p-Tolunitrile → Letrozole

HRID 646658

반응식

HRID 646658 반응식
[NH:1]1[CH:5]=[N:4][C:3]([Na])=[N:2]1.Br[CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[C:17]1(C)[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1.N1C=NC(CC2C=CC(C#N)=CC=2)=N1.FC1C=CC(C#N)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CC(N(C)C)=O>[CH:11]1[C:12]([C:13]#[N:14])=[CH:15][CH:16]=[C:9]([CH:8]([N:2]2[N:1]=[CH:5][N:4]=[CH:3]2)[C:17]2[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)[CH:10]=1

참가 물질

9

반응물 6

HCID 7724p-TolunitrileHCID 145174-FluorobenzonitrileHCID 869964-(Bromomethyl)benzonitrileHCID 2724254Sodium bis(trimethylsilyl)amideHCID 178507082HCID 178507082, 화합물HCID 178509721HCID 178509721, 화합물

생성물 1

HCID 3902Letrozole

시약·촉매·용매 2

HCID 8028Tetrahydrofuran용매HCID 31374Dimethylacetamide용매

실험 절차

A glass reactor was charged with 46 grams of 1,2,4-triazolylsodium and 1350 grams of dimethylacetamide. At a temperature between −15° C. and −10° C., 90 grams of 4-(bromomethyl)benzonitrile (95 grams of industrial grade having a purity of about 94 percent by weight, containing about 6 percent by weight of 4-tolunitrile) were added over a period of 30 minutes. After stirring at a temperature between −15° C. and −10° C. for 1 hour, and then at a temperature between −5° C. and 0° C. for 1 hour, an HPLC analysis indicated a ratio of intermediate III to isomer IV of 18:1. Then, 52.8 grams of 4-fluorobenzonitrile were added, and, while maintaining a temperature of −8° C. to 0° C., 480 grams of a 40 percent solution of sodium bis(trimethylsilyl)amide in THF were added dropwise. After the addition was completed, the reaction was stirred at a temperature between −2° C. and −2° C. for 1 hour, and then the reaction was quenched by the addition of a mixture of 180 grams of acetic acid and 540 grams of water, followed by precipitation of the product by the addition of 3510 grams of water. The resulting suspension was stirred overnight at ambient temperature, i.e., from 15° C. to 25° C., and then the precipitate was collected and rinsed with water. The wet precipitate was dissolved in 630 grams of dichloromethane and 63 grams of acetone, and the solution washed with 450 grams of water. The organic phase was separated at 30° C., diluted with 450 grams of toluene, concentrated at atmospheric pressure until all the dichloromethane was removed, and then further concentrated under vacuum to a weight of about 300 grams. The suspension was diluted with a further 450 grams of toluene and again concentrated under vacuum to a weight of 500 grams. The resulting suspension was stirred at a temperature between 10° C. and 15° C. for 1 hour, and the precipitate was collected, rinsed with toluene, and dried, yielding 99 grams of letrozole with a purity of 99.3 HPLC area percent. The only detectable impurity was 0.7 HPLC area percent of letrozole related compound A. The final purification of the letrozole product is described in Example 6.

후처리

  1. additionwere added over a period of 30 minutes
  2. waitat a temperature between −5° C. and 0° C. for 1 hour
  3. additionwere added dropwise
  4. additionAfter the addition
  5. stirringthe reaction was stirred at a temperature between −2° C. and −2° C. for 1 hour
  6. customthe reaction was quenched by the addition of a mixture of 180 grams of acetic acid and 540 grams of water
  7. customfollowed by precipitation of the product by the addition of 3510 grams of water
  8. stirringThe resulting suspension was stirred overnight at ambient temperature
  9. customi.e., from 15° C. to 25° C., and then the precipitate was collected
  10. washrinsed with water
  11. dissolutionThe wet precipitate was dissolved in 630 grams of dichloromethane
  12. wash63 grams of acetone, and the solution washed with 450 grams of water
  13. customThe organic phase was separated at 30° C.
  14. additiondiluted with 450 grams of toluene
  15. concentrationconcentrated at atmospheric pressure until all the dichloromethane
  16. customwas removed
  17. concentrationfurther concentrated under vacuum to a weight of about 300 grams
  18. additionThe suspension was diluted with a further 450 grams of toluene
  19. concentrationagain concentrated under vacuum to a weight of 500 grams
  20. stirringThe resulting suspension was stirred at a temperature between 10° C. and 15° C. for 1 hour
  21. customthe precipitate was collected
  22. washrinsed with toluene
  23. customdried

출처 및 근거

ORD 기록
ord-5558c8406ce74806b80cfb41c0a9cfed
출처 데이터셋
uspto-grants-2010_04
특허 번호
US07705159B2

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