CN103864730B - The preparation technology of Telbivudine key intermediate - Google Patents
The preparation technology of Telbivudine key intermediate Download PDFInfo
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- CN103864730B CN103864730B CN201210549840.4A CN201210549840A CN103864730B CN 103864730 B CN103864730 B CN 103864730B CN 201210549840 A CN201210549840 A CN 201210549840A CN 103864730 B CN103864730 B CN 103864730B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses one and prepare Telbivudine important intermediate Hoffer ˊ s? the novel process of chlorosugar, be characterized in known compound (R)-3-((S)-2, 2-dimethyl-1, 3-dioxolane-4-base)-3-hydroxypropionitrile (compound 2) is starting raw material, through hydroxyl protection, reduction, open loop under acidic conditions, the aldol condensation again step such as chloro obtains target compound---Hoffer ˊ s? chlorosugar, i.e. 1-chloro-3, two-the O-of 5-is to toluyl-2-deoxidation-L-ribose, this route total recovery 42%, product purity > 98.8%.
Description
Technical field
The invention belongs to field of medicine and chemical technology, particularly relate to a kind of novel process preparing Telbivudine key intermediate Hoffer'schlorosugar.
Background technology
Telbivudine, the thymidine analog of a kind of synthesis of being developed by Novartis Co., Ltd, has the activity suppressing by force and optionally HBV DNA polysaccharase, gets permission listing in the U.S., European Union, China etc. at present.As the key intermediate Hoffer'schlorosugar in this kind synthetic route; i.e. 1-chloro-3; two-the O-of 5-is to toluyl-2-deoxidation-L-ribose (shown in following chemical formula); although have research both at home and abroad and produce; but because its synthesis technique difficulty is large, production cost is high; and industrialization is difficult, therefore market demand cannot be met far away.
At present, the domestic preparation about this intermediate, adopts 2-deoxyribosyl to be starting raw material usually; methylate through hydrogenchloride/methanol solution and obtain α; the 1-position methoxy substitution ribose of β-type mixing, then with to toluyl protection alcoholic extract hydroxyl group, after by methoxychlor generation target product.Although this route yield can reach more than 40%, its raw materials used 2-deoxyribosyl selling at exorbitant prices, causes product cost to remain high, is unfavorable for market competition.
Therefore, develop a preparation technology being really suitable for the Hoffer'schlorosugar of suitability for industrialized production to be even more important.
Summary of the invention
The invention provides a kind of novel process of synthesizing the important intermediate Hoffer'schlorosugar of Telbivudine, this technique has the features such as yield is high, cost is low, environmental pollution is little, is a kind of novel process being suitable for industrialized production.
The object of this invention is to provide the novel process of the important intermediate Hoffer'schlorosugar of a synthesis Telbivudine.
In embodiments of the invention, the invention provides a kind of novel process preparing Hoffer'schlorosugar, comprise the steps:
(note: Tol represents toluyl)
A) by compound 2 under organic solvent and catalyzer exist, with to toluyl protective material protection hydroxyl, obtain compound 3;
B) under reductive agent effect, reducing compound 3, obtains compound 4;
C) compound 4 open loop in acid condition, the pH value of rear adjustment reaction solution is 8.0-11.0, obtains compound 5;
D) by compound 5 under solvent and catalyzer exist, with to toluyl protective material protection hydroxyl, obtain compound 6;
E) compound 6 and dry hydrogen chloride react, and obtain compound 1.
In a kind of preferred embodiment of the present invention, preferably, step a) described in organic solvent be selected from methylene dichloride, chloroform, acetonitrile or wherein the two mixture; Described catalyzer is selected from ammoniacal liquor, triethylamine, sodium bicarbonate, sodium carbonate, pyridine, more preferably, is selected from triethylamine, sodium bicarbonate; Described is selected from Butyltriphenylphosphonium chloride, paratolunitrile acid anhydride to toluyl protective material.
In a kind of preferred embodiment of the present invention, preferably, step b) described in reductive agent be selected from SnCl
2, LiAlH
4, LiAlH (OEt)
3, LiAlH (NR
2)
3, DIBAL-H, when reductive agent is selected from LiAlH (NR
2)
3time, R is the straight or branched alkyl of C1-C4, and preferably, described reductive agent is selected from SnCl
2or LiAlH
4.
In a kind of preferred embodiment of the present invention, preferably, step c) described in acidic conditions, refer to and to react under hydrochloric acid soln, sulphuric acid soln existence condition, most preferably, react under the aqueous hydrochloric acid of 10 ~ 23 volume % or the aqueous sulfuric acid existence condition of 5 ~ 75 volume %.
In a kind of preferred embodiment of the present invention, step c) comprising: compound 4 is reacted 30-100min in acid condition, preferably, reaction 30-50min, regulates the pH value of reaction solution for 8.0-9.0 with pH adjusting agent, organic solvent extraction, get organic layer, concentrating under reduced pressure, obtain compound 5.
In a kind of preferred embodiment of the present invention, preferably, step c) described in pH adjusting agent be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, salt of wormwood, saleratus, triethylamine, pyridine, most preferably, be selected from triethylamine, sodium bicarbonate.In a kind of preferred embodiment of the present invention, step c) carry out under methyl alcohol does solvent condition.In a kind of preferred embodiment of the present invention, preferably, step c) and steps d) described in organic solvent be selected from methylene dichloride, chloroform, acetonitrile or wherein the two mixture.
In a kind of preferred embodiment of the present invention, preferably, steps d) described in compound (5) be 1.0:0.85 ~ 1.0 with the mol ratio fed intake to toluyl protective material.
In a kind of preferred embodiment of the present invention, preferably, steps d) described in catalyzer be selected from ammoniacal liquor, triethylamine, sodium bicarbonate, sodium carbonate, pyridine, preferred triethylamine, sodium bicarbonate; Described p-toluenesulfonyl protective material is selected from Butyltriphenylphosphonium chloride, paratolunitrile acid anhydride.
In a kind of preferred embodiment of the present invention, preferably, step e) at anhydrous condition, carry out under making solvent with methyl alcohol.
More electedly, the invention provides the synthesis technique of a kind of Telbivudine key intermediate Hoffer'schlorosugar, comprise the steps:
A). by compound 2 through to toluyl protection, obtain compound 3;
B). by compound 3 with SnCl
2or LiAlH
4reduction, obtains compound 4;
C). compound 4 reacts 30-50min under the aqueous hydrochloric acid of 10-23 volume % or the aqueous sulfuric acid existence condition of 5-75 volume %, regulate the pH value of reaction solution to 8.0-9.0 with triethylamine or sodium bicarbonate, extract with methylene dichloride or chloroform or acetonitrile, get organic layer, concentrating under reduced pressure, obtains compound 5;
D). compound 5, through to toluyl protection, obtains compound 6;
E). compound 6 reacts in the methanol solution of dry hydrogen chloride, obtains compound 1, i.e. Hoffer'schlorosugar.
Advantageous Effects of the present invention is embodied in: 1) operational path is simple, and the reaction related to is popular response, easy realization easy and simple to handle, and without the need to the reaction conditions of harshness, also without the need to using special reagent, and aftertreatment is simple; 2) yield is high: total recovery can reach 42%, is greatly improved compared with the literature; 3) cost is low: starting material compound 2 can be that raw material obtains by the vitamins C of domestic a large amount of supply, and technical maturity, production cost is lower than 200 yuan/kg, and more commercially available price is low by 1/3; 4) product purity is high: the purity of this technique gained finished product Hoffer'schlorosugar is greater than 98.8%.
Embodiment
Explain the present invention further by following examples, but the present invention is not limited by the following examples:
Embodiment 1:
Weigh Compound 2 (100g, 0.58mol) (reference literature Tetrahedron, 61 (2005): 4341-4346 obtain), Butyltriphenylphosphonium chloride (132g, 0.69mol) in 1000ml reaction flask, add methylene dichloride 200ml stirring and be cooled to-5 ~ 0 DEG C, slow dropping triethylamine 410ml, after in room temperature reaction 9 hours, washing (200ml × 2), gets organic layer, with anhydrous magnesium sulfate drying, filtration, underpressure distillation, obtain the compound 3152.8g of colorless liquid, yield 90.5%.
1H-NMR(400MHz,CDCl
3)δ1.28(s,6H),2.36(s,3H),2.72(m,1H),2.96(m,1H),3.75(m,1H),3.98(m,1H),4.4(m,1H),4.5(m,1H),7.36(d,J＝8.0Hz,2H),7.96(d,J＝8.0Hz,2H)；
1CNMR(100MHz,CDCl
3)δ16.5，26.2，21.5，26.4，66.2，70.4，77.2，109.6，117.8，127.2，128.9，129.8，142.8，127.1。
Embodiment 2:
In 1L reaction flask, add anhydrous stannic chloride (115g, 0.6mol), dry ether (200ml), pass into hydrogen chloride gas under stirring at room temperature to saturated, drip compound 3 (100g, 0.31mol), vigorous stirring 1 hour, latter standing 8 hours, layering, filter, and with 100ml washed with diethylether twice.Concentrating under reduced pressure obtains the compound 482.3g of colorless oil, yield 81.5%.
1hNMR (400MHz, CDCl
3) δ 1.29 (s, 6H), 2.36 (s, 3H), 2.69 (m, 1H), 2.96 (m, 1H), 3.98 (m, 1H), 4.08 (m, 1H), 4.50 (m, 1H), 7.38 (d, J=8.0Hz, 2H), 7.98 (d, J=8.0Hz, 2H); MSforC
16h
20o
5(M+Na): theoretical value 292.33 measured value: 292.28
Embodiment 3
Get compound 4 (50g, 0.17mol), 25% aqueous hydrochloric acid (2.5g, 0.017mol), methyl alcohol 200ml in reaction flask, stirring at room temperature 35min.The sodium bicarbonate aqueous solution of 35% is added in 0-10 DEG C of downhill reaction bottle, adjust ph is to 8.0-9.0, in reaction flask, add methylene dichloride 200ml again dissolve, washing (150ml × 2), gets organic layer, with anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, obtains the compound 530.9g of pale yellow oil, yield 72.3%.
Embodiment 4
Weigh Compound 5 (25g, 0.1mol), triethylamine 15ml in 500ml reaction flask, add methylene dichloride 100ml stirring and dissolving, ice-water bath is cooled to 0 ~ 5 DEG C, drip paratolunitrile acid anhydride (25g, dichloromethane solution 200ml 0.1mol), drips and finishes, rise to stirring at room temperature 6 hours, be washed to neutrality, get organic layer drying, concentrating under reduced pressure obtains compound 632.6g, yield 88%.
1hNMR (400MHz, CDCl
3): 2.2 (s, 3H), 2.4 (s, 3H), 2.8 (m, 2H), 4.3 (m, 2H), 4.6 (m, 2H), 7.6 (d, J=8.4,2H), 7.8 (d, J=8.4,2H), 8.0 (d, J=8.4,4H), 9.6 (m, 1H), MSforC
16h
20o
5(M+Na): theoretical value 292.33 measured value: 292.28
Embodiment 5
Get compound 6 (30g, 0.08mol), the saturated hydrogen chloride solution 115ml of methyl alcohol is in reaction flask, and stirring at room temperature 3 hours, adds saturated sodium bicarbonate solution in reaction flask, and adjust ph, to neutral, concentrates removing methyl alcohol.In residue, add methylene dichloride 150ml again dissolve, after washing (100ml × 2), anhydrous sodium sulfate drying 30min, filter, underpressure distillation, obtains compound (1) 22.6g, yield 72.7%.Mp:112 ~ 114 DEG C; [α]
d 25=-125.6 ° (c=0.81, DMF); HPLC purity 99.2% (testing conditions: the chromatographic column taking silica gel as filler; With normal heptane: ethyl acetate (70:30) is moving phase; Flow velocity is 1.0ml/min; Determined wavelength is 254nm; Detection method: get this product and be about 10mg, puts in 25ml measuring bottle, adds the flowing mutual-assistance and dissolves, and be diluted to scale, shake up, as need testing solution, get need testing solution 20 μ l injection liquid chromatography, record color atlas, calculates main peak content by area normalization method);
1hNMR (400MHz, CDCl
3) δ 7.99 (d, J=8.4Hz, 2H), 7.9 (d, J=8.0Hz, 2H), 7.3-7.2 (m, 4H), 6.48 (d, J=5.1Hz, 1H), 5.56 (dd, J7.3,2.6Hz, 3H), 4.83-4.85 (m, 1H), 4.72-4.56 (ddd, J=12.1,4.4,3.Hz, 2H), 2.92-2.82 (ddd, J=15.2,7.5,5.3Hz, 1H), 2.75 (d, J=15.0Hz, 1H), 2.42 (s, 3H), 2.41 (s, 3H).
Claims (18)
1. a preparation method of Telbivudine key intermediate Hoffer'schlorosugar, comprises the steps:
A). with compound 2 for starting raw material, under catalyst action, protect with to toluyl
Protect agent protection hydroxyl, obtain compound 3;
B). under reductive agent effect, reducing compound 3, obtains compound 4;
C). compound 4 open loop in acid condition, regulates the pH value of reaction solution to 8.0-11.0, obtains compound 5;
D). by compound 5 under solvent and catalyzer exist, with to toluyl protective material protection hydroxyl, obtain compound 6;
E). compound 6 in anhydrous conditions, with hcl reaction, obtains compound 1;
2. preparation method according to claim 1, wherein step a) described in catalyzer be selected from ammoniacal liquor, pyridine, triethylamine, sodium carbonate, sodium bicarbonate.
3. preparation method according to claim 2, wherein step a) described in catalyzer be selected from triethylamine, sodium bicarbonate.
4. preparation method according to claim 1, wherein, step a) is carried out at methylene dichloride, chloroform, acetonitrile or under wherein the two mixture does solvent condition.
5. preparation method according to claim 1, wherein step a) described in Butyltriphenylphosphonium chloride, paratolunitrile acid anhydride are selected to toluyl protective material.
6. preparation method according to claim 1, wherein step b) described in reductive agent be selected from SnCl
2, LiAlH
4, LiAlH (OEt)
3, LiAlH (NR
2)
3, DIBAL-H, when reductive agent is selected from LiAlH (NR
2)
3time, R is the straight or branched alkyl of C1-C4.
7. preparation method according to claim 6, wherein step b) described in reductive agent be selected from SnCl
2, LiAlH
4.
8. preparation method according to claim 1, wherein, step c) comprising: compound 4 is reacted 30-100min in acid condition, and regulate the pH value of reaction solution for 8.0-9.0 with pH adjusting agent, organic solvent extraction, concentrating under reduced pressure, obtains compound 5.
9. preparation method according to claim 8, wherein, step c) comprising: compound 4 is reacted 30-50min in acid condition, and regulate the pH value of reaction solution for 8.0-9.0 with pH adjusting agent, organic solvent extraction, concentrating under reduced pressure, obtains compound 5.
10. the preparation method according to claim 1 or 8, wherein, step c) described in acidic conditions, refer to and to react under content is the aqueous hydrochloric acid of 10 ~ 23 volume % or content is the aqueous sulfuric acid existence condition of 5 ~ 75 volume %.
11. preparation methods according to claim 1 or 8, wherein, step c) described in pH adjusting agent be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, pyridine.
12. preparation methods according to claim 11, wherein, step c) described in pH adjusting agent be selected from triethylamine or sodium bicarbonate.
13. preparation methods according to claim 1, wherein, step c) carry out under methyl alcohol does solvent condition.
14. preparation methods according to claim 1, steps d) described in compound 5 be 1:0.85 ~ 1.0 with the mol ratio fed intake to toluyl protective material.
15. preparation methods according to claim 1, wherein, step c) and d) be all carry out at methylene dichloride, chloroform, acetonitrile or under wherein the two mixture does solvent condition.
16. preparation methods according to claim 1, wherein, steps d) described in catalyzer be selected from ammoniacal liquor, triethylamine, sodium bicarbonate, sodium carbonate, pyridine; Described is selected from Butyltriphenylphosphonium chloride, paratolunitrile acid anhydride to toluyl protective material.
17. preparation methods according to claim 16, wherein, steps d) described in catalyzer be selected from triethylamine, sodium bicarbonate; Described is selected from Butyltriphenylphosphonium chloride, paratolunitrile acid anhydride to toluyl protective material.
18. preparation methods according to claim 1, wherein, step e) at anhydrous condition, carry out under making solvent with methyl alcohol.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1842535A (en) * | 2003-06-30 | 2006-10-04 | 艾登尼科斯（开曼）有限公司 | Synthesis of beta-l-2'-deoxy nucleosides |
| CN102477051A (en) * | 2010-11-30 | 2012-05-30 | 重庆礼邦药物开发有限公司 | Technology for preparing key intermediate of telbivudine |
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2012
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1842535A (en) * | 2003-06-30 | 2006-10-04 | 艾登尼科斯（开曼）有限公司 | Synthesis of beta-l-2'-deoxy nucleosides |
| CN102477051A (en) * | 2010-11-30 | 2012-05-30 | 重庆礼邦药物开发有限公司 | Technology for preparing key intermediate of telbivudine |
Non-Patent Citations (3)
| Title |
|---|
| A new efficient and practical synthesis of 2-deoxy-L-ribose;Bong Hwan Cho et al.;《Tetrahedron》;20050319;第61卷;第4341-4346页 * |
| Development of a Novel Synthetic Process for 2-Deoxy-3,5-di-O-p-toluoyl-α-L-ribofuranosyl Chloride: A Versatile Intermediate in the Synthesis of 2’-Deoxy-L-ribonucleosides;Narayan C. Chaudhuri et al.;《Organic Process Research & Development》;20050610;第9卷;第457-465页 * |
| Synthesis of an enantiomeric DNA oligomer and its T-HgⅡ-T base-pair formation;Kaichiro Haruta et al.;《Nucleic Acids Symposium Series》;20071231;第51卷;第187-188页 * |
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