Process for the asymmetric synthesis of isopiperitenol
The present invention refers to a process for the asymmetric synthesis of isopiperitenol and successor compounds.
1 . A process for the asymmetric synthesis of isopiperitenol of formula (I),
comprising subjecting a substrate containing at least one of Neral [(Z)-3,7-dimethylocta-2,6-dienal] and Geranial [(E)-3,7-dimethylocta-2,6-dienal] to a treatment, optionally in an organic solvent, with a dimeric phosphazene-derived catalyst represented by the following formula (II) whereby a reaction mixture containing isopiperitenol is obtained:
wherein in said formula (II):
R is the same or different on each position and is each selected from hydrogen, halogen, SF 5 , NO 2 , cyano, C 1 to C 20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more halogens, SF 5 , NO 2 or cyano on the aliphatic hydrocarbon, C 6 to C 18 aromatic hydrocarbons or C 5 to C 18 heteroaromatic hydrocarbons, each aromatic or heteroaromatic hydrocarbon optionally being substituted by one or more substituents selected from halogen, SF 5 , NO 2 , cyano, C 1 to C 20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more halogens, SF 5 , NO 2 or cyano on the aliphatic hydrocarbon,
R P is the same or different on each position and has the meaning of R, or two R P on the same aryl ring may form a ring with each other which may be an aromatic ring structure or an aliphatic ring structure, which aromatic ring and/or aliphatic ring structure may be substituted with one or more substituents R,
X and Y are the same or different and are either oxygen or NR N ; wherein:
R N is an electron withdrawing or electron donating group, being the same or different on each position and being selected from:
i. -alkyl, —CO-alkyl, —(CO)—O-alkyl, sulfinyl alkyl, sulfonyl alkyl, sulfonyl iminoalkyl, sulfonyl bisiminoalkyl, phosphinyl dialkyl, phosphonyl alkyl, alkyl phosphorane, N,N′-alkylimidazolidin-2-iminyl wherein alkyl is a C 1 to C 20 straight chain, branched chain or cyclic aliphatic hydrocarbon, optionally having at least one substituent selected from C 1 to C 6 alkoxy, halogen, cyano, nitro, or SF 5 ;
ii. -aryl, —CO-aryl, —(CO)—O-aryl, sulfinyl aryl, sulfonyl aryl, sulfonyl iminoaryl, sulfonyl iminosulfonylaryl, sulfonyl bisiminoaryl, phosphinyl diaryl, phosphinyl alkylaryl, phosphonyl aryl, aryl phosphoranes, aryl alkyl phosphoranes, N,N′-arylimidazolidin-2-iminyl, N-aryl-N′-alkylimidazolidin-2-iminyl wherein aryl is a C 6 to C 18 aromatic hydrocarbon, optionally having at least one substituent selected from C 1 to C 6 alkyl optionally substituted by at least one halogen, C 1 to C 6 alkoxy, halogen, cyano, nitro, or SF 5 ;
iii. -heteroaryl, —CO-heteroaryl, —(CO)—O-heteroaryl, sulfinyl heteroaryl, sulfonyl heteroaryl, -(P=O)-di-heteroaryl, phosphinyl diheteroaryl, phosphinyl arylheteroaryl, phosphinyl heteroaryl alkyl, phosphonyl heteroaryl, heteroaryl phosphoranes, heteroaryl aryl phosphoranes, heteroaryl aryl alkyl phosphoranes, N,N′-heteroarylimidazolidin-2-iminyl, N-heteroaryl-N′-alkylimidazolidin-2-iminyl, N-heteroaryl-N′-arylimidazolidin-2-iminyl wherein heteroaryl is a C 2 to C 18 heteroaromatic hydrocarbon, optionally having at least one substituent selected from C 1 to C 6 alkyl optionally substituted by at least one halogen, C 1 to C 6 alkoxy, halogen, cyano, nitro, or SF 5 ;
and
W is selected from hydrogen, halogen, a metal selected from Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ru, Rh, Pd, Ag, Cd, W, Re, Os, Ir, Pt, Au, Hg, Al, Ga, In, Ge, Sn, Pb, As, Sb, Bi, Se, Te, La, Sm, Eu, Yb, U or a cationic organic group, a substituted borane —BR I R II R III or a substituted silicon —SiR I R II R III , wherein R I , R II and R III may be same or different and each stands for hydrogen, halogen, an optionally —O— bonded C 1 to C 20 straight chain, branched chain or cyclic aliphatic hydrocarbon, optionally having one or more unsaturated bonds or one or more hetero atoms in the chain, a C 5 to C 18 heteroaromatic hydrocarbon, a C 6 to C 18 aromatic hydrocarbon or partially arene-hydrogenated forms thereof, each hydrocarbon optionally being substituted by one or more groups selected from C 1 to C 20 straight chain, branched chain or cyclic aliphatic hydrocarbons, or one or more heterosubstituents.
2 . Process according to claim 1 , wherein the dimeric phosphazene-derived catalyst is represented by the following formula (III):
wherein the substituent R is the same or different on each position and is defined as in claim 1 , X and Y have the meanings as defined in claim 1 and W represents hydrogen, an alkali metal or an earth alkaline metal.
3 . Process according to claim 1 , wherein the dimeric phosphazene-derived catalyst is represented by the following formula (IVa):
wherein the substituent R is the same or different on each position and is defined as in claim 1 , X and Y have the meanings as defined in claim 1 and W represents hydrogen, an alkali metal or an earth alkaline metal.
4 . Process according to claim 1 , wherein the dimeric phosphazene-derived catalyst is represented by the following formula (IVb):
wherein the substituent R is the same or different on each position and is defined as in claim 1 , X and Y have the meanings as defined in claim 1 and W represents hydrogen, an alkali metal or an earth alkaline metal.
5 . Process according to claim 1 , wherein the substituent R is the same or different on each position and represents halogen, a straight chain, branched chain or cyclic C 1 to C 20 aliphatic hydrocarbon or a C 6 to C 18 aromatic hydrocarbon, said aliphatic hydrocarbon and/or aromatic hydrocarbon being substituted by one or more halogens, SF 5 , NO 2 or a straight chain, branched chain or cyclic C 1 to C 20 aliphatic hydrocarbon, being substituted by one or more halogens, SF 5 , NO 2 on the aliphatic hydrocarbon.
6 . Process according to claim 1 , wherein Y is defined as O or NR N and X is defined as NR N , wherein R N is an electron withdrawing or electron donating group, being the same or different on each position and being selected from:
i. sulfinyl alkyl or sulfonyl alkyl, wherein alkyl is a C 1 to C 20 straight chain, branched chain or cyclic aliphatic hydrocarbon, optionally having at least one substituent selected from C 1 to C 6 alkoxy, halogen, cyano, nitro or SF 5 ;
ii. sulfinyl aryl, or sulfonyl aryl, wherein aryl is a C 6 to C 18 aromatic hydrocarbon, optionally having at least one substituent selected from C 1 to C 6 alkyl optionally substituted by at least one halogen, C 1 to C 6 alkoxy, halogen, cyano, nitro or SF 5 ;
iii. sulfinyl heteroaryl, or sulfonyl heteroaryl, wherein heteroaryl is a C 2 to C 18 heteroaromatic hydrocarbon, optionally having at least one substituent selected from C 1 to C 6 alkyl optionally substituted by at least one halogen, C 1 to C 6 alkoxy, halogen, cyano, nitro or SF 5 ; and
wherein R, R P and W have the meanings as defined in claim 1 .
7 . Process according to claim 1 , wherein the substrate comprises a ratio of Neral and Geranial ranging from Neral (Z:E=>99:1) to Geranial (Z:E=<1:99).
8 . Process according to claim 1 , wherein the obtained reaction mixture is additionally subjected to a hydrogenation treatment whereby a reaction mixture containing at least one of menthol, isomenthol, neomenthol and neoisomenthol is obtained.
9 . Process according to claim 1 , wherein the obtained reaction mixture is further reacted with olivetol in the presence of a Lewis or Brønsted acid, whereby a reaction mixture containing THC and/or CBD is obtained.
10 . A process for the asymmetric synthesis of isopiperitenol of formula (I),
wherein a Neral-derivative of the formula (V)
is cyclized in the presence of a dimeric phosphazene-derived catalyst of formula (II):
wherein in said formula (II):
R is the same or different on each position and is each selected from hydrogen, halogen, SF 5 , NO 2 , cyano, C 1 to C 20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more halogens, SF 5 , NO 2 or cyano on the aliphatic hydrocarbon, C 6 to C 18 aromatic hydrocarbons or C 5 to C 18 heteroaromatic hydrocarbons, each aromatic or heteroaromatic hydrocarbon optionally being substituted by one or more substituents selected from halogen, SF 5 , NO 2 , cyano, C 1 to C 20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more halogens, SF 5 , NO 2 or cyano on the aliphatic hydrocarbon,
R P is the same or different on each position and has the meaning of R, or two R P on the same aryl ring may form a ring with each other which may be an aromatic ring structure or an aliphatic ring structure, which aromatic ring and/or aliphatic ring structure may be substituted with one or more substituents R,
X and Y are the same or different and are either oxygen or NR N ; wherein:
R N is an electron withdrawing or electron donating group, being the same or different on each position and being selected from:
i. -alkyl, —CO-alkyl, —(CO)—O-alkyl, sulfinyl alkyl, sulfonyl alkyl, sulfonyl iminoalkyl, sulfonyl bisiminoalkyl, phosphinyl dialkyl, phosphonyl alkyl, alkyl phosphorane, N,N′-alkylimidazolidin-2-iminyl wherein alkyl is a C 1 to C 20 straight chain, branched chain or cyclic aliphatic hydrocarbon, optionally having at least one substituent selected from C 1 to C 6 alkoxy, halogen, cyano, nitro, or SF 5 ;
ii. -aryl, —CO-aryl, —(CO)—O-aryl, sulfinyl aryl, sulfonyl aryl, sulfonyl iminoaryl, sulfonyl iminosulfonylaryl, sulfonyl bisiminoaryl, phosphinyl diaryl, phosphinyl alkylaryl, phosphonyl aryl, aryl phosphoranes, aryl alkyl phosphoranes, N,N′-arylimidazolidin-2-iminyl, N-aryl-N′-alkylimidazolidin-2-iminyl wherein aryl is a C 6 to C 18 aromatic hydrocarbon, optionally having at least one substituent selected from C 1 to C 6 alkyl optionally substituted by at least one halogen, C 1 to C 6 alkoxy, halogen, cyano, nitro, or SF 5 ;
iii. -heteroaryl, —CO-heteroaryl, —(CO)—O-heteroaryl, sulfinyl heteroaryl, sulfonyl heteroaryl, -(P=O)-di-heteroaryl, phosphinyl diheteroaryl, phosphinyl arylheteroaryl, phosphinyl heteroaryl alkyl, phosphonyl heteroaryl, heteroaryl phosphoranes, heteroaryl aryl phosphoranes, heteroaryl aryl alkyl phosphoranes, N,N′-heteroarylimidazolidin-2-iminyl, N-heteroaryl-N′-alkylimidazolidin-2-iminyl, N-heteroaryl-N′-arylimidazolidin-2-iminyl wherein heteroaryl is a C 2 to C 18 heteroaromatic hydrocarbon, optionally having at least one substituent selected from C 1 to C 6 alkyl optionally substituted by at least one halogen, C 1 to C 6 alkoxy, halogen, cyano, nitro, or SF 5 ;
and
W is selected from hydrogen, halogen, a metal selected from Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ru, Rh, Pd, Ag, Cd, W, Re, Os, Ir, Pt, Au, Hg, Al, Ga, In, Ge, Sn, Pb, As, Sb, Bi, Se, Te, La, Sm, Eu, Yb, U or a cationic organic group, a substituted borane —BR I R II R III or a substituted silicon —SiR I R II R III , wherein R I , R II and R III may be same or different and each stands for hydrogen, halogen, an optionally —O— bonded C 1 to C 20 straight chain, branched chain or cyclic aliphatic hydrocarbon, optionally having one or more unsaturated bonds or one or more hetero atoms in the chain, a C 5 to C 18 heteroaromatic hydrocarbon, a C 6 to C 18 aromatic hydrocarbon or partially arene-hydrogenated forms thereof, each hydrocarbon optionally being substituted by one or more groups selected from C 1 to C 20 straight chain, branched chain or cyclic aliphatic hydrocarbons, or one or more heterosubstituents,
and the reaction mixture is further reacted, in the presence of a Lewis or Brønsted acid with a resorcin-derived compound of the formula (VI)
whereby a reaction mixture containing racemic or optically active CBD- and/or THC-derivatives of the general formula (VIIa) and (VIIb) is obtained;
wherein R A is, independently from each other, the same or different and is each hydrogen, a C 1 to C 6 alkyl group, —CH 2 OH, or —COOR e with Re being H or a C 1 to C 6 alkyl group;
R B is, independently from each other, the same or different and is each hydrogen, a C 1 to C 6 alkyl group, or two of R B or two of R C , respectively, may form a ring amongst each other,
R C is, independently from each other, the same or different and is each a C 1 to C 6 alkyl group, or two of R B or two of R C , respectively, may form a ring amongst each other,
R 5 and R 7 are, independently from each other, the same or different and are each hydrogen or —COOR e with Re being H or a C 1 to C 6 alkyl group;
R 6 represents hydroxy, a C 1 to C 12 alkyl group, optionally being further substituted by one or more hydroxyl groups.
11 . A process according to claim 1 , wherein the dimeric phosphazene-derived catalyst, wherein R, R P , Y, X and W are as defined in claim 1 , is bound to a solid support, optionally through a linker;
wherein the linker is an aliphatic, heteroaliphatic, aromatic or heteroaromatic hydrocarbon group, each hydrocarbon group optionally being further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic or heteroaromatic hydrocarbon groups, each hydrocarbon group optionally being substituted by one or more heterosubstituents; and
wherein the solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen, hydroxy, sulfonyl, alkoxy, halogen-substituted alkoxy on the aliphatic hydrocarbon or oxygen in the aliphatic hydrocarbon chain.
12 . A process according to claim 11 , wherein the dimeric phosphazene-derived catalyst is bound to a solid support via a linker between the solid support and an aromatic or cycloaliphatic backbone of the dimeric phosphazene-derived catalyst, Y and X are defined as oxygen or NR N , R N is defined as in claim 1 , R and R P are as defined in claim 1 .
13 . A process according to claim 11 , wherein the dimeric phosphazene-based catalyst is bound to a solid support via linker between an NR N substituent and the solid support, wherein the linker and the solid support are as defined in claim 10 and, in the dimeric phosphazene-derived catalyst Y is oxygen or NR N , X is NR N , R N is a straight or branched alkyl chain or a polyether alkyl chain, said alkyl chain having at least one halogen.