DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

IMPROVED PROCESS FOR PREPARATION OF TBD INTERMEDIATE AND USE THEREOF

We, SUVEN LIFE SCIENCES LIMITED,
a company incorporated under the companies act, 1956 having address at Serene Chambers, Road No 5, Avenue 7, Banjara Hills, Hyderabad, Telangana 500034, India

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of bicyclic guanidines.

The present invention relates to an improved process for the preparation of 1,5,7-Triazobicyclo[4.4.0]dec-5-ene (TBD).

The present invention relates to a purification method for 1,5,7-Triazobicyclo[4.4.0]dec-5-ene.

BACKGROUND OF THE INVENTION
It is well known that bicyclic guanidines, such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) is chemically active and, therefore, can be used to catalyze a variety of chemical reactions. An important consideration in the commercial exploitation of bicyclic guanidines as a catalyst (for any reaction) is that bicyclic guanidines be relatively inexpensive to purchase or easily produced. Published methods for synthesizing bicyclic guanidines, however, are often complicated, often involve the use of a multiple step synthesis process, and/or require the use of prohibitively expensive starting materials which may be hazardous in a variety of ways.

For example, some methods utilize carbon disulfide (CS2) in the production of bicyclic guanidines. However, there are regulatory and handling issues associated with the use of carbon disulfide. For instance, air transport of carbon disulfide is typically prohibited. Additionally, contact with carbon disulfide with air should be avoided because the combination of high volatility, wide flammability range, and low ignition temperature results in a readily combustible mixture.

US 4,797,487 describes a process for the production of bicyclic guanidines which process comprises reacting in one step a bis(aminoalkyl)amine selected from the group consisting of bis(2-aminoethyl)amine and bis(3-aminopropyl)amine at a temperature in the range from 10 oC o 200 oC with carbon disulfide (CS2) and in a high boiling hydrocarbon solvent. The process is carried out in an acid catalyst selected from mineral acids, organic acids and Lewis acids in high boiling solvents like xylene.
The process is shown in the scheme given below

US 9,108,968 B2 describes a method for preparing 1,5,7-Triazabicyclo[4.4.0]dec-5-ene comprising forming a mixture of di substituted carbodiimide, dipropylene triamine and an ethereal solvent or alcohol followed by heating the said mixture at a temperature of 160 oC. The process of US ‘ 968 can be depicted in the following scheme as shown below :

US 8,039,618 claims a method of producing 1,5,7-Triazobicyclo[4.4.0]dec-5-ene comprising reacting bis(3-aminopropyl)amine with a carbonate to form a cyclic urea, wherein the carbonate comprises propylene carbonate, dimethyl carbonate, diethyl carbonate, ethylene carbonate, or combinations thereof and heating a cyclic urea to a temperature > 200 oC in the presence of ethereal solvent or an alcohol solvent to form 1,5,7-Triazobicyclo[4.4.0]dec-5-ene

US 8,148,490 B2 describes a method for preparing a cyclic guanidine comprising reacting (i) a guanidinium salt, (ii) a polyamine and (iii) a weak acid as shown in the below scheme :

Chem Ber. 1990, 113, 2175-2182 discloses the process for the preparation of guanidines as shown below:
Scheme 1

Scheme 2

Synthetic Communications 1993, 23(22), 3191-3194 discloses the below given process for the preparation of 1,5,7-Triazobicyclo[4.4.0]dec-5-ene (TBD) .

Synthetic Communications 2011, 41(24), 3683-3688 and this journal discloses the following process.

Organic Letters 2011, 13, (17), 4562-4565 describes Ti-amide catalyzed synthesis of cyclic guanidines from di-Triamines and carbodiimides. This journal discloses the following process which is catalyzed by titanacarborane monoamine complex.

The above published methods for synthesizing bicyclic guanidines, however, are often complicated, such as using a multiple step and/or time consuming synthesis process. Others use prohibitively expensive and/or hazardous starting materials. Further, many of the above published methods do not produce high yields of the desired products, or produce byproducts, such as aniline, that are difficult to separate from the bicyclic guanidines and may themselves be hazardous. Also, many of the above mentioned methods produce bicyclic guanidines of different types that may be difficult to separate from one another, and/or produce bicyclic guanidines in forms that are difficult to handle.

Accordingly, there is a need for a process for producing bicyclic guanidines at relatively high yields while not using hazardous materials, such as carbon disulfide, as an ingredient to produce the bicyclic guanidines.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a process for the preparation of bicyclic guanidines.

The main objective of the present invention is to provide an improved process for preparation of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD).

In another objective of the present invention is to provide a purification process for the preparation of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD), which is commercially feasible / industrially scalable.

It is therefore an object of the present invention to provide a simple, economical and commercially feasible process for the synthesis of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), with a high yield and high purity.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of compound of Formula (I)

Formula (I)
wherein the process comprises the steps of:
condensing the compound of Formula II

Formula (II)
wherein R is alky, aryl or cycloalkyl; with compound of Formula (III)

Formula (III)
in the presence of an aromatic solvent or ethereal solvent or absence of solvent to obtain
compound of Formula (I).

In an yet another aspect, the present invention provides a process for producing solid 1,5,7-Triazabicyclo[4.4.0]dec-5- ene compound of Formula (I) comprising:
i) mixing N,N-dicyclohexylcarbodiimide and bis(3-aminopropyl)amine in an aromatic solvent or ethereal solvent,
ii) heating the reaction mixture to 60-65 oC,
iii) stirring the reaction mixture with ethereal solvent or hydrocarbons solvent, and
iv) isolating the product.

In an yet another aspect, the present invention provides a process for producing solid 1,5,7-Triazabicyclo[4.4.0]dec-5- ene compound of Formula (I) comprising:
i) mixing N,N-dicyclohexylcarbodiimide and bis(3-aminopropyl)amine,
ii) heating the reaction mixture to 25-50 oC,
iii) stirring the reaction mixture with ethereal solvent or hydrocarbons solvent, and
iv) isolating the product.

In yet anther aspect, the present invention provides a method of purifying 1,5,7-Triazabicyclo[4.4.0]dec-5-ene compound of Formula (I) having less than about 3.0 %, wt/wt, water comprising the steps of
i) dissolving the crude 1,5,7-Triazabicyclo[4.4.0]dec-5-ene in acetonitrile/methyl t-butyl ether/hexane, or mixture thereof, and
ii) isolating the purified 1,5,7-Triazabicyclo[4.4.0]dec-5-ene as solid having less than about 3.0% wt/wt water.

In yet another aspect, the present invention provides 1,5,7-Triazabicyclo[4.4.0]dec-5-ene compound of Formula (I) in a purity equal to or in excess of 98 %.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of intermediate compound of Formula (I) i.e. 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) by condensation of compounds of Formula (II) and Formula (III).

“Alkyl” as used herein refers to but not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, octyl, isopentyl and t-butyl.

Aryl as used herein is and not limited to benzyl, phenyl, naphthyl, thienyl, indolyl, toluene, xylene and O-xylyl.

Cycloalkyl as used herein is and not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclohexylmethane.

In another embodiment the, the aromatic solvents employed are toluene, xylene, phenol, styrene, diethylbenzene, ethylbenzene and/or mixtures thereof.

In another embodiment the ethereal solvents used in the present invention are selected from di-tert-butylether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane, anisole, diphenyl ether, 1,4-dioxane 2-methoxyethanol and dimethoxyethane, and/or mixtures thereof.

In yet another embodiment suitable hydrocarbon solvents used in the present invention are selected from toluene, xylene, cyclohexane and the like.

The condensation of compound of Formula (II) with the compound of Formula (III) can also be carried out without the solvent also.

This invention also entails isolation and purification process for producing solid 1,5,7-Triazabicyclo[4.4.0]dec-5-ene. The process is best performed by mixing N,N-dicyclohexylcarbodiimide and bis(3-aminopropyl)amine in an aromatic solvent or ethereal solvent and heating the reaction mixture to 60-65 oC . The resulting mixture is refluxed under nitrogen atmosphere for 75 hrs and allowed to cool to room temperature. To the cooled reaction mixture, is added methyl t-butyl ether and hexane and allowed to stir till the fine solid is crystallized out. The obtained fine solid is washed with methyl t-butyl ether and hexane to obtain crude product. This crude was further recrystallized in acetonitrile/hexane to obtain fine solid.

The isolated 1,5,7-Triazabicyclo[4.4.0]dec-5-ene product has moisture content no more than 3 % wt/wt.

The purity of the product 1,5,7-Triazabicyclo[4.4.0]dec-5-ene in a purity equal to or in excess of 98 % (NMR assay).

The obtained pure 1,5,7-Triazabicyclo[4.4.0]dec-5-ene is confirmed by spectrometric methods like 1H NMR, 13C NMR and IR spectroscopy.

The main advantages of the present invention is in isolation of compound of Formula (I) i.e. 1,5,7-Triazabicyclo[4.4.0]dec-5-ene as fine solid. This is achieved by using a mixture of solvents which are hitherto unreported in prior-art. The obtained solid was further purified in nitrile solvents to yield highly pure Formula (I) i.e. 1,5,7-Triazabicyclo[4.4.0]dec-5-ene > 98% (NMR assay).

By the present improvisation of the process conditions and purification methods the inventors of the present application were able to prepare the 1,5,7-Triazabicyclo[4.4.0]dec-5-ene. Moreover, the inventors were able to overcome the challenges of the already reported procedures in isolation of the product thereby providing a solution to the existing isolation methods.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example-1: Preparation of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene using N,N-dicyclohexylcarbodiimide:
To a stirred solution of N,N-Dicyclohexylcarbodiimide (188.7 g, 0.914 mol) in o-xylene (200ml) was added Bis(3-aminopropyl)amine (100.0 g, 0.762 mol) at 60-65°C, and stirred for 15min. The resulting mixture was refluxed under nitrogen atmosphere for 75 h, allowed to cool to room temperature, diluted with methyl t-butyl ether (0.5 Lt) and hexane (0.25 Lt). Then the solution was cooled to 5-10°C and stirred for 4h, filtered the solid, washed with methyl t-butyl ether and hexane under nitrogen atmosphere and dried under vacuum to obtain crude product, which on purification with acetonitrile and isolation using hexane gave 53g of the desired product as a solid.
Moisture content: NMT 3.0%
Purity: > 98% (NMR assay)
1H NMR (400MHz, D2O): d 3.19 (t, 4H, J=6.0 Hz), 3.12 (t, 4H, J=5.8Hz), 1.84 ( m,4H)
13C NMR (100.6MHz, D2O): d 151.13, 46.48, 37.89, 20.27
IR (KBr cm-1): 3276.65, 3213.64, 2943.93, 2870.94, 1647.64, 1523.64, 1445.78, 1376.24, 1322.95, 1201.71, 1068.04, 1018.33, 881.31, 710.87

Example-2: Preparation of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene using N,N-dicyclohexylcarbodiimide (without solvent):
Bis(3-aminopropyl)amine (100.0 g, 0.762 mol) was added to N,N-Dicyclohexyl carbodiimide (188.7 g, 0.914 mol) at room temperature. In the process the addition of Bis(3-aminopropyl)amine was exothermic, temperature increases from 25 to 50°C. To perform this phase of reaction safely, the amine was added over a period of one hour while the temperature was maintained between 25-50°C by occasional cooling. The temperature was maintained for an additional 30min even after the addition was complete and then it was slowly raised to 150°C. The resulting mixture was maintained at 140-150°C for 40h under nitrogen atmosphere, allowed to cool to room temperature, diluted with methyl t-butyl ether (0.5 Lt) and hexane (0.25 Lt). Then the solution was cooled to 5-10°C and stirred for 4h, filtered the solid, washed with methyl t-butyl ether and hexane and dried under vacuum to obtain crude 1,5,7-triazabicyclo[4.4.0]dec-5-ene, which on purification with acetonitrile and isolation using hexane gave 52g of the desired product as a solid.
Moisture content: NMT 3.0%
Purity: > 98% (NMR assay)

Example-3: Preparation of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene using N,N-diisopropyl carbodiimide:
To a stirred solution of N,N-Diisopropylcarbodiimide (115.6 g, 0.916 mol) in o-xylene (200ml) was added Bis(3-aminopropyl)amine (100.0 g, 0.762 mol) at 60-65°C, and stirred for 15min. The resulting mixture was refluxed under nitrogen atmosphere for 75 h, allowed to cool to room temperature, diluted with methyl t-butyl ether (0.5 Lt) and hexane (0.25 Lt). Then the solution was cooled to 5-10°C and stirred for 4h, filtered the solid, washed with methyl t-butyl ether and hexane and dried under vacuum provided 48g of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene.
Moisture content: NMT 3.0%
Purity: > 98% (NMR assay)
Example-4: Preparation of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene using N,N-diisopropyl carbodiimide (without solvent):
Bis(3-aminopropyl)amine (100.0 g, 0.762 mol) was added to N,N-Diisopropylcarbodiimide (115.6 g, 0.916 mol) at room temperature. In the process the addition of Bis(3-aminopropyl)amine was exothermic, temperature increases from 25 to 50°C. To perform this phase of reaction safely, the amine was added over a period of one hour while the temperature was maintained between 25-50°C by occasional cooling. The temperature was maintained for an additional 30min even after the addition was complete and then it was slowly raised to 125°C. The resulting mixture was maintained at 120-130°C for 50h under nitrogen atmosphere, allowed to cool to room temperature, diluted with methyl t-butyl ether (0.5 Lt) and hexane (0.25 Lt). Then the solution was cooled to 5-10°C and stirred for 4h, filtered the solid, washed with methyl t-butyl ether and hexane and dried under vacuum to give 42.5 g of 1,5,7-Triazabicyclo[4.4.0] dec-5-ene.
Moisture content: NMT 3.0%
Purity: > 98% (NMR assay)

Preparation of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) using diphenyl ether as a solvent:

Example 5: TBD preparation using N,N-Dicyclohexylcarbodiimide:
To a stirred solution of N,N-Dicyclohexylcarbodiimide (188.7 g, 0.914 mol) in diphenyl ether (200ml) was added Bis(3-aminopropyl)amine (100.0 g, 0.762 mol) at 60-65°C over a period of 30min, and stirred for 15min. The resulting mixture was heated to 170-175°C for 18h under nitrogen atmosphere. The reaction was allowed to cool to ambient temperature, diluted with methyl t-butyl ether (0.5 Lt) and hexane (0.25 Lt). Then the solution was cooled to 5-10°C and stirred for 4h, filtered the solid, washed with methyl t-butyl ether and hexane and dried under vacuum to give crude product, which on purification with acetonitrile and isolation using hexane gave 47g of 1,5,7-triazabicyclo[4.4.0]dec-5-ene.
Moisture content: NMT 3.0%
Purity: > 98% (NMR assay)

Example 6: TBD preparation using N,N-diisopropyl carbodiimide:
To a stirred solution of N,N-diisopropyl carbodiimide (115.6 g, 0.916 mol) in diphenyl ether (200ml) was added Bis(3-aminopropyl)amine (100.0 g, 0.762 mol) at 60-65°C over a period of 30min, and stirred for 15min. The resulting mixture was heated to 150-160°C for 28h under nitrogen atmosphere. The reaction was allowed to cool to ambient temperature, diluted with methyl t-butyl ether (0.5 Lt) and hexane (0.25 Lt). Then the solution was cooled to 5-10°C and stirred for 4h, filtered the solid, washed with methyl t-butyl ether and hexane and dried under vacuum provided 55 g of 1,5,7-triazabicyclo[4.4.0]dec-5-ene.
Moisture content: NMT 3.0%
Purity: > 98% (NMR assay)
,CLAIMS:We Claim:
1. An improved process for the preparation of compound of Formula (I)

Formula (I)
wherein the process comprises the steps of:
condensing the compound of Formula II

Formula (II)
wherein R is alky, aryl or cycloalkyl; with compound of Formula (III)

Formula (III)
in the presence of an aromatic solvent or ethereal solvent or absence of solvent to obtain
compound of Formula (I).

2. The process as claimed in claim 1, wherein the process for producing solid 1,5,7-triazabicyclo[4.4.0]dec-5- ene compound of Formula (I) comprising:
i) mixing N,N-dicyclohexylcarbodiimide and bis(3-aminopropyl)amine in an aromatic solvent or ethereal solvent,
ii) heating the reaction mixture to 60-65 oC,
iii) stirring the reaction mixture with ethereal solvent or hydrocarbons solvent, and
iv) isolating the product.

3. The process as claimed in claim 1, wherein the process for producing solid 1,5,7-triazabicyclo[4.4.0]dec-5- ene compound of Formula (I) comprising:
i) mixing N,N-dicyclohexylcarbodiimide and bis(3-aminopropyl)amine,
ii) heating the reaction mixture to 25-50 oC,
iii) stirring the reaction mixture with ethereal solvent or hydrocarbons solvent, and
iv) isolating the product.

4. The process as claimed in claim 1, wherein the process involves method of purifying 1,5,7-Triazabicyclo[4.4.0]dec-5-ene compound of Formula (I) having less than about 3.0 %, wt/wt, water comprising the steps of:
i) dissolving the crude 1,5,7-triazabicyclo[4.4.0]dec-5-ene in acetonitrile/methyl t-butyl ether/hexane, or mixture thereof, and
ii) isolating the purified 1,5,7-triazabicyclo[4.4.0]dec-5-ene as solid having less than about 3.0% wt/wt water.

5. The process as claimed in claim 4, wherein the method of purifying 1,5,7-triazabicyclo[4.4.0]dec-5-ene compound of Formula (I) having less than about 3.0 %, wt/wt, water comprising the steps of:
i) dissolving the crude 1,5,7-triazabicyclo[4.4.0]dec-5-ene in acetonitrile/methyl t-butyl ether/hexane or mixture thereof, and
ii) isolating the purified 1,5,7-triazabicyclo[4.4.0]dec-5-ene as solid having less than about 3.0% wt/wt water.

6. The process as claimed in claim 1, wherein 1,5,7-triazabicyclo[4.4.0]dec-5-ene compound of Formula (I) in a purity equal to or in excess of 98 %.

7. The process as claimed in claims 1 and 2, wherein the aromatic solvents employed are toluene, xylene, phenol, styrene, diethylbenzene, ethylbenzene and/or mixtures thereof.

8. The process as claimed in claims 1 and 2, wherein the ethereal solvents used in the present invention are selected from di-tert-butylether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane, anisole, diphenyl ether, 1,4-dioxane 2-methoxyethanol and dimethoxyethane, and/or mixtures thereof.

9. The process as claimed in claims 2 and 3, wherein the hydrocarbon solvents used in the present invention are selected from toluene, xylene, cyclohexane and the like.

10. The process as claimed in claim 1, wherein the isolated 1,5,7-triazabicyclo[4.4.0]dec-5-ene product has moisture content no more than 3 % wt/wt.

Dated this Sixth (06th) day of March, 2020

______________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883