Process for preparing enantiomerically and diastereomerically enriched cyclobutaneamines and cyclobutaneamides
阅读说明：本技术 用于制备富含对映异构体和非对映异构体的环丁烷胺和环丁烷酰胺的方法 (Process for preparing enantiomerically and diastereomerically enriched cyclobutaneamines and cyclobutaneamides ) 是由 R·杜梅尼尔 T·斯梅杰卡尔 B·P·米施拉 V·R·格帕尔萨慕斯拉姆 E·戈迪诺 A·C 于 2018-11-14 设计创作，主要内容包括：本发明涉及一种用于制备富含对映异构体和非对映异构体的环丁烷胺和环丁烷酰胺的方法,所述方法通过使(a)环丙基腈反应成环丙基醛,(b)进一步反应成环丁酮,或(d’)进一步反应成烯胺,(c)进一步反应成富含对映异构体和非对映异构体的环丁烷胺或(d)进一步反应成烯胺和(e)富含对映异构体和非对映异构体的环丁基酰胺以获得(f)富含对映异构体和非对映异构体的环丁烷胺,并且(g)进一步反应成富含对映异构体和非对映异构体的环丁烷酰胺。(The present invention relates to a process for the preparation of enantiomerically and diastereomerically enriched cyclobutaneamines and cyclobutaneamides by reacting (a) cyclopropanecarbonitrile to cyclopropylaldehyde, (b) further to cyclobutanone, or (d') further to enamine, (c) further to enantiomerically and diastereomerically enriched cyclobutaneamine or (d) further to enamine and (e) enantiomerically and diastereomerically enriched cyclobutyl amide to obtain (f) enantiomerically and diastereomerically enriched cyclobutaneamine and (g) further to enantiomerically and diastereomerically enriched cyclobutaneamide.)
1. A process for preparing an enantiomerically and diastereomerically enriched cyclobutaneamide comprising
(a) Reduction of the nitrile moiety of a compound having formula (I) to an aldehyde
Wherein A is selected from aryl, heteroaryl, C1-C6Alkyl radical, C2-C6-alkenyl, C2-C6-alkynyl and C3-C7-cycloalkyl, said aryl, heteroaryl, C1-C6Alkyl radical, C2-C6-alkenyl, C2-C6-alkynyl and C3-C7-cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from: halogen, cyano, C1-C6Alkyl radical, C1-C6-haloalkyl group, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6Alkyl sulfanyl, C1-C6Halogenoalkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C2-C6-haloalkenyl and C2-C6-haloalkynyl;
wherein the reduction of the nitrile moiety of the compound of formula (I) is by using H2And a metal catalyst to the corresponding intermediate imine, followed by subsequent hydrolysis to said compound of formula (II)
Then the
(b) Reacting the compound having formula (II) in the presence of a suitable Lewis acid to obtain a compound having formula (III)
Wherein denotes a stereocenter, then
(c) Reacting a compound having formula (III) with an ammonium salt and H2In the presence of a chiral transition metal catalyst to obtain enantiomerically and diastereomerically enriched amines of formula (IV),
wherein denotes a stereocenter, and then
Further reacting the amine having formula (IV) with a compound having formula (X)
Wherein Y is suitableA leaving group such as OH, OR OR halogen, preferably chlorine, R is C1-C6-alkyl, and E is selected from aryl, heteroaryl, hydrogen, C1-C6Alkyl radical, C2-C6-alkenyl, C2-C6-alkynyl and C3-C7-cycloalkyl, said aryl, heteroaryl, C1-C6Alkyl radical, C2-C6-alkenyl, C2-C6-alkynyl and C3-C7-cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from: halogen, cyano, C1-C6Alkyl radical, C1-C6-haloalkyl group, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6Alkyl sulfanyl, C1-C6Halogenoalkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C2-C6-haloalkenyl and C2-C6-haloalkynyl;
to form enantiomerically and diastereomerically enriched amides of formula (VII)
2. The method of claim 1, wherein,
a and E are selected from aryl and heteroaryl, which are unsubstituted or substituted with one or more substituents independently selected from: halogen, cyano, C1-C6Alkyl radical, C1-C6-haloalkyl group, C1-C6-alkoxy and C1-C6-haloalkoxy.
3. The method of claim 1, wherein,
a is phenyl and E is heteroaryl, said phenyl and heteroaryl being unsubstituted or substituted with one or more substituents independently selected from: halogen, cyano, C1-C6Alkyl radical, C1-C6-haloalkyl group, C1-C6-alkoxy and C1-C6-haloalkoxy.
4. The method of any one of claims 1 to 3,
in step (b), the compound having formula (II) is in a solvent selected from AlCl3And GaCl3Preferably AlCl3In the presence of a Lewis acid.
5. The method of claim 4, wherein,
the solvent used in step (b) is a chlorinated hydrocarbon or chlorinated aromatic solvent, in particular dichloromethane, chlorobenzene or dichlorobenzene.
6. The method of claim 4 or 5,
adding 1.0-1.5 molar equivalents of AlCl relative to the compound of formula (II) in step (b)3Or GaCl3。
7. The method of any one of claims 1 to 6,
said chiral transition metal catalyst in step (c) comprises a transition metal selected from the group consisting of Ru, Rh, Ir and Pd, preferably Ru, and a bidentate phosphorus-containing chiral ligand of general formula (VIII)
Wherein Z is a linking group and R1、R2、R3And R4Independently selected from aryl, heteroaryl, C1-C6-alkyl and C1-C6-cycloalkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from: c1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl, and halogen.
8. The method of claim 7, wherein,
the linking group Z is selected from the group consisting of (R and S) -1,1 '-binaphthyl, (R and S) -4,4' -bi-1, 3-benzodioxole, (R and S) -2,2',6,6' -tetramethoxy-3, 3 '-bipyridine, (R and S) -6,6' -dimethoxy-1, 1 '-biphenyl, (R and S) -4,4',6,6 'tetramethoxy-1, 1' -biphenyl, 2 '-bis- [ (R) -cx- (dimethylamino) benzyl ] ferrocene, ferrocenylmethyl, ferrocene, benzene and ethyl, preferably (R and S) -1,1' -binaphthyl.
9. The method of claim 7 or 8, wherein the chiral ligand is selected from
(R) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl,
(R) -2,2 '-bis (di-p-tolylphosphino) -1,1' -binaphthyl,
(R) -2,2 '-bis [ di (3, 5-xylyl) phosphino ] -1,1' -binaphthyl,
(R) -5,5 '-bis (diphenylphosphino) -4,4' -bi-1, 3-benzodioxole,
(R) -5,5 '-bis (di [3, 5-xylyl ] phosphino) -4,4' -bi-1, 3-benzodioxole,
(R) -5,5 '-bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphino ] -4,4' -bi-1, 3-benzodioxole,
(S) -1, 13-bis (diphenylphosphino) -7, 8-dihydro-6H-dibenzo [ f, H ] [1,5] dioxine,
(R) -2,2',6,6' -tetramethoxy-4, 4 '-bis (di (3, 5-xylyl) phosphino) -3,3' -bipyridine,
(R) -2,2' -bis (diphenylphosphino) -6,6' -dimethoxy-1, 1' -biphenyl,
(R) -2,2 '-bis (diphenylphosphino) -4,4',6,6 '-tetramethoxy-1, 1' -biphenyl,
(R) -6,6 '-bis (diphenylphosphino) -2,2',3,3 '-tetrahydro-5, 5' -bi-1, 4-benzodioxin,
(R) - (+) -2,2 '-bis (diphenylphosphino) -5,5',6,6',7,7',8,8 '-octahydro-1, 1' -binaphthyl,
(R) - (+) -2,2 '-bis (di-3, 5-xylylphosphino) -5,5',6,6',7,7',8,8 '-octahydro-1, 1' -binaphthyl,
(R) -5,5 '-bis (diphenylphosphino) -2,2,2',2 '-tetrafluoro-4, 4' -bi-1, 3-benzodioxole,
(S) -1- [ (S) -1- [ di (3, 5-xylyl) phosphino ] ethyl ] -2- [2- [ di (3, 5-xylyl) phosphino ] phenyl ] ferrocene,
and
(S) -1- [ (S) -1- [ bis [3, 5-bis (trifluoromethyl) phenyl ] phosphino ] ethyl ] -2- [2- (diphenylphosphino) phenyl ] ferrocene.
10. The method of claim 7 or 8,
the chiral transition metal catalyst is selected from [ RuCl (p-cymene) ((S) -DM-SEGPHOS)]Cl, [ RuCl (p-cymene) ((R) -DM-SEGPHOS)]Cl、[NH2Me2][(RuCl((R)-xylbinap))2(u-Cl)3]、[NH2Me2][(RuCl((S)-xylbinap))2(u-Cl)3]、Ru(OAc)2[(R)-binap]、Ru(OAc)2[(S)-binap]、Ru(OAc)2[(R)-xylbinap]、Ru(OAc)2[(S)-xylbinap]、RuCl2[(R)-xylbinap][(R)-daipen]、RuCl2[(S)-xylbinap][(S)-daipen]、RuCl2[(R)-xylbinap][(R,R)-dpen]And RuCl2[(S)-xylbinap][(S,S)-dpen]。
11. A process for the preparation of a compound having formula (III),
wherein A is as defined in any one of claims 1 to 3 and represents a stereocentre,
the method comprises reacting a compound having formula (II)
In the presence of a catalyst selected from AlCl3And GaCl3Preferably AlCl3In the presence of a lewis acid.
12. The process of claim 11, wherein 1.0-1.5 molar equivalents of AlCl relative to the compound of formula (II) is added3Or GaCl3。
13. The process according to claims 11 and 12, wherein the reaction is carried out in a chlorinated aromatic hydrocarbon solvent at a temperature of 50 ℃ to 60 ℃.
14. A process for the preparation of enantiomerically and diastereomerically enriched cyclobutaneamines having the formula (IV),
wherein denotes a stereocenter and wherein A is as defined in any one of claims 1 to 3,
the method comprises reacting a compound having the formula (III)
With ammonium salts and H2In the presence of a chiral transition metal catalyst, wherein the amount of chiral transition metal catalyst added to the reaction mixture is between 0.0001 and 0.1 molar equivalents relative to the compound of formula (III), preferably between 0.0005 and 0.01 molar equivalents relative to the compound of formula (III), and wherein the chiral transition metal catalyst is added to the reaction mixture
(i) 1-10 molar equivalents, relative to the compound having formula (III), of a preformed ammonium salt selected from: ammonium acetate, ammonium 2-methoxypropionate, ammonium tetrahydrofuran-2-carboxylate, ammonium o-methoxybenzoate, ammonium p-methoxybenzoate, ammonium chloroacetate, ammonium methoxyacetate, ammonium phenoxyacetate, ammonium p-chlorophenoxyacetate, ammonium 4-tert-butylphenoxyacetate, ammonium furan-2-carboxylate and ammonium salicylate, or
(ii) 1-10 molar equivalents of ammonia and an acid selected from the group consisting of: acetic acid, methoxyacetic acid, 2-methoxypropionic acid, tetrahydrofuran-2-carboxylic acid, o-methoxybenzoic acid, p-methoxybenzoic acid, phenoxyacetic acid, 2-furan-carboxylic acid, p-chlorophenoxyacetic acid, salicylic acid, 4-tert-butylphenoxyacetic acid and chloroacetic acid, even more particularly phenoxyacetic acid, to form the ammonium salt in situ.
15. A process for the preparation of a compound having formula (V),
wherein A is as defined in any one of claims 1 to 3, comprising reacting a compound having formula (II)
In the presence of a catalyst selected from AlCl3And GaCl3Preferably AlCl3In the presence of a Lewis acid to obtain a compound of formula (III)
And further reacting the compound having formula (III) with acetonitrile and a suitable additive, wherein the additive is selected from the group consisting of an acid chloride, an acid anhydride or an ester, preferably the additive is selected from the group consisting of acetyl chloride, isopropenyl acetate, 4-methoxybenzoyl chloride and p-methoxybenzoic anhydride.
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