A method for preparing a cyclic chiral nitrile compound and its application in preparing ramelteon

Abstract

The invention discloses a method for preparing a cyclic chiral nitrile compound and its application in preparing ramelteon, and the preparation steps are as follows: first, a chiral rhodium catalyst is prepared using a rhodium metal precursor and a chiral diphosphine ligand as raw materials; then, a chiral rhodium catalyst is used to catalyze an α, β-unsaturated nitrile outside the ring for asymmetric hydrogenation reaction, and a cyclic chiral nitrile compound is successfully prepared. Compared with the existing method for synthesizing cyclic chiral nitrile compounds, the method of the present invention is simple and practical to operate, has high atom economy, high catalytic efficiency, high yield and high ee value. The present invention also provides a reduction acylation reaction of 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile with propionic anhydride and sodium borohydride under nickel catalysis, and ramelteon is successfully prepared. The method has the characteristics of simple operation and higher yield, which provides a more efficient, convenient and safe method for the synthesis of ramelteon.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a cyclic chiral nitrile compound and application of the cyclic chiral nitrile compound in the preparation of ramelteon. Background Art

[0002] Optically pure chiral nitrile compounds are key intermediates for many biologically active compounds and drug molecules (such as anti-epileptic drugs, antidepressants, insomnia treatment drugs, etc.). Among them, Ramelteon is the first melatonin receptor agonist approved by the FDA and can be used to treat insomnia caused by difficulty falling asleep. It can selectively induce MT1 and MT2 receptors and has no affinity for MT3. Compared with other similar drugs approved by the FDA, Ramelteon has no risk of drug dependence and addiction. Based on the importance of Ramelteon in the future treatment of insomnia, the development of more efficient and concise synthesis methods has very important research significance in the fields of organic synthesis and drug synthesis.

[0003] At present, there are many reports on the asymmetric synthesis of ramelteon. For example, Takeda Corporation of Japan (J. Med. Chem., 2002, 45, 4212-4221.) reported an asymmetric synthesis of ramelteon; Takeda Corporation of Japan reported that Ru(OAc)2[(S)-BINAP] was used as a catalyst to achieve an enantioselective hydrogenation reaction of allyl amide, and the corresponding hydrogenated product showed excellent enantioselectivity (92% ee), and then ramelteon was obtained by reducing the amide group. Japanese patent JP11140073 discloses that (E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride was obtained with an ee value of 88.88% under a hydrogen pressure of 100 atm by using Ru2Cl2[(R)-BINAP]2Net3 as a catalyst for an asymmetric hydrogenation reaction, and an optically pure product was obtained after two recrystallizations, with a total yield of 68%. Yamashita et al. (Chem. Lett., 2009, 38, 100-101.) used the complex formed by [Rh(COD)Cl]2 and JosiPhos as a catalyst to achieve the asymmetric hydrogenation reaction of allylamine and synthesize the corresponding chiral primary amine. Lv Wei et al. (Hetreocycles, 2012, 85, 73-84.) synthesized ramelteon by highly enantioselective asymmetric Michael addition. Chinese patent CN102924410 discloses the use of a resolution agent (such as S-ibuprofen, L-(-)-dibenzoyltartaric acid, L-pyroglutamic acid, etc.) to obtain the key chiral intermediate of ramelteon by resolution of racemic primary amines;

[0004] Cluzeaud et al. (J. Org. Chem., 2022, 87, 2129-2135.) developed a six-step all-asymmetric synthesis of ramelteon using 3-hydroxyacetophenone as a substrate, including iridium-catalyzed o-vinylation, rhodium-catalyzed cyclization of vinyl ethers via directional CH bond activation, copper-catalyzed hydrosilylation of exocyclic α,β-unsaturated nitriles, and nickel-catalyzed cyano reduction (see the specific synthesis route for details). Figure 1 ). Among them, Cu(OAc)2 / WalPhos catalyzed the asymmetric reduction of exocyclic α,β-unsaturated nitriles to obtain the corresponding chiral nitrile products with a yield of 85% and an ee value of 97%.

[0005] However, the above methods have limitations such as many by-products, high environmental pollution, cumbersome operations, and high production costs. Therefore, the development of more efficient and highly enantioselective methods is still of great significance and application value. Asymmetric hydrogenation reactions have the characteristics of high atom economy, high efficiency, and low environmental impact, and are considered to be one of the most efficient methods for synthesizing optically pure products using prochiral substrates. The synthesis of the corresponding chiral nitrile is achieved through the rhodium-catalyzed asymmetric hydrogenation reaction of α,β-unsaturated nitrile, and its application in the preparation of ramelteon has high synthetic practicality.

[0006] To date, researchers have developed many methods for the synthesis of chiral nitriles with high enantioselectivity. Traditional methods include the enantioselective addition of cyanide to highly reactive electrophilic reagents (including aldehydes, ketones, imines, and electron-deficient olefins). In addition, copper-catalyzed enantioselective radical cyanation functionalization of olefins and enantioselective radical cyanation by carbon-carbon bond cleavage have also been developed in recent years. However, the substrate types of these methods are very limited and the catalyst dosage is high. In comparison, the transition metal-catalyzed asymmetric hydrogenation of α,β-unsaturated nitriles has the characteristics of high efficiency, atom economy, and low environmental impact. It is one of the most effective and widely used reactions for synthesizing optically pure products using prochiral substrates. At present, this strategy has been used in the asymmetric synthesis of chiral nitriles. In the reported transition metal-catalyzed asymmetric hydrogenation reactions of α,β-unsaturated nitriles, it is usually necessary to introduce auxiliary coordination groups to achieve high efficiency and excellent enantioselectivity, for example, β-aminoacrylonitrile (Chem. Eur. J., 2010, 16, 5301-5304.), β-aryloxy / alkoxycinnamonitrile (Org. Lett., 2016, 18, 4916-4919.), α,β-unsaturated nitriles containing ester or amide groups (Org. Biomol. Chem., 2016, 14, 4046-4053.), α-aminoacrylonitrile (Chem. Commun., 2017, 53, 1313-1316.), β-cyanocinnamyl ester (Chem. Sci., 2018, 9, 1919-1924.), etc. Pfaltz et al. (Angew. Chem. Int. Ed., 2014, 53, 8668-8671.) achieved the asymmetric hydrogenation of 3,3-disubstituted α,β-unsaturated nitriles catalyzed by iridium / N,P-complexes, and obtained a series of corresponding chiral nitrile compounds with moderate to excellent enantioselectivity. Hou Guohua et al. (J. Am. Chem. Soc., 2015, 137, 10177-10181.) reported the asymmetric hydrogenation of (E)- and (Z)-configured 3,3-substituted α,β-unsaturated nitriles catalyzed by rhodium / f-spiroPhos, showing excellent catalytic activity (up to 99.9% ee, turnover number up to 10000).

[0007] Although the transition metal-catalyzed asymmetric hydrogenation of non-functionalized α,β-unsaturated nitriles has been achieved, there have been no reports on the asymmetric hydrogenation of cyclic α,β-unsaturated nitriles to prepare cyclic chiral nitrile compounds and the use of the hydrogenation products to prepare ramelteon. Summary of the invention

[0008] In view of the problems existing in the above-mentioned prior art, the object of the present invention is to provide a method for preparing a cyclic chiral nitrile compound and its application in preparing ramelteon. The preparation method has the advantages of simple operation, environmental friendliness, high atom economy, high catalytic efficiency (up to 4000 turnover number), and high ee value.

[0009] In order to achieve the above object, the present invention adopts the following technical solutions:

[0010] The first aspect of the present invention provides a method for preparing a cyclic chiral nitrile compound, comprising the following steps:

[0011] S1. Under a protective gas atmosphere, a rhodium metal precursor and a chiral diphosphine ligand are added to a solvent, and stirred for reaction to obtain a chiral rhodium catalyst;

[0012] S2, subjecting the exocyclic α,β-unsaturated nitrile of structure as shown in formula I to an asymmetric hydrogenation reaction under the action of a hydrogen atmosphere and a chiral rhodium catalyst to obtain a cyclic chiral nitrile compound of structure as shown in formula II;

[0013]

[0014] In formula II, * represents a chiral carbon atom;

[0015] In formula I or II, R is selected from any one of C1-C8 alkyl, C1-C6 alkoxy or halogen;

[0016] In formula I or II, X is selected from any one of C1-C3 alkylene, C1-C2 alkyleneoxy, -NHCH2-, -N(Ac)CH2-, and -N(Bn)CH2-.

[0017] Preferably, in step S1, the molar ratio of the rhodium metal precursor to the chiral diphosphine ligand is 1:1.1 to 1.6; for example, it can be selected from: 1:1.1, 1:1.2, 1:1.3 or 1:1.6; more preferably 1:1.1.

[0018] Preferably, in step S1, the reaction time is 10 to 60 min; for example, it can be selected from 10 min, 20 min, 30 min, 40 min or 60 min; more preferably, it is 20 to 30 min;

[0019] Preferably, in step S1, the reaction temperature is 20-40°C; for example, the reaction temperature is selected from: 20°C, 25°C, 30°C or 40°C, and more preferably 25°C.

[0020] Preferably, the rhodium metal precursor is di(1,5-cyclooctadiene) rhodium tetrafluoroborate; the chiral diphosphine ligand is any one of (R,R)-f-spiroPhos, (S)-BINAP, (S)-Segphos or JosiPhos, wherein the JosiPhos includes (S,R P )-JosiPhos-1, (R,S P )-JosiPhos-2, (R,S P )-JosiPhos-3, (R,S P )-JosiPhos-4, (S,R P )-JosiPhos-5, (S,R P )-JosiPhos-6, (R,S P )-JosiPhos-7, etc., wherein the chiral diphosphine ligand is further preferably (S, R P )-JosiPhos-5.

[0021] Preferably, in step S1, the solvent is one or a combination of two or more of dichloromethane, toluene, 1,2-dichloroethane, tetrahydrofuran and methanol, and more preferably 1,2-dichloroethane.

[0022] Preferably, step S1 further comprises the step of: after the reaction is completed, purifying the obtained reaction product, wherein the purification is to filter the obtained reaction product through a silica gel column to filter out the chiral rhodium catalyst.

[0023] Preferably, the molar ratio of the rhodium metal precursor to the exocyclic α,β-unsaturated nitrile is 1 to 2:100.

[0024] Preferably, in step S2, the hydrogen pressure during the reaction is 300-1200 psi, for example, the reaction pressure is selected from 300 psi, 600 psi, 900 psi or 1200 psi; more preferably, it is 1200 psi.

[0025] Preferably, in step S2, the reaction temperature is room temperature to 60°C, more preferably 60°C.

[0026] Preferably, in step S2, the reaction time is 18 to 24 hours, more preferably 24 hours.

[0027] Preferably, in step S2, the concentration of the exocyclic α,β-unsaturated nitrile in the organic solvent is 0.04-0.08 mmol / mL, for example, can be selected from 0.04 mmol / mL, 0.6 mmol / mL, 0.8 mmol / mL, and more preferably 0.04 mmol / mL.

[0028] Preferably, in step S2, the organic solvent is one or a combination of two or more of dichloromethane, toluene, 1,2-dichloroethane, tetrahydrofuran and methanol, and more preferably 1,2-dichloroethane.

[0029] The second aspect of the present invention provides a cyclic chiral nitrile compound prepared by the above preparation method.

[0030] The third aspect of the present invention provides the use of the above-mentioned cyclic chiral nitrile compound in the preparation of ramelteon, wherein the cyclic chiral nitrile compound is 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile.

[0031] Preferably, the method for preparing ramelteon using 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile comprises the following steps: subjecting a cyclic chiral nitrile compound to a reductive acylation reaction with propionic anhydride and sodium borohydride in the presence of a nickel catalyst to obtain ramelteon.

[0032] Preferably, the method further comprises the following steps: after the reaction is completed, extracting the obtained reaction product with dichloromethane, then concentrating the extract under reduced pressure to obtain a crude extract, and purifying the crude product by silica gel column chromatography to obtain ramelteon.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] (1) The present invention firstly uses rhodium metal precursor and chiral diphosphine ligand as raw materials to prepare rhodium chiral catalyst, which has the advantages of low toxicity, high atom economy and environmental friendliness; then, the exocyclic α, β-unsaturated nitrile is subjected to asymmetric hydrogenation reaction under the action of hydrogen atmosphere and rhodium chiral catalyst to successfully prepare cyclic chiral nitrile compounds. Compared with the existing method for synthesizing cyclic chiral nitrile compounds, the method of the present invention has the advantages of simple and practical operation, high atom economy, high catalytic efficiency (up to 4000 turnover number), high yield and high ee value.

[0035] (2) The present invention also provides a method for preparing (S)-N-(2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)propionamide, i.e., ramelteon, by subjecting the obtained cyclic chiral nitrile compound, specifically 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile, propionic anhydride and sodium borohydride to a reduction acylation reaction under the catalytic action of nickel. Compared with the existing method of synthesizing ramelteon by reducing chiral nitrile with Raney nickel, this method has the characteristics of simple operation and higher yield, which provides a more efficient, convenient and safe method for the synthesis of ramelteon. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0037] Figure 1 A roadmap for the existing six-step all-asymmetric synthesis of ramelteon;

[0038] Figure 2 A synthetic route diagram of the cyclic chiral nitrile compounds provided by the present invention;

[0039] Figure 3 is the chemical structural formula of the typical chiral bisphosphine ligand JosiPhos in the present invention;

[0040] Figure 4 The present invention provides a synthetic route diagram of ramelteon. DETAILED DESCRIPTION

[0041] In the following description, for the purpose of illustration rather than limitation, specific details such as specific system structures and technologies are provided to provide a thorough understanding of the embodiments of the present invention. However, it should be clear to those skilled in the art that the present invention may also be implemented in other embodiments without these specific details.

[0042] Example 1

[0043] Reference Figure 2 , which is a synthetic route for cyclic chiral nitrile compounds, specifically (E)-olefin-2-(6-methoxy-2,3-dihydro-1H-inden-1-yl)acetonitrile.

[0044] Specific steps: In a glove box filled with nitrogen, di(1,5-cyclooctadiene) rhodium tetrafluoroborate (the molar ratio of di(1,5-cyclooctadiene) rhodium tetrafluoroborate to (E)-2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene) acetonitrile is 1:100), (S,R P )-JosiPhos-5(bis(1,5-cyclooctadiene)tetrafluoroborate rhodium and (S,R P )-JosiPhos-5 (molar ratio of 1:1.1) and dichloromethane were added to a dry reaction bottle and stirred at 25° C. for 20 min to obtain a chiral rhodium catalyst solution;

[0045] 1.0 mL of the obtained chiral rhodium catalyst solution was taken and transferred to a dry reaction bottle pre-added with (E)-2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile (compound 1a) (23.2 mg, 0.125 mmol) and dichloromethane (2.0 mL), and the reaction bottle was moved to a reactor, hydrogen was introduced, and the hydrogen pressure was set to 1200 psi, and the reaction was carried out at 60°C for 24 hours; after the reaction was completed, hydrogen was released, and the reaction product was filtered through a silica gel column to filter out the chiral rhodium catalyst to obtain a light yellow oil, namely compound 2a; 23.2 mg, yield: 99%; 97% ee; [α] D 20 =+27.2(c=1.0,CH2Cl2); SFC condition:Lux 5uAmylose-1(250×4.60mm),CO2:MeOH=90:10, 3 mL / min, 210 nm; t R = 3.7 min(minor), t R = 3.8 min (major); mp104-106℃. 1 H NMR(400MHz,Chloroform-d)δ7.15(d,J=8.2Hz,1H),6.84-6.83(m,1H),6.78( dd,J=8.3,2.5Hz,1H),3.80(s,3H),3.49-3.42(m,1H),2.98-2.91(m,1H),2.88 -2.80(m,1H),2.68(dd,J=16.7,6.1Hz,1H),2.54(dd,J=16.7,7.7Hz,1H),2.50-2.41(m,1H),1.94-1.85(m,1H). 13 C NMR (101MHz, Chloroform-d) δ158.9,144.7,135.5,125.3,118.7,113.4,109.0,55.4,41.4,32.2,30.0,22.7.

[0046] Example 2

[0047] The steps are basically the same as those in Example 1, except that the chiral bisphosphine ligand used is different. The chiral bisphosphine ligand used in this example is (S)-BINAP.

[0048] Example 3

[0049] The steps are basically the same as those in Example 1, except that the chiral bisphosphine ligand used is different. The chiral bisphosphine ligand used in this example is (S)-SegPhos.

[0050] Example 4

[0051] The steps are basically the same as those in Example 1, except that the chiral bisphosphine ligands used are different. The chiral bisphosphine ligands used in this example are (R, S P )-JosiPhos-1.

[0052] Example 5

[0053] The steps are basically the same as those in Example 1, except that the chiral bisphosphine ligands used are different. The chiral bisphosphine ligands used in this example are (R, S P )-JosiPhos-2.

[0054] Example 6

[0055] The steps are basically the same as those in Example 1, except that the chiral bisphosphine ligands used are different. The chiral bisphosphine ligands used in this example are (R, S P )-JosiPhos-3.

[0056] Example 7

[0057] The steps are basically the same as those in Example 1, except that the chiral bisphosphine ligands used are different. The chiral bisphosphine ligands used in this example are (R, S P )-JosiPhos-4.

[0058] Example 8

[0059] The steps are basically the same as those in Example 1, except that the chiral bisphosphine ligand used is different. The chiral bisphosphine ligand used in this example is (R,R)-f-spiroPhos.

[0060] Example 9

[0061] The steps are basically the same as those in Example 1, except that the chiral bisphosphine ligands used are different. The chiral bisphosphine ligands used in this example are (S, R P )-JosiPhos-6.

[0062] Example 10

[0063] The steps are basically the same as those in Example 1, except that the chiral bisphosphine ligands used are different. The chiral bisphosphine ligands used in this example are (R, S P )-JosiPhos-7.

[0064] The conversion rate and ee value of the target product prepared in the above examples 1-10 are shown in Table 1 below.

[0065] Table 1. Different chiral bisphosphine ligands (structural formula see Figure 3 ) and ee value results

[0066] Chiral phosphine ligand Conversion rate (%) ee.(%) Example 1 <![CDATA[(S,R P )-JosiPhos-5]]> >99％ 97 Example 2 (S)-BINAP trace ND Example 3 (S)-SegPhos trace ND Example 4 <![CDATA[(S,R P )-JosiPhos-1]]> >99％ 68 Example 5 <![CDATA[(R,S P )-JosiPhos-2]]> 26％ 24 Example 6 <![CDATA[(R,S P )-JosiPhos-3]]> 25％ 63 Example 7 <![CDATA[(R,S P )-JosiPhos-4]]> >99％ 27 Example 8 (R,R)-f-spiroPhos trace ND Example 9 <![CDATA[(S,R P )-JosiPhos-6]]> >99％ 67 Example 10 <![CDATA[(R,S P )-JosiPhos-7]]> >99％ 50

[0067] From the results in Table 1 above, it can be seen that when the chiral phosphine biligand used is (S, R P )-JosiPhos-5 (Example 1), the conversion rate and ee value of compound 2a are the highest.

[0068] Embodiment 11

[0069] The steps are basically the same as those in Example 1, except that a different solvent is used. The solvent used in this example is toluene.

[0070] Example 12

[0071] The steps are basically the same as those in Example 1, except that a different solvent is used. The solvent used in this example is tetrahydrofuran.

[0072] Example 13

[0073] The steps are basically the same as those in Example 1, except that a different solvent is used. The solvent used in this example is methanol.

[0074] Embodiment 14

[0075] The steps are basically the same as those in Example 1, except that a different solvent is used. The solvent used in this example is 1,2-dichloroethane.

[0076] The conversion rate and ee value of compound 2a obtained in the above Examples 1 and 11-14 are shown in Table 2 below.

[0077] Table 2

[0078]

[0079] From the results in Table 2 above, it can be seen that when the organic solvent used is dichloromethane, the conversion rate and ee value of compound 2a are the highest.

[0080] Embodiment 15

[0081] The steps are basically the same as those in Example 1, except that the hydrogen pressure is different. The hydrogen pressure in this example is 600 psi.

[0082] Example 16

[0083] The steps are basically the same as those in Example 1, except that the hydrogen pressure is different. The hydrogen pressure in this example is 300 psi.

[0084] Embodiment 17

[0085] The steps are basically the same as those in Example 1, except that the reaction temperature is different. The reaction temperature in this example is room temperature.

[0086] The conversion rate and ee value of compound 2a obtained in the above Examples 1 and 15-17 are shown in Table 3 below.

[0087] Table 3

[0088]

[0089] From the results in Table 3 above, it can be seen that when the hydrogen pressure is 1200 psi and the reaction temperature is 60° C. (Example 1), the conversion rate and ee value of compound 2a are the highest.

[0090] Embodiment 18

[0091] Preparation of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile:

[0092]

[0093] The experimental conditions were the same as those in Example 1, except that the compound 1a in Example 1 was replaced by 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile, and a white solid was finally obtained; 24.2 mg, yield: 97%; 96% ee; [α] D 20 =+89.3 (c=1.0, CH2Cl2); SFC condition: Lux 5u Amylose-1 (250×4.60mm), CO2:MeOH=90:10, 3mL / min, 210nm; t R =4.7min(minor),t R =5.2min(major);mp90-92℃. 1H NMR(400MHz,Chloroform-d)δ6.99(d,J=8.1Hz,1H),6.67(d,J=8.0Hz,1H),4.65-4.51(m,2H),3.53-3.46(m,1H),3.33-3.25(m,1H),3.18-3.10 (m,1H),3.01-2.93(m,1H),2.86-2.79(m,1H),2.69(dd,J=16.7,5.3Hz, 1H),2.52(dd,J=16.9,8.2Hz,1H),2.47-2.38(m,1H),2.05-2.96(m,1H).

[0094] Embodiment 19

[0095] Preparation of 2-(6-methoxy-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0096]

[0097] The experimental conditions were the same as those in Example 1, except that (Z)-2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile (Compound 1a) in Example 1 was replaced by (Z)-2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a light yellow oil was finally obtained; 22.0 mg, yield: 94%; 83% ee; [α] D 20 =-18.5 (c=1.0, CH2Cl2); HPLCcondition: Lux 5u Cellulose-1 (250×4.60mm), ipa:hex=1:99, 1mL / min, 210nm; t R =24.4min(minor),t R =25.7min(major).

[0098] Embodiment 20

[0099] Preparation of 2-(5-methoxy-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0100]

[0101] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(5-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a light yellow oil was finally obtained; 22.7 mg, yield: 97%; 92% ee; [α] D 20=+7.1 (c=1.0, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250×4.60mm), ipa:hex=2:98, 1mL / min, 210nm; t R =13.9min(major),t R =15.0min(minor). 1 H NMR(400MHz,Chloroform-d)δ7.19(d,J=8.3Hz,1H),6.81-6.79(m,1H),6.78-6.75(m,1H),3.79(s,3H),3.47-3.40 (m,1H),3.02-2.95(m,1H),2.91-2.84(m,1H),2.65(dd,J=16.7,6.2Hz,1H),2.56-2.41(m,2H),1.93-1.84(m,1H). 13 C NMR (101MHz, Chloroform-d) δ159.5,145.3,135.4,124.0,118.9,112.5,110.0,55.3,40.4,32.1,31.0,23.0.

[0102] Embodiment 21

[0103] Preparation of 2-(4-methoxy-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0104]

[0105] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(4-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a light yellow oil was finally obtained; 22.5 mg, yield: 96%; 90% ee; [α] D 20 =+5.6(c=1.0, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250×4.60mm), ipa:hex=20:80, 1mL / min, 210nm; t R =8.2min(major),t R =13.1min(minor). 1H NMR(400MHz,Chloroform-d)δ7.24-7.20(m,1H),6.91(d,J=7.5Hz,1H),6.76(d,J=8.1Hz,1H),3.84(s,3H),3.54-3.47(m,1H),2.99(ddd,J= 16.4,8.7,5.1Hz,1H),2.88-2.80(m,1H),2.68(dd,J=16.8,6.0Hz,1H),2.54(dd,J=16.8,7.7Hz,1H),2.50-2.41(m,1H),1.93-1.84(m,1H). 13 C NMR(151MHz,Chloroform-d)δ156.1,145.2,131.3,128.3,118.7,115.6,109.1,55.1,41.7,31.4,27.5,22.8.TOF-HRMS Calcd.for C 12 H 14 NO[M+H + ]:188.1070,found 188.1065.

[0106] Embodiment 22

[0107] Preparation of 2-(6-methyl-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0108]

[0109] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(6-methyl-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a pale yellow solid was finally obtained; 21.0 mg, yield: 98%; 93% ee; [α] D 20 =+30.5 (c=1.0, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250×4.60mm), ipa:hex=10:90, 1mL / min, 210nm; t R =7.4min(major),t R =8.2min(minor);mp61-62℃. 1H NMR(600MHz,Chloroform-d)δ7.17(d,J=7.6Hz,1H),7.14-7.13(m,1H),7.08-7.06(m,1H),3.49-3.45(m,1H),3.02 -2.97(m,1H),2.92 -2.87(m,1H),2.70(dd,J=16.8,6.1Hz,1H),2.55(dd,J=16.7,7.7Hz,1H),2.49-2.44(m1H),2.39(s,3H),1.93-1.87(m,1H). 13 C NMR(151MHz,Chloroform-d)δ143.4,140.5,136.1,128.3,124.4,123.9,118.8,41.0,31.9,30.3,22.6,21.1.TOF-HRMS Calcd.for C 12 H 14 N[M+H + ]:172.1121,found 172.1119.

[0110] Embodiment 23

[0111] Preparation of 2-(5-methyl-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0112]

[0113] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(5-methyl-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a light yellow oil was finally obtained; 20.3 mg, yield: 95%; 91% ee; [α] D 20 =+9.2 (c=1.0, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250×4.60mm), ipa:hex=2:98, 1mL / min, 210nm; t R =10.3min(major),t R =11.5min(minor). 1HNMR(400MHz,Chloroform-d)δ7.20(d,J=7.7Hz,1H),7.11-7.09(m,1H),7.07-7.04(m,1H),3.51-3.44(m,1H),3.03-2.96(m,1H), 2.93-2.85(m,1H),2.69(dd,J=16.7,6.1Hz,1H),2.54(dd,J=16.7,7.6Hz,1H),2.50-2.42(m,1H),2.37(s,2H),1.93-1.84(m,1H). 13 C NMR(151MHz,Chloroform-d)δ143.8,140.4,137.4,127.4,125.5,123.1,118.8,40.9,32.0,30.7,22.9,21.2.TOF-HRMSCalcd.for C 12 H 14 N[M+H + ]:172.1121,found 172.1119.

[0114] Embodiment 24

[0115] Preparation of 2-(4-methyl-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0116]

[0117] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(4-methyl-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a light yellow oil was finally obtained; 20.8 mg, yield: 97%; 92% ee; [α] D 20 =+5.3(c=1.0, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250×4.60mm), ipa:hex=10:90, 1mL / min, 210nm; t R =8.6min(major),t R =10.4min(minor). 1HNMR(600MHz,Chloroform-d)δ7.17-7.13(m,2H),7.08-7.06(m,1H),3.54-3.50(m,1H),2.99-2.94(m,1H),2.87-2.82 (m,1H),2.71(dd,J=16.8,6.0Hz,1H),2.56(dd,J=16.8,7.8Hz,1H),2.51-2.45(m,1H),2.30(s,2H),1.93-1.88(m,1H). 13 CNMR(151MHz,Chloroform-d)δ143.0,142.4,134.2,128.37,126.8,120.7,118.8,41.4,31.2,29.4,22.9,18.9.TOF-HRMS Calcd.for C 12 H 14 N[M+H + ]:172.1121,found 172.1119.

[0118] Embodiment 25

[0119] Preparation of 2-(2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0120]

[0121] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a pale yellow oil was finally obtained; 18.9 mg, yield: 96%; 90% ee; [α] D 20 =+3.6 (c=1.0, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250×4.60mm), ipa:hex=2:98, 1mL / min, 210nm; t R =13.9min(major),t R =16.9min(minor). 1 H NMR(400MHz,Chloroform-d)δ7.32-7.21(m,4H),3.54-3.47(m,1H),3.07-3.00(m,1H),2.97-2.89(m, 1H),2.71(dd,J=16.7,6.1Hz,1H),2.57(dd,J=16.7,7.6Hz,1H),2.51-2.42(m,1H),1.94-1.85(m,1H).13 C NMR (101MHz, Chloroform-d) δ143.6,143.2,127.5,126.6,124.8,123.3,118.8,41.2,31.7,30.8,22.7.

[0122] Embodiment 26

[0123] Preparation of 2-(6-fluoro-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0124]

[0125] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(6-fluoro-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a light yellow oil was finally obtained; 21.2 mg, yield: 97%; 94% ee; [α] D 20 =+9.6 (c=1.0, CH2Cl2); HPLC condition: Lux 5u Amylose-1 (250×4.60mm), ipa:hex=2:98, 1mL / min, 210nm; t R =8.9min(major),t R =9.5min(minor). 1 HNMR(600MHz,Chloroform-d)δ7.18-7.15(m,1H),6.96(dd,J=8.7,2.4Hz,1H),6.92-6.88(m,1H),3.49-3.44(m,1H),2.99-2.9 3(m,1H),2.89-2.83(m,1H),2.67(dd,J=16.8,6.1Hz,1H),2.56(dd,J=16.8,7.4Hz,1H),2.50-2.44(m,1H),1.95-1.89(m,1H). 13 C NMR (151MHz, Chloroform-d) δ 162.1 (d, J = 244.1Hz), 145.3 (d, J = 7.3Hz), 139.0 (d, J = 2.8Hz), 125. 8(d,J=8.6Hz),118.4,114.6(d,J=22.4Hz),110.6(d,J=22.4Hz),41.3,32.3,30.2,22.6.TOF-HRMS Calcd.for C 11 H 11 FN[M+H +]:176.0870,found 176.0868.

[0126] Embodiment 27

[0127] Preparation of 2-(5-fluoro-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0128]

[0129] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(5-fluoro-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a light yellow oil was finally obtained; 21.5 mg, yield: 98%; 96% ee; [α] D 20 =+11.5 (c=1.0, CH2Cl2); HPLC condition: Lux 5u Amylose-1 (250×4.60mm), ipa:hex=2:98, 1mL / min, 210nm; t R =8.8min(major),t R =9.2min(minor). 1 HNMR(600MHz,Chloroform-d)δ7.24-7.21(m,1H),6.94-6.88(m,2H),3.48-3.43(m,1H),3.03-2.98(m,1H),2.92 -2.87(m,1H),2.66(dd,J=16.7,6.3Hz,1H),2.56(dd,J=16.7,7.3Hz,1H),2.51-2.45(m,1H),1.95-1.89(m,1H). 13 CNMR(101MHz,Chloroform-d)δ162.7(d,J=244.8Hz),146.0(d,J=8.3Hz),138.8(d,J=2.5Hz),124.5 (d,J=9.1Hz),118.8,113.6(d,J=22.8Hz),111.9(d,J=22.2Hz),40.5,32.1,30.9(d,J=2.3Hz),23.0.

[0130] Embodiment 28

[0131] Preparation of 2-(5-chloro-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0132]

[0133] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(5-chloro-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a pale yellow oil was finally obtained; 23.2 mg, yield: 97%; 91% ee; [α] D 20 =+5.7(c=1.0, CH2Cl2); HPLC condition: Lux 5u Amylose-1 (250×4.60mm), ipa:hex=2:98, 1mL / min, 210nm; t R =9.5min(major),t R =10.0min(minor). 1 HNMR(400MHz,Chloroform-d)δ7.23-7.16(m,3H),3.49-3.42(m,1H),3.03-2.96(m,1H),2.93-2.85(m, 1H), 2.66 (dd, J=16.8, 6.3Hz, 1H), 2.56 (dd, J=16.8, 7.3Hz, 1H), 2.51-2.42 (m, 1H), 1.95-1.86 (m, 1H). 13 CNMR(101MHz,Chloroform-d)δ145.7,141.8,133.4,126.9,125.1,124.5,118.5,40.7,31.9,30.8,22.7.TOF-HRMS Calcd.for C 11 H 11 ClN[M+H + ]:192.0575,found 192.0573.

[0134] Embodiment 29

[0135] Preparation of 2-(6-bromo-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0136]

[0137] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(6-bromo-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a pale yellow oil was finally obtained; 28.0 mg, yield: 95%; 92% ee; [α] D 20=+47.2 (c=1.0, CH2Cl2); HPLC condition: Lux 5u Amylose-1 (250×4.60mm), ipa:hex=2:98, 1mL / min, 210nm; t R =9.5min(major),t R =10.1min(minor). 1 HNMR(600MHz,Chloroform-d)δ7.40-7.39(m,1H),7.34(dd,J=8.0,1.6Hz,1H),7.13-7.11(m,1H),3.51-3.46(m,1H),2.99-2.9 4(m,1H),2.88-2.83(m,1H),2.69(dd,J=16.8,5.9Hz,1H),2.56(dd,J=16.8,7.5Hz,1H),2.49-2.43(m,1H),1.94-1.88(m,1H). 13 C NMR (151MHz, Chloroform-d) δ145.6,142.7,130.7,126.6,126.4,120.3,118.3,41.2,31.9,30.5,22.6.

[0138] Embodiment 30

[0139] Preparation of 2-(5-bromo-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0140]

[0141] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(5-bromo-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a light yellow oil was finally obtained; 28.3 mg, yield: 96%; 93% ee; [α] D 20 =+3.6 (c=1.0, CH2Cl2); HPLC condition: Lux 5u Amylose-1 (250×4.60mm), ipa:hex=2:98, 1mL / min, 210nm; t R =10.0min(major),t R =10.5min(minor). 1HNMR(400MHz,Chloroform-d)δ7.40-7.38(m,1H),7.35-7.32(m,1H),7.16(d,J=8.0Hz,1H),3.48-3.41(m,1H),3.04-3.96( m,1H),2.94-2.86(m,1H),2.66(dd,J=16.7,6.3Hz,1H),2.56(dd,J=16.8,7.3Hz,1H),2.50-2.41(m,1H),1.94-1.85(m,1H). 13 C NMR(101MHz,Chloroform-d)δ146.1,142.3,129.8,128.1,124.9,121.5,118.4,40.8,31.8,30.7,22.7.TOF-HRMS Calcd.for C 11 H 11 BrN[M+H + ]:236.0069,found 236.0065.

[0142] Embodiment 31

[0143] Preparation of 2-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-yl)acetonitrile:

[0144]

[0145] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile, and a yellow solid was finally obtained; 25.8 mg, yield: 95%; 92% ee; [α] D 20 =+9.4(c=1.0, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250×4.60mm), ipa:hex=20:80, 1mL / min, 210nm; t R =10.0min(minor),t R =11.6min(major);mp68-69℃. 1H NMR(600MHz,Chloroform-d)δ6.83(s,1H),6.77(s,1H),3.87(s,3H),3.86(s,3H),3.48-3.43(m,1H),2.98-2.93(m,1H ),2.87-2.82(m,1H),2.63(dd,J=16.7,6.5Hz,1H),2.54(dd,J=16.7,7.3Hz,1H),2.47-2.42(m,1H),1.91-1.85(m,1H). 13 C NMR (151MHz, Chloroform-d) δ149.0,148.3,135.4,134.9,118.9,107.8,106.7,56.1,56.0,41.4,32.1,30.8,23.2.

[0146] Embodiment 32

[0147] Preparation of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)acetonitrile:

[0148]

[0149] The experimental conditions were the same as those in Example 1, except that the compound 1a in Example 1 was replaced by 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile, and a white solid was finally obtained; 24.2 mg, yield: 97%; 96% ee; [α] D 20 =+89.3 (c=1.0, CH2Cl2); SFC condition: Lux 5u Amylose-1 (250×4.60mm), CO2:MeOH=90:10, 3mL / min, 210nm; t R =4.7min(minor),t R =5.2min(major);mp90-92℃. 1H NMR(400MHz,Chloroform-d)δ6.99(d,J=8.1Hz,1H),6.67(d,J=8.0Hz,1H),4.65-4.51(m,2H),3.53-3.46(m,1H),3.33-3.25(m,1H),3.18-3.10 (m,1H),3.01-2.93(m,1H),2.86-2.79(m,1H),2.69(dd,J=16.7,5.3Hz, 1H),2.52(dd,J=16.9,8.2Hz,1H),2.47-2.38(m,1H),2.05-2.96(m,1H).

[0150] Embodiment 33

[0151] Preparation of 2-(1,2,3,4-tetrahydronaphthalen-1-yl)acetonitrile:

[0152]

[0153] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(1,2,3,4-tetrahydronaphthalene-1-ylidene)acetonitrile, and a white solid was finally obtained; 20.8 mg, yield: 97%; 91% ee; [α] D 20 =+11.8(c=1.0, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250×4.60mm), ipa:hex=20:80, 1mL / min, 210nm; t R =7.0min(major),t R =10.1min(minor). 1 H NMR(400MHz,Chloroform-d)δ7.23-7.15(m,3H),7.15-7.11(m,1H),3.26-3.20(m,1H),2.89-2.77(m, 2H), 2.73(dd,J=16.9,5.0Hz,1H),2.62(dd,J=16.9,9.3Hz,1H),2.13-2.05(m,1H),1.96-1.79(m,3H). 13 C NMR (101MHz, Chloroform-d) δ137.0,136.5,129.4,127.9,126.7,126.0,118.8,34.6,29.2,27.9,24.6,19.3.

[0154] Embodiment 34

[0155] Preparation of 2-(6,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)acetonitrile:

[0156]

[0157] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(6,7-dimethyl-1,2,3,4-tetrahydronaphthalene-1-ylidene)acetonitrile, and a pale yellow solid was finally obtained; 24.4 mg, yield: 98%; 97% ee; [α] D 20 =+4.0(c=1.0,CH2Cl2); HPLC condition:Lux 5u Cellulose-1(250×4.60mm), ipa:hex = 20:80, 1 mL / min, 210 nm; t R = 5.4 min (major), t R = 8.3 min (minor); mp60-61℃. 1 H NMR(600MHz,Chloroform-d)δ6.92(s,1H),6.88(s,1H),3.17-3.13(m,1H),2.76-2.66(m,3H),2.5 9-2.55(m,1H),2.22(s,3H),2.20(s,3H),2.06-2.00(m,1H),1.90-1.84(m,1H),1.84-1.74(m,2H). 13 C NMR(101MHz,Chloroform-d)δ135.2,134.3,133.9,130.6,129.0,119.0,34.3,28.8,28.2,24.7,19.5,19.3,19.2.TOF-HRMS Calcd.for C 14 H 18 N[M+H + ]:200.1434,found 200.1433.

[0158] Embodiment 35

[0159] Preparation of 2-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)acetonitrile:

[0160]

[0161] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(7-fluoro-1,2,3,4-tetrahydronaphthalene-1-ylidene)acetonitrile, and a pale yellow oil was finally obtained; 22.7 mg, yield: 96%; 97% ee; [α] D 20 =+27.7(c=1.0, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250×4.60mm), ipa:hex=5:95, 1mL / min, 210nm; t R =11.1min(major),t R =12.1min(minor). 1 HNMR(600MHz,Chloroform-d)δ7.06-7.04(m,1H),6.87-6.84(m,2H),3.19-3.15(m,1H),2.79-2. 67(m,3H),2.60(dd,J=17.0,9.1Hz,1H),2.07-2.02(m,1H),1.89-1.83(m,2H),1.82-1.76(m,1H). 13 C NMR(151MHz,Chloroform-d)δ161.1(d,J=244.3Hz),138.4(d,J=6.5Hz),132.7(d,J=3.0Hz),130.9(d ,J=7.8Hz),118.4,114.2(d,J=21.1Hz),114.1(d,J=21.0Hz),34.9,28.6,27.9,24.6,19.6.TOF-HRMS Calcd.for C 12 H 13 FN[M+H + ]:190.1027,found 190.1027.

[0162] Embodiment 36

[0163] Preparation of 2-(chroman-4-yl)acetonitrile:

[0164]

[0165] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(chroman-4-ylidene)acetonitrile, and a light yellow oil was finally obtained; 21.0 mg, yield: 97%; 94% ee; [α] D 20=+12.1(c=1.0,CH2Cl2);HPLCcondition:Lux 5u Cellulose-1(250×4.60mm),ipa:hex=30:70,1mL / min,210nm;t R =8.2min(major),t R =11.6min(minor). 1 H NMR(400MHz,Chloroform-d)δ7.17-7.12(m,2H),6.91(td,J=7.5,1.3Hz,1H),6.84(dd,J=8.1,1.3Hz,1H),4.26-4.15(m, 2H),3.27-3.21(m,1H),2.81(dd,J=17.0,5.1Hz,1H),2.60(dd,J=17.0,9.5Hz,1H),2.30-2.22(m,1H),2.06-1.98(m,1H).

[0166] Embodiment 37

[0167] Preparation of 2-(6-methylchroman-4-yl)acetonitrile:

[0168]

[0169] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(6-methylchroman-4-ylidene)acetonitrile, and a light yellow oil was finally obtained; 22.5 mg, yield: 96%; 92% ee; [α] D 20 =+28.5(c=1.0, CH2Cl2); SFC condition: Lux 5u Cellulose-3 (250×4.60mm), CO2:MeOH=95:5, 3mL / min, 210nm; t R =4.1min(major),t R =4.3min(minor). 1 H NMR(600MHz,Chloroform-d)δ6.96(dd,J=8.3,2.2Hz,1H),6.94-6.91(m,1H),6.74(d,J=8.3Hz,1H),4.22-4.14(m,2H) ,3.23-3.18(m,1H),2.82(dd,J=17.0,4.9Hz,1H),2.59(dd,J=17.0,9.8Hz,1H),2.29-2.23(m,4H),2.04-1.99(m,1H). 13CNMR(151MHz,Chloroform-d)δ152.2,130.0,129.4,128.6,121.7,118.2,117.2,62.7,30.7,27.2,24.3,20.5.TOF-HRMS Calcd.for C 12 H 14 NO[M+H + ]:188.1070,found 188.1065.

[0170] Embodiment 38

[0171] Preparation of 2-(8-chlorochroman-4-yl)acetonitrile:

[0172]

[0173] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(8-chlorochroman-4-ylidene)acetonitrile, and a pale yellow solid was finally obtained; 24.4 mg, yield: 94%; 92% ee; [α] D 20 =-4.3 (c=1.0, CH2Cl2); SFCcondition: Lux 5u Amylose-1 (250×4.60mm), CO2:MeOH=80:20, 3mL / min, 230nm; t R =2.8min(major),t R =3.1min(minor);mp66-67℃. 1 H NMR(600MHz,Chloroform-d)δ7.27-7.25(m,1H),7.07-7.05(m,1H),6.85(t,J=7.8Hz,1H),4.38-4.35(m,1H),4.31-4.27(m ,1H),3.29-3.25(m,1H),2.80(dd,J=17.0,5.2Hz,1H),2.62(dd,J=17.0,9.3Hz,1H),2.31-2.26(m,1H),2.09-2.04(m,1H). 13 C NMR(151MHz,Chloroform-d)δ150.2,129.4,126.8,123.7,122.2,120.8,117.8,63.4,30.8,26.7,24.2.TOF-HRMS Calcd.for C 11 H 11 ClNO[M+H +]:208.0524,found 258.0521.

[0174] Embodiment 39

[0175] Preparation of 2-(7-bromochroman-4-yl)acetonitrile:

[0176]

[0177] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(7-bromochroman-4-ylidene)acetonitrile, and a white solid was finally obtained; 30.6 mg, yield: 97%; 97% ee; [α] D 20 =+39.3(c=1.0, CH2Cl2); SFCcondition: Lux 5u Amylose-1 (250×4.60mm), CO2:MeOH=80:20, 3mL / min, 230nm; t R =5.3min(major),t R =6.1min(minor);mp130-132℃; 1 HNMR(600MHz,Chloroform-d)δ7.25-7.23(m,2H),6.74-6.71(m,1H),4.24-4.16(m,2H),3.23-3.19(m,1H),2 .80(ddd,J=17.0,4.9,2.0Hz,1H),2.59(ddd,J=17.0,9.7,2.0Hz,1H),2.27-2.22(m,1H),2.05-2.00(m,1H). 13 C NMR(151MHz,Chloroform-d)δ153.7,131.7,130.9,124.1,119.3,117.7,112.6,62.9,30.6,26.7,24.1.TOF-HRMS Calcd.for C 11 H 11 BrNO[M+H + ]:252.0019,found 252.0013.

[0178] Embodiment 40

[0179] Preparation of 2-(1,2,3,4-tetrahydroquinolin-4-yl)acetonitrile:

[0180]

[0181] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(1,2,3,4-tetrahydroquinolin-4-ylidene)acetonitrile, and a light yellow oil was finally obtained; 20.7 mg, yield: 96%; 94% ee; [α] D 20 =-1.7 (c=1.0, CH2Cl2); SFC condition: Lux 5u Amylose-1 (250×4.60mm), CO2:MeOH=80:20, 3mL / min, 210nm; t R =4.0min(major),t R =4.6min(minor). 1 H NMR(600MHz,Chloroform-d)δ7.05-702(m,2H),6.66(td,J=7.4,1.2Hz,1H),6.51(dd,J=8.5,1.3Hz,1H),3.94(br s,1H),3.37-3.30(m,2H),3.22-3.18(m,1H),2.73(dd,J=16.9,5.3Hz,1H),2.56(dd,J=17.0,9.8Hz,1H),2.16-2.10(m,1H),2.05-2.00(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.1,128.6,128.2,120.6,118.6,117.1,114.5,37.6,32.6,26.2,24.4.TOF-HRMS Calcd.for C 11 H 13 N2[M+H + ]:173.1073,found 173.1072.

[0182] Embodiment 41

[0183] Preparation of 2-(8-fluoro-1,2,3,4-tetrahydroquinolin-4-yl)acetonitrile:

[0184]

[0185] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(8-fluoro-1,2,3,4-tetrahydroquinolin-4-ylidene)acetonitrile, and a light yellow oil was finally obtained; 22.6 mg, yield: 95%; 90% ee; [α] D 20=-13.2 (c=1.0, CH2Cl2); SFC condition: Lux 5u Amylose-1 (250×4.60mm), CO2:MeOH=80:20, 3mL / min, 230nm; t R =2.9min(major),t R =3.0min(minor). 1 H NMR(600MHz,Chloroform-d)δ6.88-6.82(m,2H),6.56(td,J=7.9,5.3Hz,1H),4.18(br s,1H),3.43-3.40(m,1H),3.37-3.33(m,1H),3.25-3.21(m,1H),2.72(dd,J=17.0 ,5.5Hz,1H),2.57(dd,J=17.0,9.4Hz,1H),2.15-2.10(m,1H),2.06-2.02(m,1H). 13 C NMR(151MHz,Chloroform-d)δ150.7(d,J=238.6Hz),132.8(d,J=12.5Hz),123.6(d,J=3.2Hz),122.6(d,J=3.5 Hz),118.3,115.8(d,J=7.4Hz),113.4(d,J=18.0Hz),37.1,32.3(d,J=2.9Hz),26.0,24.3.TOF-HRMSCalcd.for C 11 H 12 FN2[M+H + ]:191.0979,found 191.0976.

[0186] Embodiment 42

[0187] Preparation of 2-(6-bromo-1,2,3,4-tetrahydroquinolin-4-yl)acetonitrile:

[0188]

[0189] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(6-bromo-1,2,3,4-tetrahydroquinolin-4-ylidene)acetonitrile, and a light yellow oil was finally obtained; 30.4 mg, yield: 97%; 90% ee; [α] D 20=-2.0 (c=1.0, CH2Cl2); SFC condition: Lux 5u Amylose-1 (250×4.60mm), CO2:MeOH=80:20, 3mL / min, 210nm; t R =6.8min(major),t R =8.2min(minor). 1 H NMR(400MHz,Chloroform-d)δ7.11-7.07(m,2H),6.38(d,J=8.3Hz,1H),4.02(br s,1H),3.37-3.27(m,2H),3.18-3.12(m,1H),2.69(dd,J=17.0,5.2Hz,1H),2.54(dd,J=16.9,9.7Hz,1H),2.12-1.97(m,2H). 13 CNMR(101MHz,Chloroform-d)δ143.1,131.0,130.9,122.3,118.1,116.0,108.2,37.5,32.5,25.7,24.2.TOF-HRMS Calcd.for C 11 H 12 BrN2[M+H + ]:251.0718,found 251.0713.

[0190] Embodiment 43

[0191] Preparation of 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-4-yl)acetonitrile:

[0192]

[0193] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-4-ylidene)acetonitrile, and a light yellow oil was finally obtained; 26.2 mg, yield: 98%; 95% ee; [α] D 20 =+21.4(c=1.0, CH2Cl2); SFC condition: Lux 5u Amylose-1 (250×4.60mm), CO2:MeOH=80:20, 3mL / min, 210nm; t R =3.5min(minor),t R =3.9min(major). 1H NMR(600MHz,Chloroform-d)δ7.28(t,J=7.7Hz,1H),7.23-7.18(m,2H),3.96(br s,1H),3.76-3.71(m,1H),3.21-3.17(m,1H),2.75(dd,J=16.8,5.9Hz,1H),2.64(dd,J=16.9,7.9Hz,1H),2.29-2.24(m,4H),1.95-1.89(m,1H). 13 C NMR(151MHz,Chloroform-d)δ169.9,127.6,126.8,125.7,125.0,117.9,33.4,29.6,29.5,23.0,22.9.TOF-HRMS Calcd.for C 13 H 15 N2O[M+H + ]:215.1179,found215.1178.

[0194] Embodiment 44

[0195] Preparation of 2-(1-benzyl-1,2,3,4-tetrahydroquinolin-4-yl)acetonitrile:

[0196]

[0197] The experimental conditions were the same as those in Example 1, except that compound 1a in Example 1 was replaced by 2-(1-benzyl-1,2,3,4-tetrahydroquinolin-4-ylidene)acetonitrile, and a light yellow oil was finally obtained; 31.5 mg, yield: 96%; 93% ee; [α] D 20 =-27.9 (c=1.0, CH2Cl2); SFC condition: Lux 5u Cellulose-1 (250×4.60mm), CO2:MeOH=80:20, 3mL / min, 210nm; t R =5.3min(minor),t R =5.6min(major). 1H NMR(600MHz,Chloroform-d)δ7.34(dd,J=8.2,6.9Hz,2H),7.29-7.27(m,1H), 7.26-7.24(m,2H),7.08-7.05(m,2H),6.65(td,J=7.4,1.1Hz,1H),6.59-6.57( m,1H),4.53(s,2H),3.45-3.37(m,2H),3.28-3.24(m,1H),2.74(dd,J=16.9,5 .5Hz,1H),2.60(dd,J=17.0,9.7Hz,1H),2.26-2.20(m,1H),2.13-2.09(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.7,138.1,128.7,128.6,128.4,127.0,126.5,121.6,118.5,116.3,111.6,54.9,45.1,33.6,26.1,24.1.TOF-HRMS Calcd.forC 18 H 19 N2[M+H + ]:263.1543,found 263.1540.

[0198] Embodiment 45

[0199] Preparation of 2-(6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)acetonitrile:

[0200]

[0201] The experimental conditions were the same as those in Example 1, except that the compound 1a in Example 1 was replaced with 2-(6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-ylidene)acetonitrile, and the (bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, the chiral bisphosphine ligand (S,R P )-JosiPhos-5 and 2-(6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-ylidene)acetonitrile in a molar ratio of 1:1.1:50], and finally a white solid was obtained; 22.0 mg, yield: 95%; 94% ee; [α] D 20 =+27.4(c=1.0,CH2Cl2);HPLCcondition:Lux 5u Amylose-1(250×4.60mm),ipa:hex=2:98,1mL / min,210nm;t R =7.2min(minor),t R=7.6min(major);mp61-62℃. 1 H NMR(400MHz,Chloroform-d)δ7.22-7.12(m,3H),7.10(dd,J=6.8,2.1Hz,1H),3.35-3. 29(m,1H),2.91-2.80(m,2H),2.78-2.76(m,2H),2.00-1.83(m,3H),1.81-1.59(m,3H). 13 C NMR (151MHz, Chloroform-d) δ142.1,141.4,130.1,127.0,126.4,119.0,41.0,35.9,32.7,28.6,27.4,21.9.

[0202] Embodiment 46

[0203] Preparation of 2-(6-methoxy-2,3-dihydro-1H-inden-1-yl)acetonitrile by gram-scale hydrogenation reaction:

[0204] In a nitrogen-filled glove box, di(1,5-cyclooctadiene)rhodium tetrafluoroborate (the molar ratio of di(1,5-cyclooctadiene)rhodium tetrafluoroborate to E)-2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile was 1:100), a chiral bisphosphine ligand (S,R P )-JosiPhos-5(bis(1,5-cyclooctadiene)tetrafluoroborate rhodium and (S,R P )-JosiPhos-5 (the molar ratio is 1:1.1) and dichloromethane are added to a dry reaction bottle, and the reaction is stirred at 25°C for 20 minutes to obtain a chiral rhodium catalyst solution; then (1.2 mL, 0.0015 mmol) of the chiral catalyst solution is transferred to a dry reaction bottle pre-added with (E)-2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile (6.0 mmol, 1.11 g) and dichloromethane (4.0 mL), and the reaction bottle is moved to a reactor, hydrogen (1200 psi) is introduced, and the reaction is carried out at 60°C for 5 days; hydrogen is released, the reaction mixture is filtered through a silica gel column, and after filtering out the catalyst, the conversion rate of the substrate is determined by GC to be >99%. The hydrogenation product 2-(6-methoxy-2,3-dihydro-1H-inden-1-yl)acetonitrile was separated by a short silica gel column as a colorless oil (1.09 g) with a yield of 97% and an enantioselectivity of 92% ee.

[0205] Embodiment 47

[0206] Preparation of 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile by gram-scale hydrogenation reaction:

[0207] In a nitrogen-filled glove box, di(1,5-cyclooctadiene)rhodium tetrafluoroborate (the molar ratio of di(1,5-cyclooctadiene)rhodium tetrafluoroborate to (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile was 1:100), a chiral bisphosphine ligand (S,R P )-JosiPhos-5(bis(1,5-cyclooctadiene)tetrafluoroborate rhodium and (S,R P )-JosiPhos-5 (the molar ratio is 1:1.1) and dichloromethane are added to a dry reaction bottle, and the reaction is stirred at 25°C for 20 minutes to obtain a chiral rhodium catalyst solution; then (1.02mL, 0.001275mmol) of the chiral rhodium catalyst solution is transferred to a dry reaction bottle pre-added with (E)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile (5.1mmol, 1.00g) and dichloromethane (4.0mL), and the reaction bottle is moved to a reactor, hydrogen (1200psi) is introduced, and the reaction is carried out at 60°C for 3 days; hydrogen is released, the reaction mixture is filtered through a silica gel column, and after filtering out the catalyst, the conversion rate of the substrate is determined to be 90% by GC. The hydrogenation product 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile was separated by a short silica gel column as a white solid (0.89 g) with a yield of 88% and an enantioselectivity of 96% ee. After recrystallization, a hydrogenation product with an ee of 98% was obtained.

[0208] Test Example 1

[0209] Use 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile to prepare (S)-N-(2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl)propionamide, namely ramelteon. The specific synthetic route is shown in Figure 4 .

[0210] 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile (98% ee, 0.5 mmol) was dissolved in methanol (7.5 mL), followed by the addition of NiCl2·6H2O (1.0 mmol, 2 equiv), propionic anhydride (1.0 mmol, 2 equiv), sodium borohydride (4.0 mmol, 8 equiv) in batches at 0°C, stirred for 1 h, then the reaction system was returned to room temperature and stirred for 2 h, monitored by TLC until the reaction was complete, quenched with water, extracted with dichloromethane several times, combined the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (PE / EA=5:1 to EA) gave a white solid; 118.2 mg, yield: 91%; 99% ee; [α] D 20 =+64.2(c=1.0, CH2Cl2); SFC condition: Lux 5uAmylose-1 (250×4.60mm), CO2:MeOH=80:20, 3mL / min, 210nm; t R =4.8min(minor),t R =6.0min(major); mp115-116℃. 1 H NMR(600MHz,Chloroform-d)δ6.94(d,J=8.0Hz,1H),6.60(dd,J=8.0,2.0Hz,1H),5.56(br s,1H),4.59-4.54(m,1H),4.52-4.47(m,1H),3.35-3.30(m,2H),3.26-3. 21(m,1H),3.19-3.15(m,1H),3.11-3.06(m,1H),2.9-2.85(m,1H),2.78- 2.73(m,1H),2.30-2.23(m,1H),2.16(qd,J=7.6,1.8Hz,2H),2.04-1.98( m,1H),1.84-1.78(m,1H),1.66-1.59(m,1H),1.13(td,J=7.6,2.0Hz,3H).

[0211] The present invention is not limited to the above-mentioned specific implementation modes. Various changes made by ordinary technicians in this field based on the above-mentioned concepts without creative work are all within the protection scope of the present invention.

Claims

1. A method for preparing a cyclic chiral nitrile compound, characterized in that: The following steps are involved: S1. Under a protective gas atmosphere, a rhodium metal precursor and a chiral diphosphine ligand are added to a solvent, and stirred for reaction to obtain a chiral rhodium catalyst; S2, subjecting the exocyclic α,β-unsaturated nitrile of structure as shown in formula I to an asymmetric hydrogenation reaction in an organic solvent under the action of a hydrogen atmosphere and a chiral rhodium catalyst to obtain a cyclic chiral nitrile compound of structure as shown in formula II; In formula II, * represents a chiral carbon atom; In formula I or II, R is selected from any one of C1-C8 alkyl, C1-C6 alkoxy or halogen; In formula I or II, X is selected from any one of C1-C3 alkylene, C1-C2 alkyleneoxy, -NHCH2-, -N(Ac)CH2-, and -N(Bn)CH2-; In step S1, the molar ratio of the rhodium metal precursor to the chiral diphosphine ligand is 1:1.1-1.6; the reaction time is 10-60 min, and the reaction temperature is 20-40° C.; the rhodium metal precursor and the exocyclic α , β -The molar ratio of unsaturated nitrile is 1 to 2:100; In step S2, the hydrogen pressure during the reaction is 300-1200 psi; the reaction temperature is room temperature-60°C, and the reaction time is 18-24 hours; the concentration of the exocyclic α,β-unsaturated nitrile in the organic solvent is 0.04-0.08 mmol / mL; The rhodium metal precursor is di(1,5-cyclooctadiene) rhodium tetrafluoroborate; the chiral diphosphine ligand is ( S , R P )-JosiPhos-5; the organic solvent is dichloromethane.

2. A method for preparing a cyclic chiral nitrile compound, wherein the cyclic chiral nitrile compound is 2-(1,2,6,7-tetrahydro-8 H -Indeno[5,4- b ]furan-8-yl)acetonitrile, characterized in that The specific preparation steps are: In a glove box filled with nitrogen, di(1,5-cyclooctadiene)rhodium tetrafluoroborate, ( S , R P )-JosiPhos-5 and dichloromethane were added to a dry reaction bottle and stirred at 25 °C for 20 min to obtain a chiral rhodium catalyst; wherein, di(1,5-cyclooctadiene) tetrafluoroborate rhodium and ( S , R P The molar ratio of )-JosiPhos-5 is 1:1.1; 1.0 mL of the obtained chiral rhodium catalyst was taken and transferred to a dry reaction bottle pre-added with 0.125 mmol 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile and 2.0 mL dichloromethane, and the reaction bottle was moved to a reactor, hydrogen was introduced, the hydrogen pressure was set to 1200 psi, and the reaction was carried out at 60°C for 24 h; after the reaction was completed, hydrogen was released, and the reaction product was filtered through a silica gel column to remove the chiral rhodium catalyst, and 24.2 mg of white solid, namely 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)acetonitrile; wherein the molar ratio of bis(1,5-cyclooctadiene)rhodium tetrafluoroborate to 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile is 1:100.

Images