CN108727242A - A kind of preparation method of the trans- -4- cyclohexyl-L-PROLINE of blood-pressure drug key intermediate - Google Patents
A kind of preparation method of the trans- -4- cyclohexyl-L-PROLINE of blood-pressure drug key intermediate Download PDFInfo
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- CN108727242A CN108727242A CN201810548300.1A CN201810548300A CN108727242A CN 108727242 A CN108727242 A CN 108727242A CN 201810548300 A CN201810548300 A CN 201810548300A CN 108727242 A CN108727242 A CN 108727242A
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- proline
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- 0 *N(*CC1)C1=O Chemical compound *N(*CC1)C1=O 0.000 description 7
- HGCIXCUEYOPUTN-UHFFFAOYSA-N C1CC=CCC1 Chemical compound C1CC=CCC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N C1CCCCC1 Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- UAEPNZWRGJTJPN-UHFFFAOYSA-N CC1CCCCC1 Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 1
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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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a kind of preparation methods of trans- -4- cyclohexyl-L-PROLINE, include the following steps：(1) under the action of acid binding agent, 4SHydroxyl-N- Boc-L- proline esters 6 generate sulphonic acid ester 5 with sulfonic acid chloride condensation, and wherein R is C1~4Alkyl；(2) under the action of copper catalyst, lithium salts and organic base, sulphonic acid ester 5 occurs nucleophilic substitution with cyclohexyl magnesium bromide and generates compound 4；(3) compound 4 is obtained (4S)-with lithium hydrateN- Boc-4- cyclohexyl-L-PROLINE（Compound 3）；(4) compound 3 removes Boc under the conditions of hydrochloric acid or trifluoroacetic acid/dichloromethane, and target product 2 is made.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 noble metal 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 blood-pressure drug key intermediate, more particularly to a kind of trans-4- hexamethylenes
The preparation method of base-L-PROLINE.
Background technology
Trans-4- cyclohexyl-L-PROLINE is among the blood-pressure drug fosinopril sodium key developed by BMS companies
Body.The drug is the angiotensin converting enzyme inhibitors uniquely containing hypophosphorous acid ester group, and lipophilicity is strong, works slow, has
Good heart and vascular protection effect, since 1991 since American-European approval listing, market sale is excellent.
Fosinopril sodium (Fosinopril sodium) structural formula is as follows：
Its key intermediate trans-4- cyclohexyl-L-PROLINE is shown below：
The synthesis for the compound 1 reported at present, mainly there is following two methods：
Method 1:Kronenethal etc., using (4S)-OH-L-proline methyl ester as raw material, leads in patent US4912231
The protection of N- nitrogen is crossed, then target product (anti-)-N- benzoyl -4- phenyl-L- dried meat ammonia is made through mesyl chloride esterification, benzene alkylation
Sour methyl esters finally hydrolyzes, restores obtained target product 2.
Method 2：Chen Xiao etc. are in Tetrahedron:Asymmetry, 2002,13 (1)：5- oxygen is reported in 43-46
Generation-L-PROLINE is raw material, and through carbon hydrocarbonylation, trans--N- benzyls -4- cyclohexyl -5- oxo-L- dried meat ammonia is then obtained under catalytic hydrogenation
Acid, then another sequence of transformations restore to obtain target product.
Above-mentioned two method route is more complicated, and operating condition is harsh, it is crucial that precious metal catalyst reduction is used for multiple times,
Cost is higher.
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
Drop mild, easy to operate, of low cost and environmentally protective that the purpose of the present invention is to provide a kind of reaction conditions
The preparation method of the trans- -4- cyclohexyl-L-PROLINE of blood pressure medication key intermediate.
In the first aspect of the present invention, a kind of trans- -4- cyclohexyl-L- dried meat ammonia of blood-pressure drug key intermediate is provided
The preparation method of acid comprising following steps：
(1) under the action of acid binding agent, 4S- hydroxy-n-Boc-L- proline esters 6 generate sulphonic acid ester 5 with sulfonic acid chloride condensation,
Wherein R is C1~4Alkyl；
(2) under the action of copper catalyst, lithium salts and organic base, with cyclohexyl magnesium bromide nucleophilic displacement of fluorine occurs for sulphonic acid ester 5
Reaction generates compound 4；
(3) lithium hydroxide of compound 4, sodium hydroxide or potassium hydroxide water solution obtain (4S)-N-Boc-4- cyclohexyl-L-
Proline (compound 3)；
(4) compound 3 removes Boc under the conditions of hydrochloric acid or trifluoroacetic acid/dichloromethane, and target product 2 is made.
Preferably, the 4S- hydroxy-n-Boc-L- proline esters 6 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, acid binding agent is selected from pyridine, triethylamine or DEPEA in the step (1).
Preferably, in the step (1) 4S- hydroxy-n-Boc-L- proline esters 6, sulfonic acid chloride and acid binding agent molar ratio
It is 1：1.1~1.3：2~3；Further, 4S- hydroxy-n-Boc-L- proline esters 6 in the step (1), sulfonic acid chloride with
The molar ratio of acid binding agent is 1：1.2~1.3：2.2~3.
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 DIPEA.
Preferably, the sulphonic acid ester 5 used in the step (2), cyclohexyl magnesium bromide, copper catalyst, lithium salts and organic base
Molar ratio is 1：1~3：0.05~0.2：0.5~2：0.2~1.
Preferably, the solvent used in the step (2) is anhydrous tetrahydro furan or anhydrous methylene chloride.
Preferably, compound 4 and lithium hydroxide in the step (3), sodium hydroxide or potassium hydroxide molar ratio be 1：1
~1.2.
Preferably, compound 3 and the molar ratio of trifluoroacetic acid or hydrochloric acid are 1 in the step (4)：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 noble metal method, and the method is easy to operate, and mild condition, yield is good, chemical purity and optics
Purity is higher, 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 methyl esters (5)
Compound 6 (4R)-hydroxy-n-Boc-L- proline methyl esters (25g, 87mmol, 1eq) are dissolved in 150ml dichloromethane
In, pyridine (15.4ml, 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 (23.3g, 104.4mmol, 1.2eq), finishes, and is stirred to react 3h, it is complete that TLC detects raw material fundamental reaction.To reaction solution
Middle addition 50ml water stirs 15min, stratification, and water layer is extracted with 50ml dichloromethane, combined dichloromethane, salt washing,
Anhydrous sodium sulfate is dried, concentration.Residue column chromatography (PE:EA=8:1) about 33.8g colorless oils (yield 88.0%) are obtained.
1H-NMR(CDCl3,400MHz)：δ 7.78 (d, 2H, J=8)；7.35 (d, 2H, J=8)；5.01(d,1H)；4.40-
4.32(m,1H)；3.71(s,3H)；3.62-3.57(m,2H)；2.56-2.50(m,1H)；2.45(s,3H)；2.18-2.11(m,
1H)；1.39(s,9H).
The preparation of (2. 4S)-N-Boc-4- cyclohexyl-L-PROLINE methyl esters (4)
CuI (0.86g, 4.5mmol, 0.1eq) and LiOMe (1.7g, 45.3mmol, 1eq) are sequentially added in reaction bulb,
The anhydrous THF of 100ml, stir 10min, later be added compound 5 (20g, 45.3mmol, 1eq), tetramethylethylenediamine (1g,
9.1mmol, 0.2eq) and cyclohexyl 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 5 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)：δ11.51(s,1H)；8.11(s,1H)；4.02(s,1H)；3.71(s,3H)；
3.50(t,1H)；2.97(t,1H)；2.45-2.40(m,1H)；1.93(m,1H)；1.70-1.63(m,5H)；1.38(s,9H)；
1.25-1.20(m,4H)；0.95-0.92(m,2H).
The preparation of (3. 4S)-N-Boc-4- cyclohexyl-L-PROLINE (3)
Compound 4 (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)：δ11.51(s,1H)；8.11(s,1H)；4.02(s,1H)；3.50(t,1H)；
2.97(t,1H)；2.45-2.40(m,1H)；1.93(m,1H)；1.70-1.63(m,5H)；1.38(s,9H)；1.25-1.20(m,
4H)；0.95-0.92(m,2H).
4. the preparation of trans-4- cyclohexyl-L-PROLINE (2)
Compound 3 (5g, 31.7mmol, 1eq) is dissolved in 50ml dichloromethane, addition trifluoroacetic acid (0.76g,
31.7mmol, 1eq), 2~4h is stirred at room temperature, the reaction was complete for TLC detections.Reaction solution adjusts pH to 6~8, is extracted with dichloromethane
(50ml X2) merges organic layer, anhydrous sodium sulfate drying, concentration.Residue ethyl acetate：N-hexane=1：1 mixing is molten
Agent recrystallizes, and obtains about 4.20g off-white powders, yield 90.0%.
1H-NMR(CDCl3,400MHz)：δ11.51(s,1H)；8.11(s,1H)；4.02(s,1H)；3.50(t,1H)；
2.97(t,1H)；2.45-2.40(m,1H)；1.93(m,1H)；1.70-1.63(m,5H)；1.38(s,9H)；1.25-1.20(m,
4H)；0.95-0.92(m,2H).
Embodiment 2
The preparation of (1. 4R)-p-methyl benzenesulfonic acid ester group-N-Boc-L- proline methyl esters (5)
Compound 6 (4R)-hydroxy-n-Boc-L- ethyl prolinates (26.2g, 87mmol, 1eq) are dissolved in 150ml dichloromethanes
In alkane, triethylamine (36.2ml, 261mmol, 3eq) is added, ice bath is cooled to 0~5 DEG C.It is added portionwise at this temperature to methylbenzene
Sulfonic acid chloride (25.2g, 113.1mmol, 1.3eq), finishes, and is stirred to react 3h, it is complete that TLC detects raw material fundamental reaction.To reaction
50ml water is added in liquid, stirs 15min, stratification, water layer is extracted with 50ml DCM, combined dichloromethane, salt washing, nothing
Aqueous sodium persulfate is dried, concentration.Residue column chromatography (PE:EA=8:1) about 34.1g colorless oils (yield 88.7%) are obtained.
1H-NMR(CDCl3,400MHz)：δ 7.78 (d, 2H, J=8)；7.35 (d, 2H, J=8)；5.01(d,1H)；4.40-
4.32(m,1H)；3.71(s,3H)；3.62-3.57(m,2H)；2.56-2.50(m,1H)；2.45(s,3H)；2.18-2.11(m,
1H)；1.39(s,9H).
The preparation of (2. 4S)-N-Boc-4- cyclohexyl-L-PROLINE methyl esters (4)
CuI (1.72g, 9.1mmol, 0.2eq) and LiCl (3.9g, 90.6mmol, 2eq) are sequentially added in reaction bulb,
The anhydrous THF of 100ml, stir 10min, later be added compound 4 (20g, 45.3mmol, 1eq), tetramethylethylenediamine (1g,
9.1mmol, 0.2eq) and cyclohexyl magnesium bromide (20.3g, 135.9mmol, 3eq), it is stirred overnight for 0 DEG C under room temperature, TLC inspections
It surveys raw material compound 5 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 11.9g colorless oils are obtained
Object, yield 83.6%.
The preparation of (3. 4S)-N-Boc-4- cyclohexyl-L-PROLINE (3)
Compound 4 (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 (5ml), 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 powder, yield 91.3%.
4. the preparation of trans-4- cyclohexyl-L-PROLINE (2)
Compound 3 (5g, 31.7mmol, 1eq) is dissolved in 50ml dichloromethane, 30% hydrochloric acid of addition (7.71g,
63.4mmol, 2eq), 2~4h is stirred at room temperature, the reaction was complete for TLC detections.Reaction solution adjusts pH to 6~8, is extracted with dichloromethane
(50ml X2) merges organic layer, anhydrous sodium sulfate drying, concentration.Residue ethyl acetate：N-hexane=1：1 mixing is molten
Agent recrystallizes, and obtains about 4.27g off-white powders, yield 91.5%.
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 the trans- -4- cyclohexyl-L-PROLINE of blood-pressure drug key intermediate, it is characterised in that including
Following steps：
(1) under the action of acid binding agent, 4S- hydroxy-n-Boc-L- proline esters 6 generate sulphonic acid ester 5 with sulfonic acid chloride condensation, wherein
R is C1~4Alkyl；
(2) under the action of copper catalyst, lithium salts and organic base, with cyclohexyl magnesium bromide nucleophilic substitution occurs for sulphonic acid ester 5
Generate compound 4；
(3) lithium hydroxide of compound 4, sodium hydroxide or potassium hydroxide water solution obtain (4S)-N-Boc-4- cyclohexyl-L- dried meat ammonia
Sour (compound 3)；
(4) compound 3 removes Boc under the conditions of hydrochloric acid or trifluoroacetic acid/dichloromethane, and target product 2 is made；
2. the preparation method of trans- -4- cyclohexyl-L-PROLINE as described in claim 1, which is characterized in that the step
(1) the 4S- hydroxy-n-Boc-L- proline esters 6 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 trans- -4- cyclohexyl-L-PROLINE 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 trans- -4- cyclohexyl-L-PROLINE as described in claim 1, which is characterized in that the step
(1) acid binding agent in is selected from pyridine, triethylamine or DEPEA.
5. the preparation method of trans- -4- cyclohexyl-L-PROLINE as described in claim 1, which is characterized in that the step
(1) molar ratio of 4S- hydroxy-ns-Boc-L- proline esters 6, sulfonic acid chloride and acid binding agent is 1 in：1.1~1.3：2~3.
6. the preparation method of trans- -4- cyclohexyl-L-PROLINE 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 DIPEA.
7. the preparation method of trans- -4- cyclohexyl-L-PROLINE as described in claim 1, which is characterized in that the step
(2) molar ratio of sulphonic acid ester 5, cyclohexyl 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.
8. the preparation method of trans- -4- cyclohexyl-L-PROLINE as described in claim 1, which is characterized in that the step
(2) solvent used in is anhydrous tetrahydro furan or anhydrous methylene chloride.
9. the preparation method of trans- -4- cyclohexyl-L-PROLINE as described in claim 1, which is characterized in that the step
(3) compound 4 and lithium hydroxide in, sodium hydroxide or potassium hydroxide molar ratio be 1：1~1.2.
10. the preparation method of trans- -4- cyclohexyl-L-PROLINE as described in claim 1, which is characterized in that the step
(4) compound 3 and the molar ratio of trifluoroacetic acid or hydrochloric acid are 1 in：1~2.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111205251A (en) * | 2020-02-28 | 2020-05-29 | 苏州楚凯药业有限公司 | Preparation method of chiral ligand (3S,4S) -2, 5-dioxy tetrahydrofuran-3, 4-bis-carbamic acid benzyl ester |
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| US4912231A (en) * | 1987-06-15 | 1990-03-27 | E. R. Squibb & Sons, Inc. | Process for preparing (trans)-4-phenyl-L-proline derivatives |
| CN101445475A (en) * | 2008-12-30 | 2009-06-03 | 浙江工业大学 | Method for preparing (trans)-4-cyclohexyl-L-proline |
| CN101462996A (en) * | 2007-12-21 | 2009-06-24 | 上海医药工业研究院 | Preparation of 4-cyclohexyl proline derivative |
| CN107365268A (en) * | 2016-05-11 | 2017-11-21 | 常州制药厂有限公司 | A kind of preparation method of depressor fosinopril sodium and its key intermediate |
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2018
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| US4912231A (en) * | 1987-06-15 | 1990-03-27 | E. R. Squibb & Sons, Inc. | Process for preparing (trans)-4-phenyl-L-proline derivatives |
| CN101462996A (en) * | 2007-12-21 | 2009-06-24 | 上海医药工业研究院 | Preparation of 4-cyclohexyl proline derivative |
| CN101445475A (en) * | 2008-12-30 | 2009-06-03 | 浙江工业大学 | Method for preparing (trans)-4-cyclohexyl-L-proline |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111205251A (en) * | 2020-02-28 | 2020-05-29 | 苏州楚凯药业有限公司 | Preparation method of chiral ligand (3S,4S) -2, 5-dioxy tetrahydrofuran-3, 4-bis-carbamic acid benzyl ester |
| CN111205251B (en) * | 2020-02-28 | 2022-04-15 | 苏州楚凯药业有限公司 | Preparation method of chiral ligand (3S,4S) -2, 5-dioxy tetrahydrofuran-3, 4-bis-carbamic acid benzyl ester |
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Application publication date: 20181102 |