CN117917412A - Process for preparing chiral lactones - Google Patents

Process for preparing chiral lactones Download PDF

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CN117917412A
CN117917412A CN202311355806.8A CN202311355806A CN117917412A CN 117917412 A CN117917412 A CN 117917412A CN 202311355806 A CN202311355806 A CN 202311355806A CN 117917412 A CN117917412 A CN 117917412A
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catalyst
rucl
compound
formula
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马克-安德烈·米勒
乔纳森·艾伦·米德洛克
维尔纳·邦拉蒂
罗曼·戈伊
高搏
维克多·齐默尔曼
诺亚·贝拉科维奇
费利克斯·赫伯特·斯宾德勒
阿希姆·林克
拉尔夫·韦克特
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DSM IP Assets BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a novel process for preparing chiral lactone compounds. The process of the present invention produces lactone compounds in improved yields and selectivities over the prior art and, more importantly, reduces the amount of expensive chiral catalyst used and is therefore more cost-effective.

Description

Process for preparing chiral lactones
Technical Field
The present invention relates to a process for preparing chiral lactones.
Background
Lactones are widely used as pharmaceutical or nutraceutical actives or as intermediates for the manufacture of such actives. In particular, (3 aS,6 aR) -lactone is an important intermediate for the manufacture of biotin
Is benzyl group
(3 As,6 ar) -lactone.
An efficient process for the preparation of (3 as,6 ar) -lactone intermediates involves reacting a cyclic carboxylic anhydride with a chiral alcohol to obtain a dicarboxylic acid monoester, which is then reduced and further cyclized to obtain the lactone (see: WO2004094367 A2). Another approach is to asymmetrically hydrogenate the cyclic carboxylic anhydride with a chiral catalyst to directly obtain the chiral lactone in 1 step (see ：Bonrath,W.,Karge,R.,Netscher,T.,Roessler,F.and Spindler,F.Chiral Lactones by Asymmetric Hydrogenation–A Step Forward in(+)-Biotin Production,Asymmetric Catalysis on Industrial Scale(2010),edited by H.U.Blaser and H.J.Federsel). however, there is still a need for a more efficient process.
Disclosure of Invention
The present invention provides an improved process for the preparation of chiral lactone compounds of formula (I),
Wherein R 1 and R 2 are independently-NR 3R4,
And R 3 and R 4 are independently H, alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkylalkyl, heterocyclyl, acyl, alkylsulfonyl, arylsulfonyl, or silylisi (alkyl) 3, si (aryl) 3, or Si (alkyl) m (aryl) n, optionally substituted with 1 or more substituents, and m and n are independently 1 or 2;
Or two R 3 may alternatively together form a carbonyl group and two R 4 are independently as defined above.
According to the process of the present invention, the lactone compounds of formula (I) can be prepared in improved yields and selectivities, while being less costly than the prior art.
Detailed Description
In the present invention, the term "alkyl", when used as such or as part of a group such as arylalkyl, cycloalkylalkyl, alkylsulfonyl and silylsi (alkyl) 3 and Si (alkyl) m (aryl) n, refers to branched and straight chain saturated aliphatic hydrocarbon groups having up to 12 carbon atoms, more preferably up to 6 carbon atoms. Examples of "alkyl" are C 1-C6 alkyl groups including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, t-pentyl, hexyl, isohexyl, t-hexyl, octyl, isooctyl, t-octyl, nonyl, isononyl, t-nonyl, decyl, isodecyl, and t-decyl.
In the present invention, the term "cycloalkyl" as used by itself or as part of a group such as cycloalkylalkyl refers to a monocyclic, bicyclic or spiro saturated aliphatic hydrocarbon group having the indicated number of carbon atoms. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.
In the present invention, the term "alkenyl", when used as such or as part of a group such as arylalkenyl, refers to a straight, branched or cyclic non-aromatic hydrocarbon group having up to 12 carbon atoms, more preferably up to 6 carbon atoms (depending on the number of carbon atoms), containing up to three double bonds, preferably 1 double bond. Examples of "alkenyl" are ethenyl, propenyl, allyl, butenyl, 2-methylbutenyl and cyclohexenyl.
In the present invention, the term "aryl", when used as such or as part of an arylalkyl, arylalkenyl, arylsulfonyl, or silyl Si (aryl) 3 and Si (alkyl) m (aryl) n group, refers to a carbocyclic aromatic system containing 1 ring or 2 or 3 rings fused together, wherein the ring atoms are all carbon. Examples of "aryl" groups include, but are not limited to, phenyl, benzyl, xylyl, naphthyl, and the like.
In the present invention, the term "heterocyclyl", when used as such or as part of a group, refers to a non-aromatic saturated monocyclic, bicyclic, tricyclic or spiro ring system containing up to 7 atoms in each ring, or containing from 3 to 14 or 5 to 10 ring atoms, wherein 1 or more atoms in the ring system are elements other than carbon, such as nitrogen, oxygen, phosphorus or sulfur, alone or in combination. Preferred heterocyclyl groups contain from about 5 to about 6 ring atoms. Non-limiting examples of suitable heterocyclyl rings include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1, 4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, lactams, lactones, and the like.
In the present invention, the term "acyl", when used as such or as part of a group, refers to a structure represented by R 1 -C (=o) -, wherein R 1 is alkyl or aryl as defined herein.
In the present invention, the term "alkoxy", when used as such or as part of a group, refers to a structure represented by (alkyl) -O-, wherein alkyl is as defined herein.
In the present invention, the term "halo" or "halogen", when used as such or as part of a group, refers to groups of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably to Cl or Br, and thus the halide used is an anion of halogen.
In the present invention, the term "substituent" is used to refer to C 1-C6 alkyl, C 1-C6 alkoxy, C 1-C6 alkylthio, aryl, hydroxy, halo, halide, -NH 2、-NO2, cyano and/or isocyano.
In the present invention, the symbols as used in the formulae of the compounds of the present inventionMeaning that the attached groups are attached to the chiral carbon in the S-and/or R-configuration according to the Cahn-Ingold-Prelog priority rules.
In the present invention, the structures in the formula of the compounds of the present inventionMeaning that the group R is oriented away from the viewer compared to the chiral carbon to which it is attached.
In the present invention, the structures in the formula of the compounds of the present inventionMeaning that the group R' is oriented closer to the viewer than the chiral carbon to which it is attached.
Surprisingly, the inventors of the present invention have found that achiral catalysts can additionally be used for asymmetric hydrogenation of cyclic carboxylic anhydrides to increase the yield and selectivity of chiral lactones.
Accordingly, in a first aspect, the present invention provides a process for the preparation of a compound of formula (I), the process comprising:
a) Asymmetrically hydrogenating a compound of formula (II); and
B) Adding an achiral catalyst to the reaction mixture obtained in step a) to obtain a compound of formula (I)
Wherein R 1 and R 2 are independently as defined above.
Preferably, R 1 and R 2 are independently-NR 3R4 optionally substituted with 1 or more substituents, and two R 3 together form a carbonyl group, and two R 4 are independently H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, heterocycloalkyl, acyl, alkylsulfonyl, arylsulfonyl, or silyl Si (alkyl) 3, si (aryl) 3, or Si (alkyl) m (aryl) n, and m and n are independently 1 or 2.
More preferably, the compound of formula (II) is a compound of formula (IIa)
And the compound of formula (I) is a compound of formula (Ia):
Wherein each R 4 is independently as defined above.
In the present invention, the asymmetric hydrogenation in step a) is carried out in the presence of a chiral catalyst. Preferably, the chiral catalyst is a transition metal catalyst, such as an iridium (Ir) catalyst and a ruthenium (Ru) catalyst. More preferably, the chiral catalyst contains a chiral ligand, such as a bisphosphine ligand. Examples of biphosphine ligands include, but are not limited to:
(R) -1- { (R P) -2- [2- (diphenylphosphino) phenyl ] ferrocenyl } ethyldi (2-norbornyl) phosphine (SL-W022-1),
(S) -1- [ (S) -1- [ bis [3, 5-bis (trifluoromethyl) phenyl ] phosphino ] ethyl ] -2- [2- (diphenylphosphino) phenyl ] ferrocene (SL-W001-2),
(R) - (+) -5,5 '-bis- [ bis- (3, 5-di-tert-butyl-4-methoxyphenyl) -phosphino ] -4,4' -bis-1, 3-benzodioxole ((R) -DTBM-SEGPHOS),
[ (1R) -6,6' -dimethoxy [1,1' -biphenyl ] -2,2' -diyl ] bis [3, 5-bis (1, 1-dimethylethyl) -4-methoxyphenyl ] phosphine ] ((R) -DTBM-MeOBiPHEP),
(+) -1,1' -Bis ((2R, 4R) -2, 4-diethylphosphono) ferrocene ((R, R) - i PrXANTANE),
(S, S) -Et-FerroTANE and/or
(S,S)-(R,R)-Ph-TRAP。
Preferably, the chiral catalyst contains a chiral ligand selected from the group consisting of: SL-W022-1, SL-W001-2, (R) -DTBM-SEGPHOS and/or (R) -DTBM-MeOBiPHEP.
In the present invention, the chiral catalyst may be prepared from a metal catalyst precursor and a chiral ligand according to methods known in the art. The metal catalyst precursor may be selected from:
Ir catalyst precursors including, but not limited to [Ir(COD)Cl]2、[Ir(NBD)Cl]2、[Ir(CH2CH2)2Cl]2、[Ir(COD)2]Y or [ Ir (NBD) 2 ] Y (COD is an abbreviation for 1,5-cyclooctadiene (1, 5-cyclooctadiene) and NBD is an abbreviation for 2, 5-norbornadiene (2, 5-norbonadiene)), wherein Y is an anion such as a halogen anion, BF 4 -、B(Ar)4 - (e.g., BARF, i.e., tetrakis [3, 5-bis (trifluoromethyl) phenyl ] borate (Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate))、ClO4 -、SbF6 -、PF6 - and/or CF 3SO3 -; and/or
Ru catalyst precursors including, but not limited to [ RuI 2 (p-isopropyl toluene) ] 2、[RuCl2 (p-isopropyl toluene )]2、[RuCl2(C6Me6)]2、[RuCl2(C6H6)]2 and/or [ RuCl 2 (. Eta.6-mesitylene) ] 2(C6Me6 is an abbreviation for hexamethylbenzene (hexamethylbenzene)).
The chiral ligand may be selected from:
·SL-W022-1、SL-W001-2、(R)-DTBM-SEGPHOS、(R)-DTBM-MeOBiPHEP、(R,R)-iPrXANTANE、(S,S)-Et-FerroTANE And/or (S, S) - (R, R) -Ph-TRAP.
Examples of chiral catalysts for use in the methods of the invention include, but are not limited to:
Ir catalysts, such as complexes formed from the metal precursor [ Ir (COD) Cl ] 2 and the ligand (R) -DTBM-SEGPHOS or (R) -DTBM-MeOBiPHEP; and/or
Ru catalysts such as [ Rul (p-isopropyltoluene) (SL-W001-2) ] BF 4, [ Rul (p-isopropyltoluene) (SL-W022-1) ] BF 4, [ RuCl (p-isopropyltoluene) (SL-W022-1) ] BF 4, [ RuCl (p-isopropyltoluene) (SL-W022-1) ] BARF, [ RuCl (p-isopropyltoluene) (SL-W022-1) ] SbF 6, [ RuCl (p-isopropyltoluene )(SL-W022-1)]PF6、[RuCl(C6Me6)(SL-W022-1)]BF4、[RuCl(C6Me6)(SL-W022-1)]BARF、[RuCl(C6H6)(SL-W022-1)]BARF、[RuCl( mesitylene) (SL-W022-1) ] BARF, [ RuCl (mesitylene) (SL-W022-1) ] PF 6 and [ RuCl (mesitylene) (SL-W022-1) ] BF 4.
The chiral catalyst of the present invention may be used after separation or prepared in situ. Preferably, the catalyst is generated in situ. For example, according to methods known in the art, [ RuI (para-isopropyl toluene) (SL-W022-1) ] BF 4 is formed in situ by mixing [ RuI 2 (para-isopropyl toluene) ] 2 with the ligand SL-W022-1, followed by addition of HBF 4 (1.0 eq.) in THF.
In the process of the present invention, the molar ratio (S/C) between the compound of formula (II) and the chiral catalyst ranges from 50:1 to 1,000,000:1, preferably from 200:1 to 800,000:1, more preferably from 500:1 to 500,000:1, and most preferably from 5,000:1 to 200,000:1, such as 6,000:1, 8,000:1, 10,000:1, 20,000:1, 30,000:1, 40,000:1, 50,000:1, 60,000:1, 80,000:1, 100,000:1, 150,000:1 and 200,000:1.
In some embodiments, the chiral catalyst in the present invention is a complex formed from a metal precursor [ Ir (COD) Cl ] 2 and a chiral ligand DTBM-seghos, preferably (R) -DTBM-seghos, and S/C is not less than 5,000:1, preferably not less than 6,000:1, not less than 7,000:1, not less than 8,000:1, not less than 9,000:1, not less than 10,000:1, not less than 15,000:1, or not less than 20,000:1. In some other embodiments, the chiral catalyst is a complex formed from a metal precursor [ Ir (COD) Cl ] 2 and a chiral ligand DTBM-MeOBiPHEP, preferably (R) -DTBM-MeOBiPHEP, and S/C is not less than 10,000:1, preferably not less than 12,000:1, not less than 15,000:1, not less than 16,000:1, or not less than 18,000:1, and more preferably not less than 20,000:1.
In step a) of the process of the invention, a solvent may or may not be used. Preferably, a solvent is used in step a). The solvent may be selected from: hydrocarbons, chlorinated hydrocarbons, ethers, and esters. Preferred solvents are THF, dichloromethane (DCM), 2-methyltetrahydrofuran (Me-THF), cyclopentylmethyl ether (CPME), diethyl ether (Et 2 O), ethyl acetate (EtOAc) and isopropyl acetate (iPrOAc). The solvent may be used in step a) in an amount of 1mL to 20mL, preferably 5mL to 15mL, such as 5mL, 6mL, 7mL, 8mL, 9mL and 10mL, per 1mmol of the compound of formula (II).
The reaction in step a) may be carried out at 0 ℃ to 150 ℃, preferably 20 ℃ to 120 ℃. The pressure of the reaction may be from 1 bar to 150 bar, preferably from 50 bar to 150 bar, such as 80 bar.
In step b) of the present invention, the achiral catalyst may be a homogeneous catalyst or a heterogeneous catalyst. Examples of heterogeneous catalysts include, but are not limited to:
Metal catalysts supported on carriers such as carbon, calcium carbonate, alumina, calcium carbonate, deloxan, and silica, such as Ru, platinum (Pt), palladium (Pd), and Pd (OH) 2; and
Alloy catalysts, such as Raney Ni andSeries (Switzerland Cortain).
Examples of homogeneous catalysts include, but are not limited to:
[ Ir (COD) Cl ] 2 with or without achiral ligands such as (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) (Xantphos), 1, 2-bis (diphenylphosphino) ethane (DPPE) and Triphenylphosphine (TPP),
{ Bis [2- (diphenylphosphino) ethyl ] amine } carbonyl ruthenium (II) hydrochloride (Ru-MACHO),
Carbonyl hydride (boron tetrahydroide) [ bis (2-diphenylphosphinoethyl) amino ] ruthenium (II) (Ru-MACHO BH),
Dichloro triphenylphosphine [ bis (2- (ethylsulfanyl) ethyl) amine ] ruthenium (II),
Dichloro triphenylphosphine [2- (diphenylphosphino) -N- (2-pyridylmethyl) ethylamine ] ruthenium (II),
[2- (Di-tert-butylphosphinomethyl) -6- (diethylaminomethyl) pyridine ] -carbonyl ruthenium (II) hydrochloride, and
Dichloro-bis- [2- (diphenylphosphino) -ethylamino ] -ruthenium (II)
Preferably, the achiral catalyst is selected from: [ Ir (COD) Cl ] 2、Pt/C、Pd/C、Ru/C、Pd(OH)2/C and Raney Ni. More preferably, the achiral catalyst is selected from [ Ir (COD) Cl ] 2 and Raney Ni.
The achiral catalyst in step b) may be used in an amount of 0.0001 to 50mol%, preferably 0.001 to 5mol%, more preferably 0.005 to 1mol%, most preferably 0.01 to 0.1mol%, based on the amount of the compound of formula (II).
The reaction in step b) may be carried out at 0 ℃ to 150 ℃, preferably 90 ℃ to 140 ℃. The pressure of the reaction may be from 1 bar to 100 bar, such as 5 bar.
The obtained compound of formula (I) can be easily isolated by any known method such as extraction, nanofiltration and/or crystallization.
Even more surprisingly, the inventors of the present invention have further found that in an asymmetric hydrogenation as described above only part of the compound of formula (II) is converted into the desired compound of formula (I), while the remaining part of the compound of formula (II) is converted into an intermediate compound of formula (III), which may be further converted into the target compound of formula (I) in the presence of a chiral or achiral catalyst.
Accordingly, in a second aspect, the present invention provides a process for the preparation of a compound of formula (I), the process comprising the steps of:
a') asymmetrically hydrogenating the compound (II) to a compound of the formula (III), and
B') hydrogenating the compound of the formula (III) to a compound of the formula (I),
Wherein R 1 and R 2 are as defined above.
Preferably, R 1 and R 2 are independently-NR 3R4 optionally substituted with 1 or more substituents, and two R 3 together form a carbonyl group, and two R 4 are independently H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, heterocycloalkyl, acyl, alkylsulfonyl, arylsulfonyl, or silyl Si (alkyl) 3, si (aryl) 3, or Si (alkyl) m (aryl) n, and m and n are independently 1 or 2.
More preferably, the compound of formula (I) is a compound of formula (Ia):
the compound of formula (II) is a compound of formula (IIa)
And
The compound of formula (III) is a compound of formula (IIIa):
Wherein each R 4 is independently as defined above.
In step a') of the present invention, the asymmetric hydrogenation may be carried out as described in step a) above.
The compound of formula (III) obtained according to step a ') can be easily isolated by any known method, such as evaporation, extraction and/or crystallization, or used directly in step b').
In step b') of the present invention, the hydrogenation is carried out in the presence of a catalyst, which may be a chiral catalyst or an achiral catalyst.
The chiral catalyst suitable for step b ') may be selected from the chiral catalysts as described in step a) above and may be the same as or different from the chiral catalyst used in step a'). Achiral catalysts suitable for step b') may be selected from the catalysts as described in step b) above.
Preferably, the catalyst suitable for step b') of the present invention is selected from: [ Ir (COD) Cl ] 2; a complex formed from [ Ir (COD) Cl ] 2 and a ligand selected from (R) -DTBM-SEGPHOS, xantphos, DPPE and TPP; pt/C; pd/C; ru/C; pd (OH) 2/C; and Raney Ni. More preferably, the catalyst suitable for step b') is selected from: a complex formed from [ Ir (COD) Cl ] 2 and a ligand selected from (R) -DTBM-SEGPHOS; and Raney Ni.
More preferably, the catalyst suitable for step b') of the present invention is an achiral catalyst, such as Raney Ni.
The catalyst in step b') may be used in an amount of 50 to 0.0001mol%, preferably 5 to 0.001mol%, most preferably 0.05 to 0.005mol%, based on the amount of the compound of formula (III).
In step b'), a solvent may or may not be used. Preferably, a solvent is used in step b'). The solvent may be selected from: hydrocarbons, chlorinated hydrocarbons, ethers, esters, alcohols, and toluene. Preferred solvents are THF, dichloromethane (DCM), 2-methyltetrahydrofuran (Me-THF), cyclopentylmethyl ether (CPME), diethyl ether (Et 2 O), ethyl acetate (EtOAc), isopropyl acetate (iPrOAc), methanol, ethanol, and toluene. The solvent may be used in an amount of 0.3 to 20L, preferably 0.5 to 15L, more preferably 1 to 12L, per 1mol of the compound of formula (III).
The reaction in step b') may be carried out at 0℃to 150℃and preferably at 90℃to 140 ℃. The pressure of the reaction may be from 1 bar to 100 bar, such as 5 bar.
The obtained compound of formula (I) can be easily isolated by any known method such as extraction, nanofiltration and/or crystallization.
The process of the present invention provides the compounds of formula (I) in high yields and selectivities. More importantly, the process offers the possibility of reducing the amount of chiral catalyst used, which is often expensive in step a) and/or step a'), thus reducing the cost of the overall process.
The process of the invention is further illustrated by the following examples.
Examples
Example 1
The reactor was charged with [ Ir (COD) Cl ] 2, compound 1 (10.42 g,30.0 mmol) and ligand (1 equivalent to iridium) and the solvent as shown in Table 1. The reactor was purged with nitrogen. The reaction mixture was stirred for 20 hours at the given hydrogen pressure and temperature. The reactor was cooled to room temperature, the hydrogen pressure was released and the reactor was purged with nitrogen. The desired compound 3 and intermediate compound 2 were obtained in the yields and/or e.e. values (both determined by HPLC) as shown in table 1.
TABLE 1
Example 2
To the reaction mixture obtained according to entry 5 of example 1 was added wet Raney Ni (5.0 g) under a stream of argon. The reactor was closed and purged with nitrogen (3×5 bar) and hydrogen (3×5 bar). Hydrogen was added to a pressure of 80 bar. The reaction mixture was heated to 90℃and stirred (1400 rpm) for 16 hours. It was then cooled to room temperature and the pressure was released. The reactor was purged with nitrogen (3×5 bar). The reaction mixture was filtered through a small syringe filter and washed with THF (about 5 mL) to give the desired compound 3 in 96% (based on compound 1) and 95% yield as determined by HPLC.
Example 3
To the reaction mixture obtained according to entry 4 of example 1 were added [ Ir (COD) Cl ] 2 (5.25 mg, 7.8. Mu. Mol) and Xantphos (9.2 mg,0.016 mmol) under a stream of argon. The reactor was closed and purged with nitrogen (3×5 bar) and hydrogen (3×5 bar). Hydrogen was added to a pressure of 30 bar. The reaction mixture was heated to 100℃and stirred (1400 rpm) for 16 hours. It was then cooled to room temperature and the pressure was released. The autoclave was purged with nitrogen (3×5 bar). The reaction mixture was filtered through a small syringe filter and washed with Me-THF (about 5 ml) to give the desired compound 3 in 71% yield and 95.4% e.e. as determined by HPLC.
Example 4
The reactor was charged with [ Ir (COD) Cl ] 2 (0.5 mg, 0.75. Mu. Mol), compound 1 (10.42 g,30.0 mmol) and (R) -DTBM-MeOBiPHEP (1.55 mg, 1.5. Mu. Mol) and anhydrous THF (200 mL). The reactor was purged with nitrogen. The reaction mixture was stirred for 20 hours at 100℃under a hydrogen pressure of 70 bar. The reactor was cooled to room temperature, the hydrogen pressure was released and the reactor was purged with nitrogen. The desired compound 2 was obtained in the reaction mixture in a yield of 82%, e.e. 96%, both determined by HPLC method.
1 H NMR δ:7.35-7.23 (10H, m, CH (9,10,11,12,13,16,17,18,19 and 20)),5.47(1H,s.CH(6)),5.19(1H,br.s,OH),4.94(1H,d,J＝14.9Hz,CH2(14)),4.51(1H,d,J＝14.9Hz,CH2(7)),4.36(1H,d,J＝14.9Hz,CH2(7)),4.29(1H,d,J＝14.9Hz,CH2(14)),4.04(1H,d,J＝7.9Hz,CH(3a)),3.87(1H,d,J＝8.1Hz,CH(6a)).
Example 5
The autoclave was charged with Compound 1 (500 mg,1.49 mmol), THF (15 mL) and preformed [ RuCl (p-isopropyl toluene) (SL-W022-1) ] BF 4 (0.5 mol%). The autoclave was purged with nitrogen and the reaction was carried out at 80℃and 80 bar (H 2). After 6 hours, the reaction mixture was cooled to room temperature, hydrogen was released, and the reactor was purged with nitrogen. The desired compound 2 was obtained in the reaction mixture in a yield of 85%, e.e. 80%, both determined by qHPLC.
Example 6
The steam autoclave was charged under argon flow with wet Raney Ni (0.50 g) and Compound 2 (9.05 g,3.3%,0.88mmol,93.6% e.e.) in Me-THF. The autoclave was closed and purged with nitrogen (3×5 bar) and hydrogen (3×5 bar). Hydrogen was added to a pressure of 5 bar. The reaction mixture was heated to 90℃and stirred (1400 rpm) for 16 hours. It was then cooled to room temperature and the pressure was released. The autoclave was purged with nitrogen (3×5 bar). The reaction mixture was filtered through a small syringe filter and washed with Me-THF (about 5 mL) to give the desired compound 3 in 99.4% yield and 93.6% e.e. as determined by HPLC.

Claims (19)

1. A process for preparing a compound of formula (I), the process comprising:
a) Asymmetrically hydrogenating a compound of formula (II); and
B) Adding an achiral catalyst to the reaction mixture obtained in step a),
To obtain a compound of formula (I)
Wherein R 1 and R 2 are independently-NR 3R4,
And R 3 and R 4 are independently H, alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkylalkyl, heterocyclyl, acyl, alkylsulfonyl, arylsulfonyl, or silylisi (alkyl) 3, si (aryl) 3, or Si (alkyl) m (aryl) n, optionally substituted with 1 or more substituents, and m and n are independently 1 or 2;
Or two R 3 may alternatively together form a carbonyl group and two R 4 are independently as defined above.
2. The process according to claim 1, wherein step a) is performed in the presence of a chiral catalyst of a transition metal, such as an iridium (Ir) catalyst and a ruthenium (Ru) catalyst.
3. The process according to claim 2, wherein the chiral catalyst contains a chiral ligand such as a biphosphine ligand selected from the group consisting of:
(R) -1- { (R P) -2- [2- (diphenylphosphino) phenyl ] ferrocenyl } ethyldi (2-norbornyl) phosphine (SL-W022-1),
(S) -1- [ (S) -1- [ bis [3, 5-bis (trifluoromethyl) phenyl ] phosphino ] ethyl ] -2- [2- (diphenylphosphino) phenyl ] ferrocene (SL-W001-2),
(R) - (+) -5,5 '-bis- [ bis- (3, 5-di-tert-butyl-4-methoxyphenyl) -phosphino ] -4,4' -bis-1, 3-benzodioxole ((R) -DTBM-SEGPHOS),
[ (1R) -6,6' -dimethoxy [1,1' -biphenyl ] -2,2' -diyl ] bis [3, 5-bis (1, 1-dimethylethyl) -4-methoxyphenyl ] phosphine ] ((R) -DTBM-MeOBiPHEP),
(+) -1,1' -Bis ((2R, 4R) -2, 4-diethylphosphono) ferrocene ((R, R) - i PrXANTANE),
(S, S) -Et-FerroTANE and/or
(S,S)-(R,R)-Ph-TRAP。
4. The process according to claim 1, wherein step a) is carried out in the presence of a chiral catalyst selected from the group consisting of:
Ir catalysts, such as complexes formed from the metal precursor [ Ir (COD) Cl ] 2 and the ligand (R) -DTBM-SEGPHOS or (R) -DTBM-MeOBiPHEP; and/or
Ru catalysts such as [ Rul (p-isopropyltoluene) (SL-W001-2) ] BF 4, [ Rul (p-isopropyltoluene) (SL-W022-1) ] BF 4, [ RuCl (p-isopropyltoluene) (SL-W022-1) ] BF 4, [ RuCl (p-isopropyltoluene) (SL-W022-1) ] BARF, [ RuCl (p-isopropyltoluene) (SL-W022-1) ] SbF 6, [ RuCl (p-isopropyltoluene )(SL-W022-1)]PF6、[RuCl(C6Me6)(SL-W022-1)]BF4、[RuCl(C6Me6)(SL-W022-1)]BARF、[RuCl(C6H6)(SL-W022-1)]BARF、[RuCl( mesitylene) (SL-W022-1) ] BARF, [ RuCl (mesitylene) (SL-W022-1) ] PF 6 and [ RuCl (mesitylene) (SL-W022-1) ] BF 4.
5. The process according to any one of claims 1 to 4, wherein the molar ratio (S/C) between the compound of formula (II) and the chiral catalyst ranges from 50:1 to 1,000,000:1, preferably from 200:1 to 800,000:1, more preferably from 500:1 to 500,000:1, and most preferably from 5,000:1 to 200,000:1, such as 6,000:1, 8,000:1, 10,000:1, 20,000:1, 30,000:1, 40,000:1, 50,000:1, 60,000:1, 80,000:1, 100,000:1, 150,000:1 and 200,000:1.
6. The method according to any one of claims 1 to 4, wherein step a) is performed in a solvent selected from the group consisting of: hydrocarbons, chlorinated hydrocarbons, ethers and esters, such as THF, dichloromethane (DCM), 2-methyltetrahydrofuran (Me-THF), cyclopentylmethyl ether (CPME), diethyl ether (Et 2 O), ethyl acetate (EtOAc) and isopropyl acetate (iPrOAc).
7. The process of any one of claims 1 to 4, wherein the achiral catalyst is a homogeneous catalyst or a heterogeneous catalyst.
8. The method of any one of claims 7, wherein the heterogeneous catalyst is selected from the group consisting of:
Metal catalysts such as Ru, platinum (Pt), palladium (Pd) and Pd (OH) 2 supported on a carrier such as carbon, calcium carbonate, alumina, calcium carbonate, deloxan and silica; and
Alloy catalysts, such as Raney Ni andA series.
9. The process of any one of claims 7, wherein the homogeneous catalyst is selected from the group consisting of:
[ Ir (COD) Cl ] 2 with or without achiral ligands such as (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) (Xantphos), 1, 2-bis (diphenylphosphino) ethane (DPPE) and Triphenylphosphine (TPP),
{ Bis [2- (diphenylphosphino) ethyl ] amine } carbonyl ruthenium (II) hydrochloride (Ru-MACHO),
Carbonyl hydride (boron tetrahydroide) [ bis (2-diphenylphosphinoethyl) amino ] ruthenium (II) (Ru-MACHO BH),
Dichloro triphenylphosphine [ bis (2- (ethylsulfanyl) ethyl) amine ] ruthenium (II),
Dichlorophenyl phosphine [2- (diphenylphosphino) -N- (2-pyridylmethyl) ethylamine ] ruthenium (II), [2- (di-tert-butylphosphinomethyl l) -6- (diethylaminomethyl) pyridine ] -carbonyl ruthenium (II), and
Dichloro-bis- [2- (diphenylphosphino) -ethylamino ] -ruthenium (II).
10. The process according to any one of claims 1 to 4, wherein the achiral catalyst is selected from [ Ir (COD) Cl ] 2、Pt/C、Pd/C、Ru/C、Pd(OH)2/C and RaneyNi.
11. The process according to any one of claims 1 to 4, wherein the achiral catalyst in step b) may be used in an amount of 0.0001 to 50mol%, preferably 0.001 to 5mol%, more preferably 0.005 to 1mol%, most preferably 0.01 to 0.1mol%, based on the amount of the compound of formula (II).
12. A process for preparing a compound of formula (I), the process comprising the steps of:
a') asymmetrically hydrogenating the compound (III) to a compound of the formula (II), and
B') hydrogenating the compound of the formula (II) to a compound of the formula (I),
Wherein R 1 and R 2 are independently-NR 3R4,
And R 3 and R 4 are independently H optionally substituted with 1 or more substituents,
Alkyl, cycloalkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl
Alkyl, heterocyclyl, acyl, alkylsulfonyl, arylsulfonyl, or silyl Si (alkyl) 3, si (aryl) 3, or Si (alkyl) m (aryl) n, and m and n are independently 1 or 2;
Or two R 3 may alternatively together form a carbonyl group and two R 4 are independently as defined above.
13. The process according to claim 12, wherein the step a') is performed in the presence of a chiral catalyst of a transition metal, such as an iridium (Ir) catalyst and a ruthenium (Ru) catalyst.
14. The method of claim 12, wherein the chiral catalyst comprises a chiral ligand selected from the group consisting of:
(R) -1- { (R P) -2- [2- (diphenylphosphino) phenyl ] ferrocenyl } ethyldi (2-norbornyl) phosphine (SL-W022-1),
(S) -1- [ (S) -1- [ bis [3, 5-bis (trifluoromethyl) phenyl ] phosphino ] ethyl ] -2- [2- (diphenylphosphino) phenyl ] ferrocene (SL-W001-2),
(R) - (+) -5,5 '-bis- [ bis- (3, 5-di-tert-butyl-4-methoxyphenyl) -phosphino ] -4,4' -bis-1, 3-benzodioxole ((R) -DTBM-SEGPHOS),
[ (1R) -6,6' -dimethoxy [1,1' -biphenyl ] -2,2' -diyl ] bis [3, 5-bis (1, 1-dimethylethyl) -4-methoxyphenyl ] phosphine ] ((R) -DTBM-MeOBiPHEP),
(+) -1,1' -Bis ((2R, 4R) -2, 4-diethylphosphono) ferrocene ((R, R) - i PrXANTANE), (S, S) -Et-FerroTANE and/or (S, S) - (R, R) -Ph-TRAP.
15. The process according to claim 12, wherein step a) is carried out in the presence of a chiral catalyst selected from the group consisting of:
Ir catalysts, such as complexes formed from the metal precursor [ Ir (COD) Cl ] 2 and the ligand (R) -DTBM-SEGPHOS or (R) -DTBM-MeOBiPHEP; and/or
Ru catalysts such as [ Rul (p-isopropyltoluene) (SL-W001-2) ] BF 4, [ Rul (p-isopropyltoluene) (SL-W022-1) ] BF 4, [ RuCl (p-isopropyltoluene) (SL-W022-1) ] BF 4, [ RuCl (p-isopropyltoluene) (SL-W022-1) ] BARF, [ RuCl (p-isopropyltoluene) (SL-W022-1) ] SbF 6, [ RuCl (p-isopropyltoluene )(SL-W022-1)]PF6、[RuCl(C6Me6)(SL-W022-1)]BF4、[RuCl(C6Me6)(SL-W022-1)]BARF、[RuCl(C6H6)(SL-W022-1)]BARF、[RuCl( mesitylene) (SL-W022-1) ] BARF, [ RuCl (mesitylene) (SL-W022-1) ] PF 6 and [ RuCl (mesitylene) (SL-W022-1) ] BF 4.
16. The process according to any one of claims 12 to 15, wherein the molar ratio (S/C) between the compound of formula (II) and the chiral catalyst ranges from 50:1 to 1,000,000, preferably from 200:1 to 800,000:1, more preferably from 500:1 to 500,000:1, and most preferably from 5,000:1 to 200,000:1, such as 6,000:1, 8,000:1, 10,000:1, 20,000:1, 30,000:1, 40,000:1, 50,000:1, 60,000:1, 80,000:1, 100,000:1, 150,000:1 and 200,000:1.
17. The process according to any one of claims 12 to 15, wherein said step b') is performed in the presence of a chiral catalyst and/or an achiral catalyst.
18. The process according to claim 17, wherein the catalyst used in step b') is selected from the group consisting of: [ Ir (COD) Cl ] 2; a complex formed from [ Ir (COD) Cl ] 2 and a ligand selected from (R) -DTBM-SEGPHOS, xantphos, DPPE and TPP; pt/C; pd/C; ru/C; pd (OH) 2/C; and Raney Ni.
19. The process according to any one of claims 12 to 15, wherein the catalyst in step b') may be used in an amount of 50 to 0.0001mol%, preferably 5 to 0.001mol%, most preferably 0.05 to 0.005mol%, based on the amount of the compound of formula (III).
CN202311355806.8A 2022-10-20 2023-10-19 Process for preparing chiral lactones Pending CN117917412A (en)

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