(2-cyclopropylethynyl)lithium -Drug Synthesis Database

【结构式】

【分子编号】36611

【品名】(2-cyclopropylethynyl)lithium

【CA登记号】

【分子式】C₅H₅Li

【分子量】72.0357

【元素组成】C 83.37% H 7% Li 9.64%

与该中间体有关的原料药合成路线共 7 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7

合成路线1

该中间体在本合成路线中的序号：(IV)

Condensation of 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (I) with trimethylsilyl isocyanate in the presence of dimethylaminopyridine, followed by desilylation with tetrabutylammonium fluoride provided the quinazoline derivative (II). Dehydration of the tertiary alcohol of (II) to afford imine (III) was carried out employing molecular sieves in refluxing toluene. Subsequent addition of lithium cyclopropylacetylide (IV) to (III) in the presence of BF3-Et2O yielded the racemic adduct (V). The desired (S)-enantiomer was finally isolated by means of chiral HPLC.

参考文献中间体

合成目标

【1】 Rodgers, J.D.; Koo, S.S.; Corbett, J.W.; et al.; Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1. Antimicrob Agents Chemother 1999, 43, 12, 2893.
【2】 Corbett, J.W.; Ko, S.S.; Rodgers, J.D.; et al.; Inhibition of clinically relevant mutant variant of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors. J Med Chem 2000, 43, 10, 2019.
【3】 Corbett, J.W.; Ko, S.S. (DuPont Pharmaceuticals Co.); 4,4-Disubstd.-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors. US 6124302; WO 9845276 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	16572	1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone	C₈H₅ClF₃NO	详情	详情
(II)	36609	6-chloro-4-hydroxy-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone	C₉H₆ClF₃N₂O₂	详情	详情
(III)	36610	6-chloro-4-(trifluoromethyl)-2(1H)-quinazolinone	C₉H₄ClF₃N₂O	详情	详情
(IV)	36611	(2-cyclopropylethynyl)lithium	C₅H₅Li	详情	详情
(V)	36612	6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone	C₁₄H₁₀ClF₃N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The condensation of 6-chloro-4-(trifluoromethyl)quinazolin-2(1H)-one (V) with lithium cyclopropylacetylene (VI) (LiHMDS is used as strong base) catalyzed by the chiral moderator (IV) in toluene/THF gives the target compound. The chiral moderator (IV) has been obtained as follows: The epoxidation of (+)-3-carene (I) with MCPBA in dichloromethane gives the corresponding epoxide (II), which is then condensed with morpholine (III) by means of MgBr2 as catalyst.

参考文献中间体

合成目标

【1】 Kauffman, G.S.; Dorow, R.L.; Davulcu, A.H.; Radesca, L.A.; Harris, G.D.; Fortunak, J.M.; Parsons, R.L.; Nugent, W.A. (DuPont Pharmaceuticals Co.); Asymmetric synthesis of quinazolin-2-ones useful as HIV reverse transcriptase inhibitors. WO 0170707 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	47239	(1S,6R)-3,7,7-trimethylbicyclo[4.1.0]hept-3-ene	13466-78-9	C₁₀H₁₆	详情	详情
(II)	47240	(1S,3S,5R,7R)-3,8,8-trimethyl-4-oxatricyclo[5.1.0.0(3,5)]octane		C₁₀H₁₆O	详情	详情
(III)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(IV)	47241	(1S,3S,4S,6R)-3,7,7-trimethyl-4-(4-morpholinyl)bicyclo[4.1.0]heptan-3-ol		C₁₄H₂₅NO₂	详情	详情
(V)	36610	6-chloro-4-(trifluoromethyl)-2(1H)-quinazolinone		C₉H₄ClF₃N₂O	详情	详情
(VI)	36611	(2-cyclopropylethynyl)lithium		C₅H₅Li	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Condensation of 6'-amino-2,2,2,2',3'-pentafluoroacetophenone (I) with trimethylsilyl isocyanate in the presence of dimethylaminopyridine, followed by desilylation with tetrabutylammonium fluoride provided the quinazoline derivative (II). Dehydration of the tertiary alcohol of (II) to afford imine (III) was carried out employing molecular sieves in refluxing xylene. Subsequent addition of lithium cyclopropylacetylide (IV) to (III) in the presence of BF3-Et2O yielded the racemic adduct (V). The desired (S)-enantiomer was isolated by means of chiral HPLC.

参考文献中间体

合成目标

【1】 Corbett, J.W.; Ko, S.S.; Rodgers, J.D.; et al.; Inhibition of clinically relevant mutant variant of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors. J Med Chem 2000, 43, 10, 2019.
【2】 Rodgers, J.D.; Koo, S.S.; Corbett, J.W.; et al.; Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1. Antimicrob Agents Chemother 1999, 43, 12, 2893.
【3】 Corbett, J.W.; Ko, S.S. (DuPont Pharmaceuticals Co.); 4,4-Disubstd.-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors. US 6124302; WO 9845276 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	36614	1-(6-amino-2,3-difluorophenyl)-2,2,2-trifluoro-1-ethanone	C₈H₄F₅NO	详情	详情
(II)	36615	5,6-difluoro-4-hydroxy-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone	C₉H₅F₅N₂O₂	详情	详情
(III)	36616	5,6-difluoro-4-(trifluoromethyl)-2(1H)-quinazolinone	C₉H₃F₅N₂O	详情	详情
(IV)	36611	(2-cyclopropylethynyl)lithium	C₅H₅Li	详情	详情
(V)	36617	4-(2-cyclopropylethynyl)-5,6-difluoro-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone	C₁₄H₉F₅N₂O	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

The condensation of 5,6-difluoro-4-(trifluoromethyl)quinazolin-2(1H)-one (V) with lithium cyclopropylacetylene (VI) (LiHMDS is used as strong base) catalyzed by the chiral moderator (IV) in toluene/THF gives the target compound with an enantiomeric excess of 94%, which increases up to 99.6% after working up (crystallization in heptane). The chiral moderator (IV) has been obtained as follows: The epoxidation of (+)-3-carene (I) with MCPBA in dichloromethane gives the corresponding epoxide (II), which is then condensed with morpholine (III) using MgBr as a catalyst.

参考文献中间体

合成目标

【1】 Kauffman, G.S.; et al.; An efficient chiral moderator prepared for inexpensive (+)-3-carene: Synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963. Org Lett 2000, 2, 20, 3119.
【2】 Kauffman, G.S.; Dorow, R.L.; Davulcu, A.H.; Radesca, L.A.; Harris, G.D.; Fortunak, J.M.; Parsons, R.L.; Nugent, W.A. (DuPont Pharmaceuticals Co.); Asymmetric synthesis of quinazolin-2-ones useful as HIV reverse transcriptase inhibitors. WO 0170707 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	47239	(1S,6R)-3,7,7-trimethylbicyclo[4.1.0]hept-3-ene	13466-78-9	C₁₀H₁₆	详情	详情
(II)	47240	(1S,3S,5R,7R)-3,8,8-trimethyl-4-oxatricyclo[5.1.0.0(3,5)]octane		C₁₀H₁₆O	详情	详情
(III)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(IV)	47241	(1S,3S,4S,6R)-3,7,7-trimethyl-4-(4-morpholinyl)bicyclo[4.1.0]heptan-3-ol		C₁₄H₂₅NO₂	详情	详情
(V)	36616	5,6-difluoro-4-(trifluoromethyl)-2(1H)-quinazolinone		C₉H₃F₅N₂O	详情	详情
(VI)	36611	(2-cyclopropylethynyl)lithium		C₅H₅Li	详情	详情

合成路线5

该中间体在本合成路线中的序号：(IV)

参考文献中间体

合成目标

【1】 Corbett, J.W.; Ko, S.S.; Rodgers, J.D.; et al.; Inhibition of clinically relevant mutant variant of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors. J Med Chem 2000, 43, 10, 2019.
【2】 Rodgers, J.D.; Koo, S.S.; Corbett, J.W.; et al.; Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1. Antimicrob Agents Chemother 1999, 43, 12, 2893.
【3】 Corbett, J.W.; Ko, S.S. (DuPont Pharmaceuticals Co.); 4,4-Disubstd.-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors. US 6124302; WO 9845276 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	16572	1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone	C₈H₅ClF₃NO	详情	详情
(II)	36609	6-chloro-4-hydroxy-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone	C₉H₆ClF₃N₂O₂	详情	详情
(III)	36610	6-chloro-4-(trifluoromethyl)-2(1H)-quinazolinone	C₉H₄ClF₃N₂O	详情	详情
(IV)	36611	(2-cyclopropylethynyl)lithium	C₅H₅Li	详情	详情
(V)	36612	6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone	C₁₄H₁₀ClF₃N₂O	详情	详情
(VI)	36613	(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone	C₁₄H₁₀ClF₃N₂O	详情	详情

合成路线6

该中间体在本合成路线中的序号：(V)

DPC-961 (I) can be obtained by several different related ways: 1) Condensation of 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (II) with trimethylsilyl isocyanate in the presence of dimethylaminopyridine in THF, followed by desilylation with tetrabutylammonium fluoride in THF, provides the quinazoline derivative (III), which is dehydrated employing molecular sieves in refluxing toluene to yield the imine (IV). Treatment of compound (IV) with lithium cyclopropylacetylide (V) in THF in the presence of BF3.Et2O gives the racemic adduct (VI). Finally, the desired (S)-enantiomer (I) is isolated by means of chiral HPLC . 2) Condensation of 6-chloro-4-(trifluoromethyl)quinazolin-2(1H)-one (IV) with lithium cyclopropylacetylide (V) catalyzed by the chiral auxiliary (X) in toluene/THF gives directly DPC-961. The chiral auxiliary (X) can be synthesized as follows: Epoxidation of (+)-3-carene (VII) with MCPBA in dichloromethane gives the corresponding epoxide (VIII), which is then condensed with morpholine (IX) by means of MgBr2 as catalyst.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Leeson, P.A.; DPC-083. Drugs Fut 2002, 27, 4, 331.
【2】 Rodgers, J.D.; Koo, S.S.; Corbett, J.W.; et al.; Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1. Antimicrob Agents Chemother 1999, 43, 12, 2893.
【3】 Corbett, J.W.; Ko, S.S.; Rodgers, J.D.; et al.; Inhibition of clinically relevant mutant variant of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors. J Med Chem 2000, 43, 10, 2019.
【4】 Corbett, J.W.; Ko, S.S. (DuPont Pharmaceuticals Co.); 4,4-Disubstd.-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors. US 6124302; WO 9845276 .
【5】 Kauffman, G.S.; Dorow, R.L.; Davulcu, A.H.; Radesca, L.A.; Harris, G.D.; Fortunak, J.M.; Parsons, R.L.; Nugent, W.A. (DuPont Pharmaceuticals Co.); Asymmetric synthesis of quinazolin-2-ones useful as HIV reverse transcriptase inhibitors. WO 0170707 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	36613	(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone		C₁₄H₁₀ClF₃N₂O	详情	详情
(II)	16572	1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone		C₈H₅ClF₃NO	详情	详情
(III)	36609	6-chloro-4-hydroxy-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone		C₉H₆ClF₃N₂O₂	详情	详情
(IV)	36610	6-chloro-4-(trifluoromethyl)-2(1H)-quinazolinone		C₉H₄ClF₃N₂O	详情	详情
(V)	36611	(2-cyclopropylethynyl)lithium		C₅H₅Li	详情	详情
(VI)	47241	(1S,3S,4S,6R)-3,7,7-trimethyl-4-(4-morpholinyl)bicyclo[4.1.0]heptan-3-ol		C₁₄H₂₅NO₂	详情	详情
(VII)	47239	(1S,6R)-3,7,7-trimethylbicyclo[4.1.0]hept-3-ene	13466-78-9	C₁₀H₁₆	详情	详情
(VIII)	47240	(1S,3S,5R,7R)-3,8,8-trimethyl-4-oxatricyclo[5.1.0.0(3,5)]octane		C₁₀H₁₆O	详情	详情
(IX)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情

合成路线7

该中间体在本合成路线中的序号：(IV)

参考文献中间体

合成目标

【1】 Corbett, J.W.; Ko, S.S.; Rodgers, J.D.; et al.; Inhibition of clinically relevant mutant variant of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors. J Med Chem 2000, 43, 10, 2019.
【2】 Rodgers, J.D.; Koo, S.S.; Corbett, J.W.; et al.; Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1. Antimicrob Agents Chemother 1999, 43, 12, 2893.
【3】 Corbett, J.W.; Ko, S.S. (DuPont Pharmaceuticals Co.); 4,4-Disubstd.-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors. US 6124302; WO 9845276 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	36614	1-(6-amino-2,3-difluorophenyl)-2,2,2-trifluoro-1-ethanone	C₈H₄F₅NO	详情	详情
(II)	36615	5,6-difluoro-4-hydroxy-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone	C₉H₅F₅N₂O₂	详情	详情
(III)	36616	5,6-difluoro-4-(trifluoromethyl)-2(1H)-quinazolinone	C₉H₃F₅N₂O	详情	详情
(IV)	36611	(2-cyclopropylethynyl)lithium	C₅H₅Li	详情	详情
(V)	36617	4-(2-cyclopropylethynyl)-5,6-difluoro-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone	C₁₄H₉F₅N₂O	详情	详情
(VI)	36618	(4S)-4-(2-cyclopropylethynyl)-5,6-difluoro-4-(trifluoromethyl)-3,4-dihydro-2(1H)-quinazolinone	C₁₄H₉F₅N₂O	详情	详情

Extended Information