A process for the preparation of a parp inhibitor intermediate

Abstract

The application belongs to the field of pharmaceutical chemistry, and discloses a preparation method of a PARP inhibitor intermediate. The preparation method provided by the application does not involve the steps of noble metal catalytic coupling and chiral resolution, has low requirements on equipment, is simple to operate, is beneficial to industrial production, and when the amino protecting group is a trifluoroacetic acid group, the yield of the ring closure reaction is significantly improved.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and more specifically, relates to a method for preparing a PARP inhibitor intermediate. Background Technology

[0002] Compound X is an orally administered small-molecule PARP (Poly ADP-ribose polymerase) inhibitor that preferentially kills cancer cells by exploiting defects in the DNA repair pathway. This drug is indicated for maintenance therapy in adult patients with advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have achieved complete or partial remission after first-line platinum-based chemotherapy. Its chemical structure is as follows:

[0003]

[0004] In the disclosed synthetic route, (S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester is an important intermediate (see the background section of patent CN109265390B). Its specific structure is shown in formula (I):

[0005]

[0006] The synthetic route for compound of formula (I) disclosed in patent CN109265390B is as follows:

[0007]

[0008] The cyclization reaction yield of this route is low and purification is difficult, only around 30%; product purification uses column chromatography, which is not conducive to industrial-scale production. Therefore, it is still necessary to develop a preparation method suitable for industrial-scale production. Summary of the Invention

[0009] On one hand, the present invention provides a method for preparing compound 2, comprising the following steps: compound 1 undergoes a cyclization reaction under the conditions of a base and a solvent to obtain compound 2.

[0010]

[0011] In some embodiments, the base is potassium tert-butoxide.

[0012] In some embodiments, the solvent is selected from dichloromethane, THF, 1,4-dioxane, or DMF; preferably, the solvent is selected from THF, 1,4-dioxane, or DMF; more preferably, the solvent is DMF.

[0013] In some embodiments, the molar ratio of the base to compound 1 is selected from 2:1 to 4:1; preferably, the molar ratio of the base to compound 1 is selected from 3:1.

[0014] In some embodiments, the method for preparing compound 2 further includes: a condensation reaction of compounds 1-1 and 1-2 to obtain compound 1.

[0015]

[0016] In some embodiments, the method for preparing compound 2 further includes: compound 2 undergoing a deprotection reaction to obtain compound 3.

[0017]

[0018] On the other hand, the present invention provides a method for preparing compound 1, comprising the following steps: compounds 1-1 and 1-2 undergo a condensation reaction to obtain compound 1.

[0019]

[0020] In some embodiments, the condensation reaction uses a condensing agent selected from CDI, DCC, or EDCI; preferably, the condensing agent is EDCI.

[0021] In some embodiments, the condensation reaction further uses an activator selected from DMAP, HOAt, or HOBt; preferably, the activator is HOBt.

[0022] On the other hand, the present invention provides a method for preparing a compound of formula (I), comprising the following steps:

[0023]

[0024] (1) Compounds 1-1 and 1-2 undergo a condensation reaction to give compound 1;

[0025] (2) Compound 1 undergoes a cyclization reaction in a base and solvent to give compound 2;

[0026] (3) Compound 2 undergoes a deprotection reaction to give compound 3;

[0027] (4) Compound 3 undergoes a reduction reaction to give compound 4;

[0028] (5) Compound 4 undergoes a reduction reaction to give compound 5;

[0029] (6) Compound 5 was given by introducing a Boc protecting group to obtain compound (I).

[0030] In some embodiments, the condensation reaction in step (1) uses a condensing agent selected from CDI, DCC, or EDCI; preferably, the condensing agent is EDCI.

[0031] In some embodiments, the condensation reaction in step (1) also uses an activator selected from DMAP, HOAt, or HOBt; preferably, the activator is HOBt.

[0032] In some implementations, the base in step (2) is potassium tert-butoxide.

[0033] In some embodiments, the solvent in step (2) is selected from THF, 1,4-dioxane or DMF; preferably, the solvent is DMF.

[0034] In some embodiments, the molar ratio of the base to compound 1 in step (2) is selected from 2:1 to 4:1; preferably, the molar ratio of the base to compound 1 in step (2) is selected from 3:1.

[0035] In some embodiments, the deprotection reaction in step (3) uses an alkali and an alcohol solution; preferably, the alkali is selected from potassium carbonate, lithium hydroxide or sodium hydroxide; the alcohol solution is selected from methanol or ethanol; more preferably, the deprotection reaction in step (3) uses a sodium hydroxide and methanol solution.

[0036] In some embodiments, the reducing agent used in step (4) is sodium borohydride and one or more combinations selected from boron trifluoride diethyl ether, boron trifluoride tetrahydrofuran complex and aluminum trichloride; preferably, the reducing agent is selected from a combination of sodium borohydride and boron trifluoride tetrahydrofuran complex.

[0037] In some implementations, the reducing agent used in step (5) is palladium on carbon.

[0038] In some embodiments, the solvent used in the reduction reaction of step (5) is selected from ethanol or methanol; preferably, the solvent used in the reduction reaction of step (5) is selected from ethanol.

[0039] In some embodiments, the solvent used in step (6) is selected from DMF, dichloromethane, acetonitrile, methanol or 1,4-dioxane; preferably, the solvent is selected from dichloromethane.

[0040] On the other hand, the present invention provides compounds:

[0041]

[0042] In this invention, unless otherwise stated, the water or aqueous solution referred to refers to analytical water commonly used in the analytical field, including but not limited to purified water, ultrapure water, deionized water, etc.

[0043] The relevant abbreviations in this invention are defined as follows:

[0044] Boc: tert-butyloxycarbonyl;

[0045] (Boc)2O: Ditert-butyl dicarbonate;

[0046] CDI: N,N-Carbodiimidazole;

[0047] DCM: Dichloromethane;

[0048] DMF: N,N-dimethylformamide;

[0049] DIPEA: N,N-diisopropylethylamine;

[0050] EA: Ethyl acetate;

[0051] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

[0052] HOBt: 1-Hydroxybenzotriazole;

[0053] HOAt: N-hydroxy-7-azabenzotriazole;

[0054] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide;

[0055] N: represents mol / L;

[0056] h: indicates time in hours.

[0057] The present invention has the following beneficial effects:

[0058] The preparation method provided by this invention does not involve noble metal catalytic coupling and chiral resolution steps, has low equipment requirements, is easy to operate and is conducive to industrial production, and the yield of the cyclization reaction is significantly improved when the amino protecting group is a trifluoroacetic acid group. Detailed Implementation

[0059] The present invention will be explained in more detail below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and the nature and scope of the present invention are not limited thereto.

[0060] Compound 1-1 of the present invention can be prepared by methods disclosed in the prior art, such as WO2019179798A1; or it can be obtained from commercial sources.

[0061] Compounds 1-2 of the present invention can be prepared by methods disclosed in the prior art, such as CN107793414A; or they can be purchased from commercial sources.

[0062] The liquid chromatography conditions used in Example 2 of this invention are as follows:

[0063] Chromatographic column: Waters SunFire (2.1x50mm, 3.5μm)

[0064] Mobile phase: 0.1% formic acid aqueous solution as mobile phase A, and acetonitrile as mobile phase B.

[0065] Column temperature: 30℃

[0066] Gradient elution, the procedure is as follows:

[0067]

[0068] Example 1: Preparation of Compound 1

[0069]

[0070] Example 1-1

[0071] 200 mL of DCM was added to a 500 mL three-necked flask, followed by 10.3 g of compound 1-1. The mixture was cooled to 0–5 °C, and then 5.35 g of EDCI, 3.6 g of HOBt, 12 g of compound 1-2, and 17.1 g of DIPEA were added sequentially. After the additions were complete, the mixture was reacted at 0–10 °C for 2 h. After the reaction was complete, 50 mL of purified water was slowly added to quench the reaction. The mixture was separated, and the organic phase was concentrated to give compound 1 in 88.7% yield. MS: 427.17 (M+H) +

[0072] Examples 1-2

[0073] 100 mL of DCM was added to a 250 mL three-necked flask, followed by 10 g of compound 1-1. The temperature was lowered to 0–10 °C, and then 8.88 g of CDI and 12 g of compound 1-2 were added sequentially. After the additions were complete, the reaction was carried out at 20–30 °C for 8 hours. After the reaction was complete, 50 mL of purified water was slowly added to the system to quench the reaction. The mixture was separated, and the organic phase was concentrated to obtain compound 1, with a yield of 57.6%.

[0074] Example 2 Preparation of Compound 2

[0075]

[0076] (1) Investigate the effect of different bases on the ring-closing reaction.

[0077] Compound 1 was dissolved in DMF (5 mL / g relative to the volume of compound 1), and then a base was added at a molar ratio of 1:3. The reaction was carried out at 20–30 °C for 4 h. The effect of different bases on the reaction was investigated, and the specific experimental data are shown in Table 1 below.

[0078] Table 1. Effect of base on ring-closing reaction

[0079]

[0080]

[0081] (2) Investigate the effect of different solvents on the cyclization reaction.

[0082] Compound 1 was dissolved in a solvent (5 mL / g relative to the volume of compound 1), and then potassium tert-butoxide was added, with a molar ratio of compound 1 to potassium tert-butoxide of 1:3. The effect of different solvents on the reaction was investigated, and specific experimental data were obtained.

[0083] As shown in Table 2 below:

[0084] Table 2. Effect of solvent type on ring-closing reaction

[0085] Solvent types purity(%) NMP 32.75 DMF 87.38 THF 78.64 1,4-Dioxane 75.62

[0086] (3) Investigate the effect of base stoichiometry on the ring-closing reaction.

[0087] Compound 1 was dissolved in DMF (5 mL / g relative to compound 1), and potassium tert-butoxide was added. The reaction was carried out at 20–30 °C for 4 h. The effect of different amounts of potassium tert-butoxide on the reaction was investigated. The specific experimental data are shown in Table 3 below.

[0088] Table 3. Effect of base equivalent (relative to compound 1) on the ring-closing reaction.

[0089] Base equivalent (eq) purity(%) 2.0 44.61 3.0 91.31 4.0 69.90

[0090] (4) Preparation of compound 2

[0091] 15 g of compound 1, 75 mL of DMF, and 11.83 g of potassium tert-butoxide were added to a 250 mL three-necked flask. After the addition was complete, the mixture was reacted at 20–30 °C for 4 h. After the reaction was complete, 45 mL of purified water was added, and the pH was adjusted to 7–8 by adding 2N hydrochloric acid. The mixture was then extracted with 150 mL of ethyl acetate. The organic phase was washed once with 45 mL of purified water and once with 45 mL of saturated brine. The organic phase was concentrated to obtain a yellow oily substance. 30 mL of methyl tert-butyl ether was added, and the mixture was rotary evaporated until a yellow foamy solid was formed. Then, 75 mL of methyl tert-butyl ether was added, and the mixture was heated to 50–55 °C and stirred for 1 h. The mixture was then cooled to 10–20 °C to crystallize for 6 h. The crystals were filtered and dried to obtain compound 2, with a yield of 62.2%. MS: 391.18 (M+H) +

[0092] Example 3 Preparation of Compound 3

[0093]

[0094] Add 6.0 g of compound 2 and 60 mL of methanol to a 250 mL three-necked flask, then add 30 mL of 3N sodium hydroxide solution. Heat the mixture to 35–40 °C and react. After the reaction is complete, cool the mixture to 20–30 °C and adjust the pH to 6–7 with 2N hydrochloric acid solution. Concentrate the reaction mixture until no droplets remain, add 60 mL of EA extract, and separate the liquid. Collect the organic phase and concentrate the organic phase to obtain compound 3, with a yield of 84.8%.

[0095] Example 4: Preparation of Compound 4

[0096]

[0097] Add 15 mL of tetrahydrofuran to a 100 mL three-necked flask, cool to 0–10 °C, and maintain the temperature at 0–10 °C. Add 1.37 g of sodium borohydride and a tetrahydrofuran solution containing 3.50 g of compound 3 (compound 3 is dissolved in 20 mL of tetrahydrofuran) in one step. Add 4.94 g of a tetrahydrofuran complex solution of boron trifluoride dropwise. After the addition is complete, raise the temperature to 20–30 °C to react. After the reaction is complete, cool to 0–5 °C, add 10 mL of purified water to quench the reaction, adjust the pH to 1–2 with 2N hydrochloric acid, raise the temperature to 45–55 °C to react, and after the reaction is complete, cool to 20–30 °C, adjust the pH to above 12 with 10% sodium hydroxide solution, add EA to extract and separate the liquid, collect the organic phase, concentrate the organic phase to obtain compound 4, with a yield of 94.6%.

[0098] Example 5: Preparation of Compound 5

[0099]

[0100] Add 3.0 g of compound 4 and 30 mL of ethanol to a 100 mL three-necked flask, followed by the addition of 0.60 g of 10% palladium on carbon and 0.30 g of acetic acid. Purge the mixture three times with nitrogen and three times with hydrogen. Heat the mixture to 40–50 °C and react. After the reaction is complete, filter the mixture, collect the filtrate, and concentrate the filtrate until no droplets remain. Dissolve the residue in 30 mL of purified water, adjust the pH to 10–12 with 10% sodium hydroxide solution, extract with 30 mL of EA, and concentrate the organic phase to obtain compound 5 in 76.7% yield. 1 H NMR(400MHz,DMSO)δ1.453(2H,m),1.616-1.645(1H,m),1.779-1.798(1H,m),2.413(2H,m),2.90 8-3.852(2H,m),4.010-4.746(4H,m),6.477-6.498(2H,d),6.851-6.872(2H,d)MS:177.10(M+H) +

[0101] Example 6 Preparation of compound (I)

[0102]

[0103] Add 1.45 g of compound 5 and 15 mL of dichloromethane to a 100 mL three-necked flask, and cool to 0–10 °C. Maintaining the temperature at 0–10 °C, add 12 mL of a dichloromethane solution containing 1.80 g of di-tert-butyl dicarbonate dropwise. After the addition is complete, maintain the temperature at 0–10 °C and allow the reaction to proceed. After the reaction is complete, add 30 mL of purified water to quench the reaction, stir for 0.5 h, separate the liquids, wash the organic phase with 30 mL of purified water, concentrate the organic phase, and add 7 mL of a mixed solvent of n-heptane and EA (volume ratio of n-heptane to EA:1). Heat to 60–70 °C, dissolve and stir for 1 h, cool to 10–20 °C to crystallize for 6 h, filter, and dry to obtain compound I, with a yield of 77.1%.

[0104] 1 HNMR(400MHz,DMSO)δ1.401(9H,s),1.423-1.554(2H,m),1.649-1.695(1H,m),

[0105] 1.794-1.825(1H,m),2.376-2.424(1H,m),2.517(2H,s),3.935-3.967(2H, m),4.89(2H,s),6.501-6.524(2H,d),6.883-6.901(2H,d)MS:299.09(M+Na) + .

Claims

1. A method for preparing compound 2, characterized in that, The process includes the following steps: Compound 1 undergoes a cyclization reaction in a base and solvent to give Compound 2.

2. The preparation method according to claim 1, characterized in that, The alkali is potassium tert-butoxide.

3. The preparation method according to claim 1, characterized in that, The solvent is selected from dichloromethane, THF, 1,4-dioxane, or DMF; preferably, the solvent is selected from THF, 1,4-dioxane, or DMF; more preferably, the solvent is DMF.

4. The preparation method according to claim 1, characterized in that, The molar ratio of the base to compound 1 is selected from 2:1 to 4:1; preferably, the molar ratio of the base to compound 1 is selected from 3:

1.

5. The preparation method according to claim 1, characterized in that, Also includes: Compounds 1-1 and 1-2 undergo a condensation reaction to give compound 1.

6. The preparation method according to claim 1, characterized in that, Also includes: Compound 2 undergoes a deprotection reaction to give compound 3.

7. A method for preparing compound 1, comprising the following steps: compounds 1-1 and 1-2 undergo a condensation reaction to obtain compound 1.

8. A method for preparing a compound of formula (I), comprising the following steps: (1) Compounds 1-1 and 1-2 undergo a condensation reaction to give compound 1; (2) Compound 1 undergoes a cyclization reaction in a base and solvent to give compound 2; (3) Compound 2 undergoes a deprotection reaction to give compound 3; (4) Compound 3 undergoes a reduction reaction to give compound 4; (5) Compound 4 undergoes a reduction reaction to give compound 5; (6) Compound 5 was given by introducing a Boc protecting group to obtain compound (I).

9. Compounds:

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