Description:DESCRIPTION:
Field of the invention:
[0001] The present disclosure generally relates to the technical field of organic and medicinal chemistry, and in specific relates to a green, solvent-free, and rapid synthesis method for nitrogen-containing heterocyclic compounds, utilizing microwave irradiation to enhance reaction efficiency.
Background of the invention:
[0002] In the existing state of the art, organic solvents are widely used in chemical synthesis, pharmaceuticals, polymer production, and material processing. However, these solvents pose significant health hazards, requiring personnel to wear protective gear to minimize exposure risks. Additionally, their environmental impact is considerable, necessitating stringent disposal protocols that contribute to high operational costs. Industries such as pharmaceuticals and specialty chemicals often face regulatory challenges due to the toxicity and volatility of these solvents, further complicating compliance and sustainability efforts.
[0003] Beyond safety and environmental concerns, current methods suffer from inefficiencies in reaction time. Many chemical reactions, particularly in pharmaceutical drug synthesis, polymerization, and fine chemical production, require extended durations—often exceeding 24 hours—to achieve the desired product formation. This prolonged reaction time increases production costs and limits throughput.
[0004] Furthermore, continuous monitoring of reaction progress is often necessary, requiring periodic collection of aliquots from the reaction mixture. This process is labor-intensive and introduces variability, increasing the risk of contamination and inconsistencies in product quality. In large-scale industrial setups, such monitoring adds to operational complexity, requiring skilled personnel and advanced analytical instrumentation.
[0005] These limitations highlight the need for alternative solvent systems or process modifications that enhance efficiency, reduce toxicity, and minimize environmental and economic burdens.
[0006] Therefore, there is a need for a green, solvent-free, and rapid synthesis method for nitrogen-containing heterocyclic compounds, utilizing microwave irradiation to enhance reaction efficiency. There is also a need for a synthesis method that eliminates the use of hazardous organic solvents, reducing environmental pollution and health risks. There is also a need for a synthesis method for 4-(pyrrolidin-1-yl)-piperidine and its derivatives for applications in pharmaceuticals, medicinal chemistry, and synthetic chemistry.
Objectives of the invention:
[0007] The primary objective of the invention is to provide a green, solvent-free, and rapid synthesis method for nitrogen-containing heterocyclic compounds, utilizing microwave irradiation to enhance reaction efficiency.
[0008] The other objective of the invention is to provide a synthesis method for 4-(pyrrolidin-1-yl)-piperidine and its derivatives for applications in pharmaceuticals, medicinal chemistry, and synthetic chemistry.
[0009] The other objective of the invention is to provide a synthesis method that reduces the reaction time from over 24 hours to just 3-5 minutes, significantly increasing efficiency.
[0010] Another objective of the invention is to provide a microwave-assisted method that achieves a product yield of over 90%, compared to 40%-50% in traditional methods.
[0011] The other objective of the invention is to provide a synthesis method that eliminates the use of hazardous organic solvents, reducing environmental pollution and health risks.
[0012] Yet another objective of the invention is to provide a synthesis method that adheres to green chemistry principles, making the process eco-friendly and sustainable.
[0013] Another objective of the invention is to provide a synthesis method that reduces costs by eliminating expensive solvents and purification steps.
[0014] Another objective of the invention is to provide a synthesis method that lower energy consumption due to shorter reaction times.
[0015] Yet another objective of the invention is to provide a synthesis method that provides rapid and solvent-free synthesis 4-(pyrrolidin-1-yl)-piperidine and its derivatives, which is suitable for large-scale pharmaceutical manufacturing.
[0016] Further objective of the invention is to provide a synthesis method that avoids time-consuming purification processes, making the synthesis method more efficient for bulk production.
Summary of the invention:
[0017] The present disclosure proposes a green, solvent-free, and rapid synthesis method for pyrrolidine-piperidine derivative compounds. The following presents a simplified summary in order to provide a basic understanding of some aspects of the claimed subject matter. This summary is not an extensive overview. It is not intended to identify key/critical elements or to delineate the scope of the claimed subject matter. Its sole purpose is to present some concepts in a simplified form as a prelude to the more detailed description that is presented later.
[0018] In order to overcome the above deficiencies of the prior art, the present disclosure is to solve the technical problem to provide a green, solvent-free, and rapid synthesis method for nitrogen-containing heterocyclic compounds, utilizing microwave irradiation to enhance reaction efficiency.
[0019] According to an aspect, the invention provides a pyrrolidine-piperidine derivative comprises 4-(pyrrolidin-1-yl)-piperidine.
Formula (1)

[0020] According to another aspect, the invention provides a method for synthesizing the pyrrolidine-piperidine derivative. First, N-Boc-piperidone and pyrrolidine are mixed in equimolar ratio in a reaction vessel to formulate a first mixture. In one embodiment, the reaction vessel is a round-bottomed glass flask. Next, a reducing agent is added in the first mixture to obtain a reaction mixture. The reducing agent includes sodium borohydride (NaBH4). Later, the reaction mixture is subjected to microwave irradiation for a time period, thereby obtaining the pyrrolidine-piperidine derivative. In one embodiment, the microwave irradiation is applied at a power level between 300W and 800W. The method for synthesizing the pyrrolidine-piperidine derivative is performed at an ambient pressure environment.
[0021] In one embodiment, the method provides a reaction yield of the pyrrolidine-piperidine derivative of greater than 90% and a total reaction time of less than one hour. The presence of the pyrrolidine-piperidine derivative is confirmed by the absence of a red color in a sodium nitroprusside ketone test. The pyrrolidine-piperidine derivative is isolated and characterized using nuclear magnetic resonance (NMR), infrared (IR), and mass spectroscopy.
[0022] Further, objects and advantages of the present invention will be apparent from a study of the following portion of the specification, the claims, and the attached drawings.
Detailed description of drawings:
[0023] The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate an embodiment of the invention, and, together with the description, explain the principles of the invention.
[0024] FIG. 1 illustrates a synthesis scheme of a pyrrolidine-piperidine derivative, in an exemplary embodiment of the invention.
[0025] FIG. 2 illustrates a flowchart of a method for synthesizing the pyrrolidine-piperidine derivative, in an exemplary embodiment of the invention.
[0026] FIGs. 3A – 3B illustrate nuclear magnetic resonance (NMR) spectral of the N-boc-4-(pyrrolidin-1-yl)-piperidine, depicting both the full spectrum and an expanded view of the aliphatic region, respectively, in an exemplary embodiment of the invention.
[0027] FIGs. 4A – 4B illustrate carbon-13 nuclear magnetic resonance (13C NMR) spectrum of the N-boc-4-(pyrrolidin-1-yl)-piperidine, in an exemplary embodiment of the invention.
[0028] FIG. 5 illustrates a two-dimensional correlation spectroscopy (2D-COSY) nuclear magnetic resonance (NMR) spectrum of the synthesized compound N-Boc-4-(pyrrolidin-1-yl)-piperidine, in an exemplary embodiment of the invention.
[0029] FIG. 6 illustrates an infrared (IR) spectrum of the synthesized N-boc-4-(pyrrolidin-1-yl)-piperidine, in an exemplary embodiment of the invention.
[0030] FIG. 7 illustrates an image depicting a set of four vertically aligned transparent test tubes, in an exemplary embodiment of the invention.
Detailed invention disclosure:
[0031] Various embodiments of the present invention will be described in reference to the accompanying drawings. Wherever possible, same or similar reference numerals are used in the drawings and the description to refer to the same or like parts or steps.
[0032] The present disclosure has been made with a view towards solving the problem with the prior art described above, and it is an object of the present invention to provide a green, solvent-free, and rapid synthesis method for nitrogen-containing heterocyclic compounds, utilizing microwave irradiation to enhance reaction efficiency.
[0033] According to an exemplary embodiment of the invention, FIG. 1 refers to a synthesis scheme 100 of a pyrrolidine-piperidine derivative (4-(1-Pyrrolidine) piperidine). The pyrrolidine-piperidine derivative is synthesized from N-Boc-piperidone and pyrrolidine using a microwave-assisted procedure, which eliminates the need for organic solvents, improves reaction efficiency and reduces the overall process time to under 1 hr.
Formula (1)

[0034] According to another exemplary embodiment of the invention, FIG. 2 refers to a flowchart 200 of a method for synthesizing the pyrrolidine-piperidine derivative. At step 202, N-Boc-piperidone and pyrrolidine are mixed in equimolar ratio in a reaction vessel to formulate a first mixture. In one embodiment, the reaction vessel is a round-bottomed glass flask. At step 204, a reducing agent is added in the first mixture to obtain a reaction mixture. The reducing agent includes sodium borohydride (NaBH4). In a preferred embodiment, 0.6 grams of N-Boc-piperidone (ketone) and 0.35 grams (0.3 ml) of pyrrolidine in a beaker to which 0.1 grams of sodium borohydride (NaBH4).
[0035] At step 206, the reaction mixture is subjected to microwave irradiation for a time period of 3 to 5 minutes, thereby obtaining the pyrrolidine-piperidine derivative. In one embodiment, the microwave irradiation is applied at a power level between 300W and 800W. The method for synthesizing the pyrrolidine-piperidine derivative is performed at an ambient pressure environment. In one embodiment, the pyrrolidine-piperidine derivative is N-boc-4-(pyrrolidin-1-yl)-piperidine.

[0036] According to another exemplary embodiment of the invention, FIGs. 3A – 3B refer to nuclear magnetic resonance (NMR) spectral (300, 302) of the N-boc-4-(pyrrolidin-1-yl)-piperidine, depicting both the full spectrum and an expanded view of the aliphatic region, respectively. NMR spectral analysis is performed on the synthesized N-boc-4-(pyrrolidin-1-yl)-piperidine, to confirm its structural identity and purity. The analysis comprised individual acquisition and interpretation of both proton (1H) and carbon (13C) NMR spectra. Additionally, two-dimensional correlation spectroscopy (COSY) is employed to identify scalar coupling relationships and to verify the proton-proton connectivity within the molecule.
[0037] In one embodiment, the acquired 1H NMR spectrum of the N-boc-4-(pyrrolidin-1-yl)-piperidine. FIG. 3A displays the full-range proton NMR spectrum, capturing all chemical shift regions relevant to the compound, ranging from approximately 0 to 12 parts per million (ppm). FIG. 3B presents a zoomed-in view of the aliphatic region (approximately 2.6 to 4.3 ppm), facilitating detailed analysis of the chemical shifts, multiplicities, and coupling patterns associated with aliphatic and heteroatom-adjacent protons. The observed spectral features are consistent with the expected chemical structure of N-boc-4-(pyrrolidin-1-yl)-piperidine, with signal assignments corroborated by COSY analysis.
[0038] According to another exemplary embodiment of the invention, FIGs. 4A – 4B refer to carbon-13 nuclear magnetic resonance (13C NMR) spectrum (400, 402) of the N-boc-4-(pyrrolidin-1-yl)-piperidine. FIG. 4A displays the aliphatic region of the 13C NMR spectrum, ranging from approximately 70 ppm to 20 ppm, capturing carbon signals corresponding to the aliphatic and Boc-protected nitrogen-containing ring systems. FIG. 4B presents the downfield region of the spectrum, covering approximately 160 ppm to 180 ppm, which includes signals attributed to carbonyl carbon atoms, specifically the Boc carbamate functional group. The spectral data exhibit distinct and well-resolved peaks, each corresponding to specific carbon environments within the molecular structure. The observed chemical shifts are consistent with the expected positions for aliphatic methylene and methine carbons, as well as quaternary and carbonyl carbons, thereby confirming the successful synthesis and structural integrity of the N-boc-4-(pyrrolidin-1-yl)-piperidine.

[0039] Table 1:
S.No Carbon number Proton δppm Carbon δppm
1. C2 3.846 (2H) 79.56
2. C3 a. 2.773(1H)
b. 2.582(1H) 31.25
3. C4 4.061 (1H) 51.37
4. C5 a. 2.136(1H)
b. 1.309(1H) 41.24
5. C6 3.846(2H) 79.42
6. C8 3.03(2H) 67.72
7. C9 1.469(2H) 34.17
8. C10 1.469(2H) 34.17
9. C11 3.03 (2H) 67.72
10. C12 - 154.84
11. C13 - 61.92
12. C14 1.854 (3H) 28.43
13. C15 1.854 (3H) 28.43
14. C16 1.854 (3H) 22.31
[0040] In one embodiment, the molecular structure of the synthesized compound, N-boc-4-(pyrrolidin-1-yl)-piperidine, was confirmed via comprehensive nuclear magnetic resonance (NMR) spectroscopy, including both proton (1H) and carbon-13 (13C) analyses. The observed chemical shifts (δ, in ppm), signal multiplicities, and integration values obtained from the 1H NMR spectrum were consistent with the proposed molecular framework, thereby validating the successful synthesis of the target compound.
[0041] In the 1H NMR spectrum, distinct resonances corresponding to chemically non-equivalent proton environments were identified. The methylene protons associated with carbon atoms C2 and C6 produced signals at δ 3.846 ppm (2H each), indicative of proximity to electron-withdrawing groups such as nitrogen or oxygen. The protons at C3 were resolved into two separate signals at δ 2.773 ppm and δ 2.582 ppm (1H each), suggesting a diastereotopic nature caused by adjacency to a chiral center. A downfield resonance at δ 4.061 ppm (1H) was attributed to the proton at C4, consistent with deshielding effects from nearby electronegative atoms.
[0042] Additional resonances in the aliphatic region were assigned to methylene groups at C5 (δ 2.136 and 1.309 ppm), C8 and C11 (δ 3.03 ppm), and C9 and C10 (δ 1.469 ppm), in alignment with their expected electronic environments. Three singlet peaks observed at δ 1.854 ppm, each integrating for 3H, were attributed to methyl groups located at C14, C15, and C16, consistent with terminal methyl substituents.
[0043] The 13C NMR spectrum displayed 14 distinct carbon signals. The resonances at δ 79.56 ppm (C2) and δ 79.42 ppm (C6) are characteristic of carbons bonded to electronegative atoms such as oxygen or nitrogen. The downfield signal at δ 154.84 ppm (C12) suggests the presence of a carbamate or conjugated functional group, while the resonance at δ 61.92 ppm (C13) is indicative of a quaternary carbon or a carbon bonded to an electronegative atom. Aliphatic carbon signals corresponding to C3, C4, C5, C8–C11, and the methyl groups at C14, C15, and C16 were observed at δ 28.43 ppm and δ 22.31 ppm, respectively. The observed equivalence in chemical shifts at C14 and C15 supports the proposed symmetrical substitution pattern of the molecule.
[0044] In one embodiment, the combined proton (1H) and carbon (13C) nuclear magnetic resonance (NMR) spectral data are consistent with the proposed molecular structure of the synthesized compound, N-Boc-4-(pyrrolidin-1-yl)-piperidine. The observed chemical shifts, multiplicity patterns, and integral values correlate with the expected chemical environments and substitution pattern, thereby confirming the successful formation and structural fidelity of the target compound.
[0045] According to another exemplary embodiment of the invention, FIG. 5 refers to a two-dimensional correlation spectroscopy (2D-COSY) nuclear magnetic resonance (NMR) spectrum 500 of the synthesized N-Boc-4-(pyrrolidin-1-yl)-piperidine. The full COSY plot is shown with a magnified view of the aliphatic proton correlation region (1.2–4.5 ppm) provided on the right. The COSY spectrum 500 exhibits multiple cross-peaks within the aliphatic region (1.2–2.7 ppm), indicating the presence of –CH₂– and –CH₃– spin systems characteristic of aliphatic chains or branched hydrocarbon structures. These off-diagonal correlations confirm scalar couplings between adjacent protons within methylene and methyl groups.
[0046] Notably, correlations between signals in the range of δ 3.00–3.07 ppm and δ 3.83–3.87 ppm, as well as further interactions extending to δ 4.47 ppm, are indicative of protons residing on carbon atoms bonded to electronegative substituents such as oxygen or nitrogen. The pattern and magnitude of these correlations are consistent with chemical environments associated with ether, ester, or amine functionalities. The appearance of interconnected cross-peaks in the δ 3.8–4.5 ppm region strongly supports the presence of functional groups such as ester or amino ester moieties, in alignment with the corresponding IR spectral data indicating stretching vibrations of carbonyl (C=O) and N–H bonds.
[0047] The COSY spectrum 500 thus confirms a continuous network of proton-proton couplings consistent with the structure of N-Boc-4-(pyrrolidin-1-yl)-piperidine. The observed spin systems validate the presence of (i) aliphatic chains comprising –CH₂–CH₂–CH₃ groups, (ii) protons adjacent to electronegative atoms, such as –CH₂–O– or –CH₂–N– units, and (iii) functionalized linkages indicative of ester or amine substitution patterns. Additionally, infrared (IR) spectroscopic analysis of the final product was performed over the spectral range of 4000–400 cm⁻¹. The resulting spectrum exhibited characteristic absorption bands corresponding to amine (N–H) and ester (C=O) functional groups, further corroborating the presence of Boc-protected nitrogen functionalities and ester linkages in the molecular structure.
[0048] According to another exemplary embodiment of the invention, FIG. 6 refers to an infrared (IR) spectrum 600 of the synthesized N-boc-4-(pyrrolidin-1-yl)-piperidine. A strong absorption band at 3463.21 cm⁻¹ corresponds to N–H stretching vibrations, indicative of primary or secondary amine groups. The peak at 2950.91 cm⁻¹ is associated with C–H stretching in sp³-hybridized alkanes, confirming the presence of saturated hydrocarbon chains. A prominent absorption at 1672.32 cm⁻¹ indicates carbonyl (C=O) stretching, characteristic of esters, amides, or other carbonyl-containing groups. The band at 1240.20 cm⁻¹ corresponds to C–O stretching, supporting the presence of an ester functionality, while the absorption at 1074.00 cm⁻¹ is attributed to C–N stretching, reinforcing the identification of amine groups. Collectively, these spectral features confirm that the compound contains both nitrogenous (amine) and oxygenated (ester/carbonyl) functionalities, aligning well with the proposed structure of N-Boc-4-(pyrrolidin-1-yl)-piperidine.
[0049] Table 2:
Wavenumber (cm⁻¹) Assignment Interpretation/Functional Group
~3300–3400 N–H Stretch Presence of primary or secondary amine group
~1650 C=O Stretch Indicative of ester or possibly amide group
~1200–1300 C–O Stretch Confirms ester functionality
~2850–2960 C–H Stretch Due to sp³ hybridized C–H bonds (alkane)
~1000–1100 C–N Stretch Associated with amine functional group
[0050] Table 3:
Wavenumber (cm⁻¹) Assignment Functional Group Identified
3463.21 N–H Stretch Amine group (primary or secondary)
2950.91 C–H Stretch Alkane (sp³ hybridized C–H)
1672.32 C=O Stretch Carbonyl group (possibly ester/amide)
1240.20 C–O Stretch Ester group
1074.00 C–N Stretch Amine group
[0051] According to another exemplary embodiment of the invention, FIG. 7 refers to an image 700 depicting a set of four vertically aligned transparent test tubes (SM, RM1, RM2, RM3) positioned within a standard laboratory test tube rack. The respective test tubes contain liquid samples representative of sequential stages of a chemical reaction involving a ketone-containing compound, namely N-Boc piperidone.
[0052] In one embodiment, the progression and completion of the chemical reaction are monitored using a sodium nitroprusside-based ketone detection assay, which is a qualitative colorimetric test capable of identifying the presence of ketone functional groups in an alkaline medium. The starting material (SM) includes N-Boc piperidone, which contains a ketone moiety. Upon treatment with sodium nitroprusside, test tube SM exhibits a distinct brownish coloration, confirming the presence of the unreacted ketone functional group.
[0053] In one embodiment, test tube RM1 contains a reaction mixture obtained after approximately one minute of microwave-assisted treatment. Upon subjecting RM1 to the sodium nitroprusside test, a faint brown coloration is observed, indicating a partial consumption of the ketone functionality during the early stages of the reaction.
[0054] In one embodiment, test tube RM2 contains the reaction mixture after approximately two minutes of microwave exposure. The colorimetric response upon addition of sodium nitroprusside remains faintly brown, further indicating a progressive reduction in the ketone content as the reaction advances.
[0055] In one embodiment, test tube RM3 corresponds to the final reaction mixture following approximately three minutes of microwave-assisted processing. Notably, the addition of the sodium nitroprusside reagent to RM3 yields no observable coloration, thereby indicating the complete consumption of the ketone group. The absence of coloration confirms that the reaction has proceeded to completion, with the ketone functional group being fully utilized under the specified microwave reaction conditions.
[0056] This systematic colorimetric transition observed in FIG. 7 serves as a visual confirmation of the temporal evolution and completion of the reaction, validating the effectiveness of the microwave-assisted method for achieving complete ketone group transformation within a three-minute duration.
[0057] Numerous advantages of the present disclosure may be apparent from the discussion above. In accordance with the present disclosure, a green, solvent-free, and rapid synthesis method is disclosed herein for nitrogen-containing heterocyclic compounds, utilizing microwave irradiation to enhance reaction efficiency.
[0058] In one embodiment, the synthesis method for 4-(pyrrolidin-1-yl)-piperidine and its derivatives for applications in pharmaceuticals, medicinal chemistry, and synthetic chemistry. The synthesis method reduces the reaction time from over 24 hours to just 3-5 minutes, significantly increasing efficiency. The proposed microwave-assisted synthesis method achieves a product yield of over 90%, compared to 40%-50% in traditional methods.
[0059] In one embodiment, the synthesis method eliminates the use of hazardous organic solvents, reducing environmental pollution and health risks. The synthesis method adheres to green chemistry principles, making the process eco-friendly and sustainable. The synthesis method reduces costs by eliminating expensive solvents and purification steps. The synthesis method lower energy consumption due to shorter reaction times. The synthesis method provides rapid and solvent-free synthesis 4-(pyrrolidin-1-yl)-piperidine and its derivatives, which is suitable for large-scale pharmaceutical manufacturing. The synthesis method avoids time-consuming purification processes, making the synthesis method more efficient for bulk production.
[0060] It will readily be apparent that numerous modifications and alterations can be made to the processes described in the foregoing examples without departing from the principles underlying the invention, and all such modifications and alterations are intended to be embraced by this application.
, Claims:CLAIMS:
I / We Claim:
1. A method for synthesizing a pyrrolidine-piperidine derivative, comprising:
mixing N-Boc-piperidone and pyrrolidine in equimolar ratio in a reaction vessel to formulate a first mixture;
adding a reducing agent in the first mixture to obtain a reaction mixture; and
subjecting the reaction mixture to microwave irradiation for a time period, thereby obtaining the pyrrolidine-piperidine derivative,
wherein the method provides a reaction yield of the pyrrolidine-piperidine derivative of greater than 90% and a total reaction time of less than one hour.
2. The method for synthesizing the pyrrolidine-piperidine derivative as claimed in claim 1, wherein presence of the pyrrolidine-piperidine derivative is confirmed by the absence of a red color in a sodium nitroprusside ketone test.
3. The method for synthesizing the pyrrolidine-piperidine derivative as claimed in claim 1, wherein the pyrrolidine-piperidine derivative is isolated and characterized using nuclear magnetic resonance (NMR), infrared (IR), and mass spectroscopy.
4. The method for synthesizing the pyrrolidine-piperidine derivative as claimed in claim 1, wherein the microwave irradiation is applied at a power level between 300W and 800W.
5. The method for synthesizing the pyrrolidine-piperidine derivative as claimed in claim 1, wherein the reaction vessel is a round-bottomed glass flask.
6. The method for synthesizing the pyrrolidine-piperidine derivative as claimed in claim 1, wherein the method for synthesizing the pyrrolidine-piperidine derivative is performed at an ambient pressure environment.
7. The method for synthesizing the pyrrolidine-piperidine derivative as claimed in claim 1, wherein the reducing agent includes sodium borohydride (NaBH4).