. (1*S,1"R,3S,4R) -form:-

Colorless oil;

[_α]²⁰ -26.7° (c = 0.73, CHC1₃) ; '

IR (neat) _v 3490, 2960, 1740, 1615, 1515, 1250,

1180 cm^"1;

NMR (CDC1₃) : δ = 0.93 (d, J = 7.0 Hz, 3H) , 1.22 (d, J = 6.4 Hz, 3H) , 1.9 - 2.2 ( , IH) , 2.35 (d, J = 4.5 Hz, IH) , 2.99 (dd, J = 7.2 and 2.4 Hz, IH) , 3.33 (d, J. = 5.5 Hz, 2H) , 3.55 (dd, J = 5.1 and 2.4 Hz, IH) , 3.78 (s, 6H) , 3.9 - 4.1 (m, IH) , 4.42 (s, 2H) , 5.52 (s, IH) , 6.82 (d, ^" = 8.8 Hz, 4H) , 7.17 (d, J = 8.8 Hz, 2H) , 7.19 (d, J = 8.8 Hz, 2H) , 7.31 (s, 5H) ;

Mass m/e: 489 (M)⁺, 444 (M-45)⁺, 3.98 (M-91)⁺.

Reference Example 11

To a solution of (1'R,1"R,3S,4R)-1-(di-p-anisyl¬ methyl) -3-(1'-hydroxyethyl)-4-[1"-(benzyloxymethyl)ethyl]- azetidin-2-one (88 mg; 0.18 mM) in acetonitrile (2 ml), a 0.27 M aqueous solution of ceric (IV) ammonium nitrate (2.0 ml; 0.54 mM) was added under ice-cooling, followed by stirring at the same temperature for 1.5 hours. The reac¬ tion mixture was diluted with ethyl acetate and washed successively with water, a saturated sodium bicarbonate solution and a saturated sodium sulfite solution, a satu¬ rated sodium bicarbonate solution and a saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel colum chromato¬ graphy (acetone : methylene chloride = 1 : 3) to give (1'R,1"R,3S,4R) -3-(1'-hydroxyethyl) -4-[1"-(benzyloxymethyl) - ethyl] azetidin-2-one (43 mg; 91 % yield). Colorless oil;

, 20

[α] -5.0° (c = 0.44, CHC1₃) ; IR (neat) v: 3600 - 3200, 2995, 1745, 1450, 1370,

NMR (CDC1₃) : δ = 0.98 (d, J = 6.8 Hz, 3H) , 1.29

(d, J = 6.4 Hz, 3H) , 1.8 - 2.1 (m, IH) , 2.53 (d, J = 4.8 Hz, IH) , 2.99 (ddd, J = 7.7, 2.2 and 1.0 Hz, IH) , 3.3 - 3.7 (m, 3H) , 3.9 - 4.2 (m, IH) , 4.49 (s, 2H) , 5.90 (bs, IH) , 7.32 (s, 5H) .

Mass m/e: 264 (M+l)⁺

Reference Example 12

To a solution of (l'R,l"R,3S,4R) -3-(1^«-hydroxy¬ ethyl) -4- [1"- (benzyloxymethyl) ethyl] azetidin-2-one (33 mg; 0.13 mM) in dimethylformamide (1 ml) , imidazole (51 mg; 0.75 mM) and t-butyl dimethylchlorosilane (95 mg; 0.63 mM) were added, and the resultant mixture was stirred at room temper¬ ature for 14 hours. The reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. After removal of the solvent by -distil¬ lation under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate : hexane = 1 : 2) to give (1'R,1"R,3S,4R) -3- (I'-t-butyldimethylsilyl- oxyethyl) -4- [1"- (benzyloxymethyl) ethyl] azetidin-2-one (47 mg; 99 % yield) .

Colorless oil;

[α]²⁰ -13.1° (c = 0.35, CHC1₃) ;

IR (neat) v: 3260, 2960, 2890, 1755, 1460, 1375, 1260, 1100 cm^"1;

NMR (CDC1₃) : δ = 0.07 (s, 6H) , 0.88 (s, 9H) , 1.01 (d, J - 6.8 Hz, 3H) , 1.20 (d, J = 6.4 Hz, 3H) - 1.9 - 2.2 (m, IH) , 2.92 (ddd, J = 5.7, 2.2 and 1.0 Hz, IH) , 3.41 (d, J = 5.3 Hz, 2H) , 3.68 (dd, J = 5.5 and 2.2 Hz, IH) , 4.1 - 4.3 (m, IH) , 4.47 (s, 2H) , 5.80 (bs, IH) , 7.31 (s, 5H) ;

Mass m/e: 362 (M-15)⁺, 320 'M-57)⁺.

Reference Example 13

To a solution of (1'R,1"R,3S,4R)-3- (1'-t-butyl- dimethylsilyloxyethyl) -4- [1"-(benzyloxymethyl)ethyl]- azetidin-2-one (45 mg; 0.12 mM) in ethyl acetate (2 ml), 5 palladium-carbon (10 mg) was added, and the resultant mixture was stirred at room temperature for 20 hours under hydrogen stream. Insoluble materials were collected by fitration and washed with ethyl acetate. The filtrate and the washings were combined together and concentrated under reduced pressure to give (1*R,1"R,3S,4R)-3-(1'-t-butyldi- methyIsilyloxyethyl)-4-[1"-(hydroxymethyl)ethyl]azetidin-2- one (35 mg; 100 % yield) in a pure state.

Colorless crystals (recrystallized from a mixture of ether and hexane) ;

M.P. : 90 - 91°C; [α]²° -21.7° (c = 0.46, CHC1₃) ;

IR (KBr) v: 3450, 3190, 3115, 2960, 1755, 1375, 1255 cm^"1;

NMR (CDC1₃) : = 0.13 (s, 6H) , 0.90 (d, J = 6.8 Hz, 3H) , 0.92 (s, 9H) , 1.35 (d, J = 6.2 Hz, 3H) , 1.8 - 2.1 (m, IH) , 2.95 (dd, J = 8.3 and 5.3 Hz, IH) , 3.17 (ddd, J = 9.0, 2.2 and 1.0 Hz, IH) , 3.29 (dd, J = 9.0 and 2.2 Hz, IH) , 3.4 - 3.7 (m, 2H) , 4.13 (dq, J = 9.0 and 5.4 Hz, IH) , 5.93 (bs, IH) ;

Mass m/e: 272 (M-15)⁺, 230 (M-57)⁺, 200 (M-87)⁺, 156 (M-131) ;

Elementary analysis for C..H__qNO,Si:

Calcd.: C, 58.50 %; H, 10.17 %; N, 4.87 %.

Found: C, 58.38 %; H, 9.90 %; N, 4.80 %. Reference Example 14

A suspension of (l'R,l"R,3S,4R)-3-(l'-t-butyl- dimethyIsilyloxyethyl)-4-[l"-(hydroxymethyl)ethyl] zetidin- 2-one (22 mg; 0.077 mM) and pyridinium dichromate (144 mg; 0.38 mM) in dimethylformamide (1 ml) was stirred at room temperature for 15 hours and poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography (dichloromethane : ethyl acetate : acetic acid = 60 : 40 : 0.5) to give (1'R,1"R,3S,4R) -3-(1*-t-butyldimethylsilyloxy- ethyl) -4-(l"-carboxyethyl)azetidin-2-one (21 mg; 91 % yield) .

Colorless crystals (recrystallized from a mixture of ethyl acetate and hexane) ;

M.P.: 148 - 149°C (decomp.);

[α]²⁰ -34.6° (c = 0.26, MeOH) ;

IR (KBr) v: 3280, 2950, 1720, 1460, 1280, 1140,

1040 cm^" ;

NMR (CDC1₃) : δ = 0.07 (s, 6H) , 0.80 (s, 9H) , 1.19 (d, J = 5.7 Hz, 3H) , 1.26 (d, J = 6.6 Hz, 3H) , 2.74 (dq, J = 5.4 and 6.8 Hz, IH) , 3.03 (dd, J = 4.5 and 2.2 Hz, IH) , 3.94 (dd, J = 5.4 and 2.2 Hz, IH) , 4.20 (dq, J = 4.5 and 7.7 Hz, IH) , 6.05 (bs, IH) ;

Mass m/e: 286 (M-15) ⁺, 244 (M-57)⁺;

Elementary analysis for C..H^NO^Si:

Calcd.: C, 55.78 %; H, 9.03 %; N, 4.65 %.

Found: C, 55.89 %; H, 8.97 %; N, 4.60 %.

Reference Example 15

A mixture of (1'R,1"R,3S,4R) - and (1 'S,1"R,3S,4R) -. 1-(di-p-anisylmethyl) -3-(1'-hydroxyethyl) -4-[1"-(benzyloxy¬ methyl)ethyl]azetidin-2-one (12 : 1) was treated in the same manner as in Reference Example 16 (i.e. CAN oxidation, silylation, hydrogenation and oxidation) to give the corre¬ sponding carboxylic acid, which was recrystallized from a mixture of ethyl acetate and hexane to give (1'R,1"R,3S,4R) - 3-(1'-t-butyldimethylsilyloxyethyl) -4-(l"-carboxyethyl)- azetidin-2-one in a pure state. This product was confirmed to be identical with the product in Reference Example 16 by measurement of melting point, optical rotation, IR, NMR and mass spectrum.

Industrial Applicability

As understood from the above, this invention provides the 1'-methyl-beta-lactam compounds (I), which can be readily converted into the beta-lactam compounds (II) , which are known as the intermediates in the synthesis of 1^t-methylcarbapenem compounds having a potential anti-microbial activity.

Claims

C L A I M S

1. A 1'-methyl-beta-lactam compound of the formula:

wherein R is an optionally substituted diarylmethyl group or an optionally substituted aryl group and R 2 is a protective group for hydroxyl.

2

2. The compound according to claim 1, wherein R is a straight or branched Cm -C. alkyl group, a C,-C_β alkenyl group, a C.-C- alkoxy(C.-Cj.)alkyl group, a group of the formula: R 40(CH₂CH₂0) CH₂~ wherein R4 is a .-Cg alkyl group and n is an integer of 1 to 4, a C.-C,- alkylthio(C,-C_ς)alkyl group, an optionally substituted arylthiomethyl group, a tetrahydropyranyl group, an optionally substituted arylmethyl group or an acyl group.

3. The compound according to claim 1, wherein R' is a methoxymethyl group, a methylthiomethyl group, a phenylthiomethyl group, a 2-methoxyethoxymethyl group, a methoxy(triethyleneoxy)methyl group, an isopropoxymethyl group, a 1-ethoxyethyl group, a 1-methyl-1-methoxyethy1 group, a 1-isopropoxyethyl group, an allyl group, a t-butyl group or a benzyl group.

4. The compound according to any of claims 1 to 3, wherein R^"1" is a di-p-anisylmethyl group.

5. The compound according to any of claims 1 to

3, wherein R is a p-methoxyphenyl group.

6. The compound according to any of claims 1 to

4, wherein the 1*-methyl group in the side chain at the 4-position takes a R-configuration.

7. A process for producing a beta-lactam compound of the formula:

3 wherein R is a protective group for hydroxyl, which comprises (a) reacting a compound of the formula:

2 . wherein R is a protective group for hydroxyl with an amine of the formula:

R¹-NH₂ (IV) wherein R is an optionally substituted diarylmethyl group or an optionally substituted aryl group to give a compound of the formula:

wherein R 1 and R2 are each as defined above;

(b) reacting the compound (V) with diketene to give a compound of the formula:

wherein R 1 and R2 are each as defined above;

(c) reducing the compound (I) for converting the acetyl group into a hydroxyethyl group to give a compound of the formula:

wherein R 1 and R2 are each as defined above;

(d) subjecting the compound (VI) to protection of a hydroxyl group to give a compound of the formula:

wherein R1, R2 and R3 are each as defined above; (e) removing the protecting groups R 1 and R2 m the compound (VII) to give a compound of the formula:

wherein R is as defined above; and

(f) oxidizing the hydroxymethyl' group in the compound (VIII) to a carboxyl group.

8. A process for producing a beta-lactam compound of the formula:

wherein R is a protective group for hydroxyl, which comprises (a) reacting a compound of the formula:

wherein R is a protective group for hydroxyl with an amine of the formula: R¹-NH. (IV) wherein R is an optionally substituted or diarylmethyl group or an optionally substituted aryl group to give a compound of the formula:

wherein R 1 and R2 are each as defined above;

(b) reacting the compound (V) with diketene to give a compound of the formula:

wherein R 1 and R2 are each as defined above;

(c) reducing the compound (I) for converting the acetyl group into a hydroxyethyl group to give a compound o the formula:

wherein R 1 and R2 are each as defined above;

(g) removing the protective group R .1 i^■n the compound (VI) to give a compound of the formula:

wherein R is as defined above;

(h) protecting the hydroxyl group in the compound (IX) to give a compound of the formula:

wherein R~ and R^" are each as defined above;

2 (i) removing the protective group R in the compound (X) to give a compound of the formula:

wherein R is as defined above; and

(j) oxidizing the hydroxymethyl group in the compound (XI) to a carboxyl group.