A preparation method of quinine

Abstract

The present invention relates to the field of medicinal chemistry, and more particularly to a method for preparing quinine. The method involves introducing two chiral centers in a one-step reaction using a transition metal catalyst, has high selectivity, simplifies the process, and produces a high-purity product with a high yield, facilitating industrial production.

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of quinine. Background Art

[0002] Cis-2-substituted-3-quininamine compounds are an important class of pharmaceutical intermediates. Currently, there are few reports on the preparation methods of this type of compounds, especially the preparation of cis-3-quininamine with a single substituted group at the 2-position, as there is still a lack of efficient synthetic methods.

[0003] The approved drug Maropitant contains this type of structural fragment in its chemical formula. Because this type of structure contains two chiral centers, it has one enantiomer and two diastereomers, for a total of three optical isomer impurities. These impurities can affect the quality of the drug.

[0004] Existing splitting methods have complicated processes and high costs, which are not conducive to industrial production. Summary of the Invention

[0005] The present invention provides a preparation method. The preparation method of the present invention comprises using a transition metal catalyst to react with a sulfonamide compound to construct two chiral centers in a one-step reaction, and has high selectivity, simplicity, efficiency, and controllable quality.

[0006] According to one aspect of the present invention, a method for preparing compound III is provided, which comprises reacting compound I and compound II in an organic solvent under the protection of an inert gas, using a catalytic promoter, a hydrogen donor, an optional base reagent, and a transition metal catalyst. After the reaction is completed, compound III is prepared by post-processing.

[0007]

[0008] Wherein, R1 is a C1-C6 (1 carbon to 6 carbon) alkyl group, a phenyl group, or an optionally substituted phenyl group; R2 is CH2R3 or CH(R3)2, and R3 is selected from H, an optionally substituted or unsubstituted group of the following groups: an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and * represents a chiral carbon atom.

[0009] In some embodiments, R3 is selected from the following groups, which are optionally substituted or unsubstituted: C1-C6 (1 carbon to 6 carbon) alkyl, C3-C10 (3 carbon to 10 carbon) cycloalkyl, C2-C10 (2 carbon to 10 carbon) heterocycloalkyl, C6-C10 (6 carbon to 10 carbon) aryl, or C4-C10 (4 carbon to 10 carbon) heteroaryl.

[0010] In some embodiments, R3 is selected from the following groups, which are optionally substituted or unsubstituted: methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl, p-methoxyphenyl, pyridyl, pyrrolyl, 2-furyl, 2-thienyl, 3-methylphenyl, 2,5-difluorophenyl, 3,4-(methylenedioxy)phenyl, 3,5-dimethoxyphenyl, 3,4-dimethylphenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 3-hydroxy-4-methoxyphenyl, 4-fluorophenyl, or 4-methoxyphenyl.

[0011] In some embodiments, R1 is phenyl or optionally substituted phenyl, such as p-methylphenyl. In some embodiments, R1 is methyl.

[0012] The auxiliary agent is tetraisopropyl titanate, tetraethyl titanate, triisopropyl borate, p-toluenesulfonic acid or its hydrate, camphorsulfonic acid, or acetic acid, or a combination thereof. In some embodiments, the auxiliary agent includes or is tetraisopropyl titanate, which is beneficial to the reaction and the acquisition of the target product. In some embodiments, the auxiliary agent includes or is p-toluenesulfonic acid or its hydrate, which is beneficial to the reaction and the acquisition of the target product.

[0013] The molar ratio of the auxiliary reagent to compound II is 3:1-1:1. In some embodiments, the molar ratio of the auxiliary reagent to compound II is 1.2:1-2.0:1, which is more conducive to the reaction.

[0014] The molar ratio of compound I to compound II can be 2.5:1-1:1. In some embodiments, the molar ratio of compound I to compound II is 1.1:1-1.4:1, which is more conducive to the reaction.

[0015] The hydrogen donor reagent can be any suitable reagent capable of providing hydrogen. In some embodiments, the hydrogen donor reagent includes any one of formic acid, ammonium formate, sodium formate or potassium formate. In some embodiments, the hydrogen donor reagent is formic acid.

[0016] The molar ratio of the hydrogen donor reagent to compound II is 20:1-1:1. In some embodiments, the molar ratio of the hydrogen donor reagent to compound II is 15:1-1:1. In some embodiments, the molar ratio of the hydrogen donor reagent to compound II is 10:1-1:1. In some embodiments, the molar ratio of the hydrogen donor reagent to compound II is 6:1-1:1, which is more conducive to operation control and acquisition of target product.

[0017] In the preparation method, an alkaline reagent may be added or not. The alkaline reagent may be any suitable organic base. In some embodiments, the alkaline reagent includes any one of triethylamine, diethylamine, N,N-diisopropylethylamine, or 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the alkaline reagent is triethylamine, diethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane or a combination thereof. In some embodiments, the alkaline reagent is triethylamine, diethylamine, or a combination thereof, which is more conducive to the reaction and the acquisition of the target product.

[0018] The molar ratio of the alkali reagent to compound II can be 12:1-1:1. In some embodiments, the molar ratio of the alkali reagent to compound II is 10:1-1:1. In some embodiments, the molar ratio of the alkali reagent to compound II is 5:1-1:1. In some embodiments, the molar ratio of the alkali reagent to compound II is 3:1-1:1, which is more conducive to reaction progress and control.

[0019] In the preparation method provided by the present invention, the hydrogen-donating reagent and the alkali reagent can be fed separately or mixed according to the feeding amount before being added to the reaction system.

[0020] The transition metal catalyst is shown in formula CAT:

[0021]

[0022] Wherein, R4 is a C1-C6 (1 carbon to 6 carbon) alkyl group, an optionally substituted C1-C6 (1 carbon to 6 carbon) alkyl group, a phenyl group or an optionally substituted phenyl group; R5 and R6 are independently a phenyl group or an optionally substituted phenyl group, or R5 and R6 together are a butylene group; X is absent, or X is chlorine (Cl), hydrogen (H), trifluoromethanesulfonyl (OTf) or tetrafluoroborate (BF4); M is selected from ruthenium, rhodium or iridium; when M is ruthenium, Ar is a phenyl group or an optionally substituted phenyl group; when M is rhodium or iridium, Ar is a cyclopentadienyl group or an optionally substituted cyclopentadienyl group; * represents a chiral carbon atom.

[0023] In some embodiments, M is iridium, which is more conducive to obtaining the target product.

[0024] In some embodiments, R4 is 2,4,6-triisopropylphenyl, 2,4,6-trimethylphenyl, p-methylphenyl, p-trifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, pentafluorophenyl, methyl or trifluoromethyl.

[0025] In some embodiments, R5 and R6 are both phenyl.

[0026] In some embodiments, X is chlorine, or hydrogen.

[0027] In some embodiments, Ar is phenyl, 4-methylisopropylphenyl, cyclopentadienyl or an optionally substituted cyclopentadienyl. In some embodiments, Ar is cyclopentadienyl or an optionally substituted cyclopentadienyl, which is more conducive to obtaining the target product.

[0028] In some embodiments, R4 is 2,4,6-triisopropylphenyl, 2,4,6-trimethylphenyl, p-methylphenyl, p-trifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, pentafluorophenyl, methyl or trifluoromethyl; R5 and R6 are both phenyl; and X is chlorine or hydrogen.

[0029] The substitution or optional substitution may be alkyl, haloalkyl, or halogen. The halogen may be fluorine, chlorine, bromine, or iodine.

[0030] The heteroatom of the heterocyclic ring may be nitrogen, oxygen or sulfur.

[0031] In some embodiments, when the transition metal catalyst is in (R,R) configuration, compound III in (S,S) configuration can be obtained; when the transition metal catalyst is in (S,S) configuration, compound III in (R,R) configuration can be obtained.

[0032] In some embodiments, a method for preparing compound III comprises reacting compound I with compound II shown in the following formula in an organic solvent, optionally under the protection of an inert gas, using a promoter, a hydrogen donor, an optional base reagent, and a transition metal catalyst. After the reaction is completed, compound III shown in the following formula is prepared after post-treatment. The reaction formula is shown below:

[0033] or

[0034]

[0035] Wherein, R3 is as defined above; * represents a chiral carbon atom, and the two chiral carbon atoms in compound III may be in (R, R) configuration or (S, S) configuration; the transition metal catalyst is shown in the following formula CAT:

[0036]

[0037] In some embodiments, the transition metal catalyst may be at least one of the following transition metal catalysts:

[0038]

[0039] The feeding molar ratio of the transition metal catalyst to compound II may be 0.001:1-0.1:1. In some embodiments, the feeding molar ratio of the transition metal catalyst to compound II may be 0.001:1-0.01:1. In some embodiments, the feeding molar ratio of the transition metal catalyst to compound II may be 0.01:1-0.1:1. In some embodiments, the feeding molar ratio of the transition metal catalyst to compound II may be 0.005:1-0.05:1. In some embodiments, the feeding molar ratio of the transition metal catalyst to compound II may be 0.05:1-0.1:1.

[0040] The organic solvent can be tetrahydrofuran, dichloromethane, toluene, N,N-dimethylformamide or a combination thereof. In some embodiments, the organic solvent is tetrahydrofuran or toluene, which is more conducive to reaction and processing.

[0041] The amount of the organic solvent used is 1 mL to 30 mL for each gram of Compound II. In some embodiments, the amount of the organic solvent used is 3 mL to 15 mL for each gram of Compound II, which is beneficial for control and obtaining the target product.

[0042] In the method for preparing compound III, the reaction temperature is 0°C-100°C. In some embodiments, the reaction temperature is 0°C-50°C. In some embodiments, the reaction temperature is 0-30°C. In some embodiments, the reaction temperature is 15°C-35°C. In some embodiments, the reaction temperature is 20°C-30°C. In some embodiments, the reaction temperature is 25°C-35°C. In some embodiments, the reaction temperature is 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C or 40°C.

[0043] In the preparation method of the compound III, an alkaline reagent may be added or not, but preferably an alkaline reagent is added.

[0044] In the preparation method of the compound III, the various reaction materials or reagents can be added to the reaction vessel simultaneously or separately. For example, the organic solvent, compound I, compound II and the auxiliary reagent can be added to the reaction vessel first, and then the hydrogen donor reagent, the optional base reagent and the transition metal catalyst can be added after a period of reaction, and the reaction can be completed. Alternatively, the organic solvent, compound I, compound II, the auxiliary reagent, the hydrogen donor reagent, the optional base reagent and the transition metal catalyst can all be added to the reaction vessel and the reaction can be completed.

[0045] According to some embodiments of the present invention, in some implementations, the method for preparing a compound III comprises, optionally under the protection of an inert gas, in an organic solvent, mixing compound I, compound II and a promoter, and reacting for a first period of time; then adding a hydrogen donor, an alkali reagent and a transition metal catalyst, or adding a mixture of the hydrogen donor and the alkali reagent and a transition metal catalyst, or adding a hydrogen donor and a transition metal catalyst, and reacting for a second period of time; and after post-treatment, preparing compound III.

[0046] The first period of time may be 0h-20h (0h means that compound I, compound II, a promoter, a hydrogen donor, an optional alkaline agent and a transition metal catalyst are added to the reactor together). In some embodiments, the first period of time may be 0h-18h. In some embodiments, the first period of time may be 0h-14h. In some embodiments, the first period of time may be 1h-18h. In some embodiments, the first period of time may be 10h-20h. In some embodiments, the first period of time may be 10h-14h. In some embodiments, the first period of time may be 1h-8h. In some embodiments, the first period of time may be 1h-6h. In some embodiments, the first period of time may be 4h-8h. In some embodiments, the first period of time may be 8h, 10h, 12h, 14h, 15h, 16h, or 18h.

[0047] The second period of time may be from 8 am to 30 pm. In some embodiments, the second period of time may be from 12 pm to 30 pm. In some embodiments, the second period of time may be from 12 pm to 24 pm. In some embodiments, the second period of time may be from 12 pm to 20 pm. In some embodiments, the second period of time may be from 15 pm to 24 pm. In some embodiments, the second period of time may be from 15 pm to 20 pm. In some embodiments, the second period of time may be from 15 pm, 18 pm, 20 pm, 22 pm, or 24 pm.

[0048] In the process of preparing compound III, an inert gas such as nitrogen, helium, argon, etc. is optionally used for protection. In some embodiments, the reaction is carried out under nitrogen protection.

[0049] In some embodiments, the preparation method of the compound III comprises, optionally under the protection of an inert gas, mixing compound I, compound II and a chemical promoter in an organic solvent, reacting at 0°C-50°C for 1 hour-20 hours; then adding a hydrogen donor, an optional base reagent and a transition metal catalyst, and then reacting at 0°C-50°C for 8 hours-30 hours; after post-treatment, compound III is prepared.

[0050] In some embodiments, the preparation method of the compound III comprises, optionally under the protection of an inert gas, mixing compound I, compound II and a promoter in an organic solvent, and reacting at 0°C-50°C for 8-16 hours; then adding a hydrogen donor, an alkaline reagent and a transition metal catalyst, or adding a mixture of the hydrogen donor and the alkaline reagent and a transition metal catalyst, or adding a hydrogen donor and a transition metal catalyst, and continuing the reaction at 0°C-50°C for 12-24 hours; after post-treatment, compound III is prepared.

[0051] According to some embodiments of the present invention, in some embodiments, the method for preparing a compound III comprises: optionally under the protection of an inert gas, in an organic solvent, mixing compound I, compound II, a catalytic agent, a hydrogen donor, an optional base reagent, and a transition metal catalyst, reacting at 0°C-50°C for 8-36 hours; and after post-treatment, preparing compound III. In some embodiments, a method for preparing compound III comprises: optionally under the protection of an inert gas, in an organic solvent, mixing compound I, compound II, a catalytic agent, a hydrogen donor, an optional base reagent, and a transition metal catalyst, reacting at 0°C-50°C for 12-24 hours; and after post-treatment, preparing compound III.

[0052] The post-treatment includes: extracting and / or washing to obtain a crude product; the crude product is crystallized with a suitable solvent to obtain Compound III. In some embodiments, the post-treatment includes: optionally removing the solvent from the reaction solution, adjusting the pH to 2-4 with acid, washing with an organic solvent, separating the aqueous phase and cooling to 10°C-30°C, adjusting the pH to 10 or above; then optionally filtering, washing the filter cake with an organic solvent, and extracting the filtrate with an organic solvent; combining the resulting organic phases and concentrating to dryness to obtain a crude product; and crystallizing the crude product with a suitable solvent to obtain Compound III. In some embodiments, the post-treatment includes: removing the solvent from the reaction solution under reduced pressure, adjusting the pH to 2-4 with hydrochloric acid, washing with an organic solvent, separating the aqueous phase and cooling to 10°C-20°C, adjusting the pH to above 10; then filtering through diatomaceous earth, washing the filter cake with an organic solvent, and extracting the filtrate with an organic solvent; combining the organic phases and concentrating the resulting organic phases to dryness to obtain a crude product; dissolving the crude product with a solvent, then cooling to -5°C-5°C to precipitate a solid, filtering, and drying to obtain Compound III.

[0053] The organic solvent used for the extraction or washing can be toluene, dichloromethane, ethyl acetate, isopropyl acetate, or a combination thereof. The solvent used for the crystallization can be at least one of isopropyl alcohol, ethanol, methanol, and toluene, or a combination of at least one of isopropyl alcohol, ethanol, methanol, and toluene with n-hexane and / or cyclohexane.

[0054] In some embodiments, the post-treatment includes: distilling the reaction solution under reduced pressure, adjusting the pH to 2-4 with hydrochloric acid, washing with toluene, separating the aqueous phase and cooling to 10°C-20°C, and adjusting the pH to above 10; then filtering through diatomaceous earth, washing the filter cake with toluene, and adding toluene to the filtrate for extraction; combining the organic phases, and concentrating the obtained organic phase to dryness to obtain a crude product; heating and dissolving the crude product with toluene and n-hexane, and then cooling to -5°C-5°C to precipitate a solid, filtering, and drying to obtain compound III.

[0055] The aforementioned method can prepare compound III with an ee value of 95% or more. In some embodiments, the aforementioned method can prepare compound III with an ee value of 98% or more. In some embodiments, the aforementioned method can prepare compound III with an ee value of 99% or more.

[0056] The aforementioned compound III can be reacted to obtain compound IV, and other required intermediate compounds can be prepared from compound IV, wherein R1 and R2 are as defined above; * represents a chiral carbon atom.

[0057]

[0058] In some embodiments, in the aforementioned preparation method, R3 is any substituted or unsubstituted group: phenyl, 2-furyl, pyridyl, pyrrolyl, thienyl, 2-thienyl, 1-naphthyl, or 2-naphthyl; R1 is any substituted or unsubstituted group: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, or benzyl.

[0059] In some embodiments, in the aforementioned preparation method, R3 is any substituted or unsubstituted group: phenyl, p-methylphenyl, p-methoxyphenyl, 2-furyl, or 2-thienyl; R1 is methyl, phenyl, or p-methylphenyl.

[0060] In some embodiments, in the aforementioned preparation method, R1 is methyl, phenyl, p-methylphenyl or p-methoxyphenyl; R3 is phenyl, p-methylphenyl, p-methoxyphenyl, 2-furyl, or 2-thienyl.

[0061] The preparation method provided by the present invention can introduce two chiral centers in a high yield in a one-step reaction, has high selectivity, simplifies the process and is environmentally friendly. At the same time, the product has high purity and high yield, which is conducive to cost control and industrial production. DETAILED DESCRIPTION

[0062] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0063] The present invention can use TLC (thin layer chromatography) or HPLC (high performance liquid chromatography) to monitor the reaction degree of the raw materials. If HPLC monitoring is used, the reaction is considered to be complete when the peak area of ​​the raw materials is less than 4.0%, 2.0%, 1.0% or 0.5%.

[0064] In the present invention, THF represents tetrahydrofuran, NaOH represents sodium hydroxide, Ph represents phenyl, i-Pr represents isopropyl, and Me represents methyl; h represents hour, min represents minute, ml or mL represents milliliter, g represents gram, mol represents mole, and MPa represents megapascal; and ee represents enantiomeric excess.

[0065] In the present invention, expressions such as "compound A" and "compound represented by formula A" refer to the same compound.

[0066] In the present invention, when it comes to drying, it means drying to constant weight. "Optional" means that it may or may not be included.

[0067] In the description of this specification, the reference terms "one embodiment", "some implementation methods", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0068] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0069] Comparative Example 1: Preparation of Compound III-0

[0070]

[0071] Compound II-01 (10 g), benzylamine (6.0 g) and 30 mL of tetrahydrofuran were added to the reaction flask in sequence. Tetraisopropyl titanate (17.2 g) was added under nitrogen protection and reacted at 25°C-30°C for 12-18 h. 1.1 g of CAT01 was added to the system, and triethylamine (12.7 g) and formic acid (14.7 g) were added. The reaction was continued at 25°C-30°C for 15h-20h until the raw material compound II-01 was <2.0%, and the reaction was stopped; the solvent was removed under reduced pressure at 40°C-50°C, 2 mol / L aqueous hydrochloric acid solution was added to adjust the pH to 2-4, stirred for about 30-60 min, 60 mL of toluene was added to wash once, and the aqueous phase was retained; the aqueous phase was cooled to 10°C-20°C and dissolved in 50% NaOH. The pH of the liquid (mass fraction) was adjusted to 12-13, and the mixture was filtered through diatomaceous earth. The filter cake was washed once with 25 mL of toluene, and the resulting filtrate was extracted twice with 50 mL of toluene (2*50 mL), respectively. The organic phases were combined and concentrated to dryness under alkaline pressure at 40-50°C to obtain an oily crude product; the crude product was recrystallized from isopropanol / n-hexane (40 mL, 7:1, volume ratio) to obtain 13.5 g of white solid compound III-0, with a yield of 95%, HPLC purity of 98%, and ee of 81%.

[0072] When p-anisidine or diphenylmethylamine was used instead of benzylamine and other conditions were the same, it was found that the reaction did not proceed and no product was generated.

[0073] Comparative Example 2: Preparation of Compound III-0

[0074]

[0075] Compound II-01 (10 g), benzylamine (6.0 g) and 30 mL of tetrahydrofuran were added to the reaction flask in sequence. Tetraisopropyl titanate (17.2 g) was added under nitrogen protection and reacted at 25°C-30°C for 12-18 h. 0.78 g of CAT02 was added to the system, and triethylamine (12.5 g) and formic acid (15.1 g) were added. The reaction was continued at 25°C-30°C for 15 h-20 h until the raw material compound II-01 was <2.0%, and the reaction was stopped; the solvent was removed under reduced pressure at 40°C-50°C, 2 mol / L aqueous hydrochloric acid solution was added to adjust the pH to 2-4, stirred for about 30-60 min, 60 mL of toluene was added to wash once, and the aqueous phase was retained; the aqueous phase was cooled to 10°C-20°C and dissolved in 50% NaOH. The pH of the mixture (mass fraction) was adjusted to 12-13, and the mixture was filtered through diatomaceous earth. The filter cake was washed once with 25 mL of toluene, and the filtrate was extracted twice with 50 mL of toluene (2*50 mL). The organic phases were combined and concentrated under reduced pressure at 40-50°C to dryness to obtain an oily crude product; the crude product was recrystallized from isopropanol / n-hexane (40 mL, 7:1, volume ratio) to obtain 12.7 g of white solid compound III-0, with a yield of 89%, HPLC purity of 98%, and ee of 46%.

[0076] Comparative Example 3: Preparation of Compound III-0

[0077]

[0078] Compound II-01 (10 g), benzylamine (6.0 g) and 30 mL of tetrahydrofuran were added to the reaction flask in sequence. Tetraisopropyl titanate (17.2 g) was added under nitrogen protection and reacted at 25°C-30°C for 12-18 h. 0.68 g of CAT03 was added to the system, and triethylamine (12.3 g) and formic acid (14.9 g) were added. The reaction was continued at 25°C-30°C for 15 h-20 h until the raw material compound II-01 was <2.0%, and the reaction was stopped; the solvent was removed under reduced pressure at 40°C-50°C, 2 mol / L aqueous hydrochloric acid solution was added to adjust the pH to 2-4, stirred for about 30-60 min, 60 mL of toluene was added to wash once, and the aqueous phase was retained; the aqueous phase was cooled to 10°C-20°C and dissolved in 50% NaOH. The pH of the mixture (mass fraction) was adjusted to 12-13, filtered through diatomaceous earth, the filter cake was washed once with 25 mL of toluene, and the resulting filtrate was extracted twice with 50 mL of toluene (2*50 mL), the organic phases were combined, and concentrated under reduced pressure at 40-50°C to dryness to obtain an oily crude product; the crude product was recrystallized from isopropanol / n-hexane (32 mL, 7:1, volume ratio) to obtain 9.5 g of white solid compound III-0, with a yield of 67%, HPLC purity of 97%, and ee of 53%.

[0079] Example 1: Preparation of Compound III-01

[0080]

[0081] Compound II-01 (10 g), p-methylbenzenesulfonamide (8.0 g) and 30 mL of toluene were added to the reaction flask in sequence. Tetraisopropyl titanate (17.2 g) was added under nitrogen protection, and the reaction was carried out at 25°C-30°C for about 12 h. 1.0 g of CAT01 was added to the system, and triethylamine (12.2 g) and formic acid (13.9 g) were added. The reaction was continued at 25°C-30°C for 15h-20h until the raw material compound II-01 was <2.0%, and the reaction was stopped; the solvent was removed under reduced pressure at 40°C-50°C, 2 mol / L aqueous hydrochloric acid solution was added to adjust the pH to 2-4, stirred for about 30min-60min, and 60 mL of toluene was added to wash once, retaining the aqueous phase; the aqueous phase was cooled to 10°C-20°C and washed with 50% NaOH aqueous solution. The pH was adjusted to 12-13 (mass fraction), filtered through diatomaceous earth, the filter cake was washed once with 25 mL of toluene, and the resulting filtrate was extracted twice with 60 mL of toluene (2*60 mL), the organic phases were combined, and concentrated under reduced pressure at 40°C-50°C to dryness to obtain a crude oil; the crude product was recrystallized from isopropanol / n-hexane (40 mL, 7:1, volume ratio) to obtain 16.3 g of white solid compound III-01, with a yield of 95%, HPLC purity of 99.3%, and ee of 98%.

[0082] Example 2: Preparation of Compound III-02

[0083]

[0084] Compound II-02 (8 g), p-methylbenzenesulfonamide (6.2 g) and 30 mL of toluene were added to the reaction flask in sequence. Tetraisopropyl titanate (10.2 g) was added under nitrogen protection and the reaction was carried out at 25°C-30°C for about 12 h. 0.55 g of CAT01 was added to the system, and triethylamine (7.8 g) and formic acid (8.8 g) were added. The reaction was continued at 25°C-30°C for 15h-20h until the raw material compound II-02 was <2.0%, and the reaction was stopped; the solvent was removed under reduced pressure at 40°C-50°C, 2 mol / L aqueous hydrochloric acid solution was added to adjust the pH to 2-4, stirred for about 30-60 min, washed once with 40 mL of toluene, and the aqueous phase was retained; the aqueous phase was cooled to 10°C-20°C and washed with 50% aqueous NaOH solution (mass fraction). The reaction mixture was purified by centrifugation (HPLC) to obtain a crude oil. The reaction mixture was stirred for 24 hours (min / min) for 3 hours. The pH was adjusted to 12-13 by mass fraction (volume fraction), and the mixture was filtered through diatomaceous earth. The filter cake was washed once with 20 mL of toluene. The resulting filtrate was extracted twice with 40 mL of toluene (2*40 mL), respectively. The organic phases were combined and concentrated under reduced pressure at 40-50°C to dryness to obtain a crude oil. The crude product was recrystallized from isopropanol / n-hexane (40 mL, 7:1, volume ratio) to obtain 11.9 g of white solid compound III-02, with a yield of 97%, HPLC purity of 99.2%, and ee of 99%.

[0085] Example 3: Preparation of Compound III-03

[0086]

[0087] Compound II-03 (10 g), p-methylbenzenesulfonamide (7.3 g) and 30 mL of toluene were added to the reaction flask in sequence. Tetraisopropyl titanate (15.7 g) was added under nitrogen protection, and the reaction was carried out at 25°C-30°C for 12-18 h. 0.96 g of CAT01 was added to the system, and triethylamine (12.5 g) and formic acid (14.5 g) were added. The reaction was continued at 25°C-30°C for 15h-20h until the raw material compound II-03 was <2.0%, and the reaction was stopped; the solvent was removed under reduced pressure at 40°C-50°C, 2 mol / L aqueous hydrochloric acid solution was added to adjust the pH to 2-4, stirred for about 30-60 min, 50 mL of toluene was added to wash once, and the aqueous phase was retained; the aqueous phase was cooled to 10°C-20°C and washed with 50% NaOH aqueous solution. The pH was adjusted to 12-13 (mass fraction), filtered through diatomaceous earth, the filter cake was washed once with 25 mL of toluene, and the resulting filtrate was extracted twice with 60 mL of toluene (2*60 mL), the organic phases were combined, and concentrated under reduced pressure at 40-50°C to dryness to obtain a crude oil; the crude product was recrystallized from isopropanol / n-hexane (32 mL, 7:1, volume ratio) to obtain 15.3 g of white solid compound III-03, with a yield of 92%, HPLC purity: 99%, and ee: 96%.

[0088] Example 4: Preparation of Compound III-04

[0089]

[0090] Compound II-04 (10 g), p-methylbenzenesulfonamide (8.3 g) and 30 mL of toluene were added to the reaction flask in sequence. Tetraisopropyl titanate (18 g) was added under nitrogen protection and reacted at 25°C-30°C for about 12 h. 1.1 g of CAT01 was added to the system, and triethylamine (13.8 g) and formic acid (15.8 g) were added. The reaction was continued at 25°C-30°C for 15h-20h until the raw material compound II-04 was <2.0%, and the reaction was stopped; the solvent was removed under reduced pressure at 40°C-50°C, 2 mol / L aqueous hydrochloric acid solution was added to adjust the pH to 2-4, stirred for about 30-60 min, washed once with 50 mL of toluene, and the aqueous phase was retained; the aqueous phase was cooled to 10°C-20°C and washed with 50% aqueous NaOH solution ( The reaction mixture was purified by centrifugation and filtration. The pH was adjusted to 12-13 with 1% HCl (50 mL / min) and filtered through diatomaceous earth. The filter cake was washed once with 25 mL of toluene. The resulting filtrate was extracted twice with 50 mL of toluene (2*50 mL). The organic phases were combined and concentrated under reduced pressure at 40-50°C to dryness to obtain a crude oil. The crude product was recrystallized from isopropanol / n-hexane (32 mL, 7:1, volume ratio) to obtain 16.7 g of white solid compound III-04, with a yield of 95%, HPLC purity of 99.1%, and ee of 95%.

[0091] Example 5: Preparation of Compound III-05

[0092]

[0093] Compound II-05 (10 g), p-methylbenzenesulfonamide (7.0 g) and 30 mL of toluene were added to the reaction flask in sequence. Tetraisopropyl titanate (15.1 g) was added under nitrogen protection and the reaction was carried out at 25°C-30°C for about 12 h. 1.0 g of CAT01 was added to the system, and triethylamine (11.5 g) and formic acid (13.2 g) were added. The reaction was continued at 25°C-30°C for 15 h-20 h until the raw material compound II-05 was <2.0%, and the reaction was stopped; the solvent was removed under reduced pressure at 40°C-50°C, 2 mol / L aqueous hydrochloric acid solution was added to adjust the pH to 2-4, stirred for about 30-60 min, washed once with 50 mL of toluene, and the aqueous phase was retained; the aqueous phase was cooled to 10°C-20°C and washed with 50% aqueous NaOH solution ( The reaction mixture was purified by centrifugation and filtration. The pH was adjusted to 12-13 with 1% HCl (50 mL / min) and filtered through diatomaceous earth. The filter cake was washed once with 25 mL of toluene. The resulting filtrate was extracted twice with 50 mL of toluene (2*50 mL). The organic phases were combined and concentrated under reduced pressure at 40-50°C to dryness to obtain a crude oil. The crude product was crystallized from isopropanol / n-hexane (40 mL, 7:1, volume ratio) to obtain 15.7 g of white solid compound III-05, with a yield of 96%, HPLC purity of 99.3%, and ee of 99%.

[0094] The methods of the present invention have been described through preferred embodiments. It is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and spirit of the present invention to implement and apply the technology of the present invention. Those skilled in the art may refer to the disclosure herein and appropriately modify the process parameters to achieve the desired effect. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

Claims

1. A method for preparing compound III, comprising: Under the protection of inert gas, in an organic solvent, using a catalytic agent, a hydrogen donor, an alkaline agent and a transition metal catalyst, compound I reacts with compound II. After the reaction is completed, compound III is prepared after post-treatment. in: R1 is phenyl or p-methylphenyl; R2 is CH2R3 or CH(R3)2, R3 is phenyl, p-methoxyphenyl, 2-furyl or 2-thienyl; * represents a chiral carbon atom, and the chiral carbon is in (S, S) configuration; The auxiliary reagent is tetraisopropyl titanate; the hydrogen donor reagent is formic acid; and the alkaline reagent is triethylamine. The transition metal catalyst is 2. The preparation method according to claim 1, wherein the molar ratio of the auxiliary reagent to compound II is 3:1-1:1, and the molar ratio of the transition metal catalyst to compound II is 0.001:1-0.1:

1.

3. The preparation method according to claim 1, wherein the reaction temperature is 0°C-100°C.

4. The preparation method according to claim 1, wherein the organic solvent is tetrahydrofuran, dichloromethane, toluene, N,N-dimethylformamide, or a combination thereof.

5. The preparation method according to claim 1, wherein the post-processing comprises: After extraction and / or washing, a crude product is obtained; the crude product is crystallized with a solvent to obtain Compound III; wherein the solvent used for extraction is toluene, dichloromethane, ethyl acetate, isopropyl acetate or a combination thereof; the solvent used for crystallization is at least one of isopropanol, ethanol, methanol, and toluene, or a combination of at least one of isopropanol, ethanol, methanol, and toluene with n-hexane and / or cyclohexane.

6. The preparation method according to claim 1, comprising: In an organic solvent, compound I, compound II and a chemical promoter are mixed and reacted for a first period of time; Then, a hydrogen donor, an alkali reagent and a transition metal catalyst, or a mixture of the hydrogen donor and the alkali reagent and a transition metal catalyst are added, and the reaction is carried out for a second period of time; after post-treatment, compound III is prepared; the first period of time is 0-20 hours, and the second period of time is 8 hours to 30 hours.

7. The preparation method according to claim 1, comprising: In an organic solvent, compound I, compound II, a catalytic promoter, a hydrogen donor, an alkaline reagent and a transition metal catalyst are mixed, reacted at 0° C.-50° C. for 8 hours-36 hours, and post-treated to prepare compound III.

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