CN103086948A - Preparation method of (S,S,S)-2-azabicyclo[3,3,0]octane-3-carboxylic acid - Google Patents
Preparation method of (S,S,S)-2-azabicyclo[3,3,0]octane-3-carboxylic acid Download PDFInfo
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Abstract
The invention relates to a preparation method of a ramipril intermediate (S,S,S)-2-azabicyclo[3,3,0]octane-3-carboxylic acid. According to the invention, a protecting group triphenylmethyl (Trt) is removed from a compound represented by a formula (II) under an acidic condition, and the compound is converted into imine or enamine; catalytic hydrogenation is carried out, such that a compound represented by a formula (I) is obtained. The invention also relates to a preparation method of the compound represented by the formula (II). According to the invention, L-serine is adopted as an initial raw material; and triphenylmethyl is selected as an amino protecting group, such that an amino racemization problem during an addition reaction of the compound and cyclopentanone can be avoided. Trt is triphenylmethyl, and R1 and R2 are respectively independently hydrogen or carboxy protecting group.
Description
Technical field
The present invention relates to the preparation method of Altace Ramipril Ramipril chiral intermediate, more specifically, the present invention relates to the method for asymmetric synthesis of a kind of (S, S, S)-2-azabicyclo [3,3,0] octane-3-carboxyl acid.
Background technology
Ramipril (Ramipril) is a kind of long-acting, efficient angiotensin-converting enzyme (ACE) inhibitor, and is clinical in treatments such as hypertension, congestive heart failures.(S, S, S)-2-azabicyclo [3,3,0] octane-3-carboxyl acid (I) is the key intermediate of synthetic Ramipril, and existing synthetic method all needs the technique through splitting, adopt the L-amygdalic acid to split azabicyclo [3 as US2007262380,3,0] octane-3-carboxyl acid benzyl ester, WO2007079871 adopt hydroamidase to split 2-amino-3-(2-oxocyclopentyl)-propionic acid.
Formula (I) compound contains the chirality unit of Serine; if but adopt conventional synthetic method (Scheme 1); with the Serine chloro thing of ethanoyl protection under alkaline condition with the cyclopentanone linked reaction; reaction process is to carry out (Tetrahedron Letters by the mechanism of first eliminating addition again; 4479 (25); 1984), and the chiral building block of Serine is destroyed.
The inventor passes through great many of experiments; the selection trityl as protecting group is amino; iodo thing and cyclopentanone coupling with Serine; can avoid the elimination reaction of coupling reaction process to occur; the coupled product of gained has kept the chiral structure of Serine, thereby obtains formula (I) compound with the method for asymmetric synthesis.It is starting raw material that the method adopts the Serine that cheaply is easy to get, and adopts the method for asymmetric synthesis, has avoided the loaded down with trivial details operation of resolution process, without discarded isomer discharging, not only economy but also environmental protection.
Summary of the invention
(S, S, S)-2-azabicyclo [3,3,0] octane-3-carboxyl acid (I) is the crucial chiral intermediate of preparation Ramipril, existing bibliographical information method (WO2007079871), can adopt (S)-2-amino-3-(2-oxocyclopentyl)-propionic acid is reaction substrate and on-the-spot imines or the enamine of generating, and then imines or enamine compound is prepared (scheme2) by catalytic hydrogenation.
but the reaction substrate of aforesaid method is to obtain by the method that splits, the chiral building block that comprises Serine in described reaction substrate, can be by the halides of Serine and the method preparation of cyclopentanone coupling, but adopt conventional amino protecting group such as ethanoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), little and have a Serine halides of the protecting group of drawing electronic property with these steric hindrances, elimination reaction with amino adjacent halogen easily occurs under alkaline condition, this is also to prepare dehydroalanine method (J.Org.Chem. commonly used, 1690 (35), 1970).
The inventor finds by great many of experiments, and when iodo thing (III) and the cyclopentanone of the Serine that adopts trityl as protecting group carried out linked reaction, resulting coupled product (II) was keeping the chiral structure consistent with Serine.Described coupled product (II) deprotection base and situ conversion under acidic conditions are imines or enamine, and then the method by catalytic hydrogenation, can obtain the pure formula of mapping (I) compound (scheme3).
Wherein, Trt is trityl, R
1, R
2Independent respectively is hydrogen or carboxyl-protecting group.Carboxyl-protecting group is selected from alkyl or substituted alkyl; aryl or substituted aryl; alkylene or substituted olefine base; carbalkoxy or substituted alkoxycarbonyl; silylation, alkylsulfonyls etc. preferably remove the Trt protecting group at acidic conditions and conveniently are hydrolyzed simultaneously the protecting group that removes; or the protecting group that conveniently is removed in the catalytic hydrogenation process, more preferably C
1-4Alkyl or benzyl.Work as R
2During for carboxyl-protecting group, can be converted into hydrogen under acidic conditions or under the condition of Pd/C hydrogenation.Work as R
1During for hydrogen, also can be translated into carboxyl-protecting group by the esterification process of routine.
Formula (II) compound through type (III) compound and the reaction of formula (IV) compound are prepared, and can also be prepared with the reaction of formula (IV) compound under the existence of the iodide of catalytic amount by the formula V compound.
Wherein, R
2Be hydrogen or carboxyl-protecting group, Trt is trityl, and X is methanesulfonates, p-toluenesulfonic esters, chlorine or bromine.
Described iodide are an alkali metal salt of iodine, as potassiumiodide, sodium iodide.Formula (V) compound is converted into formula (III) compound, perhaps reacts under iodide exist, because increased the activity of substitution reaction leavings group, can improve the yield of linked reaction.
Formula (III) or formula (V) compound with trityl as protecting group amino; with the enamine compound linked reaction of formula (IV) in; can first not eliminate into α; beta-unsaturated esters; again with the enamine addition; but directly replace with enamine, so just guaranteed the chirality of the middle amino of intermediate (II).Then formula (II) compound deprotection base and be converted into imines or enamine under acidic conditions carries out with resulting imines or enamine (S, S, S)-2-azabicyclo [3,3,0] octane-3-carboxyl acid that catalytic hydrogenation obtains formula (I).In this process, work as R
2Conveniently be hydrolyzed simultaneously for remove the Trt protecting group at acidic conditions the protecting group that removes, or when the protecting group that the catalytic hydrogenation process conveniently is removed, R
2Be converted into hydrogen.
Formula (V) compound can be starting raw material by Serine; adopt known method to be prepared; as first with Serine esterification under the catalysis of acid; obtain Serine ester (Synthesis, 2010,2816); then under the existence of alkali; the employing trityl as protecting group is amino, then hydroxyl is converted into methanesulfonates, obtains the formula that X is methanesulfonates (V) compound (US20110021482).
Embodiment
The preparation of embodiment 1:(S)-3-mesyloxy-2-trityl alanine methyl esters (1-2)
The preparation of the first step Serine methyl esters (1-1)
Add Serine 21.2g and methyl alcohol 200mL in reaction flask, ice-water bath is cooling, slowly splashes into thionyl chloride 30.0mL under stirring, and in controlling, temperature is below 30 ℃.This reaction (25 ℃) was at normal temperatures stirred 12 hours, showed that to TLC reaction finishes.Remove solvent under reduced pressure, then dissolve, be spin-dried for methylene dichloride, remove the hydrochloric acid of generation, obtain crystal Serine methyl ester hydrochloride (1-1) 31.4g of white, productive rate: 99.9%.HNMR(300MHz，CDCl
3)：δ8.61(br?s，3H)，5.47-5.86(m，1H)，4.07-4.14(m，1H)，3.80-3.86(m，2H)，3.74(s，3H).
The preparation of second step (S)-3-mesyloxy-2-trityl alanine methyl esters (1-2)
Serine methyl ester hydrochloride (1-1) 5.0g is joined in the 300mL methylene dichloride, then add triethylamine 16.0mL, raw material slowly dissolves, and then adds triphenylmethyl chloride 9.0g in batches, and in controlling, temperature is below 30 ℃.This reaction (25 ℃) was at normal temperatures stirred after 12 hours, more slowly splashed into methylsulfonyl chloride 2.7mL, continued normal-temperature reaction 3h, and TLC shows that reaction finishes.Add 200mL water in reaction system, the methylene dichloride of telling with the 100mL washing once, the washing of 100mL saturated common salt once, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, obtain oyster white glycocoll shape solid (S)-3-mesyloxy-2-trityl alanine methyl esters (1-2) 13.6g, productive rate: 96.5%.HNMR(300MHz，CDCl
3)：δ7.49(ddd，J＝8，8，1Hz，6H)，7.28(dd，J＝8，8Hz，6H)，7.20(ddd，J＝8，8，1Hz，3H)，4.43(dd，J＝4，10Hz，1H)，4.25(dd，J＝6，10Hz，1H)，3.64-3.68(m，1H)，3.28(s，3H)，3.00(s，3H)，2.89(d，J＝10Hz，1H).
The preparation of embodiment 2:(S)-3-iodo-2-trityl alanine methyl esters (2-1)
Under nitrogen protection, with (S)-3-mesyloxy-2-trityl alanine methyl esters (1-2) 13.6g, join in 200mL acetone; add again sodium iodide 6.0g;, reaction (75 ℃) at the temperature that refluxes was stirred 12 hours, showed that to TLC reaction finishes.The pressure reducing and steaming partial solvent, add again 5% sodium sulfite solution 200mL in the reaction system, system 100mL ethyl acetate extraction 2 times, the organic phase that merges washes twice with water, and saturated common salt is washed once, anhydrous sodium sulfate drying, filter, the pressure reducing and steaming solvent obtains pale yellow oily liquid body (S)-3-iodo-2-trityl alanine methyl esters (2-1) 14.4g, productive rate: 98.5%.HNMR (300MHz, CDCl
3), (two kinds of conformers, 1: 1): δ 7.52-7.43 (m, 6H), (7.32-7.19 m, 9H), 4.39 (dd, J=6.2,8.3Hz, 0.5H), 3.48 (dd, J=3.5,7.0Hz, 0.5H), 3.76 (s, 1.5H), (3.30 s, 1.5H), 3.35 (dd, J=3.5,6.2Hz, 0.5H), 3.21 (dd, J=7.0,9.8Hz, 0.5H), 2.70 (dd, J=8.3,13.0Hz, 0.5H), 2.54 (dd, J=6.2,13.0Hz, 0.5H), 2.3 (bs, 1H).
The preparation of embodiment 3:(2S)-3-(2-oxocyclopentyl)-2-trityl alanine methyl esters (3-2)
The preparation of the first step 1-pyrrolidyl-1-cyclopentenes (3-1)
Cyclopentanone 50.0mL and Pyrrolidine 60.0mL are joined in 250mL toluene, be heated to reflux, minute water, reaction approximately 4 hours is not till having moisture to go out.First remove low boiling point solvent, then underpressure distillation, 52～55 ℃ of lower fractions when collecting 2mmHg get colourless liquid 1-pyrrolidyl-1-cyclopentenes (3-1) 65.3g, productive rate: 84.3%).This product is unstable in air, 0 ℃ of preservation under nitrogen protection.
The preparation of second step (2S)-3-(2-oxocyclopentyl)-2-trityl alanine methyl esters (3-2)
Under nitrogen is protected; (S)-3-iodo-2-trityl alanine methyl esters (2-1) 14.4g and 1-pyrrolidyl-1-cyclopentenes (3-1) 5.4g are joined in 200mL toluene; this reaction (135 ℃) at the temperature that refluxes was reacted approximately 4 hours, and TLC shows that reaction finishes.Reaction system is washed with 5% sodium sulfite solution 100mL, washing, the saturated common salt washing, anhydrous sodium sulfate drying, filter, the pressure reducing and steaming solvent obtains pale yellow oily liquid body (2S)-3-(2-oxocyclopentyl)-2-trityl alanine methyl esters (VI) 13.0g, productive rate: 99.8%.Product is a pair of epimer.
1H?NMR(300MHz，CDCl
3)δ7.51-7.44(m，6H)，7.31-7.18(m，9H)，3.77(s，1.5H)，3.64(s，1.5H)，3.17-3.15(m，0.5H)，2.83-2.80(m，0.5H)，2.49-1.56(m，9H).LCMS：26.94(m/z：450，M+Na
+)，27.37(m/z：450，M+Na
+).
The preparation of embodiment 4:(2S)-3-(2-oxocyclopentyl)-2-trityl alanine methyl esters (3-2)
Under nitrogen protection; with (S)-3-mesyloxy-2-trityl alanine methyl esters (1-2) 5.0g; join in 200mL acetone; add again sodium iodide 0.3g and 1-pyrrolidyl-1-cyclopentenes (3-1) 2.0g; reaction (75 ℃) at the temperature that refluxes was stirred 12 hours, showed that to TLC reaction finishes.The pressure reducing and steaming partial solvent, add again 5% sodium sulfite solution 200mL in the reaction system, system 100mL ethyl acetate extraction 2 times, the organic phase that merges washes twice with water, and saturated common salt is washed once, anhydrous sodium sulfate drying, filter, the pressure reducing and steaming solvent obtains pale yellow oily liquid body (S)-3-iodo-2-trityl alanine methyl esters (3-2) 4.6g, productive rate: 94.6%.The HNMR data are seen embodiment 3.
Embodiment 5:(S, S, S)-preparation of 2-azabicyclo [3,3,0] octane-1-carboxylic acid (5-1)
(2S)-3-(2-oxocyclopentyl)-2-trityl alanine methyl esters (3-2) 13.0g is joined in the dilute hydrochloric acid of 100mL 2M, and reaction system is heated to reflux (125 ℃), stirs 3 hours, shows that to TLC raw material disappears.Remove by filter the solid that reaction produces, and with 50mL ethyl acetate extraction twice, remove little polar impurity, water is spin-dried for, and obtains yellow thick intermediate 4.1g.This intermediate is dissolved in the 100mL Glacial acetic acid, adds 10% Pd/C0.2g, at the H of 1.0MPa
2Catalytic hydrogenation under pressure, normal-temperature reaction 48h is until it is complete to inhale hydrogen.Reacting liquid filtering, be spin-dried for, add methylene dichloride to separate out solid, filtration washing, drying obtains white crystal (S, S, S)-2-azabicyclo [3,3,0] octane-1-carboxylic acid (5-1) 4.0g, productive rate: 84.7%.
1H NMR (300MHz, DMSO-d
6) δ 4.23 (dd, J=11.1,6.9Hz, 1H), 3.95 (t, J=6.6Hz, 1H), 2.82-2.76 (m, 1H), 2.43-2.37 (m, 1H), 1.95-1.90 (m, 1H), 1.76-1.54 (m, 5H), 1.46-1.42 (m, 1H); MS-ESI:m/z:156 (M
++ 1); Ee value＞99.8%.
Embodiment 6:(S, S, S)-preparation of 2-azabicyclo [3,3,0] octane-1-carboxylic acid (5-1)
(2S)-3-(2-oxocyclopentyl)-2-trityl alanine methyl esters (3-2) 10.0g is joined in the dilute hydrochloric acid of 100mL 2M, and reaction system is heated to reflux (125 ℃), stirs 3 hours, shows that to TLC raw material disappears.Remove by filter the solid that reaction produces, and with 50mL ethyl acetate extraction twice, remove little polar impurity, the water of gained is regulated its PH to 4～6 with NaOH, then adds Raney's nickel 0.1g, in the time of 80 ℃, the H of 1.0MPa
2Catalytic hydrogenation under pressure, reaction 24h is until it is complete to inhale hydrogen.Reacting liquid filtering, directly be spin-dried for, obtain white solid (S, S, S)-2-azabicyclo [3,3,0] octane-1-carboxylic acid (5-1) 3.3g, productive rate: 90.9%.Spectral data is seen embodiment 5.
Embodiment 7:(S, S, S)-preparation of 2-azabicyclo [3,3,0] octane-1-benzyl carboxylate hydrochloride (7-1)
(S, S, S)-2-azabicyclo [3,3,0] octane-1-carboxylic acid (5-1) 1.0g is dissolved in 6.0mL benzylalcohol, and ice-water bath is cooling, slowly splashes into thionyl chloride 2.0mL under stirring, and reaction normal temperature (25 ℃) under the protection of nitrogen stirred 12 hours.Add the 50mL isopropyl ether in reaction system, separate out white crystal and filter, wash, dry, get (S, S, S)-2-azabicyclo [3,3,0] octane-1-benzyl carboxylate hydrochloride (7-1) 1.5g, productive rate: 82.5%.
1H NMR (300MHz, CDCl
3) δ 11.38 (br s, 1H), 8.30 (br s, 1H), (7.43-7.27 m, 5H), 5.23 (dd, J=24.0,12.0Hz, 2H), 4.44 (m, 1H), (4.31 m, 1H), 2.86 (m, 1H), (2.65-2.55 m, 1H), 2.28-2.25 (m, 1H), (1.99-1.59 m, 5H), 1.40-1.34 (m, 1H) .MS-ESI:m/z:246 (M
++ 1); Ee value＞99.8%.
Claims (9)
1. the method for a preparation formula (I) compound, is characterized in that, the method comprises the following steps:
(1) formula (II) compound deprotection base Trt and be converted into imines or enamine under acidic conditions;
(2) described imines or enamine are obtained formula (I) compound by catalytic hydrogenation;
Wherein, R
1, R
2Independent respectively is hydrogen or carboxyl-protecting group, and Trt is trityl.
2. method according to claim 1, is characterized in that, formula (I) compound is free amine group or amide.
3. method according to claim 1, the catalyzer of catalytic hydrogenation is palladium carbon.
4. method according to claim 1, the catalyzer of catalytic hydrogenation is Raney's nickel.
5. the method for a preparation formula (II) compound, is characterized in that, formula (II) compound through type (III) compound and the reaction of formula (IV) compound are prepared,
Wherein, R
2Be hydrogen or carboxyl-protecting group, Trt is trityl.
6. the method for a preparation formula (II) compound, is characterized in that, formula (II) compound is prepared with the reaction of formula (IV) compound under iodide exist by the formula V compound,
Wherein, X is methanesulfonates, p-toluenesulfonic esters, chlorine or bromine, and R2 is hydrogen or carboxyl-protecting group, and Trt is trityl.
7. method claimed in claim 6, is characterized in that, described iodide are sodium iodide or potassiumiodide.
8. a compound, is characterized in that, the structural formula of described compound is shown in formula (II), wherein R
2Be hydrogen or carboxyl-protecting group, Trt is trityl.
9. compound according to claim 8, described carboxyl-protecting group is C
1-4Alkyl or benzyl etc.
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| CN104513292A (en) * | 2013-09-29 | 2015-04-15 | 山东新时代药业有限公司 | Preparation method of ramipril |
| CN104817486A (en) * | 2015-03-31 | 2015-08-05 | 浙江工业大学 | Ramipril intermediate synthesis method |
| CN104926712A (en) * | 2014-03-20 | 2015-09-23 | 上海医药工业研究院 | Telaprevir synthesis intermediate and preparation method thereof |
| CN105777611A (en) * | 2016-03-17 | 2016-07-20 | 浙江工业大学 | Synthetic method for preparing ramipril key intermediate from serine |
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| CN104513292A (en) * | 2013-09-29 | 2015-04-15 | 山东新时代药业有限公司 | Preparation method of ramipril |
| CN104926712A (en) * | 2014-03-20 | 2015-09-23 | 上海医药工业研究院 | Telaprevir synthesis intermediate and preparation method thereof |
| CN104926712B (en) * | 2014-03-20 | 2018-03-23 | 上海医药工业研究院 | Synthesize intermediate of VX-960 and preparation method thereof |
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