CN114907348B - Preparation method of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine - Google Patents
Preparation method of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine Download PDFInfo
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- CN114907348B CN114907348B CN202210828694.2A CN202210828694A CN114907348B CN 114907348 B CN114907348 B CN 114907348B CN 202210828694 A CN202210828694 A CN 202210828694A CN 114907348 B CN114907348 B CN 114907348B
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- CBWBJFJMNBPWAL-UHFFFAOYSA-N 4-chloro-5-iodo-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C(I)=CN2 CBWBJFJMNBPWAL-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 60
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 37
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 21
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 17
- 239000011630 iodine Substances 0.000 claims abstract description 17
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006467 substitution reaction Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 238000005406 washing Methods 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 6
- 239000002699 waste material Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000003880 polar aprotic solvent Substances 0.000 abstract description 2
- 239000002912 waste gas Substances 0.000 abstract description 2
- 239000002351 wastewater Substances 0.000 abstract description 2
- 238000004064 recycling Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 20
- 239000012065 filter cake Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- 239000012452 mother liquor Substances 0.000 description 13
- 239000008213 purified water Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000012043 crude product Substances 0.000 description 10
- 239000011259 mixed solution Substances 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 239000008187 granular material Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000007664 blowing Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000007599 discharging Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 210000003298 dental enamel Anatomy 0.000 description 4
- 238000011010 flushing procedure Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- OEBVSWXVRBMFGI-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine;hydroiodide Chemical compound I.CN(C)C(=N)N(C)C OEBVSWXVRBMFGI-UHFFFAOYSA-N 0.000 description 1
- JDUBGYFRJFOXQC-KRWDZBQOSA-N 4-amino-n-[(1s)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide Chemical compound C1([C@H](CCO)NC(=O)C2(CCN(CC2)C=2C=3C=CNC=3N=CN=2)N)=CC=C(Cl)C=C1 JDUBGYFRJFOXQC-KRWDZBQOSA-N 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- MKCYPWYURWOKST-INIZCTEOSA-N NC1=NC=NC2=C1C(=C1C(=C[C@@H](CN21)NC(C=C)=O)C)C=1C=NC2=CC=CC=C2C=1 Chemical compound NC1=NC=NC2=C1C(=C1C(=C[C@@H](CN21)NC(C=C)=O)C)C=1C=NC2=CC=CC=C2C=1 MKCYPWYURWOKST-INIZCTEOSA-N 0.000 description 1
- 239000004012 Tofacitinib Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- -1 pevinedist Chemical compound 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
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- 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 provides a preparation method of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine, which relates to the technical field of biological medicines and comprises the following steps: 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine is subjected to substitution reaction with simple substance iodine in tetrahydrofuran which is a medium polar aprotic solvent under the action of a tetramethylguanidine accelerator to be converted into 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine. Compared with the known method in the prior art, the preparation method reduces the generation of byproducts, improves the yield of products, can recycle tetramethylguanidine, ethyl acetate and tetrahydrofuran, reduces the cost by recycling, reduces the discharge of waste water, waste gas and waste residue in the production process, avoids environmental pollution, and is suitable for industrial production.
Description
Technical Field
The application relates to the technical field of biological medicines, in particular to a preparation method of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine.
Background
4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine is a key intermediate for the preparation of active pharmaceutical ingredients. It is known in the literature that this substance is prepared as an intermediate, including but not limited to, for example ruxolitinib, tofacitinib, olacetinib, barrecetinib (barocetinib), itacetinib (itacetinib), AZD-5363, pevinedist, TAS-6417 and nucleoside antiviral drugs.
Patent documents with publication numbers CN107033206A and CN106488910A disclose methods for synthesizing target compounds. Under the protection of inert gas, 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine reacts with N-iodosuccinimide in a strong polar aprotic solvent DMF to obtain a target product. The process needs to be carried out in an anhydrous and anaerobic environment, and the reaction conditions are harsh. And the used anhydrous DMF has high boiling point and is difficult to recycle, so that the difficulty in waste liquid treatment is increased. The column chromatography used in the final purification process increases the production cost and affects the product yield.
In the prior art, the problems of harsh reaction conditions, excessive waste liquid, difficult recovery of unreacted substances and difficult recovery and reuse of a reaction system in the synthesis method of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine are urgently needed to be solved.
Disclosure of Invention
In order to solve the problems, the invention provides a novel method for preparing 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine, which has the advantages of few byproducts, convenient recovery and reuse of a reaction system, low cost and simple reaction conditions, and provides a safe, economic and environment-friendly production environment.
In one aspect, the present invention provides a process for the preparation of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine, said process comprising the steps of:
4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and an iodine substitution reagent are mixed at a molar ratio of 1: (0.9 to 1.5) to obtain the 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine;
the promoter of the substitution reaction is tetramethyl guanidine.
Further, the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and iodine substitution reagent is substituted with 1: (0.99 to 1.1) in a molar ratio.
Further, the iodine substitution reagent is elemental iodine.
Further, the molar ratio of the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine to the tetramethylguanidine is 1: (2.5 to 3.0).
Further, the reaction temperature of the substitution reaction is-10 ℃ to 10 ℃, and the reaction time is 3 to 5 hours.
Further, the reaction temperature of the substitution reaction is-5 ℃ to 0 ℃, and the reaction time is 3 hours.
Preferably, wherein 0.2% or less of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine remains as a reaction end point as measured by HPLC after the completion of the reaction.
Further, the method also comprises a purification step, wherein the purification step comprises heat filtration, reduced pressure concentration, reflux, temperature reduction crystallization, filtration and drying.
Further, after the concentration under reduced pressure is finished, ethyl acetate is added for dissolution, and the mixture is washed by saturated sodium chloride, dried by anhydrous sodium sulfate and filtered.
Wherein the heat filtering is used for removing tetramethylguanidine hydroiodide, and the saturated sodium chloride is used for removing residual tetramethylguanidine.
Further, the temperature for cooling and crystallization is 0-20 ℃, and the time is 2-5 h.
Preferably, the temperature for cooling and crystallizing is 0-5 ℃ and the time is 3 h.
Further, the method also comprises a post-treatment step, wherein the post-treatment step comprises the step of recovering the tetramethylguanidine, tetrahydrofuran and ethyl acetate by decompression and concentration.
In a preferred embodiment, the tetramethylguanidine, tetrahydrofuran, and ethyl acetate are recovered and recycled.
In a preferred embodiment, a process for the preparation of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine, said process comprising the steps of:
(1) Adding anhydrous tetrahydrofuran into a reaction kettle, adding 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine, and stirring to dissolve clearly.
(2) And adding anhydrous tetrahydrofuran into the other reaction kettle, adding solid iodine particles, stirring and dissolving, and dropwise adding tetramethylguanidine into the mixed solution at-5-0 ℃ for about 1 h.
(3) And (3) dropwise adding the tetrahydrofuran solution of the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine in the step (1) into the mixed solution in the step (2), and dropwise adding the tetrahydrofuran solution at the temperature of between 5 ℃ below zero and 0 ℃ for about 3 hours. After the dripping is finished, carrying out heat preservation reaction at-5 to 0 ℃, and monitoring the reaction by using TLC.
(4) Discharging, filtering, and transferring the mother liquor to another concentration kettle for vacuum concentration until the mother liquor is dry.
(5) After completion of the concentration, ethyl acetate was added to the residue, followed by stirring, washing with a saturated aqueous sodium chloride solution, liquid separation, drying over anhydrous sodium sulfate, and filtration. And transferring the mother liquor to a concentration kettle, and concentrating under reduced pressure until the mother liquor is dry to obtain a yellow solid crude product.
(6) And (3) adding absolute ethyl alcohol into the crude product obtained in the step (5), stirring and heating until reflux, adding purified water to separate out crystals, cooling to 0-5 ℃, preserving heat for crystallization for 3 hours, and centrifuging and drying. And (3) drying the filter cake at 55-60 ℃ by blowing air to obtain white solid powder, namely 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine.
The invention has the following beneficial effects:
1. the method generates few byproducts in the preparation process, and the generated substances such as tetrahydrofuran, ethyl acetate, tetramethylguanidine and the like can be recycled, so that the production cost is reduced, the generation of waste liquid is reduced, and the problem of difficult recovery of unreacted substances is solved.
2. The invention has mild reaction condition, no harsh reaction condition and simple and safe operation in the preparation process.
3. The invention has the advantages of low price of the used reagent in the preparation process, simple production process, recyclable reaction substances and greatly reduced production cost.
4. The waste water, waste gas and waste residue produced in the preparation process are easy to treat, the environmental pollution is reduced, and the method is suitable for industrial production.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the application and together with the description serve to explain the application and not to limit the application. In the drawings:
FIG. 1 is a scheme showing the synthesis of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine.
Detailed Description
In order to more clearly explain the overall concept of the present application, the following detailed description is given by way of example. In the following description, numerous specific details are set forth in order to provide a more thorough understanding of the present application. It will be apparent, however, to one skilled in the art, that the present application may be practiced without one or more of these specific details. In other instances, well-known features of the art have not been described in order to avoid obscuring the present application.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer.
In the following embodiments, reagents or instruments used are not indicated by manufacturers, and are all conventional products available by commercial purchase, unless otherwise specified.
Example 1
(1) At room temperature, 265 kg of anhydrous tetrahydrofuran is added into a 500L enamel reaction kettle, 77 kg of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine is added under stirring, and the mixture is stirred and dissolved clearly for standby.
(2) 175 kg of anhydrous tetrahydrofuran is added into a 1000L reaction kettle, stirring is started, 127 kg of solid iodine granules are added, and stirring is carried out to dissolve the iodine granules. And (3) dripping 172 kg of tetramethylguanidine into the mixed solution at the temperature of-5-0 ℃ for about 1 hour.
(3) And (3) dropwise adding the tetrahydrofuran solution of the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine in the step (1) into the mixed solution in the step (2), completely dropping for about 3 hours at the temperature of-5-0 ℃, and flushing a kettle for dissolving the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine with 22 kg of tetrahydrofuran and dropwise adding. After the dripping is finished, carrying out heat preservation reaction at-5 to 0 ℃, and monitoring the reaction by using TLC.
(4) Discharging, filtering, washing kettle wall with 22 kg tetrahydrofuran, filtering the washing solution, washing filter cake with 22 kg tetrahydrofuran, transferring the mother liquor to another 1000L concentration kettle, and concentrating under reduced pressure to dryness (concentration temperature is less than or equal to 50 deg.C, vacuum degree is less than or equal to-0.08 Mpa).
(5) After completion of the concentration, 450 kg of ethyl acetate was added to the residue, stirred, washed with a saturated aqueous sodium chloride solution, and separated. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with 45 kg of ethyl acetate. Transferring the mother liquor to a 500L concentration kettle, concentrating under reduced pressure to dryness (concentration temperature is 50 deg.C at most, and vacuum degree is less than or equal to-0.08 Mpa) to obtain yellow solid crude product.
(6) Adding 305 kg of absolute ethyl alcohol into the crude product obtained in the step (5), stirring and heating until reflux, adding 190 kg of purified water to separate out crystals, cooling to 0-5 ℃, preserving heat and crystallizing for 3 hours, centrifugally drying, washing the kettle wall with 25 kg of purified water, and filtering the washing liquid together. The filter cake was washed with 50 kg of purified water and centrifuged. And (3) drying the filter cake at 55-60 ℃ by blowing air to obtain white solid powder, namely 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine.
110.5g of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine was obtained with a product yield of 79.10% and a purity: more than or equal to 98.0 percent.
1 H NMR (500 MHz, DMSO-d6) d 12.95 (s, 1H), 8.59 (s, 1H), 7.93 (d, J = 2.2 Hz, 1H). 13 C NMR (126 MHz, DMSO-d6) d 151.5, 150.8, 150.5, 133.9, 115.8, 51.7. LC/MS: m/z calcd for [C 6 H 3 N 3 ICl + H] + 280.47, found 280.18.
Example 2
(1) At room temperature, 265 kg of anhydrous tetrahydrofuran is added into a 500L enamel reaction kettle, 77 kg of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine is added under stirring, and the mixture is stirred and dissolved clearly for standby.
(2) 175 kg of anhydrous tetrahydrofuran is added into a 1000L reaction kettle, stirring is started, 134.7 kg of solid iodine granules are added, and stirring is carried out to dissolve the solid iodine granules. And (3) dropwise adding 165.9 kg of tetramethylguanidine into the mixed solution at the temperature of-5-0 ℃, and finishing dropping for about 1 hour.
(3) And (3) dropwise adding the tetrahydrofuran solution of the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine in the step (1) into the mixed solution in the step (2), completely dropping for about 4 hours at the temperature of-5-0 ℃, and flushing a kettle for dissolving the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine with 22 kg of tetrahydrofuran and dropwise adding. After the dripping is finished, carrying out heat preservation reaction at-5 to 0 ℃, and monitoring the reaction by using TLC.
(4) Discharging, filtering, washing kettle wall with 22 kg tetrahydrofuran, filtering the washing solution, washing filter cake with 22 kg tetrahydrofuran, transferring the mother liquor to another 1000L concentration kettle, and concentrating under reduced pressure to dryness (concentration temperature is less than or equal to 50 deg.C, vacuum degree is less than or equal to-0.08 Mpa).
(5) After completion of the concentration, 450 kg of ethyl acetate was added to the residue, stirred, washed with a saturated aqueous sodium chloride solution, and separated. The ethyl acetate layer anhydrous sodium sulphate was dried, filtered and the filter cake was washed with 45 kg ethyl acetate. Transferring the mother liquor to a 500L concentration kettle, concentrating under reduced pressure to dryness (concentration temperature is 50 deg.C at most, and vacuum degree is less than or equal to-0.08 Mpa) to obtain yellow solid crude product.
(6) Adding 305 kg of absolute ethyl alcohol into the crude product obtained in the step (5), stirring and heating until reflux, adding 190 kg of purified water to separate out crystals, cooling to 0-5 ℃, preserving heat for crystallization for 2 hours, centrifugally drying, washing the kettle wall with 25 kg of purified water, and filtering the washing liquid together. The filter cake was washed with 50 kg of purified water and centrifuged. And (3) drying the filter cake at 55-60 ℃ by blowing air to obtain white solid powder, namely 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine.
102.14kg of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine is obtained, the product yield is 73.1 percent, and the purity is as follows: more than or equal to 97.5 percent.
Example 3
(1) At room temperature, 265 kg of anhydrous tetrahydrofuran is added into a 500L enamel reaction kettle, 77 kg of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine is added under stirring, and the mixture is stirred and dissolved clearly for standby.
(2) 175 kg of anhydrous tetrahydrofuran is added into a 1000L reaction kettle, stirring is started, 139.9 kg of solid iodine granules are added, and stirring is carried out to dissolve the iodine granules. And (3) dripping 158.8 kg of tetramethylguanidine into the mixed solution at the temperature of-5-0 ℃ for about 1 hour.
(3) And (3) dropwise adding a tetrahydrofuran solution of the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine in the step (1) into the mixed solution in the step (2), dropwise adding the tetrahydrofuran solution at the temperature of between 5 ℃ below zero and 0 ℃ for about 5 hours, and flushing a kettle for dissolving the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine by using 22 kg of tetrahydrofuran and dropwise adding the tetrahydrofuran solution. After the dripping is finished, carrying out heat preservation reaction at-5 to 0 ℃, and monitoring the reaction by using TLC.
(4) Discharging, filtering, washing kettle wall with 22 kg tetrahydrofuran, filtering the washing solution, washing filter cake with 22 kg tetrahydrofuran, transferring the mother liquor to another 1000L concentration kettle, and concentrating under reduced pressure to dryness (concentration temperature is less than or equal to 50 deg.C, vacuum degree is less than or equal to-0.08 Mpa).
(5) After completion of the concentration, 450 kg of ethyl acetate was added to the residue, stirred, washed with a saturated aqueous sodium chloride solution, and separated. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with 45 kg of ethyl acetate. The mother liquor is transferred to a 500L concentration kettle and concentrated under reduced pressure until the mother liquor is dry (the maximum concentration temperature is 50 ℃, and the vacuum degree is less than or equal to-0.08 Mpa) to obtain a yellow solid crude product.
(6) Adding 305 kg of absolute ethyl alcohol into the crude product obtained in the step (5), stirring and heating until reflux, adding 190 kg of purified water to separate out crystals, cooling to 0-5 ℃, preserving heat for crystallization for 4 hours, centrifugally drying, washing the kettle wall with 25 kg of purified water, and filtering the washing liquid together. The filter cake was washed with 50 kg of purified water and centrifuged. And (3) drying the filter cake at 55-60 ℃ by blowing air to obtain white solid powder, namely 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine.
109.27kg of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine is obtained, the yield of the product is 78.20%, and the purity is as follows: more than or equal to 98.0 percent.
Example 4
(1) 265 kg of anhydrous tetrahydrofuran is added into a 500L enamel reaction kettle at room temperature, 77 kg of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine is added under stirring, and the mixture is stirred and dissolved clearly for later use.
(2) 175 kg of anhydrous tetrahydrofuran is added into a 1000L reaction kettle, stirring is started, 140.3 kg of solid iodine granules are added, and stirring is carried out to dissolve the solid iodine granules. And dripping 161.7 kg of tetramethylguanidine into the mixed solution at the temperature of-5-0 ℃ for about 1 hour.
(3) And (3) dropwise adding the tetrahydrofuran solution of the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine in the step (1) into the mixed solution in the step (2), completely dropping for about 3 hours at the temperature of-5-0 ℃, and flushing a kettle for dissolving the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine with 22 kg of tetrahydrofuran and dropwise adding. After the dripping is finished, carrying out heat preservation reaction at-5 to 0 ℃, and monitoring the reaction by using TLC.
(4) Discharging, filtering, washing kettle wall with 22 kg tetrahydrofuran, filtering the washing liquid, washing filter cake with 22 kg tetrahydrofuran, transferring the mother liquor to another 1000L concentration kettle, and concentrating under reduced pressure to dry (concentration temperature is less than or equal to 50 deg.C, vacuum degree is less than or equal to-0.08 Mpa).
(5) After completion of the concentration, 450 kg of ethyl acetate was added to the residue, stirred, washed with a saturated aqueous sodium chloride solution, and separated. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with 45 kg of ethyl acetate. Transferring the mother liquor to a 500L concentration kettle, concentrating under reduced pressure to dryness (concentration temperature is 50 deg.C at most, and vacuum degree is less than or equal to-0.08 Mpa) to obtain yellow solid crude product.
(6) Adding 305 kg of absolute ethyl alcohol into the crude product obtained in the step (5), stirring and heating until reflux, adding 190 kg of purified water to separate out crystals, cooling to 0-5 ℃, preserving heat for 5 hours of crystallization, centrifugally drying, washing the kettle wall with 25 kg of purified water, and filtering the washing liquid together. The filter cake was washed with 50 kg of purified water and centrifuged. And (3) drying the filter cake at 55-60 ℃ by blowing air to obtain white solid powder, namely 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine.
96.55kg of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine was obtained, the product yield was 69.10%, the purity was: more than or equal to 97.0 percent.
The above description is only an example of the present application and is not intended to limit the present application. Various modifications and changes may occur to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the scope of the claims of the present application.
Claims (9)
1. A process for the preparation of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine, comprising the steps of:
4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and an iodine-substituting reagent are mixed in a ratio of 1: (0.9 to 1.5) to obtain the 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine;
the promoter of the substitution reaction is tetramethyl guanidine;
the iodine substitution reagent is elemental iodine;
the solvent for the substitution reaction is tetrahydrofuran.
2. The method of claim 1, wherein the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and iodine substitution reagent is substituted with a 1: (0.99 to 1.1) in a molar ratio.
3. The method of claim 1, wherein the molar ratio of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine to tetramethylguanidine is 1: (2.5 to 3.0).
4. The method according to claim 1, wherein the reaction temperature of the substitution reaction is-10 ℃ to 10 ℃ and the reaction time is 3 to 5 hours.
5. The method of claim 4, wherein the substitution reaction is carried out at a temperature of-5 ℃ to 0 ℃ for a reaction time of 3 hours.
6. The method according to claim 1, wherein the preparation method further comprises a purification step, and the purification step comprises heat filtration, concentration under reduced pressure, reflux, crystallization under reduced temperature, filtration and drying.
7. The method according to claim 6, wherein after the concentration under reduced pressure, ethyl acetate is added for dissolution, saturated sodium chloride is used for washing, and anhydrous sodium sulfate is used for drying and filtering.
8. The method as claimed in claim 6, wherein the temperature of the cooling crystallization is 0-20 ℃, and the time is 2-5 h.
9. The method of claim 7, wherein the preparation method further comprises a post-treatment step, wherein the post-treatment step comprises concentrating under reduced pressure to recover tetramethylguanidine, tetrahydrofuran and ethyl acetate.
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