**Synthesis, Structure and Biological Activity of Ephedra Heterocycles**

Alejandro Cruz, Itzia I. Padilla‐Martínez and María Esther Bautista‐Ramírez

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67387

#### **Abstract**

Ephedra compounds are well known due to their biological activity. They have been widely used in asymmetric synthesis during the last decades. Recently, we have pre‐ pared reviews about the synthesis of acyclic and heterocyclic ephedra derivative com‐ pounds reported in the literature. In this chapter, the synthetic methodology to access acyclic and heterocyclic compounds derived from ephedra alkaloids and its structural analysis are discussed, included those due to the substitution of the hydroxy group by chlorine, sulfur, selenium, or nitrogen atoms. Biological activity analysis of some synthe‐ sized compounds was done, and some of them have displayed biological activity.

**Keywords:** ephedrines, chirality, configuration, biological activity, stereoespecificity

#### **1. Introduction**

Chirality in biological systems is of main significance since in enzymes and drug receptors, the active sites are chiral, and they only interact with molecules of specific configuration. This has synthetic chemists became convinced to accept that all compounds used as pharma‐ ceuticals must be in one of their enantiomeric forms. As a consequence, in the 1980s decade, the Food and Drug Administration (FDA) required pharmaceutical industry to acquire drug candidates in details of the toxic effects of the enantiomers. By this, chemical substances to be used as drugs candidates must be synthetized as optically pure compounds or to be highly enriched.

Biologically active chiral molecules have been extracted from natural products has plants. Extracts from the *Ephedra* sp. genus have been traditionally used in Chinese medicine as nasal

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descongestives, cardiac stimulant, and antiasthma agents. The active principle from this plant was first extracted in 1885, isolated, and then purified in 1887 by Nagai [1] who called it ephed‐ rine. The herb, "Ma‐Huang" is the best source of ephedrine, up to 1% bulk weight has been obtained from this material. Amounts of *pseudo*ephedrine, N‐methylephedrine, N‐methyl*pseudo*ephedrine, *nor*ephedrine, and *norpseudo*ephedrine were found from this herb [2]. Since phar‐ macologycal studies done by Chen and Schmidt in 1924 [3], the chemists have been interested in the synthesis of physiologically active analogous of ephedrine derivatives [4]. At the present time, large quantities are used in Western medicine to relieve mucous membrane congestion [5].

Today, ephedrine is a pharmaceutical classified as sympathomimetic agent, weaker but lon‐ ger acting than adrenaline. It acts as cardiac stimulant, hypertensive agent, hyperglycaemic, and bronchodilator. Ephedrine has been clinically used against hay feber, bronchial asthma, myasthenia gravis, whooping cough, Heart block (Stokes‐Adam syndrome), and dysmenor‐ rhea. Because ephedrine crosses the hematoencephalic and placentary barriers, have effects on the central nervous system, in consequence, decrease fatigue, sleep (insomnia), and hun‐ gry sensations (anorexia) [4].

The no‐polar structure of ephedrine makes this substance more liposoluble than catecholamines. It is thermodynamically more stable, in consequence, it is not a substrate for monoamineoxi‐ dase (MAO) or the catechol‐O‐methyltranspherase. Thus, it is a diffusible pharmaceutical that has a more prolonged effect as catecholamines [6].

On the other hand, the modern chemistry is interested in the development of new synthetic meth‐ ods to produce drugs, antibiotics, alimentary additives, etc., with high optical purity. Asymmetric synthesis design requires catalysts, chiral auxiliaries, and reagents able to control the stereochem‐ istry of the reaction products and to be efficiently recycled [7]. Ephedrines, *nor*ephedrines and its derivatives, have been broadly used as chiral auxiliaries in asymmetric synthesis [8]. Thiols, sulfides, and disulfides obtained from ephedrines have been proven to be very good chiral cata‐ lysts [9]. It has been found the use of polymer‐supported catalysts applied to organic synthesis with emphasis given to the use of ephedrine chiral catalyst to promote asymmetric reactions [10].

#### **2. Structure of ephedrines**

The structure of ephedrine and *pseudo*ephedrine was studied by Ladenburg and Oelschägel. They suggested the formula PhCH(OH)CH(CH3 )NHCH3 now accepted for the alkaloids [11]. Studies that support this formula were provided by Schmith and Bümming [12]. The more important fact that ephedrine and *pseudo*ephedrine are stereoisomers is easy with which ephedrine can be isomerized to *pseudo*ephedrine by acylation or by boiling with HCl (25%) [13], this change has been found to be reversible [14, 15].

Freudenberg and Leithe investigated the configuration about C1 and C2 for ephedrine and *pseudo*ephedrine [16–18], and represented the distribution about these centers of asymmetry, for ephedrine by structure **1a** and for *pseudo*ephedrine by structure **2a**, **Figure 1**.

**Figure 1.** Freudenberg and Leithe representation of ephedrine **1a** and p*seudo*ephedrine **2a**.

descongestives, cardiac stimulant, and antiasthma agents. The active principle from this plant was first extracted in 1885, isolated, and then purified in 1887 by Nagai [1] who called it ephed‐ rine. The herb, "Ma‐Huang" is the best source of ephedrine, up to 1% bulk weight has been obtained from this material. Amounts of *pseudo*ephedrine, N‐methylephedrine, N‐methyl*pseudo*ephedrine, *nor*ephedrine, and *norpseudo*ephedrine were found from this herb [2]. Since phar‐ macologycal studies done by Chen and Schmidt in 1924 [3], the chemists have been interested in the synthesis of physiologically active analogous of ephedrine derivatives [4]. At the present time, large quantities are used in Western medicine to relieve mucous membrane congestion

Today, ephedrine is a pharmaceutical classified as sympathomimetic agent, weaker but lon‐ ger acting than adrenaline. It acts as cardiac stimulant, hypertensive agent, hyperglycaemic, and bronchodilator. Ephedrine has been clinically used against hay feber, bronchial asthma, myasthenia gravis, whooping cough, Heart block (Stokes‐Adam syndrome), and dysmenor‐ rhea. Because ephedrine crosses the hematoencephalic and placentary barriers, have effects on the central nervous system, in consequence, decrease fatigue, sleep (insomnia), and hun‐

The no‐polar structure of ephedrine makes this substance more liposoluble than catecholamines. It is thermodynamically more stable, in consequence, it is not a substrate for monoamineoxi‐ dase (MAO) or the catechol‐O‐methyltranspherase. Thus, it is a diffusible pharmaceutical that

On the other hand, the modern chemistry is interested in the development of new synthetic meth‐ ods to produce drugs, antibiotics, alimentary additives, etc., with high optical purity. Asymmetric synthesis design requires catalysts, chiral auxiliaries, and reagents able to control the stereochem‐ istry of the reaction products and to be efficiently recycled [7]. Ephedrines, *nor*ephedrines and its derivatives, have been broadly used as chiral auxiliaries in asymmetric synthesis [8]. Thiols, sulfides, and disulfides obtained from ephedrines have been proven to be very good chiral cata‐ lysts [9]. It has been found the use of polymer‐supported catalysts applied to organic synthesis with emphasis given to the use of ephedrine chiral catalyst to promote asymmetric reactions [10].

The structure of ephedrine and *pseudo*ephedrine was studied by Ladenburg and Oelschägel.

Studies that support this formula were provided by Schmith and Bümming [12]. The more important fact that ephedrine and *pseudo*ephedrine are stereoisomers is easy with which ephedrine can be isomerized to *pseudo*ephedrine by acylation or by boiling with HCl (25%)

Freudenberg and Leithe investigated the configuration about C1 and C2 for ephedrine and *pseudo*ephedrine [16–18], and represented the distribution about these centers of asymmetry,

for ephedrine by structure **1a** and for *pseudo*ephedrine by structure **2a**, **Figure 1**.

)NHCH3

now accepted for the alkaloids [11].

[5].

gry sensations (anorexia) [4].

**2. Structure of ephedrines**

They suggested the formula PhCH(OH)CH(CH3

[13], this change has been found to be reversible [14, 15].

has a more prolonged effect as catecholamines [6].

26 Alkaloids – Alternatives in Synthesis, Modification and Application

Zhu et al. analyzed the relationship of the substituents of the stereogenic center and to the specific optical rotation. The variables used as matrix elements include (1) the substituent masses (**m**), (2) radii (**r**), (3) symmetries (**s**), and (4) electronegativities (**χ**) of the atoms or groups bounded to the stereogenic center. For ephedrine and *pseudo*ephedrine, the calculated values were approximate to the observed rotation values [19]. The preferred conformation of ephedrine **1** and *pseudo*ephed‐ rine **2** was theme of controversy [20–25]. The questions could be answered by the X‐ray technique.

Several crystal structures of ephedrine salts were reported: the hydrochloride by Bergin [26] and the hydrogen and the di‐hydrogen phosphates by Bugg [27, 28] showed the conformation **1b**. On the other hand, in an X‐ray study, Mathew et al. demonstrated the conformation **2b** in structures of (+)‐*pseudo*ephedrine and (+)‐*pseudo*ephedrine hydrochloride [29]. There was found one strong intermolecular hydrogen bond OH….N in *pseudo*ephedrine which links the molecules into infinite chains around the screw axis. An intramolecular contact N—H‐‐‐O was observed, but the angle of 108° is not favorable. On the other hand, the C(2)—N bond is nearly parallel to the C(1)—C(*ipso*) bond. This conformation was also found in a bis‐(+)‐*pseudo*ephedrine complex of Koper II [30], (−)‐*nor*adrenaline [31], and dopamine [32]. Similar conformations for *nor*ephed‐ rines were found [33] but the difference in energy levels between the various possible conforma‐ tions in the *nor*‐series is less than in the ephedrine series, and interconversion is carried out with ease. This was explained because of the hindering effect of the N‐methyl group, **Figure 2** [34].

Finally, ephedrines **1,2** and *nor*ephedrines **3,4** have the β‐aminoalcohol structure where the phe‐ nyl and methyl groups create two chiral centers on each carbon atom and generate four opti‐ cally active stereoisomers, **Figures 4** and **5**. Freudenberg et al. [16] and Leithe [17] established

**Figure 2.** Stable conformations of ephedrine **1b** and *pseudo*ephedrine **2b.**

the relative configuration about the asymmetric centers for (−)‐ephedrine and its optical isomers, hence the configurational relationship between ephedrines **1a**,**b** and *pseudo*‐ephedrines **2a**,**b** series is well known. The stereoisomers with methyl on nitrogen atom are *l*‐(1*R*,2*S*)‐ephedrine **1a** and *d*‐(1*S*,2*R*)‐ephedrine **1b**; *d*‐(1*S*,2*S*)‐*pseudo*ephedrine **2a,** and *l*‐(1*R*,2*R*)‐*pseudo*ephedrine **2b**, **Figure 3**.

The *l*‐ephedrine **1a** is the stereoisomer that produces a more pronounced stimulus on the central nervous system, compared with other drugs [35].

The stereoisomers without methyl on nitrogen atom are called *nor*ephedrines: *l*‐(1*R*,2*S*)‐ *nor*ephedrine **3a** and *d*‐(1*S*,2*R*)‐*nor*ephedrine **3b**; *d*‐(1*S*,2*S*) *norpseudo*ephedrine **4a,** and *l*‐(1*R*,2*R*)‐ *norpseudo*ephedrines **4b**, **Figure 4**.

**Figure 3.** Ephedrine stereoisomers.

**Figure 4.** *Nor*ephedrine stereoisomers.

### **3. Physical properties of ephedrines**

the relative configuration about the asymmetric centers for (−)‐ephedrine and its optical isomers, hence the configurational relationship between ephedrines **1a**,**b** and *pseudo*‐ephedrines **2a**,**b** series is well known. The stereoisomers with methyl on nitrogen atom are *l*‐(1*R*,2*S*)‐ephedrine **1a** and *d*‐(1*S*,2*R*)‐ephedrine **1b**; *d*‐(1*S*,2*S*)‐*pseudo*ephedrine **2a,** and *l*‐(1*R*,2*R*)‐*pseudo*ephedrine **2b**, **Figure 3**. The *l*‐ephedrine **1a** is the stereoisomer that produces a more pronounced stimulus on the

The stereoisomers without methyl on nitrogen atom are called *nor*ephedrines: *l*‐(1*R*,2*S*)‐ *nor*ephedrine **3a** and *d*‐(1*S*,2*R*)‐*nor*ephedrine **3b**; *d*‐(1*S*,2*S*) *norpseudo*ephedrine **4a,** and *l*‐(1*R*,2*R*)‐

central nervous system, compared with other drugs [35].

28 Alkaloids – Alternatives in Synthesis, Modification and Application

*norpseudo*ephedrines **4b**, **Figure 4**.

**Figure 3.** Ephedrine stereoisomers.

**Figure 4.** *Nor*ephedrine stereoisomers.

Physical properties of some optical isomers of ephedrines as free bases or as acidic salts have been summarized, **Tables 1**–**4** [36].

#### **Table 1.** (1*R*, *2*S)‐(−)‐ephedrine forms.

**Table 3.** (1*R*, 2*S*)‐(−)‐ *nor*ephedrine forms.

**Table 4.** (1*R*, 2*R*)‐(−)‐ *norpseudo*ephedrine forms.

#### **4. Biological activity of ephedra heterocycles**

A wide approach for the synthesis of new compounds that possess some kind of biologi‐ cal activity is the cyclization of substituted phenethylamines as ephedrines into heterocycles, such as morpholine (phenmetrazine) [37] and 2‐amine‐oxazolines (4‐methylaminorex and 3,4‐dimethylaminorex) [38], in such a way that the ephedrine skeleton becomes part of the heterocyclic ring, **Figure 5**.

Some other heterocycles as oxazolidine [39], di‐ and tetrahidro‐1,3,4‐oxadiazines [40, 41], 2‐thiazoline [42], thiazolidine [43], dihidro‐1,3,4‐thiadiazine [44], tetrahydro‐ triazine [45], and imidazolidine [46] derived from ephedrines and *nor*ephedrines have been reported. Certain of these heterocycles exhibit different biological effects as central nervous system, stimulating, appetite‐depressing [37, 38], monoamine oxidase inhibiting antidepressant [40g, 44b], central nervous system depressant [40e, f, 41, 45], analgetic [45], hypocholesterolemic [41], anti‐inflammatory [41], antimicrobial [41, 44b], or catechol‐ amine‐potentiating [43] activities. On the other hand, 3,4‐dimethyl‐5‐phenyl‐oxazolidine is used as a prodrug [47].

**Figure 5.** Some heterocyclic compounds with biological activity.

#### **5. Reactions to get chlorodeoxyephedrine derivatives**

The bromination reaction of ephedrine hydrochloride **2a** with PBr5 produce the bro‐ modeoxy‐derivative [48]. On the other hand, ephedrine **1a** or *nor*ephedrine **3a** or its hydrochlorides reacts with SOCl2 to give chlorodeoxy*pseudo*ephedrine **5a** or chlorode‐ oxy*norpseudo*ephedrine **5b**. The same reaction with *pseudo*ephedrines **2a** or **4a** give a 60:40 diastereomeric mixture of *threo*:*erytho* **5a**:**6a**, **Scheme 1** [49]. In order to improve the stere‐ oselectivity, chlorination reaction of *pseudo*ephedrine stereoisomers **2** at 0°C was carried out. In these conditions, only the corresponding *threo* chlorodeoxystereoisomers **3** were stereoselectively obtained (SNi mechanism), **Scheme 1**, the X‐ray diffraction structure of **5a** is depicted in **Figure 6**.

**Scheme 1.** Chlorodeoxyephedrine hydrochlorides from chlorination reaction of ephedrines **2**.

**4. Biological activity of ephedra heterocycles**

**Characteristic mp (°C) [α]D**

30 Alkaloids – Alternatives in Synthesis, Modification and Application

Hemihydrate – –

Hydrobromide – –

Oxalate 235 (dec.) – Aurichloride 137–138 – Platinilchloride 198 –

Free base (B) 77–8 (corr.) −37.9 (MeOH)

Hydrochloride 180–183 (corr.) −41.7° (H2

Sulphete 295 (dec.) −48.7° (H2

heterocyclic ring, **Figure 5**.

**Table 4.** (1*R*, 2*R*)‐(−)‐ *norpseudo*ephedrine forms.

is used as a prodrug [47].

**Figure 5.** Some heterocyclic compounds with biological activity.

A wide approach for the synthesis of new compounds that possess some kind of biologi‐ cal activity is the cyclization of substituted phenethylamines as ephedrines into heterocycles, such as morpholine (phenmetrazine) [37] and 2‐amine‐oxazolines (4‐methylaminorex and 3,4‐dimethylaminorex) [38], in such a way that the ephedrine skeleton becomes part of the

O)

O)

Some other heterocycles as oxazolidine [39], di‐ and tetrahidro‐1,3,4‐oxadiazines [40, 41], 2‐thiazoline [42], thiazolidine [43], dihidro‐1,3,4‐thiadiazine [44], tetrahydro‐ triazine [45], and imidazolidine [46] derived from ephedrines and *nor*ephedrines have been reported. Certain of these heterocycles exhibit different biological effects as central nervous system, stimulating, appetite‐depressing [37, 38], monoamine oxidase inhibiting antidepressant [40g, 44b], central nervous system depressant [40e, f, 41, 45], analgetic [45], hypocholesterolemic [41], anti‐inflammatory [41], antimicrobial [41, 44b], or catechol‐ amine‐potentiating [43] activities. On the other hand, 3,4‐dimethyl‐5‐phenyl‐oxazolidine

**Figure 6.** X‐ray diffraction structure of Chlorodeoxyephedrine hydrochloride **5a.**

#### **6. Heterazolidines‐2‐heterounsaturated from ephedrines**

In 1950, Close reported the solvent‐free dehydration of ephedrine hydrochloride **1** in the pres‐ ence of urea at 180–200°C to afford the imidazolidinone **11a**‐(*t*) and oxazolidinone **15a**‐(*c*), **Scheme 2** [34]. In that work, it was proposed that urea is converted into ammonium oxo‐ cyanate at 180–200°C, which in the presence of hydrogen chloride, ammonium chloride and oxocyanic acid are produced. Finally, ephedrine reacts with oxocyanide acid to produce the nonisolated urea intermediate **7a**‐(*e*), which cyclization by dehydration affords the *trans*‐imid‐ azolidone **11a**‐(*t*). On the other hand, in a simultaneous manner, cyclization of urea **7a**‐(*e*) by nucleophylic attack of the oxygen atom of ephedrine to the ureidic carbonyl and ammonia elimination produces the oxazolidone heterocycle **15a**‐(*c*).

The same reaction was revisited with the use of K+ NCO− instead of urea, and the study was extended with thiocyanates and *pseudo*ephedrine **2a**‐(*th*), *nor*ephedrine **3b**‐(*e*), and *norpseudo*ephedrine **4b**‐(*th*), as stereoisomers to produce a series of optically active 1,3‐heteroazoli‐ dine‐2‐heterounsaturated compounds **9**–**15**, **Scheme 3**.

**Scheme 2.** Dehydration of ephedrine 1a‐(*e*) with urea according to Close.

**Scheme 3.** 1,3‐heterazolidines‐2‐heterounsaturated from ephedrines.

#### **6.1. Reaction of ephedrines with oxocyanate**

Urea intermediate **7a**‐(*e*), proposed in the Close's reaction, was isolated when K+ NCO− is reacted with ephedrine hydrochloride **1** in refluxing ethanol for 72 h (78% yield). The reac‐ tion was also performed with *pseudo*ephedrine **2**, *nor*ephedrine **3,** and *norpseudo*ephedrine to afford, the urea derivatives **7a**‐(*th*), **7b**‐(*e*), and **7b**‐(*th*) in 83, 80, and 86% yield, respectively (**Scheme 4**). In the case of the reaction of Na+ NCS− with ephedrine stereoisomers series **1–4**, only chloride by thiocyanate anion was exchanged to give the corresponding hydrothiocya‐ nates **8a,b** (*e,th*) (Scheme 4). The urea intermediate **7a**‐(*e*) derived from ephedrine could be crystallized from ethanol and its structure studied by X‐ray diffraction (**Figure 7**).

**Scheme 4.** Reaction of K+ NCO− and NH4 + NCS− with ephedrines 1a,b‐(*e,th*) in refluxing ethanol.

**Scheme 2** [34]. In that work, it was proposed that urea is converted into ammonium oxo‐ cyanate at 180–200°C, which in the presence of hydrogen chloride, ammonium chloride and oxocyanic acid are produced. Finally, ephedrine reacts with oxocyanide acid to produce the nonisolated urea intermediate **7a**‐(*e*), which cyclization by dehydration affords the *trans*‐imid‐ azolidone **11a**‐(*t*). On the other hand, in a simultaneous manner, cyclization of urea **7a**‐(*e*) by nucleophylic attack of the oxygen atom of ephedrine to the ureidic carbonyl and ammonia

extended with thiocyanates and *pseudo*ephedrine **2a**‐(*th*), *nor*ephedrine **3b**‐(*e*), and *norpseudo*ephedrine **4b**‐(*th*), as stereoisomers to produce a series of optically active 1,3‐heteroazoli‐

NCO−

instead of urea, and the study was

NCO− is

elimination produces the oxazolidone heterocycle **15a**‐(*c*).

The same reaction was revisited with the use of K+

32 Alkaloids – Alternatives in Synthesis, Modification and Application

dine‐2‐heterounsaturated compounds **9**–**15**, **Scheme 3**.

**Scheme 2.** Dehydration of ephedrine 1a‐(*e*) with urea according to Close.

**6.1. Reaction of ephedrines with oxocyanate**

**Scheme 3.** 1,3‐heterazolidines‐2‐heterounsaturated from ephedrines.

Urea intermediate **7a**‐(*e*), proposed in the Close's reaction, was isolated when K+

reacted with ephedrine hydrochloride **1** in refluxing ethanol for 72 h (78% yield). The reac‐ tion was also performed with *pseudo*ephedrine **2**, *nor*ephedrine **3,** and *norpseudo*ephedrine to afford, the urea derivatives **7a**‐(*th*), **7b**‐(*e*), and **7b**‐(*th*) in 83, 80, and 86% yield, respectively An intramolecular hydrogen bonding interaction between the hydrogen atom of the hydroxyl group and the ureidic oxygen atom to form a seven membered ring was observed. The O1H1···O6 distance of 1.820(24) Å [angle of 166.72° (2.25)] represents a strong interaction [50]. The formed hydrogen bond forces the NH2 group to adopt a syn conformation to the N‐Me group [C8N4C5N7 angle of −6.00 (0.26)°]. In addition, both N—CO bond distances are of inter‐ mediate value between a single (1.469 Å) and a double (1.279) N—C bond (1.35 Å mean) [51].

When the intermediate **7a**‐(*e*) was free of solvent heated at 180–200°C for 1 hour, an equi‐ molar mixture of imidazolidone **11a**‐(*c*) and oxazolidone **15a**‐(*c*) was formed (**Scheme 5**). Imidazolidinone **11a**‐(*c*) was separated by precipitation from a CHCl3 and purified by recrys‐ tallization from ethanol. The structure of *cis* (*c*) isomer instead of the expected *trans* (*t*) iso‐ mer [52] was observed on the 1 H and 13C NMR spectra and confirmed by X‐ray diffraction analysis. The formation of an aziridinim isocyanate **I** then the isocyanate **II** as intermediates

**Figure 7.** Molecular structure of ephedrine‐urea **7a**‐(*e*).

**Scheme 5.** Mechanistic pat way for the cyclization of ephedrine‐urea **7a**‐(*e*) to get imidazolidinone **11a**‐(t).

are proposed to explain the retention of C1 configuration in the formation of the *cis*‐imidazoli‐ done **11a**‐(*c*) (**Scheme 5**) [53]. On the other hand, the oxazolidone **15a**‐(*c*) is formed in accord to the Close's idea (**Scheme 2**). The *in situ* formation of amides from aminoalcohols involved in oxazolidine formation has been reported in the literature [34, 54].

On the basis of these previous findings, the free of solvent reaction of ephedrines **1,4** with sodium or ammonium thiocyanates were performed.

#### **6.2. Reaction of ephedrines with thiocyanate**

In the direct heating of one equimolar of Na+ NCS− with ephedrine 1 at 180–200°C during 0.5 h, ephedrine hydrothiocyanate 8a‐(*e*) from the aqueous phase and *trans*‐thiazolidine‐2‐imino hydrothiocyanate 9a‐(*t*) from the chloroform phase (10% yield) were separated, after CHCl3 /H2 O partition, **Scheme 6**. Deamination of ephedrine hydrothiocyanate 8a‐(*e*) proceeded to give Ethylphenylketone as lateral product.

The reaction with two molar equivalents of NH4 SCN for 4 hours afforded the thiazoli‐ dine‐2‐imino hydrothiocyanate **9a**‐(*t*) in 50% yield as precipitate from CHCl3 . The use of NH4 SCN instead of NaSCN salt, avoided deamination, due to its lower melting point (153°C). Compound **9a**‐(*t*) was identified on comparing the structure obtained from chlorodeoxy*pseudo*ephedrine [55]. On the other hand, several heterocycles were separated when the remaining chloroform mixture was eluted in a chromatographic column. The mass spectrometry of the separated fractions showed the presence of heterocycles summarized in **Table 5**.

As described above for ephedrine **1**, two molar equivalents of NH4 + NCS− were heated with *pseudo*ephedrine **2**, *nor*ephedrine **3**, and *norpseudo*ephedrine **4**. The identified compounds are listed in **Table 5**.

The reaction mixture of *pseudo*ephedrine hydrochloride **2** was treated with a 50:50 of CHCl3 / H2 O mixture. The chloroform phase was eluted in a column chromatography. Using chloro‐ form as eluent, the imidazolidine‐2‐thione **10a**‐(*c*) was separated in 40% yield as first fraction.

**Scheme 6.** Heating reaction of ephedrine **1** with NaSCN.

are proposed to explain the retention of C1 configuration in the formation of the *cis*‐imidazoli‐ done **11a**‐(*c*) (**Scheme 5**) [53]. On the other hand, the oxazolidone **15a**‐(*c*) is formed in accord to the Close's idea (**Scheme 2**). The *in situ* formation of amides from aminoalcohols involved

**Scheme 5.** Mechanistic pat way for the cyclization of ephedrine‐urea **7a**‐(*e*) to get imidazolidinone **11a**‐(t).

On the basis of these previous findings, the free of solvent reaction of ephedrines **1,4** with

NCS−

ephedrine hydrothiocyanate 8a‐(*e*) from the aqueous phase and *trans*‐thiazolidine‐2‐imino hydrothiocyanate 9a‐(*t*) from the chloroform phase (10% yield) were separated, after CHCl3

partition, **Scheme 6**. Deamination of ephedrine hydrothiocyanate 8a‐(*e*) proceeded to give

SCN instead of NaSCN salt, avoided deamination, due to its lower melting point (153°C). Compound **9a**‐(*t*) was identified on comparing the structure obtained from chlorodeoxy*pseudo*ephedrine [55]. On the other hand, several heterocycles were separated when the remaining chloroform mixture was eluted in a chromatographic column. The mass spectrometry of the

*pseudo*ephedrine **2**, *nor*ephedrine **3**, and *norpseudo*ephedrine **4**. The identified compounds are

The reaction mixture of *pseudo*ephedrine hydrochloride **2** was treated with a 50:50 of CHCl3

O mixture. The chloroform phase was eluted in a column chromatography. Using chloro‐ form as eluent, the imidazolidine‐2‐thione **10a**‐(*c*) was separated in 40% yield as first fraction.

dine‐2‐imino hydrothiocyanate **9a**‐(*t*) in 50% yield as precipitate from CHCl3

separated fractions showed the presence of heterocycles summarized in **Table 5**.

As described above for ephedrine **1**, two molar equivalents of NH4

with ephedrine 1 at 180–200°C during 0.5 h,

SCN for 4 hours afforded the thiazoli‐

+ NCS− /H2 O

. The use of

were heated with

/

in oxazolidine formation has been reported in the literature [34, 54].

sodium or ammonium thiocyanates were performed.

The reaction with two molar equivalents of NH4

**6.2. Reaction of ephedrines with thiocyanate**

34 Alkaloids – Alternatives in Synthesis, Modification and Application

In the direct heating of one equimolar of Na+

**Scheme 6.** Heating reaction of ephedrine **1** with NaSCN.

Ethylphenylketone as lateral product.

NH4

H2

listed in **Table 5**.

**Table 5.** Carbonyl carbon chemical shift in ppm, proportion (%) and mass spectrometry data [M+ (%)] of heterocycles **9–15**.

Imidazolidones **11a**‐(*c*) and **11a**‐(*t*), thiazolidinedione **12a**‐(*c*), and thiazolidinones **13a**‐(*c*) and **13a**‐(*t*) were separated in small quantities in the subsequent three remaining fractions, respec‐ tively. On the other hand, after evaporation of the aqueous phase, thiazolidine‐2‐imino hydro‐ thiocyanate **9a**‐(*c*) and oxazolidinones **15a**‐(*c*) and **15a**‐(*t*) as solid mixtures were identified by mass spectrometry. NMR spectral data of compound **10a**‐(*c*) show a broad signal at 6.32 ppm (1 H) and at 183 ppm (13C) of the N—H and C—S groups, respectively. The molecular ion [z/e = 206 (100%), M+ ] and X‐ray diffraction analysis confirmed the structure, **Figure 8**. The bond distances C2—N1 [1.345(14) Å] and C2—N3 [1.332(13) Å] show an intermediate value between a single and a double bond [51], due to a conjugation through the N1—C2—N3 fragment.

From the reaction mixture of *nor*ephedrine hydrochloride **3**, compounds **13b**‐(*c*) and **13b**‐(*t*) in a 1:8 proportion were separated by chromatography. Compound **13b**‐(*t*) (40% yield) was separated from **13b**‐(*c*) in a second column using CHCl3 . The spectra data, molecular ion [z/e = 193 (25%), M+ ], and the X‐ray diffraction structures of compound **13b**‐(*t*) confirm the *trans* configuration (**Figure 9**). A conjugation through the N—C2—S fragment is observed because the bond distances C2‐N [1.332(3) Å] and C2‐S [1.775(2) Å] are shorter than the cor‐ responding single bonds.

The reaction mixture of *norpseudoe*phedrine hydrochloride **4** was separated in a chromato‐ graphic column and each fraction analyzed by mass spectrometry, **Table 5**. The fourth frac‐ tion contained thiazoline‐2‐amine hydrothiocyanate **9b**‐(*c*).

**Figure 8.** Structure of imidazolidinethione **10a**‐(*c*).

**Figure 9.** Structure of*trans*‐thiazolidinone **13b**‐(*t*).

At least four competitive mechanisms are proposed to explain the formation of heterocy‐ cles **9‐15a**,**b** in the heating reaction of NH4 SCN with ephedrines **1**,**2** and *nore*phedrines **3**,**4** (**Scheme 7**). In general, with exception of heating reaction of *nor*ephedrine **3**, a SN2 dehydra‐ tion mechanism by the thiocyanate = isothiocyanate anions as nucleophiles and the subsequent cyclization of the ephedrinethiocyanate (**IV**) and/or ephedrineisothiocyanate (**III**) intermedi‐ ates formed operate to give the corresponding thiazolidine‐2‐imino hydrothiocyanates **9a,b** and/ or imidazolidinetiones **10a,b**. The product from thiocyanate predominate in the heating reaction of ephedrine **1**, and for *pseudo*ephedrine **2**, the product from isothiocyanate predomi‐ nate. A stable alkyl ephedrinethiocynate analogue to **IV** has been isolated, which support the proposed mechanism [56].

In the heating reaction of *nor*ephedrine **3**, the H2 S obtained by hydrolysis of thiocyanate acts as nucleophyle in competitive SN1 and SN2 mechanisms to form the thiolephedrine thiourea

**Scheme 7.** Proposed mechanisms to explain the formation of heterocycles **9**–**15**.

At least four competitive mechanisms are proposed to explain the formation of heterocy‐

(**Scheme 7**). In general, with exception of heating reaction of *nor*ephedrine **3**, a SN2 dehydra‐ tion mechanism by the thiocyanate = isothiocyanate anions as nucleophiles and the subsequent cyclization of the ephedrinethiocyanate (**IV**) and/or ephedrineisothiocyanate (**III**) intermedi‐ ates formed operate to give the corresponding thiazolidine‐2‐imino hydrothiocyanates **9a,b** and/ or imidazolidinetiones **10a,b**. The product from thiocyanate predominate in the heating reaction of ephedrine **1**, and for *pseudo*ephedrine **2**, the product from isothiocyanate predomi‐ nate. A stable alkyl ephedrinethiocynate analogue to **IV** has been isolated, which support the

as nucleophyle in competitive SN1 and SN2 mechanisms to form the thiolephedrine thiourea

SCN with ephedrines **1**,**2** and *nore*phedrines **3**,**4**

S obtained by hydrolysis of thiocyanate acts

cles **9‐15a**,**b** in the heating reaction of NH4

**Figure 9.** Structure of*trans*‐thiazolidinone **13b**‐(*t*).

**Figure 8.** Structure of imidazolidinethione **10a**‐(*c*).

36 Alkaloids – Alternatives in Synthesis, Modification and Application

In the heating reaction of *nor*ephedrine **3**, the H2

proposed mechanism [56].

**VI**‐(*e*,*th*), which cyclization afford thiazolidinethiones **12b**(*c*,*t*). A desulphurization by hydro‐ lysis of thiazolidinethiones **12b**‐(*c*,*t*) explains the formation of thiazolidinones **13b**‐(*c*,*t*). A mechanism through thioureidic intermediate **V** operates simultaneously, its cyclization affords oxazolidinethione **14b**‐(*c*), which desulphurization gives oxazolidinone **15b**‐(*c*).

Desulphurization of the oxazolidinethione **14a**‐(*t*) explains the formation of oxazolidinone **15a**‐(*t*) (20%) in the heating reaction of *pseudo*ephedrine **2**, **Scheme 6**, this mechanism is favored when one molar equivalent of NH4 + NCS− is used. In this case, oxazolidinone **15a**‐(*t*) (40%) and imidazolidinethione **10a**‐(*c*) (20%) were obtained as the major products. Similar results were observed in the heating reaction of *norpseudo*ephedrine **4**. If NH4 + NCS− is changed from two to one molar equivalents, thiazoline‐2‐amine hydrothiocyanates **9b**‐(*c*) decreased from 40 to 15% and oxazolidinone **15b**‐(*t*) increased from 3 to 45%.

In general, in the 1 H NMR spectral data of ephedracycles, the C—CH3 group of the *cis* isomers appears at low frequency shifts in the range between 0.9 and 0.7 ppm, compared with the same group of the *trans* isomers, appearing between 1.1 and 1.4 ppm, this is due to the shield‐ ing effect of the phenyl group.

#### **7. Heterazolidines‐2‐heteroinsaturated from chloro***pseudo* **ephedrines**

In continuation with our investigations on the design of new heterocycles derived from ephedrines **1**, in this work, we revisited the cyclization reactions of chlorodeoxy*pseudo*ephedrine hydrochloride **5a**‐(*th*) (R = Me) with one or two molar equivalents of potassium oxocyanate, sodium thiocyanate, and potassium selenocyanate nucleophiles as cyclizing agents in refluxing ethanol. In addition, the results of the reaction of chlorodeoxy*nor*p‐ seudoephedrine hydrochloride **5b**‐(*th*) (R = H) with the above mentioned nucleophiles are reported. An interesting finding of this study was the synthesis of the *trans* isomer of 1,3‐oxazolidine‐2‐iminium chloride **18a‐**(*t*) through the *in situ* chlorinated urea intermedi‐ ate **7a**‐(*e*), **Scheme 8**.

**Scheme 8.** Reactivity of chlorodeoxy*pseudo*ephedrine hydrochlorides **5** with heterocyanates.

#### **7.1. Reaction of chlorodeoxy***pseudo***ephedrine hydrochlorides 5 with potassium oxocyanate**

Chlorodeoxy*pseudo*ephedrine hydrochloride **5a**‐(*th*) was reacted with two molar equiva‐ lents of KOCN in stirring ethanol at room temperature. The reaction was monitored at 24, 48, and 72 h by 1 H NMR. Two compounds, in 80:20, 60:40, and 40:60 proportions, respec‐ tively, were observed. The NMR tube of the 40:60 proportion in DMSO‐d6 was heated at 92°C during 1 h, to quantitatively transform the minor proportion compound into the 1,3‐oxazolidine‐2‐iminium oxocyanate **18a**‐(*c*) identified as the only product. The *N*‐(1‐ chloro‐1‐phenyl‐2‐methyl‐ethyl)‐*N*‐methyl urea **17a**‐(*th*) in the 80:20 mixture with **18a‐**(*c*) was identified as the intermediate. The use of one molar equivalent of potassium oxocya‐ nate in the same reaction in refluxing 16 h afforded the hydrochloride of the oxazolidine‐2‐ imine **18a‐**(*c*), which was crystallized from ethanol to be analyzed by X‐ray diffraction, the structure is shown in the **Figure 10**.

The reaction is general; the reaction of one molar equivalent of KOCN with chlorodeoxy*norpseudo*ephedrine hydrochloride **5b**‐(*th*) (R = H) in refluxing ethanol 8 h afforded the chlorourea derivative **17b**‐(*th*). The proposed mechanistic pathway represented in **Scheme 9** explains why the reaction is carried out with inversion of the Cl configuration to get the *cis* isomer.

Synthesis, Structure and Biological Activity of Ephedra Heterocycles http://dx.doi.org/10.5772/67387 39

**Figure 10.** Molecular structure of hydrochloride compound **18a‐**(*c*).

**7. Heterazolidines‐2‐heteroinsaturated from chloro***pseudo* **ephedrines**

ate **7a**‐(*e*), **Scheme 8**.

38 Alkaloids – Alternatives in Synthesis, Modification and Application

48, and 72 h by 1

structure is shown in the **Figure 10**.

In continuation with our investigations on the design of new heterocycles derived from ephedrines **1**, in this work, we revisited the cyclization reactions of chlorodeoxy*pseudo*ephedrine hydrochloride **5a**‐(*th*) (R = Me) with one or two molar equivalents of potassium oxocyanate, sodium thiocyanate, and potassium selenocyanate nucleophiles as cyclizing agents in refluxing ethanol. In addition, the results of the reaction of chlorodeoxy*nor*p‐ seudoephedrine hydrochloride **5b**‐(*th*) (R = H) with the above mentioned nucleophiles are reported. An interesting finding of this study was the synthesis of the *trans* isomer of 1,3‐oxazolidine‐2‐iminium chloride **18a‐**(*t*) through the *in situ* chlorinated urea intermedi‐

**7.1. Reaction of chlorodeoxy***pseudo***ephedrine hydrochlorides 5 with potassium oxocyanate**

Chlorodeoxy*pseudo*ephedrine hydrochloride **5a**‐(*th*) was reacted with two molar equiva‐ lents of KOCN in stirring ethanol at room temperature. The reaction was monitored at 24,

92°C during 1 h, to quantitatively transform the minor proportion compound into the 1,3‐oxazolidine‐2‐iminium oxocyanate **18a**‐(*c*) identified as the only product. The *N*‐(1‐ chloro‐1‐phenyl‐2‐methyl‐ethyl)‐*N*‐methyl urea **17a**‐(*th*) in the 80:20 mixture with **18a‐**(*c*) was identified as the intermediate. The use of one molar equivalent of potassium oxocya‐ nate in the same reaction in refluxing 16 h afforded the hydrochloride of the oxazolidine‐2‐ imine **18a‐**(*c*), which was crystallized from ethanol to be analyzed by X‐ray diffraction, the

The reaction is general; the reaction of one molar equivalent of KOCN with chlorodeoxy*norpseudo*ephedrine hydrochloride **5b**‐(*th*) (R = H) in refluxing ethanol 8 h afforded the chlorourea derivative **17b**‐(*th*). The proposed mechanistic pathway represented in **Scheme 9** explains why the reaction is carried out with inversion of the Cl configuration to get the *cis* isomer.

tively, were observed. The NMR tube of the 40:60 proportion in DMSO‐d6

**Scheme 8.** Reactivity of chlorodeoxy*pseudo*ephedrine hydrochlorides **5** with heterocyanates.

H NMR. Two compounds, in 80:20, 60:40, and 40:60 proportions, respec‐

was heated at

**Scheme 9.** Mechanistic pathway involved in the synthesis of compounds **18a**‐(*c*) and **18b**‐(*c*).

Chlorourea compound **17b**‐(*th*) could be isolated and characterized by NMR. Two signals are observed in the 1 H NMR spectrum 6.04, (d, 3 *J* = 8.5 Hz) and 5.55 ppm (s, broad) in a 1:2 propor‐ tion, respectively, assigned to NH and NH2 urea hydrogen atoms, respectively. The NH coupling constant value proposes a hydrogen bonding NH‐‐‐Cl interaction, which makes this hydrogen and H2 to be in an *anti*position. In addition, the small H1 , H2 coupling constant (3 J = 5.28 Hz) supports this proposed interaction, **Figure 11**. The 13C NMR spectrum shows the carbonyl car‐ bon signal at 159.6 ppm, according to the proposed structure.

The chlorourea derivative **17b**‐(*th*) was refluxed in ethanol during 24 h. The 1 H NMR spectrum of the solid precipitated showed a 80:20 mixture of two heterocycles. The 1 H NMR chemical shift of the+NH3 group appears in 9.65 ppm as a broad signal, H5 and H4 appear at 6.49 (d) and 4.56 ppm (dq), for the major compound. For the minor compound, H5 and H4 appear at 5.26 (d) and 5.41ppm (dq), respectively. In both compounds, the

**Figure 11.** Hydrogen bonding interaction proposed in compound **17b**‐(*th*).

coupling constants are of the same value. In addition, the multiplicity of these signals are interchanged for the minor compound, which are correlated with 13C NMR signals at 65.9 (C4) and 84.6 (C5) ppm, respectively. These results allowed us to assign the *cis*‐4‐ methyl‐5‐phenyloxazoline‐2‐ammonium chloride **18b‐**(*c*) as the major compound the *cis*‐5‐methyl‐4‐phenyl‐oxazoline‐2‐ammonium hydrochloride **23b**‐(*c*), as the minor com‐ pound, whose formation is explained due to the participation of an aziridine intermedi‐ ate III, **Scheme 10** [52].

It is known that in chlorination reaction of ephedrine derivatives with thionyl chloride, the C1 configuration is retained through a SNi mechanism, when ephedrine bears a bulky group as oxamide or sulfonamide on the nitrogen atom [57]. In this sense, we obtained the *erythro* isomer of ephedrineurea intermediate **7a**‐(*e*) by the reaction of ephedrine hydro‐ chloride **1a**‐(*e*) with KOCN [58]. This ephedrineurea was chlorinated with thionyl chlo‐ ride in CHCl3 to get, *in situ*, 1‐(2‐chloro‐1‐methyl‐2‐phenyl‐ethyl)‐1‐methyl‐urea **17a**‐(*e*). Compound **17a**‐(*e*) was refluxed in ethanol during 8 h. 1 H and 13C NMR spectroscopic data of the solid obtained after solvent removal allowed us to identify the *trans* isomer of 3,4‐dimethyl‐5‐phenyl‐oxazolidine‐2‐iminium chloride **18a**‐(*t*). This result showed that chlorodeoxyephedrine urea **17a**‐(*e*) was obtained with retention of C1 configuration, which was cyclized with the inversion of C1 configuration to obtain **18a**‐(*t*). In a similar

**Scheme 10.** Mechanistic pathway proposed to explain the formation of compound **23b**‐(*c*).

manner, the same reaction with *nor*ephedrine hydrochloride **1b**‐(*e*) is stereoselective to get the *cis* isomer of the oxazoline‐2‐ammonium chloride **18b‐**(*c*). In contrast, the same procedure for *pseudo*ephedrine **1a**‐(*th*) and *norpseudo*ephedrine **1b**‐(*th*) hydrochlorides gave a mixture of oxazolidine‐2‐iminium chlorides **18a** (60:40, *c:t*) and oxazoline‐2‐ammo‐ nium chlorides **18b** (75:25, *c*:*t*), respectively [59].

#### **7.2. Reaction of chlorodeoxy***pseudo***ephedrine hydrochlorides 2 with sodium thiocyanate**

It is known that the condensation reaction of chlorodeoxy*pseudo*ephedrine hydrochloride **5a**‐(*th*) with two molar equivalents of NaSCN in refluxing ethanol for 8 h stereoselectively affords the *trans*‐thiazolidine‐2‐iminio thiocyanate **9a‐**(*t*) [51].

The reaction of chlorodeoxy*norpseudo*ephedrine hydrochloride **5b**‐(*th*) (R = H) with two molar equivalents of KSCN in refluxing ethanol, only chloride is interchanged by thiocyanate anion to give chlorodeoxy*norpseudo*ephedrine hydrothiocyanate **16b**‐(*th*) (*ν* = 2057 cm−1, − SCN), even at 24 h of reflux. If hydrothiocyanate **16b**‐(*th*) in DMSO‐d6 is heated (90°C) 1 h in a NMR tube, a 50:50 *cis/trans* mixture of 1,3‐thiazoline‐2‐ammonium thiocyanate **9b** was detected in the 1 H NMR spectrum. However, only the *cis* isomer of **9b**‐(*c*) was stereoselectively produced if the reaction is solvent free heated at 170°C during 3 hours, **Scheme 8**.

#### **7.3. Reaction of chlorodeoxy***pseudo***ephedrine hydrochlorides 2 with potassium selenocyanate**

As previous result reported for chlorodeoxy*pseudo*ephedrine hydrochloride **5a**‐(*th*) [51], the reaction of chlorodeoxy*norpseudo*ephedrine hydrochloride **5b**‐(*th*) with two equivalents of KSeCN in refluxing ethanol for 10 hours affords *trans*‐selenazoline‐2‐ammonium selenocya‐ nate **19b‐**(*t*). On the other hand, if only one equivalent of KOCN, NaSCN, or KSeCN is used in the reactions, the corresponding hydrochloride salts of the 2‐aminoheterocyles are obtained. Both XCN− (X = O, S, Se) and Cl− salts were liberated with aqueous NaOH to give the cor‐ responding imine **20–22a** or amine **20–22b** compounds. Compound **20b**‐(*c*) and **22b**‐(*t*) were crystallized from ethanol and chloroform, respectively. The structures could be established for X‐ray diffraction analysis, **Figures 12** and **13**, respectively.

**Figure 12.** X‐ray diffraction structure of **20b**‐(*c*).

coupling constants are of the same value. In addition, the multiplicity of these signals are interchanged for the minor compound, which are correlated with 13C NMR signals at 65.9 (C4) and 84.6 (C5) ppm, respectively. These results allowed us to assign the *cis*‐4‐ methyl‐5‐phenyloxazoline‐2‐ammonium chloride **18b‐**(*c*) as the major compound the *cis*‐5‐methyl‐4‐phenyl‐oxazoline‐2‐ammonium hydrochloride **23b**‐(*c*), as the minor com‐ pound, whose formation is explained due to the participation of an aziridine intermedi‐

It is known that in chlorination reaction of ephedrine derivatives with thionyl chloride, the C1 configuration is retained through a SNi mechanism, when ephedrine bears a bulky group as oxamide or sulfonamide on the nitrogen atom [57]. In this sense, we obtained the *erythro* isomer of ephedrineurea intermediate **7a**‐(*e*) by the reaction of ephedrine hydro‐ chloride **1a**‐(*e*) with KOCN [58]. This ephedrineurea was chlorinated with thionyl chlo‐

data of the solid obtained after solvent removal allowed us to identify the *trans* isomer of 3,4‐dimethyl‐5‐phenyl‐oxazolidine‐2‐iminium chloride **18a**‐(*t*). This result showed that chlorodeoxyephedrine urea **17a**‐(*e*) was obtained with retention of C1 configuration, which was cyclized with the inversion of C1 configuration to obtain **18a**‐(*t*). In a similar

Compound **17a**‐(*e*) was refluxed in ethanol during 8 h. 1

**Scheme 10.** Mechanistic pathway proposed to explain the formation of compound **23b**‐(*c*).

**Figure 11.** Hydrogen bonding interaction proposed in compound **17b**‐(*th*).

40 Alkaloids – Alternatives in Synthesis, Modification and Application

to get, *in situ*, 1‐(2‐chloro‐1‐methyl‐2‐phenyl‐ethyl)‐1‐methyl‐urea **17a**‐(*e*).

H and 13C NMR spectroscopic

ate III, **Scheme 10** [52].

ride in CHCl3

**Figure 13.** X‐ray diffraction structure of **22b‐**(*t*).

#### **8.** *CIS***‐thiazolidinethiones from chloro***pseudo***ephedrines**

In 1995, we reported the reaction of chlorodeoxy*pseudo*ephedrine.hydrochloride **5a**‐(*th*) with 33% aqueous solution of sodium trithiocarbonate (Na2 CS3 ) in refluxing ethanol to give *cis*‐ thiazolidinethione **12a**‐(*c*) (53% yield), **Scheme 11** [60]. However, the same reaction with chlo‐ rodeoxy*norpseudo*ephedrine **5b**‐(*th*) failed to give the corresponding *cis*‐thiazolidinethione derivative **12b**‐(*c*).

By this, we encourage us the goal to selectively obtain *cis*‐ or *trans*‐thiazolidinethiones **12a,b** from either chlorodeoxy*norpseudo*ephedrine **5b** or chlorodeoxy*pseudo*ephedrine **5a** derived from ephedrines **1**,**3**.

To get thiazolidinethiones **12a**,**b**, the chlorhydrates of chlorodeoxy*pseudo*ephedrines **5a** or **5b** were reacted with one molar equivalent of sodium dithiocarbonate in ethanol solution at room temperature. In the case of chlorodeoxy*norpseudo*ephedrine·HCl **5b**, a white powder solid was precipitated in stirring ethanol for 6 h. The *cis* and *trans* relationships between the phenyl and the methyl groups in thiazolidinethiones **12b** was deduced from the analysis of their 1 H and 13C NMR spectral data and are in agreement with data reported [49d]. On this bases, the product represented a mixture of *cis*:*trans*‐thiazolidinethiones of **8** in a 9:1 proportion. A SN2 mechanism to explain the C1 inversion of configuration, then cyclization to get the *cis*‐isomer is proposed to be carried out, **Scheme 11**. In addition, a competitive double SN2 mechanism on C1, then cyclization in which *cis*‐aziridine **24b**‐(*c*) as intermediate is involved to explain the presence of the *trans*‐isomer **12b‐**(*t*). Analogous mechanistic observations were proposed

**Scheme 11.** Mechanistic transformation to get *cis*‐thiazolidinethiones from chlorodeoxy*pseudo*ephedrines.

to get stereospecifically thiazolidinethiones from the reaction of viciodoalkanecarbamates with potassium ethylxanthate [61]. When the same reaction at 0°C for 6 h was performed, only *cis*‐thiazolidinethione **12b‐**(*c*) was precipitated as a white powder in 95% yield. Thiazolidine‐ thione **12b‐**(*c*) is stable as thione tautomer in concentrated solution (*δ* NH at 8.3 ppm). However, in a diluted solution, the thiol tautomer is present (*δ* SH at 1.6 ppm).

The reaction of chlorodeoxy*pseudo*ephedrine·HCl **5a** at 0°C was performed, and after 3 days off, white orthorhombic crystals of *cis*‐thiazolidinethione **12a**‐(*c*) precipitated in 81% yield. The X‐ray diffraction structure showed the *cis*‐isomer.

To confirm that the *cis*‐aziridine is responsible of the *trans*‐thiazolidinethione formation, the Kelloggs method was used with the previously obtained *cis*‐aziridine **24a**‐(*c*) and **24b**‐(*c*) [62] from chlorodeoxy*pseudo*ephedrines **5a** or **5b**. The corresponding *cis*‐aziridine was reacted with CS2 in stirring ethanol by 48 h at 0°C. In the case of the reaction of *cis*‐aziridine **24b**‐(*c*), two compounds in a 70:30 mixture were observed in the 1 H NMR spectra. The CH3 groups of the two compounds were in 1.35 and 1.44 ppm, respectively. After comparison with reported data, both compounds were identified as *trans* isomers of thiazolidinethiones [63]. The major heterocycle was the *trans*‐thiazolidine‐thione **12b**‐(*t*) and the minor heterocycle, the *trans*‐iso‐ thiazolidinethione **25b**‐(*t*). The ring opening on C3 and C2 of the aziridinium by the aziridi‐ nethiocarbamate anion of the intermediate **III** explains the formation of both heterocycles, **Scheme 12**. This aziridinium opening reaction has been observed elsewere [59, 62].

**8.** *CIS***‐thiazolidinethiones from chloro***pseudo***ephedrines**

33% aqueous solution of sodium trithiocarbonate (Na2

**Figure 13.** X‐ray diffraction structure of **22b‐**(*t*).

42 Alkaloids – Alternatives in Synthesis, Modification and Application

derivative **12b**‐(*c*).

from ephedrines **1**,**3**.

In 1995, we reported the reaction of chlorodeoxy*pseudo*ephedrine.hydrochloride **5a**‐(*th*) with

thiazolidinethione **12a**‐(*c*) (53% yield), **Scheme 11** [60]. However, the same reaction with chlo‐ rodeoxy*norpseudo*ephedrine **5b**‐(*th*) failed to give the corresponding *cis*‐thiazolidinethione

By this, we encourage us the goal to selectively obtain *cis*‐ or *trans*‐thiazolidinethiones **12a,b** from either chlorodeoxy*norpseudo*ephedrine **5b** or chlorodeoxy*pseudo*ephedrine **5a** derived

To get thiazolidinethiones **12a**,**b**, the chlorhydrates of chlorodeoxy*pseudo*ephedrines **5a** or **5b** were reacted with one molar equivalent of sodium dithiocarbonate in ethanol solution at room temperature. In the case of chlorodeoxy*norpseudo*ephedrine·HCl **5b**, a white powder solid was precipitated in stirring ethanol for 6 h. The *cis* and *trans* relationships between the phenyl and the methyl groups in thiazolidinethiones **12b** was deduced from the analysis of their 1

and 13C NMR spectral data and are in agreement with data reported [49d]. On this bases, the product represented a mixture of *cis*:*trans*‐thiazolidinethiones of **8** in a 9:1 proportion. A SN2 mechanism to explain the C1 inversion of configuration, then cyclization to get the *cis*‐isomer is proposed to be carried out, **Scheme 11**. In addition, a competitive double SN2 mechanism on C1, then cyclization in which *cis*‐aziridine **24b**‐(*c*) as intermediate is involved to explain the presence of the *trans*‐isomer **12b‐**(*t*). Analogous mechanistic observations were proposed

**Scheme 11.** Mechanistic transformation to get *cis*‐thiazolidinethiones from chlorodeoxy*pseudo*ephedrines.

CS3

) in refluxing ethanol to give *cis*‐

H

When *cis*‐aziridine **24a**‐(*c*) was reacted with CS2 , in the same reaction conditions, c*is*‐thia‐ zolidinethione **12a**‐(*c*) was stereoselectively obtained instead of the expected *trans*‐isomer in agreement with the Kellog's method, **Scheme 13**. In this case, the retention of the C1 configu‐ ration is explained by attack of the aziridinium thiocarbamate zwitterion **VI** on the benzylic carbon, followed by the closure of the intermediate **VII** to recover the initial C1 configuration.

Crystals of *Cis*‐thiazolidinethione **12a**‐(*c*) were separated from ethanol and its structure studied by X‐ray diffraction analysis, **Figure 14**. The N3—C2(S2)—S1 conjugated system is proposed since the distances are of an intermediate value between a single (1.469 Å) and a double (1.279 Å) N—C bond (N3—C2 = 1.35 Å) and a single (1.789 Å) and a double (1.600 Å) C—S bond (S1—C2 = 1.741Å and S2—C2 = 1.659) [51]. Conjugation makes N3 to be in a sp2 hybridation, as the angles C(4)—N(3)—C(12) = 119.9(3), C(2)—N(3)—C(4) = 116.2(3), and C(2)—N(3)—C(12) = 121.6(3) show values close to 120°. On the other hand, the five membered ring is almost planar since

**Scheme 12.** Mechanistic transformation of *cis*‐aziridine **4***c* into a mixture of *trans*‐thiazolidinethione **8***t* and *trans*‐ isothiazolidinethione **10***t*.

**Scheme 13.** Mechanistic transformation of *cis*‐aziridine **24a**‐(*c*) into *cis*‐thiazolidinethione **12a**‐(*c*).

**Figure 14.** X‐ray diffraction structure of *cis*‐tiazolidinethione **12a**‐(*c*).

the torsion angles N(3)—C(2)—S(1)—C(5) of 5.3(3)°, S(2)—C(2)—N(3)—C(12) of −1.8(5)° are very close to 0°, and S(2)—C(2)—S(1)—C(5) of −177.4(2)°, S(1)—C(2)—N(3)—C(12) of 175.1(3) are close to 180°. An intramolecular contact between a hydrogen atom of the N—CH3 group and the sulfur atom of the thiocarbonyl group occurred to form a five member ring. The C12H12…S2 distance of 2.72(4) Å [angle of 111(3)°] is in the range for a strong interaction [50].

#### **9. Thiazaborolidines from thioephedrines**

The synthesis of N‐alkyloxazaborolidines **26**–**28** derived from ephedrines has been reported (**Figure 15**) [64]. In 1995, we reported the analogous compounds made from thioephedrines, and herein, we report several borohydrides derived from thioephedrine (compounds **12a, 29–37**) following the syntheses depicted in **Scheme 14**.

Hydrolysis of thiosulfate **29** obtained with retention of C1configuration from the substitution reaction of chloride **5** give the disulfide **30**, **Scheme 14**. The disulfide **30** reacts with BH3 ‐THF

**Figure 15.** Borolidines from ephedrines.

**Scheme 14.** Thiazaborolidines from ephedrines.

the torsion angles N(3)—C(2)—S(1)—C(5) of 5.3(3)°, S(2)—C(2)—N(3)—C(12) of −1.8(5)° are very close to 0°, and S(2)—C(2)—S(1)—C(5) of −177.4(2)°, S(1)—C(2)—N(3)—C(12) of 175.1(3)

the sulfur atom of the thiocarbonyl group occurred to form a five member ring. The C12H12…S2

The synthesis of N‐alkyloxazaborolidines **26**–**28** derived from ephedrines has been reported (**Figure 15**) [64]. In 1995, we reported the analogous compounds made from thioephedrines, and herein, we report several borohydrides derived from thioephedrine (compounds **12a,**

Hydrolysis of thiosulfate **29** obtained with retention of C1configuration from the substitution reaction of chloride **5** give the disulfide **30**, **Scheme 14**. The disulfide **30** reacts with BH3

group and

‐THF

are close to 180°. An intramolecular contact between a hydrogen atom of the N—CH3

distance of 2.72(4) Å [angle of 111(3)°] is in the range for a strong interaction [50].

**Scheme 13.** Mechanistic transformation of *cis*‐aziridine **24a**‐(*c*) into *cis*‐thiazolidinethione **12a**‐(*c*).

44 Alkaloids – Alternatives in Synthesis, Modification and Application

**9. Thiazaborolidines from thioephedrines**

**Figure 14.** X‐ray diffraction structure of *cis*‐tiazolidinethione **12a**‐(*c*).

**29–37**) following the syntheses depicted in **Scheme 14**.

to give a mixture of the stable N‐epimers disulfide amine boranes **31** and **32** detected by 11B NMR. This N‐epimers are comparable with the N‐BH3 adducts of *pseudo*‐ephedrines.

Heating the N‐epimers mixture of **31** + **32**, affords the borinic ester **33** as the only product, which in the 11B NMR spectra appears as a triplet [(*δ* = −6.4 ppm, J(BH) = 103 Hz, in CDCI3 or *δ* = −4.5 ppm, in *THF*‐*d*8 ]. Two methyl groups in *trans* position was found for borinic ester **33** on the 1 H and 13C NMR data. This allows us to assign the configuration at the nitrogen atom. No borinic esters with a BH2 group derived from ethanolamines as stable compounds have been observed. Borinic ester **33** was distilled *in vacuo*, and on the 11B NMR spectra of the dis‐ tillated, a mixture of thiazaborolidine **33**, 10%, and thiazaboroline **34** were observed. Slowly elimination of H2 transforms borinic ester **33** into thiazaboroline **34**. In the 11B NMR spectrum, compound **34** shows a doublet (*δ* = +40.8 ppm, J(BH) = 154 Hz). From the distilled, a crystal of compound **33** was separated and its X‐ray diffraction structure obtained (**Figure 16**). The thia‐ zaboroline **34** reacted with BH3 ‐THF to afford the N—BH3 adduct **35** (**Scheme 1**). The struc‐ ture has been deduced from the 11B NMR data, which indicated a N—BH3 bond (quadruplet at *δ* = −22.0 ppm, J(BH)= 71 Hz) and a doublet which is strongly shifted to lower frequencies (*δ* = −7.0, J(BH)= 148 Hz). A diborane group in which a hydrogen atom from the N—BH3 adduct is bridging the boron atom of the heterocycle was found. These findings are similar to that found in the *pseudo*ephedrine oxazaborolidine [64a].

**Figure 16.** X‐ray diffraction structure of borolidine **33**.

Thiazolidine‐2‐thione **12a**‐(*c*) obtained from compound **5a** with sodium trithiocarbonate has been isolated and its reactivity towards BH3 ‐THF studied, **Scheme 14**. The reaction was fol‐ lowed by 11B NMR, and a S—BH3 adduct **36** (*δ* = −23 ppm, broad signal) was first detected. The analysis of 1 H NMR spectrum of compound **36** indicates that BH3 is linked to the thione sulfur atom. Heating the S—BH3 adduct **36** afforded the thiazaborolidine **37** which is a triplet at *δ* = −3.8 ppm (J(BH) = I I 1.5 Hz) in 11B NMR spectra. This compound **37** is obtained pure when **12a**‐(*c*) is reacted with 3 equivalents of BH3 ‐THF. The 1 H and 13C NMR were recorded. The diasterotopic N‐methyl groups show that the nitrogen has a stable configuration, the assign‐ ment of the 1 H and 13C signals was done by comparison with similar compounds [64b, 65].

Compound **33** has the C‐5 atom out of the plane of an envelope conformation of the five member ring. The N—B bond distance is 1.58(1) Å and B—S of 1.922(9) Å. Boron and nitrogen atoms are tetrahedral. The nitrogen atom was found to be of "*S*" configuration, as deduced from the 1 H and 13C NMR data. The methyl groups are *trans* position. The angles on the nitrogen atom are close to a sp3 hybridation, C4—N3—C13 112.3(5)°, B2—N3—C13 111.3(5)°, and C4—N3—B2 112.0(5)°.

#### **10. Biological properties of ephedrines and their derivatives**

#### **10.1. Ephedrines**

Mao (Ephedra sinica Stapf), which provides similar effects to ephedrine [66, 67], is used as a component of several herbal medicines. It has been utilized in the treatment of cold and allergy [68, 69]. Clinically, it is utilized to lower fever, relieve pain and headaches, control body weight, relieve inflammatory responses [70, 71], and also rheumatoid arthritis [72].

Ephedrine **1a** and *pseudo*ephedrine **2a** are also used to treat cancerous diseases in modern clinical practice, they combined with other preparations relieve arterial spasms, neurotoxic reactions after radiation therapy and chemotherapy [73, 74].

Since 1938, ephedrine was regulated as a drug; however, the herbal source was regulated as a food. However, after the Dietary Supplement Health and Education Act of 1994 (DSHEA) [75] was passed, the herbal products escaped drug regulation. As a consequence, ephedra extracts remains available as a "dietary supplement." However, after years of battling, stimulant com‐ bination products (e.g., ephedra and caffeine) are yet available.

#### **10.2. Chloroephedrine derivatives**

Previously was demonstrated that N‐β‐chloroalkylamine derivatives **5a,b** (**Figure 17**) possess a different spectrum of anticancer activities [76]. On the other hand, cytotoxic and antitumor activ‐ ities of ephedrine and N‐β‐chloroalkylamine derivatives **5a**(**1**–**3**), **5b**(**1**–**3**) were determined [77].

It was found compounds **5b1**, **5b2**, and **5b3** were active in the cytotoxicity test for 3 H‐thymi‐ dine incorporation. The concentrations causing 50% cytotoxicity were in the range 11.0–45.0 mg/mL. However, derivatives **5a1**, **5a2**, and **5a3** were more active.

Compounds **5a2**, **5b2**, **5a3**, and **5b3** investigated *in vitro* suppressed growth of EAC and S‐180 tumor strains to various degrees.

It has been shown that the introduction of phosphorus‐and sulfur‐containing fragments con‐ siderably lowers the toxicity of the alkaloids.

With respect to substances **5a1** and **5b1**, they had similar toxicity to *l*‐ephedrine, while the other substances were less toxic. It has been found that the replacement of the oxygen atom in the structure of a thio salt of/l‐ephedrine **5a3** by a second sulfur atom led to a slight rise in toxicity.

#### **10.3. Dithiocarbamate derivatives**

Thiazolidine‐2‐thione **12a**‐(*c*) obtained from compound **5a** with sodium trithiocarbonate has

*δ* = −3.8 ppm (J(BH) = I I 1.5 Hz) in 11B NMR spectra. This compound **37** is obtained pure when

diasterotopic N‐methyl groups show that the nitrogen has a stable configuration, the assign‐

Compound **33** has the C‐5 atom out of the plane of an envelope conformation of the five member ring. The N—B bond distance is 1.58(1) Å and B—S of 1.922(9) Å. Boron and nitrogen atoms are tetrahedral. The nitrogen atom was found to be of "*S*" configuration, as deduced from the 1

13C NMR data. The methyl groups are *trans* position. The angles on the nitrogen atom are close to

Mao (Ephedra sinica Stapf), which provides similar effects to ephedrine [66, 67], is used as a component of several herbal medicines. It has been utilized in the treatment of cold and allergy [68, 69]. Clinically, it is utilized to lower fever, relieve pain and headaches, control body weight, relieve inflammatory responses [70, 71], and also rheumatoid arthritis [72].

Ephedrine **1a** and *pseudo*ephedrine **2a** are also used to treat cancerous diseases in modern clinical practice, they combined with other preparations relieve arterial spasms, neurotoxic

hybridation, C4—N3—C13 112.3(5)°, B2—N3—C13 111.3(5)°, and C4—N3—B2 112.0(5)°.

‐THF. The 1

H and 13C signals was done by comparison with similar compounds [64b, 65].

H NMR spectrum of compound **36** indicates that BH3

**10. Biological properties of ephedrines and their derivatives**

reactions after radiation therapy and chemotherapy [73, 74].

‐THF studied, **Scheme 14**. The reaction was fol‐

is linked to the thione sulfur

H and

H and 13C NMR were recorded. The

adduct **36** (*δ* = −23 ppm, broad signal) was first detected. The

adduct **36** afforded the thiazaborolidine **37** which is a triplet at

been isolated and its reactivity towards BH3

**Figure 16.** X‐ray diffraction structure of borolidine **33**.

46 Alkaloids – Alternatives in Synthesis, Modification and Application

**12a**‐(*c*) is reacted with 3 equivalents of BH3

lowed by 11B NMR, and a S—BH3

atom. Heating the S—BH3

analysis of 1

ment of the 1

**10.1. Ephedrines**

a sp3

*N*‐methyl‐*l*‐ephedrinedithiocarbamates derived from *l*‐ephedrine **1a** and *d*‐*pseudo*ephedrine **2a** has been obtained. Dithiocarbamic acid derivatives exhibit a broad‐spectrum physiologi‐ cal activity [78]. They were found to act as fungicides, herbicides, insecticides, acaricides, zoocides, nematocides, growth regulators, bactericides, etc. Such dithiocarbamic acid deriva‐ tives as Carbathion, Cineb, Vegadex, and Cyram have found practical application in agricul‐ ture as pesticides.

#### **10.4. Oxazolidines derivatives**

Due to the reversibility of the reaction of ephedrines **1**–**4** with aldehydes or ketones to get oxa‐ zolidine heterocycles (**Scheme 15**), these compounds could be used as prodrugs [79]. Some

**Figure 17.** Structures of N‐β‐chloroalkylamine derivatives **5a**,**b**.

**Scheme 15.** Oxazolidines from ephedrine.

of these compounds significantly increased locomotor activity in rats at 50‐mg/kg dose. The formaldehyde derivative had similar activity as ephedrine. All other compounds were less active.

Four such compounds were tested in rats for ephedrine‐like activity using the hyperthermia and anorexia models. The results showed that all of the compounds decreased food intake significantly, but only the acetone and the salicylaldehyde derivatives caused a significant elevation of body temperature [80].

On this bases, we probed the antioxidant and antimicrobial activity of some heterocyclic com‐ pounds derived from ephedrines **1**–**4** previously synthetized.

#### **11. Determination of biological activity of ephedracycles**

Ephedrine is a very good pharmaceutical but it acts as central nervous system stimulant, and ephedrine and their derivatives have been used as drugs of abuse so its prescription has been restricted, we proposed ephedra heterocycles as new derived compounds as pharmaceutical candidates with low central nervous system. We decided to prove the antioxidant and anti‐ biotic activities of several heterocycles synthetized in our laboratory represented in **Tables 6** and **7**, respectively.

**Table 6.** Antioxidant activity (IC50 mol/L) of some synthetized heterocyclic compounds.

**Table 7.** Antibiotic activity of some synthetized heterocyclic compounds derived from ephedrine **1–8**.

#### **11.1. Antioxidant activity**

of these compounds significantly increased locomotor activity in rats at 50‐mg/kg dose. The formaldehyde derivative had similar activity as ephedrine. All other compounds were less

Four such compounds were tested in rats for ephedrine‐like activity using the hyperthermia and anorexia models. The results showed that all of the compounds decreased food intake significantly, but only the acetone and the salicylaldehyde derivatives caused a significant

On this bases, we probed the antioxidant and antimicrobial activity of some heterocyclic com‐

Ephedrine is a very good pharmaceutical but it acts as central nervous system stimulant, and ephedrine and their derivatives have been used as drugs of abuse so its prescription has been restricted, we proposed ephedra heterocycles as new derived compounds as pharmaceutical candidates with low central nervous system. We decided to prove the antioxidant and anti‐ biotic activities of several heterocycles synthetized in our laboratory represented in **Tables 6**

active.

elevation of body temperature [80].

**Scheme 15.** Oxazolidines from ephedrine.

48 Alkaloids – Alternatives in Synthesis, Modification and Application

and **7**, respectively.

pounds derived from ephedrines **1**–**4** previously synthetized.

**11. Determination of biological activity of ephedracycles**

**Table 6.** Antioxidant activity (IC50 mol/L) of some synthetized heterocyclic compounds.

The DPPH radical scavenging activity of plants was estimated according to the method explained by Cheung, with some modifications. Aliquots of 2 ml of 6 × 10−5 M DPPH methanol were mixed with 50 μL of the extracts. The mixtures were vigorously shaken and left to stand for 10 min under subdued light. The absorbance at 540 nm was measured against methanol as a blank. The decolorization was spectrophotometrically measured at 517 nm. The radical scavenging activity (RSA) was calculated using the equation:

$$\% \text{RSA} = 100 \times \left(1 - A\_{\text{E}} / \text{AD} \right)^{\text{E}}$$

*A*E is the absorbance of the solution containing antioxidant extract, whereas AD is the absor‐ bance of the DPPH\* solution.

Compounds **34**, **19t**, and **12t** showed antioxidant activity, **Table 6**.

#### **11.2. Antimicrobial activity**

Disk diffusion assay: extracts were tested for antibiotic activity against *Escherichia coli*, *Salmonella thypi*, *Staphylococcus aureus*, *Bacillus subtilis*, and *Candida albicans*. About 50 μL of extract was solubilized in ETOH and placed on the surface of the inoculated agar and incubated at 30°C, using antibiotic no. 1 medium, and the antibiotic activity was recorded as the diameter of clear zones of inhibited microbial growth around the paper disk.

The antimicrobial activity was determined using strains *S. aureus*, *B. subtilis*, *S. thypi*, and *E. coli* using sensidiscs. The antioxidant activity was measured by the radical 2‐2‐diphenyl‐1‐ picrihydrazil. Compound **34** presented antimicrobial activity against all microorganisms used and the compound **21a** showed activity only against *S. aureus* and *B. subtilis*, **Table 7**.

#### **Author details**

Alejandro Cruz1 \*, Itzia I. Padilla‐Martínez1 and María Esther Bautista‐Ramírez2

\*Address all correspondence to<EMAIL_ADDRESS>
1 Department of Basic Sciences, UPIBI, National Polytechnic Institute, Mexico City, Mexico

2 Department of Pharmaceutical Technology, UPIBI, National Polytechnic Institute, Mexico City, Mexico

#### **References**

[9] (a) Jahyo Kang\* , Dong Soo Kim, Joo In Kim "Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by A Drug‐Unrelated Chiral Amino Thiol and the Corresponding Disulfide" Synlett 1994(10): 842‐844. DOI: 10.1055/s‐1994‐23025. (b) Kang, J., Kim, D. S., Kim, J. H. Enantioselective addition of diethylzinc to aldehydes catalyzed by drugun‐ related chiral amino thiol and the correponding disulfide. Synlett 1994, 842‐844. doi: 10.1055/s‐1994‐23025. (c) Fitzpatrick, K., Hulst, R., Kellogg, R. M. Thiol and disulfide derivatives of ephedra alkaloids 2: a mechanistic study of their effect on the addition of diethylzinc to benzaldehyde. Tetrahedron: Asymm. 1995, 6, 1861‐1864.

**Author details**

Alejandro Cruz1

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\*, Itzia I. Padilla‐Martínez1

\*Address all correspondence to<EMAIL_ADDRESS>
50 Alkaloids – Alternatives in Synthesis, Modification and Application

and María Esther Bautista‐Ramírez2

1 Department of Basic Sciences, UPIBI, National Polytechnic Institute, Mexico City, Mexico

2 Department of Pharmaceutical Technology, UPIBI, National Polytechnic Institute, Mexico

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