CN101429204B

CN101429204B - (3aS,4S,6aR)-4-(5'-oxohexyl)-tetrahydrothiophen-3, 6-and-imidazolin-2-one and its synthesis method

Info

Publication number: CN101429204B
Application number: CN2007101565625A
Authority: CN
Inventors: 陈建辉; 吴志刚; 陈钢; 顾立新
Original assignee: Zhejiang Medicine Co Ltd Xinchang Pharmaceutical Factory
Current assignee: Zhejiang Medicine Co Ltd Xinchang Pharmaceutical Factory
Priority date: 2007-11-08
Filing date: 2007-11-08
Publication date: 2010-12-29
Anticipated expiration: 2027-11-08
Also published as: CN101429204A

Abstract

The invention discloses a novel substance, namely (3aS,4S,6aR)-4-(5'-oxohexyl)- tetrahydrothiophene-[3,6-b]imidazoline-2-ketone and a synthesis method thereof. The method for preparing the novel substance comprises the following steps: under the protection of nitrogen, acetylacetic ether is dripped into sodium hydride, sodium alkoxide or metal sodium and an anhydrous solvent, the temperature is increased to be between 100 and 110 DEG C, and a reaction system is clarified and cooled to normal temperature; then sulfonium salt is added into the solution for a thermal insulation reaction at a temperature of between 70 and 90 DEG C, and then the solution is cooled to normal temperature; an organic layer is separated out, a yellowish liquid is obtained through vacuum recovery, then a hydrogen bromide solution is directly added into the yellowish liquid to be heated to reflux, and then the solution is cooled to normal temperature; and a white solid, namely a target product is obtained through the post-treatment. The novel substance provides the comparison of impurities in a pure product for the measurement of impurity content in biotin, thereby improving the quality of the biotin.

Description

(3aS, 4S, 6aR)-4-(5 '-oxo-hexyl)-tetrahydrochysene thiophene phenol-[3,6-is also] tetrahydroglyoxaline-2-ketone and synthetic method thereof

Technical field

The invention discloses the impurity that produces in a kind of d-vitamin H building-up process (3aS, 4S, 6aR)-4-(5 '-oxo-hexyl)-tetramethylene sulfide-[3,6-is also] tetrahydroglyoxaline-2-ketone and synthetic method thereof.

Background technology

The d-vitamin H (d-Biotin) claim vitamin H or vitamin H again, and with free or be distributed widely in the vegeto-animal tissue with the form of protein bound, vitamin H has been widely used in nutrition and the fodder additives aspect of medicine, poultry, domestic animal.Relatively authority's vitamin H quality standard is European Pharmacopoeia EP.2005.1073 at present, and it has proposed the TLC control of 5 related substances (impurity A, B, C, D, E).Because the specificity of vitamin H production technique can produce plurality of impurities in process of production, the existence of impurity directly has influence on the quality of vitamin H product.

Summary of the invention

The purpose of this invention is to provide the impurity that a kind of vitamin H produces in producing (3aS, 4S, 6aR)-4-(5 '-oxo-hexyl)-tetramethylene sulfide-[3,6-is also] tetrahydroglyoxaline-2-ketone, should pure product impurity product in contrast, thereby the content of impurity in the control vitamin H improves the quality of vitamin H.

By the process analysis to vitamin H, because the specificity of its production technique, we pass through impurity enriched, found new impurity (3aS, 4S, 6aR)-4-(5 '-oxo-hexyl)-tetramethylene sulfide-[3,6-is also] tetrahydroglyoxaline-2-ketone (1), its structural formula is as follows:

That another object of the present invention provides is a kind of (3aS, 4S, 6aR)-and the synthetic method of 4-(5 '-oxo-hexyl)-tetramethylene sulfide-[3,6-is also] tetrahydroglyoxaline-2-ketone, it adopts following technical scheme:

(3aS, 4S, 6aR)-4-(5 '-oxo-hexyl)-tetramethylene sulfide-[3,6-is also] synthetic method of tetrahydroglyoxaline-2-ketone, its step is as follows: under the drying nitrogen protection, drip methyl aceto acetate in sodium hydride, sodium alkoxide (sodium methylate or sodium ethylate) or sodium Metal 99.5 and anhydrous solvent, be warming up to 100-110 ℃, make the reaction system clarification, be cooled to normal temperature; Then in above-mentioned solution, add sulfosalt, carry out insulation reaction, be cooled to normal temperature afterwards at 70-90 ℃; With the pH value that gained solution is regulated in acid, tell organic layer, reclaim under reduced pressure gets weak yellow liquid, directly drops into hydrogen bromide solution afterwards, and heat temperature raising is cooled to normal temperature afterwards to refluxing; Add stirring solvent at last, heat up, divide the layer that deoils while hot, reclaim under reduced pressure sour water layer adds dehydrated alcohol, separates out white solid, is target product, and mp:153.2-155.8 ℃, structure is through IR, MS, NMR, HMBS and hsqc spectrum conclusive evidence.The route of above-mentioned synthetic method is as follows:

Synthetic route

Above-mentioned synthetic method, the pH value is controlled at 1-2; Solvent is toluene or dimethylbenzene; Acid is hydrochloric acid or sulfuric acid; Temperature during reflux is controlled at 120 ℃-130 ℃.

The present invention obtain (3aS, 4S 6aR)-4-(5 '-oxo-hexyl)-tetramethylene sulfide-[3,6-also] tetrahydroglyoxaline-2-ketone, for the dirt content test in the vitamin H provides pure product impurity comparison, have improved the quality of vitamin H.

Below in conjunction with embodiment the present invention is done into-goes on foot explanation.

Embodiment

Embodiment 1

Taking back the stream prolong, balance minim pipette, stirring arm; thermometer in the 250ml four-hole boiling flask of drying nitrogen protection, adds sodium hydride 2g; dry toluene 100ml drips methyl aceto acetate 39g (0.3mol) below 40 ℃, be warming up to 100-110 ℃; make the reaction system clarification, be cooled to normal temperature, add sulfosalt (2) 15g (0.0337mol); heat up, control 70-90 ℃ of insulation reaction 6hr, be cooled to normal temperature; sulfuric acid with 10% is regulated pH=1; tell organic layer, water layer divides reextraction with toluene 30ml, merges organic layer; sodium bicarbonate aqueous solution 20ml washing organic layer secondary with 5%; reclaim under reduced pressure gets weak yellow liquid, directly drops into 48%HBr100ml heat temperature raising to 126 ℃, refluxes 4 hours; be cooled to room temperature; add toluene 50ml and stir, be warming up to more than 90 ℃, divide the layer that deoils while hot; reclaim under reduced pressure is the sour water layer to the greatest extent; add dehydrated alcohol 50ml, separate out white solid 7.2g, yield 88%; it is 95% that HPLC measures its content, mp:153.2-155.8 ℃.

From the carbon spectrum and the hsqc spectrum of product 1, can find out has 11 carbon in the molecule, and wherein 2 is quaternary carbon, 3 CH, 5 CH ₂, 1 CH ₃Its hydrogen spectrum shows in the molecule that 18 hydrogen are arranged, and compares one group of hydrogen signal with the hydrogen spectrum of vitamin H: and δ H6.01 (1H, s), δ H5.65 (1H, s), δ H4.51 (1H, m), δ H4.31 (1H, m) δ H3.16 (1H, m) δ H2.91 (1H, dd, J=5.0HZ, J=13.0HZ), δ H2.74 (1H, d, J=12.4HZ), in conjunction with in the infrared spectrum 3289, there is absorption peak at the 1697cm-1 place, can infer to have the vitamin H mother nucleus structure in the molecule.ESIMS prompting molecular weight is 242, thereby may molecular formula be C ₁₁H ₁₈O ₂N ₂S.In CNMR, be positioned at δ C201.1 place and show a quaternary carbon signal, can belong to according to its chemical shift and be carbonyl carbon, remove above-mentioned functional group, also have 4 CH in the molecule ₂With 1 CH ₃, according to CH ₃Chemical shift, can infer sorrowful chain is methyl butyl ketone.

By anatomizing its carbon spectrum, hydrogen is composed, and HMBS and hsqc spectrum belong to its each hydrocarbon signal, see Table 1.

Table 1: compound 1 carbon spectrum, hydrogen spectrum and HMBS spectrum data (CDCl ₃)

Numbering	δC?	δH?	HMBC?
				2?	163.7(C)?	/?	H-3a，H-6a，N-H?
3a?	61.7(CH)?	4.31(1H，m)?	H-6，H-1’，H-3’，N-H?
				4?	55.4(CH)?	3.16(1H，m)?	H-3a，H-6a，H-1’，H-2’，H-3’，H-6?
6?	40.5(CH2)?	2.91(1H，dd，J＝5.0HZ，J＝13.0HZ)2.74(1H，d，J＝12.4HZ)?	H-3?a，H-6a?
				6a?	60.1(CH)?	4.51(1H，m)?	H-6，H-H?

1’?	28.4(CH2)?	1.78(2H，m)?	H-4，H-2’，H-3’?
				2’?	28.4(CH2)?	1.47(2H，m)?	H-4，H-1’，H-3’，H-4’?
3’?	23.6(CH2)?	1.78(2H，m)?	H-1’，H-3’，H-4’，H-6’?
				4’?	43.3(CH2)?	2.46(2H，m)?	H-1’，H-2’，H-3’，H-6’?
5’?	209.1(C)?	/?	H-1’，H-3’，H-4’，H-6’?
				6’?	29.9(CH3)?	2.14(3H，s)?	/?

Embodiment 2

Taking back the stream prolong, balance minim pipette, stirring arm; thermometer in the 250ml four-hole boiling flask of drying nitrogen protection, adds sodium methylate 2.5g; dry toluene 100ml is warming up to 100-110 ℃ time and heats up in a steamer, and drips methyl aceto acetate 39g (0.3mol); drip Bi Baowen and refluxed 1 hour, be cooled to normal temperature, add sulfosalt (2) 15g (0.0337mol); heating and heat preservation back flow reaction 3hr; be cooled to normal temperature, regulate pH=1, tell organic layer with 1N hydrochloric acid; water layer divides reextraction with toluene 30ml; merge organic layer, reclaim under reduced pressure gets weak yellow liquid, directly drops into 48%HBr100ml heat temperature raising to 126 ℃; refluxed 4 hours; be cooled to room temperature, add toluene 50ml and stir, be warming up to more than 90 ℃; divide the layer that deoils while hot; reclaim under reduced pressure is the sour water layer to the greatest extent, adds anhydrous methanol 50ml, separates out white solid 6.5g; yield 79%; it is 92% that HPLC measures its content, and mp:153.2-155.8 ℃ is same target compound after testing.

Embodiment 3

Taking back the stream prolong, balance minim pipette, stirring arm; thermometer in the 250ml four-hole boiling flask of drying nitrogen protection, adds sodium Metal 99.5 1.5g; dry toluene 100ml is warming up to 100-110 ℃ time and heats up in a steamer, and drips methyl aceto acetate 39g (0.3mol); drip Bi Baowen and refluxed 1 hour, be cooled to normal temperature, add sulfosalt 15g (0.0337mol); heating and heat preservation back flow reaction 1hr is cooled to normal temperature, regulates pH=1 with 1N hydrochloric acid; tell organic layer; reclaim under reduced pressure gets weak yellow liquid, directly drops into 48%HBr150ml heat temperature raising to 126 ℃, refluxes 3 hours; be cooled to room temperature; add toluene 50ml and stir, be warming up to more than 90 ℃, divide the layer that deoils while hot; reclaim under reduced pressure is the sour water layer to the greatest extent; add anhydrous methanol 50ml, separate out white solid 6g, yield 74%; it is 90% that HPLC measures its content, is same target compound after testing.

The above only is preferred embodiment of the present invention.Every foundation technical spirit of the present invention all falls within the scope of protection of the present invention any simple modification, equivalent variations and modification that above embodiment did.

Claims

1. (3aS, 4S, 6aR)-and 4-(5 '-oxo-hexyl)-tetramethylene sulfide-[3,6-is also] tetrahydroglyoxaline-2-ketone, its structural formula is as follows:

2. according to the synthetic method of the described compound of claim 1, its step is as follows: under nitrogen protection, drip methyl aceto acetate in sodium hydride, sodium alkoxide or sodium Metal 99.5 and dry toluene or anhydrous dimethyl benzene, be warming up to 100-110 ℃, make the reaction system clarification, be cooled to normal temperature afterwards; Then in the above-mentioned solution adding (8bS)-1,3-dibenzyl-2-oxo-decahydro imidazoles [3,4-d] thieno-[1,2-a] sulfonium bromide carries out insulation reaction at 70-90 ℃, is cooled to normal temperature afterwards for 3aR, 8aS; The pH value of regulating gained solution with hydrochloric acid or sulfuric acid is told organic layer at 1-2, and reclaim under reduced pressure gets weak yellow liquid, directly drops into hydrogen bromide solution afterwards, is heated to backflow, is cooled to normal temperature afterwards; The back adds toluene or dimethylbenzene stirring again, heats up, and divides the layer that deoils while hot, and reclaim under reduced pressure sour water layer adds dehydrated alcohol, separates out white solid, is target product.

3. according to the synthetic method of the described compound of claim 2, the temperature when it is characterized in that refluxing is controlled at 120 ℃-130 ℃.