CN101033216A - Oxazolidine compound for synthesizing taxone pharmaceutical side-chain and preparation method thereof - Google Patents
Oxazolidine compound for synthesizing taxone pharmaceutical side-chain and preparation method thereof Download PDFInfo
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Abstract
This invention relates to a method for preparing oxazolidine side chain ester of taxanes kind medicines with chiral mellow such as natural menthol and synthesized chiral mellows, which first of all esterifies natural or synthesized chiral mellows with acyl chloride and then shrink with benzaldehyde under a certain condition to get a chiral epoxy compound, which is synthesized in several times to get the product of oxazolidine side chain ester for preparing taxanes kind medicines.
Description
The technical field this patent is about being used to prepare the technology of taxol and docetaxel De oxazolidine side chain series ester and preparation method thereof, be starting raw material about the chiral alcohol that utilizes chirality natural alcohol or synthetic exactly specifically, induce synthetic taxol and docetaxel De oxazolidine side chain series ester and preparation method thereof of preparing of chipal compounds.
Technical background
(or Docetaxel Docetaxel) is two important members in the bearing taxanes family, also is the most effective two kinds of medicines of treatment cancer for taxol (Taxol) and docetaxel.Taxol is a kind of crude substance with highly effective antineoplastic activity that extracts from the Chinese yew genus plants the inside, docetaxel is that French Rhone-Poulenc Rorer and French national natural science center were the parent nucleus skeleton in 1985 with 10-DAB, be synthesized by semisynthetic method, be the representative of s-generation taxanes anticarcinogen, its cytotoxicity is identical with taxol.
Because the taxol and the Docetaxel market requirement constantly increase, the research of taxone is a focus always.At present the source of taxol mainly is a plant extract, semi-synthetic etc., and it is complete synthesis because step is oversize, and yield is low, is difficult to carry out suitability for industrialized production.Docetaxel mainly is to be basic parent nucleus skeleton by 10-DAB, and is semi-synthetic with chemical process.
The semi-synthetic of taxol and Docetaxel roughly can be divided three parts: side chain synthetic; The protection of 10-DAB and 10 last acylation reactions thereof; The 10-DAB after the protection and the esterification of side chain and last esterification products deprotection.
At present taxol and Docetaxel side chain mainly contain and contain the lactan tetra-atomic ring with the oxazolidine five-ring, and Chinese patent CN1428337A has just protected the synthetic of taxol C-13 side chain precursor; Eur Pat ApplEP 400971, TeTrahedron, 1992,48 (34): it is synthetic that 6985-7012 has also introduced relevant lactan tetra-atomic ring side chain; Tetrahedron Lett, 1992,33 (36): 5185-5188, TetrahedronLett, 1994,35 (1): 105-108, and French Luo Na-Blang Crow Lai Er company applies for a patent CN1087905 etc. in China and reported that the five-ring knot structure oxazolidine side-chain acid of taxol and docetaxel is synthetic, different with synthetic route of the present invention or intermediate.The present invention is easy to suitability for industrialized production than patent and the literature method that other contains five-membered ring Jie Gou oxazolidine side chain, than lactan tetra-atomic ring side chain patent and literature method bigger cost advantage is arranged.In formula (I), R has reported literature to see Angew ChemInt Ed Engl, 1996,35 (15) during for phenyl: 1723-1725, but its synthetic route and ours is complete different.
The present invention is mainly used in preparation taxol and docetaxel De oxazolidine side chain series ester and preparation method thereof.
R is menthol or other chiral alcohol derivatives in the formula, R
*Be phenyl or tert.-butoxy; Work as R
*During for phenyl, this side chain is used for the preparation of taxol; R
*During for tert.-butoxy, this side chain is used for the preparation of Docetaxel.
Embodiment
Embodiment 1
The preparation of Mono Chloro Acetic Acid (-) menthol ester (II)
In exsiccant 2000mL there-necked flask, add 313g (-) menthol, mechanical stirring is installed, prolong, the hydrogen chloride gas absorption unit, the oil bath heating adds an amount of chloroacetyl chloride.Add the back that finishes and continue to stir 1 hour under this temperature, reaction solution adds 250mL95% ethanol, stirs, and cooling crystallization, filtration drying obtain the 441g white crystal.[a]
20 D-80.9°(c＝0.8，CHCl
3)
Nucleus magnetic hydrogen spectrum 400MHz
1HNMR (CDCl
3) δ ppm:0.76 (3H, d, CH
3); 0.88 (1H, CH); 0.90 (3H, d, CH
3);
0.91(3H，d，CH)；1.03(1H，CH)；1.06(1H，CH)；1.41(1H，CH)；1.52(1H，CH)；
1.68(2H，d，CH
2)；1.84(1H，CH)；2.01(1H，d，CH)；4.02(2H，s，ClCH
2)；4.75(1H，OCH)；
Embodiment 2
(2R, 3S)-preparation of beta-phenyl glycidic acid (-) menthyl ester compound (III)
Add 144gNaH in the 10L there-necked flask, 5LTHF stirs cooling; Add 0.3Kg phenyl aldehyde and 0.6kg compound (II), reinforced finishing is stirred to reaction and finishes.
Add glacial acetic acid and continue to stir, filter, add ethyl acetate, use saturated sodium bicarbonate solution more respectively, organic carbonate hydrogen sodium drying is isolated in the saturated common salt water washing.Recrystallization after the solvent evaporated obtains 255g compound (III).[a]
20 D-137.9°(c＝0.8，CHCl
3)
Nucleus magnetic hydrogen spectrum 400MHz
1HNMR (CDCl
3) δ ppm:0.78 (3H, d, CH
3); 0.86 (1H, CH); 0.91 (3H, d, CH
3); 0.95 (3H, d, CH
3); 1.09 (2H, CH
2); 1.4-1.5 (2H, CH
2); 1.69 (2H, d, CH
2); 1.86 (1H, CH); 2.06 (1H, d, CH); 3.50 (1H, s, CH); 4.06 (1H, s, CH); 4.82 (1H, dt, OCH); 7.3-7.5 (5H, m, Ar-H);
Embodiment 3
(2R, 3R)-preparation of 3-bromo-2-hydroxyl-phenylpropionic acid (-) menthol ester compound (IV)
In the 1L there-necked flask, and adding 95g (2R, 3S)-beta-phenyl glycidic acid (-) menthyl ester compound (III), the 150mL anhydrous diethyl ether stirs the cooling cooling, adds the MgBr2 diethyl ether solution, reacts 1 hour, and reaction finishes, dropping 1N hydrochloric acid.
Reaction solution is told organic layer, and the water layer ether extraction merges organic phase, uses the saturated common salt water washing, anhydrous magnesium sulfate drying organic phase, evaporate to dryness obtain yellow dope, with ether and sherwood oil recrystallization, obtain the 78g white crystal, (2R, 3S)-3-bromo-2-hydroxyl-phenylpropionic acid (-) menthol ester.[a]
20 D-121.6°(c＝0.8，CHCl
3)
Nucleus magnetic hydrogen spectrum 400MHz
1HNMR (CDCl
3) δ ppm:0.73 (3H, d, CH
3); 0.84 (1H, CH); 0.88 (6H, d, CH
3); 0.98 (1H, CH); 1.01 (1H, CH); 1.41 (2H, CH
2); 1.68 (2H, d, CH
2); 1.75 (1H, CH); 1.91 (1H, d, CH); 3.0 (1H, d, OH); 4.65 (1H, dt, OCH); 4.69 (1H, OCH); 5.29 (1H, d, BrCH); 7.3-7.5 (5H, m, Ar-H);
Embodiment 4
(2R, 3S)-preparation of 3-nitrine-2-hydroxyl-phenylpropionic acid (-) menthol ester compound (IV)
Add (2R in the 10L there-necked flask, 3S)-3-bromo-2-hydroxyl-phenylpropionic acid (-) menthol ester 488g, excessive sodium azide, 3LDMF, add an amount of 15-hat-5 under the mechanical stirring, add the excessive acetic acid ethyl ester after reaction finishes, silicagel column filters fast, obtain ethyl acetate solution through saturated common salt water washing, anhydrous magnesium sulfate drying.Decompression steams solvent, obtains thick thing ether and sherwood oil recrystallization.Obtain 274g compound (IV) after the drying.[a]
20 D+115.6°(c＝1.0，CHCl
3)
Nucleus magnetic hydrogen spectrum 400MHz
1HNMR (CDCl
3) δ ppm:0.80 (3H, d, CH
3); 0.88 (1H, CH); 0.93 (6H, d, CH
3); 1.06 (2H, CH
2); 1.45 (1H, CH
2); 1.72 (2H, d, CH
2); 1.83 (1H, CH); 2.06 (1H, d, CH); 3.12 (1H, d, OH); 4.33 (1H, d, NCH); 4.83 (1H, m, OCH); 4.87 (1H, d, OCH);
7.3-7.5(5H，m，Ar-H)；
Embodiment 5
(2R, 3S)-preparation (VII) of 3-amino-2-formyl hydroxy base phenylpropionic acid (-) menthol ester compound
In 1L hydrogenation instrument, add 500mL ethyl acetate and 1gPd/C, (the 2R that adds 50g, 3S)-3-nitrine-2-hydroxyl-phenylpropionic acid (-) menthol ester compound (IV) stirring, logical hydrogen, pressure keeps 3.8MP, and reaction finishes and removes by filter Pd/C, concentrate ethyl acetate and recrystallization, obtain the 43g white crystal.[a]
20 D-62.5°(c＝0.7，CHCl
3)
Nucleus magnetic hydrogen spectrum 400MHz
1HNMR (CDCl
3) δ ppm:0.72 (3H, d, CH
3); 0.82 (1H, CH); 0.86 (3H, d, CH
3); 0.90 (3H, d, CH
3); 1.02 (1H, CH); 1.04 (1H, CH); 1.41 (1H, CH); 1.47 (1H, CH);
1.71(2H，d，CH
2)；1.74(1H，CH)；2.23(1H，d，CH)；2.32(1H，bs，NH
2)；4.33(1H，d，NCH)；4.27(2H，d，CH)；4.76(1H，dt，OCH)；7.3-7.5(5H，m，Ar-H)；
Embodiment 6 (1)
(2R, 3S) preparation of 2-hydroxyl-uncle's 3-fourth oxygen formamido group-phenylpropionic acid (-) menthol ester compound
Add 9.2g3-amino-2-formyl hydroxy base phenylpropionic acid (-) menthol ester, 50mL ethyl acetate, 3.6gNaHCO in the 100mL there-necked flask
3, 7.2g (Boc)
2O, stirring at room is to reacting completely.With saturated sodium bicarbonate and saturated common salt water washing, use anhydrous MgSO again
4Dry.Steam solvent to the greatest extent, obtain the 14.2g crude product.The recrystallization after drying obtains the 11.8g white crystal.[a]
20 D-27.2°(c＝0.7，CHCl
3)
Nucleus magnetic hydrogen spectrum 400MHz
1HNMR (CDCl
3) δ ppm:0.74 (3H, d, CH
3); 0.92 (6H, CH
3); 1.05 (2H, d, CH
2); 1.25 (1H, CH); 1.40 (9H, s, CH
3); 1.46 (2H, CH
2); 1.51 (2H, CH
2); 1.95 (1H, CH); 2.01 (1H, d, CH); 3.16 (1H, bs, OH); 4.40 (1H, s, OCH); 4.82 (1H, dt, OCH); 5.14 (1H, d, CNH, J=8.5Hz); 5,45 (1H, NCH, J=8.5Hz); 7.2-7.5 (8H, m, Ar-H);
Embodiment 6 (2)
(2R, 3S) preparation of 2-benzamido-3-hydroxyl-phenylpropionic acid (-) menthol ester compound
Add 6.4g3-amino-2-formyl hydroxy base phenylpropionic acid (-) menthol ester, 50mL ethyl acetate, 2.0gNaHCO in the 100mL there-necked flask
3, the 3.9g Benzoyl chloride, stirring at room reacts completely.With saturated sodium bicarbonate and saturated common salt water washing several, use anhydrous MgSO
4Dry.Solvent evaporated re-crystallizing in ethyl acetate, drying obtain the 7.8g white crystal.[a]
20 D-54.0°(c＝O.7，CHCl
3)
Nucleus magnetic hydrogen spectrum 400MHz
1HNMR (CDCl
3) δ ppm:0.53 (3H, d, CH
3); 0.76 (3H, d, CH
3); 0.88 (1H, CH); 0.91 (3H, d, CH
3); 1.05 (2H, CH
2); 1.46 (2H, CH
2); 1.67 (2H, CH
2); 1.80 (1H, CH); 1.96 (1H, d, CH); 3.12 (1H, bs, OH); 4.56 (1H, s, OCH); 4.84 (1H, dt, OCH); 5.69 (1H, NCH, J=8.7Hz); 7,11 (1H, d, CNH, J=8.7Hz); 7.2-7.5 (8H, m, Ar-H); 7.77 (2H, d, Ar-H);
Embodiment 7 (1)
Uncle's N-fourth oxygen formyl radical-2, the preparation of 2-dimethyl-4-phenyl-5-Bao lotus Chun Zhi oxazolidine compound
In the 100mL there-necked flask, add 5g embodiment 6 (1) products, 1.5gPPTS, excessive 2-methoxyl group propylene, 30mL toluene, the oil bath heating is back to reaction and finishes.Cool to room temperature is used saturated sodium bicarbonate and saturated common salt water washing respectively, anhydrous magnesium sulfate drying.Filter the back and steam solvent to the greatest extent, obtain oily matter 4.6g.
Nucleus magnetic hydrogen spectrum 400MHz
1HNMR (CDCl
3) δ ppm:0.75 (3H, d, CH
3); 0.88 (3H, d, CH
3); 0.91 (3H, d, CH
3); 1.00 (1H, CH); 1.17 (9H, Boc-CH
3); 1.25 (2H, CH
2); 1.40 (2H, CH
2); 1.67 (2H, CH
2); 1.69 (3H, s, CH
3); 1.76 (1H, CH), 1.80 (3H, s, CH
3); 2.05 (1H, d, CH); 4.46 (1H, d, OCH); 4.80 (1H, dt, OCH); 5.12 (1H, NCH); 7.3-7.5 (5H, m, Ar-H);
Embodiment 7 (2)
N-benzoyl-2, the preparation of 2-dimethyl-4-phenyl-5-Bao lotus Chun Zhi oxazolidine compound
In the 100mL there-necked flask, add 5g embodiment 6 (2) products, 1.5gPPTS, excessive 2-methoxyl group propylene, 30mL toluene, the oil bath heating is back to reaction and finishes.Cool to room temperature is used saturated sodium bicarbonate and saturated common salt water washing respectively, anhydrous magnesium sulfate drying.Filter the back and steam solvent to the greatest extent, obtain oily matter 4.2g.
Nucleus magnetic hydrogen spectrum 400MHz
1HNMR (CDCl
3) δ ppm:0.68 (3H, d, CH
3); 0.78 (1H, d, CH
3); 0.85 (1H, CH); 0.90 (3H, CH
3); 1.25 (2H, CH
2); 1.40 (2H, CH
2); 1.67 (2H, CH
2); 1.69 (3H, s, CH
3); 1.76 (1H, CH), 1.80 (3H, s, CH
3); 2.05 (1H, d, CH); 4.46 (1H, d, OCH); 4.80 (1H, dt, OCH); 5.12 (1H, NCH); 7.3-7.5 (5H, m, Ar-H).
Claims (9)
1. oxazolidine side chain acid esters that is used to prepare taxol and docetaxel, its chemical formula such as figure below:
R is menthol or other chiral alcohol derivatives in the formula, R
*Be phenyl or tert.-butoxy.
2. the method for a synthesizing series compound (I).
3. by claim 2, the starting raw material that it is characterized in that synthetic this compound is natural (-) chiral alcohol or synthetic (-) chiral alcohol etc., preferred (-) menthol; Its initial chiral alcohol and bromoacetyl chloride or chloroacetyl chloride react, and the temperature of reaction is 90 ℃-110 ℃ and prepares chiral ester compound (II), with 80%-99% ethanol crystallization.R is the chirality alkane group, and X is Br, Cl;
4. by claim 2, compound (II) and phenyl aldehyde condensation under the highly basic effect, temperature of reaction for-30 ℃-30 ℃ prepare (2R, 3S)-beta-phenyl glycidic acid (-) chiral ester compound (III);
5. by claim 2, compound (III) is at MgBr
2Open bromine in ring in the diethyl ether solution, temperature of reaction is-60 ℃-0 ℃, prepare (2R, 3S)-3-bromo-2-hydroxyl-phenylpropionic acid R chiral ester compound (IV);
6. by claim 2, compound (IV) under crown ether catalysis, its preferably crown ether use NaN with 18-hat-6 or 15-hat-5
3Carry out substitution reaction, temperature of reaction obtains compound (VI) for-30 ℃-60 ℃;
7. by claim 2, compound (VI) is at Pd/C, PtO
2Under the catalysis, be reduced with hydrogen to compound (VII); Temperature of reaction is 0 ℃-60 ℃;
8. by claim 2, compound (VII) and acid anhydrides be (Boc) for example
2The for example Benzoyl chloride reaction of O or acyl chlorides prepares compound (VIII);
Wherein, R
*Be phenyl or tert.-butoxy.
9. by claim 2, compound (VIII) is in toluene solvant, and with PPTS, tosilate is a catalyzer, and with 2-methoxyl group propylene or 2,2-dimethoxy propane generation cyclization obtains the oxazolidine compound (IX) of 5 yuan of rings;
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| CN106117058A (en) * | 2016-06-30 | 2016-11-16 | 山东诚汇双达药业有限公司 | A kind of process for purification of monoxone menthol ester |
| WO2017006573A1 (en) * | 2015-07-07 | 2017-01-12 | 忠勝 萬代 | Method for producing side chain precursor of paclitaxel and docetaxel |
| CN111100026A (en) * | 2019-12-30 | 2020-05-05 | 重庆市碚圣医药科技股份有限公司 | Preparation method of taxol oxazole ring side chain intermediate |
| CN114621985A (en) * | 2020-12-10 | 2022-06-14 | 湖南引航生物科技有限公司 | Method for synthesizing paclitaxel side chain by biological catalysis |
| CN114621986A (en) * | 2020-12-10 | 2022-06-14 | 湖南引航生物科技有限公司 | Method for biosynthesis of paclitaxel side chain |
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| WO2017006573A1 (en) * | 2015-07-07 | 2017-01-12 | 忠勝 萬代 | Method for producing side chain precursor of paclitaxel and docetaxel |
| JPWO2017006573A1 (en) * | 2015-07-07 | 2017-08-17 | 忠勝 萬代 | Method for producing side chain precursor of paclitaxel and docetaxel |
| CN107848990A (en) * | 2015-07-07 | 2018-03-27 | 万代忠胜 | The manufacture method of the side chain precursor of taxol and Docetaxel |
| CN106117058A (en) * | 2016-06-30 | 2016-11-16 | 山东诚汇双达药业有限公司 | A kind of process for purification of monoxone menthol ester |
| CN111100026A (en) * | 2019-12-30 | 2020-05-05 | 重庆市碚圣医药科技股份有限公司 | Preparation method of taxol oxazole ring side chain intermediate |
| CN114621985A (en) * | 2020-12-10 | 2022-06-14 | 湖南引航生物科技有限公司 | Method for synthesizing paclitaxel side chain by biological catalysis |
| CN114621986A (en) * | 2020-12-10 | 2022-06-14 | 湖南引航生物科技有限公司 | Method for biosynthesis of paclitaxel side chain |
| CN114621986B (en) * | 2020-12-10 | 2024-04-12 | 湖南引航生物科技有限公司 | Method for biosynthesis of taxol side chain |
| CN114621985B (en) * | 2020-12-10 | 2024-04-16 | 湖南引航生物科技有限公司 | Method for synthesizing taxol side chain by biocatalysis |
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