Preparation method of related substances of imine intermediate

Abstract

The invention discloses a preparation method of a related substance of an imine intermediate, the related substance can be used as an impurity reference substance of a D fragment of the imine intermediate, and is used for separating and determining the D fragment of the imine intermediate and an impurity in a formula (I) by a high performance liquid chromatography method, the existence and the research property of the impurity are clearly indicated in pharmacopoeia, and the related substance can be used as an impurity reference substance of the D fragment of the imine intermediate. So far, a synthetic route and a synthetic method are not reported in literatures, and the preparation difficulty is relatively high. The preparation method provided by the invention is mild in reaction condition and simple in post-treatment, and can be used for preparing the compound shown in the formula (I) with the purity meeting the requirement on a large scale, and the compound is used as an impurity reference substance for quality research of the Irebulin intermediate D fragment.

Description

TECHNICAL FIELD

[0001] The present application relates to the synthesis of pharmaceutical impurities, in particular to a preparation method of a related substance of an intermediate of Eribulin. BACKGROUND

[0002] Eribulin is an important anticancer drug, which is a derivative of halichondrin B, a macrolide compound extracted from the marine sponge Halichondria okadai. In 1986, Japanese scientists Hriata and Uemura isolated halichondrin B from the sponge. However, halichondrin B has a very low content in the sponge and a complex structure, making it difficult to be directly used for drug development. After more than ten years of effort, Nippon Shinyaku Co., Ltd. developed Eribulin through chemical synthesis method and structural modification. Eribulin is one of the most complex drugs developed and produced by pure chemical synthesis method so far, containing 19 chiral carbon atoms in the molecule, which is synthesized from simple industrial raw materials through 62-step reaction, resulting in great difficulty in industrial production. There are few generic drug manufacturers of Eribulin or its preparations. The structural formula of Eribulin is as follows:

[0003] WO2005118565A discloses the synthesis of Eribulin by converging fragments F1, F-2 and F3:

[0004] The quality control of drug substances and preparations has always been the focus and difficulty in the process of drug research and development, and the research on impurities is the most important. The synthesis process of Eribulin is complex, the types of impurities are various, and the synthesis difficulty is great. The Japanese original pharmacopoeia clearly points out that the related substance at C18 / C19 (internal olefin) should not exceed the identification limit (0.10%), and the related substance at C18 / C19 (internal olefin) is introduced by the intermediate fragment F-2, so the research on the related substance of F-2 is of great significance.

[0005]

[0006] Eribulin D fragment is a structure of the aforementioned F-2 fragment, which is an important intermediate for preparing Eribulin selected by the applicant. The research on the related substance of the intermediate found the impurity of the compound of formula (I), which can be continuously transmitted in the subsequent synthesis process and finally introduce the C18 / C19 (internal olefin) impurity in Eribulin. Therefore, it is necessary to control the impurity compound of formula (I) when preparing Eribulin D fragment, but due to the large number of chiral centers of the impurity compound, the synthesis difficulty is great, and the synthesis process is complex, and there is no report so far. SUMMARY

[0007] The application aims to provide a preparation method of a related substance generated in a synthesis process of eribulin intermediate.

[0008] The eribulin intermediate of the application is an eribulin D fragment, and the related substance is a compound of formula (I), and the specific structure is as follows:

[0009] The synthesis route of the related substance is as follows: ; Step 1: double bond isomerization migration of formula I-a in the presence of a base to obtain compound I-b; Step 2: oxidation of formula I-b in the presence of an oxidizing agent to obtain compound I-c; Step 3: classical asymmetric NHK coupling reaction of formula I-c under the co-catalysis of nickel and chromium to obtain compound I-d; Step 4: removal of the silyl ether protecting group of formula I-d in the presence of TBAF to obtain compound I-e; Step 5: acylation of formula I-e in a base under the catalysis of DMAP to obtain compound I.

[0010] Preferably, the solvent used in step 1 is selected from one of N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, and more preferably dimethyl sulfoxide; Preferably, the base in step 1 is selected from sodium methoxide, sodium tert-butoxide, sodium hydride, potassium tert-butoxide, and sodium amide, and more preferably potassium tert-butoxide; Preferably, the molar ratio of I-a to potassium tert-butoxide in step 1 is 1:0.4-0.6, and more preferably 1:0.5.

[0011] Preferably, the reaction temperature in step 1 is 45-55°C, and more preferably 50°C, and it is noted that too high temperature will damage the silicon protecting group.

[0012] Preferably, the oxidizing agent in step 2 is selected from PCC, PDC and DMP, and more preferably DMP; Preferably, the solvent used in step 3 is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetonitrile, N,N-dimethylformamide, and more preferably tetrahydrofuran.

[0013] Preferably, the reaction system of step 3 is isolated from oxygen, and the charging process needs to be completed under nitrogen protection conditions.

[0014] Preferably, the reaction temperature in step 3 is 30-40°C, and more preferably 35°C.

[0015] Preferably, the molar ratio of I-d and TBAF in step 4 is 1:1.0-1.2.

[0016] Preferably, the base used in step 5 is selected from triethylamine, pyridine, DIPEA, DIEA, more preferably pyridine.

[0017] Each of the abbreviations of reagents or groups is explained as follows: TBDPSCl: tert-butyldiphenylsilyl group; Piv: pivaloyl group; TBAF: tetra-n-butylammonium fluoride; DMAP: 4-dimethylaminopyridine; PCC: pyridinium chlorochromate; PDC: pyridinium dichromate; DMP: Dess-Martin periodinane; DCM: dichloromethane; DIPEA: N , N diisopropylethylamine; DIEA: diisopropylamine; t t-BuOK: potassium tert-butoxide; DMSO: dimethyl sulfoxide; DME: dimethoxyethane; ACN: acetonitrile; NHK: Nozaki-Hiyama-Kishi reaction; THF: tetrahydrofuran; Py: pyridine.

[0018] Advantages: Compared with the prior art, the present application has the following remarkable advantages: the present application discloses a related substance formula (I) compound in the synthesis process of eribulin intermediate D fragment, and provides an effective preparation method which is mild in conditions and strong in operability. The impurities prepared by the method are used as impurity control samples in the quality research of eribulin intermediates. It is clearly pointed out in the Japanese original pharmacopoeia that the related substance of C18 / C19 (internal olefin) should not be higher than the identification limit (0.10%), which is of great significance for the related substance research. However, due to the large number of chiral centers of the compound, the synthesis is extremely difficult, and the synthesis process is complex, so there are few reports at present. The present application has important significance for the quality control and research of eribulin intermediate synthesis process. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 is the hydrogen spectrum of compound I-b.

[0020] Figure 2 is the hydrogen spectrum of compound I.

[0021] Figure 3 HPLC profile of compound I.

[0022] Figure 4 HPLC profile of eribulin D fragment test sample (21.045 min peak is eribulin fragment D, 23.498 min peak is compound of formula (I)). DETAILED DESCRIPTION

[0023] The technical solutions of the present application are further described below in conjunction with the accompanying drawings and examples.

[0024] Eribulin D fragment was prepared by Nanjing Zhengji Pharmaceutical Research Co., Ltd.

[0025] Example 1

[0026] Preparation of compound I-b:

[0027] Into a 250 mL single neck flask was added I-a (30.00 g, 68.39 mmol, 1.0 eq), DMSO (342 mL) was dissolved completely, potassium tert-butoxide (4.17 g, 34.20 mmol, 0.5 eq) was added at room temperature, after addition was completed, the oil bath was warmed to 50 °C for 1 hour, TLC monitoring showed that the starting material was consumed, the reaction was completed, the reaction liquid was poured into ice 2N HCl aqueous solution for quenching, extracted with ethyl acetate, washed with saturated brine once, dried over anhydrous sodium sulfate, suction filtered and the organic phase was rotary evaporated to dryness, the obtained crude product was columned with 10% ethyl acetate / n-heptane, and finally the yellowish oily product I-b 6.05 g was obtained, with a yield of 20.17%.

[0028] 1 H NMR (400 MHz, DMSO- d 6) δ 7.66–7.56 (m, 4H), 7.50–7.39 (m, 6H), 5.45(q, J = 1.7 Hz, 1H), 4.64 (d, J = 6.0 Hz, 1H), 4.52 (s, 1H), 4.34 (t, J = 5.2Hz, 1H), 3.65 (t, J = 6.0 Hz, 2H), 3.38 (q, J = 6.3 Hz, 2H), 1.63 (q, J = 1.4Hz, 3H), 1.61–1.27 (m, 8H), 0.99 (s, 9H) ppm. Preparation of compound I-c

[0029] Into a 250 mL three-necked flask was placed I-b (6 g, 13.68 mmol, 1.0 eq), dichloromethane (68 mL), dissolved completely, ice bath cooling, 0 ℃ batched in Dess-Martin reagent (6.38 g, 15.05 mmol, 1.10 eq), after adding, remove the ice bath room temperature reaction 1-2 hours, TLC monitoring of raw materials disappear, the reaction was completed, the reaction liquid was quenched with Na2S2O3 . 5H2O and aqueous KHCO3 solution, separated and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, suction filtration and rotary evaporation of the organic phase, the obtained crude product was columned with 5% ethyl acetate / n-heptane to obtain the product I-c 3.88 g as a light yellow oil, yield 65%.

[0030] Synthesis of compound I-d

[0031] Into a 100 mL single-necked flask was placed Ligand (2.98 g, 6.29 mmol, 1.50 eq), 1,8-bisdimethylaminonaphthalene (1.35 g, 6.29 mmol, 1.5 eq), nitrogen replacement, dry DME (21 mL) was added, dissolved and then transferred to a dry four-necked flask, nitrogen protection, mechanical stirring. CrCl2(773 mg, 6.29 mmol, 1.5 eq), CoPc (120 mg, 0.21 mmol, 0.05 eq) were quickly added, and the reaction was carried out at room temperature for 2 h. Then LiCl (355 mg, 8.38 mmol, 2.0 eq), Mn powder (460 mg, 8.38 mmol, 2.0 eq), I-c (1.83 g, 4.19 mmol, 1.0 eq), diiodo compound (2.36 g, 7.33 mmol, 1.75 eq), ZrCp2Cl2(2.45 g, 8.38 mmol, 2.0 eq) were quickly added. After the addition was completed, the reaction was carried out at 35 ℃ oil bath for 24 h. After the reaction was completed, magnesium silicate was added to the reaction liquid to quench the reaction, stirred for 30 min, and then suction filtered through diatomite. The filtrate was rotary evaporated to obtain the crude product, which was columned with 10% ethyl acetate / n-heptane to obtain the product I-d 790 mg as a light yellow oil, yield 30%.

[0032] Synthesis of compound I-e

[0033] Into a 50 mL single necked flask was placed I-d (740 mg, 1.17 mmol, 1.0 eq), THF(5 mL), all dissolved, ice bath cooling, 0 °C dropwise added 1M TBAF / THF (1.4 mL, 1.4 mmol, 1.2 eq), after adding all, removed ice bath, room temperature reaction 12 h, the reaction liquid was quenched with tap water, extracted with ethyl acetate, separated to separate the organic phase, washed with saturated brine once, dried over anhydrous sodium sulfate, suction filtered and the organic phase was rotary evaporated to give a yellowish oil product I-e 330 mg, yield 71.6%. Synthesis of compound I

[0034] Into a 50 mL single necked flask was placed I-e (300 mg, 0.76 mmol, 1.0 eq), DCM(5 mL), Py(180 mg, 2.28 mmol, 3.0 eq), DMAP (5.6 mg, 0.046 mmol, 0.06 eq), all dissolved, ice bath cooling, 0 °C dropwise added pivaloyl chloride (97 mg, 0.80 mmol, 1.05 eq) / DCM (1 mL), room temperature reaction 1 h, the reaction liquid was quenched with tap water (10 mL), extracted with ethyl acetate, separated to separate the organic phase, washed with saturated brine once, dried over anhydrous sodium sulfate, suction filtered and the organic phase was rotary evaporated to give a yellowish oil product I3 20 mg, yield 71.6%, HPLC purity 91.6%.

[0035] 1 H NMR (400 MHz, DMSO- d 6) δ 6.29 (d, J = 1.0 Hz, 1H), 5.73 (d, J =1.3 Hz, 1H), 5.48 (q, J = 1.7 Hz, 1H), 4.66 (d, J = 6.0 Hz, 1H), 4.55 (s,1H), 4.36 (d, J = 5.6 Hz, 1H), 4.00 (t, J = 6.5 Hz, 2H), 3.29–3.21 (m, 1H),2.07 (ddt, J= 8.4, 5.6, 2.8 Hz, 1H), 1.75–1.21 (m, 13H), 1.13 (s, 9H), 0.89(d, J = 6.6 Hz, 3H) ppm. Figure 1 The hydrogen spectrum of compound I-b. Figure 2 The hydrogen spectrum of compound I. Figure 3 The HPLC spectrum of compound I. Figure 4 The HPLC spectrum of compound I-b.

[0036] Example 2

[0037] Preparation of compound I-b: Refer to the preparation method of compound I-b in Example 1. Change the conditions: the reaction temperature is changed to 45℃; the amount of potassium tert-butoxide is changed to a molar ratio of 1:0.4; the solvent is N-methyl pyrrolidone. Result: 5.70 g of product I-b in light yellow oil is obtained, with a yield of 19.00%.

[0038] Preparation of compound I-c: Put in 5.70 g of I-b, and the rest of the operation and the feeding ratio are the same as in Example 1. 3.69 g of product I-c in light yellow oil is obtained, with a yield of 65%.

[0039] Synthesis of compound I-d: Put in 1.81 g of I-c, and refer to the synthesis method of compound I-d in Example 1. Change the conditions: the reaction temperature is changed to 30℃, and the solvent is acetonitrile, and the rest of the conditions (catalyst, feeding ratio, nitrogen protection, etc.) remain unchanged. Result: After 24 hours of reaction, TLC monitoring shows that the raw material is completely converted. The post-treatment is the same as in Example 1, and 720 mg of product I-d in light yellow oil is obtained, with a yield of 27.4% Synthesis of compound I-e: Put in 700 mg of I-d, and refer to Example 1, using TBAF with a molar ratio of 1:1.2, to obtain 309 mg of product I-e in light yellow oil, with a yield of 70.8%.

[0040] Synthesis of compound I: Put in 300 mg of I-e, and use DIPEA as a base, and the rest of the operation and the feeding ratio are the same as in Example 1. Compound I is prepared, with a yield of 68.1%, and an HPLC purity of 90.8%.

[0041] Example 3

[0042] Preparation of compound I-b: Refer to the preparation method of compound I-b in example 1. Change the reaction temperature to 55℃; change the molar ratio of potassium tert-butoxide to 1:0.6; change the base to sodium hydride; change the solvent to DMSO. Result: obtain the product I-b 6.20 g in yellowish oil, with a yield of 20.67%.

[0043] Preparation of compound I-c: Put in I-b 6.10 g, and the rest of the operation and the feeding ratio are the same as example 1. Obtain the product I-c 4.01 g in yellowish oil, with a yield of 66.0 %.

[0044] Synthesis of compound I-d: Put in I-c 1.81 g, and refer to the synthesis method of compound I-d in example 1. Change the conditions: change the reaction temperature to 40℃, change the solvent to N,N-dimethylformamide, and the rest of the conditions (catalyst, feeding ratio, nitrogen protection, etc.) remain unchanged. Result: after 24 hours of reaction, TLC monitoring shows that the raw material is completely converted. The post-processing is the same as example 1, and the product I-d 750 mg in yellowish oil is obtained, with a yield of 28.6% (calculated from I-c).

[0045] Synthesis of compound I-e: Put in I-d 738 mg, and refer to the synthesis method of compound I-e in example 1. Change the conditions: change the molar ratio of TBAF to 1:1.0. Result: after 12 hours of reaction, TLC monitoring shows that the raw material disappears. The post-processing is the same as example 1, and the product I-e 310 mg in yellowish oil is obtained, with a yield of 67.4%.

[0046] Synthesis of compound I: Put in I-e 300 mg, and use triethylamine as the base, and the rest of the operation and the feeding ratio are the same as example 1. Compound I 256 mg is prepared, with a yield of 70.3% and an HPLC purity of 91.2%.

Claims

1. A method for preparing related substances of an erythrin intermediate, characterized in that, The eribulin intermediate is the eribulin D fragment, and the related substances are compounds of formula (I): ； The synthesis includes the following steps: ； Step 1: Formula Ia undergoes double bond isomerization migration in the presence of a base to give compound Ib; Step 2: Formula Ib is oxidized in the presence of an oxidizing agent to obtain compound Ic; Step 3: Formula Ic undergoes an asymmetric NHK coupling reaction under the co-catalysis of nickel and chromium to obtain compound Id; Step 4: Formula I-d is deprotected with a silyl ether protecting group in the presence of TBAF to obtain compound I-e; Step 5: Formula I-e undergoes acylation in a base under DMAP catalysis to yield compound I.

2. The preparation method according to claim 1, characterized in that, The alkali mentioned in step 1 is selected from sodium methoxide, sodium tert-butoxide, sodium hydride, potassium tert-butoxide, and sodium amino acid.

3. The preparation method according to claim 1, characterized in that, The molar ratio of Ia to alkali in step 1 is 1:0.4~0.

6.

4. The preparation method according to claim 1, characterized in that, The reaction temperature in step 1 is 45~55℃.

5. The preparation method according to claim 1, characterized in that, The solvent used in step 1 is selected from N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and 2-methyltetrahydrofuran.

6. The preparation method according to claim 1, characterized in that, The oxidant used in step 2 is selected from PCC, PDC, and DMP.

7. The preparation method according to claim 1, characterized in that, The solvent used in step 3 is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetonitrile, and N,N-dimethylformamide.

8. The preparation method according to claim 1, characterized in that, Step 3 requires the reaction system to be isolated from oxygen, and the feeding process must be completed under nitrogen protection. The reaction temperature is 30~40℃.

9. The preparation method according to claim 1, characterized in that, The molar ratio of Id to TBAF in step 4 is 1:1.0~1.

2.

10. The preparation method according to claim 1, characterized in that, The base mentioned in step 5 is selected from triethylamine, pyridine, DIPEA, and DIEA.

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