CN117820190A - Synthesis method of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine and intermediate thereof - Google Patents
Synthesis method of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine and intermediate thereof Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- ZTBYPLYMOIIANS-UHFFFAOYSA-N 4,6-dichloro-1h-pyrrolo[3,2-c]pyridine Chemical compound ClC1=NC(Cl)=CC2=C1C=CN2 ZTBYPLYMOIIANS-UHFFFAOYSA-N 0.000 title claims description 27
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- -1 ethoxycarbonylmethyl Chemical group 0.000 claims abstract description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 38
- 239000000243 solution Substances 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- NMPVEAUIHMEAQP-UHFFFAOYSA-N 2-Bromoacetaldehyde Chemical compound BrCC=O NMPVEAUIHMEAQP-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- 230000002194 synthesizing effect Effects 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 8
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 claims description 5
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- OKSCSBYHIMCKQY-UHFFFAOYSA-N diethyl 3-aminopent-2-enedioate Chemical compound CCOC(=O)CC(N)=CC(=O)OCC OKSCSBYHIMCKQY-UHFFFAOYSA-N 0.000 claims description 4
- ZSANYRMTSBBUCA-UHFFFAOYSA-N diethyl 3-oxopentanedioate Chemical compound CCOC(=O)CC(=O)CC(=O)OCC ZSANYRMTSBBUCA-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 23
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- RFKFGKSLNIJSQT-UHFFFAOYSA-N 3-aminopent-2-enedioic acid Chemical compound NC(=CC(=O)O)CC(=O)O RFKFGKSLNIJSQT-UHFFFAOYSA-N 0.000 description 1
- XMGGCBJKTROPMA-UHFFFAOYSA-N ClP(Cl)(=O)[ClH]C1=CC=CC=C1 Chemical compound ClP(Cl)(=O)[ClH]C1=CC=CC=C1 XMGGCBJKTROPMA-UHFFFAOYSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- PZDFQDIKMABNEE-UHFFFAOYSA-N ethyl 2-(2-amino-2-oxoethyl)-1h-pyrrole-3-carboxylate Chemical compound CCOC(=O)C=1C=CNC=1CC(N)=O PZDFQDIKMABNEE-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
Classifications
-
- 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to the technical field of pharmaceutical intermediates, in particular to a 4, 6-dichloro-1H-pyrrolo [3,2-c]The synthesis method of pyridine and an intermediate thereof, wherein the intermediate is 2- (ethoxycarbonylmethyl) pyrrole-3-ethyl formate, the synthesis route is as follows,the method has low price of the initial raw materials; in addition, the preparation method of the key intermediate can be a one-pot method, can be used as a next reaction without additional purification, reduces the time and labor hour of equipment and personnel, and is particularly suitable for industrial production. In the method, the reaction yield of the key intermediate is high; the volume concentration of the reaction is large, which is beneficial to improving the productivity and reducing the generation of waste.
Description
Technical Field
The invention relates to the technical field of pharmaceutical intermediates, in particular to a synthesis method of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine and an intermediate thereof.
Background
4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine is an important drug molecular block, and is a synthetic intermediate of multiple drugs. For example, the compound can be used for synthesizing ribonucleoside medicaments, and the medicaments have wide application prospects in anti-tumor, antiviral and ATR kinase inhibitors. In addition, the compound is also an intermediate for synthesizing pyridyl and pyrimidinyl substituted thiazole and thiadiazole derivatives, and is applied to pesticide production.
With the clinical recommendation of the medicines and the continuous discovery of new similar structures, the requirement of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine is continuously increased, and in particular, the analogues are widely applied to pesticides. However, the existing laboratory preparation method of the compound severely limits the productivity of the compound, and a safe, environment-friendly and low-cost industrial preparation process needs to be developed to meet the demands.
In the prior art, the synthesis method of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine is synthesized by 5 steps, and specifically comprises the following steps:
wherein, key intermediate Key int. (i.e., ethyl 2- (ethoxycarbonylmethyl) pyrrole-3-carboxylate) is prepared by: firstly, condensing diethyl 1, 3-acetonedicarboxylate and alpha-amino acetal to obtain an imine intermediate; and secondly, intramolecular condensation ring closure is carried out on the imine intermediate under alkaline conditions to obtain the imine intermediate. The first and second steps are key factors limiting the synthesis of the final desired product, which have the following drawbacks: (1) The yield of Key intermediate Key int was low, only 15% (j.chem.soc. (C), 1970, 285); (2) Column chromatography purification is needed, so that the method is not suitable for the requirement of industrial production; (3) The reaction concentration is low, the productivity is limited, and a large amount of waste liquid is generated.
After the preparation of the key intermediate (key int.) is completed, the subsequent reaction steps are all common methods in the art (Journal ofMedicinal Chemistry,1978, vol.21, no. 9991) and have already formed the established process.
Therefore, the optimization of the process route of the 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine is critical to find a brand new synthesis method of a Key intermediate (Key Int.).
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a method for synthesizing 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine, in particular to a method for synthesizing a key intermediate namely 2- (ethoxycarbonylmethyl) pyrrole-3-ethyl formate.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a method for synthesizing an intermediate of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine, wherein the intermediate is ethyl 2- (ethoxycarbonylmethyl) pyrrole-3-carboxylate, the synthetic route is as follows,
the first step of synthesis of the intermediate is nucleophilic substitution of enamine and alpha-halogenated aldehyde, and the second step of condensation of amino group in molecule and aldehyde to obtain key intermediate.
The preparation method of the compound 2a comprises the steps of adding HBr solution into bromoacetaldehyde diethyl acetal aqueous solution at room temperature, heating, stirring, cooling the obtained mixture, and then adding NaOAc to obtain 2-bromoacetaldehyde, namely the compound 2a. Wherein, the heating temperature of the aqueous solution of bromoacetaldehyde diethyl acetal and the HBr solution is 40 ℃, and the stirring time is 3h; the temperature was cooled to 0 ℃.
The preparation method of the compound 3 comprises the steps of adding a diethyl 3-amino-2-pentene-1, 5-diacid solution into a 2-bromoacetaldehyde solution, and stirring the obtained mixture at room temperature; after the reaction, the reaction mixture was extracted with ethyl acetate, and the resultant organic phases were combined, washed with saturated brine and separated into layers, and then concentrated to dryness under reduced pressure to give a yellow oily crude product of ethyl 2- (ethoxycarbonylmethyl) pyrrole-3-carboxylate, namely, compound 3. Preferably, during the preparation of the compound 3, a solution of diethyl 3-amino-2-pentene-1, 5-dioate is added to a solution of 2-bromoacetaldehyde at 0℃and the resulting mixture is stirred at room temperature for 16 hours.
Wherein, the synthetic route of the compound 2b is as follows,
the compound 2b is prepared by adding NH to a methanol solution of diethyl 1, 3-acetonedicarboxylate 4 HCO 3 Heating and stirring the obtained mixture; the mixture was then concentrated under reduced pressure, and the resulting yellow oil was dissolved in acetone to give a diethyl 3-amino-2-pentene-1, 5-dioate solution, compound 2b. Preferably, the heating temperature is 40℃and the stirring time is 4 hours.
The invention also provides a synthesis method of the 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine, the synthesis route is as follows,
wherein, the preparation method of the intermediate 2- (ethoxycarbonylmethyl) pyrrole-3-ethyl formate adopts the synthesis method.
Compared with the prior art, the invention has the beneficial effects that:
the cost of the starting materials of the synthesis method is low, which is only half of the cost of the starting materials of the traditional route. In addition, the preparation method of the key intermediate can be a one-pot method, can be used as a next reaction without additional purification, reduces the time and labor hour of equipment and personnel, and is particularly suitable for industrial production. In the method, the reaction yield of the key intermediate is high; the volume concentration of the reaction is large, which is beneficial to improving the productivity and reducing the generation of waste.
Drawings
FIG. 1 is a HNMR spectrum of the product of example 1.
FIG. 2 is a HNMR spectrum of the product of example 3.
FIG. 3 is a HNMR spectrum of the product 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine of example 4.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 12 preparation of Ethyl- (ethoxycarbonylmethyl) pyrrole-3-carboxylate
The preparation of a 2-bromoacetaldehyde solution and a 3-amino-2-pentene-1, 5-diacid diethyl ester solution is carried out as synchronously as possible, and the preparation of the two solutions is carried out at present.
(1) Preparation of 2-bromoacetaldehyde solution
A solution of bromoacetaldehyde diethyl acetal (4.87 kg,3.81L,24.73mol,1 eq) in water (15L) was added at room temperature to a solution of HBr (4.17 kg,48%,1.34L,24.73mol,1 eq) and the resulting mixture stirred at 40℃for 3 hours. The mixture was cooled to 0deg.C, then NaOAc (4.06 kg,2.80L,49.46mol,2 eq) was added to give an aqueous solution of bromoacetaldehyde for use.
(2) Preparation of 3-amino-2-pentene-1, 5-diacid diethyl ester solution
In another reaction vessel, a solution of diethyl 1, 3-acetonedicarboxylate (5 kg,4.50L,24.73mol,1 eq) in methanol (5L) was added NH 4 HCO 3 (2.44 kg,1.54L,30.91mol,1.25 eq) and the resulting mixture was heated to 40℃and stirred for 4 hours. The mixture was then concentrated under reduced pressure, and the resulting yellow oil was dissolved in acetone (5L x 3) to give a solution of 3-amino-2-pentene-1, 5-dioic acid in diethyl ester.
(3) Preparation of ethyl 2- (ethoxycarbonylmethyl) pyrrole-3-carboxylate
The diethyl 3-amino-2-pentene-1, 5-dioate solution was added to the bromoacetaldehyde solution at 0℃and the resulting mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate three times (5 L×3), and the combined organic phases were washed with saturated brine (3 L×2) and separated, and concentrated to dryness under reduced pressure to give a yellow oily crude product of ethyl 2- (ethoxycarbonylmethyl) pyrrole-3-carboxylate (5.57 kg, yield: 100%) having a purity of more than 90% and used as a raw material for the next step. The product correlation spectrum is shown in figure 1.
MS＝225.8(M+1). 1 H NMR(400MHz,Chloroform-d)δ9.58(s,1H),6.67(t,J＝2.7Hz,
1H),6.59(t,J＝2.9Hz,1H),4.31-4.22(m,4H),4.12(s,2H),1.37-1.29(m,6H)。
Example 2 2 preparation of ethyl carbamoylmethyl-3-pyrrolidinecarboxylate
An aqueous ammonia (11.39 kg,28%,12.66L,91.01mol,5 eq) solution of ethyl 2- (ethoxycarbonylmethyl) pyrrole-3-carboxylate (4.10 kg,18.20mol,1 eq) was heated to 40℃and stirred for 18 hours. TLC (petroleum ether/ethyl acetate=1/1, rf=0.2) showed the disappearance of starting material. The obtained reaction solution was an aqueous ammonia solution of ethyl 2-carbamoylmethyl-3-pyrrolecarboxylate (reaction yield 99.9%, quantitative determination of nuclear magnetism) having a content of 3.57kg, and was directly used for the next reaction.
Example 3 1 preparation of H-pyrrolo [3.2-c ] -4, 6-dihydroxypyridine
NaOH (2.18 kg,54.58mol,3 eq) was dissolved in 8L water, cooled to 0℃and then the inner temperature was kept below 15℃and the lye was slowly added dropwise to the ethyl 2-carbamoylmethyl-3-pyrrolidinecarboxylate aqueous ammonia solution of the previous step. After the completion of the dropwise addition, the reaction solution was heated to 40℃and stirred for 1 hour. After the reaction, the reaction solution is cooled to 0 ℃, the pH value is regulated to 2-3 by 6M hydrochloric acid solution, and a large amount of solids are separated out to obtain suspension. After stirring the suspension at 0℃for 16 hours, it was filtered and the solid was collected and dried at 40℃under vacuum for 48 hours to give a crude 1-hydro-pyrrolo [3.2-c ] -4, 6-dihydroxypyridine product. The crude product was suspended in 10 volumes of methanol, heated to 70 ℃ and stirred for 2 hours, then cooled to room temperature, filtered and the filtrate collected. The filter cake was washed with 1 volume of methanol and the filtrate was collected by filtration. The combined filtrates were concentrated to dryness under reduced pressure to give pure 1-hydro-pyrrolo [3.2-c ] -4, 6-dihydroxypyridine (1.10 kg, yield: 40.27%). The product correlation spectrum is shown in figure 2.
1 H NMR (400MHz,DMSO-d6)δ11.49(s,1H),10.53(s,1H),6.86(t,J＝2.5Hz,1H),6.42-6.29(m,1H),3.86(s,2H).MS＝150.6(M+1).
EXAMPLE 4 preparation of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine
A mixture of 1-hydro-pyrrolo [3.2-c ] pyridine-4, 6-dihydroxy (2.20 kg,14.65mol,1 eq) and phenyl phosphorus oxychloride (9.17 kg,6.60L,47.05mol,3.211 eq) was heated to 160℃and stirred for 4 hours. After the reaction, the temperature of the reaction solution was lowered to 70℃and then 5L of tetrahydrofuran was added for dilution. The resulting mixture was slowly added to 20L of ice water and then stirred at 0deg.C for 16 hours, and a dark waxy solid precipitated. The mixture was settled, the aqueous phase was removed by slow decantation, the remaining mixture was added to an ethyl acetate/methanol mixed solvent (ethyl acetate/methanol=3/1, 15L), broken up with rapid stirring, and the filtrate was collected by filtration. The filter cake was then added to a mixed solvent of ethyl acetate/tetrahydrofuran (ethyl acetate/tetrahydrofuran=3/1,5L) and broken up by rapid stirring, and the filtrate was collected by filtration. The filtrates were combined and concentrated under reduced pressure to about 8L, with a significant amount of yellow solid precipitated. The suspension was filtered and the solid collected to give 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine (2.30 kg, yield: 83.93%) in dark yellow.
Pulping by NaOH:
4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine (2.20 kg,11.76mol,1 eq) was dispersed in aqueous NaOH (264.02 g,6.60L,6.60mol,0.5611eq, 1M). The suspension was stirred at 20℃for 16 hours and then filtered, the filter cake was rinsed three times with water (1L x 3), the filter cake was collected and dried under vacuum at 40℃for 24 hours to give a crude product of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine (2.10 kg, YIeld: 95.45%) in dark yellow.
Decolorizing with active carbon, pulping with EtOAc:
4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine (2 kg,10.69mol,1 eq) was dissolved in a mixed solvent of ethyl acetate (20L) and tetrahydrofuran (10L) to give a dark brown solution, and activated carbon (500 g,200 mesh) was added. The resulting mixture was heated to the 65 ℃ and stirred for 1 hour, the solution changing to pale yellow in color. The suspension was filtered and the filtrate was collected. The filter cake was washed with 8L of a mixed solution of ethyl acetate/tetrahydrofuran (ethyl acetate/tetrahydrofuran=2/1), and the filtrate was collected by filtration. The filtrates were combined and concentrated to about 4L, and a yellow solid precipitated. The solid was collected by filtration and the filter cake was washed with 4 volumes of ethyl acetate to give 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine (1.10 kg, yield: 55%) as white. The product correlation spectrum is shown in figure 3.
MS＝187.0(M+1). 1 H NMR(400MHz,DMSO-d 6 )δ12.04(s,1H),7.62(dd,J＝3.3,2.4Hz,
1H),7.53(d,J＝0.9Hz,1H),6.59(ddd,J＝3.1,2.0,1.0Hz,1H).
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A method for synthesizing an intermediate of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine is characterized by comprising the following steps: the intermediate is 2- (ethoxycarbonylmethyl) pyrrole-3-ethyl formate, the synthetic route is as follows,
2. the method for synthesizing the intermediate of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine according to claim 1, wherein: the preparation method of the compound 2a comprises the steps of adding HBr solution into bromoacetaldehyde diethyl acetal aqueous solution at room temperature, heating, stirring, cooling the obtained mixture, and then adding NaOAc to obtain 2-bromoacetaldehyde, namely the compound 2a.
3. The method for synthesizing the intermediate of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine according to claim 2, wherein: in the preparation process of the compound 2a, the heating temperature of the aqueous solution of bromoacetaldehyde diethyl acetal and the HBr solution is 40 ℃, and the stirring time is 3 hours; the temperature was cooled to 0 ℃.
4. The method for synthesizing the intermediate of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine according to claim 1, wherein: the preparation method of the compound 3 comprises the steps of adding 3-amino-2-pentene-1, 5-diethyl diacid solution into 2-bromoacetaldehyde solution, and stirring the obtained mixture at room temperature; after the reaction, the reaction mixture was extracted with ethyl acetate, and the resultant organic phases were combined, washed with saturated brine and separated into layers, and then concentrated to dryness under reduced pressure to give a yellow oily crude product of ethyl 2- (ethoxycarbonylmethyl) pyrrole-3-carboxylate, namely, compound 3.
5. The method for synthesizing the intermediate of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine according to claim 1, wherein: in the preparation process of the compound 3, 3-amino-2-pentene-1, 5-diethyl diacid solution is added into 2-bromoacetaldehyde solution at the temperature of 0 ℃, and the obtained mixture is stirred for 16 hours at room temperature.
6. The method for synthesizing the intermediate of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine according to claim 1, wherein: the synthetic route of the compound 2b is as follows,
7. 4, 6-dichloro-1H-pyrrolo [3,2-c ] according to claim 4]A method for synthesizing an intermediate of pyridine,the method is characterized in that: the compound 2b is prepared by adding NH to a methanol solution of diethyl 1, 3-acetonedicarboxylate 4 HCO 3 Heating and stirring the obtained mixture; the mixture was then concentrated under reduced pressure, and the resulting yellow oil was dissolved in acetone to give a diethyl 3-amino-2-pentene-1, 5-dioate solution, compound 2b.
8. The method for synthesizing an intermediate of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine according to claim 7, wherein: in the preparation process of the compound 2b, the heating temperature is 40 ℃, and the stirring time is 4 hours.
9. A method for synthesizing 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine is characterized by comprising the following steps: the synthetic route of the synthetic route is as follows,
10. the method for synthesizing 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine according to claim 9, wherein: wherein, the preparation method of the intermediate 2- (ethoxycarbonylmethyl) pyrrole-3-ethyl formate of 4, 6-dichloro-1H-pyrrolo [3,2-c ] pyridine adopts the synthesis method of any one of claims 1-8.
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