CN101735242A - Method for preparing D-(+)-biotin intermediate - Google Patents
Method for preparing D-(+)-biotin intermediate Download PDFInfo
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- CN101735242A CN101735242A CN200910260123A CN200910260123A CN101735242A CN 101735242 A CN101735242 A CN 101735242A CN 200910260123 A CN200910260123 A CN 200910260123A CN 200910260123 A CN200910260123 A CN 200910260123A CN 101735242 A CN101735242 A CN 101735242A
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Abstract
The invention provides a method for preparing a D-(+)-biotin intermediate. The method comprises the steps of: taking L-cysteine monohydrochloride as a starting material; using benzaldehyde and sodium cyanate as a ring closure reagent to synthesize (7aR)-3-phenyl-6-benzyl-1H, 3H-imidazo[1, 5-C]thiazole-(6H, 7aH)-5, 7-dione through the cyclization; then utilizing benzyl bromide to perform benzyl protection on N atoms; then taking zinc as a reducing agent to perform ring-opening synthesis on N, N-dibenzyl-L-sulfhydryl hydantoin; introducing a side chain through an esterification reaction with monomethyl adipate acyl chloride; and taking titanium as the reducing agent to perform reductive ring closure to generate the intermediate. According to the method, the cheap and readily available sodium cyanate is used as the ring closure reagent to replace sodium isocyanate which is toxic and difficult to purchase in an original method, reaction conditions are optimized and reaction order is adjusted, so the disadvantages of harsh reaction conditions and low yield in the original method of ring opening first and then benzyl protection are overcome by the method of performing benzyl protection on the N atoms of an imidazole part first and then performing ring opening; and the total yield reaches 34.0-38.0 percent.
Description
Technical field
The present invention relates to the synthetic method of a kind of compound, specifically, relate to a kind of biotin intermediate: (6aR)-1, the preparation method of 3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3,4-d] imidazoles-2-ketone.Belong to the synthetic field of chemical machine.
Background technology
(6aR)-1,3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3,4-d] imidazoles-2-ketone has following structural:
This compound is the key intermediate of stereospecificity method synthesizing biotinylated, and cis hydrogenation under the inducing of chiral carbon takes off the benzyl hydrolysis again and can obtain the D-vitamin H.
Itself has the material of opticity as starting raw material with L-halfcystine or L-Gelucystine etc., carrying out the stereotaxis of vitamin H synthetic is a kind of more stable synthetic method, compare with traditional Hoffmann-La Roche production technology, this method has many superior parts.1) need not carry out complicated optical stereo and split, thereby need not use the optical resolution agent of high price, shortage such as ephedrine etc., reduce production cost.2) total reaction yield is higher, has improved production efficiency.L-halfcystine or L-Gelucystine meet the requirement of vitamin H structure most, and they include two heteroatomss (N and S atom) in the vitamin H dicyclo skeleton, and three carbon atoms also have a chiral centre that matches with D-vitamin H configuration.
Up to the present, existing more than ten kind is the method that initiator stereospecificity ground synthesizes the D-vitamin H with L-halfcystine or L-Gelucystine, wherein with calendar year 2001 Japan the JP 2001-002679 disclosed method of TakahashiMasami the easiest, 8 steps reaction altogether.Set out by the L-cysteine hydrochloride; earlier through phenyl aldehyde cyclization protection S and N atom; form imidazole ring with the sodium isocyanate effect again; open loop generates N-monobenzyl-L-sulfydryl glycolylurea under the Zn/HOAc condition; use the adipic acid monomethyl ester acyl chlorides to the mercaptan acidylate then; obtain (4aR)-3-monobenzyl-4-(1-adipic acid monomethyl ester acyl group thiomethyl)-imidazoles-2,5-diketone with benzyl protection N atom again.Utilize the Mcmurry linked reaction, with the titanium is that reductive agent makes carbonyl coupling reductive ring closure close (6aR)-1 that ring forms structural formula I, 3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3,4-d] imidazoles-2-ketone, last under the inducing of chiral carbon the cis hydrogenation, take off the benzyl hydrolysis again and obtain the D-vitamin H, synthesis flow as shown in Figure 1.
Though this method is easy, also there are many problems, rare as some raw material (as sodium isocyanate), and intermediate (4aR)-1,3-dibenzyl-4-(1-adipic acid monomethyl ester acyl group thiomethyl)-imidazoles-2, the synthesis condition harshness of 5-diketone, reaction needs continuously stirring 7d; Sulfydryl glycolylurea productive rate is low, is difficult to realize suitability for industrialized production; The stability of carbonyl reduction linked reaction and poor reproducibility or the like.
Summary of the invention
The objective of the invention is to overcome above-mentioned deficiency provides (6aR)-1 that a kind of cost is low, yield is high, the preparation method of 3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3,4-d] imidazoles-2-ketone.
The present invention is directed to the described method of Japanese Patent JP 2001-002679 and improve, select raw material cheap and easy to get for use, optimize reaction conditions; adjust response hierarchy; nitrogen-atoms to the imidazole ring part carries out benzyl protection earlier, and open loop generates the response hierarchy of mercaptan then, makes it more reasonable and practical.The present invention is a starting raw material with the L-cysteine hydrochloride still, by 6 steps reaction synthesizing biotinylated intermediate (6aR)-1,3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3,4-d] imidazoles-2-ketone.
In order to realize the object of the invention, D-(+)-biotin intermediate of a kind of structural formula I of the present invention: (6aR)-1, the preparation method of 3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3,4-d] imidazoles-2-ketone, it comprises the steps:
A) earlier with the L-cysteine hydrochloride through phenyl aldehyde cyclization protection S and N atom, obtain tetrahydrochysene-(4R)-carboxyl-(2s)-phenyl thiazole (II);
B) Compound I I closes cyclization reagent then, is that water-bath forms imidazole ring under the solvent action at Glacial acetic acid, obtains (7aR)-3-phenyl-1H, 3H-imidazo [1,5-C] thiazole-(6,7aH)-5,7-diketone (III);
C) at N, dinethylformamide is under the solvent, and compound III and cylite and salt of wormwood water-bath back flow reaction are to N atom benzyl protection, freezing and crystallizing generates (7aR)-3-phenyl-6-benzyl-1H, 3H-imidazo [1,5-C] thiazole-(6H, 7aH) 5,7-diketone (IV);
D) with zinc be reductive agent again, compound IV is reacting by heating ring opening synthesis N in Glacial acetic acid, N-dibenzyl-L-sulfydryl glycolylurea (V);
E) with the tetrahydrofuran (THF) be solvent, under the ice-water bath condition, compound V generates (4aR)-1,3-dibenzyl-4-(1-adipic acid monomethyl ester acyl group thiomethyl)-imidazoles-2,5-diketone (VI) through introducing side chain with the esterification of adipic acid monomethyl ester acyl chlorides;
F) under argon shield, the zinc-copper powder is under the catalyst action, is reductive agent with the titanium, and the compound VI reductive ring closure generates (6aR)-1,3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3,4-d] imidazoles-2-ketone (I).
Wherein, in the step a) with water and ethanol as solvent, cyclization protection S and N atom take place in L-cysteine hydrochloride and Sodium acetate trihydrate and phenyl aldehyde reaction, the ice-water bath cold filtration obtains tetrahydrochysene-(4R)-carboxyl-(2s)-phenyl thiazole (II).
Temperature of reaction is 20～30 ℃, under agitation reacts 2～3h, is preferably 2h; Ice-water bath cooling time is 2～3h, is preferably 2h.
Mol ratio is 1: 1～1.1: 1 between L-cysteine hydrochloride, Sodium acetate trihydrate and the phenyl aldehyde.
The water-bath temperature is 85～90 ℃ in the step b), is preferably 90 ℃; Return time is 12～15h, is preferably 12h.The mol ratio of Compound I I and Zassol is 1: 2.4～2.5.
Water bath reflux temperature is 50～60 ℃ in the step c), and preferred 50 ℃, the water-bath return time is 3～5h, is preferably 3h.
Mol ratio between compound III, salt of wormwood and the cylite is 1: 1～1.1: 1.
Solvent for use is methyl alcohol or ethanol during freezing and crystallizing.
Temperature of reaction is 90～95 ℃ in the step d), and preferred 90 ℃, the time is 7～9h, is preferably 9h, feeds nitrogen or argon shield.The mol ratio of compound IV and zinc powder is 1: 20～30, is preferably 1: 30.
Temperature of reaction is below 0 ℃ in the step e), and the time is 6～8h, is preferably 6h.Mol ratio between compound V and the adipic acid monomethyl ester acyl chlorides is 1: 1.
Temperature of reaction is 70～80 ℃ in the step f), is preferably 75 ℃, feeds nitrogen or argon shield.The mol ratio of compound VI and titanium reductive agent is 1: 9～10, is preferably 1: 9.
Described titanium reductive agent is a titanium tetrachloride.Reaction solvent is a tetrahydrofuran (THF).
The mol ratio of copper and zinc is 1: 1 in the catalyzer copper zinc powder.
The post-treating method of gained compound all can adopt this area method commonly used to carry out in each step of the present invention.
The present invention compares with prior art (as patent JP2001-002679), has the following advantages:
1) using Zassol replacement sodium isocyanate in step b) is to close cyclization reagent, and sodium isocyanate obtains relatively difficulty, and synthesis technique generally will be used such as highly toxic substances such as sodium cyanide, phosgene dangerous height.Therefore consider demand of practical production, use Zassol to replace sodium isocyanate, the Zassol relative toxicity is less, buys easily, and can produce sodium isocyanate in Glacial acetic acid, and this step yield still reaches more than 75% after the replacement.
2) the prior art reflux time reaches 17h in step b), and temperature of reaction is 80 ℃.By improving temperature of reaction to 85～90 ℃, return time 12～15h can reach the reaction purpose, and reaction solution becomes yellow transparent solution by white opacity liquid, and yield is constant.
3) existing method is after step b); employing is to (7aR)-3-phenyl-1H of structural formula II I, 3H-imidazo [1,5-C] thiazole-(6; 7aH)-5; the first open loop of the thiazole ring part of 7-diketone generates mercaptan, then introduces side chain, and the N atom to the imidazoles part carries out benzyl protection then; last under the reduction of low valent titanium reagent; make the carbonyl coupling close (6aR)-1 that ring forms structural formula I, 3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3,4-d] imidazoles-2-ketone.React according to this method condition; yield is extremely low; and by (4aR)-3-monobenzyl-4-(1-adipic acid monomethyl ester acyl group thiomethyl)-imidazoles-2; the 5-diketone synthesizes (4aR)-1; 3-dibenzyl-4-(1-adipic acid monomethyl ester acyl group thiomethyl)-imidazoles-2; 5-diketone reaction conditions is very harsh, needs sustained reaction 7d, can't adapt to suitability for industrialized production; the present invention is by adjusting response hierarchy; adopt (the 7aR)-3-phenyl-1H of elder generation, 3H-imidazo [1,5-C] thiazole-(6 to structural formula II I; 7aH)-5; the N atom benzyl protection of the imidazole ring of 7-diketone part, and then open loop generates the step that mercaptan is introduced side chain at last, overcome the weak point of former method.
4) patent JP2001-002679 is when using at a low price titanium and zinc powder to make catalyzer to carry out carbonyl coupling ring closure reaction, and reaction is violent, and test stability is relatively poor with circulation ratio, product decomposes easily, the present invention uses the zinc-copper powder instead as catalyzer, obtains better effects, addresses the above problem.
The present invention is a starting raw material with the L-cysteine hydrochloride; with phenyl aldehyde; Zassol is for closing synthetic (the 7aR)-3-phenyl of cyclization reagent cyclisation-6-benzyl-1H; 3H-imidazo [1; 5-C] thiazole-(6H; 7aH)-5, the 7-diketone utilizes bromobenzyl to N atom benzyl protection then; then with zinc reductive agent ring opening synthesis N; N-dibenzyl-L-sulfydryl glycolylurea through introducing side chain with the esterification of adipic acid monomethyl ester acyl chlorides, generates (6aR)-1 with the titanium for the reductive agent reductive ring closure; 3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3; 4-d] imidazoles-2-ketone, successfully set up the stereochemistry skeleton of vitamin H, total recovery 34.0～38.0%.
Description of drawings
Fig. 1 is the synthetic route chart of patent JP2001-002679;
Fig. 2 is the synthetic route chart of D-(+)-biotin intermediate of structural formula I of the present invention.
Embodiment
Below in conjunction with embodiment and operational path shown in Figure 2, the specific embodiment of the present invention is described in further detail.Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Embodiment 1 tetrahydrochysene-(4R)-carboxyl-(2s)-phenyl thiazole
50g (0.32mol) L-cysteine hydrochloride is dissolved in the 500mL water, adds 42g (0.31mol) Sodium acetate trihydrate, stirs 0.5h.Add w (C again
2H
5OH)=95% ethanol 250mL, phenyl aldehyde 35mL is at 20 ℃ of following stirring reaction 3h.Ice bath is cooled to below 5 ℃ and stirs 2h.After reaction finishes, filter, filter cake cleans twice with ethanol, gets white solid Compound I I 70g (yield 90%).
1HNMR(DMS0)，δ：7.40(m，5H)，6.8(bm，1H)，5.8(s，1H)，4.4～4.0(dd，1H)，3.5～3.0(m，2H)。
Ultimate analysis C
10H
11NO
2S (209.27) measured value (theoretical value), %:w (C)=56.87 (57.40), (H)=5.28 (5.30), w (N)=6.81 (6.69), w (S)=15.89 (15.32).
Embodiment 2 (7aR)-3-phenyl-1H, 3H-imidazo [1,5-C] thiazole-(6,7aH)-5, the 7-diketone
Be dissolved in the 300mL Glacial acetic acid obtaining Compound I I30g and 22g Zassol among the embodiment 1,90 ℃ of following reflux of water-bath 12 hours become yellow transparent liquid until reaction heat, and rotation concentrates and obtains the oily yellow liquid, it is dissolved in the 1000mL water, produces the yellow-white precipitation.Filter the back filter cake and use the 500mL tetrahydrofuran (THF), saturated common salt water washing then, anhydrous magnesium sulfate drying, rotation concentrates removes solvent, adds the normal hexane crystallization and obtains yellow solid compound III 27g (yield 80%).
IR (KBr compressing tablet), v/cm
-1: 1725,1394;
1HNMR (CDCl
3), δ: 3.20～3.37 (m, 2H), 4.58～4.63 (t, J=7.4Hz, 1H), 7.26～7.46 (m, 5H), 8.67 (br, 1H).
Embodiment 3 (7aR)-3-phenyl-6-benzyl-1H, 3H-imidazo [1,5-C] thiazole-(6H, 7aH) 5,7-diketone
(0.043mol) is dissolved in 30mL N with the 10.0g compound III, in the dinethylformamide, stirs adding 6g salt of wormwood and 5.5mL cylite down, 50 ℃ of following reflux 5h of water-bath.After reaction finishes, remove by filter insolubles, rotation concentrate sticky shape liquid, it is dissolved in the 45mL methyl alcohol, stirring at room 20min, 0 ℃ of following crystallization is filtered, 12g white crystal compound IV (yield 85.7%).
1HNMR(CDCl
3)，δ：7.30～7.45(m，1OH)，6.41(s，1H)，4.67(s，2H)，4.52(t，1H)，3.30(dd，1H)，3.15(dd，1H)。
Ultimate analysis C
18H
16N
2O
2S (324.4) measured value (theoretical value), %:w (C)=66.41 (66.58), w (H)=4.91 (4.93), w (N)=8.71 (8.63), w (S)=9.95 (9.86).
Embodiment 4N, N-dibenzyl-L-sulfydryl glycolylurea
Compound IV 10g (0.03mol) adds in the 100mL Glacial acetic acid; behind the heating in water bath to 90 ℃; add people's zinc powder 60g (0.92mol); the 9h that under nitrogen protection, refluxes, reaction finishes postcooling to room temperature, removes by filter zinc; rotation concentrate sticky shape liquid; it is dissolved in the ethyl acetate, uses aqueous hydrochloric acid, water, the saturated aqueous common salt of c (HCl)=1mol/L to clean anhydrous magnesium sulfate drying 1 time successively.Rotation is concentrated into dried colourless oil liquid V8.8g (yield 90%).
1HNMR(CDCl
3)，δ：7.26～7.43(m，10H)，4.88(d，1H)，4.70(dd，2H)，4.23(d，1H)，4.10(dd，1H)，2.93(dd，1H)，2.79(dd，1H)，1.15(dd，1H)。
Ultimate analysis C
18H
18N
2O
2S (326.4) measured value (theoretical value), %:w (C)=66.06 (66.18), w (H)=5.50 (5.51), w (N)=87.70 (87.58), w (S)=9.90 (9.80).
Embodiment 5 (4aR)-1,3-dibenzyl-4-(1-adipic acid monomethyl ester acyl group thiomethyl)-imidazoles-2,5-diketone
Compound V 10g (0.031mol) and triethylamine 4.9mL (0.031mol) are dissolved in the 100mL tetrahydrofuran (THF), under 0 ℃, adipic acid monomethyl ester acyl chlorides 5.8g (0.032mol) are dissolved in and slowly are added drop-wise in the 5mL tetrahydrofuran (THF) in the reactor, stir 6h.Reaction finishes, mixture is dissolved in the ethyl acetate, water, sodium bicarbonate aqueous solution and saturated aqueous common salt clean 1 time successively, anhydrous magnesium sulfate drying, rotation is concentrated into dried yellow oily liquid, silicagel column is refining, and it is V (ethyl acetate): V (normal hexane)=1: 3 that Xian takes off agent, VI 12g (yield 83%).
IR (KBr compressing tablet), v/cm
-1: 1771,1713.1445；
1HNMR(CDCl
3)，δ：1.25～1.70(m，4H)，2.04～2.48(m，4H)，3.30(dd，J＝14.4，3.1Hz。1H)，3.44(dd，J＝14.4，4.4Hz，1H)，3.67(S，3H)，3.97(dd，J＝4.4，3.1Hz，1H)，4.06(d，J＝15.2Hz，1H)，4.62(d，J＝15.2Hz，1H)，4.72(d，J＝14.5Hz，1H)，5.03(d，J＝15.2Hz，1H)，7.25～7.4(m，1OH)。Mass(ESI)，m/Z：491.4(MNa
+?H，100)。
Embodiment 6 (6aR)-1,3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3,4-d] imidazoles-2-ketone
10g zinc-copper powder adds in the 80mL tetrahydrofuran (THF).Feed argon gas, 75 ℃ of following reflux 0.5h of water-bath, after be added dropwise to the 4.8mL titanium tetrachloride, backflow 5h.Then, be cooled to 50 ℃, 5gVI be dissolved in the solution that the 30mL tetrahydrofuran (THF) is mixed with slowly be added drop-wise in the reactor.The synthermal backflow 6h that continues down, ice bath was cooled to 0 ℃ after reaction finished, and dripped the 10.8mL quadrol, stirred 10min.The filtering insolubles, filtrate is cleaned with tetrahydrofuran (THF), anhydrous magnesium sulfate drying.Filter then, decompression distillates solvent, and rotation is concentrated into dried 3.75g oily liquids I (yield 80.5%).
1HNMR(CDCl
3)，δ：0.93～1.23(m，4H)，2.05(t，4H)，2.74(dd，J＝17.0，13.9Hz，1H)，2.94(dd，J＝9.9，7.1Hz，1H)，3.57(s，3H)，4.34～4.59(m，3H)，4.73(d，J＝16.9Hz，1H)，4.80(d，J＝16.9Hz，2H)，7.20～7.40(m，1OH)。
Embodiment 7 tetrahydrochysenes-(4R)-carboxyl-(2s)-phenyl thiazole
50g (0.32mo1) L-cysteine hydrochloride is dissolved in the 500mL water, adds 47.6g (0.35mol) Sodium acetate trihydrate, stirs 3h.Add w (C again
2H
5OH)=95% ethanol 250mL, phenyl aldehyde 35mL is at 30 ℃ of following stirring reaction 3h.Ice bath is cooled to below 0 ℃ and stirs 3h.After reaction finishes, filter, filter cake cleans twice with ethanol, gets white solid Compound I I 69.7g (yield 89.6%).
1HNMR(DMS0)，δ：7.40(m，5H)，6.8(bm，1H)，5.8(s，1H)，4.4～4.0(dd，1H)，3.5～3.0(m，2H).
Ultimate analysis C
10H
11NO
2S (209.27) measured value (theoretical value), %:w (C)=56.87 (57.40), (H)=5.28 (5.30), w (N)=6.81 (6.69), w (S)=15.89 (15.32).
Embodiment 8 (7aR)-3-phenyl-1H, 3H-imidazo [1,5-C] thiazole-(6,7aH)-5, the 7-diketone
Be dissolved in the 300mL Glacial acetic acid obtaining Compound I I 30g and 22g Zassol among the embodiment 7,85 ℃ of following reflux of water-bath 15 hours become yellow transparent liquid until reaction heat, and rotation concentrates and obtains the oily yellow liquid, it is dissolved in the 1000mL water, produces the yellow-white precipitation.Filter the back filter cake and use the 500mL tetrahydrofuran (THF), saturated common salt water washing then, anhydrous magnesium sulfate drying, rotation concentrates removes solvent, adds the normal hexane crystallization and obtains yellow solid compound III 26.3g (yield 78%).
IR (KBr compressing tablet), v/cm
-1: 1725,1394;
1HNMR (CDCl
3), δ: 3.20～3.37 (m, 2H), 4.58～4.63 (t, J=7.4Hz, 1H), 7.26～7.46 (m, 5H), 8.67 (br, 1H).
Embodiment 9 (7aR)-3-phenyl-6-benzyl-1H, 3H-imidazo [1,5-C] thiazole-(6H, 7aH) 5,7-diketone
Be dissolved in 30mL N with obtaining 10g compound III (0.043mol) among the embodiment 8, in the dinethylformamide, stir adding 6.5g salt of wormwood and 5.5mL bromobenzyl down, 60 ℃ of following reflux 3h of water-bath.After reaction finishes, remove by filter insolubles, rotation concentrate sticky shape liquid, it is dissolved in the 45mL methyl alcohol, stirring at room 30min, 0 ℃ of following crystallization is filtered, 11.1g white crystal compound IV (yield 79.2%).
1HNMR(CDCl
3)，δ：7.30～7.45(m，10H)，6.41(s，1H)，4.67(s，2H)，4.52(t，1H)，3.30(dd，1H)，3.15(dd，1H).
Ultimate analysis C
18H
16N
2O
2S (324.4) measured value (theoretical value), %:w (C)=66.41 (66.58), w (H)=4.91 (4.93), w (N)=8.71 (8.63), w (S)=9.95 (9.86).
Embodiment 10N, N-dibenzyl-L-sulfydryl glycolylurea
Add in the 100mL Glacial acetic acid obtaining compound IV 10g (0.03mol) among the embodiment 9; behind the heating in water bath to 95 ℃; add people's zinc powder 60g (0.92mol); the 7h that under nitrogen protection, refluxes, reaction finishes postcooling to room temperature, removes by filter zinc; rotation concentrate sticky shape liquid; it is dissolved in the ethyl acetate, uses aqueous hydrochloric acid, water, the saturated aqueous common salt of c (HCl)=1mol/L to clean anhydrous magnesium sulfate drying 1 time successively.Rotation is concentrated into dried colourless oil liquid V8.38g (yield 85.7%).
1HNMR(CDCl
3)，δ：7.26～7.43(m，10H)，4.88(d，1H)，4.70(dd，2H)，4.23(d，1H)，4.10(dd，1H)，2.93(dd，1H)，2.79(dd，1H)，1.15(dd，1H)。
Ultimate analysis C
18H
18N
2O
2S (326.4) measured value (theoretical value), %:w (C)=66.06 (66.18), w (H)=5.50 (5.51), w (N)=87.70 (87.58), w (S)=9.90 (9.80).
Embodiment 11 (4aR)-1,3-dibenzyl-4-(1-adipic acid monomethyl ester acyl group thiomethyl)-imidazoles-2,5-diketone
To obtain compound V 10g (0.31mol) among the embodiment 10 and triethylamine 5.1mL (0.34mol) is dissolved in the 100mL tetrahydrofuran (THF), under 0 ℃, adipic acid monomethyl ester acyl chlorides 5.8g (0.31mol) is dissolved in and slowly is added drop-wise in the 5mL tetrahydrofuran (THF) in the reactor, stir 8h.Reaction finishes, mixture is dissolved in the ethyl acetate, water, sodium bicarbonate aqueous solution and saturated aqueous common salt clean 1 time successively, anhydrous magnesium sulfate drying, rotation is concentrated into dried yellow oily liquid, silicagel column is refining, and it is V (ethyl acetate): V (normal hexane)=1: 3 that Xian takes off agent, VI11.8g (yield 82.8%).
IR (KBr compressing tablet), v/cm
-1: 1771,1713.1445；
1HNMR(CDCl
3)，δ：1.25～1.70(m，4H)，2.04～2.48(m，4H)，3.30(dd，J＝14.4，3.1Hz。1H)，3.44(dd，J＝14.4，4.4Hz，1H)，3.67(S，3H)，3.97(dd，J＝4.4，3.1Hz，1H)，4.06(d，J＝15.2Hz，1H)，4.62(d，J＝15.2Hz，1H)，4.72(d，J＝14.5Hz，1H)，5.03(d，J＝15.2Hz，1H)，7.25～7.4(m，1OH)。Mass(ESI)，m/Z：491.4(MNa
+H，100)。
Embodiment 12 (6aR)-1,3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3,4-d] imidazoles-2-ketone
10g zinc-copper powder adds in the 80mL tetrahydrofuran (THF).Feed argon gas, 80 ℃ of following reflux 1h of water-bath, after be added dropwise to the 4.8mL titanium tetrachloride, backflow 4h.Then, be cooled to 5 ℃, be dissolved in the solution that the 30mL tetrahydrofuran (THF) is mixed with and slowly be added drop-wise in the reactor obtaining 5gVI among the embodiment 11.The synthermal backflow 6h that continues down, ice bath was cooled to 0 ℃ after reaction finished, and dripped the 10.8mL quadrol, stirred 10min.The filtering insolubles, filtrate is cleaned with tetrahydrofuran (THF), anhydrous magnesium sulfate drying.Filter then, decompression distillates solvent, and rotation is concentrated into dried 3.71g oily liquids I (yield 79.4%).
1HNMR(CDCl
3)，δ：0.93～1.23(m，4H)，2.05(t，4H)，2.74(dd，J＝17.0，13.9Hz，1H)，2.94(dd，J＝9.9，7.1Hz，1H)，3.57(s，3H)，4.34～4.59(m，3H)，4.73(d，J＝16.9Hz，1H)，4.8O(d，J＝16.9Hz，2H)，7.20～7.40(m，1OH)。
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a method for preparing D-(+)-biotin intermediate of structural formula I is characterized in that,
It comprises the steps:
A) earlier the L-cysteine hydrochloride is protected S and N atom through the phenyl aldehyde cyclization, obtain Compound I I;
B) Compound I I closes cyclization reagent then, is that water-bath forms imidazole ring under the solvent action at Glacial acetic acid, obtains compound III;
C) at N, dinethylformamide is under the solvent, and compound III and cylite and salt of wormwood water-bath back flow reaction are to N atom benzyl protection, and freezing and crystallizing generates compound IV;
D) with zinc be reductive agent again, compound IV is reacting by heating ring opening synthesis compound V in Glacial acetic acid;
E) with the tetrahydrofuran (THF) be solvent, under the ice-water bath condition, compound V generates compound VI through introducing side chain with the esterification of adipic acid monomethyl ester acyl chlorides;
F) under argon shield, the zinc-copper powder is under the catalyst action, is reductive agent with the titanium, (6aR)-1 of compound VI reductive ring closure generating structure formula I, 3-dibenzyl-4-(4-methoxycarbonyl butyl)-dihydro-thieno-[3,4-d] imidazoles-2-ketone.
2. preparation method according to claim 1 is characterized in that, in the step a) with water and ethanol as solvent, cyclization protection S and N atom take place in L-cysteine hydrochloride and Sodium acetate trihydrate and phenyl aldehyde reaction, the ice-water bath cold filtration obtains Compound I I; Mol ratio is 1: 1～1.1: 1 between L-cysteine hydrochloride, Sodium acetate trihydrate and the phenyl aldehyde.
3. preparation method according to claim 1 and 2 is characterized in that, temperature of reaction is 20～30 ℃ in the step a), under agitation reacts 2～3h, is preferably 2h; Ice-water bath cooling time is 2～3h, is preferably 2h.
4. according to any described preparation method of claim 1-3, it is characterized in that the water-bath temperature is 85～90 ℃ in the step b), be preferably 90 ℃; Return time is 12～15h, is preferably 12h; The mol ratio of Compound I I and Zassol is 1: 2.4～2.5.
5. according to any described preparation method of claim 1-4, it is characterized in that water bath reflux temperature is 50～60 ℃ in the step c), preferred 50 ℃, the water-bath return time is 3～5h, is preferably 3h; Mol ratio between compound III, salt of wormwood and the cylite is 1: 1～1.1: 1.
6. according to any described preparation method of claim 1-5, it is characterized in that solvent for use is methyl alcohol or ethanol during freezing and crystallizing.
7. according to any described preparation method of claim 1-6, it is characterized in that temperature of reaction is 90～95 ℃ in the step d), preferred 90 ℃, the time is 7～9h, is preferably 9h, feeds nitrogen or argon shield; The mol ratio of compound IV and zinc powder is 1: 20～30, is preferably 1: 30.
8. according to any described preparation method of claim 1-7, it is characterized in that temperature of reaction is below 0 ℃ in the step e), the time is 6～8h, is preferably 6h.
9. according to any described preparation method of claim 1-8, it is characterized in that temperature of reaction is 70～80 ℃ in the step f), be preferably 75 ℃, feed nitrogen or argon shield; The mol ratio of compound VI and titanium reductive agent is 1: 9～10, is preferably 1: 9.
10. preparation method according to claim 9 is characterized in that, the reductive agent of titanium described in the step f) is a titanium tetrachloride; Reaction solvent is a tetrahydrofuran (THF).
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104277054A (en) * | 2013-07-03 | 2015-01-14 | 浙江新和成股份有限公司 | Preparation method of 7-alkoxy-3-phenyltetrahydroimidazo[1,5-c]thiazole-5(1H)-one compound |
| CN104497009A (en) * | 2014-12-12 | 2015-04-08 | 新发药业有限公司 | Simple method for preparing D-biotin |
| WO2018189108A1 (en) | 2017-04-12 | 2018-10-18 | Dsm Ip Assets B.V. | A process for preparation of an imidazothiazolone compound |
-
2009
- 2009-12-25 CN CN2009102601238A patent/CN101735242B/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104277054A (en) * | 2013-07-03 | 2015-01-14 | 浙江新和成股份有限公司 | Preparation method of 7-alkoxy-3-phenyltetrahydroimidazo[1,5-c]thiazole-5(1H)-one compound |
| CN104277054B (en) * | 2013-07-03 | 2016-08-10 | 浙江新和成股份有限公司 | The preparation method of 7-alkoxyl-3-phenyl imidazolidine also [1,5-c] thiazole-5 (1H)-one compound |
| CN104497009A (en) * | 2014-12-12 | 2015-04-08 | 新发药业有限公司 | Simple method for preparing D-biotin |
| WO2018189108A1 (en) | 2017-04-12 | 2018-10-18 | Dsm Ip Assets B.V. | A process for preparation of an imidazothiazolone compound |
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