CN115160205A - Method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salt thereof - Google Patents
Method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salt thereof Download PDFInfo
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- CN115160205A CN115160205A CN202210806783.7A CN202210806783A CN115160205A CN 115160205 A CN115160205 A CN 115160205A CN 202210806783 A CN202210806783 A CN 202210806783A CN 115160205 A CN115160205 A CN 115160205A
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- 238000000034 method Methods 0.000 title claims abstract description 38
- 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 57
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 229940125782 compound 2 Drugs 0.000 claims abstract description 34
- 229940126214 compound 3 Drugs 0.000 claims abstract description 34
- 239000003960 organic solvent Substances 0.000 claims abstract description 29
- 238000005086 pumping Methods 0.000 claims abstract description 25
- 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 17
- 238000003379 elimination reaction Methods 0.000 claims abstract description 10
- 238000000746 purification Methods 0.000 claims abstract description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 210
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 29
- 238000003756 stirring Methods 0.000 claims description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 14
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- 229940125904 compound 1 Drugs 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 229960000517 boceprevir Drugs 0.000 claims description 8
- 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 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000003443 antiviral agent Substances 0.000 claims description 6
- 125000001664 diethylamino group Chemical class [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 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
- 239000012141 concentrate Substances 0.000 claims description 2
- 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000012295 chemical reaction liquid Substances 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000003810 ethyl acetate extraction Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- -1 (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic diethylamine salt Chemical compound 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
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004519 manufacturing process 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
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OGGZSVXCHFNXKA-SFYZADRCSA-N (2s,4r)-1-[(2-methylpropan-2-yl)oxycarbonyl]-4-methylsulfonyloxypyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(O)=O OGGZSVXCHFNXKA-SFYZADRCSA-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
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 239000012065 filter cake Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000002920 hazardous waste Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 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 1
- 229950003504 narlaprevir Drugs 0.000 description 1
- 229940125674 nirmatrelvir Drugs 0.000 description 1
- 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 1
- 238000005406 washing Methods 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-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salt thereof, 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-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic 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 the antiviral drugs nemadevir (nirmatrelvin), boceprevir (boceprevir) and naraprevir (narraprevir), and the structural formulae are as follows:
CN1226231A (WO 1998004523A 1) 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 retention time is 6 minutes, and the external standard yield of the system obtained by the two-stage reaction is 55-60 percent (the target product)
And positional isomers
Ratio 3), the reaction formula is as follows:
disclosure of Invention
Aiming at the technical background, the problems that the double-bond position isomer in the prior art has high impurity content, and the middle kettle type process has high safety risk and low production efficiency are solved. The invention provides a method for continuously synthesizing (S) -1- (tert-butyloxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid and salt, which has the advantages of safety, controllability, short reaction time and higher yield.
The invention provides a method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid and salt by a continuous flow reactor, which has the following reaction formula:
comprises the following steps:
step 1: adding an organic solvent into the compound 2 to form a solution A, and pumping the solution A into the 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, performing elimination reaction on the compound 2 and the compound 3 under the condition of setting proper temperature and pressure on the continuous flow reactor, and selectively performing 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-butyloxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine salt.
The further scheme of the invention is as follows: in step 1, the volume mL of the organic solvent is 1 to 5 times, preferably 1 to 3 times, the weight g of the compound 2.
The further scheme of the invention is as follows: step 1, the organic solvent is selected from one or any combination of methyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 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 further scheme of the invention is as follows: in the step 1, the organic solvent is selected from acetonitrile or tetrahydrofuran, and the volume mL of the dosage of the acetonitrile or tetrahydrofuran is 1 to 5 times, preferably 1 to 3 times of the dosage of the compound 2 by mass g.
The further scheme of the invention is as follows: step 1, pumping the solution A into the 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; further scheme: the solution A is selected from acetonitrile solution of compound 2 or tetrahydrofuran solution of compound 2, and the flow rate of the acetonitrile solution of compound 2 or the 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 further scheme of the invention is as follows: step 2, the organic solvent is selected from one or any combination of methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile, toluene, 1, 2-dichloroethane or dichloromethane; further preferred is one or any combination of tetrahydrofuran, acetonitrile and toluene, most preferred is one or a combination of acetonitrile and tetrahydrofuran.
The further scheme of the invention is as follows: in step 2, the 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 weight g of the compound 3.
The further scheme of the invention is as follows: 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; further scheme: the solution B is selected from acetonitrile solution of compound 3 or tetrahydrofuran solution of compound 3, and the flow rate of acetonitrile solution 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 further scheme of the invention is as follows: and 2, setting the proper temperature of the reactor to be 0-20 ℃, preferably 5-15 ℃, and most preferably 10-15 ℃.
The further scheme of the invention is as follows: 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 further scheme of the invention is as follows: 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.
In the post-treatment purification of the step 2, the weight g of the organic solvent is 2 to 5 times of that of the compound 1, preferably 4 to 5 times; the organic solvent in the organic solvent extraction is selected from methyl tert-butyl ether or ethyl acetate, preferably ethyl acetate.
The further scheme of the invention is as follows: in the further reaction with diethylamine, the molar ratio of diethylamine to the compound 1 is (1-1.10): 1, preferably (1 to 1.05). 1.
The further scheme of the invention is as follows: the above technical scheme or a method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid or a salt thereof (such as diethylamine salt) by continuous flow is applied to preparing antiviral intermediate drugs, in particular to preparing antiviral drugs of nermantrvir (nirmatrelvir), boceprevir (boceprevir) and naraprevir (narrapevir).
The further scheme of the invention is as follows: a process for the preparation of antiviral drugs, such as the nervativir, boceprevir and narloprevir drugs, comprising a continuous flow process as described above for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid or a salt thereof, such as the diethylamine salt.
The invention also provides a preparation method of (S) -1- (tert-butyloxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine, which comprises the following steps:
comprises the following steps:
s1, adding sodium tert-butoxide into a toluene solution, and adding a compound 1 to react under the protection of nitrogen; to obtain a compound 2;
s2, adding acetonitrile into the compound 3 for dissolving, and cooling; adding acetonitrile solution of a compound 2, and controlling the temperature to be 0-15 ℃; stirring for 1-3 hours to react completely, adding water, adding hydrochloric acid solution to adjust the pH value to 1.5-2, adding organic solvent to extract and concentrate to obtain a compound I;
s3, adding diethylamine into the organic solvent of the compound I dropwise, and separating out solids and continuing stirring; cooling, stirring at a constant temperature, and performing suction filtration to obtain the diethylamine salt of the compound I.
In a further embodiment of the present invention, the organic solvent of step S2 or S3 is selected from ethyl acetate.
In a further embodiment of the present invention, a method for preparing (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine, comprises the steps of:
s1, adding sodium tert-butoxide into a toluene solution, and adding a compound 1 to react under the protection of nitrogen; heating to 55-60 ℃, and stirring for reaction for 1-2 hours; concentrating under reduced pressure; to obtain a compound 2;
s2, adding acetonitrile into the compound 3 for dissolving, and cooling to-5-0 ℃; adding acetonitrile solution of a compound 2, controlling the temperature to be 0-15 ℃, stirring for 1-3 hours, reacting completely, adding water, adding hydrochloric acid solution to adjust the pH value to be 1.5-2, adding ethyl acetate, extracting and concentrating to obtain a compound I;
s3, heating the ethyl acetate solution of the compound I to 35-45 ℃, dropwise adding diethylamine, and separating out solids to continue stirring; cooling, stirring at a constant temperature, and performing suction filtration to obtain the diethylamine salt of the compound I.
In a further embodiment of the present invention, in step S1, the molar ratio of sodium tert-butoxide to compound 1 is 1.01 to 1.20, preferably 1.05 to 1.10.
In a further embodiment of the present invention, in step S2, the compound 3 is dissolved by adding acetonitrile, wherein the amount of acetonitrile used is 1 to 2 times, preferably 1.2 to 1.8 times, the volume (mL) of acetonitrile used is 1 to 2 times of 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 amount of acetonitrile used is 1 to 2 times, preferably 1 to 1.2 times, the weight (g) of compound 2;
the further scheme of the invention is that in the step S2, the molar concentration of the hydrochloric acid is 6-12 mol/L;
in a further embodiment of the present invention, in step S2, the concentration to obtain compound I is directly concentrating and drying to obtain compound I or concentrating to remove most of the organic phase to obtain an ethyl acetate solution of compound I.
According to the further scheme, in the step S3, the volume ratio of the compound I to the ethyl acetate is 1;
in a further embodiment of the present invention, in step S3, the molar ratio of diethylamine to compound 3 (1 to 1.10): 1, preferably 1 to 1.05;
in a further scheme of the invention, in the step S3, the precipitated solid is continuously stirred for 1 to 3 hours, preferably 1 to 2 hours;
according to a further scheme of the invention, in the step S3, the temperature is reduced to 10-15 ℃; the stirring time at the temperature is 1 to 2 hours, preferably 1 to 1.5 hours.
The further scheme of the invention is as follows: a process for the preparation of antiviral drugs, such as the nerametryvir (nimetrelvir), boceprevir (boceprevir) and naprevir (narlaprevir) drugs, comprising a process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine as described above.
The further scheme of the invention is as follows: the continuous flow reaction apparatus of the present invention comprises a microreactor, preferably a channel reactor, which may be equipped with: the preheating equipment is used for preheating materials; temperature detection means for monitoring the reaction temperature in the continuous reaction means; the temperature control system is used for adjusting the reaction temperature; a pressure detection device for monitoring the reaction pressure in the continuous reaction device; an automated control system; the automatic control system is connected with the liquid pump, the gas flow controller, the cooling system (heat exchange equipment such as a condenser and the like), the temperature detection equipment or the pressure detection equipment and the like.
The beneficial technical effects of the invention are as follows:
1) The synthesis method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine salt by continuous flow provided by the invention has the advantages that one-step reaction can be adopted, the process that the temperature rise is severe in the reaction process of kettle type elimination reaction to increase the isomer can be reduced, the double bond isomer is reduced from 40% to 20% by continuous flow reaction, preferably can be reduced to 5%, the yield is improved, and the cost is reduced.
2) Compared with the traditional kettle type reaction, the continuous flow preparation method greatly reduces the amount of the compound 2 participating in the reaction in unit time, thereby solving the problems of high safety risk and low reaction degree of the kettle type process in the prior art. In addition, according to the method of the comparative example, the compound 1 is prepared into organic base by adopting sodium methoxide, 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 danger degree is increased, the reaction degree is reduced, the generation of byproducts is increased, the material residue is excessive, the post-treatment is extremely troublesome, and the impurity of the isomer at the double bond position is high.
3) By adopting the continuous flow preparation method, the concentration of local reaction raw materials is greatly improved, so the reaction time is greatly shortened, and the production efficiency is obviously improved.
4) After the reaction is finished, the product can be obtained by concentrating and purifying the product, the yield is up to 85 percent, and the purity is up to more than 99 percent. The synthesis method provided by the invention is safe and controllable, has less generation amount of hazardous waste, higher yield and good product quality.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Comparative example 1
Adding 250.3g of toluene into a 1L three-necked bottle, adding 116.2g of 2- [2- (dimethylamino) ethoxy ] ethanol, adding 145.5g of a methanol solution of sodium methoxide, reacting at 20 ℃ for 1 hour, distilling the methanol under reduced pressure to obtain 50.5g of a yellow oily substance, adding 100mL of acetonitrile into the oily substance, controlling the temperature to be 20-25 ℃ under the protection of nitrogen, dropwise adding 100g of an acetonitrile solution of (2S, 4R) -4- [ (methylsulfonyl) oxy ] -1, 2-pyrrolidinedicarboxylic acid 1-tert-butyl ester, reacting at 20-25 ℃ for 20 hours, 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 the organic phase into water for 3 times, adding MTBE into the aqueous phase for extraction for 3 times, combining the organic phases, concentrating the organic phase to obtain 68.7g of a yellow oily substance, adding 84mL of ethyl acetate into the crude product for dissolving, dropwise adding 19.2g of diethylamine after the crude product is finished, reacting at room temperature for 2.5 hours, adding 130mL of MTBE into the reaction solution, stirring, and filtering the white oily substance overnight to obtain a white isomeric solid with a yield of less than 60.60 percent.
Example 1
Compound I was prepared as follows:
adding 87.2mL of toluene into the reaction kettle R1; sodium tert-butoxide (93.2g, 3.0 eq) was added to reactor R1; stirring is started, nitrogen is replaced for three times, and nitrogen flow is protected; dropwise adding the raw material compound 1 (139.5g, 3.24eq) into the reaction kettle R1, and controlling the temperature to be below 60 ℃; after finishing dripping, controlling the temperature to be between 55 and 60 ℃ and concentrating under reduced pressure; then adding 78.6g of acetonitrile, completely dissolving, and cooling to-5-0 ℃;
adding 110g of acetonitrile into a reaction kettle R2; adding the compound 3 (100g, 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 the acetonitrile solution of the compound 3 into a reaction kettle R1, and controlling the temperature to be 0-15 ℃; after the dripping is finished, the temperature is kept between 10 and 15 ℃ for reaction for 1 to 2 hours; controlling the temperature to be between 5 ℃ below zero and 15 ℃ and dripping 200g of water; controlling the temperature to be 0-15 ℃, dropwise adding 320g of 6mol/L hydrochloric acid, and adjusting the pH value to be 1.5-2; adding ethyl acetate 90g for extraction, washing the organic phase with saturated saline solution, and concentrating under reduced pressure at 40 ℃ to dry; adding 180g of ethyl acetate, heating to 35-45 ℃, dropwise adding diethylamine (24.59, 1.04eq), keeping the temperature at 40-45 ℃, and stirring for 1-2 hours; cooling to 10-15 ℃, stirring for 1h, and filtering; the filter cake is dried by air blast for 2 to 4 hours at the temperature of between 45 and 55 ℃; to obtain off-white compound i: 56g, yield: 60.4 percent; HPLC 98.0%, double bond isomer impurity content 20%.
Example 2
A method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts thereof specifically comprises the following steps:
1) Adding 40g of compound 2 and 40mL of acetonitrile into a reaction bottle R1, stirring until a clear solution is obtained, and pumping the acetonitrile solution of the compound 2 into a reactor at the flow rate of 0.7 mL/min; dissolving 3 40g of the compound in 56mL of acetonitrile in a reaction bottle R2, pumping a compound 3 acetonitrile solution into a reactor at the flow rate of 1mL/min, setting the temperature of the reactor at 10 ℃, allowing reaction liquid to stay 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 the pH value to 1.5-2 by 6mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form a salt, filtering and drying to obtain a white solid compound I, wherein HPLC (high performance liquid chromatography) is 98.0%, the yield is 72%, and the content of double-bond isomer impurities is 20.0%.
Example 3
A method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts thereof specifically comprises the following steps:
1) Adding 2 40g of compound into a reaction bottle R1, adding 40mL of acetonitrile, stirring until the solution is clear, and pumping the acetonitrile solution of the compound 2 into a reactor at the flow rate of 0.8 mL/min; dissolving 3 40g of the compound in 56mL of acetonitrile in a reaction bottle R2, pumping a compound 3 acetonitrile solution into a reactor at the flow rate of 1mL/min, setting the temperature of the reactor at 10 ℃, allowing reaction liquid to stay in the reactor for 50min, and collecting the reaction liquid through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting the pH value to 1.5-2 by 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 (high performance liquid chromatography) content is 98.2%, the yield is 71%, and the double bond isomer impurity content is 19.3%.
Example 4
A method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts thereof specifically comprises the following steps:
1) Adding 2 40g of the compound into a reaction bottle R1, adding 40mL of acetonitrile, stirring to obtain a clear solution, and pumping the acetonitrile solution of the compound 2 into a reactor at the flow rate of 0.9 mL/min; dissolving 3 40g of the compound in 56mL of acetonitrile in a reaction bottle R2, pumping a compound 3 acetonitrile solution into a reactor at the flow rate of 1mL/min, setting the temperature of the reactor at 10 ℃, allowing reaction liquid to stay in the reactor for 65min, and collecting the reaction liquid through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting the pH value to 1.5-2 by using 12mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form a salt, filtering and drying to obtain a white solid compound I, wherein the HPLC (high performance liquid chromatography) content is 98.3%, the yield is 75%, and the content of double-bond isomer impurities is 20.0%.
Example 5
A method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts thereof, which comprises the following steps:
1) Adding 2 40g of compound into a reaction bottle R1, adding 40mL of acetonitrile, stirring until the solution is clear, and pumping the acetonitrile solution of the compound 2 into a reactor at the flow rate of 1.1 mL/min; dissolving 3 40g of the compound in 56mL of acetonitrile in a reaction bottle R2, pumping a compound 3 acetonitrile solution into a reactor at the flow rate of 1mL/min, setting the temperature of the reactor at 10 ℃, keeping the reaction liquid in the reactor for 71min, and collecting the reaction liquid through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting the pH value to 1.5-2 by 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 HPLC (high performance liquid chromatography) is 98.5%, the yield is 76%, and the content of double-bond isomer impurities is 15.0%.
Example 6
A method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts thereof, which comprises the following steps:
1) Adding 2 40g of compound into a reaction bottle R1, adding 40mL of acetonitrile, stirring until the solution is clear, and pumping the acetonitrile solution of the compound 2 into a reactor at the flow rate of 1.8 mL/min; dissolving 3 40g of the compound in 56mL of acetonitrile in a reaction bottle R2, pumping a compound 3 acetonitrile solution into a reactor at the flow rate of 2mL/min, setting the temperature of the reactor at 10 ℃, allowing reaction liquid to stay in the reactor for 55min, and collecting the reaction liquid through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting the pH value to 1.5-2 by 6mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form a salt, filtering and drying to obtain a white solid compound I, wherein HPLC (high performance liquid chromatography) is 99.3%, the yield is 85%, and the content of double-bond isomer impurities is 5.0%.
Example 7
A method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts thereof, which comprises the following steps:
1) Adding 2 400g of compound into a reaction bottle R1, adding 400mL of acetonitrile, stirring to obtain a clear solution, and pumping the acetonitrile solution of the compound 2 into a reactor at the flow rate of 1.5 mL/min; dissolving 3 400g of the compound in 560mL of acetonitrile in a reaction bottle R2, pumping the acetonitrile solution of the compound 3 into a reactor at the flow rate of 2.1mL/min, setting the temperature of the reactor at 10 ℃, allowing the reaction liquid to stay in the reactor for 68min, and collecting the reaction liquid through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting the pH value to 1.5-2 by 6mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form a salt, filtering and drying to obtain a white solid compound I, wherein HPLC (high performance liquid chromatography) is 99.0%, the yield is 86%, and the content of double-bond isomer impurities is 5.8%.
Example 8
A method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts thereof, which comprises the following steps:
1) Adding 2 40g of compound 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 the flow rate of 1.7 mL/min; dissolving 3 40g of the compound in 60mL of acetonitrile from a reaction bottle R2, pumping a compound 3 acetonitrile solution into a reactor at the flow rate of 2mL/min, setting the temperature of the reactor at 10 ℃, allowing reaction liquid to stay in the reactor for 63min, and collecting the reaction liquid through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting the pH value to 1.5-2 by 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 HPLC (high performance liquid chromatography) is 99.2%, the yield is 87%, and the content of double-bond isomer impurities is 5.5%.
Example 9
A method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts thereof, which comprises the following steps:
1) Adding 2 40g of the compound into a reaction bottle R1, adding 40mL of acetonitrile, stirring to obtain a clear solution, and pumping the acetonitrile solution of the compound 2 into a reactor at the flow rate of 2.7 mL/min; dissolving 3 40g of the compound in 56mL of acetonitrile in a reaction bottle R2, pumping a compound 3 acetonitrile solution into a reactor at the flow rate of 3mL/min, setting the temperature of the reactor at 10 ℃, allowing reaction liquid to stay in the reactor for 90min, and collecting the reaction liquid through a condenser and a gas-liquid separator;
2) Adding water into the reaction solution, adjusting the pH value to 1.5-2 by 6mol/L hydrochloric acid, concentrating an organic phase to 1/3 volume after ethyl acetate extraction, adding diethylamine to form a salt, filtering and drying to obtain a white solid compound I, wherein the HPLC (high performance liquid chromatography) content is 98.5%, the yield is 75%, and the content of double-bond isomer impurities is 12%.
Claims (10)
1. A process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrole-2-carboxylic acid and salts thereof, of the formula:
comprises the following steps:
step 1: adding an organic solvent into the compound 2 to form a solution A, and pumping the solution A into the 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, performing elimination reaction on the compound 2 and the compound 3 under the condition of setting proper temperature and pressure on the continuous flow reactor, and selectively performing 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-butyloxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine salt.
2. The method of claim 1, wherein: in step 1, the volume mL of the organic solvent is 1 to 5 times, preferably 1 to 3 times of the weight g of the compound 2.
3. The method of claim 2, wherein: step 1 or step 2, the organic solvent is one or any combination of methyl tert-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.
4. The method of claim 1, wherein: 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;
or step 2, the flow rate of the solution B pumped into the continuous flow reactor is 0.4-3 mL/min, preferably 1-3 mL/min, and most preferably 2.0-2.5 mL/min.
5. The method of claim 2, wherein: step 2, the volume mL of the dosage of the organic solvent is 1 to 5 times, preferably 1 to 2 times, and most preferably 1 to 1.5 times of the dosage of the compound 3;
or step 2, the flow rate of the solution B is 0.4-3 mL/min; preferably 1 to 3mL/min, most preferably 2.0 to 2.5mL/min;
or step 2, setting the proper temperature of the reactor to be 0-20 ℃, preferably 5-15 ℃, and most preferably 10-15 ℃;
or step 2, the reaction time of the elimination reaction in the continuous flow reactor is 30 to 120min, preferably 50 to 90min.
6. The method of claim 4, wherein: 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 in the step 2 is carried out, and the concentration of hydrochloric acid is 6-12 mol/L;
in the post-treatment purification of the step 2, the weight g of the organic solvent is 2 to 5 times of that of the compound 1, preferably 4 to 5 times; the organic solvent in the organic solvent extraction is selected from methyl tert-butyl ether or ethyl acetate, preferably ethyl acetate;
or in the further reaction with the diethylamine, the molar ratio of the diethylamine to the compound 1 is (1 to 1.10): 1, preferably (1 to 1.05). 1.
7. A method for preparing (S) -1- (tert-butyloxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine has the following reaction formula:
comprises the following steps:
s1, adding sodium tert-butoxide into a toluene solution, and adding a compound 1 for reaction under the protection of nitrogen; to obtain a compound 2;
s2, adding acetonitrile into the compound 3 for dissolving, and cooling; adding acetonitrile solution of a compound 2, and controlling the temperature to be 0-15 ℃; stirring for 1-3 hours to react completely, adding water, adding hydrochloric acid solution to adjust the pH value to 1.5-2, adding organic solvent to extract and concentrate to obtain a compound I;
s3, adding diethylamine into the organic solvent of the compound I dropwise, and separating out solids and continuously stirring; cooling, stirring at a constant temperature, and performing suction filtration to obtain a diethylamine salt of the compound I; the organic solvent of step S2 or S3 is selected from ethyl acetate.
8. The method of claim 7, wherein: a method for preparing (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid diethylamine, comprising the steps of:
s1, adding sodium tert-butoxide into a toluene solution, and adding a compound 1 to react under the protection of nitrogen; heating to 55-60 ℃, and stirring for reaction for 1-2 hours; concentrating under reduced pressure; to obtain a compound 2;
s2, adding acetonitrile into the compound 3 for dissolving, and cooling to-5-0 ℃; adding acetonitrile solution of a compound 2, controlling the temperature to be 0-15 ℃, stirring for 1-3 hours, reacting completely, adding water, adding hydrochloric acid solution to adjust the pH value to be 1.5-2, adding ethyl acetate, extracting and concentrating to obtain a compound I;
s3, heating the ethyl acetate solution of the compound I to 35-45 ℃, dropwise adding diethylamine, and separating out solids and continuously stirring; cooling, stirring at a constant temperature, and performing suction filtration to obtain the diethylamine salt of the compound I;
step S1, the molar weight ratio of the sodium tert-butoxide to the compound 1 is 1.01-1.20, preferably 1.
9. The method of claim 8, wherein: step S2, adding acetonitrile into the compound 3 for dissolving, wherein the volume number (mL) of the acetonitrile used is 1-2 times, preferably 1.2-1.8 times of the weight (g) of the compound 3;
or step S2, wherein the amount of acetonitrile used is 1 to 2 times, preferably 1 to 1.2 times, the weight (g) of compound 2 in volume (mL);
or step S2, the molar concentration of the hydrochloric acid is 6-12 mol/L;
or step S3, the volume ratio of the compound I to the ethyl acetate is 1-1;
or step S3, the molar weight ratio of the diethylamine to the compound 3 is (1-1.10): 1, preferably 1 to 1.05;
or step S3, the precipitated solid is continuously stirred for 1 to 3 hours, preferably 1 to 2 hours;
or step S3, cooling to 10-15 ℃; the stirring time at the temperature is 1 to 2 hours, preferably 1 to 1.5 hours.
10. A process for the preparation of the antiviral drugs nemadefovir, boceprevir or naprevivir comprising a continuous flow process for the preparation of (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid and salts thereof as claimed in any one of the preceding claims 1-6 or a process for the preparation of diethylamine comprising (S) -1- (tert-butoxycarbonyl) -2, 5-1H-pyrrole-2-carboxylic acid as claimed in any one of the claims 7-9.
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