CN113480484A - Preparation method of medical intermediate - Google Patents
Preparation method of medical intermediate Download PDFInfo
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- CN113480484A CN113480484A CN202110738419.7A CN202110738419A CN113480484A CN 113480484 A CN113480484 A CN 113480484A CN 202110738419 A CN202110738419 A CN 202110738419A CN 113480484 A CN113480484 A CN 113480484A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 24
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 16
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 16
- 150000002430 hydrocarbons Chemical class 0.000 claims abstract description 16
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims abstract description 16
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000019445 benzyl alcohol Nutrition 0.000 claims abstract description 7
- 239000012046 mixed solvent Substances 0.000 claims abstract description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims abstract description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000008096 xylene Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- 239000000543 intermediate Substances 0.000 claims description 51
- 239000002904 solvent Substances 0.000 claims description 22
- 239000012074 organic phase Substances 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000000605 extraction Methods 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 7
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract description 7
- 238000001953 recrystallisation Methods 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 31
- 239000007787 solid Substances 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 238000005191 phase separation Methods 0.000 description 15
- 238000001035 drying Methods 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 8
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- -1 5, 6-diphenylpyrazin-2-yl Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000003651 drinking water Substances 0.000 description 4
- 235000020188 drinking water Nutrition 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 238000010009 beating Methods 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 102000009079 Epoprostenol Receptors Human genes 0.000 description 1
- 108010073099 Epoprostenol Receptors Proteins 0.000 description 1
- 241000400611 Eucalyptus deanei Species 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229960003841 selexipag Drugs 0.000 description 1
- QXWZQTURMXZVHJ-UHFFFAOYSA-N selexipag Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)NS(C)(=O)=O)C(C)C)=CN=C1C1=CC=CC=C1 QXWZQTURMXZVHJ-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical class CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
- C07D241/20—Nitrogen atoms
Abstract
The invention provides a preparation method of a medical intermediate tert-butyl 2- {4- [ (5, 6-diphenylpyrazin-2-yl) (propane-2-yl) amino ] butoxy } acetate, which can obtain a high-purity product through a specific recrystallization method, is beneficial to industrial production and improves the yield of subsequent reactions. The crystallization method uses a mixed solvent composed of a hydrocarbon selected from one or more of n-hexane, cyclohexane, n-heptane, toluene and xylene, and an alcohol selected from one or more of propanol, isopropanol, n-butanol, isobutanol, benzyl alcohol.
Description
Technical Field
The invention relates to the field of compound preparation, in particular to a preparation method of a medical intermediate.
Background
Selepag, the name of England Selexipag, the chemical name of 2- {4- [ (5, 6-diphenylpyrazin-2-yl) (propane-2-yl) amino ] butoxy } -N- (methylsulfonyl) acetamide, is an excellent PGI2 receptor agonist, has a plurality of effects of platelet aggregation inhibition, vasodilatation, bronchodilator, lipid precipitation inhibition, leukocyte activation inhibition and the like, is a good drug for treating pulmonary hypertension, and is marketed in China in 2018, and the demand is large.
The synthesis of selepatag requires an intermediate, tert-butyl 2- {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetate (hereinafter referred to as intermediate 2), which is a substituted tert-butyl acetate obtained by etherification of 2- {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butanol (intermediate 1), which is hydrolyzed to substituted acetic acid (intermediate 3) and then subjected to mesylating reaction to obtain selepatag. As shown in the following formula:
the intermediate 2 is more critical in the synthesis of selepag and is a difficult material. The intermediate obtained in the prior art has low purity, and is oil or paste. For example, CN107365275A reports that the work-up procedure for preparing this intermediate is only extraction and drying, and is a reddish brown gum in appearance with a high level of impurities. The post-treatment method reported in US2009264407 is: after the reaction, phases are separated, an organic phase is dried by sodium sulfate, sodium sulfate is removed by filtration, filtrate is concentrated, and column purification is carried out to obtain yellow oily matter with the purity of 98%, and a picture of the matter is shown in figure 1. CN107365275 reports that after the reaction is finished, the product is acidified, extracted and concentrated, and is directly used for the next reaction.
The product directly enters the next reaction without purification, and obviously carries more impurities, which affects the yield and purity of the product in the next reaction. For the intermediate 2 obtained by column chromatography purification, on one hand, the column chromatography is not convenient for industrial production, the solvent consumption is high, the environment is not friendly, and on the other hand, the obtained oily substance is not easy to be accurately measured, so the feeding accuracy of the next reaction is affected.
Disclosure of Invention
The invention aims to provide a preparation method of a medical intermediate tert-butyl 2- {4- [ (5, 6-diphenylpyrazin-2-yl) (propane-2-yl) amino ] butoxy } acetate, which can obtain a high-purity product through a specific recrystallization method, is beneficial to industrial production and improves the yield of subsequent reactions.
According to the present invention, a process for preparing tert-butyl 2- {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetate, a pharmaceutical intermediate, comprises the following steps:
1) reacting an intermediate 1 in the following formula with tert-butyl bromoacetate to obtain a mixed solution containing an intermediate 2;
2) obtaining crude intermediate 2 from the mixture;
3) recrystallizing the crude product with a mixed solvent, wherein the mixed solvent consists of hydrocarbon and alcohol, the hydrocarbon is selected from one or more of n-hexane, cyclohexane, n-heptane, toluene and xylene, and the alcohol is selected from one or more of propanol, isopropanol, n-butanol, isobutanol and benzyl alcohol. Wherein the volume ratio of hydrocarbon to alcohol is 3:1 to 20:1, preferably 5 to 10: 1.
Drawings
Figure 1 is a photograph of intermediate 2 obtained according to US2009264407, which has undergone column chromatography;
FIG. 2 is a photograph of intermediate 2 obtained in examples 1 to 3 of the present invention.
Detailed Description
In the invention, the step 1) adopts the operation of the prior art, the intermediate 1 and the bromoacetic acid tert-butyl alcohol are subjected to etherification reaction in the presence of tetrabutylammonium hydrogen sulfate and 40% potassium hydroxide aqueous solution, and toluene or benzene is used as a solvent. The reaction is controlled at 20-30 ℃, and the progress of the reaction is monitored by thin-layer chromatography.
After the reaction is finished, in a typical embodiment, water and ethyl acetate are added to the system, preferably in a volume ratio of 1: 1-3, more preferably 1: 1.2-2.0. It is advantageous here to use a larger proportion of ethyl acetate, as much of the intermediate 2 as possible being extracted from the aqueous solution. The separated organic phase is washed by water and then concentrated to obtain crude oily matter. Other embodiments are not excluded from the present invention to obtain crude intermediate 2 from the reacted solution.
In the invention, the prepared solvent is used for carrying out recrystallization treatment on the intermediate 2 crude product, thereby obtaining the granular intermediate 2 product which is easy to dry for the first time. The hydrocarbon is selected from one or more of n-hexane, cyclohexane, n-heptane, toluene and xylene, and the alcohol is selected from one or more of propanol, isopropanol, n-butanol, isobutanol and benzyl alcohol. Although this "multiple" approach may be implemented, it is generally feasible to select a single solvent for each, so as to facilitate solvent recycling. The volume ratio of hydrocarbon to alcohol is from 3:1 to 20:1, preferably the volume ratio of hydrocarbon to alcohol is from 3 to 10:1, more preferably the volume ratio of hydrocarbon to alcohol is from 5 to 7: 1.
In a more preferred embodiment, the recrystallization solvent is composed of n-hexane and n-butanol in a volume ratio of 5 to 1. In another more preferred embodiment, the recrystallization solvent is composed of n-hexane and n-propanol in a volume ratio of 5 to 1. . In another more preferred embodiment, the recrystallization solvent is composed of n-heptane, benzyl alcohol and n-propanol in a volume ratio of 5-6:1:0.2-0.3, the latter giving the most desirable yield.
In the recrystallization operation, the intermediate 2 is preferably dissolved in an alcohol in a vessel, and then a hydrocarbon solvent is added thereto. After the addition, the system became cloudy and the precipitate was redissolved by heating. Then stirring and cooling to 10-20 ℃, and preserving heat for 1-2 hours at the temperature. In a preferable mode, the temperature is naturally reduced at room temperature, and after the crystal is fully crystallized, the temperature is slowly reduced to 10-15 ℃ for 0.5-2 hours. At this temperature for half an hour. Thus, the crystallization can be more sufficient. Yellowish particulate solids or crystals can be obtained by the process of the invention.
Example 1
To a 1L reaction flask was added 153g of toluene, 25g of intermediate 1 was added with stirring, and 11.78g of tetrabutylammonium hydrogen sulfate and about 40% aqueous potassium hydroxide solution were added. The temperature of the system is reduced to 5-10 ℃, and 12g of bromoacetic acid tert-butyl ester is dripped at 7 ℃. Controlling the temperature to be 5-10 ℃, stirring for 45 minutes, then heating the system to room temperature, controlling the temperature to be 23-25 ℃, and stirring for 1 hour. TLC (n-hexane: ethyl acetate 2:1) and the starting material was reacted completely. Adding 150g of water, then adding 160g of ethyl acetate for extraction and phase separation, collecting an organic phase, washing the organic phase with 152g of water for phase separation, transferring the organic phase into a 1L flask, and concentrating under reduced pressure at 50-55 ℃ until no solvent is evaporated. After concentration, 32g of a reddish brown oil was obtained. Adding 28ml of benzyl alcohol and 8ml of n-propanol into the oily substance, stirring for dissolving, then adding 160ml of n-heptane to ensure that the system is turbid, heating for refluxing for dissolving, then stirring for cooling to 10-20 ℃, and carrying out heat preservation and crystallization for 1-2 hours. Filtering, leaching the filter cake with 20ml of normal hexane, and draining. The filter cake was collected and dried under vacuum at 50-60 ℃ for 8-12 hours to give about 24g of intermediate 2 as a yellow solid in 72% yield. HPLC purity: 99.58 percent.
Example 2
153g of toluene were charged into a 1L reaction flask, 25g of intermediate 1 were added with stirring, and 11.78g of tetrabutylammonium hydrogen sulfate and an aqueous solution of about 40% potassium hydroxide were added (116g of potassium hydroxide was added to 174g of drinking water, and the solution was stirred). The temperature of the system is reduced to 5-10 ℃, and 12g of bromoacetic acid tert-butyl ester is dripped at 7 ℃. Controlling the temperature to be 5-10 ℃, stirring for 45 minutes, then heating the system to room temperature, controlling the temperature to be 23-25 ℃, and stirring for 1 hour. TLC (n-hexane: ethyl acetate 2:1) and the starting material was reacted completely. Adding 150g of water, then adding 160g of ethyl acetate for extraction and phase separation, collecting an organic phase, washing the organic phase with 152g of water for phase separation, transferring the organic phase into a 1L flask, and concentrating under reduced pressure at 50-55 ℃ until no solvent is evaporated. After concentration, 32g of oil was obtained. Adding 48ml of n-propanol into the oily matter, stirring for dissolving, then adding 240ml of n-hexane into the oily matter to obtain a turbid system, heating for refluxing for dissolving, then stirring and cooling to 10-20 ℃, and carrying out heat preservation and crystallization for 1-2 hours. Filtering, leaching the filter cake with 20ml of normal hexane, and draining. The filter cake was collected and dried under vacuum at 50-60 ℃ for 8-12 hours to give about 23g of intermediate 2 as a yellow solid in 69% yield. HPLC purity: 99.2 percent.
Example 3
To a 1L reaction flask was added 153g of toluene, 25g of intermediate 1 was added with stirring, and 11.78g of tetrabutylammonium hydrogen sulfate and about 40% aqueous potassium hydroxide solution were added. The temperature of the system is reduced to 5-10 ℃, and 12g of bromoacetic acid tert-butyl ester is dripped at 7 ℃. Controlling the temperature to be 5-10 ℃, stirring for 45 minutes, then heating the system to room temperature, controlling the temperature to be 23-25 ℃, and stirring for 1 hour. TLC (n-hexane: ethyl acetate 2:1) and the starting material was reacted completely. Adding 150g of water, then adding 160g of ethyl acetate for extraction and phase separation, collecting an organic phase, washing the organic phase with 152g of water for phase separation, transferring the organic phase into a 1L flask, and concentrating under reduced pressure at 50-55 ℃ until no solvent is evaporated. After concentration, 32g of oil was obtained. Adding 48ml of n-butanol into the oily matter, stirring for dissolving, then adding 240ml of n-hexane to obtain a turbid system, heating for refluxing for dissolving, then stirring and cooling to 10-20 ℃, and carrying out heat preservation and crystallization for 1-2 hours. Filtration was carried out and the filter cake was rinsed with 20ml of n-heptane and drained. The filter cake was collected and dried under vacuum at 50-60 deg.C for 8-12 hours to give intermediate 2 as a yellow solid, approximately 23.5g, 70% yield. HPLC purity: 99.5 percent.
To further verify the technical effects of the present invention, the intermediate 2 obtained in example 1, the intermediate 2 product obtained by column chromatography, and the unpurified intermediate 2 product were subjected to subsequent reactions to prepare serapage, and the yield and product purity of each reaction were examined and compared.
Comparative example 1: preparation of slapagog from intermediate 2 of example 1
(1) Preparation of intermediate 3: adding 63g of methanol into a 100mL reaction bottle, starting stirring, then sequentially adding 8.26g of an intermediate 2, 1N sodium hydroxide aqueous solution (after the addition is finished, heating the system to reflux, keeping the temperature for reaction for 1.5 hours, monitoring by TLC (normal hexane: ethyl acetate is 5:1), completely reacting, concentrating the reaction solution at 50-55 ℃ under reduced pressure until no solvent is evaporated, concentrating to obtain a light yellow solid, adding 81g of drinking water into the residue, stirring for dissolving, then adding 39g of normal hexane, washing, standing for phase separation, collecting a water phase, sequentially adding 1N hydrochloric acid and 79g of ethyl acetate, extracting for phase separation, collecting an organic phase, adding 10g of anhydrous magnesium sulfate, drying for 1 hour, drying, filtering to remove the magnesium sulfate, transferring the filtrate into a 100mL flask, transferring to the end, concentrating the filtrate at 50-55 ℃ under reduced pressure until no solvent is left, concentrating to obtain a yellow solid, 19.93g of n-hexane was added and the mixture was washed by beating. And (3) carrying out suction filtration, collecting the solid, and concentrating the solid at 50-55 ℃ under reduced pressure to obtain 5.23g of an intermediate 3 which is a light yellow solid with a yield of 72%. And (4) HPLC (high performance liquid chromatography) detection: the purity was 99.91%.
(2) Slalipag preparation: to a 100mL reaction flask was added 55g of tetrahydrofuran, and 3.75g of intermediate 3 was added with stirring and dissolved with stirring. Then, 1.63g of N, N' -Carbonyldiimidazole (CDI) was added thereto, and the mixture was stirred at room temperature for 30 minutes, then, the mixture was refluxed and stirred for 30 minutes. After cooling to room temperature, 0.86g of methanesulfonamide was added, and after stirring for 10 minutes, 1.39g of 1, 8-diazabicycloundecen-7-ene (DBU) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. TLC monitoring (ethyl acetate: methanol 5:1) and reaction was complete. 30g of water were added, followed by extraction with 30g of ethyl acetate, phase separation and drying of the organic phase over 7.50g of anhydrous magnesium sulfate for 1 hour. After the completion of drying, magnesium sulfate was removed by filtration, and the filtrate was transferred to a 100mL flask. After the transfer is finished, the filtrate is decompressed and concentrated at 50-55 ℃ until no solvent is evaporated. After concentration, 2.5g of crude product was obtained. And adding 10g of ethyl acetate into the flask, adding 15g of absolute ethyl alcohol, heating, refluxing, dissolving, cooling to 0-10 ℃, crystallizing, filtering, and drying a filter cake at 55-60 ℃ for 10 hours to obtain 2.68g of a light yellow serpag product with the yield of 60.5%. And (4) HPLC (high performance liquid chromatography) detection: the purity was 99.4%.
Comparative example 2: intermediate 2 preparation of slapag by column chromatography purification
(1) Preparation of intermediate 3: to a 100mL reaction flask was added 63g of methanol, stirring was turned on, and then 8.26g of intermediate 2 (column chromatography purification, HPLC purity 98.9%), 1N aqueous sodium hydroxide solution was added in order. After the addition, the system was heated to reflux and the reaction was held for 1.5 hours. TLC monitoring (n-hexane: ethyl acetate 5:1) and reaction was complete. And concentrating the reaction solution at 50-55 ℃ under reduced pressure until no solvent is evaporated. After the concentration, a pale yellow solid was obtained, and 81g of drinking water was added to the residue and dissolved with stirring. Then, 39g of n-hexane was added thereto, and the mixture was washed, allowed to stand for phase separation, and the aqueous phase was collected. Then 1N hydrochloric acid and 79g of ethyl acetate are added in sequence, extraction phase separation is carried out, and an organic phase is collected. Magnesium sulfate anhydride (10 g) was added thereto, and the mixture was dried for 1 hour. After the completion of drying, magnesium sulfate was removed by filtration, and the filtrate was transferred to a 100mL flask. After the transfer is finished, the filtrate is decompressed and concentrated at 50-55 ℃ until no solvent is evaporated. After the concentration, a yellow solid was obtained, which was washed by adding 19.93g of n-hexane and beating. And (3) carrying out suction filtration, collecting the solid, and concentrating the solid at 50-55 ℃ under reduced pressure to obtain 5.02g of an intermediate 3 which is a light yellow solid with the yield of 68.8%. And (4) HPLC (high performance liquid chromatography) detection: the purity was 99.4%.
(2) Slalipag preparation: to a 100mL reaction flask was added 55g of tetrahydrofuran, and 3.75g of intermediate 3 was added with stirring and dissolved with stirring. Then, 1.63g of N, N' -Carbonyldiimidazole (CDI) was added thereto, and the mixture was stirred at room temperature for 30 minutes, then, the mixture was refluxed and stirred for 30 minutes. After cooling to room temperature, 0.86g of methanesulfonamide was added, and after stirring for 10 minutes, 1.39g of 1, 8-diazabicycloundecen-7-ene (DBU) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. TLC monitoring (ethyl acetate: methanol 5:1) and reaction was complete. 30g of water were added, followed by extraction with 30g of ethyl acetate, phase separation and drying of the organic phase over 7.50g of anhydrous magnesium sulfate for 1 hour. After the completion of drying, magnesium sulfate was removed by filtration, and the filtrate was transferred to a 100mL flask. After the transfer is finished, the filtrate is decompressed and concentrated at 50-55 ℃ until no solvent is evaporated. After concentration, 2.5g of crude product was obtained. And adding 10g of ethyl acetate into the flask, adding 15g of absolute ethyl alcohol, heating, refluxing, dissolving, cooling to 0-10 ℃, crystallizing, filtering, and drying a filter cake at 55-60 ℃ for 10 hours to obtain 2.58g of a light yellow serpag product, wherein the yield is 58.3%. HPLC purity 99.0%.
Comparative example 3: preparation of slapagog from unpurified intermediate 2
(1) Preparation of intermediate 3: to a 100mL reaction flask was added 63g of methanol, stirring was turned on, and then 8.26g of intermediate 2 (reddish brown oil from example 1, HPLC purity 92.3%), 1N aqueous sodium hydroxide solution was added in that order. After the addition, the system was heated to reflux and the reaction was held for 1.5 hours. TLC monitoring (n-hexane: ethyl acetate 5:1) and reaction was complete. And concentrating the reaction solution at 50-55 ℃ under reduced pressure until no solvent is evaporated. After the concentration, a pale yellow solid was obtained, and 81g of drinking water was added to the residue and dissolved with stirring. Then, 39g of n-hexane was added thereto, and the mixture was washed, allowed to stand for phase separation, and the aqueous phase was collected. Then 1N hydrochloric acid and 79g of ethyl acetate are added in sequence, extraction phase separation is carried out, and an organic phase is collected. Magnesium sulfate anhydride (10 g) was added thereto, and the mixture was dried for 1 hour. After the completion of drying, magnesium sulfate was removed by filtration, and the filtrate was transferred to a 100mL flask. After the transfer is finished, the filtrate is decompressed and concentrated at 50-55 ℃ until no solvent is evaporated. After the concentration, a yellow solid was obtained, which was washed by adding 19.93g of n-hexane and beating. And (3) carrying out suction filtration, collecting the solid, and concentrating the solid at 50-55 ℃ under reduced pressure to obtain 3.9g of an intermediate 3 which is a light yellow solid with a yield of 53.5%. And (4) HPLC (high performance liquid chromatography) detection: the purity was 98.9%.
(2) Slalipag preparation: to a 100mL reaction flask was added 55g of tetrahydrofuran, and 3.75g of intermediate 3 was added with stirring and dissolved with stirring. Then, 1.63g of N, N' -Carbonyldiimidazole (CDI) was added thereto, and the mixture was stirred at room temperature for 30 minutes, then, the mixture was refluxed and stirred for 30 minutes. After cooling to room temperature, 0.86g of methanesulfonamide was added, and after stirring for 10 minutes, 1.39g of 1, 8-diazabicycloundecen-7-ene (DBU) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. TLC monitoring (ethyl acetate: methanol 5:1) and reaction was complete. 30g of water were added, followed by extraction with 30g of ethyl acetate, phase separation and drying of the organic phase over 7.50g of anhydrous magnesium sulfate for 1 hour. After the completion of drying, magnesium sulfate was removed by filtration, and the filtrate was transferred to a 100mL flask. After the transfer is finished, the filtrate is decompressed and concentrated at 50-55 ℃ until no solvent is evaporated. After concentration, 2.5g of crude product was obtained. And adding 10g of ethyl acetate into the flask, adding 15g of absolute ethyl alcohol, heating, refluxing, dissolving, cooling to 0-10 ℃, crystallizing, filtering, and drying a filter cake at 55-60 ℃ for 10 hours to obtain 2.2g of a light yellow serpag product with the yield of 49.5%. HPLC purity 98.8%.
Summary of the comparative examples
As can be seen from the comparative examples, the intermediate 2 obtained by the crystallization method of the invention is used as a raw material, so that the prepared selepagide product has the highest purity, and the total yield is relatively highest. The crystallization method of the intermediate 2 is more suitable for commercial production due to the factors of comprehensive cost, simplicity and convenience of test operation and the like.
Claims (7)
1. A process for the preparation of a pharmaceutical intermediate, tert-butyl 2- {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetate, comprising the steps of:
1) reacting an intermediate 1 in the following formula with tert-butyl bromoacetate to obtain a mixed solution containing an intermediate 2;
2) obtaining crude intermediate 2 from the mixture;
3) recrystallizing the crude product with a mixed solvent, wherein the mixed solvent consists of hydrocarbon and alcohol, the hydrocarbon is selected from one or more of n-hexane, cyclohexane, n-heptane, toluene and xylene, and the alcohol is selected from one or more of propanol, isopropanol, n-butanol, isobutanol and benzyl alcohol.
2. The method of claim 1, wherein the volume ratio of hydrocarbon to alcohol is from 3:1 to 20: 1.
3. The method of claim 1, wherein the volume ratio of hydrocarbon to alcohol is 5-10: 1.
4. The method of claim 1, wherein the hydrocarbon is n-hexane and the alcohol is n-propanol in a volume ratio of 5:1 to 7: 1.
5. The method of claim 1, wherein the hydrocarbon is n-hexane and the alcohol is n-butanol at a volume ratio of 5:1 to 7: 1.
6. The process of claim 1, wherein the hydrocarbon is n-heptane and the alcohols are benzyl alcohol and n-propanol in a volume ratio of 5-6:1: 0.2-0.3.
7. The process of claim 1, wherein in step 2, water and ethyl acetate are added to the solution after the reaction for extraction, the organic phase is separated, and the solvent is concentrated to obtain the crude product as an oil.
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| CN107365275A (en) * | 2017-06-14 | 2017-11-21 | 杭州华东医药集团新药研究院有限公司 | The Sai Lexipa of high-purity |
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| CN106279047A (en) * | 2015-05-13 | 2017-01-04 | 上海适济生物科技有限公司 | A kind of preparation method of prostacyclin receptor agonist |
| CN107365275A (en) * | 2017-06-14 | 2017-11-21 | 杭州华东医药集团新药研究院有限公司 | The Sai Lexipa of high-purity |
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