IE46675B1 - New thiazole compounds and processes for preparation thereof - Google Patents

Description

The present invention relates to compounds having the formula:- 1 i ί C-COOR3 <*> 0-R wherein R^ is amino, substituted or unsubstituted i I (lower) alkanamido or tritylamino; ί R is alkyl having 2 to 8 carbon atoms, cyclo-alkyl, », lower alkenyl having 2 to 6 carbon atoms, lower ; alkynyl having 2 to 6 carbon atoms, halo (lower) alkyl, carboxy (lower) alkyl or lower alkoxy carbonyl (lower) alkyl; R is hydrogen or lower alkyl; provided that when R is ethyl, isopropyl or allyl, then R is amino or unsubstituted (lower) alkanamido and 3 > R is hydrogen.

The thiazole compounds , of t)he present invention are useful as Intermediates in the preparation of the cephem and cepham compounds having the formula:- 4fe675 wherein R Is thiazolyl of the formula: in which R is amino or protected amino, 1) 11) A ie a group of the formula: -CM N 5 2 2 O-R in which R is hydrogen or an aliphatic hydrocarbon residue which may be substituted with halogen, carboxy or esterified carboxy, 6 R is hydrogen or lower alkyl, R? is hydrogen, halogen, lower alkyl or a group of 8 8 the formula:-O-R in which R ie hydrogen, loweri 1» alkyl or acyl, Is carboxy or functionally modified carboxy, and the dotted line represents 3-cephem and cepham nuclei, Inclusively, provided that R is hydrogen, halogen or a group of the formula! 8ft 6 -O-R in which R° is as defined above, when R is hydrogen, and R^ is lower alkyl, when R$ is lower alkyl. -346675 The cephem and cepham compounds described above are described and claimed in Patent Specification no. Jd'iDyc t The terms and definitions described in this specification and claims are illustrated as follows: a) Partial structure of the formula: -C-COOR3 Π N 2 0-R is intended to mean both of the geometric formulae: -C-COOR3 -C-COOR3 «• 7 7 w N-O-R and R-O-N (5) (A) The geometry of the formula (S j is referred to as syn" and another formula (A) is referred to as ’’anti.

Accordingly, one isomer of the compound having the partial structure shown by the ahove formula (S) is ^referred to as Msyn isomer and another isomer of the compound having the alternative one shown by the ahove formula (A) is referred to as anti isomer, respectively. (b) The thiazolyl group of the formula: 6 6 7 (wherein R1 is as defined above) is well known to lie in tautomeric relation with a thiazolinyl group of the formula · (wherein R is imino, substituted or unsubstituted lower alkanimido or trityliminoj.

The tautomerism between the said thiazolyl and thiazolinyl groups can be illustrated by the following equilibrium: HN 1 (wherein R and R are each as defined above).

Accordingly, it is to be understood that both of the said groups are substantially the same, and the tautomers consisting of such groups are regarded as the same compounds, especially in the manufacturing chemistry. Therefore, both of the tautomeric forms of the compounds having such groups in their molecule are included in the scope of this invention and designated inclusively with one expression ’’thiazolyl" and represented (by the formula: (wherein R1 is as defined above) only for the convenient sake throughout this specification and claims.

In the above and subsequent descriptions of this specification, suitable examples and illustration of the various definitions which this invention intends to include within the scope thereof are explained in detail as follows 6 6 7 5 The term lower is used to intend a group having 1 to 6 carbon atoms, unless otherwise provided.

Alkyl may include a residue of straight or branched alkane having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, hexyl, heptyl and octyl, preferably lower alkyl, i.e. alkyl having from 1 to 6 carbon atoms, and more preferably one having 1 to 4 carbon atoms.

Lower alkenyl may include a residue of a straight 2q or branched alkene having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and hexenyl, and preferably one having from 2 to 4 carbon atoms.

Lower alkynyl may include a residue of a straight or branched alkyne having 2 to 6 carbon atoms, such as ethynyl, propargyl, 1-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-pentynyl, 1-pentynyl and 5-hexynyl, and preferably one having from 2 to 4 carbon atoms.

Cycloalkyl may include a residue of a cycloalkane 2θ having from 3 to 8 carbon atoms, preferably lower cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyi and cyclohexyl, and more preferably cyclohexyl.

Suitable examples of the halogen of halo(lower)alkyl may include chlorine, bromine, iodine and fluorine. ' Preferred examples of the halo(lower)alkyl may be chloromethyl, bromomethyl, iodomethyl, fluoromethyl, trichloromethyl, trifluoromethyl, 2-chloroethyl, 1,2-dichloroethyl, 2,2,2-trifluoroethyl, 3-chloropropyl, 4-iodobutyl, 5-fluoropentyl or 6-bromohexyl. 3q Preferred examples of the carboxy(lower)alkyl may be carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1-carboxyisopropyl, 1-ethyl-l-carboxy/ 6 6 7 5 ethyl or 2-methyl-2-carboxypropyl.

Preferred examples of the lower alkoxycarbonyl (lower)- alkyl may be methoxycarbonylmethyl, ethoxycarbonyImethyl, propoxycarbonylmethyl, t-butoxycarbonyl5 methyl, 2-ethoxy-carbonylethyl, 2-ethoxycarbonylpropyl, 4- ethoxycarbonylbutyl, 1-t-butoxycarbonylisopropyl, i-t-butoxycarbonyl-i-methyl-propyl, 4-t-butoxycarbonylbutyl, - t-butoxycarbonylpentyl or 6-butoxycarbonylhexyl, and preferably lower alkoxycarbonyl-inethyl. Ιθ When R is a lower alkyl, as defined above, it is preferably one having from 1 to 4 carbon atoms.

"Halogen"for X may be chlorine, bromine, iodine or fluorine. Preferably X is chlorine or bromine.

Examples of the substituted or unsubstituted 15 lower alkanoyl" of the substituted or unsubstituted (lower) alkanamido include formyl,acetyl, chloroacetyl or trifluoroacetyl. 466*75 The compound (I) can be prepared as illustrated below X-CH,CO-C-COOZ L I N OH (Ia) R -C-NH, a , 2 s (Ila) N-pC-COOZ (Ic) X-CH^CQ-C-COOZ N Ϊ 2 0-Rz (Ib) R*-C-Nh2 (na) XJ J OH H.N-C-NH j, 2 S (Id) C-COOZ (Ie) Ra 'S C-COOH (If) ί 2 0-RzN- --,--C-COOH N ί 2 0-Rz (Ig) V0NH2 N—-Γ--C-CO°H (Ih) 6 6 7 5 wherein R is alkyl having 2 to 8 carbon atoms, cycloalkyi, lower alkenyl having 2 to 6 carbon atoms, lower alkynyl having 2 to 6 carbon atoms, halo(lower) alkyl, carboxy(lower)alkyl or lower alkoxycarboxyl· (lower)alkyl, R1 is substituted or unsubstituted(lower)alkanamido or tritylamino, X is halogen and Z is lower alkyl.

Each of the above processes are explained in the following.

Process 1 : Etherification The compound (Ib) and (Id) can be prepared by reacting a compound (la) or (lc) with an etherifying 15 agent, respectively.

Suitable examples of the etherifying agent may include a conventional alkylating agent such as dialkyl sulfate (e.g. dimethyl sulfate, diethyl sulfate), diazoalkane (e.g..diazomethane, diazoethane), alkyl halide (e.g. methyl iodide, ethyl iodide, ethyl bromide), alkyl sulfonate (e.g. methyl tosylate), the corresponding lower alkenylating-, lower alkynylating-, cycloalkylating halo(lower^alkylating-, carboxy(lower)alkylating or lower alkoxycarbonyl(lower)alkylating-agent, for example, lower alkenyl halide (e.g. allyl iodide), lower alkynyl halide (e.g. propargyl bromide), cycloalkyl halide (e.g. cyclohexyl bromide), and lower alkoxycarbonyl(lower)alkyl halide (e.g« ethoxycarbonylmethyl iodide.

In case of using diazoalkane as an etherifying agent, the reaction is usually conducted in a solvent such as diethyl ether, dioxane or any other solvent which does not adversely influence the reaction, at a temperature within 46678 a range of cooling to an ambient temperature.

In case of using the other etherifying agent, the reaction is usually conducted in a solvent such as water, acetone, ethanol, diethyl ether, dimethylformamide or any other solvent which does not adversely influence the reaction within a temperature range of cooling to heating, preferably in the presence of a base such as an inorganic or organic base, suitable examples of which include an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate), alkali metal bicarbonate (e.g..sodium bicarbonate, potassium bicarbonate), alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate) or alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate, dipotassiura hydrogen phosphate), and an organic base such as alkali metal acetate (e.g. sodium 20 acetate, potassium acetate), trialkylamine (e.g. trimethylamine, triethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo/^,3,07-5-nonene, 1,4-diazabicyclo/j2,2,2/octane, or 1.5-diazabicyclo/5~.4.j?7-7undecene or anion-exchange resin.

Process 2 : Thiazole ring formation The compound (Ic) and (Id) can be prepared by reacting a compound (Ia) or (Ib) with a thiourea compound (Ila), respectively, and further the compound (Ie) can be prepared by reacting a compound (Ib) with thiourea.

The reaction is usually conducted in a solvent such as water, alcohol (e.g. methanol, ethanol), benzene dimethylformamide, tetrahydrofuran or any other solvent which does not adversely influence the reaction within a a temperature range of an ambient temperature to heating.

Process 3 : Elimination of substituted or unsubstituted lower alkanoyl or trityl for jThe compound (Ie) and (Ig) can be prepared hy subjecting a compound (Id) or (If) to elimination reaction of substituted or unsubstituted lower alkanoyl or trityl in substituted or unsubstituted lower alkanamido or trltylamino group for R1, S respectively.

The elimination reaction may be conducted in accordance with a conventional method such as hydrolysis or reduction, ι These methods may be selected according to tbe kind of the protective group to be eliminated.

The hydrolysis may include a method using an acid (acidic hydrolysis), a base (basic hydrolysis) or hydrazine.

Among these methods, hydrolysis using an acid is one of the common arid preferable methods for eliminating substituted or unsubstituted lower alkanoyl, particulars of vdiich are to be referred to those as illustrated for the N-protective group, respectively.

Suitable acid to be used in this acidic hydrolysis may include an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesuifonic acid, pI toluenesulfonic acid, hydrochloric acid and cation-exchange resin. Preferable acid is the one which can be easily separated out from the reaction product by a conventional manner such as neutralization or distillation under reduced pressure, for example, formic acid, trifluoroacetic acid or hydrochloric acid. The acid suitable for the reaction can be selected in consideration of tbe chemical property of the starting compound and the product as well as the kind of the protective group to be eliminated. The acidic hydrolysis can be conducted in the presence or absence of 46675 of a solvent.

The hydrolysis using hydrazine can be applied for eliminating the protective group such as a dibasic acyl group, for example, a succinyl group.

The reduction can be applied for eliminating trityl.

Suitable reduction may include, for example, reduction using an alkali metal borohydride (e.g. sodium borohydride^ or conventional catalytic hydrogenolysis.

The reaction temperature is not critical and may be 10 optionally selected in consideration of the chemical property of the starting compound and reaction product as well as the kind of the N-protective group and the method to be applied, and the reaction is preferably carried out under mild conditions,such as under cooling, 15 at ambient temperature or slightly elevated temperature.

Process 4 : Carboxy formation The compound (If) and (lg) can be prepared by transforming the esterified carboxy group of a compound (Id) or (le) into free carboxy group, respectively. 2o The method to be applied to this process includes conventional ones such as hydrolysis.

The method of hydrolysis includes a conventional one using an acid, base, enzyme or enzymatic preparation.

Suitable examples of the acid and base are to be referred to those as exemplified in the above Process 3, and the acidic or basic hydrolysis can be carried out in a similar manner to that of the Process 3.

Process 5 : Oximation The compound (If) can be also prepared by reacting 30 a compound (Ih) with a hydroxylamine derivative (III) or its salt.

The hydroxylamine derivative (III) may be hydroxylamine substituted with alkyl having 2 to 8 carbon atoms, cycloalkyl, lower alkenyl having 2 to 6 carbon atoms, ' i2 4667S lower alkynyl having 2 to 6 carbon atoms, halo(lower)alkyl, carboxy(lower)alkyl or lower alkoxycadbotnyl (lower )alkyl, particulars of which are to be referred to those as exemplified before. Suitable salt of the hydroxylamine derivative (III) may be hydrochloride, hydrobromide or sulfate.

The reaction is usually conducted in a conventional solvent such as water, alcohol, tetrahydrofuran, acetonitrile, dimethylsulfoxide, pyridine or any other solvent which does not adversely, influence the -reaction, or a mixture thereof, and the reaction temperature is not critical.

In case that a salt of the hydroxylamine derivative (III) is used as a reagent, the reaction is preferably conducted in the presence of a conventional base.

Following examples are given only for explaining this invention in.more detail.

Example 1 (1) Pulverized potassium carbonate (160 g.) was addec to a solution of ethyl 2-hydroxyiminoacetoacetate (a mixture of syn and anti isomers) (152 g.) in acetone (500 ml.).

Dimethyl sulfate (130 g.) was.dropwise added thereto with stirring over 1 hour at 45 to 50°C and the mixture was stirr for 2 hours. An insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The filtered insoluble material was dissolved in water (500 ml.) and this solution was added to the residue. The mixture was extracted twice with ethyl acetate (300 ml.). The extraci was washed twice with water ( 200 ml.) and with a saturated sodium chloride aqueous solution (200 ml.) and dried over ΐ magnesium sulfate. The solvent was distilled off under reduc pressure and the residue was distilled under reduced pressure to give colorless oil of ethyl 2-methoxyiminoacetoacetate5 (a mixture of syn arid anti isomers) (145.3 g.), bp 55 to 64°C/O. mm Hg.

I.R. vFllm : 1745, 1695, 1600 cm'1 max N.M.R. δ ppm (CDC13): 4.33 (4H, q, J=8Hz) 4.08 (3H, s), 3.95 (3H, s), 25 2.40 (3H, s), 1.63 (3H, s), 1.33 (6H, t, J=8Hz) ; (2) Sulfuryl chloride (235 ml.) was dropwise added, over 20 minutes with stirring and ice-cooling to a solution of ethyl 2-methoxyiminoacetoa:cetate (syn isomer) (500 g.) in acetic acid (500 ml.), and the mixture was stirred overnight under cooling with water. Nitrogen gas was 6675 introduced to the reaction mixture for 2 hours, and the resulting mixture was poured into water (2.5 I.) After extracting with methylene chloride (500ml.) and twice with methylene chloride (200 ml.), the extracts were combined. The combined extract were washed with a saturated aqueous solution of sodium chloride, and adjusted to pH 6.5 by adding water (800 ml.) and sodium bicarbonate. Methylene chloride layer was separated, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give ethyl 2-methoxyimino-4chloroacetoacetate (syn isomer) (559 g.).

I.R. v Film : 1735, 1705 cm1 max (3) Ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (50 g.) was added over 3 minutes with stirring at ambient temperature to a solution of thiourea (18.4 g.) and sodium acetate (19.8 g.) in a mixture of methanol (250 ml.) and water (250 ml.). After stirring for 35 minutes at 40 to 45°C, the reaction mixture was cooled with ice and adjusted to pH 6.3 with a saturated aqueous solution of sodium bicarbonate. After stirring for 30 minutes at the same temperature, precipitates were collected by filtration, washed with water (200 ml.) and then with diisopropyl ether (100 ml.), and dried to give colorless crystals of ethyl 2-methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetate (syn isomer) (37.8 g.), m.p. 161 to 162°C.

I.R. v Nujol . 34θ0, 33OO, 315O, 1725, 163O/ max , 1559 cm·*· N.M.R. ppm : 6.72 (IH, s), 5.91 (2H, broad s), 4.38 (2H, q, J=7Hz), 4.03 (3H, s), 1.38 (3H, t, J=7Hz) (4) Ethanol (10 ml.) was added to a suspension of ethyl 2-methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetate (syn isomer) (2.2 g.) in a IN aqueous solution of sodium hydroxide (12 ml.) and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid and ethanol was distilled off under reduced pressure. The residual aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acid and stirred under ice-cooling to precipitate10 crystals. The crystals were collected by filtration, washed with acetone and recrystallized from ethanol to give colorless needles of 2-methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetic acid (syn isomer) (1.1 g.) (Nu3o1 · 3150, 1670, 1610, 1585 cm' max N.M.R.

A (d,-DMSO) ppm 6 6.85 (IH, : 7.20 (2H, broad s), s), 3.83 (3H, s) Example 2 (1) Sulfuryl chloride (35.2 g.) was added all at once to the stirred solution of ethyl 2-ethoxyimino-3-oxobutyrate (syn isomer, 48.2 g.) in acetic acid (49 ml.) at room temper5 ature, and stirred at the same temperature for an hour. After adding the resultant 'solution into water (200 ml.), the solution was extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, neutralized with ah aqueous solution of sodium bi10 carbonate and washed with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure to give ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer, 53.8 g.), pale yellow oil. (2) A mixture of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer 38.7 g.), thiourea (13.2 g.) , sodium acetate (14.3 g.), methanol (95 mlj and water (95 ml) was stirred at 48°C for 40 minutes. After the resultant solution was adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate, the appeared precipitates were collected by filtration and washed with diisopropyl ether to give ethyl 2-(2-amino-4-thiazolyl)2-ethoxyiminoacetate· (syn isomer, 14.7 g.) , mp 130 to 131°C.

I.R. vNU3°L :3450, 3275, 3125, 1715, 1620 cm1 max 46673 (3) Ethyl 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetate (syn Isomer, 5 g.) was added to a mixture of IN sodium hydroxide (45.9 ml.) and ethanol (30 ml.) and stirred at room temperature for 5 hours. After removing ethanol from tho resultant solution under reduced pressure, the residue was dissolved in water (60 ml.) and adjusted to pH 2.0 with 10% hydrochloric acid. The solution was subjected to salting-out, and the precipitates were collected by filtration and dried to give 2-(2-amino-4-thiazolyl)10 2-ethoxyiminoacetic acid (syn isomer, 2.9 g.).

I.R. vNu3o1 : 3625, 3225 (shoulder), 3100, maX 1650, 1615 cm1 N.M.R.Sppm (DMSO-dg) : 1.20 (3H, t, J=7Hz), -..... - 4.09 (2R-; q, J=7Hz) , 6.82 (IH, s) , 7.24 (2H; broad s) (4) 2·^ (2-Aminothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 100 g.), formic acid (85.5 g.) and acetic anhydride (190.1 g.) were treated in a similar manner to that of Example 5 - (5) to give 2-(2-formamidothiazol-4-yl)2-ethoxyimin0acetic acid (syn isomer, 99.1 g.).

I.R. vNu3Ql : 3200, 3140, 3050, 1700 cm1 max N.M.R.δ(DMSO-dg, ppm) : 1.18 (3H, t, J=6Hz)> 4.22 (2H, q, J=6Hz), 7.56 V (IH, s), 8.56 (IH, s), 12.62 (IH, broad s) ! ί Example 3 (1) To a suspension of ethyl 2-hyroxyiminor-3-oxobutyrate (syn isomer, 15 g.) and potassium carbonate (19,8 g.) in acetone (75 ml.) was added dropwise propyliodide (16.2 g.) with stirring, and the mixture was stirred at ambient temperature for 1.5 hours. The Insoluble substance was collected by filtration and washed with acetone. The washings and the filtrate were combined and evaporated to dryness under reduced pressure. To the resultant residue was added water and the aqueous solution was extracted twice with chloroform. The extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure to give ethyl 3-oxo-2-pr0poxyiminobutyrate (syn isomer, 15.4 g.), oil. (2) Ethyl 3-oxo-2*propoxyiminobutyrate (syn isomer, 15.4 g.) and sulfuryl chloride (10.6 g.) were dissolved in acetic acid (15.4 ml.), warmed at 35 to 40°C for 10 minutes with stirring and , then starred at ambient temperature for additional 6 hours. The reaction mixture was poured into ice-water (200 ml.) and the resultant mixture was extracted : twice with chloroform. The extract was washed with an aqueous solution of sodium chloride, twice a saturated aqueous solution of sodium bicarbonate and once with water in turn, dried over magnesium sulfate, and then evaporated to dryness Under reduced pressure to give ethyl 4-chloro3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), oil.

I.R. vFilm : 1740, 1710, 1695, 1455 cm1 max i. ν · 4667« (3) Ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate (syn isomer, 15^ g.) , thiourea (4.97 g.) and sodium acetate hydrate (8.&9 g.)were dissolved in a mixture of water (40 ml.) ethanflH^TSd^ jnl.) , and stirred at 40°C for an hour.

The reaction mixture was adjusted to pH 6.5 with a saturated aqueous solution of potassium carbonate under cooling and stirred at the same temperature for half an hour. The precipitating crystals were collected by filtration, washed with water and diisopropyl ether, and then dried to give crystalline ethyl 2- (2-amino-4-thiazolyl)-2?-propoxyiminoacetate (syn isomer , 10.55 g. ) , mp 142. - 144°C. ,..

R~. Nujol . 346Q, 326Oi 3120, 1720, 1620, max 1540 cm"1 N.M.R δ ppm (dg-DMSO) : 0.88 (3H, t, J=7Hz), 1.27 (3H, t, J=6Hz), 1.60 (2H, sextet, J=7Hz), 4.04 (2H, t, J=7HZ ), 4.28 (2H, q, J=6Hz), 6.86 (IH, s), 7.23 (2H, s) (4) A solution of ethyl 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetate (syn isomer, 10 g.) in a mixture of tetrahydrofuran (39 ml.), methanol (39 ml.) and IN sodium hydroxide (75.8 ml.) was stirred at 35 to 40°C for 5 hours.

After the resultant solution was concentrated under reduced pressure, the aqqeous residue was adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates were collected by filtration and dried to give 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetic acid (syn isomer, 6.2 g.), mp 161°C (dec.) I.R.

N.M.R. , Νυ3θ1: 3380, 3120 (broad), 1630, maX 1610, 1460 -cm"1 ppm (DMSO-dg): 0.89 (3H, t, J=7Hz), 1.63 (2H, sextet, J=7Hz), 4.05 (2H, t, J=7Hz), 6.83 (IH, s), 6.9 - 8.8 (3H, broad) (5) 2-(2-Aminoth±azol-4-yl)-2-n-propoxyiminoacetic acid (syn isomer, 21.8 g.), acetic anhydride (38.8 g.) and formic acid (17.5 g.) were treated in a similar manner to that of Example 5 -(5), and then the obtained oil was triturated with diisopropyl ether to give 2-(2-formamidothiazol-4-yl)-2-npropoxyiminoacetic acid ( syn isomer, 19.2 g.), mp. 164°C (dec.). i I.R. v Nuio1 : 3200, 3120, 3050, 1700, max ,--- -l 1550 cm N.M.R. 6(DMS0-dg, ppm): 0.92 (3H, t, J=7Hz), 1.67 (2H, sextet, J=7Hz), 4.12 (2H, t, J=7Hz), 7.53 (IH, s), 15 8.54 (IH, s) Example 4 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 30 g.), iso-p.ropyl iodide (32.5 g.) , potassium carbonate (39.5 g.) and acetone (150 ml.) were treated in a similar manner to that of Example 3 -(1) to give ethyl 2-iso-propoxyimino-3-oxobutyrate (syn isomer, 35.4 g.), oil.

I.R. υ "χ : 1745> 1690, 1600 cm N.M.R 6(CC14, ppm):,1.33 (3H, t, J=7Hz), 1.35 (6tf, d, J=6Hz), 2.32 (3H, s), 4.1M.7 (3H, m). (2) Ethyl 2-iso-propoxyimino-3-oxobutyrate (syn isomer .4 g.), sulfuryl chloride (24.5 g.) and acetic acid (35.4 ml.) were treated in a similar manner to that of Example 3(2) to give ethyl 4-chloro-3-oxo-2-iso-propoxyiminobutyrate (syn isomer, 41.5 g.), oil-. (3) I'.R. : 1745, 1715, 1375 cm1 IUclX .

Ethyl 4-chi0ro-3-axo*-2-iso-propoxyiminobutyrate (syn isomer, 41.5 g.), thiourea (13.4 g.) , sodium acetate (14.4 g.), water (110 ml.) and ethanol (110 ml.) were treated in a similar manner to that of Example 3 -(3) to give ethyl 2-(2, , aminothiazol-4-yl)-2-iso-propoxyiminoacetate (syn isomer, 27.3 g.), mp. 162 to 164°C.

I.R. v : 34-60/ 3430, 3260, 3150, 1725, 1615 IuaX η 1540 cm N.M.R. 6(DMSO-dg, ppm): 1.17 (6H, d, J=6Hz), 1.24 (3H, t, J=7Hz), 4M.7 (3H, m), 6.86 (IH, s), 7.24 (2H, s) 6 6 7 5 (4) Ethyl 2-(2-aminothiazol-4-yl)-2-iso-propoxyiminoacetate (syn isomer, 26.8 g.) , IN aqueous| solution of sodium hydroxide (156 ml.), methanol^(156 ml.) and tetrahydrofuran <100 ml,) were treate&in a Similar manner to that of Example 3-(4) to give 2-(2-amOothiazol-4-yl) -2-iso-propoxyiminoo acetic acid (syn is'omer, 15.3 g.), mp. 151 C (dec.).

I.R. v Nujol ' max 3610, 3580, 3080, 1650, 1610 cm -i N.M.R., g, ppm) : 1.22 (6H, d, J=6Hz) , 4.33 (IH, quintet, J=6Hz) , 6.80 (l.H, s) , 7.22 (2H, broad s) (5) 2-(2-Aminothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 4 g.), acetic anhydride (7.6 g.) and formic acid (3.4 g.) were treated in a similar manner to that of Example 5-(5) to give 2- (2-formamidothiazol-4-yl) -2-isopropoxyiminoacetic acid (syn isomer, 3.75 g.j, mp. 168 to 169°C (dec.).

I.R. ν Nujo1: 3200, 3130, 1710, 1600, 1560 cm1 max N.M.R. 0(DMS0-dg, ppm) : 1.26 (6H,d) , 4.4 (IH,.m) , 7.54 (IH, s), 8.52 (IH, s), 12.56 (IH, broad s) 46678 Example 5 (1) η-Butyl iodide (46.9 g.) was added dropwise to a stirred suspension of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), potassium carbonate (52.7 g.) and acetone (200 ml.) under ice-cooling over 5 minutes, and stirred at room temperature for 4 hours. The resultant solution was filtered, and washed with acetone. The filtrate and washing solution were combined together and concentrated in vacuo. After;adding water (300 ml.) to the residue, the solution was extracted with methylene chloride three times. The solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-nbutoxyimino-3-oxobutyrate (syn isomer, 48.8 g.), oil.

I.R. υ max : 1750' 1700' 1470' 1370' 1320 cm I (2) A solution of ethyl 2-n-butoxyimino-3-oxobutyrate (syn Isomer, 48.8 g.), sulfuryl chloride (31.5 g.) and 2o acetic acid (48.8 ml.) was stirred at 40°C for 10 minutes and further at room temperature for 5.5 hours. After water (300 ml.) was added to the resultant solution under ice cooling, the solution was extracted with methylene chloride three times. The extract was washed with water, an aqueous solution of sodium bicarbonate ahd a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. The solution was- concentrated in vacuo to give ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 52.1 g.), oil.

I.R.

Film max 1740, 1710, 1470, 1370 cm' 466 75 (3) A solution of ethyl 2-n-butoxyimino-4-chloro-3oxobutyrate (syn isomer, 52.1 g.), thiourea (15.9 g.), sodium'acetate,3 hydrate (28.4 g.) , water (130 ml.) and ethanol (180 ml.) was stirred at 40°C for 1.25 hours.

The resultant solution was adjusted to pH 6.5 with an aqueous solution of sodium carbonate under ice cooling, and stirred for 20 minutes under ice cooling. The precipitates were collected by filtration, and washed with water and diisopropyl ether in turn to give ethyl 2-(2-aminothiazol10 4-yl)-2-n-butoxyiminoacetate (syn isomer, 36.1 g.), mp 126 to 128°C.

I.R. ν ^°1 5 3460' 3370' 1550 cm1 3230, 1720, 1620, N.M.R. 6(DMS0-dg, ppm) : 0.6 - 2.0 (6H, m), 1.28 (3H, t, J=7Hz), 4.12 (3H, t, J=6Hz)7 4.31 (2H, q, J=7Hz), 6.89 (IH, s), j,. 7.24 (2H, S) (4) A solution of ethyl 2-(2-aminothiazol-4-yl)-2-nbutoxyiminoacetate (syn isomer, 36 g.), methanol (133 ml.), tetrahydrofuran (133 ml.) and 2N aqueous solution of sodium hydroxide (133 ml.) was stirred at 30°C for 5 hours. After the resultant solution was concentrated in vacuo, the residue was dissolved in water. The solution was adjusted to pH 7 with 10% hydrochloric acid and treated with activated charcoal. The solution was adjusted to pH 2.0 with j % hydrochloric acid and stirred for lo minutes under ice i cooling. The precipitates were collected by filtration, washed with water and acetone in turn, and dried to give 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetic acid (syn isomer, 25.4 g.).

I.R. V max°1: 3325' 3190» 1660, 1620 cm1 N.M.R. δ (DMSO-dg, ppm) : 0.88 (3H, t, J=7Hz), 1.0-1.9 (4H, m), 4.06 (2H, t, J=7Hz), 6.81 (IH, s), 7.21 (2H, broad s) {5) Formic acid (18.95 g.) was added dropwise to acetic anhydride (42.0 g.) under stirring at room temperature over 5 minutes, and stirred at 50°C for an hour. 2-(2-Aminothiazol10 4-yl)-2-n-butoxyiminoacetic acid (syn isomer, 25 g.) was added to the solution under ice cooling, and stirred at room temperature for 3 hours and additionally at 30°C for an hour. After concentrating the resultant solution in vacuo, the residue was dissolved in diethyl ether. The solution was washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo. The obtained oil was triturated with a solution of n-hexane (1 part) and diisopropyl ether (1 part), and collected by filtration to give 2-(2-formamidothiazol-4-yl)20 2-n-butoxyiminoacetic acid (syn isomer, 20.1 g.).

I.R. 3350, 3160, 3050, 1700, 1680, IuclX 1570 cm N.M.R. 6(DMS0-dg, ppm) : 0.91 (3H, t, J=6Hz), 1.0 - 2.2 (4H, m), 4.18 (2H, t, J=6Hz), 7.57 (IH, s), 8.59 (IH, s), 12.66 (IH, broad s) Example 6 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, g.), N,N-dimethylformamide (200 ml.), potassium carbonate (52.7 g.) and iso-butyl bromide (34.94 g.) were treated in a similar manner to that of Example 5-(1) to give ethyl 6 6 7 5 2-iso-butoxyimino-3-oxo-butyrate (syn isomer, 42 g.).

! I ' 1 ’ I.R. . ^3°1 : 1740, 1670 (broad) cm-1 . (2) Ethyl 2-iso-butoxyimino-3-oxobutyrate (syn isomer, g.), acetic acid (42 ml.) and sulfuryl chloride (27.1 g.) were treated in a similar manner to that of Example 5-(2) to give ethyl 2-iso-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 31.9 g.). l-R- : 1750, 1720, 1680 cm1 (3) Ethyl 2-iso-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 31.9 g.), thiourea (9.72 g.), sodium acetate 3-hydrate (17.4 g.), ethanol (120 ml.) and water (80 ml.) were treated in a similar manner to that of Example 5-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetate (syn isomer, 17.6 g.), mp 122 to 124°C.

I.R. v^301 ί 3470, 3260, 3120, 1730, 1620, 1545 cm-1 N.M.R. <5 (DMSO-dg, ppm) : 0.86 (6H, d, J=7Hz), 1.28 (3H, t, J=7Hz), 1.6-2.2 (IH, m) , 25 3.86 (2H, d, J=7Hz), 4.28 (2H, q, J=7Hz), 6.86 (IH, s), 7.22 (2H, s) (4) Ethyl 2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetate (syn isomer, 19.6 g.), 2N aqueous solution of sodium hydroxide (72.2 ml.), methanol (72.2 ml.) and tetrahydrofuran (72.2 ml.) were treated in a similar manner to that of Example 5-(4) to give 2-(2-aminothiazol-4-yl)-2-isobutoxyiminoacetic acid (syn isomer, 16.1 g.), mp 180°C (dec.). ν^3θ1 : 3375, 3300, 3130, 3050, 164-0 cm1 max δ(DMSO-dg, ppm) : 0.91 (6H, d, J=7Hz), 1.5-2.3 (IH, m), 3.90 (2H, d, J=7Hz), 6.87 (IH, s), 7.26 (2H, broad s) I.R.

N.M.R. (5) i 2-(2-Aminothiazol-4-yl)-2-iso-butoxyiminoacetic acid (syn isomer, 11.5 g.), acetic anhydride .(19.3 g.) and formic acid (8.7 g.) were treated in a similar manner to that of Example 5-(5) to give 2-(2-formamidothiazol-4-yl)2-iso-butoxyiminoacetic acid (syn isomer, 11.15 g.), mp 163CC (dec.).

I.R.

N.M.R.

Nujol max 3175, 3110, 3050, 1695, 1550 cm δ (DMSO-dg, ppm) : 0.91 (6H, d, J=7Hz), 1.7-2.3 (IH, m), 3.92 (2H, d, J=7Hz), 7.52 (IH, s), 8.52 (IH, s) , 12.58 (IH, broad s) Example 7 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 30 g.) , Ν,Ν-dimethylformamide (100 ml.), potassium carbonate (39.5 g.) and cyclohexyl bromide (31.1 g.) were treated in a similar manner to that of Example 5-(1) to give ethyl 2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 41.8 g.), oil.

I.R.

Film max 1740, 1680 cm (2) Ethyl 2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 41.3 g.), acetic acid' (41.3 ml.) and sulfuryl chloride (23.8 g.) were treated in a similar manner to that of Example ; 5-(2) to give ethyl 4-chloro-2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 27.8 g.), oil.

I.R. υ F1£m : 1745' 1715< 1680 cm"1 30 max (3) Ethyl 4-chloro-2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 27.8 g.), thiourea (7.7 g.), sodium acetate 3-hydrate (13.7 g.), water (70 ml.) and ethanol (140 ml.) were treated in a similar manner to that of Example 5 (3) to give ethyl 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetate (syn isomer, 3.6 g.), mp. 125 to 126°C.

I I.R.

Nujol max I : 3430/ 3250, 3160, 3130, 1715, 1635 cm 1 N.M.R. 5(DMSO-dg, ppm) : 1.28 (3H, t, J=7Hz), 1.0^2.2 (10H, m), 4.22 (IH, m), 4.32 (2H, q, J=7Hz), 6.88 (IH, s) , 7.24 (2H, broad s) (4) Ethyl 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetate (syn isomer, 3.5 g.), 2N aqueous solution of sodium hydroxide (11.8 ml.), methanol (11.8 ml.) and tetrahydrofuran (11.8 ml.) were treated in a similar manner to that of Example 5 -(4) to give 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 2.1 g.), mp. 148°C (dec.).

I.R.

N.M.R.

Nujol max 3110, 1630, 1450 cm δ(DMSO-dg, ppm) : 0.8^2.3 (10H, m), 4.14 (IH, m), 6.86 (IH, s), 7.5 (2H, broad s) (5) 2—(2-Aminothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 1.5 g.), acetic anhydride (2.27 g.) and formic acid (1.03 g.) were treated in a similar manner to that of Example 5 (5), and the oil obtained was suspended in an aqueous solution of sodium bicarbonate. The suspension was adjusted to pH 3.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 2-(2-formamidothiazol-4-yl)-2-cyclo hexyloxyiminoacetic acid (syn isomer, 1.0 g.), mp. above 23O°C.

I.R. υ ^°1 -- 3175, 3100, 3060, 1680 cm1 ΠΙαΧ Example 8 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 56.7 g.), N,N-dimethylformamide (280ml.), potassium carbonate (72.3 g.) - and propargyl bromide (43 g.) were treated in a similar manner to that of Example 5 (1) to give ethyl 2-propargyloxyimino-3oxobutyrate (syn isomer, 71.2 g.).

I.R.

Film max 3280, 3220, 2120, 1735, 1670 cm (2) Ethyl 2-propargyloxyimino-3-oxobutyrate (syn isomer, 71.2 g.), acetic acid (81 ml.) and sulfuryl chloride (50.2 g.) were treated in a similar manner to that of Example 5-(2) to give ethyl 4-chloro-3-oxo-2-propargyloxyiminobutyrate (syn isomer, 61.6 g.), oil.

I.R.

Film max 3300, 2130, 1745, 1720, 1675 cm N.M.R. 6(CC14, ppm) : 1.39 (3H, t, J=7Hz), 2.57 (IH, t, J=2Hz), 4.36 (2H, q, J=7Hz), 4.56 (2H, s), 4.86 (2H, d, J=2Hz) (3) Ethyl 4-chloro-3-oxo-2-propargyloxyiminobutyrate (syn isomer, 61 g.), thiourea (20 g.), sodium acetate 3-hydrate (35.8 g.), water (150 ml.) and ethanol ( 180 ml.) were treated in a similar \manner to that of Example 5-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 35.6 g.). \ I.R. max01 : 3290' 2220' 1729 01,-1 N.M.R. δ;(DMSO-dg, ppm) : 1.28 (3H, t, J=7Hz), 3.49 (IH, t, J=3Hz), 4.31 (2H, q, J=7Hz), 4.76 (2H, d, J=3Hz), / \ 6.95 (IH, s), 7.29 (2H, s). / Lnbt (4) Ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 2.8 g.), methanol (23 ml.), tetrahydrofuran (20 ml.) and IN aqueous solution of sodium hydroxide (22.17 ml.) were treated in a similar manner to that of Example 5-(4) to give 2^- (2-aminothiazol-4-yl) -2-propargyloxyiminoacetic acid (syn isomer, 1.924 g.).

I.R.

V Nujol max 2190, 1740 N.M.R. fi (DMSO-d , ppm) : 3.47 (IH, t, J=1.5Kz), 4.74 (2H, d, J=1.5Hz), 6.90 (1H, s) Example 9. ί (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), Ν,Ν-dimethylformamide (200 ml.), potassium carbonate (52 g.) and n-hexyl bromide (41.4 g.) were treated in a similar manner to that of Example 5-X1) to give ethyl 2-n-hexyloxyimino-3-^oxobutyrate (syn isomer, 60.7 g.), oil.

I.R. υ Fllm : 1740, 1705, 1700 cm1 N.M.R. fi(CCl4, ppm): 0.6^2.1 (14H, m), 2.37 (3H, s), 4.1-4.6 (4H, m) (2) Ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn isomer, 60.7 g.), acetic acid (61 ml.) and sulfuryl chloride (34.7 g.) were treated in a similar manner to that of Example 5-(2) to give ethyl 2-n-hexyloxyimino-4"Chloro-3-oxobutyrate (syn isomer, 55.6 g.).

I.R.

V Fllm : 1740, 1720, 1470 cm1 N.M.R. fi(CCl4, ppm): 0.6-2.2 (14H, m) , 4.1-4.6 (4H. m), 4.47 (2H, s) (3) Ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 55.6™g.), thiourea (15.2 g.), sodium acetate 3-hydrate (27.2 g.), ethanol (280 ml.) and water (140 ml.) were treated in a similar i manner to that of Example 5-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetate (syn isomer, 29.3 g.), mp 77 to 78°C.

I.R. v SQl : 3460, 3250, 3140, 1720, 1535 cm1 HlciX N.M.R. fi (DMSO-dg) : 0.85 (3H, t, J=6Hz) , l,0~1.9 (11H, m), 2.07 (2H, t, J=6Hz), 2.26 (2H, q, J=7Hz), 6.85(IH, s) , 7.22(2H, s) (4) Ethyl 2-(2-aminothiazol-4-yl)2-n-hexyloxyiminoacetate (syn isomer, 29.1 g.), methanol (97.2 ml.), 2N aqueous solution of sodium hydroxide (97.2 ml.) and tetrahydrofuran (50 ml.) 466*75 were treated in a similar manner to that of Example 5-(4) to give 2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 24.0 g.) , mp. 174°C (dec.).

' I.R. υ . 1660, 1625, 1425 cm1 IuclX N.M.R. · δ(DMSO-dg, ppm) O.6~2.1 (11H, m), 4.07 (2H, t, J=6Hz) , 6.83 (IH, s), 7.19 (2H, s) Example 10 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn I * ί isomer, 40 g.) , Ν,Ν-dimethylformamide (200 ml.), potassium carbonate (52 g.) and pentyl bromide (37.9 g.) were treated in a similar manner to ;that of Example 5-(1) to give ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer, 57.5 g.), oil.

I.R.

Fx lm max : 1745, 1680, 1470 cm / N.M.R. 6(CC1., ppm): 0.7-2.2 (12H, m), 2.36 (3H, s), 4.1 - 4.6 (4H, m) (2) Ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer, 57.5 g.) , acetic acid (58.5 ml.) and sulfuryl chloride (20.9 ml.) were treated in a similar manner to that of Example 5--(2) to give ethyl 2-pentyloxyimino-4-chloro3-oxobutyrate (syn isomer, 51.1 g.), oil.

I I.R. υ max™ : 1750' 1715' 1470 cm1 N.M.R. δ (CC14, ppm) : 0.7 - 2.1 (11H, m) , 4.1 - 4.6 (4H, m), 4.48 (2H, s) (3) Ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 51.1 g.), thiourea (14.7 g.) , sodium acetate trihydrate (26.4 g.), ethanol (175 ml.) and water (125 ml.) i were treated in a similar manner to that of Example 5-(3) fco give ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer, 28.,7 g.), mp 86 to 88°C. - 32 4 6 6 7 5 I I.R. v Nujo1 : 3450, 3250, 3130, 1715, 1535 cm"1 max N.M.R. 6(DMS0-dg, ppm) : 0.6 - 2.0 (12H, m), 4.11 (2H, t, J=6Hz), 4.32 (2H, q, J=7Hz), 6.90 (IH, s), 7.25 (2H, s) (4) Ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer, 28.6 g.), 2N aqueous solution of sodium hydroxide (100.2 ml·.), methanol (100 ml.) and tetrahydrofuran (100 ml.) were treated in a similar manner to that of Example 5-(4) to give 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 22.4 g.), mp 176°C (dec.).

I.R. v1^01 : 3160, 1655, 1620, 1460 cm'1 15 max N.M.R. δ(DMSO-dg, ppm) : 0.6 - 2.2 (9H, m), 4.07 (2H, t, J=6Hz), 6.82 (IH, s) , 7.20 (2H, s) (5) 2-(2-Aminothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 15 g.), acetic anhydride (23.8 g.) and I formic acid (10.7 g.) were treated in a similar manner to that of Example 5-(5) to give 2-(2-formamidothiazol-4-yl)2-pentyloxyiminoacetic acid (syn isomer, 14.7 g.), mp 125°C (dec.).

I.R.

Nujol max 3200, 3140, 1700, 1565 cm N.M.R. δ(DMSO-d,, ppm) : 0.6 - 2.0 (9H, m) , 0 4.13 (2H, t, J=6Hz), 7.53 (IH, s), 7.54 (IH, s), 12.66 (IH, s) Example 11 (1) Allyl bromide (2.91 g.) was added dropwise to a stirred suspension of ethyl 2-(2-tritylaminothiazol-4-yl)2-hydroxyiminoacetate (syn isomer, 10 g.), Ν,Ν-dimethylformamide (100 ml.) and potassium carbonate (4.54 g.) under ice cooling over 5 minutes, and stirred at the same temperature for 4 hours.

After adding water (200 ml.) to the resultant solution, the solution was extracted with diethyl ether twice. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with a solution of n-hexane and diethyl ether. The precipitates were collected by filtration to give ethyl 2-(2-tritylaminothiazol-4-yl)-2-allyioxyiminoacetate (syn isomer, 9.4 g.), mp. 130 to 132°C. l-R. V ^3°1 : 3380, 1735, 1520, 1500 cm1 max N.M.R. δ(DMSO-dg, ppm) : 1.08 (3H, t, J=7Hz), 3.96 (2H, q, J=7Hz), 4.54 (2H, broad d, J=5Hz) 5.0~5.5 (2H, m) , .6~6.3 (IH, m), 6.90 (15H, broad s), 7.74 (IH, s) (2) A solution of ethyl 2-(2-tritylaminothiazol-4-yl)-2allyloxyiminoacetate (syn isomer, 8.7 g.), 50% formic acid (42.5 ml.) and tetrahydrofuran (42.5 ml.) was stirred at 60°C for 40 minutes. After concentrating the resultant solution in vacuo, the residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. After concentrating the resultant solution in vacuo, the residue was subjected to column chromatography on silica gel with benzene and ethyl acetate in turn, to give ethyl 2-(2-aminothiazol-4-yl)-2allyloxyiminoacetate (syn isomer, 3.7 g.), mp. 102 to 104°C.

I.R. V N"£o1 : 3460, 3260, 3130, 1725, 1620, ΙΏαΧ , 1540, 1460 cm N.M.R. δ(DMSO-dg, ppm) : 1.25 (3H, t, J=7Hz), 4.30 (2H, q, J=7Hz), 4.61 (2H, dd, J=5Hz, 1Hz), 5.0-5.5 (2H, m), .6^6.5 (lB,m), 6.95 (lH,s)z 7.28 (2H,s). (3) A solution of ethyl 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 3.6 g.), 2N aqueous solution of 6675 sodium hydroxide (14.1 ml.), tetrahydrofuran (14.1 ml.) and methanol (15 ml.) was stirred at 40°C for 1.5 hours.

The resultant solution was concentrated in vacuo, and the residue was dissolved in water. After the solution was adjusted to pH 2.8 with 10% hydrochloric acid under ice cooling, the precipitates were collected by filtration, washed with water and acetone in turn and dried to give 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer, 1.91 g.), mp. 187°C (dec.).

I.R. v max01 : 3350' 1630' 1580' 1460 ^1 N.M.R. δ(DMSO-dg, ppm) : 4.61 (2H, d, J=6Hz), ! 5.1^5.5 (2H, m), 5.7^6.2 (IH, m) , ί 6.84 (IH, s), 7.25 (2H, broad s) Example 12. (1)· Propargyl bromide (4.17 g.) was added to a suspension of ethyl 2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate (syn isomer, 10 g.), potassium carbonate (4.84 g.) and N,N-dimethyIformamide (22 ml.) under atmosphere of nitrogen gas and stirred at room temperature for 100 minutes. The insoluble substance was filtered off and washed with a little of Ν,Ν-dimethylf ormaihide. The filtrate and washing solution were combined together, and water (400 ml.) was added to the solution. After the suspension was extracted with ethyl acetate (400 ml.), the extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After treating the solution with activated charcoal, the solution was concentrated in vacuo. The residue was triturated with diisopropyl ether. The precipitates were collected by filtration, and washed with diisopropyl ether to give ethyl 2-(2-tritylaminothiazol-4-yl)-2propargyloxyiminoacetate (syn isomer, 8.34 g.).

I.R. 3290, 2225, 1735 cm Nujol max N.M.R. δ(DMSO-d θ, ppm) : 1.12 (3H, t, J=7Hz), 3.47 (IH, t, J= 3Hz), 3.97 (2H, q, J=7Hz), 4.67 (2H, d, J=3Hz), 6.95 (1H^ s), 7.26 (15H, s), 8.77 (IH, s) · (2) 50% Formic acid (41 ml.) was added to a solution of ethyl 2-(2-tritylaminothiazolr4-yl)-2-propargyloxyiminoacetate (syn isomer, 8.2 g.) and tetrahydrofuran (41 ml.), and stirred at 60°C for an hour. The resultant solution was concentrated to a half of initial volume under reduced pressure, and the precipitates were collected by filtration and washed with diisopropyl ether. The filtrate and washing solution were combined together and concentrated in vacuo.

The residue was added to ethyl acetate (200 ml.) under stirring. The insoluble substance was collected by filtration, and washed with diethyl ether to give ethyl 2-(220 aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 0.3 g.). The filtrate and ethyl acetate washing solution were combined together, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride twice in turn, and dried over magnesium sulfate.

The solution was treated with activated charcoal and concentrated in vacuo. The residue was dried in vacuo after adding benzene. The residue was subjected to column chromatography on silica gel with benzene and ethyl acetate in turn. The eluate was concentrated in vacuo, and the residue was triturated with diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether to give the same compound as mentioned above (syn isomer, 2.658 g.). The I.R. spectrum and N.M.R. spectrum are the same as those of the compound obtained in Example 8-(3). 6 6 7 5 Example 13.

Sodium bicarbonate (0.84 g.) was added to a suspension of 2-(2-fprmamidothiazol-4-yl)oxalic acid (2 g.) in water (120 ml.) to prepare a solution. Ethyl 2-aminoxyacetate hydrochloride (4.56 g.) was added to the solution and stirred at room temperature for 3 hours while adjusting to pH 6 with sodium bicarbonate. The resultant solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted with ethyl acetate three times. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 2-(2-formamidothiazol-4-yl) -2-e'thoxycarbonylmethoxyiminoacetic acid (syn isomer, 1.44 g.), mp 112°C (dec.). i '3 I.R. v jjjjj01 : 3150, 1740, 1670, 1550 cm-1 N.M.R. δ (DMSO-d,., ppm) : 1.23 (3H, t, o J=7Hz), 4.16 C2H, q, J=7Hz), 4.77 (2H, s), 7.56 (lH, s), 8.54 (IH, s) Example 14. (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 60 g.)·, l-bromo-2-chloroethane (54.1 g.), potassium carbonate (78 g.) and N,N-dimethylformamide (200 ml.) were treated in a similar manner to that of Example 5-(1) to give ethyl 2-(2-chloroethoxyimino)-3-oxobutyrate (syn isomer, 83.6 g.), oil. (2) Ethyl 2-(2-chloroethoxyimino)-3-oxobutyrate 35 (syn isomer, 83.6 g.), sulfurylchloride (52.4 g.) and acetic acid (83.6 ml.) were treated in a similar manner to that of Example 5-(2) to give Ethyl 2-(2-chloroethoxyI.R. v max : 1740' 1680, 1430 cm N.M.R. δ (CC14, ppm) : 1.34 (3H, t, J=7Hz), 2.34 (3H, s), 3.72 (2H, t, J=6Hz), 4.28 (2H, q, J=7Hz), 4.46 (2H, t, H=6Hz) >46675 imino)-3-oxo-4-chlorobutyrate (syn isomer, 68 g.), oil.

I.R. V : 1740, 1720 cm-1 N.M.R. δ (CC14, ppm) : 1.32 (3H, t, J=7Hz), 3.70 (2H, t, J=6Hz), 4.29 (2H, q, J=7Hz), 4.47 (2H, s), 4.48 (2H, t, J=6Hz) (3) Ethyl 2-(2-chloroethoxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 68 g.), thiourea (20.2 g.), sodium acetate trihydrate (36.2 g.), ethanol (270 ml.) and water (170 ml.) were treated in a similar manner to that of Example 5-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino) acetate (syn isomer, 33.7 g.), mp 126 to 128°C.

I.R. V Nu3o1 . 3440, 3260, 3140, 1725, > IUcLX 1620, 1540 cm-1 N.M.R. δ(DMS0-d6, ppm) : 1.30 (3H, t, J=7Hz), 3.78 (2H, t, J=6Hz), 4.1-4.6 (4H, m) , 6.96 (IH, s), 7.27 (2H, s) (4) Ethyl 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetate (syn Isomer, 3O.5gJ, IN aqueous solution of sodium hydroxide (220 ml.), methanol (110 ml.) and tetrahydrofuran (140 ml.) were treated in a similar manner to that of Example 5-(4) to give 2-(2-aminothiazol-4-yl)-2-(2chloroethoxyimino)acetic acid (syn isomer, 23.4 g.), mp 201°C (dec.).

I.R. v ^3°1 : 3210' 3100' 1640' 1620' 1580 cm-1 N.M.R. δ(DMSO-dg, ppm) : 3.83 (2H, t, J=6Hz) , 4.36 (2H, t, J=6Hz), 6.92 (IH, s) , 7.30 (2H, s) (5) 2-(2-Aminothiazol-4-yl)-2-(2-chloroethoxyimino)35 acetic acid (syn isomer, 15 g.), acetic anhydride (24.5 g.), formic acid (11.0 g.) and tetrahydrofuran (50 ml.) were treated in a similar manner to that of Example 5-(5) to give 2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino) i acetic acid (syn isomer, 13.4 g.), mp 155°C (dec.) I.R. υ ^°1 : 3100, 1740, 1690, 1660 cm1 N.M.R. fi(DMSO-dg, ppm) : 3.87 (2H, t, J=6Hz), 4.40 (2H, t, J=6Hz), 7.60 (1H, s), 8.56 (IH, s), 12.62 (IH, broad s) Example 15 A suspension of 2-(2-formamidothiazol-4-yl)oxalic acid (3.0 g.) in methanol (60 ml.) and water (60 ml.) was adjusted to pH 8 with IN aqueous solution of sodium hydroxide under stirring. 2,2,2-Trifluoroethoxyamine hydrochloride (2.24 g.) was added to the solution, and the solution was adjusted to pH 2.5 to 3 with IN aqueous solution of sodium hydroxide. After the solution was stirred at room temperature for 1.5 hours, methanol was removed from the resultant solution under reduced pressure. The concentrated aqueous solution' was adjusted to pH 7 with IN aqueous solution of sodium hydroxide and washed with ethyl acetate. Ethyl acetate was added to the aqueous solution and adjusted to pH 1.5 with 10% hydrochloric acid, and then extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The extracts were combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to give 2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetic acid (syn isomer, 2.4 g.), mp 162 to 163°C (dec.).

I.R. v ; 3200, 1700, 1600, 1560 cm1 N.M.R. fi(DMSO-dg, ppm) : 4.83 (2H, q, J=8.5Hz), 7.65 (IH, s), 8.58 (IH, s), 12.60 (IH, broad s) i l Example 16. 2-(2-Formamidothiazol-4-yl)oxalic acid (10 g.), sodium bicarbonate (4.2 g.)and tert-butyl 2-aminooxyaCetate (8.1 g.) were treated in a similar manner to that of Example 13 to give an oil. The oil was triturated with n-hexane and the precipitates were collected by filtration and dried to give 2-(2-formamidothiazol-4-yl)-2-tertbutoxycarbonylmethoxyiminoacetic acid (syn isomer, 11.3 g. ) , mp 117°C (dec.).

Q I.R. V : 3180, 3140, 1750, 1690, 1630 cm1 N.M.R. δ(DMSO-dg, ppm) : 1.46 (9H, s) , 4.66 (2H, s), 7.56 (IH, s), 8.56 (IH, s), 12.67 (IH, broad s) Example 17 (1) Ethyl 2-hydr oxy imino-3-oxobutyrate (syn isomer 100 g.), Ν,Ν-dimethylformamide (300 ml.), potassium carbonate (130,g.) and bromooctane (121 g.) were treated in a similar manner to that of Example 5-(1) to give ethyl 2-n-octyloxyimino-3-oxobutyrate (syn isomer, 165.5 g.), oil.

I.R. v * 1745, 1695, 1470 cm1 iucix N;M.R. 6(CC14, ppm) : 0.6^2.1 (18H, m), 2.35 (3H, s) , 4.OM.6 (4H, m) (2) Ethyl 2-n-octyloxyimino-3-oxobutyrate (syn isomer, 165.5 g.), sulfuryl chloride (84.7 g.) and acetic acid (165 m]..) were treated in a similar manner to that of Exampld 5-(2) to give ethyl 2-n-octyloxyimino-4-chloro-3oxobutyrate (syn isomer, 169.6 g.), oil.

I.R. υ ^llm : 1745, 1710, 1465 cm1 N.M.R. δ(ΟΟ14, ppm) : 0.6^2.1 (18H, m), 4.0M.6 (4H, m) , 4.48 (2H, s). (3) Ethyl 2-n-octyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 169.6 g.) , thiourea (42.3 g.), sodium acetate trihydrate (7 5.5 g.), water (420 ml.) and ethanol(1020 ml.) were treated in a similar manner to that of Example 5-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetate (syn isomer, 65 g.), mp. 77 to,78°C.

I.R. ν ΐ*701 ; 347o, 3250, 3125, 1735, 1545, IUcLX . 1465 crn N.M.R. δ(DMSO-dg, ppm): 0.81 (3H, t, J=6Hz), 0.6%1.9 (15H, m), 4.07 (2H, t, J=6Hz), 4.28 (2H, q, J=7Hz), 6.86 (IH, s), 7.02 (2H, broad s) (4) Ethyl 2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetate (syn isomer, 64 g.), 2N-aqueous solution of sodium hydroxide (196 ml.), methanol (196 ml.) and tetrahydrofuran (300 ml.) were treated in a similar manner to that of Example 5-(4) to give 2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetic acid (syn isomer, 52.5 g.), mp. 146°C (dec.).

I.R. v ^3°1 : 3170, 1635, 1565, 1460 cm-1 IUcLX N.M.R. δ(DMSO-dg, ppm) : 0.86 (3H, t, J=6Hz), 0.6^1.9 (12H, m), 4.06 (2H, t, J=6Hz), 6.81 (IH, s), 7.22 (2H, s) (5) 2-(2-Aminothiazol-4-yl)-2-n-octyloxyiminoacetic acid (syn isomer, 20 g.), acetic anhydride (27.3 g.) and formic acid (12.3 g.) were treated in a similar manner to that of Example 5-(5) to give 2-(2-formamidothiazol-4-yl)-2-noctyloxyiminoacetic acid (syn isomer, 21.3 g.), mp. 122°C (dec.).

I.R. V ^3°1 ί 3350, 3150, 3050, 1700, 1675, 1560 cm1 N.M.R. δ(DMSO-dg, ppm) : 0.6^2.0 (15H, m) , 4.16 (2H, t, J=6Hz), 7.56 (1H, s) , 8.57 (IH, s), 12.67 (IH, s)

Claims (2)

CLAIMS :A compound of the formula: COOR3 ? R~ LO .5 :o wherein R1 is amino, substituted or unsubstituted(lower)alkanamido or tritylamino; R is alkyl having 2 to 8 carbon atoms, cycloalkyl, lower alkenyl having 2 to 6 carbon atoms, lower alkynyl having 2 to 6 carbon atoms, halo(lower)alkyl, carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyi, 3 ' R is hydrogen or lower alkyl, provided that when 2 R is ethyl, isopropyl or allyl, then . R1 is amino or unsubstituted(lower)alkanamido, and R is hydrogen. 2. The syn isomer of the compound of the claim 1. 3. The compound of the claim 2, wherein

1. 2 wherein R and.R are each as defined above, or (5) subjecting a compound of the formula: J ί— c - GUUf' 3 R ι x S I 2 O-R wherein R is substituted or unsubstituted lower alkanamido a 2 3 or tritylamino, and R and R are each as each as defined above, ! to elimination reaction of Substituted or unsubstituted ; ι lower alkanoyl or . trityl in substituted or unsubstituted lower alkanamido or tritylamino for R 1 , to provide a compound of the formula: JT» - COOR' S 2 O-R 1 3 wherein R and R are each as defined above, with a hydroxylamine derivative of the formula: R 2 - ONH 2 2 wherein R is as defined above, to provide a compound of the formula: , .3— c R '‘-ΖΪΓ; tv e 3 2 0-R 12 3 wherein R , R and R are each as defined above, ! (4) subjecting a compound of the formula: wherein R^ is lower alkyl, and R and R are each as defined above, to transforming reaction of the esterified carboxy group 3 for R into the free carboxy group, to provide a compound & of the formula: - COOH 5 2 0 - R z 1 I R is amino. | 4. The compound of the claim 3, wherein R is alkyl having 2 to 8 carbon atoms. 5. The compound of the claim 4, which is 2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetic acid or its ethyl ester. 6. The compound of the claim 4, which is 2-(2-aminothiazol-4-yl)-2-propoxyiminoacetic acid or its ethyl ester. 7. The compound of the claim 4, which is 2-(2-aminothiazol-4-yl)-2-isopropoxyiminoacetic acid or its ethyl ester. 8. The compound of the claim 4, which is 2-(2-amino:5 4 6 6 7 5 thiazol-4-yl)-2-butoxyiminoacetic acid or its ethyl ester. 9. The compound of the claim 4, which is 2-(2-aminothiazol-4-yl)-2-isobutoxyiminoacetic acid or its ethyl ester. 10. The compound of the claim 4, which is 2-(2-aminothiazoI-4-yl)2-pentyloxyiminoacetic acid or its ethyl ester. · 11. The compound of the claim 4, which is 2-(2-aminothiazol-4-yl)-2-hexyloxyiminoacetic acid or its ethyl ester. 12. The compound of the claim 3, wherein R is cycloalkyl . 13. The compound of the claim 12, which is 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid. 14. The compound of the claim 3, wherein R is lower alkenyl having 2 to 6 carbon atoms. 15. The compound of the claim 14, which is 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetic acid. 16. The compound of the claim 3, wherein R is lower alkynyl having 2 to 6 carbon atoms. 17. The compound of the claim 16, which is 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetic acid or its ethyl ester. ο 18. The compound of the claim 3., wherein R 1 is halo(lower)alkyl, 19. The compound of the claim 18, which is 2-(2-aminothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetic acid. 20. The compound of the claim 18, which is 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid or its ethyl ester. 21» The compound of the claim 3, wherein R is carboxy(lower)alkyl. 22. The compound of the claim 21, which is 2-(2-amino30 4 667 5 thiaz'ol-4-yl)-2-carboxyme thoxy iminoace tic acid. 23. The compound of the claim 3, wherein R is lower alkoxycarbonyl (lower )alkyl. 24. , The compound of the claim 23, which is 2-(2-aminothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetic acid. 25. The compound of the claim 23, which is 2-(2-amino: Ithiazo 1-4-yl )-2-tert-butoxycarbonylmethoxyiminoacetic acid. 26. The compound of the claim 2, wherein R 1 is lower alkanamido. 27. The compound of the claim 26, wherein R is alkyl having 2 to 8 carbon atoms. 28* The Compound of the claim 27, which is 2-(2-formamidothiazol-4-yl)-2-ethoxyiminoace tic acid. 29. The compound of the claim 27, 'which is 2-(2-formamidothiazol-4-yl)-2-propoxyiminoacetic acid. 30. The compound of the claim 27, which is 2-(2-formamidothiazol-4-yl)-2-isopropoxyiminoacetic acid. 31. The compound of the claim 27, which is 2-(formamidothiazol-4-yl)-2rbutoxyiminoacetic acid. 32. The compound of the claim 27, which is 2-(2-formamidothiazql-4-yl)-2-isobutoxyiminoacetic acid. 33. The compound of the claim 27, which is 2-(2-formamidothiazo 1-4-y 1)-2-pentyloxyimindacetic acid. 34. The compound of the claim 27, which is 2-(2-formamidothiazol-4-yl)-2-hexyloxyiminoacetic acid. 35. The compound of the claim 26, wherein is halo(lower)· alkyl. 36. The compound of the claim 35, which is 2-(2-formamidotniazol-4-yl)-2-(2-chloroethoxyimino)acetic acid. 37. The compound of the claim 35, which is 2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetic acid. 3jB. The compound of the claim 26, wherein R is carboxy44 4 6 (ί 7 fj (lower)alkyl. 39. The compound of the claim 38, which is 2-(2-^1^1301100thiazol-4-yl)-2-carboxymethoxyiminoacetic acid. ' 2 40. The compound of the claim 26, wherein R is lower I alkoxycarbonyl(lower)alkyl. 41. . The compound of. the claim 40, which is 2-(2-formamidothiazol-4-yl)-2-ethoxycarbonyImethoxyiminoacetic acid. 42. The compound of the claim 40, which is 2-(2-formamidothiazol-4-yl),-2-tert-butoxycarbonylmethoxyiminoacetic acid. 43. The compound of the claim 26, wherein R is cycloalkyl. 44. The compound of the claim 43, which is 2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid. 45. The compound of the claim 2, wherein R 1 is tritylamino. 46. The, compound of the claim 45, which is 2-(2rtritylaminothiazol-4-yl)-2-propargyloxyiminoacetic acidlpr its ethyl ester. 47. ' The compound of the claim 4, which is 2-(2-aminothiazol4-yl)-2-octyloxyiminoacetic acid (syn isomer) or its ethyl ester. 48. The compound of the claim 27, which is 2-(2.-formamidothiazol-4-yl)-2-octyloxyiminoacetic acid (syn isomer). 49. A process for preparing a compound of the formula: C - COOR 3 II N ? 2 ; 0-R i wherein R^ is amino, substituted or unsubstituted(lower)alkanamido or tritylamino; wherein R is lower alkyl having 2 to 8 carbon atoms, cycloalkyl, lower alkenyl having 2 to 6 carbon atoms, lower alkynyl having 2 to 6 carbon· atoms, halo(lower)alkyl, carboxy(lower)alkyl, or lower alkoxycarbonyl(lower)alkyl; R is hydrogen or lower alkyl, provided that when R is ethyl, isopropyl or allyl, then j 3 R is amino or unsubstituted lower alkanamido and R is hydrogen, which comprises (1) reacting a compound of the formula: X - CH.CO-C-COOR 3 2 , a N J-R 2 3 2 wherein X is halogen, R is lower alkyl and R is as a defined above, with a thiourea compound of the formula: R - C - NH, wherein R 1 is as defined above, to provide a compound of the formula; •XjT! C - COOR' 12 3 wherein R , R , and R are each as defined above, a * (2) reacting a compound of the formula: .3 - COOR' £>H wherein R 1 is amino, substituted or unsubstituted(lower)3 alkanamido, and R is as defined above, 46673 with an etherifying agent, to provide a compound of the formula: - COOR' S 2 0-R 12 3 wherein R , R , and R are each as defined above, (3) reacting a compound of the formula: .3 'ΛJT C - COOR'

2. 3 wherein R and R are each as defined above.