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All 6 posts Subject: Novel route to cathinone analogs Please login to post Down

Rhodium
(Chief Bee)
06-02-04 15:37
No 510961
User Picture       Novel route to cathinone analogs
(Rated as: good read)

Convenient Syntheses of Aroylamino Acids and α-Amino Ketones¹
M. Suzuki, T. Iwasaki, K. Matsumoto, and K. Okumura
Synthetic Communications, 2(4), 237-242 (1972) (https://www.rhodium.ws/pdf/cathinones.isocyanoester.pdf)

C-Acylamino acid, especially aroylamino acid is a key and still currently interest compound for the pharmaceutical intermediate in which (β-arylserine prepared by the reduction in an example would be physiologically important. On the other hand, phenyl derivatives of α-amino ketone are also more useful compounds for the synthesis of those of amino alcohol which are important compounds including physiologically interest substances such as ephedrine and adrenalin used as sympathomimetic agents.

Several syntheses methods of the aroylamino acid² and α-amino ketone³ have been reported. However those methods require various limited conditions and are not advantageous for the practical preparation.

Within the framework of our studies on the synthesis of amino acid, isocyano compound which is readily synthesized from N-formyl amino acid ester⁴ was known to be particularly interest and valuable. In this paper we report that a new convenient synthesis which we believe is more generally suited for the preparation of aroylamino acids and α-amino ketones as shown in scheme.

The reaction of α-isocyano acetate (I, R'=H) with various acyl halides (II) in the presence of base afforded oxazole compounds (III) in good yield (step 1). In most recent, the reaction by the use of BuLi or t-BuOK as a base was independently described by Schöllkopf et al.⁵. However, in the course of studies on the synthesis of amino acids from the isocyanide, we found the same reaction took place too in the presence of not only metallic base such as NaH, but also organic base such as triethylamine or 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU).

A typical example is as follows; A mixture of methyl α-isocyano acetate (2.0 g), benzoylchloride (2.8 g) and triethylamine (8.4 ml) in THF (30 ml) was stirred for 48 hr at room temperature. After the reaction was over, the mixture was evaporated to remove the solvent. To the obtained residue was added ethyl acetate, and the solution was washed with water, dried and then evaporated in vacuo. The obtained precipitate was washed with n-hexane and collected by filtration. Recrystallization from methanol gave 4-carbomethoxy-5-phenyloxazole (III, R=H) in 91% yield. In a similar way, several oxazole derivatives were prepared and those results were shown in Table I.

The oxazole compounds (III) were readily converted into aroylamino acid derivatives (V, R'=H) under heating at 50-60°C in 3N HCl-MeOH for 3 hr in high yield. (Table I)

In the reaction of α-alkyl isocyano compounds (I, R'=CH3, CH(CH3)2) with various acyl halides (step 3), the oxazole compounds described above were not formed, but aroyl compounds (IV) were obtained.

For example; To a suspension of 69% NaH (1.5 g) in THF (80 ml) was added a mixture of methyl α-isocyano propionate (4.5 g) and THF (20 ml) at room temperature under stirring. After stirring for 2 hr at the same temperature, 3,4-methylenedioxybenzoyl chloride (7.24 g) dissolved in THF (20 ml) was added gradually to the mixture for a period of 1 hr at room temperature. After stirring was continued overnight, the solvent was removed under reduced pressure. To the residue was added ethyl acetate, and the solution was washed with water, dried and then evaporated in vacuo. The resulted compound (IV) without purification was subsequently hydrolyzed with 1N HCl-MeOH for 1 hr at 50°C to obtain α-(3,4-methylenedioxy)benzoyl alanine methyl ester hydrochloride (V, R=3,4-methylenedioxy, R'=CH3).

In a similar way, several aroylamino acid derivatives were prepared and these results were shown in Table II.

Furthermore, when the aroylamino acid and oxazol compound obtained in this experiment were treated with 6N HCl-MeOH under refluxing for 5-6 hr, the corresponding α-amino ketone hydrochlorides (VI) were obtained in nearly quantitative yield accompanying with decarboxylation (step 4/5 Table III).

An example of the decarboxylation reaction is as follows; α-Benzoyl glycine methyl ester hydrochloride (V, R, R'=H, 4.58 g) was dissolved in a mixture of conc. HCl (50 ml) and MeOH (50 ml) and refluxed for 5 hr. After the solvent was removed under reduced pressure, to the residue was added ethyl acetate to precipitate. The precipitate was collected by filtration and washed with ethyl acetate. Recrystallization from ethyl acetate-methanol gave phenacylamine hydrochloride (VI, R, R'=H) in 90% yield (step 4). In the same way, the phenacylamine hydrochloride was obtained also from oxazole compound (III, R=H) in 92% yield. (step 5)

References

1. Synthesis of amino acid and the related compound, part 2. Part 1 will appear in Chem. Ind. 1972. The present study was presented at the 92nd Annual Meeting of the Pharmaceutical Society of Japan, Osaka, April, 1972.
2. W. A. Bolhofer, J. Am. Chem. Soc., 74, 5459 (1952); J. Sallay, F. Dutka, and G. Fodor, Helv. Chin. Acta., 37, 778 (1954); S. H. Pines, S. Karady, and M. Sletzinger, J. Org. Chem., 33, 1758 (1968).
3. For example; Org. Synth. Vol 41, John Wiley 4 Sons, Inc., New York (1961), p. 82.
4. I. Ugi, U. Fetzer, U. Eholzer, H. Knupfer and K. Offermann, Angew. Chem., 77, 492 (1965).
5. U. Schöllkopf and R. Schröder, Angew. Chem., 83, 358 (1971).

Another procedure for the preparation of methyl isocyanoacetate is given in Bioorganic & Medicinal Chemistry Letters 8(13), 1665-1668 (1998):

To a solution of [glycine methyl ester] in ethyl formate was added dropwise triethylamine (1.1 eq) while refluxing in a round bottomed flask. The reaction mixture was refluxed overnight while protected with a drying tube, cooled to room temp, filtered, to remove triethylamine hydrochloride removed by washing with ether, the ether evaporated and then purified by chromatography [to yield N-formyl-glycine methyl ester].

POCl3 was added dropwise to a CH2Cl2 solution at 0°C of the previously formed [N-formyl-glycine methyl ester] and triethylamine. The solution was allowed to stir at 0°C for 30 minutes after which the reaction was quenched with cold Na2CO3 (2.0 eq.), the aqueous layer was extracted with CH2Cl2, dried over anhydrous MgSO4 and then chromatographed to give [methyl isocyanoacetate].

^{The Hive - Clandestine Chemists Without Borders}

Lego
(Hive Bee)
07-09-04 20:14
No 518433
User Picture       MAO inhibition by cathinones and derivatives
(Rated as: excellent)

MAO inhibition by arylisopropylamines: the effect of oxygen substituents at the beta-position
Mauricio Osorio-Olivares, Marcos Caroli Rezende, Silvia Sepulveda-Boza, Bruce K. Casselsc and Angelica Fierro
Bioorg. Med. Chem., 2004, 12(15), 4055-4066
DOI:10.1016/j.bmc.2004.05.033

Abstract: Twenty-nine arylisopropylamines, substituted at the beta-position of their side chain by an oxo, hydroxy, or methoxy group, were evaluated in vitro as MAO-A and MAO-B inhibitors. The oxo derivatives (‘cathinones’) were in general less active as MAO-A inhibitors than the corresponding arylisopropylamines, but exhibited an interesting MAO-B inhibiting activity, which was absent in the hydroxy, methoxy, and b-unsubstituted analogues. These results suggest that selective affinity for the two MAO isoforms in this family of compounds is modulated not only by the aryl substitution pattern but also by the side-chain substituents on the arylalkylamine scaffold.

The tendency is to push it as far as you can

phenethyl_man
07-18-04 08:22
      prepn. via phenyl-2-halopropanes?
(Rated as: UTFSE!)

Rhodium
(Chief Bee)
09-13-04 12:51
No 531142
User Picture       Chiral Nor(pseudo)ephedrine & Cathinone Synth
(Rated as: excellent)

A New Approach to the Synthesis of Optically Active Norephedrine, Norpseudoephedrine and Cathinone via Double Asymmetric Induction
Dong Jun Kim and Byung Tae Cho
Bull. Korean Chem. Soc. 24(11), 1641 (2003) (https://www.rhodium.ws/pdf/chiral.norephedrine.cathinone.pdf)

Abstract
New and facile synthetic routes for preparation of optically active norephedrine, norpseudoephedrine and cathinone with high optical purities via double asymmetric induction by employing asymmetric reduction of 2-N-protected amino (or azido)-1-phenylpropanone and 2-methanesulfonyloxy-1-phenylpropanone with CBS-catalyzed-borane and ^dIpc₂BCl as chiral reducing agents are described.
____ ___ __ _

Enantioselective Synthesis of Both Enantiomers of Cathinone via the Microbiological Reduction of 2-Azido-1-phenyl-1-propanone
Pascale Besse, Henri Veschambre, Michael Dickman, Robert Chenevert
J. Org. Chem. 59, 8288-8291 (1994) (https://www.rhodium.ws/pdf/chiral.cathinone.2-azido-p1p.pdf)

^{The Hive - Clandestine Chemists Without Borders}

psychokitty
09-14-04 07:04
      Here's a two more articles of interest:
(Rated as: redundant)

Lego
(Hive Bee)
09-14-04 08:58
No 531257
User Picture       Articles already posted

Two step method for preparation of homochiral cathinones:
Post 475692 (Rhodium: "A two-step method for chiral cathinones", Novel Discourse)

Serotonin Receptor Affinities of Psychoactive Phenalkylamines:
Post 453729 (Rhodium: "Phenylalkylamine Serotonin Receptor Affinities", Serious Chemistry)

The tendency is to push it as far as you can

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	All 6 posts		Subject: Novel route to cathinone analogs		Please login to post		Down


		Rhodium (Chief Bee) 06-02-04 15:37 No 510961				Novel route to cathinone analogs (Rated as: good read)
						Convenient Syntheses of Aroylamino Acids and α-Amino Ketones¹ M. Suzuki, T. Iwasaki, K. Matsumoto, and K. Okumura Synthetic Communications, 2(4), 237-242 (1972) (https://www.rhodium.ws/pdf/cathinones.isocyanoester.pdf) C-Acylamino acid, especially aroylamino acid is a key and still currently interest compound for the pharmaceutical intermediate in which (β-arylserine prepared by the reduction in an example would be physiologically important. On the other hand, phenyl derivatives of α-amino ketone are also more useful compounds for the synthesis of those of amino alcohol which are important compounds including physiologically interest substances such as ephedrine and adrenalin used as sympathomimetic agents. Several syntheses methods of the aroylamino acid² and α-amino ketone³ have been reported. However those methods require various limited conditions and are not advantageous for the practical preparation. Within the framework of our studies on the synthesis of amino acid, isocyano compound which is readily synthesized from N-formyl amino acid ester⁴ was known to be particularly interest and valuable. In this paper we report that a new convenient synthesis which we believe is more generally suited for the preparation of aroylamino acids and α-amino ketones as shown in scheme. The reaction of α-isocyano acetate (I, R'=H) with various acyl halides (II) in the presence of base afforded oxazole compounds (III) in good yield (step 1). In most recent, the reaction by the use of BuLi or t-BuOK as a base was independently described by Schöllkopf et al.⁵. However, in the course of studies on the synthesis of amino acids from the isocyanide, we found the same reaction took place too in the presence of not only metallic base such as NaH, but also organic base such as triethylamine or 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU). A typical example is as follows; A mixture of methyl α-isocyano acetate (2.0 g), benzoylchloride (2.8 g) and triethylamine (8.4 ml) in THF (30 ml) was stirred for 48 hr at room temperature. After the reaction was over, the mixture was evaporated to remove the solvent. To the obtained residue was added ethyl acetate, and the solution was washed with water, dried and then evaporated in vacuo. The obtained precipitate was washed with n-hexane and collected by filtration. Recrystallization from methanol gave 4-carbomethoxy-5-phenyloxazole (III, R=H) in 91% yield. In a similar way, several oxazole derivatives were prepared and those results were shown in Table I. The oxazole compounds (III) were readily converted into aroylamino acid derivatives (V, R'=H) under heating at 50-60°C in 3N HCl-MeOH for 3 hr in high yield. (Table I) In the reaction of α-alkyl isocyano compounds (I, R'=CH3, CH(CH3)2) with various acyl halides (step 3), the oxazole compounds described above were not formed, but aroyl compounds (IV) were obtained. For example; To a suspension of 69% NaH (1.5 g) in THF (80 ml) was added a mixture of methyl α-isocyano propionate (4.5 g) and THF (20 ml) at room temperature under stirring. After stirring for 2 hr at the same temperature, 3,4-methylenedioxybenzoyl chloride (7.24 g) dissolved in THF (20 ml) was added gradually to the mixture for a period of 1 hr at room temperature. After stirring was continued overnight, the solvent was removed under reduced pressure. To the residue was added ethyl acetate, and the solution was washed with water, dried and then evaporated in vacuo. The resulted compound (IV) without purification was subsequently hydrolyzed with 1N HCl-MeOH for 1 hr at 50°C to obtain α-(3,4-methylenedioxy)benzoyl alanine methyl ester hydrochloride (V, R=3,4-methylenedioxy, R'=CH3). In a similar way, several aroylamino acid derivatives were prepared and these results were shown in Table II. Furthermore, when the aroylamino acid and oxazol compound obtained in this experiment were treated with 6N HCl-MeOH under refluxing for 5-6 hr, the corresponding α-amino ketone hydrochlorides (VI) were obtained in nearly quantitative yield accompanying with decarboxylation (step 4/5 Table III). An example of the decarboxylation reaction is as follows; α-Benzoyl glycine methyl ester hydrochloride (V, R, R'=H, 4.58 g) was dissolved in a mixture of conc. HCl (50 ml) and MeOH (50 ml) and refluxed for 5 hr. After the solvent was removed under reduced pressure, to the residue was added ethyl acetate to precipitate. The precipitate was collected by filtration and washed with ethyl acetate. Recrystallization from ethyl acetate-methanol gave phenacylamine hydrochloride (VI, R, R'=H) in 90% yield (step 4). In the same way, the phenacylamine hydrochloride was obtained also from oxazole compound (III, R=H) in 92% yield. (step 5) References 1. Synthesis of amino acid and the related compound, part 2. Part 1 will appear in Chem. Ind. 1972. The present study was presented at the 92nd Annual Meeting of the Pharmaceutical Society of Japan, Osaka, April, 1972. 2. W. A. Bolhofer, J. Am. Chem. Soc., 74, 5459 (1952); J. Sallay, F. Dutka, and G. Fodor, Helv. Chin. Acta., 37, 778 (1954); S. H. Pines, S. Karady, and M. Sletzinger, J. Org. Chem., 33, 1758 (1968). 3. For example; Org. Synth. Vol 41, John Wiley 4 Sons, Inc., New York (1961), p. 82. 4. I. Ugi, U. Fetzer, U. Eholzer, H. Knupfer and K. Offermann, Angew. Chem., 77, 492 (1965). 5. U. Schöllkopf and R. Schröder, Angew. Chem., 83, 358 (1971). Another procedure for the preparation of methyl isocyanoacetate is given in Bioorganic & Medicinal Chemistry Letters 8(13), 1665-1668 (1998): To a solution of [glycine methyl ester] in ethyl formate was added dropwise triethylamine (1.1 eq) while refluxing in a round bottomed flask. The reaction mixture was refluxed overnight while protected with a drying tube, cooled to room temp, filtered, to remove triethylamine hydrochloride removed by washing with ether, the ether evaporated and then purified by chromatography [to yield N-formyl-glycine methyl ester]. POCl3 was added dropwise to a CH2Cl2 solution at 0°C of the previously formed [N-formyl-glycine methyl ester] and triethylamine. The solution was allowed to stir at 0°C for 30 minutes after which the reaction was quenched with cold Na2CO3 (2.0 eq.), the aqueous layer was extracted with CH2Cl2, dried over anhydrous MgSO4 and then chromatographed to give [methyl isocyanoacetate]. ^{The Hive - Clandestine Chemists Without Borders}



		Lego (Hive Bee) 07-09-04 20:14 No 518433				MAO inhibition by cathinones and derivatives (Rated as: excellent)
						MAO inhibition by arylisopropylamines: the effect of oxygen substituents at the beta-position Mauricio Osorio-Olivares, Marcos Caroli Rezende, Silvia Sepulveda-Boza, Bruce K. Casselsc and Angelica Fierro Bioorg. Med. Chem., 2004, 12(15), 4055-4066 DOI:10.1016/j.bmc.2004.05.033 Abstract: Twenty-nine arylisopropylamines, substituted at the beta-position of their side chain by an oxo, hydroxy, or methoxy group, were evaluated in vitro as MAO-A and MAO-B inhibitors. The oxo derivatives (‘cathinones’) were in general less active as MAO-A inhibitors than the corresponding arylisopropylamines, but exhibited an interesting MAO-B inhibiting activity, which was absent in the hydroxy, methoxy, and b-unsubstituted analogues. These results suggest that selective affinity for the two MAO isoforms in this family of compounds is modulated not only by the aryl substitution pattern but also by the side-chain substituents on the arylalkylamine scaffold. The tendency is to push it as far as you can



		phenethyl_man 07-18-04 08:22				prepn. via phenyl-2-halopropanes? (Rated as: UTFSE!)



		Rhodium (Chief Bee) 09-13-04 12:51 No 531142				Chiral Nor(pseudo)ephedrine & Cathinone Synth (Rated as: excellent)
						A New Approach to the Synthesis of Optically Active Norephedrine, Norpseudoephedrine and Cathinone via Double Asymmetric Induction Dong Jun Kim and Byung Tae Cho Bull. Korean Chem. Soc. 24(11), 1641 (2003) (https://www.rhodium.ws/pdf/chiral.norephedrine.cathinone.pdf) Abstract New and facile synthetic routes for preparation of optically active norephedrine, norpseudoephedrine and cathinone with high optical purities via double asymmetric induction by employing asymmetric reduction of 2-N-protected amino (or azido)-1-phenylpropanone and 2-methanesulfonyloxy-1-phenylpropanone with CBS-catalyzed-borane and ^dIpc₂BCl as chiral reducing agents are described. ____ ___ __ _ Enantioselective Synthesis of Both Enantiomers of Cathinone via the Microbiological Reduction of 2-Azido-1-phenyl-1-propanone Pascale Besse, Henri Veschambre, Michael Dickman, Robert Chenevert J. Org. Chem. 59, 8288-8291 (1994) (https://www.rhodium.ws/pdf/chiral.cathinone.2-azido-p1p.pdf) ^{The Hive - Clandestine Chemists Without Borders}



		psychokitty 09-14-04 07:04				Here's a two more articles of interest: (Rated as: redundant)



		Lego (Hive Bee) 09-14-04 08:58 No 531257				Articles already posted
						Two step method for preparation of homochiral cathinones: Post 475692 (Rhodium: "A two-step method for chiral cathinones", Novel Discourse) Serotonin Receptor Affinities of Psychoactive Phenalkylamines: Post 453729 (Rhodium: "Phenylalkylamine Serotonin Receptor Affinities", Serious Chemistry) The tendency is to push it as far as you can

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