KR20080042460A - Thienamycin solvate and its process - Google Patents

Abstract

A process for preparing thienamycin solvate useful as an intermediate for preparing imipenem is provided to improve preparation yield and convenience and purity of the compound by using easily obtainable raw materials and reagents and performing the reaction under mild condition. A process for preparing thienamycin solvate represented by the formula(IV) comprises the steps of: reacting compounds represented by the formula(II) with diphenylchloro phosphate in a solvent selected from 1,3-dimethyl-2-imidazolidinone(DMI), 1,3-diethyl-2-imidazolidinone(DEI), 1,3-dipropyl-2-imidazolidonone(DPI), 1,3-dibutyl-2-imidazolidinone(DBI), 1,3-diisopropyl-2-imidazolidinone(DIPI) and 1,3-di-t-butyl-2-imidazolidinone(DTBI) or a mixture of the solvent with dichloromethane in the presence of secondary amine at -10 to -60 deg. C; and coupling the reaction product with 2-aminoethanthiol or its hydrochlorate under in-situ reaction condition, wherein R1 is easily removable carboxyl-protecting group and is selected from benzyl, p-nitrobenzyl and methoxybenzyl; and R2 is alkyl group or aryl group. Further, the secondary amine is an N,N-diisopropylethylamine.

Description

Thienamycin solvate and its preparation method {Thienamycin solvate and its process}

The present invention relates to a thienamycin solvent compound of formula (IV), which is an important intermediate in the process of preparing a imipenem compound of formula (I), which is a beta-lactam-based carbapenem antibiotic, and a method for preparing the same .

In the above formula, R ₁ is a carboxyl protecting group that can be easily removed, and may be selected from the group consisting of benzyl, p-nitrobenzyl and methoxybenzyl, and R ₂ is the same or different from each other and is an alkyl group or an aryl group.

As can be seen from the above formula, imipenem is an N-formimidoyl derivative of thienamycin, represented by Formula I, wherein imipenem monohydrate is a very broad antibacterial agent for gram-positive and gram-negative aerobic and anaerobic species. Spectrum and strong antimicrobial activity. This is partly due to its high stability in the presence of β-lactamase.

Conventionally, imipenem is disclosed for the first time in US Pat. No. 4,194,047, and the method for preparing imipenem disclosed herein reveals that an intermediate product of low yield and poor quality is produced due to the instability of the starting compound, ie, thienamycin. It is also purified by tube chromatography during the preparation process, and the product obtained through lyophilization is amorphous and then very thermodynamically unstable.

U.S. Patent No. 4,292,436 discloses an in-situ reaction state without reacting N-formimidoyl 2-aminoethanethiol compounds protecting an amine group from a bicycloketone precursor represented by the following Chemical Formula II, without separating various intermediates. A method of synthesizing imipenem monohydrate through a hydrogenation reaction has been disclosed, which provides an alternative method for preparing imipenem, but the process to the final product is long and shows low yield.

US Pat. No. 4,894,450 obtained an enolphosphate compound as an intermediate using a new reagent, bis (chloro-substituted phenyl) phosphochloridate, to activate the bicycloketone precursor of formula (II). The reagents used in the above are not commercially available, and the preparation method includes cumbersome multi-stage purification methods.

WO 02/36594 is similar to Merck, USA, but uses tetrahydrofuran and an expensive 1,3-dimethyl-3,4,5,6-tetrahydro- (2H) -pyrimidinone (DMPH) as a reaction solvent. The crystalline imipenem was synthesized from the starting bicyclic ketoester as a very low yield by using column chromatography using a mixed solvent.

As described above, the process seen in the prior art method is long, the yield is low, and in view of various disadvantages such as the difficulty of the purification process, it is convenient to work on an industrial scale, and the purchase of raw materials and reagents is easy, and commercial There is a need to develop a new intermediate of the imipenem and a method for using the same that can be used as, and can provide a substantially pure product in excellent yield.

Therefore, the present invention improves this problem, and 1,3-dimethyl-2-imidazolidinone (DMI), which is not a known method of thienamycin, which is an important substance for producing industrially available imipenem monohydrate, 1,3-diethyl-2-imidazolidinone (DEI), 1,3-dipropyl-2-imidazolidinone (DPI), 1,3-dibutyl-2-imidazolidinone (DBI) Thienamycin Solvent Compound, a Novel Substance Using 1,3-Diisopropyl-2-imidazolidinone (DIPI) and 1,3-di-t-butyl-2-imidazolidinone (DTBI) IV And to provide a method for producing the same.

The present invention relates to thienamycin solvent compound (IV), which is an imipenem intermediate, and a process for preparing the same.

In the above formula, R ₁ is a carboxyl protecting group that can be easily removed, and may be selected from the group consisting of benzyl, p-nitrobenzyl and methoxybenzyl, and R ₂ is the same or different from each other and is an alkyl group or an aryl group.

In order to achieve the above object, in the present invention to prepare a novel intermediate of formula Imiphenem during the process of formula (IV), the compound of formula (II) as shown in Scheme I below 1,3-dimethyl-2-imidazolidinone (DMI), 1,3-diethyl-2-imidazolidinone (DEI), 1,3-dipropyl-2-imidazolidinone (DPI), 1,3-dibutyl-2-imidazoli One solvent alone selected from dinon (DBI), 1,3-diisopropyl-2-imidazolidinone (DIPI), 1,3-di-t-butyl-2-imidazolidinone (DTBI), or A mixture of dichloromethane and diphenylchlorophosphate was reacted with diphenylchlorophosphate in the presence of a base secondary to prepare an enolphosphate compound (Formula III), followed by in-situ reaction to 2-aminoethanethiol or its hydrochloride salt. The present invention provides a method for preparing a novel thienamycin solvent compound of Formula IV by coupling.

Scheme Ⅰ

Wherein R ₁ is a carboxyl protecting group that can be easily removed, and may be selected from the group consisting of benzyl, p-nitrobenzyl and methoxybenzyl, R ₂ is the same or different from each other and is an alkyl group or an aryl group, X is OP (O) (oR) ₂ or OS (O) ₂ R, wherein R is C _{1 ~ 6} alkyl, aryl alkyl, including methyl, ethyl, propyl, isopropyl, butyl, t- butyl, and It may be a straight or branched chain, and may be a cyclic group including cyclopropyl, cyclopentyl, cyclohexyl and cyclopropylmethyl. Here, aryl means an aromatic ring comprising phenyl, substituted phenyl and naphthyl.

In the presence of a suitable N-substituted lactam or a base in a N, N-disubstituted amide, a secondary amine, optionally in combination with an inert organic solvent to activate the compound of formula (II) to obtain an activated enol phosphate compound of formula (III) , 2-aminoethanethiol or its hydrochloride is reacted in-situ to prepare a thienamycin solvent compound of Formula IV.

The present invention, unlike the conventional synthesis method 1,3-dimethyl-2-imidazolidinone (DMI), 1,3-diethyl-2-imidazolidinone (DEI), 1,3-dipropyl-2 Imidazolidinone (DPI), 1,3-dibutyl-2-imidazolidinone (DBI), 1,3-diisopropyl-2-imidazolidinone (DIPI), 1,3-di- A thienamycin solvent compound of a novel substance, which is a key intermediate of crystalline imipenem monohydrate, was prepared using one solvent selected from t-butyl-2-imidazolidinone (DTBI). N, N-diisopropylethylamine is used as the secondary amine which is a salt group. The reaction temperature is in the range of -10 ° C to -60 ° C.

Using the thienamycin solvent compound, a novel form of intermediate of the present invention, the crystalline imipenem monohydrate of formula (I) can be efficiently produced in high yield.

J. Chem . Soc 1947 . Based on 307, the following compounds which are reactive solvents of the present invention can be prepared.

After dissolving 170 g of carbonyl chloride in 1000 mL of toluene, the reaction temperature is cooled to 0 to -15 ° C. 145 g of N, N'-dimethylethylenediamine dissolved in 500 mL of toluene was added to the reaction solution for 20 minutes. After stirring for 1 hour at this temperature, the amine hydrochloride was filtered off, and the filtrate was distilled under reduced pressure to give 1,3-dimethyl-2-imidazolidinone (DMI) (b · p 104 ° / 15 mm). Can be.

In a similar manner, 1,3-diethyl-2-imidazolidinone (DEI) (b.p 122 ° / 22 mm) can be obtained from N, N'-diethylethylenediamine, and N, N ' 1,3-dipropyl-2-imidazolidinone (DPI) (b.p 148 ° / 23 mm) can be obtained from -di-n-propylethylenediamine.

In addition, 1,3-diisopropyl-2-imidazolidinone (DIPI) (b.p 130 ° / 15 mm) can be obtained from N, N'-diisopropylethylenediamine, using these compounds The experiment of the following examples can be carried out.

Hereinafter, examples of the present invention will be described.

Example  One

To a mixture of 220 mL of 1,3-dimethyl-2-imidazolidinone (DMI) and 110 mL of dichloromethane, (5R, 6S) -p-nitrobenzyl-6-[(1R) -1-hydroxy of formula II After dissolving 23.0 g of ethyl] -1-azabicyclo [3.2.0] hept-3,7-dione-2-carboxylate, the reaction temperature is cooled to 0-10 C.

19.6 g of N, N-diisopropylethylamine and 18.65 g of diphenylchlorophosphate were added sequentially. The reaction solution was prepared by stirring for 1 to 2 hours while maintaining the reaction temperature, and the enol phosphate compound was used as it is in the next step without separation. Check for the presence of enolfostate compound in the reaction solution.

Example  2

2-amino was dissolved in 44 mL of 1,3-dimethyl-2-imidazolidinone (DMI) after cooling the reaction solution of the enolphosphate compound of Chemical Formula III prepared in Example 1 to −50 to −55 ° C. 8.8 g of ethanethiol hydrochloride were added to the reaction solution for 20 minutes. It stirred for 3 hours at this temperature and then crystallized. Acetonitrile was added to the reaction solution, the reaction temperature was raised to 0--5 ° C., followed by stirring for 2 hours. The crystallized precipitate was filtered, washed with acetonitrile, and dried under reduced pressure at room temperature. 29.5 g (80.20%) of Namaicin DMI solvent compound (Formula IV) were obtained.

¹ H-NMR (DMSO-d6, ppm):

1.13 (d, J = 6 Hz, 3H), 2.63 (s, 6H), 3.03-3.05 (m, 2H), 3.1-3.12 (m, 2H), 3.19 (s, 4H), 3.34 (m, 2H), 3.97 (m, 1H), 4.18 (m, 1H), 5.18 (d, J = 5.2 Hz, 1H), 5.28-5.45 (q, J = 14.4 Hz, 41.6 Hz, 2H), 7.71 (d, J = 9.2 Hz, 2H), 8.18 (s, 2H), 8.25 (d, J = 8.8 Hz, 2H)

Example  3

29.3 g (75.75%) of a novel off-white thienamycin DEI solvent compound (Formula IV) using 1,3-diethyl-2-imidazolidinone (DEI) in a similar manner to Examples 1 and 2 above Obtained.

¹ H-NMR (DMSO-d6, ppm):

1.12-1.14 (m, 9H), 3.03-3.05 (m, 2H), 3.1-3.12 (m, 2H), 3.3-3.4 (m, 6H), 3.97 (m, 1H), 4.18 (m, 1H), 5.18 (d, J = 5.2 Hz, 1H), 5.28-5.45 (q, J = 14.4 Hz, 41.6 Hz, 2H), 7.71 (d, J = 9.2 Hz, 2H), 8.18 (s, 2H), 8.25 ( d, J = 8.8 Hz, 2H)

Example  4

28.9 g (71.30%) of a novel off-white thienamycin DPI solvent compound (Formula IV) using 1,3-dipropyl-2-imidazolidinone (DPI) in a similar manner to Examples 1 and 2 above Obtained.

¹ H-NMR (DMSO-d6, ppm):

0.89 (t, 6H), 1.13 (d, J = 6 Hz, 3H), 1.4-1.5 (m, 4H), 2.32-2.38 (m, 4H), 3.03-3.05 (m, 2H), 3.1-3.12 (m , 2H), 3.34 (m, 2H), 3.97 (m, 1H), 4.18 (m, 1H), 5.18 (d, J = 5.2 Hz, 1H), 5.28-5.45 (q, J = 14.4 Hz, 41.6 Hz , 2H), 7.71 (d, J = 9.2 Hz, 2H), 8.18 (s, 2H), 8.25 (d, J = 8.8 Hz, 2H)

Example  5

31.5 g (74.30%) of a novel off-white thienamycin DBI solvent compound (Formula IV) using 1,3-dibutyl-2-imidazolidinone (DBI) in a similar manner to Examples 1 and 2 above Obtained.

¹ H-NMR (DMSO-d6, ppm):

0.91 (t, 6H), 1.13 (d, J = 6 Hz, 3H), 1.25-1.35 (m, 4H), 1.35-1.45 (m, 4H), 2.35-2.4 (m, 4H), 3.03-3.05 (m , 2H), 3.1-3.12 (m, 2H), 3.34 (m, 2H), 3.97 (m, 1H), 4.18 (m, 1H), 5.18 (d, J = 5.2 Hz, 1H), 5.28-5.45 ( q, J = 14.4 Hz, 41.6 Hz, 2H), 7.71 (d, J = 9.2 Hz, 2H), 8.18 (s, 2H), 8.25 (d, J = 8.8 Hz, 2H)

Example  6

29.6 g (73.03%) of a novel off-white thienamycin DIPI solvent compound (Formula IV) using 1,3-diisopropyl-2-imidazolidinone (DIPI) in a similar manner to Examples 1 and 2 above ) Was obtained.

¹ H-NMR (DMSO-d6, ppm):

1.05-1.08 (d, 12H), 1.13 (d, J = 6 Hz, 3H), 2.87-2.94 (m, 2H), 3.03-3.05 (m, 2H), 3.1-3.12 (m, 2H), 3.34 (m , 2H), 3.97 (m, 1H), 4.18 (m, 1H), 5.18 (d, J = 5.2 Hz, 1H), 5.28-5.45 (q, J = 14.4 Hz, 41.6 Hz, 2H), 7.71 (d , J = 9.2 Hz, 2H), 8.18 (s, 2H), 8.25 (d, J = 8.8 Hz, 2H)

Example  7

30.5 g of a novel off-white thienamycin DTBI solvent compound (Formula IV) using 1,3-di-t-butyl-2-imidazolidinone (DTBI) in a similar manner to Examples 1 and 2 ( 71.97%) was obtained.

¹ H-NMR (DMSO-d6, ppm):

1.1 (s, 18H), 1.13 (d, J = 6Hz, 3H), 3.03-3.05 (m, 2H), 3.1-3.12 (m, 2H), 3.34 (m, 2H), 3.97 (m, 1H), 4.18 (m, 1H), 5.18 (d, J = 5.2 Hz, 1H), 5.28-5.45 (q, J = 14.4 Hz, 41.6 Hz, 2H), 7.71 (d, J = 9.2 Hz, 2H), 8.18 ( s, 2H), 8.25 (d, J = 8.8 Hz, 2H)

As described, the present invention improves the problems of the conventional manufacturing method and provides a method for producing a compound of formula IV, which is a novel thienamycin imidazolidinone derivative solvent compound, which is an important intermediate of imipenem monohydrate, under high reaction conditions under mild reaction conditions. According to the present invention, there is a merit that a crystalline imipenem monohydrate can be produced with high yield and high purity by solving a problem of a method of preparing a crude imipenem monohydrate obtained in a conventional low yield from a new compound IV.

Claims (4)

Thienamycin solvent compound of formula (IV)

In the above formula, R ₁ is a carboxyl protecting group that can be easily removed, and may be selected from the group consisting of benzyl, p-nitrobenzyl and methoxybenzyl, and R ₂ is the same or different from each other and is an alkyl group or an aryl group. In preparing the thienamycin solvent compound of formula (IV), the compound of formula (II) is prepared as 1,3-dimethyl-2-imidazolidinone (DMI), 1,3-diethyl-, as shown in Scheme I below. 2-imidazolidinone (DEI), 1,3-dipropyl-2-imidazolidinone (DPI), 1,3-dibutyl-2-imidazolidinone (DBI), 1,3-diiso Secondary base, using one solvent alone or a mixture of dichloromethane selected from propyl-2-imidazolidinone (DIPI), 1,3-di-t-butyl-2-imidazolidinone (DTBI) After reacting with diphenylchlorophosphate in the presence of an amine to prepare an enolphosphate compound of Formula III, the compound of Formula IV is prepared by coupling 2-aminoethanethiol or its hydrochloride salt in an in-situ reaction state. How to manufacture. Scheme I

Wherein R ₁ is a carboxyl protecting group that can be easily removed, and may be selected from the group consisting of benzyl, p-nitrobenzyl and methoxybenzyl, R ₂ is the same or different from each other and is an alkyl group or an aryl group, X is OP (O) (oR) ₂ or OS (O) ₂ R, wherein R is C _{1 ~ 6} alkyl, aryl alkyl, including methyl, ethyl, propyl, isopropyl, butyl, t- butyl, and It may be a straight or branched chain, and may be a cyclic ring comprising cyclopropyl, cyclopentyl, cyclohexyl and cyclopropylmethyl, with aryl being an aromatic ring comprising phenyl, substituted phenyl and naphthyl. The method according to claim 2, wherein the secondary amine, which is a suitable base, uses N, N-diisopropylethylamine. The method of claim 2, wherein the compound of formula IV is prepared at a reaction temperature of -10 ° C to -60 ° C.