DESC:Technical filed:
The present invention relates to novel method for the preparation of Pyrrolidine compound; Sarmentine and its analogous.

Background and prior art:
In traditional medicinal practice, P. longum fruits have been advocated to be beneficial in treatment of diseases such as gonorrhea, menstrual pain, tuberculosis, sleeping problems, respiratory tract infections, chronic gut-related pain, arthritic conditions, analgesic and diuretic effects, relaxation of muscle tension, and alleviation of anxiety.

Sarmentine, chemically known as 1-(1-pyrrolidinyl)-(2E,4E)-2,4-decadien-1-one, is a natural amide isolated from the fruits of Piper sarmentosum in 1987 [Tetrahedron 1987 (43) 3689-3694] and also from Piper nigrum in 1988 [Kiuchi, F., Nakamura, N., Tsuda, Y., Kondo, K and Yoshimura, H. Studies on Crude Drugs Effective on Visceral Larva Migrans].Sarmentine is reported to possesses sedative,analgesic, and antibacterial activities [Strunz, G.M., Stud. Nat. Prod. Chem., 2000, vol. 24, p. 683]. Sarmentine was found to manifest antitubercular and antiplazmodial activities [Rukachaisirikul, T., Siriwattanakit, P., Sukcharoenphol, K., Wongvein, C., Ruttanaweang, P., Wongwattanavuch, P.,and Suksamrarn, A., J. Ethnopharmacol., 2004, vol. 93, p. 173.].In addition, pipernonaline, a piperidine amide from P. longum has been found to possess larvicidal activity against Aedes aegypti Mosquito Larvae (J. Agric. Food Chem., 2002, 50, 3765-3767).

Sarmentine has a broad-spectrum activity on weeds as a contact herbicide. Initial studies highlighted a similarity in response between plants treated with sarmentine and herbicidal soaps such as pelargonic acid (nonanoic acid). Sarmentine was reported to be 10 to 30 times more active than pelargonic acid on wild mustard, velvetleaf, redroot pigweed and crabgrass. However, the mechanism of action involved in rapid desiccation of foliage, treated by sarmentine was not known. Therefore, the herbicidal activity of sarmentine appears to be a complex process associated with multiple mechanisms of action.

Synthetic herbicides not only prevent economic loss in food production, but also improves quality of crop products; however, the use of synthetic herbicides may cause side-effects on environment and human health. Therefore, it is very necessary to synthesise natural sarmentine or its analogues for weed management that are eco-friendly, cost-effective and bio-efficacious.

The main task in a sarmentine synthesis is thestereoselective construction of conjugated (2E,4E)-diene system bonded with the amide function.Previously for this purpose were used the elimination[Mandai, T., Moriyama, T., Tsujimoto, K., Kawada, M., and Otera, J., Tetrahedron Lett., 1986, vol. 27, p. 603] and homologenization of (2E,4E)-pentadienyl-1-carbonyl precursors [Lewis, N., McKen, P.W., and Taylor, R.J.K., Synlett, 1991, p. 898; and Babudri, F., Fiandanese, V., Naso, F., and Punzi, A.,Tetrahedron Lett., 1994, vol. 35, p. 2067], isomerization of alkynylamides [Trost, B.M. and Kazmaier, U., J. Am. Chem. Soc., 1992,vol. 114, p. 7933] and stereoselective iodosulfonylation of(2E,4E)-pentadienamide followed by the crosscoupling with n-pentylmagnesium bromide [Bernabeu, M.C., Chinchilla, R., and Najera, C.,Tetrahedron Lett., 1995, vol. 36, p. 3901].

Further, CN103788022A discloses synthesis of Sarmentine, which comprises reaction of pyrrolidine(Compound A)withchloroacetyl chloride(Compound B) to obtain compound C, which is reacted with diethyl phosphite(Compound D) to obtain phosphoric acid ester(compound E). The compound E thus obtained is reacted with 17-hydroxy-corticosterone octenal (compound F)in presence of lithium bromide and N, N-diisopropyl ethyl amine at 10-25 ?, to obtain Sarmentiune in a yield of 40%. The synthetic method of CN’022 is shown in scheme 1 below.

Scheme 1:

Stereo selective Synthesis of Sarmentine reported in Russian Journal of General Chemistry, 2011, Vol. 81, No. 9, pp. 1915–1917, by R. N. Shakhmaev et al. discloses stereoselectivesynthesis of 1-[(2E,4E)-deca-2,4-dienoyl]pyrrolidine by reaction of (1E)-1-iodohept-1-ene with 1-acrciloylpyrrolidine in the presence of Pd(OAc)2, abase, and tetrabutylammonium chloride in DMF to yield 1-[(2E,4E)-deca-2,4-dienoyl]pyrrolidine. The reaction is shown in scheme 2.
Scheme 2

Another method for synthesis of sarmentine disclosed by N. Lewis et al in Synlett 1991; 1991(12): 898-900. This article reports the reaction of decadienoic acid chloride with pyrrolidine to obtain Sarmentine in 75% yield.
These methods are characterized by the low overall yield of the Sarmentine; low stereo selectivity and also involve recrystallization or column chromatography for the purification.

Therefore, there remains a need in the art to provide an improved process for the synthesis of Sarmentine with high yields and purity.

Summary of the invention:
In order to overcome the low yields of Sarmentineand to make simple process, the present invention provides two novel synthetic routes.

According to first aspect, the synthetic scheme-3 proceeds with the formation of inexpensive Diethyl phosphono acetic acid in stage-1, which can be prepared easily in high yields and it is also commercially available.Diethyl phophono acetic acid treated with variety of amines in presence of oxalyl chloride to make peptide formation that yields corresponding phosphonate esters, which are easily purified by simultaneous acid base work up. The resulting phosphonate ester was reacted with (E)-oct-2-enal to make Sarmentine and its various analogues in high yields.
According to this aspect, the process for synthesis of Sarmentine or its analogues which comprises;
a) Reacting Diethyl phosphonoacetic acid with an amine in presence of oxalyl chloride to obtain corresponding diethyl phosphonate;
b) Reacting the diethyl phosphonate with (E)-oct-2-enal to obtain Sarmentine or its corresponding analogues.
According to another aspect (synthetic scheme 5), Sarmentine and its analogues are prepared by reacting Diethyl phosphonoacetic acid with (E)-Oct-2-enal to form (2E, 4E)-deca-2, 4-dienoic acid. The Dienoic acid, thus obtained is reacted with corresponding amines to get Sarmentine and its analogues.
Accordingly, the process for synthesis of Sarmentine or its analogues which comprises;
a) Reacting diethyl phosphonoacetic acidwith (E)-oct-2-enal to obtain(2E, 4E)-deca-2, 4-dienoic acid; and
b) Reacting the 2E, 4E)-deca-2, 4-dienoic acid with an amine to obtain the Sarmentine or its corresponding analogues.

Detailed description of the invention:
The invention now will be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

According to first aspect, the synthetic scheme-3 proceeds with the formation of inexpensive Diethyl phosphono acetic acid in stage-1, which can be prepared easily in high yields and it is also commercially available. Diethyl phophono acetic acid treated with variety of amines in presence of oxalyl chloride to make peptide formation that yields corresponding phosphonate esters, which are easily purified by simultaneous acid base work up. The resulting phosphonate ester was reacted with (E)-oct-2-enal to make Sarmentine and its various analogues in high yields.
According to this aspect, the process for synthesis of Sarmentine or its analogues which comprises;
a) Reacting Diethyl phosphonoacetic acid with an amine in presence of oxalylchloride to obtain corresponding diethyl phosphonate esters;
b) Reacting the diethyl phosphonate esters with (E)-oct-2-enal to obtain Sarmentine or its corresponding analogues.
The reaction of step a) is carried out in presence of catalytic amounts of DMF, DMAP in dicholoromethane solvent at 40-45°C for 4 to 10hrs.
The reaction of step b) is carried out in presence of DIPEA, Lithium bromide in THF at 0-30°C for 10- 15 hrs.
The amine is selected from the group consisting of Pyrrolidine, isobutyl amine, morpholine, piperidine, isopropylamine, tertiary butylamine, pyrrole and bicyclo[2.2.1]heptane.
The corresponding Sarmentine analogues thus obtained are selected from the group consisting of;
a)
;
b)

c)
;

d)
;
e)
;
f)
; and
g)
.

The synthetic process is shown in Scheme 3 below.
Scheme 3:

By employing the process of scheme 3, the present invention has provided various Sarmentine analogues as shown in table 1. The following compounds were synthesized using the above synthetic scheme.
Table 1
Structure of Amine (R) Structures of Sarmentine analogues

7-aza-bicyclo[2.2.1]heptane

In one specific embodiment, the invention provides synthesis of Sarmentine (as shown in scheme 4) which process comprises;
a) Reacting Diethyl phosphonoacetic acid with oxalyl chloride in presence of Pyrrolidine to obtain corresponding diethyl phosphonate;
b) Reacting the diethyl phosphonate with (E)-oct-2-enal to obtain Sarmentine.
Scheme 4

According to another aspect (synthetic scheme 5), Sarmentine or its analogues are prepared by reacting Diethyl phosphonoacetic acid with (E)-Oct-2-enal to form (2E, 4E)-deca-2, 4-dienoic acid. The Dienoic acid, thus obtained is reacted with corresponding amines to get Sarmentine and its analogues.
Accordingly, the process for synthesis of Sarmentine or its analogues which comprises;
a) Reacting diethyl phosphonoacetic acid with (E)-oct-2-enal to obtain (2E, 4E)-deca-2, 4-dienoic acid; and
b) Reacting the 2E, 4E)-deca-2, 4-dienoic acid with an amine to get Sarmentine or its corresponding analogues.

The reaction of step a) is carried out in presence of Zinc triflate, TMEDA and DBU in THF at room temperature for 10- 15 hrs.
The reaction of step b) is carried out in presence of catalytic amounts of DMF, DMAP in dicholoromethane solvent at 40-45°C for 4 to 10hrs.
The amine is selected from the group consisting of Pyrrolidine, isobutyl amine, morpholine, piperidine, isopropylamine, tertiary butylamine, pyrrole and bicyclo[2.2.1]heptane.
The process is shown in scheme 5.
Scheme 5

The present invention is explained further in detail by illustrating examples below. Some typical examples illustrating the embodiments of the present invention are provided; however, these are exemplary only and should not be regarded as limiting the elements of the present invention.

Examples:
Procedure for the synthesis of Diethyl phosphonoacetic acid:
To the solution of Chloroacetic acid 50 g (0.529 moles, 1.0Equiv) in Toluene250 ml (5.0 Vol); was added Triethyl phospite 131.8 g (0.79 moles) 1.5 Equiv dropwise at room temperature. Reaction mixture was stirred at 100-110oC for 24 hours. The progress of the reaction was monitored by thin layer chromatography using 5% Methanol in Dichloromethane as mobile phase.
Workup: After completion of the reaction, excess of Triethyl phosphite was distilled at 85-90oC and 10 millibar pressure. The evolution of ethyl chloride gas as byproduct was observed during the progress of reaction.
Weight: 80 g, Yield: 77.6%.

1H NMR of Diethyl phosphonoacetic acid :( 400MHz;CDCl3):d1.1 (6H, t), 2.71(2H, s) 4.07-4.13(4H, m).
Procedure for the synthesis of Diethyl 2-oxo-2-(pyrrolidin-1-yl) ethylphosphonate:
To the solution of Diethyl phosphonoacetic acid 25g (0.12moles, 1.0Equiv) in Dichloromethane250 ml (10 Vol); was added oxalyl chloride 20.2 g (0.15 mol, 1.25 Equiv) and N, N-Dimethylformamide(0.9 g, 0.1Equiv). The reaction mixture was heated at 40-45oC for 3.0 hours under nitrogen atmosphere. Dichloromethane and excess Oxalyl chloride was recovered under reduced pressure. This compound in freshly added Dichloromethane (250 ml, 10 Vol) was added to the mixture of Pyrrolidine and DMAP(2.3g, 0.019moles; 0.15 Equiv) in Dichloromethane (125 ml, 5 Vol) at 0-5oC.The reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by thin layer chromatography using 30 % Ethyl acetate in Hexane as mobile phase.
Workup: After the completion of the reaction, the reaction mixture was diluted with Dichloromethane 125 ml and washed with 5% sodium carbonate solution 125 ml to remove excess Diethylphosphono acetic acid. Reaction mixture was stirred with 2.0 N Hydrochloric acid (100ml) to remove excess of amine. Dichloromethane was recovered under reduced pressure to get the titled compound as pale yellow oily liquid.
Weight: 22 g, Yield: 69.2%.
1H NMR of Diethyl 2-oxo-2-(pyrrolidin-1-yl) ethylphosphonate:( 400MHz;CDCl3): d0.98-1.2(6H,t),1.9-2.0(4H,t),3.46-3.54(4H,t),2.46-2.5(2H,s),4.07-5.0(4H,m)

Preparation of (2E, 4E)-1-(pyrrolidin-1-yl) deca-2, 4-dien-1-one (Sarmentine):
To the solution of Diethyl 2-oxo-2-(pyrrolidin-1-yl) ethylphosphonate 5g (0.02 mol; 1.0 Equiv.) in Tetrahydrofuran (50 ml); was added Lithium bromide1.73g (0.024 mol; 1.2 Equiv.) and Diisopropylethyl amine 3.0g (0.024 mol; 1.2 Equiv.) at 0-5oC followed by the addition of Trans-2-Octenal 2.0g(0.016 mol,0.8 Equiv.).Reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by thin layer chromatography using 5 % Ethyl acetate in Hexane as mobile phase.

After the completion of the reaction, the reaction mass was filtered off on Buchner funnel to remove lithium bromide. The solvengt, Tetrahydrofuran was recovered under reduced pressure to obtain crude compound. The crude compound was purified using the mixture of hexane and acetonitrile.
Weight: 2.5 g, Yield: 56.4%.

1HNMR of (2E, 4E)-1-(pyrrolidin-1-yl) deca-2, 4-dien-1-one (Sarmentine)(400MHz;CDCl3): d0.87-0.95(4H,m),1.25-1.32(5H,m)1.39-1.42(2H,m),1.84-1.89(2H,m),1.94-2.17(2H,m),3.51-3.55(2H,m), 3.49-3.55(4H,m),6.04-6.11(2H,m), 6.14-6.21(1H,dd)(j=6.19HZ),7.26-7.30(1H,dd)(j =7.28 HZ).

The compounds listed in table 1 have been prepared using the process similar to that of example 1, by charging the amine instead of Pyrrolidine to obtain corresponding Sarmentine analogues.

Example 2:
Procedure for the synthesis of Diethyl phosphonoacetic acid:
To the solution of Chloroacetic acid 50 g (0.529 moles, 1.0Equiv) in Toluene250 ml (5.0 Vol); was added Triethyl phospite 131.8 g (0.79 moles; 1.5 Equiv.) dropwise at room temperature. Reaction mixture was stirred at 100-110oC for 24 hours. The progress of the reaction was monitored by thin layer chromatography using 5% Methanol in Dichloromethane as mobile phase.
Workup: After completion of the reaction, the excess of Triethyl phosphite was distilled at 85-90oC and 10 milli bar pressure. The evolution of ethyl chloride gas as byproduct was observed during the progress of reaction.
Weight: 80 g, Yield: 77.6%.
1H NMR of Diethyl phosphonoacetic acid :( 400MHz;CDCl3):d1.1 (6H, t), 2.71(2H, s) 4.07-4.13(4H, m).

Procedure for the synthesis of (2E, 4E) Deca-2,4dienoic acid:
To the solution of Diethylphosphono acetic acid 5.0 g( 0.025 mol, 1 equiv) in anhydrous THF (25 mL) was added Zinc triflate 18.5 g(2.0 equiv, 0.05 mol).TMEDA 3.54g (0.03 mol),DBU 15.4g (4 equiv, 0.10 mol) was added followed by (E)-oct-2-enal, 3.5 g (1.1 equiv, , 0.58 mmol). The reaction mixture was stirred at 25 °C for 12 h under nitrogen atmosphere. Progress of the reaction was monitored by thin layer chromatography using 5% Methanol in Dichloromethane as mobile phase.
Workup: After completion of the reaction, the reaction mass was quenched with 1 N HCl (5 mL) and extracted with Dichloromethane (4 × 15 mL). The organic phases were combined and dried over sodium sulphate. Solvent was removed in vacuo to yield crude (2E, 4E) Deca-2,4dienoic acid.

Weight: 2.0 g, Yield: 45.1%.
1H NMR of (2E, 4E) Deca-2,4dienoic acid: :( 400MHz;CDCl3): d0.98(3H,t),1.29(2H,q),1.33(4H,m),1.96(2H,m),5.72(1H,m),6.07(1H,dd),6.27(1H,dd),7.47(1H,dd),11.05(1H,bs).
Preparation of (2E, 4E)-1-(pyrrolidin-1-yl) deca-2, 4-dien-1-one (Sarmentine):
To the solution of (2E, 4E) Deca-2,4dienoic acid 5g (0.029moles, 1.0Equiv) in Dichloromethane50 ml (10 Vol); was added oxalyl chloride 4.7 g (0.037 mol, 1.25 Equiv) and N, N-Dimethylformamide 0.2 g(0.1Equiv). The reaction mixture was heated at 40-45oC for 3.0 hours under nitrogen atmosphere. Dichloromethane and excess Oxalyl chloride was recovered under reduced pressure. This compound in freshly added Dichloromethane 50 ml (10 Vol) was added to the mixture of pyrrolidine 2.5g (0.035mol; 1.2 Equiv.) and DMAP0.5 g (0.004 mol; 0.15 Equiv) in Dichloromethane 25 ml (5 Vol) at 0-5oC.The reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by thin layer chromatography using 30 % Ethyl acetate in Hexane as mobile phase.

Workup: After completion of the reaction, the reaction mixture was diluted with Dichloromethane 50 ml and washed with 5% sodium carbonate solution 50 ml to remove excess Diethylphosphono acetic acid. Reaction mixture was stirred with 2.0 N Hydrochloric acid (100ml) to remove excess of amine. Dichloromethane was recovered under reduced pressure to get the titled compound as viscous colorless oily liquid.
Weight: 4.5 g, Yield: 69.2%.
1HNMR of (2E, 4E)-1-(pyrrolidin-1-yl) deca-2, 4-dien-1-one (Sarmentine)(400MHz;CDCl3): d0.87-0.95(4H,m),1.25-1.32(5H,m)1.39-1.42(2H,m),1.84-1.89(2H,m),1.94-2.17(2H,m),3.51-3.55(2H,m), 3.49-3.55(4H,m),6.04-6.11(2H,m), 6.14-6.21(1H,dd)(j=6.19HZ),7.26-7.30(1H,dd)(j =7.28 HZ).
,CLAIMS:
1. A process for synthesis of Sarmentine or its analogues comprising the steps of;
a) Reacting Diethyl phosphonoacetic acid with an amine in presence of oxalylchloride to obtain corresponding diethyl phosphonate esters; and
b) Reacting the diethyl phosphonate esters with (E)-oct-2-enal to obtain Sarmentine or its corresponding analogues.
2. The process as claimed in claim 1, wherein, the reaction of step a) is carried out in presence of catalytic amounts of DMF, DMAP in dicholoromethane solvent at 40-45°C for 4 to 10hrs.
3. The process as claimed in claim 1, wherein, the reaction of step b) is carried out in presence of DIPEA, Lithium bromide in THF at 0-30°C for 10- 15 hrs.
4. The process as claimed in claim 1, wherein, the amine is selected from the group consisting of Pyrrolidine, isobutyl amine, morpholine, piperidine, isopropylamine, tertiary butylamine, pyrrole and bicyclo[2.2.1]heptane.
5. The process as claimed in claim 1, wherein, the corresponding Sarmentine analogues are selected from the group consisting of;
a)
;
h)

i)
;

j)
;
k)
;
l)
; and
m)
.
6. The process as claimed in claim 1, wherein the process for preparation of Sarmentine comprises the following steps;
a) Reacting Diethyl phosphonoacetic acid with oxalyl chloride in presence of Pyrrolidine to obtain corresponding diethyl phosphonate; and
b) Reacting the diethyl phosphonate with (E)-oct-2-enal to obtain Sarmentine.
7. A process for synthesis of Sarmentine or its analogues comprising the steps of;
a) Reacting diethyl phosphonoacetic acid with (E)-oct-2-enal to obtain (2E, 4E)-deca-2, 4-dienoic acid; and
b) Reacting the (2E, 4E)-deca-2, 4-dienoic acid with an amine to get Sarmentine or its corresponding analogues.
8. The process as claimed in claim 7, wherein, the reaction of step a) is carried out in presence of Zinc triflate, TMEDA and DBU in THF at room temperature for 10- 15 hrs.
9. The process as claimed in claim 7, wherein, the reaction of step b) is carried out in presence of catalytic amounts of DMF, DMAP in dicholoromethane solvent at 40-45°C for 4 to 10hrs.
10. The process as claimed in claim 7, wherein, the amine is selected from the group consisting of Pyrrolidine, isobutyl amine, morpholine, piperidine, isopropylamine, tertiary butylamine, pyrrole and bicyclo[2.2.1]heptane.
11. The process as claimed in claim 7, wherein the process for preparation of Sarmentine comprises the following steps;
a) Reacting diethyl phosphonoacetic acid with (E)-oct-2-enal to obtain (2E, 4E)-deca-2, 4-dienoic acid; and
b) Reacting the (2E, 4E)-deca-2, 4-dienoic acid with Pyrrolidine to get Sarmentine or its corresponding analogues.