CN115160205B - Method for preparing (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salt thereof - Google Patents
Method for preparing (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salt thereof Download PDFInfo
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- CN115160205B CN115160205B CN202210806783.7A CN202210806783A CN115160205B CN 115160205 B CN115160205 B CN 115160205B CN 202210806783 A CN202210806783 A CN 202210806783A CN 115160205 B CN115160205 B CN 115160205B
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 150000003839 salts Chemical class 0.000 title claims abstract description 26
- BMIGSRMSSCUMAZ-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]-2,5-dihydropyrrole-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC=C[C@H]1C(O)=O BMIGSRMSSCUMAZ-ZETCQYMHSA-N 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 66
- 229940126214 compound 3 Drugs 0.000 claims abstract description 47
- 229940125782 compound 2 Drugs 0.000 claims abstract description 36
- 239000003960 organic solvent Substances 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 238000005086 pumping Methods 0.000 claims abstract description 19
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 12
- 238000003379 elimination reaction Methods 0.000 claims abstract description 11
- 238000000746 purification Methods 0.000 claims abstract description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 183
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 229940125904 compound 1 Drugs 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229960000517 boceprevir Drugs 0.000 claims description 6
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 claims description 6
- 239000003443 antiviral agent Substances 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- -1 t-butoxycarbonyl Chemical group 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 238000005112 continuous flow technique Methods 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 12
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000003810 ethyl acetate extraction Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- RICZEKWVNZFTNZ-LFGITCQGSA-N narlaprevir Chemical compound N([C@H](C(=O)N1C[C@H]2[C@H](C2(C)C)[C@H]1C(=O)N[C@@H](CCCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C(=O)NC1(CS(=O)(=O)C(C)(C)C)CCCCC1 RICZEKWVNZFTNZ-LFGITCQGSA-N 0.000 description 4
- 229950003504 narlaprevir Drugs 0.000 description 4
- 229940125674 nirmatrelvir Drugs 0.000 description 4
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 125000001664 diethylamino group Chemical class [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- UVQZQJWQDGQASW-UHNVWZDZSA-N (2s,4r)-4-methylsulfonyloxypyrrolidine-1,2-dicarboxylic acid Chemical compound CS(=O)(=O)O[C@@H]1C[C@@H](C(O)=O)N(C(O)=O)C1 UVQZQJWQDGQASW-UHNVWZDZSA-N 0.000 description 1
- OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical class OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 description 1
- YSAANLSYLSUVHB-UHFFFAOYSA-N 2-[2-(dimethylamino)ethoxy]ethanol Chemical compound CN(C)CCOCCO YSAANLSYLSUVHB-UHFFFAOYSA-N 0.000 description 1
- 206010024769 Local reaction Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000002920 hazardous waste Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
Classifications
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- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention provides a method for preparing (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salt, which has the following reaction formula:
Description
Technical Field
The invention relates to a preparation method for synthesizing an antiviral drug intermediate, in particular to a preparation method for synthesizing (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid diethylamine salt by using a continuous flow reactor, belonging to the technical field of drug synthesis.
Background
(S) -1- (tert-Butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid (compound of formula I) and its salts are important intermediates for the synthesis of antiviral drugs, namacitevir (NIRMATRELVIR), boceprevir and Nalaprevir (narlaprevir), and have the following structural formula:
CN1226231a (WO 1998004523 A1) discloses a process for the preparation of 3-pyrroline-2-carboxylic acid derivatives; WO2005123632A1 discloses a process for the preparation of olefins by removing water from alcohols using alkylphosphonic anhydrides, in particular using a one-step elimination reaction of cyclic phosphonic anhydrides.
CN114085180A discloses that DBU is dissolved in DCM, the back pressure is 0.5-0.7 MPa, the external bath temperature is 25-30 ℃, the residence time is 6 minutes, and the yield of the external standard system of the two-stage reaction is 55-60% (target product)And positional isomers/>Ratio 3:1), the reaction formula is as follows:
Disclosure of Invention
Aiming at the technical background, the problems of high impurity content of double bond position isomers, high safety risk of a medium kettle type process and low production efficiency in the prior art are solved. The invention provides a method for continuously synthesizing (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid and salt, which is safe and controllable, short in reaction time and high in yield.
The invention provides a method for preparing (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid and salt by a continuous flow reactor, which comprises the following steps:
Comprises the following steps:
Step 1: adding an organic solvent to compound 2to form solution a, and pumping the solution a into a continuous flow reactor;
step 2: adding an organic solvent into the compound 3 to form a solution B, pumping the solution B into a continuous flow reactor, carrying out elimination reaction on the compound 2 and the compound 3 at a proper temperature and a proper pressure on the continuous flow reactor, and optionally carrying out post-treatment purification to obtain a compound I (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid;
or further reacting with diethylamine to obtain the high-purity (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine salt.
The invention further provides the following scheme: in the step 1, the dosage volume mL of the organic solvent is 1 to 5 times, preferably 1 to 3 times of the dosage weight g of the compound 2.
The invention further provides the following scheme: step 1, the organic solvent is selected from one or any combination of methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile, toluene, 1, 2-dichloroethane or dichloromethane; further preferred is one or any combination of tetrahydrofuran, acetonitrile, toluene, most preferred is one or a combination of acetonitrile or tetrahydrofuran.
The invention further provides the following scheme: step 1, the organic solvent is selected from acetonitrile or tetrahydrofuran, and the dosage volume mL of the acetonitrile or the tetrahydrofuran is 1-5 times, preferably 1-3 times of the dosage mass g of the compound 2.
The invention further provides the following scheme: step 1, pumping the solution A into a continuous flow reactor at a flow rate of 0.1-3 mL/min, preferably 0.9-2 mL/min, and most preferably 1.5-2 mL/min; the further scheme is as follows: solution A is selected from acetonitrile solution of compound 2 or tetrahydrofuran solution of compound 2, and the flow rate of acetonitrile of compound 2 or tetrahydrofuran solution of compound 2 is 0.1-3 mL/min, preferably 0.9-2 mL/min, and most preferably 1.5-2 mL/min.
The invention further provides the following scheme: step 2, the organic solvent is selected from one or any combination of methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile, toluene, 1, 2-dichloroethane or dichloromethane; further preferred is one or any combination of tetrahydrofuran, acetonitrile, toluene, most preferred is one or a combination of acetonitrile or tetrahydrofuran.
The invention further provides the following scheme: in the step 2, the dosage volume mL of the organic solvent (such as acetonitrile or tetrahydrofuran) is 1 to 5 times, preferably 1 to 2 times, and most preferably 1 to 1.5 times of the dosage weight g of the compound 3.
The invention further provides the following scheme: step 2, pumping the solution B into the continuous flow reactor at a flow rate of 0.4-3 mL/min, preferably 1-3 mL/min, and most preferably 2.0-2.5 mL/min; the further scheme is as follows: solution B is selected from acetonitrile solution of compound 3 or tetrahydrofuran solution of compound 3, and the flow rate of acetonitrile of compound 3 or tetrahydrofuran solution of compound 3 is 0.4-3 mL/min, preferably 1-3 mL/min, and most preferably 2.0-2.5 mL/min.
The invention further provides the following scheme: step 2, the reactor is set to a suitable temperature of 0 ℃ to 20 ℃, preferably 5 ℃ to 15 ℃, most preferably 10 ℃ to 15 ℃.
The invention further provides the following scheme: step 2, the reaction time of the elimination reaction in the continuous flow reactor is 30 to 120min, preferably 50 to 90min, such as 60min or 71min.
The invention further provides the following scheme: the post-treatment purification of the step 2 comprises the following steps of adjusting the pH of the reaction solution to 1.5-2 by hydrochloric acid and extracting by using an organic solvent.
And (3) carrying out post-treatment purification in the step (2), wherein the concentration of hydrochloric acid is 6-12 mol/L.
The post-treatment purification of the step 2 is carried out, and the weight g of the organic solvent is 2-5 times, preferably 4-5 times, of the weight g of the compound 1; the organic solvent in the organic solvent extraction is selected from methyl tertiary butyl ether or ethyl acetate, preferably ethyl acetate.
The invention further provides the following scheme: in the further reaction with diethylamine, the molar ratio of diethylamine to compound 1 is (1 to 1.10): 1, preferably (1 to 1.05): 1.
The invention further provides the following scheme: the technical scheme or the method for preparing (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid or salt thereof (such as diethylamine salt) by continuous flow is used for preparing antiviral intermediate medicaments, in particular to antiviral medicaments of Namaceravir (NIRMATRELVIR), boceprevir and Nalaprevir (narlaprevir).
The invention further provides the following scheme: a process for preparing an antiviral drug, such as Nemortevir (NIRMATRELVIR), boceprevir and nalapivir (narlaprevir) drug, comprising a continuous flow process for preparing (S) -1- (t-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid or a salt thereof, such as diethylamine salt, as described above.
The invention also provides a preparation method of the (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine, which comprises the following steps:
Comprises the following steps:
S1, adding sodium tert-butoxide into toluene solution, and adding a compound 1 for reaction under the protection of nitrogen; obtaining a compound 2;
S2, adding acetonitrile into the compound 3 for dissolution, and cooling; adding acetonitrile solution of the compound 2, and controlling the temperature to be 0-15 ℃; stirring for 1-3 hours, completely reacting, adding water, adding hydrochloric acid solution to adjust pH to 1.5-2, adding organic solvent, extracting and concentrating to obtain a compound I;
S3, dropwise adding diethylamine into the organic solvent of the compound I, and continuously stirring the precipitated solid; cooling, preserving heat, stirring, and suction filtering to obtain diethylamine salt of the compound I.
According to a further embodiment of the invention, the organic solvent of step S2 or the organic solvent of S3 is selected from ethyl acetate.
According to a further aspect of the invention, a process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine comprises the steps of:
S1, adding sodium tert-butoxide into toluene solution, and adding a compound 1 for reaction under the protection of nitrogen; heating to 55-60 ℃, and stirring for reacting for 1-2 hours; concentrating under reduced pressure; obtaining a compound 2;
S2, adding acetonitrile into the compound 3 for dissolution, and cooling to-5-0 ℃; adding acetonitrile solution of the compound 2, controlling the temperature to be 0-15 ℃, stirring for 1-3 hours, completely reacting, adding water, adding hydrochloric acid solution to adjust the pH to be 1.5-2, adding ethyl acetate, extracting and concentrating to obtain the compound I;
s3, heating the ethyl acetate solution of the compound I to 35-45 ℃, dropwise adding diethylamine, precipitating a solid, and continuously stirring; cooling, preserving heat, stirring, and suction filtering to obtain diethylamine salt of the compound I.
According to a further scheme of the invention, in the step S1, the molar ratio of the sodium tert-butoxide to the compound 1 is 1:1.01-1.20, preferably 1:1.05-1.10.
In a further embodiment of the present invention, step S2, the compound 3 is dissolved by adding acetonitrile, wherein the volume (mL) of acetonitrile is 1-2 times, preferably 1.2-1.8 times, the weight (g) of the compound 3;
In a further embodiment of the present invention, step S2, the acetonitrile solution of compound 2 is added, wherein the volume of acetonitrile (mL) is 1-2 times, preferably 1-1.2 times the weight (g) of compound 2;
in a further scheme of the invention, in the step S2, the molar concentration of the hydrochloric acid is 6-12 mol/L;
In a further scheme of the invention, in the step S2, the concentration is performed to obtain the compound I, and the compound I is directly concentrated and dried or the ethyl acetate solution of the compound I is obtained after most of organic phases are removed by concentration.
In a further scheme of the invention, in the step S3, the volume ratio of the compound I to the ethyl acetate is 1:1-1:3;
According to a further scheme of the invention, in the step S3, the mol ratio of the diethylamine to the compound 3 is (1-1.10): 1, preferably 1 to 1.05:1;
In a further scheme of the invention, in the step S3, the precipitated solid is continuously stirred for 1-3 hours, preferably 1-2 hours;
In a further scheme of the invention, in step S3, the temperature is reduced to 10-15 ℃; the stirring time is 1 to 2 hours, preferably 1 to 1.5 hours.
The invention further provides the following scheme: a method for preparing antiviral drugs such as Nemrotevir (NIRMATRELVIR), boceprevir (boceprevir) and nalapir (narlaprevir) drugs, comprising the preparation method of one of the above-mentioned (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine.
The invention further provides the following scheme: the continuous flow reaction apparatus of the present invention comprises a microreactor, preferably a pipeline reactor, which may be equipped with: the preheating device is used for preheating materials; a temperature detection device for monitoring the reaction temperature in the continuous reaction device; the temperature control system is used for adjusting the reaction temperature; pressure detection means for monitoring the reaction pressure in the continuous reaction means; an automated control system; the automatic control system is connected with a liquid pump, a gas flow controller, a cooling system (a heat exchange device such as a condenser and the like), a temperature detection device or a pressure detection device and the like.
The beneficial technical effects of the invention are as follows:
1) The synthesis method for continuously preparing the (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine salt provided by the invention has the advantages that one-step reaction can be realized, the process of increasing isomers caused by severe temperature rise in the reaction process of kettle type elimination reaction can be reduced, the double bond isomers are reduced from 40% to 20%, more preferably to 5%, through continuous flow reaction, the yield is improved, and the cost is reduced.
2) Compared with the traditional kettle-type reaction, the continuous flow preparation method has the advantages that the quantity of the compound 2 participating in the reaction in unit time is greatly reduced, and the problems of high safety risk and low reaction degree in the kettle-type process in the prior art are solved. In addition, in the method of the comparative example, sodium methoxide is adopted to prepare the compound 1 into organic base, and then the organic base and the raw material compound 3 are subjected to elimination reaction to obtain a compound I; and salifying the compound I with diethylamine in an organic solvent to obtain a compound diethylamine salt. In the elimination reaction process, the dangerous degree is increased, the reaction degree is reduced, the generation of byproducts is increased, the material surplus is excessive, the post-treatment is very troublesome, and the double bond position isomer impurity is high.
3) By adopting the continuous flow preparation method, the concentration of the local reaction raw materials is greatly improved, so that the reaction time is greatly shortened, and the production efficiency is remarkably improved.
4) Concentrating and purifying the product after the reaction is finished to obtain the product with the yield up to 85% and the purity up to more than 99%. The synthesis method provided by the invention is safe and controllable, the hazardous waste production amount is less, the yield is higher, and the product quality is good.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
Comparative example 1
Taking 1L of a three-port bottle, adding 250.3g of toluene, adding 116.2g of 2- [2- (dimethylamino) ethoxy ] ethanol, adding 145.5g of methanol solution of sodium methoxide, reacting for 1 hour at 20 ℃, distilling methanol under reduced pressure to obtain 50.5g of yellow oily substance, adding 100mL of acetonitrile into the oily substance, dropwise adding 100g of acetonitrile solution of (2S, 4R) -4- [ (methylsulfonyl) oxy ] -1, 2-pyrrolidine dicarboxylic acid at the temperature of 20-25 ℃ under the protection of nitrogen, reacting for 20 hours at 20-25 ℃, cooling to 0-10 ℃, adding 250g of water, adding concentrated hydrochloric acid to adjust the pH of the system to 2.5, standing for layering, adding water into an organic phase for 3 times, adding MTBE into the water phase for 3 times, merging the organic phase, concentrating the organic phase to obtain a yellow 68.7g of crude product, adding 84mL of ethyl acetate into the crude product for dissolution, dropwise 19.2g of diethylamine, reacting for 2.5 hours at room temperature, adding 130mL of MTBE into the reaction liquid, adding the product into the solution, filtering to obtain a white solid with the total purity of more than 28.37 percent, and the total MTBE of the total purity of the product being higher than 28.37 percent, and standing overnight, stirring to obtain the product, wherein the product is obtained after the MTBE is stirred and has high purity.
Example 1
The preparation method of the compound I comprises the following steps:
87.2mL of toluene is added into the reaction kettle R1; sodium tert-butoxide (93.2 g,3.0 eq) was added to reactor R1; stirring is started, nitrogen is replaced for three times, and nitrogen flow is used for protection; raw material compound 1 (139.5 g,3.24 eq) was added dropwise to the reaction vessel R1, and the temperature was controlled at 60 ℃; after dripping, the mixture is decompressed and concentrated at the temperature of 55 to 60 ℃; then adding 78.6g of acetonitrile, completely dissolving, and cooling to-5-0 ℃;
110g of acetonitrile is added into a reaction kettle R2; adding a compound 3 (100 g,1.0 eq) into a reaction kettle R2, and cooling to-5 ℃ to 0 ℃ to obtain an acetonitrile solution of the compound 3;
Dropwise adding an acetonitrile solution of the compound 3 into a reaction kettle R1, and controlling the temperature to be 0-15 ℃; after the dripping is finished, preserving heat for 10-15 ℃ and reacting for 1-2 hours; 200g of water is dripped at the temperature of-5 ℃ to 15 ℃; controlling the temperature to be 0-15 ℃, dropwise adding 320g of 6mol/L hydrochloric acid, and adjusting the pH to be 1.5-2; 90g of ethyl acetate is added for extraction, and the organic phase is washed by saturated saline water and concentrated to dryness at 40 ℃ under reduced pressure; 180g of ethyl acetate is added, the temperature is raised to 35-45 ℃, diethylamine (24.59, 1.04 eq) is added dropwise, the temperature is kept at 40-45 ℃ and the stirring is carried out for 1-2 hours; cooling to 10-15 ℃, stirring for 1h, and filtering; drying the filter cake at 45-55 ℃ for 2-4 hours in a blowing way; obtaining an off-white compound I: 56g, yield: 60.4%; HPLC 98.0%, double bond isomer impurity content 20%.
Example 2
A process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts, comprising in particular the following steps:
1) 40g of compound 2 and 40mL of acetonitrile are added into a reaction bottle R1, the mixture is stirred to clear solution, and the compound 2 acetonitrile solution is pumped into a reactor at a flow rate of 0.7 mL/min; the reaction bottle R2 is used for taking 40g of a compound 3, dissolving the compound 3 in 56mL of acetonitrile, pumping the acetonitrile solution of the compound 3 into a reactor at a flow rate of 1mL/min, setting the temperature of the reactor to 10 ℃, keeping the reaction liquid in the reactor for 61min, and collecting the reaction liquid through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting pH to 1.5-2 with 6mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form salt, filtering, and drying to obtain a white solid compound I, wherein the HPLC is 98.0%, the yield is 72%, and the double bond isomer impurity content is 20.0%.
Example 3
A process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts, comprising in particular the following steps:
1) 40g of compound 2 and 40mL of acetonitrile are added into a reaction bottle R1, the mixture is stirred to clear solution, and the acetonitrile solution of the compound 2 is pumped into a reactor at a flow rate of 0.8 mL/min; taking 40g of a compound 3 from a reaction bottle R2, dissolving the compound 3 in 56mL of acetonitrile, pumping the acetonitrile solution of the compound 3 into a reactor at a flow rate of 1mL/min, setting the temperature of the reactor to 10 ℃, keeping the reaction solution in the reactor for 50min, and collecting the reaction solution through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting pH to 1.5-2 with 6mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form salt, filtering, and drying to obtain a white solid compound I, wherein the HPLC is 98.2%, the yield is 71%, and the double bond isomer impurity content is 19.3%.
Example 4
A process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts, comprising in particular the following steps:
1) 40g of compound 2 and 40mL of acetonitrile are added into a reaction bottle R1, the mixture is stirred to clear solution, and the acetonitrile solution of the compound 2 is pumped into a reactor at a flow rate of 0.9 mL/min; taking 40g of a compound 3 from a reaction bottle R2, dissolving the compound 3 in 56mL of acetonitrile, pumping the acetonitrile solution of the compound 3 into a reactor at a flow rate of 1mL/min, setting the temperature of the reactor to 10 ℃, keeping the reaction solution in the reactor for 65min, and collecting the reaction solution through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, regulating the pH to 1.5-2 by 12mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form salt, filtering and drying to obtain a white solid compound I, wherein the HPLC is 98.3%, the yield is 75%, and the double bond isomer impurity content is 20.0%.
Example 5
A process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts, comprising in particular the following steps:
1) 40g of compound 2 and 40mL of acetonitrile are added into a reaction bottle R1, the mixture is stirred to clear solution, and the acetonitrile solution of the compound 2 is pumped into a reactor at a flow rate of 1.1 mL/min; taking 40g of a compound 3 from a reaction bottle R2, dissolving the compound 3 in 56mL of acetonitrile, pumping the acetonitrile solution of the compound 3 into a reactor at a flow rate of 1mL/min, setting the temperature of the reactor to 10 ℃, keeping the reaction solution in the reactor for 71min, and collecting the reaction solution through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting pH to 1.5-2 with 6mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form salt, filtering, and drying to obtain a white solid compound I, wherein the HPLC is 98.5%, the yield is 76%, and the double bond isomer impurity content is 15.0%.
Example 6
A process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts, comprising in particular the following steps:
1) 40g of compound 2 and 40mL of acetonitrile are added into a reaction bottle R1, the mixture is stirred to clear solution, and the acetonitrile solution of the compound 2 is pumped into a reactor at a flow rate of 1.8 mL/min; taking 40g of a compound 3 from a reaction bottle R2, dissolving the compound 3 in 56mL of acetonitrile, pumping the acetonitrile solution of the compound 3 into a reactor at a flow rate of 2mL/min, setting the temperature of the reactor to 10 ℃, keeping the reaction solution in the reactor for 55min, and collecting the reaction solution through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting pH to 1.5-2 with 6mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form salt, filtering, and drying to obtain a white solid compound I, wherein the HPLC is 99.3%, the yield is 85%, and the double bond isomer impurity content is 5.0%.
Example 7
A process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts, comprising in particular the following steps:
1) 400g of compound 2 is added into a reaction bottle R1, 400mL of acetonitrile is added, the mixture is stirred to clear solution, and the acetonitrile solution of the compound 2 is pumped into a reactor at a flow rate of 1.5 mL/min; taking 400g of a compound 3 from a reaction bottle R2, dissolving the compound 3 in 560mL of acetonitrile, pumping the acetonitrile solution of the compound 3 into a reactor at a flow rate of 2.1mL/min, setting the temperature of the reactor to 10 ℃, keeping the reaction solution in the reactor for 68min, and collecting the reaction solution through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting pH to 1.5-2 with 6mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form salt, filtering, and drying to obtain a white solid compound I, wherein the HPLC is 99.0%, the yield is 86%, and the double bond isomer impurity content is 5.8%.
Example 8
A process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts, comprising in particular the following steps:
1) Adding 40g of compound 2 into a reaction bottle R1, adding 48mL of acetonitrile, stirring to obtain a clear solution, and pumping the acetonitrile solution of the compound 2 into a reactor at a flow rate of 1.7 mL/min; taking 40g of a compound 3 from a reaction bottle R2, dissolving the compound 3 in 60mL of acetonitrile, pumping the acetonitrile solution of the compound 3 into a reactor at a flow rate of 2mL/min, setting the temperature of the reactor to 10 ℃, keeping the reaction solution in the reactor for 63min, and collecting the reaction solution through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting pH to 1.5-2 with 6mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form salt, filtering, and drying to obtain a white solid compound I, wherein the HPLC is 99.2%, the yield is 87%, and the double bond isomer impurity content is 5.5%.
Example 9
A process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts, comprising in particular the following steps:
1) 40g of compound 2 and 40mL of acetonitrile are added into a reaction bottle R1, the mixture is stirred to clear solution, and the acetonitrile solution of the compound 2 is pumped into a reactor at a flow rate of 2.7 mL/min; taking 40g of a compound 3 from a reaction bottle R2, dissolving the compound 3 in 56mL of acetonitrile, pumping the acetonitrile solution of the compound 3 into a reactor at a flow rate of 3mL/min, setting the temperature of the reactor to 10 ℃, keeping the reaction solution in the reactor for 90min, and collecting the reaction solution through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting pH to 1.5-2 with 6mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form salt, filtering, and drying to obtain a white solid compound I, wherein the HPLC is 98.5%, the yield is 75%, and the double bond isomer impurity content is 12%.
Claims (12)
1. A process for preparing (S) -1- (t-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts according to the following formulae:
Comprises the following steps:
step 1: adding an organic solvent into the compound 2 to form a solution A, pumping the solution A into a continuous flow reactor, and pumping the solution A into the continuous flow reactor at a flow rate of 1.5-2 mL/min;
step 2: adding an organic solvent into the compound 3 to form a solution B, pumping the solution B into a continuous flow reactor, pumping the solution B into the continuous flow reactor at a flow rate of 2.0-2.5 mL/min, carrying out elimination reaction on the compound 2 and the compound 3 at a proper temperature on the continuous flow reactor, and optionally carrying out post-treatment purification to obtain a compound I (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid; the reactor is set at a proper temperature of 0-20 ℃;
step 1 or step 2, wherein the organic solvent is selected from one or any combination of methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile, toluene, 1, 2-dichloroethane or dichloromethane;
The post-treatment purification of the step 2 comprises the following steps of adjusting the pH of the reaction solution to 1.5-2 by hydrochloric acid and extracting by using an organic solvent; the post-treatment purification of the step 2 is carried out, and the concentration of hydrochloric acid is 6-12 mol/L; the post-treatment purification of the step 2 is carried out, and the weight g of the organic solvent is 2-5 times of the weight g of the compound 1; the organic solvent is selected from methyl tertiary butyl ether or ethyl acetate; or further reacting with diethylamine to obtain the high-purity (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine salt.
2. The method according to claim 1, characterized in that: and step 1, the dosage volume mL of the organic solvent is 1-5 times of the dosage weight g of the compound 2.
3. The method according to claim 2, characterized in that: the dosage volume mL of the organic solvent is 1-3 times of the dosage weight g of the compound 2.
4. The method according to claim 1, characterized in that: and step 1 or step 2, wherein the organic solvent is selected from one or any combination of tetrahydrofuran, acetonitrile and toluene.
5. The method according to claim 1, characterized in that: step 2, the dosage volume mL of the organic solvent is 1-5 times of the dosage weight g of the compound 3;
Or step 2, the reaction time of the elimination reaction in the continuous flow reactor is 30-120min.
6. The method of manufacturing according to claim 5, wherein: step 2, the dosage volume mL of the organic solvent is 1-2 times of the dosage weight g of the compound 3; or step 2, the reaction time of the elimination reaction in the continuous flow reactor is 50-90 min.
7. The method according to claim 1, characterized in that: and 2, setting a proper temperature of 5-15 ℃ in the reactor.
8. The method of manufacturing according to claim 6, wherein: and 2, the dosage volume mL of the organic solvent is 1 to 1.5 times of the dosage weight g of the compound 3.
9. The method according to claim 7, wherein: and 2, setting the proper temperature of the reactor to be 10-15 ℃.
10. The method according to claim 1, characterized in that: the post-treatment purification of the step 2 is carried out, and the weight g of the organic solvent is 2-5 times of the weight g of the compound 1; or in the further reaction with diethylamine, the molar ratio of diethylamine to compound 1 is (1 to 1.10): 1.
11. The method according to claim 10, wherein: the post-treatment purification of the step 2 is carried out, and the weight g of the organic solvent is 4-5 times of the weight g of the compound 1; or the organic solvent in the organic solvent extraction is selected from ethyl acetate; or further reacting with diethylamine, wherein the molar ratio of diethylamine to compound 1 is (1-1.05): 1.
12. A process for the preparation of the antiviral drug nemaltevir, boceprevir or nalapivir comprising a continuous flow process for the preparation of (S) -1- (t-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid and salts according to any of the preceding claims 1-11.
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