synthetic reductions in clandestine amphetamine laboratories a review

8/9/2019 Synthetic Reductions in Clandestine Amphetamine Laboratories a Review

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Forensie

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nternntionar, 42

(1989)

83-199

Elsevier Scientific Publishers reland Ltd.

183

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SYNTHETIC REDUCTIONS

IN

CLANDESTINE

AMPHETAMINE

AND

METHAMPHETAMINE LABORATORIES: A REVIEW

ANDREW ALLEN" and THOMAS S.

CANTRELLb

"Ashtabuln

County

Laborotory, 345

Rogers

Plate, Ashtobuln,

OH

4+004

ond.

bChemistry

Departtnent

Arnerican

Uniaersity,

Washingtoq

DC 20016

U.S.A.)

(Received

une

8th,

1988)

(Revision eceivedNovember 29th, 1988)

(Accepted

December5th,

1988)

Sumnar5l

A review

of

synthetic reductions utilized

in the

elandestine

manufacture

of

amphetamineand

methamphetamine s

presented.

General discussionson

the

mechanism

of

heterogeneous

ata-

lysis, dissolving

metals, hydrides and non-metal

eductions used in

the

manufacture of amphe-

tamine

and

methamphetamine

with

over

80 referencesare

presented.

Key

usords;

mphetamine;Methamphetamine;

Synthesis;

Clandestine

aboratories

Introduction

This review

addresses

eductions in clandestine

methamphetamineand

amphetamine

ynthesis.

Central

to the diverse

routes

published

or the syn-

thesis of

methamphetamineand

amphetamine

s

a

reductive step at

some

point

in the synthesis.

Of

95 references

surveyed

concerning

he synthesis

of

these

controlled

drugs, all

but ten

utilize

a

reductive approach.

Since

such

diversity

exists in these

approaches,

we

felt that a composite

iterature

review

and

discussionof

the

chemistry

involved would

help forensic chem-

ists charged

with investigating these

clandestine aboratories.Secondly,

we

felt that

a

composite

reference

list

would

be

of

assistance

n

correlating

notes

or

procedures

ound

in

elandestine

aboratory sites to

the

open

itera-

ture. Finally,

only two

open literature

review articles

in this forensic area

have appearedand both were devoidof extensive eferences 1,2].

An overview of

synthetic approaches

to methamphetamine and

amphetamine

tilizing reductive

routes is outlined n

Tables

L

and

2.

Table 1

is organizedby the type

of catalytic

surfaee

or

reductive species;

.e. Pd,

Pt ,

LiAlH4,

HCOOH,etc. Table 2

is organizedby the synthetic

route or

interme-

diate;

.e. Leuckart, Schiff

base,oxime, nitrostyrene,

etc.

Figures

t-tz

illus-

trate

the chemical

ormulas of the

chemical eduction routes

to

amphetamine

and

methamphetamine.

References

13,721

rc annotated

with

the

type of

reductive

catalyst/reagent and

route

utilized. Chemical

Abstract citations

0379-0738/89/$03.50

O

1989

Elsevier

Scientific

Publishers

reland

Ltd.

Printed and

Published

n Ireland


2/17

184

TABLE

1

METHAMPHETAMINE

OR

AMPHETAMINE

Refs.

Hetero

gene

us

reductions

krternal

source of

hydrogen)

A. Pd

B. Pd/C

C.

Pd/BaSOo

D. Pt

E.

Pt/C

F.

CuO,

CaSOo,

aSOn

G. Raney Nickel

(Ni-Al)

H e ero geneous reductions

(intental

source of hydrogen)

H.

CaHr/Pd,

HCI

Dis

soluing

metal reductions

('

nternal'

e e

c

r olg tic)

I . AI-Hg

J. AI-Pd,

HC I

K. Na

alcohol

L. Na-Hg

M. Fe, HCI

N. Zn, HCI

O.

Zn-Cu,

HC I

P.

Zn-Pd,

HC I

a.

Zn-Cu-Pd,

HCI

M e

al

hydride

reduc

tions

bource

of hydride)

R.

NaBHn

S. NaCNBH,

T. LiAlHl

Non-metal reductions

U. HI

V. HCOOH

3- 17,89

7,9,12,L5-17

5,8

18-24

23

25

26-38

39

40-45

54

46-49

50,51

52,53

64

54

54

54

55,56

o ,

58-62

63;

pers.

comm.l

64-72

"J.

Heagy,

personal

communication,

rom information

gathered

by

attending

clandestine abora-

tory sites.

Drug Enforcement Administration,

450

Golden

Gate

Avenu,

San

Francisco,

CA

94102.

[C.A.

Vol.:

page

(year)]

are

included or

each eference

or

ease

of

cross

efer-

enee

with

cryptic

notes

often

found

in

clandestine

aboratory

sites. Finally,

the

recurrent

use of t he

terminology

"open

literature"

refers

to

legitimate,

accredited

ournals

as opposed o underground publieations

or

notes

passed

betweenclandestinemanufacturers.


3/17

r85

TABLE 2

METHAMPHETAMINE

AND AMPHETAMINE VIA

REDUCTION

Route no.

Methamphetamine

u'in

Ephedrine

(A)

Direct

[3,8,17;

.

Heagy"]

(B)

Halo analog

3-5,17,18,19,39,541

(C)

Sulfate

ester

[6]

(Dl

Phosphateester

[?]

(E)

Perchlorate ester

[8]

Schiff

s base

10,20,2\,22,25,40 44,46,55,57

Thiazole

[47]

Leuckart [58,64,66]

d-Phenylalanine

arbamate

591

N-Formyl

[58,66]

Amphetwnine

2

9

8

10

8

Oxime

1

1,12,30,31,48,49,60]

Nitrostyrene

[13,32,33,35,50,6U

2-Ketooxime

14-

16,36,38,5U

Hydrazone

23,34]

Schiffs

base

26-29,45]

8-Iodo

analog

62]

Leuckart

[65,67

701

Demercuration

56]

3

4

5

6

2

1 1

8

T2

'See

footnote

Table 1.

Heterogeneouscatalysis

The role of heterogeneous

atalytic

hydrogenation

and hydrogenolysis

n

organic synthesis

s replete in

the

literature. However,

he mechanism

f the

catalyst's role has

remained

elusive due mainly

to the difficulty of

studying

sueh

heterogenous

ystems.

Recent

researeh n

this area has shown

that

a

system charged

with

H, and

D, in

the

presence

of a

catalyst

yields

HD.

This

has

been

interpreted

as

the

catalyst's coordination

with

molecular H,

and

weakening

or disruption

of

the H-H bond

[87,881.

tudies

by

Maier

et

al .

(pers.

commun.,

Dept.

of

Chemistry,

Univ. of

California,

Berkeley,

CA

947201,

in

which

the

catalytic

surface

has been

coated

with

SiO2,

ave

revealed

hat

the H-H

(which

penetrates

the SiO,

layer to coordinate with

the catalytic

surface)

s

truly

ruptured,

yielding

%I. Furthermore, hydrogenation

of an

organic species

incapable

f

penetrating

the SiO,

layer)

occurred.This

sug-

gests

hat coordinationbetween

he

organic

moiety and the catalytic

surface

may not be necessary.

Selectivity"

for

an organic substrate n some cataly-

tic metal hydrogenation

systems

has recently

been

shown

to

be dependent

upon he

topology

of the catalytie surface

89].

Further

work

in

this area will

be

followedwith

interest.


4/17

h

>.

H/H,l

.-r,

,ru,

, ,

Pt/ .ai l

re' s

Zn/ucti

sc

H l / P l o 3 , o " r *

" ^ - -

'o'

1Yb8


5/17

d**

3**

1d-&

u"J

4.

re/nct1u''u"'/

,/

r'

P

H E N

Y

L - 2 . P R O P A N O N E

frfr

,.>.B-cJH'

_*

fy-fJ*,

l :

l l

B

+

NH2oH

\ , 2 v . ' \ "

5,

Figs.

4-6.

Hydrogenolysis

of ephedrine

or

phenylpropanolamine

here

hydrogenolysis

s

defined as reduction of C-X) is not a result of reduction of the benzylic

carbon-OH

bond.

The actual

moiety

reduced

s

C-X,

where

X

refers

to halo-

gen

[3-5,

1?-19,39,54]

sulfate

[6],

phosphate

7]

or

perchli i ;"ate

8]

esters

(pig.

1).

This

moiety

(C-X)

may be

produced

n situ

[3,17i

or

synthesized

externally,

isolated and

then

reduced

[4,9,18,19,39,541.

he stereoehemistry

and

analytical

methodology

or methamphetamine

repared

from ephedrine

and

pseudoephedrine as recently

been

addressed

92'931.

H=c-No2

l -

l l

C H r

\,/

I

m/.n,1,"

I

Ni/

Hr

sz' s

I

NaHglso

I

LiAt

H4161

Y

A M P H E T A M I N E

|

*7r,1. ,

I

Ni /Hz

I

so,

e

I

* "

Hs ls t

c H 3 c H z N O z


6/17

v?-\

P H E N Y L A C E T I C

A C I D

P H E N L - 2 - P R O P A N O N E

B

ffH'-c-':'

"8-.a.

o

l l

c {H3

+

>?-

\l

Br

A,-"

,,}J

s

l l

H .c \H ,

9.

F igs .7 -9 .

Heterogeneous

atalysis

has

been used

o

reduce

he

imine

bond of Schiff

bases

ormed with

phenyl-2-propanone

nd ammonia

or

methylamine

n

order

to

produce

amphetamine

126-291

or methamphetamine

9,10,20

22,251(Fig.

2).

When

heterogeneous atalysis s

utilized

in

this Schiffs base eduction,

a

competing eaetion, hat of

P-2-P eduction

o

1-phenyl-2-propanol,

imits

the

yield

of

amphetamineor methamphetamine.Additions of

large

excesses f

the amine

component

n these

reactions

have

been employed o suppress

he

/

/Na/arc

47

/


TfSli:

R

Aqoizs

A\/CH2-C-CHr

^,_E

puoec),tzo,

(l

-

r

cxi\oH


7/17

189

H;CH-NHt

ts"

O H

10.


4

H\ra

q-t

+

11.

/

/LiAlH.

62

/


afH''gg*H'

q2

'-..'Hg(NoJ,

/cH -cN

Ott'-t'f"\HsNo'

\,/

\-.",

12'

/ , ' ,b6

J*o'

n t /e

cHr..a;c"t

I

t*-f

-t"'

Figs.

10

12.


8/17

190

ketone reduction. This has limited applicability, since the optimum pH for

the

Schiffs

base

production

s

between

pH

6 and

7.

Other

clandestine

routes,

although

less

popular, which have open

literature references

utilizing

heterogenous

catalysis

for

the synthesis

of

amphetamineare

oxime

reduction

[12,30,31,351

Fig.

3),

nitrostyrene

reduc-

tion

[13,32,33]

Fig.

4), 2-keto-oxime

eduction

[16,36,38]

Fig.

5)

and

hydrazone

reduetion

23,341

FiS.

6) .

Precursors to amphetamine

(phenylpropanolamine)

nd

methamphetamine

(ephedrine)

have been synthesized

with the aid of

heterogeneous

atalysis

11.6,38J,

ig.

5) .

Dissolving metal

reductions

Dissolving metal reductions, n particular aluminum, continue to be the

most

popular

synthetic

routes to

methamphetamine

and

amphetamine

n

clandestine

aboratories

n the United

States.

Although

molecular

H,

is

pro'

duced

as

the

metal dissolves,

his

is

generally

considered

a

detriment

to

the

reduction

of

the organic

species.

The

actual

reductive

mechanism

does

not

involve molecular

H, but

is, in

fact,

a

result of an

"internal

electrolytic

pro-

cess".

Electron

transfer

from

the

metal

to a

heteroatom

esults

in

a

radical

carbon

which abstracts

hydrogen

from solution

to complete

reduction. In

metals

where

higher

oxidation

states

are

present

(i.e.

Al,

Mg, Zn) dimers

may

form as

a result

of

intramolecular

adical combination

54,90,911.

Poisoning

of catalysis

s one approach

used

to minimize

rapid

dissolution

of the

metal

and to

abate

evolution

of

Hr.

Amalgams

made

between sodium

and mercury have the effect of diminishing the activity of the parent metal

thus

slowing

dissolution

of the

reducing

species. Amalgamation

between

aluminum

and

mercury

has

the added

benefit

of

preventing oxide

formation

on the surface

of aluminum

in contact

with

air.

Aluminium-mercury

amal-

gram

serves

to

poison

the

metal

somewhere

between

the

extremes

of the

over-active

metal and

the

inactive

metal oxide.

In the clandestine

manufacture

of

amphetamine

and

methamphetamine

the most

popular

route is

via aluminum-mercury

amalgam

eduetion

of

the

Schiff

base adduct

of

phenyl-Z-propanone

P-2-P)

and

the appropriate

amine

[40-a5]

(Fig.

2).

This

popularity

persists

despite

U.S.

Government

control

(Schedule

I) of

P-z-P

in

1980.

This controlled

status

has

resulted

in

an

upsurge

in the

clandestine

manufacture

of

P-Z-P.

A

variety

of synthetie

routes

have

surfaced

n elandestine

aboratories,

primarily through

phenyl-

acetie acid

[?3

-771(Fig. 7). Alternatives to the phenylaceticacid (now on a

reporting schedule

n some

states)

synthesis

of

P-2-P

have appeared

78-891-

One approach

o

P-2-P

utilizes

a

dissolving

metal

reduction

of

nitrostryene

with

iron and

hydrochloric

acid

[52,53]

Fig.

a] .

Clandestine

aboratories

which utilize

other dissolving

metal

reduction

routes have been

infrequently

encountered.

However,

reduction

of

a Schiff

base

to

methamphetamine

46]

Fig.

2) and of

5-phenyl-4-methylthiazole

o


9/17

191

amphetamine 47] (Fig. 9) using sodium in alcoholare cited in the open litera-

ture. Additionally, Naialcohol reduction of an oxime

[48,49]

Fig.

3], NalHg

amalgam eduction

of a nitrostryene

[50J

FiS.

4)

or a 2-keto-oxime

51]

(Fig.

5]

to

amphetamine and zinelHcl reduetion

of

chloro

analogs of

ephedrine

to

methamphetamine

5 J

Fig.

1)

are also cited

in the literature.

Metal

hydride reduetion

Metal hydride reductions

have not

captured

the imagination of clandestine

laboratory

chemists ike the

remainder of the scientific community.

This

fact

is

probably

the

result of their inability to utilize current

Chemieal

Abstracts

nomenclature,

wherein most literature

references

o

metal hydrides

appear.

Metal

hydrides

function by

transfer

of

a

hydride to the electrondeficient

center (typically carbon)of a double bond. Protonation is effeeted on the elec-

tron rich

center

via

the

solvent media in the caseof

NaBHo

or

product

work-

up

in

caseof LiAlH'.

The infrequent

use

of metal hydride

reducing

agents in

clandestine

laboratories cannot be attributed to the

lack

of

open

literature references

n

these

agents

[55-62].

Methamphetamine

has

been

produced

n

clandestine

laboratory sites

via

NaBHn

reduetion of the

Sehiff

Base

adduct of

P-Z-P

and

methylamine following a

procedure

outlined by

Weichet

et al.

[55]

Fig.

2).

Unfortunately, the activity

of NaBHn s sufficient to reduce the ketone

of

P-

2-P

and this

is

a

competing

reaction. This is not the case

with

the more

selective edueingagent

NaCNBH' whose

activity is

dependent

on

the

pH

of

the

reaction

media

[57J.

ithium aluminum

hydride, whose

activity

is

greater

and therefore less seleetive han NaBHn,has been used to produeemetham-

phetamine

or amphetamine hrough

the reduction of

a

variety

of functional

groups;

.e.

formyl

[58]

(Fig.

8), carbamate

59]

(Fig.

10),

oxime

[60J

Fig.

3] ,

nitrostyrenes

[61]

(Fig.

4] and halogenanalogs

62]

(Fig.

t1). Sodium borohy-

dride has also been

used in

a

demercuration

procedure

route followed

by

acid

hydrolysis to amphetamine

(in

a clandestine

laboratory)

as outlined

in

Fig. 12

[56].

Non-metal

reductions

Non-metal

reduction

routes

to

methamphetamine nd

amphetamine

have

been

what might

be termed

as

"fads"

in

clandestine aboratory

synthesis

within

the United

States.

In the

early and

mid 1970s,

he Leuekart Syn-

thesis,which employs ormic acid,was the most popular elandestine oute to

amphetamine

nd

methamphetamine.

or

whatever

reason, his

route, which

is

still

very common

n Western

Europe, ost

popularity

in the

United

States

by the

end

of the

1970s.

n the

early

1980s, he hydriodic acid

reduction

of

ephedrine

o

methamphetamine

egan

ncreasing

n frequency n

the South-

western

and

Western areasof

the

United

States.

Although several iterature

references

ink

the

Leuchart synthesis

Fig.

8) to amphetamine

67

69] and

methamphetamine

64-661,

"no"

open literature

referenee

directly

links


10/17

192

hydriodic

acid

reduction

of

a benzylie

alcohol

to

the

production

of metham-

phetamine

(F'ig.

1).

Several

general

benzylic

alcohols

have

been

reduced

to

their

aliphatie

counterparts

63].

However,

this

'eross

application'

of chemical

syntheses

would

require

a

level

of

chemical

knowledge

not

common

among

clandestine

hemists.

The

mechanism

of

the

Leuckart

reaction

has

been

studied

165,71,721

nd

shown

to be

a

free

radical process

nitiated

by

formie

acid.

Unfortun"t"ly,

the meehanism

of

the hydriodic

acid reduction

has not

been

established.

t

seems

elear

that

the

benzylic

alcohol

of

ephedrine

undergoes

a substitution

reaction

with

iodine.

However,

the

mechanism

of the

carbon-halogen

educ-

tion is

in

conjeeture;

.e. hydride

transfer,

internal

electrolysis

via

dispropor-

tionation of iodine,or elevated emperature decomposition f HI to H, and I,

whereby

H, reduces

he

C-I bond

[GB].

Conclusion

In

this review

we

have

addressed

eductive

approaches

o

amphetamine

and

methamphetamine

ia

heterogeneous

atalysis,

dissolving

metals,

metal

hydrides

and non-metal

reductions.

The

chemistry

of

these

varied

approaches

as

been highlighted

with

emphasis

on the

role

of

the reducing

species.

t may

be

eoncluded

hat

there

are many

options

available

o

elan-

destine

chemists

(see

Figs.

1- 12).

However,

in

actutal

practice,

the

three

most

frequently

encountered

outes

in the

United

States

are

(I.)

he

alumi-

num

foil

reduction

of

the Schiff

Base

adduct

of P-2-P

and

methylamine

40441,21 he palladium

catalyzed eduetion

of

the chloro

analog

of

ephedrine

o

methamphetamine

[4,5]

and

(3)

the

hydriodic

acid

reduction

of ephedrine

o

methamphetamine

[63;

pers.

comm.*].

References

@

e.

Sinnema

and

A.M.A. Verweji, Impurities in

illicit amphetamine:

review.

BulL

Narc.,

Vol.

XXXIII,

no. 3

(1981)

7

54 .

2

C.L. Hider',

Preparation f

evidencen

illicit amphetamine.

. Forensic

Sci.,9

1969)

5-79.

3

Pd,

Figure 1.

Ephedrine

with HCI

(gas)reduced

o methamphetamine

H.

Metzger,

Bases

of

the

1-phenyl-2-aminopropane

eries.

German Patent No.

968,545

Mar.

r\

6, 1958.

C.A. 54:7654b

1960).

(.4 \ Pd, Figure 1.

v

Chloro

ephedrine

educed o methamphetamine

A.

Gero, Some

eactions

of 1-phenyl-1-chloro-2-methylaminopropane.

.

Reactionwith

metals

and hydrogen.

.

Org. Chern.,16

1951)

731-1735.

C.A.46:66069

1952).

5

Pd/BaSOn, igure 1.

Bromo

or

chloro

ephedrine

educed o

methamphetamine

H.

Emde,

Concerning

diastereoisomers

.

Configuration

of ephedrine.HeIu.

Chem.

Acto,

12

(1929)

65-376. C.A.

23:

3452-9454

1929).

'J.

Heagy, pers.

eommun. rom

information

gathered

by

attending

clandestine

aboratory

sites.

Drug

Enforcement

Administration,

450

Golden

Gate Avenue,

SanFraneisco,

A 94102,

U.S.A.


11/17

r98

Pd and Pt, Figure 1.

Ephedrine

ester

reduced o methamphetamine

W.

Dobke

and

F. Keil, Amines.

British Patent

No.

509,661,

Oct., 3, 1938.

C.A. 34: 3761

.d*--_a_--

10

11940).

7

Pd/C,

Figure

1.

Ephedrine

phosphate

ester

reduced

o methamphetamine

A.

Lafizza,

G.

Brancaccio and A. Segre, l-, d- and d,l-Ephedrine

phosphates.

"/.

Med

Chem",

I

(1966)996-997.

C.A.

66:28945y

196?).

(

8) Pd/BaSO., igure 1.

\-/

Ephedrine

with

perchloric

acid reduced o methamphetamine

K.W.

Rosenmund,

E. Karg and F.K. Marcus,

Concerning

he

preparation

of beta-Aryl-Atky-

lamines.Beriehte, TSB

1942)

850-1859.

C.A.

38: 1219

1944).

Pd/C,

Figure 2.

Schiff base


Ameriean Home Products

Corp.

Imines. British Patent No. 702,985,

an.

27, 1954.

C.A.

49:

5515s 1955).

ilFi-F"?.

Schiff base

P-Z-P

+

MeNHr) reduced o methamphetamine

M. Tsutsumi,

An

illegal

preparation

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amphetaminelike

compound.

Science

Crime

DetecL,

Japan)O1953)

0-52.

C.A.

l:11661h

1953).

r

11) Pd/HCl

\-/

Chloro

nalog

f

phenylpropanolamine

o amphetamine

W.H.

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Munch, Amino

Alcohols.

VI. The

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isomeric

phenylpropylamines.

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C.A.

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1981).

Pd/c

Nitrile

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Catalytic

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370

7\

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1929).

( 13

\

Pd and Pt

with

a slurry

of

Ni,

Figure 4.

\-/ Nitrostyrene reduction to amphetamine

L.A. Bryan, Hydrogenationof

1-phenyl-2-nitropropeneo

alpha-methylphenethylamines.

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Patent No. 3,456,576.

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91049c

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14 Pd, Figure 3.

E

'----

Oxime

reduction o amphetamine

K. Kindler, B. Hedemannand

E. Scharfe,A study of mechanisms

f

chemical

eactions.

X.

Phenyl

and cyclohexyl-alkylamine

y hydrogenation. zsfas

Liebigs

Ann Chern,

560

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,r\

216-22L.

C.A. 43: 1025h

1949).

\15\

Pd/C,Figure 1.

\J

Pseudoephedrineeduced o methamphetamine

H. Temmler, Amines, French Patent No. 844,227

uly

20, 1939.

C.A.

34:72971(1940).

Pd/C,Figure5.

-

Z-keto

oxime

reduction

to

phenylpropanolamine

lV.H.

Hartung and Y.

Chang,

Palladium catalysis. V.

Change

n

behavior

of

palladium+har-

coal in hydrogenation reactions.

J. Am.

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Soc.,74

{'19621

927

692F

C.A.

48: 1159

e (1954).

(rz

)

ealc,Figure1.

-

Ephedrineeduction

o methamphetamine

K.

Kindler, B.

Hedemann

and

E.

Scharfe,

Study of mechanismsof chemical

reaction. X,

Phenyl and cyclohexyl-alkyl

amines by

hydrogenation. Justus Liebigs Amt^ Chem.,

560

(1948)

15-22r.

C.A.43:

0259

1949).

1ta)

rt, Figure .

\"'/

Chloroephedrine

eductiono

methamphetamine

W.

Dobke and F. Keil,

Amines.

German

Patent No. 767,186,

an.

31

(1952).

C.A.

49: 1598c

t1955) .Br i t ishPaten tNo.509 '661,oct .3 (1938) . ry


12/17

194

20

23

24

25

30

31

o

28

nitrogen-substituted

beta-phenyliso

169-171.

C.A.

34: 16278

1940).

&\

tr ,Figure1

\-/

Cltloroephedrine

reduction to methamphetamine

S. Nakajima, 1-Phenyl-2-methylaminopropane,apanese

Patent No. 2307

(1951),

May

15

(1951).

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1953).

Pt, Figure

2

Schiff base eduction

(P-2-P

+ NHs)

o

amphetamine

E.R. Alexander

and A.L.

Misegades,

A low

pressure

reductive

alkylation method for the

conversion

of ketones o

primary

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(1948)

1315-1316.

C.A.42:

5411d

1948).

Pt

or activated Al, Figure

2

Schiff

base

eduction

(P-2-P

+

MeNHr)

to methamphetamine

D.

Shiho, A new

process

of alkylation of amines. J. Chem. Soc.

Jpn^,

65

(1944)

23?

239.

ry

rt, ^tigure

z.

Schiff base eduction(P-2-P+ MeNHr) to methamphe tamine

W.

Dobke

and F. Keil, beta-Arylalkylamines.French

Patent

No. 844,227

C.A.

34:

72976

(1940).

erman

Patent

No.

767,263

1952).

.A.47:2772c

1953).

Pt/C

also

Ni

and

Al, Figure

6.

*

Phenylacetoneydrazones

eduction

o amphetamine

T.H. Temmler,

Reduction

o

hydrazones. erman

Patent No.

870,265Mar.12

1953).

.A.52:

lffiOrd

(1958).

Pt, Figure 5.

2-ketooxime reduced o ephedrine

R.H.F. Manske

and

T.B.

Johnson,

Synthesis

of

ephedrine and structurally similar com-

pounds.

.

J. Am. Chem.Soc.,51

(1929)

80-

582.

C.A. 232 404

1929).

CuO,CaSOo, aSOo,

igure 2.

Schiffbase eduction

P-2-P

+

MeNHr) o methamphetamine

J.B. Tindall,

Process for the

production

of

secondary amines. U.S. Patent

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Mar.25,

1958.

C.A.

52:73775f.

1958).

Ni-Al, Figure 2.

Schiffbase eduction

P-2-P

+

NH3) o amphetamine

P.

Mastigle, M.

Metayer

and

A. Bricard,

Study of the aminolysisof some

ketones and alde-

hydes.

BulL

Soc.Chim.

France

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045-1048.

C.A.45:8970h

1951).

Ni-Al,

Figure

2.

Schiff

base eduction

(P-2-P

+ NHr)

to

amphetamine

L.

Haskelberg,

Aminative

reduction

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,Soc., 0

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28tl-28t2.

C.A. 43: 1349f

1940).

Ni-Al,

Figure 2.

Schiff base educed

P-2-P

+

NHr)

to

amphetamine

A. Novelli,

Sympathicomimetics,

preparation

of

propylamin

es.AnnL .4ssoc.

Quim.

Ar

g

entinn

27

(1939)

Ni-Al, Figure

2.

Schiff

base educed

P-2-P

+

NHB) o amphetamine

M.

Green,

Reductiveamination

of

ketones.

U.S.

Patent No. 3,187,047,

une

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C.A.

63 :

9873f 1965).

-

Ni-Al, Figure 3.

Oxime

redueed o

amphetamine

J.W.

Wilson,

Synthesis

of dl-amphetamine

ulfate

labeled

with

C'{.

J.

Am. Phorm. r4,ssoc.,

(Sci.

Ed.),39

(1950)

87.

C.A.

452

728d

1951).

Ni-Al, Figure

3.

Oxime educed

o amphetamine

T. Kametani and

Y. Nomura,

Reduction of nitrogen

compoundsby Raney

nickel alloy

and

alkali solution.

. J. Pharm. Soc.

pn.,74

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13-416.

C.A.

49:

5342d

1955).


13/17

195

32 Ni-Al, Figure

4.

Nitrostyrene reduced o amphetamine

J.B.

Tindall, Reduction

of nitro oletins. U.S.

Patent No. 2,636,901,

pr.

28, 1953.

C.A.

48:

277rt

{'19541.

33

Ni-Al,

Figure 4.

Nitrostyrene reduced o

amphetamine

G. Stochdorphand

O. Schickh,Saturated

amines.German Patent

No. 848,197,

ept. 1, 1952.

C.A..47:5438b

1953).

34 Ni-Al, Figure 6.

Hydrazone educed o

amphetamine

R.

Fusco

and L.

Canonica,Reduction

of

phenylhydrazone-p-sulfonic

cids.

Chim..Ind

(Milan),

r-\

32

(1950)

08-210. C.A.45: 4645a

1951).

/

35

)

Ni-Al, Figure

3.

V

O*i-e reduction to

amphetamine

H.B. Hass,A.G.

Susie

and

B.L. Heider,

Nitroalkane

derivatives. . Org. Chem.,15

1949)

-

14.

C.A.

44:44t2d,

1950).

36 Ni-Al, Figure 5.

2-ketooxime

reduced o

phenylpropanolamine

P.L.

Cook,

The

reduction of

aldehydes

and ketones

with

nickel-aluminumalloy

in

aqueous

alkalinesolution.

. Am. Chem.

Soc.,27

1962)

873-3875.

C.A.

58:464c

1963).

37

Ni-Al

Chloroephedrine


W. Leithe,

Configuration

of

the ephedrine

bases.Berichte, 65

(1932)

60

666.

C.A.

26:

3495.

38

Ni-Al, Figure

5.

2-Keto oxime reduced o

phenylpropanolamine

V. Evdokimoff, Reduction eaction with

nickel-aluminum lloy.

Applications

o the

synthesis

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other

pharmacologically

ctive

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81

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725-734.

C.A.

46:7070d

1952).

CaHr-Pd,

Cl, Figure 1.

Chloroephedrine


A.

Gero,

Some eactions

of

1-phenyl-1-chloro-2{methylamino)propane

Reaction

with

metals

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40 Al-Hg,

Figure 2.

Schiff base educed

P-2-P

+

MeNH") o methamphetamine

Laboratoires

Amido, French Patent

No. M2782,

Oct.

5,

1964.

C.A.

62: 5228b

1965).

Al-Hg, Figure 2.

Schiff base educed

F-2-P

+

MeNHr)

to

methamphetamine

F. Keil and

W. Dobke,

N-Monomethyl-beta-phenylamines,

erman

Patent

No. 871,155,

Mar.

19,1953.

C.A.

52-20055e

1958h

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Patent

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508,756,

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34:7765

1940).

42

Al-Hg, Figure 2.

Schiff base educed

P-Z-P

+

MeNHr)

o

methamphetamine

D. Shiho,A new

process

of alkylation

of amines. . Chem.Soc. Jpn.,65

(1944)

35-140.

C.A.

41:3800e

1947).

[a\

ar-ng,

Figure

2.

L-/

Schitf

base educed

P-z-P

+

MeNHr) to methamphetamine

H Temmler, Amines. French Patent No. 844,288,

uly

20, 1939.

Q.A.

34:

75447

19401.

44 Al-Hg,Figure2.

-

#

Schiff

base

educed

P-2-P

+

NH3)

o amphetamine

B.H.G. Wassink,

A.

Duijndam and A.C.A.

Jansen,

A synthesisof

amphetamine. . Chem.

Ed,5l

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71.

No

C.A.

citation.

45 Al-Hg, Figure

6.

Hydrazone

eduction to

amphetamine

T.H Temmler,

Reduction f

hydrazones.

erman

Patent No.

870,265,

ar. 12, 1953.

C.A. 52:

16301d

1958).


14/17

196

@

47

Na/Ale,Figure 2.

Schiff base educed

P-2-P

+

MeNHr) to

methamphetamine

A. Ogata,

Constitution

of ephedrine.

Desoxyephedrine. . Pharm.

Soc. pn.,451

(19f9)

761-

764.

C.A.

L4:745

1920).

Na/Alc, Figure 9.

alpha-BromobenzylMethyl ketone

+

Thioformamide

-

$Phenyl-4-methylthiazole

+

Na/

Alc to methamphetamine

H.

Erlenmeyer

and

M. Simon,

nvestigation in

structure

chemistry VI.

Concerninga reduc-

tive cleavageof $phenyl-4-methylthiazole.

eIu. Chirn. Acto" 25

(1942)

528-580.

C.A. 36:

65396

1942).

Na/Ale, Figure

3.

Oxime

reduced

o

amphetamine

F.M. Jaeger and J.A.

van

Dijk,

Preparation of 2-phenylisopropylamine.

roc.

Acad-

Sci

Amsterdom,

44

(1941)

6-40.

C.A.

37:621'g

1943).

Na/Alc, Figure 3.

Oxime redueed o amphetamine.

W. Leithe,

Configuration

f ephedrine ases.

eri,chte,65

1932)

60-666.

C.A.26:3495

48

51

Friedel Crafts

followed by

nitrostyrene

reduction

in

situ) R.V.

Heinzelman,

Alkyl arylalkyl ketones.

and

hydrolysis

to

phenyl-2-propanone

al l

U.S.

Patent No.

2,557,051

1951)

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rF -(1932).

\q1)N"-ng,

Figure4.


G.A.

Alles,

Salts

of

1-phenyl-2-aminopropane.

.S.

Patent No.

1,879,003,

ept. 1932.

C.A.27:

373

1933).

Na-Hg, Figure 3.

Oxime reduced

o

amphetamine

D.H. Hey, dl-Phenylisopropylamine

nd

related

compounds.

.

Chem.

Soc.

(1930)

8-ZI.

C.A.24z

851

1930).

Fe, HCl,

Figure 4.

Nitrostyrene reduced o

phenyl-2-propanone

H.B.

Ilass, A.G.

Susieand

R.L. Heider,

Nitro-alkane

erivatives. .

Org.

Chem.,15

(1950)

-14.

C.A.

44:44r2d

1950).

Fe,

HCl,

Figure 4.

,-r-

ifllsJl95lL

(

54

)

Zn,HCl,Figure1.

v

zn-Cu,

cl

Zn-Pd,HCI

Zn-Cu-Pd, CI

Chloroephedrine

educed

o methamphetamine

A. Gero,

Some reaetions of

1-phenyl-1-chloro-2{methylamino)-propane.. Reactions with

metalsand

with

hydrogen.

.

Org. Chem.,16

1951)

731-1735.

C.A.46:66069

1952).

55

NaBH,

Schiff base

educed

ketone

+

MeNHr) to ephedrine

J.

Weichet,

J.

Hodrova

and L. Blaha, Reductive amination

of

phenylacetylcarbinols

by

sodium borohydride. ColL

Czech. Chem. Comrnun, 26

(1961)

2040-2044.

C.A. 56: 5864c

z-..

(1962)'

(

56/

NaBHn, igure

12.

\/

Demercuration

followed

by acid

hydrolysis to

amphetamine.

H.C.

Brown

and

J.T.

Kurek, Solvomercuration-demercuration

f representativeolifins in

the

presence

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acetonitrile. Convenient

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647-5649.

C.A.

71: 1012619

1969).

57

NaCNBH.,

Figure 2.

(Ketone

+

Amine) reduced o

amines.

R.F.

Borch,

M.D. Bernsteinand H.D.

Durst

The

Cyanohydridoborate nion as

a

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2897

2904.

C.A.

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49525n

1971).


15/17

L97

58

LiAlH4, Figure 8.

N-formylamphetamineeduced o methamphetamine

O.

Cervinka, E. Kroupova

and O. Belovsky,

Asymmetric

reactions.

XXIX. Absolute

configu-

ration of

phenyl-2-alkylamines

nd their N-methyl

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CoIL

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551-3557.

C.A. 70:

37323d

1969).

(^sb,

t

iualHn,

Figure 10.

t*-z

d-Phenylalanine

arbamate

educed o

amphetamine

R.B.

Repke, D.K. Bates

and W.J. Ferguson, Synthesis

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dextroamphetamine

sulfate and

methamphetamine

ydrochloride rom

d-phenylalanine.

"I.

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C.A.

89: 163164h

1978).

60

LiAIH{,

Figure 3.

Oxime educed o amphetamine

K. Kotera, T.

Okada and

S. Miyazaki, Stereochemistryof

aziridine formation

by reduction

of oximes

with

lithium

aluminium hydride on

arylalkyl alkyl ketoximes

and their tosylates.

Tetrahedron

24 {.196$

677-5690.

C.A.

69: 67158a

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LiAIH{, Figure 4.


R.T.

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and F.F. Nord, Reverse

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lithium

aluminum hydride

to nitroolefins.

J. Am.

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837-1843.

C.A.

48: 553c

1954).

LiAIH{,

Figure 11.

1-Phenyl-2-amino-8-iodopropane

o amphetamine

(2,2-dimethyl-5-amino{-phenyl-1,3-dioxane

+

HI +

P

in

HOAc/Ac,O

=

1-phenyl-2-amino-3-iodopropane)

(1964)

une

17.1961.C.A.

6L: 1t930cd

1964).

61

62

K. Shinohara, M Tamura

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apan

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Reductionof a benzylic

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T. Ho

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)

W.E.

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K.N.F. Shaw,

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1149-1151.

d)

A.C.

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W.

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R.

LeMahiem,

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C.S.

Marvel, F.D. Hager

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Sunth.,ColL,Yol.I,224-225.

O

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64 HCOOH,Figure 8.

Ketone

+

HCONHCH,

=

formyl

+

HCI

to amine

A.L Vogel, Tertbook of

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65 HCOOH,

Figure

8.

Leuckart meehanism

tudy

and synthesis

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amphetamine

F.S.

Crossley nd M.L. Moore,Studies

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the Leuckart reaction. . Org.

Chem.,9

1944)

29

r\

-536.

C.4.39:

114?6

1945).

(

66

)

HCOOH,Figure 8.

\-/ Leuckart to N-formylamphetamine

ollowed

by LiAlH.

reduction to methamphetamine

O.

Cervinka,

E. Kroupova and O. Belovsky, Asymmetric

Reactions.XIX. Absolute configu-

ration

of

1-phenyl-2-alkylamines

nd

their

N-methyl derivatives.

CoIL Czech.Chem.

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C.A.

?0:37323d.

HCOOH,Figure 8.

Leuckart to amphetamine

O.Y. Magidson and G.A. Garkuska,Synthesisof beta-phenyl-isopropylamine."I. Gen Chem.

(U.S.S.R.),

1

1941)

39-343.C.A.

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58695

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HCOOH,Figure

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Leuckart

to amphetamine

B.R. Bobranskii

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4

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I0-414. C.A.

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67


16/17

198

@

HCOOH, igure8.

Leuckart reaction

o

amphetamine nd

methamphetamine

A.

Ogata,

alpha and beta-Aminoalkyl(aryl)benzenes

nd

their derivatives. J. Phorm.

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Jpn.,

445

1919)

93-216.C.A.

13:1709

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70 HCOOH,

Figure 8.

77

Leuekartmeehanism tudy

M.L. Moore,

The Leuekart eaction.Org. React.,5

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01-330.

C.A.

44:5$c

(f950).

HCOOH,

Figure 8.

Leuckart

mechanism tudy

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Alexander and R.B.

Wildman, Studies on the mechanismof

the Leuckart

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C.A.

42:7263e

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HCOOH,

igure

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Leuekart

mechanism tudy

A. Lukasiewicz,

The mechanism

of

the Leuckart-Wallach

eaction

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the reduction of

Schiff

bases y formic acid.Tetrahedron,19

1963)

?89-1?99.

C.A.60:

1549f

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P-2-Pvia Phenylaceticacid and AcrO

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Phenamine).

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35:

5868s

1941).

P-2-Pvia

phenylacetic

acid and

ead

acetate

M. Tsutsumi,

An illegal

preparation

of an amphetaminelike

compound.

Sci.enceCrirne

Detect.

Japan),6

1953)

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C.A.

E7:11661h

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P-2-P ia

phenylacetic

cid and

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