TW460446B - Thiol compounds - Google Patents

Abstract

This invention relates to 3-mercapto-1-(1,3-thiazoline-2-yl)azetidine represented by the following formula and its acid addition salts and to the production process therefor. The above compounds are useful as intermediates for preparing carbapenem compounds, which have strong antibacterial activity, with convenience and high yield.

Description

4 6 0 4 4 6 _ charge se. 3. A7 B7 V. Description of the invention (/) For combination and modification, open B) The material has ne custom pe, baB ar sulfur U class and new details read . And the e-, S-intermediate chemical combination of alcohol _ sulphur application has oral pseudo-clarifiable hair this kind of some physical properties of live bacteria show strong resistance to its salt to add two acids, the person who Combining and Refining * This should be done with alcohol sulfur. Customs and materials are combined and used to make the new system. There is a mid-step method1. This system is printed by the consumer cooperation of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). ) Sinochem's anti-drug drug critics and Cheng Zhida can take the perimeter shots and watch the period of attention. The Shangjingwu only goes to the bed to face the discussion. It was built for the quilt before the forestry, and it has a low intake, and it has some characteristics. It is a combination of Xu Hua and Xu Hua. It should be taken for granted. And, at present, the supervised part of the sex-synaptic viable spouse partner is in a selective therapy station □ In comparison with fcfc, it can be injected and injected. . Drug path application. For road and floor use, there are regular and non-easy container medicines that are applied on the ground, and the best medicines are applied to the Chinese medicine family fungus resistance. Zhan Shuofa's essential medicine box, Shi Liefu, has a strong mouth. This can be caused by the fact that the live drug is attached to the drug that is resistant to the strong environment. / 1 can be related (f should be reproduced, etc. i should be reproduced i hair meridian and human, Mingfa's § quinolinazole if expressing X) of the thiol 3-generation-take the top 2-chain main alkanecycloaza

The size of this paper is applicable to the Chinese national standard (CNS > M specification (210X297 mm), with a formula of 4 6 0 4 4 6 C, " —- f; .〆. · * Dagger ·:-: >A7; ik ft, 86. 3. 2 〇B7 V. Description of the invention (>) 'or a master compound which is typically represented by the following formula (IX)

The best esters are based on the residues of the esters derived from the bio-based residues of the It. To be prepared, the bases are carboxyl, and the repositioned 3-S antibodies are highly conformable. A brief description of Shishengjieshuishui ester is quickly activated on the inner body. This is due to the fact that it is outside-this thing * the combined rate of the received X) Suction (I's style on the tube to nourish and change from the degree of change to the above, on m You Shifu has a good idea for this purpose and is, S-type to be shaped * 0 agent before the antibacterial agent is resistant to foreign matter, and you can go to the bed. 73 6 B 2 / IV 8 / If you are suffering from dysentery, please apply for it). Wuli et al., Etc., established the solid ester No. 39 and 20; No. 6 and No. 96, No. 96, 04IS, and 17)-. —, X 6 and (the first formula Zhuzhou 1-type is shown in the table above as X) its / 1 / V formula is based on sulfur-based radicals 3-· with the purpose of the extraction of the basic 2-main Commanded zomine f pi hair-ιπ Ben 3 'Alkane dopant 0 Complementary to ground effect \ / Basic substitution of the material I 2 (Please read the precautions on the back before filling in this Page) 袈. Economy Central Bureau of Standards staff consumer cooperative printing equipment which provide for engagement of the heterocyclic nitrogen of claiming Hair *) containing 2 was read books -¾

The neck is clear. In order to change the size of the paper sheet, the Chinese National Standards Standard (CNS) A4 (210X297 mm) * 460446Ί A7-· JjC.; :: B7 Employee cooperation of the Central Bureau of Standards, Ministry of Economic Affairs. Du Yin Preparation 5. Description of the invention (80. The compound represented by the above formula (I) and its acid addition salt are very effective for the effective preparation of clinically very effective master compound compounds represented by the above formula (IX). Intermediate, the compound (IX) itself exhibits high antibacterial activity and can be administered orally after esterification. Examples of the acid addition salts of the compounds of the above formula (I) include oligoacids such as low fluorene aliphatic acids such as acetic acid , Propionic acid, butyric acid, trifluoroacetic acid, and triacetic acid; substituted or unsubstituted benzoic acid such as benzoic acid, p-nitrobenzoic acid benzenesulfonic acid; (dentate) lower alkyl sulfonic acid such as methanesulfonic acid And trifluoromethanesulfonic acid; substituted or unsubstituted aromatic sulfonic acids such as benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid and 2,4,6-triiso Propylbenzenesulfonic acid; and organic knee acids such as diphenylphosphonic acid; and with inorganic acids like hydrogen acid, sulfuric acid, hydrobromic acid Addition salts of hydroiodic acid, boronic acid, peroxyacid and nitrous acid The compound of formula (I) above can be prepared by any of the following three special methods A, B and C of tantalum, for example: Method A: In this method, the compound of the above formula (I) is prepared by following the path shown in the following reaction scheme (A) by using 2-halomethylazepine as the starting material: (Please read the precautions on the back before (Fill in this page)-° Chinese Standard for Quick Use of Paper Size {CNS) A4 Specification (210X297 mm) 4 6 0 44 6 ^-11 i. ·; A7 B7 V. Description of the Invention (4) _ (A)

This paper is again applicable to the Chinese National Standard (CNS) A4 specification (21 Ox 297 mm) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4 6 0 4 4 6 A7 B7 V. Description of the invention (了) In the above formula, R represents a leaven group, a substituted or unsubstituted lower alkyl or aryl group; and X represents a halogen atom. In the description, the term "lower" means the number of 硪 atoms, preferably 6 or less, preferably Is 4 or less. "Lower alkyl" may be a straight-chain alkyl group or a branched alkyl group. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and Di-butyl, tertiary-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl and isoheptyl. Of these, methyl, ethyl, n-propyl, and isopropyl are preferred. , N-butyl, isobutyl, second-butyl, third-butyl. In these cases, the lower alkyl group may be substituted by a phenyl group, and the benzyl group may be further substituted by at least one (preferably One or two diphenyl) hydrazone is substituted with a substituent consisting of a methyl group, a methyl group, an ethyl group, and a nitro group. The "fluorenyl group" may be a carboxyl moiety from an organic carboxylic acid group. Residual part of the hydroxyl group. Examples of aldehyde groups include lower alkyl groups such as acetoyl, propionyl and butyraldehyde, or substituted or unsubstituted benzoyl groups. "Aryl" may be mono- or Polycyclic, and Yu Chen may further have one or more substituents such as lower alkyl, nitro or halogen atom. Examples of aryl include phenyl, tolyl, xylyl, cr-lyl and S-Lacky. "Tooth Atoms" includes ", gas, bromine and iodine atoms, and among them preferably cyanide, molybdenum and iodine atoms. In the following, it is shown in Scheme 圏 (A) in detail according to each step ®. Method: (Please read the notes on the back before filling in this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (21 OX297 mm) 46044 6 A7 B7 Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 2. Description of the invention () 1 1 Step (a) 1 i In this step 9 the 2-halomethylazetidinyl group is reacted 1 1 > Therefore it is converted into 1 represented by formula (VII) -Azabicyclic C 1 .1 .0 ] -Μ- JI 丁 院 〇k, read 1 I read 1 I The above reaction proceeds as follows 1 1 Dissolve it 1 2 · Halomethylazepines are dissolved or suspended in the reactive alkaline blue. Note 1 ( The inert solvent is selected from the group consisting of fermented solvents such as methanol. Ethanol, propionate and normal matters 1 \ 1 1 Butyl fermented ether solvents such as diethyl ether and tetrahydrofuran 1 m solvents such as n-heptane%% ▲ hexane t-hexane »Shujiyuan 9 Wuyuan and Wuyuanyuan are soluble in solvents such as methyl acetate 1 esters and ethyl acetate: halogen solvents such as dioxane methyl compounds» Aeroform and tetranitride m 1 1 r or acetonitrile t dimethylformamide m amine dimethylacetamide 9 dimethyl acetone 1 I and the like preferably 9 m type solvents such as diethyl ether and tetramethylfuran), and 1 1 is suitably added to the obtained solution or m float ( The article is selected from organic or inorganic I Metals such as rhenium metals such as lithium sodium and potassium earth gold K such as calcium and m »1 I Alkali metal hydrides such as lithium hydride and sodium hydride earth metal halides such as osmium 1 1 m hydrogen hydrides such as hydrogenated m and m gas Chemicals such as sodium sulfonate and potassium osmium acid, etc. Salts such as sodium hydrogen sulfonate and potassium hydrogen sulfonate, metal alkyls such as methyl lithium alkyl Surface 1 1 m metal aldehyde amines such as lithium amidated »lithium diisopropyl aminated t aminated m I and potassium aminated metal alkane vapors such as sodium methoxide» sodium ethanoate and third alcohol 1 1 potassium alkali gold Pinane sulfonate 9 such as sodium acetate 1 m arsenic acid salt such as shuo i 1 acid m and carbonic acid m; tri (lower) alkylamines such as = methylamine > triethylamine »N, N 1 | -diiso Propyl-N-ethylaminopyridine compounds and pyridine > Methylpyridine * Dimethyl 1 1 Pyridine N, N- (lower) Amine 8 Pyridine such as N, N-Methylpyrimidine 9 1 1 1 1 1 i The size of this paper applies to Chinese National Standard (CNS) A4 (2 丨 〇〆297 mm) 460446 Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives for the Year of Repair 3 A7 B7 V. Description of the invention (86. ~ 1 Γ, Of morpholine; N- (lower) morpholine such as N- (methyl) morpholine S, N-di (lower) alkylbenzylamine such as h, N-dimethylbenzylamine; and from dimethyl The dimethyl arsenic salts produced by sulfonium and trihalide or lithium trihalide are preferably lithium bases such as methyl lithium and n-butyl lithium and m metal aldehyde amines such as lithium amines> diisopropyl amination Lithium), and then mix the resulting mixture. There is no other restriction on the eggs used for this reaction. Generally, this is used for about 1 to about 20 mols of mol 2 -halomethylazepine. A ratio of 1.5 to 5 moles is preferred. The reaction temperature is not strictly limited, and may be appropriately changed according to the kind and amount of m used. Generally, the reaction is suitable for about -7 eC to about 10 [TC range is preferably about -78-C to about 60 " C It is carried out at a temperature of 1 and under this condition, the reaction can be completed in about 10 minutes to several days. The reaction is preferably performed in a stream of an inert gas such as nitrogen or argon. The above steps produce a compound of formula UII with good yield. And the reaction liquid can be used by itself in the subsequent steps. If necessary, the reaction liquid can be subjected to conventional purification adjustments such as distillation »extraction» wash m, solvent evaporation * and column or thin layer chromatography can be isolated And purification of the compound 6 of formula (VII). Examples of 2-halomethylcyclopropane used as a synthetic substance in the following reactions include 2-methylaminoazapiridine i 2-bromomethylazapine Cyclopropane The compound is easily synthesized from dilute propylamine on the market according to the method described in Example 1 or 1 below. Step) In this step> 1-m miscellaneous formula (VII) obtained from the above step (a) (please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297mm) '4 6044 6 5 Printed by the Industrial Standards and Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 2 / (N clearly stated 1. Solution t fenchen agent double soluble A7 B7 K [IV trans t acid carboxamidine The marching compound is chemically obtained and the formula is converted to the solvent-soluble argon cyanide reaction of the cause and the alkanecycloazazine hydroxy-3, and the transether is dissolved in the second solution such as the first dissolve of the first solvent. ) Mentioned in VI Λα • / V The steps should be reversed, as described in the above agent C Dagger :: (I mixed type, mixed into the shape and mixed with the solution of the acid before dissolving the acid from S to the ground When the carboxylic acid is suitable, the acid will be followed by the carboxylic acid-as described in the previous paragraph. Often acidic acid and acidic acid are limited to the special treatment. The organic acid of the Dong acid has a carboxylic acid. Adding the acid to the compound makes the compound 1. Good rate to be more than the ear than, ear and its braking limit of about 20 cells to about Μ 1 is provided with a temperature of the object to be bonded of I) Anti changed appropriately depending on the kind and amount of carboxylic acid used. In general, the reaction is suitable for a range of about-to about 100 »°. • It is preferably carried out at a temperature of about -78 ° to about 6 (rc), and under this condition, the reaction can be completed in about 10 minutes to several days. This reaction is preferably carried out in a stream of inert gas such as nitrogen or argon β. Next, the compound obtained by the above reaction is subjected to solvolysis (such as hydrolysis), and thus 3-hydroxyazepines of formula (IV) can be produced. The solvolysis reaction is carried out in a mixture of water or an alcoholic solvent such as methanol, ethanol and isobutanol or an organic solvent such as acetonitrile, tetrahydrofuran and dipentane, and as described in step (a) above. A suitable age or an inorganic acid such as atmospheric acid, bromic acid and hydroiodic acid is treated at about -2 ° C to about 51TC, preferably at a temperature as low as about 0 * C to room temperature. The compound is carried out from about 10 minutes to several hours. If necessary, S is known by the reaction solution obtained from the above-mentioned Bu Si-1 0- This paper size applies to the Chinese national standard car {CNS) M specification (2 丨 0 > < 297 mm) ^^^ 1 II--^^^ 1 l 1 * .¾, ve (Please read the precautions on the back first (Write this page) The consumer cooperation of the Central Standards Bureau of the Ministry of Economic Affairs Du Yinshang A7 _____B7 V. Description of the invention (9) Purification adjustments such as steaming, extraction, washing, solvent evaporation, and column or thin layer chromatography, which can be isolated and purified However, the compound 6 of formula (IV) does not have the single separation step, and the reaction liquid may be used in the subsequent step itself. Step sleep frO In this step, formula (IV) obtained from the above step "(b)" The 2-hydroxyazepine butane is converted to 3-hydroxy-fluorene- (ι, 3-carazolin-2-yl) pyrazine butanidine of formula (III). This step can be carried out by the following method (i) Or (ii): (i) the above conversion is performed by converting 3-hydroxycyanobutane of formula (IV) to a 2-substituted oxazoline derivative represented by the following formula (V): In a solvent (preferably a yeast-based solution such as formazan or ethyl), and it is preferably mixed in the presence of acetic acid, sodium acetic acid, hydrogen acetic acid, hydrogen acid, and acetic acid. Perform: nfl ^ l nn «Hi p-d ^ i ^ ni TJ (Please read the notes on the back before filling this page) Νι (V) S, where L represents the leaving group β in the compound of formula (V) above Expressed by L Examples of the leaving group include an azide group; a halogen atom such as helium, bromine, and sulfonic acid; a lower alkanoyl group such as ethoxy group and propionyl group; a sulfonyl group such as benzenesulfonyl group, toluene Fluorenyl and methanesulfonyl: Low alkane groups such as methyl and ethyl groups; and lower alkylthio groups such as methyl and ethyl thio groups. Among them, lower alkylthio groups are particularly preferred. Used here There are no particular restrictions on the age of the reaction and the egg of the compound of formula (V). "In general, the compound of formula (V) and formula (V) are used for each mole of formula (IV). 1-This paper applies to Chinese national standard (CNS). A4 specification (210X297 mm) 13 ^ 4 6044 6 iL ·; i ί A7 B7 V. Invention description The composition is about 1 to about 3 moles, preferably a ratio of about 1 to about 1.5 moles. The reaction temperature is not strictly limited and may be appropriately changed depending on the kind and amount of the compound (X) and the formula (V) used. However, in general, the reaction is suitable for a temperature ranging from room temperature to about 1 GOT :, preferably from about room temperature to about 8Q ° C, and under this condition, the reaction can be completed in about 1 hour to about 24 hours. By appropriate borrowing. 1 ^ up in the flow Y gas r from 0 Η-such as II salt gas {I acid deuterium cyanide. Such as sulfurization of heterogeneous gas transesterification of acetal and halogenated compounds and line V) into {1 The reformation should be from V) should be 1) (1 inverse (i-form will be three as 0 machine is described on the better and middle nitrile is better than the better, 0 middle and lower _ in the case of dissolved ammonium acetone) The iodine salt of ethyl and the acid salt of thiocyanate isothioisoethyl haloethyl bromide-the original salt is acid as cyanocyanine, and the isocyanato group is used as the salt. The chloro acid is used to make the cyanosulfuryl group 5 in the ethyl salt. With about S, the amount of acid in the salt 1 is about 60%. The acid sulfur is different from that of m, the thiol isethoxy molybdenum 3, and the halogen is about 1 to the common thing 0, which is usually the same. This is V) Yu. (I use the standard to make the ears of Mo (please read the precautions on the back before filling this page). Printed by the Central Consumers ’Bureau of the Ministry of Economic Affairs and the Consumer Cooperatives. Species C 0 ° C Degree salt-2 Warm acid should be around the desulfurization α The isoproperty base should be 10 times lower than the second half of the halogen and the regular mole to the completion of the decimal to 10 minutes to With - and so the data then becomes the root and can be changed relatively good temperatures of around Fan

-7 Enter the greenhouse to 'C. Gas inertia is less than »1 line. The method of advancing is better or farther. Or you can defer to the next article. The medium-term gas argon or nitrogen is like 0. Yes 0 If 0-Any paper size applies Chinese National Standard (CNS) A4 specification (210 乂 297 mm) 4 6044 6 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _______B7___ 5. Description of the invention (") The liquid mash can be subjected to conventional purification adjustments such as steamed preserves, extraction, washing, solvent evaporation, and column or thin layer chromatography, and then the compound of the formula < ιιη can be isolated and purified. Furthermore, when organic and inorganic acids (which form an acid addition salt of a compound of formula (I) in a coupling solvent as described above) are stirred together, the UII can be isolated by the acid addition salt. The formula (II: II compound 制备) prepared in the above method is a novel compound not mentioned in any other literature and constitutes part of the present invention. Step a (ri) In this step, from step (c) above 3-Hydroxy-1- (1,3-carazolin-2-yl) pyridinium butane of formula (III) obtained in the above is converted into oxidyl-1- (1,3-oxazole) of formula (II) Phenolin-2-yl) fluoroheterobutane derivative. This step can be carried out by the following method (i) or (ii): (i) the hydration can be activated by activating the hydroxyl group of the compound of formula (III), The activated derivative reacts with a compound represented by the formula RSH (where R is as defined above) or a salt thereof. Examples of thiol compounds represented by the formula RSfl include thioacetic acid, thiopropionic acid, thiobenzoic acid, and tert-butylthio Fermentation, benzyl thiol, benzhydryl thiol, trityl thiol, in which the phenyl group is substituted by one or two «hydroxy * methylamino, ethyl S«, or nitro Thiolase is substituted by lower alkyl, nitro, or halogen atoms, benzenesulfonate, or lysozyme. Of these, the alcoholization of lower alkyl alkyl or substituted or unsubstituted benzyl is preferred. In addition, the thiol compound can be used in the form of S and Y. The activated hydroxyl group of the UII compound can be reacted by the formula Π11) -1 3- I ----- ----- Installation ------ Order ------ ^ ^ (Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (2! 〇 ΧΜ7mm) 4 6 0 4 4 6 1 £ Revision instructions issued '5

V years S5. Ft and acetonitrile, sulphur-solubilizing properties, such as inert agents, and alkaloid aldehyde, acetaldehyde, sulfonyl sulfonate, etc., such as organic chlorine, have a fermented image or seed gas. The methylation of 4- 0 «bispyridyl amine is better than that of Erjia S-, which is different from that of ethanylfuranil in amines. Forty-two, and two, three, two, three, two, three, two, three, two, three, two, three, two, three, two, two, and three, such as the mixture of 鹾, 溶, 溶, 溶, 醚, 醚, 醚, 限, 限, 耳, 耳, 蛋, 蛋Each dose is used to make the base hydroxylate and the hydroxyl radical of the active base and the reverse should be done, and the flux rate is often inferior to that of the ear. 20-Reduce the liveness of the active ingredient. The covenant is often based on Gentong1, which is better and better, but less compelling. The limited-variable ear lattice is modified to Moxuedi3. When the covenant S is appropriate to measure 1, the mild covenant should be the opposite.

C (Please read the notes on the back before filling this page)

One / ίι The temperature of the greenhouse to " C When the completion is completed, the decimal to the clock is as low as 10 cents. In the best, it should be better than the surrounding pattern. Love 50, which should be about to the middle of the air 0 or f I gas I * J T1 fcw (For example, the gasification activity of the formula body is better compared with the hydroxyl group that has already been formed. After the reaction, the salt is mixed or the compound is shown in the formula. The compound is suitable for formulating η in the formula to be obtained. The intermediate step is as shown in the table below. The amount of the salt of the amine 0 methyl group or the amount of the compound is shown in the table. E SR Instead, use the CO of the Central Bureau of Standards of the Ministry of Economic Affairs to print the ears of its CO 毎 to 1. Use better than 0, and its ears or mou 00 will be contracted to 1. The normal thing will be combined. The limitation of the system is limited by the existence of the existing bases, which should be used to counteract the reasons. The roots are often accessible and 0, and the system should be modified to limit the amount of material and temperature. The combination ratio is smaller than that of the alcohol's thiol and approx. From about 12 minutes to bell to about room temperature to about 10 can best be compared with trans - the Wai, Ρ member 50 to and from about I to this lower range ρ

Wen Zhi • C The paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 4 6 0 44 6 V. Description of the invention

A7 B7 Du printed the work of the Central Government Bureau of the Ministry of Economic Affairs. The reaction is preferably treated in a stream of an inert gas such as nitrogen or argon. (ii) Conversion of a compound of formula (III) into a compound of formula (II) can also be achieved by combining a compound of formula (III) with bis (low fluorene) alkyl azodicarboxylate, triphenylsulfonium and RSH The compound represented by the formula is reacted. Examples of the di (lower) alkylazodicarboxylate used in the present invention include diethylazodicarboxylate and diisopropylazodicarboxylate. Is a compound represented by RSΗ, which can be used as described in (i) above. The reaction is also carried out by combining a compound of formula (III) with a bis (lower) alkyl azodicarboxylate, triphenyl _ Together with the compound represented by RSH in the above formula! Ft is mixed with suitable solvents in the formula like _ solvents such as diethylban and tetrahydrofuran. The second (lower) alkyl dimethane diformate used in this reaction There is no particular limitation on the amount of triphenylphosphonium and the above-mentioned compound represented by RSH. However, these compounds are usually used in an amount of about 1 to about 3 moles, preferably about 1 to about 3 moles per mole of the compound of formula (III). The ratio of 2 deciles. The reaction temperature is not limited and can be appropriately determined according to the type and amount of reagents and compounds used. However, in general, the reaction is suitable for a temperature in the range of about -2 trc to about 50 ° C, preferably about o ° c to room temperature, and under these conditions, the reaction can be completed in about 10 minutes to several hours. The reaction is preferably performed in a stream of inert gas such as nitrogen or argon. Using either (i) or Ui), if necessary, the reaction solution can be subjected to conventional purification adjustments such as distillation, extraction, washing, solvent Evaporation, and column or thin-layer chromatography, then the compound of formula (II) can be isolated and purified -15- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ^^ 1. -1 --I i 1-_ II —1 i ^^^ 1 [^ 1J 、 -tl (#Read the precautions on the back before filling this page) 4 6044 6 A7 B7 Printed by the Employees' Cooperatives of the Bureau of Bid Rates in the Ministry of Economic Affairs Preparation 5. Description of the Invention (^) 1 1 物 e Moreover t When mixed with the above organic and eucalyptus acid in a suitable noodle mixture 1 1 • The (II) can be acid-added salt list _. 1 t thus obtained (I η compound is also the novel compound f of 1 1 | at the end of any other literature and constitutes a part of the present invention. Read II read 1 step 骝) Back 1 | At this step In the formula I, the 2-Weiyl group of the formula (II) obtained from the step (d) above is noted 1 1 1- (1,3-Brazazoline-2-yl) «heterobutane derivative or its acid Adding salt, matter I \ From this, it is further 1 »ϋ from which the R group is cleaved to convert it to 3-S f in the formula (I), which is charged with 1- (1, 3- Ilfazole-2 -yl) aza The butan derivative or its hydrazone addition is complete 1 salt 〇1 | The R can be cleaved by the above solvolysis reaction such as hydrolysis, or by the following U 1 1 decomposition reaction. By treating the compound of formula UI), for example, a buffer solution of PH5-7 and I, such as an acetic acid backwash solution, morpholinopropanesulfonic acid-hydrogen 1 | gasification m buffer solution Equally buffer solution and mixed solvent of fermented cocoon 1 1, or mixed solvent such as tetrahydrofuran-water, tetrahydrofuran · acetase-water, di 1 I alkane water, dimorphin-acetase-water, and Ding Fermentation-water (each containing 2km of phosphorus, sulfonium sulfonate, etc.) using about 1 to 4 at · hydrogen, hydrogenating 1 1 catalysts such as vaporized platinum S gasification rake-active sulfonic acid hydrogenation- Active fluorene is present in the presence of I at a temperature of about 0 ° C to about 50 * C for about 0 • 2 5 to about 5 hours 1 hour 0 1 1 The above steps produce compounds of formula (I) of the invention in good yield . If! I need to perform conventional purification of the reaction solution if necessary, such as steaming 1 1 Extraction »Wash 1 Solvent evaporation, and column or thin layer chromatography, can be isolated and I 1 -16- 1 1 1 1 The paper size is in accordance with the Chinese National Standard (CNS) A4 (21 OX 297 mm) 460446 · A7 B7 V. Description of the invention (β) Purification of the compound of formula (I) "Method B: In the second suggestion In the method, the compound (I) is replaced with a compound of the formula (VII) (which can be prepared by the above-mentioned method from 2-halomethylazepinepropane (i) by the reaction route shown in the following scheme (B). Stream plaque (m

N (vn) (a) S = < HN-

r—N X) ^-S— <, NH (VI) (b) _ — Order (Please read the note on the back ^ before filling this page) Central Bureau of Standards, Ministry of Economic Affairs

Ν N—i α) In the following, the method of displaying the circle (B) will be described in detail according to each step: -17- This paper size is applicable to China National Standard (CNS) A # specification (210X297 mm) Central standard of the Ministry of Economic Affairs The consumer cooperation of the Bureau of Staff Du Yinhua 460446 A7 B7 V. Description of the invention (4) Step 皤 U) In this step, by using the formula (VII) 1-doped Shuangchen [1.1.0] butane and 1 2,3-oxazolyl-2-sulfide_inverse plaque to prepare 2 · (azetidin-3-ylthio) -1,3-oxazoline β of formula (VI) can be obtained by formula (VII) The 1- «heterofluorene ring [1.1.0] butane and -1,3-pyridin-2-thiamine are stirred in a suitable solvent such as (preferably tetrahydrofuran) and preferably hydrogenated as the image age This reaction is carried out with sodium hydride or fusarium pinane gaseous vapor and sodium methoxide. The amounts of 1,3-oxazoline-2-thione and base used in this reaction are set to be subject to other restrictions. Generally, each of them is used at about 1 to about 3 decibels, preferably about 1 to about 1.5 deciles per mole of ()) heterobipyrene [1.1.0] butane. The reaction temperature is not limited by lattice, and may be locally changed according to the kind and amount of 1,3-JIazoline-2-thione and fluorene used. Generally, the reaction is suitable to be performed at a temperature of about -78 T to about 1G (TC Fanyuan, preferably -78 ° C to room temperature, and under this condition, the reaction can be completed in about 1 hour to 24 hours. The reaction is preferably performed in a stream of inert gas such as nitrogen or argon β. The above steps produce compounds of the formula UI) of the present invention with good yields. The reaction liquid is subjected to conventional purification adjustments such as steaming, extraction, washing Solvent evaporation and column or thin layer chromatography can isolate and purify the compound of formula (VI). Furthermore, when the organic and inorganic acids are stirred together in a suitable solvent, the compound (VI) may be subjected to suitable acid addition fluorene isolation. The obtained compound of formula (VI) is a novel compound not mentioned in any other literature and forms part of the present invention β -1 8-" Binding · " (Please read the precautions on the back before filling (This page) This paper size applies to China National Standards (CNS) Α4 size (210x297 mm)

4 6 0 4 4S A7 B7 V. Description of the invention (V) Difficult to get in the way \ / β / 1- From the description of the step, this step is heteroaerobic / 1% 2 The basis -3 is based on the ring of sulfur The basic formula of the chemist ’s slm is 丨 this] 2 due to I and phthaloline, oxali if at 3-acid 1 / V 1-and T phosphonozole cough 3-3- The general formula is described by It can be mixed with the acidic acid 1 and the combination of the materials) o For example, the salt is added to the acid and the acid is described into a shape \ Jr o I, and the hydrogen is better It is more suitable for making acidity than organic solvent-free and acid-free machines. It is usually acidic. The acid of sulfonyl formazan is sulfonyl, which has a low level of alkane. The use of acid is low. It is better than using it to make the limit 0. It has OOSE, and the temperature of the material should be adjusted. «1 / I ο (V-rate-type mole of Mo Er is more than about 1 per ear. (Please read the notes on the back and fill in this page again.) Packing. To the best. 1 According to nj roots and can often be changed. The amount of 10 acid and the amount of 10 kinds of acid are used to make the temperature around the temperature. p good compared to the plurality of cells in the chamber should be appropriate to the trans

In and line • ri 1P. At the completion of the flow, the argon gas is reduced to the cyanocyanide, such as the split 10, and the gas is about as good as it should be, but it should be treated better than the next application. Pure knowledge rate, good practice, good production, good liquid production, and the reverse steps will be borrowed. If you want to extract the consumption cooperation of the Central Standards Bureau of the Ministry of Economic Affairs, the printing and washing methods should be used. Purification and separation of analyzable layers «Thin or column tube and evaporating agent solution to combine the Θ formula from TX / 1. The combination of Chinese and French methods Nitrogen-based methyl chloride prepared from 2-methods from the road method fi side C) / 1 ^ ^ 0 可 程 Μ ί Θ The stream is combined to apply the Chinese National Standard (CNS) Α4 on this paper scale Specifications (210X29? Mm) 460446 Α7 Β7 V. Description of the invention (θ 流 稃 园 (η

(VII) (a)

V

HS

X) NH (VIII) (b)

HS o: / s ”(i) Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. In the following, the method shown in flow 豳 (c) is explained in detail according to each step. Step g (a) In this step, 1-azabischen [1.1.0] butane of formula (νΊI) is converted into 3-weiyl Ifazoline β of formula (VIII). The compound of the above formula is compounded with the compound represented by the formula RSH · The mediator or a salt thereof is stirred in the suitable solvent, and then the R group is cleaved from the obtained compound to perform the compound represented by the formula RSH or the lithium group. Examples include the compounds described above. Among them, the better one is fluorene-based lower alkyl or substituted _, " r (Please read the precautions on the back before filling this page) This paper size is applicable to Chinese national standard {CMS) A4 specification (210X297 (Mm) 4 60446 A7 B7 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (M) or unsubstituted phenylfluorenyl, or its salt with sodium and potassium β is used in this reaction There is no particular limitation on the arrangement of the compound represented by the formula RS 反应 or the 猡 thereof which reacts with the formula (VII). Generally, they each have a ratio of about 1 to about 5 moles, preferably about 1 to 3 moles, of the compound used in mol (VII). The reaction temperature is not specifically limited, and may be appropriately changed depending on the kind and amount of the compound of the formula RSH used. Generally, the reaction is suitable for a temperature of about -78BC to about β0T range, preferably -50 * C to room temperature, and under these conditions, the reaction can be completed in about 10 minutes to several hours. The reaction is preferably carried out in a stream of unique gas such as nitrogen or argon *. Next, the reaction of cleavage of the R group from the compound obtained by the above reaction can be carried out according to the method shown in Step A ("(e)"). Incidentally, when the above reaction is performed using a thiol compound whose R group is a fluorenyl group as a starting material, add 2 eq. Of its ear equivalent under the environment (# see: Example 9 described later). R is even in compounds of formula (VII). However, in this case, the R group can also be cleaved according to the method shown in step A of step (e) of changing the above method (see Example 10 described later). The above steps produce compound β of formula (VIII) in good yield. If necessary, by subjecting the reaction liquid to conventional purification adjustments such as distillation, extraction, washing, solvent evaporation, and column or thin layer chromatography, The compound of formula (VIII) can be isolated and purified. Furthermore, when stirred with the above organic and inorganic acids in a suitable solvent, the compound (VIII) can be added with a suitable acid. Β m fb) in this step "in, from the above step" (a) The obtained formula < VIII) Compound-2 1-(Please read the precautions on the back before filling in this page) Binding and binding paper size applicable to China National Standard (CNS) A4 # L grid (210X297 mm) 4 60446 __ 1. I B7_ V. Description of the invention IfA) ^ 3 '2 shovel and 2-substituted-1,3-oxazoline derivative of the above formula (V), instead, to prepare the compound of formula (I) according to the present invention . This step is performed in the same way as the method (i) or (ii) in the above method variation A. Using either (i) or (ii), if necessary, the reaction liquid can be subjected to conventional purification adjustments such as steaming, extraction, washing, solvent evaporation, and column or thin layer chromatography, which can then be isolated and purified. The compound of formula (I). When mixed with the above organic and inorganic acids in a suitable solvent, the compound of formula (I) obtained by changing A to C from the above method may be isolated in the form of an acid addition salt. In the acid addition salt thus obtained (especially the hydrochloride salt), a crystalline form having excellent storage stability as shown in the following examples can be easily obtained, which is very suitable as an intermediate for long-term storage. As detailed in Example 13 below, when the compound of formula (I) provided by the present invention is used according to the following scheme (D), a compound of formula (IX) with good yield can be obtained. Excellent antibacterial activity and can be administered orally when it is esterified. I Loading f ^ (Please read the notes on the back before filling this page) Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Printed by the Consumer Cooperatives-2-This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) 460446 A7 B7 V. Description of the invention (w) Stream stalk (D)

HCI

(谙 Please read the notes on the back before filling out this page) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(IX) Hereinafter, the present invention will be described in more detail by way of Examples, Preparation Practices and Experimental Examples. However, the present invention is not limited to the following descriptions:-2 3-This paper size applies to the Chinese National Standard (CNS) A4 specification (2! 0X297 mm) 460446 A7 B7 V. Description of the invention (incidentally, the symbols in the description have The following meanings: Ac: EthyloxyPO: p-nitrobenzylphenone Example 1 M HBr (1) (2) In 94 ml of bromine solution dissolved in 110 ml of ether, 80 g of dilute propylamine (1) was added to 15 ° C or below is added dropwise and stirred at room temperature for 1 day. After the reaction is completed, the deposited crystals are removed by filtration, washed with 55 ml of ether, and then dried in vacuum, so 302.6 is obtained G (yield: 99.6¾) of 2-bromomethylcyanelanine hydrobromide (2). 1 H-NMR (CD3 OD) δ: 3.35 (dd, 1H, J = 9.89Hz, 14.19Hz) , 3.71 (dd, 1H, J = 3.30Hz, 14.19Hz), 3.86 (dd, 1H, J = 8.58Hz, 10.89Hz), 4.01 (dd, 1H, J = 4.62Hz; 10.89Hz), 4.4-4.6 ( m, 1H) Example 2 '

H (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

HCI (1) (3) 900 ml of a diazomethane dry solution containing 9.M * liter of thiosulfur nitrogen and a catalytic amount of iodine dissolved therein was refluxed at 40 " C, and 100 -24- this paper size Applicable to China National Standard (CNS) A4 specification (2 丨 0X297 mm) 86.460446 Repair-work A7 B7 V. Description of the invention (4) ml of dimethylamine containing 7.6 ml of dilute propylamine (1) dissolved in it The solution was added to this solution, and after the addition was completed, the solution was stirred at the same temperature for 2 hours. After the reaction was completed, the reaction solution was left to room temperature, and then one of the residues obtained by filtration was washed with methane and n-hexane, and then vacuum-dried. Therefore, 8.37 g (yield: 65.8¾) was obtained. ) Azidomethylazepine (2) 0 H-NMR (DjO) δ: 3.26 (dd, 1H, J = 9.57Hz, 13.85Hz), 3.53 (dd, 1H, J = 3.30 Hz, 13.85Hz), 3.78 (dd 1H, 6.60Hz, 12.21Hz), 3.88 (dd, 1H, J = 4.95Hz, 12.21Hz), 4.38-4.47 (m, 1H) Example 3 H N. • HCi

m-hci --------- Loading-(Please read the notes on the back before filling in this page) Printed by the Central Automobile Industry Bureau Industrial and Consumer Cooperatives of the Ministry of Economic Affairs (3) ⑷ (5) Under nitrogen pressure 25 ml of a tetrahydrofuran suspension containing 1.28 g of the 2-gas methylazepine propane cyanate (3) obtained in the above Example 2 was stirred at -78 ° C, and 21 millimoles of n-butyl Lithium was added dropwise to the solution over a period of 5 minutes. After the end of the addition, the solution was searched and stirred at the same temperature for 1 hour, and at the same time, a reverse dipping solution was placed to allow it to reach room temperature, and the solution was stirred for another 1 minute. 2 ml of a 50% potassium hydroxide aqueous solution was added to the reaction liquid, and stirred for 1D minutes. After that, the reaction liquid was distilled under normal pressure, so a diazabicyclic ring having a boiling point of about 51 eC was obtained. [1.1.0 -25 This paper is in accordance with China National Standard (CNS) A4 specification (2! 0 > < 297 Mm) Agricultural Year and Month "86.3.25 A7 B7 V. Description of the invention (> 4) Butane (4). The obtained distilling solution was dried with hydrogenated hydrogen and potassium acetate, and then cooled to -4Q ° C, and 5 ml of a tetrahydrofuran solution containing 1.13 ml of formic acid was added dropwise to the distilling solution. Allow to reach room temperature. Then stir for 18 hours, then concentrate the solvent under reduced pressure, and add 16 pieces of 1 formic acid solution containing 60 millipod concentrated hydrochloric acid to the solution, and then add The solution was stirred for 20 hours. After the back dipping was completed, the solvent was evaporated under vacuum. Therefore, 570 mg (yield: 52.0%) of 3-hydroxydeuterated butane hydrofluoric acid was obtained in the form of colorless needle crystals. (5) β 1 H-NMR CD? 〇) δ: 4.0 ^ 4.3 (m, 2H), 4.1-4.3 (m, 2H). 4.6-4.8 (m, 1H) window oil 4

ΝΗ · HGi

N- ^ N ~ i S—1 < Please read the notes on the back before filling out this page) Printed by Shelley Consumer Cooperative, China Standards Bureau, Ministry of Economic Affairs (i) 5.G9 grams of sour acid at room temperature Add 73 Jg liter of the solution containing 7.95 g of 3-hydroxyazepine butane chlorochloride (5) formic anhydride obtained in Example 3, and then dropwise add 9.67 g of 2- (methylthio). -1,3-oxazoline, and then the resulting solution was heated and refluxed for 20 hours. Β The reaction solution was left to 逹 room temperature, and then 3_63 g of potassium hydrogen sulfonate was added, and the solution was stirred at the same temperature for 1 hour. After the reaction was completed, the precipitate was removed by filtration, and the solvent was evaporated under vacuum, and then 1 g (4 ml) of four g of furan was added to the residue and the resulting mixture was stirred at room temperature for 1 hour. Remove insoluble materials by filtration, and evaporate the solvent under vacuum. Then use -26-paper 9L scale with China National Car (CNS) A4 * MM 210X297 mm) 460

丨 丨 V V Α7 Β7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

The residue was subjected to silica gel column chromatography (eluent: gas-form-methanol) and, as a result, 8.23 g (yield: 71,5! Ϊ) of 3-hydroxy-1- (1) was obtained in the form of colorless crystals. , 3-thiazolin-2-yl) azetidine (6). ®.p.108 ~ 110C IR (K B r): v cnr 1 1 6 1 5, 1 3 7 2, 1 1 28, 1 010

SI3X 1 H-NMR (CDClj) δ: 3.356 (t, 2H, J = 7.26Hz), 3.70 ~ 4.00 (fn, 4H), 4.211 (t, 2H, J = 8.21Hz), 4.622 ~ 4.705 (m , 1H), 4.971 (s, 1H) (ii) Under a krypton current, cool 1.5 ml of an acetonitrile solution containing 219 mg of < 3-hydroxyazetidine (5) to 0-C, and cool 0.31 Ml of triethylamine was added to this solution and then 0.3 ml of an acetonitrile solution containing 25.0 mg of gas ethyl isothionitrate dissolved therein was added, and the resulting solution was stirred at the same temperature for 30 minutes and the reaction was After the solution was allowed to reach room temperature, the solution was stirred for another 2 hours. Next, digas methane was added to the reaction solution, and the resulting solution was washed with a saturated aqueous solution of potassium nitrate, and then the digas methane layer was dried with magnesium sulfate, and then concentrated under reduced pressure. Therefore, 300 mg (product Yield: 95%) of 3-hydroxy-1- (1,3-! Fazolin-2-yl) azepine butane (6) in the form of colorless needle-like crystals. The HMR spectrum of this product is exactly the same as that of the product obtained in (i) above.

(i) Add 6 mg of Ν, Ν-dimethylaminopyridine to 2 ml containing 790 mg of 3-hydroxy3-carazoline-2- -2 7 obtained in Example 4 above-This paper is for China National Standard (CNS) Α4 Specification (210X297 mm) --------- • Installation ------ Order ------ Wire (Please read the precautions on the back before filling this page ) 460446 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (> fc) 1 1) Tetrahydrofuran anhydride suspension of azabutane (6) and the suspension 1 1 to Ice cooling * Subsequently, 5 5 7 mg of triethylamine and E 75 mg of methylmmyl 1 1 gas were added while the suspension was cooled with ice, and the resulting fart mixture was stirred at the same temperature for 1 1 and stirred for 40 minutes. The reaction was completed After that, the solvent was evaporated under vacuum, and then ethyl acetate was added to the residue first »and dissolved in saturated water of sodium hydrogen sulfonate. Λ back 1 1 was washed with m to obtain m compound. Then, the water was obtained. Step by step-note with ethyl acetate Extraction 〇 After drying the organic layer obtained with magnesium sulfate 9 Evaporation under vacuum ·! I re-agent 9 and the residue was subjected to silica gel column chromatography (eluent: aeroform-filled with methanol) and Thus, 9 95 mg (yield 84.396) was obtained in colorless crystals. This page was packed in the form of 3-methylsulfanyl-1- (1,3-If oxazoline-2-yl) azetidine. Β I 1 I 1 H-NMR (CDC1. .270 MHz, ppm) δ: 3. 07 (sp 3Η), 1 1 | 3. 39 (t, 2H r J = 7.6Hz), 4.03 (t · 2H , J = 7.6Hz), 4 14-4 · 19 1 order 1 1 (m, 2H), 4, 37-4.31 (m, 2H), 5.28-5.33 (m, 1Η) then 箸 t at room temperature Add 228 mg of potassium thioacetate to 1 ml containing 1 18 1 1 mg of 3-methanesulfonium m-airyl-1-(1,3-in oxazoline ™ 2-1 1yl) azepine The solution of dimethylformamide anhydride and the mixed red product were stirred at 80 ° C for 4 hours. After the reaction was completed, the solvent 9 was evaporated under vacuum and then ethyl acetate was added. Then the solution was washed with a saturated aqueous solution of hydrogen acid 1 i> then »the resulting aqueous layer was back-extracted with ethyl acetate 0 [I after the organic layer obtained was dried with sulfuric acid m and the residue was subjected to silica gel 1 m Column chromatography (eluent: aeroform) and therefore) 8 8 mg (yield:! I 8 1, 2%) was obtained in the form of a pale yellow substance in the form of 3-J-acetaldehydethiol-1 -(1,3 -it 1 1 oxazoline-2 -yl) 氡 heterocycline. 1 I -2 8- 1! 1 1 This paper size applies to Chinese national standards (CNS specifications (210X 297 mm) B7 sputum 86L3.25 V. Description of the invention (>?) 1 R (Net): V ίί 1 1 6 9 5, 1 6 1 6, 1 3 6 1, 1 1 3 2 〇 (Please read the notes on the back before filling out this page) 1 H-NMR (CDCIj > δ: 2.333 (s, 3Η), 3.352 (t. 2Η, J = 7.26Hz), 3.885 (dd, 2H, J = 8.24, 5.28Hz) p 4.012 (t, 2H, J = 7.26Hz), 4.250 ~ 4.374 (m, 1H), 4.426 (t .2H, J = 8.25Hz) (ii) Add 119 mg of 3-caproyl-1-U, 3-carazolin-2-yl) azapine butane (6) and 2 kel equivalents of ethyl sulfate To a tetrahydrofuran solution containing 2 mole equivalents of triphenyl addition and 2 mole equivalents of β-azadicarboxylate, and the solution was stirred at the same temperature for 1 hour and at room temperature for another 1 hour. Under vacuum The solvent in the reaction liquid was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: chloroform-acetase). Thus, 107 mg (yield: 65%) of 3- Acetylthio-1- (1,3-brazolyl W-2-yl) azazenbutane (?) Β The NHR spectrum of this product is complete Same as (i) the spectrum of the product obtained above, a window of I fi pennant

N ~~ N-η

HCI (8) Printed by the Zhengong Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 12.98 grams of 3-ethionylthio-1- (1,3 oxazoline-2-yl) obtained in Example 5 of Shangying Azetane (7) was dissolved in 58 ml of isopropanol. The ice-cooled solution was added to 37.3 ml of a potassium hydroxide solution (1.69 N) dissolved in methanol, and the obtained solution was stirred. 1D minutes β Then, at the same temperature, 66 ml of a hydrogen acid solution (2N) was added to the above solution to extinguish it, and the resulting solution was stirred at room temperature for 15 minutes.圉 National Standard (CNS) (210 X 297 mm) A7 B7 4 6 to 4 4 6 8S.3. 2 5 V. Description of the Invention (M) Xue You removed insoluble matter by filtration. The residue obtained by concentrating the filtrate was dissolved in 33 ml of isopropanol, and insoluble matters were removed by filtration. Concentrate. 58.5 ml of n-butanol was added to the obtained residue so that the residue could be concentrated, and thus, 3-fluorenyl-1- (1,3-¾azolin-2-yl) azetidine was obtained. White solid β of alkane hydrochloride (8) 22.8 ml of acetonitrile was added to the solid, and the mixture was stirred at room temperature for 15 minutes to dissolve the mixture, and then 113.4 ml of acetone was added dropwise over a period of 30 minutes. Then, 113.4 ml of acetone was added dropwise over a period of 15 minutes, and the resulting solution was stirred for 30 minutes while cooling with ice. The deposited solid was filtered, and then washed with 150 ml of propylene, followed by drying under reduced pressure for one day, and thus, 10.41 g (purity: 97.5%, yield: 80.3%) was obtained in a colorless needle. 3-Wieryl-1-(1,3-thiazolin-2-yl) azetidine hydrochloride U).

® · ρ. 1 2 4 to 1 2 6 CIR (Κ Β Γ): V cr 1 1 6 3 8, 1 4 5 5, 1 1 3 2 〇iaax 1H-NMR (C0C13) δ: 2.57 (d, 1H , J = 8.2Hz), 3.59 (t, 2H, J = 7.4Hz), 4.02-4.18 (m, 4H), 4.63 (t, 2H, J = 7.4Hz), 5.19-5.26 (m, 1H), 12.19 (s, 1H) This product was confirmed to be crystalline by observation with a tritiated microscope. In addition, the X-ray winding diagram is shown in the following lattice spaces (d) (unit: A): 7.32, 5.96, 5.04, 5.00, 4.90, 4.44, 4.23, 4.08, 3.79, 3.71, 3.66, 3.29, 3.14, 3.10, 2.98, 2.91, 2.82, 2.55, 2.50 Incidentally, the supernatant crystal filtrate and the acetone washing solution were concentrated, and the obtained residue was dissolved in ml of n-butase and then concentrated.箸 Decompression-3 0-This paper size applies to Chinese National Standards (CNS > A4 size (210X297 mm) * ginseng I order (please read the notice on the back before filling this page) Central Ministry of Economic Affairs Printed by the Employees 'Cooperative of the Bureau of Standards, printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed 4 6 0 4 4 6 A7 B7 V. Description of the invention (M) and dried for one day. Add 1.7 milliliters of acetonitrile to 1.7 grams of the obtained orange solid. The resulting mixture was stirred at room temperature for 15 minutes to dissolve it, 17 ml of acetone was added dropwise to the resulting solution over a period of 15 minutes, and the resulting solution was stirred for 30 minutes while cooling with ice, and thus, 1.2 g ( Purity: 89.3¾; Yield: 8.5%} 3- 镟 in colorless needle-like crystal form 1- (1,3-blind 2-yl) azetidine hydrochloride (8).

(2) ⑷ (―N-^ —S (9) At -78 ° C, 5.94 ml (1.63M) of n-butyllithium was added dropwise to 12 ml containing 1.00 g of 2- obtained in Example 1 above. In a tetrahydrofuran suspension of bromomethylazepine bromate (2), and the resulting solution was stirred for 1 hour. The reaction solution was distilled in a water bath (30 ° C) under normal pressure, and each evaporation part group was taken out. And thus, 1-fluorobicyclo [1.1.0] butane (4) dissolved in tetrahydrofuran was obtained. On the other hand, 181 mg (55%) of sodium hydride was added to 5 ml containing 550 mg (4.61 mmol) The ice-cooled solution of 1,3-carazolin-2-fluorenone in dry tetrahydrofuran was stirred with the M compound for 1 hour. The above-mentioned azabicyclic ring dissolved in tetrahydrofuran was dissolved at -78 ° C. 〔1.1.0〕 -3 1-

.1 ^ ------. Π ------ line (read the precautions on the back before filling in this page) The paper size applies to China National Standard (CNS) Α4 size (210X297 mm) d604r4 ^

A7 B7 5. Description of the invention (>) Butane was added dropwise to the resulting solution, and the resulting solution was stirred at room temperature for 20 hours, and then the reaction liquid was subjected to high-performance liquid chromatography, and thus, white powder 2- (nitrogen Heteridine-3-ylthio) -1,3-oxazoline (9). b. p. 181 ~ 184¾ IRCKBr): v 1 1628, 1510, 1309, 1237 max 1044 H-NMR (CDj 〇D) 6: 3.32 (t, 2H, J = 8Hz), 3.46 (dd, 2H, J = 6Hz, 10Hz) (3.90 (dd, 2H, J = 8Hz, 10Hz), 4.06 (t, 2H, J = 8Hz), 4.3-4.5 (m, 1H)

r—N

(9) N—S—1 (10) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, adding 0.329 ml of methanesulfonic acid to 2- (azaazapropan-3-yl) obtained from Example 7 above -1,3-carazoline (9) in a solution of tetrahydrofuran anhydride, and then the solvent was concentrated under reduced pressure, methanol was added to the obtained solution, and the obtained solution was heated and refluxed for 3 hours. After the end, the solvent was distilled off, and the residue was separated and purified by high-performance liquid chromatography, and thus, 1δ6 mg (yield: 23.2%) of the light yellow oily substance of the present invention 3-neck-l- (lt3 -oxazolyl-2-yl) azetidine (10). Ιίί (net): i / C01: 1 1616, 1359, 1 007 〇 The NMR spectrum of the above-mentioned compound (10) treated with hydrogen acid was the same as the spectrum of the above-mentioned compound (8) of Example 6. Example Q fj «HBrZA ^ r —

(4) -------- 政 ------ tr ------ ^ (Please read the precautions on the back before filling out this page) ⑵ 3 2- This paper size is applicable to Chinese households Standard Mou (CNS > A4 Washer (210X297 mm)

NAc 4 60446 Employees' Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Cooperatives, India, A7 _B7 V. Description of the Invention (~) By the same method as in Example 7 above, 2.00 g of 2-bromomethylazapine obtained in Example 1 was used. Cyclopropane hydrobromide (2) to prepare a solution of diazabicyclo [1.1.0] butane (4) dissolved in tetrahydrofuran. Next, a solution of the compound (4) dissolved in tetrahydrofuran was added dropwise to a solution containing 1-32 ml of thioacetic acid in a dry tetrahydrofuran at a temperature of -4 ° C or lower, and the resulting mixture was stirred for 18 hours in a crude chamber. β After the reaction was completed, the cocoon was distilled off, and the residue was separated and purified by "inner silica gel column chromatography (eluent: chloroform-propyl copper), and 828 mg (yield: 51.8%) diethylsulfanyl-3-ethylsulfanylazetidine butane (11 >. 1 H-NMR (CDClj) δ: 1.87 {s, 3H), 2.35 (s, 3H), 3.89 (dd. 1/2 x 2H, J = 5Hz, 10Hz), 4.01 (dd, 1/2 x 2H, J = 5Hz, 9Hz), 4.1-4.2 (m, 1H), 4.42 (t, 1/2 x 2H, J = tOHz), 4.61 (t, 1/2 x 2H, J = 10Hz) >-hs- ^ Q \ h HCI (12) Add 1 ml of 2.6N hydrogen dicarboxylic acid to 104¾ g in the above example In the obtained 1-ethoxy-3-ethynylthioazapropane (11), the obtained solution was heated and refluxed for 1 hour. After the reaction was completed, water was added, and the solution was washed with ethyl acetate. And then the water layer was evaporated in vacuo. The residue obtained was dried in vacuum and, as a result, 71 mmol was obtained G (yield: 94.4%) 3-fluorenyl-fluorenbutane (12). -3 3-

AcS

(11) This paper U applies the Chinese National Standard (CNS) A4 specification (210 x 297 mm) f Please read the notes on the back before filling in this page) 丨 Installation · π 460446 A7 B7 V. Description of the invention (θ) 1 H-NMR (D, Ο) δ: 4.0-4.3 (m. 3H), 4.5-4.7 (m, 2H) (3) N · HCI ^ 丨

+ HS

(12)

HCI used 1. 28 g of 2-cyanomethylcyanazinepropane hydrocyanic acid BM3) obtained in Example 2 to prepare a solution containing 1-cyanobischen [1.1.0] butane (4) in argonfuran. After the solution was dried with osmium potassium and potassium sulphate, 0.85 ml of thioacetic acid was added dropwise to the chamber, and the resulting solvent was stirred at the same thickness * for 1 hour. The reaction was concentrated under reduced pressure. Then, 3.33 ml of 3N argon acid was added, and the resulting solution was heated and Θ flow for 1 hour. Β was placed in the reaction solution to make it a greenhouse, 30 ml of water was added thereto, and the obtained solution was washed with ethyl acetate. Solution. The aqueous phase obtained by separating males was put together with the aqueous phase obtained from the extraction of the organic layer, and then the solvent was evaporated in a vacuum, and thus, 91.3 mg (yield: 72.7%) of 3-methyl- 1- »heterobutane butane hydrohelium salt (12). The HMR spectrum of compound (12) is exactly the same as that of the compound of Example 10 above. I-^ I ^^ (Please read the precautions on the back before filling this page)

ΝΗ · HCI

HCI 34 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 X W7 mm). The NMR spectrum of this product is exactly the same as that obtained in Example 6 above. 4 6 0 4 4 'A7 B7 V. Description of the invention (4) 26.6 g of 2- (methylamidino) -1,3-carazoline and 5.2 mg of tribenzylline were added to dissolve 95% methanol (including 1 ml) 22.7 mg of water) in a solution of the 3-fluorenyl-1-azetidine hydrochloride (12) obtained in Example 11 above, and the resulting solution was heated and refluxed for 6 hours. After the reaction was completed, the solvent was distilled off in vacuo, and the resulting residue was dissolved in K1H aquatic acid, and the resulting mixture was washed with ethyl acetate. The solvent in the resulting aqueous phase was evaporated in vacuo, and The obtained residue was separated and purified by high performance liquid hydration chromatography, and thus, 29.1 mg (yield: 73.4%) of 3-neckyl-1- (1,3-carazolin-2-yl) azetidine was obtained. Alkyl hydrochloride (8). ------------ ^ ------ ΪΤ ------ WEI (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, adding 0.07 ml of triethylamine to 1.0 ml of dry tetrahydrofuran dissolved in 1.0 ml of dry tetrahydrofuran in a nitrogen stream at room temperature. In a solution of propane hydrochloride (12), and the resulting solution was stirred for 30 minutes. 70.3 mg of 2-chloroethyl isocyanate dissolved in dry tetrahydrofuran was added to this solution, and the resulting solution was re-simmered Stir for 1 hour. After the reaction solution is cooled to 0 ° C, 0.04 ml of methanesulfonic acid is added dropwise, and the resulting solution is stirred for 30 minutes, then in a vacuum. -35--

(12) (13) This paper size applies Chinese National Standard (CNS) A4 specification (2IOX29? Mm) 4 6CUUL · ^ 修 ίν ^ fi free h 86. 3. 25 A7 B7 V. Description of the invention (Knowledge and 1; The heat will dissolve the agent-into the liquid to dissolve the hair to the dry place with alcohol and dry the residue to obtain the neutrals and flow back to dissolve the hair.

Boyou borrowed m-2Λ 琳 § Tian (isBi residual thiodermide 3-so 4 1 '3 (05 t agent to I base, neck S3) so 3 and the quality of salt-like acid pure oil Sulfur and chroman are separated from flavane, and they are separated into small ring layer and W heterocycle 1 layer at 2 ° m ffl, P ·-IR (net): 1 ^^ 1 1 6 5 3, 1 56 0, 1 1 50 , 1 05 0 1 H-NMR (CDCla) 5ppui: 2.97 (s, 3H), 3.63 (t, 2H, J = 7.3Hz), 3.94 ~ 4.17 (®, 4H), 4.38.67 (m, 1H), 4.99 (iri, 1H).

HCI (8) — ^ 1 1_--! 1 _1 I-IJ ^ III ---- I. \ ~~ Ψ -3 (Please read the notes on the back before filling out this page) Staff Consumption of the Central Bureau of Standards, Ministry of Economic Affairs Cooperative print

(i) 700 mg of 3-Weiyi-1- (1,3-carazolin-2-yl) azetidine hydrochloride (8) obtained in Example 6 was dissolved in 15 ml of water and acetonitrile In a mixed solution of chloroform and chloroform, 1668 mg of p-nitrobenzyl (1R, -3 6-this paper size applies the Chinese National Standard (CNS) A4 specification (21 ο X 297 mm)

A 6 Printed by Shelley Consumer Cooperative of the Central Standards Bureau of Didi A7 B7 V. Description of the invention (shirt) 5R, 6S) -2- (diphenylphosphine) -6- [(R) -Buhydroxyethyl ] -Methylmethyl-sulfonyl-2-ene (em) -3-carboxylate (14) was added to the obtained solution. To the resulting solution, which was cooled with ice in a stream of m, 2,8 milliliter was added. f = isopropyl s ethylamine, and the resulting mixture was stirred at the same temperature S for 2 hours. Ethyl acetate was added to the reaction solution, and the resulting solution was washed with a saturated aqueous solution of sodium hydrogen oxalate and a saturated aqueous solution of sodium hydride, and evaporated to dissolve in a bin, and the obtained residue was subjected to silica gel_column layer. (Eluent: aeroform-propionate) and, as a result, 1339¾ g (yield: 92¾) of p-nitrobenzyl (lR, 5S, 6S) -2- [oxazoline-2-yl) azacyclo Butane-3-yl

] Sulfur-6-[(R) -hydroxylethyl] -1-methyl-sulfonan-2-ene-3-carboxylic acid ester (15K 1 H-NMR (CDClj) 6: 1.235 (d; 3H , J = 7.26Hz), 1.349 (d, 3H, J = 6.27Hz), 3.160 (quintet. 1H, J = 7.26Hz). 3.265 (dd, 1H, 0 = 2.3, 6.26Hz), 3.367 (t. 2H , J = 7.26HZ). 3.898 ~ 4.038 (m, 4H), 4.071 ~ 4.147 (m, 1H), 4.212 ~ 4,278 (m, 2H >, 4.372 (2H, J = 7.92Hr), 5.255 and 5.517 (d ( AB), 2H, J = 13.85Hz), 7.665 (d, 2H, J = 8.58Hz), 8.226 (d, 2H, J = 8.58Hz) (ii) 1339 mg of the compound obtained from the above reaction (i) (which Like a solution dissolved in 20 ml of tetrahydrofuran), add 60 ml of 0.38K phosphate buffer solution (PH6.G) and 11.2 g of zinc powder, and stir the mixture vigorously for 2 hours. Celite® The reaction solution was filtered to remove insoluble matters, and then the mash was adjusted to pH 5.5 after washing with ethyl acetate. Then, the resulting solution was concentrated under reduced pressure, and the concentrated solution was subjected to column chromatography Diaion HP-40® (from Mitsubishi Chemical Corporation (Mitsubishi -3 7-This paper size applies to Chinese National Standard (CNS) A4 specification U 丨 OX297 mm} ^-(Please read the back first Fill in the above notes and refill this I) • π

A7 B7 V. Description of the invention (6) Chemical Corporation) Cracking) (Eluent: 5% aqueous solution of isopropanol, isopropanol) Isolation and purification, and therefore, 861 mg (yield: 87%) The desired (1!?, 53,65) -2- [1- (1,3 -__ line-2-yl) azetidin-3-yl] thio-6-[(R) -bu Hydroxyethyl] -p-methyl-sulfonyl-2-ene-3-carboxylate (16). 1 H-NMR (D2 0) δ: 1.093 (d. 3H, J = 6.93Hz), 1.207 (d, 3H, J = 6.27Hz), 3.05- 3.20 (m, 1H). 3.357 (dd, 1H, J = 2.3, 5.94Hz), 3.558 (t, 2H, J = 7.26Hz), 3.920 (t. 2H, J = 7.26Hz) 4.00 ~ 4.20 (m, 5H), 4.20 ~ 4.30 (m, 1H), 4.60 -4.70 (m. 1H) IR (KBr): 1740, 1640, 1590 cm " 1 Example 1 5 (Please read the precautions on the back before filling this page)

N— S—J (8) HC!

ch3 cooh The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed 2.1 grams of the compound banknote obtained in Example 6 into 40 ml of digas methane and 20 ml of a 50% K 2 C 0 3 aqueous solution and Stir vigorously. The diazomethane layer was separated, dried over MgSh, and filtered. To this filtrate was added 600 mg of osmic acid and stirred. The resulting solution was concentrated under reduced pressure to obtain 2.34 g of the compound (17) as a pale yellow oil. 1 Η-NMR (CDC] 3) δ ppu: 2.0 3 (s, 3 Η), 3. 3 8 (t, 2 Η, J = 7 · 6 Η ζ), 3 '8 0 U, 1 Η ), 3. 9 4 (m, 2 Η), 4.03 (t, 2 Η, J = 7.6 Η 2), 4. 4 8 (m, 2 Η) IR (net): ϋ1 1652, 1612, 1361, 1258, 1008〇〇) α × ~ 3 8 _ This paper size applies to Chinese National Standards (CNS) A4 specifications (210 × 297 mm) 460446 ^ βΐ f] Mechanical charge 3. 25 A7 B7 V. Description of the invention ㈠1 ) Example 16

HC

Obtained 0 gram of compound 11 2 0 0 8) Formula (1 cubes in the same phase and described the oil and color yellow light gram 8 3 3 3 9 9 7 0 3 1X 9 3 ΛΙΤ Η 1 w (. 9 7 II H 2 m / IV 1 5 ro 7 (5 2 2 11 IX 8, 2 7 8 0 3 * r * H 8, 3 ΤΛ Η 6 3 1 m2 (5 5 6 \ — / \ ly \ 1 / Η Η Η 2 2 2 ra Γ \ Gewei I 3's gains 6 cases of the formula described in the above description 1 · • Example color} Shi Wujing's test of I will be the month of thiazolium, a thiazide, a 3-state 1, Base knot (pure salt, pure acid, phosphonium salt, alkylated butyl ring, and heterocyclic nitrogen-丨 fruit wet removal in the middle of the room to change or not (please read the precautions on the back before filling this page) The goodness of Ding'an Storage 2 is an example of its implementation, which is based on the method of loss measurement.

In the preparation room of the material synthesis, it is used as \ 1 / I —_ / IV for the chemical composition of the material and donated towels. U 4 6 1 1 / | \ Example of bactericidal method test XT / 1

οMethod eln release ch thin e base es raise a n training ap purpose 3 RH (J Qiong will use synergy therapy to treat the standard specimens of By, according to et root cl ο S volume e rty 1 * 2 1 th ue r M py ra物 生生 ot e e test c test

V contains 3 enveloping culture entities. Liquid 3 fat 1) Joan 00 V—ί 9 Η 1 Μ / IV / (V The policy of the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs makes the package thinner than the liquid.) W) Incubate SG liters ((B gelatin) \ About water cells, each salt, fine liquid, food, e, release, 10, dilute, and think about Γ), the basic degree te, enriched with an anesthesia, P1, and Γ, 1C and micro (Π., Test tube night test drip to make the amount of nutrition Release the best test of the test w using the w test, and then test the test result. The test is performed on the small I 8 test 1 when the test is completed and the test is completed. Jun V Test 37 Contained in degrees. The quasi-suppressed standard made by the thick plant is the most fake. It is the most pseudo-physical degree. This is used to make the zone attached. The table below shows the fruit results. Paper size applies to Chinese national standards (CNS > A4 specifications (210X25 · 7 mm > 46044- A7 B7) V. Description of the invention (from) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 1: μ τr (». G / n. η Test organisms Aureobasidium aureus FDA2 0 9 P JC-1 Aureus aureus® Teraji viscera aureus aureus MS353 The pus key ball see Cook Bacillus subtilis A TCC 6633 Garcinia coccineus ATCC 9 3 4 1 E. coli NIHJ JC-2 E.coli® K- 1 2 C800 Enterobacter cloacae 963 Enterobacter aerogenes ATCC 1 3 0 4 8 Klebsiella pneumonia PCI-602 Typhoid typhoid UD971 Typhoid fever Bacillus 301 Paratyphoid 1 0 1 5 M. steamer 80fl6 Enterobacter (314 Pseudomonas I AH 1 184 Proteus Moor IF0 3848 Proteus mirabilis IF 0 3 8 4 9 Common Proteus 0P19 Common Deformation_ HX- 19 Proteus raisii IF0 3850 Test combination., (16) 0.013 £ 0.006 < 0.006 < 0.006 0.025 0.2 0.013 0.1 0.05 0.1 0.013 0.025 g 0.006 0.05 0.025 0.39 0.05 0.39 0.39 0.39 According to the above results, it can be known that: provided by the present invention: The compound of formula (I) is an effective intermediate with a compound with excellent antibacterial activity. The size of this paper is applicable to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) Ding- °

Claims (1)

460446 Application for patent scope A "9G)" M No.8411311) No. 4-disulfide-curtain-also compound patent (as amended on August 14, 1990) Λ scope of patent application: 1. A preparation of the following formula (I) Represented compound or its acid addition salt This method is characterized by reacting 2- (azetidin-3-ylthio) thiazoline p-N-S represented by the following formula (VI) with a monoacid. ° 〆 2. A method for preparing a compound of formula (I) or an acid addition salt thereof according to item 1 of the patent application, which is characterized in that 3-mercaptoazetidine represented by the following formula (VIII) HS (VIII) Reaction with a 2-substituted-1,3-thiazoline derivative represented by the following formula (V): (V) s · ^ -1 460446 6. Application scope Where L represents a leaving group. 3. A method for preparing a compound of formula (I) or an acid addition salt thereof according to item I in the scope of the patent application, the method is characterized in that the 3-amidinoazetidine HS represented by the following formula (VIII) is used: (VIII) c VIII Reacts with haloethyl isothiocyanate. 4. A method for preparing a compound of formula (I) or an acid addition salt thereof according to item i in the scope of the patent application, the method is characterized by: U) making 1 · azabicyclo [1.1.0] represented by the following formula (VII) ] Butane After reacting with a compound represented by the following formula or a salt thereof, RSH wherein R represents a lower carbofluorenyl group, the R group is cleaved from the obtained compound, and (b) the obtained 3-oxoylaza is represented by the following formula (VIII) Cyclobutane HS (VIII) Reaction with a 2-substituted-1,3-thiazoline derivative represented by the following formula (V) (V) 460446, the scope of patent application, where L is the leaving group. 5. A method for preparing a compound of formula (I) or an acid addition salt thereof according to item 1 of the scope of the patent application, the method is characterized by: U) making a 1-azabicyclic ring represented by the following formula (VII) [1.1. 0] butane (VII) After reacting with a compound represented by the following formula or a salt thereof, RSH wherein R represents a lower carbofluorenyl group, the R group is cleaved from the obtained compound, and (b) the obtained 3- 锍 represented by the following formula (VIII) is obtained Azetidine Reacts with haloethyl isothiocyanate. 6. A method for preparing a compound represented by the following formula (III), H0 N—) S ” (III) The method is characterized in that the compound H0 represented by the following formula (IV) is used: (IV) 460445 6. Scope of patent application Reaction with haloethyl isothiocyanate. 7.—A method for preparing a compound of formula (ill) according to item 6 of the scope of the patent application. The method is characterized by: U) making 1-azabicyclo [i.i.o] butane (VII) represented by the following formula (VII) After reacting with a carboxylic acid, the obtained compound is subjected to solvolysis, and (b) the obtained 3-hydroxyazetidine HO-<^ &gt; H '(IV) represented by the following formula (IV) is represented by the following formula (V The 2-substituted-1,3-thiazoline derivative represented by) reacts N— (V) S ″ ο) 4? Where L represents a leaving group. 8.—A method for preparing a compound of formula (Η) in item 6 of the patent application, the method is characterized by: U) making 1-azabicyclo [丨 · 1 · 0] represented by the following formula (VII) D hospital (VII) 4 60446 6. Application scope After reacting with carboxylic acid, the obtained compound is solvolyzed, and (b) the obtained 3-hydroxyazetidine represented by the following formula (IV) is obtained: (IV) Reaction with haloethyl isothiocyanate. 9. A compound represented by the following formula (VI) -N -S (VI) 10. A method for preparing a compound of formula (VI) such as item 9 in the scope of the patent application, which is characterized by: making 1-azabicyclo [1.1.0] butane represented by the following formula (VII) Reacts with 1,3-thiazoline-2-thione (VII) Invented a new Chinese thiol compound name (as amended on May 25, 1990) English THIOL COMPOUNDS First name surname Guo Yan Qian Sheng Yi Huan Jing Lin Zuoyu 12 3 people created the original version of the book BB housing, residence 8 ο ϋ 1 2U, room 7-White M1--S Machidai Ikai Minami-Maichi-shi Prefecture Okazaki-Fukugawa Renshang County Prefectural Prefecture Kawata Tamana Nagami 12 3 Baifan 3-104 Order Name (Name) Ministry of Economic Affairs Intellectual Property Wealth Xiao Gong Consumer Cooperative Co., Ltd. prints the applicant's nationality residence and residence (office). Representative's name is not Wise Ridley Co., Ltd. (Japan! 7 Chongbufu !; No. 1 Co., Ltd.). 1 chome 1 〇fan No. 3 Guan Heng (Guan Heng) The brother of this paper is free to use the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 4 6 0 4 4 6 _ charge se. 3. A7 B7 V. Description of the invention (/) For the combination and conversion, B) the material has ne custom pe, the baB ar sulfur U class and new details. And the e substance, S interstitial material in the combination of alcohol _ Sulfur treatment has oral pseudo-clarifiable hair types Shows significant salt thereof into two acids are added, the objects are re-engagement of the side SULFUR * of alcohols. Customs and materials are combined and used to make the new system. There is a mid-step method1. This system is printed by the consumer cooperation of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). ) Sinochem's anti-drug drug critics and Cheng Zhida can take the perimeter shots and watch the period of attention. The Shangjingwu only goes to the bed to face the discussion. It was built for the quilt before the forestry, and it has a low intake, and it has some characteristics. It is a combination of Xu Hua and Xu Hua. It should be taken for granted. And, at present, the supervised part of the sex-synaptic viable spouse partner is in a selective therapy station □ In comparison with fcfc, it can be injected and injected. . Drug path application. For road and floor use, there are regular and non-easy container medicines that are applied on the ground, and the best medicines are applied to the Chinese medicine family fungus resistance. Zhan Shuofa's essential medicine box, Shi Liefu, has a strong mouth. This can be caused by the fact that the live drug is attached to the drug that is resistant to the strong environment. / 1 can be related (f should be reproduced, etc. i should be reproduced i hair meridian and human, Mingfa's § quinolinazole if expressing X) of the thiol 3-generation-take the top 2-chain main alkanecycloaza The size of this paper is applicable to the Chinese national standard (CNS &gt; M specification (210X297 mm), with a formula of 4 6 0 4 4 6 C, &quot; —- f; .〆. · * Dagger ·:-: &gt;A7; ik ft, 86. 3. 2 〇B7 V. Description of the invention (&gt;) 'or a master compound which is typically represented by the following formula (IX) The best esters are based on the residues of the esters derived from the bio-based residues of the It. To be prepared, the bases are carboxyl, and the repositioned 3-S antibodies are highly conformable. A brief description of Shishengjieshuishui ester is quickly activated on the inner body. This is due to the fact that it is outside-this thing * the combined rate of the received X) Suction (I's style on the tube to nourish and change from the degree of change to the above, on m You Shifu has a good idea for this purpose and is, S-type to be shaped * 0 agent before the antibacterial agent is resistant to foreign matter, and you can go to the bed. 73 6 B 2 / IV 8 / If you are suffering from dysentery, please apply for it). Wuli et al., Etc., established the solid ester No. 39 and 20; No. 6 and No. 96, No. 96, 04IS, and 17)-. —, X 6 and (the first formula Zhuzhou 1-type is shown in the table above as X) its / 1 / V formula is based on sulfur-based radicals 3-· with the purpose of the extraction of the basic 2-main Commanded zomine f pi hair-ιπ Ben 3 'Alkane dopant 0 Complementary to ground effect \ / Basic substitution of the material I 2 (Please read the precautions on the back before filling in this Page) 袈. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs The neck is clear. In order to change the size of the paper sheet, the Chinese National Standards Standard (CNS) A4 (210X297 mm) * 460446Ί A7-· JjC.; :: B7 Employee cooperation of the Central Bureau of Standards, Ministry of Economic Affairs. Du Yin Preparation 5. Description of the invention (80. The compound represented by the above formula (I) and its acid addition salt are very effective for the effective preparation of clinically very effective master compound compounds represented by the above formula (IX). Intermediate, the compound (IX) itself exhibits high antibacterial activity and can be administered orally after esterification. Examples of the acid addition salts of the compounds of the above formula (I) include oligoacids such as low fluorene aliphatic acids such as acetic acid , Propionic acid, butyric acid, trifluoroacetic acid, and triacetic acid; substituted or unsubstituted benzoic acid such as benzoic acid, p-nitrobenzoic acid benzenesulfonic acid; (dentate) lower alkyl sulfonic acid such as methanesulfonic acid And trifluoromethanesulfonic acid; substituted or unsubstituted aromatic sulfonic acids such as benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid and 2,4,6-triiso Propylbenzenesulfonic acid; and organic knee acids such as diphenylphosphonic acid; and inorganic acids like hydrogen acid, sulfuric acid, Addition salts of bromic acid, hydroiodic acid, boronic acid, peroxyacid, and nitrous acid The compound of formula (I) can be prepared by any of the following three special methods A, B, and C of tantalum, for example: A: In this method, the compound of the above formula (I) is prepared by using 2-halomethylazacyclopropane as a starting material according to the route shown in the following reaction scheme (A): (Please read the note on the back first Please fill in this page for more details)-° Quick-use Chinese Standard for Paper Size {CNS) A4 specification (210X297 mm) '4 6044 6 5 Printed by the Industrial and Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1. Solvent t-synthetic agent double-soluble A7 B7 K [IV trans t acid carboxylic acid and alkane butane adducts are combined to obtain the formula and the conversion is due to this factor and the alkanyl cycloaza nitrogen hydroxy-3 is soluble The argon cyanide should react with the transether in the second solution as the first solution of the first agent and etherify it. I) Λα • / V in step VI. The above steps should be described step by step. C ::： 合 (I Mix the mixture and stir the mixture and dissolve the acid in the liquid to obtain the formazan. Tranquil carboxylic acid-as described in the previous rumors. Often acidic acid and acetic acid are limited to those that are particularly good. No organic acid of dong acid with carboxylic acid should be added to this acid. It is better to use the acid 1. Carboxylic acid is better than the ear mol, and the ear. The system is limited from 20 to M 1 and the temperature and temperature should be adjusted. The kind and amount of the acid are appropriately changed. In general, the reaction is suitable for a range of about-to about 100 »°. • It is preferably carried out at a temperature of about -78 ° to about 6 (rc), and under this condition, the reaction can be completed in about 10 minutes to several days. This reaction is preferably carried out in a stream of inert gas such as nitrogen or argon β. Next, the compound obtained by the above reaction is subjected to solvolysis (such as hydrolysis), and thus 3-hydroxyazepines of formula (IV) can be produced. The solvolysis reaction is carried out in a mixture of water or an alcoholic solvent such as methanol, ethanol and isobutanol or an organic solvent such as acetonitrile, tetrahydrofuran and dipentane, and as described in step (a) above. A suitable age or an inorganic acid such as atmospheric acid, bromic acid and hydroiodic acid is treated at about -2 ° C to about 51TC, preferably at a temperature as low as about 0 * C to room temperature. The compound is carried out from about 10 minutes to several hours. If necessary, S is known by the reaction solution obtained from the above-mentioned Bu Si-1 0- This paper size applies to the Chinese national standard car {CNS) M specification (2 丨 0 &gt; &lt; 297 mm) ^^^ 1 II--^^^ 1 l 1 * .¾, ve (Please read the notes on the back first (Fill in this page) 13 ^ 4 6044 6 iL ·; i ίί A7 B7 V. Description of the invention The composition is about 1 to about 3 moles, preferably about 1 to about 1.5 moles. The reaction temperature is not strictly limited and can be It is appropriately changed depending on the kind and amount of the compound (I) and the compound of formula (V) used. However, generally, the reaction is suitable for a temperature ranging from room temperature to about 1 G0T :, preferably from about room temperature to about 8Q ° C, and here Under the conditions, the reaction can be completed in about 1 hour to about 24 hours. According to appropriate description. 1 ^ on the flow Y gas r from 0 Η-such as II salt gas {I acid deuterium cyanide. Such as sulfur formation The heterogeneous substance is converted to acetonitrile and halogenated. V) The product is introduced into {1. The combination is better than from V. The response should be 1) (1. The reverse (i type will be three as 0.) Nitrile is better than 0, lower and middle _ in the presence of dissolved amines. Examples of iodine salts of isethionyl and the bromide of thiocyanate, isothioisoethyl, and ethyl halide. The original salt is acid as cyanamide. Different bases. Use chloric acid in ethyl salt to make cyanosulfurium sulfide 恃 5. 1. It is necessary to use S to make the amount of acid in salt 1 gas is better. Sulfur is different from sulfur. Isopropyl ethyl molybdenum 3 B and halol il to the common thing 0 with this 1 鹾, and vice versa V) and y. (I use the standard to make the ear mo (please read the precautions on the back first) (Fill in this page again.) Printed by the Central Consumer Bureau of the Ministry of Economic Affairs of the Industrial Cooperatives, when the production limit and the strict type are C, 0 ° C degrees, salt-2, warm acid should be around antisulfide α The rate base should be lower than the second and the second half of the ear and the regular Mo Yantong to the completion of the decimal to about minutes, such as 10 minutes lower than the appointment-so justified. The root change can be changed and the temperature is better than the temperature range -7 Enter the greenhouse to 'C temperament inertia »1 line Mid-range gas argon or gas nitrogen such as a body 0 Eccentric to 0 if 0-Any paper size applicable to Chinese National Standard (CNS) Α4 size (210 规格 297 mm) 4 6 0 4 4 6 1 £ '' Five V years S5. Ft and acetonitrile like sulphur-solubilizing agent, such as inert agent, living on the basis of the hydroxyl radical of the gas, halogen aldehyde acetosulfone, such as organic chlorine has a fermented image or seed gas a 0 with sulfonate Benzomethylation 4- 0 «bispyridyl amine is better than dijia S- than κ, and and, ethoxyfuryl propyl hydrogen is different in amine. Forty-two, and two, three, two, three, two, three, two, three, two, three, two, three, two, three, two, two, and three, such as the mixture of 鹾, 溶, 溶, 溶, 醚, 醚, 醚, 限, 限, 耳, 耳, 蛋, 蛋Each dose is used to make the base hydroxylate and the hydroxyl radical of the active base and the reverse should be done, and the flux rate is often inferior to that of the ear. 20-Reduce the liveness of the active ingredient. The covenant is usually as good as Gentong1, covenant is better, but more compelling., The limited-variable ear lattice reform Moxuedi 3 has a covenant S suitable to measure 1 mild covenant type C (please listen first (Please read the notes on the back and fill in this page again.) A / ίι The temperature of the greenhouse to &quot; C When the completion is completed, the decimal is about 10 minutes lower than 10 minutes. In the best, it should be better than the surrounding pattern. Love 50 should be about And mid-stream gas 0 or f I gas I * J T1 fcw (eg, the gasification activity of the formula body is compared with the basic hydroxyl group, and it should be mixed with a salt or a compound If the formula is expressed in the form of an agent and a solvent, it is suitable for formulating η in the formula. In this case, such as the amine 0 methyl group, the amount of methylation of the salt, or the synthesis of the sulfur sulfonate E SR should be reversed, and printed by the Ministry of Economic Affairs Central Standards Bureau Off-line Consumer Cooperatives Its CO is as low as 1, and its value is better than 0, and its ears or Mo 00 are contracted to this 1. The limit of the normal chemical composition is limited by the existing base. On the contrary, the roots are often accessible and 0, and the transformation and limitation of the grid should be appropriate when the amount is not the same as that of the temperature species. The ratio of the ratio of the sulfur to the alcohol is about 12 when the degree of advancing is in the advancing degree. The clock is about 10 minutes and the temperature is about 10%. The room is about the same as the one in Kyokai. This area is below 50 pieces. I is here and is about ρ temperature. • This paper size applies Chinese National Standard (CNS) Α4 size (210 X 297 mm) 4 6 0 44 6 V. Description of the invention A7 B7 Du printed the work of the Central Government Bureau of the Ministry of Economic Affairs. The reaction is preferably treated in a stream of an inert gas such as nitrogen or argon. (ii) Conversion of a compound of formula (III) into a compound of formula (II) can also be achieved by combining a compound of formula (III) with bis (low fluorene) alkyl azodicarboxylate, triphenylsulfonium and RSH The compound represented by the formula is reacted. Examples of the di (lower) alkylazodicarboxylate used in the present invention include diethylazodicarboxylate and diisopropylazodicarboxylate. Is a compound represented by RSΗ, which can be used as described in (i) above. The reaction is also carried out by combining a compound of formula (III) with a bis (lower) alkyl azodicarboxylate, triphenyl _ Together with the compound represented by RSH in the above formula! Ft is mixed with suitable solvents in the formula like _ solvents such as diethylban and tetrahydrofuran. The second (lower) alkyl dimethane diformate used in this reaction There is no particular limitation on the amount of triphenylphosphonium and the above-mentioned compound represented by RSH. However, these compounds are usually used in an amount of about 1 to about 3 moles, preferably about 1 to about 3 moles per mole of the compound of formula (III). The ratio of 2 deciles. The reaction temperature is not limited, and can be appropriate according to the type and amount of reagents and compounds used. However, in general, the reaction is suitable for a temperature in the range of about -2 trc to about 50 ° C, preferably about o ° c to room temperature, and under this condition, the reaction can be performed in about 10 minutes to several hours. The reaction is preferably carried out in a stream of an inert gas such as nitrogen or argon. Using either (i) or Ui), if necessary, the reaction solution can be subjected to conventional purification adjustments such as distillation, extraction, washing, Solvent evaporation, and column or thin layer chromatography, then the compound of formula (II) can be isolated and purified. -15- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ^^ 1.- 1--I i 1-_ II —1 i ^^^ 1 [^ 1J 、 -tl (#Read the notes on the back before filling this page) 4 60446 __; 1.I B7_ V. Description of the invention IfA) ^ The 3 '2 shovel is used instead of the 2-substituted-1,3-oxazoline derivative of the above formula (V) to prepare a compound of formula (I) according to the present invention. This step is performed in the same way as the method (i) or (ii) in the above method variation A. Using either (i) or (ii), if necessary, the reaction liquid can be subjected to conventional purification adjustments such as steaming, extraction, washing, solvent evaporation, and column or thin layer chromatography, which can then be isolated and purified. The compound of formula (I). When mixed with the above organic and inorganic acids in a suitable solvent, the compound of formula (I) obtained by changing A to C from the above method may be isolated in the form of an acid addition salt. In the acid addition salt thus obtained (especially the hydrochloride salt), a crystalline form having excellent storage stability as shown in the following examples can be easily obtained, which is very suitable as an intermediate for long-term storage. As detailed in Example 13 below, when the compound of formula (I) provided by the present invention is used according to the following scheme (D), a compound of formula (IX) with good yield can be obtained. Excellent antibacterial activity and can be administered orally when it is esterified. I installed f ^ (Please read the precautions on the back before filling out this page) Printed by the Central Laboratories of the Ministry of Economic Affairs and Consumer Cooperatives-2-This paper size applies to China National Standard (CNS) A4 (210X297 mm) Agriculture Year and month "86.3.25 A7 B7 V. Description of the invention (&gt; 4) Butane (4). The obtained distilling solution was dried with hydrogenated hydrogen and potassium acetate, and then cooled to -4Q ° C, and 5 ml of a tetrahydrofuran solution containing 1.13 ml of formic acid was added dropwise to the distilling solution. Allow to reach room temperature. Then stir for 18 hours, then concentrate the solvent under reduced pressure, and add 16 pieces of 1 formic acid solution containing 60 millipod concentrated hydrochloric acid to the solution, and then add The solution was stirred for 20 hours. After the back dipping was completed, the solvent was evaporated under vacuum. Therefore, 570 mg (yield: 52.0%) of 3-hydroxydeuterated butane hydrofluoric acid was obtained in the form of colorless needle crystals. (5) β 1 H-NMR CD? 〇) δ: 4.0 ^ 4.3 (m, 2H), 4.1-4.3 (m, 2H). 4.6-4.8 (m, 1H) window oil 4 ΝΗ · HGi N- ^ N ~ i S—1 &lt; Please read the notes on the back before filling out this page) Printed by Shelley Consumer Cooperative, China Standards Bureau, Ministry of Economic Affairs (i) 5.G9 grams of sour acid at room temperature Add 73 Jg liter of the solution containing 7.95 g of 3-hydroxyazepine butane chlorochloride (5) formic anhydride obtained in Example 3, and then dropwise add 9.67 g of 2- (methylthio). -1,3-oxazoline, and then the resulting solution was heated and refluxed for 20 hours. Β The reaction solution was left to 逹 room temperature, and then 3_63 g of potassium hydrogen sulfonate was added, and the solution was stirred at the same temperature for 1 hour. After the reaction was completed, the precipitate was removed by filtration, and the solvent was evaporated under vacuum, and then 1 g (4 ml) of four g of furan was added to the residue and the resulting mixture was stirred at room temperature for 1 hour. The insoluble matter was removed by filtration, and the solvent was evaporated under vacuum. Then, the -26-paper 9L was applied to the Chinese National Car (CNS) A4 * MM 210X297 mm. 460 Han Ϊ 丨 丨 V Α7 Β7 Central Standard of the Ministry of Economy Printed by Bureau Shelley Consumer Cooperative Co., Ltd. 5. Description of the invention () The residue was subjected to silica gel column chromatography (eluent: gas-form-methanol) and, as a result, 8.23 g was obtained (yield: 71,5! Ϊ) 3-Hydroxy-1- (1,3-thiazolin-2-yl) azetidine (6) in colorless crystalline form. ®.p.108 ~ 110C IR (KB r): v cnr 1 1 6 1 5, 1 3 7 2, 1 1 28, 1 010 SI3X 1 H-NMR (CDClj) δ: 3.356 (t, 2H, J = 7.26Hz), 3.70 ~ 4.00 (fn, 4H), 4.211 (t, 2H, J = 8.21Hz), 4.622 ~ 4.705 (m, 1H), 4.971 (s, 1H) (ii) 1.5 ml of an acetonitrile solution containing 219 mg of <3-hydroxyazetidine (5) was cooled to 0-C, and 0.31 ml of triethylamine was added to this solution and then 0.3 ml of the An acetonitrile anhydride solution in which 250 mg of gas ethyl isothionitrate was dissolved, and the resulting solution was stirred at the same temperature for 30 minutes and the reaction solution was left to reach room temperature, and the solution was stirred for another 2 hours. Next, digas methane was added to the reaction solution, and the resulting solution was washed with a saturated aqueous solution of potassium nitrate, and then the digas methane layer was dried with magnesium sulfate, and then concentrated under reduced pressure. Therefore, 300 mg (product Yield: 95%) of 3-hydroxy-1- (1,3-! Fazolin-2-yl) azepine butane (6) in the form of colorless needle-like crystals. The HMR spectrum of this product is exactly the same as that of the product obtained in (i) above. (i) Add 6 mg of Ν, Ν-dimethylaminopyridine to 2 ml containing 790 mg of 3-hydroxy3-carazoline-2- -2 7 obtained in Example 4 above-This paper is for China National Standard (CNS) Α4 Specification (210X297 mm) --------- • Installation ------ Order ------ Wire (Please read the precautions on the back before filling this page ) B7 smolder 86L3.25 V. Description of the invention (&gt;?) 1 R (Net): V ίί 1 1 6 9 5, 1 6 1 6, 1 3 6 1, 1 1 3 2 〇 (Please read the back first Please fill in this page for the matters needing attention) 1 H-NMR (CDCIj &gt; δ: 2.333 (s, 3Η), 3.352 (t. 2Η, J = 7.26Hz), 3.885 (dd, 2H, J = 8.24, 5.28Hz) p 4.012 (t, 2H, J = 7.26Hz), 4.250 ~ 4.374 (m, 1H), 4.426 (t.2H, J = 8.25Hz) (ii) Transfer 119 mg of 3-meryl-1-U, 3- Carazolin-2-yl) azapine butane (6) and 2 equivalents of ethanesulfuric acid are added to a tetrahydrofuran containing 2 mole equivalents of triphenyl division and 2 mole equivalents of β-azadicarboxylate The solution and the solution were stirred at the same temperature for 1 hour and at room temperature for another 1 hour. The solvent in the reaction liquid was evaporated under vacuum, and the obtained residue was subjected to silica gel column chromatography (eluent: chloroform-acetase). Thus, 107 mg (yield: 65%) of a light yellow oily substance was obtained. 3-Acetylthio-1- (1,3-brazolyl W-2-yl) azazenbutane (?) Β The NHR spectrum of this product is exactly the same as the spectrum of the product obtained in (i) above. I fi N ~~ N-η HCI (8) Printed on 12.98 grams of 3-ethionylthio-1- (1,3 blindazole) obtained from the Example 5 of Shangying by the Central Labor Bureau of the Ministry of Economic Affairs Porphyrin-2-yl) azetidine (7) was dissolved in 58 ml of isopropanol. The ice-cooled solution was added to 37.3 ml of a potassium hydroxide solution (1.69 N) dissolved in methanol, And the resulting solution was stirred for 1D minutes β, then at the same temperature, 66 ml of a hydrogen acid solution (2N) was added to the above solution to extinguish it, and after the resulting solution was stirred at room temperature for 15 minutes, -29- this paper Zhang Zhishi. Use the Chinese National Standard (CNS) (210 X 297 mm) A7 B7 4 6 to 4 4 6 8S.3. 2 5 V. Description of the invention (M) Xue You filtered to remove insoluble matter. The residue obtained by concentrating the filtrate was dissolved in 33 ml of isopropanol, and insoluble matters were removed by filtration. Concentrate. 58.5 ml of n-butanol was added to the obtained residue so that the residue could be concentrated, and thus, 3-fluorenyl-1- (1,3-¾azolin-2-yl) azetidine was obtained. White solid β of alkane hydrochloride (8) 22.8 ml of acetonitrile was added to the solid, and the mixture was stirred at room temperature for 15 minutes to dissolve the mixture, and then 113.4 ml of acetone was added dropwise over a period of 30 minutes. Then, 113.4 ml of acetone was added dropwise over a period of 15 minutes, and the resulting solution was stirred for 30 minutes while cooling with ice. The deposited solid was filtered, and then washed with 150 ml of propylene, followed by drying under reduced pressure for one day, and thus, 10.41 g (purity: 97.5%, yield: 80.3%) was obtained in a colorless needle. 3-Wieryl-1-(1,3-thiazolin-2-yl) azetidine hydrochloride U). ® · ρ. 1 2 4 to 1 2 6 CIR (Κ Β Γ): V cr 1 1 6 3 8, 1 4 5 5, 1 1 3 2 〇iaax 1H-NMR (C0C13) δ: 2.57 (d, 1H , J = 8.2Hz), 3.59 (t, 2H, J = 7.4Hz), 4.02-4.18 (m, 4H), 4.63 (t, 2H, J = 7.4Hz), 5.19-5.26 (m, 1H), 12.19 (s, 1H) This product was confirmed to be crystalline by observation with a tritiated microscope. In addition, the X-ray winding diagram is shown in the following lattice spaces (d) (unit: A): 7.32, 5.96, 5.04, 5.00, 4.90, 4.44, 4.23, 4.08, 3.79, 3.71, 3.66, 3.29, 3.14, 3.10, 2.98, 2.91, 2.82, 2.55, 2.50 Incidentally, the supernatant crystal filtrate and the acetone washing solution were concentrated, and the obtained residue was dissolved in ml of n-butase and then concentrated.箸 Decompression-3 0-This paper size applies to Chinese National Standards (CNS &gt; A4 size (210X297 mm) * ginseng I order (please read the notice on the back before filling this page) Central Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperatives 4 6CUUL · ^ 修 ίν ^ fi free h 86. 3. 25 A7 B7 V. Description of the invention (Knowledge and 1; heat the solution-entering agent to dissolve the fat to the alcohol Dry and dry to get the remaining substance and flow back to dissolve the hair. The hollow is really thin and then thin by borrowing m-2Λ 琳 § Tian (isBi residual gram of thioderm 3-so 4 1 '3 (05 t agent to I group) Get the base, neck S3 ο 3 and quality ί-the salt of acidic pure oil sulphur and chloroform flavones, separated into small ring when separated Layer W 1 Layer 2 ° m ffl, P ·-IR (net): 1 ^^ 1 1 6 5 3, 1 56 0, 1 1 50, 1 05 0 1 H-NMR (CDCla) 5ppui: 2.97 (s , 3H), 3.63 (t, 2H, J = 7.3Hz), 3.94 ~ 4.17 (®, 4H), 4.38.67 (m, 1H), 4.99 (iri, 1H). HCI (8) — ^ 1 1_--! 1 _1 I-IJ ^ III ---- I. \ ~~ Ψ -3 (Please read the notes on the back before filling out this page) Staff Consumption of the Central Bureau of Standards, Ministry of Economic Affairs Cooperative print (i) 700 mg of 3-Weiyi-1- (1,3-carazolin-2-yl) azetidine hydrochloride (8) obtained in Example 6 was dissolved in 15 ml of water and acetonitrile In a mixed solution of chloroform and chloroform, 1668 mg of p-nitrobenzyl (1R, -3 6-this paper size applies the Chinese National Standard (CNS) A4 specification (21 ο X 297 mm) A 6 through the central standard of the dripping department Printed by Bureau Coconut Consumer Cooperative A7 B7 V. Description of Invention (Shirt) 5R, 6S) -2- (Diphenylphosphino) -6- [(R) -Bulkylethyl] _Bumethyl-Shubi The 2-ene (em) -3-carboxylate (14) was added to the obtained solution. To the resulting solution, which was cooled with ice in a stream of m, 2,8 milliliter was added. f = isopropyl s ethylamine, and the resulting mixture was stirred at the same temperature S for 2 hours. Ethyl acetate was added to the reaction solution, and the resulting solution was washed with a saturated aqueous solution of sodium hydrogen oxalate and a saturated aqueous solution of sodium hydride, and evaporated to dissolve in a bin, and the obtained residue was subjected to silica gel_column layer. (Eluent: aeroform-propionate) and, as a result, 1339¾ g (yield: 92¾) of p-nitrobenzyl (lR, 5S, 6S) -2- [oxazoline-2-yl) azacyclo Butane-3-yl] sulfur-6-[(R) -butoxyethyl] -1-methyl-sulfobin-2-ene-3-carboxylic acid ester (15K 1 H-NMR (CDClj) 6 : 1.235 (d; 3H, J = 7.26Hz), 1.349 (d, 3H, J = 6.27Hz), 3.160 (quintet. 1H, J = 7.26Hz). 3.265 (dd, 1H, 0 = 2.3, 6.26Hz) , 3.367 (t. 2H, J = 7.26HZ). 3.898 ~ 4.038 (m, 4H), 4.071 ~ 4.147 (m, 1H), 4.212 ~ 4,278 (m, 2H &gt;), 4.372 (2H, J = 7.92Hr), 5.255 and 5.517 (d (AB), 2H, J = 13.85Hz), 7.665 (d, 2H, J = 8.58Hz), 8.226 (d, 2H, J = 8.58Hz) (ii) 1339 mg from the above reaction (i ) To a solution of the obtained compound (which was dissolved in 20 ml of tetrahydrofuran), 60 ml of 0.38K phosphate buffer solution (PH6.G) and 11.2 g of zinc powder were added, and the mixture was vigorously stirred for 2 hours. The reaction solution was filtered through Celite® to remove insoluble matter, and then the mash was adjusted to pH 5.5 after washing with ethyl acetate. Then, the resulting solution was concentrated under reduced pressure, and the concentrated solution was subjected to column chromatography. Diaion HP-40® (Mitsubishi -3 7-This paper size applies to Chinese National Standard (CNS) A4 specification U 丨 OX297 mm} ^-(Please read the notes on the back before filling in this I) • π A7 B7 V. Description of the invention (6) Chemical Corporation) Cracking) (Eluent: 5% aqueous solution of isopropanol, isopropanol) Isolation and purification, and therefore, 861 mg (yield: 87%) The desired (1!?, 53,65) -2- [1- (1,3 -__ line-2-yl) azetidin-3-yl] thio-6-[(R) -bu Hydroxyethyl] -p-methyl-sulfonyl-2-ene-3-carboxylate (16). 1 H-NMR (D2 0) δ: 1.093 (d. 3H, J = 6.93Hz), 1.207 (d, 3H, J = 6.27Hz), 3.05- 3.20 (m, 1H). 3.357 (dd, 1H, J = 2.3, 5.94Hz), 3.558 (t, 2H, J = 7.26Hz), 3.920 (t. 2H, J = 7.26Hz) 4.00 ~ 4.20 (m, 5H), 4.20 ~ 4.30 (m, 1H), 4.60 -4.70 (m. 1H) IR (KBr): 1740, 1640, 1590 cm &quot; 1 Example 1 5 (Please read the precautions on the back before filling this page) N— S—J (8) HC! ch3 cooh The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed 2.1 grams of the compound banknote obtained in Example 6 into 40 ml of digas methane and 20 ml of a 50% K 2 C 0 3 aqueous solution and Stir vigorously. The diazomethane layer was separated, dried over MgSh, and filtered. To this filtrate was added 600 mg of osmic acid and stirred. The resulting solution was concentrated under reduced pressure to obtain 2.34 g of the compound (17) as a pale yellow oil. 1 Η-NMR (CDC] 3) δ ppu: 2.0 3 (s, 3 Η), 3. 3 8 (t, 2 Η, J = 7 · 6 Η ζ), 3 '8 0 U, 1 Η ), 3. 9 4 (m, 2 Η), 4.03 (t, 2 Η, J = 7.6 Η 2), 4. 4 8 (m, 2 Η) IR (net): ϋ1 1652, 1612, 1361, 1258, 1008〇〇) α × ~ 3 8 _ This paper size applies to Chinese National Standards (CNS) A4 specifications (210 × 297 mm) 460446 ^ βΐ f] Mechanical charge 3. 25 A7 B7 V. Description of the invention ㈠1 ) Example 16 HC Obtained 0 gram of compound 11 2 0 0 8) Formula (1 cubes in the same phase and described the oil and color yellow light gram 8 3 3 3 9 9 7 0 3 1X 9 3 ΛΙΤ Η 1 w (. 9 7 II H 2 m / IV 1 5 ro 7 (5 2 2 11 IX 8, 2 7 8 0 3 * r * H 8, 3 ΤΛ Η 6 3 1 m2 (5 5 6 \ — / \ ly \ 1 / Η Η Η 2 2 2 ra Γ \ Gewei I 3's gains 6 cases of the formula described in the above description 1 · • Example color} Shi Wujing's test of I will be the month of thiazolium, a thiazide, a 3-state 1, Base knot (pure salt, pure acid, phosphonium salt, alkylated butyl ring, and heterocyclic nitrogen-丨 fruit wet removal in the middle of the room to change or not (please read the precautions on the back before filling this page) The goodness of Ding'an Storage 2 is an example. The implementation of this test is actually made in the prepared material room combined with borrowed materials under the method of loss measurement method. The official donated a towel U 4 6 1 1 / | \ Example of bacterial fungal method test XT / 1 ο method eln release 稀 diluent e based es culture aη training ap purpose 3 RH (J Qiong will use co-operative therapy According to et roots of Fang Xuezheng specimens cl ο S volume e rty 1 * 2 1 The first ue r M py of the he ot micro-test C test V contains 3 encapsulation-cultivation entities on the base. Liquid 3 lipid 1) Qiong 00 V—ί 9 Η 1 Μ / IV / (V The policy of the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs makes the package thinner than the liquid.) W Incubate SG liters ((B gelatin \ about each salt of the water cells, liquid, food, e) 10 I think that it is considered to be Γ) the basic degree te is enriched with an anion of P1 and the product ΓΟ is produced by 1C and micro (Π.) The test specimen was born for the test. The test was performed on the small I 8 object 1 when the cultivars were cultivated in the base of Chicha Yangguan. There was a degree of concentration in the test. 37 Concentration. The standard is the most fake, and the quality of the product is very strong. It is used to attach the TAA table to show the results of the fruit.) ¾ The size of this paper applies the Chinese national standard (CNS &gt; A4 specifications ( 210X25 · 7 mm &gt; 160 44 6, £ Yarn α Pain Right Muscle 3.2¾ A5 B5 IV. Abstract of Chinese Invention (Declaration: Thiozyme Compounds The present invention is related to the following formula Π) Shows the 3-mercapto-1- (1,3-Ka miles 2-yl) azetidine their acid addition salts, N s— &gt; and its preparation method, the above compounds are useful intermediates for the preparation of carbapenen compounds, which have high anti-g activity, convenience and high yield. Abstract of the invention in English (Name of the invention: THIOL COMPOUNDS I This invention relates to 3-mereapto-1- (1 I 3't hiazol in-2-y1)) azetidine represented by the fol-lowing formula and its acid addition salts --- -------- Installation ------ Order -------. (Please read the note on the back before filling in this page) Co-operative India N—i $ — and to the production process t hereto r. The above compounds are useful as intermediates for preparing carbapenem compounds, which have strong antibacterial activity, with convenience and high yield · This paper standard uses Chinese national standards (CNS &gt; A4 see the grid (210X297) 460 460446 Patent application scope A "9G)" M No. 841111) No. 4 ~ -disulfide-curtain-also compound patent (Amended on August 14, 1990) Λ Patent scope: 1 A method for preparing a compound represented by the following formula (I) or an acid addition salt thereof This method is characterized by reacting 2- (azetidin-3-ylthio) thiazoline p-N-S represented by the following formula (VI) with a monoacid. ° 〆 2. A method for preparing a compound of formula (I) or an acid addition salt thereof according to item 1 of the patent application, which is characterized in that 3-mercaptoazetidine represented by the following formula (VIII) HS (VIII) Reaction with a 2-substituted-1,3-thiazoline derivative represented by the following formula (V) (V) s · ^ -1