CN103351424A - Preparation method of paclitaxel or docetaxel octreotide conjugate - Google Patents
Preparation method of paclitaxel or docetaxel octreotide conjugate Download PDFInfo
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- CN103351424A CN103351424A CN201310232603XA CN201310232603A CN103351424A CN 103351424 A CN103351424 A CN 103351424A CN 201310232603X A CN201310232603X A CN 201310232603XA CN 201310232603 A CN201310232603 A CN 201310232603A CN 103351424 A CN103351424 A CN 103351424A
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Abstract
The invention relates to a preparation method of a paclitaxel or docetaxel octreotide conjugate. The method comprises the steps that: 1, in an aprotic solvent, paclitaxel-2'-linker sequence acid or docetaxel-2'-acid linker sequence and diphenyl N-succinimidyl phosphate (SDPP) are subjected to the catalysis of tertiary amine, such that N-hydroxysuccinimide paclitaxel-2'-linker sequence ester or N-hydroxysuccinimide docetaxel-2'-linker sequence ester is obtained; 2, in an aprotic solvent, N-hydroxysuccinimide paclitaxel-2'-linker sequence ester or N-hydroxysuccinimide docetaxel-2'-linker sequence ester and octreotide are conjugated under the catalysis of tertiary amine, such that paclitaxel or docetaxel octreotide conjugate is obtained. The invention assists in solving problems of impossibility of purchasing octreotide resin compositions and expensive catalysts. The conjugate provided by the invention can be synthesized in large batches by using raw materials in the market and a cheap reagent diphenyl N-succinimidyl phosphate (SDPP).
Description
Technical field
The invention provides the synthetic method of the Sostatin conjugate of a kind of taxol or Docetaxel.Belong to the synthetic technical field of medicine.
Background technology
Somatostatin (SST) is a kind of neuropeptide hormone that is present in stomach mucous membrane, pancreas islet, gi tract nerve, posterior pituitary and the central nervous system, and it is confirmed to be can regulate primary processes such as secretion, cell fission, propagation and apoptosis.Sostatin (octreotide) is a kind of Sandostatin derivative of synthetic, and biological half-life is longer to the action spectrum of Somatostatin is similar for it, and has stronger more lasting effect and stronger selectivity.From nineteen eighty-three so far, many bibliographical informations treatment impact and the system evaluation of Sostatin for some diseases, it has been proved kinds of tumors such as neuroendocrine tumor, digestive tract tumor, mammary cancer and leukemia inhibited.Find that by practice Sostatin can be used for improving the untoward reaction of chemotherapy and the multiple symptom of patient with advanced cancer, is used to diagnosis or assisting therapy kinds of tumors disease.
Taxol and Docetaxel are the first-line drugs of present chemotherapy in ovarian cancer, but considerable ovarian cancer patients causes the chemotherapy failure because producing resistance, and the recurrent ovarian carcinoma result for the treatment of is very undesirable, existing bibliographical information Sostatin taxol is suppressed the synergism of non-small cell lung cancer cell, these achievements are impelled the exploitation Sostatin to transport some antitumor drugs (such as taxol) as a kind of specific carrier by the endocytosis of somatostatin receptor to enter tumour cell.
The Taiwan's scholars reported first activity of taxol Sostatin conjugate in tumour cell
[1]It adopts phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus (PyBOP) is catalyzer, the Sostatin reaction that taxol succinate and solid phase synthesis obtain, freeze-drying gets taxol Sostatin conjugate behind the resin purification that dissociates, the Sostatin resin complexes can not have been bought on market in this method, catalyst P yBOP is expensive, and this gives the synthetic of taxol Sostatin conjugate and uses and bring difficulty.
[1]Chun-Ming?Huang,Ying-Ta?Wu,Shui-Tein?Chen.Targeting?delivery?of?paclitaxel?into?tumor?cells?via?somatostatin?receptor?endocytosis[J].Chemistry&Biology,2000,7(7):453-461.
Summary of the invention
Technical problem: the Sostatin conjugate preparation method who the object of the invention is to carry a kind of taxol or Docetaxel, above-mentioned conjugate overcomes and to have bought in the market the Sostatin resin complexes and use an expensive catalyzer difficult problem, so that can adopt marketable material and cheap reagent phenylbenzene N-succinimide phosphoric acid ester (SDPP) to synthesize in a large number.
Technical scheme: the preparation method of taxol of the present invention or Docetaxel Sostatin conjugate may further comprise the steps:
Step 1: in aprotic solvent, taxol-2 '-catenation sequence acid 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 phenylbenzene N-succinimide phosphoric acid ester (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 Sostatin LAR coupling under the catalysis of tertiary amine obtain taxol or Docetaxel Sostatin conjugate.
In the described step 1, aprotic solvent is preferably acetonitrile, and tertiary amine is preferably triethylamine; Described catenation sequence Linker is-CO-CH
2-(X) n-CH
2-CO-;
Wherein, X is O (CH
2CH
2OCH
2CH
2CH
2NHCOCH
2-)
2,-CO-,-O-,-S-,-CH
2-,-CHCH
3-or-C (CH
3)-; N is 0 or 1,
In the described step 2, described aprotic solvent is preferably dimethyl formamide DMF, and tertiary amine is preferably triethylamine,
In the described step 2, when the mol ratio of N-maloyl imines taxol or Docetaxel catenation sequence ester and Sostatin LAR was 1～1.5 to 1, primary product was single taxol or single Docetaxel Sostatin conjugate; When the mol ratio of N-maloyl imines taxol or Docetaxel catenation sequence ester and Sostatin LAR was 2～5 to 1, primary product was two taxols or two Docetaxel Sostatin conjugates.
The mol ratio of described N-maloyl imines taxol or Docetaxel catenation sequence ester and Sostatin LAR is preferred 1.1 to 1, and primary product is single taxol or single Docetaxel Sostatin conjugate; When the mol ratio of N-maloyl imines taxol or Docetaxel catenation sequence ester and Sostatin LAR was preferably 2.2 to 1, primary product was two taxols or two Docetaxel Sostatin conjugates.
The preparation method of another kind of easy taxol or Docetaxel Sostatin conjugate may further comprise the steps:
Step a: Sostatin LAR is dissolved in the water, after semi-permeable membranes or column chromatography removal acetate drying, obtains free Sostatin;
Step b: in aprotic solvent, the Sostatin that will dissociate, SDPP, taxol-2 '-catenation sequence acid or Docetaxel-2 '-catenation sequence acid mixes, and coupling obtains taxol or Docetaxel Sostatin conjugate under tertiary amine catalytic.
Among the described step b, described aprotic solvent is preferably dimethyl formamide DMF, and tertiary amine is preferably triethylamine.
Among the described step b, when the mol ratio of taxol-2 '-catenation sequence acid or Docetaxel-2 '-catenation sequence acid and free Sostatin was 1～1.5 to 1, primary product was single taxol or single Docetaxel Sostatin conjugate; Taxol-2 '-catenation sequence acid or Docetaxel-2 '-catenation sequence acid is 2～5 o'clock with the mol ratio of free Sostatin, and primary product is two taxols or two Docetaxel Sostatin conjugates.
When the mol ratio of described taxol-2 '-catenation sequence acid or Docetaxel-2 '-catenation sequence acid and free Sostatin was preferably 1.1 to 1, primary product was single taxol or single Docetaxel Sostatin conjugate; Taxol-2 '-catenation sequence acid or Docetaxel-2 '-catenation sequence acid is preferably at 2.2 o'clock with the mol ratio of free Sostatin, and primary product is two taxols or two Docetaxel Sostatin conjugates.
Beneficial effect: the taxol that employing can extensively obtain, Docetaxel, Sostatin LAR and cheap reagent SDPP prepare above-mentioned conjugate, above-mentioned conjugate overcomes and to have bought in the market the Sostatin resin complexes and use an expensive catalyzer difficult problem, so that can adopt marketable material and cheap reagent phenylbenzene N-succinimide phosphoric acid ester (SDPP) to synthesize in a large number.
Embodiment
One, taxol, Docetaxel react with catenation sequence at 2 ', usually adopt into the mode of ester and react.
Can be used for linking agent of the present invention such as glycol ether acid anhydride, Succinic anhydried, Pyroglutaric acid, 3-carbonyl Pyroglutaric acid, 3-methylglutaric acid acid anhydride, 3,3 '-dimethylated pentanedioic acid acid anhydride etc.When taxol or Docetaxel and linking agent reaction, for different linking agents, the condition of ligation is basic identical.
Two, taxol or Docetaxel link thing ester reacts with Sostatin LAR under the SDPP effect.
Taxol or Docetaxel link thing ester at first react with SDPP, and adding Sostatin LAR solution after detection taxol or the reaction of Docetaxel link thing ester are finished obtains taxol or Docetaxel Sostatin conjugate (TM).
Taxol or Docetaxel link thing ester react with the Sostatin that does not contain acetic acid and/or acetate under the catalysis of SDPP, obtain taxol or Docetaxel Sostatin conjugate (TM).
In aforesaid operations, must come catalyzed reaction with amine, the amine that can be used for this reaction is tertiary amine, is preferably triethylamine.
In aforesaid operations, the mol ratio that can regulate taxol or Docetaxel link thing ester and Sostatin obtains 1 to 1 taxol or Docetaxel Sostatin conjugate, 2 to 1 taxol or Docetaxel Sostatin conjugate.
In aforesaid operations, temperature of reaction is controlled at-10～50 ℃, is preferably 0～30 ℃.
In aforesaid operations, taxol or Docetaxel link thing ester and SDPP reaction are reacted in aprotic solvent, and aprotic solvent can be acetonitrile, dimethyl formamide (DMF), DMI, dimethyl sulfoxide (DMSO) (DMSO), HMPA (HMPA) is preferably acetonitrile.
In aforesaid operations, the reaction that has Sostatin LAR, Sostatin to participate in, use solvent to be aprotic solvent, aprotic solvent can be acetonitrile, dimethyl formamide (DMF), DMI, dimethyl sulfoxide (DMSO) (DMSO), HMPA (HMPA) is preferably dimethyl formamide (DMF).
The present invention is described by the synthesis preparation method of following examples to each intermediate and conjugates.Embodiment does not limit the present invention, and protection scope of the present invention is defined by the claims.
Embodiment 1:
With taxol 200mg(0.234mmol), Succinic anhydried 300mg(3mmol) vacuum-drying 5 hours, be dissolved in the pyridine of 5ml drying, 30 ℃ of stirring reaction 24h, decompression and solvent recovery is to doing, residue stirs with the 10ml frozen water, residue is dissolved in 10ml acetone after filtering, and stirs the lower 10ml of dropping water, filters and separates out solid, drying under reduced pressure obtains the taxol succinate, yield 65%, purity 96%, ESI-MS(m/z): 976[M+Na]
+992[M+K]
+
Embodiment 2:
With Docetaxel 200mg(0.248mmol), glycol ether acid anhydride 348mg(3mmol) vacuum-drying 5 hours, be dissolved in the pyridine of 5ml drying, 30 ℃ of stirring reaction 24h, decompression and solvent recovery is to doing, residue stirs with the 10ml frozen water, residue is dissolved in 10ml acetone after filtering, and stirs the lower 10ml of dropping water, filters and separates out solid, drying under reduced pressure obtains Docetaxel glycol ether acid esters, yield 63%, purity 93%, ESI-MS(m/z): 946[M+Na]
+
Embodiment 3:
With taxol succinate 25mg(0.025mmol), SDPP30mg(0.086mmol), triethylamine 30mg(0.296mmol) be dissolved in the 0.5ml anhydrous acetonitrile, stirred overnight at room temperature, after the TLC detection reaction is complete, vacuum concentration, the crude product mixed solution is dissolved in ethyl acetate, the saturated common salt water washing, the dry rear solvent that reclaims gets 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 among the 3ml DMF, add Sostatin LAR 20mg(0.020mmol) and triethylamine 30mg(0.296mmol), 5 ℃ of reaction 24h are at Alltima C18 post 22*250mm, the 30min linear gradient elution, 30%B in A (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 Sostatin conjugate 23mg (0.012mmol), yield 60%, purity is 98%, ESI-MS(m/z): 1954[M+H]
+
Embodiment 5;
Docetaxel glycol ether acid esters 60mg(0.065mmol), SDPP60mg(0.172mmol), triethylamine 60mg(0.592mmol) be dissolved in the 1ml anhydrous acetonitrile, stirred overnight at room temperature, after the TLC detection reaction is complete, vacuum concentration, the crude product mixed solution is dissolved in ethyl acetate, the saturated common salt water washing, the dry rear solvent that reclaims gets target product, do not need to be further purified, be directly used in next step reaction.
Embodiment 6:
Embodiment 5 products are dissolved among the 3ml DMF, add Sostatin LAR 20mg(0.020mmol) and triethylamine 60mg(0.592mmol), 5 ℃ of reaction 24h are at Alltima C18 post 22*250mm, the 30min linear gradient elution, 30%B in A (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 Sostatin conjugate 33mg (0.012mmol), yield 60%, purity is 98%, ESI-MS(m/z): 2852[M+Na]
+
Above content is the further description of the present invention being done in conjunction with concrete preferred implementation, can not assert that implementation of the present invention is confined to these explanations.For the general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, can also make some simple deduction or replace, all should be considered as belonging to protection scope of the present invention.
Claims (9)
1. the preparation method of a taxol or Docetaxel Sostatin conjugate is characterized in that this preparation method may further comprise the steps:
Step 1: in aprotic solvent, taxol-2 '-catenation sequence acid 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 phenylbenzene N-succinimide phosphoric acid ester 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 Sostatin LAR coupling under the catalysis of tertiary amine obtain taxol or Docetaxel Sostatin conjugate.
2. the preparation method of a kind of taxol according to claim 1 or Docetaxel Sostatin conjugate is characterized in that aprotic solvent is preferably acetonitrile in the described step 1, and tertiary amine is preferably triethylamine; Described catenation sequence Linker is-CO-CH
2-(X) n-CH
2-CO-;
Wherein, X is O (CH
2CH
2OCH
2CH
2CH
2NHCOCH
2-)
2,-CO-,-O-,-S-,-CH
2-,-CHCH
3-or-C (CH
3)-; N is 0 or 1,
3. the preparation method of a kind of taxol according to claim 1 or Docetaxel Sostatin conjugate is characterized in that in the described step 2, described aprotic solvent is preferably dimethyl formamide DMF, and tertiary amine is preferably triethylamine,
4. the preparation method of a kind of taxol according to claim 1 or Docetaxel Sostatin conjugate, it is characterized in that in the described step 2, when the mol ratio of N-maloyl imines taxol or Docetaxel catenation sequence ester and Sostatin LAR was 1～1.5 to 1, primary product was single taxol or single Docetaxel Sostatin conjugate; When the mol ratio of N-maloyl imines taxol or Docetaxel catenation sequence ester and Sostatin LAR was 2～5 to 1, primary product was two taxols or two Docetaxel Sostatin conjugates.
5. the preparation method of a kind of taxol according to claim 4 or Docetaxel Sostatin conjugate, the mol ratio that it is characterized in that described N-maloyl imines taxol or Docetaxel catenation sequence ester and Sostatin LAR is preferred 1.1 to 1, and primary product is single taxol or single Docetaxel Sostatin conjugate; When the mol ratio of N-maloyl imines taxol or Docetaxel catenation sequence ester and Sostatin LAR was preferably 2.2 to 1, primary product was two taxols or two Docetaxel Sostatin conjugates.
6. the preparation method of a taxol or Docetaxel Sostatin conjugate is characterized in that this preparation method may further comprise the steps:
Step a: Sostatin LAR is dissolved in the water, after semi-permeable membranes or column chromatography removal acetate drying, obtains free Sostatin;
Step b: in aprotic solvent, the Sostatin that will dissociate, SDPP, taxol-2 '-catenation sequence acid or Docetaxel-2 '-catenation sequence acid mixes, and coupling obtains taxol or Docetaxel Sostatin conjugate under tertiary amine catalytic.
7. the preparation method of a kind of taxol according to claim 6 or Docetaxel Sostatin conjugate is characterized in that among the described step b, described aprotic solvent is preferably dimethyl formamide DMF, and tertiary amine is preferably triethylamine.
8. the preparation method of a kind of taxol according to claim 6 or Docetaxel Sostatin conjugate, it is characterized in that among the described step b, when the mol ratio of taxol-2 '-catenation sequence acid or Docetaxel-2 '-catenation sequence acid and free Sostatin was 1～1.5 to 1, primary product was single taxol or single Docetaxel Sostatin conjugate; Taxol-2 '-catenation sequence acid or Docetaxel-2 '-catenation sequence acid is 2～5 o'clock with the mol ratio of free Sostatin, and primary product is two taxols or two Docetaxel Sostatin conjugates.
9. the preparation method of a kind of taxol according to claim 8 or Docetaxel Sostatin conjugate, when the mol ratio that it is characterized in that described taxol-2 '-catenation sequence acid or Docetaxel-2 '-catenation sequence acid and free Sostatin was preferably 1.1 to 1, primary product was single taxol or single Docetaxel Sostatin conjugate; Taxol-2 '-catenation sequence acid or Docetaxel-2 '-catenation sequence acid is preferably at 2.2 o'clock with the mol ratio of free Sostatin, and primary product is two taxols or two Docetaxel Sostatin conjugates.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105233298A (en) * | 2015-09-18 | 2016-01-13 | 东南大学 | Paclitaxel phospholipid compound and drug combination and application thereof |
Citations (2)
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|---|---|---|---|---|
| US20100305030A1 (en) * | 2007-11-27 | 2010-12-02 | Centre National De La Recherche Scientifique | Nanoparticles of therapeutic agents having low water solubility |
| 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 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100305030A1 (en) * | 2007-11-27 | 2010-12-02 | Centre National De La Recherche Scientifique | Nanoparticles of therapeutic agents having low water solubility |
| 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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| 王健 等: "奥曲肽紫杉醇偶联物靶向治疗小细胞肺癌的实验研究", 《山东大学学报（医学版）》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105233298A (en) * | 2015-09-18 | 2016-01-13 | 东南大学 | Paclitaxel phospholipid compound and drug combination and application thereof |
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