KR101774132B1 - A process for preparation of (2s, 5r)-7-oxo-6-sulphooxy-2-[((3r)-piperidine-3-carbonyl)-hydrazino carbonyl]-1,6-diaza-bicyclo[3.2.1]-octane - Google Patents

Abstract

In the present invention, (2S, 5R) -7-oxo-6-sulfooxy-2 - [(3R) -piperidine-3-carbonyl) -hydrazinocarbonyl] -1, Bicarb [3.2.1] octane, which comprises reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV). The compounds of formula (I), which are crystalline forms, are claimed.

Description

(2S, 5R) -7-oxo-6-sulfooxy-2 - [((3R) -piperidine-3- carbonyl) -hydrazinocarbonyl] -1,6-diaza- bicyclo [3.2 (3R) -PIPERIDINE-3-CARBONYL) -HYDRAZINO CARBONYL] - 1,6-OXO-6-SULPHOOXY- -DIAZA-BICYCLO [3.2.1] -OCTANE}

Related patent application

This application claims priority of Indian Patent Application No. 717 / MUM / 2013, filed March 8, 2013, the disclosure of which is incorporated herein by reference in its entirety as if recited in full herein. All references, including patents, patent applications and literature, mentioned in the specification are expressly incorporated herein by reference in their entirety.

Field of invention

The present invention relates to (2S, 5R) -7-oxo-6-sulfooxy-2 - [((3R) -piperidine-3- carbonyl) Cyclo [3.2.1] octane. ≪ / RTI >

Chemically, (2S, 5R) -7-oxo-6-sulfooxy-2 - [((3R) -piperidine-3- carbonyl) -hydrazinocarbonyl] -1,6-diaza- bicyclo The compounds of formula (I), known as [3.2.1] octane, have antibacterial properties and are disclosed in PCT International Patent Application No. PCT / IB2012 / 054290.

In one general embodiment, there is provided a process for preparing a compound of formula (I)

(a) reacting a compound of formula (II): < EMI ID = 15.1 >

(b) hydrolyzing the compound of formula (IV) to obtain a compound of formula (V);

(c) sulfonating a compound of formula (V) to obtain a compound of formula (VI); And

(d) converting the compound of formula (VI) to a compound of formula (I).

The details of one or more embodiments of the invention are set forth in the description that follows. Other features, objects, and advantages of the present invention will become apparent from the following description, including the claims.

Reference will now be made to the exemplary embodiments, and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Variations and further modifications of the features of the invention that occur to those skilled in the relevant art and which are illustrated in the present disclosure and are included in this disclosure are considered to be within the scope of the present invention as well as additional applications of the principles of the invention as illustrated herein . It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural forms unless the content clearly dictates otherwise. All references, including patents, patent applications and literature, mentioned in the specification are expressly incorporated herein by reference in their entirety as if fully recited herein.

The term "HOBt" as used herein refers to 1-hydroxybenzotriazole.

The term "EDC " as used herein refers to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide.

In one general embodiment, there is provided a process for preparing a compound of formula (I)

(a) reacting a compound of formula (II): < EMI ID = 15.1 >

(b) hydrolyzing the compound of formula (IV) to obtain a compound of formula (V);

(c) sulfonating a compound of formula (V) to obtain a compound of formula (VI); And

(d) converting the compound of formula (VI) to a compound of formula (I).

Compounds of formula (IV) are obtained by reacting compounds of formula (II) with compounds of formula (III). In some embodiments, the reaction is carried out in the presence of 1-hydroxybenzotriazole. In some other embodiments, the compound of formula (IV) is reacted with a compound of formula (II) in the presence of 1-hydroxybenzotriazole and 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride, (III). ≪ / RTI > In some embodiments, the reaction is carried out in water as a reaction solvent.

Compounds of formula (V) are obtained by hydrolysis of compounds of formula (IV). The hydrolysis reaction may be carried out using a suitable hydrocracker. In some embodiments, the hydrolysis of the compound of formula (IV) to obtain the compound of formula (V) is carried out in the presence of a transition metal catalyst and a hydrogen source. In some other embodiments, the transition metal catalyst is carbon-supported palladium and the hydrogen source is hydrogen gas. In some other embodiments, the hydrolysis reaction is carried out in the presence of a suitable solvent, such as an alcohol (e. G., Methanol). In some embodiments, the hydrolysis of the compound of formula (IV) to obtain the compound of formula (V) is carried out in methanol as solvent, in the presence of hydrogen gas, using a 10% palladium on carbon catalyst.

Compounds of formula (VI) are obtained by sulfonation of compounds of formula (V). The sulfonation reaction can be carried out in the presence of a suitable solvent. In some embodiments, sulfonation of a compound of formula (V) to obtain a compound of formula (VI) is performed by reacting a compound of formula (V) with a sulfur trioxide-pyridine complex followed by treatment with tetrabutylammonium hydrogen sulphate.

The compound of formula (VI) is converted into a compound of formula (I) in the presence of a suitable reagent. In some embodiments, the compound of formula (VI) is converted to a compound of formula (I) by reacting the compound of formula (VI) with trifluoroacetic acid.

In some embodiments, the compound of formula (I) is prepared using the method described in the following scheme-1.

In some embodiments, a compound of formula (I) is provided which is crystalline.

In some other embodiments, it is crystalline and has a crystal form of 10.28 (± 0.2), 10.57 (± 0.2), 12.53 (± 0.2), 13.82 (± 0.2), 15.62 (± 0.2), 18.16 0.2, 25.35 (± 0.2), 22.99 (± 0.2), 23.18 (± 0.2), 24.27 (± 0.2), 24.81 (± 0.2), 25.45 (± 0.2), 29.85 (I) having an X-ray powder diffraction pattern comprising a peak selected from the group consisting of: (1) a compound of the formula .

In some other embodiments, it is crystalline and has a crystal form of 10.28 (± 0.2), 10.57 (± 0.2), 12.53 (± 0.2), 13.82 (± 0.2), 15.62 (± 0.2), 18.16 And a peak selected from the group consisting of 20.35 (± 0.2), 20.64 (± 0.2), 21.33 (± 0.2), 24.27 (± 0.2), 24.81 (± 0.2), and 25.45 Compounds of formula (I) having a powdered diffraction pattern are provided.

In some other embodiments, there is provided a compound of formula (I) which is crystalline and has an X-ray powder diffraction pattern substantially identical to that shown in Fig.

In some embodiments, there is provided a process for preparing a compound of formula (II):

(a) esterifying a compound of formula (VII) < EMI ID = 25.1 > with a compound of formula (VIII)

(b) converting the compound of formula (VIII) to a compound of formula (II).

Generally, the esterification of a compound of formula (VII) with a compound of formula (VIII) may be carried out using a suitable esterifying agent. Typical examples of suitable esterification agents include ethyl iodide in the presence of potassium carbonate. The esterified compound of formula (VIII) is then converted to a compound of formula (II) using a suitable reagent such as hydrazine hydrate. A schematic diagram for the synthesis of compounds of formula (II) is provided in Scheme-2 below.

Those skilled in the art will readily appreciate that various substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, those skilled in the art will appreciate that the invention may be practiced using a variety of different compounds within the overall description set forth.

Example

The following examples illustrate the presently best described embodiments of the present invention. However, it should be understood that the following are merely illustrative or exemplary of the application of the principles of the present invention. Without departing from the spirit and scope of the invention, those skilled in the art will be able to devise numerous changes and alternative compositions, methods and systems. The appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been particularly described above, the following examples provide additional details that are presently contemplated to be the most practical and preferred embodiments of the present invention.

Example  One

Preparation of (R) -N-Boc-piperidine-3-carboxylic acid hydrazide (II)

Step 1 : Preparation of (R) -ethyl-N-Boc-piperidine-3-carboxylate (VIII)

To a solution of (R) -N-Boc-piperidine-3-carboxylic acid (1 kg, 4.36 mol) in N, N-dimethylacetamide (3 L) was added potassium carbonate (0.664 kg, 4.80 mol ) And the resulting suspension was stirred at room temperature for 30 minutes. To the reaction was added ethyl iodide (0.75 kg, 4.80 mol) via an additional funnel and the reaction was stirred at room temperature for 15 minutes and then 1 hour at 50 < 0 > C. The reaction was monitored using TLC (ethyl acetate: hexane 1: 1). After the reaction was complete, the reaction was cooled to room temperature and diluted with ethyl acetate (5 L). The suspension was filtered under suction and the wet cake was washed with ethyl acetate (5 L). The filtrate was stirred with 5% w / v sodium thiosulfate (15 L) and the layers were separated. The aqueous layer was re-extracted with additional ethyl acetate (5 L). The combined organic layers were washed with water (5 L) and dried over sodium sulfate. The organic layer was evaporated in vacuo to give a semi-solid which solidified as (R) -ethyl-N-Boc-piperidine-3-carboxylate in an amount of 1.1 kg of 99.5% yield.

analysis:

NMR: (CDCl3): 4.63 ( q, 2H), 3.90 (d, 1H), 2.87-2.95 (m, 2H), 2.73 (td, 1H), 2.32-2.39 (m, 1H), 1.66-2.01 (m , 2H), 1.52-1.68 (m, 2H), 1.39 (s, 9H), 1.19 (t, 3H).

Mass : (M + 1): 258.1 for C13H23NO4;

Step-2 : Preparation of (R) -N-Boc-piperidine-3-carboxylic acid hydrazide (II)

(1.1 kg, 4.28 mol) was liquefied by warming and transferred to a round bottom flask (10 L), followed by addition of hydrazine hydrate (0.470 kg, 9.41 < RTI ID = 0.0 & mol) and stirring was started. The reaction mixture was stirred at about 120 < 0 > C to 125 < 0 > C for 5 hours. As TLC (chloroform: methanol 9: 1) indicated completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (5.5 L) and then dichloromethane (11 L) and stirred for 20 min. The layers were separated and the aqueous layer was extracted with additional dichloromethane (5.5 L). The combined organic layers were washed with water (2.75 L). The organic layer was dried over sodium sulphate and evaporated in vacuo to give a thick gel which, upon stirring and seeding in the presence of cyclohexane (5.5 L), provided a white solid. The suspension was filtered and the wet cake was washed with fresh cyclohexane (0.5 L). The cake was dried under vacuum at 35 [deg.] C to give (R) -N-Boc-piperidine-3-carboxylic acid hydrazide as a white solid in an amount of 0.90 kg of 87% yield.

analysis

NMR: (CDCl3): 7.42 ( br s, 1H), 3.92 (d, 1H), 3.88 (s, 2H), 3.54-3.65 (br s, 1H), 3.17 (br t, 1H), 2.98 (br s 2H), 1.76 (s, 1H), 1.60-1.70 (m, 1H), 1.45 (s, 9H).

Mass (M + 1): 244.1 for C11H21N3O3.

Specific _{^{rotation: [α] 25 D = -53.5}} ° (c 0.5, methanol).

HPLC purity: 99%

Example  2

(2S, 5R) -7-oxo-6-sulfooxy-2 - [((3R) -piperidine-3- carbonyl) -hydrazinocarbonyl] -1,6-diaza- bicyclo [3.2 .1] octane (I): < EMI ID =

Step 1 : (2S, 5R) -6-Benzyloxy-7-oxo-2 - [((3R) -N-Boc-piperidine-3-carbonyl) -hydrazinocarbonyl] -Diaza-bicyclo [3.2.1] octane (IV): < EMI ID =

Sodium (2S, 5R) -7-oxo-6-benzyloxy-1,6-diaza-bicyclo [3.2.1] octane- 2-carboxylate (III, 200 gm, 0.67 mol; / MUM / 2013) was dissolved in water (2.8 L) to give a clear solution under stirring at room temperature. (171 gm, 0.70 mol), EDC hydrochloride (193 gm, 1.01 mol), and HOBt (90.6 gm, 0.67 mol) in succession to a clear solution of (R) mol) and then water (0.56 L) was added under stirring at 35 < 0 > C. The reaction mixture was stirred for 20 h at 35 < 0 > C. As the maximum precipitation was achieved, TLC (acetone: hexane 35:65) indicated completion of the reaction. The suspension was filtered under suction and the wet cake was washed with additional water (2 L). The wet cake was suspended in warm water (10 L) and stirred for 5 hours. This was filtered off under suction and dried under vacuum at 45 ° C to give (2S, 5R) -6-benzyloxy-7-oxo-2 - [((3R) -N- Piperidine-3-carbonyl) -hydrazinocarbonyl] -1,6-diaza-bicyclo [3.2.1] octane (IV).

analysis

NMR: (CDCl3): 8.40 ( br s, 1H), 7.34-7.44 (m, 5H), 5.05 (d, 1H), 4.90 (d, 1H), 4.00 (br d, 1H), 3.82 (br s, 1H), 3.30 (br s, 1H), 3.16-3.21 (m, 1H), 3.06 (br d, , 4H), 1.60-1.75 (m, 4H), 1.45-1.55 (m, 2H), 1.44 (s, 9H).

Mass : (M + 1) = 502.1 for C25H35N5O6

HPLC purity: 98.4%

Step 2 : (2S, 5R) -6-Hydroxy-7-oxo-2 - [((3R) -N-Boc- piperidine- 3-carbonyl) -hydrazinocarbonyl] -Diaza-bicyclo [3.2.1] octane (V): < EMI ID =

(2S, 5R) -6-benzyloxy-7-oxo-2 - [((3R) -N- Boc- piperidine- 3- carbonyl) -hydrazino- carbonyl] -1,6-diaza - bicyclo [3.2.1] octane (153 gm, 0.305 mol) was dissolved in methanol (1.23 L) to give a clear solution. To this solution was added 10% Pd-C (15.3 gm, 50% wet) catalyst. The suspension was stirred at 35 < 0 > C under 100 psi hydrogen atmosphere for 3 hours. As the reaction was complete on TLC (TLC system methanol: chloroform 10:90), the catalyst was filtered through celite under suction. The catalyst was washed with additional methanol (600 ml). The filtrate was evaporated under vacuum at less than 40 < 0 > C to give a crude residue. The residue was stirred with cyclohexane (1.23 L) for 1 hour. The solids were filtered off with suction and the wet cake was washed with additional cyclohexane (0.25 L) to give (2S, 5R) -6-hydroxy-7-oxo-2 - [((3R ) -N-Boc-piperidine-3-carbonyl) -hydrazinocarbonyl] -1,6-diaza-bicyclo [3.2.1] octane (V). The labile product was used immediately for the next reaction.

Analysis :

NMR: (CDCl3): 9.0 ( br s, 2H), 4.01 (br d, 2H), 3.80 (br s, 1H), 3.74 (br s, 1H), 3.48 (s, 1H), 3.13-3.26 (m (Br s, 1 H), 2.96 (br s, 1 H), 2.96 (br s, (m, 3 H) 1.44 (s, 9 H).

Mass : (M-1): 410.3 for C18H29N5O6

HPLC purity : 96.34%

Step 3 : (2S, 5R) -6-Sulfooxy-7-oxo-2 - [((3R) -N-Boc- piperidine- 3-carbonyl) -hydrazinocarbonyl] -Diaza-bicyclo [3.2.1] octane (VI): < EMI ID =

A solution of (2S, 5R) -6-hydroxy-7-oxo-2 - [((3R) -N-Boc- piperidine-3- carbonyl) -hydrazinocarbonyl] -1,6-diaza-bicyclo [3.2.1] octane (113 gm, 0.274 mol) was charged with stirring with triethylamine (77 ml, 0.548 mol) to give a clear solution. To this clear solution was added pyridine sulfur trioxide complex (57 gm, 0.356 mol) with stirring at 35 < 0 > C. The reaction mixture was stirred for 3 hours. The reaction mixture was worked up by the addition of 0.5 M aqueous potassium dihydrogenphosphate (1.13 L) followed by ethyl acetate (2.26 L) and the biphasic mixture was stirred at 35 < 0 > C for 15 min. The phases were separated. The aqueous layer was re-extracted with a dichloromethane ethyl acetate mixture (1: 2 v / v, 2.26 L 2 times). The layers were separated. To the water layer was added solid hydrogen tetrabutylammonium hydrogen sulfate (84 gm, 0.247 mol) and stirring was continued at room temperature for 3 hours. Dichloromethane (1.13 L) was added to the reaction mixture. The layers were separated. The aqueous layer was reextracted with additional dichloromethane (0.565 L). The layers were separated. Silica gel (226 gm) was added to the combined organic layers and the suspension was stirred for 1 hour. The suspension was filtered and the silica gel was washed with dichloromethane (1 L). The combined filtrates were evaporated in vacuo to give a solid. Cyclohexane (0.9 L) was added to the solid and stirred until complete solidification occurred (about 1-2 hours). The suspension was filtered under suction and the wet cake was dried under vacuum at 40 ° C to give (2S, 5R) -6-sulfo-2- -N-Boc-piperidine-3-carbonyl) -hydrazinocarbonyl] -1,6-diaza-bicyclo [3.2.1] octane (VI).

analysis

NMR: (CDCl3): 8.50 ( br s, 2H), 4.32 (br s, 1H), 3.97 (d, 2H), 3.15-3.37 (m, 12H), 2.43 (br s, 1H), 2.33 (d, 1H), 2.10-2.2 (br m, 1H), 1.84-1.95 (m, 3H), 1.60-1.73 (m, 13H), 1.39-1.48 (m, 19H), 0.98 (t, 12H).

Mass : (M-1): 490.4 as free sulfonic acid with respect to C18H28N5O9S.N (C4H9) 4;

HPLC purity : 96.3%

Step 4 : (2S, 5R) -6-Sulfooxy-7-oxo-2 - [((3R) -piperidine-3- carbonyl) -hydrazinocarbonyl] Synthesis of bicyclo [3.2.1] octane (I):

(2S, 5R) -6-sulfooxy-7-oxo-2 - [((3R) -N-Boc- piperidine- 3- carbonyl) -hydrazinocarbonyl] The tetrabutylammonium salt of bicyclo [3.2.1] octane (113 gm, 0.154 mol) was dissolved in dichloromethane (280 ml) and trifluoroacetic acid (280 ml) was slowly added to the clear solution at 0 ° C to 5 ° C Respectively. The reaction mixture was stirred at 0 < 0 > C to 5 < 0 > C for 1 hour. The solvent and excess trifluoroacetic acid were evaporated at less than 40 < 0 > C under vacuum to about 1/3 of its original volume to give a pale yellow oily residue. The oily residue was stirred with diethyl ether (2.25 L) for 1 hour to give a suspension. The precipitate was filtered under suction and transferred to a round bottom flask to which was added diethyl ether (1.1 L) with stirring. The suspension was stirred for 30 minutes and filtered under suction to give a solid. The solid was charged to a round bottom flask and to this was added acetone (1.130 L). The pH of the suspension was adjusted to 4.5-5.5 by careful addition of a 10% solution of sodium 2-ethylhexanoate in acetone. The resulting suspension was filtered under suction and the wet cake was washed with acetone (550 ml) to give a crude solid. The resulting solid was dried under vacuum at < RTI ID = 0.0 > 40 C < / RTI > to provide 65 gm of crude. The crude was dissolved in water (65 ml) with stirring and isopropyl alcohol (455 ml) was added to the clear solution. The suspension was stirred for 24 hours and filtered under suction. The wet cake was washed with isopropyl alcohol (225 ml) and dried under vacuum at less than 40 ° C to yield crystalline (2S, 5R) -6-sulfooxy-7- [((3R) -piperidine-3-carbonyl) -hydrazinocarbonyl] -1,6-diaza-bicyclo [3.2.1] octane (I).

Analysis :

NMR: (DMSO-d6) = 9.97 (d, 2H), 8.32 (br s, 2H), 4.00 (br s, 1H), 3.81 (d, 1H), 3.10-3.22 (m, 3H), 2.97-3.02 (m, 2H), 2.86-2.91 (m, 1H), 2.65-2.66 (m, 1H), 1.97-2.03 (m, 1H), 1.57-1.88 (m, 7H).

Mass : (M-1): 390.3 for C13H21N5O7S

HPLC purity : 95.78%

Nonlinearity : [?] ²⁵ _D : - 32.6 (c 0.5, water)

X-ray powder diffraction patterns including peaks at the following (2? Values): 10.28 (± 0.2), 10.57 (± 0.2), 12.53 (± 0.2), 13.82 (± 0.2), 15.62 (± 0.2), 18.16 0.2), 18.49 (占 0.2), 20.35 占 0.2, 20.64 占 0.2, 21.33 占 0.2, 22.99 占 0.2, 23.18 占 0.2, 24.27 占 0.2, , 25.45 (± 0.2), 29.85 (± 0.2), 30.45 (± 0.2), 32.39 (± 0.2), 36.84 (± 0.2).

Conventional X-ray analysis is performed as follows. Pass the test material through a Sieve # 100 BSS or lightly crush it using a mortar and pestle. The test material was uniformly placed on a sample holder having a cavity surface on one side, the sample was compressed and the thin, uniform film was cut using a glass slide so that the surface of the sample was smooth and flat. X-ray diffraction charts were recorded using the following device parameters.

Apparatus : X-ray diffractometer

(PANalytical, Model X'Pert Pro MPD)

target Source : Cu k (?)

Scattering slit (incidence beam) : 1 °

Programmable diverging slit : 10 mm (fixed)

Scattering prevention slit (diffraction beam) : 5.5 mm

Step width : 0.02 属

Voltage : 40 kV

electric current : 40 mA

Time per step : 30 seconds

Scanning range : 3 to 40 °

Claims (11)

CLAIMS What is claimed is: 1. A process for preparing a compound of formula (I)

(a) reacting a compound of formula (II) with a compound of formula (III) in the presence of water as a solvent to obtain a compound of formula (IV);

(b) hydrolyzing the compound of formula (IV) to obtain a compound of formula (V);

(c) sulfonating a compound of formula (V) to obtain a compound of formula (VI); And

(d) converting the compound of formula (VI) to a compound of formula (I). The process according to claim 1, wherein the reaction of the compound of formula (II) with the compound of formula (III) to obtain the compound of formula (IV) is carried out by reacting 1-hydroxybenzotriazole and 1-ethyl-3- (3- Propyl) carbodiimide hydrochloride. ≪ / RTI > The process according to claim 1, wherein the hydrolysis of the compound of formula (IV) to obtain a compound of formula (V) is carried out in the presence of a transition metal catalyst and a hydrogen source. 4. The process of claim 3, wherein the transition metal catalyst is carbon supported palladium and the hydrogen source is hydrogen gas. The process according to claim 1, wherein the sulfonation of the compound of formula (V) to obtain the compound of formula (VI) is carried out by reacting the compound of formula (V) with a sulfur trioxide-pyridine complex followed by treatment with tetrabutylammonium hydrogen sulfate How to do it. The method of claim 1, wherein the compound of formula (VI) is converted to a compound of formula (I) by reacting a compound of formula (VI) with trifluoroacetic acid.

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