( 1 2 ) United S ta tes Pa tent

Borza tta et a l .
US 006342 61 3B1
( 1 0) Pa tent N 0. :
( 45 ) Da te of Pa tent:
US 6, 342 , 61 3 B1
J a n. 2 9 , 2 002
( 5 4) PROCES S FOR THE S YN THES IS OF
5 - ( ot- HYDROX YA L K YL ) BEN Z O[ 1 , 3]
DIOX OL S
( 7 5 ) Inv entors : V a l erio Borza tta , Bol og na ; Da rio
Bra nc a l eoni, S a s s o M a rc oni, b oth of
( IT)
( 7 3) A s s ig nee: Endu ra S . p . A . , Bol og na ( IT)
ot1 c e: u ec t to a n 1 s c a 1 mer, t e term 0 t is * N ' S b j yd'l ' h f h '
p a tent is ex tended or a dju s ted u nder 35
U. S . C. 1 5 4( b ) b y 0 da ys .
( 2 1 ) A p p l . N 0. : 09 / 8 5 6, 7 5 2
( 2 2 ) PCT Fil ed: Oc t. 1 4, 1 9 9 9
( 8 6) PCT N o. : PCT/ EP9 9 / 07 7 43
37 1 Da te: M a y 2 3, 2 001
1 02 ( e) Da te: M a y 2 3, 2 001
( 8 7 ) PCT Pu b . N o. : WO00/ 405 7 5
PCT Pu b . Da te: J u l . 1 3, 2 000
( 30) Foreig n A p p l ic a tion Priority Da ta
Dec . 30, 1 9 9 8 ( IT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M I9 8 A 2 8 5 7
( 5 1 ) Int. Cl . 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C07 D 31 7 / 5 0
( 5 2 ) US . Cl . . . . . . . . . . . . . . . . . . . . . . . . . 5 49 / 434; 5 49 / 430; 5 49 / 445
( 5 8 ) Fiel d of S ea rc h . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 49 / 430, 434,
5 49 / 445
( 5 6) Ref erenc es Cited
U. S . PA TEN T DOCUM EN TS
5 , 5 1 4, 8 1 6 A * 5 / 1 9 9 6 A c kerma nn et a 1 . . . . . . . . . 5 49 / 2 1 2
5 , 5 2 5 , 7 39 A * 6/ 1 9 9 6 A ndres et a 1 . . . . . . . . . . . . . . . 5 49 / 434
5 , 69 6, 301 A * 1 2 / 1 9 9 7 Ha ra da et a l . . . . . . . . . . . . . . . 5 68 / 7 63
* c ited b y ex a miner
Prima ry Ex a miner Fl oyd D. Hig el
A s s is ta nt Ex a miner Gol a m M . M . S h a meem
( 7 4) A ttorney, A g ent, or Firm A b el ma n, Fra yne &
S c h Wa b
( 5 7 ) A BS TRA CT
Th e p res ent inv ention reg a rds a th ree- s tep p roc es s f or th e
s ynth es is of 5 - ( ot- h ydrox ya l kyl ) b enZ o[ 1 , 3] dioX ol s . Th e p ro
c es s c omp ris es : th e rea c tion of p yroc a tec h in ( 1 , 2
dih ydroX yb enZ ene) With a dih a l o or di- a l kox ya l ka ne, With
th e f orma tion of a b enZ o[ 1 , 3] dioX ol deriv a tiv e; ( ii)
5 - s el ec tiv e c a ta l ytic a c yl a tion of th e b enZ o[ 1 , 3] dioX ol , With
f orma tion of a 5 - a l ka noyl b enZ o[ 1 , 3] diox ol a nd its s u b s e
q u ent ( iii) redu c tion to 5 - ( ot- h ydrox ya l kyl ) b enZ o[ 1 , 3]
dioX ol . A l s o des c rib ed a re neW b enZ odioX ol s ob ta ina b l e
u s ing th e a b ov e- mentioned p roc es s . Th e p roc es s of th e
inv ention is indu s tria l l y s imp l e a nd h a s l oW env ironmenta l
imp a c t; it a l l oWs to ob ta in in h ig h yiel ds deriv a tiv es of
c ons idera b l e interes t, in p a rtic u l a r f or th e p erf u mery
indu s try, a nd in th e s ec tor of ins ec tic ides .
1 4 Cl a ims , N o Dra w ing s
US 6, 342 , 61 3 B1
1
PROCES S FOR THE S YN THES IS OF
S - ( a - HYDROX YA L K YL ) BEN Z O[ 1 , 3]
DIOX OL S
Th is a p p l ic a tion is a 37 1 of PCT/ EP9 9 / 07 7 43 ? l ed Oc t.
1 4, 1 9 9 9 .
FIEL D OF THE IN V EN TION
Th e p res ent inv ention reg a rds th e ? el d of s ynth es is of
b enZ odioX ol s , With p a rtic u l a r in th e p erf u mery indu s try a nd
in th e s ec tor of ins ec tic ides .
PRIOR A RT
V a riou s b iol og ic a l l y a c tiv e na tu ra l s u b s ta nc es , s u c h a s
? a v ones a nd a l ka l oids c onta in th e meth yl ene dioX y- 1 , 2
b enZ ene ( a l s o knoWn a s b enZ o[ 1 , 3] dioX ol ) g rou p . For
ex a mp l e, deriv a tiv es of b enZ o[ 1 , 3] dioX ol a re u s ed in th e
trea tment of l iv er dis orders ( Ch em. A b s tra c ts , 1 9 9 0,
45 2 5 34) .
Th e mos t Wides p rea d a p p l ic a tions of th es e deriv a tiv es
a re, h oWev er, th os e in th e ? el d of p erf u mery, ? a v ou ring , a nd
ins ec tic ides . Comp ou nds h a v ing ins ec tic ida l a c tion c onta in
ing th e b enZ o[ 1 , 3] dioX ol g rou p h a v e b een des c rib ed in
v a riou s p u b l ic a tions ( e. g . , Bu l l . S oc . Ch im. Fra nc e, 1 9 64,
1 8 9 2 1 8 9 5 ) . 5 - ( 2 - p rop enyl ) - b enZ o[ 1 , 3] dioX ol ( s a f rol e) is a
c ons titu ent of ma ny es s entia l oil s a mong Wh ic h oil of
s a s s a f ra s , of Wh ic h it c ons titu tes a p p rox ima tel y 7 5 %.
( Os Wa l d et a l . , Bioc h im. Biop h ys . A c ta 2 30, 2 37 ( 1 9 7 1 ) . ) .
5 - ( 1 - p rop enyl ) - b enZ o[ 1 , 3] dioX c l ( is os a f rol e) , is a n
es s enc e u s ed in p erf u mery a nd a s a deodora nt f or s oa p s ;
is os a f rol e is in tu rn u s ed in th e s ynth es is of p ip erona l
( h el iotrop in, b enZ o[ 1 , 3] dioX ol - 5 - c a rb oX ya l deh yde) , a noth er
es s enc e u s ed indu s tria l l y f or p rodu c ing p erf u mes a nd a ro
ma s .
L ikew is e, a l s o 5 - h ydroX ymeth yl - b enZ o[ 1 , 3] dioX ol
( p ip eronyl a l c oh ol ) a nd its deriv a tiv es a re of c ons idera b l e
indu s tria l interes t in th e s ec tors c ited a b ov e. Th e p res ent
inv ention meets th e need of identif ying ef f ec tiv e meth ods
f or th e s ynth es is of p ip eronyl a l c oh ol a nd its deriv a tiv es .
Th e p rior a rt des c rib es a nu mb er of p roc es s es h a v ing th is
p u rp os e. Th e mos t Widel y u s ed meth od c ons is ts in rea c ting
a n a l deh yde of f ormu l a
0
o
o ( 3%
H
With Grig na rd rea g ents , ( a l kyl ma g nes iu m b romides ) , to
ob ta in b enZ odioX ol deriv a tiv es s u b s titu ted in p os ition 5 With
a n a - h ydroX ya l kyl g rou p ( s ee, f or ex a mp l e, US . Pa t. N o.
39 46040) . Th e s a me c omp ou nds ma y b e ob ta ined s ta rting
f rom 5 - keto- s u b s titu ted deriv a tiv es of b enZ o[ 1 , 3] dioX ol
( DE- A - 2 2 1 037 4) .
Th e a b ov e p roc es s es of s ynth es is , a l b eit u s ef u l f rom th e
a na l ytic a l s ta ndp oint, p res ent s ig ni? c a nt l imita tions a s
reg a rds th eir indu s tria l a p p l ic a b il ity. Th es e rea c tions , in f a c t,
c a l l f or th e a v a il a b il ity of p rodu c ts a l rea dy c onta ining th e
b enZ odioX ol c yc l e: s u c h p rodu c ts a re f a r f rom b eing rea dil y
a v a il a b l e a nd a re v ery c os tl y. In a ddition, Grig na rd rea c tions
a re c a rried ou t With rea g ents a nd a nh ydrou s s ol v ents th a t a re
h ig h l y u ns ta b l e a nd dif ? c u l t to h a ndl e ( e. g . , ma g nes iu m,
eth yl eth er, tetra h ydrof u ra n) , s o enta il ing th e a dop tion of
c os tl y s a f ety p rec a u tions f or th e p rodu c tion p l a nts .
1 0
1 5
2 0
2 5
30
35
40
45
5 0
5 5
60
65
2
S el ec tiv e a c yl a tion, a s a mea ns f or introdu c ing s u b s titu
ents on th e b enZ odioX ol c yc l e, h a s s o f a r p rov ed dif f ic u l t to
a p p l y indu s tria l l y in v ieW of th e l oW yiel ds a nd th e dif ? c u l ty
of p u ri? c a tion of th e a c yl a ted p rodu c t; f or eX a mp l e, in
WOA - 9 639 1 33 th e a c yl a ted b enZ odioX ol Wa s dif f ic u l t to
p u rif y a nd inv ol v ed rep ea ted trea tments of dec ol ou riZ a tion.
Oth er a u th ors h a v e ob ta ined s el ec tiv e a c yl a tion of b enZ o
dioX ol s u s ing c os tl y s ol u tions , s u c h a s p a s s ing th e p rodu c t
ov er a b ed of Z eol ite c a ta l ys ts ( J . Ch em. S oc . Ch em.
Commu n. , 1 9 9 4, 7 1 7 ) . In v ieW of th e l imita tions p ointed ou t,
th e need is f el t f or a n ef f ec tiv e p roc es s f or th e p rodu c tion of
5 - h ydroX ya l kyl b enZ odioX ol s . In p a rtic u l a r, a p roc es s is
s ou g h t Wh ic h is indu s tria l l y a p p l ic a b l e on a Wide s c a l e a nd
Wh ic h ma y b e c a rried ou t With rea c tions th a t a re ea s y to
a p p l y a nd With a l oW env ironmenta l imp a c t. Fina l l y, th e
need is f el t f or a s ynth etic p roc es s th a t u s es a s rea g ents
p rodu c ts Wh ic h a re rea dil y a v a il a b l e a nd of l oW c os t.
S UM M A RY
Th e p res ent inv ention reg a rds a th ree- s tep p roc es s f or th e
s ynth es is of 5 - ( ot- h ydroX ya l kyl ) b enZ o[ 1 , 3] dioX ol s . Th e p ro
c es s c omp ris es : th e rea c tion of p yroc a tec h in ( 1 , 2
dih ydroX yb enZ ene) With a dih a l o or di- a l kox ya l ka ne, With
th e f orma tion of a b enZ o[ 1 , 3] dioX ol deriv a tiv e; ( ii)
5 - s el ec tiv e c a ta l ytic a c yl a tion of th e b enZ o[ 1 , 3] dioX ol
deriv a tiv e, With f orma tion of a 5 - a l ka noyl b enZ o[ 1 , 3] dioX ol
a nd its s u b s eq u ent ( iii) redu c tion to 5 - ( ot- h ydroX ya l kyl )
b enZ o[ 1 , 3] dioX ol . A l s o des c rib ed a re neW b enZ odioX ol s
ob ta ina b l e u s ing th e a b ov e- mentioned p roc es s . Th e p roc es s
of th e inv ention is indu s tria l l y s imp l e a nd h a s l oW env iron
menta l imp a c t; it a l l oWs to ob ta in in h ig h yiel ds deriv a tiv es
of c ons idera b l e interes t, in p a rtic u l a r f or th e p erf u mery
indu s try, a nd in th e s ec tor of ins ec tic ides .
DETA IL ED DES CRIPTION OF THE
IN V EN TION
Th e s u b jec t of th e p res ent inv ention is a neW p roc es s f or
th e s ynth es is of 5 - ( ot- h ydroX ya l kyl ) b enZ o[ 1 , 3] dioX ol s . Th e
p roc es s c omp ris es th e f ol l oWing s tep s :
a ) rea c ting 1 , 2 - dih ydroX yb enZ ene ( p yroc a tec h in) ( I) in a
dip ol a r a p rotic s ol v ent, a t a temp era tu re c omp ris ed
b etWeen 7 0 C. a nd 1 9 0 C. , With a c omp ou nd of
f ormu l a ( II) , Wh ere R1 is c h os en f rom H, a nd a C1 C3
l inea r or b ra nc h ed a l kyl , a nd X is c h os en f rom c h l orine,
? u orine, b romine, iodine, a nd a C1 C5 l inea r or
b ra nc h ed a l koX y, ob ta ining th e p rodu c t of f ormu l a ( Il l ) ,
Wh ere R1 h a s th e mea ning s des c rib ed a b ov e.
OH O'CH
OH + CHX 2 > 0
R1
( 1 1 )
( I) ( III)
b ) Rea c ting th e c omp ou nd ( III) With a n a l ip h a tic a nh y
dride of f ormu l a ( IV ) or With a n a l ip h a tic a c id of
f ormu l a ( V ) , Wh ere R2 is a C1 C1 9 l inea r or b ra nc h ed
a l kyl , in th e p res enc e of a n a c yl a tion c a ta l ys t, ob ta ining
a c omp ou nd of f ormu l a ( V I) , Wh ere R1 a nd R2 h a v e th e
a f ores a id mea ning s .
US 6, 342 , 61 3 B1
( IV )
R2 COOH
( V )
( III)
c ) Redu c ing of th e c omp ou nd ( V I) , ob ta ining th e 5 - ( ot
h ydrox ya l kyl ) b enZ o[ 1 , 3] diox ol of f ormu l a ( V II)
R1 R1
/ /
O/ CH O/ CH
\ \
O , 0
To ( | : H OH
R2 R2
( V I) ( V II)
Rea c tion a ) is c a rried ou t in dip ol a r a p rotic s ol v ents . Pre
f erred s ol v ents of th is typ e a re N , N - dimeth yl f orma mide,
N , N - dimeth yl a c eta mide a nd dimeth yl s u l p h ox ide. Th e tem
p era tu re of th e rea c tion is th a t of re? u x of th e rea c tion
mix tu re, a nd is g enera l l y b etWeen 7 0 C. a nd 1 9 0 C. In th e
c a s e Wh ere N , N - dimeth yl f orma mide is u s ed a s rea c tion
s ol v ent, th is temp era tu re is g enera l l y b etWeen 1 1 0 C. a nd
1 5 0 C. , or more p ref era b l y b etWeen 1 1 0 C. a nd 1 30 C.
Rea c tion a ) ma y b e c a rried ou t in th e p res enc e of a n iodine
s a l t. In th is c a s e, th e s a l t is p ref era b l y c h os en f rom a mong
L il , N a l , K I, Ca l 2 .
Th e c h oic e of th e rea g ent of f ormu l a ( II) to b e u s ed in
rea c tion a ) / dep ends u p on th e na tu re of th e ? na l p rodu c t
( V II) th a t is to b e s ynth es iZ ed: if th e a im is to ob ta in
b enZ o[ 1 , 3] diox ol s not s u b s titu ted in p os ition 2 , rea g ents of
f ormu l a ( II) Wil l b e c h os en in Wh ic h R1 =H . Ex a mp l es of
s u c h p rodu c ts a re meth yl ene c h l oride a nd
dimeth ox ymeth a ne. If th e a im is to ob ta in b enZ o[ 1 , 3] diox ol s
a l kyl - s u b s titu ted in p os ition 2 , th e rea g ent of f ormu l a ( II)
Wil l b e c h os en in Wh ic h R1 is th e s a me a s th e a l kyl ra dic a l
th a t it is intended to introdu c e on th e b enZ odiox ol ring .
A p p rop ria te R1 ra dic a l s a re meth yl , eth yl , n- p rop yl , a nd
is op rop yl .
A s h a s b een s een a b ov e, th e rea g ent of f ormu l a ( II)
c onta ins tWo X =h a l og en g rou p s or el s e tWo X =C1 C5
a l kox y g rou p s , eith er l inea r or b ra nc h ed. If deriv a tiv es of
f ormu l a ( II) a re u s ed, Wh ere X =h a l og en, rea c tion a ) is
c a rried ou t in th e p res enc e of a n inorg a nic b a s e, p ref era b l y
c h os en f rom a mong N a OH, K OH, N a 2 CO3, a nd K 2 CO3.
Th e inorg a nic b a s es of a s ol id na tu re ( e. g . , c a rb ona tes ) a re
p ref era b l y a dded to th e rea c tion mix tu re in a ? nel y g rou nd
f orm.
In th e c a s e Wh ere deriv a tiv es of f ormu l a ( II) a re u s ed,
Wh ere X =C1 C5 l inea r or b ra nc h ed a l kox y, rea c tion a ) is
c a rried ou t in th e p res enc e of a tra ns es teri? c a tion c a ta l ys t,
p ref era b l y c h os en f rom a mong CH3ON a , CZ HS ON a ,
( C4H9 ) 2 S nO, a nd Ti ( OC4H9 ) 4.
1 0
2 0
2 5
30
35
40
45
5 0
5 5
60
65
4
V a riou s Wa ys of mix ing th e a f ores a id rea g ents a re p os
s ib l e.
In a p ref erred emb odiment, rea c tion a ) is c a rried ou t a s
f ol l oWs : Comp ou nd ( II) is mix ed With th e dip ol a r a p rotic
s ol v ent a nd With th e inorg a nic b a s e ( or tra ns es teri? c a tion
c a ta l ys t) . To th e res u l ting mix tu re, h ea ted u p to th e re? u x
temp era tu re, p yroc a tec h in is th en a dded. Th is a ddition is
p ref era b l y ma de b y drip p ing a l iq u id mix tu re ob ta ined b y
mix ing p yroc a tec h in, deriv a tiv e ( II) a nd dip ol a r a p rotic
s ol v ent.
Th e mix tu re th u s ob ta ined is h ea ted u p to re? u x f or a
p eriod of b etWeen 1 a nd 3 h ou rs , th u s termina ting th e
rea c tion. Th e ? na l p rodu c t ( III) is s ep a ra ted f rom th e rea c
tion s ol v ent a nd f rom th e non- rea c ted deriv a tiv e ( II) b y
mea ns of f ra c tiona ted dis til l a tion or dis til l a tion in a v a p ou r
s trea m.
Th e rea g ents a re p ref era b l y u s ed in th e f ol l oWing mol a r
p rop ortions : p yroc a tec h in : inorg a nic b a s e : c omp ou nd ( II) =
1 : 1 : 2 , th e s a id p rop ortion of c omp ou nd ( II) b eing p ref era b l y
s h a red b etWeen th e initia l mix tu re a nd th e one drip p ed
Wh ic h c onta ins th e p yroc a tec h in.
Th e rea c tion des c rib ed a b ov e l ea ds to th e p rodu c ts of
f ormu l a ( III) With yiel ds of more th a n 9 0%, typ ic a l l y of
a rou nd 9 5 %.
Th e a c yl a tion rea c tion b ) l ea ds to th e f orma tion of th e
5 - a l ka noyl b enZ o[ 1 , 3] diox ol s of f ormu l a ( V I) . Th is rea c tion
inv ol v es th e a dop tion of a p p rop ria te a c ids or a nh ydrides a s
a c yl a ting a g ents , a nd is c a ta l ys ed p ref era b l y b y a c omp ou nd
c h os en f rom a mong Z nO, Z nCl 2 , FeCl 2 , FeCl 3, FeS O4,
Fe2 ( S O4) 3, FeO, Fe2 O3, H3PO4, HCl O4, a nd p ol yp h os p h oric
a c id. Th e p a rtic u l a rl y p ref erred c a ta l ys t f or th is rea c tion is
p erc h l oric a c id ( HCl O4) . Op tiona l l y th e rea c tion ta kes p l a c e
in th e p res enc e of inert s ol v ents ; ex a mp l es of s u c h s ol v ents
a re c yc l oh ex a ne, meth yl c yc l oh ex a ne, dec a l in,
dic h l oroeth a ne, a nd tetra c h l oroeth a ne.
In th e c a s e Wh ere th e a c id ( V ) is u s ed a s a c yl a ting a g ent,
th e b enZ odiox ol / a c id ( V ) mol a r ra tio u s ed ra ng es b etWeen
5 : 1 a nd 05 : 1 , a nd is p ref era b l y 1 : 1 . In th e c a s e Wh ere th e
a nh ydride ( IV ) is u s ed a s a c yl a ting a g ent, th e b enZ odiox ol /
a nh ydride ( IV ) mol a r ra tio ra ng es b etWeen 3: 1 a nd 1 : 1 , a nd
is p ref era b l y 2 : 1 .
Th e rea c tion temp era tu re is b etWeen 0 C. a nd th e b oil ing
p oint of th e mos t l oW- b oil ing c omp onent of th e rea c tion
mix tu re.
V a riou s Wa ys of mix ing th e a f ores a id rea g ents a re p os
s ib l e. In a p ref erred emb odiment, th e b enZ o[ 1 , 3] diox ol ( III)
is mix ed With th e a c yl a tion c a ta l ys t, a nd to th e mix tu re th e
a c id or a nh ydride c h os en f or th e rea c tion is th en a dded
s l oWl y.
Th e rea c tion is c omp l eted in a p eriod of b etWeen 1 a nd 7
h ou rs . Th e 5 - a l ka noyl b enZ o[ 1 , 3] diox ol ( V I) is ob ta ined
f rom th e rea c tion mix tu re b y ex tra c tion With org a nic s ol v ent,
p ref era b l y meth yl ene c h l oride, a nd b y s u b s eq u ent f ra c tion
a ted dis til l a tion of th e org a nic p h a s e.
In a p ref erred emb odiment, th e rea c tion mix tu re ob ta ined
a t th e end of s tep b ) u nderg oes rec yc l ing : th is p roc es s is
c a rried ou t b y a dding to th e ex h a u s ted mix tu re a f res h
a mou nt of th e a c yl a tion c a ta l ys t p rev iou s l y u s ed a nd a
f u rth er a mou nt of th e a c yl a ting a g ent of f ormu l a ( IV ) or ( V ) ;
p os s ib l y, b u t not nec es s a ril y, a f u rth er a mou nt of b enZ o[ 1 ,
3] diox ol of f ormu l a ( III) ma y b e a dded; th es e a dditions a re
ma de p ref era b l y keep ing th e mol a r ra tio of b enZ odiox ol a nd
a c yl a ting a g ent With in th e ra ng e of v a l u es indic a ted a b ov e.
Th e mix tu re th u s enric h ed is th en l ef t to rea c t in th e s a me
rea c tion c onditions ( times a nd temp era tu re) a s th os e of th e
? rs t c yc l e. Th e s a id rec yc l ing op era tion ma y b e c a rried ou t
onc e or a nu mb er of times .
US 6, 342 , 61 3 B1
5
In s tep c ) , th e 5 - a l ka noyl b enZ o[ 1 , 3] diox ol ( V I) is redu c ed
to 5 - ( ot- h ydrox ya l kyl ) b enZ o[ 1 , 3] diox ol ( V II) . In g enera l ,
a ny redu c tion rea c tion ma y b e u s ed in th is s tep . For
ex a mp l e, it is p os s ib l e to u s e h ydrog en in th e p res enc e of
c a ta l ys ts s u c h a s p a l l a diu m, p l a tinu m or ru th eniu m. Th e
c a ta l ys t ma y b e on a n inert ma trix s u b s tra te: ex a mp l es of
s u c h s ys tems a re Pd on c a rb on, Pt on c a rb on, Ru on c a rb on,
Pd on a l u mina , a nd Pd on b a riu m s u l p h a te. A mong th e oth er
redu c tion rea g ents it is p os s ib l e to mention PtO2 , PtO,
N i- Ra ney, N a BH4, a nd L iA IH4.
Th e rea c tion c onditions ( times , temp era tu re, p res s u re)
a nd th e p rop ortions of th e rea g ents a re th os e c ommonl y u s ed
in th e s ta te of th e a rt f or th es e typ es of rea c tions . For
ex a mp l e, in th e c a s e Wh ere g a s eou s h ydrog en on c a ta l ys t is
u s ed, th e op era ting temp era tu re is p ref era b l y b etWeen 2 0 C.
a nd 1 00 C. , With a p res s u re of b etWeen 1 b a r a nd 60 b a r,
p os s ib l y in th e p res enc e of a n a p p rop ria te s ol v ent s u c h a s
meth a nol , eth a nol , p rop a nol , is op rop a nol , a nd b u ta nol .
Th e p roc es s des c rib ed in th e p res ent inv ention rep res ents
th e ? rs t ex a mp l e of s ynth es is of 5 - ( ot- h ydrox ya l kyl ) b enZ o
[ 1 , 3] diox ol s , s ta rting f rom a non- h eteroc yc l ic rea g ent th a t is
rea dil y a v a il a b l e a nd h a s a l oW c os t ( p yroc a tec h in) . Th e h ig h
yiel d ob ta ina b l e in th e th ree s tep s of th e rea c tion des c rib ed
a b ov e ena b l es l a rg e q u a ntities of ? na l p rodu c t to b e
ob ta ined.
Rea c tion s tep a ) moreov er ena b l es 2 - a l kyl - s u b s titu ted
b enZ o[ 1 , 3] diox ol s to b e ob ta ined, With ou t res orting to a
s ep a ra te a l kyl a tion s tep in p os ition 2 .
Th e 2 - a l kyl - s u b s titu ted p rodu c ts ob ta ina b l e b y mea ns of
th e p roc es s des c rib ed a b ov e a re neW a nd a s s u c h c ons titu te
a f u rth er a s p ec t of th e p res ent inv ention.
Th es e c omp ou nds h a v e th e f ormu l a of s tru c tu re ( V III) :
R2
Wh ere R1 is c h os en f rom a mong C1 C3 l inea r or b ra nc h ed
a l kyl , a nd R2 is a C1 C1 9 a l kyl , eith er l inea r or b ra nc h ed
a l kyl .
A p ref erred g rou p of p rodu c ts of f ormu l a V III is th e one
in Wh ic h R1 rep res ents meth yl , eth yl , n- p rop yl , a nd is op ro
p yl
Th e deriv a tiv es of f ormu l a ( V II) , irres p ec tiv e of Wh eth er
th ey a re s u b s titu ted or not in p os ition 2 on th e b enZ o[ 1 , 3]
diox ol ring , in a ddition to b eing of interes t on th eir oWn
a c c ou nt a s es s enc es a nd a roma s , a re a l s o u s a b l e a s rea g ents
in th e p rep a ra tion of s imil a r deriv a tiv es , a nd a re of p a rtic u l a r
interes t f or th e p erf u mery indu s try or in th e p rodu c tion of
ins ec tic ides . Th e p ref erred ex a mp l e of th es e c omp ou nds is
rep res ented b y th e 5 - a l kyl b enZ o[ 1 , 3] diox ol s , a nd in p a rtic u
l a r b y 5 - p rop yl b enZ o[ 1 , 3] diox ol ( dih ydros a f rol e) . Th e
p res ent inv ention th u s inc l u des a l s o th e p rep a ra tion of th es e
p rodu c ts , Wh ic h a re ob ta ined b y s u b jec ting th e deriv a tiv es of
f ormu l a ( V II) , p rev iou s l y ob ta ined b y mea ns of s tep c ) , to a
f u rth er redu c tion. Th e 5 - a l kyl b enZ o[ 1 , 3] diox ol s ma y a l s o b e
ob ta ined direc tl y With a s ing l e redu c tion rea c tion s ta rting
f rom th e c omp ou nds of f ormu l a ( V I) . Proc eeding in th is
1 0
1 5
2 0
2 5
30
35
40
45
5 0
5 5
60
65
6
Wa y, th e deriv a tiv es of f ormu l a ( V II) a re f ormed a s
intermedia tes , b u t a re not is ol a ted: in th is c a s e it is p ref er
a b l e to u s e, a s redu c tion c a ta l ys ts , meta l s on a n inert
s u b s tra te, s u c h a s Pd/ C, Pt/ C, a nd Pd/ Ba S O4.
5 - ( 1 - p rop enyl ) - b enZ o[ 1 , 3] diox ol , ( is os a f rol e) is a noth er
ex a mp l e of a deriv a tiv e ob ta ina b l e th rou g h th e p roc es s th a t
f orms th e s u b jec t of th e p res ent inv ention. In th is c a s e, th e
5 - h ydrox ya l kyl b enZ o[ 1 , 3] diox ol s of f ormu l a V II) ob ta ined
in s tep c ) u nderg o deh ydra tion rea c tions . S u c h deh ydra tion
rea c tions , Wh ic h a re in th ems el v es knoWn in th e l itera tu re,
ma y b e c a rried ou t in th e p res enc e of a s u ita b l e s ol v ent, s u c h
a s b enZ ene, tol u ene, x yl ene, mes ith yl ene, dic h l oroeth a ne,
a nd tetra c h l oroeth a ne, in th e p res enc e of a n org a nic or
inorg a nic a c id, s u c h a s , f or ex a mp l e, nitric a c id, s u l p h u ric
a c id, h ydroc h l oric a c id, p erc h l oric a c id, a c etic a c id, tri? u o
roa c etic a c id, b enZ enes u l p h onic a c id, a nd
p - tol u enes u l p h onic a c id a t th e b oil ing temp era tu re of th e
s ol v ent, a nd b y remov ing th e rea c tion Wa ter b y mea ns of
a Z eotrop a tion.
5 - ( 1 - p rop enyl ) - b enZ o[ 1 , 3] diox ol is in tu rn c onv ertib l e
into p ip erona l , or el s e, b y mea ns of a f u rth er redu c tion
rea c tion, into 5 - p rop yl b enZ o[ 1 , 3] diox ol ( dih ydros a f rol e) .
Th e inv ention in q u es tion is il l u s tra ted in th e s eq u el b y th e
f ol l oWing non- l imiting ex a mp l es .
EX PERIM EN TA L PA RT
1 . Prep a ra tion of b enZ o[ 1 , 3] diox ol
To a mix tu re of 1 04 g ( 0. 7 5 mol ) of p ota s s iu m c a rb ona te
? nel y g rou nd in 440 ml of N , N - dimeth yl f orma mide Were
a dded 45 ml ( 0. 7 mol ) of meth yl ene c h l oride, a nd th e
mix tu re th u s ob ta ined Wa s h ea ted u p to th e re? u x temp era
tu re ( 1 2 8 1 30 C. ) . Th en a s ol u tion of 7 5 g ( 0. 68 mol ) of
p yroc a tec h in dis s ol v ed in 1 1 0 ml of N , N
dimeth yl f orma mide a nd 45 ml ( 0. 7 mol ) of meth yl ene
c h l oride Wa s a dded drop b y drop .
A t th e end of drip p ing , th e mix tu re Wa s h ea ted u p to re? u x
f or a f u rth er 2 h ou rs , c ool ed a nd th en ? l tered. Th e s ol u tion
th u s ob ta ined Wa s dis til l ed a t room p res s u re, a nd 42 ml of
dic h l orometh a ne Were c ol l ec ted ( 40 41 C. ) . To th is Wa s
s u b s eq u entl y a dded, a t p ortions of 5 0 ml ea c h , 400 ml of
Wa ter, dis til l ing a t 9 8 1 00 C. a n a Z eotrop e c ons is ting of
b enZ o[ 1 , 3] diox ol a nd Wa ter, a nd, ? na l l y dis til l ing th e N , N
dimeth yl f orma mide a t 1 5 2 1 5 3 C.
From th e mix tu re of b enZ o[ 1 , 3] diox ol a nd Wa ter Wa s
s ep a ra ted th e p rodu c t, a nd th e a q u eou s p h a s e Wa s a dded
With a s a tu ra ted s ol u tion of s odiu m c h l oride, f ol l oWed b y
tWo ex tra c tions With 60 ml of dic h l orometh a ne.
Th e p rodu c t a nd th e org a nic s ol u tion Were reu nited,
ev a p ora ted a t 2 5 C. / 2 0 mb a r, ob ta ining 7 8 g of b enZ o[ 1 , 3]
diox ol .
2 . Prep a ra tion of 5 - p rop a noyl b enZ o[ 1 , 3] diox ol
To a mix tu re of 7 3. 2 g ( 0. 6 mol ) of b enZ o[ 1 , 3] diox ol a nd
1 ml of 7 0% p erc h l oric a c id, c ool ed to 0 5 C. , Were s l oWl y
a dded 38 . 1 ml ( 0. 3 mol ) of p rop ionic a nh ydride, keep ing th e
temp era tu re a t 0 5 C. du ring th e a ddition.
Onc e th e a ddition Wa s c omp l ete, th e mix tu re Wa s l ef t
u nder s tirring f or a f u rth er 3 h ou rs , a l l oWing th e temp era tu re
to ris e to room temp era tu re. Th e mix tu re Wa s dil u ted With 5 0
ml of dic h l orometh a ne a nd 5 0 ml of Wa ter, s tirred f or h a l f a n
h ou r, a nd th e org a nic p h a s e Wa s th en s ep a ra ted. Th e org a nic
p h a s e Wa s Wa s h ed With 30 ml of s odiu m h ydrox ide 2 M
a q u eou s s ol u tion a nd With Wa ter, a nd, ? na l l y dried on
s odiu m s u l p h a te.
Th e org a nic p h a s e Wa s dis til l ed a t room p res s u re, c ol l ec t
ing th e dic h l orometh a ne a t 40 41 C. , dis til l ing th e b enZ o
US 6, 342 , 61 3 B1
7
[ 1 , 3] diox ol th a t h a d not rea c ted ( 44 g ) a t 5 5 C. / 1 . 3 mb a r
a nd, ? na l l y, th e p rodu c t ( 34. 5 g ) a t 1 2 5 1 30 C. / 1 . 3 mb a r.
To th e rea c tion mix tu re c onta ining th e 44 g of non- rea c ted
b enZ o[ 1 , 3] diox ol Were a dded 2 9 . 2 g ( 0. 2 4 mol ) of b enZ o
[ 1 . 3] diox ol a nd 1 ml of 7 0% p erc h l oric a c id. To th e res u l ting
mix tu re, c ool ed to 0 5 C. , Wa s a dded 38 . 1 ml ( 0. 3 mol ) of
p rop ionic a nh ydride. Us ing th e meth od des c rib ed in th e
p rev iou s p a ra g ra p h , 44 g of non- rea c ted b enZ o[ 1 , 3] diox ol
a nd 34. 5 g of th e des ired p rodu c t Were is ol a ted.
3. Prep a ra tion of 5 - ( ot- h ydrox yp rop yl ) b enZ o[ 1 , 3]
diox ol
Into a 2 5 0- ml mu l tip l e- nec ked ? a s k Were introdu c ed,
u nder nitrog en ? oW, 30 g of 5 - p rop a noyl b enZ o[ 1 , 3] diox ol
( 0. 2 68 mol ) dis s ol v ed in 1 00 ml of meth a nol . A t 2 5 C. , 7
g of N a BH4 ( 0. 1 8 5 mol ) dis s ol v ed in 5 0 ml of meth a nol
Were drip p ed in 2 0 minu tes ; th en th e rea c tion mix tu re Wa s
b rou g h t to re? u x . A f ter 2 h ou rs th e mix tu re Wa s c ool ed, th e
meth a nol Wa s remov ed a t redu c ed p res s u re, a nd th e mix tu re
Wa s dil u ted With 1 00 ml of HCl 2 M a nd ex tra c ted tWic e With
CHZ CIZ . Th e reu nited org a nic p h a s es Were Wa s h ed With 1 00
ml of H2 0 a nd c onc entra ted a t redu c ed p res s u re to ob ta in
30. 07 g of dens e, c l ea r oil , th e a na l ys is of Wh ic h GC, M S ,
N M R ( 1 H, 1 3C, DEPT) Wa s in c onf ormity With th e des ired
p rodu c t. A l terna tiv el y, 5 - ( ot- h ydrox yp rop yl ) b enZ o[ 1 , 3]
diox ol Wa s p rep a red a s f ol l oWs : Into a 1 - l itre a u toc l a v e, 30
g of 5 - p rop a noyl b enZ o[ 1 , 3] diox ol ( 0. 1 68 mol ) dis s ol v ed in
1 5 0 ml of is op rop a nol a nd 1 g of Ru / C 5 % Were p ou red. Th e
a u toc l a v e Wa s c l os ed, rendered inert With nitrog en, a nd
b rou g h t to th e p res s u re of 1 b a r With H2 u nder s tirring . Th e
mix tu re Wa s l ef t u nder s tirring With H2 p res s u re c ons ta nt a t
1 b a r f or 1 h ou r; th en it Wa s Wa s h ed With N 2 a nd ? l tered. By
ev a p ora tion of th e s ol v ent a t redu c ed p res s u re, 30 g of a
dens e oil Were ob ta ined, th e a na l ys is of Wh ic h GC, M S ,
N M R ( 1 H, 1 3C, DEPT) Wa s in c onf ormity With th e des ired
p rodu c t.
Prep a ra tion of 5 - p rop yl b enZ o[ 1 , 3] diox ol
( dih ydros a f rol e)
34. 5 g of 5 - p rop a noyl b enZ o[ 1 , 3] diox ol ( 0. 1 9 mol ) Were
dis s ol v ed in 1 00 ml of is op rop a nol , a nd 2 g of 5 0% Wet Pd/ C
5 % Were a dded.
Th e mix tu re Wa s p u t into a n a u toc l a v e a nd h ydrog ena ted
a t a p res s u re of 4 b a r a nd a temp era tu re of 40 C.
Th e mix tu re Wa s ? l tered, a nd ev a p ora ted a t 40 C. / 2 0
mb a r, to ob ta in a n oil ( 31 g ) , Wh ic h Wa s dis til l ed a t 1 08 1 09
C. / 1 8 mb a r, th e a na l ys is of Wh ic h GC, M S , N M R ( 1 H, 1 3C,
DEPT) Wa s in c onf ormity With th e des ired p rodu c t.
5 . Prep a ra tion of 5 - [ ( E) 1 - p rop enyl ] - 1 , 3
b enZ odiox ol
Into a 1 00- ml mu l tip l e- nec ked ? a s k Were introdu c ed 5 g
of 5 - ( ot- h ydrox yeth yl ) b enZ o[ 1 , 3] diox ol ( 2 7 mmol ) dis
s ol v ed in 5 0 ml of tol u ene a nd a c rys ta l of
p - tol u enes u l p h onic a c id. Th e rea c tion mix tu re Wa s b rou g h t
to re? u x , a nd th e Wa ter f ormed b y th e rea c tion Wa s c ol l ec ted
b y a Z eotrop a tion. A f ter 2 h ou rs , 1 0 ml of N a OH 2 M Were
a dded to th e c ool ed mix tu re, a nd th e mix tu re Wa s l ef t u nder
s tirring f or 1 5 minu tes . Onc e th e tWo p h a s es h a d b een
s ep a ra ted, th e org a nic p h a s e Wa s c onc entra ted a t redu c ed
p res s u re ob ta ining a yel l oW oil , Wh ic h Wa s p u ri? ed b y
dis til l a tion ( 9 0 C. , 1 mmHg ) .
4. 1 g of c l ea r, yel l oWis h oil Were ob ta ined, th e a na l ys is of
Wh ic h GC, M S , N M R, ( 1 H, 1 3C, DEPT) Wa s in c onf or
mity With th e des ired p rodu c t.
1 0
1 5
2 0
2 5
30
35
40
45
5 0
5 5
60
65
8
Wh a t is c l a imed is :
1 . A p roc es s f or th e s ynth es is of 5 - ( ot- h ydrox ya l kyl ) b enZ o
[ 1 , 3] diox ol s , c omp ris ing th e f ol l oWing s tep s :
a ) rea c ting th e 1 , 2 - dih ydrox yb enZ ene ( p yroc a tec h in) ( I) in
a dip ol a r a p rotic s ol v ent a t a temp era tu re of b etWeen
7 0 C. a nd 1 9 0 C. , With a c omp ou nd of f ormu l a ( II) ,
Wh ere R1 is c h os en f rom H, a C1 C3, l inea r or b ra nc h ed
a l kyl , a nd X is c h os en f rom c h l orine, ? u orine, b romine,
iodine, a nd a C1 C5 l inea r or b ra nc h ed a l kox y, ob ta in
ing th e p rodu c t of f ormu l a ( III) , Wh ere R1 h a s th e
mea ning s des c rib ed a b ov e,
( H)
( I) ( III)
b ) rea c ting th e c omp ou nd ( III) With a n a l ip h a tic a nh ydride
of f ormu l a ( IV ) or With a n a l ip h a tic a c id of f ormu l a
( V ) , Wh ere R2 is a C1 C1 9 l inea r or b ra nc h ed a l kyl , in
th e p res enc e of a n a c yl a tion c a ta l ys t, ob ta ining a c om
p ou nd of f ormu l a ( V I) , Wh ere R1 a nd R2 h a v e th e
a f ores a id mea ning s ,
( IV )
R2 COOH
( V )
( III)
c ) redu c ing c omp ou nd ( V I) , ob ta ining th e 5 - ( ot
h ydrox ya l kyl ) b enZ o[ 1 , 3] diox ol of f ormu l a ( V II)
R1 R1
/ /
o c g o c g
O , 0
To CH OH .
R2 R2
( V I) ( V II)
2 . Th e p roc es s a c c ording to c l a im 1 , Wh erein th e dip ol a r
a p rotic s ol v ent u s ed in rea c tion a ) is c h os en f rom N , N
dieth yl f orma mide, N , N - dimeth yl a c eta mide, a nd dimeth yl
s u l p h ox ide.
3. Th e p roc es s a c c ording to c l a im 1 , Wh erein rea c tion a )
is c a rried ou t in th e p res enc e of a n iodine s a l t.
4. Th e p roc es s a c c ording to c l a im 1 , Wh erein th e rea c tion
b ) is c a ta l ys ed b y a c omp ou nd c h os en f rom HCl O4, Z nO,
Z nCl 2 , FeCl 2 , FeCl 3, FeS O4, Fe2 ( S O4) 3, FeO, Fe2 O3,
H3PO4, a nd p ol yp h os p h oric a c id.
US 6, 342 , 61 3 B1
9
5 . Th e p roc es s a c c ording to c l a im 1 , w h erein rea c tion b )
ta kes p l a c e in th e p res enc e of inert s ol v ents .
6. Th e p roc es s a c c ording to c l a im 1 , Wh erein rea c tion b )
th e b enZ odioX ol / a c id ( V ) mol a r ra tio is b etWeen 5 : 1 a nd
0. 5 : 1 .
7 . Th e p roc es s a c c ording to c l a im 1 , Wh erein rea c tion b )
th e b enZ odioX ol / a nh ydride ( IV ) mol a r ra tio is b etWeen 3: 1
a nd 1 : 1 .
8 . Th e p roc es s a c c ording to c l a im 1 , Wh erein th e rea c tion
mix tu re res u l ting f rom rea c tion b ) u nderg oes rec yc l ing .
9 . Th e p roc es s a c c ording to c l a im 1 , Wh erein th e deriv a
tiv e of f ormu l a ( V II) is s u b jec ted to f u rth er redu c tion, With
th e f orma tion of a 5 - a l kyl b enZ o[ 1 , 3] dioX ol .
1 0. Th e p roc es s a c c ording to c l a im 9 , Wh erein th e deriv a
tiv e of f ormu l a ( V II) is 5 - ( ot- h ydroX yp rop yl ) b enZ o[ 1 , 3]
dioX ol , a nd th e s a id 5 - a l kyl b enZ o[ 1 , 3] dioX ol is
5 - p rop yl b enZ o[ 1 , 3] dioX ol ( dih ydros a f rol e) .
1 1 . Th e p roc es s a c c ording to c l a im 1 , Wh erein th e deriv a
tiv e of f ormu l a ( V II) is f u rth er s u b jec ted to deh ydra tion,
With th e f orma tion of a 5 - ( 1 - a l kenyl ) b enZ o[ 1 , 3] dioX ol .
1 2 . Th e p roc es s a c c ording to c l a im 1 1 , Wh erein th e
deriv a tiv e of f ormu l a ( V II) is 5 - ( ot- h ydroX yp rop yl ) b enZ o[ 1 ,
3] dioX ol a nd th e s a id 5 - ( 1 - a l kenyl ) b enZ o[ 1 , 3] dioX ol is 5 - ( 1
p rop enyl ) b enZ o[ 1 , 3] dioX ol ( is os a f rol e) .
1 5
1 0
1 3. Th e c omp ou nds of f ormu l a ( V III)
( V III)
R2
Wh ere R1 is c h os en f rom C1 C3 l inea r or b ra nc h ed a l kyl , a nd
R2 is a C1 C1 9 l inea r or b ra nc h ed a l kyl .
1 4. Th e c omp ou nds a c c ording to c l a im 1 3, Wh ere R1
rep res ents meth yl , eth yl , n- p rop yl , or is op rop yl .