CN1216036C - Chiral aminoalcohol ligands and their application in the asymmetric addition of terminal alkynes to imines - Google Patents

Abstract

The present invention provides a new class of chiral ligands (1R, 2R)-2-N, N-substituted-1-(4-substituted phenyl)-3-O-substituted-1-propanol, which has a general structure The formula is as the right formula, wherein R ¹ and R ² are amino protecting groups, R ³ is oxygen protecting groups; Z is H, an electron-withdrawing group or an electron-pushing group. The ligand is applied to asymmetric synthesis, especially through its application to the precursor of asymmetric synthesis of DPC961 and DPC083. Symmetrical addition, a highly active inhibitor of HIV transferase, DPC961 and DPC083, can be synthesized chirally and efficiently.

Description

Chiral aminoalcohol ligands and their application in the asymmetric addition of terminal alkynes to imines

technical field

The present invention relates to a novel chiral ligand and its use for the asymmetric addition of terminal alkynes to imines.

Background technique

Human immunodeficiency virus (HIV, Human immunodeficiency virus) is prone to mutations, which can lead to drug resistance. As we all know, some transferase inhibitor drugs have been discovered and used for the treatment of HIV and similar diseases, such as azidothymidine or AZT. DPC 961 and DPC 083 are second-generation HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs, non-nucleoside reverse transcriptase inhibitors), which have stronger activity than the already-marketed transferase inhibitor drug Efavirenz (Sustiva ^TM ). DPC-961 and DPC 083 are currently undergoing clinical research testing (Journal of Medicinal Chemistry vol.43, NO.10, 2000, 2019-2030).

Some methods have been used for the synthesis of DPC 961 and DPC 083. The reported methods for the synthesis of DPC 961 and DPC 083 are either by fractional recrystallization resolution of diastereomers or by substrate-controlled diastereoselective 1,4-addition, which require manual Sexual prosthetic groups (Journal of Organic Chemistry vol.68, no.3, 2003, 754-761; Tetrahedron Letter vol.41, 2000, 3015-3019). Recently, WO 0170707 reported a chiral ligand-controlled asymmetric addition method for the synthesis of DPC 961. However, in this method, a large excess of chiral ligands and strong bases (lithiumalkyl and LHMDS) must be used, and the reaction must be carried out at minus 20 degrees. The conditions are harsh and industrialization is not easy.

Contents of the invention

The problem to be solved by the present invention is to provide a new class of chiral ligands.

The problem to be solved by the present invention is to provide the above-mentioned ligands for the application of asymmetric synthesis, for the asymmetric addition of terminal alkynes to imines, the high optical activity of the product and very mild reaction conditions make the process have good prospects for industrialization. In particular, the application of the process for the direct synthesis of the precursors of optically active DPC 961 and DPC 083, that is, the incompatibility of trifluoromethylimino intermediates with copper alkynes or zinc alkynes with the participation of novel chiral ligands aminoalcohols Symmetrical addition generates the product tertiary ammonia, and the compound can be easily transformed to generate the products HIV transferase inhibitor drugs DPC 961 and DPC 083.

The present invention provides a class of novel chiral ligands (1R, 2R)-2-N, N-substituted-1-substituted phenyl-3-O-substituted-1-propanol, the general structural formula of which is as follows:

Wherein R ¹ and R ² are amino protecting groups, R ³ is oxygen protecting groups; Z is H, an electron-withdrawing group or an electron-pushing group. The electron-withdrawing group is recommended to be halogen, CH ₃ O, OH, NO ₂ , CF ₃ , CH ₃ SO ₂ or CH ₃ CH ₂ SO ₂ , and the electron-withdrawing group is recommended to be alkyl, especially C ₁ ~C ₂₀ alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, especially recommended Z is H, Cl, Br, CH ₃ SO ₂ or NO ₂ . It is recommended that R ¹ , R ² =Me.; Z=NO ₂ ., it is further recommended that R ¹ , R ² =Me; Z=NO ₂ ; R ³ =tBu, especially recommended that R ¹ , R ² =Me; Z=NO ₂ ; R ³ = tert-butyldimethylsilyl or trityl, the recommended chiral ligand is a compound with the following structure:

A further recommended chiral ligand is a compound with the following structure:

Where R ¹ , R ² , and R ³ are as described above, and it is further recommended that R ¹ =R ² =Me.

Especially recommended chiral ligands are compounds with the following structure

为原料经过常规的上保护基方法进行保护得到

上保护基的方法参照T.W Greene et al.，Protectivegroups in Organic Synthesis 3rd Ed.John Wiley 1999。例如 中的2氨基可以在有机溶剂中先用相应的脂肪醛或芳香醛缩合再用还原剂还原实现氨基的保护，其中还原剂例如甲酸、NaBH₄、KBH₄LiAlH₄或Pd/C等；或者用R¹X或R²X在有机溶剂中和碱的作用下进行氨基保护，其中X为卤素；用异丁烯在酸催化下实现端羟基的叔丁基保护，或者用R³Cl实现端羟基的R³保护，得到上述配体；上述反应条件为常规的反应条件，所述的碱为无机碱或有机碱，例如K₂CO₃、Na₂CO₃、NaOH、KOH、NEt₃等。所述的有机溶剂例如：醇、卤代烷烃、醚等。具体例如，用甲醛和甲酸回流可以实现氨基双甲基保护，用苯甲醛缩合再用NaBH₄还原可以实现氨基的苄基保护。The above chiral ligands were synthesized with

The raw material is protected by a conventional protecting group method to obtain

The method of adding a protecting group refers to TW Greene et al., Protective groups in Organic Synthesis 3rd Ed. John Wiley 1999. For example The 2 amino groups in the organic solvent can be condensed with the corresponding aliphatic aldehyde or aromatic aldehyde in an organic solvent and then reduced with a reducing agent to realize the protection of the amino group, wherein the reducing agent is such as formic acid, NaBH ₄ , KBH ₄ LiAlH ₄ or Pd/C, etc.; or use R ¹ X or R ² X undergoes amino protection in an organic solvent and under the action of a base, where X is a halogen; use isobutylene to achieve tert-butyl protection of the hydroxyl terminal under acid catalysis, or use R ³ Cl to realize the R of the terminal hydroxyl ³ protection to obtain the above ligand; the above reaction conditions are conventional reaction conditions, and the base is an inorganic base or an organic base, such as K ₂ CO ₃ , Na ₂ CO ₃ , NaOH, KOH, NEt ₃ and the like. The organic solvents are, for example, alcohols, halogenated alkanes, ethers and the like. For example, reflux with formaldehyde and formic acid can achieve amino dimethyl protection, and condensation with benzaldehyde followed by reduction with NaBH ₄ can achieve benzyl protection of amino.

The present invention provides the use of the above-mentioned chiral ligands for asymmetric addition reactions, including asymmetric addition of terminal alkynes to imines. Specifically, it can be used for asymmetric synthesis of compounds with the following structures:

In the formula, Y is H, an electron-withdrawing group or an electron-pushing group, and the electron-withdrawing group is recommended to be halogen, CH ₃ O, OH, NO ₂ , CF ₃ , CH ₃ SO ₂ or CH ₃ CH ₂ SO ₂ , the electron-pushing group is recommended to be an alkyl group, especially a C ₁ -C ₂₀ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, It is further recommended that Y is H, Cl, Br, CH ₃ SO ₂ , CH ₃ CH ₂ SO ₂ , NO ₂ or F, especially that Y is Cl or F.

P is H or an amino protecting group,

Rf is a fluorine-containing hydrocarbon group, recommended as a C ₁ -C ₂₀ fluorine-containing alkyl group, and further recommended as a C ₁ -C ₄ fluorine-containing alkyl group, R is a trialkylsilyl group, aryl, alkyl or cycloalkyl , recommended as C ₁ -C ₂₀ alkyl or cycloalkyl, further recommended as C ₁ -C ₄ alkyl or cyclopropane, the aryl recommended as phenyl, naphthyl, substituted phenyl, N-containing , S or O heteroaryl such as pyridyl, furyl, thienyl, pyrrolyl, pyranyl, etc.;

Including the following steps:

(a) The chiral ligand (1R,2R)-2-N,N-substituted-1-substituted phenyl-3-O-substituted-1-propanol has the following structure

In the formula, R ¹ , R ² , R ³ ; Z is as described above;

mixed with a terminal alkyne and a metal salt in an organic solvent, and then adding an organic base, the terminal alkyne is R as previously described;

(b) adding a substrate with the following structure

In the formula, Y, P, Rf are as previously described;

The reaction formula is as follows:

It is recommended to add a proton source to quench the reaction and then isolate the product. The proton source is recommended saturated ammonium chloride aqueous solution, water, dilute or concentrated hydrochloric acid, or citric acid aqueous solution.

In the above method, the reaction molar ratio of ligand to substrate imine is recommended to be 0.1-3:1, further recommended to be 0.5-3:1, especially recommended to be 1.2-1.5:1.

The reaction molar ratio of the metal salt and the substrate imine in the above method is recommended to be 0.1-3:1, further recommended to be 0.5-3:1, especially recommended to be 1.2-1.5:1.

The molar ratio of ligand to terminal alkyne in the above method is recommended to be 0.1-3:1, further recommended to be 0.5-3:1, especially recommended to be 1.2-1.5:1.

The metal salt is recommended to be zinc salt or copper salt, further recommended to be Zn(II) or Cu salt, further recommended to be ZnCl ₂ , ZnBr ₂ , ZnF ₂ , ZnI ₂ , Zn(OTf) ₂ , Zn(SO ₃ CF ₂ H) ₂ , CuCl ₂ , CuBr ₂ , Cu(OTf) ₂ CuCl, CuBr, CuI, CuOTf, especially Zn(OTf) ₂ or Zn(SO ₃ CF ₂ H) ₂ .

The organic base is recommended to be an amine with a lone pair of electrons on the nitrogen atom, further recommended to be MeNiPr ₂ , HNEt ₂ , NiPr ₃ , Pyridine, piperidine, EtNiPr ₂ , NBu ₃ , NEt ₃ , especially recommended to be NEt ₃ .

The reaction molar ratio of organic base and substrate imine is 1-4:1, and 3:1 is recommended

In the above method, the organic solvent is recommended to be aprotic solvent or ether, further recommended to be THF, dioxane, Et ₂ O, benzene, DME, toluene, n-hexane, and cyclohexane or their mixtures, especially toluene is the recommended solvent.

In the above method, the reaction temperature is between 0°C and 100°C, preferably 0°C and 50°C, especially the recommended reaction temperature is 20-40°C.

The ligands of the present invention are recommended for the asymmetric synthesis of compounds with the following structures:

The reaction formula is as follows:

In the formula, P, Rf are as previously described;

It is further recommended that the ligand of the present invention is used for the asymmetric synthesis of the following structural compounds, and the reaction formula is as follows:

It is especially recommended that the ligand of the present invention is applied to the process of synthesizing compounds of the following structure

Including the following steps:

(a) It is recommended to use the chiral ligand (1R,2R)-2-N,N-substituted-1-(4-substituted phenyl)-3-O-substituted-1-propanol at 20-40°C , has the following structure

Where R ¹ and R ² are amino protecting groups, R ³ is oxygen protecting groups; R ¹ and R ² are recommended to be methyl, R ³ is recommended to be tert-butyl, Z is recommended to be H, Cl, Br, CH ₃ SO ₂ or NO ₂ ;

Mix with terminal alkyne and Zn(II) salt or Cu salt in an organic solvent, it is recommended to dissolve in an aprotic solvent, and then add an organic base, in which the terminal alkyne is as mentioned above, recommended to be cyclopropylacetylene, copper salt Or divalent zinc salt is recommended as zinc trifluoromethanesulfonate, protic solvent is recommended as toluene, organic base is recommended as triethylamine,

(b) Add a substrate with the following structure, and the reaction is recommended for 10 hours,

(c) adding a proton source to quench the reaction;

(d) The product is isolated.

Unless otherwise specified, the alkyl group described in the present invention refers to a branched or straight chain saturated aliphatic hydrocarbon functional group; the recommended alkyl group is 1 to 20 carbon numbers, and further recommended to be a branched or straight chain with 1 to 4 carbon numbers Saturated aliphatic hydrocarbon functional groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. Halogen is fluorine, chlorine, bromine or iodine.

In the present invention, R ¹ and R ² are any suitable amino protecting groups including but not limited to alkyl, substituted alkyl, benzyl, substituted benzyl or N-trialkylsilyl protecting groups and the like. The amino protecting group mentioned above is recommended to be C ₁ -C ₂₀ alkyl, substituted alkyl, benzyl, substituted benzyl or N-trialkylsilyl protecting group, etc. The substituents on the alkyl or benzyl are recommended phenyl, naphthyl, halogen, nitro, C ₁ ~C ₃ hydroxyl, C ₁ ~C ₃ hydroxyalkyl, C ₁ ~C ₃ alkoxy, CN wait. P, R ¹ and R ² such as C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl substituted or unsubstituted benzyl; p-methoxybenzyl; p-nitrobenzyl; p-chlorobenzyl 2,4-dichlorobenzyl; 2,4-dimethoxybenzyl; or N-trimethylsilyl protecting group, other amino protecting groups refer to TWGreene et al., Protective groups in Organic Synthesis 3rd Ed .John Wiley 1999, pp.494-653. A recommended amino protecting group is p-methoxybenzyl.

In the present invention, P is H or any suitable amino protecting group, the amino protecting group is as described above.

In the present invention, ^R3 is any suitable oxygen protecting group including but not limited to alkyl, substituted alkyl, benzyl, substituted benzyl or O-trialkylsilyl protecting group and the like. The above oxygen protecting group is recommended to be C ₁ -C ₂₀ alkyl, substituted alkyl, benzyl, substituted benzyl or O-trialkylsilyl protecting group. The substituents on the alkyl or benzyl are recommended phenyl, naphthyl, halogen, nitro, C ₁ ~C ₃ hydroxyl, C ₁ ~C ₃ hydroxyalkyl, C ₁ ~C ₃ alkoxy, CN wait. R ³ such as C ₁ -C ₄ alkyl, benzhydryl, tert-butyldimethylsilyl, C ₁ -C ₄ alkyl substituted or unsubstituted benzyl, p-methoxybenzyl, p-nitro Benzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 2,4-dimethoxybenzyl p-methoxybenzyl; p-nitrobenzyl; p-chlorobenzyl; 2,4-dichlorobenzyl Benzyl; 2,4-dimethoxybenzyl; or tert-butyldimethylsilyl protecting group. For other oxygen protecting groups, refer to TW Greene et al., Protective groups in Organic Synthesis 3rd Ed. John Wiley 1999, pp.17-245. The recommended oxygen protecting group is tert-butyl.

The ligand provided by the present invention can be further applied to the synthesis of DPC 961 and DPC 083, the synthesis method is:

DPC 083 was obtained after reduction of DPC 961 (Journal of Medicinal Chemistry vol.43, NO.10, 2000, 2019-2030).

The present invention provides a new ligand, which is applied to asymmetric synthesis, especially through the asymmetric addition of copper alkyne or zinc alkyne to trifluoromethylimino intermediates involved in the ligand to generate products The ee value of propargyl ammonia is as high as 99%, the high optical activity of the product and very mild reaction conditions, and the chiral ligands in the reaction can be easily recycled and reused. These advantages make this process have good industrialization prospects. The compound can generate HIV transferase inhibitor drugs DPC 961 and DPC 083 through simple transformation.

The following examples help to understand the patent but do not limit the scope.

Example 1

(1R, 2R)-2-N, the preparation of N-dimethylamino 3-p-nitrophenyl-1,3-propanediol:

Reference Jiang, B.; Chen, Z.L.; Tang, X.X.Org.Lett.2002, 4, 3451. Synthesis

Example 2

(1R, 2R)-3-tert-butoxy-2-N, the preparation of N-dimethylamino-1-p-nitrophenyl-1-propanol:

At 0-5°C, add 0.8 g of concentrated sulfuric acid dropwise into (1R, 2R)-2-N, N-dimethylamino-3-p-nitrophenyl-1,3-propanediol (1.8 g, 7.5 mmol) in CH ₂ Cl ₂ (20mL) solution. Isobutene gas was maintained at 0-5°C for one hour. Then 0.2 g of concentrated sulfuric acid was added dropwise, the mixture was returned to room temperature and stirred vigorously for 5-7 h, and isobutene gas was continuously introduced. The mixture was cooled to 0-5°C and saturated K ₂ CO ₃ solution was added. The organic phase was dried (Na ₂ SO ₄ ), concentrated and purified by recrystallization to obtain ligand 1.44g (65%).mp 100.0-101.3°C; [α] _D ²⁰ =+23.5 (c, 1.00, CHCl ₃ ); )3333, 2972, 1606, 1523, 1357, 1197, 861cm ^-1 ; ¹ HNMR (300MHz, CDCl ₃ ) δ8.19 (d, J=8.8Hz, 2H), 7.60 (d, J=8.4Hz, 2H) , 4.59(d, J=9.9Hz, 1H), 3.34(dd, J=3.0Hz, and 9.9Hz, 1H), 3.21(dd, J=6.5Hz, and 10Hz, 1H), 2.56(m, 1H) , 2.47(s, 6H), 1.06(s, 9H); ¹³ CNMR (75MHz, CDCl ₃ ) δ150.6, 147.6, 128.46, 123.49, 73.3, 70.3, 69.8, 56.0, 41.8, 27.4; MS(EI)m /e 223 (M+-73, 3), 209 (21), 144 (68), 88 (100), 71 (10), 57 (31); Anal.calcd.for C ₁₅ H ₂₄ N ₂ O ₄ : C, 60.81; H, 8.11; N, 9.46. Found: C, 60.72; H, 8.26; N, 914.

Example 3

Preparation of (1R, 2R)-3-tert-butyldimethylsilyloxy-2-N, N-dimethylamino-1-p-nitrophenyl-1-propanol: (1R, 2R)-2-N , N-dimethylamino-3-p-nitrophenyl-1,3-propanediol (1.946 g, 8.1 mmol) was dissolved in CH ₂ Cl ₂ (30 mL), TBDMSCl (1.28 g, 5.3 mmol) and imidazole were added at 0° C. (1.4g, 20.6mmol) After the mixture was stirred overnight, the product 2.72g was obtained. FTIR (KBr) 3344, 2954, 1606, 1525, 1349cm ^-1 ; ¹ HNMR (300MHz, CDCl ₃ ) δ8.25-8.20 (d, J =8.5Hz, 2H), 7.6-7.55 (d, J = 8.5Hz, 2H), 4.65 (d, J = 9.7Hz, 1H), 3.77-3.6 (dd, J = 11.3Hz, 2.7Hz 1H), 3.5 -3.45(dd, J=11.3Hz, 6.0Hz 1H 2.50(m, 7H), 1.85(s, 8H), 0.1(s, 6H); ¹³ CNMR(75MHz, CDCl ₃ ) δ150.2, 147.4, 128.0, 123.3, 69.0, 57.1, 41.6, 25.7, 17.9, -5.9; MS (EI) m/e 297 (M+-57, 0.3), 209 (8.2), 202 (100). Anal.calcd.for C ₁₇ H ₃₀ N ₂ O ₄ Si: C, 57.60; H, 8.53; N, 7.90. Found: C, 57.82; H, 8.18; N, 7.77.

Example 4

(1R, 2R)-3-trityloxy-2-N, the preparation of N-dimethylamino-1-p-nitrophenyl-1-propanol:

(1R,2R)2-N,N-Dimethylamino-3-p-nitrophenyl-1,3-propanediol (1.946g, 8.1mmol) was dissolved in CH ₂ Cl ₂ (50mL), and triphenyl was added at 0°C The mixture of methyl chloride (3.34g, 12mmol) and triethylamine (2mL) was stirred overnight to obtain 4.8g of the product. FTIR (KBr) 3344, ²⁹⁵⁴ , 1606, 1525, _1349cm ^-1 ; δ8.09-8.06(d, J=8.4Hz, 2H), 7.36-7.33(d, J=8.6Hz, 2H), 7.25-7.17(m, 5H), 4.27(d, J=10.0Hz, 1H) , 3..28(dd, J=10.2Hz, 6.4Hz 1H), 3.01(dd, J=10.7Hz, 3.9Hz 1H), 2.71(m, 1H), 2.45(s, 6H), 0.1(s, 6H); ¹³ CNMR (75MHz, CDCl ₃ ) δ150.1, 147.6, 143.6, 128.9, 128.8, 128.7, 128.6, 128.4, 128.1, 127.9, 127.8, 127.3, 123.7, 87.7, 70.9, 70.6, 58.6, 41.6

Example 5

Preparation of (1R,2R)-2-N-benzyl-N-methylamino-3-p-nitrophenyl-1,3-propanediol:

(1R,2R)-2-Amino-3-p-nitrophenyl-1,3-propanediol (2.12g, 10mmol) and benzaldehyde (1.2g, 10.5mmol) were added to methanol (10mL), and CuSO ₄ ( 0.2g). The mixture was refluxed for 7 hr, cooled to room temperature, filtered, and THF (10 mL) was added to the filtrate. Then NaBH ₄ (0.4 g) was added in portions. The mixture was refluxed for 2 hrs and then cooled. 5% HCl was added to acidify the solution. It was extracted and concentrated with ether. The residue was reacted with HCHO (10 mL) and HCOOH (10 mL) at reflux for 8 hr. Cooled and neutralized with NaOH. After extraction with CH ₂ Cl ₂ , drying with NaSO ₄ and recrystallization and purification, 1.2 g of the product was obtained, which was directly reacted in the next step.

Example 6

(1R,2R)-3-tert-butyldimethylsilyloxy-2-N-benzyl-N-methylamino-1-(p-nitrophenyl)-1-propanol:

(1R,2R)-2-N-Benzyl-N-methylamino-3-p-nitrophenyl-1,3-propanediol (632mg) was dissolved in CH ₂ Cl ₂ (15mL), cooled to 0°C and then Tert-butyldimethylsilyl chloride (300 mg, 2 mmol) and pyrimazole (136 mg, 2 mmol) were added. The mixture was reacted overnight. After treatment, 600 mg of the product was obtained. FTIR (KBr) 3344, 2972, 1606, 1525, 1348cm ^-1 ; ¹ HNMR (300MHz, CDCl ₃ ) δ8.17 (d, J=8.8Hz, 2H), 7.50 (d, J=8.4Hz, 2H), 7.38-7.31(m, 5H), 4.70(d, J=9.6Hz, 1H), 4.04(d, J=13.0Hz, 1H), 3.77-3.55(m, 3H), 2.70(m, 1H), 2.43 (s, 3H), 0.90 (s, 9H), 0.01 (s, 6H); ¹³ CNMR (75MHz, CDCl ₃ ) δ150.6, 147.6, 138.46, 129.2, 128.8, 128.4, 127.7, 123.69, 70.3, 69.8, 60.1, 58.0, 37.5, 26.0, 18.3, -5.4; MS(EI) m/e 415(M+-15, 0.9), 278(100), 91(73);

Example 7

(1R,2R)-3-(triphenylmethoxy)-2-N-benzyl-N-methylamino-1-(p-nitrophenyl)-1-propanol:

(1R,2R)-2-N-Benzyl-N-methylamino-3-p-nitrophenyl-1,3-propanediol (380 mg, 1.2 mmol) was dissolved in CH ₂ Cl ₂ (15 mL) at 0° C. Triphenylchloromethane (334 mg, 1.2 mmol) and _Et3N (0.2 mL) were added. After stirring overnight, 500 mg of the product was isolated. mp58.0-59.3°C; FTIR (KBr) 3314, 2926, 1602, 1521, 1346cm ^-1 ; ¹ HNMR (300MHz, CDCl ₃ ) δ8.07(d, J=8.8Hz, 2H), 7.40-7.19(m , 22H), 4.30(d, J=9.6Hz, 1H), 3.94(d, J=13.0Hz, 1H), 3.73(d, J=6.8Hz, 1H), 3.36(m, 1H), 3.06(m , 1H) 2.89 (m, 1H), 2.33 (s, 3H); ¹³ CNMR (75MHz, CDCl ₃ ) δ150.6, 147.6, 143.46, 138.2, 129.3, 128.8, 128.7, 128.6, 128.4, 128.0, 127.7 127.4, 123.7, 87.8, 70.5, 69.8, 60.1, 58.0, 37.0; MS (EI) m/e 406 (M+-152, 24.9), 243 (100); Anal.calcd.for C ₁₅ H ₂₄ N ₂ O ₄ : C , 77.42; H, 6.09; N, 5.02.Found: C, 77.26; H, 6.06; N, 4.65..

Example 8

Synthesis of (1R, 2R)-3-(triphenylmethoxy)-2-N,N-dimethylamino-1-(phenyl)-1-propanol (1R,2R)-2-N, N-Dimethylamino-1-(phenyl)-1,3-propanediol (1.95g, 10mmol) was dissolved in CH ₂ Cl ₂ (50mL), triphenylchloromethane (3.33g, 12mmol) was added at 0°C and Triethylamine (2mL) was stirred overnight at room temperature to obtain 4.0g of the product. FTIR (KBr) 3344, 2954, 1609, 1525, 1349cm ^-1 ; ¹ HNMR (300MHz, CDCl ₃ ) δ 7.26-7.06 (m, 20H) , 4.87(d, J=10.0Hz, 1H), 3.76(dd, J=10.2Hz, 6.4Hz 1H), 3.51(dd, J=10.7Hz, 3.9Hz 2H), 2.80(m, 1H), 2.38( s, 6H); ¹³ CNMR (75MHz, CDCl ₃ ) δ143.6, 138.9, 128-129 (16C), 125.7-126.6 (4C), 84.9, 72.9, 68.6, 69.6, 49.6, 39.6.

Example 9

Synthesis of (1R,2R)-3-(triphenylmethoxy)-2-N,N-dimethylamino-1-(p-methylsulfonylphenyl)-1-propanol

(1R,2R)-2-N,N-Dimethylamino-1-(p-methylsulfonylphenyl)-1,3-propanediol (5.46 g, 20 mmol) was dissolved in CH ₂ Cl ₂ (80 mL), 0 °C Triphenylchloromethane (6.8g, 25mmol) and triethylamine (4mL) were added under the same conditions and stirred overnight at room temperature to obtain 9.10g of the product. FTIR (KBr) 3344, 2954, 1609, 1525, 1349cm ^-1 ; ¹ HNMR (300MHz, CDCl ₃ ) δ7.48-7.40(d, J=8.4Hz, 2H), 7.27-7.19(d, J=8.6Hz , 2H), 7.12-7.04(m, 15H), 4.86(d, J=10.0Hz, 1H), 3.72(dd, J=10.2Hz, 6.4Hz 1H), 3.56(dd, J=10.2Hz, 6.4Hz 2H), 2.94(s, 3H), 2.81(m, 1H), 2.38(s, 6H); ¹³ CNMR (75MHz, CDCl ₃ ) δ143.8, 143.0, 138.6, 135.0, 129-126(16C), 84.9 , 72.9, 69.6, 68.0, 49.6, 41.0, 39.6.

Example 10

Addition of cyclopropylacetylene to imino

At 25°C, the aminoalcohol ligand (1R,2R)-3-tert-butoxy-2-N,N-dimethylamino-1-p-nitrophenyl-1-propanol (2.96g, 10mmol) and Zn (OTf) ₂ (3.6 g, 10 mmol) was dissolved in toluene (10 mL). Additional _NEt3 (2.1 mL, 15 mmol) was added. After one hour cyclopropylacetylene (1.2 mL, 12 mmol) and p-methoxybenzyl protected imine (3.69 g, 10 mmol) were added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with saturated citric acid. Ethyl acetate extraction. The organic phases were combined and dried, then concentrated to obtain the product (95% yield, 99.3% ee), and the aqueous phase was neutralized with sodium hydroxide to recover the ligand.

Example 11

Preparation of DPC 961

N-p-methoxybenzyl protected DPC 961 (2 mmol) was dissolved in 10% aqueous CH ₃ CN (10 mL), and ceric ammonium nitrate (4.4 g, 8 mmol) was added. React at 25°C for 4 hours. The system was extracted with ethyl acetate diluted with water. DPC 961 was obtained after concentration (80% yield).

Example 12

Addition of cyclopropylacetylene to imino

At 25°C, the aminoalcohol ligand (1R, 2R)-3-tert-butyldimethylsilyloxy-2-N, N-dimethylamino-1-p-nitrophenyl-1-propanol (3.54g , 10 mmol) and Zn(OTf) ₂ (3.6 g, 10 mmol) were dissolved in toluene (10 mL). Additional _NEt3 (2.1 mL, 15 mmol) was added. After one hour cyclopropylacetylene (1.2 mL, 12 mmol) and p-methoxybenzyl protected imine (3.69 g, 10 mmol) were added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with saturated citric acid. Ethyl acetate extraction. The organic phases were combined, dried and concentrated to obtain the product (72% yield, 99.1% ee).

Example 13

Addition of cyclopropylacetylene to imino

Amino alcohol ligand (1R,2R)-3-triphenylmethoxy-2-N,N-dimethylamino-1-p-nitrophenyl-1-propanol (4.82g, 10mmol) at 25°C and Zn(OTf) ₂ (3.6 g, 10 mmol) were dissolved in toluene (10 mL). Additional _NEt3 (2.1 mL, 15 mmol) was added. After one hour cyclopropylacetylene (1.2 mL, 12 mmol) and p-methoxybenzyl protected imine (3.69 g, 10 mmol) were added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with saturated citric acid. Ethyl acetate extraction. The organic phases were combined, dried and concentrated to obtain the product (76% yield, 98.0% ee).

Example 14

Addition of cyclopropylacetylene to imino

At 25°C, the aminoalcohol ligand (1R, 2R)-3-triphenylmethoxy-2-N-benzyl-N-methylamino-1-p-nitrophenyl-1-propanol (5.58g , 10 mmol) and Zn(OTf) ₂ (3.6 g, 10 mmol) were dissolved in toluene (10 mL). Additional _NEt3 (2.1 mL, 15 mmol) was added. After one hour cyclopropylacetylene (1.2 mL, 12 mmol) and p-methoxybenzyl protected imine (3.69 g, 10 mmol) were added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with saturated aqueous ammonium chloride. Ethyl acetate extraction. The organic phases were combined and dried to obtain the product (80% yield, 51.0% ee).

Example 15

Addition of cyclopropylacetylene to imino

At 25°C, the aminoalcohol ligand (1R, 2R)-3-triphenylmethoxy-2-N-benzyl-N-methylamino-1-p-nitrophenyl-1-propanol (5.58g , 10 mmol) and Cu(OTf) ₂ (3.6 g, 10 mmol) were dissolved in toluene (10 mL). Additional _NEt3 (2.1 mL, 15 mmol) was added. After one hour cyclopropylacetylene (1.2 mL, 12 mmol) and p-methoxybenzyl protected imine (3.69 g, 10 mmol) were added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with saturated citric acid. Ethyl acetate extraction. The organic phases were combined, dried and concentrated to obtain the product (68% yield, 98.0% ee).

Example 16

Addition of cyclopropylacetylene to imino

At 25°C, the aminoalcohol ligand (1R, 2R)-3-tert-butyldimethylsilyloxy-2-N, N-dimethylamino-1-p-nitrophenyl-1-propanol (354mg, 1mmol ) and Zn(OTf) ₂ (0.36 g, 1 mmol) were dissolved in toluene (10 mL). Additional _NEt3 (0.21 mL, 1.5 mmol) was added. After one hour cyclopropylacetylene (1.2 mL, 12 mmol) and p-methoxybenzyl protected imine (3.69 g, 10 mmol) were added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with dilute hydrochloric acid. Ethyl acetate extraction. The organic phases were combined, dried and concentrated to obtain the product. (75% yield, 98.1% ee).

Example 17

Addition of cyclopropylacetylene to imino

At 25°C, the aminoalcohol ligand (1R, 2R)-3-triphenylmethoxy-2-N-benzyl-N-methylamino-1-p-nitrophenyl-1-propanol (558 mg, 1 mmol) and Cu(OTf) ₂ (0.36 g, 1 mmol) were dissolved in toluene (10 mL). Additional _NEt3 (0.21 mL, 1.5 mmol) was added. After one hour cyclopropylacetylene (1.2 mL, 12 mmol) and p-methoxybenzyl protected imine (3.69 g, 10 mmol) were added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with saturated citric acid. Ethyl acetate extraction. The organic phases were combined, dried and concentrated to obtain the product (67% yield, 45% ee).

Example 18

Addition of tert-butylacetylene to imino

At 25°C, the aminoalcohol ligand (1R, 2R)-3-tert-butyldimethylsilyloxy-2-N, N-dimethylamino-1-p-nitrophenyl-1-propanol (3.54g , 10 mmol) and Zn(OTf) ₂ (3.6 g, 10 mmol) were dissolved in toluene (10 mL). Additional _HNiPr2 (2.0 mL) was added. After one hour tert-butylacetylene (1.3 mL, 12 mmol) and p-methoxybenzyl protected imine (3.69 g, 10 mmol) were added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with saturated citric acid. Ethyl acetate extraction. The organic phases were combined, dried and concentrated to obtain the product (45% yield, 96.5% ee).

Example 19

Addition of cyclopropylacetylene to imino

At 25°C, the aminoalcohol ligand (1R, 2R)-3-tert-butyldimethylsilyloxy-2-N, N-dimethylamino-1-p-nitrophenyl-1-propanol (3.54kg , 10 mol) and Zn(OTf) ₂ (3.6 kg, 10 mol) were dissolved in toluene (10 L). Additional triethylamine (2.0 L, 15 mol) was added. After one hour cyclopropylacetylene (1.2 L, 12 mol) and p-methoxybenzyl protected imine (3.69 kg, 10 mmol) were added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with saturated citric acid. Ethyl acetate extraction. The organic phases were combined and dried to obtain the product (90.9% yield, 99.1% ee)

Example 20

Addition of phenylacetylene to imine

At 25°C, the aminoalcohol ligand (1R,2R)-3-tert-butoxy-2-N,N-dimethylamino-1-p-nitrophenyl-1-propanol (2.96g, 10mmol) and Zn (OTf) ₂ (3.6 g, 10 mmol) was dissolved in THF (10 mL). Additional _NEt3 (2.1 mL, 15 mmol) was added. After one hour phenylacetylene (1.1 mL, 12 mmol) and p-methoxybenzyl protected imine (3.69 g, 10 mmol) were added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with saturated citric acid. Ethyl acetate extraction. The organic phases were combined, dried and concentrated to obtain the product (91% yield, 99.0% ee).

Example 21

Addition of cyclopropylacetylene to imino

At 25°C, the aminoalcohol ligand (1R, 2R)-3-tert-butyldimethylsilyloxy-2-N, N-dimethylamino-1-p-nitrophenyl-1-propanol (3.54g , 10 mmol) and Zn(OTf) ₂ (3.6 g, 10 mmol) were dissolved in toluene (10 mL). Additional _NEt3 (2.1 mL, 15 mmol) was added. One hour later, cyclopropylacetylene (1.2 mL, 12 mmol) was added, the mixture was reacted at 50° C. for 2 hrs and then heated to 25° C., and p-methoxybenzyl-protected imine (3.69 g, 10 mmol) was added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with saturated citric acid. Ethyl acetate extraction. The organic phases were combined and dried to obtain the product (81% yield, 97.1% ee).

Example 22

Addition of cyclopropylacetylene to imino

At 25°C, the aminoalcohol ligand (1R, 2R)-3-tert-butyldimethylsilyloxy-2-N, N-dimethylamino-1-p-nitrophenyl-1-propanol (3.54g , 10 mmol) and ZnBr ₂ (2.3 g, 10 mmol) were dissolved in toluene (10 mL). Additional _NEt3 (2.1 mL, 15 mmol) was added. One hour later, cyclopropylacetylene (1.2 mL, 12 mmol) was added, the mixture was reacted at 50° C. for 2 hrs and then heated to 25° C., and p-methoxybenzyl-protected imine (3.69 g, 10 mmol) was added. The mixture was reacted at 25°C for 10 hr. The reaction was quenched with saturated citric acid. Ethyl acetate extraction. The organic phases were combined, dried and concentrated to obtain the product (31% yield, 63.1% ee).

Claims (10)

1 one kinds of chiral amino alcohol ligands have following general structure:

, R wherein ¹, R ²Be amino protecting group, R ³It is the oxygen protecting group; Z is H, electron-withdrawing group or electron donating group, and described amino protecting group comprises alkyl, substituted alkyl, benzyl, substituted benzyl or trialkyl silyl protecting group; Described oxygen protecting group comprises C ₁～C ₂₀Alkyl, replace C ₁～C ₂₀Alkyl, benzyl, substituted benzyl or trialkyl silyl protecting group, the substituting group on described alkyl or the benzyl comprises phenyl, naphthyl, halogen, nitro, C ₁～C ₃Hydroxyl, C ₁～C ₃Hydroxyalkyl, C ₁～C ₃Alkoxyl group, CN, described electron-withdrawing group are halogen, CH ₃O, OH, NO ₂, CF ₃, CH ₃SO ₂Perhaps CH ₃CH ₂SO ₂, described electron donating group is C ₁～C ₂₀Alkyl.

2. part as claimed in claim 1 has following general structure:

R wherein ¹, R ², R ³According to claim 1.

3. the described part of claim 1 has following general structure:

4. part as claimed in claim 1 is characterized in that described electron donating group is C ₁～C ₄Alkyl, described trialkyl silyl is the silica-based or trityl of tertiary butyl dimethyl.

5. the application of the part of claim 1 in asymmetric synthesis, the technology that it is characterized in that being used for synthesizing following structure chipal compounds:

Wherein P is H or amino protecting group, and Rf contains C ₁～C ₂₀Fluoroalkyl, R is trialkyl silyl, C ₁～C ₂₀Alkyl, C ₃～C ₁₀Cycloalkyl or aryl, Y is H, electron-withdrawing group or electron donating group, described amino protecting group, electron-withdrawing group or electron donating group are according to claim 1.

6. technology as claimed in claim 4 is characterized in that comprising the steps:

(a) (1R, 2R)-2-N, N-replacement-1-substituted-phenyl-3-O-replacement-1-propyl alcohol has following structure with chiral ligand

R wherein ¹, R ², R ³Z according to claim 1;

Be mixed in a kind of organic solvent with Terminal Acetylenes and metal-salt, described Terminal Acetylenes is

R such as preceding

Described, add organic bases again;

(b) adding has the substrate of following structure to react

P is H or amino protecting group as claimed in claim 1 in the formula, and Rf and Y are as described in the claim 4.

7. the described technology of claim 6 is characterized in that reacting the back and adds proton source cancellation reaction, separates obtaining product, chiral ligand by in the alkali and water extract again and reclaim use.

8. as technology as described in the claim 6, it is characterized in that being used for synthetic following structure chipal compounds

Comprise the steps:

(a) (1R, 2R)-2-N, N-replacement-1-(4-substituted-phenyl)-3-O-replacement-1-propyl alcohol has following structure with chiral ligand

R wherein ¹, R ²And R ³According to claim 1; Z is H, Cl, Br, CH ₃SO ₂Perhaps NO ₂Be mixed in the organic solvent with Terminal Acetylenes and Zn (II) salt or Cu salt, described Terminal Acetylenes is

R adds organic bases again as described in the claim 5;

(b) add the substrate that following structure is arranged

(a) add proton source cancellation reaction;

(b) separate and to obtain product, in the water alkali and reclaim part.

9. as technology as described in the claim 6, wherein the reaction mole proportioning of organic bases, part and substrate imido is 1-4: 0.1-3: 1.

10. as technology as described in the claim 6, described metal-salt is for comprising ZnCl ₂, ZnBr ₂, ZnF ₂, ZnI ₂, Zn (OTf) ₂, Zn (SO ₃CF ₂H) ₂, CuCl ₂, CuBr ₂, Cu (OTf) ₂, a kind of in interior Zn (II) or Cu salt of CuCl, CuBr, Cu (OTf), CuI; Described organic bases is dimethyl Isopropylamine, diethylamine, tri-isopropyl amine, pyridine, piperidines, ethyl diisopropylamine, Tributylamine or triethylamine.