JPS60120881A - 2-azacycloalkylthiopenem derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a series of antimicrobial agents containing a 2-azetidinone (beta-lactam) ring. Chemically, one antimicrobial agent of the present invention is identified as a 6-alpha-1-hydroxyethyl-2-substituted-2-enemu-3-carboxylic acid compound.

Although certain prior art 02-flil-2-venemu 3-carboxylic acid compounds have been previously published, there is a need for new compounds with desirable antimicrobial therapeutic properties.

PROBLEM TO BE SOLVED BY THE INVENTION The present invention seeks to provide a set of compounds or pharmaceutically acceptable salts thereof. In the formula; 2A is an alkylene group having 2-4 carbon atoms.

2 carbon atoms in which one carbon atom has an oxo substituent
B is a carbonyl group; , thiocarbonyl group, methylene group or imino group; R1 is hydrogen or forms an ester group that is hydrolyzed in vivo; R2 is hydrogen, formyl group, alkylcarbonyl group, N-
alkylaminocarbonyl group, N-alkylaminesulfonyl group, aminosulfonyl group, aminocarbonyl group,
Alkoxycarbonyl group, alkylsulfonyl group, alkyl group or aminocarbonyl group, alkyl-8 (01m-, hydroxyl group,
an alkyl group (wherein each alkyl group has 1-4 carbon atoms) substituted by an amino group, an alkylcarbonylamino group, a formamido group or an alkylsulfonylamino group; R3 is hydrogen, a methyl group; , formyl group, methylcarbonyl group or methylsulfonyl group: alk is 1-4
is an alkylene group having 4 carbon atoms; n is 0 or 1; and m is 0.1 or 2.

Included within the scope of this invention is a compound of Formula 1, or a pharmaceutically acceptable salt thereof. where R is as defined above for compounds of formula 1.

Preferred compounds of formulas 1 and 2 are those in which A is an alkylene group, B is a carbonyl group), R2 is hydrogen or a methyl group, and n is 0. Particularly preferred is when R1 is hydrogen.

R is 2-pyrrolidon-3-yl group, 2-pyrrolido9-4-yl group, py is lysin-2-one-3-yl group, 1-
methyl-biyridin-2-one-3-yl group, or 2
-biyridon-5-yl group.

Also preferred are compounds in which A is an alkylene group, B is a methylene group, R2 is a formyl group, and n is 0. It is particularly preferable that R□ is hydrogen and R is 1-
Formyl-3-pyrrolidinyl group or 1-formylpi is a compound that is a lysin-3-yl group.

Furthermore, compounds in which A is a carbonylethylene group or a carbonylethylene group, B is a carbonyl group, and *R2 is hydrogen or a methyl group, provided that the ethylene or propylene group of A is bonded to B: especially R A compound in which □ is hydrogen and R is a pyrrolidin-2,5-dione-3-yl group.

is also preferable.

Furthermore, A is a 1-oxaalkylene group, B
is a carbonyl group; 9. Compounds in which R2 is hydrogen or a methyl group and n is 1, but the oxygen of the 1-oxaalkylene group is bonded to B: Specially 1cR□ is hydrogen, and R is (3-methyl-1 ,3-oxazolidine-2-
on-4-yl)methyl group, (3-methyl-1,3-oxazolidin-2-on-5-yl)methyl group, (1,
3-oxazolidin-2-one-4-yl)methyl group,
Also preferred are compounds which are (1,3-oxazolidin-2-one-5-yl)methyl group.

Compounds in which A is a 1-oxaalkylene group, B is a carbonyl group, R2 is hydrogen or a methyl group, and o'' is 0; in particular, R1 is hydrogen.

Compounds in which R is 3-methyl-ylhydro-1,3-oxazolidin-2-one-5-yl are included in the present invention.

Further, A is a 1-theaalkylene group, B is a carbonyl group, hR2 is hydrogen or a methyl group, and n is 1
In particular, a compound in which R1 is hydrogen and R is (1,3-
Compounds that are thiazolidin-2-one-4-yl)methyl groups are also encompassed by the present invention.

and a pharmaceutical composition comprising a compound of formula I or ■ and a pharmaceutically acceptable diluent or carrier; Methods of treating infections are encompassed by the invention.

Compounds of formulas I and ■ are useful as antibacterial agents and are of formula 91. is a derivative of the bicyclic nucleus of.

Throughout this specification, the nucleus of formula 1 is defined as [2- is pene
It is identified by the designation ml and the ring atoms are numbered as shown above. The carbon atom bonded to ring carbon 6 is numbered 8. Also, throughout this specification the abbreviation 1'-P N BJ is used for the p-nitrobenzyl group.

In compounds of formula 1, the relationship between the hydrogen on bridgehead carbon 5 and the residual hydrogen on carbon 6 can be either cis or trans. The present invention includes both isomers as well as mixtures thereof. The trans isomer is generally preferred for use as a drug.

Cis isomers can be easily converted to trans-isomers.

In general, carbon 5 will have an absolute entity chemistry designated as Prolog-Ingold's Dan, using the dead entity chemistry notation.

And this is what is used in this application. Therefore.

For example, the compound of formula (1) in which R2 is hydrogen and R is 2-pyrrolidon-3-yl group is -(5B, 5fi)-6-
It is named ((R)-1-human90quinethyl)-2-(2-pyrrolido9-3-yl)thio-3-carboxyl-2-benem.

It will be appreciated that various optically active isomers of these new compounds are possible; the present invention encompasses such optically active isomers as well as mixtures thereof. .

The present invention includes benems in which the 3-carboxyl group is esterified with a nontoxic ester group that is hydrolyzed in vivo. These esters are rapidly cleaved in mammalian blood or tissue to liberate the corresponding 4-nemu-3-carboxylic acid.

Typical examples of such readily hydrolyzable ester-forming residues are alkanoyloxymethyl groups with 3-8 carbon atoms, 1-(alkanoyloxy)ethyl groups with 4-9 carbon atoms, Base.

1-methyl-1-(alkanoyloxy)ethyl with 5-10 carbon atoms, alkoxy-carbonyloxymethyl with 3-6 carbon atoms, 1-( with 4-7 carbon atoms) Alkoxycarbonyloxy7)
Ethyl group, 1-methyl-1 with 5-8 carbon atoms
-(alkoxycarbonyloxy)ethyl group, N-(alkoxycarbonyl)aminomethyl group with 3-9 carbon atoms, 1-(N-
[Alkoxycarbonylcoamino)ethyl group, 3-phtha, lysyl group, 4-crotonochonyl &.

gamma-butyrolactone-4-yl group, carboxy7alkyl-carbonyloxymethyl group having 4-12 carbon atoms, t or 5-methyl-2-suquino-1,3-dioxolen-4-yl-methyl It is the basis.

Formula 1 is used to produce a compound of Formula 1 or ■, in which R1 is a group that forms an ester that is hydrolyzed in vivo! or ■ acid (R, is hydrogen) -.

React with a base to form the corresponding anion.

Suitable cations are sodium, potassium, calcium, tetra-alkylammonium and the like. The anion is an aqueous solution of 1 or 1, for example,
It can be prepared by lyophilizing an aqueous solution containing tetrahydrofuran and sodium bicarbonate or tetrabutylammonium hydroxide.

This is how you get it! or (2) is reacted with the corresponding chloride or bromide of R1 at about 20 to about 50°C, preferably 25°C, in a reaction-inert solvent such as acetone or dimethylformamide P.

Compounds of formula (1) can be synthesized according to steps A-GK.

As shown in Step A, the compound of formula 1 is obtained from the known dipromuinam of formula 1 by Chem.

Pharm, Bull, 29.2899-290
9 (1981).

This dibrome a hydroxide is heated at a temperature of about -90 to -40°C (preferably about -78 ℃) to perform an exchange reaction with t-butylmagnesium chloride.

Other organometallic reagents can also be used.

The reaction mixture thus obtained is treated in situ with a suitable aldehyde; for example acetaldehyde for the 1-hyrroquinethyl derivative. This aldehyde is about -8
0 to -60°C (approx. -7°C for acetaldehyde)
(preferably at 8°C).

The bromohydro-90xybenam V thus obtained is hydrogenated to remove the 6-bromo substituent. A suitable hydrogenation catalyst is a noble metal catalyst such as palladium.
:1 methanol-water or 1:1 tet2hydrofura/-
in a proton-donating solvent such as water (preferably 1:1 methanol-water) at a pressure of about 1 to 4 atmospheres (preferably 4
pressure) and temperature of about 0 to 30°C (preferably about 25°C).
℃).

The alcohol of the formula (1) thus formed is converted into a trialkyl alcohol of the formula R9 R, -8i-Q9 (wherein R8 is each an alkyl group having 1 to 6 carbon atoms p and Q is chlorine, bromine or iodine). It can be protected by Rokura/.

i.e., in a polar proto/non-donating medium such as N,N-dimethylformamide at a temperature range of about 5 to 4
At 0°C, preferably about 25°C, dimethyl-t-butylchloride in the presence of an amide/proto/acceptor such as imidazole forms a trialkylinylhydroxyl protecting group as shown in formula 1. do.

Treatment of ■ with mercuric acetate in acetic acid at a temperature of about 90°C yields olefin/■.

To obtain the desired azetidine/2, the olefin (2) is oxidized in a reaction-inert solvent such as dichlorometh/2 at a temperature of about -80 to -40'C, preferably about -78C. Treatment of this reaction product with an alkanol such as methanol-8 gives azetidi/.

As shown in Step B, the compound of formula (1) is mixed with two M+R.

-8-qSl-8- (in the formula' RlG is a carbon atom 1-4
an alkyl group, preferably an ethyl group.

Treatment with a trithiocarbonate (1M is a metal such as sodium or potassium) gives a compound of formula X. This conversion of (1) to X is carried out at a temperature in the range of about 0-35°C, preferably about 25°C, in an organic solvent or water, preferably a mixture of water and dichloromethane.

A compound of formula x can be a tertiary alkyl amine/(each alkyl group is ethyl-di-isopropyl amine/).

chlorooxalic acid p-nitrobe/silt condensation in the presence of
A compound of formula XI is obtained. This condensation reaction is about 5-25
C., preferably about 10.degree. C., in a reaction-inert solvent, preferably dichloromethane.

The martial compound thus obtained is heated in the temperature range of about 40-80℃.
trialkyl phosphite (each alkyl group having 1-4 carbon atoms), such as triethyl phosphite, in a reaction-inert solvent such as trichlormeth/, preferably about 60' cyclization using (2) gives the penem of formula (2).

The thio group of compound ] can be oxidized using an oxidizing agent such as m-chloroperbenzoic acid in a reaction-inert solvent such as dichloromethane at a temperature range of about -10 to -30°C, preferably -20°C. When oxidized, it becomes the corresponding sulfoxide X■.

The sulfoxide 0 in the compound of formula x is 1, for example using the appropriate sodium or potassium salt of the mercaptide at a temperature range of about -10 to -50°C.

The mercaptide of formula 1 R-8- is substituted by reaction with sulfoxide X in a polar organic solvent such as ethanol or acetonitrile, preferably at about -35°C.

Starting material mercaptan of formula R-8H or formula R-8-
Thioacetate esters of C(0)CH3 are known for many R's (1), but those not known can be prepared by analogous methods known in the art. VC for re-investigation
td,, 1974 London, John. Willy, a/
Do, Su/zu (John Wiley & 5ons) 1 Editor Nis, Patai (S, Patai), The.

Chemistry, Op, The, Thiol, Group (The
Chemistry of the Th1ol G
roup) in Chapter 4, J.E., L., Wardell (J.
L, Wardell) [Fureparaikyon, Ono,
Thiols (Preparation of Th1
ols) J. Also.

For the conversion of alcohols to thiols and thiol esters using triphenylphosphine and dialkyl azodicarbo7ates in the presence of an alcohol and the appropriate thiol acid, see Hiro, Volante, Tetrahedron Letters.
Please refer to ``Letters''.

For compounds of formula XIV, an acid retaining group (PIITB
Preferably, the trialkylcryl group is removed prior to the hydrogenolysis to remove ) to give the compound of formula XV. The trialkylcryl group is used at a temperature range of about 15 to 40°C, preferably about 25°C.

The solution is removed using dialkyla/monium fluoride in an ethereal solvent such as tetrahydrofuran.

The conversion of a compound of formula

That is, a solution of a compound of formula Stir or shake under an atmosphere of hydrogen mixed with an inert diluent such as. Convenient solvents for this hydrogenolysis include lower alkanols such as methanol; ethers such as tetrahydrofuran and dioxa; low molecular weight esters such as ethyl acetate and butyl acetate; water; and various of these solvents. is a mixture of; However, it is common to choose conditions in which the starting material is soluble, such as aqueous tetrahydrofuran.

Hydrogenolysis is typically performed at room temperature and from about 0.5 to about 5 kg I
/cIIL2. The catalyst is usually present in an amount from about 10 weight percent based on the starting material to a weight equal to the starting material, although larger amounts can be used. This reaction typically takes about 1 hour, after which the compound of Formula 1 is simply recovered by filtration followed by removal of the solvent in vacuo. If palladium on calcium carbonate is used as the catalyst, the product will be isolated as the calcium salt; if palladium on Celite is used, the product will be isolated as the sodium salt.

The compound of formula 1 or 2 can be purified using conventional methods for R-tallactam compounds. For example, a compound of formula 1 can be purified by gel filtration on Sephadex or by recrystallization.

Another synthetic method is shown in step CIC. Azechiji/ of the formula ■,
using the method described above for the preparation of formula M''R-8-
C(S)-8- (where M is a metal such as sodium or potassium) is reacted with a trithiocarbonate.

The trithiocarbonate XVA thus obtained was heated in a temperature range of about 25
(p-Nitrobenzyloxycarbony~)(dihydroxy) in a proton-donating solvent such as toluene or dimethylformamide 8°C, preferably at -110°C, preferably about 80°C. Treatment with methane provides alcohol of formula XVI.

The corresponding chloride X■ has a temperature range of about -10 to 75°C
, preferably at 0° C., in the presence of a sterically hindered amino acid acting as an acid acceptor, such as 2,6-citedi, in a reaction-inert organic solvent such as dichlormeth/, with thionyl chloride. By processing, Irecole XV
Manufactured from I.

The chloride When reacted with lylphosphine/, formula 1
A compound is obtained which is cyclized by refluxing in an aromatic solvent such as toluene to give a penem of formula 1 XtV.

The trithiocarbo/acid acid of 2M"R-8-(C-8)-8- is prepared from the appropriate mercaptan of formula R-8H or the thioacetate of formula R8C(0)CH3 It is produced by treating A with cooxide and then with carbon disulfide.

By using the method of Yoshida et al. described so far, the hydroxyethyl group bonded to carbon 6 as well as that shown in the stereochemical line formula (2) at carbon 6 of the penem. Therefore, the predominant stereochemistry for the product of ring closure using Steps B or C is:

The hydrogen at position #5 of the penem ring is in a trans and sia I reference configuration with respect to the hydrogen on carbon 6.

Alternatively, the stereochemistry is 5Rt 68;6-(R)-
It can be written as 1-hydroxyethyl.

Compounds of formula 1 or 2 are acidic and will form salts with basic reagents. Such salts are considered within the scope of this invention. These lump ores.

In an aqueous, non-aqueous or partially aqueous medium, as appropriate.

These can be prepared by standard techniques, usually contacting acidic and basic components in stoichiometric proportions, which are then optionally filtered, precipitated with a non-solvent, followed by filtration, and the solvent Evaporation of.

Alternatively, in the case of an aqueous solution, it can be recovered by freeze-drying.

Basic reagents suitable for use in the formation of salts belong to both organic and inorganic types, including ammonia, organic amines, alkali metal hydroxides, carbonates monobicarbonates, hydrides. and acykoxy P, and alkaline earth metal hydroxides.

Carbonates, hydrides and alkoxides9. is included.

Representative examples of such bases are n-propylamine,
n-ptyamine, aniline, p-hexylamine,
Primary amines, such as indylamine and octamine;
N-ethylpyridy, N-methyvmoshiphory/and 1
．． Tertiary amide 7s such as 5-diazabicyclo(4,3,0) non-5-ene; hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; sodium ethoxide and alkoxides such as potassium ethoxide: hydrides such as calcium hydride and sodium hydride; carbonates such as potassium carbonate and sodium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate: and 2 - fully alkaline salts of long chain fatty acids such as sodium ethylhexanoate;

Preferred salts of compounds of formula I or ■ are the sodium, potassium and calcium salts.

formula! or (2) Pharmaceutically acceptable lump ore 1 At normal usage levels, the major disadvantage is the absence of side effects, including, for example, its sodium, potassium or calcium salts.

The in vitro antibacterial activity of compounds of the formula I or their salts can be demonstrated by measuring their minimum inhibitory concentration (M) against various microorganisms. , International Collaborative Research on Antibiotic Susceptibility Testing
Co11aborative 5tudy 0nAn
tibiotic 5sensitivity Test
ing) (Ericsson and Sherris.

Act'a, Pathologica et Mic
robiologia Scandinav, appendix 217
．． Section B: 64-68 (1971)).

Brain heart infusion (BH) agar and a repeat inoculum device are used.

Overnight growth tubes were grown at 100 mL for use as standard inoculum.
Dilute 2 times (approximately 20.000 in 0.0021 Ll)
-10,000 cells are placed on the agar surface: 20 dBHI agar/dish), 12 2-fold dilutions of the test compound are used, the initial concentration of the test drug being 200 mcg/R1. Single colonies are ignored when reading the plates after 18 hours at 37°C. The susceptibility (MIC) of a test microorganism is understood as the lowest concentration of a compound that can completely inhibit growth as determined by the naked eye.

Compounds of formula It or ■, and pharmaceutically acceptable salts thereof, are suitable for inhibiting bacterial infections in mammals, including humans.

These are infections caused by susceptible bacteria in human patients, such as Staphylococcus aureus (8taph
It may find use in the control of infections caused by susceptible strains of Ylococcus aureus).

The compounds of the invention may be administered orally or parenterally.

i.e. intramuscularly, subcutaneously, intraperitoneally or intravenously.

It can be administered alone or in combination with pharmaceutically acceptable carriers according to standard pharmaceutical practices. The ratio of active ingredient to carrier will depend on the chemical nature, solubility and stability of the active ingredient, as well as the intended dosage.

The ratio of pharmaceutically acceptable carrier to inem compound will normally be within the range of 1:10 to 4:1. For oral administration, a compound of the invention may be used in the form of tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like. For tablets, carriers that may be used include lactose, sodium citrate and phosphoric acid salts. Various disintegrants such as starch.

Lubricants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used in a tablet. Useful diluents for capsules are lactose and high molecular weight polyethylene Dalicose. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying agents and suspending agents. Sweeteners and/or flavoring agents can be added. For parenteral administration, sterile solutions of the active ingredient are usually prepared, the pH of which is suitably adjusted and buffered. For intravenous use, the total concentration of solutes, Fi, must be adjusted to make the formulation isochrotic. The prescribing physician will ultimately determine the appropriate dosage for a given human patient, which will depend on the age, weight, and response of the individual patient, as well as the nature and severity of the patient's symptoms. Compounds of Formula 1 and ■, which are believed to vary, are usually administered orally at doses of about 10 to about 200 kg per kilogram of body weight per day, and parenterally at doses of about 10 to about 200 per kilogram of body weight per day. Doses from about 10 to about 400 cm will be used. It may be necessary to use doses outside this limit in some cases.

EXAMPLES The following examples and preparations are presented merely for illustrative purposes. Infrared (TER) spectra can be obtained using potassium bromide disks (KBr disks), chloroform (CHCJ3), methylene chloride (CH2C
12) or as a solution in dimethyl resulfoxide (DMSO) and report the characteristic absorption bands in either microns or wavenumbers (cIn-”).Nuclear magnetic resonance (
NMR) Spectrum is deuterochloroform (CD
C13), AlII reducedromethanol (CD30
D) i or kI reduced dimethyl sulfoxide (
DMSO-d, ), or various mixtures thereof, and peak positions are given in parts per million downfield from nat-2-methylsilane. Use the following abbreviations for peak shapes = 5+
, single line; d, double line: t, triple line: q, quartet: m,
Multiplet: b.

Broad; c, compound, abbreviations "8β" and "5ssJ" throughout these Examples and Preparations indicate that the particular proton was present as two or three single lines, respectively, due to the presence of diastereomers. , omitted 1'-PNBJ
represents a p-nitroindici group.

Tetrahydrofuran 20+117 and distilled water 20m/
of a suspension of 10% pd73 on diatoms in a mixture of p
H using 0.02M aqueous sodium bicarbonate solution
．． Next, (5R,68)-6-((R)-1 in a mixture of tetrahydrofuran 8d and water 8-
-human 90xethylv)-2-(2-pyrrolidone-3-
IL/)Thio-2-,,2nemu-3-carbon atp
- Add a solution of Nitro 973119 and hydrogenate the resulting mixture with 55 p, s, i of hydrogen for 75 minutes; then add a further 73 μ of 10% Pd on diatoms and pH.

7.0 using 0.02M 11L sodium carbonate aqueous solution
Adjusted to. The mixture was hydrogenated at 55 p, s, i for 75 min, then the catalyst was removed by filtration and the filtrate was concentrated in vacuo to remove tetrahydrofuran.

The pH of the resulting aqueous solution was adjusted to 7.0.

Extracted with 2 parts of 15d acetic acid. This aqueous solution was then lyophilized to give the title compound 38 (69% yield) as an amorphous solid.

The infrared spectrum of the title compound as a potassium bromide disk showed absorptions at 2.94, 5.65 and 6.3 microns.

Example 2 Using the method of Example 1 with the appropriate compound of Formula XV, the sodium salt of the compound of Formula 1 was obtained.

The yields, potassium bromide discs (unless otherwise indicated) infrared spectra and R of these salts are shown in Table 1.

Table 1 2-pyrrolidon-4-yl 2.92.5.68,6.
0 88 and 6.15 1-formyl-3-pyrrolidinyl 2.92.5.64
．． 6.03 89 and 6.3 (3-methyl-1,3-oxacyly 2.94.5.7
and 78 din-2-one-5-yl)methy 6.2
58〆(3-methyl-1,3-oxacyl 2.94.5.7
and 90 din-2-one-4-yl)methy 6.2
8-2-piperidon-5-yl 5.64.6.02 and 936.3 (DMSO) Piperidin-2-on-3-yl 2.94.5.66
, 6.06 79 and 6.25 1-methidipiperidin-2-one 2.93.5.64
and 98-3-i Ishi 6.15 1-Hoνmiνpinilysine-3-i 2.9.5.65 and 73ru 6.03 Table 1 (continued) 3-Methyl-4ruhydro-1 ,3-2,92,5,63
, 5,9957 oxazin-2-one-5-ia and 6.08 (from the less soluble diastereomer) 3-methyl-4-hydro 1.3-5.65 (DMSO
) 84Oxazin-2-one-5-yl (from diastereomers with high solubility)! ! The method of Example 1 was used except that the initial pH was 7.5 and R was a pyrrolidin-2,5-dione-3-yl group for the starting compound of formula XV. This compound was obtained with a yield of 90%, as potassium bromide disks, 2
．． Infrared radiation at 92.5, 63, 5.8 and 6.2 microns has a strong absorption.

Example 4 Using the method of Example 3 with the appropriate compound of Formula XV, the IJ salt of the compound of Formula 1 was obtained.

The yields of these salts, potassium bromide disks (unless otherwise indicated) infrared sweetness v and R are as shown in Table IA.

Table IA
on-4-yl)methyl(1,3-oxazolidine-2-5,72(b) 87
on-5-yl)methyV (l,3-thiazolidin-2-o 5.65 100-4-yl)methyltetrahydro-6-((
R)-1-t-butyldimethane siri νoxyetha)-
2-(2-pyrrolidon-3-yl)thio-2-benem-
3-Kayaponic acid p-2)a Benja 118M9 (0°2
Add vinegar #0.11*Jl' (2,
0.612 tJ of a 1 M solution of nat-di-ammonium fluoride in hydrofuran (0.04 mmodi) and nat-2
612 moji) was added. After stirring for 20 hours at room temperature over nitrogen, 50 d of methiacetate was added and the resulting solution was diluted with 1
Washed with 40 d of a saturated aqueous solution of sodium bicarbonate, 40 ic of water and 40 d of a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (11011p) was dissolved in silica gel (50#
) and eluting with 95:5 ethyl acetate vmethanol to give 73ml (77% yield) of the title compound as an amorphous solid.

The NMRx ectv of the deuterochlorofoshim solution of the title compound is % 1.32 (d, 3H); 2.0-3
-2 (C,3H) t 3.2-4.37 (C#
5H) ; 5,3 (qt 2H) ; 5.6 (d
, IH); 6.64 (b, IH); 7.6
(d, 2H); and 8.2 (d, 2H)pp
The infrared sweetness ν of the dichloromethane solution of the title compound which had a peak at m is 5.58, 5.85 and 6
．． It showed absorption at 57 microns.

Preparation Example B Using a compound of formula Xff and using the method of Preparation Example A, 1
A compound of formula XV was obtained. Properties of these compounds and R
has the same width as shown in Table 2. Solvents for which vectors were measured are shown in parentheses.

Table 2 2-pyrrolidone-5,58,5,87 and 1.3(
d, 3H); 874-I/I/ 6.58 (OH2C
J2) 2.0-4.42 ((!.

BH); 5.3 (qt 2H): 5.68 (d.

IH); 6.25 (b.

1)1);7.56(dt 2H); and 8.18 (dt 2h).

(CDCJ3) Table 2 Continued t-HoVmi&-3557,5,96 and 1.35(
d, 3H); 42-pyrrolidinine n/6.56 (CH2
C12) 1.8-2.6 (c, 2H); 3.2 (b,
IH); 3.3-4.46 (c, 7H); 5.3 (q, 2H) 5.64 (to IH); 7.6 (tun 2H); and 8.2 (s and d, 3H ); (CDCIW) (3-Methy n/-1,5,56,5,66 and 1.
36(d,3H); 383-oxazoline 6.57
(CH2C12) 2.4(bnlH): No-2-one-52,9(8,3H) s-iA/) methyl 3.1
7-3.92 (c.

5)1) ;4.0-4.86 (c, 2fl) 5.31 ((It　2B)　;5.69 (d, 1) 1); 7.6 Table 2 continued (d, 2H); and 8.2 (d, 2H).

(CDCj3) (3-Methy n/-1,5,56,5,67 and 1.
35 (d, 3H); 253-j-ser, r-riji 6.
56CCH2c12) 22 (ζ IH); Nor 2-one-42,8 ShinB) and -Iruramethyl 2.81-3.5 (C'J t (5H overall); 3.6-4.49 (C# 5H); 5.3 (q, 21 (2H); 5.67 (tun 11 (); 7.56 (to 2H): and 8.16 (d, 2H).

(CDCj3) Pyrrolidine-2,55,57,5,75 and 1.3
(d, 3H); 32-dione-3-y 6.54 (
CH2CAr2) 2.1 (b, IH);” 2.5
-4.4 (c, aH) *5.3 (q, 2H); Table 2 continued 5.65 (to IH); 7.56 (d, 2H): and 8.16 (naki 2H).

(CDC/3) 2-Viridocy 5.64 and 6.0 1.18 (
(in 3H): 865-yl (nujolmal)
1.74-2.8 (c, 4H) *3.05-3
．． 74 (c-4H)s 4.03 (Yu IH): 5.25 (Naru IH); 5.37 (q, 2HL 5.78 (d, 1) r; 7.66 (b, 1) 1) ; 7.7 (d, 2H); and 8.25 (d, 2H).

(DMSO-d, , 250 0MHz) (1,3-oxazo 5.5, 5.67.5.91 2
．． 0(b, II(); 57 lysin-2-one and 6.58 1.27(d, 3Hn; Table 2 continued -4-yl)methy(CH,O),) 3.1(
2H); 3.7 (dA IH); 3.8-4.67 (c, 4H): 5-31 (Qp 2 H): 5.68 (d, 1) 1); 7.1 (b, IH); 7.6 (a, 2H); and 8.18 (d, 2H).

(CDCj 3/CD, 0D) (1,3-oxazo 5.58.5.67 and 1.
29(d,3H); 56 lysin-2-one 6.58
(CH2(4'2) 2.2(b, IH); 3.1-5
-irimechi -a, 9s (C, 5H) eshi 4.1
(Chicken IH); 4.83 (c, 2H); 5.3 (qj2H); 5.7 (Tun 1) 1); 7.1 (by IH); 7.58 (Naki 2H); and 8. 17 (to 2H).

Table 2 continued (1,3-+7zo U 5.61. 5.97. 6.0
6. 1.18 (d, 3H); '64 Jin-2-Or 6.6 and 6.7 (KBr) 3.13-3.46
(c.

4-Iomechiji 3) 1); 3.62 (dc!.

1) I); 3.88 (dd.

1K); 4.02 (Pigeon IH); 4.1 (m, IH): 5.25 (d, IHL 5.38 (Q, 2H); 5.76 (d, IH); 7.7 (a, 2H); s, 24 (a.

2H); and 8.42 (a, IH).

(250MHz, DMSO-d6) Pylysine-2-5,56,5,9,6,01,3(d
, 3H); 1.65 65 or 3-4sz and 6
56 -2.45(c, 4H); (CHzClz)
3.28 (c -2H); Table 2 continued 3.52-4.42 (c.

4H); 5.32 (Q+ 2H); 5.65 and and 5.7 (2d, whole 〒IH); 7.12 (b, IH); 7.6 (d, 2H); and 8.2 (d, 2I().

(CDC7! Me-endu-C6) 1-mena ν pi〈ri 5.56, 5.92, 6.07 1
．． 3(d, 3H); 1.7-40 zin-2-one- and 6.56 2.45(c, 5HL3-i, (CH
zCl2) 2.96 (s, 3H);3.
3 (m, 2H); 3.65 -4.45 (c, 3H); 5.3 (q, 2H); 5.6 (d, IH); 7.57 (a, 2M); and 8. 2 (d, 2H).

Table 2 continued (CDC13) l-ho/L/mi-sho-pi! :5.57.5.97 and
1.12-2.33(c) 64 lysin-3-yl
6.56(CH2CA'2) and 1.3(dl(t
otal 8H); 2.78-4.62 (c.

7H); 5.28 (q.

2H); 5.63 (dp IH); 7.54 (d.

2H); 7.98 (s.

IH); and 8.16 (2H), (CDCI13) Tetranotium ammonium fluoride (1.25g, 1.25mmol of a 1M solution in tetrahydro7ran) and acetic acid (o, 2sy) in anhydrous tetrahydro72 2 in (
5R. -on-5-i/I/
) was added to a solution of thio-2-benem-3-kayaponic acid p-nitrobendi A/(0,24,9,0,39 mmodi). The solution thus obtained was stirred at 25° C. for 20 hours under nitrogen. The reaction solution was then diluted with 100 mj of acetic acid etcha, washed with 1011j of water, 2 parts of 20 Id of Prine, 20 tnl of water and 2ON of Prine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The remaining solid was triturated with methanol and then washed with 15 g of diethyl ν.
Etesi was added and the mixture thus obtained was filtered to obtain diastereomer 71, which has low solubility, as a light brown solid. The filtrate was concentrated in vacuo, and the residue was poured into 1 l of silica gel (
7519), eluting with 9:1 ethyl acetate v-methanol, afforded the highly soluble diastereomer as a solid. This solid was triturated with 1:1 diethyethete V-Petroleum Ezo ν and filtered to obtain the more soluble diastereomer, 52 µ, as a light brown solid (total yield 63%).

NMR of the diastereomer with lower solubility (DMSOde = 250 MHz);
1-2 (d-3H); 2.86CB, 3H); 3
．． 4 (dd, IH); 3.83 (dd, IH); 3.
9-4.1 (at 3H); 4.25 (ad,
IH); 4.51 (dd, IH); 5.26 (d, I
H); 5.38 (qe 2H); s, s (a, tH);
7.7(a, 2H); and 8.26(a, 2H)p
pm- Diastereomer with higher solubility NMR (DMS O-da, 250 MHz)
: 1.2 (cIt 3 H) p2.86 (s,
3H); 3.35 (dd, IH); 3.81
(dd.

IH); 3.9-4.1 (c, 3H) * 4.2
9 (dd, 1)1) ;4.54 (dd= IH
) t 5.26 (d-IH); 5.39 (q
.

2H); 5.83 (d, IH) near, 7 (d, 2H);
and 8.26 (d, 2H) ppm, IR (KBr)
:2.92.5.61°5.85.5.91 and 6.
61 microns.

2-pyrrolidone thioacetate (2-pyrrolidone thioacetate) in anhydrous ethanol 5d cooled to -30°C under nitrogen. After -30 minutes, the crude (5R,68) of Preparation Example 1 in 5d of anhydrous tetrahydrofuran was cooled to -50°C. -6-((R)-x-i-puchadimethyvsillaoxyethyv)-2-ethylsciphiniy
-2-A! nemu 3-power siphonic acid p-nitrobenja 3
A solution of 0.00 mm (0.5 mm) was added. The solution thus obtained was stirred at -30°C for 60 minutes.

0.029 mJ (0.5 mmol) of acetic acid was added and the solution was concentrated in vacuo. The residue was dissolved in 50+tA' of ethyl acetate, and the resulting solution was washed with 401% water (4Q@t) of a saturated aqueous solution of IJium bicarbonate, and 40ml of a saturated aqueous solution of sodium chloride. The ethylacetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (3701 ny) was chromatographed on silicage v (120, lh 7K) eluting with l:1 chloroform/ethya acetate to give 118 m9 (41% yield) of the title compound as a sticky gum. .

The infrared spectra of a dichloromethane solution of the title compound had absorptions at 5.58, 5.86, and 6.58 microns. The NMR spectrum of a deuterochloroform solution of the title compound is 0.06 (813H); 0
．． 1 (st 3H); 0.84 (S, 9H)
;1.24(d=3H);1.92 2.98(c-
2H) *3.23-4.4 (ct 5H); 5.2
9 (q, 2H); 5.6 (d, IH); 6
．． 6 (b, IH); 7.55 (d, 2H); and 8.
16 (d.

It had a peak at 2H) ppm.

Preparation Example E Using the appropriate thioacetate ester v and using the method described in Preparation Example, compound 2XIV was obtained. The properties and R of these compounds are as shown in Table 3.

Production Example F Purified (5dan, 6dan)-6-((R)-1 of Production Example H
-t-butyldimethylsilyloxyethyl]-2-ethylsulfinyl-2-,,2nemu-3-carboxylic acid p-
Compound 2XH was obtained using nitrobenzyl and the appropriate thioacetate using the same method as in the Preparation Example. The properties and R of these compounds are as shown in Table 3A.

Preparation Example G Sodium methoxide (54w9, 1.0 mmol) was cooled to -35<0>C under nitrogen. Anhydrous ethanol 5T
Pyrrolidine-2,5-dione-3-thioacetate in ILl
87 ml (0.5 mmol) was added to the solution. -35
The crude M (5R,68)-6-((R
)-t-i-butyldimethylsilyloxyethyl]-2
-ethylsulfinyl-2-4nemu-3-carboxylic acid p
- A solution of 300 Mg (approximately 0.5 mmol) of nitrobenzyl was added.

The solution thus obtained was stirred for 60 minutes at -40°C to -35°C, 0.058 d (t, o mmol) of acetic acid was added and the solution was concentrated in vacuo. 5011j residue
of ethyl acetate and the resulting solution is dissolved in a saturated aqueous solution of sodium bicarbonate 40-1 water and chlorinated)
It was washed with 40 yil of a saturated aqueous solution of U. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (360 μ) was applied to Chromadog 27 on silica gel (1201?) and eluted with 3:1 tetraroform-ethyl acetate to give 123 # (42% yield) of the title compound as a viscous J. Obtained.

The infrared spectrum of the title compound in dichloromethane solution had absorptions at 5.56, 5.72 and 6.5 microns. NMR spectrum of a solution of the title compound in deuterochloroform U, 0.04 (s, 3B); 0.
08(s, 3H); 0.86(s, 9H)*1.25(
d, 3H); 2.54-4.54 (c, 5H); 5.3
(q=2H)s5.7(d,IH);7.6(d,2
H) and 8.2 (d, 2H) ppm.

Title 4 nem sulfoxide prepared according to the Purification Preparation Example 8.
09 was chromatographed on silica gel (500,9). Elution with hexane-ethyl acetate (1:1) gave 4.6 g of the purified title compound as a mixture of diastereomers.

m-chloroperbenzoic acid 970■ in silyl methylene chloride 25d
A solution of (4,78ξ mol, 85% purity) in methylene chloride 125d cooled to -20°C under nitrogen atmosphere was prepared by
5R,6dan)-6-((dan)-1-1,--/Tyldimethylsilyloxyethyl]-2-ethelthio-2--!
! Nemu p-nitrobenzyl 3-carboxylate 2.5 g
(4.78 mmol) of solution i. After stirring this mixture at -20°C for 3 hours, carbonic acid was added.
It was washed with 2 parts of 701 Lt of a saturated aqueous solution of J2+, 7QWLt of water, and 7Qml of a saturated aqueous solution of +7+7 Um. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow foam (2,2II, 86%
Yield) was obtained.

The infrared spectrum of the title compound as a dichloromethane solution is 5.54% 5.86. and had an absorption of 6.53 micrometers. The NMR spectrum of the title compound as a solution in deuterochloroform is 0.06.0.0
8,0.1 and 0.12 (413*6H overall); 0
．． 8 (s, 9H); 1.12-1.58 (m.

6H); 3.1 (m, 2H); 3.86 (m,
IH); 4.3 (m, IH); 5.3 (m, 2H)
; 5.67 and 5.78 (2d, I H overall);
7.54 (d, 2H); and 8, 18 (dt
2H) with a peak at ppm.

p-nitrobenzyloxalyl chloride (5,85&,
(3-alpha-t-butyldimethylsilyloxyethyl-4-ethylthio(thiocarbonyl)thio-2-oxo-azetidine) in methylene chloride 7Qm cooled to 10°C under nitrogen atmosphere. 7.3.9
(0,02 mol) and calcium carbonate 4.810.0
48 mol) was added to the mixture. 4.17 ml of sillable pyruethylamine (0,02
A solution of 4 mol) was added dropwise at such a rate that the temperature was kept below 1"2°C.

This mixture was stirred at 10° C. for 60 minutes.

Wash with 2 parts of 50 m ice-cold water and pour over anhydrous sodium sulfate.
Dry and concentrate in vacuo to give a viscous oil. The crude (3-alpha-t-butyldimethylsilyloxyethyl-2-oxo-azetidinyl)oxoacetic acid p thus obtained
- nitrobenzyl is dissolved in 300 iaj of ethanol-free chloroform and the solution thus formed is refluxed under nitrogen, while 6.85 d of triethyl phosphite (0,04
mol) solution was added dropwise over a period of 2 hours. The solution thus obtained was refluxed for 16 hours and then concentrated in vacuo.

The residue was chromatographed on silica gel (sooy), eluting with 95:5 toluene-ethyl acetate.
5.5# (53% yield) of the title compound was obtained as a yellow foam.

Infrared spectroscopy of the title compound as a dichloromethane solution had absorptions at 5.56, 5.89 and 6.54 microns. NMR spectrum of the title compound as a solution in deuterochloroform.

0.07 (s, 3H); 0.1 (s, 3H)
;0.85 (s.

9H); 1.12-1.53 (m, 6H); 2.97 (
q, 2H); 3.7 (m, IB); 4.25 (
m, 11(); 5.3 (q, 2H); 5.6
3 (d, IH); 7.38 (d, 2H); and 8.1
It had a peak at 8(a,l)ppm.

NMR spectrum of intermediate (1-7zetidinyl)oxoacetic acid ester as deuterochloroform solution (4p)
Le Jd,,,0.06 (s-6H) ;0.8 (
s-9H),"1.14-1.62(m, 6H)
;3.14-3.63 (m, 3B);4.33 (
me IH); 4.16 (s-2H); 6.7
(dlIH); had peaks at 7.5 (ds 2H) * and 8.17 (d, 2H) ppm.

Ethanethiol (8,5+nJ, 0.115 mol) is used as a production example.

It was added to a solution of 4.18 II (0.104 mol) sodium hydroxide in 250 d of water cooled to 0-5° C. under a nitrogen atmosphere. After 15 minutes, 7.73 m (0.12 mol) of carbon disulfide were added and the mixture was stirred at O-5°C for 35 minutes. A solution of 4-7 setoxy 3-t-butyldimethylsilyloxyethyl-2-azetidinone 15.O,S' (0,0522 mol) in methylene chloride 50 (lj) was added and the mixture was stirred vigorously for 24 hours at room temperature. .Separate the aqueous phase.

Extracted with 2 parts of 150xj methylene chloride. The combined methylene chloride fractions were dissolved in 2 parts of 200 m water and 200 WL.
Wash with a saturated aqueous solution of sodium chloride.

Dry over anhydrous sodium sulfate and concentrate in vacuo.

The crude title product (18,9) was dissolved in silica gel (500 g
) and eluting with 99:1 chloroform-ethyl acetate to give the title trithiocarbonate 9.1,1 it (48% yield) as a yellow foam.

The infrared spectrum of the title compound in dichloromethane solution had absorptions at 5.62 and 9.2 microns. The NMR spectrum of the deuterochloroform solution of the title compound is 0.08 (s, 6H); 0.8
(s, 9H); 1.02-1.5 (m, 6H
); 3.0-3-48 (m, 3 H) z 4,1
It had peaks at 2 (m, IH); 5-54 (d*IH); and 6.57 (b, IH) ppm.

3 in 50 WLl of methylene chloride cooled to 0°C under soil nitrogen.
- In a solution of hydroxy-2-pyrrolidone L, 0II (0.01 mol), 4-dimethylaminopyridine 2.44 #
(0.02 mol) 1st p-toluenesulfonyl chloride 1
．． 9 F (0.01 mol) was added. After stirring the resulting vinegar solution at θ° for 30 minutes.

Stir overnight at room temperature. This solution was mixed with IN hydrochloric acid 5c)
ml, water 59d and IJ chloride), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as an amorphous solid (2, IJ,
83% yield) was obtained.

NMR spectrum of deuterochloroform solution of the title compound 4
vector is 2.44 (sl) and 1.83-2.64 (
cl (5 H in total); 3-1 3-44 (m,
2H); 4.86 (tl tH); 7. a3(d, 2
H); and 7. It had a peak at s(a+b,3H)ppm.

Preparation Example M Using 1-formyl-3-hydroxypyrrolidine as starting material and using the same method as Preparation Example.

p-1 Rue/1-formyA/-3-hyrolidinyl sulfonate was obtained with a yield of 82%. The NMR spectrum of a solution of the product in deuterochloroform is 1.9-2.3 (
c, 2H); 2.46 (s, 3H); 3.3
6-3.78 (c, 4H) ;5.1 ((!,
IH); 7.32 (d.

2H); 7.77 (a, 2H); and 8.13 (d,
IH) had a peak at ppm.

Under the same pressure, 3-methyl-berchtyl p-)luenesulfonate 90-1,3-oxazin-2-one-5-yl was prepared from the corresponding alcohol (81%). The N M and Rs of the deuterochloroform solution are 2.4
4 (s, 3H); 2.9 (s, 3H); 3.46 (m
, 2H); 4.18 (m, 2H); 4.
9 (m.

IH); 7.3 (d, 2H); and 7.74 (a, 2
H) 4 in 35 mt of methylene chloride, cooled to fO 0 C under nitrogen, having a peak at ppm
-Human 90xy-2-pyrrolidone 0.71.9 (7,
1.02 mmol) of dimethylaminopyridine.
72 g (14.04%) and then 1.3417.02 mmol of p-toluenesulfonyl chloride were added. The resulting solution was warmed to room temperature and stirred for 3 hours. This solution was then washed with 2×30111 J of 1N hydrochloric acid, 30 liters of irises carbonate, and 30 liters of saturated aqueous sodium chloride solution.

Dry over anhydrous sulfuric acid and concentrate in vacuo.

The title compound was obtained as an amorphous solid (1,511,84% yield).

NMRx- of a solution of the title compound in deuterochloroform
! : Kutle is 2.46 (s) and 2.02-2,
s 4 (C1 (5 H in total); 3.24-3.8
6 (c, 2H); 5.17 (C, I H);
7.1 (b-I H); 7.34 (d-2H)
; and had a peak at 99 m at 7.76 (d, 2H).

Production Example 0 5-Hroxymethyl-3- as starting material alcohol
Using the method of Preparation N with methyl-1,3-oxazolidin-2-one, p-)luenesulfonic acid (3-methyl-1,3-oxazolidin-2-
On-5-yl)methyl was obtained, and the NMR spectrum of this as a deuterochloroform solution was m 2
．． 44 (B, 3B); 2.82 (a, 3H); 3
．． 16-3.8 (m, 2H); 4.12 (d, 2H)
H); 4.66 (c, IB); 7.33 (d, 2H);
and had a peak at 7.74 (d, 2H) ppIn. Similarly, 4-human as starting alcohol.

Roxymethyl-3-methyl-1,3-oxazolidine-
Using 2-one, sp-(3-methyl-1,3-oxazolidin-2-one-4-yl)methyl sp-toluenesulfonate was obtained in 88% yield. This one is 2.45 (s,
3H); 2.77 (s, 3H); 3.66-
4.52 (C,5H); 7.32 (d12]H
),” and had an NMR spectrum as a deuterochloroform solution with a peak at 7.74 (d, 2H) ppm.

Similarly, from the corresponding alcohol, 1-formyl p-)luenesulfonic acid 61J 9-3-yl was prepared from 7
5%' [Manufactured at 51. NMR (CDC/3)
: 1.22-2.17 (c, 4H); 2.46 (s, 3
H); 2.96-3.9 (c, 4H); 4.53
(m, IH); 7.34 (d, 2H); 7
．． 8 (d, 2H); 7.93 (d, IH)
.

7-k) Potassium thioacetate 855Iv (7
, 5ξlimok) crude p-toluenesulfonic acid 2
- pyrrolin-3-yl 1°27. fF (5 mmol)
The mixture was refluxed under nitrogen for about 20 hours. The mixture was then filtered and the filtrate was concentrated in vacuo.

The residue was partitioned between 50 ml of ethyl acetate and 50 ml of water, and the ethyl acetate layer was washed with 40 ml of water and 4 Qml of saturated aqueous sodium chloride dispersion. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel and stripped with ethyl acetate.

180a7 (23% yield) of the title compound was obtained.

Title compound ty) as a solution in deuterochloroform
NMRx-? vector is 2.38(s) and 1.7
-2, 981cl (5 H in total); 2.27-
3.6 (m, 2H); 4, t7 (i, IH); and 7.74 (b+ IH) with peaks at ppm.

Preparation Q Using the starting material p-toluenesulfonic acid ester shown in Table 4 and using the method of Preparation P, the corresponding thioacetate was obtained. The yield and NMR spectrum as a deuterochloroform solution are as shown in the table.

Table 4 2-pyrrolidon-4-yl 61 2.3 hawk 8) and 2.0-4.4 (C) (8H overall); and 7.44 (q IH).

l-formyl-3-pyrrolidinyl 95 2. subS) and 1.63-3.06 (cl (5H overall); 3.14-426 (c, 4H); and 8.14 (h, IH).

(3-methyl-1,3-oxitizolidi 77 2.38
(s, 3H); s-2-on-5-yl)methyl 2.
82 (s, 3H); 3.03-3.81 (c.

4H); and 4.57 (For IH).

Table 4 continued (3-methyl-1,3-omonazoli 68 2.36 (
s, 3H); zin-2-one-4-yl)methy 2.8
2Isl and Le 2.75-34 Nu4 (total 5H): and 3.64-4.57 (c, 3H).

Maleimide” (5,O,SJ, 01051 mol) was added to 10 mA! (0,14 mol) of thioacetic acid cooled to 0°C under nitrogen. The mixture was stirred at 0°C for 70 min and then filtered. The filtrate was diluted with 10 ml of ethyl acetate and the resulting solution was washed with 5 Qrxl of saturated aqueous sodium bicarbonate and 59 mj of saturated aqueous sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. A yellow oil (S, 411) was obtained. The crude product was purified by chromatography on silica gel (350I) for 7 washes, eluting with 1:3 ethyl acetate-hexanes to give 3.811 (43%) The title compound was obtained as a white solid.

NM of surface compound as deuterochloroform solution
The R spectra are 2.38 (s) and 2.3-3.
It was 99m with peaks at 54 (mD total 5H); 4.24 (m, IH); and 8.86 (b, IH).

-2-Piperidon-5-ol (0,57511,5 mmol) was dissolved in 151 dimethylformamide and the solution was diluted with 5 Qal dichloromethane.

The solution was cooled to 0° C. under nitrogen and 0.9515 mmol) p-)luenesulfonyl chloride 1.221 mmol) 4-dimethylaminopyridine! (10 mmol) was added. This solution was stirred at 0°C for 3 hours and then at 25°C for 20 hours. The reaction mixture was then diluted with 125-dichloromethane and the solution was dissolved in 20 ml of IN hydrochloric acid/
2011/2 parts of water and 2 parts of saturated aqueous sodium chloride solution
Washed with 01.

The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Addition of diethyl ether to the residue gave the title compound as a solid product resulting from filtration (0.8.9.6
0% yield). The NMR spectra of the title compound as a solution in deuterochloroform are 2.4 (s) and 1
．． 67-2.6 (C) (7H overall): 3.43 (c
, 2H); 4.86 (m, IH); 6.96
(b.

IH); 7.3 (a, 2H); and 7.76 (d,
2H) had a peak.

A solution of 1.919 (6 mmol) of tetrabutylammonium thioacetate and 0.807.9 (3 mmol) of 2-piperin-5-yl p-toluenesulfonate in 15-99m acetone was heated under nitrogen for 70 min. Refluxed. The solution was then concentrated in vacuo and the residue was dissolved in 7511111') ethyl acetate. Add this ethyl acetate solution to 1 liter of water
)yal, chloride) 101 of a saturated aqueous solution of IJum, 10d of water, and 10s+j of a saturated aqueous solution of sodium chloride. The combined aqueous extracts were washed with 2 parts of 501j ethyl acetate. The combined ethyl acetate fractions were dried over anhydrous sulfuric acid and concentrated in vacuo. The crude product was chromatographed on silica gel (100,9),
Elution with ethyl acetate gave 0.229144%) of the title compound as a yellowish solid. The NMR spectral of the title compound as a solution in deuterochloroform is:
It had peaks at 2.4 (sl and 1.64-2.68 (C1 (7H in total); 2.73-4.1 (c, 3H); and 7.05 (b, IB) .

99m p-)luenesulfonyl chloride (1,011I.

0.0053 mol) of 2-oxazol 1°3-oxazolidine-4-methanol (0.619 #, 0.00
53 mol) and 4-dimethylaminopyridine (x, 3
o, p, 0.0106 mol). 1 at 0℃
After an hour, an additional 0.12111 p-)luenesulfonyl chloride was added and the reaction mixture was stirred for 30 minutes at 0°C and 1 hour at 25°C. The reaction solution was then mixed with 2 parts of 50 ml of IN hydrochloric acid, 50 ml of water. Washed with 50 WL of saturated aqueous sodium bicarbonate solution and 50 WL of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound as a white solid (1.22 L).
85% 1 rate). NMR (CDC13): 2.
45 (s r 3 H); 3.87-4.54 (
c, 5H); 6.18 ('b, IB); 7.
3 (d, 2H); and 7.73 (d, 2H)p
p.m.

Using the method of Preparation U, the appropriate starting alcohol was converted to the corresponding toluene sulfonic ester. The R1 yield and NMR spectrum are shown in Table 4.

Table 4 (1,3-oxazolidine-2,46(s,3H);3
．． 54 842-one-5-yl)methy (m, 2H
) ;4.13 (cl.

2H); 4.8 (Nail IH): 6.23 (b, IH); 7.33 (dt2H); and 7°8 (d, 2H).

(1,3-teazolidiy-22,45(s,3H);3
．． 32 88-one-4-yl)methyl (1n12H
); 3.86-4.32 (c, 3H); 6.06 (b, IH); 7.32 (d.

2H): and 7.74 (Tun 2H).

No-3-yl methanesulfonic acid chloride (0, gyrJ, 0.01 mol)
was stirred under nitrogen at 0°C in methylene chloride 5011.
1-methyl-2-oxo-3-piperiditul in 1 (
1,29 g, 0.01 mol) and 4-dimethylaminopyridine (2,44,9,0,02 mol). The resulting solution was stirred for 15 minutes at 0°C and for 2.5 hours at 25°C.

The reaction mixture was then washed with 50 ynl of a saturated aqueous solution of IJ chloride containing 6.8 d of 6N hydrochloric acid,
Dry over anhydrous sodium sulfate and concentrate in vacuo to give the title compound I7 as a thick oil. (1, 8, 9, 87% yield)
. N MR (CD (J3): 1.6-2.37 (c
, 4H); 2.96 (s, 3H); 3.
1-3.4(cl) and 3.24(83(5H total)
and 4.9 (m e IH) ppm.

Similarly, 2-oxopi converts lysin-3-ol into 25
% yield of piperidin-2-one-3-methylsulfonate
I changed it to il. NMR(CD(J3):2.03
(c, 4H); 3.06-3.45 (cl and 3
．． 25 (8) (5 H in total); 4.96 (mt
IH); 6.26 (b.

p-)luenesulfonic acid 2-oxo-1,3-oxazolidin-4-ylmethyl(1,
A solution of 22 g, 0.0045 mol) and tetrazotylammonium thioacetate (1.71 g, 0.0054 mol) was refluxed under nitrogen for 90 minutes.

The reaction mixture was concentrated to dryness, and the residue was purified with silica gel (2s
Chromatographed on ol. 4:1 ethyl acetate
Elution with hexane gave 580 Tv of the title compound (75% yield). NMR (cI)cz3): 2
．． 38 (s, 3H); 3.06 (d, 2H)
; 3.84-4.67 (c, 3H); and 6.3
(b, tH) ppm Preparation Example Y Using the method of Preparation Example X, the appropriate p-toluenesulfonic acid ester was converted to the corresponding thioacetic acid ester. The NMR spectral and yield of this compound in R1 deuterochloroform are shown in Table 5.

Table 5 RNMR (ppm) Yield hook (1,3-oxazolidine 2.37 (s, 3H); 3
．． 22 76-2-one-5-yl) (d, 2H);
3.47 (Tame methyl 2H); 4.7 (Tame IH); and 6.26 (b, IH); (1,3-thiazolidine-2,4 (s*3H); 3.1
3 582-on-4-yl)methane (d, 2H); 3.
32 (m.

Chill 2H); 3.93 (-IH); and 6.63 (b, IH).

3-Methyl- is Ruhibiro 2.4 (s, 3H); 2.9
8 61-1,3-oxazine-5 (s, 3H); and -yl 3.0-4.6 (c, 5H).

p-Toluenesulfonic acid 1-formyl-3-hy6 !J synyl (1,
12L O,007 mol) and potassium thioacetate (0
, 91,9,0,008 mol) under nitrogen.
The mixture was heated to 70°C for an hour. The reaction mixture was diluted with ethyl acetate 15011/1 and the resulting solution was washed with 4 parts of 50 ml of water and 5 g ml of syline, dried over anhydrous sodium acetate and concentrated in vacuo. The residue was chromatographed on silica gel (125,9) and
:1 ethyl acetate-hexane elution with 0.16, F
The title compound was obtained (21%'Iy, yield). N M
R (CDC/3): 1.13-2.3 (C1 and 2.32 (sl (7H overall); 2.84-4.0 (
c, 5H); and 7.9 (d, IH) ppm0 Methanesulfonated 1-methyl-2- in ylacetone 801
Oxo-3-piperidinyl (L, 7g.

o, oos mol) and potassium thioacetate (1,39#
, 0.012 mol) was refluxed under nitrogen for 20 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in 50 ml of ethyl acetate and 50 dl of water. The ethyl acetate layer was mixed with 50 ml of water and 5 ml of a saturated aqueous sodium chloride solution.
Washed with 01 and dried over anhydrous sodium t1,
Concentrated in vacuo. The residue was chromatographed on silica gel eluting with 6001rU9 (40
% yield) of the title compound. NMR(CDC/3
): 1.7-2.5(cl and 2.38(sl)
(71 in total): 30 (s, 3H); 3.36 (m12
and 4.2 (mp ” H) ppm 0 Similarly, methylsulfo/acid pyharidin-2-one-3-
py4-lysin-2-one-thioacetate with a yield of 56%.
Changed to 3-il. NMR (CDC1a): t,
5-2.5 (cl and 2.36+S) (7 H overall); 3.32 (c, 2H) s 4.13
(m-IH) ; and 7.18 (be IH)
ppm.

Claims (1)

[Scope of Claims] 1) A compound of formula 2 or a pharmaceutically acceptable salt thereof 2 A is an alkylene group having 2 to 4 carbon atoms, a C 2-4 alkylene group in which one carbon atom has an oxo substituent; 4 alkylene group or an alkylene group having 2-4 carbon atoms in which one methylene group is replaced with oxygen, 5(0)ln, or NR3; B is a carbonidi group, a thiocarbonyl group, a methylene group or is an imino group: R1 is hydrogen or forms an esthetic group that is hydrolyzed in vivo; R2 is hydrogen, formyl group, alkylcarbonyl group, N
-Alkylaminocarbonyl JL N-Alkylaminosulfonyl group, aminosulfonyl group, aminocarbonyl group, alkoxycarbonyl group having 2-5 carbon atoms, alkylsulfonyl group, alkyl group, or aminocarbonyl group, alkyl-carbonyl group, -, human tetraxyl group, amino group, alkylcarbonylamino group. an alkyl group substituted by formamide 3 or an alkylsulfonylamino group (wherein each alkyl group has 1-4 carbon atoms); R3 is hydrogen, methyl, formyl, methylcarbonyl alk is an alkylene group having 1-4 carbon atoms; n is 0 or 1; and m is 0.1 or 2. 2) The compound according to claim 1, wherein A is an alkylene group (LJ), B is a carbonyl group, R2 is hydrogen or a methyl group, and n is O. 3) A is an alkylene group &! 1. B is a methylene group, R2 is a formyl group, and n is O. A compound according to claim 1. 4) A is a carbonylethylene group or a carbonylpropylene group, and B is a carbonyl group. And R2 is hydrogen or a methyl group, provided that the ethylene group or propylene group of A is BK-bonded. A compound according to claim 1. 5) A is a 1-oxaalkylene or 1-thioalkylene group, and B is a carbonyl group. R2 is hydrogen or a methyl group, and n is 1. A compound according to claim 1. 6) A is a 1-oxaalkylene group, B is a carbonyl group, R2 is hydrogen or a methyl group, and n is O. A compound according to claim 1. 7) R1 is hydrogen, R is 2-pyrrolidon-3-yl group, 2-pyrrolidon-4-yl group, biyridin-2-one-3-yl group, 1-methylbivoridin-2-one- 3
-yl group, 2-biyridon-5-yl group % 1-formyl-3-pyrrolidinyl group or 1-formylbiyridin-3-yl group, pyrrolidin-2,5-yone-3-yl group, (3- Methyl-1,3-oxazolidin-2-one-4-yl)methyl group, (3-methyl-1,3-oxazolidin-2-one-5-yl)methyl group, (1,3-
oxazolidin-2-one-4-yl)methyl group, (1
, 3-oxazolidin-2-one-5-yl)methyl group, (1,3-thiazolidin-2-one-4-yl)methyl group. or 3-methyl-berhydro-1,3-oxazolidin-2-one-5-yl group. ! FF Compound according to claim 1. 8) The compound according to claim 1, which is a compound of formula or a pharmaceutically acceptable salt thereof. 2 A is a fullkylene group having 2 to 4 carbon atoms, an alkylene group having 2 to 4 carbon atoms in which one carbon atom has an oxo substituent, or one methylene group having oxygen, 5(O)rn, or 2-4 carbons replaced by N-R3
B is a carbonyl group, thiocarbonyl group, methylene group or imino group; Ro is hydrogen or forms an ester group that is hydrolyzed in vivo; R2 is Hydrogen, formyl group, alkylcarbonyl group, N
-Flukylaminocarbonyl group, N-alkylaminosulfonyl group, aminosulfonyl group, aminocarbonyl group, alkoxycarbonyl group having 2 to 5 carbon atoms, alkylsulfonyl group, alkyl group, or aminocarbonyl group, alkyl S (Q I-, an alkyl group substituted with a hydroxyl group, an amino group, an alkylcarbonylamino group, a formamide group, or an alkylsulfonylamino group (
where each alkyl group has 1-4 carbon atoms; R3 is hydrogen, methyl, formyl, methylcarbonyl or methylsulfonyl; alk is a carbon atom; It is an alkylene group having 1 to 4 atoms; n is 0 or 1; and mij: 0, 1 or Hiro 2. ]9) R1 is hydrogen and %R is 2-pyrrolidon-3-yl group, 2-pyrrolidon-4-yl group, 1-formyl-3-
Pyrrolidinyl group S pyrrolidine-2,5-dione-3-
yl group, (3-methyl-1゜3-oxazolidine-2-
on-4-yl)methyl group, (3-methyl-1,3-oxazolidin-2-one-5-yl)methyl group, 2-piperidon-5-yl group, piperidin-2-one-3-yl group , 1-methyl bihard lysine-2-one-3-yl group,
2-♂Verito9-5-yl group % 1-formyl-biyridin-3-yl group, (1,3-oxazolidine-2-
on-4-yl)methyl group, (1,3-oxazolidin-2-one-5-yl)methyl group, or (1,3-thiazolidin-2-one-4-yl)methyl group. A compound according to claim 8.