CN109456340B - Preparation method of 5-oxohexahydroimidazo [1,5-c ] thiazole-7-yl-6-oxohexanoate compound - Google Patents
Preparation method of 5-oxohexahydroimidazo [1,5-c ] thiazole-7-yl-6-oxohexanoate compound Download PDFInfo
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a preparation method of a 5-oxohexahydroimidazo [1,5-c ] thiazole-7-yl-6-oxohexanoate compound, which comprises the following steps: reacting the (3S,7aR) -6-substituted benzyl-3-substituted phenyldihydro-3H, 5H-imidazo [1,5-c ] thiazole-5, 7(6H) -dione compound with a carbonyl protection reagent to generate a (3S,7aR) -6-substituted benzyl-7, 7-dialkoxy-3-substituted phenyltetrahydro-3H, 5H-imidazo [1,5-c ] thiazole-5-one compound; and carrying out condensation reaction on the obtained product and 1, 2-bis (trimethylsiloxy) cyclohex-1-ene to generate the 5-oxohexahydroimidazo [1,5-c ] thiazol-7-yl-6-oxohexanoate compound. The preparation method has the advantages of easily available raw materials, less side reactions, high yield, environmental friendliness, no toxicity, mild and easily-controlled reaction conditions and suitability for production.
Description
Technical Field
The invention relates to the field of synthesis of medical raw materials, in particular to a preparation method of a 5-oxohexahydroimidazo [1,5-c ] thiazol-7-yl-6-oxohexanoate compound.
Background
d-biotin (biotin), also known aS vitamin H, coenzyme R, chemical name (3aS,4S,6aR) -hexahydro-2-oxo-1H-thieno [3,4-d ] imidazole-4-pentanoic acid, belongs to a water-soluble B-group vitamin, and is used aS a medicine and feed additive. The d-biotin is distributed in animal and plant tissues, can be separated from liver extracts and egg yolk, is a component of various carboxylase prosthetic groups, and is an essential substance for the growth and development of animals and plants. d-biotin is now commonly obtained by chemical synthesis.
The structure of d-biotin is as follows:
d-biotin has several synthetic methods as follows:
chen Fener et al reported a method for d-biotin synthesis in the Proc. higher school Chemicals, 2001, 22(7), 1141-: 1, 3-dibenzylimidazoline-2-ketone-cis-4, 5-dicarboxylic acid is used aS a raw material, and a d-biotin product is obtained through debenzylation protection and decarboxylation of cis-1, 3-dibenzyl-tetrahydro-2H-furo [3,4-d ] imidazole-2, 4, 6-trione, (3aS,6aR) -1, 3-dibenzyl-tetrahydro-4H-thieno [3,4-d ] imidazole-2, 4(1H) -diketone, (3aR,8aS,8bS) -1, 3-dibenzyl-2-oxo-decahydroimidazo [4,5-c ] thieno [1, 2-a ] sulfonium bromide, dibenzyl biotin diester and the like. The synthetic route needs to use sulfuration reagents such as potassium thioacetate and the like, so that the environmental protection pressure is great.
Chavan et al in Journal of Organic Chemistry 2005,70(5), 1901-: taking cysteine hydrochloride as a raw material, reacting (3S,7aR) -6-benzyl-7-hydroxy-3-phenyltetrahydroimidazo [1,5-c ] thiazol-5 (3H) -one with 1, 2-bis (trimethylsilica) cyclohexene to obtain (3S,7aR) -6-benzyl-7- (1-hydroxy-2-oxocyclohexyl) -3-phenyltetrahydroimidazo [1,5-c ] thiazol-5 (3H) -one, oxidizing and esterifying with tert-butyl peroxide to obtain methyl 6- ((3S,7aR) -6-benzyl-5-oxo-3-phenyltetrahydroimidazo [1,5-c ] thiazol-7-yl) -6-oxohexanoate, reducing and opening the ring by zinc powder/acetic acid, cyclizing by acetic acid/piperidine to obtain 5- ((3aS,6aR) -1, 3-dibenzyl-2-oxo-tetrahydro-1H-thieno [3,4-d ] imidazole-4 (2H) -alkenyl) -methyl valerate, and then hydrogenating and debenzylating to obtain the d-biotin. The route uses tert-butyl peroxide, the industrial implementation is dangerous, and the intermediate methyl esterification also needs dangerous diazomethane. The yield of (3S,7aR) -6-benzyl-7-hydroxy-3-phenyltetrahydroimidazo [1,5-c ] thiazol-5 (3H) -one to 6- ((3S,7aR) -6-benzyl-5-oxo-3-phenyltetrahydroimidazo [1,5-c ] thiazol-7-yl) -6-oxohexanoic acid methyl ester was reported to be 68.6%.
Chenkexi et al, in organic chemistry 2006, 26(9), 1309-1312, reported a d-biotin synthesis method: taking cysteine hydrochloride as a raw material, reacting (3S,7aR) -6-benzyl-7-hydroxy-3-phenyltetrahydroimidazo [1,5-c ] thiazol-5 (3H) -ketone with 1-trimethylsiloxy-1-cyclohexene to obtain (3S,7S, 7aR) -6-benzyl-7- (2-oxocyclohexyl) -3-phenyltetrahydroimidazo [1,5-c ] thiazol-5 (3H) -ketone, oxidizing with perbenzoic acid to obtain 6- ((3S,7R, 7aR) -6-benzyl-5-oxo-3-phenylhexahydroimidazo [1,5-c ] thiazol-7-yl) -6-hydroxyhexanoic acid, oxidizing and esterifying by chromium trioxide to obtain 6- ((3S,7R, 7aR) -6-benzyl-5-oxo-3-phenylhexahydroimidazo [1,5-c ] thiazole-7-yl) -6-oxomethyl hexanoate, performing ring opening-cyclization by zinc powder/acetic acid/piperidine to obtain 5- ((3aS,6aR) -1, 3-dibenzyl-2-oxotetrahydro-1H-thieno [3,4-d ] imidazole-4 (2H) -alkenyl) -methyl valerate, and then hydrogenating and debenzylating to obtain d-biotin. The route uses peroxybenzoic acid with high risk as an oxidant and chromium trioxide as an oxidant, and chromium-containing waste after the chromium trioxide is used is difficult to treat and high in treatment cost. The yield of (3S,7aR) -6-benzyl-7-hydroxy-3-phenyltetrahydroimidazo [1,5-c ] thiazol-5 (3H) -one to methyl 6- ((3S,7aR) -6-benzyl-5-oxo-3-phenyltetrahydroimidazo [1,5-c ] thiazol-7-yl) -6-oxohexanoate was reported to be 71.5%.
The methods reported by Subhash p.chavan and chenkeli all adopt chemical oxidants, and have the disadvantages of many reaction impurities, serious side reaction, difficult separation and purification and high risk.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects in the prior art and provide a synthesis method of a 5-oxohexahydroimidazo [1,5-c ] thiazol-7-yl-6-oxohexanoate compound, which has the advantages of easily available raw materials, less side reactions, high yield, environmental friendliness, no toxicity, mild and easily-controlled reaction conditions and suitability for production.
Therefore, the technical scheme adopted by the invention is as follows:
a method for preparing 5-oxohexahydroimidazo [1,5-c ] thiazol-7-yl-6-oxohexanoate compounds, comprising:
(1) reacting the (3S,7aR) -6-substituted benzyl-3-substituted phenyldihydro-3H, 5H-imidazo [1,5-c ] thiazole-5, 7(6H) -dione compound with a carbonyl protection reagent to generate a (3S,7aR) -6-substituted benzyl-7, 7-dialkoxy-3-substituted phenyltetrahydro-3H, 5H-imidazo [1,5-c ] thiazole-5-one compound;
(2) carrying out condensation reaction on the (3S,7aR) -6-substituted benzyl-7, 7-dialkoxy-3-substituted phenyltetrahydro-3H, 5H-imidazo [1,5-c ] thiazole-5-one compound obtained in the step (1) and 1, 2-bis (trimethylsiloxy) cyclohex-1-ene to generate the 5-oxohexahydroimidazo [1,5-c ] thiazole-7-yl-6-oxohexanoate compound;
the structure of the (3S,7aR) -6-substituted benzyl-3-substituted phenyldihydro-3H, 5H-imidazo [1,5-c ] thiazole-5, 7(6H) -diketone compound is shown as the formula (1):
the structure of the (3S,7aR) -6-substituted benzyl-7, 7-dialkoxy-3-substituted phenyltetrahydro-3H, 5H-imidazo [1,5-c ] thiazol-5-one compound is shown as the formula (2):
the general formula of the 5-oxohexahydroimidazo [1,5-c ] thiazole-7-yl-6-oxohexanoate compound is shown as the formula (3):
in the formulae (1) to (3), R1Is selected from substituted or unsubstituted phenyl, and the substituent on the phenyl is C1～C4Alkyl, halogen or C1～C4Alkoxy, preferably methyl, chloro or methoxy; preferably, R is1Is phenyl, p-tolyl, p-chlorophenyl, p-methoxyphenyl, o-tolyl, o-chlorophenyl or o-methoxyphenyl;
R2is selected from substituted or unsubstituted benzyl, and the substituent on the benzyl is selected from C1～C5Alkyl, halogen or C1～C4Alkoxy, preferably methyl, chloro or methoxy; preferably, R is2Is benzyl, p-methylbenzyl, p-chlorobenzyl, p-methoxybenzyl, o-methylbenzyl, o-chlorobenzyl or o-methoxybenzyl;
R3is selected from C1～C4Alkyl, preferably methyl or ethyl.
Wherein the reaction mechanism of the step (2) is as follows:
and (3) removing one alkoxy from the compound of the general formula (2) under the action of Lewis acid to form a carbonium ion intermediate of the compound of the general formula (2), attacking the carbonium ion intermediate to an electron cloud of a 1, 2-bis (trimethylsiloxy) cyclohex-1-ene double bond to form a condensation compound, removing the other alkoxy from the condensation compound to form a carbonium ion intermediate of the condensation compound under the action of Lewis acid, transferring the carbonium ion molecule to form a double bond, simultaneously opening a cyclohexanone ring to form ester, and then removing trimethylsilyl through acidic hydrolysis to generate the compound of the general formula (3).
In the step (1), the carbonyl protection reagent consists of trialkoxy onium tetrafluoroborate and metal alkoxide;
the metal alkoxide is selected from sodium alkoxide, potassium alkoxide or lithium alkoxide;
the carbonyl protecting agent is preferably a combination of trimethyloxonium tetrafluoroborate and sodium methoxide or a combination of triethyloxonium tetrafluoroborate and sodium ethoxide.
In the step (1), during the reaction, trialkoxy onium tetrafluoroborate is added for full reaction, and then metal alkoxide is added for reaction;
the solvent used in the reaction of the trialkoxy onium tetrafluoroborate is alkyl halide or ether solvent, preferably dichloromethane, dichloroethane or isopropyl ether;
the metal alkoxide is added in the form of a corresponding alcoholic solution.
In the step (1), the reaction temperature is-30-80 ℃, and the preferable reaction temperature is-20-50 ℃.
In the step (1), the molar amount of the trialkoxy onium tetrafluoroborate is 1-5 times, preferably 1-1.1 times that of the (3S,7aR) -6-substituted benzyl-3-substituted phenyl dihydro-3H, 5H-imidazo [1,5-c ] thiazole-5, 7(6H) -diketone compound;
the molar amount of the metal alkoxide is 1-5 times, preferably 1-1.1 times of that of the (3S,7aR) -6-substituted benzyl-3-substituted phenyldihydro-3H, 5H-imidazo [1,5-c ] thiazole-5, 7(6H) -diketone compound.
In the step (2), the condensation reaction is carried out under the catalysis of Lewis acid, and the Lewis acid is boron trifluoride diethyl etherate, boron trifluoride acetonitrile, titanium tetrachloride or tin tetrachloride.
In the step (2), the molar amount of the 1, 2-bis (trimethylsiloxy) cyclohex-1-ene is 1 to 3 times of that of the (3S,7aR) -6-substituted benzyl-7, 7-dialkoxy-3-substituted phenyltetrahydro-3H, 5H-imidazo [1,5-c ] thiazol-5-one compound, preferably 1 to 1.05 times.
In the step (2), the reaction temperature of the condensation reaction is-80 to 80 ℃, and preferably-50 to 30 ℃.
In the step (2), the solvent for the condensation reaction is one or more of alkyl halide, alkane, aromatic hydrocarbon, ester and ether, preferably dichloromethane, n-hexane, toluene or butyl acetate.
In the step (2), after the condensation reaction is completed, acid is added for treatment, and the acid is preferably hydrochloric acid, sulfuric acid or phosphoric acid.
The invention has the following advantages: the safety is good, no toxicity exists, the reaction condition is mild and easy to control, and the environment is protected; the reaction condition yield is high, the separation is easy, and the high-purity 6-substituted benzyl-5-oxo-3-substituted phenyl hexahydroimidazo [1,5-c ] thiazole-7-yl-6-oxohexanoate compound can be obtained.
Detailed Description
The present invention will be further described with reference to the following embodiments.
Example 1: preparation of (3S,7aR) -6-benzyl-7, 7-dimethoxy-3-phenyltetrahydro-3H, 5H-imidazo [1,5-c ] thiazol-5-one
In a 500mL three-necked flask with a mechanical stirrer and a thermometer, 200mL of methylene chloride was added, and Compound (1a) (3S,7aR) -6-benzyl-3-phenyldihydro-3H, 5H-imidazo [1, 5-c) was charged]Thiazole-5, 7(6H) -dione 32.4g (0.1mol) (R1Is phenyl, R2Under the protection of nitrogen, stirring and cooling to 30 ℃ below zero, adding 16.3g (0.11mol) of trimethyloxonium tetrafluoroborate in batches, continuing to stir and react at 30 ℃ below zero to 10 ℃ below zero for 20 hours, then dropwise adding 21.2g (containing 5.94g and 0.11mol of sodium methoxide) of 28% sodium methoxide methanol solution, stirring and reacting at 5 ℃ below zero to 0 ℃ for 15 minutes, filtering, washing a filter cake with 100mL of dichloromethane, and combining filtrates to obtain a target product (2a) (3S,7aR) -6-benzyl-7, 7-dimethoxy-3-phenyltetrahydro-3H, 5H-imidazo [1,5-c ], (3S,7aR) -6-benzyl-7, 7-dimethoxy-3-phenyltetrahydro-3H]Methylene chloride solution of Thiazol-5-one (R)1Is phenyl, R2Is benzyl, R3Methyl), the HPLC purity was 98.7%, and the purities of the target product (3S,7aR) -6-benzyl-7, 7-dimethoxy-3-phenyltetrahydro-3H, 5H-imidazo [1, 5-c) were calibrated]Thiazol-5-one (2a) weighed 34.5g, and the yield was 93.1%.
Example 14: preparation of methyl 6-benzyl-5-oxo-3-phenylhexahydroimidazo [1,5-c ] thiazol-7-yl-6-oxohexanoate
In a 500mL three-necked flask with a mechanical stirrer and a thermometer, the compound (2a) (3S,7aR) -6-benzyl-7, 7-dimethoxy-3-phenyltetrahydro-3H, 5H-imidazo [1,5 ] prepared according to example 1 is charged-c]Solution of thiazol-5-one in dichloromethane, concentration about 8%, (R)1Is phenyl, R2Is benzyl, R3Methyl) purified (3S,7aR) -6-benzyl-7, 7-dimethoxy-3-phenyltetrahydro-3H, 5H-imidazo [1,5-c]37.0g (0.1mol) of thiazole-5-ketone, nitrogen protection, cooling to-70 ℃, adding 26g (0.1mol) of stannic chloride, dropwise adding 25.9g (0.1mol) of 1, 2-bis (trimethylsiloxy) cyclohex-1-ene at-70 ℃, heating to-30 ℃ for reaction for 1 hour, then heating to 0 ℃, dropwise adding 30mL (1.1g, 30mmol) of 1N HCl, and stirring for reaction for 0.5 hour; after the reaction is finished, the layers are separated, the water layer is extracted twice by using 100mL multiplied by 2 of dichloromethane, the combined dichloromethane extract is washed twice by using 50mL multiplied by 2 of water, the dichloromethane extract is decompressed and evaporated to dryness, recrystallized by using toluene and filtered to obtain the target product (3a) 6-benzyl-5-oxo-3-phenylhexahydroimidazo [1, 5-c)]Thiazol-7-yl-6-oxohexanoic acid methyl ester (R)1Is phenyl, R2Is benzyl, R3Methyl), oven dried, 43.2g by weight, 99.3% content, 95.4% yield.
The above are only a few embodiments of the present invention, and it is also possible for those skilled in the art to change the catalyst combination, change the solvent combination, change the reaction parameters, and the like, and all changes and modifications are considered to fall within the scope of the present invention.
Claims (19)
1. A method for producing a 5-oxohexahydroimidazo [1,5-c ] thiazol-7-yl-6-oxohexanoate compound, comprising:
(1) reacting the (3S,7aR) -6-substituted benzyl-3-substituted phenyldihydro-3H, 5H-imidazo [1,5-c ] thiazole-5, 7(6H) -dione compound with a carbonyl protection reagent to generate a (3S,7aR) -6-substituted benzyl-7, 7-dialkoxy-3-substituted phenyltetrahydro-3H, 5H-imidazo [1,5-c ] thiazole-5-one compound;
(2) carrying out condensation reaction on the (3S,7aR) -6-substituted benzyl-7, 7-dialkoxy-3-substituted phenyltetrahydro-3H, 5H-imidazo [1,5-c ] thiazole-5-one compound obtained in the step (1) and 1, 2-bis (trimethylsiloxy) cyclohex-1-ene to generate the 5-oxohexahydroimidazo [1,5-c ] thiazole-7-yl-6-oxohexanoate compound;
the structure of the (3S,7aR) -6-substituted benzyl-3-substituted phenyldihydro-3H, 5H-imidazo [1,5-c ] thiazole-5, 7(6H) -diketone compound is shown as the formula (1):
the structure of the (3S,7aR) -6-substituted benzyl-7, 7-dialkoxy-3-substituted phenyltetrahydro-3H, 5H-imidazo [1,5-c ] thiazol-5-one compound is shown as the formula (2):
the general formula of the 5-oxohexahydroimidazo [1,5-c ] thiazole-7-yl-6-oxohexanoate compound is shown as the formula (3):
in the formulae (1) to (3), R1Is selected from substituted or unsubstituted phenyl, and the substituent on the phenyl is C1～C4Alkyl, halogen or C1～C4An alkoxy group;
R2is selected from substituted or unsubstituted benzyl, and the substituent on the benzyl is selected from C1～C5Alkyl, halogen or C1～C4An alkoxy group;
R3is selected from C1～C4An alkyl group.
2. The process according to claim 1, wherein in the step (1), the carbonyl protecting agent is composed of a trialkoxy onium tetrafluoroborate and a metal alkoxide;
the metal alkoxide is selected from sodium alkoxide, potassium alkoxide or lithium alkoxide.
3. The process of claim 2, wherein the carbonyl protecting agent is a combination of trimethyloxonium tetrafluoroborate and sodium methoxide or a combination of triethyloxonium tetrafluoroborate and sodium ethoxide.
4. The preparation method according to claim 2, wherein in the step (1), the trialkoxy onium tetrafluoroborate is added to react sufficiently, and then the metal alkoxide is added to react;
the solvent used in the reaction of trialkoxy onium tetrafluoroborate is alkyl halide or ether solvent;
the metal alkoxide is added in the form of a corresponding alcoholic solution.
5. The process according to claim 4, wherein the solvent used in the reaction of the trialkoxy onium tetrafluoroborate is dichloromethane, dichloroethane or isopropyl ether.
6. The method according to claim 1, wherein the reaction temperature in the step (1) is-30 to 80 ℃.
7. The method according to claim 6, wherein the reaction temperature is-20 to 50 ℃.
8. The method according to claim 2, wherein in the step (1), the molar amount of the trialkoxyonium tetrafluoroborate used is 1 to 5 times that of the (3S,7aR) -6-substituted benzyl-3-substituted phenyldihydro-3H, 5H-imidazo [1,5-c ] thiazole-5, 7(6H) -dione compound;
the molar amount of the metal alkoxide is 1-5 times of that of the (3S,7aR) -6-substituted benzyl-3-substituted phenyldihydro-3H, 5H-imidazo [1,5-c ] thiazole-5, 7(6H) -diketone compound.
9. The preparation method according to claim 8, wherein the molar amount of the trialkoxy onium tetrafluoroborate is 1-1.1 times that of the (3S,7aR) -6-substituted benzyl-3-substituted phenyldihydro-3H, 5H-imidazo [1,5-c ] thiazole-5, 7(6H) -dione compound;
the molar amount of the metal alkoxide is 1-1.1 times of that of the (3S,7aR) -6-substituted benzyl-3-substituted phenyldihydro-3H, 5H-imidazo [1,5-c ] thiazole-5, 7(6H) -diketone compound.
10. The method according to claim 1, wherein in the step (2), the condensation reaction is carried out under catalysis of a Lewis acid.
11. The process according to claim 10, wherein the Lewis acid is boron trifluoride diethyl etherate, boron trifluoride acetonitrile, titanium tetrachloride or tin tetrachloride.
12. The method according to claim 1, wherein in the step (2), the 1, 2-bis (trimethylsiloxy) cyclohex-1-ene is used in an amount of 1 to 3 times by mole the (3S,7aR) -6-substituted benzyl-7, 7-dialkoxy-3-substituted phenyltetrahydro-3H, 5H-imidazo [1,5-c ] thiazol-5-one compound.
13. The method according to claim 12, wherein the 1, 2-bis (trimethylsiloxy) cyclohex-1-ene is used in a molar amount of 1 to 1.05 times that of the (3S,7aR) -6-substituted benzyl-7, 7-dialkoxy-3-substituted phenyltetrahydro-3H, 5H-imidazo [1,5-c ] thiazol-5-one compound.
14. The method according to claim 1, wherein in the step (2), the condensation reaction is carried out at a reaction temperature of-80 to 80 ℃.
15. The method according to claim 14, wherein the condensation reaction is carried out at a temperature of-50 to 30 ℃.
16. The method according to claim 1, wherein in step (2), the solvent for the condensation reaction is one or more of alkyl halide, alkane, aromatic hydrocarbon, ester and ether.
17. The method according to claim 16, wherein in the step (2), the solvent for the condensation reaction is dichloromethane, n-hexane, toluene or butyl acetate.
18. The method according to claim 1, wherein in the step (2), an acid is added after the condensation reaction is completed.
19. The method of claim 18, wherein the acid is hydrochloric acid, sulfuric acid, or phosphoric acid.
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