Fifth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-5), http://www.mdpi.org/ecsoc-5.htm, 1-30 September 2001

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[E0021]

HANTZSCH ESTER SYNTHESIS BY USING AN AQUEOUS HYDROTROPE SOLUTION AS A SOLVENT, IN CONTINUOUS MICROWAVE REACTOR (CMR) 

Bhushan M. Khadilkar^* & Virendra R. Madyar

email: [email protected], [email protected] 

Applied Organic Chemistry Laboratory, University Department of Chemical Technology, University of Mumbai, Nathalal Parikh Marg, Matunga, Mumbai 400 019, India

Received: 15 August 2001 / Uploaded 22 August 2001

ABSTRACT

KEYWORDS

INTRODUCTION

RESULTS AND DISCUSSION: 

EXPERIMENTAL

CONCLUSION

REFERENCES

ACKNOWLEDGEMENT

ABSTRACT

After 1995, rapid development in microwave equipment and modification of ovens was witnessed. To develop microwaves assisted large scale reaction methodologies has become a need of an hour. We report here a simple design of continuous microwave reactor (CMR) for carrying out reactions on a large scale in a domestic microwave oven. We report Hantzsch ester synthesis, scaled up to 75 gm., using a novel reusable aqueous hydrotrope solution as a safe alternative to inflamable organic solvents, in microwave cavity. Separation of the product was very easy as it separated as a separate solid phase, when cooled outside the microwave cavity. The solvent was recycled. We could obtain high yields of dihydropyridines. 

KEYWORDS

Continuous microwave reactor (CMR), scale-up, aqueous hydrotrope solution, Hantzsch synthesis, dihydropyridines, calcium channel blocker.

INTRODUCTION

Marked growth in a field of microwave technology development is evident from number of papers and patents, in the areas of  organic synthesis [1], polymer synthesis [2], material science [3], food technology [4], environmental technology [5], etc. We have been in the field and in last five years have published a number of papers.

We have been working [6,7] in the synthesis of commercially important calcium channel blockers such as nifedipine, nitrendipine and various other 1,4-dihydropyridines. Some recent reviews [8-11] are available on dihydropyridine chemistry.

Hydrotropy is the phenomenon by which otherwise water insoluble compounds can be solubilized in the aqueous solution of certain compounds like arene sulphonates. These compounds, known as hydrotopes, are readily water soluble. The aqueous concentrated solutions (20 to 50 %) of the hydrotopes can significantly increase water solubility of many water insoluble compounds. The hydrotope solutions can be safe solvents, as they are non-inflamable, and non-toxic as water is the bulk medium. Hence the use of aqueous hydrotrope solution can be considered as a replacement for organic solvents, in a step towards development of environmentally friendly processes.  Though not many reports are available on hydrotope solutions as reaction media, reactions such as hydrolysis of ester and oximation of cyclodecanone [12], cross-Cannizzaro reactions of benzaldehydes and formaldehyde [13], Claisen-Schmidt condensation reactions [14] have been reported in aqueous hydrotrope solution. Use of inflamable solvents like methanol, isopropyl alcohol, etc. can be very dangerous for the use in the microwave cavity. 

RESULTS AND DISCUSSION

BATCH PROCESS - 

In order to determine the parameters like resident cavity time of the reaction mixture, suitable hydrotope, etc. for the continuous reactor synthesis it was necessary to study the reactions in batch process. We have used for the first time aromatic hydrotrope solution system such as 50% sodium p-toluene sulphonate aqueous solution (NaPTSA), 40% sodium cumene sulphonate aqueous solution (NaCuS) and 20% sodium p-xylene sulphonate (NaXS) aqueous solution to carry out Hantzsch ester synthesis to give high yields of 4-aryl-1,4-dihydropyridines under microwave exposure. 

We studied two routes (Route A and B) for Hantzsch ester synthesis to give 4-aryl-1,4-dihydropyridines under microwave exposure. Initially each route is studied and optimized for a batch process in 50% NaPTSA under microwave exposure. We studied the reaction in 40% NaCuS and 20% NaXS hydrotrope solution too. We found that the yields of DHPs were higher in 50% NaPTSA than in the other two hydrotrope solutions. The route B was found more covenient for CMR. Route A requires aq. ammonium hydroxide which is difficult to handle in CMR.

Dihydropyridine ester synthesis using aqueous hydrotrope solutions under microwave irradiation

Route A

Route B

Optimization for batch process

Figure 1 Optimization of DHP synthesis under microwave exposure in 50% NaPTSA by routes A & B.

Hantzsch reaction for DHP synthesis was optimized for batch process in a modified IFB Neutron (760W, 2450MHz) microwave domestic oven.  

Figure2. Modified domestic microwave oven fitted with stirring an reflux facility for a batch process

Development of continuous microwave reactor (CMR) for Scale-up 

We have developed two types of reactors to be used in CMR for our initial study, a glass coil reactor and another a planer, circular glass reactor (see Figure 3). In case of glass coil reactor resistance to the flow of reaction solution was observed and also the chances of clogging of DHP formed during the final stages of reaction was more probable in coil shaped reactor.

A circular glass reactor was then constructed for CMR study to avoid the problems observed in the coil shaped reactor. The reactor was found to be suitable for our study as the reaction solution moved smoothly and also chances of clogging of DHP formed during the final stages of reaction was avoided by this kind of reactor design. The glass reactor was placed in such a way that it traversed along the circumference of the turntable (glass plate without a rotor) inside the microwave cavity. At the rear wall of the domestic microwave oven two holes of 1 cm diameter and 5 cm apart from each other were drilled as inlet and outlet ports for the two ends of glass reactor to come out. To these ends teflon tubing was connected. The tubes were cooled to control the temperature during microwave irradiation.

The reactor volume was 65 ml and that of connecting teflon tubes was 35 ml (dead volume). Therefore the total volume for CMR was 100 ml and the reaction was carried out in a closed loop mode. The reaction mixture was taken in a three-necked round bottom flask of 500 ml capacity and the mixture was stirred using magnetic needle. A condenser was fitted to one of the central neck while remaining two were used as inlet and outlet ports.

Optimization study for MW irradiation time for nitrendipine synthesis in CMR

The flow rate of 50% NaPTSA with respect to mw irradiation time was optimized to get controlled heating of the solution. The best heating profile was obtained at 24 rpm of the pump and flow rate of 100 ml/min can be easily maintained using a peristaltic pump. This homogeneous solution was then pumped through omega shaped glass reactor via Teflon tubing using peristaltic pump (Electrolab, model PP-VT 100 series).

The reaction mixture containing equivalent amounts of 3-nitrobenzaldehyde, ethyl acetoacetate and methyl 3-aminocrotonate were solubilized in 50 % NaPTSA and circulated through microwave cavity for known microwave exposure time. It was observed that at 24 min maximum yield for nitrendipine was obtained (table 3, figure 3).

Figure 3  Schematic diagram for continuous microwave reactor (CMR)

Table 3 Optimization of MW irradiation time for nitrendipine synthesis in CMR

 

MW time min		Nitrendipine isolated yield %#
6		55
12 (6´ 2 cycles)		87
18 (6´ 3 cycles)		92
24 (6´ 4 cycles)		94

# Route B: equimolar amount of aldehyde, alkyl acetoacetate and methyl 3-aminocrotonate in 50% NaPTSA solution. Entry no. 1 structure R₁= Et; Sr. no. 2-5 structure R₁ = Me

Figure 3 Optimization of MW irradiation time for nitrendipine synthesis in CMR

  Figure 4    Continuous microwave reactor set-up for continuous reaction for scale up

EXPERIMENTAL

The Hantzsch dihydropyridine ester synthesis was carried out in aqueous hydrotrope solution using two different routes.

BATCH PROCESS

Route A:

In a round bottom flask an aldehyde (5 mmol) was added to the hydrotrope solution (7 ml) and solubilized (by warming to 40^oC if necessary), to this solution alkyl acetoacetate (10 mmol) and 2 ml ammonia (sp. gravity 0.91) solution were added. The reaction mixture was then irradiated at full power in a modified domestic microwave oven provided with reflux and stirring facility. Immediately after the irradiation, reaction temperature was noted. The reaction was then cooled to room temperature or in ice as needed, to give 4–aryl-1,4-dihydropyridine ester as the solid product. The solid product obtained after filtration was washed with 10 ml of water and 5 ml of methanol. The product was air dried which showed the correct melting point (table 1). Small amount of the product was recovered as a second crop. Yields reported are combined yields. The completion of reaction was monitored by TLC (toluene–ethyl acetate 8:2 v/v).

Route B:

Aldehyde (5 mmol) was added to the hydrotrope solution (7 ml) and was solubilized by warming when necessary. To this solution alkyl acetoacetate (5 mmol) and methyl 3-aminocrotonate (5 mmol) were added and the reaction mixture was irradiated as per the above procedure. The results are summarized in (table 2).

For all the substrates in the above routes the amount of hydrotrope was sufficient to solubilize the reactant. Solubility of reactants (solid aldehydes) in aqueous hydrotrope solution was found by loss in weight method [12]. The alkyl acetoacetate and methyl 3-aminocrotonate were completely soluble in the hydrotrope solutions. In both the methods it was noted that when the same reactions were performed in a water bath under microwave irradiation (end temperature 86⁰C) they failed to give significant yields for the comparable time. This supports the utility of microwave assistance to carry out the reactions.

Table 1 Optimized % yields for the synthesis of DHPs by route A

 

Entry No.		R		MW (min.)		50% NaPTSAa		40% NaCuSa		20% NaXSa		Lit. Yield		MP °Cb  Obsd [8-11].
1.		H		4		81		45		45		35		198
2.		4-Cl		4		52		30		34		55		195-196
3.		3,4-di Cl		6		50		41		41		-		163-164
4.		4-Br		6		70		51		29		66		193-194
5.		2-NO2		1		28		-		-		-		172-173
6.		3-NO2		5		71		45		20		65		209-210
7.		4-NO2		4		64		45		38		66		197-198
8.		3-NO2		6		39		45		34		-		160-161

^a Yield of pure, isolated product. ^b The melting point and spectral data of products were identical with

those of authentic samples.

Entry no. 1-7 structure R₁= Me; Sr. no. 8 structure R₁ 

Table 2 Optimized % yields for the synthesis of DHPs by route B

 

Entry No		R		MW (min)		50% NaPTSAa		40% NaCuSa		20% NaXSa		Lit.		MP oCb Obsd [8-11].
1.		H		5		81		53		50		35		198
2.		4-Cl		5		34		29		33		55		195-196
3.		3,4 di-Cl		6		67		75		60		-		163-164
4.		4-Br		6		49		48		35		66		193-194
5.		2-NO2		1		11		-		-		-		172-174
6.		3-NO2		3		71		38		52		65		209-210
7.		4-NO2		6		83		35		44		66		197-198
8.		3-NO2		6		76		46		18		-		158-159

^aYield of pure, isolated product^bThe melting point and spectral data of products were identical

with those of authentic samples.

^#Entry no. 1-7 structure R₁ = Me; Sr. no. 8 structure R₁= Et

CMR STUDY (for nitrendipine preparation)

125 ml of 50% NaPTSA solution were introduced in a 500 ml three necked round bottom flask. To that solution m–nitrobenzaldehyde (0.15 mole, 22.68 g) was added. The mixture was stirred for 15 min in order to solublize the aldehyde completely. To this clear solution ethyl acetoacetate (0.15 mole, 19.52 g) and methyl 3–aminocrotonate (0.15 mole, 17.25 g) was added. This homogeneous solution was then pumped through omega shaped glass reactor via Teflon tubing using peristaltic pump (Electrolab, model PP-VT 100 series). The flow rate was optimized to 100 ml/min. The reaction mixture was circulated through microwave cavity in 4 cycles of 6 min each. A 2 min gap between each cycle (only to avoid excessive heating) was imposed. The reaction mixture was cooled to room temperature and then into crushed ice for 10 min. The solid product obtained after cooling was filtered, washed two times with 25 ml of water, then by 15 ml of methanol and air dried to give 94 % (50.76 g) yield. The hydrotrope solution can be reused. Similarly, other DHPs were also synthesized in continuous microwave reactor (CMR) (Table 4).

Table 4. Optimized results for the synthesis of DHPs by route B in CMR

 

Entry No.		R#		MW min.		% Isolated yield a		MP°C Obsd. (Lit)
1		3-NO2 (nitrendipine)		24 (6 × 4 cycles)		94		158-159 (158)
2		2-NO2 (nifedipine)		18 (6 × 3 cycles)		42		172-174 (174)
3		3-NO2		18 (6 × 3 cycles)		98		209-210 (209)
4		4-NO2		8 (6 + 2 )		88		197-198 (197)
5		2-Cl		24 (6 × 3 cycles)		86		184-185 (184)

# Route B: equimolar amount of aldehyde, alkyl acetoacetate and methyl 3-amino crotonate in

50% NaPTSA solution. Entry no. 1 structure R₁= Et; Sr. no. 2-5 structure R₁ = Me

^aYield of pure isolated product. The melting point and spectral data of products were identical

with those of authentic samples.

Nifedipine was obtained in relatively low yields, as the reaction time was not increased due to development of brown coloration to the reaction mixture. We have observed that development of such color effects the quality of the product, moreover o-substituted DHPs are known to form lower yields.

CONCLUSION

Following conclusion can be drawn form this work:

• Aqueous hydrotrope is a green and safe alternative to organic solvents under MW exposure.
• MW and hydrotrope combination reduces reaction time, with ease in isolation of products.
• Though the concentration of the aq. hydrotope solution is high, the products separate out as solid phase and aqueous hydrotrope solution is reusable.
• Continuous microwave reactor (CMR) helps in scaling up reaction within a domestic microwave oven, much cheaper than the commercial systems available.
• Its would be easily possible to scale up the reaction further by designing an appropriate planer glass coil.
• The reaction time could be further reduced by choosing an appropriate planer glass coil.

REFERENCES

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ACKNOWLEDGEMENT

Thankful to All India Council for Technical Education (AICTE), New Delhi, India for Financial assistance.