CN106831731A - Novel synthesis method of Selinexor active pharmaceutical ingredient - Google Patents

Novel synthesis method of Selinexor active pharmaceutical ingredient Download PDF

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CN106831731A
CN106831731A CN201710031845.0A CN201710031845A CN106831731A CN 106831731 A CN106831731 A CN 106831731A CN 201710031845 A CN201710031845 A CN 201710031845A CN 106831731 A CN106831731 A CN 106831731A
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compound
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dmf
organic phase
synthesis
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陈新颖
徐亮
刘文忠
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广州市闻皓生物科技有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention provides a novel synthesis method of a Selinexor active pharmaceutical ingredient. The method comprises the following steps: mixing a compound 6, dichloromethane and ethyl acetate, adding a compound 4, T3P and DIPEA (diisopropylethylamine) at low temperature, reacting, adding water and ethyl acetate, skimming, and drying up the organic phase by distillation to obtain a compound 7 crude product; mixing the compound 7, glacial acetic acid and sodium iodide, heating and reacting; after the reaction finishes, cooling, adding water and dichloromethane, standing to stratify, washing the organic phase, drying, and distilling to obtain a compound 8; mixing the compound 1, DBACO and DMF (N,N-dimethylformamide), dropwisely adding a compound 8 DMF solution, and reacting; and after the reaction finishes, adding water and ethyl acetate, drying up the organic phase by distillation, and recrystallizing to obtain the compound 5. The synthesis method solves the problem that the traditional synthesis technique can easily generate trans impurities, reduces the synthesis steps, enhances the yield, and provides a new technique for synthesizing the Selinexor active pharmaceutical ingredient.

Description

一种Sel inexor原料药的新型合成方法 Sel inexor novel method of synthesis of the drug

技术领域 FIELD

[0001] 本发明涉及生物医药技术领域,特别地,涉及一种Sel inexor原料药的新型合成方法。 [0001] The present invention relates to the field of biotechnology medicine, in particular, it relates to a novel method of synthesis Sel inexor API.

背景技术 Background technique

[0002] Selinexor是一种口服生物有效的选择性核输出蛋白抑制剂,2012年首次进入临床,迄今为止共开展了21项临床试验,适应症包括慢性髓性白血病、急性髓性白血病、急性淋巴细胞白血病、前列腺癌、黑素瘤、非小细胞肺癌、胶质瘤、成神经母细胞瘤、妇科肿瘤、弥漫性大B细胞淋巴瘤、鳞状细胞癌、直肠癌等。 [0002] Selinexor is an orally bioavailable selective nuclear export inhibitors, 2012 for the first time in clinical, so far carried out a total of 21 trials, indications include chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphatic leukemia, prostate cancer, melanoma, non-small cell lung cancer, glioma, neuroblastoma into, gynecological cancer, diffuse large B-cell lymphoma, squamous cell carcinoma, colorectal cancer and the like. 2014年5月,FDA授予Selinexor治疗急性髓性白血病和弥漫性大B细胞淋巴瘤的孤儿药称号,2014年6月,EMA同样授予了Selinexor治疗这两种疾病的孤儿药称号。 May 2014, FDA granted orphan drug designation Selinexor treatment of acute myeloid leukemia and diffuse large B-cell lymphoma, in June 2014, EMA is also granted orphan drug designation Selinexor treatment of both diseases. 2015年1月,获得FDA治疗多发性骨髓瘤孤儿药认定。 January 2015, received FDA orphan drug to treat multiple myeloma identified.

[0003] 目前,已经公开的合成工艺,其反应方程式如下所示: [0003] Currently, the synthesis process has been disclosed, the following reaction equation:

Figure CN106831731AD00041

[0006] 其中,化合物5为Selinexor原料药。 [0006] wherein the compound is 5 Selinexor drug.

[0007] 但是该方法中,从中间体1到2双键很容易翻转,合成生产时容易产生反式的杂质, 比较难除,影响收率;在中间体3与中间体4合成原料药5时,需要超低温,并且产品需要过柱纯化,收率仅为20 %。 [0007] In this method, however, easy to produce Intermediate 1-2 double bond is easily reversed when synthetically produced from trans impurities, in addition to more difficult to impact yield; Intermediate 3 Intermediate 4 Synthesis APIs 5 when required ultra-low temperature, and the product was purified by column required, only a yield of 20%.

发明内容 SUMMARY

[0008] 本发明目的在于提供一种Selinexor原料药化合物5的新型合成方法,以解决技术问题。 [0008] The object of the present invention to provide a novel compound Selinexor drug synthesis of 5, in order to solve technical problems.

[0009] —种Se I inexor原料药的新型合成方法,包括以下步骤: [0009] - novel synthetic method of Se species I inexor drug, comprising the steps of:

[0010] A、化合物7的合成 Synthesis [0010] A, Compound 7

[0011] 将化合物6、二氯甲烷和乙酸乙酯混合,搅拌溶解后,在低温下加入化合物4、T3P (正丙基磷酸酐)和DIPEA(N,N-二异丙基乙胺);低温下搅拌25-35min进行反应,待反应结束后加入二氯甲烷和水,分液,有机相蒸干得到化合物7粗品,粗品不纯化直接往下投; [0011] Compound 6, dichloromethane and ethyl acetate mixture, stirred and dissolved, compound 4, T3P (n-propyl phosphoric anhydride) and DIPEA (N, N- diisopropylethylamine) at a low temperature; the reaction was stirred for 25-35min at a low temperature, dichloromethane and water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0012] B、化合物8的合成 [0012] B, Synthesis of Compound 8

[0013] 将上步所得化合物7、冰醋酸和碘化钠混合,升温至110-120°C,反应2.5-3.5h;反应结束后,体系降至室温,加入水和二氯甲烷,搅拌8-15min后,静置分层,有机相用饱和碳酸氢钠和饱和氯化钠洗涤,无水硫酸钠干燥后蒸馏得到化合物8粗品,溶于DMF (富马酸二甲酯)中,得到化合物8的DMF溶液; [0013] the compound obtained in Step 7, and mixed sodium iodide acetic acid, warmed to 110-120 ° C, the reaction 2.5-3.5h; After completion of the reaction, the system cooled to room temperature, water and dichloromethane were added, stirred for 8 after -15min, standing layered organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in DMF (dimethyl fumarate) to give compound in DMF 8;

[0014] C、化合物5的合成 Synthesis [0014] C, of ​​Compound 5

[0015] 将化合物1、DBAC0 (三乙烯二胺)、DMF混合后,搅拌溶解后,向反应体系滴加上步所得化合物8的DMF溶液,滴加完毕后,继续搅拌3-4小时;反应完毕后,向体系中加入水和乙酸乙酯,有机相蒸干后乙酸乙酯和石油醚重结晶得到化合物5。 [0015] Compound 1, DBAC0 (triethylenediamine), the DMF mixed and dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring was continued for 3-4 hours; the reaction after completion, water and ethyl acetate were added to the system, the organic phase is evaporated to dryness and petroleum ether and recrystallized from ethyl acetate to give compound 5.

[0016] 优选的,所述的步骤A中,所述的低温为0-2°C。 [0016] Preferably, said step A, the low temperature is 0-2 ° C.

[0017] 优选的,所述的步骤B中的DMF溶液中,化合物8粗品的浓度低于1 %。 [0017] Preferably, said step B in DMF, the crude compound 8 concentration of less than 1%.

[0018] 本发明的Selinexor原料药的新型合成方法,其化学方程式如下: [0018] The novel synthetic methods of the present invention Selinexor drug, the chemical equation is as follows:

Figure CN106831731AD00051

[0020] 本发明具有以下有益效果:本发明的Selinexor原料药的新型合成方法,克服了传统的合成工艺中,容易产生反式的杂质,比较难除,影响收率以及需要超低温,并且产品需要过柱纯化,收率非常低的问题,减少了合成步骤,提高了收率,为Selinexor原料药的合成提供了一种新的工艺。 [0020] The present invention has the following advantages: novel synthetic method Selinexor drug of the present invention to overcome the conventional synthesis process, is easy to produce trans impurities, more difficult in addition, the influence the yield and the need for ultra-low temperature, and the product requires problems purified by column, the yield is very low, reducing the synthetic steps, increased yield, there is provided a new process for the synthesis of the drug Selinexor.

[0021] 除了上面所描述的目的、特征和优点之外,本发明还有其它的目的、特征和优点。 [0021] In addition to the above-described objects, features and advantages of the present invention as well as other objects, features and advantages. 下面将对本发明作进一步详细的说明。 Below the invention will be described in further detail present.

具体实施方式 Detailed ways

[0022] 以下对本发明的实施例进行详细说明,但是本发明可以根据权利要求限定和覆盖的多种不同方式实施。 [0022] Hereinafter, embodiments of the present invention will be described in detail, but the present invention can be defined according to the claims and to cover the many different embodiments.

[0023] 实施例1 [0023] Example 1

[0024] —种Se I inexor原料药的新型合成方法,包括以下步骤: [0024] - novel synthetic method of Se species I inexor drug, comprising the steps of:

[0025] A、化合物7的合成 Synthesis [0025] A, Compound 7

[0026] 50ml的三□瓶中,加入0.2g化合物6、15ml二氯甲烷和15ml乙酸乙酯,搅拌溶解后, 在0°C下加入0.3g化合物4和3gT3P、0.75gDIPEA;体系在0°C搅拌30min进行反应,待反应结束后加入50ml二氯甲烷和30ml水,分液,有机相蒸干得到化合物7粗品,粗品不纯化直接往下投; [0026] 50ml three □ flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 0 ° C; the system at 0 ° C the reaction was stirred for 30min, 50ml of dichloromethane and 30ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0027] B、化合物8的合成 [0027] B, Synthesis of Compound 8

[0028] 50ml的三口瓶中,加入上步所得化合物7、40ml冰醋酸和1.38g碘化钠,升温至115 。 [0028] 50ml three-necked flask, added the compound obtained in Step 7,40ml of glacial acetic acid and 1.38g of sodium iodide was heated to 115. (:,反应3h;反应结束后,体系降至室温,将体系转入500ml瓶中,加入50ml水和IOOml二氯甲烷,搅拌IOmin后,静置分层,有机相用饱和碳酸氢钠和饱和氯化钠洗涤,无水硫酸钠干燥后蒸馏得到化合物8粗品,溶于IOmL DMF中,得到化合物8的DMF溶液; (:, The reaction 3H; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 50ml of water was added and IOOml dichloromethane, after stirring IOmin, standing separation, the organic phase was washed with saturated sodium bicarbonate and saturated washed with sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in IOmL DMF to give DMF solution of compound 8;

[0029] C、化合物5的合成 Synthesis [0029] C, of ​​Compound 5

[0030] 50ml三口瓶中加入0.2g化合物1、0.24gDBAC0、20mlDMF,搅拌溶解后,向反应体系滴加上步所得化合物8的DMF溶液,滴加完毕后,继续搅拌3.5小时;反应完毕后,向体系中加入20ml水和50ml乙酸乙酯,有机相蒸干后乙酸乙酯和石油醚重结晶得到0.158g化合物5,收率50.9%。 [0030] After 50ml 3-necked flask was added 0.2g compound 1,0.24gDBAC0,20mlDMF, dissolved with stirring, dropwise adding to the reaction system in DMF compound obtained in Step 8, after the addition was complete, stirring continued for 3.5 hours; after completion of the reaction, 20ml water was added to the system and 50ml ethyl acetate, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.158g of compound 5, yield 50.9%.

[0031] 实施例2 [0031] Example 2

[0032] —种Se Iinexor原料药的新型合成方法,包括以下步骤: [0032] - new type Se Iinexor drug synthesis, comprising the steps of:

[0033] A、化合物7的合成 Synthesis [0033] A, Compound 7

[0034] 50ml的三□瓶中,加入0.2g化合物6、15ml二氯甲烷和15ml乙酸乙酯,搅拌溶解后, 在1°C下加入0.3g化合物4和3gT3P、0.75gDIPEA;体系在1°C搅拌35min进行反应,待反应结束后加入50ml二氯甲烷和30ml水,分液,有机相蒸干得到化合物7粗品,粗品不纯化直接往下投; [0034] 50ml three □ flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 1 ° C; system at 1 ° C the reaction was stirred for 35min, 50ml of dichloromethane and 30ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0035] B、化合物8的合成 [0035] B, Synthesis of Compound 8

[0036] 50ml的三口瓶中,加入上步所得化合物7、40ml冰醋酸和1.38g碘化钠,升温至120 。 Three-neck flask [0036] 50ml of addition of the compound obtained in Step 7,40ml glacial acetic acid and 1.38g of sodium iodide was heated to 120. (:,反应2.5h;反应结束后,体系降至室温,将体系转入500ml瓶中,加入60ml水和120ml二氯甲烷,搅拌15min后,静置分层,有机相用饱和碳酸氢钠和饱和氯化钠洗涤,无水硫酸钠干燥后蒸馏得到化合物8粗品,溶于12mLDMF中,得到化合物8的DMF溶液; (:, The reaction for 2.5 h; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 60ml water and 120ml dichloromethane was added, after stirring for 15min, allowed to stand for separation, the organic phase was washed with saturated sodium bicarbonate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, 12mLDMF was dissolved in DMF to give a solution of compound 8;

[0037] C、化合物5的合成 Synthesis [0037] C, of ​​Compound 5

[0038] 50ml三口瓶中加入0.2g化合物1、0.24gDBAC0、20mlDMF,搅拌溶解后,向反应体系滴加上步所得化合物8的DMF溶液,滴加完毕后,继续搅拌3小时;反应完毕后,向体系中加入25ml水和50ml乙酸乙酯,有机相蒸干后乙酸乙酯和石油醚重结晶得到0.152g化合物5,收率49.0%〇 [0038] After 50ml 3-necked flask was added 0.2g compound 1,0.24gDBAC0,20mlDMF, dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring continued for 3 hours; after completion of the reaction, 25ml of water and 50ml of ethyl acetate was added to the system, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.152g of compound 5, yield 49.0% billion

[0039] 实施例3 [0039] Example 3

[0040] —种Se I inexor原料药的新型合成方法,包括以下步骤: [0040] - novel synthetic method of Se species I inexor drug, comprising the steps of:

[0041] A、化合物7的合成 Synthesis [0041] A, Compound 7

[0042] 50ml的三口瓶中,加入0.2g化合物6、15ml二氯甲烷和15ml乙酸乙酯,搅拌溶解后, 在2°C下加入0.3g化合物4和3gT3P、0.75gDIPEA;体系在0°C搅拌25min进行反应,待反应结束后加入40ml二氯甲烷和35ml水,分液,有机相蒸干得到化合物7粗品,粗品不纯化直接往下投; Three [0042] 50ml of flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 2 ° C; system from 0 ° C the reaction was stirred for 25min, 40ml of dichloromethane and 35ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0043] B、化合物8的合成 [0043] B, Synthesis of Compound 8

[0044] 50ml的三口瓶中,加入上步所得化合物7、35ml冰醋酸和1.38g碘化钠,升温至110 。 Three-neck flask [0044] 50ml of addition of the compound obtained in Step 7,35ml glacial acetic acid and 1.38g of sodium iodide was heated to 110. (:,反应3.5h;反应结束后,体系降至室温,将体系转入500ml瓶中,加入50ml水和IOOml二氯甲烷,搅拌Smin后,静置分层,有机相用饱和碳酸氢钠和饱和氯化钠洗涤,无水硫酸钠干燥后蒸馏得到化合物8粗品,溶于IOmL DMF中,得到化合物8的DMF溶液; (:, The reaction for 3.5 h; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 50ml of water was added and dichloromethane IOOml After Smin of stirring, standing separation, the organic phase was washed with saturated sodium bicarbonate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in IOmL DMF to give DMF solution of compound 8;

[0045] C、化合物5的合成 Synthesis [0045] C, of ​​Compound 5

[0046] 50ml三口瓶中加入0.2g化合物1、0.24gDBA⑶、20mlDMF,搅拌溶解后,向反应体系滴加上步所得化合物8的DMF溶液,滴加完毕后,继续搅拌4小时;反应完毕后,向体系中加入20ml水和40ml乙酸乙酯,有机相蒸干后乙酸乙酯和石油醚重结晶得到0.155g化合物5,收率49.9%〇 [0046] 50ml three-neck flask was added 0.2g compound 1,0.24gDBA⑶, 20mlDMF, and dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring was continued for 4 hours; after completion of the reaction, 20ml of water and 40ml ethyl acetate were added to the system, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.155g of compound 5, yield 49.9% billion

[0047] 以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。 [0047] The above description is only preferred embodiments of the present invention, it is not intended to limit the invention to those skilled in the art, the present invention may have various changes and variations. 凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。 Any modification within the spirit and principle of the present invention, made, equivalent substitutions, improvements, etc., should be included within the scope of the present invention.

Claims (5)

1. 一种Selinexor原料药的新型合成方法,其特征在于,其化学方程式如下: A novel synthetic method of drug Selinexor, wherein the chemical equation is as follows:
Figure CN106831731AC00021
2. 如权利要求1所述的Selinexor原料药的新型合成方法,其特征在于,包括以下步骤: A、 化合物7的合成将化合物6、二氯甲烷和乙酸乙酯混合,搅拌溶解后,在低温下加入化合物4、T3P和DIPEA;搅拌25-35min进行反应,待反应结束后加入二氯甲烷和水,分液,有机相蒸干得到化合物7粗品,粗品不纯化直接往下投; B、 化合物8的合成将上步所得化合物7、冰醋酸和碘化钠混合,升温至110-120 °C,反应2.5-3.5h;反应结束后,体系降至室温,加入水和二氯甲烷,搅拌8-15min后,静置分层,有机相用饱和碳酸氢钠和饱和氯化钠洗涤,无水硫酸钠干燥后蒸馏得到化合物8粗品,溶于DMF中,得到化合物8 的DMF溶液; C、 化合物5的合成将化合物I、DBAC0、DMF混合后,搅拌溶解后,向反应体系滴加上步所得化合物8的DMF溶液,滴加完毕后,继续搅拌3-4小时;反应完毕后,向体系中加 2. The novel synthetic method of claim 1 Selinexor drug claim, wherein, comprising the steps of: after A, Synthesis of Compound 6 Compound 7 were mixed, methylene chloride and ethyl acetate, stirred and dissolved at low temperature was added compound 4, T3P, and DIPEA; the reaction was stirred for 25-35min, after the completion of the reaction was added methylene chloride and water, separated, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down; B, compound synthesis of the compound 8 obtained in step 7, and mixed sodium iodide acetic acid, warmed to 110-120 ° C, the reaction 2.5-3.5h; after completion of the reaction, the system cooled to room temperature, water and dichloromethane were added, stirred for 8 after -15min, standing layered organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in DMF, to give DMF solution of compound 8; C, compound 5 synthesis of compound I, DBAC0, the DMF mixed and dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring was continued for 3-4 hours; after completion of the reaction, the system plus 水和乙酸乙酯,有机相蒸干后乙酸乙酯和石油醚重结晶得到化合物5。 After water and ethyl acetate, the organic phase was evaporated to dryness and petroleum ether and recrystallized from ethyl acetate to give compound 5.
3. 如权利要求2所述的SeIinexor原料药的新型合成方法,其特征在于,所述的步骤A 中,所述的低温为〇_2°C。 The novel synthetic method 2 SeIinexor API claim, wherein, in said step A, the low temperature is 〇_2 ° C.
4. 如权利要求2所述的Selinexor原料药的新型合成方法,其特征在于,所述的步骤B中的DMF溶液中,化合物8粗品的浓度低于1 %。 4. The novel synthetic method of Selinexor drug according to claim 2, wherein said step B in DMF, the crude compound 8 concentration of less than 1%.
5. 如权利要求2所述的Selinexor原料药的新型合成方法,其特征在于,包括以下步骤: A、 化合物7的合成50ml的三口瓶中,加入0.2g化合物6、15ml二氯甲烷和15ml乙酸乙酯,搅拌溶解后,在0 °C下加入0.3g化合物4和3gT3P、0.75gDIPEA;体系在0°C搅拌30min进行反应,待反应结束后加入50ml二氯甲烷和30ml水,分液,有机相蒸干得到化合物7粗品,粗品不纯化直接往下投; B、 化合物8的合成50ml的三口瓶中,加入上步所得化合物7、40ml冰醋酸和1.38g碘化钠,升温至115°C,反应3h;反应结束后,体系降至室温,将体系转入500ml瓶中,加入50ml水和IOOml二氯甲烷,搅拌IOmin后,静置分层,有机相用饱和碳酸氢钠和饱和氯化钠洗涤,无水硫酸钠干燥后蒸馏得到化合物8粗品,溶于IOmL DMF中,得到化合物8的DMF溶液; C、化合物5的合成50ml三口瓶中加入0.2g化合物1、0.24gDBA⑶、20mlDMF,搅拌溶解 5. The method of Selinexor new synthetic drug according to claim 2, characterized by comprising the steps of: A, compound 7 synthesized 50ml three-neck flask, 0.2g of the compound of dichloromethane and 15ml of acetic acid 6,15ml ethyl and dissolved with stirring, was added at 0 ° C 0.3g of compound 4 and 3gT3P, 0.75gDIPEA; stirred at 0 ° C 30min the reaction, 50ml of dichloromethane and 30ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down; B, three of the synthesis of compound 8 50ml flask, added the compound obtained in step 7,40ml of glacial acetic acid and 1.38g of sodium iodide was heated to 115 ° C the reaction 3H; after completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 50ml of water was added and IOOml dichloromethane, after stirring IOmin, standing separation, the organic phase was washed with saturated sodium bicarbonate and saturated chloride sodium washed, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in IOmL DMF to give DMF solution of compound 8; C, 50ml 3-necked flask synthesis of compound 5 0.2g of compound 1,0.24gDBA⑶, 20mlDMF, stirring dissolve ,向反应体系滴加上步所得化合物8的DMF溶液,滴加完毕后,继续搅拌3.5小时;反应完毕后,向体系中加入20ml水和50ml乙酸乙酯,有机相蒸干后乙酸乙酯和石油醚重结晶得到化合物5。 , Dropwise adding to the reaction system in DMF compound obtained in Step 8, after the addition was complete, stirring continued for 3.5 hours; after the completion of the reaction, 20ml of water and 50ml ethyl acetate system, ethyl acetate and the organic phase evaporated to dryness petroleum ether to give compound 5.
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CN103874690A (en) * 2011-07-29 2014-06-18 卡尔约药物治疗公司 Hydrazide containing nuclear transport modulators and uses thereof
WO2014205393A1 (en) * 2013-06-21 2014-12-24 Karyopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
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Publication number Priority date Publication date Assignee Title
CN103842340A (en) * 2011-07-29 2014-06-04 卡尔约药物治疗公司 Nuclear transport modulators and uses thereof
CN103874690A (en) * 2011-07-29 2014-06-18 卡尔约药物治疗公司 Hydrazide containing nuclear transport modulators and uses thereof
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