CN86101512A - The synthesis technique of vitamin B6 intermediate 4-methyl-5-alkoxy-oxazole - Google Patents
The synthesis technique of vitamin B6 intermediate 4-methyl-5-alkoxy-oxazole Download PDFInfo
- Publication number
- CN86101512A CN86101512A CN86101512.6A CN86101512A CN86101512A CN 86101512 A CN86101512 A CN 86101512A CN 86101512 A CN86101512 A CN 86101512A CN 86101512 A CN86101512 A CN 86101512A
- Authority
- CN
- China
- Prior art keywords
- methyl
- alkoxy
- oxazole
- vitamin
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title claims abstract description 15
- 239000011726 vitamin B6 Substances 0.000 title claims description 7
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 title description 4
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title description 3
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 title description 2
- 235000019158 vitamin B6 Nutrition 0.000 title description 2
- 229940011671 vitamin b6 Drugs 0.000 title description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Substances OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 238000005886 esterification reaction Methods 0.000 claims abstract description 15
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 14
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 13
- 230000032050 esterification Effects 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 7
- 230000007062 hydrolysis Effects 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 239000011720 vitamin B Substances 0.000 claims abstract description 6
- 235000019156 vitamin B Nutrition 0.000 claims abstract description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 5
- 239000011574 phosphorus Substances 0.000 claims abstract description 5
- 230000001360 synchronised effect Effects 0.000 claims abstract description 5
- 230000018044 dehydration Effects 0.000 claims abstract description 4
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 4
- 150000002148 esters Chemical class 0.000 claims abstract description 4
- 238000005580 one pot reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims description 9
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 9
- 230000020477 pH reduction Effects 0.000 claims description 8
- 235000006408 oxalic acid Nutrition 0.000 claims description 7
- 229930003270 Vitamin B Natural products 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 238000010533 azeotropic distillation Methods 0.000 claims description 2
- 108700026215 vpr Genes Proteins 0.000 claims 2
- 239000002184 metal Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 3
- 150000003851 azoles Chemical class 0.000 abstract 3
- 238000005516 engineering process Methods 0.000 abstract 1
- 238000011084 recovery Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- FWPDSAJKWKRRJD-UHFFFAOYSA-N 5-ethoxy-4-methyl-1,3-oxazole Chemical compound CCOC=1OC=NC=1C FWPDSAJKWKRRJD-UHFFFAOYSA-N 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- PQRKGFMROBZFIM-UHFFFAOYSA-N ethyl 5-ethoxy-4-methyl-1,3-oxazole-2-carboxylate Chemical compound CCOC(=O)C1=NC(C)=C(OCC)O1 PQRKGFMROBZFIM-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- -1 aliphatic tertiary amine Chemical class 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 238000011112 process operation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- ILYVXUGGBVATGA-UHFFFAOYSA-N 1-carboxyethylazanium;chloride Chemical compound Cl.CC(N)C(O)=O ILYVXUGGBVATGA-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical group CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- SRBATDDRZARFDZ-UHFFFAOYSA-N 2-formamidopropanoic acid Chemical compound OC(=O)C(C)NC=O SRBATDDRZARFDZ-UHFFFAOYSA-N 0.000 description 1
- RFONJRMUUALMBA-UHFFFAOYSA-N 2-methanidylpropane Chemical compound CC(C)[CH2-] RFONJRMUUALMBA-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 239000004223 monosodium glutamate Substances 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to vitamins B
6The preparation technology of intermediate 4-methyl-5-alkoxyl group azoles.The present invention becomes 4-methyl-5-alkoxyl group-2- azoles acid esters with N-alcoxyl oxalyl-α-An Jibingsuan ester dehydration cyclization in phosphorus oxychloride-fat tertiary amine-aromatic hydrocarbon ring mixture system of the synchronous esterification preparation of α-An Jibingsuan-oxalic acid, the latter is through basic hydrolysis, and acidifying, decarboxylation three go on foot one pot of synthetic 4-methyl-5-alkoxyl group azoles.This process recovery ratio height, cost is low, and production unit is not had harsh requirement, is suitable for suitability for industrialized production.
Description
The invention relates to a synthesis process of a drug intermediate, in particular to vitamin B6A preparation process for synthesizing a necessary key intermediate 4-methyl-5-alkoxy oxazole.
Vitamin B6The oxazole synthesis method is started in the early 60 s (MerCR company U.S. Pat. No. 3227721), and the key intermediate 4-methyl-5-alkoxy oxazole is synthesized from N-formyl-alpha-amino propionate which is synthesized by taking alpha-amino propionic acid as a starting material under the action of phosphorus pentoxide and chloroform, materials in the reaction process are often agglomerated into hard blocks, and the process operation is difficult. To overcome the above difficulties, Japan monosodium glutamate (British patent 1195854) has been proposed to overcome the above problems byAnd (2) hydrolyzing and acidifying the prepared 4-methyl-5-alkoxy-2-oxazole ester under the action of a phosgene-fatty tertiary amine-chloroform cyclization agent system by N-alkoxy oxalyl-alpha-aminopropionate synthesized by amino propionic acid, separating out corresponding 4-methyl-5-alkoxy-2-oxazole acid, drying and decarboxylating to obtain the key intermediate 4-methyl-5-alkoxy oxazole. Although the method avoids the defect that phosphorus pentoxide-chloroform is used as a cyclization agent, the cyclization reaction is incomplete, and phosgene is transported and carried out by the process operation, so that a series of safe operation problems needing to be solved are brought to manufacturers who do not produce phosgene.
In view of the above, we sought for a cyclization agent system having practical value for industrial production other than phosphorus pentoxide-chloroform and phosgene-fatty tertiary amine-chloroform for the preparation of vitamin B64-methyl-5-alkoxy oxazole, especially 4-methyl-5-ethoxy oxazole.
The invention adopts N-alkoxy oxalyl-alpha-amino propionate obtained by synchronous esterification of alpha-amino propionic acid and oxalic acid to synthesize 4-methyl-5-alkoxy-2-oxazole acid ester through dehydration and cyclization in a new cyclization agent system, and the vitamin B is successfully prepared through three-step one-pot operation of hydrolysis, acidification and decarboxylation6The intermediate 4-methyl-5-alkoxy oxazole has the following chemical process:
a compound of the series: r is CH3
A compound of the b series: r ═ C2H5
A compound of the c series: r is n-C3H7(C1)；i-C3H7(C2)
A compound of the d series: r is n-C4H9(d1)；i-C4H9(d2) The "a" compound refers to the compound I, II, III, IV or V, wherein R is CH3And so on, unless otherwise specified. The compound V is passed through the Diel in a known mannerThe s-Alder reaction and dienophile compound react to synthesize vitamin B6Or a derivative thereof.
The preparation of compounds I from alpha-aminopropionic acid generally employs esterification with saturated alcoholic solutions of hydrogen chloride, the resulting alpha-aminopropionate hydrochloride being reacted with excess dialkyl oxalate in the presence of organic bases. The invention adopts a method which is more favorable for production, and the alpha-aminopropionic acid and the oxalic acid are synchronously esterified in the same reactor. In the preparation of compound Ia, the esterification is repeated with a methanol solution containing hydrogen chloride; in the preparation of compounds Ib, Ic1 and IC2When the method is used, hydrochloric acid is used as an esterification catalyst, and water in a reaction system and water generated in the esterification process are taken out in a ternary azeotropic distillation mode of alcohol-azeotropic agent-water, so that the esterification reaction gradually tends to be finished; in the preparation of the compound Id1、Id2In the process, the azeotropic agent is not added, and the water in the reaction system is taken out by utilizing the characteristic that the butanol or isobutanol and the water form an azeotropic substance, so that the synchronous esterification of azeotropic rectification is realized. After the esterification reaction is finished, adding a proper amount of corresponding dialkyl oxalate and alkali carbonate serving as an acid removal agent into the esterification solution, reacting at 30-60 ℃ until carbon dioxide does not occur any more, preparing compounds Ia-Id after treatment, and equivalently recovering the added dialkyl oxalate for the next batch, so that the method only consumes oxalic acid, has more obvious industrial production value when esterification is carried out in an azeotropic rectification mode, and can use hydrochloric acid and aqueous alcohol. The above-mentioned azeotropic agent is benzene, cyclohexane or cyclohexene. Taking Ib as an example, after the alpha-aminopropionic acid, industrial oxalic acid, 95 percent ethanol and hydrochloric acid are subjected to azeotropic rectification synchronous esterification in the presence of an azeotropic agent benzene, diethyl oxalate and powdery sodium carbonate are added for N-ethoxyoxalic acylation, and the yield can reach 88 percent.
The preparation of compounds II from compounds I is known to be of practical interest as a method of preparation using phosgene-aliphatic tertiary amine-chloroformazan as the cyclization agent system, with the limitations already described. We find that the phosphorus oxychloride-fatty tertiary amine-aromatic hydrocarbon system has good dehydration cyclization effect on the compound I no matter two R substituents are the same or different, and the conversion rate can reach 100%. In the cyclization agent system, the dosage of phosphorus oxychloride is 1.0-1.5 times of the mole number of the compound I; the aliphatic tertiary amine refers to trimethylamine, triethylamine, tripropylamine, tributylamine and N-methyl or N-ethyl piperidine, and the dosage of the aliphatic tertiary amine is 3-4 times of the mole number of phosphorus oxychloride; the aromatic hydrocarbon is benzene, toluene, various xylenes, etc., and the amount of the aromatic hydrocarbon is 6 to 12 times the mole number of the compound I. The cyclization reaction can be carried out at any temperature of 50-100 ℃, and the reaction time is 6-20 hours. The reaction mass is decomposed by water, and the separated organic layer is distilled under reduced pressure to obtain the compound II with high yield, wherein the two R substituents are the same or different. The compound II can be prepared with high yield under the conditions that the molar ratio of the compound I (comprising two compounds with different R), phosphorus oxychloride, fatty tertiary amine and aromatic hydrocarbon is 1: 1-1.5: 3-4: 6-12, the reaction temperature is 80 ℃ and the reaction time is 10 hours. When Ib is taken as an example, phosphorus oxychloride is added in a molar ratio Ib; compound IIb was obtained in 90% yield under conditions of triethylamine to toluene ratio of 1: 1.3: 4.5: 9, reaction temperature of 80 ℃ and reaction time of 10 hours.
The preparation of compounds V from compounds II, the two R substituents of which may be identical or different, is known from the separation of compounds IV by sequential alkaline hydrolysis and acidification of compounds II, followed by drying and thermal decarboxylation to compounds V. We have found that compound IV occasionally decomposes at room temperature and that one of the decomposition products is compound V. The decarboxylation decomposition phenomenon is utilized, no matter two R substituents of the compound II are the same or different, after the alkaline hydrolysis reaction liquid is acidified to a certain PH value, necessary decarboxylation decomposition conditions are established in the same reactor, and the compound V is prepared. The acidification end point of the reaction in the step is crucial, the acid amount is not, and partial compound III does not participate in decarboxylation; the excess in turn leads to ring-opening hydrolysis of the already formed compound V to N-formyl-alpha-aminopropionate. The alkali used for the alkali hydrolysis is an aqueous solution of sodium hydroxide or potassium hydroxide; the acid used for acidification is sulfuric acid, hydrochloric acid or phosphoric acid aqueous solution; the pH value of the acidification end point is 2.1-2.7; the decarboxylation temperature is below 65 ℃, and the reaction solution after the alkalization and decarboxylation is adjusted to the PH 8-10. Taking IIb as an example, the sodium salt aqueous solution of IIIb obtained after hydrolysis by the sodium hydroxide aqueous solution is acidified to pH2.5 by the sulfuric acid aqueous solution, then heated to below 65 ℃ for decarboxylation, the reaction solution after the alkalization and decarboxylation is subjected to pH8-10, and then purified and refined to obtain the compound Vb with the yield of 90%.
Using the process of the invention, vitamin B is prepared from alpha-aminopropionic acid via compounds Ib, IIb6The total yield of the intermediate Vb can reach about 70 percent.
Example one: preparation of ethyl N-ethoxyoxalyl-alpha-aminopropionate (Ib)
Prepare for
45 g of alpha-aminopropionic acid were added. 82 g of industrial oxalic acid, 60 ml of 31 percent hydrochloric acid, 500 ml of 95 percent ethanol and 150 ml of benzene are respectively added into a three-neck round-bottom flask, heated, rectified, dehydrated and esterified, an aqueous layer is continuously separated from a water separator at the top of a rectifying tower, and a benzene layer flows into the tower until the aqueous layer is not separated. Removing the fractionating tower, adding 219 g diethyl oxalate and 35 g powdery anhydrous sodium carbonate into the esterification reaction liquid, stirring and reacting at 50 ℃ until carbon dioxide does not occur, evaporating the volatile solvent under reduced pressure, adding a proper amount of water to dissolve the solid, separating an organic layer, extracting the lower layer liquid with toluene, combining the organic layer and the toluene extracting solution, recovering toluene and diethyl oxalate through reduced pressure distillation, and collecting distillate with the temperature of 128-135 ℃/2mm to obtain 96.7 g Ib with the yield of 88.1%.
Compounds Ic and Id can be prepared analogously.
Example two: process for preparation of ethyl 4-methyl-5-ethoxy-2-oxazolate (IIb)
Preparation of
87.3 g of phosphorus oxychloride, 420 ml of toluene, 206 g of triethylamine and 96.7 g of Ib are added into a three-neck round-bottom flask in sequence, and the mixture is stirred and reacted for 10 hours at 80 ℃. Cooling to room temperature, adding 350 ml of water to dissolve solid matter, separating an organic layer, extracting lower water solution by using toluene, washing the combined organic layer and toluene extract to be nearly neutral, carrying out reduced pressure distillation to recover toluene, and collecting fractions at 106-120 ℃/2mm to obtain 80.1 g of IIb with the yield of 90.4%. The lower water solution extracted by toluene is alkalized by sodium hydroxide and triethylamine is recovered.
Compounds IIa, IIc, IId and compounds in which the two R groups are different can be prepared analogously.
Example three: preparation of 4-methyl-5-ethoxyoxazole (Vb)
A mixture of 80.1 g of IIb and 100 ml of 4.96N aqueous sodium hydroxide solution was stirred until the contents became clear, 50 ml of water were added, the low-boiling substance ethanol was distilled off under reduced pressure, cooled to below 30 ℃ and approximately 98 ml of 5.04N aqueous sulfuric acid solution was added dropwise to a pH of 2.5 and then gradually heated to 60 ℃ until carbon dioxide was no longer released. Adjusting the pH of the reaction solution to 8 with sodium hydroxide aqueous solution, distilling with water vapor, collecting distillate at 95-100 deg.C, drying the chloroform extract with sodium sulfate, recovering chloroform, and distilling under reduced pressure to collect 50-70 deg.C/30-50 mm fraction to obtain 46 g Vb with yield of 89.9%.
Compounds Va, Vc, Vd and two compounds with different R groups can be prepared by the same method.
Claims (4)
1. Vitamin B6The preparation process of the intermediate 4-methyl-5-alkoxy oxazole is characterized in that N-alkoxy oxalyl-alpha-amino propionate (I) prepared by synchronous esterification of alpha-aminopropionic acid and oxalic acid is cyclized into 4-methyl-5-alkoxy-2-oxazole ester (II) in a phosphorus oxychloride-fatty tertiary amine-aromatic hydrocarbon cyclization agent system, and the 4-methyl-5-alkoxy oxazole is synthesized in one pot through three steps of hydrolysis, acidification and decarboxylation.
2. Vitamin B as claimed in claim 16Preparation of intermediate 4-methyl-5-alkoxy oxazoleThe process is characterized in that alpha-aminopropionic acid and oxalic acid are subjected to azeotropic distillation, dehydration and esterification in the same reactor in the presence of hydrochloric acid and an entrainer, and the deacidification agent is metal alkali carbonate.
3. Vitamin B as claimed in claim 16The preparation process of the intermediate 4-methyl-5-alkoxy oxazole is characterized in that the 4-methyl-5-alkoxy-2-oxazole acid ester can be prepared by the action of a cyclization agent system consisting of phosphorus oxychloride, fatty tertiary amine and aromatic hydrocarbon no matter two R genes of the compound I are the same or different. The molar ratio of the compound I (comprising two compounds with different R), phosphorus oxychloride, fatty tertiary amine and aromatic hydrocarbon is as follows: 1: 1-1.5; 3-4: 6-12, the reaction temperature is 50-100 ℃, and the reaction time is 5-20 hours.
4. Vitamin B as claimed in claim 16The preparation process of the intermediate 4-methyl-5-alkoxy oxazole is characterized in that no matter two R genes of a compound II are the same or different, three steps of alkaline hydrolysis, acidification and decarboxylation are combined in the same reactor to complete the preparation process. The pH value of the acidification end point is 2.1-2.7, the decarboxylation temperature is below 65 ℃, and the pH value of the reaction liquid after the alkalization decarboxylation is 8-10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN86101512.6A CN1003515B (en) | 1986-07-07 | 1986-07-07 | Synthetizing technology of vit. b6 intermediate 4-methyl-5-alkoxy-oxazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN86101512.6A CN1003515B (en) | 1986-07-07 | 1986-07-07 | Synthetizing technology of vit. b6 intermediate 4-methyl-5-alkoxy-oxazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN86101512A true CN86101512A (en) | 1988-01-13 |
| CN1003515B CN1003515B (en) | 1989-03-08 |
Family
ID=4801417
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN86101512.6A Expired CN1003515B (en) | 1986-07-07 | 1986-07-07 | Synthetizing technology of vit. b6 intermediate 4-methyl-5-alkoxy-oxazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1003515B (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7056935B2 (en) | 1995-06-07 | 2006-06-06 | Gpi Nil Holdings, Inc. | Rotamase enzyme activity inhibitors |
| CN101830821A (en) * | 2010-05-12 | 2010-09-15 | 浙江工业大学 | Chemical synthesis method of N-alcoxyloxalyl alanine ester |
| CN102060801A (en) * | 2010-12-31 | 2011-05-18 | 浙江工业大学 | Method for synthesizing 5-alkoxy-substituted oxazole compound |
| CN102249946A (en) * | 2011-05-13 | 2011-11-23 | 上海海嘉诺医药发展股份有限公司 | Preparation method of N-alkyloxy oxalyl alanine alkyl ester |
| CN102898321A (en) * | 2011-07-24 | 2013-01-30 | 上海海嘉诺医药发展股份有限公司 | Method for preparing N-butoxy oxalyl butyl alaninate |
| CN103435568A (en) * | 2013-08-30 | 2013-12-11 | 大丰海嘉诺药业有限公司 | Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl |
| CN103880766A (en) * | 2014-03-31 | 2014-06-25 | 新发药业有限公司 | Simple and convenient preparation method of 4-methyl-5-alkoxy oxazole |
| CN105985297A (en) * | 2015-01-30 | 2016-10-05 | 湖北得正医药科技有限公司 | Synthesis technology of vitamin B6 intermediate 4-methyl-5-ethyoxyl-2-oxazole acid ethyl |
| CN109293525A (en) * | 2018-09-26 | 2019-02-01 | 山东新和成精化科技有限公司 | A kind of micro passage reaction and the method for preparing N- alkyloxy oxalyl alanine ester using the micro passage reaction |
| CN109836373A (en) * | 2017-11-28 | 2019-06-04 | 新发药业有限公司 | A kind of environmentally friendly method prepared and circulation of tail gas utilizes of vitamin B6 |
| CN111153869A (en) * | 2020-01-19 | 2020-05-15 | 浙江新和成股份有限公司 | Method for preparing oxazole compound |
| CN111793038A (en) * | 2019-04-08 | 2020-10-20 | 新发药业有限公司 | Environment-friendly preparation method of substituted oxazole compound |
| WO2022077196A1 (en) | 2020-10-12 | 2022-04-21 | 新发药业有限公司 | Environmentally friendly preparation method for substituted oxazole compound |
-
1986
- 1986-07-07 CN CN86101512.6A patent/CN1003515B/en not_active Expired
Cited By (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7056935B2 (en) | 1995-06-07 | 2006-06-06 | Gpi Nil Holdings, Inc. | Rotamase enzyme activity inhibitors |
| CN101830821A (en) * | 2010-05-12 | 2010-09-15 | 浙江工业大学 | Chemical synthesis method of N-alcoxyloxalyl alanine ester |
| CN101830821B (en) * | 2010-05-12 | 2013-09-11 | 浙江工业大学 | Chemical synthesis method of N-alcoxyloxalyl alanine ester |
| CN102060801A (en) * | 2010-12-31 | 2011-05-18 | 浙江工业大学 | Method for synthesizing 5-alkoxy-substituted oxazole compound |
| CN102060801B (en) * | 2010-12-31 | 2013-04-17 | 浙江工业大学 | Method for synthesizing 5-alkoxy-substituted oxazole compound |
| CN102249946B (en) * | 2011-05-13 | 2013-11-06 | 上海海嘉诺医药发展股份有限公司 | Preparation method of N-alkyloxy oxalyl alanine alkyl ester |
| CN102249946A (en) * | 2011-05-13 | 2011-11-23 | 上海海嘉诺医药发展股份有限公司 | Preparation method of N-alkyloxy oxalyl alanine alkyl ester |
| CN102898321B (en) * | 2011-07-24 | 2015-10-28 | 上海海嘉诺医药发展股份有限公司 | A kind of method preparing N-fourth oxygen butoxalyl-alaninate |
| CN102898321A (en) * | 2011-07-24 | 2013-01-30 | 上海海嘉诺医药发展股份有限公司 | Method for preparing N-butoxy oxalyl butyl alaninate |
| CN103435568A (en) * | 2013-08-30 | 2013-12-11 | 大丰海嘉诺药业有限公司 | Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl |
| CN103880766A (en) * | 2014-03-31 | 2014-06-25 | 新发药业有限公司 | Simple and convenient preparation method of 4-methyl-5-alkoxy oxazole |
| CN103880766B (en) * | 2014-03-31 | 2016-01-13 | 新发药业有限公司 | A kind of easy 4-methyl-5-Wan Yang Ji oxazole preparation method |
| CN105985297A (en) * | 2015-01-30 | 2016-10-05 | 湖北得正医药科技有限公司 | Synthesis technology of vitamin B6 intermediate 4-methyl-5-ethyoxyl-2-oxazole acid ethyl |
| CN105985297B (en) * | 2015-01-30 | 2018-08-10 | 湖北得正医药科技有限公司 | The synthesis technology of vitamin B6 intermediate 4- methyl -5- ethyoxyl -2- oxazole acetoacetic esters |
| CN109836373B (en) * | 2017-11-28 | 2020-10-02 | 新发药业有限公司 | Environment-friendly preparation method of vitamin B6 and tail gas recycling method |
| CN109836373A (en) * | 2017-11-28 | 2019-06-04 | 新发药业有限公司 | A kind of environmentally friendly method prepared and circulation of tail gas utilizes of vitamin B6 |
| CN109293525A (en) * | 2018-09-26 | 2019-02-01 | 山东新和成精化科技有限公司 | A kind of micro passage reaction and the method for preparing N- alkyloxy oxalyl alanine ester using the micro passage reaction |
| CN109293525B (en) * | 2018-09-26 | 2021-04-20 | 山东新和成精化科技有限公司 | Micro-channel reactor and method for preparing N-alkoxy oxalyl alanine ester by using same |
| CN111793038A (en) * | 2019-04-08 | 2020-10-20 | 新发药业有限公司 | Environment-friendly preparation method of substituted oxazole compound |
| CN111793038B (en) * | 2019-04-08 | 2022-08-12 | 新发药业有限公司 | Environment-friendly preparation method of substituted oxazole compound |
| CN111153869A (en) * | 2020-01-19 | 2020-05-15 | 浙江新和成股份有限公司 | Method for preparing oxazole compound |
| CN111153869B (en) * | 2020-01-19 | 2021-06-01 | 浙江新和成股份有限公司 | Method for preparing oxazole compound |
| WO2022077196A1 (en) | 2020-10-12 | 2022-04-21 | 新发药业有限公司 | Environmentally friendly preparation method for substituted oxazole compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1003515B (en) | 1989-03-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3841834B2 (en) | Malonic acid and its esters | |
| CN86101512A (en) | The synthesis technique of vitamin B6 intermediate 4-methyl-5-alkoxy-oxazole | |
| CA2608388A1 (en) | A process for the dynamic resolution of (substituted) (r) - or (s) -mandelic acid | |
| EP0044158B1 (en) | Novel optically active imidazolidin-2-one derivatives and their production | |
| CN117229136A (en) | Preparation method of azelaic acid | |
| CN100579955C (en) | Process for the manufacture of N-alkoxyoxaloalaninate | |
| US6162946A (en) | Processing for producing allyl 2-hydroxyisobutyrate | |
| IE42425B1 (en) | Aryloxy-and arythio-alkanoates having cholesterol-reducing properties | |
| EP0239992B1 (en) | Process for the preparation of 2,3,4,5-tetrafluorobenzoyl acetates | |
| US4987231A (en) | Optical resolution method for 3R-(3-carboxybenzyl)-6-(5-fluoro-2-benzothiazolyl)methoxy-4R-chromanol | |
| JPH0352881A (en) | Preparation of tetronic alkylate | |
| CA1056848A (en) | Process for the preparation of 3-alkyl-cyclopentane-1,2-diones, and intermediates therefor | |
| EP0093511A1 (en) | Method for producing and optically active 2,2-dimethylcyclopropanecarboxylic acid | |
| US5208342A (en) | Conversion of pyridine-2,3-dicarboxylic acid esters to cyclic anhydrides | |
| CN115074404B (en) | A method for synthesizing (2S, 4R)-2-amino-4-methylnonanoic acid | |
| CN116655484B (en) | Preparation method of L-4-chloro-2-aminobutyric acid ester hydrochloride | |
| US3965168A (en) | 3-Carbamoyl-3-hydroxyglutaric acid and salts | |
| KR100190773B1 (en) | Method for racemization of non-racemic 3-oxyocylopentane or 3-oxocyclohexane carboxylic acids and their esters with c1-c6 alcohol | |
| EP0138468B1 (en) | Method for preparing optically active dialkyl trans-epoxysuccinates | |
| SU899553A1 (en) | Process for preparing 2-methyl-3-ethoxycarbonylquinoxalines | |
| SU878763A1 (en) | Method of preparing 3-aminocyclopentane derivatives | |
| CN111253244A (en) | Recycling method of (S) -2-benzylsuccinic acid resolution mother liquor | |
| SU1018937A1 (en) | Process for preparing ethyl esters of alpha-n-fluorobenzyloxy carboxylic acids | |
| CN116217394A (en) | Method for preparing valproic acid intermediate diethyl dipropylmalonate | |
| KR100228737B1 (en) | Process for producing malonic acid dialkyl ester from malonic acid waste liquid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C13 | Decision | ||
| GR02 | Examined patent application | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CX01 | Expiry of patent term |