Imine intermediate and cis-indanamine intermediate of indaziflam and preparation method of imine intermediate and cis-indanamine intermediate

Abstract

The invention discloses an imine intermediate of indaziflam, a cis-indanamine intermediate and a preparation method thereof, and the method comprises the following steps: step 1, taking indanone and benzylamine or methylbenzylamine as raw materials to prepare the imine intermediate; and 2, under the action of a reducing agent, reducing the imine intermediate into an indene amine material containing cis-indene amine and the like. In the amine source, benzyl is used as an induction prothetic group, a reducing agent is adopted for reduction, the cis-indene amine intermediate is prepared in a low-cost and high-selectivity manner, the selectivity reaches 80% or above, and SS indene amine with the yield of 80% can be obtained through further resolution.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to an imine intermediate of indoxazine fluazifop, a cis-indeneamine intermediate and a preparation method thereof. Background Art

[0002] Indoxazine fluazifop is an alkylazine herbicide newly developed by Bayer CropScience in 2010. It is a new member of plant cellulose biosynthesis inhibitors (CBIs) with a unique resistance mode of action and broad-spectrum activity at low application rates. Indoxazine fluazifop had global sales of US$82 million in 2019; the compound annual growth rate from 2014 to 2019 was 5.1%. Bayer predicts that its peak sales will reach US$220 million, and the market prospects are broad. From a synthetic point of view, the molecule consists of two fragments, the indoxamine fragment and the triazine fragment (see the formula below). Among them, the synthesis of the indoxamine fragment is the difficulty of the project.

[0003]

[0004] At present, the synthesis of indene amine fragments is mainly based on the splitting method. According to patent CN108794339B, after obtaining the racemic indene amine, the split monomers undergo multiple steps of crystallization and low free yield, and the splitting efficiency is low; Bayer CropScience's patent CN106414420A also announced its synthesis scheme, using Pd(PPh3)4 catalyst to obtain the trans isomer and further split to obtain the (1R,2S)-2,6-dimethyl-1-aminoindane (RS indene amine) intermediate, and the catalyst used is relatively expensive.

[0005] Enantioselective synthesis of cis-α-substituted cycloalkanols and trans-cycloalkyl amines thereof Tetrahedron 2007, 63(29), 6755-6763 reported that 2,6-dimethyl-1-2,6-dimethylindan-1-one was used as a raw material and asymmetric hydrogenation was carried out using a chiral catalyst containing rhodium or ruthenium to obtain (1S,2S)-2,6-dimethyl-1-hydroxyindan (hereinafter referred to as SS indanamine), and then the hydroxyl group was replaced by an azide group, and then reduced to obtain (1R,2S)-2,6-dimethyl-1-aminoindan (hereinafter referred to as RS indanamine). This scheme uses a chiral catalyst and precious metal ruthenium, and the reaction is relatively complicated. It can only be prepared in the laboratory and is not suitable for process-scale production.

[0006] The disadvantages of the methods reported in the above literature are: poor reaction selectivity, low resolution yield, high cost; or the asymmetric synthesis method using noble metal complexes, which is complicated and not suitable for industrial production. Currently, there is no method for preparing indazine fluazifop intermediates that is simple to operate, has high yield, and is low in cost and suitable for industrial production. Summary of the invention

[0007] Purpose of the Invention

[0008] In order to overcome the above-mentioned shortcomings, the purpose of the present invention is to provide an imide intermediate of indoxazine fluazifop, a cis-indenylamine intermediate and a preparation method thereof which are simple to operate, high in yield and low in cost and suitable for industrial production. The present invention can prepare the cis-indenylamine intermediate at low cost and high selectivity; the method of the present invention can significantly increase the cis-indenylamine content in the reaction, and obtain the cis-isomer monomer SS of indoxazine fluazifop by splitting, and obtain the key intermediate 1R2S inddenylamine of indoxazine fluazifop with high yield by enzyme-catalyzed reaction.

[0009] Solution

[0010] To achieve the purpose of the present invention, the technical solution adopted by the present invention is as follows:

[0011] In a first aspect, the present invention provides a method for preparing an indazine fluazifop-amid cis-indaneamine intermediate, the method comprising the following steps:

[0012] Step 1: using indanone and benzylamine or substituted benzylamine as raw materials, reacting to obtain an imine intermediate;

[0013] Step 2: Under the action of a reducing agent, the imine intermediate is reduced to an indenamine material containing cis-indenamine;

[0014]

[0015] In step 2, the imine intermediate is reduced to obtain racemic indene amine. Racemic indene amine includes the following four isomers:

[0016]

[0017] Further, in step 1, the substituted benzylamine is selected from one or more of methylbenzylamine, ethylbenzylamine, propylbenzylamine, and butylbenzylamine; optionally, the substituted benzylamine is selected from S(-)-α-methylbenzylamine or R(+)-α-methylbenzylamine;

[0018] Preferably, indanone and benzylamine are used as raw materials to prepare the imine intermediate.

[0019] And / or, in step 1, the molar ratio of indanone and benzylamine or substituted benzylamine is 1:(1-10), optionally 1:(1-8), optionally 1:(1-6), optionally 1:(2-6), optionally 1:(2-5).

[0020] And / or, in step 1, the reaction temperature is 150-260°C, optionally 150-200°C, optionally 160-180°C.

[0021] Further, in step 1, the imine intermediate includes at least one of the following structural formulas:

[0022]

[0023] Furthermore, in step 2, the reducing agent is selected from sodium cyanoborohydride and / or hydrogen; optionally, when the reducing agent is hydrogen, palladium carbon is used as a catalyst.

[0024] Further, in step 2, the molar ratio of the imine intermediate to the reducing agent is 1:(1-10), optionally 1:(2-6), optionally 1:(2-4);

[0025] Furthermore, in step 2, the reduction temperature is 60-70°C, optionally 60-65°C.

[0026] Furthermore, the method further comprises the following steps:

[0027] Step 3: reacting an indenylamine material containing cis-indenylamine with an organic acid in a solvent to generate a cis-indenylamine salt;

[0028] Step 4: Under the action of a chiral resolving agent, the cis-indeneamine salt is split to obtain the SS indeneamine salt.

[0029] Further, in step 3, the organic acid is one or more of benzenesulfonic acid and succinic acid, preferably succinic acid;

[0030] Further, in step 3, the molar ratio of the indenylamine material of cis-indenylamine to the organic acid is 1:(1-5), optionally 1:(1-2), optionally 1:(1.05-1.5);

[0031] Further, in step 3, the solvent is one or more of isopropanol, ethanol, and ethyl acetate, and optionally, the solvent is a mixed solvent of ethanol and ethyl acetate; optionally, the volume ratio of ethanol to ethyl acetate is 1:1 to 1:3, and optionally 1:2;

[0032] Further, in step 3, the temperature is 40°C to reflux temperature, optionally 50°C to reflux temperature.

[0033] Further, in step 4, the chiral resolving agent is one or more of D-tartaric acid, R-mandelic acid, and S-mandelic acid, and optionally S-mandelic acid;

[0034] Further, in step 4, the molar ratio of the cis-indene amine salt to the resolving agent is 1:(1-5), optionally 1:(1-2), optionally 1:(1.05-1.5), optionally 1:(1.08-1.3), optionally 1:(1.1-1.3);

[0035] Further, in step 4, the reaction temperature is between 0°C and 100°C, optionally between 20°C and 80°C, optionally between 40°C and 45°C;

[0036] Further, step 4 is carried out in an organic solvent, and optionally the organic solvent is selected from ethanol and / or isopropanol;

[0037] Furthermore, in step 4, the purification of SS indenylamine includes: heating to dissolve and then cooling to precipitate, adding an organic solvent to the precipitate and heating to dissolve and crystallize to obtain SS indenylamine salt. Optionally, the precipitation or crystallization temperature is controlled between 0°C and 40°C, preferably 20 to 25°C.

[0038] Furthermore, the method further comprises step 5: using an enzyme to perform configuration inversion on the SS indenylamine salt to obtain RS indenylamine.

[0039] Further, it comprises the following steps:

[0040] Step 1: Using indanone and benzylamine as raw materials, an imine intermediate is prepared;

[0041] Step 2: Under the action of palladium carbon and hydrogen, the imine intermediate is reduced to an indenamine material containing cis-indenamine;

[0042] Step 3: reacting an indenylamine material containing cis-indenylamine with succinic acid in a solvent to generate a cis-indenylamine salt;

[0043] Step 4: Under the action of S-mandelic acid, the cis-indeneamine salt is split to obtain SS indeneamine mandelate;

[0044] Step 5: Use enzymes to perform configurational inversion on SS indenylamine mandelate to obtain RS indenylamine.

[0045]

[0046] Beneficial Effects

[0047] The invention uses the benzyl group in the amine source as an inducing auxiliary group, adopts a reducing agent for reduction (which may be palladium carbon / hydrogen), and prepares a cis-indeneamine intermediate at low cost and high selectivity, with a selectivity of more than 80%. Further splitting can obtain SS indeneamine with a yield of 80%, and the total yield based on racemic indeneamine reaches 28%, which is much higher than the yield of the splitting method reported in the prior art. The method has the advantages of cheap and easily available starting raw materials, a simple process flow, high selectivity and low cost, and provides an industrial route for preparing key intermediates for preparing indoxazine fluazifop-amid, and has good practical value. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] One or more embodiments are exemplarily described by the pictures in the accompanying drawings, and these exemplary descriptions do not constitute limitations on the embodiments. The special word "exemplary" here means "used as an example, embodiment or illustrative". Any embodiment described as "exemplary" here is not necessarily interpreted as being superior or better than other embodiments.

[0049] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of cis-indeneamine succinate of Example 10 of the present invention.

[0050] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of SS indenylamine mandelate of Example 16. DETAILED DESCRIPTION

[0051] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0052] In addition, in order to better illustrate the present invention, numerous specific details are provided in the specific embodiments below. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In some embodiments, raw materials, schemes, methods, means, etc. well known to those skilled in the art are not described in detail, so as to highlight the main purpose of the present invention.

[0053] Unless explicitly stated otherwise, throughout the specification and claims, the term “comprise” or variations such as “include” or “comprising”, etc., will be understood to include the stated elements or components but not to exclude other elements or components.

[0054] The method of the present invention can significantly increase the content of cis-indeneamine in the reaction, and obtain the cis-isomer monomer SS of indeneamine after splitting. The obtained 1S2S monomer can be transposed with high yield by enzyme-catalyzed reaction according to the literature (Deracemization of Racemic Amine Using ωTransaminase and a Nickel-Based Nanocatalyst ACS Catal.2022,12,15600-15608) to obtain the key intermediate 1R2S indeneamine of indeneazithromycin.

[0055] The product purity in the following examples was determined by the area normalization method, and the chiral purity was determined by the HPLC chiral detection area normalization method.

[0056] LC-MS: Liquid chromatography mass spectrometry, liquid quality.

[0057] HPLC: High Performance Liquid Chromatography, high pressure liquid chromatography.

[0058] NMR: Nuclear magnetic resonance spectrometry.

[0059] The reagents in the following examples are commercially available; if not otherwise specified, the reaction process and results were detected by high performance liquid chromatography (HPLC), and the purity and selectivity were determined by the area normalization method.

[0060] The method for preparing the indazine fluazifop cis-indaneamine intermediate and the splitting monomer thereof of the present invention is shown in the following formula:

[0061]

[0062] Racemic indaneamine includes the following four isomers:

[0063]

[0064] In the following examples and comparative examples, the proportion of cis-indenamine refers to the mass ratio of cis-indenamine in the total indenamine (the sum of four indenamine isomers).

[0065] Comparative Example 1: Synthesis of cis-indeneamine using hydroxylamine hydrochloride as an amine source

[0066] To a four-necked reaction bottle, 10.0 g (62.1 mmol) of 2,6-dimethylindan-1-one, 6.5 g (93.5 mmol) of hydroxylamine hydrochloride, 10.24 g (124.9 mmol) of sodium acetate, and 50 g of a 50% ethanol aqueous solution were added in sequence, and the mixture was reacted at 20-25° C. for 4 hours. The reaction was considered complete when 0.5% of 2,6-dimethylindan-1-one remained as detected by LC-MS. The reaction solution was concentrated to remove ethanol, and the mixture was extracted twice with ethyl acetate. The organic phases were combined and concentrated to obtain a crude product. The crude product was added to an autoclave, and 3.7 g (62.4 mmol) of acetic acid, 0.5 g of 5% palladium carbon, and 30 g of methanol were added. After nitrogen replacement, hydrogen was introduced, and the reaction temperature was controlled at 50° C. and the hydrogen pressure was 2.5 MPa. The reaction was carried out for 3 hours, and the reaction was detected to be complete. The reaction solution was filtered through palladium carbon, and the filtrate was concentrated to obtain 12.4 g of indeneamine acetate. The purity was 93.8% as determined by HPLC, and the yield was 84.3%; cis-indeneamine accounted for 47.3%.

[0067] Examples 1 to 3: Preparation of cis-indeneamine using R(+)-α-methylbenzylamine as an amine source

[0068] Example 1

[0069] Add 20.0 g (124.2 mmol) of 2,6-dimethylindan-1-one and 75.7 g (625 mmol) of R (+)-α-methylbenzylamine to the reaction bottle, heat to 180°C, react for 6 hours, and LC-MS detects that 0.5% of 2,6-dimethylindan-1-one remains, which is considered to be the completion of the reaction. The distillation temperature is controlled at 160°C and the vacuum degree is 200 mbar. After the reaction liquid is distilled under reduced pressure to recover R (+)-α-methylbenzylamine, 31.3 g of R-imine intermediate is obtained. The purity of the imine intermediate is 94.3% and the yield is 90.2% by HPLC.

[0070] Example 2

[0071] Add 10 g (38.0 mmol, 94.3%) of the R-imine intermediate obtained in Example 1 and 0.5 g of 5% palladium carbon to the reaction bottle, replace the nitrogen with hydrogen, and control the reaction temperature to 65 ° C and the hydrogen pressure to 2.2 MPa. React for 20 hours, and the reaction is considered complete when LC-MS detects that the remaining 0.5% of the imine intermediate is detected. The reaction solution is filtered through palladium carbon, and the solvent is concentrated to obtain 5.5 g of indeneamine. HPLC detects that the purity of indeneamine is 90%, the yield is 85.8%, and cis-indeneamine accounts for 63.3%.

[0072] Example 3

[0073] Add 10g (38.0mmol, 94.3%) of the R-imine intermediate obtained in Example 1 and 9.25g (152.0mmol) of sodium cyanoborohydride and 50g of methanol as solvent to the reactor, react at 20-25°C for 12 hours, and LC-MS detects that the R-imine intermediate remains 0.2%, and the reaction is complete. The residual sodium cyanoborohydride is quenched with saturated ammonium chloride, extracted three times with ethyl acetate, and the organic phases are combined and concentrated to obtain a crude product, which is added to an autoclave, 0.5g of 5% palladium carbon and 30g of methanol are added as solvents, and hydrogen is introduced after nitrogen replacement, and the reaction temperature is controlled at 65°C and the hydrogen pressure is 2.2Mpa for 3 hours. LC-MS detects that the undebenzylimine intermediate remains 0.5%, which is considered to be complete. The reaction solution is filtered through palladium carbon, and the solvent is concentrated to obtain 5.3g of indeneamine. HPLC detects that the purity of indeneamine is 91.7%, and the yield is 84.3%; cis-indeneamine accounts for 64.0%.

[0074] Examples 4-6 Preparation of S(-)-α-methylbenzylamine as amine source cis-indeneamine

[0075] Example 4

[0076] Refer to Example 1, except that R(+)-α-methylbenzylamine is replaced by S(-)-α-methylbenzylamine 75.6 g (624.2 mmol) to obtain 30.5 g of S-imine intermediate. The purity of the imine intermediate detected by HPLC is 93.7%, and the yield is 86.7%.

[0077] Example 5

[0078] Referring to Example 2, Pd-C / H2 was used for reduction, except that the R-imine intermediate in Example 2 was replaced by the S-imine intermediate (38 mmol, 93.7%) obtained in Example 4 to obtain 5.6 g of indeneamine. The purity of indeneamine detected by HPLC was 88.0%, and the yield was 85.9%; cis-indeneamine accounted for 60.4%.

[0079] Example 6

[0080] Referring to Example 3, sodium cyanoborohydride was used for reduction, except that the R-imine intermediate in Example 3 was replaced by the S-imine intermediate (38 mmol, 93.7%) obtained in Example 4 to obtain 5.4 g of indeneamine. The purity of indeneamine detected by HPLC was 88.3%, and the yield was 83.2%; cis-indeneamine accounted for 49.2%.

[0081] Examples 7-9: Preparation of cis-indeneamine using benzylamine as an amine source

[0082] Example 7

[0083] Add 40.0 g (248.4 mmol) of 2,6-dimethylindan-1-one and 133.8 g (1250 mmol) of benzylamine to the reaction flask, heat to 180°C, react for 6 hours, and LC-MS detects that 0.5% of 2,6-dimethylindan-1-one remains, which is considered to be the completion of the reaction. The distillation temperature is controlled at 160°C and the vacuum degree is 200 mbar. After the reaction liquid is distilled under reduced pressure to recover benzylamine, 60.4 g of benzyl imine intermediate is obtained. The purity of the benzyl imine intermediate is 98.3% and the yield is 95.4% by HPLC.

[0084] Example 8

[0085] Add 20 g (80.0 mmol, 98.3%) of the benzyl imine intermediate obtained in Example 7 and 1.0 g of 5% palladium carbon to the reaction bottle, introduce hydrogen after nitrogen replacement, and control the reaction temperature to 65 ° C and the hydrogen pressure to 2.2 MPa. React for 20 hours, and the reaction is considered complete when LC-MS detects that the benzyl imine intermediate remains 0.5%. The reaction solution is filtered through palladium carbon, and the solvent is concentrated to obtain 11.6 g of indeneamine. HPLC detects that the purity of indeneamine is 97.0%, and the yield is 88.5%; cis-indeneamine accounts for 80.7%.

[0086] Example 9

[0087] Referring to Example 3, sodium cyanoborohydride was used for reduction, except that the R-imine intermediate in Example 3 was replaced by 10.0 g (40 mmol, 98.3%) of the benzyl imine intermediate obtained in Example 7 to obtain 5.6 g of indeneamine. The purity of indeneamine detected by HPLC was 94.1%, the yield was 82.9%, and cis-indeneamine accounted for 70.2%.

[0088] Examples 1 to 9 show that the present invention can improve the cis-trans selectivity in the reduction process by introducing a cofactor into the amine source to increase steric hindrance, while in Comparative Example 1, 2,6-dimethylindan-1-one is condensed with hydroxylamine to obtain oxime, which is further reduced with sodium cyanoborohydride to obtain indeneamine, and the indeneamine obtained in this way has no stereoselectivity. Some comparison results are shown in Table 1.

[0089] Table 1. Effects of amine source and reduction method on cis-trans selectivity of indene amine

[0090]

[0091] The results show that the amine source is the determining factor for the selection of cis and trans forms. For amine sources containing larger substituents, no matter which reduction method is used, the product is mainly cis. However, different reaction methods can obtain different absolute dominant configurations. When (S)-1-phenethyl-1-amine, (R)-1-phenethyl-1-amine or benzylamine is used as the amine source, the cis configuration (cis-indenylamine) obtained by Pd-C / H2 hydrogenation reaches more than 60%; when benzylamine is used as the amine source, the cis configuration (cis-indenylamine) obtained by Pd-C / H2 hydrogenation reaches more than 80%, so the amine source is preferably benzylamine, and the reduction method is preferably Pd-C / H2 hydrogenation.

[0092] Therefore, the cis-indenylamine with the advantageous configuration was prepared by Example 8, and the acid species were further screened to obtain cis-indenylamine with higher purity by salt formation. Some of the results are as follows:

[0093] In the following examples, indeneamine salts show two peaks for indeneamine and salt, respectively, in HPLC detection (for example, indeneamine benzenesulfonate will show an indeneamine peak and a benzenesulfonate peak), and cis-indeneamine refers to the mass ratio of total indeneamine (the sum of four indeneamine isomers).

[0094] Examples 10-15 Preparation of cis-indene amine salt

[0095] Example 10

[0096] Add 10g of indaneamine (62.1mmol, 97.0%, cis-indaneamine: 80.7%; trans-indaneamine: 19.3%) and 50g of isopropanol prepared in Example 8 into a four-necked flask, and add 10g of benzenesulfonic acid (66.7mmol) at 40°C. Raise the temperature to reflux, the system becomes clear, and keep warm for 1 hour. Slowly cool down to 50°C, the system becomes turbid. Continue to cool down to 25°C, stir and crystallize for 1 hour, and obtain 12g of indaneamine benzenesulfonate product. HPLC detection shows that cis-indaneamine accounts for 81.8%, and the yield is 61.5%.

[0097] Embodiment 11

[0098] Refer to Example 10, except that benzenesulfonic acid is replaced by succinic acid to obtain 9.9 g of indeneamine succinate product. HPLC detection shows that cis-indeneamine accounts for 95.4% and the yield is 67.3%.

[0099] 1H NMR (400MHz, DMSO-d6), δ0.97 (d, J = 8.0Hz, 3H), 2.26 (s, 2H), 2.29 (s, 3H), 2.56 (m, 2H), 2.88 (q, 1H), 4.29 (d, J = 8.0Hz, 1H), 7.03 (d, J = 8.0Hz, 1H), 7.11 (d, J = 8.0Hz, 1H), 7.20 (s, 1H). See attached Figure 1

[0100] Example 12

[0101] Refer to Example 11, except that the solvent is replaced by ethyl acetate instead of isopropanol to obtain 12.9 g of indeneamine succinate product, with HPLC detection showing that cis-indeneamine accounts for 82.5% and a yield of 76.1%.

[0102] Example 13

[0103] In a four-necked flask, 10 g of indeneamine prepared in Example 8 (62.1 mmol, purity 97.0%, of which cis-indeneamine accounts for 80.7%; trans-indeneamine accounts for 19.3%) and 50 g of solvent (ethyl acetate / ethanol = 3:1 (V / V)) were added, and 8.0 g of succinic acid (66.7 mmol) was added at 40°C. After heating to reflux, the system became clear. The temperature was slowly lowered to 50°C, and the system became obviously turbid. The temperature was further lowered to 25°C, and the crystallization was stirred for 1 hour. 12.4 g of indeneamine succinate product was obtained by filtration. HPLC detected that cis-indeneamine accounted for 92.4%, and the yield was 81.9%.

[0104] Embodiment 14

[0105] Refer to Example 13, except that the solvent is replaced with ethyl acetate / ethanol = 2:1, and 12.2 g of indenylamine succinate product is obtained. The purity of cis-indenylamine detected by HPLC is 98.4%, and the yield is 85.8%.

[0106] Embodiment 15

[0107] Refer to Example 13, except that the solvent is replaced with ethyl acetate / ethanol = 1:1, to obtain 10.8 g of indenylamine succinate product, HPLC detection of cis-indenylamine purity of 96.0%, yield 73.9%.

[0108] Comparative Example 2

[0109] Refer to Example 10, except that benzenesulfonic acid was replaced with an equal molar amount of acetic acid, resulting in no solid precipitation.

[0110] The comparison results of Examples 10 and 14 are as follows:

[0111] Table 2. Statistical table of the proportion of cis-indeneamine after salt formation with different acids

[0112] Group Acid type cis proportion (%) Yield (%) Comparative Example 2 Acetic acid No solid precipitated / Example 10 Benzenesulfonic acid 81.8 61.5 Embodiment 14 Succinic acid 98.4 85.8

[0113] From the data in Table 2, it can be seen that the indenylamine obtained by the reaction in step 2 is salified with acetic acid, benzenesulfonic acid and succinic acid respectively, and the yield of succinic acid is higher. After salt purification, the cis-form accounts for more than 98%, and succinic acid is preferred.

[0114] Based on the screening results in Table 2 above, it is preferred that succinic acid and indenylamine be salified to obtain cis-indenylamine, and the solvent for salification is further screened to obtain cis-indenylamine with a higher yield and higher purity. Some of the results are shown in Table 3:

[0115] Table 3. Screening of cis-indeneamine salt-forming solvents

[0116] Example Solvent type Purity of cis-indeneamine (%) Yield (%) Embodiment 11 Isopropyl alcohol 95.4 67.3 Example 12 Ethyl acetate 82.5 76.1 Example 13 Ethyl acetate / ethanol=3:1 92.4 81.9 Embodiment 14 Ethyl acetate / ethanol = 2:1 98.4 85.8 Embodiment 15 Ethyl acetate / ethanol = 1:1 96.0 73.9

[0117] According to Table 3, the indeneamine obtained in the step 2 reaction and the succinic acid salt formation have a high proportion of cis-indeneamine in the ethyl acetate / ethanol mixed solvent, and the yield is high. The ratio of the solvent ethyl acetate / ethanol mixed solvent is further screened. When the ethanol / ethyl acetate ratio is 2:1, the purity of the cis-indeneamine salt reaches 98.4% and the yield reaches 85.8%. The indeneamine obtained in the step 2 and the succinic acid salt formation, the solvent ethyl acetate / ethanol ratio is 1:1 to 3:1; preferably 2:1.

[0118] The cis-indenylamine was split, and some results of splitting the cis-indenylamine of Example 14 (wherein the chiral HPLC detected that the RR indenylamine accounted for 49.0%, and the SS indenylamine accounted for 51.0%) were as follows:

[0119] Examples 16-22 Resolving cis-indenylamine to obtain SS indenylamine

[0120] Example 16

[0121] In a four-necked flask, 10.0 g (62.1 mmol, RR indamine: 49.0%, SS indamine: 51.0%) of cis-indamine prepared in Example 14 and 80 g of isopropanol were added, and 10 g of S-mandelic acid (67.1 mmol) was added at 40°C. The temperature was raised to 70°C and the reaction system was clear. The temperature was lowered to 25°C and stirred for 2 hours. The solution became turbid and a white solid was slowly precipitated. The crude product was obtained by filtration.

[0122] The crude product was added with 50.0g of isopropanol and stirred and dispersed, and the temperature was raised to 70°C to dissolve. The temperature was lowered to 55°C, and the system became turbid. Stirring and crystallization were continued for 2 hours. 8.1g of indeneamine mandelate was obtained by filtration. The purity of SS indeneamine was 98.9% and the yield was 81.6% according to chiral HPLC. The product NMR data is shown in Figure 2 .

[0123] 1H NMR (400MHz, DMSO-d6), δ1.03(d,J=8.0Hz,3H),2.25(s,3H),2.64(m,2H),2.91(m,1H),4.46(d,J=8.0Hz,1H),4 .58(s,1H),7.08(d,J=8.0Hz,1H),7.14(d,J=8.0Hz,1H),7.18(m,1H),7.23-7.28(m,3H),7.38(d,J=8.0Hz,2H).

[0124] Embodiment 17

[0125] Refer to Example 16, except that the solvent type isopropanol is changed to ethanol. 7.0 g of indenylamine mandelate is obtained, and the purity of SS indenylamine is 92.9%. The yield is 66.0%.

[0126] Comparative Example 3

[0127] Refer to Example 16, except that the resolving agent S-mandelic acid was replaced with an equimolar amount of D-tartaric acid, resulting in no precipitation of SS indenylamine.

[0128] By investigating different splitting agents and solvents, it was found that SS indenylamine could be obtained when S-mandelic acid and isopropanol were used as solvents.

[0129] The results of Examples 16, 17 and Comparative Example 3 are shown in Table 4.

[0130] Table 4. Screening of SS indene amine resolution reagents

[0131] Group Splitting agent Solvents SS indaneamine percentage (%) Yield (%) Comparative Example 3 D-Tartaric acid Isopropyl alcohol No precipitation / Example 16 S-Mandelic acid Isopropyl alcohol 98.9 81.6 Embodiment 17 S-Mandelic acid Ethanol 92.9 66.0

[0132] As can be seen from Table 4, the resolving agent in step 4 is S-mandelic acid; the solvent in step 4 is ethanol or isopropanol; isopropanol is preferred.

[0133] Embodiment 18

[0134] Refer to Example 16, except that the equivalent of the resolving agent is changed to 1.0 to obtain 6.9 g of indenylamine mandelate, with a purity of 78.0% and a yield of 54.6%.

[0135] Embodiment 19

[0136] Refer to Example 16, except that the equivalent of the resolving agent is changed to 1.3 to obtain 8.1 g of indenylamine mandelate, with a purity of 82.0% and a yield of 67.2%.

[0137] Based on the types of resolving agents and solvents obtained, the resolving agent equivalents were further screened, and it was found that the molar ratio of indene amine to S-mandelic acid was 1:1.1, and the yield and purity were relatively high, as shown in Table 5.

[0138] Table 5. Screening table of equivalents of indene amine and resolution reagent

[0139] Example Molar ratio of indeneamine to resolving agent SS indaneamine percentage (%) Yield (%) Embodiment 18 1：1.0 78.0 54.6 Example 16 1：1.1 98.9 81.6 Embodiment 19 1：1.3 82.0 67.2

[0140] Table 5 shows that the molar ratio of indenamine to S-mandelic acid can be 1:1.0 to 1:1.3, preferably 1:1.1.

[0141] Embodiment 20

[0142] Refer to Example 16, except that the crystallization temperature is changed to 30-40° C. 6.7 g of indenylamine mandelate salt is obtained, the purity of SS indenylamine is 96.0%, and the yield is 65.3%.

[0143] Embodiment 21

[0144] Refer to Example 16, except that the crystallization temperature is changed to 25-30° C. 7.4 g of indenylamine mandelate salt is obtained, the purity of SS indenylamine is 91.0%, and the yield is 68.3%.

[0145] Embodiment 22

[0146] Refer to Example 16, except that the crystallization temperature is changed to 15-20° C. 8.1 g of indenylamine mandelate salt is obtained, the purity of SS indenylamine is 92.5%, and the yield is 75.9%.

[0147] Based on the amount of splitting agent, the crystallization temperature was further screened, and it was found that when the crystallization temperature was between 20 and 25°C, the chiral purity and yield of the obtained monomer were relatively high, as shown in Table 6.

[0148] Table 6. Screening of the amount of optically pure indene amine resolution reagent and crystallization temperature

[0149] Example Crystallization temperature(℃) SS indaneamine percentage (%) Yield (%) Embodiment 20 30-40 96.0 65.3 Example 16 20-25 98.9 81.6 Embodiment 21 25-30 91.0 68.3 Embodiment 22 15-20 92.5 75.9

[0150] The crystallization temperature of the reaction system in step 4 is controlled between 15 and 40°C, preferably between 20 and 25°C.

[0151] The SS indenylamine is subjected to a configuration flip using an enzyme to obtain RS indenylamine. The configuration flip method adopts the literature method Deracemization of Racemic Amine Using ω-Transaminase and a Nickel-Based Nanocatalyst ACS Catal. 2022, 12, 15600-15608.

[0152] The invention discloses a preparation method for an indazine fluazifop-amid cis-indeneamine intermediate and a split monomer thereof. The method uses benzyl as an inducing auxiliary group and adopts a palladium carbon / hydrogen reduction method to prepare a cis-indeneamine intermediate at low cost and high selectivity, wherein the selectivity reaches more than 80%. Further splitting is performed to obtain SS indeneamine with a yield of 80%, and the total yield based on racemic indeneamine reaches 28%, which is much higher than the yield of the splitting method reported in the existing patent. The method has cheap and easily available starting raw materials, a simple process flow, and the advantages of high selectivity and low cost. The method provides an industrial route for preparing a key intermediate for preparing indazine fluazifop-amid and has good practical value.

[0153] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing an indazine fluazifop-amid cis-indaneamine intermediate, characterized in that: The method comprises the following steps: Step 1: using indanone and benzylamine or substituted benzylamine as raw materials, reacting to obtain an imine intermediate; Step 2: Under the action of a reducing agent, the imine intermediate is reduced to an indenamine material containing cis-indenamine; 2. The preparation method according to claim 1, characterized in that: In step 1, the substituted benzylamine is selected from one or more of methylbenzylamine, ethylbenzylamine, propylbenzylamine, and butylbenzylamine; optionally, the substituted benzylamine is selected from S(-)-α-methylbenzylamine or R(+)-α-methylbenzylamine; And / or, in step 1, the molar ratio of indanone and benzylamine or substituted benzylamine is 1:(1-10), optionally 1:(1-8), optionally 1:(1-6), optionally 1:(2-6), optionally 1:(2-5); And / or, in step 1, the reaction temperature is 150-260°C, optionally 150-200°C, optionally 160-180°C.

3. The preparation method according to claim 1, characterized in that: In step 1, the imine intermediate includes at least one of the following structural formulas:

4. The preparation method according to any one of claims 1 to 3, characterized in that: In step 2, the reducing agent is selected from sodium cyanoborohydride and / or hydrogen; optionally, when the reducing agent is hydrogen, palladium carbon is used as a catalyst; and / or, in step 2, the molar ratio of the imine intermediate to the reducing agent is 1:(1-10), optionally 1:(2-6), optionally 1:(2-4); And / or, in step 2, the reduction temperature is 60-70°C, optionally 60-65°C.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The following steps are also included: Step 3: reacting an indenylamine material containing cis-indenylamine with an organic acid in a solvent to generate a cis-indenylamine salt; Step 4: Under the action of a chiral resolving agent, the cis-indeneamine salt is split to obtain the SS indeneamine salt.

6. The preparation method according to claim 5, characterized in that: In step 3, the organic acid is one or more of benzenesulfonic acid and succinic acid, preferably succinic acid; and / or, in step 3, the molar ratio of the indenylamine material containing cis-indenylamine to the organic acid is 1:(1-5), optionally 1:(1-2), optionally 1:(1.05-1.5); And / or, in step 3, the solvent is one or more of isopropanol, ethanol, and ethyl acetate, optionally, the solvent is a mixed solvent of ethanol and ethyl acetate; optionally, the volume ratio of ethanol to ethyl acetate is 1:1 to 1:3, optionally 1:2; And / or, in step 3, the temperature is 40°C to reflux temperature, optionally 50°C to reflux temperature.

7. The preparation method according to claim 5 or 6, characterized in that: In step 4, the chiral resolving agent is one or more of D-tartaric acid, R-mandelic acid, and S-mandelic acid, and optionally S-mandelic acid; and / or, in step 4, the molar ratio of the cis-indene amine salt to the resolving agent is 1:(1-5), optionally 1:(1-2), optionally 1:(1.05-1.5), optionally 1:(1.08-1.3), optionally 1:(1.1-1.3); and / or, in step 4, the reaction temperature is between 0°C and 100°C, optionally between 20°C and 80°C, optionally between 40°C and 45°C; And / or, step 4 is carried out in an organic solvent, optionally the organic solvent is selected from ethanol and / or isopropanol.

8. The preparation method according to claim 5 or 6, characterized in that: In step 4, the purification of SS indenylamine includes: heating to dissolve and then cooling to precipitate, adding an organic solvent to the precipitate and heating to dissolve, cooling and crystallizing to obtain SS indenylamine salt. Optionally, the precipitation or crystallization temperature is controlled between 0°C and 40°C, preferably 20 to 25°C.

9. The preparation method according to any one of claims 5 to 8, characterized in that: The method further comprises step 5: using an enzyme to perform configuration inversion on the SS indenylamine salt to obtain the RS indenylamine.

10. The preparation method according to any one of claims 1 to 9, characterized in that: It includes the following steps: Step 1: Using indanone and benzylamine as raw materials, an imine intermediate is prepared; Step 2: Under the action of palladium carbon and hydrogen, the imine intermediate is reduced to an indenamine material containing cis-indenamine; Step 3: reacting an indenylamine material containing cis-indenylamine with succinic acid in a solvent to generate a cis-indenylamine salt; Step 4: Under the action of S-mandelic acid, the cis-indeneamine salt is split to obtain SS indeneamine mandelate; Step 5: Use enzymes to perform configurational inversion on SS indenylamine mandelate to obtain RS indenylamine.

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