CN118255705A - Preparation method of (1H-pyrrole-1-yl) carbamic acid tert-butyl ester - Google Patents
Preparation method of (1H-pyrrole-1-yl) carbamic acid tert-butyl ester Download PDFInfo
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- CN118255705A CN118255705A CN202211672590.3A CN202211672590A CN118255705A CN 118255705 A CN118255705 A CN 118255705A CN 202211672590 A CN202211672590 A CN 202211672590A CN 118255705 A CN118255705 A CN 118255705A
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- 238000002360 preparation method Methods 0.000 title claims description 12
- JDOTVVAIWOCYFL-UHFFFAOYSA-N tert-butyl n-pyrrol-1-ylcarbamate Chemical compound CC(C)(C)OC(=O)NN1C=CC=C1 JDOTVVAIWOCYFL-UHFFFAOYSA-N 0.000 title abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- PKRHOIOVOBITKL-UHFFFAOYSA-N 2,3-dimethylpyridine;hydrochloride Chemical compound Cl.CC1=CC=CN=C1C PKRHOIOVOBITKL-UHFFFAOYSA-N 0.000 claims description 3
- OMSBSIXAZZRIRW-UHFFFAOYSA-N 2-methylpyridine;hydrochloride Chemical compound Cl.CC1=CC=CC=N1 OMSBSIXAZZRIRW-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000005086 pumping Methods 0.000 claims description 3
- HBMJWWWQQXIZIP-UHFFFAOYSA-N silicon carbide Chemical compound [Si+]#[C-] HBMJWWWQQXIZIP-UHFFFAOYSA-N 0.000 claims description 3
- 229910010271 silicon carbide Inorganic materials 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 239000011521 glass Substances 0.000 claims description 2
- 229910000856 hastalloy Inorganic materials 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 229910001220 stainless steel Inorganic materials 0.000 claims description 2
- 239000010935 stainless steel Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 229910052715 tantalum Inorganic materials 0.000 claims description 2
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims 1
- GFISDBXSWQMOND-UHFFFAOYSA-N 2,5-dimethoxyoxolane Chemical compound COC1CCC(OC)O1 GFISDBXSWQMOND-UHFFFAOYSA-N 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- -1 (1H-pyrrole-1-yl) tert-butyl Chemical group 0.000 description 2
- ZEBGLCLVPCOXIV-UHFFFAOYSA-N 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound NC1=NC=NN2C(I)=CC=C12 ZEBGLCLVPCOXIV-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IVZDQBFNKJAJRN-UHFFFAOYSA-N CC(C)(C)OC(=O)NNN Chemical compound CC(C)(C)OC(=O)NNN IVZDQBFNKJAJRN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 101710118046 RNA-directed RNA polymerase Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- FBXVOTBTGXARNA-UHFFFAOYSA-N bismuth;trinitrate;pentahydrate Chemical compound O.O.O.O.O.[Bi+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O FBXVOTBTGXARNA-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 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
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/50—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The application discloses a continuous synthesis method of (1H-pyrrole-1-yl) carbamic acid tert-butyl ester, which uses carbamic acid tert-butyl ester and 2, 5-dimethoxy tetrahydrofuran as raw materials to react under the action of pyridine hydrochloride or substituted pyridine hydrochloride by a continuous reaction device to obtain a product compound shown as a formula I. The process shortens the production period, reduces the production cost, is suitable for industrial production, and has higher economic benefit.
Description
Technical field:
The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of (1H-pyrrole-1-yl) carbamic acid tert-butyl ester.
Background
Tert-butyl (1H-pyrrol-1-yl) carbamate is an important intermediate for synthesizing prodrugs common to many commercial large products of pharmaceutical companies, such as the triazinamine derivative 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine, which can be used to prepare nucleoside drugs such as Ruidexivir via a multi-step reaction (J.Med. Chem.2017,60,1648). A nucleotide analogue prodrug developed by Rede Wei Shiji Lide company, which can be triphosphorylated in human body, inhibits RNA dependent RNA synthetase (RdRp), thereby blocking the replication of viral RNA, and has good broad-spectrum antiviral activity.
7-Iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine
However, prodrugs of nucleoside analogs have problems in the actual synthesis process, such as low yields, long reaction times, etc., which have largely limited their large-scale preparation and use.
CN101466710B discloses a preparation method of (1H-pyrrol-1-yl) carbamic acid tert-butyl ester, which takes 2, 5-dimethoxy tetrahydrofuran and hydrazino carbamic acid tert-butyl ester as raw materials, takes 1, 4-dioxane as solvent, heats for a plurality of hours under the action of 2N hydrochloric acid at the temperature of 90 ℃ under the protection of nitrogen, and obtains the product (1H-pyrrol-1-yl) carbamic acid tert-butyl ester through quenching, extraction, concentration and other post-treatments. However, the yield of the method is only 40%, and the yield is not ideal.
CN113980024a discloses a preparation method of (1H-pyrrol-1-yl) carbamic acid tert-butyl ester, the reaction raw material and solvent are the same as CN101466710B, but the method disclosed in CN113980024a is different in that bismuth nitrate pentahydrate is added under the mixing and stirring of the raw material and solvent, the pH of the reaction system is kept at 6.0, the reaction is carried out at 50 ℃ for 3 hours, the reaction is continued at 58 ℃ for 4 hours, and then the product is obtained through post-treatment. The yield of the method can reach 90 percent, but the reaction time is longer.
CN113382997A discloses a preparation method of (1H-pyrrol-1-yl) carbamic acid tert-butyl ester, in the presence of pyridine hydrochloride, 2, 5-dimethoxy tetrahydrofuran and carbamic acid tert-butyl ester are reacted for 7 hours at the temperature of 102+/-3 ℃ in a solvent mixture of dioxane and pyridine, and the product is obtained through post-treatment such as distillation, liquid separation and the like, wherein the yield of the method is about 60 percent. The process has the advantage of reducing the formation of side components, especially for large-scale production, by using pyridine and pyridine hydrochloride as reagents, but the reaction time is longer and the efficiency is lower in industrial production.
The industrial preparation method of the (1H-pyrrol-1-yl) carbamic acid tert-butyl ester reported in the published literature and patent at present is mostly carried out in a reaction kettle, 2, 5-dimethoxy tetrahydrofuran and hydrazino carbamic acid tert-butyl ester are dissolved in solvents such as dioxane, N-methyl pyrrolidone, N-dimethyl formamide or tetrahydrofuran, and the like, and the reaction is heated under the action of hydrochloric acid, the yield is about 40 to 85 percent, but the problem of longer reaction time generally exists; CN113382997a discloses a new process for reacting 2, 5-dimethoxy tetrahydrofuran with t-butyl hydrazinoformate in the presence of pyridine hydrochloride in a solvent mixture of dioxane and pyridine, the process yields around 60%, yields are not high and the reaction time is long. Therefore, the development of a simple and convenient (1H-pyrrol-1-yl) carbamic acid tert-butyl ester synthesis process which is easy to amplify, short in reaction time, high in yield and low in cost has important significance.
Disclosure of Invention
The invention aims to: the invention aims to provide a continuous synthesis method of (1H-pyrrole-1-yl) tert-butyl carbamate, which accurately controls the reaction end point through a continuous flow technology, improves and stabilizes the yield, so as to solve the defects that the reaction end point is difficult to control in the existing synthesis process of (1H-pyrrole-1-yl) tert-butyl carbamate, the separation yield of the prior art is only 50%, the reaction period is longer, the yield is lower, and the like.
In one aspect, the invention provides a method of preparing a compound of formula I:
And (3) pumping the compound of the formula II and the compound of the formula III into a continuous reactor for reaction under the action of acid 1, and then treating to obtain the compound of the formula I.
Preferably, the acid 1 is selected from one or more of pyridine hydrochloride, 2-picoline hydrochloride or 2, 3-lutidine hydrochloride;
More preferably, the acid 1 is pyridine hydrochloride.
Preferably, the molar ratio of the compound of formula III to the acid 1 is in the range of 1:0.01 to 1:0.1.
Preferably, the organic solvent is one or more selected from dioxane, water, 2-methyl-tetrahydrofuran and N-methyl pyrrolidone, and the dosage of the organic solvent is 5-15 times of the volume of the compound of the formula III.
Preferably, the reaction liquid is pumped into a continuous reactor for reaction, and the reaction temperature ranges from 100 ℃ to 160 ℃.
Preferably, the reaction liquid is pumped into a continuous reactor for reaction, and the reaction time is 2-40 minutes.
Preferably, the continuous reactor is a microchannel reactor, a tubular reactor, a dynamic tubular reactor or a continuous stirred tank reactor.
Preferably, the continuous reactor is made of PFTE, glass, hastelloy, tantalum, silicon carbide, stainless steel or PFA.
Preferably, after the reaction is completed, the compound of formula I is purified by recrystallization from toluene.
Advantageous effects
The invention aims to overcome the defects of difficult control of a reaction end point, longer reaction period, lower yield and the like in the prior art, and provides a safe, simple and convenient continuous synthesis method which is easy to amplify, higher in yield and lower in cost. The process takes tert-butyl carbazate and 2, 5-dimethoxy tetrahydrofuran as raw materials, and the product (1H-pyrrole-1-yl) carbamic acid tert-butyl ester is obtained by reaction under the action of pyridine hydrochloride or substituted pyridine hydrochloride, and the reaction end point is accurately controlled by a continuous flow technology, so that the yield is improved and stabilized, compared with the literature process, the process has no obvious amplification effect, the synthesis difficulty is reduced, the production period is greatly shortened, and the production cost is reduced. In conclusion, the technical scheme provided by the invention is suitable for industrial production and has higher economic benefit.
Drawings
For a clearer description of embodiments of the invention or of solutions according to the prior art, the drawings that are used in the description of the embodiments or of the prior art will be briefly described, it being apparent that the drawings in the description that follow are some embodiments of the invention.
FIG. 1 is a schematic diagram of a continuous reaction apparatus for preparing a compound of formula I according to the present invention.
FIG. 2 is a 1 H NMR spectrum of the final product of example 1 according to the invention.
FIG. 3 is a GC spectrum of the final product of example 1 of the invention.
Detailed Description
The invention will be further illustrated by the following examples, which are carried out on the basis of the technical solutions of the invention, and it should be understood that these examples are only intended to illustrate the invention and are not intended to limit the scope of the invention.
Example 1
Preparation of the compound of formula I:
in a 10L four-necked flask, tert-butyl carbazate (1000 g,7.57mol,1 eq.) and 2, 5-dimethoxytetrahydrofuran (1100 g,8.32mol,1.1 eq.) were dissolved in dioxane (7.23 kg) and mixed well as solution a for use.
The temperature of the continuous reactor is set to 140 ℃, the prepared solution A flows into the silicon carbide plate reactor at 46ml/min through a tetrafluoro plunger pump, the residence time is 4.35min, and the back pressure of a back pressure valve is 1.0Mpa. After the reaction was completely detected by GC, the reaction solution was introduced into a stirred 10L four-necked flask containing sodium hydrogencarbonate solid through a cooling section and a back pressure valve, the reaction solution was distilled to 3kg, cooled, stirred with water (2L), filtered, and rinsed with 400mL of water to obtain 1498g of crude product. Transferring the wet material into a 5L reaction bottle, adding toluene (2.5L), heating and refluxing at about 84 ℃ for 2 hours, naturally cooling to 20 ℃, filtering and draining, soaking and washing a filter cake with toluene (400 mL), and draining and drying to obtain 1055g of the compound shown in the formula I. The filtrate was distilled off to a residual of about 400g, cooled naturally to room temperature and filtered to give 64g of crude product, which was recrystallized from 64mL of toluene to give 45g of the compound of formula I, which was combined to give 1100g of the compound of formula I in a yield of 79.8%.
1 HNMR (400 mhz, d 6-DMSO): 1.43 (9H, s); 5.97-5.98 (2H, t), 6.68-6.69 (2H, t), 10.25 (1H, s); the purity was 98.4% by HPLC.
Comparative example 1
The results of examining the acid 1, the reaction temperature and the reaction time by the method of example 1 are shown in tables 1 to 3 below.
TABLE 1 conditional screening of 2-methylpyridine hydrochloride for different reaction times
TABLE 2 screening of 2, 3-lutidine hydrochloride for conditions at various temperatures and reaction times for acid 1
TABLE 3 screening of pyridine hydrochloride for different temperatures and reaction times
Claims (10)
1. A process for the preparation of a compound of formula I, characterized in that:
And (3) pumping the compound of the formula II and the compound of the formula III into a continuous reactor for reaction under the action of acid 1, and then treating to obtain the compound of the formula I.
2. The method of manufacturing according to claim 1, characterized in that: the acid 1 is selected from one or more of pyridine hydrochloride, 2-picoline hydrochloride and 2, 3-lutidine hydrochloride.
3. The preparation method according to claim 1 or 2, characterized in that: the acid 1 is pyridine hydrochloride.
4. A method of preparation according to claims 1-3, characterized in that: the mol ratio of the compound of the formula III to the acid 1 is 1:0.01-1:0.1.
5. The method of manufacturing according to claim 1, characterized in that: the organic solvent is one or more selected from dioxane, water, 2-methyl-tetrahydrofuran and N-methyl pyrrolidone, and the dosage is 5-15 times of the volume of the compound in the formula III.
6. The method of manufacturing according to claim 1, characterized in that: the reaction liquid is pumped into a continuous reactor for reaction, and the reaction temperature ranges from 100 ℃ to 160 ℃.
7. The method of manufacturing according to claim 1, characterized in that: pumping the reaction liquid into a continuous reactor for reaction for 2-40 minutes.
8. The method of manufacturing according to claim 1, characterized in that: the continuous reactor is a micro-channel reactor, a tubular reactor, a dynamic tubular reactor or a continuous stirring kettle reactor.
9. The method of manufacturing according to claim 1, characterized in that: the continuous reactor is made of PFTE, glass, hastelloy, tantalum, silicon carbide, stainless steel or PFA.
10. The method of manufacturing according to claim 1, characterized in that: after the reaction is finished, the compound of the formula I is prepared by recrystallization and purification by using toluene.
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|---|---|---|---|
| CN202211672590.3A CN118255705A (en) | 2022-12-26 | 2022-12-26 | Preparation method of (1H-pyrrole-1-yl) carbamic acid tert-butyl ester |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211672590.3A CN118255705A (en) | 2022-12-26 | 2022-12-26 | Preparation method of (1H-pyrrole-1-yl) carbamic acid tert-butyl ester |
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