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WO2018234962A1 - PROCESS FOR O-SULFONATION OF 1,6-DIAZABICYCLO [3.2.1] OCTANE COMPOUNDS - Google Patents

PROCESS FOR O-SULFONATION OF 1,6-DIAZABICYCLO [3.2.1] OCTANE COMPOUNDS Download PDF

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WO2018234962A1
WO2018234962A1 PCT/IB2018/054420 IB2018054420W WO2018234962A1 WO 2018234962 A1 WO2018234962 A1 WO 2018234962A1 IB 2018054420 W IB2018054420 W IB 2018054420W WO 2018234962 A1 WO2018234962 A1 WO 2018234962A1
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formula
compound
tetra
process according
butyl ammonium
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Inventor
Shivaji Sampatrao Pawar
Bharat Daulatrao DOND
Satish Bhavsar
Ashok Sukadev JADHAV
Vinod Kashinath AHIRRAO
Kiran Ramchandra PATIL
Ravindra Dattatraya Yeole
Prasad Keshav Deshpande
Mahesh Vithalbhai Patel
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Wockhardt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the invention relates to a process for O-sulfonation of l,6-diazabicyclo[3.2.1]octane compounds.
  • the compound of Formula (I) may be obtained by O-sulfonation of a compound of Formula (II) using various sulfonation agents such as, for example, pyridine- sulfur trioxide complex.
  • the present invention provides an improved process for O-sulfonation of compounds of general Formula (II) to obtain the corresponding compounds of general Formula (I).
  • Rl and R2 are independently selected from hydrogen or an amine protecting groups; the process comprising steps of:
  • step (c) removing triethyl amine hydrochloride from the reaction mixture obtained in step (b), by addition of anti-solvent; (d) adding aqueous buffer solution having a pH between about 4 to 8, to the reaction mass obtained in step (c) to obtain organic and aqueous layers;
  • step (f) extracting the reaction mass obtained in step (e) above with an organic solvent to obtain tetra-butyl ammonium salt of Formula (III);
  • Rl and R2 are independently selected from hydrogen or an amine protecting groups; the process comprising steps of:
  • step (c) removing triethyl amine hydrochloride from the reaction mixture obtained in step (b), by addition of anti-solvent;
  • step (d) adding aqueous buffer solution having a pH between about 4 to 8, to the reaction mass obtained in step (c) to obtain organic and aqueous layers;
  • step (e) adding tetra-butyl ammonium hydrogen sulfate to the aqueous layer; (f) extracting the reaction mass obtained in step (e) above with an organic solvent to obtain tetra-butyl ammonium salt of Formula (III);
  • amine protecting groups refers to the protecting groups that are used in the synthetic chemistry procedures to prevent the amine group for reacting with one or more of the reagents. Typical non-limiting example of such groups include ie/t-Butyloxycarbonyl (BOC) group.
  • the process according to the invention involves preparation of an O- sulfonation reagent by reacting chlorosulfonic acid with triethyl amine in presence of an organic solvent.
  • solvents can be used for this step. Typical, non-limiting examples of such solvents include chlorinated solvents such as dichloromethane, ethylene dichloride, chloroform and so on. In some embodiment, the solvent used is dichloromethane.
  • the O-sulfonation reagent is prepared by reacting one equivalent of chlorosulfonic acid with two equivalents of triethyl amine. The O-sulfonation reagent may be used as such in further steps. Alternatively, the O-sulfonation reagent may be isolated and then used in the solid form in the further reactions.
  • the compound of Formula (II) is reacted with the O-sulfonation reagent in presence of a base and organic solvent.
  • solvents can be used for this step. Typical, non-limiting examples of such solvents include chlorinated solvents such as dichloromethane, ethylene dichloride, chloroform and so on. In some embodiment, the solvent used is dichloromethane.
  • the reaction of the compound of Formula (II) with the O-sulfonation reagent is carried in presence of a base.
  • bases can be used in this step. In some embodiments, the based used in this step is an organic base. In some other embodiments, the base used in this step is triethyl amine.
  • the reaction of the compound of Formula (II) with the O-sulfonation reagents results in the formation of triethyl amine hydrochloride, which can be removed by addition of an anti-solvent into the reaction mixture obtained in step (b).
  • an anti-solvent A wide variety of solvents that result in removal of triethyl amine hydrochloride can be used as anti-solvents.
  • the triethyl amine hydrochloride is removed by addition of ethyl acetate.
  • triethyl amine hydrochloride separates as solid and can removed by a simple filtration.
  • an aqueous buffer solution having a pH in the range within about 4 to 8 is added to the reaction mixture obtained in step (c), which results in the separation of organic and aqueous layers.
  • aqueous buffer solutions can be used to obtain separation of organic and aqueous layers.
  • the organic and aqueous layers are obtained by addition of aqueous potassium hydrogen phosphate solution. The aqueous layer is used as such in further reactions.
  • step (c) tetra-butyl ammonium hydrogen sulfate is added to the aqueous layer obtained in step (d) to obtain the tetra-butyl ammonium salt of Formula (III).
  • organic solvent is added to the aqueous layer obtained in the step (e) above to extract the tetra-butyl ammonium salt of Formula (III). Addition of the organic solvent results in the separation of organic and aqueous layers.
  • the tetra-butyl ammonium salt of Formula (III) is present in the organic solvent.
  • a wide variety of organic solvents can be used in this step.
  • the organic solvent used in this step is dichloro methane.
  • the tetra-butyl ammonium salt of Formula (III) may be isolated or used such in the further reactions.
  • the tetra-butyl ammonium salt of Formula (III) obtained in step (f) above is converted into corresponding compound of Formula (I) or a salt thereof.
  • a wide variety of reagents can be used to convert the tetra-butyl ammonium salt of Formula (III) into the corresponding compound of Formula (I) or a salt thereof.
  • the compound of Formula (I) is obtained by treating the tetra-butyl ammonium salt of Formula (III) with trifluoro acetic acid.
  • the corresponding compound of Formula (I) may or may not contain the amine protecting group depending on the reagents used in the conversion of the tetra- butyl ammonium salt of Formula (III) into the corresponding compound of Formula (I).
  • the compound of Formula (I) obtained can be converted into the corresponding salt by procedures known in the art.
  • tetra-butyl ammonium salt of Formula (III) can be treated with a suitable reagent to obtain the compound of Formula (I) in a salt form.
  • the tetra-butyl ammonium salt of Formula (III) is converted into a sodium salt of the compound of Formula (I) by treating the tetra-butyl ammonium salt of Formula (III) with sodium-2- ethyl hexanoate or a suitable ion-exchange resin.
  • the O-sulfonation reagent was prepared as follows. A solution of triethyl amine (20.2 gm, 0.1996 mol) in dichloro methane (125 ml) was cooled to about 0 - 5°C under stirring. To the clear solution so obtained, chlorosulfonic acid (11.68 gm, 0.0998 mol) was added via addition funnel by maintaining temperature between within the range of about 0 - 5°C. The reaction contents were stirred for 1 hour at room temperature. The reagent suspension so obtained is used as it is in the further steps.
  • the compound of Formula (Il-a) (20.5 gm, 0.0499 mol) was dissolved in dichloromethane (125 ml) and triethyl amine (15.12 gm, 0.1497 mol) was added to this solution to obtain a clear solution.
  • the solution was cooled to about 0 - 5°C.
  • the O-sulfonation reagent (in the form of a suspension) obtained above was added to this solution using addition funnel while maintaining the temperature in the range within about 0 - 5°C.
  • the reaction contents were stirred for about 1.5 hours at room temperature and the reaction progress was monitored with the help of TLC.
  • ethyl acetate 500 ml was added to the reaction contents to precipitate out triethyl amine hydrochloride as a solid.
  • the suspension thus obtained was cooled to about 0 - 5°C and the solids were removed by filtration.
  • 0.5 N aqueous potassium hydrogen phosphate solution 500 ml was added and the contents were stirred for about 15 minutes at room temperature to obtain organic and aqueous layers, which were separated.
  • Tetra-butyl ammonium hydrogen sulfate (15.24 gm, 0.0449 mol) was added to the aqueous layer and the contents were stirred overnight at room temperature before adding dichloromethane (375 ml) to separate aqueous and dichloromethane layers. The dichloromethane layer was evaporated under vacuum to provide the tetra-butyl ammonium salt of Formula (Ill-a) as a solid (33.5 gm, 92% yield), which was analyzed.
  • Example 2 The compounds according to Examples 2 - 5 were prepared following the general procedure given in Example 1.
  • Example 2 The compounds according to Examples 2 - 5 were prepared following the general procedure given in Example 1.
  • the O-sulfonation reagent suspension was prepared according to the procedure in Example 1.
  • Compound of Formula (Il-b) (2.37 gm, 0.0069 mol) was reacted with the O-sulfonation reagent in the form of a suspension prepared above in presence of triethyl amine (2.09 gm, 0.020 mol) and dichloromethane, to obtain 3.3 gm of tetra-butyl ammonium salt of Formula (Ill-b).
  • the O-sulfonation reagent was prepared according to the procedure given in Example 1 using triethyl amine (3.08 gm, 0.030 mol) and chlorosulfonic acid (1.77 gm, 0.015 mol).
  • the O-sulfonation reagent was prepared according to the procedure given in Example 1 using triethyl amine (2.46 gm, 0.0244 mol) and chloro sulfonic acid (1.43 gm, 0.0123 mol).
  • the O-sulfonation reagent was prepared according to the procedure given in Example g triethylamine (4.41 gm, 0.0436 mol) and chloro sulfonic acid (2.55 gm, 0.0218 mol).
  • Example 2 the procedure in Example 1 was followed except for a change that the O- sulfonation reagent was isolated as a solid and then used in the further reactions.
  • a solution of triethyl amine (26 gm, 0.2564 mol) in dichloromethane (100 ml) was cooled to 0° to 5°C under stirring.
  • chloro sulfonic acid (10 gm, 0.0854 mol) was added via addition funnel by maintaining temperature between 0°C - 5°C. Precipitation was observed in the reaction mixture. The mixture was stirred for additional 1 hour at room temperature.
  • the O-sulfonation reagent in the form of a solid obtained earlier was added to this cooled solution maintaining the temperature in the range of about 0 - 5°C. Following completing of addition, the reaction mixture was stirred for further 1.5 hours at room temperature and the reaction progress was monitored using TLC. After completion of the reaction, ethyl acetate (20 ml) was added to the reaction mixture followed by addition of 0.5N aqueous potassium hydrogen phosphate solution (20 ml) and the biphasic mixture thus obtained was stirred for about 15 minutes at room temperature. Aqueous layer was separated.
  • Tetra-butyl ammonium hydrogen sulfate (0.74 gm, 0.0022 mol) was added into the aqueous layer under stirring and the reaction mixture was stirred overnight at room temperature.
  • Dichloromethane (15 ml) was added to the reaction mixture and the contents were stirred for 15 minutes.
  • Organic layer was separated, and evaporated under vacuum on rotatory evaporator to provide the tetra-butyl ammonium salt of Formula (Ill-a) as a solid (1.39 gm), which further converted into the compound of Formula (I-a) following the procedure given in Example 1.

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Abstract

A process for preparation of a compound of Formula (I), or a salt thereof is disclosed.

Description

Process for O-sulfonation of l,6-diazabicyclor3.2.11octane compounds
RELATED PATENT APPLICATIONS
This application claims the priority to and benefit of Indian Provisional Patent Application No. 201721021620 filed on June 20, 2017; the disclosures of which are incorporated herein by reference in its entirety as if fully rewritten herein.
FIELD OF THE INVENTION
The invention relates to a process for O-sulfonation of l,6-diazabicyclo[3.2.1]octane compounds.
BACKGROUND OF THE INVENTION
Several l,6-diazabicyclo[3.2.1]octane compounds are disclosed in the prior art as antibacterial compounds or beta-lactamase inhibitors. A few examples of such compounds include those described in the US Patent Nos. 7,112,592; 7,612,087; 8,822,450; 9,127,004; and 9,505,761. A key step in the synthesis of such compounds involves O-sulfonation of a hydroxy intermediate compound to get the sulfonated compound of a general Formula (I):
Formula (I)
Figure imgf000002_0001
In general, the compound of Formula (I) may be obtained by O-sulfonation of a compound of Formula (II) using various sulfonation agents such as, for example, pyridine- sulfur trioxide complex.
Formula (II)
Figure imgf000002_0002
The present invention provides an improved process for O-sulfonation of compounds of general Formula (II) to obtain the corresponding compounds of general Formula (I).
SUMMARY OF THE INVENTION
Accordingly, there is provided a process for preparing a compound of general Formula (I) by O-sulfonation of a compound of general Formula (II).
In one general aspect, there is provided a process for preparation of a compound of Formula
(I): Formula (I)
Figure imgf000003_0001
or a salt thereof, wherein R is:
Figure imgf000003_0002
R1
\
N
/
R2
R1
\
N- CH2 - CH2 O - NH -
/
R2
Rl and R2 are independently selected from hydrogen or an amine protecting groups; the process comprising steps of:
(a) preparing a O-sulfonation reagent by reacting chlorosulfonic acid with triethyl amine in presence of an organic solvent;
(b) reacting a compound of Formula (II) with the O-sulfonation reagent in presence of a base and organic solvent;
Formula (II)
Figure imgf000003_0003
(c) removing triethyl amine hydrochloride from the reaction mixture obtained in step (b), by addition of anti-solvent; (d) adding aqueous buffer solution having a pH between about 4 to 8, to the reaction mass obtained in step (c) to obtain organic and aqueous layers;
(e) adding tetra-butyl ammonium hydrogen sulfate to the aqueous layer;
(f) extracting the reaction mass obtained in step (e) above with an organic solvent to obtain tetra-butyl ammonium salt of Formula (III); and
Formula (III)
Figure imgf000004_0001
(g) converting the tetra-butyl ammonium salt of Formula (III) into a compound of Formula (I), or a salt thereof.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the following description including claims.
DETAILED DESCRIPTION OF THE INVENTION
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. Alterations and further modifications of the inventive features illustrated herein, and additional applications of the principles of the invention as illustrated herein, which would occur to one of ordinary skills in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. All references including patents, patent applications, and literature cited in the specification are expressly incorporated herein by reference in their entirety.
In one general aspect, there is provided a process for the preparation of a compound of Formula (I):
Formula (I)
Figure imgf000004_0002
or a salt thereof, wherein R is
Figure imgf000005_0001
R1
\
N
/
R2
R1
\
N- CH2 - CH2 O - NH -
/
R2
Rl and R2 are independently selected from hydrogen or an amine protecting groups; the process comprising steps of:
(a) preparing a O-sulfonation reagent by reacting chlorosulfonic acid with triethyl amine in presence of an organic solvent;
(b) reacting a compound of Formula (II) with the O-sulfonation reagent in presence of a base and organic solvent;
Formula (II)
Figure imgf000005_0002
(c) removing triethyl amine hydrochloride from the reaction mixture obtained in step (b), by addition of anti-solvent;
(d) adding aqueous buffer solution having a pH between about 4 to 8, to the reaction mass obtained in step (c) to obtain organic and aqueous layers;
(e) adding tetra-butyl ammonium hydrogen sulfate to the aqueous layer; (f) extracting the reaction mass obtained in step (e) above with an organic solvent to obtain tetra-butyl ammonium salt of Formula (III); and
Formula (III)
Figure imgf000006_0001
(g) converting the tetra-butyl ammonium salt of Formula (III) into a compound of Formula (I), or a salt thereof.
Although the process is exemplified here with the help of specific R group, a person of ordinary skills in the art will appreciate the general process for O-sulfonation may be used for a variety of other R groups. Accordingly, all such reactions with different R groups are within the scope of the present invention. The term amine protecting groups refers to the protecting groups that are used in the synthetic chemistry procedures to prevent the amine group for reacting with one or more of the reagents. Typical non-limiting example of such groups include ie/t-Butyloxycarbonyl (BOC) group.
Step (a)
In one general aspect, the process according to the invention involves preparation of an O- sulfonation reagent by reacting chlorosulfonic acid with triethyl amine in presence of an organic solvent. A wide variety of solvents can be used for this step. Typical, non-limiting examples of such solvents include chlorinated solvents such as dichloromethane, ethylene dichloride, chloroform and so on. In some embodiment, the solvent used is dichloromethane. In some other embodiments, the O-sulfonation reagent is prepared by reacting one equivalent of chlorosulfonic acid with two equivalents of triethyl amine. The O-sulfonation reagent may be used as such in further steps. Alternatively, the O-sulfonation reagent may be isolated and then used in the solid form in the further reactions.
Step (b)
The compound of Formula (II) is reacted with the O-sulfonation reagent in presence of a base and organic solvent. A wide variety of solvents can be used for this step. Typical, non-limiting examples of such solvents include chlorinated solvents such as dichloromethane, ethylene dichloride, chloroform and so on. In some embodiment, the solvent used is dichloromethane. The reaction of the compound of Formula (II) with the O-sulfonation reagent is carried in presence of a base. A wide variety of bases can be used in this step. In some embodiments, the based used in this step is an organic base. In some other embodiments, the base used in this step is triethyl amine.
Step (c)
The reaction of the compound of Formula (II) with the O-sulfonation reagents results in the formation of triethyl amine hydrochloride, which can be removed by addition of an anti-solvent into the reaction mixture obtained in step (b). A wide variety of solvents that result in removal of triethyl amine hydrochloride can be used as anti-solvents. In some embodiments, the triethyl amine hydrochloride is removed by addition of ethyl acetate. On the addition of the anti-solvent, triethyl amine hydrochloride separates as solid and can removed by a simple filtration.
Step (d)
In this step, an aqueous buffer solution having a pH in the range within about 4 to 8 is added to the reaction mixture obtained in step (c), which results in the separation of organic and aqueous layers. A wide variety of aqueous buffer solutions can be used to obtain separation of organic and aqueous layers. In some embodiments, the organic and aqueous layers are obtained by addition of aqueous potassium hydrogen phosphate solution. The aqueous layer is used as such in further reactions.
Step (e)
In this step, tetra-butyl ammonium hydrogen sulfate is added to the aqueous layer obtained in step (d) to obtain the tetra-butyl ammonium salt of Formula (III).
Step (f)
In this step, organic solvent is added to the aqueous layer obtained in the step (e) above to extract the tetra-butyl ammonium salt of Formula (III). Addition of the organic solvent results in the separation of organic and aqueous layers. The tetra-butyl ammonium salt of Formula (III) is present in the organic solvent. A wide variety of organic solvents can be used in this step. In some embodiments, the organic solvent used in this step is dichloro methane. The tetra-butyl ammonium salt of Formula (III) may be isolated or used such in the further reactions.
Step (g)
The tetra-butyl ammonium salt of Formula (III) obtained in step (f) above is converted into corresponding compound of Formula (I) or a salt thereof. A wide variety of reagents can be used to convert the tetra-butyl ammonium salt of Formula (III) into the corresponding compound of Formula (I) or a salt thereof. In some embodiments, the compound of Formula (I) is obtained by treating the tetra-butyl ammonium salt of Formula (III) with trifluoro acetic acid. When the R group contains an amine protecting group, the corresponding compound of Formula (I) may or may not contain the amine protecting group depending on the reagents used in the conversion of the tetra- butyl ammonium salt of Formula (III) into the corresponding compound of Formula (I).
The compound of Formula (I) obtained can be converted into the corresponding salt by procedures known in the art. Alternatively, tetra-butyl ammonium salt of Formula (III) can be treated with a suitable reagent to obtain the compound of Formula (I) in a salt form. In some embodiments, the tetra-butyl ammonium salt of Formula (III) is converted into a sodium salt of the compound of Formula (I) by treating the tetra-butyl ammonium salt of Formula (III) with sodium-2- ethyl hexanoate or a suitable ion-exchange resin.
A wide variety of other reagents which can bring about these functional group transformations can be used.
It will be readily apparent to one skilled in the art that varying 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 recognize that the invention may be practiced using a variety of different compounds within the described generic descriptions. EXAMPLES
The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.
Example 1
Preparation of a compound of Formula (I-a)
Figure imgf000008_0001
The O-sulfonation reagent was prepared as follows. A solution of triethyl amine (20.2 gm, 0.1996 mol) in dichloro methane (125 ml) was cooled to about 0 - 5°C under stirring. To the clear solution so obtained, chlorosulfonic acid (11.68 gm, 0.0998 mol) was added via addition funnel by maintaining temperature between within the range of about 0 - 5°C. The reaction contents were stirred for 1 hour at room temperature. The reagent suspension so obtained is used as it is in the further steps.
The compound of Formula (Il-a) (20.5 gm, 0.0499 mol) was dissolved in dichloromethane (125 ml) and triethyl amine (15.12 gm, 0.1497 mol) was added to this solution to obtain a clear solution. The solution was cooled to about 0 - 5°C. The O-sulfonation reagent (in the form of a suspension) obtained above was added to this solution using addition funnel while maintaining the temperature in the range within about 0 - 5°C. The reaction contents were stirred for about 1.5 hours at room temperature and the reaction progress was monitored with the help of TLC. After the completion of the reaction, ethyl acetate (500 ml) was added to the reaction contents to precipitate out triethyl amine hydrochloride as a solid. The suspension thus obtained was cooled to about 0 - 5°C and the solids were removed by filtration. To the filtrate thus obtained, 0.5 N aqueous potassium hydrogen phosphate solution (500 ml) was added and the contents were stirred for about 15 minutes at room temperature to obtain organic and aqueous layers, which were separated.
Formula (Il-a)
Figure imgf000008_0002
Tetra-butyl ammonium hydrogen sulfate (15.24 gm, 0.0449 mol) was added to the aqueous layer and the contents were stirred overnight at room temperature before adding dichloromethane (375 ml) to separate aqueous and dichloromethane layers. The dichloromethane layer was evaporated under vacuum to provide the tetra-butyl ammonium salt of Formula (Ill-a) as a solid (33.5 gm, 92% yield), which was analyzed.
Figure imgf000009_0001
1H NMR (CDC13): 8.50 (br s, 2H), 4.33 (br s, IH), 3.98 (d, IH), 3.37 (d, 2H), 3.27-3.31 (m, 8H), 3.18 (d, 2H), 2.41-2.44 (m, IH), 2.32-2.37 (m, IH), 2.13-2.16 (m, IH), 1.89-1.93 (m, 2H), 1.62-1.68 (m, 13H), 1.42-1.49 (m, 18H), 1.00 (t, 12H).
HPLC Purity: 96.29%
The tetra-butyl ammonium salt of Formula (Ill-a) (33 gm, 0.045 mol) was dissolved in dichloromethane (83 ml) to obtain a clear solution, to which trifluoro acetic acid (123.7 gm, 1.08 mol) was added slowly at about 0 - 5°C under stirring. The reaction mixture was stirred for 1 hour, before evaporating the solvent and excess trifluoro acetic acid under vacuum below 30°C. The pale yellow oily residue thus obtained was stirred with tert-Butyl methyl ether (660 ml) for 30 minutes to provide a suspension, which was filtered under suction and solid was stirred with fresh tert-Butyl methyl ether (495 ml) for 30 minutes and again filtered at the suction. The solids so obtained were suspended in acetone (495 ml) and pH of the suspension was adjusted to about 5.5 to 7.0 using 10% solution of sodium-2-ethyl hexanoate in acetone, and the suspension was filtered under suction to obtain 25.8 gm of solids, which on drying under vacuum below 40°C furnished 16 gm of the compound of Formula (I-a) having HPLC purity of about 90.82%.
The crude compound of Formula (I-a) (15.7 gm) was further dissolved in water (78.5 ml) under stirring to provide a clear solution. To the clear solution, isopropyl alcohol (314 ml) was added using addition funnel and the suspension so obtained was stirred for 18 hours, and then filtered under the suction. The wet cake was washed with a mixture of isopropyl alcohol (25.2 ml) and water (3.2 ml), and the solids were dried under vacuum below 40° C to provide l lgm of pure compound of Formula (I-a), with the following analysis.
Analysis:
1H NMR (DMSO-de): 9.97 (br s, 2H), 8.40 (br s, 2H), 4.02 (s, IH), 3.83 (d, IH), 3.20 (d, 2H), 3.13 (d, IH), 3.02 (d, 2H), 2.87-2.92 (m, IH), 2.64-2.67 (m, IH), 1.99-2.04 (m, IH), 1.56-1.89 (m, 7H).
HPLC Purity: 95.43%
The compounds according to Examples 2 - 5 were prepared following the general procedure given in Example 1. Example 2
Preparation of a compound of Formula (I-b)
Formula (I-b)
Figure imgf000010_0001
The O-sulfonation reagent suspension was prepared according to the procedure in Example 1. Compound of Formula (Il-b) (2.37 gm, 0.0069 mol) was reacted with the O-sulfonation reagent in the form of a suspension prepared above in presence of triethyl amine (2.09 gm, 0.020 mol) and dichloromethane, to obtain 3.3 gm of tetra-butyl ammonium salt of Formula (Ill-b).
Figure imgf000010_0002
The compound of Formula (Illb) was analyzed as follows.
1H NMR (DMSO-de): 11.38 (br s, IH), 6 .76 (t, IH), 3.99 (br s, IH), 3.71-3.76 (m, 3H), 3.12-3.18 (m, 10 H), 1.96-2.01 (m, IH), 1.83-1,86 (m, IH), 1.64-1.68 (m, 2H), 1.53-1.58 (m, 10 H), 1.38 (s, 9H), 1.26-1.35 (m, 8H), 0.93 (t, 12H).
Following the procedure according to Example 1, the tetra-butyl ammonium salt of Formula (Ill-b) (2.0 gm, 0.003 mol) was reacted with trifluoro acetic acid (7.45 gm, 0.065 mol) to provide 0.61 gm of the compound of Formula (I-b) as a solid.
Analysis:
1H NMR (DMSO-de): 11.68 (s, IH), 7.81 (br s, 3H), 4.03 (s, IH), 3.97 (t, 2H), 3.84 (d, IH), 3.03-3.37 (m, 3H), 2.96 (d, IH), 2.01-2.05 (m, IH), 1.88-1.91 (m, IH), 1.68-1.80 (m, IH), 1.53- 1.58 (m, IH).
HPLC Purity: 93.81%. Example 3
Preparation of a compound of Formula (I-c)
Formula (I-c)
Figure imgf000011_0001
The O-sulfonation reagent was prepared according to the procedure given in Example 1 using triethyl amine (3.08 gm, 0.030 mol) and chlorosulfonic acid (1.77 gm, 0.015 mol).
Formula (II-c)
Figure imgf000011_0002
The compound of Formula (II-c) (2.81 gm, 0.0076 mol) was reacted with the O-sulfonation reagent in presence of triethyl amine (2.31 gm, 0.022 mol) in dichloro methane to obtain 4.1 gm of tetra-butyl ammonium salt of Formula (III-c).
Formula (III-c)
Figure imgf000011_0003
The compound of Formula (III-c) was analyzed as follows.
1H NMR (CDCI3): 6.63 (d, IH), 4.35 (br s, IH), 3.90-4.11 (m, 2H), 3.85 (d, IH), 3.27-3.32 (m, 8H), 3.19 (d, IH), 2.84-2.87 (m, 2H), 2.73 (d, IH), 2.37-2.44 (m, IH), 2.15-2.17 (m, IH), 1.80- 1.93 (m, 4H), 1.62-1.71 (m, 11H), 1.40-1.49 (m, 17H), 1.00 (t, 12H).
Following the procedure according to Example 1, the tetra-butyl ammonium salt of Formula (III-c) (4.0 gm, 0.005 mol)) was reacted with trifluoroacetic acid (14.9 gm, 0.13 mol) to provide 1.3 gm of the compound of Formula (I-c) as a solid.
Analysis:
1H NMR (DMSO-de): 8.22 (d, 3H), 3.99 (s, IH), 3.85-3.90 (m, IH), 3.71 (d, IH), 3.26 (d, 3H), 2.93-2.99 (m, 3H), 1.90-2.10 (m, IH), 1.86 (t, 3H), 1.60-1.70 (m, 4H). HPLC Purity: 98.10%
Example 4
Preparation of a compound of Formula (I-d)
Formula (I-d)
Figure imgf000012_0001
The O-sulfonation reagent was prepared according to the procedure given in Example 1 using triethyl amine (2.46 gm, 0.0244 mol) and chloro sulfonic acid (1.43 gm, 0.0123 mol).
Formula (Il-d)
Figure imgf000012_0002
The compound of Formula (Il-d) (2.44 gm, 0.006 mol) was reacted with the O-sulfonation reagent in presence of triethyl amine (1.85 gm, 0.018 mol) in dichloro methane to obtain 3.51 gm of tetra-butyl ammonium salt of Formula (Ill-d).
Figure imgf000012_0003
The compound of Formula (Ill-d) was analyzed as follows.
Analysis:
1H NMR (CDCI3): 8.78 (br s, IH), 8.62 (br s, IH), 4.26 (br s, IH), 3.99 (d, IH), 3.49-3.54 (m, 2H), 3.43 (d, IH), 3.25-3.33 (m, 9H), 3.11-3.21 (m, 2H), 2.31-2.34 (m, IH), 2.10-2.20 (m, 4H), 1.86-1.90 (m, IH), 1.62-170 (m, 9H), 1.41-1.48 (m, 17H), 0.99 (t, 12H).
Following the procedure according to Example 1, the tetra-butyl ammonium salt of Formula (Ill-d) (3.4 gm, 0.0047 mol)) was reacted with trifluoro acetic acid (12.66 gm, 0.111 mol) to provide 0.9 gm of the compound of Formula (I-d) as a solid.
Analysis 1H NMR (DMSO-de): 9.46 (br s, 2H), 9.36 (br s, 2H), 4,02 (s, IH), 3.84 (d, IH), 3.18-3.38 (m, 5H), 3.10 (t, IH), 3.01 (d, IH), 2.13-2.22 (m, IH), 1.95-2.08 (m, 2H), 1.85-1.87 (m, IH), 1.67- 1.77 (m, IH), 1.56-1.63 (m, IH).
HPLC Purity: 95.06%
Example 5
Preparation of a compound of Formula (I-e)
Formula (I-e)
Figure imgf000013_0001
The O-sulfonation reagent was prepared according to the procedure given in Example g triethylamine (4.41 gm, 0.0436 mol) and chloro sulfonic acid (2.55 gm, 0.0218 mol).
Formula (II- e)
Figure imgf000013_0002
The compound of Formula (Il-e) (2.00 gm, 0.0109 mol) was reacted with the O-sulfonation reagent in presence of triethyl amine (3.31 gm, 0.0327 mol) in dichloro methane to obtain 4.2 gm of tetra-butyl ammonium salt of Formula (Ill-e).
Figure imgf000013_0003
The compound of Formula (Ill-e) was analyzed as follows.
Analysis:
IH NMR (CDC13): 6.66 (br s, IH), 5.59 (br s, IH), 4 34 (br s, IH), 3 .91 (d, IH), 3.28-3.38 (m, 9H), 3.14 (d, IH), 2.36-2.41 (m, IH), 2.13-2.15 (m, IH), 1.87-1.94 (m, 2H), 1.62-170 (m, 8H), 1.36-1.49 (m, 8H), 1.00 (t, 12H). The tetra-butyl ammonium salt of Formula (Ill-e) (4.1 gm, 0.0081 mol) was dissolved in ethanol (16.4 ml) to obtain a clear solution. To the clear solution, was charged ethanolic solution of sodium-2-ethyl-hexanoate (2.68 gm, 0.016 mol; dissolved in 16.4 ml ethanol) at a temperature range within 20 - 35°C, under stirring. The reaction mixture was stirred for 18 hours and the suspension so obtained was filtered under suction. The wet cake was washed with acetone (10 ml X 2), and dried below 40°C under vacuum to provide 1.1 gm of the compound of Formula (I-e).
Analysis:
1H NMR (DMSO-d6): 7.44 (br s, 1H), 7.29 (br s, 1H), 3.97 (br s, 1H), 3.67 (d, 1H), 3.01 (d, 1H), 2.91 (d, 1H), 2.01-2.10 (m, 1H), 1.80-1.90 (m, 1H), 1.57-1.68 (m, 2H).
HPC Purity: 99.09%
Example 6
In example, the procedure in Example 1 was followed except for a change that the O- sulfonation reagent was isolated as a solid and then used in the further reactions. Typically, a solution of triethyl amine (26 gm, 0.2564 mol) in dichloromethane (100 ml) was cooled to 0° to 5°C under stirring. To the clear solution thus obtained, chloro sulfonic acid (10 gm, 0.0854 mol) was added via addition funnel by maintaining temperature between 0°C - 5°C. Precipitation was observed in the reaction mixture. The mixture was stirred for additional 1 hour at room temperature. Ethyl acetate (100 ml) was added into the reaction mixture and the contents were stirred for further 15 minutes at room temperature. Triethyl amine hydrochloride separated in the form of a solid was removed by filtration through Buckner funnel. The filtrate thus obtained was evaporated under vacuum on rotatory evaporator to provide 22 gm of the O-sulfonation reagent as a light brown coloured solid. The compound of Formula (Il-a) (1.0 gm, 0.0024 mol) was dissolved in dichloromethane (10 ml) and to this solution was added triethyl amine (0.74 gm, 0.0073 mol) to obtain a clear solution. This solution was cooled to 0 - 5°C. The O-sulfonation reagent in the form of a solid obtained earlier was added to this cooled solution maintaining the temperature in the range of about 0 - 5°C. Following completing of addition, the reaction mixture was stirred for further 1.5 hours at room temperature and the reaction progress was monitored using TLC. After completion of the reaction, ethyl acetate (20 ml) was added to the reaction mixture followed by addition of 0.5N aqueous potassium hydrogen phosphate solution (20 ml) and the biphasic mixture thus obtained was stirred for about 15 minutes at room temperature. Aqueous layer was separated. Tetra-butyl ammonium hydrogen sulfate (0.74 gm, 0.0022 mol) was added into the aqueous layer under stirring and the reaction mixture was stirred overnight at room temperature. Dichloromethane (15 ml) was added to the reaction mixture and the contents were stirred for 15 minutes. Organic layer was separated, and evaporated under vacuum on rotatory evaporator to provide the tetra-butyl ammonium salt of Formula (Ill-a) as a solid (1.39 gm), which further converted into the compound of Formula (I-a) following the procedure given in Example 1.

Claims

Claims
1. A process for preparation of a compound of Formula (I)
Formula (I)
Figure imgf000015_0001
or a salt thereof, wherein R is
Figure imgf000015_0002
R1
\
N
/
R2
R1
V CH2 CI-L - O - NH—
R2
Rl and R2 are independently selected from hydrogen or an amine protecting groups; the process comprising steps of:
(a) preparing a O-sulfonation reagent by reacting chlorosulfonic acid with triethyl amine in presence of an organic solvent;
(b) reacting a compound of Formula (II) with the O-sulfonation reagent in presence of a base and organic solvent; Formula (II)
Figure imgf000016_0001
(c) removing triethyl amine hydrochloride from the reaction mixture obtained in step (b), by addition of anti-solvent;
(d) adding aqueous buffer solution having a pH between about 4 to 8, to the reaction mass obtained in step (c) to obtain organic and aqueous layers;
(e) adding tetra-butyl ammonium hydrogen sulfate to the aqueous layer;
(f) extracting the reaction mass obtained in step (e) above with an organic solvent to obtain tetra-butyl ammonium salt of Formula (III); and
Formula (III)
Figure imgf000016_0002
(g) converting the tetra-butyl ammonium salt of Formula (III) into a compound of Formula (I), or a salt thereof.
2. The process according to Claim 1, wherein the O-sulfo nation reagent is prepared by reacting one equivalent of chlorosulfonic acid with two equivalents of triethyl amine.
3. The process according to Claim 1, wherein the O-sulfo nation reagent is prepared by reacting chlorosulfonic acid with triethyl amine in presence of dichloromethane as a solvent.
4. The process according to Claim 1, wherein the compound of Formula (II) is reacted with the O-sulfonation reagent in presence of dichloromethane.
5. The process according to Claim 1, wherein the base used in step (b) is an organic base.
6. The process according to Claim 1, wherein the base used in step (b) is triethyl amine.
7. The process according to Claim 1, wherein the anti-solvent used in step (c) is ethyl acetate.
8. The process according to Claim 1, wherein organic and aqueous layers are obtained in step (d) by addition of aqueous potassium hydrogen phosphate solution.
9. The process according to Claim 1, wherein the tetra-butyl ammonium salt of Formula (III) is converted into a compound of Formula (I) using trifluoro acetic acid.
10. The process according to Claim 1, wherein the tetra-butyl ammonium salt Formula (III) is converted into a sodium salt of the compound of Formula (I).
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