CN108569991A - A kind of preparation method of anti-hepatitis C virus key intermediate of medicament - Google Patents
A kind of preparation method of anti-hepatitis C virus key intermediate of medicament Download PDFInfo
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- CN108569991A CN108569991A CN201810550176.2A CN201810550176A CN108569991A CN 108569991 A CN108569991 A CN 108569991A CN 201810550176 A CN201810550176 A CN 201810550176A CN 108569991 A CN108569991 A CN 108569991A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D207/16—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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention discloses a kind of preparation methods of anti-4 methoxy L proline of hepatitis C virus key intermediate of medicament (4S) N Boc, include the following steps：Under the action of acid binding agent, 4S hydroxyl N Boc L proline esters generate sulphonic acid ester 4 with sulfonic acid chloride condensation；Wherein R is C1~4Alkyl；Under the action of copper catalyst, lithium salts and organic base, sulphonic acid ester 4 occurs necleophilic reaction with methoxy magnesium bromide and generates compound 3；Compound 3 obtains 4 methoxy L proline of (4S) N Boc with lithium hydrate.The beneficial effects of the invention are as follows：Target product structure and chirality are introduced by sulphonic acid ester and Grignard Reagent nucleophilic substitution, overcomes existing fractionation and chiral source method, the method is easy to operate, and mild condition, yield is good, and chemical purity and optical purity are higher, are suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of anti-hepatitis C virus key intermediate of medicament, more particularly to (4S)-N-Boc-
The preparation method of 4- methoxies-L-PROLINE.
Background technology
(4S)-N-Boc-4- methoxies-L-PROLINE are the anti-hepatitis medicines developed by Gilead Science companies
On object Velpatasvir key intermediates, the drug 2016 and Suo Feibuwei are ratified with the breakthrough drug of compound through U.S. FDA
City, folk prescription carry out the clinical second phase, are a kind of general genotype NS5A inhibitor, have compared with existing therapeutic scheme great at present
Progress.
Wei Patawei (Velpatasvir) structural formula is as follows：
Its key intermediate (4S)-N-Boc-4- methoxies-L-PROLINE is shown below：
The synthesis for the compound 2 reported at present, mainly there is following three kinds of methods：
Method 1:Fujimori etc. is in patent US20150361073 with (4S)-N-Boc-4- cyano-L-PROLINE methyl esters
For raw material, alcohol, then hydroxymethylation are restored to obtain by cyan-hydrolysis esterification, ester hydrolysis, carboxyl chloride, prepared by last basic hydrolysis
Target product 2.
But this method raw material need to use the Cymag to severe toxicity, source limited.
Method 2：Fujimori etc. in patent US20150361073 also using Boc protected amino acids ester as starting material, with
Acetic formic anhydride cyclization, Pd/C reduction double bond, ester group reduction, hydroxymethylation, hydrolysis obtain product again.
The route is succinct, but its raw material amino-acid ester is expensive, and production cost is high.
Method 3：Fujimori etc. in patent US20150361073 using 4- vinyl-N-Boc-L- proline as raw material,
Racemization target product is obtained through carboxy protective, double bond borane reduction, hydroxymethylation, finally splits to obtain target product 2.
Undoubtedly splitting causes route yield low, and environmental pollution is serious.
Therefore, for above-mentioned route problem, find that a kind of raw material is cheap and easily-available, reaction condition is mild, easy to operate, cost
Cheap and environmentally protective route can smoothly be used for the synthesis of target compound 2, be that the technology that current this field is badly in need of solving is asked
Topic.
Invention content
It is mild, easy to operate, of low cost and environmentally protective anti-that the purpose of the present invention is to provide a kind of reaction conditions
The preparation method of hepatitis C virus key intermediate of medicament (4S)-N-Boc-4- methoxies-L-PROLINE.
In the first aspect of the present invention, a kind of anti-hepatitis C virus key intermediate of medicament (4S)-N-Boc-4- first is provided
The preparation method of oxygroup methyl-L-proline comprising following steps：
(1) under the action of acid binding agent, 4S- hydroxy-n-Boc-L- proline esters generate sulphonic acid ester 4 with sulfonic acid chloride condensation；
Wherein R is C1~4Alkyl；
(2) under the action of copper catalyst, lithium salts and organic base, with methoxy magnesium bromide nucleophilic occurs for sulphonic acid ester 4
Reaction generates compound 3；
(3) lithium hydroxide of compound 3, sodium hydroxide or potassium hydroxide water solution obtain (4S)-N-Boc-4- methoxy methyls
Base-L-PROLINE (compound 2).
Preferably, the 4S- hydroxy-n-Boc-L- proline esters 5 used in the step (1) are 4S- hydroxy-ns-Boc-L-
Proline methyl ester, 4S- hydroxy-n-Boc-L- ethyl prolinates, 4S- hydroxy-n-Boc-L- proline n-propyl, 4S- hydroxy-ns-
Boc-L- proline isopropyl ester or 4S- hydroxy-n-Boc-L- proline tert-butyl esters.
Preferably, the sulfonic acid chloride used in the step (1) is paratoluensulfonyl chloride, mesyl chloride, p-nitrophenyl sulphonyl
Chlorine or trifluoromethanesulfchloride chloride.
Preferably, 4S- hydroxy-n-Boc-L- proline esters 5 and sulfonic acid chloride, the molar ratio of Fu's acid agent in the step (1)
It is 1：1.1~1.3：2.2~3.
Preferably, Fu's acid agent includes pyridine, triethylamine or n,N-diisopropylethylamine in the step (1).
Preferably, the copper catalyst used in the step (2) is cuprous iodide；Lithium salts includes LiOMe or LiX, and wherein X is
Fluorine, chlorine, bromine or iodine；Organic base includes pyridine, tetramethylethylenediamine, ethylenediamine, triethylamine or N, N- diisopropylethylamine.
Preferably, the solvent used in the step (2) is anhydrous tetrahydro furan or anhydrous methylene chloride.
Preferably, the sulphonic acid ester 4 used in the step (2), methoxy magnesium bromide, copper catalyst, lithium salts and organic
The molar ratio of alkali is 1：1~3：0.05~0.2：0.5~2：0.2~1；Further, sulphonic acid ester 4, methoxy magnesium bromide,
The molar ratio of copper catalyst, lithium salts and organic base is 1：2~3：0.1~0.2：0.5~1：0.2~1.
Preferably, compound 4 and lithium hydroxide in the step (3), sodium hydroxide or potassium hydroxide molar ratio be 1：1
~1.2.
The beneficial effects of the invention are as follows：By sulphonic acid ester and Grignard Reagent nucleophilic substitution introduce target product structure and
Chirality overcomes existing fractionation and chiral source method, and the method is easy to operate, and mild condition, yield is good, chemical purity and light
It is higher to learn purity, is suitable for industrialized production.
Specific implementation mode
Illustrate technical scheme of the present invention below by way of specific embodiment, but the scope of the present invention is not limited thereto.
Embodiment 1
The preparation of (1. 4R)-p-methyl benzenesulfonic acid ester group-N-Boc-L- proline tert-butyl esters (4)
Compound 5 (4R)-hydroxy-n-Boc-L- proline tert-butyl esters (25g, 87mmol, 1eq) are dissolved in 150ml dichloromethanes
In alkane, pyridine (18ml, 191mmol, 2.2eq) is added, ice bath is cooled to 0~5 DEG C.It is added portionwise at this temperature to methylbenzene sulphur
Acyl chlorides (21.4g, 95.7mmol, 1.1eq), finishes, and is stirred to react 3h, it is complete that TLC detects raw material fundamental reaction.Into reaction solution
50ml water is added, stirs 15min, stratification, water layer is extracted with 50ml DCM, combined dichloromethane, salt washing, anhydrous sulphur
Sour sodium drying, concentration.Residue column chromatography (PE:EA=8:1) 33.8g colorless oils (yield 88.0%) are obtained.1H-NMR
(CDCl3,400MHz)：δ9.80(t,2H)；2.75-2.73(m,4H)；.ESI-MS(m/z):87.1[M+H]+。
The preparation of (2. 4S)-N-Boc-4- methoxies-L-PROLINE tert-butyl ester (3)
CuI (0.86g, 4.5mmol, 0.1eq) and LiOMe (1.8g, 45.3mmol, 1eq) are sequentially added in reaction bulb,
The anhydrous THF of 100ml, stir 10min, later be added compound 4 (20g, 45.3mmol, 1eq), tetramethylethylenediamine (1g,
9mmol, 0.2eq) and methoxyl methyl magnesium bromide (13.5g, 90.6mmol, 2eq), it is stirred overnight for 0 DEG C under room temperature, TLC inspections
It surveys raw material compound 4 to consume completely, saturated ammonium chloride solution 50ml is added and is quenched, reaction solution extracts (60ml with dichloromethane
X2), merge organic layer, anhydrous sodium sulfate drying, concentration.Residue column chromatography (PE:EA=15:1) about 11.7g colorless oils are obtained
Object, yield 82.1%.1H-NMR(CDCl3,400MHz)：δ7.51-7.45(m,2H)；1.61-1.60(m,4H)；1.33(s,
18H).ESI-MS(m/z):315.5[M+Na]+。
The preparation of (3. 4S)-N-Boc-4- methoxies-L-PROLINE (2)
Compound 3 (10g, 31.7mmol, 1eq) is dissolved in 50ml THF, and LiOH (0.76g, 31.7mmol, 1eq) is added
6h is stirred at room temperature in aqueous solution (5ml), and the reaction was complete for TLC detections.Reaction solution adjusts pH to 6~8, and (50ml is extracted with dichloromethane
X2), merge organic layer, anhydrous sodium sulfate drying, concentration.Residue n-hexane：It is white to obtain about 7.2g classes for recrystallize with dichloromethane
Color solid, yield 90.0%.
1H-NMR(CDCl3,400MHz)：δ8.3(br,2H)；7.36-7.24(m,10H)；3.39(m,2H)；3.0-2.97
(dd,2H)；2.81-2.77(dd,2H)；1.76-1.57(m,4H)；1.22(s,18H).ESI-MS(m/z):477.7[M+H]+。
Embodiment 2
The preparation of (1. 4R)-p-methyl benzenesulfonic acid ester group-N-Boc-L- proline tert-butyl esters (4)
Compound 5 (4R)-hydroxy-n-Boc-L- proline tert-butyl esters (25g, 87mmol, 1eq) are dissolved in 150ml dichloromethanes
In alkane, triethylamine (36.2ml, 260mmol, 3eq) is added, ice bath is cooled to 0~5 DEG C.Mesyl chloride is added portionwise at this temperature
(13.0g, 113.1mmol, 1.3eq), finishes, and is stirred to react 3h, it is complete that TLC detects raw material fundamental reaction.Add into reaction solution
Enter 50ml water, stir 15min, stratification, water layer is extracted with 50ml DCM, combined dichloromethane, salt washing, anhydrous slufuric acid
Sodium is dried, concentration.Residue column chromatography (PE:EA=8:1) 34.1g colorless oils (yield 88.7%) are obtained.1H-NMR
(CDCl3,400MHz)：δ9.80(t,2H)；2.75-2.73(m,4H)；.ESI-MS(m/z):87.1[M+H]+。
The preparation of (2. 4S)-N-Boc-4- methoxies-L-PROLINE tert-butyl ester (3)
CuI (1.72g, 9.0mmol, 0.2eq) and LiBr (1.97g, 22.7mmol, 0.5eq) are sequentially added in reaction bulb,
The anhydrous THF of 100ml, stir 10min, later be added compound 4 (20g, 45.3mmol, 1eq), triethylamine (4.5g, 45mmol,
It 1eq) with methoxyl methyl magnesium bromide (20.3g, 135.9mmol, 3eq), is stirred overnight for 0 DEG C under room temperature, TLC detects raw material
It closes object 4 to consume completely, saturated ammonium chloride solution 50ml is added and is quenched, reaction solution extracts (60ml X2) with dichloromethane, is associated with
Machine layer, anhydrous sodium sulfate drying, concentration.Residue column chromatography (PE:EA=15:1) about 11.9g colorless oils, yield are obtained
83.5%.1H-NMR(CDCl3,400MHz)：δ7.51-7.45(m,2H)；1.61-1.60(m,4H)；1.33(s,18H).ESI-
MS(m/z):315.5[M+Na]+。
The preparation of (3. 4S)-N-Boc-4- methoxies-L-PROLINE (2)
Compound 3 (10g, 31.7mmol, 1eq) is dissolved in 50ml THF, addition NaOH (1.52g, 38.0mmol,
6h is stirred at room temperature in 1.2eq) aqueous solution (6ml), and the reaction was complete for TLC detections.Reaction solution adjusts pH to 6~8, is carried with dichloromethane
It takes (50ml X2), merges organic layer, anhydrous sodium sulfate drying, concentration.Residue n-hexane：Recrystallize with dichloromethane obtains about
7.3g off-white powders, yield 90.8%.
1H-NMR(CDCl3,400MHz)：δ8.3(br,2H)；7.36-7.24(m,10H)；3.39(m,2H)；3.0-2.97
(dd,2H)；2.81-2.77(dd,2H)；1.76-1.57(m,4H)；1.22(s,18H).ESI-MS(m/z):477.7[M+H]+。
It is enlightenment with above-mentioned desirable embodiment according to the present invention, through the above description, relevant staff is complete
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property range is not limited to the contents of the specification, it is necessary to determine its technical scope according to right.
Claims (10)
1. a kind of preparation method of anti-hepatitis C virus key intermediate of medicament, it is characterised in that include the following steps：
(1) under the action of acid binding agent, 4S- hydroxy-n-Boc-L- proline esters generate sulphonic acid ester 4 with sulfonic acid chloride condensation；Wherein R
For C1~4Alkyl；
(2) under the action of copper catalyst, lithium salts and organic base, with methoxy magnesium bromide necleophilic reaction occurs for sulphonic acid ester 4
Generate compound 3；
(3) lithium hydroxide of compound 3, sodium hydroxide or potassium hydroxide water solution obtain (4S)-N-Boc-4- methoxies-L-
Proline；
2. the preparation method of anti-hepatitis C virus key intermediate of medicament as described in claim 1, which is characterized in that the step
(1) the 4S- hydroxy-n-Boc-L- proline esters 5 used in are 4S- hydroxy-n-Boc-L- proline methyl esters, 4S- hydroxy-ns-
Boc-L- ethyl prolinates, 4S- hydroxy-n-Boc-L- proline n-propyl, 4S- hydroxy-ns-Boc-L- proline isopropyl ester or
4S- hydroxy-n-Boc-L- proline tert-butyl esters.
3. the preparation method of anti-hepatitis C virus key intermediate of medicament as described in claim 1, which is characterized in that the step
(1) sulfonic acid chloride used in is paratoluensulfonyl chloride, mesyl chloride, 4-Nitrobenzenesulfonyl chloride or trifluoromethanesulfchloride chloride.
4. the preparation method of anti-hepatitis C virus key intermediate of medicament as described in claim 1, which is characterized in that the step
(1) molar ratio of 4S- hydroxy-ns-Boc-L- proline esters 5 and sulfonic acid chloride, Fu's acid agent is 1: 1.1~1.3: 2.2~3 in.
5. the preparation method of anti-hepatitis C virus key intermediate of medicament as described in claim 1, which is characterized in that the step
(1) agent of Fu's acid includes pyridine, triethylamine or N, N- diisopropylethylamine in.
6. the preparation method of anti-hepatitis C virus key intermediate of medicament as described in claim 1, which is characterized in that the step
(2) copper catalyst used in is cuprous iodide；Lithium salts includes LiOMe or LiX, and wherein X is fluorine, chlorine, bromine or iodine；Organic base includes
Pyridine, tetramethylethylenediamine, ethylenediamine, triethylamine or N, N- diisopropylethylamine.
7. the preparation method of anti-hepatitis C virus key intermediate of medicament as claimed in claim 6, which is characterized in that the step
(2) solvent used in is anhydrous tetrahydro furan or anhydrous methylene chloride.
8. the preparation method of anti-hepatitis C virus key intermediate of medicament as claimed in claim 6, which is characterized in that the step
(2) molar ratio of sulphonic acid ester 4, methoxy magnesium bromide, copper catalyst, lithium salts and organic base used in is 1：1~3：0.05
~0.2：0.5~2：0.2~1.
9. the preparation method of anti-hepatitis C virus key intermediate of medicament as claimed in claim 8, which is characterized in that the step
(2) sulphonic acid ester 4 in, methoxy magnesium bromide, copper catalyst, lithium salts and organic base molar ratio be 1：2~3：0.1~0.2：
0.5~1：0.2~1.
10. the preparation method of anti-hepatitis C virus key intermediate of medicament as described in claim 1, which is characterized in that the step
Suddenly compound 4 and the molar ratio of sodium hydroxide or potassium hydroxide are 1 in (3)：1~1.2.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2338878A2 (en) * | 2005-12-15 | 2011-06-29 | Vicuron Pharmaceuticals, Inc. | N-hydroxyamide derivatives possessing antibacterial activity |
| CN106543062A (en) * | 2016-05-22 | 2017-03-29 | 上海清松制药有限公司 | A kind of preparation method of medicine intermediate N-Boc- allohydroxyprolines |
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2018
- 2018-05-31 CN CN201810550176.2A patent/CN108569991A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2338878A2 (en) * | 2005-12-15 | 2011-06-29 | Vicuron Pharmaceuticals, Inc. | N-hydroxyamide derivatives possessing antibacterial activity |
| CN106543062A (en) * | 2016-05-22 | 2017-03-29 | 上海清松制药有限公司 | A kind of preparation method of medicine intermediate N-Boc- allohydroxyprolines |
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Application publication date: 20180925 |