CN108069933A - A kind of synthetic method of Suo Feibuwei intermediates - Google Patents
A kind of synthetic method of Suo Feibuwei intermediates Download PDFInfo
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- CN108069933A CN108069933A CN201611010943.8A CN201611010943A CN108069933A CN 108069933 A CN108069933 A CN 108069933A CN 201611010943 A CN201611010943 A CN 201611010943A CN 108069933 A CN108069933 A CN 108069933A
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- suo feibuwei
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The present invention provides a kind of 3 [(4S) 2 of Suo Feibuwei intermediates (2E), 2 dimethyl 1, 3 dioxolanes, 4 base] 2 methyl 2 ethyl acrylate synthetic method, it is using (R) epoxychloropropane as raw material, it is protected by acetonylidene, triethyl phosphite is phosphonylation, last and ethyl pyruvate is obtained by the reaction, the present invention is using (R) epoxychloropropane as raw material, it is cheap and easily-available, and other raw materials are market conventional products, greatly reduce industrial production cost, the production cost of intermediate can reduce by more than 30%, the purity of target product obtained is higher simultaneously, with great industrial production prospect.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to a kind of Suo Feibuwei intermediates (2E) -3- [(4S) -2,2- bis-
Methyl-1,3- dioxolanes -4- bases] -2- methyl -2- ethyl acrylates synthetic method.
Background technology
Hepatitis C is a kind of liver diseases as caused by Hepatitis C Virus, and as hepatitis B, it is hard that it will also result in liver
Change or liver cancer threaten the health of numerous the infecteds.The World Health Organization (WHO) recent statistics numerical monitor, the whole world has 1.3
Hundred million to 1.5 hundred million people suffer from chronic hepatitis C infection.It is estimated that in having infected the patient of hepatitis C, 80% can develop into chronic sense
Dye.In chronic hepatitis C, 20% patient can develop into hepatic sclerosis, have 25% may develop into liver cancer.Annual 350000
It is died of and the relevant liver diseases of hepatitis to 500,000 people.Hepatitis C Virus is that a kind of blood born is viral, most common infection side
Formula includes unsafe medical care precess and spreads through sex intercourse.Hepatitis is treated in the whole world with antiviral drugs always, but still remains and control
More rate is not high, the course for the treatment of is long and the problems such as being susceptible to drug side-effect.
Suo Feibuwei (Sofosbuvir) is the newly developed anti-hepatitis drug of lucky Leadd B.V, is obtained on December 6th, 2013
To the approval of FDA (Food and Drug Adminstration) (FDA), for treating chronic hepatitis C (CHC) infection.Suo Feibuwei is a kind of
The inhibitor of NS5B polymerases, it can act on the RNA polymerase of virus, inhibit RNA synthesis, and thus blocking virus are answered
System.FDA approveds sofosbuvir joint Ribavirins are for 3 chronic hepatitis C adult patient of genotype 2 and genotype
Treatment.Suo Feibuwei is therefore as the first full Oral compositions without using interferon simultaneously in the whole world for treating hepatitis c
Treatment, it may be said that Suo Feibuwei and its combination drug are the current treatment most effective drugs of hepatitis C.The birth certainly of Suo Feibuwei pieces
It is become from life as industry focus of attention, the 2014-2016 sales volumes of continuous 3 years have been more than 10,000,000,000 dollars, are had
Vast market prospect, therefore, the upstream key intermediate of Suo Feibuwei will also face the huge market demand.But Suo Fei
The price of the 8.4 ten thousand dollars/course for the treatment of of cloth Wei piece (1000 dollars/piece) also endures each side's dispute to the fullest extent.
In the prior art, the preparation method of Suo Feibuwei has seen rope in many reports, such as patent WO2008045419
The synthetic route of Fei Buwei is：
Wherein compound A, compound B and compound C are the necessary important source materials of synthesis Suo Feibuwei and intermediate, are changed
Scientific name claims as follows：
Compound A：(R)-(+) -2,2- dimethyl -1,3-dioxolane -4- formaldehyde；
Compound B：(2E) -3- [(4S) -2,2- dimethyl -1,3-dioxolane -4- bases] -2- methyl -2- acrylic acid second
Ester；
Compound C：(2S, 3R) -3- [(4R) -2,2- dimethyl -1,3-dioxolane -4- bases] -2,3- dihydroxy -2- first
Base ethyl propionate.
The following US20150284351 of the preparation method of compound B and compound C at present：
Initial feed is mannitol, cheap to be easy to get, but shortcoming is obvious：(1) price of sodium metaperiodate (KIO4)
It is very high, directly constrain compound A, the cost of compound B；(2) route is by the pure of the compound A compound B synthesized
Degree is inadequate, and the purity and quality for causing compound C can be subject to bigger influence, high so as to which price be caused to occupy to downstream bulk pharmaceutical chemicals
Influence under not.
The content of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of Suo Feibuwei intermediates (2E) -3- [(4S) -2,2- bis-
Methyl-1,3- dioxolanes -4- bases] -2- methyl -2- ethyl acrylates synthetic method.
In order to achieve the above object, the present invention is achieved by the following technical programs：
One kind such as formula (I)：
The synthetic method of shown Suo Feibuwei intermediates, synthetic route are：
(1) reacted with (R)-epoxychloropropane (II) for raw material with acetone, generation intermediate product is protected through acetonylidene
(III)；
(2) phosphonylation reaction, generation intermediate product (IV) are occurred into for intermediate product (III) and triethyl phosphite；
(3) under alkali effect, intermediate product (IV) and ethyl pyruvate is reacted, obtain target product：As shown in formula (I)
Suo Feibuwei midbody compound (2E) -3- [(4S) -2,2- dimethyl -1,3-dioxolane -4- bases] -2- methyl -2-
Ethyl acrylate.
Preferably, the reaction temperature of the step (1) is -15~10 DEG C, reaction time 12-36h.
Preferably, the reaction temperature of the step (2) is 60~70 DEG C, reaction time 12-36h.
Preferably, the reaction temperature of the step (3) is -10~25 DEG C, reaction time 12-36h.
Preferably, the one kind of alkali in sodium methoxide, sodium ethoxide and potassium tert-butoxide in the step (3).
Compared with prior art, the present invention it has the following advantages：It is cheap and easily-available using (R)-epoxychloropropane as raw material, and
Other raw materials are market conventional products, greatly reduce industrial production cost, intermediate (2E) -3- [(4S) -2,2- diformazans
Base -1,3-dioxolane -4- bases] production costs of -2- methyl -2- ethyl acrylates can reduce by more than 30%, so as to reduce down
The cost of bulk pharmaceutical chemicals is swum, while the purity of target product obtained is higher, is conducive to the steady production of downstream intermediate product, has
Great industrial production prospect.
Specific embodiment
To make the purpose, technical scheme and advantage of the embodiment of the present invention clearer, below in conjunction with the embodiment of the present invention,
Technical solution in the embodiment of the present invention is clearly and completely described, it is clear that described embodiment is the present invention one
Divide embodiment, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art are not making
All other embodiments obtained under the premise of creative work, belong to the scope of protection of the invention.
Embodiment 1：The synthesis of intermediate product (III)
300mL acetone and 0.3mL boron trifluoride ether are added in clean clean 500mL there-necked flasks, stirring is cooled to
0 DEG C, 18.5g (R)-epoxychloropropane is slowly added dropwise thereto, is added dropwise in 30min, reacts 13h, stops reaction, boils off
Acetone is evaporated under reduced pressure to sterling 24g, yield 80%.
Embodiment 2：The synthesis of intermediate product (IV)
200mL triethyl phosphites are added in clean clean 500mL there-necked flasks, add in 24g intermediate products thereto
(III), 65 DEG C are heated to, back flow reaction for 24 hours, stops reaction, the excessive triethyl phosphite of distillation removal will be in there-necked flask
Remaining liq crosses silicagel column purification, obtains product 36.2g, yield 89.2%.
Embodiment 3：The synthesis of intermediate (I)
Intermediate product (IV) is added in 500mL toluene, is cooled to 0 DEG C, 18g potassium tert-butoxides are added portionwise, is stirred
17g ethyl pyruvates are added dropwise in 30min thereto, and controlling reaction temperature is 0-5 DEG C, drips off and finishes, and reacts 12h, stops reaction,
5 DEG C are cooled to, the salt acid for adjusting pH of 2N is added dropwise to 6-7, addition 300mL water stirs layering, and organic layer washing is dry, concentrates,
Distill to obtain intermediate product (I) sterling 24g, yield 79.1%, purity 99.82%.1H-NMR (400Hz, CDCl3), δ=6.66
(dd, J=6.8,8.0Hz, 1H), 4.81-4.86 (m, 1H), 4.11-4.21 (m, 3H), 3.60 (t, J=8.4Hz, 1H),
1.87 (d, J=1.2Hz, 3H), 1.43 (s, 3H), 1.38 (s, 3H), 1.27 (t, J=6.8Hz, 3H).
It should be noted that herein, relational terms such as first and second and the like are used merely to a reality
Body or operation are distinguished with another entity or operation, are deposited without necessarily requiring or implying between these entities or operation
In any this actual relation or order.Moreover, term " comprising ", "comprising" or its any other variant are intended to
Non-exclusive inclusion, so that process, method, article or equipment including a series of elements not only will including those
Element, but also including other elements that are not explicitly listed or further include as this process, method, article or equipment
Intrinsic element.In the absence of more restrictions, the element limited by sentence "including a ...", it is not excluded that
Also there are other identical elements in process, method, article or equipment including the element.
The above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations；Although with reference to the foregoing embodiments
The present invention is described in detail, it will be understood by those of ordinary skill in the art that：It still can be to foregoing each implementation
Technical solution recorded in example modifies or carries out equivalent substitution to which part technical characteristic；And these modification or
It replaces, the essence of appropriate technical solution is not made to depart from the spirit and scope of various embodiments of the present invention technical solution.
Claims (5)
1. one kind is such as formula (I)：
The synthetic method of shown Suo Feibuwei intermediates, which is characterized in that synthetic route is：
(1) reacted with (R)-epoxychloropropane (II) for raw material with acetone, generation intermediate product is protected through acetonylidene
(III)；
(2) phosphonylation reaction, generation intermediate product (IV) are occurred into for intermediate product (III) and triethyl phosphite；
(3) under alkali effect, intermediate product (IV) and ethyl pyruvate is reacted, obtain target product：Rope as shown in formula (I)
Midbody compound (2E) -3- [(4S) -2,2- dimethyl -1,3-dioxolane -4- bases] -2- methyl -2- propylene of Fei Buwei
Acetoacetic ester.
2. the synthetic method of Suo Feibuwei intermediates as described in claim 1, which is characterized in that the reaction of the step (1)
Temperature is -15~10 DEG C, reaction time 12-36h.
3. the synthetic method of Suo Feibuwei intermediates as described in claim 1, which is characterized in that the reaction of the step (2)
Temperature is 60~70 DEG C, reaction time 12-36h.
4. the synthetic method of Suo Feibuwei intermediates as described in claim 1, which is characterized in that the reaction of the step (3)
Temperature is -10~25 DEG C, reaction time 12-36h.
5. the synthetic method of Suo Feibuwei intermediates as described in claim 1, which is characterized in that alkali selects in the step (3)
One kind from sodium methoxide, sodium ethoxide and potassium tert-butoxide.
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| CN201611010943.8A CN108069933B (en) | 2016-11-10 | 2016-11-10 | Synthetic method of sofosbuvir intermediate |
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| CN201611010943.8A CN108069933B (en) | 2016-11-10 | 2016-11-10 | Synthetic method of sofosbuvir intermediate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013013009A2 (en) * | 2011-07-19 | 2013-01-24 | Nanjing Molecular Research, Inc. | 2',3'-DIDEOXY-2'-α-FLUORO-2'-β-C-METHYLNUCLEOSIDES AND PRODRUGS THEREOF |
| CN104788419A (en) * | 2014-12-30 | 2015-07-22 | 西华大学 | Chiral (2,2-dimethyl-1,3-dioxolane-4-yl)hydroxy mesylates, and preparing method and applications thereof |
-
2016
- 2016-11-10 CN CN201611010943.8A patent/CN108069933B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013013009A2 (en) * | 2011-07-19 | 2013-01-24 | Nanjing Molecular Research, Inc. | 2',3'-DIDEOXY-2'-α-FLUORO-2'-β-C-METHYLNUCLEOSIDES AND PRODRUGS THEREOF |
| CN104788419A (en) * | 2014-12-30 | 2015-07-22 | 西华大学 | Chiral (2,2-dimethyl-1,3-dioxolane-4-yl)hydroxy mesylates, and preparing method and applications thereof |
Non-Patent Citations (1)
| Title |
|---|
| 王治国等: "《索非布韦中间体的合成》", 《化学试剂》 * |
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