JPS61191681A - 4-imidazolin-2-one derivative - Google Patents

Abstract

NEW MATERIAL:A 4-imidazolin-2-one derivative shown by the formula I [R<1> is H, lower alkyl, cyclo lower alkyl, lower alkenyl, halo(lower)alkyl, etc.; r<2> is H, or lower alkyl; group shown by the formula II and neighboring benzene are bonded to form heterocylic benzothiazolinyl, benzoxazolinyl group, 1,4- benzoxazinyl, qunolyl, etc., and the heterocyclic group may be hydrogenated) and its salt. EXAMPLE:1,4-Dimethyl-5-(3-methyl-2-oxobenzoxazolin-5-yl)-4-imidazolin- 2-one. USE:Having cardiac action, useful for remedying heart diseases such as cardiac incompetence, etc. Being administered orally or parenterally or through external use. PREPARATION:For example, as shown by the reaction formula, a compound shown by the formula III is reacted with a substituted isocyanate shown by the formula IV, to give a compound shown by the formula I.

Description

Detailed Description of the Invention [Field of Industrial Application] This invention relates to a novel 4-imidacillin-2-one derivative having cardiotonic action and represented by the general formula C-13 below, and is useful in the medical field. used.

[Conventional technology]

It is known from JP-A-57-175171 that certain imidacillin derivatives have anti-inflammatory, analgesic, and antipyretic effects.

[Structure of the invention]

The 4-imidacillin-2-one derivative which is the object compound of this invention is represented by the following general formula 1-D'C''.

Low grade a! A lower alkyl V group, a lower alekenylv group, a halo (lower) alkyl group, a piperazini JV (lower) ayxy group, or a lower alkyl IV amino (lower) ayxy group, and the nitrogen in these substituents The atom may be substituted with a lower alkyl group or an a/I/(low i)alkyl group, R is a hydrogen atom, or fc is a lower alkyl group, and the lower alkyl group is a carboxy group or a lower alkoxy group! It may be substituted with a levonyl group, and O together with the adjacent benzene ring is a benzothiazolinyl group, a penzoxazolinyl group, a 1,4-benzoxazinyl group,
Represents a heterocyclic group selected from a quinolyl group, a 1,4-penzothiazinyl νL 2,1-benzothiazinyl group, and the heterocyclic group may be hydrogenated, and an oxo group,
The sulfur atom constituting the heterocyclic group may be substituted with a substituent selected from a lower alkyl group, an imino group, a lower alkanoyl imino group, and a lower anolekyl amino (lower) ale group. The 4-imidacillin-2-one moiety and the heterocyclic moiety represented by O of the co-objective compound C1), which may be oxidized, may alternatively represent either one depending on its tautomer. can. For example, for oxo-substituted heterocyclic groups such as "4-imidacylin-2-one" and "2-oxopencinnaazolinyl group", their tautomers, i.e. "2-hydroxyimidazole" and "2-hydroxyimidazole" and "2-oxo-substituted heterocyclic group" -hydroxybenzothiazolyl group", and both of these tautomers are in a state of tautomeric equilibrium as shown by the following balanced equation.

It is well known to those skilled in the art that these tautomers are in equilibrium and can change with each other, and both of these isomers are included in the dynamic composition of the target compound C-13. shall be

However, in this Mei NJ document, only one expression is used for convenience, for example, "4-imidacylin-2-one" and "
2-oxobenzonazoly=lv group.

O is an imino group or a lower alecanoid! In the case of a heterocyclic group substituted with a leimino group, these tautomers are also included, and the tautomerism is substantially the same as above.

The object compound [1] of the present invention and its salts can be produced by the following production method.

Manufacturing method 1 (1) C1] (laJ
[Ib13 Production Method 6 LIQ] CIdCo Production Method 4 (18) Llf, 1 [In the above formula, R
1, R2 and O each have the same meaning as before, R3 is a lower alkylene group, R is a hydrogen atom or a lower alkyl group, R is a lower V-kyl group, A/I/(lower) A-V key y group or R4 and N atom together form a piperazinyl group optionally substituted with a lower alkyl group, R6 represents a lower alkanoyl V group, and 01 together with the adjacent benzene ring form a pencinnazoli group. Nyl group, 1,4-benzothiazinyl group and 2.1
- Represents a heterocyclic group selected from pensinaazinyl group, which heterocyclic group may be hydrogenated, and furthermore represents an oxo group, a lower 7ykyl group, an imino group, a lower alkanoylimino group, and a lower alkylamino lower Optionally substituted with a substituent selected from acyl groups,
The constituent sulfur atoms are assumed to be oxidized, 03
together with the adjacent benzene ring, pensinazolinyl group, benzoxazolinyl group, 1,4-benzoxazinyl group, quinoli V group, 1,4-pensinaazinyl group and 2,1-penzothiazidi represents a polycyclic group selected from the group w, the heterocyclic group may be hydrogenated, and the sulfur atom constituting the heterocyclic group may be oxidized, and Y respectively mean acid residues. ] Various substituents described in this specification will be explained in detail below.

"Lower" means 1 to 1 carbon atom, unless otherwise specified.
It means 6 pieces.

Examples of the "lower alkyl group" include straight-chain or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butylene, isobutyl, tertiary carbonyl, and hexyl. Illustrated. The "lower alkyl group" in R2 may be substituted with a carboxy group or a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.
Preferred examples thereof include carboxy groups, methoxycarbonylmethyl, 2-(methoxycarbonyl/L/)
Examples include ethyl, 2-(ethoxycarbonyl) and the like.

Examples of the "lower alkyrin group" include methylene, ethylene, methylmethylene, propylene, trimethylene,
Examples include linear or branched alkyrin groups such as tetramethylene, pentamethylene, and hexamethylene.

Examples of the "cyclolower acyl group" include cyclic hydrocarbon groups such as cyclopropyv, IV-klobutyv1, cyclobennal, and cyclohexyl.

Examples of "lower alkenyl group" include vinyl y1 allyl, 1
-propenyl, improbenyl, 2-butenyl, 3-
Butenyl, 1,3-pentenyl, 2-pentenyl, 5-pentenyl, 4-pentenyl, 5-hexenyl
Examples include unsaturated hydrocarbon groups such as.

A "halo (lower) acyl group" is one in which any carbon atom of the above-mentioned lower alkyl group is substituted with a halogen such as chlorine, bromine, iodine, or fluorine. , 2-chloroethyl, 1-bromomethyl, 2-90 loprovir,
Examples include 3-furomopropyl, 4-chlorobutyl, 5-chlorobennal, 6-chlorohexyl and the like.

"Piperazinyl (lower) acyl group" is a lower alkyl group as described above, in which any carbon atom is substituted with a piperazinyl group, such as 1-piperazinylmethyl, 2-piperazinylmethyl,
-piperazinylmethyl, 2-(1-piperazinyl)ethyl, 3-(1-biverazinyl/)propyl, and the like. The nitrogen atom of this "piperazinyl (lower) alkyl group" is further a lower alkyl group as described above or a lower alkyl group such as benzene, phenethyl, trimethyl, naphthyl methyl, etc. It may be substituted with an alkyl group, and preferred examples thereof include 2-(4-methylbiperazin-1-yl)ethyl to 4-benzyl, and any carbon atom of the lower alkyl group may be substituted with an alkyl group. Substituted with a mono- or di(lower aykyl)amino group such as methylamino, dimethylamino, ethylamino, propyamino, for example, dimethylaminomethyl, 2
-dimethine aminoethyl ν, 2-diethylamizenal,
Examples include enalaminomethyl, 2-ena JV amitzena V, and the like.

The nitrogen atom of this "lower acetylimino (low m > alkyl V group") may be further substituted with a lower alkyl group or an al(low i)alkyl group as described above, and preferred examples thereof include: Examples include N-benzyl-N-methylaminomethy&, 2-(N-benziy-N-menalamino)ethyl, and the like.

Preferred examples of the case where R4, R5 and the N atom together represent "a piperazinyl group optionally substituted with a lower alkyl V group" include, for example, 1-piperazinyl, 4-
Examples include methyl-1-piperazinyl-v14-ena-1v-1-piperazinyl.

Examples of the "lower alkanoyl V group" include straight chain or branched lower alkanoyl groups such as acetyl, propionic n/J butyryl, imbutyryl, valeryl, and isoparelli pivaloyl. The "lower alkanoyl!reimino group" is one in which an imino group is substituted with a lower alkanoyl group as described above, and examples thereof include formi-v imino, acetylimino, propionylimino, and the like.

In addition to the above-mentioned halogens, examples of "acid residues" include halogens such as benzenesulfonate, tosylate, mesylate, etc.
Examples include a lephonate group.

rOJ together with the adjacent benzene ring is a benzothiazolinyl group, a penzoxazolinyl group, a 1,4-benzoxazinyl group, a quinolinyl group, a 1,4-pencinazine vm, and a 2.1 - Represents a heterocyclic group selected from pensinaazinyl group, and the heterocyclic group may be hydrogenated. Examples of hydrogenated heterocyclic groups include:
3,4-dihydro-2H-1,4-penzoxazinino V group, 1,2-dihydroquinolyl group, 3.4-dihydroquinolyl group, 1,2.3.4-tetrahydroquinolyl group
group, 3,4-dihydro-2H-1,4-benzothiazinyl group, 6,4-dihydro-IH-2,1-benzothiazinyl group, and the like.

These heterocyclic groups (including when hydrogenated) are selected from oxo groups, lower alkyl groups, imino groups, lower alkanoylimino groups, and lower alkylamino lower alkyl groups at any position thereof. may be substituted with a substituent. Such substituted nine heterocyclic groups include:
For example, 2-iminobenzonazolinyl, 2-acetyliminobenzothiasolinyl, 3-methyl-2-oxopenshinazolinyl, 3-isopropyl! v-2-oxobenzothiazolinyl, 2-oxobenzoxazolinyl, 15-methyl-2-oxobenzoxazolinyl,
2-Methyl-3(4H)-oxo-2H-1,4-benzoxazinyl, 2,4-dimethyl 3(4H)-oxo-2H-1,4-pencinazinyl, 1-methyl Thousand I
2(IH)-oxoquinol, 1-methyl-2(
4!
2H-1,4-penzonazinyl, 2,4-dimethy/
L/-3(4H)-oxo-2H-1,4-pencinazinyl, 4-diethylamizenal-2-methyl-3(
4H)-oxo-2H-1,4-pencinazinyl, 1
-Methyl-3,4-dihydro-IH-2,1-pencinazinyl and the like.

Further, among heterocyclic groups, those containing a sulfur atom as a constituent quarter of the ring may have the sulfur atom oxidized, such as, for example, 2,4-dimethyl-3
(4H)-oxo-2H-1,4-benzothiazine 1
-oxide, 3,4-dihydro-IH-2,1-pensinaazine 2,2-dioxide, 1-methyA/-3,4
-dihydro-IH-2,1-benzothiazine 2.2-
Examples include dioxide.

It is defined as a group appropriately selected from various heterocyclic groups.

4-imidacillin-2-one derivative [1] and CI&
3-(Salts of lfl are not particularly limited as long as they are pharmacologically acceptable salts, but examples include formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, and benzene. Organic acid salts such as sulfonates and toluene-nulphonates, inorganic acids such as hydrochlorides, hydrobromides, sulfates, and phosphates, I-reginine, glutamate,
Blessings with amino acids such as orthin salts, alkali metal salts such as sodium salts, potassium salts, and power! Metal salts such as alkaline earth metal salts such as lesium salts, magnesilla salts, ammonium salts, trimenalamine salts, triethylleamine salts, pyridyl salts, picoline salts, dicyclohexylamine m%N, N-dibenzylethylenediamine salts Examples include conventional bottles of organic base salts such as.

The target compound [1] and its production method will be explained in detail below.

Production method 1 4-imidacylin-2-one derivative [1] and its salt can be produced by reacting the compound (-13 or its derivatives) with substituted isocyanate [I].

A suitable weir for compound [Il] is target compound [1]
The same bottles as those exemplified are mentioned.

The reaction proceeds by reacting a bottle of the compound CH3 with the substituted incyanate 1] in the presence or absence of a solvent at room temperature or under heat. Examples of solvents include alcohols such as methano-v1 ethano-IV and propatool, hydrocarbon solvents such as benzene, toluene, and xylene, halogenated hydrocarbons such as methylene chloride and chlorophorem, acetonitrile V, dimethyl sulfoxide, pyridine, Examples include basic solvents such as N,N-dimethyVholemamide, and any other solvent can be used as long as it does not adversely affect this reaction.

Production method 2 4-imidacylin-2-one derivative [11)] and its mass are prepared by mixing compound [1a] or its bottle with compound [ffU
Alternatively, it can be produced by reacting with that stage.

This reaction is carried out in the presence or absence of a solvent, at room temperature or under heating, to form a compound (Ia or its base) into a compound (G).
or its salt. Examples of the salt of the compound σ] include the above-mentioned organic acid salts and inorganic acid salts.

Examples of the solvent include monobasic solvents such as alcohols, hydrocarbon solvents, halogenated carboxylic solvents, acetonitrile/L/, dimethyv sulfoxide, N,, N-dimethy/V photoamide, Other conventional solvents that do not adversely affect this reaction can be used.

This reaction is carried out in the presence of a base, such as triamine (trimethyamine, triamine, triamine, etc.), pyridine, picoline, trimethylalumine, λ potassium tertiary compound S4, etc.), hydrogen Alkali metal hydroxides (sodium hydride, potassium hydride, etc.), alkali metal hydroxides (
Sodium hydroxide, hydroxide power! rosium, etc.), alkaline earth metal hydroxides (ZK magnesium oxide, hydroxide power V
), alkali metal carbonates (sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (magnesium IR acid, acid-returning acid I lesium, etc.), alkali metal hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), etc. The reaction may be carried out in the presence of

Production method 3 The 4-imidacillin-2-one derivative [1d] and its salt can be produced by oxidizing the compound ClO3 or its salt with an oxidizing agent in a solvent.

As the solvent used in this reaction, any solvent can be used as long as it does not adversely affect the reaction. Examples include various solvents such as fluorine oxide, halogenated hydrocarbons, and hydrocarbon solvents. Further, this reaction may be carried out in the presence of an acid or a base depending on the case.

Examples of oxidizing agents include permanganate, permanganate and periodate, chromic acid, ruthenium tetroxide, ozone, hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid, monoperoxy phthalate, performic acid, peracetic acid,
One or a combination of two or more of organic peracids such as Triph IV oloperacetic acid, nitric acid, and electrolytic oxidation can be used.

The reaction temperature is not particularly limited, but it is usually under cooling or 7J.
The reaction takes place at room temperature.

Production method 4 4-imidacylin-2-one derivative (If) and its salt are prepared by converting the compound [1θ] or its salt into lower 7N Kanoi I
It can be produced by subjecting the group to a cleavage reaction.

This reaction can be carried out in a conventional manner, for example by a solvolysis reaction using an acid or a base.

Preferred examples of acids include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids such as formic acid, acetic acid, triphroacetic acid, propionic acid, benzenesulfonic acid, and p-toluene/dichloromethane. and acidic ion exchange resins.

As the base, those exemplified in Production Method 2 can be used, but it is preferable to carry out under mild conditions.

7X+ solvent decomposition typically involves water, methanol, ethanol, dioxane, tetrahydrofuran, dimethyls! Conventional solvents which do not adversely affect the reaction, such as refoxide, can be carried out in the mixture.

If the acid mentioned above is a liquid, it can also be used as a solvent.

The reaction temperature is not particularly limited, and the reaction is usually carried out at 7JO temperature or under heating.

The raw material compound CM) and its properties also include new compounds, which can be produced by the method described below or by a method equivalent thereto.

[1] [In the formula, R2 and O each have the same meaning as before,
Z means an acid residue] The first step compound (VD and its salt can be produced by reacting the compound [VD and its salt with an and-forming agent such as sodium azide) .Compound [v]
Examples of the salt include the same fuku as exemplified for chemical compound (1).

This reaction usually proceeds in a solvent such as water, methanol, ethanol, etc., acetone such as diethylacetone, diethylacetone, etc., diethyl ether, diethyl ether, tetrahydrofuran, etc., with cooling or at 710°C. do.

Compound (Vl) obtained in this reaction and its bottle can be isolated by a conventional method, but without isolation, the following second step (
(reduction).

The second step compound [■] and its salt can be produced by reducing the compound (-VD or a salt thereof. The salt of the compound [[] is the same as that exemplified for the compound [1]. can be mentioned.

In addition to catalytic reduction, this reduction reaction includes lithium borohydride, sodium borohydride, potassium borohydride,
Sodium cyanoborohydride, lithium hydride atv
Reduction using a reducing agent such as zinc, iron, copper, etc. and an acid such as hydrochloric acid, sulfuric acid, etc., or metal such as sodium, lithium, zinc, and a base such as ammonia, sodium hydroxide, etc. This can be carried out by conventional methods such as chemical reduction using. Catalytic reduction is usually carried out as described above in the presence of a conventional catalyst such as Raney nickelization, palladium, platinum, rhodium, copper, etc., preferably at room temperature and atmospheric pressure, in the presence or absence of an acid such as hydrochloric acid. After-recording can be carried out in a conventional solvent such as Aether V.

Compounds [l] are obtained in the form of acid salts when an acid is used during the reaction, and these compounds and their amplifications can be isolated by conventional methods, but they can be isolated in the following reaction ( fM
It may be used in manufacturing method 1).

[Effects of the Invention] The 4-imidacillin-2-one derivative L13 and its pharmaceutically acceptable salts, which are the objects of the present invention, have cardiotonic effects and are useful, for example, in the treatment of heart diseases such as heart failure.

In order to demonstrate the medicinal activity of the 4-imidacillin-2-one derivative CI), pharmacological test results are described below.

Cardiotonic effect test Method for testing the effect on left ventricular pressure in anesthetized dogs: Male and female mongrel dogs were treated with bendoparivital sodium 3511.
Anesthetize by intraperitoneal injection of g/&q. The left carotid artery was dissected and a heparin-saline filled catheter /l/ (
A USCI (4+8F) was inserted and placed in the left ventricle. Catheter V with pressure cadence juicer (Nihon Kohdensha,
MPU-Q, 5A) to measure left ventricular pressure,
Calculate p/(li, Max). Catheter A/ was inserted into the right femoral vein for administering the test compound.

Left ventricular pressure and dp Max are recorded on a polygraph (Nihon Kohdensha, R: RA-4008).

The test compound was distilled (dose volume: 0.2 zl/kLi) or tahadimethyl sulfoxide (dose volume: 0.04 g//k
q) and intravenously administered the test compound at 1.011 fl/ml.
Administer to obtain a total amount of 1 kg. The intraventricular pressure after administration was compared with that before administration.

The test results are expressed as the rate of change (dp/dt M, c) of dp/dt Max calculated using the following formula.

Test results: *6-amino-5-(4-viridi”)-2(IH)-
Viridinone (known compound actually used as a cardiotonic drug) As is clear from the above test results, the target compound of this invention, 4-imidacillin-2-one derivative, has an effect of increasing myocardial contractility (positive inotropy). It is useful as a cardiotonic drug, for example, as a therapeutic agent for congestive heart failure.

The object compounds of this invention (IJ and its pharmaceutically acceptable carriers) may be combined with conventional pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or external administration. Mixed and used in the form of conventional pharmaceutical preparations.

Pharmaceutical formulations may be formulated in a solid form, such as a tablet, dragee, or skewer, or in a liquid form, such as a solution, suspension, or emaffletion. If necessary, the above formulation may contain auxiliary agents, stabilizers, wetting agents or emulsifiers, buffers, or any other commonly used additives.

The active ingredient is usually administered in unit doses of 0.05 Da/kti to 5 C1Olly/kg 1 to 4 times per day. However, the above-mentioned dosage may be increased or decreased as appropriate depending on the patient's age, weight, and symptoms 1fC, depending on the administration method.

Hereinafter, this invention will be explained in more detail with reference to manufacturing examples and examples.

Production Example 1 5-Methyl-5-valerylbenzothiazolin-2-one (7,7F) and 30% hydrogen bromide-acetic acid solution (IDgt
) and acetic acid (50 liters) at room temperature, add pyridinium hydrobromide/perbromide (9.98F), and at the same temperature
Stir for an hour. Pour the reaction solution into ice water (300ml), separate the resulting precipitate, and dissolve the separated crystals in a mixed solvent of ethyl acetate and water. Separate the organic layer and carbonate it) I
After sequentially washing with a saturated aqueous solution of Jium and brine, drying with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from diisopropylethe to give 5-(2-promoparyl)-3-methylbenzonazolin-2-one (5,41). get.

Melting point = 177~180"C"): 1690, 1670.1600a
1HMR(DMSO-d6.δC0,94(3H,t,
, r=7az) 1.1 to 1.8 (2H, m) 1.8
~2.3 (2F!, m) 3.45 (3H, 8) 5.
78 (1H, t, , r = 7Hz) 7.42 (IH
,d,,r=9Hz)8. C13(IFi, dd',,
T=2Hz, 9Hz) 8.38(IH, d,, T=2H
2) Production Example 2 (1) Aminium chloride (19,7F) and 2-
Carbon disulfide of bromobutyrybromide (14,7F) (
40g) Stir the solution for 30 minutes at room temperature. Add 3 to this solution
-Methodibenzoxazoline-2-one (8,15F)
and heat the mixture to reflux for 2 hours. The solvent is removed under reduced pressure and the residue is stirred for 1.5 hours at 60-70°C.

The reaction solution was poured into ice water, and the precipitated crystals were dissolved in a mixed solvent of tetrahydrofuran and ethyl acetate. The organic layer is separated, washed successively with a dilute aqueous solution of sodium bicarbonate and brine, and then dried over magnesium sulfate. Distill the solvent,
The residue was crystallized from diisopropyl V ether V to give 5-
(2-bromobutyl)-3-methylbenzoxazolin-2-one (10,742) was obtained.

Melting point: 108-110℃ Engineering R (Nugeot/I/): 1770.1675.161
0n 1HMR (CDC13, δ): 1.10 (3a
,t,,J=7az)1.8~2.5(2H,m)3.
49(3H,8)5.11(1a,t,,J=7Hz)
7.08(IHld,,y==8H2)7.30(IH
,d,,r==2az)8.00 (I H,aa,
J=2H2, 8H2) Above Production Example 1 or 2-(1
) The following compounds are obtained by a similar or equivalent method.

(2) 5-(2-bromobutyl 1)-3-isoprohy/
L/-2-benzothiazolin-2-one R (film): 3030.2980.1770.1690.167
0.

1595.157g NMR (DMSO-a6.δ): 1.02 (3H, t
, :r=7gz)1.52(6F!,d,,r=7
H2) 1.8-2.4 (2H, 111) 4.6-5.1
(IH, m)5.72 (1a, t, y==7Hz)7.
65 (1a, d.

J=8Hz) 8.12 (1a, d, a, J=2az.

8H2) 8.41(IH, (1,, T=2H2) (3)
6-(2-bromobutyl ν)-2,4-dime 1,000 A/-4
H-1.4-benzoxazin-3(4H)-one Melting point = 96-97°C Engineering R (=-1): 1710.1670.1655.1
595.1520rNMR (CDCl3.δ): 1.2
0(3H,t,, J=7az)1.54(3a,d,
J==7az) 1.8-2.4 (2a, m), 3.
40 (3a, s) 4.70 (IH.

q,, r=7Hz) 5.02 (1a, t, J=7a
z) 7.03 (IH, d, J=9az) 7.5~7
．． 8(2H, m) (4) 6-(2-Bromov"Nari Ishin-1-Menalquinoline-2(1B)-ONE R (Film): 1725,1650.t620.1
590.157hi1 4HMn (d6-DMSO, δC
1,06 (3H, t, J=7az) 1.7-2.5 (2
H, m) 3.66 (3H, l) 5.70 (I H, t
, :r=7Hz) 6.5~6.8(2H, m
) 7.0-8.5 (3H, m) (5) 6-(2-1
0 Moptili 7) -1-Methyl 6.4-Dihydro-
IH-2,1-Pensinaazine 2,2-dioxide R (film): 1680.1610.1345.1
330.1150゜116゜1 NMR (DMSO-d6.δ): 1.00 (3a, t,
y=7nz) 1.6 to 2.4 (2H, m) 3.26
(3H, s) 3.4-5.9C4H, m) 5.62
(IH, t, J=7Hz) 7.18 (1a, d,,y=
9az) 7.93 (IH, d, r=2az) 8.0
1 (IH.

d4,2Hz, 9Hz) (6) 6-(2-bromobutyryl)-3,4-dihydro-IH-2,1-benzothiazine 2,2-dioxide melting point = 151-153''C Engineering R (Nushor): 3250. 1665.1600.
1325.114 1HMR (DMSO-d6.δ)
:1. QQ (3H, s, J=7Hz) 1.7-2.4 (
2H, m) 3.4 (4u, a) 5.58 (IH, t, ,
T=7Hz) 6.88(IFI, (1°J=9H2
) 7.86 (IH, dd,, T=2H2゜9Hz)
7.95 (IH, d, , T = 2Hz) (7) 6-(
2-bromobutyrv) -2,4-dimethyl-2H
-1,4-benzothiazin-3(4H)-one Melting point: 99-102°C IR (g-zt'): 1740.1670.159
L1.1560nNMR (CDCd3.δ): 1.10
(3H, t, J=7Hz) 1.48 (3H, a, J=7
．． 5Hz) 1.9-2.4 (2u, m) 3.52 (
3H, s) 3.51 (IH.

q,, T=7.5az), 5.03(1a, t,,y=
7Hz) 7.1-7.6 (2H, m) 7.73
(IH, 8) (8) 6-(2-bromobutyry/I/)-
2-Methyl-2H-1,4-pensinaazine-3C4E
! )-on melting point: 154-157"C IR (nujir/shi): 1665.1590.156 [1
HMR (DMSO-d6.δ): 1.00 (3a, t,
,, r=7az) 1.36 (3H, d,, r=7Hz)
1.7-2.4 (2H, m) 3.77 (IH,
q, J = 7Hz) 5.51 (1a, q,, r = 7EIz
)7.5[1(ITl.

d, J=8E! Z) 7.67 (IH, dl, T=2
Hz).

7.75 (IH, d, d, J=2Hz, 8Hz) (9)
6-(2-bromobutyl)-4-methyl-2H-1
,4-Pensinaazin-3(4H)-one Melting point: 89~
92”C Engineering R (nuji g-I): 1670.1590.15sC
r1′ NMR (DMSO-46, δ): 1.
02 (3a, t,, y=7az) 1.7-2.4 (2a
, m) 3.44 (3H, s) 3.62 (2H, s)
5.34 (1a, t, J=7Hz) 7.60 (IH
,a,,r=9Hz)7.79(1a,d,J=2az
, 9az) 7.83 (IH, a, y = 2Hz) α0 5-(2-bromo-3-methoxycarbonylpropionyl)-3-methyl-benzothiazolin-2-one R (film): 3020.1730.1640. 1
590.1495Yen-1HMR(DMSO-(16,δ
): 3.47 (3a, s) 3.63 (3H.

8) 3.1-3.4 (2H, m) 5.7-6.1 (IH
.

m) 7.44 (11Ld, J=8.5Hz) F3.
13 (IH, ad, J=2az, 8.5az) 8.45
(IH, (1,, T=2H2) αυ 2-7 cetyl imino 5-(2-bromobutyryl)benzothiazoline Melting point: 191-195°C NMR (DMSO-d6.δ): 1.05 (3a, t,
J=7Hz) 1.8-2.2 (2a, m) 2.27 (3
H, s) 5.80 (IH, t, , r=7Hz) 7
．． 96 (IEI.

aa,, r=2az, 8.5H2) 8.18(IH
.

d, J=5.5Hz) 8.44(1H, d, J=2
Hz) (6) 6-(2-bromopropioni”)-4-
Me+IV-2H-1,4-penzothiazi:/-3(4H
) - One R (nujo I): 1680.1590.156 Ji shoulder -1 HMR (DMSO-d 6.δ): 1.80 (3
H, d, J=7az) 3.42 (3H, 8) 3.6
0 (2H, s) 5.88 (IH, q, J=7Hz)
7.55 (IH, d.

J=6Hz) 7.63 (IH, d, J=2Hz)7
．． 73 (IHdd J=2.6H2) (135-(2-
BromopropioniN)-3-methylbenzothiazoline-
2-one melting point: 115-116℃ Engineering R (Nujol): 1650.1591J, 1500
BiNM DMSO-d6. δ, l: 1.48 (3H, d
, J=6Hz).

3.45 (3a, s), 5.82 (IH, q, J=6H
2) 7.41J (IH, d,, r=9Hz) 8.0
7(IH, (1(1,, T=2.9H2)8.35(I
H, do, r=2Hz) Mass, 301 (M+1) Q4) 5-(2-bromobutyl jv)-3-metholebenzothiazoline-2-one R: 1690.1680. 1670.
1660.159Of1HMR(DMSO-(16,δ
): 1.02 (3a, t, y==7az) 1.7-2.
4 (2a, m) 3.45 (3H, 8) 5.65 (1a,
t,, r=7az) 7.42 (IEI.

d,,r=9az)8.10(1a,da,J=2Hz
, 9H2) 8.36 (IH, d, J=2Hz) α, f9
5-(2-bromopropionyl)benzoxazoline-
2-one melting point: 191-193''C Engineering R: 3170.1780.1662.
1625.161On"1HMR(DMSO-1116
, δ): 1.82 (3a, a, -r=7Hz) 4.43
(IH, br, s), 5.80 (2H, q.

J:=7Hz)7.2Q(IH,d,J=9Hz)7.
90 (1a, a, J=2az) 7.92 (IH.

ad, J=2.9Hz) αI 6-(2-bromobutylene)-2-methoxyV-
4-(2-dieminoethyl)-2H-1,4
-From benzothiazin-3(4H)-one (film): 1675.1590.156α-
1HMR (CDC/3.δ): 1,1[](6E,t,
, T=7Hz) 1.18 (3a, t, J=7az)1.
49 (3H.

d,:r=7.5Hz)1.9~2.5(2a,m)2
．． 63 (4H, (L,, T=7Hz) 3.13 (2H.

(1,-r=7H2)3.50(2H,(1,J=7H
z) 5.9-4.4 (1a, m) 4.4-4.9 (iH
, m) 7.4-7.7 (IH, m) 7.9-8.6
(2H, m) Production Example 3 In a mixing column M containing methanol (150+m?) and water (23Ml) containing sodium azide (2.34g),
5-(2-Bromopropionyl)-3-methybenzoxazolin-2-one (8,5M)' was incubated at room temperature and then stirred at 35-40"C for 4 hours.

The reaction solution is concentrated under reduced pressure, the residue is dissolved in a mixture of ethyl acetate and water, and the organic layer is separated.

After washing with 7X sodium chloride, drying over magnesium sulfate, evaporating the solvent under reduced pressure, and washing the residue with diisopropyl ether to give 5-(2-azidopropionyl)-3-methylbenzoxazolin-2-one ( 6,2f) is obtained.

Melting point: 110-112°C ■R (nuji*-'): 2200.1770.1680.
1625.1605rIr1 Production Example 4 In the same manner as Production Example 3, the following compound (1) was prepared using the nine compounds obtained in Production Examples 1 and 2 or their derivatives as raw materials.
~Ql were obtained, respectively.

(1) 5-(2-Azidobutyry/I/)-3-methylbenzoxazolin-2-one Melting point: 99-100°C Engineering R(Nuji*-/I/): 2120.1790.16
70.161oc1f1NuR(aDed3.δ): 1
．． 08 (3u, t,, J=8uz) 1.6-2.3 (2
H, m) 3.45 (3H, s) 4.50 (IH, t,,
r=6Hz) 7.06CIH.

(1, J=8H2)7.76CIH, d, y=2az)
7.85 (IH, da, y=2az, 8Hz) (2) 5
-(2-andbutyryl)-3-isopropylbenzothiazoline-2-one R (film): 29B0.2110.1690.1
670.1590mNMR (DMSQ-(16,δ):
0.96 (3u, t, J=7az) 1.35 (6a, d
, y=7az) 4.4-5.3 (2H, m) 7.6
2 (IH, d, , r=8Hz) 8, Q2 (IH, d, d
, J==2Hz, 8Hz) 8.34(IH,d, J=
2H2) (3) 6-(2-7didobutyrinoV)-2,4-dimethyl-2H-1,4-benzoxazin-3(4H)-one Melting point: 177-179°C Engineering R (cyto): 213D , 1690.1605.151
51HMR (CDCl2.δ): 1.06 (3a, t,
, J=7uz)'+1.56(3H,d,J-Jaz
) 1.5-2.2 (2H, m) 3.40 (3H
,8) 4.3~4.6(IH,m) 4.72(
IH, q, J = 3Hz) 7.00 (IH, d, J = 9E
Iz) 7.4-7.7 (2a, m) (4) 6-(2-azidobutyryw)-1-methylrequinolin-2(IH)-one Melting point: 134-137°C (decomposition) Nuji = i-I): 2220.1700.1650
．． 157001r11MR (DMSO-46, δ): 1
．． 03 (3H, t, J=7uz) 1.6-2.2 (2H
, m) 3.63 (3H, s) 5.1 to 5.4 (IH
, m) 6.5-6.9 (2H, m) 7.2-8.6 (3
F1. (5) 6-(2-azidobutyric)-1-methyl-6
,4-dihydro-IH-2,1-benzothiazine 2.2
-Dioxide engineering R (film): 2120.1735.169[1,
168 [1,161D.

1335.116CI, 113CI "1 HMR (DMSO-46, δ): 0.97 (3H,
t, , T=7H2)1.6~2.0(2H,m)3
．． 27 (3H, s) 3.4-3.8 (4a, m) 5
．． 0 to 5.2 (I H, m) 7.24 (1a, d,
, r=9Hz) 7.93 (1H.

s) 7.98 (IH, d, J = 9Hz) (6) 6-(2
-azidobutyric I)-5,4-dihydro-IH-2,
1-Benzothiazine 2,2-dioxide Melting point: 168-171 ”C Engineering R (Nushor C3240, 2125, 1730, 1
680, 1610°1330, 115Qc! r1 HMR (DMSO-d6.δ): 0.96 (3H, t,
J=7uz) 1.5-2.1 (2H, m) 3.2-3
．． 7 (4H, m) 3.45 (3H, s) 4.97 (1a
, dd, y=7Hz, 8Hz) 6.89 (1a, a, ,
y=JHz) 7.85 (IH, dd, J=2Hz, 8H
z) (7) 6-(2-azidobutyryl)-2,4-dimethy n/-2H-1,4-benzo'? -7 Jin-3 (4H
)-one melting point: 144-147°C Engineering R (nuji H-/L one: 2220.1675.159
r1NMR (CDCl5.δ): 1.27 (3a, t,
, r=7Hz) 1.47 (3H, d, J=7H2)1.
6-2.3 (2a, m) 3.50 (3a, s) 3.53
(1a.

q, J = 7Hz) 4.48 (1H, t, , r = 7Hz
)7.20 (1a, a,,y=11az) 7.50
(IH.

s) 7.68 (IH, d, y = 11Hz) (8) 6
-(2-azidobutyryA/)-2-methyl-2H-1,
4-Benzothiazin-3(4H)-one melting point 289-9
2”C Engineering R: 3200.2120.2080.
1690.160α NMR (DMSO-d6.δ):
1.07 (3H, t, J==8uz) 1.54 (3H,
a, J=8az) 1.7-2.2 (2H, m)3.
65 (IH, q, , T = 3EIz) 4.4-4.6 (I
H, m) 7.4-7.8 (3H, m) (9) 6-(
2-azidobutyrv) -4-methyl-2H-1,
4-Benzothiazin-3(4H)-one Melting point: 86-8
7°C IR (dicarbonate: 2220, 1670, 157
0cIIINMR (CDCl3.δ): 1.07 (3H
,t,,y=7Hz)1.7~2.3(2H,m)3.
51 (3H, s) 3.49 (2H, s) 4.3-4.7
(IH, m) 7.52 (Hr, d,, r=2az)
7.64 (IH.

(1, J=10H2) 7.64 (IH, aa, J=2H
2, IQHz) α0 5-(2-azido-3-methoxycarbonylreprobioni-)-3-methyllevenzothiazolin-2-one i (film): 2950.2100.1730.16
70.1590n"1HMR(DMSO-(16,δ)
:2.8~3.1(2H,m) 3.48(3H,s
) 3.65 (3H, 8) 5.48 (IH.

t, J=7Hz) 7.48(IB, d,, T=
8,5H2) 8.10(IH, dd,, r=2Hz, 8
．． 5Hz) 8.4(J(IH,a,,T=2az) αυ
5-(2-Azidobutyryl)-3-7 Senna V iminovencinnaazoline Melting point: 167-169°C Engineering R (Nugital): 3290.2100.1695.
1670.165 di f1HMR (DMSO-d6.δ)
:0.98(3H,t,,T=7H2)1.5~2.2
(2H, m) 2.23 (3H1) 5.1 to 5.5 (
1a, m) 7.83 (1a, da.

J=2H2,8Hz)8.16(IH,a,,r=8H
z) 8.33 (IH, d, J=2Hz) U6-(2
-Azidopropionyl v) -1-me thousand! Ray 6.4-dihydroquinoline-2(IH)-one Melting point near 8-80°C IR (nuji!-/shi): 2130.2080.1660
．． 1590.157 [NMR (DMSO-d6.δ):
1.45(3H,d,,r=7H2)2.5~3.5(
4H, m) 3.33 (3H, s) 5.13 (IH,
q, J=7Hz) 7.11 (IEl.

(1, J=8H2) 7.86 (IH, a, J=2H
z) 7.96 (I H, aa, J=2H2, 8H
2) (136-(2-azidopropionyl)-4-methyl-2H-1,4-benzothiazine-3 (4F monomer melting point = 211-214°C (decomposition) IR (Nuji*-A/): 2120 .2070.1690
．． 1580c! r1HMR(cDc113-aD3oD
, δ): 1.52 (3H, d, y=7Hz) 3.4
7 (5H, s) 4.83 (IH.

(1, -r=7H2) 7.47 (1a, da, y=
2Hz, 8H2) 7.63 (IH, d,, r=8H
z) α4) 5-(2-7Didoprobione)-6-Methitvhenzothiazolin-2-one Melting point: 167-169°C Engineering R (Nujo I): 2090.1700.1690
．． 1670.1590°1570.1490.1425
．． 1290.1250.120Of”NMR(CD01
3. δ): 1.58 (3H, d,, r=7H!i,)3
．． 51 (3H, s) 4.71 (IH, (1, J = 7Hz
)7.12(iH,a,,r=8al 7.96(I
H.

dd, J = 2Hz, 8Hz) 8.07 (IH, (1°J
=2H2) αf9 5-(2-azidobutyric)-3-methylbenshinazolin-2-one Melting point: 167-169°C Engineering R (nudicol): 2080.1690.1670.
1590.1570°1485.1415.1330.
1270.1240.119 NMR (cDa13.δ
): 1.08 (3H, t,, J=7uz) 1.7-2.
3 (2H, m) 3.50 (3H, s) 4.50 (IH,
t,,T=7Hz)7.13(IH.

d,, r=8H2) 7.37(IH, dlJ=2H
z.

8Hz) 8.06 (IH, d, J=2Hz) α* 5
-(2-7 didovaleryl)-3-methylbenzothiazolin-2-one Melting point: 164-166"CxR: 2150.2120.1690.
168C1, 159c1FlNMR (DMSO-d 6
．． δ): 0.90 (3H, t, J=7H2) 1.1~
2.1 (1, m) 3.45 (3F!, s) 4.9-5.
3 (1a, m) 7.43 (1a, a,,y=9Hz
) 8. [12(IH, dd, J=2Hz, 9E[z
)8.31 (IH, (1,, T=2Hz)Qi6-
(2-azidobutyryl)-2-methyl-2H-1,4-
Benzoxazin-3(4H)-one Melting point = 104-105.5"C Engineering R (Nujol): 2180.1680.1595°150-NMR (CDC43, δC1,05(3H, t
,,T=6.5Hz)1.61 (3H,σ,-r=7
Hz) 1.6-2.3 (2H1l) 4.47 (
IFl, t, J = 7Hz) 4.78 (IH, q, J = 7
H2) 6.98 (IE.

d, J=9HZ) 7.4~7.7 (2H, m
)9j31(IH,s) (to) 5-(2-azidopropionyl)benzene oxazolin-2-one Melting point: 114-116"C Engineering R (Nujol): filtration 120.2150.2090.
1830.1770゜1670.160 body "1 NMR (CF3COOH, δC1,80 (3a, t, J
=7az)5.20(IH, (1,J=7H2) 7
．． 49 (1H.

d, J=9Eiz) 8.05 (IH, s) Shishichi 8.1
2(IH, d, J=9Hz) 016-(2-azidobutyl)-4-(2-diena-aminoethyl)-2-methyl-2H-1,4-pencinazin-3(4H)-one IME (cDa13.δ): 0.7 to 1.6 (12
H, m) 1.6-2.2 (2H, m) 2.2-3
．． 0 (6H, m) 3.2~3.7 (1a, m) 3.8~
4.2(2H,m)3)-1,* 4.3~4.8 (IH,m) 7.0~8.1
(Thunder; Kaya) Production Example 5 5-(2-acy)-7''ropionyl)-3-methylbenzoxazolin-2-one (6,[JF/)t-methanol-7''300 penalty) and 1 stipulated Dissolve in a mixture of hydrochloric acid (50 ml) and hydrogenate by stirring with 10% palladium on carbon (C2,41) under a hydrogen stream at room temperature for 3 hours.

The reaction solution is filtered, and the filtrate is concentrated under reduced pressure. After dissolving the residue in water, it is washed with acetic acid chloride. 7 to layer vacuum source RfiL
, Nft-methanol and dienal ether are crystallized to obtain 5-(2-7 minoprubioni/)-3-methylbenzoxazolin-2-one hydrochloride C4,21).

Melting point: 242-243"C Engineering R (w-Iv): 1810.1675.1630
．． 1606c'm'' Production Example 6 In the same manner as Production Example 5, the following compounds were prepared from the compounds described in Production Example 4-(1) to aη [Production Example 6-(1) to
αη] is obtained.

(1) '5-(2-Aminobutyl)-6-methyl-benzoxazolin-2-one hydrochloride Melting point = 227-228-C
, 1610.151 (C+ 1NMR (DMS O-d
6. δC0,89 (3H, t, J=7Hz) 1.7~
2.2 (2H, m) 3.43 (3H, FI) 4.9-5
．． 5 (1H, m) 7.47 (1a, a, J=8.5
H2)8. (J2 (IH, S) 8.10 (1H.

d, J=3.5H2)8.7(2H,b8)(2)5-
(2-Aminobutyryl)-3-isopropylbenzothiazolin-2-one hydrochloride Melting point = 191-194''C Engineering R (Nujol): 1690.1670.1598.
151α-1NMR (DMSO-d, , δ): 0
．． 87 (3H, t, J=7Hz) 1.50 (6
H, a, J=7az) 1.6 to 2.2 (2n, m)
4.7-5.1 (IH, m) 5.0-5.4
(I H, m) 7.70 (I H, d, ,
T=3Hz)8.16(IH,d,d,,T=2Hz
, 8Hz) 8.53 (IH, d, J=2Hz) 8.
76 (2H, bs) (3) 6-(2-7 Minobunari/L
/)-2+4-dimethylene 2H-1,4-benzoxazin-3(4B)-one hydrochloride Melting point: 252-253"C IR (nujol: 1705.1685.1605.
1515 C-1HMR (DMSO-d 6.δ): 0.
90 (3H, t, J = 7Hz) 1.52 (3a, d, J
=7az)1.7~2.3(2H,m)3.40(3H
, s) 4.90 (IH.

'1-J=7FfZ) 5.0-5.4 (IH, m) Otsu 1
5 (IH, (!,, J=9H2) 7.80 (Dr.

d, y=9Hz) 7.75 (1/H, s) 8.7 (
3H1B) (4) 6-(2-Aminobutyryl)-1-methylquinoline-2 (IF dione hydrochloride Melting point: 244-248°C (decomposition) rR (nudi w-I): 3400.1690. 16so
, 1625.1590a “1HMR (DMSO-d6.
δC0,9(3H,t,J=7uz)1.6~2.3(
2H, m) 3.97 (3H, s) 4.9 to 5.4 (IH
, m) 6.72 (1H, d, J=10H2) 7
．． 3-8.7 (4a, m) 8.8 (b+q.

2'B) (5) 6-(2-aminobutyric)-1-methyl-3
,4-dihydro-IH-2,1-benzothiazine 2.2
-Dioxide hydrochloride Melting point: 281"C (decomposition) IR (NujiM-ru): 1680.1620.1575.
1335.116[1HMR(DMSO-d, ,δ
C0,87 (3H, t, J=7Fiz) 1.5-2.3
(2H, m) 3.30 (3H, s) 3.3 to 3.9
(4H, m) 4.9-5.3 (IH, m) 7.23 (H
r, d, y=9Hz) 7.8-8.2 (2H1m)
8.7 (3 g, bs) (6) 6-(2-aminobutyry/shi)-3,4-dihydro-IH-2,i-benzothiazine 2.2-dioxide hydrochloride Melting point: 277-279°C (decomposition) IR (nuji v-ztzc345 (J, 1695.161
(1,1330,115ocIr”NMR(DMSO-
d6. δ): 0.86 (3H, t, I=7Hz) 1.6
~2.2 (2H, m) 3.43 (41T, s) 4.
8-5.2 (1H, m) 7. [+5(1a, d, y
=8H2) 7.95(1a, da,, r=2Hz,
3'Hz) 8, Lll(1H, d,:r=2Hz)
8.7 (3H, bs) (7) 6-(2-aminobutyryl)-2,4-dumenal-2H-1,4-benzothiazin-3(4H)-one hydrochloride Melting point: 225-228°C Engineering R (Nujo Ishi C1675, 1590, 1565,
151r”NMR (D20+DI4!, δC1,13(
3H, t, , J = 7Hz) 1.43 (3H, d, J = 8
Hz) 1.9-2.5 (2H, m) 3.51 (3
H, l) 3.65 (IH.

(1, J=8H2) 5.40 (IH, t, J=7Hz)
7.5-8.0 (3H, m) (8) 6-(2-aminobutyryl)-2-methyl-2H
-1,4-Pensinaazin-3(4H)-one hydrochloride Melting point: 244-248"
1600.15[JOr”NMR(DMSO-d6.δ
): 0.9 [] (3H, t, J=8Hz) 1.3
5 (3a, d, J=7F1z)1.6~2jC2H,m
)3.83(iH,q,J=7Frz)4.98(11
T, m) 7.57 (Hr, ci, J=9Hz)
7°71 (IH, d, J = 2Hz) 7.76 (IH, d
d, J = 2Hz, 9Hz) (9) 6-(2-aminobutyl)-4-7,000I2 E! -1,4-Benzothiazin-3(4H)-one hydrochloride Melting point = 277-279°C (decomposition) IR (nujigol C1690, 1590, 1565, 1
510f”NMR (DMSO-d 6.δ): o, a
s (3H, t, J=8H2)1.6~2.2(2
H, m) 3.45 (3n, s) 3.64 (2H1s) 5
．． 25 (1n, t,,,y=7Hz) 7.65(1
u, d, J=8Hz) 7.78(IHldd, J=2H
z, 8Hz) 7.85 (IH, d, -r=2Hz)8.
76 (3H, bs) αI 5-(2-amino-3-methoxycarponylpropionyl)-3-methyl v pencinnazolin-2-one Asahi salt Melting point: 216-218°C (decomposition) IR (Nujol ):1735.1685.1660
．． 1595! Yo-1HMR (DMSO-d6.δ): 3
．． 10 (2H, d, J=6Hz) 3.47 (3E!, s
) 3.56 (3H, a) 5.47 (1H, t, J=6a
z), 7.51 (IHod.

J=9Hz) 8. Q9(IH, d4., r=7!H
z.

9Hz) 8.42 (IH, dl, T = 2Hz) 3.9 (
'bs, 3H) Q1) 5-(2-Aminobutyl)-6-acetiniminobenzothiazoline hydrochloride Melting point: 182-184°C IR (Nujig-ru): 17 [J5.1695.1590
,156o17r1HMBCDMSO-46,δ):0
．． 92(3H,t,,y=7az)1.7~2.3(2
H, m) 2.31 (3H, 8) 5.1-5.5 (1a,
m)8. [11 (La, a,,y=8Hz) 8.2
6(IH,a,J=8Hz)8.5[J(IHls)8
．． 83(3H,1)8)(2) 6-(2-aminopropionyl)-1-nonal-6,4-dihydroquinoline-
2(IH)-one hydrochloride Melting point: 177-179°C IR: 3350.2700°2600.
2500.1680゜1650.1605.150[J
, 1408.1305.12B0゜27f1 NMR (DMSO-t16.δ): 1.48 (3H, d
,,T=7H2)2.5~3.1(4a,m)3.30
(3H, s) 4.10 (2H, 1) 8) 5.00 (11
(L, J=7H2) 7.0-7.5 (2H, m)
7.94(IH,suriU 6-(2-aminopropionyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one hydrochloride Melting point: 224-229°C (decomposition) Engineering R( Eyes: 1670.1630.158g1
α4 5-(2-Aminopropionyl)-3-methylbencinaazolin-2-one hydrochloride Melting point = 241-246°C (decomposition) Engineering R (Nujo I): 2680.2600.1690
．． 1595.1500゜1430.1330.1310
．． 1250.121g 1HMR (CD30D, δ): 1
．． 61 (3H, i, T=7H2) 3.51 (3a, s)
5.17 (IH4-T=7Hz) 7°43 (1
u, a, J=9az) 3.15 (I H, di, ,
r=2az, 9EIZ)8.32CIH,a,,
y=2az) α homogeneous 5-(2-aminobutyric)-3-methypencinnazolin-2-one hydrochloride Melting point: 214-216°C (decomposition) Engineering R (Nujol: 1680, 1590.1510.
1490.1330°1280, 1250, 123
f1 HMR (DMSQ-d6.δ): 0.90 (3H, t
, J=7 Hz)7.53(1a,d,,T=9
Erz) 8.18 (IH.

dd,, r=2az, 9az) 8.52 (1a, a.

J:2H2) 8.73(1)8.2H) α65-(
2-Aminobutyryl)-3-Methyl lebenzonazolin-2-one folic acid salt Melting point: 211-215"C (decomposition) Engineering R: 1680,159[1,150α
Flat-1HMR (DMSO-d 6.δ): 0.81 (3
H,t,,,r=7Hz)1.1~1.6(2H,m)
1.6-2.1 (2H, m) 3.47 (3H, s)
4.9-5.4 (IH, m) 7.49 (IH, d, , T
=9Hz) 8.13 (IH.

dd, J=2H2, 9H2) 8.48 (1a, a.

J=2Hz) 8.76 (2E1.bs) αη 6-
(2-aminobutyry/I/)-2-methyl-2H-1,
4-benzoxazine-3 (4F 1-oxylic acid bottle melting point: 236-237"C (decomposition) Engineering R (nujo I): 3300.320 [J, 170
0.1605.150 g 1 Production example 7 5-bromoacetyl-3-methylbenzothiazoline-2
-one (14,31 chlorobenzene (200j+/)
The solution was heated and stirred at 80°C for 10 minutes. A solution of hexamethylinetetramine (7,71) in chlorobenzene (45 g/) was boiled in this solution at 50"C, and
Stir at 5°C for 4 hours.

After cooling the reaction solution, it was filtered to collect crystals, stirred with ethanol, the resulting crystals were collected, washed with ethanol, and dried with phosphorus pentoxide to give 5-aminoacena A/-3-notyl rebenzo. Crystals of naazolin-2-one hydrochloride are obtained.

Melting point: 184-187°C (decomposition) Engineering R (nuji!l /I/): 3150.1690.1
680.159Upf1NMR (DMSO-46, δ)
: 3.49 (3H, R) 4.60 (2H, bs) 7.5
Q(IIIl, d, J=9Hz) 7.52(IH, d,
J=2Hz) 8.13 (IH.

di, J = 2 Hz, 9 Hz) - HCl 5-(2-aminopropionyl)-3-methylbenzoxazolin-2-one i acid salt (2,56 L) in pyridine (50 g?) solution was added methyl isocyaner B0. 68f
) After gradually adding at room temperature, stir for 1 hour at the same temperature.

After further stirring for 2 hours at 50"C, the solvent was distilled off under reduced pressure.

The residue was dissolved in water and ethyl acetate, and then acidified with 10% hydrochloric acid. The precipitated crystals were fixed, washed with water, and then recrystallized from an aqueous ethanol solution to give 1,4-dimethyl-5-(3-
Methi IV-2-oxobenzoxazolin-5-yl)
-4-imidacillin-2-one (0,951 is obtained.

Melting point: 267-272-C IR (Nuji*-V): 1795.1675.1510
cmNMR (DMSO-(16, δ): 1.95 (3a
, s), 3.00 (3H, s) 3.37 (3F1.s)
7.07-7.32 (3H, m) 10.17 (Hr, b
r, s) Example 2 In the same manner as in Example 1, the following compounds (Example 2-<1
) ~ α7) Obtain J.

(1) 4-ena/I/-1-methyl-5-(6-methyl-2-oxobenzoxazolin-5-itv) -
4-Imidacillin-2-one Melting point: 280"C (decomposition) Engineering R (nuji effect/I/): 1790.1670.161
0.1505 Yen-1NMR (CF3COO1δ): 1.
26 (3H, t, J=7H2) 2.68 (2H, (1
,,T=7H2) 3.45(3H08) 3.67(
3H,S)7.4.6(3H,8)Mass m/e:
273 M” (2) 4-Ethyl-1-methifure 5-(ro-isoderobin/-2-oxobenzothiazolin-5-iA/)-
4-Imidacillin-2-one Melting point = 279-280''C (decomposed) DingR: 3140.1680.1660.
1640.1570゜149゜1 NMR(CF3COOH,δC1,24(3H,t,,
T=7Hz) 1.75 (6H, d, J=8Hz) 2
．． 26 (2H.

(1, J=7Hz)' 3.46 (3H, S)4. E
3-5.5 (1a, m) 7.51 (1a, d, a,
J=2H2,8Hz) 7.68(ta, a, J=2
az) 7.73 (IH, d, J = 8H2) Mass m/e: 317 M+ (3) 4-enal-1-methyl-5-(2,4-dimethyl-3(4H)-oxo- 2H-1,4-benzoxazin-6-yl]-4-imidacillin-2-one Melting point = 194-195°C Engineering El (KBr): 2750.1700.1661:1
．． 1600.151-l51--1N! DCJl? 3+
CD, OD, δ): 1.22 (3H, t, y=8Hz)
1.58 (3a, d, J = 7Hz) 2.47 (2H
, q, J=8Hz) 3.17 (3H.

s) 3.37 (3H, 8) 4.67 (1u, q
.

J=7Hz) 6.8~7.1 (3H, m) Mass
m/e:! +[II M+ (4) 4-ethyl-1-methyl-5-(1-methifle-2(IH)-oxoquinolin-6-yl)-4-imidacylin-2-one Melting point: 300-C or less ( Disassembly) Engineering R (nuji, -y): 167s, 164s, 159o,
1s6oy1NMR (CF3COOH, δ): 1.28
(3a, t,, J=7az)2.68(2H, (1,,
T=7Hz) 3.47 (3Fr.

s) 4.37 (3H, 8) 7.62 (in, d
.

J==9Hz) 7.9~8.4 (3H, m) 8
．． 7 (IE, d, J = 2 Hz) Mass m/e: 283 M+ (5) 1-i th rv-6-(4-eth tv j-methyl-2-oxo-4-imidacillin-5-ia L/ )
-6,4-dihydro-IH-2,1-pensinaazine 2
．． 2-dioxide melting point: 156-157"C Engineering R (nuzisil): 1680.15 [J5.1335
．． 116 [1°116α Fuji NMR (, CF3000F!
, δ): 1.23 (3H, t, J = 7H2) 2.64 (
2H,q,,y=7Hz)3.43(3EI.

s) 3.50 (3H, 8) 3.68 (4H98) (6)
6-(4-sinarv-1-metalre2-oxo-4-
imidacillin-5-ia+/)-3,4-dihydro-1
FI-2,1-benzothiazine 2.2-dioxide melting point = 236°C (decomposition) IR (Nujiwo-Isu: 3360, 1675.1508.
1325.1160°NMR (CF3COOH, δ):
1.23 (3H, t, , T = 7H2) 2.61 (2H9
q,,T=2Hz) 3.4[J(3H.

s) 3.63 (4H,!3) 7. o6ua,a
.

J=8Hz) 7.1~7.5(2H,m)Mass
m/e: 308 M+1 (7) 4-ethyl-1-methyl-5-42,4-dimethyl-3(4H)-oxo-2H-1,4-benzothiazin-6-yl]-4-imidacylin-2 -On melting point: 218-221°C IR (nus/v): 1690.1595.155
C1cf1NMR (aDa13.δ): 1.21 (3H
, t, J=7Hz) 1.48(3H, d,, r=8Hz
) 2.54 (2H.

q, :f=7H2) 3.13(3H,8) 3.
41 (3H, s) 3.46 (IH, q, , r=7u
z) 6.79 (1a, aa, y=2az, 9Hz)6.
82CIH, a, J=2az) 7.25 (IH.

d,, T=9Hz) Mass m/e: 317 M” (8) 4-ethyl-1-methyl-52[2-methyM-3
(4H)-oxo-2H-1,4-benzothiazine-6
-yl)-4-imidacylin-2-one Melting point: 244~
247°C (decomposition) Engineering R (nudicol): 1690.1680.1630.
156α “1NMR (DMSO-d6.δ): 1.08
(3H, t,, T=7H2) 1.34 (3H, a, J=
7Hz) 2.28 (2H.

q,, T=7Hz) 2.96 (3H, s) 3.
46 (IH, (1, J=7H2) 6.80 (IH8
d.

J=9Hz) 6.81 (1F!, s) 7.21
(1H.

d,, r=9Hz) Mass m/e: 303 M+ (9) 4-enaI-methy/I/-5-[4-methyl-3(4H)-oxo-2H-1,4-pencinazine -6-Ilk 4-imidacilin-2-one Melting point = 2
79~300"C 2,58 (2H, q, T=8Hz) 3.35 (3
H.

s) 3.53 (5a, s) 7.02 (1a, a
.

J”9H2) 7.12(IH,s) 7.48(
IH.

d. imidacillin-2-one melting point = 1
98-200°C rR: 3380.1725.1690.
1670C1r1NMR (CF3000F!, δ): 3
．． 42 (3H, s) 3.70 (6H 1 day) 3.
76 (2H, 8) 3.90 (3H.

8) 7.4-7.8 (3H, m) Ma88 m/e: 333 M+ αυ 4-ethyl-1-methyl-5-(2-acetyliminobenshinazolin-5-I)-4- Imidacillin-2-one Melting point: 300″C or less (decomposition) Engineering R(, (diw-/L/): 1670.1650.16
1[], 1570f”NMR (CF3COOH, δC1
,26(3H,t,,T=7H2)2.66(3H,s
)3.67(2H,[1,,T=7Hz)3.47(3
H, 8) 7.63 (IH.

dd, J=2Hz, 8Hz) 8.12 (IH, a.

J=2Hz)8.29CIH,d,J=8az)Mas
s m/e: 316 M+ (2) 1,4-dimethy/'-5-[1-methyl-2CI
H)-oxo-6,4-dihydroquinolin-6-yl]
-14-Imidacillin-2-one Melting point: 265-269"C (decomposition) Engineering R: 314 [J, 1670.1610
,1575.1505゜139□□□"1 NMR (CF3COOH, δ): 2.27 (3H, s)
3.12 (4+a, a) 3.45 (3E1.8) 3.6
9 (31°8) 7.13~7.6 (3a, m)
IQ, 7 (IEI.

bs) Mass m/e: 271 M+ α31,4-dimethyl-5-[4-methyl-3(4E
I)-monooxo 2H-1,4-benzothiazine-6-
yl]-4-imidacillin-2-one Melting point: 288-290°C (decomposition) Engineering R (Nushor): 3150.1670.1590.
1405.1390°1340, 113[I NMR (CF3COOH, δ): 2.26 (3H,
B) 3.46 (3H, 8) 3.68 (5H, 8)
7.22 (IH9d, d, J=2az, 7.5az)
7.31 (IEI.

d, J=2Hz) 7.69 (IH, d, J=7.5
Hz) Mass m/e: 289 M+ α◆ 1,4-dimethyl-5-(3-methyl-2-oxobenzothiazolin-5-yl)-4-imidacillin-
2-one melting point: 299-301°C (decomposition)
, 1490, 1320° 1120ar” NMR (CF3COOH, δ): 2.26 (3H, s)
3.46 (3H, 8) 3.78 (3H, 8) 7
．． 55 (IH.

d, J=2Hz)7.3~7.7(2H,m)Mass
m/e: 275 M+ (lI19 1-(2-chloromethyA/)4-methy7+
/-5-(3-methyn/-2-oxobenzothiazolin-5-yl)-4-imidacylin-2-one Melting point: 23
7-239°C IR (Nujirutsu: 3350.3250.1695.
1685.1500a! INMR(cncg3+cn2
oD, δ): 1.12 (3H, t,, r==7H2)
2.40 (2H, q, J=2az) 3.48 (3H,
8) 3.56 (2a, t, J=6az) 3.9Q (
2H0t, J=6H2) 7.0~7.3(2H,m
) 7.37 (1, s) Mass m/e: 337 M+ αQ 1-Methyl-4-propifure 5-(3-methyl-2-oxobenzothiazolin-5-yl)-4-imidacillin-2-one Melting point : 262-264”C Engineering R (eye-I): 3220.3120.1660
．． 159g 1HMR (CF3COOH, δ): 0.97
(3a, t, , r=7az).

1.4-2.1(2H,m)2.66(2E[,t,,
T=7H2) 3.45(3H,8) 3.73(3H
.

8) 7.4-7.8 (3H, m) aη 4-enal 1-methyl 5-[2-methyl
Re-3(4H)-oxo-2H-1,4-benzoxazin-6-yl)-4-imidacillin-2-one Melting point: 126-124°C Engineering R (Nugir): 3200.3130.1680.
1610.149(:h+ 1HMR(cDc13.
δ): 1.13 (3a, t, y = 8Hz) 1.55 (3
H, (1,, T=8Hz) 2.36 (2H.

q, J=8Hz) 3.05 (3H1s) 4.6
0(IH, (1, J=8Hz) 6.6-7.0
(3E, m) Mass m/e: 287 M+ (g) Production Example 4-The compound obtained in Ql19 was added to Production Example 5.
was subjected to a reduction reaction similar to the method described in
The following compound is obtained by subjecting it to a ring-closing reaction similar to the method described in Example 1 without isolating the compound.

1.4-dimethyl-5-(2-oxobenzoxazolin-5-i)V) 4-imidacillin-2-one Melting point: 297-301"C (decomposition) Engineering R (Nujol C3230, 2650, 1755, 1
650,j610゜150゜1 δ uMa(aF3coon, 4c2.25(3H,s)3
．． 46 (3H, S) 7.2-7.8 (3H, m)
9.9 (IH, b8) 10.71 (IH, 'bs
)Mass m/e: 245, +αOu Production Example 4-0 The compound obtained in Production Example 4-0 is subjected to a reduction reaction similar to the method described in Production Example 5. This first product can be obtained by adjusting the reaction solution to pH 7.0 with 20% potassium carbonate and then extracting with ethyl acetate. This product is then subjected to a reduction reaction similar to the method described in Example 1 to obtain the following compound.

4-ethyl-1-menal-5-(4-(2-diethyl-aminoenal)-2-methyl-3(4H)-oxo-2H-1,4-benzothiazin-6-yl ]-4-
Imidacillin-2-one Melting point: 142-146''C Engineering R, (KBz.): 2900.1690.1665.
1590.1430°164P1 NMR (aDa13.δ): 0.98 (6E, t,,y
=8az) 1.22 (3H, t, J=7Hz) 1.
48 (3H.

d,, T=7H2) 2.3 to 2.9 (8H, m)3
．． 18 (3H, s) 3.50 (1a, q, J=7H
z) 4.05 (2H, t,, r=Baz) 6.91
(IH, d, J=2Hz, 9Hz) 7.20 (IH, d
, J=2az) 7.36 (IH.

d, J=9H2) Mass m/e: 4Q2M+ Kan The fixed compound obtained in Production Example 7 is subjected to a ring-closing reaction similar to that described in Example 1 to obtain the following compound.

1-Methyl-5-(6-methyl-2-oxobenzothiazolin-5-yl)-4-imidacillin-2-one Melting point: 258-260°C Technique R: 3250.1720. 1675.
1560.1500°166g1 NMR (CF3COOH, δ): 3.42 (3H, s)
3.70 (3H, s) 7.47 (1a, dd, J=2H
z.

9H2) 7.51 (1u, a, J=2az) 7.6
2 (IH, d, y=9Hz) 7.27 (IH, s)
Mass m/e: 261 M+ Ql) The compound obtained in Production Example 6-αG is treated with various isocyanate derivatives in the same manner as described in Example 1 to obtain the following desired product.

(21a) 1,4-diethyl-5-(6-methicy-2-
Oxobenzothiazolin-5-yl)-4-imidacylin-2-one Melting point: 245-246 "C": 1700.1670.1560a
“1HMR (OF3C!OOH, δ): 1.25 (3a
, t, J=8H2) 1.28(3H, t, J=8H
z) 2.63 (2H, (1, J=8H2) 3.75
(,3H,8) 3.95(2H,q,-T=8Hz
) 7.4-7.8 (3H, m) (21b) 4-enajv-1-cyclohexy7L/-5-(3-methy/I
/-2-Oxobenzothiazolin-5-yl)-4-imidacillin-2-one Melting point: 202-203''C IR (Nujico I): 3330.3280.1715
．． 1685°1670, 162IC+ NMR (cncd3+cp3oD, δ): 0.90 (
3H.

t, J=8H2), 1.0-2.2 (12H.

m) 3.49 (3H, s) 5.2-5.6 (IH,
m) 7.19(,IH,d,,y=8Hz)8.05(
1a, d, a,, y=2Hz, 8Hz) 8.15 (1a
, d.

, r=2az) Mass m/e: 357 M+ (210) 4-ethyl-1-propy&-5-(3-methyIv-2-oxobenzothiazolin-5-yl)-4-
Imidacillin-2-one Melting point: 261-265°C (decomposition) Engineering R: 3130.1670.1595
．． 1565°1495cf1 NMR (CF3COOH, δ): 0.83 (3H, t,
, T=7Hz) 1.26 (3H, t, J=7Hz)
1.68 (2H, q, J=7Hz) 2.61 (2H
, q, J=7Hz) 3.82 (2H.

[1, J=7H2) 3.73 (3a, q) 7.4~
7.7 (3a, m) Mass m/e: 317 M-)- (21cl) 1-allylcy4-ethyl-5-(3
-Methitv 2-oxobenzothiazolin-5-yl)-4-imidacillin-2-one Melting point = 236-265
°C rR (y<di, -tv): 3120.1670.159
0゜1555.1490cIr1 NMR (CDC/3・CD30D, δ) ~ 1゜22(3
H.

t, J = 7Hz) 2.35 (2H, q, J = 7Hz
) 3.42 (3H, s) 4.07 (2H.

d, y=5az) 4.8~5°1 (2H, m)5.
4-5.9 (IH, m) 7.08 (IH.

+1. J=9H2) 7.18(1a, d,, r=9
H2) 7.28 (11,8) Mass m/e: 315 M+ (218) 4-enant-1-methy7'-5-(3-methy/I/-2-oxobenzothiazolin-5-yl )−
4-Imidacylin-2-one melting point = 291-293"C
(Disassembly) Engineering R (Nuji-en-/I/): 1665.1590.149
0゜1320.127□□□"1 NMR (CF3COOH, δ): 1.26 (3a, t,
, J=7mz), 2.67C2H,q, J=7Hz)3
．． 43 (3H, 833, 72C5H, B) 7.53 (1
a, a,, r=2az) 7.4 to 7.8 (2H, m
) Mass m/e: 289 M+ t21r) 4-ethyl-5-(6-methyl-2-oxobenzothiazolin-5-itev) 4-imidacillin-2
-On melting point: 295-297°C (decomposition) Engineering R (Nujo M): 6400.1645.1625
゜1610.1575.150Of” NMR (CDC13-CD30D, δ): 1.31 (3
H0t,,r==3Hz)2.73(2H,q,-T=
8EIZ) 3.68 (3H, 8) 7.24 (IHod,
, T=9H2) 7.44 (IH.

d,:r=9Hz) 7.48(IH,s)Mass
m/e: 275 M+ (21 g) 4-methy7L/-1-(2-(N-methylsoN-benzylamino)ethyl]-5- (6-methyIv-2-oxobenzothiazoline-5- yl)-4-imidacillin-2-one hydrochloride Melting point: 166-167°C Engineering R (KBr): 1670.1650.1500cIf
1NMR (CF3COOH, δ): 1.18 (3E1.
t.

J=7az)2.46(2n,q,J=7H2)3.1
0(3H,8)3.68(3H,8)3.4~3.7(
2H, m) 4.0 to 4.3 (2H, m) 4.46 (
2Fi.

B) 7.2 to 7.7 (8H, m) Mass m/e: 422 y” (21h) 4-ena/l'-1-(2-dimethylamitzena v)-5-(3-methyl- 2-Oxobenzothiazolin-5-iw)-4-imidacylin-2-one Melting point: 262-264°C Engineering R: 3100.2750.1710.16
90゜1650.1600.1575.149゜1N
MB (cDc13.δ): 1.16 (3a, t, J=8
Hz) 2.12 (6H, s) 2.25 (2H, (1, J
=7H2)2.37(2H.

t, J=7Hz) 3.49 (3H, 8) 3.66 (2n
,t,,,r==7az,) 7.03(IH,d,
J=5Hz) 7.27 (IH.

d, d, y=2Hz, 8Hz) 7.38(lH, d, J
=2Hz) Mass m/e:346 M+ (211)4-ethyl-1-(2-(4-methyl-repiverazin-1-yl)methyly:)-5-(6-methyl-2
-Oxobenzothiazolin-5-yl)-4-imidacylin-2-one Melting point: 168-170°C Engineering R (KBr): 3650.3150.2950.
2800.

1710.1670.1600.1490.145Of
1NMR (CDCl3.δ): 1.15 (3a, t, J
=7H2)2.25(3H,Fl)2.38(3H,s
) 2.2 to 2.6 (6H, m) 3.50 (3H, s) 3
．． 68 (2H, t.

,y=7aZ)7.06(IH,a,J=9Hz)
7.27 (1, d, d, J=2az, 9uz) 7.28
(1a, d.

J=2H2) 10.2 (IH, 8) Mass m/e: 401 M+ (a) Methyl isocyanate and the corresponding amine compound are reacted to obtain the following adduct.

(22a) 6-(4--r-stv-4-me?-71
7-2-oxo-4-imidacylin-5-yl)-2,
4-dimethyl-3(4H)-oxo-21'(-1,4
-Pensinaazine 1-oxide Melting point: 191-196°C (decomposed) IR (KBr): 2900.1690.1670.15
90゜1565.1410Cr", y=7Hz) 1.48 (2H, q, J=8Hz)
Evening 3.20 (31 (, s) 3.48 and tv (3H, s) 3.74:=Tachi 4.14 (1H.

q,,T=-7H2) 7.0~7.4C3H,m)
7.78 (jH, d, J = 88.Z) Mass m/e: 333 M+ (22b) 4-xq-ru 1-i Chi Jv-5-(2-iminopensinazolin-5-yl)- 4-Imidacillin-2-one Melting point: 277-278°C (decomposed) IR (Nujo I): 3450.3310.1670
゜1635.152゜1 NMR (CF3COOH, δ): 1.23 (3H, t
.

, T=7Hz) 2.59(2H,q,, J=7Hz
)3.37(3a,s) 7.35(IH,(1,J
=8Hz) 7.51(1H,s) 7.78(I
H.

d,,T=8H2) The structural formulas of the compounds described in Examples 2-(1) to (221) are as follows.

(9) α0Ql)
(J2z cH30
α 荀α UNI α・σ7) (To) αI 翰 (21a) ' (21b) (21c
) (21d) (21e)
(21f) (Z2a) (
22b) 1-(2-chloroethyl)-4-ethyl-5-
(3-Methyl-2-oxobenzothiazolin-5-yl)-4-imidacillin-2-one (1,69 g) and N-
N, N of methyl-N-bendicyamine (3,02f/)
-Dimethylform 7m)- (30 g/) solution is heated to 100° C. for 8 hours in a sealed tube. The reaction solution was poured into ice water and extracted with ethyl acetate. After washing the extract three times with brine and drying over magnesium sulfate, the solvent was distilled off under reduced pressure.

The residue is subjected to silica gel column chromatography (eluted with a mixed solvent of methanol:chloroform=1:20), and the eluate is concentrated under reduced pressure. The residue was dissolved to a concentration of 5% in isopropidial alcohol containing hydrochloric acid and concentrated under reduced pressure. The obtained crystals were recrystallized from a mixed solvent of isopropyl alcohol-1 and diisopropyl-ether V to yield 4-2,000! 5-(3-Methyl-2-oxobenzothiazolin-5-y&)-4-imidacillin-2-one folic acid salt (
0,66f) t-obtain.

Melting point = 166-167℃ IR (lr): 1670.1650.150o17r"
NMR (CF3COOD, δ): 1.18 (3H,t,
, r=7H2) 2.46 (2H, q, J=7Hz)
3.10 (3H.

s) 5.68C5H, 8) 3.4~3.7(2
H.

m) 4.0-4.3 (2a, m) 4.46 (2
H.

8) 7.2 to 7.7 (8H, m) Mass m/e: 422 free M+Example 4 In place of N-methyl-N-benzylamine in Example B, Shimethyamine'! The following compound is obtained using ffl-methI repiverazine.

(1) 4-Ethyl-1-(2-dimethylaminoethyl V)-5-(3-methifle-2-oxobenzothiazolin-5-i A/)-4-imidacylin-2-o Melting point:
232-264℃ Engineering R (Kpr): 3100.275[1,1710,1
690,1650.

1600.1575.149 1 HMR (cDcl6.δ): 1.16 (3H, t, J=
8az)2.12(6H,s)2.25(2H,q,,
y=7H2)2.37(2a,t,,,r=7Hz)3
．． 49(3a,a) s, 66<2H,t, :r=7H
z) 7.03 (IH, d, J = 8Hz) 7.27 (
1H, d, a, y=2Hz, 8Hz) 7.38CIH,
d, J = 2uz) Mass m/e: 346M+ (2) 4-ethyl-1-(2-(4-methylpiverazin-1-yl) dithi~), -5-(3-methifle 2- Oxobenzothiazolin-5-yl)-4-imidacylin-2-one Melting point: 168-170"C Engineering R (KBr): 3650, 3150.2950.28
00.1710゜1670.1600.1490.14
5 Master “1HMR (CDC13, δ): 1.15 (3H,
t,,,r = f7Fiz)2.25(3H,S)
2.38 (8H, 8) 2.2-2.6 (6H, m)
3.50 (3H, 8) 3.68 (2u, t,,
y=7az) 7.06(IH, d.

J=9Hz) 7.27(1a, a, a, J=2az
.

9Hz) 7.28 (IH, d,, T=2H2) 10
．． 2 (I H, s ) Mass m/e: 4Q1M" The structural formula of the compound described in Example 4 above is as follows.

Example 5 4-Ethyl-1-methy7+/-5-(2,4-dimenal-3(4H)-oxo-2H-1,4-benzothiazin-6-yl)-4-imidacillin-2-one (1 ,27
To the chloroform (<50xl) solution of f), a chloroform (40sgl) solution of m-ri-perbenzoic acid (1,72F) is added dropwise at 0 to 5''C over about 30 minutes.
After stirring for an hour, concentrate under reduced pressure.

The residue is dissolved in water, washed with methyl acetate, saturated with sodium chloride, and further extracted with a mixed solvent of tetrahydrofuran and methyl acetate. The extract is washed with brine, dried over magnesium sulfate, and then the solvent is concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution with a mixed solvent of methano-IV:chloroform=1:20 v/v), and the eluate is concentrated under reduced pressure.

The residue was crystallized from a mixed solvent of chloroform and methano-V to give 6-(4-xq-tv-1-methylrv-2-oxo-4-imidacylin-5-ylv)-2,4-dimethyl-3( 4H)-oxo-2H-1,4-benzothiazine 1-oxide (0,35F) is obtained.

Melting point = 191-193°C (decomposition) Engineering R (KBr): 2900.1690.1670.15
90.1565°141 1 NMR (cDc13.δ): 1.21 (3'H, t
, , T=8Hz) and φζ 1.48-4i,78(3H,d, J==7 Hz
) 1.48 (2H, (L,, T=8Hz) 3.2
0 (3H.

Base t" l1l) 3.48 (3g, 8) 3.74ee4
4.14 (IH, (L,, T=7H2) 7.0~7
．． 4 (3H.

m) 7.78 (IH, d,, r=8az) Mass
m/e: 333 M+ The following compound is obtained by the same oxidation reaction as in Example 5.

(1) 6-(4-methyw-1-methyl-2-oxo-4
-Imidacillin-5-yl)-1-methifle 6.4
-dihydro-IH-2,1-benzothiazine 2.2-dioxide Melting point: 156-157-C IR (nudv=shi): 1680.1505.1335.
1160.113(llf 1HMR(OF3COOH
, δ): 1.23 (3H, t, , T=7H2) 2.64
(2H, q, J=7Hz) 3.43 (3H.

8) 3.50 (3H88) 3.68 (4H, l
3) 7.2 to 7.6 (3H, m) ・Mass m/e: Honghui M+1 (2) 6-(4-dimethyl-1-methyl-2-oxo-
4-imidacylin-5-yl)-3,4-dihydro-
IH-2,1-benzothiazine 2.2-dioxide melting point = 266"C (decomposition) Engineering R (Nujol): 3360.1675.1508.
1325.1160°1140cr1 NMR (CF3000H, δ): 1.23 (3H, t,
, r=7Hz) 2.61 (2H,q,, r=2Hz)
3.40 (3H.

s) 3.63 (4H, 1ll) 7.06 (1a
, a.

J=8az) 7.1~7.5(2H,m)Mass
m/e: 308 M+1 The structural formula of the compound described in Example 6 above is as follows.

Example 7 4-ena/I/-1-mena2re5-(2-7cenaliminobenzothiazolin-5-i/L/)-4-imidacillin-2-one (3,4f) in 10% hydrochloric acid (10fl
+/) and ethanol-Iv (100+m?) and heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water, and the pH was adjusted to 0 with a 20% aqueous potassium subacid solution. The resulting crystals were separated, washed with water and dried to give 4-2-1v-1-methyl-5-(2-iminopencinnazolin-5-yl)-4-imidacylin-2-one (2
,811 are obtained.

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 is a hydrogen atom, lower alkyl group, cyclo-lower alkyl group, lower alkenyl group, halo (lower) alkyl group, piperazinyl (lower) It is an alkyl group or a lower alkylamino (lower) alkyl group, and the nitrogen atom in these substituents may be substituted with a lower alkyl group or an alkyl group, and R^2 is a hydrogen atom or a lower alkyl group. , and the lower alkyl group may be substituted with a carboxy group or a lower alkoxycarbonyl group, ▲ Numerical formulas, chemical formulas, tables, etc. are available. ▼ together with the adjacent benzene ring represents a benzothiazolinyl group,
Benzoxazolinyl group, 1,4-benzoxazinyl group, quinolyl group, 1,4-benzothiazinyl group and 2
, 1-benzothiazinyl group, the heterocyclic group may be hydrogenated, and represents a heterocyclic group selected from oxo group, lower alkyl group, imino group, lower alkanoylimino group and lower alkylamino group ( 4-imidazolin-2-one derivatives and That salt.