CN102795972A - Method for preparing 2S,3R-2-benzyloxy-3-pentanol - Google Patents
Method for preparing 2S,3R-2-benzyloxy-3-pentanol Download PDFInfo
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- CN102795972A CN102795972A CN2011101363723A CN201110136372A CN102795972A CN 102795972 A CN102795972 A CN 102795972A CN 2011101363723 A CN2011101363723 A CN 2011101363723A CN 201110136372 A CN201110136372 A CN 201110136372A CN 102795972 A CN102795972 A CN 102795972A
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Abstract
The invention discloses a method for preparing a 2S,3R-2-benzyloxy-3-pentanol intermediate for preparing posaconazole. The method comprises the following steps of: performing addition on 2S-benzyloxy-propanal and ethyl magnesium bromide at the temperature of 60 DEG C below zero to 5 DEG C under induction of a chiral aid, and performing post treatment on the reactants to obtain a crude 2S,3R-2-benzyloxy-3-pentanol product of which the enantiomeric excess (ee) value is more than 99 percent, wherein the crude product is directly used for synthesizing the posaconazole without refining. The preparation method is environment-friendly, high in optical selectivity and high in yield, and greatly reduces the cost.
Description
Technical field
The present invention relates to a kind of midbody that is used for the synthetic drugs posaconazole, more specifically say, relate to a kind of midbody 2S that is used for synthetic posaconazole, the chirality compound method of 3R-2-benzyloxy-3-amylalcohol.
Background technology
Posaconazole (posaconazole; Commodity are called Noxafil) be the third generation antifungal drug of Schering-Plough pharmaceutical Co. Ltd research and development, in December, 2005, went on the market in Britain in March, 2006 in German Initial Public Offering; On September 18th, 2006, obtain FDA and ratify.The posaconazole has a broad antifungal spectrum is for Candida, Histoplasma capsulatum, the many pityrosporion ovales of plug, bipolar bacterium zygomycetes, sickle-like bacteria, yeast.The non-Candida albicans strain, Cryptococcus neoformans and the aspergillus tubigensis that comprise anti-fluconazole all have powerful inhibition active; Especially also effective to rarer but life-threatening fungal disease (zygomycosis, fusaridiosis and coccidioidomycosis etc.).
Posaconazole is a micromolecular compound with 4 chiral centres, and the compound method under the prior art condition all is the convergence type compound method that adopts, 2S; 3R-2-benzyloxy-3-amylalcohol is a kind of midbody for preparing posaconazole, the 2S of existing bibliographical information, the preparation method of 3R-2-benzyloxy-3-amylalcohol; All be to form a pair of non-corresponding isomer earlier, the recrystallization through solvent obtains then, because the formation of second chiral centre; There is not optical selective; Therefore have at least half the unwanted isomer to produce, cause yield low, production cost increases greatly.
US 5661151 discloses the method for second chiral centre of a kind of formation, is that the addition through grignard reagent obtains, and existing research bibliographical information has multiple chiral reagent to carry out the chirality addition with grignard reagent; Such as the chirality tartaric acid derivatives, chiral diamine reagent, chirality binaphthol reagent or the like; But these chiral reagents are all very valuable, are not easy to obtain without exception; And under the prior art condition, be not easy to realize amplifying to produce.
WO 9633178 discloses the method for second chiral centre of another kind of formation, is through carbonyl addition reductive mode is obtained, and the mode of carbonyl reduction; Also can under the catalysis of multiple chiral reagent, carry out the chirality addition, such as some borane reagent of modifying through chirality; Chiral diamine or the like, same, these chiral reagents are all very valuable; Be not easy to obtain, under the prior art condition, be not easy to realize amplifying to produce simultaneously.
Through the method that grignard reagent carries out addition, raw material is easy to get, and synthetic route is short, and the carbonyl reduction method is simpler relatively.But conventional form addition does not have optical selective, and yield is low; Cost is high, and posaconazole is the bigger medicine of a kind of specification, and its bulk drug cost accounts for the ratio of whole production cost; And the midbody of expensive certainly will be unfavorable for the production cost of posaconazole bulk drug, therefore, is necessary to select a kind of asymmetric addition method that can implement; Reduce the cost of product, improve its economic worth.
Chiral catalysis is induced grignard reaction is carried out asymmetric addition, under existing technical conditions, generally through following two kinds of approach:
(1) through using stoichiometry perhaps greater than stoichiometric chiral induction agent, like TADDOL-Ti, chiral diamine etc.
(2) (78 ℃ or-30 ℃) change into alkyl titanium, zinc alkyl(s) or other the more weak alkylmetal reagent of metal alkylide isoreactivity to RMgBr fully under lower temperature.
More than two kinds of approach can realize that grignard reagent to the asymmetric addition of the highly selective of aldehyde, still, also has significant disadvantage.Article one, the chiral induction agent of approach needs is not easy to obtain, and therefore prices are rather stiff, and it has been originated into maximum defective; The second approach need carry out metal exchange with grignard reagent equivalent or greater than metallic compound and the grignard reagent of grignard reagent dosage, operates quite loaded down with trivial detailsly, be difficult to control, and Atom economy is relatively poor.
Summary of the invention
Order of the present invention provides a kind of 2S, and the preparation method of 3R-2-benzyloxy-3-amylalcohol, this method are green, safety, cheaply, suitable suitability for industrialized production.
For achieving the above object, technical scheme provided by the invention is: a kind of midbody 2S that is used to prepare posaconazole, the compound method of 3R-2-benzyloxy-3-amylalcohol; 2S-benzyloxy-propionic aldehyde is under the inducing of chiral auxiliary(reagent); Carry out addition in temperature for-60～5 ℃ with ethylmagnesium bromide, reactant obtains 2S through aftertreatment, 3R-2-benzyloxy-3-amylalcohol bullion; The ee value need not refining the synthetic of posaconazole that directly be used for greater than 99%.
Chiral auxiliary(reagent) described in the present invention is the trimethyl silicane yl acetamide, two (TMS) trifluoroacetamide.
Chiral auxiliary(reagent) described in the present invention is two (TMS) trifluoroacetamides.
Temperature described in the present invention is-40 ℃～0 ℃, preferable range-20 ℃～0 ℃, more preferably scope-10 ℃～-5 ℃.
The present invention has following characteristics: (1) present method environmental protection, pollute little; (2) optical selective is strong, and product ee value is high; (3) temperature of reaction is relatively gentleer, does not need very low temperature; (4) impurity is few in the product, and the ee value is high, need not refining can directly the use; (5) yield is high, greatly reduces cost.
Embodiment
Adopt embodiment that the present invention is further explained below, but content of the present invention is not limited to present embodiment.
Instance 1:
2S-benzyloxy-propionic aldehyde 16.4g (0.1mol) drops in the there-necked flask, adds anhydrous THF 200ml, adds two (TMS) trifluoroacetamides (0.2mol) of 51.5g, stirs 1 hour; Cryosel is bathed cooling ,-10 ℃～(3M 267ml) maintains the temperature at-10 ℃～-5 ℃, dropwises in about 1 hour to drip the tetrahydrofuran solution of the ethylmagnesium bromide for preparing in advance below-5 ℃; Continued to keep this thermotonus 8 hours, stopped reaction, the water collection is gone out, and product is with dichloromethane extraction; Organic phase is used salt solution and water washing respectively, and anhydrous magnesium sulfate drying filters, and concentrates; The isopropyl ether making beating gets title product 16.3g, yield: 84.9%, and ee value: 99.2%.
1H-NMR(CD
3Cl，400MZ)：0.96(3H)1.20-1.24(3H)1.46-1.48(2H)1.97-2.04(2H)3.07-3.09(1H)4.65-4.67(2H)7.10-7.22(5H)
MS(H
+)：195
Wherein, the preparation of 2S-benzyloxy-propionic aldehyde can prepare referring to the description of US 5661151.
Instance 2:
2S-benzyloxy-propionic aldehyde 16.4g (0.1mol) drops in the there-necked flask, adds anhydrous THF 200ml, adds two (TMS) trifluoroacetamides (0.4mol) of 103g, stirs 1 hour; Cryosel is bathed cooling ,-10 ℃～(3M 267ml) maintains the temperature at-10 ℃～-5 ℃, dropwises in about 1 hour to drip the tetrahydrofuran solution of the ethylmagnesium bromide for preparing in advance below-5 ℃; Continued to keep this thermotonus 8 hours, stopped reaction, the water collection is gone out, and product is with dichloromethane extraction; Organic phase is used salt solution and water washing respectively, and anhydrous magnesium sulfate drying filters, and concentrates; The isopropyl ether making beating gets title product 15.9g, yield: 82.8%, and ee value: 99.1%.
Instance 3:
2S-benzyloxy-propionic aldehyde 16.4g (0.1mol) drops in the there-necked flask, adds anhydrous THF 200ml, adds two (TMS) trifluoroacetamides (0.1mol) of 25.8g, stirs 1 hour; Cryosel is bathed cooling ,-10 ℃～(3M 267ml) maintains the temperature at-10 ℃～-5 ℃, dropwises in about 1 hour to drip the tetrahydrofuran solution of the ethylmagnesium bromide for preparing in advance below-5 ℃; Continued to keep this thermotonus 8 hours, stopped reaction, the water collection is gone out, and product is with dichloromethane extraction; Organic phase is used salt solution and water washing respectively, and anhydrous magnesium sulfate drying filters, and concentrates; The isopropyl ether making beating gets title product 15.2g, yield: 79.2%, and ee value: 99.0%.
Instance 4:
2S-benzyloxy-propionic aldehyde 16.4g (0.1mol) drops in the there-necked flask, adds anhydrous THF 200ml, adds two (TMS) trifluoroacetamides (0.12mol) of 30.9g, stirs 1 hour; Cryosel is bathed cooling ,-10 ℃～(3M 267ml) maintains the temperature at-10 ℃～-5 ℃, dropwises in about 1 hour to drip the tetrahydrofuran solution of the ethylmagnesium bromide for preparing in advance below-5 ℃; Continued to keep this thermotonus 8 hours, stopped reaction, the water collection is gone out; Product is with dichloromethane extraction, and organic phase is used salt solution and water washing, anhydrous magnesium sulfate drying respectively; Filter, concentrate, the isopropyl ether making beating; Get title product 16.1g, yield: 83.9%, ee value: 99.6%.
Instance 5:
2S-benzyloxy-propionic aldehyde 16.4g (0.1mol) drops in the there-necked flask, adds anhydrous THF 200ml, adds two (TMS) trifluoroacetamides (0.15mol) of 38.6g, stirs 1 hour; Cryosel is bathed cooling ,-10 ℃～(3M 267ml) maintains the temperature at-10 ℃～-5 ℃, dropwises in about 1 hour to drip the tetrahydrofuran solution of the ethylmagnesium bromide for preparing in advance below-5 ℃; Continued to keep this thermotonus 8 hours, stopped reaction, the water collection is gone out; Product is with dichloromethane extraction, and organic phase is used salt solution and water washing, anhydrous magnesium sulfate drying respectively; Filter, concentrate, the isopropyl ether making beating; Get title product 15.8g, yield: 82.3%, ee value: 99.6%.
Instance 6:
2S-benzyloxy-propionic aldehyde 16.4g (0.1mol) drops in the there-necked flask, adds anhydrous THF 200ml, adds 30.9g trimethyl silicane yl acetamide (0.12mol), stirs 1 hour; Cooling ,-40 ℃～(3M 267ml) maintains the temperature at-40 ℃～-30 ℃, dropwises in about 3 hours to drip the tetrahydrofuran solution of the ethylmagnesium bromide prepare in advance below-30 ℃; Continued to keep this thermotonus 8 hours, stopped reaction, the water collection is gone out, and product is with dichloromethane extraction; Organic phase is used salt solution and water washing respectively, and anhydrous magnesium sulfate drying filters, and concentrates; The isopropyl ether making beating gets title product 12.8g, yield: 66.7%, and ee value: 99.8%.
Instance 7:
2S-benzyloxy-propionic aldehyde 16.4g (0.1mol) drops in the there-necked flask, adds anhydrous THF 200ml, adds two (TMS) trifluoroacetamides (0.12mol) of 30.9g, stirs 1 hour; Cooling ,-40 ℃～(3M 267ml) maintains the temperature at-40 ℃～-30 ℃, dropwises in about 3 hours to drip the tetrahydrofuran solution of the ethylmagnesium bromide prepare in advance below-30 ℃; Continued to keep this thermotonus 8 hours, stopped reaction, the water collection is gone out, and product is with dichloromethane extraction; Organic phase is used salt solution and water washing respectively, and anhydrous magnesium sulfate drying filters, and concentrates; The isopropyl ether making beating gets title product 13.4g, yield: 70.0%, and ee value: 99.8%.
Claims (6)
1. 2S, the preparation method of 3R-2-benzyloxy-3-amylalcohol is characterized in that; 2S-benzyloxy-propionic aldehyde is under the inducing of chiral auxiliary(reagent); Carry out addition in temperature for-60～5 ℃ with ethylmagnesium bromide, reactant obtains 2S through aftertreatment, 3R-2-benzyloxy-3-amylalcohol.
2. according to the described preparation method of claim 1, it is characterized in that described chiral auxiliary(reagent) is trimethyl silicane yl acetamide or two (TMS) trifluoroacetamide.
3. according to the described preparation method of claim 1, it is characterized in that described chiral auxiliary(reagent) is two (TMS) trifluoroacetamides.
4. according to the described preparation method of claim 1, it is characterized in that described temperature is-40 ℃～0 ℃.
5. according to the described preparation method of claim 1, it is characterized in that described temperature is-20 ℃～0 ℃.
6. according to the described preparation method of claim 1, it is characterized in that described temperature is-10 ℃～-5 ℃.
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| CN2011101363723A CN102795972A (en) | 2011-05-25 | 2011-05-25 | Method for preparing 2S,3R-2-benzyloxy-3-pentanol |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112063680A (en) * | 2020-08-21 | 2020-12-11 | 甘肃皓天医药科技有限责任公司 | Biological catalysis preparation method of posaconazole intermediate (2S,3R) -2-benzyloxy-3-pentanol |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112063680A (en) * | 2020-08-21 | 2020-12-11 | 甘肃皓天医药科技有限责任公司 | Biological catalysis preparation method of posaconazole intermediate (2S,3R) -2-benzyloxy-3-pentanol |
| CN112063680B (en) * | 2020-08-21 | 2022-05-20 | 甘肃皓天医药科技有限责任公司 | Biological catalysis preparation method of posaconazole intermediate (2S,3R) -2-benzyloxy-3-pentanol |
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Application publication date: 20121128 |