A process for the preparation of 2,2-disubstituted-4-phenylbutyronitrile derivatives

Abstract

The application belongs to the field of medicine synthesis, and particularly relates to a preparation method of 2,2-disubstituted-4-phenyl butyronitrile derivative, which comprises the following steps: mixing phenetole, nitrile and alkali agent in a molar ratio of 1.0:3.5-4.5:2.5-3.5 in aprotic solvent with a dielectric constant (epsilon) less than 20 at 60-100 DEG C for 12-30 hours; after the reaction is completed, the cooled reaction system is adjusted to be neutral, and the product is collected and purified. The phenetole is subjected to elimination reaction under alkaline conditions to generate a carbon-carbon double bond, and is subjected to addition reaction with the nitrile to obtain the 2,2-disubstituted-4-phenyl butyronitrile derivative. Meanwhile, the raw materials used are low in price and easy to synthesize, the cost is greatly reduced, the industrialization prospect is wider, and the operation is simple, so that the process technology has more competitive value.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, and specifically relates to a method for preparing a 2,2-disubstituted-4-phenylbutyronitrile derivative. Background Technology

[0002] Fingolimod, developed by Novartis, is a revolutionary, novel, single-use transplant therapy. It is the first commercially available drug in a new class of drugs called sphingosine monophosphate receptor (SIP-R) blockers. It reversibly removes lymphocytes from the graft, preventing T-cell damage. In September 2010, the US FDA approved fingolimod as a first-line treatment for relapsing-remitting multiple sclerosis (RFMS) under the brand name Gilenya. Subsequently, it was approved for marketing in the US, Europe, Australia, and other countries. It is primarily used to treat RFMS and reduce the frequency of clinical exacerbations. Therefore, the synthesis of key intermediates of fingolimod is of great significance. The structural formulas of fingolimod and its key intermediates are shown in Formulas 1 and 2 below:

[0003]

[0004] Among them, the synthetic routes for 2,2-disubstituted-4-phenylbutyronitrile in Formula 2 are currently mainly as follows:

[0005] (1) Zhang, Hongwei et al. (Organic Letters, 2020, 22(3), 997-1002) reported that p-fluorophenylethanol and carbon tetrabromide undergo a substitution reaction under the catalysis of triphenylphosphine, and the substitution reaction continues in the presence of a base such as lithium diisopropylamino. This can be represented by the following formula:

[0006]

[0007] The reaction requires harsh conditions and has a low yield.

[0008] (2) Feng, Yisi et al. (Organic Letters, 2013, 15(7), 1472-1475) reported a substitution reaction of 1-(bromoethynyl)-4-fluorobenzene with potassium 2-cyano-2-methylpropionate using CuBr as a catalyst, 8-hydroxyquinoline as a ligand, Ag2CO3 as an additive, and DMAc as a solvent. The target product was then obtained by reduction with Pd / C and H2, and can be represented by the following formula:

[0009]

[0010] The reaction requires substitution followed by reduction and is carried out under high temperature and pressure, which poses safety risks.

[0011] It is evident that current production processes for 2,2-disubstituted-4-phenylbutyronitrile generally suffer from drawbacks such as high cost, low yield, harsh reaction conditions, poor safety, and significant waste generation. Therefore, developing a low-cost, simple-to-operate, low-waste, and high-purity synthesis process for 2,2-disubstituted-4-phenylbutyronitrile is of significant value. Summary of the Invention

[0012] To address the aforementioned technical problems, this invention provides a method for preparing a 2,2-disubstituted-4-phenylbutyronitrile derivative.

[0013]

[0014] Where X is F, Cl or Br, and R 1 It is alkyl or benzyl, R 2 H or alkyl, R 3 It is H or alkyl, and R 2 and R 3 Not both H

[0015] The aforementioned alkyl groups include chain alkyl groups and cycloalkyl groups having 1 to 6 carbon atoms, with cycloalkyl groups including cyclopropyl or cyclohexyl groups.

[0016] The preparation reaction was carried out under strongly alkaline conditions at a temperature of 60℃ to 100℃.

[0017] As a preferred method, phenethyl ether, nitrile, and alkali are mixed and reacted in a solvent at 60°C to 100°C under a protective atmosphere. After the reaction is completed, the cooled reaction system is adjusted to neutral, and the product is collected and purified.

[0018] Furthermore, the protective atmosphere is argon, nitrogen, or helium.

[0019] Furthermore: the pK of the alkali agent a The pK values ​​are 17–30 for alkali and nitriles. a The difference between the values ​​should not exceed 6, preferably not exceed 4.

[0020] Furthermore, the alkali is a potassium, sodium, or lithium salt of bis(trimethylsilyl)amine (HMDS), with the sodium salt of HMDS (NaHMDS, structural formula below) preferred over the potassium or lithium salt of HMDS, and the potassium salt of HMDS (KHMDS) preferred over the lithium salt of HMDS (LiHMDS).

[0021]

[0022] Furthermore, the solvent is an aprotic solvent with a dielectric constant (ε) less than 20, such as toluene, tetrahydrofuran, etc.

[0023] Furthermore, the molar ratio of phenethyl ether, nitrile, and alkali is 1.0:3.5-4.5:2.5-3.5.

[0024] Preferably, the reaction temperature is 70℃~80℃.

[0025] Preferably, the reaction time should be between 12h and 30h, and more preferably between 16h and 24h.

[0026] The beneficial effects of this invention are as follows: In this scheme, phenethyl ether is prepared by mixing phenethyl ether with a nitrile and then carrying out a one-step reaction. Structurally, because the second carbon atom connecting the ether bond from right to left is acidic, phenethyl ether can undergo an elimination reaction under alkaline conditions to form a carbon-carbon double bond, which then undergoes an addition reaction with a nitrile to give a 2,2-disubstituted-4-phenylbutyronitrile derivative. Since nitrile is inexpensive, an excess of it is used in the reaction to ensure that the generated carbon-carbon double bond intermediate is reacted off quickly, preventing the unstable olefin bond from remaining in the reaction system for an extended period. Furthermore, the raw materials used are inexpensive and easy to synthesize, significantly reducing costs and broadening the prospects for industrialization. The simple operation also makes this process technology more competitive. Detailed Implementation

[0027] The present invention will be further described below with reference to the embodiments (the raw materials used in the following embodiments are all industrial grade products):

[0028] A method for preparing a 2,2-disubstituted-4-phenylbutyronitrile derivative: Under a protective atmosphere, phenethyl ether, nitrile, and alkali in a molar ratio of 1.0:3.5-4.5:2.5-3.5 are mixed and reacted in an aprotic solvent with a dielectric constant (ε) less than 20 at 60℃-100℃ for 12-30 h. After the reaction is completed, the cooled reaction system is adjusted to neutral, and the product is collected and purified.

[0029] The protective atmosphere is argon, nitrogen, or helium.

[0030] pK of alkaline agents a The pK values ​​are 17–30 for alkali and nitriles. a The difference between the values ​​is no greater than 6, preferably no greater than 4, and the alkali is specifically a potassium salt, sodium salt, or lithium salt of bis(trimethylsilyl)amine (HMDS).

[0031] The solvent is toluene or tetrahydrofuran.

[0032] The preferred reaction temperature is 70℃~80℃, and the preferred reaction time is 16h~24h.

[0033] The reaction formula for the above preparation method is:

[0034]

[0035] Where X is F, Cl or Br, and R 1 It is alkyl or benzyl, R 2 H or alkyl, R 3 It is H or alkyl, and R 2 and R 3 Not both H

[0036] The aforementioned alkyl groups include chain alkyl groups and cycloalkyl groups having 1 to 6 carbon atoms, and cycloalkyl groups include cyclopropyl or cyclohexyl.

[0037] Example 1

[0038] Preparation of 4-fluoro-2,2-dimethylphenylbutyronitrile:

[0039] The phenylethyl ether in this embodiment is synthesized according to the method described in the reference, and the synthesis method is as follows:

[0040]

[0041] The preparation method is as follows: Under nitrogen protection, the synthesized phenethyl ether (1.0 g, 4.34 mmol) was added to tetrahydrofuran (8 mL), followed by a tetrahydrofuran solution of sodium bis(trimethylsilyl)amino(NaHMDS) (6.5 mL, NaHMDS concentration 2 mol / L). After thorough mixing, a tetrahydrofuran solution of isobutyronitrile (1.20 g, 17.37 mmol) (2 mL) was added dropwise. After the addition was complete, the temperature was raised to 80 °C for reflux reaction. The reaction formula is as follows:

[0042]

[0043] The reaction endpoint was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature (25℃, the same below). 3 mol / L hydrochloric acid was added to adjust the pH to neutral. The reaction system was extracted with ethyl acetate and water. The organic phase was collected, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain a yellow oily crude product. The target product was then obtained by vacuum distillation with a yield of 72% (moles of target product ÷ moles of phenethyl ether in the raw material × 100%, the same below). The product structure characterization is shown in Table 6.

[0044] Examples 2 to 10

[0045] Based on Example 1, with other experimental conditions remaining unchanged, the effect of changing only the type and amount of alkali on the reaction results was investigated and compared with Example 1. The results are shown in Table 1:

[0046] Table 1

[0047]

[0048]

[0049] It is evident that the choice of alkali has a significant, sometimes even decisive, impact on the progress of the target reaction. Specifically, according to the applicant's experiments, when t-BuOK is used as the alkali, the reactant phenethyl ether undergoes the following reaction:

[0050]

[0051] 1H NMR (400MHz, Chloroform-d) δ7.48–7.37(m,7H),6.97(d,J=8.2Hz,2H),6.70(dd,J=17.6,10.8Hz,1H),5.65(d,J=17.6Hz,1H),5.14(d,J=34.8Hz,3H).

[0052] And the products generated Without further reaction with isobutyronitrile, the reaction ends. Therefore, this reaction cannot be used for the synthesis in this scheme, and the resulting product... It can only be used as a benzene ring-containing polymer monomer for carbon-carbon double bond polymerization modification, and cannot be used for the preparation of 2,2-disubstituted-4-phenylbutyronitrile derivatives.

[0053] Examples 11 to 14

[0054] Based on Example 1, with other experimental conditions remaining unchanged, the effect of changing the molar ratio of phenethyl ether to nitrile on the reaction results was investigated and compared with Example 1. The results are shown in Table 2:

[0055] Table 2

[0056]

[0057] Examples 15 to 18

[0058] Based on Example 1, with other experimental conditions remaining unchanged, the effect of changing only the reaction temperature on the reaction results was investigated and compared with that of Example 1. The results are shown in Table 3:

[0059] Table 3

[0060] Reaction temperature (°C) Yield (%) Example 1 80 72 Example 15 60 65 Example 16 70 70 Example 17 90 67 Example 18 100 60

[0061] Examples 19 to 21

[0062] Based on Example 1, with other experimental conditions remaining unchanged, the effect of changing only the solvent type on the reaction results was investigated and compared with Example 1. The results are shown in Table 4:

[0063] Table 4

[0064] solvent Yield (%) Example 1 THF 72 Example 19 NMP 64 Example 20 Toluene 70 Example 21 DMSO 58

[0065] Examples 22 to 29

[0066] Based on Example 1, with all other experimental conditions remaining unchanged, only the experimental conditions were changed.

[0067]

[0068] The influence of the types of substituents on the reactants on the reaction results was investigated and compared with those in Example 1. The results are shown in Tables 5 and 6.

[0069] Table 5

[0070]

[0071]

[0072] Table 6: Structural detection data of the products prepared in each example in Table 5

[0073]

[0074]

[0075]

[0076] Example 30

[0077] Based on Example 1, all other experimental conditions remained unchanged, except that the raw material "phenethyl ether" was replaced in equimolar amounts with one of the reactants used in its synthesis. The effect of the reaction on the results was investigated and compared with that of Example 1. The results are shown in Table 7.

[0078] Table 7

[0079]

[0080] It is evident that not every chemical functional group at this position can undergo the target reaction.

[0081] Example 31

[0082] Based on Example 1, with other experimental conditions remaining unchanged, the only difference was that the fluorinated benzene ring on the raw material "phenethyl ether" was replaced with a pyridine ring, i.e., using an equimolar amount of pyridine ethyl ether as the raw material. The effect on the reaction results was investigated and compared with that of Example 1. The results are shown in Table 8:

[0083] Pyridine ethyl ether was synthesized according to the method in Example 1:

[0084]

[0085] Table 8

[0086]

[0087] As seen in Example 31, the molecular structural environment in which the ether bond group is located has an almost decisive influence on the occurrence of the target reaction.

Claims

1. A method for preparing a 2,2-disubstituted-4-phenylbutyronitrile derivative, characterized in that: The preparation method is as follows: Where X is F, Cl or Br, and R 1 It is alkyl or benzyl, R 2 H or alkyl, R 3 It is H or alkyl, and R 2 and R 3 Not both H The preparation reaction was carried out under strongly alkaline conditions at a temperature of 60℃ to 100℃. Among them, the pK of the alkali agent under strong alkaline conditions a The pK values ​​are 17–30 for alkali and nitriles. a The difference between the values ​​is no greater than 6, and the alkali agent of the strong base is a potassium salt, sodium salt or lithium salt of bis(trimethylsilyl)amine.

2. The method for preparing the 2,2-disubstituted-4-phenylbutyronitrile derivative as described in claim 1, characterized in that: The preparation method involves mixing phenethyl ether, nitrile, and alkali in a solvent at 60°C to 100°C under a protective atmosphere. After the reaction is complete, the cooled reaction system is adjusted to neutral, and the product is collected and purified.

3. The method for preparing the 2,2-disubstituted-4-phenylbutyronitrile derivative as described in claim 2, characterized in that: The protective atmosphere is argon, nitrogen, or helium.

4. The method for preparing the 2,2-disubstituted-4-phenylbutyronitrile derivative as described in claim 3, characterized in that: The solvent is an aprotic solvent with a dielectric constant of less than 20.

5. The method for preparing the 2,2-disubstituted-4-phenylbutyronitrile derivative as described in claim 2, characterized in that: The molar ratio of the phenethyl ether, the nitrile, and the alkaline agent is 1.0:3.5-4.5:2.5-3.

5.

6. The method for preparing the 2,2-disubstituted-4-phenylbutyronitrile derivative as described in claim 2, characterized in that: The reaction temperature is 70℃~80℃.

7. The method for preparing the 2,2-disubstituted-4-phenylbutyronitrile derivative as described in claim 2, characterized in that: The reaction time is 12h to 30h.

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