CN112574119B - Process for preparing hydantoin derivatives - Google Patents
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- CN112574119B CN112574119B CN202010999866.3A CN202010999866A CN112574119B CN 112574119 B CN112574119 B CN 112574119B CN 202010999866 A CN202010999866 A CN 202010999866A CN 112574119 B CN112574119 B CN 112574119B
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- 150000001469 hydantoins Chemical class 0.000 title claims abstract description 14
- 229940053195 antiepileptics hydantoin derivative Drugs 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 30
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 6
- 238000009833 condensation Methods 0.000 claims abstract description 3
- 230000005494 condensation Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- IAJOBQBIJHVGMQ-UHFFFAOYSA-N 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid Chemical compound CP(O)(=O)CCC(N)C(O)=O IAJOBQBIJHVGMQ-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 238000006462 rearrangement reaction Methods 0.000 claims description 5
- 239000005561 Glufosinate Substances 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- UTZAXPKCGJZGLB-UHFFFAOYSA-N diethyl methyl phosphite Chemical compound CCOP(OC)OCC UTZAXPKCGJZGLB-UHFFFAOYSA-N 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 claims description 2
- 239000003495 polar organic solvent Substances 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 1
- 229910017604 nitric acid Inorganic materials 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- ZBMRKNMTMPPMMK-UHFFFAOYSA-N 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid;azane Chemical compound [NH4+].CP(O)(=O)CCC(N)C([O-])=O ZBMRKNMTMPPMMK-UHFFFAOYSA-N 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- BVERFRYWSPRASF-UHFFFAOYSA-N 5-(2-hydroxyethyl)imidazolidine-2,4-dione Chemical compound OCCC1NC(=O)NC1=O BVERFRYWSPRASF-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 3
- ZPKLHZSTXKNUST-UHFFFAOYSA-N 2-(carbamoylamino)-4-hydroxybutanoic acid Chemical compound NC(=O)NC(C(O)=O)CCO ZPKLHZSTXKNUST-UHFFFAOYSA-N 0.000 description 3
- SMLNOLMFKFBXMS-UHFFFAOYSA-N 5-(2-chloroethyl)imidazolidine-2,4-dione Chemical compound ClCCC1NC(=O)NC1=O SMLNOLMFKFBXMS-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- NSSMTQDEWVTEKN-UHFFFAOYSA-N diethoxy(methyl)phosphane Chemical compound CCOP(C)OCC NSSMTQDEWVTEKN-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- -1 nitro, sulfonyl Chemical group 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- FFNNVNAMCNAOIW-UHFFFAOYSA-N 5-(2-bromoethyl)imidazolidine-2,4-dione Chemical compound BrCCC1NC(=O)NC1=O FFNNVNAMCNAOIW-UHFFFAOYSA-N 0.000 description 2
- 239000005562 Glyphosate Substances 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- XDDAORKBJWWYJS-UHFFFAOYSA-N glyphosate Chemical compound OC(=O)CNCP(O)(O)=O XDDAORKBJWWYJS-UHFFFAOYSA-N 0.000 description 2
- 229940097068 glyphosate Drugs 0.000 description 2
- 230000002363 herbicidal effect Effects 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 150000007970 thio esters Chemical class 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- AWONIZVBKXHWJP-UHFFFAOYSA-N 1-methoxy-2,3,5-trimethylbenzene Chemical compound COC1=CC(C)=CC(C)=C1C AWONIZVBKXHWJP-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 238000005654 Michaelis-Arbuzov synthesis reaction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- FIKAKWIAUPDISJ-UHFFFAOYSA-L paraquat dichloride Chemical compound [Cl-].[Cl-].C1=C[N+](C)=CC=C1C1=CC=[N+](C)C=C1 FIKAKWIAUPDISJ-UHFFFAOYSA-L 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000010010 raising Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000005068 transpiration Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
- C07D233/78—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a process for the preparation of hydantoin derivatives by reacting a compound of formula (II), or a salt, enantiomer or a mixture of enantiomers in all ratios thereof, with a compound of formula (III) to give a compound of formula (IV), or a salt, enantiomer or a mixture of enantiomers in all ratios thereof; and then subjecting the compound of formula (IV) to intramolecular condensation in the presence of an acid to give the compound of formula (I) or a salt, enantiomer or mixture of enantiomers in all proportions thereof. The hydantoin derivative provided by the invention is used for synthesizing glufosinate-ammonium, so that the problems of high cost, low efficiency and the like in the prior art can be solved, and the hydantoin derivative is a method with a high cost advantage.
Description
Technical Field
The present invention relates to a process for the preparation of hydantoin derivatives.
Background
Glufosinate is a broad-spectrum organophosphorus contact-type herbicide developed successfully in 80 s by hoechst, is a glutamine synthesis inhibitor, has weak internal absorption effect, is different from the early glyphosate root killing, firstly kills leaves by glufosinate, then can be conducted on plant xylem through plant transpiration, has quick-acting performance between paraquat and glyphosate, and is a non-selective contact-type herbicide. In the prior art, the preparation method of glufosinate-ammonium generally has the problems of complex reaction, low efficiency and high production cost.
Disclosure of Invention
The present invention provides a process for the preparation of a hydantoin derivative of formula (I):
or a salt, an enantiomer or a mixture of enantiomers thereof in all proportions, in particular a mixture of enantiomers thereof, in particular a racemic mixture thereof, comprising the steps of:
(a) reacting a compound of formula (II)
Or salts, enantiomers or mixtures of enantiomers in all ratios thereof, in particular enantiomers in the L-configuration thereof,
with compounds of the formula (III)
Reaction to give the compound of formula (IV)
Or salts, enantiomers or mixtures of enantiomers thereof in all proportions, in particular mixtures of enantiomers thereof, especially in particular racemic mixtures thereof;
(b) intramolecular condensation of the compound of formula (IV) in the presence of an acid to give the compound of formula (I) or a salt, enantiomer or mixture of enantiomers in all ratios thereof;
wherein:
x is halogen, -OR 3 or-SR 4 ;
Y is O or S;
R 1 is hydrogen or an amino protecting group;
R 2 is hydrogen or C 1 -C 4 An alkyl group;
R 3 is hydrogen or a hydroxy protecting group;
R 4 is hydrogen or a mercapto protecting group.
Further, X is O, R 1 Is hydrogen.
Further, Y is O, R 2 Is hydrogen.
Further, in the step (a), the temperature of the reaction is 80 to 120 ℃, preferably 90 to 110 ℃. In step (a), the reaction time is between 1 to 30 hours, 3 to 30 hours, 5 to 20 hours, or 5 to 10 hours. By carrying out the step (a) reaction in this temperature range and time range, the compound of formula (IV) can be more easily prepared.
Further, in step (a), the aforementioned reaction is carried out in a solvent selected from water or a polar organic solvent.
Further, in the step (b), the acid is any one of hydrochloric acid, sulfuric acid, acetic acid, or a mixture thereof.
Further, the step (b) is carried out at 60 to 120 ℃.
Preferably, the aforementioned process is a one-pot process, i.e. the compound of formula (IV) prepared by step (a) is directly involved in step (b) without isolation from the reaction medium.
The invention also provides a preparation method of glufosinate-ammonium, the compound of formula (I) is prepared by the method, the compound of formula (I) and diethyl methylphosphite undergo Arbuzov rearrangement reaction, and glufosinate-ammonium is obtained through hydrolysis reaction. The Arbuzov rearrangement reaction, also known as Michaelis-Arbuzov reaction, is carried out in a manner known to the person skilled in the art, for example by adding elemental iodine.
Further, in the rearrangement reaction, the reaction temperature is 60 to 200 ℃.
Furthermore, the rearrangement reaction is carried out under the catalysis of Lewis acid, and the reaction temperature is 20-200 ℃.
Further, the aforementioned hydrolysis reaction is carried out in the presence of an acid or a base.
The invention provides a method for preparing a hydantoin derivative, and the hydantoin derivative is used for synthesizing glufosinate-ammonium, can solve the problems of high cost, low efficiency and the like in the prior art, and has the advantage of high cost.
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 18 carbon atoms. Alkyl groups having 1 to 6 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.
The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent may be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.
The term "aryl" refers to a group having at least one aromatic ring structure. The aryl group is preferably a phenyl group or a benzyl group. Phenyl and benzyl groups may be substituted or unsubstituted.
The term "amino protecting group" refers to a group that can be attached to a nitrogen atom on an amino group to protect the amino group from reaction and which can be easily removed in a subsequent reaction. Suitable amino protecting groups include, but are not limited to, the following:
a carbamate group of the formula-C (O) O-R, wherein R is, for example, methyl, ethyl, tert-butyl, benzyl, phenethyl, CH 2 =CH-CH 2 -, etc.; amide groups of the formula-c (o) -R ', wherein R' is, for example, methyl, ethyl, phenyl, trifluoromethyl, and the like; formula-SO 2 The N-sulfonyl derivative-group of-R ', wherein R' is, for example, tolyl, phenyl, trifluoromethyl, 2,5,7, 8-pentamethylchroman-6-yl-, 2,3, 6-trimethyl-4-methoxybenzene, and the like.
C 1 -C 4 Alkyl groups are linear or branched, saturated hydrocarbon chains containing from 1 to 4 carbon atoms. It may be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group.
Detailed Description
All of the features disclosed in this specification, or all of the steps in any method or process so disclosed, may be combined in any combination, except combinations of features and/or steps that are mutually exclusive.
Any feature disclosed in this specification may be replaced by alternative features serving equivalent or similar purposes, unless expressly stated otherwise. That is, unless expressly stated otherwise, each feature is only an example of a generic series of equivalent or similar features.
The preparation process of the present invention will be further described with reference to examples.
The ee value of the raw material L-homoserine is more than 95%.
Example 1
Adding L-homoserine (140g, 1.18mol), urea (106g, 1.76mol) and water (250mL) into a 500mL three-necked flask, heating to raise the internal temperature to 100 ℃ for reaction for 8 hours, cooling to room temperature, drying the water by spinning, pulping by using methanol (100mL), washing by using methanol for three times (50mL x 3), and drying to obtain white crystals of 4-hydroxy-2-ureidobutyric acid 181.7g, wherein the yield is 95%, the HPLC purity is 96%, and the white crystals are detected to be a racemic mixture.
Product structure analysis data are as follows: MS (ESI) M/z [ M + H] + calcd for C 5 H 11 N 2 O 4 :163.06;found:163.1.
Example 2
In a 250mL three-necked flask, 4-hydroxy-2-ureidobutyric acid (28g, 172.7mmol) prepared in example 1 and 18% HCl (57.6mL, 345.4mmol) were added, the mixture was heated and stirred to an inner temperature of 90 ℃ for reaction for 6 hours, cooled to room temperature, and water was spun off to obtain a white solid, and the white solid was washed with ethanol (100mL × 3) and dried to obtain 5- (2-hydroxyethyl) imidazolidine-2, 4-dione as a white solid in a yield of 97%, purity by HPLC of 97%, which was detected as a racemic mixture.
Product structure analysis data are as follows:
MS(ESI):m/z[M+H] + calcd for C 5 H 9 N 2 O 3 :145.06;found:145.3.
1 H NMR(D 2 O,400MHz)δ:4.22(dd,J=8.0,4.0Hz,1H),3.72–3.50(m,2H),1.97(dtd,J=14.4,6.0,4.8Hz,1H),1.87(dtd,J=14.4,7.2,6.0Hz,1H).
13 C NMR(D 2 O,100MHz)δ:179.0,159.3,57.4,56.2,32.7.
example 3
Into a 250mL three-necked flask, 4-hydroxy-2-ureido butane prepared in example 1 was addedAcid (28g, 172.7mmol), 18% H 2 SO 4 (57.6mL, 345.4mmol), heating and stirring, raising the temperature to the internal temperature of 100 ℃, reacting for 4h, cooling to room temperature, removing part of water by rotation, cooling to 0 ℃, crystallizing, washing the white solid with ethanol (50mL x 3), and drying to obtain 23.6g of white solid 5- (2-hydroxyethyl) imidazolidine-2, 4-dione, wherein the yield is 95%, the HPLC purity is 99%, and the product is detected to be a racemic mixture.
Example 4
Into a 250mL three-necked flask, 4-hydroxy-2-ureidobutyric acid (28g, 172.7mmol) prepared in example 1 and CH were added 3 COOH (50mL), heated and stirred until the internal temperature reaches 80 ℃ for reaction for 8h, cooled to room temperature, and CH is removed 3 COOH gave a white solid which was washed with ethanol (50mL x 3) and dried to give 22.4g of 5- (2-hydroxyethyl) imidazolidine-2, 4-dione as a white solid in 90% yield and 95% HPLC purity as a racemic mixture.
Example 5
Adding L-homoserine (140g, 1.18mol), urea (85.5g, 1.42mol) and water (250mL) into a 500mL three-necked flask, heating to an internal temperature of 100 ℃ for reaction for 8h, detecting the disappearance of raw materials by MS, cooling to room temperature, dropwise adding 36% HCl (200mL, 2.36mol), heating and stirring to an internal temperature of 90 ℃ for reaction for 6h, cooling to room temperature, spin-drying water to obtain a white solid, washing the white solid with ethanol (150mL x 3), and drying to obtain 163.2g of 5- (2-hydroxyethyl) imidazolidine-2, 4-dione as the white solid, wherein the yield is 96%, the HPLC purity is 97.5%, and detecting that the white solid is a racemic mixture.
Example 6
Adding 5- (2-hydroxyethyl) imidazolidine-2, 4-dione (12g, 83.2mmol) and a 48% hydrobromic acid acetic acid solution (34mL, 50g, 300mmol) into a 250mL sealed tube, sealing and pressing, reacting at 90 ℃ for 10h, naturally cooling to room temperature, spin-drying a solvent in a reaction system, recrystallizing with ethyl acetate, performing suction filtration, and drying to obtain a white solid product, namely 14.6g of 5- (2-bromoethyl) imidazolidine-2, 4-dione, wherein the yield is 85% and the HPLC purity is 96.5%.
Example 7
Adding 5- (2-hydroxyethyl) imidazolidine-2, 4-dione (20g, 138.8mmol) and 37% hydrochloric acid into a 250mL sealed tube, sealing and pressing, reacting at 100 ℃ for 10h, naturally cooling to room temperature, spin-drying a solvent in a reaction system, recrystallizing with ethyl acetate, performing suction filtration and drying to obtain a white solid product, namely 20.3g of 5- (2-chloroethyl) imidazolidine-2, 4-dione, wherein the yield is 90% and the HPLC purity is 98%.
Product structure analysis data are as follows:
1 H NMR(DMSO-d6,400MHz)δ:10.69(s,1H),8.05(s,1H),4.19–4.11(m,1H),3.92–3.65(m,2H),2.16(dtd,J=14.8,7.6,4.8Hz,1H),2.01(ddt,J=14.4,8.4,6.0Hz,1H).
example 8
Diethyl methylphosphonite (20.5g,150.1mmol), 5- (2-bromoethyl) imidazolidine-2, 4-dione (25.7g,125mmol) and 20mL of toluene were added to a 250mL three-necked flask, replaced with argon gas three times, stirred, heated to 100 ℃ to react for 5 hours, and the solvent and unreacted raw materials were removed by desolventization under reduced pressure to obtain 25.2g of a pale yellow viscous liquid with a yield of 86.0% and an HPLC purity of 97%.
Product structure analysis data are as follows:
1 H NMR(DMSO-d6,400MHz)δ:1.20(t,J=7.0Hz,3H),1.40(d,J=13.7Hz,3H),1.64(dq,J=15.2,7.6Hz,4H),3.93–3.89(m,2H),4.07(t,J=5.6Hz,1H),8.05(s,1H),10.75(s,1H).
example 9
The method comprises the following steps: diethyl methylphosphonite (20.5g,150.1mmol), 5- (2-chloroethyl) imidazolidine-2, 4-dione (20.3g,125mmol) and chlorobenzene (20mL) were added to a 250mL three-necked flask, replaced with argon, stirred, heated to 140 ℃ to react for 20h, and the solvent and unreacted raw materials were removed by desolventization under reduced pressure to obtain 23.1g of a pale yellow viscous liquid with a yield of 79% and a purity of HPLC of 96%.
The second method comprises the following steps: diethyl methylphosphonite (20.5g,150.1mmol), 5- (2-chloroethyl) imidazolidine-2, 4-dione 3(20.3g,125mmol), tetrabutylammonium bromide (2.1g, 6.25mmol) and 20mL of chlorobenzene were added to a 250mL three-necked flask, and replaced with argon for three times, followed by stirring, heating to 140 ℃ for reaction for 8 hours, and removing the solvent and unreacted raw materials by desolvation under reduced pressure to obtain 24.0g of a pale yellow viscous liquid, the yield is 82%, and the HPLC purity is 96.5%.
Example 10
The product from example 8 (24g,102.5mmol), 36% HCl (40mL) was added to a sealed tube, the reaction was allowed to warm to 130 ℃ for 40h, desolventized under reduced pressure to give a pale yellow viscous liquid, ethanol (20mL) was added and stirred at room temperature for 3h to give a large amount of white solid, which was filtered, washed with ethanol (20mL x 3), and dried to give 17.6g of glufosinate-ammonium in 95% yield and 98.7% HPLC purity.
Example 11
A250 mL three-necked flask was charged with the product from example 9 (24g,102.5mmol), water 100mL, Ba (OH) 2 ·8H 2 O (31.6g,100mmol) was heated under reflux for 30 h. Addition of H 2 SO 4 Adjusting the pH value to 5-6, filtering, adjusting the pH value of the filtrate to 12 by using ammonia water, performing rotary evaporation to remove the solvent, and adding methanol for recrystallization. Drying to obtain 17.8g of glufosinate-ammonium with the yield of 96% and the HPLC purity of 98.5%.
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (13)
1. A process for the preparation of a hydantoin derivative of formula (I) or a salt, enantiomer or a mixture of enantiomers in all ratios thereof:
the method is characterized in that: the method comprises the following steps:
(a) reacting a compound of formula (II)
Or salts, enantiomers or mixtures of enantiomers in all ratios thereof with a compound of the formula (III)
Reaction to give the compound of formula (IV)
Or salts, enantiomers or mixtures of enantiomers in all ratios thereof;
(b) intramolecular condensation of the compound of formula (IV) in the presence of an acid to give the compound of formula (I) or a salt, enantiomer or mixture of enantiomers in all ratios thereof;
wherein:
x is-OR 3 ;
Y is O;
R 1 is hydrogen or an amino protecting group;
R 2 is hydrogen or C 1 -C 4 An alkyl group;
R 3 is hydrogen.
2. The method of claim 1, wherein: in said step (a), the compound of formula (II) or a salt, enantiomer or mixture of enantiomers thereof in all proportions is the L-configured enantiomer of the compound of formula (II).
3. The method of claim 1, wherein: the hydantoin derivatives of formula (I) or salts, enantiomers or mixtures of enantiomers in all ratios thereof refer to mixtures of enantiomers of hydantoin derivatives of formula (I);
in said step (a), the compound of formula (IV) or a salt, enantiomer or mixture of enantiomers in all proportions thereof is a mixture of enantiomers of the compound of formula (IV).
4. The method of claim 1, wherein: the hydantoin derivatives of formula (I) or salts, enantiomers or mixtures of enantiomers in all ratios thereof refer to racemic mixtures of hydantoin derivatives of formula (I);
in said step (a), the compound of formula (IV) or a salt, enantiomer or mixture of enantiomers in all ratios thereof is a racemic mixture of the compound of formula (IV).
5. The method of claim 1, wherein: said R is 1 Is hydrogen.
6. According to claimThe method of 1, characterized by: the R is 2 Is hydrogen.
7. The method of claim 1, wherein: in the step (a), the reaction temperature is 80-120 ℃.
8. The method of claim 1, wherein: in step (a), the reaction is carried out in a solvent selected from water or a polar organic solvent.
9. The method of claim 1, wherein: in step (b), the acid is any one of hydrochloric acid, nitric acid, sulfuric acid and acetic acid or a mixture thereof.
10. The method of claim 1, wherein: the step (b) is carried out at 60-120 ℃.
11. The method of claim 1, wherein: said step (b) is carried out in water or an organic solvent.
12. The method of claim 1, wherein: the method is a one-pot method.
13. A process for the preparation of glufosinate, characterized in that a compound of formula (I) is prepared according to any one of claims 1 to 12, and is subjected to an Arbuzov rearrangement reaction with diethyl methylphosphite and hydrolysis reaction to obtain glufosinate.
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