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CN107973796A - A kind of preparation method of Tadalafei isomers - Google Patents

A kind of preparation method of Tadalafei isomers Download PDF

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Publication number
CN107973796A
CN107973796A CN201711295146.3A CN201711295146A CN107973796A CN 107973796 A CN107973796 A CN 107973796A CN 201711295146 A CN201711295146 A CN 201711295146A CN 107973796 A CN107973796 A CN 107973796A
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isomers
tadalafei
preparation
mixing
compound
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CN107973796B (en
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刘宏宇
乔明福
许华锋
窦振国
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ZHUHAI LIANBANG PHARMACEUTICAL CO Ltd
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ZHUHAI LIANBANG PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

The invention discloses a kind of preparation method of Tadalafei isomers, belong to technical field of medicine synthesis.The preparation method of the present invention includes Tadalafei being placed in non-proton intensive polar solvent, and carrying out part racemization using organic base obtains isomers I；Using L tryptophans as raw material, isomers II is obtained by the way that four-step reaction is fully synthetic；Isomers II is placed in non-proton intensive polar solvent, carrying out part racemization using organic base obtains isomers III；And structural identification is carried out to three above isomers.Preparation method process provided by the present invention is simple, high income, and post processing is simple, is easy to purify.

Description

A kind of preparation method of Tadalafei isomers
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to a kind of preparation method of Tadalafei isomers.
Background technology
Tadalafei (Tadalafil), chemical name：(6R, 12aR) -6- (1,3- benzos two dislike cyclopentadienyl -5- bases) -2- methyl - 2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1 ', 2 ':1,6] pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone, it is public by Lilly Department's exploitation, trade name Xi Aili (Cialis), in November, 2002, the Tadalafil of Li Lai companies obtain European Union's approval and are used for ED Treatment, 2 months 2003 first Britain, Sweden, Denmark, Germany and Australia etc. it is multiple country listing；In November, 2003, U.S. FDA approval Tadalafil is used to treat ED；In July, 2007, obtains the approval listing of Japan PMDA.
Structural formula is as shown in formula 1-1：
There are 2 chiral centres in the molecular structure of Tadalafei, containing 3 isomers, wherein there is an enantiomter II, two diastereoisomers I, III, as shown in formula 1-2：
Formula 1-2 Tadalafei isomer structure formulas
Three above isomers is particularly critical among Tadalafei drug development and verification, in whole isomers risk control Important function has been played in system, can effectively help the completion researched and developed and produced.But currently for the preparation of above isomers There is the problems such as yield is low, purifying is difficult, complex procedures for method, it is impossible to meets the needs of research and development and reference substance well.
The content of the invention
For overcome the deficiencies in the prior art, it is an object of the invention to provide a kind of preparation side of Tadalafei isomers Method, the preparation method process is simple, high income, and post processing is simple, is easy to purify.
To solve the above problems, the technical solution adopted in the present invention is as follows：
A kind of preparation method of Tadalafei isomers I, it is organic by Tadalafei with non-proton intensive polar solvent Part racemization is carried out under conditions of alkali, isomers I is obtained, is shown below：
Preferably, the non-proton intensive polar solvent is one kind in DMF, DMSO, NMP or the mixing more than any two.
Preferably, the organic base is DMAP, DBU, one kind in triethylamine or the mixing more than any two.
Present invention also offers a kind of preparation method of Tadalafei isomers II, it comprises the following steps：
The first step, L-Trp is mixed with chlorination reagent carries out esterification, obtains compound 1；
Second step, compound 1 and 3,4- methylenedioxy benzene formaldehyde react under conditions of non-protonic solvent, are changed Compound 2；
3rd step, compound 2 are reacted with chloracetyl chloride under conditions of anhydrous tetrahydro furan, obtain compound 3；
4th step, compound 3 are reacted with acetonitrile and methylamine water solution, obtain isomers II；
Synthetic route is as follows：
Preferably, in first step reaction, chlorination reagent is the mixing of one or both of oxalyl chloride, thionyl chloride.
Preferably, second step reaction in, non-protonic solvent for acetonitrile, one kind in DMF, THF or any two more than Mixing.
Preferably, in three-step reaction, the dropping temperature of chloracetyl chloride is -5~10 DEG C.
Preferably, in four-step reaction, the concentration of methylamine water solution is preferably 30~40%.
Present invention also offers a kind of preparation method of Tadalafei isomers III, its be by above-mentioned isomers II with Non-proton intensive polar solvent carries out part racemization under conditions of organic base, obtains isomers III, is shown below：
Preferably, the non-proton intensive polar solvent is one kind in DMF, DMSO, NMP or the mixing more than any two； The organic base is DMAP, DBU, one kind in triethylamine or the mixing more than any two.
Compared with prior art, the beneficial effects of the present invention are：
The present invention is by purifying the racemization of Tadalafei part to obtain isomers I, by being closed entirely using L-Trp as raw material React to obtain isomers II into 4 steps, by purifying to obtain isomers III to isomers II part racemizations, process made above is equal It can be monitored by HPLC, it is easily controllable, and these three isomers have been carried out with structural identification, obtained isomery bulk optics Purity is high, meets research and development and the requirement of reference substance, can effectively help the completion researched and developed and produced, be conducive to isomers risk Control.Preparation method process of the invention is simple and reliable, high income, and post processing is simple, is easy to purify.
Embodiment
The present invention is described in further detail with reference to embodiment.
Used all reagents and raw material are all from commercially available in following embodiments.
Embodiment 1：The preparation of Tadalafei isomers I
Tadalafei (3.9g, 0.01mol) is added in the dimethylformamide of 40mL, stirs 10min, added DMAP (1.2g, 0.01mol), reacts 6h at 80 DEG C, is down to room temperature, growing the grain 1h, filtering, acetone washing, is dried in vacuo to obtain isomery Body I 3.1g, yield 79.5%.
MS：M/z (%)=390.5 (M+H+)；
1HNMR(DMSO-d6, 400MHz) and δ：2.85 (s, 3H), 2.96 (m, 1H), 3.27 (dd, 1H), 4.05 (d, 1H), 4.09 (dd, 1H), 4.26 (d, 1H), 6.01 (dd, 2H), 6.62 (dd, 1H), 6.77 (d, 1H), 6.84 (s, 2H), 6.88 (d, 1H), 7.02 (m, 1H), 7.02 (m, 1H), 7.32 (d, 1H), 7.51 (d, 1H), 11.07 (s, 1H).
Embodiment 2：The preparation of Tadalafei isomers II
The synthetic route of Tadalafei isomers II is as follows：
The first step is reacted：L-Trp is mixed with chlorination reagent carries out esterification
Add absolute methanol 100mL, L-Trp (10g, 0.05mol), be slowly added dropwise at room temperature thionyl chloride (7.1g, 0.06mol), finish, 50 DEG C of insulation reaction 3h, add isopropyl ether 100mL after having reacted, be cooled to 0~5 DEG C, growing the grain 1h, mistake Filter, isopropyl ether washing, is dried in vacuo to obtain 10.5g compounds 1, yield 105%.
Second step reacts：Compound 1 and 3,4- methylenedioxy benzene formaldehyde reacts under conditions of non-protonic solvent
Add anhydrous THF80mL, compound 1 (10g, 0.04mol), 3,4- methylenedioxy benzenes formaldehyde (6g, 0.04mol), back flow reaction 10h, is down to room temperature, is cooled to 0~5 DEG C, growing the grain 1h, filtering, THF washings, are dried in vacuo 13.5g compounds 2, yield 135%.
Three-step reaction：Compound 2 is reacted with chloracetyl chloride under conditions of anhydrous tetrahydro furan
Add anhydrous tetrahydro furan 100mL, compound 2 (11.6g, 0.03mol), triethylamine (3g, 0.03mol), cooling To 0~5 DEG C, chloracetyl chloride (3.4g, 0.03mol) is slowly added dropwise, is added dropwise, be warmed to room temperature reaction 2h, be concentrated under reduced pressure half Solvent, room temperature growing the grain 1h, filtering, tetrahydrofuran washing, is dried in vacuo to obtain 11.0g compounds 3, yield 94.8%.
Four-step reaction：Compound 3 is reacted with acetonitrile and methylamine water solution
Acetonitrile 90mL, compound 2 (8.5g, 0.02mol) are added, 20mL methylamine water solutions are slowly added dropwise at room temperature, is added dropwise Finish, 50 DEG C of insulation reaction 3h, are down to room temperature, and be concentrated under reduced pressure about 1/3rd solvents, and growing the grain 1h is stirred at room temperature, filtering, acetonitrile Washing, it is dried in vacuo to obtain isomers II 6.8g, yield 80%.
MS：M/z (%)=390.5 (M+H+)；
1HNMR(DMSO-d6, 400MHz) and δ：2.93 (s, 3H), 2.99 (m, 1H), 3.52 (dd, 1H), 3.94 (d, 1H), 4.18 (dd, 1H), 4.39 (dd, 1H), 5.92 (s, 2H), 6.14 (s, 1H), 6.78 (m, 2H), 6.87 (s, 1H), 7.00 (m, 1H), 7.06 (m, 1H), 7.30 (d, 1H), 7.54 (d, 1H), 11.01 (s, 1H).
Embodiment 3：The preparation of Tadalafei isomers III
Isomers II (3.9g, 0.01mol) is added in the dimethylformamide of 40mL, stirs 10min, added DMAP (1.2g, 0.01mol), 80 DEG C of reaction 6h, are down to room temperature, growing the grain 1h, filtering, acetone washing, is dried in vacuo to obtain isomers III 3.0g, yield 76.9%.
MS：M/z (%)=390.5 (M+H+)；
1HNMR(DMSO-d6, 400MHz) and δ：2.86 (s, 3H), 2.95 (m, 1H), 3.27 (dd, 1H), 4.04 (d, 1H), 4.09 (dd, 1H), 4.25 (d, 1H), 6.01 (d, 2H), 6.62 (dd, 1H), 6.77 (d, 1H), 6.84 (s, 1H), 6.87 (d, 1H), 7.03 (m, 1H), 7.02 (m, 1H), 7.11 (m, 1H), 7.32 (d, 1H), 7.51 (d, 1H), 11.04 (s, 1H).
The above embodiment is only the preferred embodiment of the present invention, it is impossible to the scope of protection of the invention is limited with this, The change and replacement for any unsubstantiality that those skilled in the art is done on the basis of the present invention belong to institute of the present invention Claimed scope.

Claims (10)

  1. A kind of 1. preparation method of Tadalafei isomers, it is characterised in that：Tadalafei and non-proton intensive polar solvent are existed Part racemization is carried out under conditions of organic base, isomers I is obtained, is shown below：
  2. 2. the preparation method of Tadalafei isomers according to claim 1, it is characterised in that：It is described non-proton highly polar Solvent is one kind in DMF, DMSO, NMP or the mixing more than any two.
  3. 3. the preparation method of Tadalafei isomers according to claim 1, it is characterised in that：The organic base is One kind in DMAP, DBU, triethylamine or the mixing more than any two.
  4. A kind of 4. preparation method of Tadalafei isomers, it is characterised in that：Comprise the following steps：
    The first step, L-Trp is mixed with chlorination reagent carries out esterification, obtains compound 1；
    Second step, compound 1 and 3,4- methylenedioxy benzene formaldehyde react under conditions of non-protonic solvent, obtain compound 2；
    3rd step, compound 2 are reacted with chloracetyl chloride under conditions of anhydrous tetrahydro furan, obtain compound 3；
    4th step, compound 3 are reacted with acetonitrile and methylamine water solution, obtain isomers II；
    Synthetic route is as follows：
  5. 5. the preparation method of Tadalafei isomers according to claim 4, it is characterised in that：In first step reaction, chlorine Change reagent is the mixing of one or both of oxalyl chloride, thionyl chloride.
  6. 6. the preparation method of Tadalafei isomers according to claim 4, it is characterised in that：It is non-in second step reaction Protonic solvent is acetonitrile, one kind in DMF, THF or the mixing more than any two.
  7. 7. the preparation method of Tadalafei isomers according to claim 4, it is characterised in that：In three-step reaction, chlorine The dropping temperature of chloroacetic chloride is -5~10 DEG C.
  8. 8. the preparation method of Tadalafei isomers according to claim 4, it is characterised in that：In four-step reaction, first The concentration of amine aqueous solution is preferably 30~40%.
  9. A kind of 9. preparation method of Tadalafei isomers, it is characterised in that：By the isomers II described in claim 4 and non-matter Sub- intensive polar solvent carries out part racemization under conditions of organic base, obtains isomers III, is shown below：
  10. 10. the preparation method of Tadalafei isomers according to claim 9, it is characterised in that：The non-proton strong pole Property solvent be DMF, DMSO, NMP in one kind or the mixing more than any two；The organic base is DMAP, DBU, in triethylamine One kind or the mixing more than any two.
CN201711295146.3A 2017-12-08 2017-12-08 Preparation method of tadalafil isomer Active CN107973796B (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111253399A (en) * 2020-03-30 2020-06-09 苏州弘森药业股份有限公司 Production process of tadalafil raw material medicine
WO2020218941A1 (en) * 2019-04-26 2020-10-29 Obshestvo S Ogranichennoy Otvetstvennostuy "Baltfarma" Tadalafil synthesis method
CN113214251A (en) * 2021-04-30 2021-08-06 湖北丽益医药科技有限公司 Preparation method of tadalafil intermediate impurity

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103772384A (en) * 2014-01-23 2014-05-07 苏州大学 Preparation method of tadalafil

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103772384A (en) * 2014-01-23 2014-05-07 苏州大学 Preparation method of tadalafil

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ALAIN DAUGAN ET AL: "The Discovery of Tadalafil: A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione Analogues", 《J. MED. CHEM.》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020218941A1 (en) * 2019-04-26 2020-10-29 Obshestvo S Ogranichennoy Otvetstvennostuy "Baltfarma" Tadalafil synthesis method
CN111253399A (en) * 2020-03-30 2020-06-09 苏州弘森药业股份有限公司 Production process of tadalafil raw material medicine
CN113214251A (en) * 2021-04-30 2021-08-06 湖北丽益医药科技有限公司 Preparation method of tadalafil intermediate impurity
CN113214251B (en) * 2021-04-30 2024-06-11 湖北丽益医药科技有限公司 Preparation method of tadalafil intermediate impurity

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