CN105085510B - A kind of preparation method of the carboxylic acid tert-butyl ester of (S) 4 oxo 2 (carbonyl of thiazolidine 3) pyrrolidines 1 - Google Patents
A kind of preparation method of the carboxylic acid tert-butyl ester of (S) 4 oxo 2 (carbonyl of thiazolidine 3) pyrrolidines 1 Download PDFInfo
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- CN105085510B CN105085510B CN201510576595.XA CN201510576595A CN105085510B CN 105085510 B CN105085510 B CN 105085510B CN 201510576595 A CN201510576595 A CN 201510576595A CN 105085510 B CN105085510 B CN 105085510B
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- oxos
- thiazolidine
- carboxylic acid
- pyrrolidines
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- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 150000003235 pyrrolidines Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 title abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 title abstract 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 16
- 239000011230 binding agent Substances 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 230000008878 coupling Effects 0.000 claims abstract description 10
- 238000010168 coupling process Methods 0.000 claims abstract description 10
- 238000005859 coupling reaction Methods 0.000 claims abstract description 10
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960003151 mercaptamine Drugs 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- 150000007530 organic bases Chemical group 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 150000003233 pyrroles Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 abstract 1
- 238000006073 displacement reaction Methods 0.000 abstract 1
- 229910052731 fluorine Inorganic materials 0.000 abstract 1
- 239000011737 fluorine Substances 0.000 abstract 1
- 230000000269 nucleophilic effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000009413 insulation Methods 0.000 description 8
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 8
- 229950000034 teneligliptin Drugs 0.000 description 8
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 239000003880 polar aprotic solvent Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229960002668 sodium chloride Drugs 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 230000003595 spectral effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- -1 diisopropyl Ethamine Chemical compound 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The present invention relates to the preparing technical field of pharmaceutical intermediate synthesis technical field, more particularly to heterocyclic compound, specifically discloses a kind of preparation method of the carboxylic acid tert-butyl ester of (S) 4 oxo 2 (carbonyl of thiazolidine 3) pyrrolidines 1.Comprise the following steps：Using the oxo L proline of N Boc 4 and Mercaptamine as raw material, in the presence of coupling reagent and acid binding agent, reacted again with formalin, the carboxylic acid tert-butyl ester of (S) 4 oxo 2 (carbonyl of thiazolidine 3) pyrrolidines 1 is obtained by nucleophilic displacement of fluorine.This method operating condition is easily controllable, and raw material is easy to get, and reactions steps are short, can obtain product by one kettle way single step reaction, high income, the cycle is short, and cost is low, and pollution is small, is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparing technical field of pharmaceutical intermediate synthesis technical field, more particularly to heterocyclic compound.
Background technology
Teneligliptin, English name：Teneligliptin, entitled 3- [[(2S, 4S) -4- [4- (the 3- methyl isophthalic acids-benzene of chemistry
Base -1H- pyrazoles -5- bases) -1- piperazinyls] -2- pyrrolidinyls] formoxyl] thiazolidine, trade name Tenelia, structural formula is such as
Under：
The medicine is by the company's joint study exploitations altogether of Mitsubishi Tian Bianyu the one or three.Teneligliptin is in September, 2011 in Japan
Granted listing, the clinically treatment for type-II diabetes.
(S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters（Formula）It is hypoglycemic for synthesizing
The important intermediate of medicine teneligliptin,
Wherein, Boc is tertbutyloxycarbonyl.
In its existing preparation method, chemical synthesis step is longer, and environmental pollution is heavier, it is difficult to realizes extensive
Industrialization；Biological fermentation process is had a great influence by external environment, and the purity of product is low, and industrialized production is restricted.
The content of the invention
The technical problem to be solved in the present invention is to provide one kind (S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrrolidines -1-
The preparation method of carboxylic acid tert-butyl ester, this method operating condition is easily controllable, and raw material is easy to get, and reactions steps are short, passes through one kettle way one
Step reaction can obtain product, and high income, the cycle is short, and cost is low, and pollution is small, be particularly suitable for application as producing teneligliptin medicine
The preparation of intermediate, is suitable for industrialized production.
In order to solve the above technical problems, the technical solution used in the present invention is：One kind (S) -4- oxos -2- (thiazolidine -
3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters preparation method, with N-Boc-4- oxos-L-PROLINE（Formula）And cysteamine salt
Hydrochlorate（Formula）For raw material, be dissolved in polar aprotic solvent, in the presence of coupling reagent and acid binding agent, then with formaldehyde（Formula）
Reactant aqueous solution, (S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters are made（Formula）.
Reaction equation is as follows：
Wherein, Boc is tertbutyloxycarbonyl.
Further, the coupling reagent is 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, 1- hydroxyls
BTA, the one or more in dicyclohexylcarbodiimide.
Further, the polar aprotic solvent is dichloromethane, tetrahydrofuran or acetone.
Further, the acid binding agent is organic base.
Preferably, the acid binding agent is N, N diisopropylethylamine or triethylamine.
Further, the reaction temperature is -10~20 DEG C.
Preferably, the reaction temperature is 0~10 DEG C.
Further, the ratio between amount of material of the N-Boc-4- oxos-L-PROLINE, Mercaptamine and formaldehyde is
1:(1.05~1.5):(1.2~1.5).
Preferably, the ratio between amount of material of the N-Boc-4- oxos-L-PROLINE, Mercaptamine and formaldehyde is 1:
1.1:1.2。
Further, after adding coupling reagent and acid binding agent, temperature control, which is reacted to HPLC, detects N-Boc-4- oxygen in reaction solution
Generation-L-PROLINE≤1%, reaction solution is concentrated, then reacted with formalin.
It is using beneficial effect caused by above-mentioned technical proposal：
1）The inventive method prepares simplicity, and cost of material is low, activity stabilized；
2）The inventive method operating condition is easily controllable, and coupling agent performance is good, and reactions steps are short, passes through single step reaction
Product is obtained, high income, the cycle is short, and cost is low, pollution-free, is particularly suitable for application as producing the system of teneligliptin pharmaceutical intermediate
It is standby, it is suitable for industrialized production.
Embodiment
The present invention is with N-Boc-4- oxos-L-PROLINE（Formula）, Mercaptamine（Formula）And formaldehyde（Formula）It is water-soluble
Liquid is raw material, in the presence of coupling reagent and acid binding agent, is reacted in polar aprotic solvent, obtained (S) -4- oxos -
2- (thiazolidine -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters（Formula）.
Reaction equation is as follows：
Wherein, Boc is tertbutyloxycarbonyl.
The inventive method raw material is easy to get, apparent availability is big, and quality control is good, and one kettle way is prepared among teneligliptin
Body formulaCompound, reaction is gentle, and easily-controlled reaction conditions, reactions steps are few, reacts and product purity height is made, suitable for industrialization
Production, has the high market competitiveness.
Illustrate below and preparation method of the present invention is described in further detail.
Embodiment 1
Polar aprotic solvent dichloromethane 500ml is added in the 1L four-hole bottles of dried and clean, stirring, adds 50.0g
（218mmol）Compound IV and 27.3g（240mmol）Compound III, system is cooled to -10~0 DEG C, adds 32.4g
（240mmol）Coupling reagent I-hydroxybenzotriazole, 46.0g 240mmol coupling reagents 1- (3- dimethylamino-propyls) -3- second
Base carbodiimide hydrochloride, in N2Under protection, temperature control -10~0 DEG C, 59.2g is added dropwise（458mmol）Acid binding agent N, N diisopropyl
Ethamine, 0.5~1h of control are dripped off.After drop finishes, temperature control -10~0 DEG C insulation 2h, HPLC track to compound IV≤1%.Will reaction
Liquid is concentrated into 80~120ml of residue, and compound II is added dropwise to system（40% formalin）19.6g（262mmol）, drop complete -10
Start to process after~0 DEG C of insulation 10h, adds 250ml running water, makes to be extracted with ethyl acetate（Each 300ml, is extracted twice）,
Organic phase merges, and using 150ml 1mol/L salt acid elution 1 time, reuses 100ml 20% sodium-chloride water solution washing 1
Secondary, organic phase is concentrated into 60~100ml, and 250ml normal heptane crystallizations are added dropwise, and separates out off-white powder, is cooled between 0~5 DEG C
1h is incubated, filtering, obtains compound (S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters（I）, yield
For 85.7%.High-efficient liquid phase color spectral purity is 99.6%.H-NMR (CDCl3) d1.47 (9H, s), 2.45–2.57 (1H,
m), 2.70–2.93 (1H, m),2.97–3.22 (2H, m), 3.66–3.78 (0.6H, m), 3.80–4.10 (3H,
m), 4.28–4.38 (0.4H, m), 4.45–5.08 (3H, m)。
Embodiment 2
Dichloromethane 500ml is added in dried and clean 1L four-hole bottles, stirring, adds 50.0g（218mmol）Compound
IV and 27.3g（240mmol）Compound III, system is cooled to 0~10 DEG C, adds 32.4g（240mmol）1- hydroxy benzenes
And triazole, 46.0g 240mmol 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, in N2Under protection, temperature control-
10~0 DEG C, 59.2g is added dropwise（458mmol）N, N diisopropylethylamine, control 0.5-1h are dripped off.After drop finishes, 0~10 DEG C of guarantor of temperature control
Warm 2h, HPLC track to compound IV≤1%.Reaction solution is concentrated into 80~120ml of residue, compound II is added dropwise to system
（40% formalin）19.6g（262mmol）, start to process after complete 0~10 DEG C of insulation 10h is dripped, 250ml running water is added, makes
It is extracted with ethyl acetate（Each 300ml, is extracted twice）, organic phase merges, using 150ml1mol/L salt acid elution 1 time, then
Washed 1 time using the sodium-chloride water solutions of 100ml 20%, organic phase is concentrated into 60~100ml, and 250ml normal heptane crystallizations, analysis is added dropwise
Go out off-white powder, 1h is incubated between being cooled to 0-5 DEG C, filter, obtain compound (S) -4- oxos -2- (thiazolidine -3- carbonyls
Base) pyrrolidines -1- carboxylic acid tert-butyl esters（I）, yield 88.5%.High-efficient liquid phase color spectral purity is 99.4%.H-NMR (CDCl3)
d1.47 (9H, s), 2.45–2.57 (1H, m), 2.70–2.93 (1H, m),2.97–3.22 (2H, m), 3.66–
3.78 (0.6H, m), 3.80–4.10 (3H,m), 4.28–4.38 (0.4H, m), 4.45–5.08 (3H, m)。
Embodiment 3
Dichloromethane 500ml is added in dried and clean 1L four-hole bottles, stirring is opened, adds 50.0g（218mmol）Chemical combination
Thing IV and 27.3g（240mmol）Compound III, system is cooled to 10~20 DEG C, adds 32.4g（240mmol）1- hydroxyls
BTA, 46.0g 240mmol 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, in N2Under protection, control
10~20 DEG C of temperature, 59.2g is added dropwise（458mmol）N, N diisopropylethylamine, control 0.5-1h are dripped off.After drop finishes, temperature control 0~10
A DEG C DEG C insulation 2h, HPLC tracks to compound IV≤1%.Reaction solution is concentrated into 80~120ml of residue, chemical combination is added dropwise to system
Thing II（40% formalin）19.6g（262mmol）, start to process after complete 10~20 DEG C of insulations 10h is dripped, adds 250ml originally
Water, make to be extracted with ethyl acetate（Each 300ml, is extracted twice）, organic phase merges, and uses 150ml1mol/L salt acid elution
1 time, reuse the sodium-chloride water solutions of 100ml 20% and wash 1 time, organic phase is concentrated into 60~100ml, and 250ml normal heptanes are added dropwise
Crystallization, off-white powder is separated out, 1h is incubated between being cooled to 0-5 DEG C, filtered, obtain compound (S) -4- oxo -2- (thiazoles
Alkane -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters（I）, yield 89.0%.High-efficient liquid phase color spectral purity is 99.2%.H-NMR
(CDCl3) d1.47 (9H, s), 2.45–2.57 (1H, m), 2.70–2.93 (1H, m),2.97–3.22 (2H,
m), 3.66–3.78 (0.6H, m), 3.80–4.10 (3H,m), 4.28–4.38 (0.4H, m), 4.45–5.08
(3H, m)。
Embodiment 4
Dichloromethane 500ml is added in dried and clean 1L four-hole bottles, stirring is opened, adds 50.0g（218mmol）Chemical combination
Thing IV and 37.1g（327mmol）Compound III, system is cooled to 0~10 DEG C, adds 32.4g（240mmol）1- hydroxyls
BTA, 46.0g 240mmol 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, in N2Under protection, control
- 10~0 DEG C of temperature, 59.2g is added dropwise（458mmol）N, N diisopropylethylamine, control 0.5-1h are dripped off.After drop finishes, temperature control 0~10
DEG C insulation 2h, HPLC tracks to compound IV≤1%.Reaction solution is concentrated into 80~120ml of residue, compound is added dropwise to system
II（40% formalin）24.5g（327mmol）, start to process after complete 0~10 DEG C of insulation 10h is dripped, adds 250ml running water,
Make to be extracted with ethyl acetate（Each 300ml, is extracted twice）, organic phase merges, using 150ml1mol/L salt acid elution 1 time,
The sodium-chloride water solutions of 100ml 20% are reused to wash 1 time, organic phase is concentrated into 60~100ml, and 250ml normal heptane crystallizations are added dropwise,
Off-white powder is separated out, 1h is incubated between being cooled to 0-5 DEG C, filters, obtains compound (S) -4- oxos -2- (thiazolidine -3- carbonyls
Base) pyrrolidines -1- carboxylic acid tert-butyl esters（I）, yield 88.5%.High-efficient liquid phase color spectral purity is 99.3%.H-NMR (CDCl3)
d1.47 (9H, s), 2.45–2.57 (1H, m), 2.70–2.93 (1H, m),2.97–3.22 (2H, m), 3.66–
3.78 (0.6H, m), 3.80–4.10 (3H,m), 4.28–4.38 (0.4H, m), 4.45–5.08 (3H, m)。
Embodiment 5
Dichloromethane 500ml is added in dried and clean 1L four-hole bottles, stirring is opened, adds 50.0g（218mmol）Chemical combination
Thing IV and 26g（229mmol）Compound III, system is cooled to 0~10 DEG C, adds 32.4g（240mmol）1- hydroxy benzenes
And triazole, 46.0g 240mmol 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, in N2Under protection, temperature control-
10~0 DEG C, 59.2g is added dropwise（458mmol）N, N diisopropylethylamine, control 0.5-1h are dripped off.After drop finishes, 0~10 DEG C of guarantor of temperature control
Warm 2h, HPLC track to compound IV≤1%.Reaction solution is concentrated into 80~120ml of residue, compound II is added dropwise to system
（40% formalin）21.3g（283mmol）, start to process after complete 0~10 DEG C of insulation 10h is dripped, 250ml running water is added, makes
It is extracted with ethyl acetate（Each 300ml, is extracted twice）, organic phase merges, using 150ml1mol/L salt acid elution 1 time, then
Washed 1 time using the sodium-chloride water solutions of 100ml 20%, organic phase is concentrated into 60~100ml, and 250ml normal heptane crystallizations, analysis is added dropwise
Go out off-white powder, 1h is incubated between being cooled to 0-5 DEG C, filter, obtain compound (S) -4- oxos -2- (thiazolidine -3- carbonyls
Base) pyrrolidines -1- carboxylic acid tert-butyl esters（I）, yield 87.0%.High-efficient liquid phase color spectral purity is 99.0%.H-NMR (CDCl3)
d1.47 (9H, s), 2.45–2.57 (1H, m), 2.70–2.93 (1H, m),2.97–3.22 (2H, m), 3.66–
3.78 (0.6H, m), 3.80–4.10 (3H,m), 4.28–4.38 (0.4H, m), 4.45–5.08 (3H, m)。
Coupling reagent used in the embodiment of the present invention can select 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide hydrochlorides
Salt, I-hydroxybenzotriazole, the one or more in dicyclohexylcarbodiimide.
The preferred dichloromethane of polar aprotic solvent used in the embodiment of the present invention, tetrahydrofuran or acetone.
Acid binding agent used in the embodiment of the present invention selects organic base, preferably N, N diisopropylethylamine or triethylamine.
Claims (7)
1. a kind of preparation method of (S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters, its feature exist
In：Using N-Boc-4- oxos-L-PROLINE and Mercaptamine as raw material, it is dissolved in solvent, in coupling reagent and acid binding agent
In the presence of, temperature control is reacted to high performance liquid chromatography（HPLC）N-Boc-4- oxos-L-PROLINE≤1% in reaction solution is detected,
Reaction solution is concentrated, then reacted with formalin, it is post-treated that (S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrroles is made
Alkane -1- carboxylic acid tert-butyl esters；The solvent is dichloromethane, tetrahydrofuran or acetone；The coupling reagent is 1- (3- dimethylaminos
Propyl group) -3- ethyl-carbodiimide hydrochlorides, I-hydroxybenzotriazole, the one or more in dicyclohexylcarbodiimide.
2. one kind (S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters according to claim 1
Preparation method, it is characterised in that the acid binding agent is organic base.
3. one kind (S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters according to claim 2
Preparation method, it is characterised in that the acid binding agent is N, N- diisopropylethylamine or triethylamine.
4. one kind (S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters according to claim 1
Preparation method, it is characterised in that the reaction temperature be -10~20 DEG C.
5. one kind (S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters according to claim 1
Preparation method, it is characterised in that the reaction temperature be 0~10 DEG C.
6. one kind (S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters according to claim 1
Preparation method, it is characterised in that the amount of the material of the N-Boc-4- oxos-L-PROLINE, Mercaptamine and formaldehyde it
Than for 1:(1.05~1.5):(1.2~1.5).
7. one kind (S) -4- oxos -2- (thiazolidine -3- carbonyls) pyrrolidines -1- carboxylic acid tert-butyl esters according to claim 1
Preparation method, it is characterised in that the amount of the material of the N-Boc-4- oxos-L-PROLINE, Mercaptamine and formaldehyde it
Than for 1:1.1:1.2.
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