CN108440377A - A kind of synthetic method of the final intermediate of chronic myelocytic leukemia drug - Google Patents
A kind of synthetic method of the final intermediate of chronic myelocytic leukemia drug Download PDFInfo
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- CN108440377A CN108440377A CN201810454317.0A CN201810454317A CN108440377A CN 108440377 A CN108440377 A CN 108440377A CN 201810454317 A CN201810454317 A CN 201810454317A CN 108440377 A CN108440377 A CN 108440377A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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Abstract
The present invention relates to a kind of synthetic methods of the final intermediate of chronic myelocytic leukemia drug, it includes the following steps：（a）By trichloroacetaldehyde hydrate water dissolution, the aqueous solution, the hydrochloric acid solution of 3,4 dimethoxyanilines and the aqueous solution filtration drying of hydroxylamine hydrochloride for sequentially adding anhydrous sodium sulfate obtain compound 2；（b）The compound 2 is mixed with polyphosphoric acids, obtains compound 3；（c）By the compound 3 and rhodanine pyridinium dissolution, dry compound 4；（d）After the compound 4 and KOH solution are mixed, it is heated to 40 ~ 60 DEG C and is stirred reaction, dry compound 5；（e）After the compound 5 and aniline are mixed, it is stirred to react under conditions of nitrogen protection, 100 ~ 150 DEG C；It is dry to obtain compound 6.The synthesis to derivatives of indirubin intermediate can be realized in this way, and there is higher yield and purity, be conducive to industrialized mass production.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, are related to a kind of synthesis side of the final intermediate of chronic myelocytic leukemia drug
Method.
Background technology
Indigo red is a kind of drug, there is antitumaous effect, is clinically used for treatment chronic myelocytic leukemia；It is a pair of indoles
Series antineoplastic medicament；It has inhibiting effect to a variety of transplanted animal tumors, can destroy leukaemia cell；In the effect of this product
Under, the cell of degeneration necrosis is in swelling, lytic necrosis more.Currently, indigo red is typically from Chinese medicine indigo naturalis (Indigofera
Tinctoria L) in separate, the method for this extraction not only needs to expend a large amount of Chinese medicine, but also yield is relatively low.Such as
Fruit can be obtained by chemically synthesized mode indigo red and its derivative (Also there is treatment
The effect of chronic myelocytic leukemia), its purity can not only be greatly improved, and be conducive to improve the yield of indigo red and make
Good fortune patient；Obviously the intermediate of synthesis indigo red is important step.
Invention content
It is final that a kind of chronic myelocytic leukemia drug is provided the invention aims to overcome the deficiencies in the prior art
The synthetic method of intermediate.
In order to achieve the above objectives, the technical solution adopted by the present invention is：During a kind of chronic myelocytic leukemia drug is final
The synthetic method of mesosome, it includes the following steps：
(a) by trichloroacetaldehyde hydrate water dissolution, aqueous solution, 3, the 4- dimethoxy benzenes of anhydrous sodium sulfate are sequentially added
The hydrochloric acid solution of amine and the aqueous solution of hydroxylamine hydrochloride, are heated to back flow reaction 30~60 minutes；20~25 DEG C are then cooled to, mistake
It is filtered dry dry compound 2
(b) compound 2 is mixed with polyphosphoric acids, reaction is stirred at 60~100 DEG C；Be added ice water into
Row stirring, filtering, dry compound 3
(c) by the compound 3 and rhodanine pyridinium dissolution, water is added and is stirred, add tetrahydrofuran progress
It is heated to reflux；It is cooled to 5~10 DEG C, filtering is washed with toluene, dry compound 4
(d) after mixing the compound 4 and KOH solution, 40~60 DEG C is heated to and is stirred reaction；It is cooled to 0~5
DEG C, it is neutralized, is filtered with concentrated hydrochloric acid, dry compound 5
(e) it after mixing the compound 5 and aniline, is stirred to react under conditions of nitrogen protection, 100~150 DEG C；It is cold
But NaOH solution is added afterwards, is washed with ethyl acetate, phase of fetching water, then it is 2~4 to be acidified to pH with hydrochloric acid, filtering, being dried to obtain
Close object 6.
Optimally, in step (d), the mass concentration of the KOH solution is 5~15%.
Further, the mass concentration of step (e), the NaOH solution is 5~15%.
Since above-mentioned technical proposal is used, the present invention has following advantages compared with prior art：The chronic grain of the present invention is thin
The synthetic method of the final intermediate of born of the same parents' leukemia medicament obtains compound 2, change respectively by designing new synthetic route
The intermediate products such as object 3, compound 4 are closed, can realize the synthesis to derivatives of indirubin intermediate in this way, there is higher yield
And purity, be conducive to industrialized mass production.
Description of the drawings
Attached drawing 1 be the final intermediate of chronic myelocytic leukemia drug of the present invention synthetic method in compound 6 nuclear-magnetism
Spectrogram；
Attached drawing 2 is the nuclear magnetic spectrogram of derivatives of indirubin of the present invention.
Specific implementation mode
The synthetic method of the final intermediate of chronic myelocytic leukemia drug of the present invention, it includes the following steps：(a) by three
Chloroethene aldehyde hydrate water dissolution, sequentially add the aqueous solution of anhydrous sodium sulfate, 3,4- dimethoxyanilines hydrochloric acid solution and
The aqueous solution of hydroxylamine hydrochloride is heated to back flow reaction 30~60 minutes；20~25 DEG C are then cooled to, filtration drying obtains compound
2(b) compound 2 is mixed with polyphosphoric acids, is stirred at 60~100 DEG C
Mix reaction；Ice water is added and is stirred, filters, drying and to obtain compound 3(c) by 3 He of the compound
Rhodanine pyridinium dissolution is added water and is stirred, adds tetrahydrofuran and be heated to reflux；5~10 DEG C are cooled to, mistake
Filter, is washed with toluene, dry compound 4(d) after the compound 4 and KOH solution being mixed,
It is heated to 40~60 DEG C and is stirred reaction；It is cooled to 0~5 DEG C, is neutralized with concentrated hydrochloric acid, is filtered, dry compound 5(e) it after mixing the compound 5 and aniline, is stirred under conditions of nitrogen protection, 100~150 DEG C
Mix reaction；NaOH solution is added after cooling, is washed with ethyl acetate, phase of fetching water, then it is 2~4 to be acidified to pH with hydrochloric acid, filtering,
It is dried to obtain compound 6.Chemical combination is obtained respectively by designing new synthetic route
The intermediate products such as object 2, compound 3, compound 4 can realize the synthesis to derivatives of indirubin in this way, have higher yield
And purity, be conducive to industrialized mass production.In step (d), the mass concentration of the KOH solution is preferably 5~15%.Step
(e), the mass concentration of the NaOH solution is preferably 5~15%.
It is described in detail below in conjunction with to the preferred embodiment of the invention：
Embodiment 1
The present embodiment provides a kind of synthetic methods of the final intermediate of chronic myelocytic leukemia drug, it includes following step
Suddenly：
(a) trichloroacetaldehyde hydrate (37.4g, 0.22mol) water (1000ml) is dissolved, is added in 1L there-necked flasks, then
Aqueous solution (300ml), the hydrochloric acid of 3,4- dimethoxyanilines (25g, 0.20mol) for sequentially adding anhydrous sodium sulfate (334g) are molten
The aqueous solution (200ml) of liquid (commercially available 16mL concentrated hydrochloric acids and 130mL water) and hydroxylamine hydrochloride (46g, 0.66mol), is heated to reflux 40
Minute；20~25 DEG C are then cooled to, filtration drying obtains compound 2(24g, yield 65%,
Purity 99.5%)；
(b) compound 2 (23.4g, 50mmol) is mixed with polyphosphoric acids (200g), is added in 500mL there-necked flasks,
It is stirred to react 1h at 80 DEG C；After being cooled to room temperature, ice water is added and is stirred, filters, drying and to obtain compound 3(15g, yield 70%, purity 99.5%)；
(c) by compound 3 (15g, 72.6mmol) and rhodanine (10.8g, 40.8mmol, CAS：141-84-4) use 70ml
Pyridinium dissolution imports in 500mL single port bottles, and water (10ml) is added and is stirred, stirs 1 hour；Be added tetrahydrofuran 70mL into
Row is heated to reflux 1 hour, is cooled to 5~10 DEG C, and filtering is washed with toluene, dry compound 4
(18.4g, yield 78%, purity 99.5%)；
(d) in 500mL single port bottles by compound 4 (18.4g, 56.8mmol) and KOH solution (mass fraction 10%,
After 250ml) mixing, it is heated to 50 DEG C and is stirred reaction 1h；Be cooled to 0~5 DEG C with ice-water bath, with concentrated hydrochloric acid (it is commercially available,
It 70ml) neutralizes, filtering, dry compound 5(11.6g, 74%, purity 99.5%)；
(e) it after mixing compound 5 (11.6g, 41.4mmol) and aniline (70g) in 500mL single port bottles, is protected in nitrogen
It protects, be stirred to react 1h under conditions of 120 DEG C；40ml10%NaOH solution (mass fraction) is added after cooling, is washed with ethyl acetate
It washs, phase of fetching water, then it is 2~4 to be acidified to pH with dilute hydrochloric acid (mass fraction is about 15%), filtering is dried to obtain compound 6(3.2g, 22.8%, purity 99.0%), nuclear magnetic spectrogram is as shown in Figure 1；
Above-mentioned compound 6 can synthesize derivatives of indirubin by following steps：Poly is added in 100ml there-necked flasks
Phosphoric acid (32g), is heated to 120 DEG C, and compound 6 (3.2g, 9.4mmol) is added under conditions of being stirred continuously and is stirred at 120 DEG C
React 1h；Ice water (20ml) is added after cooling, reaction is quenched, organic phase is concentrated after being extracted with ethyl acetate, what is obtained is thick
Product are purified with column chromatography, afford target compound 220mg (purity 99.6%), and nuclear magnetic spectrogram is as shown in Fig. 2, tool
Body is：1H NMR(400MHz,DMSO-d6)δ(ppm):10.79(s,1H),10.66(s,1H),8.58(s,1H),7.64(d,J
=4.0Hz, 1H), 7.55 (t, J=4.0Hz, 1H), 7.39 (d, J=4.0Hz, 1H), 6.99 (d, J=4.0Hz, 1H), 6.54
(s, 1H), 3.80 (d, J=2.0Hz, 6H) .ESI-MS m/z calcd:C18H14N2O4([M-H]-)；321.10,found:
321.4。
Embodiment 2
The present embodiment provides a kind of synthetic method of the final intermediate of chronic myelocytic leukemia drug, it and embodiment 1
In it is almost the same, unlike：In step (b), there-necked flask is placed in ice-water bath after cooling, filtering, dry compound 3(12.9g, yield 60%, 99.5%).
Embodiment 3
The present embodiment provides a kind of synthetic method of the final intermediate of chronic myelocytic leukemia drug, it and embodiment 1
In it is almost the same, unlike：In step (d), a concentration of 15wt% of KOH solution of addition, obtained compound 5 is still
11.6g, yield 74%, purity 99.5%.
Comparative example 1
A kind of synthetic method of the final intermediate of chronic myelocytic leukemia drug of this example, it with it is basic in embodiment 1
Unanimously, unlike：In step (c), be directly added into after compound 3 and rhodanine 70ml pyridinium dissolutions tetrahydrofuran 70mL into
Row is heated to reflux 1 hour, is cooled to 5~10 DEG C, and filtering is washed with toluene, dry 13.0g compounds 4, yield 55%, pure
Degree is 90%).
Comparative example 2
A kind of synthetic method of the final intermediate of chronic myelocytic leukemia drug of this example, it with it is basic in embodiment 1
Unanimously, unlike：In step (c), unused 70ml pyridinium dissolutions, dry compound 4 (14.4g, yield 61%, purity
92%).
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art
Scholar cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention, all according to the present invention
Equivalent change or modification made by Spirit Essence, should be covered by the protection scope of the present invention.
Claims (3)
1. a kind of synthetic method of the final intermediate of chronic myelocytic leukemia drug, which is characterized in that it includes the following steps：
(a) by trichloroacetaldehyde hydrate water dissolution, the aqueous solution of anhydrous sodium sulfate, 3,4- dimethoxyanilines are sequentially added
The aqueous solution of hydrochloric acid solution and hydroxylamine hydrochloride is heated to back flow reaction 30~60 minutes；20~25 DEG C are then cooled to, crosses and is filtered dry
It is dry to obtain compound 2
(b) compound 2 is mixed with polyphosphoric acids, reaction is stirred at 60~100 DEG C；Ice water is added to be stirred
Mix, filter, drying and to obtain compound 3
(c) by the compound 3 and rhodanine pyridinium dissolution, water is added and is stirred, adds tetrahydrofuran and is heated
Reflux；It is cooled to 5~10 DEG C, filtering is washed with toluene, dry compound 4
(d) after mixing the compound 4 and KOH solution, 40~60 DEG C is heated to and is stirred reaction；It is cooled to 0~5 DEG C,
It is neutralized, is filtered with concentrated hydrochloric acid, dry compound 5
(e) it after mixing the compound 5 and aniline, is stirred to react under conditions of nitrogen protection, 100~150 DEG C；After cooling
NaOH solution is added, is washed with ethyl acetate, phase of fetching water, then it is 2~4 to be acidified to pH with hydrochloric acid, filtering is dried to obtain compound
6.
2. the synthetic method of the final intermediate of chronic myelocytic leukemia drug according to claim 1, it is characterised in that：
In step (d), the mass concentration of the KOH solution is 5~15%.
3. the synthetic method of the final intermediate of chronic myelocytic leukemia drug according to claim 1 or 2, feature exist
In：The mass concentration of step (e), the NaOH solution is 5~15%.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101786980A (en) * | 2010-03-31 | 2010-07-28 | 滨海康杰化学有限公司 | Synthesis method of isatin derivatives |
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2018
- 2018-05-14 CN CN201810454317.0A patent/CN108440377A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101786980A (en) * | 2010-03-31 | 2010-07-28 | 滨海康杰化学有限公司 | Synthesis method of isatin derivatives |
Non-Patent Citations (2)
| Title |
|---|
| RIEPL, HERBERT M.，等: "Improved Synthesis of Indirubin Derivatives by Sequential Build-Up of the Indoxyl Unit: First Preparation of Fluorescent Indirubins", 《HELVETICA CHIMICA ACTA》 * |
| YASUHIRO KOSUGE，等: "Indirubin derivatives protect against endoplasmic reticulum stressinduced cytotoxicity and down-regulate CHOP levels in HT22 cells", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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Effective date of registration: 20200612 Address after: 211106 A024, building 2, No. 157, zhuangpai Road, Jiangning Development Zone, Nanjing City, Jiangsu Province Applicant after: Nanjing juke Biotechnology Co., Ltd Address before: 463000 East Household of West Unit 11 of Jade 1001 Building at the Intersection of Civilization Road and Dadalu Road, Zhumadian Development Zone, Henan Province Applicant before: HENAN FUMENG TRADING Co.,Ltd. |
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Application publication date: 20180824 |
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