CN103351424B - The preparation method of a kind of taxol or Docetaxel Octreotide conjugate - Google Patents
The preparation method of a kind of taxol or Docetaxel Octreotide conjugate Download PDFInfo
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- CN103351424B CN103351424B CN201310232603.XA CN201310232603A CN103351424B CN 103351424 B CN103351424 B CN 103351424B CN 201310232603 A CN201310232603 A CN 201310232603A CN 103351424 B CN103351424 B CN 103351424B
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Abstract
The present invention is the preparation method of a kind of taxol or Docetaxel Octreotide conjugate, this preparation method comprises the following steps: step 1: in aprotic solvent, the acid of taxol-2 '-catenation sequence or Docetaxel-2 '-catenation sequence acid obtains N-maloyl imines taxol-2 '-catenation sequence ester or N-maloyl imines Docetaxel-2 '-catenation sequence ester with diphenyl N-succinimide phosphate (SDPP) under the catalysis of tertiary amine; Step 2: in aprotic solvent, N-maloyl imines taxol-2 '-catenation sequence ester or N-maloyl imines Docetaxel-2 '-catenation sequence ester and octreotide acetate coupling under the catalysis of tertiary amine obtain taxol or Docetaxel Octreotide conjugate. The present invention overcomes cannot buy Octreotide resin complexes and the expensive catalyst difficult problem of use in the market, make above-mentioned conjugate can adopt marketable material and cheap reagent diphenyl? N-succinimide phosphate (SDPP) synthesizes in a large number.
Description
Technical field
The invention provides the synthetic method of the Octreotide conjugate of a kind of taxol or Docetaxel. Belonging to medicine closesThe technical field becoming.
Background technology
Growth hormone release inhibiting hormone (SST) is that one is present in gastric mucosa, pancreas islet, intestines and stomach nerve, posterior pituitary and central nervous systemNeuropeptide hormone in system, it is confirmed to be and can regulates basic mistakes such as secretion, cell division, propagation and ApoptosisJourney. Octreotide (octreotide) is a kind of artificial synthetic Sandostatin derivative, the action spectrum of it and growth hormone release inhibiting hormoneSimilar and biological half-life is longer, and there is stronger more lasting effect and stronger selective. From nineteen eighty-three so far, Bu ShaowenOffer and reported treatment impact and the system evaluation of Octreotide for some diseases, it has been proved neuroendocrine swollenThe kinds of tumors such as knurl, tumor in digestive tract, breast cancer and leukaemia are inhibited. Find by practice, Octreotide can be used forImprove the bad reaction of chemotherapy and the multiple symptom of patient with advanced cancer, be used to diagnosis or supplemental treatment kinds of tumors disease.
Taxol and Docetaxel are the first-line drugs of current chemotherapy in ovarian cancer, but considerable ovarian cancer patients is because producingRaw resistance causes chemotherapy failure, and recurrent ovarian carcinoma result for the treatment of is very undesirable, existing bibliographical information Octreotide to Japanese yewAlcohol suppresses the synergistic effect of non-small cell lung cancer cell, and these achievements impel exploitation Octreotide to pass through as the specific carrier of oneThe encytosis of somatostatin receptor is transported some antineoplastics (as taxol) and is entered tumour cell.
Taiwan's scholars reported first the activity of taxol Octreotide conjugate in tumour cell[1], it adopts hexafluoro phosphorusAcid BTA-1-base-oxygen base tripyrrole alkyl phosphorus (PyBOP) is catalyst, and taxol succinate and solid phase are synthetic to be obtainedOctreotide reaction, after the purifying resin that dissociates, freeze-drying obtains taxol Octreotide conjugate, Octreotide resin compounded in the methodThing can not have been bought on market, and catalyst P yBOP is expensive, and this brings to the synthetic and application of taxol Octreotide conjugateDifficulty.
[1]Chun-MingHuang,Ying-TaWu,Shui-TeinChen.Targetingdeliveryofpaclitaxelintotumorcellsviasomatostatinreceptorendocytosis[J].Chemistry&Biology,2000,7(7):453-461.
Summary of the invention
Technical problem: the Octreotide conjugate preparation side that the object of the invention is to carry a kind of taxol or DocetaxelMethod, overcomes and cannot buy in the market Octreotide resin complexes and use an expensive catalyst difficult problem, makes above-mentioned couplingThing can adopt marketable material and cheap reagent diphenyl N-succinimide phosphate (SDPP) to synthesize in a large number.
Technical scheme: the preparation method of taxol of the present invention or Docetaxel Octreotide conjugate comprises following stepRapid:
Step 1: in aprotic solvent, the acid of the acid of taxol-2 '-catenation sequence or Docetaxel-2 '-catenation sequence withDiphenyl N-succinimide phosphate (SDPP) obtains N-maloyl imines taxol-2 '-Lian under the catalysis of tertiary amineConnect sequence ester or N-maloyl imines Docetaxel-2 '-catenation sequence ester;
Step 2: in aprotic solvent, N-maloyl imines taxol-2 '-catenation sequence ester or N-hydroxyl fourth twoThe coupling under the catalysis of tertiary amine of acid imide Docetaxel-2 '-catenation sequence ester and octreotide acetate obtains taxol or polyenoidTaxol Octreotide conjugate.
In described step 1, aprotic solvent is preferably acetonitrile, and tertiary amine is preferably triethylamine; Described catenation sequenceLinker is-CO-CH2-(X)n-CH2-CO-；
Wherein, X is O (CH2CH2OCH2CH2CH2NHCOCH2-)2,-CO-,-O-,-S-,-CH2-,-CHCH3-or-C(CH3)-; N is 0 or 1,
In described step 2, described aprotic solvent is preferably dimethyl formamide DMF, and tertiary amine is preferably triethylamine,
In described step 2, N-maloyl imines taxol or Docetaxel catenation sequence ester and acetic acid are difficult to understand bentWhen the mol ratio of peptide is 1～1.5 to 1, primary product is single taxol or single Docetaxel Octreotide conjugate; N-hydroxyl fourthWhen imidodicarbonic diamide taxol or Docetaxel catenation sequence ester are 2～5 to 1 with the mol ratio of octreotide acetate, primary productTwo taxols or two Docetaxel Octreotide conjugates.
Described N-maloyl imines taxol or Docetaxel catenation sequence ester and octreotide acetate moleThan being preferably 1.1 to 1, primary product is single taxol or single Docetaxel Octreotide conjugate; N-maloyl iminesWhen taxol or Docetaxel catenation sequence ester are preferably 2.2 to 1 with the mol ratio of octreotide acetate, primary product is two purplesChina fir alcohol or two Docetaxel Octreotide conjugates.
The preparation method of another kind of easy taxol or Docetaxel Octreotide conjugate comprises the following steps:
Step a: octreotide acetate is dissolved in the water, removes acetate through pellicle or column chromatography and dissociated after dryOctreotide;
Step b: in aprotic solvent, the Octreotide that will dissociate, SDPP, the acid of taxol-2 '-catenation sequence or polyenoid Japanese yewThe acid of alcohol-2 '-catenation sequence mixes, and under tertiary amine catalytic, coupling obtains taxol or Docetaxel Octreotide conjugate.
In described step b, described aprotic solvent is preferably dimethyl formamide DMF, and tertiary amine is preferably triethylamine.
In described step b, the acid of taxol-2 '-catenation sequence or Docetaxel-2 '-catenation sequence acid is with free difficult to understandWhen the mol ratio of bent peptide is 1～1.5 to 1, primary product is single taxol or single Docetaxel Octreotide conjugate; Japanese yewThe acid of alcohol-2 '-catenation sequence or Docetaxel-2 '-catenation sequence acid is 2～5 o'clock with the mol ratio of free Octreotide, mainly producesThing is two taxols or two Docetaxel Octreotide conjugates.
Described taxol-2 '-catenation sequence acid or Docetaxel-2 '-catenation sequence acid rubs with free OctreotideYou are when being preferably 1.1 to 1, and primary product is single taxol or single Docetaxel Octreotide conjugate; Taxol-2 '-LianConnect sequence acid or Docetaxel-2 '-catenation sequence acid and be preferably at 2.2 o'clock with the mol ratio of free Octreotide, primary product isTwo taxols or two Docetaxel Octreotide conjugates.
Beneficial effect: taxol, Docetaxel, octreotide acetate and cheap reagent SDPP that employing can extensively obtainPrepare above-mentioned conjugate, overcome and cannot buy in the market Octreotide resin complexes and use an expensive catalyst difficult problem,Make above-mentioned conjugate can adopt marketable material and cheap reagent diphenyl N-succinimide phosphate (SDPP) to carry outA large amount of synthetic.
Detailed description of the invention
One, taxol, Docetaxel react with catenation sequence at 2 ', and the mode that conventionally adopts into ester is reacted.
Can be used for bridging agent of the present invention as diethylene glycol (DEG) acid anhydride, succinic anhydride, glutaric anhydride, 3-carbonyl glutaric anhydride, 3-firstBase glutaric anhydride, 3,3 '-dimethylated pentanedioic acid acid anhydride etc. When taxol or Docetaxel react with bridging agent, for differentBridging agent, the condition of coupled reaction is basic identical.
Two, taxol or Docetaxel link thing ester react with octreotide acetate under SDPP effect.
First taxol or Docetaxel link thing ester react with SDPP, detect taxol or Docetaxel link thingAfter ester has reacted, add octreotide acetate solution, obtain taxol or Docetaxel Octreotide conjugate (TM).
Taxol or Docetaxel link thing ester under the catalysis of SDPP with the Octreotide containing acetic acid and/or acetate notReaction, obtains taxol or Docetaxel Octreotide conjugate (TM).
In aforesaid operations, must carry out catalytic reaction with amine, can be tertiary amine for the amine of this reaction, be preferably three secondAmine.
In aforesaid operations, can regulate the mol ratio of taxol or Docetaxel link thing ester and Octreotide to obtain 1Than 1 taxol or Docetaxel Octreotide conjugate, 2 to 1 taxol or Docetaxel Octreotide conjugate.
In aforesaid operations, reaction temperature is controlled at-10～50 DEG C, is preferably 0～30 DEG C.
In aforesaid operations, taxol or Docetaxel link thing ester react in aprotic solvent and react with SDPP,Aprotic solvent can be acetonitrile, dimethyl formamide (DMF), DMI, dimethyl sulfoxide (DMSO) (DMSO), HMPA(HMPA), be preferably acetonitrile.
In aforesaid operations, the reaction that has octreotide acetate, Octreotide to participate in, use solvent is aprotic solvent, non-matterSub-solvent can be acetonitrile, dimethyl formamide (DMF), and DMI, dimethyl sulfoxide (DMSO) (DMSO), HMPA (HMPA),Be preferably dimethyl formamide (DMF).
The present invention is described the synthesis preparation method of each intermediate and conjugates by following examples. Embodiment is notRestriction the present invention, protection scope of the present invention is defined by the claims.
Embodiment 1:
By taxol 200mg(0.234mmol), succinic anhydride 300mg(3mmol) vacuum drying 5 hours, be dissolved in 5mlIn dry pyridine, 30 DEG C of stirring reaction 24h, decompression and solvent recovery is to dry, and residue stirs with 10ml frozen water, and after filtering, residue is moltenIn 10ml acetone, stir the lower 10ml of dropping water, filter and separate out solid, drying under reduced pressure obtains taxol succinate, yield 65%,Purity 96%, ESI-MS(m/z): 976[M+Na]+；992[M+K]+。
Embodiment 2:
By Docetaxel 200mg(0.248mmol), diethylene glycol (DEG) acid anhydride 348mg(3mmol) vacuum drying 5 hours, be dissolved inIn the dry pyridine of 5ml, 30 DEG C of stirring reaction 24h, decompression and solvent recovery is to dry, and residue stirs with 10ml frozen water, residual after filteringSlag is dissolved in 10ml acetone, stirs the lower 10ml of dropping water, filters and separates out solid, and drying under reduced pressure obtains Docetaxel diglycolic acidEster, yield 63%, purity 93%, ESI-MS(m/z): 946[M+Na]+。
Embodiment 3:
By taxol succinate 25mg(0.025mmol), SDPP30mg(0.086mmol), triethylamine 30mg(0.296mmol) be dissolved in 0.5ml anhydrous acetonitrile, stirred overnight at room temperature, after TLC detection reaction, Vacuum Concentration, by crude productMixed liquor dissolves in ethyl acetate, saturated common salt water washing, the dry rear solvent that reclaims obtains target product, ESI-MS(m/z):1052.15[M+H]+, do not need to be further purified, be directly used in next step reaction.
Embodiment 4:
Embodiment 3 products are dissolved in 3mlDMF, add octreotide acetate 20mg(0.020mmol) and triethylamine30mg(0.296mmol), 5 DEG C of reaction 24h, at AlltimaC18 post 22*250mm, 30min linear gradient elution, 30%BinA (A:5% acetonitrile/95% water/0.1%TFA; B:95% acetonitrile/5% water/0.1%TFA) to 90%B, collect about 10min main peak part,Freeze-drying obtains taxol Octreotide conjugate 23mg (0.012mmol), yield 60%, purity is 98%, ESI-MS(m/z): 1954[M+H]+。
Embodiment 5;
Docetaxel diethylene glycol (DEG) acid esters 60mg(0.065mmol), SDPP60mg(0.172mmol), triethylamine 60mg(0.592mmol) be dissolved in 1ml anhydrous acetonitrile, stirred overnight at room temperature, after TLC detection reaction, Vacuum Concentration, crude product is mixedClose liquid and dissolve in ethyl acetate, saturated common salt water washing, the dry rear solvent that reclaims obtains target product, does not need to be further purified, straightConnect for next step reaction.
Embodiment 6:
Embodiment 5 products are dissolved in 3mlDMF, add octreotide acetate 20mg(0.020mmol) and triethylamine60mg(0.592mmol), 5 DEG C of reaction 24h, at AlltimaC18 post 22*250mm, 30min linear gradient elution, 30%BinA (A:5% acetonitrile/95% water/0.1%TFA; B:95% acetonitrile/5% water/0.1%TFA) to 90%B, collect about 15min main peak part,Freeze-drying obtains two Docetaxel Octreotide conjugate 33mg (0.012mmol), yield 60%, and purity is 98%, ESI-MS(m/z）：2852[M+Na]+。
Above content is in conjunction with concrete preferred embodiment further description made for the present invention, can not assertSpecific embodiment of the invention is confined to these explanations. For general technical staff of the technical field of the invention,Do not depart under the prerequisite of the present invention's design, can also make some simple deduction or replace, all should be considered as belonging to of the present inventionProtection domain.
Claims (2)
1. a preparation method for taxol or Docetaxel Octreotide conjugate, it is characterized in that this preparation method comprise withLower step:
Step 1: in aprotic solvent, the acid of taxol-2 '-catenation sequence or Docetaxel-2 '-catenation sequence acid and hexicholBase N-succinimide phosphate SDPP obtains N-maloyl imines taxol-2 '-catenation sequence under the catalysis of tertiary amineEster or N-maloyl imines Docetaxel-2 '-catenation sequence ester;
Step 2: in aprotic solvent, N-maloyl imines taxol-2 '-catenation sequence ester or N-maloyl AsiaThe coupling under the catalysis of tertiary amine of amine Docetaxel-2 '-catenation sequence ester and octreotide acetate obtains taxol or polyenoid Japanese yewAlcohol Octreotide conjugate;
In described step 1, aprotic solvent is acetonitrile, and tertiary amine is triethylamine; Catenation sequence Linker is-CO-CH2-(X)n-CH2-CO-；
Wherein, X is O (CH2CH2OCH2CH2CH2NHCOCH2-)2,-CO-,-O-,-S-,-CH2-,-CHCH3-or-C (CH3)-; N is0 or 1,
In described step 2, described aprotic solvent is dimethyl formamide DMF, and tertiary amine is triethylamine,
In described step 2, N-maloyl imines taxol or Docetaxel catenation sequence ester and octreotide acetateWhen mol ratio is 1～1.5 to 1, primary product is single taxol or single Docetaxel Octreotide conjugate; N-maloylWhen imines taxol or Docetaxel catenation sequence ester are 2～5 to 1 with the mol ratio of octreotide acetate, primary product is twoTaxol or two Docetaxel Octreotide conjugates.
2. a preparation method for taxol or Docetaxel Octreotide conjugate, it is characterized in that this preparation method comprise withLower step:
Step a: octreotide acetate is dissolved in the water, removes acetate through pellicle or column chromatography and obtain after dry free difficult to understand bentPeptide;
Step b: in aprotic solvent, the Octreotide that will dissociate, SDPP, the acid of taxol-2 '-catenation sequence or Docetaxel-The acid of 2 '-catenation sequence mixes, and under tertiary amine catalytic, coupling obtains taxol or Docetaxel Octreotide conjugate;
In described step b, described aprotic solvent is dimethyl formamide DMF, and tertiary amine is triethylamine;
In described step b, the acid of taxol-2 '-catenation sequence or Docetaxel-2 '-catenation sequence acid and free OctreotideMol ratio while being 1～1.5 to 1, primary product is single taxol or single Docetaxel Octreotide conjugate; Taxol-2 '-Catenation sequence acid or Docetaxel-2 '-catenation sequence acid is 2～5 o'clock with the mol ratio of free Octreotide, and primary product is twoTaxol or two Docetaxel Octreotide conjugates.
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| WO2011124031A1 (en) * | 2010-04-08 | 2011-10-13 | 江苏天一时制药有限公司 | Polypeptide conjugate of paclitaxel or docetaxel |
Non-Patent Citations (2)
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| 奥曲肽紫杉醇偶联物靶向治疗小细胞肺癌的实验研究;王健 等;《山东大学学报（医学版）》;20110331;第49卷(第3期);全文 * |
| 紫杉醇奥曲肽偶合物对A549裸鼠移植瘤的靶向治疗研究;申洪昌 等;《中华医学杂志》;20080916;第88卷(第35期);全文 * |
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