CN103304488B - Optical purity 2-(1-hydroxyethyl) preparation method of-5-hydroxy pyrimidine - Google Patents
Optical purity 2-(1-hydroxyethyl) preparation method of-5-hydroxy pyrimidine Download PDFInfo
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- CN103304488B CN103304488B CN201310233006.9A CN201310233006A CN103304488B CN 103304488 B CN103304488 B CN 103304488B CN 201310233006 A CN201310233006 A CN 201310233006A CN 103304488 B CN103304488 B CN 103304488B
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Abstract
Present invention is disclosed a kind of optical purity 2-(1-hydroxyethyl) preparation method of-5-hydroxy pyrimidine, with 2-hydroxyl third amidine hydrochloride for starting raw material, carry out pyrimidine cyclization reaction, obtained 2-(1-hydroxyethyl)-5-benzyloxy pyrimidines; Using lipase as biological catalyst, by 2-(1-hydroxyethyl)-5-benzyloxy pyrimidines and vinyl-acetic ester react, be separated with obtained (<i>S</iGreatT.Gr eaT.GT)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidines and (<i>R</iGreatT.Gr eaT.GT)-2-(1-Acetoxvethyl)-5-benzyloxy pyrimidines; By (<i>S</iGreatT.Gr eaT.GT)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidines carries out hydrogenation debenzylation reaction, obtained (<i>S</iGreatT.Gr eaT.GT)-2-(1-hydroxyethyl)-5-hydroxy pyrimidine; By (<i>R</iGreatT.Gr eaT.GT)-2-(1-Acetoxvethyl)-5-benzyloxy pyrimidines (compound 5) is hydrolyzed reaction, and then carry out hydrogenation debenzylation reaction, obtained (<i>R</iGreatT.Gr eaT.GT)-2-(1-Acetoxvethyl)-5-benzyloxy pyrimidines.Reaction process of the present invention is efficiently single-minded, environmental protection, simple to operate, there is good prospects for commercial application.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, particularly relate to a kind of optical purity 2-(1-hydroxyethyl) preparation method of-5-hydroxy pyrimidine.
Background technology
2-(1-hydroxyethyl)-5-hydroxy pyrimidine be synthesis helicase inhibitors (GyraseInhibitor) a key intermediate, patent WO2012125746A1 reports the synthetic method of its raceme: with 2-hydroxyl third amidine hydrochloride for starting raw material, carry out pyrimidine cyclization reaction, then take off benzyl through hydrogenation and obtain 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 medicine, its effect may be mutually far short of what is expected, even causes great side effect, so it is very necessary to obtain single optically pure isomer.And in prior art, there is not yet and prepare optical purity 2-(1-hydroxyethyl) method of-5-hydroxy pyrimidine.
Lipase, as a kind of lytic enzyme, can carry out the alcohol compound of resolution of racemic by catalyzed transesterification, react efficiently single-minded, mild condition.Meanwhile, lipase low production cost, much commercialization all, this also makes scale operation become possibility.
Summary of the invention
In view of the defect that above-mentioned prior art exists, the object of the invention is to propose a kind of optical purity 2-(1-hydroxyethyl) preparation method of-5-hydroxy pyrimidine.
Object of the present invention will be achieved by the following technical programs:
A kind of optical purity 2-(1-hydroxyethyl) preparation method of-5-hydroxy pyrimidine, comprise the following steps:
Step one: with 2-hydroxyl third amidine hydrochloride for starting raw material, carry out pyrimidine cyclization reaction, obtained 2-(1-hydroxyethyl)-5-benzyloxy pyrimidines;
Step 2: in aprotic solvent, using lipase as biological catalyst, the 2-(1-hydroxyethyl by obtained for step one)-5-benzyloxy pyrimidines reacts with vinyl-acetic ester, be separated obtaining (
s)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidines and (
r)-2-(1-Acetoxvethyl)-5-benzyloxy pyrimidines;
Step 3: step 2 is obtained (
s)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidines carries out hydrogenation debenzylation reaction, obtained (
s)-2-(1-hydroxyethyl)-5-hydroxy pyrimidine;
Step 4: step 2 is obtained (
r)-2-(1-Acetoxvethyl)-5-benzyloxy pyrimidines (compound 5) to be hydrolyzed reaction, and then to carry out hydrogenation debenzylation reaction, obtained (
r)-2-(1-Acetoxvethyl)-5-benzyloxy pyrimidines.
Preferably, above-mentioned optical purity 2-(1-hydroxyethyl) preparation method of-5-hydroxy pyrimidine, wherein: the aprotic solvent in described step 2 is the tertiary ether of first, isopropyl ether, ether, any one in normal heptane or tetrahydrofuran (THF).
Preferably, above-mentioned optical purity 2-(1-hydroxyethyl) preparation method of-5-hydroxy pyrimidine, wherein: the lipase in described step 2 is lipase PSSD, lipase ay S, any one in lipase A S or lipase A K.
Outstanding effect of the present invention is: the invention provides one and utilize with low cost, and the lipase be conveniently easy to get carrys out the pure 2-(1-hydroxyethyl of synthesizing optical of highly-solid selectively as catalyzer) method of-5-hydroxy pyrimidine.The present invention effectively utilizes that biological enzyme is efficiently single-minded, the feature of environmental protection, resolution of racemic alcohol intermediate, obtain a pair optical isomer in single step reaction simultaneously, further reaction obtains the 2-(1-hydroxyethyl of R type and S type respectively)-5-hydroxy pyrimidine, reaction process is simple to operate, improves Atom economy, reduces the generation of reaction waste, making industrial production optical purity 2-(1-hydroxyethyl)-5-hydroxy pyrimidine becomes possibility, has good prospects for commercial application.
Below just accompanying drawing in conjunction with the embodiments, is described in further detail the specific embodiment of the present invention, is easier to understand, grasp to make technical solution of the present invention.
Accompanying drawing explanation
Fig. 1 is raceme 2-(1-hydroxyethyl in prior art) its synthetic route chart of-5-hydroxy pyrimidine;
Fig. 2 is synthetic route chart of the present invention.
Embodiment
Be described method of the present invention below by specific embodiment, as shown in Figure 2, but the present invention is not limited thereto for its synthetic route chart.Experimental technique described in 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) preparation method of-5-hydroxy pyrimidine, specifically comprise the following steps:
(1) 2-(1-hydroxyethyl) synthesis of-5-benzyloxy pyrimidines (compound 3)
1.5L acetonitrile and 150g2-hydroxyl third amidine hydrochloride (compound 1) is added in 2L reaction flask, add 378gN again, N-dimethyl-(2-benzyloxy-3-dimethylamino) allyl group imines hexafluorophosphate (compound 2), adds potassium carbonate powder 414g under stirring, heating reflux reaction 24 hours.After the most of solvent of decompression removing, in impouring water, with extraction into ethyl acetate, anhydrous sodium sulfate drying, obtains 205g pale yellowish oil product Compound 3, productive rate 89% after concentrated.
1HNMR（400MHz，CDCl
3）
δ8.45（s，2H），7.39（m，5H），5.18（s，2H），4.94（m，1H），3.93（d，
J=4.8Hz，1H），1.56（d，
J=6.4Hz，3H）。
(2) (
s)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidines (compound 4) and (
r)-2-(1-Acetoxvethyl) synthesis of-5-benzyloxy pyrimidines (compound 5)
In 250mL reaction flask, add the tertiary ether of 23g compound 3,140mL first, 2.3g lipase PSSD and 25.8g vinyl-acetic ester, 50 DEG C are reacted 60 hours.Chirality HPLC display reaction conversion 50%, stopped reaction.Removal of solvent under reduced pressure, silica gel column chromatography is separated and obtains 11.1g compound 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=4.8Hz, 1H), 1.53(d, J=6.4Hz, 3H), optical purity >99%ee; And 12.9g compound 5, productive rate 47%,
1hNMR(400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q, J=6.8Hz, 1H) and, 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
j=6.8Hz, 3H), optical purity >99%ee.
(3) (
s)-2-(1-hydroxyethyl)-5-hydroxy pyrimidine (compound
s-6) synthesis
Be dissolved in 200mL methyl alcohol by 23g compound 4, add 2.3g10%Pd/C, normal pressure hydrogenation takes off benzyl, and react 12 hours, filtering and concentrating obtains 12.5g compound S-6, productive rate 89%,
1hNMR(400MHz, DMSO-
d 6 )
δ10.24(s, br, 1H), 8.31(s, 2H) and, 4.92(s, 1H), 4.71(q,
j=6.4Hz, 1H), 1.37(d,
j=6.4Hz, 3H), optical purity >99%ee.
(4) (
r)-2-(1-hydroxyethyl)-5-hydroxy pyrimidine (compound
r-6) synthesis
Be dissolved in 200mL tetrahydrofuran (THF) by 27.2g compound 5, add 6g hydration LiOH, 10mL water, stirring at room temperature 12 hours, removal of solvent under reduced pressure, acetic acid ethyl dissolution, once, anhydrous sodium sulfate drying, obtains yellow oil after concentrated in washing.Yellow oil is dissolved in 200mL methyl alcohol, adds 2.3g10%Pd/C, and normal pressure hydrogenation takes off benzyl, and react 12 hours, filtering and concentrating obtains 12.3g compound R-6, productive rate 88%,
1hNMR(400MHz, DMSO-
d 6 )
δ10.27(s, br, 1H), 8.30(s, 2H) and, 4.92(s, 1H), 4.71(q,
j=6.8Hz, 1H), 1.37(d,
j=6.8Hz, 3H), optical purity >99%ee.
Present embodiments providing one utilizes with low cost, and the lipase be conveniently easy to get carrys out the pure 2-(1-hydroxyethyl of synthesizing optical of highly-solid selectively as catalyzer) method of-5-hydroxy pyrimidine.The present embodiment effectively utilizes that biological enzyme is efficiently single-minded, the feature of environmental protection, resolution of racemic alcohol intermediate, obtain a pair optical isomer in single step reaction simultaneously, further reaction obtains the 2-(1-hydroxyethyl of R type and S type respectively)-5-hydroxy pyrimidine, reaction process is simple to operate, improves Atom economy, reduces the generation of reaction waste, making industrial production optical purity 2-(1-hydroxyethyl)-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) preparation method of-5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), specific as follows:
In 250mL reaction flask, add the tertiary ether of 23g compound 3,140mL first, 2.3g lipase ay S and 25.8g vinyl-acetic ester, 50 DEG C are reacted 48 hours.Chirality HPLC display reaction conversion 50%, stopped reaction.Removal of solvent under reduced pressure, silica gel column chromatography is separated and obtains 11.0g compound 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=4.8Hz, 1H), 1.53(d,
j=6.4Hz, 3H), optical purity >99%ee; And 12.9g compound 5, productive rate 47%,
1hNMR(400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
j=6.8Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
j=6.8Hz, 3H), optical purity >99%ee.
Embodiment 3:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment) preparation method of-5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), specific as follows:
In 250mL reaction flask, add the tertiary ether of 23g compound 3,140mL first, 2.3g lipase A S and 25.8g vinyl-acetic ester, 50 DEG C are reacted 72 hours.Chirality HPLC display reaction conversion 50%, stopped reaction.Removal of solvent under reduced pressure, silica gel column chromatography is separated and obtains 11.1g compound 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=4.8Hz, 1H), 1.53(d,
j=6.4Hz, 3H), optical purity >99%ee; And 12.9g compound 5, productive rate 47%,
1hNMR(400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
j=6.8Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
j=6.8Hz, 3H), optical purity >99%ee.
Embodiment 4:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment) preparation method of-5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), specific as follows:
In 250mL reaction flask, add the tertiary ether of 23g compound 3,140mL first, 2.3g lipase A K and 25.8g vinyl-acetic ester, 50 DEG C are reacted 60 hours.Chirality HPLC display reaction conversion 50%, stopped reaction.Removal of solvent under reduced pressure, silica gel column chromatography is separated and obtains 11.1g compound 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=4.8Hz, 1H), 1.53(d,
j=6.4Hz, 3H), optical purity >99%ee; And 12.9g compound 5, productive rate 47%,
1hNMR(400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
j=6.8Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
j=6.8Hz, 3H), optical purity >99%ee.
Embodiment 5:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment) preparation method of-5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), specific as follows:
In 250mL reaction flask, add 23g compound 3,140mL isopropyl ether, 2.3g lipase A K and 25.8g vinyl-acetic ester, 50 DEG C are reacted 72 hours.Chirality HPLC display reaction conversion 50%, stopped reaction.Removal of solvent under reduced pressure, silica gel column chromatography is separated and obtains 11.1g compound 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=4.8Hz, 1H), 1.53(d,
j=6.4Hz, 3H), optical purity >99%ee; And 12.9g compound 5, productive rate 47%,
1hNMR(400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
j=6.8Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
j=6.8Hz, 3H), optical purity >99%ee.
Embodiment 6:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment) preparation method of-5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), specific as follows:
In 250mL reaction flask, add 23g compound 3,140mL ether, 2.3g lipase A K and 25.8g vinyl-acetic ester, 35 DEG C are reacted 84 hours.Chirality HPLC display reaction conversion 50%, stopped reaction.Removal of solvent under reduced pressure, silica gel column chromatography is separated and obtains 11.0g compound 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=4.8Hz, 1H), 1.53(d,
j=6.4Hz, 3H), optical purity >99%ee; And 12.8g compound 5, productive rate 47%,
1hNMR(400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
j=6.8Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
j=6.8Hz, 3H), optical purity >99%ee.
Embodiment 7:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment) preparation method of-5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), specific as follows:
In 250mL reaction flask, add 23g compound 3,140mL normal heptane, 2.3g lipase A K and 25.8g vinyl-acetic ester, 50 DEG C are reacted 72 hours.Chirality HPLC display reaction conversion 50%, stopped reaction.Removal of solvent under reduced pressure, silica gel column chromatography is separated and obtains 11.1g compound 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=4.8Hz, 1H), 1.53(d,
j=6.4Hz, 3H), optical purity >99%ee; And 12.7g compound 5, productive rate 47%,
1hNMR(400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
j=6.8Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
j=6.8Hz, 3H), optical purity >99%ee.
Embodiment 8:
A kind of optical purity 2-(1-hydroxyethyl of the present embodiment) preparation method of-5-hydroxy pyrimidine is similar to above-described embodiment 1, and difference is step (2), specific as follows:
In 250mL reaction flask, add 23g compound 3,140mL tetrahydrofuran (THF), 2.3g lipase A K and 25.8g vinyl-acetic ester, 50 DEG C are reacted 60 hours.Chirality HPLC display reaction conversion 50%, stopped reaction.Removal of solvent under reduced pressure, silica gel column chromatography is separated and obtains 11.1g compound 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=4.8Hz, 1H), 1.53(d,
j=6.4Hz, 3H), optical purity >99%ee; And 12.7g compound 5, productive rate 47%,
1hNMR(400MHz, CDCl
3)
δ8.46(s, 2H), 7.39(m, 5H), 5.92(q,
j=6.8Hz, 1H), 5.17(s, 2H), 2.16(s, 3H), 1.63(d,
j=6.8Hz, 3H), optical purity >99%ee.
The present invention still has numerous embodiments, all employing equivalents or equivalent transformation and all technical schemes formed, and all drops within protection scope of the present invention.
Claims (1)
1. optical purity 2-(1-hydroxyethyl) preparation method of-5-hydroxy pyrimidine, it is characterized in that comprising the following steps:
Step one: with 2-hydroxyl third amidine hydrochloride for starting raw material, carry out pyrimidine cyclization reaction, obtained 2-(1-hydroxyethyl)-5-benzyloxy pyrimidines;
Step 2: in aprotic solvent, using lipase as biological catalyst, the 2-(1-hydroxyethyl by obtained for step one)-5-benzyloxy pyrimidines reacts with vinyl-acetic ester, be separated obtaining (
s)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidines and (
r)-2-(1-Acetoxvethyl)-5-benzyloxy pyrimidines;
Step 3: step 2 is obtained (
s)-2-(1-hydroxyethyl)-5-benzyloxy pyrimidines carries out hydrogenation debenzylation reaction, obtained (
s)-2-(1-hydroxyethyl)-5-hydroxy pyrimidine;
Step 4: step 2 is obtained (
r)-2-(1-Acetoxvethyl)-5-benzyloxy pyrimidines (compound 5) to be hydrolyzed reaction, and then to carry out hydrogenation debenzylation reaction, obtained (
r)-2-(1-Acetoxvethyl)-5-benzyloxy pyrimidines;
Aprotic solvent in described step 2 is the tertiary ether of first, isopropyl ether, ether, any one in normal heptane or tetrahydrofuran (THF), and the lipase in described step 2 is lipase PSSD, lipase ay S, any one in lipase A S or lipase A K.
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