CN102633673A - Synthesis method of tamibarotene - Google Patents
Synthesis method of tamibarotene Download PDFInfo
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- CN102633673A CN102633673A CN2012100905071A CN201210090507A CN102633673A CN 102633673 A CN102633673 A CN 102633673A CN 2012100905071 A CN2012100905071 A CN 2012100905071A CN 201210090507 A CN201210090507 A CN 201210090507A CN 102633673 A CN102633673 A CN 102633673A
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- tamibarotene
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- MBKHWULDOVUDOL-UHFFFAOYSA-N CC1(C)C(CCC(C2)NC(c(cc3)ccc3C(OC)=O)=O)=C2C(C)(C)CC1 Chemical compound CC1(C)C(CCC(C2)NC(c(cc3)ccc3C(OC)=O)=O)=C2C(C)(C)CC1 MBKHWULDOVUDOL-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a synthesis method of tamibarotene, which comprises the steps of: 1)taking aniline and monomethyl ester terephthalate as raw materials, and synthesizing p-carbaniloyl methyl benzoate (III); 2) under the protection of nitrogen in an anhydrous condition, carrying out cyclization on the intermediate III and 2, 5-dimethyl-2, 5-hexanediol at a low temperature, to obtain an intermediate II; and 3) hydrolyzing the intermediate II to obtain the tamibarotene (I), wherein dicyclohexyl carbodiimide (DCC)/ hydroxyl benzotriazole (HOBt), diisopropylcarbodiimide (DIC)/ HOBt, HATU or HBTU taken as a condensing agent as well as triethylamine and diisopropylethylamine (DIEA) taken as acid-binding agents can be added into the step 1); halogen acid taken as a catalyst is added into the step 2); and the reaction solvent is halogenated alkanes. The synthesis method of the tamibarotene avoids the link with high pollution, thus reducing the environmental cost.
Description
Technical field
The present invention relates to a kind of compound method of Tamibarotene.
Background technology
According to statistics, acute progranulocyte accounts for acute myelogenous cell from 6.5%～32.4% of blood disease at home from blood sick (APL), in the FAB classification, is the M3 type.The all-trans-retinoic acid of domestic initiation in 1986 (all trans retinoicacid; ATRA) induce differentiation therapy that APL complete remission rate (CR) is reached more than 85%; Along with clinical further application, find that it can form resistance and make the recurrence patient be difficult to obtain once more alleviate.Current most of patient APL treats with ATRA or with white arsenic (being arsenic) or combination chemotherapy.But ATRA treats activation RAR and induces the differentiation and the maturation of promyelocyte, stops their propagation, alleviates the state of an illness.With the vitamin A acid be after the therapy on basis is alleviated the APL disease fully again recurrence from the blood patient, (tamibarotene I) obtains to alleviate fully can to use Tamibarotene.
(tamibarotene I), is the new selective retinoid receptor agonist of Japanese Nippon Shinyaku company exploitation to Tamibarotene, and go on the market in Japan in June, 2005 first.This medical instrument effective in cure good, be difficult for developing immunity to drugs, advantage, clinical various types of recurrences of treatment or the intractable acute promyelocytic leukemia (APL) of being mainly used in such as untoward reaction is little.As the kind than the new listing, Tamibarotene is in the rare production of China at present, and the price of each midbody is extremely expensive, develops and produce this series of products, can inexpensive more effective quality medicine be provided for numerous leukaemics.
Compound method the earliest is representative (referring to Fig. 2) with the route that is published in " Chinese Journal of Pharmaceuticals " 2009 40 the 1st phases of volume.This route is from 2, and 5-dimethyl--2,5-pinakon are that reaction obtains midbody 5,6,7 to starting raw material through 4 steps; 8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthylamines; Again with 4-chloroformyl oil of Niobe reaction obtain key intermediate 4-((5,5,8,8-tetramethyl--5; 6,7,8-tetrahydrochysene-2-naphthalene) formamyl) oil of Niobe (II), this posthydrolysis obtains ultimate aim product-Tamibarotene (I).The shortcoming of this route is: synthetic route is long; Relate to halogenating reaction, mixed acid nitrification that concentrated hydrochloric acid is participated in, and the heavy metal catalytic reduction reaction, not only yield is low, and environmental pollution is serious.
Patent WO9114673 substitutes benzene and 2 with Acetanilide, 5-two chloro-2, the reaction of 5-dimethylhexane; Obtain 2-acetylaminohydroxyphenylarsonic acid 5,5,8; 8-tetramethyl--5,6,7; The 8-naphthane carries out transesterify with 4-chloroformyl oil of Niobe again and obtains intermediate II, and further hydrolysis obtains title product I (referring to Fig. 3).This two step of nitrated-reduction that this method has been avoided is polluted the step big, that yield is low, thereby has simplified technology greatly.But still have following shortcoming: need nitrogen protection in the transesterification reaction, and low-temp reaction, operate loaded down with trivial detailsly, cost is higher; Step is still found sth. annoying or trying trivial.
Patent CN101121675 further improves on this basis; Obtain the aniline acyl radical methyl benzoate with 4-chloroformyl oil of Niobe and aniline reaction, then with 2,5-two chloro-2; The reaction of 5-dimethyl-obtains intermediate II, and further hydrolysis obtains title product I (referring to Fig. 4).This method on the basis of SOME METHODS, further reduces production technique, and has further reduced and polluted the step big, that yield is low in front, and whole industrial production cost is further reduced.
But the link of two high pollutions, promptly crucial starting raw material 4-chloroformyl oil of Niobe and 2,5-two chloro-2, the production of 5-dimethylhexane have all been covered in this method and the design of all operational paths before this.This shows:
The production of 4-chloroformyl oil of Niobe is to be raw material with terephthalic acid monomethyl ester, (referring to the Fig. 5) that obtains with the sulfur oxychloride halo.No matter be with sulfur oxychloride solution, still directly with sulfur oxychloride as solvent production, all produce a large amount of toxic gases and acidic waste, very big to the infringement of environment and production unit.And 4-chloroformyl oil of Niobe itself is also very unstable, can not long storage, must do existing usefulness at present.This has limited the normal operation of whole production operational path.
2,5-two chloro-2, the 5-dimethylhexane is with 2,5-dimethyl--2, the 5-pinakon is a raw material, is (referring to Fig. 6) that solvent reaction obtains with the concentrated hydrochloric acid.The aftertreatment of a large amount of concentrated hydrochloric acid waste liquids, environmental cost is too big.
So existing compound method also need be improved.
Summary of the invention
The technical problem that the present invention will solve provides a kind of easier, compound method of the Tamibarotene of subenvironment cost more.
The compound method of Tamibarotene of the present invention comprises step:
1) be raw material with aniline, terephthalic acid monomethyl ester, synthetic to carbanilino oil of Niobe (III);
2) under anhydrous, nitrogen protection, intermediate III and 2,5-dimethyl--2, the cyclization of 5-pinakon low temperature obtains intermediate II;
3) the intermediate II hydrolysis obtains Tamibarotene (I).
In the step 1), add DCC/HOBt, DIC/HOBt, HATU or HBTU as condensing agent.
In the step 1), be acid binding agent with triethylamine, DIEA.
Step 2) in, the adding hydracid is a catalyzer.
Said hydracid is AlCl
3
Step 2) in, reaction solvent is the haloalkane hydro carbons; Reaction solvent is CH
2Cl
2, CHCl
3Or ClCH
2CH
2Cl.
The present invention connects under the catalysis of efficient acidylate condensing agent directly with terephthalic acid monomethyl ester and aniline, has avoided the production of 4-chloroformyl oil of Niobe, has avoided a large amount of toxic gases and acidic waste; Directly with 2,5-dimethyl--2, the 5-pinakon is with cyclization obtains intermediate II to the benzoyl-oil of Niobe; Although need the inflated with nitrogen protection that cost is slightly risen in the reaction; But avoided producing a large amount of concentrated hydrochloric acid waste liquids, thereby avoided the link of high pollution, more reduced environmental cost.
Description of drawings
Fig. 1 is the compound method synoptic diagram of Tamibarotene provided by the invention;
Fig. 2 is the compound method synoptic diagram of the Tamibarotene of " Chinese Journal of Pharmaceuticals " announcement;
Fig. 3 is the Tamibarotene compound method synoptic diagram that patent WO9114673 announces;
Fig. 4 is the Tamibarotene compound method synoptic diagram that patent CN101121675 announces;
Fig. 5 is the synthetic synoptic diagram of 4-chloroformyl oil of Niobe;
Fig. 6 is 2,5-two chloro-2, the synthetic synoptic diagram of 5-dimethylhexane.
Embodiment
Combine accompanying drawing and embodiment that the present invention is done further explain at present.
Referring to Fig. 1, be synthetic route chart of the present invention.
The compound method of Tamibarotene of the present invention (I) comprises the steps:
1) be raw material with aniline, terephthalic acid monomethyl ester, synthetic to carbanilino oil of Niobe (III);
2) under anhydrous, nitrogen protection, intermediate III and 2,5-dimethyl--2, the cyclization of 5-pinakon low temperature obtains intermediate II;
3) the intermediate II hydrolysis obtains title product-Tamibarotene (I).
Above-mentioned steps 1) in, adds DCC/HOBt, DIC/HOBt, HATU, HBTU etc. as condensing agent.
Above-mentioned steps 1) in, be acid binding agent with triethylamine, DIEA;
Above-mentioned steps 2) in, adds hydracid, like AlCl
3Be catalyzer.
Above-mentioned steps 2) in, reaction solvent is the haloalkane hydro carbons, like CH
2Cl
2, CHCl
3, ClCH
2CH
2Cl.
Patent CN101121675 obtains the benzoyl-oil of Niobe with 4-chloroformyl oil of Niobe and aniline reaction; The present invention connects under the catalysis of efficient acidylate condensing agent directly with terephthalic acid monomethyl ester and aniline, has avoided the production of 4-chloroformyl oil of Niobe.Patent CN101121675 is earlier with 2, and 5-dimethyl--2,5-pinakon are handled with concentrated hydrochloric acid and obtained 2,5-two chloro-2, and the 5-dimethylhexane is then with cyclization obtains intermediate II to the benzoyl-oil of Niobe; The present invention is directly with 2,5-dimethyl--2, and the 5-pinakon is with cyclization obtains intermediate II to the benzoyl-oil of Niobe.Although need the inflated with nitrogen protection that cost is slightly risen in the reaction, avoid producing a large amount of concentrated hydrochloric acid waste liquids.Thereby avoided the link of high pollution, more reduced environmental cost.
The above only is preferred embodiment of the present invention; Not being that the present invention is done any pro forma restriction, though the present invention with the preferred embodiment exposure as above, yet is not in order to limit the present invention; Anyly be familiar with the professional and technical personnel; In the scope that does not break away from technical scheme of the present invention, make a little change or be modified to the equivalent embodiment of equivalent variations when the technology contents of above-mentioned announcement capable of using, be the content that does not break away from technical scheme of the present invention in every case;, all still belong in the scope of technical scheme of the present invention any simple modification, equivalent variations and modification that above embodiment did according to technical spirit of the present invention.
Claims (7)
1. the compound method of a Tamibarotene is characterized in that comprising step:
1) be raw material with aniline, terephthalic acid monomethyl ester, synthetic to carbanilino oil of Niobe (III);
2) under anhydrous, nitrogen protection, intermediate III and 2,5-dimethyl--2, the cyclization of 5-pinakon low temperature obtains intermediate II;
3) the intermediate II hydrolysis obtains Tamibarotene (I).
2. the compound method of Tamibarotene as claimed in claim 1 is characterized in that: in the step 1), add DCC/HOBt, DIC/HOBt, HATU or HBTU as condensing agent.
3. the compound method of Tamibarotene as claimed in claim 1 is characterized in that: in the step 1), be acid binding agent with triethylamine, DIEA.
4. the compound method of Tamibarotene as claimed in claim 1 is characterized in that: step 2) in, the adding hydracid is a catalyzer.
5. the compound method of Tamibarotene as claimed in claim 4, it is characterized in that: said hydracid is AlCl
3
6. the compound method of Tamibarotene as claimed in claim 1 is characterized in that: step 2) in, reaction solvent is the haloalkane hydro carbons.
7. the compound method of Tamibarotene as claimed in claim 6, it is characterized in that: reaction solvent is CH
2Cl
2, CHCl
3Or ClCH
2CH
2Cl.
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| CN2012100905071A CN102633673A (en) | 2012-03-30 | 2012-03-30 | Synthesis method of tamibarotene |
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|---|---|---|---|
| CN2012100905071A CN102633673A (en) | 2012-03-30 | 2012-03-30 | Synthesis method of tamibarotene |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664680A (en) * | 2012-09-26 | 2014-03-26 | 山东鲁北药业有限公司 | New process for synthesizing tamibarotene |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0478787A1 (en) * | 1990-03-20 | 1992-04-08 | Shionogi & Co., Ltd. | Novel process for producing benzoic acid derivative |
| CN101121675A (en) * | 2007-07-25 | 2008-02-13 | 中国药科大学 | A new synthesis process of tamibarotene |
| CN101200435A (en) * | 2006-12-12 | 2008-06-18 | 江苏恒瑞医药股份有限公司 | Method for preparing tamibaroteneII crystal |
-
2012
- 2012-03-30 CN CN2012100905071A patent/CN102633673A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0478787A1 (en) * | 1990-03-20 | 1992-04-08 | Shionogi & Co., Ltd. | Novel process for producing benzoic acid derivative |
| EP0478787A4 (en) * | 1990-03-20 | 1992-07-01 | Shionogi & Co., Ltd. | Novel process for producing benzoic acid derivative |
| CN101200435A (en) * | 2006-12-12 | 2008-06-18 | 江苏恒瑞医药股份有限公司 | Method for preparing tamibaroteneII crystal |
| CN101121675A (en) * | 2007-07-25 | 2008-02-13 | 中国药科大学 | A new synthesis process of tamibarotene |
Non-Patent Citations (2)
| Title |
|---|
| 肖健等: "抗白血病药他米巴罗汀的合成工艺改进", 《中国药物化学杂志》, vol. 19, no. 04, 20 August 2009 (2009-08-20), pages 268 - 269 * |
| 边海勇等: "他米巴罗汀的合成", 《中国医药工业杂志》, vol. 40, no. 01, 10 January 2009 (2009-01-10), pages 9 - 11 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664680A (en) * | 2012-09-26 | 2014-03-26 | 山东鲁北药业有限公司 | New process for synthesizing tamibarotene |
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Application publication date: 20120815 |