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All 3 posts Subject: Grignard synthesis of amphetamines Please login to post Down

Rhodium
(Chief Bee)
12-09-03 18:06
No 475661
User Picture       Grignard synthesis of amphetamines

New resolution approach for large-scale preparation of enantiopure didesmethylsibutramine (DDMS)
Zhengxu Han, Dhileepkumar Krishnamurthy, Q. Kevin Fang, Stephen A. Wald and Chris H. Senanayake
Tetrahedron: Asymmetry 14, 3553–56 (2003)

After a series of experiments an optimum procedure was established, which uses the addition of iBuMgCl to 2 at >105°C for 2 h, followed by quenching with methanol. The imine intermediate 3 was reduced using one equivalent of NaBH4 at 0–25°C for 1 h. An efficient quenching process was identified by adding the reaction mixture to a 2 M HCl aqueous solution at 0°C, which generated a homogeneous reaction mixture that can be easily stirred. After work-up, this optimized process afforded a crude racemic DDMS 1b in toluene with excellent yield (>95%), The optimized experimental conditions proved highly desirable for large-scale production (Scheme 1).

3.1. Preparation of (RS)-DDMS·D-TA

A 1 L three-necked round-bottomed flask was charged with 1-(4-chlorophenyl)-1-cyclobutylcarbonitrile (CCBC, 50.0 g, 261 mmol) and toluene (150 mL), followed by iso-butyl magnesium chloride (395 mL, 1.0 M in MTBE), and the resulting mixture was distilled until the internal temperature reached >105°C. After stirring at that temperature for 2 h, the mixture was cooled to 0°C and methanol was added slowly (295 mL), followed by sodium borohydride (10.4 g, 1.06 equiv.) portion-wise. The resulting mixture was stirred at rt for 15 min and was added to a 2N HCl solution (330 mL) slowly, stirred for 15 min and the phases were separated. The aqueous phase was extracted with toluene (300 mL), the combined organic phases were distilled to remove methanol, and then washed with aqueous NaOH solution (1.5 M, 100 mL) and water (100 mL) twice. The resulting organic phase was heated to 50–60°C, followed by an addition of D-tartaric acid (40.0 g) in water (80 mL) and acetone (40 mL) slowly. The reaction mixture was azeotrope distilled until the internal temperature reached >92°C and then cooled to ambient temperature in 1–2 h. The slurry was filtered, and the wet cake was washed with MTBE (100 mL) and dried at 40–45°C under reduced pressure to afford (RS)-DDMS·D-TA (100.5 g) in 95.8% yield.

GC_MS
(Hive Addict)
12-09-03 21:22
No 475702
User Picture       Butanamines from scratch?

Would my interpretation of this article be correct if I'd conclude that a new route to butanamines is within reach?

The article reacts a carbonitrile with isobutyl magnesium chloride; they obtain a phenethylamine with an isobutyl chain at the alfa-carbon. Hence I'd think that reacting the same carbonitrile with e.g. ethyl magnesium bromide would yield the corresponding butanamine.

I think the carbonitriles can easily be prepared from scratch. Rhodium's site holds an article that describes the synthesis of carbonitriles from benzyl alcohols: https://www.rhodium.ws/chemistry/pea.benzyloh.html However, the same benzyl alcohols can be prepared from the corresponding substituted benzene and formaldehyde. Instead of using the benzyl alcohol as intermediate, a direct halomethylation can be applied equally well. Only problem is NaCN... frown

EtBr is rather cheap. Preparing the Grignard reagent and reacting it with the previously synthesized carbonitrile might yield an imine, which after reduction with NaBH4 might yield the butanamine.

Comments?

Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".

moo
(Hive Bee)
12-10-03 05:53
No 475862
      one pot 1-phenyl-2-butanamine etc
(Rated as: excellent)

Quite like https://www.rhodium.ws/chemistry/amphetamine.html isn't it? Phenylacetonitrile could be even prepared from toluene through benzyl bromide, see Post 468077 (moo: "Oxidations and brominations w/ H2O2/Br2/HBr", Methods Discourse). smile

Also, I consider relevant to this thread what is described hereinafter tongue :

Hydrogenating ketiminomagnesium intermediates with lithium aluminum hydride to produce amines
Pohland, Albert (Eli Lilly & Co.)
Patent US2772311

EXAMPLE 2

Preparation of 2-amino-1-phenylbutane

A Grignard reagent was prepared from 38.0 g. (0.30 mol.) of benzyl chloride, 19.0 g. (0.78 mol.) of magnesium and 300 ml. of ether. The solution of the Grignard reagent was stirred and 13.8 g. (0.25 mol.) of propionitrile were added dropwise. The reaction mixture was refluxed for two hours, and 7.6 g. (0.2 mol.) of lithium aluminum hydride in 100 ml. of tetrahydrofuran were added thereto. The resulting mixture was refluxed for about sixteen hours, and thereafter decomposed, with cooling, by the addition of successive portions of 8 ml. of water, 6 ml. of 20 percent aqueous sodium hydroxide and 28 ml. of water. The precipitated salts were removed by filtration and washings were dried over magnesium sulfate and fractionally distilled in vacuo. The 2-amino-1-phenylbutane formed in the reaction was collected and found to boil at about 98-99° C. at a pressure of 10 mm. of mercury. There were obtained 21 g. (yield 47%) of 2-amino-1-phenylbutane having the following index of refraction: n_D²⁵=1.5128.

Lithium aluminum hydride reduction of Grignard-nitrile adducts to primary amines
Pohland, A.; Sullivan, H. R.
Journal of the American Chemical Society 75, 5898-9 (1953)

Abstract
The prepn. of 5 disubstituted carbinamines by the LiAlH4 reduction of Grignard-nitrile adducts is described. EtCN (13.8 g.) added with stirring dropwise to PhMgBr from 47.3 g. PhBr, 7.2 g. Mg, and 300 cc. Et2O, the mixt. refluxed 2 hrs., treated slowly with a slurry of 11.4 g. LiAlH4 in 100 cc. tetrahydrofuran, refluxed 18 hrs., and decompd. carefully with cooling with 12 cc. H2O, 9 cc. 20% aq. NaOH, and finally 42 cc. H2O, the solid filtered off and washed with Et2O, and the combined filtrate and washing dried with MgSO4 and distd. gave 27.1 g. (80%) EtPhCHNH2 (I), b7 78-80 Deg, nD25 1.5186. In another run, the org. layer obtained after the decompn. of the mixt. with H2O and base was added to 200 cc. dil. HCl, concd. in vacuo to 75 cc., and treated with 50% aq. NaOH to give 26.5 g. (78%) I, b7 78-9 Deg, nD25 1.5185. In a similar run with only 3.8 g. LiAlH4, 2.8 g. (8%) I and 15.8 g. (51%) EtPhCHN:CEtPh (II), b3.4 156-7 Deg, were obtained; with 7.6 g. LiAlH4, 19.5 g. (62%) I, b10 84-5 Deg, nD25 1.5182, and 3.2 g. (10%) II, b2.8 100-50 Deg, were formed. Similarly were prepd. PhCH2CH(NH2)Et, 26.2 g. (71%) (Yield based on benzyl chloride instead of the nitrile is 59%), b9.5 96-7 Deg, nD25 1.5130, from PhCH2MgCl from 38 g. PhCH2Cl, 19 g. Mg, and 300 cc. Et2O; PhCH(NH2)Am, 23.6 g. (54%), b0.9 82-3 Deg, nD25 1.5070, from 24.3 g. AmCN; Et2CHNH2, 4.8 g. (23%), nD25 1.4030 [HCl salt, m. 215-16 Deg (from MeOH-EtOAc)], from EtMgBr and EtCN; Et2N(CH2)3CHPhNH2, 27.5 g. (62%), b0.8 115-16 Deg, nD25 1.5081, from 28 g. Et2N(CH2)3CN. BzEt (26.8 g.), 26.8 g. I, 4.8 g. NaH, and 150 cc. C6H6 refluxed overnight did not give the imine; a similar run with 6 g. Et3N was also unsuccessful. EtPhCHNHMgBr prepd. in the usual manner from 13.8 g. EtCN and treated dropwise with 33.8 g. I, the mixt. stirred 3 hrs., decompd. by 4 cc. H2O, 3 cc. 20% aq. NaOH, and finally 24 cc. H2O, and stirred 2 hrs. at room temp., and the Et2O soln. decanted, dried with MgSO4, and distd. gave 46.0 g. (74%) II, b0.6 125-6 Deg, nD25 1.5552. II (7.0 g.) in 100 cc. dil. HCl refluxed 1 hr., the resulting oil dissolved in Et2O, the Et2O removed, and the residue treated with 2,4-(O2N)2C6H3NHNH2 gave 2.0 g. 2,4-(O2N)2C6H3NHN:CEtPh, m. 188-9 Deg; the acid aq. phase evapd. to dryness in vacuo gave 3.6 g. I.HCl, m. 193-4 Deg (from MeOH-EtOAc). II (10.0 g.) in 200 cc. EtOH hydrogenated over 200 mg. PtO2, the mixt. filtered, the filtrate concd. in vacuo, the residual oil dissolved in Et2O, the soln. treated with dry HCl, and the cryst. ppt. fractionally crystd. from MeOH-EtOAc gave 0.8 g. a-form of (EtPhCH)2NH, m. 252-3 Deg, and 2.7 g. more sol. b-form, m. 242-3 Deg; mixed m.p., 215-17 Deg.

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	All 3 posts		Subject: Grignard synthesis of amphetamines		Please login to post		Down


		Rhodium (Chief Bee) 12-09-03 18:06 No 475661				Grignard synthesis of amphetamines
						New resolution approach for large-scale preparation of enantiopure didesmethylsibutramine (DDMS) Zhengxu Han, Dhileepkumar Krishnamurthy, Q. Kevin Fang, Stephen A. Wald and Chris H. Senanayake Tetrahedron: Asymmetry 14, 3553–56 (2003) After a series of experiments an optimum procedure was established, which uses the addition of iBuMgCl to 2 at >105°C for 2 h, followed by quenching with methanol. The imine intermediate 3 was reduced using one equivalent of NaBH4 at 0–25°C for 1 h. An efficient quenching process was identified by adding the reaction mixture to a 2 M HCl aqueous solution at 0°C, which generated a homogeneous reaction mixture that can be easily stirred. After work-up, this optimized process afforded a crude racemic DDMS 1b in toluene with excellent yield (>95%), The optimized experimental conditions proved highly desirable for large-scale production (Scheme 1). 3.1. Preparation of (RS)-DDMS·D-TA A 1 L three-necked round-bottomed flask was charged with 1-(4-chlorophenyl)-1-cyclobutylcarbonitrile (CCBC, 50.0 g, 261 mmol) and toluene (150 mL), followed by iso-butyl magnesium chloride (395 mL, 1.0 M in MTBE), and the resulting mixture was distilled until the internal temperature reached >105°C. After stirring at that temperature for 2 h, the mixture was cooled to 0°C and methanol was added slowly (295 mL), followed by sodium borohydride (10.4 g, 1.06 equiv.) portion-wise. The resulting mixture was stirred at rt for 15 min and was added to a 2N HCl solution (330 mL) slowly, stirred for 15 min and the phases were separated. The aqueous phase was extracted with toluene (300 mL), the combined organic phases were distilled to remove methanol, and then washed with aqueous NaOH solution (1.5 M, 100 mL) and water (100 mL) twice. The resulting organic phase was heated to 50–60°C, followed by an addition of D-tartaric acid (40.0 g) in water (80 mL) and acetone (40 mL) slowly. The reaction mixture was azeotrope distilled until the internal temperature reached >92°C and then cooled to ambient temperature in 1–2 h. The slurry was filtered, and the wet cake was washed with MTBE (100 mL) and dried at 40–45°C under reduced pressure to afford (RS)-DDMS·D-TA (100.5 g) in 95.8% yield.



		GC_MS (Hive Addict) 12-09-03 21:22 No 475702				Butanamines from scratch?
						Would my interpretation of this article be correct if I'd conclude that a new route to butanamines is within reach? The article reacts a carbonitrile with isobutyl magnesium chloride; they obtain a phenethylamine with an isobutyl chain at the alfa-carbon. Hence I'd think that reacting the same carbonitrile with e.g. ethyl magnesium bromide would yield the corresponding butanamine. I think the carbonitriles can easily be prepared from scratch. Rhodium's site holds an article that describes the synthesis of carbonitriles from benzyl alcohols: https://www.rhodium.ws/chemistry/pea.benzyloh.html However, the same benzyl alcohols can be prepared from the corresponding substituted benzene and formaldehyde. Instead of using the benzyl alcohol as intermediate, a direct halomethylation can be applied equally well. Only problem is NaCN... EtBr is rather cheap. Preparing the Grignard reagent and reacting it with the previously synthesized carbonitrile might yield an imine, which after reduction with NaBH4 might yield the butanamine. Comments? Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".



		moo (Hive Bee) 12-10-03 05:53 No 475862				one pot 1-phenyl-2-butanamine etc (Rated as: excellent)
						Quite like https://www.rhodium.ws/chemistry/amphetamine.html isn't it? Phenylacetonitrile could be even prepared from toluene through benzyl bromide, see Post 468077 (moo: "Oxidations and brominations w/ H2O2/Br2/HBr", Methods Discourse). Also, I consider relevant to this thread what is described hereinafter: Hydrogenating ketiminomagnesium intermediates with lithium aluminum hydride to produce amines Pohland, Albert (Eli Lilly & Co.) Patent US2772311 EXAMPLE 2 Preparation of 2-amino-1-phenylbutane A Grignard reagent was prepared from 38.0 g. (0.30 mol.) of benzyl chloride, 19.0 g. (0.78 mol.) of magnesium and 300 ml. of ether. The solution of the Grignard reagent was stirred and 13.8 g. (0.25 mol.) of propionitrile were added dropwise. The reaction mixture was refluxed for two hours, and 7.6 g. (0.2 mol.) of lithium aluminum hydride in 100 ml. of tetrahydrofuran were added thereto. The resulting mixture was refluxed for about sixteen hours, and thereafter decomposed, with cooling, by the addition of successive portions of 8 ml. of water, 6 ml. of 20 percent aqueous sodium hydroxide and 28 ml. of water. The precipitated salts were removed by filtration and washings were dried over magnesium sulfate and fractionally distilled in vacuo. The 2-amino-1-phenylbutane formed in the reaction was collected and found to boil at about 98-99° C. at a pressure of 10 mm. of mercury. There were obtained 21 g. (yield 47%) of 2-amino-1-phenylbutane having the following index of refraction: n_D²⁵=1.5128. Lithium aluminum hydride reduction of Grignard-nitrile adducts to primary amines Pohland, A.; Sullivan, H. R. Journal of the American Chemical Society 75, 5898-9 (1953) Abstract The prepn. of 5 disubstituted carbinamines by the LiAlH4 reduction of Grignard-nitrile adducts is described. EtCN (13.8 g.) added with stirring dropwise to PhMgBr from 47.3 g. PhBr, 7.2 g. Mg, and 300 cc. Et2O, the mixt. refluxed 2 hrs., treated slowly with a slurry of 11.4 g. LiAlH4 in 100 cc. tetrahydrofuran, refluxed 18 hrs., and decompd. carefully with cooling with 12 cc. H2O, 9 cc. 20% aq. NaOH, and finally 42 cc. H2O, the solid filtered off and washed with Et2O, and the combined filtrate and washing dried with MgSO4 and distd. gave 27.1 g. (80%) EtPhCHNH2 (I), b7 78-80 Deg, nD25 1.5186. In another run, the org. layer obtained after the decompn. of the mixt. with H2O and base was added to 200 cc. dil. HCl, concd. in vacuo to 75 cc., and treated with 50% aq. NaOH to give 26.5 g. (78%) I, b7 78-9 Deg, nD25 1.5185. In a similar run with only 3.8 g. LiAlH4, 2.8 g. (8%) I and 15.8 g. (51%) EtPhCHN:CEtPh (II), b3.4 156-7 Deg, were obtained; with 7.6 g. LiAlH4, 19.5 g. (62%) I, b10 84-5 Deg, nD25 1.5182, and 3.2 g. (10%) II, b2.8 100-50 Deg, were formed. Similarly were prepd. PhCH2CH(NH2)Et, 26.2 g. (71%) (Yield based on benzyl chloride instead of the nitrile is 59%), b9.5 96-7 Deg, nD25 1.5130, from PhCH2MgCl from 38 g. PhCH2Cl, 19 g. Mg, and 300 cc. Et2O; PhCH(NH2)Am, 23.6 g. (54%), b0.9 82-3 Deg, nD25 1.5070, from 24.3 g. AmCN; Et2CHNH2, 4.8 g. (23%), nD25 1.4030 [HCl salt, m. 215-16 Deg (from MeOH-EtOAc)], from EtMgBr and EtCN; Et2N(CH2)3CHPhNH2, 27.5 g. (62%), b0.8 115-16 Deg, nD25 1.5081, from 28 g. Et2N(CH2)3CN. BzEt (26.8 g.), 26.8 g. I, 4.8 g. NaH, and 150 cc. C6H6 refluxed overnight did not give the imine; a similar run with 6 g. Et3N was also unsuccessful. EtPhCHNHMgBr prepd. in the usual manner from 13.8 g. EtCN and treated dropwise with 33.8 g. I, the mixt. stirred 3 hrs., decompd. by 4 cc. H2O, 3 cc. 20% aq. NaOH, and finally 24 cc. H2O, and stirred 2 hrs. at room temp., and the Et2O soln. decanted, dried with MgSO4, and distd. gave 46.0 g. (74%) II, b0.6 125-6 Deg, nD25 1.5552. II (7.0 g.) in 100 cc. dil. HCl refluxed 1 hr., the resulting oil dissolved in Et2O, the Et2O removed, and the residue treated with 2,4-(O2N)2C6H3NHNH2 gave 2.0 g. 2,4-(O2N)2C6H3NHN:CEtPh, m. 188-9 Deg; the acid aq. phase evapd. to dryness in vacuo gave 3.6 g. I.HCl, m. 193-4 Deg (from MeOH-EtOAc). II (10.0 g.) in 200 cc. EtOH hydrogenated over 200 mg. PtO2, the mixt. filtered, the filtrate concd. in vacuo, the residual oil dissolved in Et2O, the soln. treated with dry HCl, and the cryst. ppt. fractionally crystd. from MeOH-EtOAc gave 0.8 g. a-form of (EtPhCH)2NH, m. 252-3 Deg, and 2.7 g. more sol. b-form, m. 242-3 Deg; mixed m.p., 215-17 Deg. _{fear fear hate hate}

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