WO1984002703A1 - Process for preparing aminothiazolylacetic acid derivatives - Google Patents

Abstract

A process for preparing novel aminothiazolylacetic acid derivatives useful as intermediates for synthesizing beta-lactam antibiotics, starting with diketene as shown in formula (I), wherein R represents lower alkyl or phenyl, R1 and R2 each represents hydrogen or lower alkyl, and X and X' each represents halogen.

Description

 Light box

 Aminothiazol »Extrusion of acid ϋ conductor

 Technical field

 The present invention relates to a method for producing a novel aminothiazo-enzymatic acid derivative which is useful in the synthesis of -pactam-based products.

 Back * _ ¾ _ _

 Conventionally, the usefulness of -lactam antibiotics such as berlin and sepasbolin having excellent antibacterial activity fr * Aminothiazo derivatives containing i-substituent i * boki group t are known as anomers during synthesis. For example, the one used for the 7-position chain of sepdin, which is known as a third-generation antibiotic, and the azetidinones that are considered to be used for the fourth-generation antibiotic, are also «ί» It is thought that aminothiazo-acetic acid derivatives containing β-substituted moieties (C carboxy ^ group *) will be increasingly used in future species.

As described above, methods for producing a diaminothiazo-/ ^ drunkic acid derivative have been disclosed, but among these methods, the industrially advantageous method can be roughly divided into the following two methods. It is considered possible. One of them is to use acetic acid acetate as a raw material, oxidize it with potassium hydroxide to obtain okiminino wood acid ester, and then, after etching the kimchi, halogenate it. * The other method is to close the ring with urea, and the other is to use 4-chloroacetoenzyme lactide as a raw material, and to react with eno, butano, etc. to obtain 4- ff naceto # acid este. After oxidizing with ¾ ァ 力》》 し 、 、 、 、 、 、 、 で で で で で 2 2 2 2 2 2 2 2 2 2-2 と し 2 2-と し と し と し-. It is a way to make it. one The aminothiazole derivative thus obtained is used as a halide, ahydrate, and an active amide in the form of a 1, ctam antibiotic. In order to prevent side reactions, it is necessary to use a protected aminothiazo-acetic acid, which has a protected jc amino group, and the conventional synthesis method mainly protects the amino group. Amino thiazole ゾ Invitation: »The body is synthesized. In addition, the chemical properties of the carboxyl group in the amino-substituted part of the conductor and the carboxylic group of the permeated part are similar, so that the reactivity of acid halides, acid anhydrides, active amides, etc.導 く Before leading to the conductor, it is necessary to protect the 置換 group at the substitution site and remove the urine of the reaction. For example, a protecting group that can be removed by a chemical reaction, such as Ρ- --to-ρ-pene S ^, is used, but it is difficult to protect the compound after the oxidation reaction. A tert-butyl group, which is considered to be removable in the above process, is also used, but in the second production method of the aminothiazo-conductor described above, in which the carboxyl group in the perturbed portion is mainly converted into an ethyl group. However, at the same time, the tert-butyl group is also removed at the same time as the S-I-Nation reaction before leading to the reactive derivative. Therefore, an industrially advantageous method for producing an aminothiazo->> acid derivative in which the amino group and the carboxyl group of acetic acid て お are not protected and only the carboxy group in the a-position is protected is not yet available. Established *

 Indication of the invention

 The present inventors have studied the use of an aminothiazo- »acid derivative as an intermediate for β-ββ-type antibiotics« I-type intermediates>. Knowing that the step of protection can be omitted, the power of the amino group and the hydroxyl group in the urine is not protected and the β group is not protected.

OMPI Power of the displacing unit Aminothiazo-based key conductor with a protected boxoxy group is industrially advantageous. * Production method Various inspections were conducted. As a result, among the possible combinations of various processes, diketin and hagen are reacted, and then reacted with 級 -grade aki or phospho-thiacco, and then oxidized with nitrous acid. However, after the reaction with thiourea, the reaction of the kimchi is advantageously prevented, and the W group of the carboxyl group in the peroxidized portion of the resulting compound is selectively and easily removed.

[I]

C (CH ₃ ) ₃

 I

 l2

 [In the formula, Bi, i? 2 represents hydrogen or an IS-class alkyl group.] A novel diaminothiazo-acetic acid derivative represented by the following formula: : I] was easily led to the activity of the lactam, and was found to be an advantageous synthetic intermediate of a lactam antibiotic, and based on these, the present invention was completed.

 That is, the present invention

 The reaction between diketene and hagen is performed.

HS0 ₂ C ₂ H ₄ 0H [I]

 [Wherein B represents a lower ac group or a fu- ^ group]

XCH ₂ C0CH ₂ C00C _e H ₄ S0 ₃ H (I)

[Wherein, ∑ represents a halogen, B represents the same meaning as described above], and a compound represented by the formula: XCH _e C0CC00C _e B .S0.HI?

 OE

Where the symbol ^ is equivalent to IS

In the formula, B is the same as defined above.) * And the formula X -C to G00C (CH,) ₃ (VI)

Wherein X ′ is halogen and the others are as defined above.

[W]

 c The symbol in the formula is a compound represented by the same meaning as described above) .The method for producing an aminothiazo-drinoic acid derivative [I] is characterized by hydrolysis under the presence of a group. .

In the above formulas, and H ₂ are the same or different and represent hydrogen or a B-rank group. , B ₂ are, for example, methyl, ethyl, isobutyl, isobutyl, iso-butyl, sec-butyl A \ tert-butyl. Group is used. , B ₂ is preferably a hydrogen atom or a methyl group, or one of them is hydrogen and the image is a methyl group. B is ®

OMPI One S—

Class Aki group or Pue group * Shown. As a ft Kyua key group represented by B includes, for example, described in B _a; Gotoki Λ prime t of ¾ to 4 ® Kyua year group ¾ etc. is use. Examples of the preferred B are: チ, _β , which is represented by チ, ェ, た と え ば, and 棄. X may be the same, or may represent different * σ-gens. The halogens commonly used as X and χ 'are * element and autum.

 In the method of the present invention, diketin and a halogen are first reacted to give a 4-halogenoacetic acid halide.

 This production method is carried out by dissolving ヅ ketin in a solvent and cooling it. “F: This * or a little less ゲ ン ゲ ン ¾ reaction. ¾ MU * C is for example as planted methylene,ス テ Stenoles such as halogenated hydrocarbons, acetic acid, and ethers such as ether and dioxane are used The reaction is usually performed under cooling at −70 * to 10 τ: Reaction time Is short and short-lived.

You only need to stir for about 30 minutes. The 4-halogenoatoacetic halide to be masked can be isolated and purified by known means, for example, (1) solvent extraction, liquid conversion, sugar A, chromatography, etc. It is advantageous to use it as a raw material for the next process

 4-Halogenoacetate, acid, and coco-

Reaction of [I] gives compound [a].

 4- It is advisable to react * with a slightly lesser amount of alcohol [I] * with the genoacetone drunk halide. Reaction is performed during rubbing *. As a dragon, any substance that does not hinder the reaction * may be used, such as methylene dichloride, chloromethane, tetradecane, halogenated and widened water such as nitrogen, and the like.

OMPI , N, dioxane, di-thieth, etc., are preferred (used β also the presence of the soil group "R reaction" For example, Bi! Gin, Bi: Iri, aromatic amide such as Iff 'dimethylamine, trimethamine, tertiary amici, etc. iSS aliphatic tertiary amine etc. The «dose of the lump group is a ³ — class [2] Ί

In contrast, it is about I ~ 3 *. The reaction is usually carried out in a room without cooling ¾ (-20-40 η).

 ら れ る 4 夏 -Halogenoacetone distillate [Summer] is eaten by purification using normal purification methods such as steaming, phase transfer, reconstitution, etc.- Since this reaction proceeds in high yield, * c It is also possible to proceed to the next step without changing the name of the reaction mixture.

Next, the _β -halogenoacetase ester (direct) is oxidized by reacting with hypochlorite to form _β.

In this reaction, the compound [I] is generally reacted with nitrous acid in an approximately equivalent amount, but it may be used in a slightly different manner. The nitrous acid may be used as it is, but may be used as, for example, aluminum metal such as sodium and potassium. In general, the reaction is carried out in a water-cooled medium-cooled insulator room (−50−50X: preferably 110−40c). Examples of 11 used include, for example, ethyl ufurans, dioxane, ethiues of jetiate, fatty acids such as glazed acid, or a mixture thereof. The water to be added to these may be arbitrarily added. ₀ Also, by adding an aqueous solution of Ajun (for example, Nato Udium) to these mixed solvents! The _β reaction, which can add water to the reaction system, varies depending on the amount of the raw material, the solvent, etc., but usually progresses quickly in W (20 minutes to 3 hours). The body [] can be purified by known means S, for example, steaming, solvent extraction, concentration, reconstitution, etc., but it is necessary to purify it in the end.

OMPI

, Ί beginning ο , Used as a fee.

 Then, the compound of formula [V] can be obtained by reacting the oxime compound [W] with thiourea.

Usually, one thiourea is reacted with one compound [nr], but it is eaten with the use of urine which has no adverse effect on the reaction. This reaction is usually carried out in a solvent. *) Water and a port medium mixed with water, such as alcohols such as methanol and ethanol, ketones such as acetone and jetiketone, and citrahydroplan , Di; * Ethanes such as xane and thietate; Ν, If-dimethy ^ formamide; acid amides such as N, K-dimethyacetoamide; and organic amides such as ir-methibiberidone. It is preferable to perform * in a compound with a similar compound, and when the compound is used in the presence of a basic substance, the syn II form [V] is transitively selected. As the basic substance, a lower fat travel power, an acid or an alkaline earth metal bed of boric acid, and an inorganic or organic plant of ^ 9.5 or more, more preferably ρ¾ι 9.8-10 are used for the purpose of this reaction. Used. © Bag aliphatic power plants include sodium vinegar, sodium acetate, potassium acetate, barium acid, barium citrate, potassium nut, sodium provinate, sodium hexane, and hexane potassium. Lower aliphatic carboxylic acids of the formulas 1 to 6; for example, sodium diacid, potassium, and any other organic group; for example, trimethylene Triamine, triXthiamin, triptiamine, etc., which are tri-substituted amines having a low alkyl number of 1 to 4 and, for example, a-methylidine, H-ethylamine P-Resin, If-Metibidurazine, Kotibiperazine * 5 to 8 cyclic amines with 1 to 2 carbon atoms each having 1 to 2 carbon atoms. The ir, H-dimethylformamide, ir, ir-dimethylacetamide, u-methide When using dong as a solvent, it is necessary to add the basic substance described above *. The amount of the basic substance to be added is 0.5 to 1.3 * for the compound [W] and the molybdenum, depending on the raw material, the type of the solvent, and the like. The reaction is usually performed at 0 to 4 O x:, but depending on the * U cooling or heating that does not hinder the reaction! You can also adjust the reaction speed. ―Generally

The reaction is completed in 10 minutes to 4 hours. The compound of the formula [V] thus obtained can be purified by a known method such as steam S, liquid conversion, crystallization, and re-transfer ft. When the anti-isomer is mixed, it can be separated according to a known method. Also, since compound [V] has a basic amino group at the 2-position of the thiazo ring, it is possible to use an organic acid, such as »jun, tartaric acid, methanol, etc., in accordance with a conventional method. It can also be isolated and purified as inorganic acids such as hydrogen acid, acetic acid, phosphoric acid, agin, asparagine kin, glutamic acid and other perfect amino.

 Next, the compound [V] and the compound [VI] are reacted to produce a compound ^ of the formula [].

 As the compound [V], a compound in which an amino group is left free or a compound formed with a spear as described above is used as a raw material. Compound !: V] or 1 m of the soil! The compound [VI] of molybdenum may be reacted, but usually the compound [V] or the compound [VI] of 1.5 to 2.0 ^ with respect to 1 mol thereof is used. The reaction is performed in a solvent.

Examples of the solvent used include, for example, acetone, methetic; u ketone, such as ketones, and acetate tri, fi-. Solvents are commonly used in similar reactions, but the disadvantages of using amides such as Κ, Η-dimethylformamide, etc. are rather improved. Is done. $ * In addition, a ¾ group may be added to the reaction system in order to deviate the reaction by an advantageous tC. The ¾ group used is a special 特 group that can promote the reaction. However, it is preferable to use * acids such as sodium acid carbonate, sodium carbonate, and sodium hydrogen carbonate (organic organic groups may cause a side reaction and the yield may decrease). . ¾The amount of group used is urine compound

[]! The ratio is preferably 5 to 10 times, preferably 1.5 to 5 times. Further, in order to favor this reaction, it is preferable to add water to the reaction system, especially to the solvent, and the amount of water to be added is << 0 J Jt * 2 Jt volume for the solvent to be used. It is 1.5% volume, and if it is out of this range, the reaction will be extended and one prolonged decomposed product will be generated. * The reaction is between 0 and 60. 20 to 50 c is preferable.反 応 Under the conditions, the reaction quantitatively escapes, and the raw materials disappear * in 0.5 to 3 hours. Therefore, the reaction can be terminated at this point. After completion of the reaction, the target isomer [VI] can be isolated and purified by a known means such as extraction, liquid conversion, crystallization, distillation, chromatography and the like. Compound [W] is a compound

As in the case of [V], it has an amino group * at the 2-position of thiazo-, so it can be isolated as a compound as described in [〔] according to a conventional method. However, in the subsequent hydrolysis step, it is more convenient to use the reaction compound as a raw material without isolating the compound [V]. When the compound [W] obtained as in the above is hydrolyzed in the presence of the ¾ group, the desired product (: I) is obtained.

 As the compound [M] used as a raw material, it is convenient to use the reaction compound obtained in the synthesis of the compound [W] as described above, but a single compound may be used and in that case, the compound is left free. Alternatively, it is used in the form of a salt as described in the above ¾. The decomposition of (\ 1) is the combination of hydrophilic port medium and water

 CMPI

No k WIPO It is actually flagged by the fact that 亊 groups * act on the object [w]. When using a base in the synthesis reaction of compound [¾], simply add water to the reaction mixture.

[W] <p ^ tiC total; ^ solution occurs. As the hydrophilic solvent, for example, alcohols such as mono- and eno-, ketones such as acetone, and birds such as a-to-tri may be used. It is better to use 0.5 to 10 times as much water as the port medium. The degree of hydrolysis is

5 to 50 c is appropriate, and there is a risk of decomposition at high temperatures. (The base used may be any one having a pH of about 3 to 12; for example, organic amines such as carbon dioxide lime, carbon dioxide lime, carbon lime, triethylamine, isopropylamine, etc. The amount of the group to be used may be more than about 5 times, and the hydrolysis is usually completed in about 30 minutes or 2 hours. It can be isolated and purified by known means such as: The target compound [I] is a 2-amino group of the thiazo ring, which can be isolated as an acid of the same dicarboxylic acid as described in the compounds [V] and [¾], and has a carboxyl group *. For example, sodium metal, potassium and other metals, metals, magnesium, etc. It can also be separated from the metal in the soil.

The purpose I: I] thus obtained can be easily led to an active thioester in the form of a carboxylic acid group, and is advantageous for the synthesis of / 3-pactam antibiotics. Then, the step of introducing and removing the necessary protecting group for the amino group is eliminated. Specifically, 2- (2-aminothiazo !! 4-14-) 1- (Z) -2-1 (t-butoxy power V-methoxyethoxy) -vinegar or 2- (2-aminothiazo--4-4- I - (Z) - 2 one (t - t one butoxy ^ mosquitoes ball - one t Mechi E door Kishiimino> Ichiyoi the Hayao 2 - Penzuchiazo Chi year old: as X steel ^ body, ⁷

-BU EA GMPI WIPO -ί 1

 -Amino 3-Bilidinome 1-3-Seppemu 4 After reacting with <Bokilate and then removing the protecting group of the carboxyl group, 7- [2- (2-Aminothiazo 1-4 A— (z) 1- (Power Boxime Toki ^ Imino) Cetamide] "· 3-Biridinomechi 1-3-Cefume 4 Chiropractic or Ceftazidime is available.

 Next, the present invention will be described specifically with reference to examples and related examples. The value of WMH Svetat was measured with a Varian T60 (60 MHz) and expressed in ppm with reference to citrahmethy silane. Also, 7ts is the gritlet d is doublet, 7 is triblet, -¾ is force test, m is machiblet, J is integration constant, DS0 is dimethyl Vhod, br is g t »-de, arom means aromatic.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Example 1

 Diketene 87.9 / (1.047 monole) was dissolved in methylene sulphide 260 »and cooled to -35. The hydrogen gas was introduced at 74.2 ^ (1.045 mol)? R- 35 ~ -30 in about 2 hours to produce a methylene chloride solution of 4-acetone-low-acetyl chloride. Methyl methanoate 00 ^ (0.805 mol) methylene oxide! Dissolved in 3 and added pyridine 63.7. To this greedy solution was added dropwise a solution of 4-chloroacetoacetyl chloride in methylene dioxide at -5 to 0 over about 1.5 hours. After the dropwise addition, the mixture was poured into stirred water for 30 minutes, and 80 ml of methylene chloride was added for phase transfer. The aqueous layer was extracted with methylene chloride, and the extracted organic layers were combined and washed with water. The organic layer was dried, then dissolved in methylene planted 5 and then added to isopropieate 200W: added and crystallized to give a white methyl methacrylate. Mech ws w Jetano-/ 1 /

 C PI

^/ v ^{v; [i} ' ⁰ Rate 80 SI> was bricked.

_{KHB (60MHz, CDC1 3) 9} : 3.00 (? 3H, s, .S0 CH 3),

3.38 (2H, t, J- 7H2S, -c¾3S0 2 ->, 3.72 (2H, 3 · boCHgCO), 4.25 (2 Η, a, CICH ^ CO), 4.60 (2Η, t, J

IB max ¹ : 3430. 1745. 1730 Example Example of methosho-ヱ 4 ク ク ア ア ス テ ア X S 5 5 5 5 5 モ 5 5 5 5 5: Cooled below. Nitrite dissolved in water 1 (Natrium 44.4 f

(0.644> solution was added at 0 to 5 over about 2 hours. After stirring for 30 minutes, the mixture was added to perpetual water and extracted with acetonitrile. The organic layer was washed with water and then dried with sodium hydroxide. After drying and distilling off the solvent, an oily methyl sulfate to 4-chloro-2-hydroxyiminoacetate esde 18.7 was obtained.

»MH (60MHz, DMS0-d ₆ ) ^: 1.90 (3H, s, S0 ₂ C¾), 3.52

(2H, t, J = 7 Hz, -CH2SO2-), 4.58 (2H, t, J = 7 Hz, CH3CH2SO2), 4.87 (2H, s, cicH _2- )

IH (Neat) ^ " ¹ : 3250. 1750.1710, 1635

Example 3

 Mixture of oily methionine obtained in Experiment 2 4- 4-chloro-2-hydric σ-key minoacetate, 48.7 f (0.61 3 * ^) ¾ enol 59 and water 6尿 50.Q ^ (0.656 * ^) and sodium vinegar 74.4 (0.547 * ^) were added as solids. After about 30 minutes at 25-30? After ethanol

 CMPI

wiFO l 300W¾r added and cooled to 0c or less. The precipitated crystals were collected by filtration to give a white meth; I-Sho-echi 121- (2-Aminothiazo 14-i) 12-Hydroxymino acid sulphate S 10.4.3 f. Sulfate 4-Yield from chloroacetate 55.2 *) Elemental analysis Ca HU N3 0 ₅ S2-293.3 1

 Total recruitment bale C 32.76SK, H 3.78%. H 14.33S5

 Exact c 32.22. H 3.72 ^. N 13.95 ^

_{NHB (60MHz, DMS0 - d e} ) 3.00 (3 H, s, S0 2 CH_3),

3.58 (2H, t, J-7Hz, -CH- ₂ so ₂ ), 4.62 (2Η »t, ί- 7 Ηζ, C0CH ^ CH2) .6.30 (1Η, 3, thiazole 5-s), 7 Ten

(2Η, a, ΝΗ _2- )

IB ^ΚΒτ cm ¹ : 3450.3300, 1720.1610.

 max

 1535, 1408. 1290

 Example 4

 Example 2-(2-Aminothia Zo-4-)-2-Droxy Mino Aya Este 1 09

(0.034 1 乇 A was added to acetone 200 W, and bromo »鲮 t-buty 9.9 87 (0.05 12 A was added. Water 0.6ι ^ was added, and anhydrous sodium carbonate 13.85 f was further added. C. The mixture was stirred for 2 hours, and water 20 was added to the resulting reaction solution. After stirring for about 1 hour at 30 to 35, the methyl methoxide group was hydrolyzed and desorbed. The organic layer was extracted with water, the aqueous layers were combined, and the pH was adjusted to pH * 2 with 2 HHC1 water to precipitate a white precipitate. The precipitate A was collected by filtration and dried. Then, the white 2- (2-aminothiazo-1-4-A- (z) 1-2- (t-butoxy-force methoxymethoxymino) -vinegar) 9.0 f Was. (Yield 87. S 51)

As elemental析僮CnHxsHa o ₅ s. Α5Η ₈ 0

Calculation 饈 C 42.58 »Η b.2Q% _t 13.54 *. S 10.33 * Real charge C 42.82. H 5.23K. H 13.7451, S 10.87 *

_{HMB (60MHz, DMSO-d 6} ) *:. 1.42 (SH> s C (CH 3 ¾),

4.55 (2 Η, s, 0CH s C0), 6.82 (1 Η, a ' Chiazo - Η) 7.20 (. 2Η, br, ίΤΗ 2)

ΙΗ α ¹ :

 max 3350. 1745. 1 S40

 ο Synthetic intermediate meth-s-foet 2- (2-aminothiazo-1-4-)-(Ζ)-(t-butoxy); u-methoxy-imino) -acetic acid: method for isolating styrene Properties 德

 The reaction solution is poured into water and extracted with a water heater. Arigami layer After water »Reduced to dryness and solidified vinegar sorbet Isoprobech (t: 5) Obtained from i 欲 * A from greed.

IT MB (6QMH2, DMS0-d ₆ ) #: 1.42 (9H, s, C (CH ₃ ) ₃ ), 2.99

(3H, s, CH2SO2). 3.58 (2 Η, t, J = 7 Η ζ, -GH2SO2).

4.59 (binary, a, OCSgCOO), 4.61 (binary, t.J-7Hz,

.. -0CH3CH2S02) 6.98 (1 Η , 8, Chiazo one Η) 7.26 C 2Η, s, ΝΗ 2 -)

IB ^ ll Λ " ¹ : 3410. 1750, ί 715.1623. 1540

Methyl phosphate obtained in Example 3 <ν 2-1 (2-aminothia zo-4-4-A-2 -hydroxyimino »acid s-8, (0.0205 *) with acetone 1 20" Add στι »acid t-buty 4 · β § (0.0307¾). Add water 0.36» * Add more acid anhydride! One 1 δ—

 Pt 1 t.31 f, sodium aluminide 8J 3-was added, and the mixture was stirred at 40 c for 5 hours. Reaction solution fC water, 20 * heating 30 to 35 hours. The organic layer separated by adding ft-acid and ft was separated and extracted with water. Water SS Conclusion When pH was adjusted to 2 with 2HHC1, white precipitate precipitated. Precipitated matter * After filtration and drying, a white 2 (2-aminothiazo-4-y) -1 (z) —21- (t-butoki-kabo-methoxy-mino) -1 »ί¾4.63-(yield 75 )was gotten.

 Example 6

 (1) Diketin (840 f) was dissolved in methylene chloride (2.52) and cooled to less than 30 c TF. Oxygen gas 708 was introduced at -35 to 130 C for about 2 hours. After stirring for 30 minutes or less, -20 c or less of methyl ethanoethanol 353 and pyridine 608-were dissolved in methylene chloride L2, and the solution was added within 30 minutes. The reaction solution was allowed to react for about 1 hour with an extra bowl a-5. After the completion of the reaction, methylene dioxide 8 was added to the reaction solution, and then the mixture was poured into water 7. Organic layer and aqueous layer * Liquid separation was performed, and the aqueous layer was extracted again with methylene chloride. The organic layers were combined and washed with water. The organic layer was dried under reduced pressure to obtain colorless knot A.

 (2) The obtained box に was cooled to a concentration of less than 5 in yeast acid 1.87 and ice 齚 醆 3.75 io. A solution of sodium nitrite 53Of dissolved in water 65 was added at 0-5 over about 2 hours. After reacting for 30 minutes after the dropwise addition, the reaction solution was added to ice water 10 and the solution was transferred. The separated aqueous layer fC »«: チ ^ 5 was added and re-extracted. The lemon layers were combined and washed with water. Existence: The concentrated box was dried under reduced pressure to obtain an oily substance.

 The oily substance with (3) was dissolved in an aqueous solution of tr ethano- ^ 8.3 and water 0.43.

_ΟΪ'ΡΙ Seo One 1β—

For example, at room 1 a reaction occurred. After the reaction was completed, the pressure was reduced. Ethanol 8 was added to the residue, and the mixture was cooled to 5 c or less. The filtrated ΛιίΑ is vacuum dried at 40 C to obtain t 25 (J f methine * d: r 2- 2- (2-aminothiazoline 4〉) 2 一 一 イThe yield from methyl ethanoate was 55.5 St.

_{SlfR (60MHz, DMS0-d e} ) *: 3.02 (. 3 H s, S0 2 CH 3), 158 (2 H, t, J = «7Hz, CHj2 S0 2), 4.60 (2 H, t, J- 7Ha, 0C¾ CHJJ), 0 (1 H, s, thiazole ^ 5-H), 7.18 (2H, a, Η¾-)

I Η (KBr) oT ¹ : 3450, 3300, 1720.1610.1535 * 1410

Actual translation 7

Methyl square 2- (2-aminothiazol-1-41) obtained in Example 3 and 2-hydroxyimino vinegar (ester) 0 / are added to acetate-tori 20. t-butyl 7.7 fir was added. Further powder Fushimi anhydrous Sumi黢potassium adding water 1.2 W, 8 · 85 f ¾ , it reacted in the last ^three click of diisocyanato Li um 5. room added S f conc. After the reaction was completed, the precipitate was removed by filtration. Water 30 was added to the filtrate, and potassium carbonate solution 40 was maintained at pH 1 10.5 and hydrolyzed by dropwise addition. When the pH was adjusted to 2 at 2 H¾ after the completion of the reaction, a white precipitate was deposited. After cooling to T in 5 and filtering out the precipitate, dry-explode to give a white 2- (2-aminothiazo-4-1A) — (Z) 12- (t-gutoxyca-methoxyimino) S¾7. 03 f has been obtained, et al _β

_{NMH (60MH 2, D SO-} de) *: 1.40 (33, β, C (C%) 3), 4.53

OMPI one (2H, a, 0CH ₂ C0), δ.80 (1 H, 3, thiazole 5-H), 7.20 (2H, br "HH ₂ )

IB ^ lW ¹ : 3350. 1745, 1840

 (1) The 2- (2-amino-2-azo) -4- (Z)-(Z-butoxycarbo- ^ methoximino) enzyme obtained in Example 4 was fermented 5.429 with r * tori, 40 », added Ν-Methyl * Hole 2« 3 SW, and added 2,2-diethyl bis-pentazothiazo-7.2-. The suspension was cooled to 0, and a solution of 5.38 W of triethyl phosphite dissolved in 0.3-acetate was filtered over 4 hours and 30 minutes. After stirring for 30 minutes, the reaction solution was cooled under −10, and the precipitated precipitate was collected by filtration. The precipitate is washed with cold acetate-tri 2 and dried in vacuo at room temperature to give pale yellow S- (2-Penzothiazoli) 2- (2-aminothiazo-1-4-A- (Z) -2-1 (t) Thus, 6.29 (yield 76.5 *) of butoxyca-methoxymethoxymino vinegar was obtained.

_{NHE (60MHz, DMS0-d e} ) *: 1.47 (9H, s, C (CH 3) 3), .71

(2, a, 0CH ₂ C0), 7.05 (13, 3, thiazo-5- £ [).

7.39 (2 Η, s, ΝΗ 2), 7.45-7.62 (2Η, m, arom),

8.00 ~ 8.28 (2Η, m, arom)

i BC KBr) ^ ^-1 : 3425.3150, 1740, 1710, 1620.

 1540

 (2) 7-Amino-3-methythiomethycemate4. One-pot boric acid 1.5- was added to the solution of titan, hydrofuran-water (4: t) S 4 and triethylamine was added at room temperature. Ji-sai esthetics obtained in (1) above

2.86 was added and reacted at room temperature for 2 hours. After the reaction is completed, the solvent is distilled off.

One 13—

Water 5 was added, and the mixture was washed with ethyl acetate. After adjusting to about 5 with pHfr, the extract was extracted with vinegar. After drying in anhydrous shoiso, the port medium jS: ® was removed under ε. To the residue was added trifluoroacetic acid 2 under permanent cooling, and the mixture was reacted for 2 hours and 30 minutes. After completion of the reaction, the trifluoro * 饞 was removed and water * was added to the residue. This solution was applied to Amberlite XAD-I 200 W, and then dissolved with water. 7-C2- (2-Aminothiazo-1-4-a) as a white powder after collecting the effective components and freezing and drying.

-2-(Power Pometoximino) Acetamide] 1-3-Methyl Thiomethi-3-Sefmue 4 One-strength Boronic Acid 2 Nat-Rudium 89 was obtained.

Elemental analysis 值 Ci _e E ₁₅ i ₅ o ₇ s ₃ κ¾ · 5Η ₂ ο

 Calculate 30.90%, Η 4.05 .Ν 11.31 *

 Measured c 30.35, Η 3.86, Ν 11.26 ^

NMS (60MH25, D.O: 2.00 ( 3 H, s, SCH 3), 3.10-3.95

(H, m, 2-position methylene and _{CH 2 SCH 3), 4.56 (} 2H, 3,

 -NOC¾2), 5.21 (1 fl, d, J »5Hz, S-rank>), 5.75

(l B, d, J »5H _Z , 7th position proton), 7.03 (iH, s, thiazoe ^ 5 -H)

IB (ΚΒΓ) ΟΓ ¹ : 3400 .1 760 .1 61 0, 1 535

(3) 7-Amino-31 [(5-Meth-1,3,4-thiadiazo-2-1y) thiometh]]-3-Cefem-4 Four-strength bond and the thioeste obtained in (1) above According to the method described in (2) above, 73- [2- (2-aminothiazole-4-1 ^)-1 2- (force boxymethoxymino) aceamide] 1-3-[(5—meth-1 , 3,4-thia asiazo-2-y A thiomethyi) -1-3 -sefm "" 4.

,, ^r ATlO Calculated value C 31.44 .H 3.37, H 14.265 *

 Measured C 31.50 .H 3.37%, H 13.48 *

_{HMS (60MHz, Ώ 2 0)} #: 2.80 (3 Η, β, CH 3), 3.65 (2Η, q,

4th place β beta), 4.ί5 (2Η, 3, NOCH ^ CO), 5.25 (1Η, d, 6th place) · 5,85 (ί Η, d, 7th place), 7.00

 (t Η, s, thiazo ν 5-H)

 Industrial applicability

 The aminothiazo-firewood derivative [I] is used as an advantageous synthetic intermediate for synthesizing ^ -pectam antibiotics having excellent antibacterial activity.

Ο ΡΙ

 '' · '. Ο.

Claims

 The scope of the claims

 Diketene and halogen ίanti ίδ, obtained 4-halogenoacetodrane halide and formula

 BSO C3 Ξ 0Η

[Wherein, 袋 represents a low-carboxy group or a fu-group].

 XCH2COCH2COOC2H4SO2B

Wherein X represents a halogen and 、 represents the same meaning as described above.

 H0H

 The symbols in the formula C are as defined above), and thiourea is reacted with the compound represented by the formula

 B in the formula C is as defined above) and the formula

X -C-C00C (CH ₃ ) ₃

Wherein, sigma 'is a halogen, Eta _chi, B ₂ is hydrogen or lower Hi / u key; a group] by reacting the compound represented by the obtained formula

One 31—

 Wherein the compound represented by the formula (IB in the formula is as defined above) is dissolved in the presence of the ¾ group.

[The symbols in the formula are as defined above.] A method for producing an aminothiazo-vinegar derivative represented by the formula: