CN102336767A - Method for preparing high-purity chiral alpha-substituted-6,7-thiaindan[3,2-c]pyridine derivative - Google Patents
Method for preparing high-purity chiral alpha-substituted-6,7-thiaindan[3,2-c]pyridine derivative Download PDFInfo
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- CN102336767A CN102336767A CN201110191789XA CN201110191789A CN102336767A CN 102336767 A CN102336767 A CN 102336767A CN 201110191789X A CN201110191789X A CN 201110191789XA CN 201110191789 A CN201110191789 A CN 201110191789A CN 102336767 A CN102336767 A CN 102336767A
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 150000003222 pyridines Chemical class 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000032050 esterification Effects 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- 238000006683 Mannich reaction Methods 0.000 claims abstract 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 37
- -1 (S)-α-substituted-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid Chemical class 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 229910052808 lithium carbonate Inorganic materials 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 36
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract description 15
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 abstract description 10
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 abstract description 9
- 229960003009 clopidogrel Drugs 0.000 abstract description 8
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 7
- 238000001514 detection method Methods 0.000 abstract 2
- DCASRSISIKYPDD-AWEZNQCLSA-N (2s)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-ium-5-yl)acetate Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)O)=CC=CC=C1Cl DCASRSISIKYPDD-AWEZNQCLSA-N 0.000 abstract 1
- LMIZLNPFTRQPSF-UHFFFAOYSA-N 2-azaniumyl-2-(2-chlorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=CC=C1Cl LMIZLNPFTRQPSF-UHFFFAOYSA-N 0.000 abstract 1
- DCASRSISIKYPDD-UHFFFAOYSA-N clopidogrel carboxylic acid Chemical compound C1CC=2SC=CC=2CN1C(C(=O)O)C1=CC=CC=C1Cl DCASRSISIKYPDD-UHFFFAOYSA-N 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 239000007791 liquid phase Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 20
- 238000000967 suction filtration Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 238000010025 steaming Methods 0.000 description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- 239000004471 Glycine Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 5
- UIQVGMBTAXORQL-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;methanol Chemical compound OC.OC(=O)C(O)C(O)C(O)=O UIQVGMBTAXORQL-UHFFFAOYSA-N 0.000 description 4
- VMJOFTHFJMLIKL-UHFFFAOYSA-N 2-thiophen-2-ylethanol Chemical compound OCCC1=CC=CS1 VMJOFTHFJMLIKL-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 3
- XSSHGQFBKZBOPH-UHFFFAOYSA-N C(=O)(OCC)Cl.C(C)(=O)O.NC(=N)N Chemical compound C(=O)(OCC)Cl.C(C)(=O)O.NC(=N)N XSSHGQFBKZBOPH-UHFFFAOYSA-N 0.000 description 2
- SUDFFTSADNHGEO-UHFFFAOYSA-N C(=O)(OCC)Cl.NCC(=O)O Chemical compound C(=O)(OCC)Cl.NCC(=O)O SUDFFTSADNHGEO-UHFFFAOYSA-N 0.000 description 2
- JOXHILFLNPPELN-UHFFFAOYSA-N C(CC)Cl.NCC(=O)O Chemical compound C(CC)Cl.NCC(=O)O JOXHILFLNPPELN-UHFFFAOYSA-N 0.000 description 2
- ZDMWSYXPZCVAOH-ZVGUSBNCSA-N C([C@H](O)[C@@H](O)C(=O)O)(=O)O.COC(CN)=O Chemical compound C([C@H](O)[C@@H](O)C(=O)O)(=O)O.COC(CN)=O ZDMWSYXPZCVAOH-ZVGUSBNCSA-N 0.000 description 2
- XRCKIPQZEZHEDG-UHFFFAOYSA-N Cl.COC(C)=O.NC(=N)N Chemical compound Cl.COC(C)=O.NC(=N)N XRCKIPQZEZHEDG-UHFFFAOYSA-N 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 2
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- YLGOWOYJZYKTDO-UHFFFAOYSA-N propan-2-yl 2-aminoacetate Chemical compound CC(C)OC(=O)CN YLGOWOYJZYKTDO-UHFFFAOYSA-N 0.000 description 2
- UBKCIXXGQRZHRO-UHFFFAOYSA-N propan-2-yl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)OC(=O)CN UBKCIXXGQRZHRO-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229940020573 plavix Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及一种制备高纯度(S)-α-(2’-氯苯基)-6，7-二氢噻吩并[3，2-c]吡啶-5(4H)-乙酸的方法。所述方法包括：由邻氯苯甘氨酸经过酯化、拆分、与2-(2’-噻吩基)乙醇对甲苯磺酸酯发生反应、在甲醇中与甲醛发生曼尼希反应实现关环及水解得到α-(2’-氯苯基)-6，7-二氢噻吩并[3，2-c]吡啶-5(4H)-乙酸等步骤。本发明操作简单、原料廉价易得，产品经HPLC检测纯度达到99％以上。为氯吡格雷产品质量的检测提供了液相定位的依据。The present invention relates to a method for preparing high-purity (S)-α-(2'-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid. The method comprises: undergoing esterification, resolution, reaction with 2-(2'-thienyl)ethanol p-toluenesulfonate from o-chlorophenylglycine, Mannich reaction with formaldehyde in methanol to realize ring closure and Hydrolysis to obtain α-(2'-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid and other steps. The invention has simple operation, cheap and easy-to-obtain raw materials, and the product has a purity of more than 99% through HPLC detection. It provides the basis for liquid phase positioning for the detection of the quality of clopidogrel products.
Description
Technical field
The present invention relates to a kind of preparation high purity chirality alpha-substitution-6, the 7-dihydro-thiophene is the method for [3,2-c] pyridine derivate also; Specifically; Relate to a kind of preparation high purity (S)-α-(2 '-chloro-phenyl-)-6, the 7-dihydro-thiophene is the method for [3,2-c] pyridines-5 (4H)-acetate also.
Background technology
Clopidogrel (Clopidogrel); Chemical name: (S)-α-(2 '-chloro-phenyl-)-6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-methyl acetate also; Trade(brand)name: Pohle dimension (Plavix); Structure is suc as formula shown in the A, is the anticoagulant of new generation of French Sano-Synth labo drugmaker research and development, is mainly used in restenosis and thrombotic complications etc. in treatment arteriosclerosis disease, acute coronary artery syndrome, the prevention intracoronary stent implantation after poppet.
So far, the compound of known effect clopidogrel drug effect mainly contains three, suc as formula compound shown in B, C or the D, or its hydrochloride or vitriol.The height of its content directly influences the clopidogrel drug effect.Stipulate like U.S. FDA: in the clopidogrel medicine, the content of said three kinds of compounds (compound shown in formula B, C or the D) must not surpass 0.1% (HPLC content).
Usually, prepare in the process, adopt performance liquid chromatography (HPLC) that product is carried out quality monitoring at clopidogrel.Therefore prepare compound shown in highly purified formula B, C or the D (as standard specimen), most important to clopidogrel quality monitoring.
Summary of the invention
The objective of the invention is to, a kind of preparation high purity (S)-alpha-substitution-6 is provided, the 7-dihydro-thiophene is the method for [3,2-c] pyridines-5 (4H)-acetate or its salt also.
Described (S)-alpha-substitution-6,7-dihydro-thiophene also the structure of [3,2-c] pyridines-5 (4H)-acetate suc as formula shown in the B:
The method for preparing compound or its salt shown in the high purity formula B provided by the present invention, it comprises the steps:
(1) by the step of compound shown in the formula I through compound shown in the esterification acquisition formula II;
(2) compound shown in the split-type II gets the step of compound shown in the formula III;
(3) under the condition that has alkali to exist,, get the step of compound shown in the formula IV by compound shown in the formula III and the reaction of 2-(2 '-thienyl) ethanol p-toluenesulfonic esters;
(4) compound shown in the formula IV is through the step of compound shown in Mannich (Mannich) the reaction acquisition formula V; With
(5) compound shown in the formula V obtains the step of target compound (compound shown in the formula B) through hydrolysis reaction;
Wherein, R is a carbonatoms more than or equal to two straight or branched alkyl, C
*The R type that is configured as or S type.
Contriver of the present invention finds: as R when being the former hand number of carbon more than or equal to two straight or branched alkyl, and the purity of gained target compound and yield height, on the contrary quite different.So, above-mentioned preparation method is proposed.By prepared (the S)-alpha-substitution-6 of above-mentioned preparation method, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-acetate also, and its purity can reach more than 99% (HPLC).In addition, method provided by the present invention also has reaction conditions gentleness and yield advantages of higher.
Embodiment
In optimized technical scheme of the present invention, R is C
2～C
6Straight or branched alkyl, preferred R are C
2～C
4The straight or branched alkyl, best R is ethyl, n-propyl, sec.-propyl, normal-butyl or isobutyl-.
In another optimized technical scheme of the present invention, step (1) is performed such: promptly compound shown in the formula I earlier with carboxylic acid halides reagent (like sulfur oxychloride etc.) reaction, corresponding carboxylic acid halides (its structure is suc as formula shown in the VI), and then by compound and C shown in the formula VI
2～C
6Aliphatic monobasic alcohol reaction, compound shown in the formula II;
In the formula VI, X is halogen (F, Cl, Br or I).
In another optimized technical scheme of the present invention, compound shown in the split-type II is to adopt resolution reagent to split in the step (2), and used resolution reagent is: L-(+)-tartrate.
In another optimized technical scheme of the present invention, the alkali described in the step (3) is: Quilonum Retard, yellow soda ash or salt of wormwood.
Through embodiment the present invention is done further elaboration below, its purpose is through being better to understand content of the present invention.The example of therefore, being lifted does not limit protection scope of the present invention.
Embodiment 1
In the 250ml there-necked flask, add 15.0g o-chlorobenzene glycine and 120ml absolute ethyl alcohol,, treat to dissolve fully the back and drip the 14.4g sulfur oxychloride, dropwise the afterreaction system and be warming up to 80 ℃ of back flow reaction 21-24h 0-5 ℃ of stirring.Ethanol is removed in steaming, adds slowly to lower the temperature after the backflow of 40ml absolute ethyl alcohol is dissolved again, and separates out white solid, suction filtration.The filtrating recrystallization merges product and obtains the o-chlorobenzene glycine carbethoxy hydrochloride.Yield 88%, Mp:165-167 ℃.
In the 250ml beaker, add 10.0g o-chlorobenzene glycine carbethoxy hydrochloride and 50ml water; Add the 20ml methylene dichloride after the stirring and dissolving again; Regulator solution pH value is 7.0-7.2, separatory, and water layer is with 5ml dichloromethane extraction 2 times; Merge organic layer, revolve to steam and remove methylene dichloride and obtain the o-chlorobenzene glycine ethyl ester.Yield 95%.
In the 100ml there-necked flask, add 6.6g L-(+)-tartrate and 64ml anhydrous methanol; 10-13 ℃ of following stirring and dissolving; Add the 0.2ml phenyl aldehyde again; Slowly be added drop-wise to the mixing solutions of o-chlorobenzene glycine ethyl ester 8g and 16ml acetone in the tartrate methanol solution, after dropwising, be warming up to 25 ℃ of reaction 10h.Suction filtration, filtrating are cooled to 5-7 ℃ and stir 5h and separate out the solid suction filtration once more, merge product, and drying obtains (S)-o-chlorobenzene glycine ethyl ester-(L)-tartrate.Yield 75%, Mp:156 ℃, [α]
D=22 (c=1, CH
3OH).
In the 100ml there-necked flask, add 7.2g (S)-o-chlorobenzene glycine ethyl ester-(L)-tartrate, 6.8g 2-thiophene ethanol p-toluenesulfonic esters, 4.2g salt of wormwood and less water.95 ℃ are reacted 12h down.Cooling back adds 40ml water and 20ml ETHYLE ACETATE, stirs separatory after 15 minutes, and water layer is with twice of 5ml ethyl acetate extraction.Combined ethyl acetate.Use concentrated hydrochloric acid to regulate the pH value down at 0-3 ℃ and be 1.0-1.2, filter, dry (S)-α-(2-the chloro-phenyl-)-2 thiophene ethyl amine guanidine-acetic acid carbethoxy hydrochloride that gets.Yield 76%, MP:152-153 ℃, [α]
D=23 (c=1, CH
3OH).
In the 250ml flask, add 13ml methyl alcohol, 7.1g2-chloro-phenyl--2 thiophene ethyl amine guanidine-acetic acid carbethoxy hydrochloride, formaldehyde 40ml, 37-39 ℃ is reacted 16h down.After finishing, reaction adds the 20ml methylene dichloride, 30ml water, and it is 9 that aqueous sodium carbonate is regulated the pH value.Separatory, water layer is with twice of 5ml dichloromethane extraction.Revolve and use the 30ml acetone solution after methylene dichloride is removed in steaming, add the 1.7g vitriol oil down at 7 ℃.Stir 12h down at 25 ℃, suction filtration gets (S)-α-(2-chloro-phenyl-)-6, and the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-ETHYLE ACETATE vitriol also.Yield 68%, Mp:86 ℃
In the 100ml flask, add 3.9g (S)-α-(2-chloro-phenyl-)-6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-ETHYLE ACETATE vitriol also; The 25ml absolute ethyl alcohol, 8ml aqueous sodium hydroxide solution, backflow 10h; Adjust pH is 7.0, uses the 10ml dichloromethane extraction, revolves to obtain (S)-α-(2-chloro-phenyl-)-6 after methylene dichloride is removed in steaming; The 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-acetate also.Yield 65%, Mp:136-139 ℃, content (HPLC): 99.1%.
Embodiment 2
In the 250ml there-necked flask, add 30.0g o-chlorobenzene glycine and the anhydrous n-propyl alcohol of 150ml,, treat to dissolve fully the back and drip the 23.4ml sulfur oxychloride, dropwise the afterreaction system and be warming up to 80 ℃ of back flow reaction 21-24h 0-5 ℃ of stirring.N-propyl alcohol is removed in steaming, adds slowly to lower the temperature after the anhydrous n-propyl alcohol backflow of 40ml is dissolved again, and separates out white solid, suction filtration.The filtrating recrystallization merges product and obtains o-chlorobenzene glycine n-propyl hydrochloride.Yield 90.8%, Mp:167.5-168.6 ℃.
In the 250ml beaker, add 10.0g o-chlorobenzene glycine n-propyl hydrochloride and 50ml water; Add the 20ml methylene dichloride after the stirring and dissolving again; Regulator solution pH value is 7.0-7.2, separatory, and water layer is with 5ml dichloromethane extraction 2 times; Merge organic layer, revolve to steam and remove methylene dichloride and obtain the o-chlorobenzene glycine n-propyl.Yield 92%.
In the 100ml there-necked flask, add 1.32g L-(+)-tartrate and 20ml anhydrous methanol; 10-13 ℃ of following stirring and dissolving; Add the 0.2ml phenyl aldehyde again; Slowly be added drop-wise to the mixing solutions of o-chlorobenzene glycine n-propyl 2g and 5ml acetone in the tartrate methanol solution, after dropwising, be warming up to 25 ℃ of reaction 10h.Suction filtration, filtrating are cooled to 5-7 ℃ and stir 5h and separate out the solid suction filtration once more, merge product, and drying obtains (S)-o-chlorobenzene glycine n-propyl-(L)-tartrate.Yield 68%, Mp:151.9-153.5 ℃, [α]
D=4 (c=1, CH
3OH).
In the 100ml there-necked flask, add 7.4g (S)-o-chlorobenzene glycine n-propyl-(L)-tartrate, 6.08g 2-thiophene ethanol p-toluenesulfonic esters, 4.46g salt of wormwood and less water.95 ℃ are reacted 12h down.Cooling back adds 40ml water and 20ml ETHYLE ACETATE, stirs separatory after 15 minutes, and water layer is with twice of 5ml ethyl acetate extraction.Combined ethyl acetate.Use concentrated hydrochloric acid to regulate the pH value down at 0-3 ℃ and be 1.0-1.2, filter, dry (S)-α-(2-the chloro-phenyl-)-2 thiophene ethyl amine guanidine-acetic acid n-propyl hydrochloride that gets.Yield 81.29%, MP:81.1-84.4 ℃, [α]
D=-8 (c=1, CH
3OH).
In the 250ml flask, add 5ml methyl alcohol, 2.53g2-chloro-phenyl--2 thiophene ethyl amine guanidine-acetic acid n-propyl hydrochloride, formaldehyde 14ml, 37-39 ℃ is reacted 16h down.After finishing, reaction adds the 20ml methylene dichloride, 30ml water, and it is 9 that aqueous sodium carbonate is regulated the pH value.Separatory, water layer is with twice of 5ml dichloromethane extraction.Revolve and use the 30ml acetone solution after methylene dichloride is removed in steaming, add the 0.12g vitriol oil down at 7 ℃.Stir 12h down at 25 ℃, suction filtration gets (S)-α-(2-chloro-phenyl-)-6, and the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-n-propyl acetate vitriol also.Yield 96%, Mp:125.1 ℃
In the 100ml flask, add 3.9g (S)-α-(2-chloro-phenyl-)-6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-n-propyl acetate vitriol also; The 25ml absolute ethyl alcohol, 8ml aqueous sodium hydroxide solution, backflow 10h; Adjust pH is 7.0, uses the 10ml dichloromethane extraction, revolves to obtain (S)-α-(2-chloro-phenyl-)-6 after methylene dichloride is removed in steaming; The 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-acetate also.Yield 76%, Mp:137-139 ℃, content (HPLC): 96.8%.
Embodiment 3
In the 250ml there-necked flask, add 30.0g o-chlorobenzene glycine and 190ml anhydrous isopropyl alcohol,, treat to dissolve fully the back and drip the 23.4g sulfur oxychloride, dropwise the afterreaction system and be warming up to 80 ℃ of back flow reaction 21-24h 0-5 ℃ of stirring.Virahol is removed in steaming, adds slowly to lower the temperature after the backflow of 40ml anhydrous isopropyl alcohol is dissolved again, and separates out white solid, suction filtration.The filtrating recrystallization merges product and obtains o-chlorobenzene glycine isopropyl ester hydrochloride.Yield 75.3%, Mp:176.8-178.8 ℃.
In the 250ml beaker, add 10.0g o-chlorobenzene glycine isopropyl ester hydrochloride and 50ml water; Add the 20ml methylene dichloride after the stirring and dissolving again; Regulator solution pH value is 7.0-7.2, separatory, and water layer is with 5ml dichloromethane extraction 2 times; Merge organic layer, revolve to steam and remove methylene dichloride and obtain the o-chlorobenzene glycine isopropyl ester.Yield 91%.
In the 100ml there-necked flask, add 1.71g L-(+)-tartrate and 20ml anhydrous methanol; 10-13 ℃ of following stirring and dissolving; Add the 0.2ml phenyl aldehyde again; Slowly be added drop-wise to the mixing solutions of o-chlorobenzene glycine isopropyl ester 2.59g and 5ml acetone in the tartrate methanol solution, after dropwising, be warming up to 25 ℃ of reaction 10h.Suction filtration, filtrating are cooled to 5-7 ℃ and stir 5h and separate out the solid suction filtration once more, merge product, and drying obtains (S)-o-chlorobenzene glycine isopropyl ester-(L)-tartrate.Yield 57.6%, Mp:152 ℃, [α]
D=-44 (c=1, CH
3OH).
In the 100ml there-necked flask, add 5.28g (S)-o-chlorobenzene glycine isopropyl ester-(L)-tartrate, 6.20g 2-thiophene ethanol p-toluenesulfonic esters, 3.04g salt of wormwood and less water.95 ℃ are reacted 12h down.Cooling back adds 40ml water and 20ml ETHYLE ACETATE, stirs separatory after 15 minutes, and water layer is with twice of 5ml ethyl acetate extraction.Combined ethyl acetate.Use concentrated hydrochloric acid to regulate the pH value down at 0-3 ℃ and be 1.0-1.2, filter, dry (S)-α-(2-the chloro-phenyl-)-2 thiophene ethyl amine guanidine-acetic acid isopropyl ester hydrochloride that gets.Yield 75.4%, MP:107.8-111 ℃, [α]
D=-66 (c=1, CH
3OH).
In the 250ml flask, add 7ml methyl alcohol, 3.8g2-chloro-phenyl--2 thiophene ethyl amine guanidine-acetic acid isopropyl ester hydrochloride, formaldehyde 21ml, 37-39 ℃ is reacted 16h down.After finishing, reaction adds the 10ml methylene dichloride, 15ml water, and it is 9 that aqueous sodium carbonate is regulated the pH value.Separatory, water layer is with twice of 5ml dichloromethane extraction.Revolve and use the 20ml acetone solution after methylene dichloride is removed in steaming, add the 0.99g vitriol oil down at 7 ℃.Stir 12h down at 25 ℃, suction filtration gets (S)-α-(2-chloro-phenyl-)-6, and the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-isopropyl acetate vitriol also.Yield 43.86%, Mp:147 ℃
In the 100ml flask, add 3.9g (S)-α-(2-chloro-phenyl-)-6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-isopropyl acetate vitriol also; The 25ml absolute ethyl alcohol, 8ml aqueous sodium hydroxide solution, backflow 10h; Adjust pH is 7.0, uses the 10ml dichloromethane extraction, revolves to obtain (S)-α-(2-chloro-phenyl-)-6 after methylene dichloride is removed in steaming; The 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-acetate also.Yield 45%, Mp:131-136 ℃, content (HPLC): 93.6%.
Comparative Examples
In the 250ml there-necked flask, add 25.0g o-chlorobenzene glycine and 100ml anhydrous methanol,, treat to dissolve fully the back and drip the 32.3g sulfur oxychloride, dropwise the afterreaction system and be warming up to 80 ℃ of back flow reaction 21-24h 0-5 ℃ of stirring.Methyl alcohol is removed in steaming, adds slowly to lower the temperature after the backflow of 40ml anhydrous methanol is dissolved again, and separates out white solid, suction filtration.The filtrating recrystallization merges product and obtains the O-chlorobenzene glycine methyl ester hydrochloride.Yield 73.8%, Mp:184.1-187.1 ℃.
In the 250ml beaker, add 10.0g O-chlorobenzene glycine methyl ester hydrochloride and 50ml water; Add the 20ml methylene dichloride after the stirring and dissolving again; Regulator solution pH value is 7.0-7.2, separatory, and water layer is with 5ml dichloromethane extraction 2 times; Merge organic layer, revolve to steam and remove methylene dichloride and obtain O-chlorobenzene glycine methyl ester.Yield 98%.
In the 100ml there-necked flask, add 6.1g L-(+)-tartrate and 59ml anhydrous methanol; 10-13 ℃ of following stirring and dissolving; Add the 0.2ml phenyl aldehyde again; Slowly be added drop-wise to the mixing solutions of O-chlorobenzene glycine methyl ester 7.36g and 15ml acetone in the tartrate methanol solution, after dropwising, be warming up to 25 ℃ of reaction 10h.Suction filtration, filtrating are cooled to 5-7 ℃ and stir 5h and separate out the solid suction filtration once more, merge product, and drying obtains (S)-O-chlorobenzene glycine methyl ester-(L)-tartrate.Yield 63%, Mp:163 ℃, [α]
D=89 (c=1, CH
3OH).
In the 100ml there-necked flask, add 5g (S)-O-chlorobenzene glycine methyl ester-(L)-tartrate, 6.8g 2-thiophene ethanol p-toluenesulfonic esters, 3.4g salt of wormwood and less water.95 ℃ are reacted 12h down.Cooling back adds 40ml water and 20ml ETHYLE ACETATE, stirs separatory after 15 minutes, and water layer is with twice of 5ml ethyl acetate extraction.Combined ethyl acetate.Use concentrated hydrochloric acid to regulate the pH value down at 0-3 ℃ and be 1.0-1.2, filter, dry (S)-α-(2-the chloro-phenyl-)-2 thiophene ethyl amine guanidine-acetic acid methyl ester hydrochloride that gets.Yield 84.5%, MP:176.1-176.9 ℃, [α]
D=109 (c=1, CH
3OH).
In the 250ml flask, add 13ml methyl alcohol, 7.1g2-chloro-phenyl--2 thiophene ethyl amine guanidine-acetic acid methyl ester hydrochloride, formaldehyde 40ml, 37-39 ℃ is reacted 16h down.After finishing, reaction adds the 20ml methylene dichloride, 30ml water, and it is 9 that aqueous sodium carbonate is regulated the pH value.Separatory, water layer is with twice of 5ml dichloromethane extraction.Revolve and use the 30ml acetone solution after methylene dichloride is removed in steaming, add the 1.7g vitriol oil down at 7 ℃.Stir 12h down at 25 ℃, suction filtration gets (S)-α-(2-chloro-phenyl-)-6, and the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-methyl acetate vitriol also.Yield 74%, Mp:171 ℃
In the 100ml flask, add 3.9g (S)-α-(2-chloro-phenyl-)-6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-methyl acetate vitriol also; The 25ml absolute ethyl alcohol, 8ml aqueous sodium hydroxide solution, backflow 10h; Adjust pH is 7.0, uses the 10ml dichloromethane extraction, through finding behind the thin layer chromatography analysis; The yield of title product is a trace, almost can not get hydrolysate.
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| US10227301B2 (en) | 2015-01-06 | 2019-03-12 | Cellix Bio Private Limited | Compositions and methods for the treatment of inflammation and pain |
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