CN103304488A - Preparation method of optical pure 2-(1-hydroxylethyl)-5-hydroxylpyrimidine - Google Patents
Preparation method of optical pure 2-(1-hydroxylethyl)-5-hydroxylpyrimidine Download PDFInfo
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- CN103304488A CN103304488A CN2013102330069A CN201310233006A CN103304488A CN 103304488 A CN103304488 A CN 103304488A CN 2013102330069 A CN2013102330069 A CN 2013102330069A CN 201310233006 A CN201310233006 A CN 201310233006A CN 103304488 A CN103304488 A CN 103304488A
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- pyrimidine
- hydroxyethyl
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Abstract
The invention discloses a preparation method of optical pure 2-(1-hydroxylethyl)-5-hydroxylpyrimidine. The preparation method comprises the following steps of: carrying out pyrimidine cyclization reaction by taking 2-hydroxypropionamidine hydrochloride as a starting raw material to prepare 2-(1-hydroxylethyl)-5-benzyloxy-pyrimidine; subjecting the 2-(1-hydroxylethyl)-5-benzyloxy-pyrimidine and vinyl acetate to reaction by taking lipase as a biocatalyst, and separating to prepare (S)-2-(1-hydroxylethyl)-5-benzyloxy-pyrimidine and (R)-2-(1-acetoxylethyl)-5-benzyloxy-pyrimidine; subjecting the (S)-2-(1-hydroxylethyl)-5-benzyloxy-pyrimidine to hydrogenated debenzylation to prepare (R)-2-(1-acetoxylethyl)-5-hydroxylpyrimidine; and subjecting the (R)-2-(1-acetoxylethyl)-5-benzyloxy-pyrimidine (compound 5) to hydrolysis reaction, and then, carrying out the hydrogenated debenzylation to prepare the (R)-2-(1-acetoxylethyl)-5-benzyloxy-pyrimidine. The preparation method is efficient and specific in reaction processes, environment-friendly, simple in operation and favorable in industrial application prospect.
Description
Technical field
The invention belongs to the pharmaceutical chemistry synthesis technical field, relate in particular to a kind of optical purity 2-(1-hydroxyethyl)-preparation method of 5-hydroxy pyrimidine.
Background technology
The 2-(1-hydroxyethyl)-the 5-hydroxy pyrimidine is a key intermediate of synthetic helicase inhibitor (Gyrase Inhibitor), patent WO2012125746A1 has reported the synthetic method of its raceme: take 2-hydroxyl the third amidine hydrochloride as starting raw material, carry out pyrimidine cyclization reaction, take off benzyl through hydrogenation again and obtain the 2-(1-hydroxyethyl)-5-hydroxy pyrimidine (its synthetic route chart is as shown in Figure 1).As everyone knows, this compound has a chiral centre, and corresponding isomer often has different physico-chemical properties and biological activity, be applied in the medicine, its effect may be mutually far short of what is expected, even cause great side effect, so it is very necessary to obtain single optically pure isomer.And in the prior art, not yet see prepare optical purity 2-(1-hydroxyethyl)-method of 5-hydroxy pyrimidine.
Lipase can come by catalyzed transesterification the alcohol compound of resolution of racemic as a kind of lytic enzyme, reacts efficiently single-minded, mild condition.Simultaneously, the lipase low production cost, much all commercializations, this is also so that scale operation becomes possibility.
Summary of the invention
Defective in view of above-mentioned prior art exists the objective of the invention is to propose a kind of optical purity 2-(1-hydroxyethyl)-preparation method of 5-hydroxy pyrimidine.
Purpose of the present invention will be achieved by the following technical programs:
A kind of optical purity 2-(1-hydroxyethyl)-and the preparation method of 5-hydroxy pyrimidine, may further comprise the steps:
Step 1: take 2-hydroxyl the third amidine hydrochloride as starting raw material, carry out pyrimidine cyclization reaction, make the 2-(1-hydroxyethyl)-5-benzyloxy pyrimidine;
Step 2: in aprotic solvent, with lipase as biological catalyst, the 2-(1-hydroxyethyl that step 1 is made)-5-benzyloxy pyrimidine and vinyl-acetic ester reaction, separate with make (
S)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidine and (
R)-2-(1-acetoxyl group ethyl)-5-benzyloxy pyrimidine;
Step 3: with step 2 make (
S)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidine carries out the hydrogenation debenzylation reaction, make (
S)-2-(1-hydroxyethyl)-the 5-hydroxy pyrimidine;
Step 4: with step 2 make (
R)-2-(1-acetoxyl group ethyl)-5-benzyloxy pyrimidine (compound 5) reaction that is hydrolyzed, and then carry out the hydrogenation debenzylation reaction, make (
R)-2-(1-acetoxyl group ethyl)-5-benzyloxy pyrimidine.
Preferably, above-mentioned optical purity 2-(1-hydroxyethyl)-and the preparation method of 5-hydroxy pyrimidine, wherein: the aprotic solvent in the described step 2 is first uncle ether, isopropyl ether, ether, any one in normal heptane or the tetrahydrofuran (THF).
Preferably, above-mentioned optical purity 2-(1-hydroxyethyl)-and the preparation method of 5-hydroxy pyrimidine, wherein: the lipase in the described step 2 is lipase PS SD, lipase ay S, any one among lipase A S or the lipase A K.
Outstanding effect of the present invention is: the invention provides and a kind ofly utilize with low costly, the lipase that conveniently is easy to get comes the pure 2-(1-hydroxyethyl of synthesizing optical of highly-solid selectively as catalyzer)-method of 5-hydroxy pyrimidine.The present invention utilizes effectively that biological enzyme is efficiently single-minded, the characteristics of environmental protection, the resolution of racemic alcohol intermediate, in single step reaction, obtain simultaneously a pair of optical isomer, further reaction obtains respectively the 2-(1-hydroxyethyl of R type and S type)-the 5-hydroxy pyrimidine, reaction process is simple to operate, improves Atom economy, reduces the generation of reaction waste, make industrial production optical purity 2-(1-hydroxyethyl)-the 5-hydroxy pyrimidine becomes possibility, has good prospects for commercial application.
Following constipation closes the embodiment accompanying drawing, the specific embodiment of the present invention is described in further detail, so that technical solution of the present invention is easier to understand, grasp.
Description of drawings
Fig. 1 is raceme 2-(1-hydroxyethyl in the prior art)-its synthetic route chart of 5-hydroxy pyrimidine;
Fig. 2 is synthetic route chart of the present invention.
Embodiment
Below by specific embodiment method of the present invention is described, its synthetic route chart as shown in Figure 2, but the present invention is not limited thereto.Experimental technique described in the following embodiment if no special instructions, is ordinary method; Described reagent and material if no special instructions, all can obtain from commercial channels.
Embodiment 1:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment)-and the preparation method of 5-hydroxy pyrimidine, specifically may further comprise the steps:
(1) 2-(1-hydroxyethyl)-5-benzyloxy pyrimidine (compound 3) synthetic
In 2 L reaction flasks, add 1.5 L acetonitriles and 150 g2-hydroxyls the third amidine hydrochlorides (compound 1), add again 378 gN, N-dimethyl-(2-benzyloxy-3-dimethylamino) allyl group imines hexafluorophosphate (compound 2), stir lower add potassium carbonate powder 414 g, heating reflux reaction 24 hours.After most of solvent was removed in decompression, in the impouring water, with ethyl acetate extraction, anhydrous sodium sulfate drying obtained the light yellow oily product of 205 g compound 3, productive rate 89% after concentrating.
1HNMR?（400MHz，CDCl
3）
δ?8.45（s，2H），7.39（m，5H），5.18（s，2H），4.94（m，1H），3.93（d，
J=4.8?Hz，1H），1.56（d，
J=6.4?Hz，3H）。
(2) (
S)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidine (compound 4) and (
R)-2-(1-acetoxyl group ethyl)-5-benzyloxy pyrimidine (compound 5) synthetic
In 250 mL reaction flasks, add 23 g compounds, 3,140 mL first uncle ethers, 2.3 g lipase PS SD and 25.8 g vinyl-acetic esters, 50 ℃ were reacted 60 hours.Chirality HPLC shows that reaction transforms 50%, stopped reaction.Removal of solvent under reduced pressure, the silica gel column chromatography separation obtains 11.1 g compounds 4, productive rate 48%,
1HNMR (400MHz, CDCl
3)
δ8.43(s, 2H), 7.39(m, 5H), 5.17(s, 2H) and, 4.94(m, 1H), 3.93(d,
J=4.8 Hz, 1H), 1.53(d, J=6.4 Hz, 3H), optical purity〉and 99%ee; And 12.9 g compounds 5, productive rate 47%,
1HNMR (400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q, J=6.8 Hz, 1H) and, 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
J=6.8 Hz, 3H), optical purity〉99%ee.
(3) (
S)-2-(1-hydroxyethyl)-5-hydroxy pyrimidine (compound
SSynthesizing-6)
23 g compounds 4 are dissolved in the 200 mL methyl alcohol, add 2.3 g, 10% Pd/C, normal pressure hydrogenation takes off benzyl, reacts 12 hours, and filtering and concentrating obtains 12.5 g compound Ss-6, productive rate 89%,
1HNMR (400MHz, DMSO-
d 6 )
δ10.24(s, br, 1H), 8.31(s, 2H), 4.92(s, 1H), 4.71(q,
J=6.4 Hz, 1H), 1.37(d,
J=6.4 Hz, 3H), optical purity〉99%ee.
(4) (
R)-2-(1-hydroxyethyl)-5-hydroxy pyrimidine (compound
RSynthesizing-6)
27.2 g compounds 5 are dissolved in the 200 mL tetrahydrofuran (THF)s, add 6 g hydration LiOH, 10 mL water, stirring at room 12 hours, removal of solvent under reduced pressure, acetic acid ethyl dissolution is washed once, and anhydrous sodium sulfate drying obtains yellow oil after concentrating.Yellow oil is dissolved in 200 mL methyl alcohol, adds 2.3 g, 10% Pd/C, and normal pressure hydrogenation takes off benzyl, reacts 12 hours, and filtering and concentrating obtains 12.3 g compound Rs-6, productive rate 88%,
1HNMR (400MHz, DMSO-
d 6 )
δ10.27(s, br, 1H), 8.30(s, 2H), 4.92(s, 1H), 4.71(q,
J=6.8 Hz, 1H), 1.37(d,
J=6.8 Hz, 3H), optical purity〉99%ee.
The present embodiment provides a kind of and has utilized with low costly, and the lipase that conveniently is easy to get comes the pure 2-(1-hydroxyethyl of synthesizing optical of highly-solid selectively as catalyzer)-method of 5-hydroxy pyrimidine.The present embodiment utilizes effectively that biological enzyme is efficiently single-minded, the characteristics of environmental protection, the resolution of racemic alcohol intermediate, in single step reaction, obtain simultaneously a pair of optical isomer, further reaction obtains respectively the 2-(1-hydroxyethyl of R type and S type)-the 5-hydroxy pyrimidine, reaction process is simple to operate, improves Atom economy, reduces the generation of reaction waste, make industrial production optical purity 2-(1-hydroxyethyl)-the 5-hydroxy pyrimidine becomes possibility, has good prospects for commercial application.
Embodiment 2:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment)-and the preparation method of 5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), and is specific as follows:
In 250 mL reaction flasks, add 23 g compounds, 3,140 mL first uncle ethers, 2.3 g lipase ay S and 25.8 g vinyl-acetic esters, 50 ℃ were reacted 48 hours.Chirality HPLC shows that reaction transforms 50%, stopped reaction.Removal of solvent under reduced pressure, the silica gel column chromatography separation obtains 11.0 g compounds 4, productive rate 48%,
1HNMR (400MHz, CDCl
3)
δ8.43(s, 2H), 7.39(m, 5H), 5.17(s, 2H) and, 4.94(m, 1H), 3.93(d,
J=4.8 Hz, 1H), 1.53(d,
J=6.4 Hz, 3H), optical purity〉99%ee; And 12.9 g compounds 5, productive rate 47%,
1HNMR (400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
J=6.8 Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
J=6.8 Hz, 3H), optical purity〉99%ee.
Embodiment 3:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment)-and the preparation method of 5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), and is specific as follows:
In 250 mL reaction flasks, add 23 g compounds, 3,140 mL first uncle ethers, 2.3 g lipase A S and 25.8 g vinyl-acetic esters, 50 ℃ were reacted 72 hours.Chirality HPLC shows that reaction transforms 50%, stopped reaction.Removal of solvent under reduced pressure, the silica gel column chromatography separation obtains 11.1 g compounds 4, productive rate 48%,
1HNMR (400MHz, CDCl
3)
δ8.43(s, 2H), 7.39(m, 5H), 5.17(s, 2H) and, 4.94(m, 1H), 3.93(d,
J=4.8 Hz, 1H), 1.53(d,
J=6.4 Hz, 3H), optical purity〉99%ee; And 12.9 g compounds 5, productive rate 47%,
1HNMR (400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
J=6.8 Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
J=6.8 Hz, 3H), optical purity〉99%ee.
Embodiment 4:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment)-and the preparation method of 5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), and is specific as follows:
In 250 mL reaction flasks, add 23 g compounds, 3,140 mL first uncle ethers, 2.3 g lipase A K and 25.8 g vinyl-acetic esters, 50 ℃ were reacted 60 hours.Chirality HPLC shows that reaction transforms 50%, stopped reaction.Removal of solvent under reduced pressure, the silica gel column chromatography separation obtains 11.1 g compounds 4, productive rate 48%,
1HNMR (400MHz, CDCl
3)
δ8.43(s, 2H), 7.39(m, 5H), 5.17(s, 2H) and, 4.94(m, 1H), 3.93(d,
J=4.8 Hz, 1H), 1.53(d,
J=6.4 Hz, 3H), optical purity〉99%ee; And 12.9 g compounds 5, productive rate 47%,
1HNMR (400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
J=6.8 Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
J=6.8 Hz, 3H), optical purity〉99%ee.
Embodiment 5:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment)-and the preparation method of 5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), and is specific as follows:
In 250 mL reaction flasks, add 23 g compounds, 3,140 mL isopropyl ethers, 2.3 g lipase A K and 25.8 g vinyl-acetic esters, 50 ℃ were reacted 72 hours.Chirality HPLC shows that reaction transforms 50%, stopped reaction.Removal of solvent under reduced pressure, the silica gel column chromatography separation obtains 11.1 g compounds 4, productive rate 48%,
1HNMR (400MHz, CDCl
3)
δ8.43(s, 2H), 7.39(m, 5H), 5.17(s, 2H) and, 4.94(m, 1H), 3.93(d,
J=4.8 Hz, 1H), 1.53(d,
J=6.4 Hz, 3H), optical purity〉99%ee; And 12.9 g compounds 5, productive rate 47%,
1HNMR (400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
J=6.8 Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
J=6.8 Hz, 3H), optical purity〉99%ee.
Embodiment 6:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment)-and the preparation method of 5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), and is specific as follows:
In 250 mL reaction flasks, add 23 g compounds, 3,140 mL ether, 2.3 g lipase A K and 25.8 g vinyl-acetic esters, 35 ℃ were reacted 84 hours.Chirality HPLC shows that reaction transforms 50%, stopped reaction.Removal of solvent under reduced pressure, the silica gel column chromatography separation obtains 11.0 g compounds 4, productive rate 48%,
1HNMR (400MHz, CDCl
3)
δ8.43(s, 2H), 7.39(m, 5H), 5.17(s, 2H) and, 4.94(m, 1H), 3.93(d,
J=4.8 Hz, 1H), 1.53(d,
J=6.4 Hz, 3H), optical purity〉99%ee; And 12.8 g compounds 5, productive rate 47%,
1HNMR (400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
J=6.8 Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
J=6.8 Hz, 3H), optical purity〉99%ee.
Embodiment 7:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment)-and the preparation method of 5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), and is specific as follows:
In 250 mL reaction flasks, add 23 g compounds, 3,140 mL normal heptanes, 2.3 g lipase A K and 25.8 g vinyl-acetic esters, 50 ℃ were reacted 72 hours.Chirality HPLC shows that reaction transforms 50%, stopped reaction.Removal of solvent under reduced pressure, the silica gel column chromatography separation obtains 11.1 g compounds 4, productive rate 48%,
1HNMR (400MHz, CDCl
3)
δ8.43(s, 2H), 7.39(m, 5H), 5.17(s, 2H) and, 4.94(m, 1H), 3.93(d,
J=4.8 Hz, 1H), 1.53(d,
J=6.4 Hz, 3H), optical purity〉99%ee; And 12.7 g compounds 5, productive rate 47%,
1HNMR (400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
J=6.8 Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
J=6.8 Hz, 3H), optical purity〉99%ee.
Embodiment 8:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment)-and the preparation method of 5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), and is specific as follows:
In 250 mL reaction flasks, add 23 g compounds, 3,140 mL tetrahydrofuran (THF)s, 2.3 g lipase A K and 25.8 g vinyl-acetic esters, 50 ℃ were reacted 60 hours.Chirality HPLC shows that reaction transforms 50%, stopped reaction.Removal of solvent under reduced pressure, the silica gel column chromatography separation obtains 11.1 g compounds 4, productive rate 48%,
1HNMR (400MHz, CDCl
3)
δ8.43(s, 2H), 7.39(m, 5H), 5.17(s, 2H) and, 4.94(m, 1H), 3.93(d,
J=4.8 Hz, 1H), 1.53(d,
J=6.4 Hz, 3H), optical purity〉99%ee; And 12.7 g compounds 5, productive rate 47%,
1HNMR (400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
J=6.8 Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
J=6.8 Hz, 3H), optical purity〉99%ee.
The present invention still has numerous embodiments, and all employing equivalents or equivalent transformation and all technical schemes of forming all drop within protection scope of the present invention.
Claims (3)
1. optical purity 2-(1-hydroxyethyl)-and the preparation method of 5-hydroxy pyrimidine, it is characterized in that may further comprise the steps:
Step 1: take 2-hydroxyl the third amidine hydrochloride as starting raw material, carry out pyrimidine cyclization reaction, make the 2-(1-hydroxyethyl)-5-benzyloxy pyrimidine;
Step 2: in aprotic solvent, with lipase as biological catalyst, the 2-(1-hydroxyethyl that step 1 is made)-5-benzyloxy pyrimidine and vinyl-acetic ester reaction, separate with make (
S)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidine and (
R)-2-(1-acetoxyl group ethyl)-5-benzyloxy pyrimidine;
Step 3: with step 2 make (
S)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidine carries out the hydrogenation debenzylation reaction, make (
S)-2-(1-hydroxyethyl)-the 5-hydroxy pyrimidine;
Step 4: with step 2 make (
R)-2-(1-acetoxyl group ethyl)-5-benzyloxy pyrimidine (compound 5) reaction that is hydrolyzed, and then carry out the hydrogenation debenzylation reaction, make (
R)-2-(1-acetoxyl group ethyl)-5-benzyloxy pyrimidine.
2. optical purity 2-(1-hydroxyethyl according to claim 1)-and the preparation method of 5-hydroxy pyrimidine, it is characterized in that: the aprotic solvent in the described step 2 is first uncle ether, isopropyl ether, ether, any one in normal heptane or the tetrahydrofuran (THF).
3. optical purity 2-(1-hydroxyethyl according to claim 1)-and the preparation method of 5-hydroxy pyrimidine, it is characterized in that: the lipase in the described step 2 is lipase PS SD, lipase ay S, any one among lipase A S or the lipase A K.
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